JPH0238580B2 - BARIOORUAMINNONNCHIKANJUDOTAI * SONOSEIZOHOOYOBYOTO - Google Patents

Description

[Detailed description of the invention]

The present invention relates to N-substituted derivatives of valiolamine having glucoside hydrolase inhibitory activity, a method for producing the same, and α-glucosidase inhibitors containing said derivatives. The inventors have developed the formula Valienamine, represented by
Journal of Antibiotics) Volume 33, Page 1575, 1979
[2009] and also found that a formula with α-glucosidase inhibitory activity was found in actinomycete cultures. discovered and isolated the compound represented by
-55907), and this biolamine was also successfully produced from valienamine using organic chemical synthesis means (Japanese Patent Application No. 56-64370). As a result of further research on various new derivatives of variolamine, the present inventors found that a group of N-substituted derivatives of variolamine have stronger α-glucosidase activity than valienamine or variolamine itself. They found that it has inhibitory activity and completed the present invention. That is, the present invention has the following features: 1 General formula [In the formula, A is a hydroxyl group, phenoxy, thienyl,
It represents a chain hydrocarbon group having 1 to 10 carbon atoms which may have furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.). ] Variolamine derivatives represented by 2 hydroxyl groups, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.), a chain having 1 to 10 carbon atoms; A method for producing a variolamine derivative [] characterized by reacting an aldehyde or ketone with variolamine and then subjecting it to a reduction reaction, 3 General formula [In the formula, R is a hydroxyl group, phenoxy, thienyl,
Furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen or the like), W represents a divalent chain hydrocarbon group having 1 to 8 carbon atoms, and n represents 0 or 1. A general formula characterized by reacting an oxirane derivative represented by ] with variolamine [In the formula, A' is a hydroxyl group, phenoxy, thienyl,
It represents a chain hydrocarbon group having 2 to 10 carbon atoms which may have furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.). ] A method for producing a variolamine derivative represented by 4. A chain hydrocarbon halide having 1 to 10 carbon atoms that can have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.) and variolamine. 5. A method for producing a variolamine derivative [], which is characterized by reacting it. 5. An α-glucosidase inhibitor containing variolamine or a derivative thereof []. In the variolamine derivative [], the chain hydrocarbon group having 1 to 10 carbon atoms represented by A is, for example, a straight chain hydrocarbon group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Chain saturated aliphatic hydrocarbon groups, e.g. isopropyl, isobutyl, sec
-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2
-Methylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl; Methylhexyl such as 5-methylhexyl; Methylheptyl such as 1-methylheptyl; Methyloctyl, methylnonyl, 1-ethylpropyl , ethylbutyl, ethylpentyl, ethylhexyl, ethylheptyl, ethyl octyl, 1-methylisobutyl, 1-methylisopentyl, 1,
Dimethylbutyl such as 1-dimethylbutyl; 1,1
-Dimethylpentyl such as dimethylpentyl, 1,4-dimethylpentyl; dimethylhexyl, dimethylheptyl, dimethyloctyl; 1-ethyl-
Ethylmethylpropyl such as 1-methylpropyl;
1-ethyl-2-methylbutyl, 1-ethyl-3
- Ethylmethylbutyl such as methylbutyl; branched saturated aliphatic hydrocarbon groups such as propylbutyl such as 1-isopropylbutyl; for example, vinyl; propenyl such as allyl; butenyl such as 3-butenyl;
-Pentenyl such as pentenyl; hexenyl, heptenyl, octenyl, nonenyl, decenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl,
Decadienyl, hexatrienyl, heptatrienyl, octatrienyl, nonatrienyl, decatriethyl, octatetraenyl, nonatetraenyl, decatetraenyl, decapentaenyl, isopropenyl; methylpropenyl such as 2-methylallyl; 1,1-dimethylallyl, etc. Dimethylpropenyl; Methylbutenyl such as 3-methyl-2-butenyl, 3-methyl-3-butenyl; 3,7-
Examples include hydrocarbon groups such as linear and branched unsaturated hydrocarbon groups such as dimethyldienyl such as dimethyl-2,6-octadienyl. Note that these hydrocarbon groups may have a hydroxyl group, cyclohexyl, phenoxy, thienyl, furyl, pyridyl, or phenyl. The phenyl is substituted with lower alkoxy such as hydroxy, methoxy, ethoxy, carboxy, halogen atom such as chlorine, bromine, iodine, lower alkyl such as phenyl, methyl, ethyl, propyl, imepropyl, butyl, sec-butyl, tert-butyl, etc. may have been done. Furthermore, specific examples of N-substituted variolamine derivatives represented by the general formulas [] and ['] include (1) N-benzylvariolamine, (2) N-phenethylvariolamine, (3) N- (3-phenylpropyl)variolamine, (4) N-(4-phenylbutyl)variolamine, (5) N-(5-phenylpentyl)variolamine, (6) N-(6-phenylhexyl) ) Variolamine, (7) N-(3-phenylallyl)variolamine, (8) N-furfurylvariolamine, (9) N-thenylvariolamine, (10) N-(3-pyridylmethyl ) Variolamine, (11) N-(4-methylbenzyl)variolamine, (12) N-(4-methoxybenzyl)variolamine, (13) N-(3-phenoxypropyl)variolamine Amine, (14) N-(2-phenylpropyl)variolamine, (15) N-n-butylvariolamine, (16) N-(4-promobenzyl)variolamine, (17) N- (4-Carboxybenzyl)variolamine, (18) N-(β-hydroxyphenethyl)variolamine, (19) N-(β-hydroxy-2-methoxyphenethyl)variolamine, (20 ) N-(β-hydroxy-2-chlorophenethyl)variolamine, (21) N-(α-methylbenzyl)variolamine, (22) N-(α-methylphenethyl)variolamine, (23) N- (4-hydroxybenzyl)variolamine, (24) N-(3,4-dihydroxybenzyl)variolamine, (25) N-(3,5-di-tert-butyl-4-hydroxybenzyl)variol Amine, (26) N-(2-diphenylethyl)variolamine, (27) N-(cyclohexylmethyl)variolamine, (28) N-geranylvariolamine, (29) N-(1,3-dihydroxy -2-propyl)variolamine, (30) N-(1,3-dihydroxy-1-phenyl-2-propyl)variolamine, (31) N-(α-(hydroxymethyl)benzyl)variolamine , (32) N-(D-gluco-2,3,4,5,6-
pentahydroxyhexyl)variolamine, (33) N-(D-manno-2,3,4,5,6-
pentahydroxyhexyl)variolamine, (34) N-(D-galacto-2,3,4,5,6
-pentahydroxyhexyl)variolamine, (35) N-(D-arabo-2,3,4,5,-tetrahydroxypentyl)variolamine, (36) N-(D-ribo-2,3, 4,5-tetrahydroxypentyl)variolamine, (37) N-(D-xylo-2,3,4,5-tetrahydroxypentyl)variolamine, (38) N-(D-arabou2,3 , 4,5-tetrahydroxy-1-hydroxymethylbentyl)variolamine, (39) N-(L-xylo-2,3,4,5-tetrahydroxy-1-hydroxymethylpentyl)variolamine, etc. can be mentioned. The α-glucosidase inhibitor of the present invention suppresses carbohydrate metabolism in humans and non-human animals, so it has an effect of suppressing, for example, blood sugar rise, and is effective against hyperglycemic symptoms and various diseases caused by hyperglycemia, such as It is a compound useful for the prevention of obesity, adiposity, hyperlipidemia (arteriosclerosis), diabetes, prediabetes, and diseases caused by sugar metabolism by oral microorganisms, such as dental caries. Foods produced by adding N-substituted derivatives of variolamine are also suitable for healthy people as food for patients with metabolic disorders and as preventative food for metabolic disorders. It is also useful as a feed additive for livestock to obtain low-fat, high-quality edible meat. Therefore, the α-glucosidase inhibitor of the present invention is useful as a pharmaceutical, food additive, and animal feed additive. The α-glucosidase inhibitor of the present invention is administered orally or parenterally, preferably orally. The above N-substituted derivatives of variolamines are stable crystals or powders with little toxicity (Rat LD ₅₀ >500 mg/Kg), can be used as free bases or hydrates, and can be used as pharmaceutical agents by conventional methods. It can also be used as any non-toxic acid addition salt with any acid acceptable to the compound. Such acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Inorganic acids such as nitric acid, acetic acid, malic acid, citric acid,
Organic acids such as ascorbic acid, mandelic acid, and methanesulfonic acid are used. Such variolamine derivatives are used alone or in combination with a non-toxic carrier. For example, it may be used with liquid or solid foods such as coffee, soft drinks, fruit juices, beer, milk, jam, raw bean paste, and jelly, seasonings, or various staple foods and side foods, and can be used directly or as a food additive. or can be taken before or after meals. Furthermore, it can also be used as a feed additive for livestock to obtain low-fat, high-quality edible meat. The α-glucosidase inhibitor of the present invention 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 as an ampoule. 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. Specifically, for example, by taking a tablet containing about 20 to 400 mg of the variolamine derivative after every meal, it is possible to suppress the increase in blood glucose concentration caused by eating. Further, for example, variolamine derivatives may be added to various foods in an amount of about 0.005 to 1% of the carbohydrate content in the foods. When mixed with feed, check the carbohydrate content of the feed.
0.005 to 1% is desirable. All of the N-substituted derivatives of variolamine included in the present invention are new compounds that have not been described in any literature, and can be synthesized, for example, by the method described below. That is, variolamine is dissolved in a suitable solvent in a chain form having 1 to 10 carbon atoms that may have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.). It can be synthesized by subjecting a Schiff base (azomethine derivative) obtained by reacting an aldehyde or ketone with variolamine to a reduction reaction. The condensation reaction between the amino group of variolamine and aldehydes or ketones and the subsequent reduction reaction may be carried out continuously in the same reaction vessel, or both reactions may be carried out separately in two stages. It's okay to get old. Examples of reaction solvents include water, alcohols such as methanol, propanol, and butanol, glymes such as dimethyl sulfoxide, dimethylformamide, N-methylacetamide, methyl cellosolve, dimethyl cellosolve, and diethylene glycol dimethyl ether, dioxane,
Polar solvents such as tetrahydrofuran and acetonitrile, mixed solvents thereof, or mixtures of these polar solvents and nonpolar solvents such as chloroform and dichloromethane can be used. The reaction temperature in the Schiff base formation reaction is not particularly limited, but it is usually carried out at room temperature to about 100°C. The reaction time varies depending on the reaction temperature and the type of aldehyde or ketone used, but it is usually several minutes to 24 minutes.
The purpose can be achieved by allowing the reaction to take some time. 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, alkali metal cyanoborohydrides such as sodium cyanoborohydride, alkali metal aluminum hydrides such as lithium aluminum hydride, and dialkylamineboranes such as dimethylamineborane are advantageously used. In addition, when using an alkali metal cyanohydride, 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 means can also be used for the reduction reaction of the Schiff base formed. That is,
This 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 stream of hydrogen. Examples of catalysts for catalytic reduction include:
Platinum black, platinum dioxide, palladium black, palladium carbon, Raney nickel, etc. are used, and commonly used solvents include water, alcohols such as methanol and ethanol, dioxane,
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. N-substituted derivatives of variolamine can also be synthesized by the method described below. That is, variolamine is converted into a chain having 1 to 10 carbon atoms that can have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.) in a suitable solvent. It can be synthesized by reacting a hydrocarbon halide with variolamine. Suitable reaction solvents include, for example, water, lower alkanols such as methanol, ethanol, propanol and butanol, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, dimethyl sulfoxide, dimethyl formamide, N
- Glymes such as methyl acetamide, methyl cellosolve, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, polar solvents such as dioxane, tetrahydrofuran, acetonitrile, or mixed solvents thereof, or non-polar solvents such as benzene, hexane, chloroform, dichloromethane, ethyl acetate, etc. 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. The reaction is usually carried out in the presence of a deoxidizing agent, such as alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydroxide, trimethylamine, triethylamine, tributylamine, N
-Methylmorpholine, N-methylpiperidine,
Inorganic and organic bases such as N,N-dimethylaniline, pyridine, picoline, lutidine and the like 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. The N-substituted derivative of variolamine can also be synthesized by reacting an oxirane derivative represented by the general formula [] with variolamine. 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, etc.
dimethyl sulfoxide, dimethyl formamide,
Glymes such as N-methylacetamide, methyl cellosolve, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, polar solvents such as dioxane, tetrahydrofuran, acetonitrile, or mixtures thereof, or nonpolar solvents such as benzene, hexane, chloroform, dichloromethane, ethyl acetate, etc. 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. 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. The N-substituted derivatives of variolamine [] included in the present invention can also be obtained by first synthesizing an N-acyl variolamine derivative, and converting the carbonyl of the amide bond to an alkali metal aluminum hydride such as lithium aluminum hydride. It can also be synthesized by reducing it to methylene using Here, the N-acyl group is a group having 1 to 1 carbon atoms and may have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.).
Ten alkanoyl groups are used. The content of the present invention will be explained in detail by referring to Reference Examples and Examples below, but the scope of the invention is not limited thereto. Reference example Method for measuring glucosidase inhibitory activity α-glucosidase (yeast, type, manufactured by Sigma) using maltose and sucrose as substrates and maltase and satucalase prepared from pig small intestine mucosa [B.Borgstro¨ m) and Dahlquist (A.
Dahlqvist, Acta Chem.Scand., Volume 12, 1997-2006
[prepared according to the method described in J. P., 1958] was determined by adding 0.25 ml of an enzyme solution appropriately diluted with 0.02 M phosphate buffer solution (PH 6.8) to 0.5 ml of the same buffer solution of the inhibitor to be tested. and 0.25ml of the same buffer solution of 0.05M maltose or 0.05M sucrose as substrate
was added, the mixture was allowed to react at 37°C for 10 minutes, 3 ml of glucose B-test reagent (glucose oxidase reagent for glucose measurement, manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was further heated at 37°C for 20 minutes. Calculated by measuring the absorbance at When p-nitrophenyl-α-D-glucopyranoside was used as a substrate, the inhibitory activity against α-glucosidase (yeast, type, Sigma, USA) and glucoamylase (Arachnoid fungus, Sigma, USA) was
0.02M phosphate buffer containing 0.005mg/ml (PH6.8)
0.5ml of the same buffer solution of the inhibitor and 0.01M in 0.25ml
Add 0.25 ml of the same buffer solution of p-nitrophenyl-α-D-glucopyranoside and react at 37°C for 15 minutes, then add 3 ml of 0.1 M sodium carbonate aqueous solution to stop the reaction, and measure the absorbance of the reaction solution at 400 nm. Calculate by The 50% inhibitory concentration is calculated by determining the inhibition rate (%) for samples of 3 to 5 different concentrations of the inhibitor. Table 1 shows the 50% inhibitory concentration (IC 50 ) of N-substituted derivatives of variolamine against sutucarase (pig, intestinal mucosa), and Table 2 shows the 50% inhibitory concentration (IC ₅₀ ) of N-substituted derivatives of variolamine against maltase (pig, intestinal mucosa). 50 for mucous membranes)
The percentage inhibitory concentration (IC ₅₀ ) is shown.

【table】

【table】

[Table] Example 1 N-(1,3-dihydroxy-2-propyl)
Variolamine Dissolve 2.0g of variolamine in 50ml of N,N-dimethylformamide and add dihydroxyacetone.
Add 6.4 g, 1.5 ml of 2N hydrochloric acid, and 2.6 g of sodium cyanoborohydride, and stir at 60 to 70°C for 16 hours.
The reaction solution was concentrated under reduced pressure to remove as much N,N-dimethylformamide as possible, and the residue was dissolved in 100 ml of water. The solution was made acidic with 2N hydrochloric acid and kept on ice for 30 min.
Stir for ~40 min and PH with 1N sodium hydroxide solution.
4.5, and subjected to column chromatography (250 ml) using Dowex 50W x 8 (H ⁺ type) (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 concentrated solution (approximately 10
ml) and Amberlite CG-50 (NH ⁺ ₄ type)
(Rohm & Haas, USA) column chromatography (250 ml) and elute with water. After concentrating the eluted fraction under reduced pressure, it was lyophilized to obtain N-(1,3-
2.0 g of white powder of variolamine (dihydroxy-2-propyl) is obtained. Elemental analysis: C ₁₀ H ₂₁ NO ₇・1/2H ₂ O Calculated value (%): C43.46; H8.03; N5.07 Experimental value (%): C43.56; H8.36; N5.00 [ α] ²⁶ _D +27.2° (c=1, H ₂ O) NMR (D ₂ O) δ: 1.65 (1H, dd, J=3 and
15.5), 2.23 (1H, dd, J = 3.5 and 15.5), 3.01
(1H, quin., J=5), 3.5-4.2 (10H). Freeze-dried product of the above N-(1,3-dihydroxy-2-propyl)variolamine (1.2g)
Add ethanol (approximately 60 ml) to the solution, warm in a water bath at a temperature of 90 to 95°C for 30 minutes, and then leave in a cool place. The obtained crystalline substance is collected by filtration, washed with ethanol, and then dried under reduced pressure in a desiccator. Yield 0.95g. Elemental analysis: C ₁₀ H ₂₁ NO ₇ Calculated value (%): C44.93; H7.92; N5.24 Experimental value (%): C44.62; H7.79; N5.09 [α] ²⁵ _D +27. 2゜(c=1, H ₂ O) Example 2 N-(β-hydroxyphenethyl)variolamine and N-[α-(hydroxymethyl)
[Benzyl] Variolamine 10g of Variolamine and 12ml of styrene oxide
Dissolve in 500 ml of methanol and heat to reflux while stirring. After 4 hours, 12 ml of styrene oxide was added, and the mixture was heated to reflux with stirring for an additional 6 hours. The reaction solution was concentrated under reduced pressure, the residue was partitioned between water and ethyl acetate, and the aqueous layer was separated. After concentrating the aqueous layer under reduced pressure, the residue was mixed with Amberlite CG-50 (NH ⁺ ₄ , 1.6
) (manufactured by Rohm and Haas) and eluted with water to obtain three fractions.
Each eluted fraction is purified by repeating the same chromatographic operation once again, concentrated under reduced pressure, and lyophilized. Amine (3.7g) followed by N
-(β-hydroxyphenethyl)variolamine isomer showing [α] ²⁴ _D −11° (c = 1, H ₂ O),
Furthermore, [α] of N-(β-hydroxyphenethyl)variolamine ²⁴ _D +17° (c=1, H ₂ O)
An isomer (4.3 g) is obtained. When the N-[α-(hydroxymethyl)benzyl]variolamine obtained by the above method is dissolved in water with heating and stirring and left to cool on ice, [α] ²⁴ _D
An isomer exhibiting −10.6° (c=1, H ₂ O) is obtained as a crystal. In addition, the white powder obtained by lyophilizing the crystal mother liquor after concentrating it under reduced pressure is [α] ²⁴ _D +43.2° (c=1,
_H2O ). N-(β-hydroxyphenethyl)variolamine ([α] ²⁴ _D −11° optical isomer): Elemental analysis: C ₁₅ H ₂₃ NO ₆・1/4H ₂ O Calculated value (%) : C56.68; H7.45; N4.41 Experimental value (%): C56.86; H7.65; N4.68 NMR (D ₂ O) δ: 1.56 (1H, dd, J=3 and
15.5), 2.17 (1H, dd, J = 3.5 and 1.55), 2.91
(1H, dd, J=8 and 12.5), 3.19 (1H, dd,
J = 5 and 12.5) 3.2-4.05 (6H), 4.97 (1H,
dd, J=5 and 8), 7.60 (5H, s). N-(β-hydroxyphenethyl)variolamine (optical isomer showing [α] ²⁴ _D +17°): Elemental analysis: C ₁₅ H ₂₃ NO ₆・1/4H ₂ O Calculated value (%): C56.68; H7.45; N4.41 Experimental value (%): C56.75; H7.43; N4.50 NMR (D ₂ O) δ: 1.57 (1H, dd, J=3 and
15.5), 2.19 (1H, dd, J = 3.5 and 15.5), 2.95
(1H, dd, J=5 and 12.5), 3.20 (1H, dd,
J=8 and 12.5), 3.2-4.05 (6H), 5.01 (1H,
dd, J=5 and 8), 7.60 (5H, s). N-(α-(hydroxymethyl)benzyl)variolamine ([α] ²⁴ _D −10.6° (c=1, H ₂ O)
Elemental analysis: C ₁₅ H ₂₃ NO ₆・1/4H ₂ O Calculated value (%): C56.68; H7.45; N4.41 Experimental value (%): C56.76; H7. 81; N4.58 NMR (D ₂ O) δ: 1.43 (1H, dd, J=3 and
15), 1.73 (1H, dd, J = 3.5 and 15), 3.2-4.1
(9H), 7.58 (5H, s). N-[α-(hydroxymethyl)benzyl]variolamine ([α] ²⁴ _D +43.2° (c=1, H ₂ O)
) Elemental analysis: C ₁₅ H ₂₃ NO ₆・1/2H ₂ O Calculated value (%): C55.89; H7.50; N4.35 Experimental value (%): C55.88; H7. 60;N4.43 Example 3 N-(β-hydroxyphenethyl)variolamine 1.0g of variolamine and 1.5g of phenylglyoxal monohydrate were dissolved in 20ml of methanol, and 2.5g of magnesium sulfate was added. 20 at room temperature
Stir for an hour. The reaction solution is filtered, the filtrate is concentrated under reduced pressure to remove methanol, ethyl ether is added to the residue, and the resulting precipitate is collected by filtration and dried. Dissolve 1.1 g of the obtained Schizuff hydrochloric acid in 20 ml of methanol,
After adding 400 ml of sodium borohydride under ice cooling, stir for 3 hours. Water, acetone and n-butyl alcohol are added to the reaction solution and concentrated under reduced pressure. The resulting aqueous solution is adjusted to pH 2 and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, and MCI gel CHP20P (180
ml) (manufactured by Mitsubishi Chemical Industries, Ltd.) column chromatography,
Elutes with water. Adjust the eluate fraction to pH 10 with 1N sodium hydroxide solution and concentrate under reduced pressure to approximately 20 ml. The concentrated solution was subjected to Amberlite CG-50 (NH ⁺ ₄ type) (manufactured by Rohm and Haas) column chromatography (180 ml),
When eluted with water, N-(β-hydroxyphenethyl)variolamine is separated into two optical isomers and eluted. When the first eluted fraction is concentrated under reduced pressure and lyophilized, [α] ²⁶ _D -9.3° (c=1,
An isomer exhibiting H ₂ O) was obtained, and the fraction eluted later was concentrated under reduced pressure and lyophilized to obtain an isomer exhibiting [α] ²⁶ _D +15.8° (c = 1, H ₂ O). It will be done. Example 4 N-(D-gluco-2,3,4,5,6-pentahydroxyhexyl)valiolamine 1.0 g of varyolamine and D-glucose
Suspend 1.5 g in 9 ml of N,N-dimethylformamide and stir at 37°C for 6 hours. Acetone in the reaction solution
Add 90 ml and filter the resulting precipitate. 2.5 g of the obtained Schiff base was dissolved in 50 ml of water, 800 mg of sodium borohydride was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was adjusted to pH 4 with acetic acid and adsorbed onto a column of Dowex 50W x 8 (H ⁺ type, 75 ml) (manufactured by Dow Chemical). After washing the column with water, elute with 0.5N aqueous ammonia. After concentrating the eluted fraction under reduced pressure, the residue was washed with Dowex 1×2 (OH
250 ml column chromatography (manufactured by Dow Chemical Company) and eluted with water. The eluted fraction was concentrated under reduced pressure and then lyophilized to obtain N-(D-gluco-2,
3,4,5,6-pentahydroxyhexyl)variolamine is obtained. Yield: 1.6g. Elemental analysis: C ₁₃ H ₂₇ NO ₁₀・1/2H ₂ O Calculated value (%): C42.61; H7.70; N3.82 Experimental value (%): C42.54; H7.83; N3.83 [ α] ²⁶ _D −9.0° (c=1, H ₂ O) Example 5 N-(L-xylo-2,3,4,5-tetrahydroxy-1-hydroxymethylpentyl)variolamine Variolamine 2.0g and L-sorbose 4.4g
was dissolved in 50 ml of N,N-dimethylformamide,
Add 1.5 ml of 2N hydrochloric acid and 2.6 g of sodium cyanoborohydride, and stir at 60-70°C for 45 hours. After distilling off as much of the reaction solvent as possible under reduced pressure, the residue was dissolved in 100 ml of water and poured into a Dowex 50W x 8 (H ⁺ type).
(manufactured by Dow Chemical Company) and stirred for 30 minutes at room temperature. Another dowex 50W x 8 (H ⁺ type)
Pour the above mixture of aqueous solution and ion exchange resin into a chromatographic column packed with 150 ml, wash the column with water, and elute with 0.5N aqueous ammonia. After combining the elution fractions and concentrating under reduced pressure, Amberlite CG-
50 (NH ⁺ ₄ , 250 ml) (manufactured by Rohm and Haas) and eluted with water. The eluted fractions were combined and concentrated under reduced pressure, and then subjected to column chromatography (250 ml) using Dowex 1×2 (OH ^- type) (manufactured by Dow Chemical Company), eluted with water, and concentrated under reduced pressure. Freeze drying to obtain N-(L-xylo-2,3,4,5-tetrahydroxy-1-hydroxymethylpentyl)variolamine. Yield 375mg. Elemental analysis: C ₁₃ H ₂₇ NO ₁₀・1/2H ₂ O Calculated value (%): C42.61; H7.70; N3.82 Experimental value (%): C42.74; H8.04; N3.79 [ α〕 ²⁶ _D +23.8゜ (c=1, H ₂ O) Example 6 N-geranylvariolamine Dissolve 2.0g of variolamine in 55ml of N,N-dimethylformamide and add sodium bicarbonate.
Add 3.4 g and 5.5 ml of geranyl chloride, and stir at room temperature for 48 hours. The reaction solution is filtered, toluene is added to the filtrate, and the solvent is distilled off under reduced pressure. Add water to the residue, adjust the pH to 2, and wash with ethyl acetate. The aqueous layer was concentrated under reduced pressure, and the concentrated solution was subjected to MCI gel CHP20P (manufactured by Mitsubishi Chemical Industries, Ltd.) column chromatography (180 ml).
After washing with water, elute with a water-methanol gradient. The eluted fractions are collected and concentrated under reduced pressure, and the resulting aqueous solution is freeze-dried to obtain N-geranylvariolamine hydrochloride. Yield 2.3g. Elemental analysis: _{C17H31NO5 ・}HCl・_H2O Calculated value (%): C53.18; H8.92; N3.65; Cl9.24 Experimental _value (%): C52.92; H9.18; N3.29; Cl9.48 [α] ²⁶ _D +17.4゜ (c=1, H ₂ O) Example 7 N-(cyclohexylmethyl)variolamine Variolamine 2.0 was dissolved in dimethylformamide
Add 3.4 g of sodium hydrogen carbonate and 2.7 ml of cyclohexylmethyl bromide to the solution and heat at 60 to 70℃ for 40 minutes.
Stir for an hour. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. Water (80 ml) and ethyl acetate (80 ml) were added to the residue.
ml), adjust the pH to 2 with 2N hydrochloric acid, and distribute.
Separate the aqueous layer. After washing the aqueous layer with ethyl acetate, it is concentrated under reduced pressure, and the concentrated solution is subjected to MCI gel CHP20P (manufactured by Mitsubishi Chemical Industries, Ltd.) column chromatography (250 ml) and eluted with water. The eluted fraction was concentrated under reduced pressure, adjusted to pH 10 with N-sodium hydroxide solution, and applied to MCI gel again.
Subjected to CHP column chromatography (180 ml), washed with water, eluted with a gradient of water to 60% methanol, concentrated the eluted fraction under reduced pressure, and lyophilized to N-
(Cyclohexylmethyl)variolamine is obtained. Yield 220mg. Elemental analysis: C ₁₄ H ₂₇ NO ₅ Calculated value (%): C58.11; H9.41; N4.84 Experimental value (%): C58.09; H9.66; N4.71 [α] ²⁶ _D +3. 3゜(c=1, H ₂ O) Example 8 N-phenethylvariolamine 2.0g of variolamine was dissolved in 40ml of methanol, 5ml of a 50% diethyl phthalate solution of phenylacetaldehyde was added, and the mixture was dissolved at room temperature for 4 hours. Stir for an hour. After concentrating the reaction solution under reduced pressure, ethyl ether is added to the residue, and the resulting precipitate is collected by filtration and dried under reduced pressure.
The obtained Schiff base (3.0 g) was added to 25 ml of methanol.
Sodium borohydride dissolved in 400 ml of sodium borohydride under ice cooling
mg and stir for 6 hours. After adding water, acetone and n-butyl alcohol to the reaction solution, the organic solvent was distilled off under reduced pressure. The resulting aqueous solution was adjusted to PH2
After washing with ethyl acetate, the aqueous layer was concentrated under reduced pressure, and the concentrated solution was transferred to MCI Gel CHP20P (manufactured by Mitsubishi Chemical Corporation).
Column chromatography (250ml) and elute with water. The eluted fraction is concentrated under reduced pressure and then lyophilized to obtain 1.0 g of N-phenethylvariolamine hydrochloride. Elemental analysis: C ₁₅ H ₂₃ NO ₅・HCl・1/2H ₂ O Calculated value (%): C52.55; H7.35; N4.09; Cl10.34 Experimental value (%): C52.36; H7. 73; N4.13; Cl10.83 [α] ²⁶ _D +35.2゜ (c=1, H ₂ O) Example 9 N-(4-promobenzyl)variolamine Dissolve 900 mg of variolamine in 50 ml of methanol. 40 ml of dioxane, 1.6 ml of sodium bicarbonate
Add 3.0 g of p-bromobenzyl, and stir at room temperature for 20 hours. The reaction solution is filtered and insoluble matter is washed with methanol. The filtrate and washing liquid were combined and concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and while stirring, the pH was adjusted to 2 with 2N hydrochloric acid, and the aqueous layer was separated.
After washing with ethyl acetate, concentrate under reduced pressure. concentrate
Apply to column chromatography (300 ml) using MCI gel CHP20P (manufactured by Mitsubishi Chemical Industries, Ltd.), wash the column with water, and then
Elute with a methanol gradient. Combine the eluted fractions, distill off the methanol under reduced pressure, and adjust the concentrated solution to pH 10 to precipitate crystals. yield
750mg. When recrystallized from ethanol, N-(4-
Promobenzyl)variolamine is obtained as crystals. Melting point 206-208°C (decomposition). Elemental analysis: C ₁₄ H ₂₀ NO ₅ Br Calculated value (%):
C46.42; H5.57; N3.87; Br22.06 Experimental value (%):
C46.39; H5.49; N3.86; Br22.23 [α] ²⁴ _D +3.9゜(c=1,MeOH) As a result of crystal structure analysis, it was confirmed that it has the following structural formula. Example 10 N-(3-phenylallyl)variolamine 1.0 g of variolamine is dissolved in 20 ml of methanol, 1.3 ml of cinnamaldehyde is added, and the mixture is stirred at room temperature for 2 hours. The precipitated Schiff base was collected by filtration,
dry. Suspend 1.5 g of Schiff's base in 20 ml of methanol, and cool with ice to obtain 210 mg of sodium borohydride.
and stirred at the same temperature for 2 hours. water to the reaction solution,
Acetone and n-butyl alcohol are added, and the mixture is concentrated under reduced pressure to remove the organic solvent. pH of aqueous solution
2, washed with ethyl acetate, and the aqueous layer further
Concentrate under reduced pressure to 20ml. MCI gel concentrate
Apply to CHP20P (manufactured by Mitsubishi Chemical Industries) column chromatography (250 ml), wash with water, and elute with a water-methanol gradient. The eluted fraction is concentrated under reduced pressure and lyophilized to obtain N-(3-phenylallyl)variolamine hydrochloride. Yield: 1.3g. Elemental analysis: C ₁₆ H ₂₃ NO ₅・HCl・1/2H ₂ O Calculated value (%): C54.16; H7.10; N3.95; Cl9.99 Experimental value (%): C54.22; H7. 14; N4.04; Cl10.45 [α] ²⁶ _D +36.0゜ (c=1, H ₂ O) Example 11 N-Furfurylvariolamine Dissolve 1.0g of variolamine in 15ml of methanol, - Add 1 ml of furaldehyde and let it cool at room temperature.
Stir for 2.5 hours. The reaction solution was concentrated under reduced pressure, ethyl ether was added to the residue, and the resulting precipitate was collected by filtration.
dry. 1.33 g of the obtained Schiff base was suspended in 15 ml of methanol, 200 mg of sodium borohydride was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Water, acetone and n-butyl alcohol were added to the reaction solution, and the mixture was concentrated under reduced pressure to remove the organic solvent. The resulting aqueous solution was applied to MCI gel CHP20P (manufactured by Mitsubishi Chemical Industries, Ltd.) column chromatography (180 ml), washed with water, and then washed with water.
Elute with a 60% methanol/water gradient. The eluted fraction is concentrated under reduced pressure and then lyophilized to obtain 1.1 g of N-furfurylvariolamine. Elemental analysis: C ₁₂ H ₁₉ NO ₆ Calculated value (%): C52.74; H7.01; N5.13 Experimental value (%): C52.68; H7.25; N5.38 [α] ²⁶ _D +20. 1° (c=1, H ₂ O) Example 12 N-thenylvariolamine 1.0 g of variolamine is dissolved in 20 ml of methanol, 1.0 ml of thiophenecarbaldehyde is added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated, ethyl ether is added, and the resulting precipitate is collected by filtration and dried. 1.35 g of the obtained Schiff base was added to 50 ml of methanol.
210 mg of sodium boron is added under ice water, and the mixture is stirred at room temperature for 4 hours. After adding water, acetone and n-butyl alcohol to the reaction solution, the mixture was concentrated under reduced pressure to remove the organic solvent. Apply the concentrated solution to a 180 ml chromatograph using MCI Gel CHP20P (manufactured by Mitsubishi Chemical Industries, Ltd.), wash the column with water, and elute with a water-methanol gradient. When the eluted fraction was concentrated under reduced pressure, 2
-Crystals of thenylvariolamine precipitate. Yield 500mg. An additional 550 mg is recovered from the mother liquor. Elemental analysis: C ₁₂ H ₁₉ NO ₅ S Calculated value (%): C49.81; H6.62; N4.84; S11.08 Experimental value (%): C49.87; H6.59; N4.18; S11 .06 [α] ²⁶ _D +25.6° (c=1, H ₂ O) Example 13 N-(3-pyridylmel)variolamine Dissolve 1.0g of variolamine in 10ml of methanol, and add 0.6ml of nicotinaldehyde. Add and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl ether was added to the residue to form a precipitate. Remove the supernatant and dry the precipitate. The resulting Schiff base
Add 15 ml of methanol to 1.5 g, add 270 mg of sodium borohydride under ice water, stir at the same temperature for 1 hour, add 5 ml of water, and stir at room temperature for 1 hour. Water, acetone and n-butyl alcohol were added to the reaction solution, and the mixture was concentrated under reduced pressure to remove the organic solvent. The obtained aqueous solution was subjected to MCI gel CHP20P (manufactured by Mitsubishi Chemical Industries, Ltd.) column chromatography (250 ml),
After washing with water, elute with a water-60% methanol/water gradient. After concentrating the eluted fraction under reduced pressure, it was subjected to column chromatography (250 ml) using Dowex 1×2 (OH ^- type) (manufactured by Dow Chemical Company) and eluted with water. After concentrating the eluted fraction under reduced pressure and lyophilizing it, N-(3-
pyridylmethyl)variolamine is obtained. yield
0.6g. Elemental analysis: C ₁₃ H ₂₀ N ₂ O ₅・H ₂ O Calculated value (%): C51.64; H7.34; N9.27 Experimental value (%): C51.91; H7.42; N8.92 [ α] ²⁶ _D +9.2° (c=1, H ₂ O) Example 14 N-(2-hydroxy-3-phenoxypropyl)variolamine In an aqueous solution (10 ml) of 2.2 g of sodium hydroxide,
Dissolve 4.7 g of phenol in a nitrogen stream, add 5 g of epichlorohydrin, and stir at room temperature for 24 hours. Add 50ml of water to the reaction solution and add 50ml of dichloromethane.
Extract twice. The dichloromethane layer was washed with water, dried over sodium sulfate, and the solvent was distilled off to give 1-
Phenoxy-2,3-epoxypropane and 1
7 g of a mixture of -chloro-2-hydroxy-3-phenoxypropane are obtained. Dissolve 2.0 g of variolamine in 55 ml of N,N-dimethylformamide and add sodium bicarbonate.
After adding 5.8g, the above 1-phenoxy-2,
7g mixture of 3-epoxypropane and 1-chloro-2-hydroxy-3-phenoxypropane
and stir for 5 hours at a bath temperature of 90°C. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to remove the solvent.
Add water and n-butyl alcohol to the residue,
Adjust the pH to 2 with 2N hydrochloric acid, and remove the n-butyl alcohol layer after distribution. The water washes of the aqueous layer and n-butyl alcohol layer are combined, concentrated under reduced pressure, and then subjected to column chromatography using MCI gel CHP20P (250 ml) (manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with water. After concentrating the eluted fraction under reduced pressure and lyophilizing it, N-(2-hydroxy-
540 mg of white powder of variolamine hydrochloride (3-phenoxypropyl) was obtained. Elemental analysis: C ₁₆ H ₂₅ NO ₇・HCl・1/2H ₂ O Calculated value (%): C49.42; H7.00; N3.60; Cl9.12 Experimental value (%): C49.11; H7. 45; N3.79; Cl9.59 [α] ²⁴ _D +15.3゜ (c=1, H ₂ O) Example 15 Add 7 kg of sugar to 10 kg of fresh strawberries according to the usual method,
Bring to a boil while stirring. When the product temperature has decreased by about 50°C, N-(β-hydroxyphenethyl)variolamine is uniformly mixed in at a ratio of 0.5% to the product weight, and then cooled to obtain a strawberry jam product. Example 16 N-(1,3-dihydroxy-2-propyl)variolamine for 200 ml of fruit juice beverage
Add 100 mg and stir to dissolve uniformly to obtain a fruit juice-containing beverage. Example 17 N-phenethylvariolamine hydrochloride
20 parts by weight of lactose, 80 parts by weight of crystalline cellulose are mixed, kneaded with water, dried and made into a powder or fine granules.

Claims (1)

[Claims] 1. General formula [Wherein A is a chain hydrocarbon group having 1 to 10 carbon atoms that may have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.) show. ] Variolamine derivative or its hydrate or acid addition salt. 2. A chain aldehyde or ketone having 1 to 10 carbon atoms that can have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.) and variolamine. General formula characterized by reacting and then subjecting to reduction reaction [Wherein A is a chain hydrocarbon group having 1 to 10 carbon atoms that may have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.) show. ] A method for producing a variolamine derivative or its hydrate or acid addition salt. 3 General formula [Wherein, R is a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with a halogen, etc.), and W is a divalent chain hydrocarbon having 1 to 8 carbon atoms. group, n represents 0 or 1. A general formula characterized by reacting an oxirane derivative represented by ] with variolamine [In the formula, A' is a hydroxyl group, phenoxy, thienyl,
It represents a chain hydrocarbon group having 2 to 10 carbon atoms that may have furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.). ] A method for producing a variolamine derivative or its hydrate or acid addition salt. 4. A chain hydrocarbon halide having 1 to 10 carbon atoms that can have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.) and variolamine. General formula characterized by reaction [Wherein A is a chain hydrocarbon group having 1 to 10 carbon atoms that may have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.) show. ] A method for producing a variolamine derivative or its hydrate or acid addition salt. 5 General formula [Wherein A is a chain hydrocarbon group having 1 to 10 carbon atoms that may have a hydroxyl group, phenoxy, thienyl, furyl, pyridyl, cyclohexyl, or phenyl (the phenyl may be substituted with halogen, etc.) show. ] An α-glucosidase inhibitor containing a variolamine derivative or its hydrate or acid addition salt.