CN110128498B - Diosgenin derivative, pharmaceutical composition thereof, preparation method and application thereof - Google Patents
Diosgenin derivative, pharmaceutical composition thereof, preparation method and application thereof Download PDFInfo
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- CN110128498B CN110128498B CN201910458982.1A CN201910458982A CN110128498B CN 110128498 B CN110128498 B CN 110128498B CN 201910458982 A CN201910458982 A CN 201910458982A CN 110128498 B CN110128498 B CN 110128498B
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- diosgenin
- nitroisosorbide
- succinic acid
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- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical class O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 claims abstract description 67
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 claims abstract description 66
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 59
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
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- Obesity (AREA)
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- Hematology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to Diosgenin (Diosgenin) succinic acid 5-nitroisosorbide shown in a formula I, a pharmaceutical composition taking the compound as an active ingredient, a pancreatic lipase inhibitor taking the compound as an active ingredient, a preparation method of the compound, and application of the compound in preparation of medicines for preventing and treating hyperlipidemia. In-vitro activity experiments prove that the compound has higher in-vitro hypolipidemic activity, can be used for preparing medicines for treating or/and preventing hyperlipidemia, and provides a new solution and scheme for synthesis of other similar compounds.
Description
Technical Field
The invention belongs to the field of medicaments, and particularly relates to diosgenin succinic acid 5-nitroisosorbide derivatives which are used as a strong pancreatic lipase inhibitor and are combined with pancreatic lipase to inhibit the activity of the enzyme so as to treat or/and prevent hyperlipidemia diseases.
Background
Hyperlipidemia is a common disease caused by abnormal lipid metabolism in human body, and mainly refers to overhigh total cholesterol, triglyceride and low-density lipoprotein or overlow high-density lipoprotein level in serum. Hyperlipidemia has no obvious clinical symptoms at the early stage, but has invisibility, progressive and systemic effects on human body injury. Hyperlipidemia can cause atherosclerosis, and can also cause other various high-risk diseases such as hypertension, coronary heart disease, diabetes, myocardial infarction and the like, thereby causing serious threat to human health. According to the statistics of the world health organization, about 1700 thousands of people die from cardiovascular and cerebrovascular diseases every year, and account for about 30 percent of the total death number in the world. Cardiovascular and cerebrovascular diseases become the leading cause of death of the middle-aged and elderly people, and are the first killers of human health. The main means of blood lipid lowering treatment still depends on drug therapy, so the research and development of blood lipid lowering drugs are always the key points of medical research.
Diosgenin (Diosgenin) is an important natural steroid sapogenin, has wide source, is an important raw material for synthesizing steroid hormone medicaments, has various obvious pharmacological activities of reducing blood fat, blood sugar, coronary heart disease and the like, and has high medicinal value. Particularly, the pharmacological activity of reducing blood fat of the composition is more concerned by scholars at home and abroad.
The pharmacokinetics research shows that the diosgenin has strong hydrophobicity, poor dissolution rate in digestive juice and low bioavailability, and hardly absorbs the diosgenin into blood, so that the clinical application of the diosgenin and the preparation thereof in reducing blood fat is limited to a great extent. How to improve the selectivity, bioavailability and pharmacological activity of diosgenin administration route becomes the key point of development and utilization of diosgenin. The diosgenin is subjected to specific structural modification, so that the selectivity and bioavailability of the medicine are improved, and the practical significance is very good. In recent years, a series of structural modifications and alterations of the diosgenin skeleton are carried out by many scholars, and partial derivatives show good hypolipidemic activity, but the defects of the diosgenin are not completely solved. Therefore, reasonable structural modification is carried out on diosgenin, a novel derivative is designed and synthesized, a more effective chemical structure is screened out, and certain challenges are still provided.
At present, diosgenin succinic acid 5-nitroisosorbide derivatives which are used as a strong pancreatic lipase inhibitor and inhibit the activity of enzymes by combining with pancreatic lipase are not seen in the prior art, so that the report of treating or/and preventing hyperlipidemia diseases is provided.
Disclosure of Invention
The invention aims to provide a novel diosgenin succinic acid 5-nitroisosorbide derivatives which have good lipase activity inhibiting effect and low toxic and side effects. Also provides a preparation method of the compound and application of the compound in preparing medicaments for preventing and treating hypolipidemia. The 5-nitroisosorbide derivative has a unique structure with biological activity for reducing blood fat, so the diosgenin derivative with the structure is designed and synthesized, and in-vitro activity experiments prove that the derivative has higher in-vitro blood fat reducing activity, can be used for preparing medicines for treating or/and preventing hyperlipidemia, and simultaneously provides a new solution and scheme for the synthesis of other similar compounds.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
diosgenin (Disogenin) succinic acid 5-nitroisosorbide derivatives represented by the following structural formula (I).
The compound shows good pancreatic lipase inhibitory activity and less toxicity through the experimental study of porcine pancreatic lipase, and can be further developed into a medicament for treating and preventing hyperlipidemia.
The invention also provides a method for preparing diosgenin succinic acid 5-nitroisosorbide, which comprises the following steps:
firstly, diosgenin reacts with succinic anhydride to generate corresponding diosgenin butyric acid monoester, and then the diosgenin succinic acid monoester reacts with 5-nitroisosorbide to obtain the diosgenin succinic acid 5-nitroisosorbide derivatives.
More specifically, the method comprises the steps of:
step A: preparing diosgenin succinic acid monoester:
weighing purified diosgenin, succinic anhydride and pyridine, performing oil bath at 80 ℃ to react in a reaction bottle, adding activated carbon after the reaction is finished, filtering, removing part of pyridine by using a rotary evaporation evaporator, adding pure water into the remainder, separating out a large amount of white solid, filtering, adding EtOH into the white solid, pulping to obtain a solid, and developing with 10% sulfuric acid ethanol;
and B: preparation of diosgenin succinic acid 5-nitroisosorbide derivative of compound 1:
adding succinic acid saponin monoester, DMAP, DCC and 5-isosorbide dinitrate into a reaction bottle, injecting DCM, stirring and dissolving, stirring and reacting for 6h at the room temperature of 25 ℃, and carrying out aftertreatment: and cooling the reaction solution, performing column chromatography, and eluting with petroleum ether and ethyl acetate in a ratio of 10:1 to obtain a white solid compound 1.
Example 1 of the present invention details the preparation of the compound.
In addition, the application of the diosgenin succinic acid 5-nitroisosorbide in preparing the medicine for preventing and/or treating hyperlipidemia is also provided.
The invention also provides a pharmaceutical composition, which comprises at least one of diosgenin succinic acid 5-nitroisosorbide derivatives or diosgenin succinic acid ester derivatives or pharmaceutically acceptable salts thereof as an active ingredient, and the active ingredients are singly or combined with one or more pharmaceutically acceptable carriers.
And the application of the pharmaceutical composition in preparing the medicine for preventing and/or treating hyperlipidemia.
And the application of the compound and the pharmaceutical composition in preparing pancreatic lipase inhibitors.
Also provides a pancreatic lipase inhibitor which takes the diosgenin succinic acid 5-nitroisosorbide as an active ingredient.
The invention takes Diosgenin as a parent body, and the Diosgenin reacts with 5-nitroisosorbide through a condensation product of succinic anhydride, so that compared with a prototype compound (Diosgenin), the pancreatic lipase inhibition activity of the obtained derivative reaches nanomolar (98nM) IC 50. The compound has a similar action mechanism with the prior-marketed original-manufacturer drug Orlistat.
When used as a medicament, the compounds of the present invention may be used as such or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90% of the compound of the invention, and the balance pharmaceutically acceptable carriers and/or excipients which are nontoxic and inert to human bodies and animals.
The pharmaceutical excipients are one or more of diluents (fillers), wetting agents (binders), disintegrants and lubricants. The pharmaceutical composition is administered in the form of a dose per unit body weight. The medicament of the invention can be administered by oral administration and injection.
The oral preparation can be in solid or liquid form, such as granule, tablet, capsule, solution, suspension, emulsion, etc.
The injection preparation can be solid or liquid preparation, such as sterile powder for injection, etc.
Description of the drawings:
FIG. 1 is a schematic structural diagram of diosgenin (Disogenin) 5-nitroisosorbide succinate derivatives according to the present invention;
FIG. 2 is a flow chart of the preparation of diosgenin (Disogenin) succinic acid 5-nitroisosorbide derivatives of the present invention.
Detailed Description
The following describes the essence of the present invention with reference to the embodiments of the present invention, but the present invention is not limited to the embodiments.
Example 1
1H-and13C-NMR was determined by Bruker AVANCE III-600, DRX-500 or AM-400 with internal standard TMS, which1H NMR was measured at 400MHz, 500MHz and 600MHz,13c NMR measurements at 100MHz, 125MHz and 150 MHz; mass spectra HRESI-MS and ESI-MS were determined on a Finnigan LCQ-Advantage MAT type mass spectrometer; RE-2000A rotary evaporator: shanghai Yangrong Biochemical Instrument factory; DF-101S heat collection type constant temperature heating magnetic stirrer: consolidate City Prohua instruments, Inc.; model JJ5000 electronic balance: double Jie test Instrument works in ever-maturing markets.
Column chromatography material: silica gel (80-100 meshes and 200-300 meshes) for column chromatography and a prefabricated GF 254TLC plate are produced by Qingdao ocean chemical factories. The color development method is to observe fluorescence at 254 and 365nm under fluorescent lamp, I2And (3) carrying out vapor color development, and heating and developing after 10% sulfuric acid ethanol treatment.
The other reagents are from Shanghai Saen chemical technology Co., Ltd or from the national drug group chemical reagent Co., Ltd, and are commercial analytical or chemical pure reagents, and the anhydrous reagents (such as DCM, etc.) adopted in the experimental part of the paper are prepared according to the standard processing procedure of the anhydrous solvent.
1. Preparation of Diosgenin (Diosgenin):
diosgenin (Diosgenin) is obtained from Shanghai leaf biotechnology, Inc., 100 g of raw material is weighed in 1L conical flask, and 200ml of methanol is dissolved by heating, slowly cooled and kept at rest to obtain white precipitate; repeating for three times to obtain Diosgenin (Diosgenin) with purity of more than 95%.
Step A: preparation of diosgenin succinic acid monoester
Weighing purified diosgenin (1.2g,30mmol), succinic anhydride (4.5g,45mmol) and pyridine (2ml) in a 100ml reaction flask, and reacting in an oil bath at 80 deg.C. After the reaction, activated carbon was added, filtration was carried out, a part of pyridine was removed by using a rotary evaporator, and the residue was added to about 100ml of pure water, whereby a large amount of white solid was precipitated. Filtration and slurrying of this white solid with EtOH gave 1.45g of solid in 100% yield. Developing with 10% sulfuric acid ethanol.
HR-ESI-MS：m/z537.3302[M+Na]+(Calc.for C31H46O6,537.3302).1H-NMR(400MHz,CDCl3):δ5.37(d,J＝4.9Hz,1H),5.30(s,1H),4.70-4.56(m,1H),4.41(dd,J＝15.0,7.5Hz,1H),3.53-3.42(m,1H),3.37(t,J＝10.9Hz,1H),2.73-2.64(m,2H),2.64-2.54(m,2H),2.32(d,J＝6.9Hz,2H),2.08-1.93(m,2H),1.86(dd,J＝12.3,5.4Hz,3H),1.82–1.69(m,3H),1.70-1.55(m,4H),1.53-1.39(m,4H),1.27(dd,J＝12.0,6.5Hz,2H),1.13(d,J＝10.4Hz,3H),1.03(s,3H),0.97(d,J＝6.9Hz,4H),0.79(t,J＝3.1Hz,6H).13C-NMR(100MHz,CDCl3):δ176.96,171.58,139.60,122.46,109.34,80.84,74.46,66.85,62.08,56.44,49.95,41.63,40.27,39.73,37.99,36.93,36.73,32.05,32.05,31.82,31.40,31.40,30.28,29.28,28.85,27.67,20.82,19.32,17.12,16.27,14.50.
And B: preparation of Compound 1
The succinic acid saponin monoester (5.37g,10mmol), DMAP (3.67g,30mmol), DCC (6.19g,30mmol) and isosorbide 5-nitrate (2.87g,15mmol) are added into a reaction bottle, DCM is injected for stirring and dissolution, and the reaction is stirred at room temperature (25 ℃) for 6 hours. And (3) post-treatment: and (3) cooling the reaction solution, performing column chromatography, and performing petroleum ether: ethyl acetate 10:1 elution gave 7.06g of a white solid in 99% yield.
HR-ESI-MS：m/z 710.8326[M+Na]+(Calc.for C37H53NO11,710.8326).1H-NMR(400MHz,CDCl3):δ5.36(d,J＝5.5,3.7Hz,2H),5.30(s,1H),5.24(d,J＝2.6Hz,1H),4.97(s,1H),4.69-4.55(m,1H),4.49(d,J＝4.9Hz,1H),4.41(d,J＝7.4Hz,1H),4.08-4.02(m,1H),4.01(d,J＝2.9Hz,2H),3.90(dd,J＝11.3,5.6Hz,1H),3.46(d,J＝4.0Hz,1H),3.37(s,1H),2.61(s,4H),2.32(d,J＝6.7Hz,2H),2.06-1.91(m,3H),1.87(s,3H),1.82-1.65(m,5H),1.68-1.52(m,8H),1.54-1.38(m,4H),1.26(s,3H),1.14(d,J＝5.4Hz,1H),1.03(s,3H),0.97(d,J＝6.9Hz,1H),0.79(t,J＝3.1Hz,6H).13C-NMR(100MHz,CDCl3):δ171.44,139.55,122.51,109.2,86.56,81.49,81.25,80.81,76.70,74.46,73.48,69.25,66.85,62.12,56.45,49.95,41.63,40.27,39.73,38.03,36.83,33.97,33.97,31.95,31.41,30.31,30.31,29.21,28.82,27.71,25.63,24.95,20.82,19.31,17.13,16.28,14.51.
Example 2:
this example is a pharmacological test of the compounds of the invention.
Experiments on the pharmacological activity of pancreatic lipase in vitro:
assay compounds and drugs
The test compound was diosgenin succinic acid 5-nitroisosorbide obtained in example 1; the positive drug is Orlistat (Orlistat, N-Formyl-L-leucine (1S) -1- [ [ (2S,3S) -3-hexyl-4-oxo-2-oxolanyl ] methyl ] dodekel ester) which is purchased from pharmaceutical industry Limited liability company in Yunnan province; the compound and Orlistat were dissolved in dimethyl sulfoxide (DMSO) and stored in a refrigerator at 4 ℃.
II, reagent and solution
(1) Reagent
Porcine Pancreatic Lipase (PPL), p-nitrophenyl butyrate (p-NPB), PBS and anhydrous calcium chloride were purchased from Shanghai Michelin Biochemical technology Ltd; Tris-HCl was purchased from Sigma-Aldrich Sigma Aldrich (Shanghai) trade, Inc.
(2) Solutions of
Tris-HCl buffer containing 100mM Tris, 5mM CaCl2The pH value is 8.0, and the mixture is stored in a refrigerator at 4 ℃; preparing PPL solution into 1000U/mL stock solution with D-PBS, subpackaging, and storing at-80 deg.C; the p-NPB solution was prepared as a 10mM solution in Dimethylformamide (DMF) and stored at-20 ℃.
Detection of inhibitory effect of diosgenin succinic acid 5-nitroisosorbide on PPL (pentatricopeptide repeat)
On a 96-well enzyme label plate, fully mixing a compound to be detected (with the final concentration of 50 mu M) with a PPL solution (with the final concentration of 1U/mL), setting 3 repeated wells, and carrying out 15min at 37 ℃; adding p-NPB (final concentration of 0.5mM), mixing, measuring OD (400nm/630nm) with TACAN infinitieM 200 microplate reader at 37 deg.C for 15min, with detection wavelength of 400nm and reference wavelength of 630 nm. The experiment was performed in parallel with a blank control well, a DMSO reagent control well, and an Orlistat positive control well. Calculated IC50Value, i.e. the concentration of compound that inhibits PPL 50% activity. The calculation is as follows: PPL Activity inhibition (%) - (1-sample OD/Experimental control OD). times.100%
As a result:
the invention takes Diosgenin (Diosgenin) as a parent, and the pancreatic lipase inhibition activity of the synthesized Diosgenin butyric acid 5-nitroisosorbide is compared with that of a prototype compound (Diosgenin), and the IC of the synthesized Diosgenin is IC50Reaching nanomolar scale (98 nm). The compound has a similar action mechanism with the prior-marketed original-manufacturer drug Orlistat.
TABLE 1 IC of control Compounds with Compounds of the invention50Value of
| Name of Compound | IC50Value (unit: mum) |
| Orlistat | 0.001 |
| Diosgenin | 72.000 |
| Compound 1 | 0.098 |
And (4) conclusion:
compared with the prior art, the invention has the following outstanding characteristics:
1. the compounds of the present invention belong to a new class of pancreatic lipase inhibitors, having a different structure from all the pancreatic lipase inhibitors of today.
2. The material of the invention has rich and cheap sources, simple preparation process and ensured sources.
3. The Diosgenin succinic acid 5-nitroisosorbide is obtained by taking Diosgenin as a parent through a conventional chemical reaction, the pancreatic lipase inhibition activity of the Diosgenin succinic acid 5-nitroisosorbide is compared with that of a prototype compound (Diosgenin), and the IC of the Diosgenin succinic acid 5-nitroisosorbide is integrated50Reach nanomolar (98 nM).
The following examples 3-5 are dosage form examples of the compounds of the present invention.
Example 3:
the compound was prepared as in example 1, and the excipient was added in a weight ratio of compound crystals to excipient of 1:1, followed by granulation and tableting.
And (3) tablet preparation: example 1 preparation of 100mg Compound
Starch 100mg
Proper amount of 18 percent starch slurry
Proper amount of talcum powder
Example 4:
the compound was prepared according to example 1 and encapsulated according to the conventional capsule formulation method.
And (3) capsule preparation: example 1 preparation of 100mg Compound
Starch 100mg
Proper amount of talcum powder
The preparation method comprises the following steps: the compound prepared in example 1 was mixed with adjuvants, sieved, mixed homogeneously in a suitable container and the resulting mixture was filled into empty capsules.
Example 5:
an ampoule agent: example 1 preparation of 50mg Compound
The preparation method comprises the following steps: the compound obtained in example 1 was dissolved in 0.5 ml of polyethylene glycol 400, an appropriate amount of pure water was added thereto, and the resulting solution was filtered (0.45 μm) and aseptically filled in an ampoule.
Claims (9)
1. Diosgenin succinic acid 5-nitroisosorbide derivatives with the structural formula shown in the specification,
2. a method of preparing the diosgenin succinate 5-nitroisosorbide derivative of claim 1, comprising the steps of: firstly, diosgenin and succinic anhydride are condensed to form corresponding butyric acid monoester, then the butyric acid monoester reacts with 5-isosorbide mononitrate to obtain diosgenin succinic acid 5-nitroisosorbide derivatives,
3. a method of preparing the diosgenin succinate 5-nitroisosorbide derivative of claim 1, comprising the steps of:
step A: preparing diosgenin succinic acid monoester:
weighing purified diosgenin, succinic anhydride and pyridine, performing oil bath at 80 ℃ to react in a reaction bottle, adding activated carbon after the reaction is finished, filtering, removing part of pyridine by using a rotary evaporation evaporator, adding pure water into the remainder, separating out a large amount of white solid, filtering, adding EtOH into the white solid, pulping to obtain a solid, and developing with 10% sulfuric acid ethanol;
and B: preparing a compound 1 diosgenin succinic acid 5-nitroisosorbide derivatives:
adding succinic acid saponin monoester, DMAP, DCC and 5-isosorbide dinitrate into a reaction bottle, injecting DCM, stirring and dissolving, stirring and reacting for 6h at the room temperature of 25 ℃, and carrying out aftertreatment: and cooling the reaction solution, performing column chromatography, and eluting with petroleum ether and ethyl acetate in a ratio of 10:1 to obtain a white solid compound 1.
4. The use of a diosgenin succinic acid 5-nitroisosorbide derivative of claim 1 in the preparation of a medicament for the prevention and/or treatment of hyperlipidemia.
5. The use of a diosgenin succinic acid 5-nitroisosorbide derivative of claim 1 in the preparation of a pancreatic lipase inhibitor.
6. A pancreatic lipase inhibitor comprising the diosgenin succinic acid 5-nitroisosorbide derivative of claim 1, 2 or 3 as an active ingredient.
7. A pharmaceutical composition comprising a diosgenin succinic acid 5-nitroisosorbide derivative of formula (I) in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, alone or in combination with one or more pharmaceutically acceptable carriers.
8. Use of the pharmaceutical composition of claim 7 for the preparation of a medicament for the prevention and/or treatment of hyperlipidemia.
9. Use of the pharmaceutical composition of claim 7 for the preparation of pancreatic lipase inhibitors.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003086411A1 (en) * | 2002-04-15 | 2003-10-23 | Chengdu Di'ao Pharmaceutical Group Co., Ltd. | Compounds and preparation methods of carboxylate and monoester succinate derivative of diosgenin |
| WO2004098538A2 (en) * | 2003-03-13 | 2004-11-18 | Nitromed, Inc. | Nitrosated and nitrosylated compounds, compositions and methods of use |
| CN101787069A (en) * | 2010-03-22 | 2010-07-28 | 四川大学 | Diosgenin piperazine derivatives and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003086411A1 (en) * | 2002-04-15 | 2003-10-23 | Chengdu Di'ao Pharmaceutical Group Co., Ltd. | Compounds and preparation methods of carboxylate and monoester succinate derivative of diosgenin |
| WO2004098538A2 (en) * | 2003-03-13 | 2004-11-18 | Nitromed, Inc. | Nitrosated and nitrosylated compounds, compositions and methods of use |
| CN101787069A (en) * | 2010-03-22 | 2010-07-28 | 四川大学 | Diosgenin piperazine derivatives and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 薯蓣皂甙元丁二酸单酯氨基酸盐的合成及其动物实验——薯蓣皂甙元衍生物的研究I;叶仲林等;《天然产物研究与开发》;20031231;第15卷(第4期);304-307 * |
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