WO2005110981A1 - Aminoalcohol derivatives - Google Patents

Abstract

The present invention relates to a compound formula[I]: wherein X is bond or -O-, R1 is formula[A] or formula [B] in which R5, R6 and R7 are each as defined in the description, R2 is hydrogen or lower alkyl, R3 is hydrogen or an amino protective group , R4 is formula[C], [D] or [E] in which R8, R9, R10, R11, R12, R13 and R16 are each as defined in the description, and R14 and R15 are each independently hydrogen or lower alkyl, or a prodrug thereof or a salt thereof. The compound [I] of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of overactive bladder, micturiation disorder and the like.

Description

DESCRIPTION

AMINOALCOHOL DERIVATIVES TECHNICAL FIELD This invention relates to new aminoalcohol derivatives and salts thereof which are beta-3 (β₃) adrenergic receptor agonists and useful as a medicament. BACKGROUND OF THE INVENTION International Publications No. WO 02/094770 A2 , published November 28, 2002, and No. WO 2004/045610 Al , published June 3, 2004, describe aminoalcohol derivatives useful as β₃ adrenergic receptor agonists.

DISCLOSURE OF INVENTION This invention relates to new aminoalcohol derivatives which are β₃ adrenergic receptor agonists and salts thereof. More particularly, it relates to new aminoalcohol derivatives and salts thereof which have gut sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-overactive bladder, anti-urinary incontinence, anti-pollakiuria activities, anti-diabetes and anti-obesity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in a human being or an animal. One object of this invention is to provide new and useful aminoalcohol derivatives and salts thereof which have gut sympathomimetic, anti-ulcerous, lipolytic, anti- overactive bladder, anti-urinary incontinence, anti- pollakiuria activities, anti-diabetes and anti-obesity. 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 pharmaceutical composition comprising, as an active ingredient, said aminoacohol 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 a human being or an animal, using said aminoalcohol derivatives and salts thereof. The object aminoalcohol derivatives of this invention are new and can be represented by compound of the following formula [ I ] :

wherein

X is bond or -0-,

R¹ is

in which R^ is hydrogen, halogen, hydroxy or protected hydroxy, and R⁶ is hydrogen or (lower alkylsulfonyl)amino. or

in which R^ is hydrogen, halogen or lower alkyl, R² is hydrogen or lower alkyl, R³ is hydrogen or an amino protective group.

in which R⁸ is hydrogen or halogen , and R^ is carboxy, carbamoyl or mono ( or di ) ( lower ) alkylcarbamoyl ,

in which R¹⁰ is amino, mono(or di) (lower)alkylamino, hydroxy or protected hydroxy, R¹¹ is hydrogen or lower alkyl, R¹² is hydrogen, lower alkyl, cyclo( lower)alkyl, hydroxy( lower) alkyl, mono(or di or tri)halo(lower)alkyl, lower alkylsulfonyl or aryl, and R¹^ is hydrogen, lower alkyl or lower alkoxy, or

in which R¹³ is hydrogen or methyl, provided that (i) when R¹³ is hydrogen, then R⁵ is not hydrogen or halogen, or (ii) when R¹³ is methyl, then R⁵ is not hydrogen, and R¹⁴ and R¹⁵ are each independently hydrogen or lower alkyl, or a prodrug thereof or a pharmaceutically acceptable salt thereof. According to this invention, the object compounds can be prepared by processes which are illustrated in the following schemes .

Process 1

[ I I ] [III] or a salt thereof

[I] or a salt thereof

Process 2

[la] or a salt thereof elimination reaction of the amino protective group

[ lb ] or a salt thereof Process 3

[lc] [IV] or a reactive derivative or a salt thereof at the carboxy group or a salt thereof

or a salt thereof

wherein X, R¹, R², R³ , R⁴ , R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵ and R¹⁶ are each as defined above, and R is an amino protective group.

As to the starting compounds [II], [III], [la], [lc] and [IV], some of them are novel and can be prepared by the procedures described in the Preparations and Examples mentioned later or a conventional manner.

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

The term "lower" is intended to mean a group having 1 to 6, preferably 1 to 4 , carbon atom(s), unless otherwise indicated. Suitable "lower alkyl" and "lower alkyl" moiety in the terms of "(lower alkylsulfonyl)amino" , "mono(or di) (lower)- alkylcarbamoy1" , "mono(or di) ( lower)alkylamino" , "mono(or di or tri)halo(lower)alkyl" ,^' etc. may include straight or branched one having 1 to 6 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, in which more preferable one is C^- -C^ alkyl, and the most preferable one is methyl or ethyl.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, in which preferable one is C₁-C₄ alkoxy, and the most preferable one is methoxy or ethoxy.

Suitable "cyclo(lower)alkyl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, in which more preferable one is cyclo(C₃-Cg)alkyl, and the most preferred one is cyclopentyl.

Suitable "aryl" may include phenyl, naphthyl, anthryl and the like, in which the preferred one is phenyl.

Suitable "halogen" may be fluoro, chloro, bromo and iodo, in which the preferred one is fluoro or chloro .

Suitable "mono(or di or tri)halo(lower)alkyl" may include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, fluoro ethyl, difluoromethyl, trifluoromethyl, 1 or 2-chloroethyl, 1 or 2- bromoethyl, 1 or 2-fluoroethyl, 1 , 1-difluoroethyl, 2,2- difluoroethyl , 2,2,2-trifluoroethyl and the like, in which more preferable one is mono(or di or tri)halo(C₁-C₄)alkyl. and the most preferable one is 2,2,2-trifluoroethyl.

Suitable example of "amino protective group" moiety may be common amino protective group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar( lower)alkyl [e.g. trityl, benzyl, etc.] and the like, in which the preferred one is benzyl or tert-butoxycarbonyl. Suitable "hydroxy protective group" in the term

"protected hydroxy" may include acyl, phenyl( lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri( lower)alkylsilyl (e.g., trimethylsilyl, t- butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like, in which the preferred one is benzyl.

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

The Processes 1 to 3 for preparing the object compounds of the present invention are explained in detail in the following. Process 1 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 ] . The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri(lower) 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, dioxane, or any other organic solvent which does not adversely influence the reaction. The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Process 2 The object compound [lb] or a salt thereof can be prepared by subjecting a compound [la] or a salt thereof to elimination reaction of the amino protective group. Suitable salts of the compounds [la] and [lb] may be the same as those exemplified for the compound [I]. This reaction can be carried out in a similar manner to that of Example 4 or 26 mentioned below.

Process 3 The object compound [Id] or a¹ salt thereof can be prepared by reacting a compound [lc] or a reactive derivative at the carboxy group or a salt thereof with a compound [IV] or a salt thereof. Suitable salts of the compounds [lc] and [IV] may be the same as those exemplified for the compound [ I ] . This reaction can be carried out in a similar manner to that of Example 3, 7 or 13.

The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary. It is to be noted that the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the effect of the light, acid base or the like, and the compound obtained as the result of said isomerization or rearrangement if 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 of the compound [ I ] are included within the scope of the present invention.

The object compound [I] or a salt thereof are useful for the treatment and/or prevention of gastro-intestinal disorders in human beings or animals , and more particularly for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholantitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, or the like; for the treatment and/or prevention of overactive bladder such as nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis, prostatic hypertrophy or the like; for the treatment and/or prevention of micturiation disorder such as stress incontinence, urge incontinence, mixed incontinence, functional incontinence, overflow incontinence; for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression or the like; for the treatment and/or prevention of diseases as the result of insulin resistance (e.g. hypertension, hyperinsulinemia, etc.); for the treatment and/or prevention of neurogenetic inflammation; and for reducing a wasting condition, and the like. Additionally, β₃ adrenergic receptor agonists are known to lower triglyceride and cholesterol levels and to raise high density lipoprotein levels in mammals (US Patent No. 5,451,677). Accordingly, the object compound [I] is useful in the treatment and/or prevention of conditions such as hyper-triglyceridaemia, hypercholesterolaemia and in lowering high density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and relates conditions . Moreover, the object compound [I] is useful for inhibiting uterine contractions, preventing premature labor, and treating and preventing dysmenorrhea.

Additionally, the object compound [I] may be expected, when used together with an anticholinergic agent for overactive bladder such as propiverine hydrochloride, oxybutinin hydrochloride, flavoxate hydrochloride, tolterodine tartrate or the like, to exert an enhanced anti- overactive-bladder effect. For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds , as an active ingredient , in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration. The pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, or the like. If desired, there may be included in these preparations , auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives. While the dosage of the compound (I) will vary depending upon the age and condition of a patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating diseases such as overactive bladder, micturiation disorder and the like. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

In order to show the usefulness of the compound [I] for the prophylactic and therapeutic treatment of above- mentioned disease in human being or animals, the pharmacological test data of a representative compound thereof are shown in the following.

Test Effect on the increase in intravesical pressure induced by carbachol in anesthetized dog

Test Compound

(1) 2-Hydroxy-5-[ [4-[2-[ [ ( 2R) -2-hydroxy-2- (3-pyridyl) - ethyl] amino] ethyl]phenyl]sulfonyl]benzoic acid dihydrochloride (the object compound of Example 26 mentioned below)

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, inserted into the urethral orifice and advanced approximately 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 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. Intravenous administration of test compound (I) inhibited carbachol (1.8 μg/kg) -induced increase in intravesical pressure (IVP).

Test Result

% inhibition of carbachol-induced Treatment increase in IVP Test Compound (1) (0.010 mg/kg) ^

Preferred embodiments of the object compound [I] are as follows :

R¹ is

in which R⁵ is hydrogen, halogen (more preferably fluoro or chloro) or hydroxy, and R⁶ is hydrogen or (lower alkylsulfonyl)amino (more preferably (C₁-C₄ alkylsulfonyl) - amino, most preferably (methylsulfonyl)amino) , or

in which R⁷ is hydrogen, halogen (more preferably chloro) or lower alkyl (more preferably C₁-C₄ alkyl, most preferably methyl),

R^ is hydrogen or lower alkyl (more preferably C^-C^ alkyl, most preferably methyl),

R- is hydrogen,

in which R¹^ is amino, mono(or di)( lower)alkylamino (more preferably C₁-C₄ alkylamino, most preferably methylamino) or hydroxy, ,11 is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, most preferably methyl), R 1^±2^Λ is hydrogen, lower alkyl (more preferably C₁-C₄ alkyl, most preferably methyl, ethyl or propyl), cyclo(lower)alkyl (more preferably cyclo(C₃-Cg) - alkyl, most preferably cyclopentyl), hydroxy(lower)alkyl (more preferably hydroxy- (C₁-C₄)alkyl, most preferably 1-hydroxyethyl) , mono(or di or tri)halo(lower)alkyl (more preferably mono(or di or tri)halo(C₁-C₄)alkyl, most preferably 2,2,2-trifluoroethyl), lower alkylsulfonyl (more preferably C₁-C₄ alkylsulfonyl, most preferably methylsulfonyl) or aryl (more preferably phenyl) , and R¹⁶ is hydrogen, lower alkyl (more preferably C₁-C₄ alkyl, most preferably methyl or propyl) or lower alkoxy (more preferably C -C4 alkoxy, most preferably methoxy) , and R¹⁴ and R¹⁵ are each independently hydrogen or lower alkyl (more preferably C-L-C alkyl, most preferably methyl) .

More preferred embodiments of the object compound [I] are as follows:

X is bond.

R¹ is

in which R⁵ is hydrogen, halogen (more preferably fluoro or chloro) or hydroxy, and R⁶ is hydrogen, or

in which R' is hydrogen, halogen (more preferably chloro) or lower alkyl (more preferably (-l~^c4 alkyl, most preferably methyl), R² is hydrogen or lower alkyl (more preferably - alkyl, most preferably methyl), R³ is hydrogen,

in which R¹⁰ is amino or hydroxy, R¹¹ is hydrogen or lower alkyl (more preferably C₁-C₄ alkyl, most preferably methyl), R¹² is hydrogen, lower alkyl (more preferably C₁-C₄ alkyl, most preferably methyl, ethyl or propyl), hydroxy( lower)alkyl (more preferably hydroxy- (C₁-C₄)alkyl, most preferably 1-hydroxyethyl) or mono(or di or tri)halo(lower)alkyl (more preferably mono(or di or

most preferably 2,2,2-trifluoroethyl), and ° is hydrogen, lower alkyl (more preferably C^-C₄ alkyl, most preferably methyl or propyl) or lower alkoxy (more preferably C₁-C₄ alkoxy, most preferably methoxy) , and R¹⁴ and R¹^ are each independently hydrogen.

The following Preparations and Examples are given for the purpose of illustrating this invention.

Preparation 1 Under nitrogen at room temperature, to (2-phenylethyl) - amine (20 g) was added dropwise ethyl formate (49.6 g) , and the mixture was stirred at 50°C for 1.5 hours. The resulting mixture was evaporated and dried in vacuo to give (2- phenylethyl)formamide (25 g). (-)ESI-MS m/z: 148 (M-H)^"

Preparation 2 To a solution of (2-phenylethyl)formamide (500 mg) and methyl 5- (chlorosulfonyl) -2-hydroxybenzoate (840 mg) in 1,2- dichlorobenzene (5 ml) was added aluminum chloride (1.56 g) by portions at room temperature under nitrogen, and the mixture was stirred at 80°C for 3.5 hours. The resulting mixture was cooled to room temperature, and to this one were added ice, ethyl acetate and IN hydrochloric acid. After 5 being stirred for 40 minutes, followed by separation, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. To a solution of the residue in N,N- dimethylformamide (5 ml) were added potassium carbonate (6950 mg) and benzyl bromide (631 mg) at room temperature under nitrogen. The mixture was stirred at 60°C for 135 minutes. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water two times and brine,5 dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. To the residue was added hydrogen chloride (about 2M in methanol, 5 ml) at room temperature under nitrogen, and the mixture was stirred at 35°C for 4 hours. The resulting mixture was evaporated under reduced0 pressure. To the residue was added ethyl acetate (25 ml) at room temperature, and the mixture was stirred at the same temperature for 2.5 days . The precipitates were collected by filtration, washed with ethyl acetate, and then dissolved into a mixture of saturated aqueous sodium bicarbonate and5, chloroform/methanol (5:1). After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give methyl 5- [ [4- (2-aminoethyl) - phenyl] sulfonyl] -2- (benzyloxy)benzoate (1.11 g). (+)ESI-MS m/z: 426 (M+H)⁺,0 Preparation 3 To a solution of methyl 5- [ [4- (2-aminoethyl)phenyl] - sulfonyl] -2- (benzyloxy)benzoate (2.19 g) in chloroform (22 ml) was added benzaldehyde (573 mg) at room temperature5 under nitrogen, and the mixture was stirred at the same temperature for 20 minutes. After the resulting mixture was evaporated under reduced pressure, to a solution of the residue in tetrahydrofuran (22 ml) was added sodium borohydride (214 mg) at 5°C under nitrogen, followed by methanol (22 ml), and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. To a solution of the residue in ethyl acetate (33 ml) was added 4N hydrogen chloride in ethyl acetate (3.0 ml) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 2 hours . The precipitates were collected by filtration, washed with ethyl acetate, and then dissolved into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. After separation, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give methyl 5- [ [4- [2- (benzylamino)ethyl]phenyl] - sulfonyl] -2- (benzyloxy)benzoate (2.01 g) . (+)ESI-MS m/z: 516 (M+H)⁺

Preparation 4 To a solution of 5- [ [4- [2- [benzyl[ ( 2R) -2- ( 3- chlorophenyl) -2-hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzole acid (720 mg) in N,N-dimethylformamide (7 ml) were added imidazole (336 mg) and tert- butyldimethylsilyl chloride (662 mg) at 5°C under nitrogen, and the mixture was stirred at room temperature for 5 hours. The resulting mixture was poured into 0. IN hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. To a solution of the residue in methanol (30 ml) was added potassium carbonate (152 mg) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, and dissolved into a mixture of 0. IN hydrochloric acid and ethyl acetate. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 50:1 to 20:1) to give 5- [ [4- [2- [benzyl[ (2R) -2- [ [ tert-butyl-

(dimethyl)silyl]oxy] -2- ( 3-chlorophenyl)ethyl]amino]ethyl] - phenyl] sulfonyl] -2- (benzyloxy)benzole acid (798 mg) . (-)ESI-MS m/z: 768 (M-H)^~

Preparation 5 The following compound was obtained according to a similar manner to that of Example 1.

Methyl 5-[ [ 4- [ 2- [benzyl[ ( 2R) -2-hydroxy-2- phenylethyl] mino]ethyl]phenyl] sulfonyl] -2-hydroxybenzoate (+)ESI-MS m/z: 546 (M+H)⁺

Preparation 6 To a solution of methyl 5- [ [4- [2- [benzyl[ (2R) -2- hydroxy-2-phenylethyl] amino] ethyl]phenyl] sulfonyl] -2- hydroxybenzoate (158 mg) in methanol (5 ml) was added hydrogen chloride (about 2M in methanol, 0.5 ml), and the mixture was evaporated under reduced pressure. A mixture of the residue and 10% palladium on activated carbon (50% wet, 8 mg) in methanol (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5 hours. After filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved into a mixture of saturated aqueous sodium bicarbonate and chloroform/methanol (4:1). After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Under nitrogen at room temperature, to a solution of the residue in a mixture of tetrahydrofuran (5 ml) and N,N-dimethylformamide (5 ml) was added di-tert-butyl dicarbonate (65 g), and the mixture was stirred at the same temperature for 2.5 hours. The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed successively with water two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2:1 to 4:3) to give methyl 5- [[ 4- [2- [(tert-butoxycarbonyl) [( 2R) -2- hydroxy-2-phenylethyl] amino] ethyl]phenyl] sulfonyl] -2- hydroxybenzoate (112 mg) . (+)ESI-MS m/z: 578 (M+Na)⁺

Preparation 7 To a solution of methyl 5- [ [ 4- [2- [ ( tert- butoxycarbonyl) [ (2R) -2-hydroxy-2-phenylethyl]amino]ethyl] - phenyl] sulfonyl] -2-hydroxybenzoate (111 mg) in methanol (3 ml) was added IN sodium hydroxide ( 1.0 ml) at room temperature, and the mixture was stirred at 45°C for 10 hours, The resulting mixture was poured into IN hydrochloric acid and the aqueous mixture was extracted with a mixture of chloroform and methanol (4:1). After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 5- [ [4- [2- [ (tert- butoxycarbonyl) [ ( 2R) -2-hydroxy-2-phenylethyl]amino]ethyl] - phenyl] sulfonyl] -2-hydroxybenzoic acid (119 mg). (-)ESI-MS m/z: 540 (M-H)^~

Preparation 8 Under nitrogen at room temperature, to a solution of 5- [ [4- [2-[ (tert-butoxycarbonyl) [ ( 2R) -2-hydroxy-2- ^J phenylethyl] amino ]ethyl]phenyl] sulfonyl] -2-hydroxybenzoic acid (117 mg) in ethyl acetate (0.5 ml) was added 4N hydrogen chloride in ethyl acetate (1 ml), and the mixture was stirred at the same temperature for 2 hours. The precipitates were collected by filtration, followed by dryness to give 2-hydroxy- 5- [ [4- [2- [ [ (2R) -2-hydroxy-2- phenylethyl ] amino ] ethyl ]phenyl] sulfonyl ]benzole acid hydrochloride (76 mg) . NMR (DMSO-d₆, d) : 2.9-3.35 (6H, m) , 4.85-5.0 (IH, m) , 7.05-7.15 (IH, m) , 7.25-7.45 (5H, m) , 7.50 (2H, d, J=8.3Hz), 7.8-8.0 (3H, m) , 8.25-8.3 (IH, m) (-)ESI-MS m/z: 440 (M-HC1-H)^"

Preparation 9 To the solution of methyl 5- [ [4- [ 2- (benzylamino)ethyl] - phenyl] sulfonyl] -2- (benzyloxy)benzoate (13.5 g) in a mixture of tetrahydrofuran (160 ml) and water (80 ml) was added di- tert-butyl dicarbonate (8.57 g) in tetrahydrofuran (20 ml) dropwise at room temperature with adjusting pH to 8 by IN sodium hydroxide, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was diluted with ethyl acetate, followed by separation. The organic layer was washed successively with water two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3:1 to 2:1) to give methyl 5- [[ 4- [2- [benzyl( tert-butoxycarbonyl) - amino ] ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoate (10.4 g). (+)ESI-MS m/z: 638 (M+Na)⁺

Preparation 10 To a solution of methyl 5- [[ 4- [2- [benzyl( tert- butoxycarbonyl)amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy) - benzoate (4.3 g) in ethanol (43 ml) was added IN sodium hydroxide (10 ml) at room temperature, and the mixture was stirred at 45°C for 1.5 hours. To the resulting mixture was added IN hydrochloric acid (10 ml), and ethanol was removed under reduced pressure, followed by addition of ethyl acetate. After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 5- [ [4- [2- [benzyl(tert-butoxycarbonyl)amino]ethyl] - phenyl] sulfonyl] -2- (benzyloxy)benzoic acid (4.21 g) . (-)ESI-MS m/z: 600 (M-H)^~

Preparation 11 The following compound was obtained according to a similar manner to that of Example 3 starting from the object compound of Preparation 10. tert-Butyl [ 2- [4- [ [3-carbamoyl-4- (benzyloxy) - phenyl] sulfonyl]phenyl]ethyl]benzylcarbamate (+)ESI-MS m/z: 623 (M+Na)⁺

Preparation 12 To a suspension of tert-butyl [2- [4- [ [3-carbamoyl-4- (benzyloxy)phenyl]sulfonyl]phenyl]ethyl]benzylcarbamate (1.46 g) in ethyl acetate (23 ml) was added 4N hydrogen chloride in ethyl acetate (23 ml) at room temperature under nitrogen, .and the mixture was stirred at the same temperature for 24 hours. To the resulting mixture were added ethyl acetate and saturated aqueous sodium bicarbonate, and the mixture was stirred at room temperature for 2 hours . After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 5- [ [4- [2- (benzyla ino)ethyl]phenyl] - sulfonyl] -2- (benzyloxy)benzamide (1.23 g) . (+)ESI-MS m/z: 501 (M+H)⁺

Example 1 A solution of methyl 5- [ [ 4- [ 2- (benzylamino)ethyl] - phenyl] sulfonyl] -2- (benzyloxy)benzoate (2.74 g) and (2R)-2- (3-chlorophenyl)oxirane (986 mg) in ethanol (30 ml) was refluxed for 48 hours under nitrogen. The resulting mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2:1 to 4:3) to give methyl 5-[[4-[2- [benzyl[ (2R) -2- ( 3-chlorophenyl) -2-hydroxyethyl]amino] ethyl] - phenyl] sulfonyl] -2- (benzyloxy)benzoate (2.25 g) . (+)ESI-MS m/z: 670 (M+H)⁺

Example 2 To a solution of methyl 5- [ [4- [2- [benzyl[ (2R) -2- ( 3- chlorophenyl) -2-hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoate (414 mg) in ethanol (7 ml) was added IN sodium hydroxide (1.85 ml) at room temperature, and the mixture was stirred at 45°C for 3.5 hours. To the resulting mixture were added IN hydrochloric acid (1.85 ml) at room temperature, and then stirred at the same temperature for 30 minutes . The precipitates were collected by filtration and washed with water, followed by dryness in vacuo to give 5- [ [4- [2- [benzyl[ ( 2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoic acid (359 mg) . (-)ESI-MS m/z: 654 (M-H)^~

Example 3 To a solution of 5- [ [4- [2- [benzyl[ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoic acid (300 mg) in N,N-dimethylformamide (5 ml) were added 1-hydroxybenzotriazole (80 mg) , dimethylamine hydrochloride (49 mg) and 1- [3- ( imethylamino) ropyl] -3- ethylcarbodiimide (92 mg) at 5°C under nitrogen, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/ethyl acetate = 5:1 to 2:1) to give 5-[[4- [ 2- [ benzyl [ ( 2R) -2- ( 3-chlorophenyl ) -2-hydoxyethyl] amino ] - ethyl]phenyl] sulfonyl] -2- (benzyloxy) -N ,N-dimethylbenzamide (305 mg) . (+)ESI-MS m/z: 683 (M+H)⁺

Example 4 To a solution of 5- [ [4- [2- [benzyl[ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl ] amino ] ethyl]phenyl ] sulfonyl] -2- (benzyloxy) -N,N-dimethylbenzamide (300 mg) in ethyl acetate (3 ml) was added 4N hydrogen chloride in ethyl acetate (0.5 ml), and the mixture was evaporated under reduced pressure. A mixture of the residue and 10% palladium on activated carbon (50% wet, 15 mg) in a mixture of chlorobenzene (2.1 ml) and methanol (0.9 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 4 hours. After filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved into a mixture of aqueous sodium bicarbonate and chloroform/methanol (5:1). After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel (chloroform/methanol = 10:1 to 5:1), followed by treatment of 4N hydrogen chloride in ethyl acetate to give 5- [ [4-[2-[ [ (2R) -2- ( 3-chlorophenyl) -2-hydroxyethyl] amino] - ethyl]phenyl] sulfonyl] -2-hydroxy-N,N-dimethylbenzamide hydrochloride (219 mg). NMR (DMSO-d₆, d): 2.6-3.6 (12H, m) , 4.9-5.05 (IH, m) , 7.09 (IH, d, J=8.7Hz), 7.25-7.65 (6H, m) , 7.65 (IH, d, J=2.4Hz), 7.7-7.95 (3H, m) (+)ESI-MS m/z: 503 (M-HC1+H)⁺ Example 5 The following compounds were obtained according to a similar manner to that of Example 3.

(1) 5-[ [ 4- [2- [Benzyl [(2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino ] ethyl] henyl ] sulfonyl ] - 2- (benzyloxy) -N-ethylbenzamide (-)ESI-MS m/z: 681 (M-H)^~

(2) 5-[ [ 4- [ 2- [ Benzyl [(2R) -2- [4- (benzyloxy) -3- [ (methylsulfonyl)amino]phenyl] -2-hydroxyethyl]amino] ^■ ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzamide (+)ESI-MS m/z: 842 (M+Na)⁺

Example 6 To a solution of 5- [ [4- [2- [benzyl[ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino ] ethyl]phenyl ] sulfonyl] - 2- (benzyloxy) -N-ethylbenzamide (96 mg) in a mixture of ethyl acetate (3 ml) and methanol (3 ml) was added 4N hydrogen chloride in ethyl acetate (0.5 ml), and the mixture was evaporated under reduced pressure. A mixture of the residue and 10% palladium on activated carbon (50% wet, 5 mg) _*in a mixture of chlorobenzene (1.4 ml) and methaol ^' ( 0.6 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3.5 hours. After filtration, the filtrate was evaporated and dried in vacuo to give 5- [ [4- [2- [ [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] - ethyl]phenyl] sulfonyl] -N-ethyl-2-hydroxybenzamide hydrochloride (71 mg) . NMR (DMSO-d₆, d) : 1.15 (3H, t, J=7.2Hz), 2.95-3.4 (8H, m), 4.9-5.05 (IH, m) , 7.10 (IH, d, J=8.7Hz), 7.3- 7.55 (6H, m) , 7.85-7.95 (3H, m) , 8.51 (IH, d, J=2.3Hz) (+)ESI-MS m/z: 503 (M-HC1+H)⁺ Example 7 To a solution of 5- [ [4- [ 2- [benzyl[ ( 2R) -2- ( 3- chlorophenyl ) - 2-hydroxyethyl] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzole acid (348 mg) in N,N-dimethylformamide (5 ml) were added propylamine (36 mg), 1- [3- (dimethylamino) - propyl] -3-ethylcarbodiimide hydrochloride (112 mg), and 1- hydroxybenzotriazole (79 mg) at 5°C under nitrogen, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The organic layer was washed susccessively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/ethyl acetate = 5:1 to 2:1) to give 5- [ [4- [2- [benzyl [ (2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy) -N- propylbenzamide (237 mg) . (+)ESI-MS m/z: 697 (M+H)⁺

Example 8 The following compound was obtained according to a similar manner to that of Example 4.

5-[[4-[2-[[( 2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino ] ethyl ]phenyl] sulfonyl] -2-hydroxy-N-propylbenzamide hydrochloride NMR (DMSO-d₆, d) : 0.90 (2H, t, J=7.3Hz), 1.45-1.7 (2H, m) , 2.9-3.45 (8H, m) , 4.95-5.1 (IH, m) , 7.13 (IH, d, J=8.8Hz), 7.25-7.6 (6H, m) , 7.8-8.0 (3H, m) , 8.53 (IH, d. J=2.2Hz) ( + )ESI-MS m/z: 517 (M-HC1+H)^"1"

Example 9 The following compounds were obtained according to a similar manner to that of Example 7.

(1) 5- [[4- [2- [Benzyl [ ( 2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl] amino ] ethyl]phenyl] sulfonyl] -2- (benzyloxy) -N-phenylbenzamide (+)ESI-MS m/z: 731 (M+H)⁺

(2) 5-[ [ 4- [ 2- [Benzyl [(2R) -2-(3-chlorophenyl) -2- hydroxyethyl] mino] ethyl] phenyl] sulfonyl] -2- (benzyloxy) -N- (2,2 , 2-trifluoroethyl)benzamide (+)ESI-MS m/z: 737 (M+H)⁺

(3) 5-[ [4-[2-[Benzyl[ ( 2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy) -N- (2-hydroxyethyl)benzamide (-)ESI-MS m/z: 697 (M-H)-

Example 10 A mixture of 5- [ [4- [2- [benzyl [ (2R) -2- (3-chlorophenyl) - 2-hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy) -N- phenylbenzamide (55 mg) , hydrogen chloride (4N in ethyl acetate, 0.038 ml) and 10% palladium on activated carbon (50% wet, 3 mg) in a mixture of chlorobenzene (1.4 ml) and methanol (0.6 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours, After filtration, the filtrate was evaporated and dried in vacuo to give 5- [ [4- [2- [[ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino ] ethyl ]phenyl] sulfonyl ] -2-hydroxy-N- phenylbenzamide hydrochloride (44 mg) . NMR (DMSO-d₆, d) : 2.9-3.5 (6H, m) , 4.85-5.0 (IH, m) , 7.1-7.2 (2H, m), 7.3-7.55 (8H, m) , 7.69 (2H, d, J=7.8Hz), 7.9-80 (3H, m) , 8.38 (IH, d, J=2.4Hz) (+)ESI-MS m/z: 551 (M-HC1+H)⁺ Example 11 The following compounds were obtained according to a similar manner to that of Example 10.

(1) 5-[[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]- amino] ethyl ]phenyl ] sulfonyl ] -2-hydroxy-N- (2,2,2- trifluoroethyl)benzamide hydrochloride NMR (DMSO-d₆, d) : 2.9-3.5 (6H, m) , 4.05-4.3 (2H, m) , 4.9-5.05 (IH, m). 7.19 (IH, d, J=8.8Hz), 7.25-7.6 (6H, m), 7.8-8.0 (3H, m) , 8.43 (IH, d, J=2.4Hz) (+)ESI-MS m/z: 557 (M-HC1+H)⁺

(2) 5-[ [4-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]- amino] ethyl]phenyl] sulfonyl] -N-cyclopropyl-2- hydroxybenzamide hydrochloride NMR (DMSO-d₆, d) : 0.60-0.85 (4H, m) , 2.8-3.4 (7H, m) , 4.9-5.0 (IH, m), 7.09 (IH, d, J=8.7Hz), 7.3-7.6 (6H, m), 7.85-7.95 (3H, m) , 8.49 (IH, d, J=2.2Hz) (+)ESI-MS m/z: 515 (M-HC1+H)^"1"

(3) 2-Hydroxy-5-[ [4-[2-[ [ (2R) -2-hydroxy-2- [4-hydroxy-3- [ (methylsulfonyl) amino]phenyl ] ethyl] amino ] ethyl] - phenyl] sulfonyl]benzoic acid hydrochloride NMR (DMSO-d₆, d) : 4.75-7.85 (IH, m) , 6.90 (IH, d, J=8.3Hz), 7.0-7.1 (IH, m) , 7.11 (IH, d, J=8.9Hz), 7.23 (IH, d, J=1.8Hz), 7.50 (2H, d, J=8.3Hz), 7.91 (IH, dd, J=2.5, 8.8Hz), 8.26 (IH, d, J=2.5Hz) (-)ESI-MS m/z: 549 (M-HC1-H)- (4) 2-Hydroxy-5-[ [4-[2-[ [ (2R) -2-hydroxy-2- [ 4-hydroxy-3- [ (methylsulfonyl ) amino ] phenyl ] ethyl] amino ] ethyl ] - phenyl] sulfonyl]benzamide hydrochloride NMR (DMSO-d₆, d) : 2.8-3.5 (9H, m) , 7.75-7.85 (IH, m) , 6.85-7.3 (4H, m) , 7.50 (2H, d, J=8.3Hz), 7.9-7.95 (3H, m), 8.53 (IH, d, J=2.2Hz) ( + ) ESI -MS m/ z : 572 (M-HCl+Na ) ⁺

(5) 5-[[4-[2-[ [(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]~ amino] ethyl ]phenyl] sulfonyl] - 2-hydroxybenzamide hydrochloride NMR (DMSO-d₆, d): 2.9-3.4 (6H, m) , 4.9-5.0 (IH, m) , 7.09 (IH, d, J=8.8Hz), 7.35-7.6 (6H, m) , 7.85-8.0 (3H, m), 8.54 (IH, d, J=2.3Hz) (+)ESI-MS m/z: 475 (M-HC1+H)⁺

Example 12 A mixture of 5- [[ 4- [2- [benzyl[ (2R) -2- ( 3-chlorophenyl) - 2-hydroxyethyl] amino] ethyl]phenyl] sulfonyl ] -2- (benzyloxy) -N- (2-hydroxyethyl)benzamide (98 mg) , hydrogen chloride (4N in 1,4-dioxane, 0.070 ml) and 10% palladium on activated carbon (50% wet, 5 mg) in a mixture of chlorobenzene (1.4 ml) and methanol (0.6 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2.5 hours. After filtration, the filtrate was evaporated and dried in vacuo to give 5- [ [4- [2- [[ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino ] ethyl]phenyl] sulfonyl] -2-hydroxy-N- ( 2 - hydroxyethyl)benzamide hydrochloride (81 mg) . NMR (DMSO-d₆, d) : 2.95-3.45 (8H, m) , 3.45-3.65 (2H, m) , 4.85-5.05 (IH, m) , 7.10 (IH, d, J=8.7Hz), 7.3-7.65 (6H, m), 7.85-7.95 (3H, m) , 8.55 (IH, d, J=2.4Hz) ( + )ESI-MS m/z: 519 (M-HC1+H) ^"

Example 13 To a solution of 5- [ [4- [2- [benzyl[ (2R) -2- (3- chlorophenyl ) -2-hydroxyethyl ] amino] ethyl ] phenyl] sulfonyl ] -2- (benzyloxy)benzoic acid (174 mg) in N,N-dimethylformamide (2 ml) were added 1-hydroxybenzotriazole (54 mg) , l-[3- (dimethylamino)propyl] -3-ethylcarbodiimide hydrochloride ( 76 mg) and aqueous ammonia (0.183 ml) at 5°C under nitrogen, and the mixture was stirred at room temperature for 2.5 days. The resulting mixture was poured into 0. IN hydrochloric acid and the aqueous layer was extracted with ethyl acetate . The organic layer was washed successively with saturated aqueous sodium bicarbonate two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel (chloroform/ethyl acetate = 3:1 to 1:1) to give 5-[[4- [2- [benzyl [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] - ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzamide (124 mg) . (+)ESI-MS m/z: 655 (M+H)⁺

Example 14 To a solution of 5- [ [4- [ 2- [benzyl[ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzamide (96 mg) in a mixture of ethyl acetate

(3 ml) and methanol (3 ml) was added 4N hydrogen chloride in ethyl acetate (0.5 ml), and the mixture was evaporated under reduced pressure. A mixture of the residue and 10% palladium on activated carbon (50% wet, 5 mg) in a mixture of chlorobenzene (0.7 ml) and methanol (0.3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 4 hours. After filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved into a mixture of aqueous sodium bicarbonate and chloroform/methanol (5:1). After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 10:1 to 4:1), followed by treatment of 4N hydrogen chloride in ethyl acetate to give 5-[[4-[2-[[(2R)-2-(3- chlorophenyl ) -2-hydroxyethyl ] amino ] ethyl ]phenyl] sulfonyl ] -2- hydroxybenzamide hydrochloride (37 mg) . NMR (DMSO-d₆, d): 2.9-3.4 (6H, m) , 4.85-5.0 (IH, m) , 7.09 (IH, d, J=8.8Hz), 7.25-7.55 (6H, m) , 7.85- 7.95 (3H, m) , 8.54 (IH, d, J=2.2Hz) (+)ESI-MS m/z: 475 (M-HC1+H)⁺

Example 15 To a solution of 5- [ [4- [2- [benzyl[ (2R) -2- [ [ tert- butyl(dimethyl) silyl] oxy] -2- ( 3-chlorophenyl)ethyl]amino] - ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoic acid (150 mg) in N,N-dimethylformamide (2 ml) were added cyclopropylamine (22 mg) , 1-hydroxybenzotriazole (34 mg) and l-[3- (dimethylamino)propyl] -3-ethylcarbodiimide hydrochloride ( 49 mg) at 5°C under nitrogen, and the mixture was stirred at room temperature for 22 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. To a solution of the residue in tetrahydrofuran (3 ml) was added tetrabutylammonium fluoride ( 1M in tetrahydrofuran, 0.39 ml) at 5°C under nitrogen, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/ethyl acetate = 5:1 to 3:1) to give 5- [[4- [2-

[benzyl[ (2R)-2- (3-chlorophenyl) -2-hydroxyethyl]amino]ethyl] - phenyl] sulfonyl] -2- (benzyloxy) -N-cyclopropylbenzamide ( 125 mg) . (+)ESI-MS m/z: 695 (M+H)⁺

Example 16 To a solution of 5- [ [4- [2- [benzyl[ (2R) -2- [ [tert- butyl(dimethyl) silyl]oxy] -2- (3-chlorophenyl)ethyl]amino] - ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzole acid (351 mg) in N,N-dimethylformamide (5 ml) was added carbodiimidazole (81 mg) at room temperature under nitrogen. After being stirred at the same temperature for 50 minutes, methanesulfonamide (48 mg) and 1 , 8-diazabicyclo[ 5.4 i 0]undec-7-ene (90 mg) were added, and the mixture was stirred at the same temperature for 4 hours . The resulting mixture was poured into dilute hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. To a solution of the residue in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1M in tetrahydrofuran, 1.37 ml) at 5°C under nitrogen, and the mixture was stirred at room tempeature for 8 hours . The resulting mixture was poured into 0. IN hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 200:1 to 50:1) to give 5- [ [4- [2- [benzyl[ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy) -N- (methylsulfonyl)benzamide (268 mg) . (+)ESI-MS m/z: 733 (M+H)⁺

Example 17 The following compound was obtained according to a similar manner to that of Example 6.

5-[ [4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]- amino] ethyl ]phenyl] sulfonyl] -2-hydroxy-N- (methylsulfonyl ) - benzamide hydrochloride NMR (DMSO-d₆, d) : 2.9-3.35 (9H, m) , 4.85-5.0 (IH, m) , 7.08 (IH, d, J=8.8Hz), 7.25-7.65 (6H, m) , 7.85- 7.95 (3H, m), 8.24 (IH, d, J=2.5Hz) (+)ESI-MS m/z: 575 (M-HCl+Na)⁺ Example 18 To a solution of 2-hydroxy-5- [ [4- [ 2- [ [ (2R) -2-hydroxy-2- phenylethyl]amino] ethyl]phenyl] sulfonyl]benzoic acid hydrochloride (200 mg) in tetrahydrofuran (5 ml) were added N,N-diisopropylethylamine (0.26 ml), di-tert-butyl dicarbonate (548 mg) and a catalytic amount of 4- (dimethylamino)pyridine at 5°C under nitrogen, and the mixture was stirred at room temperature for 3 hours. The resulting mixture was poured into 0. IN hydrochloric acid and the aqueous layer was extracted with chloroform/methanol

(5:1). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. To a solution of the residue in N,N-dimethylformamide (5 ml) were added ammonium chloride (45 mg) , 1-hydroxybenzotriazole (113 mg) , and 1- [3- (dimethylamino)propyl] -3-ethylcarbodiimide

(130 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 40:1 to 20:1) to give tert-butyl [2- [4-[ [ 3-carbamoyl-4-hydroxyphenyl] sulfonyl]phenyl] - ethyl] [ (2R)-2-hydroxy-2-phenylethyl]carbamate (87 mg) . (+)ESI-MS m/z: 597 (M+Na)⁺

Example 19 To a solution of tert-butyl [ 2- [4- [ [ 3-carbamoyl-4- hydroxyphenyl] sulfonyl]phenyl]ethyl] [ ( 2R) -2-hydroxy-2- phenylethyl]carbamate (85 mg) in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethyl acetate (2 ml) at room temperature under nitrogen, and the mixture was stirred at the same temperature -for 9 hours. To the resulting mixture was added diisopropyl ether (3 ml), and the precipitates were collected by filtration and dried in vacuo to give 2- hydroxy-5- [ [4- [2- [ [ (2R) -2-hydroxy-2-phenylethyl] amino] - ethyl]phenyl] sulfonyl] benzamide hydrochloride (62 mg) . NMR (DMSO-d₆, d): 2.9-3.3 (6H, m) , 4.85-5.0 (IH, m) , 7.09 (IH, d, J=8.7Hz), 7.25-7.45 (5H, m) , 7.51 (2H, d, J=8.3Hz), 7.9-8.0 (3H, m) , 8.54 (IH, d, J=2.2Hz) (+)ESI-MS m/z: 441 (M-HC1+H)⁺

Example 20 The following compounds were obtained according to a similar manner to that of Example 1. (1) Methyl 5-[ [ 4- [ 2- [benzyl[ ( 2R) -2- [4- (benzyloxy) -3- nitrophenyl] -2-hydroxyethyl] amino ] ethyl ]phenyl ] - sulfonyl] -2- (benzyloxy)benzoate (+)ESI-MS m/z: 809 (M+Na)⁺ (2) Methyl 5-[ [ 4- [ 2- [benzyl[ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl ] amino ] ethyl]phenyl ] sulfonyl] -2- (benzyloxy)benzoate (+)ESI-MS m/z: 693 (M+Na)⁺ (3) 5-[[4-[2-[Benzyl[ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl ] amino] ethyl]phenyl ] sulfonyl] -2- (benzyloxy)benzamide (+)ESI-MS m/z: 678 (M+Na)⁺ (4) 5-[ [4-[2-[Benzyl[ ( 2R) -2- ( 4-chlorophenyl) -2- hydroxyethyl] amino ] ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzamide (+)ESI-MS m/z: 655 (M+H)⁺

Example 21 To a suspension of 5- [ [4- [ 2- [benzyl[ (2R) -2- [4- (benzyloxy) -3-nitrophenyl] -2-hydroxyethyl] amino] ethyl] - phenyl] sulfonyl] -2- (benzyloxy)benzoate (882 mg) in a mixture of ethanol (10 ml), 1,4-dioxane (5 ml) and water (3 ml) were added reduced iron (188 mg) and ammonium chloride (30 mg) at room temperature under nitrogen, and the mixture was refluxed for 1 hour. The insoluble materials were filtered through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure, followed by dryness in vacuo to give methyl 5-[ [4-[2-[ [ ( 2R) -2- [3-amino-4- (benzyloxy)phenyl] -2- hydroxyethyl] (benzyl)amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoate (859 mg) . (+)ESI-MS m/z: 757 (M+H)⁺

Example 22 To a solution of methyl 5- [ [ 4- [2- [ [ ( 2R) -2- [ 3-amino-4- (benzyloxy)phenyl] -2-hydroxyethyl] (benzyl)amino]ethyl] - phenyl] sulfonyl] -2- (benzyloxy)benzoate (919 mg) in dichloromethane (10 ml) were added pyridine (0.147 ml) and methanesulfonyl chloride (0.103 ml) at 5°C under nitrogen, and the mixture was stirred at room temperature for 12 hours, The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1:1 to 1:2) to give methyl 5-[[4-[2- [benzyl[ (2R) -2- [4- (benzyloxy) -3- [ (methylsulfonyl)amino] - phenyl] -2-hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoate (858 mg) . (+)ESI-MS m/z: 857 (M+Na)⁺

Example 23 To a solution of methyl 5- [ [4- [ 2- [benzyl[ ( 2R) -2- [4- (benzyloxy) -3- [ (methylsulfonyl) amino]phenyl] -2- hydroxyethyl ] amino ] ethyl ] phenyl ] sulfonyl] -2- (benzyloxy) - benzoate (708 mg) in a mixture of ethanol (14 ml) and tetrahydrofuran (7 ml) was added IN sodium hydroxide (2.54 ml) at room temperature, and the mixture was stirred at the same temperature for 6.5 hours. To the resulting mixture were added IN hydrochloric acid (2.54 ml), and this one was concentrated under reduced pressure,, followed by addition of water. After being stirred at room temperature for 12 hours, the precipitates were collected by filtration, and then dissolved into chloroform/methanol (4:1). The solution was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 20:1 to 15:1) to give 5- [ [4- [2- [benzyl [ (2R) -2- [4- (benzyloxy) -3- [ (methylsulfonyl )amino ]phenyl ] -2-hydroxyethyl] amino] ethyl ] - phenyl] sulfonyl] -2- (benzyloxy)benzole acid (730 mg) . (-)ESI-MS m/z: 819 (M-H)^~

Example 24 To a solution of methyl 5- [ [ 4- [ 2- [benzyl[ (2R) -2- ( 6- chloro-3-pyridyl) -2-hydroxyethyl] amino] ethyl]phenyl] - sulfonyl] -2- (benzyloxy)benzoate (615 mg) in a mixture of methanol (6 ml) and ethyl acetate (6 ml) was added hydrogen chloride (about 2M in methanol, 2 ml), and the mixture was evaporated under reduced pressure. A mixture of the residue and 10% palladium on activated carbon (50% wet, 31 mg) in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2 hours. After filtration, the filtrate was evaporated under reduced pressure. A mixture of the residue and 10% palladium on activated carbon (50% wet, 62 mg) in a mixture of methanol (3 ml) and chlorobenzene (7 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 10 hours. After filtration, the filtrate was evaporated under reduced pressure. To the solution of the residue in a mixture of tetrahydrofuran (4 ml) and water (4 ml) was added di-tert- butyl dicarbonate (220 mg) in tetrahydrofuran (2 ml) dropwise at 5°C with adjusting pH to 8.6 by IN sodium hydroxide, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with ethyl acetate and water, followed by separation. The aqueous layer was extracted with chloroform/methanol (9:1) two times, The combined organic layers were dried over anhydrous magnesium sulfate and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel (chloroform/methanol = 100:1 to 40:1) to give methyl 5- [ [4-[2-[ (tert-butoxycarbonyl) [ (2R) -2-hydroxy-2- (3-pyridyl) - ethyl]amino] ethyl]phenyl] sulfonyl] -2-hydroxybenzoate (216 mg) . (+)ESI-MS m/z: 557 (M+H)⁺

Example 25 To a solution of methyl 5- [ [4- [2- [ (tert- butoxycarbonyl) [ ( 2R) -2-hydroxy-2- ( 3-pyridyl)ethyl]amino] - ethyl]phenyl] sulfonyl] -2-hydroxybenzoate (212 mg) in ethanol (4 ml) was added IN sodium hydroxide (1.52 ml) at room temperature, and the mixture was stirred at 45°C for 11 hours, To the resulting mixture was added IN hydrochloric acid (1.52 ml), and the mixture was concentrated under reduced pressure, followed by decantation. The residue was dissolved into chloroform/methanol (4:1), dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 5- [ [4- [2- [( tert-butoxycarbonyl) [ (2R) -2-hydroxy-2- (3- pyridyl) ethyl]amino] ethyl]phenyl] sulfonyl] -2-hydroxybenzoic acid ( 222 mg ) . ( - ) ESI -MS m/ z : 541 ( M-H ) -

Example 26 ' To a solution of 5- [ [4- [ 2- [( tert-butoxycarbonyl) [( 2R) - 2-hydroxy-2- ( 3-pyridyl ) ethyl] amino] ethyl]phenyl] sulfonyl ] -2- hydroxybenzoic acid (220 mg) in 1,4-dioxane (1 ml) was added 4N hydrogen chloride in 1,4-dioxane (3 ml) at room temperature under nitrogen, and the mixture was stirred at- the same temperature for 4 hours. The resulting mixture was decanted and the residue was washed with ethyl acetate, followed by dryness in vacuo to give 2-hydroxy-5- [ [ 4- [2- [ [ (2R)-2-hydroxy-2-(3-pyridyl) ethyl] amino ] ethyl]phenyl] - sulfonyl]benzole acid dihydrochloride (242 mg) . NMR (DMSO-d₆, d) : 3.05-3.5 (6H, m) , 5.25-5.35 (IH, m) , 7.16 (IH, d, J=8.7Hz), 7.48 (2H, d, J=7.4Hz), 7.85-8.1 (4H, m), 8.27 (IH, d, J=2.4Hz), 8.45-8.55 (IH, m) , 8.8-8.95 (2H, m) (-)ESI-MS m/z: 441 (M-2HC1-H)^"

Example 27 A mixture of 5- [ [ 4- [ 2- [benzyl[ ( 2R) -2- ( 6-chloro-3- pyridyl ) -2-hydroxyethyl] amino ] ethyl ]phenyl ] sulfonyl] -2- (benzyloxy)benzamide (203 mg) , hydrogen chloride (4N in ethyl acetate, 0.155 ml) and 10% palladium on activated carbon (50% wet, 20 mg) in a mixture of methanol (2 ml) and tetrahydrofuran (1 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 11 hours. After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by reversed phase chromatography to give 2-hydroxy- 5- [ [4- [2- [ [ (2R) -2- hydroxy-2- ( 3-pyridyl ) ethyl ] amino ] ethyl]phenyl] sulfonyl ] - benzamide dihydrochloride (130 mg) . NMR (DMSO-d₆, d) : 3.0-3.45 (6H, m) , 5.15-5.3 (IH, m) , 7.10 (IH, d, J=8.7Hz), 7.52 (2H, d, J=8.3Hz), 7.85-8.0 (4H, m), 8.37 (IH, d, J=8.0Hz), 8.54 (IH, d, J=2.2Hz), 8.7-8.9 (2H, m) (+)ESI-MS m/z: 442 (M-2HC1+H)⁺

Preparation 13 The following compounds were obtained according to a similar manner to that of Preparation 1.

(1) (3-Phenylpropyl)formamide (+)ESI-MS m/z: 164 (M+H)⁺

(2) (2-Phenoxyethyl)formamide (+)ESI-MS m/z: 188 (M+Na)⁺

Preparation 14 The following compounds were obtained according to a similar manner to that of Preparation 36.

( 1 ) 2- (Benzyloxy)-5-[ [ 4- [ 2- ( formylamino) ethoxy]phenyl ] - sulfonyl]benzamide (+)ESI-MS m/z: 477 (M+Na)⁺

(2) 2- [ 4- [ [ 3- (Aminocarbonyl) - 4- (benzyloxy)phenyl] sulfonyl ] - phenyl] ethyl acetate (+)ESI-MS m/z: 476 (M+Na)⁺

( 3 ) 2- (Benzyloxy)-5-[ [ 4- [ 2- ( formylamino) -2-methylpropyl ] - phenyl] sulfonyl ]benzamide (+)ESI-MS m/z: 489 (M+Na)⁺

(4) Methyl 2- (benzyloxy) -5- [[ 4- [ 2- (formylamino ) ethyl] - phenyl] sulfonyl] -3-propylbenzoate (+)ESI-MS m/z: 518 (M+Na)⁺

Preparation 15 The following compound was obtained according to a similar manner to that of Preparation 37.

5- [ [ 4- ( 2-Aminoethoxy)phenyl] sulfonyl ] -2 - (benzyloxy) - benzamide (+)ESI-MS m/z: 427 (M+H)⁺

Preparation 16 The following compound was obtained according to a similar manner to that of Preparation 38.

2- [4- [ [3- (Aminocarbonyl) -4-hydroxyphenyl] sulfonyl] - phenyl] ethyl acetate (+)ESI-MS m/z: 386 (M+Na)

Preparation 17 Formic acid (14 ml) was added to acetic anhydride (18 ml) dropwise at 5°C under nitrogen, and the mixture was stirred at room temperature for 1.5 hours . To this one was added ( 1, 1-dimethyl-2-phenylethyl)amine (25 ml) dropwise at 5°C, and the mixture was stirred at room temperature for 12 hours . The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. To the organic layer was added water, and made basic with ammonia. After being stirred for 1 hour, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give ( 1 , 1-dimethyl-2-phenylethyl)formamide (23 g) . (+)ESI-MS m/z: 200 (M+Na)⁺

Preparation 18 The following compound was obtained according to a similar manner to that of Preparation 43. 5-[[4-[2- ( Formylamino ) -2-methylpropyl] henyl] sulfonyl] - 2-hydroxybenzamide ( + ) ESI -MS m/ z : 399 (M+Na ) ⁺

Preparation 19 A solution of 2- (benzyloxy) -5- [[ 4- [ 2- (formylamino) -2- methylpropyl]phenyl] sulfonyl]benzamide (4.8 g) and hydrogen chloride (10% in methanol, 48 ml) was stirred at room temperature for 12 hours. The resulting mixture was evaporated under reduced pressure. The residue was dissolved into a mixture of saturated aqueous sodium bicarbonate and chloroform-methanol (5:1). After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 20:1 to 10:1) to give 5- [ [4- ( 2-amino- 2-methylpropyl)phenyl] sulfonyl] -2-(benzyloxy)benzamide (2.7 g). (+)ESI-MS m/z: 439 (M+H)⁺

Preparation 20 To a solution of 2- [4- [ [3- (aminocarbonyl) -4-

(benzyloxy)phenyl] sulfonyl] henyl] ethyl acetate (2.3 g) in a mixture of tetrahydrofuran (45 ml) and water (11 ml) was added IN sodium hydroxide (5.0 ml) at room temperature, and the mixture was stirred at the same temperature for 8.5 hours. To the resulting mixture was added IN hydrochloric acid (5.0 ml) and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 200:1 to 20:1) to give 2- (benzyloxy) - 5- [ [4- (2-hydroxyethyl)phenyl] sulfonyl] benzamide (1.6 g) . (+)ESI-MS m/z: 434 (M+Na)⁺

Preparation 21 To a suspension of 2- (benzyloxy) -5- [[ 4- ( 2- hydroxyethyl)phenyl] sulfonyl]benzamide (100 mg) in dichloromethane (5 ml) was added tribromoboran ( 1M in dichloromethane, 0.53 ml) in dry ice-acetone bath under nitrogen, and the temperature of the resulting mixture was allowed to rise slowly to room temperature, and the mixture was stirred at the same temperature for 2.5 days. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with IN hydrochloric acid and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 100:1 to 20:1) to give 5- [ [4- ( 2-bromoethyl)phenyl] sulfonyl] -2- hydroxybenzamide (83 mg) . (-)ESI-MS m/z: 382, 384 (M-H)^"

Preparation 22 To a solution of ethyl 5- [ [4- [2- [ (tert- butoxycarbonyl) [ (2R) -2-(3-chlorophenyl) -2- (tetrahydro-2H- pyran-2-yloxy)ethyl]amino]ethyl]phenyl] sulfonyl] -2-

(methylamino)benzoate (240 mg) in a mixture of methanol (4.8 ml) and tetrahydrofuran (1.2 ml) was added IN sodium hydroxide (0.856 ml) at room temperature, and the mixture was stirred at the same temperature for 12 hours. To the resulting mixture were added IN hydrochloric acid (0.856 ml) and ethyl acetate followed by separation. The organic layer was dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 5- [ [4- [2- [ (tert-butoxycarbonyl) [2- (3- chlorophenyl) -2- (tetrahydro-2H-pyran-2-yloxy)ethyl]amino] - ethyl]phenyl] sulfonyl] -2- (methylamino)benzoic acid (244 mg) . (-)ESI-MS m/z: 671, 673 (M-H)^"

Preparation 23 The following compounds were obtained according to a similar manner to that of Example 3. (1) tert-Butyl [ 2- [4- [ [3- (aminocarbonyl) -4- (methylamino) - phenyl ] sulfonyl ]phenyl ] ethyl] [ ( 2R) -2- ( 3-chlorophenyl ) - 2- ( tetrahydro-2H-pyran-2-yloxy) ethyl] carbamate (+)ESI-MS m/z: 694, 696 (M+Na)⁺

(2) 5-Fluoro-2-nitrobenzamide (+)ESI-MS m/z: 207 (M+Na)⁺

Preparation 24 To a solution of 5- [ [4- ( 2-bromoethyl)phenyl] sulfonyl ] - 2-hydroxybenzamide (323 mg) in tetrahydrofuran (8.5 ml) were added 2,2-dimethoxypropane (5.2 ml) and p-toluenesulfonic acid (14 mg) at room temperature under nitrogen, and the resulting mixture was stirred at the same temperature for 59 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 100:1 to 40:1) to give 6- [ [4- (2-bromoethyl)phenyl ] - sulfonyl] -2, 2-dimethyl-2 , 3-dihydro-4H-l , 3-benzoxazin-4-one (343 mg). (+)ESI-MS m/z: 446, 448 (M+H)⁺

Preparation 25 Chlorosulfonic acid (31.4 ml) was added to methyl 2- hydroxy-3-methylbenzoate (15.7 g) dropwise at 5°C under nitrogen, and the mixture was stirred at the room temperature. The resulting mixture was added to ice water to give precipitates. After being stirred for 15 minutes, the precipitates were collected by filtration and washed with water followed by dryness in vacuo to give methyl 5- (chlorosulfonyl) -2-hydroxy-3-methylbenzoate (21.3 g) . NMR ( DMSO- d₆ , d ) : 2 . 20 ( 3H , s ) , 3 . 93 ( 3H , s ) , 7 . 64 ( IH , m) , 7 . 93 ( IH , m)

Preparation 26 The following compounds were obtained according to a similar manner to that of Preparation 25.

(1) Methyl 5- (chlorosulfonyl) -2 -hydroxy-3-methoxybenzoate NMR (DMSO-d₆, d) : 3.82 (3H, s), 3.91 (3H, s), 7.34 (IH, d, J=1.9 Hz), 7.65 (IH, d, J=1.9 Hz)

(2) Methyl 5- (chlorosulfonyl) -2-hydroxy-3-propylbenzoate NMR (DMSO-d₆, d) : 0.91 (3H, t, J=7.3 Hz), 1.45-1.65 (2H, m) , 2.58 (2H, t, J=7.2 Hz), 3.93 (3H, s), 7.61 (IH, d, J=2.1 Hz), 7.94 (IH, d, J=2.1 Hz)

(3) Methyl 3- (chlorosulfonyl) -2-hydroxy-5-methylbenzoate NMR (DMSO-d₆, d) : 2.23 (3H, s), 3.78 (3H, s), 7.46 (IH, m) , 7.51 (IH, m)

Preparation 27 The following compound was obtained according to a similar manner to that of Preparation 2. Methyl 5- [ [4- ( 2-aminoethyl )phenyl] sulfonyl] -2- (benzyloxy) -3-methylbenzoate (+)ESI-MS m/z: 440 (M+H)⁺

Preparation 28 To a solution of methyl 5- [ [4- ( 2-aminoethyl)phenyl] - sulfonyl] -2- (benzyloxy) -3-methylbenzoate (12.6 g) in chloroform (120 ml) was added benzaldehyde (3.19 g) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 30 minutes. After the resulting mixture was evaporated under reduced pressure, to a soution of the residue in tetrahydrofuran (126 ml) was added sodium borohydride (1.19 g) at 5°C under nitrogen, followed by methanol (25 ml), and the mixture was stirred at the same temperature for 2 hours . The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 200:1 to 30:1) to give methyl 5- [ [ 4- [ 2- (benzylamino)ethyl]phenyl] - sulfonyl] -2- (benzyloxy) -3-methylbenzoate (7.4 g) . (+)ESI-MS m/z: 530 (M+H)⁺

Preparation 29 To a solution of ( 2-phenylethyl)formamide (3.0 g) and methyl 5- (chlorosulfonyl) -2-hydroxy-3-methoxybenzoate (5.6 g) in nitromethane (45 ml) was added iron(III) chloride (11.4 g) by portions at room temperature under nitrogen, and the mixture was stirred at room temperature for 3.5 days. The resulting mixture was poured into ice water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water two times and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. To a solution of the residue in N,N- dimethylformamide (30 ml) were added potassium carbonate (8.3 g) and benzyl bromide (5.2 g) at room temperature under nitrogen, and the mixture was stirred at 60°C for 3 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water three times and brine, dried over anhydrous magnesium sulfate, evaporated under reduce. The residue was purified by column chromatography on silica gel (chloroform/methanol=200 : 1 to 50:1) to give methyl 2- (benzyloxy)-5-[[4-[2-( formylamino)ethyl]phenyl] - sulfonyl] -3-methoxybenzoate (5.4 g) . ( + ) ESI -MS m/ z : 506 (M+Na ) ⁺

Preparation 30 Methyl 2- ( benzyloxy)-5-[[4-[2-( formylamino ) ethyl ] - phenyl] sulfonyl ] -3-methoxybenzoate (5.4 g) and hydrogen chloride (10% in methanol, 54 ml) was stirred at room temperature 23 hours under nitrogen. The resulting mixture was evaporated under reduced pressure. The residue was dissolved into a mixture of saturated aqueous sodium bicarbonate and chloroform/methanol (5:1). After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give methyl 5- [[4- (2- aminoethyl )phenyl ] sulfonyl] -2- (benzyloxy) -3-methoxybenzoate . (5.1 g). (+)ESI-MS m/z: 456 (M+H)⁺

Preparation 31 A mixture of methyl 3-allyl-2-hydroxybenzoate (25.4 g) and 10% palladium on activated carbon (50% wet, 2.54 g) in methanol (250 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 under reduced pressure. The residue was distilled to give methyl 2-hydroxy-3-propylbenzoate (100-104°C, 2 mmHg, 15.3 g) . (+)ESI-MS m/z: 217_. (M+Na) ⁺

Preparation 32 The following compounds were obtained according to a similar manner to that of Preparation 28.

(1) Methyl 5- [ [4- [ 2- (benzylamino) ethyl ]phenyl] sulfonyl] -2- (benzyloxy) -3-methoxybenzoate (+)ESI-MS m/z: 546 (M+H)⁺ (2) Methyl 5- [ [4- [ 2- (benzylamino ) ethyl] phenyl] sulfonyl] -2- (benzyloxy) -3-propylbenzoate (+)ESI-MS m/z: 558 (M+H)⁺

(3) Methyl 3- [[ 4- [ 2- (benzylamino) ethyl] phenyl] sulfonyl] -2- (benzyloxy) -5-methylbenzoate (+)ESI-MS m/z: 530 (M+H)⁺

Preparation 33 To a solution of ( 2-phenylethyl)formamide (5.0 g) and methyl 5- (chlorosulfonyl) -2-hydroxy-3-propylbenzoate (9.8 g) in 1, 2-dichloroethane (50 ml) was added aluminium chloride (15.6 g) by portions at room temperature under nitrogen, and the mixture was refluxed for 4 hours. The resulting mixture was poured into ice water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with IN hydrochloric acid and brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give methyl 5- [ [4- [2- (formylamino)ethyl]phenyl] sulfonyl] - 2-hydroxy-3-propylbenzoate (12.8 g) . (+)ESI-MS m/z: 428 (M+Na)⁺

Preparation 34 The following compounds were obtained according to a similar manner to that of Preparation 30.

(1) Methyl 5- [ [ 4- (2-aminoethyl)phenyl] sulfonyl] -2- (benzyloxy) -3-propylbenzoate (+)ESI-MS m/z: 468 (M+H)⁺

(2) Methyl 3- [[ 4- ( 2-aminoethyl)phenyl] sulfonyl] -2- (benzyloxy) -5-methylbenzoate (+)ESI-MS m/z: 440 (M+H)⁺

Preparation 35 The following compound was obtained according to a similar manner to that of Preparation 29.

Methyl 2- (benzyloxy)-3-[[4-[2-( formylamino ) ethyl] - phenyl ] sulfonyl ] - 5-methylbenzoate (+)ESI-MS m/z: 490 (M+Na)⁺

Preparation 36 To a solution of 5- [ [4- [3- (formylamino )propyl] henyl] - sulfonyl] -2-hydroxybenzamide (10 g) in N,N-dimethylformamide (100 ml) were added potassium carbonate (7.6 g) and benzyl bromide (5.6 ml) at room temperature under nitrogen, and the mixture was stirred at 60°C for 7 hours. The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed successively with water two times and brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 2-benzyloxy-5- [ [4- [3- (formylamino)propyl]phenyl] - sulfonyl]benzamide (13 g) . (+)ESI-MS m/z: 453 (M+H)⁺

Preparation 37

To a solution of 2-benzyloxy-5- [ [4- [3- (formylamino)propylj - phenyl] sulfonyl]benzamide (12.9 g) in methanol (65 ml) was added concentrated hydrochloric acid (22 ml), and the mixture was stirred at room temperature for 2.5 days. The resulting mixture was evaporated under reduced pressure, and to the residue was added acetone (130 ml) followed by being stirred for 2 hours. The precipitates were collected by filtration, washed with acetone and dried in vacuo to give 5- [ [4- ( 3-aminopropyl) henyl] sulfonyl] -2-benzyloxybenzamide (4.4 g). (+)ESI-MS m/z: 425 (M+H)⁺

Preparation 38 To a solution of (2-phenoxyethyl)formamide (6.0 g) and 5- (chlorosulfonyl) -2-hydroxybenzamide (8.6 g) in nitrobenzene (60 ml) was added aluminium chloride (17.0 g) by portions at room temperature under nitrogen, and the mixture was stirred at 50°C for 2.5 hours. The resulting mixture was cooled to room temperature, and to this one were added ice, ethyl acetate and IN hydrochloric acid. After being stirred for 2 hours followed by separation, to the organic layer was added water, and the mixture was adjusted pH to 8 with IN sodium hydroxide. After separation, to the aqueous layer was added ethyl acetate, and the mixture was adjusted pH to 5 with IN hydrochloric acid. After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/ methanol = 20:1 to 20:3) to give 5-[[4-[2- ( formylamino ) ethoxy]phenyl ] sulfonyl] -2-hydroxybenzamide (5.1g). (+)ESI-MS m/z: 387 (M+Na)⁺

Preparation 39 To a solution of 5-fluoro-2-nitrobenzamide (10 g) in N,N-^'dimethylformamide (100 ml) were added 2,2,2-trifluoro-N- [2- (4-mercaptophenyl)ethyl]acetamide (8.1 g) and potassium carbonate (7.2 g) at room temperature under nitrogen, and the mixture was stirred at 60°C for 1.5 hours. The resulting mixture was poured into a mixture of water and ethyl acetate to give precipitates . The precipitates were collected by filtration, wash with ethyl acetate and dried in vacuo to give 2, 2,2-trifluoro-N-[2-[4- [ [ 3- (aminocarbonyl) -4- nitrophenyl] thio]phenyl]ethyl] acetamide (10.7 g) . (+)ESI-MS m/z: 436 (M+Na)⁺

Preparation 40 To a solution of 2 , 2 , 2-trifluoro-N- [ 2- [ 4- [ [ 3- ( aminocarbonyl) -4-nitrophenyl] thio]phenyl] ethyl] acetamide (10.7 g) in N,N- imethylformamide (100 ml) was added m- chloroperoxybenzoic acid (13.4 g) at 5°C under nitrogen, and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water to give precipitates. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2,2,2- trifluoro-N- [2- [4- [ [3- (aminocarbonyl) -4-nitrophenyl] - sulfonyl] henyl]ethyl] acetamide (12.5 g) . (+)ESI-MS m/z: 468 (M+Na)⁺

Preparation 41 To a solution of 2, 2, 2-trifluoro-N- [2- [4- [ [3- (aminocarbonyl) -4-nitrophenyl] sulfonyl]phenyl]ethyl] - acetamide (12.5 g) in a mixture of N,N-dimethylformamide (40 ml), ethanol (80 ml) and water (40 ml) were added reduced iron (4.7 g) and ammonium chloride (750 mg) at room temperature under nitrogen, and the mixture was refluxed for 80 minutes'. The insoluble materials were removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. After separation, the organic layer was washed successively with water two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 20:1 to 10:1) to give 2,2, 2-trifluoro-N- [2- [4- [ [4-amino-3- (aminocarbonyl)phenyl] - sulfonyl]phenyl]ethyl] acetamide (9.5 g) . (+)ESI-MS m/z: 438 (M+Na)⁺

Preparation 42 To a solution of 2, 2, 2-trifluoro-N- [2- [ 4- [ [4-amino-3-

(aminocarbonyl)phenyl] sulfonyl]phenyl]ethyl] acetamide (4.0 g) in a mixture of methanol (200 ml) and water (12 ml) was added potassium carbonate (6.7 g) at room temperature, and the mixture was stirred at the same temperature for 2.5 days. The insoluble materials were removed by filtration, and the fitrate was concentrated to about 100 ml under reduced pressure. This one was treated with anhydrous magnesium sulfate, and the filtrate was evaporated under reduced pressure. The residue was pulverized with diisopropyl ether, collected by filtration and dried in vacuo to give 2-amino- 5- [ [4- (2-aminoethyl)phenyl] sulfonyl]benzamide (2.4 g) . (+)ESI-MS m/z: 320 (M+H)⁺

Preparation 43 To a solution of (3-phenylpropyl)formamide (5.0 g) and 5- (chlorosulfonyl) -2-hydroxybenzamide (7.2 g) in nitrobenzene (50 ml) was added aluminum chloride (14.3 g) by portions at room temperature under nitrogen, and the mixture was stirred at 90°C for 4.5 hours. The resulting mixture was cooled to room temperature, and to this one were added ice, ethyl acetate and IN hydrochloric acid. After being stirred for 2 hours followed by separation, to the organic layer was added water, and the mixture was adjusted pH to 8 with IN sodium hydroxide. After separation, to the aqueous layer was added ethyl acetate, and the mixture was adjusted pH to 1.3 with IN hydrochloric acid. After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 5- [ [4- [3- (formylamino)propyl]phenyl] sulfonyl] -2-hydroxybenzamide (10 g) . (+)ESI-MS m/z: 363 (M+H)⁺

Example 28 A mixture of 2- (benzyloxy) -5- [ [ 4- [ 3- [ [ ( 2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino]propyl]phenyl] sulfonyl] - benzamide (125 mg) and 10% palladium on activated carbon (50% wet, 6.3 mg) in a mixture of chlorobenzene (7 ml) and methanol (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 10 hours. After removal of palladium on activated carbon by filtration, the filtrate was evaporated under reduced pressure followed by dryness in vacuo to give 5- [ [4- [3- [ [ ( 2R) -2- (3-chloro- phenyl) -2-hydroxyethyl] amino]propyl] phenyl] sulfonyl] -2- hydroxybenzamide hydrochloride (115 mg) . NMR (DMSO-d₆, d): 1.85-2.1 (2H, m) , 3.65-3.4 (6H, m) , 4.95-5.1 (IH, m). 7.08 (IH, d, J=5.8 Hz), 7.3-7.55 (6H, m), 7.8-8.0 (3H, m) , 8.53 (IH, d, J=2.2 Hz) (+)ESI-MS m/z: 489 (M-HC1+H)⁺

Example 29 The following compounds were obtained according to a similar manner to that of Example 28.

(1) 5-[ [4-[3-[ [ (2R)-2- (4-Chlorophenyl) -2-hydroxyethyl ] - amino ]propyl]phenyl] sulfonyl ] -2-hydroxybenzamide hydrochloride NMR (DMSO-d₆, d) : 1.85-2.1 (2H, m) , 2.65-3.3 (6H, m) , 4.85-5.0 (IH, m) , 7.05-7.15 (IH, m) , 7.35-7.5 (6H, m) , 7.8-8.0 (3H, m) , 8.53 (IH, d, J=2.1 Hz) (+)ESI-MS m/z: 489 (M-HC1+H)⁺

(2) 5-[[4-[2-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]- amino]ethoxy]phenyl] sulfonyl] -2-hydroxybenzamide hydrochloride NMR (DMSO-d₆, d) : 3.0-3.6 (4H, m) , 4.3-4.45 (2H, m) , 4.9-5.1 (IH, m), 7.05-8.0 (10H, m) , 8.51 (IH. d, J=2.3 Hz) (+)ESI-MS m/z: 491, 493 (M-HC1+H)⁺

(3) 2-Hydroxy-5-[ [4-[2-[ [( 2R) -2-hydroxy-2-phenylethyl ] - amino ] -2-methylpropyl ]phenyl ] sulfonyl ]benzamide hydrochloride NMR (DMSO-d₆, d) : 1.2 (6H, s), 2.9-3.5 (4H, m) , 4.85- 5.0 (IH, m), 7.10 (IH, d, J=8.7 Hz), 7.25-7.55 (7H, m), 7.85-8.0 (3H, m) , 8.55 (IH, d, J=2.3 Hz) ( + )ESI-MS m/z: 469 (M-HC1+H)^"*^"

(4) 5-[[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]- • amino ] -2-methylpropyl]phenyl] sulfonyl ] -2-hydroxy- benzamide hydrochloride NMR (DMSO-d₆, d) : 1.21 (6H, s), 3.0-3.4 (4H, m) , 4.9- 5.05 (IH, m), 7.10 (IH, d, J=8.7 Hz), 7.35-7.6 (6H, m) , 7.85-8.0 (3H, m) , 8.55 (IH, d, J=2.2 Hz) (+)ESI-MS m/z: 503, 505 (M-HC1+H)⁺

Example 30 The following compounds were obtained according to a similar manner to that of Example 27.

( 1 ) 2-Hydroxy- 5-[[4-[3-[[(2R)-2-hydroxy-2- (3-pyridyl) - ethyl] amino]propyl ]phenyl] sulfonyl ]benzamide dihydrochloride NMR (DMSO-d₆, d) : 1.85-2.1 (2H, m) , 2.75-3.5 (6H, m) , 5.1-5.3 (IH, m), 7.10 (IH, d, J=8.8 Hz), 7.48 (2H, d, J=8.2 Hz), 7.8-8.0 (4H, m) , 8.41 (IH, d, J=8.1 Hz), 8.53 (IH, d, J=2.3 Hz), 8.75-8.9 (2H, m) ( + )ESI-MS m/z: 456 (M-2HC1+H)^"1"

(2) 2-Amino-5-[ [4-[2-[ [ ( 2R) -2-hydroxy-2- ( 3-pyridyl) ethyl]_,- amino ] ethyl ]phenyl ] sulfonyl] benzamide trihydrochloride NMR (DMSO-d₆, d) : 3!θ-3.5 (6H, m) , 5.2-5.35 (IH, m) , 6.79 (IH, d, J=8.9 Hz), 7.48 (IH, d, J=8.3 Hz), 7.59 (IH, dd, J=8.8, 2.0 Hz), 7.90 (2H, d, J=8.2 Hz), 8.02 (IH, dd, J=8.0, 5.6 Hz), 8.14 (IH, d, J=2.0 Hz), 8.52 (IH, d, J=8.2 Hz), 8.8-8.95 (2H, m) (+)ESI-MS m/z: 441 (M-3HC1+H)⁺ ( 3 ) 2-Hydroxy-N- ( 2-hydroxyethyl)-5-[[4-[2-[[(2R)-2-hydroxy- 2- (6-methyl-3-pyridyl) ethyl] mino] ethyl]phenyl] - sulfonyl]benzamide dihydrochloride NMR (DMSO-d₆, d) : 2.69 (3H, s), 3.0-3.9 (10H, m) , 5.1- 5.25 (IH, m) , 7.13 (IH, d, J=8.7 Hz), 7.52 (2H, d, J=8.2 Hz), 7.7-8.0 (4H, m) , 8.25-8.4 (IH, m) , 8.55 (IH, d, J=2.3 Hz), 8.70 (IH, m) (+)ESI-MS m/z: 500 (M-2HC1+H)⁺

Example 31 ' The following compound was obtained according to a similar manner to that of Example 2. 5-[ [4-[2-[Benzyl[ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] amino ] ethyl]phenyl ] sulfonyl] -2- (benzyloxy)benzole acid (-)ESI-MS m/z: 655, 657 (M-H)^"

Example 32 The following compounds were obtained according to a similar manner to that of Example 39.

(1) 2-(Benzyloxy)-5-[[4-[2-[ [( 2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl] amino] ethoxy]phenyl ] sulfonyl] benzamide (+)ESI-MS m/z: 581, 583 (M+H)⁺

(2) 2-(Benzyloxy)-5-[[4-[2-[ [ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] amino]ethoxy]phenyl] sulfonyl]benzamide (+)ESI-MS m/z: 604, 606 (M+Na)⁺

(3) 2- (Benzyloxy) -5- [ [4-[2-[ [ ( 2R) -2-hydroxy-2- phenylethyl]amino]ethoxy]phenyl] sulfonyl]benzamide (+)ESI-MS m/z: 457 (M+H)⁺ ( 4 ) 2- ( Benzyloxy)-5-[[4-[2-[[(2R)-2-(3-fluorophenyl ) - 2- hydroxyethyl]amino ]ethyl]phenyl] sulfonyl]benzamide (+)ESI-MS m/z: 549 (M+H)⁺

( 5 ) 2- ( Benzyloxy)-5-[[4-[2-[[(2R)-2-(6-chloro-3-pyridyl ) -2- hydroxyethyl] amino ] -2-methylpropyl ]phenyl] sulfonyl ] - benzamide (+)ESI-MS m/z: 594, 596 (M+H)⁺

(6) 2- (Benzyloxy) -5- [[ 4- [ 2- [ [ ( 2R) -2- (3-chlorophenyl) -2- hydroxyethyl ] mino ] -2-methylpropyl ]phenyl ] sulfonyl] - benzamide (+)ESI-MS m/z: 593, 595 (M+H)⁺

( 7 ) 2- ( Benzyloxy)-5-[[4-[2-[[(2R)-2-hydroxy-2-phenylethyl] ■ amino] -2-methylpropyl ] phenyl ] sulfonyl ]benzamide (+)ESI-MS m/z: 559 (M+H)⁺

Example 33 A mixture of 2-amino-5- [ [4- (2-aminoethyl)phenyl ] - sulfonyl]benzamide (400 mg) and ( 2R) -2- ( 3-chlorophenyl) - oxirane (194 mg) in dimethylsulfoxide (2 ml) was stirred at 70°C for 20 hours. To the resulting mixture were added hydrogen chloride (4N in ethyl acetate) and diethyl ether to deposit. After decantation, the deposits were washed with diethyl ether and dried in vacuo. The deposits were purified by reverse phase column chromatography followed by treatment of IN hydrochloric acid to give 2-amino-5- [ [4- [ 2- [ [ (2R) - 2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] - phenyl] sulfonyl]benzamide dihydrochloride (163 mg) . NMR (DMSO-d₆, d) : 2.9-3.4 (6H, m) , 4.9-5.05 (IH, m) , 6.79 (IH, d, J=8.9 Hz), 7.2-7.6 (7H, m) , 7.89 (2H, d, J=8.2 Hz), 8.14 (IH, d, J=2.1 Hz) (+)ESI-MS m/z: 474, 476 (M-2HC1+H)⁺ Example 34 A mixture of 2- (benzyloxy) -5- [ [4- [2- [ [ (2R) -2- (6-chloro- 3-pyridyl) -2-hydroxyethyl ] amino ] ethoxy] phenyl ] sulfonyl ] - benzamide (346 mg), ammonium formate (225 mg) and 10% palladium on activated carbon (50% wet, 104 mg) in a mixture of ethanol (10 ml), tetrahydrofuran (1 ml) and water (0.7 ml) was refluxed for 30 minutes. Palladium on activated carbon was removed by filtration and evaporated under reduced pressure. The residue was purified by reverse phase column chromatography followed by treatment with IN hydrochloric acid to give 2-hydroxy-5- [ [4- [2- [ [ (2R) -2-hydroxy-2- (3- pyridyl ) ethyl ] amino ] ethoxy]phenyl] sulfonyl ]benzamide dihydrochloride (206 mg) . NMR (DMSO-d₆, d) : 3.0-4.0 (4H, m) , 4.3-4.55 (2H, m) , 5.15-5.3 (IH, m), 7.08 (IH, d, J=8.7 Hz), 7.18 (2H, d, J=8.9 Hz), 7.8-8.0 (4H, m) , 8.37 (IH, d, J=8.0 Hz), 8.51 (IH, d, J=2.2 Hz), 8.75-8.9 (2H, m) (+)ESI-MS m/z: 458 (M-2HC1+H)⁺

Example 35 The following compounds were obtained according to a similar manner to that of Example 33.

(1) 2-Amino-5-[[4-[2-[ [ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] amino ] ethyl]phenyl] sulfonyl] benzamide dihydrochloride NMR (DMSO-d₆, d) : 2.95-3.35 (6H, m) , 5.0-5.2 (IH, m) , 6.79 (IH, d, J=8.8 Hz), 7.4-7.65 (5H, m) , 7.8-7.95 (2H, m) , 8.14 (IH, d, J=2.1 Hz), 8.44 (IH, d, J=2.3 Hz) (+)ESI-MS m/z: 475, 477 (M-2HC1+H)⁺

(2) 2-Hydroxy-5-[ [4-[2-[ [ ( IS, 2R) -2-hydroxy- 1-methyl-2- phenylethyl] amino ] ethyl ]phenyl] sulfonyl ] benzamide hydrochloride NMR (DMSO-dg, d) : 0.93 (3H, d, J=6.7 Hz), 3.05-3.6 (5H, m), 5.15-5.2 (IH, m) , 7.09 (IH, d, J=8.7 Hz), 7.2- 7.4 (5H, m), 7.55 (2H, d, J=8.3 Hz), 7.9-8.0 (3H, m) , 8.54 (IH, d, J=2.2 Hz) (+)ESI-MS m/z: 455 (M-HC1+H)⁺

Example 36 The following compounds were obtained according to a similar manner to that of Example 3.

(1) 5-[[4-[2-[Benzyl[(2R)-2-(6-chloro-3-pyridyl)-2- hydroxyethyl] amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy) -N-methylbenzamide (+)ESI-MS m/z: 692, 694 (M+Na)⁺

(2) 5-[ [4-[2-[Benzyl[ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] amino ] ethyl] phenyl] sulfonyl ] -2- (benzyloxy) -N-ethylbenzamide NMR (DMSO-d₆, d) : 0.93 (3H, d, J=6.7 Hz), 3.05-3.6 (5H, m), 5.15-5.2 (IH, m) , 7.09 (IH, d, J=8.7 Hz), 7.2- 7.4 (5H, m) , 7.55 (2H, d, J=8.3 Hz), 7.9-8.0 (3H, m) , 8.54 (IH, d, J=2.2 Hz) (+)ESI-MS m/z: 706, 708 (M+Na)⁺

(3) 5-[[4-[2-[Benzyl [ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] amino ] ethyl] phenyl ] sulfonyl ] -2- (benzyloxy) -N- ( 2-hydroxyethyl)benzamide (+)ESI-MS m/z: 722, 724 (M+Na)⁺

(4) 5-[ [4-[2-[Benzyl[ ( 2R) -2-hydroxy-2- ( 6-methyl-3- pyridyl)ethyl] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzamide (+)ESI-MS m/z: 636 (M+H)⁺ (5) 5- [ [ 4- [ 2- [Benzyl [ ( 2R) -2-hydroxy- 2 - ( 6-methyl-3- pyridyl ) ethyl ] amino ] ethyl] phenyl ] sulfonyl ] -2- (benzyloxy) -N-methylbenzamide (+)ESI-MS m/z: 650 (M+H)⁺

(6) 5-[ [4-[2-[Benzyl[ ( 2R) -2-hydroxy-2- ( 6-methyl-3- pyridyl ) ethyl ] amino ] ethyl] phenyl ] sulfonyl ] -2- (benzyloxy) -N- (2-hydroxyethyl)benzamide (+)ESI-MS m/z: 680 (M+H)⁺

(7) 5-[ [ 4- [2- [Benzyl [(2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl]phenyl ] sulfonyl ] -2- (benzyloxy) -3-methylbenzamide (+)ESI-MS m/z: 669, 671 (M+H)⁺

(8) 5-[[4-[2-[ Benzyl [ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl ] amino] ethyl ]phenyl ] sulfonyl ] -2- (benzyloxy) -3-methylbenzamide (+)ESI-MS m/z: 670, 672 (M+H)⁺

(9) 5-[ [ 4- [2- [Benzyl[(2R) -2 -(3-chlorophenyl ) -2- hydroxyethyl] mino] ethyl]phenyl ] sulfonyl] -2- (benzyloxy) -3-methoxybenzamide (-)ESI-MS m/z: 683, 685 (M-H)^"

(10) 5-[ [4-[2-[Benzyl[(2R)-2-(6-chloro-3-pyridyl)-2- hydroxyethyl ] amino] ethyl]phenyl ] sulfonyl] -2- (benzyloxy) -3-methoxybenzamide (-)ESI-MS m/z: 684, 686 (M-H)^"

(11) 5-[ [ 4- [2- [Benzyl [(2R) -2- (3-chlorophenyl ) -2- hydroxyethyl] amino ]ethyl]phenyl] sulfonyl] -2- (benzyloxy) -3-propylbenzamide (+)ESI-MS m/z: 697, 699 (M+H)⁺ (12) 5-[ [4-[2-[Benzyl[(2R)-2-(6-chloro-3-pyridyl)-2- hydroxyethyl ] amino ] ethyl ] phenyl ] sulfonyl ] -2- (benzyloxy) -3-propylbenzamide (+)ESI-MS m/z: 698, 700 (M+H)⁺

(13) 5-[ [4-[2-[Benzyl[(2R)-2-(3-fluorophenyl)-2- hydroxyethyl ] amino ] ethyl]phenyl] sulfonyl] -2- (benzyloxy) -3-methylbenzamide (+)ESI-MS m/z: 697, 699 (M+H)⁺

(14) 3-[ [4-[2-[Benzyl[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl ] amino ] ethyl ]phenyl] sulfonyl ] -2- (benzyloxy) -5-methylbenzamide (+)ESI-MS m/z: 669, 671 (M+H)⁺

(15) 3-[ [4-[2-[Benzyl[(2R)-2-(6-chloro-3-pyridyl)-2- hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy) - 5-methylbenzamide (+)ESI-MS m/z: 670, 672 (M+H)⁺

Example 37 To a mixture of 5- [ [ 4- [ 2- [benzyl[ (2R) -2- ( 6-chloro-3- pyridyl ) -2-hydroxyethyl] amino ] ethyl] phenyl] sulfonyl] -2- (benzyloxy) -N-methylbenzamide (104 mg) , hydrogen chloride (4N in 1,4-dioxane, 0.078 ml), and 10% palladium on activated carbon (50% wet, 30 mg) in methanol (2 ml) was added 1 , 4-cyclohexadiene (0.51 ml) at 50°C under nitrogen, and the mixture was refluxed for 12 hours. Palladium on activated carbon was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by reverse phase column chromatography followed by treatment with IN hydrochloric acid to give 2-hydroxy-5- [ [4- [ 2 - [ [ ( 2R ) -2-hydroxy-2- ( 3-pyridyl) ethyl] amino ] ethyl ]phenyl ] - sulfonyl] -N-methylbenzamide dihydrochloride (58 mg) . NMR (DMSO-dg, d) : 2.82 (3H, d, J=4.5 Hz), 3.0-3.6 (6H, c m) , 4.9-5.05 (IH, m) , 7.03 (IH, d, J=8.8 Hz), 7.35-7.55 (3H, m) , 7.75-7.95 (4H, m) , 8.46 (IH, d, J=2.3 Hz), 8.53 (IH, dd, J=4.8, 1.'5 Hz), 8.60 (IH, d, J=1.8 Hz) (+)ESI-MS m/z: 456 (M-2HC1+H)⁺

Example 38 The following compounds were obtained according to a similar manner to that of Example 37.

(1) N-Ethyl-2-hydroxy-5- [ [4- [2- [ [ ( 2R) -2-hydroxy-2- ( 3- pyridnyl) ethyl] amino] ethyl ]phenyl ] sulfonyl] benzamide dihydrochloride NMR (DMSO-dg, d): 1.15 (3H, t, J=7.2 Hz), 3.05-3.45 (8H, m), 5.15-5.3 (IH, m) , 7.12 (IH, d, J=8.8 Hz), 7.52 (2H, d, J=8.3 Hz), 7.8-8.0 (4H, m) , 8.38 (IH, d, J=8.1 Hz), 8.52 (IH, d, J=2.3 Hz), 8.75-8.9 (2H, m) (+)ESI-MS m/z: 470 (M-2HC1+H)⁺

(2) 2-Hydroxy-N-( 2-hydroxyethyl)- 5- [ [4-[2-[ [ (2R) -2-hydroxy- 2- ( 3-pyridyl.) ethyl]amino]ethyl]phenyl] sulfonyl] - benzamide dihydrochloride NMR (DMSO-dg, d) : 3.0-3.7 (10H, m) , 5.15-5.3 (IH, m) , 7.13 (IH, d, J=8.7 Hz), 7.52 (2H, d, J=8.3 Hz), 7.8-8.0 (4H, m), 8.39 (IH, d, J=8.0 Hz), 8.56 (IH, d, J=2.2 Hz), 8.75-8.9 (2H, m) (+)ESI-MS m/z: 486 (M-2HC1+H)⁺ (3) 2-Hydroxy-5-[ [4- [2- [ [ (2R) -2-hydroxy-2- (3-pyridyl) - ethyl] amino] -2-methylpropyl ]phenyl ] sulfonyl ]benzamide dihydrochloride NMR (DMSO-dg, d): 1.24 (6H, s), 3.0-3.6 (4H, m) , 5.25- 5.4 (IH, m) , 7.13 (IH, d, J=8.8 Hz), 7.48 (2H, d, J=8.3 Hz), 7.8-8.15 (5H, m) , 8.5-8.7 (2H, m) , 8.87 ( IH , d , J=5 . 2 Hz ) , 8 . 9 - 9 . 1 ( IH , m ) ( + ) ESI -MS m/ z : 470 (M- 2HC1+H ) ⁺

Example 39 A mixture of 5- [ [4- ( 3-aminopropyl)phenyl] sulfonyl] -2- (benzyloxy)benzamide (300 mg) and (2R) -2-phenyloxirane (85 mg) in a mixture of acetonitrile (6 ml) and N,N- dimethylformamide (2 ml) was stirred at 70°C for 30 minutes. The resulting mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 20:1 to 8:1) to give 2- (benzyloxy) -5-[[4-[3-[[ (2R) -2-hydroxy-2-phenylethyl] amino] - propyl]phenyl] sulfonyl]benzamide (62 mg) . (+)ESI-MS m/z: 545 (M+H)⁺ I

Example 40 To a solution of 5- [ [4- [2- [benzyl[ (2R) -2- (6-chloro-3- pyridyl) -2-hydroxyethyl] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzole acid (1.0 g) in N,N-dimethylformamide (10 ml) were added potassium carbonate (273 mg) and iodoethane

(261 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water two times and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/ethyl acetate = 1:0 to 10:1) to give ethyl 5- [ [ 4- [ 2- [benzyl[ ( 2R) -2- ( 6-chloro-3- pyridyl) -2-hydroxyethyl]amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoate (869 mg) . (+)ESI-MS m/z: 685, 687 (M+H)⁺

Example 41 To a solution of ethyl 5- [ [ 4- [ 2- [benzyl[ (2R) -2- (6- chloro-3-pyridyl ) -2-hydroxyethyl ] amino ] ethyl ]phenyl ] - sulfonyl] -2- (benzyloxy)benzoate (854 mg) in tetrahydrofuran (17 ml) were added tetrakis( triphenylphosphine)palladium(O) (72 mg) and methylzine chloride (2M in tetrahydrofuran, 3.74 ml) at room temperature under nitrogen, and the mixture was stirred at 80°C for 4 hours. The resulting mixture was poured into a mixture of an aqueous solution (30 ml) of ethylenediaminetetraacetic acid disodium salt (3.1 g) , and ethyl acetate, and then the mixture was stirred for 20 minutes. To this one was added saturated aqueous sodium bicarbonate to be made basic. After separation, the organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel

(chloroform/ethyl acetate = 5:1 to 2:1) to give ethyl 5-[[4- [ 2- [benzyl[ ( 2R) -2-hydroxy-2- ( 6-methyl-3-pyridyl)ethyl] - amino ] ethyl]phenyl] sulfonyl] -2- (benzyloxy)benzoate (618 mg) . (+)ESI-MS m/z: 665 (M+H)⁺

Example 42 The following compounds were obtained according to a similar manner to that of Example 43.

(1) 2-Hydroxy-5-[ [4-[2-[ [ ( 2R) -2-hydroxy-2-phenylethyl] - amino ] ethoxy]phenyl ] sulfonyl]benzamide hydrochloride NMR (DMSO-dg, d): 2.9-3.5 (4H, m) , 4.3-4.45 (2H, m) , 4.9-5.0 (IH, m), 7.08 (IH, d, J=8.7 Hz), 7.18 (2H, d, J=8.8 Hz), 7.25-7.55 (4H, m) , 7.85-8.0 (3H, m) , 8.1-8.2 (IH, m), 8.51 (IH, d, J=2.3 Hz) (+)ESI-MS m/z: 457 (M-HC1+H)⁺

(2) 5-[[4-[2-[ [ (2R) -2- (3-Fluorophenyl ) -2-hydroxyethyl ]- amino] ethyl]phenyl] sulfonyl] -2-hydroxybenzamide hydrochloride NMR (DMSO-dg, d) : 2.9-3.7 (6H, m) , 4.95-5.15 (IH, ) , 7.05-7.7 (7H, m) , 7.85-8.1 (3H, m) , 8.54 (IH, d, J=2.2 Hz) (+)ESI-MS m/z: 459 (M-HC1+H)⁺

(3) 2-Hydroxy-5-[ [4-[2-[ [ ( 2R) -2-hydroxy-2- ( 6-methyl-3- pyridyl )ethyl] amino ] ethyl ]phenyl ] sulfonyl]benzamide dihydrochloride NMR (DMSO-dg, d) : 2.70 (3H, s), 2.9-3.9 (6H, m) , 5.1- 5.3 (IH. m) , 7.10 (IH, d, J=8.7 Hz), 7.52 (2H, d, J=8.2 Hz), 7.8-8.0 (4H, m) , 8.35 (IH, d, J=8.2 Hz), 8.53 (IH. d, J=2.2 Hz), 8.71 (IH, br s) (+)ESI-MS m/z: 456 (M-2HC1+H)⁴ (4) 2-Hydroxy-5-[ [4-[2-[ [ (2R)-2-hydroxy-2-(6-methyl-3- pyridyl) ethyl ] amino] ethyl] phenyl] sulfonyl] -N- methylbenzamide dihydrochloride NMR (DMSO-dg, d) : 2.70 (3H, s), 2.83 (3H, d, J=4.5 Hz), 3.0-3.9 (6H, m), 5.1-5.3 (IH, m) , 7.12 (IH, d, J=8.8 Hz), 7.42 (2H, d, J=8.3 Hz), 7.8-8.0 (4H, ) , 8.49 (IH, d, J=2.4 Hz), 8.71 (IH, d, J=1.5 Hz) (-t-)ESI-MS m/z: 470 (M-2HC1+H)⁺

(5) 2-Hydroxy-5-[ [4-[2-[ [ ( 2R) -2-hydroxy-2- ( 3-hydroxy- phenyl)ethyl ] amino ] ethyl]phenyl ] sulfonyl ]benzamide hydrochloride NMR (DMSO-dg, d) : 2.8-4.0 (6H, m) , 4.8-4.95 (IH, m) , 6.6-6.9 (3H, m), 7.0-7.25 (2H, m) , 7.50 (2H, d, J=8.3 Hz), 7.8-8.0 (3H, m) , 8.5-8.6 (IH, m) (+)ESI-MS m/z: 457 (M-HC1+H)⁺

Example 43 A mixture of 2- (benzyloxy) -5- [ [4- [3- [ [ ( 2R) -2-hydroxy-2- phenylethyl] amino]propyl] phenyl] sulfonyl] benzamide (58 mg) , hydrogen chloride (10% in methanol, 0.040 ml) and 10% palladium on activated carbon (50% wet, 12 mg) in methanol (2 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 3 hours. After removal of palladium on activated carbon by filtration, the filtrate was evaporated under reduced pressure. The residue was . purified by reverse phase column ehromatograpy followed by treatment of IN hydrochloric acid to give 2-hydroxy-5- [[4-[3-[[(2R)~2-hydroxy-2-phenylethyl] amino ]propyl] - phenyl] sulfonyl]benzamide hydrochloride (20 mg) . NMR (DMSO-dg, d) : 1.85-2.1 (2H, m) , 2.6-3.2 (6H, m) , 4.85-5.0 (IH, m), 7.09 (IH, d, J=8.7 Hz), 7.25-7.5 (6H, m) , 7.8-7.95 (3H, m) , 8.15-8.2 (IH, m) , 8.53 (IH, d, J=2.3 Hz) (+)ESI-MS m/z: 455 (M-HC1+H)⁺

Example 44 A solution of ethyl 5- [ [4- [2- [benzyl [ (2R) -2-hydroxy-2- ( 6 -methyl-3-pyridyl ) ethyl] amino ] ethyl]phenyl] sulfonyl ] -2- (benzyloxy)benzoate (605 mg) and IN sodium hydroxide (1.8 ml) in methanol (12 ml) was stirred at room temperature for 6 hours . To the resulting mixture were added IN hydrochloric acid (1.8 ml) and water, and the aqueous layer was extracted with a mixture of chloroform and methanol (5:1). The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 20:1 to 10:1) to give 5-[[4-[2- [benzyl[ (2R) -2-hydroxy-2- (6-methyl-3-pyridyl) ethyl] amino] - ethyl]phenyl ] sulfonyl] -2- (benzyloxy)benzoic acid (545 mg) . (-)ESI-MS m/z: 635 (M-H)^"

Example 45 To a solution of tert-butyl [2- [ 4- [ [3- (aminocarbonyl) - 4- (methylamino) phenyl] sulfonyl ]phenyl ] ethyl ] [ ( 2R) -2- ( 3- chlorophenyl) -2- (tetrahydro-2H-pyran-2-yloxy) ethyl] carbamate (213 mg) in methanol (4.3 ml) was added a catalytic amount of p-toluenesulfonic acid at room temperature, and the mixture was stirred at the same temperature for 7 hours . The resulting mixture was poured into saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol = 50:1 to 30:1) to give tert-butyl [2- [4- [[ 3- (aminocarbonyl) -4- (methylamino )phenyl] sulfonyl ]phenyl] ethyl] [ ( 2R) -2- ( 3- chlorophenyl) -2-hydroxyethyl] carbamate (179 mg) . (+)ESI-MS m/z: 610, 612 (M+Na)⁺

Example 46 To a solution of tert-butyl [2- [4- [ [3- (aminocarbonyl) - 4- (methylamino )phenyl] sulfonyl ]phenyl] ethyl ] [ ( 2R) -2- ( 3- chlorophenyl) -2-hydroxyethyl] carbamate (175 mg) in 1,4- dioxane (1 ml) was added hydrogen chloride (4N in 1,4- dioxane, 2 ml) at room temperature, and the mixture was stirred at the same temperature for 8.5 hours . The resulting mixture was decanted and washed with ethyl acetate followed by dryness in vacuo to give 5-[[4-[2-[[(2R)-2-(3- chlorophenyl ) -2-hydroxyethyl ]amino]ethyl]phenyl] sulfonyl ] -2- (methylamino)benzamide dihydrochloride (150 mg) . NMR (DMSO-d₆, d) : 2.82 (3H, d, J=4.2 Hz), 2.9-3.4 (6H, m) , 4.85-5.0 (IH, m) , 6.74 (IH, d. J=9.1 Hz), 7.3- 7.55 (6H, m), 7.73 (IH, dd, J=9.0, 2.1 Hz), 7.91 (2H, d, J=8.3 Hz), 8.16 (IH, d, J=2.1 Hz) (+)ESI-MS m/z: 488, 490 (M-2HC1+H)⁺

Example 47 The following compounds were obtained according to a similar manner to that of Example 1. (1) Methyl 5- [[ 4- [ 2- [benzyl[ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl ]phenyl ] sulfonyl ] - 2- (benzyloxy) -3-methylbenzoate (+)ESI-MS m/z: 684, 686 (M+H)⁺

(2) Methyl 5- [ [ 4- [ 2- [benzyl[ (2R) -2- (6-chloro-3-pyridyl) -2- hydroxyethyl ] amino ] ethyl ]phenyl ] sulfonyl] - 2- (benzyloxy) -3-methylbenzoate (+)ESI-MS m/z: 685, 687 (M+H)⁺

(3) Methyl 5- [[ 4- [2- [benzylf ( 2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl ] amino ] ethyl]phenyl ] sulfonyl ] -2- (benzyloxy) -3-methoxybenzoate (-)ESI-MS m/z: 698, 700 (M-H)^"

(4) Methyl 5- [ [4- [2- [benzyl[ (2R) -2- (6-chloro-3-pyridyl) -2- hydroxyethyl ] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy) -3-methoxybenzoate (-)ESI-MS m/z: 699 (M-H)^"

(5) Methyl 5- [[ 4- [ 2- [benzylf ( 2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl] amino] ethyl]phenyl ] sulfonyl ] -2- (benzyloxy) -3-propylbenzoate (+)ESI-MS m/z: 734, 736 (M+Na)⁺

(6) Methyl 5- [ [4- [ 2- [benzyl[ ( 2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl ] amino] ethyl]phenyl ] sulfonyl] -2- (benzyloxy) -3-propylbenzoate (+)ESI-MS m/z: 535, 537 (M+Na)⁺

(7) Methyl 5- [ [ 4- [ 2- [benzyl[ ( 2R) -2- (3-fluorophenyl) -2- hydroxyethyl ] amino ] ethyl]phenyl ] sulfonyl ] -2- (benzyloxy) -3-methylbenzoate (+)ESI-MS m/z: 668 (M+H)⁺ (8) Methyl 3- [[ 4- [ 2- [benzyl[ ( 2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl ] amino ] ethyl ]phenyl] sulfonyl ] -2- (benzyloxy) -5-methylbenzoate (+)ESI-MS m/z: 684, 686 (M+H)⁺

(9) 5- [ [ 4- [ 2- [Benzyl [ ( 2R) -2- [ 3- (benzyloxy)phenyl ] -2- hydroxyethyl] amino ] ethyl ]phenyl ] sulfonyl ] -2- (benzyloxy)benzamide (+)ESI-MS m/z: 727 (M+H)⁺

(10) Methyl 3- [ [4- [ 2- [benzyl[ (2R) -2- (6-chloro-3-pyridyl) -2- hydroxyethyl] amino ] ethyl]phenyl ] sulfonyl] -2- (benzyloxy) -5-methylbenzoate (+)ESI-MS m/z: 686 (M+H)⁺

Example 48 The following compounds were obtained according to a similar manner to that of Preperation 22.

(1) 5-[ [4-[2-[Benzyl[(2R)-2-(6-chloro-3-pyridyl)-2- hydroxyethyl]amino ] ethyl ]phenyl] sulfonyl ] -2- (benzyloxy) -3-methylbenzoic acid (-)ESI-MS m/z: 669, 671 (M-H)^"

(2) 5-[ [4- [2- [Benzyl[(2R) -2- (3-chlorophenyl) -2- hydroxyethyl ] amino ] ethyl]phenyl ] sulfonyl ] -2- (benzyloxy) -3-methylbenzoic acid (-)ESI-MS m/z: 668, 670 (M-H)^"

(3) 5-[ [4-[2-[Benzyl[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl ] amino ] ethyl ]phenyl ] sulfonyl ] -2- (benzyloxy) -3-methoxybenzoic acid (-)ESI-MS m/z: 684, 686 (M-H)^"

(4) 5-[ [4-[2-[Benzyl[(2R)-2-(6-chloro-3-pyridyl)-2- hydroxyethyl ] amino] ethyl ] phenyl ] sulfonyl] - 2- (benzyloxy) -3-methoxybenzoic acid (-)ESI-MS m/z: 685. 687 (M-H)^"

(5) 5-[ [ 4- [2- [Benzyl[(2R) -2- (3-chlorophenyl) -2- hydroxyethyl ] amino] ethyl ]phenyl ] sulfonyl ] -2- (benzyloxy) -3-propylbenzoic acid (-)ESI-MS m/z: 696, 698 (M-H)^"

(6) 5-[ [4-[2-[Benzyl[(2R)-2-(6-chloro-3-pyridyl)-2- hydroxyethyl ] amino] ethyl]phenyl ] sulfonyl ] -2- (benzyloxy) -3-propylbenzoic acid (-)ESI-MS m/z: 697, 699 (M-H)^"

(7) 5-[ [4-[2-[Benzyl[(2R)-2-(3-fluorophenyl)-2- hydroxyethyl ] amino] ethyl] phenyl ] sulfonyl] -2- (benzyloxy) -3-methylbenzoic acid (-)ESI-MS m/z: 652 (M-H)^"

(8) 3-[ [4-[2-[Benzyl[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl] amino] ethyl]phenyl ] sulfonyl] -2- (benzyloxy) -5-methylbenzoic acid (-)ESI-MS m/z: 668, 670 (M-H)^"

(9) 3-[ [4-[2-[Benzyl[(2R)-2-(6-chloro-3-pyridyl)-2- hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2- (benzyloxy) -5-methylbenzoic acid (-)ESI-MS m/z: 669, 671 (M-H)^"

Example 49 A mixture of 5- [ [4- [2- [benzyl [( 2R) -2- (3-chlorophenyl) - 2-hydroxyethyl] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy) -3- methylbenzamide (331 mg) , hydrogen chloride ( 4N in 1,4- dioxane, 0.247 ml) and 10% palladium on activated carbon (50% wet, 16 mg) in a mixture of chlorobenzene (2.3 ml) and methanol (1 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 5 hours. After removal of palladium on activated carbon by filtration, the filtrate was evaporated and dried in vacuo to give 5- [ [4- [2- [ [ (2R) -2- ( 3-chlorophenyl) -2-hydroxyethyl] amino] - ethyl]phenyl ] sulfonyl] -2-hydroxy-3-methylbenzamide hydrochloride (259 mg) . NMR (DMSO-dg, d) : 2.19 (3H, s), 2.9-3.55 (6H, m) , 4.9- 5.1 (IH, m), 7.3-7.6 (6H, m) , 7.85-8.0 (3H, m) , 8.46 (IH, d, J=2.0 Hz) (+)ESI-MS m/z: 489 (M-HC1+H)⁺

Example 50 To a mixture of 5- [ [4- [2- [benzyl[ (2R) -2- (6-chloro-3- pyridyl ) -2-hydroxyethyl] amino ] ethyl]phenyl] sulfonyl] -2-

(benzyloxy) -3-methyIbenzamide (286 mg), hydrogen chloride (4N in 1,4-dioxane, 0.213 ml), and 10% palladium on activated carbon (50% wet, 86 mg) in methanol (9 ml) was added 1, 4-cyclohexadiene (0.60 ml) at 50°C under nitrogen, and the mixture was stirred at 70°C for 3 hours. Palladium on activated carbon was removed by filtration. After IN hydrochloric acid (1 ml) was added to the filtrate, the mixture was evaporated and dried in vacuo to give 2-hydroxy- 5-[ [4-[2-[ [ (2R)-2-hydroxy-2- (3-pyridyl)ethyl]amino]ethyl ]- phenyl] sulfonyl] -3-methyIbenzamide dihydrochloride (231 mg) . NMR (DMSO-dg. d): 2.19 (3H, s), 3.0-3.5 (6H, m) , 5.15- 5.35 (IH. m), 7.42 (2H. d, J=8.3 Hz), 7.8-8.0 (4H, m) , 8.4-8.5 (2H, m) , 8.75-8.9 (2H, m) (+)ESI-MS m/z: 456 (M-2HC1+H)⁺

Example 51 The following compounds were obtained according to a similar manner to that of Example 49.

(1) 5-[ [4-[2-[ [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]- amino ] ethyl ] phenyl ] sulfonyl ] -2-hydroxy-3-methoxybenzamide hydrochloride NMR (DMSO-dg, d): 2.9-3.5 (6H, m) , 3.87 (3H, s), 4.9- 5.05 (IH, m) , 7.3-7.6 (7H, m) , 7.98 (2H, d, J=8.2 Hz), 8.19 (IH, d, J=1.9 Hz) (+)ESI-MS m/z: 505 (M-HC1+H)⁺

(2) 5-[ [4-[2-[ [ (2R) -2-(3-Chlorophenyl ) -2-hydroxyethyl ]- amino ] ethyl ] phenyl] sulfonyl ] -2-hydroxy-3-propyl- benzamide hydrochloride NMR (DMSO-dg, d) : 0.87 (3H, t, J=7.2 Hz), 1.4-1.7 (2H, m) , 2.57 (2H, t, J=7.1 Hz), 2.9-3.45 (6H, m) , 4.9- 5.1 (IH, m) , 7.3-7.65 (6H, m) , 7.82 (IH, d, J=1.8 Hz), 7.94 (2H, d, J=8.2 Hz), 8.45 (IH, d, J=2.0 Hz) (+)ESI-MS m/z: 517, 519 (M-HC1+H)⁺

(3) 3-[[4-[2-[ [(2R) -2- ( 3-Chlorophenyl) -2-hydroxyethyl ]- amino] ethyl]phenyl] sulfonyl] -2-hydroxy-5-methyl- benzamide hydrochloride NMR (DMSO-dg, d) : 2.34 (3H, s), 2.9-3.7 (6H, m) , 4.95- 5.1 (IH, m), 7.3-7.6 (5H, m) , 7.8-8.0 (3H, m) , 8.09 (IH, m) (+)ESI-MS m/z: 489, 491 (M-HC1+H)⁺

Example 52 The following compounds were obtained according to a similar manner to that of Example 50.

(1) 2-Hydroxy-5-[[4-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)- ethyl] amino ] ethyl ]phenyl ] sulfonyl ] -3-methoxybenzamide dihydrochloride NMR (DMSO-dg, d): 3.05-3.45 (6H, m) , 3.87 (3H, s), 5.15-5.3 (IH, m) , 7.45-7.6 (3H, m) , 7.88 (IH, dd, J=7.9, 5.4 Hz), 7.98 (2H, d, J=8.2 Hz), 8.19 (IH, d, J=1.8 Hz), 8.35 (IH, d, J=8.0 Hz), 8.7-8.9 (2H, m) (+)ESI-MS m/z: 472 (M-2HC1+H)⁺

(2) 2-Hydroxy-5-[ [4- [ 2- [[( 2R) -2-hydroxy-2- ( 3-pyridyl) - ethyl ] amino ] ethyl ]phenyl ] sulfonyl ] -3-propylbenzamide dihydrochloride NMR (DMSO-dg, d): 0.87 (3H, t, J=7.3 Hz), 1.45-1.65 (2H, m), 2.58 (2H, t, J=7.1 Hz), 3.05-3.5 (6H, m) , 5.15-5.3 (IH, m) , 7.52 (2H, d, J=8.3 Hz), 7.8-8.0 (4H. m), 8.2-8.4 (IH, m) , 8.46 (IH, d, J=2.2 Hz), 8.75-8.9 (2H, m) (+)ESI-MS m/z: 484 (M-2HC1+H)⁺

(3) 2-Hydroxy-3-[ [4- [2- [ [ (2R) -2-hydroxy-2- ( 3-pyridyl) - ethyl] amino ] ethyl] phenyl ] sulfonyl ] -5-methylbenzamide dihydrochloride NMR (DMSO-dg, d) : 2.34 (3H, s), 3.05-3.5 (6H, m) , 2.25-5.4 (2H, m) , 7.50 (2H, d, J=8.3 Hz), 7.8-8.15 (5H\ m), 8.55 (IH, d, J=8.0, Hz), 8.85-8.95 (2H, m) (+)ESI-MS m/z: 456 (M-2HC1+H)⁺

Example 53 A mixture of 5- [ [ 4- [2- [benzyl[ ( 2R) -2- ( 3-fluorophenyl) - 2-hydroxyethyl] amino] ethyl]phenyl] sulfonyl] -2- (benzyloxy) -3- methyIbenzamide (295 mg)¹, hydrogen chloride (4N in 1,4- dioxane, 0.226 ml) and 10% palladium on activated carbon (50% wet, 15 mg) in methanol (3 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 2.5 hours. After removal of palladium on activated carbon by filtration, the filtrate was evaporated and dried in vacuo to give 5- [ [4- [2- [[ (2R) -2- (3-fluorophenyl ) -2-hydroxyethyl ] amino ] ethyl ]phenyl ] sulfonyl ] -2- hydroxy-3-methylbenzamide hydrochloride (226 mg). NMR (DMSO-dg, d) : 2.19 (3H, s), 2.9-3.3 (6H, m) , 5.0- 5.15 (IH, m), 7.1-7.65 (6H, m) , 7.85-8.0 (3H, m) , 8.47 (IH, d, J=2.0 Hz) (+)ESI-MS m/z: 473 (M-HC1+H)⁺

Example 54 To a solution of 5- [ [4- (3-aminopropyl)phenyl] sulfonyl] - 2-benzyloxybenzamide (300 mg) in dimethylsulfoxide (1 ml) was added N,N' -bis (trimethylsilyl)urea (267 mg) at room temperature under nitrogen, and the mixture was stirred at 65°C for 80 minutes. To this one was added a solution of

(2R) -2- (3-chlorophenyl) oxirane (131 mg) in dimethylsulfoxide (1 ml) at room temperature, and the mixture was sitrred at 65°C for 40 hours. The resulting mixture was diluted with tetrahydrofuran (2 ml ) , and to this one was added concentrated hydrochloric acid (0.33 ml) at 5°C. After being stirred at room temperature for 1 hour, the resulting mixture was cooled to 5°C, and then a mixture of chloroform and methanol (4:1), and saturated aqueous sodium bicarbonate were added. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chlomatography on silica gel (chloroform/methanol = 20:1 to 20:3) to give 2- (benzyloxy) -5- [[ 4- [3- [[( 2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino]propyl]phenyl] sulfonyl ] - benzamide (133 mg) . (+)ESI-MS m/z: 579, 581 (M+H)⁺

Example 55 The following compounds were obtained according to a similar manner to that of Example 54.

(1) 2- (Benzyloxy) -5- [ [4-[3-[ [ ( 2R) -2- ( 4-chlorophenyl) -2- hydroxyethyl ] amino ] propyl ] henyl ] sulfonyl ]benzamide (+)ESI-MS m/z: 579, 581 (M+H)⁺ (2) 2- (Benzyloxy) -5- [ [4-[3-[ [ ( 2R) -2- ( 6 -chloro-3-pyridyl) -2- hydroxyethyl] amino ]propyl ] phenyl ] sulfonyl ]benzamide NMR (DMSO-dg, d) : 0.87 (3H, t, J=7.3 Hz), 1.45-1.65 (2H, m), 2.58 (2H, t, J=7.1 Hz), 3.05-3.5 (6H, m) , 5.15-5.3 (IH, m), 7.52 (2H. d, J=8.3 Hz), 7.8-8.0 (4H, m), 8.2-8.4 (IH, m) , 8.46 (IH, d, J=2.2 Hz), 8.75-8.9 (2H, m) (+)ESI-MS m/z: 580, 582 (M+H)⁺

Claims

1. A compound of the formula [ I ] :

wherein X is bond or -O- , R¹ is

in which R⁵ is hydrogen, halogen, hydroxy or protected hydroxy, and R^> is hydrogen or (lower alkylsulfonyl) amino, or

in which R' is hydrogen, halogen or lower alkyl, R² is hydrogen or lower alkyl, R³ is hydrogen or an amino protective group. is

in which R⁸ is hydrogen or halogen, and R' is carboxy, carbamoyl or mono(or di) ( lower)alkylcarbamoyl ,

in which R¹⁰ is amino, mono(or di) (lower)alkylamino, hydroxy or protected hydroxy, R¹¹ is hydrogen or lower alkyl, R¹² is hydrogen, lower alkyl, cyclo( lower) alkyl, hydroxy( lower) - alkyl, mono(or di or tri)halo(lower)alkyl, lower alkylsulfonyl or aryl, and R¹^ is hydrogen, lower alkyl or lower alkoxy, or

in which R¹³ is hydrogen or methyl, provided that (i) when R¹³ is hydrogen, then R⁵ is not hydrogen or halogen , or (ii) when R¹³ is methyl, then R⁵ is not hydrogen, and R¹⁴ and R¹⁵ are each independently hydrogen or lower alkyl, or a prodrug thereof or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein R¹ is

in which R⁵ is hydrogen, halogen or hydroxy, and R^> is hydrogen or (lower alkylsulfonyl) - amino, or

in which R⁷ is hydrogen, halogen or lower alkyl, R² is hydrogen or lower alkyl, R³ is hydrogen,

in which R¹^ is amino, mono(or di)(lower)alkylamino or hydroxy, R¹¹ is hydrogen or lower alkyl, R¹² is hydrogen, lower alkyl, cyclo(lower)alkyl, hydroxy( lower) alkyl, mono(or di or tri)halo(lower)alkyl, lower alkylsulfonyl or aryl, and R¹⁶ is hydrogen, lower alkyl or lower alkoxy, and R¹⁴ and R¹⁵ are each independently hydrogen or lower alkyl .

A compound of claim 2 , wherein X is bond.

R¹ is

in which R⁵ is hydrogen, halogen or hydroxy, and R^ is hydrogen, or

in which R⁷ is hydrogen, halogen or lower alkyl, R² is hydrogen or lower alkyl, R³ is hydrogen.

in which R¹⁰ is amino or hydroxy, R¹¹ is hydrogen or lower alkyl, R¹² is hydrogen, lower alkyl, hydroxy(lower) alkyl or mono (or di or tri)halo(lower) alkyl, and R¹⁶ is hydrogen, lower alkyl or lower alkoxy, and R ⁴ and R^⁵ are each independently hydrogen.

4. A compound of claim 3, which is selected from a group of (1) 5- [ [4- [2- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino ] ethyl] phenyl ] sulfonyl] -2-hydroxy-N , - dimethylbenzamide, (2) 5-[ [4-[2-[ [(2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino ] ethyl]phenyl] sulfonyl ] -2-hydroxy-N- (2,2, 2-trifluoroethyl )benzamide , (3) 5-[ [4-[2-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxy- ethyl] amino] ethyl]phenyl] sulfonyl] -2-hydroxybenzamide, (4) 2-Amino-5-[ [4-[2-[ [ ( 2R) -2- ( 3-chlorophenyl) -2- hydroxyethyl]amino] ethyl]phenyl] sulfonyl]benzamide , (5) 2-Hydroxy-N- ( 2-hydroxyethyl) -5- [ [4-[2-[[(2R)-2- hydroxy-2- ( 3-pyridyl) ethyl] amino] ethyl] phenyl] - sulfonyl]benzamide, (6) 5-[ [4-[2-[ [ (2R) -2- (3-Fluorophenyl) -2-hydroxyethyl] amino] ethyl]phenyl] sulfonyl] -2-hydroxybenzamide, (7) 2-Hydroxy-5-[ [4-[2-[ [ ( 2R) -2-hydroxy-2- (3-hydroxy- phenyl)ethyl]amino] ethyl]phenyl] sulfonyl]benzamide, (8) 5-[ [4- [2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2- ( ethyl- amino)benzamide, (9) 5-[ [4- [2- [[(2R) -2- (3-Chlorophenyl) -2-hydroxyethyl]amino]ethyl]phenyl] sulfonyl] -2-hydroxy-3- methylbenzamide, (10) 5-[ [4-[2-[ [ (2R) -2- ( 3-Chlorophenyl) -2-hydroxyethyl ]amino] ethyl]phenyl] sulfonyl] -2-hydroxy-3- methoxybenzamide, and (11) 2-Hydroxy-5-[ [4-[2-[ [( 2R) -2-hydroxy-2- (3-pyridyl) - ethyl] amino] ethyl]phenyl] sulfonyl] -3-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

5. A process for preparing a compound of claim 1, or a salt thereof, which comprises, (i) reacting a compound [II] of the formula:

wherein R¹ and R² are each defined in claim 1 , with a compound [III] of the formula:

wherein X, R³, R⁴ , R¹⁴ and R¹⁵ are each as defined in claim 1, or a salt thereof, to give a compound [I] of the formula:

wherein X, R¹, R² , R³ , R⁴ , R¹⁴ and R¹⁵ are each as defined in claim 1 , or a salt thereof,

(ii) subjecting a compound [la] of the formula:

wherein X, R¹, R² , R⁴ , R¹⁴ and R¹⁵ are each as defined in claim 1, and Rr_j is an amino protective group, or a salt thereof, to elimination reaction of the amino protective group, to give a compound [lb] of the formula:

wherein X, R¹, R², R⁴ , R¹⁴ and R¹⁵ are each as defined in claim 1 , or a salt thereof, and

(iii) reacting a compound [lc] of the formula:

wherein X, R¹, R², R³ , R¹⁰, R¹⁴, R¹⁵ and R¹⁶ are each as defined in claim 1 , or a reactive derivative at the carboxy group or a salt thereof, with a compound [IV] of the formula: _Rn HN [IV] ^_R12 wherein R¹¹ and R¹² are each as defined in claim 1, or a salt thereof, to give a compound [Id] of the formula:

wherein X, R¹, R², R³ , R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵ and R¹⁶ are each as defined in claim 1 , or a salt thereof.

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

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

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

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as selective β₃ adrenergic receptor agonists.

10. A method for the prophylactic and/or the therapeutic treatment of overactive bladder or micturiation disorder which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.