JPH0325412B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [In the formula, Z represents a hydroxyl group or an amino group. ]
It relates to a compound represented by The compound of the present invention [] is a pseudo-amino sugar [The Journal of Organic Chemistry (J.Org.Chem.) Vol. 31, pp. 1516-1521 (1966)
The term "pseudo-sugar" is defined in So far,
Regarding pseudo-amino sugars and their N-substituted derivatives, valienamine and N-substituted derivatives of valienamine have α-glucosidase inhibitory activity [The Journal.
Of Antibiotics (J.Antibiotics)
Volume 33, pages 1575-1576 (1980), JP-A-57-
59813 and JP-A-57-64648], but the α-glucosidase inhibitory activity of these compounds is still not satisfactory. The present inventors have discovered that one of the pseudo-amino sugars, valiolamine, has the formula As a result of intensive research on various N-substituted derivatives of the compound represented by [the hydroxyl group in the formula may be protected], it was found that the N-substituted derivative of the pseudo-amino sugar represented by the general formula [] is the strongest. α
- It was discovered that the present invention has glucosidase inhibitory activity, and as a result of various studies based on these findings, the present invention was completed. That is, the present invention provides (1) a compound represented by the general formula [], [In the formula, Z′ represents a protected amino group.
The hydroxyl group in the formula may be protected] is reacted with a cyclic ketone, then subjected to a reduction reaction, and optionally subjected to a deprotection reaction. [In the formula, Z'' represents an amino group.] A method for producing a compound represented by (3) a compound represented by the formula [] and the general formula []
The general formula obtained by reacting with a cyclic ketone represented by and then subjecting it to a reduction reaction [Symbols in the formula have the same meanings as above. The hydroxyl group in the formula may be protected] After removing the protecting group of the amino group of the compound represented by the formula, the general formula obtained by reacting with an oxidative deaminating agent A general formula characterized in that a compound represented by [the hydroxyl group in the formula may be protected] is reacted with a reducing agent and optionally subjected to a deprotection reaction. The present invention relates to a method for producing a compound represented by the formula (4) and an α-glucosidase inhibitor containing the compound represented by the general formula []. In addition, when the terms validamine and variolamine are used as common names of compounds in the specification of the present invention, the chemical structure of each compound and the position number of each carbon atom are represented by the following formula.

【formula】

[Formula] N- of the pseudo-amino sugar represented by the general formula []
The N-substituted moiety in the substituted derivative is represented by the following formula (with the position number of each carbon atom added): 4-substituted-2,
3-dihydroxy-6-methylcyclohexyl group, [Symbols in the formula have the same meanings as above] Various stereoisomers exist due to differences in steric configuration of the substituent represented by Z, two hydroxyl groups, and one methyl group. Examples of these are (2, 4, 6/3)-, (2, 3, 6/4)-, (2,
3,4/6)-,(2,3/4,6)-,(2,4/
3,6)-, (2,6/3,4)-, (2/3,4,
6)-, (2,3,4,6/0)-isomer, etc. [For the nomenclature of this configuration, IuPAC-
IuB Cyclitol 1973 Recommendation (IuPAC-
IuB1973Recommendation for cyclitol), Pure and Applied Chemistry (Pure
Appl.Chem.) Vol. 37, pp. 285-297 (1975)]. Furthermore, the N-substituted derivative of the pseudo-amino sugar represented by the general formula [] has the amino group of the variolamine moiety and the 4-substituted-2,3-dihydroxy-6
-N-[(1R)-4-substituted-2,
3-dihydroxy-6-methylcyclohexyl]
Variolamine (hereinafter referred to as (1R)-isomer) and N-[(1S)-4-substituted-2,3-dihydroxy-6-methylcyclohexyl]variolamine (hereinafter referred to as (1S)-isomer) ) There are two types of stereoisomers. (1R) - Preferred isomers are shown more specifically by the general formula [Symbols in the formula have the same meanings as above, the bond ~ ~ is R
It is a compound represented by [(1R,2R)-(2,6/3,4)-4] as a specific example of such a compound.
-amino-2,3-dihydroxy-6-methylcyclohexyl]variolamine, N-[(1R,
2S)-(2,6/3,4)-2,3,4-trihydroxy-6-methylcyclohexyl]variolamine, N-[(1R,2S)-(2,4,6/3)-
Examples include 2,3,4-trihydroxy-6-methylcyclohexyl variolamine. (1S) - Preferred isomers are shown more specifically by the general formula [Symbols in the formula have the same meanings as above, the bond ~ ~ is R
[(1S,2S)-(2,6/3,4)-4-]
Amino-2,3-dihydroxy-6-methylcyclohexyl]variolamine, N-[(1S,2S)
-(2,6/3,4)-2,3,4-trihydroxy-6-methylcyclohexyl]variolamine, N-[(1S,2S)-(2,4,6/3)-2,
Examples include 3,4-trihydroxy-6-methylcyclohexyl variolamine. The above compounds [a] and [b] both have α-glucosidase inhibitory activity, but [
The a] or (1R, 2S) isomer generally has stronger α-glucosidase inhibitory activity than the corresponding [b] or (1S, 2S) isomer. Protecting groups for the amino group in the above formula include amino sugars, aminocyclitol, and protecting groups used as amino group protecting groups in peptide chemistry, such as formyl, acetyl, propionyl, butyryl, trifluoroacetyl, trichloroacetyl. 1 carbon number which may be substituted with halogen such as
to 5 alkanoyl groups, nitro groups such as benzoyl, p-chlorobenzoyl, p-nitrobenzoyl, p-methoxybenzoyl, carbon atoms 1 to 4
lower alkoxy group, aroyl group optionally substituted with halogen, methoxycarbonyl group, ethoxycarbonyl, 1-propoxycarbonyl,
2 to 6 carbon atoms such as tert-butoxycarbonyl
alkoxycarbonyl group, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, 2,4
- Nitro groups such as dichlorobenzyloxycarbonyl, lower alkoxy groups having 1 to 4 carbon atoms, aralkyloxycarbonyl groups optionally substituted with halogen, nitro-substituted phenyl groups such as 2,4-dinitrophenyl groups, phthalyl groups, etc. is used. 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 be substituted with lower alkoxy group having 1 to 4 carbon atoms 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-mentioned lower alkoxyl group having 1 to 4 carbon atoms include methoxyl, ethoxyl, propoxyl, butoxyl groups, which may be substituted with the above-mentioned halogen. Examples of the alkanoyl group having 1 to 5 carbon atoms include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and pivaloyl groups. Examples of the alkoxyl group in the above alkoxycarbonyl group having 2 to 6 carbon atoms include the above-mentioned methoxyl, ethoxyl, propoxyl, butoxyl, pentyloxyl, vinyloxyl, allyloxyl group which may be substituted with halogen, etc. . Examples of the alkenyl group having 2 to 4 carbon atoms in the above alkenyloxycarbonyl group having 2 to 4 carbon atoms include vinyl, allyl, isopropenyl, 1-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl. More specific examples of acyl protecting groups include formyl, 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, optionally substituted with lower alkoxyl group having 1 to 4 carbon atoms, benzyloxyl group, or phenyl group; Alkenyl group having 2 to 4 carbon atoms; Lower alkyl group 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, pentyl, isopentyl, neopentyl, 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, etc. 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, etc. can be similarly used. The compounds [ ] of the present invention are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid, and organic acids such as acetic acid, malic acid, citric acid, ascorbic acid, mandelic acid, and methanesulfonic acid. These salts are also included in the present invention. The above-mentioned N-substituted derivatives of pseudo-amino sugars [ ] or salts thereof are stable crystals or powders and have almost no toxicity (rat LD ₅₀ , 500 mg/Kg or more). 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 the prevention of 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 [ ] of the present invention or a salt thereof can be diluted with a non-toxic carrier such as a liquid carrier such as water, ethanol, ethylene glycol, or polyethylene glycol, or a solid carrier such as starch, cellulose, or polyamide powder, and then prepared into ampules. , granules, tablets,
Pills, capsules, syrups, etc. can be prepared according to conventional methods and used for the various uses mentioned above. In addition, sweeteners, preservatives, dispersants, and coloring agents can also be used. The compound [ ] of the present invention or a salt thereof is administered orally or parenterally, preferably orally, with each meal, with a meal, before or after a meal, either alone or mixed with a non-toxic carrier. . Specifically, for example, by taking a preparation containing about 10 to 200 mg of the compound [ ] or its salt per meal, with, before, or after a meal per adult, blood glucose levels caused by 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 [ ] of the present invention 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. N-substituted derivatives of pseudo-amino sugars of the present invention []
Among these, compounds in which Z is an optionally protected amino group, ie, compounds represented by the formula [], can be produced by the following method. That is, it can be produced by subjecting a Schiff base obtained by reacting variolamine [ ] with a cyclic ketone [ ] in an appropriate solvent to a reduction reaction. The condensation reaction between the amino group of variolamine [] and the cyclic ketone [] (i.e., Schiff base formation reaction), and the subsequent Schiff base reduction reaction may be performed continuously in the same reaction vessel. However, it may be carried out in two stages. Cyclic ketone []
is usually used in an amount of about 1 to 2 times the mole of variolamine []. Examples of reaction solvents for the condensation reaction of variolamine [] and cyclic ketone [] and the subsequent reduction reaction include water, alcohols such as methanol, ethanol, propanol, and butanol, dimethyl sulfoxide, dimethylformamide, and N-methyl. Acetamide, methyl cellosolve, dimethyl cellosolve, glymes such as diethylene glycol dimethyl ether, dioxane,
Ethers such as tetrahydrofuran, polar solvents such as acetonitrile, or mixed solvents thereof,
Alternatively, a mixture of these polar solvents and a nonpolar solvent such as chloroform or 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 hydrogen complexes, diborane and substituted diborane,
For example, alkali metal borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, sodium trimethoxyborohydride, potassium tri-sec-butylborohydride, lithium tri-sec-butylborohydride, etc. ,
For example, alkali metal cyanoborohydride such as sodium cyanoborohydride, tetra-n-butylammonium cyanoborohydride, alkali metal aluminum hydride such as lithium aluminum hydride, lithium trimethoxyaluminum hydride, etc. 3-dimethyl-2-butylborane, bis-3-methyl-2-butylborane,
Alkylboranes such as diisopinocamphenylborane, dicyclohexylborane, 9-borabicyclo[3,3,1]nonane, dimethylamineborane,
Alkylamine borane such as tetramethylammonium borohydride and the like are advantageously used. In addition,
When using an alkali metal cyanoborohydride, such as sodium cyanoborohydride, the reaction is preferably carried out under acidic conditions, such as in the presence of hydrochloric acid, acetic acid, or the like. The 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 ice cooling, and in some cases heated to about 100°C. There are differences depending on the type of Schiff base and reducing agent used. 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. As the catalyst for catalytic reduction, for example, platinum black, platinum dioxide, palladium black, palladium carbon, Raney nickel, etc. are used. Commonly used solvents include, for example, water, methanol,
Alcohols such as ethanol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, 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 obtained in this way [] (i.e.
In the compound represented by the general formula [],
Compounds in which Z″ is a protected amino group) are removed to form the general formula A compound represented by [the hydroxyl group in the formula may be protected] (i.e., a compound represented by the general formula [], in which Z'' is an amino group)
In the case of conversion, the reaction of removing the protecting group of the amino group can be carried out using a method known per se. For example, the protecting group for the amino group may be substituted with an alkanoyl group having 1 to 5 carbon atoms, a nitro group, a lower alkoxy group having 1 to 4 carbon atoms, or a halogen, which may be substituted with the above-mentioned halogen. For aroyl groups, alkoxycarbonyl groups having 2 to 6 carbon atoms, nitro groups, lower alkoxy groups having 1 to 4 carbon atoms, aralkyloxycarbonyl groups that may be substituted with halogen, etc., and phthalyl groups, ammonia, water, etc. By hydrolysis in the presence of alkalis such as sodium oxide, barium hydroxide, hydrazine hydrate, or by hydrolysis in the presence of sulfuric acid,
By hydrolysis in the presence of an acid such as hydrochloric acid, tert-butoxycarbonyl group can be hydrolyzed in the presence of an acid such as trifluoroacetic acid; The lower alkoxy group or benzyloxycarbonyl group which may be substituted with halogen in 4 can be removed from the protective group by hydrogenolysis by catalytic reduction in the presence of a reduction catalyst such as palladium carbon or palladium black. can. When the above-mentioned compound has a protected hydroxyl group, the elimination reaction of the protecting group for 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 sulfonic acid type ion exchange resins, acyl type protecting groups such as acetyl groups and benzoyl groups can be hydrolyzed with alkalis such as ammonia, sodium hydroxide, barium hydroxide, and sodium methoxide. By doing so, benzyl ether type protecting groups such as benzyl group and p-methoxybenzyl group can be removed by hydrogenolysis by catalytic reduction or reductive decomposition with metallic sodium in liquid ammonia. can. If the compound [] is obtained in the form of a free base,
For example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, organic acids such as acetic acid, malic acid, citric acid, ascorbic acid, mandelic acid, methanesulfonic acid, etc., in a suitable solvent according to methods known per se. A salt of the compound [] can be produced by reacting with an acid or the like. The compounds represented by the above general formula [] and their synthetic intermediates obtained in this way can be prepared by means known per se, such as filtration, centrifugation, concentration, etc.
Vacuum concentration, drying, freeze-drying, adsorption, desorption, methods that utilize differences in solubility in various solvents (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. N-substituted derivatives of pseudo-amino sugars of the present invention []
Among these, the compound in which Z is a hydroxyl group, that is, the compound represented by the formula [], can be produced, for example, by the following method. That is, the primary amine moiety of compound [] is converted into a ketone using oxidative deaminating agents to form compound [], and then the ketone moiety of compound [] is reduced to a secondary hydroxyl group. By doing so, the desired compound [] can be produced. As an oxidative deamination agent, 3,5-di-tert
-Butyl-1,2-benzoquinone, mesitylglyoxal, 3-nitromesityglyoxal, 3-nitromesityglyoxal, 3,5
- dinitromesitylglyoxal, preferably 3,5-di-tert-butyl-1,2-benzoquinone [Corey, Achiwa; Journal of the American Chemical Society]. (J.Am.Chem.
Soc.), Vol. 91, pp. 1429-1432 (1969)]. The above-mentioned oxidative deamination agent may be used in an amount of about 1 to 5 moles, preferably about 1 to 3 moles, per mole of the starting compound []. Usually the reaction is carried out in a solvent that is inert to the oxidative deaminating agent. The reaction solvent varies depending on the type of protecting group when the hydroxyl group is protected by a protecting group, but usually,
For example, methanol, ethanol, etc. with a carbon number of 1
or 4 lower alcohols, ethers such as tetrahydrofuran and dioxane, water, halogenated hydrocarbons such as dimethyl sulfoxide, dichloromethane and chloroform, and lower fatty acid esters such as methyl acetate and ethyl acetate, used alone or in appropriate mixtures. It will be done. The reaction temperature is about -30° to 80°C, preferably about -
The temperature ranges from 10° to 40°C. The reaction time varies depending on the reaction solvent, reaction temperature, type of oxidative deamination agent, etc., but is usually about 1 to 25 hours. 3,5-di-tert- as an oxidative deamination agent
When butyl-1,2-benzoquinone is used, the imine intermediate (Schiff base) generated between the amino group of the compound [] is subjected to prototropic isomerization and then hydrolyzed. Next, adjust the reaction solution to a pH of 1 to 5 with an aqueous solution of an inorganic acid (sulfuric acid, hydrochloric acid, etc.) or an aqueous solution of an organic acid (acetic acid, oxalic acid, etc.).
Depending on the type of oxidizing agent used, triethylamine, sodium methoxide, potassium tert-butoxide,
It may be advantageous to use 0.1 to 1.0 equivalents of a base such as DBN (1,5-diazabicyclo[4,3,0]non-5-ene). Compound [] can be produced by subjecting the thus obtained compound [] to a reduction reaction using a metal hydrogen complex compound, diborane, and substituted diborane. As reducing agents such as metal hydrogen complex compounds, diborane, and substituted diborane used in this reaction, those similar to those used in the reduction reaction of the Schiff base obtained by reacting the above-mentioned compound [] and compound [] are used. used. These reducing agents are used in an amount of about 1 to 10 mol, usually about 2 to 5 mol, per 1 mol of the starting compound. The reaction is usually carried out in a solvent. Examples of such solvents include water, alcohols such as methanol, ethanol, propanol, and butanol, glymes such as dimethyl sulfoxide, dimethylformamide, N-methylacetamide, methyl cellosolve, dimethyl cellosolve, and diethylene glycol dimethyl ether, dioxane, and tetrahydrofuran. ethers such as
A polar solvent such as acetonitrile, a mixed solvent thereof, or a mixture of these polar solvents and a nonpolar solvent such as chloroform or dichloromethane is used. The temperature of this reduction reaction is usually room temperature (10-35℃)
In some cases, especially in the early stages of the reaction, the reaction is carried out under ice-cooling, or in some cases heated to about 100°C, which varies depending on the type of reducing agent and reaction solvent. The reaction time also varies depending on the reaction temperature and the type of reducing agent, but is usually about several minutes to 24 hours. Furthermore, the reduction reaction of compound [] to compound [] can also be carried out using a catalytic reduction method used in the reduction reaction of Schiff's base obtained by reacting compound [] and compound []. When the obtained compound [] has a protected hydroxyl group, the elimination reaction of the protecting group can be carried out in the same manner as described above. In addition, when the compound [] is obtained in the form of a free base, it can be converted into a salt of the compound [] with the above-mentioned inorganic acid or organic acid according to a method known per se as in the case of the compound []. The compounds thus obtained and their synthetic intermediates can be isolated and purified by the above-mentioned means known per se. Variolamine (a compound represented by the formula []) as a raw material compound used in the present invention is, for example,
56-55907, and organic chemistry using valienamine or validamine as a raw material as described in Japanese Patent Applications 1982-64370 and 1987-144309. It can be produced by synthetic means. Further, the cyclic ketone represented by the general formula [] can be produced, for example, by the method shown in Figure 1 using validamine as a raw material. In addition, the protecting groups for the amino group and hydroxyl group in the formula are shown in Table 1 below.
In addition to the above-mentioned protecting groups for amino groups (such as those used as protecting groups for amino groups in the chemistry of amino sugars, aminocyclitol, and peptides) and protecting groups for hydroxyl groups (for example, acyl type, ether type), , acetal type and ketal type protecting groups) can also be used in the same manner. [In the above formula, Cbz is benzyloxycarbonyl, Ph is phenyl, Bu is butyl, Bz is benzoyl, NBS is N-bromosuccinimide, TosOH
indicates p-toluenesulfonic acid, AIBM indicates α,α′-azobis-iso-butyronitrile, and DMSO indicates dimethylsulfoxide. ] The resulting compounds and synthetic intermediates 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 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 prepared from pig small intestine mucosa using maltose and sucrose as substrates [B. Borgstro¨
m) and Acta Chemica Scandinavica (Acta Chemica Scandinavica) by A. Dahlqvist.
Chem. Scand.) Vol. 12, pp. 1997-2006, 1958]
Add the enzyme solution (0.25 ml) appropriately diluted with 0.02M phosphate buffer solution (PH6.8) and the same buffer solution (0.5 ml) of the inhibitor (compound [] or its salt) to be tested.
and a substrate solution of 0.05M maltose or 0.05M sucrose in the same buffer (0.25 ml), and this mixture is reacted at 37°C for 10 minutes. This includes glucose B
- Add test reagent (glucose oxidase reagent for glucose measurement, manufactured by Wako Pure Chemical Industries, Ltd.) (3 ml), and
505nm of the reaction solution heated at 37℃ for 20 minutes to develop color.
It was calculated by measuring the absorbance at . 50% inhibitory concentration for maltase (pig, intestinal mucosa) [hereinafter abbreviated as IC ₅₀ (maltase)] and 50% inhibitory concentration for satucalase (pig, intestinal mucosa) of the compound [ ] or a salt thereof 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).
The components contained were examined, and fractions containing the necessary components were collected and used in the next step. Unless otherwise specified, the TLC Rf values for each compound described in the Examples are based on the thin layer plate being pre-coated (pre-coated).
n- coated) TLC plate silica gel 60F ₂₅₄ (Merck & Co., West Germany) was used as the developing solvent.
Propyl alcohol/acetic acid. It was measured using water (4:1:1). (Rf value of pseudo-amino sugar measured by the above method as a control sample: Valienamine Rf
= 0.42, Validamine Rf = 0.35, Variolamine
Rf=0.30) The symbols used in the reference examples and examples have the following meanings. s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet; J, coupling constant reference example 1 4,7-O-benzylidene-N-benzyloxycarbonylvalidamine N -Benzyloxycarbonylvalidamine (manufactured according to the method described in Japanese Patent Application No. 144309, p. 30)
(55.3g) was dissolved in dimethylformamide (190ml), and α,α-dimethoxytoluene (27.7g) and p-toluenesulfonic acid (177mg) were added.
Stir at 60-65° C. for 1 hour under reduced pressure (60-65 mmHg). The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (600 ml). The ethyl acetate extract is washed with water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add toluene to the residue and concentrate again under reduced pressure, and add ethyl ether (200ml) and petroleum ether (2) to the residue.
A white powder (67.7 g) of 4,7-O-benzylidene-N-benzyloxycarbonylvalidamine is obtained. [α] ²⁴ _D +54.1° (c=1, CH ₃ OH) Elemental analysis: C ₂₂ H ₂₅ NO ₆ Calculated value (%): C66.15; H6.31; N3.51 Experimental value (%): C66.07; H6.43; N3.39 NMR (DMSO-d ₆ ) δ: 0.8-2.2 (3H, m),
3.1~4.2 (6H, m), 4.70 (1H, d, J=5
Hz), 4.78 (1H, d, J = 4.5Hz), 5.02 (2H,
s), 5.47 (1H, s), 6.98 (1H, d, J = 7.5
Hz), 7.2-7.6 (10H, m). Reference example 2 4-O-benzoyl-N-benzyloxycarbonyl-7-promo-7-deoxyvalidamine 4,7-O-benzylidene-N-benzyloxycarbonylvalidamine (42.5 g) was dissolved in carbon tetrachloride (500 ml). and 1,1,2,2-tetrachloroethane (100 ml), and added N-bromosuccinimide (21.5 g) and barium carbonate (35 g).
Heat to reflux for 1 hour while stirring. The reaction solution is filtered while hot, and after washing insoluble matter with carbon tetrachloride, the filtrate and washing solution are combined and concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with 2N hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel (600 ml) (Kieselgel 60, Merck, West Germany, the same applies to the silica gel used below), and after washing the column with toluene-ethyl acetate (4:1), toluene-ethyl acetate was added. (1:1). The eluted fraction was concentrated under reduced pressure, ethyl ether-petroleum ether (1:5, about 800 ml) was added to the residue, and the mixture was left in the refrigerator overnight to give 4-O-benzoyl-N-benzyloxycarbonyl-7-bromo-7. -White precipitate of deoxyvalidamine (29.8g)
is obtained. Elemental analysis: C ₂₂ H ₂₄ NO ₆ Br Calculated value (%): C55.24; H5.06; N2.93; Br16.70 Experimental value (%): C55.14; H5.02; N2.62; Br16 .65 NMR (DMSO-d ₆ ) δ: 1.3-1.75 (1H, m),
1.8~2.6 (2H, m), 2.9~4.2 (m), 4.87 (1H,
t, J=9Hz), 5.07 (2H, s), 7.08 (1H,
d, J=8Hz), 7.40 (5H, s), 7.25-7.75
(3H, m), 7.95-8.15 (2H, m). Reference example 3 4-O-benzoyl-N-benzyloxycarbonyl-2,3-O-cyclohexylidene-7
-Bromo-7-deoxyvalidamine 4-O-benzoyl-N-benzyloxycarbonyl-7-bromo-7-deoxyvalidamine (20 g) was dissolved in dimethylformamide (50 ml), and 1,1-dimethoxycyclohexane (20 ml) was dissolved in dimethylformamide (50 ml). )
and p-toluenesulfonic acid (0.5 g), and stirred at 55° C. for 2 hours under reduced pressure (45-50 mmHg). The reaction solution is dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Pour the residue into silica gel (550ml)
After washing with toluene, the mixture was eluted with toluene-ethyl acetate (19:1). The eluted fractions were concentrated under reduced pressure, and the residue was dried under reduced pressure in a desiccator to give 4-O-benzoyl-N-benzyloxycarbonyl-2,3-O-cyclohexylidene-7-bromo-7-deoxyvalidamine. (25.5 g) is obtained as a syrupy substance. Elemental analysis: C ₂₈ H ₃₂ NO ₆ Br Calculated value (%): C60.21; H5.78; N2.51; Br14.31 Experimental value (%): C60.69; H5.71; N2.49; Br14 .61 NMR (CDCL ₃ ) δ: 1.2-1.8 (10H, m), 3.42
(2H, d, J=5Hz), 3.66 (1H, dd, J=
4Hz, 10Hz), 3.88 (1H, t, J = 10Hz),
4.27 (1H, m), 4.97 (1H, d, J=5Hz),
5.13 (2H, s), 5.33 (1H, t, J=10Hz),
7.1~7.7 (3H, m), 7.38 (5H, s), 8.0~8.2
(2H, m). Reference example 4 4-O-benzoyl-N-benzyloxycarbonyl-2,3-O-cyclohexylidene-7
-deoxyvalidamine 4-O-benzoyl-N-benzyloxycarbonyl-2,3-O-cyclohexylidene-7-
Bromo-7-deoxyvalidamine (25 g) was dissolved in toluene (300 ml), tri-n-butyltin hydride (20 ml) and α,α'-azobis-iso-butyronitrile (0.1 g) were added and heated for 1 hour. Reflux. After cooling the reaction solution to room temperature, it is washed with IN hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (600ml), and after washing the column with toluene, toluene-ethyl acetate (9:1)
It elutes with The eluted fractions were concentrated under reduced pressure, and the residue was dried under reduced pressure in a desiccator to give 4-O-benzoyl-N-benzyloxycarbonyl-2,3.
-O-cyclohexylidene-7-deoxyvalidamine (21 g) is obtained as a syrupy substance. Elemental analysis: _{C28H33NO6 Calculated} value (%): C70.12; H6.94; N2.92 Experimental value (% ₎ : C70.58; H6.95; N2.71 NMR ( _CDCl3 ) δ: 0.96 (3H, d, J = 6.5Hz),
1.15~2.2 (12H, m), 2.2~2.6 (1H, m),
3.63 (1H, dd, J=4Hz, 10Hz), 3.83 (1H,
t, J=10Hz), 4.22 (1H, m), 4.9-5.25
(2H, m), 5.13 (2H, s), 7.15~7.7 (3H,
m), 7.38 (5H, s), 8.0-8.2 (2H, m). Reference example 5 N-benzyloxycarbonyl-2,3-O-
Cyclohexylidene-7-deoxyvalidamine 4-O-benzoyl-N-benzyloxycarbonyl-2,3-O-cyclohexylidene-7-
Deoxyvalidamine (20 g) was dissolved in acetone-ethanol (3:2, 500 ml), 1N sodium hydroxide (100 ml) was added, and the mixture was stirred at room temperature for 1 hour.
Adjust the reaction solution to PH4.5 with 2N hydrochloric acid while cooling with ice water, then adjust the pH to 7.5 with 25-28% ammonia water, add water (about 500ml), and distill off the organic solvent under reduced pressure. . The resulting oil is extracted with ethyl acetate, the extract is washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure.
The residue was subjected to column chromatography on silica gel (550 ml) and eluted with toluene-ethyl acetate (3:1). The eluted fraction was concentrated under reduced pressure, ethyl ether-petroleum ether (1:4500 ml) was added to the residue, and the mixture was left in the refrigerator overnight to give N-benzyloxycarbonyl-2,3-O-cyclohexylidene-7-
Deoxyvalidamine crystals (13.9 g) are obtained. Elemental analysis: _{C21H29NO5 Calculated} value (%): C67.18; _H7.79 ; N3.73 Experimental value (%): C67.02; H7.70; N3.55 NMR ( _CDCl3 ) δ: 1.03 (3H, d, J=7Hz),
1.1~1.9 (12H, m), 2.1~2.4 (1H, m),
2.45 (1H, d, J = 4Hz), 3.15~3.6 (3H,
m), 4.17 (1H, m), 4.89 (1H, d, J=6
Hz), 5.10 (2H, s), 7.37 (5H, s). Reference example 6 (2R)-(2,6/3,4)-2,3-O-cyclohexylidene-4-benzyloxycarbonylamino-2,3-dihydroxy-6-methylcyclohexanone in dimethyl sulfoxide (9 ml) Trifluoroacetic anhydride (13.5
ml) in dichloromethane (50 ml) was added dropwise while cooling to below -65°C, stirred at the same temperature for 20 minutes, and then
-benzyloxycarbonyl-2,3-O-cyclohexylidene-7-deoxyvalidamine (12
g) is added while cooling to below -70°C, and further stirred at the same temperature for 1 hour. Add a solution of triethylamine (26.7 ml) in dichloromethane (50 ml) to the reaction solution at -65
After dropping the mixture while cooling to below ℃, remove the cooling bath and stir until the temperature of the reaction solution rises to 20℃. Add the reaction solution to ice water (approximately 300 ml), stir for 1 hour, separate the dichloromethane layer, and extract the aqueous layer once again with dichloromethane. Collect dichloromethane extract
Wash with 2N hydrochloric acid and saturated sodium bicarbonate solution,
Dry over anhydrous sodium sulfate and concentrate under reduced pressure. The residue was subjected to column chromatography on silica gel (400 ml) and eluted with toluene-ethyl acetate (5:1). The eluted fraction was concentrated under reduced pressure and the residue was dried under reduced pressure in a desiccator to give (2R)-(2,6/3,
4) -2,3-O-cyclohexylidene-4-benzyloxycarbonylamino-2,3-dihydroxy-6-methylcyclohexanone (9.8g)
is obtained as a syrupy substance. Elemental analysis: _{C21H27NO5 Calculated} value (%): C67.54; _H7.29 ; N3.75 Experimental value (%): C67.49; H7.41; N3.67 NMR ( _CDCl3 ) δ: 1.06 (3H, d, J=6Hz),
1.2~1.9 (11H, m), 2.3~2.85 (2H, m),
3.74 (1H, dd, J=4Hz, 10.5Hz), 4.2~
4.45 (1H, m), 4.43 (1H, d, J = 10.5Hz),
5.14 (2H, s), 5.15-5.4 (1H, m), 7.40
(5H, s). Example 1 N-[(1R,2S)-(2,6/3,4)-4-amino-2,3-dihydroxy-6-methylcyclohexyl]variolamine and N-[(1S,
2S)-(2,6/3,4)-4-amino-2,3
-dihydroxy-6-methylcyclohexyl]
Variolamine Variolamine (4.0g) and (2R)-(2,
6/3,4)-2,3-O-cyclohexylidene-4-benzyloxycarbonylamino-2,3
-Dihydroxy-6-methylcyclohexanone (9.2 g) is dissolved in dimethylformamide (120 ml), 2N hydrochloric acid (3 ml) and sodium cyanoborohydride (5.6 g) are added, and the mixture is stirred at 50-60°C for 18 hours. The reaction solution was concentrated under reduced pressure, toluene was further added, and dimethylformamide was distilled off azeotropically.
The residue is partitioned into a mixture of ethyl acetate and water. The ethyl acetate layer is separated, washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Ethyl ether (500 ml) was added to the residue and left in the refrigerator overnight, and the resulting precipitate was collected by filtration, washed with ethyl ether, and dried under reduced pressure in a desiccator. The obtained powder (3.0g) was mixed with 80% acetic acid (100ml).
and stir at 50-60°C for 1 hour. The reaction solution is concentrated under reduced pressure, the acid distillate is added to a mixture of ethyl acetate and water for partitioning, the aqueous layer is separated, washed with ethyl acetate, and the solvent is distilled off under reduced pressure. The residue was dissolved in water-methanol-acetic acid (50:30:2100 ml), palladium black (600 mg) was added, and the solution was dissolved at room temperature in a hydrogen stream for 80 minutes.
Stir for an hour. After removing the catalyst by filtration and washing with water, the filtrate and washing liquid are collected and concentrated under reduced pressure. amber light residue
When subjected to column chromatography using CG-50 (NH ₄ ⁺ form, 250 ml) (manufactured by Rohm and Haas, USA), the column was washed with water and eluted with 0.1N aqueous ammonia.
It is separated and eluted into two components: the first eluted fraction (0.8 to 1.0) and the second eluted fraction (1.3 to 1.7). The fraction eluted first was concentrated under reduced pressure, and the residue was purified using Amberlite CG-50 (NH ₄ ⁺ type,
400ml) column chromatography, eluted with 0.1N aqueous ammonia, concentrated the eluted fraction under reduced pressure, and lyophilized it to obtain N-[(1R,2S)-(2,6/3,4)-4-
Amino-2,3-dihydroxy-6-methylcyclohexyl]variolamine (505 mg) is obtained as a white powder. The fraction eluted later was concentrated under reduced pressure, and the resulting residue was passed through a 1×2 Dowex tube.
(OH ^- type, 150ml) (manufactured by Dow Chemical Company, USA)
column chromatography and elute with water. The eluted fraction was concentrated under reduced pressure and lyophilized to give N-[(1S, 2S)
-(2,6/3,4)-4-amino-2,3-dihydroxy-6-methylcyclohexyl]variolamine (490 mg) is obtained. N-[(1R,2S)-(2,6/3,4)-4-amino-2,3-dihydroxy-6-methylcyclohexyl]variolamine (isomer eluted first, isomer (a ) Elemental analysis: C ₁₄ H ₂₈ N ₂ O ₇・H ₂ O Calculated value (%): C47.45; H8.53; N7.90 Experimental value (%): C47.59; H8.30; N8.03 [α] ²⁶ _D +42.6° (c=1, H ₂ O) NMR (D ₂ O) δ: 1.25 (3H, d, J=6Hz),
1.4-2.7 (6H, m), 3.4-4.2 (9H, m). IC ₅₀ (maltase): 2.8×10 ^-8 M IC ₅₀ (satucarase): 7.5×10 ^-9 M N-[(1S,2S)-(2,6/3,4)-4-amino-2,3 -dihydroxy-6-methylcyclohexyl]variolamine (isomer eluted later, abbreviated as isomer (b)) Elemental analysis: C ₁₄ H ₂₈ N ₂ O ₇・H ₂ O Calculated value (%): C47. 45; H8.53; N7.90 Experimental value (%): C47.50; H8.87; N7.98 [α] ²⁶ _D +2.0° (c=1, H ₂ O) NMR (D ₂ O) δ: 1.24 (3H, d, J = 6.5Hz),
1.5-2.7 (5H, m), 3.1-3.3 (1H, m), 3.3
~4.3 (9H, m). IC ₅₀ (maltase): 1.5×10 ^-6 M IC ₅₀ (satucalase): 5.3×10 ^-8 M Example 2 N-[(1R,2S)-(2,6/3,4)-2,3,
4-trihydroxy-6-methylcyclohexyl]variolamine and N-[(1R,2S)-
(2,4,6/3)-2,3,4-trihydroxy-6-methylcyclohexyl]variolamine N-[(1R,2S)-(2,6/3,4)-4-amino- 2,3-dihydroxy-6-methylcyclohexyl]variolamine (200 mg) was dissolved in methanol (5 ml), 3,5-di-tert-butyl-1,2-benzoquinone (180 mg) was added, and the solution was heated to 150 mg at room temperature. Stir for an hour. Adjust the reaction solution to PH1-2 with 1N sulfuric acid.
The mixture was stirred at room temperature for 3 hours, and water (100 ml) and chloroform (50 ml) were added. Separate the aqueous layer,
After washing with chloroform, concentrate under reduced pressure to approximately 50 ml. While cooling with ice water, add sodium borohydride (200 mg) to the concentrated solution, and stir at the same temperature for 2 hours and then at room temperature for 1 hour. The reaction solution was adjusted to pH 5 with acetic acid, then subjected to column chromatography using DOWEX 50W x 8 (H ⁺ type, 160 ml) (manufactured by Dow Chemical Co., USA), washed with water, and eluted with 0.5N aqueous ammonia. The eluted fraction was concentrated under reduced pressure, and the residue was applied to Amberlite CG-50 (NH ₄ ⁺ type, 180 ml) (Rohm & Haas, USA) column chromatography and eluted with water. fraction (320
~480ml) and later eluted fractions (510-900ml)
It is separated into two components and eluted. After concentrating each eluted fraction under reduced pressure and freeze-drying, a white powder (57 mg) showing [α] ²⁶ _D +18.9° (c = 1, H ₂ O) was eluted later from the first eluted fraction. A white powder (31 mg) exhibiting [α] ²⁶ _D +31.1° (c=1, H ₂ O) is obtained from the fraction. Isomer eluted first (abbreviated as isomer (a)) Elemental analysis: C ₁₄ H ₂₇ NO ₈・1/2H ₂ O Calculated value (%): C48.55; H8.15; N4.04 Experimental value (%): C48.45; H8.69; N3.92 NMR (D ₂ O) δ: 1.28 (3H, d, J = 6Hz),
1.3~2.4 (5H, m), 2.50 (1H, t, J=10
Hz), 3.3-4.2 (9H, m). TLC Rf=0.29 IC ₅₀ (maltase): 7.0×10 ^-8 M IC ₅₀ (satucalase): 3.5×10 ^-8 M Isomer eluted later (abbreviated as isomer (b)) Elemental analysis: C ₁₄ H ₂₇ NO ₈・1/2H ₂ O Calculated value (%): C48.55; H8.15; N4.04 Experimental value (%): C48.23; H8.45; N3.92 NMR (D ₂ O) δ: 1.26 (3H, d, J = 6Hz),
1.5-2.4 (5H, m), 2.45 (1H, t, J=10
Hz), 3.5-4.35 (9H, m). TLC Rf=0.30 IC ₅₀ (maltase): 6.8×10 ^-8 M IC ₅₀ (satucalase): 3.6×10 ^-8 M Example 3 N-[(1S, 2S)-(2,6/3)-2, 3,4-
trihydroxy-6-methylcyclohexyl]
Variolamine N-[(1S,2S)-(2,6/3,4)-4-amino-2,3-dihydroxy-6-methylcyclohexyl] Variolamine (300 mg) was dissolved in methanol (5 ml). Then, 3,5-di-tert-butyl-1,2-benzoquinone (300 mg) was added, and the mixture was stirred at room temperature for 18 hours. Adjust the reaction solution to PH1-2 with 1N sulfuric acid.
After adjusting to , stir at room temperature for 3 hours. Add water (100 ml) and chloroform (100 ml) to the reaction solution, separate the aqueous layer, wash with chloroform, and concentrate under reduced pressure to about 50 ml. Sodium borohydride (400 mg) was added to the concentrated solution while cooling with ice water, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 2 hours. The reaction solution was diluted with acetic acid.
Adjust to PH4.5, Dowex 50W x 8 (H ⁺ type,
After washing the column with water, elute with 0.5N aqueous ammonia. The eluted fraction was concentrated under reduced pressure, and the residue was subjected to column chromatography using Amberlite CG-50 (NH ₄ ⁺ type, 150 ml) (Rohm & Haas, USA). After washing the column with water, 0.1N ammonia was added. Elutes with water. The eluted fractions are concentrated under reduced pressure, and the residue is subjected to column chromatography using Amberlite CG-50 (NH ₄ ⁺ type, 75 ml) (manufactured by Rohm and Haas, USA) and eluted with 0.025N aqueous ammonia. The eluted fraction (150-270ml) was concentrated under reduced pressure and then lyophilized to give N-[(1S,2S)-(2,6/3)-2,3,4
-trihydroxy-6-methylcyclohexyl]
White powder (30 mg) of variolamine (however, the configuration of the hydroxyl group at the 4-position of the 2,3,4-trihydroxy-6-methylcyclohexyl moiety has not been determined)
is obtained. Elemental analysis: C ₁₄ H ₂₇ NO ₈・1/2H ₂ O Calculated value (%): C48.55; H8.15; N4.04 Experimental value (%): C48.16; H8.34; N3.95 [ α] ²⁶ _D +25.9° (c=1, H ₂ O) NMR (D ₂ O) δ: 1.28 (3H, d, J = 6.5Hz),
1.5-2.25 (4H, m), 2.43 (1H, dd, J=3
Hz, 15Hz), 3.13 (1H, t, J = 3.5Hz), 3.37
(1H, q, J = 3.5Hz), 3.5-4.25 (8H, m). TLC: Rf=0.28 Example 4 Add 10 mg of the isomer (a) of Example 1 to 200 ml of a beverage containing 10% tangerine juice, stir and dissolve uniformly to obtain a fruit juice beverage containing an α-glucosidase inhibitor. obtain. Example 5 20 parts by weight of the isomer (a) of Example 2, 80 parts by weight of lactose, 20 parts by weight of crystalline cellulose were mixed uniformly, kneaded with water, dried, and processed into powder or fine granules according to a conventional method. Use as a powder.

Claims (1)

[Claims] 1. General formula [In the formula, Z represents a hydroxyl group or an amino group. ]
A compound represented by 2 formulas Compounds represented by [In the formula, the hydroxyl group may be protected] and the general formula [In the formula, Z′ represents a protected amino group.
The hydroxyl group in the formula may be protected] is reacted with a cyclic ketone, then subjected to a reduction reaction, and optionally subjected to a deprotection reaction. A method for producing a compound represented by [In the formula, Z'' represents an amino group.] 3 General formula Compounds represented by [In the formula, the hydroxyl group may be protected] and the general formula [In the formula, Z′ represents a protected amino group.
The general formula obtained by reacting with a cyclic ketone represented by [the hydroxyl group in the formula may be protected] and then subjecting it to a reduction reaction [Symbols in the formula have the same meanings as above. The general formula obtained by removing the protecting group of the amino group of the compound represented by [the hydroxyl group in the formula may be protected] and then reacting with an oxidative deaminating agent A general formula characterized in that a compound represented by [the hydroxyl group in the formula may be protected] is reacted with a reducing agent and optionally subjected to a deprotecting group reaction. A method for producing a compound represented by 4 General formula [In the formula, Z represents a hydroxyl group or an amino group. ]
An α-glucosidase inhibitor containing a compound represented by: