NOVEL AMINOALKYLBENZOTHIAZEPINE DERIVATIVES AND USES THEREOF

Abstract

The present invention relates to a novel aminoalkylbenzothiazepine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating constipation comprising the same as an active ingredient.

Claims

1. A compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof: ##STR00039## wherein R.sub.1 is hydroxy, carboxy, or hydroxysulfonyl(C.sub.1-4 alkyl); R.sub.2 and R.sub.3 are each independently hydrogen, C.sub.1-4 alkyl, hydroxy (C.sub.1-4 alkyl), carbamoyl(C.sub.1-4 alkyl), carboxy, carboxy(C.sub.1-4 alkyl), (C.sub.5-10 heteroaryl)(C.sub.1-4 alkyl), or (C.sub.5-10 aryl)(C.sub.1-4 alkyl), or R.sub.2 and R.sub.3, taken together with the respective carbon atom to which they are attached, form C.sub.3-7 cycloalkylene; R.sub.4 is hydrogen or carboxy(C.sub.1-4 alkyl); R.sub.5 is hydrogen, halogen, (C.sub.1-4 alkyl)thio, (C.sub.1-4 alkyl)amino, or di(C.sub.1-4 alkyl)amino; R.sub.6 and R.sub.7 are each independently C.sub.1-6 alkyl; R.sub.8 and R.sub.9 are each independently hydrogen, hydroxy, C.sub.1-4 alkoxy, C.sub.1-4 alkyl, halogen, nitro, cyano, amino, (C.sub.1-4 alkyl)amino, di(C.sub.1-4 alkyl)amino, acetamido, formyl, C.sub.1-4 alkanoyl, carboxy, carbamoyl, (C.sub.1-4 alkyl)carbamoyl, di(C.sub.1-4 alkyl)carbamoyl, carbamoyloxy, (C.sub.1-4 alkyl)carbamoyloxy, di(C.sub.1-4 alkyl)carbamoyloxy, (C.sub.1-4 alkyl)sulfonyloxy, sulfamoyloxy, (C.sub.1-4 alkyl)sulfamoyloxy, or di(C.sub.1-4 alkyl)sulfamoyloxy; Q is C.sub.5-10 aryl or C.sub.5-10 heteroaryl; and n is an integer of 0 to 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is hydroxy, carboxy, or hydroxysulfonyl(C.sub.1-4 alkyl); R.sub.2 and R.sub.3 are each independently hydrogen, C.sub.1-4 alkyl, hydroxy(C.sub.1-4 alkyl), carbamoyl(C.sub.1-4 alkyl), carboxy, carboxy(C.sub.1-4 alkyl), or (C.sub.5-10 heteroaryl)(C.sub.1-4 alkyl), or R.sub.2 and R.sub.3, taken together with the respective carbon atom to which they are attached, form C.sub.3-7 cycloalkylene; R.sub.4 is hydrogen or carboxy(C.sub.1-4 alkyl); R.sub.5 is (C.sub.1-4 alkyl)thio; R.sub.6 and R.sub.7 are each independently C.sub.1-6 alkyl; R.sub.8 and R.sub.9 are each independently hydrogen, hydroxy, halogen, or C.sub.1-4 alkoxy; Q is C.sub.5-10 aryl; and n is an integer of 0 to 3.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is hydroxy, carboxy, or hydroxysulfonylmethyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.2 and R.sub.3 are each independently hydrogen, carboxy, methyl, isobutyl, carbamoylmethyl, carboxymethyl, carboxyethyl, hydroxymethyl, imidazolylmethyl, indolylmethyl, or ethyl, or R.sub.2 and R.sub.3, taken together with the respective carbon atom to which they are attached, form cyclopropylene.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.4 is hydrogen, carboxymethyl, or carboxyethyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.5 is methylthio, ethylthio, or dimethylamino.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.6 and R.sub.7 are both butyl or both ethyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sub.8 and R.sub.9 are each independently hydrogen, hydroxy, methoxy, methyl, ethyl, fluoro, chloro, nitro, cyano, amino, methylamino, ethylamino, dimethylamino, acetyl, carboxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, carbamoyloxy, methylcarbamoyloxy, dimethylcarbalnoyloxy, methylsulfonyloxy, sulfamoyloxy, methylsulfamoyloxy, or dimethylsulfamoyloxy.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is phenyl, pyridinyl, pyrimidinyl, or thiophenyl.

10. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from the group consisting of: 1) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid; 2) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid; 3) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)succinic acid; 4) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid; 5) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid; 6) 4-amino-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-4-oxobutanoic acid; 7) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid; 8) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-methylpropanoic acid; 9) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-(1H-imidazol-4-yl)propanoic acid; 10) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-(1H-indol-2-yl)propanoic acid; 11) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-4-methylpentanoic acid; 12) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid; 13) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic acid; 14) 3-((carboxymethyl)((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid; 15) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid; 16) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid; 17) 1-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid; 18) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid; 19) 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid; 20) 2-(((3,3-dibutyl-5-(4-hydroxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid; 21) 2-(((3,3-dibutyl-5-(3-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid; 22) 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid; 23) 2-(((3,3-dibutyl-5-(3-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid; 24) 2-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid; 25) 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid; 26) 1-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid; 27) 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid; 28) (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid; 29) (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic acid; and 30) 1-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid.

11. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound according to claim 10 or a pharmaceutically acceptable salt thereof.

13. A method for preventing or treating constipation in a subject in need thereof, the method comprising administering the compound according to claim 1 or a pharmaceutically acceptable salt thereof to the subject, thereby preventing or treating constipation.

14. A method for preventing or treating constipation in a subject in need thereof, the method comprising administering the compound according to claim 10 or a pharmaceutically acceptable salt thereof to the subject, thereby preventing or treating constipation.

Description

BEST MODE

[0088] Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are for illustrative purposes only, and the invention is not intended to be limited by these Examples.

[0089] Various methods for synthesizing the starting materials to synthesize the compounds of the present invention have been known, and if available on the market, the starting materials may be purchased from the providers. Examples of the reagents suppliers include Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, and Dae-Jung, but are not limited thereto. Additionally, all the materials on the commercial market were used without further purification, unless specified otherwise.

[0090] First, the compounds used for syntheses in Examples were prepared as described in Preparation Examples. Preparation Examples are exemplary embodiments of Reaction Scheme 1, and may be appropriately adjusted corresponding to the structures of the compounds in Examples.

Preparation Example 1: Preparation of 3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbaldehyde 1,1-dioxide

Step 1) Preparation of 2-(((2-amino-5-methoxyphenyl)thio)methyl)-2-butylhexanoic acid

[0091] ##STR00003##

[0092] 6-Methoxybenzo[d]thiazol-2-amine (25 g, 139.7 mmol) was added to 250 mL of 30% potassium hydroxide and stirred at 140° C. for 18 hours. The reaction mixture was checked with TLC to confirm the formation of 2-amino-5-methoxybenzenethiol, and cooled to room temperature. Then, 2-bromomethyl-2-butylhexanoate (44.6 g, 167.7 mmol) was added thereto and stirred at room temperature for about 17 hours. A saturated ammonium chloride solution and dichloromethane were added thereto, stirred for 10 minutes, and the dichloromethane layer was extracted, and this entire process was repeated three times. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated. The thus-obtained concentrated compound was charged with t-butyl methyl ether and 6 N HCl solution to extract an ester layer and then concentrated again. The concentrated compound was a brown solid, and hexane was added thereto, stirred, and filtered to obtain 25 g of an ivory solid with 51% yield.

Step 2) Preparation of 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one

[0093] ##STR00004##

[0094] 2-(((2-Amino-5-methoxyphenyl)thio)methyl)-2-butylhexanoic acid (25 g, 71.78 mmol) obtained in Step 1) was added to 900 mL of dichloromethane and cooled to −40° C. When the temperature reached −40° C., 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (41 g, 107.68 mmol; HATU) was slowly added thereto and stirred for about 10 minutes. Then, diisopropylamine (58.15 mL, 358.9 mmol) was added slowly dropwise thereto. Upon completion of the addition of diisopropylamine, the mixture was stirred for about 5 hours. A saturated ammonium chloride solution was added thereto and the dichloromethane layer was extracted, and this entire process was repeated three times. The extracted dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated to obtain 23 g of 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one. The thus-obtained compound was charged with 480 mL of dichloromethane and cooled to 0° C. Upon cooling, N-bromosuccinimide (14.51 g, 81.54 mmol) was slowly added thereto and stirred for about 4 hours. Then, a saturated ammonium chloride solution was added thereto and the dichloromethane layer was extracted. The extracted dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated compound was charged with 200 mL of a mixture of hexane and ethyl acetate (hexane:ethyl acetate=30:1) and further charged with 200 mL of hexane while stirring, and the resulting solid was filtered to obtain 14 g of 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one as a title compound, with 50% yield.

[0095] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.58 (s, 1H), 6.99 (d, J=2.8 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.77 (dd, J=8.8 Hz, 2.8 Hz, 1H), 3.78 (s, 3H), 2.97 (s, 2H), 1.78-1.85 (m, 2H), 1.55-1.62 (m, 2H), 1.18-1.30 (m, 8H), 0.87 (t, J=6.8 Hz, 6H).

Step 3) Preparation of 3,3-dibutyl-8-hydroxy-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide

[0096] ##STR00005##

[0097] 7-Bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one (5.77 g, 14.44 mmol) obtained in Step 2) was charged with iodobenzene (50 mL), copper iodide (0.55 g, 2.89 mmol), potassium carbonate (4 g, 28.9 mmol), and tris[2-(2-methoxyethoxy)ethyl]amine (0.5 mL, 1.44 mmol), stirred at room temperature for about 5 minutes, and refluxed at 190° C. for 17 hours. The resultant was cooled to room temperature, filtered with silica, and washed with hexane to remove iodobenzene. The silica-captured compound was eluted with ethyl acetate and dichloromethane, and the recovered solution was concentrated to obtain 5.8 g of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one. Lithium aluminum hydride (1.4 g, 36.88 mmol) was added to a 500 mL round-bottom flask and dried under vacuum. Diethyl ether (150 mL) was added thereto, cooled to −10° C., and then anhydrous sulfate (1 mL, 18.44 mmol) was added slowly dropwise thereto. The thus-obtained 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepine-4(5H)-one was dissolved in diethyl ether and added dropwise to the reaction flask. The resultant was stirred at room temperature for 2 hours, and charged with a saturated ammonium chloride solution to extract the diethyl ether layer. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 5 g of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine. The thus-obtained compound (5 g, 10.98 mmol) was charged with 75 mL of a mixed solvent (tetrahydrofuran:t-butanol=1:1), osmium tetroxide (0.07 g, 0.27 mmol), and N-methylmorpholine N-oxide (3.96 g, 32.94 mmol), and stirred at room temperature for 12 hours. A saturated ammonium chloride solution and dichloromethane were added thereto to extract the dichloromethane layer, and the extract was concentrated to obtain 3.55 g of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide as an ivory solid. The thus-obtained compound (3.55 g, 7.18 mmol) was charged with dimethylformamide (100 mL), sodium thiomethoxide (5.032 g, 71.79 mmol), and sodium borohydride (5.43 g, 143.6 mmol), and stirred at 60° C. for 15 hours. A saturated ammonium chloride solution and t-butyl methyl ether were added thereto to extract the ether layer, and this was concentrated. The concentrated compound was charged with hexane, and the solid was filtered to obtain 2.7 g of 3,3-dibutyl-8-hydroxy-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide, with 84% yield.

[0098] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31 (s, 1H), 7.16 (t, J=8 Hz, 2H), 6.92 (d, J=8 Hz, 2H), 6.84 (t, J=6.8 Hz, 1H), 6.67 (s, 1H), 3.61 (s, 2H), 3.07 (s, 2H), 2.15 (s, 3H), 1.28-1.44 (m, 4H), 1.97-1.19 (m, 8H), 0.74 (t, J=6.8 Hz).

Step 4) Preparation of 3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl trifluoromethanesulfonate

[0099] ##STR00006##

[0100] 3,3-Dibutyl-8-hydroxy-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide (2.7 g, 5.98 mmol) obtained in Step 3) was charged with dichloromethane (30 mL) and pyridine (0.63 mL, 7.77 mmol), and cooled to 0° C. Trifluoromethanesulfonic anhydride (1.3 mL, 7.77 mmol) was added slowly dropwise thereto and stirred at room temperature for 5 hours. A saturated ammonium chloride solution was added thereto to extract the dichloromethane layer, and then dried over anhydrous magnesium sulfate, filtered, and concentrated. The resultant was purified by silica column chromatography using a mixed solvent (hexane:ethyl acetate=8:1). As a result, 2.96 g of 3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl trifluoromethanesulfonate was obtained, with 86% yield.

[0101] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.81 (s, 1H), 7.39 (t, J=7.6 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 7.18 (d, J=7.2 Hz, 1H), 6.46 (s, 1H), 3.89 (s, 2H), 3.26 (s, 2H), 2.13 (s, 3H), 1.48-1.85 (m, 2H), 1.35-1.42 (m, 2H), 1.01-1.20 (m, 8H), 0.74 (t, J=6.8 Hz).

Step 5) Preparation of 3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbonitrile dioxide

[0102] ##STR00007##

[0103] 3,3-Dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl trifluoromethanesulfonate (2.96 g, 5.12 mmol) obtained in Step 4) was charged with dimethylformamide (60 mL), zinc powder (0.034 g, 0.512 mmol), zinc cyanide (0.66 g, 5.632 mmol), tris(dibenzylideneacetone)dipalladium (0.47 g, 0.51 mmol), and 1,1-bis(diphenylphosphino)ferrocene (0.34 g, 0.614 mmol), and stirred at 80° C. for 20 hours. The resultant was cooled to room temperature, and a saturated ammonium chloride solution and ethyl acetate were added to extract the ethyl acetate layer. The extracted ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated compound was purified by silica column chromatography using a mixed solvent (hexane:ethyl acetate=6:1) to obtain 1 g of the title compound, with 50% yield.

[0104] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.19 (s, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.24-7.31 (m, 3H), 6.26 (s, 1H), 4.02 (s, 2H), 3.30 (s, 2H), 2.11 (s, 3H), 1.26-1.58 (m, 4H), 0.83-1.19 (m, 8H), 0.74 (t, J=6.8 Hz).

Step 6) Preparation of 3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbaldehyde dioxide

[0105] ##STR00008##

[0106] 3,3-Dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbonitrile dioxide (1 g, 2.1 mmol) obtained in Step 5) was charged with dichloromethane, cooled to 0° C., and 5 mL of diisobutylaluminum hydride (DIBAL-H) was added slowly dropwise thereto. The resultant was heated to room temperature and stirred for 1 hour. Then, the resultant was again cooled to 0° C., charged with distilled water, ethyl acetate, and sodium potassium tartrate, and stirred for 30 minutes. After extracting the ethyl acetate layer, this was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated compound was purified by silica column chromatography using a mixed solvent (hexane:ethyl acetate=4:1) to obtain 600 mg of the title compound, with 63% yield.

[0107] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.91 (s, 1H), 8.37 (s, 1H), 7.46 (t, J=7.6 Hz, 2H), 7.26-7.30 (m, 3H), 6.27 (s, 1H), 4.08 (s, 2H), 3.34 (s, 2-1), 0.88-1.40 (m, 12H), 0.77 (t, J=6.8 Hz).

Example 1: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid

[0108] ##STR00009##

[0109] 3,3-Dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbaldehyde dioxide (31 mg, 0.067 mnol) obtained in Preparation Example 1 was added to 2 mL of dichloroethane, and ethyl glycine methyl ester hydrochloride (11 mg, 0.088 mmol) was added thereto, and stirred at room temperature for 20 minutes. Then, sodium triacetoxyborohydride (28 mg, 0.131 mmol) was added thereto and stirred at room temperature for 17 hours. Upon completion of the reaction, an extraction was performed by adding dichloromethane and distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified with PTLC (dichloromethane:methanol=50:1) to obtain 20.5 mg of ethyl 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetate, with 57% yield.

[0110] The thus-obtained compound (20.5 mg, 0.038 mmol) was added to 3 mL of a mixed solution (tetrahydrofuran:methanol:distilled water=1:1:1), charged with lithium hydroxide (16 mg, 0.40 mmol), and stirred at room temperature for 12 hours. Upon completion of the reaction, ethyl acetate and 1 N HCl were added thereto for extraction, and the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified with PTLC (dichloromethane:methanol=20:1) to obtain 10 mg of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid as the title compound (yield: 44%).

[0111] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.22 (s, 1H), 7.34 (t, J=7.6 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.12 (t, J=7.6 Hz, 1H), 6.47 (s, 1H), 4.46 (s, 2H), 3.73-3.93 (m, 4H), 3.33 (s, 2H), 2.15 (s, 3H), 1.47-1.52 (m, 2H), 1.33-1.39 (m, 2H), 1.08-1.15 (m, 4H), 1.00-1.03 (m, 4H), 0.78 (t, J=6.8 Hz, 6H).

Example 2: Preparation of 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid

[0112] ##STR00010##

[0113] The title compound was synthesized in a manner similar to that of Example 1, except that ethyl 3-aminopropanoate was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 65%).

[0114] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.14 (s, 1H), 7.38-7.34 (m, 2H), 7.26-7.22 (m, 2H), 7.17-6.97 (m, 1H), 6.46 (s, 1H), 4.35 (s, 2H), 3.88 (s, 2H), 3.26 (s, 4H), 2.93 (s, 2H), 2.15 (s, 3H), 1.60-1.46 (m, 2H), 1.40-1.29 (m, 2H), 1.14-0.99 (m, 8H), 0.81-0.74 (m, 6H).

Example 3: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)succinic acid

[0115] ##STR00011##

[0116] The title compound was synthesized in a manner similar to that of Example 1, except that diethyl aspartate was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 52%).

[0117] 1H NMR (400 MHz, CDCl.sub.3) δ 8.21 (s, 1H), 7.34 (s, 3H), 7.24 (s, 1H), 7.12 (s, 1H), 6.46 (s, 1H), 4.62-4.35 (m, 2H), 4.02-3.88 (m, 2H), 3.50-3.10 (m, 5H), 2.17 (s, 3H), 1.66-1.35 (m, 4H), 1.22-0.89 (m, 8H), 0.75 (s, 6H).

Example 4: Preparation of (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid

[0118] ##STR00012##

[0119] The title compound was synthesized in a manner similar to that of Example 1, except that diethyl alanine ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 61%).

[0120] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.16 (s, 1H), 7.32 (s, 2H), 7.16-7.12 (m, 3H), 6.45 (s, 1H), 4.24-4.19 (m, 2H), 3.81 (s, 2H), 3.52 (s, 1H), 3.27 (s, 2H), 2.09 (s, 3H), 1.52-1.42 (m, 5H), 1.41-1.25 (m, 2H), 1.24-0.92 (m, 8H), 0.88-0.65 (m, 6H).

Example 5: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid

[0121] ##STR00013##

[0122] The title compound was synthesized in a manner similar to that of Example 1, except that diethyl glutamine ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 36%).

[0123] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (s, 1H), 7.35-7.33 (m, 2H), 7.19-7.18 (m, 2H), 7.12-7.09 (m, 1H), 6.43 (s, 1H), 4.97 (d, J=14 Hz, 1H), 4.17 (d, J=15.2 Hz, 1H), 3.85 (s, 3H), 3.26 (s, 2H), 1.21-0.96 (m, 8H), 0.82-0.76 (m, 6H).

Example 6: Preparation of 4-amino-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-4-oxobutanoic acid

[0124] ##STR00014##

[0125] The title compound was synthesized in a manner similar to that of Example 1, except that diethyl arginine ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 23%).

[0126] MS: 576.25 [M+H]+.

Example 7: Preparation of (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid

[0127] ##STR00015##

[0128] The title compound was synthesized in a manner similar to that of Example 1, except that diethyl alanine ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 56%).

[0129] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.00 (s, 1H), 7.19-7.26 (m, 2H), 7.08-7.10 (m, 3H), 6.38 (s, 1H), 4.03-7.09 (m, 2H), 3.76 (s, 2H), 3.41 (s, 1H), 3.20 (s, 2H), 2.89-2.99 (m, 1H), 2.02 (s, 3H), 1.43 (s, 3H), 1.29-1.36 (m, 2H), 1.18-1.23 (m, 2H), 0.81-1.08 (m, 8H), 0.69-0.7 (m, 6H).

Example 8: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-methylpropanoic acid

[0130] ##STR00016##

[0131] The title compound was synthesized in a manner similar to that of Example 1, except that ethyl 2-amino-2-methylpropanoate was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 57%).

[0132] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.99 (s, 1H), 7.33 (t, J=7.6 Hz, 2H), 7.17-7.18 (m, 2H), 7.11-7.12 (m, 1H), 6.48 (s, 1H), 3.96 (s, 2H), 3.81 (s, 2H), 3.21 (s, 2H), 2.14 (s, 3H), 1.53 (s, 6H), 1.25-1.34 (m, 4H), 0.85-1.14 (m, 8H), 0.76 (t, J=6.8 Hz, 6H).

Example 9: Preparation of (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-(1H-imidazol-4-yl)propanoic acid

[0133] ##STR00017##

[0134] The title compound was synthesized in a manner similar to that of Example 1, except that ethyl histidine ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 43%).

[0135] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.77 (s, 1H), 7.54 (s, 1H), 7.28-7.30 (m, 2H), 7.04-7.11 (m, 3H), 6.78 (s, 1H), 6.38 (s, 1H), 3.78 (s, 4H), 3.41-4.11 (m, 2H), 3.18 (s, 2H), 2.94-2.98 (m, 1H), 1.86 (s, 3H), 1.27-1.43 (m, 4H), 0.82-1.10 (m, 8H), 0.71 (t, J=6.8 Hz, 6H).

Example 10: Preparation of (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-(1H-indol-2-yl)propanoic acid

[0136] ##STR00018##

[0137] The title compound was synthesized in a manner similar to that of Example 1, except that ethyl tryptophan ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 37%).

[0138] MS: 648.29 [M+H].sup.+.

Example 11: Preparation of (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo I[b][1,4]thiazepine-8-yl)methyl)amino)-4-methylpentanoic acid

[0139] ##STR00019##

[0140] The title compound was synthesized in a manner similar to that of Example 1, except that ethyl leucine ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 58%).

[0141] MS: 575.29 [M+H]+.

Example 12: Preparation of (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid

[0142] ##STR00020##

[0143] The title compound was synthesized in a manner similar to that of Example 1, except that diethyl glutamine ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 25%).

[0144] MS: 591.27 [M+H].sup.+.

Example 13: Preparation of (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic acid

[0145] ##STR00021##

[0146] The title compound was synthesized in a manner similar to that of Example 1, except that diethyl serine ester was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 45%).

[0147] MS: 549.25 [M+H]+.

Example 14: Preparation of 3-((carboxymethyl)((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid

[0148] ##STR00022##

[0149] The title compound was synthesized in a manner similar to that of Example 1, except that 3-((2-ethoxy-2-oxoethyl)amino)propanoate was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 49%).

[0150] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.16 (s, 1H), 7.34-7.43 (m, 2H), 7.27 (s, 2H), 7.12-7.16 (m, 1H), 6.45 (s, 1H), 4.60-4.72 (m, 2H), 4.48-4.59 (m, 211), 4.00-4.13 (m, 2H), 3.34 (s, 2H), 3.12-3.23 (m, 2H), 2.14 (s, 3H), 1.36-1.60 (m, 4H), 1.24-1.30 (m, 8H), 0.71 (t, J=6.8 Hz, 6H).

Example 15: Preparation of 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid

[0151] ##STR00023##

[0152] The title compound was synthesized in a manner similar to that of Example 1, except that diethyl 2,2′-azanediyldiacetate was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 41%).

[0153] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.02 (s, 1H), 7.32 (t, J=7.6 Hz, 2H), 7.21 (d, J=7.2 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H), 6.48 (s, 1H), 4.47 (s, 2H), 4.03 (s, 1H), 3.85 (m, 2H), 3.29 (s, 2H), 3.06-3.17 (m, 4H), 2.16 (s, 3H), 1.35-1.46 (m, 4H), 1.23-1.32 (m, 8H), 0.71 (t, J=6.8 Hz, 6H).

Example 16: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid

[0154] ##STR00024##

[0155] 3,3-Dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-carbonitrile dioxide (160 mg, 0.350 mmol) obtained in Step 5) of Preparation Example 1 was dissolved in 5 mL of a mixed solution (dichloromethane:diethyl ether=3:2). The resultant was cooled to 0° C., and lithium aluminum hydride (66 mg, 1.752 mmol) was added in divided allocations, and stirred at room temperature for 12 hours. Upon completion of the reaction, diethyl ether and distilled water were added thereto for extraction, and the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified with PTLC (dichloromethane:methanol=50:1) to obtain 40 mg of 8-aminomethyl-3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide (yield: 25%).

[0156] The thus-obtained compound (0.023 g, 0.05 mmol) was added to 5 mL of dichloromethane, and triethylamine (0.01 mL, 0.1 mmol) and 4-dimethylaminopyridine (0.003 g) were added thereto and stirred at room temperature for 10 minutes. The reaction solution was cooled to 0° C., slowly charged with ethyl 2-chloro-2-oxoacetate, and stirred at room temperature for 18 hours. An ammonium chloride solution and dichloromethane were added thereto to extract the dichloromethane layer. The extracted dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated compound (0.02 g) was charged with tetrahydrofuran (1 mL), methanol (1 mL), distilled water (1 mL), and lithium hydroxide (0.03 g), and stirred at room temperature for 12 hours. Then, 6 N HCl and dichloromethane were added thereto for extraction followed by concentration, and the concentrated compound was purified with PTLC (dichloromethane:methanol=13:1) to obtain 0.015 g of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid as the title compound (yield: 78%).

[0157] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (s, 1H), 7.25-7.33 (m, 2H), 6.97-7.11 (m, 3H), 6.50 (s, 1H), 3.72-4.40 (m, 2H), 3.19 (s, 2H), 2.50-2.68 (m, 2H), 2.06 (s, 3H), 1.27-1.43 (m, 4H), 0.93-1.20 (m, 8H), 0.71 (t, J=6.8 Hz, 6H).

Example 17: Preparation of 1-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid

[0158] ##STR00025##

[0159] The title compound was synthesized in a manner similar to that of Example 1, except that ethyl 1-aminocyclopropane carboxylate was used as a reactant instead of ethyl glycine methyl ester hydrochloride (yield: 52%).

[0160] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.11 (s, 1H), 7.42-7.35 (m, 2H), 7.21-7.15 (m, 2H), 7.13-7.12 (m, 1H), 6.49 (s, 1H), 4.53 (s, 2H), 3.88 (s, 2H), 3.24 (s, 2H), 2.04 (s, 3H), 1.68-1.61 (m, 2H), 1.55-1.48 (m, 2H), 1.21-0.92 (m, 12H), 0.78-0.71 (in, 6H).

Example 18: Preparation of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid

[0161] ##STR00026##

[0162] 8-Aminomethyl-3,3-dibutyl-7-methylthio-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine dioxide was prepared in the same manner as in Example 16. The compound (40 mg, 0.087 mmol) was dissolved in 4 mL of dichloromethane. The resultant was cooled to 0° C., triethylamine (36 μL, 0.260 mmol) was added slowly dropwise thereto, and stirred for 10 minutes. Bromoacetyl chloride (15 μL, 0.174 mmol) was added slowly dropwise thereto, and stirred at room temperature for 16 hours. Upon completion of the reaction, dichloromethane and an ammonium chloride solution were added thereto for extraction, and the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified with PTLC (dichloromethane:methanol=30:1) to obtain mg of 2-bromo-N-((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)acetamide (yield: 50%).

[0163] The thus-obtained compound (25 mg, 0.043 mmol) was dissolved in 3 mL of a mixed solution (ethanol:distilled water=1:1). Sodium sulfite (271 mg, 2.149 mmol) was added thereto and stirred at 80° C. for 17 hours. Upon completion of the reaction, the resultant was cooled to room temperature. Ethyl acetate and distilled water were added thereto for extraction, and the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified with PTLC (dichloromethane:methanol=10:1) to obtain 12.5 mg of 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid (yield: 50%).

[0164] MS: 583.20 [M+H].sup.+.

Example 19: Preparation of 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid

[0165] ##STR00027##

[0166] The title compound was synthesized in a manner similar to that of Example 1, except that 1-iodo-4-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene (yield: 64%).

[0167] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.01 (s, 1H), 7.13-7.15 (m, 2H), 6.80-6.89 (m, 2H), 6.31 (s, 1H), 4.22 (s, 2H), 3.70-3.81 (m, 5H), 3.42 (s, 2H), 3.21 (s, 2H), 2.08 (s, 3H), 1.30-1.55 (m, 4H), 0.86-1.06 (m, 8H), 0.71-0.76 (m, 6H).

Example 20: Preparation of 2-(((3,3-dibutyl-5-(4-hydroxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid

[0168] ##STR00028##

[0169] The title compound was synthesized in a manner similar to that of Example 1, except that 4-iodophenol was used in Step 3 of Preparation Example 1 instead of iodobenzene (yield: 37%).

[0170] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (s, 1H), 7.20 (d, J=8.8 Hz, 2H), 6.89 (d, J=8 Hz, 2H), 6.43 (s, 1H), 4.30 (s, 2H), 3.89-3.93 (m, 4H), 3.30-3.36 (m, 2H), 2.21 (s, 3H), 1.40-1.61 (m, 4H), 1.20-1.29 (m, 8H), 0.81 (t, J=6.8 Hz, 6H).

Example 21: Preparation of 2-(((3,3-dibutyl-5-(3-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid

[0171] ##STR00029##

[0172] The title compound was synthesized in a manner similar to that of Example 1, except that 1-iodo-3-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene (yield: 47%).

[0173] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.05 (s, 1H), 7.27-7.23 (m, 1H), 6.78-6.67 (m, 2H), 6.66-6.57 (m, 1H), 6.54 (s, 1H), 4.20 (s, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 3.42 (s, 2H), 3.29 (s, 2H), 1.53-1.47 (m, 2H), 1.43-1.32 (m, 2H), 1.24-1.04 (m, 8H), 0.88-0.78 (m, 6H).

Example 22: Preparation of 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid

[0174] ##STR00030##

[0175] The title compound was synthesized in a manner similar to that of Example 1, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0176] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.12 (s, 1H), 7.17-7.20 (m, 2H), 7.03 (t, J=8.4 Hz, 2H), 6.40 (s, 1H), 4.16 (s, 2H), 3.70 (s, 2H), 3.33 (s, 2H), 3.21 (s, 2H), 2.08 (s, 3H), 1.37-1.46 (m, 4H), 0.82-1.06 (m, 8H), 0.77 (t, J=6.8 Hz, 6H).

Example 23: Preparation of 2-(((3,3-dibutyl-5-(3-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid

[0177] ##STR00031##

[0178] The title compound was synthesized in a manner similar to that of Example 1, except that 1-fluoro-3-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0179] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.15 (s, 1H), 7.23-7.13 (m, 1H), 6.89-6.83 (m, 2H), 6.75-6.71 (m, 1H), 6.65 (s, 1H), 4.27 (s, 2H), 3.73 (s, 2H), 3.52 (s, 2H), 3.26 (s, 2H), 2.20 (s, 3H), 1.57-1.46 (m, 2H), 1.43-1.33 (m, 2H), 1.26-1.07 (m, 8H), 0.86-0.78 (m, 6H).

Example 24: Preparation of 2-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid

[0180] ##STR00032##

[0181] The title compound was synthesized in a manner similar to that of Example 1, except that 2-fluoro-4-iodo-1-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0182] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.10 (brs, 1H), 6.70-6.90 (brs, 3H), 6.30-6.50 (brs, 1H), 3.90-4.20 (brs, 2H), 3.30-3.89 (brs, 3H), 3.55-3.29 (brs, 2H), 3.45-2.95 (m, 4H), 1.98-2.22 (brs, 3H), 1.23-1.49 (m, 4H), 0.73-1.24 (8H), 0.73 (brs, 6H).

Example 25: Preparation of 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid

[0183] ##STR00033##

[0184] The title compound was synthesized in a manner similar to that of Example 18, except that 1-iodo-4-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0185] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.70 (s, 1H), 7.09-6.94 (m, 2H), 6.82-6.64 (m, 2H), 6.27 (s, 1H), 3.80-3.63 (m, 7H), 3.12 (s, 2H), 2.43 (s, 2H), 1.97 (s, 3H), 1.52-1.27 (m, 4H), 1.07-0.88 (m, 8H), 0.82-0.78 (m, 6H).

Example 26: Preparation of 1-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid

[0186] ##STR00034##

[0187] The title compound was synthesized in a manner similar to that of Example 17, except that 2-fluoro-4-iodo-1-methoxybenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0188] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.89 (s, 1H), 6.98-6.82 (m, 3H), 6.48 (s, 1H), 3.97 (s, 2H), 3.88 (s, 3H), 3.70 (s, 2H), 3.19 (s, 2H), 2.17 (s, 3H), 1.51-1.32 (m, 4H), 1.20-0.94 (m, 8H), 0.81-0.78 (m, 6H).

Example 27: Preparation of 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid

[0189] ##STR00035##

[0190] The title compound was synthesized in a manner similar to that of Example 16, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0191] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (s, 1H), 7.10 (brs, 2H), 6.95 (brs, 2H), 6.42 (s, 1H), 4.22-4.36 (m, 2H), 3.66-3.97 (m, 2H), 3.19-3.47 (m, 2H), 2.07 (s, 3H), 1.30-1.33 (m, 4H), 0.88-1.12 (m, 8H), 0.75-0.83 (m, 3H).

Example 28: Preparation of (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid

[0192] ##STR00036##

[0193] The title compound was synthesized in a manner similar to that of Example 4, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0194] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (s, 1H), 7.10 (brs, 2H), 6.95 (brs, 2H), 6.42 (s, 1H), 4.22-4.36 (m, 2H), 3.66-3.97 (m, 2H), 3.19-3.47 (m, 2H), 2.07 (s, 3H), 1.30-1.33 (m, 4H), 0.88-1.12 (m, 8H), 0.75-0.83 (m, 3H).

Example 29: Preparation of (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic acid

[0195] ##STR00037##

[0196] The title compound was synthesized in a manner similar to that of Example 13, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0197] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.15 (s, 1H), 7.17 (brs, 2H), 6.95 (brs, 2H), 6.51 (s, 1H), 4.36 (brs, 2H), 3.95 (brs, 2H), 6.63 (brs, 2H), 3.46 (s, 1H), 3.26 (brs, 2H), 2.01 (s, 3H), 1.25-1.43 (m, 4H), 0.70-0.87 (m, 8H), 0.59-0.67 (m, 3H).

Example 30: Preparation of 1-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid

[0198] ##STR00038##

[0199] The title compound was synthesized in a manner similar to that of Example 17, except that 1-fluoro-4-iodobenzene was used in Step 3 of Preparation Example 1 instead of iodobenzene.

[0200] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92 (s, 1H), 7.17-7.14 (m, 2H), 7.09-7.02 (m, 2H), 6.42 (s, 1H), 4.11 (s, 2H), 3.77 (s, 2H), 3.22 (s, 2H), 2.15 (s, 3H), 1.68-1.46 (m, 4H), 1.40-1.30 (m, 4H), 1.21-0.92 (m, 8H), 0.88-0.76 (in, 6H).

Experimental Example 1: Feces Excretion Time and Evaluation of Efficiency

[0201] Eight-week-old SD rats were purchased and allowed to adapt to breeding conditions under 12-hour illumination at 24° C. for 7 days. The rats were made to fast for 16 hours before the experimental day, and orally administered on the experimental day with a vehicle (0.5% methylcellulose) and a test material, which were prepared at a concentration of 0.2 mg/mL and a dose of 5 mg/kg, respectively. Thirty minutes after the administration, the rats fed with 3 g of a barium-containing diet were placed into a metabolism cage and observed to record the time required for the barium to be excreted as feces in each rat after being passed through the intestines for 10 hours. Additionally, the percentage of rats that excreted barium-containing feces within 10 hours were calculated, and the results are shown in Table 1 below.

TABLE-US-00001 TABLE 1 Feces excretion Percentage of subjects time (min) @ excreting feces within Example volume (mg/kg) 10 hours (%) Vehicle D C 1 C @ 0.1 B @ 0.1 B @ 1 A @ 1 A @ 5 A @ 5 18 B @ 1 B @ 1 19 C @ 1 A @ 1 B @ 5 A @ 5 20 C @ 0.1 A @ 0.1 B @ 1 A @ 1 A @ 5 A @ 5 22 B @ 0.1 A @ 0.1 B @ 1 A @ 1 A @ 5 A @ 5 24 C @ 1 A @ 1 A @ 5 A @ 5

[0202] Feces Excretion Time

[0203] A: 301-400 min, B: 401-500 min, C: 501-590 min, D: 591-600 min

[0204] Percentage of subjects excreting feces within 10 hours (%)

[0205] A: 76-100%, B: 50-75%, C: <50%

[0206] The reduction in feces excretion time and the increase in percentage of rats excreting feces within 10 hours are closely related to relief from constipation symptoms. As shown in Table 1, the experimental rats administered with the compounds of the present invention excreted feces within a reduced time and also a significantly higher percentage in the number of rats showed excretion of feces within 10 hours, compared to the control rats administered with a methylcellulose vehicle, which is known to prevent constipation by controlling intestinal functions. Additionally, when the administration dose of the compounds of the present invention was lowered to a level from 1/5 to 1/50, the resulting effects were shown to be equal to or better than that of the vehicle administration. This suggests that the compounds of the present invention can effectively prevent or treat constipation.