JP6272604B2 - Glucose uptake promoter - Google Patents

Description

  The present invention relates to a sugar uptake promoter, a hyperglycemia improving agent containing a sugar uptake promoter, a preventive or therapeutic agent for diabetes or diabetic complications, a composition for food or drink containing a sugar uptake promoter, or the composition for food or drink It relates to food and drink including food.

  The glucose concentration (blood glucose level) in blood is constantly adjusted within a certain range by the action of various hormones. If the blood sugar level rises too much, insulin is secreted from the pancreas into the blood, and the blood sugar level is lowered by stimulating the cells so that the cells take up excess sugar in the blood. On the other hand, if the blood glucose level is too low, the blood glucose level rises due to the action of hormones such as glucagon, adrenaline, cortisol, and growth hormone. By such a mechanism, the blood glucose level is maintained in a very narrow normal range. However, insulin is only known as a hormone having a hypoglycemic action, and when there is an abnormality in insulin secretion or sensitivity, the blood glucose level becomes high.

  Diabetes is a disease that results in abnormally high blood glucose levels caused by insulin resistance in target tissues and insulin secretion from pancreatic β cells. Along with this, it has continued to increase. Various prophylactic and therapeutic drugs for diabetes have been proposed, but it has been clarified that the amount of glucose uptake in skeletal muscle is reduced in diabetic patients (non- Patent Documents 1 to 3) and compositions having an action of promoting sugar uptake of muscle cells have been proposed (Patent Documents 1 and 2).

JP 2009-51751 A International Publication No. 2001/133217

The Journal of clinical investigation, 1985, 76, 149-155 Diabetologia, 2000, 43, 821-835 Biochemical Society transactions, 2005, 33, 354-357

  The present invention relates to a sugar uptake promoter for cells, particularly muscle (skeletal muscle) cells, a hyperglycemia improving agent, a preventive or therapeutic agent for diabetes or diabetic complications, and a food and drink containing a sugar uptake promoter. It is intended to provide a composition for food or a food or drink containing the composition for food or drink.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a predetermined isoquinoline derivative has an action of promoting sugar uptake of cells, particularly muscle (skeletal muscle) cells, and completed the present invention. .

（式中、Ｒ¹、Ｒ²およびＲ³は、それぞれ独立して、水素またはＣ_1〜6アルキル、Ｒ⁴はＣ_1〜6アルキル、Ｃ_3〜6シクロアルキル、Ｃ_6〜14アリール、Ｃ_6〜14アリールＣ_1〜6アルキル、５〜１０員の不飽和複素環またはフェロセニルであって、Ｃ_6〜14アリール、Ｃ_6〜14アリールＣ_1〜6アルキル、５〜１０員の不飽和複素環は、それぞれ独立して、無置換、またはハロゲン、ヒドロキシ、ニトロおよびＣ_1〜6アルコキシからなる群より選択される少なくとも１つの置換基を有する）
で表される化合物またはその配糖体を活性成分として含んでなる糖取り込み促進剤に関する。 That is, the present invention relates to the general formula (I):

Wherein R ¹ , R ² and R ³ are each independently hydrogen or C _1-6 alkyl, R ⁴ is C _1-6 alkyl, C _3-6 cycloalkyl, C _6-14 aryl, C _6-14 aryl C _1-6 alkyl, 5-10 membered unsaturated heterocycle or ferrocenyl, wherein C _6-14 aryl, C _6-14 aryl C _1-6 alkyl, 5-10 membered unsaturated heterocycle Each ring independently is unsubstituted or has at least one substituent selected from the group consisting of halogen, hydroxy, nitro and C _1-6 alkoxy)
Or a glycoside thereof, as an active ingredient.

In the general formula (I), R ¹ , R ² and R ³ are each independently hydrogen or methyl, R ⁴ is C _6-14 aryl or C _6-14 aryl C _1-6 alkyl, It is preferred that the C _6-14 aryl or C _6-14 aryl C _1-6 alkyl has a hydroxy or C _1-6 alkoxy substituent.

In the general formula (I), R ⁴ is more preferably benzyl having a hydroxy or methoxy substituent.

  Furthermore, the present invention relates to a hyperglycemia improving agent comprising the sugar uptake promoter.

  The present invention also relates to a preventive or therapeutic agent for diabetes or diabetic complications comprising the sugar uptake promoter.

  Furthermore, this invention relates to the composition for food-drinks containing the said sugar uptake | capture promoter.

  This invention relates to the food / beverage products containing the said composition for food / beverage products.

  Since the sugar uptake promoter of the present invention can promote glucose uptake in cells, particularly muscle (skeletal muscle) cells, it is useful for improving hyperglycemia and further preventing or treating diabetes and diabetic complications. . Moreover, the use of the sugar uptake promoter of the present invention can provide a composition for food and drink and a food and drink useful for improving hyperglycemia, and further for preventing and improving diabetes and diabetic complications.

  The present invention relates to a sugar uptake promoter containing a predetermined isoquinoline derivative as an active ingredient, a hyperglycemia improving agent or a preventive or therapeutic agent for diabetes or diabetic complications containing the sugar uptake promoter, and a food or drink containing a sugar uptake promoter. The present invention relates to a composition for food or a food or drink containing the composition for food or drink.

（式中、Ｒ¹、Ｒ²およびＲ³は、それぞれ独立して、水素またはＣ_1〜6アルキル、Ｒ⁴はＣ_1〜6アルキル、Ｃ_3〜6シクロアルキル、Ｃ_6〜14アリール、Ｃ_6〜14アリールＣ_1〜6アルキル、５〜１０員の不飽和複素環またはフェロセニルであって、Ｃ_6〜14アリール、Ｃ_6〜14アリールＣ_1〜6アルキル、５〜１０員の不飽和複素環は、それぞれ独立して、無置換、またはハロゲン、ヒドロキシ、ニトロおよびＣ_1〜6アルコキシからなる群より選択される少なくとも１つの置換基を有する） The active ingredient of the present invention is a predetermined isoquinoline derivative, that is, a compound represented by the general formula (I) or a glycoside thereof.

Wherein R ¹ , R ² and R ³ are each independently hydrogen or C _1-6 alkyl, R ⁴ is C _1-6 alkyl, C _3-6 cycloalkyl, C _6-14 aryl, C _6-14 aryl C _1-6 alkyl, 5-10 membered unsaturated heterocycle or ferrocenyl, wherein C _6-14 aryl, C _6-14 aryl C _1-6 alkyl, 5-10 membered unsaturated heterocycle Each ring independently is unsubstituted or has at least one substituent selected from the group consisting of halogen, hydroxy, nitro and C _1-6 alkoxy)

  The compound represented by the general formula (I) or the glycoside thereof according to the present invention may be a racemate, an optical isomer, or any mixture thereof.

In the present specification, “C _1-6 alkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl, ethyl, n-propyl, isopropyl, Examples include n-butyl, sec-butyl, tert-butyl, hexyl and the like, and methyl or ethyl is preferable.

In the present specification, “C _3-6 cycloalkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include cyclopropyl, cyclopentyl, cyclohexyl and the like. Cyclopropyl is preferred.

In the present specification, “C _6-14 aryl” means an aromatic carbocyclic group having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl and the like, and phenyl is preferable, among which halogen, hydroxy, nitro and C It preferably has at least one substituent selected from the group consisting of _1-6 alkoxy, and more preferably has a hydroxy or C _1-6 alkoxy substituent. The position of the substituent is not particularly limited, but in the case of phenyl, the para position is preferred.

In the present specification, “C _6-14 aryl C _1-6 alkyl” means C _1-6 alkyl as defined above bonded to C _6-14 aryl as defined above, and includes benzyl, phenylethyl, phenylpropylene. Benzyl is preferred, and in particular, it preferably has at least one substituent selected from the group consisting of halogen, hydroxy, nitro and C _1-6 alkoxy, and is hydroxy or C _1-6 alkoxy substituent. It is more preferable to have. The position of the substituent is not particularly limited, but in the case of benzyl, the para position is preferred.

In the present specification, the “5- to 10-membered unsaturated heterocyclic ring” is not particularly limited as long as it is a 5- to 10-membered unsaturated heterocyclic ring having one or more heteroatoms. Specific examples include thienyl, pyridyl, quinolinyl and the like. The 5- to 10-membered unsaturated heterocycle is unsubstituted or has at least one substituent selected from the group consisting of halogen, hydroxy, nitro and C _1-6 alkoxy.

  In the present specification, “halogen” includes fluorine, chlorine, bromine, iodine and the like, and fluorine or bromine is preferable.

In the present specification, “glycoside” includes glycosides such as monosaccharides, disaccharides, and trisaccharides, and can be composed of sugar units such as allose, galactose, glucose, fructose, etc. Specifically, a glycoside by fructose, glucose or sucrose is preferable, and a glycoside by glucose is more preferable. These sugars are preferably bonded to the R ⁴ substituent of the compound of general formula (I), and in particular, R ⁴ is a C _6-14 aryl having a hydroxy or C _1-6 alkoxy substituent. , C _6-14 aryl C _1-6 alkyl or a 5- to 10-membered unsaturated heterocyclic ring, wherein the sugar is ether-linked using the hydroxy or C _1-6 alkoxy substituent moiety More preferred.

  Specific examples of the compound represented by the general formula (I) include 1- (4-hydroxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (8), 1- (4- Hydroxybenzyl) -6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (9), 6,7-dihydroxy-1- (4-methoxybenzyl) -1,2,3,4 -Tetrahydroisoquinoline (10), 6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline, 1-cyclopropyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 6,7-dihydroxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline, 6,7-dihydroxy-1- (4-nitrophenyl) -1,2,3,4- Trahydroisoquinoline, 6,7-dihydroxy-1- (4-methoxyphenyl) -1,2,3,4-tetrahydroisoquinoline, 1- (4-hydroxyphenyl) -6,7-dihydroxy-1,2,3 , 4-tetrahydroisoquinoline, 1- (3-hydroxyphenyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 1- (2-hydroxyphenyl) -6,7-dihydroxy-1,2 , 3,4-tetrahydroisoquinoline, 1- (4-bromophenyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 1- (4-fluorophenyl) -6,7-dihydroxy-1 , 2,3,4-tetrahydroisoquinoline, 1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino 6,7-dihydroxy-1- (2-thienyl) -1,2,3,4-tetrahydroisoquinoline, 6,7-dihydroxy-1- (3-pyridinyl) -1,2,3,4-tetrahydro Isoquinoline, 6,7-dihydroxy-1- (3-quinolinyl) -1,2,3,4-tetrahydroisoquinoline, 1-ferrocenyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and the like It is done.

  Specific examples of the glycoside of the compound represented by the general formula (I) include 1- (4- (bD-glucopyranosyloxy) benzyl) -6,7-dimethoxy-2-methyl-1. , 2,3,4-Tetrahydroisoquinoline (hygenamine glucoside) (1), (S) -1- (4- (bD-glucopyranosyloxy) benzyl) -6,7-dimethoxy-2-methyl -1,2,3,4-tetrahydroisoquinoline, 1- (4- (bD-glucopyranosyloxy) benzyl) -6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro And isoquinoline (12).

（式中、Ｒ⁴は一般式（Ｉ）で定義したものである） The isoquinoline derivative represented by the general formula (I) of the present invention can be isolated from lotus wick or by using an organic synthesis reaction known to those skilled in the art, for example, Chem. Commun., 2011, 47, 3242- As described in 3244, it can be produced by the coupling reaction of dopamine hydrochloride and aldehyde as shown in the following scheme.

(In the formula, R ⁴ is defined in the general formula (I))

In Scheme 1, R ⁴ may be protected by a protecting group. In that case, after the reaction, the protecting group can be eliminated to give R ⁴ .

  Further, the glycoside of the compound represented by the general formula (I) of the present invention is isolated from the lotus wick, or glycosylation reaction known to those skilled in the art for the compound of the general formula (I), for example, glucosyl It can be produced using a coupling reaction (Chem. Rev. 1993, 93, p. 1503-1531) between imidad or glucosyl bromide and the compound of general formula (I).

  The compound represented by the general formula (I) of the present invention or a glycoside thereof is basically a racemate when synthesized according to Scheme 1 or the like, but thereafter, by various known methods, if necessary, For example, it can be separated into optically active substances by liquid chromatography using an optically active column or the like. Further, after glycosylation to form a diastereomer, it can be separated by liquid chromatography or the like.

(Pharmaceutical preparation)
The compound represented by the general formula (I) of the present invention or a glycoside thereof has excellent cellular sugar uptake-promoting activity and can reduce the blood glucose level of humans or warm-blooded animals. By blending as an ingredient, as a sugar uptake promoter or hyperglycemia improving agent, hyperglycemia, diabetes, diabetes-related diseases (eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fat Liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout) or diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection) Can be used to prevent or treat symptom and ketosis.

  The administration route of the sugar uptake promoter or hyperglycemia improving agent of the present invention may be either oral administration or parenteral administration. The dosage form can be appropriately selected depending on the route of administration. For example, powders, granules, tablets, capsules, pills, intestinal solvents, troches, liquids for internal use, suspensions, emulsions, syrups, External liquid preparations, poultices, nasal drops, ear drops, eye drops, inhalants, ointments, lotions, suppositories, enteral nutrients and the like can be mentioned. These can be used alone or in combination depending on the symptoms. In these preparations, auxiliary agents commonly used in this field such as excipients, binders, preservatives, oxidation stabilizers, disintegrants, lubricants, and corrigents are used as necessary.

  The dose of the sugar uptake promoter or hyperglycemia-improving agent of the present invention varies depending on the compound of the active ingredient, the purpose of administration, the situation of the subject of administration (sex, age, weight, etc.), the degree of disease, etc. For example, it is preferably 1 mg to 10 g, more preferably 5 mg to 5 g, in the case of oral administration per day for an adult, in terms of active compound.

(Quasi-drugs)
The sugar uptake promoter or hyperglycemia-improving agent of the present invention can be used not only as a pharmaceutical as described above but also as a quasi drug. When used as a quasi-drug, it can be used together with various adjuvants usually used in the technical field such as a quasi-drug as necessary. Any of the above-mentioned adjuvants can be used. Further, it may be used in a desired shape such as solution, suspension, syrup, granule, cream, paste, jelly, etc., or as necessary. The amount of the active ingredient of the present invention contained in these is not particularly limited and can be appropriately selected according to the purpose of use and the form of use. For example, the amount corresponding to the above-mentioned dose should be used. Can do.

(High blood sugar improving composition for food and drink, food and drink)
The composition for food and drink according to the present invention can be prepared by adding, as necessary, an auxiliary agent usually used in this field to the active ingredient of the present invention having an effect of promoting sugar uptake, as such an auxiliary agent. Any of the above can be used.

  Since the composition for food and drink of the present invention can exhibit an effect of improving hyperglycemia, the food and drink having the pharmacological effect, for example, health food, health drink, food for specified health use, functional food, nutritional supplement It can be used for food and other feeds for warm-blooded animals other than humans. Among them, when the composition for food or drink of the present invention is added to a food or drink material containing a large amount of saccharides, it exerts an efficient energy supply effect due to the promotion of muscle cell sugar uptake, and the accompanying muscle tissue Since there are effects such as activation / enhancement / increase, reduction of physical fatigue, and improvement of exercise ability, an excellent energy-assisted food / beverage product can be provided.

  When using the composition for food or drink of the present invention for food or drink, as necessary, for example, sweeteners, spices, seasonings, preservatives, preservatives, bactericides, antioxidants and other additives commonly used in foods An agent can be blended. Further, it may be used in a desired shape such as solid, powder, granule, solution, suspension, syrup, cream, paste, jelly, etc., or as necessary. The amount of the active ingredient of the present invention contained in these is not particularly limited and can be appropriately selected according to the purpose of use and the form of use. For example, the amount corresponding to the above-mentioned dose should be used. Can do.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to these examples.

Production Example 1: Synthesis of (S) -hygenamine glucoside (1) (a) Synthesis of 2- (4-((tert-butyldimethylsilyl) oxy) phenyl) acetaldehyde (2) 4- (2-hydroxyethyl) Phenol (2.55 g, 18.5 mmol) was dissolved in dimethyl sulfoxide (DMSO) (18.5 mL) and triethylamine (5.2 mL) was added. To this solution, sulfur trioxide-pyridine complex (7.05 g, 44.3 mmol) dissolved in DMSO (22 mL) was added dropwise at 0 ° C. with stirring. After completion of the dropwise addition, the mixture was stirred for 1 hour at room temperature, water was added and the mixture was extracted with chloroform. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (DMF) (50 mL) and imidazole (2.07 g, 30.4 mmol), N, N-dimethyl-4-aminopyridine (DMAP) (28.6 mg, 0.234 mmol). ), Tert-butyldimethylchlorosilane (TBSCl) (2.70 g, 17.3 mmol) was added, and the mixture was stirred under an argon atmosphere for 2 hours. The reaction solution was diluted with water and extracted with a mixed solvent of ethyl acetate / hexane = 1/1. The organic layer was washed sequentially with 1M aqueous hydrochloric acid and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / chloroform = 3/1, hexane / ethyl acetate = 20/1 sequentially eluted) to obtain the title compound (2) in a yield of 1.44 g and a yield of 32%. .

(B) Synthesis of 1- (4-((tert-butyldimethylsilyl) oxy) benzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (3) Compound (2) (1.02 g 4.08 mmol) and dopamine hydrochloride (515.3 mg, 2.72 mmol) were dissolved in a mixed solvent of acetonitrile (20 mL) and 0.1 M potassium phosphate buffer (pH 6.0, 5 mL), and 50 ° C. For 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted sequentially with chloroform / methanol = 9/1, 4/1) to obtain the title compound (3) in a yield of 186.4 mg and a yield of 18%.

(C) Synthesis of 6,7-diacetoxy-2-carbobenzyloxy-1- (4-hydroxybenzyl) -1,2,3,4-tetrahydroisoquinoline (4) Compound (3) (186.4 mg, 0. 484 mmol) was dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (5 mL), and benzyl chloroformate (CbzCl) (120 μL, 0.840 mmol) was added. While stirring the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8. After 10 minutes, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and triethylamine (TEA) (0.7 mL, 5.00 mmol) was added. Acetyl chloride (0.2 mL, 2.81 mmol) was added thereto, and the mixture was stirred for 15 minutes under an argon atmosphere. Next, a tetrahydrofuran (THF) solution of tetra-n-butylammonium fluoride (TBAF) (1M, 0.5 mL) was added to the reaction solution, and the mixture was further stirred for 5 minutes. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted successively with hexane / acetone = 3/1, 2/1) to obtain the title compound (4) in a yield of 140.5 mg and a yield of 59%.

(D) 6,7-diacetoxy-2-carbobenzyloxy-1- (4- (2,3,4,6-tetra-O-acetyl-bD-glucopyranosyloxy) benzyl) -1, Synthesis of 2,3,4-tetrahydroisoquinoline (6) Compound (4) (50.2 mg, 0.103 mmol) and 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl trichloroacetimi Date (5) (80.8 mg, 0.164 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), activated powdered molecular sieve 4A (219 mg) was added, and the mixture was stirred at 0 ° C. for 10 minutes under an argon atmosphere. did. A dichloromethane solution of boron trifluoride diethyl ether complex (10% (v / v), 150 μL) was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes in an argon atmosphere. The reaction mixture was filtered through celite, saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer silica gel chromatography (hexane / acetone = 2/1) to give the title compound (6) quantitatively in a yield of 84.2 mg.

(E) Synthesis of 6,7-dihydroxy-2-carbobenzyloxy-1- (4- (bD-glucopyranosyloxy) benzyl) -1,2,3,4-tetrahydroisoquinoline (7) Compound (6) (84.2 mg, 0.103 mmol) was dissolved in methanol (2 mL), 5 M sodium methoxide in methanol (0.1 mL) was added, and the mixture was stirred for 5 min. A strongly acidic cation exchange resin (Dowex (registered trademark) 50WX8, manufactured by Dow Chemical Co., Ltd.) was added to the reaction solution, and the filtrate obtained by filtering with a cotton plug was concentrated under reduced pressure. The residue was purified by preparative thin layer silica gel chromatography (chloroform / methanol = 7/1) to obtain the title compound (7) in a yield of 34.1 mg, a yield of 58%.

(F) Synthesis of (S) -hygenamine glucoside (1) Compound (7) (17.1 mg, 0.03 mmol) was dissolved in methanol (1 mL), and a catalytic amount of palladium hydroxide was added under hydrogen atmosphere. Stir for hours. The filtrate obtained by filtering the reaction solution through Celite was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Interstain C18 column, manufactured by GL Sciences, Inc .: 0.1% trifluoroacetic acid, 10% MeCN aqueous solution) to give the title compound (1) in a yield of 5.3 mg, a yield of 17 %.

Production Example 2: Synthesis of 1- (4-hydroxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (8) Compound (3) obtained in Production Example 1 (b) above was prepared. The title compound (8) can be obtained by removing the tert-butyldimethylsilyl group by treatment with TBAF in THF.

Production Example 3: Synthesis of 1- (4-hydroxybenzyl) -6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (9) Compound obtained in Production Example 1 (b) (3) is methylated in DMF with potassium carbonate and methyl iodide, and then the tert-butyldimethylsilyl group is removed in the same manner as in Production Example 2 to give the title compound (9). be able to.

Production Example 4: Synthesis of 6,7-dihydroxy-1- (4-methoxybenzyl) -1,2,3,4-tetrahydroisoquinoline (10) (a) 6,7-diacetoxy-2-carbobenzyloxy-1 Synthesis of-(4-hydroxybenzyl) -1,2,3,4-tetrahydroisoquinoline (11) Compound (3) obtained in Preparation Example 1 (b) was mixed with 1,4-dioxane and water. In the same manner as in Preparation Example 1 (c), benzyl chloroformate (CbzCl) was allowed to act, and the amine was protected with carbobenzyloxy, and then treated with potassium carbonate and benzyl bromide (BnBr) in DMF. The group can be benzylated, and then the tert-butyldimethylsilyl group can be removed in the same manner as in Production Example 2 to give the title compound (11).

(B) Synthesis of 1- (4-methoxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (10) The compound (11) obtained in (a) is carbonated in DMF. The hydroxyl group can be methylated with potassium and methyl iodide and then treated with hydrogen in a catalytic amount of palladium hydroxide in methanol to give the title compound (10).

Production Example 5 Synthesis of 1- (4- (b-D-glucopyranosyloxy) benzyl) -6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (12) (a ) 6,7-dibenzyloxy-2-carbobenzyloxy-1- (4- (2,3,4,6-tetra-O-acetyl-bD-glucopyranosyloxy) benzyl) -1, Synthesis of 2,3,4-tetrahydroisoquinoline (13) Compound (11) obtained in Preparation Example 4 (a) and 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl trichloroacetate The title compound (13) can be obtained by using imidate (5) in the same manner as in Production Example 1 (d).

(B) Synthesis of 6,7-dibenzyloxy-1- (4- (bD-glucopyranosyloxy) benzyl) -1,2,3,4-tetrahydroisoquinoline (14) Obtained by (a) The title compound (14) can be obtained by treating the obtained compound (13) in the same manner as in Production Example 1 (f).

(C) Synthesis of 6,7-dimethoxy-2-methyl-1- (4- (bD-glucopyranosyloxy) benzyl) -1,2,3,4-tetrahydroisoquinoline (12) (b) The amino group and the hydroxyl group were methylated with potassium carbonate and methyl iodide in N, N-dimethylformamide (DMF) in the compound (14) obtained in (1). The acetyl group can be deprotected to give the title compound (12).

Example: Sugar uptake test by L6 skeletal muscle cells (production of L6 skeletal muscle cells)
L6 myoblasts (obtained from the Human Science Foundation, Human Science Research Resource Bank) were adjusted to a cell density of 5 × 10 ⁴ cells / mL with DMEM medium (containing 10% (v / v) FBS). Was seeded in a 48-well tissue culture plate (500 μL per well) and cultured in a 5% carbon dioxide incubator at 37 ° C. for 2 to 3 days. When the cells became confluent, the medium was replaced with DMEM medium (containing 2% (v / v) horse serum (HS)), the medium was changed every other day, and the medium was cultured at 37 ° C. with 5% carbon dioxide gas. The cells were cultured in a vessel for 7 days and differentiated into L6 skeletal muscle cells. The cells thus obtained were used for the “sugar uptake test”.

(Sugar uptake test)
After aspirating and removing the medium from each well of the tissue culture plate of L6 skeletal muscle cells, 300 μL of a sample prepared by diluting an aqueous solution of (S) -hygamine glucoside of each concentration with DMEM containing 2% HS ((S) in each sample) -Concentration of hygamine glucoside: (Sample 1: 100 μM, Sample 2: 10 μM, Sample 3: 1 μM)) was added and incubated in a 5% carbon dioxide incubator at 37 ° C. for 4 hours. Here, 30 μL of 1 μM insulin prepared by further diluting 10 μM insulin dissolved in KPPH buffer with ultrapure water was used as a negative control in place of the hygamine glucoside aqueous solution instead of the same amount. 100 nM insulin consisting of 270 μL of DMEM medium was used. The test was performed in duplicate, each time n = 6, and the activity was calculated from the results of each experiment.

The medium was then removed from each well and Krebs-Ringer-Phosphate-Hepes (KRPH) buffer (20 mM HEPES, 5 mM KH ₂ PO ₄ , 1 mM MgSO ₄ , 1 mM CaCl ₂ , 136 mM NaCl, 4.7 mM KCl, pH 7. 4) After washing twice, 500 μL / well of KRPH buffer containing 1.0 mM 2-DG (2-deoxyglucose, manufactured by SIGMA) was added, and each well mixture was treated with 5% carbon dioxide at 37 ° C. The cells were incubated for 20 minutes in an incubator, and 2-DG was taken into the cells. In addition, the same operation was performed using the KRPH buffer solution which does not contain 2-DG for the background at the time of subsequent fluorescence value measurement.

  Next, after removing the KRPH buffer from each well, the cells were washed three times with the KRPH buffer and further air-dried. 0.05 M NaOH 60 μL / well was added, and the cells were lysed by stirring with a microplate mixer. The plate was placed in a freezer and frozen at −80 ° C., then removed from the freezer and thawed. It was treated in an oven at 85 ° C. for 1 hour to destroy the inherent NADPH. After allowing to cool to room temperature, 50 mM triethanolamine buffer (pH 8.1) was adjusted to pH 8.1 by adding 90 μL / well and 0.1 M hydrochloric acid 30 μL / well, and the plate was stirred with a microplate mixer. For the mixture in each well of the plate, the amount of 2-DG was measured as follows, and the sugar uptake promoting action was evaluated by the difference from the measured value as the background.

(Measurement of 2-DG amount)
50 μL / well of the above mixture of each well was placed in a 96-well black plate for fluorescence measurement, and assay cocktail (1.3 mM ATP (produced by Oriental Yeast Co., Ltd.), 0.2 mM NADP + (Oriental Yeast Industry Co., Ltd.) ), 12 unit / mL hexokinase (manufactured by SIGMA), 32 unit / mL glucose-6-phosphate dehydrogenase, 4 unit / mL diaphorase, 50 μM resazurin sodium) 50 μL / well was added and stirred with a microplate mixer Thereafter, each well mixture was incubated in a 37 ° C. incubator for 60 minutes.

  For each well of the plate, the fluorescence value (excitation wavelength: 530 nm, measurement wavelength: 590 nm) was measured with a microplate reader (Bio-tech Instruments Inc, Synergy ™ MX). The background value was subtracted from each measured fluorescence value. The relative value of the 2-DG uptake amount under each condition was obtained with the 2-DG uptake amount of the negative control as 1 (relative sugar uptake ability).

The results are shown in Table 1. Significant differences by t-test were ^* : P <0.01 and ^** : P <0.02.

  From Table 1, it can be seen that (S) -hygenamine glucoside has an excellent sugar uptake promoting action in skeletal muscle cells.

Claims (6)

General formula (1):

(Wherein, R ^1, R ² and R ³ are each independently hydrogen or alkyl of C _{1 ~ 6,} R ⁴ is benzyl having a hydroxy or methoxy substituent)
A monosaccharide composed of at least one sugar unit selected from the group consisting of allose, galactose, glucose and fructose, wherein the sugar uptake promoter contains a compound represented by the formula: , A sugar uptake promoter which is a glycoside by disaccharide or trisaccharide . R ^1, R ² and R ³ are each independently, glucose uptake enhancer according to claim 1, wherein is hydrogen or methyl. A hyperglycemia-improving agent comprising the sugar uptake promoter according to claim 1 or 2 . A preventive or therapeutic agent for diabetes or diabetic complications comprising the sugar uptake promoter according to claim 1 or 2 . General formula (1):

(Wherein, R ^1, R ² and R ³ are each independently hydrogen or alkyl of C _{1 ~ 6,} R ⁴ is benzyl having a hydroxy or methoxy substituent)
In a compound represented by or glucose uptake-promoting food or beverage products set Narubutsu containing the glycoside, glycoside is allose, galactose, at least one sugar unit selected from the group consisting of glucose and fructose A food and drink composition for promoting sugar uptake, which is a glycoside composed of a monosaccharide, disaccharide or trisaccharide . Glucose uptake-promoting food or beverage product containing food or drink sets composition as claimed in claim 5, wherein.