CN1842536A - Glycoside having 4-methylergost-7-en-3-ol skeleton and drug for ameliorating hyperglycemia - Google Patents

Abstract

3-O-beta-D-Glucopyranosyl-4-methylerogst-7-en-3-ol or an extract of a liliaceae plant or a fraction thereof containing this compound, which is a composition containing 0.001% by mass or more of the above compound, is used as the active ingredient of a drug for ameliorating hyperglycemia.

Description

Glucosides and ameliorating agent for hyperglycemia with 4-methyl ergot steroid-7-alkene-3-ol skeleton

Technical field

The present invention relates to have the novel glycoside 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene of 4-methyl ergot steroid-7-alkene-3-ol skeleton-3-alcohol and contain the composition of this glucosides, and the pharmaceuticals or the diet product that contain them.

Background technology

Known 4-methyl ergot steroid-7-alkene-3-alcohol is for being present in the material (non-patent literature 1) in the plant.But, prior art for this compound, only relate to and have the technology (non-patent literature 2) that flies the intercrescence architectonical of enol (one of steric isomer of 4-methyl courage steroid-7-alkene-3-alcohol) to the Lip river of the similar structure of this compound, still unknown fully for the purposes of these compounds.

The Liliaceae Aloe is to contain Aloe vulgaris (Aloe barbadensis Miller), the flora of Aloe arborescens var. natalensis (Aloe arborescen Miller var.natalensis Berger) etc., known on the experience have various effects, in the prior art that relates to the aloe plant purposes, immune modification polyose (patent documentation 1) is arranged, the immunosuppression activator (patent documentation 2) that is feature with the butanols cut that contains Aloe extract or aloin, the synthetic inhibitor that contains the aloin derivative (patent documentation 3～5) that belongs to the HSP60 family protein, derive from the phytohemagglutinin active protein (patent documentation 6) of Folium Aloe skin etc.

As the prior art that improves blood glucose value that relates to aloe plant, polyose (patent documentation 7) in clinical trial (non-patent literature 3) in the U.S., the hypoglycemic activity in animal (non-patent literature 4 and non-patent literature 5), the aloe plant is disclosed, but in these prior arts, the hypoglycemic activity composition of aloe plant is speculated as polyose or sugar-protein.In addition, disclose at the Aloe vulgaris pressed liquor and in the antidiabetic drug (patent documentation 8) of this pressed liquor as effective constituent, the distinctive peak of ester group is with active relevant in the FT-IR spectrogram, effective constituent is polyose, amino acid, oxysuccinic acid etc., and in commercially available aloe vera gel powder, aloe vera gel liquid or aloe vera gel extracting solution, above-mentioned effective constituent is destroyed.And, the antioxygenation (patent documentation 10) of the 7-hydroxyl chromone that contains in the hypoglycemic activity (patent documentation 9), aloe of Aloe polysaccharide class is also disclosed respectively in other documents.

In addition, in the Aloe Barbadensis Miller skin, contain Barbaloin A and rhabarberone, in the past industrial not preferred with laxative action.

Hemoglobin A lc is the binding substances of glucose and oxyphorase, exist with ... sugared concentration and increase along with the degree of hyperglycemia, once the hemoglobin A lc of Sheng Chenging finishes up to the erythrocytic life-span (120 days) and can not subdue, therefore reflection glycemic control state (non-patent literature 6) over a long period of time.During hemoglobin A lc checks since the selection of the basic healthy examination that was used in the aged health method in 1996, therefore the auxiliary diagnosis index that also is used as diabetes in the new Case definition of diabetes in 1999 thinks that it is the index (non-patent literature 7) that is significant clinically.

In case the state continuance of hyperglycemia is then thought glucose specificity hypoinsulinism and insulin resistance, become the essential factor (non-patent literature 8) that causes hyperglycemia further to worsen.Because in order to prevent from the hyperglycemia state to the onset diabetes essential long-term control blood glucose value, therefore think the rising that is necessary to suppress hemoglobin A lc value.In order to control the blood glucose value in the preceding diabetes (states of doubtful diabetes), sitotherapy and motion have been promoted.Though the functional foodstuff (specific food for health care) that the blood glucose value that causes after being used to suppress to take food on sale various rises, any all is nothing but to cross the property blood glucose value to one to rise inhibited.Therefore, can not expect the long-term control blood glucose value, be anxious for the research that this time hemoglobin A lc is reduced working substance.

In addition, now as the treatment of diabetes medicine, alpha-glucosidase inhibitor, as the sulfonylureas of insulin secretion stimulators, all be used as pharmaceuticals as tetrahydrothiazole derivates of insulin resistant property improvement medicine etc.But their drug effect is also unsatisfactory, and has owing to the rapid decline of blood sugar causes problems such as comatose side effect more.

Consider above-mentioned condition, be anxious for discovery and do not cause hypoglycemia, can absorb safely, and have the material of the long-term blood glucose value control action kou that makes the decline of hemoglobin A lc value.

In the past, formerly have in the technical literature, as have the material that suppresses ascending effect on the blood glucose value disclose as contain the blood glucose value rising inhibitor (patent documentation 11) that derives from the Flos Caryophylli Lagerstroemia indica L. composition, with the concentrated extract of wheat class fermented product as the blood glucose value rising inhibitor (patent documentation 12) of effective constituent etc.

In addition, as being the technology of effective constituent with the triterpene glucosides, disclose as the glucosides that will from the Largeleaf Gymnema of Guangdong, extract as the diabetes mellitus prevention agent (patent documentation 13) of effective constituent, contain the corosolic acid that from Flos Caryophylli Lagerstroemia indica L., extracts as the metabolism improving method of effective constituent and be used for this composition (patent documentation 14), lipase inhibitor (patent documentation 15), tetraterpene derivatives (patent documentation 16) with immunosuppressive activity.

In addition, disclose based on having lanostane skeleton or 3, in the insulin action enhanced activity (patent documentation 17) of the compound of 4-open loop lanostane skeleton, though indeterminate to the effect of pancreatic disease, its effect is the insulin action in the differentiation adjusting that strengthens adipocyte.

And, disclose will be selected from not double bond containing 24-alkyl cholestene-3-ketone and 24-alkyl cholestane-3-ketone in the part of steroid basic framework compound as blood sugar depressant (patent documentation 18).

As having the glucosides that analog is 4-methyl beans steroid-7-alkene-3-ol skeleton, reported that 3-O-β-D-glucopyranosyl-4-methyl beans steroid-7-alkene-3-alcohol is present in in the white bryony of melon section plant (Bryonia alba) (non-patent literature 9), but be not to have edible empirical plant usually, and do not have complete synthesis example yet.

Patent documentation 1: special table 2001-520019 communique

Patent documentation 2: the spy opens flat 08-208495 communique

Patent documentation 3: the spy opens flat 10-120576 communique

Patent documentation 4: the spy opens flat 10-045604 communique

Patent documentation 5: the spy opens flat 10-036271 communique

Patent documentation 6: the spy opens flat 09-059298 communique

Patent documentation 7: the spy opens clear 60-214741 communique

Patent documentation 8: the spy opens the 2003-286185 communique

Patent documentation 9: No. 4598069 specification sheets of United States Patent (USP)

Patent documentation 10: No. 2003/0207818 specification sheets of U.S. Patent Application Publication

Patent documentation 11: the spy opens the 2003-095941 communique

Patent documentation 12: the spy opens the 2002-371003 communique

Patent documentation 13: the spy opens flat 05-247086 communique

Patent documentation 14: the spy opens the 2002-205949 communique

Patent documentation 15: the spy opens flat 09-040689 communique

Patent documentation 16: the flat 11-511482 communique of special table

Patent documentation 17: the spy opens flat 10-330266 communique

Patent documentation 18: the spy opens the 2003-048837 communique

Non-patent literature 1:Chem.Pharm.Bull., the 624th～626 page, 1993 years

Non-patent literature 2:Biochemica Biophysica Acta, the 63rd～88 page, 2000 years

Non-patent literature 3:Phytomedicine, the 3rd volume, the 245th～248 page, 1996 years

Non-patent literature 4:Phytotherapy Research, the 15th volume, the 157th～161 page, calendar year 2001

Non-patent literature 5:Phytotherapy Research, the 7th volume, the 37th～42 page, 1993 years

Non-patent literature 6: Japan is clinical, No. the 748th, logical volume, the 1st volume, the 615th～617 page, 1999 years

Non-patent literature 7: Japan is clinical, No. the 808th, logical volume, the 2nd volume, the 405th～409 page, 2002 years

Non-patent literature 8: vow rugged Yi Xiong village Song Zhengkuan chief editor, " forefronts of diabetes ", the 126th～139 page, Yang Tushe, 1997 years

Non-patent literature 9:Khimiya Prirodnykh Soedinenii, the 3rd volume, the Soviet Union, 1977

Summary of the invention

Problem of the present invention is to provide and does not cause hypoglycemia, can absorb safely, and has the novel cpd of the long-term blood glucose value control action kou that reduces hemoglobin A lc value.Other problems of the present invention are to study by the feedstock production that can absorb safely on edible experience and obtain easily and do not contain industrial not preferred composition and contain the method for compositions of the above-claimed cpd of significant quantity.

The inventor etc. have carried out deep research in order to solve above-mentioned problem, found that: from mesophyll (transparent colloid part) extraction and the purified novel glycoside of Aloe vulgaris (Aloe barbadensis Miller) is 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol, it does not cause hypoglycemia, can absorb safely, and has the long-term blood glucose value control action kou that reduces hemoglobin A lc value.Finished the present invention based on above-mentioned discovery.

That is, the present invention is for having the compound (below be also referred to as " The compounds of this invention ") of structure shown in the following chemical formula (1).

[changing 1]

In addition, the invention provides to contain and count composition more than or equal to 0.001 quality % The compounds of this invention (below be also referred to as " present composition ") by dry mass.The present composition is preferably extract or its cut of liliaceous plant, and liliaceous plant is preferably Aloe vulgaris (Aloe barbadensis Miller) especially.

The present invention also provides ameliorating agent for hyperglycemia that The compounds of this invention or the present composition are contained as effective constituent (below be also referred to as " medicament of the present invention ").

The present invention also provides pharmaceuticals or the diet product that contain above-mentioned ameliorating agent for hyperglycemia.

The present invention also provides the diet product that have the explanation that is used to improve hyperglycemia, it is characterized in that, the The compounds of this invention or the present composition is contained as effective constituent, and have hyperglycemia improvement effect.

Below, above-mentioned pharmaceuticals or diet product are generically and collectively referred to as " pharmaceuticals of the present invention or diet product ".

The present invention further provides a kind of method, it is the preparation method of the The compounds of this invention or the present composition, it is characterized in that, from contain liliaceous plant or its part or their crushed material just like compound described in the claim 1, with organic solvent or hot water extraction and the concentrated cut that contains same compound, liliaceous plant is preferably Aloe vulgaris (Aloe barbadensis Miller) especially.

The present invention also is provided at hyperglycemia and improves with in the preparation of pharmaceuticals, The compounds of this invention or contain the application of this compound compositions.For application of the present invention, above-mentioned composition is preferably to contain by dry mass counts extract or its cut more than or equal to the liliaceous plant of 0.001 quality % above-claimed cpd, and liliaceous plant is preferably Aloe vulgaris (Aloe barbadensis Miller) especially.

The present invention also provides a kind of method, and it is a method of improving hyperglycemia, it is characterized in that, with The compounds of this invention or contain this compound compositions and give the object that desire is improved hyperglycemia.Method of the present invention, above-mentioned composition is preferably to contain by dry mass counts extract or its cut more than or equal to the liliaceous plant of 0.001 quality % above-claimed cpd, and liliaceous plant is preferably Aloe vulgaris (Aloe barbadensis Miller) especially.

Description of drawings

[Fig. 1] is the GC-MS spectrogram (photo that replaces accompanying drawing: the half tone image that shows on the indicating meter) of the aglycon partial acetylation thing of glucosides of the present invention

[Fig. 2] is the aglycon partial acetylation thing of glucosides of the present invention ¹³C-NMR spectrogram (the photo that replaces accompanying drawing: the half tone image that shows on the indicating meter).

[Fig. 3] be the expression given The compounds of this invention mouse usual blood glucose value through hourly variation.

[Fig. 4] be the expression given The compounds of this invention mouse blood glucose value on an empty stomach through hourly variation.

Embodiment

Next, preferred implementation of the present invention is elaborated.But the present invention is not limited to following preferred implementation, can carry out within the scope of the invention freely changing.

The compound of compound of the present invention for having structure shown in the above-mentioned chemical formula (1), i.e. 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol.That is, compound of the present invention has the structure of 1 hydroxyl dehydrating condensation of 3 hydroxyls of 4-methyl ergot steroid-7-alkene-3-alcohol and D-glucose.

In addition, composition of the present invention be contain by dry mass count more than or equal to 0.001 quality %, be preferably more than equal 0.01 quality %, more preferably more than or equal to extract or its cut of the liliaceous plant of 0.1 quality % The compounds of this invention.The upper limit of the content of the The compounds of this invention that contains in the composition of the present invention is not particularly limited, and can enumerate 50 quality %, 70 quality % or 90 quality %.

Compound of the present invention or contain this compound compositions, can be prepared as follows: for example belong to liliaceous plant, contain in the plant or its part or their crushed material of The compounds of this invention, utilize organic solvent or hot water extraction and concentrate the cut that contains same compound.

Belong to liliaceous plant and can enumerate the plant that belongs to Aloe or allium as above-mentioned.Can enumerate Aloe vulgaris (Aloe barbadensisMiller) as aloe plant, Aloe ferox Miller (Aloe ferox Miller), Africa aloe (Aloe africanaMiller), Aloe arborescens var. natalensis (Aloe arborescen Miller var.natalensis Berger), queen brocade aloe (Aloe spicata Baker) etc.When preparing compound of the present invention or containing this compound compositions, can use the whole of above-mentioned plant, but preferably use mesophyll (transparent colloid part).The preferred homogenizer etc. of using of this kind of plant or its part is pulverized and become aqueously, and extract with organic solvent or hot water.As organic solvent, can enumerate alcohol such as methyl alcohol, ethanol, butanols; Esters such as ritalin, vinyl acetic monomer, propyl acetate, N-BUTYL ACETATE; Ketone such as acetone, methyl iso-butyl ketone (MIBK); Ether such as ether, sherwood oil; Hydrocarbon such as hexane, hexanaphthene, toluene, benzene; Halohydrocarbon such as tetracol phenixin, methylene dichloride, chloroform; Heterogeneous ring compounds such as pyridine, dibasic alcohol such as ethylene glycol; Polyvalent alcohols such as polyoxyethylene glycol; Mixed solution of nitrile solvents such as acetonitrile and these solvents etc.In addition, these solvents can be anhydrous, also can be saturation states.In these solvents, preferred especially vinyl acetic monomer/butanol mixed liquid (3: 1) or chloroform/methanol mixed solution (2: 1).

Can use the method for in common plant constituent extracts, using as extracting method.These methods can be enumerated: usually with respect to 1 mass parts fresh plant or dried plant, use the organic solvent of 1～300 mass parts, stir on one side or vibration, on one side under smaller or equal to the temperature of solvent boiling point reflux or extract with ultrasonic wave at normal temperatures.Extracting solution can separate insolubles by proper methods such as filtration or centrifugations, obtains crude extract.

Crude extract can be by making with extra care such as the various chromatographic processes of positive or anti-phase silica gel column chromatography.In the normal phase silica gel column chromatography method, if use the gradient solvent of chloroform/methanol mixed solution as eluting solvent, at chloroform: methyl alcohol=left and right sides compound of the present invention will be by wash-out in 5: 1.And in the reversed-phase silica gel column chromatography method, if use the gradient solvent of methanol mixed solution as eluting solvent, in concentration was about 95% methyl alcohol, The compounds of this invention will be by wash-out.

The cut that obtains can further be made with extra care with HPLC etc.

For example, can confirm by the method shown in the aftermentioned embodiment: the compound that as above obtains or contain this compound compositions and all contain compound of the present invention.For example can pass through ¹³Affirmations such as C-NMR: it is the glucosides that is combined with glucose on the aglycon part, and aglycon partly is 4-methyl ergot steroid-7-alkene-3-alcohol.

Compound of the present invention can also be prepared by condensation D-glucose and 4-methyl ergot steroid-7-alkene-3-alcohol.4-methyl ergot steroid-7-alkene-3-alcohol can obtain by extracting from plant and making with extra care.The condensation of D-glucose and 4-methyl ergot steroid-7-alkene-3-alcohol can be made up method shown in the 4th edition experimental chemistry lecture 26,1992 (record in the 272nd page, the 297th page and the 342nd page) and be carried out.That is, after the complete acetylize of D-glucose, different bit map become α-bromide.In ether, make 4-methyl ergot steroid-7-alkene-3-alcohol after carrying out β-glycosylation, in sodium methylate methyl alcohol, make the ethanoyl hydrolysis, obtain target compound with α-bromide reaction.

Compound of the present invention has the effect that reduces hemoglobin A lc value, and its result can the long-term control blood glucose value.Therefore, can use as the effective ingredient of ameliorating agent for hyperglycemia.

In addition, in the leaf skin of Aloe vulgaris, contained Barbaloin A and rhabarberone in the past, thereby thought not preferred as pharmaceuticals or the diet product of not wishing to have laxative action with laxative action.On the other hand, in the optimal way of the present composition, owing to can obtain by extracting with fractionation the Aloe vulgaris mesophyll (transparent colloid part) that on edible experience, can absorb safely, therefore do not contain Barbaloin A and rhabarberone, and contain the The compounds of this invention of significant quantity.Therefore, the also preferred effective constituent of composition of the present invention as ameliorating agent for hyperglycemia.

Compound of the present invention or composition, can former state as the effective constituent of medicament of the present invention or diet product.And composition of the present invention can be a solution, also can carry out lyophilize or spraying drying by ordinary method and preserves, uses as powder.

Medicament of the present invention can make up with compound of the present invention or composition or with the preparations carrier that allows on they and the technology of pharmaceutics, comprises people's Mammals by oral or non-oral way.In addition, in medicament of the present invention, compound of the present invention can use pharmacologically acceptable salt.As pharmacologically acceptable salt, comprise two kinds of metal-salt (inorganic salt) and organic salts, their inventory can be enumerated disclosed material in " Remington ' s PharmaceuticalSciences, the 17th edition, the 1418th page, 1985 ".Particularly, inorganic acid salts such as example hydrochloric acid salt, vitriol, phosphoric acid salt, diphosphate and hydrobromate, organic acid salts such as malate, maleate, fumarate, tartrate, succinate, Citrate trianion, acetate, lactic acid salt, mesylate, tosilate, embonate, salicylate and stearate, but the present invention is not limited thereto.Can also be metal-salts such as sodium, potassium, calcium, magnesium, aluminium, perhaps with amino acids formed salt such as Methionins.In addition, the hydrate equal solvent compound of above-claimed cpd or its pharmacologically acceptable salt is also contained among the present invention.

The preparation way of medicament of the present invention is not particularly limited, can suitably select according to therapeutic purpose, particularly, can enumerate tablet, pill, powder, liquor, clouding agent, emulsion, granule, capsule, syrup, suppository, injection, ointment, patch, eye drops, nasal drop etc.In preparationization, can use in common hyperglycemia as preparations carrier and to improve with widely used vehicle in the pharmaceuticals, tackiness agent, disintegrating agent, lubricant, stablizer, correctives, thinner, tensio-active agent, injection with additives such as solvents.In addition, only otherwise damage effect of the present invention, can also be also has the medicament of hyperglycemia improvement effect with compound of the present invention or composition and other.

The The compounds of this invention that contains in the medicament of the present invention or the amount of composition are not particularly limited, can suitably select, as amount, can be 0.001～10 quality % in preparation, be preferably 0.01～1 quality %, be preferably 0.05～1 quality % especially as compound of the present invention.

The disease that medicament of the present invention helps to treat or prevent to be caused by hyperglycemia state, as diabetes and preceding diabetes (doubtful be the state of diabetes).Particularly can be used for prevention from the hyperglycemia state to the onset diabetes.

The medicament (ameliorating agent for hyperglycemia) that contains the invention described above in the pharmaceuticals of the present invention helps treatment or prevention to cause disease as diabetes and preceding diabetes (doubtful be the state of diabetes) by hyperglycemia state.Particularly can be used for prevention from the hyperglycemia state to the onset diabetes.And various diseases complication that is caused by hyperglycemia state etc. can be treated or prevent to pharmaceuticals of the present invention, and the danger that alleviates these disease complication etc.

As the various diseases complication that this hyperglycemia state causes, can enumerate the cerebral apoplexy that diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic gangrene, diabetes cause, myocardial infarction that diabetes cause etc.

In addition, hyperglycemia state is meant the state beyond normal range, normal range be meant general provision be on an empty stomach blood glucose value for (Japan is clinical for the state smaller or equal to 120mg/dl for the blood glucose value smaller or equal to 160mg/dl and 2 hours smaller or equal to the back 1 hour blood glucose value of 110mg/dl, load 75g sugar, No. the 806th, logical volume, the 1st volume, the 28th～35 page, 2002).Pharmacy optimization of the present invention is used for the treatment of state that hemoglobin A lc value is higher than healthy ordinary person, as hemoglobin A lc value for more than or equal to 5.8% patient.

The administration time of medicament of the present invention or pharmaceuticals is not particularly limited, and can select suitable administration time according to the methods of treatment of disease object.In addition, administering mode preferably decides according to degree of preparation form, patient age, sex, other conditions and patient's symptom etc.

The dosage of the effective constituent of medicament of the present invention is suitably selected according to the degree of usage, patient age, sex, disease and other conditions etc.Usually, as the amount of the The compounds of this invention of effective constituent can be preferably 0.01～10mg/kg/ day, more preferably the amount of 0.1～1mg/kg/ daily range is as standard, in addition, when using the present composition, as the dry weight of composition can be preferably 0.1～1000mg/kg/ day, more preferably the amount of 1～100mg/kg/ daily range is as standard.Under any circumstance can 1 time on the 1st or be divided into multiple dosing.

Medicament of the present invention or pharmaceuticals or be the The compounds of this invention or the composition of their effective constituent can be included in the diet product (beverage or food).As the diet product, but so long as do not damage the material of the effect orally ingestible of above-mentioned effective constituent, on form, proterties, just be not particularly limited, except containing above-mentioned effective constituent, can use the raw material that is generally used for the diet product, and utilize usual method to be prepared.

The The compounds of this invention that contains in the diet product of the present invention or the amount of composition are not particularly limited, can suitably select, for example as the amount of The compounds of this invention, can be in the diet product, be preferably 0.001～1 quality %, be preferably 0.005～1 quality % especially for 0.0001～1 quality %.

As the purposes of diet product of the present invention, can be to utilize hyperglycemia to improve the various uses of effect and so on.For example, can enumerate the person that is suitable for beginning to note the blood glucose value the diet product, help to reduce the purposes such as diet product of the dangerous essential factor of removing diseases due to habit disturbances such as diabetes.

In addition, in diet product of the present invention, " hyperglycemia improvement " is meant all infringements to health that improve or prevent to be caused by hyperglycemia, as with above-mentioned " hyperglycemia improvement " words and phrases equivalent in meaning, can also exemplify out " hyperglycemia prevention ", " suppress blood glucose value rise ", " improving blood glucose value rises ", " the prevention blood glucose value rises ", " improving hyperglycemia albumin A lc value " etc. in the present invention.

In addition, diet product of the present invention help to prevent by hyperglycemia state cause as diabetes and before the disease of diabetes (doubtful be the state of diabetes).Particularly can also be used for prevention from the hyperglycemia state to the onset diabetes.And diet product of the present invention can prevent all disease complication that caused by hyperglycemia etc., and the risk that reduces these disease complication etc.

As all disease complication that hyperglycemia state thus causes, can enumerate the cerebral apoplexy that diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic gangrene, diabetes cause, myocardial infarction that diabetes cause etc.

Diet product of the present invention are preferred to be sold as diet product that have the explanation that is used to improve hyperglycemia etc., described diet product for example " be expressed as be used for hyperglycemia improve, contain have the diet product that hyperglycemia is improved the effect compound " or " being expressed as the diet product that are used for the hyperglycemia improvement, contain plant milk extract " reach " being recited as the diet product that are used for the hyperglycemia improvement, contain aloe vera extract " etc.

In addition, compound of the present invention or composition etc. are owing to have a hyperglycemia improvement effect, therefore think also to contain in the explanation that hyperglycemia improves and suppress the meaning that blood sugar rises.Therefore, diet product of the present invention can be expressed as " being used to suppress blood sugar rises ".That is, the above-mentioned expression that is used for the hyperglycemia improvement also can be expressed as this " being used to suppress blood sugar rises ".

In addition, be not limited only to " being used for hyperglycemia improves " or " being used to suppress blood sugar rises " in order to carry out the employed statement of above-mentioned expression, also can be other statement, so long as expression improves the statement of the effect of hyperglycemia or the rising of inhibition blood glucose value, just comprise within the scope of the present invention naturally.As this statement, also can be as with respect to the needs person, based on confirming that hyperglycemia improves or suppress the expression of the various uses of the effect that blood glucose value rises.For example can enumerate " being suitable for blood glucose value is begun attention person ", expressions such as " are beneficial to and alleviate the dangerous essential factor (risk) of removing diseases due to habit disturbances such as diabetes ".

Above-mentioned " expression " is meant in order to make the person of needs recognize whole behaviors of such use, so long as make the expression of remembering class release such use, be not limited to any expression purpose, expression content, indicated object thing medium etc., all be equivalent to " expression " of the present invention.But, preferably can recognize directly that by the person of needs the statement of such use represents.Particularly, can exemplify out: the behavior of record such use in commodity that diet product of the present invention relate to or commodity packaging; The expression that will record such use in commodity or commodity packaging is transferred the possession of or is paid, in order to transfer the possession of or pay the displaying of being carried out, the behavior of import; On the advertisement relevant, priced catalogue or trade file, put down in writing such use with commodity, the behavior that they are showed or distribute, perhaps with these as the information of content in record such use and the behavior that provides by electromagnetism (Internet etc.) method etc.

On the other hand, as expression, (for example be preferably by the expression of approvals such as administrative department, approved based on the various systems of administrative department's regulation, mode based on this approval is represented), particularly be preferably at packing, container, catalogue, brochure, POP etc. and sell expression on on-the-spot show and colour and other book classes etc.

In addition, for example can enumerate expression as protective foods, functional foodstuff, enteral nutrition food, special used food, trophic function food, quasi drug etc., other expressions of being approved by MHLW can be enumerated: as specific food for health care, and the expression of quilt system approval similarly.Example as the latter, can enumerate expression of expression as specific food for health care, expression, the expression that is intended to influence body make-up and function, the risk that palliates a disease etc. as specific food for health care provisory, specifically, can enumerate as expression (the particularly expression of health caring use) and the expression similarly of promoting the specific food of stipulating in the method detailed rules for the implementation (put down on April 30th, 15 Japanese MHLW make No. 86) for health care in health as typical example.

Embodiment 1

The present invention will be described in more detail then to provide embodiment, but the present invention is not limited to following examples.

[preparation example 1]

Below provide the example of preparation 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol from Aloe vulgaris.

From Aloe vulgaris, extract and refining 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol as follows.

It is aqueous to utilize homogenizer that the mesophyll (transparent colloid part) of 100kg Aloe vulgaris is formed, and to wherein adding 100L vinyl acetic monomer/butanol mixed liquid (3: 1), and stirs.

After placing an evening, be layered as vinyl acetic monomer/butanol mixed liquid and water layer, reclaim vinyl acetic monomer/butanol mixed liquid.This vinyl acetic monomer/butanol mixed liquid is under reduced pressure concentrated, and the weight of the vinyl acetic monomer that obtains/butanol mixed liquid extract is 13.5g.

Use above-mentioned water layer and vinyl acetic monomer/butyl ester mixed solution extract, use diabetic mice described later to carry out the evaluation of hyperglycemia improvement effect, results verification with the effect that vinyl acetic monomer/the butanol mixed liquid extract is identical, therefore attempted the separation, refining of this extract component.At first, (Merck corporate system, silica gel 60F254 and RP-18F2543) studies the said extracted thing by tlc, and the result thinks that the separation method of the normal phase silica gel column chromatography method of having used the chloroform/methanol mixed solution is fit to.Therefore, in the post that is filled with 400g silica gel 60 (Merck corporate system), last sample is dissolved with the solution of 13g said extracted thing in 1ml chloroform/methanol mixed solution (1: 1), after making it be adsorbed in post, use the chloroform/methanol mixed solution, progressively linear gradient elution method by methanol concentration is progressively risen (each ratio of mixture be chloroform/methanol=100: 1,25: 1,10: 1,5: 1 and 1: 1) is carried out wash-out, fractionation elutriant under the ratio of mixture of each above-mentioned mixed solution.The receipts amount of removing the thick refining thing behind each cut solvent is respectively 1.44g, 3.0g, 1.17g, 1.28g, 2.27g.In these cuts, confirmed at chloroform: have activeconstituents in the cut of methyl alcohol=5: 1 times wash-outs (slightly refining thing A) by the method for having used above-mentioned animal pattern.And, after utilizing tlc to analyze, fail to confirm to exist Barbaloin A and rhabarberone.

In order further from above-mentioned thick refining thing A, to carry out the separation and purification of activeconstituents, use tlc (Merck corporate system, silica gel 60F254 and RP-18F2543) this slightly refining thing A studied after, think that the separation method of the reversed-phase silica gel column chromatography method of having used methyl alcohol is fit to.Therefore, above-mentioned thick refining thing A is dissolved in the 1ml chloroform/methanol mixed solution (1: 1), and be splined on the post that is filled with 180g COSMOSIL 140 (Nacalai Tesque corporate system), after making it be adsorbed on the post, carry out wash-out with 85% methanol solution of 600ml, 95% methanol solution of 600ml and 100% methyl alcohol of 100ml successively.3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol is concentrated from the eluting fraction of 95% methyl alcohol and separates, and the weight of removing behind its solvent is 370mg.Below, claim that this compound is a compound 1.

Compound 1 is carried out tlc research, and the result has shown the Rf value very approaching with the β-Gu Zaichun glucoside, therefore infers that it is the glucosides that partly is combined with 1 molecular saccharides at aglycon.And,, compound 1 is carried out after the methanolysis as the TMS derivative, and utilizes GC-MS to measure for the sugar of studying compound 1 is formed.Its result is as follows: the TMS derivative of measuring compound 1 sugar moieties, the retention time of its main peak is 14.28min, 14.61min, 16.34min, with retention time 14.27min, 14.60min, the 16.33min basically identical of glucose standard substance (Nacalai Tesque corporate system) main peak.In addition, do not see the suitable peak of main peak with semi-lactosi standard substance (Kishida corporate system) and wood sugar standard substance (Kishida corporate system).Therefore, the kind of the sugar that contains in the affirmation compound 1 is a glucose.

By above results presumption compound 1 is the glucosides that partly is combined with 1 molecule glucose at aglycon.But, use ¹³C-NMR (125MHz, CDCl ₃) measure compound 1, its results verification the existence of impurity, therefore think on structure is determined, also must carry out further refining.Therefore, after compound 1 methanolysis, carry out acetylize, thereby confirmed the combining site of the structure of aglycon part and aglycon part and sugar.Below provide its method.

After 50mg compound 1 was dissolved in the methyl alcohol (50ml) that contains 5% hydrochloric acid, reflux was carried out the methyl alcohol hydrolysis in 6 hours, carried out drying then, promptly got residue (about 30mg).(hexane: refining this residue chloroform=9: 1) promptly gets compound 2 (10mg) with silica gel column chromatography.Add acetic anhydride pyridine (each 2) in this compound 2 (5mg), heat down at 70 ℃ and carried out acetylize in 30 minutes, the solvent of reaction solution is removed in distillation then, promptly gets compound 3.With GC-MS and ¹³C-NMR (125MHz, CDCl3) analyzes this compound 3, and the result is shown in respectively among Fig. 1 and Fig. 2.Condition determination and result are as follows.In addition, as 3-acetoxyl group-4-methylergostane-7-alkene that standard substance uses, be after extraction is made with extra care from aloe, to use ¹³C-NMR has confirmed that the laggard capable acetylize of structure makes.

[ ¹³C-NMR collection of illustrative plates (d value, CDCl ₃In)]; C-1:36.8, C-2:27.3, C-3:78.7, C-4:37.0, C-5:46.9, C-6:26.8, C-7:117.4, C-8:139.4, C-9:49.7, C-10:34.9, C-11:21.6, C-12:39.7, C-13:43.6, C-14:55.1, C-15:23.1, C-16:28.2, C-17:56.3, C-18:12.0, C-19:14.2, C-20:36.5, C-21:19.0, C-22:33.9, C-23:30.6, C-24:39.1, C-25:32.6, C-26:20.4, C-27:18.4, C-28:15.6, C-29:15.3

[GC-MS]

Device: GC-17A/GCMS5050A (Tianjin, island)

GC post: NEUTRA BOND-5 (GL Scienses)

Column temperature: 100 ℃ (2 minutes) → (10 ℃/minute) → 300 ℃ (28 minutes)

Sample introduction temperature: 250 ℃

Carrier gas: He (1.3mL/ branch)

Interface temperature: 300 ℃

MS mode: EI

Ionization energy: 70eV

[result]

Reference material: 3-acetoxyl group-4-methyl ergot steroid-7-alkene: 4tR[min]=39.4; M/z456[M] ⁺, 441[M-CH ₃] ⁺, 396[M-AcOH] ⁺, 381[M-CH ₃-AcOH] ⁺

Compound 3:tR[min]=39.2; M/z 456[M] ⁺, 441[M-CH ₃] ⁺, 396[M-AcOH] ⁺, 381[M-CH ₃-AcOH] ⁺

By the measurement result of NMR as can be known, compound 3 consistent with the literature value of 3-acetoxyl group-4-methyl ergot steroid-7-alkene (oiling is learned, the 36th volume, No. 5, the 301st～319 page, 1987 years).The result can confirm that compound 2 is 4-methyl ergot steroid-7-alkene-3-alcohol thus.Use FAB-MS to measure, the result is that the molecular weight of compound 1 is 576.When dehydrating condensation compound 2 (aglycon part) and glucose, the molecular weight of gained compound is 414 (glucose)-18, (compound 2)+180 (water)=576, and is consistent with the molecular weight of compound 1.

Can confirm that by The above results the structure of compound 1 is 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol.

Below provide separately molecular formula, molecular weight and chemical formula.

(compound 1)

Molecular formula: C ₃₅H ₆₀O ₆

Molecular weight: 576

Chemical formula: following chemical formula (1)

[changing 2]

(compound 2)

Molecular formula: C ₂₉H ₅₀O

Molecular weight: 414

Chemical formula: following chemical formula (2)

[changing 3]

(compound 3)

Molecular formula: C ₃₁H ₅₂O ₂

Molecular weight: 456

Chemical formula: following chemical formula (3)

[changing 4]

[preparation example 2]

The mesophyll of heat drying Aloe vulgaris (transparent colloid part), in the dry Aloe vulgaris powder that 0.3g pulverizes, add 60%, 80% or 100% ethanol of 60ml after, 60 ℃ of following reflux 1 hour.With extracting solution centrifugation 20 minutes under 1500rpm, supernatant liquor is under reduced pressure concentrated, remove ethanol fully, promptly get crude extract.The crude extract dry weight that the extraction using alcohol of use 60%, 80% and 100% obtains is respectively 65mg, 42mg, 18mg.Confirm all to contain in these crude extracts 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol by tlc.

[preparation example 3]

The mesophyll of heat drying Aloe vulgaris (transparent colloid part), in the dry Aloe vulgaris powder that 0.3g pulverizes, add 60ml water after, 95 ℃ of following reflux 5 hours.With extracting solution centrifugation 20 minutes under 1500rpm,, promptly get the 75mg crude extract with the supernatant liquor lyophilize.Confirm to contain in this crude extract 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol by tlc.

[preparation example 4]

The mesophyll of heat drying Aloe vulgaris (transparent colloid part), with its pulverizing and carry out drying, in the Aloe vulgaris powder that 21kg prepares thus, after adding 90 liters of chloroform/methanol mixed solutions (2: 1), at room temperature flood an evening, filter then, in filtration residue, add 90 liters of chloroform/methanol mixed solutions (2: 1) once more, carry out 4 same operations.Concentrate the filtrate (350 liters) that obtains down at 28 ℃, finally obtain the 784g crude extract.Wherein, in the 780g crude extract, add 2 liters of chloroform/methanol mixed solutions (2: 1), stir 1 hour after-filtration, reclaim chloroform/methanol and mix liquid layer (A).In filtration residue, add 2.5 premium on currency and 2 liters of vinyl acetic monomers successively, stir and reclaim vinyl acetic monomer layer (B) after 1 hour, in the water layer of remnants, add 5 liters of chloroforms once more, stir and reclaim chloroform layer (C) after 1 hour.

Mix A, the B and the C organic solvent extraction liquid that reclaim, after concentrating under 23 ℃, be splined on silicagel column (glass column: 52mm * 350mm, weighting agent: IR-63/210-W (Daiso Co., Ltd. system)).Then, detect eluate with tlc, simultaneously use 10 liters of hexane/chloroform mixed solutions (1: 1), 10 liters of chloroforms, 20 liters of chloroform/methanol mixed solutions (10: 1) and 20 liters of chloroform/methanol mixed solutions (5: 1) to carry out wash-out successively, by the order of each eluting solvent, reclaim cut 1 (about 1 liter), cut 2 (about 1.5 liters), cut 3 (about 1.5 liters) and cut 4 (about 1.5 liters).

Wherein, after containing the target glucosides in the tlc affirmation cut 3, remove and desolvate, promptly get the 131.6g crude extract.This 130g crude extract is splined on silicagel column [glass silicagel column: 70mm * 500mm once more, weighting agent: SP-60-40/60 (Daiso Co., Ltd. system)], respectively with 10 liters of chloroform/methanol mixed solutions (30: 1), 50 liters of chloroform/methanol mixed solutions (20: 1), 10 liters of chloroform/methanol mixed solutions (10: 1), 10 liters of chloroform/methanol mixed solutions (1: 1) as eluting solvent, at pressure: 10kgfcm ^-2, flow velocity: 40ml/min condition under wash-out successively.With run tank elutriant is divided into cut of every 100ml, reclaims cut 1～8.

Utilize tlc to confirm the cut that reclaims, the result exists target glucosides and impurity as can be known in cut 7, therefore concentrate this cut, be splined on silicagel column [glass column: 70mm * 500mm once more, weighting agent: SP-60-40/60 (Daiso Co., Ltd. system)] respectively with 10 liters of chloroform/methanol mixed solutions (20: 1), 10 liters of chloroform/methanol mixed solutions (10: 1) as eluting solvent, at pressure: 10kgfcm ^-2, flow velocity: 40ml/min condition under wash-out successively.The result has obtained 25.3g in chloroform/methanol mixed solution (10: 1) eluting fraction be the 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol of target glucosides.

[test example 1]

This test is used to estimate the improve effect of 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol to hyperglycemia state.

(1) preparation of sample

The 3-O-β that will obtain in above-mentioned preparation example 1-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol is as test sample.

(2) test method

6 ages in week, male db/db mouse (buying) have been used as the type ii diabetes model mice from CLEA JAPAN company.With this mice group is 1 group 7.After test sample is dissolved in DMSO, the concentration of 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol is transferred to 15 μ g/ml with physiological saline.Final DMSO concentration transfers to 0.2%.Use irrigation stomach device to this type ii diabetes model mice 1 time on the 1st orally give 1ml test sample solution day after day.And will not contain the solution of test sample as negative sample.Use AntsenseII (Bayer three is corporate systems altogether) through the time measure blood glucose value and usual blood glucose value on an empty stomach.Blood glucose value is measured after going on a hunger strike 15 hours on an empty stomach.

(3) hyperglycemia is improved effect

Shown among Fig. 3 and Fig. 4 usual blood glucose value and on an empty stomach blood glucose value during the test sample administration through the time change.Though observe in the mouse that has given negative sample, usual blood glucose value and on an empty stomach in any one of blood glucose value blood glucose value all sharply rise, in the mouse that has given test sample continuously, observed the effect that suppresses the blood glucose value rising significantly.

[test example 2]

This test is used to estimate the reduction effect of 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol to hemoglobin A lc.

(1) preparation of sample

3-O-β-D-glucopyranosyl-4-methylergostane-7-alkene-3-the alcohol that will prepare in above-mentioned preparation example 1 is as test sample.

(2) test method

6 ages in week, male db/db mouse (buying) have been used as the type ii diabetes model mice from CLEA JAPAN company.With this mice group is 1 group 7.After test sample is dissolved in DMSO, with concentration furnishing 1,5, the 15 μ g/mls of physiological saline with 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol.Final DMSO concentration transfers to 0.2%.Use irrigation stomach device to this type ii diabetes model mice 1 time on the 1st orally give 1ml test sample solution day after day.And will not contain the solution of test sample as negative sample.In beginning the 35th day after the administration, use DCA2000 (Bayer three is corporate systems altogether) to measure hemoglobin A lc.

(3) the reduction effect of hemoglobin A lc

The 35th day hemoglobin A lc measurement result is shown in Table 1 after the beginning administration.Hemoglobin A lc value when having given negative sample is compared, and the hemoglobin A lc that the test sample group that has as seen given 5 or 15 μ g on the statistics continuously all has significance descends, and has shown long-term blood glucose value control effect.In addition, during administration, take place to cause that the example of glycopenia state does not once all have after side effect symptom and the administration that body weight and pathologic finding are also no abnormal.

[table 1]

Table 1

Sample	The 35th day blood hemoglobin Alc relative value (%) of administration	The p value
			Test sample (1 μ g) test sample (5 μ g) test sample (15 μ g) negative sample	98.6±7.3 89.6±7.9 * 73.5±8.6 * 100	0.017 0.00001

*: significant difference is arranged on the statistics.

[test example 3]

This test is used to extract thick refining thing A to the reduction effect of hemoglobin A lc and the research of dosage, and wherein, this slightly refining thing A contains the 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol that is derived from Aloe vulgaris.

(1) preparation of sample

The slightly refining thing A of the extraction that contains 3-O-β-D-glucopyranosyl-4-methyl ergot steroid-7-alkene-3-alcohol that use obtains in above-mentioned preparation example 1.

(2) test method

6 ages in week, male db/db mouse (buying) have been used as the type ii diabetes model mice from CLEA JAPAN company.With this mice group is 1 group 7.After test sample is dissolved in DMSO, will extract concentration furnishing 25,100, the 200 μ g/ml of thick refining thing A with physiological saline.Final DMSO concentration transfers to 0.2%.Use irrigation stomach device to this type ii diabetes model mice 1 time on the 1st orally give 1ml test sample solution day after day.And will not contain the solution of test sample as negative sample.In beginning the 35th day after the administration, use DCA2000 (Bayer three is corporate systems altogether) to measure hemoglobin A lc.

(3) blood glucose value and hemoglobin A lc value

The 35th day hemoglobin A lc measurement result is shown in Table 2 after the beginning administration.Compare with the hemoglobin A lc value of negative test, the hemoglobin A lc that has as seen given 100 or 200 μ g test sample groups continuously reduces, and has shown the long-term blood glucose value control effect that significant difference is arranged statistically.And, during administration, take place to cause that the example of glycopenia state does not once take place after side effect symptom and the administration that body weight and pathologic finding are also no abnormal.

[table 2]

Table 2

Sample	The 35th day blood hemoglobin Alc relative value (%) of administration	The p value
			Test sample (slightly refining thing 25 μ g) test sample (slightly refining thing 100 μ g) test sample (slightly refining thing 200 μ g) negative sample	92.5±7.1 84.9±8.2 * 82.0±8.6 * 100	0.1571 0.0275 0.0129

*: significant difference is arranged on the statistics.

Industrial applicability

Compound of the present invention is for causing hypoglycemia, safely administration or picked-up, and has the long-term blood glucose value control action that can reduce the HbAlc value. In addition, composition of the present invention can be prepared with the liliaceous plant that can absorb safely, obtain easy plant such as Aloe or allium on the edible experience. In addition, composition of the present invention is the material that contains the compounds of this invention of effective dose, does not contain barbaloin or the aloe-emodin of not preferred composition in promising pharmaceuticals or the diet product in the optimal way.

Claims (16)

1. compound, it has structure shown in the following chemical formula (1).

[changing 1]

2. composition, it contains by dry mass counts more than or equal to the described compound of the claim 1 of 0.001 quality %.

3. composition as claimed in claim 2, it is extract or its fraction of liliaceous plant.

4. composition as claimed in claim 3, wherein, liliaceous plant is Aloe vulgaris (Aloe barbadensis Miller).

5. ameliorating agent for hyperglycemia, its with the described compound of claim 1 or each described composition of claim 2～4 as effective constituent.

6. pharmaceuticals is characterized in that, contain the described ameliorating agent for hyperglycemia of claim 5.

7. diet product is characterized in that, contain the described ameliorating agent for hyperglycemia of claim 5.

8. diet product, it has to be used to the improving explanation that hyperglycemia is an aim, it is characterized in that, the described compound of claim 1 or each described composition of claim 2～4 is contained as effective constituent, and have hyperglycemia improvement effect.

9. method, it is described compound of claim 1 or the preparation of compositions method that contains same compound, it is characterized in that, from the liliaceous plant or its part or their crushed material that contain the described compound of claim 1, with organic solvent or hot water extraction and the concentrated cut that contains same compound.

10. method as claimed in claim 9, wherein, liliaceous plant is Aloe vulgaris (Aloe barbadensis Miller).

11. be used for improving the pharmaceuticals of hyperglycemia in preparation, to compound with structure shown in the following chemical formula (1) or the application that contains this compound compositions.

[changing 2]

12. application as claimed in claim 11, wherein, above-mentioned composition is to contain by dry mass to count extract or its fraction more than or equal to the liliaceous plant of 0.001 quality % above-claimed cpd.

13. application as claimed in claim 12, wherein, liliaceous plant is Aloe vulgaris (Aloe barbadensis Miller).

14. a method, it is a method of improving hyperglycemia, it is characterized in that, the object that improves hyperglycemia to desire has the compound of structure shown in the following chemical formula (1) or contains this compound compositions to son.

[changing 3]

15. method as claimed in claim 14, wherein, above-mentioned composition is to contain by dry mass to count extract or its substep isolate more than or equal to the liliaceous plant of 0.001 quality % above-claimed cpd.

16. method as claimed in claim 15, wherein, liliaceous plant is Aloe vulgaris (Aloe barbadensis Miller).

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