CN105998004A - Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-heart failure drugs - Google Patents
Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-heart failure drugs Download PDFInfo
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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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
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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Abstract
The invention discloses an application of a composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-heart failure drugs, relates to the fields of organic synthesis and medicinal chemistry, and particularly relates to the composition of the Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives and the application thereof in preparation of the anti-heart failure drugs. Provided are the composition of the Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives and a preparation method thereof. Pharmacological experiments indicate that the composition has an anti-heart failure effect and has the value for development of the anti-heart failure drugs.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and use thereof
On the way.
Background technology
Heart failure (hear failure, HF) refers to that cardiac function is abnormal and causes heart pump blood volume can not meet tissue generation
Thank to a kind of pathological and physiological condition of needs.The cause of disease is that cardiac overload, myocardium diastole own are limited and any
The initial myocardial damage that reason causes；And infect, anemia, gestation, childbirth, cardiac arrhythmia, pulmonary infarction, first
High, diabetes, suppression heart medicine induction increases the weight of HF.Pathogeny is it is considered that there is the mechanism of development in HF
It it is abnormal hemodynamics；The later stage eighties 20th century recognizes that the activation of nerve-endocrine hormone plays important work
With (sympathetic ↑ NE ↑ RAS ↑ wait activation)；" Myocardial Remodeling " (remodelling) is gradually specify that after the nineties
It it is the fundamental mechanism that development occurs causing heart failure.Heart failure is divided into again acute heart failure and chronic heart failure.
At present for the treatment of heart failure, specific medicament, major part medicine is not had to alleviate symptoms of heart failure clinically
There is inevitable toxic and side effects simultaneously, from natural product, find compound or lead compound and tie
Structure is modified and is obtained its derivant, thus the potential drug obtaining high-efficiency low-toxicity most has important value.
The compound I that the present invention relates to be one within 2011, deliver (Ayumi Ohsaki et al., 2011.
Salviskinone A,a diterpene with a new skeleton from Salvia przewalskii.Tetrahedron
Letters 52 (2011) 1,375 1377) compound, we have carried out structural modification to compound I, it is thus achieved that
Two new derivants i.e. compound III and compound IV, and be prepared for compound III and compound IV
Compositions heart failure activity anti-to said composition are evaluated, and it has anti-heart failure activity.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, should
In compositions, the mass percent of compound III and compound IV is respectively 10% and 90%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the compositions of the present invention has preferable anti-heart failure effect.The present invention is pharmaceutically
Acceptable salt has same drug effect.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not had
Any restriction of body embodiment, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Salviskinone A
The document that the preparation method of compound Salviskinone A (I) is delivered with reference to Ayumi Ohsaki et al.
(Ayumi Ohsaki et al.,2011.Salviskinone A,a diterpene with a new skeleton from
Salvia przewalskii.Tetrahedron Letters 52 (2011) 1,375 1377) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2Salviskinone A
Compound I (312mg, 1.00mmol) is dissolved in 15mL benzene, in solution, adds tetrabutyl phosphonium bromide
Ammonium (TBAB) (0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 6mL
Sodium hydroxide solution.Mixture stirs 12h at 35 degrees Celsius.After 12h, reactant liquor is poured in frozen water, vertical
I.e. it is extracted twice with dichloromethane, merges organic phase solution.Then to organic phase solution successively with water and saturated food
Saline washs 4 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Produce
Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collects brown collection
Middle elution band is also flung to solvent and is i.e. obtained the brown ceramic powder (327mg, 78%) of compound II.
1H NMR(500MHz,DMSO-d6)δ6.63(s,1H),6.37(s,1H),5.81(s,1H),4.51(s,2H),
3.84(s,1H),3.79(s,2H),2.15(s,1H),2.04(s,1H),1.91(s,1H),1.65(s,1H),1.39(s,
3H),1.08(s,6H),0.99(s,6H).
13C NMR(125MHz,DMSO-d6)δ188.07(s),183.70(s),154.38(s),147.57(s),
140.21(s),136.40(s),134.71(s),131.25(s),128.40(s),118.83(s),72.12(s),45.49
(s),37.54(s),33.58(s),31.78(s),26.17(s),25.12(s),24.66(s),23.51(s),23.17(s),
22.65(s).
HRMS(ESI)m/z[M+H]+calcd for C22H28BrO3:419.1222；found 419.1220.
The synthesis of O-(benzimidazolyl) ethyl derivative (III) of embodiment 3Salviskinone A
Compound II (209mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (1180mg,
10mmol), mixture is heated to reflux 5h.Reactant liquor is poured in frozen water after terminating by reaction, uses equivalent dichloro
Methane extracts three times, merges organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then
Being dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product silica gel column chromatography is pure
Change (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collect brown and concentrate elution band, concentrate and i.e. obtain
The brown solid (215mg, 43%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 8.15 (s, 1H), 7.54 (d, J=25.0Hz, 2H), 7.15 (s,
1H), 7.06 (s, 1H), 6.33 (d, J=84.1Hz, 1H), 6.26 (s, 1H), 5.66 (s, 1H), 4.38 (d, J=
15.8Hz,4H),3.57(s,1H),1.96(s,1H),1.90(s,1H),1.77(s,1H),1.51(s,1H),1.20
(s,3H),0.99(s,6H),0.81(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.90(s),183.51(s),154.17(s),147.37(s),
146.27(s),139.98(s),139.63(s),136.22(s),134.51(s),133.48(s),131.05(s),
128.18 (s), 123.93 (s), 123.35 (s), 118.56 (d, J=9.6Hz), 110.85 (s), and 68.55 (s), 45.29
(s),44.74(s),37.34(s),33.36(s),25.96(s),24.94(s),24.46(s),23.32(s),22.96(s),
22.42(s).
HRMS(ESI):m/z[M+H]+calcd for C29H33N2O3:457.2491；found:457.2493.
The synthesis of O-(two hydroxyethylamines) ethyl derivative of embodiment 4Salviskinone A
Compound II (209mg, 0.5mmol) is dissolved in the middle of 30mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (690mg, 5.0mmol), potassium iodide (252mg, 1.5mmol) and diethanolamine (1051mg,
10mmol), mixture is heated to reflux 9h.Reactant liquor is poured in 25mL frozen water after terminating by reaction, with etc.
Amount dichloromethane extracts 2 times, merges organic facies.Successively with water and saturated aqueous common salt washing merge after organic
Phase, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product silicagel column
Chromatography purification (flowing is mutually: petroleum ether/acetone=100:0.5, v/v), collects yellow and concentrates elution band and fling to
Solvent i.e. obtain O-(two hydroxyethylamines) ethyl derivative of Salviskinone A faint yellow solid (159.5mg,
72%).
1H NMR(500MHz,DMSO-d6)δ6.52(s,1H),6.40(s,1H),5.71(s,1H),4.15(s,
2H),3.70(s,1H),3.37(s,4H),3.00(s,2H),2.50(s,4H),2.07(s,1H),1.96(s,1H),
1.83 (s, 1H), 1.57 (d, J=1.4Hz, 3H), 1.30 (s, 3H), 0.99 (s, 6H), 0.90 (s, 6H).
13C NMR(125MHz,DMSO-d6)δ188.01(s),183.52(s),154.08(s),147.15(s),
140.11(s),136.23(s),134.42(s),130.84(s),128.31(s),118.62(s),68.93(s),58.73
(s),56.61(s),53.94(s),45.20(s),37.13(s),33.49(s),25.96(s),24.84(s),24.26(s),
23.43(s),22.97(s),22.33(s).
HRMS(ESI):m/z[M+H]+calcd for C26H38NO5:444.2750；found:444.2746.
O-(two hydroxyethylamines) ethyl derivative of Salviskinone A
The synthesis of O-(bischloroethylamines base) ethyl derivative of embodiment 5Salviskinone A
O-(two hydroxyethylamines) ethyl derivative of Salviskinone A prepared by embodiment 4 (0.222g,
0.5mmol) being dissolved in 6mL chloroform, be added dropwise over thionyl chloride (0.238g, 2mmol), reactant heats
Backflow 1h.Reactant is cooled to room temperature, and the thionyl chloride of dropping Methanol Decomposition excess, concentrating under reduced pressure removes
Solvent.Product, through silica gel column chromatography purification (petroleum ether/acetone 100:0.3, v/v), obtains Salviskinone A
The faint yellow solid (170.0mg, 71%) of O-(bischloroethylamines base) ethyl derivative.
1H NMR(500MHz,Chloroform-d1)δ6.51(s,1H),6.22(s,1H),5.72(s,1H),4.16
(s,1H),3.66(s,1H),3.44(s,4H),3.01(s,2H),2.80(s,2H),2.64(s,2H),2.04(s,1H),
1.98(s,1H),1.85(s,1H),1.59(s,1H),1.28(s,3H),0.97(s,6H),0.93(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.90(s),183.41(s),153.97(s),147.04(s),
140.00(s),136.12(s),134.31(s),130.73(s),128.20(s),118.51(s),68.82(s),55.57
(s),53.94(s),45.20(s),39.10(s),37.02(s),33.39(s),25.87(s),24.76(s),24.19(s),
23.33(s),22.88(s),22.25(s).
HRMS(ESI):m/z[M+H]+calcd for C26H36Cl2NO3:480.2072；found:480.2070.
O-(bischloroethylamines base) ethyl derivative of Salviskinone A
The synthesis of O-(two (2-methylmercaptoethyl) amido) ethyl derivative of embodiment 6Salviskinone A
O-(bischloroethylamines base) ethyl derivative of Salviskinone A prepared by embodiment 5 (0.240g, 0.5
Mmol) being dissolved in 15mL ethanol, add sodium methyl mercaptide (0.21g, 3mmol) under room temperature, reactant heats
Backflow 1h.Concentrating under reduced pressure removes solvent, and products therefrom silica gel column chromatography is purified (petroleum ether/acetone
100:0.5, v/v), obtain yellow solid, i.e. compound IV (0.169g, 67%).
1H NMR(500MHz,Chloroform-d1)δ6.48(s,1H),6.41(s,1H),5.65(s,1H),4.12
(s, 2H), 3.99 (s, 1H), 2.94 (s, 2H), 2.53 (d, J=15.4Hz, 8H), 1.99 (s, 1H), 1.94 (s, 6H),
1.90(s,1H),1.77(s,1H),1.51(s,1H),1.23(s,3H),0.92(s,6H),0.83(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.81(s),183.42(s),154.08(s),147.28(s),
139.90(s),136.12(s),134.44(s),130.96(s),128.09(s),118.53(s),68.94(s),53.83
(s),52.15(s),45.21(s),37.24(s),33.29(s),31.87(s),25.85(s),24.86(s),24.38(s),
23.21(s),22.88(s),22.34(s),14.38(s).
HRMS(ESI):m/z[M+H]+calcd for C28H42NO3S2:504.2606；found:504.2603.
Embodiment 7 compositions anti-heart failure activity
(1) experimental example: the compositions therapeutical effect to dog acute heart failure
1 material: animal--healthy adult dog body weight 12.5～13.5kg.(Sigma, import divides pentobarbital sodium
Dress, specification: 25g)；Instrument U.S. BIC16 leads physiograph (production of BIC Corp. of the U.S.)；Electromagnetic current
Gauge (MFV-3200 type): Japanese photoelectricity company produces.
The preparation of compositions: powder and the grinding of the 10mg compound III of 200 mesh nets will be crossed after grinding
The powder of the 90mg compound IV of rear mistake 200 mesh net loads in tubule with cover and mixes with turbine stirring instrument
I.e. obtain 100mg compositions, during use, obtain the solution of compositions by the compositions of this 100mg of water dissolution.
2 test methods and result
Dog is randomly divided into NS group (waiting capacity solvent), gastric infusion compositions 1.0mg/kg group, compound
III 1.0mg/kg group and compound IV 1.0mg/kg group, often group 6.After fasting 12 hours, intravenous injection
Pentobarbital sodium 40mg/kg anaesthetizes, tracheal intubation, artificial respiration, monitoring aortic pressure (AP) and electrocardio
Figure.Breast is opened in left side, plugs in conduit to left chamber pressure and rate of pressure change (± dp/dt thereof from the apex of the heartmax).Will
Left ventricle antetheca implanted by Waltan-Brodie strain bow, measures myocardial contraction.Use electromagnetic flowmeter determination liter
ABF.Using ascending aorta flow as cardiac output (CO), calculate cardiac index (CI), often
Fight index (SI), work done (SW) of often fighting, left heart work done (LVW).Parameters record and BIC physiology
Monitor.Postoperative half an hour, parameters reaches stable.From femoral vein constant speed gasing injection pentobarbital sodium (0.5
ML/kg min), with ± dp/dtmaxDropping to about 1000mHg/s is that leading indicator forms acute heart failure.
After acute heart failure model stability, each treated animal duodenum gives relative medicine.Between group, T inspection, is carried out
Statistical procedures.
The impact (n=6) on heart failure canine dp/dt of table 1 compositions
Compare with NS group,@p<0.05
The impact (n=6) on heart failure canine cardiac work of table 2 compositions
* p < 0.05 is compared before being administered；Compare with NS group@p<0.05
Result is as shown in table 1,2, and compositions can dramatically increase the SW of Heart Failure Dogs, LVW ,+dp/dt (with mould
Type group matched group compares, p < 0.05).Compound III and compound IV can not dramatically increase Heart Failure Dogs SW,
LVW、+dp/dt。
Table 3 compositions impact kinemic on heart failure canine (n=6)
* p < 0.05 is compared before being administered；Compare with NS group@p<0.05
Result is as shown in table 3, compositions can dramatically increase Heart Failure Dogs cardiac output (compare with model control group,
p<0.05).Compound III and compound IV can not dramatically increase the cardiac output of Heart Failure Dogs.
Conclusion: compositions can significantly improve acute heart failure, can be used to preparation treatment or prevention acute heart failure
Medicine.Compound III and compound IV can not significantly improve acute heart failure, should not be used to preparation treatment or pre-
The medicine of anti-acute heart failure.
(2) the experimental example compositions impact on chronic heart failure rat
Test method and result
Rat 50, male and female half and half.10 are only used as Normal group.40 lumbar injection doxorubicin hydrochlorides
2mg/kg, 1 times a week, totally 6 weeks, is randomly divided into 4 groups when the 5th week, i.e. normal NS group and 3 gavages
It is administered 2.5mg/kg group.Gastric infusion compositions 2.5mg/kg group, compound III 2.5mg/kg group and chemical combination
Thing IV 2.5mg/kg group rose at the 5th week and gives compositions, compound III and compound IV gavage respectively every day
Each group, it is administered 21 days.20% urethane 1.1g/kg intraperitoneal injection of anesthesia, peeling operation trachea also intubates, with
Time dissociate the total tremulous pulse in right side, insert homemade heart catherization (diameter 1mm is full of 1% heparin) through it,
Trace blood pressure curve；It is further continued for inserting so that it is enter left ventricle by left arterial lobe, trace intraventricular pressure curve,
Automatic analysis left ventricular systolic pressure (LVSP), intraventricular pressure maximum climbing speed (+dp/dtmax), ventricle
Intrinsic pressure maximum falling speed (-dp/dtmax) and survey the data such as cardiac muscle maximal velocity of contraction (Vpm).Separately take
10 rats, as Normal group, do not give doxorubicin hydrochloride, and remaining operation is with above-mentioned, and between group, T checks,
Carry out statistical procedures.
The impact (n=10) on chronic heart failure Cardiac Function in Rat of table 4 compositions
Compare with NS group,△: p < 0.05
It is big that table 4 result of the test shows that compositions 2.5mg/kg can significantly raise the heart failure caused by doxorubicin hydrochloride
The LVSP of Mus ,+dp/dtmax,-dp/dtmaxReduction (comparing with NS group, P < 0.05) with Vpm；Chemical combination
It is big that thing III 2.5mg/kg and compound IV 2.5mg/kg can not significantly raise the heart failure caused by doxorubicin hydrochloride
The LVSP of Mus ,+dp/dtmax,-dp/dtmaxReduction with Vpm.
Conclusion: compositions has significantly treatment or the effect of preventing chronic heart failure, can be used to preparation treatment or
The medicine of preventing chronic heart failure.Compound III and compound IV does not have significantly treatment or preventing chronic heart failure
Effect, it is not possible to be used for prepare treatment or the medicine of preventing chronic heart failure.
The preparation of embodiment 8 composition tablet involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant 18 grams of tablet is prepared in addition, and mixing, conventional tablet presses makes 100
Sheet.
The preparation of embodiment 9 composition capsule involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixing, encapsulated system
Become 100.
Claims (10)
1. a compositions, is characterized by that said composition is made up of, in said composition compound III and compound IV
The mass percent of compound III and compound IV is respectively 10% and 90%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: by powder and the change of compound III
The powder of compound IV is sufficiently mixed according to mass percent respectively 10% and 90%.
A kind of compositions the most as claimed in claim 1 application in cardiotonic agents.
4. compositions application in cardiotonic agents as claimed in claim 3, it is characterised in that: described heart failure
For acute heart failure.
5. compositions application in cardiotonic agents as claimed in claim 4, it is characterised in that: described combination
Thing can increase the heart acting of acute heart failure.
A kind of compositions the most as claimed in claim 4 application in cardiotonic agents, it is characterised in that: described
Compositions can increase the cardiac output of acute heart failure.
7. compositions application in cardiotonic agents as claimed in claim 3, it is characterised in that: described heart failure
For chronic heart failure.
8. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described combination
Thing can increase the left ventricular systolic pressure of chronic heart failure.
9. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described combination
Thing can increase the intraventricular pressure maximum climbing speed of chronic heart failure.
10. compositions application in cardiotonic agents as claimed in claim 7, it is characterised in that: described combination
Thing can increase the myocardium maximal velocity of contraction of chronic heart failure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610256650.1A CN105998004A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-heart failure drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610256650.1A CN105998004A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-heart failure drugs |
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| Publication Number | Publication Date |
|---|---|
| CN105998004A true CN105998004A (en) | 2016-10-12 |
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| CN201610256650.1A Pending CN105998004A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in anti-heart failure drugs |
Country Status (1)
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| CN (1) | CN105998004A (en) |
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2016
- 2016-04-22 CN CN201610256650.1A patent/CN105998004A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| AYUMI OHSAKI等: "Salviskinone A，a diterpene with a new skeleton from Salvia przewalskii", 《TETRAHEDRON LETTERS》 * |
| 刘克强: "丹参酮IIA磺酸钠治疗慢性心衰临床研究", 《基层医学论坛》 * |
| 杨苏: "丹参注射液在肺源性心脏病治疗中的作用", 《海南医学》 * |
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Application publication date: 20161012 |