CN112979733B - Anti-hepatitis B virus compound and preparation method and application thereof - Google Patents
Anti-hepatitis B virus compound and preparation method and application thereof Download PDFInfo
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- CN112979733B CN112979733B CN202110445327.XA CN202110445327A CN112979733B CN 112979733 B CN112979733 B CN 112979733B CN 202110445327 A CN202110445327 A CN 202110445327A CN 112979733 B CN112979733 B CN 112979733B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention provides an anti-hepatitis B virus compound, a preparation method and application thereof, wherein the compound is 4-thiouridine isobutyrate, and the molecular formula is C13H18N2O6S, the structural formula is as follows:
. The compound of the invention can effectively inhibit the activity of hepatitis B virus, can be used as a substitute drug of lamivudine and telbivudine, solves the problem of drug resistance of lamivudine and the like in the aspect of resisting hepatitis B virus, has high drug effect, low toxicity and low price, and provides a direction for developing drugs for treating hepatitis B. In addition, the invention discloses a preparation method of the compound 4-thiouridine isobutyrate, which has mild conditions, is easy to synthesize and is suitable for industrial production.
Description
Technical Field
The invention relates to an anti-hepatitis B virus compound and a preparation method and application thereof, belonging to the technical field of medicinal chemistry.
Background
Hepatitis B Virus (HBV) infection is one of the major diseases affecting human health, and about 100 million patients died due to hepatitis b virus each year account for the first 10 causes of disease death worldwide.
At present, the drugs for treating chronic viral hepatitis are mainly of three types, the first type is nucleoside (nucleotide) drugs, such as lamivudine, adefovir, entecavir, telbivudine, tenofovir and the like; the second class is interferon drugs, such as: interferon alpha and pegylated interferon alpha; the third category is traditional Chinese medicine, such as fructus Schisandrae chinensis, kurarinone, oleanolic acid and its derivatives, and plant polysaccharide. These drugs for treating hepatitis B virus still face many problems, such as drug resistance, unclear drug target, etc., and research and development of new anti-hepatitis B virus drugs with high drug efficacy, low toxicity and low price are still needed.
In view of the above, there is a need to provide an anti-hepatitis B virus compound to solve the above problems.
Disclosure of Invention
The invention aims to provide an anti-hepatitis B virus compound with high drug effect, low toxicity and low price.
In order to achieve the above object, the present invention provides an anti-hepatitis b virus compound, wherein the molecular formula of the anti-hepatitis b virus compound is C13H18N2O6S, and the structural formula is as follows:
。
as a further improvement of the invention, the anti-hepatitis B virus compound is a yellow solid.
The invention also aims to provide the application of the anti-hepatitis B virus compound in preparing medicaments for preventing or treating hepatitis B virus.
As a further improvement of the invention, the medicine can be prepared into any dosage form in pharmacy, including tablets, capsules, granules, pills, oral liquid and injections.
The invention also aims to provide a preparation method of the anti-hepatitis B virus compound with high drug effect, low toxicity and low price.
In order to achieve the above object, the present invention provides a method for preparing an anti-hepatitis b virus compound, comprising the steps of:
step one
Reacting uracil 1, (2S,3R,4R,5R) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-tri-acetic acid triester 2, N, O-bis (trimethylsilyl) acetamide and acetonitrile under the protection of argon, adding trimethylsilyl trifluoromethanesulfonate for continuous reaction, cooling, adding sodium bicarbonate and ethyl acetate, filtering and concentrating to obtain a compound 3; step two
Dissolving the compound 3 in toluene, adding a Lawson reagent for reaction, and separating by first column chromatography to obtain a compound 4;
step three
Reacting the compound 4 with ammonia methanol to obtain a compound 5;
step four
Dissolving the compound 5 in acetone, adding p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane for reaction, adding a pH adjusting reagent, adjusting the pH to be alkalescent, and performing first column chromatography separation to obtain a compound 6; step five
Dissolving a compound 6 and dimethylaminopyridine in an organic reagent, reacting under the protection of nitrogen, sequentially adding triethylamine and isobutyric anhydride, continuing to react, adding methanol into a reaction liquid for quenching, and separating by a second column chromatography to obtain a compound 7, wherein the organic reagent is acetonitrile or tetrahydrofuran;
step six
And reacting the compound 7 with a formic acid solution, and separating by using a third column chromatography to obtain a compound 8, wherein the compound 8 is the anti-hepatitis B virus compound.
As a further improvement of the invention, the concentration of the formic acid solution in the sixth step is 80% or 100%.
As a further improvement of the present invention, said compound 3 and said compound 4 are both yellow oils; the compound 5 was a dark yellow oil, and the compound 6, the compound 7, and the compound 8 were all yellow solids.
As a further improvement of the present invention, the first column chromatography, the second column chromatography and the third column chromatography are all silica gel column chromatography, and the first column chromatography is dichloromethane/ethanol column chromatography, and the second column chromatography and the third column chromatography are petroleum ether/ethyl acetate column chromatography.
As a further improvement of the invention, the pH adjusting reagent in the fourth step is triethylamine.
The invention has the beneficial effects that: the compound can effectively inhibit the activity of hepatitis B virus, can be used as a substitute drug of lamivudine and telbivudine, solves the problem of drug resistance of lamivudine and other drugs in the aspect of resisting hepatitis B virus, has high drug effect, low toxicity and low price, and provides a direction for developing drugs for treating hepatitis B. In addition, the preparation method of the compound 4-thiouridine isobutyrate disclosed by the invention is mild in condition, easy to synthesize and suitable for industrial production.
Drawings
FIG. 1 is a structural diagram of the anti-HBV compound according to the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in detail with reference to the accompanying drawings and specific embodiments.
It should be noted that, in order to avoid obscuring the present invention with unnecessary details, only the structures and/or processing steps closely related to the aspects of the present invention are shown in the drawings, and other details not closely related to the present invention are omitted.
In addition, it is also to be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
The invention provides a compound for resisting hepatitis B virus, which is 4-thiouridine isobutyrate with a molecular formula of C13H18N2O6S, the structural formula is as follows:
。
furthermore, the anti-hepatitis B virus compound is yellow solid.
The invention also provides the application of the anti-hepatitis B virus compound, and the anti-hepatitis B virus compound can be applied to the preparation of medicaments for preventing or treating hepatitis B virus. The medicine can be prepared into any dosage form in pharmacy, including tablets, capsules, granules, pills, oral liquid, injection and the like.
The invention also provides a preparation method of the anti-hepatitis B virus compound. The preparation method comprises six steps, each of which can be accomplished by various embodiments to finally synthesize the compound 4-thiouridine isobutyrate having anti-hepatitis B virus activity. The preparation method of the anti-hepatitis B virus compound comprises the following steps:
the method comprises the following steps: process for producing Compound 3
Example 1:
25g of uracil 1, 26.4 g of (2R,3S,4S,5S) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetic acid triester 2, 48 g of N, O-bis (trimethylsilyl) acetamide were dissolved in 380 mL of acetonitrile, reacted under argon, the temperature of the oil bath was raised to 90 ℃ and the mixture was heated under reflux for 2h, 26 g of trimethylsilyl trifluoromethanesulfonate was added, and the heating under reflux was continued for 16 h. After the reaction solution was naturally cooled to room temperature, 200 mL of a saturated sodium bicarbonate solution and 500 mL of ethyl acetate were added, filtration was performed, the aqueous phase was separated from the filtrate, the organic phase was washed twice with water, once with a saturated saline solution, dried with anhydrous sodium sulfate, and after filtration, the organic phase was concentrated under reduced pressure to give compound 3.
Example 2:
20g of uracil, 14.09g of (2R,3S,4S,5S) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-triacetic acid triester and 38.3g of N, O-bis (trimethylsilyl) acetamide were dissolved in 350 mL of acetonitrile, reacted under argon, the temperature of the oil bath was raised to 90 ℃ and the mixture was heated under reflux for 2h, 20.7g of trimethylsilyl trifluoromethanesulfonate was added, and the heating under reflux was continued for 16 h. The reaction solution was naturally cooled to room temperature, 150mL of a saturated sodium bicarbonate solution and 450 mL of ethyl acetate were added, filtration was performed, the aqueous phase was separated from the filtrate, the organic phase was washed twice with water, once with a saturated saline solution, dried with anhydrous sodium sulfate, and after filtration, the organic phase was concentrated under reduced pressure to give compound 3.
Furthermore, the compound 3 obtained in example 1 and example 2 is yellow oil, and the crude compound 3 obtained by the reaction of example 1 and example 2 can directly participate in the reaction of step two without purification.
Step two: process for producing Compound 4
Example 1:
14 g of compound 3 is dissolved in 300mL of toluene, and the temperature of the oil bath is raised to 100 ℃ and the mixture is stirred until the system is clear. Then 16.8 g of Lawson reagent was added for reaction, and the reaction was continued at 100 ℃ for 2 hours. Naturally cooling the reaction solution to room temperature, filtering, directly concentrating the filtrate under reduced pressure to obtain a crude product, and separating the crude product by using first column chromatography to obtain a compound 4.
Example 2:
14 g of compound 3 is dissolved in 300mL of toluene, and the temperature of the oil bath is raised to 100 ℃ and the mixture is stirred until the system is clear. 9.2g of Lawson reagent are added for reaction, and the reaction is continued for 2h at 100 ℃. Naturally cooling the reaction solution to room temperature, filtering, directly concentrating the filtrate under reduced pressure to obtain a crude product, and separating the crude product by using first column chromatography to obtain a compound 4.
Further, the first column chromatography used in example 1 and example 2 was a dichloromethane/methanol column chromatography, and was eluted with dichloromethane/methanol at a volume ratio of 1:0, followed by a column chromatography with a volume ratio of 200:1, eluting with dichloromethane/methanol, recovering the eluent by an organic solvent, and drying to obtain a compound 4.
Step three: process for producing Compound 5
Example 1:
11.1 g of Compound 4 was dissolved in 250 mL of methanolic ammonia and stirred at room temperature for 16 h. The reaction solution is directly decompressed and concentrated to obtain a crude compound 5.
Example 2:
11.1 g of Compound 4 was dissolved in 250 mL of methanolic ammonia and stirred at room temperature for 4 h. The reaction solution is directly decompressed and concentrated to obtain a crude compound 5.
Further, the compound 5 obtained by the reaction of example 1 and example 2 is a dark yellow oil, and the crude compound 5 obtained by the reaction of example 1 and example 2 can directly participate in the reaction of step four without purification.
Step four: process for producing Compound 6
Example 1:
12.2 g of Compound 5 was dissolved in 250 mL of acetone, and 8.9g of p-toluenesulfonic acid monohydrate and 48.8 g of 2, 2-dimethoxypropane were added thereto, and the reaction was stirred at room temperature for 2 hours. And then, slowly adding a pH regulating reagent into the reaction solution, regulating the pH to be alkalescent, and separating by using first column chromatography to obtain a compound 6.
Example 2:
12.2 g of Compound 5 was dissolved in 250 mL of acetone, and 8.9g of p-toluenesulfonic acid monohydrate and 29.3 g of 2, 2-dimethoxypropane were added thereto, and the reaction was stirred at room temperature for 2 hours. And then, slowly adding a pH regulating reagent into the reaction solution, regulating the pH to be alkalescent, and separating by using first column chromatography to obtain a compound 6.
Further, the pH adjusting reagents used in example 1 and example 2 were triethylamine, and triethylamine was slowly dropped into the reaction solution until the pH of the reaction solution was adjusted to = 8. Then carrying out reduced pressure concentration to obtain a crude product, and carrying out first column chromatography separation on the crude product to obtain a compound 6. Specifically, the first column chromatography is a dichloromethane/methanol mixed solution, the first column chromatography is eluted by dichloromethane/methanol with the volume ratio of 1:0, the second column chromatography is eluted by dichloromethane/methanol with the volume ratio of 200:1, and finally the third column chromatography is eluted by dichloromethane/methanol with the volume ratio of 100:1, and the eluent is subjected to organic solvent recovery, drying and separation to obtain the compound 6.
Further, compound 6 obtained by the reaction of example 1 and example 2 was a yellow solid.
Step five: process for producing Compound 7
Example 1:
1.3 g of compound 6 and 0.1g of dimethylaminopyridine are dissolved in 55 mL of acetonitrile and reacted under nitrogen. After stirring at room temperature for 10 min, 8.66 mmol of triethylamine and 4.76 mmol of isobutyric anhydride were added in succession and the reaction was stirred at room temperature for a further 2 h. Then, 15 mL of methanol was added to the reaction solution to quench, and compound 7 was isolated by second column chromatography.
Example 2:
1.3 g of compound 6 and 0.1g of dimethylaminopyridine are dissolved in 55 mL of tetrahydrofuran and reacted under nitrogen protection. After stirring at room temperature for 10 min, 8.66 mmol of triethylamine and 4.76 mmol of isobutyric anhydride were added in succession and the reaction was stirred at room temperature for a further 2 h. Then, 15 mL of methanol was added to the reaction solution to quench, and compound 7 was isolated by second column chromatography.
Further, the second column chromatography used in example 1 and example 2 is petroleum ether/ethyl acetate column chromatography, specifically, petroleum ether/ethyl acetate with a volume ratio of 1:0 is used for elution, petroleum ether/ethyl acetate with a volume ratio of 3:1 is used for elution, finally petroleum ether/ethyl acetate with a volume ratio of 1:1 is used for elution, and the eluent is recovered with an organic solvent and dried to obtain compound 7.
Further, the compound 7 obtained by the reaction of example 1 and example 2 was a yellow solid, and the yield of the compound 7 in example 1 was 93.7%, and the yield of the compound 7 in example 2 was 90.6%.
Step six: preparation method of 4-thiouridine isobutyrate
Example 1:
1.5 g of Compound 7 was dissolved in 20 mL of 80% formic acid solution, and the reaction was stirred at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure to give a crude product, which was separated by third column chromatography to give compound 8, which was 4-thiouridine isobutyrate, as a yellow solid, in 63.2% yield.
Example 2:
1.5 g of Compound 7 was dissolved in 20 mL of 100% formic acid solution, and the reaction was stirred at room temperature for 16 h. The reaction solution was directly concentrated under reduced pressure to give a crude product, which was separated by third column chromatography to give compound 8, which was 4-thiouridine isobutyrate, as a yellow solid, in a yield of 40%.
Further, the second column chromatography used in example 1 and example 2 was petroleum ether/ethyl acetate column chromatography, and the elution was performed with petroleum ether/ethyl acetate at a volume ratio of 5:1, followed by petroleum ether/ethyl acetate at a volume ratio of 1:1, and the eluate was subjected to recovery of the organic solvent and drying to obtain compound 8.
Example 1 and example 2 in step six both yielded 4-thiouridine isobutyrate, specifically, the nuclear magnetic data for 4-thiouridine isobutyrate is shown below (FIG. 1):
1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 6.32 (dd, J = 7.5, 1.7 Hz, 1H), 5.70 (d, J = 4.1 Hz, 1H), 5.56 (d, J = 5.2 Hz, 1H), 5.31 (d, J = 5.8 Hz, 1H), 4.24 (qd, J = 12.2, 4.4 Hz, 2H), 4.13 – 3.99 (m, 2H), 3.93 (q, J = 5.6 Hz, 1H), 2.59 (p, J = 7.0 Hz, 1H), 1.10 (d, J = 7.0 Hz, 6H)。
it is understood that the preparation method of 4-thiouridine isobutyrate, an anti-hepatitis B virus compound, in the present invention includes, but is not limited to, the above six steps, each step includes, but is not limited to, the above two examples, and the various examples of each step can be arranged in any combination to finally synthesize the anti-hepatitis B virus compound, 4-thiouridine isobutyrate, in the present invention, without limitation.
In vitro anti-HBV activity assay of 4-thiouridine isobutyrate
The medicine for preventing or treating the hepatitis B virus, which is prepared from the anti-hepatitis B virus compound (4-thiouridine isobutyrate) prepared by the invention, is taken as a test medicine, and telbivudine and lamivudine are taken as positive control medicines and applied to a HepG2.2.15 cell strain containing the hepatitis B virus (provided by antiviral research laboratory of the institute of pharmacy of the Compound denier university) to carry out in-vitro anti-HBV virus efficacy evaluation test. The method comprises the following steps:
collecting HepG2.2.15 cell strain 1 bottle containing hepatitis B virus, digesting with pancreatin to obtain single cell suspension, counting with cell counting plate, and adjusting cell density to 2 × 10 with DMEM medium (Saimer Feishale Biochemical Co., Ltd.) containing 10% fetal calf serum5one/mL, inoculated in 96-well culture plates, 100uL per well. Placing the culture plate in a carbon dioxide incubator in CO2After culturing at 37 ℃ for 48 hours at a concentration of 5% and a temperature of 37 ℃, the supernatant was aspirated, 10. mu. mol/L of 4-thiouridine isobutyrate was added, and simultaneously, a culture solution of positive control drugs, telbivudine and lamivudine, was added, and a blank control well was additionally provided. 3 replicate wells were set for each concentration gradient and cell blank. Placing in carbon dioxide incubator, culturing at 37 deg.C for 3d/6d/9d, sucking supernatant, centrifuging, and collectingThe HBV-DNA content in the supernatant was determined by fluorescent quantitative PCR and the results are shown in Table 1.
TABLE 14 in vitro anti-HBV Activity test results for thiouridine isobutyrate
The results in table 1 show that 4-thiouridine isobutyrate, telbivudine and lamivudine all have good inhibitory action on HBV-DNA secreted by hepg2.2.15 cell strain, and the inhibitory rate of 4-thiouridine isobutyrate on HBV-DNA is higher than that of telbivudine and lamivudine, so that the problem of drug resistance of drugs such as telbivudine and lamivudine against hepatitis b virus can be effectively solved, and 4-thiouridine isobutyrate has high drug effect, low toxicity and low price, thus providing a direction for drug development for treating hepatitis b.
Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the spirit and scope of the present invention.
Claims (9)
1. An anti-hepatitis b virus compound characterized by: the molecular formula of the anti-hepatitis B virus compound is C13H18N2O6S, the structural formula is as follows:
。
2. the anti-hepatitis b virus compound of claim 1, wherein: the anti-hepatitis B virus compound is a yellow solid.
3. Use of the anti-hepatitis b virus compound according to claim 1 or 2 for the preparation of a medicament for the prophylaxis or treatment of hepatitis b virus-related disease.
4. The use of claim 3, wherein the medicament can be prepared into any pharmaceutical dosage form, including tablets, capsules, granules, pills, oral liquid and injections.
5. A method for preparing a compound for resisting hepatitis B virus is characterized in that: the method comprises the following steps:
step one
Reacting uracil 1, (2S,3R,4R,5R) -5- (acetoxymethyl) tetrahydrofuran-2, 3, 4-tri-acetic acid triester 2, N, O-bis (trimethylsilyl) acetamide and acetonitrile under the protection of argon, adding trimethylsilyl trifluoromethanesulfonate for continuous reaction, cooling, adding sodium bicarbonate and ethyl acetate, filtering and concentrating to obtain a compound 3;
step two
Dissolving the compound 3 in toluene, adding a Lawson reagent for reaction, and separating by first column chromatography to obtain a compound 4;
step three
Reacting the compound 4 with ammonia methanol to obtain a compound 5;
step four
Dissolving the compound 5 in acetone, adding p-toluenesulfonic acid monohydrate and 2, 2-dimethoxypropane for reaction, adding a pH adjusting reagent, adjusting the pH to be alkalescent, and performing first column chromatography separation to obtain a compound 6;
step five
Dissolving a compound 6 and dimethylaminopyridine in an organic reagent, reacting under the protection of nitrogen, sequentially adding triethylamine and isobutyric anhydride, continuing to react, adding methanol into a reaction liquid for quenching, and separating by a second column chromatography to obtain a compound 7, wherein the organic reagent is acetonitrile or tetrahydrofuran;
step six
And reacting the compound 7 with a formic acid solution, and separating by using a third column chromatography to obtain a compound 8, wherein the compound 8 is the anti-hepatitis B virus compound.
6. The method for producing an anti-hepatitis B virus compound according to claim 5, characterized in that: the concentration of the formic acid solution in the sixth step is 80% or 100%.
7. The method for producing an anti-hepatitis B virus compound according to claim 5, characterized in that: both said compound 3 and said compound 4 are yellow oils; the compound 5 was a dark yellow oil, and the compound 6, the compound 7, and the compound 8 were all yellow solids.
8. The method for producing an anti-hepatitis B virus compound according to claim 5, characterized in that: the first column chromatography, the second column chromatography and the third column chromatography are both silica gel column chromatography, the first column chromatography is dichloromethane/ethanol column chromatography, and the second column chromatography and the third column chromatography are petroleum ether/ethyl acetate column chromatography.
9. The method for producing an anti-hepatitis B virus compound according to claim 5, characterized in that: and the pH adjusting reagent in the fourth step is triethylamine.
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| CN113461760B (en) * | 2021-09-06 | 2021-12-10 | 南京颐媛生物医学研究院有限公司 | 4-thiodeoxythymidine derivative and anti-hepatitis B virus pharmaceutical application thereof |
| CN113501853B (en) * | 2021-09-13 | 2021-12-07 | 南京颐媛生物医学研究院有限公司 | 4-thiouracil deoxynucleoside phosphate and its antiviral medicine use |
| CN116199730A (en) * | 2023-04-24 | 2023-06-02 | 南京颐媛生物医学研究院有限公司 | 4-thiouracil ribonucleoside phosphate compound, and preparation method and application thereof |
| CN116217644B (en) * | 2023-04-24 | 2023-08-08 | 南京颐媛生物医学研究院有限公司 | Anti-coronavirus ribonucleoside compound, and preparation method and application thereof |
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Inventor after: Bao Fuyi Inventor after: Liu Dongping Inventor after: Zhang Zhi Inventor after: Ma Dinglai Inventor after: Zhou Ming Inventor after: Lu Dongxiao Inventor after: Li Runfeng Inventor after: Shi Xunlong Inventor after: Feng Li Inventor after: Tong Youen Inventor before: Bao Fuyi Inventor before: Liu Dongping Inventor before: Zhang Zhi Inventor before: Ma Dinglai Inventor before: Zhou Ming Inventor before: Lu Xiaodong Inventor before: Li Runfeng Inventor before: Shi Xunlong Inventor before: Feng Li Inventor before: Tong Youen |