CN102964303A - Sinomenine derivate and preparation method and application thereof - Google Patents
Sinomenine derivate and preparation method and application thereof Download PDFInfo
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- CN102964303A CN102964303A CN2012104929747A CN201210492974A CN102964303A CN 102964303 A CN102964303 A CN 102964303A CN 2012104929747 A CN2012104929747 A CN 2012104929747A CN 201210492974 A CN201210492974 A CN 201210492974A CN 102964303 A CN102964303 A CN 102964303A
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Abstract
The invention discloses a sinomenine derivate and a preparation method and an application thereof. The preparation method comprises the following steps: carrying out a reaction on the sinomenine or hydrochloride thereof and paraformaldehyde to obtain a sinomenine benzyl alcohol midbody; carrying out an esterification reaction on the obtained sinomenine benzyl alcohol midbody and C2-4 carboxylic acid anhydride to prepare the product; or, carrying out a substitution reaction on the obtained sinomenine benzyl alcohol midbody with 1-bromo-C2-4 alkane to prepare the product. Applied to preparing the medicine with the anti-inflammatory and immune regulation effects, the obtained sinomenine derivate has transdermal performance better than sinomenine and has a certain anti-inflammatory activity. The derivate is expected to be applied to treating immune diseases such as rheumatic disease and rheumatoid disease.
Description
Technical field
The present invention relates to a kind of Sinomenine derivate and its preparation method and application, belong to the synthetic field of medicine.
Background technology
Stem of Orientoine is the dry rattan of menispermaceous plants sinomenium acutum [Sinomenium acutum (Thunb.) Rehd.et Wils.] and hair sinomenium acutum [Sinomenium acutum (Thunb.) Rehd.et Wils.Var.Cinereum Rehd.et Wils.], as the history in existing over thousands of year of China's traditional Chinese medicine treatment rheumatism.The twenties in last century, Ishiwari (Journal ofchemical society Abstracts, 1921,1354.) etc. has extracted the effective constituent tuduranine (sinomenine) for the treatment of rheumatism first from Japanese Stem of Orientoine.The sixties, Chinese scholar Zhu Renhong found tuduranine first from domestic Stem of Orientoine.
Tuduranine (Sinomenine) belongs to isoquinoline alkaloid, is a kind of rheumatic, rheumatoid arthritis treatment medicine with definite clinical efficacy.But in the medication process, find the shortcomings such as tuduranine has the fash of causing, anaphylactic shock, oligoleukocythemia, gastrointestinal reaction is serious, required dosage is bigger than normal, percutaneous abilities is not good.Therefore, by the structure of modification to tuduranine, the searching side effect is little, Sinomenine derivate that biological activity is higher is the focus of present pharmaceutical chemistry research.At present the structure of modification of tuduranine is mainly concentrated in the modification to 6,7 of the C ring and 7,8 and 17 N of D ring, the structural modification that in addition tuduranine A is encircled the Isosorbide-5-Nitrae position also has some reports.For example, Wu Feichi etc. are to tuduranine A, and the C ring is transformed, and has successfully synthesized a series of Sinomenine derivates (CN1876634A).Pan Yi etc. are by to 17 (N) of tuduranine position demethylations and then carry out hydrocarbylation and derive and synthesized a series of N-alkyl tuduranine (CN1785976A).Li Jianxins etc. have obtained some disinomenine derivatives (CN101148437A) by the 1 digit pair connection of C-C mode of connection with tuduranine.Yao Zhujun etc. have carried out structural modification to tuduranine C ring, have obtained the various Sinomenine derivate of a series of structures (CN1687065A).Pharmacodynamic experiment confirms, improved Sinomenine derivate has analgesia, calmness, anti-inflammatory and the immunosuppressive effect suitable with tuduranine or sinomenine hydrochloride mostly, and the part derivative also shows toxicity and the more significant drug effect lower than tuduranine.This shows that the Sinomenine derivate through structure of modification has good medicinal application prospect.
Yet, relate at present that tuduranine A ring Isosorbide-5-Nitrae position is modified simultaneously and to improve the relevant report of transdermal absorption of sinomenine performance also very rare.
Summary of the invention
The object of the present invention is to provide a kind of aspect anti-inflammatory and immunomodulatory effective in cure good, transdermal characteristic is good, side effect is little Sinomenine derivate.
Another object of the present invention is to provide the preparation method of the above-mentioned Sinomenine derivate that a kind of method is simple, reaction conditions is gentle, productive rate is high.
A further object of the invention is to provide a kind of application of above-mentioned Sinomenine derivate, and Sinomenine derivate is applied to prepare in the medicine of anti-inflammatory and immunoregulation effect, and good effect, transdermal characteristic is good, side effect is little.
The invention provides a kind of Sinomenine derivate, have formula 1 structure:
R
1Be selected from C
1～10Alkyl or C
1～10Acyl group in a kind of;
R
2Be selected from C
1～10Acyl group in a kind of or hydrogen atom;
R in the foregoing invention
1Be preferably in ethyl, propyl group, the tertiary butyl, ethanoyl, propionyl or the butyryl radicals a kind of.
R in the foregoing invention
2Be preferably ethanoyl, propionyl, butyryl radicals or hydrogen atom.
Sinomenine derivate described in the foregoing invention most preferably is R
1And R
2Be selected from simultaneously ethanoyl, propionyl or butyryl radicals; Perhaps R
2When being selected from hydrogen atom, R
1Be selected from ethyl, propyl group or the tertiary butyl a kind of.
Most preferred Sinomenine derivate has following structure among the present invention: such as 1a, 1b, 1c and 2a, 2b, 2c.
The present invention also provides a kind of preparation method of as mentioned above Sinomenine derivate, specifically first tuduranine or its hydrochloride and polyformaldehyde reaction is obtained tuduranine benzylalcohol intermediate; With tuduranine benzylalcohol intermediate and the C that obtains
2 ~ 4Carboxylic acid anhydride generation esterification, make product; Perhaps with tuduranine benzylalcohol intermediate and the 1-bromo C of gained
2～4Alkane generation substitution reaction makes product.
Tuduranine benzylalcohol intermediate and C among the above-mentioned preparation method
2～4Acid anhydrides under DMAP catalysis, in pyridine, reflux, the reaction 2 ~ 4h.
Tuduranine benzylalcohol intermediate and 1-bromo C among the above-mentioned preparation method
2～4Alkane is at Cs
2CO
3Under 50 ~ 70 ° of C, react 1 ~ 3h under the catalysis.
The present invention also provides a kind of aforesaid Sinomenine derivate, the specifically application of Sinomenine derivate in the medicine of preparation anti-inflammatory and immunoregulation effect.
(1) tuduranine benzylalcohol intermediate, the i.e. preparation of 1-methylol tuduranine: in hydrochloric acid (2mol/L) medium, tuduranine (or its hydrochloride) and Paraformaldehyde 96 stirring reaction 2h under 60 ° of C.Reaction mixture is regulated pH value to 9 ~ 10 with 10% sodium hydroxide solution, uses the washed with dichloromethane filter cake behind the suction filtration again, gets midbody compound, and the mol ratio of described tuduranine or its hydrochloride and Paraformaldehyde 96 is 1:2 ~ 4.
(2) preparation of compound 1: take pyridine as solvent, with tuduranine benzylalcohol intermediate and C
2 ~ 4Carboxylic acid anhydride back flow reaction 2 ~ 4h under DMAP catalysis; Add saturated sodium bicarbonate solution and the pH value is adjusted to 8 ~ 9 after the lower desolventizing of decompression; Use chloroform extraction, organic phase is through washing, and anhydrous sodium sulfate drying filters; Remove trichloromethane under the decompression, resistates obtains compound 1 by column chromatography for separation [V (methylene dichloride): V (methyl alcohol)=20 ~ 30:1].
(3) preparation of compound 2: take DMF as solvent, at Cs
2CO
3Tuduranine benzylalcohol intermediate and 1-bromo C under the catalysis
2 ~ 4Alkane is stirring reaction 1 ~ 3h under 50 ~ 70 ° of C; Steam DMF under the decompression after filtering, resistates obtains compound 2 by column chromatography for separation [V (methylene dichloride): V (methyl alcohol)=10 ~ 15:1].
The syntheti c route of the Sinomenine derivate that the present invention relates to is as follows:
Beneficial effect of the present invention: Sinomenine derivate synthetic method of the present invention is simple, reaction conditions is gentle, suitable industrial production.External tumor necrosis factor alpha (TNF-α), interleukin-11 β (IL1 β) and interleukin 6 (IL6) inhibition test reach at the body experiment confirm: the Sinomenine derivate that the present invention relates to has preferably anti-inflammatory activity, is expected to become the medicine of the immune class diseases such as preparation treatment rheumatism or rheumatoid; The transdermal test in vitro experiment confirm: the Sinomenine derivate that the present invention relates to has than the better percutaneous abilities of tuduranine.
Show that through anti-inflammatory experiment and transdermal experiment the Sinomenine derivate that the present invention synthesizes compares with tuduranine that to have cytotoxicity little, the advantage that percutaneous abilities is good.In 2h, accumulate skin permeation rate such as compound 1a and 1b and can reach peak value more than 95%; Compound 2a and 2b accumulate skin permeation rate in 6h can reach peak value more than 85%; And tuduranine wants 8h just can reach accumulation skin permeation rate peak value, and peak value is starkly lower than synthetic derivative below 75%.In addition, synthetic method of the present invention has intermediate does not need column chromatography for separation, and reaction conditions is gentle, advantage simple to operate, that the reaction product productive rate is high.
Description of drawings
[Fig. 1] accumulates the transdermal measurement and attempt for Sinomenine derivate of the present invention exsomatizes: 1a, 1b, 2a and 2b represent respectively Sinomenine derivate 1a of the present invention, 1b, 2a and 2b; Sino represents tuduranine.
[Fig. 2] be the embodiment of the invention 6 Sinomenine derivates to IL1B, IL6 affects figure.
[Fig. 3] is that the embodiment of the invention 6 Sinomenine derivates are on the figure that affects of TNF-α.
Embodiment
Following examples are to further specify of the present invention, rather than restriction the present invention.
In-vitro percutaneous penetrating quality experimental procedure:
The dislocation of mouse cervical vertebra is put to death, and skin of abdomen is got in the sodium sulfide solution depilation, divests subcutis and fat; After physiological saline is cleaned, with the medicine transit dose of Transdermal absorption instrument and high performance liquid chromatograph mensuration certain hour, the accumulation transit dose of computerized compound in 10h, the relatively percutaneous abilities of each compound.
The anti-inflammatory activity experimental procedure:
Mouse Raw264.7 cell (Chinese Academy of Sciences's Shanghai cell bank) the high sugar of DMEM (Invitrogen company)+10% foetal calf serum FBS(Gibco company) cultivates, ratio in 50,000 cell count in every hole is planted on 24 orifice plates, add final concentration in the cultivation and be the lipopolysaccharides (Sigma-Aldrich company) of 1 μ g/ml and induce inflammation, add in the nutrient solution contrast isocyatic DMSO of equal-volume to after simultaneously certain density medicine being dissolved with DMSO; Cell culture incubator removes nutrient solution after cultivating certain hour, with PBS washing, collecting cell; With Trizol reagent extracting mRNA, reverse transcription cDNA, carry out the real-time quantitative PCR test with SYBR Green I reagent (Takara company), analyze medicine to the impact of inflammatory factor gene expression amount.
Mouse subcutaneous injection tuduranine solution 3.250mg/kg, the derivative 1 of standard configuration or 2 solution (heavy dose of group: 32.500mg/kg, middle dosage group: 3.250mg/kg, small dose group: 0.325mg/kg; Every group 10 together lower), continuous three days, it is scorching to be coated with the 0.03mL caused by dimethylbenzene xylene in last administration 0.5h rear left ear, punching pin with diameter 8mm behind the 4h sweeps away mouse auricle (sweep away along the auricle edge, the position of punching is consistent, and once sweeps away), weigh, about two auricle weight differences be swelling, represent anti-inflammatory action intensity with inhibitory rate of intumesce, analyze medicine to mouse ear dimethylbenzene inhibition of inflammation.
Rat causes inflammation in right back sufficient intradermal injection 1% carrageenin normal saline solution 100 μ L after measuring the ankle joint girth, 0.5h pipette the heavy dose of group of each derivative 100 μ L(32.500mg/kg with liquid-transfering gun afterwards, middle dosage group 3.250mg/kg, small dose group 0.325mg/kg) coats the rat paw position, 0.5h after measure the ankle joint girth, measure an ankle joint girth every 1h later on, continuous 6h, so that scorching front and back ankle joint girth is poor to be swelling, be coated with same position, volume physiological saline rat is that control group calculates inhibitory rate of intumesce, represent anti-inflammatory action intensity with inhibitory rate of intumesce, analyze medicine to the restraining effect of rat carrageenan foot swelling.
Embodiment 1: compound 1a's is synthetic
Take pyridine as solvent, 0.246g(0.684mmol under DMAP catalysis) tuduranine benzylalcohol intermediate and 1mL diacetyl oxide back flow reaction 3h; Steam pyridine under the decompression, add saturated sodium bicarbonate solution and regulate pH value to 8 ~ 9 rear chloroform extractions of using; The organic phase water repeatedly washs the rear anhydrous sodium sulfate drying of using, and steams under the decompression and is spin-dried for organic phase, and resistates obtains compound 1a by column chromatographic isolation and purification [V (methylene dichloride): V (methyl alcohol)=30:1].Productive rate 85.2%.
Compound 1a: faint yellow solid, mp.56 ~ 58 ° C;
1H NMR (400MHz, CDCl
3) δ=1.86 ~ 1.93 (m, 1H), 2.11 (s, 3H), 2.04 ~ 2.16 (m, 2H), 2.36 (s, 3H), 2.43 (s, 3H), 2.51 ~ 2.55 (m, 2H), 2.66 (dd, J
1=6.0Hz﹠amp; J
2=18.8Hz, 1H), 3.02 (t, J=7.2Hz, 2H), 3.27 (t, J=4.0Hz, 1H), 3.48 (s, 3H), 3.76 (s, 3H), 3.89 (d, J=16.0Hz, 1H), 5.07 (s, 2H), 5.46 (s, 1H), 6.86 (s, 1H).
13C NMR (100MHz, CDCl
3) δ=20.78,20.91,21.16,29.66,36.87,40.69,42.63,45.49,46.59,49.95,54.81,55.90,64.10,112.28,114.64,128.59,130.31,130.45,139.47,149.59,152.38,170.73,192.26.MS (EI) m/z (%): 443.2 (M
+, 93).
Embodiment 2: compound 1b's is synthetic:
Step is with embodiment 1,0.248g, and (0.684mmol) tuduranine benzylalcohol intermediate and 1.5mL propionic anhydride are that raw material prepares compound 1b.Productive rate 75.2%.
Embodiment 3: compound 2a's is synthetic
Take DMF as solvent, at Cs
2O
30.347g(0.966mmol under the catalysis) tuduranine benzylalcohol intermediate and 1-N-PROPYLE BROMIDE 0.27ml(2.90mmol) stirring reaction 2h under 60 ° of C; Steam solvent under the decompression after filtering, resistates obtains compound 2a by column chromatographic isolation and purification [V (methylene dichloride): V (methyl alcohol)=15:1].Productive rate 80.6%.
Embodiment 4: compound 2b's is synthetic:
Step is with embodiment 3,0.345g(0.966mmol) tuduranine benzylalcohol intermediate and 0.28ml(2.90mmol) isobutane bromide is that raw material prepares compound 2b.Productive rate 49.6%.
Experimental example 5: transdermal permeation in vitro
The dislocation of mouse cervical vertebra is put to death, and skin of abdomen is got in the depilation of 0.8% sodium sulfide solution, divests subcutis and fat, and physiological saline is cleaned, and 4 ℃ save backup.Adopt improved Franz diffusing cells method, effectively infiltrating area is 2.8cm
2, accept pond volume 6.5mL, accepting medium is PBS solution (ultrasonic degas 30min before using).Skin outer layer tiled up to be fixed on diffusion cell and to accept between the pond, fills with the PBS solution of accepting medium pH=6.8 by stopple coupon in accepting the pond, and liquid level is contacted with skin inner layer, gets rid of the bubble of accepting in the pond.Accurate absorption 0.2mL tuduranine and derivative need testing solution (10mg/mL) thereof are coated skin surface respectively, seasoning, the constant speed that is 600r/min at 37 ℃ of lower maintenance rotating speeds stirs, after experiment beginning 2,4,6,8,10h timing sampling 0.5mL, (in time replenish the fresh accepting medium of equal volume, get rid of the bubble in the receiving chamber with 0.45 μ m filtering with microporous membrane.), get subsequent filtrate and inject the high performance liquid phase instrument, computerized compound accumulation transit dose.The results are shown in Table 1 and Fig. 1.
The in-vitro percutaneous accumulation transit dose of table 1 Sinomenine derivate (%); (
N=3)
★Compare P＜0.05 with the Sino. group.
4 compounds of experiment are compared under same dose (10mg/mL) with tuduranine, all have stronger transdermal effect, and transdermal capability is the strongest with 1a and 1b, reaches peak value 98.05% ± 1.79 and 97.28% ± 1.59 in the 2h; 2a and 2b take second place, and reach peak value 85.78% ± 2.21 and 85.36% ± 2.12 in the 6h; And tuduranine wants 8h just can reach peak value, and peak concentration is 74.87% ± 2.08, is lower than 4 synthetic new compounds, and surpassing behind the 8h tuduranine and derivative thereof has decomposing phenomenon in accepting medium PBS solution.
Embodiment 6: the mensuration of interleukin-11 B (IL1B), interleukin 6 (IL6) mrna expression
Mouse Raw264.7 cell is cultivated with the high sugar of DMEM+10%FBS, is planted on 24 orifice plates with front ratio in 50,000 cell count in every hole, adds 1 μ g/mL lipopolysaccharides (LPS) in the cultivation and induces inflammation.Tuduranine, the sharp ketone of Roger (Ros is had anti-inflammatory action by the lot of documents report, uses as positive drug here), 1a, 1b, 2a all add in the nutrient solution by the dosage of 10 μ g/mL, remove nutrient solution behind the cell cultures 12h, with PBS washing 1 time, collecting cell.With Trizol reagent extracting mRNA, reverse transcription cDNA.Take GAPDH as the reference gene, utilize SYBR Green I reagent to carry out the quantitative PCR test, analyze the impact on inflammatory factor IL1 β, IL6 and tumor necrosis factor alpha (TNF-α) gene expression amount, employed primer is synthetic by Invitrogen company.The results are shown in Table 2, Fig. 2 and Fig. 3.
Table 2 Sinomenine derivate is to IL1 β, the impact of IL6 and TNF-α mrna expression; (
N=3)
a:(LPS
-);b:Control(LPS
+);c:10μg/mL?for?Sinomenine1a,1b,2a?and?Ros,respectively；
* compare P＜0.05 with the Control group;
★Compare P＜0.05 with the Sino. group.
3 compounds of experiment are compared under same dose (10 μ g/mL) with tuduranine, all have stronger inflammation-inhibiting factor IL1 β, IL6 and the effect of TNF-α mrna expression, and it is the strongest with 2a wherein to suppress IL1 β, and 1a and 1b take second place; It is the strongest with 1a to suppress IL6, and 1b and 2a take second place; It is the strongest with 1b to suppress TNF-α, and 2a and 1a take second place.
Embodiment 7: mouse ear dimethylbenzene inhibition of inflammation
It is scorching that mouse subcutaneous injection tuduranine 3.25mg/kg, large, medium and small three dosage of each derivative, 0.5h rear left ear are coated with the 0.03mL caused by dimethylbenzene xylene, auricle under the 4h backlash is weighed, about two auricle weight differences be swelling, represent anti-inflammatory action intensity with inhibitory rate of intumesce, the results are shown in Table 3.
Table 3 Sinomenine derivate is to mouse ear dimethylbenzene inhibition of inflammation; (
N=10)
aSwelling=left ear weight-auris dextra weight (unit: g);
bInflammation inhibiting rate=(control group swelling-medicine group swelling) * 100%/control group swelling.
*Compare P＜0.05 with the Sino. group.
3 compounds of experiment are compared under same dose (3.25mg/kg) with tuduranine, 1a and 1b have preferably antiphlogistic effects, the anti-inflammatory ability is the strongest with 1a, 1b and 2a take second place, the swelling of 1a and 1b, inflammation inhibiting rate are better than tuduranine in the experiment, the swelling of 2a is similar to tuduranine, and the inflammation inhibiting rate is weaker than tuduranine, and they are better than again model group.
Embodiment 8: the restraining effect of rat carrageenan foot swelling
Rat causes inflammation in right back sufficient intradermal injection 1% carrageenin normal saline solution 100 μ L after measuring the ankle joint girth, be equivalent to the heavy dose of group of administration 32.5mg/kg 0.5h pipette each derivative 100 μ L(with liquid-transfering gun afterwards, middle dosage group 3.25mg/kg, small dose group 0.325mg/kg) coats the rat paw position, 0.5h after measure ankle joint girth (unit: cm), measure an ankle joint girth every 1h later on, continuous 6h, so that scorching front and back ankle joint girth is poor to be swelling, be coated with same position, volume physiological saline rat is that control group calculates inhibitory rate of intumesce, represent anti-inflammatory action intensity with inhibitory rate of intumesce, the results are shown in Table 4 and table 5.
Table 4 Sinomenine derivate is to the restraining effect (X of rat carrageenan foot swelling
N=10)
* compare P＜0.05 with the Sinomenine group.
The Sinomenine derivate of experiment is compared under same dose (3.25mg/kg) with tuduranine, the effect that all has stronger inhibition rat carrageenan foot swelling, anti-inflammatory action 1a is stronger, 1b takes second place, their anti-inflammatory action all is better than tuduranine and keeps curative effect time longer, has reached 5 ~ 6h.
Table 5 Sinomenine derivate is to the restraining effect (X of rat carrageenan foot swelling
N=10, unit: cm)
★Compare P＜0.05 with the Sino. group;
●Compare P＜0.05 with model group.
Claims (8)
1. a Sinomenine derivate is characterized in that, has formula 1 structure:
Formula 1
R
1Be selected from C
1～10Alkyl or C
1～10Acyl group in a kind of;
R
2Be selected from C
1～10Acyl group in a kind of or hydrogen atom.
2. Sinomenine derivate as claimed in claim 1 is characterized in that, R
1Be selected from ethyl, propyl group, the tertiary butyl, ethanoyl, propionyl or butyryl radicals.
3. Sinomenine derivate as claimed in claim 1 is characterized in that, R
2Be selected from ethanoyl, propionyl, butyryl radicals or hydrogen atom.
4. Sinomenine derivate as claimed in claim 1 is characterized in that, R
1And R
2Be selected from simultaneously ethanoyl, propionyl or butyryl radicals, perhaps R
2When being selected from hydrogen atom, R
1Be selected from ethyl, propyl group or the tertiary butyl a kind of; Structural formula is as follows:
5. the preparation method such as claim 4 Sinomenine derivate is characterized in that, first tuduranine or its hydrochloride and polyformaldehyde reaction is obtained tuduranine benzylalcohol intermediate; With tuduranine benzylalcohol intermediate and the C that obtains
2～4Carboxylic acid anhydride generation esterification, make product; Perhaps with tuduranine benzylalcohol intermediate and the 1-bromo C of gained
2 ~ 4Alkane generation substitution reaction makes product.
6. preparation method as claimed in claim 5 is characterized in that, tuduranine benzylalcohol intermediate and C
2～4Carboxylic acid anhydride under DMAP catalysis, in pyridine, reflux, the reaction 2 ~ 4h.
7. preparation method as claimed in claim 5 is characterized in that, tuduranine benzylalcohol intermediate and 1-bromo C
2 ~ 4Alkane is at Cs
2CO
3Under 50 ~ 70 ° of C, react 1 ~ 3h under the catalysis.
8. the application such as right 1 ~ 4 each described Sinomenine derivate is characterized in that, the application of Sinomenine derivate in the medicine of preparation anti-inflammatory and immunoregulation effect.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104672142A (en) * | 2015-02-13 | 2015-06-03 | 江苏大学 | Preparation and medical purpose of dual structure sinomenine derivative |
| CN107325097A (en) * | 2017-08-04 | 2017-11-07 | 北京师范大学 | Sinomenine derivate and preparation method and application |
| CN108815434A (en) * | 2018-08-13 | 2018-11-16 | 彭水县绿忆环保科技有限公司 | Antibacterial conditioning liquid |
| CN108863932A (en) * | 2018-06-08 | 2018-11-23 | 无锡市太湖医院 | Sinomenine derivate, its esters and its preparation method and application |
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| CN104672142A (en) * | 2015-02-13 | 2015-06-03 | 江苏大学 | Preparation and medical purpose of dual structure sinomenine derivative |
| CN109096190A (en) * | 2017-06-21 | 2018-12-28 | 中国医学科学院药物研究所 | A kind of Sinomenine derivate and preparation method thereof, purposes and pharmaceutical composition |
| CN109096190B (en) * | 2017-06-21 | 2021-07-02 | 中国医学科学院药物研究所 | Sinomenine derivative, preparation method, application and pharmaceutical composition thereof |
| CN107325097A (en) * | 2017-08-04 | 2017-11-07 | 北京师范大学 | Sinomenine derivate and preparation method and application |
| CN107325097B (en) * | 2017-08-04 | 2019-05-28 | 北京师范大学 | Sinomenine derivate and the preparation method and application thereof |
| CN108863932A (en) * | 2018-06-08 | 2018-11-23 | 无锡市太湖医院 | Sinomenine derivate, its esters and its preparation method and application |
| CN108863932B (en) * | 2018-06-08 | 2022-01-11 | 无锡市太湖医院 | Sinomenine derivative, its salt, preparation method and application thereof |
| CN108938783A (en) * | 2018-08-13 | 2018-12-07 | 彭水县绿忆环保科技有限公司 | The clean antibacterial moist conditioning liquid of women and its production technology for treating cervical erosion |
| CN108815434A (en) * | 2018-08-13 | 2018-11-16 | 彭水县绿忆环保科技有限公司 | Antibacterial conditioning liquid |
| CN113493415A (en) * | 2020-04-03 | 2021-10-12 | 中国医学科学院药物研究所 | Sinomenine derivative metabolite and preparation method, pharmaceutical composition and application thereof |
| CN113493415B (en) * | 2020-04-03 | 2023-12-15 | 中国医学科学院药物研究所 | Sinomenine derivative metabolite, preparation method, pharmaceutical composition and application thereof |
| CN115260098A (en) * | 2022-06-09 | 2022-11-01 | 澳门科技大学 | Application of ABCB5 inhibitor in preparation of multi-drug-resistance rheumatoid arthritis treatment drug |
| CN116063230A (en) * | 2023-02-24 | 2023-05-05 | 大连理工大学 | Sinomenine 1-position substituted derivative, and preparation method and application thereof |
| CN116063230B (en) * | 2023-02-24 | 2024-03-29 | 大连理工大学 | Sinomenine 1-position substituted derivative, and preparation method and application thereof |
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