CN106511336A - Application of composition of Harrisotone A derivatives to anti-osteoporosis medicines - Google Patents
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- 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
- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/12—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of organic synthesis and medicinal chemistry and discloses an application of a composition of Harrisotone A derivatives to anti-osteoporosis medicines and in particular discloses a composition formed by an O-(tetrahydropyrrolyl) ethyl derivative (III) and an O-(dihydroxyethylamino) ethyl derivative (IV) of Harrisotone A in a mass ratio of 55 to 45 and a method for preparing the composition by mixing the above compounds in a mass ratio of 55 to 45. Pharmacological experiments show that the composition provided by the invention can achieve the effects of inhibiting bone turnover rate enhancement and bone destruction caused by ovariectomy and also can increase the serum calcium concentration, thus being beneficial to bone deposition. The composition has protective effects on osteoporosis caused by lack of estrogens and does not have estrogenic side effects. The invention also provides the application of the composition of the Harrisotone A derivatives to preparation of anti-osteoporosis medicines.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, and in particular to composition, preparation method and its usage.
Background technology
Osteoporosis is the bone disease of a kind of general, metabolic, it is characterized in that bone amount reduce and lose, bone fragility and
Fracture risk increases.With the aging of population, the osteoporotic incidence of disease has become harm people also with increasing sharply
The important diseases of class health, and huge society and financial burden are brought to the whole world.Although domestic and international associated specialist scholar couple
The preventing and treating of this disease is attached great importance to, but the disease still lacks effective medicine.
The clinically conventional osteoporotic medicine of preventing and treating includes estrogen replacement medicine at present, and bisphosphonates are selected
Property estrogenic agents, vitamin D, parathormone and people's recombined parathyroid hormone (1-34) etc..Bis phosphoric acid salt
Although medicine effect is pretty good, the serious adverse reactions such as jawbone necrosis, musculoskeletal pain and renal failure can be caused；Hormone is replaced
Although it is the important method for preventing and treating postmenopausal osteoporosis for therapy, but Long-Time Service has and causes breast cancer, carcinoma of endometrium
The risk of potential danger and generation thrombus also increases；And SERM can be such that thrombotic episodes substantially increase
Plus.Other drugs are expensive, or late result is imprecise, not ideal enough.As osteoporosis is a kind of chronic disease, need
Long-term taking medicine, therefore low price, the little Chinese herbal medicine of toxic and side effect is wanted to become one of osteoporotic focus of research treatment.
At present existing medicine has that toxicity is big, security is low for osteoporotic treatment, seeks from natural products
Look for compound or lead compound and carry out structural modification and obtain its derivative, so as to the potential drug for obtaining high-efficiency low-toxicity has weight
It is worth.
Compound I according to the present invention be one deliver within 2009 (Sheng Yin et al.,
2009.Harrisotones A–E,five novel prenylated polyketides with a rare
spirocyclic skeleton from Harrisonia perforata.Tetrahedron 65(2009)1147–1152)
Compound, we have carried out structural modification to compound I, obtain two new derivatives i.e. compound III and compound
IV, and be prepared for composition with compound III and compound IV and said composition anti-osteoporosis activity is evaluated, its
With anti-osteoporosis activity.
The content of the invention
The invention discloses a new composition, said composition is made up of compound III and compound IV, said composition
The mass percent of middle compound III and compound IV is respectively 55% and 45%.
Composition disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
The present invention provides the anti-osteoporosis new application of composition.
The present invention has found application of the composition in osteosporosis resistant medicament is prepared by experiment in vivo.
Further, described osteoporosis is caused due to estrogen deficiency.
The present invention has by vivo studies discovery composition and significantly prevent osteoporotic effect.Composition can suppress
The bone conversion ratio that removal ovary causes strengthens and destruction of bone, while blood calcium concentration can be improved, is conducive to the deposition of bone.It is a kind of
Osteoporotic medicine is prevented and treated preferably.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by concrete real
Any restriction of example is applied, but is defined in the claims.
Specific embodiment
The preparation of 1 compound Harrisotone A of embodiment
Document (the Sheng Yin that the preparation method of compound Harrisotone A (I) is delivered with reference to Sheng Yin et al.
et al.,2009.Harrisotones A–E,five novel prenylated polyketides with a rare
spirocyclic skeleton from Harrisonia perforata.Tetrahedron 65(2009)1147–1152)
Method.
The synthesis of O- bromoethyl derivatives (II) of embodiment 2Harrisotone A
Compound I (472mg, 1.00mmol) is dissolved in into 15mL benzene, TBAB (TBAB) is added in solution
(0.08g), 50% sodium hydroxide solution of 1,2- Bromofumes (3.760g, 20.00mmol) and 6mL.Mixture is Celsius 35
Degree stirring 3h.Reactant liquor is poured in frozen water after 3h, be extracted twice with dichloromethane immediately, merge organic phase solution.Then
Use water and saturated common salt water washing 2 times to organic phase solution successively, then with anhydrous sodium sulfate drying, last reduced pressure concentration removes molten
Agent obtains product crude product.(mobile phase is product crude product silica gel column chromatography purifying：Petroleum ether/acetone=100:1.5, v/v), receive
Collection brown concentrate elution band and fling to solvent obtain compound II yellow powder (602mg, 76%).
1H NMR(500MHz,DMSO-d6) δ 5.18 (s, 2H), 4.56 (s, 2H), 3.93 (d, J=16.7Hz, 4H), 3.79
(s, 2H), 3.62 (d, J=0.9Hz, 4H), 3.15 (s, 2H), 2.48 (s, 2H), 2.41 (d, J=9.4Hz, 4H), 2.27 (s,
1H), 1.95 (s, 1H), 1.88 1.80 (m, 8H), 1.77 (d, J=15.5Hz, 7H), 1.68 (s, 1H), 1.61 (s, 1H),
1.51 (s, 1H), 1.25 (d, J=58.1Hz, 1H), 1.15 0.75 (m, 6H).
13C NMR(125MHz,DMSO-d6)δ206.46(s),198.24(s),195.44(s),190.27(s),135.27
(s),120.09(s),115.02(s),84.45(s),76.58(s),74.12(s),63.67(s),62.76(s),60.36
(s), 50.96 (s), 45.22 (s), 39.69 (s), 36.61 (s), 34.40 (s), 32.63 (s), 30.81 (d, J=8.9Hz),
28.77 (s), 25.30 (s), 24.09 (d, J=19.2Hz), 22.77 (s), 18.20 (s).
HRMS(ESI)m/z[M+H]+calcd for C34H50Br3O6:793.1137；found 793.1134.
The synthesis of the O- (nafoxidine base) ethyl derivative (III) of embodiment 3Harrisotone A
Compound II (396mg, 0.5mmol) is dissolved in the middle of 15mL acetonitriles, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), KI (84mg, 0.5mmol) and pyrrolidines (2840mg, 40mmol), mixture is heated to reflux 3h.Reaction knot
Reactant liquor is poured in frozen water after beam, extracted 2 times with equivalent dichloromethane, merge organic phase.Water and saturated aqueous common salt are used successively
Washing merge after organic phase, then with anhydrous sodium sulfate drying, reduced pressure concentration removes solvent and obtains product crude product.Product crude product
Purify that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:1.0, v/v), collect light brown and concentrate elution band, concentration
Obtain compound III yellow solid (293.8mg, 77%).
1H NMR(500MHz,DMSO-d6)δ5.17(s,2H),4.27(s,2H),3.58(s,2H),3.56(s,2H),
3.23(s,2H),3.09(s,2H),2.90(s,1H),2.75(s,2H),2.65(s,2H),2.58–2.45(m,13H),2.43
(s, 2H), 2.39 (s, 3H), 1.92 (s, 1H), 1.85 1.72 (m, 14H), 1.68 (t, J=12.5Hz, 13H), 1.58 (s,
1H), 1.48 (d, J=3.0Hz, 2H), 1.14 (d, J=1.5Hz, 7H).
13C NMR(125MHz,DMSO-d6)δ206.54(s),198.31(s),195.54(s),190.33(s),135.36
(s),119.99(s),115.10(s),84.52(s),76.68(s),66.96(s),62.83(s),60.46(s),60.21
(s), 54.68 (d, J=13.9Hz), 54.13 (s), 51.02 (s), 45.31 (s), 39.77 (s), 36.69 (s), 30.88 (d, J
=8.9Hz), 28.87 (s), 25.41 (d, J=13.8Hz), 24.18 (d, J=19.2Hz), 22.85 (s), 18.28 (s).
HRMS(ESI):m/z[M+H]+calcd for C46H74N3O6:764.5578；found:764.5572.
The synthesis of O- (two hydroxyethylamines) ethyl derivative of embodiment 4Harrisotone A
Compound II (396mg, 0.5mmol) is dissolved in the middle of 22mL acetonitriles, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), KI (252mg, 1.5mmol) and diethanol amine (1051mg, 10mmol), mixture is heated to reflux 3h.Reaction
Reactant liquor is poured in 25mL frozen water after end, extracted 3 times with equivalent dichloromethane, merge organic phase.Water and saturation are used successively
Brine It merge after organic phase, then with anhydrous sodium sulfate drying, reduced pressure concentration removes solvent and obtains product crude product.Produce
(mobile phase is thing crude product silica gel column chromatography purifying：Petroleum ether/acetone=100:0.5, v/v), collect light brown and concentrate wash-out
Band obtain compound IV brown solid (324.4mg, 75%).
1H NMR (500MHz, DMSO-d6) δ 5.17 (s, 2H), 4.27 (s, 2H), 3.56 (d, J=2.7Hz, 4H), 3.38
(d, J=83.1Hz, 14H), 3.08 (s, 2H), 3.04 (s, 4H), 2.76 2.66 (m, 5H), 2.61 (s, 12H), 2.57 (s,
2H), 2.40 (s, 3H), 2.05 (s, 1H), 1.93 (s, 1H), 1.91 1.81 (m, 8H), 1.76 (d, J=15.5Hz, 7H),
1.68 (s, 1H), 1.61 (s, 1H), 1.51 (s, 1H), 1.28 (s, 2H), 1.18 (d, J=12.0Hz, 7H).
13C NMR(125MHz,DMSO-d6)δ206.46(s),198.23(s),195.44(s),190.26(s),135.27
(s),120.08(s),115.02(s),84.44(s),76.58(s),66.89(s),62.74(s),60.37(s),60.13
(s),59.31(s),56.85(s),53.89(s),53.08(s),50.95(s),45.22(s),39.68(s),36.61(s),
30.80 (d, J=8.9Hz), 28.77 (s), 25.29 (s), 24.09 (d, J=19.2Hz), 22.76 (s), 18.20 (s).
HRMS(ESI):m/z[M+H]+calcd for C46H80N3O12:866.5742；found:866.5737.
The detection of 5 composition function of resisting osteoporosis of embodiment
1st, materials and methods
The preparation of composition：The powder of the 55mg compound III of 200 mesh nets will be crossed after grinding and 200 is crossed after grinding
100mg compositions are obtained during the powder of the 45mg compound IV of mesh net loads tubule with cover and with the mixing of turbine stirring instrument,
The solution of composition is obtained during use with the composition of water dissolves this 100mg.
Ten week old healthy SD raettins (30, Jiangsu Province's animal center) are randomly divided into into 5 groups, 6 per group：Sham-operation group
(Sham), ovary excision model group (OVX), composition group, compound III groups and compound IV groups.Rearing conditions：Temperature is
(23 ± 2) DEG C, illumination:Dark is 12: 12.Allow each group rat to adapt to environment and after 2 weeks, start osteoporosis modeling operation：Each group is big
20% urethane anesthesia (6ml/kg body weight) is injected in the trans-abdominal chamber of mouse, and Sham groups close abdomen after opening abdomen, remaining two groups of row bilateral ovaries
Resection.From postoperative 4th week, Sham groups and the daily fed standard feed of OVX groups and deionized water, composition group, compound III
Group and the daily fed standard feed of compound IV groups and deionized water, while gavage gives composition, compound III and change respectively
Compound IV 10mg/kg, continuous 3 months, claim weekly a body weight.After experiment terminates, anaesthetized with urethane, win eyeball blood sampling,
2000r/min is centrifuged, and draws supernatant (i.e. serum).Rat uterus are extractd, is weighed rapidly.Take out rats with bilateral femur and bilateral shin
Bone, rejects soft tissue.Ashing 8h in two 800 DEG C of shin bone Jing high temperature furnaces (being provided by Chemistry and Chemical Engineering College of Nanjing University), after cooling
Claim ash weight.Ash shape is pulverized into mortar, take 0.1g bone ashes and be dissolved in 1ml, in 6mol/l hydrochloric acid, take 0.2ml when surveying bone calcium and bone phosphorus
1ml is diluted to ultra-pure water, bone calcium and bone phosphorus content is detected with automatic clinical chemistry analyzer.Fl measures bone with borne densitometers
Density (BMD).Biochemical Indices In Serum is determined：Serum 0.5ml is taken, and serum alkaline phosphatase is detected with automatic clinical chemistry analyzer
(ALP), calcium (Ca) and phosphorus (P).
2nd, result
(1) composition is to Bilateral oophorectomy rat blood serum ALP, the impact of serum Ca and blood-serum P
Table 1 is it can be seen that after removal ovary, model group rats Serum alkaline phosphatase activity increases.It is after removal ovary, female in vivo
Anhormonia, causes bone conversion ratio to increase, consistent with the high transformant osteoporosis of postmenopausal women.Give composition 3
After month, alkaline phosphatase activities is remarkably decreased, it is seen that composition can suppress the increase of the bone conversion ratio that removal ovary causes, and reduces
The destruction of sclerotin.Also show in table that model group rats serum calcium is decreased obviously, and composition significantly can be carried compared with sham-operation group
Rise serum calcium cancentration.Serum calcium is osteoplastic important marker, illustrates that composition effectively can be reversed and is led due to ovary excision
The reduction of the serum calcium of cause, is conducive to the formation of bone.And compound III and compound IV do not have the effect of composition.
1 composition of table is to Bilateral oophorectomy rat blood serum ALP, the impact of serum Ca and blood-serum P
*P<0.05vs OVX groups
(2) impact of the composition to Bilateral oophorectomy rat fl BMD
After table 2 can be seen that removal ovary, model group rats fl bone density is remarkably decreased compared with sham-operation group, is given and is combined
After thing 3 months, bone density is dramatically increased.And compound III and compound IV do not have this to act on.
Impact of 2 composition of table to Bilateral oophorectomy rat fl BMD
| Experiment group | Fl BMD (g/cm2) |
| sham | 0.312 |
| OVX | 0.221 |
| Composition | 0.308* |
| Compound III | 0.247 |
| Compound IV | 0.253 |
*P<0.05vs OVX groups
(3) impact of the composition to Bilateral oophorectomy rats with bilateral tibia parameters
Table 3 is it can be seen that compared with sham-operation group, the double shin bone ashes of model group rats are significantly reduced, and composition group is compared with mould again
Type group is significantly raised.Composition also can significantly rise processus styloideus radii calcium and bone phosphorus content.And compound III and compound IV do not have this to make
With.
Impact of 3 composition of table to Bilateral oophorectomy rats with bilateral tibia parameters
| Experiment group | Double tibial bone calcium (g/g) | Double tibial bone phosphorus (g/g) | Double shin bones ash weight (g) |
| Sham | 0.255 | 0.278 | 0.88 |
| OVX | 0.213 | 0.218 | 0.48 |
| Composition | 0.249* | 0.263* | 0.80* |
| Compound III | 0.218 | 0.225 | 0.67 |
| Compound IV | 0.223 | 0.231 | 0.61 |
*P<0.05vs OVX groups
Conclusion：Composition can suppress the bone conversion ratio that removal ovary causes to strengthen and destruction of bone, while blood can be improved
Calcium concentration, is conducive to the deposition of bone.For due to caused by estrogen deficiency osteoporosis there is preventive and therapeutic effect, and swash without female
Plain sample side effect.Composition can be used for osteoporotic preventing and treating.Compound III and compound IV can not suppress removal ovary to draw
Rise bone conversion ratio strengthen and destruction of bone, it is not possible to improve blood calcium concentration, be unfavorable for the deposition of bone, for due to estrogen lack
Caused by weary, osteoporosis does not have preventive and therapeutic effect, it is not possible to for osteoporotic preventing and treating.
The preparation of 6 composition tablet involved in the present invention of embodiment
2 grams of compositions are taken, addition prepares 18 grams of the customary adjuvant of tablet, mixed, conventional tablet presses make 100.
The preparation of 7 composition capsule involved in the present invention of embodiment
2 grams of compositions are taken, addition prepares customary adjuvant such as 18 grams of the starch of capsule, mixed, it is encapsulated to make 100.
Claims (9)
1. a kind of composition, it is characterized by said composition is made up of compound III and compound IV, compound in said composition
The mass percent of III and compound IV is respectively 55% and 45%,
2. the preparation method of composition as claimed in claim 1, it is characterized by：By the powder of compound III and compound IV
Powder be respectively according to mass percent and 55% and 45% be sufficiently mixed.
3. application of a kind of composition as claimed in claim 1 in osteosporosis resistant medicament.
4. application of the composition as claimed in claim 3 in osteosporosis resistant medicament, it is characterized by：The osteoporosis is
The osteoporosis that estrogen deficiency causes.
5. application of the composition as claimed in claim 4 in osteosporosis resistant medicament, it is characterized by：The estrogen deficiency
Caused by ovarian function disappearance.
6. application of the composition as claimed in claim 5 in osteosporosis resistant medicament, it is characterized by：The composition suppresses
The bone conversion ratio that estrogen deficiency causes strengthens and destruction of bone.
7. application of the composition as claimed in claim 5 in osteosporosis resistant medicament, it is characterized by：The composition is improved
The concentration of serum levels of ALP, serum Ca and blood-serum P.
8. application of the composition as claimed in claim 5 in osteosporosis resistant medicament, it is characterized by：The composition is improved
Femoral bmd.
9. application of the composition as claimed in claim 5 in osteosporosis resistant medicament, it is characterized by：The composition is improved
Double tibial bone calcium and double tibial bone phosphorus.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003053456A1 (en) * | 2001-12-21 | 2003-07-03 | Phenion Gmbh & Co. Kg | Use of hyperforin or st john's wort extracts against anaphylactic states of shock and for maintaining and improving bone health |
| KR20100038529A (en) * | 2008-10-06 | 2010-04-15 | 연세대학교 산학협력단 | Compositions for treatment and prevention of bone diseases comprising extract of hypericum ascyron |
| CN103796661A (en) * | 2011-07-05 | 2014-05-14 | 帕拉法姆有限责任公司 | Composition for maintaining bone health and for treating osteoarthritis and osteoarthrosis of the joints |
| KR20140120215A (en) * | 2013-04-02 | 2014-10-13 | 재단법인 전남생물산업진흥원 | Composition for treating or preventing postmenopausal syndrome containing hypericum perforatum |
-
2016
- 2016-12-16 CN CN201611173515.7A patent/CN106511336A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003053456A1 (en) * | 2001-12-21 | 2003-07-03 | Phenion Gmbh & Co. Kg | Use of hyperforin or st john's wort extracts against anaphylactic states of shock and for maintaining and improving bone health |
| KR20100038529A (en) * | 2008-10-06 | 2010-04-15 | 연세대학교 산학협력단 | Compositions for treatment and prevention of bone diseases comprising extract of hypericum ascyron |
| CN103796661A (en) * | 2011-07-05 | 2014-05-14 | 帕拉法姆有限责任公司 | Composition for maintaining bone health and for treating osteoarthritis and osteoarthrosis of the joints |
| KR20140120215A (en) * | 2013-04-02 | 2014-10-13 | 재단법인 전남생물산업진흥원 | Composition for treating or preventing postmenopausal syndrome containing hypericum perforatum |
Non-Patent Citations (2)
| Title |
|---|
| HUCHENG ZHU等: "Hyperascyrones A-H, polyprenylated spirocyclic acylphloroglucinol derivatives from Hypericum ascyron Linn.", 《PHYTOCHEMISTRY》 * |
| SHENG YIN等: "Harrisotones A–E, five novel prenylated polyketides with a rare spirocyclic skeleton from Harrisonia perforata", 《TETRAHEDRON》 * |
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Application publication date: 20170322 |