JPH0323537B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [In the formula, A represents a hydrogen atom or a hydroxyl group. ]
It relates to a compound represented by or a salt thereof. 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, Vol.
Volume 33, pages 1575-1576 (1980), JP-A-57-59813
and JP-A-57-64648], and acarbose is a compound produced by actinomycetes and has valienamine as a constituent component and has α-glucosidase inhibitory activity. , BAYg5421, Naturwissenschaften, Volume 64,
pp. 535-537 (1977), Special Publication No. 54-39474], Trestatin [(trestatin), 23rd Symposium, The
Chemistry of Natural Products;Symposium
papers), pp. 632-639 (October 1980);
-163511], adiposin [(adiposin), TAI-
A, B Others, The Japanese Journal
Of Antibiotics (Jap, J.
Antibiotics, Vol. 36, p. 119 (1981); Starch Sci., Vol. 26, pp. 134-144 (1979), Vol. 27, pp. 107-113 (1980) 1972-106402; 1977-106403; 1977-
64509; JP-A-56-123986; JP-A-56-125398],
Amylostatin, Abstracts of the 4th Carbohydrate Symposium, pp. 58-59 (August 1981)
); JP 50-123891; JP 55-71494; JP 55-157595], oligostatin [(oligostatin),
SF-1130X, JP-A-53-26398; JP-A-56-
43294, The Journal of Antibiotics, Volume 34, 1424-1433
(1981); Oligostatin C contains hydroxyvalidamine instead of valienamine, The Journal of
J.Antibiotics, No. 24
Vol., pp. 59-63 (1971)], an amino sugar compound (Japanese Unexamined Patent Publication No. 1983-92909)
etc. are known. Also, a review by E. Truscheit et al. of α-glucosidase inhibitors of microbial origin, including the above-mentioned compounds [Angewandte Chemie]
Vol. 93, pp. 738-755 (1981)]. In addition, methyl 4-[(1S,6S)-(4,6/5)-
4,5,6-trihydroxy-3-hydroxymethyl-2-cyclohexen-1-yl]amino-
It has also been reported that 4,6-dideoxy-α-D-glucopyranoside can be obtained [182nd ACS National
meeting Abstracts paper) MEDI69, 1981 8
May, New York; The Journal of Antibiotics, Volume 34,
pp. 1429-1433 (1981); and Japanese Patent Application Publication No. 1986-
24397]. However, the α-glucosidase inhibitory activity of these compounds is still not satisfactory. Furthermore, as a valienamine derivative, validoxylamine A is active against rice sheath blight fungus.
(validoxylamine A) is known [J.Chem.Soc.Chem.
Commun., 1972, pp. 747-748], and other validoxylamines and their analogs have been reported [Chemistry Letters.
Letters) 1981, pp. 947-950, 1982, 279-
282 and 749-752; Proceedings of the 45th Spring Annual Meeting of the Chemical Society of Japan, page 811 (1982)], but there is no report on their α-glucosidase inhibitory activity. In addition, when the terms valienamine, 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】

[Formula] Also, 2,3,4-trihydroxy-5-hydroxymethylcyclohexyl group (N in N-substituted derivatives of validamine and variolamine)
The position number of each carbon atom in (substituents) is represented by the following formula. The N-substituted derivatives of pseudo-amino sugar represented by the above general formula [] are new compounds, and it is not known that these compounds exhibit α-glucosidase inhibitory activity. As a result of research on various pseudo-amino sugars and their various N-substituted derivatives, including validamine, variolamine, etc., the present inventors found that N-substituted derivatives of pseudo-amino sugars represented by the general formula [] The present invention was completed based on the findings that the N-substituted derivative of a pseudo-amino sugar represented by the general formula [] has a stronger α-glucosidase inhibitory activity than the above-mentioned known compounds. That is, the present invention provides (1) a compound represented by the general formula [ ] or a salt thereof; (2) a compound represented by the general formula [In the formula, A represents a hydrogen atom or a hydroxyl group. Any of the hydroxyl groups may be protected] and a compound represented by the formula A general formula characterized by reacting a cyclic ketone represented by [in the formula, any of the hydroxyl groups may be protected], followed by a reduction reaction, and optionally a deprotection reaction. The present invention relates to a method for producing a compound represented by or a salt thereof. The N-substituted derivatives of validamine and variolamine represented by the general formula [] have three hydroxyl groups and one N-substituted 2,3,4-trihydroxy-5-hydroxymethylcyclohexyl group. Various stereoisomers exist due to differences in the configuration of the hydroxymethyl group. Examples of these include: N-[(2,4/3,5)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]validamine or variolamine; 5)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]validamine or variolamine; N-[(2/3,4,5)-2,3,4-trihydroxy-5-hydroxymethyl cyclohexyl]validamine or variolamine; N-[(2,3,5/4)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]validamine or variolamine; N-[(2,4, 5/3)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]validamine or variolamine, and the like. A more specific example is the general formula [Symbols in the formula have the same meanings as above] A compound represented by, that is, N-[(2S)-(2,
4/3,5)-2,3,4-trihydroxy-5
-Hydroxymethylcyclohexyl]validamine or N-[(2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine, and the like. Furthermore, the compound represented by the general formula [] is 2,
N-[(1R) of validamine or variolamine due to the difference in steric configuration at the bonding site between the 3,4-trihydroxy-5-hydroxymethylcyclohexyl group and the amino group of the pseudo amino sugars validamine and variolamine. -2,3,4-trihydroxy-5-hydroxymethylcyclohexyl] derivative and N-[(1S)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl] derivative. do. Specific examples of these various isomers are shown in the general formula [Symbols in the formula have the same meanings as above] A compound represented by N-[(1R,2S)-
(2,4/3,5)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]validamine or N-[(1R,2S)-2,4/3,5)-
2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine, and the general formula [Symbols in the formula have the same meanings as above] A compound represented by N-[(1S,2S)-
(2,4/3,5)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]validamine or N-[(1S,2S)-(2,4/3,5)-
2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine, and the like. The above compounds [b] and [c] both have α-glucosidase inhibitory activity, but [
b] That is, the (1R, 2S) isomer is more [c]
In other words, α is generally stronger than the (1S, 2S) isomer.
-Has glucosidase inhibitory effect. Further, in the general formulas [], [a], [b], and [c], A represents a hydrogen atom or a hydroxyl group, preferably a hydroxyl group. Any of the hydroxyl groups in the above formula may be protected, and examples of protecting groups for the hydroxyl groups include protecting groups used as hydroxyl protecting groups in sugar chemistry, for example,
Acyl-type protecting groups, ether-type protecting groups, acetal-type or ketal-type protecting groups are used. Examples of acyl protecting groups include benzoyl,
Trifluoromethyl, phenoxy or 1 carbon number
Alkanoyl group having 1 to 5 carbon atoms which may be substituted with ~5 alkoxy; Alkoxycarbonyl group having 2 to 6 carbon atoms; Benzoyl group which may be substituted with nitro or phenyl; Even if substituted with nitro Good phenoxycarbonyl groups; benzyloxycarbonyl groups, etc. are used. Examples of the alkanoyl group having 1 to 5 carbon atoms include formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl, and pivaloyl. The above alkoxy having 1 to 5 carbon atoms or 2 carbon atoms
As the alkoxy in the alkoxycarbonyl of -6, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc. are used. More specific examples of acyl protecting groups include:
Formyl, acetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, propionyl, isopropionyl, butyryl, valeryl,
Isovaleryl, pivaloyl, benzoyl, p-nitrobenzoyl, p-phenylbenzoyl, ethoxycarbonyl, isobutyloxycarbonyl,
These include benzyloxycarbonyl, p-nitrophenoxycarbonyl, 3-benzoylpropionyl, benzoylformyl, and the like. Examples of ether-type protecting groups include those having 1 to 1 carbon atoms.
5 alkyl group; C2-4 alkenyl group;
Trialkylsilyl group having 3 to 6 carbon atoms; 1 carbon number
A benzyl group which may be substituted with -3 alkoxy or the like is used. More specific examples of ether protecting groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
Ethoxyethyl, allyl, trityl, trimethylsilyl, dimethylethylsilyl, benzyl, p-
Such as methoxybenzyl. The acetal type or ketal type protecting group preferably consists of 1 to 10 carbon atoms. Specific examples include methylene, ethylidene, isopropylidene,
These include methoxymethylene, ethoxymethylene, methoxyethylidene, dimethoxymethylene, cyclopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, tetrahydropyranyl, and methoxytetrahydropyranyl. As the salt of the compound [ ] included in the present invention, an acid addition salt of the compound [ ] with a pharmaceutically acceptable acid is used. Such acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and organic acids such as acetic acid, malic acid, citric acid, ascorbic acid, mandelic acid, methanesulfonic acid, etc. etc. are used. N- of the pseudo-amino sugar represented by the general formula []
Specifically, substituted derivatives or salts thereof include N-
[(1R,2S)-(2,4/3,5)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine; N-[(1R,2S)-(2,4/ 3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]validamine; N-[(1S,2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine; N-[(1S,2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]validamine; N-[(1R,2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine sulfate; N-[(1S,2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine hydrochloride; N-[(1R,2S)-(2,4/3,5)-2,3,
4-Tribenzyloxy-5-benzyloxymethylcyclohexyl]variolamine; N-[(1R,2S)-(2,4/3,5)-2,3:
4,7-di-O-isopropylidene-2,3,4
-trihydroxy-5-hydroxymethylcyclohexyl]variolamine; N-[(1R,2S)-(2,4/3,5)-4,7-
O-cyclohexylidene-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]
Validamine; N-[(1S,2S)-(2,4/3,5)-2,3,
4-Triacetoxy-5-acetoxymethylcyclohexyl]variolamine; N-[(1S,2S)-(2,4/3,5)-2,3,
and 4-trihydroxy-5-trityloxymethylcyclohexylvalidamine. 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. Useful for the prevention of various diseases caused by obesity, such as obesity, hyperlipidemia, hyperlipidemia (arteriosclerosis), diabetes, prediabetes, and diseases caused by sugar metabolism by oral microorganisms, such as dental caries. It is a chemical 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 alone or in combination with a non-toxic carrier, orally or parenterally, preferably orally, with, before or after a meal. Specifically, for example, by taking a preparation containing about 10 to 200 mg of the compound [) or its salt per adult with a meal, before or after a meal, it is possible to increase the concentration of glucose in the blood by eating. 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 in the feed should be 0.0001~
1% is desirable. N-substituted derivatives of pseudo-amino sugars of the present invention []
Or its salt can be manufactured by the following method. That is, it can be produced by subjecting a Schiff base obtained by reacting a pseudo amino sugar such as validamine or variolamine [ ] with a cyclic ketone represented by the formula [ ] in an appropriate solvent to a reduction reaction. can. The condensation reaction between the amino group of the pseudo-amino sugar [] and the cyclic ketone [] and the subsequent reduction reaction may be carried out continuously in the same reaction vessel, or may be carried out in two stages. . Examples of reaction solvents for the condensation reaction between the pseudo-amino sugar [] and the cyclic ketone [] and the subsequent reduction reaction include water, methanol,
Alcohols such as propanol and butanol, dimethyl sulfoxide, dimethyl formamide, N
- Methyl acetamide, glymes such as methyl cellosolve, dimethyl cellosolve, diethylene glycol dimethyl ether, ethers such as dioxane and tetrahydrofuran, polar solvents such as acetonitrile, or mixed solvents thereof, or these polar solvents and chloroform, dichloromethane Mixtures with non-polar solvents such as can be used. The reaction temperature in the Schiff base formation reaction is not particularly limited, but it is usually carried out at room temperature to about 100°C. Although the reaction time varies depending on the reaction temperature, the purpose can usually be achieved by allowing the reaction to occur for a few minutes to 24 hours. Various metal hydride complex reducing agents such as sodium borohydride, potassium borohydride, lithium borohydride, sodium trimethoxyborohydride, etc. can be used for the reduction reaction of the Schiff base formed. Metals such as alkali metal cyanoborohydrides such as sodium cyanoborohydride, alkali metal aluminum hydrides such as lithium aluminum hydride, dialkylamineboranes such as dimethylamineborane, etc. are advantageously used. In addition, when using an alkali metal cyanoborohydride, for example, sodium cyanoborohydride, it is preferable to carry out the reaction under acidic conditions, for example, in the presence of hydrochloric acid, acetic acid, or the like. The reaction temperature is not particularly limited, but is usually room temperature,
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., and the reaction varies depending on the Schiff base to be reduced and the type of reducing agent. The reaction time also varies depending on the reaction temperature and the type of Schiff base and reducing agent to be reduced, but the purpose can usually be achieved by allowing the reaction to occur for about several minutes to 24 hours. Catalytic reduction can also be used to reduce the Schiff base formed. That is, the reaction is carried out by shaking or stirring Schiff's base in a suitable solvent in the presence of a catalyst for catalytic reduction in a hydrogen stream. Examples of catalysts used for catalytic reduction include platinum black, platinum dioxide, palladium black, palladium carbon, Raney nickel, etc., and commonly used solvents include water, alcohols such as methanol and ethanol, etc. Ethers such as dioxane and tetrahydrofuran,
Dimethylformamide or a mixed solvent thereof is used. The reaction is usually carried out at room temperature and normal pressure, but may also be carried out under pressure or with heating. When the 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. That is,
For example, acetal type or ketal type protecting groups such as cyclohexylidene group, isopropylidene group, benzylidene group, trityl group, etc. can be treated by hydrolyzing with an acid such as hydrochloric acid, acetic acid, or sulfonic acid type ion exchange resin. Acyl type protecting groups such as acetyl group and benzoyl group are treated with ammonia water,
By hydrolysis with an alkali such as barium hydroxide, the benzyl group can also be removed by hydrogenolysis by catalytic reduction. If the compound [] is obtained in the form of a free base,
Hydrochloric acid in a suitable solvent according to a method known per se,
Inorganic acids such as hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid,
A salt of the compound [ ] can be produced by reacting with an organic acid such as acetic acid, malic acid, citric acid, ascorbic acid, mandelic acid, methanesulfonic acid, etc. The compound [] or a salt thereof can also be synthesized by the following method. In other words, the compound [] is prepared with the general formula [In the formula, X represents a halogen such as chlorine, bromine, or iodine. Any of the hydroxyl groups may be protected]. Suitable reaction solvents include, for example, water, lower alkanols such as methanol, ethanol, propanol, butanol, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethyl sulfoxide, dimethyl formamide, N-methyl acetamide, such as methyl Glymes such as cellosolve, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether, ethers such as dioxane and tetrahydrofuran, polar solvents such as acetonitrile, or mixed solvents thereof, or non-polar solvents such as benzene, hexane, chloroform, dichloromethane, and ethyl acetate. A mixed solvent with a solvent is used, and if the mixed solvent is not a homogeneous phase, the reaction may be carried out in the presence of a phase transfer catalyst. To accelerate the reaction, inorganic bases such as alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate), alkali metal carbonate (e.g., sodium carbonate), alkali metal hydroxide (e.g., potassium hydroxide), trimethylamine, triethylamine, Tributylamine, N-methylmorpholine, N-methylpiperidine, N,N-dimethylaniline, pyridine,
Organic bases such as picoline and lutidine can also be used. Although the reaction temperature is not particularly limited, it is usually carried out by heating from room temperature to about 100°C. The reaction time varies depending on the reaction temperature, but is usually within a few minutes.
The purpose can be achieved by reacting for about 24 hours. Variolamine as a raw material compound used in the present invention (a compound in which A is a hydroxyl group in the general formula [])
For example, by the method of culturing microorganisms belonging to the genus Streptomyces described in Japanese Patent Application No. 56-55907,
It can be produced by an organic chemical synthesis method using valienamine or validamine as a raw material as described in 144309. Validamine as a raw material compound (a compound in which A is a hydrogen atom in the general formula [])
is publicly known, for example, The Journal of Antibiotics, Vol. 33,
1575-1576 (1980)). The cyclic ketone represented by the formula [], which is one of the raw material compounds used in the present invention, can be produced, for example, by oxidizing the primary amine moiety in validamine with an oxidizing agent. For example, as an oxidizing agent, 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)] by oxidizing the primary amine moiety in validamine to convert it into a ketone. Furthermore, the cyclic alkyl halide represented by the general formula
52, pp. 1174-1176 (1979)) from a cyclic alkyl compound. The above general formula obtained in this way [],
Compounds represented by [], [], [] and their synthetic intermediates can be prepared by methods known per se, such as filtration, centrifugation, concentration, vacuum concentration, drying, freeze-drying, adsorption, desorption, and their solubility in various solvents. Methods that utilize differences (e.g., solvent extraction, dissolution, precipitation,
(crystallization, recrystallization, etc.), chromatography (e.g., chromatography using ion exchange resins, activated carbon, high porous polymers, Cephadex, Cephadex ion exchangers, cellulose, ion exchange cellulose, silica gel, alumina, etc.) It can be isolated and purified by methods such as 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
505n of the reaction solution heated at 37℃ for 20 minutes to develop color.
It was calculated by measuring the absorbance at m. 50% inhibitory concentration against maltase (pig, intestinal mucosa) [hereinafter abbreviated as IC ₅₀ (maltase)] and 50% inhibitory concentration against satucalase (pig, intestinal mucosa) of the compound [ ] or its salt described in the Examples [ Hereinafter, abbreviated as IC ₅₀ (Satsucalase)] is the inhibition rate (%) measured using the above measurement method at 3 to 5 different concentrations of each inhibitor.
I asked for it from. The elution fraction of column chromatography in the purification process of each compound described in Reference Examples and Examples is usually thin layer chromatography (TLC).
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.
Measurement was performed using propyl alcohol, acetic acid, and 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; dt, double triplet; m, multiplet; J, coupling constant reference example 1 (2R)-(2,4/3 ,5)-2,3,4-trihydroxy-5-hydroxymethylcyclohexanone Validamine (1.8g) and 3,5-di-tert-butyl-1,2-benzoquinone (2.3g) were dissolved in methanol (100ml). and stir at room temperature for 24 hours under nitrogen flow. After adding water (10ml) to the reaction solution,
Adjust the pH to 1 with 3N sulfuric acid and stir at room temperature for 3 hours.
Add water (500ml) to the reaction solution and dilute with chloroform.
Wash twice. Dowex the resulting aqueous layer 1×8
(OH ^- type, manufactured by Dow Chemical Co., USA) to adjust the pH to 5.5. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and then lyophilized to give (2R)-(2,4/3,5)-
A white powder (1.3 g) of 2,3,4-trihydroxy-5-hydroxymethylcyclohexanone is obtained. Elemental analysis: _{C7H12O5.3 / 4H2O} Calculated value (%): C, 44.33; H, 7.17 Experimental value (% ₎ : C, 44.33; H, 7.23. IRν ^KBr _nax cm ^-1 : 1735 (C=O). NMR (D ₂ O) δ: 4.51 (1H, d, J = 10Hz, 2-
CH ). Reference example 2 N-[(1R,2S)-(2,4/3,5)-2,3,
Octa-O-acetyl derivative of 4-trihydroxy-5-hydroxymethylcyclohexyl]validamine N-[(1R,2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexylvalidamine (50 mg) was dissolved in pyridine (2
ml), add acetic anhydride (1.0 ml), and leave at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was dried under reduced pressure in a desiccator overnight, ethyl ether/petroleum ether (1:2, about 30 ml) was added, and the mixture was left in the refrigerator overnight. The resulting precipitate is collected by filtration and dried to obtain a white powder (75 mg) of the title octa-O-acetyl derivative. [α] ²⁵ _D +33.8° (c=0.5, CH ₃ OH) Elemental analysis: C ₃₀ H ₄₃ NO ₁₆ Calculated value (%): C, 53.49; H, 6.43; N, 2.08. Experimental values (%): C, 53.13; H, 6.50; N, 1.97. NMR ( _CDCl3 ) δ: 1.1~2.5 (6H, m), 1.97~
2.10 (24H, CH ₃ COO-×8), 2.5-2.9
(1H, m), 3.43 (1H, m), 3.91 (2H, dd,
J = 3.5Hz, 11Hz), 4.11 (2H, dd, J = 4.8
Hz, 11Hz), 4.73-5.13 (5H, m), 5.43 (1H,
t, J = 10Hz). Reference example 3 N-[(1S, 2S)-(2,4/3,5)-2,3,
Octa-O-acetyl derivative of 4-trihydroxy-5-hydroxymethylcyclohexylvalidamine. N-[(1S, 2S)-(2,4/3,5)-2,3,
When 4-trihydroxy-5-hydroxymethylcyclohexylvalidamine (100 mg) is treated in the same manner as in Reference Example 2, the title octa-O-acetyl derivative (115 mg) is obtained. [α] ²⁵ _D +101.2° (c=0.5, CH ₃ OH) Elemental analysis: C ₃₀ H ₄₃ NO ₁₆ Calculated value (%): C, 53.49; H, 6.43; N, 2.08. Experimental values (%): C, 53.28; H, 6.57; N, 2.13. NMR ( _CDCl3 ) δ: 1.14-2.6 (6H, m), 2.00
~2.07 (24H, CH ₃ COO-×8), 3.23 (2H,
m), 3.89 (2H, dd, J=3.5Hz, 11.5Hz),
4.16 (2H, dd, J=5.4Hz, 11.5Hz), 4.88
(2H, dd, J = 4.5Hz, 10.5Hz), 4.96 (2H,
dd, J=9Hz, 10Hz), 5.36(2H, dd, J=
9Hz, 10.5Hz). Reference example 4 N-[(1R, 2S)-(2,4/3,5)-2,3,
Octa-O of 4-trihydroxy-5-hydroxymethylcyclohexyl variolamine
-acetyl derivative N-[(1R,2S)-(2,4/3,5)-2,3,
When 4-trihydroxy-5-hydroxymethylcyclohexyl variolamine (100 mg) was treated in the same manner as in Reference Example 2, the titled octa-O
- Acetyl derivative (124 mg) is obtained. [α] ²⁵ _D −3.9° (c=1, CH ₃ OH) Elemental analysis: C ₃₀ H ₄₃ NO ₁₇ Calculated value (%): C, 52.25; H, 6.28; N, 2.03. Experimental values (%): C, 51.91; H, 6.36; N, 2.30. NMR ( _CDCl3 ) δ: 1.2~2.5 (5H, m), 1.9~
2.2 (24H, CH ₃ COO-×8), 2.6-3.2 (1H,
m), 3.3 to 3.6 (1H, m), 3.6 to 4.2 (4H, m),
4.6-5.3 (5H, m), 5.57 (1H, t, J=10
Hz). Reference example 5 N-[(1S, 2S)-(2,4/3,5)-2,3,
Octa-O of 4-trihydroxy-5-hydroxymethylcyclohexyl variolamine
-acetyl derivative N-[(1S,2S)-(2,4/3,5)-2,3,
When 4-trihydroxy-5-hydroxymethylcyclohexyl variolamine (200 mg) was treated in the same manner as in Reference Example 2, the titled octa-O
- Acetyl derivative (330 mg) is obtained. [α] ²⁵ _D +79.7° (c=1, CH ₃ OH) Elemental analysis: C ₃₀ H ₄₃ NO ₁₇ Calculated value (%): C, 52.25; H, 6.28; N, 2.03. Experimental values (%): C, 52.11; H, 6.36; N, 2.22. NMR ( _CDCl3 ) δ: 1.2~2.4 (5H, m), 1.9~
2.07 (24H, CH ₃ COO-×8), 3.2-3.46
(2H, m), 3.65 (1H, d, J=11.5Hz),
3.84 (1H, dd, J=3Hz, 11.5Hz), 4.00
(1H, d, J = 11.5Hz), 4.12 (1H, dd, J =
6Hz, 11.5Hz), 4.80 (1H, dd, J=4.5Hz,
10.5Hz), 4.89 (1H, dd, J=9Hz, 10Hz),
5.01 (1H, dd, J=4.5Hz, 10Hz), 5.06 (1H,
d, J = 10Hz), 5.26 (1H, dd, J = 9Hz,
10.5Hz), 5.62 (1H, t, J = 10Hz). Reference example 6 N-[(1R, 2S)- for 200ml of fruit juice beverage
Add 100 mg of (2,4/3,5)-trihydroxy-5-hydroxymethylcyclohexylvalidamine and stir to dissolve uniformly to obtain a fruit juice beverage containing an α-glucosidase inhibitor. Reference example 7 N-[(1R, 2S)-(2,4/3,5)-2,3,
20 parts by weight of 4-trihydroxy-5-hydroxymethylcyclohexyl variolamine sulfate, 80 parts by weight of lactose, and 20 parts by weight of crystalline cellulose are mixed, kneaded with water, dried, and made into a powder or fine granules. Example 1 N-[(1R, 2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]validamine and N-[(1S,
2S)-(2,4/3,5)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]validamine Validamine (1.0g) and (2R)-(2,4/3,
5) Dissolve -2,3,4-trihydroxy-5-hydroxymethylcyclohexanone (1.0 g) in dimethylformamide (25 ml) and add 2N hydrochloric acid (0.8
ml) and sodium cyanoborohydride (1.3g)
and stir at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure, toluene is further added, and dimethylformamide is distilled off under reduced pressure under azeotropic distillation. Water (100ml) with residue
Dissolve in Dowex 50W x 8 (H ⁺ type, DOWEX
Chemical Co., USA, 100 ml) and stir at room temperature.
Stir for an hour. This mixture is added onto a column previously filled with another Dowex 50W x 8 (H ⁺ type, 50 ml), and after washing the column with water, it is eluted 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, manufactured by Rohm and Haas, USA, 550 ml), and when eluted with water, it was separated into two components. Ru.
After concentrating the first eluted fraction (270 to 360 ml) under reduced pressure,
Freeze-drying yields a white powder (1.0 g) of the (1S, 2S) isomer. The fraction eluting later (430~
580ml) was concentrated under reduced pressure and lyophilized (1R,
A white powder (320 mg) of the 2S) isomer is obtained. N-[(1S, 2S)-(2,4/3,5)-2,3,
4-Trihydroxy-5-hydroxymethylcyclohexyl]validamine (isomer obtained from the earlier eluted fraction): [α] ²⁵ _D +115.5° (c=1, H ₂ O). Elemental analysis: _{C14H27NO8.H2O Calculated} values (%): C, 47.31; _H , 8.23; _N , 3.94. Experimental values (%): C, 47.32; H, 8.26; N, 4.06. NMR (D ₂ O) δ: 1.2-1.75 (2H, m), 1.75-
2.4 (4H, m), 3.2-4.15 (12H, m). TLC: Rf=0.24 N-[(1R, 2S)-(2,4/3,5)-2,3,
4-Trihydroxy-5-hydroxymethylcyclohexyl]validamine (isomer obtained from the later eluted fraction): [α] ²⁵ _D +35.5° (c=1, H ₂ O). Elemental analysis: _{C14H27NO8.H2O Calculated} values (%): C, 47.31; _H , 8.23; _N , 3.94. Experimental values (%): C, 47.28; H, 8.01; N, 3.86. NMR (D ₂ O) δ: 1.34 (1H, q, J = 12Hz),
1.5~2.5 (5H, m), 2.82 (1H, m), 3.25~
4.15 (11H, m). IC ₅₀ (Satucalase): 2.7×10 ^-7 M IC ₅₀ (Maltase): 2.2×10 ^-6 M TLC: Rf=0.25 Example 2 N-[(1R,2S)-(2,4/3,5) -2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine and N-
[(1S, 2S) - (2, 4/3, 5) - 2, 3, 4 -
Trihydroxy-5-hydroxymethylcyclohexyl]variolamine Variolamine (2.1g) and (2R)-(2,
4/3,5)-2,3,4-trihydroxy-5
-Hydroxymethylcyclohexanone (1.9g)
Dissolved in dimethylformamide (50ml) and diluted with 2N
Add hydrochloric acid (1.5 ml) and sodium cyanoborohydride (2.6 g) and stir at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure, toluene is further added, and dimethylformamide is distilled off under reduced pressure under azeotropy. Dissolve the residue in water (200 ml) and use Dowex 50W x 8
(H ⁺ form, Dow Chemical Co., USA, 250 ml) and stirred at room temperature for 1 hour. Pour this mixture in advance into another Dowex 50W x 8 (H ⁺ type, 100ml).
Add on top of the packed column, wash the column with water,
Elute with 0.5N ammonia water. The eluted fraction was concentrated under reduced pressure, and the residue was purified using Amberlite CG-50 (NH ₄ ⁺
(Mold, Rohm & Haas, USA, 450ml)
When subjected to column chromatography and eluted with water, it is separated into two components. Fraction eluting first (400-580ml)
Concentrate under reduced pressure and transfer the residue to Dowex 1×2
(OH ^- type, Dow Chemical Company, USA, 270ml)
column chromatography and elute with water. The eluted fraction (200-550ml) was concentrated under reduced pressure and then lyophilized to obtain a white powder (1.53g) of the (1S, 2S) isomer.
The later eluted fraction (0.63-1.00) is concentrated under reduced pressure and then lyophilized to obtain a white powder (570 mg) of the (1R, 2S) isomer. N-[(1S, 2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine (isomer obtained from the fraction eluted earlier): [α] ²⁵ _D +48.5° (c=1, H ₂ O). Elemental analysis: _{C14H27NO9.1 / 2H2O} Calculated values (%): C, 46.40; _H , 7.79; N, 3.87. Experimental values (%): C, 46.29; H, 7.94; N, 3.73. NMR (D ₂ O) δ: 1.43 (1H, dt, J = 3.3Hz,
13.5Hz, 13.5Hz), 1.67 (1H, dd, J=3.5Hz,
15.5Hz), 1.7~2.7 (2H, m), 2.32 (1H, dd,
J = 3Hz, 15.5Hz), 3.35-4.25 (12H, m). IC ₅₀ (Satsucalase): 5.6×10 ^-6 M TLC: Rf=0.21 N-[(1R,2S)-(2,4/3,5)-2,3,
4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine (isomer obtained from later eluting fractions): [α] ²⁵ _D +5.2° (c=1, H ₂ O). Elemental analysis: _{C14H27NO9.H2O Calculated} values (%): C, 45.27; _H , 7.87; _N , 3.77. Experimental values (%): C, 45.04; H, 7.97; N, 3.59. NMR (D ₂ O) δ: 1.1~2.55 (5H, m), 2.65~
3.3 (1H, m), 3.4-4.45 (11H, m). IC ₅₀ (maltase): 4.4×10 ^-8 M IC ₅₀ (satucalase): 4.8×10 ^-8 M TLC: Rf=0.23 Example 3 N-[(1R,2S)-(2,4/3,5) -2,3,
4-Trihydroxy-5-hydroxymethylcyclohexyl]variolamine sulfate N-[(1R,2S)-(2,4/3,5)-2,3,
4-Trihydroxy-5-hydroxymethylcyclohexyl]variolamine (500 mg) was dissolved in water (20 ml), 1N sulfuric acid was added dropwise to adjust the pH to 3, and the solution was concentrated under reduced pressure to about 5 ml. The concentrated solution was subjected to activated carbon column chromatography (100 ml) and eluted with water.
After concentrating the eluted fraction under reduced pressure and lyophilizing it, N-
[(1R,2S)-(2,4/3,5)-2,3,4-trihydroxy-5-hydroxymethylcyclohexyl]variolamine sulfate is obtained.

Claims (1)

[Claims] 1. General formula [In the formula, A represents a hydrogen atom or a hydroxyl group. ]
A compound represented by or a salt thereof. 2 General formula [In the formula, A represents a hydrogen atom or a hydroxyl group. Any of the hydroxyl groups may be protected] and a compound represented by the formula A general formula characterized by reacting with a cyclic ketone represented by [in the formula, any of the hydroxyl groups may be protected], then subjecting it to a reduction reaction, and optionally subjecting it to a deprotection reaction. [In the formula, A has the same meaning as above. ] A method for producing a compound represented by or a salt thereof.