CN104887670A - Application of Daphmalenine A ramification to preparing acute-gout-resisting medicine - Google Patents
Application of Daphmalenine A ramification to preparing acute-gout-resisting medicine Download PDFInfo
- Publication number
- CN104887670A CN104887670A CN201510241137.0A CN201510241137A CN104887670A CN 104887670 A CN104887670 A CN 104887670A CN 201510241137 A CN201510241137 A CN 201510241137A CN 104887670 A CN104887670 A CN 104887670A
- Authority
- CN
- China
- Prior art keywords
- daphmalenine
- ramification
- gout
- iii
- acute gout
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, and in particular to a Daphmalenine A ramification, a preparing method and application of the Daphmalenine A ramification to preparing an acute-gout-resisting medicine. The new Daphmalenine A ramification is synthesized, and the preparing method of the new Daphmalenine A ramification is disclosed. Pharmacological tests show that the Daphmalenine A ramification has the acute-gout-resisting effect, and the Daphmalenine A ramification has the value for developing the acute-gout-resisting medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Daphmalenine A derivant, preparation method and its usage.
Background technology
Gout (gouty), also known as gouty arthritis (gouty arthritis), be the disease in body caused by purine metabolic disturbance, show as uric acid in blood too much, be easy to make urate (MSU) organize crystallization in joint etc.The acute attack of gout is that the MSU owing to being deposited on joint causes neutrophilic granulocyte local infiltration and inflammatory reaction.
Western medicine selects three kinds of medicines at acute gout arthritis: colchicine, NSAID (non-steroidal anti-inflammatory drug) and adrenocortical hormone.The mechanism of action of colchicine is the tubulin binding with neutrophilic granulocyte, thus hinders granulocytic activity, suppresses granulocyte to infiltrate.NSAID (non-steroidal anti-inflammatory drug), as indomethacin, suppresses epoxidase (COX) active and plays antiinflammatory action, and selective COX-2 2 depressant.Although their anti-inflammatory analgetic effects are fast, but toxic and side effects is also quite obvious, as effective dose and the comparable doses producing gastrointestinal symptoms such as suffering from diarrhoea of colchicine, NSAID (non-steroidal anti-inflammatory drug) is definitely forbidden having in active peptic ulcer, gastrointestinal hemorrhage situation, and Phenylbutazone medication is as short as 3 weeks also can cause serious granulocytopenia or aplastic anemia.
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus the potential drug obtaining high-efficiency low-toxicity there is important value most.
The Compound D aphmalenine A that the present invention relates to is one and within 2011, delivers (Yu Zhang et al., 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) compound, we have carried out structural modification to Compound D aphmalenine A, obtain a new Daphmalenine A derivant, and its anti-acute gout activity is evaluated, it is active that it has anti-acute gout.
Summary of the invention
The invention discloses a Daphmalenine A derivant, its structure is:
Daphmalenine A derivant (III) of the present invention is by method preparation below:
(1) Daphmalenine A (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Daphmalenine A;
(2) O-bromoethyl derivant (II) and the pyrrolidine generation substitution reaction of Daphmalenine A obtain O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
The preparation method of the O-(nafoxidine base) ethyl derivative (III) of further Daphmalenine A is:
(1) 419mg Compound D aphmalenine A (I) is dissolved in 10mL benzene, in solution, adds the tetrabutyl ammonium bromide of 0.08g, the glycol dibromide of 7.520g and 50% sodium hydroxide solution of 6mL; Mixture stirs 12h at 35 degrees Celsius; After 12h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution; Then use water and saturated common salt water washing 4 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1.5, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Daphmalenine A.
(2) the O-bromoethyl derivant (II) of the Daphmalenine A of 263mg is dissolved in the middle of 20mL acetonitrile, adds the Anhydrous potassium carbonate of 345mg wherein, the potassium iodide of 84mg and the pyrrolidine of 2840mg, mixture reflux 12h; After reaction terminates, reactant liquor is poured in 20mL frozen water, with equivalent dichloromethane extraction four times, merge organic facies; Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1.5, v/v, collects the brown gummy solid 183.2mg that namely brown concentrated elution band obtains the O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
The present invention's Monosodium urate (MSU) causes the acute gout model evaluation display that human vascular endothelial (HUVEC) damages; the compounds of this invention causes HUVEC damage to MSU and has protective effect; and suppress ICAM-1 to express, can be used for preparation treatment acute gout anti-inflammatory drugs.The object of the present invention is to provide the novelty teabag of the compounds of this invention in medical science, specifically relate to the application of the compounds of this invention in preparation treatment acute gout medicine.
The object of the invention is to be realized by following technical scheme:
The explanation of modern medicine pathological study, gouty arthritis is that MSU causes neutrophilic granulocyte local infiltration and inflammatory reaction, the essence that acute gout produces is that neutrophilic granulocyte (PMN)-vascular endothelial cell (HUVEC) is adhered enhancing (Terkeltaub R, et al.The murine homolog of the interleukin-8 receptorcxcr-2 is essential for the occurrence of neutrophilic inflammation in air pouch model of acute urate crystal-induced gouty synovitis.Arthritis Rheum, 1998, 41 (5): 900-909.), HUVEC damages, its molecular biology mechanism is the interaction (FujiwaraY of PMN and HUVEC surface adhesion molecule, et al.Interleukin-8 stimulates leukocyte migration across amonolayer of cultured rabbit NF-α, IL-1 β, IL-8, and IL-1 rain Monosodium Urate Crystal induced rabbit arthritis.Labinvest, 19998, 78 (5): 559-569.), wherein ICAM-1 (ICAM-1) is the closest with adhesion function relation, one of the important indicator of acute gout inflammation (Zhang Chun, Tang Yi, Liu Jun, Deng. gout spirit side causes the impact of rat model soft tissue of joint ICAM-1 expression to Monosodium urate, Chongqing Medical, 2002, 31 (12): 1211-1213.).
Therefore, HUVEC damage is caused for acute gout MSU, the pathological characters of ICAM-1 increasing expression, the present invention MSU causes external acute gout model (Yang Yanhua, the Yin Lian of HUVEC damage, Wang Mingyan, Deng. the acute gout model research of Monosodium urate induction HUVEC damage, Chinese Chinese medicine academic periodical, 2010,28 (3): 592-594.), the anti-acute gout inflammatory activity of the compounds of this invention is evaluated.MSU causes the acute gout model evaluation display that human vascular endothelial (HUVEC) damages, and the compounds of this invention causes HUVEC damage to MSU and has protective effect, and suppresses ICAM-1 to express.
Beneficial effect
Result of study shows; the acute gout model evaluation display of HUVEC damage is caused with MSU; the compounds of this invention can protect MSU to cause HUVEC damage; reduce apoptosis; improve cytoactive; suppress ICAM-1 to express, have the activity of anti-acute gout inflammation, the compounds of this invention can be used for preparation treatment acute gout anti-inflammatory drugs.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 Compound D aphmalenine A
Document (the Yu Zhang et al. that the people such as the preparation method reference Yu Zhang of Compound D aphmalenine A (I) deliver, 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Daphmalenine A
By Compound I (419mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (7.520g, 40.00mmol) and 6mL.Mixture stirs 12h at 35 degrees Celsius.After 12h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 4 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1.5, v/v), collects the yellow yellow solid (320mg, 61%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ3.84(d,J＝1.6Hz,2H),3.76–3.50(m,5H),3.42(s,2H),3.09(s,1H),2.99(s,1H),2.88(s,1H),2.70(s,1H),2.64(d,J＝19.1Hz,3H),2.45(d,J＝5.6Hz,3H),2.33(s,1H),2.19–2.12(m,5H),2.07(s,1H),1.97(d,J＝9.2Hz,3H),1.84–1.76(m,3H),1.69(s,1H),1.15(s,1H),1.04(s,3H)。
13C NMR(125MHz,DMSO-d6)δ219.71(s),211.07(s),176.65(s),66.24(s),65.38(s),63.59(s),59.42(s),54.79(s),52.18(s),46.22(s),46.01(s),45.50(s),45.27(s),40.33(s),37.86(s),37.61(s),36.27(s),34.26(s),30.89(s),28.52(s),26.04(s),25.24(s),8.50(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
25H
37BrNO
6:526.1804；found 526.1801.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3 Daphmalenine A
Compound II per (263mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (2840mg, 40mmol), mixture reflux 12h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction four times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:1.5, v/v), collect the brown gummy solid (183.2mg, 71%) that namely brown concentrated elution band obtains the O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
1H NMR(500MHz,DMSO-d6)δ3.80(s,1H),3.71(s,3H),3.50(s,2H),3.14(s,1H),3.06(s,1H),2.86(s,1H),2.73(d,J＝2.7Hz,2H),2.67(d,J＝5.3Hz,4H),2.55(s,4H),2.53–2.36(m,4H),2.21–2.15(m,5H),2.16–1.86(m,4H),1.85(d,J＝7.5Hz,2H),1.78(s,1H),1.72(d,J＝10.7Hz,5H),1.14(s,1H),1.08(s,3H)。
13C NMR(125MHz,DMSO-d6)δ219.76(s),211.10(s),176.66(s),66.23(s),63.55(s),61.51(s),59.41(s),54.83(s),54.50(s),53.87(s),52.18(s),46.20(s),46.04(s),45.53(s),45.24(s),40.32(s),37.87(s),37.64(s),36.26(s),30.85(s),28.50(s),25.95(s),25.18(d,J＝8.8Hz),8.42(s)。
HRMS(ESI):m/z[M+H]
+calcd for C
29H
45N
2O
6:517.3278；found:517.3271。
The anti-acute gout inflammation test of embodiment 4 compound III
1, solution preparation
5g uric acid adds 1000ml distilled water and boils, and add 5%NaOH solution and adjust PH 7.4, stir, cooling crystallization makes Monosodium urate crystallization (MSU).By the MSU 10mg autoclaving made, add not containing the DMEM culture fluid 10ml of serum, grinding is made into the DMEM solution of 1mg/ml.During experiment, this solution adds the MSU solution that DMEM culture fluid is made into variable concentrations DMEM again.
1-ethyl pyrrolidine (compound IV) is commercially available analytical pure.
Compound III, Compound I or 1-ethyl pyrrolidine 2.5mg, dissolve with dimethyl sulfoxide (DMSO), DMSO final concentration <0.02%, then the DMEM culture fluid adding serum-free, be mixed with concentration 25ug/ml.
2, the In vitro culture of vascular endothelial cell
Human umbilical vein endothelial cell HUVEC strain is provided by preclinical medicine institute of Nanjing University of Traditional Chinese Medicine, cell is through detection of mycoplasma, without mycoplasma contamination, cell is through 0.25% trypsinization, and the DMEM culture fluid containing 10% calf serum neutralizes, centrifugal (1000r/min × 6min), remove supernatant, add the DMEM culture fluid containing 10% calf serum, move in Tissue Culture Flask, put 37 DEG C, 5%CO
2secondary Culture in incubator.
3, MSU is stimulated to the impact of HUVEC vigor
HUVEC cultivates in culture bottle, and in time growing to 70% ~ 80% and merge, with 0.25% trypsinization, centrifugal, 10% calf serum DMEM culture fluid washs 3 times, with 10% calf serum DMEM culture fluid furnishing 4 × 10
4/ ml cell suspension, implant 96 orifice plates (every hole 200ul), cultivate light sucking-off original fluid after 24 hours, carry out following experiment, often organize each 8 holes, concrete grouping and liquid feeding as follows: matched group (200ul DMEM culture fluid), model group (100ug/ml MSU solution), intervention group (100ug/ml MSU solution+25ug/ml compound III, Compound I or 1-ethyl pyrrolidine), continue after liquid feeding to put 37 DEG C, 5%CO
2cultivate 24 hours in incubator, collect supernatant, remaining HUVEC is for measuring cytoactive, and every hole adds 5mg/ml MTT liquid 20ul again, continues to put 37 DEG C, 5%CO
2cultivate after 4 hours in incubator, abandon MTT liquid, add dimethyl sulfoxide 200ul and dissolve, concussion, read absorbance in microplate reader, wavelength 490nm.
Data statistics processes, and cell viability (%)=experimental group absorbance/matched group absorbance × 100%, the results are shown in Table 1.
Compared with matched group, model group cell viability significantly reduces (P<0.01, P<0.05), after compound III intervention, cell viability significantly improves (P<0.01, P<0.05), and be better than matched group, and Compound I and 1-ethyl pyrrolidine are without this activity.
Table 1 compound III is on the impact of the vascular endothelial cell vigor that MSU stimulates
Note: compared with model group, * * P<0.01; Compared with matched group,
△ △p<0.01,
△p<0.05
4 express impact to ICAM-1
To be in the HUVEC trypsinization of 0.25% of exponential phase, and blow and beat gently, make cell suspension, adjustment cell density is 5 × 10
9/ L, is inoculated in Tissue Culture Flask.After cell covers with (about 24h), abandoning supernatant, be divided into following group: matched group, model group (100ug/ml MSU solution), intervention group (100ug/ml MSU solution+25ug/ml compound III, Compound I or 1-ethyl pyrrolidine), continue cultivation 24 hours, PBS collecting cell, centrifugally remove supernatant, add CD54 monoclonal antibody, after 30min, PBS washs, re-suspended cell, application its positive percentage of flow cytomery (n=10000), repeat 3 times, the results are shown in Table 2.
Table 2 compound III is on the impact of the ICAM-1 Expression in Vascular Endothelial Cells that MSU stimulates
Note: compared with model group, * * P<0.01; Compared with matched group,
△ △p<0.01,
△p<0.05
Result shows, and blank group HUVEC almost expresses without ICAM-1, and the expression of model group ICAM-1 is the highest, and compared with model group, the expression of compound III to ICAM-1 has stronger inhibitory action, and Compound I and 1-ethyl pyrrolidine are without this activity.
Conclusion: the acute gout model evaluation display causing HUVEC damage with MSU; compound III can protect MSU to cause HUVEC damage; reduce apoptosis; improve cytoactive; ICAM-1 is suppressed to express; have the activity of anti-acute gout inflammation, compound III can be used for preparation treatment acute gout anti-inflammatory drugs.And Compound I and 1-ethyl pyrrolidine can not protect MSU to cause HUVEC damage; can not apoptosis be reduced, can not cytoactive be improved, ICAM-1 can not be suppressed to express; not there is the activity of anti-acute gout inflammation, can not for the preparation for the treatment of acute gout anti-inflammatory drugs.
The preparation of embodiment 5 compound III tablet involved in the present invention
Get the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of embodiment 6 compound III capsule involved in the present invention
Get the one in the middle of 20 g of compound III or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (4)
1. one kind has Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment acute gout medicine thereof of structure shown in formula III:
2. a kind of Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment acute gout medicine thereof with structure shown in formula III as claimed in claim 1, is characterized by: described acute gout is induced by Monosodium urate.
3. a kind of Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment acute gout medicine thereof with structure shown in formula III as claimed in claim 1 or 2, it is characterized by: Daphmalenine A derivant (III) reduces the damage of HUVEC cell, improve the activity of HUVEC cell.
4. a kind of Daphmalenine A derivant (III) and the application of pharmaceutically acceptable salt in treatment acute gout medicine thereof with structure shown in formula III as claimed in claim 1 or 2, is characterized by: Daphmalenine A derivant (III) reduces the expression of ICAM-1 in acute gout process.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510241137.0A CN104887670A (en) | 2015-05-12 | 2015-05-12 | Application of Daphmalenine A ramification to preparing acute-gout-resisting medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510241137.0A CN104887670A (en) | 2015-05-12 | 2015-05-12 | Application of Daphmalenine A ramification to preparing acute-gout-resisting medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104887670A true CN104887670A (en) | 2015-09-09 |
Family
ID=54020916
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510241137.0A Pending CN104887670A (en) | 2015-05-12 | 2015-05-12 | Application of Daphmalenine A ramification to preparing acute-gout-resisting medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104887670A (en) |
-
2015
- 2015-05-12 CN CN201510241137.0A patent/CN104887670A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| YU ZHANG,ET AL.: "Daphmalenines A and B: Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense", 《EUR.J.ORG.CHEM.》 * |
| 李震宇等: "虎皮楠生物碱研究进展", 《有机化学》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104107179B (en) | The application in preparing anti-acute gout medicine of the diethylamine derivative of Cleistanone Cleistanone | |
| CN104288160B (en) | The application in preparing anti-acute gout medicine of O-(piperazinyl) ethyl derivative of Cleistanone | |
| CN104825470A (en) | Application of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for treating acute gout | |
| CN105343043A (en) | Composition and application thereof in drug for resisting acute gout | |
| CN105078987A (en) | Composition 38083001030527 and application of composition 38083001030527 to drug for resisting acute gout | |
| CN104771392B (en) | Class I histone deacetylase inhibitor and application | |
| CN104873505A (en) | Application of O-(diethylamino) ethyl derivative of Daphmalenine A in preparation of anti-acute-gout drug | |
| CN104666311A (en) | Application of O-(triazolyl) ethyl derivative of Cleistanone in preparation of medicine resistant to acute gout | |
| CN104887670A (en) | Application of Daphmalenine A ramification to preparing acute-gout-resisting medicine | |
| CN105287579A (en) | Composition and application thereof to acute gout resistant medicines | |
| CN105193789A (en) | Composition and application thereof in anti-acute gout drugs | |
| CN105287590A (en) | Composition and application of composition in medicine for resisting acute gout | |
| CN105250302A (en) | Composition and application thereof in acute gout resisting drugs | |
| CN105250288A (en) | Composition and application thereof to acute gout resistant medicines | |
| CN103372010B (en) | The application of Chukrasone B in preparation treatment acute gout medicine | |
| CN105250297A (en) | Composition and application thereof to acute gout resistant medicines | |
| CN105287596A (en) | Composition and application of composition in medicine for resisting acute grout | |
| CN103405426B (en) | Application of compound in preparation of medicines for treating acute gout | |
| CN105343039A (en) | Composition and application thereof to drugs for resisting acute gout | |
| CN105497036A (en) | Composition and application thereof to acute gout resistant medicament | |
| CN105326832A (en) | Composition and application of composition to acute-gout-resisting medicine | |
| CN105193812A (en) | Composition and application thereof in anti-acute gout drugs | |
| CN105998008A (en) | Application of composition of Salviskinone A derivatives in anti-acute gout drugs | |
| CN103381163B (en) | The application of Chukrasone A in preparation treatment acute gout medicine | |
| CN106074531A (en) | The composition of Ah draw'sing Bick acid triazolyl and 1H tetrazole radical derivative is for preparing anti-acute gout medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150909 |
|
| RJ01 | Rejection of invention patent application after publication |