JPH0372637B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [In the formula, R ¹ and R ² each represent a hydroxyl group or together represent an oxygen atom, the bonds ~ ~ represent either the R configuration or the S configuration, and the hydroxyl group in the formula may be protected] or a salt thereof. The compound of the present invention [ ] or its salt contains a pseudo-amino sugar [The Journal of Organic Chemistry (J.Org.
Chem.) Vol. 31, pp. 1516-1521 (1966), the term pseudo-sugar is defined as a variolamine (valiola-sugar).
mine) expression

It is a pseudo-oligosaccharide that has a compound represented by the formula [] in its molecule. Conventionally, acarbose, a type of pseudo-oligosaccharide
and its related compounds (e.g., amylostatin
Volume 64, pp. 535-537 (1977), Special Publication Showa 54-39474
and Angewandte Hemy
Chemie) Vol. 93, pp. 738-755 (1981), Agricultural &. Biological Chemistry (Agric.Biol.Chem.); 46 , 1941-1945
(1982)], but the α-glucosidase inhibitory activity of these compounds is still not satisfactory. The present inventors conducted research on various N-substituted derivatives of the compound [], and found that the compound represented by the general formula [] has strong α-glucosidase inhibitory activity, and further based on these findings. As a result of various studies based on the above, the present invention was completed. That is, the present invention provides (1) a compound represented by the general formula [] or a salt thereof, (2) a compound represented by the formula [] [in which any hydroxyl group may be protected], and a compound represented by the general formula [In the formula, each hydroxyl group may be protected] is reacted with a compound represented by the formula, and then subjected to a reduction reaction, and optionally subjected to an anhydro ring bond cleavage reaction or (and) a deprotecting group reaction. (3) A method for producing a compound represented by the general formula [] or a salt thereof; (3) An α-glucosidase inhibitor characterized by containing the compound represented by the general formula [] or a salt thereof. The compound represented by the general formula [] or its salt has an amino group of the variolamine moiety and a 4,6-
Due to the difference in configuration at the bonding site with the dideoxy-D-glucopyranosyl moiety, the general formula [Symbols in the formula have the same meanings as above] Compound or its salt and general formula There are two types of stereoisomers of the compound represented by [the symbols in the formula have the same meanings as above] or a salt thereof. Specific examples of the compound represented by general formula [a] or its salt include 4-O-α-[4-[(1S)-(1,2,4,5
(OH)/3,5( _CH2OH ))-(2,3,4,5-
Tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-
D-glucopyranosyl]-D-glucopyranose 1,6-anhydro-4-O-α-[4-
[(1S)-(1,2,4,5(OH)/3,5( _CH2
OH))-2,3,4,5-tetrahydroxy-5
-(hydroxymethyl)cyclohexyl)amino]
-4,6-dideoxy-D-glucopyranosyl]
-β-D-glucopyranose has the general formula [b]
Specific examples of compounds represented by or salts thereof include 4-O-α-[4-[(1S)-(1,2,4,5
(OH)/3,5( _CH2OH ))-(2,3,4,5-
Tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-
D-galactopyranosyl]-D-glucopyranose 1,6-anhydro-4-O-α-[4-
[(1S)-(1,2,4,5(OH)/3,5( _CH2
OH))-(2,3,4,5-tetrahydroxy-
Examples include 5-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-D-galactopyranosyl]-β-D-glucopyranose [For the nomenclature of this configuration, see
IUPAC-IUB Cyclitol 1973 Recommendation for
cyclitol), Pure Appl.Chem. Volume 37, 285-297
(1975)]. The above compounds [a] and [b] both have α-glucosidase inhibitory activity, but [
A] generally has stronger α-glucosidase inhibitory activity than [b]. The hydroxyl-protecting group in the above formula is a protecting group used as a hydroxyl-protecting group in sugar chemistry, such as an acyl-type protecting group, an ether-type protecting group, an acetal-type protecting group, a ketal-type protecting group, orthoester-type protecting group. Protective groups etc. are used. Examples of acyl-type protecting groups include halogen, lower alkoxy groups having 1 to 4 carbon atoms; alkanoyl groups having 1 to 5 carbon atoms optionally substituted with phenoxy groups optionally having halogen; nitro group, phenyl a benzoyl group optionally substituted with a group;
Alkoxycarbonyl group having 2 to 6 carbon atoms which may be substituted with halogen; Alkenyloxycarbonyl group having 2 to 4 carbon atoms; Benzyloxy which may have 1 to 4 carbon atoms substituted with lower alkoxy group or nitro group A carbonyl group or a nitro-substituted phenoxycarbonyl group is used. The above halogens include fluorine, chlorine, bromine,
Iodine etc. are used. Examples of the above lower alkoxy group having 1 to 4 carbon atoms include methoxyl, ethoxyl, propoxyl, and poxyl groups which may be substituted with the above halogen. Examples of the alkanoyl group having 1 to 5 carbon atoms include formina, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, and pivaloyl groups. Examples of the alkoxy group in the above alkoxycarbonyl group having 2 to 6 carbon atoms include the above-mentioned methoxyl, ethoxyl, propoxyl, butoxyl, pentyloxyl, pinyloxyl, and allyloxyl groups which may be substituted with halogen. As the alkenyl group having 2 to 4 carbon atoms in the above alkenyloxycarbonyl group having 2 to 4 carbon atoms, vinyl, allyl, isopropenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, etc. are used. More specific examples of acyl protecting groups include formina, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, triphenylmethoxyacetyl, phenoxyacetyl, p-chlorophenoxyacetyl. , propionyl, isopropionyl, 3-phenylpropionyl, isobutyryl,
Pivaloyl; benzoyl, p-nitrobenzoyl, p-phenylbenzoyl; methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isobutyloxycarbonyl; vinyloxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, p-methoxy These include benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; p-nitrophenoxycarbonyl, and the like. Examples of ether-type protecting groups include halogen,
Lower alkyl group having 1 to 5 carbon atoms which may be substituted with a lower alkoxyl group having 1 to 4 carbon atoms, benzyloxyl group, or phenyl group; Alkenyl group having 2 to 4 carbon atoms; Lower alkyl having 1 to 5 carbon atoms tri-substituted silyl group whose substituents are phenyl group, benzyl group, etc.; lower alkoxyl group having 1 to 4 carbon atoms;
A benzyl group which may be substituted with a nitro group; a lower alkoxyl group having 1 to 4 carbon atoms, a tetrahydropyranyl group or a tetrahydrofuranyl group which may be substituted with a halogen, etc. are used. Examples of the lower alkyl group having 1 to 5 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert
-Butyl, bentyl, isobentyl, neobentyl, etc. are used. The above halogens, carbon number 1~
As the lower alkoxyl group and the alkenyl group having 2 to 4 carbon atoms in 4, the same ones as in the case of the acyl type protecting group are used. More specific examples of ether protecting groups include methyl, methoxymethyl, benzyloxymethyl,
tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloromethoxymethyl,
Ethyl, 1-ethoxyethyl, 1-methyl-1-
Methoxyethyl, 2,2,2-trichloroethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, ethoxyethyl, triphenylmethyl, p-methoxyphenyldiphenylmethyl; allyl; trimethylsilyl,
tert-butylsilyl, tert-butyldiphenylsilyl; benzyl, p-methoxybenzyl, p-nitrobenzyl, p-chlorobenzyl; tetrahydropyranyl, 3-bromotetrahydropyranyl,
4-methoxytetrahydropyranyl, tetrahydrofuranyl, and the like. Acetal type, ketal type and orthoester type protecting groups preferably consist of 1 to 10 carbon atoms. Specific examples include methylene, ethylidene, 1-tert-butylethylidene, 1-phenylethylidene, 2,2,2-trichloroethylidene; isopropylidene, butylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene. ; Benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, p-dimethylaminobenzylidene, o-nitrobenzylidene; methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1,
2-dimethoxyethylidene and the like. Furthermore, stanoxane-type protective groups, cyclic carbonate-type protective groups, cyclic boronate-type protective groups, and the like can be similarly used. As the salt of the compound [ ] included in the present invention, an addition salt of the compound [ ] with a pharmaceutically acceptable acid is used. Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid; for example, acetic acid, malic acid, citric acid,
Organic acids such as ascorbic acid, mandelic acid, and methanesulfonic acid are used. The above compound [] or its salt is a crystal or powder with almost no toxicity (Ratto LD ₅₀ 500mg/Kg
that's all). Compound [ ] or a salt thereof has an α-glucosidase inhibitory effect, and in order to suppress carbohydrate metabolism in humans and non-human animals, it has, for example, a blood sugar rise suppressing effect, and is effective against hyperglycemic symptoms and hyperglycemia. It is useful for preventing various diseases caused by obesity, obesity, hyperlipidemia (arteriosclerosis), diabetes, prediabetes, and diseases caused by sugar metabolism by oral microorganisms, such as dental caries. It is a compound. The compound [] or a salt thereof can be used, for example, in a liquid carrier such as water, ethanol, ethylene glycol, or polyethylene glycol, starch, cellulose,
It is diluted with a non-toxic carrier such as a solid carrier such as polyamide powder, prepared into ampoules, granules, tablets, pills, capsules, syrups, etc. according to a conventional method, and used for the various uses mentioned above. be able to. In addition, sweeteners, preservatives, dispersants, and coloring agents can also be used. Compound [] or a salt thereof is administered alone or mixed with a non-toxic carrier, orally or parenterally, preferably orally, with each meal, before or after a meal. Specifically, for example, by taking a preparation containing about 10 to 200 mg of the compound [ ] or its salt per adult with each meal, before or after a meal, blood glucose levels due to eating can be reduced. Since the increase in concentration can be suppressed, it is effective in preventing and treating the above-mentioned diseases. The compound [ ] or a salt thereof is useful as an α-glucosidase inhibitor not only as a medicine but also as a food additive and an animal feed additive for obtaining low-fat, high-quality edible meat. The compound [] or its salt may be added to foods. That is, it may be used with liquid or solid foods such as coffee, soft drinks, fruit juices, beer, milk, diam, bean paste, and jelly, seasonings, or various staple foods and side foods. Foods produced by adding the compound [ ] or its salts are suitable as foods for patients with metabolic disorders, and also for healthy people as preventive foods for metabolic disorders. As for the addition amount, for example, the compound [] or its salt may be added to various foods in an amount of about 0.0001 to 1% of the carbohydrate content in the food. When mixed with feed, the carbohydrate content of the feed should be 0.0001~
1% is desirable. In the compound represented by the general formula [ ] of the present invention or a salt thereof, when R ¹ and R ² together represent an oxygen atom, that is, the formula A compound or a salt thereof represented by [In the formula, the bond . It can be produced by subjecting the Schiff base obtained by the reaction to a reduction reaction and, if desired, to a deprotecting group reaction. In this reaction, compound [] and compound []
The Schiff base formation reaction by condensation reaction with the Schiff base and the reduction reaction of this Schiff base can also be carried out continuously in the same reaction vessel. The raw material compound [] can be used in an amount usually about 1 to 2 times the molar amount of the compound []. The condensation reaction between compound [] and compound [] and the reduction reaction of the resulting Schiff base are generally carried out in a solvent. Suitable solvents include, for example, water, alcohols such as methanol, propanol, butanol, dimethyl sulfoxide, dimethyl formamide, N-methyladetamide, glymes such as methyl cellosolve, dimethyl cellosolve, diethylene glycol dimethyl ether, e.g. Ethers such as dioxane and tetrahydrofuran, polar solvents such as acetonitrile, mixed solvents thereof, or mixtures of these polar solvents or mixed solvents with nonpolar solvents such as chloroform and dichloromethane can be used. The reaction temperature in the Schiff base formation reaction is not particularly limited, but it is usually carried out at room temperature to about 100°C. Although the reaction time varies depending on the reaction temperature, the purpose can usually be achieved by allowing the reaction to occur for a few minutes to 24 hours. Various metal hydride complex reducing agents such as sodium borohydride, potassium borohydride, lithium borohydride, sodium trimethoxyborohydride, etc. can be used for the reduction reaction of the Schiff base formed. Metals such as alkali metal cyanoborohydrides such as sodium cyanoborohydride, alkali metal aluminum hydrides such as lithium aluminum hydride, dialkylamineboranes such as dimethylamineborane, etc. are advantageously used. In addition, when using an alkali metal cyanoborohydride, for example, sodium cyanoborohydride, it is preferable to carry out the reaction under acidic conditions, for example, in the presence of hydrochloric acid, acetic acid, or the like. The reaction temperature for this reduction reaction is not particularly limited, but is usually room temperature, in some cases, especially at the beginning of the reaction, under ice cooling, and in some cases, 100°C.
It is carried out by heating to a certain degree, and there are differences depending on the Schiff base to be reduced and the type of reducing agent. The reaction time also varies depending on the reaction temperature and the type of Schiff base and reducing agent to be reduced, but the purpose can usually be achieved by allowing the reaction to occur for about several minutes to 24 hours. Catalytic reduction can also be used to reduce the Schiff base formed. That is, the reaction is carried out by shaking or stirring Schiff's base in a suitable solvent in the presence of a catalyst for catalytic reduction in a hydrogen stream. Examples of catalysts used for catalytic reduction include platinum black, platinum dioxide, palladium black, palladium carbon, Raney nickel, etc., and commonly used solvents include water, alcohols such as methanol and ethanol, etc. Ethers such as dioxane and tetrahydrofuran,
Dimethylformamide or a mixed solvent thereof is used. The reaction is usually carried out at room temperature and normal pressure, but may also be carried out under pressure or with heating. general formula The compound represented by [In the formula, the bond ~ ~ represents either the R configuration or the S configuration, and the hydroxyl group in the formula may be protected] is the above compound []
A compound obtained by the reaction between and []
c] is subjected to a cleavage reaction of the 1,6-anhydro ring bond, and optionally subjected to a deprotection reaction. This cleavage reaction of the 1,6-anhydro ring bond can also be carried out continuously in the same reaction vessel as the above-described condensation reaction of compound [] and compound [] and the subsequent reduction reaction. This cleavage reaction is carried out by treating compound [c] with, for example, a mixture of sulfuric acid, acetic anhydride, and acetic acid [G, G, S, Dutton et al.: Canadian Journal of Chemistry] (Can.J.Chem.) Volume 44, 1069
~1074 pages (1966); Mori et al.: Chemical and.
Pharmaceutical. Bulletin (Chem.
Pharm.Bull.) Volume 23, pp. 1480-1487 (1975)
etc.]. The amount of sulfuric acid used in this reaction is a catalytic amount or twice the amount (weight) of the starting material compound [c].
It is enough. Further, the amounts of acetic anhydride and acetic acid are usually added in large excess relative to the starting compound [c]. This reaction is usually carried out at about room temperature, but may also be carried out under cooling, for example under ice cooling. Although the reaction time varies depending on the reaction temperature, generally about 2 hours is sufficient. As the solvent, a large excess of acetic anhydride and acetic acid as the reaction reagents described above may be added to serve as a solvent, and further, a halogenated carbon such as dichloromethane, chloroform, or carbon tetrachloride may be added. When the compounds [c] and [d] have a protected hydroxyl group, the elimination reaction of the protecting group of the hydroxyl group can be carried out using a method known per se. For example, acetal type or ketal type protecting groups such as cyclohexylidene group, isopropylidene group, benzylidene group, trityl group, etc.
By hydrolyzing with acids such as acetic acid and sulfonic acid type ion exchange resins, acyl type protecting groups such as acetyl groups and benzoyl groups can be converted to ammonia,
Hydrolysis with an alkali such as sodium hydroxide, barium hydroxide, or sodium methoxide can be performed, and benzyl ether-type protecting groups such as benzyl groups and p-methoxybenzyl groups can be hydrolyzed by catalytic reduction or with liquid ammonia. It can be desorbed by reductive decomposition using metallic sodium in the reaction mixture. The above-mentioned compounds [] and their synthetic intermediates obtained in this manner can be obtained by methods known per se, such as filtration, centrifugation, concentration, vacuum concentration, drying, freeze-drying, adsorption, desorption, and the difference in solubility in various solvents. The method utilized (e.g., solvent extraction, dissolution, precipitation, crystallization, recrystallization, etc.), chromatography (e.g., ion exchange resin, activated carbon, high porous polymer, Cephadex, Cephadex ion exchanger, cellulose, It can be isolated and purified by chromatography using ion-exchange cellulose, silica gel, alumina, etc. The raw material compound [] used in the present invention can be obtained by, for example, the method of culturing a microorganism belonging to the genus Streptomyces described in JP-A-57-169446, or by the method disclosed in JP-A-57-179174 or Patent Application 56−
Valienamine (formula

Compound represented by [Formula]) or is validamine (formula

It can be produced by a method using a compound represented by the formula as a raw material. The raw material compound [] can be produced, for example, using maltose as a raw material according to the following method. That is, for example, 2,3-di-O-benzyl-1,
To synthesize 6-anhydro-4-O-(2,3-di-O-benzyl-6-deoxy-α-D-xylo-4-hexopyranose urosyl)-β-D-glucopyranose, 2,3-di-O-benzyl-1,6 by known methods from maltose
-anhydro-4-O-(2,3-di-O-benzyl-6-deoxy-α-D-glucopyranosyl)-β-D-glucopyranose, and this compound is converted by oxidizing the secondary hydroxyl group of the sugar. It can be produced using oxidation conditions for synthesizing ulose, such as a method of oxidizing dimethyl sulfoxide-trifluoroacetic anhydride in the presence of triethylamine. (See formula below). In the above formula, B _o represents a benzyl group, and DMSO represents dimethyl sulfoxide. In the above formula, the protecting group for the hydroxyl group may of course be other than the benzyl group. The elimination reaction of the protecting group of the compound [] can be carried out using a method known per se or using the above-mentioned compounds [c] and [d].
It can be carried out in the same manner as the protecting group removal reaction. The compounds [], [] and their synthetic intermediates obtained in this manner can be isolated and purified by the above-mentioned means known per se. The content of the present invention will be explained in detail with reference to Test Examples, Reference Examples, and Examples below, but the scope of the invention is not limited thereto. Test Example Method for Measuring Glucosidase Inhibitory Activity Maltase and satucalase [Borgström (B.
Borgetrom) and Dahlquist (A.
Dahlqvist, Acta Chem.Scand., Volume 12, 1997-2006
The inhibitory activity against the inhibitory substance (compound) to be tested [prepared according to the method described in 1958] was determined by adding the inhibitory substance (compound [] or its salt) in the above buffer solution (0.5 ml) and the above buffer solution (0.25 ml) in which the substrate 0.005M maltose or 0.05M sucrose is added.
was added and the mixture was allowed to react at 37°C for 10 minutes.
Add glucose B-test reagent (glucose oxidase reagent for glucose measurement, Wako Pure Chemical Industries, Ltd.)
(3 ml) was added and further heated at 37°C for 20 minutes, and the absorbance of the color-developed reaction solution was measured at 505 nm. 50% inhibitory concentration against maltase (pig, intestinal mucosa) [hereinafter abbreviated as IC ₅₀ (maltase)] and 50% inhibitory concentration against satucalase (pig, intestinal mucosa) of the compound [ ] or its salt described in the Examples [ Hereinafter, abbreviated as IC ₅₀ (Satsucalase)] is the inhibition rate (%) measured using the above measurement method at 3 to 5 different concentrations of each inhibitor.
I asked for it from. The elution fraction of column chromatography in the purification process of each compound described in Reference Examples and Examples is usually thin layer chromatography (TLC).
Check the components contained in the sample, or check the elution curve using a differential refractometer (Waters R403, USA), and collect the fractions containing the necessary components.
Next, it was subjected to a process. For each compound described in the examples
Unless otherwise specified, the Rf value of TLC is calculated using a precoated TLC plate silica gel 60F ₂₅₄ (manufactured by Merck & Co., West Germany) as the thin layer plate, and n-propyl alcohol, acetic acid, water (4 ml) as the developing solvent. :1:1). (Rf value of variolamine [ ] measured by the above method as a control sample: Rf = 0.30) In column chromatography, the silica gel packing material for the column is Kieselgel 60 (70-230
Dowex 50W x 8 (H ₊ type) and 1 x 2 (OH _- type) are manufactured by Dow Chemical Co. (USA); Amberlite CG-50
(NH ⁺ ₄ type) manufactured by Rohm and Haas (USA) was used. Note that the symbols used in Reference Examples and Examples have the following meanings. s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet;
Unless otherwise specified, the volume ratio (V/V) is shown, and in the assignment of NMR chemical shifts, the position number of the carbon atom of each compound is used as the position number shown by the following formula. Reference example 1 2,3-di-O-benzyl-1,6-anhydro-4-O-(2,3-di-O-benzyl-6
-Deoxy-α-D-xylo-4-hexopyranoseurosyl)-β-D-glucopyranose Dimethyl sulfoxide (19.5 ml) was dissolved in dichloromethane (195 ml), and trifluoroanhydride was added while cooling to below -65°C. A dichloromethane solution (130 ml) of acetic acid (29 ml) was added dropwise, stirred at the same temperature for 15 minutes, and -70
2,3-di-O-benzyl- while cooling to below °C.
1,6-anhydro-4-O-(2,3-di-O
-benzyl-6-deoxy-α-D-glucopyranomyl)-β-D-glucopyranose [2,3,
2',3'-tetra-O-benzyl-1,6-anhydro-6'-deoxymaltose] (45.3 g) was added, and the mixture was stirred at the same temperature for 2 hours. A solution of triethylamine (54.5 ml) in dichloromethane (160 ml) was added dropwise to the reaction solution while cooling it to below -65°C, then the cooling bath was removed and the mixture was stirred until the reaction temperature rose to room temperature. After adding the reaction solution to ice water (1.3) and stirring, separate the dichloromethane layer and extract the aqueous layer twice with dichloromethane (200 ml). The dichloromethane layers are combined, washed with 0.5N hydrochloric acid, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is silica gel (1)
After washing with toluene (1.5), the solution was eluted with toluene-ethyl acetate (9:1) and toluene-ethyl acetate (4:1). After concentrating the eluted fraction under reduced pressure, it was further dried under reduced pressure in a desiccator to obtain 2,3-di-O-benzyl-1,6
-Anhydro-4-O-(2,3-di-O-benzyl-6-deoxy-α-D-xylo-4-hexopyrano-suurosyl)-β-D-glucopyranose as syrup (40.7 g) can get. [α] ²⁵ _D +55.7° (c=1, CH ₃ OH) Elemental analysis: C ₄₀ H ₄₂ O ₉ Calculated value (%): C, 72.05; H, 6.35 Experimental value (%): C, 72.29; H, 6.43 IR ν Nujiol max cm ^-1 : 1745 NMR (CDCL ₃ ) δ: 1.26 (3H, d, j = 7Hz), 3.30 ~ 3.85 (6H, m), 4.02 (1H, d, J = 9Hz), 4.30-4.95 (10H, m), 5.02 (1H, d, J=3Hz), 5.38 (1H, s), 7.2-7.5 (20H, m) Example 1 1,6-anhydro-4-O-α- [4-
[(1S)-(1,2,4,5,(OH)/3,5
( _CH2OH ))-(2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-D-glucopyranosyl]-β-D-glucose and 1,
6-Anhydro-4-O-α-[4-[(1S)-
(1,2,4,5,(OH)/3,5( _CH2OH ))
-(2,3,4,5-tetrahydroxy-5-
(hydroxymethyl)cyclohexyl)amino]
-4,6-dideoxy-D-galactopyranosyl]-β-D-glucopyranose 2,3-di-O-benzyl-1,6-anhydro-4-O-(2,3-di-O- benzyl-6-
Deoxy-α-D-xylo-4-hexopyranose urosyl)-β-D-glucopyranose (40.5 g) and variolamine (12.0 g) were dissolved in dimethylformamide (300 ml), and 2N hydrochloric acid (9 ml) was dissolved in dimethylformamide (300 ml). Add sodium cyanoborohydride (15.6 g) and stir at 60-65°C for 13 hours. The reaction solution is concentrated under reduced pressure, toluene is further added, and dimethylformamide is distilled off azeotropically. The residue was added to a mixture of water (300 ml) and ethyl acetate (300 ml) for partition, the ethyl acetate layer was separated, and the aqueous layer was extracted twice with ethyl acetate (200 ml). The ethyl acetate layers were combined, washed with water, dried over sodium sulfate, concentrated under reduced pressure, and the residue was diluted with ethyl ether (1
), a syrupy substance is obtained. The syrupy substance was subjected to column chromatography on silica gel (550 ml), and after washing the column with chloroform, it was eluted with chloroform-methanol (9:1).
The eluted fractions are concentrated under reduced pressure, and the residue is further dried under reduced pressure in a desiccator. The obtained white powder (5.8 g) was suspended in liquid ammonia (about 200 ml) in a dry ice-acetone bath, sodium was added until the blue color of the solution disappeared, and the mixture was stirred for an additional hour at the same temperature. Add ethanol (30
ml) and sodium (1.0 g), and stirred at the same temperature for 2 hours. Ammonium acetate is added to the reaction mixture until the blue color of the reaction mixture disappears, the cooling bath is removed, ammonia is distilled off with stirring, and the reaction mixture is concentrated under reduced pressure. Ethyl acetate (350ml) to the residue
After adding and distributing a mixture of and water (350ml),
Separate the aqueous layer, adjust the pH to 7 with 2N hydrochloric acid, add Dowex 50W x 8 (H ⁺ form, 350 ml), and stir at room temperature for 1 hour. This dowex 50W x 8 (H ⁺
mold) in advance in another Dowex 50W x 8 (H ⁺
After washing the column with water (3), elute with 0.5N aqueous ammonia. The eluted fractions (1.3-2.4) were concentrated under reduced pressure,
Residue Amberlite CG-50 (NH ⁺ ₄ , 450ml)
column chromatography and elute with water. The eluted fraction (235-350 ml) was concentrated under reduced pressure, and the residue was subjected to Dowex 1x2 (OH ^- type, 270 ml) column chromatography. When eluted with water, the fraction eluted first (310-665 ml) and the fraction eluted later (680-1640
ml). Concentrate each eluted fraction under reduced pressure, and transfer the concentrated solution once again to Dowex 1.
Subjected to x2 (OH ^- type, 160ml) column chromatography,
Elute with water, concentrate the eluted fraction under reduced pressure, and lyophilize. From the first eluted fraction, 1,6-anhydro-4-O-α-[4-[(1S)-(1,2, 4,
5,(OH)/3,5( _CH2OH ))-(2,3,4,
5-tetrahydroxy-5-(hydroxymethyl)
cyclohexyl)amino]-4,6-dioxy-
A white powder (520 mg) of 1,6-anhydro-4-O-α-D-galactopyranosyl]-β-D-glucopyranose was also obtained from the later eluted fraction.
[4-[(1S)-(1,2,4,5,(OH)/3,5
(CH ₂ OH))-(2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)
A white powder (1.25 g) of amino]-4,6-dideoxy-D-glucopyranosyl]-β-D-glucopyranose is obtained. Compound [isomer (a)] obtained from the fraction eluted first: [α] ²⁵ _D +86.5° (c=1, H ₂ O) Elemental analysis: C ₁₉ H ₃₃ NO ₁₃・H ₂ O Calculated value (%): C, 45.51; H, 7.03; N; 2.79 Experimental value (%): C, 45.22; H, 7.00; N; 2.79 NMR (D ₂ O) δ: 1.53 (3H, d, J = 6.5Hz, 6′−
C H ₃ ), 1.71 (1H, dd, J = 3Hz, 15.5Hz, 6-
C H ), 2.33 (1H, dd, J = 3Hz, 15.5Hz, 6-
C H ), 3.22 (1H, dd, J = ~1Hz, 3Hz, 4'-
C H ), 3.45-4.65 (15H, m), 5.32 (1H, d, J
=4.5Hz, 1′-C H ), 5.70 (1H, s, 1″-C H ) TLC: Rf = 0.24 Compound [isomer (b)] obtained from the fraction eluted later: [α] ²⁶ _D +65.2° (c=1, H ₂ O) Elemental analysis: C ₁₉ H ₃₃ NO ₁₃・H ₂ O Calculated value (%): C, 45.51; H, 7.03; N, 2.79 Experimental value (%): C, 45.48; H, 7.07; N, 2.86 NMR ( _D2 ) δ: 1.54 (3H, d, J = 6.5Hz, 6'-C
H ₃ ), 1.78 (1H, dd, J = 3Hz, 15.5Hz, 6-C
H), 2.30 (1H, dd, J=3Hz, 15.5Hz, 6-C
H), 2.71 (1H, t, J = 10Hz, 4'- CH ), 3.5~
4.6 (15H, m), 5.28 (1H, d, J = 3.8Hz, 1'-C
H), 5.69 (1H, s, 1″-C H ) TLC: Rf=0.33 IC ₅₀ (Satucalase): 2.5×10 ^-8 M IC ₅₀ (Maltase): 1.3×10 ^-7 M Example 2 Octa-O -acetyl-[1,6-anhydro-4-O-α-[4-[(1S)-(1,2,4,
5,(OH)/3,5( _CH2OH ))-(2,3,
4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-
dideoxy-D-glucopyranosyl]-β-D
-glucopyranose] 1,6-anhydro-4-O-α-[4-
[(1S)-(1,2,4,5,(OH)/3,5( _CH2
OH))-(2,3,4,5-tetrahydroxy-
5-(Hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-D-glucopyranosyl]-β-D-glucopyranose] (1.0 g) was dissolved in pyridine (25 ml), and acetic anhydride (12.5 ml) was added. and stir at room temperature for 15 hours. The reaction solution was concentrated to dryness under reduced pressure, and further dried overnight under reduced pressure in a desiccator. Ethyl ether-petroleum ether (1:10, about 100 ml) was added to the residue and left in the refrigerator overnight to give the title octa-O. A white crystalline powder (1.67 g) of -acetyl-1,6-anhydro derivative is obtained. [α] ²⁵ _D +22.3° (c=1, CH ₃ OH) Elemental analysis: C ₃₅ H ₄₉ NO ₂₁ Calculated value (%): C, 51.28; H, 6.02; N; 1.71 Experimental value (%): C, 51.37; H, 6.20; N; 1.68 NMR (CDC1 ₃ ) δ: 1.35 (3H, d, J = 6Hz,
6′- CH ₃ )), 1, 5-2.4-(2H, m, 6- CH
₂ ) _, 1.97~2.28 (24H, CH3COO- ×8), 2.5~
2.73 (1H, m, 4′-C H , adding D ₂ O gives t, J
= 10Hz), 3.33 to 3.47 (1H, m, 1-C
H), 3.63-4.2 (6H, m), 4.5-5.7 (12H, m) Example 3 Deca-O-acetyl-[4-O-α-[4-
[(1S)-1,2,4,5(OH)/3,5( _CH2
OH))-(2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)
amino]-4,6-dideoxy-D-glucopyranosyl]-D-glucopyranose] octa-O-acetyl-[1,6-anhydro-4-O-α-[4-[(1S)-(1,2 ,4,5,
(OH)/3,5( _CH2OH ))-(2,3,4,5-
Tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-
D-glucopyranosyl]-β-D-glucopyranose] (1.57 g) was mixed with acetic acid (40 ml) and acetic anhydride (40 ml).
ml) and sulfuric acid (1 ml) and stirred at room temperature for 2 hours. The reaction solution was added to ice water (1), and while stirring, sodium hydrogen carbonate (10 g) was added under ice cooling, and the mixture was further stirred at the same temperature for 2 hours.
The reaction mixture is extracted with chloroform, and the chloroform extract is washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (250 ml) and chloroform-methanol (30:
Elute with 1). The eluted fraction (340-640g) was concentrated to dryness under reduced pressure to give deca-O-acetyl-[4-O-
α-[4-[(1S)-1,2,4,5(OH)/3,
5( _CH2OH ))-(2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)
A white powder (1.58 g) of amino]-4,6-dideoxy-D-glucopyranosyl-D-glucopyranose is obtained. [α] ²⁵ _D +70.4° (c=1, CH ₃ OH) Elemental analysis: C ₃₉ H ₅₅ NO ₂₄ Calculated value (%): C, 50.81; H, 6.01; N; 1.52 Experimental value (%): C, 50.78; H, 5.62; N; 1.58 Example 4 4-O-α-[4-[(1S)-1,2,4,5
(OH)/3,5( _CH2OH ))-(2,3,4,5
-tetrahydroxy-5-(hydroxymethyl)
cyclohexyl)amino]-4,6-dideoxy-D-glucopyranosyl]-D-glucopyranose]deca-O-acetyl-[4-O-α-[4-
[(1S)-1,2,4,5(OH)/3,5( _CH2
OH))-(2,3,4,5-tetrahydroxy-
5-(Hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-D-glucopyranosyl]-D-glucopyranose] (985 mg) was dissolved in methanol (50 ml), and 28% aqueous ammonia (10
ml) and stir at room temperature for 20 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with Dowex 50W x 8
(H ⁺ type, 50 ml) column chromatography, and after washing the column with water, elute with 0.5N aqueous ammonia. The eluted fraction (155-485 ml) is concentrated under reduced pressure, and the concentrated solution is subjected to Amberlite CG-50 (NH ⁺ ₄ type, 360 ml) column chromatography and eluted with water. Elution fraction (215-290
ml) was concentrated under reduced pressure and lyophilized to give 4-O-α-
[4-[(1S)-1,2,4,5(OH)/3,5
(CH ₂ OH))-(2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)
Amino]-4,6-dideoxy-D-glucopyranosyl]-D-glucopyranose (400 mg) is obtained. ] [α] ²⁵ _D +97.7° (c=1, H ₂ O) Elemental analysis: C ₁₉ H ₃₅ NO ₁₄・2H ₂ O Calculated value (%): C, 42.46; H, 7.31; N, 2.61 Experiment Value (%): C, 42.65; H, 7.23; N, 2.87 NMR ( _D2O ) δ: 1.54 (3H, d, J = 6Hz, 6'-
C H ₃ ), 1.78 (1H, dd, J = 3.5Hz, 15Hz, 6-C
H), 2.28 (1H, dd, J = 3Hz, 15Hz, 6-C
H), 2.70 (1H, t, J = 9.5Hz, 4'- CH ), 3.3~
4.5 (15H, m), 4.85 (1″ -CH β, overlaps with HOD), 5.45 (d, J=3.5Hz, 1″ -CH α), 5.52
(1H, d, J=3.5Hz, 1'-C H ) TLC: Rf=0.27 IC ₅₀ (Satucalase): 8.0×10 ^-8 M IC ₅₀ (Maltase): 1.2×10 ^-7 M Example 5 Octa- O-acetyl-[1,6-anhydro-4-O-α-[4-[(1S)-(1,2,4,
5,(OH)/3,5( _CH2OH ))-(2,3,
4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-
dideoxy-D-galactopyranosyl]-β-
D-glucopyranose] 1,6-anhydro-4-O-α-[4-
[(1S)-(1,2,4,5,(OH)/3,5( _CH2
OH))-(2,3,4,5-tetrahydroxy-
5-(Hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-D-galactopyranosyl]-β-D-glucopyranose (320 mg) was dissolved in pyridine (10 ml), and acetic anhydride (5 ml) was added. and stir at room temperature for 15 hours. The reaction solution was concentrated to dryness under reduced pressure, and then dried overnight under reduced pressure in a desiccator. Ethyl ether-petroleum ether (1:10, about 50 ml) was added to the residue, and the mixture was left in the refrigerator overnight to give the title octa-O. A white powder (430 mg) of -acetyl-1,6-anhydro derivative is obtained. [α] ²⁵ _D +62.0° (c=0.5, CH ₃ OH) Elemental analysis: C ₃₅ H ₄₉ NO ₂₁ Calculated value (%): C, 51.28; H, 6.02; N, 1.71 Experimental value (%): C, 51.22; H, 5.88; N, 1.69 NMR (CDC1 ₃ ) δ: 1.12 (3H, d, J = 6.5Hz,
6′- CH ₃ ), 1.45-2.2-(2H, m, 6- CH ₂ ),
1.98~2.17 (24H, CH3COO- ×8), 3.06 _~ 3.27
(Adding 1H, m, 4′-C H , D ₂ O gives dd, J=~
1Hz, changes to 4.5Hz), 3.33 to 4.17 (7H, m),
4.3~5.5 (11H, m), 5.69 (1H, t, J=10Hz,
3-C H ) Example 6 Deca-O-acetyl-[4-O-α-[4-
[(1S)-1,2,4,5(OH)/3,5( _CH2
OH))-(2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)
amino]-4,6-dideoxy-D-galactopyranosyl]-D-glucopyranose] octa-O-acetyl-[1,6-anhydro-4-O-α-[4-[(1S)-( 1, 2, 4, 5,
(OH)/3,5( _CH2OH ))-(2,3,4,5-
Tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-
D-galactopyranosyl]-β-D-glucopyranose] (450 mg) was mixed with acetic acid (10 ml) and acetic anhydride (10
ml) and sulfuric acid (0.25 ml) and stirred at room temperature for 2 hours. The reaction solution was added to ice water (250 ml), and while stirring, sodium hydrogen carbonate (2.5 g) was added under ice cooling, and the mixture was further stirred at the same temperature for 2 hours. The reaction mixture is extracted with chloroform, and the chloroform extract is washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (150 ml) and eluted with chloroform-methanol (30:1). Elution fraction (200-480g)
When concentrated to dryness under reduced pressure, deca-O-acetyl-[4
-O-α-[4-[(1S)-1,2,4,5
(OH)/3,5( _CH2OH ))-(2,3,4,5-
Tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-
A white powder (550 mg) of D-galactopyranosyl-D-glucopyranose is obtained. [α] ²⁵ _D +98.9° (c=1, CH ₃ OH) Elemental analysis: C ₃₉ H ₅₅ NO ₂₄ Calculated value (%): C, 50.81; H, 6.01; N, 1.52 Experimental value (%): C, 50.55; H, 5.88; N, 1.56 Example 7 4-O-α-[4-[(1S)-1,2,4,5
(OH)/3,5( _CH2OH ))-(2,3,4,5
-tetrahydroxy-5-(hydroxymethyl)
cyclohexyl)amino]-4,6-dideoxy-D-galactopyranosyl]-D-glucopyranose deca-O-acetyl-[4-O-α-[4-
[(1S)-1,2,4,5(OH)/3,5( _CH2
OH))-(2,3,4,5-tetrahydroxy-
5-(Hydroxymethyl)cyclohexyl)amino]-4,6-dideoxy-D-galactopyranosyl]-D-glucopyranose] (450 mg) was dissolved in methanol (25 ml), and 28% aqueous ammonia (5
ml) and stir at room temperature for 15 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with Dowex 50W x 8
(H ⁺ type, 25 ml) column chromatography, and after washing the column with water, elute with 0.5N aqueous ammonia. The eluted fraction (97-255 ml) is concentrated under reduced pressure, and the concentrated solution is applied to Amberlite CG-50 (NH ⁺ ₄ type, 180 ml) column chromatography and eluted with water. Elution fraction (120~
150ml) was concentrated under reduced pressure and lyophilized to give 4-O-
α-[4-[(1S)-1,2,4,5(OH)/3,
5(CH ₂ OH))-(2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)
Amino]-4,6-dideoxy-D-galactopyranosyl]-D-glucopyranose (170 mg) is obtained. [α] ²⁵ _D +119.6° (c=1, H ₂ O) Elemental analysis: C ₁₉ H ₃₅ NO ₁₄・2H ₂ O Calculated value (%): C, 42.46; H, 7.31; N, 2.61 Experimental value (%): C, 42.54; H, 7.20; N, 2.89 NMR (D ₂ O) δ: 1.54 (3H, d, J = 6,5Hz,
6'-C H ₃ ), 1.71 (1H, dd, J = 3.5Hz, 15Hz, 6
-C H ), 2.33 (1H, dd, J = 3Hz, 15Hz, 6-
C H ), 3.22 (1H, dd, J = ~1Hz, 4Hz, 4'-
C H ), 3.33~4.67 (15H, m), ~4.85 (1″-C H
β, overlaps with HOD), 5.47 (d, J = 3.5Hz, 1″−
C H α), 5.55 (1H, d, J = 3.5 Hz, 1'-C H ) TLC: Rf = 0.23 Example 8 Add 10 ml of the isomer b of Example 1 to 200 ml of a beverage containing 20% tangerine juice. The mixture is stirred and dissolved uniformly to obtain a fruit juice-containing beverage containing an α-glucosidase inhibitor. Example 9 4-O-α-[4-[(1S)-1,2,4,5
(OH)/3,5( _CH2OH ))-(2,3,4,5
-tetrahydroxy-5-(hydroxymethyl)
cyclohexyl)amino]-4,6-dideoxy-D-glucopyranosyl]-D-glucopyranose 20 parts by weight Lactose 80 parts by weight Crystalline cellulose 20 parts by weight were mixed uniformly, kneaded with water, dried, and processed in a conventional manner. Therefore, it is used as a powder or fine granule.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ and R ² each represent a hydroxyl group or together represent an oxygen atom, the bonds ~ ~ represent either the R configuration or the S configuration, and the hydroxyl group in the formula may be protected] compound or its salt. 2 formulas Compounds represented by [In the formula, each hydroxyl group may be protected] and the general formula A compound represented by [in the formula, each hydroxyl group may be protected] is reacted, then subjected to a reduction reaction, and optionally subjected to an anhydro ring bond cleavage reaction or (and) a deprotecting group reaction. General formula for [In the formula, R ¹ and R ² each represent a hydroxyl group or together represent an oxygen atom, the bonds ~ ~ represent either the R configuration or the S configuration, and the hydroxyl group in the formula may be protected] A method for producing a compound or its salt. 3 General formula [In the formula, R ¹ and R ² each represent a hydroxyl group or together represent an oxygen atom, the bonds ~ ~ represent either the R configuration or the S configuration, and the hydroxyl group in the formula may be protected] An α-glucosidase inhibitor characterized by containing a compound or a salt thereof.