CN101781302B - Adduct generated from phosphodiesterase inhibitor and isoflavone and application thereof - Google Patents
Adduct generated from phosphodiesterase inhibitor and isoflavone and application thereof Download PDFInfo
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- CN101781302B CN101781302B CN2009101438173A CN200910143817A CN101781302B CN 101781302 B CN101781302 B CN 101781302B CN 2009101438173 A CN2009101438173 A CN 2009101438173A CN 200910143817 A CN200910143817 A CN 200910143817A CN 101781302 B CN101781302 B CN 101781302B
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- affixture
- virga
- phosphodiesterase
- inhibitor
- isoflavone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
- C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to adduct generated from phosphodiesterase inhibitor and isoflavone and an application thereof. The invention provides phosphodiesterase-5 inhibitor to combine with phytoestrogens such as isoflavone substances to cure male and female sexual dysfunction. Preferably, the invention provides the adduct which is made from the phosphodiesterase-5 inhibitor and the isoflavone substances, wherein the phosphodiesterase-5 inhibitor is any one of the compounds which can cure the male sexual dysfunction in disclosed documents and the compounds include on-sale compounds such as sildenafil, vardenafil, tadalafil, etc.
Description
Technical field:
The present invention relates to the affixture that a kind of phosphodiesterase inhibitor and isoflavones form, their preparation and its composition are in the application for the treatment of men and women sexual dysfunction.
Background technology:
Use the phosphodiesterase inhibitor for treating male sexual disorder and obtained good effect, the application of Virga is exactly an example wherein.
The women has sexual dysfunction (Female Sexual Dysfunction FSD) equally.It is generally acknowledged that the women has continues or recurrent sexuality weakens, to the resistance of sexuality, can not come to orgasm or during sexuality pain etc. all be concrete manifestation (J Urol 2000, the 163:888-93 of Female sexual dysfunction; Eur Urol2000,38:20-9).
The origin cause of formation of Female sexual dysfunction is many-sided, and not clear fully as yet so far.The women with advancing age, internal secretion changes or lacks of proper care, pressure, constrain, medicine that the diseases such as damage, nerve and immunity of fatigue and other diseases such as hypertension, diabetes, cardiovascular disorder, pelvis, belly or spinal cord all may cause Female sexual dysfunction even handle above-mentioned disease also may influence femal sexual function (AJOG 2003,188:286-293).
Because Female sexual dysfunction cause of disease complexity, manifestation is various, does not also have formal approved medicine at present.But some medicine or is tried out in Female sexual dysfunction.For example sexual hormoue and femal sexual function are closely related, and improving femal sexual function with sexual hormoue is very natural thing.Healthy postmenopausal women can obviously be improved femal sexual function (J Clin Edocrinol Metab1991,72:336-43 with Hormone Replacement Therapy (HRT); J Reprod.Med.1998,43:847-56).Women's transdermal to ovary and hysterectomy replenishes testosterone (N Eng J Med 2000,343:682-8), the postmenopausal women takes the tibolone (Tibolone is that profit is only liked) that has oestrogenic hormon, progestogen and androgenic activity concurrently, and (Climacteric2001 4:28-41) all can obviously improve the symptom of some Female sexual dysfunction.The regrettably danger that has increased mammary cancer and heart disease bigger than normal of the hormone dosage in the HRT therapy.The transdermal testosterone paster is also vetoed by the brainstrust of FDA because of safety issue that contingent side effect causes.
In view of using safety issue natural and that steroid hormone synthetic may cause, people consider that can phytoestrogen such as the soybean isoflavones in the food help Female sexual dysfunction.Clinical trial shows that soybean isoflavones has oestrogenic hormon and the effect of estrogen antagonist sample, can improve symptom such as hectic fever (Maturitas2006,53:49-58, Obstatrics﹠amp behind the postmenopausal women; Gynecology 2002,99:389--394), and improve situation because of menopausal women vasomotion disorder (Menopause, 2004,11:400-404).Phytoestrogen also can make the nitric oxide synthetase vigor increase, and causes the nitrogen protoxide resultant quantity to improve, and the diastole of promotion vascular endothelium (chemistry 2006 of life, 26:59).Normal male is taken big legumin or four months quality and quantities to sperm of genistein continuously, sex hormone level is influence (Clin Sci 2001 not, 100:613-618), these researchs are laid a good foundation for phytoestrogen is applied to the male sexual disorder patient.
Another kind of trying out in the medicine for the treatment of Female sexual dysfunction is that is non-for phosphodiesterase-5 (the be called for short PDE-5) inhibitor for the treatment of male erectile disorder such as Virga, Vardenafil and its ground.All once declared in the patent of these medicines to be used for the treatment of Female sexual dysfunction, and done many clinical trials, obtained definite results but go back art so far.Be that example 583 routine femal sexual functions arouse obstacle (FSAD) case and comprise hyposexuality with the Virga, patient such as pain when organism has problem and sexual intercourse, took 10 in preceding 1 hour in sexuality, 50 or 100mg Virga or placebo, be no more than every day 1 time, took for 12 weeks, do not find any property physiological change (Obset﹠amp; Gyncol2000,95:54S).FSAD patient after the 202 routine menopause, their testosterone levels＞0.9pg/ml, estradiol level＞40pg/ml or carrying out oestrogenic hormon and male sex hormone the treatment.Dosage is based on Virga 50mg, can be adjusted to down 25mg or on be transferred to 100mg, sexuality was taken in preceding 1 hour, be no more than every day 1 time, treated for 12 weeks after, property sensitivity, sexuality are had clear improvement by (P=0.017) and sexual intercourse satisfactory degree (P=0.015), but the hyposexuality person is not influenced (J Urol2003,170:2333-2338). routine FSAD patient was on probation surplus Pfizer gave 3000, did not obtain Virga and can treat the clear and definite conclusion of FSAD (BMJ 2004,328 (7439); 542).Phosphodiesterase-5 inhibitor for treating male erectile dysfunction is obtained good effect, its mechanism is that the activity that phosphodiesterase-5 inhibitor has suppressed phosphodiesterase-5 increases cGMP, smooth muscle loosening, the volume of blood flow that enters corpus cavernosum penis increase and cause erection.The structure of female sexual organ and the male sex have some similarity, and there is the people to think that the reaction of femal sexual function originates from the blood vessel of neurotransmitter mediation and the lax pelvis volume of blood flow that causes of non-vascular smooth muscle increases, vaginal lubrication, the hyperemia of clitoris and labia is deciding factor (the Int JImpot Res 1998 that keeps normal femal sexual function, 10:s84-90, S98-101).Further studies show that in the unstriated muscle of corpora cavernosa clitoridis phosphodiesterase-5 (Eur Urol 2003 is arranged, (Suppl2): 118), the nitric oxide synthetase relevant with cGMP also can detect (J Anat1996 in nerve fiber, blood vessel epithelium and the vaginal wall of vagina, 188:633-644), the cGMP of nitrogen protoxide initiation increases the volume of blood flow that may regulate female sexual organs such as vagina as can be known, and same phosphodiesterase-5 inhibitor increases cGMP also same effect can take place.Therefore to influence femal sexual function be possible to phosphodiesterase-5 inhibitor.
The amount of messenger RNA(mRNA) (mRNA) in female sexual organ that molecular biology research shows various phosphodiesterases seldom, the expression ratio of mRNA in clitoral tissue of coding phosphodiesterase-5 hangs down 20 times in penis sponge, and the expression that is transcribed into the mRNA of phosphodiesterase-5 in the vaginal wall has only (the World J Urol 2005 of 1/2nd in the clitoral erection tissue, Oct 25 1-5), these preliminary molecular biology data declarations by nitrogen protoxide-cGMP or phosphodiesterase-5 approach to the influence of femal sexual function less than to male influence.
From above-mentioned data as can be seen, phosphodiesterase-5 inhibitor and sexual hormoue comprise that phytoestrogen can produce certain influence to femal sexual function under certain condition, but because the complex genesis of Female sexual dysfunction, single material with a kind of mechanism of action can not solve Female sexual dysfunction preferably as phosphodiesterase-5 inhibitor for treating impotence.To be that the treatment impotence takes like that as required be that Virga was taken in sexual intercourse in preceding 1 hour the time that the women takes phosphodiesterase-5 inhibitor of being tried in the above-mentioned data in addition, can cause that erection provides the male sex essential condition for sexual intercourse this moment concerning the male sex, but concerning the Female sexual dysfunction patient, only take prerequisite required when providing sexual intercourse for the women not enough as required.Therefore, imagination influences the material of femal sexual function and takes to improve female dysfunction for a long time with many-side is possible, and the present invention just provides such a solution.
The invention provides phosphodiesterase-5 inhibitor and sexual hormoue and comprise that phytoestrogen treats man, female dysfunction with chemical combination or the form of mixing.
Summary of the invention:
The invention provides phosphodiesterase-5 inhibitor and phytoestrogen such as isoflavone like substance and unite to treat man, female dysfunction.
The described associating comprises that both mix and uses or both form affixture by chemical combination, or both distinguish independent packaging, takes simultaneously.
Preferably, the invention provides a kind of affixture, isoflavone like substance by phosphodiesterase-5 inhibitor and formula (II) forms, wherein, phosphodiesterase-5 inhibitor is any compound with treatment male sexual disorder in the open source literature, comprise gone on the market as Virga (sildenafil, viagra), Vardenafil (vardenafil) and Tadalafei (tadalafil) and analogue thereof.
The preferred following affixture of a kind of structure that the invention provides is formed by the Virga of formula (I) and the isoflavone like substance of derivative and formula (II) thereof,
Wherein, R=CH in the formula (I)
3, C
2H
5Or CH
2CH
2OH, n=1 or 2 in the formula (II).
During n=1, OH is 7 and 4 ' position in its Chinese style (II), and OH is at 57 and 4 ' during n=2.
The Virga of formula (I) and derivative thereof are weak base, generally with than strong acid form salt, the present invention find its can with the natural isoflavone that contains the polyphenol structure such as big legumin (7 during n=1,4 ' dihydroxyl), genistein (5 during n=2,7,4 ' trihydroxy-) etc. form affixture, and existence that can be stable.
The Virga of formula (I) and derivative thereof be R=CH wherein
3Be Virga, it is called the big legumin affixture of Virga with the affixture that big legumin forms, and the affixture that itself and genistein form is called Virga genistein affixture (GS), and these two kinds of materials are the preferred affixture of the present invention.
Affixture of the present invention can obtain by the Virga of (I) and the isoflavone like substance reaction of derivative and formula (II) thereof.They can be formed directly in affixture in appropriate solvent.Solvent for use is selected from organic solvents such as methyl alcohol, ethanol, isoflavones, acetone, DMF.Preferred solvent is ethanol, and temperature of reaction is 50-100 ℃, and preferred temperature is 80 ℃.
Affixture fusing point of the present invention is constant, but recrystallization, and fusing point is constant substantially before and after the recrystallization.
The fusing point of each affixture of table 1
According to detection, Virga (R=CH of the present invention
3) and the HPLC of genistein reaction product spectrum the peak that is equivalent to Virga and genistein is arranged, the molecular ion peak that M/e743.3 is arranged in the two area sum＞99.8% electrospray ionization mass spectrum, what prove the formation of Virga (S) and genistein (G) is an affixture (the following GS that is called in experiment) rather than a mixture.
It is the pharmaceutical composition of activeconstituents with affixture of the present invention that the present invention also provides a kind of, said composition can contain the medicine acceptable carrier in case of necessity, wherein the amount of affixture can be 1-99%, the amount of medicine acceptable carrier can be 1-99%, described medicine acceptable carrier can be, but to be not limited to be following product: water, alcohol, honey, starch, sucrose, lactose, caramel, mannitol, silicon derivative, cellulose family and derivative thereof, alginate, gelatin, polyvinylpyrrolidone, glycerine, soil temperature 80, agar, calcium carbonate, Calcium hydrogen carbonate, tensio-active agent, polyoxyethylene glycol, cyclodextrin, β--cyclodextrin, the phospholipid material, kaolin, talcum powder, calcium stearate, Magnesium Stearate and soybean isoflavones etc.
Pharmaceutical composition of the present invention can be by oral, sucks or other modes are taken, and as injection system, outer obedient mode, vagina administration mode, intranasal administration mode etc.
Composition of the present invention can be made any formulation that is fit to take, and these formulations can be: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, pulvis, solution, injection, suppository, ointment, plaster, creme, sprays, drops, patch.Composition of the present invention, oral dosage form preferably, as: capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, paste.
Composition of the present invention can also contain the composition of other treatment effect, also can together take with the medicine of other treatment disease.
Affixture of the present invention is through experiment showed, the effect with treatment male sexual disorder effect and treatment Female sexual dysfunction.The present invention also provides affixture of the present invention and the application of pharmaceutical composition in treatment women, male sexual disorder thereof.
Following data declaration beneficial effect of the present invention by experiment.
Experimentation on animals shows that the existing promotion erection of GS also has the double activity (institute of materia medica, Chinese Academy of Sciences Shanghai) of estrogen-like effects
The oral GS 10 of male rabbit or 30mg can promote its penis obviously to erect and certain dose-effect relationship is arranged, and point out GS that stronger yang invigorating functions is arranged, and its intensity and positive control sildenafil citrate are similar.
Table 2:GS and sildenafil citrate are to the influence (mean value SE) of male rabbit erection maximum length and time of occurrence
The oral GS of female rats of excision bilateral ovaries makes uterus weight and vaginal smear oestrus cycle proof GS occur estrogenic activity
The situation of oestrus cycle after each treated animal administration of table 3
The table rat uterus weight in wet base of 4GS and with the ratio of 100g body weight
* *, P＜0.001 is compared with model control group
*, P＜0.01 is compared with model control group
GS 25mg/ days one month on probation of numerical example postmenopausal women volunteer, vaginal secretions increases, and sexual function makes moderate progress, and is ready to continue to take.
The numerical example male volunteers is taken GS 80mg (containing the about 50mg of S) as required can cause erection.
The present invention also comprises, a kind of compound medicament composition contains phosphodiesterase-5 inhibitor and phytoestrogen suc as formula the isoflavone like substance of (II).Preferably containing the Virga of (I) and the isoflavone like substance of derivative and formula (II) thereof is active constituents of medicine, both part by weight are 1: 100-100: 1, preferred 1: 10-10: 1, more preferably 1: 1, said composition can contain the medicine acceptable carrier in case of necessity, wherein the active constituents of medicine amount can be 1-99%, and the amount of medicine acceptable carrier can be 1-99%.
Wherein, R=CH in the formula (I)
3, C
2H
5Or CH
2CH
2OH, n=1 or 2 in the formula (II).
Affixture of the present invention and composition have the effect of improving the masculinity and femininity sexual function, have synergy, easy administration, adaptability is good, and is with low cost, can take for a long time for the women, compound of the present invention and composition also have good stability, the characteristics that are easy to synthesize.
Embodiment:
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1:
Virga (R=CH
3) the genistein affixture
Virga base 42.6g and genistein 24.3g reflux to solid in ethanol (95%) 750ml dissolves fully, and filtered while hot is removed a little insolubles, is cooled to room temperature and places a few hours, filters, and use washing with alcohol, dries 56.2g, mp 202-3 ℃.
Embodiment 2:
Virga derivative (R=CH
2CH
2OH) genistein affixture
Virga correlative (R=-CH
2CH
2OH) the 0.5g heating is dissolved in ethanol (95%) 6ml, genistein 0.28g heating is dissolved among ethanol (95%) 10ml, after in the former the impouring genistein solution, reflux 30 minutes, cooling is placed, and filters, get 214-6 ℃ of product 0.5gmp, get 216-8 ℃ of 0.28g mp with alcohol 95 %12ml recrystallization.
Embodiment 3:
The big legumin affixture of Virga
Virga 2.37g heating for dissolving is in ethanol (95%) 30ml.Big legumin (extracting from soybean) 1.27g heating for dissolving is in ethanol (95%) 150ml.With Virga solution impouring soybean cellulose solution, and will be with turbid solution to filter after reflux 30 ' cooling slightly, filtrate decompression will be concentrated into about 80ml volume, placed 2 hours, and leached solid, % washes with alcohol 95, dry 2.1 grams, with ethyl alcohol recrystallization mp＞260 ℃.
Embodiment 4:
The preparation of Virga genistein affixture (GS) tablet
Prescription: Virga genistein affixture 78.5g
Microcrystalline Cellulose 80.0g
Lactose 100.0g
Secondary calcium phosphate 18.0g
Starch 8.0g
Magnesium Stearate 30g
Pregelatinized Starch 20g
Vltra tears E50 6g
Sodium starch glycolate 1g
With 1000 of GS sheets, contain GS 78.5mg/ sheet through pelletizing press sheet, Virga 50mg/ sheet.
Embodiment 5:
Virga genistein affixture (GS) capsule
Prescription: Virga genistein affixture 25g
Soybean isoflavone (40%) 100g
Encapsulated 1000 of mixing contains GS 25mg/ grain, contains the non-16mg/ grain of Xi Nadi, contains genistein 9mg/ grain.
Embodiment 6:
Virga is the pharmaceutical composition of activeconstituents with the mixture that big legumin forms, and both ratios are 1: 1.
Embodiment 7:
The mixture that Virga and genistein form is the pharmaceutical composition of activeconstituents, and both ratios are 1: 1.
Embodiment 8:
Vardenafil (vardenafil) is the pharmaceutical composition of activeconstituents with the mixture that big legumin forms, and both ratios are 1: 1.
Embodiment 9:
The mixture that Vardenafil (vardenafil) and genistein form is the pharmaceutical composition of activeconstituents, and both ratios are 1: 1.
Embodiment 10:
The mixture that Tadalafei (tadalafil) and genistein form is the pharmaceutical composition of activeconstituents, and both ratios are 1: 1.
Embodiment 11:
Tadalafei (tadalafil) is the pharmaceutical composition of activeconstituents with the mixture that big legumin forms, and both ratios are 1: 1.
Embodiment 12:
The affixture that Vardenafil (vardenafil) and genistein form is the pharmaceutical composition of activeconstituents, and both ratios are 1: 1.
Embodiment 13:
Tadalafei (tadalafil) is the pharmaceutical composition of activeconstituents with the affixture that big legumin forms, and both ratios are 1: 1.
Claims (3)
1. an affixture is formed by the Virga of formula (I) and the isoflavone like substance genistein of formula (II)
2. the affixture that contains claim 1 is the pharmaceutical composition of activeconstituents.
3. the application of the affixture of claim 1 in preparation treatment sex sexual dysfunction medicine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101438173A CN101781302B (en) | 2009-05-31 | 2009-05-31 | Adduct generated from phosphodiesterase inhibitor and isoflavone and application thereof |
| PCT/CN2010/073365 WO2010139256A1 (en) | 2009-05-31 | 2010-05-28 | Adduct formed by phosphodiesterase inhibitor and isoflavone and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101438173A CN101781302B (en) | 2009-05-31 | 2009-05-31 | Adduct generated from phosphodiesterase inhibitor and isoflavone and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101781302A CN101781302A (en) | 2010-07-21 |
| CN101781302B true CN101781302B (en) | 2013-07-10 |
Family
ID=42521466
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101438173A Expired - Fee Related CN101781302B (en) | 2009-05-31 | 2009-05-31 | Adduct generated from phosphodiesterase inhibitor and isoflavone and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101781302B (en) |
| WO (1) | WO2010139256A1 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69833671T2 (en) * | 1997-12-16 | 2006-11-30 | Pfizer Products Inc., Groton | COMBINATION OF AN ALPHA-1 ADRENORE RECEPTOR ANTAGONIST AND A CGM PDEV HEMMER TO TREAT IMPOTENCE |
| LV12979B (en) * | 2001-09-07 | 2003-05-20 | Ivars Kalvins | Pharmaceutical composition |
| CN1988915A (en) * | 2004-05-27 | 2007-06-27 | 帕拉丁科技公司 | Multiple agent therapy for sexual dysfunction |
-
2009
- 2009-05-31 CN CN2009101438173A patent/CN101781302B/en not_active Expired - Fee Related
-
2010
- 2010-05-28 WO PCT/CN2010/073365 patent/WO2010139256A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010139256A1 (en) | 2010-12-09 |
| CN101781302A (en) | 2010-07-21 |
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Effective date of registration: 20170907 Address after: 400050 Chongqing Jiulongpo democratic village 5-1-5-4 Co-patentee after: Yan Shenhe Patentee after: Duan Bo Address before: 400050 Chongqing Jiulongpo democratic village 5-1-5-1 Patentee before: Duan Bo |
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| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130710 Termination date: 20180531 |