CN1699357A - Plant-derived estrogens analogs for treating osteoporosis after menopause - Google Patents
Plant-derived estrogens analogs for treating osteoporosis after menopause Download PDFInfo
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Abstract
The invention relates to a plant-derived estrogens analogs for treating osteoporosis after menopause and is preparation, the pharmaceutical compositions containing the compound, and the use of the compound in preparing the medicament for the treatment of postmenostasis osteoporosis, more specifically, the compound being 2,3-dihydro-6-methoxy-4H-1-benzopyran-4-thioacetazone (XY9906) and 3-(4'-dimethylaminobenzylidene)-6-methoxyl-H-1-methoxybenzopyrylospiran-4-one (XY2004). The compounds have rather strong protection action for bone and blood vessel tissue.
Description
Technical field the present invention relates to similar thing of phytoestrogen for the treatment of post-menopausal osteoporosis and preparation method thereof, also relates to the pharmaceutical composition and the application of described compound in the medicine of preparation treatment post-menopausal osteoporosis that contain described compound.Specifically, described compound is 2,3-dihydro-6-methoxyl group-4H-1-chromene-4-amithiozone (XY9906) and 3-(4 '-dimethylamino Ben Yajiaji)-6-methoxyl group-4H-1-chromanone (XY2004).
The background technology osteoporosis is to reduce with the bone amount, the osseous tissue microtexture destroys a kind of systematicness, the general metabolic osteopathy that causes increase of bone fragility and fracture risk to increase to feature, be more common in menopausal women, its incidence is 6-8 a times of male sex's osteoporosis, and is main relevant with the reduction of endogenous estrogen level.Lumbar and back pain, myasthenia of the limbs are not only in the harm that osteoporosis caused, if continue development, height reduction, figure's distortion also can appear, severest consequences are fracture, wherein especially the most very with Hip Fracture, be to disable and dead most important reason, wherein 10～20% patient is dead in 1 year, and 50% patient can't take care of oneself.According to estimating in World Bank's global evolution report in 1993, from the nineteen ninety to the year two thousand thirty, the women of the whole world more than 50 years old will rise to 1,200,000,000 from 4.67 hundred million, and the number of suffering from postmenopausal osteoporosis from now on will can not be ignored, and osteoporosis has become the public health problem of attracting attention in the whole world.
The women is to spend after menopause 1/3 time throughout one's life, and post-menopausal osteoporosis has had a strong impact on postmenopausal women's quality of life.The important means of tradition clinical practice is controversies in hormone replacement in the elderly (ERT).Yet, because the significant prolongation of human mean lifetime, enough long ERT behind postmenopausal women may increase the danger that mammary cancer and carcinoma of endometrium take place, and this threat and worry and people require the contradiction between the high-quality life in old age more prevalent and outstanding.Through behind a large amount of clinical evaluations, developed country such as U.S. has stopped or has proposed to stop to implement ERT recently.Therefore, people's an urgent demand modern medicine can be taken out safe and effective countermeasure and solve such contradiction.The ideal medicine is both to have kept the provide protection of oestrogenic hormon to bone and cardiovascular systems, and no estrogen is to the side effect of uterus and mammary gland again.
Side effect at ERT in 1998; selective estrogen receptor modulators raloxifene (raloxifene) by the exploitation listing of U.S. Lilly company; though can prevent and treat post-menopausal osteoporosis effectively; uterus and mammary gland are also had no side effect; but its provide protection to cardiovascular systems waits secular clinical evaluation; and exist and feel sick; hectic fever; headache; drug rash; stomachache; blurred vision; side effect such as itch and breast swell and pain; it should be noted that especially; some these medicines of adverse drug reaction report reflection can increase thrombotic danger; cause venous thrombosis and cerebrovascular disease that (Australian Adverse Drug ReactionsBulletin takes place; 2001; 12; Vol 20:4), do not make us very satisfied.
It not is that all postmenopausal womens are all suffered from osteoporosis that the epidemiology survey result shows, being starkly lower than with animal tallow and meat based on the east women's osteosporosis after menopause of the vegetarian diet that is rich in the osajin phytoestrogen and fracture incidence is the west women of staple food, as genistein (genistein), therefore, the phytoestrogen therapy that searching has no side effect replaces the estrin treatment osteoporosis, is the common hot research problem of paying close attention to of current international the world of medicine.Yet genistein is weaker than oestrogenic hormon and raloxifene far away to the result of treatment of postmenopausal osteoporosis, can not satisfy people's needs.How to improve the preventive and therapeutic effect of phytoestrogen to post-menopausal osteoporosis?
Scientists finds that estrogen receptor (ER) exists α and two kinds of hypotypes of β at present, the distribution proportion difference of these two kinds of acceptors in the different tissues, and reproductive organ (as uterus, mammary tissue) is rich in ER α usually; But not reproductive organ (as bone, cardiovascular systems) is based on ER β.Estradiol (E
2) be the full agonist of ER, the biological effect that its exciting ER α is caused be exciting ER β 35-60 doubly, so E
2When bone and cardiovascular systems are had provide protection, uterus, mammary gland are produced severe side effect.And osajin phytoestrogen genistcin has more weak ER agonist/antagonist effect, but it is to ER α 30 times to the avidity of ER β, and the usefulness that exciting ER β produces is 4-5 times of ER α, illustrates that genistein has the selectivity of height to ER β.According to above analysis, we propose the women's osteosporosis after menopause disease treatment new drug that design alternative is better, effect is stronger, side effect is littler, should be target spot with ER α and ER β, with genistein is lead compound, be conceived to improve the avidity of aglucon, make can the selectivity exciting ER β of aglucon and antagonism ER α ER β.
Brzozowski was to E in 1997
2, raloxifene the illustrating of binding site (Fig. 1) on ER alpha-crystal structure, provide theoretical foundation for Pharmaceutical Chemist designs the similar thing of new phytoestrogen.Comparative analysis E
2, raloxifene, genistein chemical structure (structure is as follows): 1) three is contained similar A, B ring (Fig. 2 empty frame in show).Discover A/B ring (thionaphthene) and the E of raloxifene
2The A/B ring binding site on ER α similar, the phenolic hydroxyl group on both A rings all is combined on 353 L-glutamic acid and 394 arginine of ER α.Because the ligand-binding domain of ER α and ER β has 53.5% homology, thus we to analyze A, B ring may be different aglucons and ER α/ER β bonded basic structural unit.2) the structure difference of genistein and raloxifene is to have basic side chain on the raloxifene ring.Discover that the aspartic acid on 351 of this side chain and the ER α combines, changed ER α carboxyl terminal configuration, having blocked the aglucon receptor complex combines with assisting activation factor, make the AF-2 functional zone can not activate estrogen response element (ERE) and drive the genetic transcription effect, make raloxifene show the effect of ER alpha-2 antagonists; This side chain also is the key factor that raloxifene has stronger anti-osteoporosis activity simultaneously.Just think, can be by introducing basic side chain composition optimizes isoflavones phytoestrogen, in the hope of improving the preventive and therapeutic effect of phytoestrogen to post-menopausal osteoporosis?
Summary of the invention for this reason, according to above analysis, it is lead compound that the present invention proposes first with genistein, with chromene ring (A/B) is basic structural unit, has synthesized the compound (chemical structure is seen Fig. 3) of the new plant estrogen analogue of 2 treatment post-menopausal osteoporosiss according to the isostere principle design:
The molecular formula of The compounds of this invention XY2004: C
19H
19NO
3=309
The physico-chemical property of The compounds of this invention XY2004: MP 182-184 ℃; Water insoluble, be soluble in chloroform, ether, ethanol, acetone, ethyl acetate, diluted acid.
The molecular formula of The compounds of this invention XY9906: C
11H
13N
3O
2S=251
The physico-chemical property of The compounds of this invention XY9906: MP 215-217 ℃; Water insoluble, be soluble in chloroform, ether, ethanol, acetone, ethyl acetate.
Compound of the present invention can be unformed powder or crystalline form.
Salt of the present invention is inorganic acid salt or the organic acid salt of compounds X Y2004, for example include but not limited to hydrochloride, nitrate, vitriol, hydrobromate, phosphoric acid salt, formate, acetate, benzoate, malate, maleate, Citrate trianion etc., be preferably hydrochloride, vitriol or Citrate trianion.
Another object of the present invention provides the synthetic method of described compound or its salt.Compounds X Y2004 and XY9906 prepare (see figure 4) with Scheme1,2 described two kinds of methods respectively among the present invention.
The salt of The compounds of this invention XY2004 is normally obtained by basic nitrogen in the compound and acid generation salt-forming reaction.Described acid can be to have any material of tart usually.For example include but not limited to mineral acid example hydrochloric acid, nitric acid, sulfuric acid, Hydrogen bromide, phosphoric acid etc., organic acid such as formic acid, acetate, phenylformic acid, oxysuccinic acid, toxilic acid, citric acid etc.
A further object of the present invention is a kind of pharmaceutical composition for the treatment of post-menopausal osteoporosis, wherein contains formula compounds X Y2004 of the present invention or its salt, XY9906 and the pharmaceutically acceptable carrier for the treatment of significant quantity.Described pharmaceutically acceptable carrier be to The compounds of this invention or its salt do not have a negative impact at the operable any excipients of pharmaceutical field, thinner or additive.The concrete formulation that can prepare according to desired route of administration is selected the carrier that uses.Compounds X Y2004 of the present invention or its salt, XY9906 can pass through oral or parenteral administration.Parenteral administration can comprise injection, suction, transdermal or rectal administration.The formulation of described pharmaceutical composition includes but not limited to tablet, capsule, suspension agent, solution, liposome, microballoon or suppository etc.What described carrier can exemplify is tamanori, disintegrating agent, lubricant, isotonic agent, tensio-active agent, sanitas, sweeting agent, flavouring agent, tinting material etc., for example starch, sucrose, sodium-chlor, glucose, cyclodextrin, Magnesium Stearate, phosphatide, cholesterol, corn wet goods.The compounds of this invention or the content of its salt in composition can change within a large range, as long as can reach the purpose of treatment and be convenient to the preparation of pharmaceutical preparation and patient's use.For example, press the weight of composition and calculate, contain The compounds of this invention or its salt of 0.1-99.9%.Preferred 1-99%.In addition, composition of the present invention can also contain other can with other activeconstituentss of The compounds of this invention or its salt Combined Preparation, for example help the activeconstituents of post-menopausal osteoporosis treatment.
Pharmaceutical composition of the present invention can prepare by ordinary method, for example each component of composition is mixed, and perhaps is mixed with in certain sequence according to this area ordinary method.As when preparing tablet, active ingredient and tamanori mixing granulation can be added disintegrating agent and lubricant and compacting in flakes.This is known to those skilled in the art.
Another object of the present invention provides compounds X Y2004 or its salt, the application of XY9906 in the medicine of preparation treatment post-menopausal osteoporosis.As being confirmed in this specification sheets, compounds X Y2004 of the present invention or its salt, XY9906 have the effect of good curing post-menopausal osteoporosis.Route of administration is diversified, as oral, injection, suction etc.Dosage can change within a large range, and this depends on approach, patient's body situation, age, sex of administration etc.In general, the dosage of The compounds of this invention or its salt is 0.1-200mg/ days, kg body weight, preferred 1-100mg/ days, kg body weight, more preferably 10-50mg/ days, kg body weight.
Through cells in vitro MTT experiment sieving, compounds X Y2004 can significantly promote the propagation of human osteoblast cell HOS TE85, helps bone forming, and its intensity is higher than genistein; XY2004 can significantly promote the propagation of human vascular endothelial ECV-304, and significantly alleviates H
2O
2To the injury of vascular endothelial cells degree, show certain vascular protection effect; In addition; XY2004 does not have obvious influence to the propagation of human breast cancer cell MCF-7; pharmacodynamic result shows that XY9906 has the effect of obvious antagonism removal ovary female rats bone loss in the animal body; point out the similar thing XY2004 of phytoestrogen, the XY9906 of the design of this problem both to keep the provide protection of oestrogenic hormon to bone and cardiovascular systems; there be not the side effect of oestrogenic hormon again to uterus and mammary tissue; so be of value to the treatment of women's osteosporosis after menopause disease, be better than controversies in hormone replacement in the elderly.
Description of drawings Fig. 1 E
2(A), raloxifene (B) is at ER alpha-crystal structure binding site
Fig. 2 genistein, raloxifene and E
2Chemical structure
The chemical structure of Fig. 3 XY2004 and XY9906
The preparation method of Fig. 4 XY2004 and XY9906
Fig. 5 XY2004 is to the influence of the propagation of human osteoblast cell HOS TE85
Fig. 6 XY2004 and estradiol drug combination are to the influence of human osteoblast cell HOS TE85 propagation
Fig. 7 XY2004 is to the influence of the propagation of human vascular endothelial ECV-304
Fig. 8 XY2004 is to the influence of the propagation of human vascular endothelial ECV-304
Fig. 9 XY2004 is to the influence of the propagation of human breast cancer cell MCF-7
Figure 10 XY2004 and estradiol drug combination are to the influence of human breast cancer cell MCF-7 propagation
Embodiment
Write a Chinese character in simplified form note: the PPA polyphosphoric acid
Embodiment one
β-synthesizing to methoxyl group phenoxy group-propionitrile (I1)
With 80g (0.64mol) MEHQ, 339mL newly steams acrylon and catalytic amount sodium adds in the reaction flask, more than the temperature rising reflux reaction 48h, and TLC monitoring reaction process (chloroform launches, and ultraviolet lamp is observed down).Add the salt of wormwood saturated aqueous solution in the reaction concentrated solution, separate out solid, filter, be washed to filtrate and be neutral, drying, the dehydrated alcohol recrystallization gets β-to methoxyl group phenoxy group-propionitrile 72.5g (white crystals), 63～64 ℃ of mp.Yield 64% (the document yield: 50%, 63～64.5 ℃ of mp).
β-to methoxyl group phenoxy group-propionic acid (I
2) synthetic
With 10) g (0.56mol) β-to methoxyl group phenoxy group-propionitrile (I
1) and the 236mL concentrated hydrochloric acid add in the reaction flask, temperature rising reflux 4h separates out solid after the cooling, reacting liquid filtering, washing solid.Use the sherwood oil recrystallization behind the product drying, can get β-methoxyl group phenoxy group-propionic acid 100g (white, needle-shaped crystals), mp104～106 ℃ C.Yield 91% (the document yield: 91%, mp103～105 ℃).
6-methoxyl group-4H-1-chromene-4-ketone (I
3) synthetic
60g (0.42mol) Vanadium Pentoxide in FLAKES is dropped in the 250mL reaction flask, and the cooling of external application ice bath starts mechanical stirring, slowly drip 40mL (0.58mol) phosphoric acid, be warming up to 100 ℃, temperature is at 100～105 ℃ in the control, stir 1h, obtaining the water white transparency viscous fluid is PPA.Add 10g (0.05mol) β-to it to methoxyl group phenoxy group-propionic acid (I
2), warm 80～81 ℃ are reacted 1h in the control, and reaction solution is extremely light yellow until blood red by white, and reaction finishes to add to ice in right amount and separates.Place the refrigerator cooling, have light yellow solid to separate out, filter, be washed to neutrality, solid wet distillation purifying.Distillate places refrigerator freezing, separates out white, needle-shaped crystals after the iceization, filters, and cryodrying gets 6-methoxyl group-4H-1-chromene-4-ketone 7.1g (white, needle-shaped crystals), mp66～68 ℃, yield 78%.(document
[91]Yield: 65%, 66～68 ℃ of mp).
2,3-dihydro-6-methoxyl group-4H-1-chromene-4-amithiozone (XY9906) synthetic
100mg (0.56mmol) compound 6-methoxyl group-4H-1-chromanone is dissolved in an amount of anhydrous alcohol solution stirring heating; 103.3mg (1.12mmol) the Thioacetazone heating is dissolved in the 85% ethanol liquid, add while hot in the reaction solution, drip glacial acetic acid number droplet, backflow 4h, concentrate solid, the dehydrated alcohol recrystallization is filtered in an amount of washing, get 2,3-dihydro-6-methoxyl group-4H-1-chromene-4-amithiozone 121mg (white needle-like crystals), mp215～217 ℃, yield: 86%.
1HNMR (CDCl
3, δ ppm): 8.79 (s, 1H, NH), 7.35～6.84 (m, 3H, phH) 4.25 (t, 2H, OCH
2), 3.78 (s, 3H, OCH
3) 2.75 (t, 2H, CH
2), 1.69 (s, 2H, NH
2) .MS (EI): 251 (M
+). this compound is not seen bibliographical information.
Embodiment two
Synthesizing of 3-(4 '-dimethylamino Ben Yajiaji)-6-methoxyl group-4H-1-chromanone (XY2004)
2.5M sodium hydroxide solution 1mL, 95% ethanol 1.5mL and 300mg (1.7mmol) 6-methoxyl group-4H-1-chromene-4-ketone (I3) are added in the 5mL reaction flask successively, stir, the solid dissolving, it is yellow that reaction solution is, add the 231mg paradimethy laminobenzaldehyde again, stirring at room 36h, generate yellow solid, filter, wash 3 times with freezing 95% ethanol, 95% ethyl alcohol recrystallization gets 3-(4 '-dimethylamino Ben Yajiaji)-6-methoxyl group-4H-1-chromanone 100mg (yellow needle crystal), mp182～184 ℃, yield: 16%.This compound is not seen bibliographical information.
1HNMR (CDCl
3, δ ppm): 7.81～6.70 (m, 7H, phH), 5.37 (s, 1H ,-CH=), 3.82 (s, 3H, OCH
3), 3.03 (s, 6H, N (CH
3)
2), 1.55 (s, 2H, CH
2); MS (EI): 309 (M
+). this compound is not seen bibliographical information.
Embodiment three
XY2004 is to the influence of the propagation of human osteoblast cell HOS TE85
As seen from Figure 5: XY2004 can significantly promote the propagation of human osteoblast cell HOS TE85, shows certain osteogenesis (1.0nmol/L, P＜0.05; 0.1 μ mol/L, P＜0.01).Action intensity is suitable with positive control medicine raloxifene, but 100 times of genistein.
Embodiment four
XY2004 and estradiol drug combination are to the influence of human osteoblast cell HOS TE85 propagation
As seen from Figure 6: compare XY2004 (1.0nmol.L with estradiol
-1, 0.1 μ mol.L
-1) obviously the antagonism estradiol is to the proliferation function (P＜0.05) of HOS TE85.
Embodiment five
XY2004 is to the propagation of human vascular endothelial ECV-304
As seen from Figure 7, XY2004 can significantly promote propagation (10nmol/L, P＜0.01 of normal ECV 1; 0.1 μ mol/L, P＜0.05=.
As seen from Figure 8: compare with group of solvents, XY2004 can significantly alleviate H
2O
2To the injury of vascular endothelial cells degree, show certain vascular protection effect.(1μmol/L，P＜0.05)。
Embodiment six
XY2004 is to the influence of the propagation of human breast cancer cell MCF-7
As seen from Figure 9: XY2004 can significantly suppress MCF-7 cell proliferation (10 μ mol/L, P＜0.001), and all the other dosage groups are to the not influence of propagation of MCF-7.
Embodiment seven
XY2004 and estradiol drug combination are to the influence of human breast cancer cell MCF-7 propagation
As seen from Figure 10: compare with estradiol, XY2004 obviously the antagonism estradiol to proliferation function (0.1 μ mol/L, P＜0.05 of MCF-7 cell; 10 μ mol/L, P＜0.01).
Embodiment eight
XY9906 is to the influence of removal ovary rats with osteoporosis
By table 1 as seen, successfully set up SD female rats bilateral ovaries and extractd 3 months osteoporosis animal model.The whole animal test shows, XY9906 can improve bone density, osteoclasia stress and the Young's modulus of removal ovary SD female rats, resist removal ovary rat bone loss to a certain extent, the scheme that XY9906 treatment post-menopausal osteoporosis is described is feasible, and action intensity is suitable with Raloxifene.
Tab.1?Effect?of?XY9906?on?BMD、blood?biochemical?and?bone?biomechanical?parameters?of?ovariectory?rats(n＝10，x±s)??-
| Group | ?Normal | ?Modcl | ?XY9906 ?(3mg/kg) | ??XY9906 ?(6mg/kg) | ??XY9906 ??(9mg/kg) | ????raloxifene ????(6mg/kg) |
| 3MD(10g/m 2) Ca 2+(mol/L) P(mol/L) ALP(U/L) Aσ s(Mpa) Bσ f(Mpa) AE f(Gpa) BF f(Gpa) | ?63.6±7.1 ?2.77±0.31 ?1.82±0.17 ?22.9±11.5 ?298.0±26.2 ?159.8±26.2 ?20.5+1.9 ?9.7±2.7 | ?46.6±9.7 ##?2.47±0.26 #?1.45±0.23 ##?79.0±24.5 ##?239.8±51.0 ##?125.2±51.0 ?7.4±4.2 #?5.0±1.0 ## | ?56.4±13.1 ?2.63±0.28 ?1.56±0.21 ?48.3±19.7 **?269.4±14.0 ?140.3±21.4 ?16.6±2.0 ?6.7±2.6 | ?62.6±12.8 **?2.75±0.27 *?1.68±0.35 ?37.5±11.8 **?299.2±18.4 **?151.9±20.1 ?20.9±1.5 *?8.4±1.8 ** | ??67.6±12.0 **??2.89±0.26 **??1.71±0.45 ??35.0±10.6 **??374.6±99.2 **??158.3±18.5 ??18.6±2.2 ??8.9±2.4 ** | ????65.7±12.8 **????2.78±0.43 **????1.65±0.36 ????38.6±15.1 **????300.4+50.2 **????153.2±28.1 ????22.1±1.8 *????7.5±1.6 ** |
*P＜0.05，
**P＜0.01?vs?Model：#P＜0.05，##P＜0.01??vs?Normal
A：three-point?bending?test；B：contraction?test。
Embodiment nine
Tablet (ten thousand amounts)
| Component | Weight |
| XY9906 | 100g |
| Starch | 700g |
| Starch slurry (10%) | 10g |
| Magnesium Stearate | 8g |
| Total amount | 818g |
Preparation method: XY9906 is pulverized and crosses 100 mesh sieves, after weighing, the starch of crossing 100 mesh sieves with oneself mixes, and adds 10% starch slurry and makes softwood, granulates with 16 order nylon mesh, wet grain is in 60 ℃ of dryings, dried particle and Magnesium Stearate mix, again through the whole grain of sieve on the 16th, behind assay, the calculating slice is heavy, selects 6mm scrobicula or flat punch die compressing tablet promptly.
Embodiment ten
Capsule (ten thousand amounts)
| Component | Weight |
| XY2004 | 100g |
| Starch | 700g |
| Starch slurry (10%) | 10g |
| Total amount | 810g |
Preparation method: XY2004 is pulverized and crosses 100 mesh sieves, after weighing, mix with the starch of crossing 100 mesh sieves, add 10% starch slurry and make softwood, granulate with 16 order nylon mesh, wet grain is in 60 ℃ of dryings, dried particle through the whole grain of 16 mesh sieves, is sub-packed in hard capsule case No. 3 again, covers joint, flatten, polishing gets final product.
Embodiment 11
Injection
| Component | Amount |
| The hydrochloride of XY2004 | 0.5g |
| Sodium-chlor | 8.5g degree |
| Water for injection | Add to 1000mL |
The preparation method: take by weighing hydrochloride, the sodium-chlor of XY2004 respectively, be dissolved in an amount of water for injection, add adding to the full amount of water for injection, stir evenly, filter, the filtrate can in ampoule, sealing by fusing, in 100 ℃ of flowing steam sterilization 30min promptly.
Claims (12)
1, the compound or its salt shown in the formula I:
2, the compound or its salt of claim 1 is unformed powder.
3, the compound or its salt of claim 1 is a crystalline form.
4, the compound or its salt of claim 1, described salt are inorganic acid salt or the organic acid salts of formula I compounds X Y2004.
5, the compound or its salt of claim 4, described salt are hydrochloride, nitrate, vitriol, hydrobromate, phosphoric acid salt, formate, acetate, benzoate, malate, maleate or the Citrate trianions of formula I compounds X Y2004.
6, the synthetic method of the compound or its salt of claim 1 is when needing and the pharmaceutically acceptable acid salify.
7, the method for claim 6, described method is by carrying out.
8, a kind of pharmaceutical composition for the treatment of post-menopausal osteoporosis wherein contains the described arbitrary compound or its salt of the claim 1-5 that treats significant quantity and pharmaceutically acceptable carrier.
9, the pharmaceutical composition of claim 8 is tablet, capsule, suspension agent, solution, liposome, microballoon or suppository.
10, claim 8 or 9 pharmaceutical composition, the content of wherein said compound or its salt is calculated as 0.1-99.9% by the weight of composition.
11, the application of the described arbitrary compound or its salt of claim 1-5 in the medicine of preparation treatment post-menopausal osteoporosis.
12, the application of claim 11, described medicine are oral, injections, suck medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510041811 CN1699357A (en) | 2005-03-17 | 2005-03-17 | Plant-derived estrogens analogs for treating osteoporosis after menopause |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510041811 CN1699357A (en) | 2005-03-17 | 2005-03-17 | Plant-derived estrogens analogs for treating osteoporosis after menopause |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1699357A true CN1699357A (en) | 2005-11-23 |
Family
ID=35475627
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510041811 Pending CN1699357A (en) | 2005-03-17 | 2005-03-17 | Plant-derived estrogens analogs for treating osteoporosis after menopause |
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2005
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