WO1994025427A1

WO1994025427A1 - Ethanolamine derivatives useful for the treatment of gastrointestinal disorders

Info

Publication number: WO1994025427A1
Application number: PCT/JP1994/000671
Authority: WO
Inventors: Youichi Shiokawa; Kiyoshi Taniguchi; Masanobu Nagano; Kazuhiko Take; Takeshi Kato; Kazunori Tsubaki; Seiichiro Tabuchi
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1993-04-26
Filing date: 1994-04-22
Publication date: 1994-11-10
Also published as: JPH08509491A; HUT69285A; AU6581294A

Abstract

This invention relates to new ethanolamine derivatives having gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities and represented by general formula (I), wherein R1 is aryl, aryloxy(lower)alkyl or a heterocyclic group, each of which may be substituted with substituent(s) selected from the group consisting of halogen, hydroxy, protected hydroxy, aryloxy, lower alkoxy, halo(lower)alkoxy, nitro, cyano, amino and acylamino, R2 is hydrogen or an N-protective group, R3 is lower alkoxy substituted with acyl, R4 is lower alkoxy substituted with acyl, and A is lower alkylene, and pharmaceutically acceptable salts thereof, to processes for the preparation thereof and to a pharmaceutical composition comprising the same.

Description

DESCRIPTION

ETHANOLAMINE DERIVATIVES USEFUL FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS

TECHNICAL FIELD

This invention relates to new ethanolamine derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.

BACKGROUND ART

Some ethanolamine derivatives having spasmolytic activity and relaxing activity on smooth muscle contraction have been known as described, for example, in European Patent Application Publication Nos. 0 211 721, 0 255 415 and 0 383 686, and International Publication Nos. WO 92/18461 and WO 93/15041.

DISCLOSURE OF INVENTION

This invention relates to new ethanolamine derivatives and pharmaceutically acceptable salts thereof. More particularly, it relates to new ethanolamine derivatives and pharmaceutically acceptable salts thereof which have gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to a method for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis or the like; and for the treatment and/or prevention of pancreatitis, obesity, diabetes, glaucoma, melancholia and the like. One object of this invention is to provide new and useful ethanolamine derivatives and pharmaceutically acceptable salts thereof which have gut selective sympathomimetic, anti-ulcerous, lipolytic and anti-pollakiuria activities. Another object of this invention is to provide processes for the preparation of said ethanolamine derivatives and salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said ethanolamine derivatives and pharmaceutically acceptable salts thereof.

Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in human beings or animals, using said ethanolamine derivatives and pharmaceutically acceptable salts thereof.

The object ethanolamine derivatives of this invention are new and can be represented by the following general formula [I] :

94/00671

- 3 -

wherein R is aryl, arγloxy(lower)alkyl or a heterocyclic group, each of which may be substituted with substituent(s) selected from the group consisting of halogen, hydroxy, protected hydroxy, aryloxy, lower alkoxy, halo(lower)alkoxy, nitro, cyano, amino and acylamino,

R is hydrogen or an N-protective group, R^" is lower alkoxy substituted with acyl, R is lower alkoxy substituted with acyl, and A is lower alkylene, and pharmaceutically acceptable salts thereof

The object compound [I] or its salt can be prepared by the following processes.

Process 1

R1-CH

[II] [III] or its salt

[I] or its salt Process 2

elimination of the N-protective group

[la] or its salt

[lb] or its salt

Process 3

[IC] or its salt

deesterification

[Id] or its salt Process 4

esterification

[Id] or its reactive derivative at the carboxy group or a salt thereof

[Ic] or its salt

Process 5

[IV] or its salt

[Ie] or its salt 1 9 ""* A wherein R , R , R^J, R and A are each as defined above,

R 2 i.s an N-protective group,

R^a3 is lower alkoxy substituted with esterified carboxy,

Ra is lloowweerr aallJkoxy substituted with esterified carboxy,

₃ R, is lower alkoxy substituted with carboxy,

R, is lower alkoxy substituted with carboxy, R 5 is lower alkyl substituted with acyl, and x is acid residue.

In the above and subsequent description of the present specification, suitable examples of the various definition to be included within the scope of the invention are explained in detail in the following.

The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.

Suitable "halogen" and halo moiety in the term "halo(lower)alkoxy" may be fluorine, chlorine, bromine, and iodine, in which preferable one is chlorine or bromine.

Suitable "lower alkyl" and lower alkyl moiety in the term "aryloxy(lower)alkyl" may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or the like.

Suitable "lower alkylene" may be a straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylethylene, ethylethylene, dimethylethylene or the like, in which preferable one is .,-C₄ ones and more preferably ethylene, methylethylene, ethylethylene or dimethylethylene. Suitable "lower alkoxy" and lower alkoxy moiety in the term "halo(lower)alkoxy" may be a straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy or the like, in which preferable one is C.-C. ones and more preferably methoxy. "Protected hydroxy" may be commonly protected hydroxy such as substituted lower alkoxy such as lower alkoxy(lower)alkoxy [e.g. methoxy ethoxy, etc.], lower alkoxy(lower)alkoxy(lower)alkoxy [e.g. methoxyethoxymethoxy, etc.], substituted or unsubstituted ar(lower)alkoxy [e.g. benzyloxy, nitrobenzyloxy, etc.], etc., acyloxy such as lower alkanoyloxy [e.g. acetoxy, propionyloxy, pivaloyloxy, etc.], aroyloxy [e.g. benzoyloxy, fluorenecarbonyloxy, etc.], lower alkoxycarbonyloxy [e.g. methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyloxy [e.g. benzyloxycarbonyloxy, bromobenzyloxycarbonyloxy, etc.] etc., tri(lower)alkylsilyloxy [e.g. tri ethylsilyloxy, etc.] or the like.

Suitable "aryl" and aryl moiety in the terms "aryloxy" and "aryloxy(lower)alkyl" may be uncondensed or condensed aromatic hydrocarbon group such as phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.], indenyl, indanyl or the like, in which preferable one is phenyl or naphthyl. Suitable "aryloxy(lower)alkyl" may be phenoxy(lower)- alkyl such as phenoxymethyl, phenoxyethyl, etc. , naphthoxy(lower) alkyl such as naphthoxymethyl, naphthoxyethyl, etc., and the like, in which preferable one is phenoxymethyl. Suitable "heterocyclic group" may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and preferable heterocyclic group may be N-containing heterocyclic group such as unsaturated 3 to 6-membered hetero onocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g. 4H-l,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.], tetrazolyl [e.g. lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, guinolyl, isoguinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g. tetrazolo[l,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc. ; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, etc. ; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc. ] , etc. ; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. orpholinyl, etc. ] ; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzofurazanyl, benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. , thiazolidinyl, etc. ] ; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms [e.g. benzofuranyl, benzodioxolyl, etc.] and the like, in which preferable one is pyridyl.

Suitable "acyl" and acyl moiety in the term "acylamino" may be carboxy; esterified carboxy; carbamoyl optionally substituted with lower alkyl, lower alkoxy(lower)alkyl, arylsulfonyl, lower alkylsulfonyl or a heterocyclic group; lower alkanoyl; aroyl; a heterocycliccarbonyl and the like.

The esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl,

2,2,2-trichloroethoxycarbonyl, etc.], substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.] and the like, in which preferable one is lower alkoxycarbonyl.

The carbamoyl substituted with lower alkyl may be methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-methyl-N-ethylcarbamoyl and the like.

The carbamoyl substituted with lower alkoxy(lower)alkyl may be methoxymethylcarbamoyl, methoxyethylcarba oyl, ethoxymethylcarbamoyl, ethoxyethylcarbamoyl and the like.

The carbamoyl substituted with arylsulfonyl may be phenylsulfonylcarbamoyl, tolylsulfonylcarbamoyl and the like.

The carbamoyl substituted with lower alkylsulfonyl may be methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl and the like.

The carbamoyl substituted with a heterocyclic group may be one substituted with a heterocyclic group as mentioned above. The lower alkanoyl may be substituted or unsubstitued one such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like, in which preferable one is acetyl, propionyl, butyryl or pivaloyl. The aroyl may be benzoyl, naphthoyl, toluoyl, di(tert-butyl)benzoyl and the like.

The heterocyclic moiety in the term "a heterocyclic- carbonyl" may be one mentioned above as a heterocyclic group. "N-Protective groμp" may be common N-protective group such as acyl, for example, substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxγcarbonyl, etc. ] , substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl, benzyl, etc.] or the like, in which preferable one is phenyl(lower)alkyl such as benzyl. Suitable "aryloxy(lower)alkyl which is substituted with substituent(s) selected from the group consisting of halogen, hydroxy, protected hydroxy, aryloxy, lower alkoxy, halo( lower)alkoxy, nitro, cyano and acyla ino" may be lower alkyl which is substituted with aryloxy substituted with substituent(s) selected from the group mentioned above.

Suitable "acid residue" may be halogen [e.g. fluoro, chloro, bro o, iodo], arenesulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy, etc.], alkanesulfonyloxy

[e.g. mesyloxy, ethanesulfonyloxy, etc.], and the like, in which preferable one is halogen.

Preferable compound [I] is one which has phenyl optionally substituted with halogen, naphthyl, phenoxymethyl, or pyridyl for R 1, hydrogen for R2, lower alkoxy substituted with esterified carboxy or carboxy for

3 R , lower alkoxy substituted with esterified carboxy or

4 carboxy for R , and lower alkylene for A.

More preferable compound [I] is one which has phenyl substituted with halogen for R 1, hydrogen for R2, lower alkoxy substituted with lower alkoxycarbonyl or carboxy

3 for R , lower alkoxy substituted with lower alkoxycarbonyl

4 or carboxy for R , and lower alkylene for A.

Most preferable compound [I] is one which has phenyl substituted with halogen for R 1, hydrogen for R2, methoxy

3 substituted with lower alkoxycarbonyl for R , methoxy

4 substituted with lower alkoxycarbonyl for R , and lower alkylene for A.

Suitable pharmaceutically acceptable salts of the object compound [I] are conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.

The processes for preparing the object compound [I] is explained in detail in the following.

Process 1

The object compound [I] or its salt can be prepared by reacting a compound [II] with a compound [III] or its salt. Suitable salt of the compound [III] may be the same as those exemplified for the compound [I].

The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkyla ine [e.g. trimethylamine, triethylamine, etc.], picoline or the like. The reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction. The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Process 2

The object compound [lb] or its salt can be prepared by subjecting a compound [Ia] or its salt to elimination reaction of the N-protective group.

Suitable salts of the compounds [Ia] and [lb] may be the same as those exemplified for the compound [I].

This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like .

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, l,5-diazabicyclo[4.3.0]- non-5-ene, l,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, or the like.

Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.] and an acid addition salt compound [e.g. pyridine hydrochloride, etc. ] .

The elimination using trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nikel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ull an copper, etc.] and the like.

In case that the N-protective group is benzyl, the reduction is preferably carried out in the presence of a combination of palladium catalysts [e.g. palladium black, palladium on carbon, etc. ] and formic acid or its salt ' [e.g. ammonium formate, etc.].

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], chlorobenzene, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof. The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.

In this reaction, in case that the compound [Ia] having lower alkoxy substituted with esterified carboxy ₃ for R and/or lower alkoxy substituted with esterified

4 carboxy for R is used as a starting compound, the compound [lb] having lower alkoxy substituted with carboxy ₃ 4 for R and/or lower alkoxy substituted with carboxy for R may be obtained according to reaction conditions. This case is included within the scope of the present reaction.

Process 3

The object compound [Id] or its salt can be prepared by subjecting a compound [Ic] or its salt to deesterification reaction.

Suitable salt of the compound [Ic] may be an inorganic or organic acid addition salt as exemplified for the compound [I] . Suitable salt of the compound [Id] may be the same as those exemplified for the compound [I].

The reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like. The hydrolysis is_ preferably carried out in the presence of a base or an acid including Lewis acid. Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. lithium, sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, l,5-diazabicyclo[4.3.0]- non-5-ene, 1,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, or the like. Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.] and Lewis acid [e.g. boron tribromide, etc. ] .

The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. The reduction can be applied preferably for elimination of the ester moiety such as 4-nitrobenzyl, ^■2-iodoethyl, 2,2,2-trichloroethyl, or the like. The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction. Suitable reduction agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc. ] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid., etc.].

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalyst [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalyst [e.g. reduced nickel nickel oxide, Raney nickel,i etc.], cobalt catalyst [e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reduced iron, Raney iron, etc.], copper catalyst [e.g. reduced copper, Raney copper, Ullman copper, etc.] or the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. , or a mixture thereof. The reaction temperature of this reaction is not critical and the reaction is usually carried out under cooling to warming.

In this reaction, in case that the compound [Ic]

2 having an N-protective group for R is used as a starting

2 compound, the compound [Id] having hydrogen for R may be obtained according to reaction conditions. This case is included within the scope of the present reaction.

Process 4 The object compound [Ic] or its salt can be prepared by reacting a compound [Id] or its reactive derivative at the carboxy group or a salt thereof with a hydroxy compound.

Suitable salts of the compounds [Ic] and [Id] and its reactive derivative at the carboxy group may be the same as those exemplified for the compound [I].

Suitable reactive derivative at the carboxy group of the compound [Id] may be acid halide [e.g. acid chloride, acid bromide, etc. ] and the like. Suitable hydroxy compound may be an alcohol [e.g. methanol, ethanol, propanol, benzyl alcohol,

2-dimethylaminoethanol, etc.], phenol, naphthol and the like.

The reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride or any other organic solvent which does not adversely influence the reaction.

Additionally, in case that the above-mentioned hydroxy compound is in liquid, it can also be used as a solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. When the compound [Id] is used in a free acid form in the reaction, the reaction is preferably carried out in the presence of an acid or a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;

N-cyclohexyl-N'-morpholinoethylcarbodiimide;

N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;

N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;

N,N' -carbonylbis-(2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene;

1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; diphenyl chlorophosphate; diphenylphosphinic chloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;

2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; l-(p-chlorobenzenesulfonyloxy)-6- chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. ; or the like.

Suitable acid may be an organic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, trichloroacetic acid, etc.], an inorganic acid [e.g. hydrogen chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.].

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 5

The object compound [Ie] or its salt can be prepared by reacting a compound [IV] or its salt with a compound [V]. Suitable salts of the compounds [Ie] and [IV] may be the same as those exemplified for the compound [I].

When the compound [V] having halogen for X is used in this reaction, the reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.], alkaline earth metal alkoxide [e.g. magnesium methoxide, magnesium ethoxide, etc.] or the like, or alkali metal iodide [e.g. sodium iodide, potassium iodide, etc.] or the like.

Additionally, the reaction is also preferably carried out in the presence of phase transfer catalyst [e.g. tetra-n-butylammonium bromide, etc.].

This reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, aromatic hydrocarbon [e.g. benzene, toluene, xylene, etc.], N,N-dime hylformamide, dimethyl sulfoxide, acetone, a mixture thereof, or any other solvent which does not adversely influence the reaction. Additionally, in case that the compound (V) is in liquid, it can also be used as a solvent.

The starting compounds [Ilia], [Illb], [IIIc], [IV] and [IVb] or a salt thereof can be prepared by the following processes.

Process A

[VI ] or its salt

[VII ] or its salt Process B

elimination of the N-protective group

[Vila] or its salt

[Vllb] or its salt

Process C

introduction of the N-protective group

[Vllb] or its salt

[Vila] or its salt Process D

[VII] or its salt

[Ilia] or its salt

Process E

elimination of the N-protective group

[Illb] or its salt

[IIIc] or its salt Process F

R- introduction of the N-protective group

[IIIc] or its salt

[ IHb] or its salt

Process G

[II] [VII] or its salt

[IV] or its salt Process H

elimination of the N-protective group

[IVa] or its salt

[IVb] or its salt

wherein R 2, R3, R4 R5, A and X are each as defined above,

R^a6 is lower alkyl, and

7 . R is lower alkyl.

The above-mentioned processes for preparing the starting compounds are explained in detail in the following.

Process A

The compound [VII] or its salt can be prepared by subjecting a compound [VI] or its salt to dealkylation reaction.

Suitable salt of the compound [VI] may be an inorganic or organic acid addition salt as exemplified for the compound [I] .

Suitable salt of the compound [VII] may be the same as those exemplified for the compound [I]. The reaction is carried out in the presence of an acid including Lewis acid [e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, boron trichloride, etc.], boron tribromide-methyl sulfide complex, or tri(lower alkyl)silyliodide [e.g. trimethylsilyliodide, etc.].

The reaction is usually carried out in a solvent such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.

Additionally, in case that the above-mentioned acids are in liquid, they can also be used as a solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

Process B

The compound [Vllb] or its salt can be prepared by subjecting a compound [Vila] or its salt to elimination reaction of the N-protective group. Suitable salts of the compounds [Vila] and [Vllb] may be the same as those exemplified for the compound [I].

This reaction can be carried out in substantially the same manner as Process 2 , and therefore the reaction mode and the reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 2.

Process C

The compound [Vila] or its salt can be prepared by subjecting a compound [Vllb] or its salt to introduction reaction of the N-protective group.

Suitable salts of the compounds [Vila] and [Vllb] may be the same as those exemplified for the compound [I].

Suitable introducing agent of the N-protective group used in this reaction may be a halogen compound of the N-protective group afore-mentioned such as acetyl chloride, tert-butoxycarbonyl chloride, benzyl chloride,., benzyl bromide or the like, di-tert-butyl dicarbonate, a combination of benzaldehyde and a reducing agent [e.g. sodium cyanoborohydride, etc.], and the like.

The reaction is preferably carried out in the presence of a base as explained in Process 1.

The reaction is usually carried out in a conventional solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], tetrahydrofuran, dioxane, pyridine,

N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction, or a mixture thereof.

The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Process D

The compound [Ilia] or its salt can be prepared by reacting a compound [VII] or its salt with a compound [V] . Suitable salts of the compounds [Ilia] and [VII] may be the same as those exemplified for the compound [I].

When the compound [V] having halogen for X is used in this reaction, the reaction is preferably carried out in the presence of a base such as alkali metal [e.g. lithium, sodium, potassium, etc. ] , the hydroxide or carbonate or bicarbonate thereof [e.g. sodium hydroxide, potassium carbonate, potassium bicarbonate, etc.], alkaline earth metal [e.g. calcium, magnesium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], alkaline earth metal hydride [e.g. calcium hydride, etc.], alkali metal alkoxide [e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.], alkaline earth metal alkoxide [e.g. magnesium methoxide, magnesium ethoxide, etc.] or the like, or alkali metal iodide [e.g. sodium iodide, potassium iodide, etc.] or the like. Additionally, the reaction is also preferably carried out in the presence of phase transfer catalyst [e.g. tetra-n-butylammonium bromide, etc.].

This reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, aromatic hydrocarbon [e.g. benzene, toluene, xylene, etc.], N,N-dimethylformamide, dimethyl sulfoxide, acetone, a mixture thereof, or any other solvent which does not adversely influence the reaction. Additionally, in case that the compound [V] is in liquid, it can also be used as a solvent.

Process E

The compound [IIIc] or its salt can be prepared by subjecting a compound [Illb] or its salt to elimination reaction of the N-protective group.

Suitable salts of the compounds [Illb] and [IIIc] may be the same as those exemplified for the compound [I].

This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 2.

Process F

The compound [Illb] or its salt can be prepared by subjecting a compound [IIIc] or its salt to introduction reaction of the N-protective group.

This reaction can be carried out in substantially the same manner as Process C, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process C.

Process G The compound [IV] or its salt can be prepared by reacting a compound [II] with a compound [VII] or its salt. Suitable salts of the compounds [IV] and [VII] may be the same as those exemplified for the compound [I].

This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction condition [e.g. solvent, reaction temperature, etc.] of this reaction are to be referred to those explained in Process 1.

Process H

The compound [IVb] or its salt can be prepared by subjecting a compound [IVa] or its salt to elimination reaction of the N-protective group.

Suitable salts of the compounds [IVa] and [IVb] may be the same as those exemplified for the compound [I].

The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary.

It is to be -noted that the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention. The object compound [I] and pharmaceutically acceptable salts thereof possess gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastrointestinal disorders caused by smooth muscle contractions in human beings or animals, and more particularly to methods for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, doudenal ulcer, enteritis, cholecystopathy, cholangitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, doudenal ulcer, peptic ulcer, ulcer caused by non steroidal anti-inflammatory drugs, or the like; for the treatment and/or prevention of dysuria such as pollakiuria, urinary incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis or the like; and for the treatment and/or prevention of pancreatitis, obesity, diabetes, glaucoma, melancholia and the like.

In order to illustrate the usefulness of the object compound [I], the pharmacological data of the compound [I] are shown in the following.

Test 1

Effect on isolated rat distal colon :

(1) Test Method : Male SD rats (180-230 g) were used. Animals were fasted for 24 hours prior to experiment. Distal colon was removed immediately after sacrifice and placed in an organ bath containing 25 ml Tyrode solution aerating with 95% 0₂, 5% CO- at 37°C. The strip was mounted under 0.5 g tension and spontaneous contractions were recorded isometrically. After the mobility was of a uniform size, test compound was added to an organ bath and the contractions were observed over a 30 minutes period. Effect of test compound was calculated by comparing contractions before and after test compound.

(ii) Test Results

Test Compound (Example No. ) Inhibition % at 10^~8M

3 80.3

5-4) 86.1

6 71.5

10 84.3

Test 2

Effect on isolated non-pregnant rat uterus

(i) Test Method :

Female SD rats (150-180 g) were used. 48 and 24 hours prior to use, rats were given estradial (ovahormon benzoat : Trademark, Teikoku Hormone Mfg. Co., Ltd.) subcutaneously at a dose of 40 μg/rat to induce oestrus. The animals were killed and uterine horns were removed. Each strip was placed in an organ bath containing 25 ml Locke solution aerating with 95% 0₂, 5% C0₂ at 37°C under 1 g tension. Contractions were recorded isometrically. After the spontaneous contractions were of a uniform size, test compound was added to organ bath. The motility was observed over a 20 minutes period. Effect of test compound was calculated by comparing contractions before and after test compound. (ii) Test Results

Test Compound (Example No. ) Inhibition % at 10~⁵ M

3 87.5

6 21.5

10 78.7

For therapeutic purpose, the compound [I] and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for oral, parenteral or external (topical) administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, suppositories, solutions, lotion, inhalant, ophthalmic preparations, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives. While the dosage of the compound [I] will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 g, 10 g, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I] may be effective for treating the above-mentioned diseases. in general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day. The following Preparations and Examples are given for the purpose of illustrating this invention.

Preparation 1 To a mixture of 3,3-bis(4-methoxyphenyl)propionic acid (1.00 g) and benzylamine (0.56 g) in methanol (20 ml) was added portionwise 1,1'-carbonyldiimidazole (0.62 g). The reaction mixture was stirred at ambient temperature for 2 days and partitioned between ethyl acetate and IN hydrochloric acid. The organic layer was washed successively with IN hydrochloric acid, IN aqueous sodium hydroxide solution (twice), and brine, dried over magnesium sulfate, and evaporated in vacuo to give N-benzy1-3,3-bis(4-methoxyphenyl)propionamide (0.78 g) as a colorless powder, mp : 118-120°C

IR (Nujol) : 3250, 1630, 1600, 800, 740, 720 cm^"1 NMR (CDC1₃, <5) : 2.86 (2H, d, J=8.0Hz) , 3.77 (6H, 3), 4.30 (2H, d, J=5.7Hz), 4.50 (IH, t, J=8.0Hz), 5.55 (IH, t, J=5.7Hz), 6.70-6.90 (6H, m), 7.10-7.30 (7H, m) MASS (m/z) : 375 (M⁺) , 227, 91

Preparation 2 To a mixture of N-benzyl-3,3-bis(4-methoxyphenyl)- propionamide (0.78 g) in dry tetrahydrofuran (20 ml) was added lithium aluminum hydride (100 mg) at ambient temperature. The reaction mixture was refluxed for 6 hours. After cooling, brine and diethyl ether were added to the reaction mixture and the resulting mixture was filtered. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane:methanol = 50:1) to give N-benzyl-3,3-bis(4-methoxγphenyl)propylamine (0.56 g) as a pale yellow oil.

IR (film) : 3300, 2840, 1610, 740, 700 cm^"1 NMR (CDC1₃, <5) : 1.49 (IH, br s), 2.10-2.35 (2H, m) , 2.59 (2H, t, J=6.8Hz), 3.71 (2H, s), 3.76 (6H, s), 3.92 (IH, t, J=7.9Hz), 6.70-6.90 (4H, m) ,

7.10-7.35 (9H, m) MASS (m/z) : 361 (M⁺) , 227, 91

Preparation 3 To a mixture of 3,3-bis(4-methoxγphenyl)propionic acid (1.41 g) in dry dichloromethane (10 ml) was added portionwise 1,1'-carbonyldiimidazole (1.5 g) and stirred for 2 days at ambient temperature. Water was added to the mixture, and then the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. To a solution of the residue in dry tetrahydrofuran (1.5 ml) was added dropwise 3N ethylmagnesium bromide in diethyl ether (1.8 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and IN hydrochloric acid. The organic layer was washed with IN sodium hydroxide solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography (silica gel, n-hexane:ethyl acetate_= 5:1) to give l,l-bis(4-methoxyphenyl)-3-pentanone (0.96 g) as a colorless oil, which was used for the next reaction without further purification.

Preparation 4

A solution of N-benzyl-4,4-bis(4-methoxyphenyl)-2- butylamine (1.357 g) in a 1.0 M solution of boron tribromide-methyl sulfide complex in methylene chloride (18.1 ml) was stirred at ambient temperature for 16 hours and under reflux for 10.5 hours, poured into sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and treated with 4N hydrogen chloride in ethyl acetate to afford N-benzyl-4,4-bis(4-hydroxyphenyl)- 2-butylamine hydrochloride (1.53 g) as an amorphous powder. mp : 86-94°C (dec.)

IR (film) : 3450, 2800-2350, 1230 cm^"1 NMR (DMS0-d₆, δ) : 1.29 (3H, d, J=6.5Hz) , 2.0 (IH, m), 2.6-2.85 (2H, m) , 3.87 (IH, m) , 4.14 (2H, br s), 6.65 (4H, d, J=8.5Hz), 7.04 (2H, d, J=8.5Hz), 7.08 (2H, d, J=8.5Hz), 7.39 (3H, m) , 7.55 (2H, m), 9.23 (2H, s), 9.26 (2H, s), 11.97 (IH, br s) MASS (m/z) : 347 (M⁺) , 134, 91 (base)

Preparation 5

The following compounds were obtained according to a similar manner to that of Preparation 4.

1) N-Benzyl-4,4-bis(4-hγdroxyphenyl)-2-methyl-2- butylamine mp : 203-208°C

IR (Nujol) : 3250, 2500, 1610, 830, 820, 770, 740 cm^-1

NMR (DMSO-d₅, δ) : 0.93 (6H, s), 1.30-1.50 (IH, br s), 2.15 (2H, d, J=6.1Hz), 3.52 (2H, s), 3.99 (IH, t, J=6.1Hz), 6.62 (4H, d, J=8.4Hz) , 7.11 (4H, d, J=8.4Hz), 7.15-7.35 (5H, ) , 9.07 (2H, s) MASS (m/z) : 361 (M⁺) , 254, 148

2) N-Benzyl-3 ,3-bis(4-hydroxyphenyl)propylamine mp : 126-128°C

IR (Nujol) : 3600-3100, 2800-2200, 1610, 840, 760, 700 cm^-1 NMR (DMSO-dg, δ) : 1.95-2.15 (2H, m) , 2.30-2.45 (2H, m), 3.65 (2H, s), 3.75-3.90 (IH, m) , 6.62 (4H,. d, J=8.5Hz), 7.00 (4H, d, J=8.5Hz) , 7.15-7.30 (5H, m), 9.12 (2H, s)

MASS (m/z) : 333 (M⁺) , 226, 199, 91

3) N-Benzyl-1,1-bis(4-hydroxyphenyl)-3-pentylamine IR (CH₂C1₂) : 3300, 1600, 830, 730, 700 cm^"1 NMR (DMSO-dg, δ) : 0.78 (3H, t, J=7.1Hz) , 1.30-1.50 (2H, m), 1.85-2.05 (2H, m) , 2.10-2.25 (IH, m) ,

3.57 (IH, d, J=13.6Hz), 3.67 (IH, d, J=13.6Hz), 3.88 (IH, t, J=7.5Hz), 6.50-6.70 (4H, m) , 6.90-7.10 (4H, m), 7.10-7.35 (5H, m) , 9.10 (2H, s) MASS (m/z) : 361 (M⁺) , 199, 91

Preparation 6

1 M Boron tribromide in dichloromethane (63 ml) was added dropwise to a stirred solution of (-)-N-benzyl-4,4- bis(4-methoxyphenyl)-2-butylamine hydrochloride (8.24 g) in dichloromethane (41 ml) under ice cooling over 40 minutes. The resulting mixture was stirred at the same temperature for 1 hour and 45 minutes, and poured slowly into a stirred 2N aqueous sodium hydroxide solution (105 ml) under ice cooling._ The resulting mixture was extracted with ethyl acetate. The aqueous layer was adjusted to pH ca. 8 with IN hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed twice with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to afford (+)-N-benzyl-4,4-bis(4-hydroxyphenyl)-2-butylamine (6.36 g) as a colorless powder. mp : 171-176°C (dec.) ^[α^D° ^{= +20}'⁶⁴° ⁽C=0.935, DMSO⁾ IR (Nujol) : 3260, 3200, 2700-2300, 1250 cm^"1 NMR (DMSO-dg, δ) : 0.98 (3H, d, J=6.0Hz), 1.7-1.85- (IH, m), 2.0-2.2 (IH, m) , 2.25-2.35 (IH, m) , 3.34 (IH, br s), 3.57 (IH, d, J=13.6Hz), 3.70 (IH, d, J=13.6Hz), 3.91 (IH, t, J=7.7Hz), 6.55-6.65 (4H, m) , 6.95-7.05 (4H, ) , 7.15-7.3 (5H, m), 9.11 (2H, s) (+) APCI-MASS (m/z) : 348 (M⁺+l), 147 (base)

Preparation 7

A mixture of N-benzyl-4,4-bis(4-hydroxyphenyl)-2- butylamine hydrochloride (1.49 g) , ammonium formate (2.45 g), and 10% palladium on carbon (0.75 g) in ethanol (41 ml) and methanol (21 ml) was stirred under reflux for 6 hours and filtered. The filtrate was evaporated in vacuo, diluted with sodium bicarbonate aqueous solution, and extracted three times with ethyl acetate. The extract was dried over sodium sulfate and evaporated in vacuo. The residue was washed with diethyl ether to afford 4,4-bis(4- hydroxyphenyl)-2-butylamine (713 mg) as a pale yellow powder. mp : 93°C (dec.)

IR (Nujol) : 3400-3100, 2750-2300, 1250 cm^"1 NMR (DMSO-dg, δ) : 0.94 (3H, d, J=6Hz) , 1.78 (2H, m), 2.45 (IH, m) , 3.3 (2H, br), 3.87 (IH, t,

J=8Hz), 6.63 (4H, d, J=8.5Hz), 7.02 (4H, d, J=8.5HZ) MASS (m/z) : 257 (M⁺) , 240 (base), 199

Preparation 8

A solution of di-tert-butyl dicarbonate (382 mg) in N,N-dimethylformamide (4 ml) was added dropwise to a stirred solution of 4,4-bis(4-hydroxyphenyl)-2- butylamine (386 mg) and triethylamine (334 mg) in N,N-dimethylformamide (7.7 ml) at ambient temperature. The resulting mixture was stirred at the same temperature for 2 days, poured into water, and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford 4,4-bis(4-hydroxypheny1)-N-tert-butoxycarbonyl-2- butyla ine (560 mg) as an oil, which was used for the next step without further purification.

IR (film) : 3300, 1660, 1240 cm^"1

NMR (DMSO-dg, δ) : 0.97 (3H, d, J=6.5Hz), 1.37 (9H, s), 1.98 (2H, m), 3.18 (IH, sextet, J=6.5Hz),

3.73 (IH, t, J=6.5Hz), 6.6-6.65 (4H, m) , 6.75 (IH, br), 6.98 (2H, d, J=9.5Hz), 7.03 (2H, d, J=9.5Hz), 9.12 (2H, s) MASS (m/z) : 357 (M⁺) , 301, 240, 199 (base)

-Preparation 9

A solution of 4,4-bis(4-ethoxycarbonylmethoxyphenyl)- N-tert-butoxycarbonyl-2-butylamine (280 g) in 4N hydrogen chloride in ethyl acetate (2.8 ml) was stirred under ice cooling for 1 hour and evaporated in vacuo to afford 4,4-bis(4-ethoxycarbonylmethoxyphenyl)-2-butylamine hydrochloride (233 mg) as an oil.

IR (film) : 2800-2500, 1750, 1200 cm^"1 NMR (DMSO-dg, δ) : 1.18 (3H, d, J=7Hz), 1.20 (6H, t, J=7Hz), 1.2 J1H, m) , 2.35 (IH, m) , 2.85 (IH, m) ,

4.05 (IH, ) , 4.14 (4H, quartet, J=7Hz), 4.71 (2H, s), 4.72 (2H, s), 6.8-6.9 (4H, ) , 7.15-7.25 (4H, m) , 7.85 (3H, br) MASS (m/z) : 429 (M⁺) , 371

Preparation 10

To a solution of ethyl 3,3-bis(4-methoxyphenyl)- propionate (2.50 g) in dry diethyl ether (10 ml) was added dropwise 3N methylmagnesium bromide in diethyl ether (11 ml) under ice-bath cooling. The resulting mixture was stirred for 1 day at ambient temperature. The reaction mixture was poured into ice-lN-hydrochloric acid and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo to give 4,4-bis( -methoxyphenyl)-2-methyl-2-butanol (2.41 g) as a colorless oil.

IR (film) : 3450, 2830, 1600, 830, 800, 760 cm^"1 NMR (CDC1₃, δ) : 1.18 (6H, s), 1.40 (IH, br s), 2.28 (2H, d, J=7.2Hz) , 3.75 (6H, s), 4.11 (IH, t, J=7.2Hz), 6.75-6.85 (4H, m) , 7.15-7.25 (4H, m) MASS (m/z) : 300 (M⁺) , 227, 197

Preparation 11

To a mixture of 4,4-bis(4-methoxγphenyl)-2-methyl-2- butanol (2.41 g) and azidotrimethylsilane (1.11 g) in dry benzene (8 ml) was added dropwise boron trifluoride etherate (1.37 g) at 25°C-26°C. The reaction mixture was stirred at ambient temperature for 2 days. The mixture was poured into ethyl acetate and water. The organic layer was separated and washed with aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo to give crude azido form. A mixture of this crude azido form (2.36 g) , ammonium formate (1.52 g) , and 10% palladium on carbon (50% wet, 0.24 g) in methanol (23 ml) was refluxed for 2 hours. After cooling, the catalyst was filtered off, and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate and IN aqueous sodium hydroxide solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was treated with 4N hydrogen chloride in ethyl acetate to give 4,4-bis(4- methoxyphenyl)-2-methyl-2-butylamine hydrochloride (1.82 g) as a colorless powder, mp : 189-190°C

IR (Nujol) : 3300, 2570, 1610, 830, 820, 740 cm^"1 NMR (DMSO-dg, δ) : 1.13 (6H, s) , 2.39 (2H, d, J=6.7Hz), 3.69 (6H, s), 4.20 (2H, t, J=6.7Hz),

6.75-6.90 (4H, m) , 7.20-7.30 (4H, m) , 8.24 (3H, br s) MASS (m/z) : 299 (M⁺) , 227

Preparation 12

A solution of 4,4-bis(4-methoxyphenyl)-2-butanone (1.42 g) and benzylamine (0.536 g) in methanol (19.5 ml) and acetic acid (1.49 ml) was stirred at ambient temperature for 30 minutes, and then sodium cyanoborohydride (0.471 g) was added to the solution. The resulting mixture was stirred at the same temperature for 15 hours, cooled with ice-water, treated with cone, hydrochloric acid, diluted with water, basified with ammonia solution, and extracted with ethyl acetate. The extract was washed twice with brine, dried over sodium sulfate, evaporated in vacuo, and chromatographed over silica gel using methylene chloride-methanol to afford N-benzyl-4,4-bis(4-methoxyphenyl)-2-butylamine (1.64 g) as a pale yellow oil. IR (film) : 3320, 1245 cm^"1

NMR (CDC1₃, δ) : 1.12 (3H, d, J=6Hz) , 1.72 (IH, br), 1.98 (IH, ), 2.21 (IH, m) , 2.57 (IH, sextet, J=6Hz), 3.62 (IH, d, J=13Hz), 3.76 (3H, s), 3.77 (IH, d, J=13Hz), 4.01 (IH, t, J=8Hz) , 6.79 (4H, d, J=9Hz), 7.05-7.35 (9H, m)

MASS (m/z) : 375 (M⁺) , 268, 227, 134, 91 (base)

Preparation 13

The following compound was obtained according to a similar manner to that of Preparation 12. N-Benzyl-1,1-bis(4-methoxyphenyl)-3-pentylamine IR (film) : 3500-3250, 3030, 1610, 830, 740,

700 cm^"1 NMR (CDC1₃, δ) : 0.86 (3H, t, J=7.3Hz), 1.37 (IH, br s), 1.40-1.60 (2H, m), 2.06 (2H, t, J=7.7Hz), 2.30-2.50 (IH, m), 3.58 (IH, d, J=13.0Hz), 3.70 (IH, d, J=13.0Hz), 3.76 (6H, s), 4.04 (IH, t, J=7.7Hz), 6.70-6.90 (4H, m) , 7.05-7.40 (9H, m)

MASS (m/z) : 389 (M⁺) , 227, 148

Preparation 14

The following compound was obtained by reacting 4,4-bis(4-methoxyphenyl)-2-methyl-2-butylamine hydrochloride with benzaldehyde according to a similar manner to that of Preparation 12.

N-Benzyl-4,4-bis(4-methoxyphenyl)-2-methyl-2- butylamine hydrochloride mp : 192-194°C IR (Nujol) : 2610, 2420, 1610, 830, 810, 760, 740,

700 cm^"1 NMR (DMSO-dg, δ) : 1.22 (6H, s), 2.60 (2H, d,

J=6.5Hz), 3.70 (6H, s) , 4.00-4.15 (2H, m) , 4.19 (IH, t, J=6.5Hz), 6.84 (4H, d, J=8.7Hz) , 7.31 (4H, d, J=8.7Hz), 7.35-7.45 (3H, m) , 7.60-7.70

(2H, m) , 9.28 (2H, br s) MASS (m/z) : 389 (M⁺) , 227, 148, 91

Preparation 15 Sodium borohydride (3.84 g) was added by portions to a stirred solution of 4,4-bis(4-methoxyphenyl)-2- butanone in methanol (580 ml) under ice cooling. The resulting solution was stirred at the same temperature and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford 4,4-bis(4-methoxyphenyl)-2-butanol (54.8*8 g) as an oil.

IR (film) : 3400, 1245 cm^"1

NMR (CDC1₃, δ) : 1.21 (3H, d, J=6.2Hz), 1.45 (IH, br), 2.11 (2H, dd, J=8.0, 6.2Hz), 3.66 (IH, sextet, J=6.2Hz), 3.76 (3H, s), 3.77 (3H, s), 4.08 (IH, t, J=8Hz), 6.75-6.9 (4H, m) , 7.16 (4H, d, J=8.6Hz)

Preparation 16

A mixture of 4,4-bis(4-methoxyphenyl)-2-butanol (50.03 g) , isopropenyl acetate (52.47 g) , and lipase Amano PS (50.03 g) in diisopropyl ether was stirred at ambient temperature for 27 hours and filtered. The filtrate was evaporated in vacuo and chromatographed over silica gel (500 g) using n-hexane-dichloromethane, dichloromethane, and dichloromethane-methanol successively as eluents. The first eluate afforded (-)-4,4-bis(4-methoxyphenyl)-2- butyl acetate (19.57 g) as an oil.

[α]^¹ = -9.06° (C=1.125, CH₂C1₂) IR (film) : 1725, 1245 cm^"1

NMR (CDC1₃, δ) : 1.21 (3H, d, J=6.2Hz) , 1.96 (3H, s), 2.0-2.2 (IH, m), 2.25-2.45 (IH, m) , 3.75 (3H, s), 3.76 (3H, s), 3.91 (IH, t, J=7.8Hz),

4.75 (IH, m), 6.75-6.85 (4H, m) , 7.07 (2H, d, J=8.7Hz), 7.16 (2H, d, J=8.7Hz) MASS (m/z) : 328 (M⁺) , 268, 227 (base)

The second eluate afforded (+)-4,4-bis(4-methoxy- phenyl)-2-butanol as a crude oil (24.55 g) . A mixture of the crude oil, isopropenyl acetate (25.8 g) , and lipase Amano PS (24.5 g) in diisopropyl ether was stirred at ambient temperature for 47 hours and filtered. The filtrate was evaporated in vacuo and chromatographed over silica gel (250 g) using the solvents described above as eluents. The obtained solid was washed with n-hexane to- afford (+)-4,4-bis(4-methoxyphenyl)-2-butanol (21.83 g) as a yellow powder. mp : 80-88°C

[α]¹⁸ = +24.97° (C=1.005, CH₂Cl₂) IR (Nujol) : 3520, 1240 cm^"1

NMR (CDC1₃, δ) : 1.20 (3H, d, J=6.2Hz), 1.32 (IH, br s), 2.11 (2H, dd, J=8.0, 6.2Hz), 3.66 (IH, sextet, J=6.2Hz), 3.76 (3H, s), 3.76 (3H, s),

4.08 (IH, t, J=8.0Hz), 6.75-6.9 (4H, m) , 7.16 (4H, d, J=8.8Hz) FAB-MASS (m/z) : 286 (M⁺) , 227 (base)

Preparation 17

A solution of (-)-4,4-bis(4-methoxγphenyl)-2-butyl acetate (22.89 g) and sodium hydroxide (4.74 g) in methanol (229 ml) and water (10 ml) was stirred at ambient temperature for 2.5 hours and allowed to stand at the same temperature overnight. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford a solid, which was washed with n-hexane to afford (-)-4,4-bis(4-methoxyphenyl)-2-butanol (18.23 g) as a pale yellow powder, mp : 87-91.5°C

[α]^¹ = -27.49° (C=1.04, CH₂C1₂) IR (Nujol) : 3520, 1240 cm^"1 NMR (CDC1₃, δ) : 1.20 (3H, d, J=6.2Hz), 1.31 (IH, br d, J=3.2Hz), 2.11 (2H, dd, J=8.0, 6.4Hz) , 3.65 (IH, m), 3.76 (3H, s), 3.76 (3H, s), 4.08 (IH, t, J=8.0Hz), 6.75-6.9 (4H, m) , 7.16 (4H, d, J=8.8Hz) FAB-MASS (m/z) : 286 (M⁺) , 227 (base) Preparation 18

4-Methylbenzenesulfonyl chloride (13.89 g) was added by portions to a stirred solution of (-)-4,4-bis(4- methoxyphenyl)-2-butanol (17.39 g) in pyridine (34 ml) under ice cooling. The resulting mixture was stirred at the same temperature for 1 hour and at ambient temperature for 17 hours. The precipitate was filtered off and washed with toluene. The filtrate and washings were combined and evaporated in vacuo. The residue was extracted with ethyl acetate. The extract was washed successively with IN hydrochloric acid, water, aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel using a mixture of toluene and ethyl acetate as an eluent to afford (+)-4,4-bis(4-methoxyphenyl)-2-butyl 4-methylbenzenesulfonate (21.37 g) as a pale yellow oil. [α]¹⁸ = +15.66° (C=0.97, CH₂C1₂) IR (film) : 1350, 1250, 1170 cm^"1

NMR (CDC1₃, δ) : 1.29 (3H, d, J=6.2Hz), 2.13 (IH, ddd, J=14.2, 8.6, 5.8Hz), 2.25-2.45 (IH, ) ,

2.45 (3H, s), 3.76 (6H, s), 3.81 (IH, ) , 4.43 (IH, m), 6.76 (4H, d, J=8.7Hz), 6.96 (2H, d, J=8.7Hz), 6.99 (2H, d, J=8.7Hz) , 7.29 (2H, d, J=8.2Hz), 7.70 (2H, d, J=8.2Hz) FAB-MASS (m/z) : _m440 (M⁺) , 269, 227 (base)

Preparation 19

A mixture of (+)-4,4-bis(4-methoxyphenyl)-2-butyl 4-methylbenzenesulfonate (20.45 g) and benzylamine (29.85 g) was stirred at 55°C for 8 hours, and then benzylamine was removed by distillation under a reduced pressure. The residue was triturated with ethyl acetate, and the precipitated powder was filtered off and washed with ethyl acetate. The filtrate and washings were combined, washed successively with IN hydrochloric acid, brine, 5% aqueous sodium hydroxide solution, and brine, dried over sodium sulfate, treated with 4N hydrogen chloride in ethyl acetate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to afford (-)-N-benzyl-4,4-bis(4-methoxyphenyl)-2-butylamine hydrochloride (16.97 g) as a colorless powder, mp : 70-77°C

[α]¹⁹ = -17.20° (C=0.93, CH₂Cl₂) IR (Nujol) : 2700-2000, 1245 cm^"1 NMR (CDC1₃, δ) : 1.36 (3H, d, J=6.4Hz), 2.25 (IH, m), 2.65-2.85 (2H, m) , 3.71 (6H, s), 3.75-4.1 (3H, m) , 6.68 (2H, d, J=8.8Hz), 6.69 (2H, d, J=8.8Hz), 7.04 (2H, br d, J=8.8Hz), 7.25-7.3 (3H, m), 7.4-7.5 (2H, m) , 9.85 (2H, br) (+) APCI-MASS (m/z) : 376 (M⁺+l)

Preparation 20

A solution of (+)-N-benzyl-4,4-bis(4-hydroxyphenyl)- 2-butylamine (4.92 g) in dimethyl sulfoxide (35 ml) was added dropwise to a stirred suspension of 60% sodium hydride (1.25 g) (washed with n-hexane) in dimethyl sulfoxide (12.5 ml) at ambient temperature in an atmosphere of nitrogen over 20 minutes. The resulting mixture was stirred at the same temperature for 10 minutes and at 50°C for 10 minutes, and then cooled to ambient temperature. Tetrabutylammonium bromide (0.916 g) was added to the reaction mixture and ethyl bromoacetate was added dropwise to the stirred mixture at ambient temperature over 10 minutes. The resulting mixture was stirred at the same temperature for 2 hours and 45 minutes, poured into ice water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo to afford a crude oil (6.86 g) . The crude oil was chromatographed over silica gel using a mixture of toluene and ethyl acetate as an eluent to afford (+)-N-benzyl-4,4-bis(4-ethoxycarbonylmethoxyphenyl)-2- butylamine (5.24 g) as a pale brown oil. [α]¹⁷ = +23.49° (C=1.06, CH₂Cl₂) IR (film) : 3310, 1745, 1200, 1170 cm^"1

NMR (CDC1₃, δ) : 1.09 (3H, d, J=6.2Hz) , 1.29 (6H, t, J=7.1Hz), 1.4 (IH, br), 1.85-2.05 (IH, m), 2.05-2.25 (IH, m) , 2.45-2.6 (IH, m) , 3.60 (IH, d, J=12.8Hz), 3.76 (IH, d, J=12.8Hz), 4.02 (IH, t, J=7.8Hz), 4.26 (4H, quartet, J=7.1Hz), 4.56

(4H, s), 6.79 (2H, d, J=8.6Hz), 6.80 (2H, d, J=8.6Hz), 7.05-7.15 (4H, m) , 7.15-7.35 (5H, m) (+) APCI-MASS (m/z) : 520 (M⁺+l)

Preparation 21

The following compounds were obtained according to a similar manner to that of Preparation 20, except that N,N-dimethylformamide was used instead of dimethyl sulfoxide.

1) N-Benzyl-4,4-bis(4-ethoxycarbonylmethoxyphenyl)-2- methyl-2-butylamine

IR (film) : 3330, 1740, 1610, 830, 730, 700 cm^"1 NMR (CDC1₃, δ) : 1.05 (6H, s), 1.28 (6H, t, J=7.1Hz), 2.25 (2H, d, J=6.6Hz), 3.58 (2H, s),

4.00-4.20 (2H, m), 4.25 (4H, q, J=7.1Hz), 4.53 (4H, s), 6.70-6.90 (4H, m) , 7.10-7.40 (9H, m) MASS (m/z) : 533 (M⁺) , 339, 148

2) N-Benzyl-3,3-bis(4-ethoxycarbonylmethoxyphenyl)- propylamine

IR (film) : 3330, 1740, 1620, 1600, 830, 740, 700 cm^"1

NMR (CDC1₃, δ) : 1.28 (6H, t, J=7.lHz), 1.59 (IH, br s), 2.10-2.25 (2H, m) , 2.59 (2H, t, J=6.9Hz), 3.71 (2H, s), 3.93 (IH, t, J=7.8Hz), 4.26 (4H, q, J=7.1Hz), 4.56 (4H, s), 6.70-6.85 (4H, m) , 7.05-7.15 (4H, ) , 7.20-7.30 (5H, m) MASS (m/z) : 505 (M⁺) , 311, 227, 91

) N-Benzyl-1,1-bis( 4-ethoxycarbonylmethoxyphenyl)-3- pentylamine

IR (film) : 3320, 1740, 1610, 830, 730, 700 cm^"1 NMR (CDC1₃, δ) : 0.85 (3H, t, J=7.3Hz) , 1.28 (6H, t, J=7.1Hz), 1.35-1.70 (3H, m) , 2.03 (2H, dd,

J=7.6, 7.6Hz), 2.25-2.50 (IH, m) , 3.57 (IH, d, J=12.9Hz), 3.70 (IH, d, J=12.9Hz), 4.05 (IH, t, J=7.6Hz), 4.26 (4H, q, J=7.1Hz) , 4.56 (4H, ε), 6.70-6.85 (4H, m) , 7.00-7.35 (9H, ) MASS (m/z) : 533 (M⁺) , 371, 148, 91

) N-Benzyl-2,2-bis(4-ethoxycarbonylmethoxγphenyl)-1- ethylamine

IR (film) : 3320, 1740, 1600 cm^"1 NMR (CDC1₃, δ) : 1.29 (6H, t, J=7.1Hz) , 1.57 (IH, br s), 3.14 (2H, d, J=7.6Hz), 3.79 (2H, s), 4.12 (IH, t, J=7.6Hz), 4.22 (4H, q, J=7.1Hz) , 4.57 (4H, s), 6.75-6.85 (4H, m) , 7.05-7.15 (4H, m) , 7.20-7.35 (5H, m) (+) APCI-MASS (m/z) : 492 (M⁺+l)

) N-Benzyl-1,1-bis(4-ethoxycarbonylmethoxyphenyl)-2- propylamine

IR (film) : 3350, 1740, 1600 cm^"1 NMR (CDC1₃, δ) : 1.01 (3H, d, J=6.0Hz), 1.28 (6H, t,

J=7.1Hz), 1.61 (IH, br s), 3.20-3.35 (IH, m) , 3.62 (IH, d, J=13.2Hz), 3.60-3.65 (IH, m) , 3.84 (IH, d, J=13.2Hz), 4.20-4.35 (4H, ) , 4.55 (2H, s), 4.56 (2H, s), 6.75-6.85 (4H, m) , 7.09-7.17 (6H, m) , 7.22-7.34 (3H, ) (+) APCI-MASS (m/z) : 506 (M⁺+l)

6) N-Benzyl-3,3-bis(3-ethoxycarbonylmethoxyphenyl)- propylamine IR (film) : 3320, 1740, 1600, 1200 cm^"1

NMR (CDC1₃, δ) : 1.27 (6H, t, J=2.7Hz) , 1.95-2.05 (2H, m), 2.59 (2H, t, J=7.2Hz), 3.71 (2H, s), 3.97 (IH, t, J=7.7Hz), 4.15 (4H, q, J=7.7Hz), 4.56 (4H, s), 6.65-6.70 (2H, m) , 6.75-6.90 (4H, m), 7.14-7.35 (7H, m)

(+) APCI-MASS (m/z) : 506 (M⁺+l)

7) N-Benzyl-4,4-bis(4-ethoxycarbonylmethoxyphenyl)- butylamine IR (film) : 3300, 1740, 1600, 1200 cm^"1

NMR (CDC1₃, δ) : 1.29 (6H, t, J=7.1Hz), 1.30-1.60 (3H, m), 1.90-2.05 (2H, m) , 2.62 (2H, t, J=7.1Hz), 3.73 (2H, s), 3.77 (IH, t, J=7.8Hz), 4.25 (4H, q, J=7.1Hz) , 4.56 (4H, s), 6.75-6.85 (4H, ), 7.05-7.15 (4H, m) , 7.20-7.35 (5H, )

(+) APCI-MASS (m/z) : 520 (M⁺+l)

Preparation 22

A mixture of 4,4-bis(4-hydroxyphenyl)-N-tert-butoxy- carbonyl-2-butylamine .(520 mg) , ethyl bromoacetate (243 mg) , and potassium carbonate (200 mg) in N,N-dimethylformamide (5.2 ml) was stirred at ambient temperature for 2 hours, and then another ethyl bromoacetate (243 mg) and potassium carbonate (200 mg) was added to the mixture. The resulting mixture was stirred at the same temperature for 3 days, diluted with water, and extracted with ethyl acetate. The extract was washed twice with brine, dried, evaporated in vacuo, and chromatographed over silica gel using toluene-ethyl acetate to afford 4,4-bis(4-ethoxycarbonylmethoxyphenyl)- N-tert-butoxycarbonyl-2-butylamine (320 mg) as a colorless oil.

IR (film) : 3390, 1755, 1700, 1200 cm^"1 NMR (CDC1₃, δ) : 1.10 (3H, d, J=6.5Hz), 1.29 (6H, t, J=7Hz), 1.42 (9H, s), 2.00 (2H, m) , 2.51 (IH, br), 3.93 (IH, t, J=8Hz), 4.26 (4H, quartet, J=7Hz), 4.57 (4H, s), 6.75-6.85 (4H, m) , 7.05-7.3 (5H, ) MASS (m/z) : 529 (M⁺) , 371 (base)

Preparation 23

The following compounds were obtained according to a similar manner to that of Preparation 6.

1) (-)-N-Benzyl-4,4-bis(4-hydroxγphenyl)-2-butylamine mp : 172.5-174.5°C [ ]^18,2 = -20.33° (C=0.95, DMSO) IR (Nujol) : 3250 cm^"1

NMR (CDC1₃, δ) : 1.0-1.2 (3H, br) , 1.9-2.0 (IH, m) , 2.14 (IH, ), 2.56 (IH, br), 3.5-3.9 (3H, br),

6.6-6.7 (4H, br), 6.9-7.0 (4H, br), 7.2-7.4 (5H, br) MASS (m/z) : 348 (M⁺+l), 213

2) N-Benzyl-1,1-bis(4-hydroxyphenyl)-2-propylamine mp : 208-210°C

IR (Nujol) : 3270, 2300-2700, 1610, 1590 cm^"1 NMR (DMSO-dg, δ) : 1.00 (3H, d, J=6.0Hz) , 2.71 (IH, br s), 3.20-3.35 (IH, ) , 3.55-3.70 (2H, m) , 3.84 (IH, d, J=13.3Hz), 6.65-6.75 (4H, m) ,

7.00-7.40 (9H, m), 8.57 (2H, br s) (+) APCI-MASS (m/z) : 334 (M⁺+l)

3) N-Benzyl-3,3-bis(3-hydroxyphenyl)propylamine mp : 139-141°C (dec. ) IR (Nujol) : 3250, 2720-2300, 1600 cm^"1 NMR (DMSO-dg, δ) : 2.00-2.15 (2H, m) , 2.35-2.50 2H, m) , 3.67 (2H, s), 3.85 (IH, t, J=7.2Hz) , 6.50-6.70 (6H, ) , 7.00-7.30 (7H, m) , 9.13 (2H, br s)

(+) APCI-MASS (m/z) : 334 (M⁺+l)

4) N-Benzyl-4,4-bis(4-hydroxyphenyl)butylamine p : 171-173°C IR (Nujol) : 3250, 3150, 1610, 1220 cm^"1

NMR (DMSO-dg, δ) : 1.20-1.40 (2H, m) , 1.80-2.00 (2H, m), 2.40-2.50 (2H, ) , 3.2 (IH, br), 3.50-3.65 (IH, m), 3.62 (2H, s), 6.64 (4H, d, J=8.4Hz), 7.00 (4H, d, J=8.4Hz), 7.10-7.30 (5H, m) , 9.15 (2H, br s)

(+) APCI-MASS (m/z) : 348 (M⁺+l)

Preparation 24

The following compound was obtained according to a similar manner to that of Preparation 18.

(-)-4,4-Bis(4-methoxyphenyl)-2-butyl 4-methylbenzenesulfonate

[α]^17,2 = -17.55° (C=1.35, CH₂C1₂) IR (film) : 1350, 1175 cm^"1

NMR (CDC1₃, δ) : 1.29 (3H, d, J=6.2Hz), 2.0-2.2 (IH, m), 2.2-2.4 (IH, m) , 2.45 (3H, s), 3.76 (6H, s), 3.7-3.9 (IH, m) , 4.1-4.5 (IH, m) , 6.7-6.8 (4H, m), 6.9-7.0 (4H, ) , 7.2-7.3 (2H, ) , 7.6-7.8 (2H, )

MASS (m/z) : 439 (M⁺-l), 332, 268

Preparation 25

The following compound was obtained according to a similar manner to that of Preparation 19. (+)-N-Benzyl-4,4-bis(4-methoxyphenyl)-2-butylamine hydrochloride mp : 64-71°C

[ ]^16,0 = +16.81° (C=1.011, CH₂C1₂) IR (Nujol) : 2700 cm^"1

NMR (CDC1₃, δ) : 1.36 (3H, d, J=6.1Hz), 2.2-2.3 (IH, br), 2.6-2.8 (2H, br), 3.71 (6H, s), 3.7-4.0 (3H, br), 6.6-6.7 (4H, br) , 7.0-7.1 (4H br), 7.2-7.3 (3H, br), 7.47 (2H, br) MASS (m/z) : 376 (M⁺+l), 346, 317, 227

Preparation 26

The following compound was obtained according to a similar manner to that of Preparation 20.

(-)-N-Benzyl-4,4-bis(4-ethoxycarbonylmethoxyphenyl)- 2-butylamine

[α]^16-2 = -24.21° (C=0.95, H₂C1₂) IR (film) : 3400, 1750, 1605, 1585, 1503 cm^-1 NMR (CDC1₃, δ) : 1.08 (3H, d, J=6.2Hz),

1.28 (6H, t, J=7.1Hz), 1.8-2.0 (IH, m) , 2.0-2.3 (IH, m), 2.4-2.6 (IH, m) , 3.64 (IH, d, J=12.9Hz), 3.70 (IH, d, J=12.9Hz), 4.02 (IH, t, J=7.8Hz), 4.25 (4H, q, J=7.1Hz) , 4.56 (4H, s)., 6.7-6.9 (4H, m) , 7.0-7.4 (9H, m)

MASS (m/z) : 520 (M⁺+l), 506

Preparation 27

The following compound was obtained by reacting a compound, which was prepared according to a similar manner to that of Preparation 4, with hydrogen chloride.

N-Benzyl-2,2-bis(4-hydroxγphenyl)-1-ethylamine hydrochloride mp : 204-206°C IR (Nujol) : 3470, 2800, 2730, 1610, 1600 cm^"1 NMR (DMSO-dg, δ) : 3.30-3.55 (2H, m) , 4.10 (2H, br s), 4.28 (IH, t, J=7.7Hz), 6.70 (4H, d, J=8.5Hz), 7.06 (4H, d, J=8.5Hz), 7.30-7.45 (3H, m) , 7.45-7.55 (2H, m) , 9.06 (2H, br s), 9.39

(2H, br s) (+) APCI-MASS (m/z) : 320 (M⁺+l)

Preparation 28 The following compound was obtained by reacting a compound, which was prepared according to a similar manner to that of Preparation 12, with hydrogen chloride.

N-Benzyl-2,2-bis(4-methoxyphenyl)ethylamine hydrochloride mp : 231-234°C

IR (Nujol) : 2730, 2500, 1610 cm^"1

NMR (DMSO-dg, δ) : 3.45-3.65 (2H, m) , 3.71 (6H, s) , 4.05-4.20 (2H, ) , 4.35-4.50 (IH, m) , 6.88 (4H, d, J=8.7Hz), 7.24 (4H, d, J=8.7Hz), 7.35-7.45

(3H, m) , 7.45-7.55 (2H, m) , 9.05 (2H, m) (+) APCI-MASS (m/z) : 348 (M⁺+l)

Preparation 29 The following compounds were obtained according to a similar manner to that of Example 1.

1) (-)-(lR)-N-Benzyl-l-(3-chlorophenyl)-2-[[(2R or

2S)-4,4-bis(4-hydroxyphenγl)-2-butyl]amino]ethanol IR (film) : 3340 cm^"1

(+) APCI-MASS (m/z) : 502 and 504 (M⁺+l)

2) (-)-(lR)-N-Benzyl-l-(3-chlorophenyl)-2-[[(2R or 2S)- 4,4-bis(4-hydroxyphenyl)-2-butyl]amino]ethanol hydrochloride mp : 143-156°C

NMR (DMSO-dg, δ) : 1.17 (3H, d, J=7.1Hz), 2.18 (2H, br), 2.75 (IH, br), 3.1-3.3 (2H, br) , 3.79 (IH, br), 4.38 (IH, br), 4.5-4.7 (2H, br) , 6.4-6.7, 6.9-7.1, 7.2-7.4 and 7.7 (total 17H, m)

Preparation 30

The following compound was obtained according to a similar manner to that of Example 3.

(-)-(IR)-1-(3-Chlorophenyl)-2-[ [ (2R or 2S)-4,4-bis(4-hydroxypheny1)-2-butyl]amino]ethanol hydrochloride mp : 118-124°C [α]^22,0 = -21.27 (C=0.59, MeOH)

IR (Nujol) : 3200, 2650-2300, 1220 cm^"1 NMR (DMSO-dg, δ) : 1.22 (3H, d, J=6.2Hz), 1.98 (2H, br), 2.6-3.3 (3H, br), 3.9 (IH, br), 4.97 (IH, br), 6.29 (IH, br), 6.6-6.7 (4H, m) , 7.0-7.2 (4H, m), 7.3-7.5 (4H, br) , 9.2 (3H, br)

(+) APCI-MASS (m/z) : 412 and 414 (M⁺+l)

Preparation 31

A mixture of AD-mix-β (purchased from Aldrich Chemical Company, Inc..) (3.5 g) , tert-butanol (10 ml) and water (12.5 ml) was stirred at ambient temperature for 5 minutes. After the mixture was cooled to 0°C, a solution of 3-chlorostyrene (346.5 mg) in tert-butanol (2.5 ml) was added at once and the heterogeneous slurry was stirred vigorously at 0°C for 4 hours. While stirring at 0°C, solid sodium sulfite (3.75 g) was added and the mixture was allowed to warm to ambient temperature and stirred for 1 hour. Ethyl acetate was added to the reaction mixture and after separation of the layer, the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (20 g) , with n-hexane - ethyl acetate (2:1) to give (R)-l-(3-chlorophenyl)-l,2-ethanediol (0.41 g) as an oil. IR (film) : 3300, 1590, 1565 cm^"1

NMR (CDC1₃, 5) : 2.32 (IH, t, J=6.5Hz), 2.86 (IH, d, J=3.4Hz), 3.56-3.81 (2H, m) , 4.76-4.83 (IH, ), 7.20-7.39 (4H, m)

Preparation 32

(R)-l-(3-Chlorophenyl)-l,2-ethanediol (0.4 g) was dissolved in 25% hydrogen bromide - acetic acid (2.4 ml) at 0°C and then the solution was stirred at ambient temperature for 1 hour. It was diluted with cold water, and the aqueous solution was extracted with portions of ethyl acetate. The combined organic layers were washed with a saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was dissolved in methanol (5 ml) at 0°C and then 2N sodium hydroxide solution (5 ml) was added. The mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with water and extracted with portions of ethyl .acetate. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (R)-3-chlorostyrene oxide (0.3 g) as 97.6% ee.

NMR (CDC1₃, δ) : 2.76 (IH, dd, J=2.5, 5.5Hz) , 3.15 (IH, dd, J=4.0, 5.5Hz), 3.84 (IH, dd, J=2.5,

4.0Hz), 7.14-7.29 (4H, m)

Preparation 33

Trimethylsilyl chloride (0.35 ml) was added to a solution of (R)-l-(3-chlorophenyl)-1,2-ethanediol (0.4 g) and trimethyl orthoacetate (0.35 ml) in dichloromethane (6.8 ml) at 0°C. The solution was stirred for 2.5 hours, and then evaporated to obtain crude (2S)-2-chloro-2-(3- chlorophenylethyl)acetate. The crude product was dissolved in dry methanol (4.5 ml) and potassium carbonate (770 mg) was added. The suspension was stirred vigorously for 3 hours and then filtered, and the residue was washed with dichloromethane. The filtrate was evaporated in vacuo and the residue purified by column chromatography on silica gel (10 g) with n-hexane - diethyl ether (10:1) to give (R)-3-chlorostyrene oxide (0.25 g) as 98.1 % ee.

The NMR spectrum data of this compound coincided with that of the compound of Preparation 32.

Preparation 34

A solution of 2,2-bis(4-methoxyphenyl)acetic acid (20.0 g) in thionyl chloride (21.3 ml) was refluxed for 3 hours, and evaporated in vacuo. Toluene was added to the residue and the resulting mixture was evaporated in vacuo to give the crude acid chloride (22.77 g) as a pale yellowish green powder. To a mixture of N,θ-dimethylhydroxylamine hydrochloride (3.69 g) in dry dichloromethane (37 ml) was added dropwise a solution of triethylamine (10.6 ml) in dry dichloromethane (15 ml) at 0°C-2°C. A solution of the crude acid chloride (10 g) in dry dichloromethane (15 ml) was added to the mixture at 0°C-9°C, and the resulting mixture was stirred for 30 minutes. The reaction mixture was poured into ice-water, and then the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 2,2-biε(4-methoxγphenyl)-N-methoxy- N-methylacetamide as a colorless powder (7.84 g). mp : 130-132°C IR ( Nuj ol ) : 1650 , 1600 cm^{" 1}

NMR (CDC1₃, δ) : 3.22 (3H, s), 3.50 (3H, s), 3.77 (6H, s), 5.43 (IH, s), 6.80-6.95 (4H, m) , 7.15-7.25 (4H, m) (+) APCI-MASS (m/z) : 316 (M⁺+l)

Preparation 35

A solution of 2 ,2-bis(4-methoxyphenyl)-N-methoxy-N- methylacetamide (4.00 g) in dry diethyl ether (10 ml) was added dropwise to 3 M methyl magnesium bromide in diethyl ether (4.6 ml) at 3°C-9°C. After 30 minutes, the another methyl magnesium bromide in diethyl ether (2.0 ml) was added dropwise to the reaction mixture and the resulting mixture was stirred for 3 days. The mixture was poured into ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from n-hexane to give 1,1-bis(4-methoxyphenyl)acetone (3.25 g) as a pale orange powder. mp : 71-72°C

IR (Nujol) : 1705, 1600 cm^"1

NMR (CDC1₃, δ) : 2.22 (3H, s), 3.78 (6H, ε) , 5.01 (IH, s), 6.80-6.90 (4H, m) , 7.05-7.15 (4H, m) (+) APCI-MASS (m/z) : 270 (M⁺)

Preparation 36

A solution of 1,1-bis(4-methoxyphenyl)acetone (2.00 g) , benzylamine (0.79 g) and p-toluenesulfonic acid monohydrate (0.01 g) in toluene (16 ml) was refluxed under azeotropic dehydration for 5 hours. The solvent was evaporated in vacuo and methanol (15 ml) was added to the residue. To the solution was added portionwise sodium borohydride (0.28 g) under ice cooling and the mixture waε stirred for 1.5 hours. The solution was evaporated in vacuo and the residue was partitioned between ethyl acetate and IN aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo, and the residue was purified by column chromatography on silica gel to give N-benzyl-1,1-bis(4-methoxyphenyl)-2-propylamine (1.70 g) as a colorless oil.

IR (film) : 3320, 1610 cm^"1

NMR (CDC1₃, δ) : 1.03 (3H, d, J=6.1Hz) , 1.63 (IH, br s), 3.20-3.50 (IH, m) , 3.64 (IH, d, J=13.3Hz),

3.70 (3H, s), 3.74 (3H, s), 3.86 (IH, d, J=13.3Hz), 3.60-3.95 (IH, m) , 6.70-6.90 (4H, m) , 7.10-7.35 (9H, m)

(+) APCI-MASS (m/z) : 362 (M⁺+l)

Preparation 37

1) A solution of triethyl phosphonoacetate (32.06 g) in tetrahydrofuran (32 ml) was added dropwise to a suspension of sodium hydride (60%, 5.98 g, washed with n-hexane) in tetrahydrofuran (158 ml) under an atmosphere of nitrogen at -3°C - 0°C. The mixture was stirred at ambient temperature for 20 minutes. A solution of 3,3' -dimethoxybenzophenone (31.50 g) in tetrahydrofuran (150 ml) was added dropwise to the mixture at ambient temperature and the reaction mixture was refluxed for 5.5 hours. The mixture was evaporated in vacuo and the residue was poured into IN hydrochloric acid, and extracted with ethyl acetate. The organic layer was separated, washed with 5% aqueous sodium hydroxide solution and brine, and evaporated in vacuo to give ethyl 3,3-bis( 3-methoxyphenyl)acrylate.

2) A solution of ethyl 3,3-bis(3-methoxyphenyl)- acrylate and sodium hydroxide (4.0 g) in methanol (100 ml) and water (20 ml) was refluxed overnight. The solution was evaporated in vacuo and partitioned between 5% aqueous sodium hydroxide solution and ethyl acetate; The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give 3,3-bis(3-methoxyphenyl)aerylie acid (4.51 g) as a pale yellow powder. mp : 117-118°C IR (Nujol) : 2400-2900, 1690, 1610, 780 cm^"1

NMR (CDC1₃, δ) : 3.77 (3H, s), 3.78 (3H, s), 6.32 (IH, s), 6.70-6.95 (6H, m) , 7.20-7.35 (2H, m) (-) APCI-MASS (m/z) : 283 (M⁺-l)

Preparation 38

The following compound was obtained according to a similar manner to that of Preparation 37-1).

Ethyl 4,4-bis(4-methoxyphenyl)-2-butenoate IR (film) : 1710, 1640, 1600 cm^"1

NMR (CDC1₃, δ) : 1.29 (3H, t, J=7.1Hz) , 3.79 (6H, s), 4.18 (2H, q, J=7.1Hz) , 4.77 (IH, d, J=7.1Hz), 5.69 (IH, dd, J=15.6, 1.5Hz), 6.75-6.90 (4H, m) , 7.00-7.10 (4H, m) , 7.36 (IH, dd, J=15.6,.7.lHz)

(+) APCI-MASS (m/z) : 327 (M⁺+l)

Preparation 39

A mixture of 3,3-bis(3-methoxyphenyl)acrylic acid (4.20 g), ammonium formate (2.79 g) and 10% palladium on carbon (50% wet, 0.42 g) in methanol (42 ml) was refluxed for 1 hour. The palladium on carbon was filtered off and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 3,3-bis(3-methoxyphenyl)propionic acid (4.23 g) as a colorless powder, mp : 136°C

IR (Nujol) : 2400-2600, 1700, 1610 cm^"1 NMR (CDC1₃, δ) : 3.04 (2H, d, J=7.9Hz) , 3.76 (6H, s), 4.46 (IH, t, J=7.9Hz), 6.70-6.85 (6H, ) , 7.15-7.25 (2H, m)

FAB-MASS (m/z) : 286 (M⁺)

Preparation 40

The following compound was obtained according to a similar manner to that of Preparation 39.

Ethyl 4,4-Bis(4-methoxyphenyl)butyrate IR (film) : 1725, 1610 cm^"1

NMR (CDC1₃, δ) : 1.23 (3H, t, J=7.2Hz) , 2.15-2.40 (4H, m), 3.76 (6H, s), 3.82 (IH, t, J=7.5Hz), 4.12 (2H, q, J=7.2Hz), 6.75-6.85 (4H, m) , 7.05-7.15 (4H, m)

FAB-MASS (m/z) : 328 (M⁺)

Preparation 41

To a solution of 3,3-bis(3-methoxyphenyl)propionic acid (4.00 g) in dry diethyl ether (80 ml) and dry tetrahydrofuran (10 ml) was added portionwise lithium aluminum hydride (0.64 g) under an atmosphere of nitrogen at ambient temperature. The mixture was refluxed for 30 minutes and poured into ice-lN hydrochloric acid, and extracted with diethyl ether. The organic layer was washed with 5% aqueous sodium hydroxide solution and brine, dried over magnesium sulfate, and evaporated in vacuo to give 3,3-bis(3-methoxyphenyl)propanol (3.59 g) as a colorless oil. IR (film) : 3100-3700, 1600 cm^"1 NMR (CDC1₃, δ) : 1.31 (IH, br s), 2.28 (2H, dt,

J=7.8, 6.4Hz), 3.61 (2H, t, J=6Hz), 3.77 (6H, s), 4.06 (IH, t, J=7.8Hz), 6.65-6.90 (6H, m) , 7.16-7.34 (2H, )

FAB-MASS (m/z) : 273 (M⁺+l)

Preparation 42

The following compound was obtained according to a similar manner to that of Preparation 41.

4,4-Bis(4-methoxyphenyl)butanol

IR (film) : 3350, 1610 cm^"1

NMR (CDC1₃, δ) : 1.21 (IH, br s), 1.40-1.60 (2H, m) ,

1.95-2.15 (2H, m) , 3.64 (2H, m) , 3.76 (6H, s), 3.81 (IH, t, J=7.9Hz), 6.75-6.85 (4H, m) ,

7.05-7.15 (4H, m) (+) APCI-MASS (m/z) ; 269 ( ⁺+1-H₂0)

Preparation 43 To a solution of 3,3-bis(3-methoxyphenyl)propanol

(3.50 g) and triethylamine (1.95 g) in dry dichloromethane (35 ml) was added dropwise a solution of methanesulfonyl chloride (1.62 g) in dry dichloromethane (2 ml) at 6°C-17°C. The mixture was stirred at ambient temperature for 4 hours and poured into water. The organic layer was separated, washed with brine, treated with magnesium sulfate and active carbon, and evaporated in vacuo to give 3,3-bis(3-methoxyphenyl)propyl methanesulfonate (4.40 g) as a pale yellow oil. IR (film) : 1600, 1350, 1170 cm^"1

NMR (CDC1₃, δ) : 2.46 (2H, dt, J=6.4, 7.9Hz), 2.91 (3H, s), 3.77 (6H, s), 4.06 (IH, t, J=7.9Hz) , 4.16 (2H, t, J=6.4Hz), 6.70-6.85 (6H, m) , 7.15-7.25 (2H, m) FAB-MASS (m/z) : 351 (M⁺+l), 350 (M⁺) Preparation 44

The following compound was obtained according to a similar manner to that of Preparation 43.

4,4-Bis(4-methoxyphenyl)butyl methanesulfonate IR (film) : 1600, 1360, 1170 cm^"1

NMR (CDC1₃, δ) : 1.55-1.80 (2H, m) , 2.00-2.15 (2H, m), 2.96 (3H, s), 3.76 (6H, s) , 3.82 (IH, t, J=7.9Hz), 4.21 (2H, t, J=6.4Hz) , 6.70-6.80 (4H, m), 7.05-7.20 (4H, )

FAB-MASS (m/z) : 364 (M⁺)

Preparation 45

A mixture of 3,3-bis(3-methoxyphenyl)propyl methanesulfonate (4.30 g) and benzylamine (13.5 ml) was stirred at ambient temperature for 24 hours, and poured into ethyl acetate and IN hydrochloric acid. The organic layer was separated, washed with 5% aqueous sodium hydroxide and brine, dried over magnesium sulfate, and evaporated in vacuo to give N-benzyl-3,3-bis(3- methoxyphenyDpropylamine (4.03 g) as a pale yellow oil. IR (film) : 3300, 1600, 750 cm^"1 NMR (CDC1₃, δ) : 2.15-2.30 (2H, m) , 2.61 (2H, t,

J=7.2Hz), 3.72 (2H, s), 3.76 (6H, s), 3.97 (IH, t, J=7.8Hz) , .6.60-6.85 (6H, m) , 7.10-7.35 (7H, m) (+) APCI-MASS (m/z) : 362 (M⁺+l)

Preparation 46 The following compound was obtained according to a similar manner to that of Preparation 45.

N-Benzyl-4,4-bis(4-methoxyphenyl)butylamine IR (film) : 3300, 1610, cm^"1 NMR (CDC1₃, δ) : 1.35-1.55 (2H, m) , 1.90-2.10 (2H, in), 2.63 (2H, t, J=7.1Hz), 3.74 (2H, s), 3.75 (6H, s), 3.70-3.85 (IH, m) , 6.75-6.85 (4H, m) , 7.00-7.15 (4H, m), 7.20-7.35 (5H, m) (+) APCI-MASS (m/z) : 376 (M⁺+l)

Example 1

1) A solution of (R)-3-chlorostyrene oxide (2.44 g) and (+)-N-benzyl-4,4-bis( 4-ethoxycarbonylmethoxyphenyl)- 2-butylamine (6.31 g) in ethanol (18.5 ml) was refluxed for 39 hours, evaporated in vacuo, and chromatographed over silica gel using toluene and ethyl acetate as eluents to afford (-)-(lR)-N-benzyl-l-(3-chlorophenyl)-2-[[ (2S or 2R)-4,4-bis( 4-ethoxycarbonylmethoxyphenyl)-2-butyl]- amino]ethanol as an oil.

2) The obtained compound was treated with 4N hydrogen chloride in ethyl acetate and powdered in n-hexane to afford ( -)-(IR) -N-benzyl-1-(3-chlorophenyl) -2-[ [ (2S or 2R)-4,4-bis( 4-ethoxycarbonylmethoxyphenyl)-2- butyl]amino]ethanol hydrochloride (A iso er) (7.02 g) as a colorless powder, mp : 70-78°C

[α]²⁰ = -7.34° (C=0.94, EtOH) IR (Nujol) : 3230, 2700-2300, 1750, 1205 cm^"1 NMR (CDC1₃, δ) : 1.2-1.4 (6H, m) , 1.54 (3H, d,

J=6.4Hz), 2.0-2.2 and 2.85-3.55 (total 5H, m) , 3.8-3.95, 4.15-4.35, 4.45-4.6 and 4.85-4.95 (total 12H, m), 5.65-5.75 (IH, m) , 6.65-7.9 (17H, m), 11.35 and 11.66 (IH, br s)

FAB-MASS (m/z) : 674 and 676 (M⁺+l)

Example 2

The following compounds were obtained according to a similar manner to that of Example 1-1). - o _

1) (R)-1-( 3-Chlorophenyl)-2-[N-benzyl-[4,4-bis(4-ethoxy¬ carbonylmethoxyphenyl)-2-methyl-2-butyl]amino]ethanol [ ]^° = +8.36° (C=1.16, EtOH)

IR (Nujol) : 3500, 1740, 1600, 820, 780, 740, 690 cm^"1

NMR (CDC1₃, δ) : 1.03 (6H, s), 1.28 (6H, t,

J=7.1Hz), 1.59 (IH, br ε), 2.20-2.45 (2H, m) , 2.66 (2H, d, J=7.0Hz), 3.58 (IH, d, J=14.0Hz), 3.88 (IH, t, J=7.0Hz), 3.99 (IH, d, J=14.0Hz), 4.05-4.20 (IH, ) , 4.25 (4H, q, J=7.1Hz) , 4.56

(4H, ε), 6.75-6.85 (4H, m) , 6.85-7.35 (13H, m) FAB-MASS (m/z) : 688 (M⁺+l), 690 (M⁺+2+l)

2) (lR)-l-(3-Chlorophenyl)-2-[( (3RS)-N-benzyl-1,1-biε- ( 4-ethoxycarbonylmethoxyphenyl)-3-penty1)amino]- ethanol

IR (film) : 3450, 1730, 1600, 830, 790, 740,

700 cm^"1 NMR (CDC1₃, δ) : 0.75-0.95 (6H, m) , 1.10-1.35 (12H, ra), 1.10-2.80 (16H, m) , 3.37 (IH, d, J=13.2Hz),

3.47 (IH, d, J=13.2Hz), 3.77 (IH, d, J=13.2Hz), 3.78 (IH, d, J=13.2Hz), 3.50-4.40 (12H, m) , 4.50-4.60 (8H, m) , 6.70-7.35 (34H, m)

FAB-MASS (m/z) : 688 and 690 (M⁺+l)

) (IR) -N-Benzyl-1-(2-naphthyl)-2-[ [ ( 2RS)-4,4-biε( 4- ethoxycarbonylmethoxypheny1)-2-butyl]amino]ethanol IR (film) : 3400, 1745 cm^"1

NMR (CDC1₃, δ) : 0.9-1.07 (6H, m) , 1.20-1.32 (12H, m), 1.98-2.76 (10H, m) , 3.39-4.03 (8H, m) ,

4.19-4.31 (8H, m) , 4.45-4.69 (10H, m) , 6.7-7.8 (40H, m) MASS (m/z) : 690 (M⁺+l), 658, 644, 616, 532 Example 3

A suspension of (-)-(lR)-N-benzyl-l-(3-chloropheny )- 2-[[(2S or 2R)-4,4-bis(4-ethoxycarbonyMethoxyphenyl)-2- butyl]amino]ethanol hydrochloride (A isomer) (5.97 g) and 10% palladium on carbon involving water (50% Wt/Wt) (0.597 g) in chlorobenzene (91 ml) and ethanol (10 ml) was stirred for 2 hours and 15 minutes in an atmosphere of hydrogen and filtered. The filtrate was evaporated in vacuo and partitioned between ethyl acetate and aqueous εodium bicarbonate εolution. The organic layer waε washed with brine, dried over sodium sulfate, evaporated in vacuo, and chromatographed over silica gel using a mixture of dichloromethane and ethanol to afford an oil, which was converted to the hydrochloride in a usual manner. The hydrochloride was washed with n-hexane to afford (-)-(lR)- l-(3-chlorophenyl)-2-[[(2S or 2R)-4,4-bis(4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol hydrochloride (A isomer) (4.42 g) as a colorlesε powder,

⁽C=1.03, EtOH⁾ 200, 2700-2300, 1745, 1200 cm^"1 NMR (CDC1₃, δ) : 1.29 (6H, t, J=7.1Hz), 1.42 (3H, d, J=6.4Hz), 2.2-2.3 (IH, m) , 2.7-3.25 (4H, m) , 4.11 (IH, br t, J=8.0Hz), 4.25 (4H, quartet, J=7.1Hz), 4.51 (4H, ε), 5.24 (IH, br d,

J=10.0Hz), 5.45 (IH, br), 6.72 (2H, d, J=8.8Hz), 6.76 (2H, d, J=8.8Hz), 7.10 (2H, d, J=8.8Hz), 7.15 (2H, d, J=8.8Hz), 7.15-7.3 (3H, m) , 7.37 (IH, br ε), 8.3 (IH, br), 10.15 (IH, br) (+) APCI-MASS (m/z) : 584 and 586 (M⁺+l)

Example 4

A mixture of (R)-l-(3-chlorophenyl)-2-[N-benzyl-[4,4- bis(4-ethoxycarbonylmethoxyphenyl)-2-methyl-2-butyl]- amino]ethanol (320 mg) and 10% palladium on carbon involving water (50% Wt/Wt) (32 mg) in chlorobenzene (4 ml) , ethanol (4 ml) , and 4N hydrogen chloride in ethyl acetate (0.12 ml) was stirred for 2 hours in an atmosphere of hydrogen. The catalyst was filtered off, and the filtrate was evaporated in vacuo. The residue was triturated with diisopropyl ether, n-hexane and ethyl acetate to give (R)-1-(3-chlorophenyl)-2-[ [4,4- biε(4-ethoxycarbonylmethoxyphenyl)-2-methyl-2-butyl]- amino]ethanol hydrochloride as a white powder (0.24 g) . mp : 139-141°C

[α]²⁸ = -11.26° (C=0.95, DMSO)

IR (Nujol) : 3310, 2370, 1740, 1610, 800, 720 cm^"1

NMR (DMSO-dg, δ) : 1.14 (6H, ε), 1.19 (6H, t,

J=7.1Hz), 2.40-2.60 (2H, m) , 2.85-3.20 (2H, m) , 4.14 (4H, q, J=7.1Hz) , 4.05-4.25 (IH, m) , 4.70

(4H, s), 4.90-5.10 (IH, m) , 6.20-6.35 (IH, m) , 6.70-6.90 (4H, ) , 7.25-7.50 (8H, m) , 8.50 (IH, br s) , 9.25 (IH, br s)

FAB-MASS (m/z) : 598 and 600 (M⁺+l)

Example 5

The following compounds were obtained by reacting the compound, which was prepared according to a similar manner to that of Example 3, with oxalic acid or fumaric acid.

1) (lR)-l-(3-Chlorophenyl)-2-[( (3RS)-1,1-bis(4- ethoxycarbonylmethoxypheny1)-3-penty1)amino]ethanol oxalate (1:1)

IR (CHC1₃) : 3450, 2850, 1750, 1600, 830, 790, 700 cm^"1

NMR (DMSO-dg, δ) : 0.75-1.0 (6H, m) , 1.19 (12H, t,

J=7.1Hz), 1.50-1.80 (4H, m) , 2.00-3.20 (10H, m) , 4.14 (8H, q, J=7.1Hz) , 3.95-4.25 (2H, m) , 4.71 (8H, s), 4.0-5.6 (10H, m) , 6.75-7.00 (8H, m) , 7.15-7.60 (16H, m) FAB-MASS (m/z) : 598 and 600 (M⁺+l)

) ( IR)-1-( 2-Naphthyl)-2-[ [ ( 2RS)-4,4-bis( 4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol oxalate (1:1) mp : 62-69°C

IR (EtOH) : 3400, 2910, 1750, 1600 cm^"1 NMR (CDC1₃, δ) : 1.22-1.29 (18H, m) , 2.20 (2H, br), 2.59 (2H, br), 3.11 (8H, br), 3.87 (2H, br), 4.15-4.45 (16H, m) , 5.25 (2H, br), 6.6-7.8

(30H, m) MASS (m/z) : 600 (M⁺+l), 568, 554, 526, 442 Analysiε Calcd. for C₃gH₄₁N0₇ -C-H-O.-H-O

C 64.49, H 6.41, N 1.98 Found : C 64.54, H 6.61, N 2.03

) (IR)-1-(3-Chlorophenyl)-2-[ ( (2RS)-1,1-bis( 4- ethoxycarbonylmethoxyphenyl)-2-propyl)amino]ethanol oxalate (1:1) mp : 93-100°C

IR (Nujol) : 3500-3000, 1740, 1600 cm^"1

NMR (DMSO-dg, δ) : 1.10-1.30 (18H, m) , 2.70-3.10

(4H, m) , 4.00-5.20 (30H, m) , 6.80-7.00 (8H, m) , 7.30-7.50 (16H, m) (+) APCI-MASS (m/z) : 570 and 572 (M⁺+l)

) (IR)-1-(3-Chlorophenyl)-2-[ [3 ,3-bis(3-ethoxycarbonyl¬ methoxyphenyl)propyl]amino]ethanol fumarate (1:1) mp : 96-98°C £α]²³ = -10.61° (C=0.81, DMSO)

IR (Nujol) : 3500-3000, 2750-2300, 1740, 1700, 1600,

1200 cm^"1 NMR (DMSO-dg, δ) : 1.18 (6H, t, J=7.1Hz) , 2.20-2.40 (2H, ), 2.60-3.10 (4H, m) 3.80-4.00 (IH, m) , 4.13 (4H, q, J=7.1Hz) , 4.73 (4H, ε), 4.80-4.90 (IH, m), 6.52 (2H, s), 6.70-6.75 (2H, m) , 6.85-7.00 (4H, m) , 7.15-7.20 (2H, m) , 7.30-7.45 (4H, m) (+) APCI-MASS (m/z) : 570 and 572 (M⁺+l)

5) (IR)-1-(3-Chlorophenyl)-2-[ [4,4-bis(4- ethoxycarbonylmethoxyphenyl)butyl]amino]ethanol fumarate (1:1) mp : 58°C [α]²³ = -13.95° (C=0.86, DMSO)

IR (Nujol) : 3300, 2700-2300, 1740, 1700, 1195 cm^"1 NMR (DMSO-dg, δ) : 1.20 (6H, t, J=7Hz) , 1.30-1.50 (2H, m), 1.90-2.10 (2H, m) , 2.70-3.05 (4H, m) , 3.20-4.00 (4H, m), 3.82 (IH, br t) , 4.15 (4H, q, J=7.1Hz), 4.70 (4H, s), 4.80-4.87 (IH, m) , 6.49

(2H, ε), 6.81 (4H, d, J=8.7Hz), 7.17 (4H, d, J=8.7Hz), 7.30-7.45 (4H, m) (+) APCI-MASS (m/z) : 584 and 586 (M⁺+l)

Example 6

The following compound was obtained according to similar manners to those of Examples 1 and 3.

(R)-l-(3-Chlorophenyl)-2-[ (3,3-bis(4-ethoxycarbonyl- methoxyphenyl)-l_Tpropyl)amino]ethanol hydrochloride mp : 134-136°C [α]²⁵ = -12.40° (C=0.25, DMSO) IR (Nujol) : 3350, 1760, 1720, 790 cm^-1 NMR (DMSO-dg, δ) : 1.20 (6H, t, J=7.1Hz), 2.25-2.45 (2H, m), 2.70-2.90 (2H, m) , 2.90-3.10 (IH, m) ,

3.10-3.20 (IH, ra), 3.90-4.05 (IH, m) , 4.15 (4H, q, J=7.1Hz), 4.71 (4H, s), 4.85-5.00 (IH, m) , 6.28 (IH, d, J=4.lHz), 6.80-6.90 (4H, m) , 7.15-7.25 (4H, m), 7.35-7.55 (4H, m) , 8.65-9.30 (2H, m) ' FAB-MASS (m/z) : 570 and 572 (M⁺+l) Example 7

4,4-Biε(4-ethoxycarbonylmethoxyphenyl)-2-butylamine hydrochloride (210 rag) waε converted to the free baεe in a usual manner. A solution of the obtained free base and (R)-3-chlorostyrene oxide (69.7 mg) in ethanol (2.1 ml) was refluxed for 21.5 hours, evaporated in vacuo, and chromatographed over silica gel using methylene chloride-methanol to afford an oil, which was converted to the oxalate in a usual manner. The oxalate was washed with diisopropyl ether to afford (lR)-l-(3-chlorophenyl)- 2-[ (2RS)-4,4-biε(4-ethoxycarbonylmethoxyphenyl)-2-butyl)- amino]ethanol oxalate (79 mg) as a colorlesε powder, mp : 53-58°C

IR (Nujol) : 3550-3100, 2700-2300, 1750, 1630, 1605, 1200 cm^"1

NMR (DMSO-dg, δ) : 1.20 (9H, m) , 2.02 (IH, m) , 2.65 (IH, m), 2.91 (IH, ra), 3.11 (2H, m) , 4.0 (IH, m), 4.15 (4H, quartet, J=7Hz), 4.70 (4H, s), 4.85 (IH, m), 6.85 (4H, m) , 7.2-7.5 (8H, m) FAB-MASS (m/z) : 584 (M⁺+l)

Example 8

The following compounds were obtained according to a similar manner to that of Example 1.

1) (-)-(lR)-N-Benzyl-l-(3-chlorophenyl)-2-[[(2R or 2S)- 4,4-bis(4-ethoxycarbonylmethoxyphenyl)-2-butyl]- amino]ethanol hydrochloride (B isomer) mp : 73-88°C [ ]^18,0 = -20.72° (C=1.18, EtOH)

IR (Nujol) : 3170, 2600, 1750, 1200 cm^"1 NMR (CDC1₃, δ) : 1.2-1.4 (9H, m) , 1.98-2.13 (IH, br) 2.87-3.98 (4H, br), 4.2-6.2 (13H, m) , 6.7-7.9 (17H, m) MASS (m/z) : 674 and 676 (M⁺+l), 640, 532 2) (-)-(2S)-N-Benzyl-3-phenoxy-l-[[(2R or 2S)-4,4-bis(4- ethoxycarbonylmethoxyphenyl) -2-butyl]amino]-2- propanol hydrochloride mp : 48-55°C [ct]^20,8 = -21.93° (C=0.31, CH-,Cl₂)

IR (Nujol) : 3400, 2600, 1750 cm^"1

NMR (CDC1₃, δ) : 0.8-1.3 (9H, m) , 1.42-1.53 (IH, m) , 2.0 (IH, br), 3.1-3.3 (4H, br), 3.4-4.1 (4H, m) , 4.2-4.3 (5H, m) , 4.54 (2H, ε), 4.55 (2H, ε), 6.6-7.6 (18H, m)

MASS (m/z) : 670 (M⁺+l), 642, 596

3) (-)-(lR)-N-Benzyl-l-phenyl-2-[[(2R or 2S)-4,4-biε(4- ethoxycarbonylraethoxyphenyl)-2-butyl]amino]ethanol hydrochloride rap : 106-116°C

[a]^17-6 = -20.38° (C=0.61, EtOH)

IR (Nujol) : 3200, 2720-2300, 1740, 1200 cm^"1

NMR (CDC1₃, δ) : 1.28 (9H, br) , 2.08 (IH, br) , 3.2 (5H, br), 3.9 (2H, br), 4.2 (4H, br), 4.6 (5H, br) , 6.7-7.4 (18H, br) (+) APCI-MASS (m/z) : 640 (M⁺+l)

4) (IR)-1-( 3-Chlorophenyl)-2-[ ( (2RS)-N-benzyl-1,1-bis(4- ethoxycarbonylmethoxyphenyl) -2-propyl)amino]ethanol hydrochloride mp : 110-118°C

IR (Nujol) : 3700-3000, 2700-2100, 1740, 1600, 1195 cm^"1

NMR (DMSO-dg, δ) : 1.00-1.25 (18H, m) , 3.2-4.0 (16H, m) , 4.10-4.25 (8H, m) , 4.50-4.85 (10H, m) , 6.50-7.50 (34H, m)

(+) APCI-MASS (m/z) : 660 and 662 (M⁺+l)

5) (lR)-l-(3-Chlorophenyl)-2-[N-benzyl-3,3-bis[3- (ethoxycarbonylmethoxy)phenyl]propylamino]ethanol hydrochloride

[α]¹⁸ = -18.90° (C=1.28, EtOH)

IR (CHC1₃) : 3250, 2570, 1740, 1600, 1205 cm^"1 NMR (DMSO-dg, δ) : 1.19 (6H, t, J=7.1Hz), 2.40-2.80

(2H, m) , 2.80-3.20 (2H, m) , 3.60-4.20 (3H, m) , 4.13 (4H, q, J=7.1Hz), 4.10-4.60 (2H, m) , 4.73 (4H, s), 5.00-5.20 (IH, m) , 6.42 (IH, br s), 6.70-6.80 (2H, m) , 6.85-7.00 (4H, m) , 7.15-7.60 (11H, m), 10.30-10.50 (IH, br s)

(+) APCI-MASS (m/z) : 660 and 662 (M⁺+l)

6) (IR)-1-(3-Chlorophenyl)-2-[N-benzγl-4,4-bis(4- ethoxycarbonylmethoxyphenyl)butylamino]ethanol hydrochloride

[α]¹⁹ = -17.78 (C=1.04, EtOH)

IR (CHC1₃) : 3250, 2700, 2560, 2470, 2330, 1750,

1600, 1200 cm^"1 NMR (DMSO-dg, δ) : 1.19 (6H, t, J=7.1Hz) , 1.40-1.80 (2H, m), 1.80-2.10 (2H, m) , 2.80-3.40 (4H, m) ,

3.70-4.70 (3H, m) , 4.14 (4H, q, J=7.1Hz), 4.71 (4H, s), 4.80-5.10 (IH, m) , 6.45 (IH, br), 6.80-6.90 (4H, m) , 7.15-7.25 (4H, m) , 7.35-7.55 (9H, m) , 10.12 (IH, br ε) (+) APCI-MASS (m/z) : 674 and 676 (M⁺+l)

Example 9

The following compounds were obtained according to a similar manner to that of Example 3.

1) (-)-(lR)-l-(3-Chlorophenyl)-2-[[(2R or 2S)-4,4-bis(4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol hydrochloride (B iεomer) mp : 64-72°C ^Cα^^{9'6 =} "¹⁷'⁶²° ⁽C=0.91, EtOH⁾ IR (Nujol) : 3270, 2750-2650, 1745 cm^"1

NMR (DMSO-dg, δ) : 1.20 (6H, t, J=7.1Hz), 1.24 (3H<, d, J=5.2Hz), 2.04 (IH, br), 2.7-3.3 (5H, br) ,

4.04 (IH, m), 4.14 (2H, q, J=7.1Hz), 4.15 (2H, q, J=7.1Hz), 4.71 (2H, ε), 4.72 (2H, s), 4.98

(IH, br), 6.31 (IH, d, J=4.0Hz), 6.8-6.9 (4H, m), 7.1-7.5 (7H, m) APCI-MASS (m/z) : 584 and 586 (M⁺+l)

2) (-)-(2S)-3-Phenoxy-l-[[(2R or 2S)-4,4-bis(4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]-2- propanol hydrochloride mp : 52-58°C

[a]^18-9 = -9.20 (C=0.251, EtOH) IR (film) : 3370, 2960, 1745, 1500 cm^"1

NMR (DMSO-dg, δ) : 1.16-1.27 (9H, m) , 2.05 (IH, br), 2.7-3.3 (4H, br, 3.96 (2H, d, J=5.0Hz), 4.05 (2H, br), 4.14 (2H, q, J=7.1Hz), 4.15 (2H, q, J=7.1Hz), 4.71 (2H, s), 4.72 (2H, ε), 5.87 (IH, br), 6.8-7.0 (7H, m) , 7.1-7.4 (6H, m)

MASS (m/z) : 580 (M⁺+l), 552, 506

3) (-)-(lR)-l-Phenyl-2-[[(2S or 2R)-4,4-biε(4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol hydrochloride mp : 62-75°C

[α]^20*8 = -22.80 (C=0.25, EtOH)

IR (Nujol) : 3300 (br), 2720-2500, 1740, 1200 cm^"1 NMR (DMSO-dg, δ) : 1.20 (6H, t, J=7.1Hz) , 1.26 (3H, br), 2.04 (IH, br) , 2.6-3.3 (4H, br), 4.1 (IH, br), 4.14 (4H, q, J=7.1Hz), 4.71 (2H, ε), 4.72 (2H, ε), 4.92 (IH, br), 6.15 (IH, br), 6.8-6.9 (4H, m), 7.1-7.4 (9H, m) , 8.62 (IH, br) , 9.15 (IH, br) (+) APCI-MASS (m/z) : 550 (M⁺+l) Example 10

(-)-(lR)-l-(3-Chlorophenyl)-2-[[(2R or 2S)-4,4-bis(-4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol hydrochloride (B iεomer) was converted to the free base in a usual manner using sodium bicarbonate aqueous solution. A solution of the free base (460 mg) in IN sodium hydroxide solution (1.58 ml) and methanol (6.3 ml) was stirred at ambient temperature for 2 hours and evaporated in vacuo. The residue was disεolved in water (7.9 ml) and neutralized with IN hydrochloric acid (1.58 ml). The precipitated powder waε collected by filtration, waεhed successively with water and ethyl acetate, and dried to afford (-)-(lR)-l-(3-chlorophenyl)-2-[[(2R or 2S)-4,4-bis(4-carboxymethoxyphenyl)-2-butyl]amino]ethanol (B isomer) (364 mg) as a white powder, mp : 143-147°C

[ ]^18*2 = -27.67° (C=0.43, DMSO) IR (Nujol) : 3300, 2650, 1720, 1220 cm^"1 NMR (DMSO-dg, δ) : 1.13 (3H, d, J=6.1Hz) , 1.99 (IH, br), 2.5-3.0 (4H, m) , 3.94 (IH, m) , 3.2-5.2 (2H, br), 4.43 (2H, s), 4.45 (2H, ε), 4.90-4.95 (IH, br), 6.69-6.78 (4H, m) , 7.05-7.13 (4H, m) , 7.34-7.44 (4H, m) FAB-MASS (m/z) : 528 and 530 (M⁺+l) Analyεiε Calcd. for C_2gH₃₀ClNO₇-H-O

C 61.59, H 5.91, N 2.57 Found : C 61.43, H 5.88, N 2.56

Example 11 The following compound was obtained according to similar manners to those of Examples 1 and 3, except that the obtained compound was converted to the oxalate instead of the hydrochloride.

(lR)-l-(3-Chlorophenyl)-2-[ [2,2-bis[4-(ethoxy- carbonylmethoxyphenyl)ethyl]amino]ethanol oxalate (1:1) mp : 112°C

IR (Nujol) : 3500-3000, 1740, 1720, 1600 cm^"1 NMR (DMSO-dg, δ) : 1.21 (6H, t, J=7Hz) , 2.80-4.20 (8H, m), 4.15 (4H, q, J=7.1Hz) , 4.30-4.40 (IH, m) , 4.73 (4H, s), 4.90-5.00 (IH, m) , 6.85-6.90 (4H, m), 7.20-7.40 (8H, m) (+) APCI-MASS (m/z) : 556 and 558 (M⁺+l)

Example 12

The following compounds were obtained according to a similar manner to that of Example 7.

1) (lS)-l-[2-(6-Chloropyridyl) ]-2-[ [ ( 2RS)-4,4-bis( 4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol oxalate (1:1) mp : 42-58°C

IR (film) : 3440, 2950, 1745, 1600 cm^"1

NMR (CDC1₃, δ) : 1.27 (12H, t, J=7.1Hz) , 1.30-1.35 (6H, br), 2.2 (2H, br) , 2.66 (2H, br) , 3.13 (4H, br), 3.49 (2H, br) , 3.93 (2H, br), 4.23 (8H, q, J=7.1Hz), 4.52 (4H, ε), 4.54 (4H, ε), 5.09 (2H, br), 6.7-6.8 (8H, m) , 7.0-7.2 (10H, ra) , 7.40-7.43 (2H, m) , 7.5-7.7 (2H, m) MASS (m/z) : 587 and 585 (M⁺+l), 551

2) (2S)-3-Phenoxy-l-[ [ (2RS)-4,4-biε(4-ethoxycarbonyl¬ methoxyphenyl)-2-butyl]amino]-2-propanol oxalate (1:1) mp : 52-56°C

IR (film) : 3400, 1750, 2980, 1600 cm^"1 NMR (CDC1₃, δ) : 1.23-1.30 (18H, m) , 2.0-3.4 (10H, br), 3.85 (6H, br), 4.1-4.3 (10H, m) , 4.45-4.50 (8H, m) , 6.7-7.3 (26H, m) MASS (m/z) : 580 (M⁺+l), 506, 494 Example 13

(-)-(lR)-l-(3-Chlorophenyl)-2-[[ (2S or 2R)-4,4-bis('4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol hydrochloride (A iεomer) (4.07 g) was converted to the corresponding free base in a usual manner. The obtained free base was dissolved in a mixture of IN sodium hydroxide solution (13.8 ml) and methanol (61 ml), and then the reεulting εolution waε εtirred at ambient temperature for 2 hours and evaporated in vacuo. The residue was disεolved in water and the εolution was neutralized with IN hydrochloric acid (13.8 ml). The precipitated powder was collected by filtration, dried, and powdered from ethyl acetate to afford (-)-(lR)-l-(3-chlorophenyl)-2-[[(2S or 2R)-4,4-biε(4- carboxymethoxyphenyl)-2-butyl]amino]ethanol (A iεomer) (3.35 g) aε a powder. mp : 147°C (dec.) [α]J⁸ = -10.37° (C=0.53, DMSO)

IR (Nujol) : 3650-3100, 2750-2300, 1725, 1210 cm^"1 NMR (DMSO-dg, δ) : 1.16 (3H, d, J=7.1Hz) , 1.85 (IH, m), 2.5-3.1 (4H, m) , 3.93 (IH, m) , 3.2-5.2 (2H, br), 4.43 (4H, ε), 4.87 (IH, br d, J=8.8Hz), 6.75 (4H, m), 7.08 (2H, d, J=8.6Hz), 7.17 (2H, d, J=8.6Hz), 7.36 (3H, m) , 7.44 (IH, br ε) FAB-MASS (m/z) : 528 and 530 (M⁺+l)

Example 14

A suspension of (-)-(lR)-l-(3-chlorophenyl)-2-[ [ (2S or 2R)-4,4-bis(4-carboxymethoxyphenyl)-2-butyl]amino]- ethanol (A iεomer) (3.14 g) in ethanolic hydrogen chloride (63 ml) waε εtirred at ambient temperature for 5.5 hourε and evaporated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel using a mixture of dichloromethane and ethanol to afford an oil, which was crystallized from diisopropyl ether to afford (-)-(lR)-l-(3-chlorophenyl)-2-[[(2S or 2R)-4,4-bis(4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol (A isomer) (2.16 g) as a powder, mp : 55-60°C

[α]²⁰ = -13.39° (C=0.515, CH₂C1₂) IR (KBr) : 3500, 3288, 1753, 1203 cm^"1 NMR (CDC1₃, δ) : 1.08 (3H, d, J=6.2Hz) , 1.28 (6H, t, J=7.1Hz), 1.6-2.4 (IH, br) , 1.86-2.01 (IH, m) ,

2.03-2.18 (IH, m), 2.37 (IH, dd, J=12.1, 9.0Hz), 2.46 (IH, m), 2.94 (IH, dd, J=12.1, 3.5Hz), 4.01 (IH, t, J=7.8Hz), 4.25 (2H, q, J=7.1Hz) , 4.26 (2H, q, J=7.1Hz), 4.50 (IH, dd, J=9.0, 3.5Hz), 4.57 (4H, ε), 6.82 (4H, d, J=8.7Hz), 7.08-7.27

(7H, m) , 7.33 (IH, br ε) (+) APCI-MASS (m/z) : 584 and 586 (M⁺+l) Analysis Calcd. for C_,_H₃₈ClN0₇ :

C 65.80, H 6.56, N 2.40 Found : C 65.98, H 6.53, N 2.34

Example 15

The following compound was obtained according to a εimilar manner to that of Example 14.

(-)-(lR)-l-(3-Chlorophenyl)-2-[[(2R or 2S)-4,4-biε(4- ethoxycarbonylmethoxyphenyl)-2-butyl]amino]ethanol (B iεomer) mp : 66.7-69.2°C [ ]^20,4 = -20.64° (C=0.31, EtOH) IR (Nujol) : 3100, 1750 cm^"1

NMR (DMSO-dg, δ) : 0.955 (3H, d, J=6.1Hz), 1.19 (6H, t, J=7.1Hz), 1.81 (IH, m), 1.99 (IH, m) , 2.25 (IH, m), 2.50 (IH, m) , 2.6 (IH, m) , 3.96 (IH, m), 4.14 (4H, q, J=7.1Hz) , 4.53 (IH, m) , 4.690 (2H, s), 4.695 (2H, s), 6.7-6.8 (4H, m) , 7.0-7.2 (4H, m), 7.2-7.4 (4H, m) MASS (m/z) : 586 and 584 (M⁺+l)

Example 16

A solution of (-)-(lR)-N-benzyl-l-(3-chlorophenyl)-2- [[(2R or 2S)-4,4-biε(4-hydroxyphenyl)-2-butyl]amino]- ethanol (200 mg) in dimethyl sulfoxide (2 ml) was added slowly to a stirred suεpension of 60% sodium hydride (31.9 mg, washed with n-hexane) in dimethyl sulfoxide (0.5 ml) at ambient temperature. The resulting mixture was stirred at 50°C for a while and cooled to ambient temperature, and then tetra-n-butylammonium bromide (25.6 mg) waε added thereto. Ethyl bromoacetate (133 mg) was added to the reaction mixture under ice-cooling and the resulting mixture was stirred at ambient temperature for 3 days. The reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was waεhed with water (twice) and brine, dried over εodium sulfate, and evaporated in vacuo. The oily residue waε chromatographed over εilica gel using a mixture of toluene and ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to afford (-)-(IR)-N-benzyl-l-(3-chlorophenyl)-2- [[(2R or 2S)-4,4-biε(4-ethoxycarbonylmethoxyphenyl)-2- butyl]amino]ethanol hydrochloride (B iεomer) (152 mg) aε an amorphouε powder, mp : 73-88°C

[α]¹⁸ = -20.72° (C=1.18, EtOH) IR (Nujol) : 3170, 2600, 1750, 1200 cm^"1 NMR (CDC1₃, δ) : 1.2-1.4 (9H, m) , 1.98-2.13,

2.87-3.28 and 3.93-3.98 (total 5H, br), 4.2-4.3, 4.5-4.7 and 4.4-6.2 (total 13H, m) , 6.7-7.9 (17H, m)

(+) APCI-MASS (m/z) : 674 and 676 (M⁺+l)

Claims

C L A I M S

1. A compound of the formula :

wherein R is aryl, aryloxy(lower)alkyl or a heterocyclic group, each of which may be εubεtituted with subεtituent(s) selected from the group consisting of halogen, hydroxy, protected hydroxy, aryloxy, lower alkoxy, halo(lower)alkoxy, nitro, cyano, amino and acylamino,

2 R is hydrogen or an N-protective group,

3 R is lower alkoxy substituted with acyl,

4 R is lower alkoxy εubεtituted with acyl, and

A iε lower alkylene, and pharmaceutically acceptable εalts thereof.

2. A compound according to claim 1, wherein R is aryl, aryloxy(lower)alkyl or a heterocyclic group, each of which may be substituted with halogen.

A compound according to claim 2, wherein R is phenyl optionally substituted with halogen, naphthyl, phenoxymethyl, or pyridyl,

2 R is hydrogen, 3 R is lower alkoxy substituted with esterified carboxy or carboxy, 4 R is lower alkoxy substituted with esterified carboxy or carboxy, and

A iε lower alkylene.

4. A compound according to claim 3, wherein R iε phenyl substituted with halogen.

5. A compound according to claim 4,

3 wherein R is mmeetthhooxxyy sεuubbεεttiittuutteed* with lower alkoxycarbonyl, and

4 R iε mmeetthhooxxyy εεuubbεεttiittui ted with lower alkoxycarbonyl.

A proceεε for preparing a compound of the formula

wherein R iε aryl, aryloxy(lower)alkyl or a heterocyclic group, each of which may be εubstituted with substituent(s) selected from the group consisting of halogen, hydroxy, protected hydroxy, aryloxy, lower alkoxy, halo(lower)alkoxy, nitro, cyano, amino and acylamino, R 2 i.s hydrogen or an N-protective group,

3 R is lower alkoxy subεtituted with acyl, 4 R lε lower alkoxy substituted with acyl, and A iε lower alkylene, or salts thereof, which comprises

a) reacting a compound of the formula

0 / \ [II]

R -CH-CH.

with a compound of the formula

or its salt to provide a compound of the formula :

or its salt, in the above formulas, R 1, R2, R3, R4 and A are each as defined above, or

b) εubjecting a compound of the formula

or its salt to elimination reaction of the N-protective group to provide a compound of the formula :

or itε salt, in the above formulas, R 1, R3, R4 and A are each as defined above, and R 2_ i.s an N-protective group, or

subjecting a compound of the formula :

or its salt to deesterification reaction to provide a compound of the formula :

or its salt, in the above formulas, R 1, R2 and A are each as defined above,

3

R 3_. is lower alkoxy substituted with esterified carboxy,

ias lower alkoxy substituted with esterified carboxy, 3 R, is lower alkoxy substituted with carboxy, and

R. , is lower alkoxy subεtituted with carboxy, or

d) reacting a compound of the formula :

or itε reactive derivative at the carboxy group or a εalt thereof with a hydroxy compound to provide a compound of the formula :

or itε εalt, in the above formulaε, R 1, R2, R3, R_b3, R4, R_b4 and A are each aε defined above, or

e) reacting a compound of the formula :

or itε salt with a compound of the formula :

X - R⁵ [V] to provide a compound of the formula :

or its salt, in the above formulas, R 1, R2 and A are each as defined above,

R is lower alkyl substituted with acyl, and

X is acid residue.

7. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in asεociation with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

8. A compound of claim 1 for use as a medicament.

9. A method for therapeutic treatment and/or prevention of dysuria, spasm-, hyperanakinesia, ulcer, pancreatitiε, obeεity, diabetes, glaucoma or melancholia which comprises administering the effective amount of a compound of claim 1 to human beings or animals.

10. Use of a compound of claim 1 for the manufacture of a medicament for the treatment and/or prevention of dysuria, εpasm, hyperanakinesia, ulcer, pancreatitis, obesity, diabetes, glaucoma or melancholia in human beings or animals.