JPS5995297A - Pseudo-oligosaccharide, its preparation and use - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> and R<2> are OH, or combined to form oxygen atom; bond of wavy line is in R is S configuration; OH may be protected) and its salt. EXAMPLE:1,6-Anhydro-4-O-alpha-[4-{(1S)-[1, 2, 4, 5(OH)/3,5( CH2OH )]-[2,3,4,5-tertrahydroxy-5-( hydroxymethyl )cyclohexyl]amino}-4, 6-dideoxy-D-galactopyranosyl]- beta-D-glucopyranose. USE:An alpha-glucosidase inhibitor. Having inhibitory action on rise in blood sugar. PROCESS:A compound shown by the formula II (OH may be protected) is reacted with a compound shown by the formula III (OH may be protected) in a molar ratio preferably 1:(1-2) in a solvent such as usually water, organic solvent, etc., then reduced, and optionally subjected to cleavage reaction of anhydro ring bond and/or deprotecting reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [wherein R,) i each represents a hydroxyl group or a combination of oxygen atoms, the bond - represents either the R configuration or the S configuration, and the hydroxyl group in the formula may be protected] or a salt thereof.

The compound CI) of the present invention or a salt thereof has a pseudo-amino sugar [The Journal of, t-, IJ
-='/riichi'fmi7. Tory (J, Org, C
hem,) Volume 31, pp. 1516-1521 (1966
The term pseudosugar (pseud□-Bugar) was defined in
do-oligosaccharide). Conventionally, acarbose (aca
rbose) and related compounds (e.g., amylonutatin)
XG has α-glucondase inhibitory activity such as saccharase inhibitory activity CBAYg5421, Naturvvissenschaften
aften), Vol. 64, pp. 535-537 (19
1977), Special Publick Publication No. 54-39474 and Angewante.
Hemie (AngewandteChemie) No. 93
Vol., pp. 738-755 (1981).

Agricultural μ and 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 compound (II) and found that the compound represented by the general formula CI) has strong α-glucondase inhibitory activity. As a result of various studies based on the findings, the present invention was completed.

That is, the present invention relates to (1) a compound represented by the general formula [E] or a salt thereof, (2) a compound represented by the formula [■] (in the formula, any hydroxyl group may be protected) and the general formula [In the formula, each hydroxyl group may be protected] is reacted with a compound represented by -, then subjected to a reduction reaction, and optionally subjected to a cleavage reaction of a cyanhydro ring bond or (and) a debinding reaction. A general formula characterized by the addition of
(3) An α-gμ cosidase inhibitor characterized by containing a compound represented by the general formula CI or a salt thereof.

The compound represented by the general formula [I] or its salt has an amino group in the pariolamine moiety and a 4,6-sideoxy-D
- Due to the difference in steric configuration at the bonding part with the p-moiety, the general formula [Symbols in the formula indicate the same meanings as above]
There are two stereoisomers of the compound represented by the above formula or a salt thereof and the compound represented by the general formula [the symbols in the formula have the same meanings as above] or a salt thereof.

Specific examples of the compound represented by general formula (I'a) or its salt include 4-0-α-C4-((1s)-1,2,4゜5(O
H)/3.5(CH20H))-(2,3,4,5-tetrahydroxy-5-(hydroxymethy/L/)cyclohexy/1/)amino, l-4,6-sideoxy-D-
gμcobilano7μ]-D-glucobylanose 1,6-anhydro-4-0-α-[4-C(18)J
(1,2,4,5(OH)/3.5 (CH20H)
)-2,3,4,5-tetrahydroxy-5-(hydroxymethylcyclohexyl/I/)amino)-4,6-sideoxy-D-glucopyranosyp]-β-D-gμcopyranose is Specific examples of compounds represented by or salts thereof include 4-0-α-[4-[l8)-(+, 2,4°5(OH
)/3,5(CH20H))-(2,3,4°5-tetrahydroxy-5-(hydroxymethy/1/)cyclohexyl)amino)-4,6-sideoxy-D-galactopyranosiμ]-D-gluco Vilanose 1,6-anhydro-4-〇-α-C4-C(IS)-
(+, 2,4.5(OH)/3.5(CH20H))-
(2,3,4,5-tetrahydroxy-5-(hydroxymethy/L/)cyclohexy/l')7mino)-4,6
-sideoxy-D-galactopyranosi μ〕-β-・D-
Glucobylanose, etc. [For the nomenclature of this configuration, IUPAC-Engineering UB Cicryto/'19
1973 Recommendation (Engineering UPAC-Engineering UB i 973 R
eco-commendation
1), Pure and Applied Chemistry (Pure Appl, Chem,) Volume 37.

See pages 285-297 (1975)].

The above compounds (Ia, 1 and [more]) both have α-glucosidase inhibitory activity, but [1a] is better than (
Ib) Yoshishi also generally has strong α-glucosidase inhibitory activity.

The protecting group for the hydroxyl group in the above formula may be a protecting group used as a protecting group for the hydroxyl group in sugar chemistry, such as AS//I.
/ type protecting group, ether type protecting group, aceter/I/ type protecting group, ketal type protecting group, orthoester type protecting group, etc. are used.

Examples of the acyl-type protecting group include halogen, carbon number 1 to
Lower alkoxy group of 4; 1 with 1 to 5 carbon atoms, which may be substituted with a phenoxy group which may be present in halogen'
Lucanoy/l/ group; benzyi/1/ group optionally substituted with nitro group, phenyl group; al7oxycarbonyl group having 2 to 6 carbon atoms and optionally substituted with halogen; carbon number 2 to 4 γμ 2μ oxycarponic μ group; return prime number 1 ~
A lower alkoxy group of 4 or a penzyloxycarpo(2μ) group which may be substituted with a nitro group or a nitro-substituted phenoxycarboni)V group is used.

The above halogens include fluorine, chlorine, and bromine.

Iodine etc. are used.

The above lower alkoxy group having 1 to 4 carbon atoms is
For example, the above-mentioned methoxyl, ethoxyl, fluorboxyμ, butoxyμ groups, etc., which may be substituted with halogen, are used.

Examples of the above alkanoyls having 1 to 5 carbon atoms: Eva, Hopmip, Acetyl, Propionyl, Fuchiri μ
, isobutyryl, valeryl, isovaleryl.

pivaloy) V group, etc. are used.

Examples of the alkoxy group in the above alkoxy μbonyl group having 2 to 6 carbon atoms include methoxyl, ethoxy V/L/, propoxyl, gutoxyl, bench poxyl, vinyloxyl, which may be substituted with the above halogen. , allyloxyl group, etc. are used.

Examples of the γμ kenyl group having 2 to 4 carbon atoms in the above γμ kenyloxycarbonyl group having 2 to 4 carbon atoms include vinyl, allyl, impropenyl, 1-proveni/l/jl-butenyl, 2-butenyl, 3 -gutinyl etc. are used.

More specific examples of acyl protecting groups include formyl,
Acetyl μ, chloroacetyl, dichloroacetyl ρ, trichloroacetyl μ, triph I leoloacetyl μ, methoxyacetyl, triphenylmethoxyacetyl, phenoxyheptyl, p-chlorophenoxyacetyl, fluoropionyl, impropionyl, 3-phenylpropionyl, Imbutyril.

pivaloy μ; benzyi μ, p-nitrobenzoyl.

p-phenylbenzoyl; methoxycarbonylethoxycarbonyl/l', 2,2.2-trichloroethoxycarbonylμ, inbutyloxycarbonyl; vinylμoxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, p- Methoxybendiμoxycarboniμ, 3
j4-dimethoxybenzipoxycarbonyp, p-nitrobenzylo/xycarbonyl; p-nitrophenoxycarbonyl, and the like.

Examples of ether-type protecting groups include halogen.

A lower alkyl group having 1 to 5 carbon atoms which may be substituted with a lower alkoxyl group having 1 to 4 carbon atoms, a benzyloxyl group, or a pheniμ group; an alkyl group having 2 to 4 carbon atoms; an alkyl group having 1 to 5 carbon atoms; A trisubstituted silyl group whose substituent is a lower alkyl μ group, a phenyl group, a benzi μ group, etc.; a lower alkoxyl group having 1 to 4 carbon atoms.

Benzyl group optionally substituted with nitro group; carbon number 1
to 4 lower alkoxyl groups, a tetrahydropyranyl group which may be substituted with halogen, or a tetrahydrofuranyl group, etc. are used.

Examples of the lower alkyl group having 1 to 5 carbon atoms include methyl, ethyl, propyl, and isopropyl.

Glythyl, isobutyl, ethyl ethyl, tert-butyl, benchi, impentyl, neobenchi and the like are used. The above-mentioned halogen, lower alkoxyl group having 1 to 4 carbon atoms, and γμ Keni/l' group having 2 to 4 carbon atoms are the same as in the case of the acyl type protecting group.

More specific examples of ether protecting groups include methyl, methoxymethyl, and benzyloxymethy/I/.

tert-gutoxymethyμ, 2-methoxyethoxymethy#, 2,2.2-hlichloromethoxymethyl.

Ethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl tvs2s2,2-trichloroethyl name propymu,
Isopropyl, butyμ, isobutyl.

Tert-petit μ, tert-buty μ, ethoxyethyltriphenylmethy/L/, p-methoxyphenyldiphenylmethyl; allyl; trimethylsilyl.

tert-7-flsilyl, tert-ethyldipheny/VS/suμ; benzyμ, p-methoxybenzyl, p-
Ninidobenziμ, p-chlorobenzyl; tetrahydropyranyl, 3-promotetrahydrobiraniμ, 4-methoxytetrahydropyranyl, tetrahydrofuranyl, and the like.

The aceter/l' type, ketal type and orthoester type protecting groups preferably consist of 1 to 1o carbon atoms. Specific examples include methylene and ethylidene.

1-tert-butylethylidene, 1-phenylethylidene, 2,2,2-)lichloroethylidene; isopropylidene, butylidene, cyclopentylidene, cyclohexylidene, cyclo1tylidene; benzylidene, p-methoxybenzylidene, 2゜4-dimethoxybenzylidene, p-dimethylaminobenzylidene jO-nitrobenzylidene; methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1,2-dimethoxyethylidene, and the like.

In addition, stanoxane type protective groups, cyclic polonate type protective groups, cyclic polonate type protective groups, etc. can be similarly used.

As the salt of the compound CI) 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, such as acetic acid, sinlic acid, and citric acid.

Organic acids such as anucobic acid, mandeic acid, methanesulfonic acid, etc. are used.

The above compound [11 or a salt thereof is crystalline or powdery and has almost no toxicity (rat LD5o500Trg/=9 or more).

Compound CII) or a salt thereof has an α-glucosidase inhibitory effect and suppresses carbohydrate metabolism in humans and non-human animals. various diseases caused by
For example, it is a compound useful for preventing obesity, adiposity, hyperlipidemia (arteriosclerosis), diabetes, prediabetes, and diseases caused by sugar metabolism by oral microorganisms, such as dental caries.

Compound CI) or a salt thereof can be used, for example, in water, ethanol, ethylene glycol-μ, polyethylene glycol:2-A/
Liquid carriers such as starch and cellulose.

Dilute with a non-toxic carrier such as a solid carrier such as polyamide powder to form an ampoule, granules, 1 tablet, 9 tablets, or a cuff.

It can be prepared into serums, syrups, etc. according to conventional methods and used for the various uses mentioned above. In addition, sweeteners, preservatives, dispersants, and shielding agents can also be used.

Compound CI) or a salt thereof is administered orally or parenterally, preferably orally, at each meal, with a meal, before or after a meal.

Specifically, for example, for adults, a preparation containing about 10 to 200 wI of the compound or its salt can be taken with each meal, before or after a meal, to reduce blood levels caused by eating. Since the increase in glucose concentration can be suppressed, it is effective in preventing and curing the above-mentioned diseases.

Compound CI) 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.

Compound CI) or a salt thereof 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, jams, bean paste, and jelly, seasonings, or various staple foods and side foods.

Foods produced by adding compound CI) or its salts are suitable as foods for patients with metabolic disorders, and also for healthy people as preventive foods for metabolic disorders.

For example, compound [I] or a salt thereof may be added to various foods in an amount of about 0.0001 to 1% of the carbohydrate content in the food. When mixing with f4 ingredients,
A carbohydrate content of 0.0001-1% of the feed is desirable.

In the compound represented by the general formula [E] of the present invention or a salt thereof, when R1 and R2 together represent an oxygen atom, that is, when R1 and R2 together represent an oxygen atom, The compound represented by [I[) and the compound C
It can be produced by subjecting the Schiff base obtained by reacting with M) to a reduction reaction and, if desired, to a deprotecting group reaction.

In this reaction, the Schiff base formation reaction by the condensation reaction of compound CII) and compound [111) and the reduction reaction of this Schiff base can also be performed continuously in the same reaction vessel.

Compound CIIL) as a raw material can be used in a molar amount usually about 1 to 2 times that of compound [■].

The condensation reaction between compound CII) and compound C11 and the reduction reaction of the resulting Schiff base are generally carried out in a solvent.

Suitable solvents include, for example, water, methanol,
Propanol, butanol and other alcohols, dimethic acid, dimethylformamide, N-methylacetamide, grime such as methyl cellosolve, dimethyl cellosolve, diethylene glycol dimethyl ether, etc. /L/, a polar solvent such as acetonitrile, a mixed solvent thereof, or a mixture of these polar solvents or mixed solvents with a nonpolar solvent such as chloroform or dichloromethane.

The reaction temperature in the reaction for forming the ship base 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 about several minutes to 24 hours.

For the reduction reaction of the formed ship base, a metal hydride complex reducing agent such as sodium borohydride,
Alkali metal borohydrides such as potassium borohydride, lithium borohydride, sodium trimethoxyborohydride, alkali metal cyanoborohydrides such as sodium cyanoborohydride, aluminum hydride such as lithium aluminum hydride Advantageously, alkali metals, such as sia μkylamineboranes such as ehadimethylamineboranes, are 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 of this reduction reaction is not particularly limited, but it is usually carried out at room temperature, in some cases, especially at the beginning of the reaction, under water cooling, and in some cases heated to about 100°C, and the Schiff base to be reduced and There are differences depending on the type of 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.

It is also possible to use means of catalytic reduction as a reduction reaction of the Schiff base formed. That is, the reaction is carried out by shaking or stirring the ship base in a hydrogen stream in the presence of a catalyst for catalytic reduction in a suitable solvent. Catalytic reduction catalysts used include, for example, platinum black, platinum dioxide, palladium black, palladium carbon, Raney nickel, etc., and commonly used solvents include water, methanol, alcohol-IV such as ethanol-μ, etc. For example, ethers such as dioxane and tetrahydrofuran, dimethyl μformamide, or a mixed solvent thereof are used.

The reaction is usually carried out at room temperature and normal pressure, but may also be carried out under pressure or with heating.

The compound represented by the general formula [in the formula, the bond shows either the P configuration or the S configuration, and the hydroxyl group in the formula may be protected] is a reaction between the above compound CII] and [11] Compound C obtained by [C]i1.6-Anhydro ring bond is subjected to a cleavage reaction and, if desired, to a deprotecting group reaction. This cleavage reaction of the 1,6-anhydro ring bond can also be carried out continuously in the same reaction vessel as the condensation reaction of the above-mentioned compound [■] and compound Cm) and the subsequent reduction reaction.

This cleavage reaction is carried out by reacting compound (Ic) with, for example, a mixture of sulfuric acid, acetic anhydride, and acetic acid [G, G, S, Dutton et al.:
Canadian Journal of Chemistry (ca.
l'1. J, Chem, ) Volume 44, 1069-1
074 page (1966); Mori et al.: Chemical and Ph.
arm, Bull, ) Volume 23, 1480-148
7 (1975) etc.].

The amount of sulfuric acid used in this reaction is based on the starting compound (Ic)
It is sufficient to use a catalyst amount or about twice the amount (weight) of the catalyst. Further, the amounts of acetic anhydride and acetic acid are usually added in large excess relative to the starting compound [IC].

This reaction is usually carried out at about room temperature, but may also be carried out under cooling, for example under water 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 compound [IC) or Dd) has a protected water e group, the elimination reaction of the protecting group of the hydroxyl group can be carried out using a method known per se.

For example, cyclohexylidene group, isopropylidene group,
Acetal type or keter/L' such as benzylidene group
Type protecting groups and trithi/L/ groups are hydrochloric acid and acetic acid.

By hydrolyzing with an acid such as a sulfonic acid type ion exchange resin, for example, acetyl group, pencil μ group, etc., can be hydrolyzed with an alkali such as ammonia, sodium hydroxide, barium hydroxide, sodium methoxide, etc. By doing so, it can be eliminated by benzyl ether elementary decomposition such as benzyl ether, benzyl μ group, p-methoxybendi A/M, or reductive decomposition with total sodium chloride in liquid ammonia.

The above-mentioned compounds CI) and their synthetic intermediates obtained in this way can be processed by means known per se, such as filtration, centrifugation, concentration, vacuum concentration, drying, freeze-drying, adsorption, desorption,
Methods that utilize differences in solubility in various solvents (e.g.
(solvent extraction, dissolution transfer, precipitation, crystallization, recrystallization, etc.), chromatography (e.g., ion exchange resin, activity, high porous polymer, Sephadex, Sephadex ion exchanger, cellulose, ion exchange cell) Lerose,
It can be purified by chromatography using silica gel, alumina, etc.

The present invention also broadly includes compounds of the general formula CIV) or salts thereof.
[In the formula, R1 and R2 are each a hydroxyl group or a combined oxygen atom, n is 0 or an integer from 1 to 4,
m is 0 or an integer of 1 to 3, or hydrogen or a hydroxyl group, the bond - represents either the R configuration or the S configuration, and the hydroxyl group in the formula may be protected] The present invention also provides an invention of a salt thereof.

The compound represented by the above general formula CIV) is a compound represented by the general formula [in the formula, m represents 0 or an integer of 1 to 3, and each hydroxyl group may be protected] and the general formula [in the formula, n is an integer of 0 or 1 to 4, or represents hydrogen or a hydroxyl group, each hydroxyl group may be protected] The ship base obtained by the reaction is subjected to a reduction reaction, and as desired. Alternatively, it can be prepared by subjecting it to an anhydro ring bond cleavage reaction and/or a deprotecting group reaction. Further, compounds in which m is 0; n is 0 or an integer of 1 to 4 in the general formula CIV), and examples include def1, soluble starch, and dequinut.

Cyclodequinutrin, oligosaccharide, etc./l/:l/: In the presence of α-1,4 conjugates of cyclodequinutrin, glucose transferases such as bacterial saccharifying amylase or cyclodextrin glycosyltransferase in an aqueous medium. It can also be produced by acting on

More specific examples of the compound represented by the general formula CIV) include (hereinafter referred to as blank spaces). These compounds CIV) have α-curcosidase inhibitory activity and are useful for hyperglycemic symptoms and various diseases caused by them, like compounds CI, 1 and their salts.

The raw material compound CHI) used in the present invention is, for example,
7-169446, or by the method of culturing a microorganism belonging to the genus Streptomyces described in JP-A-57-179174O)! It can be manufactured by using the method as a raw material.

Raw material compound Cff1. 1) can be produced, for example, using Maμ dose as a raw material according to the following method. That is, for example, 2,3-di-0-bendi)v-1゜6-anhydro-4-0-(2,3-di-0-bendi/l'-6-
To synthesize zooxy-α-D-xylo-4-hexobyranone/L/)-β-D-glucopyranone, 2,3-diO-
Bendi/L/-1,6-anhydro-4-0-(2,3
-Z-0-bendi/l/-6-zooxy-α-D-gup
(copyranosyl)-β-D-gμ cobylanose, the oxidation conditions for synthesizing ulose by total oxidation of the secondary hydroxyl group of the saccharide, such as dimethyl/resμ-hoxy-trifluoroacetic anhydride, were used to synthesize ulose. It can be produced by oxidation in the presence of ammonium. (See formula below).

In the above formula, Bn represents a benzene/L' group, and DMSO represents a dimethic acid μ group. In the above formula, the protecting group for the hydroxyl group may of course be other than the benzene μ group.

The protecting group elimination reaction of compound (■) can be carried out by a method known per se or in the same manner as the protecting group elimination reaction of the above-mentioned compounds CIcI) and CId).

Compound (II), CI[l) and their synthetic intermediates obtained in this manner can be isolated and purified by the above-mentioned methods known per se.

The content of the present invention will be explained in detail by describing all 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 saccharase prepared from pig small intestine mucosa [Porgestrem (B, Borgs tram)
) and Acta C. Scandinavica by Dahlqvist A.
hem.

3cand, ) Volume 12, 1997-2oo6u,,
The inhibitory activity against [prepared according to the method described in 195 Chiang] was 0.02M! Add the inhibitory substance (compound or its salt) to be tested to the enzyme solution (0.25 g/) suitably diluted with J acid buffer solution (pH 6.8) in the above buffer solution (0.25 g/).
, 5 tsl) and the above buffer solution (0.25 tsl) of substrate 0.05M maltose or 0.05M sucrose.
) and the mixture is allowed to react at 37° C. for 10 minutes.

To this, add Glucose B-Test as a reagent (glucose measuring solution/
Reconu oxidase reagent, manufactured by Wako Tsumugi Pharmaceutical) (3+yl)
was added, 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 of Compound CI) or a salt thereof described in Examples against mucosal mucosa (pig, intestinal mucosa) [hereinafter referred to as CI
3o (abbreviated as maltase)] and saccharase (abbreviated as
50% inhibitory concentration for pigs, intestinal mucosa) [hereinafter referred to as Engineering C3
o (saccharase) and #J6] was determined from the inhibition rate (%) measured using the above measurement method at 3 to 5 different concentrations of each inhibitor.

The eluate fractions of column chromatography in the purification process of each compound described in Reference Examples and Examples are usually examined for the contained components by thin layer chromatography (TLC'1) or by differential refractometer (R403 manufactured by Waters, USA). ) was used to examine the elution curve, and fractions containing the necessary components were collected and subjected to the next step.The 'I' LC Pf values of each compound described in the examples are not particularly specified. Limited, the thin plate is precoated.
ed) TLC plate Silikage/L/60F2.4 (
Manufactured by Merck.

(West Germany), and n-7'ropyrua μ was used as the developing solvent.
Measurement was performed using co-μ/acetic acid/water (4:i:i). (
In the column chromatography (Rf value of Rf = 0.30) measured by the above method as a control sample, the column packing material silicage/Kiese I Rege/L'60 (70~ 230 mesh), manufactured by Meμri (West Germany)! + DOWEX 50WX8 (E [type) and +X2 (OH-
Type) is manufactured by Dow Chemical Company (USA); Amberlite CG
-50 (NH+, type) is manufactured by Rohm and Haas (
USA) A 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, calcite; m, ma μ
Unless otherwise specified, the mixing ratio of the mixed solvents used in the reference examples and examples is the volume ratio (V
/V ), and in the assignment of NMRO chemical shifts, the position number of the atom of each compound is shown by the following formula.

Reference example 1 2.3-di-0-benzifuray 1,6-anhydro-4
-0-(2,3-diO-bendiμm6-zooxy-α
-D-xylo-4-hexopyranoseuroshi A/)-β
-D-gμcobylanose dimethysμphoxite (19,
5g/)i dissolved in dichloromethane (195g/), -
Trifluoroacetic anhydride (29m/
) in dichloromethane solution (130g)'f! : Dripping,
Stir for 15 minutes at the same temperature, then cool to -70℃ or less for 2-3 minutes.
-diO-benzi/L/-1,6-anhydro-4-〇-(2,3-di0-bendi7re6-deoxy-α-
D-glucobylanose/L/)-β-D-glucobylanose [2,3,2',3'-tetra-O-benzi/l'
-1,6-anhydrolo7-deoxima μ dose) (
Add 45.3 nM and stir at the same temperature for 2 hours. The reaction solution was cooled to below -65°C and triethylleamine (54,
After dropwise addition of a dichloromethane solution (160 ml) of 5 ml), the cooling bath is removed and the mixture is stirred until the reaction temperature rises to room temperature. After adding the reaction solution to ice water (1,36) and stirring, the dichloromethane layer was separated, and the aqueous layer was added to dichloromethane (1,36).
Extract twice with 200 ml). The dichloromethane layers are combined, washed with 0.5N hydrochloric acid, saturated sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The residue was subjected to silicage A/(ld) column chromatography, washed with toluene (1,5n), and then toluene-methylacetate/shoku9:1) and toluene-i! acid ethyl/l/(4
: Elutes at 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-benzi
Re 1,6-anhydro-4-.

-(2,3-diO-bendi/re6-deoxy-α-
D-xylo-4-hequinpyranosuroshi/L/)-β
-D-g/recopyranose is a syrupy substance (40,7
f).

[αl, 5+ 55.7° (c = l, CH30
H) Elemental analysis: C4oH4209 Calculated value (%): C,72,05; H,6,35 Experimental value (%): C,72,29; H,6,43IR
IJ5 car” Oil: 1745aX NMR (CDCl5) δ: 1.26 (3H, d,,T
=7Hz).

3.30-3.85 (6H, m), 4.02 (IH, d
, J=9Hz).

4.30-4.95 (ioH, m), 5.02 (IH,
d, J=3Hz).

5.38 (IH, s), 7.2-7.5 (20H, m)
Example 1 1.6-anhydro-4-〇-α-C+-[Cl8)-
(1,2,4,5(OH)/3.5(CH20)I))
-(2,3,4,5-tetrahydroxy-5-(hydroxymethy/X/)cyclohexyl)amino, :)-4,
6-Sideoxy-D-gμcopyranosyμ]-β-D-gucose and l,6-anhydro-470-α-C4
-C,Cl5)-(1,2°4.5(OH)/3,5(
OH20H))-(2,3゜4.5-tetrahydroxy-5-(hydroxymethyμ)cyclohexy/L/)amino)-4,6-sideoxy-D-galactopyranosyl]
-β-D-gμcopyranose 2,3-diO-benzyl-1,6-anhydro-4-
0-(2,3-di-O-benzyl-6-deoxycoup α-
D-xylo-4-hexobiononuuroshiμ〕-β-D
- glucopyranose (40,51) and Palio μ amine (12,0 g) 2 dimethy/reform μ amide (300
ml) and added 2Hm acid (9 g/) and sodium cyanoborohydride (15.6 g) at 60-65°C.
Stir for 133 hours. The reaction solution was concentrated under reduced pressure, and toluene was further added to distill off dimethyl, hopam, and mido under azeotrope. @ Distillate water (300g/) and vinegar e-koflV (3G
(l ml) and partitioned, the aqueous layer was separated with methylene acetate and 11/(200
fft ) twice. The ethyl acetate layers were combined, washed with water, dried over sodium sulfate, concentrated under reduced pressure, and when ethyl acetate (1e) was added to the residue, a syrup-like substance (1e) was obtained.
can get. Syrup-like substance whole silica/shiku 550g/
), and after washing the column with chloroform, the column was eluted with chloroform-methanol-I (9:i). The eluted fraction was concentrated under reduced pressure, and the residue was further placed in a desiccator.
Dry in vacuum under vacuum. The obtained white powder (5,819
)'t Liquid ammonia (
Add the total sodium solution until the blue color no longer disappears, and stir for an additional hour at the same temperature. Ethano-IV (30 tnl) and sodium (1,Of)'ir were added to the reaction mixture and stirred at the same temperature for 2 hours. Add ammonium acetate to the reaction mixture until the blue color of the reaction mixture disappears, remove the cooling bath, distill off the ammonia with stirring, and concentrate the reaction mixture under reduced pressure. A mixture of ethyl acetate (350 ml) and water (350 ml) was added to the residue for partition, and the aqueous layer was separated and adjusted to pH 7 with 2N hydrochloric acid.
Adjust to DOWEX 5QWX3 (H+ type).

350 ygl) and stirred for 1 hour at room temperature. This DOWEX 50WX8 (E [type)] was added onto a column packed with another DOWEX 50WX8 (C type, 100th edition) in advance, and after washing the column with water (3e), 0.5
Elute with N ammonia water. Elution fraction (1,3-2.4
1) Concentrate under complete pressure and convert the residue to amber phytoca
-50 < yH+ type, 450 edition) column chromatography and elute with water. Elution quarter (235-350 ml
) was concentrated under reduced pressure, and the residue was purified with DOWEX 1X2 (OK
When subjected to column chromatography (type 270d) and eluted with water, it is divided into two parts eluted first (310 to 665 ml) and two parts eluted later (680 to 164 (1 ml). Both fractions were concentrated under reduced pressure, and each concentrated solution was once again subjected to DOWEX 1X2 (on-type, 16o resistant) column chromatography, eluted with water, and the eluted fraction was concentrated under reduced pressure and lyophilized to remove the eluted solution first. From the fraction, 1
,6-anhydro-4-o-α-[4-C(Is)-(
1,2,4,5(OH)/3,5(0M20H))
-(2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyamino)-4,6-cyoxy-D-galac)pyranosyμ]-β-D-gμ white powder of copyranose (5201811) However, 1°6-anhydro-4-0-α-[4-
C(18)-(1,2,4,5(OH)/3,5(O
H20H)7(2,3,4,5-tetrahydroxy-5
-(Hydroxymethyμ)cyclohexy/I/)amine]
-4゜6-Sideoxy-D-gμ Kobyranoshiμ〕-β-
A white powder of D-gμcopyranose (i, 2!M) is obtained.

The compound obtained from the first eluted fraction [isomer (a)
): [α)25 + 86.5° (c = i s % 0
) Elemental analysis: C engineering, lll33' N O engineering, ・H20
Calculated value (%): C, 45, 5i; H, ? ,03;'
N, 2.79 Experimental value (%): C, 45,22;
n, 7.00; J2.79IMR (D20) a
: 1.53 (3H, d, J=6.5]Ez,
6'-Cdan, ), 1°7i (IH, dd, J=3H
z, 15.5Hz.

6'-Cdan), 2.33 (IH, dd, J=3Hz, f
5.5Hz.

6-Cdan), 3.22 (IH, dd, J=-IHz, 3
:Ez.

4'-Cdan) 73.45-4.65 (15H, m),
5.32 (IH, dJ=4.5Hz, i'-Cdan), 5
,7Q(IH,s,1"-Cdan) TLC: Rf=
0.24 Compound obtained from one minute eluted later [isomer (b)
): [α)fi6+65.2° (c-1r H2O) Elemental analysis: C19H2S N013” H20 calculated value (%
): c, 45.51; H, 7,03; N, 2.7
9 Experimental value (%>: c, 45.48; uj7.07
; N, 2.86 IMR (D20) δ: 1.54 (3
H, d, J = 6.5Hz.

6'-Cru), 1.78 (IH, dd, J=3Hz,
15.5Hz.

6-CH), 2.3[1(IH, dd, J=3Hz, 1
5.5Hz.

6-Cdan), 2.7i (iH, t, J=i0Hz, 4'
-CH).

3.5-4.6 (15H, m), 5.28 (IH, d,
J=3.13I(z.

1'-Cdan), 5.69 (iH,s, 1"-Cdan) TL
c: Rf = 0.33 Engineering C3o (maltase): 1.3X10 M Example 2 Octa-O-acetyl μm (If, 6-anhydro-4-
〇-α-C4-C<l5)-(i, 2.4゜5(OH
)/3,5(C1(20H))-(2,3,4°5-tetrahydroxy-5-(hydroxymethyl)cyclohexy/I/)amino)-4,6-sideoxy-D-gμ
cobylanosyl]-β-D-JIV copylanonu] 1,6-anhydro-4-〇-α-C4-C (Is)
-(1,2,4,5(OE[)/3,5(CH20H)
)-(2,3,4,5-tetrahydroxy-5-(hydroxymethy/shi)cyclohexyl)amino) -4゜6
-Sideoxy-D-gu μ
Copyranose (1°0f) was dissolved in pyridine (25 g/), acetic anhydride (12.5 gt) was added, and the mixture was stirred 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, and to the residue was added ethyl ether-petroleum ether/V (1:10, about 100 g/V).
If left overnight in the refrigerator, the labeled octa-O-acetate/
White crystalline powder of L/-1.6-anhydro derivative (1
, 67 g) is obtained.

[α) 25 + 22.3° (c −1, CH30n
) Elemental analysis' C35H49NO2, calculated value (%): c, 5i, 28; n, 6.02;
N, 1.71 Experimental value (%): c, 51.37; H
, 6, 20; N, 1.68HMP (CDC: 13)
δ: i, 35 (3a, d, J=6az.

g CH3), 1.5-2.4 (2H, m, 6-CH2
), 1.97-2.28 (24) I, October, COO-X
8), 2.5-2.73 (iH, m, 4'-CH, D2
When 0f is added, t, J=10Hz K changes), 3.3
3-3.47 (IH, m, 1-CH), 3.63-4.
2 (6H, m), 4.5-5.7 (12H, m) Example 3 Decac O-acetyl μ-(4-0-α-C4((1s)-
1,2,4,5(on)/3.5(cu2ou))-(
2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)-amino)-4゜6-sideoxy-D-glucopyranosyl)-D-glucopyranose] Octa-O-acetyl[1 ,6-anhydro-4-0
-α-C4-C(l5)-(1,2,4゜5(OH)/
3.5(CH8OH))-(2,3,4.

5-tetrahydroxy-5-(hydroxymethy/shi)cyclohexy/L/)amino)-4,6-sibuoxy-D
-ri/L/copiwonosyl]-β-D-riμcopyranose) (1,51) in vinegar! 2 (40m?), acetic anhydride (
40 ml) and sulfuric acid (1 ml), and stirred at room temperature for 2 hours. The reaction solution was added to ice water (1e), and while stirring, 1 um (10y) of frozen acid solution I-' was added while cooling with water, and the mixture was further stirred at the same temperature for 2 hours. The entire reaction mixture is extracted with chloroform, and the chloroform extract is washed with a saturated sodium hydrogen oxide solution and water, dried over sodium sulfate, and concentrated under reduced pressure. Silicage A
/(250at) and eluted with chloroform methanol (30:1). Elution fraction (
340 to 640 g) was concentrated to dryness under reduced pressure to obtain deca O-acetyl/re[4-〇-α-[4-C(18)-(1,2
,4,5(OH)/3.5(CH20H) )-(2,
3,4,5-tetrahydroxy-5-(hydroxymethyl
cyclohexy/L/)amino)-4,6-sideoxy-D-gμcopyranosyl)-D-glucopyranose]
A white powder (1,58f) is obtained.

[α) 25+70.4° ('c = i, CH30H)
Elemental analysis"391155 N024 Calculated value (%): C, 50, 8i; L6. Old i N
, 1.52 Experimental value (%): C, 50,78; H,
5,62i N, 1.58 Example 4 4-0-α-C4-C(l5)-(1,2,4,5(O
K)/3 j5 (CEI20H))-(2,3,4,
5-tetrahydroxy-5-(hydroxymethyl)cyclohexy/amino)-4,6-sideoxy-D-gμcopyranosy/shi]-D-gμcopyranomedecar〇-
Acetyl μ-[4-o-α-[4-((IS)-(1,
2,4,5(OR)/3.5(CH20H))-(2,
3,4,5-tetra to droxy-5-(hydroxymethyl)S/cyclohexyv)amino')-4゜6-sideoxy-D-glucopyranosylμ1)-D-glucopyranose)(985"-&)' and methanol (50ml)
Add 28% aqueous ammonia (1(b+/)) and stir at room temperature for 20 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to column chromatography on DOWEX 50wxs+ (■ type, 50 ml). What are you doing?
After washing the column with water, elute with 0.5N aqueous ammonia.

Both elution fractions (155-485 vol) were concentrated under reduced pressure, and the concentrated solution was transferred to Amberlite CG-50 (1 type, 360 txt).
) column chromatography and elute with water. Both elution portions (2
15-2901I/)ff: When concentrated under reduced pressure and freeze-dried, 4-〇-α-[4-C(l8)-(1,2゜4.5 (
OK ) /3-5 (CH20H) ) C2,3
,4p5-tetrahydroxy-5-(hydroxymethyl
cyclohexyl)amino)-4,6-sibuoxy-
D-y"μcopyranosyl)-D-1"/recopyranone (400 noda) is obtained.

Cα]25 + 97.7° (c=1. H20) Elemental analysis "19 H35" 014・2H20 calculated value (%)
: C, 42,46; H, 7,31; N, 2.61
Experimental value (%): C, 42, 65; Hj-23; N
, 2.87HMI? CH20) δ: 1.54 (3H
, d, J=5Hz.

ff; ” CH3n, f, 78 (IH, dd, J=3
．． 5Hz, 15Hz.

6-CH), 2.28(1)I, dd, J=3Hz,
15Hz.

6-Cdan), 2.70 (iH, t, J=9.5Hz, 4
'-CH).

3.3-4.5 (i5H,m), -4,85(
1”-CHβ, overlaps with HOD), 5.45 (d
, J=3.5Hz, l″-cdan α).

5.52 (IH, d, J=3.5Hz, 1'-C,H)
TLC: Rf=0.27 IC50 (t7 case): 8.010'''M Engineering C
3o (Malta-f): L2xlOM Example 5 Octa-0-acetyum (1,6-anhydro-4-0
-α-C4-C(H5)-(1,2,4゜5(OH)/
3,5(CH20E[))-(2,3,4゜5-tetrahydroxy-5-(hydroxymethy/L/)cyclohexV/shi)amino, l-4,6-sideoxy-D-galactopyranosyμ]- β-D-g/recopyranose] 1.6-anhydro-4-〇-α-C4-C(Is)-
(1,2,4,5(OE[)/3.5(CI(20H)
)-(2,3,4,5-tetrahydroquine-5-(hydroxymethy/l/)cyclohexy/shi)amino) -4
゜6-sideoxy-D-galactopyranosi μ]-β-D
- μcopyranose (320IIg) to pyridine (10
Dissolve in acetic anhydride (5th edition Z) and add 1 at room temperature.
Stir for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, and after drying in a desiccator overnight under reduced pressure, ethyl μether-petroleum ether/l/(+=10°, approx. 50 ml) was added to the residue, and the mixture was placed in a refrigerator. If left overnight, the marked off-coat 0-
White powder of a7tyl-1,6-anhydro derivative (43
0mf) is obtained.

[C4” + 62.0° (c = 0.5, CH
30H) Elemental analysis "35 H49NO2□ Calculated value (%): c, 51.28; H, 6,02;
N, 1.71 Experimental value (%): C, 51,22i H
,5,88i N,1.69HME (CDC13)δ
:1.12 (3H, d, J=6.5Hz.

6'-Cdan 3), i, 45-2.2 (2H, m, 6
CH2), i, 98-2,1γ (24LC 亙, co
o-x8), 3.06-3.27 (l Hz m
When p 4' CH, H20 is added, dd, J=~1■z
s 4.5 Hz),' 3.33-41
7 (7H.

m), 4.3-5.5 (IIH, m), 5.69 (IH
, t, :r=10Hz, 3-CH) Example 6 Decac 0-acetifle [4-o-α-C4-C(IS
)-(1,2,4,5(OH)/3.5(CH20H)
)-(2,3,4,5-tetrahydroxy-5-(hydroxymethy/I/)cyclohexyl)-amino)-4゜6
-Sideoxy-D-galactopyranosyl 1)-D-glucopifnose] Octa-0-acetyl-[1, loadihydro-4-〇-α-[4-C(m5)-(H2,4゜5 (OH) /
3.5(CI(20H))-(2,3,4,5-tetrahydroxy-5-(hydroxymethy/I/)cyclohexylamine)-4,6-sideoxy-D-gavocopyranosyl ]-β-D-gμcobylanome) (45
0fflL)i Acetic acid (10tzt), anhydrous (5%
Dissolve in a mixture of acid (10 ml) and sulfuric acid (0.25 m/l) and stir for 2 hours at room temperature. The reaction solution was poured into ice water (25
0 t/), and while stirring, add sodium hydrogen chlorate (2°5f)'e while cooling with water, and further stir at the same temperature for 2 hours.The reaction mixture was extracted with chloroform, and the chloroform extract was diluted with chloroform. Washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was subjected to column chromatography on silicage (50 g/l) and chromatographed with chloroform-methanol/silk (30:l). Elute. The eluted fraction (200-480f) is concentrated to dryness under reduced pressure to give deca-acetyl-[4-0-α-C4-CC
IS )-(1,2,4,5(OH)/3.5(CH2
0H))-(2,3,4,5-tetrahydroxy-5-
(Hydroxymethyl)cyclohexy/L/)amino)-
4.

6-Sideoxy-D-galactopyranosiμ]-D-g/
A white powder (550 Da) of Lecopyranone was obtained.

Elemental analysis "39 H55N024 Calculated value (%): c, 50.81in, 6.01i
N, 1.52 Experimental value (%): C, 50,55;
H, 5,88; N, 1.56 Example 7 4-0-α-[4-C(1s)-u,z,+.

5(on)/3,5(cm2on))-(2,3,4,
5-tetrahydroxy-5-(hydroxymethy/V)
cyclohexy/L/)amino, :]-]4.6-sideoxy-D-galactopyranosyμ]D-glucopyranose decar〇-acetyμ[4-〇-α-[4-C(+S)
−(+, 2, 4, 5(OH)/3.5(CH
20I())-(2,3,4,5-tetrahydroxy-
5-(hydroxymethy/I/)cyclohexy/l/)amino 1)-4.

6-Sideoxy-D-galactopyranosi-D-glucobylanose) (450) was mixed with methano-μ (25stl
), add 28% aqueous ammonia (5 gt), and stir at room temperature for 15 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to column chromatography using DOWEX 50WX8 (H+ type, 25s+/). After washing the column with water, it was eluted with 0.5N aqueous ammonia.

Both eluate fractions (97 to 255 ml) were concentrated under reduced pressure, and the concentrated solution was mixed into an/<-Light CG-50<NIT+ type, 1
80 g/) column chromatography and eluted with water. After concentrating the eluted fraction (120 to 150 ysl) under reduced pressure,
When freeze-dried, 4-o-α-C4-1n(l5)-(1
,2゜4.5(OH)/3,5(CH20H))-(2
,3,4゜5-tetrahydroxy-5-(hydroxymethyl)cyclohexyl)amino]-4,6-sideoxy-D-galactopyranosi/shi)-D-glucopyrano-7
, (1702 da) is obtained.

[α) 25+ l 19.6° (cml, H2O) Elemental analysis: C engineering 9H35”14・2■20 Calculated value (%)
: C, 42,46; H, 7,31; N, 2.61
Experimental value (%): C, 42,54i H, 7,20i
N, 2.89HMP(D20)δ: 1.54 (3
H, d, J=6.5Hz, 6'-CH5).

1.71 (IH, dd, J=3.5Hz, 15Hz, 6
-CH).

2.33 (IH, dd, J=3Hz, 15Hz, 6
CH), 3.22 (In, dd, J=-IHz, 4Hz
, 4'-CH), 3.33-4.67 (15H, m),
-4,85 (i"-CHβ, overlaps with HOD), 5
．． 47 (d, J=3.5Hz, 1"-Cdan α), 5.5
5 (IH, d, J=3.5Hz, l'-CH) TLC:
Rf=0°23 Example 8 Isomer (b) of Example 1 to 200 ml of drink containing 20% tangerine juice 10. WI is added and uniformly dissolved by stirring to obtain a fruit juice-containing beverage containing an α-glucosidase inhibitor.

Example 9 4-0-α-[4-C(1s)-(1,2,4゜5 (
OH)/3.5(CH20H))-(2, 3, 4, 5
-tetrahydroxy-5-(hydroxymethy/shi)cyclohexy/L/)amino)-4,6-dideogycyD-
20 parts of lactose, 80 M parts of crystalline 20 parts of μ rose are mixed uniformly, kneaded with water, dried, and made into powder or fine granules according to a conventional method. Use as a powder.

85

Claims (3)

[Claims] (1) General formula [In the formula, R1 and R2 each represent a hydroxyl group or together represent an oxygen atom, the bond represents either a P configuration or an S configuration, and the hydroxyl group in the formula may be protected] A compound represented by or a salt thereof. (2) A compound represented by the formula [in the formula, each hydroxyl group may be protected] is reacted with a compound represented by the general formula [in the formula, each hydroxyl group may be protected], followed by a reduction reaction. and optionally cleavage reaction of the cyanhydro ring bond or (and)
A general formula characterized by subjecting to a deprotecting group reaction [wherein R and R each represent a water V group or a combined oxygen atom, and the bond represents either 'R configuration or S configuration, The hydroxyl group in the formula may be protected] or a salt thereof. (3) General formula [wherein, I? 1 and R2 each represent a hydroxyl group or together represent an oxygen atom, the bond represents either an R configuration or an S configuration, and the hydroxyl group in the formula may be protected] or a salt thereof. An α-glucosidase inhibitor characterized by: