CN101574338A - Pharmaceutical composition for restraining activity of aromatizing enzyme and application thereof - Google Patents
Pharmaceutical composition for restraining activity of aromatizing enzyme and application thereof Download PDFInfo
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- CN101574338A CN101574338A CNA200810036981XA CN200810036981A CN101574338A CN 101574338 A CN101574338 A CN 101574338A CN A200810036981X A CNA200810036981X A CN A200810036981XA CN 200810036981 A CN200810036981 A CN 200810036981A CN 101574338 A CN101574338 A CN 101574338A
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Abstract
The invention discloses a pharmaceutical composition for restraining the activity of aromatizing enzyme, containing a flavone compound and a fatty acid compound. The flavone compound refers to a compound of formula I, wherein a substituent R1 is selected from H or OH, and a substituent R2 is selected from H, OH or OCH3; the fatty acid compound refers to a compound with a molecular formula of CH3-CnHm-COB, wherein n is greater than 8 and less than 24, m is greater than or equal to 2n-8 and less than or equal to 2n, and B is a hydroxyl, an N-hydroxyethyl, a fructosyl or a glyceryl. The pharmaceutical composition can effectively restrain the activity of the aromatizing enzyme and can be used for preparing medicaments for treating or preventing estrogen dependent diseases.
Description
Technical field
The invention belongs to field of medicinal compositions, particularly a kind of pharmaceutical composition and application thereof that suppresses activity of aromatizing enzyme.
Background technology
Estrogen is the important gonadal hormone of a class, and is closely related with physiology, pathological process that body is numerous.The intravital estrogen of postmenopausal women and male mainly is transformed by the androgen precurosor of acth secretion, transform the position and occur in fatty tissue, liver, kidney etc. and locate, by paracrine and (or) mode of autocrine, mainly play a role in the part.Aromatase P450 is key enzyme, the rate-limiting enzyme of this transition process, plays an important role in multiple physiology, pathological process, thereby becomes prevention and an important target spot for the treatment of estrogen-dependent diseases.
Flavone compound, fatty acid compound extensively are present in occurring in nature, have multiple physiologically active.Bibliographical information, flavone compound, fatty acid compound, coumarin kind compound and terpenoid etc. all have aromatic enzyme-tion suppressioning activity, be used as the active component in the pharmaceutical composition that suppresses activity of aromatizing enzyme respectively individually, but the drug effect of these pharmaceutical compositions is lower.
Summary of the invention
The technical problem to be solved in the present invention is exactly at the lower deficiency of the pharmaceutical composition drug effect of existing inhibition activity of aromatizing enzyme, a kind of pharmaceutical composition that suppresses activity of aromatizing enzyme and its production and application is provided, and the activity of this pharmaceutical composition obviously is better than the existing pharmaceutical composition that comprises an active component.
There are not at present the open flavone compound of report, coumarin kind compound, terpenoid and fatty acid compound whether the inhibition activity of aromatase is had synergism each other as yet.The inventor is through many tests, flavone compound, the fatty acid compound of finding to have aromatic enzyme-tion suppressioning activity have synergism pleasantly surprisedly each other, the activity that comprises the compositions of this two compounds obviously is better than only comprising the wherein activity of the compositions of a compounds, thereby has finished the present invention.
The present invention solves the problems of the technologies described above the technical scheme that is adopted: a kind of pharmaceutical composition that suppresses activity of aromatizing enzyme comprises flavone compound and fatty acid compound.
" flavone compound " described in the present invention is meant the chemical compound that has as general formula I,
General formula I
Substituent R wherein
1Be selected from H or OH, R
2Be selected from H, OH or OCH
3
" fatty acid compound " described in the present invention is meant that molecular formula satisfies CH
3-C
nH
m-COB, 8＜n＜24 wherein, the chemical compound of 2n-8≤m≤2n, B are hydroxyl, N-ethoxy, fructosyl or glyceryl.
Among the present invention, what the weight ratio of described flavone compound and fatty acid compound was preferable is 1: 10～10: 1, better is 1: 3～3: 1.
Among the present invention, described flavone compound is preferable is selected from kaempferol, Quercetin, isorhamnetin and the apigenin one or more.In general formula I, Quercetin: R
1=OH, R
2=OH; Kaempferol: R
1=OH, R
2=H; Isorhamnetin: R
1=OH, R
2=OCH
3Apigenin: R
1=H, R
2=H.
Among the present invention, being selected from that described fatty acid compound is preferable is sad, in linolenic acid, linoleic acid, Palmic acid, suitable-15-tetracosenoic acid and the derivant thereof one or more.It is the chemical compound of parent nucleus that described derivant is meant with described fatty acid compound, comprises the ester of fatty acid, as linolenamide ester, glyceryl linolenate, linolenic acid fructose ester and linolenic acid sterol ester; On the two keys of fatty acid is substituent chemical compound, as the dihydroxy linoleic acid.Described derivant is preferable is selected from linolenamide ester, glyceryl linolenate, linolenic acid sterol ester and dihydroxy linoleic acid.
What described flavone compound and fatty acid compound were preferable can be made by the method that may further comprise the steps: pollen (processed by breaking wall) is adopted supercritical carbon dioxide (CO
2) extract, obtain the fatty acid compound part with macroporous resin enrichment then; Pollen (processed by breaking wall) is adopted supercritical carbon dioxide (CO
2) residue part after the extraction, adopt alcoholic solvent to extract, obtain the flavone compound part; These two parts are mixed.Described pollen (processed by breaking wall) is better is Pollen Brassicae campestris behind the breaking cellular wall, and what described alcoholic solvent was better is ethanol.The preparation of this chemical compound can be 200710043856.7 Chinese patent application referring to application number, and this patent application is quoted by the present invention in full.
Pharmaceutical composition of the present invention also can comprise pharmaceutically acceptable carrier.Described pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, wherein, and diluent, excipient such as water etc.; Binding agent such as cellulose derivative, gelatin or polyvinylpyrrolidone etc.; Filler such as starch etc.; Agent such as calcium carbonate or sodium bicarbonate burst apart; In addition, can also in this pharmaceutical composition, add other adjuvant such as flavouring agent and/or sweeting agent.This active ingredient in pharmaceutical is any above-mentioned pharmaceutical composition that comprises flavone compound and fatty acid compound of the present invention of treatment effective dose.This pharmaceutical composition can adopt the method for medical domain routine, and described active component and pharmaceutically acceptable carrier are made various dosage forms.When being used for when oral, it can be prepared into conventional solid preparation such as tablet, powder or capsule etc.; When being used to inject, it can be prepared into injection.In various preparations, the weight content of active component is 20%～90%, and preferred weight content is 40%～70%.
Each pharmaceutical composition of the present invention can put on the patient who needs this treatment by dosage form by intravenous injection, subcutaneous injection or oral form.The general dosage that imposes on the patient who needs treatment is 1.0～5.0mg/ kg body weight/sky, specifically can change according to patient's age, the state of an illness etc.
Each raw material addressed among the present invention or reagent in the present invention, particularly point out, all commercially available getting.
Preparation of drug combination method of the present invention can be to adopt the conventional method of this area to mix by said components the existing commercially available raw material that gets.
The present invention also provides the application of above-mentioned any pharmaceutical composition of the present invention in the medicine of preparation inhibition activity of aromatizing enzyme or treatment of diseases for the treatment of by the inhibition activity of aromatizing enzyme or prevention.Described disease is estrogen-dependent diseases preferably, can be breast carcinoma, endometriosis or hyperplasia of prostate etc.
Than prior art, beneficial effect of the present invention is as follows: the pharmaceutical composition of inhibition activity of aromatizing enzyme of the present invention comprises flavone compound and fatty acid compound two compounds, utilize the synergism between flavone compound and the fatty acid compound, its activity obviously is better than existing any and comprises the wherein activity of the pharmaceutical composition of a compounds, can efficiently suppress activity of aromatizing enzyme, can be used for preparation treatment or prevention estrogen-dependent diseases medicine.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Embodiment 1
With 60 ℃ of drying under reduced pressure of commercially available rape pollen with broken wall (production of Xuancheng City, Anhui Province hundred health apicultures) 24 hours, then with dried pollen (processed by breaking wall) at 40 ℃, extraction kettle pressure 40MPa, 35 ℃ of separation reactor I temperature, pressure 12MPa, 25 ℃ of separation reactor I I temperature, pressure 5MPa, with pollen weight 8% heavy concentration is that 95v/v% ethanol is that entrainer carries out supercritical carbon dioxide (45L/ hour circulation consumption) extraction 2.0 hours, obtains the supercritical extraction part, collects supercritical extract.
The supercritical extract that obtains is steamed to there not being the alcohol flavor, the macroporous resin of getting dress post amount 20～60% (v/v) stirs with extract, it is fully adsorbed, macroporous resin behind the sample macroporous resin column top of packing into will be mixed, wherein macroporous resin is selected polar macroporous resin DA201 (production firm: Tianjin sea light chemical industry company limited), with the ethanol elution of 50% (v/v), collect eluent for use, drying promptly obtains fatty acid part (i).
Detect this fatty acid part (i) with HPLC, it contains following component in percentage by weight: linolenic acid 15%～30%, linolenamide ester 20%～40%, glyceryl linolenate 20%～40%, linolenic acid fructose ester 1%～10%, linolenic acid sterol ester 1%～5%, Palmic acid 10%～30%.
With the residue part behind the supercritical carbon dioxide extraction,, obtain the flavone part (ii) with the ethanol extraction of 75%～100% (v/v).
Detect this flavone part (ii) with HPLC, it contains following component in percentage by weight: kaempferol 40%～60%, Quercetin 20%～50%, isorhamnetin 10%～20%, apigenin 5%～10%.
With above-mentioned two parts respectively according to fatty acid part (i) and flavone part (ii) weight ratio be to mix in 1: 10,1: 5,1: 1,5: 1 and 10: 1, promptly get pharmaceutical composition A of the present invention, B, C, D and E.
Embodiment 2
To mix and promptly get pharmaceutical composition F of the present invention, G, H and I available from press component described in the table 1 and content in the kaempferol of sigma company, Quercetin, isorhamnetin, apigenin, sad, Palmic acid, dihydroxy linoleic acid, suitable-the 15-tetracosenoic acid, linolenamide ester, glyceryl linolenate and linolenic acid sterol ester respectively.
The component of table 1. pharmaceutical composition F of the present invention, G and H
Further specify beneficial effect of the present invention below by effect embodiment.
Effect embodiment 1
The employing document (Quan Haitian, Lou Liguang. the foundation of arimedex screening model. the Chinese Pharmacological circular, 2004,20 (10): method 1189-1192), use the enzyme source of the microsome of Placenta Hominis as aromatase, with [1 β-
3H] androstenedione is as reaction substrate, by recording product
3H
2The radiant of O detects the activity of aromatase, counts with liquid scintillation counter
3H
2The emissivity of O, calculation sample is to the inhibitory action of aromatase.Specimen in use is each pharmaceutical composition A, B, C, D and the E of embodiment 1 preparation gained, be control sample with fatty acid mixt and flavone mixture wherein, fatty acid mixt and flavone mixture are respectively the fatty acid part (i) of embodiment 1 and flavone part (ii).Each sample and the suppression ratio of aromatase seen Table 2.
Table 2. specimen in use and to the suppression ratio of aromatase
Claims (12)
1, a kind of pharmaceutical composition that suppresses activity of aromatizing enzyme is characterized in that, it comprises flavone compound and fatty acid compound; Described flavone compound is meant the chemical compound that has as general formula I, wherein substituent R
1Be selected from H or OH, R
2Be selected from H, OH or OCH
3Described fatty acid compound is meant that molecular formula satisfies CH
3-C
nH
m-COB, 8＜n＜24 wherein, the chemical compound of 2n-8≤m≤2n, B are hydroxyl, N-ethoxy, fructosyl or glyceryl.
General formula I
2, pharmaceutical composition according to claim 1 is characterized in that, the weight ratio of described flavone compound and fatty acid compound is 1: 10～10: 1.
3, pharmaceutical composition according to claim 2 is characterized in that, the weight ratio of described flavone compound and fatty acid compound is 1: 3～3: 1.
4, pharmaceutical composition according to claim 1 is characterized in that, described flavone compound is selected from one or more in kaempferol, Quercetin, isorhamnetin and the apigenin.
5, pharmaceutical composition according to claim 1 is characterized in that, that described fatty acid compound is selected from is sad, in linolenic acid, linoleic acid, Palmic acid, suitable-15-tetracosenoic acid and the derivant thereof one or more.
6, pharmaceutical composition according to claim 5 is characterized in that, described derivant comprises linolenamide ester, glyceryl linolenate, linolenic acid sterol ester and dihydroxy linoleic acid.
7, pharmaceutical composition according to claim 1, it is characterized in that, described flavone compound and fatty acid compound, make by the method that may further comprise the steps: pollen (processed by breaking wall) is adopted supercritical carbon dioxide extraction, obtain the fatty acid compound part with macroporous resin enrichment then; Pollen (processed by breaking wall) is adopted residue part behind the supercritical carbon dioxide extraction, adopt alcoholic solvent to extract, obtain the flavone compound part.
8, pharmaceutical composition according to claim 7 is characterized in that, described pollen (processed by breaking wall) is the Pollen Brassicae campestris of breaking cellular wall.
9, pharmaceutical composition according to claim 7 is characterized in that, described alcoholic solvent is an ethanol.
10, pharmaceutical composition according to claim 1 is characterized in that, also comprises pharmaceutically acceptable carrier.
11, each described pharmaceutical composition of claim 1～10 is at preparation activity of aromatizing enzyme inhibitor, or prevents or treat application in the medicine of disease by suppressing activity of aromatizing enzyme.
12, application according to claim 11 is characterized in that, described disease is estrogen-dependent diseases, breast carcinoma, endometriosis or hyperplasia of prostate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810036981XA CN101574338B (en) | 2008-05-05 | 2008-05-05 | Pharmaceutical composition for restraining activity of aromatizing enzyme and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810036981XA CN101574338B (en) | 2008-05-05 | 2008-05-05 | Pharmaceutical composition for restraining activity of aromatizing enzyme and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101574338A true CN101574338A (en) | 2009-11-11 |
| CN101574338B CN101574338B (en) | 2012-01-11 |
Family
ID=41269501
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810036981XA Active CN101574338B (en) | 2008-05-05 | 2008-05-05 | Pharmaceutical composition for restraining activity of aromatizing enzyme and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101879156B (en) * | 2009-05-07 | 2013-01-30 | 上海医药工业研究院 | Medicinal composition and application thereof |
| WO2019092579A1 (en) * | 2017-11-09 | 2019-05-16 | Sistemi Salute S.R.L. | Substances and compositions for the use in the treatment of endometriosis and endometriosis associated symptoms |
| WO2022118183A1 (en) * | 2020-12-01 | 2022-06-09 | Bionexa S.R.L | Senotherapeutic substance |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1852115A1 (en) * | 2001-03-15 | 2007-11-07 | DSM IP Assets B.V. | Composition for the prevention of osteoporosis comprising a combination of isoflavones and polyunsaturated fatty acids |
| CN1837226B (en) * | 2005-03-23 | 2010-06-16 | 中国科学院上海药物研究所 | Separation of medical derivatives from phoenix-tail fern and use thereof |
-
2008
- 2008-05-05 CN CN200810036981XA patent/CN101574338B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101879156B (en) * | 2009-05-07 | 2013-01-30 | 上海医药工业研究院 | Medicinal composition and application thereof |
| WO2019092579A1 (en) * | 2017-11-09 | 2019-05-16 | Sistemi Salute S.R.L. | Substances and compositions for the use in the treatment of endometriosis and endometriosis associated symptoms |
| CN111315376A (en) * | 2017-11-09 | 2020-06-19 | 萨鲁特系统有限公司 | Substances and compositions for use in the treatment of endometriosis and endometriosis-related conditions |
| WO2022118183A1 (en) * | 2020-12-01 | 2022-06-09 | Bionexa S.R.L | Senotherapeutic substance |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101574338B (en) | 2012-01-11 |
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Effective date of registration: 20161019 Address after: 222001 Jiangsu city of Lianyungang Province Economic and Technological Development Zone Jiangning industrial city Kanion Road No. 58 Patentee after: Kangyuan Pharmceutical Co., Ltd. Patentee after: Shanghai Institute of pharmaceutical industry Address before: 200040 Beijing West Road, Shanghai, No. 1320 Patentee before: Shanghai Institute of pharmaceutical industry |