JP2005041817A - Curcuminoid glycoside and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new curcuminoid glycoside, a coloring matter composition containing the glycoside and a medicine composition for allergic treatment containing the curcuminoid glycoside, etc., and to provide a method for efficiently producing various curcuminoid glycosides. <P>SOLUTION: The curcuminoid glycoside is represented by formula (I) (when R<SP>1</SP>is a methoxy group, R<SP>3</SP>is a methoxy group or hydrogen and when R<SP>1</SP>is hydrogen, R<SP>3</SP>is hydrogen, R<SP>2</SP>is hydrogen, a sugar residue or an acetylated sugar residue, R<SP>4</SP>is a sugar residue or an acetylated sugar residue, R<SP>5</SP>and R<SP>6</SP>are each an oxygen functional group or hydrogen). The method for producing the curcuminoid glycoside comprises reacting a phenolic hydroxy group-containing benzaldehyde compound with an acetylacetone-B<SB>2</SB>O<SB>3</SB>complex and removing boron from the reaction product in the presence of an alcohol solvent. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel curcuminoid glycoside and a method for producing the same. More specifically, the present invention relates to a method for producing a wide range of curcuminoid glycosides, including novel curcuminoid glycosides, tetrahydrocurcuminoid glycosides, and curcumin glycosides.

  Curcumin, a kind of curcuminoid and contained in turmeric, has long been used as a yellow dye, antibacterial drug and the like. Further, among curcuminoids, active oxygen removal action (Non-Patent Document 2), anti-inflammatory action (Non-Patent Document 3), cholesterol lowering (Non-Patent Documents 4 and 5), anti-tumor (Non-Patent Documents 6 and 7), Some have antiallergic action (Non-patent Document 8) and nematicidal action (Non-patent Document 10). However, since curcuminoids are generally poorly soluble in water, their use has been limited, and in particular, their use as pharmaceuticals has been limited.

  The curcuminoid can be synthesized by reacting a predetermined 2,4-diketone and an aromatic aldehyde in the presence of boron oxide, trialkoxyboron, and an organic amine catalyst (Non-patent Document 9). In order to obtain a glycoside having a sugar at its hydroxyl group in order to make it water-soluble, the conventional method uses hydrochloric acid to remove boron compounds and neutralize organic amino acids. There was a problem that the group was cleaved.

A method for producing curcumin diglucoside and curcumin monoglucoside by reacting curcumin and acetobromoglucose in the presence of benzyltriethylammonium bromide and then deacetylating was developed. It was quite low (Patent Document 1). Moreover, since this method is a method in which acetobromoglucose is directly reacted with curcumin, it has been difficult to use it for the production of glycosides of other curcuminoids.
International Publication No. 02/02582 (Hergenhahn M.et.al) Asai Akira et al., Research paper; Absorption metabolism of food yellow pigment curcuminoids and body fat accumulation inhibitory effect, FOODS & FOOD INGREDIENTS JOURNAL OF JAPAN, Vol.208, No.2, pp95-105 (2003) Sreejayan AM, Rao MN, J. Pharm. Pharmacol., 46, 1013-1016 (1994). Srimal RC, Dhawan BN, J. Pharm. Pharmacol., 25, 447-452 (1973) Rao DS, Sekhara NC, Satyanarayana MN, Srinivasan M., J. Nutr., 100, 1307-1316 (1970). Babu PS, Srinivasan K., Mol.Cell.Biochem., 166 169-175 (1997). Samaha HS, Kellof GJ, Steele V., Rao CV, Reddy BS, Cancer Res., 57, 1301-1305 (1997). Huang MT, Lou YR, Newmark HL, Reuhi KR, Conney AH, Cancer Res., 54, 5841-5847 (1994). Yano S. et.al.Natural Medicines (Tokyo), 54, 325-329 (2000). Roughley PJ, Whiting DA, JCS Perkin Trans I, 2379-2383 (1973) Kiuchi F., Goto Y., Sugimoto N., Akao N., Kondo K., Tsuda Y., Chem. Pharm. Bull., 41 (9), 1640-1646 (1993).

  The present invention provides novel curcuminoid glycosides and tetrahydrocurcuminoid glycosides that could not be produced so far, and can efficiently produce a wide range of curcuminoid glycosides including curcumin glycosides. It aims to provide a method.

As a result of studies conducted by the present inventors to solve the above-mentioned problems, a glycoside-modified aromatic aldehyde compound is used as a starting material and condensed with an acetylacetone-boron oxide complex to form a curcuminoid glycoside, and a reaction product The present inventors have found that a wide range of curcuminoid glycosides can be efficiently produced by removing boron by heating with a lower alcohol. The present invention has been completed based on this finding.
Accordingly, the present invention provides a curcuminoid glycoside of the following formula (I), or a physiologically acceptable salt thereof:

(Wherein R1 is a methoxy group, R3 is a methoxy group or hydrogen, R1 is hydrogen, R3 is hydrogen, R2 is hydrogen, a sugar residue or an acetylated sugar residue, and R4 Is a sugar residue or an acetylated sugar residue, and R5 and R6 are oxygen functional groups or hydrogen).
The present invention also provides a tetrahydrocurcuminoid glycoside of the following formula (II) or a physiologically acceptable salt thereof:

(In the formula, when R7 is a methoxy group, R9 and R11 are both methoxy groups or hydrogen, and when R7 is hydrogen, R9 and R11 are both hydrogen, and R8 is hydrogen or a sugar residue. And R10 is a sugar residue.);
Furthermore, the present invention provides a curcuminoid glycoside comprising reacting a benzaldehyde compound having a phenolic hydroxyl group and an acetylacetone-B ₂ O ₃ complex, and deboronating the reaction product in the presence of an alcohol solvent. A method for manufacturing a body is provided.

Furthermore, the present invention provides a benzaldehyde compound having a phenolic hydroxyl group, a benzaldehyde compound of the following formula (III), or a mixture of the benzaldehyde compounds of the following formulas (III) and (IV), and an acetylacetone-B ₂ O ₃ complex: There is provided a method for producing a curcuminoid glycoside comprising reacting and deboronating the reaction product in the presence of an alcohol solvent.

  (Wherein R12 is hydrogen, oxygen functional group, amino group, amide group or halogen, and R13 is a sugar residue, and R14 is hydrogen, oxygen functional group, amino group, amide group or halogen. );

(Wherein R15 and R16 are each independently hydrogen, oxygen functional group, amino group, amide group or halogen);
Furthermore, the present invention provides a dye composition comprising at least one selected from the group consisting of the curcuminoid glycoside and a salt of the curcuminoid glycoside.
Furthermore, the present invention provides a pharmaceutical composition comprising at least one selected from the group consisting of the curcuminoid glycoside, the tetrahydrocurcuminoid glycoside, and a physiologically acceptable salt of the glycoside. To do.
As used herein, the term “oligosaccharide residue” refers to a residue of a sugar molecule in which 2 to 20 monosaccharides are polymerized.

The term “acetylated sugar residue” used in the present invention refers to a group in which the hydrogen atom of the OH group of a monosaccharide or oligosaccharide is replaced with an acetyl group. The basic monosaccharide or oligosaccharide is an ordinary sugar residue. Same as group.
The term “curcuminoid” used herein means curcumin (* 1), demethoxycurcumin (* 2), bisdemethoxycurcumin (* 3) and analogs thereof.
* 1) 1,7-bis- (4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione
* 2) 1- (4-Hydroxy-3-methoxyphenyl) -7- (4-hydroxyphenyl) -1,6-heptadiene-3,5-dione
* 3) 1,7-bis (4-hydroxyphenyl) -1,6-heptadiene-3.5-dione

  The present invention provides novel curcuminoid glycosides and tetrahydrocurcuminoid glycosides that could not be produced so far, and the production method of the present invention efficiently uses a wide range of curcuminoid glycosides including curcumin glycosides. Have the effect of producing the same.

BEST MODE FOR CARRYING OUT THE INVENTION

  In the formula (I) representing the curcuminoid glycoside of the present invention, the sugar residues R2 and R5 represent monosaccharide residues or oligosaccharide residues. Examples of the monosaccharide residue include hexose or pentose monosaccharide residues. The hexose residue includes a glucosyl group, a galactosyl group, a mannosyl group, and a fructosyl group, and the pentose residue includes a lyxosyl group, a xylosyl group, an arabinosyl group, and a ribosyl group. Also preferred as oligosaccharides are maltose and lactose.

Specific examples of the curcuminoid glycoside of the present invention include the following.
Diglucosil-Lucmine Octaacetate Diglucosyl-bis-demethoxycurcumin Octaacetate Digalactosilkrucumin Octaacetate Monoglucosyl-Lucmine Tetraacetate Monoglucosyl-bis-demethoxycurcumin Tetraacetate Monogalactosyl-Lucmine Tetraacetate Diglucosyl-Lucmine Diglucosyl-bis-demethoxycurcumin Di Galactosylrucumin Monoglucosilcumin Monoglucosyl-bis-demethoxycurcumin Monogalactosilcumin In formula (II) representing the tetrahydrocurcuminoid glycoside of the present invention, the sugar residues R8 and R10 are monosaccharide residues or oligosaccharide residues. There is a group. Examples of the monosaccharide residue include hexose or pentose monosaccharide residues. The hexose residue includes a glucosyl group, a galactosyl group, a mannosyl group, and a fructosyl group, and the pentose residue includes a lyxosyl group, a xylosyl group, an arabinosyl group, and a ribosyl group. Also preferred as oligosaccharides are maltose and lactose.

Specific tetrahydrocurcuminoid glycosides of the present invention include the following.
Diglucosyltetrahydrocurcumin Monoglucosyltetrahydrocurcumin The curcuminoid glycoside and tetrahydrocurcuminoid glycoside of the present invention are basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, carbonate Salts can be formed using sodium hydrogen, potassium hydrogen carbonate, magnesium hydroxide, and the like. The salt can be formed by a conventional method.
The present invention provides a dye composition comprising at least one selected from the curcuminoid glycosides.
When the dye composition of the present invention is prepared, the curcuminoid glycoside is pulverized with a powder or mixed into an aqueous solution and then dried to obtain a desired form such as granule or fine powder. Moreover, the pigment composition of the present invention may contain other components as long as the properties of the curcuminoid glycoside, which is the main component, are not impaired.

Conventionally, curcuminoid compound-based yellow pigments are poorly water-soluble, but the curcuminoid glycosides contained in the pigment composition of the present invention are water-soluble and can be used without limitation for many applications. For example, coloring of foods and drinks, cosmetics, fragrances, pharmaceuticals and the like.
Examples of foods and drinks for which the coloring composition of the present invention can be used include fruitless beverages, fruit juice-containing beverages, lactic acid bacteria beverages, tea beverages, coffee beverages, soy milk beverages, soups and other beverages; ice cream, There are frozen desserts such as sherbet and sleet; dessert foods such as pudding, bavaroa, jelly, yogurt and other instant foods The amount of the dye composition of the present invention to be added to these foods and drinks is not particularly limited and can be selected according to the type of the food or drink. Generally, curcuminoid glycosides are It is preferable to add 0.005 to 1.0% by weight of the food or drink.

  Examples of the cosmetic include cosmetics for hair, face and skin, perfume products such as perfume and colon, and oral products such as mouthwash and toothpaste. The addition amount of the dye composition of the present invention is not particularly limited, and can be selected according to the type of the cosmetic, but is generally added to be 0.1 to 1.0% by weight of the cosmetic. Is preferred.

  When the curcuminoid glycoside and tetrahydrocurcuminoid glycoside of the present invention are used as a pharmaceutical composition, for example, a pharmaceutical composition for allergy treatment, they can be administered orally or parenterally. For oral administration, hard capsule, soft capsule, tablet, granule, granule, powder, fine granule, pill, troche tablet, active ingredient continuous release agent, elixir, emulsion, syrup, liquid, It can be dispensed in the form of a suspension or the like. For parenteral administration, administration by infusion, intravenous injection, subcutaneous injection, intramuscular injection, etc., transdermal administration by external preparations such as ointments and transdermal agents, oil suppositories, water-soluble suppositories, suppositories It can be in the form of rectal administration, eye drops and the like. In addition, the preparation can be easily performed by a conventional method using a normal carrier in the pharmaceutical field.

  When the pharmaceutical composition of the present invention is formulated into an oral dosage form, it is generally used for pharmaceutical ingredients such as carriers, for example, fillers, extenders, binders, disintegrants, disintegration inhibitors, buffers, isotonic agents. Agents, emulsifiers, dispersants, stabilizers, coating agents, surfactants, absorption promoters, humectants, wetting agents, adsorbents, lubricants, excipients, and the like can be used. Moreover, you may use additives, such as a coloring agent, a preservative, a fragrance | flavor, a flavor agent, and a sweetener, as needed.

  Specific examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, simple syrup, glucose solution, starch solution, Gelatin solution, binders such as carboxymethylcellulose, ceramic, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate , Disintegrating agents such as stearic acid monoglyceride, starch, lactose, sucrose, stearic acid, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium salts, absorption promoters such as sodium lauryl sulfate, glycerin Moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, and the like lubricants such as stearic acid salts.

  Moreover, although the dosage of the curcuminoid glycoside of the present invention varies depending on the age, weight, symptoms, dosage form, treatment period, etc. of the patient, the curcuminoid glycoside is 0.01 to 1000 mg / kg body weight / day, Preferably, the dose is administered once a day or in multiple doses so that the dose is 1.00 to 500 mg / kg body weight / day.

When the pharmaceutical composition for treatment of allergy of the present invention is used in the form of an external preparation, it is applied as a liquid preparation such as lotion, suspension, emulsion, etc., as a paste preparation such as gel, cream, ointment, etc. Can be applied. The dosage form to be applied can be appropriately selected according to the age, sex, constitution, symptom, timing of treatment, etc. of the patient.
The external preparation is produced by a conventional method by appropriately blending the curcuminoid glycoside, tetrahydrocurcuminoid glycoside of the present invention, and / or physiologically acceptable salts thereof with normal pharmaceutical ingredients. be able to.

  Examples of pharmaceutical ingredients that can be used in the present invention include purified water, buffer solutions such as phosphate buffer, physiological saline solutions such as physiological saline, Ringer's solution, lock solution, lanolin, mink oil, horse oil. , Almond oil, castor oil, jojoba oil, medfoam oil, olive oil, sesame oil, cocoa butter and other animal and vegetable oils, mineral oil, polyoxyethylene polyoxypropylene glycol, isopropyl myristate, isopropyl palmitate, cetostearyl isooctanoate, isostearic acid Synthetic oils such as alkyl esters, sterols such as cholesterol, lanolin alcohol, phytosterols, waxes such as solid paraffin, ceresin, whale wax, beeswax, carnauba wax, hydrocarbon oils such as liquid paraffin, squalane, lauric acid, stearic acid, Oh Higher fatty acids such as inic acid, lower alcohols such as ethanol, higher alcohols such as lauryl alcohol, cetanol, cetostearyl alcohol, and oleyl alcohol, polyhydric alcohols such as glycerin, sorbit, propylene glycol, and 1,3-butylene glycol Polyoxyethylene alkyl ether sulfate, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, N-coconut oil fatty acid acyl-L-glutamate, polyoxyethylene higher alcohol ether, polyoxyethylene Surfactants such as higher fatty acid esters, polyoxyethylene hydrogenated castor oil, moisturizers such as hyaluronate, pyrrolidone carboxylate, hydrolyzed collagen solution, seaweed extract, carrageenan, xanthan Arm, polyvinyl alcohol, and the like thickeners such as carboxyvinyl polymers.

  Moreover, various additives can be added as needed. Examples of such additives include alkyl oxybenzoates, cetylbilidinium chloride, benzalkonium chloride, alkyltrimethylammonium chloride, phenoxyethanol, triclosan, trichlorocarbanilide, zinc pyrithione and other antiseptics, bactericides, BHT , BHA, Vitamin A, C, E, and other antioxidants, benzophenone derivatives, paraaminobenzoic acid derivatives, methoxycinnamic acid derivatives, ultraviolet absorbers such as urocanic acid, and cation rinses such as cationized dextran Agents, talc, kaolin, mica, bentonite, mica, mica titanium, titanium oxide, bengara, iron oxide and other pigments, fragrances and the like.

The concentration of the curcuminoid glycoside contained in the external preparation varies depending on the administration form, the type and degree of disease, the target dose, etc., but is generally 0.1 to the total weight of the external preparation. 90%, preferably 1-80%.
The amount of the glycoside administered by the external preparation varies depending on the age, weight, symptoms, administration mode, treatment period, etc. of the patient, but is 0.01 to 1000 mg / kg body weight / day as a curcuminoid glycoside. In such a range, the dose is administered once a day or in multiple doses.
Next, a method for producing the curcuminoid glycoside and tetrahydrocurcuminoid glycoside of the present invention will be described.
In the method for producing curcumin glycosides of M. Hergenhahn et al. Disclosed in Patent Document 1, as shown in the reaction diagrams of FIGS. 2 and 3, curcumin is present in the presence of a phase transfer catalyst in each step (1). And α-acetylbromose glucose are condensed to obtain curcumin monoglycoside and diglycoside, but the yields are considerably low, 8% and 3%, respectively. In addition, since the bromose glucose is directly reacted with curcumin in this method, it is difficult to produce other curcuminoid derivatives even though curcumin glycosides can be synthesized.

  On the other hand, in the production method of the present invention, as shown in FIG. 1, a curcuminoid monoglycoside is obtained by performing a condensation reaction between the aromatic aldehyde previously glycosylated in step (1) and an acetylacetone-boron oxide complex. Alternatively, the diglycoside can be selectively obtained in a good yield. The step (1) is an application of the method of Whiting et al. (Non-patent Document 9). In addition, in the step (2) for removing boron, since the conventional method used hydrochloric acid, the sugar residue was cleaved and the glycoside was easily decomposed. In contrast, in the method of the present invention, the reaction product of step (1) is heated with an alcohol solvent in step (2) to remove boron, thereby preventing decomposition of the obtained glycoside and curcuminoid It made it possible to produce glycosides.

In step (2) of FIG. 1, boron is heated in alcohol, for example, trimethyl borate (B (OMe) ₃ ) when methanol is used, and is distilled off together with the solvent by distillation. By adding sodium hydroxide to the distillate and heating, (B (OMe) ₃ ) is decomposed and regenerated to methanol. Therefore, the alcohols can be collected and reused without being consumed. In the step (2) in FIG. 1, when other lower alcohols such as ethanol, propanol, mixed solutions of these and other lower alcohols, or mixed solutions with other solvents containing these lower alcohols are used. Gives similar results.

Although the benzaldehyde compound having a phenolic hydroxyl group used in the production method of the present invention varies depending on the target compound, the method (A) using only a glycated benzaldehyde compound, a glycated benzaldehyde compound, a sugar There is a method (B) using a mixture of benzaldehyde compounds having no residue.
The benzaldehyde compound compound used in the present invention includes a benzaldehyde compound represented by the following formula (III).

In formula (III), R12 is hydrogen, oxygen functional group, amino group, amide group or halogen, and R13 is a sugar residue, and R14 is hydrogen, oxygen functional group, amino group, amide group or halogen. is there. Examples of the monosaccharide residue include hexose or pentose monosaccharide residues. The hexose residue includes a glucosyl group, a galactosyl group, a mannosyl group, and a fructosyl group, and the pentose residue includes a lyxosyl group, a xylosyl group, an arabinosyl group, and a ribosyl group. Also preferred as oligosaccharides are maltose and lactose.
The benzaldehyde compound used in the method (B) of the present invention includes a benzaldehyde compound represented by the following formula (IV).

In the formula (IV), R15 and R16 are each independently hydrogen, oxygen functional group, amino group, amide group or halogen.
Next, a process for producing a curcuminoid diglycoside by the method (A) of the present invention will be described. The method is illustrated in FIG. In the method, first, in step (1), tributyl borate (BuO) ₃ B, acetylacetone-B ₂ O ₃ complex, and butylamine are added to the benzaldehyde compound that has been glycosylated, and at room temperature, preferably 15 to The reaction is carried out at 25 ° C. for 5 to 40 hours, preferably 10 to 20 hours. The reaction forms the curcuminoid-boron complex of FIG.

In this case, 1 to 5 mol, preferably 2 to 4 mol of tributyl borate, 0.4 to 0.8 mol of acetylacetone-B ₂ O ₃ complex, preferably 0.4 to 1 mol with respect to 1 mol of the benzaldehyde compound. 0.6 mol and 0.05 to 0.2 mol of butylamine, preferably 0.05 to 0.15 mol are added.
Then, the obtained curcuminoid-boron complex is obtained in the presence of an alcohol solvent.
Boron is removed by refluxing at a temperature of 50 to 100 ° C, preferably 80 to 85 ° C. The alcohol solvent used here is preferably a lower aliphatic alcohol such as methyl alcohol, ethyl alcohol or propyl alcohol.

After removing boron, curcuminoid glycoside obtained by treatment at 10-30 ° C., preferably 15-25 ° C. in an alcohol solvent containing 3-10% ammonia, preferably 4-6% Deacetylate the body.
Next, a process for producing a curcuminoid glycoside by the method (B) of the present invention will be described. In this method, as shown in FIG. 5, three types of monoglycoside, diglycoside and curcuminoid having no sugar residue are synthesized, and thus separated and purified as necessary. First, in step (1) of the method, a mixture of a glycosylated benzaldehyde compound and a benzaldehyde compound having no sugar residue, tributyl borate (BuO) ₃ B, acetylacetone-B ₂ O ₃ complex, and Add butylamine to react. The mixture of the obtained curcuminoid-boron complex was refluxed in the presence of an alcohol solvent to remove boron, and from the reaction product, a monoglycoside tetraacetate and a diglycoside octaacetate were obtained in a conventional manner. The body is separated and treated in an alcohol solvent containing ammonia to deacetylate to obtain curcuminoid mono- and diglycosides. The reaction conditions and reagents used in the production method may be the same as those in the method (A) for obtaining the diglycoside.

Next, a method for producing a tetrahydrocurcuminoid glycoside will be described.
Curcuminoids are known to be metabolized to tetrahydrocurcuminoids in the living body by reducing the olefin moiety (Holder GM et al., J., Xenobiotica, 8, 61-68 (1978)). Then, it is reported that curcumin has an improved ability to remove active oxygen (Sugiyama Y et al., Biochem Pharmacol., 52, 519-525 (1996)).

  The tetrahydrocurcuminoid glycoside of the present invention can be produced by hydrogenation by reduction contact in an organic solvent in the presence of activated carbon containing a platinum group element such as palladium or platinum. The organic solvent used in the method is, for example, a low molecular alcohol such as methyl alcohol or ethyl alcohol.

Synthesis of tetra-O-acetyl-β-D-glucopyranosylvanillin (compound 1)
Compound 1 which is a glycosylated aromatic aldehyde was synthesized by the method of Kreger R. et al. Disclosed in JP-A No. 2000-109494. That is, 13.6 g of vanillin and 18.3 g of acetobromoglucose are subjected to a condensation reaction for 1 hour at room temperature in 150 ml of chloroform-1N aqueous sodium hydroxide solution together with 14.6 g of tetrabutylammonium bromide as a phase transfer catalyst. Was synthesized.

The analytical values of the obtained compound were as follows.
mp 135-137 ° C (lit. mp 142 ° C); ¹ H-NMR δ: 9.90 (1H, s, CHO), 7.47-7.16 (3H, m, Ar-H), 5.35-5.06 (4H, m, Glc-H), 4.28-4.22 (2H, m, Glc-H), 3.90 (3H, s, OMe), 2.07-2.05 (12H, OAc).

Synthesis of tetra-O-acetyl-β-D-glucopyranosyl-4-hydroxy-benzaldehyde (compound 2)
Compound 2 which is an aromatic aldehyde glycosylated was obtained in the same manner as in Example 1 except that 4-hydroxybenzaldehyde was used instead of vanillin. The analytical values of the obtained compound were as follows.

mp 142-143 ° C (lit. mp 145-147 ° C); ¹ H-NMR δ: 9.93 (1H, s, CHO), 7.86 (2H, d, J = 8.6 Hz, Ar-H), 7.11 (2H, d, J = 8.6 Hz, Ar-H), 5.34-5.16 (4H, m, Glc-H), 4.33-4.16 (2H, m, Glc-H), 3.97-3.92 (1H, m, Glc-H) , 2.08-2.05 (12H, OAc).

Synthesis of tetra-O-acetyl-β-D-galactopyranosylvanillin (compound 3)
Compound 3 which is an aromatic aldehyde glycosylated in the same manner as in Example 1 was obtained except that 18.3 g of acetobromogalactose was used instead of acetobromoglucose. The analytical values of the obtained compound were as follows.

Mp 124-125 ° C (lit. mp 123-124 ° C); ¹ H-NMR δ: 9.90 (1H, s, CHO), 7.43-7.22 (3H, m, Ar-H), 5.59- 5.46 (2H, m, Gal-H), 5.15-5.05 (2H, m, Gal-H), 4.28-4.14 (3H, m, Gal-H), 3.90 (3H, s, OMe), 2.18-2.03 ( 12H, OAc).

Synthesis of diglucosilkrucumin octaacetate (compound 4)
Reaction of 2.5 g of acetylacetone and 1.5 g of boron oxide at room temperature for 30 minutes to form an acetylacetone-boron complex in which 30 ml of an ethyl acetate solution containing 2.4 g of compound 1 and 2.5 ml of tributyl borate Then, 0.05 ml of n-butylamine was added and stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, 200 ml of methyl alcohol was added and refluxed for 4 hours. After removing boron from the reaction system as trimethylborate, the unreacted raw material and amine were separated by silica gel chromatography. The target compound 4 was obtained with a yield of 51%. The analytical values of the obtained compound were as follows.

Yellow amorphous powder; mp 172-174 ° C; IR (KBr): 3450, 1760, 1630 cm ^-1 .; ¹ H-NMR δ: 7.59 (2H, d, J = 15.6 Hz, H-1, 7 ), 7.27-7.10 (6H, m, Ar-H), 6.56 (2H, d, J = 15.6 Hz, H-2, 6), 5.84 (1H, s, H-4), 5.26-5.06 (10H, m, Glc-H), 4.32-4.15 (4H, m, Glc-H), 3.87 (6H, s, OMe), 2.08-2.04 (24H, m, OAc).

Synthesis of diglucosyl-bis-demethoxycurcumin octaacetate (compound 5)
Compound 5 was obtained in a yield of 51% in the same manner as in Example 4 except that 2.26 g of Compound 2 was used instead of Compound 1. The analytical values of the obtained compound were as follows.
Yellow amorphous powder; mp 185-188 ° C; IR (KBr): 1760, 1740 cm ^-1 ; ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 7.61 (2H, d, J = 15.6 Hz, H-1, 7), 7.52, 7.01 (each 4H, d, J = 8.7 Hz, Ar-H), 6.53 (2H, d, J = 15.6 Hz, H-2, 6), 5.82 (1H, s, H-4), 5.35-3.87 (14H, m, Glc-H), 2.30-2.06 (24H, m, OAc).

Synthesis of digalactosilcumin octaacetate (Compound 6)
Compound 6 was obtained in a yield of 56% in the same manner as in Example 4 except that 2.4 g of Compound 3 was used instead of Compound 1. The analytical values of the obtained compound were as follows.
Amorphous yellow powder; mp 102-105 ℃; IR (KBr ):. 1770, 1740 cm -1; 1 H-NMRδ: 7.60 (2H, d, J = 15.8 Hz, H-1, 7), 7.12 -7.08 (6H, m, Ar-H), 6.53 (2H, d, J = 15.8 Hz, H-2, 6), 5.85 (1H, s, H-4), 5.56-5.45 (4H, m, Gal -H), 5.14-4.96 (4H, m, Gal-H), 4.25-4.02 (6H, m, Gal-H), 3.88 (6H, s, OMe), 2.18-2.02 (24H, m, OAc)

Synthesis of monoglucosilkrucumin tetraacetate (compound 7)
The reaction was performed in the same manner as in Example 4 except that equimolar compound 1 (1.2 g) and vanillin (0.383 g) were used. As a result of purification and separation of the product, the target compound 7, curcumin and compound 4 could be obtained in yields of 34%, 15% and 4%, respectively. The analytical value of the obtained compound 7 was as follows.

mp 86-88 ° C; IR (KBr): 3420, 1750 cm ^-1 ; ¹ H-NMR δ: 7.61, 7.56 (each 1H, d, J = 15.8 Hz, H-7 and H-1), 7.12-6.91 ( 6H, m, Ar-H), 6.52, 6.47 (each 1H, d, J = 15.6 Hz, H-6 and H-2), 5.81 (1H, s, H-4), 5.31-4.15 (7H, m , Glc-H), 3.94, 3.86 (each 3H, s, OMe), 2.09-2.05 (12H, m, OAc)

Synthesis of monoglucosyl-bis-demethoxycurcumin tetraacetate (compound 8)
The reaction was performed in the same manner as in Example 4 except that equimolar compound 2 (1.13 g) and 4-hydroxybenzaldehyde (0.305 g) were used. As a result of purification and separation of the product, the target compound 8 could be obtained in a yield of 31%. The analytical value of the obtained compound 8 was as follows.
Mp 232-233 ° C; IR (KBr): 3400, 1750, 1740 cm ^-1 .; ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ: 7.61, 7.59 (each 1H, d, J = 15.8 Hz, H-1 and H-7), 7.50, 7.45, 7.00, 6.85 (each 2H, d, J = 8.6 Hz, Ar-H), 6.52, 6.48 (each 1H, d, J = 15.8 Hz, H-2 and H-6), 5.79 (1H, s, H-4), 5.32-4.16 (7H, m, Glc-H), 2.18-2.03 (12H, m, OAc).

Synthesis of monogalactosilcumin tetraacetate (Compound 9)
The reaction was performed in the same manner as in Example 4 except that equimolar compound 3 (2.4 g) and vanillin (0.765 g) were used. As a result of purification and separation of the product, the target compound 9 could be obtained in a yield of 28%. The analytical value of the obtained compound 9 was as follows.
Mp 98-100 ° C; IR (KBr): 3400, 1750 cm ^-1 .; ¹ H-NMR δ: 7.60, 7.58 (each 1H, d, J = 15.8 Hz, H-1 and H- 7), 7.14-6.92 (6H, m, Ar-H), 6.52, 6.48 (each 1H, d, J = 15.8 Hz, H-2 and H-6), 5.82 (1H, s, H-4), 5.56-4.03 (7H, m, Gal-H), 3.93, 3.88 (each 3H, s, OMe), 2.18-2.02 (12H, m, OAc).

Production of diglucosilcumin (compound 10)
Ammonolysis of the acetoxy group of the compound 4 was carried out in 5% aqueous ammonia-methyl alcohol by stirring at room temperature for 2 hours. The residue after evaporation of the solvent was purified by reverse phase column chromatography to obtain the corresponding deacetylated target compound 10 in 79% yield. The analytical value of the obtained compound 10 was as follows.

. Orange amorphous powder; mp 155-159 IR (KBr): 3400, 1630 cm -1 1 H-NMR (pyridine-d 5) δ: 7.94 (2H, d, J = 15.7 Hz, H-1, 7 ), 7.41 (6H, m, Ar-H), 6.94 (2H, d, J = 15.7 Hz, H-2, 6), 6.13 (1H, s, H-4), 5.79 (2H, d, J = 6.8 Hz, Glc-H-1), 4.60-4.18 (12H, m, Glc-H), 3.76 (6H, s, OMe).

Manufacture of monoglucosilcumin (compound 11)
The treatment was performed in the same manner as in Example 11 except that the compound 7 was used instead of the compound 4, and the corresponding target compound 11 as a deacetylated product was obtained in a yield of 63%. The analytical value of the obtained compound 11 was as follows.
Orange amorphous powder; mp 110-113 ℃; IR (KBr): 3400, 1630 cm ^-1 .; ¹ H-NMR (pyridine-d ₅ ) δ: 7.96 (1H, d, J = 15.8 Hz, H- 1 or H-7), 7.93 (1H, d, J = 15.8 Hz, H-7 or H-1), 7.61-7.24 (6H, m, Ar-H), 6.95 (1H, d, J = 15.8 Hz , H-2 or H-6), 6.92 (1H, d, J = 15.8 Hz, H-6 or H-2), 6.14 (1H, s, H-4), 5.78 (1H, d, J = 6.8 Hz, Glc-H-1), 4.59-4.18 (7H, m, Glc-H), 3.78, 3.76 (each 3H, s, OMe).

Synthesis of diglucosyl-bis-demethoxycurcumin (compound 12)
The treatment was performed in the same manner as in Example 11 except that the compound 5 was used instead of the compound 4, and the corresponding deacetylated target compound 12 was obtained in a yield of 64%. The analytical value of the obtained compound 12 was as follows.
Mp 157-161 ° C; IR (KBr): 3380, 1660 cm ^-1 .; ¹ H-NMR (pyridine-d ₅ ) δ: 7.89 (2H, d, J = 15.7 Hz, H- 1, 7), 7.57, 7.37 (each 4H, d, J = 8.5, Ar-H), 6.81 (2H, d, J = 15.7 Hz, H-2, 6), 6.13 (1H, s, H-4 ), 5.72 (2H, d, J = 7.1 Hz, Glc-H-1), 4.61-4.18 (12H, m, Glc-H).

Synthesis of monoglucosyl-bis-demethoxycurcumin (compound 13)
The treatment was conducted in the same manner as in Example 11 except that the compound 8 was used instead of the compound 4, and the corresponding target compound 13 as a deacetylated product was obtained in a yield of 68%. The analytical value of the obtained compound 13 was as follows.

Mp 112-117 ℃; IR (KBr): 3420, 1620 cm ^-1 .; ¹ H-NMR (pyridine-d ₅ ) δ: 7.96 (1H, d, J = 15.8 Hz, H- 1 or H-7), 7.93 (1H, d, J = 15.8 Hz, H-7 or H-1), 7.69, 7.57, 7.40, 7.20 (each 2H, d, J = 8.8 Hz, Ar-H), 6.85 (1H, d, J = 15.8 Hz, H-2 or H-6), 6.81 (1H, d, J = 15.8 Hz, H-6 or H-2), 6.13 (1H, s, H-4) , 5.73 (1H, d, J = 7.2 Hz, Glc-H-1), 4.61-4.18 (7H, m, Glc-H).

Synthesis of digalactosilcumin (compound 14)
The treatment was performed in the same manner as in Example 11 except that the compound 6 was used in place of the compound 4, and the corresponding deacetylated target compound 14 was obtained in a yield of 77%. The analytical value of the obtained compound 14 was as follows.
Orange amorphous powder; mp 155-159 ° C; IR (KBr): 3400, 1630 cm ^-1 .; ¹ H-NMR (pyridine-d ₅ ) δ: 7.91 (2H, d, J = 15.7 Hz, H- 1, 7), 7.62-7.20 (6H, m, Ar-H), 6.91 (2H, d, J = 15.7 Hz, H-2, 6), 6.13 (1H, s, H-4), 5.70 (2H , d, J = 6.8 Hz, Gal-H-1), 4.84-4.30 (12H, m, Gal-H), 3.73 (6H, s, OMe).

Synthesis of monogalactosilcumin (compound 15)
The treatment was performed in the same manner as in Example 11 except that the compound 9 was used instead of the compound 4, and the corresponding target compound 15 as a deacetylated product was obtained in a yield of 85%. The analytical value of the obtained compound 15 was as follows.
Orange amorphous powder; mp 110-113 ℃; IR (KBr): 3420, 1620 cm ^-1 .; ¹ H-NMR (pyridine-d ₅ ) δ: 8.01 (1H, d, J = 15.8 Hz, H- 1 or H-7), 7.95 (1H, d, J = 15.8 Hz, H-7 or H-1), 7.59-7.17 (6H, m, Ar-H), 6.95 (1H, d, J = 15.8 Hz , H-2 or H-6), 6.91 (1H, d, J = 15.8 Hz, H-6 or H-2), 6.14 (1H, s, H-4), 5.70 (1H, d, J = 7.7 Hz, Gal-H-1), 3.79, 3.73 (each 3H, s, OMe).

Production of diglucosyltetrahydrocurcumin (compound 16)
0.102 g of diglucosylrucumin (compound 10) was dissolved in 50 ml of 10% methyl alcohol solution and stirred at a hydrogen pressure of 2.5 atm in the presence of 10% palladium activated carbon for 2 hours to obtain the target compound 16 in a yield of 80%. . The analytical value of the obtained compound 16 was as follows.
Light yellow amorphous powder; mp 92-96 ° C; IR (KBr): 3370, 1700 cm ^-1 .; ¹ H-NMR (pyridine-d ₅ ) δ: 7.72-6.77 (6H, m, Ar-H) , 6.80 (1H, s, H-4), 5.68 (2H, d, J = 5.7 Hz, Glc-H-1), 4.57-4.11 (12H, m, Glc-H), 3.72 (6H, s, OMe ), 2.94 (3H, t, J = 15.2 Hz, H-1, 7), 2.66 (3H, t, J = 15.2 Hz, H-2, 6).
As will be apparent to those skilled in the art, other curcuminoid glycosides can be converted to tetrahydro forms by the same catalytic reduction method as in Example 16.

Anti-allergic action of curcuminoid glycosides According to the method described in Non-Patent Document 8, in a cell experiment system, curcumin, tetrahydrocurcumin, diglucosilcumin, monoglucosillucumin, diglucosyl-bisdemethoxycurcumin, monoglucosyl-bisu The antiallergic action was measured by measuring the histamine release inhibitory action of demethoxycurcumin, diglucosyltetrahydrocurcumin, digalactosilccumin, and monogalactosilccumin. Add 50 μl each of the test compound solution (50 μg / ml) to 400 μl of suspension of mast cell line RBL-2H3 (1 × 10 ⁵ cells / ml) in 0.05% BSA-Tyrode buffer, Subsequently, 25 μl of a solution (100 μg / ml) of histamine release stimulating substance conacavalin A was added and incubated at 37 ° C. for 60 minutes, and histamine in the supernatant was measured by a post-column label HPLC method. As a result, it was revealed that the compound of the present invention suppresses histamine release and has an antiallergic action. While curcumin and hydroxycurcumin, which have antiallergic action, are sparingly soluble in water, the compound of the present invention is a water-soluble glycoside, which is advantageous in gastrointestinal absorption, metabolism in the body, etc., and has excellent drug efficacy in vivo. Can be expected.

  The novel curcuminoid glycoside of the present invention has a wide use in foods, pharmaceuticals, cosmetics and the like as a water-soluble yellow colorant in place of curcuminoids that have been sparingly water-soluble, and is a water-soluble physiologically active substance. It has the use as. Moreover, the curcuminoid glycoside which has the said use can be efficiently manufactured by the manufacturing method of this invention.

FIG. 1 shows the basic reaction of curcuminoid glycoside synthesis by the production method of the present invention. FIG. 2 shows the synthesis reaction of monoglucosylcumin disclosed in the method described in Patent Document 1. FIG. 3 shows a synthesis reaction of diglucosylcumin disclosed in the method described in Patent Document 1. FIG. 4 shows a synthesis reaction of curcuminoid glycoside by the production method (A) of the present invention. FIG. 5 shows the synthesis reaction of curcuminoid glycoside by the production method (B) of the present invention.

Claims (27)

Curcuminoid glycosides of the following formula (I):

(Wherein R1 is a methoxy group, R3 is a methoxy group or hydrogen, R1 is hydrogen, R3 is hydrogen, R2 is hydrogen, a sugar residue or an acetylated sugar residue, and R4 Is a sugar residue or an acetylated sugar residue, and R5 and R6 are oxygen functional groups or hydrogen). A physiologically acceptable salt of the curcuminoid glycoside according to claim 1. The curcuminoid glycoside according to claim 1, wherein R2 is a monosaccharide residue or an oligosaccharide residue. The curcuminoid glycoside of claim 1, wherein R2 is a hexose or pentose monosaccharide residue. The curcuminoid glycoside according to claim 1, wherein R4 is a monosaccharide residue selected from the group consisting of a glucosyl group, a galactosyl group, a mannosyl group, a fructosyl group, a lysosyl group, a xylosyl group, an arabinosyl group, and a ribosyl group. The curcuminoid glycoside according to claim 1, wherein R4 is a monosaccharide residue or an oligosaccharide residue. The curcuminoid glycoside according to claim 1, wherein R4 is a hexose or pentose monosaccharide residue. The curcuminoid glycoside according to claim 1, wherein R4 is a monosaccharide residue selected from the group consisting of a glucosyl group, a galactosyl group, a mannosyl group, a fructosyl group, a lysosyl group, a xylosyl group, an arabinosyl group, and a ribosyl group. Tetrahydrocurcuminoid glycoside of formula (II):

(In the formula, when R7 is a methoxy group, R9 and R11 are both methoxy groups or hydrogen, and when R7 is hydrogen, R9 and R11 are both hydrogen, R8 is hydrogen, sugar residue or An acetylated sugar residue and R10 is a sugar residue or an acetylated sugar residue). A physiologically acceptable salt of the tetrahydrocurcuminoid glycoside according to claim 9. The tetrahydrocurcuminoid glycoside according to claim 9, wherein R8 is a monosaccharide residue or an oligosaccharide residue. The curcuminoid glycoside of claim 9, wherein R8 is a hexose or pentose monosaccharide residue. The tetrahydrocurcuminoid glycoside according to claim 9, wherein R8 is a monosaccharide residue selected from the group consisting of a glucosyl group, a galactosyl group, a mannosyl group, a fructosyl group, a lysosyl group, a xylosyl group, an arabinosyl group, and a ribosyl group. The tetrahydrocurcuminoid glycoside according to claim 9, wherein R10 is a monosaccharide residue or an oligosaccharide residue. The curcuminoid glycoside of claim 9, wherein R10 is a hexose or pentose monosaccharide residue. The tetrahydrocurcuminoid glycoside according to claim 9, wherein R10 is a monosaccharide residue selected from the group consisting of a glucosyl group, a galactosyl group, a mannosyl group, a fructosyl group, a lysosyl group, a xylosyl group, an arabinosyl group, and a ribosyl group. A pigment composition comprising at least one selected from the group consisting of curcuminoid glycosides according to claim 1 and salts of the curcuminoid glycosides. A pharmaceutical composition comprising at least one selected from the group consisting of the curcuminoid glycoside according to claim 1, the tetrahydrocurcuminoid glycoside according to claim 9, and a physiologically acceptable salt of the glycoside. object. A method for producing a curcuminoid glycoside comprising reacting a benzaldehyde compound having a phenolic hydroxyl group and an acetylacetone-B ₂ O ₃ complex, and deboronating the reaction product in the presence of an alcohol solvent. Furthermore, the manufacturing method of Claim 19 including deacetylating a reaction product in presence of the alcohol solvent containing ammonia. The production method according to claim 19, wherein the benzaldehyde compound having a phenolic hydroxyl group is a benzaldehyde compound of the following formula (III) or a mixture of benzaldehyde compounds of the following formulas (III) and (IV):

(Wherein R12 is hydrogen, oxygen functional group, amino group, amide group or halogen, and R13 is a sugar residue, and R14 is hydrogen, oxygen functional group, amino group, amide group or halogen. );

(Wherein R15 and R16 are each independently hydrogen, oxygen functional group, amino group, amide group or halogen); The production method according to claim 21, wherein the oxygen functional groups of R12 and R14 are each independently a methoxy group or a hydroxyl group. The production method according to claim 21, wherein R13 in the formula (III) is a monosaccharide residue or an oligosaccharide residue. The production method according to claim 21, wherein R13 in the formula (III) is a hexose or pentose monosaccharide residue. The production according to claim 21, wherein R13 in the formula (III) is a monosaccharide residue selected from the group consisting of a glucosyl group, a galactosyl group, a mannosyl group, a fructosyl group, a lysosyl group, a xylosyl group, an arabinosyl group, and a ribosyl group. Method. The production method according to claim 19 or 20, wherein the alcohol solvent contains at least one lower alcohol selected from the group consisting of methyl alcohol, ethyl alcohol, and propyl alcohol. The production method according to claim 26, wherein the alcohol solvent comprises methyl alcohol.

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