CN101781173B - Stilbene compound and application thereof in preparing medicament for treating and preventing diseases related to prostatic hyperplasia - Google Patents
Stilbene compound and application thereof in preparing medicament for treating and preventing diseases related to prostatic hyperplasia Download PDFInfo
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- 206010004446 Benign prostatic hyperplasia Diseases 0.000 title claims abstract description 44
- 208000004403 Prostatic Hyperplasia Diseases 0.000 title claims abstract description 44
- 239000003814 drug Substances 0.000 title claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 23
- 201000010099 disease Diseases 0.000 title abstract description 19
- -1 Stilbene compound Chemical class 0.000 title abstract description 8
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- 235000021286 stilbenes Nutrition 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
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- 238000011282 treatment Methods 0.000 claims description 13
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- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a stilbene compound and application thereof in preparing a medicament for treating and preventing diseases related to prostatic hyperplasia, in particular to a compound shown in a formula I and pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein the definitions of R1, R2, R3 and R4 are shown in a specification. The invention also relates to an application of the compound shown in the formula I in treating and/or preventing the diseases related to the prostatic hyperplasia, a medicament composition containing the compound shown in the formula I and a method for treating and/or preventing the diseases related to the prostatic hyperplasia by the compound shown in the formula I. The compound shown in the formula I has good effect of treating and/or preventing the diseases related to the prostatic hyperplasia.
Description
The present invention claims priority from chinese patent application No. 200910001090.5 filed on 21/1/2009, which is incorporated herein by reference in its entirety.
Technical Field
The invention relates to a stilbene compound or pharmaceutically acceptable salt, solvate and prodrug thereof. The invention also relates to a new application of the stilbene compound or the pharmaceutically acceptable salt, the solvate and the prodrug thereof, in particular to an application in preparing medicines for treating and/or preventing diseases related to prostatic hyperplasia. The invention also relates to pharmaceutical compositions comprising said compounds and to methods of treating and/or preventing diseases associated with prostatic hypertrophy with said compounds.
Background
Prostatic hypertrophy refers to a series of symptoms caused by fibrocyte hyperplasia in prostate due to decreased secretion of sex hormone or inflammatory hyperplasia, and pressing urethra. Prostate hypertrophy occurs at a relatively high rate in menopause, and early prevention and treatment should be performed. Prostate hypertrophy is a very common disease of the elderly in men, and clinical medical statistics show that: the incidence of Benign Prostatic Hypertrophy (BPH) in men over 50 years of age is about 40% to 50%, while the incidence of BPH in older men over 65 years of age is as high as 60% to 65%. With the advance of our country into the aging society, it is estimated that about ten million people suffer from prostatic hyperplasia and other prostate-related diseases in the country. This is a problem that should be taken into account.
According to the research results of Chinese scholars, the following components are shown: many traditional natural medicines also have the effect of relieving the symptoms of frequent micturition and urgent micturition of patients with prostatic hyperplasia, and although the traditional natural medicines are expected to become future natural therapeutic medicines for prostatic hypertrophy, the development of medicines with exact curative effects on diseases related to prostatic hypertrophy still remains the research topic of research and development of people in the field.
Disclosure of Invention
The invention aims to provide a novel medicine which can be used for treating and/or preventing diseases related to prostatic hyperplasia. The inventor finds that the compound shown in the formula I has good effect of treating and/or preventing diseases related to prostatic hyperplasia, and thus can be used for treating and preventing the diseases related to prostatic hyperplasia. The present inventors have achieved the present invention based on the above findings.
Brief description of the invention:
in a first aspect, the present invention provides compounds of formula I:
wherein,
R1、R2、R3and R4Each independently selected from: h, hydroxy, straight or branched C1-6Alkyl, hydroxy-substituted C1-6Alkyl radical, C1-6Alkoxy radical, C6-10Aryl (e.g., phenyl or naphthyl), a glycoside containing a sugar such as-O-glucosyl (i.e., -O-glucosyl, e.g., -O- β -D glucosyl), glucosyl (i.e., -glucosyl), or a pharmaceutically acceptable salt, solvate, prodrug thereof.
In a first aspect of the invention are compounds of formula I wherein R is as defined above1、R2、R3And R4Each independently selected from: h, hydroxy, C1-6An alkyloxy group, -an O-glucosyl group.
In a first aspect of the invention are compounds of formula I wherein said compound of formula I is selected from the compounds shown in the following table:
the compounds of formula I according to any one of the first aspect of the invention are useful for the treatment and/or prevention of diseases associated with prostatic hypertrophy.
In one embodiment of the compounds of formula I according to the first aspect of the present invention, wherein said prostatic hypertrophy is benign prostatic hypertrophy.
In a second aspect, the present invention provides a plant extract comprising at least one compound of formula I:
wherein,
R1、R2、R3and R4Each independently selected from: h, hydroxy, straight or branched C1-6Alkyl, hydroxy-substituted C1-6Alkyl radical, C1-6Alkoxy radical, C6-10Aryl (e.g., phenyl or naphthyl), a glycoside containing a sugar such as-O-glucosyl (i.e., -O-glucosyl, e.g., -O- β -D glucosyl), glucosyl (i.e., -glucosyl), or a pharmaceutically acceptable salt, solvate, prodrug thereof.
In one embodiment of the plant extract of the second aspect of the present invention, wherein R is1、R2、R3And R4Each independently selected from: h, hydroxy, C1-6An alkyloxy group, -an O-glucosyl group.
In one embodiment of the plant extract of the second aspect of the present invention, wherein said compound of formula I is selected from the compounds shown in the following table:
in one embodiment of the plant extract of the second aspect of the present invention, at least one compound selected from the group consisting of:
3, 4', 5-trihydroxy stilbene,
3, 3 ', 4 ', 5-tetrahydroxystilbene-4 ' -O-beta-D-glucoside,
3, 3 ', 5-trihydroxy-4' -methoxystilbene-3-O-beta-D-glucoside,
3, 5-dihydroxy-4' -methoxystilbene-3-O-beta-D-glucoside, and
3, 4', 5-trihydroxy stilbene-3-O-beta-D-glucoside.
The plant extract according to the second aspect of the present invention is extracted from a plant selected from the group consisting of: vitaceae plants such as genus Vitis, genus Ampelopsis; leguminous plants such as arachis, cassia, sophora; plants of the liliaceae family such as the genus veratrum; myrtaceae plant such as Eucalyptus, Polygonaceae plant such as Rheum emodi, Rheum Officinale, or Polygonum cuspidatum.
The plant extract according to the second aspect of the present invention is extracted from a plant selected from the group consisting of: the plant of Polygonaceae may be Rheum emodi wall, Rheum officinale, Rheum palmatum or Polygonum cuspidatum.
The plant extract according to the second aspect of the present invention is extracted from a plant selected from the group consisting of: radix et rhizoma Rhei, radix et rhizoma Rhei Hedgersiae, radix et rhizoma Rhei Tianshan, radix et rhizoma Rhei Franzenbachii or rhizoma Polygoni Cuspidati.
The plant extract according to the second aspect of the present invention is extracted from a plant selected from the group consisting of: radix et rhizoma Rhei, radix et rhizoma Rhei Hedgersiae, radix et rhizoma Rhei Franzenbachii or rhizoma Polygoni Cuspidati.
The plant extract according to the second aspect of the present invention is obtained by the following method: i) extraction with 90-98% ethanol (e.g. about 95% ethanol), ii) defatting with diethyl ether or chloroform, iii) extraction with ethyl acetate or elution, and optionally extraction with n-butanol, iv) silica gel column chromatography (e.g. with 60-100 mesh silica gel), elution with ethyl acetate and/or elution with an ethyl acetate-methanol gradient (e.g. a gradient of 4: 1-2). In one embodiment, the extract obtained by elution through the above silica gel column chromatography is further recrystallized from acetone or acetone-water to obtain the compound of formula I of the first aspect of the present invention. Thus the above-described methods comprising extraction, defatting, extraction or elution, chromatography, recrystallization may be used as a method for preparing the compounds of formula I according to the first aspect of the invention.
In a third aspect, the present invention provides a process for the preparation of a compound of formula I according to any one of the first aspect of the invention or a plant extract according to any one of the second aspect of the invention, comprising the steps of: i) extracting with 90-98% ethanol (e.g. about 95% ethanol), ii) defatting with diethyl ether or chloroform, iii) extracting with ethyl acetate or eluting, and optionally extracting with n-butanol, iv) performing silica gel column chromatography (e.g. with 60-100 mesh silica gel), eluting with ethyl acetate and/or with ethyl acetate-methanol gradient (e.g. gradient of 4: 1-2) to obtain a plant extract containing a compound of formula I of the present invention; the extract obtained by elution through the above silica gel column chromatography is further recrystallized with acetone or acetone-water to obtain the compound of formula I of the first aspect of the present invention.
In a fourth aspect, the present invention provides the use of a compound of formula I according to any one of the first aspect of the present invention or a plant extract according to any one of the second aspect of the present invention in the manufacture of a medicament for the treatment and/or prevention of a disease associated with prostatic hypertrophy.
In one embodiment of the use of the fourth aspect of the present invention, wherein said prostatic hypertrophy is benign prostatic hypertrophy.
In a fifth aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I according to any one of the first aspect of the present invention or at least one plant extract according to any one of the second aspect of the present invention, and optionally a pharmaceutically acceptable carrier.
The pharmaceutical composition according to any of the fifth aspects of the invention comprises a therapeutically and/or prophylactically effective amount of at least one compound of formula I according to any of the first aspects of the invention or at least one plant extract according to any of the second aspects of the invention.
The pharmaceutical composition according to the fifth aspect of the present invention is useful for treating and/or preventing a disease associated with prostatic hypertrophy.
In one embodiment of the pharmaceutical composition of the fifth aspect of the present invention, wherein the prostatic hypertrophy is benign prostatic hypertrophy.
In a sixth aspect, the present invention provides a method for the treatment and/or prevention of diseases associated with prostatic hypertrophy comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I according to any one of the first aspects of the invention or a plant extract according to any one of the second aspects of the invention.
In one embodiment of the method of the sixth aspect of the present invention, wherein said prostatic hypertrophy is benign prostatic hypertrophy.
Detailed description of the invention:
various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
According to the invention, the compounds of the formula I according to the invention can be derived from natural plants or can be obtained synthetically. For example, the compound of formula I can be obtained from natural plants such as Vitis, Ampelopsis of Vitaceae; arachis, Cassia, and Sophora of Leguminosae; veratrum genus of liliaceae family; is extracted from Rheum emodi, Rheum Palmatum, Rheum Officinale, Rheum palmatum or Polygonum cuspidatum of Eucalyptus of Myrtaceae.
In the structural formula I of the present invention, in which the vinylidene group is a trans-structure, for the sake of convenience of naming, the carbon atoms on the benzene ring are represented according to the following structure:
according to the present invention, the term "prostatic hypertrophy-associated disease" as used herein refers to a disease, disorder, condition, or the like associated with prostatic hypertrophy, or to a complication, secondary disease, or the like, caused by prostatic hypertrophy. In one embodiment of the present invention, the term "prostate hypertrophy-associated disease" refers to prostatic hypertrophy.
According to the invention, the term "prostatic hypertrophy" according to the invention preferably refers to benign prostatic hypertrophy.
According to the present invention, the term subject as used in the present invention means a mammal such as a human.
According to the present invention, the term "alkyl" refers to a straight or branched chain lower hydrocarbon group containing 1 to 6 carbon atoms, which may contain one or more double or triple bonds, and is preferably a saturated alkyl group. Examples of alkyl groups of the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, allyl, propenyl, propynyl, preferably: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl.
The compounds of the formula I according to the invention can be obtained, for example, by extraction from plants as mentioned in the introduction, or by chemical synthesis using the knowledge available to the person skilled in the art. The plant extracts of the present invention are obtained by extraction using methods taught herein or known to those skilled in the art. In the process for extracting or synthesizing the compound of formula I or the plant extract of the present invention, various starting materials for the reaction may be prepared by those skilled in the art according to the prior knowledge, or may be prepared by methods well known in the literature, or may be commercially available. The intermediates, starting materials, reagents, reaction conditions, etc. used in the above reaction schemes may be appropriately modified according to the knowledge of those skilled in the art. Alternatively, other compounds of formula I not specifically recited herein or plant extracts containing such compounds of formula I may also be prepared by those skilled in the art according to the method of the third aspect of the present invention.
According to the invention, the term "Glc" in the chemical formula denotes glucosyl.
According to the present invention, the stilbene derivative can be formulated in a known manner into preparations for enteral or parenteral administration, such as tablets, capsules, granules, injections, and the like.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. According to the invention, said "composition" can be used interchangeably with "pharmaceutical composition".
The actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is common practice in the art to start doses of the compound or extract at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved.
When used in the above-described therapeutic and/or prophylactic or other therapeutic and/or prophylactic applications, a therapeutically and/or prophylactically effective amount of a compound of the present invention may be employed in pure form, or in the form of a pharmaceutically acceptable ester or prodrug, where such forms are present. Alternatively, the compounds may be administered in a pharmaceutical composition comprising the compound of interest together with one or more pharmaceutically acceptable excipients. The phrase "therapeutically and/or prophylactically effective amount" of a compound of the present invention refers to a sufficient amount of the compound to treat a disorder at a reasonable benefit/risk ratio applicable to any medical treatment and/or prophylaxis. It will be appreciated, however, that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. In general, the dosage of the compounds of formula I according to the invention for mammals, in particular humans, may be between 0.001 and 1000mg/kg body weight/day, such as between 0.01 and 100mg/kg body weight/day, such as between 0.01 and 50mg/kg body weight/day, such as between 0.01 and 10mg/kg body weight/day, such as between 0.1 and 10mg/kg body weight/day, such as between 0.01 and 0.1mg/kg body weight/day, such as between 10 and 50mg/kg body weight/day. In the case of oral administration, a dose of 0.01 to 100mg/kg body weight/day is more preferable, a dose of 0.01 to 50mg/kg body weight/day is still more preferable, and a dose of 0.01 to 10mg/kg body weight/day is still more preferable, as a human dose. The plant extracts of the invention also have the same characteristics as the compounds of formula I described above, for example the dosages described above for the compounds of formula I are also applicable to the plant extracts of the invention, which, of course, in determining the dosage of the plant extract may be used in amounts corresponding to the amounts containing the corresponding compounds of formula I. For example, when a plant extract containing a compound of formula I is administered to a human at a dose of 5mg/kg body weight/day, the plant extract is administered in an amount wherein the compound of formula I is contained at 5 mg/kg/day.
The present inventors have surprisingly found that compounds of formula I or plant extracts containing compounds of formula I can be effectively used for the prevention and/or treatment of diseases associated with prostatic hypertrophy.
Detailed Description
The invention is further illustrated by the following specific examples, which, however, are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified.
Example 1: preparation of 3, 4', 5-trihydroxystilbene (Compound S)
Taking giant knotweed rhizome decoction pieces, adding 8 times of 95% ethanol for reflux extraction for three times, and each time for 2 hours. Mixing extractive solutions, and concentrating under reduced pressure. Dispersing the concentrate with water, extracting with diethyl ether for removing ester, and sequentially extracting with ethyl acetate and n-butanol. Recovering ethyl acetate fraction, n-butanol fraction, and water fraction respectively. Performing silica gel column chromatography (60-100 mesh) on the ethyl acetate part, performing gradient elution with ethyl acetate-methanol to obtain S crude product (namely the plant extract of the invention), and recrystallizing with acetone to obtain the final product. Performing silica gel column chromatography on the n-butanol part, performing gradient elution with ethyl acetate to obtain S crude product (the plant extract of the invention), and recrystallizing with acetone-water to obtain the final product.
And (3) identification:
the compound S is white needle crystal and mp253-255 ℃. Is easily melted in methanol, ethanol, acetone, etc. FeCl3The reaction is green, and the blue-violet fluorescence is obtained under an ultraviolet lamp. UV lambdamax MeOH(nm)：216，303。IR(KBr)cm-1：3240，1880，1585，965。1H NMR (acetone-d)6)δ：8.79(1H，Br.s，4′-OH)，8.48(2H，Br.s，3，5-OH)，7.36(2H，dd，J＝2.4/8.5Hz，H-2′，6′)，6.95(1H，d，J＝16.2Hz，H-β)，6.81(1H，d，J＝16.2Hz，H-α)，6.78(2H，dd，J＝2.4/8.5Hz，H-3′，5′)，6.77(2H，d，J＝2.2Hz，H-2，6)，6.48(1H，t，J＝2.4Hz，H-4)。13C NMR (acetone-d)6)δ：159.47(C-3，5)，158.08(C-4′)，140.73(C-1)，129.78(C-1′)，128.98(C-2′，6′)，128.60(C-α)，126.74(C-β)，116.29(C-3′，5′)，105.47(C-2，6)，102.51(C-4)。EI-MS m/z：228(M+，100)，227(M+-1)，211(M+-OH), 181, 157, 115, 91, 76. Compound S was identified as 3, 4 ', 5-trihydroxystilbene (3, 4', 5-trihydroxystilbene), i.e., resveratrol (resveratrol).
3, 4', 5-trihydroxy stilbene (resveratrol)
Example 2:preparation of 3, 3 ', 4 ', 5-tetrahydroxystilbene-4 ' -O-beta-D-glucoside (Compound S-1)
Reflux-extracting radix et rhizoma Rhei and rhizome with 8 times of 95% ethanol for three times (2 hr each time). Mixing extractive solutions, and concentrating under reduced pressure. Dispersing the ethanol extract with diatomite, and drying. The liposoluble fraction was washed with chloroform, followed by ethyl acetate elution to obtain an ethyl acetate-soluble fraction. The fraction is subjected to silica gel column chromatography (60-100 mesh), eluted with ethyl acetate, and then eluted with ethyl acetate/methanol (4: 1-2) to obtain a crude product (i.e., the plant extract of the present invention containing the compound S-1), and the crude product is recrystallized with water-acetone to obtain S-1.
And (3) identification:
the compound S-1 is white amorphous powder (dilute acetone) and mp.138-140 ℃. The fluorescent material shows bluish purple fluorescence under ultraviolet light, and the Molisch reaction is positive.1H NMR (acetone-d)6)δppm：7.14(1H，d，J＝8.5Hz，H-5′)，7.06(1H，d，J＝2.1Hz，H-2′)，6.97(1H，d，J＝16.3Hz，H-β)，6.94(1H，dd，J＝2.1/8.5Hz，H-6′)，6.89(1H，d，J＝16.3Hz，H-α)，6.52(2H，d，J＝2.1Hz，H-2，6)，6.24(1H，t，J＝2.1Hz，H-4)，4.79(1H，d，J＝7.5Hz，anomeric-H)，3.9-3.3(sugar-H)；13C NMR (acetone-d)6)δppm：aglycone 159.5(C-3，5)，148.5(C-4′)，146.0(C-3′)，140.3(C-1)，134.2(C-1′)，128.6(C-α，β)，119.3(C-5′)，118.9(C-6′)，114.2(C-2′)，105.6(C-2，6)，104.0(C-4)，glucosyl：102.9(C-1″)，77.8(C-3″)，77.1(C-5″)，74.4(C-2″)，70.9(C-4″)，62.2(C-6″)。1HNMR and13the CNMR data are consistent with those reported by Yoshiki Kashiwada et al (2Yoshiki Kashiwada et al chem. pharm. Bull.1988, 36 (4): 1545), Compound E1Identified as 3, 3 ', 4', 5-tetrahydroxystilbene-4 '-O-beta-D-glucoside (Piceatannol-4' -O-beta-D-glucopyranoside).
3, 3 ', 4', 5-tetrahydroxystilbene-4 '-O-beta-D-glucoside (Piceatannol-4' -O-beta-D-glucopyranoside)
Example 3:preparation of 3, 3 ', 5-trihydroxy-4' -methoxystilbene-3-O-beta-D-glucoside (Compound S-2)
Collecting root and rhizome of Rheum emodi in the same or similar manner as described in example 2 to obtain plant extract containing compound S-2 or recrystallizing to obtain compound S-2.
And (3) identification:
the compound S-2 is white needle crystal (dilute methanol) and mp.228-230 ℃. The fluorescent material shows bluish purple fluorescence under ultraviolet light, and the Molisch reaction is positive.1H NMR (acetone-d)6)δppm：7.07(1H，d，J＝2.0Hz，H-2′)，7.02(1H，d，J＝16.5Hz，H-β)，6.96(1H，dd，J＝2.0/8.3Hz，H-6′)，6.90(1H，d，J＝7.9Hz，H-5′)，6.89(1H，d，H＝16.5Hz，H-α)，6.77(1H，Br.s，H-2)，6.66(1H，Br.s，H-2)，6.48(1H，t，J＝1.8Hz，H-4)，4.90(1H，d，J＝7.7Hz，anomeric-H)，3.82(3H，s，-OCH3)，4.0-3.3(sugar-H)；13C NMR (acetone-d)6) δ ppm: aglycone160.1(C-5), 159.5(C-3), 148.4(C-4 '), 147.5 (C-3'), 140.5(C-1), 131.5(C-1 '), 129.5 (C-beta), 127.2 (C-alpha), 119.7 (C-6'), 113.3(C-2 '), 112.5 (C-5'), 108.0(C-2), 106.5(C-6), 103.8(C-4), 56.2(-OCH 3); glucosyl group: 101.9(C-1 '), 77.7 (C-3', 5 '), 74.4 (C-2'), 71.1(C-4 '), 62.5 (C-6'). The compound S-2 is identified as 3, 3 ', 5-trihydroxy-4' -methoxystilbene-3-O-beta-D-glucoside (3, 3 ', 5-trihydroxy-4' -methoxystilbene-3-O-beta-D-glucoside, namely rhaponticin).
3, 3 ', 5-Trihydroxyl-4' -Methoxystilbene-3-O-beta-D-glucoside (rhaponticin)
Example 4:3, 5-dihydroxy-4 '-methoxystilbene-3-O-beta-D-glucoside (compound S-3) and 3, 4', 5-trihydroxystilbene-3-O-beta-D-glucoside (compound S-5).
Respectively and/or simultaneously collecting radix et rhizoma Rhei Franzenbachii and rhizome and rhizoma Polygoni Cuspidati, and performing the same or similar method as described in example 2 to obtain plant extract containing compound S-3 and/or S-5 or recrystallizing to obtain compound S-3 and/or S-5.
The compound S-3 is colorless needle crystals (acetone), mp210 ℃. The fluorescent material shows bluish purple fluorescence under ultraviolet light, and the Molisch reaction is positive. UV lambdamax MeOH(nm)：216，296。IR(KBr)cm-1：3455，3320(OH)，1595，1505，830，772，675。1H NMR (acetone-d)6)δppm：7.51(2H，d，J＝8.6Hz，H-2′，6′)，7.08(1H，d，J＝16.6Hz，H-α)，6.94(1H，d，J＝16.6Hz，H-β)，6.91(1H，d，J＝8.6Hz，H-3′，5′)，6.70(2H，Br.s，H-2，6)，6.35(1H，t，J＝2.2Hz，H-4)，4.81(2H，d，J＝7.6Hz，anomerica-H)，3.76(3H，s，OCH3)，3.3-3.9(6H，m，sugar-H)；13C NMR (acetone-d)6)δ：159.2(C-5)，158.5(C-3)，159.0(C-4′)，139.0(C-1)，129.2(C-1′)，128.0(C-β)，127.3(C-2′，6′)，126.0(C-α)，114.5(C-3′，5′)，107.2(C-6)，104.8(C-2)，103.0(C-4)，55.2(OCH3) Glucosyl group: 101.8(C-1 '), 74.0 (C-2'), 77.2(C-3 '), 70.8 (C-4'), 76.8(C-5 '), 61.8 (C-6'). FAB-MS m/z: 404 (M)+)，242(M+-Glc). The data are consistent with the data reported by Minder et al (1 Minde et al, J. Chinese materia Medica, 1998, 23 (8): 486), and therefore S-3 is identified as 3, 5-dihydroxy-4 '-methoxystilbene-3-O-beta-D-glucoside (3, 5-dihydroxy-4' -methoxystilbene-3-O-beta-D-glucoside, i.e. desoxyyro halophilic).
3, 5-dihydroxy-4' -methoxystilbene-3-O-beta-D-glucoside (desoxyyrhapositicin)
The compound S-5 is white long needle crystal (acetone-water), mp228-230 ℃. Is easily dissolved in acetone. The fluorescent material shows bluish purple fluorescence under ultraviolet light, and the Molisch reaction is positive. UV lambdamax MeOH(nm)：220，303。IR(KBr)cm-1：3510，3310，2975，2923，2880，1610，1589，1516，1450，1360，1320，1250，1170，1075，965，840。1H NMR (acetone-d)6)δppm：8.89(1H，Br.s，4′-OH)，8.86(1H，Br.s，5-OH)，7.35(2H，dd，J＝2.4/8.5Hz，H-2′，6’)，7.20(1H，d，J＝16.2Hz，H-β)，6.84(1H，d，J＝16.2Hz，H-α)，6.78(2H，dd，J＝2.4/8.5Hz，H-3′，5’)，6.73(1H，Br.s，H-6)，6.62(1H，Br.s，，H-2)，6.45(1H，Br.s，H-4)，4.88(1H，d，J＝7.7Hz，anomerica-H)，3.8-3.2(sugar-H)；13C NMR (acetone-d)6) δ ppm: 160.10(C-3), 159.33(C-5), 158.19(C-4 '), 140.73(C-1), 129.64 (C-1'), 129.56(C-2 ', 6'), 128.70(C- α), 126.33(C- β), 116.31(C-3 ', 5'), 108.00(C-2), 106.49(C-6), 103.72(C-4), glucosyl: 101.90(C-1 '), 77.76 (C-3'), 77.64(C-5 '), 74.57 (C-2'), 71.26(C-4 '), 62.48 (C-6'). FAB-MSm/z: 389 (M)+-H)，242(M+-Glc). Therefore, the compound S-5 is identified as 3, 4 ', 5-trihydroxystilbene-3-O-beta-D-glucoside (3, 4', 5-trihydroxystilbene-3-O-beta-D-glucoside), namely polydatin (ploydatin).
3, 4', 5-Trihydroxystilbene-3-O-beta-D-glucoside (ploydatin)
Experimental example 1:determination of biological Activity
In the following biological experiments, the prevention and treatment effects of the representative compound of the invention on the castrated rat prostatic hyperplasia model caused by testosterone propionate are mainly observed, and the treatment effect is preliminarily evaluated by taking Baoenzhi as a positive control drug.
Rats with the weight of 120-150 g and 6-7 weeks are selected for the experiment, except a normal control group, animals in each group are anesthetized by pentobarbital sodium ip, bilateral testicles are aseptically excised, and the animals are randomly divided into a model control group, a positive control drug group and a test drug group according to the weight after natural recovery for one week. Except for the normal control group, the remaining rats had 0.5 mg/mouse 0.1ml of SC testosterone propionate per day, once per day for 4 weeks. Normal animals SC equal volume saline. Each group contained 10 rats. The administration route was intragastric once a day for 4 weeks, and the following results were obtained:
(1) influence on urine flow Rate
30min after the non-administration, a water load of 2ml/100g body weight was administered, i.e. the animals were placed in a metabolic cage and the urine volume was measured over 2h and 6h, respectively, and the results are shown in Table 1.
Table 1: influence of S-2 on the protestosterone induced castration rat prostatic hyperplasia micturition flow rate
Note: 1. the # model group was compared with the normal control group,###p＜0.001；
2、＊the ratio of the administration group to the model group,＊p＜0.05、＊＊p＜0.01、＊＊＊p＜0.001。
the above results show that: urine output within 2 hours after water load was about 50% and about half of the load in normal group animals. The urine output of the model animals within 2 hours after water load is obviously reduced, the urine output is only 33.7 percent, the difference between the urine output and the urine output is very obvious (p is less than 0.001), and the urine flow rate is obviously slowed down after the prostate hyperplasia of the rats. The urine output of the rats treated by S-2 and Baoen treatment is 43-49% in the first 2 hours and is obviously higher than that of the model group (p is less than 0.001). There was no significant difference between the groups in urine output within 2-6 hours after water load. However, the total urine output within 6 hours after water loading was significantly or very significantly higher in the administered group than in the model group (p < 0.05 or p < 0.001).
(2) Influence on prostate wet weight and coefficient
The animals were anesthetized and exsanguinated, and then weighed, dissected, and the dorsal and ventral prostate lobes were taken, weighed and the coefficients calculated, and the results are listed in table 2.
Table 2: influence of S-2 on prostate wet weight and coefficient of testosterone propionate-induced castration rat
Note: 1. the # model group was compared with the normal control group,###p＜0.001；
2、＊the ratio of the administration group to the model group,＊p＜0.05、＊＊＊p＜0.001。
the results in the table show that: the model group prostate leaves and total weight (wet weight) and their coefficients were all significantly greater than the normal control group (p < 0.001). The rat is irrigated with baoenzhi 1.0mg/kg and S-250-150mg/kg, which can obviously reduce the weight and coefficient of the prostate of the rat, and compared with the model group, the weight and coefficient of the prostate of the rat are very obvious (p is less than 0.01-0.001). The effect of the S-2150mg/kg dose group on the reduction of the total wet weight of the prostate is similar to the effect of 1.0mg/kg positive drug Bao Luo Zhi, but the wet weight of the dorsal leaves is obviously smaller than that of Bao Luo Zhi.
(3) Effect on prostate volume and factor
The prostates of the above groups of animals were weighed and the volume was measured again by the drainage method, and the results are shown in Table 3.
Table 3: influence of S-2 on prostate volume and coefficient of testosterone propionate-induced castration rats
Note: 1. the # model group was compared with the normal control group,###p＜0.001；
2、＊the ratio of the administration group to the model group,＊p＜0.05、＊＊＊p＜0.001。
as can be seen from the results in Table 3, the change in prostate volume in each group of animals was substantially consistent with the wet weight of the prostate, yet minimized the volume of the dorsal lobe of the prostate in the S-2 group of animals at 150 mg/kg.
(3) Effect on prostate Dry weight and coefficient
The volume of the prostate dorsal and ventral lobes of each group of animals was measured, and the prostate was baked in an oven at 60 ℃ for 16 hours to measure the dry weight, and the prostate dry weight coefficient was calculated, and the results are shown in table 4.
Table 4: influence of S-2 on prostate dry weight and coefficient of testosterone propionate-induced castration rats
Note: 1. the # model group was compared with the normal control group,###p＜0.001；
2、＊the ratio of the administration group to the model group,＊p＜0.05、＊＊＊p＜0.001。
the results show that: both 1.0mg/kg of Baoerit treatment and S-2 can obviously reduce the dry weight of the prostate and the dry weight coefficient. Wherein the inhibiting effect of 150.0mg/kg of S-2 on the prostatic hyperplasia is not inferior to that of positive drug treatment.
The results of the biological activity assay of compounds S, S-1, S-3 and S-5 or plant extracts containing compounds S, S-1, S-2, S-3 and S-5, respectively, using the same method as described above for compound S-2, show that the results for the above compounds or plant extracts are substantially the same as or similar to the results for compound S-2.
Experimental example 2:determination of toxicity
Mice were drenched with representative compounds of the invention to determine their toxicity. The results are shown in Table 5.
Table 5: maximum tolerability of the compounds of the invention by drenching mice
As can be seen from Table 3, the compound of the present invention has low toxicity when administered by drenching, and the compound is judged to be a low-toxicity or actual nontoxic substance according to WHO1977 acute toxicity classification standard, and is safe and practical.
Claims (3)
1. The use of a compound of formula I for the preparation of a medicament for the treatment and/or prevention of prostatic hypertrophy,
wherein R is1、R2、R3And R4Each independently selected from: h, hydroxy, C1-6An alkyloxy group, -O-glucosyl group, and R1、R2、R3And R4At least one substituent is-O-glucosyl.
2. The use of claim 1, wherein the compound of formula I is selected from: 3, 3 ', 4 ', 5-tetrahydroxystilbene-4 ' -O- β -D-glucoside; 3, 3 ', 5-trihydroxy-4' -methoxystilbene-3-O- β -D-glucoside; 3, 5-dihydroxy-4' -methoxystilbene-3-O- β -D-glucoside; and 3, 4', 5-trihydroxystilbene-3-O-beta-D-glucoside.
3. The use of claim 1 or 2, wherein the prostatic hypertrophy is benign prostatic hypertrophy.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270804A (en) * | 1999-02-17 | 2000-10-25 | 莱雅公司 | use of diphenyl styrene in cosmetic composition as deodoring active content |
| CN1386499A (en) * | 2001-05-21 | 2002-12-25 | 曹治国 | Application of diphenylvinyl phenol glucosides in preparing hypolipemic medicine |
| CN1398838A (en) * | 2001-07-26 | 2003-02-26 | 中国人民解放军军事医学科学院放射医学研究所 | Diphenylethylene compound and its prepn and application in preventing and treating diabetes |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270804A (en) * | 1999-02-17 | 2000-10-25 | 莱雅公司 | use of diphenyl styrene in cosmetic composition as deodoring active content |
| CN1386499A (en) * | 2001-05-21 | 2002-12-25 | 曹治国 | Application of diphenylvinyl phenol glucosides in preparing hypolipemic medicine |
| CN1398838A (en) * | 2001-07-26 | 2003-02-26 | 中国人民解放军军事医学科学院放射医学研究所 | Diphenylethylene compound and its prepn and application in preventing and treating diabetes |
Non-Patent Citations (2)
| Title |
|---|
| 朱元全等.白藜芦醇对正常幼龄大鼠前列腺的影响研究.《现代中西医结合杂志》.2007,第16卷(第35期),5248-5249,5343. |
| 白藜芦醇对正常幼龄大鼠前列腺的影响研究;朱元全等;《现代中西医结合杂志》;20071231;第16卷(第35期);5248-5249,5343 * |
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