AU5305199A - Aminoalcohol derivatives and their use as beta 3 adrenergic agonists - Google Patents

Description

WO 00/12462 PCT/JP99/04538 AMINOALCOHOL DERIVATIVES AND THEIR USE AS BETA 3 ADRENERGIC AGONISTS 5 TECHNICAL FIELD This invention relates to new aminoalcohol derivatives and salts thereof which are P 3 adrenergic receptor agonists and useful as a medicament. 10 DISCLOSURE OF INVENTION This invention relates to new aminoalcohol derivatives which are P 3 adrenergic receptor agonists and salts thereof. More particularly, it relates to new aminoalcohol derivatives and salts thereof which have gut selective 15 sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence 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 20 gastro-intestinal disorders caused by smooth muscle contractions in human beings or animal. One object of this invention is to provide new and useful aminoalcohol derivatives and salts thereof which have gut selective sympathomimetic, anti-ulcerous, lipolytic, 25 anti-urinary incontinence and anti-pollakiuria activities. Another object of this invention is to provide processes for the preparation of said aminoalcohol derivatives and salts thereof. A further object of this invention is to provide a 30 pharmaceutical composition comprising, as an active ingredient, said aminoalcohol derivatives and 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 35 aminoalcohol derivatives and salts thereof.

WO 00/12462 PCT/JP99/04538 2 The object aminoalcohol derivatives of this invention are new and can be represented by the following general formula [I] :

R

2

R

3 5 OH R 1

/

R3

A-X-CH-CH

2 -N-Z-Y [I] R4 5 10 wherein A is a heterocyclic group or aryl, each of which may have 1 to 3 same or different substituent(s) selected from a group consisting of halogen, hydroxy, amino, lower alkyl, lower alkylsulfonylamino, phenyl(lower)alkoxy and 15 phenyl(lower)alkoxycarbonylamino, -X- is bond, -CH 2 -, -CH 2

-CH

2 -, -NH-CH 2 -, -O-CH 2 -, -S-CH2-,

-SO-CH

2 - or -SO 2

-CH

2 -, Y is -C (in which R II is hydrogen, hydroxy, 20 lower alkoxy or acyloxy) and

R

6

R

8 -Z- is -(CH2)n-7(CH2)m-9(CH2)k-,

-(CH

2 )n

-

~ C (CH 2 )m-'

(CH

2 ) r 25 (CH2)nQ4C(C)m _ (CH 2 ) q -(CH2)n-Q-(CH2)m-, -(CH2)n-CH -- (CH2)q CH-(CH2)m-'

-(CH

2 )n-CH=CH-(CH 2 )m - or -(CH 2 )n-C-C-(CH 2

)

m - (in which 30 -Q- is -0-, -S-, -SO-, -SO 2 -, -N-CO-, -CO-N-, 10 R10 -CH-CO-N-, -CH-CH 2 -N-, -SO 2 -N-, 35R1 10 11 R1 10 35R RR1R WO00/12462 PCT/JP99/04538 3

-N-SO

2 -, -CO- or -N-, wherein R i0 is hydrogen or R10 R10 lower alkyl, and R I is lower alkyl, 5 R 6 , R 7 , R 8 and R 9 are each independently hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy(lower)alkyl or aryl which may have 1 to 3 lower alkoxy, n, m and k is each independently 0 to 6, 10 p is 0 to 4, q is 1 to 4, and r is 2 to 7) and -Z-Y:1 is -(CH 2 )i-CH=C' (in which i is 0 to 6),

R

1 is hydrogen or an amino protective group, and 15 R 2 , R 3,

R

4 and R 5 are each independently hydrogen; lower alkyl; lower alkylthio; lower alkylsulfonyl; hydroxy; lower alkoxy; amino; lower alkylamino; acylamino; N-(lower alkyl)acylamino; carboxy; lower alkoxycarbonyl; 20 carbamoyl optionally substituted with one or two lower alkyl; hydroxy(lower)alkyl; lower alkoxy(lower)alkyl; N-acylamino(lower)alkyl; N-(lower alkyl)-N acylamino(lower)alkyl; carboxy(lower)alkyl; lower alkoxycarbonyl(lower)alkyl; carbamoyl(lower)alkyl 25 optionally substituted with one or two lower alkyl; or

R

12 12 13

-(CH

2 )j-Nz RI 3 (in which R 12 and R 13 are each independently hydrogen or lower alkyl, or R 12 and R 13 may be bonded to form a lower alkylene chain, and j is 0 to 6). 30 The object compound [I] or a salt thereof can be prepared by the following processes. 35 WO00/12462 PCT/JP99/04538 4 Process 1

R

2

R

3 0 RR

A-X-CH-CH

2 + HN-Z-Y 5/\ [II]

R

4 or a salt thereof 5 [III] or a salt thereof 10

R

2 OH R 1 R3 S A-X-H-CH 2 -N -Y 15 R4

R

5 [I] or a salt thereof Process 2 20 R2

R

3 OH Ra R 3 A-X- H-CH 2 -N-Z-Y R4 25 5 [Ia] or a salt thereof

R

2 elimination reaction R 3 of amino protective OH H 30 group I I 30 group

A-X-CH-CH

2 -N-Z-Y R4 R5 [Ib] or a salt thereof 35 WO00/12462 PCT/JP99/04538 5 wherein A, X, Y, Z, R1, R 2 , R 3 , R 4 and R 5 are each as defined above, and a is an amino protective group. 5 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. 10 The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided. Suitable example of "lower alkyl" and "lower alkyl" moiety may include straight or branched one having 1 to 6 15 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl and the like. 20 Suitable "lower alkenyl" may include vinyl, 1-(or 2-)propenyl, l-(or 2- or 3-)butenyl, l-(or 2- or 3- or 4-)pentenyl, l-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, l-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2 or 3-)ethyl-1-(or 2-)propenyl, l-(or 2- or 3- or 4-)methyl-l 25 (or 2- or 3-)butenyl, and the like, in which more preferable example may be C 2

-C

4 alkenyl. Suitable "lower alkoxy" and "lower alkoxy" moiety may be a straight or branched one such as methoxy, ethoxy, propoxy, 30 isopropoxy, l-ethylpropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, and the like, in which the preferred one may be C 1

-C

4 alkoxy, and the most preferred one may be methoxy. 35 Suitable example of "halogen" may be fluoro, chloro, WO00/12462 PCT/JP99/04538 6 bromo and iodo. Suitable example of "aryl" and "ar" moiety may include phenyl, naphthyl, anthryl, and the like, in which the 5 preferred one may be phenyl. Suitable example of "heterocyclic group" may include unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 nitrogen 10 atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3 triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H tetrazolyl, 2H-tetrazolyl, etc.), etc.; 15 saturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 20 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 oxygen 25 atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 oxygen 30 atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; 35 unsaturated 3 to 8-membered (more preferably 5 or 6- WO00/12462 PCT/JP99/04538 7 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 5 etc.), dihydrothiazinyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; 10 unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensed heterocyclic group containing.1 to 15 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.; 20 saturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing an oxygen atom, for example, tetrahydrofuran, tetrahydropyran, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6 membered) heteromonocyclic group containing an oxygen atom 25 and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.; 30 unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; 2-oxo-2,3-dihydro-1H-benzimidazolyl; and the like. 35 Suitable example of "amino protective group" moiety may WO00/12462 PCT/JP99/04538 8 be common amino 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-amyloxy 5 carbonyl, etc.], substituted or unsubstituted aralkyloxy carbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar(lower)alkyl [e.g. trityl,.benzyl, etc.], and the like, in 10 which preferable one is phenyl(lower)alkyl such as benzyl. Suitable "acyl" and "acyl" moiety may be carboxy; esterified carboxy; carbamoyl optionally substituted with one or two lower alkyl; lower alkylsulfonyl [e.g. methylsulfonyl, 15 ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.]; substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, trifluoroacetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2 dimethylpropanoyl, hexanoyl, etc.]; and the like. 20 The esterified carboxy may be substituted or unsubstituted lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 25 etc.], substituted or unsubstituted aryloxycarbonyl [e.g. phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 30 4-nitrobenzyloxycarbonyl, etc.] and the like, in which the preferred one may be lower alkoxycarbonyl, and the most preferred one may be ethoxycarbonyl. Suitable example of "lower alkylsulfonylamino" may include methylsulfonylamino, ethylsulfonylamino, 35 propylsulfonylamino, butylsulfonylamino, pentylsulfonylamino, WO00/12462 PCT/JP99/04538 9 hexylsulfonylamino, and the like, in which the preferred one may be (C 1

-C

4 )alkylsulfonylamino, and the most preferred one may be methylsulfonylamino. Suitable example of "heterocyclic group" in A can be 5 referred to aforementioned "heterocyclic group", in which the preferred one may be unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s) or unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), and the most 10 preferred one may be pyridyl, indolyl or 2-oxo-2,3-dihydro 1H-benzimidazolyl. The lower alkylene chain formed by R 7 and R 8 is a straight or branched chain alkylene having 1 to 6 carbon 15 atoms and is exemplified by methylene, ethylene, trimethylene, propylene, butylene, 1,2-dimethylethylene, pentamethylene and hexamethylene. Preferred embodiments of the object compound [I] are as 20 follow: A is pyridyl, indolyl, 2-oxo-2,3-dihydro-lH-benzimidazolyl or phenyl, each of which may have 1 to 3 same or different substituent(s) selected from a group of hydroxy, amino 25 lower alkyl (more preferably methyl), lower alkylsulfonylamino (more preferably methanesulfonylamino), phenyl(lower)alkoxy (more preferably benzyloxy) and phenyl(lower)alkoxycarbonylamino (more preferably 30 benzyloxycarbonylamino), -X- is bond, -CH 2 -, -CH 2

-CH

2 -, -O-CH 2 - or -SO 2

-CH

2 -, -Y: is -CC (in which R 11 is hydrogen or hydroxy) and 11 35

R

6

R

8 I I -Z- is -(CH 2 )n-C(CH2)m-C-(CH2)k-, -(CH2)n C-(CH2)m- or R R (CH2)r WO00/12462 PCT/JP99/04538 10

-(CH

2 )n-Q-(CH 2 )m - (in which -Q- is -CH-CO-N- or -CH-CH 2 -N-, wherein 11 10 11 10 5

R

i0 is hydrogen or lower alkyl (more preferably methyl) and R11 is lower alkyl (more preferably methyl),

R

6 , R 7 , R and R 9 are each independently hydrogen, 10 lower alkyl (more preferably methyl) or aryl (more preferably phenyl) which may have 1 to 3 lower alkoxy (more preferably methoxy), n, m and k is each independently 0 to 6, and r is 2 to 7) and 15 -Z-Yz1 is -(CH 2 )i-CH=Ct (in which i is 0 to 6),

R

1 is hydrogen or ar(lower)alkyl (more preferably benzyl), and

R

2 , R 3 , R 4 and R 5 are each independently hydrogen; lower alkyl (more preferably methyl); lower alkylthio 20 (more preferably methylthio); lower alkylsulfonyl (more preferably methanesulfonyl); hydroxy; lower alkoxy (more preferably methoxy or ethoxy); amino; lower alkylamino (more preferably methylamino); acylamino (more preferably lower alkoxycarbonylamino, 25 lower alkylsulfonylamino, lower alkanoylamino, ureido or trifluoroacetylamino, most preferably methoxycarbonylamino, ethoxycarbonylamino, methanesulfonylamino, formylamino, acetylamino or propionylamino); N-(lower alkyl)acylamino [more 30 preferably N-(lower alkyl)-[(lower)alkoxycarbonyl]amino, most preferably N-methyl-methoxycarbonylamino]; carboxy; or lower alkoxycarbonyl (more preferably methoxycarbonyl). 35 More preferred embodiments of the object compound [I] WO00/12462 PCT/JP99/04538 11 are as follow: A is phenyl each of which may have 1 to 3 same or different substituent(s) selected from a group of hydroxy, amino, 5 lower alkylsulfonylamino (more preferably methanesulfonylamino) and phenyl(lower)alkoxy (more preferably benzyloxy), -X- is bond, -CH 2 -, -CH 2 -CH2-, -O-CH 2 - or -SO 2

-CH

2 -, 10 -Y:1 is -CC (in which R 11 is hydrogen or hydroxy), R11

R

6

R

8 -Z- is -(CH 2 )n--(CH 2 )m- -(CH 2 )k- (in which 7 9

R

6 , R 7 , R 8 and R 9 are each independently hydrogen, 15 lower alkyl (more preferably methyl) or phenyl which may have 1 to 3 lower alkoxy (more preferably methoxy), n, m and k is each independently 0 or 1),

R

1 is hydrogen or phenyl(lower)alkyl (more preferebly 20 benzyl), and

R

2 , R 3 , R 4 and R 5 are each independently hydrogen; lower alkyl (more preferably methyl); lower alkylthio (more preferably methylthio); lower alkylsulfonyl (more preferably methanesulfonyl); hydroxy; lower alkoxy (more 25 preferably methoxy or ethoxy); amino; lower alkylamino (more preferably methylamino); lower alkoxycarbonylamino (more preferably methoxycarbonylamino or ethoxycarbonylamino); lower alkylsulfonylamino (more preferably methanesulfonylamino); lower alkanoylamino 30 (more preferably formylamino, acetylamino or propionylamino); ureido; trifluoroacetylamino; N-(lower alkyl)-[(lower)alkoxycarbonyl]amino (more preferably N methyl-methoxycarbonylamino); carboxy; or lower alkoxycarbonyl (more preferably methoxycarbonyl). 35 WO00/12462 PCT/JP99/04538 12 Suitable salts of the object aminoalcohol derivatives [I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, 5 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. 10 The processes for preparing the object compound [I] are explained in detail in the following. Process 1 15 The object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof. Suitable salt of the compound [III] may be the same as those exemplified for the compound [I]. 20 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, 25 potassium bicarbonate, etc.], tri(lower)alkylamine [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, 30 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. 35 Process 2 WO00/12462 PCT/JP99/04538 13 The object compound [Ib] or a salt thereof can be prepared by subjecting a compound [Ia] or a salt thereof to elimination reaction of the amino protective group. Suitable salts of the compounds [Ia] and [Ib] may be the 5 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 10 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, 15 hydrazine, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec 7-ene, or the like. Suitable acid may include an organic acid [e.g. formic 20 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, 25 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.]. 30 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 35 used as the solvent. The reaction temperature is not WO00/12462 PCT/JP99/04538 14 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 5 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 10 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 15 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 20 catalysts [e.g. reduced nickel, nickel 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, Ullman copper, etc.] and the like. 25 In case that the amino 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.]. 30 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 35 acids to be used in chemical reduction are in liquid, they WO00/12462 PCT/JP99/04538 15 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. 5 The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating. The compounds obtained by the above processes can be 10 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 15 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. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the 20 effect of the light acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compound [I] (e.g. hydrate, etc.) and any form of the crystal 25 of the compound [I] are included within the scope of the present invention. The object compound [I] or a salt thereof possesses gut selective sympathomimetic, anti-ulcerous, anti-pancreatitis, 30 lipolytic and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastro-intestinal 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 35 case of irritable bowel syndrome, gastritis, gastric ulcer, WO00/12462 PCT/JP99/04538 16 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 causes by non steroidal anti-inflammatory 5 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, prostatic hypertrophy or the 10 like; and for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression or the like; and for the treatment and/or prevention of diseases as the result of insulin resistance 15 (e.g. hypertension, hyperinsulinemia, etc.), and the like. In order to show the usefulness of the compound [I] for the prophylactic anc therapeutic treatment of above-mentioned disease in human beings or animals, the pharmacological test 20 data of a representative compound thereof are shown in the following. Test Effect on the increase in intravesical pressure induced 25 by carbachol in anesthetized dog Test Compouund (1) ( 2 S)-l-[[(2RS)-4,4-bis(4-hydroxyphenyl)-2-butyl]amino] 3-phenoxy-2-propanol hydrochloride 30 Test Method Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours and maintained under halothane anesthesia. A 12F Foley catheter was lubricated with water soluble jelly, 35 inserted into the urethral orifice and advanced approximately WO00/12462 PCT/JP99/04538 17 10 cm until the balloon tip was placed well inside the bladder. The balloon was then inflated with 5 ml of room air and catheter slowly withdrawn just part the first resistance that is felt at the bladder neck. Urine was completely 5 drained out through the catheter, and 30 ml of biological saline was infused. The catheter was connected to pressure transducer, and intravesical pressure was continuously recorded. The test compound was injected intravenously at 5 minutes before the administration of carbachol (1.8 Rg/kg). 10 Test Results Treatment Increase in intravesical pressure (mmHg) 15 Control 4.5 ± 0.3 Test Compound (1) (0.01 mg/kg) 2.5 ± 0.3** **P<0.01 vs Control (ANOVA) (N=3) 20 The following Preparations and Examples are given for the purpose of illustrating this invention. Example 1 A solution of ( 2

S)-

3 -phenoxy-1,2-epoxypropane (195 mg) 25 (IL FARMACO, 50 (10), 643 (1995)) and 4,4-bis(4 hydroxyphenyl)-2-butylamine (257 mg) in ethanol (2 ml) was stirred under reflux for 24 hours and evaporated in vacuo. The residue was chromatographed (chloroform-methanol) over silica gel (9 g) and the eluate was treated with 4N hydrogen 30 chloride in ethyl acetate to afford a crude oil, which was powdered from diethyl ether to afford (2S)-l-[[(2RS)-4,4 bis(4-hydroxyphenyl)-2-butyl]amino]-3-phenoxy-2-propanol hydrochloride (117 mg) as a pale brown powder. mp : 73oC (dec.) 35 IR (Nujol) : 3600-3100, 2700-2400, 1230 cm-1 NMR (DMSO-d 6 , 6) : 1.21-1.27 (3H, m, CH 3 ), 1.94 (1H, m, WO 00/12462 PCT/JP99/04538 18

CH

2 ), 2.60 (1H, m, CH 2 ), 2.85-3.2 (3H, m, CH 2 NCH), 3.95 (1H, m, CHAr 2 ), 4.01-4.05 (2H, m, ArOCH 2 ), 4.16 (1H, m, CHOH), 5.85 (1H, br s, OH), 6.64-6.72 (4H, m, aromatic H), 6.92-7.16 (7H, m, aromatic H), 5 7.26-7.35 (2H, m, aromatic H), 8.62 (1H, br, NH), 8.92 (1H, br, HC1), 9.23 (1H, br s, OH), 9.28 (1H, br s, OH) MS m/z : 408 (M +1) 0LO Example 2 (2R)-N-Benzyl-4,4-bis(4-methoxyphenyl)-2-butylamine hydrochloride (412 mg) was converted to the corresponding free base in a usual manner. 1.0M Solution of tin(IV) chloride in dichloromethane (1.5 ml) was added dropwise to a L5 stirred solution of the free base and (2S)-3-phenoxy-l,2 epoxypropane (225 mg) (IL FARMACO, 50 (10), 643 (1995)) in dichloromethane (4 ml) at -10 - -5C under a nitrogen atmosphere over 10 minutes and the resulting mixture was stirred for 1.5 hours at the same temperature. The reaction 0 mixture was poured into 1N hydrochloric acid and the mixture was stirred under ice cooling for 20 minutes. The organic layer was separated, washed with an aqueous solution of sodium fluoride and a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and evaporated in 5 vacuo. The residue was chromatographed (ethyl acetate) over silica gel (11 g) and the eluate was treated with 4N hydrogen chloride in ethyl acetate to afford (2S)-l-[N-benzyl-[(2R) 4,4-bis (4-methoxyphenyl)-2-butyl]amino]-3-phenoxy-2-propanol hydrochloride (136 mg) as an oil. 0 IR (Film) : 3292, 2850-2400, 1243 cm - 1 NMR (CDCl 3 , 6) : 1.27 and 1.47 (3H, each d, J=6.2 and 6.6Hz), 2.08 (1H, m), 2.9-3.5 (4H, m), 3.68-4.0 (2H, m), 3.74, 3.75 and 3.76 (6H, each s), 4.02 4.08 (2H, m), 4.10-4.26 (1H, m), 4.3-4.6 (1H, m), 5 6.72-7.43 and 7.64-7.68 (18H, m) WO 00/12462 PCT/JP99/04538 19 MS m/z : 526 (M++l) Example 3 (2S)-N-Benzyl-4,4-bis(4-methoxyphenyl)-2-butylamine 5 hydrochloride (412 mg) was converted to the corresponding free base in a usual manner. A solution of the free base and (2S)-3-phenoxy-1,2-epoxypropane (195 mg) (IL FARMACO, 50 (10), 643 (1995)) in ethanol (4 ml) was stirred under reflux for 10 hours, cooled to room temperature, and evaporated in LO vacuo. The residue was chromatographed (chloroform) over silica gel and the eluate was treated with 4N hydrogen chloride in ethyl acetate to afford (2S)-1-[N-benzyl-[(2S) 4,4-bis (4-methoxyphenyl)-2-butyl] amino] - 3 -phenoxy-2-propanol hydrochloride (549 mg) as an amorphous powder. 5 [a]2 4 : -22.59' (c=0.54, MeOH) IR (KBr) : 3300 (br), 2850-2400, 1248 cm-1 NMR (CDC1 3 , 5) : 1.41 and 1.56 (3H, each d, J=6.6Hz), 1.64 and 2.05 (1H, m), 2.94-3.6 (4H, m), 3.74, 3.75, 3.76 and 3.77 (6H, each s), 3.87-3.96 (2H, 0 m), 4.05-4.25 (3H, m), 4.5-4.65 and 4.8 (1H, m), 5.9 (1H, br), 6.69-6.98 (8H, m), 7.08-7.17 (4H, m), 7.22-7.41 (4H, m), 7.65-7.73 (2H, m) MS m/z : 526 (M++l) .5 Example 4 A mixture of (2S)-1-[N-benzyl-[(2R)-4,4-bis(4 methoxyphenyl)-2-butyl]amino]-3-phenoxy-2-propanol hydrochloride (96 mg) and 10% Pd/C (50% wet, 60 mg) in methanol (4 ml) was stirred at room temperature in the 0 presence of hydrogen at an atmospheric pressure for 6 hours and filtered. The filtrate was evaporated in vacuo and the residue was partitioned between dichloromethane and an aqueous solution of sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and evaporated in 5 vacuo. The residue was chromatographed (dichloromethane- WO 00/12462 PCT/JP99/04538 20 methanol) over silica gel (2 g) to afford an oil, which was converted to the corresponding oxalate in a usual manner to afford ( 2 S)-l-[[(2R)-4,4-bis(4-methoxyphenyl)-2-butyl]amino] 3-phenoxy-2-propanol oxalate (1:1) (26 mg) as a colorless 5 powder. mp : 121-123oC (from diethyl ether) IR (KBr) : 3423 (br), 2850-2650, 1734, 1701, 1633, 1603, 1250 cm

-

1 NMR (DMSO-d 6 , 5) : 1.23 (3H, d, J=6.3Hz), 1.99 (1H, m), 10 2.58 (1H, m), 2.85-3.01 (2H, m), 3.11-3.17 (1H, m), 3.69 (3H, s), 3.71 (3H, s), 3.9-4.6 (8H, m), 6.81 6.99 (7H, m), 7.16-7.35 (6H, m) MS m/z : 436 (M+1) 15 Example 5 The following compound was obtained according to a similar manner to that of Example 4.

(

2 S)-l-[[( 2 S)-4,4-Bis(4-methoxyphenyl)-2-butyl]amino]-3 20 phenoxy-2-propanol oxalate (1:1) a]2D 4 : 11.060 (c=0.515, MeOH) mp : 79-94°C (from diethyl ether) IR (KBr) : 3423 (br), 2750-2400, 1739-1691 (m), 1643, 1608, 1247 cm-1 25 NMR (DMSO-d 6 , 6) : 1.25 (3H, d, J=6.3Hz), 1.96 (1H, m), 2.66 (1H, m), 2.86 (1H, m) 2.95-3.15 (2H, m), 3.69 (3H, s), 3.70 (3H, s), 3.94-4.15 (4H, m), 5.1 (4H, br), 6.81-6.88 (4H, m), 6.92-6.99 (3H, m), 7.17 7.35 (6H, m) 30 MS m/z : 436 (M+1) Preparation 1 A mixture of methyl 3-aminobutyrate (4.3 g), (2S)-3 phenoxy-1,2-epoxypropane (4.59 g), ytterbium(III) 35 trifluoromethanesulfonate (1.8 g) and dichloromethane (25 ml) WO 00/12462 PCT/JP99/04538 21 was stirred at 40 0 C for 2 hours and at room temperature overnight, worked up in the usual manner and purified by silica gel column chromatography (toluene:ethanol: concentrated ammonia water = 9:1:0.1) to give (3RS)-3-[((2S) 5 2 -hydroxy-3-phenoxypropyl)amino]butyric acid methyl ester (2.59 g). IR (Neat): 3400 (br m), 1734 (s), 1599 (mn), 1495 (mn), 1458 (m), 1298 (mn), 1246 (s), 1041 (m), 756 (mn) cm-1 10 NMR (CDCl 3 , 5): 1.16 (3H, d, J=5.2Hz), 2.41-2.46 (2H, m), 2.6-3.0 (2H, m), 3.14 (1H, quartet, J=6.4Hz), 3.68 (3H, s), 3.9-4.1 (3H, m), 6.90-6.99 (3H, m), 7.24-7.33 (2H, m) MS m/z: 268 (M+1) 15 Preparation 2 A mixture of (2S)-N-benzyl-(2-hydroxy-3 phenoxypropyl)amine (142 mg), 5-bromopentanoic acid ethyl ester (173 mg), potassium carbonate (153 mg) and N,N 20 dimethylformamide (2 ml) was stirred at 80 0 C for 4.5 hours, worked up in the usual manner and purified by silica gel column chromatography (20% ethyl acetate-hexane) to give (2S)-5-[N-benzyl-(2-hydroxy-3-phenoxypropyl)amino]pentanoic acid ethyl ester (93 mg). 25 NMR (CDCl 3 , 5): 1.25 (3H, t, J=7.1Hz), 1.5-1.7 (5H, broad), 2.2-2.4 (2H, m), 2.4-2.8 (4H, m), 3.5 3.7 (1H, m), 3.7-3.9 (1H, m), 3.94 (2H, t, J=3.9Hz), 4.0-4.2 (1H, m), 4.12 (2H, quartet, J=7.1Hz), 6.86-6.98 (4H, m), 7.2-7.4 (6H, m) 30 MS m/z: 386 (M+1) Preparation 3 The following compound was obtained according to a similar manner to that of Preparation 2. 35 WO 00/12462 PCT/JP99/04538 22 (2S)-4-[N-Benzyl-(2-hydroxy-3-phenoxypropyl)amino] butanoic acid methyl ester IR (Neat): 3482 (br m), 2949 (m), 1736 (s), 1599 (w), 1495 (m), 1456 (m), 1246 (s), 1041 (m), 754 (m), 5 696 (m) cm

-

1 NMR (CDC1 3 , 5): 1.88 (2H, quintet, J=7.1Hz), 2.32 (2H, t, J=7.2Hz), 2.5-2.8 (4H, m), 3.5-3.7 (1H, m), 3.64 (3H, s), 3.84 (1H, d, J=13.0Hz), 3.89-4.0 (2H, m), 4.0-4.2 (1H, m), 6.86-6.99 (4H, m), 7.2-7.4 (6H, m) LO MS m/z: 358 (M+1) Preparation 4 The following compounds were obtained according to a similar manner to that of Example 6. L5 (1) 1-[2,2-Bis(4-methoxyphenyl)- 2 -hydroxyethyl]cyclopentanol IR (KBr): 3347 (s), 3240 (mn), 2958 (s), 1608 (mn), 1510 (s), 1466 (m), 1248 (s), 1174 (mn), 1034 (s), 835 (m) cm-1 0 NMR (CDCl 3 , 5): 1.2-1.7 (8H, m), 2.39 (1H, br s), 2.70 (2H, s), 3.78 (6H, s), 4.87 (1H, br s), 6.82 (4H, d, J=8.9Hz), 7.37 (4H, d, J=8.9Hz) (2) 3-(Dibenzylamino)-1,1-bis(4-bromophenyl) -1-propanol 5 NMR (CDC1 3 , 5): 2.3-2.4 (2H, m), 2.6-2.7 (2H, m), 3.51 (4H, s), 7.07 (2H, d, J=8.5Hz), 7.1-7.4 (16H, m) MS m/z: 564, 566 (M++l), 568 (3) (3RS)-3-(Dibenzylamino)-1,1-bis(4-bromophenyl)-1-butanol 0 NMR (CDC1 3 , 5): 1.10 (3H, d, J=6.7Hz), 2.09 (1H, d, J=14.8Hz), 2.45 (1H, dd, J=11.2 and 14.8Hz), 3.1 3.3 (1H, m), 3.18 (2H, d, J=12.8Hz), 3.91 (2H, d, J=12.7Hz), 6.82 (2H, d, J=8.7Hz), 7.11 (2H, d, J=8.7Hz), 7.2-7.3 (12H, m), 7.40 (2H, d, J=9.4Hz) 5 WO 00/12462 PCT/JP99/04538 23 (4) (2S)-1-Phenoxy-3-[N-benzyl-[(3RS)-1,1-bis(4 bromophenyl) -1l-hydroxy-3-butyll]amino]-2-propanol MS m/z: 638, 640 (M++1) , 642 5 (5) N-Benzyl-[4,4-bis(4-methoxyphenyl)butyl]amine NMR (CDC1 3 , 5): 1.4-1.7 (2H, m), 2.00 (2H, quartet, J=7.8Hz), 2.64 (2H, t, J=7.1Hz), 3.76 (6H, s), 3.72-3.79 (3H, m), 6.80 (4H, d, J=8.7Hz), 7.11 (4H, d, J=8.7Hz), 7.28 (5H, s) .0 MS m/z: 376 (M+1) (6) N-Benzyl-[3,3-bis(4-ethoxyphenyl)propyl]amine MS m/z: 390 (M+1) L5 Preparation 5 1-[2,2-Bis(4-methoxyphenyl)-2-hydroxyethyll]cyclopentanol (0.79 g) was hydrogenated in the usual manner to give 1-[2,2 bis(4-methoxyphenyl)ethyl]cyclopentanol (0.76 g). IR (Neat): 3563 (m), 3448 (mn), 2956 (s), 1610 (w), 1510 ?0 (s), 1460 (m), 1246 (s), 1178 (mn), 1036 (s), 829 (Mn) cm -1 NMR (CDC1 3 , 5): 1.5-1.9 (9H, m), 2.40 (2H, d, J=7.3Hz), 3.77 (6H, s), 4.17 (1H, t, J=7.2Hz), 6.81 (4H, d, J=6.6Hz), 7.21 (4H, d, J=6.6Hz) 25 Preparation 6 To a mixture of 1-[2,2-bis(4-methoxyphenyl)ethyl] cyclopentanol (0.76 g), azidotrimethylsilane (0.32 g) and benzene (5 ml), boron trifluoride diethyl etherate (0.34 ml) 30 was added dropwise at 0OC. The reaction mixture was stirred at room temperature for 30 minutes and worked up in the usual manner. The crude product was hydrogenated in the usual manner to give [1-[2,2-bis(4-methoxyphenyl)ethyl] cyclopentyl]amine (0.74 g). 35 IR (Neat): 2949 (s), 1610 (m), 1510 (s), 1460 (m), 1248 WO 00/12462 PCT/JP99/04538 24 (s), 1178 (m), 1038 (s), 829 (s) cm-1 NMR (CDCl 3 , 6): 1.3-1.8 (10H, m), 1.20 (2H, t, J=6.8Hz), 3.77 (6H, s), 4.09 (1H, quartet, J=6.8Hz), 6.81 (4H, dd, J=2.2 and 6.6Hz), 7.14 (4H, d, J=6.5Hz) 5 MS m/z: 326 (M+1) Preparation 7 To a solution of dibenzylamine (1.14 g) and tetrahydrofuran (4 ml), butyllithium (1.54M in hexane, 3.7 LO ml) was added dropwise at -780C under a flow of nitrogen. After 30 minutes, a solution of 3-(3,4-dimethoxyphenyl) acrylic acid methyl ester (1.06 g) in tetrahydrofuran (3 ml) was added dropwise, stirred for 1 hour and worked up in the usual manner. The crude product was purified by silica gel L5 column chromatography (hexane:ethyl acetate = 5:1) to give 3 -(dibenzylamino)-3-(3,4-dimethoxyphenyl)propionic acid methyl ester (0.53 g). IR (Neat): 1739 (s), 1514 (s), 1458 (mn), 1261 (mn), 1146 (m), 1028 (m), 744 (m) cm

-

1 .0 NMR (CDCl 3 , 5): 2.72 (1H, dd, J=7.3 and 14.4Hz), 3.07 (1H, dd, J=8.6 and 14.4Hz), 3.21 (1H, d, J=13.7Hz), 3.65 (3H, s), 3.73 (2H, s), 3.79 (2H, s), 3.89 (6H, s), 4.25 (1H, t, J=7.4Hz), 6.75-6.90 (3H, m), 7.1 7.4 (10H, m) .5 Preparation 8 A mixture of 3-(dibenzylamino)-3-(3,4-dimethoxyphenyl) propionic acid methyl ester (0.53 g), acetic acid (3 ml), methanol (3 ml), and 20% palladium hydroxide on charcoal 0 (0.05 g) was stirred under hydrogen (1 atm) at room temperature for 6 hours, filtered and evaporated to give 3 amino-3-(3,4-dimethoxyphenyl)propionic acid methyl ester acetate (0.24 g). IR (KBr): 1729 (s), 1539 (s), 1523 (s), 1398 (mn), 1265 5 (m), 1203 (m), 1155 (m), 1020 (m) cm-1 WO 00/12462 PCT/JP99/04538 25 NMR (MeOH-d 4 , 5): 1.90 (3H, s), 2.92 (2H, dd, J=5.4 and 6.6Hz), 3.63 (3H, s), 3.82 (3H, s), 3.84 (3H, s), 4.52 (1H, t, J=7.5Hz), 6.95 (2H, s), 7.02 (1H, s) 5 Preparation 9 To a solution of 3-aminopropionic acid methyl ester hydrochloride (1.12 g) in methanol (10 ml), 28% sodium methoxide-methanol solution (1.60 g) was added, filtered and evaporated. To the crude product, (2S)-2-phenoxy-1,2 10 epoxypropane (901 mg) and methanol (10 ml) were added and stirred under reflux for 2.5 hours. The reaction mixture was evaporated and purified by silica gel column chromatography to give 3-[ ( (2S)-2-hydroxy-3-phenoxypropyl)amino]propionic acid methyl ester (0.76 g). 15 IR (KBr): 1734 (s), 1601 (m), 1498 (m), 1435 (m), 1252 (s), 1196 (m), 1043 (m), 752 (m) cm-1 NMR (CDC1 3 , 5): 2.54 (2H, t, J=6.4Hz), 2.72-2.98 (4H, m), 3.69 (3H, s), 3.97-4.07 (3H, m), 6.90-6.99 (3H, m), 7.25-7.32 (2H, m) 20 MS m/z: 254 (M+1) Preparation 10 The following compound was obtained according to a similar manner to that of Preparation 9. 25 (3RS)-3-[ ((2S)-2-Hydroxy-3-phenoxypropyl)amino]-3 phenylpropionic acid methyl ester IR (KBr): 1724 (s), 1599 (m), 1495 (m), 1435 (m), 1246 (s), 1126 (m), 1038 (m), 756 (m), 698 (m) cm-1 30 NMR (CDCl 3 , 5): 2.54-2.75 (4H, m), 3.66 (1.5H, s), 3.67 (1.5H, s), 3.9-4.0 (2H, m), 4.0-4.2 (2H, m), 6.85 6.98 (3H, m), 7.2-7.4 (7H, m) MS m/z: 330 (M+1) 35 Preparation 11 WO 00/12462 PCT/JP99/04538 26 To a mixture of N-carbobenzyloxy-D-alanine (0.81 g), [bis(4-methoxyphenyl)methyl]amine (0.80 g), 1-hydroxybenzotriazole (0.58 g) and N,N-dimethylformamide (5 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 5 hydrochloride (0.76 g) was added at 0 0 C and stirred at room temperature for 30 minutes. After a usual workup, N-carbobenzyloxy-D-alanine [bis(4-methoxyphenyl)methyl]amide (1.38 g) was obtained. IR (KBr): 3296 (s), 1689 (m), 1647 (s), 1539 (s), 1512 10 (s), 1257 (s), 1176 (m), 1031 (m) cm-1 NMR (DMSO-d 6 , 5): 1.21 (3H, d, J=7.1Hz), 3.33 (6H, s), 4.17 (1H, t, J=7.2Hz), 5.01 (2H, s), 5.96 (1H, d, J=8.4Hz), 6.86 (4H, d, J=8.7Hz), 7.1-7.2 (4H, m), 7.3-7.5 (5H, m), 8.60 (1H, d, J=8.5Hz) 15 Preparation 12 To a solution of N-carbobenzyloxy-D-alanine [bis(4 methoxyphenyl)methyl]amide (0.33 g) in methanol and tetrahydrofuran (1:2, 10 ml), 50% wet 10% palladium on 20 charcoal was added and stirred under hydrogen atmosphere (1 atm) for 30 minutes. After a usual workup, D-alanine [bis(4 methoxyphenyl)methyl]amide (0.25 g) was obtained. IR (Neat): 3357 (br s), 1678 (s), 1649 (s), 1538 (s), 1513 (s), 1259 (m), 1176 (m), 1032 (s), 831 (m), 25 812 (m) cm- 1 NMR (DMSO-d 6 , 5): 1.13 (3H, d, J=6.9Hz), 3.33 (6H, s), 3.3-3.4 (3H, br), 5.96 (1H, d, J=8.2Hz), 6.87 (4H, d, J=8.7Hz), 7.15 (4H, d, J=8.4Hz), 8.44 (1H, d, J=8Hz) 30 Preparation 13 To a solution of 4-methoxyphenylmagnesium bromide (IM in tetrahydrofuran, 35 ml) a solution of 3-(dibenzylamino) propionic acid ethyl ester (4.87 g) in terahydrofuran (2 ml) 35 was added, stirred under reflux for 1 hour, worked up in the WO00/12462 PCT/JP99/04538 27 usual manner and purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to give 3-dibenzylamino-1,1 bis(4-methoxyphenyl)-l-propanol (3.45 g). 5 Preparation 14 3-(Dibenzylamino)-1,1-bis(4-methoxyphenyl)-1-propanol (2.0 g) was hydrogenated by the usual manner to give N-benzyl-[3,3-bis(4-methoxyphenyl)propyl]amine, which was further hydrogenated by heating with 20% palladium on 10 charcoal and ammonium formate in methanol to give [3,3-bis(4 methoxyphenyl)propyl]amine (165 g). Preparation 15 To a solution of 4-benzyloxy-3-nitrophenyl acetate (4.20 15 g) in methanol (20 ml), 28% sodium methoxide-methanol solution (2.96 g) was added and evaporated. To the crude residue, N,N-dimethylformamide (20 ml) and (2S)-3-[(3 nitrophenyl)sulfonyloxy]-1l,2-epoxypropane (3.80 g) were added. The mixture was stirred at room temperature ?0 overnight, and worked up in the usual manner to give (2S)-3

(

4 -benzyloxy-3-nitrophenoxy)-1,2-epoxypropane (4.30 g). NMR (CDCl 3 , 5): 2.72-2.77 (1H, m), 2.92 (1H, quintet, J=4.8Hz), 3.32-3.37 (1H, m), 3.91 (1H, quartet, J=5.9Hz), 4.27 (1H, dd, J=2.8 and 11.4Hz), 5.18 5 (2H, s), 7.07-7.15 (2H, m), 7.34-7.46 (6H, m) Preparation 16 A mixture of 3-(dibenzylamino)-1,1-bis(4-bromophenyl)-1 propanol (8.42 g), benzophenone imine (10.8 g), 30 tris(dibenzylideneacetone)dipalladium (546 mg), (RS)-2,2' bis(diphenylphosphino)-1,1'-binaphthyl (1.11 g), sodium tert-butoxide (5.7 g) and toluene (90 ml) was stirred at 1000C for 6 hours. The reaction mixture was added to tetrahydrofuran (300 ml), and 3N hydrochloric acid (300 ml) 5 and stirred at room temperature for 1.5 hours. The aqueous WO00/12462 PCT/JP99/04538 28 phase was separated, neutralized by sodium hydroxide and extracted with ethyl acetate. The ethyl acetate solution was evaporated and purified by silica gel column chromatography (hexane:ethyl acetate =1:1) to give 3-(dibenzylamino)-1,1 5 bis(4-aminophenyl)-1-propanol (1.76 g). MS m/z: 438 (M+1) Preparation 17 The following compound was obtained according to a L0 similar manner to that of Preparation 16. (3RS)-3-(Dibenzylamino)-1,1-bis(4-aminophenyl)-1-butanol IR (Neat): 3356 (m), 3219 (m), 2964 (mn), 1622 (s), 1512 (s), 1454 (mn), 1383 (w), 1271 (mn), 1246 (m), 1176 L 5 (m), 1142 (m), 831 (m) cm-1 NMR (CDCl 3 , 5): 1.03 (3H, d, J=6.7Hz), 2.02 (1H, d, J=11.7Hz), 2.50 (1H, dd, J=11.2 and 14.7Hz), 3.10 3.2 (1H, m), 3.21 (2H, d, J=13.0Hz), 3.92 (2H, d, J=12.9Hz), 6.35 (2H, d, J=6.5Hz), 6.55 (2H, d, ?0 J=6.6Hz), 6.76 (2H, d, J=6.6Hz), 7.13 (2H, d, J=6.5Hz), 7.24 (10H, s) MS m/z: 452 (M+1) Preparation 18 ?5 To a mixture of 3-(dibenzylamino)-1,1-bis(4 aminophenyl)-1-propanol (0.64 g), pyridine (0.5 ml) and dichloromethane (10 ml), methyl chlorocarbonate (0.34 ml) was added at 0OC and the reaction mixture was worked up in a usual manner. The crude product was dissolved in methanol 30 (10 ml), followed by addition of 4N hydrogen chloride in 1,4 dioxane (0.5 ml) and 20% palladium hydroxide on charcoal. The mixture was stirred under hydrogen (1 atm) at room temperature overnight, worked up in a usual manner and purified by silica gel column chromatography 35 (dichloromethane:methanol:concentrated ammonia water = WO00/12462 PCT/JP99/04538 29 20:1:0.1) to give N-benzyl-[3,3-bis[4-[(methoxycarbonyl) amino]phenyl]propyl]amine (466 mg). MS m/z: 448 (M+1) 5 Preparation 19 A mixture of (3RS)-3-aminobutyric acid methyl ester hydrochloride (5.0 g), benzyl bromide (11.7 g), potassium carbonate (18 g) and N,N-dimethylformamide (40 ml) was stirred at room temperature overnight, worked up in the usual 10 manner and purified by silica gel column chromatography (hexane:ethyl acetate = 15:1) to give (3RS)-3 (dibenzylamino)butyric acid methyl ester (7.27 g). IR (Neat): 2968 (m), 1741 (s), 1454 (m) 1259 (m), 1196 (m), 1146 (m), 1072 (m), 1022 (m), 744 (m), 15 698 (m) cm-1 NMR (CDCl 3 , 5): 1.10 (3H, d, J=6.7Hz), 2.28 (1H, dd, J=6.9 and 13.9Hz), 2.64 (1H, dd, J=8.01 and 13.9Hz), 3.30 (1H, dd, J=6.8 and 14.7Hz), 3.44 (2H, d, J=13.7Hz), 3.60 (3H, s), 3.66 (2H, d, J=13.7Hz), 20 7.18-7.35 (10H, m) MS m/z: 298 (M++l) Preparation 20 The following compound was obtained according to a 25 similar manner to that of Preparation 19. (3RS)-3-[N-Benzyl-((2S)-2-hydroxy-3-phenoxypropyl) amino]butyric acid methyl ester MS m/z: 358 (M+1) 30 Preparation 21 To a mixture of (3RS)-3-(dibenzylamino)-l,1-bis(4 aminophenyl)-1-butanol (360 mg), triethylamine (0.44 ml) and dichloromethane (4 ml), methanesulfonyl chloride (0.20 ml) 35 was added dropwise at 0OC. The reaction mixture was stirred WO 00/12462 PCT/JP99/04538 30 at room temperature for 30 minutes and worked up in the usual manner. The crude product was dissolved in methanol followed by addition of 10% palladium on charcoal (50% wet) and ammonium formate, heated under reflux for 1.5 hours, 5 filtrated and extracted by water. The aqueous solution was treated with benzyl chlorocarbonate (136 pl) in the usual Shotten method, worked up in the usual manner and purified by silica gel column chromatography (hexane:ethyl acetate = 2:3) to give (3RS)-[3,3-bis[4-(methanesulfonylamino)phenyl]-1 0 methylpropyl]carbamic acid benzyl ester (138 mg). IR (Neat): 3259(m), 1680 (s), 1512 (s), 1331 (m), 1153 (s), 974 (m) cm

-

1 NMR (CDCl 3 , 5): 1.13 (3H, d, J=6.8Hz), 2.4-2.6 (2H, m), 2.98 (6H, s), 3.7-3.9 (1H, m), 4.6-4.8 (1H, m), 5 6.52 (2H, s), 7.07-7.15 (5H, m), 7.2-7.5 (8H, m) Preparation 22 (3RS)-1,1-Bis[4-(methanesulfonylamino)phenyl]-3 butylamine (77.4 mg) was obtained from (3RS)-[3,3-bis[4 0 (methanesulfonylamino)phenyl] -1-methylpropyl] carbamic acid benzyl ester (101 mg) by hydrogenation in the usual manner. IR (KBr): 3425 (br s), 1635 (m), 1506 (m), 1325 (m), 1151 (s), 1103 (m), 980 (w) cm-1 NMR (MeOH-d 4 , 5): 1.13 (3H, d, J=6.4Hz), 2.05 (2H, 5 quartet, J=7.7Hz), 2.73 (1H, quartet, J=6.5Hz), 2.89 (6H, s), 4.06 (1H, dd, J=7.8Hz and 14.8Hz), 7.16 (4H, d, J=8.5Hz), 7.26 (4H, d, J=8.5Hz) MS m/z: 412 (M+1) 0 Preparation 23 To a mixture of (3RS)-3-(dibenzylamino)-1,1-bis(4 aminophenyl)-1-butanol (0.40 g), triethylamine (0.37 ml) and dichloromethane (4 ml), acetic anhydride (0.18 ml) was added at 0 0 C, followed by addition of additional triethylamine (0.1 5 ml) and acetic anhydride (0.09 ml). The reaction mixture was WO 00/12462 PCT/JP99/04538 31 worked up in the usual manner to give (3RS)-3 (dibenzylamino)-1,1-bis[4-(acetylamino)phenyl] -l1-butanol (0.49 g). IR (Neat): 2300 (m), 1666 (s), 1623 (m), 1539 (s), 1514 5 (m), 1319 (m), 1265 (m), 1142 (w), 837 (m) cm -1 NMR (CDCl 3 , 5): 1.06 (3H, d, J=6.6Hz), 2.12 (3H, s), 2.16 (3H, s), 2.0-2.2 (1H, m), 2.45-2.58 (1H, m), 3.0-3.2 (1H, m), 3.20 (2H, d, J=12.9Hz), 3.92 (2H, d, J=13.0Hz), 6.72 (2H, d, J=6.8Hz), 7.09-7.36 0 (16H, m) MS m/z: 536 (M+1) Preparation 24 (3RS)-3-Amino-1,1-bis [4-(acetylamino)phenyl] -1-butanol 5 (0.23 g) was obtained from (3RS)-3-(dibenzylamino)-1,1-bis[4 (acetylamino)phenyl]-1-butanol (0.32 g) by the usual hydrogenation. IR (KBr): 3294 (m), 1666 (s), 1623 (s), 1537 (s), 1514 (m), 1406 (m), 1321 (n), 1014 (m) cm-1 0 NMR (MeOH-d 6 , 5): 1.10-1.15 (3H, m), 2.07 (3H, s), 2.11 (3H, s), 2.5-3.1 (3H, m), 4.23 (2H, d, J=10.6Hz), 4.55 (2H, d, J=10.6Hz), 7.21-7.58 (8H, m) Preparation 25 5 The following compound was obtained according to a similar manner to that of Example 33. (3RS)-3-(Dibenzylamino)-1,1-bis[4-(methoxycarbonyl amino)phenyl]-1-butanol 0 MS m/z: 568 Preparation 26 (3RS)-1,1-Bis[4-(methoxycarbonylamino)phenyl] -3 butylamine hydrochloride (191 mg) was obtained from (3RS)-3 5 (dibenzylamino)-1,1-bis(4-methoxycarbonylaminophenyl)butanol WO00/12462 PCT/JP99/04538 32 (173 mg) by hydrogenation in the usual manner. MS m/z: 372 (M++1) (free) Preparation 27 5 Methanesulfonyl chloride (1.4 ml) was added dropwise to a solution of 3-amino-4-benzyloxyphenyl acetate (4.3 g) in pyridine (20 ml) under ice cooling over 10 minutes and the mixture was stirred at room temperature for a further 1 hour. To the reaction mixture was added water (100 ml) and was 10 stirred at the same temperature for 1 hour. The precipitates were collected by filtration and dissolved into chloroform (100 ml), followed by its dryness over magnesium sulfate and its evaporation in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford 4-benzyloxy 15 3-(methanesulfonylamino)phenyl acetate (1.6 g). NMR (CDC1 3 , 5): 2.27 (3H, s), 2.95 (3H, s), 5.09 (2H, s), 6.80-7.03 (3H, m), 7.25-7.45 (6H, m) MS m/z: 336 (M+1) 20 Preparation 28 A solution of 4-benzyloxy-3-(methanesulfonylamino)phenyl acetate (1.6 g) and potassium hydroxide (2.67 g) in methanol (10 ml) was stirred for 18 hours at room temperature. The reaction mixture was acidified with 1N hydrochloric acid to 25 pH 5-7 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford N-(2 benzyloxy-5-hydroxyphenyl)methanesulfonamide (750 mg). 30 NMR (CDCl 3 , 5): 2.90 (3H, s), 5.04 (2H, s), 6.58 (1H, dd, J=2.9 and 8.8Hz), 6.80-6.90 (2H, m), 7.09 (1H, d, J=2.9Hz), 7.30-7.50 (6H, m) MS m/z: 294 (M++l) 35 Preparation 29 WO00/12462 PCT/JP99/04538 33 Under nitrogen, to a solution of N-(2-benzyloxy-5 hydroxyphenyl)methanesulfonamide (740 mg) and sodium hydride (92.4 mg) in N,N-dimethylformamide (30 ml) was added (2S) glycidyl tosylate (616 mg) at 0OC and the mixture was stirred 5 at the same temperature for 0.5 hour. The mixture was allowed to warm to room temperature and stirred for 2.5 hours at the same temperature. The resulting mixture was poured into 10% aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with brine, .0 dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S)-3-[4-benzyloxy-3 (methanesulfonamino)phenoxy]-l,2-epoxypropane (440 mg). NMR (CDCl 3 , 5): 2.75 (1H, dd, J=2.7 and 4.9Hz), 5 2.84-2.95 (4H, m), 3.30-3.37 (1H, m), 3.90 (1H, dd, J=5.8 and 11.08Hz), 4.07-4.25 (1H, m), 5.05 (2H, s), 6.63-7.48 (9H, m) MS m/z: 350 (M++l) 0 Preparation 30 Under nitrogen, a solution of N-benzyl-[3,3-bis(4 methoxyphenyl)-1-methylpropyl]amine (480 mg), N-[2-benzyloxy 5-[(lR)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl] methanesulfonamide (600 mg) and N,N-diisopropylethylamine 5 (0.74 ml) in tetrahydrofuran (6 ml) was sealed with stirring at 110 0 C for 58 hours, followed by at 160 0 C for 92 hours. The resulting mixture was poured into aqueous sodium hydrogen sulfite and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium 0 bicarbonate and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 10:1 to 5:1) to give N-[5-[(1R)-2-[N-benzyl-[(1RS)-3,3-bis(4 methoxyphenyl)-1-methylpropyl]amino]-1-(triethylsilyloxy) 5 ethyl]-2-(benzyloxy)phenyl]methanesulfonamide (226 mg).

WO 00/12462 PCT/JP99/04538 34 NMR (CDCl 3 , 5): 0.25-0.5 (6H, m), 0.7-0.95 (12H, m), 1.5-2.25 (2H, m), 2.35-2.9 (6H, m), 3.45-3.9 (8H, m), 4.25-4.4 (1H, m), 5.0-5.1 (2H, m), 6.65-7.75 (21H, m) 5 Preparation 31 N-Benzyl-[ (IS)-3,3-bis( 4 -methoxyphenyl)-1-methylpropyl] amine hydrochloride (800 mg) was dehydrochlorinated with saturated aqueous sodium bicarbonate and extracted with ethyl 10 acetate. A mixture of the above obtained product and 10% palladium on activated carbon (50% wet, 300 mg) in methanol (10 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5.5 hours. After filtration, the filtrate was evaporated in vacuo to give 15 [(lS)-3,3-bis( 4 -methoxyphenyl)-l-methylpropyl]amine (568 mg). NMR (CDCl 3 , 6): 1.10 (3H, d, J=6.3Hz), 1.95-2.1 (2H, m), 2.7-2.9 (1H, m), 3.76 (6H, m), 3.98 (1H, t, J=8.0Hz), 6.75-6.9 (4H, m), 7.1-7.2 (4H, m) 20 Preparation 32 The following compound was obtained according to a similar manner to that of Preparation 31. 25 [(1R)-3,3-Bis(4-methoxyphenyl) -1-methylpropyl]amine NMR (CDCl 3 , 5): 1.19 (3H, d, J=6.3Hz), 1.9-2.1 (2H, m), 2.7-2.85 (1H, m), 3.76 (6H, m), 3.98 (1H, t, J=7.9Hz), 6.75-6.9 (4H, m), 7.15 (4H, d, J=8.0Hz) 30 Preparation 33 A mixture of N-benzyl-[3,3-bis(4-hydroxyphenyl)-1 methylpropyl]amine (300 mg) and 10% palladium on activated carbon (50% wet, 100 mg) in methanol (5 ml) was stirred at room temperature in the presence of hydrogen at an 35 atmospheric pressure for 4 hours. After filtration, the WO00/12462 PCT/JP99/04538 35 filtrate was evaporated in vacuo to give [3,3-bis(4 hydroxyphenyl)-l-methylpropyl]amine (230 mg). NMR (DMSO-d 6 , 5): 0.96 (3H, d, J=6.3Hz), 1.75-1.9 (2H, m), 2.4-2.6 (1H, m), 3.87 (1H, t, J=7.9Hz), 6.63 5 (4H, d, J=8.5Hz), 7.03 (4H, d, J=8.2Hz) Preparation 34 The following compound was obtained according to a similar manner to that of Preparation 33. 0 N-Benzyl-[3,3-bis(4-methoxyphenyl)-l-methylpropyl]amine Preparation 35 A mixture of 6-[(4-nitrophenyl)azo]pyridin-3-ol (J. Am. 5 Chem. Soc. 1959, 81, 6049, 300 mg) and 20% palladium hydroxide on carbon (60 mg) in a mixture of acetic acid (30 ml) and methanol (30 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 70 minutes. After filtration, the filtrate was evaporated in 0 vacuo. Under nitrogen, to a mixture of the residue in dichloromethane (10 ml) was added bis(trimethylsilyl) acetamide (6.0 ml) at 5 0 C. After being stirred at room temperature for 30 minutes, to the resulting mixture was added benzyl chloroformate (0.54 ml) at 5C, and the mixture 5 was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. To the residue was added 0 chloroform and insoluble materials were filtered off. After the filtrate was evaporated in vacuo, the residue was purified by column chromatography on silica gel (chloroform:methanol = 50:1 to 20:1), followed by crystallization from toluene-methanol to give (5 5 hydroxypyridin-2-yl)carbamic acid benzyl ester (159 mg).

WO00/12462 PCT/JP99/04538 36 MS m/z: 245 (M+1) Preparation 36 Under nitrogen, a suspension of sodium hydride (60% in 5 oil, 189 mg) in N,N-dimethylformamide (20 ml) was dropwise added (5-hydroxypyridin-2-yl)carbamic acid benzyl ester (1.1 g) in N,N-dimethylformamide (12 ml) at 50C, and the mixture was stirred at room temperature for 1 hour. To this one was added (2S)-glycidyl tosylate (1.1 g) at 50C, and the mixture LO was stirred at room temperature for 7 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column L5 chromatography on silica gel (chloroform:ethyl acetate = 9:1) to give ( 2

S)-

3

-[

2 -(benzyloxycarbonylamino)pyridin-5-yloxy] 1,2-epoxypropane (780 mg). MS m/z: 301 (M+1) ?0 Preparation 37 To a suspension of but-3-enylbenzene (3 ml) and sodium bicarbonate (2.5 g) in a mixture of dichloromethane (200 ml) and water (60 ml) was added small portions of m-chloroperbenzoic acid (3.5 g) at room temperature, and the .5 mixture was stirred at the same temperature for 4 hours. After separation, the organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica 0 gel (hexane:ethyl acetate = 100:3) to give phenethyloxirane (970 mg). NMR (CDCl 3 , 6): 1.7-1.9 (2H, m), 2.45-2.5 (1H, m), 2.7-3.0 (4H, m), 7.1-7.4 (5H, m) 15 Preparation 38 WO00/12462 PCT/JP99/04538 37 Under nitrogen, to a solution of (2R)-glycidyl tosylate (3.0 g) in tetrahydrofuran (30 ml) were added N,N diisopropylethylamine (2.5 ml) and thiophenol (1.3 ml) at 5 0 C, and the mixture was stirred at room temperature for 12 5 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography 0 on silica gel (hexane:ethyl acetate = 5:1 to 3:1) to give toluene-4-sulfonic acid (2S)-2-hydroxy-3-(phenylthio)propyl ester (3.9 g). NMR (CDCl 3 , 5): 2.44 (3H, m), 2.75-3.25 (3H, m), 3.85-4.3 (3H, m), 7.15-7.4 (7H, m), 7.7-7.8 (2H, m) 5 Preparation 39 Under nitrogen, to a solution of toluene-4-sulfonic acid (2S)-2-hydroxy-3-(phenylthio)propyl ester (3.9 g) in ethanol (40 ml) was added 20% sodium methoxide in ethanol (4.7 ml) at 0 5 0 C, and the mixture was stirred at the same temperature for 30 minutes. After being filtrated off to remove precipitates, the filtrate was concentrated in vacuo. The residue was dissolved into a mixture of aqueous 0.1N sodium hydroxide and diethyl ether. After separation, the organic 5 layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 20:1 to 10:1) to give (2S)-3 (phenylthio)-l,2-epoxypropane (1.5 g). ) MS m/z: 167 (M+1) Example 6 To a solution of 4-bromothioanisole (508 mg) in tetrahydrofuran, butyllithium (1.54M in hexane, 1.62 ml) was added at -78 0 C. After 30 minutes, ( 3 RS)-3-[((2S)-2-hydroxy- WO 00/12462 PCT/JP99/04538 38 3-phenoxypropyl)amino]butyric acid methyl ester (131 mg) was added and warmed to 00C. The reaction mixture was worked up in the usual manner and purified by a silica gel column chromatography to give (2S)-l-phenoxy-3-[(3RS)-1, 1-bis[4 5 (methylthio)phenyl]-1-hydroxy-3-butyl]amino-3-propanol (58.5 mg). IR (Neat): 3400 (br s), 2921 (s), 1594 (s), 1492 (s), 1243 (s), 1093 (m), 1043 (m), 817 (s), 754 (s) cm-1 NMR (CDC1 3 , 5): 1.14 (3H, d, J=6.3Hz), 2.4-2.6 (2H, 10 m), 2.43 (3H, s), 2.46 (3H, s), 2.7-2.8 (2H, m), 2.88 (1H, dd, J=ll.9 and 8.0Hz), 3.9-4.1 (3H, m), 6.9-7.0 (3H, m), 7.1-7.4 (12H, m) Example 7 L5 The following compounds were obtained according to a similar manner to that of Example 6. (1) (2S)-1-Phenoxy-3-[(3RS)-1,1-bis(3-methoxyphenyl)-1 hydroxy-3-butyl] amino-2-propanol -0 IR (Neat): 3296 (br m), 2933 (s), 1599 (s), 1491 (s), 1464 (m), 1246 (s), 1171 (m), 1045 (s), 756 (m), 694 (m) cm-1 NMR (CDCl 3

+D

2 0, 5): 1.09 (3H, d, J=6.3Hz), 2.04 (1H, dd, J=11.4 and 14.2Hz), 2.39-2.49 (2H, m), 2.6-2.8 .5 (1H, m), 2.83 (1H, dd, J=8.3 and 11.9Hz), 3.74 (3H, s), 3.76 (3H, s), 3.8-3.9 (2H, m), 3.9-4.1 (1H, m), 6.72-6.75 (2H, m), 6.8-7.1 (7H, m), 7.12-7.31 (4H, m) MS m/z: 452 (M++l) 30 (2) ( 2 S)-l-Phenoxy-3-((3RS)-1,1-diphenyl-1-hydroxy-3-butyl) amino-2-propanol IR (Neat): 3292 (br m), 2925 (m), 1597 (m), 1495 (s), 1456 (m), 1244 (s), 1043 (m), 754 (s), 698 (s) cm-1 35 MS m/z: 392 (M+1) WO 00/12462 PCT/JP99/04538 39 (3) (2S)-1-Phenoxy-3-[(3RS)-1,1-bis(4-methoxyphenyl)-1 hydroxy-3-butyl] amino-2-propanol IR (Neat): 3292 (br m), 2929 (m), 1604 (mn) , 1508 (s), 1460 (m), 1248 (s), 1176 (m), 1038 (m), 833 (m), 5 756 (mn) cm - I NMR (CDCl 3 , 5): 1.12 (1.5H, d, J=5.1Hz), 1.16 (1.SH, d, J=6.2Hz), 2.0-2.5 (2H, m), 2.6-3.2 (3H, m), 3.74 (1.5H, s), 3.75 (1.5H, s), 3.78 (3H, s), 3.8-4.2 (3H, m), 6.77-7.01 (7H, m), 7.2-7.4 (6H, m) 10 MS m/z: 452 (M+1) (4) (2S)-1-Phenoxy-3-[(3RS)-1,1-bis(3,4-dimethoxyphenyl)-1 hydroxy-3-butyl] amino-2-propanol IR (Neat): 3294 (br m), 2933 (m), 1597 (w), 1510 (s), 15 1460 (m), 1257 (s), 1146 (mn), 1028 (m), 760 (mn) cm - I MS m/z: 512 (M+1) (5) (2S)-1-Phenoxy-3-[(3RS)-1,1-bis(4-methylphenyl)-1 20 hydroxy-3-butyll]amino-2-propanol IR (Neat): 3400 (br s), 2923 (s), 1596 (m), 1498 (s), 1457 (s), 1243 (s), 1087 (mn), 1043 (m), 817 (s), 754 (s) cm - I NMR (CDCl 3 , 6): 1.13 (2H, d, J=6.2Hz), 2.16 (3H, s), 25 2.31 (3H, s), 2.4-2.5 (2H, m), 2.6-2.9 (3H, m), 3.9-4.1 (3H, m), 6.9-7.4 (13H, m) MS m/z: 420 (M+1) (6) 5-[N-Benzyl-((2S)-2-hydroxy-3-phenoxypropyl)amino]-1,1 30 bis(4-methoxyphenyl) -1-pentanol IR (Neat): 3446 (br m), 2943 (m), 1604 (m), 1508 (s), 1458 (m), 1248 (s), 1176 (m), 1036 (m), 831 (m), 752 (m) cm - I 1 NMR (CDC1 3 , 5): 1.2-1.3 (2H, m), 1.4-1.7 (2H, m), 2.1 35 2.2 (2H, m), 2.4-2.7 (4H, m), 3.4-3.6 (1H, m), 3.78 WO 00/12462 PCT/JP99/04538 40 (6H, s), 3.7-3.8 (1H, m), 3.8-3.9 (2H, m), 3.9-4.1 (1H, m), 6.77-6.97 (7H, m), 7.2-7.4 (11H, m) MS m/z: 556 (M +1) 5 (7) 4-[N-Benzyl-(( 2 S)-2-hydroxy-3-phenoxypropyl)amino]-1,1 bis(4-methoxyphenyl)-1-butanol IR (Neat): 3446 (br m), 2951 (m), 1604 (m), 1508 (s), 1458 (m), 1248 (s), 1176 (m), 1036 (s), 831 (m), 752 (mn) cm - 1 10 NMR (CDC1 3 , 5): 1.5-1.7 (2H, m), 2.1-2.4 (2H, m), 2.4 2.7 (4H, m), 3.4-3.5 (1H, m), 3.77 (6H, s), 3.7-3.8 (1H, m), 3.8-4.0 (2H, m), 4.1-4.3 (1H, m), 6.78 6.98 (7H, m), 7.2-7.4 (11H, m) MS m/z: 542 (M +1) 15 (8) (2S)-1-Phenoxy-3-[ (1RS)-3,3-bis(4-methoxyphenyl)-3 hydroxy-1-(3,4-dimethoxyphenyl)propyl] amino-2-propanol IR (Neat): 3361 (br m), 2929 (m), 1602 (m), 1512 (s), 1459 (m), 1248 (s), 1032 (s), 833 (m), 756 (m) cm - 1 20 NMR (CDCl 3 , 6): 2.3-2.8 (SH, m), 3.74 (3H, s), 3.82 (3H, s), 3.86 (6H, s), 3.9-4.1 (3H, m), 6.6-7.1 (8H, m), 7.2-7.5 (8H, m) MS m/z: 574 (M +1) 25 (9) ( 2 S)-l-Phenoxy-3-[(1RS)-3,3-bis(4-methoxyphenyl)-3 hydroxy-1-phenylpropyl] amino-2-propanol IR (Neat): 3361 (br m), 2929 (m), 1603 (m), 1506 (s), 1458 (mn), 1246 (s), 1176 (m), 1035 (m), 833 (m), 756(m), 698 (m) cm

-

1 30 NMR (CDC13, 5): 2.3-2.8 (4H, m), 3.6-3.7 (1H, m), 3.74 (3H, s), 3.82 (3H, s), 3.8-4.2 (4H, m), 6.7-7.0 (9H, m), 7.1-7.2 (2H, m), 7.2-7.4 (5H, m), 7.4-7.5 (2H, m) MS m/z: 514 (M +1) 35 WO 00/12462 PCT/JP99/04538 41 (10) (2S)-1-Phenoxy-3-[3,3-bis(4-methoxyphenyl)-3 hydroxyphenyl] amino-2-propanol IR (Neat): 3313 (br m), 2931 (m), 1602 (s), 1508 (s), 1462 (m), 1248 (s), 1176 (m), 1036 (m), 831 (m), 5 756 (m) cm-1 NMR (CDC1 3

+D

2 0, 5): 2.3-2.5 (2H, m), 2.7-2.9 (4H, m), 3.77 (6H, s), 3.9-4.2 (4H, m), 6.80-7.01 (7H, m), 7.2-7.4 (6H, m) MS m/z: 438 (M ++1) 10 Example 8 The following compounds were obtained according to a similar manner to that of Preparation 33. 15 (1) (2S)-1-Phenoxy-3-[5,5-bis(4-methoxyphenyl)pentyl] amino-2-propanol hydrochloride IR (Neat): 3322 (br m), 1602 (m), 1510 (s), 1460 (m), 1246 (s), 1178 (m), 1036 (m), 831 (m) cm-1 NMR (MeOH-d 4 , 5): 1.2-1.4 (2H, m), 1.6-1.8 (2H, m), 20 2.04 (2H, quartet, J=7.5Hz), 2.99 (2H, t, J=8.0Hz), 3.09-3.22 (2H, m), 3.73 (6H, s), 3.6-3.85 (1H, m), 3.9-4.0 (2H, m), 4.1-4.3 (1H, m), 6.84 (4H, d, J=8.7Hz), 6.9-7.0 (3H, m), 7.14 (4H, d, J=8.6Hz), 7.28 (2H, t, J=7.9Hz) 25 MS m/z: 450 (M +1I) (free) (2) (2S)-1-Phenoxy-3-[4,4-bis(4-methoxyphenyl)butyl]amino-2 propanol hydrochloride IR (Neat): 3355 (br m), 1602 (mn), 1510 (s), 1460 (m), 30 1246 (s) 1178 (m), 1036 (m), 831 (m) cm-1 NMR (MeOH-d 4 , 5): 1.6-1.8 (2H, m), 2.08 (1H, quartet, J=7.9Hz), 2.55 (1H, quartet, J=7.6Hz), 3.0-3.2 (4H, m), 3.73 (6H, s), 3.7-4.3 (4H, m), 6.8-7.0 (7H, m), 7.1-7.4 (6H, m) 35 MS m/z: 436 (M+ +1) (free) WO 00/12462 PCT/JP99/04538 42 Example 9 A mixture of (2S)-l-phenoxy-3-[(3RS)-1,1-bis[4 (methylthio)phenyll-1-hydroxy-3-butyl]amino-2-propanol (47 mg), water (2 ml), methanol (3 ml) and OXONE® (potassium 5 peroxymonosulfate) (180 mg) was stirred at room temperature overnight and worked up in the usual manner to give (2S)-1 phenoxy-3- [ (3RS)-1,1-bis(4-methanesulfonylphenyl) -1-hydroxy 3-butyl]amino-2-propanol (52 mg). IR (Neat): 3521 (br m), 2927 (m), 1595 (m), 1494 (s), .0 1309 (s), 1244 (mn), 1149 (s), 1091 (m), 958 (m), 771 (s), 694 (m) cm-1 NMR (CDCl 3 , 5): 1.19 (3H, d, J=6.3Hz), 2.3-2.8 (4H, m), 2.9 (1H, m), 3.00 (3H, s), 3.05 (3H, s), 3.9-4.1 (3H, m), 6.9-7.1 (3H, m), 7.2-7.4 (1H, m), 7.5-7.74 5 (5H, m), 7.8-7.9 (4H, m) MS m/z: 548 (M +1) Example 10 A mixture of (2S)-3-phenoxy-1,2-epoxypropane (40 mg), 0 3 -amino-3-(3,4-dimethoxyphenyl)propionic acid methyl ester acetate (80 mg), triethylamine (0.5 ml) and methanol (3 ml) was heated under reflux, evaporated and purified by silica gel column chromatography (hexane:ethyl acetate:methanol = 1:1:0.07) to give ( 3 RS)-3-((2S)-2-hydroxy-3-phenoxypropyl) 5 amino-3-(3,4-dimethoxyphenyl)propionic acid methyl ester (92 mg). IR (Neat): 2925 (m), 1738 (s), 1597 (m), 1514 (s), 1460 (m), 1263 (m), 1138 (m), 1027 (s), 758 (m) cm - 1 NMR (CDCl 3 , 5): 2.6-2.8 (4H, m), 3.67 (3H, s), 3.87 0 (6H, s), 3.9-4.0 (2H, m), 4.0-4.1 (2H, m), 6.8-7.0 (7H, m), 7.26 (1H, t, J=8.9Hz) MS m/z: 390 (M +1) Example 11 5 The following compound was obtained according to a WO 00/12462 PCT/JP99/04538 43 similar manner to that of Example 10. (2S) -1-Phenoxy-3-[1, 1-bis(4-methoxyphenyl)-3-methyl-3 butyl] amino-2-propanol 5 IR (Neat): 3350 (br m), 2962 (m), 1606 (m), 1508 (s), 1460 (m), 1248 (s), 1178 (m), 1036 (m), 829 (m), 756(m) cm

-

1 NMR (CDCl 3 , 5):1.03 (3H, s), 1.05 (3H, s), 2.22 (2H, d, J=6.8Hz), 2.55 (1H, dd, J=7.0 and 11.7Hz), 2.68 10 (1H, dd, J=3.6 and 11.7Hz), 3.73 (6H, s), 3.8-3.9 (3H, m), 4.04 (1H, t, J=6.7Hz), 6.7.7-6.99 (7H, m), 7.1-7.4 (6H, m) MS m/z: 450 (M +1) 15 Example 12 A mixture of (2S)-3-phenoxy-l,2-epoxypropane (0.12 g), 1-[2,2-bis(4-methoxyphenyl)ethyl]cyclopentylamine (0.24 g) and methanol (5 ml) was heated under reflux, evaporated and purified by silica gel column chromatography (hexane:ethyl 20 acetate:methanol = 1:1:0.07) to give N-((2S)-2-hydroxy-3 phenoxypropyl)-[1- [2,2-bis(4-methoxyphenyl)ethyl] cyclopentyl]amine (40.9 mg). IR (Neat): 2954 (m), 1606 (w), 1510 (s), 1460 (m), 1246 (m), 1176 (m), 1038(s), 825 (m), 754 (m) cm-1 25 NMR (CDC1 3 , 5): 1.2-1.8 (8H, m), 2.25 (2H, t, J=6.8Hz), 2.46 (1H, dd, J=6.9 and 12.0Hz), 2.61 (1H, dd, J=4.4 and 12.0Hz), 3.73 (6H, s), 3.8-3.9 (2H, m), 4.0-4.1 (2H, m), 6.78 (4H, d, J=8.2Hz), 6.9-7.0 (3H, m), 7.19 (4H, d, J=8.7Hz), 7.24-7.33 (2H, m) 30 MS m/z: 476 (M +1) Example 13 The following compounds were obtained according to a similar manner to that of Example 12. 35 WO 00/12462 PCT/JP99/04538 44 (1) (lR)-l-(3-Pyridyl)-2-[[(3RS)-1,1-bis(4-methoxyphenyl)-3 butyl]amino]ethanol MS m/z: 407 (M +1) 5 (2) ( 2 S)-l-(3-Pyridyloxy)-3-[(3RS)-1,1-bis(4-methoxyphenyl) 3-butyl]amino-2-propanol dihydrochloride MS m/z: 437 (M ++1) (free) (3) ( 2 S)-I-(lH-Indol-4-yloxy)-3-[3,3-bis(4-methoxyphenyl) 0 propyll]amino-2-propanol MS m/z: 461 (M +1) (4) ( 2 RS)-l-( 2 -Oxo-2,3-dihydro-lH-benzimidazol-4-yloxy)-3 [(3RS)-1,1-bis(4-methoxyphenyl)-3-butyl]amino-2-propanol 5 MS m/z: 492 (M +1) (5) ( 2

R)-

3

-[

4 -Benzyloxy-3-(methanesulfonylamino)phenyl]-l [(3RS)-1,1-bis(4-methoxyphenyl)-3-butyl]amino-2-propanol 0 (6) ( 2 S)-l-Phenoxy-3-[(3RS)-1,1-bis[4-(methanesulfonyl amino)phenyl]-3-butyll]amino-2-propanol IR (KBr): 3440 (br s), 1603 (mn), 1508 (m), 1325 (mn), 1242 (mn), 1151 (s), 1103 (mn), 974 (m), 758 (m) cm-1 NMR (CDCl 3 , 5): 1.11 (3H, d, J=6.2Hz), 2.0-2.2 (2H, m), 5 2.2-2.9 (3H, m), 2.97 (6H, s), 3.9-4.0 (3H, br s), 4.1-4.2 (1H, m), 6.88-7.00 (4H, m), 7.10-7.33 (9H, m) MS m/z: 562 (M +1) 0 (7) ( 2 S)-l-Phenoxy-3-[(3RS)-1,1-bis[4-(acetylamino)phenyl] 1-hydroxy-3-butyl] amino-2-propanol MS m/z: 506 (M +1) (8) ( 2 S)-l-Phenoxy-3-[(3RS)-1,1-bis[4-(acetylamino)phenyl] 5 3-butyl] amino-2-propanol WO 00/12462 PCT/JP99/04538 45 MS m/z: 490 (M +1) Example 14 A mixture of (1S)-1-phenoxy-3-[3,3-bis(4-methoxyphenyl) 5 3-hydroxypropyl]amino-2-propanol (93 mg), p-toluenesulfonic acid hydrate (53 mg) and toluene was heated under reflux for 1.5 hours, evaporated and purified (preparative TLC, silica gel, 10% methanol-dichloromethane) to give (1S)-l-phenoxy-3 [3,3-bis(4-methoxyphenyl)-2-propenyl]amino-2-propanol (80.5 10 mg). IR (Neat): 3359 (br m), 1604 (s), 1510 (s), 1460 (m), 1248 (s), 1176 (m), 1034 (m), 835 (m), 756 (m), 686 (m) cm-1 NMR (CDCl 3

+D

2 0, 5): 2.9-3.1 (2H, m), 3.58 (2H, d, 15 J=7.0Hz), 3.77 (3H, s), 3.82 (3H, s), 3.9-4.0 (2H, m), 4.2-4.3 (1H, m), 6.07 (1H, t, J=7.1Hz), 6.73 7.29 (13H, m) Example 15 20 To a mixture of (2S)-1-phenoxy-3-[3,3-bis(4 methoxyphenyl)-3-hydroxypropyl]amino-2-propanol (34 mg), triethylsilane (0.5 ml) and dichloromethane (1 ml), trifluoroacetic acid (0.1 ml) was added dropwise at room temperature. The reaction mixture was worked up immediately 25 in the usual manner and purified by silica gel preparative TLC (eluent; 10% methanol/dichloromethane) to give (2S)-1 phenoxy-3-[3,3-bis(4-methoxyphenyl)propyl] amino-2-propanol trifluoroacetate (21 mg). IR (Neat): 3400 (br m), 2933 (m), 1680 (s), 1604 (m), 30 1508 (s), 1248 (s), 1203 (m), 1180 (s), 1134 (m), 1036 (mn), 829 (m), 756 (m) cm-1 NMR (CDCl 3 , 5): 2.3-2.5 (2H, m), 2.7-2.9 (2H, m), 2.9 3.1 (2H, m), 3.74 (6H, s), 3.8-4.0 (3H, m), 4.1-4.3 (1H, m), 6.7-6.9 (6H, m), 6.95 (2H, t, J=7.4Hz), 35 7.10 (4H, d, J=8.5Hz), 7.26 (1H, t, J=7.9Hz) WO 00/12462 PCT/JP99/04538 46 MS m/z: 422 (M+1) Example 16 A mixture of ( 2 S)-3-phenoxy-1,2-epoxypropane (0.11 g), 5 D-alanine bis(4-methoxyphenyl)methylamide (0.25 g) and methanol (4 ml) was heated under reflux overnight, evaporated and purified by silica gel column chromatography to give N ((2S)-2-hydroxy-3-phenoxypropyl)-D-alanine [bis(4 methoxyphenyl)methyl]amide (217 mg). 10 IR (KBr): 3290 (s), 1643 (s), 1606 (m), 1512 (s), 1642 (m), 1250 (s), 1176 (m), 1034 (s), 831 (w), 812 (m), 752 (m) cm-1 NMR (CDCl 3 , 6): 1.27 (3H, d, J=7.2Hz), 2.66 (1H, dd, J=3.8 and 12.0Hz), 2.80 (1H, dd, J=7.6 and 12.0Hz), 15 3.24 (1H, quartet, J=6.9Hz), 3.74 (3H, s), 3.78 (3H, s), 3.8-4.0 (3H, m), 6.14 (1H, d, J=8.6Hz), 6.8-6.9 (6H, m), 6.98 (1H, t, J=7.3Hz), 7.13 (4H, dd, J=2.0 and 8.6Hz), 7.29 (2H, t, J=7.4Hz), 7.71 (1H, d, J=8.6Hz) 20 MS m/z: 465 (M +1) Example 17 To a suspension of lithium aluminum hydride (10 mg) in tetrahydrofuran (0.5 ml), a solution of N-((2S)-2-hydroxy-3 25 phenoxypropyl)-D-alanine [bis(4-methoxyphenyl)methyl]amide (52.4 mg) in tetrahydrofuran was added dropwise at 00C under a flow of nitrogen. The reaction mixture was heated under reflux. After 2 hours, additional lithium aluminum hydride (50 mg) was added to the reaction mixture under a flow of 30 nitrogen at 0oC. The reaction mixture was heated under reflux for 2.5 hours, worked up in the usual manner and purified (preparative TLC, 10% methanol-ethyl acetate) to give ( 2 S)-l-phenoxy-3-[(2R)-1-[[bis(4-methoxyphenyl)methyl] amino]- 2 -propyl]amino-2-propanol (31.4 mg). 35 IR (Neat): 3316 (br s), 2931 (m), 1606 (m), 1508 (s), WO 00/12462 PCT/JP99/04538 47 1458 (m), 1292 (s), 1174 (mn), 1036 (s), 820 (m), 756 (m) cm-1 NMR (CDC1 3 , 5): 1.06 (3H, d, J=6.3Hz), 2.46 (1H, dd, J=8.7 and 12.0Hz), 2.62 (1H, dd, J=4.2 and 12.0Hz), 5 2.80 (2H, d, J=4.7Hz), 3.76 (6H, s), 3.9-4.1 (3H, m), 4.71 (1H, s), 6.82 (4H, dd, J=2.0 and 6.7Hz), 6.9-7.0 (3H, m), 7.2-7.3 (6H, m) MS m/z: 451 (M+1) 0 Example 18 A mixture of (2R)-2-[4-benzyloxy-3 (methanesulfonylamino)phenyl]-2-(triethylsilyloxy) -1 iodoethane (156 mg), [3,3-bis( 4 -methoxyphenyl)propyl]amine (75 mg), N,N-diisopropylethylamine (0.19 ml) and 5 dimethylacetamide (0.75 ml) was heated at 110'C overnight and worked up in the usual manner. The crude product was treated with 4N hydrogen chloride in ethyl acetate (2 ml), worked up in the usual manner and purified by preparative TLC (10% methanol-dichloromethane) to give (1R)-1-[4-benzyloxy-3 0 (methanesulfonylamino)phenyl]-2-[3,3-bis(4-methoxyphenyl) propyl]aminoethanol (47 mg). IR (Neat): 3310 (br m), 1608 (w), 1510 (s), 1460 (m), 1329 (m), 1248 (s), 1157 (s), 1120 (s), 1034 (m), 818 (mn), 739 (m) cm-1 5 NMR (CDCl 3 , 6): 2.16 (2H, quartet, J=7.1Hz), 2.5-2.7 (3H, m), 2.81 (1H, dd, J=3.6 and 12.2Hz),.2.90 (3H, s), 3.79 (6H, s), 3.95 (1H, t, J=7.9Hz), 4.55 (1H, dd, J=3.5 and 8.9Hz), 5.09 (2H, s), 6.81 (4H, d, J=8.6Hz), 6.95 (1H, d, J=8.5Hz), 7.13 (5H, d, 0 J=8.6Hz), 7.35 (5H, s), 7.47 (1H, d, J=2.0Hz) MS m/z: 591 (M+1) Example 19 The following compound was obtained according to a 5 similar manner to that of Example 18.

WO 00/12462 PCT/JP99/04538 48 (IR) -1- [4-Benzyloxy-3-(methanesulfonylamino)phenyl]-2 [[(3RS)-1,1-bis[4-(methoxycarbonylamino)phenyl] -3-butyl] amino]ethanol 5 Example 20 (IR) -- [4-Benzyloxy-3-(methanesulfonylamino)phenyll]-2 [[3,3-bis(4-methoxyphenyl)propyl]amino]ethanol (35 mg) was hydrogenated by the usual manner to give (1R)-1-[4-hydroxy-3 (methanesulfonylamino)phenyl.]-2-[ [3,3-bis(4-methoxyphenyl) 10 propyl]amino]ethanol (19.3 mg). IR (KBr): 3430 (br m), 1608 (w), 1510 (s), 1319 (m), 1304 (m), 1248 (s), 1153 (mn), 1034 (mn), 825 (mn) cm- 1 NMR (CDCl 3 , 5): 2.1-2.3 (2H, m), 2.5-2.7 (2H, m), L5 2.7-2.9 (2H, m), 2.90 (3H, s), 3.74 (6H, s), 3.83 (1H, t, J=7.8Hz), 4.5-4.7 (1H, m), 6.79 (5H, d, J=8.3Hz), 7.01 (1H, d, J=8.1Hz), 7.13 (4H, d, J=8.4Hz), 7.13 (IH, br s) MS m/z: 501 (M +1) .0 Example 21 A mixture of (2S)-3-(4-benzyloxy-3-nitrophenoxy)-1,2 epoxypropane (197 mg), N-benzyl-[3,3-bis(4-methoxyphenyl) propyl]amine (236 mg) and ethanol (3 ml) was heated under .5 reflux for 12 hours. Iron powder, ammonium chloride and water were added to the reaction mixture and heating was continued for 1 hour. The reaction mixture was filtrated and worked up in the usual manner to give (2S)-1-(3-amino-4 benzyloxyphenoxy)-3-[N-benzyl-[3,3-bis(4-methoxyphenyl) 0 propyl]amino]-2-propanol (412.7 mg). NMR (CDCl 3 , 5): 2.1-2.3 (2H, m), 2.4-2.7 (4H, m), 3.50 (1H, d, J=14Hz), 3.75 (6H, s), 3.7-4.0 (5H, m), 5.01 (2H, s), 6.15-6.4 (2H, m), 6.71-6.80 (5H, m), 7.03-7.08 (4H, m), 7.2-7.4 (10H, m) 5 MS m/z: 633 (M+1) WO 00/12462 PCT/JP99/04538 49 Example 22 The following compounds were obtained according to a similar manner to that of Example 21. 5 (1) ( 2 S)-l-(3-Amino-4-benzyloxyphenoxy)-3-[N-benzyl-[4,4 bis(4-methoxyphenyl)butyl] amino] -2-propanol NMR (CDCl 3 , 5): 1.45 (2H, quintet, J=7.5Hz), 1.93 (2H, quintet), 2.3-2.6 (4H, m), 3.44 (1H, d, J=13.5Hz), 3.69-4.1 (4H, m), 3.76 (6H, s), 5.00 (2H, s), 6.17 10 (1H, dd, J=2.9 and 8.8Hz), 6.31 (1H, d, J=2.8Hz), 6.73 (1H, d, J=8.8Hz), 6.79 (4H, d, J=8.7Hz), 7.07 (4H, d, J=7.7Hz), 7.2-7.4 (10H, m) MS m/z: 647 (M +1) 15 (2) (lRS)-1-(3-Amino-4-benzyloxyphenyl)-2-[N-benzyl-[4,4 bis(4-methoxyphenyl)butyl] amino]ethanol NMR (CDC1 3 , 5): 1.4-1.6 (2H, m), 1.8-2.1 (2H, m), 2.4-2.7 (4H, m), 3.41 (1H, d, J=13.5Hz), 3.76 (6H, s), 3.7-3.9 (2H, m), 4.51 (1H, t), 5.05 (2H, s), 20 6.50-6.65 (2H, m), 6.75-6.85 (5H, m), 7.05-7.15 (4H, m), 7.2-7.5 (10H, m) MS m/z: 617 (M +1) (3) ( 2 S)-l-Phenoxy-3-[[3,3-bis(4-ethoxyphenyl)propyl] 25 amino]-2-propanol IR (Neat): 3305 (br m), 1604 (m), 1510 (s), 1392 (w), 1300 (w), 1246 (s), 1176 (m), 1047 (s), 822 (m), 756 (m) cm-1 NMR (MeOH-d 6 , 5): 1.34 (6H, t, J=7.0Hz), 2.2-2.4 (2H, 30 m), 2.6-2.9 (4H, m), 3.97 (4H, quartet, J=7.0Hz), 3.9-4.1 (4H, m), 6.80 (4H, d, J=8.6Hz), 6.89-7.0 (3H, m), 7.14 (4H, d, J=8.6Hz), 7.26 (2H, t, J=7.9Hz) MS m/z: 450 (M +1) 35 WO00/12462 PCT/JP99/04538 50 Example 23 To a mixture of ( 2 S)-1-(3-amino-4-benzyloxyphenoxy)-3 [N-benzyl-[3,3-bis(4-methoxyphenyl)propyl]amino]-2-propanol (59 mg), pyridine (0.1 ml) and dichloromethane (1 ml), 5 methanesulfonyl chloride (27 pl) were added at 0OC and stirred for 30 minutes. The reaction mixture was worked up in the usual manner. The crude product was hydrogenated in the usual manner to give (2S)-1-[4-hydroxy-3 (methanesulfonylamino)phenoxy]-3-[[3,3-bis(4-methoxyphenyl) 10 propyl]amino]-2-propanol (17.2 mg). IR (KBr): 3440 (br s), 1610 (w), 1510 (s), 1460 (m), 1325 (m), 1248 (s), 1176 (m), 1151 (m), 1115 (w), 1034 (m), 816 (m) cm-1 NMR (MeOH-d 4 , 5): 2.1-2.3 (2H, m), 2.5-2.8 (4H, m), 15 2.91 (3H, s), 3.74 (6H, s), 3.8-4.1 (4H, m), 6.6 6.7 (1H, m), 6.7-6.9 (5H, m), 6.97 (1H, d, J=2.7Hz), 7.1-7.2 (4H, m) MS m/z: 531 (M+1) 20 Example 24 The following compounds were obtained according to a similar manner to that of Example 23. (1) (IR)-l-[4-Hydroxy-3-(methanesulfonylamino)phenyl]-2 25 [[3,3-bis[4-[(methoxycarbonyl)amino]phenyl]propyl] amino]ethanol MS m/z: 587 (M+1) (2) (2S)-1-[( 4 -Hydroxy-3-(methanesulfonylamino)phenoxy]-3 30 [[3,3-bis[4-[(methoxycarbonyl)amino]phenyl]propyl] amino]-2-propanol MS m/z: 617 (M+1) (3) ( 2 S)-l-[ 4 -Hydroxy-3-(methanesulfonylamino)phenoxy]-3 35 [4,4-bis( 4 -methoxyphenyl)butyl]amino-2-propanol WO 00/12462 PCT/JP99/04538 51 IR (KBr): 3480 (br m), 1612 (m), 1512 (s), 1460 (m), 1321 (w), 1248 (s), 1178 (m), 1113 (m), 1034 (m), 826 (m) cm-1 NMR (MeOH-d 4 , 5): 1.4-1.6 (2H, m), 1.9-2.1 (2H, m), 5 2.6-2.8 (4H, m), 2.89 (3H, s), 3.73 (6H, s), 3.8 4.1 (4H, m), 6.61 (1H, dd, J=2.9 and 8.8Hz), 6.76 (1H, d, J=8.5Hz), 6.80 (4H, d, J=8.6Hz), 6.96 (1H, d, J=2.9Hz), 7.13 (4H, d, J=8.6Hz) MS m/z: 545 (M+1) 0 (4) (IRS)-1-[4-Hydroxy-3-(methanesulfonylamino)phenyl]-2 [[4,4-bis(4-methoxyphenyl)butyl]lamino]ethanol IR (KBr): 3420 (br m), 1560 (m), 1512 (s), 1321 (m), 1248 (s), 1153 (m), 1113 (w), 1034 (m), 817(m) cm-1 5 NMR (MeOH-d 4 , 5): 1.4-1.7 (2H, m), 1.9-2.1 (2H, m), 2.7-2.9 (4H, m), 2.90 (3H, s), 3.73 (6H, s), 3.7 3.9 (1H, m), 4.6-4.8 (1H, m), 6.81 (4H, d, J=8.7Hz), 6.85 (1H, m), 7.05 (1H, m), 7.14 (4H, d, J=8.6Hz), 7.34 (1H, s) 0 MS m/z: 515 (M+1) Example 25 To a solution of (2S)-1-phenoxy-3-[N-benzyl-[3,3-bis(4 methoxyphenyl)propyl]amino]-2-propanol (47 mg) and 5 dichloromethane (1 ml), IM boron tribromide-dichloromethane solution (0.28 ml) was added at -78 0 C. The reaction mixture was stirred at 0oC for 50 minutes and worked up in the usual manner to give (2S)-1-phenoxy-3-[N-benzyl-[3,3-bis(4 hydroxyphenyl)propyl]amino]-2-propanol (44 mg). 0 MS m/z: 484 (M+1) Example 26 To a mixture of (2S)-1-phenoxy-3-[N-benzyl-[3,3-bis(4 hydroxyphenyl)propyl]amino]-2-propanol (40 mg), N,N 5 diisopropylethylamine (43 pl) and dichloromethane (1 ml), WO00/12462 PCT/JP99/04538 52 trifluoromethanesulfonic anhydride (31 il) was added at -78 0 C. The reaction mixture was worked up in the usual manner. A mixture of the obtained crude product, palladium acetate (5.6 mg), 1,3-bis(diphenylphosphino)propane (10.2 5 mg), triethylamine (46 pl), N,N-dimethylformamide (1 ml) and methanol (0.5 ml) was stirred at 100'C under carbon monoxide atmosphere (1 atm) for 3.5 hours, worked up in the usual manner and purified by preparative TLC (hexane:ethyl acetate = 3:1) to give (2S)-1-phenoxy-3-[N-benzyl-[3,3-bis[4 10 (methoxycarbonyl)phenyl]propyl]amino]-2-propanol (21 mg). MS m/z: 568 (M++l) Example 27 N-[5-[(2S)-3-[N-Benzyl-[(1RS)-3,3-bis(4-hydroxyphenyl) 15 l-methylpropyl]amino]-2-hydroxypropoxy]-2-benzyloxyphenyl] methanesulfonamide (120 mg) and 10% palladium on activated carbon (50% wet, 30 mg) in methanol (10 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3 hours, and filtered. The filtrate 20 was evaporated in vacuo and treated with 4N hydrogen chloride in ethyl acetate to afford N-[5-[(2S)-3-[[(lRS)-3,3-bis(4 hydroxyphenyl)-1-methylpropyl]amino]-2-hydroxypropoxy]-2 hydroxyphenyl]methanesulfonamide hydrochloride (50 mg). MS m/z: 516 (M++l) (free) 25 Example 28 The following compound was obtained according to a similar manner to that of Example 27. 30 N-[5-[( 2 S)-3-[[(1RS)-3,3-Bis(4-methoxyphenyl)-1 methylpropyl]amino]-2-hydroxypropoxy]-2-hydroxyphenyl] methanesulfonamide hydrochloride MS m/z: 544 (M++l) (free) 35 Example 29 WO00/12462 PCT/JP99/04538 53 (2S)-1l-Phenoxy-3-[N-benzyl-[3,3-bis[4-(methoxycarbonyl) phenyl]propyl]amino]-2-propanol (14 mg) was treated with sodium hydroxide in the usual manner and hydrogenated in the usual manner to give (2S)-1-phenoxy-3-[3,3-bis(4 5 carboxyphenyl)propyl]amino-2-propanol (12 mg). MS m/z: 450 (M++l) Example 30 A mixture of ( 2 S)-3-phenoxy-l,2-epoxypropane (0.36 g), 10 N-benzyl-[3,3-bis[4-[(methoxycarbonyl)amino]phenyl]propyl] amine (0.97 g) and ethanol (10 ml) was heated under reflux for 12 hours and cooled to room temperature. To the reaction mixture, 10% palladium on charcoal (50% wet, 0.4 g), 4N hydrogen chloride in 1,4-dioxane (1.1 ml) and methanol (5 ml) 15 was added. The mixture was stirred under hydrogen (1 atm) for 3.5 hours, filtrated, diluted with ethyl acetate, neutralized by washing with aqueous sodium bicarbonate solution and the organic layer was evaporated. The crude product was purified by silica gel column 20 chromatography(dichloromethane:methanol:concentrated ammonia water = 20:1:0.05) to give (2S)-1-phenoxy-3-[[3,3-bis[4 [(methoxycarbonyl)amino]phenyl]propyl]amino]-2-propanol, which was converted to the corresponding hydrochloride salt (0.71 g) in a usual manner. 25 IR (KBr): 3400 (br m), 1711 (s), 1599 (m), 1537 (s), 1317 (m), 1238 (s), 1072 (m), 758 (m) cm-1 NMR (MeOH-d 4 , 6): 2.3-2.5 (2H, m), 2.9-3.3 (4H, m), 3.65 (3H, s), 3.71 (3H, s), 3.9-4.00 (3H, m), 4.1 4.3 (1H, m), 6.91-6.98 (3H, m), 7.18-7.39 (10H, m) 30 MS m/z: 508 (M++1) (free) Example 31 The following compound was obtained according to a similar manner to that of Example 30. 35 WO00/12462 PCT/JP99/04538 54 (2S)-1-(4-Hydroxyphenoxy)-3-[(3RS)-1,1-bis(4 methoxyphenyl)-3-butyl]amino-2-propanol MS m/z: 452 (M +1) 5 Example 32 The following compound was obtained according to a similar manner to that of Preparation 16. (2S)-1l-Phenoxy-3-[N-benzyl-[(3RS)-l,l-bis(4 10 aminophenyl)-1-hydroxy-3-butyl]amino]-2-propanol MS m/z: 512 (M ++l) Example 33 To a mixture of (2S)-1l-phenoxy-3-[N-benzyl-[(3RS)-1,1 15 bis(4-aminophenyl)-l-hydroxy-3-butyl]amino]-2-propanol (100 mg), pyridine (48 p1l) and dichloromethane (2 ml), methyl chlorocarbonate (33 pl) was added at 00C. The reaction mixture was worked up in the usual manner to give (2S)-I phenoxy-3-[N-benzyl-[(3RS)-1,1-bis[4-[(methoxycarbonyl) 20 amino]phenyl]-1-hydroxy-3-butyl]amino]-2-propanol (125 mg). MS m/z: 628 (M +1) Example 34 The following compound was obtained according to a 25 similar manner to that of Example 33. (2S)-1-Phenoxy-3-[N-benzyl-[(3RS)-1,1-bis[4-[N-methyl (methoxycarbonyl)amino]phenyl]-1-hydroxy-3-butyl]amino]-2 propanol 30 MS m/z: 656 (M +1) Example 35 (2S)-1-Phenoxy-3-[N-(benzyl-[(3RS)-1,1-bis[4 [(methoxycarbonyl)amino]phenyl]-1-hydroxy-3-butyl]amino]-2 35 propanol (99 mg) was hydrogenated in the usual manner to give WO00/12462 PCT/JP99/04538 55 (2S)-l-phenoxy-3-[(3RS)-l,l-bis[4-[(methoxycarbonyl)amino] phenyl]-3-butyl]amino-2-propanol (58 mg). MS m/z: 522 (M +1) 5 Example 36 The following compounds were obtained according to a similar manner to that of Preparation 18. (1) (2S)-l-Phenoxy-3-[(3RS)-1,l-bis[4-[(ethoxycarbonyl) 10 amino]phenyl]-3-butyl]amino-2-propanol hydrochloride MS m/z: 550 (M +1) (free) (2) ( 2 S)-l-Phenoxy-3-[(3RS)-1,l-bis[4-[(trifluoroacetyl) amino]phenyl]-1-hydroxy-3-butyl]amino-2-propanol 15 hydrochloride MS m/z: 614 (M +1) (free) (3) ( 2 S)-l-Phenoxy-3-[(3RS)-1,1-bis[4-(propionylamino) phenyl]-3-butyl]amino-2-propanol 20 MS m/z: 518 (M +1) Example 37 To a mixture of (2S)-1-phenoxy-3-[N-benzyl-[(3RS)-1,l bis(4-aminophenyl)-1-hydroxy-3-butyl]amino]-2-propanol (120 25 mg), acetic acid (3 ml) and water (0.6 ml), potassium cyanate (77 mg) was added. The reaction mixture was worked up in the usual manner to give (2S)-1-phenoxy-3-[N-benzyl-[(3RS)-l,1 bis(4-ureidophenyl)-l-hydroxy-3-butyl]amino]-2-propanol (65 mg). 30 MS m/z: 598 (M ++l) Example 38 Formic acid (650 pl) and acetic anhydride (540 pi) were mixed and started at room temperature for 30 minutes. The 35 mixture was added to a solution of (2S)-1-phenoxy-3-[N- WO00/12462 PCT/JP99/04538 56 benzyl-[(3RS)-l,1-bis(4-aminophenyl)-1-hydroxy-3-butyl] amino]-2-propanol (325 mg) in dichloromethane (2 ml) at 0oC, warmed to room temperature and worked up in the usual manner. The crude product was stirred with potassium carbonate (0.62 5 g) in methanol (4 ml) at room temperature for 4 hours and worked up in the usual manner to give (2S)-1-phenoxy-3-[N benzyl-[(3RS)-l,1-bis[4-(formylamino)phenyl]-l-hydroxy-3 butyl]amino]-2-propanol (342.4 mg) MS m/z: 568 (M+1) 10 Example 39 To a mixture of lithium aluminum hydride (0.1 g) and tetrahydrofuran (1 ml), a solution of (2S)-l-phenoxy-3-[N benzyl-[(3RS)-1,1-bis[4-(formylamino)phenyl]-l-hydroxy-3 15 butyl]amino]-2-propanol (280 mg) in tetrahydrofuran (2 ml) was added dropwise at 0°C. The reaction mixture was stirred for 2.5 hours and worked up in the usual manner to give (2S) l-phenoxy-3-[N-benzyl-[(3RS)-l,1-bis[4-(methylamino)phenyl] 1-hydroxy-3-butyl]amino]-2-propanol (273 mg). 20 MS m/z: 540 (M +1) Example 40 (2S)-l-Phenoxy-3-[(3RS)-l,1-bis[4-[N-methyl (methoxycarbonyl)amino]phenyl]-1-hydroxy-3-butyl]amino-2 25 propanol (30 mg) was obtained from (2S)-1-phenoxy-3-[N benzyl-[(3RS)-l,1-bis[4-[N-methyl-(methoxycarbonyl)amino] phenyl]-1-hydroxy-3-butyl]amino]-2-propanol (60 mg) by the usual hydrogenation. MS m/z: 566 (M+1) 30 Example 41 (IR)-1-[4-Hydroxy-3-(methanesulfonylamino)phenyl]-2 [[(3RS)-1,1-bis[4-[(methoxycarbonyl)amino]phenyl]-3-butyl] amino]ethanol (14.3 mg) was obtained from (lR)-l-[4-bezyloxy 35 3-(methanesulfonylamino)phenyl]-2-[[(3RS)-1,1-bis[4- WO00/12462 PCT/JP99/04538 57 (methoxycarbonyl)amino]phenyl]-3-butyl]amino]ethanol (46.1 mg) by hydrogenation in the usual manner. MS m/z: 601 (M +1) 5 Example 42 The following compound was obtained according to a similar manner to that of Example 41. (2R)-3-[4-Hydroxy-3-(methanesulfonylamino)phenyl]-1 LO [(3RS)-1,1-bis(4-methoxyphenyl)-3-butyl]amino-2-propanol (5.0 mg) MS m/z: 529 (M +1) Example 43 L5 A mixture of (R)-(4-benzyloxy-3-nitrophenyl)oxirane (34.4 mg), N-benzyl-[3,3-bis[4-(methoxycarbonylamino)phenyl] propyl]amine (56.7 mg) and ethanol (2 ml) was heated under reflux for 12 hours. Iron powder, ammonium chloride and water was added to the reaction mixture and heating was ?0 continued for 1 hour. The reaction mixture was filtrated and worked up in the usual manner to give crude (1R)-l-(3-amino 4-benzyloxyphenyl)-2-[N-benzyl-[3,3-bis[4-[(methoxy carbonyl)amino]phenyl]propyl]amino]ethanol (111.7 mg). MS m/z: 689 (M +1) .5 Example 44 The following compound was obtained according to a similar manner to that of Example 43. 30 ( 2 S)-l-( 3 -Amino-4-benzyloxyphenoxy)-3-[N-benzyl-[3,3 bis[4-[(methoxycarbonyl)amino]phenyl]propyl]amino]-2-propanol MS m/z: 719 Example 45 5 Under nitrogen, to a solution of 4,4-bis(4- WO00/12462 PCT/JP99/04538 58 methoxyphenyl)-2-butanone (187 mg) and (1RS)-2-amino-l-(2 methylpyridin-6-yl)ethanol (100 mg) prepared from 6 methylpyridin-2-carboxaldehyde and trimethylsilylcyanide catalized with zinc iodide followed by reduction with lithium 5 aluminum hydride, in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (257 mg) at room temperatue, and the mixture was stirred at the same temperature for 24 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution,, and extracted with ethyl .0 acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was treated with 4N hydrogen chloride in 1,4-dioxane to afford (IRS)-2-[[(IRS)-3,3-bis(4-methoxyphenyl)-l-methylpropyl] amino]-1-(6-methylpyridin-2-yl)ethanol (140 mg) 5 dihydrochloride. MS m/z: 421 (M +1) (free) Example 46 Under nitrogen, to a solution of (2S)-3-[4-benzyloxy-3 0 (methanesulfonylamino)phenoxy]-l,2-epoxypropane (198 mg) and N-benzyl-[(IRS)-3,3-bis(4-hydroxyphenyl)-1-methylpropyl]amine (200 mg) in methanol (20 ml) was refluxed for 18 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The 5 organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford N-[5-[(2S)-3-[N-benzyl-[(lRS)-3,3-bis(4 hydroxyphenyl)-l-methylpropyl]amino]-2-hydroxypropoxy]-2 0 (benzyloxy)phenyl]methanesulfonamide (120 mg). MS m/z: 696 (M +1) Example 47 Under nitrogen, to a solution of (2S)-3-[4-benzyloxy-3 5 (methanesulfonylamino)phenoxy]-1,2-epoxypropane (200 mg) and WO00/12462 PCT/JP99/04538 59 N-benzyl-[(lRS)-3,3-bis(4-methoxyphenyl)-1-methylpropyl]amine (163 mg) in dichloromethane (10 ml) was added ytterbium(III) trifluoromethanesulfonate (1.0 g) at room temperature, and the mixture was stirred at the same temperature for 3 hours. 5 The resulting mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to 10 afford N-[5-[(2S)-3-[N-benzyl-[(lRS)-3,3-bis(4 methoxyphenyl)-1-methylpropyl]amino]-2-hydroxypropoxy]-2 (benzyloxy)phenyl]methanesulfonamide (50 mg). MS m/z: 724 (M++l) 15 Example 48 Under nitrogen, to a solution of N-benzyl-[3,3-bis(4 hydroxyphenyl)-l-methylpropyl]amine (300 mg) and phenethyloxirane (130 mg) in a mixture of ethyl acetate (5 ml) and tetrahydrofuran (5 ml) was added ytterbium(III) 20 trifluoromethanesulfonate (110 mg) at room temperature, and the mixture was stirred at the same temperature for 96 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous 25 magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol =20:1) to give l-[N-benzyl-[3,3-bis(4 hydroxyphenyl)-l-methylpropyl]amino]-4-phenyl-2-butanol (240 mg). 30 NMR (CDCl 3 , 5): 0.95-1.10 (3H, m), 1.45-2.9 (9H, m), 3.2-3.75 (3H, m), 3.75-3.9 (1H, m), 6.55-6.8 (4H, m), 6.85-7.3 (14H, m) Example 49 The following compound was obtained according to a 35 similar manner to that of Example 48.

WO00/12462 PCT/JP99/04538 60 (2S)-l-[N-Benzyl-[(lRS)-3,3-bis(4-hydroxyphenyl)-1 methylpropyl]amino]-3-(phenylthio)-2-propanol NMR (CDC1 3 , 5): 0.85-1.1 (3H, m), 1.7-3.1 (7H, m), 3.3 3.75 (3H, m), 3.75-3.9 (1H, m), 6.55-6.75 (4H, m), 5 6.8-7.25 (14H, m) Example 50 Under nitrogen, to a solution of N-[5-[(1R)-2-[N-benzyl [(IRS)-3,3-bis(4-methoxyphenyl)-1-methylpropyl]amino]-1 0 (triethylsilyloxy)ethyl]-2-(benzyloxy)phenyl]methane sulfonamide (221 mg) in tetrahydrofuran (3 ml) were added acetic acid (63 il) and tetrabutylammonium fluoride (lM solution in tetrahydrofuran, 0.68 ml) at room temperature, and the mixture was stirred at the same temperature for 4.5 5 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer -was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl 0 acetate = 2:1) to give N-[5-[(1R)-2-[N-benzyl [(1RS)-3,3-bis( 4 -methoxyphenyl)-l-methylpropyl]amino]-1 hydroxyethyl]-2-(benzyloxy)phenyl]methanesulfonamide (164 mg). NMR (CDCl 3 , 5): 0.95-1.1 (3H, m), 1.7-2.85 (5H, m), 5 2.88 (3H, m), 3.35-4.05 (8H, m), 4.25-4.5 (1H, m), 5.08 (2H, m), 6.7-7.5 (21H, m) Example 51 A mixture of N-[5-[(1R)-2-[N-benzyl-[(lRS)-3,3-bis(4 0 methoxyphenyl)-1-methylpropyl]amino]-1-hydroxyethyl]-2 (benzyloxy)phenyl]methanesulfonamide (149 mg) and 10% palladium on activated carbon (50% wet, 50 mg) in methanol (5 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 6 hours. After 5 filtration, the filtrate was evaporated in vacuo, followed by WO 00/12462 PCT/JP99/04538 61 treatment with 4N hydrogen chloride in ethyl acetate to give N-[5-[(1R)-2-[(1RS)-3,3-bis(4-methoxyphenyl)-1-methylpropyl] amino-1-hydroxyethyl ] -2-hydroxyphenyl ] methanesulfonamide hydrochloride (90 mg). 5 NMR (DMSO-d 6 , 5): 1.1-1.35 (3H, m), 1.9-2.2 (1H, m), 2.55-3.1 (7H, m), 3.70 (6H, m), 3.95-4.1 (1H, m), 4.7-4.9 (1H, m), 6.8-7.4 (11H, m) Example 52 0 The following compounds were obtained according to a similar manner to that of Example 51. (1) 1-[3,3-Bis(4-hydroxyphenyl)-l-methylpropyl]amino-4 phenyl-2-butanol hydrochloride 5 NMR (CD 3 OD, 5): 1.1-1.5 (3H, m), 1.7-1.9 (2H, m), 1.95 2.2 (1H, m), 2.45-3.2 (6H, m), 3.6-4.0 (1H, m), 6.5-6.8 (4H, m), 7.0-7.35 (9H, m) (2) (2S)-1-Benzenesulfonyl-3-[ (lRS)-3,3-bis(4-hydroxy 0 phenyl) -1-methylpropyl] amino-2-propanol hydrochloride NMR (CD 3 OD, 5): 1.25-1.4 (3H, m), 1.95-2.2 (1H, m), 2.45-2.7 (1H, m), 2.9-3.55 (5H, m), 3.85-4.0 (1H, m), 4.25-4.4 (1H, m), 6.65-6.85 (4H, m), 7.05-7.2 (4H, m), 7.6-7.8 (3H, m), 7.95-8.05 (2H, m) 5 (3) (2S)-1-Phenoxy-3-[(3RS)-1,1-bis(4-ureidophenyl)-3 butyl] amino-2-propanol hydrochloride MS m/z: 492 (M++1) (free) 0 Example 53 Under nitrogen, a solution of [(1S)-3,3-bis(4 methoxyphenyl)-1-methylpropyl]amine (0.55 g), N-[2-benzyloxy 5-[ (1R)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl] methanesulfonamide (1.1 g) and N,N-diisopropylethylamine (1.4 5 ml) in N,N-dimethylacetamide (5 ml) was stirred at 110 0 C for WO 00/12462 PCT/JP99/04538 62 24 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate and evaporated in 5 vacuo. Under nitrogen, to the residue in ethyl acetate (10 ml) was added 4N hydrogen chloride in ethyl acetate (2 ml) at 5 0 C, and the mixture was stirred at room temperature for 45 minutes. The resulting mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. 10 The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 50:1 to 20:1) to give N-[2-benzyloxy 5- [ (IR)-2-[(IS)-3,3-bis(4-methoxyphenyl) -1-methylpropyl] 15 amino-1-hydroxyethyl]phenyl]methanesulfonamide (0.65 g). NMR (CDCl 3 , 5): 1.09 (3H, d, J=6.3Hz), 1.85-2.3 (2H, m), 2.35-2.6 (2H, m), 2.9-3.2 (4H, m), 3.76 (6H, s), 4.0-4.1 (1H, m), 4.45-4.6 (1H, m), 5.10 (2H, m), 6.82 (4H, d, J=8.1Hz), 6.96 (1H, d, J=8.5Hz), 20 7.1-7.2 (5H, m), 7.35-7.5 (6H, m) Example 54 The following compounds were obtained according to a similar manner to that of Example 53. 25 (1) N-[2-Benzyloxy-5-[(1R)-2-[ (1R)-3,3-bis(4-methoxyphenyl) 1-methylpropyl ] amino-1-hydroxyethyl] phenyl] methanesulfonamide NMR (CDCl 3 , 5): 1.08 (3H, d, J=6.2Hz), 1.9-2.2 (2H, m), 30 2.5-2.85 (3H, m), 2.90 (3H, s), 3.76 (6H, s), 4.03 (1H, t, J=8.2Hz), 4.47 (1H, dd, J=3.6 and 8.5Hz), 5.10 (2H, s), 6.8-6.9 (4H, m), 6.96 (1H, d, J=8.5Hz), 7.1-7.2 (5H, m), 7.35-7.5 (6H, m) 35 (2) N-[2-Benzyloxy-5-[ (1R)-2-[ (1RS)-3,3-bis(4-hydroxy- WO 00/12462 PCT/JP99/04538 63 phenyl) -1-methylpropyl]amino-1-hydroxyethyl]phenyl] methanesulfonamide NMR (DMSO-d 6 , 6): 1.0-1.1 (3H, m), 1.7-1.95 (1H, m), 2.1-2.85 (4H, m), 2.90 (3H, s), 3.8-3.95 (1H, m), 5 4.5-4.6 (1H, m), 5.17 (2H, s), 6.6-6.75 (4H, m), 6.95-7.2 (6H, m), 7.25-7.6 (6H, m) Example 55 A mixture of N-[2-(benzyloxy)-5-[(1R)-2-[(1S)-3,3-bis(4 10 methoxyphenyl) -1-methylpropyl] amino-l-hydroxyethyl]phenyl] methanesulfonamide (620 mg) and 10% palladium on activated carbon (50% wet, 300 mg) in methanol (10 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 7.5 hours. After filtration, the 15 filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 20:1 to 10:1), followed by treatment with 4N hydrogen chloride in ethyl acetate to give N-[5-[(1R)-2-[(1S)-3,3-bis( 4-methoxyphenyl) -1-methylpropyll]amino-1-hydroxyethyl] -2 20 hydroxyphenyl]methanesulfonamide hydrochloride (290 mg) NMR (DMSO-d 6 , 6): 1.15-1.4 (3H, m), 1.85-2.2 (1H, m), 2.4-3.2 (7H, m), 3.70 (6H, s), 3.95-4.1 (1H, m), 4.7-4.9 (1H, m), 6.7-7.4 (11H, m) 25 Example 56 The following compounds were obtained according to a similar manner to that of Example 54. (1) N-[5-[(lR)-2-[(1R)-3,3-Bis(4-methoxyphenyl)-l 30 methylpropyl] amino-1-hydroxyethyl] -2 hydroxyphenyl]methanesulfonamide hydrochloride NMR (DMSO-d 6 , 5): 1.15-1.4 (3H, m), 1.9-2.15 (1H, m), 2.4-3.15 (7H, m), 3.70 (6H, m), 3.95-4.1 (1H, m), 4.75-4.9 (1H, m), 6.8-7.4 (11H, m) 35 WO 00/12462 PCT/JP99/04538 64 (2) N-[5-[ (1R)-2-[[3,3-Bis(4-hydroxyphenyl)-1-methylpropyl] amino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride NMR (DMSO-d 6 , 6): 1.15-1.3 (3H, m), 1.85-2.1 (1H, m), 5 2.55-3.2 (7H, m), 3.8-4.0 (1H, m), 4.7-4.9 (1H, m), 6.6-6.75 (4H, m), 6.9-7.3 (7H, m) (3) (2S)-l-(6-Aminopyridin-3-yloxy)-3-[[ (1RS)-3,3-bis(4 methoxyphenyl) -1-methylpropyl] amino] -2-propanol 0 trihydrochloride, starting from the objective compound of Example 57. NMR (DMSO-d 6 , 6): 1.05-1.4 (3H, m), 1.9-2.2 (1H, m), 2.5-3.2 (4H, m), 3.55-3.85 (7H, m), 3.85-4.3 (3H, m), 6.9-7.4 (9H, m), 7.5-7.9 (2H, m) 5 Example 57 A mixture of [3,3-bis(4-methoxyphenyl)-1-methylpropyl] amine and ( 2 S)-3-[2-(benzyloxycarbonylamino)pyridin-5-yloxy] 1,2-epoxypropane (98 mg) in methanol (5 ml) was refluxed for 0 19 hours. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel (chloroform:methanol = 30:1 to 20:1) to give [5-[(2S)-3 [(IRS)-3,3-bis(4-methoxyphenyl) -1-methylpropyl]amino-2 hydroxypropoxy]pyridin-2-yl]carbamic acid benzyl ester (110 5 mg). NMR (CDC1 3 , 6): 1.1-1.2 (3H, m), 1.7-2.3 (2H, m), 2.45 2.6 (2H, m), 2.7-2.75 (1H, m), 3.76 (6H, s), 3.85 3.95 (3H, m), 4.0-4.1 (1H, m), 5.22 (2H, s), 6.8 (4H, d, J=8.6Hz), 7.1-7.45 (10H, m), 7.9-7.95 (2H, 0 m) Example 58 To a solution of (2S)-1-[N-benzyl-[(1RS)-3,3-bis(4 hydroxyphenyl) -1-methylpropyl] amino] -3-phenylthio-2-propanol 5 (300 mg) in methanol (10 ml) was added OXONE® (potassium WO00/12462 PCT/JP99/04538 65 peroxymonosulfate) (710 mg) in water (2 ml) at room temperature, and the mixture was stirred at the same temperature for 4 hours. The resulting mixture was poured into a mixture of ethyl acetate and water, and was made basic 5 with saturated aqueous sodium bicarbonate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol = 20:1).to give (2S)-l-benzenesulfonyl LO 3-[N-benzyl-[(IRS)-3,3-bis(4-hydroxyphenyl)-1-methylpropyl]am ino]-2-propanol (220 mg). NMR (CDCl 3 , 5): 0.9-1.1 (3H, m), 1.75-2.3 (2H, m), 2.35-2.7 (3H, m), 2.9-3.25 (2H, m), 3.3-4.0 (4H, m), 6.65-6.8 (4H, m), 6.9-7.35 (9H, m), 7.5-7.7 L5 (3H, m), 7.75-7.9 (2H, m) Example 59 A mixture of (2S)-l-phenoxy-3-[N-benzyl-[3,3-bis[4 (methoxycarbonyl)phenyl]propyl]amino]-2-propanol (103 mg), 20 methanol (2 ml), 1,4-dioxane (2 ml) and 1N aqueous sodium hydroxide solution (1 ml) was stirred at 50 0 C for 2 hours. The reaction mixture was acidified with 3N hydrochloric acid (1 ml) and worked up in a usual manner to give (2S)-i phenoxy-3-[N-benzyl-[3,3-bis(4-carboxyphenyl)propyl]amino]-2 .5 propanol (75.1 mg). Example 60 A mixture of (2S)-l-phenoxy-3-[N-benzyl-[3,3-bis(4 carboxyphenyl)propyl]amino]-2-propanol (75 mg), 30 diphenylphosphoryl azide (96 mg), triethylamine (58 pl), toluene (1 ml) and 1,4-dioxane (1 ml) was stirred at 50 0 C for 0.5 hour, then at 100oC for 45 minutes. Methanol (1 ml) was added to the reaction mixture, and the heating was continued for 15 hours. The reaction mixture was worked up in a usual 35 manner followed by purification by preparative thin-layer WO 00/12462 PCT/JP99/04538 66 chromatography to afford (2S)-1-phenoxy-3-[N-benzyl [3,3-bis[4-[(methoxycarbonyl)amino]phenyl]propyl]amino]-2 propanol (21.5 mg). MS m/z: 598 (M+1) 5 Example 61

(

2 S)-l-Phenoxy-3-[N-benzyl-[3,3-bis[4-[(methoxy carbonyl)amino]phenyl]propyl]amino]-2-propanol (18.8 mg) was hydrogenated in a usual manner to give (2S)-1-phenoxy-3-[[3, 0LO 3-bis[4-[(methoxycarbonyl)amino]phenyl]propyl]amino]-2 propanol (8.1 mg). IR (KBr): 1710 (s), 1601 (m), 1537 (s), 1315 (w), 1238 (s), 1070 (m) cm-1 NMR (MeOH-d 4 , 5): 2.2-2.3 (2H, m), 2.6-2.9 (4H, m), L5 3.72 (6H, s), 3.9-4.1 (4H, m), 6.9-7.0 (3H, m), 7.2-7.4 (10H, m) MS m/z: 508 (M+1) .0 .5 5

Claims (11)

1. A compound of the general formula [I] : 5 R 2 R 3 OH R R 3 A-X-CH-CH 2 -N-Z-Y [I] 10 R R4 R5 wherein A is a heterocyclic group or aryl, each of which may have 15 1 to 3 same or different substituent(s) selected from a group consisting of halogen, hydroxy, amino, lower alkyl, lower alkylsulfonylamino, phenyl(lower)alkoxy and phenyl(lower)alkoxycarbonylamino, -X- is bond, -CH 2 -, -CH2-CH 2 -, -NH-CH 2 -, -O-CH 2 -, -S-CH2- ' 20 -SO-CH 2 - or -SO 2 -CH2-, -YC is -cCC (in which R11 is hydrogen, hydroxy, lower alkoxy or acyloxy) and 25 R6 R 8 -Z- is -(CH2)n- (CH2)m- (CH2)k-, -(CH 2 )n C -(CH2)m- , (CH2) r __--(CH 2 ) p -(CH2)n-Q-(CH 2 )m-, -(CH 2 )n-CH CH-(CH 2 )m - , 30 -(CH2) q -(CH 2 )n-CH=CH-(C 2 )m- or (CH 2 )n-CC-(CH 2 ) m - (in which -Q- is -0-, -S-, -SO-, -SO 2 -, -N-CO-, -CO-N-, 3510 R1 0 WO00/12462 PCT/JP99/04538 68 -CH-CO-N-, -CH-CH 2 -N-, -S0 2 -N-, Ri Ri R11 R10 10 5 -N-SO 2 -, -CO- or -N-, wherein R i0 is hydrogen or R10 10 lower alkyl, and R I is lower alkyl, R 6 , R 7 , R 8 and R are each independently hydrogen, 10 hydroxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkoxy(lower)alkyl or aryl which may have 1 to 3 lower alkoxy, n, m and k is each independently 0 to 6, p is 0 to 4, 15 q is 1 to 4, and r is 2 to 7) and -Z-Yc is -(CH 2 )i-CH=C' (in which i is 0 to 6), R 1 is hydrogen or an amino protective group, and R 2 , R 3 , R 4 and R 5 are each independently hydrogen; 20 lower alkyl; lower alkylthio; lower alkylsulfonyl; hydroxy; lower alkoxy; amino; lower alkylamino; acylamino; N-(lower alkyl)acylamino; carboxy; lower alkoxycarbonyl; carbamoyl optionally substituted with one or two lower 25 alkyl; hydroxy(lower)alkyl; lower alkoxy(lower)alkyl; N-acylamino(lower)alkyl; N-(lower alkyl)-N acylamino(lower)alkyl; carboxy(lower)alkyl; lower alkoxycarbonyl(lower)alkyl; carbamoyl(lower)alkyl optionally substituted with one or two lower alkyl; or IR 12 123 30 -(CH 2 )j-N' R 13 (in which R 12 and R13 are each independently hydrogen or lower alkyl, or R 12 and R 13 may be bonded to form a lower alkylene chain, and j is 0 to 6), and a salt thereof. 35 WO00/12462 PCT/JP99/04538 69

2. A compound of claim 1, wherein A is pyridyl, indolyl, 2-oxo-2,3-dihydro-1H benzimidazolyl or phenyl, each of which may have 1 to 3 same or different substituent(s) selected from 5 a group of hydroxy, amino, lower alkyl, lower alkylsulfonylamino, phenyl(lower)alkoxy and phenyl(lower)alkoxycarbonylamino, -X- is bond, -CH 2 -, -CH 2 -CH 2 -, -0-CH 2 - or -SO2-CH2- , 10 -Y< is -C (in which R1 is hydrogen or hydroxy) and 1 11 R 6 R 8 / / -Z- is -(CH2 C(CH-C-(CH 2 -(CH )C -(CH 2 or 7 mR9 15 (CH2 r -(CH 2 )n-Q-(CH2) m - (in which -Q- is -CH-CO-N- or -CH-CH 2 -N-, wherein 11 10 11 10 20 R i0 is hydrogen or lower alkyl and R I is lower alkyl, R 6 , R 7 , R 8 and R are each independently hydrogen, lower alkyl or aryl which may have 1 to 3 lower alkoxy, 25 n, m and k is each independently 0 to 6, and r is 2 to 7) and -Z-Y( is -(CH 2 )i-CH=C < (in which i is 0 to 6), R 1 is hydrogen or ar(lower)alkyl, and R 2 , R

3 , R 4 and R 5 are each independently hydrogen; 30 lower alkyl; lower alkylthio; lower alkylsulfonyl; hydroxy; lower alkoxy; amino; lower alkylamino; acylamino; N-(lower alkyl)acylamino; carboxy; or lower alkoxycarbonyl. 35 3. A compound of claim 2, wherein WO00/12462 PCT/JP99/04538 70 A is pyridyl, indolyl or phenyl, each of which may have 1 to 3 same or different substituent(s) selected from a group of hydroxy, amino, lower alkyl, lower alkylsulfonylamino, phenyl(lower)alkoxy and 5 phenyl(lower)alkoxycarbonylamino, -X- is bond, -CH 2 -, -CH 2 -CH 2 -, -O-CH 2 - or -SO 2 -CH 2 -, -Y( is -CK (in which R 1 I is hydrogen or hydroxy) and R 11 10 R6 R 8 -Z- is -(CH 2) -C-(CH 2 )- 2 (C' 2 )2 -(CnH2 - C 2 ) or n @7 m k n S -'- m (CH 2 ) r -(CH2)n-Q-(CH2) m - (in which 15 -Q- is -CH-CO-N- or -CH-CH2-N-, wherein 11 R1 R1 R10 R i0 is hydrogen or lower alkyl and R I is lower alkyl, R 6 , R 7 , R 8 and R are each independently hydrogen, 20 lower alkyl or phenyl which may have 1 to 3 lower alkoxy, n, m and k is each independently 0 or 1, and r is 2 to 7) and -Z-Y( is -(CH 2 )i-CH=C < (in which i is 0 or 1), 25 R 1 is hydrogen or phenyl(lower)alkyl, and R 2 , R 3 , R 4 and R 5 are each independently hydrogen; lower alkyl; lower alkylthio; lower alkylsulfonyl; hydroxy; lower alkoxy; amino; lower alkylamino; lower alkoxycarbonylamino; lower 30 alkylsulfonylamino; lower alkanoylamino; ureido; trifluoroacetylamino; N-(lower alkyl) [(lower)alkoxycarbonyl]amino; carboxy; or lower alkoxycarbonyl. 35

4. A compound of claim 3, whrein WO00/12462 PCT/JP99/04538 71 A is phenyl which may have 1 to 3 same or different substituent(s) selected from a group of hydroxy, amino, lower alkylsulfonylamino and phenyl(lower)alkoxy,

5 -X- is bond, -CH 2 -, -CH 2 -CH 2 -, -O-CH 2 - or -S0 2 -CH 2 -, -Y( is -CK (in which R1 is hydrogen or hydroxy), R6 R 8 -Z- is -(CH2) n - 2(C ) -C-(CH 2 )- (in which 10 7 9 R 6 , R 7 , R and R are each independently hydrogen, lower alkyl or phenyl which may have 1 to 3 lower alkoxy, n, m and k is each independently 0 or 1), 15 R 1 is hydrogen or phenyl(lower)alkyl, and R 2 , R 3 , R 4 and R 5 are each independently hydrogen; lower alkyl; lower alkylthio; lower alkylsulfonyl; hydroxy; lower alkoxy; amino; lower alkylamino; lower alkoxycarbonylamino; lower 20 alkylsulfonylamino; lower alkanoylamino; ureido; trifluoroacetylamino; N-(lower alkyl) [(lower)alkoxycarbonyl]amino; carboxy; or lower alkoxycarbonyl. 25 5. A compound of claim 4, wherein A is phenyl which may have 1 or 2 same or different substituent(s) selected from a group consisting of hydroxy, amino and lower alkylsulfonylamino, -X- is bond or -O-CH2-, 30 -YC is -C , H H H -Z- is -- C-, I I H H 35 R 1 is hydrogen, and WO00/12462 PCT/JP99/04538 72 R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkoxy or lower alkoxycarbonylamino.

6. A compound of claim 5, which is 5 (2S)-1-[4-hydroxy-3-(methanesulfonylamino)phenoxy] 3-[[3,3-bis(4-methoxyphenyl)propyl]amino]-2-propanol; (iR)-1-[4-hydroxy-3-(methanesulfonylamino)phenyl]-2 [[3,3-bis(4-methoxyphenyl)propyl]amino]ethanol; 10 (2S)-l-phenoxy-3-[[3,3-bis[4-[(methoxycarbonyl)amino] phenyl]propyl]amino]-2-propanol; or a salt thereof. 15

7. A process for preparing a compound of claim 1, or a salt thereof, which comprises, (i) reacting a compound [II] of the formula : 20 /o A-X-CH-CH 2 [II] wherein A and X are each as defined in claim 1, 25 with a compound [III] of the formula : R 2 R1 R3 HN-Z -Y [III] 30 R4 R 5 wherein Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are each as defined 35 in claim 1, or a salt thereof, to give a compound [I] of WO00/12462 PCT/JP99/04538 73 the formula : 5 R 2 OH R 1 R3 A-X-H-CH 2 -N-Z-Y - [I] 10 R4 5 wherein A, X, Y, Z, R1, R 2 , R 3 , R 4 and R 5 are each as defined in claim 1, 15 or a salt thereof, or (ii) subjecting a compound [Ia] of the formula : R 2 20 OH R R 3 I I / r A-X-CH-CH 2 -N - Z - Y [Ia] R 4 R 5 25 wherein A, X, Y, Z, R 2 , R 3 , R 4 and R 5 are each as defined in claim 1, and Ra is an amino protective group, or a salt thereof, to elimination reaction of the amino 30 protective group, to give a compound [Ib] of the formula : R 2 R 3 OH H R 3 35 A-X-CH-CH 2 -N-Z-Y Ib R 5 [Ib] WO00/12462 PCT/JP99/04538 74 wherein A, X, Y, Z, R 2 , R 3 , R 4 and R 5 are each as 5 defined in claim 1, or a salt thereof.

8. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a 10 pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients.

9. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a 15 medicament.

10. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament. 20

11. A method for the prophylactic and/or the therapeutic treatment of pollakiuria or urinary incontinence which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal. 25 30 35