JP2000344753A - Azepane derivative and its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a marked glycosidase inhibitory activity and useful as a diabetes mellitus-treating agent, etc. SOLUTION: This azepane derivative is a compound of the formula [R1 to R4 are each OH, H, azido or a (substituted) amino and 2-3 of them are each OH], e.g. (3R, 4R, 5R, 6R)-hexahydro-3-azido-4,5,6-trihydroxy-1H-azepine. The compound of the formula is obtained by e.g. using pyranose as a raw material, converting primary hydroxyl group at 6 position to p-toluenesulfonyloxy group, etc., effecting sodium azide, etc., on it to form 6-azido-6-deoxypyranose, then performing a reductive aminoalkylation reaction by using palladium-carbon, etc., to obtain a tetrahydroxyazepane derivative, blocking a cyclic amino group and a part of hydroxyl groups with appropriate blocking groups, then converting the residual hydroxyl groups to desired hydrogen atom, azido group or a (substituted) amino group and then removing the blocking groups.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to azepane derivatives and salts thereof.

[0002]

2. Description of the Related Art Aza sugars (also referred to as sugar-type alkaloids and N-heterosaccharides) represented by nojirimycin, deoxynojirimycin, castanospermine, swaysonine, etc. have various glycosidase inhibitory activities, and Since it affects glycoprotein synthesis, it is expected to be useful in the fields of treatment of viral infections such as HIV, cancer metastasis, immunodeficiency and the like. On the other hand, these azasugars directly inhibit the digestive enzymes (glycosidases) to have a delayed effect on the absorption of carbohydrates, thereby reducing postprandial hyperglycemia. In the field of, usefulness is being confirmed. ["S
ci. Progress Oxford ", Vol. 74,
245 (1990)] However, most of the existing azasaccharides are derived from natural materials such as metabolites of microorganisms, and the research on the synthesis of some of their derivatives has been carried out. Contains polyhydroxypiperidine (6-membered ring amine)
, Polyhydroxypyrrolidines (5-membered ring amines) and those having a condensed ring structure having these as main skeletons. The azepan derivatives and their salts of the present invention are used as therapeutic agents for diabetes.

[0003]

An object of the present invention is to provide azepan derivatives and salts thereof.

[0004]

Means for Solving the Problems Accordingly, the present inventors have
As a result of various studies to achieve the above object, the present inventors have found that novel polyhydroxyazepanes (seven-membered amines) have a remarkable glycosidase inhibitory activity, and completed the present invention based on this finding. . That is, the present invention provides the following general formula (I)

Embedded image (Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydroxyl group, a hydrogen atom, an azido group or an amino group which may have a substituent, and R ^{1 to} R ⁴ (2 to 3 of which are hydroxyl groups) and salts thereof.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The azepan derivative represented by the general formula (I) of the present invention and
And its salts, R ¹, R^Two, R^Three, R^FourAre independent
Having a hydroxyl group, a hydrogen atom, an azide group or a substituent.
An amino group, and the R¹~ R^FourTwo of
~ 3 are hydroxyl groups. In addition, it may have a substituent
An amino group is, for example, an unsubstituted amino group,
Amino-substituted amino group, aralkyl-substituted amino group or
Means a sil-substituted amino group, and specific examples thereof include:
Amino group, methylamino group, dimethylamino group, ethyl
Amino group, diethylamino group, propylamino group, dip
Propylamino group, butylamino group, dibutylamino group,
Cyclohexylamino group, dicyclohexylamino group,
Cyclohexylmethylamino group, 2-hydroxyethyl
Amino group, 3-hydroxypropylamino group, benzyl
Amino group, dibenzylamino group, acetylamino group,
Lopionylamino group, butyrylamino group and the like.
You. In addition, the azepa represented by the general formula (I) of the present invention
Examples of the salt of the derivative include hydrochloric acid, sulfuric acid, nitric acid, and glue.
Inorganic acids such as phosphoric acid, methanesulfonic acid, benzenesulfone
Acid, organic sulfonic acid such as toluenesulfonic acid, or
Organic carbohydrates such as acid, acetic acid, succinic acid, tartaric acid and citric acid
And acid addition salts with acid. The general of the present invention
An azepan derivative represented by the formula (I) and a salt thereof were produced.
Any method can be used to fabricate, for example,
A method may be used.

Using a pyranose such as glucose, galactose or mannose as a raw material, a primary hydroxyl group at the 6-position is first converted to, for example, a p-toluenesulfonyloxy group or a naphthalenesulfonyloxy group by a known method. In a polar solvent, sodium azide or the like is allowed to act to form 6-azido-6-deoxypyranose, and then a reductive aminoalkylation reaction is performed using palladium-carbon or the like to obtain a tetrahydroxyazepane derivative . Next, the cyclic amino group and some hydroxyl groups of the tetrahydroxyazepane derivative are converted into, for example, a t-butyloxycarbonyl group, a benzyloxycarbonyl group, an isopropylidene group, a benzylidene group, a methoxymethyl group,
After protection with a protecting group such as an acetyl group or a t-butyldimethylsilyl group, the remaining unprotected hydroxyl group is converted to a desired hydrogen atom, an azide group or an amino group which may have a substituent by a known method. After the conversion, the azepane derivative represented by the general formula (I) and a salt thereof can be obtained by removing the protecting group.

A method for producing the azepane derivative represented by the general formula (I) and a salt thereof will be described below. First, examples of the starting material pyranose include, for example, commercially available D-glucopyranose, D-galactopyranose, D-mannopyranose, and the like. The primary hydroxyl group at the 6-position of pyranose is arylsulfonylated. For example, in the case of p-toluenesulfonylation, first, pyranose is dissolved in a solvent such as pyridine, and the amount of p-pyranose is 1 to 3 times the molar amount of the pyranose. Addition of -toluenesulfonyl chloride and reaction at a temperature usually in the range of -10 to 15 ° C for about 4 to 48 hours complete the p-toluenesulfonylation of the 6-hydroxyl group. If necessary, purification is performed according to a conventional method to obtain 6-Op-toluenesulfonylpyranose. In the case of performing other arylsulfonylation, similarly, arylsulfonyl chloride, arylsulfonyl bromide, and arylsulfonyl anhydride are allowed to act. After the arylsulfonylation, if necessary, a protecting group such as an acetyl group, a benzoyl group, a benzyl group, a methoxymethyl group, or an isopropylidene group may be introduced into the free hydroxyl group where pyranose remains, if necessary.

The 6-O-arylsulfonylpyranose thus obtained is dissolved in a polar solvent and
A 50-fold molar amount of sodium azide is added, usually 50-
When the reaction is carried out at a temperature in the range of 100 ° C. for about 2 to 12 hours, the arylsulfonyloxy group is replaced with an azide group.
6-Deoxypyranose is obtained. Examples of the polar solvent used in the substitution reaction include water, acetone, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, and the like. These may be used alone or as a mixture of two or more. You may. Examples of the method of purifying 6-azido-6-deoxypyranose that are performed as needed include column chromatography, crystallization, and the like. Further, as described above, when a protecting group is introduced into a free hydroxyl group where pyranose remains as necessary, a deprotection reaction is carried out by an ordinary method, following azidation. It is to be noted that, as in the case of a benzyl group or the like, which is deprotected under reducing conditions, if it can be removed simultaneously in the reduction reaction described below, it is not always necessary to deprotect here. The thus obtained 6-azido-6-deoxypyranose is dissolved in a solvent and a commercially available palladium-carbon (5-1 to 1) is dissolved.
(0% content) in the presence of ammonium formate for reduction, the reduction of azide groups to amino groups and the reductive amination reaction of pyranose to formyl groups proceed continuously,
A tetrahydroxyazepan derivative is formed. Any solvent may be used as long as it does not inhibit the reduction reaction, and water or a lower alcohol such as methanol or ethanol is usually used.
The added palladium-carbon is 5 to 50% by weight based on the starting material 6-azido-6-deoxypyranose.
The reaction is usually performed at a temperature of 10 to 100 ° C. and 3 to 50.
Done for hours. As the reduction catalyst and / or reducing agent,
In addition to palladium-carbon / ammonium formate, palladium-carbon / formic acid, palladium-carbon / hydrogen, platinum-carbon / hydrogen, Raney nickel / hydrogen, sodium borohydride and the like can also be used. After the completion of the reaction, if necessary, purification is carried out using a column chromatography method, a crystallization method, or the like, to obtain a tetrahydroxyazepane derivative.
The configuration of the hydroxyl group in the tetrahydroxyazepane derivative is limited by the configuration of the hydroxyl group of pyranose used as a starting material. For example, when D-glucopyranose is used as a starting material, (3R, 4R,
5R, 6S) -tetrahydroxy form.

Then, a protecting group is introduced into the cyclic amino group of the thus obtained tetrahydroxyazepane derivative. For example, when protecting with a t-butyloxycarbonyl group, Dissolve the bread derivative in a solvent such as water, and in the presence of a base such as sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, 1 to
A 5-fold molar amount of di-t-butyl dicarbonate is added,
When the reaction is carried out at a temperature in the range of 10 to 100 ° C. for about 1 to 24 hours, the cyclic amino group is t-butyloxycarbonylated.
(T-Butyloxycarbonyl) -tetrahydroxyazepane derivative is obtained. When other protecting groups are introduced, the reaction is similarly carried out by the action of benzyloxycarbonyl chloride or the like. Subsequently, a protecting group is introduced into three or less of the four hydroxyl groups of the tetrahydroxyazepane derivative in which the 1-position cyclic amino group thus obtained is protected. The protecting group is selected in consideration of the properties resulting from the configuration of the hydroxyl group of, and examples of the protecting group include an isopropylidene group, a benzylidene group, a methoxymethyl group, an acetyl group, and a t-butyldimethylsilyl group. These may be used alone or in combination of two or more. As a method for introducing these protecting groups, for example, when protecting with an isopropylidene group, the tetrahydroxyazepane derivative is dissolved in a solvent such as N, N-dimethylformamide and p-toluenesulfonic acid, In the presence of an acid catalyst such as pyridinium p-toluenesulfonate, 1 to 5 times the molar amount of 2,2-dimethoxypropane is added, and usually -10
When the reaction is carried out at a temperature in the range of １００100 ° C. for about 1 to 24 hours, two adjacent hydroxyl groups are isopropylidene-converted. If necessary, purification is carried out by a conventional method to obtain an O-isopropylidene-tetrahydroxyazepane derivative. Can be For example, in the case of protecting with a t-butyldimethylsilyl group, the tetrahydroxyazepane derivative is dissolved in a solvent such as pyridine, and then, in the presence of 4-dimethylaminopyridine or the like, a 1 to 5-fold molar amount. When t-butyldimethylchlorosilane is added and reacted at a temperature in the range of usually −10 to 100 ° C. for about 1 to 24 hours, a hydroxyl group having little steric hindrance is t-butyldimethylsilylated, and if necessary, purified according to a conventional method. Then, an O- (t-butyldimethylsilyl) -tetrahydroxyazepane derivative is obtained. When other protecting groups are introduced, similarly, benzaldehyde dimethyl acetal, methoxymethyl chloride,
The reaction is performed with acetic anhydride or the like.

Next, the thus-obtained cyclic amino group and the unprotected hydroxyl group of the tetrahydroxyazepane derivative in which at most three hydroxyl groups are protected are converted into desired substituents. When converting to an azide group, the azepan derivative is dissolved in a solvent such as pyridine, and methanesulfonyl chloride is added in an amount of 1 to 5 times the molar amount, usually at a temperature in the range of -10 to 100 ° C to 1 to 24.
After reacting for about an hour, the hydroxyl group is O-sulfonylated and, if necessary, purified by a conventional method to obtain an azepane derivative having a sulfonyloxy group. This is dissolved in a solvent such as N, N-dimethylformamide,
Add 50 times the molar amount of sodium azide, usually 50
When the reaction is carried out at a temperature in the range of ~ 150 ° C for about 2 to 12 hours, the sulfonyloxy group is replaced by an azide group, and if necessary, purification is carried out by a conventional method to obtain an azepane derivative having an azide group. Is inverted. In addition, for example, when converting to an amino group which may have a substituent, the azepane derivative having an azide group obtained as described above is dissolved in a solvent such as ethanol and the presence of 10% palladium-carbon. Under the above, hydrogen gas is introduced, usually at a temperature in the range of 10 to 100 ° C. and 2 to 48 ° C.
When the catalytic reduction reaction is carried out for about an hour, the azide group is reduced to an amino group, and if necessary, purification is performed according to a conventional method to obtain an amino-substituted azepane derivative. If necessary, this is dissolved in a polar solvent, and a 1 to 20-fold molar amount of an alkyl halide or acyl halide is added, and if necessary, in the presence of a base, usually at a temperature in the range of 10 to 100 ° C. When the reaction is carried out for about 24 hours, the amino group is alkylated and, if necessary, purified by a conventional method to obtain an azepan derivative substituted with an amino group having a substituent. Examples of the alkyl halide or acyl halide used in the reaction include, for example, iodomethane, bromoethane, 1-bromobutane, iodocyclohexane,
Bromomethylcyclohexane, 2-iodoethanol,
3-bromopropanol, benzyl bromide, acetyl chloride, propionyl bromide, butyryl chloride and the like can be mentioned. Examples of the polar solvent used in the reaction include acetone, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide and the like, and these may be used alone or as a mixture of two or more. . Examples of the base used in the reaction as necessary include potassium carbonate, sodium carbonate, triethylamine and the like.

Further, for example, when a hydroxyl group is converted into a hydrogen atom, that is, deoxygenated, for example, a tetrahydroxyazepane derivative in which the above-mentioned cyclic amino group and three or less hydroxyl groups are protected is converted into N, N-dimethyl Dissolved in a solvent such as formamide, added 2 to 50 times the molar amount of sodium iodide, and usually reacted at a temperature in the range of 50 to 150 ° C. for about 1 to 12 hours, the hydroxyl group was replaced with an iodine atom, If necessary, the azepane derivative substituted by an iodine atom can be obtained by purifying according to a conventional method. This is dissolved in a solvent such as toluene, and then dissolved in a solvent such as 2,2′-azobis (isobutyronitrile).
When about 20-fold molar amount of tributyltin hydride is added and the reaction is carried out usually at a temperature in the range of 50 to 120 ° C. for about 10 minutes to 5 hours, the iodine atom is reductively replaced by a hydrogen atom. Purification according to the method yields a deoxylated azepane derivative. Also, according to the usual law,
After converting the hydroxyl group to a methyldithiocarbonyloxy group or a phenyloxythiocarbonyloxy group, deoxylation can be performed by the action of a reducing agent such as tributyltin hydride. Next, the protecting group of the tetrahydroxyazepane derivative obtained by converting the thus obtained hydroxyl group into a hydrogen atom, an azide group or an amino group which may have a substituent is deprotected. A conventional method suitable for each protecting group may be used.For example, when protected with a t-butyloxycarbonyl group, an isopropylidene group, a t-butyldimethylsilyl group, etc., When dissolved in a solvent such as 4-dioxane, concentrated hydrochloric acid is added, and the mixture is allowed to react at a temperature usually in the range of 10 to 50 ° C. for about 10 minutes to 2 hours. When purified using silica gel, ODS, or the like, the azepane derivative represented by the general formula (I) and a salt thereof can be obtained.

[0012]

The present invention will be described in more detail with reference to Reference Examples, Examples and Experimental Examples. The high performance liquid chromatography in each example was performed using Tosoh Corporation as a column.
TSKgel Amide-80 column (4.6 mm ID x 250 mm), a mixture of acetonitrile / 25 mM ammonium formate-ammonia buffer (pH 8.5) as eluent, flow rate of 1.0 ml / m
In, a differential refractometer (RI) is used as a detector, and the mixing ratio (v / v) of eluent and retention time (t _R ) are shown in each example. The specific rotation in each of the examples is a value measured at 25 ° C. with a sodium D line. <Reference Example 1> (3R, 4R, 5R, 6S) -Hexahydro-3,4,5,6-
Synthesis of tetrahydroxy-1H-azepine Commercially available D-glucose (100 g, 555 mmol) in pyridine (1000 ml)
Dissolve in ice-cooled tosyl chloride 117g while stirring with ice
(611 mmol) in 500 ml of pyridine was added dropwise over 1 hour, and the mixture was reacted at 5 ° C. for 20 hours. 100 ml of water was added to the obtained reaction solution, and the mixture was concentrated to dryness under reduced pressure.The residue was dissolved in 1000 ml of water, washed twice with 500 ml of chloroform, and the aqueous layer was concentrated to dryness under reduced pressure to give crude 6-. O-Tosyl-D-glucose was obtained. Next, 6-O-tosyl-D-glucose was dissolved in dimethylformamide 500 ml, and sodium azide 50 g.
(769 mmol) was added and reacted at 80 ° C. for 4 hours. The obtained reaction solution was concentrated to dryness under reduced pressure to obtain crude 6-azido-6-deoxy-D-glucose. Next, this was dissolved in 1000 ml of water, 20 g of 10% palladium-carbon and 100 g of ammonium formate were added, and the mixture was reacted at room temperature with stirring for 1 hour. Next, 100 g of ammonium formate was added, and the reaction was carried out at 60 ° C. for 6 hours. The palladium-carbon in the obtained reaction solution was separated by filtration, the residue obtained by concentrating the filtrate to dryness under reduced pressure was subjected to activated carbon column chromatography, and after concentrating the section containing the target product eluted with water, the resulting residue anion exchange resin ^{(DOWEX 1-X4, OH -} ) purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4R, 5R , 6S) -Hexahydro-3,4,5,6-
32.5 g of tetrahydroxy-1H-azepine (199 mmol, yield 36
%). ¹³ C nuclear magnetic resonance spectrum (50 MHz, DMS
O-d6) δ: 52.4, 52.7, 74.4, 76.6, 77.3, 78.0.

Reference Example 2 Synthesis of (3R, 4R, 5R, 6R) -hexahydro-3,4,5,6-tetrahydroxy-1H-azepine 100 g (555 mmol) of commercially available D-mannose was added to 1000 ml of pyridine.
Dissolve in ice-cooled tosyl chloride under ice-cooling 117g
(611 mmol) in 500 ml of pyridine was added dropwise over 1 hour, and the mixture was reacted at 5 ° C. for 20 hours. 100 ml of water was added to the obtained reaction solution, and the mixture was concentrated to dryness under reduced pressure.The residue was dissolved in 1000 ml of water, washed twice with 500 ml of chloroform, and the aqueous layer was concentrated to dryness under reduced pressure to give crude 6-. O-tosyl-D-manose was obtained. Then, 500 ml of dimethylformamide
, 50 g (769 mmol) of sodium azide was added, and 80
The reaction was performed at ℃ for 4 hours. The obtained reaction solution was concentrated to dryness under reduced pressure to obtain crude 6-azido-6-deoxy-D-mannose. Then, 6-azido-6-deoxy-D-mannose was added to water 10
The mixture was dissolved in 00 ml, 10 g of 10% palladium-carbon and 100 g of ammonium formate were added, and the mixture was reacted at room temperature with stirring for 1 hour. Next, 100 g of ammonium formate was added, and 6
A time reaction was performed. The palladium-carbon in the obtained reaction solution was separated by filtration, the residue obtained by concentrating the filtrate to dryness under reduced pressure was subjected to activated carbon column chromatography, and after concentrating the section containing the target product eluted with water, the resulting residue anion exchange resin ^{(DOWEX 1-X4, OH -} ) purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4R, 5R , 6R) -Hexahydro-3,
2,7.8 g of 4,5,6-tetrahydroxy-1H-azepine (170 mmol,
Yield 31%). ¹³ C nuclear magnetic resonance spectrum (50 MHz, DMSO-d6) δ: 50.
3, 70.1, 73.1.

Reference Example 3 Synthesis of (3R, 4S, 5R, 6S) -hexahydro-3,4,5,6-tetrahydroxy-1H-azepine Commercially available 1,2,3,4-di-O- 50 g (192 mmol) of isopropylidene-D-galactopyranose was dissolved in 500 ml of pyridine, and a solution of 40 g (210 mmol) of tosyl chloride dissolved in 250 ml of pyridine was added dropwise with stirring under ice cooling over 1 hour. For 20 hours. 50 ml of water is added to the obtained reaction solution.
And concentrated to dryness under reduced pressure.
The organic layer was dried over anhydrous sodium sulfate and filtered off.The filtrate was concentrated to dryness under reduced pressure to give crude 6-O-tosyl-1,2,3, 4-Di-O-isopropylidene-D-galactopyranose was obtained. Then, this was dissolved in 1000 ml of dimethylformamide, and sodium azide was added.
20 g (308 mmol) was added and reacted at 120 ° C. for 5 hours. After the resulting reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in chloroform (1000 ml), washed twice with water (1000 ml), the organic layer was dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated under reduced pressure to dryness. To give crude 6-azido-6-deoxy-1,2,3,4-di-O-
Isopropylidene-D-galactopyranose was obtained. Next, 6-azido-6-deoxy-1,2,3,4-di-O-isopropylidene-D-galactopyranose was dissolved in 500 ml of a trifluoroacetic acid-water mixture (volume ratio 9: 1), and the mixture was dissolved at room temperature. The reaction was performed for 2 hours. The obtained reaction solution was concentrated to dryness under reduced pressure to obtain crude 6-azido-6-deoxy-D-galactopyranose. Next, crude 6-azido-6-deoxy-D-galactopyranose was dissolved in 500 ml of water, 10 g of 10% palladium-carbon and 50 g of ammonium formate were added, and the mixture was reacted at room temperature with stirring for 1 hour. Then, add 50 g of ammonium formate, and add
For 5 hours. The palladium-carbon in the obtained reaction solution was separated by filtration, the residue obtained by concentrating the filtrate to dryness under reduced pressure was subjected to activated carbon column chromatography, and after concentrating the section containing the target product eluted with water, the resulting residue anion exchange resin ^{(DOWEX 1-X4, OH -} ) purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4S, 5R , 6S) -Hexahydro
-3,4,5,6-tetrahydroxy-1H-azepine 10.8g (66mmo
l, yield 34%). ¹³ C nuclear magnetic resonance spectrum (5
0 MHz, DMSO-d6) δ: 50.2, 68.7, 73.5.

<Example 1> (3R, 4R, 5R, 6R) -Hexahydro-3-azido-4,5,6-trihydroxy-1H-azepine [Compound (1) of the present invention] Obtained in Reference Example 1. (3R, 4R, 5R, 6S) -Hexahydro-3,4,5,6-
20.0 g (123 mmol) of tetrahydroxy-1H-azepine in water 40
The mixture was dissolved in 0 ml, and 30 ml (135 mmol) of di-t-butyl dicarbonate and 5.4 g (135 mmol) of sodium hydroxide were added, and the mixture was reacted at room temperature with stirring for 20 hours. The obtained reaction solution was washed with 200 ml of diethyl ether, and the aqueous layer was concentrated under reduced pressure.
Purification was performed by DS column chromatography, and the fraction containing the target product eluted with an ethanol-water mixture (volume ratio of 1: 4) was concentrated to dryness, and then subjected to (3R, 4R, 5R, 6S) -hexahydro
25.6 g (97 mmol, 79% yield) of -1-N- (t-butyloxycarbonyl) -3,4,5,6-tetrahydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3381, 1704, 1651, 1
463, 1426, 1366 cm ^-1 . 20.0 g (76 mmol) of the obtained (3R, 4R, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) -3,4,5,6-tetrahydroxy-1H-azepine was added to 200 ml of dimethylformamide. Dissolved in 2,2-dimethoxypropane 2
0 ml (164 mmol) and 1.5 g of p-toluenesulfonic acid monohydrate
(8 mmol) was added and reacted while stirring at room temperature for 3 hours.
0.66 g (7.9 mmol) of sodium hydrogen carbonate was added to the obtained reaction solution.
, And concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification,
The fraction containing the target substance eluted with an ethyl acetate-hexane mixed solution (volume ratio of 3: 2) was concentrated to dryness, and (3R, 4R, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl ) -3,4-O-Isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine was obtained in an amount of 20.4 g (67 mmol, yield 88%). Infrared absorption spectrum (KBr): 3481, 1692, 1458, 1415, 1369 cm ^-1 .

The obtained (3R, 4R, 5R, 6S) -hexahydro-1-N
-(t-butyloxycarbonyl) -3,4-O-isopropylidene
-3,4,5,6-tetrahydroxy-1H-azepine 15.0g (49.4mm
ol) was dissolved in 150 ml of pyridine, 4.2 ml (54.3 mmol) of methanesulfonyl chloride was added, and the mixture was reacted at room temperature for 5 hours. After adding 15 ml of water to the obtained reaction solution and concentrating it to dryness under reduced pressure, the residue was purified by silica gel column chromatography, and an ethyl acetate-hexane mixed solution (volume ratio 3: 3).
Concentrate the fraction containing the target substance eluted in 2) to dryness,
(3R, 4R, 5R, 6S) -Hexahydro-1-N- (t-butyloxycarbonyl) -6-O-methanesulfonyl-3,4-O-isopropylidene-3,4,5,6-tetrahydroxy 18.2 g of -1H-azepine (4
7.7 mmol, 97% yield). Infrared absorption spectrum (KB
r): 3576, 1693, 1456, 1412, 1352 cm ^-1 . Obtained (3
(R, 4R, 5R, 6S) -Hexahydro-1-N- (t-butyloxycarbonyl) -6-O-methanesulfonyl-3,4-O-isopropylidene-
3,4,5,6-tetrahydroxy-1H-azepine 18.0g (47.2mmo
l) was dissolved in dimethylformamide (180 ml), sodium azide (6.2 g, 95.4 mmol) was added, and the mixture was reacted at 120 ° C. for 2 hours with stirring. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio of 3: 2) was concentrated. Dry to dry, (3R, 4R, 5
(R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl)-
10.9 g (33.2 mmol, 70% yield) of 6-azido-3,4-O-isopropylidene-3,4,5-trihydroxy-1H-azepine was obtained.
Infrared absorption spectrum (KBr): 2117, 1691, 1460, 141
6,1368 cm ^-1 . The obtained (3R, 4R, 5R, 6R) -hexahydro-1
1.0 g of -N- (t-butyloxycarbonyl) -6-azido-3,4-O-isopropylidene-3,4,5-trihydroxy-1H-azepine
(3.1 mmol) was dissolved in 10 ml of dioxane, 5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 1 hour. 15 ml of water is added to the obtained reaction solution.
Was added anion-exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4R, 5R, 6R )-
0.50 g (2.7 mmol, yield 87%) of hexahydro-3-azido-4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3329, 2112, 1631, 154
8, 1462, 1412, 1269 cm ^-1 Specific rotation [α]: -57.2 ° (c 0.146, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 47.
21, 49.93, 62.43, 69.86, 72.10, 73.15. High performance liquid chromatography (6: 4): 4.5 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₂ N ₄ O ₃ : C, 3
8.29; H, 6.43; N, 29.77. Observed value (%): C, 38.5
2; H, 6.40; N, 29.62.

Example 2 (3R, 4R, 5R, 6R) -Hexahydro-3-amino-4,5,6-trihydroxy-1H-azepine [Compound (2) of the present invention] Obtained in Example 1. (3R, 4R, 5R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-azido-5,6-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 6.0 g (18.3mmo
l) was dissolved in 120 ml of ethanol, 0.6 g of 10% palladium carbon was added, and the mixture was reacted at room temperature for 20 hours under introduction of hydrogen gas. After filtering off insolubles, the obtained filtrate was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and the fraction containing the target product eluted with a mixed solution of ethyl acetate-methanol-water (volume ratio: 20: 2: 1) was concentrated and dried, and then subjected to (3R , 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3-amino-5,6-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 4.15 g (13.7
mmol, yield 75%). Infrared absorption spectrum (KBr):
3383,1685,1579,1485,1420,1368 cm- ¹ . Got
(3R, 4R, 5R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-amino-5,6-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 1.0 g (3.3 mmol) in dioxane 1
The mixture was dissolved in 0 ml, concentrated hydrochloric acid (5 ml) was added, and the mixture was reacted at room temperature for 1 hour. The resulting water 15ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4R, 5R, 6R) -hexahydro-3-amino-4,
0.49 g (3.0 mmol, 91% yield) of 5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3341, 1541, 1474, 141
6,1300 cm ^-1 specific rotation [α]: -30.5 ° (c 0.173, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 50.
46, 50.94, 52.21, 69.70, 72.50, 73.77. High performance liquid chromatography (4: 6): 7.2 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₄ N ₂ O ₃ : C, 4
4.43; H, 8.70; N, 17.27. Observed value (%): C, 44.3
8; H, 8.73; N, 17.43.

Example 3 (3R, 4R, 5R, 6R) -Hexahydro-3- (2-hydroxyethylamino) -4,5,6-trihydroxy-1H-azepine [Compound (3) of the present invention] (3R, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3-amino-5,6-O-isopropylidene-4,5,6-triene obtained in Example 2 Hydroxy-1H-azepine 1.27g (4.2mmo
l) was dissolved in 13 ml of dimethylformamide, and 1.5 ml (21 mmol) of 2-bromoethanol and 1.5 g (11 mmo) of potassium carbonate were dissolved.
l) was added and reacted at 60 ° C. for 5 hours. The obtained reaction solution was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and ethyl acetate-
The fraction containing the target substance eluted with a methanol-water mixture (volume ratio: 100: 2: 1) was concentrated to dryness, and (3R, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxy (Carbonyl) -3- (2-hydroxyethylamino) -5,6-O-isopropylidene-4,5,6-
0.94 g (2.7 mmol, yield 64) of trihydroxy-1H-azepine
%)Obtained. Infrared absorption spectrum (KBr): 3300, 1685, 1
464, 1420, 1368 cm ^-1 . The obtained (3R, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3- (2-hydroxyethylamino) -5,6-O-isopropylidene-4,5, 0.5 g (1.4 mmol) of 6-trihydroxy-1H-azepine was dissolved in 5 ml of dioxane, 2.5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 1 hour. The resulting water 7.5ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water , (3R, 4R, 5R, 6R) -hexahydro-3- (2-
0.28 g (1.4 mmol, 94% yield) of (hydroxyethylamino) -4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3350, 1647, 1541, 147
2,1414,1297 cm ^-1 Specific rotation [α]: -23.0 ° (c 0.146, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 47.
70, 49.48, 50.35, 58.43, 60.76, 69.99, 70.99, 74.0
6. High performance liquid chromatography (4: 6): 6.3 min Elemental analysis: C ₈ H ₁₈ N ₂ O ₄ , theoretical value (%): C, 4
6.59; H, 8.80; N, 13.58. Observed value (%): C, 46.6
2; H, 8.68; N, 13.70.

Example 4 (3R, 4R, 5R, 6R) -Hexahydro-3-benzylamino-4,5,6-trihydroxy-1H-azepine dihydrochloride [Compound (4) of the present invention] (3R, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3-amino-5,6-O-isopropylidene-4,5,6-trihydroxy- obtained in 2 1.2g of 1H-azepine (4.0mmo
l) was dissolved in 12 ml of dimethylformamide, and 0.7 ml (6 mmol) of benzyl bromide and 0.4 g (3 mmo) of potassium carbonate were dissolved.
l) was added and reacted at room temperature for 3 hours. The obtained reaction solution was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and ethyl acetate-
The fraction containing the target substance eluted with a hexane mixture (volume ratio 1: 1) was concentrated to dryness and (3R, 4R, 5R, 6R) -hexahydro-1
-N- (t-butyloxycarbonyl) -3-benzylamino-5,6
1.2 g (3.1 mmol, 78% yield) of -O-isopropylidene-4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 1692, 1462, 1415, 1367 cm ^-1 . Got
(3R, 4R, 5R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-benzylamino-5,6-O-isopropylidene-4,
1.0 g (2.6 mmol) of 5,6-trihydroxy-1H-azepine was dissolved in 10 ml of dioxane, 5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with dioxane, and dried to give (3R, 4R, 5R, 6R) -hexahydro-3-benzylamino-4,5,6-trihydroxy-1H-azepine dihydrochloride. 0.68 g (2.4 mmol, yield 92%) was obtained. Melting point: 175-180 ° C Infrared absorption spectrum (KBr): 3354, 1616, 1571, 154
1,1456 cm ^-1 specific rotation [α]: + 11.0 ° (c 0.142, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 39.
33, 43.76, 48.36, 53.63, 64.61, 67.37, 73.34, 128.
. 45,128.88,130.38,131.55 high performance liquid chromatography (6: 4): 6.3 min Elemental analysis: as _{C 13 H 22 C l 2 N} 2 O 3, the theoretical value (%):
C, 48.01; H, 6.82; N, 14.76. Measured value (%): C,
48.11; H, 6.87; N, 14.59.

Example 5 (3R, 4R, 5R) -Hexahydro-
3,4,5-trihydroxy-1H-azepine hydrochloride [Compound (5) of the present invention] (3R, 4R, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) obtained in Example 1 ) -6-O-Methanesulfonyl-3,4-O-
Dissolve 5.0 g (13.1 mmol) of isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine in 50 ml of dimethylformamide, add 10.0 g (67 mmol) of sodium iodide, and react at 120 ° C. for 2 hours with stirring. I let it. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio of 2: 3) was concentrated. To dryness, (3R, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -6-iodo-3,4-O-isopropylidene-
4.1 g of 3,4,5-trihydroxy-1H-azepine (9.9 mmol,
(76% yield). Infrared absorption spectrum (KBr): 3466, 1
692, 1462, 1415, 1370 cm ^-1 . Obtained (3R, 4R, 5R, 6R)-
Hexahydro-1-N- (t-butyloxycarbonyl) -6-iodo-3,4-O-isopropylidene-3,4,5-trihydroxy-1H-
Dissolve 1.5 g (3.63 mmol) of azepine in 30 ml of toluene, add 4.5 ml (16.7 mmol) of tributyltin hydride and 0.3 g (1.8 mmol) of 2,2'-azobis (isobutyronitrile), and add
For 1 hour. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography, and mixed with ethyl acetate-hexane (volume ratio).
The fraction containing the target substance eluted in 2: 3) is concentrated to dryness and (3R, 4R, 5R) -hexahydro-1-N- (t-butyloxycarbonyl) -3,4-O-isopropylidene 1.0 g (3.48 mmol, 96% yield) of -3,4,5-trihydroxy-1H-azepine was obtained.
Infrared absorption spectrum (KBr): 3480, 1686, 1467, 141
4, 1367 cm ^-1 . The obtained (3R, 4R, 5R) -hexahydro-1-N-
(t-butyloxycarbonyl) -3,4-O-isopropylidene-
0.5 g (1.74 mmol) of 3,4,5-trihydroxy-1H-azepine was dissolved in 5 ml of dioxane, and 2.5 ml of concentrated hydrochloric acid was added.
After reacting for an hour, it was left at 5 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with dioxane, dried, and (3R, 4R, 5R)
0.19 g (1.03 mmol, 60% yield) of -hexahydro-3,4,5-trihydroxy-1H-azepine hydrochloride was obtained. Melting point: 199-202 ° C Infrared absorption spectrum (KBr): 3374, 1624, 1466, 1270
cm ^-1 specific rotation [α]: -28.7 ° (c 0.146, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 27.
31,38.61,43.29,65.47,68.28,76.27 high performance liquid chromatography (6: 4): 14.5 min Elemental analysis: as _{C 6 H 14 C l NO 3} , the theoretical value (%):
C, 39.24; H, 7.68; N, 7.63. Measured value (%): C, 3
9.20; H, 7.77; N, 7.58.

Example 6 (3S, 4S, 5R, 6R) -Hexahydro-4-azido-3,5,6-trihydroxy-1H-azepine [Compound (6) of the present invention] Obtained in Example 1. (3R, 4R, 5R, 6S) -Hexahydro-1-N- (t-butyloxycarbonyl) -3,4-O-isopropylidene-3,4,
5,6-tetrahydroxy-1H-azepine 10.0 g (33.0 mmol)
Was dissolved in 100 ml of pyridine, and 6.0 g (40 mmol) of t-butyldimethylchlorosilane and 4.0 g of 4-dimethylaminopyridine were dissolved.
(33 mmol) was added and reacted at room temperature for 20 hours with stirring. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio 1: 4) was concentrated. After drying, (3R, 4R, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) -6-O- (t-butyldimethylsilyl) -3,4-O-isopropylidene- 3,4,5,6
10.6 g (25.4 mmol, 77% yield) of -tetrahydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3449, 168
9, 1457, 1417, 1368 cm ^-1 . The obtained (3R, 4R, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) -6-O- (t-
Butyldimethylsilyl) -3,4-O-isopropylidene-3,4,
10.0 g (23.9 mmol) of 5,6-tetrahydroxy-1H-azepine
Is dissolved in 100 ml of pyridine, and methanesulfonyl chloride is dissolved.
3.7 ml (48 mmol) was added and reacted at room temperature for 20 hours. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio 1: 3) was concentrated. To dryness, (3R, 4R, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) -6-O- (t-butyldimethylsilyl) -5-O-methanesulfonyl-3, 11.0 g (22.2 mmol, 93% yield) of 4-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 1685, 1467, 1413, 1332 cm ^-1 . Got
(3R, 4R, 5R, 6S) -Hexahydro-1-N- (t-butyloxycarbonyl) -6-O- (t-butyldimethylsilyl) -5-O-methanesulfonyl-3,4-O-isopropyl Lyden-3,4,5,6-tetrahydroxy-1H-azepine 10.0 g (20.2 mmol) was dissolved in dimethylformamide 100 ml, and sodium azide 2.6 g (40 mmo
l) was added and reacted at 100 ° C. for 5 hours with stirring. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio of 1:10) was concentrated. Dry to dryness, (3S, 4S, 5R, 6R) -hexahydro
-1-N- (t-butyloxycarbonyl) -4-azido-3-O- (t-butyldimethylsilyl) -5,6-O-isopropylidene-3,5,6-
8.2 g of trihydroxy-1H-azepine (18.5 mmol, yield 9
2%). Infrared absorption spectrum (KBr): 2112, 1701,
1460, 1411, 1368 cm ^-1 . The obtained (3S, 4S, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -4-azido-3
-O- (t-butyldimethylsilyl) -5,6-O-isopropylidene
1.0 g (2.26 mmol) of -3,5,6-trihydroxy-1H-azepine
Was dissolved in 10 ml of dioxane, 5 ml of concentrated hydrochloric acid was added, and 2
Allowed to react for hours. The resulting water 15ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to Karamukuro Mato chromatography, partition was lyophilized to containing the target product was eluted with water, (3S, 4S, 5R, 6R) -Hexahydro
0.40 g of -4-azido-3,5,6-trihydroxy-1H-azepine
(2.13 mmol, 94% yield). Infrared absorption spectrum (KBr): 3332, 2110, 1647, 145
8,1417,1262 cm ^-1 Specific rotation [α]: + 38.3 ° (c 0.136, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 51.
23, 52.95, 66.53, 73.00, 74.86, 75.53. High performance liquid chromatography (6: 4): 5.9 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₂ N ₄ O ₃ : C, 3
8.29; H, 6.43; N, 29.77. Observed value (%): C, 38.1
2; H, 6.59; N, 29.65.

Example 7 (3S, 4S, 5R, 6R) -Hexahydro-4-amino-3,5,6-trihydroxy-1H-azepine [Compound (7) of the present invention] Obtained in Example 6. (3S, 4S, 5R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -4-azido-3-O- (t-butyldimethylsilyl) -5,6-O-isopropylidene-3 7.0 g (15.8 mmol) of 5,5,6-trihydroxy-1H-azepine in 140 ml of ethanol
, And 0.7 g of 10% palladium carbon was added, and the mixture was reacted at room temperature for 20 hours with stirring under introduction of hydrogen gas. After filtering off insolubles, the obtained filtrate was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and a mixed solution of ethyl acetate-methanol-water (volume ratio: 2
0: 2: 1), the fraction containing the desired product eluted was concentrated to dryness, and (3S, 4S, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -4-amino- 3-O- (t-butyldimethylsilyl)-
4.9 g (11.8 mmol, 75% yield) of 5,6-O-isopropylidene-3,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 1697, 1463, 1413, 1367 cm ^-1 . The obtained (3S, 4S, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -4-amino-3-O- (t-butyldimethylsilyl)-
Dissolve 1.0 g (2.40 mmol) of 5,6-O-isopropylidene-3,5,6-trihydroxy-1H-azepine in 10 ml of dioxane,
5 ml of concentrated hydrochloric acid was added and reacted at room temperature for 1 hour. 15 ml of water was added to the obtained reaction solution, and an anion exchange resin (DOWEX 1-X4,
OH ^-) was purified and subjected to Karamukuro Mato chromatography,
Lyophilize the category containing the target substance eluted with water,
0.36 g (2.22 mmol, 93% yield) of (S, 4S, 5R, 6R) -hexahydro-4-amino-3,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3337, 1633, 1542, 147
3,1414,1311 cm ^-1 Specific rotation [α]: + 42.9 ° (c 0.125, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 52.
37, 53.83, 55.52, 73.49, 76.02, 77.33. High performance liquid chromatography (4: 6): 10.1 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₄ N ₂ O ₃ : C, 4
4.43; H, 8.70; N, 17.27. Observed value (%): C, 44.3
8; H, 8.57; N, 17.48.

Example 8 (3S, 4S, 5R, 6R) -Hexahydro-4-benzylamino-3,5,6-trihydroxy-1H-azepine [Compound of the present invention (8)] Obtained in Example 7 (3S, 4S, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -4-amino-3-O- (t-butyldimethylsilyl) -5,6-O-isopropylidene- 2.0 g (4.8 mmol) of 3,5,6-trihydroxy-1H-azepine was dissolved in 20 ml of dimethylformamide, and 0.86 ml (7.2 mmo) of benzyl bromide was dissolved.
l) and 0.5 g (3.6 mmol) of potassium carbonate, and add
Allowed to react for hours. The obtained reaction solution was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and the fraction eluted with a mixed solution of ethyl acetate-hexane (volume ratio 1: 4) was concentrated to dryness to give (3S, 4S, 5R, 6
R) -Hexahydro-1-N- (t-butyloxycarbonyl) -4-
Dibenzylamino-3-O- (t-butyldimethylsilyl) -5,6-
1.4 g (2.3 mmol, 48% yield) of O-isopropylidene-3,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 1698, 1456, 1412, 1367 cm ^-1 . Further, the fraction containing the target substance eluted with an ethyl acetate-methanol mixture (volume ratio 1: 2) is concentrated to dryness and (3S, 4S, 5R, 6R)-
Hexahydro-1-N- (t-butyloxycarbonyl) -4-benzylamino-3-O- (t-butyldimethylsilyl) -5,6-O-isopropylidene-3,5,6-trihydroxy-1H -Azepine 1.
1 g (2.2 mmol, 46% yield) was obtained. Infrared absorption spectrum (K
Br): 1697, 1458, 1412, 1367 cm- ¹ . (3S, 4S,
5R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl)
-4-benzylamino-3-O- (t-butyldimethylsilyl) -5,6
0.5 g (0.99 mmol) of -O-isopropylidene-3,5,6-trihydroxy-1H-azepine is dissolved in 5 ml of dioxane, and concentrated hydrochloric acid is added.
2.5 ml was added and reacted at room temperature for 2 hours. 7.5 ml of water was added to the obtained reaction solution, and anion exchange resin (DOWEX 1-X4, O
H ^-) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3S,
4S, 5R, 6R) -Hexahydro-4-benzylamino-3,5,6-trihydroxy-1H-azepine was 0.21 g (2.22 mmol, yield 83
%)Obtained. Infrared absorption spectrum (KBr): 3310, 1653, 1542, 145
6, 1417, 1288 cm ^-1 Specific rotation [α]: + 60.0 ° (c 0.11
1, H2O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 50.
45, 50.84, 52.24, 61.41, 73.26, 74.79, 77.85, 126.
42, 127.82, 128.04, 141.12. High performance liquid chromatography (6: 4): 7.7 min Elemental analysis: As C ₁₃ H ₂₀ N ₂ O ₃ , theoretical value (%): C,
61.88; H, 7.99; N, 11.10. Observed value (%): C, 61.7
6; H, 8.08; N, 11.13.

<Example 9> (3S, 4S, 5R, 6R) -hexahydro-4-dibenzylamino-3,5,6-trihydroxy-1H-azepine [Compound (9) of the present invention] The obtained (3S, 4S, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -4-dibenzylamino-3-O- (t-butyldimethylsilyl) -5,6-O- Isopropylidene-3,5,6-
0.5 g (0.99 mmol) of trihydroxy-1H-azepine was dissolved in 5 ml of dioxane, 2.5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. The resulting water 7.5ml was added to the reaction mixture, an anion exchange resin (DOWEX 1-X4, OH ^-) Purification was subjected to column chromatography, ethanol - water mixture (volume ratio 1:
Lyophilize the section containing the target substance eluted in 1),
(3S, 4S, 5R, 6R) -hexahydro-4-dibenzylamino-3,
0.27 g of 5,6-trihydroxy-1H-azepine (0.79 mmol,
(Yield 80%). Infrared absorption spectrum (KBr): 3278, 1494, 1463, 142
0, 1372, 1319, 1286 cm ^-1 Specific rotation [α]: + 37.2 ° (c 0.113, EtOH) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 47.
94, 52.46, 53.67, 61.33, 71.91, 73.30, 77.12, 126.
60, 128.06, 128.41, 140.15. Elemental analysis: As C ₂₀ H ₂₆ N ₂ O ₃ , theoretical value (%): C,
H. 7.65; N, 8.18. Observed value (%): C, 70.1
1; H, 7.72; N, 8.24.

<Example 10> (3R, 4R, 6S) -Hexahydro-3,4,6-trihydroxy-1H-azepine [Compound (10) of the present invention] (3R, 4R, 5R) obtained in Example 6 , 6S) -Hexahydro-1-N- (t-butyloxycarbonyl) -6-O- (t-butyldimethylsilyl)
-3,4-O-isopropylidene-3,4,5,6-tetrahydroxy-1
2.0 g (4.8 mmol) of H-azepine in 40 ml of tetrahydrofuran
Dissolved in water, 1.0 g (25 mmol) of sodium hydride (oily)
And 2 mg of imidazole were added and reacted at room temperature for 30 minutes with stirring. Next, 2.9 ml (48 mmol) of carbon disulfide was added,
After further reacting at room temperature for 30 minutes, methyl iodide 1.2 ml
(19 mmol) was added and further reacted at room temperature for 30 minutes. 200 ml of dichloromethane was added to the obtained reaction solution, washed with a 5% aqueous sodium hydrogen carbonate solution, washed with water, and the organic layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The obtained residue was dissolved in 40 ml of toluene, 5.0 ml (19 mmol) of tributyltin hydride was added, and the mixture was heated and refluxed for 20 hours. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio of 1:10) was concentrated. Dry to (3R, 4R, 6S)-
Hexahydro-1-N- (t-butyloxycarbonyl) -6-O-
(t-butyldimethylsilyl) -3,4-O-isopropylidene-
1.6 g of 3,4,6-trihydroxy-1H-azepine (4.0 mmol,
(83% yield). Infrared absorption spectrum (KBr): 1742, 1
701, 1472, 1412, 1367 cm ^-1 . The obtained (3R, 4R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) -6-O- (t-
Butyldimethylsilyl) -3,4-O-isopropylidene-3,4,6
1.0 g (2.49 mmol) of -trihydroxy-1H-azepine was dissolved in 10 ml of dioxane, 5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. The resulting water 15ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, 0.31 g of (3R, 4R, 6S) -hexahydro-3,4,6-trihydroxy-1H-azepine (2.11 mmol, yield 85
%)Obtained. Infrared absorption spectrum (KBr): 3335, 1647, 1540, 145
7,1417,1283 cm ^-1 Specific rotation [α]: + 20.8 ° (c 0.132, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 34.
23, 44.43, 49.85, 71.98, 73.99, 80.79. High performance liquid chromatography (6: 4): 11.4 min Elemental analysis: As C ₆ H ₁₃ NO ₃ , theoretical value (%): C, 4
8.97; H, 8.90; N, 9.52. Observed value (%): C, 48.7
9; H, 8.95; N, 9.58.

Example 11 (3S, 4R, 5R, 6R) -Hexahydro-3-azido-4,5,6-trihydroxy-1H-azepine [Compound (11) of the present invention] Obtained in Reference Example 2. (3R, 4R, 5R, 6R) -Hexahydro-3,4,5,6-
20.0 g (123 mmol) of tetrahydroxy-1H-azepine in water 40
The mixture was dissolved in 0 ml, and 30 ml (135 mmol) of di-t-butyl dicarbonate and 5.4 g (135 mmol) of sodium hydroxide were added, and the mixture was reacted at room temperature with stirring for 20 hours. The obtained reaction solution was washed with 200 ml of diethyl ether, and the aqueous layer was concentrated under reduced pressure.
The residue is purified by ODS column chromatography, and the fraction containing the target product eluted with a mixture of ethanol and water (volume ratio 1: 3) is concentrated to dryness to give (3R, 4R, 5R, 6R)- Hexahydro-1-N- (t-butyloxycarbonyl) -3,4,5,6-
26.6 g of tetrahydroxy-1H-azepine (101 mmol, yield
82%). The obtained (3R, 4R, 5R, 6R) -hexahydro-1-N
-(t-Butyloxycarbonyl) -3,4,5,6-tetrahydroxy-1H-azepine (26.0 g, 99 mmol) was dissolved in dimethylformamide (260 ml), and 2,2-dimethoxypropane (15 ml, 123 mm
ol) and 1.9 g (10 mmol) of p-toluenesulfonic acid monohydrate
Was added and reacted at room temperature for 3 hours with stirring. After adding 0.83 g (10 mmol) of sodium hydrogen carbonate to the obtained reaction solution, the mixture was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and the fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio 3: 2) was concentrated and dried to give (3R, 4R, 5R (6,6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -4,5-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine.
7 g (35.3 mmol, 36% yield) was obtained. Infrared absorption spectrum (KBr): 3509, 1694, 1457, 1413, 1365 cm ^-1 .

Further, the fraction eluted with an ethyl acetate-hexane mixed solution (volume ratio: 4: 1) was concentrated to dryness to obtain (3R, 4R, 5R, 6R)
-Hexahydro-1-N- (t-butyloxycarbonyl) -3,4-O
13.0 g (42.9 mmol, yield 43%) of 1-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine was obtained. Infrared absorption
Vector (KBr): 3404, 1679, 1421, 1365 cm ^-1 . The obtained (3R, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -4,5-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine 10.0 g (33.0 mmol) of pyridine 1
Dissolved in 00ml, methanesulfonyl chloride 3.0ml (38.8m
mol) was added and reacted at room temperature for 20 hours. After adding 10 ml of water to the obtained reaction solution and concentrating to dryness under reduced pressure, the residue was purified by silica gel column chromatography,
The fraction eluted with a mixture of ethyl acetate and hexane (volume ratio 3: 2) was concentrated to dryness, and then concentrated to (3R, 4R, 5R, 6R) -hexahydro-1-N-
3.8 g of (t-butyloxycarbonyl) -3,6-di (O-methanesulfonyl) -4,5-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine (7.8 mmol, Yield 24%). Infrared absorption spectrum (KBr): 1698, 1460, 1415, 1359cm
-1. In addition, ethyl acetate-hexane mixed solution (volume ratio 3: 2)
Concentrate the fractions containing the target substance eluted in
(R, 4R, 5R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-O-methanesulfonyl-4,5-O-isopropylidene-
9.3 g of 3,4,5,6-tetrahydroxy-1H-azepine (24.4 mm
ol, yield 74%). Infrared absorption spectrum (KBr): 350
4,1684,1458,1418,1363 cm ^-1 . (3R, 4R, 5R,
6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-
O-methanesulfonyl-4,5-O-isopropylidene-3,4,5,6-
8.0 g (21.0 mmol) of tetrahydroxy-1H-azepine was dissolved in 120 ml of dimethylformamide, and sodium azide 2.7 g was dissolved.
g (41.5 mmol) was added and reacted at 120 ° C. for 2 hours with stirring. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio of 2: 3) was concentrated. Dry to (3S, 4R, 5R, 6
R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-
5.5 g (16.7 mmol, 80% yield) of azide-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine were obtained. Infrared absorption spectrum (KBr): 2111, 1698, 1459, 1415, 1
369 cm ^-1 . The obtained (3S, 4R, 5R, 6R) -hexahydro-1-N-
1.0 g of (t-butyloxycarbonyl) -3-azido-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine (3.0
5 mmol) was dissolved in 10 ml of dioxane, and 5 ml of concentrated hydrochloric acid was added.
The reaction was performed at room temperature for 2 hours. The resulting water 15ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, 0.50 g (2.66 mmol, 87% yield) of (3S, 4R, 5R, 6R) -hexahydro-3-azido-4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3335, 2112, 1640, 154
9,1453,1412,1261cm-1 Specific rotation [α]: -21.0 ° (c 0.104, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 48.
70, 51.15, 68.81, 70.80, 73.74, 75.03. High performance liquid chromatography (7:
3): 6.8 min Elemental analysis: C ₆ H ₁₂ N ₄ O ₃ , theoretical value (%): C, 3
8.29; H, 6.43; N, 29.77. Observed value (%): C, 38.4
4; H, 6.47; N, 29.68.

Example 12 (3S, 4R, 5R, 6S) -Hexahydro-3,6-diazide-4,5-dihydroxy-1H-azepine [Compound of the present invention (12)] Obtained in Example 11 ( 3R, 4R, 5R, 6R) -Hexahydro-1-N- (t-
(Butyloxycarbonyl) -3,6-di (O-methanesulfonyl)
-4,5-O-isopropylidene-3,4,5,6-tetrahydroxy-1
3.0 g (6.5 mmol) of H-azepine in 45 m of dimethylformamide
Then, 1.3 g (20.0 mmol) of sodium azide was added, and the mixture was reacted at 120 ° C. for 2 hours with stirring. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with a mixed solution of ethyl acetate-hexane (volume ratio 1: 3) was concentrated. After drying, (3S, 4R, 5R, 6S) -hexahydro-1-N-
1.7 g of (t-butyloxycarbonyl) -3,6-diazide-4,5-O-isopropylidene-4,5-dihydroxy-1H-azepine
(4.8 mmol, 74% yield). Infrared absorption spectrum (KB
r): 2125, 1686, 1460, (1415), 1372 cm- ¹ . Got
1.0 g of (3S, 4R, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) -3,6-diazide-4,5-O-isopropylidene-4,5-dihydroxy-1H-azepine (2.83 mmol) in dioxane
It was dissolved in 10 ml, concentrated hydrochloric acid (5 ml) was added, and the mixture was reacted at room temperature for 2 hours. The resulting water 15ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, 0.49 g of (3S, 4R, 5R, 6S) -hexahydro-3,6-diazide-4,5-dihydroxy-1H-azepine (2.30 mmol,
Yield 81%). Infrared absorption spectrum (KBr): 3332, 2115, 1630, 146
0, 1262 cm ^-1 Specific rotation [α]: + 24.8 ° (c 0.152, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 51.
22, 66.17, 74.33. High performance liquid chromatography (7:
3): 8.2 min Elemental analysis: As C ₆ H ₁₁ N ₇ O ₂ , theoretical value (%): C, 3
3.80; H, 5.20; N, 45.99. Observed value (%): C, 33.7
3; H, 5.34; N, 46.13.

Example 13 (3R, 4S, 5R, 6R) -hexahydro-4-azido-3,5,6-trihydroxy-1H-azepine [Compound of the present invention (13)] Obtained in Example 11. (3R, 4R, 5R, 6R) -Hexahydro-1-N- (t-
(Butyloxycarbonyl) -3,4-O-isopropylidene-3,
4,5,6-tetrahydroxy-1H-azepine 10.0 g (33.0 mmo
l) was dissolved in 100 ml of pyridine, 3.0 ml (38.8 mmol) of methanesulfonyl chloride was added, and the mixture was reacted at room temperature for 20 hours. After adding 10 ml of water to the obtained reaction solution and concentrating to dryness under reduced pressure, the residue was purified by silica gel column chromatography, and an ethyl acetate-hexane mixed solution (volume ratio: 3:
The fraction eluted in 2) was concentrated to dryness, and (3R, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3,4-di (O
-Methanesulfonyl) -5,6-O-isopropylidene-3,4,5,6-
2.9 g of tetrahydroxy-1H-azepine (6.3 mmol, yield 1
9%). Infrared absorption spectrum (KBr): 1697, 1458,
1420, 1362 cm ^-1 . Further, the fraction containing the target substance eluted with an ethyl acetate-hexane mixed solution (volume ratio of 3: 2) is concentrated to dryness, and then (3R, 4R, 5R, 6R) -hexahydro-1-N- (t-butyl (Oxycarbonyl) -3-O-methanesulfonyl-5,6-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine and (3R, 4R, 5R, 6R) -hexahydro-1-N 7.2 g of a mixture of-(t-butyloxycarbonyl) -4-O-methanesulfonyl-5,6-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine (18.9 mmol, yield 57%). (3R, 4
(R, 5R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3 (or4) -O-methanesulfonyl-5,6-O-isopropylidene-3,4,5,6-tetrahydroxy 6.0g of -1H-azepine (15.7m
mol) was dissolved in 90 ml of dimethylformamide, 2.0 g (30.8 mmol) of sodium azide was added, and the mixture was reacted at 120 ° C. for 2 hours with stirring. After concentrating the obtained reaction solution to dryness under reduced pressure,
The residue was purified by silica gel column chromatography, and the fraction eluted with an ethyl acetate-hexane mixed solution (volume ratio 2: 3) was concentrated to dryness to give (3S, 4R, 5R, 6R) -hexahydro-1- N- (t-butyloxycarbonyl) -3-azido-5,6-
2.2 g (6.7 mmol, 43% yield) of O-isopropylidene-4,5,6-trihydroxy-1H-azepine was obtained.

Further, the fraction containing the target substance eluted with an ethyl acetate-hexane mixed solution (volume ratio of 2: 3) is concentrated to dryness, and the residue is concentrated to (3R, 4S, 5R, 6R) -hexahydro-1-N- ( (t-butyloxycarbonyl) -4-azido-5,6-O-isopropylidene-3,5,6-
2.1 g of trihydroxy-1H-azepine (6.4 mmol, yield 41)
%)Obtained. Infrared absorption spectrum (KBr): 3471, 2105, 1
678, 1409 cm ^-1 . The obtained (3R, 4S, 5R, 6R) -hexahydro
-1-N- (t-butyloxycarbonyl) -4-azido-5,6-O-isopropylidene-3,5,6-trihydroxy-1H-azepine 0.5
g (1.52 mmol) in 5 ml of dioxane and 2.5 ml of concentrated hydrochloric acid
Was added and reacted at room temperature for 2 hours. Water is added to the obtained reaction solution.
7.5ml was added anion-exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4S, 5R ,
6R) -Hexahydro-4-azido-3,5,6-trihydroxy-1H-
0.20 g (1.06 mmol, 70% yield) of azepine was obtained. Infrared absorption spectrum (KBr): 3321, 2108, 1642, 145
0,1279 cm ^-1 specific rotation [α]: + 16.5 ° (c 0.133, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 46.
26, 51.65, 53.35, 65.81, 69.91, 71.14. High-performance liquid chromatography (7: 3): 6.6 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₂ N ₄ O ₃ : C, 3
8.29; H, 6.43; N, 29.77. Observed value (%): C, 38.3
5; H, 6.67; N, 29.70.

Example 14 (3S, 4S, 5R, 6R) -Hexahydro-3,4-diazide-5,6-dihydroxy-1H-azepine [Compound of the present invention (14)] Obtained in Example 13 ( 3R, 4R, 5R, 6R) -Hexahydro-1-N- (t-
(Butyloxycarbonyl) -3,4-di (O-methanesulfonyl)
-5,6-O-isopropylidene-3,4,5,6-tetrahydroxy-1
2.0 g (4.4 mmol) of H-azepine in 30 m of dimethylformamide
Then, 0.57 g (8.8 mmol) of sodium azide was added, and the mixture was reacted at 120 ° C. for 2 hours with stirring. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. Dry to dryness, (3S, 4S, 5R, 6R) -hexahydro-1-N-
1.2 g of (t-butyloxycarbonyl) -3,4-diazide-5,6-O-isopropylidene-5,6-dihydroxy-1H-azepine
(3.4 mmol, 77% yield). Infrared absorption spectrum (KB
r): 2114, 1698, 1458, 1417, 1367 cm ^-1 . Obtained (3
S, 4S, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3,4-diazide-5,6-O-isopropylidene-5,6-dihydroxy-1H-azepine 1.0 g ( 2.83 mmol) in dioxane 10
The resulting mixture was dissolved in 5 ml, concentrated hydrochloric acid (5 ml) was added and the mixture was reacted at room temperature for 2 hours. The resulting water 15ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, 0.29 g of (3S, 4S, 5R, 6R) -hexahydro-3,4-diazide-5,6-dihydroxy-1H-azepine (1.36 mmol,
Yield 48%). Infrared absorption spectrum (KBr): 3294, 2112, 2078, 164
7, 1466, 1318, 1225 cm ^-1 Specific rotation [α]: -35.4 ° (c 0.114, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 48.
69, 51.30, 55.38, 58.52, 61.64, 70.27. High-performance liquid chromatography (7: 3): 7.9 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₁ N ₇ O ₂ : C, 3
3.80; H, 5.20; N, 45.99. Observed value (%): C, 33.8
9; H, 5.17; N, 45.82.

<Example 15> (3S, 4R, 5R, 6R) -Hexahydro-3-amino-4,5,6-trihydroxy-1H-azepine dihydrochloride [Compound (15) of the present invention] Example 11 (3S, 4R, 5R, 6R) -hexahydro-1-N- (t-
Butyloxycarbonyl) -3-azido-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 6.0 g (18.3 m
mol) was dissolved in 120 ml of ethanol, and 0.6 g of 10% palladium carbon was added.
Allowed to react for hours. After filtering off insolubles, the obtained filtrate was concentrated to dryness under reduced pressure. The obtained residue was purified by subjecting it to silica gel column chromatography, and the fraction containing the target substance eluted with a mixed solution of ethyl acetate-methanol-water (volume ratio: 20: 2: 1) was concentrated to dryness, followed by (3S , 4R, 5R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-amino-4,5-O-
5.0 g (16.5 mmol, 90% yield) of isopropylidene-4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3369, 3269, 1702, 1459, 1411, 1366 c
m ^-1 . The obtained (3S, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3-amino-4,5-O-isopropylidene-4,5,6-trihydroxy-1H -Azepine 1.0g (3.31mmo
l) was dissolved in 10 ml of dioxane, 5 ml of concentrated hydrochloric acid was added, and the mixture was allowed to react at room temperature for 1 hour, and then left at 5 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with dioxane, dried, and (3S, 4
0.65 g (2.76 mmol, yield 83) of (R, 5R, 6R) -hexahydro-3-amino-4,5,6-trihydroxy-1H-azepine dihydrochloride
%)Obtained. Melting point: 219-223 ° C Infrared absorption spectrum (KBr): 3374, 3244, 1597, 151
4,1453,1372,1352cm ^-1 Specific rotation [α]: -25.3 ° (c 0.118, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 42.
. 25,45.07,50.79,66.31,71.63,75.43 high performance liquid chromatography (4: 6): 11.3 min Elemental analysis: as _{C 6 H 16 C l 2 N} 2 O 3, the theoretical value (%):
C, 30.65; H, 6.86; N, 11.92. Measured value (%): C,
30.43; H, 6.94; N, 11.99.

Example 16 (3R, 4S, 5R, 6R) -Hexahydro-4-amino-3,5,6-trihydroxy-1H-azepine [Compound (16) of the present invention] Obtained in Example 13. (3R, 4S, 5R, 6R) -Hexahydro-1-N- (t-
(Butyloxycarbonyl) -4-azido-5,6-O-isopropylidene-3,5,6-trihydroxy-1H-azepine 1.0 g (3.0 mm
ol) was dissolved in 20 ml of ethanol, 0.1 g of 10% palladium carbon was added, and the mixture was reacted at room temperature for 20 hours with stirring under introduction of hydrogen gas. After filtering off insolubles, the obtained filtrate was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and the fraction containing the target product eluted with a mixed solution of ethyl acetate-methanol-water (volume ratio: 20: 2: 1) was concentrated and dried, and then subjected to (3R , 4S, 5R, 6R) -Hexahydro-1
-N- (t-butyloxycarbonyl) -4-amino-5,6-O-isopropylidene-3,5,6-trihydroxy-1H-azepine.
86 g (2.8 mmol, 93% yield) was obtained. Infrared absorption spectrum (KBr): 3307, 1690, 1454, 1405, 1367 cm ^-1 . The obtained (3R, 4S, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -4-amino-5,6-O-isopropylidene-3,5,6-trihydroxy-1H -Azepine (0.5 g, 1.65 mmol) was dissolved in dioxane (5 ml), concentrated hydrochloric acid (2.5 ml) was added, and the mixture was reacted at room temperature for 2 hours. The resulting water 7.5ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water , 0.23 g (1.29 g) of (3R, 4S, 5R, 6R) -hexahydro-4-amino-3,5,6-trihydroxy-1H-azepine
mmol, 78% yield). Infrared absorption spectrum (KBr): 3341, 1647, 1559, 145
7,1339 cm ^-1 specific rotation [α]: + 6.4 ° (c 0.112, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 42.
97, 46.51, 54.77, 66.10, 70.84, 71.26. High performance liquid chromatography (4: 6): 9.2 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₄ N ₂ O ₃ : C, 4
4.43; H, 8.70; N, 17.27. Observed value (%): C, 44.4
8; H, 8.76; N, 17.32.

Example 17 (3S, 4R, 5R, 6S) -Hexahydro-3,6-diamino-4,5-dihydroxy-1H-azepine trihydrochloride [Compound (17) of the present invention] The obtained (3S, 4R, 5R, 6S) -hexahydro-1-N- (t-
(Butyloxycarbonyl) -3,6-diazide-4,5-O-isopropylidene-4,5-dihydroxy-1H-azepine 2.0 g (5.7 mm
ol) was dissolved in 40 ml of ethanol, 0.2 g of 10% palladium carbon was added, and the mixture was reacted at room temperature for 20 hours with stirring under introduction of hydrogen gas. After filtering off insolubles, the obtained filtrate was concentrated to dryness under reduced pressure. The obtained residue was purified by subjecting it to silica gel column chromatography, and the fraction containing the target substance eluted with a mixed solution of ethyl acetate-methanol-water (volume ratio 7: 2: 1) was concentrated to dryness, followed by (3S , 4R, 5R, 6S) -Hexahydro-1
-N- (t-butyloxycarbonyl) -3,6-diamino-4,5-O-
Isopropylidene-4,5-dihydroxy-1H-azepine
g (4.0 mmol, yield 70%) was obtained. Infrared absorption spectrum (KB
r): 3368, 1685, 1586, 1471, 1419, 1368 cm- ¹ . The obtained (3S, 4R, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) -3,6-diamino-4,5-O-isopropylidene-4,
0.5 g (1.66 mmol) of 5-dihydroxy-1H-azepine was dissolved in 5 ml of dioxane, and 2.5 ml of concentrated hydrochloric acid was added. The mixture was allowed to react at room temperature for 1 hour, and then left at 5 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with dioxane, and dried, and (3S, 4R, 5R, 6S) -hexahydro-3,6-diamino-4,5-dihydroxy-1H-azepine trihydrochloride 0.34 g (1.26 mmol, 76% yield) was obtained. Infrared absorption spectrum (KBr): 3404, 1616, 1507 cm ^-1 Specific rotation [α]: + 17.5 ° (c 0.108, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 42 .
. 19,48.85,71.97 high performance liquid chromatography (4: 6): 3.4 min Elemental analysis: C ₆ H ₁₈ as C _{l 3} N ₃ O _2, the theoretical value (%):
C, 26.63; H, 6.71; N, 15.53. Measured value (%): C,
26.88; H, 6.82; N, 15.50.

Example 18 (3S, 4R, 5R, 6R) -Hexahydro-3- (2-hydroxyethylamino) -4,5,6-trihydroxy-1H-azepine [Compound (18) of the present invention] (3S, 4R, 5R, 6R) -hexahydro-1-N- (t-
Butyloxycarbonyl) -3-amino-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 1.0 g (3.3 mm
ol) was dissolved in 10 ml of dimethylformamide, and 1.2 ml (17 mmol) of 2-bromoethanol and 1.2 g (9 mmo) of potassium carbonate were dissolved.
l) was added and reacted at 60 ° C. for 20 hours. The obtained reaction solution was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and the fraction containing the target product eluted with a mixture of ethyl acetate-methanol-water (volume ratio: 100: 2: 1) was concentrated to dryness, followed by (3S , 4R, 5R, 6R)-
Hexahydro-1-N- (t-butyloxycarbonyl) -3- (2-
(Hydroxyethylamino) -4,5-O-isopropylidene-4,
0.92 g (2.7 mmol, yield 82%) of 5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3412, 169
3, 1464, 1416, 1369 cm ^-1 . The obtained (3S, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3- (2-hydroxyethylamino) -4,5-O-isopropylidene-4,5, 6
0.5 g (1.44 mmol) of -trihydroxy-1H-azepine was dissolved in 5 ml of dioxane, 2.5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 1 hour. The resulting water 7.5ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water , (3S, 4R, 5R, 6R) -hexahydro-3
-(2-hydroxyethylamino) -4,5,6-trihydroxy-1
0.19 g (0.92 mmol, yield 64%) of H-azepine was obtained. Infrared absorption spectrum (KBr): 3320, 1647, 1541, 145
8,1418,1287 cm ^-1 Specific rotation [α]: + 13.6 ° (c 0.118, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 47.
04, 49.24, 51.75, 60.39, 63.36, 72.63, 74.80, 78.3
2. High performance liquid chromatography (4: 6): 8.2 min Elemental analysis: C ₈ H ₁₈ N ₂ O ₄ , theoretical value (%): C, 4
6.59; H, 8.80; N, 13.58. Observed value (%): C, 46.5
3; H, 8.85; N, 13.47.

Example 19 (3S, 4R, 5R, 6R) -Hexahydro-3-benzylamino-4,5,6-trihydroxy-1H-azepine [Compound (19) of the present invention] Obtained in Example 15 (3S, 4R, 5R, 6R) -Hexahydro-1-N- (t-
Butyloxycarbonyl) -3-amino-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 1.0 g (3.3 mm
ol) was dissolved in 10 ml of dimethylformamide, and 0.6 ml (5.0 mmol) of benzyl bromide and 0.35 g (2.5%) of potassium carbonate were dissolved.
mmol) and reacted at room temperature for 20 hours. The obtained reaction solution was concentrated to dryness under reduced pressure. The obtained residue was purified by subjecting it to silica gel column chromatography, and the fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio 1: 1) was concentrated to dryness, followed by (3S, 4R, 5R (6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-benzylamino
1.1 g (2.8 mmol, 85% yield) of -4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3341, 1693, 1461, 1415, 1368 c
m ^-1 . The obtained (3S, 4R, 5R, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3-benzylamino-4,5-O-isopropylidene-4,5,6-trihydroxy- 0.5 g of 1H-azepine
(1.27 mmol) was dissolved in 5 ml of dioxane, 2.5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 1 hour. The obtained reaction solution is mixed with water 7.5
ml of an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3S, 4R, 5R, 6
0.26 g (1.03 mmol, 81% yield) of R) -hexahydro-3-benzylamino-4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3302, 1544, 1455, 141
6,1280 cm ^-1 specific rotation [α]: + 27.2 ° (c 0.152, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 47.
00, 50.53, 51.82, 62.64, 72.68, 74.56, 78.33, 126.
55, 127.96, 128.08, 140.63. High performance liquid chromatography (6: 4): 7.2 min Elemental analysis: As C ₁₃ H ₂₀ N ₂ O ₃ , theoretical value (%): C,
61.88; H, 7.99; N, 11.10. Observed value (%): C, 61.7
6; H, 7.91; N, 11.18.

<Example 20> (3R, 4R, 6R) -Hexahydro-3,4,6-trihydroxy-1H-azepine [Compound of the present invention (20)] (3R, 4R, 5R) obtained in Example 11 , 6R) -Hexahydro-1-N- (t-
(Butyloxycarbonyl) -3,4-O-isopropylidene-3,
6.6 g (21.8 mmol) of 4,5,6-tetrahydroxy-1H-azepine
Was dissolved in 70 ml of pyridine, 4.0 g (26.5 mmol) of t-butyldimethylchlorosilane was added, and the mixture was reacted at 60 ° C. for 20 hours with stirring. The resulting reaction solution is concentrated to dryness under reduced pressure, and the residue is purified by silica gel column chromatography. Dry to (3R, 4R, 5R, 6
R) -Hexahydro-1-N- (t-butyloxycarbonyl) -6-O
-(t-butyldimethylsilyl) -3,4-O-isopropylidene-
6.0g of 3,4,5,6-tetrahydroxy-1H-azepine (14.4mm
ol, yield 66%). Infrared absorption spectrum (KBr): 348
8, 1701, 1460, 1421, 1366 cm ^-1 . (3R, 4R, 5R,
6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -6-
O- (t-butyldimethylsilyl) -3,4-O-isopropylidene-
2.0g of 3,4,5,6-tetrahydroxy-1H-azepine (4.8mmo
l) was dissolved in tetrahydrofuran (40 ml), 1.0 g (25 mmol) of sodium hydride (oily) and 3 mg of imidazole were added, and the mixture was reacted at room temperature for 30 minutes with stirring.

Next, 2.9 ml (48 mmol) of carbon disulfide was added, and the mixture was further reacted at room temperature for 30 minutes.
2 ml (19 mmol) was added, and the mixture was further reacted at room temperature for 30 minutes. 200 ml of dichloromethane was added to the obtained reaction solution, and 5%
After washing with an aqueous sodium hydrogen carbonate solution, washing with water, drying the organic layer with sodium sulfate, the solvent was concentrated to dryness under reduced pressure. The obtained residue was dissolved in toluene (40 ml), and tributyltin hydride (5.0 ml, 19 mmol) was added.
The reaction was performed for 0 hours. After the obtained reaction solution was concentrated to dryness under reduced pressure, the residue was purified by silica gel column chromatography, and an ethyl acetate-hexane mixed solution (volume ratio 1: 1:
Concentrate and dry the section containing the target substance eluted in 5),
(3R, 4R, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -6-O- (t-butyldimethylsilyl) -3,4-O-isopropylidene-3,4,6-tri 1.5 g of hydroxy-1H-azepine
(3.7 mmol, 77% yield). Infrared absorption spectrum (KB
r): 1701, 1462, 1417, 1366 cm- ¹ . (3R, 4R,
6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -6-
O- (t-butyldimethylsilyl) -3,4-O-isopropylidene-
0.5 g (1.24 mmol) of 3,4,6-trihydroxy-1H-azepine was dissolved in 5 ml of dioxane, and 2.5 ml of concentrated hydrochloric acid was added.
Allowed to react for hours. Water 7.5ml was added to the resulting reaction solution, an anion exchange resin (DOWEX1-X4, OH ^-) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4R, 6R) -Hexahydro-3,
0.17 g of 4,6-trihydroxy-1H-azepine (1.16 mmol,
Yield 94%). Infrared absorption spectrum (KBr): 3338, 3298, 3232, 165
3,1541,1456,1342cm ^-1 Specific rotation [α]: -28.7 ° (c 0.115, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 37.
72, 52.41, 55.72, 66.60, 68.67, 73.95. High performance liquid chromatography (6: 4): 10.4 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₃ NO ₃ : C, 4
8.97; H, 8.90; N, 9.52. Observed value (%): C, 48.9
3; H, 8.84; N, 9.48.

Example 21 (3R, 4R, 5S, 6R) -Hexahydro-3-azido-4,5,6-trihydroxy-1H-azepine [Compound of the present invention (21)] Obtained in Reference Example 3. (3R, 4S, 5R, 6S) -Hexahydro-3,4,5,6-
20.0 g (123 mmol) of tetrahydroxy-1H-azepine in water 40
The mixture was dissolved in 0 ml, and 30 ml (135 mmol) of di-t-butyl dicarbonate and 5.4 g (135 mmol) of sodium hydroxide were added, and the mixture was reacted at room temperature with stirring for 20 hours. The obtained reaction solution was washed with 200 ml of diethyl ether, and the aqueous layer was concentrated under reduced pressure. The residue was purified by ODS column chromatography, and eluted with an ethanol-water mixture (volume ratio 1: 3). The product containing fractions are concentrated to dryness and (3R, 4S, 5R, 6S) -hexahydro-1-N- (t-butyloxycarbonyl) -3,4,5,6-tetrahydroxy-1H-azepine 25.2 g (96 mmol, yield 78
%)Obtained. The obtained (3R, 4S, 5R, 6S) -hexahydro-1-N-
(t-Butyloxycarbonyl) -3,4,5,6-tetrahydroxy-1H-azepine (15.0 g, 57 mmol) was dissolved in dimethylformamide (150 ml), and 2,2-dimethoxypropane (12 ml, 98 mmo
l) and 2.1 g (11 mmol) of p-toluenesulfonic acid monohydrate
Was added and reacted at room temperature for 20 hours with stirring. After adding 1.0 g (12 mmol) of sodium hydrogen carbonate to the obtained reaction solution, the mixture was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and the fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio 3: 2) was concentrated to dryness, and then subjected to (3R, 4S, 5R 15.6 g of (6,6S) -hexahydro-1-N- (t-butyloxycarbonyl) -4,5-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine
(51 mmol, 89% yield). Infrared absorption spectrum (KB
r): 3470, 1685, 1425, 1368, 1307 cm ^-1 .

The obtained (3R, 4S, 5R, 6S) -hexahydro-1-N
-(t-butyloxycarbonyl) -4,5-O-isopropylidene
-3,4,5,6-tetrahydroxy-1H-azepine 12.5g (41.2mm
ol) was dissolved in 125 ml of pyridine, 4.0 ml (52 mmol) of methanesulfonyl chloride was added, and the mixture was reacted at room temperature for 20 hours. After adding 15 ml of water to the obtained reaction solution and concentrating it to dryness under reduced pressure, the residue was purified by silica gel column chromatography, and an ethyl acetate-hexane mixed solution (volume ratio 3: 3).
Concentrate and dry the section containing the target substance eluted in 2),
(3S, 4R, 5S, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-O-methanesulfonyl-4,5-O-isopropylidene-3,4,5,6-tetrahydroxy 12.9g of -1H-azepine (3
3.8 mmol, yield 82%). Infrared absorption spectrum (KB
r): 3506, 1698, 1409, 1348, 1296 cm ^-1 . Obtained (3
(S, 4R, 5S, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl) -3-O-methanesulfonyl-4,5-O-isopropylidene-
3,4,5,6-tetrahydroxy-1H-azepine 10.0 g (26.2 mmo
l) was dissolved in 100 ml of dimethylformamide, 3.4 g (52.3 mmol) of sodium azide was added, and the mixture was reacted at 120 ° C. for 3 hours with stirring. The resulting reaction solution is concentrated to dryness under reduced pressure, and the residue is purified by silica gel column chromatography. Dry to dry, (3R, 4R, 5
(S, 6R) -Hexahydro-1-N- (t-butyloxycarbonyl)-
6.5 g (19.8 mmol, 76% yield) of 3-azido-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3436, 2119, 1694, 1412, 1
389, 1371 cm ^-1 . The obtained (3R, 4R, 5S, 6R) -hexahydro
-1-N- (t-butyloxycarbonyl) -3-azido-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 1.0
g (3.05 mmol) was dissolved in 10 ml of dioxane, 5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. 15 m of water is added to the obtained reaction solution.
l was added anion-exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4R, 5S, 6R)-
0.53 g (2.82 mmol, 92% yield) of hexahydro-3-azido-4,5,6-trihydroxy-1H-azepine was obtained. Infrared absorption spectrum (KBr): 3440, 2114, 1499, 146
7, 1420, 1389, 1348 cm ^-1 Specific rotation [α]: + 8.7 ° (c 0.204, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 51.
48, 53.40, 65.65, 70.36, 71.81, 77.31. High performance liquid chromatography (6: 4): 4.5 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₂ N ₄ O ₃ : C, 3
8.29; H, 6.43; N, 29.77. Observed value (%): C, 38.1
7; H, 6.61; N, 29.65.

Example 22 (3R, 4R, 5S, 6R) -Hexahydro-3-amino-4,5,6-trihydroxy-1H-azepine [Compound of the present invention (22)] Obtained in Example 21 (3R, 4R, 5S, 6R) -Hexahydro-1-N- (t-
Butyloxycarbonyl) -3-azido-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 1.3 g (3.96 m
mol) was dissolved in 30 ml of ethanol, 0.13 g of 10% palladium carbon was added, and the mixture was stirred at room temperature while introducing hydrogen gas.
Allowed to react for hours. After filtering off insolubles, the obtained filtrate was concentrated to dryness under reduced pressure. The obtained residue was dissolved in 10 ml of dioxane, 5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. 15 ml of water is added to the obtained reaction solution, and an anion exchange resin (DOWEX 1-
X4, OH ^-) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4R, 5S, 6R) - hexahydro-3-amino-4,5 0.49 g of 2,6-trihydroxy-1H-azepine (3.02 mmol, yield 76
%)Obtained. Infrared absorption spectrum (KBr): 3394, 1618, 1509, 141
3,1304 cm ^-1 specific rotation [α]: + 1.7 ° (c 0.128, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 52.
86, 54.40, 59.13, 73.45, 74.25, 75.73. High performance liquid chromatography (4: 6): 6.9 min Elemental analysis: As C ₆ H ₁₄ N ₂ O ₃ , theoretical value (%): C, 4
4.43; H, 8.70; N, 17.27. Observed value (%): C, 44.3
7; H, 8.62; N, 17.17.

Example 23 (3R, 4R, 5S, 6R) -Hexahydro-3-benzylamino-4,5,6-trihydroxy-1H-azepine [Compound (23) of the present invention] Obtained in Example 21 (3R, 4R, 5S, 6R) -Hexahydro-1-N- (t-
(Butyloxycarbonyl) -3-azido-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine 2.0 g (6.09 m
mol) was dissolved in 40 ml of ethanol, 0.2 g of 10% palladium carbon was added, and the mixture was reacted at room temperature for 20 hours with stirring under introduction of hydrogen gas. After filtering off insolubles, the obtained filtrate was concentrated to dryness under reduced pressure. The resulting residue was dissolved in acetonitrile dimethylformamide 20 ml, benzyl bromide 0.86 ml
(7.2 mmol) and 0.5 g (3.6 mmol) of potassium carbonate,
The reaction was performed at room temperature for 20 hours. The obtained reaction solution was concentrated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography for purification, and the fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio 1: 1) was concentrated to dryness, followed by (3R, 4R, 5S 1.4 g of (6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3-benzylamino-4,5-O-isopropylidene-4,5,6-trihydroxy-1H-azepine
(3.57 mmol, 59% yield). Infrared absorption spectrum (KB
r): 3449, 1686, 1458, 1413, 1369 cm- ¹ . Obtained (3
(R, 4R, 5S, 6R) -hexahydro-1-N- (t-butyloxycarbonyl) -3-benzylamino-4,5-O-isopropylidene-4,5,
1.0 g (2.55 mmol) of 6-trihydroxy-1H-azepine was dissolved in 10 ml of dioxane, 5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 1 hour. The resulting water 15ml was added to the reaction mixture, an anion exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, 0.5 g of (3R, 4R, 5S, 6R) -hexahydro-3-benzylamino-4,5,6-trihydroxy-1H-azepine
8 g (2.30 mmol, 92% yield) were obtained. Infrared absorption spectrum (KBr): 3402, 1618, 1459 cm ^-1 Specific rotation [α]: -1.3 ° (c 0.142, EtOH) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 42.
86, 47.33, 47.95, 54.73, 66.01, 67.34, 73.63, 128.
56, 128.84, 130.12, 131.78. High performance liquid chromatography (6: 4): 6.1 min Elemental analysis: As C ₁₃ H ₂₀ N ₂ O ₃ , theoretical value (%): C,
61.88; H, 7.99; N, 11.10. Observed value (%): C, 61.9
4; H, 8.06; N, 10.96.

Example 24 (3R, 4S, 5R) -Hexahydro-3,4,5-trihydroxy-1H-azepine [Compound (24) of the present invention] (3R, 4S, 5R) obtained in Example 21 , 6S) -Hexahydro-1-N- (t-
(Butyloxycarbonyl) -4,5-O-isopropylidene-3,
2.0 g (6.59 mmol) of 4,5,6-tetrahydroxy-1H-azepine
Was dissolved in 100 ml of toluene, and 2.7 ml (19.5 mmol) of phenylchlorothionocarbonate and 2.7 ml (33.4 mm
ol) and 0.5 g (4.3 mmol) of N-hydroxysuccinimide were added and reacted at 80 ° C. for 2 hours. 1000 ml of toluene was added to the obtained reaction solution, which was washed three times with a 1M aqueous solution of citric acid, three times with a saturated aqueous solution of sodium hydrogen carbonate, washed with water, and the organic layer was dried over anhydrous sodium sulfate. It was concentrated and distilled off. The obtained residue is purified by subjecting it to silica gel column chromatography, and the fraction containing the target product eluted with an ethyl acetate-hexane mixed solution (volume ratio of 3: 2) is concentrated to dryness, and then subjected to (3S, 4R, 5S , 6R) -Hexahydro-1-N-
2.0 g (4.55 mmol, yield 69) of (t-butyloxycarbonyl) -3-O-phenyloxythiocarbonyl-4,5-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine %)Obtained. Infrared absorption spectrum (KBr): 3471, 1702, 1592, 1
492, 1390, 1284 cm ^-1 .

The obtained (3S, 4R, 5S, 6R) -hexahydro-1-N
1.5 g (3.41 mmol) of-(t-butyloxycarbonyl) -3-O-phenyloxythiocarbonyl-4,5-O-isopropylidene-3,4,5,6-tetrahydroxy-1H-azepine in 30 ml of toluene
And 6.5 ml (24.2 mmol) of tributyltin hydride and 0.28 g (1.7 mmo) of 2,2′-azobis (isobutyronitrile)
l) was added and reacted at 90 ° C. for 1 hour. The obtained reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fraction containing the target product eluted with an ethyl acetate-hexane mixture (volume ratio of 3: 7) was concentrated. To dryness, (3R, 4S, 5R) -hexahydro-1-N- (t-butyloxycarbonyl) -4,5-O-isopropylidene-3,4,5
0.81 g (2.82 mmol, yield) of 1-trihydroxy-1H-azepine
83%). Infrared absorption spectrum (KBr): 3476, 168
6, 1459, 1414, 1369 cm ^-1 . The obtained (3R, 4S, 5R) -hexahydro-1-N- (t-butyloxycarbonyl) -4,5-O-isopropylidene-3,4,5-trihydroxy-1H-azepine 0.7 g
(2.44 mmol) was dissolved in 7 ml of dioxane, 3.5 ml of concentrated hydrochloric acid was added, and the mixture was reacted at room temperature for 2 hours. The obtained reaction solution is mixed with water 10.
5ml was added anion-exchange resin ^{(DOWEX 1-X4, OH -} ) Purification was subjected to column chromatography, partition was lyophilized to containing the target product was eluted with water, (3R, 4S, 5R) -
Hexahydro-3,4,5-trihydroxy-1H-azepine to 0.3
2 g (2.17 mmol, 89% yield) were obtained. Infrared absorption spectrum (KBr): 3398, 1655, 1542, 147
6,1420 cm ^-1 specific rotation [α]: + 21.9 ° (c 0.122, H ₂ O) ¹³ C nuclear magnetic resonance spectrum (125 MHz, DMSO-d6) δ: 31.
35, 44.22, 49.95, 69.25, 71.09, 77.79. High performance liquid chromatography (6: 4): 8.4 min Elemental analysis: Theoretical value (%) as C ₆ H ₁₃ NO ₃ : C, 4
8.97; H, 8.90; N, 9.52. Observed value (%): C, 48.8
6; H, 9.02; N, 9.39.

<Experimental Example 1> Measurement of α-glucosidase inhibitory activity 0.5 ml of an aqueous solution of a test compound was added to 1.0 ml of a 10 mM solution of 4-nitrophenyl-α-D-glucopyranoside in 0.1 M phosphate buffer (pH 6.8). After preheating at 37 ° C for 5 minutes,
α-glucosidase (0.025 U / ml, Bacillus stearothe
0.5 ml of a 0.1 M phosphate buffer (pH 6.8) solution containing 0.2% BSA (derived from Rmopilus), and the mixture was further heated at 37 ° C. for 15 minutes to react. Then, 2.0 ml of a 0.2 M sodium carbonate solution was added.
Was added to stop the reaction. The absorbance A at 400 nm of this solution was measured, and at the same time, the absorbance B was measured using only water instead of the test compound as a control, and the activity inhibition rate (%)
Was calculated from (BA) / B × 100. When the amount of a substance showing 50% activity inhibition by this method is defined as IC ₅₀ , the IC ₅₀ value of each compound of the present invention is
1.5 mg / ml, 1.6 mg / ml for the present compound (2), 4 mg / ml for the present compound (3), and 10 mg / m for the present compound (4)
l, 4 mg / ml for the compound of the present invention (5), 0.18 mg / ml for the compound of the present invention (6), and 0.08 mg / ml for the compound of the present invention (7)
ml, 1.5 mg / ml for the compound of the present invention (8), 1.5 mg / ml for the compound of the present invention (9), and 0.0012 for the compound of the present invention (10).
mg / ml, 10 mg / ml for the present compound (11), 4 mg / ml for the present compound (13), and 3 m for the present compound (14).
g / ml, 1.5 mg / ml for the present compound (16), 5 mg / ml for the present compound (17), and 10 mg / ml for the present compound (18).
/ ml, 2.7 mg / ml for the present compound (19), 10 mg / ml for the present compound (21), and 4 m / ml for the present compound (22).
g / ml, and 1.7 mg / ml for the compound (24) of the present invention.

Experimental Example 2 Measurement of β-Glucosidase Inhibitory Activity 0.5 ml of an aqueous solution of a test compound was added to 1.0 ml of a 10 mM solution of 4-nitrophenyl-β-D-glucopyranoside in 0.1 M acetate buffer (pH 5.0). In addition, after preheating at 37 ° C for 5 minutes, β
-Glucosidase (0.025U / ml, Caldocellum saccharol
After adding 0.5 ml of a 0.1 M acetate buffer (pH 5.0) solution of ytium), the mixture was further heated at 37 ° C. for 15 minutes, and reacted.
The reaction was stopped by adding 2.0 ml of M sodium carbonate solution. The absorbance at 400 nm of this solution was measured, and the result was shown in Experimental Example 1.
When the IC ₅₀ value was determined in the same manner as in
4 mg / ml, 3 mg / ml for the compound of the present invention (2), 3 mg / ml for the compound of the present invention (3), and 0.15 mg / m for the compound of the present invention (6)
l, 0.5 mg / ml for the compound of the present invention (7), 2 mg / ml for the compound of the present invention (9), and 0.04 mg / m for the compound of the present invention (10)
l, 0.10 mg / ml for the compound of the present invention (14), 0.5 mg / ml for the compound of the present invention (22), and 0.02 mg / ml for the compound of the present invention (24).
mg / ml.

Experimental Example 3 Measurement of α-Galactosidase Inhibitory Activity A test compound was added to 1.0 ml of a 10 mM 4-nitrophenyl-α-D-galactopyranoside in a 0.1 M phosphate buffer (pH 6.5). After adding 0.5 ml of an aqueous solution and preheating at 37 ° C. for 5 minutes, α-galactosidase (0.025 U / ml, green coffe
0.5 ml of a 0.1 M phosphate buffer (pH 6.5) solution containing 0.2% BSA (derived from beans) was added, and the mixture was further heated at 37 ° C. for 15 minutes to react. Then, 2.0 ml of a 0.2 M sodium carbonate solution was added. Was added to stop the reaction. Absorbance of this solution at 400 nm
Degrees were measured and obtains the IC ₅₀ values in the same manner as in Experimental Example 1, the present invention compound (1) in 3 mg / ml, the present invention compound (2)
2.2 mg / ml, 2.4 mg / ml for the compound of the present invention (3), 3 mg / ml for the compound of the present invention (6), and 2.4 mg / ml for the compound of the present invention (7)
ml, 1.5 mg / ml for the present compound (10), 2.1 mg / ml for the present compound (11), and 3 mg / ml for the present compound (13).
ml, 3 mg / ml for the present compound (16), 3 mg / ml for the present compound (18), and 3 mg / m for the present compound (19).
l, 0.5 mg / ml for the present compound (20), 1.1 mg / ml for the present compound (21), and 0.10 mg / ml for the present compound (22).
mg / ml, and 0.8 mg / ml for the compound (24) of the present invention.

<Experimental Example 4> Measurement of β-galactosidase inhibitory activity of 5 mM 4-nitrophenyl-β-D-glucopyranoside
0.5 ml of an aqueous solution of a test compound was added to 1.0 ml of a 0.1 M acetate buffer (pH 4.0) solution, and preliminarily heated at 37 ° C. for 5 minutes.
0.5 ml of a 0.1 M acetate buffer (pH 4.0) solution of galactosidase (0.025 U / ml, derived from Aspergillus niger) was added,
After further heating at 37 ° C. for 15 minutes for reaction, the reaction was stopped by adding 2.0 ml of 0.2 M sodium carbonate solution. The absorbance of this solution at 400 nm was measured, and I
When determining the value of C _50, in the present invention Compound (1) 2.4mg / m
l, 1.8 mg / ml for the compound of the present invention (2), 2.3 mg / ml for the compound of the present invention (3), and 1.2 mg / m for the compound of the present invention (4)
l, 0.5 mg / ml for the compound of the present invention (14), 0.7 mg / ml for the compound of the present invention (22), and 0.23 mg / ml for the compound of the present invention (24).
mg / ml.

Experimental Example 5 Measurement of α-mannosidase Inhibitory Activity 5 mM 4-nitrophenyl-α-D-mannopyranoside
0.5 ml of an aqueous solution of the test compound was added to 1.0 ml of a 0.1 M acetate buffer (pH 4.5) solution, and the mixture was preliminarily heated at 37 ° C. for 5 minutes.
0.1 of mannosidase (0.025U / ml, derived from jack beans)
Add 0.5 ml of M acetate buffer (pH 4.5) solution and add 37 ml.
After heating at 15 ° C. for 15 minutes to react, the reaction was stopped by adding 2.0 ml of a 0.2 M sodium carbonate solution. 400nm of this solution
The absorbance was measured at and determine the value of similarly IC ₅₀ as in Experimental Example 1, the present invention compound (5) in 1.3 mg / ml, the present invention compound (6) in 1.9 mg / ml, the present invention compound (7) Then 1.
3 mg / ml, 0.27 mg / ml for the compound of the present invention (10), 1.6 mg / ml for the compound of the present invention (16), and mg / ml for the compound of the present invention (17).

<Experimental Example 6> Measurement of β-mannosidase inhibitory activity 5 mM 4-nitrophenyl-β-D-mannopyranoside
0.5 ml of an aqueous solution of a test compound was added to 1.0 ml of a 0.1 M acetate buffer (pH 4.0) solution, and preliminarily heated at 37 ° C. for 5 minutes.
0.5 ml of a 0.1 M acetate buffer (pH 4.0) solution of mannosidase (0.025 U / ml, derived from snail acetone powder) was added, and
After further heating at 37 ° C. for 15 minutes for reaction, the reaction was stopped by adding 2.0 ml of 0.2 M sodium carbonate solution. The absorbance of this solution at 400 nm was measured, and I
When determining the value of C _50, the present invention compound (2) in 4 mg / ml,
2.3 mg / ml of the compound of the present invention (3)
1.5 mg / ml for 1) and 1.7 mg / m for compound (18) of the present invention
l, 0.14 mg / ml for the compound of the present invention (19).

<Experimental Example 7> Measurement of α-fucosidase inhibitory activity 10 mM 4-nitrophenyl-α-D-fucopyranoside
0.5 ml of an aqueous solution of the test compound was added to 1.0 ml of a 0.1 M acetate buffer (pH 5.5) solution, and the mixture was preliminarily heated at 37 ° C. for 5 minutes.
0.1 of fucosidase (0.025U / ml, bovine kidney)
Add 0.5 ml of M acetate buffer (pH 5.5) solution,
After heating for 15 minutes at, the reaction was stopped by adding 2.0 ml of a 0.2 M sodium carbonate solution. The absorbance at 400 nm of this solution was measured, and the IC ₅₀ value was determined in the same manner as in Experimental Example 1. As a result, 0.3 mg / ml of the compound of the present invention (1), 1 mg / ml of the compound of the present invention (2), and In (3), 1mg / ml,
0.2 mg / ml for the compound of the present invention (5) and the compound of the present invention (7)
1 mg / ml, 1 mg / ml for the compound of the present invention (11), 0.1 mg / ml for the compound of the present invention (13), 0.2 mg / ml for the compound of the present invention (15), and 0.15 mg / ml for the compound of the present invention (16). ml, 0.1 mg / ml for the compound of the present invention (18),
0.05 mg / ml for 9) and 1 mg / m for compound (21) of the present invention.
l, 0.6 mg / ml for the compound of the present invention (22) and 0.021 mg / ml for the compound of the present invention (24).

[0052]

The azepan derivatives represented by the above general formula (I) and salts thereof obtained as described above are novel compounds and have an inhibitory activity against various glycosidases as described in the experimental examples. Having. Having glycosidase inhibitory activity means that it affects the intracellular and extracellular glycosylation and / or deglycosylation in a living body. For example, it affects the biosynthesis of O- and N-proteins, It shows high potential for properties such as modification of the composition of the substance, effects on chitin metabolism, bactericidal / fungicidal and / or bacteriostatic action, immunomodulatory action, and metastasis inhibitory action on malignant tumor cells. In addition, the glycosidase inhibitory activity is determined by α-
Inhibition of carbohydrate-decomposing enzymes such as amylase or α-glucosidase, which reduces the rate of absorption of glucose and the like. The azepan derivatives and their salts are used as antidiabetic agents.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Shoichi Tokutake 339 Noda, Noda-shi, Chiba Kikkoman Co., Ltd. (72) Inventor Koichiro Tobe 339 Noda, Noda-shi, Chiba Kikkoman Co., Ltd.F-term ( Reference) 4C086 AA03 BC31 NA14 ZC20 ZC35

Claims (1)

[Claims] 1. The following general formula (I): (Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydroxyl group, a hydrogen atom, an azido group or an amino group which may have a substituent, and R ^{1 to} R ⁴ Azepane derivatives represented by the formula (2 to 3 of which are hydroxyl groups) and salts thereof.