CN109952286A - Skin protection composition based on Dendrobium ingredient - Google Patents

Skin protection composition based on Dendrobium ingredient Download PDF

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Publication number
CN109952286A
CN109952286A CN201780069402.9A CN201780069402A CN109952286A CN 109952286 A CN109952286 A CN 109952286A CN 201780069402 A CN201780069402 A CN 201780069402A CN 109952286 A CN109952286 A CN 109952286A
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skin
compound
alkyl
independently selected
dihydro
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CN109952286B (en
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张宏杰
曾少慧
朱宇
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Hong Kong Baptist University HKBU
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Hong Kong Baptist University HKBU
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Priority claimed from US15/351,636 external-priority patent/US9738581B2/en
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    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
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    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
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Abstract

The present invention is to be related to the composition of skin-whitening and skin sparing; it includes the applications from the stilbene class of acquisition in Dendrobium Sw (such as dendrobium candidum and HERBA DENDROBII) and/or the extract of the class containing stilbene, and in management melanin production, skin darkening and skin aging.More particularly it relates to which Dendrobium ingredient and stilbene class are used to reduce the purposes of melanin formation in melanocyte.The present invention is also related to Dendrobium ingredient and stilbene class is used to reduce the purposes of active oxygen species and oxyradical generation.The present invention is also related to the extract of Dendrobium derivative or ingredient or stilbene class are used to deploy the purposes of skin sparing, skin-whitening and/or resisting age of skin product.The present invention, which also provides, to be used to prepare for treatment, prevention and/or delay skin darkening progress or for skin-whitening and the compound of the composition of skin sparing, which is from dihydro-resveratrol synthesis.The present invention also provides relevant synthetic method.

Description

Skin protection composition based on Dendrobium ingredient
Inventor
Zhang Hongjie, Zeng Shaohui, Zhu Yu
Cross reference to related applications
The right that present application requires is: (1) the U.S. Non-provisional Patent patent application serial numbers 15/ that on November 15th, 2016 submits 351,636；The U.S. Non-provisional Patent patent application serial numbers 15/352,903 that on November 16th, (2) 2016 submits；And (3) 2017 The U.S. Non-provisional Patent patent application serial numbers 15/633,780 submitted on June 27, wherein U.S. Non-provisional Patent application sequence Number 15/351,636, it is the U.S. Non-provisional Patent application for the patent application serial numbers 14/740,410 submitted on June 16th, 2015 Part continues, and U.S. Non-provisional Patent patent application serial numbers 15/352,903 are the patent application serial numbers submitted on June 16th, 2015 The part of 14/740,410 U.S. Non-provisional Patent application continues, U.S. Non-provisional Patent patent application serial numbers 15/633,780, It is the divisional application of the U.S. Non-provisional Patent application for the patent application serial numbers 15/351,636 submitted on November 15th, 2016, owns The disclosure of above-mentioned patent application is incorporated herein by reference.
Technical field
The present invention relates to skin protection composition, it includes from Dendrobium Sw (such as dendrobium candidum (Dendrobium Officinale) and HERBA DENDROBII (Dendrobium nobile)) in the stilbene class of acquisition and/or the extract of the class containing stilbene, and Manage the application in melanin production, skin darkening and skin aging.More particularly it relates to which Dendrobium ingredient is used for Reduce the purposes of melanin formation in melanocyte.It is also related to Dendrobium ingredient for reducing active oxygen in melanocyte Species and the purposes of oxyradical generation.The invention further relates to the extracts of Dendrobium derivative or ingredient allotment skin to protect Shield, the purposes of skin-whitening and/or resisting age of skin product.
Background technique
In general, light skin be exposed to daylight can blackening, daylight is that (UV) ultraviolet in daily life radiates it Main source.When being exposed to ultraviolet light, active oxygen (reactive oxygen species, ROS) and high volatile can be caused The generation of free radical.Then the melanocyte generated in skin epidermis can accordingly generate more melanin, by soma it Indirect injury minimizes, therefore leads to skin darkening, and [Sklar LR, Almutawa F, Lim HW, Hamzavi I. are " ultraviolet Radiation, the effect of visible light and infra-red radiation to erythema and pigmentation: (Effects of ultraviolet is commented radiation,visible light,and infrared radiation on erythema and pigmentation:a Review.) " photochemistry and photobiology (Photochemical&Photobiological Sciences) " 2013；12:54- 64].In other words, the defense mechanism of melanin increased actually for UV radiation；However, the accumulation of melanin there may be Harmful biological effect, including abnormal pigmentation, skin darkening and aesthetic problem, such as freckle or chloasma [Mishima Y, Imokawa G. " in vitro make the melanosome selectivity of malignant melanoma cell by glycosylation inhibitor The loss of not normal and pigment: premelanosome is as glycoprotein (Selective aberration and pigment loss in melanosomes of malignant melanoma cells in vitro by glycosylation Inhibitors:premelanosomes as glycoprotein.) " " dermatological studies magazine (Journal of Investigative Dermatology)"1983；81:106-114].In this regard, the formation of ROS and free radical is to cause The key mechanism of skin darkening and skin aging.Removing ROS and free radical can protect Skin Cell from oxidative damage.Mesh Before, vitamin A, vitamin C, vitamin E, ascorbic acid (ascorbic acid, AC), Butylated hydroxy anethole The external applications antioxidant such as (butylated hydroxyanisole, BHA) and/or its derivative is widely used in over the counter skin In the product of nursing.However, these products and the non-concurrent double grading with depigmentaton and anti-oxidant effective skin sparing.Cause This, these substances are very limited to the effect of skin sparing and are restricted.It is public there are a concept, that is, black and dimness Skin makes one to seem old, gloomy and become ugly；Therefore, people more thirst for keeping fair complexion in people, especially oriental countries And its it is apparent desirable.
In fact, melanin refers to one group of endogenous pigment, a variety of skin colors can be generated, the colour of skin is will cause and generates sparrow Spot, birthmark and senile plaque are also present in eyes and hair.In human body, melanin is generated and is divided by melanocyte Three main Types: eumelanin, false melanin and neuromelanin.They the difference is that chemical structure and physical characteristic, These melanin difference biological respinse as caused by outside stimulus and generate.Eumelanin and false melanin exist in skin Two types melanin.Eumelanin mainly provides dark brown to black, and false melanin generate pale red [Maresca V, " colour of skin: " pigment is thin for a New Century Planned Textbook (Skin phototype:a new perspective.) by Flori E, Picardo M. Born of the same parents and melanoma research (Pigment Cell&Melanoma Research) " 2015；28:378-389].It is raw in melanin Cheng Zhong, Tyrosinase is the prevailing rate restriction enzyme for adjusting melanin generation in epidermal melanocytes, and Tyrosinase is related Albumen (tyrosinase-related protein, TRP) is the ratio for controlling carboxylation sub-cell in melanin biopolymer Melanin generate enzyme.When being exposed to daylight, because melanocyte discharges more α-melanocyte and stimulates hormone (alpha-melanocyte-stimulating hormone, α-MSH), melanin deposition accelerate.Except obvious skin darkening it Outside, such to accelerate the defense mechanism that actually cutaneous acupuncture generates the ROS and/or free radical of UV induction, therefore cause face Generate wrinkle, freckle, fash and senile plaque.In general, continue or excessively ill-effect caused by sunshine or UV exposure includes Skin aging, skin injury even cutaneum carcinoma.The present invention provides a kind of group for effectively weakening melanin and oxidation material synthesis Close object.By any mechanism form, the present invention can limit the accumulation of the melanin in skin and/or oxidative damage, therefore can Realize skin sparing.
The composition of the present invention includes from Dendrobium (orchid family (Orchidaceae), be commonly referred to as " dendrobium nobile ") plant, especially certainly The stilbene class and/or extract of acquisition in dendrobium candidum and HERBA DENDROBII.It is generated because it effectively reduces ROS and oxyradical, and/ Or the cell melanin content in reduction melanocyte, the stilbene class, the especially white black false hellebore of trans-res-veratrol and dihydro- Alcohol and extract can be formulated into the cosmetic admixture of the protection for human skin, whitening and/or resisting age of skin product. Pigment generates enzyme, that is, Tyrosinase, TRP-1 and TRP-2, the inhibition of activity melanin can be inhibited to be formed.
Summary of the invention
Therefore, the present invention relates to skin protection composition, it includes from Dendrobium Sw (such as dendrobium candidum and golden hairpin stone Dry measure used in former times) extraction stilbene class and/or the class containing stilbene extract.The extract or ingredient that the present invention is also related to Dendrobium derivative are for reducing Melanin is formed to manage the purposes of melanin production and skin darkening in melanocyte.In specific words, the present invention is also related to The extract or ingredient of Dendrobium derivative deploy the purposes of skin sparing, skin-whitening and/or resisting age of skin product.
It is to provide in the first embodiment of the first aspect of the present invention a kind of for containing the internal organ of individual in need The compound of astrocyte fibrosis mediator present in organ or the compound prepare the internal organs for containing the individual It is middle there are astrocyte fibrosis mediator composition purposes.The compound has following formula:
Wherein,
R2And R4Respectively independently selected from-OR11And-OC (O) R11；
R1、R3、R5、R6、R7、R8、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR11And-OC (O) R11；Or R2 And R3Or R7And R8Cyclic group can be formed together together with the carbon atom of its attachment；
R11It independently is hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R12It takes Generation；
R12Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR13、-C(O)R14、-C(O)N(R13)R14、-C (O)OR13、-OC(O)R14、-S(O)2R13、-S(O)2N(R13)R14、-N(R13)R14；
R13And R14Be each independently hydrogen or selected from alkyl and heterocycle, any one optionally through 1,2,3,4 or 5 independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its enantiomter；
Or its pharmaceutically acceptable salt or prodrug；
Or the mixture of the compound, its derivative and/or chemical variation body.
In the second embodiment of the first aspect of the present invention, provide a kind of for containing internal organs within individual in need The compound of astrocyte fibrosis mediator present in official or compound preparation are deposited in the internal organs for containing the individual Astrocyte fibrosis mediator composition purposes, wherein the compound have following formula:
In the first embodiment of the second aspect of the present invention, provide a kind of for containing internal organs within individual in need The method of astrocyte fibrosis mediator present in official, it includes give to individual in need comprising formula (i) to (viii) One or more of compound or dihydro-resveratrol [that is, formula (2)] composition.
In the second embodiment of the second aspect of the present invention, provide a kind of for containing internal organs within individual in need The method of astrocyte fibrosis mediator present in official, wherein it is at least daily to give individual in need for the composition The dosage of 1.622mg/kg, wherein the composition is made of the compound with following formula:
In the 3rd embodiment of the second aspect of the present invention, provide a kind of for containing internal organs within individual in need The method of astrocyte fibrosis mediator present in official, wherein the individual is the mankind.
In the fourth embodiment of the second aspect of the present invention, provide a kind of for containing internal organs within individual in need The method of astrocyte fibrosis mediator present in official, wherein the composition orally administration individual in need.
In the 5th embodiment of the second aspect of the present invention, provide a kind of for containing internal organs within individual in need The method of astrocyte fibrosis mediator present in official, wherein internal organs include pancreas, liver, kidney and lung.
In the sixth embodiment of the second aspect of the present invention, the composition orally administration individual.
In the first embodiment of the third aspect of the present invention, provide a kind of compound, be used for therapeutically effective amount it Following formula: compound treats the Pancreatogenic diabetes (or 3c patients with type Ⅰ DM) of individual in need:
Wherein,
R2And R4It is each independently selected from-OR11And-OC (O) R11；
R1、R3、R5、R6、R7、R8、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR11And-OC (O) R11；Or R2 And R3Or R7And R8Cyclic group can be formed together together with the carbon atom of its attachment；
R11It independently is hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R12It takes Generation；
R12Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR13、-C(O)R14、-C(O)N(R13)R14、-C (O)OR13、-OC(O)R14、-S(O)2R13、-S(O)2N(R13)R14、-N(R13)R14；
R13And R14Be each independently hydrogen or selected from alkyl and heterocycle, any one optionally through 1,2,3,4 or 5 independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its enantiomter；
Or its pharmaceutically acceptable salt or prodrug；
Or the mixture of the compound, its derivative and/or chemical variation body.
In the second embodiment of the third aspect of the present invention, provide a kind of for treating the pancreas source property of individual in need The method of diabetes (or 3c patients with type Ⅰ DM), it includes use the composition comprising following formula: compound:
Wherein,
R2And R4It is each independently selected from-OR11And-OC (O) R11；
R1、R3、R5、R6、R7、R8、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR11And-OC (O) R11；Or R2 And R3Or R7And R8Cyclic group can be formed together together with the carbon atom of its attachment；
R11It independently is hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R12It takes Generation；
R12Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR13、-C(O)R14、-C(O)N(R13)R14、-C (O)OR13、-OC(O)R14、-S(O)2R13、-S(O)2N(R13)R14、-N(R13)R14；
R13And R14Be each independently hydrogen or selected from alkyl and heterocycle, any one optionally through 1,2,3,4 or 5 independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its enantiomter；
Or its pharmaceutically acceptable salt or prodrug；
Or the mixture of the compound, its derivative and/or chemical variation body.
In the 3rd embodiment of the third aspect of the present invention, provide a kind of for treating the pancreas source property of individual in need The method of diabetes (or 3c patients with type Ⅰ DM), wherein the composition gives the agent of at least daily 1.622mg/kg of individual in need Amount, wherein the composition is made of the compound with following formula:
In the fourth embodiment of the third aspect of the present invention, provide a kind of for treating the pancreas source property of individual in need The method of diabetes (or 3c patients with type Ⅰ DM), wherein the individual is the mankind.
In the 5th embodiment of the third aspect of the present invention, provide a kind of for treating the pancreas source property of individual in need The method of diabetes (or 3c patients with type Ⅰ DM), wherein composition orally administration individual in need.
In the sixth embodiment of the third aspect, which is used to prepare the Pancreatogenic diabetes for treating the individual The composition of (or 3c patients with type Ⅰ DM), and the individual is the mankind.
In the first embodiment of the fourth aspect of the present invention, provide a kind of for treating the pancreas source property sugar of individual in need The composition for urinating sick (or 3c patients with type Ⅰ DM), it includes the compounds with one of following formula of therapeutically effective amount:
In the second embodiment of the fourth aspect of the present invention, provide a kind of for treating the pancreas source property of individual in need The composition of diabetes (or 3c patients with type Ⅰ DM), wherein the composition gives the dosage of at least daily 1.622mg/kg of the individual, Wherein the composition is made of the compound with following formula:
In the 3rd embodiment of the fourth aspect of the present invention, provide a kind of for treating the pancreas source property of individual in need The composition of diabetes (or 3c patients with type Ⅰ DM), wherein the individual is the mankind.
In the first embodiment of the 5th aspect of the present invention, a kind of compound of formula (4) is provided:
Wherein,
R2、R4And R8It is each independently selected from-OR11、-OCH2R12、-OC(O)R11、-OCH2C(O)OR12And-OC (O) CH2R12；
R1、R3、R5、R6、R7、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR12And-OC (O) R12；Or R2And R3Or R7And R8Cyclic group can be formed together together with the carbon atom of its attachment；
R11Independently selected from-(CH2)-alkyl, C2-10Alkyl, alkenyl, naphthenic base, aryl and heterocycle, it is every in these groups One is optionally through 1,2,3,4 or 5 R13Replace；
R12Independently selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R13Replace；
R13Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR14、-C(O)R15、-C(O)N(R14)R15、-C (O)OR14、-OC(O)R15、-S(O)2R14、-S(O)2N(R14)R15、-N(R14)R15；
R14And R15Be each independently hydrogen or selected from alkyl and heterocycle, any one optionally through 1,2,3,4 or 5 independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its pharmaceutically acceptable salt or prodrug.
In the second embodiment of the 5th aspect of the present invention, a kind of compound of formula (4) is provided, wherein the compound is Its optics pure stereoisomers, enantiomter, racemic modification or diastereoisomer.
In the 3rd embodiment of the 5th aspect of the present invention, a kind of medical composition is provided, it includes the formulas of effective quantity (4) compound, its derivative and its pharmaceutically acceptable carrier.
In the fourth embodiment of the 5th aspect of the present invention, a kind of medical composition is provided, it includes the formulas of effective quantity (4) skin brightening and skin sparing compound, its derivative and its pharmaceutically acceptable carrier.
In the 5th embodiment of the 5th aspect of the present invention, a kind of formula (4) compound is provided, wherein the compound is choosing From DR1, DR2, DR3, DR4, DR5, DR6, DR7, DR8, DR9, DR10 or the DR11 for being respectively provided with following formula:
Or its pharmaceutically acceptable salt or prodrug.
In the sixth embodiment of the 5th aspect of the present invention, a kind of formula (4) compound and/or its derivative or change are provided Learn the purposes of variant, independent and/or other pharmaceutically acceptable skin brightenings and Derma-Guard with one or more Combination is used to prepare the composition for the skin darkening progress for treating, preventing or delaying individual in need.
In the 7th embodiment of the 5th aspect of the present invention, formula (4) compound and/or its derivative are provided or chemistry becomes The purposes of allosome, individually and/or other pharmaceutically acceptable skin brightenings and Derma-Guard combine with one or more, It is used to prepare the composition for treating, preventing or delaying skin darkening progress, wherein the individual is the mankind.
In the 8th embodiment of the 5th aspect of the present invention, provide it is a kind for the treatment of and prevention skin darkening development and into The method of exhibition, this method include to individual giving construction (4) compound in need and/or its derivative.
In the 9th embodiment of the 5th aspect of the present invention, provide it is a kind for the treatment of and prevention skin darkening development and into The method of exhibition, this method include to individual giving construction (4) compound in need and/or its derivative, and wherein the individual is people Class.
In the tenth embodiment of the 5th aspect of the present invention, formula (4) compound and/or its derivative are provided or chemistry becomes The purposes of allosome, individually and/or other pharmaceutically acceptable skin brightenings and Derma-Guard combine with one or more, It is used to prepare the composition of the skin darkening progress for treating, preventing or delaying individual in need, wherein the outer land used of the composition Coating.
In the 11st embodiment of the 5th aspect of the present invention, providing includes that individually and/or with one or more other are cured Formula (4) compound and/or its derivative or chemical variation body of pharmaceutically acceptable skin brightening and Derma-Guard combination Composition, wherein the composition be in paste, solid, powder, particle, lotion, day cream, late frost, face lotions, skin lotion, body Moisturizing after skin cream, solarization after body moisturizer, keratolytic (skin peel), facial mask, shower cream, suncream, sunlight lotion, solarization The form of dew, lipstick, lip honey or its analog.
In the first embodiment of the 6th aspect of the present invention, provide with formula (5) for UV exposure, skin injury and The skin brightening and skin sparing compound of aging:
Wherein,
R2、R4And R8It is each independently selected from-OR11、-OCH2R11、-OC(O)R11、-OCH2C(O)OR11And-OC (O) CH2R11；
R1、R3、R5、R6、R7、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR11And-OC (O) R11；Or R2And R3Or R7And R8Cyclic group can be formed together together with the carbon atom of its attachment；
R11It independently is hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R12It takes Generation；
R12Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR13、-C(O)R14、-C(O)N(R13)R14、-C (O)OR13、-OC(O)R14、-S(O)2R13、-S(O)2N(R13)R14、-N(R13)R14；
R13And R14Be each independently hydrogen or selected from alkyl and heterocycle, any one optionally through 1,2,3,4 or 5 independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its enantiomter, optics pure stereoisomers, racemic modification or diastereoisomer；
Or its pharmaceutically acceptable salt or prodrug.
In the second embodiment of the 6th aspect of the present invention, provide with following formula for UV exposure, skin injury and The skin brightening and skin sparing compound of aging:
Dihydro-resveratrol
Or its enantiomter；
Or its pharmaceutically acceptable salt or prodrug.
In the 7th aspect of the present invention, provides and a kind of synthesized respectively according to following synthesis flow from dihydro-resveratrol Formula
The method of the compound of DR1 to DR11:
The process 1 of DR1 to DR3:
Wherein,
R is-OR11、-OCH2R11Or-OCH2C(O)OR11；
R11For alkyl；
And
The process 2 of DR4 to DR11:
Wherein,
R is-R11Or-CH2R11；
R11For alkyl, optionally through 1,2,3,4 or 5 R12Replace；
R12For halogen or-OR13；And
R13For hydrogen or alkyl.
In one embodiment, according to process 1, by dihydro-resveratrol and RBr addition at dimethylformamide (DMF) And K2CO3In to form mixture.Gained mixture is stirred at room temperature, until initial substance disappears on thin-layer chromatography (TLC) It loses.Then mixture H2O is diluted and is washed three times with methylene chloride (DCM) to extract organic phase.The organic layer of merging is used full It is washed twice with sodium chloride (NaCl), through anhydrous Na2SO4It is dry, it is concentrated in a vacuum and by preparative (preparative) TLC (PE/EA=5/1 or 3/1) purifying, obtains required compound.
In other embodiments, according to process 2, dihydro-resveratrol and RCOCl are added to DCM and Et at 0 DEG C3N In, to form mixture.Gained mixture is warming up to room temperature and stirring, until initial substance disappears on TLC.Then mixture is used H2O is diluted and is washed three times with DCM to extract organic phase.The organic layer of merging is washed twice with saturation NaCl, through anhydrous Na2SO4 It is dry, it is concentrated and is purified by preparative TLC (PE/EA=5/1 or 3/1) in a vacuum, obtain required compound.
In in terms of other of the present invention, a kind of acute inflammation symptom for treating pancreas and related systemic complications are provided Method, by the composition for giving the stilbene analog derivative comprising formula (1) compound comprising effective quantity to individual in need,
Wherein R1、R2And R3It is each independently selected from alkyl.The term " alkyl " combined individually or with other groups includes referring to tool There are the linear alkyl moieties of 1,2,3,4,5 or 6 carbon atom.The term is by such as following further example of group Show: methyl, ethyl, propyl (n-propyl or isopropyl)), butyl (normal-butyl, the second butyl and third butyl), amyl, hexyl And its similar to group and its derivative or chemical variation body；Or the compound, its derivative and/or chemical variation body are mixed Close object.
In one embodiment in terms of other of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the stilbene analog derivative is trans- -3, and 5,4'- trihydroxy bibenzyls or dihydro-resveratrol are Formula (2) compound:
And its derivative or chemical variation body；Or the mixture of the compound, its derivative and/or chemical variation body.
In the other embodiments in terms of other of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the individual is mankind or animal.
In another embodiment in terms of other of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the composition orally administration.
In another embodiment in terms of other of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, the form of ownership and the correlation whole body that wherein the acute inflammation symptom of the pancreas includes acute pancreatitis are simultaneously Sending out disease includes pulmonary lesion.
In another embodiment in terms of other of the therefore present invention, provide a kind of acute inflammation symptom for treating pancreas and The method of related systemic complications, wherein the composition is no less than 3 times in one day with giving the individual not less than 20mg/kg.
In another embodiment in terms of other of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the composition is no less than 3 times in one day with giving the individual not less than 3.24mg/kg.
In the another aspect of the present invention, a kind of prepare with molecular formula C is provided14H14O3And the side of the compound of formula (2) Method,
It is with chemical name trans- -3, and the stilbene analog derivative of 5,4'- trihydroxy bibenzyls, this method is by trans--white Veratryl alcohol adds hydrogen.
In one embodiment of the another aspect of the present invention, a kind of prepare with molecular formula C is provided14H14O3And formula (2) Compound method, wherein trans-res-veratrol plus hydrogen comprise the steps of:
At room temperature in 5atm H2Under pressure in the presence of 10%Pd/C by trans-res-veratrol in dehydrated alcohol (EtOH) Solution stir 8 hours；
Catalyst is filtered off from agitating solution；
Filtrate is evaporated in vacuo to generate residue；
It is separated using silica gel column chromatography, with petroleum ether and ethyl acetate (1:1) separation residue to generate dihydro-resveratrol.
Skilled artisan will understand that the present invention described herein allow in addition to they's content of specific description into Row variation and modification.
The present invention includes all such variation and modification.The present invention also includes individually or collectively referring to or referring in this specification All steps and feature shown, and be somebody's turn to do and etc. or feature in appoint both or more than the two any and all combination.
Throughout this manual, except otherwise herein provided, otherwise word " include (comprise) " or such as " include (comprises) " or the version of " including (comprising) " is understood to mean that including stating whole or entirety Group, but it is not excluded for any other whole or whole group.In the present invention and especially in claim and/or paragraph In it should also be noted that such as " including (comprises) ", " including (comprised) ", " including (comprising) " and its similar The term of term can have the meaning that it is belonged in corresponding Patent Law；Such as its can refer to " including (includes) ", " including (included) ", " including (including) " and the like；And such as " substantially by ... form (consisting Essentially of) " and the term of " substantially by ... form (consists essentially of) " have the U.S. special Its meaning is belonged in sharp method, such as it makes element without clearly enumerating, but excludes found in prior art or influence The basis of the present invention or the element of novel feature.
In addition, this specification and claim in the whole text in, except otherwise herein provided, otherwise word " including (include) " or such as " including (includes) " or the version of " including (including) " be understood to mean that including It states whole or whole group, but is not excluded for any other whole or whole group.
Other definition of selection term used herein are found in specific embodiment and are applicable in the whole text.Unless in addition Definition, otherwise whole other technologies term used herein has is familiar with operator belonging to the present invention and is generally understood phase with general Same meaning.
Those who familiarize themselves with the technology will be by other aspects and advantage of the apparent present invention of the summary of subsequent specification.
Detailed description of the invention
When read in conjunction with the accompanying drawings, above and other targets of the invention and feature will become aobvious by the description of following present invention And it is clear to, in which:
Fig. 1 shows the influence of the pancreas oedema caused in rat due to the acute pancreatitis induced by bombesin and containing for generating Water increases.Gained weight is expressed as the ratio percentage of pancreas weight Yu weight.P value is considered as statistically significant less than 0.05 's.When compared with the control group, p < 0.05 *, and compared with bombesin group, #p < 0.05.
Fig. 2A to 2F is shown to be dyed by means of hematoxylin and eosin (H&E), control group (Fig. 2A), bombesin group (Fig. 2 B) and Dihydro-resveratrol processing group (D-Res) (structure and morphologic change in the pancreatic tissues of Fig. 2 C to 2F).Image with 50 μm it Scale bar is shown.
Fig. 3 A to 3E displaying is dyed by means of H&E, control group (Fig. 3 A), bombesin group (Fig. 3 B) and dihydro-resveratrol Processing group (D-Res) (structure and morphologic change in the lung tissue of Fig. 3 C to 3E).Image with 200 × magnifying power show.
Fig. 4 A, which is shown, is divided brightness method by means of colorimetric, measures control group, bombesin group and dihydro-resveratrol processing group (D-Res) the MPO activity of neutrophil cell sequestering effect is represented in pancreatic tissues.P value is considered as statistically less than 0.05 Significantly.When compared with the control group, p < 0.05 *, and compared with bombesin group, #p < 0.05.
Fig. 4 B, which is shown, is divided brightness method by means of colorimetric, measures control group, bombesin group and dihydro-resveratrol processing group (D-Res) the MPO activity of neutrophil cell sequestering effect is represented in lung tissue.P value is considered as statistically less than 0.05 Significantly.When compared with the control group, p < 0.05 *, and compared with bombesin group, #p < 0.05.
Fig. 5 A is shown by means of enzyme conjugation immunosorbent assays (ELISA), measures control group, bombesin group and dihydro- TNF-α content in the pancreatic tissues of resveratrol processing group (D-Res).P value is considered as statistically significant less than 0.05.When When compared with the control group, p < 0.05 *, and compared with bombesin group, #p < 0.05.
Fig. 5 B shows by means of ELISA, measure control group, bombesin group and dihydro-resveratrol processing group (D-Res) it TNF-α content in lung tissue.P value is considered as statistically significant less than 0.05.When compared with the control group, p < 0.05 *, And compared with bombesin group, #p < 0.05.
Fig. 6 A, which is shown, is divided brightness method by means of colorimetric, measures control group, bombesin group and dihydro-resveratrol processing group (D-Res) the sweet peptide content of bran Guang in pancreatic tissues.P value is considered as statistically significant less than 0.05.When with control group ratio Compared with when, p < 0.05 *, and compared with bombesin group, #p < 0.05.
Fig. 6 B shows dihydro-resveratrol (D-res) and trans--in the rat of the acute pancreatitis induced with bombesin Improvement result of the resveratrol (Res) to the water content reduction caused by pancreas oedema.Gained weight be expressed as pancreas weight with The ratio percentage of weight.P value is considered as statistically significant less than 0.05.When with the control group ratio through physiological saline water process Compared with when, p < 0.05 *, and compared with the control group handled through bombesin, #p < 0.05.
Fig. 7 is shown by means of the MTT in the pancreas acinar cells with dihydro-resveratrol and trans-res-veratrol processing Cell Proliferation measures metabolic rate.When compared with the cell without dihydro-resveratrol or trans-res-veratrol processing * p < 0.05。
Fig. 8 A to 8H shows eight kinds of derivatives from dihydro-resveratrol (that is, compound 2), and (that is, compound i is extremely Compound viii).
Fig. 8 I shows the chemical structural formula of dihydro-resveratrol (that is, compound 2).
Fig. 9 is shown and TGF-β (5ng/mL) pre-incubation and with 20 μ g/mL trans-res-veratrols (Resv) or dihydro-together Resveratrol or stilbene compounds i to viii handle the Western blot of 24 hours LTC-14PSC.Compare unused Resv or any The processing of stilbene class.
Figure 10 show with TGF-β (5ng/mL) together pre-incubation and with indicate concentration trans-res-veratrol (Resv) Or in the Western blot of dihydro-resveratrol processing LTC-14 cell α-SMA and FN1 detection.
Figure 11 shows the green florescent signal for meaning the fiber filament α-SMA of PSC activation degree in LTC-14 cell (by arrow Leader will identifies).
Figure 12 shows that the fiber in the mouse of the chronic pancreatitis with bombesin (Cer) induction in pancreatic tissues slice combines The fluorescence signal of albumen (FN1) deposition, with estimation through and without dihydro-resveratrol (D-Res, 20 mg kg days) or Degree of fibrosis under trans-res-veratrol (Res, 20 mg kg days) processing.
Figure 13 show Intraperitoneal Glucose tolerance test in pass through or without dihydro-resveratrol (D-Res, 20 milligrams/ Kg/day) normal mouse (control) of processing and the glucose response of chronic pancreatitis mouse (Cer).At all time points, Cer Significant difference (p < 0.05) is realized between group and Cer+D-Res group.
Figure 14 shows the fluorescence signal of insulin in pancreatic tissues slice, for assessing pancreas insulin secretory cell (also That is beta cell) region.At in control mice, chronic pancreatitis mouse and through 20 mg kg days dihydro-resveratrols (D-Res) It is compared between the chronic pancreatitis mouse of reason.
Figure 15 shows that Dendrobium stilbene class (25 μM) act on the containment of the cell melanin content in B16 melanocyte, Dendrobium stilbene class is dihydro-resveratrol (D-Res), trans-res-veratrol (Res) and compound DR1 to DR11.Ascorbic acid (AC) and BHA serves as positive control.Data are expressed as average value ± SEM (n=3).Relative to the cell handled through DMSO, * P < P < 0.01 0.05 and * *.
Figure 16 shows that Dendrobium stilbene class (25 μM) act on the containment of the cell melanin content in A375 melanocyte, Dendrobium stilbene class is dihydro-resveratrol (D-Res), trans-res-veratrol (Res) and compound DR1 to DR11.Ascorbic acid (AC) and BHA serves as positive control.Data are expressed as average value ± SEM (n=3).Relative to the cell handled through DMSO, * P < P < 0.01 0.05 and * *.
Figure 17 shows golden hairpin dendrobium extract (JCSH, 50 μ g/mL), dendrobium candidum extract (TPSH, 50 μ g/mL), anti- Formula-resveratrol (Res, 25 μM) and dihydro-resveratrol (D-Res, 25 μM) are to the cell melanin in B16 melanocyte The containment of content acts on.Ascorbic acid (AC) serves as positive control.Data are expressed as average value ± SEM (n=3).Relative to warp The cell of DMSO processing, P < 0.05 *.
Figure 18 shows that Dendrobium stilbene class (25 μM) make the active inhibition of cell Tyrosinase in B16 melanocyte With Dendrobium stilbene class is dihydro-resveratrol (D-Res), trans-res-veratrol (Res) and compound DR1 to DR11.It is anti-bad Hematic acid (AC) and BHA serve as positive control.Data are expressed as average value ± SEM (n=3).It is thin relative to being handled through DMSO Born of the same parents, P < 0.05 * and p < 0.01 * *.
Figure 19 shows that Dendrobium stilbene class (25 μM) make the active inhibition of cell Tyrosinase in A375 melanocyte With Dendrobium stilbene class is dihydro-resveratrol (D-Res), trans-res-veratrol (Res) and compound DR1 to DR11.It is anti-bad Hematic acid (AC) and BHA serve as positive control.Data are expressed as average value ± SEM (n=3).It is thin relative to being handled through DMSO Born of the same parents, P < 0.05 *.
Figure 20 shows golden hairpin dendrobium extract (JCSH, 50 μ g/mL), dendrobium candidum extract (TPSH, 50 μ g/mL), anti- Formula-resveratrol (Res, 25 μM) and dihydro-resveratrol (D-Res, 25 μM) are to the cell Tyrosine in B16 melanocyte The inhibiting effect of enzymatic activity.Ascorbic acid (AC) serves as positive control.Data are expressed as average value ± SEM (n=3).Relative to Cell through DMSO processing, P < 0.05 * and p < 0.01 * *.
Figure 21 shows golden hairpin dendrobium extract (JCSH, L:10 μ g/mL；M:25 μ g/mL；H:50 μ g/mL) and dendrobium candidum Extract (TPSH, L:10 μ g/mL；M:25 μ g/mL；H:50 μ g/mL), dihydro-resveratrol (D-Res, L:25 μM；H:50 μM) And ascorbic acid (AC, H:50 μ g/mL) to TRP-1, TRP-2, Phosphorylated-AKT and phosphorylation-p38 in B16 melanocyte it Containment effect.GAPDH serves as internal reference object.
Figure 22 shows golden hairpin dendrobium extract (JCSH, height: 50 μ g/mL；It is low: 25 μ g/mL), dendrobium candidum extract (TPSH, it is high: 50 μ g/mL；It is low: 25 μ g/mL), trans-res-veratrol (Res, it is high: 50 μM；It is low: 25 μM), dihydro-resveratrol (D-R, it is high: 50 μM；It is low: 25 μM) and ascorbic acid (AC, 50 μ g/mL) containment of ROS generation in B16 melanocyte is made With.Fluorescence signal measures under 488 nanometer of excitation wavelength.Data are expressed as average value ± SEM (n=3).Relative to unique TBHP It handles (that is, without Dendrobium extract or compound), p < 0.05 *.
Figure 23, which is shown, contained 2% trans-res-veratrol (Res) or 2% dihydro-resveratrol (D- at the 7th day and the 14th day Res whitening function of the stilbene class solution) to the arm of individual human individuals.
Specific embodiment
The scope of the present invention is not limited by any particular embodiment described herein.Following embodiment is merely illustrative and is in It is existing.
Definition
Alkyl
Term " alkyl " as used herein includes referring to the part being only made of hydrogen atom and carbon atom；Such part can Include aliphatic series and/or aromatic fractions.Part may include 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18, 19 or 20 carbon atoms.The example of alkyl includes C1-6Alkyl (such as C1、C2、C3Or C4Alkyl, for example, methyl, ethyl, propyl, Isopropyl, normal-butyl, the second butyl or third butyl)；C through aryl substitution1-6Alkyl (such as benzyl) takes through naphthenic base Instead of C1-6Alkyl (such as Cvclopropvlmethvl)；Naphthenic base (such as cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl)；Aryl (example Such as phenyl, naphthalene or Fluorene yl) and its similar group.
Alkyl
Term " alkyl " as used herein include refer to 1,2,3,4,5,6,7,8,9,10,11,12,13,14, 15, the straight chain of 16,17,18,19 or 20 carbon atoms or branched-chain alkyl part.The example of alkyl includes " C1-6Alkyl " and “C2-10Alkyl ".Term " C as used herein1-6Alkyl " include refer to straight chain with 1,2,3,4,5 or 6 carbon atom or Branched-chain alkyl part.Term " C as used herein2-10Alkyl " includes referring to 1,2,3,4,5,6,7,8,9 or 10 The straight chain of carbon atom or branched-chain alkyl part.This term includes referring to such as methyl, ethyl, propyl (n-propyl or isopropyl Base), butyl (normal-butyl, the second butyl or third butyl), amyl, hexyl and its similar group group.Moieties are especially There can be 1,2,3,4,5 or 6 carbon atom.
Alkenyl
Term " alkenyl " and " C as used herein2-6Alkenyl " includes referring to 2,3,4,5 or 6 carbon atoms and when suitable In addition used time has straight chain or the branched-chain alkyl part of the double bond of at least one E formula or Z formula spatial chemistry.This term includes mentioning And such as vinyl, 2- acrylic, 1- cyclobutenyl, 2- cyclobutenyl, 3- cyclobutenyl, 1- pentenyl, 2- pentenyl, 3- pentenyl, The group of 1- hexenyl, 2- hexenyl and 3- hexenyl and its similar group.
Alkynyl
Term " alkynyl " and " C as used herein2-6Alkynyl " includes referring to 2,3,4,5 or 6 carbon atoms and in addition Straight chain or branched-chain alkyl part at least one three key.This term includes referring to such as acetenyl, 1- propinyl, 2- third Alkynyl, 1- butynyl, 2- butynyl, 3- butynyl, 1- pentynyl, valerylene base, 3- pentynyl, 1- hexin base, 2- hexin base And the group of 3- hexin base and its similar group.
Alkoxy
Term " alkoxy " and " C as used herein1-6Alkoxy " include refer to-O- alkyl, wherein alkyl be straight chain or Branched chain and include 1,2,3,4,5 or 6 carbon atoms.In a kind of embodiment, alkoxy has 1,2,3 or 4 carbon atom. This term includes referring to such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, third butoxy, amoxy, own oxygen The group of base and its similar group.
Naphthenic base
Term " naphthenic base " as used herein includes referring to the alicyclic moiety with 3,4,5,6,7 or 8 carbon atoms.It should Group can be bridge joint or polycyclic loop system.More often, naphthenic base is monocycle.This term include refer to such as cyclopropyl, cyclobutyl, Cyclopenta, cyclohexyl, norborny, bicyclic [2.2.2] octyl and its group similar to group.
Aryl
Term " aryl " as used herein includes referring to comprising 6,7,8,9,10,11,12,13,14,15 or 16 ring carbons The aromatic ring systems of atom.Aryl is often phenyl, but can be aromatics for the wherein at least one ring with two or more rings Polycyclic loop system.This term includes the base for referring to such as phenyl, naphthalene, Fluorene base, azulenyl, indenyl, anthryl and its similar group Group.
Cyclic group
" cyclic group " means can be unsaturated for insatiable hunger and/or part, but usually saturation, and it is former to usually contain 5 to 13 cyclization The ring or loop system of son, such as 5 or 6 Yuans rings.Ring or loop system can replace through one or more alkyl.Cyclic group includes carbocylic radical And heterocyclyl moieties.
Carbocylic radical
Term " carbocylic radical " as used herein include refer to 3,4,5,6,7,8,9,10,11,12,13,14,15 or The saturation (such as naphthenic base) of 16 carboatomic ring atoms or unsaturated (such as aryl) loop section.Carbocylic radical especially includes 3 Yuans to 10 Member's ring or loop system and especially 5 or 6 Yuans rings, can be saturated or unsaturated.Ring or loop system can take through one or more alkyl Generation.Isocyclic part is, for example, to be selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, norborny, bicyclic [2.2.2] octyl, benzene Base, naphthalene, Fluorene base, azulenyl, indenyl, anthryl and its similar group.
Heterocycle
Term " heterocycle " as used herein include refer to 3,4,5,6,7,8,9,10,11,12,13,14,15 or The wherein at least one annular atom of 16 annular atoms is saturation (such as Heterocyclylalkyl) or insatiable hunger selected from nitrogen, oxygen, phosphorus, silicon and sulphur (such as heteroaryl) heterocyclic moiety.Heterocycle especially includes 3 Yuans to 10 Yuans rings or loop system and more specifically 5 or 6 Yuans rings, can It is saturated or unsaturated.Ring or loop system can replace through one or more alkyl.
Heterocyclic moiety be, for example, be selected from Oxyranyle, aziridinyl, 1,2- oxathiolane base, imidazole radicals, Mutter base, thio piperazine of thienyl, furyl, tetrahydrofuran base, piperazine is muttered base, thienyl, isobenzofuran-base, benzofuranyl, benzene And piperazine mutter base, 2H- pyrrole radicals, pyrrole radicals, pyrrolinyl, pyrroles's piperidinyl, pyrroles join piperidinyl, imidazole radicals, imidazoles piperidinyl, benzo miaow Oxazolyl, pyrazolyl, pyrazinyl, pyrazoles piperidinyl, thiazolyl, isothiazolyl, dithiazole base, oxazolyl, isoxazolyl, pyridyl group, Pyrazinyl, pyrimidine radicals, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thio-morpholinyl, especially N- thio-morpholinyl, indolizine Base, isoindolyl, 3H- indyl, indyl, benzimidazolyl, tonka-bean base, indazolyl, triazolyl, tetrazole radical, purine radicals, 4/ V- quinazinyl, isoquinolyl, quinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, octahydro isoquinolyl, benzo Furyl, dibenzofuran group, benzothienyl, dibenzothiophene, phthalazinyl, naphthyridines base, quinoline quinoline base, quinazolyl, Cinnoline base, pteridine radicals, carbazyl, B-carboline base, coffee piperidinyl, acridinyl, pah piperidinyl, coffee quinoline base, furan Xanthones base, coffee piperazine base, coffee thiophene Piperazine base, coffee oxazines base, benzo piperazine mutter Ji Ji, benzo dihydro piperazine of base, different benzo dihydro piperazine of muttering are muttered Ji Ji and its similar group.
Heterocyclylalkyl
Term " Heterocyclylalkyl " as used herein include refer to 3,4,5,6 or 7 ring carbon atoms and 1,2,3,4 or The saturated heterocyclic part of 5 ring hetero atoms selected from nitrogen, oxygen, phosphorus and sulphur.The group can be polycyclic loop system, but more typically single Ring.This term includes referring to such as azetidinyl, pyrroles's piperidinyl, tetrahydrofuran base, piperidyl, Oxyranyle, pyrazoles Piperidinyl, imidazole radicals, Yin piperidinyl, piperazinyl, thiazole piperidinyl, morpholinyl, thio-morpholinyl, quinazinyl and its base similar to group Group.Ring or loop system can replace through one or more alkyl.
Heteroaryl
Term " heteroaryl " as used herein includes referring to 5,6,7,8,9,10,11,12,13,14,15 or 16 The wherein at least one atom of annular atom is selected from the aromatic heterocyclic ring system of nitrogen, oxygen and sulphur.The group can be polycyclic loop system, have Two or more rings, wherein at least one ring are aromatics, but more typically monocycle.Ring or loop system can take through one or more alkyl Generation.This term include refer to such as pyrimidine radicals, furyl, benzothienyl, thienyl, pyrrole radicals, imidazole radicals, pyrroles's piperidinyl, Pyridyl group, benzofuranyl, pyrazinyl, purine radicals, indyl, benzimidazolyl, quinolyl, coffee thiazinyl, triazine radical, phthalazines Base, 2H- benzo piperazine are muttered base, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purine radicals, isoquinolyl, quinoline azoles The group of quinoline base, pteridine radicals and its similar group.
Halogen
Term " halogen " as used herein includes referring to F, Cl, Br or I.
Part containing halogen
Statement " part containing halogen " as used herein include refer to comprising 1 to 30 be selected from carbon, nitrogen, oxygen and sulphur it The part of polyad, the part include at least one halogen.Part can be alkyl, such as C1-6Alkyl or C1-6Alkoxy or carbon Ring group, such as aryl.
It is substituted
Such as herein in regard to part term " being substituted " used mean one of the part or it is multiple, especially up to 5, more The substituent group replacement through corresponding number independently of one another of especially 1,2 or 3 hydrogen atom.Term as used herein is " depending on feelings Condition is substituted " mean to be substituted or be unsubstituted.It will be understood, of course, that the substituent group only chemically position of possibility wherein, ripe Practise skilled person can need not carry out inappropriate work make decision (empirically or theoretically) it is specific replace whether may.
Enantiomter
Term " enantiomter " as used herein means one of two kinds of stereoisomers for mirror image each other.
Racemic modification
Term " racemic modification " as used herein means equivalent to the mixture of the enantiomter of palm property molecule.
Diastereoisomer
Term " diastereoisomer " as used herein means and diastereoisomer, but in one or more same palm property Center has one of a kind of stereoisomer of different configuration.The example of diastereoisomer is that difference is only one palm property The epimer of the configuration at center.
Stereoisomer
Term " stereoisomer " as used herein means there is identical molecular formula and bond atomic order, but atom exists Three-dimensional position spatially is to different one of a kind of isomer molecules.
Prodrug
Prodrug is then in vivo to pass through in inactivation (or lower than fully active) medicinal treatment that chemical derivative is given Often active agent is converted via normal metabolic processes.
Independently
In the case where two or more parts are described as " each independently " selected from a series of atoms or group, this meaning Refer to that grade part may be the same or different.Therefore, the status of each section and the status of one or more other parts are unrelated.
Embodiments of the present invention are described below.The preferable feature of the various aspects of the present invention is such as directed to each in terms of other, Make necessary modification in details.Furthermore it should be appreciated that the feature of detailed description in each embodiment can be with the feature group of other detailed descriptions It closes, to provide other embodiments.
In several animal models having been established, (i.p.) injection cholecystokinin rush is secreted in most widely used repetition peritonaeum Plain bombesin, and to generate the height reproducible method of experiment acute pancreatitis.After single injects lipopolysaccharides (LPS), lung's damage The neutrophil cell sequestering being characterized in that in lung tissue of the wound and permeability of alveolar membrane barrier increases frequently as acute pancreatitis Related complication and observe.For the breaking-out for diagnosing acute pancreatitis, largely leakage regards digestive ferment (that is, alpha-amylase) into blood flow For main pathological parameters.For diagnosis acute pancreatitis and the severity of associated lung damage, the morphologic change of organ structure, packet Interstitial edema, cellular damage, white blood cell infiltration and bleeding are included, histology and/or pathological parameters are characterized as.Except histological examination Except, constant surveys exception MPO activity, the severity of the inflammation symptom for assessing neutrophil cell mediation.It is local and complete The reaction of body inflammatory can by the homogenate of illing tissue there are high-content pro-inflammatory cytokine further confirm.This Outside, the sweet peptide reduction of bran Guang is a kind of defense mechanism, for one of the most common parameter of severity for assessing tissue damage.
Individual to the method treatment by the present invention can be mankind or animal.The present invention is suitable for the various shapes of acute pancreatitis Formula, and it is particularly suitable for the systemic complications of acute pancreatitis correlation, including pulmonary lesion.
Dihydro-resveratrol also known as trans- -3,5,4'- trihydroxy bibenzyls, for the polyphenol derivatives for belonging to Qi Lei family, Often obtained from plant extract.In fact, dihydro-resveratrol is by including orchid family and cunjah (Cannabis Sativa L.) various plants species for abiotic and biological excitation, especially in fungal infection produced by plant Object antitoxin, as reported in following: Fritzemeier, K.H., Kindl, H.1983. " 9 of the phytoalexin as orchid family, 10- dihydro phenanthrene (9,10-dihydrophenanthrenes as phytoalexins of Orchidaceae) "." in vitro And it in vivo proves to study from from L- Phenylalanine to the biosynthesis of the approach of dihydro-m-Coumaric Acid, dihydro stilbene and dihydro phenanthrene (Biosynthetic studies in vitro and in vivo proving the route from L- phenylalanine to dihydro-m-coumaric acid,dihydrostilbene and Dihydrophenanthrenes) " " european journal of biological chemistry (Eur J Biochem) " 133,545-550.
Purposes of the present invention about the polyphenol derivatives of the Qi Lei family with formula (1):
Wherein R1、R2And R3It is each independently selected from alkyl.The term " alkyl " combined individually or with other groups includes referring to tool There are the linear alkyl moieties of 1,2,3,4,5 or 6 carbon atom.The term is by such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (normal-butyl, the second butyl and third butyl), amyl, hexyl and its group similar to group It further illustrates, is used to improve the tissue damage of pancreas and lung.
The present invention further relates to the stilbene compounds containing trans- -3,5,4'- trihydroxy bibenzyls, the also known as white Chenopodiaceae of dihydro - The purposes of reed alcohol, referring to formula (2) compound:
Its tissue damage for being used to improve pancreas and lung.In the present invention, this specific stilbene analog derivative is via trans-res-veratrol Dehydrogenation, white powdered acquisition.
In addition, the present invention is about one kind for manufacturing the method for the above compound, containing the pharmaceutical preparation of such compound And this compound is used to generate the purposes of pharmaceutical preparation.
Orally administration dihydro-resveratrol shows and significantly improves through bombesin under the appropriate dosage of no less than 20mg/kg Acute pancreatitis and the severity of associated lung damage in the rat of processing.For pathological parameters, with acute pancreatitis it Rat shows since pancreas oedema weakens so that pancreas water content mitigates (Fig. 1), and the plasma content of alpha-amylase reduces (table 1), Acinus form more complete (Fig. 2 C to 2F), and alveolar wall thickening and bleeding reduction (Fig. 3 C to 3E).
Table 1: blood plasma alpha-amylase activity is expressed as U/ μ l/ minutes.P value is considered as statistically significant, and S.D. table less than 0.05 Show standard deviation.When compared with the control group, p < 0.05 *, and compared with bombesin group, #p < 0.05.
Control Bombesin Bombesin+D-Res 10mg Bombesin+D-Res 20mg Bombesin+D-Res 50mg
Average value 0.1294 0.4846* 0.2891 0.2498# 0.2431#
S.D. 0.03909 0.1457 0.05248 0.05593 0.06025
By dihydro-resveratrol is given, the quantitative frog is carried out as MPO activity in significant containment pancreas and lung tissue The neutrophil cell sequestering (Fig. 4 A and 4B) of the elevated levels of Pi Su induction.By dihydro-resveratrol is given, significantly contain The TNF-α (Fig. 5 A and Fig. 5 B) of the elevated level of bombesin induction in pancreas and lung.
The sweet peptide reduction of bran Guang is the uniqueness sign of tissue damage.By dihydro-resveratrol is given, significantly restore in pancreas The sweet peptide of bran Guang (Fig. 6 A) of the decline content of bombesin induction.
In the present invention, dihydro-resveratrol is thorough and is easy to be dissolved in 0.5% (weight/volume, w/v) methanol, and Trans-res-veratrol is dissolved in 2.5% (w/v) methanol (table 2) under violent concussion.Therefore, dihydro-resveratrol dissolution Property is at least 5 times higher than trans-resveratrol.With bombesin induction acute pancreatitis rat in dihydro-resveratrol to by The improvement result for the water content reduction that pancreas oedema causes more is hopeful (Fig. 6 B) than trans-res-veratrol.
Table 2: the dissolubility of dihydro-resveratrol and trans-res-veratrol in methyl alcohol
Trans-res-veratrol Dihydro-resveratrol
Required methanol (w/v) 2.5% 0.5%
From the assessment analyzed by means of MTT to grain wire body metabolic rate, dihydro-resveratrol in pancreas acinar cells is determined Cytotoxicity be about 500 μM, and trans-resveratrol is about 250 μM (Fig. 7).Therefore, dihydro-resveratrol cell toxicant Property lower than trans-res-veratrol 50%.
Experiment
The preparation of dihydro-resveratrol and Structure identification.Dihydro-resveratrol molecular formula is determined as C14H14O3, warp It is hydrogenated and is obtained by trans-res-veratrol, it is white powdered.By trans-res-veratrol (10g, 43.8mmol) Yu Wushui EtOH Solution in (150ml) is at room temperature in 5atm H2It is stirred in the presence of 10%Pd/C (0.2g) under pressure.After 8 hours, by Filter off catalyst quenching reaction.Filtrate is evaporated in vacuo and residue carries out silica gel column chromatography separation, with petroleum ether and acetic acid second Ester (1:1) is molten from obtaining dihydro-resveratrol (9.6g, 95% yield) of white noncrystalline powder shape: HR-ESIMS (C14H15O3[M+1]+m/z 231.1026, calculated value 231.1016)；1H NMR (methanol-d4,400MHz) δ 6.96 (2H, ABd, ), J=8.3Hz 6.67 (2H, ABd, J=8.4Hz), 6.13 (2H, brd, J=2.2Hz), 6.09 (1H, brt, J=2.2Hz), 2.74 (2H, brdd, J=8.5,5.6), 2.67 (2H, brdd, J=8.3,5.2)；13C NMR (methanol-d4,100MHz) δ 159.2(2C,s),156.3(1C,s),145.6(1C,s),134.1(1C,s),130.3(2C,d),116.0(2C,d),108.1 (2C,d),101.1(1C,d),39.6(2C,t),38.0(2C,t)。
Assess bioactivity.The more sharp big white mouse (Sprague- of 28 age in days Shi Boges-of the weight within the scope of 70 to 90g Dawley rat) it is randomly assigned into 6 groups of 6 to 8 individuals.Rat be housed in 23 ± 2 DEG C environment temperature, 60% to 80% it Under relative humidity and 12 hours light dark cycles.Before experiment, rat starvation is overnight, but allows freely to take water.By one hour The bombesin of six intraperitoneal injection super large stimulating doses (50 μ g/kg), then 1 hour after the injection of last time bombesin 7.5mg/kg single dose LPS induces experiment acute pancreatitis in rats, and this group of rat is known as bombesin group.Control group receives phase The 0.9% physiological saline water injection at same volume and same time interval, rather than bombesin.Give bombesin and oral dihydro- The processing group of resveratrol (10,20 or 50mg/kg) is known as bombesin+D-res 10 or 20 or 50mg/kg.Therapeutic intervention exists It is given within 30 minutes after the injection of first time bombesin, continuous three hours.When execution, remove pancreas at once, weighing, repair fat and It is fixed at 4 DEG C overnight in 4% metaformaldehyde-phosphate-buffered normal saline solution.Then processed sample is embedded in solid stone In wax, slice and progress H&E dyeing.The TNF-α content in pancreas and pulmonary samples is measured using business ELISA set group.Tissue Homogenate carries out biochemical analysis, to assess MPO activity and the sweet peptide content of bran Guang.
Using collagenase digestion, under slight shearing force, from the functional complete acinus of pancreatic tissues dissociation.Acinus exists It is supplemented with the Dahl Burke Improved Eagle Medium of 5% fetal calf serum (GIBCO), 1% Pen .- Strep (GIBCO) (GIBCO) in 5%CO in2, cultivated at 37 DEG C in 95% there was dampness in the air atmosphere.LTC-14 cell is with 1 × 104The density in a/hole It is seeded in 96 porose discs, and is cultivated together with various concentration dihydro-resveratrol or trans-res-veratrol (being dissolved in DMSO) 24 hours.MTT reagent is added to cell at the end of 24 hours process phases.After 3 small the reaction times, MTT product is dissolved in In DMSO and obtain the suction brightness under 570nm.
As a result
After bombesin induction, compared with the control induced without bombesin, due to there is pancreas oedema, so that acute The ratio of pancreas weight and weight increases considerably about 60% in pancreatitis rat.It is appropriate that orally administration is no less than 20mg/kg Dihydro-resveratrol of dosage substantially reduces pancreas oedema, as the significant decrease of pancreas weight and the ratio of weight reflects.Two Hydrogen-resveratrol is more hopeful the improvement result for reducing pancreas oedema than generally acknowledged antioxidant trans-res-veratrol.About people Class dosage is 3.24mg/kg:Reagan-Shaw S, Nihal M than dosage based on being converted according to following standard dose, Ahmad N (2008) " discusses dosage conversion (the Dose translation from animal from animal to human research again To human studies revisited) " 22 (3) " American Federation of Experimental Biology's magazine (FASEB J) ": 659- 661。
In the rat of the acute pancreatitis with bombesin induction, when orally administration dihydro-resveratrol, pancreas essence Focal expansion, Cytoplasmic shrinkage and the white blood cell infiltration of middle interlobular septum substantially reduce, and lung wall thickening in lung tissue and Bleeding significantly improves.
Make pancreas and lung tissue by orally administration dihydro-resveratrol to alleviate the inflammatory symptom of pancreas and lung The content and MPO activity level of middle pro-inflammatory cytokine TNF-α substantially reduce.
The content of the sweet peptide of bran Guang is substantially compared with the control handled without bombesin, in the pancreatic tissues through bombesin induction Degree reduces by more than 50%.Orally administration dihydro-resveratrol significantly contains that the sweet peptide of bran Guang in the pancreas through bombesin induction subtracts It is few.
Dissolubility of the dihydro-resveratrol in the solvent based on methanol is at least 5 times higher than trans-res-veratrol.By The grain wire body metabolic rate of acinus is assessed, dihydro-resveratrol cytotoxicity is shown as about 500 μM, and trans-res-veratrol Cytotoxicity be about 250 μM.Therefore, dihydro-resveratrol cytotoxicity lower than trans-res-veratrol 50%.
In the first embodiment of the first aspect of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications is spread out by the stilbene class comprising formula (1) compound comprising effective quantity is given to individual in need The composition of biology,
Wherein R1、R2And R3It is each independently selected from alkyl.The term " alkyl " combined individually or with other groups includes referring to tool There are the linear alkyl moieties of 1,2,3,4,5 or 6 carbon atom.The term is by such as following further example of group Show: methyl, ethyl, propyl (n-propyl or isopropyl)), butyl (normal-butyl, the second butyl and third butyl), amyl, hexyl And its similar to group and its derivative or chemical variation body；Or the compound, its derivative and/or chemical variation body are mixed Close object.
In the second embodiment of the first aspect of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the stilbene analog derivative is trans- -3,5,4'- trihydroxy bibenzyls or or dihydro-resveratrol, For formula (2) compound:
And its derivative or chemical variation body；Or the mixture of the compound, its derivative and/or chemical variation body.
In the 3rd embodiment of the first aspect of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the individual is mankind or animal.
In the fourth embodiment of the first aspect of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the composition orally administration.
In the 5th embodiment of the first aspect of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, the form of ownership and the correlation whole body that wherein the acute inflammation symptom of the pancreas includes acute pancreatitis are simultaneously Sending out disease includes pulmonary lesion.
In the sixth embodiment of the first aspect of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the composition is no less than 3 times in one day with giving the individual not less than 20mg/kg.
In the 7th embodiment of the first aspect of the present invention, a kind of acute inflammation symptom and correlation for treating pancreas is provided The method of systemic complications, wherein the composition is no less than 3 times in one day with giving the individual not less than 3.24mg/kg.
In the first embodiment of the second aspect of the present invention, one kind is provided and is used to prepare with molecular formula C14H14O3And formula (2) method of compound,
It is with chemical name trans- -3, and the stilbene analog derivative of 5,4'- trihydroxy bibenzyls, this method is by trans--white Veratryl alcohol adds hydrogen.
In the second embodiment of the second aspect of the present invention, a kind of prepare with molecular formula C is provided14H14O3And formula (2) Compound method, wherein trans-res-veratrol plus hydrogen comprise the steps of:
At room temperature in 5atm H2Solution under pressure in the presence of 10%Pd/C by trans-res-veratrol in anhydrous EtOH Stirring 8 hours；
Catalyst is filtered off from agitating solution；
Filtrate is evaporated in vacuo to generate residue；
It is separated using silica gel column chromatography, with petroleum ether and ethyl acetate (1:1) separation residue to generate dihydro-resveratrol.
The preferred embodiment of the present invention
Some previous research have reported effective inducer that TGF-β is PSC activation, including a series of fibers of FN1 Property mediator up-regulation.In immortalization PSC of the LTC-14 cell-from rat of culture, exogenous addition recombinates TGF-β (5ng/ Increase the performance amount of fiber filament α-SMA and ECM protein FN1 significantly.In another embodiment of the present invention, this hair The performance amount that dihydro-resveratrol significantly alleviates the α-SMA and FN1 in P of Rats SC in TGF-β excitation is given in bright person's discovery.Two Hydrogen-resveratrol derivative plays similar containment in PSC and acts on.Compared with famous antioxidant trans-res-veratrol, two Hydrogen-resveratrol inhibiting effect is more significant.In test stilbene class, although architectural difference is little, dihydro-resveratrol exists Most effective anti-fibrosis effect is played in PSC.
The present invention provides a kind of for containing that astrocyte fibrosis present in the internal organs of individual in need is situated between The compound of body, with following formula:
Wherein,
R2And R4It is each independently selected from-OR11And-OC (O) R11；
R1、R3、R5、R6、R7、R8、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR11And-OC (O) R11；Or R2 And R3Or R7And R8Cyclic group can be formed together together with the carbon atom of its attachment；
R11It independently is hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R12It takes Generation；
R12Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR13、-C(O)R14、-C(O)N(R13)R14、-C (O)OR13、-OC(O)R14、-S(O)2R13、-S(O)2N(R13)R14、-N(R13)R14；
R13And R14Be each independently hydrogen or selected from alkyl and heterocycle, any one optionally through 1,2,3,4 or 5 independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its enantiomter；
Or its pharmaceutically acceptable salt or prodrug；
Or the mixture of the compound, its derivative and/or chemical variation body.
The present invention further provides for containing astrocyte fibrosis present in the internal organs of individual in need Nine embodiments of the compound of mediator, the equal compounds have following formula:
Or 4- [2- (3- hydroxy-5-methyl phenyl) ethyl] -2,6- dimethoxy-phenic acid；
Or 3,4 ', 5- trihydroxy -3 '-methoxyl group bibenzyl (Tristin)；
Or 3,3', 5- trihydroxy bibenzyl；
Or 5- [2- (4- hydroxy 3-methoxybenzene base) ethyl] -2,3- dimethoxy-phenic acid；
Or 5- [2- (3- hydroxy phenyl) ethyl] -2,3- dimethoxy-phenic acid；
Or Dendrobium crepidatum lindl et paxt. is plain (Crepidatin)；
Or moscatilin (Moscatilin)；
Or dendrophnol I (Aloifol I)；
Or dihydro-resveratrol.
Internal organs can be pancreas, liver, kidney and the lung of such as individual.The individual can be human individual.
Experiment:
LTC-14 cell is at 37 DEG C in 95% air and 5%CO2Wet condition under be supplemented with 10% fetal calf serum (FBS) it is cultivated in IMDM.For the cell in all experiments between subculture 9 to 25.LTC-14 cell is with 1 × 105A/hole Density be inoculated in 12 porose discs, and recombinate TGF-β and 0,1,5,10 and 20 μ g/mL dihydros-resveratrol one with 5ng/mL It rises and is cultivated 24 hours in the IMDM for being supplemented with 0.2%FBS.Then harvest cell is used for Protein Extraction and Western Blot analysis Or immunofluorescence dyeing.
The entire protein of LTC-14 cell is extracted using the RIPA dissolution buffer containing protease inhibitors.Load is thin Cellular lysis object and by SDS- polyacrylamide gel electrophoresis separate.After carrying out wet type electricity ink dot, by Protein transfer to PVDF It on film (Bio-Rad), is blocked with 5% skimmed milk, detected with antibody and is observed by using ECL set group (GEHealthcare).
For the immunofluorescence dyeing of α-SMA, LTC-14 cell is with 1 × 105Density be seeded in 24 porose discs with poly- L- On cover plate from amino acid coating, 0.2% is being supplemented with together with 5ng/mLTGF- β and 0 and 10 μ g/mL dihydros-resveratrol It is cultivated 24 hours in the IMDM of FBS.Then cell is fixed, is blocked with 3%BSA, is detected with antibody and with containing 4 ', 6-, bis- carbonamidine The fluorescent mounting medium sealing of base -2-phenylindone (DAPI).Image is captured using Nikon microscope and by SPOT The analysis of advanced software.
Assess bioactivity.28 age in days C57/BL6 mouse of the weight within the scope of 20 to 25g are randomly assigned into 6 to 8 4 groups of body.Mouse is housed under 23 ± 2 DEG C of environment temperature, 60% to 80% relative humidity and 12 hours light dark cycles. Before glucose tolerance test, mouse starvation is overnight, but allows freely to take water.By in one day four times per hour peritonaeum The bombesin of super large stimulating dose (50 μ g/kg) is injected, 3 days one week, totally 6 weeks, experiment chronic pancreatitis is induced in mouse.Control Group receives the 0.9% physiological saline water injection at same volume and same time interval, rather than bombesin.Give bombesin and mouth The processing group for taking dihydro-resveratrol (daily 20mg/kg) is known as Cer+D-res.Also it has attempted during processing daily Dihydro-resveratrol of 50mg/kg dosage, but fibrosis formed with daily 20mg/kg dosage without it is statistically significant it Difference.However, this higher doses does not cause adverse effect in this is in vivo tested.Therefore, conclude that dihydro-resveratrol has Imitating dosage is at least daily 20mg/kg.The group for giving trans-res-veratrol is known as Cer+Res.It gives within first day from the 4th week The drug intervention of two kinds of compounds, until experiment terminates, that is, 3 weeks in total.At the end of experiment in 6 weeks, mouse is carried out in peritonaeum Glucose tolerance tests (IPGTT).Mouse hungry 14 hours before IPGTT, wherein by 15% (w/v) glucose solution with Per kilogram of body weight 1.5g glucose injection is to individual animal.About 1 μ L blood is obtained from tail vein, and 30 before glucose injection Minute (that is, fasting level) and 10,20,30 and 60 minutes later monitor blood glucose water using blood glucose meter (Medisign, Korea) It is flat.When execution, pancreas is removed at once, and weighing repairs fat and is fixed on 4% metaformaldehyde-phosphate-buffered physiology at 4 DEG C It is overnight in saline solution.Then processed sample is embedded in solid paraffin, slice and progress immunostaining.
According to dosage change type, mankind's Isodose (mg/kg)=animal dosage (mg/kg) multiplied by animal Km/ mankind Km, Wherein mouse Km is 3 and mankind Km is 37 (" about initial clinical test of the industrial evaluation therapeutic agent in adult healthy volunteer Guidance (the Guidance for Industry Estimating the Maximum Safe of middle maximum Safety Starting Dose Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers) "), the effective mankind's Isodose of dihydro-resveratrol of the present invention is at least daily 1.622mg/kg.
In another embodiment of the present invention, 8 kinds of dihydro-resveratrol other derivatives (compound i to viii) and Dihydro-resveratrol (compound 2) is shown in Fig. 8 A-8I.In this embodiment, each compound is accordingly tested as follows:
The experiment of the embodiment of compound in Fig. 8 A-8I
LTC-14 cell and TGF-β (5ng/mL) pre-incubation together, and with 20 μ g/mL trans-res-veratrols (Resv) or Dihydro-resveratrol (D-Res) or stilbene compounds i-viii are handled 24 hours.Compare unused Resv or the processing of any stilbene class.It mentions It is rounded protein and is analyzed using Western blot.This is showed in Fig. 9.
LTC-14 cell is pancreas astrocyte.α-SMA is the mark component of fiber generations, and beta-actin serve as it is interior Reference material.Therefore, the performance amount of α-SMA means PSC activation degree.Add TGF-β because its be considered as fibrotic event it is effectively Inducer.In dihydro-resveratrol and compound i between viii, relative to trans-res-veratrol (Resv), test to α- The containment of SMA performance amount acts on.All test compounds play the containment effect of α-SMA performance amount.
LTC-14 cell and TGF-β (5ng/mL) pre-incubation together, and with the trans-res-veratrol or two for indicating concentration Hydrogen-resveratrol processing.It extracts entire protein and is analyzed using Western blot.This is showed in Figure 10.
FN1 is the main cell extracellular matrix protein generated during fiber occurs or when activating pancreas astrocyte.Its Performance amount means fiber occurrence degree.Between dihydro-resveratrol (that is, compound 2) and trans-res-veratrol, test pair The containment of FN1 and α-SMA content acts on.
LTC-14 cell and TGF-β (5ng/mL) pre-incubation together, and 24 are handled with the dihydro of 20 μ g/mL-resveratrol Hour, then carry out immunofluorescence dyeing.
LTC-14 cell is pancreas astrocyte.α-SMA is the mark component of fiber generations, and beta-actin serve as it is interior Reference material.Therefore, the green florescent signal (being identified in Figure 11 by arrow mark) of α-SMA means PSC activation degree.Add TGF- β, because of its effective inducer for being considered as fibrotic event.Dihydro-resveratrol is tested to act on the containment of α-SMA performance amount.
Pancreatic tissues slice is dyed with the antibody for FN1；Therefore, immunostaining signal means the FN1 depositing in essence Degree.With daily 20mg/kg dihydro-resveratrol (Cer+D-Res) processing with more aobvious than trans-res-veratrol (Cer+Res) The mode of work reduces such depositing in chronic pancreatitis.This is showed in Figure 12.
Assess bioactivity.28 age in days C57/BL6 mouse of the weight within the scope of 20 to 25g are randomly assigned into 6 to 8 4 groups of body.Mouse is housed under 23 ± 2 DEG C of environment temperature, 60% to 80% relative humidity and 12 hours light dark cycles. As orally administration dihydro-resveratrol (daily 20mg/kg), the fasting blood glucose level (Cer) of chronic pancreatitis mouse becomes aobvious It writes and is higher than control group, show that the diabetic character that hyperglycemia-one kind can distinguish occur in these chronic pancreatitis mouse.Importantly, Its glucose-tolerant sexual abnormality is significantly corrected by 3 weeks dihydros-resveratrol processing (Cer+D-Res).Therefore, chronic pancreatitis The hyperglycemia symptom of mouse is improved.This is showed in Figure 13.
As the daily 20mg/kg dihydro of orally administration-resveratrol (Cer+D-Res), the severity and pancreas of pancreatitis Dirty, clearly the contraction and destruction of β cell significantly improve.As shown in Figure 14, pancreatic beta-cell region is glimmering by being immunized The reflection of light insulin signaling.Beta cell region or Mass lost mean to lack glucose tolerance or diabetes occur.Therefore, two The processing of hydrogen-resveratrol makes beta cell region restore to show that this stilbene class is beneficial to treat Pancreatogenic diabetes (that is, 3c type glycosuria Disease).
According to dosage change type, mankind's Isodose (mg/kg)=animal dosage (mg/kg) multiplied by animal Km/ mankind Km, Wherein mouse Km is 3 and mankind Km is 37 (" about initial clinical test of the industrial evaluation therapeutic agent in adult healthy volunteer Guidance (the Guidance for Industry Estimating the Maximum Safe of middle maximum Safety Starting Dose Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers) "), the effective mankind's Isodose of dihydro-resveratrol of the present invention is at least daily 1.622mg/kg.
Other preferred embodiments of the present invention
Dendrobium Sw be commonly referred to as " dendrobium nobile ", be widely used in Chinese medicine (traditional Chinese medicine, TCM) in system and Folk medicine, for treating various diseases, such as atrophic gastritis, diabetes and cardiovascular disease. The extract or ingredient of Dendrobium derivative contain a considerable amount of various stilbene classes, such as trans-res-veratrol and the white black false hellebore of dihydro- Alcohol, the equal substances are the potential compound to oxidative stress in human body.It is protected however, not yet disclosing these compounds for skin Shield or skin-whitening.
Because east cosmetics preference is based on the composition of plant, the present invention relates to the stilbene class of Dendrobium derivative, especially Its trans-res-veratrol, dihydro-resveratrol or dihydro-Verakanol derivative are used to reduce the purposes of melanin formation, It is able to suppress oxyradical and the generation of ROS.The composition of the present invention is suitable for individual in need and makees local use.This hair Bright composition is in day cream, late frost, face lotions, skin lotion, body moisturizer, keratolytic, facial mask, shower cream, sun-proof After frost, sunlight lotion, solarization skin cream or shine after skin cream form.
The composition of the present invention includes the extract that one or more are derived from Dendrobium Sw.
The composition of the present invention includes one or more stilbene classes with following formula:
Wherein,
R2、R4And R8It is each independently selected from-OR11、-OCH2R12、-OC(O)R11、-OCH2C(O)OR12And-OC (O) CH2R12；
R1、R3、R5、R6、R7、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl, OR12And-OC (O) R12；Or R2And R3 Or R7And R8Cyclic group can be formed together together with the carbon atom of its attachment；
R11Independently selected from-(CH2)-alkyl, C2-10Alkyl, alkenyl, naphthenic base, aryl and heterocycle, it is every in these groups One is optionally through 1,2,3,4 or 5 R13Replace；
R12Independently selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R13Replace；
R13Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR14、-C(O)R15、-C(O)N(R14)R15、-C (O)OR14、-OC(O)R15、-S(O)2R14、-S(O)2N(R14)R15、-N(R14)R15；
R14And R15Be each independently hydrogen or selected from alkyl and heterocycle, any one optionally through 1,2,3,4 or 5 independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its enantiomter；
Or its pharmaceutically acceptable salt or prodrug.
The composition of the present invention includes the stilbene class with following formula:
It is dihydro-resveratrol and its derivative or chemical variation body；Or the compound, its derivative and/or chemical variation The mixture of body, or there is following formula:
Include the stilbene class with following formula for the present composition of skin brightening and skin sparing:
Wherein,
R2、R4And R8It is each independently selected from-OR11、-OCH2R11、-OC(O)R11、-OCH2C(O)OR11And-OC (O) CH2R11；
R1、R3、R5、R6、R7、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR11And-OC (O) R11；Or R2And R3Or R7And R8Cyclic group can be formed together together with the carbon atom of its attachment；
R11It independently is hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R12Replace；
R12Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR13、-C(O)R14、-C(O)N(R13) R14、-C(O)OR13、-OC(O)R14、-S(O)2R13、-S(O)2N(R13)R14、-N(R13)R14；
R13And R14It is each independently hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 It is a or 5 independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its enantiomter；
Or its pharmaceutically acceptable salt or prodrug.
To measure oxidation resistance, using light splitting brightness decoloration analysis, it is supplemented with 2,2 '-secondary azo groups pair-(3- ethylo benzene And thiazoline -6- sulfonic acid) the free radical list cation being pre-formed, also known as ABTS.In the analysis, ABTS (Abcam, USA it) is dissolved in water to 7mM concentration, and ABTS radical cation is by ABTS stock solution and 2.45mM ammonium persulfate (Sigma-Aldrich, USA), which reacts and mixture is made to stand 16 hours at room temperature in the dark, to be generated, and is then used.Work as survey When trying Dendrobium extract sample or stilbene class sample, it is 0.70 that ABTS free-atom aqueous solution, which is diluted to suction brightness under 734nm with ethyl alcohol, And it is balanced at 30 DEG C.The dilution of test sample (0.1mL) or DMSO (0.1mL) and ABTS free-atom aqueous solution (0.9mL) one It rises and cultivates 15 minutes, then obtain under 734nm and inhale brightness.DMSO serves as mediator processing, and 0.001 to 0.05mg/mL range A kind of interior famous derivative vitamin E Trolox (Abcam, USA) refers to as positive drug.Test sample it is anti-oxidant Ability is expressed as according to Trolox standard curve, the amount equal with Trolox, with milligram (mg) for unit.
With dihydro-resveratrol (D-Res), trans-res-veratrol (Res), Dendrobium extract sample or other stilbenes Class sample (when compound DR1 to DR11) is cultivated together, removed, and its oxidation resistance phase by the ABTS free radical being pre-formed Trolox positive criteria as shown in table 3 is standardized.
The oxidation resistance of the stilbene class equal with Trolox amount (mg) of table 3.:
Cell melanin content and Tyrosinase activity are measured in B16 the and A375 melanocyte of culture.In fact, Melanocyte is the cell for generating melanin, and melanin refers to the endogenous pigment group for generating a variety of skin colors.B16 is thin Born of the same parents (Shanghai bioscience research institute (the Shanghai Institutes for Biological of the Chinese Chinese Academy of Sciences Science, Chinese Academy of Sciences, China)) and A375 cell (the American Type culture guarantor in the U.S. Hiding center (American Type Culture Collection, USA)) it is routinely grown in and is supplemented with 10% thermal activation tire ox 95% in serum (FBS, U.S. Gibco) and the DMEM culture medium (U.S. Gibco) of 1% penicillin/streptomycin (U.S. Gibco) Air and 5%CO2Humid atmosphere at 37 DEG C.
To measure cell melanin content, melanocyte is seeded in (8 × 10 in 12 porose discs4A cells/well) and with α- Melanocyte stimulates hormone (α-MSH, 100nM) to stimulate 24 hours.Such stimulation is intended to accelerate melanin in melanocyte Cell formed so that test compound or extract the reduction ability of melanin formation is become more apparent upon.In α-MSH After stimulation, cell then uses different Dendrobium extract samples or stilbene class sample (5 μ L) or DMSO (5 μ L, U.S. Sigma- Aldrich it) reprocesses 24 hours.DMSO serves as mediator processing.At the end of experiment, make cell trypsinized, to cultivate certainly Disk separation.After centrifugation, the 1N sodium hydroxide solution (U.S. Sigma-Aldrich) one of the melanin spherolite of each sample and 100 μ L It rises and is cultivated 1.5 hours at 70 DEG C.After being cooled to room temperature, solution is centrifuged 10 minutes under 15,000 × g.By the supernatant of each sample Liquid (100 μ L) is transferred to 96 porose discs, obtains and inhales brightness readings under 405nm.Its protein of the relative black cellulose content of each sample Content standard and it is rendered as variation percentage relative to the cell handled through DMSO.
With dihydro-resveratrol (D-Res), trans-res-veratrol (Res), Dendrobium extract sample or other stilbenes (when compound DR1 to DR11) is cultivated together, the cell melanin content in B16 and A375 melanocyte has subtracted class sample It is few, as shown in Figure 15 to 17.
For measurement cell Tyrosinase activity, melanocyte is seeded in 12 porose discs (8 × 104A cells/well) and with α- MSH (100nM) is stimulated 24 hours.After α-MSH stimulation, cell different test samples (5 μ L) or DMSO (5 μ L) reprocessing 24 are small When.At the end of experiment, cell is washed twice with icecold phosphate salt buffer normal saline solution (PBS, pH 6.8) (U.S. Gibco) And it is then dissolved on ice with the PBS (pH 6.8) that 150 μ L contain 0.1%Triton X-100.By cell dissolution object at 4 DEG C It is centrifuged 15 minutes at 15,000 × g.The aliquot of 50 μ L supernatants and 50 μ L L-3,4- dihydroxy benzenes alanine (L- DOPA, U.S. Abcam) solution (0.2%, pH 6.8 in PBS) is blended in 96 porose discs and cultivation 2 is small under dark at 37 DEG C When.The optical density of each sample is measured at 475nm.Inhale the protein content standardization of brightness each sample.It is thin to calculate melanin The relative activity of cell Tyrosinase and variation percentage relative to the cell handled through DMSO is rendered as in born of the same parents.In addition, receiving Collect Western point of another group of experiment for the performance amount of TRP1 and TRP2 and its upstream regulatory factor p-AKT and p-38 Analysis.
With dihydro-resveratrol (D-Res), trans-res-veratrol (Res), Dendrobium extract sample or other stilbenes (when compound DR1 to DR11) is cultivated together, the Tyrosinase activity in B16 and A375 melanocyte has been pressed down class sample System, as shown in Figure 18 to 20.Western result is shown in Figure 21.
To measure the generation of ROS into the cell in melanocyte, by B16 or A375 cell inoculation in 12 porose discs (8 × 104 A cells/well) in and with α-MSH (100nM) stimulate 24 hours.At the end of α-MSH is cultivated, make cell trypsinized, with It is separated from culture plate, and cell ROS detecting analysis (Abcam) is carried out according to manufacturer specification.In short, the cell at 37 DEG C It is dyed 30 minutes with 20 μM of DCFDA.After dyeing, cell is handled with tertbutanol peroxide (TBHP, 55nM), realizes obvious degree ROS increase, after 4 hours, cultivated together with the Test extraction object or compound or ascorbic acid (AC) of 5 μ L volumes.Using glimmering The micro disc type reader detecting ROS of light generates signal.DCF is excited by 488nm laser.The result of this analysis is presented on Figure 22 In.
All analyses are carried out and are repeated at least 3 times in triplicate in individual experiments.As a result it is rendered as average value ± mark Quasi- deviation.Variance between two groups examines (Student ' s t-test) assessment by history all Deng Shi t, and more than two groups it Between variance by means of single factor test analysis of variance (one-way ANOVA) calculate.P value is considered as statistically significant less than 0.05 's.
For the skin color for measuring individual human individuals, the 0th day, it is tested on individual arm by skin colorimeter MPA5 Initial skin state.By colorimeter, individual type angle is calculated based on brightness (L*) and yellow-blue component (b*) value (ITA°).ITA ° of value is bigger, and skin is whiter, and [" colour of skin of ultraviolet radioactive exposure changes and life by S.Del Bino and F.Bernerd. Object consequence (Variations in skin colour and the biological consequences of Ultraviolet radiation exposure) " " Britain's dermatology magazine (British Journal of Dermatology)"2013；169 (supplementary issues 3), 33-40].In fact, the colour of skin is broadly divided into 6 groups: very light, light, medium, brown Brown, brown and black, as listed in table 4.It selects two regions (each 2cm × 2cm) as processing region, and is handled on arm Region around region is considered as control zone.200 μ L volumes test stilbene class (2 weight %, be dissolved in ethyl alcohol) coats in one day Twice to indicating area, daytime and night.At the end of first week (the 7th day), individual skin coloration measures examination and is closed with recording In use 7 days data of stilbene class.Again, at the end of second week (the 14th day), individual skin coloration measures examination and is closed with recording In use 14 days data of stilbene class.ITA ° of reading is presented in table 5.It is most of individual from dihydro-resveratrol or trans--white Chenopodiaceae Reed alcohol obtains obvious whitening function.Local skin is organized presentation graphics from one of human individual of stilbene class processing and is shown in Figure 23 In.
Table 4. is based on ITA ° of skin classification:
ITA ° measurement of the table 5. in instruction time point individual human individuals:
The general route of synthesis of DR1 to DR3
To dihydro-resveratrol (0.2mmol) and bromoalkane (RBr) (1.2mmol) in dimethylformamide (DMF, 2mL) it K is added in mixture2CO3(1.2mmol).Gained mixture is stirred at room temperature, until starting material on thin-layer chromatography (TLC) Matter disappears.Mixture H2O (10mL) is diluted and is washed three times with methylene chloride (DCM, 10mL).The organic layer of merging is saturated Sodium chloride (NaCl) washes twice, through anhydrous Na2SO4It is dry, it is concentrated in a vacuum and by preparative (preparation) TLC (PE/EA =5/1 or 3/1) purify, obtain required compound.R group in RBr can be OR11、-OCH2R11Or-OCH2C(O)OR11, wherein R11For alkyl.
DR1:
High resolution mass spec (HRMS): 511.1997 [M+Na]+
Proton magnetic resonance (PMR) (1H NMR,400MHz,CDCl3) δ 1.31 (9H, t, J=7.1Hz), 2.82 (4H, s), 4.22- 4.32(6H,m),4.56(4H,s),4.60(2H,s),6.29-6.41(3H,m),6.80-6.86(2H,m),7.04-7.13 (2H,m)。
DR2:
HRMS:373.1770[M+Na]+。
1H NMR(400MHz,CDCl3) δ 2.84 (4H, d, J=2.1Hz), 4.49 (4H, dt, J=5.3,1.4Hz), 4.51- 4.53(2H,m),5.25-5.35(3H,m),5.37-5.48(3H,m),5.99-6.13(3H,m),6.36(3H,s),6.81- 6.90(2H,m),7.05-7.15(2H,m)。
DR3:
HRMS:379.2220[M+Na]+。
1H NMR(400MHz,CDCl3)δ0.98-1.08(9H,m),1.74-1.90(6H,m),2.75-2.90(4H,m), 3.85-3.95(6H,m),6.29-6.39(3H,m),6.81-6.87(2H,m),7.07-7.15(2H,m)。
The general route of synthesis of DR4 to DR11
At 0 DEG C to dihydro-resveratrol (0.2mmol) and acid chloride (RCOCl) (1.2mmol) in DCM (2mL) it Mixture adds Et3N(1.2mmol).Gained mixture is set to be warming up to room temperature and stirring, until initial substance disappears on TLC.It is mixed Close object H2O (10mL) is diluted and is washed three times with DCM (10mL).The organic layer of merging is washed twice with saturation NaCl, through nothing Water Na2SO4It is dry, it is concentrated and is purified by preparative TLC (PE/EA=5/1 or 3/1) in a vacuum, obtain required compound. R group in RCOCl can be-R11Or-CH2R11, wherein R11For alkyl, optionally through 1,2,3,4 or 5 R12Replace, and its Middle R12For halogen or-OR13, and wherein R13For hydrogen or alkyl.
DR4:
HRMS:463.2044[M+Na+]。
1H NMR(400MHz,CDCl3)δδ0.97-1.10(9H,m),1.72-1.89(6H,m),2.47-2.58(6H,m), 2.91(4H,s),6.74-6.84(3H,m),6.94-7.04(2H,m),7.13-7.21(2H,m)。
DR5:
HRMS:667.0427 and 669.0408[M+Na+]。
1H NMR(400 MHz,CDCl3)δ3.01(4H,s),6.99-7.06(3H,m),7.10-7.17(2H,m),7.22- 7.27(2H,m),7.46-7.55(6H,m),8.09-8.18(6H,m)。
DR6:
HRMS:655.1964[M+Na+]。
1H NMR(400 MHz,CDCl3)δ3.00(4H,s),3.89-3.92(9H,m),6.97-7.04(9H,m),7.11- 7.16(2H,m),7.23-7.27(2H,m),8.13-8.18(6H,m)。
DR7:
HRMS:565.1600[M+Na]+。
1H NMR(400 MHz,CDCl3)δ3.02(4H,s),7.02-7.08(3H,m),7.12-7.20(2H,m),7.25- 7.29(2H,m),7.50-7.57(6H,m),7.60-7.70(3H,m),8.17-8.28(6H,m)
DR8:
HRMS:415.1140[M+Na]+
1H NMR(400 MHz,CDCl3)δ2.94(4H,s),5.98-6.08(3H,m),6.23-6.43(3H,m),6.58- 6.70(3H,m),6.84-6.97(3H,m),7.01-7.13(2H,m),7.16-7.26(2H,m)。
DR9:
HRMS:514.2550[M+Na]+。
1H NMR(400 MHz,CDCl3)δ1.61-1.79(12H,m),1.88-2.09(12H,m),2.82-3.08(7H,m), 6.72-6.83(3H,m),6.96-7.03(2H,m),7.15-7.20(2H,m)。
DR10:
HRMS:607.2070[M+Na]+。
1H NMR(400 MHz,CDCl3)δ2.91(4H,s),5.27(6H,s),6.91-6.98(3H,m),7.08-7.12(2H, m),7.14-7.19(2H,m),7.38-7.46(15H,m)。
DR11:
HRMS:505.2550[M+Na]+。
1H NMR(400MHz,CDCl3) δ 1.34-1.38 (27H, m), 2.86-2.94 (4H, m), 6.77 (3H, d, J= 2.1Hz),6.93-7.02(2H,m),7.14-7.21(2H,m)。
Industrial applicibility
The present invention relates to a kind of skin protection compositions, and it includes extract from Dendrobium Sw (such as dendrobium candidum and Jin Chai Dendrobium nobile) stilbene class and/or the class containing stilbene extract, to manage melanin production, skin darkening and skin aging.It is more specific and Speech, is related to Dendrobium ingredient and stilbene class reduces the purposes of melanin formation in melanocyte.It is also related to Dendrobium ingredient And stilbene class is used to reduce the purposes of active oxygen species and oxyradical generation.The present invention relates to the extract of Dendrobium derivative or The purposes of ingredient or stilbene class allotment skin sparing, skin-whitening and/or resisting age of skin product.

Claims (15)

1. a kind of formula (4) compound,
It is characterized in that,
R2、R4And R8It is each independently selected from-OR11、-OCH2R12、-OC(O)R11、-OCH2C(O)OR12And-OC (O) CH2R12；
R1、R3、R5、R6、R7、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR12And-OC (O) R12；Or R2And R3 Or R7And R8Cyclic group is formed together together with the carbon atom of its attachment；
R11Independently selected from-(CH2)-alkyl, C2-10Alkyl, alkenyl, naphthenic base, aryl and heterocycle, it is each in these groups Person is optionally through 1,2,3,4 or 5 R13Replace；
R12Independently selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R13Replace；
R13Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR14、-C(O)R15、-C(O)N(R14)R15、-C (O)OR14、-OC(O)R15、-S(O)2R14、-S(O)2N(R14)R15、-N(R14)R15；
R14And R15It is each independently hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 It is a independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its pharmaceutically acceptable salt or prodrug.
2. compound as described in claim 1, which is characterized in that the compound is optics pure stereoisomers, enantiomerism Body, racemic modification or its diastereoisomer.
3. compound as described in claim 1, which is characterized in that the compound be selected from be respectively provided with following various DR1, DR2, DR3, DR4, DR5, DR6, DR7, DR8, DR9, DR10 or DR11:
Or its pharmaceutically acceptable salt or prodrug.
4. a kind of for treating, preventing and/or postponing the composition of skin darkening, which is characterized in that include effective quantity such as power Benefit require any one of 1 to the 3rd described in compound and its pharmaceutically acceptable carrier.
5. the purposes of a kind of compound as claimed any one in claims 1 to 3 and/or its derivative or chemical variation body, It is individually and/or other pharmaceutically acceptable skin brightenings and Derma-Guard combine with one or more, is used to prepare confession Treat, prevent or delay the composition of the skin darkening progress of individual one of in need.
6. purposes as claimed in claim 5, which is characterized in that the outer land used of the composition is coated to the individual.
7. such as purposes described in claim 5 or 6, which is characterized in that the individual is the mankind.
8. one kind has the skin-whitening and skin sparing compound for UV exposure, skin injury and aging of formula (5),
It is characterized in that,
R2、R4And R8It is each independently selected from-OR11、-OCH2R11、-OC(O)R11、-OCH2C(O)OR11And-OC (O) CH2R11；
R1、R3、R5、R6、R7、R9And R10It is each independently selected from hydrogen, halogen, trifluoromethyl ,-OR11And-OC (O) R11；Or R2And R3 Or R7And R8Cyclic group is formed together together with the carbon atom of its attachment；
R11It independently is hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 R12It takes Generation；
R12Independently selected from halogen, trifluoromethyl, cyano, nitro, side oxygroup ,-OR13、-C(O)R14、-C(O)N(R13)R14、-C (O)OR13、-OC(O)R14、-S(O)2R13、-S(O)2N(R13)R14、-N(R13)R14；
R13And R14It is each independently hydrogen or selected from alkyl and heterocycle, any one is optionally through 1,2,3,4 or 5 It is a independently selected from halogen, cyano, amido, hydroxyl, C1-6Alkyl and C1-6The substituent group of alkoxy replaces；
Or its enantiomter, optics pure stereoisomers, racemic modification or diastereoisomer；
Or its pharmaceutically acceptable salt or prodrug.
9. the skin-whitening and skin sparing compound for UV exposure, skin injury and aging as described in claim 8, It is characterized in that, the compound has following formula:
Or its enantiomter；
Or its pharmaceutically acceptable salt or prodrug.
10. a kind of for carrying out the composition of skin-whitening and skin sparing, feature for UV exposure, skin injury and aging It is, the composition includes a effective amount of skin-whitening as claimed in claim 8 or 9 and skin sparing compound and its medicine The carrier being subjected on.
11. a kind of purposes of compound as claimed in claim 8 or 9 is used to prepare in individual one of in need The external application composite of skin-whitening and skin sparing is carried out for UV exposure, skin injury and aging.
12. purposes as claimed in claim 11, which is characterized in that the external application composite is in paste, solid, powder, particle, cream Liquid, day cream, late frost, face lotions, skin lotion, body moisturizer, keratolytic, facial mask, shower cream, suncream, sunlight lotion, The form of skin cream after skin cream, solarization, lipstick or lip honey or its analog after solarization.
13. the purposes as described in claim 11 or 12, which is characterized in that the individual is the mankind.
14. the composition as described in claim 4 or 10, which is characterized in that the composition in paste, solid, powder, particle, It is lotion, day cream, late frost, face lotions, skin lotion, body moisturizer, keratolytic, facial mask, shower cream, suncream, sun-proof Dew, shine after skin cream or shine after skin cream form.
15. a kind of from dihydro-compound of the resveratrol synthesis as described in claim 3 or 9 method, which is characterized in that packet Synthesis flow containing following two:
The process 1 of the DR1 to the DR3:
Wherein
R is-OR11、-OCH2R11Or-OCH2C(O)OR11；
R11For alkyl；
And
The process 2 of the DR4 to the DR11:
Wherein
R is-R11Or-CH2R11；
R11For alkyl, optionally through 1,2,3,4 or 5 R12Replace；
R12For halogen or-OR13；And
R13For hydrogen or alkyl.
CN201780069402.9A 2016-11-15 2017-10-26 Skin protection composition based on dendrobe components Active CN109952286B (en)

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US15/351,636 US9738581B2 (en) 2015-06-16 2016-11-15 Method of using dihydro-resveratrol or its stilbenoid derivatives and/or chemical variants in treatments of fibrotic and diabetic conditions
US15/351636 2016-11-15
US15/352903 2016-11-16
US15/352,903 US9956152B2 (en) 2015-06-16 2016-11-16 Skin-protection composition containing dendrobium-based ingredients
US15/633,780 US9877931B2 (en) 2015-06-16 2017-06-27 Method of using dihydro-resveratrol or its stilbenoid derivatives and/or chemical variants in treatments of fibrotic and diabetic conditions
US15/633780 2017-06-27
PCT/CN2017/107798 WO2018090805A1 (en) 2016-11-15 2017-10-26 Skin-protection composition containing dendrobium-based ingredients

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