JP2002523484A - Amino alcohol derivatives and their use as β3 adrenergic receptor agonists - Google Patents

Amino alcohol derivatives and their use as β3 adrenergic receptor agonists

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Publication number
JP2002523484A
JP2002523484A JP2000567497A JP2000567497A JP2002523484A JP 2002523484 A JP2002523484 A JP 2002523484A JP 2000567497 A JP2000567497 A JP 2000567497A JP 2000567497 A JP2000567497 A JP 2000567497A JP 2002523484 A JP2002523484 A JP 2002523484A
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Prior art keywords
amino
alkyl
phenyl
bis
hydroxy
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JP2000567497A
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清 谷口
直明 藤井
稔 桜井
康代 冨島
寿 高杉
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藤沢薬品工業株式会社
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C07C217/86—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C271/06—Esters of carbamic acids
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    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
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    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Abstract

(57)【要約】 この発明は、下記の式［Ｉ］ 【化１】 ［式中、各記号は、この明細書に定義の通りである。］で表され、腸選択的交感神経作用、抗潰瘍、抗膵臓炎、脂肪分解、抗尿失禁および抗頻尿活性を有する新規アミノアルコール誘導体またはそれらの塩、それらの製造方法、それらを含有する医薬組成物、ならびに、この明細書に記載された、ヒトまたは動物の疾患の予防および／または治療方法に関する。 (57) [Summary] The present invention provides a compound represented by the following formula [I]: [Wherein each symbol is as defined in this specification. Novel amino alcohol derivatives having intestinal selective sympathetic action, anti-ulcer, anti-pancreatitis, lipolysis, anti-urinary incontinence and anti-frequent urinary activity, or salts thereof, methods for producing them, and containing them The present invention relates to a pharmaceutical composition and a method for preventing and / or treating a human or animal disease described in this specification.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】 技術分野 この発明は、β3アドレナリン性受容体作動薬であって、医薬として有用な新
規アミノアルコール誘導体およびそれらの塩に関する。TECHNICAL FIELD The present invention relates to a novel amino alcohol derivative which is a β 3 adrenergic receptor agonist, which is useful as a medicament, and a salt thereof.

【０００２】 発明の開示 この発明は、β3アドレナリン性受容体作動薬である新規アミノアルコール誘
導体およびそれらの塩に関する。DISCLOSURE OF THE INVENTION [0002] The present invention relates to novel amino alcohol derivatives that are β 3 adrenergic receptor agonists and salts thereof.

【０００３】 より詳しくは、この発明は、腸選択的交感神経作用、抗潰瘍、抗膵臓炎、脂肪
分解、抗尿失禁および抗頻尿活性を有する新規アミノアルコール誘導体およびそ
れらの塩、それらの製造方法、それらを含有する医薬組成物、ならびにそれらを
ヒトまたは動物における平滑筋収縮を要因とする胃腸疾患の治療および／または
予防に用いる方法に関する。More specifically, the present invention relates to novel amino alcohol derivatives having intestinal selective sympathetic activity, anti-ulcer, anti-pancreatitis, lipolysis, anti-urinary and anti-uriuritic activities, and salts thereof, and their production. The present invention relates to a method, a pharmaceutical composition containing them, and a method of using them for treating and / or preventing gastrointestinal diseases caused by smooth muscle contraction in humans or animals.

【０００４】 この発明の一つの目的は、腸選択的交感神経作用、抗潰瘍、脂肪分解、抗尿失
禁および抗頻尿活性を有する新規で有用なアミノアルコール誘導体およびそれら
の塩を提供することである。[0004] One object of the present invention is to provide novel and useful amino alcohol derivatives having intestinal selective sympathetic action, anti-ulcer, lipolysis, anti-urinary incontinence and anti-frequent urinary activity, and salts thereof. is there.

【０００５】 この発明の他の目的は、前記のアミノアルコール誘導体およびそれらの塩の製
造法を提供することである。[0005] Another object of the present invention is to provide a method for producing the above-mentioned amino alcohol derivatives and salts thereof.

【０００６】 この発明のさらに他の目的は、前記のアミノアルコール誘導体およびそれらの
塩を有効成分として含有する医薬組成物を提供することである。Still another object of the present invention is to provide a pharmaceutical composition containing the amino alcohol derivative and a salt thereof as an active ingredient.

【０００７】 この発明のいま一つの目的は、前記のアミノアルコール誘導体およびそれらの
塩を用いて、ヒトまたは動物における前記の疾患の治療および／または予防方法
を提供することである。[0007] Another object of the present invention is to provide a method for treating and / or preventing the above-mentioned diseases in humans or animals using the above-mentioned amino alcohol derivatives and salts thereof.

【０００８】 この発明の目的アミノアルコール誘導体は新規であり、下記の一般式［Ｉ］The object of the present invention is to provide a novel amino alcohol derivative represented by the following general formula [I]

【０００９】[0009]

【化３１】 Embedded image

【００１０】 ［式中、 Ａは複素環基またはアリールであって、そのおのおのは、ハロゲン、ヒドロキ
シ、アミノ、低級アルキル、低級アルキルスルホニルアミノ、フェニル（低級）
アルコキシおよびフェニル（低級）アルコキシカルボニルアミノよりなる群から
選択された同種または異種の置換基を１ないし３個有していてもよい、 −Ｘ−は結合、−ＣＨ2−、−ＣＨ2−ＣＨ2−、−ＮＨ−ＣＨ2−、−Ｏ−ＣＨ 2 −、−Ｓ−ＣＨ2−、−ＳＯ−ＣＨ2−または−ＳＯ2−ＣＨ2−、Wherein A is a heterocyclic group or aryl, each of which is halogen, hydroxy,
Si, amino, lower alkyl, lower alkylsulfonylamino, phenyl (lower)
From the group consisting of alkoxy and phenyl (lower) alkoxycarbonylamino
May have 1 to 3 selected same or different substituents, -X- is a bond, -CHTwo-, -CHTwo-CHTwo-, -NH-CHTwo-, -O-CH Two -, -S-CHTwo-, -SO-CHTwo-Or -SOTwo-CHTwo−,

【００１１】[0011]

【化３２】 Embedded image

【００１２】 （式中、Ｒ11は水素、ヒドロキシ、低級アルコキシまたはアシルオキシを意味す
る。）、(Wherein R 11 represents hydrogen, hydroxy, lower alkoxy or acyloxy),

【００１３】[0013]

【化３３】 Embedded image

【００１４】[0014]

【化３４】 Embedded image

【００１５】 −（ＣＨ2）n−ＣＨ＝ＣＨ−（ＣＨ2）m− または −（ＣＨ2）n−Ｃ≡Ｃ−（Ｃ
Ｈ2）m− （式中、−Ｑ−は−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ2−、-(CH 2 ) n -CH = CH- (CH 2 ) m -or-(CH 2 ) n -C≡C- (C
H 2 ) m − (wherein -Q- is —O—, —S—, —SO—, —SO 2 —,

【００１６】[0016]

【化３５】 Embedded image

【００１７】[0017]

【化３６】 Embedded image

【００１８】[0018]

【化３７】 Embedded image

【００１９】[0019]

【化３８】 Embedded image

【００２０】[0020]

【化３９】 Embedded image

【００２１】 （式中Ｒ10は水素または低級アルキル、Ｒ11は低級アルキルをそれぞれ意味する
。）、 Ｒ6、Ｒ7、Ｒ8およびＲ9はそれぞれ単独に水素、ヒドロキシ、低級アルキル、
低級アルケニル、低級アルコキシ、低級アルコキシ（低級）アルキル、または低
級アルコキシを１ないし３個有していてもよいアリール、 ｎ、ｍおよびｋはそれぞれ単独に０ないし６、 ｐは０ないし４、 ｑは１ないし４、 ｒは２ないし７、 をそれぞれ意味する。）、(Wherein R 10 represents hydrogen or lower alkyl, and R 11 represents lower alkyl, respectively), R 6 , R 7 , R 8 and R 9 each independently represent hydrogen, hydroxy, lower alkyl,
Lower alkenyl, lower alkoxy, lower alkoxy (lower) alkyl, or aryl optionally having 1 to 3 lower alkoxys, n, m and k each independently represent 0 to 6, p represents 0 to 4, and q represents 1 to 4, r means 2 to 7, respectively. ),

【００２２】[0022]

【化４０】 Embedded image

【００２３】 （式中ｉは０ないし６を意味する。）、 Ｒ1は水素またはアミノ保護基、 Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ単独に水素；低級アルキル；低級アルキル
チオ；低級アルキルスルホニル；ヒドロキシ；低級アルコキシ；アミノ；低級ア
ルキルアミノ；アシルアミノ；Ｎ−（低級アルキル）アシルアミノ；カルボキシ
；低級アルコキシカルボニル；低級アルキル１ないし２個で任意に置換されたカ
ルバモイル；ヒドロキシ（低級）アルキル；低級アルコキシ（低級）アルキル；
Ｎ−アシルアミノ（低級）アルキル；Ｎ−（低級アルキル）−Ｎ−アシルアミノ
（低級）アルキル；カルボキシ（低級）アルキル；低級アルコキシカルボニル（
低級）アルキル；低級アルキル１または２個で任意に置換されたカルバモイル（
低級）アルキル；または(Wherein i represents 0 to 6); R 1 is hydrogen or an amino protecting group; R 2 , R 3 , R 4 and R 5 are each independently hydrogen; lower alkyl; lower alkylthio; Hydroxy; lower alkoxy; amino; lower alkylamino; acylamino; N- (lower alkyl) acylamino; carboxy; lower alkoxycarbonyl; carbamoyl optionally substituted with one or two lower alkyl; Lower alkoxy (lower) alkyl;
N-acylamino (lower) alkyl; N- (lower alkyl) -N-acylamino (lower) alkyl; carboxy (lower) alkyl; lower alkoxycarbonyl (
Carbamoyl (optionally substituted with one or two lower alkyls)
Lower) alkyl; or

【００２４】[0024]

【化４１】 Embedded image

【００２５】 （式中、Ｒ12およびＲ13はそれぞれ単独に水素または低級アルキル、またはＲ12 およびＲ13は結合して、低級アルキレン鎖を形成してもよく、ｊは０ないし６を
意味する。） をそれぞれ意味する。］で表される。 目的化合物［Ｉ］またはその塩は、下記の諸方法によって製造できる。(Wherein, R 12 and R 13 may each independently be hydrogen or lower alkyl, or R 12 and R 13 may be bonded to form a lower alkylene chain, and j represents 0 to 6. )) Respectively. ]. The target compound [I] or a salt thereof can be produced by the following methods.

【００２６】 製造法１Manufacturing method 1

【化４２】 Embedded image

【００２７】[0027]

【化４３】 Embedded image

【００２８】 製造法２Manufacturing method 2

【化４４】 Embedded image

【００２９】[0029]

【化４５】 （式中、Ａ、Ｘ、Ｙ、Ｚ、Ｒ1、Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ前記定義の
通り、 Ｒ1 aはアミノ保護基、 を意味する。）Embedded image (Wherein, A, X, Y, Z , R 1, R 2, R 3, as R 4 and R 5 are defined respectively, R 1 a denotes an amino protecting group.)

【００３０】 この明細書の以上および以下の記述において、この発明の範囲に包含される種
々の定義の好適な例を次に詳細に説明する。In the above and following description of the present specification, preferred examples of various definitions included in the scope of the present invention will be described in detail below.

【００３１】 「低級」とは、特記ない限り、炭素原子１ないし６個を有する基を意味する。“Lower” means a group having 1-6 carbon atoms, unless otherwise specified.

【００３２】 「低級アルキル」および「低級アルキル」部分の好適な例としては、炭素原子
１ないし６個を有する直鎖または分枝状のもの、たとえばメチル、エチル、プロ
ピル、イソプロピル、ブチル、イソブチル、第二級ブチル、第三級ブチル、ペン
チル、１−メチルペンチル、第三級ペンチル、ネオペンチル、ヘキシル、イソヘ
キシルなどを挙げることができる。Suitable examples of “lower alkyl” and “lower alkyl” moieties are straight or branched having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Secondary butyl, tertiary butyl, pentyl, 1-methylpentyl, tertiary pentyl, neopentyl, hexyl, isohexyl and the like can be mentioned.

【００３３】 好適な「低級アルケニル」としては、ビニル、１−（または２−）プロペニル
、１−（または２−または３−）ブテニル、１−（または２−または３−または
４−）ペンテニル、１−（または２−または３−または４または５−）ヘキセニ
ル、メチルビニル、エチルビニル、１−（または２−または３−）メチル−１−
（または２−）プロペニル、１−（または２−または３−）エチル−１−（また
は２−）プロペニル、１−（または２−または３−または４−）メチル−１−（
または２−または３−）ブテニルなどを挙げることができ、より好ましい例とし
ては、Ｃ2−Ｃ4アルケニルを挙げることができる。Suitable “lower alkenyl” include vinyl, 1- (or 2-) propenyl, 1- (or 2- or 3-) butenyl, 1- (or 2- or 3- or 4-) pentenyl, 1- (or 2- or 3- or 4 or 5-) hexenyl, methylvinyl, ethylvinyl, 1- (or 2- or 3-) methyl-1-
(Or 2-) propenyl, 1- (or 2- or 3-) ethyl-1- (or 2-) propenyl, 1- (or 2- or 3- or 4-) methyl-1- (
Or 2- or 3-), etc. can be mentioned butenyl, more preferable examples, there can be mentioned the C 2 -C 4 alkenyl.

【００３４】 好適な「低級アルコキシ」および「低級アルコキシ」部分としては、直鎖また
は分枝状のもの、たとえばメトキシ、エトキシ、プロポキシ、イソプロポキシ、
１−エチルプロポキシ、ブトキシ、第二級ブトキシ、第三級ブトキシ、ペンチル
オキシ、ネオペンチルオキシ、第三級ペンチルオキシ、ヘキシルオキシなどを挙
げることができ、好ましいものとしては、Ｃ1−Ｃ4アルコキシを、最も好ましい
ものとしてはメトキシを挙げることができる。Suitable “lower alkoxy” and “lower alkoxy” moieties include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy,
1-ethylpropoxy, butoxy, secondary butoxy, tertiary butoxy, pentyloxy, neopentyloxy, tertiary pentyloxy, hexyloxy, and the like, with preferred examples being C 1 -C 4 alkoxy The most preferred is methoxy.

【００３５】 「ハロゲン」の好適な例としては、フッ素、塩素、臭素およびヨウ素を挙げる
ことができる。Suitable examples of “halogen” include fluorine, chlorine, bromine and iodine.

【００３６】 「アリール」および「アル」部分の好適な例としては、フェニル、ナフチル、
アントリルなどを挙げることができ、好ましいものとしては、フェニルを挙げる
ことができる。Suitable examples of “aryl” and “ar” moieties include phenyl, naphthyl,
Anthryl and the like can be mentioned, and a preferable example is phenyl.

【００３７】 「複素環基」の好適な例としては、 窒素原子１ないし４個を有する３ないし８員（より好ましくは５または６員）
の不飽和複素単環基、たとえばピロリル、ピロリニル、イミダゾリル、ピラゾリ
ル、ピリジル、ジヒドロピリジル、ピリミジル、ピラジニル、ピリダジニル、ト
リアゾリル、（たとえば４Ｈ−１，２，４−トリアゾリル、１Ｈ−１，２，３−
トリアゾリル、２Ｈ−１，２，３−トリアゾリルなど）、テトラゾリル（たとえ
ば１Ｈ−テトラゾリル、２Ｈ−テトラゾリルなど）など； 窒素原子１ないし４個を有する３ないし８員（より好ましくは５または６員）
の飽和複素単環基、たとえばピロリジニル、イミダゾリジニル、ピペリジル、ピ
ペラジニルなど； 窒素原子１ないし４個を有する不飽和縮合複素環基、たとえばインドリル、イ
ソインドリル、インドリニル、インドリジニル、ベンズイミダゾリル、キノリル
、イソキノリル、インダゾリル、ベンゾトリアゾリルなど；Preferred examples of the “heterocyclic group” include a 3- to 8-membered (preferably 5- or 6-membered) having 1 to 4 nitrogen atoms.
An unsaturated heteromonocyclic group such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, (for example, 4H-1,2,4-triazolyl, 1H-1,2,3-
Triazolyl, 2H-1,2,3-triazolyl, etc., tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.); 3 to 8 members having 1 to 4 nitrogen atoms (more preferably 5 or 6 members)
Unsaturated heterocyclic groups having 1 to 4 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, and the like. Benzotriazolyl and the like;

【００３８】 酸素原子１ないし２個および窒素原子１ないし３個を有する３ないし８員（よ
り好ましくは５または６員）の不飽和複素単環基、たとえばオキサゾリル、イソ
オキサゾリル、オキサジアゾリル（たとえば１，２，４−オキサジアゾリル、１
，３，４−オキサジアゾリル、１，２，５−オキサジアゾリルなど）など； 酸素原子１ないし２個および窒素原子１ないし３個を有する３ないし８員（よ
り好ましくは５または６員）の飽和複素単環基、たとえばモルホリニル、シドノ
ニルなど； 酸素原子１ないし２個および窒素原子１ないし３個を有する不飽和縮合複素環
基、たとえばベンゾオキサゾリル、ベンゾオキサジアゾリルなど； 硫黄原子１ないし２個および窒素原子１ないし３個を有する３ないし８員（よ
り好ましくは５または６員）の不飽和複素単環基、たとえばチアゾリル、イソチ
アゾリル、チアジアゾリル（たとえば１，２，３−チアジアゾリル、１，２，４
−チアジアゾリル、１，３，４−チアジアゾリル、１，２，５−チアジアゾリル
など）、ジヒドロチアジニルなど； 硫黄原子１ないし２個および窒素原子１ないし３個を有する３ないし８員（よ
り好ましくは５または６員）の飽和複素単環基、たとえばチアゾリジニルなど； 硫黄原子１ないし２個を有する３ないし８員（より好ましくは５または６員）
の不飽和複素環基、たとえばチエニル、ジヒドロジチイニル、ジヒドロジチオニ
ルなど；A 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2 , 4-oxadiazolyl, 1
, 3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); a 3- to 8-membered (more preferably 5- or 6-membered) saturated complex having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms Ring groups such as morpholinyl, sydnonyl and the like; unsaturated condensed heterocyclic groups having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzooxazolyl, benzoxdiazolyl and the like; 1 to 2 sulfur atoms and A 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl (for example, 1,2,3-thiadiazolyl, 1,2,4)
-Thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like), dihydrothiazinyl and the like; 3 to 8 members having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (more preferably 5 or 6-membered) saturated heteromonocyclic group such as thiazolidinyl; 3- to 8-membered having 1 to 2 sulfur atoms (more preferably 5 or 6-membered)
Unsaturated heterocyclic groups such as thienyl, dihydrodithiynyl, dihydrodithionyl and the like;

【００３９】 硫黄原子１ないし２個および窒素原子１ないし３個を有する不飽和縮合複素環
基、たとえばベンゾチアゾリル、ベンゾチアジアゾリル、イミダゾチアジアゾリ
ルなど； 酸素原子１個を有する３ないし８員（より好ましくは５または６員）の不飽和
複素単環基、たとえばフリルなど； 酸素原子１個を有する３ないし８員（より好ましくは５または６員）の飽和複
素単環基、たとえばテトラヒドロフラン、テトラヒドロピランなど； 酸素原子１個および硫黄原子１ないし２個を有する３ないし８員（より好まし
くは５または６員）の不飽和複素単環基、たとえばジヒドロオキサチイニルなど
；Unsaturated fused heterocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl and the like; 3 to 8 members having one oxygen atom ( More preferably a 5- or 6-membered) unsaturated heteromonocyclic group, such as furyl; a 3- to 8-membered (more preferably 5- or 6-membered) saturated heteromonocyclic group having one oxygen atom, such as tetrahydrofuran, tetrahydrofuran Pyran and the like; a 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group having one oxygen atom and one or two sulfur atoms, such as dihydrooxathiinyl;

【００４０】 硫黄原子１ないし２個を有する不飽和縮合複素環基、たとえばベンゾチエニル
、ベンゾジチイニルなど； 酸素原子１個および硫黄原子１ないし２個を有する不飽和縮合複素環基、たと
えばベンゾオキサチイニルなど； ２−オキソ−２，３−ジヒドロ−１Ｈ−ベンズイミダゾリル；などを挙げること
ができる。Unsaturated fused heterocyclic group having 1 to 2 sulfur atoms, such as benzothienyl, benzodithiynyl, etc .; Unsaturated fused heterocyclic group having 1 oxygen atom and 1 to 2 sulfur atoms, such as benzooxathiynyl 2-oxo-2,3-dihydro-1H-benzimidazolyl; and the like.

【００４１】 「アミノ保護基」部分の好適な例としては、アシルなどの通常のアミノ保護基
、たとえば、置換されたまたは置換されない低級アルカノイル ［たとえばホル
ミル、アセチル、プロピオニル、トリフルオロアセチルなど］、フタロイル、低
級アルコキシカルボニル［たとえば第三級ブトキシカルボニル、第三級アミロキ
シカルボニルなど］、置換されたまたは置換されないアラルキルオキシカルボニ
ル［たとえばベンジルオキシカルボニル、ｐ−ニトロベンジルオキシカルボニル
など］、置換されたまたは置換されないアレーンスルホニル［たとえばベンゼン
スルホニル、トシルなど］、ニトロフェニルスルフェニル、アル（低級）アルキ
ル［たとえばトリチル、ベンジルなど］などを挙げることができ、好ましいもの
としては、ベンジルなどのフェニル（低級）アルキルを挙げることができる。Suitable examples of “amino protecting group” moieties include common amino protecting groups such as acyl, for example, substituted or unsubstituted lower alkanoyl [eg formyl, acetyl, propionyl, trifluoroacetyl etc.], phthaloyl Lower alkoxycarbonyl [eg tertiary butoxycarbonyl, tertiary amyloxycarbonyl etc.], substituted or unsubstituted aralkyloxycarbonyl [eg benzyloxycarbonyl, p-nitrobenzyloxycarbonyl etc.], substituted or substituted Arenesulfonyl [eg, benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar (lower) alkyl [eg, trityl, benzyl, etc.] and the like. It may be mentioned phenyl, such as benzyl (lower) alkyl.

【００４２】 好適な「アシル」および「アシル」部分としては、カルボキシ；エステル化さ
れたカルボキシ；低級アルキル１または２個で任意に置換されたカルバモイル；
低級アルキルスルホニル［たとえばメチルスルホニル、エチルスルホニル、プロ
ピルスルホニル、ブチルスルホニル、ペンチルスルホニル、ヘキシルスルホニル
など］；置換されたまたは置換されない低級アルカノイル［たとえばホルミル、
アセチル、トリフルオロアセチル、プロパノイル、ブタノイル、２−メチルプロ
パノイル、ペンタノイル、２，２−ジメチルプロパノイル、ヘキサノイルなど］
などを挙げることができる。Suitable “acyl” and “acyl” moieties include carboxy; esterified carboxy; carbamoyl optionally substituted with one or two lower alkyls;
Lower alkylsulfonyl [eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.]; substituted or unsubstituted lower alkanoyl [eg, formyl,
Acetyl, trifluoroacetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl and the like]
And the like.

【００４３】 エステル化されたカルボキシとしては、置換されたまたは置換されない低級ア
ルコキシカルボニル［たとえばメトキシカルボニル、エトキシカルボニル、プロ
ポキシカルボニル、ブトキシカルボニル、ヘキシルオキシカルボニル、２−ヨー
ドエトキシカルボニル、トリフルオロメトキシカルボニル、２，２，２−トリク
ロロエトキシカルボニルなど］、置換されたまたは置換されないアリールオキシ
カルボニル［たとえばフェノキシカルボニル、４−ニトロフェノキシカルボニル
、２−ナフチルオキシカルボニルなど］、置換されたまたは置換されないアル（
低級）アルコキシカルボニル［たとえばベンジルオキシカルボニル、フェネチル
オキシカルボニル、ベンズヒドリルオキシカルボニル、４−ニトロベンジルオキ
シカルボニルなど］などを挙げることができ、好ましいものとしては、低級アル
コキシカルボニルを、最も好ましいものとしては、エトキシカルボニルを挙げる
ことができる。The esterified carboxy includes a substituted or unsubstituted lower alkoxycarbonyl [eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, trifluoromethoxycarbonyl, , 2,2-trichloroethoxycarbonyl etc.], substituted or unsubstituted aryloxycarbonyl [eg phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl etc.], substituted or unsubstituted al (
Lower) alkoxycarbonyl [for example, benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl and the like], and the like. Preferred are lower alkoxycarbonyl, most preferred , Ethoxycarbonyl.

【００４４】 「低級アルキルスルホニルアミノ」の好適な例としては、メチルスルホニルア
ミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、ブチルスルホニル
アミノ、ペンチルスルホニルアミノ、ヘキシルスルホニルアミノなどを挙げるこ
とができ、好ましいものとしては、（Ｃ1−Ｃ4）アルキルスルホニルアミノを、
最も好ましいものとしては、メチルスルホニルアミノを挙げることができる。Preferable examples of “lower alkylsulfonylamino” include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino and the like. , (C 1 -C 4 ) alkylsulfonylamino,
Most preferred is methylsulfonylamino.

【００４５】 Ａにおける「複素環基」の好適な例としては、前記の「複素環基」を挙げるこ
とができ、好ましいものとしては、窒素原子１ないし４個を有する３ないし８員
（より好ましくは５または６員）の不飽和複素単環基、または窒素原子１ないし
４個を有する不飽和縮合複素環基を、最も好ましいものとしては、ピリジル、イ
ンドリルまたは２−オキソ−２，３−ジヒドロ−１Ｈ−ベンズイミダゾリルを挙
げることができる。Preferable examples of the “heterocyclic group” in A include the aforementioned “heterocyclic group”, and a preferable example is a 3- to 8-membered group having 1 to 4 nitrogen atoms (more preferably). Is a 5- or 6-membered) unsaturated heteromonocyclic group or an unsaturated condensed heterocyclic group having 1 to 4 nitrogen atoms, most preferably pyridyl, indolyl or 2-oxo-2,3-dihydro -1H-benzimidazolyl.

【００４６】 Ｒ7およびＲ8によって形成される低級アルキレン鎖は、炭素原子を１ないし６
個有する直鎖または分枝鎖状のアルキレンであって、例としては、メチレン、エ
チレン、トリメチレン、プロピレン、ブチレン、１，２−ジメチルエチレン、ペ
ンタメチレンおよびヘキサメチレンを挙げることができる。The lower alkylene chain formed by R 7 and R 8 has 1 to 6 carbon atoms.
Straight-chain or branched-chain alkylene, and examples thereof include methylene, ethylene, trimethylene, propylene, butylene, 1,2-dimethylethylene, pentamethylene and hexamethylene.

【００４７】 目的化合物［Ｉ］の好ましい例としては、以下のものを挙げることができる。Preferred examples of the target compound [I] include the following.

【００４８】 Ａはピリジル、インドリル、２−オキソ−２，３−ジヒドロ−１Ｈ−ベンズイ
ミダゾリルまたはフェニルであって、その各々はヒドロキシ、アミノ、低級アル
キル（より好ましくはメチル）、低級アルキルスルホニルアミノ（より好ましく
はメタンスルホニルアミノ）、フェニル（低級）アルコキシ（より好ましくはベ
ンジルオキシ）およびフェニル（低級）アルコキシカルボニルアミノ（より好ま
しくはベンジルオキシカルボニルアミノ）よりなる群から選択された同種または
異種の置換基を１ないし３個有していてもよい、 −Ｘ−は結合、−ＣＨ2−、−ＣＨ2−ＣＨ2−、−Ｏ−ＣＨ2−または−ＳＯ2
−ＣＨ2−、A is pyridyl, indolyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl or phenyl, each of which is hydroxy, amino, lower alkyl (more preferably methyl), lower alkylsulfonylamino ( More preferably, the same or different substituents selected from the group consisting of methanesulfonylamino), phenyl (lower) alkoxy (more preferably benzyloxy) and phenyl (lower) alkoxycarbonylamino (more preferably benzyloxycarbonylamino) which may have three to no 1, -X- is a bond, -CH 2 -, - CH 2 -CH 2 -, - O-CH 2 - or -SO 2
-CH 2 -,

【００４９】[0049]

【化４６】 （式中、Ｒ11は水素またはヒドロキシを意味する。）、Embedded image (In the formula, R 11 represents hydrogen or hydroxy.)

【００５０】[0050]

【化４７】 Embedded image

【００５１】 または−（ＣＨ2）n−Ｑ−（ＣＨ2）m− （式中、−Ｑ−は[0051] or - (CH 2) n -Q- ( CH 2) m - ( wherein, -Q- is

【化４８】 Embedded image

【００５２】[0052]

【化４９】 Embedded image

【００５３】 （式中、Ｒ10は水素または低級アルキル（より好ましくはメチル）、 Ｒ11は低級アルキル（より好ましくはメチル）をそれぞれ意味する。）、 Ｒ6、Ｒ7、Ｒ8およびＲ9はそれぞれ単独に水素、低級アルキル（より好ましく
はメチル）、または低級アルコキシ（より好ましくはメトキシ）を１ないし３個
有していてもよいアリール（より好ましくはフェニル）、 ｎ、ｍおよびｋはそれぞれ単独に０ないし６、 ｒは２ないし７、 をそれぞれ意味する。）、(Wherein, R 10 represents hydrogen or lower alkyl (more preferably methyl), R 11 represents lower alkyl (more preferably methyl), respectively), R 6 , R 7 , R 8 and R 9 Is each independently hydrogen, lower alkyl (more preferably methyl), or aryl (more preferably phenyl) optionally having 1 to 3 lower alkoxy (more preferably methoxy), n, m and k are each 0 to 6, r independently represents 2 to 7, respectively. ),

【００５４】[0054]

【化５０】 Embedded image

【００５５】 （式中ｉは０ないし６を意味する。）、 Ｒ1は水素またはアル（低級）アルキル（より好ましくはベンジル）、 Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ単独に水素；低級アルキル（より好ましく
はメチル）；低級アルキルチオ（より好ましくはメチルチオ）；低級アルキルス
ルホニル（より好ましくはメタンスルホニル）；ヒドロキシ；低級アルコキシ（
より好ましくはメトキシまたはエトキシ）；アミノ；低級アルキルアミノ（より
好ましくはメチルアミノ）；アシルアミノ（より好ましくは低級アルコキシカル
ボニルアミノ、低級アルキルスルホニルアミノ、低級アルカノイルアミノ、ウレ
イドまたはトリフルオロアセチルアミノ、最も好ましくはメトキシカルボニルア
ミノ、エトキシカルボニルアミノ、メタンスルホニルアミノ、ホルミルアミノ、
アセチルアミノまたはプロピオニルアミノ）；Ｎ−（低級アルキル）アシルアミ
ノ［より好ましくはＮ−（低級アルキル）−［（低級）アルコキシカルボニル］
アミノ、最も好ましくはＮ−メチル−メトキシカルボニルアミノ］；カルボキシ
；または低級アルコキシカルボニル（より好ましくはメトキシカルボニル）、 をそれぞれ意味する。(Wherein i represents 0 to 6), R 1 is hydrogen or ar (lower) alkyl (more preferably benzyl), and R 2 , R 3 , R 4 and R 5 are each independently hydrogen. Lower alkyl (more preferably methyl); lower alkylthio (more preferably methylthio); lower alkylsulfonyl (more preferably methanesulfonyl); hydroxy;
More preferably methoxy or ethoxy); amino; lower alkylamino (more preferably methylamino); acylamino (more preferably lower alkoxycarbonylamino, lower alkylsulfonylamino, lower alkanoylamino, ureido or trifluoroacetylamino, most preferably Methoxycarbonylamino, ethoxycarbonylamino, methanesulfonylamino, formylamino,
Acetylamino or propionylamino); N- (lower alkyl) acylamino [more preferably N- (lower alkyl)-[(lower) alkoxycarbonyl]
Amino, most preferably N-methyl-methoxycarbonylamino]; carboxy; or lower alkoxycarbonyl (more preferably methoxycarbonyl), respectively.

【００５６】 目的化合物［Ｉ］のより好ましい例としては、以下のものを挙げることができ
る。More preferred examples of the target compound [I] include the following.

【００５７】 Ａはフェニルであって、ヒドロキシ、アミノ、低級アルキルスルホニルアミノ
（より好ましくはメタンスルホニルアミノ）およびフェニル（低級）アルコキシ
（より好ましくはベンジルオキシ）よりなる群から選択された同種または異種の
置換基を１ないし３個有していてもよい、 −Ｘ−は結合、−ＣＨ2−、−ＣＨ2−ＣＨ2−、−Ｏ−ＣＨ2−または−ＳＯ2
−ＣＨ2−、A is phenyl, which is the same or different and is selected from the group consisting of hydroxy, amino, lower alkylsulfonylamino (more preferably methanesulfonylamino) and phenyl (lower) alkoxy (more preferably benzyloxy). a substituent 1 to may have three, -X- is a bond, -CH 2 -, - CH 2 -CH 2 -, - O-CH 2 - or -SO 2
-CH 2 -,

【００５８】[0058]

【化５１】 Embedded image

【００５９】 （式中、Ｒ11は水素またはヒドロキシを意味する。）、(Wherein R 11 represents hydrogen or hydroxy);

【００６０】[0060]

【化５２】 Embedded image

【００６１】 （式中、Ｒ6、Ｒ7、Ｒ8およびＲ9はそれぞれ単独に水素、低級アルキル（より好
ましくはメチル）、または低級アルコキシ（より好ましくはメトキシ）を１ない
し３個有していてもよいフェニル、 ｎ、ｍおよびｋはそれぞれ単独に０または１、 をそれぞれ意味する。）、 Ｒ1は水素またはフェニル（低級）アルキル（より好ましくはベンジル）、 Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ単独に水素；低級アルキル（より好ましく
はメチル）；低級アルキルチオ（より好ましくはメチルチオ）；低級アルキルス
ルホニル（より好ましくはメタンスルホニル）；ヒドロキシ；低級アルコキシ（
より好ましくはメトキシまたはエトキシ）；アミノ；低級アルキルアミノ（より
好ましくはメチルアミノ）；低級アルコキシカルボニルアミノ（より好ましくは
メトキシカルボニルアミノまたはエトキシカルボニルアミノ）；低級アルキルス
ルホニルアミノ（より好ましくはメタンスルホニルアミノ）；低級アルカノイル
アミノ（より好ましくはホルミルアミノ、アセチルアミノまたはプロピオニルア
ミノ）；ウレイド；トリフルオロアセチルアミノ；Ｎ−（低級アルキル）−［（
低級）アルコキシカルボニル］アミノ（より好ましくはＮ−メチル−メトキシカ
ルボニルアミノ）；カルボキシ；または低級アルコキシカルボニル（より好まし
くはメトキシカルボニル）、 をそれぞれ意味する。(Wherein, R 6 , R 7 , R 8 and R 9 each independently have 1 to 3 hydrogen, lower alkyl (more preferably methyl), or lower alkoxy (more preferably methoxy)) Phenyl, n, m and k each independently represent 0 or 1, respectively), R 1 is hydrogen or phenyl (lower) alkyl (more preferably benzyl), R 2 , R 3 , R 4 And R 5 are each independently hydrogen; lower alkyl (more preferably methyl); lower alkylthio (more preferably methylthio); lower alkylsulfonyl (more preferably methanesulfonyl); hydroxy;
Amino; lower alkylamino (more preferably methylamino); lower alkoxycarbonylamino (more preferably methoxycarbonylamino or ethoxycarbonylamino); lower alkylsulfonylamino (more preferably methanesulfonylamino). Lower alkanoylamino (more preferably formylamino, acetylamino or propionylamino); ureido; trifluoroacetylamino; N- (lower alkyl)-[(
Lower) alkoxycarbonyl] amino (more preferably N-methyl-methoxycarbonylamino); carboxy; or lower alkoxycarbonyl (more preferably methoxycarbonyl), respectively.

【００６２】 目的アミノアルコール誘導体の好適な塩は、医薬として許容される塩であって
、無機酸付加塩［たとえば塩酸塩、臭化水素酸塩、硫酸塩、燐酸塩など］、有機
酸付加塩［たとえば蟻酸塩、酢酸塩、トリフルオロ酢酸塩、シュウ酸塩、マレイ
ン酸塩、フマル酸塩、酒石酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、
トルエンスルホン酸塩など］、アルカリ金属塩［たとえばナトリウム塩、カリウ
ム塩など］などの慣用の無毒の塩を挙げることができる。Suitable salts of the desired amino alcohol derivative are pharmaceutically acceptable salts, such as inorganic acid addition salts [eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.], organic acid addition salts [For example, formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate,
Conventional non-toxic salts such as toluenesulfonate] and alkali metal salts [eg, sodium salt, potassium salt and the like] can be mentioned.

【００６３】 目的化合物［Ｉ］の製造法を次に詳細に説明する。 製造法１ 目的化合物［Ｉ］またはその塩は、化合物［ＩＩ］を化合物［ＩＩＩ］または
その塩と反応させて製造することができる。 化合物［ＩＩＩ］の好適な塩としては、化合物［Ｉ］で例示したのと同じもの
を挙げることができる。 反応は塩基の存在下で行われるのが好ましく、塩基としては、たとえばアルカ
リ金属炭酸塩［たとえば炭酸ナトリウム、炭酸カリウムなど］、アルカリ土類金
属炭酸塩［たとえば炭酸マグネシウム、炭酸カルシウムなど］、アルカリ金属重
炭酸塩［たとえば重炭酸ナトリウム、重炭酸カリウムなど］、トリ（低級）アル
キルアミン［たとえばトリメチルアミン、トリエチルアミンなど］、ピコリンな
どを挙げることができる。The method for producing the target compound [I] will be described in detail below. Production Method 1 The target compound [I] or a salt thereof can be produced by reacting the compound [II] with the compound [III] or a salt thereof. Suitable salts of the compound [III] are the same as those exemplified for the compound [I]. The reaction is preferably carried out in the presence of a base. Examples of the base include alkali metal carbonates [eg, sodium carbonate, potassium carbonate, etc.], alkaline earth metal carbonates [eg, magnesium carbonate, calcium carbonate, etc.], alkali metal Examples include bicarbonate (eg, sodium bicarbonate, potassium bicarbonate, etc.), tri (lower) alkylamine [eg, trimethylamine, triethylamine, etc.], picoline and the like.

【００６４】 反応は、通常、反応に悪影響を及ぼさない慣用の溶媒、たとえばアルコール［
メタノール、エタノール、プロパノール、イソプロパノールなど］、ジエチルエ
ーテル、テトラヒドロフラン、ジオキサン、または他の有機溶媒中で行われる。 反応温度は特に限定されず、反応は、冷却ないし加熱下で行われる。The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as an alcohol [
Methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or other organic solvents. The reaction temperature is not particularly limited, and the reaction is performed under cooling or heating.

【００６５】 製造法２ 目的化合物［Ｉｂ］またはその塩は、化合物［Ｉａ］またはその塩をアミノ保
護基の脱離反応に付すことによって製造することができる。 化合物［Ｉａ］および［１ｂ］の好適な塩としては、化合物［Ｉ］で例示した
のと同じものを挙げることができる。 この反応は加水分解、還元などの慣用の方法により実施される。 加水分解は塩基、またはルイス酸などの酸の存在下で実施するのが好ましい。 好適な塩基としては、無機塩基および有機塩基、たとえばアルカリ金属［たと
えばナトリウム、カリウムなど］、アルカリ土類金属［たとえばマグネシウム、
カルシウムなど］、それらの水酸化物、炭酸塩または重炭酸塩、ヒドラジン、ト
リアルキルアミン［たとえばトリメチルアミン、トリエチルアミンなど］、ピコ
リン、１，５−ジアザビシクロ［４．３．０］ノン−５−エン、１，４−ジアザ
ビシクロ［２．２．２］オクタン、１，８−ジアザビシクロ［５．４．０］ウン
デク−７−エンなどを挙げることができる。Production Method 2 The target compound [Ib] or a salt thereof can be produced by subjecting the compound [Ia] or a salt thereof to an elimination reaction of an amino protecting group. Suitable salts of the compounds [Ia] and [1b] include the same as those exemplified for the compound [I]. This reaction is carried out by a conventional method such as hydrolysis and reduction. The hydrolysis is preferably carried out in the presence of a base or an acid such as a Lewis acid. Suitable bases include inorganic and organic bases, such as alkali metals [eg, sodium, potassium, etc.], alkaline earth metals [eg, magnesium,
Calcium, etc.], their hydroxides, carbonates or bicarbonates, hydrazine, trialkylamines [eg, trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene and the like can be mentioned.

【００６６】 好適な酸としては、有機酸［たとえば蟻酸、酢酸、プロピオン酸、トリクロロ
酢酸、トリフルオロ酢酸など］、無機酸［たとえば塩酸、臭化水素酸、硫酸、塩
化水素、臭化水素、フッ化水素など］および酸付加塩化合物［たとえば塩酸ピリ
ジンなど］を挙げることができる。 トリハロ酢酸［たとえばトリクロロ酢酸、トリフルオロ酢酸など］などを用い
る脱離は、カチオン捕捉剤［たとえばアニソール、フェノールなど］の存在下で
実施するのが好ましい。Suitable acids include organic acids [eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and inorganic acids [eg hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrofluoric acid, etc. And acid addition salt compounds [for example, pyridine hydrochloride and the like]. The elimination using trihaloacetic acid [eg, trichloroacetic acid, trifluoroacetic acid, etc.] is preferably carried out in the presence of a cation scavenger [eg, anisole, phenol, etc.].

【００６７】 反応は、通常、反応に悪影響を及ぼさない溶媒、たとえば水、アルコール［た
とえばメタノール、エタノールなど］、塩化メチレン、クロロホルム、テトラク
ロロメタン、テトラヒドロフラン、それらの混合物または他の溶媒中で行われる
。液体の塩基または酸もまた溶媒として使用できる。反応温度は特に限定されず
、通常、反応は、冷却ないし加熱下で行われる。 脱離反応に適用できる還元方法としては、化学還元および触媒還元を挙げるこ
とができる。The reaction is usually performed in a solvent that does not adversely influence the reaction, for example, water, alcohol [eg, methanol, ethanol and the like], methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, a mixture thereof or other solvents. . Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. Reduction methods applicable to the elimination reaction include chemical reduction and catalytic reduction.

【００６８】 化学還元に用いられる好適な還元剤としては、金属［たとえば錫、亜鉛、鉄な
ど］または金属化合物［たとえば塩化クロム、酢酸クロムなど］と有機酸または
無機酸［たとえば蟻酸、酢酸、プロピオン酸、トリフルオロ酢酸、ｐ−トルエン
スルホン酸、塩酸、臭化水素酸など］との組合せを挙げることができる。Suitable reducing agents used for chemical reduction include metals [eg, tin, zinc, iron, etc.] or metal compounds [eg, chromium chloride, chromium acetate, etc.] and organic or inorganic acids [eg, formic acid, acetic acid, propion] Acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].

【００６９】 触媒還元に使用される好適な触媒としては、慣用の触媒、たとえば白金触媒［
たとえば白金板、白金海綿、白金黒、コロイド白金、酸化白金、白金線など］、
パラジウム触媒［たとえばパラジウム海綿、パラジウム黒、酸化パラジウム、パ
ラジウム炭、コロイドパラジウム、パラジウム−硫酸バリウム、パラジウム−炭
酸バリウムなど］、ニッケル触媒［たとえば還元ニッケル、酸化ニッケル、ラネ
ーニッケルなど］、コバルト触媒［たとえば還元コバルト、ラネーコバルトなど
］、鉄触媒［たとえば還元鉄、ラネー鉄など］、銅触媒［たとえば還元銅、ラネ
ー銅、ウルマン銅など］などを挙げることができる。Suitable catalysts used for catalytic reduction include conventional catalysts, for example platinum catalysts [
For example, platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.],
Palladium catalysts [eg, palladium sponge, palladium black, palladium oxide, palladium charcoal, colloidal palladium, palladium-barium sulfate, palladium-barium carbonate, etc.], nickel catalysts [eg, reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [eg, reduction] Cobalt, Raney cobalt, etc.], iron catalysts (eg, reduced iron, Raney iron, etc.), copper catalysts (eg, reduced copper, Raney copper, Ullman copper, etc.) and the like.

【００７０】 アミノ保護基がベンジルである場合、還元は、パラジウム触媒［たとえばパラ
ジウム黒、パラジウム炭など］と蟻酸またはその塩［たとえば蟻酸アンモニウム
など］との組合せの存在下で実施するのが好ましい。When the amino protecting group is benzyl, the reduction is preferably carried out in the presence of a combination of a palladium catalyst [for example palladium black, palladium charcoal etc.] and formic acid or a salt thereof [for example ammonium formate etc.].

【００７１】 還元は、通常、反応に悪影響を及ぼさない慣用の溶媒、たとえば水、アルコー
ル［たとえばメタノール、エタノール、プロパノールなど］、クロロベンゼン、
Ｎ，Ｎ−ジメチルホルムアミドまたはそれらの混合物中で行われる。さらに、化
学還元に用いられる前記の酸が液体である場合、それらもまた溶媒として使用で
きる。また、触媒還元に用いられる好適な溶媒は、前記の溶媒、他の慣用の溶媒
たとえばジエチルエーテル、ジオキサン、テトラヒドロフランなど、またはそれ
らの混合物であってもよい。The reduction is usually carried out with conventional solvents which do not adversely influence the reaction, for example water, alcohols such as methanol, ethanol, propanol, etc., chlorobenzene,
The reaction is performed in N, N-dimethylformamide or a mixture thereof. Furthermore, if the acids used for chemical reduction are liquid, they can also be used as solvents. Suitable solvents for use in the catalytic reduction may also be those mentioned above, other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, and the like, or mixtures thereof.

【００７２】 この還元の反応温度は特に限定されず、通常、反応は、冷却ないし加熱下で行
われる。The reaction temperature of this reduction is not particularly limited, and the reaction is usually performed under cooling or heating.

【００７３】 上記の製造法にしたがって得られた化合物は、粉砕、再結晶、カラムクロマト
グラフィー、再沈殿などの慣用の方法で分離・精製でき、必要に応じて、慣用の
方法で所望の塩に転換できる。The compound obtained according to the above-mentioned production method can be separated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, and if necessary, converted into a desired salt by a conventional method. Can be converted.

【００７４】 化合物［Ｉ］および他の化合物は、不斉炭素原子に基づく立体異性体を１個ま
たはそれ以上有することがあるが、これらのすべての異性体およびそれらの混合
物もまたこの発明の範囲に含まれる。While compound [I] and other compounds may have one or more stereoisomers based on asymmetric carbon atoms, all of these isomers and mixtures thereof are also within the scope of this invention. include.

【００７５】 目的化合物［Ｉ］の異性化または転位が、弱酸、弱塩基などの影響により生じ
ることがあるが、この異性化または転位の結果として得られる化合物もまたこの
発明の範囲に含まれる。The isomerization or rearrangement of the target compound [I] may be caused by the influence of a weak acid, a weak base or the like, and the compound obtained as a result of this isomerization or rearrangement is also included in the scope of the present invention.

【００７６】 さらに、目的化合物［Ｉ］の溶媒和形態（たとえば水和物など）および化合物
［Ｉ］の結晶のいかなる形態もまたこの発明の範囲に含まれる。Further, any solvated form (eg, hydrate, etc.) of the target compound [I] and any crystal form of the compound [I] are also included in the scope of the present invention.

【００７７】 目的化合物［Ｉ］またはその塩は、腸選択的交感神経作用、抗潰瘍、抗膵臓炎
、脂肪分解および抗頻尿活性を有し、ヒトまたは動物における平滑筋収縮を要因
とする胃腸疾患の治療および／または予防に有用であり、より詳しくは、過敏性
腸症候群、胃炎、胃潰瘍、十二指腸潰瘍、腸炎、胆嚢症、胆管炎、尿路結石など
の場合における痙攣または運動機能亢進症の治療および／または予防；胃潰瘍、
十二指腸潰瘍、消化性潰瘍、非ステロイド系抗炎症薬に起因する潰瘍などの潰瘍
の治療および／または予防；神経性頻尿症、神経性膀胱機能障害、夜間頻尿症、
不安定膀胱、膀胱痙攣、慢性膀胱炎、慢性前立腺炎、前立腺肥大症などの場合に
おける頻尿症、尿失禁などの排尿障害の治療および／または予防；膵炎、肥満症
、糖尿病、糖尿、高脂血症、高血圧症、アテローム性動脈硬化症、緑内障、メラ
ンコリー、鬱病などの治療および／または予防；インスリン耐性に起因する疾患
（たとえば高血圧症、高インスリン血症など）などの治療および／または予防の
ための方法に有用である。The target compound [I] or a salt thereof has an intestinal selective sympathetic action, anti-ulcer, anti-pancreatitis, lipolytic and anti-uriuritic activities, and has a gastrointestinal tract caused by smooth muscle contraction in humans or animals. It is useful for the treatment and / or prevention of diseases, and more particularly for the treatment of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystitis, cholangitis, urolithiasis, etc. Treatment and / or prevention; gastric ulcer,
Treatment and / or prevention of ulcers such as duodenal ulcers, peptic ulcers, ulcers caused by non-steroidal anti-inflammatory drugs; dysuria nervosa, nervous bladder dysfunction, nocturia,
Treatment and / or prevention of dysuria such as urinary frequency and urinary incontinence in cases of unstable bladder, bladder spasm, chronic cystitis, chronic prostatitis, prostatic hypertrophy; pancreatitis, obesity, diabetes, diabetes, high fat For the treatment and / or prevention of blood, hypertension, atherosclerosis, atherosclerosis, glaucoma, melancholy, depression and the like; treatment and / or prevention of diseases caused by insulin resistance (eg, hypertension, hyperinsulinemia, etc.) Useful for methods.

【００７８】 ヒトまたは動物における前記の疾患の予防および治療のための化合物［Ｉ］の
有用性を示すために、その代表的化合物の薬理学試験データを以下に示す。In order to show the usefulness of Compound [I] for preventing and treating the above-mentioned diseases in humans or animals, pharmacological test data of representative compounds are shown below.

【００７９】 試験 麻酔したイヌにおけるカルバコールによって誘発された膀胱内圧の増加に対す
る影響 試験化合物 （１）（２Ｓ）−１−［［（２ＲＳ）−４，４−ビス（４−ヒドロキシフェニル
）−２−ブチル］アミノ］−３−フェノキシ−２−プロパノール塩酸塩Testing Effect on Increased Intravesical Pressure Induced by Carbachol in Anesthetized Dogs Test Compound (1) (2S) -1-[[(2RS) -4,4-bis (4-hydroxyphenyl) -2- [Butyl] amino] -3-phenoxy-2-propanol hydrochloride

【００８０】 試験方法 体重８．０〜１５．０ｋｇの雌性ビーグル犬を２４時間絶食させ、ハロタン麻
酔下に保持した。１２Ｆフォーリーカテーテルを、水溶性ゼリーで潤滑し、尿道
口に挿入し、バルーン先端が十分に膀胱内部に位置するまで約１０ｃｍ進入させ
た。次に、バルーンを５ｍｌの大気で膨張させ、膀胱頚で感じる最初の抵抗箇所
までカテーテルを徐々に後退させた。カテーテルを通して尿を完全に排出し、３
０ｍｌの生理食塩水を注入した。カテーテルを圧力トランスジューサーに接続し
、膀胱内圧を連続的に記録した。カルバコール（１．８μｇ／ｋｇ）投与の５分
前に、試験化合物を静脈注射した。 試験結果Test Method Female beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours and kept under halothane anesthesia. The 12F Foley catheter was lubricated with water-soluble jelly, inserted into the urethral opening, and advanced about 10 cm until the balloon tip was sufficiently inside the bladder. The balloon was then inflated with 5 ml of air and the catheter was gradually retracted to the first resistance point felt at the bladder neck. Complete drainage of urine through the catheter, 3
0 ml of saline was injected. The catheter was connected to a pressure transducer and the intravesical pressure was continuously recorded. The test compound was injected intravenously 5 minutes before the administration of carbachol (1.8 μg / kg). Test results

【００８１】[0081]

【表１】 **Ｐ＜０．０１ 対 対照（ＡＮＯＶＡ） （Ｎ＝３）[Table 1] ** P <0.01 vs control (ANOVA) (N = 3)

【００８２】 以下の製造例および実施例は、この発明を説明するために示したものである。
実施例１ （２Ｓ）−３−フェノキシ−１，２−エポキシプロパン（１９５ｍｇ）（ＩＬ ＦＡＲＭＡＣＯ、５０（１０）、６４３（１９９５））と４，４−ビス（４−
ヒドロキシフェニル）−２−ブチルアミン（２５７ｍｇ）のエタノール（２ｍｌ
）中の溶液を、還流下で２４時間攪拌し、真空中で溶媒を留去した。残留物をシ
リカゲル（９ｇ）クロマトグラフィー（クロロホルム−メタノール）に付し、溶
出液を酢酸エチル中４Ｎ塩化水素で処理して、粗製油状物を得て、これをジエチ
ルエーテルから粉末化して、（２Ｓ）−１−［［（２ＲＳ）-４，４−ビス（４
−ヒドロキシフェニル）−２−ブチル］アミノ］−３−フェノキシ−２−プロパ
ノール塩酸塩（１１７ｍｇ）を淡褐色粉末として得た。 mp : 73℃ (分解) IR (ヌシ゛ョール) : 3600-3100, 2700-2400, 1230 cm-1 NMR (DMSO-d6, δ) : 1.21-1.27 (3H, m, CH3), 1.94 (1H, m,CH2), 2.60 (1H, m, CH2), 2.85-3.2 (3H, m, CH2NCH), 3.95 (1H, m, CHAr2), 4.01-4.05 (2H,
m, ArOCH2), 4.16 (1H, m, CHOH), 5.85 (1H, br s, OH), 6.64-6.72 (4H, m,
aromatic H), 6.92-7.16 (7H, m, aromatic H), 7.26-7.35 (2H, m, aromatic
H), 8.62 (1H, br, NH), 8.92 (1H, br, HCl), 9.23 (1H, br s, OH), 9.28 (1H, br s, OH) MS m/z : 408 (M++1)The following Production Examples and Examples are provided to illustrate the present invention.
Example 1 (2S) -3-phenoxy-1,2-epoxypropane (195 mg) (IL FARMACO, 50 (10), 643 (1995)) and 4,4-bis (4-
(Hydroxyphenyl) -2-butylamine (257 mg) in ethanol (2 ml)
) Was stirred under reflux for 24 hours and the solvent was distilled off in vacuo. The residue was chromatographed on silica gel (9 g) (chloroform-methanol) and the eluate was treated with 4N hydrogen chloride in ethyl acetate to give a crude oil which was triturated from diethyl ether to give (2S ) -1-[[(2RS) -4,4-bis (4
-Hydroxyphenyl) -2-butyl] amino] -3-phenoxy-2-propanol hydrochloride (117 mg) was obtained as a light brown powder. mp: 73 ° C (decomposition) IR (nuclear): 3600-3100, 2700-2400, 1230 cm -1 NMR (DMSO-d 6 , δ): 1.21-1.27 (3H, m, CH 3 ), 1.94 (1H, m, CH 2 ), 2.60 (1H, m, CH 2 ), 2.85-3.2 (3H, m, CH 2 NCH), 3.95 (1H, m, CHAr 2 ), 4.01-4.05 (2H,
m, ArOCH 2 ), 4.16 (1H, m, CHOH), 5.85 (1H, br s, OH), 6.64-6.72 (4H, m,
aromatic H), 6.92-7.16 (7H, m, aromatic H), 7.26-7.35 (2H, m, aromatic
H), 8.62 (1H, br , NH), 8.92 (1H, br, HCl), 9.23 (1H, br s, OH), 9.28 (1H, br s, OH) MS m / z: 408 (M + + 1)

【００８３】 実施例２ （２Ｒ）−Ｎ−ベンジル−４，４−ビス（４−メトキシフェニル）−２−ブチ
ルアミン塩酸塩（４１２ｍｇ）を、常法で、対応する遊離塩基に転換した。塩化
錫（ＩＶ）のジクロロメタン中１．０Ｍ溶液（１．５ｍｌ）を、この遊離塩基と
（２Ｓ）−３−フェノキシ−１，２−エポキシプロパン（２２５ｍｇ）（ＩＬ
ＦＡＲＭＡＣＯ、５０（１０）、６４３（１９９５））のジクロロメタン（４ｍ
ｌ）中の攪拌溶液に−１０〜−５℃で窒素雰囲気下で１０分間かけて滴下し、生
じた混合物を同温で１．５時間攪拌した。反応混合物を１Ｎ塩酸に注ぎ、混合物
を氷冷下で２０分間攪拌した。有機層を分離し、フッ化ナトリウムの水溶液と飽
和重炭酸ナトリウム水溶液で洗浄し、硫酸ナトリウムで乾燥後、真空中で溶媒を
留去した。残留物をシリカゲル（１１ｇ）クロマトグラフィー（酢酸エチル）に
付して、溶出液を酢酸エチル中４Ｎ塩化水素で処理して、（２Ｓ）−１−［Ｎ−
ベンジル−［（２Ｒ）−４，４−ビス（４−メトキシフェニル）−２−ブチル］
アミノ］−３−フェノキシ−２−プロパノール塩酸塩（１３６ｍｇ）を油状物と
して得た。 IR (薄層) : 3292, 2850-2400, 1243 cm-1 NMR (CDCl3, δ) : 1.27 および 1.47 (3H, 各d, J=6.2 および6.6Hz), 2.08
(1H, m), 2.9-3.5 (4H, m), 3.68-4.0 (2H, m), 3.74, 3.75 および 3.76 (6H,
各s), 4.02-4.08 (2H, m), 4.10-4.26 (1H, m), 4.3-4.6 (1H, m), 6.72-7.43
および 7.64-7.68 (18H, m) MS m/z : 526 (M++1)Example 2 (2R) -N-benzyl-4,4-bis (4-methoxyphenyl) -2-butylamine hydrochloride (412 mg) was converted to the corresponding free base in a conventional manner. A 1.0 M solution of tin (IV) chloride in dichloromethane (1.5 ml) was combined with the free base and (2S) -3-phenoxy-1,2-epoxypropane (225 mg) (IL
FARMACO, 50 (10), 643 (1995)) in dichloromethane (4 m
To the stirred solution in l) was added dropwise at -10 to -5 ° C under a nitrogen atmosphere over 10 minutes, and the resulting mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was stirred under ice cooling for 20 minutes. The organic layer was separated, washed with aqueous sodium fluoride and saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (11 g) (ethyl acetate) and the eluate was treated with 4N hydrogen chloride in ethyl acetate to give (2S) -1- [N-
Benzyl-[(2R) -4,4-bis (4-methoxyphenyl) -2-butyl]
Amino] -3-phenoxy-2-propanol hydrochloride (136 mg) was obtained as an oil. IR (thin layer): 3292, 2850-2400, 1243 cm -1 NMR (CDCl 3 , δ): 1.27 and 1.47 (3H, d, J = 6.2 and 6.6 Hz), 2.08
(1H, m), 2.9-3.5 (4H, m), 3.68-4.0 (2H, m), 3.74, 3.75 and 3.76 (6H,
S), 4.02-4.08 (2H, m), 4.10-4.26 (1H, m), 4.3-4.6 (1H, m), 6.72-7.43
And 7.64-7.68 (18H, m) MS m / z: 526 (M + +1)

【００８４】 実施例３ （２Ｓ）−Ｎ−ベンジル−４，４−ビス（４−メトキシフェニル）−２−ブチ
ルアミン塩酸塩（４１２ｍｇ）を、常法で、対応する遊離塩基に転換した。この
遊離塩基と（２Ｓ）−３−フェノキシ−１，２−エポキシプロパン（１９５ｍｇ
）（ＩＬ ＦＡＲＭＡＣＯ、５０（１０）、６４３（１９９５））のエタノール
（４ｍｌ）中の溶液を還流下で１０時間攪拌し、室温まで冷却し、真空中で溶媒
を留去した。残留物をシリカゲルクロマトグラフィー（クロロホルム）に付して
、溶出液を酢酸エチル中４Ｎ塩化水素で処理して、（２Ｓ）−１−［Ｎ−ベンジ
ル−［（２Ｓ）−４，４−ビス（４−メトキシフェニル）−２−ブチル］アミノ
］−３−フェノキシ−２−プロパノール塩酸塩（５４９ｍｇ）を非晶質粉末とし
て得た。 [α]24 D: -22.59° (c=0.54, MeOH) IR (KBr) : 3300 (br), 2850-2400, 1248 cm-1 NMR (CDCl3, δ) : 1.41 および 1.56 (3H, 各d, J=6.6Hz), 1.64 および 2.05
(1H, m), 2.94-3.6 (4H, m), 3.74, 3.75, 3.76 および 3.77 (6H, 各ｓ), 3.87
-3.96 (2H, m), 4.05-4.25 (3H, m), 4.5-4.65 および 4.8 (1H, m), 5.9 (1H,
br), 6.69-6.98 (8H, m), 7.08-7.17 (4H, m), 7.22-7.41 (4H, m), 7.65-7.73
(2H, m) MS m/z : 526 (M++1)Example 3 (2S) -N-benzyl-4,4-bis (4-methoxyphenyl) -2-butylamine hydrochloride (412 mg) was converted to the corresponding free base in a conventional manner. This free base and (2S) -3-phenoxy-1,2-epoxypropane (195 mg)
) (IL FARMACO, 50 (10), 643 (1995)) in ethanol (4 ml) was stirred under reflux for 10 hours, cooled to room temperature and evaporated in vacuo. The residue was subjected to silica gel chromatography (chloroform) and the eluate was treated with 4N hydrogen chloride in ethyl acetate to give (2S) -1- [N-benzyl-[(2S) -4,4-bis ( 4-methoxyphenyl) -2-butyl] amino] -3-phenoxy-2-propanol hydrochloride (549 mg) was obtained as an amorphous powder. [α] 24 D : -22.59 ° (c = 0.54, MeOH) IR (KBr): 3300 (br), 2850-2400, 1248 cm -1 NMR (CDCl 3 , δ): 1.41 and 1.56 (3H, each d , J = 6.6Hz), 1.64 and 2.05
(1H, m), 2.94-3.6 (4H, m), 3.74, 3.75, 3.76 and 3.77 (6H, each s), 3.87
-3.96 (2H, m), 4.05-4.25 (3H, m), 4.5-4.65 and 4.8 (1H, m), 5.9 (1H, m
br), 6.69-6.98 (8H, m), 7.08-7.17 (4H, m), 7.22-7.41 (4H, m), 7.65-7.73
(2H, m) MS m / z: 526 (M + +1)

【００８５】 実施例４ （２Ｓ）−１−［Ｎ−ベンジル−［（２Ｒ）-４，４−ビス（４−メトキシフ
ェニル）−２−ブチル］アミノ］−３−フェノキシ−２−プロパノール塩酸塩（
９６ｍｇ）と１０％Ｐｄ／Ｃ（５０％湿潤、６０ｍｇ）のメタノール（４ｍｌ）
中の混合物を、室温で大気圧の水素存在下で６時間攪拌し、濾過した。真空中で
濾液から溶媒を留去し、残留物をジクロロメタンと重炭酸ナトリウム水溶液との
間に分配した。有機層を分離し、硫酸ナトリウムで乾燥し、真空中で溶媒を留去
した。残留物をシリカゲル（２ｇ）クロマトグラフィー（ジクロロメタン−メタ
ノール）に付し、油状物を得て、これを、常法で、対応するシュウ酸塩に転換し
て、（２Ｓ）−１−［［（２Ｒ）−４，４−ビス（４−メトキシフェニル）−２
−ブチル］アミノ］−３−フェノキシ−２−プロパノール・シュウ酸塩（１：１
）（２６ｍｇ）を無色粉末として得た。 mp : 121-123℃ (ジエチルエーテルから) IR (KBr) : 3423 (br), 2850-2650, 1734, 1701, 1633, 1603, 1250 cm-1 NMR (DMSO-d6, δ) : 1.23 (3H, d, J=6.3Hz), 1.99 (1H, m), 2.58 (1H, m),
2.85-3.01 (2H, m), 3.11-3.17 (1H, m), 3.69 (3H, s), 3.71 (3H, s), 3.9- 4.6 (8H, m), 6.81-6.99 (7H, m), 7.16-7.35 (6H, m) MS m/z : 436 (M++1)Example 4 (2S) -1- [N-benzyl-[(2R) -4,4-bis (4-methoxyphenyl) -2-butyl] amino] -3-phenoxy-2-propanol hydrochloride (
96 mg) and 10% Pd / C (50% wet, 60 mg) in methanol (4 ml)
The mixture therein was stirred at room temperature under atmospheric pressure of hydrogen for 6 hours and filtered. The filtrate was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (2 g) (dichloromethane-methanol) to give an oil, which was converted to the corresponding oxalate in a conventional manner to give (2S) -1-[[(( 2R) -4,4-bis (4-methoxyphenyl) -2
-Butyl] amino] -3-phenoxy-2-propanol oxalate (1: 1
) (26 mg) as a colorless powder. mp: 121-123 ° C (from diethyl ether) IR (KBr): 3423 (br), 2850-2650, 1734, 1701, 1633, 1603, 1250 cm -1 NMR (DMSO-d 6 , δ): 1.23 (3H , d, J = 6.3Hz), 1.99 (1H, m), 2.58 (1H, m),
2.85-3.01 (2H, m), 3.11-3.17 (1H, m), 3.69 (3H, s), 3.71 (3H, s), 3.9- 4.6 (8H, m), 6.81-6.99 (7H, m), 7.16-7.35 (6H, m) MS m / z: 436 (M + +1)

【００８６】 実施例５ 下記の化合物を実施例４と同様にして得た。 （２Ｓ）−１−［［（２Ｓ）-４，４−ビス（４−メトキシフェニル）−２−
ブチル］アミノ］−３−フェノキシ−２−プロパノール・シュウ酸塩（１：１）
[α]24 D : 11.06° (c=0.515, MeOH) mp : 79-94℃ (ジエチルエーテルから) IR (KBr) : 3423 (br), 2750-2400, 1739-1691 (m), 1643, 1608, 1247 cm-1 NMR (DMSO-d6, δ) : 1.25 (3H, d, J=6.3Hz), 1.96 (1H, m), 2.66 (1H, m),
2.86 (1H, m) 2.95-3.15 (2H, m), 3.69 (3H, s), 3.70 (3H, s), 3.94-4.15 (4H, m), 5.1 (4H, br), 6.81-6.88 (4H, m), 6.92-6.99 (3H, m), 7.17-7.35
(6H, m) MS m/z : 436 (M++1)Example 5 The following compound was obtained in the same manner as in Example 4. (2S) -1-[[(2S) -4,4-bis (4-methoxyphenyl) -2-
[Butyl] amino] -3-phenoxy-2-propanol oxalate (1: 1)
[α] 24 D : 11.06 ° (c = 0.515, MeOH) mp: 79-94 ° C (from diethyl ether) IR (KBr): 3423 (br), 2750-2400, 1739-1691 (m), 1643, 1608 , 1247 cm -1 NMR (DMSO-d 6 , δ): 1.25 (3H, d, J = 6.3 Hz), 1.96 (1H, m), 2.66 (1H, m),
2.86 (1H, m) 2.95-3.15 (2H, m), 3.69 (3H, s), 3.70 (3H, s), 3.94-4.15 (4H, m), 5.1 (4H, br), 6.81-6.88 (4H , m), 6.92-6.99 (3H, m), 7.17-7.35
(6H, m) MS m / z: 436 (M + +1)

【００８７】 製造例１ ３−アミノ酪酸メチル（４．３ｇ）、（２Ｓ）−３−フェノキシ−１，２−エ
ポキシプロパン（４．５９ｇ）、トリフルオロメタンスルホン酸イッテルビウム
（ＩＩＩ）（１．８ｇ）とジクロロメタン（２５ｍｌ）の混合物を４０℃で２時
間、室温で一夜攪拌し、常法で処理し、シリカゲルカラムクロマトグラフィー（
トルエン：エタノール：濃アンモニア水＝９：１：０．１）で精製して、（３Ｒ
Ｓ）−３−［（（２Ｓ）−２−ヒドロキシ−３−フェノキシプロピル）アミノ］
酪酸メチルエステル（２．５９ｇ）を得た。 IR (ニート): 3400 (br m), 1734 (s), 1599 (m), 1495 (m), 1458 (m), 1298 (m), 1246 (s), 1041 (m), 756 (m) cm-1 NMR (CDCl3, δ): 1.16 (3H, d, J=5.2Hz), 2.41-2.46 (2H, m), 2.6-3.0 (2H, m), 3.14 (1H, quartet, J=6.4Hz), 3.68 (3H, s), 3.9-4.1 (3H, m), 6.90-6.9
9 (3H, m), 7.24-7.33 (2H, m) MS m/z: 268 (M++1)Production Example 1 Methyl 3-aminobutyrate (4.3 g), (2S) -3-phenoxy-1,2-epoxypropane (4.59 g), ytterbium (III) trifluoromethanesulfonate (1.8 g) And dichloromethane (25 ml) were stirred at 40 ° C. for 2 hours and at room temperature overnight, treated in a conventional manner, and subjected to silica gel column chromatography (
Purification with toluene: ethanol: concentrated aqueous ammonia = 9: 1: 0.1) and (3R
S) -3-[((2S) -2-hydroxy-3-phenoxypropyl) amino]
Butyric acid methyl ester (2.59 g) was obtained. IR (neat): 3400 (br m), 1734 (s), 1599 (m), 1495 (m), 1458 (m), 1298 (m), 1246 (s), 1041 (m), 756 (m) cm -1 NMR (CDCl 3 , δ): 1.16 (3H, d, J = 5.2Hz), 2.41-2.46 (2H, m), 2.6-3.0 (2H, m), 3.14 (1H, quartet, J = 6.4 Hz), 3.68 (3H, s), 3.9-4.1 (3H, m), 6.90-6.9
9 (3H, m), 7.24-7.33 (2H, m) MS m / z: 268 (M + +1)

【００８８】 製造例２ （２Ｓ）−Ｎ−ベンジル−（２−ヒドロキシ−３−フェノキシプロピル）アミ
ン（１４２ｍｇ）、５−ブロモペンタン酸エチルエステル（１７３ｍｇ）、炭酸
カリウム（１５３ｍｇ）とＮ，Ｎ−ジメチルホルムアミド（２ｍｌ）の混合物を
８０℃で４．５時間攪拌し、常法で処理し、シリカゲルカラムクロマトグラフィ
ー（２０％酢酸エチル−ヘキサン）で精製して、（２Ｓ）−５−［Ｎ−ベンジル
−（２−ヒドロキシ−３−フェノキシプロピル）アミノ］ペンタン酸エチルエス
テル（９３ｍｇ）を得た。 NMR (CDCl3, δ): 1.25 (3H, t, J=7.1Hz), 1.5-1.7 (5H, broad), 2.2-2.4 (2H, m), 2.4-2.8 (4H, m), 3.5-3.7 (1H, m), 3.7-3.9 (1H, m), 3.94 (2H, t,
J=3.9Hz), 4.0-4.2 (1H, m), 4.12 (2H, quartet, J=7.1Hz), 6.86-6.98 (4H,
m), 7.2-7.4 (6H, m) MS m/z: 386 (M++1)Production Example 2 (2S) -N-benzyl- (2-hydroxy-3-phenoxypropyl) amine (142 mg), 5-bromopentanoic acid ethyl ester (173 mg), potassium carbonate (153 mg) and N, N- The mixture of dimethylformamide (2 ml) was stirred at 80 ° C. for 4.5 hours, treated in a conventional manner, purified by silica gel column chromatography (20% ethyl acetate-hexane), and purified by (2S) -5- [N- Benzyl- (2-hydroxy-3-phenoxypropyl) amino] pentanoic acid ethyl ester (93 mg) was obtained. NMR (CDCl 3 , δ): 1.25 (3H, t, J = 7.1Hz), 1.5-1.7 (5H, broad), 2.2-2.4 (2H, m), 2.4-2.8 (4H, m), 3.5-3.7 (1H, m), 3.7-3.9 (1H, m), 3.94 (2H, t,
J = 3.9Hz), 4.0-4.2 (1H, m), 4.12 (2H, quartet, J = 7.1Hz), 6.86-6.98 (4H,
m), 7.2-7.4 (6H, m) MS m / z: 386 (M + +1)

【００８９】 製造例３ 下記の化合物を製造例２と同様にして得た。 （２Ｓ）−４−［Ｎ−ベンジル−（２−ヒドロキシ−３−フェノキシプロピル
）アミノ］ブタン酸メチルエステル IR (ニート): 3482 (br m), 2949 (m), 1736 (s), 1599 (w), 1495 (m), 1456 (m), 1246 (s), 1041 (m), 754 (m), 696 (m) cm-1 NMR (CDCl3, δ): 1.88 (2H, quintet, J=7.1Hz), 2.32 (2H, t, J=7.2Hz), 2.5-2.8 (4H, m), 3.5-3.7 (1H, m), 3.64 (3H, s), 3.84 (1H, d, J=13.0Hz),
3.89-4.0 (2H, m), 4.0-4.2 (1H, m), 6.86-6.99 (4H, m), 7.2-7.4 (6H, m) MS m/z: 358 (M++1)Production Example 3 The following compound was obtained in the same manner as in Production Example 2. (2S) -4- [N-benzyl- (2-hydroxy-3-phenoxypropyl) amino] butanoic acid methyl ester IR (neat): 3482 (br m), 2949 (m), 1736 (s), 1599 ( w), 1495 (m), 1456 (m), 1246 (s), 1041 (m), 754 (m), 696 (m) cm -1 NMR (CDCl 3 , δ): 1.88 (2H, quintet, J = 7.1Hz), 2.32 (2H, t, J = 7.2Hz), 2.5-2.8 (4H, m), 3.5-3.7 (1H, m), 3.64 (3H, s), 3.84 (1H, d, J = 13.0Hz),
3.89-4.0 (2H, m), 4.0-4.2 (1H, m), 6.86-6.99 (4H, m), 7.2-7.4 (6H, m) MS m / z: 358 (M + +1)

【００９０】 製造例４ 下記の化合物を実施例６と同様にして得た。 （１） １−［２，２−ビス（４−メトキシフェニル）−２−ヒドロキシエチル
］シクロペンタノール IR (KBr): 3347 (s), 3240 (m), 2958 (s), 1608 (m), 1510 (s), 1466 (m), 1248 (s), 1174 (m), 1034 (s), 835 (m) cm-1 NMR (CDCl3, δ): 1.2-1.7 (8H, m), 2.39 (1H, br s), 2.70 (2H, s), 3.78 (6H, s), 4.87 (1H, br s), 6.82 (4H, d, J=8.9Hz), 7.37 (4H, d, J=8.9Hz) （２） ３−（ジベンジルアミノ）−１，１−ビス（４−ブロモフェニル）−１
−プロパノール NMR (CDCl3, δ): 2.3-2.4 (2H, m), 2.6-2.7 (2H, m), 3.51 (4H, s), 7.07 (2H, d, J=8.5Hz), 7.1-7.4 (16H, m) MS m/z: 564, 566 (M++1), 568 （３） （３ＲＳ）−３−（ジベンジルアミノ）−１，１−ビス（４−ブロモフ
ェニル）−１−ブタノール NMR (CDCl3, δ): 1.10 (3H, d, J=6.7Hz), 2.09 (1H, d, J=14.8Hz), 2.45 (1H, dd, J=11.2 および 14.8Hz), 3.1-3.3 (1H, m), 3.18 (2H, d, J=12.8Hz),
3.91 (2H, d, J=12.7Hz), 6.82 (2H, d, J=8.7Hz), 7.11 (2H, d, J=8.7Hz), 7.2-7.3 (12H, m), 7.40 (2H, d, J=9.4Hz) （４） （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，
１−ビス（４−ブロモフェニル）−１−ヒドロキシ−３−ブチル］アミノ］−２
−プロパノール MS m/z: 638, 640 (M++1), 642 （５） Ｎ−ベンジル−［４，４−ビス（４−メトキシフェニル）ブチル］アミ
ン NMR (CDCl3, δ): 1.4-1.7 (2H, m), 2.00 (2H, quartet, J=7.8Hz), 2.64 (2H,
t, J=7.1Hz), 3.76 (6H, s), 3.72-3.79 (3H, m), 6.80 (4H, d, J=8.7Hz), 7.11 (4H, d, J=8.7Hz), 7.28 (5H, s) MS m/z: 376 (M++1) （６） Ｎ−ベンジル−［３，３−ビス（４−エトキシフェニル）プロピル］ア
ミン MS m/z: 390 (M++1)Production Example 4 The following compound was obtained in the same manner as in Example 6. (1) 1- [2,2-bis (4-methoxyphenyl) -2-hydroxyethyl] cyclopentanol IR (KBr): 3347 (s), 3240 (m), 2958 (s), 1608 (m) , 1510 (s), 1466 (m), 1248 (s), 1174 (m), 1034 (s), 835 (m) cm -1 NMR (CDCl 3 , δ): 1.2-1.7 (8H, m), 2.39 (1H, br s), 2.70 (2H, s), 3.78 (6H, s), 4.87 (1H, br s), 6.82 (4H, d, J = 8.9Hz), 7.37 (4H, d, J = 8.9 Hz) (2) 3- (dibenzylamino) -1,1-bis (4-bromophenyl) -1
- propanol NMR (CDCl 3, δ): 2.3-2.4 (2H, m), 2.6-2.7 (2H, m), 3.51 (4H, s), 7.07 (2H, d, J = 8.5Hz), 7.1-7.4 (16H, m) MS m / z: 564, 566 (M ++ 1), 568 (3) (3RS) -3- (dibenzylamino) -1,1-bis (4-bromophenyl) -1- Butanol NMR (CDCl 3 , δ): 1.10 (3H, d, J = 6.7Hz), 2.09 (1H, d, J = 14.8Hz), 2.45 (1H, dd, J = 11.2 and 14.8Hz), 3.1-3.3 (1H, m), 3.18 (2H, d, J = 12.8Hz),
3.91 (2H, d, J = 12.7Hz), 6.82 (2H, d, J = 8.7Hz), 7.11 (2H, d, J = 8.7Hz), 7.2-7.3 (12H, m), 7.40 (2H, d , J = 9.4 Hz) (4) (2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1,
1-bis (4-bromophenyl) -1-hydroxy-3-butyl] amino] -2
- propanol MS m / z: 638, 640 (M + +1), 642 (5) N- Benzyl - [4,4-bis (4-methoxyphenyl) butyl] amine NMR (CDCl 3, δ): 1.4- 1.7 (2H, m), 2.00 (2H, quartet, J = 7.8Hz), 2.64 (2H,
t, J = 7.1Hz), 3.76 (6H, s), 3.72-3.79 (3H, m), 6.80 (4H, d, J = 8.7Hz), 7.11 (4H, d, J = 8.7Hz), 7.28 ( 5H, s) MS m / z: 376 (M + +1) (6) N-benzyl- [3,3-bis (4-ethoxyphenyl) propyl] amine MS m / z: 390 (M + +1)

【００９１】 製造例５ １−［２，２−ビス（４−メトキシフェニル）−２−ヒドロキシエチル］シク
ロペンタノール（０．７９ｇ）を常法で水素化して、１−［２，２−ビス（４−
メトキシフェニル）エチル］シクロペンタノール（０．７６ｇ）を得た。 IR (ニート): 3563 (m), 3448 (m), 2956 (s), 1610 (w), 1510 (s), 1460 (m), 1246 (s), 1178 (m), 1036 (s), 829 (m) cm-1 NMR (CDCl3, δ): 1.5-1.9 (9H, m), 2.40 (2H, d, J=7.3Hz), 3.77 (6H, s), 4.17 (1H, t, J=7.2Hz), 6.81 (4H, d, J=6.6Hz), 7.21 (4H, d, J=6.6Hz) 製造例６ １−［２，２−ビス（４−メトキシフェニル）エチル］シクロペンタノール（
０．７６ｇ）、アジドトリメチルシラン（０．３２ｇ）とベンゼン（５ｍｌ）の
混合物に、三フッ化ホウ素ジエチルエーテラート（０．３４ｍｌ）を０℃で滴下
した。反応混合物を室温で３０分間攪拌し、常法で処理した。 粗製生成物を常
法で水素化して、［１−［２，２−ビス（４−メトキシフェニル）エチル］シク
ロペンチル］アミン（０．７４ｇ）を得た。 IR (ニート): 2949 (s), 1610 (m), 1510 (s), 1460 (m), 1248 (s), 1178 (m), 1038 (s), 829 (s) cm-1 NMR (CDCl3, δ): 1.3-1.8 (10H, m), 1.20 (2H, t, J=6.8Hz), 3.77 (6H, s), 4.09 (1H, quartet, J=6.8Hz), 6.81 (4H, dd, J=2.2 および 6.6Hz), 7.14 (4H, d, J=6.5Hz) MS m/z: 326 (M++1)Production Example 5 1- [2,2-bis (4-methoxyphenyl) -2-hydroxyethyl] cyclopentanol (0.79 g) was hydrogenated by a conventional method to give 1- [2,2-bis (4-
[Methoxyphenyl) ethyl] cyclopentanol (0.76 g) was obtained. IR (neat): 3563 (m), 3448 (m), 2956 (s), 1610 (w), 1510 (s), 1460 (m), 1246 (s), 1178 (m), 1036 (s), 829 (m) cm -1 NMR (CDCl 3 , δ): 1.5-1.9 (9H, m), 2.40 (2H, d, J = 7.3Hz), 3.77 (6H, s), 4.17 (1H, t, J = 7.2Hz), 6.81 (4H, d, J = 6.6Hz), 7.21 (4H, d, J = 6.6Hz) Production Example 6 1- [2,2-bis (4-methoxyphenyl) ethyl] cyclopentanol (
0.76 g), boron trifluoride diethyl etherate (0.34 ml) was added dropwise to a mixture of azidotrimethylsilane (0.32 g) and benzene (5 ml) at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes and worked up in the usual way. The crude product was hydrogenated in conventional manner to give [1- [2,2-bis (4-methoxyphenyl) ethyl] cyclopentyl] amine (0.74 g). IR (neat): 2949 (s), 1610 (m), 1510 (s), 1460 (m), 1248 (s), 1178 (m), 1038 (s), 829 (s) cm -1 NMR (CDCl 3 , δ): 1.3-1.8 (10H, m), 1.20 (2H, t, J = 6.8Hz), 3.77 (6H, s), 4.09 (1H, quartet, J = 6.8Hz), 6.81 (4H, dd , J = 2.2 and 6.6Hz), 7.14 (4H, d, J = 6.5Hz) MS m / z: 326 (M + +1)

【００９２】 製造例７ ジベンジルアミン（１．０４ｇ）とテトラヒドロフラン（４ｍｌ）の溶液に、
ブチルリチウム（ヘキサン中１．５Ｍ、３．７ｍｌ）を−７８℃で窒素流下で滴
下した。３０分後、３−（３，４−ジメトキシフェニル）アクリル酸メチルエス
テル（１．０６ｇ）のテトラヒドロフラン（３ｍｌ）中の溶液を滴下し、１時間
攪拌し、常法で処理した。粗製生成物をシリカゲルカラムクロマトグラフィー（
ヘキサン：酢酸エチル＝５：１）で精製して、３−（ジベンジルアミノ）−３−
（３，４−ジメトキシフェニル）プロピオン酸メチルエステル（０．５３ｇ）を
得た。 IR (ニート): 1739 (s), 1514 (s), 1458 (m), 1261 (m), 1146 (m), 1028 (m), 744 (m) cm-1 NMR (CDCl3, δ): 2.72 (1H, dd, J=7.3 および 14.4Hz), 3.07 (1H, dd, J=8.6 および 14.4Hz), 3.21 (1H, d, J=13.7Hz), 3.65 (3H, s), 3.73 (2H, s), 3.79
(2H, s), 3.89 (6H, s), 4.25 (1H, t, J=7.4Hz), 6.75-6.90 (3H, m), 7.1-7.4
(10H, m) 製造例８ ３−（ジベンジルアミノ）−３−（３，４−ジメトキシフェニル）プロピオン
酸メチルエステル（０．５３ｇ）、酢酸（３ｍｌ）、メタノール（３ｍｌ）と２
０％水酸化パラジウム炭（０．０５ｇ）の混合物を水素雰囲気（１ａｔｍ）下で
室温で６時間攪拌し、濾過し、溶媒を留去して、３−アミノ−３−（３，４−ジ
メトキシフェニル）プロピオン酸メチルエステル酢酸塩（０．２４ｇ）を得た。
IR (KBr): 1729 (s), 1539 (s), 1523 (s), 1398 (m), 1265 (m), 1203 (m), 1155 (m), 1020 (m) cm-1 NMR (MeOH-d4, δ): 1.90 (3H, s), 2.92 (2H, dd, J=5.4 および6.6Hz), 3.63
(3H, s), 3.82 (3H, s), 3.84 (3H, s), 4.52 (1H, t, J=7.5Hz), 6.95 (2H, s), 7.02 (1H, s)Production Example 7 In a solution of dibenzylamine (1.04 g) and tetrahydrofuran (4 ml),
Butyllithium (1.5M in hexane, 3.7ml) was added dropwise at -78 ° C under a stream of nitrogen. After 30 minutes, a solution of 3- (3,4-dimethoxyphenyl) acrylic acid methyl ester (1.06 g) in tetrahydrofuran (3 ml) was added dropwise, stirred for 1 hour and treated in a conventional manner. The crude product is subjected to silica gel column chromatography (
Hexane: ethyl acetate = 5: 1) to give 3- (dibenzylamino) -3-
(3,4-Dimethoxyphenyl) propionic acid methyl ester (0.53 g) was obtained. IR (neat): 1739 (s), 1514 (s), 1458 (m), 1261 (m), 1146 (m), 1028 (m), 744 (m) cm -1 NMR (CDCl 3 , δ): 2.72 (1H, dd, J = 7.3 and 14.4Hz), 3.07 (1H, dd, J = 8.6 and 14.4Hz), 3.21 (1H, d, J = 13.7Hz), 3.65 (3H, s), 3.73 (2H , s), 3.79
(2H, s), 3.89 (6H, s), 4.25 (1H, t, J = 7.4Hz), 6.75-6.90 (3H, m), 7.1-7.4
(10H, m) Production Example 8 3- (Dibenzylamino) -3- (3,4-dimethoxyphenyl) propionic acid methyl ester (0.53 g), acetic acid (3 ml), methanol (3 ml) and 2
A mixture of 0% palladium hydroxide on charcoal (0.05 g) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 6 hours, filtered, and the solvent was distilled off to give 3-amino-3- (3,4-dimethoxy). Phenyl) propionic acid methyl ester acetate (0.24 g) was obtained.
IR (KBr): 1729 (s), 1539 (s), 1523 (s), 1398 (m), 1265 (m), 1203 (m), 1155 (m), 1020 (m) cm -1 NMR (MeOH -d 4 , δ): 1.90 (3H, s), 2.92 (2H, dd, J = 5.4 and 6.6Hz), 3.63
(3H, s), 3.82 (3H, s), 3.84 (3H, s), 4.52 (1H, t, J = 7.5Hz), 6.95 (2H, s), 7.02 (1H, s)

【００９３】 製造例９ ３−アミノプロピオン酸メチルエステル塩酸塩（１．１２ｇ）のメタノール（
１０ｍｌ）中の溶液に、２８％ナトリウムメトキシド−メタノール溶液（１．６
０ｇ）を加え、濾過し、溶媒を留去した。粗製生成物に、（２Ｓ）−２−フェノ
キシ−１，２−エポキシプロパン（９０１ｍｇ）とメタノール（１０ｍｌ）を加
え、還流下で２．５時間攪拌した。反応混合物から溶媒を留去し、シリカゲルカ
ラムクロマトグラフィーで精製して、３−［（（２Ｓ）−２−ヒドロキシ−３−
フェノキシプロピル）アミノ］プロピオン酸メチルエステル（０．７６ｇ）を得
た。 IR (KBr): 1734 (s), 1601 (m), 1498 (m), 1435 (m), 1252 (s), 1196 (m), 1043 (m), 752 (m) cm-1 NMR (CDCl3, δ): 2.54 (2H, t, J=6.4Hz), 2.72-2.98 (4H, m), 3.69 (3H, s),
3.97-4.07 (3H, m), 6.90 6.99 (3H, m), 7.25-7.32 (2H, m) MS m/z: 254 (M++1) 製造例１０ 下記の化合物を製造例９と同様にして得た。 （３ＲＳ）−３−［（（２Ｓ）−２−ヒドロキシ−３−フェノキシプロピル）
アミノ］−３−フェニルプロピオン酸メチルエステル IR (KBr): 1724 (s), 1599 (m), 1495 (m), 1435 (m), 1246 (s), 1126 (m), 1038 (m), 756 (m), 698 (m) cm-1 NMR (CDCl3, δ): 2.54-2.75 (4H, m), 3.66 (1.5H, s), 3.67 (1.5H, s), 3.9-
4.0 (2H, m), 4.0-4.2 (2H, m), 6.85-6.98 (3H, m), 7.2-7.4 (7H, m) MS m/z: 330 (M++1)Production Example 9 Methanol of 3-aminopropionic acid methyl ester hydrochloride (1.12 g)
10%) in a 28% sodium methoxide-methanol solution (1.6 ml).
0 g), and the mixture was filtered and the solvent was distilled off. (2S) -2-phenoxy-1,2-epoxypropane (901 mg) and methanol (10 ml) were added to the crude product, and the mixture was stirred under reflux for 2.5 hours. The solvent was distilled off from the reaction mixture, and the mixture was purified by silica gel column chromatography to give 3-[((2S) -2-hydroxy-3-
[Phenoxypropyl) amino] propionic acid methyl ester (0.76 g) was obtained. IR (KBr): 1734 (s), 1601 (m), 1498 (m), 1435 (m), 1252 (s), 1196 (m), 1043 (m), 752 (m) cm -1 NMR (CDCl 3 , δ): 2.54 (2H, t, J = 6.4Hz), 2.72-2.98 (4H, m), 3.69 (3H, s),
3.97-4.07 (3H, m), 6.90 6.99 (3H, m), 7.25-7.32 (2H, m) MS m / z: 254 (M ++ 1) Preparation Example 10 The following compounds were prepared in the same manner as in Preparation Example 9. I got it. (3RS) -3-[((2S) -2-hydroxy-3-phenoxypropyl)
Amino] -3-phenylpropionic acid methyl ester IR (KBr): 1724 (s), 1599 (m), 1495 (m), 1435 (m), 1246 (s), 1126 (m), 1038 (m), 756 (m), 698 (m) cm -1 NMR (CDCl 3 , δ): 2.54-2.75 (4H, m), 3.66 (1.5H, s), 3.67 (1.5H, s), 3.9-
4.0 (2H, m), 4.0-4.2 (2H, m), 6.85-6.98 (3H, m), 7.2-7.4 (7H, m) MS m / z: 330 (M + +1)

【００９４】 製造例１１ Ｎ−カルボベンジルオキシ−Ｄ−アラニン（０．８１ｇ）、［ビス（４−メト
キシフェニル）メチル］アミン（０．８０ｇ）、１−ヒドロキシベンゾトリアゾ
ール（０．５８ｇ）とＮ，Ｎ−ジメチルホルムアミド（５ｍｌ）の混合物に、１
−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．７
６ｇ）を０℃で加え、室温で３０分間攪拌した。常法による処理後、Ｎ−カルボ
ベンジルオキシ−Ｄ−アラニン［ビス（４−メトキシフェニル）メチル］アミド
（１．３８ｇ）を得た。 IR (KBr): 3296 (s), 1689 (m), 1647 (s), 1539 (s), 1512 (s), 1257 (s),
1176 (m), 1031 (m) cm-1 NMR (DMSO-d6, δ): 1.21 (3H, d, J=7.1Hz), 3.33 (6H, s), 4.17 (1H, t, J=7.2Hz), 5.01 (2H, s), 5.96 (1H, d, J=8.4Hz), 6.86 (4H, d, J=8.7Hz), 7.1-7.2 (4H, m), 7.3-7.5 (5H, m), 8.60 (1H, d, J=8.5Hz)Production Example 11 N-carbobenzyloxy-D-alanine (0.81 g), [bis (4-methoxyphenyl) methyl] amine (0.80 g), 1-hydroxybenzotriazole (0.58 g) and N , N-dimethylformamide (5 ml)
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.7
6 g) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. After a conventional treatment, N-carbobenzyloxy-D-alanine [bis (4-methoxyphenyl) methyl] amide (1.38 g) was obtained. IR (KBr): 3296 (s), 1689 (m), 1647 (s), 1539 (s), 1512 (s), 1257 (s),
1176 (m), 1031 (m) cm -1 NMR (DMSO-d 6 , δ): 1.21 (3H, d, J = 7.1 Hz), 3.33 (6H, s), 4.17 (1H, t, J = 7.2 Hz), 5.01 (2H, s), 5.96 (1H, d, J = 8.4Hz), 6.86 (4H, d, J = 8.7Hz), 7.1-7.2 (4H, m), 7.3-7.5 (5H, m ), 8.60 (1H, d, J = 8.5Hz)

【００９５】 製造例１２ Ｎ−カルボベンジルオキシ−Ｄ−アラニン［ビス（４−メトキシフェニル）メ
チル］アミド（０．３３ｇ）のメタノールとテトラヒドロフラン（１：２、１０
ｍｌ）中の溶液に、５０％湿潤１０％パラジウム炭を加え、水素雰囲気下（１ａ
ｔｍ）で３０分間攪拌した。常法による処理後、Ｄ−アラニン［ビス（４−メト
キシフェニル）メチル］アミド（０．２５ｇ）を得た。 IR (ニート): 3357 (br s), 1678 (s), 1649 (s), 1538 (s), 1513 (s), 1259 (m), 1176 (m), 1032 (s), 831 (m), 812 (m) cm-1 NMR (DMSO-d6, δ): 1.13 (3H, d, J=6.9Hz), 3.33 (6H, s), 3.3-3.4 (3H, br), 5.96 (1H, d, J=8.2Hz), 6.87 (4H, d, J=8.7Hz), 7.15 (4H, d, J=8.4 Hz), 8.44 (1H, d, J=8Hz)Production Example 12 N-carbobenzyloxy-D-alanine [bis (4-methoxyphenyl) methyl] amide (0.33 g) in methanol and tetrahydrofuran (1: 2, 10
50% wet 10% palladium on charcoal was added to the solution under hydrogen atmosphere (1a
tm) for 30 minutes. After the usual treatment, D-alanine [bis (4-methoxyphenyl) methyl] amide (0.25 g) was obtained. IR (neat): 3357 (br s), 1678 (s), 1649 (s), 1538 (s), 1513 (s), 1259 (m), 1176 (m), 1032 (s), 831 (m) , 812 (m) cm -1 NMR (DMSO-d 6 , δ): 1.13 (3H, d, J = 6.9 Hz), 3.33 (6H, s), 3.3-3.4 (3H, br), 5.96 (1H, d, J = 8.2Hz), 6.87 (4H, d, J = 8.7Hz), 7.15 (4H, d, J = 8.4 Hz), 8.44 (1H, d, J = 8Hz)

【００９６】 製造例１３ 臭化４−メトキシフェニルマグネシウムの溶液（テトラヒドロフラン中１Ｍ、
３５ｍｌ）に、３−（ジベンジルアミノ）プロピオン酸エチルエステル（４．８
７ｇ）のテトラヒドロフラン（２ｍｌ）中の溶液を加え、還流下で１時間攪拌し
、常法で処理し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル
＝５：１）で精製して、３−ジベンジルアミノ−１，１−ビス（４−メトキシフ
ェニル）−１−プロパノール（３．４５ｇ）を得た。 製造例１４ ３−（ジベンジルアミノ）−１，１−ビス（４−メトキシフェニル）−１−プ
ロパノール（２．０ｇ）を常法で水素化し、Ｎ−ベンジル−［３，３−ビス（４
−メトキシフェニル）プロピル］アミンを得て、これをメタノール中の２０％パ
ラジウム炭と蟻酸アンモニウムで、加熱することにより、さらに水素化して、［
３，３−ビス（４−メトキシフェニル）プロピル］アミン（１６５ｇ）を得た。Production Example 13 A solution of 4-methoxyphenylmagnesium bromide (1M in tetrahydrofuran,
35 ml), 3- (dibenzylamino) propionic acid ethyl ester (4.8).
7 g) in tetrahydrofuran (2 ml) was added, stirred under reflux for 1 hour, treated in a conventional manner, and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 3-dibenzyl. Amino-1,1-bis (4-methoxyphenyl) -1-propanol (3.45 g) was obtained. Production Example 14 3- (Dibenzylamino) -1,1-bis (4-methoxyphenyl) -1-propanol (2.0 g) was hydrogenated by a conventional method to give N-benzyl- [3,3-bis (4
-Methoxyphenyl) propyl] amine was obtained, which was further hydrogenated by heating with 20% palladium on carbon and ammonium formate in methanol to give [
3,3-Bis (4-methoxyphenyl) propyl] amine (165 g) was obtained.

【００９７】 製造例１５ ４−ベンジルオキシ−３−ニトロフェニル酢酸塩（４．２０ｇ）のメタノール
（２０ｍｌ）中の溶液に、２８％ナトリウムメトキシド−メタノール溶液（２．
９６ｇ）を加え、溶媒を留去した。粗製残留物に、Ｎ，Ｎ−ジメチルホルムアミ
ド（２０ｍｌ）と（２Ｓ）−３−［（３−ニトロフェニル）スルホニルオキシ］
−１，２−エポキシプロパン（３．８０ｇ）を加えた。混合物を室温で一夜攪拌
し、常法で処理して、（２Ｓ）−３−（４−ベンジルオキシ−３−ニトロフェノ
キシ）−１，２−エポキシプロパン（４．３０ｇ）を得た。 NMR (CDCl3, δ): 2.72-2.77 (1H, m), 2.92 (1H, quintet, J=4.8Hz), 3.32-
3.37 (1H, m), 3.91 (1H, quartet, J=5.9Hz), 4.27 (1H, dd, J=2.8 および 11.4Hz), 5.18 (2H, s), 7.07-7.15 (2H, m), 7.34-7.46 (6H, m) 製造例１６ ３−（ジベンジルアミノ）−１，１−ビス（４−ブロモフェニル）−１−プロ
パノール（８．４２ｇ）、ベンゾフェノンイミン（１０．８ｇ）、トリス（ジベ
ンジルイデンアセトン）ジパラジウム（５４６ｍｇ）、（ＲＳ）−２，２’−ビ
ス（ジフェニルホスフィノ）−１，１’−ビナフチル（１．１１ｇ）、ナトリウ
ム第三級ブトキシド（５．７ｇ）とトルエン（９０ｍｌ）の混合物を１００℃で
６時間攪拌した。反応混合物をテトラヒドロフラン（３００ｍｌ）と３Ｎ塩酸（
３００ｍｌ）に加え、室温で１．５時間攪拌した。水相を分離し、水酸化ナトリ
ウムで中和し、酢酸エチルで抽出した。酢酸エチル溶液から溶媒を留去し、シリ
カゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製して
、３−（ジベンジルアミノ）−１，１−ビス（４−アミノフェニル）−１−プロ
パノール（１．７６ｇ）を得た。 MS m/z: 438 (M++1)Production Example 15 A solution of 4-benzyloxy-3-nitrophenyl acetate (4.20 g) in methanol (20 ml) was added to a 28% sodium methoxide-methanol solution (2.
96 g) was added, and the solvent was distilled off. To the crude residue was added N, N-dimethylformamide (20 ml) and (2S) -3-[(3-nitrophenyl) sulfonyloxy]
-1,2-Epoxypropane (3.80 g) was added. The mixture was stirred at room temperature overnight and treated in a conventional manner to give (2S) -3- (4-benzyloxy-3-nitrophenoxy) -1,2-epoxypropane (4.30 g). NMR (CDCl 3 , δ): 2.72-2.77 (1H, m), 2.92 (1H, quintet, J = 4.8Hz), 3.32-
3.37 (1H, m), 3.91 (1H, quartet, J = 5.9Hz), 4.27 (1H, dd, J = 2.8 and 11.4Hz), 5.18 (2H, s), 7.07-7.15 (2H, m), 7.34 -7.46 (6H, m) Production Example 16 3- (Dibenzylamino) -1,1-bis (4-bromophenyl) -1-propanol (8.42 g), benzophenone imine (10.8 g), tris (di (Benzylideneacetone) dipalladium (546 mg), (RS) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (1.11 g), sodium tert-butoxide (5.7 g) and toluene (90 ml) was stirred at 100 ° C. for 6 hours. The reaction mixture was treated with tetrahydrofuran (300 ml) and 3N hydrochloric acid (
300 ml) and stirred at room temperature for 1.5 hours. The aqueous phase was separated, neutralized with sodium hydroxide and extracted with ethyl acetate. The solvent was distilled off from the ethyl acetate solution and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 3- (dibenzylamino) -1,1-bis (4-aminophenyl) -1. -Propanol (1.76 g) was obtained. MS m / z: 438 (M + +1)

【００９８】 製造例１７ 下記の化合物を製造例１6と同様にして得た。 （３ＲＳ）−３−（ジベンジルアミノ）−１，１−ビス（４−アミノフェニル
）−１−ブタノール IR (ニート): 3356 (m), 3219 (m), 2964 (m), 1622 (s), 1512 (s), 1454 (m), 1383 (w), 1271 (m), 1246 (m), 1176 (m), 1142 (m), 831 (m) cm-1 NMR (CDCl3, δ): 1.03 (3H, d, J=6.7Hz), 2.02 (1H, d, J=11.7Hz), 2.50 (1H, dd, J=11.2 および 14.7Hz), 3.10-3.2 (1H, m), 3.21 (2H, d, J=13.0 Hz), 3.92 (2H, d, J=12.9Hz), 6.35 (2H, d, J=6.5Hz), 6.55 (2H, d, J=6.6Hz), 6.76 (2H, d, J=6.6Hz), 7.13 (2H, d, J=6.5Hz), 7.24 (10H, s) MS m/z: 452 (M++1)Production Example 17 The following compound was obtained in the same manner as in Production Example 16. (3RS) -3- (Dibenzylamino) -1,1-bis (4-aminophenyl) -1-butanol IR (neat): 3356 (m), 3219 (m), 2964 (m), 1622 (s ), 1512 (s), 1454 (m), 1383 (w), 1271 (m), 1246 (m), 1176 (m), 1142 (m), 831 (m) cm -1 NMR (CDCl 3 , δ ): 1.03 (3H, d, J = 6.7Hz), 2.02 (1H, d, J = 11.7Hz), 2.50 (1H, dd, J = 11.2 and 14.7Hz), 3.10-3.2 (1H, m), 3.21 (2H, d, J = 13.0 Hz), 3.92 (2H, d, J = 12.9Hz), 6.35 (2H, d, J = 6.5Hz), 6.55 (2H, d, J = 6.6Hz), 6.76 (2H , d, J = 6.6Hz), 7.13 (2H, d, J = 6.5Hz), 7.24 (10H, s) MS m / z: 452 (M + +1)

【００９９】 製造例１８ ３−（ジベンジルアミノ）−１，１−ビス（４−アミノフェニル）−１−プロ
パノール（０．６４ｇ）、ピリジン（０．５ｍｌ）とジクロロメタン（１０ｍｌ
）の混合物に、クロロ炭酸メチル（０．３４ｍｌ）を０℃で加え、反応混合物を
常法で処理した。粗製生成物をメタノール（１０ｍｌ）に溶解し、次いで、１，
４−ジオキサン中４Ｎ塩化水素（０．５ｍｌ）と２０％水酸化パラジウム炭を加
えた。混合物を水素雰囲気（１ａｔｍ）下で室温で一夜攪拌し、常法で処理し、
シリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール：濃アンモ
ニア水＝２０：１：０．１）で精製して、Ｎ−ベンジル−［３，３−ビス［４−
［（メトキシカルボニル）アミノ］フェニル］プロピル］アミン（４６６ｍｇ）
を得た。 MS m/z: 448 (M++1) 製造例１９ （３ＲＳ）−３−アミノ酪酸メチルエステル塩酸塩（５．０ｇ）、臭化ベンジ
ル（１１．７ｇ）、炭酸カリウム（１８ｇ）とＮ，Ｎ−ジメチルホルムアミド（
４０ｍｌ）の混合物を室温で一夜攪拌し、常法で処理し、シリカゲルカラムクロ
マトグラフィー（ヘキサン：酢酸エチル＝１５：１）で精製して、（３ＲＳ）−
３−（ジベンジルアミノ）酪酸メチルエステル（７．２７ｇ）を得た。 IR (ニート): 2968 (m), 1741 (s), 1454 (m) 1259 (m), 1196 (m), 1146 (m), 1072 (m), 1022 (m), 744 (m), 698 (m) cm-1 NMR (CDCl3, δ): 1.10 (3H, d, J=6.7Hz), 2.28 (1H, dd, J=6.9 および 13.9 Hz), 2.64 (1H, dd, J=8.01 および 13.9Hz), 3.30 (1H, dd, J=6.8 および 14.7Hz), 3.44 (2H, d, J=13.7Hz), 3.60 (3H, s), 3.66 (2H, d, J=13.7Hz),
7.18-7.35 (10H, m) MS m/z: 298 (M++1)Production Example 18 3- (Dibenzylamino) -1,1-bis (4-aminophenyl) -1-propanol (0.64 g), pyridine (0.5 ml) and dichloromethane (10 ml)
)) At 0 ° C., and the reaction mixture was worked up in the usual manner. The crude product was dissolved in methanol (10 ml) and then 1,
4N Hydrogen chloride in 4-dioxane (0.5 ml) and 20% palladium hydroxide on charcoal were added. The mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight, treated in a conventional manner,
Purification by silica gel column chromatography (dichloromethane: methanol: concentrated aqueous ammonia = 20: 1: 0.1) gave N-benzyl- [3,3-bis [4-
[(Methoxycarbonyl) amino] phenyl] propyl] amine (466 mg)
Got. MS m / z: 448 (M + +1) Production Example 19 (3RS) -3-aminobutyric acid methyl ester hydrochloride (5.0 g), benzyl bromide (11.7 g), potassium carbonate (18 g) and N, N-dimethylformamide (
The mixture was stirred at room temperature overnight, treated in a conventional manner, and purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give (3RS)-
3- (Dibenzylamino) butyric acid methyl ester (7.27 g) was obtained. IR (neat): 2968 (m), 1741 (s), 1454 (m) 1259 (m), 1196 (m), 1146 (m), 1072 (m), 1022 (m), 744 (m), 698 (m) cm -1 NMR (CDCl 3 , δ): 1.10 (3H, d, J = 6.7 Hz), 2.28 (1H, dd, J = 6.9 and 13.9 Hz), 2.64 (1H, dd, J = 8.01 and 13.9Hz), 3.30 (1H, dd, J = 6.8 and 14.7Hz), 3.44 (2H, d, J = 13.7Hz), 3.60 (3H, s), 3.66 (2H, d, J = 13.7Hz),
7.18-7.35 (10H, m) MS m / z: 298 (M + +1)

【０１００】 製造例２０ 下記の化合物を製造例１９と同様にして得た。 （３ＲＳ）−３−［Ｎ−ベンジル−（（２Ｓ）−２−ヒドロキシ−３−フェノ
キシプロピル）アミノ］酪酸メチルエステル MS m/z: 358 (M++1) 製造例２１ （３ＲＳ）−３−（ジベンジルアミノ）−１，１−ビス（４−アミノフェニル
）−１−ブタノール（３６０ｍｇ）、トリエチルアミン（０．４４ｍｌ）とジク
ロロメタン（４ｍｌ）の混合物に、塩化メタンスルホニル（０．２０ｍｌ）を０
℃で滴下した。反応混合物を室温で３０分間攪拌し、常法で処理した。粗製生成
物をメタノールに溶解し、１０％パラジウム炭（５０％湿潤）と蟻酸アンモニウ
ムを加え、還流下で１．５時間加熱し、濾過し、水で抽出した。水溶液を通常の
ショッテン法によりクロロ炭酸ベンジル（１３６μｌ）で処理し、常法で処理し
、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：３）で精
製して、（３ＲＳ）-［３，３−ビス［４−（メタンスルホニルアミノ）フェニ
ル］−１−メチルプロピル］カルバミン酸ベンジルエステル（１３８ｍｇ）を得
た。 IR (ニート): 3259(m), 1680 (s), 1512 (s), 1331 (m), 1153 (s), 974 (m) cm-1
NMR (CDCl3, δ): 1.13 (3H, d, J=6.8Hz), 2.4-2.6 (2H, m), 2.98 (6H, s), 3.7-3.9 (1H, m), 4.6-4.8 (1H, m), 6.52 (2H, s), 7.07-7.15 (5H, m), 7.2-
7.5 (8H, m)Production Example 20 The following compound was obtained in the same manner as in Production Example 19. (3RS) -3- [N-benzyl-((2S) -2-hydroxy-3-phenoxypropyl) amino] butyric acid methyl ester MS m / z: 358 (M + +1) Production Example 21 (3RS) -3 Methanesulfonyl chloride (0.20 ml) was added to a mixture of-(dibenzylamino) -1,1-bis (4-aminophenyl) -1-butanol (360 mg), triethylamine (0.44 ml) and dichloromethane (4 ml). 0
It was added dropwise at ° C. The reaction mixture was stirred at room temperature for 30 minutes and worked up in the usual way. The crude product was dissolved in methanol, 10% palladium on charcoal (50% wet) and ammonium formate were added, heated under reflux for 1.5 hours, filtered and extracted with water. The aqueous solution was treated with benzyl chlorocarbonate (136 μl) by the usual Schotten method, treated in a conventional manner, and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to give (3RS)-[3,3 -Bis [4- (methanesulfonylamino) phenyl] -1-methylpropyl] carbamic acid benzyl ester (138 mg) was obtained. IR (neat): 3259 (m), 1680 (s), 1512 (s), 1331 (m), 1153 (s), 974 (m) cm -1
NMR (CDCl 3 , δ): 1.13 (3H, d, J = 6.8 Hz), 2.4-2.6 (2H, m), 2.98 (6H, s), 3.7-3.9 (1H, m), 4.6-4.8 (1H , m), 6.52 (2H, s), 7.07-7.15 (5H, m), 7.2-
7.5 (8H, m)

【０１０１】 製造例２２ （３ＲＳ）−１，１−ビス［４−（メタンスルホニルアミノ）フェニル］−３
−ブチルアミン（７７．４ｍｇ）を、常法の水素化によって、（３ＲＳ）−［３
，３−ビス［４−（メタンスルホニルアミノ）フェニル］−１−メチルプロピル
］カルバミン酸ベンジルエステル（１０１ｍｇ）から得た。 IR (KBr): 3425 (br s), 1635 (m), 1506 (m), 1325 (m), 1151 (s), 1103 (m), 980 (w) cm-1 NMR (MeOH-d4, δ): 1.13 (3H, d, J=6.4Hz), 2.05 (2H, quartet, J=7.7Hz),
2.73 (1H, quartet, J=6.5Hz), 2.89 (6H, s), 4.06 (1H, dd, J=7.8Hz および
14.8Hz), 7.16 (4H, d, J=8.5Hz), 7.26 (4H, d, J=8.5Hz) MS m/z: 412 (M++1) 製造例２３ （３ＲＳ）−３−（ジベンジルアミノ）−１，１−ビス（４−アミノフェニル
）−１−ブタノール（０．４０ｇ）、トリエチルアミン（０．３７ｍｌ）とジク
ロロメタン（４ｍｌ）の混合物に、無水酢酸（０．１８ｍｌ）を０℃で加え、次
いでトリエチルアミン（０．１ｍｌ）と無水酢酸（０．０９ｍｌ）をさらに加え
た。反応混合物を常法で処理して、（３ＲＳ）−３−（ジベンジルアミノ）−１
，１−ビス［４−（アセチルアミノ）フェニル］−１−ブタノール（０．４９ｇ
）を得た。 IR (ニート): 2300 (m), 1666 (s), 1623 (m), 1539 (s), 1514 (m), 1319 (m), 1265 (m), 1142 (w), 837 (m) cm-1 NMR (CDCl3, δ): 1.06 (3H, d, J=6.6Hz), 2.12 (3H, s), 2.16 (3H, s), 2.0-2.2 (1H, m), 2.45-2.58 (1H, m), 3.0-3.2 (1H, m), 3.20 (2H, d, J=12.9
Hz), 3.92 (2H, d, J=13.0Hz), 6.72 (2H, d, J=6.8Hz), 7.09-7.36 (16H, m) MS m/z: 536 (M++1)Production Example 22 (3RS) -1,1-bis [4- (methanesulfonylamino) phenyl] -3
-Butylamine (77.4 mg) was converted to (3RS)-[3
, 3-Bis [4- (methanesulfonylamino) phenyl] -1-methylpropyl] carbamic acid benzyl ester (101 mg). IR (KBr): 3425 (br s), 1635 (m), 1506 (m), 1325 (m), 1151 (s), 1103 (m), 980 (w) cm -1 NMR (MeOH-d 4 , δ): 1.13 (3H, d, J = 6.4Hz), 2.05 (2H, quartet, J = 7.7Hz),
2.73 (1H, quartet, J = 6.5Hz), 2.89 (6H, s), 4.06 (1H, dd, J = 7.8Hz and
14.8Hz), 7.16 (4H, d, J = 8.5Hz), 7.26 (4H, d, J = 8.5Hz) MS m / z: 412 (M ++ 1) Production Example 23 (3RS) -3- (di Acetic anhydride (0.18 ml) was added to a mixture of benzylamino) -1,1-bis (4-aminophenyl) -1-butanol (0.40 g), triethylamine (0.37 ml) and dichloromethane (4 ml) at 0 ° C. Then, triethylamine (0.1 ml) and acetic anhydride (0.09 ml) were further added. The reaction mixture was treated in the usual manner to give (3RS) -3- (dibenzylamino) -1
, 1-bis [4- (acetylamino) phenyl] -1-butanol (0.49 g
) Got. IR (neat): 2300 (m), 1666 (s), 1623 (m), 1539 (s), 1514 (m), 1319 (m), 1265 (m), 1142 (w), 837 (m) cm -1 NMR (CDCl 3 , δ): 1.06 (3H, d, J = 6.6 Hz), 2.12 (3H, s), 2.16 (3H, s), 2.0-2.2 (1H, m), 2.45-2.58 (1H , m), 3.0-3.2 (1H, m), 3.20 (2H, d, J = 12.9
Hz), 3.92 (2H, d, J = 13.0Hz), 6.72 (2H, d, J = 6.8Hz), 7.09-7.36 (16H, m) MS m / z: 536 (M + +1)

【０１０２】 製造例２４ （３ＲＳ）−３−アミノ−１，１−ビス［４−（アセチルアミノ）フェニル］
−１−ブタノール（０．２３ｇ）を、常法の水素化によって、（３ＲＳ）−３−
（ジベンジルアミノ）−１，１−ビス［４−（アセチルアミノ）フェニル］−１
−ブタノール（０．３２ｇ）から得た。 IR (KBr): 3294 (m), 1666 (s), 1623 (s), 1537 (s), 1514 (m), 1406 (m),
1321 (n), 1014 (m) cm-1 NMR (MeOH-d6, δ): 1.10-1.15 (3H, m), 2.07 (3H, s), 2.11 (3H, s), 2.5-
3.1 (3H, m), 4.23 (2H, d, J=10.6Hz), 4.55 (2H, d, J=10.6Hz), 7.21-7.58
(8H, m) 製造例２５ 下記の化合物を実施例３３と同様にして得た。 （３ＲＳ）−３−（ジベンジルアミノ）−１，１−ビス［４−（メトキシカル
ボニルアミノ）フェニル］−１−ブタノール MS m/z: 568 製造例２６ （３ＲＳ）−１，１−ビス［４−（メトキシカルボニルアミノ）フェニル］−
３−ブチルアミン塩酸塩（１９１ｍｇ）を、常法の水素化によって、（３ＲＳ）
−３−（ジベンジルアミノ）−１，１−ビス（４−メトキシカルボニルアミノフ
ェニル）ブタノール（１７３ｍｇ）から得た。 MS m/z: 372 (M++1) (遊離化合物)Production Example 24 (3RS) -3-Amino-1,1-bis [4- (acetylamino) phenyl]
-1-butanol (0.23 g) was converted to (3RS) -3- by conventional hydrogenation.
(Dibenzylamino) -1,1-bis [4- (acetylamino) phenyl] -1
-Butanol (0.32 g). IR (KBr): 3294 (m), 1666 (s), 1623 (s), 1537 (s), 1514 (m), 1406 (m),
1321 (n), 1014 (m) cm -1 NMR (MeOH-d 6 , δ): 1.10-1.15 (3H, m), 2.07 (3H, s), 2.11 (3H, s), 2.5-
3.1 (3H, m), 4.23 (2H, d, J = 10.6Hz), 4.55 (2H, d, J = 10.6Hz), 7.21-7.58
(8H, m) Production Example 25 The following compound was obtained in the same manner as in Example 33. (3RS) -3- (dibenzylamino) -1,1-bis [4- (methoxycarbonylamino) phenyl] -1-butanol MS m / z: 568 Preparation Example 26 (3RS) -1,1-bis [ 4- (methoxycarbonylamino) phenyl]-
3-Butylamine hydrochloride (191 mg) was converted to (3RS) by conventional hydrogenation.
Obtained from -3- (dibenzylamino) -1,1-bis (4-methoxycarbonylaminophenyl) butanol (173 mg). MS m / z: 372 (M + +1) (free compound)

【０１０３】 製造例２７ 塩化メタンスルホニル（１．４ｍｌ）を３−アミノ−４−ベンジルオキシフェ
ニル酢酸塩（４．３ｇ）のピリジン（２０ｍｌ）中の溶液に氷冷下で１０分間か
けて滴下し、混合物を室温でさらに１時間攪拌した。反応混合物に水（１００ｍ
ｌ）を加え、同温で１時間攪拌した。沈殿物を濾取し、クロロホルム（１００ｍ
ｌ）に溶解し、次いで硫酸マグネシウムで乾燥後、真空中で溶媒を留去した。残
留物をシリカゲルクロマトグラフィー（ヘキサン−酢酸エチル）に付して、４−
ベンジルオキシ−３−（メタンスルホニルアミノ）フェニル酢酸塩（１．６ｇ）
を得た。 NMR (CDCl3, δ): 2.27 (3H, s), 2.95 (3H, s), 5.09 (2H, s), 6.80-7.03 (3H, m), 7.25-7.45 (6H, m) MS m/z: 336 (M++1) 製造例２８ ４−ベンジルオキシ−３−（メタンスルホニルアミノ）フェニル酢酸塩（１．
６ｇ）と水酸化カリウム（２．６７ｇ）のメタノール（１０ｍｌ）中の溶液を室
温で１８時間攪拌した。反応混合物を１Ｎ塩酸で酸性ｐＨ５〜７にし、酢酸エチ
ルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥後、真空中で
溶媒を留去した。残留物をシリカゲルクロマトグラフィー（ヘキサン−酢酸エチ
ル）に付して、Ｎ−（２−ベンジルオキシ−５−ヒドロキシフェニル）メタンス
ルホンアミド（７５０ｍｇ）を得た。 NMR (CDCl3, δ): 2.90 (3H, s), 5.04 (2H, s), 6.58 (1H, dd, J=2.9 および
8.8Hz), 6.80-6.90 (2H, m), 7.09 (1H, d, J=2.9Hz), 7.30-7.50 (6H, m) MS m/z: 294 (M++1)Production Example 27 Methanesulfonyl chloride (1.4 ml) was added dropwise to a solution of 3-amino-4-benzyloxyphenylacetic acid salt (4.3 g) in pyridine (20 ml) over 10 minutes under ice cooling. The mixture was stirred at room temperature for another hour. Water (100 m) was added to the reaction mixture.
l) was added and the mixture was stirred at the same temperature for 1 hour. The precipitate was collected by filtration, and chloroform (100 m
1), then dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to silica gel chromatography (hexane-ethyl acetate) to give 4-
Benzyloxy-3- (methanesulfonylamino) phenyl acetate (1.6 g)
Got. NMR (CDCl 3 , δ): 2.27 (3H, s), 2.95 (3H, s), 5.09 (2H, s), 6.80-7.03 (3H, m), 7.25-7.45 (6H, m) MS m / z : 336 (M + +1) Production Example 28 4-Benzyloxy-3- (methanesulfonylamino) phenyl acetate (1.
6 g) and potassium hydroxide (2.67 g) in methanol (10 ml) were stirred at room temperature for 18 hours. The reaction mixture was acidified to pH 5-7 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was subjected to silica gel chromatography (hexane-ethyl acetate) to obtain N- (2-benzyloxy-5-hydroxyphenyl) methanesulfonamide (750 mg). NMR (CDCl 3 , δ): 2.90 (3H, s), 5.04 (2H, s), 6.58 (1H, dd, J = 2.9 and
8.8Hz), 6.80-6.90 (2H, m), 7.09 (1H, d, J = 2.9Hz), 7.30-7.50 (6H, m) MS m / z: 294 (M + +1)

【０１０４】 製造例２９ 窒素雰囲気下、Ｎ−（２−ベンジルオキシ−５−ヒドロキシフェニル）メタン
スルホンアミド（７４０ｍｇ）と水素化ナトリウム（９２．４ｍｇ）のＮ，Ｎ−
ジメチルホルムアミド（３０ｍｌ）中の溶液に、（２Ｓ）−グリシジルトシラー
ト（６１６ｍｇ）を０℃で加え、混合物を同温で０．５時間攪拌した。混合物を
室温まで温度上昇させ、同温で２．５時間攪拌した。生じた混合物を１０％塩化
アンモニウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、
硫酸マグネシウムで乾燥後、真空中で溶媒を留去した。残留物をシリカゲルクロ
マトグラフィー（ヘキサン−酢酸エチル）に付して、（２Ｓ）−３−［４−ベン
ジルオキシ−３−（メタンスルホンアミノ）フェノキシ］−１，２−エポキシプ
ロパン（４４０ｍｇ）を得た。 NMR (CDCl3, δ): 2.75 (1H, dd, J=2.7 および 4.9Hz), 2.84-2.95 (4H, m),
3.30-3.37 (1H, m), 3.90 (1H, dd, J=5.8 および 11.08Hz), 4.07-4.25 (1H,
m), 5.05 (2H, s), 6.63-7.48 (9H, m) MS m/z: 350 (M++1)Production Example 29 N- (2-benzyloxy-5-hydroxyphenyl) methanesulfonamide (740 mg) and N, N- of sodium hydride (92.4 mg) were prepared under a nitrogen atmosphere.
To a solution in dimethylformamide (30 ml) was added (2S) -glycidyl tosylate (616 mg) at 0 ° C. and the mixture was stirred at the same temperature for 0.5 hour. The mixture was warmed to room temperature and stirred at the same temperature for 2.5 hours. The resulting mixture was poured into a 10% aqueous ammonium chloride solution and extracted with ethyl acetate. Wash the organic layer with saline,
After drying over magnesium sulfate, the solvent was distilled off in vacuo. The residue was subjected to silica gel chromatography (hexane-ethyl acetate) to obtain (2S) -3- [4-benzyloxy-3- (methanesulfonamino) phenoxy] -1,2-epoxypropane (440 mg). Was. NMR (CDCl 3 , δ): 2.75 (1H, dd, J = 2.7 and 4.9 Hz), 2.84-2.95 (4H, m),
3.30-3.37 (1H, m), 3.90 (1H, dd, J = 5.8 and 11.08Hz), 4.07-4.25 (1H,
m), 5.05 (2H, s), 6.63-7.48 (9H, m) MS m / z: 350 (M + +1)

【０１０５】 製造例３０ 窒素雰囲気下、Ｎ−ベンジル−［３，３−ビス（４−メトキシフェニル）−１
−メチルプロピル］アミン（４８０ｍｇ）、Ｎ−［２−ベンジルオキシ−５−［
（１Ｒ）−２−ヨード−１−（トリエチルシリルオキシ）エチル］フェニル］メ
タンスルホンアミド（６００ｍｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（０
．７４ｍｌ）のテトラヒドロフラン（６ｍｌ）中の溶液を、１１０℃で５８時間
、さらに１６０℃で９２時間攪拌しながら封止した。生じた混合物を亜硫酸水素
ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を飽和重炭酸ナトリウ
ム水溶液と食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、真空中で溶媒を
留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチ
ル＝１０：１〜５：１）で精製して、Ｎ−［５−［（１Ｒ）−２−［Ｎ−ベンジ
ル−［（１ＲＳ）−３，３−ビス（４−メトキシフェニル）−１−メチルプロピ
ル］アミノ］−１−（トリエチルシリルオキシ）エチル］−２−（ベンジルオキ
シ）フェニル］メタンスルホンアミド（２２６ｍｇ）を得た。 NMR (CDCl3, δ): 0.25-0.5 (6H, m), 0.7-0.95 (12H, m), 1.5-2.25 (2H, m),
2.35-2.9 (6H, m), 3.45-3.9 (8H, m), 4.25-4.4 (1H, m), 5.0-5.1 (2H, m),
6.65-7.75 (21H, m)Production Example 30 N-benzyl- [3,3-bis (4-methoxyphenyl) -1 under a nitrogen atmosphere
-Methylpropyl] amine (480 mg), N- [2-benzyloxy-5- [
(1R) -2-Iodo-1- (triethylsilyloxy) ethyl] phenyl] methanesulfonamide (600 mg) and N, N-diisopropylethylamine (0
. (74 ml) in tetrahydrofuran (6 ml) was sealed with stirring at 110 ° C. for 58 hours and further at 160 ° C. for 92 hours. The resulting mixture was poured into aqueous sodium bisulfite and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-5: 1) to give N- [5-[(1R) -2- [N-benzyl-[(1RS) -3, 3-bis (4-methoxyphenyl) -1-methylpropyl] amino] -1- (triethylsilyloxy) ethyl] -2- (benzyloxy) phenyl] methanesulfonamide (226 mg) was obtained. NMR (CDCl 3 , δ): 0.25-0.5 (6H, m), 0.7-0.95 (12H, m), 1.5-2.25 (2H, m),
2.35-2.9 (6H, m), 3.45-3.9 (8H, m), 4.25-4.4 (1H, m), 5.0-5.1 (2H, m),
6.65-7.75 (21H, m)

【０１０６】 製造例３１ Ｎ−ベンジル−［（１Ｓ）−３，３−ビス（４−メトキシフェニル）−１−メ
チルプロピル］アミン塩酸塩（８００ｍｇ）を飽和重炭酸ナトリウム水溶液で脱
塩酸し、酢酸エチルで抽出した。上記のようにして得られた生成物と１０％パラ
ジウム活性炭（５０％湿潤、３００ｍｇ）のメタノール（１０ｍｌ）中の混合物
を室温で大気圧の水素存在下で５．５時間攪拌した。濾過後、真空中で濾液から
溶媒を留去して、［（１Ｓ）−３，３−ビス（４−メトキシフェニル）−１−メ
チルプロピル］アミン（５６８ｍｇ）を得た。 NMR (CDCl3, δ): 1.10 (3H, d, J=6.3Hz), 1.95-2.1 (2H, m), 2.7-2.9 (1H,
m), 3.76 (6H, m), 3.98 (1H, t, J=8.0Hz), 6.75-6.9 (4H, m), 7.1-7.2 (4H,
m)Production Example 31 N-benzyl-[(1S) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amine hydrochloride (800 mg) was dehydrochlorinated with a saturated aqueous solution of sodium bicarbonate, and acetic acid was added. Extracted with ethyl. A mixture of the product obtained above and 10% palladium on activated carbon (50% wet, 300 mg) in methanol (10 ml) was stirred at room temperature in the presence of hydrogen at atmospheric pressure for 5.5 hours. After filtration, the solvent was distilled off from the filtrate in vacuo to obtain [(1S) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amine (568 mg). NMR (CDCl 3 , δ): 1.10 (3H, d, J = 6.3 Hz), 1.95-2.1 (2H, m), 2.7-2.9 (1H,
m), 3.76 (6H, m), 3.98 (1H, t, J = 8.0Hz), 6.75-6.9 (4H, m), 7.1-7.2 (4H,
m)

【０１０７】 製造例３２ 下記の化合物を製造例３１と同様にして得た。 ［（１Ｒ）−３，３−ビス（４−メトキシフェニル）−１−メチルプロピル］
アミン NMR (CDCl3, δ): 1.19 (3H, d, J=6.3Hz), 1.9-2.1 (2H, m), 2.7-2.85 (1H,
m), 3.76 (6H, m), 3.98 (1H, t, J=7.9Hz), 6.75-6.9 (4H, m), 7.15 (4H, d, J=8.0Hz) 製造例３３ Ｎ−ベンジル−［３，３−ビス（４−ヒドロキシフェニル）−１−メチルプロ
ピル］アミン（３００ｍｇ）と１０％パラジウム活性炭 （５０％湿潤、１００
ｍｇ）のメタノール（５ｍｌ）中の混合物を室温で大気圧の水素存在下で４時間
攪拌した。濾過後、真空中で濾液から溶媒を留去して、［３，３−ビス（４−ヒ
ドロキシフェニル）−１−メチルプロピル］アミン（２３０ｍｇ）を得た。 NMR (DMSO-d6, δ): 0.96 (3H, d, J=6.3Hz), 1.75-1.9 (2H, m), 2.4-2.6 (1H, m), 3.87 (1H, t, J=7.9Hz), 6.63 (4H, d, J=8.5Hz), 7.03 (4H, d, J=8.2Hz) 製造例３４ 下記の化合物を製造例３３と同様にして得た。 Ｎ−ベンジル−［３，３−ビス（４−メトキシフェニル）−１−メチルプロピ
ル］アミンProduction Example 32 The following compound was obtained in the same manner as in Production Example 31. [(1R) -3,3-bis (4-methoxyphenyl) -1-methylpropyl]
Amine NMR (CDCl 3 , δ): 1.19 (3H, d, J = 6.3 Hz), 1.9-2.1 (2H, m), 2.7-2.85 (1H,
m), 3.76 (6H, m), 3.98 (1H, t, J = 7.9 Hz), 6.75-6.9 (4H, m), 7.15 (4H, d, J = 8.0 Hz) Production Example 33 N-benzyl- [ 3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amine (300 mg) and 10% palladium on activated carbon (50% wet, 100
mg) in methanol (5 ml) was stirred at room temperature under atmospheric pressure of hydrogen for 4 hours. After filtration, the solvent was distilled off from the filtrate in vacuo to obtain [3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amine (230 mg). NMR (DMSO-d 6 , δ): 0.96 (3H, d, J = 6.3 Hz), 1.75-1.9 (2H, m), 2.4-2.6 (1H, m), 3.87 (1H, t, J = 7.9 Hz) ), 6.63 (4H, d, J = 8.5 Hz), 7.03 (4H, d, J = 8.2 Hz) Production Example 34 The following compound was obtained in the same manner as in Production Example 33. N-benzyl- [3,3-bis (4-methoxyphenyl) -1-methylpropyl] amine

【０１０８】 製造例３５ ６−［（４−ニトロフェニル）アゾ］ピリジン−３−オール（Ｊ．Ａｍ．Ｃｈ
ｅｍ．Ｓｏｃ．１９５９、８１、６０４９、３００ｍｇ）と２０％水酸化パラジ
ウム炭（６０ｍｇ）の、酢酸（３０ｍｌ）とメタノール（３０ｍｌ）の混合物中
の混合物を室温で大気圧の水素存在下で７０分間攪拌した。濾過後、真空中で濾
液から溶媒を留去した。窒素雰囲気下、残留物のジクロロメタン（１０ｍｌ）中
の混合物に、ビス（トリメチルシリル）アセトアミド（６．０ｍｌ）を５℃で加
えた。室温で３０分間攪拌後、生じた混合物にクロロ蟻酸ベンジル（０．５４ｍ
ｌ）を５℃で加え、混合物を同温で３時間攪拌した。生じた混合物を飽和重炭酸
ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、無
水硫酸マグネシウムで乾燥後、真空中で溶媒を留去した。残留物にクロロホルム
を加え、不溶物を濾去した。真空中で濾液から溶媒を留去し、残留物をシリカゲ
ルカラムクロマトグラフィー（クロロホルム：メタノール＝５０：１〜２０：１
）で精製し、次いでトルエン−メタノールから結晶化して、（５−ヒドロキシピ
リジン−２−イル）カルバミン酸ベンジルエステル（１５９ｍｇ）を得た。 MS m/z: 245 (M++1)Production Example 35 6-[(4-Nitrophenyl) azo] pyridin-3-ol (J. Am. Ch.
em. Soc. A mixture of 1959, 81, 6049, 300 mg) and 20% palladium hydroxide on carbon (60 mg) in a mixture of acetic acid (30 ml) and methanol (30 ml) was stirred at room temperature in the presence of hydrogen at atmospheric pressure for 70 minutes. After filtration, the solvent was distilled off from the filtrate in vacuo. To a mixture of the residue in dichloromethane (10 ml) under a nitrogen atmosphere was added bis (trimethylsilyl) acetamide (6.0 ml) at 5 ° C. After stirring at room temperature for 30 minutes, the resulting mixture was added to benzyl chloroformate (0.54 m
l) was added at 5 ° C. and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. Chloroform was added to the residue, and insolubles were removed by filtration. The solvent was distilled off from the filtrate in vacuo, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 50: 1 to 20: 1).
) And then crystallized from toluene-methanol to give (5-hydroxypyridin-2-yl) carbamic acid benzyl ester (159 mg). MS m / z: 245 (M + +1)

【０１０９】 製造例３６ 窒素雰囲気下、水素化ナトリウム（油状物中６０％、１８９ｍｇ）のＮ，Ｎ−
ジメチルホルムアミド（２０ｍｌ）中の懸濁液を、Ｎ，Ｎ−ジメチルホルムアミ
ド（１２ｍｌ）中の（５−ヒドロキシピリジン−２−イル）カルバミン酸ベンジ
ルエステル（１．１ｇ）に５℃で滴下し、混合物を室温で１時間攪拌した。これ
に、（２Ｓ）−グリシジルトシラート（１．１ｇ）を５℃で加え、混合物を室温
で７時間攪拌した。生じた混合物を飽和重炭酸ナトリウム水溶液に注ぎ、酢酸エ
チルで抽出した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、真
空中で溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロ
ホルム：酢酸エチル＝９：１）で精製して、（２Ｓ）−３−［２−（ベンジルオ
キシカルボニルアミノ）ピリジン−５−イルオキシ］−１，２−エポキシプロパ
ン（７８０ｍｇ）を得た。 MS m/z: 301 (M++1)Production Example 36 Under a nitrogen atmosphere, sodium hydride (60% in oil, 189 mg) of N, N-
The suspension in dimethylformamide (20 ml) was added dropwise at 5 ° C. to (5-hydroxypyridin-2-yl) carbamic acid benzyl ester (1.1 g) in N, N-dimethylformamide (12 ml) and the mixture was Was stirred at room temperature for 1 hour. To this was added (2S) -glycidyl tosylate (1.1 g) at 5 ° C and the mixture was stirred at room temperature for 7 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 9: 1) to give (2S) -3- [2- (benzyloxycarbonylamino) pyridin-5-yloxy] -1,2-epoxypropane. (780 mg). MS m / z: 301 (M + +1)

【０１１０】 製造例３７ ブト−３−エンイルベンゼン（３ｍｌ）と重炭酸ナトリウム（２．５ｇ）の、
ジクロロメタン（２００ｍｌ）と水（６０ｍｌ）の混合物中の懸濁液に、少量の
ｍ−クロロ過安息香酸（３．５ｇ）を室温で加え、混合物を同温で４時間攪拌し
た。分離後、有機層を飽和重炭酸ナトリウム水溶液と食塩水で順次洗浄し、無水
硫酸マグネシウムで乾燥後、真空中で溶媒を留去した。残留物をシリカゲルカラ
ムクロマトグラフィー（ヘキサン：酢酸エチル＝１００：３）で精製して、フェ
ネチルオキシラン（９７０ｍｇ）を得た。 NMR (CDCl3, δ): 1.7-1.9 (2H, m), 2.45-2.5 (1H, m), 2.7-3.0 (4H, m), 7.1-7.4 (5H, m) 製造例３８ 窒素雰囲気下、（２Ｒ）−グリシジルトシラート（３．０ｇ）のテトラヒドロ
フラン（３０ｍｌ）中の溶液に、Ｎ，Ｎ−ジイソプロピルエチルアミン（２．５
ｍｌ）とチオフェノール（１．３ｍｌ）を５℃で加え、混合物を室温で１２時間
攪拌した。生じた混合物を水に注ぎ、酢酸エチルで抽出した。有機層を飽和重炭
酸ナトリウム水溶液と食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、真
空中で溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサ
ン：酢酸エチル＝５：１〜３：１）で精製して、トルエン−４−スルホン酸（２
Ｓ）−２−ヒドロキシ−３−（フェニルチオ）プロピルエステル（３．９ｇ）を
得た。 NMR (CDCl3, δ): 2.44 (3H, m), 2.75-3.25 (3H, m), 3.85-4.3 (3H, m), 7.15-7.4 (7H, m), 7.7-7.8 (2H, m)Production Example 37 Of but-3-enylbenzene (3 ml) and sodium bicarbonate (2.5 g),
A small amount of m-chloroperbenzoic acid (3.5 g) was added to a suspension in a mixture of dichloromethane (200 ml) and water (60 ml) at room temperature, and the mixture was stirred at the same temperature for 4 hours. After separation, the organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 3) to obtain phenethyloxirane (970 mg). NMR (CDCl 3 , δ): 1.7-1.9 (2H, m), 2.45-2.5 (1H, m), 2.7-3.0 (4H, m), 7.1-7.4 (5H, m) Production Example 38 Under a nitrogen atmosphere, To a solution of (2R) -glycidyl tosylate (3.0 g) in tetrahydrofuran (30 ml) was added N, N-diisopropylethylamine (2.5
ml) and thiophenol (1.3 ml) were added at 5 ° C. and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-3: 1) to give toluene-4-sulfonic acid (2
S) -2-Hydroxy-3- (phenylthio) propyl ester (3.9 g) was obtained. NMR (CDCl 3 , δ): 2.44 (3H, m), 2.75-3.25 (3H, m), 3.85-4.3 (3H, m), 7.15-7.4 (7H, m), 7.7-7.8 (2H, m)

【０１１１】 製造例３９ 窒素雰囲気下、トルエン−４−スルホン酸（２Ｓ）−２−ヒドロキシ−３−（
フェニルチオ）プロピルエステル（３．９ｇ）のエタノール（４０ｍｌ）中の溶
液に、エタノール中２０％ナトリウムメトキシド（４．７ｍｌ）を５℃で加え、
混合物を同温で３０分間攪拌した。沈殿物を濾去後、濾液を真空中で濃縮した。
残留物を０．１Ｎ水酸化ナトリウム水溶液とジエチルエーテルの混合物に溶解し
た。分離後、有機層を水と食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し
、真空中で溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘ
キサン：酢酸エチル＝２０：１〜１０：１）で精製して、（２Ｓ）−３−（フェ
ニルチオ）−１，２−エポキシプロパン（１．５ｇ）を得た。 MS m/z: 167 (M++1)Production Example 39 Toluene-4-sulfonic acid (2S) -2-hydroxy-3- (
To a solution of phenylthio) propyl ester (3.9 g) in ethanol (40 ml) was added 20% sodium methoxide in ethanol (4.7 ml) at 5 ° C.
The mixture was stirred at the same temperature for 30 minutes. After filtering off the precipitate, the filtrate was concentrated in vacuo.
The residue was dissolved in a mixture of 0.1N aqueous sodium hydroxide and diethyl ether. After separation, the organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 10: 1) to obtain (2S) -3- (phenylthio) -1,2-epoxypropane (1.5 g). . MS m / z: 167 (M + +1)

【０１１２】 実施例６ ４−ブロモチオアニソール（５０８ｍｇ）のテトラヒドロフラン中の溶液に、
ブチルリチウム（ヘキサン中１．５４Ｍ、１．６２ｍｌ）を−７８℃で加えた。
３０分後、（３ＲＳ）−３−［（（２Ｓ）−２−ヒドロキシ−３−フェノキシプ
ロピル）アミノ］酪酸メチルエステル（１３１ｍｇ）を加え、０℃まで加温した
。反応混合物を常法で処理し、シリカゲルカラムクロマトグラフィーで精製して
、（２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−（メチル
チオ）フェニル］−１−ヒドロキシ−３−ブチル］アミノ−３−プロパノール（
５８．５ｍｇ）を得た。 IR (ニート): 3400 (br s), 2921 (s), 1594 (s), 1492 (s), 1243 (s), 1093 (m), 1043 (m), 817 (s), 754 (s) cm-1 NMR (CDCl3, δ): 1.14 (3H, d, J=6.3Hz), 2.4-2.6 (2H, m), 2.43 (3H, s), 2.46 (3H, s), 2.7-2.8 (2H, m), 2.88 (1H, dd, J=11.9 および 8.0Hz), 3.9-4.1 (3H, m), 6.9-7.0 (3H, m), 7.1-7.4 (12H, m)Example 6 To a solution of 4-bromothioanisole (508 mg) in tetrahydrofuran was
Butyllithium (1.54M in hexane, 1.62 ml) was added at -78 ° C.
After 30 minutes, (3RS) -3-[((2S) -2-hydroxy-3-phenoxypropyl) amino] butyric acid methyl ester (131 mg) was added, and the mixture was heated to 0 ° C. The reaction mixture was treated in a conventional manner, and purified by silica gel column chromatography to give (2S) -1-phenoxy-3-[(3RS) -1,1-bis [4- (methylthio) phenyl] -1-hydroxy. -3-butyl] amino-3-propanol (
58.5 mg). IR (neat): 3400 (br s), 2921 (s), 1594 (s), 1492 (s), 1243 (s), 1093 (m), 1043 (m), 817 (s), 754 (s) cm -1 NMR (CDCl 3 , δ): 1.14 (3H, d, J = 6.3 Hz), 2.4-2.6 (2H, m), 2.43 (3H, s), 2.46 (3H, s), 2.7-2.8 ( 2H, m), 2.88 (1H, dd, J = 11.9 and 8.0Hz), 3.9-4.1 (3H, m), 6.9-7.0 (3H, m), 7.1-7.4 (12H, m)

【０１１３】 実施例７ 下記の化合物を実施例６と同様にして得た。 （１） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス（３−メ
トキシフェニル）−１−ヒドロキシ−３−ブチル］アミノ−２−プロパノール IR (ニート): 3296 (br m), 2933 (s), 1599 (s), 1491 (s), 1464 (m), 1246 (s), 1171 (m), 1045 (s), 756 (m), 694 (m) cm-1 NMR (CDCl3+D2O, δ): 1.09 (3H, d, J=6.3Hz), 2.04 (1H, dd, J=11.4 および 14.2Hz), 2.39-2.49 (2H, m), 2.6-2.8 (1H, m), 2.83 (1H, dd, J=8.3 および
11.9Hz), 3.74 (3H, s), 3.76 (3H, s), 3.8-3.9 (2H, m), 3.9-4.1 (1H, m),
6.72-6.75 (2H, m), 6.8-7.1 (7H, m), 7.12-7.31 (4H, m) MS m/z: 452 (M++1) （２） （２Ｓ）−１−フェノキシ−３−（（３ＲＳ）−１，１−ジフェニル−
１−ヒドロキシ−３−ブチル）アミノ−２−プロパノール IR (ニート): 3292 (br m), 2925 (m), 1597 (m), 1495 (s), 1456 (m), 1244 (s), 1043 (m), 754 (s), 698 (s) cm-1 MS m/z: 392 (M++1) （３） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス（４−メ
トキシフェニル）−１−ヒドロキシ−３−ブチル］アミノ−２−プロパノール IR (ニート): 3292 (br m), 2929 (m), 1604 (m), 1508 (s), 1460 (m), 1248 (s), 1176 (m), 1038 (m), 833 (m), 756 (m) cm-1 NMR (CDCl3, δ): 1.12 (1.5H, d, J=5.1Hz), 1.16 (1.5H, d, J=6.2Hz), 2.0- 2.5 (2H, m), 2.6-3.2 (3H, m), 3.74 (1.5H, s), 3.75 (1.5H, s), 3.78 (3H,
s), 3.8-4.2 (3H, m), 6.77-7.01 (7H, m), 7.2-7.4 (6H, m) MS m/z: 452 (M++1) （４） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス（３，４
−ジメトキシフェニル）−１−ヒドロキシ−３−ブチル］アミノ−２−プロパノ
ール IR (ニート): 3294 (br m), 2933 (m), 1597 (w), 1510 (s), 1460 (m), 1257 (s), 1146 (m), 1028 (m), 760 (m) cm-1 MS m/z: 512 (M++1)Example 7 The following compounds were obtained in the same manner as in Example 6. (1) (2S) -1-phenoxy-3-[(3RS) -1,1-bis (3-methoxyphenyl) -1-hydroxy-3-butyl] amino-2-propanol IR (neat): 3296 ( br m), 2933 (s) , 1599 (s), 1491 (s), 1464 (m), 1246 (s), 1171 (m), 1045 (s), 756 (m), 694 (m) cm - 1 NMR (CDCl 3 + D 2 O, δ): 1.09 (3H, d, J = 6.3Hz), 2.04 (1H, dd, J = 11.4 and 14.2Hz), 2.39-2.49 (2H, m), 2.6- 2.8 (1H, m), 2.83 (1H, dd, J = 8.3 and
11.9Hz), 3.74 (3H, s), 3.76 (3H, s), 3.8-3.9 (2H, m), 3.9-4.1 (1H, m),
6.72-6.75 (2H, m), 6.8-7.1 (7H, m), 7.12-7.31 (4H, m) MS m / z: 452 (M ++ 1) (2) (2S) -1-phenoxy-3 -((3RS) -1,1-diphenyl-
1-hydroxy-3-butyl) amino-2-propanol IR (neat): 3292 (br m), 2925 (m), 1597 (m), 1495 (s), 1456 (m), 1244 (s), 1043 (m), 754 (s), 698 (s) cm -1 MS m / z: 392 (M + +1) (3) (2S) -1-phenoxy-3-[(3RS) -1,1- Bis (4-methoxyphenyl) -1-hydroxy-3-butyl] amino-2-propanol IR (neat): 3292 (br m), 2929 (m), 1604 (m), 1508 (s), 1460 (m ), 1248 (s), 1176 (m), 1038 (m), 833 (m), 756 (m) cm -1 NMR (CDCl 3 , δ): 1.12 (1.5H, d, J = 5.1Hz), 1.16 (1.5H, d, J = 6.2Hz), 2.0-2.5 (2H, m), 2.6-3.2 (3H, m), 3.74 (1.5H, s), 3.75 (1.5H, s), 3.78 (3H ,
s), 3.8-4.2 (3H, m), 6.77-7.01 (7H, m), 7.2-7.4 (6H, m) MS m / z: 452 (M ++ 1) (4) (2S) -1- Phenoxy-3-[(3RS) -1,1-bis (3,4
-Dimethoxyphenyl) -1-hydroxy-3-butyl] amino-2-propanol IR (neat): 3294 (br m), 2933 (m), 1597 (w), 1510 (s), 1460 (m), 1257 (s), 1146 (m), 1028 (m), 760 (m) cm -1 MS m / z: 512 (M + +1)

【０１１４】 （５） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス（４−メ
チルフェニル）−１−ヒドロキシ−３−ブチル］アミノ−２−プロパノール IR (ニート): 3400 (br s), 2923 (s), 1596 (m), 1498 (s), 1457 (s), 1243 (s), 1087 (m), 1043 (m), 817 (s), 754 (s) cm-1 NMR (CDCl3, δ): 1.13 (2H, d, J=6.2Hz), 2.16 (3H, s), 2.31 (3H, s), 2.4-2.5 (2H, m), 2.6-2.9 (3H, m), 3.9-4.1 (3H, m), 6.9-7.4 (13H, m) MS m/z: 420 (M++1) （６） ５−［Ｎ−ベンジル−（（２Ｓ）−２−ヒドロキシ−３−フェノキシプ
ロピル）アミノ］−１，１−ビス（４−メトキシフェニル）−１−ペンタノール
IR (ニート): 3446 (br m), 2943 (m), 1604 (m), 1508 (s), 1458 (m), 1248 (s), 1176 (m), 1036 (m), 831 (m), 752 (m) cm-1 NMR (CDCl3, δ): 1.2-1.3 (2H, m), 1.4-1.7 (2H, m), 2.1-2.2 (2H, m), 2.4 -2.7 (4H, m), 3.4-3.6 (1H, m), 3.78 (6H, s), 3.7-3.8 (1H, m), 3.8-3.9 (2H, m), 3.9-4.1 (1H, m), 6.77-6.97 (7H, m), 7.2-7.4 (11H, m) MS m/z: 556 (M++1) （７） ４−［Ｎ−ベンジル−（（２Ｓ）−２−ヒドロキシ−３−フェノキシプ
ロピル）アミノ］−１，１−ビス（４−メトキシフェニル）−１−ブタノール IR (ニート): 3446 (br m), 2951 (m), 1604 (m), 1508 (s), 1458 (m), 1248 (s), 1176 (m), 1036 (s), 831 (m), 752 (m) cm-1 NMR (CDCl3, δ): 1.5-1.7 (2H, m), 2.1-2.4 (2H, m), 2.4-2.7 (4H, m), 3.4 -3.5 (1H, m), 3.77 (6H, s), 3.7-3.8 (1H, m), 3.8-4.0 (2H, m), 4.1-4.3 (1H, m), 6.78-6.98 (7H, m), 7.2-7.4 (11H, m) MS m/z: 542 (M++1)(5) (2S) -1-phenoxy-3-[(3RS) -1,1-bis (4-methylphenyl) -1-hydroxy-3-butyl] amino-2-propanol IR (neat) : 3400 (br s), 2923 (s), 1596 (m), 1498 (s), 1457 (s), 1243 (s), 1087 (m), 1043 (m), 817 (s), 754 (s ) cm -1 NMR (CDCl 3 , δ): 1.13 (2H, d, J = 6.2Hz), 2.16 (3H, s), 2.31 (3H, s), 2.4-2.5 (2H, m), 2.6-2.9 (3H, m), 3.9-4.1 (3H, m), 6.9-7.4 (13H, m) MS m / z: 420 (M + +1) (6) 5- [N-benzyl-((2S)- 2-hydroxy-3-phenoxypropyl) amino] -1,1-bis (4-methoxyphenyl) -1-pentanol
IR (neat): 3446 (br m), 2943 (m), 1604 (m), 1508 (s), 1458 (m), 1248 (s), 1176 (m), 1036 (m), 831 (m) , 752 (m) cm -1 NMR (CDCl 3 , δ): 1.2-1.3 (2H, m), 1.4-1.7 (2H, m), 2.1-2.2 (2H, m), 2.4 -2.7 (4H, m ), 3.4-3.6 (1H, m), 3.78 (6H, s), 3.7-3.8 (1H, m), 3.8-3.9 (2H, m), 3.9-4.1 (1H, m), 6.77-6.97 (7H , m), 7.2-7.4 (11H, m) MS m / z: 556 (M + +1) (7) 4- [N-benzyl-((2S) -2-hydroxy-3-phenoxypropyl) amino] -1,1-bis (4-methoxyphenyl) -1-butanol IR (neat): 3446 (br m), 2951 (m), 1604 (m), 1508 (s), 1458 (m), 1248 (s ), 1176 (m), 1036 (s), 831 (m), 752 (m) cm -1 NMR (CDCl 3 , δ): 1.5-1.7 (2H, m), 2.1-2.4 (2H, m), 2.4-2.7 (4H, m), 3.4 -3.5 (1H, m), 3.77 (6H, s), 3.7-3.8 (1H, m), 3.8-4.0 (2H, m), 4.1-4.3 (1H, m ), 6.78-6.98 (7H, m), 7.2-7.4 (11H, m) MS m / z: 542 (M + +1)

【０１１５】 （８） （２Ｓ）−１−フェノキシ−３−［（１ＲＳ）−３，３−ビス（４−メ
トキシフェニル）−３−ヒドロキシ−１−（３，４−ジメトキシフェニル）プロ
ピル］アミノ−２−プロパノール IR (ニート): 3361 (br m), 2929 (m), 1602 (m), 1512 (s), 1459 (m), 1248 (s), 1032 (s), 833 (m), 756 (m) cm-1 NMR (CDCl3, δ): 2.3-2.8 (5H, m), 3.74 (3H, s), 3.82 (3H, s), 3.86 (6H, s), 3.9-4.1 (3H, m), 6.6-7.1 (8H, m), 7.2-7.5 (8H, m) MS m/z: 574 (M++1) （９） （２Ｓ）−１−フェノキシ−３−［（１ＲＳ）−３，３−ビス（４−メ
トキシフェニル）−３−ヒドロキシ−１−フェニルプロピル］アミノ−２−プロ
パノール IR (ニート): 3361 (br m), 2929 (m), 1603 (m), 1506 (s), 1458 (m), 1246 (s), 1176 (m), 1035 (m), 833 (m), 756(m), 698 (m) cm-1 NMR (CDCl3, δ): 2.3-2.8 (4H, m), 3.6-3.7 (1H, m), 3.74 (3H, s), 3.82 (3H, s), 3.8-4.2 (4H, m), 6.7-7.0 (9H, m), 7.1-7.2 (2H, m), 7.2-7.4 (5H,
m), 7.4-7.5 (2H, m) MS m/z: 514 (M++1) （１０） （２Ｓ）−１−フェノキシ−３−［３，３−ビス（４−メトキシフェ
ニル）−３−ヒドロキシフェニル］アミノ−２−プロパノール IR (ニート): 3313 (br m), 2931 (m), 1602 (s), 1508 (s), 1462 (m), 1248 (s), 1176 (m), 1036 (m), 831 (m), 756 (m) cm-1 NMR (CDCl3+D2O, δ): 2.3-2.5 (2H, m), 2.7-2.9 (4H, m), 3.77 (6H, s), 3.9-4.2 (4H, m), 6.80-7.01 (7H, m), 7.2-7.4 (6H, m) MS m/z: 438 (M++1)(8) (2S) -1-phenoxy-3-[(1RS) -3,3-bis (4-methoxyphenyl) -3-hydroxy-1- (3,4-dimethoxyphenyl) propyl] amino -2-propanol IR (neat): 3361 (br m), 2929 (m), 1602 (m), 1512 (s), 1459 (m), 1248 (s), 1032 (s), 833 (m), 756 (m) cm -1 NMR (CDCl 3 , δ): 2.3-2.8 (5H, m), 3.74 (3H, s), 3.82 (3H, s), 3.86 (6H, s), 3.9-4.1 (3H , m), 6.6-7.1 (8H, m), 7.2-7.5 (8H, m) MS m / z: 574 (M ++ 1) (9) (2S) -1-phenoxy-3-[(1RS) -3,3-bis (4-methoxyphenyl) -3-hydroxy-1-phenylpropyl] amino-2-propanol IR (neat): 3361 (br m), 2929 (m), 1603 (m), 1506 ( s), 1458 (m), 1246 (s), 1176 (m), 1035 (m), 833 (m), 756 (m), 698 (m) cm -1 NMR (CDCl 3 , δ): 2.3- 2.8 (4H, m), 3.6-3.7 (1H, m), 3.74 (3H, s), 3.82 (3H, s), 3.8-4.2 (4H, m), 6.7-7 .0 (9H, m), 7.1-7.2 (2H, m), 7.2-7.4 (5H,
m), 7.4-7.5 (2H, m) MS m / z: 514 (M + +1) (10) (2S) -1-phenoxy-3- [3,3-bis (4-methoxyphenyl) -3 -Hydroxyphenyl] amino-2-propanol IR (neat): 3313 (br m), 2931 (m), 1602 (s), 1508 (s), 1462 (m), 1248 (s), 1176 (m), 1036 (m), 831 (m), 756 (m) cm -1 NMR (CDCl 3 + D 2 O, δ): 2.3-2.5 (2H, m), 2.7-2.9 (4H, m), 3.77 (6H , s), 3.9-4.2 (4H, m), 6.80-7.01 (7H, m), 7.2-7.4 (6H, m) MS m / z: 438 (M + +1)

【０１１６】 実施例８ 下記の化合物を製造例３３と同様にして得た。 （１） （２Ｓ）−１−フェノキシ−３−［５，５−ビス（４−メトキシフェニ
ル）ペンチル］アミノ−２−プロパノール塩酸塩 IR (ニート): 3322 (br m), 1602 (m), 1510 (s), 1460 (m), 1246 (s), 1178 (m), 1036 (m), 831 (m) cm-1 NMR (MeOH-d4, δ): 1.2-1.4 (2H, m), 1.6-1.8 (2H, m), 2.04 (2H, quartet,
J=7.5Hz), 2.99 (2H, t, J=8.0Hz), 3.09-3.22 (2H, m), 3.73 (6H, s), 3.6- 3.85 (1H, m), 3.9-4.0 (2H, m), 4.1-4.3 (1H, m), 6.84 (4H, d, J=8.7Hz),
6.9-7.0 (3H, m), 7.14 (4H, d, J=8.6Hz), 7.28 (2H, t, J=7.9Hz) MS m/z: 450 (M++1) (遊離化合物) （２） （２Ｓ）−１−フェノキシ−３−［４，４−ビス（４−メトキシフェニ
ル）ブチル］アミノ−２−プロパノール塩酸塩 IR (ニート): 3355 (br m), 1602 (m), 1510 (s), 1460 (m), 1246 (s) 1178 (m), 1036 (m), 831 (m) cm-1 NMR (MeOH-d4, δ): 1.6-1.8 (2H, m), 2.08 (1H, quartet, J=7.9Hz), 2.55 (1H, quartet, J=7.6Hz), 3.0-3.2 (4H, m), 3.73 (6H, s), 3.7-4.3 (4H, m),
6.8-7.0 (7H, m), 7.1-7.4 (6H, m) MS m/z: 436 (M++1) (遊離化合物)Example 8 The following compound was obtained in the same manner as in Production Example 33. (1) (2S) -1-phenoxy-3- [5,5-bis (4-methoxyphenyl) pentyl] amino-2-propanol hydrochloride IR (neat): 3322 (br m), 1602 (m), 1510 (s), 1460 (m), 1246 (s), 1178 (m), 1036 (m), 831 (m) cm -1 NMR (MeOH-d 4 , δ): 1.2-1.4 (2H, m) , 1.6-1.8 (2H, m), 2.04 (2H, quartet,
J = 7.5Hz), 2.99 (2H, t, J = 8.0Hz), 3.09-3.22 (2H, m), 3.73 (6H, s), 3.6- 3.85 (1H, m), 3.9-4.0 (2H, m ), 4.1-4.3 (1H, m), 6.84 (4H, d, J = 8.7Hz),
6.9-7.0 (3H, m), 7.14 (4H, d, J = 8.6Hz), 7.28 (2H, t, J = 7.9Hz) MS m / z: 450 (M + +1) (free compound) (2 ) (2S) -1-phenoxy-3- [4,4-bis (4-methoxyphenyl) butyl] amino-2-propanol hydrochloride IR (neat): 3355 (br m), 1602 (m), 1510 ( s), 1460 (m), 1246 (s) 1178 (m), 1036 (m), 831 (m) cm -1 NMR (MeOH-d 4 , δ): 1.6-1.8 (2H, m), 2.08 ( 1H, quartet, J = 7.9Hz), 2.55 (1H, quartet, J = 7.6Hz), 3.0-3.2 (4H, m), 3.73 (6H, s), 3.7-4.3 (4H, m),
6.8-7.0 (7H, m), 7.1-7.4 (6H, m) MS m / z: 436 (M + +1) (free compound)

【０１１７】 実施例９ （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−（メチル
チオ）フェニル］−１−ヒドロキシ−３−ブチル］アミノ−２−プロパノール（
４７ｍｇ）、水（２ｍｌ）、メタノール（３ｍｌ）とＯＸＯＮＥョ（ペルオキシ
一硫酸カリウム）（１８０ｍｇ）の混合物を室温で一夜攪拌し、常法で処理して
、（２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス（４−メタンス
ルホニルフェニル）−１−ヒドロキシ−３−ブチル］アミノ−２−プロパノール
（５２ｍｇ）を得た。 IR (ニート): 3521 (br m), 2927 (m), 1595 (m), 1494 (s), 1309 (s), 1244 (m), 1149 (s), 1091 (m), 958 (m), 771 (s), 694 (m) cm-1 NMR (CDCl3, δ): 1.19 (3H, d, J=6.3Hz), 2.3-2.8 (4H, m), 2.9 (1H, m), 3.00 (3H, s), 3.05 (3H, s), 3.9-4.1 (3H, m), 6.9-7.1 (3H, m), 7.2-7.4 (1H, m), 7.5-7.74 (5H, m), 7.8-7.9 (4H, m) MS m/z: 548 (M++1)Example 9 (2S) -1-phenoxy-3-[(3RS) -1,1-bis [4- (methylthio) phenyl] -1-hydroxy-3-butyl] amino-2-propanol (
47 mg), water (2 ml), a mixture of methanol (3 ml) and OXONE ® (potassium peroxymonosulfate) (180 mg) was stirred at room temperature overnight, and treated in the usual manner, (2S)-1-phenoxy-3- [(3RS) -1,1-bis (4-methanesulfonylphenyl) -1-hydroxy-3-butyl] amino-2-propanol (52 mg) was obtained. IR (neat): 3521 (br m), 2927 (m), 1595 (m), 1494 (s), 1309 (s), 1244 (m), 1149 (s), 1091 (m), 958 (m) , 771 (s), 694 (m) cm -1 NMR (CDCl 3 , δ): 1.19 (3H, d, J = 6.3 Hz), 2.3-2.8 (4H, m), 2.9 (1H, m), 3.00 (3H, s), 3.05 (3H, s), 3.9-4.1 (3H, m), 6.9-7.1 (3H, m), 7.2-7.4 (1H, m), 7.5-7.74 (5H, m), 7.8 -7.9 (4H, m) MS m / z: 548 (M + +1)

【０１１８】 実施例１０ （２Ｓ）−３−フェノキシ−１，２−エポキシプロパン（４０ｍｇ）、３−ア
ミノ−３−（３，４−ジメトキシフェニル）プロピオン酸メチルエステル酢酸塩
（８０ｍｇ）、トリエチルアミン（０．５ｍｌ）とメタノール（３ｍｌ）の混合
物を還流下で加熱し、溶媒を留去し、シリカゲルカラムクロマトグラフィー（ヘ
キサン：酢酸エチル：メタノール＝１：１：０．０７）で精製して、（３ＲＳ）
−３−（（２Ｓ）−２−ヒドロキシ−３−フェノキシプロピル）アミノ−３−(
３，４−ジメトキシフェニル)プロピオン酸メチルエステル（９２ｍｇ）を得た
。 IR (ニート): 2925 (m), 1738 (s), 1597 (m), 1514 (s), 1460 (m), 1263 (m), 1138 (m), 1027 (s), 758 (m) cm-1 NMR (CDCl3, δ): 2.6-2.8 (4H, m), 3.67 (3H, s), 3.87 (6H, s), 3.9-4.0 (2H, m), 4.0-4.1 (2H, m), 6.8-7.0 (7H, m), 7.26 (1H, t, J=8.9Hz) MS m/z: 390 (M++1)Example 10 (2S) -3-phenoxy-1,2-epoxypropane (40 mg), 3-amino-3- (3,4-dimethoxyphenyl) propionic acid methyl acetate acetate (80 mg), triethylamine ( A mixture of 0.5 ml) and methanol (3 ml) was heated under reflux, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: methanol = 1: 1: 0.07). 3RS)
-3-((2S) -2-hydroxy-3-phenoxypropyl) amino-3- (
3,4-Dimethoxyphenyl) propionic acid methyl ester (92 mg) was obtained. IR (neat): 2925 (m), 1738 (s), 1597 (m), 1514 (s), 1460 (m), 1263 (m), 1138 (m), 1027 (s), 758 (m) cm -1 NMR (CDCl 3 , δ): 2.6-2.8 (4H, m), 3.67 (3H, s), 3.87 (6H, s), 3.9-4.0 (2H, m), 4.0-4.1 (2H, m) , 6.8-7.0 (7H, m), 7.26 (1H, t, J = 8.9Hz) MS m / z: 390 (M + +1)

【０１１９】 実施例１１ 下記の化合物を実施例１０と同様にして得た。 （２Ｓ）−１−フェノキシ−３−［１，１−ビス（４−メトキシフェニル）−
３−メチル−３−ブチル］アミノ−２−プロパノール IR (ニート): 3350 (br m), 2962 (m), 1606 (m), 1508 (s), 1460 (m), 1248 (s), 1178 (m), 1036 (m), 829 (m), 756(m) cm-1 NMR (CDCl3, δ):1.03 (3H, s), 1.05 (3H, s), 2.22 (2H, d, J=6.8Hz), 2.55 (1H, dd, J=7.0 および 11.7Hz), 2.68 (1H, dd, J=3.6 および 11.7Hz), 3.73
(6H, s), 3.8-3.9 (3H, m), 4.04 (1H, t, J=6.7Hz), 6.77-6.99 (7H, m), 7.1-
7.4 (6H, m) MS m/z: 450 (M++1)Example 11 The following compounds were obtained in the same manner as in Example 10. (2S) -1-phenoxy-3- [1,1-bis (4-methoxyphenyl)-
3-Methyl-3-butyl] amino-2-propanol IR (neat): 3350 (br m), 2962 (m), 1606 (m), 1508 (s), 1460 (m), 1248 (s), 1178 (m), 1036 (m), 829 (m), 756 (m) cm -1 NMR (CDCl 3 , δ): 1.03 (3H, s), 1.05 (3H, s), 2.22 (2H, d, J = 6.8Hz), 2.55 (1H, dd, J = 7.0 and 11.7Hz), 2.68 (1H, dd, J = 3.6 and 11.7Hz), 3.73
(6H, s), 3.8-3.9 (3H, m), 4.04 (1H, t, J = 6.7Hz), 6.77-6.99 (7H, m), 7.1-
7.4 (6H, m) MS m / z: 450 (M + +1)

【０１２０】 実施例１２ （２Ｓ）−３−フェノキシ−１，２−エポキシプロパン（０．１２ｇ）、１−
［２，２−ビス（４−メトキシフェニル）エチル］シクロペンチルアミン（０．
２４ｇ）とメタノール（５ｍｌ）の混合物を還流下で加熱し、溶媒を留去し、シ
リカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル：メタノール＝１：
１：０．０７）で精製して、Ｎ−（（２Ｓ）−２−ヒドロキシ−３−フェノキシ
プロピル）−［１−［２，２−ビス（４−メトキシフェニル）エチル］シクロペ
ンチル］アミン（４０．９ｍｇ）を得た。 IR (ニート): 2954 (m), 1606 (w), 1510 (s), 1460 (m), 1246 (m), 1176 (m), 1038(s), 825 (m), 754 (m) cm-1 NMR (CDCl3, δ): 1.2-1.8 (8H, m), 2.25 (2H, t, J=6.8Hz), 2.46 (1H, dd, J=6.9 および 12.0Hz), 2.61 (1H, dd, J=4.4 および 12.0Hz), 3.73 (6H, s),
3.8-3.9 (2H, m), 4.0-4.1 (2H, m), 6.78 (4H, d, J=8.2Hz), 6.9-7.0 (3H, m), 7.19 (4H, d, J=8.7Hz), 7.24-7.33 (2H, m) MS m/z: 476 (M++1)Example 12 (2S) -3-phenoxy-1,2-epoxypropane (0.12 g), 1-
[2,2-bis (4-methoxyphenyl) ethyl] cyclopentylamine (0.
A mixture of 24 g) and methanol (5 ml) was heated under reflux, the solvent was distilled off, and silica gel column chromatography (hexane: ethyl acetate: methanol = 1: 1).
1: 0.07) to give N-((2S) -2-hydroxy-3-phenoxypropyl)-[1- [2,2-bis (4-methoxyphenyl) ethyl] cyclopentyl] amine (40 .9 mg). IR (neat): 2954 (m), 1606 (w), 1510 (s), 1460 (m), 1246 (m), 1176 (m), 1038 (s), 825 (m), 754 (m) cm -1 NMR (CDCl 3 , δ): 1.2-1.8 (8H, m), 2.25 (2H, t, J = 6.8Hz), 2.46 (1H, dd, J = 6.9 and 12.0Hz), 2.61 (1H, dd , J = 4.4 and 12.0Hz), 3.73 (6H, s),
3.8-3.9 (2H, m), 4.0-4.1 (2H, m), 6.78 (4H, d, J = 8.2Hz), 6.9-7.0 (3H, m), 7.19 (4H, d, J = 8.7Hz) , 7.24-7.33 (2H, m) MS m / z: 476 (M + +1)

【０１２１】 実施例１３ 下記の化合物を実施例１２と同様にして得た。 （１） （１Ｒ）−１−（３−ピリジル）−２−［［（３ＲＳ）−１，１−ビス
（４−メトキシフェニル）−３−ブチル］アミノ］エタノール MS m/z: 407 (M++1) （２） （２Ｓ）−１−（３−ピリジルオキシ）−３−［（３ＲＳ）−１，１−
ビス（４−メトキシフェニル）−３−ブチル］アミノ−２−プロパノール二塩酸
塩 MS m/z: 437 (M++1) (遊離化合物) （３） （２Ｓ）−１−（１Ｈ−インドール−４−イルオキシ）−３−［３，３
−ビス（４−メトキシフェニル）プロピル］アミノ−２−プロパノール MS m/z: 461 (M++1) （４） （２ＲＳ）−１−（２−オキソ−２，３−ジヒドロ−１Ｈ−ベンズイミ
ダゾール−４−イルオキシ）−３−［（３ＲＳ）−１，１−ビス（４−メトキシ
フェニル）−３−ブチル］アミノ−２−プロパノール MS m/z: 492 (M++1)Example 13 The following compound was obtained in the same manner as in Example 12. (1) (1R) -1- (3-pyridyl) -2-[[(3RS) -1,1-bis (4-methoxyphenyl) -3-butyl] amino] ethanol MS m / z: 407 (M + +1) (2) (2S) -1- (3-pyridyloxy) -3-[(3RS) -1,1-
Bis (4-methoxyphenyl) -3-butyl] amino-2-propanol dihydrochloride MS m / z: 437 (M ++ 1) (free compound) (3) (2S) -1- (1H-indole- 4-yloxy) -3- [3,3
-Bis (4-methoxyphenyl) propyl] amino-2-propanol MS m / z: 461 (M + +1) (4) (2RS) -1- (2-oxo-2,3-dihydro-1H-benz Imidazol-4-yloxy) -3-[(3RS) -1,1-bis (4-methoxyphenyl) -3-butyl] amino-2-propanol MS m / z: 492 (M ++ 1).

【０１２２】 （５） （２Ｒ）−３−［４−ベンジルオキシ−３−（メタンスルホニルアミノ
）フェニル］−１−［（３ＲＳ）−１，１−ビス（４−メトキシフェニル）−３
−ブチル］アミノ−２−プロパノール （６） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−（
メタンスルホニルアミノ）フェニル］−３−ブチル］アミノ−２−プロパノール
IR (KBr): 3440 (br s), 1603 (m), 1508 (m), 1325 (m), 1242 (m), 1151 (s), 1103 (m), 974 (m), 758 (m) cm-1 NMR (CDCl3, δ): 1.11 (3H, d, J=6.2Hz), 2.0-2.2 (2H, m), 2.2-2.9 (3H,
m), 2.97 (6H, s), 3.9-4.0 (3H, br s), 4.1-4.2 (1H, m), 6.88-7.00 (4H, m), 7.10-7.33 (9H, m) MS m/z: 562 (M++1) （７） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−（
アセチルアミノ）フェニル］−１−ヒドロキシ−３−ブチル］アミノ−２−プロ
パノール MS m/z: 506 (M++1) （８） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−（
アセチルアミノ）フェニル］−３−ブチル］アミノ−２−プロパノール MS m/z: 490 (M++1)(5) (2R) -3- [4-benzyloxy-3- (methanesulfonylamino) phenyl] -1-[(3RS) -1,1-bis (4-methoxyphenyl) -3
-Butyl] amino-2-propanol (6) (2S) -1-phenoxy-3-[(3RS) -1,1-bis [4- (
Methanesulfonylamino) phenyl] -3-butyl] amino-2-propanol
IR (KBr): 3440 (br s), 1603 (m), 1508 (m), 1325 (m), 1242 (m), 1151 (s), 1103 (m), 974 (m), 758 (m) cm -1 NMR (CDCl 3 , δ): 1.11 (3H, d, J = 6.2Hz), 2.0-2.2 (2H, m), 2.2-2.9 (3H,
m), 2.97 (6H, s), 3.9-4.0 (3H, br s), 4.1-4.2 (1H, m), 6.88-7.00 (4H, m), 7.10-7.33 (9H, m) MS m / z : 562 (M + +1) (7) (2S) -1-phenoxy-3-[(3RS) -1,1-bis [4- (
Acetylamino) phenyl] -1-hydroxy-3-butyl] amino-2-propanol MS m / z: 506 (M + +1) (8) (2S) -1-phenoxy-3-[(3RS) -1 , 1-bis [4- (
Acetylamino) phenyl] -3-butyl] amino-2-propanol MS m / z: 490 (M ++ 1)

【０１２３】 実施例１４ （１Ｓ）−１−フェノキシ−３−［３，３−ビス（４−メトキシフェニル）−
３−ヒドロキシプロピル］アミノ−２−プロパノール（９３ｍｇ）、ｐ−トルエ
ンスルホン酸水和物（５３ｍｇ）とトルエンの混合物を還流下で１．５時間加熱
し、溶媒を留去し、精製（シリカゲル分取ＴＬＣ、１０％メタノール−ジクロロ
メタン）して、（１Ｓ）−１−フェノキシ−３−［３，３−ビス（４−メトキシ
フェニル）−２−プロペニル］アミノ−２−プロパノール（８０．５ｍｇ）を得
た。 IR (ニート): 3359 (br m), 1604 (s), 1510 (s), 1460 (m), 1248 (s), 1176 (m), 1034 (m), 835 (m), 756 (m), 686 (m) cm-1 NMR (CDCl3+D2O, δ): 2.9-3.1 (2H, m), 3.58 (2H, d, J=7.0Hz), 3.77 (3H, s), 3.82 (3H, s), 3.9-4.0 (2H, m), 4.2-4.3 (1H, m), 6.07 (1H, t, J=7.1Hz), 6.73-7.29 (13H, m)Example 14 (1S) -1-phenoxy-3- [3,3-bis (4-methoxyphenyl)-
A mixture of 3-hydroxypropyl] amino-2-propanol (93 mg), p-toluenesulfonic acid hydrate (53 mg) and toluene was heated under reflux for 1.5 hours, the solvent was distilled off, and purification was performed (silica gel fraction). Preparative TLC, 10% methanol-dichloromethane) to give (1S) -1-phenoxy-3- [3,3-bis (4-methoxyphenyl) -2-propenyl] amino-2-propanol (80.5 mg). Obtained. IR (neat): 3359 (br m), 1604 (s), 1510 (s), 1460 (m), 1248 (s), 1176 (m), 1034 (m), 835 (m), 756 (m) , 686 (m) cm -1 NMR (CDCl 3 + D 2 O, δ): 2.9-3.1 (2H, m), 3.58 (2H, d, J = 7.0Hz), 3.77 (3H, s), 3.82 ( 3H, s), 3.9-4.0 (2H, m), 4.2-4.3 (1H, m), 6.07 (1H, t, J = 7.1Hz), 6.73-7.29 (13H, m)

【０１２４】 実施例１５ （２Ｓ）−１−フェノキシ−３−［３，３−ビス（４−メトキシフェニル）−
３−ヒドロキシプロピル］アミノ−２−プロパノール（３４ｍｇ）、トリエチル
シラン（０．５ｍｌ）とジクロロメタン（１ｍｌ）の混合物に、トリフルオロ酢
酸（０．１ｍｌ）を室温で滴下した。反応混合物を直ちに常法で処理し、シリカ
ゲル分取ＴＬＣ（溶離溶媒：１０％メタノール／ジクロロメタン）で精製して、
（２Ｓ）−１−フェノキシ−３−［３，３−ビス（４−メトキシフェニル）プロ
ピル］アミノ−２−プロパノール・トリフルオロ酢酸塩（２１ｍｇ）を得た。 IR (ニート): 3400 (br m), 2933 (m), 1680 (s), 1604 (m), 1508 (s), 1248 (s), 1203 (m), 1180 (s), 1134 (m), 1036 (m), 829 (m), 756 (m) cm-1 NMR (CDCl3, δ): 2.3-2.5 (2H, m), 2.7-2.9 (2H, m), 2.9-3.1 (2H, m), 3.74 (6H, s), 3.8-4.0 (3H, m), 4.1-4.3 (1H, m), 6.7-6.9 (6H, m), 6.95 (2H, t, J=7.4Hz), 7.10 (4H, d, J=8.5Hz), 7.26 (1H, t, J=7.9Hz) MS m/z: 422 (M++1)Example 15 (2S) -1-phenoxy-3- [3,3-bis (4-methoxyphenyl)-
To a mixture of 3-hydroxypropyl] amino-2-propanol (34 mg), triethylsilane (0.5 ml) and dichloromethane (1 ml) was added dropwise trifluoroacetic acid (0.1 ml) at room temperature. The reaction mixture was immediately processed in the usual manner and purified by silica gel preparative TLC (eluent: 10% methanol / dichloromethane).
(2S) -1-phenoxy-3- [3,3-bis (4-methoxyphenyl) propyl] amino-2-propanol trifluoroacetate (21 mg) was obtained. IR (neat): 3400 (br m), 2933 (m), 1680 (s), 1604 (m), 1508 (s), 1248 (s), 1203 (m), 1180 (s), 1134 (m) , 1036 (m), 829 (m), 756 (m) cm -1 NMR (CDCl 3 , δ): 2.3-2.5 (2H, m), 2.7-2.9 (2H, m), 2.9-3.1 (2H, m), 3.74 (6H, s), 3.8-4.0 (3H, m), 4.1-4.3 (1H, m), 6.7-6.9 (6H, m), 6.95 (2H, t, J = 7.4Hz), 7.10 (4H, d, J = 8.5Hz), 7.26 (1H, t, J = 7.9Hz) MS m / z: 422 (M + +1)

【０１２５】 実施例１６ （２Ｓ）−３−フェノキシ−１，２−エポキシプロパン（０．１１ｇ）、Ｄ−
アラニンビス（４−メトキシフェニル）メチルアミド（０．２５ｇ）とメタノー
ル（４ｍｌ）の混合物を還流下で一夜加熱し、溶媒を留去し、シリカゲルカラム
クロマトグラフィーで精製して、Ｎ−（（２Ｓ）−２−ヒドロキシ−３−フェノ
キシプロピル）−Ｄ−アラニン［ビス（４−メトキシフェニル）メチル］アミド
（２１７ｍｇ）を得た。 IR (KBr): 3290 (s), 1643 (s), 1606 (m), 1512 (s), 1642 (m), 1250 (s),
1176 (m), 1034 (s), 831 (w), 812 (m), 752 (m) cm-1 NMR (CDCl3, δ): 1.27 (3H, d, J=7.2Hz), 2.66 (1H, dd, J=3.8 および 12.0
Hz), 2.80 (1H, dd, J=7.6 および 12.0Hz), 3.24 (1H, quartet, J=6.9Hz), 3.74 (3H, s), 3.78 (3H, s), 3.8-4.0 (3H, m), 6.14 (1H, d, J=8.6Hz), 6.8-
6.9 (6H, m), 6.98 (1H, t, J=7.3Hz), 7.13 (4H, dd, J=2.0 および 8.6Hz),
7.29 (2H, t, J=7.4Hz), 7.71 (1H, d, J=8.6Hz) MS m/z: 465 (M++1)Example 16 (2S) -3-phenoxy-1,2-epoxypropane (0.11 g), D-
A mixture of alanine bis (4-methoxyphenyl) methylamide (0.25 g) and methanol (4 ml) was heated under reflux overnight, the solvent was distilled off, the residue was purified by silica gel column chromatography, and N-((2S)- 2-Hydroxy-3-phenoxypropyl) -D-alanine [bis (4-methoxyphenyl) methyl] amide (217 mg) was obtained. IR (KBr): 3290 (s), 1643 (s), 1606 (m), 1512 (s), 1642 (m), 1250 (s),
1176 (m), 1034 (s), 831 (w), 812 (m), 752 (m) cm -1 NMR (CDCl 3 , δ): 1.27 (3H, d, J = 7.2Hz), 2.66 (1H , dd, J = 3.8 and 12.0
Hz), 2.80 (1H, dd, J = 7.6 and 12.0Hz), 3.24 (1H, quartet, J = 6.9Hz), 3.74 (3H, s), 3.78 (3H, s), 3.8-4.0 (3H, m ), 6.14 (1H, d, J = 8.6Hz), 6.8-
6.9 (6H, m), 6.98 (1H, t, J = 7.3Hz), 7.13 (4H, dd, J = 2.0 and 8.6Hz),
7.29 (2H, t, J = 7.4Hz), 7.71 (1H, d, J = 8.6Hz) MS m / z: 465 (M + +1)

【０１２６】 実施例１７ 水素化アルミニウムリチウム（１０ｍｇ）のテトラヒドロフラン（０．５ｍｌ
）中の懸濁液に、Ｎ−（（２Ｓ）−２−ヒドロキシ−３−フェノキシプロピル）
−Ｄ−アラニン［ビス（４−メトキシフェニル）メチル］アミド（５２．４ｍｇ
）のテトラヒドロフラン中の溶液を窒素流中０℃で滴下した。反応混合物を還流
下で加熱した。２時間後、反応混合物に水素化アルミニウムリチウム（５０ｍｇ
）を窒素流中０℃でさらに加えた。反応混合物を還流下で２．５時間加熱し、常
法で処理し、精製（分取ＴＬＣ、１０％メタノール−酢酸エチル）して、（２Ｓ
）−１−フェノキシ−３−［（２Ｒ）−１−［［ビス（４−メトキシフェニル）
メチル］アミノ］−２−プロピル］アミノ−２−プロパノール（３１．４ｍｇ）
を得た。 IR (ニート): 3316 (br s), 2931 (m), 1606 (m), 1508 (s), 1458 (m), 1292 (s), 1174 (m), 1036 (s), 820 (m), 756 (m) cm-1 NMR (CDCl3, δ): 1.06 (3H, d, J=6.3Hz), 2.46 (1H, dd, J=8.7 および 12.0 Hz), 2.62 (1H, dd, J=4.2 および 12.0Hz), 2.80 (2H, d, J=4.7Hz), 3.76 (6H, s), 3.9-4.1 (3H, m), 4.71 (1H, s), 6.82 (4H, dd, J=2.0 および 6.7Hz), 6.9-7.0 (3H, m), 7.2-7.3 (6H, m) MS m/z: 451 (M++1)Example 17 Lithium aluminum hydride (10 mg) in tetrahydrofuran (0.5 ml)
) Is added to the suspension in N-((2S) -2-hydroxy-3-phenoxypropyl)
-D-alanine [bis (4-methoxyphenyl) methyl] amide (52.4 mg
)) In tetrahydrofuran was added dropwise at 0 ° C. in a stream of nitrogen. The reaction mixture was heated under reflux. After 2 hours, lithium aluminum hydride (50 mg) was added to the reaction mixture.
) Was added at 0 ° C. in a stream of nitrogen. The reaction mixture was heated at reflux for 2.5 hours, treated in the usual manner, purified (prep TLC, 10% methanol-ethyl acetate) and purified by (2S
) -1-Phenoxy-3-[(2R) -1-[[bis (4-methoxyphenyl)
Methyl] amino] -2-propyl] amino-2-propanol (31.4 mg)
Got. IR (neat): 3316 (br s), 2931 (m), 1606 (m), 1508 (s), 1458 (m), 1292 (s), 1174 (m), 1036 (s), 820 (m) , 756 (m) cm -1 NMR (CDCl 3 , δ): 1.06 (3H, d, J = 6.3 Hz), 2.46 (1H, dd, J = 8.7 and 12.0 Hz), 2.62 (1H, dd, J = 4.2 and 12.0Hz), 2.80 (2H, d, J = 4.7Hz), 3.76 (6H, s), 3.9-4.1 (3H, m), 4.71 (1H, s), 6.82 (4H, dd, J = 2.0 And 6.7Hz), 6.9-7.0 (3H, m), 7.2-7.3 (6H, m) MS m / z: 451 (M + +1)

【０１２７】 実施例１８ （２Ｒ）−２−［４−ベンジルオキシ−３−（メタンスルホニルアミノ）フェ
ニル］−２−（トリエチルシリルオキシ）−１−ヨードエタン（１５６ｍｇ）、
［３，３−ビス（４−メトキシフェニル）プロピル］アミン（７５ｍｇ）、Ｎ，
Ｎ−ジイソプロピルエチルアミン（０．１９ｍｌ）とジメチルアセトアミド（０
．７５ｍｌ）の混合物を１１０℃で一夜加熱し、常法で処理した。粗製生成物を
酢酸エチル中４Ｎ塩化水素（２ｍｌ）で処理し、 常法で処理し、分取ＴＬＣ（
１０％メタノール−ジクロロメタン）で精製して、（１Ｒ）−１−［４−ベンジ
ルオキシ−３−（メタンスルホニルアミノ）フェニル］−２−［３，３−ビス（
４−メトキシフェニル）プロピル］アミノエタノール（４７ｍｇ）を得た。 IR (ニート): 3310 (br m), 1608 (w), 1510 (s), 1460 (m), 1329 (m), 1248 (s), 1157 (s), 1120 (s), 1034 (m), 818 (m), 739 (m) cm-1 NMR (CDCl3, δ): 2.16 (2H, quartet, J=7.1Hz), 2.5-2.7 (3H, m), 2.81 (1H, dd, J=3.6 および 12.2Hz), 2.90 (3H, s), 3.79 (6H, s), 3.95 (1H, t,
J=7.9Hz), 4.55 (1H, dd, J=3.5 および 8.9Hz), 5.09 (2H, s), 6.81 (4H, d,
J=8.6Hz), 6.95 (1H, d, J=8.5Hz), 7.13 (5H, d, J=8.6Hz), 7.35 (5H, s), 7.47 (1H, d, J=2.0Hz) MS m/z: 591 (M++1)Example 18 (2R) -2- [4-benzyloxy-3- (methanesulfonylamino) phenyl] -2- (triethylsilyloxy) -1-iodoethane (156 mg);
[3,3-bis (4-methoxyphenyl) propyl] amine (75 mg), N,
N-diisopropylethylamine (0.19 ml) and dimethylacetamide (0
. 75 ml) was heated at 110 ° C. overnight and worked up in the usual manner. The crude product was treated with 4N hydrogen chloride in ethyl acetate (2ml), treated in a conventional manner and preparative TLC (
10% methanol-dichloromethane) to give (1R) -1- [4-benzyloxy-3- (methanesulfonylamino) phenyl] -2- [3,3-bis (
4-methoxyphenyl) propyl] aminoethanol (47 mg) was obtained. IR (neat): 3310 (br m), 1608 (w), 1510 (s), 1460 (m), 1329 (m), 1248 (s), 1157 (s), 1120 (s), 1034 (m) , 818 (m), 739 (m) cm -1 NMR (CDCl 3 , δ): 2.16 (2H, quartet, J = 7.1Hz), 2.5-2.7 (3H, m), 2.81 (1H, dd, J = 3.6 and 12.2Hz), 2.90 (3H, s), 3.79 (6H, s), 3.95 (1H, t,
J = 7.9Hz), 4.55 (1H, dd, J = 3.5 and 8.9Hz), 5.09 (2H, s), 6.81 (4H, d,
J = 8.6Hz), 6.95 (1H, d, J = 8.5Hz), 7.13 (5H, d, J = 8.6Hz), 7.35 (5H, s), 7.47 (1H, d, J = 2.0Hz) MS m / z: 591 (M + +1)

【０１２８】 実施例１９ 下記の化合物を実施例１８と同様にして得た。 （１Ｒ）−１−［４−ベンジルオキシ−３−（メタンスルホニルアミノ）フェ
ニル］−２−［［（３ＲＳ）−１，１−ビス［４−（メトキシカルボニルアミノ
）フェニル］−３−ブチル］アミノ］エタノール 実施例２０ （１Ｒ）−１−［４−ベンジルオキシ−３−（メタンスルホニルアミノ）フェ
ニル］−２−［［３，３−ビス（４−メトキシフェニル）プロピル］アミノ］エ
タノール（３５ｍｇ）を常法で水素化して、（１Ｒ）−１−［４−ヒドロキシ−
３−（メタンスルホニルアミノ）フェニル］−２−［［３，３−ビス（４−メト
キシフェニル）プロピル］アミノ］エタノール（１９．３ｍｇ）を得た。 IR (KBr): 3430 (br m), 1608 (w), 1510 (s), 1319 (m), 1304 (m), 1248 (s)
, 1153 (m), 1034 (m), 825 (m) cm-1 NMR (CDCl3, δ): 2.1-2.3 (2H, m), 2.5-2.7 (2H, m), 2.7-2.9 (2H, m), 2.90 (3H, s), 3.74 (6H, s), 3.83 (1H, t, J=7.8Hz), 4.5-4.7 (1H, m), 6.79
(5H, d, J=8.3Hz), 7.01 (1H, d, J=8.1Hz), 7.13 (4H, d, J=8.4Hz), 7.13 (1H, br s) MS m/z: 501 (M++1)Example 19 The following compound was obtained in the same manner as in Example 18. (1R) -1- [4-benzyloxy-3- (methanesulfonylamino) phenyl] -2-[[(3RS) -1,1-bis [4- (methoxycarbonylamino) phenyl] -3-butyl] Amino] ethanol Example 20 (1R) -1- [4-benzyloxy-3- (methanesulfonylamino) phenyl] -2-[[3,3-bis (4-methoxyphenyl) propyl] amino] ethanol (35 mg ) Is hydrogenated in a conventional manner to give (1R) -1- [4-hydroxy-
3- (Methanesulfonylamino) phenyl] -2-[[3,3-bis (4-methoxyphenyl) propyl] amino] ethanol (19.3 mg) was obtained. IR (KBr): 3430 (br m), 1608 (w), 1510 (s), 1319 (m), 1304 (m), 1248 (s)
, 1153 (m), 1034 (m), 825 (m) cm -1 NMR (CDCl 3 , δ): 2.1-2.3 (2H, m), 2.5-2.7 (2H, m), 2.7-2.9 (2H, m), 2.90 (3H, s), 3.74 (6H, s), 3.83 (1H, t, J = 7.8Hz), 4.5-4.7 (1H, m), 6.79
(5H, d, J = 8.3Hz), 7.01 (1H, d, J = 8.1Hz), 7.13 (4H, d, J = 8.4Hz), 7.13 (1H, br s) MS m / z: 501 (M + +1)

【０１２９】 実施例２１ （２Ｓ）−３−（４−ベンジルオキシ−３−ニトロフェノキシ）−１，２−エ
ポキシプロパン（１９７ｍｇ）、Ｎ−ベンジル−［３，３−ビス（４−メトキシ
フェニル）プロピル］アミン（２３６ｍｇ）とエタノール（３ｍｌ）の混合物を
還流下で１２時間加熱した。反応混合物に鉄粉末、塩化アンモニウムと水を加え
、１時間連続加熱した。反応混合物を濾過し、常法で処理して、（２Ｓ）−１−
（３−アミノ−４−ベンジルオキシフェノキシ）−３−［Ｎ−ベンジル−［３，
３−ビス（４−メトキシフェニル）プロピル］アミノ］−２−プロパノール（４
１２．７ｍｇ）を得た。 NMR (CDCl3, δ): 2.1-2.3 (2H, m), 2.4-2.7 (4H, m), 3.50 (1H, d, J=14Hz), 3.75 (6H, s), 3.7-4.0 (5H, m), 5.01 (2H, s), 6.15-6.4 (2H, m),
6.71-6.80 (5H, m), 7.03-7.08 (4H, m), 7.2-7.4 (10H, m) MS m/z: 633 (M++1)Example 21 (2S) -3- (4-Benzyloxy-3-nitrophenoxy) -1,2-epoxypropane (197 mg), N-benzyl- [3,3-bis (4-methoxyphenyl) A mixture of [propyl] amine (236 mg) and ethanol (3 ml) was heated under reflux for 12 hours. Iron powder, ammonium chloride and water were added to the reaction mixture, and the mixture was heated continuously for 1 hour. The reaction mixture was filtered and treated in the usual manner to give (2S) -1-
(3-amino-4-benzyloxyphenoxy) -3- [N-benzyl- [3,
3-bis (4-methoxyphenyl) propyl] amino] -2-propanol (4
12.7 mg). NMR (CDCl 3 , δ): 2.1-2.3 (2H, m), 2.4-2.7 (4H, m), 3.50 (1H, d, J = 14Hz), 3.75 (6H, s), 3.7-4.0 (5H, m), 5.01 (2H, s), 6.15-6.4 (2H, m),
6.71-6.80 (5H, m), 7.03-7.08 (4H, m), 7.2-7.4 (10H, m) MS m / z: 633 (M + +1)

【０１３０】 実施例２２ 下記の化合物を実施例２１と同様にして得た。 （１） （２Ｓ）−１−（３−アミノ−４−ベンジルオキシフェノキシ）−３−
［Ｎ−ベンジル−［４，４−ビス（４−メトキシフェニル）ブチル］アミノ］−
２−プロパノール NMR (CDCl3, δ): 1.45 (2H, quintet, J=7.5Hz), 1.93 (2H, quintet), 2.3-
2.6 (4H, m), 3.44 (1H, d, J=13.5Hz), 3.69-4.1 (4H, m), 3.76 (6H, s), 5.00 (2H, s), 6.17 (1H, dd, J=2.9 および 8.8Hz), 6.31 (1H, d, J=2.8Hz),
6.73 (1H, d, J=8.8Hz), 6.79 (4H, d, J=8.7Hz), 7.07 (4H, d, J=7.7Hz), 7.2
-7.4 (10H, m) MS m/z: 647 (M++1) （２） （１ＲＳ）−１−（３−アミノ−４−ベンジルオキシフェニル）−２−
［Ｎ−ベンジル−［４，４−ビス（４−メトキシフェニル）ブチル］アミノ］エ
タノール NMR (CDCl3, δ): 1.4-1.6 (2H, m), 1.8-2.1 (2H, m), 2.4-2.7 (4H, m), 3.41 (1H, d, J=13.5Hz), 3.76 (6H, s), 3.7-3.9 (2H, m), 4.51 (1H, t), 5.05 (2H, s), 6.50-6.65 (2H, m), 6.75-6.85 (5H, m), 7.05-7.15 (4H, m),
7.2-7.5 (10H, m) MS m/z: 617 (M++1) （３） （２Ｓ）−１−フェノキシ−３−［［３，３−ビス（４−エトキシフェ
ニル）プロピル］アミノ］−２−プロパノール IR (ニート): 3305 (br m), 1604 (m), 1510 (s), 1392 (w), 1300 (w), 1246 (s), 1176 (m), 1047 (s), 822 (m), 756 (m) cm-1 NMR (MeOH-d6, δ): 1.34 (6H, t, J=7.0Hz), 2.2-2.4 (2H, m), 2.6-2.9 (4H, m), 3.97 (4H, quartet, J=7.0Hz), 3.9-4.1 (4H, m), 6.80 (4H, d, J=8.6Hz),
6.89-7.0 (3H, m), 7.14 (4H, d, J=8.6Hz), 7.26 (2H, t, J=7.9Hz) MS m/z: 450 (M++1)Example 22 The following compound was obtained in the same manner as in Example 21. (1) (2S) -1- (3-amino-4-benzyloxyphenoxy) -3-
[N-benzyl- [4,4-bis (4-methoxyphenyl) butyl] amino]-
2-propanol NMR (CDCl 3 , δ): 1.45 (2H, quintet, J = 7.5Hz), 1.93 (2H, quintet), 2.3-
2.6 (4H, m), 3.44 (1H, d, J = 13.5Hz), 3.69-4.1 (4H, m), 3.76 (6H, s), 5.00 (2H, s), 6.17 (1H, dd, J = 2.9 and 8.8Hz), 6.31 (1H, d, J = 2.8Hz),
6.73 (1H, d, J = 8.8Hz), 6.79 (4H, d, J = 8.7Hz), 7.07 (4H, d, J = 7.7Hz), 7.2
-7.4 (10H, m) MS m / z: 647 (M + +1) (2) (1RS) -1- (3-amino-4-benzyloxyphenyl) -2-
[N-benzyl- [4,4-bis (4-methoxyphenyl) butyl] amino] ethanol NMR (CDCl 3 , δ): 1.4-1.6 (2H, m), 1.8-2.1 (2H, m), 2.4- 2.7 (4H, m), 3.41 (1H, d, J = 13.5Hz), 3.76 (6H, s), 3.7-3.9 (2H, m), 4.51 (1H, t), 5.05 (2H, s), 6.50 -6.65 (2H, m), 6.75-6.85 (5H, m), 7.05-7.15 (4H, m),
7.2-7.5 (10H, m) MS m / z: 617 (M + +1) (3) (2S) -1-phenoxy-3-[[3,3-bis (4-ethoxyphenyl) propyl] amino] -2-propanol IR (neat): 3305 (br m), 1604 (m), 1510 (s), 1392 (w), 1300 (w), 1246 (s), 1176 (m), 1047 (s), 822 (m), 756 (m) cm -1 NMR (MeOH-d 6 , δ): 1.34 (6H, t, J = 7.0Hz), 2.2-2.4 (2H, m), 2.6-2.9 (4H, m ), 3.97 (4H, quartet, J = 7.0Hz), 3.9-4.1 (4H, m), 6.80 (4H, d, J = 8.6Hz),
6.89-7.0 (3H, m), 7.14 (4H, d, J = 8.6Hz), 7.26 (2H, t, J = 7.9Hz) MS m / z: 450 (M + +1)

【０１３１】 実施例２３ （２Ｓ）−１−（３−アミノ−４−ベンジルオキシフェノキシ）−３−［Ｎ−
ベンジル−［３，３−ビス（４−メトキシフェニル）プロピル］アミノ］−２−
プロパノール（５９ｍｇ）、ピリジン（０．１ｍｌ）とジクロロメタン（１ｍｌ
）の混合物に、塩化メタンスルホニル（２７μｌ）を０℃で加え、３０分間攪拌
した。反応混合物を常法で処理した。粗製生成物を常法で水素化して、（２Ｓ）
−１−［４−ヒドロキシ−３−（メタンスルホニルアミノ）フェノキシ］−３−
［［３，３−ビス（４−メトキシフェニル）プロピル］アミノ］−２−プロパノ
ール（１７．２ｍｇ）を得た。 IR (KBr): 3440 (br s), 1610 (w), 1510 (s), 1460 (m), 1325 (m), 1248 (s), 1176 (m), 1151 (m), 1115 (w), 1034 (m), 816 (m) cm-1 NMR (MeOH-d4, δ): 2.1-2.3 (2H, m), 2.5-2.8 (4H, m), 2.91 (3H, s), 3.74
(6H, s), 3.8-4.1 (4H, m), 6.6-6.7 (1H, m), 6.7-6.9 (5H, m), 6.97 (1H, d,
J=2.7Hz), 7.1-7.2 (4H, m) MS m/z: 531 (M++1)Example 23 (2S) -1- (3-Amino-4-benzyloxyphenoxy) -3- [N-
Benzyl- [3,3-bis (4-methoxyphenyl) propyl] amino] -2-
Propanol (59 mg), pyridine (0.1 ml) and dichloromethane (1 ml)
Methanesulfonyl chloride (27 μl) was added to the mixture at 0 ° C. and stirred for 30 minutes. The reaction mixture was worked up in the usual way. The crude product is hydrogenated in a conventional manner to give (2S)
-1- [4-hydroxy-3- (methanesulfonylamino) phenoxy] -3-
[[3,3-Bis (4-methoxyphenyl) propyl] amino] -2-propanol (17.2 mg) was obtained. IR (KBr): 3440 (br s), 1610 (w), 1510 (s), 1460 (m), 1325 (m), 1248 (s), 1176 (m), 1151 (m), 1115 (w) , 1034 (m), 816 (m) cm -1 NMR (MeOH-d 4 , δ): 2.1-2.3 (2H, m), 2.5-2.8 (4H, m), 2.91 (3H, s), 3.74
(6H, s), 3.8-4.1 (4H, m), 6.6-6.7 (1H, m), 6.7-6.9 (5H, m), 6.97 (1H, d,
J = 2.7Hz), 7.1-7.2 (4H, m) MS m / z: 531 (M + +1)

【０１３２】 実施例２４ 下記の化合物を実施例２３と同様にして得た。 （１） （１Ｒ）−１−［４−ヒドロキシ−３−（メタンスルホニルアミノ）フ
ェニル］−２−［［３，３−ビス［４−［（メトキシカルボニル）アミノ］フェ
ニル］プロピル］アミノ］エタノール MS m/z: 587 (M++1) （２） （２Ｓ）−１−［（４−ヒドロキシ−３−（メタンスルホニルアミノ）
フェノキシ］−３−［［３，３−ビス［４−［（メトキシカルボニル）アミノ］
フェニル］プロピル］アミノ］−２−プロパノール MS m/z: 617 (M++1) （３） （２Ｓ）−１−［４−ヒドロキシ−３−（メタンスルホニルアミノ）フ
ェノキシ］−３−［４，４−ビス（４−メトキシフェニル）ブチル］アミノ−２
−プロパノール IR (KBr): 3480 (br m), 1612 (m), 1512 (s), 1460 (m), 1321 (w), 1248 (s)
, 1178 (m), 1113 (m), 1034 (m), 826 (m) cm-1 NMR (MeOH-d4, δ): 1.4-1.6 (2H, m), 1.9-2.1 (2H, m), 2.6-2.8 (4H, m),
2.89 (3H, s), 3.73 (6H, s), 3.8-4.1 (4H, m), 6.61 (1H, dd, J=2.9 および
8.8Hz), 6.76 (1H, d, J=8.5Hz), 6.80 (4H, d, J=8.6Hz), 6.96 (1H, d, J=2.9
Hz), 7.13 (4H, d, J=8.6Hz) MS m/z: 545 (M++1) （４） （１ＲＳ）−１−［４−ヒドロキシ−３−（メタンスルホニルアミノ）
フェニル］−２−［［４，４−ビス（４−メトキシフェニル）ブチル］アミノ］
エタノール IR (KBr): 3420 (br m), 1560 (m), 1512 (s), 1321 (m), 1248 (s), 1153 (m), 1113 (w), 1034 (m), 817(m) cm-1 NMR (MeOH-d4, δ): 1.4-1.7 (2H, m), 1.9-2.1 (2H, m), 2.7-2.9 (4H, m),
2.90 (3H, s), 3.73 (6H, s), 3.7-3.9 (1H, m), 4.6-4.8 (1H, m), 6.81 (4H,
d, J=8.7Hz), 6.85 (1H, m), 7.05 (1H, m), 7.14 (4H, d, J=8.6Hz), 7.34 (1H, s) MS m/z: 515 (M++1)Example 24 The following compound was obtained in the same manner as in Example 23. (1) (1R) -1- [4-hydroxy-3- (methanesulfonylamino) phenyl] -2-[[3,3-bis [4-[(methoxycarbonyl) amino] phenyl] propyl] amino] ethanol MS m / z: 587 (M + +1) (2) (2S) -1-[(4-hydroxy-3- (methanesulfonylamino)
Phenoxy] -3-[[3,3-bis [4-[(methoxycarbonyl) amino]
Phenyl] propyl] amino] -2-propanol MS m / z: 617 (M + +1) (3) (2S) -1- [4-hydroxy-3- (methanesulfonylamino) phenoxy] -3- [4 , 4-Bis (4-methoxyphenyl) butyl] amino-2
−Propanol IR (KBr): 3480 (br m), 1612 (m), 1512 (s), 1460 (m), 1321 (w), 1248 (s)
, 1178 (m), 1113 (m), 1034 (m), 826 (m) cm -1 NMR (MeOH-d 4 , δ): 1.4-1.6 (2H, m), 1.9-2.1 (2H, m) , 2.6-2.8 (4H, m),
2.89 (3H, s), 3.73 (6H, s), 3.8-4.1 (4H, m), 6.61 (1H, dd, J = 2.9 and
8.8Hz), 6.76 (1H, d, J = 8.5Hz), 6.80 (4H, d, J = 8.6Hz), 6.96 (1H, d, J = 2.9
Hz), 7.13 (4H, d, J = 8.6 Hz) MS m / z: 545 (M ++ 1) (4) (1RS) -1- [4-hydroxy-3- (methanesulfonylamino)
Phenyl] -2-[[4,4-bis (4-methoxyphenyl) butyl] amino]
Ethanol IR (KBr): 3420 (br m), 1560 (m), 1512 (s), 1321 (m), 1248 (s), 1153 (m), 1113 (w), 1034 (m), 817 (m ) cm -1 NMR (MeOH-d 4 , δ): 1.4-1.7 (2H, m), 1.9-2.1 (2H, m), 2.7-2.9 (4H, m),
2.90 (3H, s), 3.73 (6H, s), 3.7-3.9 (1H, m), 4.6-4.8 (1H, m), 6.81 (4H,
d, J = 8.7Hz), 6.85 (1H, m), 7.05 (1H, m), 7.14 (4H, d, J = 8.6Hz), 7.34 (1H, s) MS m / z: 515 (M + + 1)

【０１３３】 実施例２５ （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３，３−ビス（４−メト
キシフェニル）プロピル］アミノ］−２−プロパノール（４７ｍｇ）とジクロロ
メタン（１ｍｌ）の溶液に、１Ｍ三臭化ホウ素−ジクロロメタン溶液（０．２８
ｍｌ）を−７８℃で加えた。反応混合物を０℃で５０分間攪拌し、常法で処理し
て、（２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３，３−ビス（４−ヒ
ドロキシフェニル）プロピル］アミノ］−２−プロパノール（４４ｍｇ）を得た
。 MS m/z: 484 (M++1) 実施例２６ （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３，３−ビス（４−ヒド
ロキシフェニル）プロピル］アミノ］−２−プロパノール（４０ｍｇ）、Ｎ，Ｎ
−ジイソプロピルエチルアミン（４３μｌ）とジクロロメタン（１ｍｌ）の混合
物に、無水トリフルオロメタンスルホン酸（３１μｌ）を−７８℃で加えた。反
応混合物を常法で処理した。得られた粗製生成物、酢酸パラジウム（５．６ｍｇ
）、１，３−ビス（ジフェニルホスフィノ）プロパン（１０．２ｍｇ）、トリエ
チルアミン（４６μｌ）、Ｎ，Ｎ−ジメチルホルムアミド（１ｍｌ）とメタノー
ル（０．５ｍｌ）の混合物を１００℃で一酸化炭素雰囲気下（１ａｔｍ）で３．
５時間攪拌し、常法で処理し、分取ＴＬＣ（ヘキサン：酢酸エチル＝３：１）で
精製して、（２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３，３−ビス［
４−（メトキシカルボニル）フェニル］プロピル］アミノ］−２−プロパノール
（２１ｍｇ）を得た。 MS m/z: 568 (M++1)Example 25 (2S) -1-phenoxy-3- [N-benzyl- [3,3-bis (4-methoxyphenyl) propyl] amino] -2-propanol (47 mg) and dichloromethane (1 ml) A 1M boron tribromide-dichloromethane solution (0.28
ml) at -78 ° C. The reaction mixture is stirred at 0 ° C. for 50 minutes, treated in the usual manner and treated with (2S) -1-phenoxy-3- [N-benzyl- [3,3-bis (4-hydroxyphenyl) propyl] amino]- 2-propanol (44 mg) was obtained. MS m / z: 484 (M ++ 1) Example 26 (2S) -1-phenoxy-3- [N-benzyl- [3,3-bis (4-hydroxyphenyl) propyl] amino] -2-propanol (40 mg), N, N
-To a mixture of diisopropylethylamine (43 µl) and dichloromethane (1 ml) was added trifluoromethanesulfonic anhydride (31 µl) at -78 ° C. The reaction mixture was worked up in the usual way. The obtained crude product, palladium acetate (5.6 mg
), 1,3-bis (diphenylphosphino) propane (10.2 mg), a mixture of triethylamine (46 μl), N, N-dimethylformamide (1 ml) and methanol (0.5 ml) at 100 ° C. in a carbon monoxide atmosphere. 2. At the bottom (1 atm).
The mixture was stirred for 5 hours, treated in a conventional manner, and purified by preparative TLC (hexane: ethyl acetate = 3: 1) to give (2S) -1-phenoxy-3- [N-benzyl- [3,3-bis [
4- (Methoxycarbonyl) phenyl] propyl] amino] -2-propanol (21 mg) was obtained. MS m / z: 568 (M + +1)

【０１３４】 実施例２７ メタノール（１０ｍｌ）中のＮ−［５−［（２Ｓ）−３−［Ｎ−ベンジル−［
（１ＲＳ）−３，３−ビス（４−ヒドロキシフェニル）−１−メチルプロピル］
アミノ］−２−ヒドロキシプロポキシ］−２−ベンジルオキシフェニル］メタン
スルホンアミド（１２０ｍｇ）と１０％パラジウム活性炭（５０％湿潤、３０ｍ
ｇ）を室温で大気圧の水素存在下で３時間攪拌し、濾過した。真空中で濾液から
溶媒を留去し、酢酸エチル中４Ｎ塩化水素で処理して、Ｎ−［５−［（２Ｓ）−
３−［［（１ＲＳ）−３，３−ビス（４−ヒドロキシフェニル）−１−メチルプ
ロピル］アミノ］−２−ヒドロキシプロポキシ］−２−ヒドロキシフェニル］メ
タンスルホンアミド塩酸塩（５０ｍｇ）を得た。 MS m/z: 516 (M++1) (遊離化合物)Example 27 N- [5-[(2S) -3- [N-benzyl- [] in methanol (10 ml)
(1RS) -3,3-bis (4-hydroxyphenyl) -1-methylpropyl]
Amino] -2-hydroxypropoxy] -2-benzyloxyphenyl] methanesulfonamide (120 mg) and 10% palladium on activated carbon (50% wet, 30 m
g) was stirred at room temperature in the presence of hydrogen at atmospheric pressure for 3 hours and filtered. The solvent was evaporated from the filtrate in vacuo and treated with 4N hydrogen chloride in ethyl acetate to give N- [5-[(2S)-
3-[[(1RS) -3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amino] -2-hydroxypropoxy] -2-hydroxyphenyl] methanesulfonamide hydrochloride (50 mg) was obtained. . MS m / z: 516 (M + +1) (free compound)

【０１３５】 実施例２８ 下記の化合物を実施例２７と同様にして得た。 Ｎ−［５−［（２Ｓ）−３−［［（１ＲＳ）−３，３−ビス（４−メトキシフ
ェニル）−１−メチルプロピル］アミノ］−２−ヒドロキシプロポキシ］−２−
ヒドロキシフェニル］メタンスルホンアミド塩酸塩 MS m/z: 544 (M++1) (遊離化合物)Example 28 The following compound was obtained in the same manner as in Example 27. N- [5-[(2S) -3-[[(1RS) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amino] -2-hydroxypropoxy] -2-
[Hydroxyphenyl] methanesulfonamide hydrochloride MS m / z: 544 (M + +1) (free compound)

【０１３６】 実施例２９ （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３，３−ビス［４−（メ
トキシカルボニル）フェニル］プロピル］アミノ］−２−プロパノール（１４ｍ
ｇ）を常法によって水酸化ナトリウムで処理し、常法で水素化して、（２Ｓ）−
１−フェノキシ−３−［３，３−ビス（４−カルボキシフェニル）プロピル］ア
ミノ−２−プロパノール（１２ｍｇ）を得た。 MS m/z: 450 (M++1) 実施例３０ （２Ｓ）−３−フェノキシ−１，２−エポキシプロパン（０．３６ｇ）, Ｎ−
ベンジル−［３，３−ビス［４−［（メトキシカルボニル）アミノ］フェニル］
プロピル］アミン（０．９７ｇ）とエタノール（１０ｍｌ）の混合物を還流下で
１２時間加熱し、室温まで冷却した。反応混合物に、１０％パラジウム炭（５０
％湿潤、０．４ｇ）、１，４−ジオキサン中４Ｎ塩化水素（１．１ｍｌ）とメタ
ノール（５ｍｌ）を加えた。混合物を水素雰囲気下（１ａｔｍ）で３．５時間攪
拌し、濾過し、酢酸エチルで希釈し、重炭酸ナトリウム水溶液で洗浄して中和し
、有機層から溶媒を留去した。粗製生成物をシリカゲルカラムクロマトグラフィ
ー（ジクロロメタン：メタノール：濃アンモニア水＝２０：１：０．０５）で精
製して、（２Ｓ）−１−フェノキシ−３−［［３，３−ビス［４−［（メトキシ
カルボニル）アミノ］フェニル］プロピル］アミノ］−２−プロパノールを得て
、これを、常法で、対応する塩酸塩（０．７１ｇ）に転換した。 IR (KBr): 3400 (br m), 1711 (s), 1599 (m), 1537 (s),1317 (m), 1238 (s),
1072 (m), 758 (m) cm-1 NMR (MeOH-d4, δ): 2.3-2.5 (2H, m), 2.9-3.3 (4H, m), 3.65 (3H, s), 3.71
(3H, s), 3.9-4.00 (3H, m), 4.1-4.3 (1H, m), 6.91-6.98 (3H, m), 7.18-7.39
(10H, m) MS m/z: 508 (M++1) (遊離化合物)Example 29 (2S) -1-phenoxy-3- [N-benzyl- [3,3-bis [4- (methoxycarbonyl) phenyl] propyl] amino] -2-propanol (14 m
g) is treated with sodium hydroxide in a conventional manner and hydrogenated in a conventional manner to give (2S)-
1-phenoxy-3- [3,3-bis (4-carboxyphenyl) propyl] amino-2-propanol (12 mg) was obtained. MS m / z: 450 (M + +1) Example 30 (2S) -3-phenoxy-1,2-epoxypropane (0.36 g), N-
Benzyl- [3,3-bis [4-[(methoxycarbonyl) amino] phenyl]
A mixture of [propyl] amine (0.97 g) and ethanol (10 ml) was heated under reflux for 12 hours and cooled to room temperature. Add 10% palladium on charcoal (50
% Wet, 0.4 g), 4N hydrogen chloride in 1,4-dioxane (1.1 ml) and methanol (5 ml) were added. The mixture was stirred under a hydrogen atmosphere (1 atm) for 3.5 hours, filtered, diluted with ethyl acetate, washed with aqueous sodium bicarbonate and neutralized, and the organic layer was evaporated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol: aqueous ammonia = 20: 1: 0.05) to give (2S) -1-phenoxy-3-[[3,3-bis [4- [(Methoxycarbonyl) amino] phenyl] propyl] amino] -2-propanol was obtained, which was converted to the corresponding hydrochloride (0.71 g) in a conventional manner. IR (KBr): 3400 (br m), 1711 (s), 1599 (m), 1537 (s), 1317 (m), 1238 (s),
1072 (m), 758 (m) cm -1 NMR (MeOH-d 4 , δ): 2.3-2.5 (2H, m), 2.9-3.3 (4H, m), 3.65 (3H, s), 3.71
(3H, s), 3.9-4.00 (3H, m), 4.1-4.3 (1H, m), 6.91-6.98 (3H, m), 7.18-7.39
(10H, m) MS m / z: 508 (M + +1) (free compound)

【０１３７】 実施例３１ 下記の化合物を実施例３０と同様にして得た。 （２Ｓ）−１−（４−ヒドロキシフェノキシ）−３−［（３ＲＳ）−１，１−
ビス（４−メトキシフェニル）−３−ブチル］アミノ−２−プロパノール MS m/z: 452 (M++1) 実施例３２ 下記の化合物を製造例１６と同様にして得た。 （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，１−ビ
ス（４−アミノフェニル）−１−ヒドロキシ−３−ブチル］アミノ］−２−プロ
パノール MS m/z: 512 (M++1)Example 31 The following compound was obtained in the same manner as in Example 30. (2S) -1- (4-hydroxyphenoxy) -3-[(3RS) -1,1-
Bis (4-methoxyphenyl) -3-butyl] amino-2-propanol MS m / z: 452 (M ++ 1) Example 32 The following compound was obtained in the same manner as in Production Example 16. (2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1,1-bis (4-aminophenyl) -1-hydroxy-3-butyl] amino] -2-propanol MS m / z : 512 (M + +1)

【０１３８】 実施例３３ （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，１−ビ
ス（４−アミノフェニル）−１−ヒドロキシ−３−ブチル］アミノ］−２−プロ
パノール（１００ｍｇ）、ピリジン（４８μｌ）とジクロロメタン（２ｍｌ）の
混合物に、クロロ炭酸メチル（３３μｌ）を０℃で加えた。反応混合物を常法で
処理して、（２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１
，１−ビス［４−［（メトキシカルボニル）アミノ］フェニル］−１−ヒドロキ
シ−３−ブチル］アミノ］−２−プロパノール（１２５ｍｇ）を得た。 MS m/z: 628 (M++1)Example 33 (2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1,1-bis (4-aminophenyl) -1-hydroxy-3-butyl] amino] -2 -To a mixture of propanol (100 mg), pyridine (48 μl) and dichloromethane (2 ml) at 0 ° C. was added methyl chlorocarbonate (33 μl). The reaction mixture was treated in the usual manner to give (2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1
, 1-Bis [4-[(methoxycarbonyl) amino] phenyl] -1-hydroxy-3-butyl] amino] -2-propanol (125 mg) was obtained. MS m / z: 628 (M + +1)

【０１３９】 実施例３４ 下記の化合物を実施例３３と同様にして得た。 （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，１−ビ
ス［４−［Ｎ−メチル−（メトキシカルボニル）アミノ］フェニル］−１−ヒド
ロキシ−３−ブチル］アミノ］−２−プロパノール MS m/z: 656 (M++1)Example 34 The following compounds were obtained according to a similar manner to that of Example 33. (2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1,1-bis [4- [N-methyl- (methoxycarbonyl) amino] phenyl] -1-hydroxy-3-butyl] Amino] -2-propanol MS m / z: 656 (M ++ 1)

【０１４０】 実施例３５ （２Ｓ）−１−フェノキシ−３−［Ｎ−（ベンジル−［（３ＲＳ）−１，１−
ビス［４−［（メトキシカルボニル）アミノ］フェニル］−１−ヒドロキシ−３
−ブチル］アミノ］−２−プロパノール（９９ｍｇ）を常法で水素化して、（２
Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−［（メトキシカ
ルボニル）アミノ］フェニル］−３−ブチル］アミノ−２−プロパノール（５８
ｍｇ）を得た。 MS m/z: 522 (M++1) 実施例３６ 下記の化合物を製造例１８と同様にして得た。 （１） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−［
（エトキシカルボニル）アミノ］フェニル］−３−ブチル］アミノ−２−プロパ
ノール塩酸塩 MS m/z: 550 (M++1) (遊離化合物) （２） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−［
（トリフルオロアセチル）アミノ］フェニル］−１−ヒドロキシ−３−ブチル］
アミノ−２−プロパノール塩酸塩 MS m/z: 614 (M++1) (遊離化合物) （３） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−（
プロピオニルアミノ）フェニル］−３−ブチル］アミノ−２−プロパノール MS m/z: 518 (M++1)Example 35 (2S) -1-phenoxy-3- [N- (benzyl-[(3RS) -1,1-
Bis [4-[(methoxycarbonyl) amino] phenyl] -1-hydroxy-3
-Butyl] amino] -2-propanol (99 mg) was hydrogenated in a conventional manner to give (2
S) -1-Phenoxy-3-[(3RS) -1,1-bis [4-[(methoxycarbonyl) amino] phenyl] -3-butyl] amino-2-propanol (58
mg). MS m / z: 522 (M + +1) Example 36 The following compound was obtained in the same manner as in Production Example 18. (1) (2S) -1-phenoxy-3-[(3RS) -1,1-bis [4- [
(Ethoxycarbonyl) amino] phenyl] -3-butyl] amino-2-propanol hydrochloride MS m / z: 550 (M ++ 1) (free compound) (2) (2S) -1-phenoxy-3- [ (3RS) -1,1-bis [4- [
(Trifluoroacetyl) amino] phenyl] -1-hydroxy-3-butyl]
Amino-2-propanol hydrochloride MS m / z: 614 (M + +1) (free compound) (3) (2S) -1-phenoxy-3-[(3RS) -1,1-bis [4- (
Propionylamino) phenyl] -3-butyl] amino-2-propanol MS m / z: 518 (M ++ 1)

【０１４１】 実施例３７ （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，１−ビ
ス（４−アミノフェニル）−１−ヒドロキシ−３−ブチル］アミノ］−２−プロ
パノール（１２０ｍｇ）、酢酸（３ｍｌ）と水（０．６ｍｌ）の混合物にシアン
酸カリウム（７７ｍｇ）を加えた。反応混合物を常法で処理して、（２Ｓ）−１
−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，１−ビス（４−ウレイ
ドフェニル）−１−ヒドロキシ−３−ブチル］アミノ］−２−プロパノール（６
５ｍｇ）を得た。 MS m/z: 598 (M++1) 実施例３８ 蟻酸（６５０μｌ）と無水酢酸（５４０μｌ）を混合し、室温で３０分間開始
した。混合物を（２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）
−１，１−ビス（４−アミノフェニル）−１−ヒドロキシ−３−ブチル］アミノ
］−２−プロパノール（３２５ｍｇ）のジクロロメタン（２ｍｌ）中の溶液に０
℃で加え、室温まで加温し、常法で処理した。粗製生成物をメタノール（４ｍｌ
）中の炭酸カリウム（０．６２ｇ）とともに室温で４時間攪拌し、常法で処理し
て、（２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，１−
ビス［４−（ホルミルアミノ）フェニル］−１−ヒドロキシ−３−ブチル］アミ
ノ］−２−プロパノール（３４２．４ｍｇ）を得た。 MS m/z: 568 (M++1)Example 37 (2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1,1-bis (4-aminophenyl) -1-hydroxy-3-butyl] amino] -2 -To a mixture of propanol (120 mg), acetic acid (3 ml) and water (0.6 ml) was added potassium cyanate (77 mg). The reaction mixture was treated in a conventional manner to give (2S) -1
-Phenoxy-3- [N-benzyl-[(3RS) -1,1-bis (4-ureidophenyl) -1-hydroxy-3-butyl] amino] -2-propanol (6
5 mg). MS m / z: 598 (M + +1) Example 38 Formic acid (650 μl) and acetic anhydride (540 μl) were mixed and started at room temperature for 30 minutes. The mixture was treated with (2S) -1-phenoxy-3- [N-benzyl-[(3RS)
-1,1-bis (4-aminophenyl) -1-hydroxy-3-butyl] amino] -2-propanol (325 mg) in dichloromethane (2 ml).
C., warmed to room temperature, and treated in a conventional manner. The crude product was treated with methanol (4 ml
)) With potassium carbonate (0.62 g) in the mixture was stirred at room temperature for 4 hours, treated in a conventional manner to give (2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1,1-
Bis [4- (formylamino) phenyl] -1-hydroxy-3-butyl] amino] -2-propanol (342.4 mg) was obtained. MS m / z: 568 (M + +1)

【０１４２】 実施例３９ 水素化アルミニウムリチウム（０．１ｇ）とテトラヒドロフラン（１ｍｌ）の
混合物に、（２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１
，１−ビス［４−（ホルミルアミノ）フェニル］−１−ヒドロキシ−３−ブチル
］アミノ］−２−プロパノール（２８０ｍｇ）のテトラヒドロフラン（２ｍｌ）
中の溶液を０℃で滴下した。反応混合物を２．５時間攪拌し、常法で処理して、
（２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，１−ビス
［４−（メチルアミノ）フェニル］−１−ヒドロキシ−３−ブチル］アミノ］−
２−プロパノール（２７３ｍｇ）を得た。 MS m/z: 540 (M++1) 実施例４０ （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス［４−［Ｎ−メ
チル−（メトキシカルボニル）アミノ］フェニル］−１−ヒドロキシ−３−ブチ
ル］アミノ−２−プロパノール（３０ｍｇ）を、常法による水素化によって、（
２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［（３ＲＳ）−１，１−ビス［
４−［Ｎ−メチル−（メトキシカルボニル）アミノ］フェニル］−１−ヒドロキ
シ−３−ブチル］アミノ］−２−プロパノール（６０ｍｇ） から得た。 MS m/z: 566 (M++1)Example 39 A mixture of lithium aluminum hydride (0.1 g) and tetrahydrofuran (1 ml) was added to (2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1
1,1-Bis [4- (formylamino) phenyl] -1-hydroxy-3-butyl] amino] -2-propanol (280 mg) in tetrahydrofuran (2 ml)
The solution therein was added dropwise at 0 ° C. The reaction mixture was stirred for 2.5 hours, worked up in the usual way,
(2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1,1-bis [4- (methylamino) phenyl] -1-hydroxy-3-butyl] amino]-
2-Propanol (273 mg) was obtained. MS m / z: 540 (M ++ 1) Example 40 (2S) -1-phenoxy-3-[(3RS) -1,1-bis [4- [N-methyl- (methoxycarbonyl) amino] phenyl ] -1-Hydroxy-3-butyl] amino-2-propanol (30 mg) was hydrogenated by conventional methods to give (
2S) -1-phenoxy-3- [N-benzyl-[(3RS) -1,1-bis [
4- [N-methyl- (methoxycarbonyl) amino] phenyl] -1-hydroxy-3-butyl] amino] -2-propanol (60 mg). MS m / z: 566 (M + +1)

【０１４３】 実施例４１ （１Ｒ）−１−［４−ヒドロキシ−３−（メタンスルホニルアミノ）フェニル
］−２−［［（３ＲＳ）−１，１−ビス［４−［（メトキシカルボニル）アミノ
］フェニル］−３−ブチル］アミノ］エタノール（１４．３ｍｇ）を、常法によ
る水素化によって、（１Ｒ）−１−［４−ベジルオキシ−３−（メタンスルホニ
ルアミノ）フェニル］−２−［［（３ＲＳ）−１，１−ビス［４−［（メトキシ
カルボニル）アミノ］フェニル］−３−ブチル］アミノ］エタノール（４６．１
ｍｇ）から得た。 MS m/z: 601 (M++1)Example 41 (1R) -1- [4-Hydroxy-3- (methanesulfonylamino) phenyl] -2-[[(3RS) -1,1-bis [4-[(methoxycarbonyl) amino] Phenyl] -3-butyl] amino] ethanol (14.3 mg) was hydrogenated by a conventional method to give (1R) -1- [4-bedyloxy-3- (methanesulfonylamino) phenyl] -2-[[( 3RS) -1,1-bis [4-[(methoxycarbonyl) amino] phenyl] -3-butyl] amino] ethanol (46.1
mg). MS m / z: 601 (M + +1)

【０１４４】 実施例４２ 下記の化合物を実施例４１と同様にして得た。 （２Ｒ）−３−［４−ヒドロキシ−３−（メタンスルホニルアミノ）フェニル
］−１−［（３ＲＳ）−１，１−ビス（４−メトキシフェニル）−３−ブチル］
アミノ−２−プロパノール（５．０ｍｇ） MS m/z: 529 (M++1)Example 42 The following compound was obtained in the same manner as in Example 41. (2R) -3- [4-hydroxy-3- (methanesulfonylamino) phenyl] -1-[(3RS) -1,1-bis (4-methoxyphenyl) -3-butyl]
Amino-2-propanol (5.0 mg) MS m / z: 529 (M ++ 1)

【０１４５】 実施例４３ （Ｒ）−（４−ベンジルオキシ−３−ニトロフェニル）オキシラン（３４．４
ｍｇ）、Ｎ−ベンジル−［３，３−ビス［４−（メトキシカルボニルアミノ）フ
ェニル］プロピル］アミン（５６．７ｍｇ）とエタノール（２ｍｌ）の混合物を
還流下で１２時間加熱した。反応混合物に鉄粉末、塩化アンモニウムと水を加え
、 １時間連続加熱した。反応混合物を濾過し、常法で処理して、粗製の（１Ｒ
）−１−（３−アミノ−４−ベンジルオキシフェニル）−２−［Ｎ−ベンジル−
［３，３−ビス［４−［（メトキシカルボニル）アミノ］フェニル］プロピル］
アミノ］エタノール（１１１．７ｍｇ）を得た。 MS m/z: 689 (M++1)Example 43 (R)-(4-Benzyloxy-3-nitrophenyl) oxirane (34.4
mg), a mixture of N-benzyl- [3,3-bis [4- (methoxycarbonylamino) phenyl] propyl] amine (56.7 mg) and ethanol (2 ml) was heated under reflux for 12 hours. Iron powder, ammonium chloride and water were added to the reaction mixture, and the mixture was heated continuously for 1 hour. The reaction mixture was filtered and worked up in the usual manner to give the crude (1R
) -1- (3-Amino-4-benzyloxyphenyl) -2- [N-benzyl-
[3,3-bis [4-[(methoxycarbonyl) amino] phenyl] propyl]
Amino] ethanol (111.7 mg) was obtained. MS m / z: 689 (M + +1)

【０１４６】 実施例４４ 下記の化合物を実施例４３と同様にして得た。 （２Ｓ）−１−（３−アミノ−４−ベンジルオキシフェノキシ）−３−［Ｎ−
ベンジル−［３，３−ビス［４−［（メトキシカルボニル）アミノ］フェニル］
プロピル］アミノ］−２−プロパノール MS m/z: 719Example 44 The following compound was obtained in the same manner as in Example 43. (2S) -1- (3-amino-4-benzyloxyphenoxy) -3- [N-
Benzyl- [3,3-bis [4-[(methoxycarbonyl) amino] phenyl]
Propyl] amino] -2-propanol MS m / z: 719

【０１４７】 実施例４５ 窒素雰囲気下、４，４−ビス（４−メトキシフェニル）−２−ブタノン（１８
７ｍｇ）と、ヨウ化亜鉛で触媒作用され、次いで水素化アルミニウムリチウムで
還元された６−メチルピリジン−２−カルボキサルデヒドとトリメチルシリルシ
アニドから製造された（１ＲＳ）−２−アミノ−１−（２−メチルピリジン−６
−イル）エタノール（１００ｍｇ）の１，２−ジクロロエタン（１０ｍｌ）中の
溶液に、トリアセトキシ水素化ホウ素ナトリウム（２５７ｍｇ）を室温で加え、
混合物を同温で２４時間攪拌した。生じた混合物を飽和重炭酸ナトリウム水溶液
に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで
乾燥後、真空中で溶媒を留去した。残留物を１，４−ジオキサン中４Ｎ塩化水素
で処理して、（１ＲＳ）−２−［［（１ＲＳ）−３，３−ビス（４−メトキシフ
ェニル）−１−メチルプロピル］アミノ］−１−（６−メチルピリジン−２−イ
ル）エタノール（１４０ｍｇ）二塩酸塩を得た。 MS m/z: 421 (M++1) (遊離化合物)Example 45 Under a nitrogen atmosphere, 4,4-bis (4-methoxyphenyl) -2-butanone (18
7 mg) and (1RS) -2-amino-1-(-) prepared from 6-methylpyridine-2-carboxaldehyde and trimethylsilyl cyanide catalyzed by zinc iodide and then reduced with lithium aluminum hydride. 2-methylpyridine-6
-Yl) To a solution of ethanol (100 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (257 mg) at room temperature,
The mixture was stirred at the same temperature for 24 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue is treated with 4N hydrogen chloride in 1,4-dioxane to give (1RS) -2-[[(1RS) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amino] -1. -(6-Methylpyridin-2-yl) ethanol (140 mg) dihydrochloride was obtained. MS m / z: 421 (M + +1) (free compound)

【０１４８】 実施例４６ 窒素雰囲気下、（２Ｓ）−３−［４−ベンジルオキシ−３−（メタンスルホニ
ルアミノ）フェノキシ］−１，２−エポキシプロパン（１９８ｍｇ）とＮ−ベン
ジル−［（１ＲＳ）−３，３−ビス（４−ヒドロキシフェニル）−１−メチルプ
ロピル］アミン（２００ｍｇ）のメタノール（２０ｍｌ）中の溶液を１８時間還
流した。生じた混合物を飽和重炭酸ナトリウム水溶液に注ぎ、酢酸エチルで抽出
した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥後、真空中で溶媒を留
去した。残留物をシリカゲルクロマトグラフィー（ヘキサン−酢酸エチル）に付
して、Ｎ−［５−［（２Ｓ）−３−［Ｎ−ベンジル−［（１ＲＳ）−３，３−ビ
ス（４−ヒドロキシフェニル）−１−メチルプロピル］アミノ］−２−ヒドロキ
シプロポキシ］−２−（ベンジルオキシ）フェニル］メタンスルホンアミド（１
２０ｍｇ）を得た。 MS m/z: 696 (M++1) 実施例４７ 窒素雰囲気下、（２Ｓ）−３−［４−ベンジルオキシ−３−（メタンスルホニ
ルアミノ）フェノキシ］−１，２−エポキシプロパン（２００ｍｇ） とＮ−ベ
ンジル−［（１ＲＳ）−３，３−ビス（４−メトキシフェニル）−１−メチルプ
ロピル］アミン（１６３ｍｇ）のジクロロメタン（１０ｍｌ）中の溶液に、トリ
フルオロメタンスルホン酸イッテルビウム（ＩＩＩ）（１．０ｇ）を室温で加え
、混合物を同温で３時間攪拌した。生じた混合物を飽和重炭酸ナトリウム水溶液
に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸マグネシウムで
乾燥後、真空中で溶媒を留去した。残留物をシリカゲルクロマトグラフィー（ヘ
キサン−酢酸エチル）に付して、Ｎ−［５−［（２Ｓ）−３−［Ｎ−ベンジル−
［（１ＲＳ）−３，３−ビス（４−メトキシフェニル）−１−メチルプロピル］
アミノ］−２−ヒドロキシプロポキシ］−２−（ベンジルオキシ）フェニル］メ
タンスルホンアミド（５０ｍｇ）を得た。 MS m/z: 724 (M++1)Example 46 (2S) -3- [4-Benzyloxy-3- (methanesulfonylamino) phenoxy] -1,2-epoxypropane (198 mg) and N-benzyl-[(1RS) under a nitrogen atmosphere A solution of -3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amine (200 mg) in methanol (20 ml) was refluxed for 18 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was subjected to silica gel chromatography (hexane-ethyl acetate) to give N- [5-[(2S) -3- [N-benzyl-[(1RS) -3,3-bis (4-hydroxyphenyl)]. -1-methylpropyl] amino] -2-hydroxypropoxy] -2- (benzyloxy) phenyl] methanesulfonamide (1
20 mg). MS m / z: 696 (M + +1) Example 47 (2S) -3- [4-benzyloxy-3- (methanesulfonylamino) phenoxy] -1,2-epoxypropane (200 mg) under a nitrogen atmosphere And a solution of N-benzyl-[(1RS) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amine (163 mg) in dichloromethane (10 ml) was added to ytterbium (III) trifluoromethanesulfonate (III) ( 1.0 g) was added at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was subjected to silica gel chromatography (hexane-ethyl acetate) to give N- [5-[(2S) -3- [N-benzyl-
[(1RS) -3,3-bis (4-methoxyphenyl) -1-methylpropyl]
Amino] -2-hydroxypropoxy] -2- (benzyloxy) phenyl] methanesulfonamide (50 mg) was obtained. MS m / z: 724 (M + +1)

【０１４９】 実施例４８ 窒素雰囲気下、Ｎ−ベンジル−［３，３−ビス（４−ヒドロキシフェニル）−
１−メチルプロピル］アミン（３００ｍｇ）とフェネチルオキシラン（１３０ｍ
ｇ）の、酢酸エチル（５ｍｌ）とテトラヒドロフラン（５ｍｌ）の混合物中の溶
液に、トリフルオロメタンスルホン酸イッテルビウム（ＩＩＩ）（１１０ｍｇ）
を室温で加え、混合物を同温で９６時間攪拌した。生じた混合物を飽和重炭酸ナ
トリウム水溶液に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、無水
硫酸マグネシウムで乾燥後、真空中で溶媒を留去した。残留物をシリカゲルカラ
ムクロマトグラフィー（クロロホルム：メタノール＝２０：１）で精製して、１
−［Ｎ−ベンジル−［３，３−ビス（４−ヒドロキシフェニル）−１−メチルプ
ロピル］アミノ］−４−フェニル−２−ブタノール（２４０ｍｇ）を得た。 NMR (CDCl3, δ): 0.95-1.10 (3H, m), 1.45-2.9 (9H, m), 3.2-3.75 (3H, m),
3.75-3.9 (1H, m), 6.55-6.8 (4H, m), 6.85-7.3 (14H, m) 実施例４９ 下記の化合物を実施例４８と同様にして得た。 （２Ｓ）−１−［Ｎ−ベンジル−［（１ＲＳ）−３，３−ビス（４−ヒドロキ
シフェニル）−１−メチルプロピル］アミノ］−３−（フェニルチオ）−２−プ
ロパノール NMR (CDCl3, δ): 0.85-1.1 (3H, m), 1.7-3.1 (7H, m), 3.3-3.75 (3H, m),
3.75-3.9 (1H, m), 6.55-6.75 (4H, m), 6.8-7.25 (14H, m)Example 48 N-benzyl- [3,3-bis (4-hydroxyphenyl)-under a nitrogen atmosphere
1-methylpropyl] amine (300 mg) and phenethyloxirane (130 m
g) in a mixture of ethyl acetate (5 ml) and tetrahydrofuran (5 ml), ytterbium (III) trifluoromethanesulfonate (110 mg)
Was added at room temperature, and the mixture was stirred at the same temperature for 96 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 1
-[N-benzyl- [3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amino] -4-phenyl-2-butanol (240 mg) was obtained. NMR (CDCl 3 , δ): 0.95-1.10 (3H, m), 1.45-2.9 (9H, m), 3.2-3.75 (3H, m),
3.75-3.9 (1H, m), 6.55-6.8 (4H, m), 6.85-7.3 (14H, m) Example 49 The following compound was obtained in the same manner as in Example 48. (2S) -1- [N-benzyl-[(1RS) -3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amino] -3- (phenylthio) -2-propanol NMR (CDCl 3 , δ): 0.85-1.1 (3H, m), 1.7-3.1 (7H, m), 3.3-3.75 (3H, m),
3.75-3.9 (1H, m), 6.55-6.75 (4H, m), 6.8-7.25 (14H, m)

【０１５０】 実施例５０ 窒素雰囲気下、Ｎ−［５−［（１Ｒ）−２−［Ｎ−ベンジル−［（１ＲＳ）−
３，３−ビス（４−メトキシフェニル）−１−メチルプロピル］アミノ］−１−
（トリエチルシリルオキシ）エチル］−２−（ベンジルオキシ）フェニル］メタ
ンスルホンアミド（２２１ｍｇ）のテトラヒドロフラン（３ｍｌ） 中の溶液に
、酢酸（６３μｌ）とフッ化テトラブチルアンモニウム（テトラヒドロフラン中
１Ｍ溶液、０．６８ｍｌ）を室温で加え、混合物を同温で４．５時間攪拌した。
生じた混合物を飽和重炭酸ナトリウム水溶液に注ぎ、酢酸エチルで抽出した。有
機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、真空中で溶媒を留去し
た。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２
：１）で精製して、Ｎ−［５−［（１Ｒ）−２−［Ｎ−ベンジル−［（１ＲＳ）
−３，３−ビス（４−メトキシフェニル）−１−メチルプロピル］アミノ］−１
−ヒドロキシエチル］−２−（ベンジルオキシ）フェニル］メタンスルホンアミ
ド（１６４ｍｇ）を得た。 NMR (CDCl3, δ): 0.95-1.1 (3H, m), 1.7-2.85 (5H, m), 2.88 (3H, m), 3.35-4.05 (8H, m), 4.25-4.5 (1H, m), 5.08 (2H, m), 6.7-7.5 (21H, m)Example 50 N- [5-[(1R) -2- [N-benzyl-[(1RS)-] under a nitrogen atmosphere.
3,3-bis (4-methoxyphenyl) -1-methylpropyl] amino] -1-
To a solution of (triethylsilyloxy) ethyl] -2- (benzyloxy) phenyl] methanesulfonamide (221 mg) in tetrahydrofuran (3 ml) was added acetic acid (63 μl) and tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 0.1 M 68 ml) was added at room temperature, and the mixture was stirred at the same temperature for 4.5 hours.
The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2
: 1) to give N- [5-[(1R) -2- [N-benzyl-[(1RS)]
-3,3-bis (4-methoxyphenyl) -1-methylpropyl] amino] -1
-Hydroxyethyl] -2- (benzyloxy) phenyl] methanesulfonamide (164 mg) was obtained. NMR (CDCl 3 , δ): 0.95-1.1 (3H, m), 1.7-2.85 (5H, m), 2.88 (3H, m), 3.35-4.05 (8H, m), 4.25-4.5 (1H, m) , 5.08 (2H, m), 6.7-7.5 (21H, m)

【０１５１】 実施例５１ Ｎ−［５−［（１Ｒ）−２−［Ｎ−ベンジル−［（１ＲＳ）−３，３−ビス（
４−メトキシフェニル）−１−メチルプロピル］アミノ］−１−ヒドロキシエチ
ル］−２−（ベンジルオキシ）フェニル］メタンスルホンアミド（１４９ｍｇ）
と１０％パラジウム活性炭（５０％湿潤、５０ｍｇ）のメタノール（５ｍｌ）中
の混合物を室温で大気圧の水素存在下で６時間攪拌した。濾過後、真空中で濾液
から溶媒を留去し、次いで、酢酸エチル中４Ｎ塩化水素で処理して、Ｎ−［５−
［（１Ｒ）−２−［（１ＲＳ）−３，３−ビス（４−メトキシフェニル）−１−
メチルプロピル］アミノ−１−ヒドロキシエチル］−２−ヒドロキシフェニル］
メタンスルホンアミド塩酸塩（９０ｍｇ）を得た。 NMR (DMSO-d6, δ): 1.1-1.35 (3H, m), 1.9-2.2 (1H, m), 2.55-3.1 (7H, m),
3.70 (6H, m), 3.95-4.1 (1H, m), 4.7-4.9 (1H, m), 6.8-7.4 (11H, m)Example 51 N- [5-[(1R) -2- [N-benzyl-[(1RS) -3,3-bis (
4-methoxyphenyl) -1-methylpropyl] amino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] methanesulfonamide (149 mg)
A mixture of and 10% palladium on activated carbon (50% wet, 50 mg) in methanol (5 ml) was stirred at room temperature in the presence of hydrogen at atmospheric pressure for 6 hours. After filtration, the solvent was distilled off from the filtrate in vacuo and then treated with 4N hydrogen chloride in ethyl acetate to give N- [5-
[(1R) -2-[(1RS) -3,3-bis (4-methoxyphenyl) -1-
Methylpropyl] amino-1-hydroxyethyl] -2-hydroxyphenyl]
Methanesulfonamide hydrochloride (90 mg) was obtained. NMR (DMSO-d 6 , δ): 1.1-1.35 (3H, m), 1.9-2.2 (1H, m), 2.55-3.1 (7H, m),
3.70 (6H, m), 3.95-4.1 (1H, m), 4.7-4.9 (1H, m), 6.8-7.4 (11H, m)

【０１５２】 実施例５２ 下記の化合物を実施例５１と同様にして得た。 （１） １−［３，３−ビス（４−ヒドロキシフェニル）−１−メチルプロピル
］アミノ−４−フェニル−２−ブタノール塩酸塩 NMR (CD3OD, δ): 1.1-1.5 (3H, m), 1.7-1.9 (2H, m), 1.95-2.2 (1H, m), 2.
45-3.2 (6H, m), 3.6-4.0 (1H, m), 6.5-6.8 (4H, m), 7.0-7.35 (9H, m) （２） （２Ｓ）−１−ベンゼンスルホニル−３−［（１ＲＳ）−３，３−ビス
（４−ヒドロキシフェニル）−１−メチルプロピル］アミノ−２−プロパノール
塩酸塩 NMR (CD3OD, δ): 1.25-1.4 (3H, m), 1.95-2.2 (1H, m), 2.45-2.7 (1H, m),
2.9-3.55 (5H, m), 3.85-4.0 (1H, m), 4.25-4.4 (1H, m), 6.65-6.85 (4H, m),
7.05-7.2 (4H, m), 7.6-7.8 (3H, m), 7.95-8.05 (2H, m) （３） （２Ｓ）−１−フェノキシ−３−［（３ＲＳ）−１，１−ビス（４−ウ
レイドフェニル）−３−ブチル］アミノ−２−プロパノール塩酸塩 MS m/z: 492 (M++1) (遊離化合物)Example 52 The following compound was obtained in the same manner as in Example 51. (1) 1- [3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amino-4-phenyl-2-butanol hydrochloride NMR (CD 3 OD, δ): 1.1-1.5 (3H, m ), 1.7-1.9 (2H, m), 1.95-2.2 (1H, m), 2.
45-3.2 (6H, m), 3.6-4.0 (1H, m), 6.5-6.8 (4H, m), 7.0-7.35 (9H, m) (2) (2S) -1-benzenesulfonyl-3- [ (1RS) -3,3-Bis (4-hydroxyphenyl) -1-methylpropyl] amino-2-propanol hydrochloride NMR (CD 3 OD, δ): 1.25-1.4 (3H, m), 1.95-2.2 ( 1H, m), 2.45-2.7 (1H, m),
2.9-3.55 (5H, m), 3.85-4.0 (1H, m), 4.25-4.4 (1H, m), 6.65-6.85 (4H, m),
7.05-7.2 (4H, m), 7.6-7.8 (3H, m), 7.95-8.05 (2H, m) (3) (2S) -1-phenoxy-3-[(3RS) -1,1-bis ( 4-ureidophenyl) -3-butyl] amino-2-propanol hydrochloride MS m / z: 492 (M ++ 1) (free compound)

【０１５３】 実施例５３ 窒素雰囲気下、［（１Ｓ）−３，３−ビス（４−メトキシフェニル）−１−メ
チルプロピル］アミン（０．５５ｇ）、Ｎ−［２−ベンジルオキシ−５−［（１
Ｒ）−２−ヨード−１−（トリエチルシリルオキシ）エチル］フェニル］メタン
スルホンアミド（１．１ｇ）とＮ，Ｎ−ジイソプロピルエチルアミン（１．４ｍ
ｌ）のＮ，Ｎ−ジメチルアセトアミド（５ｍｌ）中の溶液を１１０℃で２４時間
攪拌した。生じた混合物を飽和重炭酸ナトリウム水溶液に注ぎ、酢酸エチルで抽
出した。有機層を水と食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、真空
中で溶媒を留去した。窒素雰囲気下、酢酸エチル（１０ｍｌ）中の残留物に酢酸
エチル中４Ｎ塩化水素（２ｍｌ）を５℃で加え、混合物を室温で４５分間攪拌し
た。生じた混合物を飽和重炭酸ナトリウム水溶液に注ぎ、酢酸エチルで抽出した
。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、真空中で溶媒を留
去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノ
ール＝５０：１〜２０：１）で精製して、Ｎ−［２−ベンジルオキシ−５−［（
１Ｒ）−２−［（１Ｓ）−３，３−ビス（４−メトキシフェニル）−１−メチル
プロピル］アミノ−１−ヒドロキシエチル］フェニル］メタンスルホンアミド（
０．６５ｇ）を得た。 NMR (CDCl3, δ): 1.09 (3H, d, J=6.3Hz), 1.85-2.3 (2H, m), 2.35-2.6 (2H,
m), 2.9-3.2 (4H, m), 3.76 (6H, s), 4.0-4.1 (1H, m), 4.45-4.6 (1H, m), 5.10 (2H, m), 6.82 (4H, d, J=8.1Hz), 6.96 (1H, d, J=8.5Hz), 7.1-7.2 (5H,
m), 7.35-7.5 (6H, m)Example 53 [(1S) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amine (0.55 g), N- [2-benzyloxy-5- [ (1
R) -2-Iodo-1- (triethylsilyloxy) ethyl] phenyl] methanesulfonamide (1.1 g) and N, N-diisopropylethylamine (1.4 m)
A solution of 1) in N, N-dimethylacetamide (5 ml) was stirred at 110 ° C. for 24 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off in vacuo. Under a nitrogen atmosphere, 4N hydrogen chloride in ethyl acetate (2 ml) was added to the residue in ethyl acetate (10 ml) at 5 ° C and the mixture was stirred at room temperature for 45 minutes. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 to 20: 1) to give N- [2-benzyloxy-5-[(
1R) -2-[(1S) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amino-1-hydroxyethyl] phenyl] methanesulfonamide (
0.65 g). NMR (CDCl 3 , δ): 1.09 (3H, d, J = 6.3 Hz), 1.85-2.3 (2H, m), 2.35-2.6 (2H,
m), 2.9-3.2 (4H, m), 3.76 (6H, s), 4.0-4.1 (1H, m), 4.45-4.6 (1H, m), 5.10 (2H, m), 6.82 (4H, d, J = 8.1Hz), 6.96 (1H, d, J = 8.5Hz), 7.1-7.2 (5H,
m), 7.35-7.5 (6H, m)

【０１５４】 実施例５４ 下記の化合物を実施例５３と同様にして得た。 （１） Ｎ−［２−ベンジルオキシ−５−［（１Ｒ）−２−［（１Ｒ）−３，３
−ビス（４−メトキシフェニル）−１−メチルプロピル］アミノ−１−ヒドロキ
シエチル］フェニル］メタンスルホンアミド NMR (CDCl3, δ): 1.08 (3H, d, J=6.2Hz), 1.9-2.2 (2H, m), 2.5-2.85 (3H,
m), 2.90 (3H, s), 3.76 (6H, s), 4.03 (1H, t, J=8.2Hz), 4.47 (1H, dd, J=3.6 および 8.5Hz), 5.10 (2H, s), 6.8-6.9 (4H, m), 6.96 (1H, d, J=8.5Hz), 7.1-7.2 (5H, m), 7.35-7.5 (6H, m) （２） Ｎ−［２−ベンジルオキシ−５−［（１Ｒ）−２−［（１ＲＳ）−３，
３−ビス（４−ヒドロキシフェニル）−１−メチルプロピル］アミノ−１−ヒド
ロキシエチル］フェニル］メタンスルホンアミド NMR (DMSO-d6, δ): 1.0-1.1 (3H, m), 1.7-1.95 (1H, m), 2.1-2.85 (4H, m),
2.90 (3H, s), 3.8-3.95 (1H, m), 4.5-4.6 (1H, m), 5.17 (2H, s), 6.6-6.75
(4H, m), 6.95-7.2 (6H, m), 7.25-7.6 (6H, m)Example 54 The following compounds were obtained in the same manner as in Example 53. (1) N- [2-benzyloxy-5-[(1R) -2-[(1R) -3,3
-Bis (4-methoxyphenyl) -1-methylpropyl] amino-1-hydroxyethyl] phenyl] methanesulfonamide NMR (CDCl 3 , δ): 1.08 (3H, d, J = 6.2 Hz), 1.9-2.2 ( 2H, m), 2.5-2.85 (3H,
m), 2.90 (3H, s), 3.76 (6H, s), 4.03 (1H, t, J = 8.2Hz), 4.47 (1H, dd, J = 3.6 and 8.5Hz), 5.10 (2H, s), 6.8-6.9 (4H, m), 6.96 (1H, d, J = 8.5 Hz), 7.1-7.2 (5H, m), 7.35-7.5 (6H, m) (2) N- [2-benzyloxy-5 -[(1R) -2-[(1RS) -3,
3-bis (4-hydroxyphenyl) -1-methylpropyl] amino-1-hydroxyethyl] phenyl] methanesulfonamide NMR (DMSO-d 6 , δ): 1.0-1.1 (3H, m), 1.7-1.95 ( 1H, m), 2.1-2.85 (4H, m),
2.90 (3H, s), 3.8-3.95 (1H, m), 4.5-4.6 (1H, m), 5.17 (2H, s), 6.6-6.75
(4H, m), 6.95-7.2 (6H, m), 7.25-7.6 (6H, m)

【０１５５】 実施例５５ Ｎ−［２−（ベンジルオキシ）−５−［（１Ｒ）−２−［（１Ｓ）−３，３−
ビス（４−メトキシフェニル）−１−メチルプロピル］アミノ−１−ヒドロキシ
エチル］フェニル］メタンスルホンアミド（６２０ｍｇ）と１０％パラジウム活
性炭（５０％湿潤、３００ｍｇ）のメタノール（１０ｍｌ）中の混合物を室温で
大気圧の水素存在下で７．５時間攪拌した。濾過後、真空中で濾液から溶媒を留
去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノ
ール＝２０：１〜１０：１）で精製し、次いで酢酸エチル中４Ｎ塩化水素で処理
して、Ｎ−［５−［（１Ｒ）−２−［（１Ｓ）−３，３−ビス（４−メトキシフ
ェニル）−１−メチルプロピル］アミノ−１−ヒドロキシエチル］−２−ヒドロ
キシフェニル］メタンスルホンアミド塩酸塩（２９０ｍｇ）を得た。 NMR (DMSO-d6, δ): 1.15-1.4 (3H, m), 1.85-2.2 (1H, m), 2.4-3.2 (7H, m),
3.70 (6H, s), 3.95-4.1 (1H, m), 4.7-4.9 (1H, m), 6.7-7.4 (11H, m)Example 55 N- [2- (benzyloxy) -5-[(1R) -2-[(1S) -3,3-
A mixture of bis (4-methoxyphenyl) -1-methylpropyl] amino-1-hydroxyethyl] phenyl] methanesulfonamide (620 mg) and 10% palladium on activated carbon (50% wet, 300 mg) in methanol (10 ml) was added at room temperature. For 7.5 hours in the presence of hydrogen at atmospheric pressure. After filtration, the solvent was distilled off from the filtrate in vacuo. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1 to 10: 1), then treated with 4N hydrogen chloride in ethyl acetate to give N- [5-[(1R) -2-[( 1S) -3,3-Bis (4-methoxyphenyl) -1-methylpropyl] amino-1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride (290 mg) was obtained. NMR (DMSO-d 6 , δ): 1.15-1.4 (3H, m), 1.85-2.2 (1H, m), 2.4-3.2 (7H, m),
3.70 (6H, s), 3.95-4.1 (1H, m), 4.7-4.9 (1H, m), 6.7-7.4 (11H, m)

【０１５６】 実施例５６ 下記の化合物を実施例５４と同様にして得た。 （１） Ｎ−［５−［（１Ｒ）−２−［（１Ｒ）−３，３−ビス（４−メトキシ
フェニル）−１−メチルプロピル］アミノ−１−ヒドロキシエチル］−２−ヒド
ロキシフェニル］メタンスルホンアミド塩酸塩 NMR (DMSO-d6, δ): 1.15-1.4 (3H, m), 1.9-2.15 (1H, m), 2.4-3.15 (7H, m), 3.70 (6H, m), 3.95-4.1 (1H, m), 4.75-4.9 (1H, m), 6.8-7.4 (11H, m) （２） Ｎ−［５−［（１Ｒ）−２−［［３，３−ビス（４−ヒドロキシフェニ
ル）−１−メチルプロピル］アミノ］−１−ヒドロキシエチル］−２−ヒドロキ
シフェニル］メタンスルホンアミド塩酸塩 NMR (DMSO-d6, δ): 1.15-1.3 (3H, m), 1.85-2.1 (1H, m), 2.55-3.2 (7H, m), 3.8-4.0 (1H, m), 4.7-4.9 (1H, m), 6.6-6.75 (4H, m), 6.9-7.3 (7H, m)
（３） 実施例５７の目的化合物から出発して、（２Ｓ）−１−（６−アミノピ
リジン−３−イルオキシ）−３−［［（１ＲＳ）−３，３−ビス（４−メトキシ
フェニル）−１−メチルプロピル］アミノ］−２−プロパノール三塩酸塩 NMR (DMSO-d6, δ): 1.05-1.4 (3H, m), 1.9-2.2 (1H, m), 2.5-3.2 (4H, m),
3.55-3.85 (7H, m), 3.85-4.3 (3H, m), 6.9-7.4 (9H, m), 7.5-7.9 (2H, m)Example 56 The following compound was obtained in the same manner as in Example 54. (1) N- [5-[(1R) -2-[(1R) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amino-1-hydroxyethyl] -2-hydroxyphenyl] Methanesulfonamide hydrochloride NMR (DMSO-d 6 , δ): 1.15-1.4 (3H, m), 1.9-2.15 (1H, m), 2.4-3.15 (7H, m), 3.70 (6H, m), 3.95 -4.1 (1H, m), 4.75-4.9 (1H, m), 6.8-7.4 (11H, m) (2) N- [5-[(1R) -2-[[3,3-bis (4- Hydroxyphenyl) -1-methylpropyl] amino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride NMR (DMSO-d 6 , δ): 1.15-1.3 (3H, m), 1.85-2.1 (1H, m), 2.55-3.2 (7H, m), 3.8-4.0 (1H, m), 4.7-4.9 (1H, m), 6.6-6.75 (4H, m), 6.9-7.3 (7H, m)
(3) Starting from the target compound of Example 57, (2S) -1- (6-aminopyridin-3-yloxy) -3-[[(1RS) -3,3-bis (4-methoxyphenyl) -1-methylpropyl] amino] -2-propanol trihydrochloride NMR (DMSO-d 6 , δ): 1.05-1.4 (3H, m), 1.9-2.2 (1H, m), 2.5-3.2 (4H, m ),
3.55-3.85 (7H, m), 3.85-4.3 (3H, m), 6.9-7.4 (9H, m), 7.5-7.9 (2H, m)

【０１５７】 実施例５７ ［３，３−ビス（４−メトキシフェニル）−１−メチルプロピル］アミンと（
２Ｓ）−３−［２−（ベンジルオキシカルボニルアミノ）ピリジン−５−イルオ
キシ］−１，２−エポキシプロパン（９８ｍｇ）のメタノール（５ｍｌ）中の混
合物を１９時間還流した。真空中で溶媒除去後、残留物をシリカゲルカラムクロ
マトグラフィー（クロロホルム：メタノール＝３０：１〜２０：１）で精製して
、［５−［（２Ｓ）−３−［（１ＲＳ）−３，３−ビス（４−メトキシフェニル
）−１−メチルプロピル］アミノ−２−ヒドロキシプロポキシ］ピリジン−２−
イル］カルバミン酸ベンジルエステル（１１０ｍｇ）を得た。 NMR (CDCl3, δ): 1.1-1.2 (3H, m), 1.7-2.3 (2H, m), 2.45-2.6 (2H, m), 2.7-2.75 (1H, m), 3.76 (6H, s), 3.85-3.95 (3H, m), 4.0-4.1 (1H, m), 5.22 (2H, s), 6.8 (4H, d, J=8.6Hz), 7.1-7.45 (10H, m), 7.9-7.95 (2H, m)Example 57 [3,3-Bis (4-methoxyphenyl) -1-methylpropyl] amine and (
A mixture of 2S) -3- [2- (benzyloxycarbonylamino) pyridin-5-yloxy] -1,2-epoxypropane (98 mg) in methanol (5 ml) was refluxed for 19 hours. After removing the solvent in vacuo, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1 to 20: 1) to give [5-[(2S) -3-[(1RS) -3,3]. -Bis (4-methoxyphenyl) -1-methylpropyl] amino-2-hydroxypropoxy] pyridine-2-
Yl] carbamic acid benzyl ester (110 mg) was obtained. NMR (CDCl 3 , δ): 1.1-1.2 (3H, m), 1.7-2.3 (2H, m), 2.45-2.6 (2H, m), 2.7-2.75 (1H, m), 3.76 (6H, s) , 3.85-3.95 (3H, m), 4.0-4.1 (1H, m), 5.22 (2H, s), 6.8 (4H, d, J = 8.6Hz), 7.1-7.45 (10H, m), 7.9-7.95 (2H, m)

【０１５８】 実施例５８ （２Ｓ）−１−［Ｎ−ベンジル−［（１ＲＳ）−３，３−ビス（４−ヒドロキ
シフェニル）−１−メチルプロピル］アミノ］−３−フェニルチオ−２−プロパ
ノール（３００ｍｇ）のメタノール（１０ｍｌ）中の溶液に、水（２ｍｌ）中の
ＯＸＯＮＥ（登録商標）（ペルオキシ一硫酸カリウム）（７１０ｍｇ）を室温で
加え、混合物を同温で４時間攪拌した。生じた混合物を酢酸エチルと水の混合物
に注ぎ、飽和重炭酸ナトリウム水溶液で塩基性とした。分離後、有機層を食塩水
で洗浄し、無水硫酸マグネシウムで乾燥後、真空中で溶媒を留去した。残留物を
シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝２０：１）
で精製して、（２Ｓ）−１−ベンゼンスルホニル−３−［Ｎ−ベンジル−［（１
ＲＳ）−３，３−ビス（４−ヒドロキシフェニル）−１−メチルプロピル］アミ
ノ］−２−プロパノール（２２０ｍｇ）を得た。 NMR (CDCl3, δ): 0.9-1.1 (3H, m), 1.75-2.3 (2H, m), 2.35-2.7 (3H, m),
2.9-3.25 (2H, m), 3.3-4.0 (4H, m), 6.65-6.8 (4H, m), 6.9-7.35 (9H, m),
7.5-7.7 (3H, m), 7.75-7.9 (2H, m)Example 58 (2S) -1- [N-benzyl-[(1RS) -3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amino] -3-phenylthio-2-propanol ( To a solution of 300 mg) in methanol (10 ml) was added OXONE® (potassium peroxymonosulfate) (710 mg) in water (2 ml) at room temperature and the mixture was stirred at the same temperature for 4 hours. The resulting mixture was poured into a mixture of ethyl acetate and water and made basic with saturated aqueous sodium bicarbonate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue is subjected to silica gel column chromatography (chloroform: methanol = 20: 1).
And purified by (2S) -1-benzenesulfonyl-3- [N-benzyl-[(1
(RS) -3,3-bis (4-hydroxyphenyl) -1-methylpropyl] amino] -2-propanol (220 mg). NMR (CDCl 3 , δ): 0.9-1.1 (3H, m), 1.75-2.3 (2H, m), 2.35-2.7 (3H, m),
2.9-3.25 (2H, m), 3.3-4.0 (4H, m), 6.65-6.8 (4H, m), 6.9-7.35 (9H, m),
7.5-7.7 (3H, m), 7.75-7.9 (2H, m)

【０１５９】 実施例５９ （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３，３−ビス［４−（メ
トキシカルボニル）フェニル］プロピル］アミノ］−２−プロパノール（１０３
ｍｇ）、メタノール（２ｍｌ）、１，４−ジオキサン（２ｍｌ）と１Ｎ水酸化ナ
トリウム水溶液（１ｍｌ）の 混合物を５０℃で２時間攪拌した。反応混合物を
３Ｎ塩酸（１ｍｌ）で酸性にし、常法で処理して、（２Ｓ）−１−フェノキシ−
３−［Ｎ−ベンジル−［３，３−ビス（４−カルボキシフェニル）プロピル］ア
ミノ］−２−プロパノール（７５．１ｍｇ）を得た。 実施例６０ （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３，３−ビス（４−カル
ボキシフェニル）プロピル］アミノ］−２−プロパノール（７５ｍｇ）、アジ化
ジフェニルホスホリル（９６ｍｇ）、トリエチルアミン（５８μｌ）、トルエン
（１ｍｌ）と１，４−ジオキサン（１ｍｌ）の混合物を５０℃で０．５時間、次
いで１００℃で４５分間攪拌した。反応混合物にメタノール（１ｍｌ）を加え、 １５時間連続加熱した。反応混合物を常法で処理し、次いで分取薄層クロマト
グラフィーで精製して、（２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３
，３−ビス［４−［（メトキシカルボニル）アミノ］フェニル］プロピル］アミ
ノ］−２−プロパノール（２１．５ｍｇ）を得た。 MS m/z: 598 (M++1)Example 59 (2S) -1-phenoxy-3- [N-benzyl- [3,3-bis [4- (methoxycarbonyl) phenyl] propyl] amino] -2-propanol (103
mg), methanol (2 ml), 1,4-dioxane (2 ml) and a 1N aqueous sodium hydroxide solution (1 ml) were stirred at 50 ° C. for 2 hours. The reaction mixture was acidified with 3N hydrochloric acid (1 ml), treated in a conventional manner to give (2S) -1-phenoxy-
3- [N-benzyl- [3,3-bis (4-carboxyphenyl) propyl] amino] -2-propanol (75.1 mg) was obtained. Example 60 (2S) -1-phenoxy-3- [N-benzyl- [3,3-bis (4-carboxyphenyl) propyl] amino] -2-propanol (75 mg), diphenylphosphoryl azide (96 mg), A mixture of triethylamine (58 μl), toluene (1 ml) and 1,4-dioxane (1 ml) was stirred at 50 ° C. for 0.5 hour and then at 100 ° C. for 45 minutes. Methanol (1 ml) was added to the reaction mixture, and the mixture was continuously heated for 15 hours. The reaction mixture was worked up in the usual way and then purified by preparative thin layer chromatography to give (2S) -1-phenoxy-3- [N-benzyl- [3
, 3-Bis [4-[(methoxycarbonyl) amino] phenyl] propyl] amino] -2-propanol (21.5 mg) was obtained. MS m / z: 598 (M + +1)

【０１６０】 実施例６１ （２Ｓ）−１−フェノキシ−３−［Ｎ−ベンジル−［３，３−ビス［４−［（
メトキシカルボニル）アミノ］フェニル］プロピル］アミノ］−２−プロパノー
ル（１８．８ｍｇ）を常法で水素化して、（２Ｓ）−１−フェノキシ−３−［［
３，３−ビス［４−［（メトキシカルボニル）アミノ］フェニル］プロピル］ア
ミノ］−２−プロパノール（８．１ｍｇ）を得た。 IR (KBr): 1710 (s), 1601 (m), 1537 (s), 1315 (w), 1238 (s), 1070 (m) cm-1 NMR (MeOH-d4, δ): 2.2-2.3 (2H, m), 2.6-2.9 (4H, m), 3.72 (6H, s), 3.9-
4.1 (4H, m), 6.9-7.0 (3H, m), 7.2-7.4 (10H, m) MS m/z: 508 (M++1)Example 61 (2S) -1-phenoxy-3- [N-benzyl- [3,3-bis [4-[(
Methoxycarbonyl) amino] phenyl] propyl] amino] -2-propanol (18.8 mg) was hydrogenated in a conventional manner to give (2S) -1-phenoxy-3-[[
3,3-Bis [4-[(methoxycarbonyl) amino] phenyl] propyl] amino] -2-propanol (8.1 mg) was obtained. IR (KBr): 1710 (s), 1601 (m), 1537 (s), 1315 (w), 1238 (s), 1070 (m) cm -1 NMR (MeOH-d 4 , δ): 2.2-2.3 (2H, m), 2.6-2.9 (4H, m), 3.72 (6H, s), 3.9-
4.1 (4H, m), 6.9-7.0 (3H, m), 7.2-7.4 (10H, m) MS m / z: 508 (M + +1)

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 31/44 Ａ６１Ｋ 31/44 31/4406 31/4406 Ａ６１Ｐ 13/02 Ａ６１Ｐ 13/02 25/02 １０４ 25/02 １０４ 43/00 43/00 Ｃ０７Ｃ 217/30 Ｃ０７Ｃ 217/30 217/84 217/84 311/08 311/08 317/32 317/32 323/25 323/25 Ｃ０７Ｄ 209/08 Ｃ０７Ｄ 209/08 213/30 213/30 213/65 213/65 213/75 213/75 235/26 235/26 Ｂ (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＣＹ， ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，Ｉ Ｔ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＧＷ，ＭＬ， ＭＲ，ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＧＨ，ＧＭ，Ｋ Ｅ，ＬＳ，ＭＷ，ＳＤ，ＳＬ，ＳＺ，ＵＧ，ＺＷ)，Ｅ Ａ(ＡＭ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ，ＲＵ，ＴＪ ，ＴＭ)，ＡＥ，ＡＬ，ＡＭ，ＡＴ，ＡＵ，ＡＺ，ＢＡ ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＣＡ，ＣＨ，ＣＮ，ＣＵ， ＣＺ，ＤＥ，ＤＫ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＤ，Ｇ Ｅ，ＧＨ，ＧＭ，ＨＲ，ＨＵ，ＩＤ，ＩＬ，ＩＮ，ＩＳ ，ＪＰ，ＫＥ，ＫＧ，ＫＰ，ＫＲ，ＫＺ，ＬＣ，ＬＫ， ＬＲ，ＬＳ，ＬＴ，ＬＵ，ＬＶ，ＭＤ，ＭＧ，ＭＫ，Ｍ Ｎ，ＭＷ，ＭＸ，ＮＯ，ＮＺ，ＰＬ，ＰＴ，ＲＯ，ＲＵ ，ＳＤ，ＳＥ，ＳＧ，ＳＩ，ＳＫ，ＳＬ，ＴＪ，ＴＭ， ＴＲ，ＴＴ，ＵＡ，ＵＧ，ＵＳ，ＵＺ，ＶＮ，ＹＵ，Ｚ Ａ，ＺＷ Ｆターム(参考） 4C055 AA01 BA01 BA02 BA53 BB04 CA01 CA02 CA16 CA43 CB15 DA01 FA15 FA32 4C086 AA01 AA03 BC13 BC17 BC37 MA01 MA04 NA14 ZA25 ZA81 ZC41 4C204 BB01 CB03 DB01 EB01 FB01 GB25 4C206 AA01 AA03 FA08 FA18 MA01 MA04 NA14 ZA25 ZA81 ZC41 4H006 AA01 AA03 AB20 AB26 BJ50 BN10 BN30 BP30 BU36 TA02 TA04 TB04 TB35 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat ゛ (Reference) A61K 31/44 A61K 31/44 31/4406 31/4406 A61P 13/02 A61P 13/02 25/02 104 25 / 02 104 43/00 43/00 C07C 217/30 C07C 217/30 217/84 217/84 311/08 311/08 317/32 317/32 323/25 323/25 C07D 209/08 C07D 209/08 213 / 30 213/30 213/65 213/65 213/75 213/75 235/26 235/26 B (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB , GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG ), AP (GH, GM, KE, LS, MW, SD, SL, SZ, G, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA , CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI , SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZWF terms (reference) 4C055 AA01 BA01 BA02 BA53 BB04 CA01 CA02 CA16 CA43 CB15 DA01 FA15 FA32 4C086 AA01 AA03 BC13 BC17 BC37 MA01 MA04 NA14 ZA25 ZA81 ZC41 4C204 BB01 CB03 DB01 EB01 FB01 GB25 4C206 AA01 AA03 FA 08 FA18 MA01 MA04 NA14 ZA25 ZA81 ZC41 4H006 AA01 AA03 AB20 AB26 BJ50 BN10 BN30 BP30 BU36 TA02 TA04 TB04 TB35

Claims (11)

【特許請求の範囲】[Claims] 【請求項１】 一般式［Ｉ］ 【化１】 ［式中、 Ａは複素環基またはアリールであって、そのおのおのは、ハロゲン、ヒドロキ
シ、アミノ、低級アルキル、低級アルキルスルホニルアミノ、フェニル（低級）
アルコキシおよびフェニル（低級）アルコキシカルボニルアミノよりなる群から
選択された同種または異種の置換基を１ないし３個有していてもよい、 −Ｘ−は結合、−ＣＨ2−、−ＣＨ2−ＣＨ2−、−ＮＨ−ＣＨ2−、−Ｏ−ＣＨ 2 −、−Ｓ−ＣＨ2−、−ＳＯ−ＣＨ2−または−ＳＯ2−ＣＨ2−、 【化２】 （式中、Ｒ11は水素、ヒドロキシ、低級アルコキシまたはアシルオキシを意味す
る。）、 【化３】 【化４】 −（ＣＨ2）n−ＣＨ＝ＣＨ−（ＣＨ2）m− または −（ＣＨ2）n−Ｃ≡Ｃ−（Ｃ
Ｈ2）m− （式中、−Ｑ−は−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ2−、 【化５】 【化６】 【化７】 【化８】 【化９】 （式中、Ｒ10は水素または低級アルキル、Ｒ11は低級アルキルをそれぞれ意味す
る。）、 Ｒ6、Ｒ7、Ｒ8およびＲ9はそれぞれ単独に水素、ヒドロキシ、低級アルキル、
低級アルケニル、低級アルコキシ、低級アルコキシ（低級）アルキル、または低
級アルコキシを１ないし３個有していてもよいアリール、 ｎ、ｍおよびｋはそれぞれ単独に０ないし６、 ｐは０ないし４、 ｑは１ないし４、 ｒは２ないし７、 をそれぞれ意味する。）、 【化１０】 （式中、ｉは０ないし６を意味する。）、 Ｒ1は水素またはアミノ保護基、 Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ単独に水素；低級アルキル；低級アルキル
チオ；低級アルキルスルホニル；ヒドロキシ；低級アルコキシ；アミノ；低級ア
ルキルアミノ；アシルアミノ；Ｎ−（低級アルキル）アシルアミノ；カルボキシ
；低級アルコキシカルボニル；低級アルキル１ないし２個で任意に置換されたカ
ルバモイル；ヒドロキシ（低級）アルキル；低級アルコキシ（低級）アルキル；
Ｎ−アシルアミノ（低級）アルキル；Ｎ−（低級アルキル）−Ｎ−アシルアミノ
（低級）アルキル；カルボキシ（低級）アルキル；低級アルコキシカルボニル（
低級）アルキル；低級アルキル１または２個で任意に置換されたカルバモイル（
低級）アルキル；または 【化１１】 （式中、Ｒ12およびＲ13はそれぞれ単独に水素または低級アルキル、またはＲ12 およびＲ13は結合して、低級アルキレン鎖を形成してもよく、ｊは０ないし６を
意味する。） をそれぞれ意味する。］で表される化合物またはその塩。1. A compound of the general formula [I]Wherein A is a heterocyclic group or aryl, each of which is halogen, hydroxy,
Si, amino, lower alkyl, lower alkylsulfonylamino, phenyl (lower)
From the group consisting of alkoxy and phenyl (lower) alkoxycarbonylamino
May have 1 to 3 selected same or different substituents, -X- is a bond, -CHTwo-, -CHTwo-CHTwo-, -NH-CHTwo-, -O-CH Two -, -S-CHTwo-, -SO-CHTwo-Or -SOTwo-CHTwo-,(Where R11Represents hydrogen, hydroxy, lower alkoxy or acyloxy
You. ), Embedded imageEmbedded image− (CHTwo)n-CH = CH- (CHTwo)m− Or − (CHTwo)n-C≡C- (C
HTwo)m-(Wherein -Q- is -O-, -S-, -SO-, -SOTwo-,Embedded imageEmbedded imageEmbedded imageEmbedded image(Where RTenIs hydrogen or lower alkyl, R11Means lower alkyl respectively
You. ), R6, R7, R8And R9Is each independently hydrogen, hydroxy, lower alkyl,
Lower alkenyl, lower alkoxy, lower alkoxy (lower) alkyl, or lower
Aryl having 1 to 3 lower alkoxy, n, m and k each independently represent 0 to 6, p represents 0 to 4, q represents 1 to 4, r represents 2 to 7, respectively. . ), Embedded image(Wherein i represents 0 to 6), R1Is hydrogen or an amino protecting group, RTwo, RThree, RFourAnd RFiveIs each independently hydrogen; lower alkyl; lower alkyl
Thio; lower alkylsulfonyl; hydroxy; lower alkoxy; amino;
Alkylamino; acylamino; N- (lower alkyl) acylamino; carboxy
Lower alkoxycarbonyl; optionally substituted with one or two lower alkyl groups;
Rubamoyl; hydroxy (lower) alkyl; lower alkoxy (lower) alkyl;
N-acylamino (lower) alkyl; N- (loweralkyl) -N-acylamino
(Lower) alkyl; carboxy (lower) alkyl; lower alkoxycarbonyl (
Carbamoyl (optionally substituted with one or two lower alkyls)
Lower) alkyl; or(Where R12And R13Is each independently hydrogen or lower alkyl, or R12 And R13May combine to form a lower alkylene chain, and j is 0 to 6.
means. ) Means respectively. Or a salt thereof. 【請求項２】 Ａがピリジル、インドリル、２−オキソ−２，３−ジヒドロ
−１Ｈ−ベンズイミダゾリルまたはフェニルであって、その各々はヒドロキシ、
アミノ、低級アルキル、低級アルキルスルホニルアミノ、フェニル（低級）アル
コキシおよびフェニル（低級）アルコキシカルボニルアミノよりなる群から選択
された同種または異種の置換基を１ないし３個有していてもよい、 −Ｘ−が結合、−ＣＨ2−、−ＣＨ2−ＣＨ2−、−Ｏ−ＣＨ2−または−ＳＯ2
−ＣＨ2−、 【化１２】 （式中、Ｒ11は水素またはヒドロキシを意味する。）、 【化１３】 または−（ＣＨ2）n−Ｑ−（ＣＨ2）m− （式中、−Ｑ−は 【化１４】 【化１５】 （式中、Ｒ10は水素または低級アルキル、 Ｒ11は低級アルキルをそれぞれ意味する。）、 Ｒ6、Ｒ7、Ｒ8およびＲ9はそれぞれ単独に水素、低級アルキル、または低級ア
ルコキシを１ないし３個有していてもよいアリール、 ｎ、ｍおよびｋはそれぞれ単独に０ないし６、 ｒは２ないし７、 をそれぞれ意味する。）、 【化１６】 （式中、ｉは０ないし６を意味する。）、 Ｒ1が水素またはアル（低級）アルキル、 Ｒ2、Ｒ3、Ｒ4およびＲ5がそれぞれ単独に水素；低級アルキル；低級アルキル
チオ；低級アルキルスルホニル；ヒドロキシ；低級アルコキシ；アミノ；低級ア
ルキルアミノ；アシルアミノ；Ｎ−（低級アルキル）アシルアミノ；カルボキシ
；または低級アルコキシカルボニル、 である請求項１に記載の化合物。2. A is pyridyl, indolyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl or phenyl, each of which is hydroxy,
-X may have 1 to 3 same or different substituents selected from the group consisting of amino, lower alkyl, lower alkylsulfonylamino, phenyl (lower) alkoxy and phenyl (lower) alkoxycarbonylamino. - is a bond, -CH 2 -, - CH 2 -CH 2 -, - O-CH 2 - or -SO 2
—CH 2 —, embedded image (Wherein, R 11 represents hydrogen or hydroxy). Or-(CH 2 ) n -Q- (CH 2 ) m- (wherein -Q- is Embedded image (Wherein, R 10 represents hydrogen or lower alkyl, and R 11 represents lower alkyl, respectively), R 6 , R 7 , R 8, and R 9 each independently represent hydrogen, lower alkyl, or lower alkoxy with 1 to The aryl which may have three, n, m and k each independently represent 0 to 6, and r represents 2 to 7, respectively. ), Embedded image (Wherein i represents 0 to 6); R 1 is hydrogen or ar (lower) alkyl; R 2 , R 3 , R 4 and R 5 are each independently hydrogen; lower alkyl; lower alkylthio; lower. The compound according to claim 1, which is alkylsulfonyl; hydroxy; lower alkoxy; amino; lower alkylamino; acylamino; N- (lower alkyl) acylamino; carboxy; or lower alkoxycarbonyl. 【請求項３】 Ａがピリジル、インドリルまたはフェニルであって、その各
々はヒドロキシ、アミノ、低級アルキル、低級アルキルスルホニルアミノ、フェ
ニル（低級）アルコキシおよびフェニル（低級）アルコキシカルボニルアミノよ
りなる群から選択された同種または異種の置換基を１ないし３個有していてもよ
い、 −Ｘ−が結合、−ＣＨ2−、−ＣＨ2−ＣＨ2−、−Ｏ−ＣＨ2−または−ＳＯ2
−ＣＨ2−、 【化１７】 （式中、Ｒ11は水素またはヒドロキシを意味する。）、 【化１８】 または−（ＣＨ2）n−Ｑ−（ＣＨ2）m− （式中、−Ｑ−は 【化１９】 【化２０】 （式中、Ｒ10は水素または低級アルキル、 Ｒ11は低級アルキルをそれぞれ意味する。）、 Ｒ6、Ｒ7、Ｒ8およびＲ9はそれぞれ単独に水素、低級アルキル、または低級ア
ルコキシを１ないし３個有していてもよいフェニル、 ｎ、ｍおよびｋはそれぞれ単独に０または１、 ｒは２ないし７、 をそれぞれ意味する。）、 【化２１】 （式中、ｉは０または１を意味する。）、 Ｒ1が水素またはフェニル（低級）アルキル、 Ｒ2、Ｒ3、Ｒ4およびＲ5がそれぞれ単独に水素；低級アルキル；低級アルキル
チオ；低級アルキルスルホニル；ヒドロキシ；低級アルコキシ；アミノ；低級ア
ルキルアミノ；低級アルコキシカルボニルアミノ；低級アルキルスルホニルアミ
ノ；低級アルカノイルアミノ；ウレイド；トリフルオロアセチルアミノ；Ｎ−（
低級アルキル）［（低級）アルコキシカルボニル］アミノ；カルボキシ；または
低級アルコキシカルボニル、 である請求項２に記載の化合物。3. A is pyridyl, indolyl or phenyl, each of which is selected from the group consisting of hydroxy, amino, lower alkyl, lower alkylsulfonylamino, phenyl (lower) alkoxy and phenyl (lower) alkoxycarbonylamino. and, 1 to same or different substituents may be three, -X- bond, -CH 2 -, - CH 2 -CH 2 -, - O-CH 2 - or -SO 2
—CH 2 —, embedded image (Wherein R 11 represents hydrogen or hydroxy). Or-(CH 2 ) n -Q- (CH 2 ) m- (wherein -Q- is Embedded image (Wherein, R 10 represents hydrogen or lower alkyl, and R 11 represents lower alkyl, respectively), R 6 , R 7 , R 8, and R 9 each independently represent hydrogen, lower alkyl, or lower alkoxy with 1 to Three phenyls, n, m and k each independently represent 0 or 1, and r represents 2 to 7, respectively. ), Embedded image (Wherein i represents 0 or 1); R 1 is hydrogen or phenyl (lower) alkyl; R 2 , R 3 , R 4 and R 5 are each independently hydrogen; lower alkyl; lower alkylthio; lower. Alkyl; sulfonyl; hydroxy; lower alkoxy; amino; lower alkylamino; lower alkoxycarbonylamino; lower alkylsulfonylamino; lower alkanoylamino; ureido; trifluoroacetylamino;
The compound according to claim 2, which is lower alkyl) [(lower) alkoxycarbonyl] amino; carboxy; or lower alkoxycarbonyl. 【請求項４】 Ａがフェニルであって、ヒドロキシ、アミノ、低級アルキル
スルホニルアミノおよびフェニル（低級）アルコキシよりなる群から選択された
同種または異種の置換基を１ないし３個有していてもよい、 −Ｘ−が結合、−ＣＨ2−、−ＣＨ2−ＣＨ2−、−Ｏ−ＣＨ2−または−ＳＯ2
−ＣＨ2−、 【化２２】 （式中、Ｒ11は水素またはヒドロキシを意味する。）、 【化２３】 （式中、Ｒ6、Ｒ7、Ｒ8およびＲ9はそれぞれ単独に水素、低級アルキル、または
低級アルコキシを１ないし３個有していてもよいフェニル、 ｎ、ｍおよびｋはそれぞれ単独に０または１、 をそれぞれ意味する。）、 Ｒ1が水素またはフェニル（低級）アルキル、 Ｒ2、Ｒ3、Ｒ4およびＲ5がそれぞれ単独に水素；低級アルキル；低級アルキル
チオ；低級アルキルスルホニル；ヒドロキシ；低級アルコキシ；アミノ；低級ア
ルキルアミノ；低級アルコキシカルボニルアミノ；低級アルキルスルホニルアミ
ノ；低級アルカノイルアミノ；ウレイド；トリフルオロアセチルアミノ；Ｎ−（
低級アルキル）［（低級）アルコキシカルボニル］アミノ；カルボキシ；または
低級アルコキシカルボニル、 である請求項３に記載の化合物。4. A is phenyl and may have 1 to 3 same or different substituents selected from the group consisting of hydroxy, amino, lower alkylsulfonylamino and phenyl (lower) alkoxy. , -X- is bonded, -CH 2 -, - CH 2 -CH 2 -, - O-CH 2 - or -SO 2
—CH 2 —, embedded image (Wherein R 11 represents hydrogen or hydroxy), (Wherein, R 6 , R 7 , R 8 and R 9 are each independently phenyl optionally having 1 to 3 hydrogen, lower alkyl or lower alkoxy, n, m and k are each independently 0 R 1 is hydrogen or phenyl (lower) alkyl, R 2 , R 3 , R 4 and R 5 are each independently hydrogen; lower alkyl; lower alkylthio; lower alkylsulfonyl; hydroxy; Lower alkoxy; amino; lower alkylamino; lower alkoxycarbonylamino; lower alkylsulfonylamino; lower alkanoylamino; ureido; trifluoroacetylamino;
The compound according to claim 3, which is lower alkyl) [(lower) alkoxycarbonyl] amino; carboxy; or lower alkoxycarbonyl. 【請求項５】 Ａがフェニルであって、ヒドロキシ、アミノおよび低級アル
キルスルホニルアミノよりなる群から選択された同種または異種の置換基を１ま
たは２個有していてもよい、 −Ｘ−が結合または−Ｏ−ＣＨ2−、 【化２４】 【化２５】 Ｒ1が水素、 Ｒ2、Ｒ3、Ｒ4およびＲ5がそれぞれ単独に水素、低級アルコキシまたは低級ア
ルコキシカルボニルアミノ、 である請求項４に記載の化合物。5. A is phenyl, which may have one or two same or different substituents selected from the group consisting of hydroxy, amino and lower alkylsulfonylamino, wherein -X- is a bond Or —O—CH 2 —, Embedded image The compound according to claim 4, wherein R 1 is hydrogen, and R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkoxy or lower alkoxycarbonylamino. 【請求項６】 （２Ｓ）−１−［４−ヒドロキシ−３−（メタンスルホニル
アミノ）フェノキシ］−３−［［３，３−ビス（４−メトキシフェニル）プロピ
ル］アミノ］−２−プロパノール； （１Ｒ）−１−［４−ヒドロキシ−３−（メタンスルホニルアミノ）フェニル
］−２−［［３，３−ビス（４−メトキシフェニル）プロピル］アミノ］エタノ
ール； （２Ｓ）−１−フェノキシ−３−［［３，３−ビス［４−［（メトキシカルボ
ニル）アミノ］フェニル］プロピル］アミノ］−２−プロパノール； またはそれらの塩 である請求項５に記載の化合物。6. (2S) -1- [4-hydroxy-3- (methanesulfonylamino) phenoxy] -3-[[3,3-bis (4-methoxyphenyl) propyl] amino] -2-propanol; (1R) -1- [4-hydroxy-3- (methanesulfonylamino) phenyl] -2-[[3,3-bis (4-methoxyphenyl) propyl] amino] ethanol; (2S) -1-phenoxy- The compound according to claim 5, which is 3-[[3,3-bis [4-[(methoxycarbonyl) amino] phenyl] propyl] amino] -2-propanol; or a salt thereof. 【請求項７】 請求項１に記載の化合物またはその塩の製造法であって、 （ｉ）式 【化２６】 （式中、ＡおよびＸはそれぞれ請求項１に定義の通りである。） で表される化合物［ＩＩ］を、式 【化２７】 （式中、Ｙ、Ｚ、Ｒ1、Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ請求項１に定義の通
りである。）で表される化合物［ＩＩＩ］またはその塩と反応させて、式 【化２８】 （式中、Ａ、Ｘ、Ｙ、Ｚ、Ｒ1、Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ請求項１に
定義の通りである。）で表される化合物［Ｉ］またはその塩を得るか、または （ｉｉ）式 【化２９】 （式中、Ａ、Ｘ、Ｙ、Ｚ、Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ請求項１に定義の
通りであり、 Ｒ1 aはアミノ保護基、 を意味する。） で表される化合物［Ｉａ］またはその塩をアミノ保護基の脱離反応に付して、式 【化３０】 （式中、Ａ、Ｘ、Ｙ、Ｚ、Ｒ2、Ｒ3、Ｒ4およびＲ5はそれぞれ請求項１に定義の
通りである。） で表される化合物［Ｉｂ］またはその塩を得ることを特徴とする前記製造法。7. A method for producing a compound or a salt thereof according to claim 1, wherein (i) a compound represented by the formula: (Wherein A and X are each as defined in claim 1). A compound [II] represented by the formula: (Wherein Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are each as defined in claim 1), and reacted with the compound [III] or a salt thereof. , The formula (Wherein A, X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are each as defined in claim 1) or a salt thereof. Or (ii) having the formula (Is as in formula, A, X, Y, Z, the R 2, R 3, R 4 and R 5 each claim 1 definitions. Where R 1 a denotes an amino protecting group) tables in The compound [Ia] or a salt thereof is subjected to an elimination reaction of an amino protecting group to give a compound of the formula (Wherein, A, X, Y, Z, R 2 , R 3 , R 4 and R 5 are each as defined in claim 1) or a salt thereof. The above-mentioned production method characterized by the above-mentioned. 【請求項８】 医薬として許容される担体または賦形剤と共に、請求項１に
記載の化合物または医薬として許容されるその塩を有効成分として含有する医薬
組成物。8. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier or excipient. 【請求項９】 請求項１に記載の化合物または医薬として許容されるその塩
の、医薬の製造への使用。9. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. 【請求項１０】 請求項１に記載の化合物または医薬として許容されるその
塩の医薬としての用途。10. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof as a medicament. 【請求項１１】 請求項１に記載の化合物または医薬として許容されるその
塩をヒトまたは動物に投与することからなる、頻尿または尿失禁の予防および／
または治療方法。11. Prevention of pollakiuria or urinary incontinence comprising administering to a human or animal a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
Or treatment method.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011517316A (en) * 2008-02-28 2011-06-02 アルミラル・ソシエダッド・アノニマ Derivatives of 4- (2-amino-1-hydroxyethyl) phenol as β2-adrenergic receptor agonists

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPQ407699A0 (en) * 1999-11-16 1999-12-09 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
AUPQ575300A0 (en) * 2000-02-21 2000-03-16 Fujisawa Pharmaceutical Co., Ltd. New compound
AUPR034000A0 (en) 2000-09-25 2000-10-19 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
AUPR120400A0 (en) * 2000-11-02 2000-11-23 Fujisawa Pharmaceutical Co., Ltd. New compound
JP4044740B2 (en) * 2001-05-31 2008-02-06 信越化学工業株式会社 Resist material and pattern forming method
WO2003024483A1 (en) * 2001-09-11 2003-03-27 Fujisawa Pharmaceutical Co., Ltd. Potentiator for inhibitory effects on urinary frequency and urinary incontinence
CN101039902B (en) * 2004-09-21 2010-11-10 安斯泰来制药有限公司 Aminoalcohol derivatives
DE102004050952A1 (en) * 2004-10-18 2006-04-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of a beta-3-adrenoreceptor-agonist for the prophylaxis and/or treatment of e.g. benign prostata hyperplasia and/or its associated symptoms and chronic pelvic base pain syndrome, pelvic myoneuropathy, prostatodynia or prostatopathy

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5451677A (en) * 1993-02-09 1995-09-19 Merck & Co., Inc. Substituted phenyl sulfonamides as selective β 3 agonists for the treatment of diabetes and obesity
US5726165A (en) * 1994-07-29 1998-03-10 Smithkline Beecham P.L.C. Derivatives of 4-(2-aminoethyl)phenoxymethyl-phosphonic and -phosphinic acid and pharmaceutical and veterinary uses therefor
AU3254695A (en) * 1994-07-29 1996-03-04 Smithkline Beecham Plc Aryloxy and arylthiopropanolamine derivatives useful as beta 3-adrenoreceptor agonists and antagonists of the beta 1 and beta 2-adrenoreceptors and pharmaceutical composition thereof
US5541204A (en) * 1994-12-02 1996-07-30 Bristol-Myers Squibb Company Aryloxypropanolamine β 3 adrenergic agonists
FR2746395B1 (en) * 1996-03-22 1998-04-17 Adir NOVEL ARYLETHANOLAMINE AND ARYLOXYPROPANOLAMINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Cited By (1)

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JP2011517316A (en) * 2008-02-28 2011-06-02 アルミラル・ソシエダッド・アノニマ Derivatives of 4- (2-amino-1-hydroxyethyl) phenol as β2-adrenergic receptor agonists

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