CN103304523A - Andrographolide derivative nitric oxide donor compound as well as preparation method and application thereof - Google Patents
Andrographolide derivative nitric oxide donor compound as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an andrographolide derivative nitric oxide donor compound as well as a preparation method and an application thereof. The derivative has a structure expressed by a formula (I), wherein R1 refers to hydrogen, organic acid radical, inorganic acid radical, alkyl, aryl or heteroaryl, R2 refers to hydrogen, organic acid radical, inorganic acid radical, alkyl, aryl or heteroaryl, R3 refers to hydrogen, organic acid radical, inorganic acid radical, alkyl, aryl or heteroaryl, and at least one of R1, R2 and R3 is a functional group capable of releasing nitric oxide or an organic acid radical substituted by nitroxide group. The andrographolide derivative nitric oxide donor compound can be used for preparing medicaments for treating diabetes, medicaments for treating cardiovascular diseases, antimicrobial medicaments and antiviral medicaments. The medicaments can be prepared to tablets, capsules, granules, fine granules, powder, pills, patches, oral liquid or injection.
Description
Technical field
The invention belongs to technical field of traditional Chinese medicines, particularly a kind of rographolide nitric oxide donors compounds and preparation method thereof and the application in pharmacy.
Background technology
Rographolide (Andrographolide) chemistry 3-[2-[decahydro by name-6-hydroxyl-5-(methylol)-5,8 alpha-alpha-dimethyls-2-methylene radical-1-naphthyl] ethylidene] dihydro-4-hydroxyl-2 (3H)-furanone, being the diterpene ginkgolide that extraction obtains in the Herba Andrographis, is one of its main active ingredient.
The research of rographolide blood sugar reducing function: modern pharmacological research shows that extract, rographolide and the derivative thereof of Chinese medicine Herba Andrographis all have hypoglycemic activity, can be used for prevention and the treatment of diabetes.The Herba Andrographis ethanol extraction of the oral various dose of discovery such as Zhang is dose-dependently and significantly reduces the diabetic mice glucose level of being induced by streptozotocin (STZ), and to normal mice without the effect (Zhang et al., Acta.Pharmacol.Sin.2000,21,1157-1164; Zhang et al., Clin.Exp.Pharmacol.Physiol.2000,27,358-363).Husen etc. studies show that 50mg/kg Herba Andrographis water extract make diabetic mice blood sugar reduce by 52.9% (Husen et al., J.Ethnopharmacol.2004,95,205-208).Yu finds also that simultaneously oral rographolide can significantly reduce the glucose level of the diabetic mice that STZ induces and be the dose-dependently relation.The glucose level of normal mice also can be reduced by rographolide and maximum efficiency more remarkable than diabetic mice.Simultaneously, rographolide (1.5mg/kg) can significantly be alleviated the blood sugar concentration that is caused by intravenous glucose tolerance experiment increases.Induce in the diabetic mice soleus muscle muscle absorption that rographolide energy dose-dependently ground improves radioactivity glucose at the STZ that separation obtains.The continuous vein of STZ diabetic mice is to rographolide 3 days, mRNA and the protein level of GLUT 4 in soleus muscle muscle (4 type glucose transporter) obviously increase (Yu et al., Planta.Med.2003,69,1075-1079).These results show in lacking the diabetic mice of Regular Insulin, and rographolide can be by increasing the lowering blood glucose level that is used to of glucose.
In order further to study the blood sugar reducing function of rographolide, disclose the hypoglycemic mechanism of rographolide and derivative thereof, the study of pharmacy personnel have done a large amount of intensive work in this respect.
The antioxygenation of rographolide: Yang Ping seminar in 2009 finds that at the research rographolide rographolide can significantly reduce the glucose level of the diabetes rat that STZ induces during on the affecting of blood glucose in diabetic rats and Function of Antioxygen Free Radical, compare with control group simultaneously, rographolide can significantly reduce mda (MDA) level, improves superoxide-dismutase (SOD) level.Therefore, the author think rographolide have the effect that alleviates diabetes rat oxygen free radical injury, lowering blood glucose (Yang Ping etc. China's medical science 2009,22,601-603).The same year, this seminar was studied rographolide blood sugar reducing function mechanism.Rats by intraperitoneal injection STZ 65mg/kg prepares diabetes rat model, treatment group is with continuous 2 weeks of gavage of rographolide, use spectrophotometric determination respectively to organize SOD activity, MDA content in blood sugar, the serum, enzyme is exempted from method and is measured serum insulin, quick immunohistochemical methods MaxVision
TMThe expression of Bcl-2 and Bax in the method mensuration pancreatic cell.Found that rographolide group rat blood sugar level, Content of MDA significantly reduce, serum insulin content, the active significantly rising of SOD; Compare with model group, administration group Bcl-2 expresses significantly and strengthens.These results show that rographolide reduces the diabetes model rat blood sugar, suppress its Intra-islet Apoptosis, these effects may with raise the Bcl-2 gene expression dose, improve SOD active, thereby alleviate oxygen free radical injury reduce lipid peroxidation generate relevant (Yang Ping etc. Chinese medicinal materials 2009,32,1577-1579).This seminar in 2011 has has inquired into the impact of rographolide on experimental diabetic rats kidney oxidative stress damage aspect.Research through 8 weeks is found: compare with model group, rographolide can improve glucose level, the renal function index of diabetes rat, improve nephridial tissue GSH-PX active, and can reduce the oxidative stress level, reduce level and the kidney MDA content of kidney SOD, CAT.This prompting rographolide has the better protecting effect to Renal of Diabetic Rats, this may be relevant with the activity of its raising GSH-PX antioxidase (vast stretch of wooded country culvert etc. Shandong medicine 2011,51,40-41).
The alpha-glycosidase restraining effect of rographolide: Dai in 2006 etc. are finding that compound 1 is a very strong alpha-glucosidase inhibitor (IC when rographolide is carried out structural modification
50=16 μ M) (Dai et al., Bioorg.Med.Chem.Lett.2006,16,2710-2713).The further research on this basis such as the Xu of this seminar in 2007 finds that 3 of rographolides and 19 bit esterified rear (compounds 2) show better alpha-glucosidase and suppress active (IC
50=6 μ M) (Xu et al., Bioorg.Med.Chem.2007,15,4247-4255).The same year or the Huang Lihua of seminar etc. have designed and synthesized the new diterpenes diterpenoids lactones derivative with optically active (8R; 13R)-8; 12; 13; 17-tetrahydrochysene rographolide (compound 3); preliminary activity rating result shows that this compound has preferably selectivity alpha-glucosidase inhibition active (inhibiting rate during 100 μ mol/L is 49.6%); and to beta-glucosidase do not show suppress active (Huang Lihua etc. high colleges and universities chemistry journal 2007; 28,1304-1306).The research such as Rammohan in 2008 Herba Andrographis ethanol extraction, rographolide are found the activity (IC of the Inhibiting α-glucosidase on Herba Andrographis ethanol extraction concentration dependent ground to the restraining effect of alpha-glucosidase and α-amylase
50=17.2 ± 0.15mg/mL), α-amylase is shown weak restraining effect (IC
50=50.9 ± 0.17mg/mL).Rographolide also shows similar effect, and (it is active that alpha-glucosidase suppresses, IC
50=11.0 ± 0.28mg/mL; The Alpha-starch enzyme inhibition activity, IC
50=11.3 ± 0.29mg/mL).Experiment same proof Herba Andrographis ethanol extract and rographolide can both be reduced hyperglycemia value and the peak area of diabetes rat postprandial blood sugar in the body, diabetes B there is energetically effect (Subramanian et al., Acta.Biochim.Pol.2008,55,391-398).
Therefore, the restraining effect of alpha-glucosidase may be one of mechanism of rographolide and derivative performance hypoglycemic activity thereof.
Rographolide suppresses the activity of NF-κ B: NF-κ B is a kind of nuclear factor that extensively is present in cells in vivo, regulate the expression of cytokine, somatomedin, chemokine, adhesion molecule, immunity receptor gene, affect the various biological functions such as the interior cytodifferentiation of body, immune response, inflammatory reaction, apoptosis, tumor growth.As a kind of composing type nuclear factor, NF-κ B keeps the continuous activity of lower level in histocyte, being related closely of the overactivity of NF-κ B signal path and various diseases (atherosclerosis, simple nephrotic syndrome, diabetes, bronchial asthma, rheumatoid arthritis, tumour etc.) therefore is subject to extensive concern.
NF-κ B family is by P50, P52, and P65 (REL-A), REL (cREL) and REL-B form, and these protein dimerizations form activated NF-κ B.NF-κ B another kind of existence form in vivo be its dimer by with tenuigenin in three supressors (I κ Ba, I κ B β, I κ B ε) thus in a combination form the state of non-activity.Trimeric form with non-activity when cell is in quiescent condition is present in the tenuigenin, and rich content.When body is subject to somatomedin, cytokine, lymphokine, ultraviolet ray, medicine, infection, hypoxic-ischemic, tissue injury etc. and stimulates, pass the signal along in the cell by the mediation of membrane receptor separately, make the Ser of the trimerical I κ of non-activity Ba subunit
32And Ser
36Residue phosphorylation (the Ser of I κ B β subunit
19And Ser
23The residue phosphorylation, the Ser of I κ B epsilon subunit
157And Ser
161The residue phosphorylation).Under the effect of ubiquitin protein ligase, the further ubiquitin of I κ Ba subunit of phosphorylation is at the Lys of its N end
21And Lys
22The place is respectively with covalent linkage form and bimolecular ubiquitin (ubiquitin) combination, soon occurred conformation changes, by the identification of ATP dependency 26S proteasome and degraded, the NF-κ B that suppressed by I κ Ba is free out, become activated NF-κ B and pass rapidly nucleopore and enter in the nucleus, be combined with the κ B sequence of the upper corresponding target genes controlling element of DNA specifically, raise the expression of target gene separately or with some other nuclear factor synergy, thereby bring into play corresponding physiology or pathological effect (Irbach et al., J.Biol.Chem.2002,277,10842-10851; Lee et al., J.Biol.Chem.2005,280,27783-22791; Ponnappan et al., Immun.Ageing 2005,2, and 15).
The research of Xia in 2004 etc. finds that rographolide can suppress the activity of nuclear factor (NF-κ B).Study on Correlative Mechanisms shows that rographolide forms the covalency adducts with the reduction halfcystine (62) of p50, and then being connected of blocking-up NF-κ B oligonucleotide and nucleic acid-protein.Rographolide stops the leukocyte adhesion of E-selectin (E-selectin) mediation by the expression of the activity decreased cell adhesion molecule E-selectin (E-selectin) of NF-κ B in the vascular endothelial cell that suppresses to induce.The peritonaeum of biting neutrophilic leukocyte that rographolide can also be eliminated cytokine and endotaxin induction is calm, weakens septic shock, stops allergic sacroiliitis in the body.It should be noted that rographolide to I κ Ba degraded, p50, p65 nuclear translocation or cell growth rate there is no restraining effect (Xia et al., J.Immul.2004,173,4207-4217).Hidalgo studies show that about the Anti-inflammatory Mechanism of rographolide rographolide suppresses some proinflammatory protein expression, and these albumen play the effect of nuclear factor (NF-κ B) connection site in their gene.The author studies NF-κ B that rographolide induced by platelet activating factor (PAF) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) effect in activating in being divided into the HL260 cell of neutrophilic granulocyte, find that rographolide is connected the performance anti-inflammatory action by suppressing NF-κ B with DNA, and then expression (the Maria et al. of minimizing anticusp albumen such as COX-2, Brit.J.Pharmacol.2005,144,680-686).
The research such as Lina is found in the 3T3-L1 adipocyte, rographolide increases the absorption of glucose to being time and dose-dependently ground, rographolide activates the phosphorylation that IRS-1 at first occurs insulin signaling pathway, and then the signal path by phosphoinositide 3 kinases (PI3K) and downstream carries out signal transduction.The more important thing is that rographolide can suppress the activation of the NF-κ B signal path that TNF-α induces, reduce the expression of downstream inflammatory factor, thereby improve insulin resistant symptom (Jina et al., Mol.Cell.Endocril.2011,332,134-139).
In sum, being suppressed in rographolide and the derivative hypoglycemic activity thereof of NF-κ B signal path plays a significant role.
Nitrogen protoxide and apoptosis: nitrogen protoxide is to react generation by L-arginine, oxygen molecule and NADPH under the catalysis of nitricoxide synthase.Nitric oxide production synthesizing regulated by nitric oxide synthase activity mainly, and nitricoxide synthase is divided into neural prototype, induction type and endothelium in type.Nitrogen protoxide participates in the adjusting of body different physiological roles, is important information transmitter substance in iuntercellular and the cell.Research finds that cell death inducing needs higher nitric oxide level, and the nitrogen protoxide of this high density may overwhelm under its physiological level concentration the nature conservation mechanism to cell, and then activates the apoptotic signal path.Nitric oxide production toxic level and body condition have certain contacting.In addition, the nitrogen protoxide threshold value of its apoptotic signal path of different types of cell-stimulating also different (Choi et al., J.Biochem.Mol.Biol.2002,35,116-126).
Nitrogen protoxide inhibited apoptosis related mechanism: although nitrogen protoxide can pass through the number of ways cell death inducing, but research also shows that keeping certain density nitric oxide level (mostly being physiological concentration) but is to keep the cell normal physiological function, avoid necessary (the Choi et al. of apoptosis, J.Biochem.Mol.Biol.2002,35,116-126).
1) nitrogen protoxide/cGMP signal path: nitric oxide production anti-apoptotic effect mechanism is to produce cGMP by activating guanylate cyclase, suppresses Caspase active, thereby realizes the effect of anti-apoptosis.The generation of the cGMP of mediated by nitric oxide can stop the apoptosis of various kinds of cell, such as liver cell, PC12 cell, lymphocyte, eosinophilic granulocyte etc. (Choi et al., J.Biochem.Mol.Biol.2002,35,116-126).But some studies show that soluble guanylate cyclase in the cell of some kinds (ODG) can not block nitric oxide production anti-apoptotic effect.The analogue 8-bromo-cGMP of cGMP does not show any provide protection, and (Sata et al., Hypertension 2000,36,83-88).These results show that nitric oxide production anti-apoptotic effect mechanism can be divided into cGMP dependent form and non-cGMP dependent form according to concrete cell category.The anti-apoptotic effect molecular mechanism of nitrogen protoxide/cGMP mediation may relate to the activation of Akt/PKB, then induces the Bad phosphorylation, and procaspase-9 and cytoprotective genetic expression (Li et al., J.Biol.Chem.2000,275,13026-13034).
2) S-nitrosylation arrestin enzymic activity: L-Cysteine HCL Anhydrous family (caspases) comprises 14 hypotypes, plays a significant role in the apoptotic signal path.The avtive spot of all caspases all comprises a cysteine residues, the peptide bond after can specific cutting target protein asparagicacid residue.In the presence of nitrogen protoxide, nitrogen protoxide carries out the nitrosylation modification to the sulfydryl of avtive spot cysteine residues, thereby the activity of protease inhibition, and then suppress apoptosis (the Choi et al. of liver cell, endotheliocyte, some tumour cells, J.Biochem.Mol.Biol.2002,35,116-126).Nitrogen protoxide can be blocked the short apoptosis cascade reaction of E2 by the activity that suppresses Caspase-3, this effect may with nitrogen protoxide to the recognition structure territory cysteine amino of estradiol receptor and relevant (the Marino et al. of chemically modified of Caspase-3 reactive site, Endocr-Relat.Cancer 2006,13,559-569).
3) suppress mitochondria dysfunction: plastosome is the center of apoptosis control.By the apoptosis that is opened in of mitochondria permeability transition pore (MPTP), plastosome in apoptosis regulation, play a significant role (Pastorino et al., J.Biol.Chem.1999,274,31734-31739).The swelling of mitochondrial outer membrane is broken and is caused the release of the mitochondrial protein factor, comprises caspases 2,3 and 9 etc., causes the opening of MPTP.Nitrogen protoxide can directly suppress the activity of caspase-8, shears thereby suppress Bid, so that the release of inhibition cytochrome c (Kim et al., J.Biol.Chem.2000,275,10954-10961).Nitrogen protoxide also can be kept the level of Bcl-2 in MCF-7 cell that TNF α and dactinomycin induce and the liver cell, the release of blocking-up cytochrome c.These phenomenons show, nitrogen protoxide can be sheared by suppressing Bid, stablize the Bcl-2 level, the inhibited apoptosis signal path.
4) regulation and control of anti-apoptosis-related genes: the Bcl-2 gene has the effect of anti-apoptosis, nitrogen protoxide can make Bcl-2 albumen S-nitrosylation, the ubiquitin that suppresses Bcl-2 albumen, the degradation pathway of blocking-up Bcl-2 albumen, thereby improve mRNA and the protein level of Bcl-2 genetic expression, stop apoptosis (Chanvorachote et al., Cancer Res.2006,66,6353-6360).Nitrogen protoxide reduces the content of glutathion inside cell; producing oxidation or nitrosylation stress; induce and produce heat shock protein(HSP) HSP32, HSP70; protection stress be to apoptosis-promoting effect (the Chung et al. of cell because of oxidative stress or nitrosylation; Biochem.Bioph.Res.Co.2001; 282,1075-1079).Nitrogen protoxide suppresses the shearing action of Caspase-3 by strengthening the interaction between acid sphingomyelinase (ASMase) and the Caspase-3, thus blocking-up Caspase cascade reaction; Nitrogen protoxide can also by inducing catalatic generation, promote H
2O
2Decompose, suppress H
2O
2The macrophage apoptosis of inducing.
Nitrogen protoxide has the dual regulation effect in the apoptosis of various kinds of cell, generally speaking when lower concentration (physiological concentration), nitrogen protoxide has and delays apoptotic effect, and promotes apoptosis when high density.Whether apoptosis depends on balance and the conversion between the interior apoptosis of cell and the anti-apoptosis factor.Large quantity research evidence shows nitrogen protoxide apoptosis inhibit signal path on multiple level of physiological concentration, makes cell avoid apoptosis.The approach of main apoptosis inhibit comprises and raises cell cGMP, induces the protectiveness stress protein, suppresses plastosome release cells pigment C, affects Bcl and NF-κ B in mechanism such as intracellular levels.The nitrogen protoxide of high density has destroyed the balance of the anti-apoptosis of apoptosis on the impact of various kinds of cell, impel cell trend apoptosis.Wherein the most important thing is the peroxynitrite (ONOO that produces under the oxidative stress status
-) destroy DNA and cause the activation of ARP and the consumption of ATP, affect simultaneously the plastosome normal function, suppress the NF-kB activity, affect the activity of enzyme system of Caspase family, make cell urge the apoptosis factor and greatly strengthened and cause necrocytosis.The apoptosis of mediated by nitric oxide is the regulatory mechanism of a complexity, affect nitrogen protoxide also more to the factor of apoptosis orientation, such as cell type, nitric oxide concentration, Cellular Oxidation reduced state, to a series of modification of enzymes etc., simultaneously popularity and the dual character of nitrogen protoxide biological action makes its mechanism of action more complicated.
Nitrogen protoxide and islet beta-cell apoptosis: type 1 diabetes is a kind of autoimmune disorder of beta Cell of islet selective destruction.Insulin resistant and islet beta cell function obstacle are two important pathogenic factorss of diabetes B.This shows that the protection of beta Cell of islet is for the important active effect for the treatment of performance of diabetes.
Great majority research is thought: nitrogen protoxide can cause the islet beta cell function obstacle, induces islet beta-cell apoptosis.But some document has proposed query to this.Cytokine, especially IL-1 β, IFN-γ and TNF-α play an important role in the islet beta-cell apoptosis process, but concrete effect is not in vivo also studied clear fully.They directly play a role by control β cellular gene expression or indirectly play a role by activating pancreas islet endotheliocyte and inflammatory cell.At present more to the effect research of IL-1 β, IL-1 β can induce the expression of iNOS and strengthen the activity of iNOS, promotes nitric oxide production synthesizing, directly destroy the β cell function (Mandrup Diabetologia 1996,39,1005-1029).Mostly relevant nitrogen protoxide of past is what the application rodent was finished to the research of islet cells effect, and some other research thinks that nitrogen protoxide has distinct effect to human pancreatic island cell.At first in the mouse β cell that separation obtains, separately IL-1 β can not induce the apoptosis of nitric oxide production synthetic and beta Cell of islet, cytokine IL-1 β, but can induce nitric oxide production synthetic when IFN-γ and TNF-α synergy, promote islet beta-cell apoptosis (Suarez-Pinzon et al., Endocrinology 1994,134,1006-1010; Pavlovic et al., Eur.Cytokine Netw.1999,10,403-412).When using the beta Cell of islet research nitrogen protoxide of iNOS and Fas gene knockout and Fas on the affecting of the β cell injury of cytokine induction, the Zumsteg philosophy finds; reduce nitrogen protoxide and can partly protect beta Cell of islet to avoid the apoptosis of cytokine induction, but to the crosslinked apoptosis of inducing of cell surface Fas and FasL but without any provide protection.Therefore, to induce the nitrogen protoxide of generation may be that (Zumsteg et al., Diabetes 2000,49,39-47) for wherein a kind of mode of β cell injury to cytokine (IL-1 β/IFN-γ).In addition, there is report to find that the nitrogen protoxide of lower concentration or physiological concentration level has effect (Tejedo et al., Cell.Signal.2001,13, the 809-817 of protection β cell; Tejedo et al., Endocrinology 2004,145,2319-2327; Cahuana et al., Cell.Signal.2008,20,301-310; Akiko et al., Life Sci.2008,83,865-870).
Summary of the invention
For overcoming above-mentioned the deficiencies in the prior art, primary and foremost purpose of the present invention is to provide a kind of rographolide nitric oxide donors compounds.
Another purpose of the present invention is to provide the preparation method of above-mentioned rographolide nitric oxide donors compounds.
A further object of the present invention is to provide the purposes of above-mentioned rographolide nitric oxide donors compounds.
Purpose of the present invention is achieved through the following technical solutions: a kind of rographolide nitric oxide donors compounds has the structure shown in formula I:
Wherein R1 is hydrogen, organic acid, inorganic acid radical, alkyl, aryl or heteroaryl, R2 is hydrogen, organic acid, inorganic acid radical, alkyl, aryl or heteroaryl, R3 is hydrogen, organic acid, inorganic acid radical, alkyl, aryl or heteroaryl, and at least one is the organic acid that can discharge nitric oxide production functional group or the replacement of nitre oxygen base among R1, R2 and the R3.
Preferably, described R1 is the organic acid that nitre oxygen base replaces, R2 is the organic acid that hydrogen, organic acid, inorganic acid radical, alkyl, aryl, heteroaryl or nitre oxygen base replace, and R3 is the organic acid that hydrogen, organic acid, inorganic acid radical, alkyl, aryl, heteroaryl or nitre oxygen base replace.
The compounds of this invention further preferably has the structure of following general formula I I:
Wherein R1 is the organic acid that nitre oxygen base replaces.
Described R1 is (CH
2=CH) CO, NO
2O (CH
2)
4CO, NO
2O (CH
2)
6CO, NO
2OCH
2CH=CHCO,
R2 and R3 are hydrogen.
Above-mentioned rographolide nitric oxide donors compounds comprises following operation steps: with nitre oxo organic acid and HBTU/DIEA at ambient temperature stirring reaction obtained active ester in 1 hour; With active ester and 3,19-isopropylidene rographolide NaHCO3 solution (7.5%, m/v) and DBU have the lower condensation reaction that occurs, obtain intermediate A; Intermediate A is sloughed the isopropylidene protecting group under acidic conditions, obtain the andrographolidume derivative nitric oxide donors compounds of structure shown in formula I.
Above-mentioned andrographolidume derivative nitric oxide donors compounds also comprises following operation steps: with bromo organic acid and HBTU/DIEA at ambient temperature stirring reaction obtain active ester after 1 hour; With active ester and 3,19-isopropylidene rographolide NaHCO3 solution (7.5%, m/v) and DBU have the lower condensation reaction that occurs, obtain intermediate B; With intermediate B and Silver Nitrate under the lucifuge condition; stirring at room obtains a white solid after 8 hours; without separation, under acidic conditions, slough the isopropylidene protecting group, obtain the andrographolidume derivative nitric oxide donors compounds of structure shown in formula I.
Above-mentioned andrographolidume derivative nitric oxide donors compounds also comprises following operation steps: with Succinic anhydried and 3,19-isopropylidene rographolide stirring at room 30 minutes in the presence of triethylamine, obtain intermediate C; Condensation reaction is occured in intermediate C and nitric oxide donors in the presence of EDCI and DMAP; products therefrom is without after separating; condenses is sloughed the isopropylidene protecting group under acidic conditions, obtain the andrographolidume derivative nitric oxide donors compounds of structure shown in formula I.
The purposes of above-mentioned rographolide nitric oxide donors compounds in preparation treatment diabetes medicament.
The purposes of above-mentioned rographolide nitric oxide donors compounds in preparation Cardiovarscular medicine.
Above-mentioned rographolide nitric oxide donors compounds is as the purposes of preparation antibacterials or antiviral.
Described medicine is made tablet, capsule, granule, granula subtilis, pulvis, pill, patch, oral liquid or injection.
Described medicine contains rographolide nitric oxide donors compounds and the pharmaceutically acceptable carrier for the treatment of significant quantity.
" pharmaceutically acceptable " refers in compound such as salt or vehicle does not have unacceptable toxicity.Pharmacy acceptable salt comprises inorganic anion, such as chlorion, bromide anion, iodide ion, sulfate radical, inferior sulfate radical, nitrate radical, nitrite anions, phosphate radical etc.Organic anion comprises acetate moiety, acetone acid group, propionate, cinnamate, tosylate, citrate, lactate, glucose acid group etc.Pharmaceutically acceptable vehicle is referring to E.W.Martin, in Remington ' s Pharmaceutical Sciences Mack Publishing Company (1995), Philadelphia, PA, 19
ThAmong the ed.
The effective dose of rographolide nitric oxide donors compounds of the present invention is 1mg～10g.
" treatment significant quantity " refers to the amount that can suppress the required medicine of mammalian diseases.Usually, proved effective amount, for reaching results needed, every kilogram of per 24 hours total amount to rographolide nitric oxide donors compounds is 0.01～800mg, and preferred total amount is 0.1～800mg/kg.If necessary, can be divided into the several times form administration of single dose, also can depart from above-mentioned consumption, namely this depends on character and the type of seriousness, preparation and administration and doctor's the judgement etc. of time of age, body weight, sex, diet, administration of experimenter to be treated and interval, disease.
Compared with prior art, the present invention has following beneficial effect: rographolide nitric oxide donors compounds of the present invention has the nitric oxide production ability of release, can significantly protect beta Cell of islet; Can be used for preparing medicine, antibacterials and the antiviral for the treatment of diabetes medicament, Cardiovarscular.
Description of drawings
Fig. 1 is take the schema of nitre oxoacid as raw material preparation formula (I) target compound.
Fig. 2 is take the schema of bromo-acid as raw material preparation formula (I) target compound.
Fig. 3 is the schema of rographolide and nitric oxide donors condensation preparation formula (I) target compound.
Fig. 4 is the external nitrogen protoxide releasability of rographolide nitric oxide donors compound measurement result figure.
The provide protection of Fig. 5 RIN-m cell injury that to be rographolide nitric oxide donors compound induce t-BHP is figure as a result.
Embodiment
Below in conjunction with embodiment the present invention is done further detailed description, but embodiments of the present invention are not limited to this.
Term used herein " organic acid " refers to saturated and undersaturated aliphatic or aromatic acid, comprising, but be not limited to, contain alkyl fatty acid, thiazolinyl lipid acid, alkynyl lipid acid." mineral acid " refers to sulfuric acid, nitric acid or phosphoric acid.
Term used herein " alkyl " refers to the alkyl carbon chain of 15 carbon atoms of as many as of unsubstituted or substituted straight chain, side chain or annular.Straight chained alkyl comprises such as methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.Branched-chain alkyl comprises such as sec.-propyl, sec-butyl, isobutyl-, the tertiary butyl, neo-pentyl.Cyclic alkyl (" cycloalkyl ") comprises such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Alkyl can be replaced by one or more substituting groups.Above-mentioned substituent indefiniteness example comprises NH
2, NO
2, N (CH
3)
2, ONO
2, F, Cl, Br, I, OH, OCH
3, CO
2H, CO
2CH
3, CN, aryl and heteroaryl.Term " alkyl " also refer to the straight chain, side chain or the ring-type that do not replace or replace contain 15 carbon atoms of as many as contain the alkyl of at least one heteroatoms (for example nitrogen, oxygen or sulphur) at chain.Above-mentioned straight chained alkyl comprises, for example, and CH
2CH
2OCH
3, CH
2CH
2N (CH
3)
2And CH
2CH
2SCH
3Branched group comprises, for example, and CH
2CH (OCH
3) CH
3, CH
2CH (N (CH
3)
2) CH
3And CH
2CH (OCH
3) CH
3Above-mentioned cyclic group comprises, for example six membered ring CH (CH
2CH
2)
2O, CH (CH
2CH
2)
2NCH
3And CH (CH
2CH
2)
2S and corresponding five-membered ring etc.Abovementioned alkyl can be replaced by one or more substituting groups.Above-mentioned substituent indefiniteness example comprises NH
2, NO
2, N (CH
3)
2, ONO
2, F, Cl, Br, I, OH, OCH
3, CO
2H, CO
2CH
3, CN, aryl and heteroaryl.
Term used herein " aryl " refers to unsubstituted or substituted aromatics, carbon ring group and heteroaryl.Aryl or monocycle or fused polycyclic compounds.For example, phenyl is monocyclic aryl.Naphthyl is to have the examples that encircle the aryl that condenses more.Aryl can be replaced by one or more substituting groups, and substituent nonrestrictive example comprises NH
2, NO
2, N (CH
3)
2, ONO
2, F, Cl, Br, I, OH, OCH
3, CO
2H, CO
2CH
3, CN, aryl and heteroaryl.
Heteroaryl relates to the group of replacement or non-substituted monocycle or many rings, comprises at least a heteroatoms in the ring, such as nitrogen, oxygen and sulphur.For instance, typical heterocyclic group comprises that one or more nitrogen-atoms such as tetrazyl, pyrryl, pyridyl are (such as the 4-pyridyl, the 3-pyridyl, 2-pyridyl etc.), pyridazinyl, indyl, quinolyl are (such as the 2-quinolyl, 3-quinolyl etc.), imidazolyl, isoquinolyl, pyrazolyl, pyrazinyl, pyrimidyl, pyriconyl or pyridazinyl; The heterocyclic group that typically contains a Sauerstoffatom comprises the 2-furyl, 3-furyl or benzofuryl; Typical sulfur heteroatom group comprises thienyl, benzothienyl; The typical heteroatom group that mixes comprises furan a word used for translation Ji, oxazolyl, isoxazolyl, thiazolyl and phenothioxin base.Heterocyclic group can be replaced by one or more substituting groups.These substituting groups comprise NH
2, NO
2, O-alkyl, NH-alkyl, N (alkyl)
2, NHC (O)-alkyl, ONO
2, F, Cl, Br, I, OH, OCF
3, OSO
2CH
3, CO
2H, CO
2-alkyl, CN and aryl and polyaryl.These situations comprise that simultaneously heteroatoms is oxidized in the ring, for example form N-oxide compound, ketone or sulfone.
The preparation of embodiment 1 compd A ndroII:
With 3mL toluene, 0.4mL DMSO, 2,2-dimethoxypropane (0.2mL, 0.85mmol), tosic acid pyridinium (3mg, 0.88mmol) and rographolide (150mg, 0.43mmol) join in the 20mL reaction flask successively, 81 ℃ of lower reaction 1h.After reacting completely, cool to room temperature adds 0.1mL triethylamine termination reaction.Reaction mixture adds toluene (20mL) dilution, water (15mL) washing, organic layer anhydrous Na
2SO
4Dry and concentrated, the pale yellow colored solid body and function ether that obtains washs to get white solid compd A ndroII(135mg, 80.8%) (Srinivas et al., Bioorg.Med.Chem.Lett.2004,14,4711-4717).
The preparation (as shown in Figure 1) of embodiment 2 compound 4b:
5-bromine valeric acid (500mg, 2.76mmol) is dissolved in the 10mL anhydrous acetonitrile, then drips the acetonitrile solution of Silver Nitrate (934mg, 5.52mmol) in the reaction solution, be warming up to 70 ° of C lucifuges reaction 6h after dropwising.Reaction is finished, the reaction solution cooling, filter, concentrated, decompression steams solvent.In residuum, add entry, use ethyl acetate extraction, merge organic layer, use anhydrous Na
2SO
4Dry and concentrated, obtain weak yellow liquid 5-nitre oxygen base valeric acid, be directly used in the next step.5-nitre oxygen base valeric acid is dissolved in the 5mL methylene dichloride, and room temperature adds DIEA(0.16mL, 0.92mmol) and HBTU(350mg, 0.92mmol), stirring at room 1h.(3 * 5mL), the reservation organic layer is stand-by through washing for reaction solution.With compound 2(300mg, 0.77mmol) be dissolved in the 5mL methylene dichloride, add 5mL water and 375mg sodium bicarbonate.Under the condition of ice bath, with DBU(0.46mL, 3.08mmol), organic layer joins in the reaction solution, reacts 2h under the condition of ice bath.Leave standstill separatory, organic layer 10mL 1%(v/v) aqueous acetic acid wash anhydrous Na 3 times
2SO
4Dry and concentrated, the mixture that obtains separates (PE:EA=2:1) through silicagel column and obtains compound 4a(146mg, 35.5%), white solid.The characterization data of 4a is as follows: MS (ESI) [M+Na]
+M/z558.3.
1H NMR (CDCl
3): 7.03 (dt, J=1.5,6.9Hz, 1H), (5.95 d, J=6.0Hz, 1H), 4.89 (s, 1H), 4.61-4.42 (m, 4H), 4.23 (dd, J=1.8,11.1Hz, 1H), 3.95 (d, J=11.7Hz, 1H), 3.50 (m, 1H), (3.18 d, J=11.7Hz, 1H), 2.53-2.32 (m, 5H), 2.10-1.91 (m, 2H), 1.90-1.65 (m, 9H), 1.41 (s, 3H), 1.37 (s, 3H), 1.32-1.25 (m, 3H), 1.20 (s, 3H), 0.94 (s, 3H).
Compound 4a is joined (HAc:H in the solution of 5mL Glacial acetic acid water
2O=7:3, v/v), stirring at room 30min.Reaction is finished, and adds entry, uses NaHCO
3Regulate pH=6.0.Use dichloromethane extraction solution, merge organic layer, anhydrous Na
2SO
4Dry and concentrated, crude product separates (PE:EA=1:2) through silicagel column and obtains target compound 4b(135mg, 88.7%), white solid.The characterization data of 4b is as follows: MS (ESI) [M+Na]
+M/z518.4.
1H NMR (CDCl
3): 7.03 (dt, J=1.5,6.9Hz, 1H), (5.96 d, J=6.0Hz, 1H), 4.89 (s, 1H), 4.57 (dd, J=6.0,11.1Hz, 1H), 4.53-4.42 (m, 2H), 4.24 (dd, J=1.8,11.1Hz, 1H), 4.20 (d, J=11.7Hz, 1H), 3.51 (m, 1H), (3.35 m, 1H), 2.80 (m, 1H), (2.58-2.26 m, 6H), 2.05-1.92 (m, 1H), (1.91-1.70 m, 9H), 1.38-1.18 (m, 10H), 0.68 (s, 3H) .Anal.Calcd for C
25H
37NO
9: C, 60.59; H, 7.53; N, 2.83.Found:C, 60.38; H, 7.51; N, 2.83.
The preparation (as shown in Figure 2) of embodiment 3 compound 6b:
4-bromine 2-butylene acid (330mg, 2.0mmol) is dissolved in the 5mL methylene dichloride, and room temperature adds DIEA(0.38mL, 2.2mmol) and HBTU(834mg, 2.2mmol), stirring at room 1h.(3 * 5mL), the reservation organic layer is stand-by through washing for reaction solution.With compound 2(390mg, 1.0mmol) be dissolved in the 5mL methylene dichloride, add 4mL water and 300mg sodium bicarbonate.Under the condition of ice bath, with DBU(0.4mL, 2.7mmol), organic layer joins in the reaction solution, reacts 40min under the condition of ice bath.Leave standstill separatory, organic layer is washed 3 times with the aqueous acetic acid of 10mL massfraction 1%, anhydrous Na
2SO
4Dry and concentrated, the mixture that obtains separates (PE:EA=2:1) through silicagel column and obtains compound 6a(300mg, 55.8%), white solid.The characterization data of 6a is as follows: MS (ESI) [M+Na]
+M/z 559.5 (
79Br), 561.5 (
81Br) (1:1).
1H NMR (CDCl
3): 7.08 (m, 2H), 6.04 (m, 2H), 4.89 (s, 1H), 4.58 (dd, J=6.0,11.4Hz, 1H), (4.52 s, 1H), 4.27 (dd, J=1.8,11.1Hz, 1H), 4.03 (dd, J=1.2,7.2Hz, 2H), (3.95 d, J=11.7Hz, 1H), 3.49 (m, 1H), 3.17 (d, J=11.4Hz, 1H), (2.45 m, 3H), 2.05-1.90 (m, 2H), (1.90-1.65 m, 5H), 1.40 (s, 3H), (1.36 s, 3H), 1.33-1.21 (m, 5H), (1.20 s, 3H), 0.93 (s, 3H).
With compound 6a(325mg, 0.61mmol) be dissolved in the 5mL anhydrous acetonitrile, then drip the acetonitrile solution of Silver Nitrate (123mg, 0.73mmol) in the reaction solution, dropwise rear room temperature lucifuge reaction 8h.Reaction is finished, and reacting liquid filtering, concentrated, decompression steam solvent.In residuum, add entry, use dichloromethane extraction, merge organic layer, use anhydrous Na
2SO
4Dry and concentrated, obtain white solid, be directly used in the next step.The white solid compound that upper step reaction is obtained joins (HAc:H in the solution of 5mL Glacial acetic acid water
2O=7:3, v/v), stirring at room 30min.Reaction is finished, and adds entry, uses NaHCO
3Regulate pH=6.0.Use dichloromethane extraction solution, merge organic layer, anhydrous Na
2SO
4Dry and concentrated, crude product separates (PE:EA=1:2) through silicagel column and obtains target compound 6b (175mg, 60.4%), white solid.The characterization data of 6b is as follows: MS (ESI) [M+H]
+M/z480.4.
1H NMR (CDCl
3): 7.04 (dt, J=1.8,6.9Hz, 1H), 6.97 (dt, J=5.1,15.9Hz, 1H), 6.12 (dt, J=1.8,15.9Hz, 1H), 6.01 (d, J=6.0Hz, 1H), (5.10 dd, J=1.8,5.1Hz, 2H), 4.86 (s, 1H), 4.57 (dd, J=6.0,11.4Hz, 1H), (4.46 s, 1H), 4.27 (dd, J=1.8,11.1Hz, 1H), 4.17 (d, J=11.1Hz, 1H), 3.48 (m, 1H), 3.33 (d, J=10.8Hz, 1H), (2.52-2.12 m, 6H), 2.02-1.67 (m, 6H), (1.32-1.15 m, 7H), 0.65 (s, 3H) .Anal.Calcd for C
24H
33NO
9: C, 60.11; H, 6.94; N, 2.92.Found:C, 59.77; H, 7.22; N, 2.65.
The preparation (as shown in Figure 3) of embodiment 4 compound 8b:
With compound 2(500mg, 1.28mmol), Succinic anhydried (300mg, 3.0mmol), triethylamine (0.21mL, 1.54mmol) be dissolved in the 5mL methylene dichloride stirring at room 30min.Reaction finish to add 10mL water, with dichloromethane extraction (3 * 5mL), merge organic layer, anhydrous Na
2SO
4Dry and concentrated, crude product obtains compound 8a(526mg, 83.7% through silicagel column (PE:EA=1:1) separation), white solid.The characterization data of 8a is as follows: MS (ESI) [M+Na]
+M/z513.5.
1H NMR (CDCl
3): 7.04 (dt, J=1.5,6.9Hz, 1H), 5.96 (dd, J=6.0Hz, 1H), 4.90 (s, 1H), (4.60-4.50 m, 2H), 4.24 (dd, J=1.8,11.4Hz, 1H), 3.96 (d, J=11.4Hz, 1H), 3.50 (m, 1H), 3.18 (d, J=11.7Hz, 1H), 2.75-2.60 (m, 4H), (2.50-2.35 m, 3H), 2.03-1.90 (m, 2H), (1.89-1.65 m, 4H), 1.41 (s, 3H), (1.36 s, 3H), 1.34-1.23 (m, 3H), (1.20 s, 3H), 0.93 (s, 3H).
With compound 8a(993mg, 2.03mmol), isosorbide mononitrate (388mg, 2.03mmol), EDCI(465mg, 2.43mmol) be dissolved in the methylene dichloride of 5mL drying, then add the DMAP(50mg of catalytic amount), stirring reaction 17min under the room temperature, the complete 1%(v/v that adds of reaction) glacial acetic acid aqueous solution (10mL) cancellation reaction, isolate organic layer, and washing (3 * 10mL), anhydrous Na
2SO
4Dry and concentrated, the crude product that obtains is directly used in the next step.The crude product that upper step reaction is obtained joins (HAc:H in the solution of 5mL Glacial acetic acid water
2O=7:3, v/v), stirring at room 30min.Reaction is finished, and adds entry, uses NaHCO
3Regulate pH=6.0.Use dichloromethane extraction solution, merge organic layer, anhydrous Na
2SO
4Dry and concentrated, crude product separates (PE:EA=1:2) through silicagel column and obtains target compound 8b(637mg, 50.5%), white solid.The characterization data of 8b is as follows: MS (ESI) [M+Na]
+M/z 646.5.
1H NMR (CDCl
3): 7.03 (dt, J=1.5,6.9Hz, 1H), 5.93 (d, J=6.0Hz, 1H), 5.36 (dt, J=2.8,5.4Hz, 1H), 5.21 (s, 1H), 4.97 (t, J=5.3Hz, 1H), 4.88 (s, 1H), 4.56-4.50 (m, 2H), 4.45 (d, J=5.1Hz, 1H), (4.25 dd, J=1.8,11.4Hz, 1H), (4.18 d, J=11.4Hz, 1H), 4.06-3.88 (m, 4H), 3.48 (m, 1H), 3.32 (m, 1H), 2.87 (d, J=7.2Hz, 1H), (2.65 s, 4H), 2.44-2.36 (m, 3H), (2.03-1.90 m, 1H), 1.90-1.70 (m, 5H), (1.40-1.10 m, 9H), 0.67 (s, 3H) .Anal.Calcd for C
30H
41NO
13: C, 57.78; H, 6.63; N, 2.25.Found:C, 57.55; H, 6.74; N, 2.19.
The external nitrogen protoxide releasability of embodiment 5 rographolide nitric oxide donors compounds is measured (result as shown in Figure 4)
With compound (4b, 5b, 6b, 7b, 8b) use respectively the PBS that contains the 5.0mM Cys to be mixed with the solution (containing 5%DMSO (v/v)) of 0.2mM, hatch 300min under 37 ℃ of conditions, respectively at 15,30,45,60,75,90,105,120,150,180,210,240,270,300min gets 50 μ L and adds in 96 well culture plates, adds the Griess Reagent I(50 μ L/ hole of room temperature in each hole) and Griess Reagent II(50 μ L/ hole), measure absorbancy (OD value) under the 540nm with microplate reader, substitution typical curve Equation for Calculating obtains NO
2 -Amount, i.e. nitric oxide production amount.
The provide protection (result as shown in Figure 5) of the RIN-m cell injury that embodiment 6 rographolide nitric oxide donors compounds are induced t-BHP
With RIN-m cell (1.0 * 10
5Cells/mL) be inoculated in respectively (100 μ L/ hole) in 96 well culture plates, place 37 ℃, 5%CO
2After cultivating 20h in the incubator, discard former substratum, be replaced into the serum free medium that 100 μ L/ holes contain serial ratio of two term weaker concn rographolide nitric oxide donors compound (Andro, 3b, 4b, 5b, 6b, 7b, 8b), place 37 ℃, 5%CO
2Cultivate 3h in the incubator, then discard old substratum, be replaced into 100 μ L/ holes and contain t-BHP(100 μ M) serum free medium, place 37 ℃, 5%CO
2Cultivate 4h in the incubator, then add the MTT(15 μ L/ hole of 5mg/mL), behind the mixing 37 ℃, 5%CO
2Hatch 4h under the condition, discard substratum, add DMSO(150 μ L/ hole), measure (570/490nm) absorbancy (OD value) with microplate reader behind the hyacinthine dissolving crystallized.Calculate the survival rate of cell according to each group OD value.
Above pharmacological experimental data demonstration, general formula of the present invention (I) compound has stronger beta Cell of islet provide protection.
Above-described embodiment is the better embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. andrographolidume derivative nitric oxide donors compounds is characterized in that: have the structure shown in formula I:
Wherein R1 is hydrogen, organic acid, inorganic acid radical, alkyl, aryl or heteroaryl, R2 is hydrogen, organic acid, inorganic acid radical, alkyl, aryl or heteroaryl, R3 is hydrogen, organic acid, inorganic acid radical, alkyl, aryl or heteroaryl, and at least one is the organic acid that can discharge nitric oxide production functional group or the replacement of nitre oxygen base among R1, R2 and the R3.
2. a kind of andrographolidume derivative nitric oxide donors compounds according to claim 1, it is characterized in that: described R1 is the organic acid that nitre oxygen base replaces, R2 is the organic acid that hydrogen, organic acid, inorganic acid radical, alkyl, aryl, heteroaryl or nitre oxygen base replace, and R3 is the organic acid that hydrogen, organic acid, inorganic acid radical, alkyl, aryl, heteroaryl or nitre oxygen base replace.
3. a kind of andrographolidume derivative nitric oxide donors compounds according to claim 1 is characterized in that described compound has the structure of following general formula I I:
Wherein, R1 is the organic acid that nitre oxygen base replaces.
4. a kind of andrographolidume derivative nitric oxide donors compounds according to claim 3, it is characterized in that: described R1 is (CH
2=CH) CO, NO
2O (CH
2)
4CO, NO
2O (CH
2)
6CO, NO
2OCH
2CH=CHCO,
R2 and R3 are hydrogen.
5. a kind of andrographolidume derivative nitric oxide donors compounds according to claim 1 is characterized in that comprising following operation steps: with nitre oxo organic acid and HBTU/DIEA at ambient temperature stirring reaction obtained active ester in 1 hour; Condensation reaction is occured in active ester and 3,19-isopropylidene rographolide in the presence of NaHCO3 solution and DBU, obtain intermediate A; Intermediate A is sloughed the isopropylidene protecting group under acidic conditions, obtain the andrographolidume derivative nitric oxide donors compounds of structure shown in formula I.
6. a kind of andrographolidume derivative nitric oxide donors compounds according to claim 1 is characterized in that comprising following operation steps: with bromo organic acid and HBTU/DIEA at ambient temperature stirring reaction obtain active ester after 1 hour; Condensation reaction is occured in active ester and 3,19-isopropylidene rographolide in the presence of NaHCO3 solution and DBU, obtain intermediate B; With intermediate B and Silver Nitrate under the lucifuge condition; stirring at room obtains a white solid after 8 hours; without separation, under acidic conditions, slough the isopropylidene protecting group, obtain the andrographolidume derivative nitric oxide donors compounds of structure shown in formula I.
7. a kind of andrographolidume derivative nitric oxide donors compounds according to claim 1, it is characterized in that comprising following operation steps: with Succinic anhydried and 3,19-isopropylidene rographolide stirring at room 30 minutes in the presence of triethylamine obtains intermediate C; Condensation reaction is occured in intermediate C and nitric oxide donors in the presence of EDCI and DMAP; products therefrom is without after separating; condenses is sloughed the isopropylidene protecting group under acidic conditions, obtain the andrographolidume derivative nitric oxide donors compounds of structure shown in formula I.
8. a kind of andrographolidume derivative nitric oxide donors compounds according to claim 1 is preparing the purposes for the treatment of in the diabetes medicament.
9. the purposes of a kind of andrographolidume derivative nitric oxide donors compounds according to claim 1 in preparation Cardiovarscular medicine.
10. a kind of andrographolidume derivative nitric oxide donors compounds according to claim 1 is as the purposes of preparation antibacterials or antiviral.
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| CN107739506A (en) * | 2017-10-25 | 2018-02-27 | 暨南大学 | Light-operated nitric oxide production composite film material of release and its preparation method and application |
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| CN111297847A (en) * | 2020-03-13 | 2020-06-19 | 广东省生物工程研究所（广州甘蔗糖业研究所） | Application of amomum kravanh extract in preparation of α -glucosidase inhibitor medicine |
| CN111297847B (en) * | 2020-03-13 | 2021-08-06 | 广东省生物工程研究所（广州甘蔗糖业研究所） | Application of amomum kravanh extract in preparation of alpha-glucosidase inhibitor medicine |
| CN113321631A (en) * | 2020-08-13 | 2021-08-31 | 云南西力生物技术股份有限公司 | Biandrographolide G, preparation method and application thereof in medicines |
| CN113321631B (en) * | 2020-08-13 | 2022-02-01 | 云南西力生物技术股份有限公司 | Biandrographolide G, preparation method and application thereof in medicines |
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