CN109305979B - Application of 4-dimethylaminobenzaldehyde in preparation of NA inhibitor - Google Patents
Application of 4-dimethylaminobenzaldehyde in preparation of NA inhibitor Download PDFInfo
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- CN109305979B CN109305979B CN201710615507.1A CN201710615507A CN109305979B CN 109305979 B CN109305979 B CN 109305979B CN 201710615507 A CN201710615507 A CN 201710615507A CN 109305979 B CN109305979 B CN 109305979B
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- C07—ORGANIC CHEMISTRY
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The invention relates to 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] as shown in formula I]Triazolo [3,4-b][1,3,4]Thiadiazines and pharmaceutically acceptable salts thereof, pharmaceutical compositions and applications thereof in preparing influenza virus neuraminidase inhibitors.
Description
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to 6- (4-dimethylaminophenyl) -3- (6-methylpyridine-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine, a preparation method thereof and application thereof in preparing an anti-influenza virus neuraminidase inhibitor.
Background
The 4-dimethylaminobenzaldehyde is an intermediate of fine chemical engineering and pharmaceutical chemical engineering, and has wide application in the field of medicine. 4- [ (4-dimethylaminophenyl) methyleneamino group prepared by reacting 4-dimethylaminobenzaldehyde with 4-amino-3-phenyl-1H-1, 2, 4-triazole-5 (4H) -thione]-3-phenyl-1H-1, 2, 4-triazole-5 (4H) -thione (a); compound A has effect in treating Entamoeba histolytica, and its IC50Are all less than 0.5 mu M [ Bioorganic&Medicinal Chemistry Letters,2012,22(8):2768-2771]。
Reaction of 4-dimethylaminobenzaldehyde with 4-amino-3- (pyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione to prepare 4- [ (4-dimethylaminophenyl) methyleneamino ] -3- (pyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione (B) [ Journal of Pharma Research,2014,3(3):20-22 ]; the compound B has better antibacterial and antifungal activity; also has a good anticonvulsant action [ Indian Journal of Heterocyclic Chemistry,2005,15(1):15-18 ];
4- [ (4-dimethylaminophenyl) methyleneamino ] -3- (pyridin-4-yl) -1H-1,2, 4-triazole-5 (4H) -thione (C) was prepared by reacting 4-dimethylaminobenzaldehyde with 4-amino-3- (pyridin-4-yl) -1H-1,2, 4-triazole-5 (4H) -thione; compound C has good antibacterial and antifungal activity [ International Journal of Pharma & Bio Sciences,2010,1(1): 1-17; 818-821 of Indian Journal of Pharmaceutical Sciences,2004,66 (6); journal of the Chilean Chemical Society,2010,55(3):359-362 ]; compound C also has anti-inflammatory effects [ Archives of pharmaceutical Research,2011,34(8):1239-1250 ].
Zhengyu et al [ organic chemistry, 2011, 31(6), 912-; wherein, when the 6- (4-dimethylaminophenyl) -3- (3,4, 5-trimethoxyphenyl) -7-benzoyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine (D) is 10 mu mol/L, the inhibition rate of the 6- (4-dimethylaminophenyl) -3- (3,4, 5-trimethoxyphenyl) -7-benzoyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine (D) on PC 35.
Disclosure of Invention
The invention solves the technical problem of providing the application of 4-dimethylaminobenzaldehyde in preparing a compound with the activity of resisting influenza virus neuraminidase.
In order to solve the technical problem, the invention provides the following technical scheme:
in a first aspect of the present invention, there is provided 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine of formula i:
in the formula (I); r is selected from: hydrogen, C1～C2Alkyl, hydroxy, methoxy, ethoxy, fluoro, chloro, bromo or iodo.
Further, preferred compounds are selected from:
6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-benzoyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine, 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7- (4-chlorobenzoyl) -6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine or 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7- (4-methoxybenzoyl) -6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine.
The second aspect of the present invention provides a process for producing 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine according to the first aspect, which comprises reacting 4-dimethylaminobenzaldehyde as a raw material with 4-amino-3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione to produce 4- [ (4-dimethylaminophenyl) methyleneamino ] -3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thioketone, and then 6- (4-dimethylaminophenyl) -3- (6-methylpyridine-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine (I) is prepared by cyclization; the preparation reaction is as follows:
in the formula (I); r is selected from: hydrogen, C1～C2Alkyl, hydroxy, methoxy, ethoxy, fluoro, chloro, bromo or iodo.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of a 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine and a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and the pharmaceutically acceptable salt thereof in the pharmaceutical composition thereof is usually 0.1 to 95% by weight.
The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including O/W type, W/O type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion and liniment; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The fourth aspect of the technical scheme of the invention provides the 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine and pharmaceutically acceptable salts thereof in the first aspect of the invention and application of the pharmaceutical composition in the third aspect in preparing influenza virus neuraminidase inhibitors.
The beneficial technical effects are as follows:
the 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine is a compound with influenza virus neuraminidase inhibitory activity.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 4- [ (4-dimethylaminophenyl) methyleneamino ] -3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione
5.0mmol of 4-amino-3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione, 5.1mmol of 4- (dimethylamino) benzaldehyde and 10mL of acetic acid, refluxing for 5.0H, cooling, precipitating solid, vacuum filtering, and drying to obtain yellow solid 4- [ (4-dimethylaminophenyl) methyleneamino]-3-(6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione in a yield of 89%, m.p. 233-235 ℃.1H NMR(400MHz，CDCl3+D2O) δ 9.63(s, 1H, N ═ CH), 9.18(d, J ═ 2.0Hz, 1H, pyridine ring 2-H), 8.23(dd, J ═ 8.0Hz, 2.0Hz, 1H, pyridine ring 4-H), 7.75(d, J ═ 8.4Hz, 2H, C), 2.46H4 3，5-H)，7.29(s，1H)，6.72(d，J＝8.4Hz，2H，C6H4，2，6-H)，3.08(s，6H，CH3NCH3)，2.65(s，3H，CH3)。
Example 2
6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-benzoyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine
1.1mmol of 2-bromoacetophenone, 2.0mmol of triethylamine and 5ml of ethanol are stirred and dissolved, and 1.0mmol of 4- [ (4-dimethylaminophenyl) methyleneamino group is added]Refluxing (to complete reaction) 3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione, cooling to separate out solid, vacuum filtering, soaking the solid in 4ml of saturated sodium bicarbonate solution, stirring for 30min to remove triethylamine hydrobromide, vacuum filtering, and drying to obtain white solid 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-benzoyl-6, 7-dihydro-5H- [1,2,4]]Triazolo [3,4-b][1,3,4]Thiadiazine, yield 66%, m.p.197-199 deg.C.1H NMR(400MHz，CDCl3+D2O) δ 9.20(d, J ═ 2.0Hz, 1H, pyridine ring 2-H), 8.24(dd, J ═ 8.4Hz, 2.0Hz, 1H, pyridine ring 4-H), 7.95(d, J ═ 7.6Hz, 2H, C)6H5 2，6-H)，7.67(t，J＝7.6Hz，1H，C6H5 4-H)，7.54(t，J＝7.6Hz，2H，C6H5 3，5-H)，7.27～7.23(m，2H，C6H4) 7.22(d, J ═ 8.4Hz, 1H, pyridine ring 4-H), 6.60(d, J ═ 8.4Hz, 2H, C6H4)，5.24(d，J＝3.2Hz，1H，CH)，5.12(d，J＝3.2Hz，1H，CH)，2.90(s，6H，CH3NCH3)，2.61(s，3H，CH3)。
Example 3
6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7- (4-chlorobenzoyl) -6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine
Prepared as in example 2: 4- [ (4-dimethylaminophenyl) methyleneamino]Reaction of (E) -3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione with 2-bromo-1- (4-chlorophenyl) ethanone for 1.0H to give 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7- (4-chlorobenzoyl) -6, 7-dihydro-5H- [1,2,4] as a white solid]Triazolo [3,4-b][1,3,4]Thiadiazine, yield 74%, m.p.182 ~ 184 ℃.1H NMR(400MHz，CDCl3+D2O) δ 9.13(d, J ═ 1.6Hz, 1H, pyridine ring 2-H), 8.14(dd, J ═ 8.4Hz, 1.6Hz, 1H, pyridine ring 4-H), 7.86(d, J ═ 8.8Hz, 2H, C6H4)，7.37～7.30(m，4H，C6H4) 7.08(d, J ═ 8.4Hz, 1H, pyridine ring 5-H), 6.58(d, J ═ 8.8Hz, 2H, C6H4)，5.67(d，J＝6.4Hz，1H，CH)，4.83(d，J＝6.4Hz，1H，CH)，2.87(s，6H，CH3NCH3)，2.54(s，3H，CH3)。
Example 4
6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7- (4-methoxybenzoyl) -6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine
Prepared as in example 2: 4- [ (4-dimethylaminophenyl) methyleneamino]Reacting (E) -3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione with 2-bromo-1- (4-methoxyphenyl) ethanone for 1.5H to obtain white solid 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7- (4-methoxybenzoyl) -6, 7-dihydro-5H- [1,2,4]Triazole compoundsAnd [3,4-b ]][1,3,4]Thiadiazine, yield 59%, m.p.199 ~ 201 ℃.1H NMR(400MHz，CDCl3+D2O) δ 9.16(d, J ═ 1.6Hz, 1H, pyridine ring 2-H), 8.19(dd, J ═ 8.0Hz, 1.6Hz, 1H, pyridine ring 4-H), 7.92(d, J ═ 8.6Hz, 2H, C)6H4)，7.36(d，J＝8.4Hz，2H，C6H4) 7.12(d, J ═ 8.0Hz, 1H, pyridine ring 5-H), 6.91(d, J ═ 8.6Hz, 2H, C6H4)，6.59(t，J＝8.4Hz，2H，C6H4)，5.46(d，J＝4.8Hz，1H，CH)，4.94(d，J＝4.8Hz，1H，CH)，3.86(s，3H，OCH3)，2.88(s，6H，CH3NCH3)，2.58(s，3H，CH3)。13C NMR(100MHz，CDCl3)δ:193.87，164.67，159.67，150.77，150.46，147.84，143.69，135.32，131.28，128.19，127.33，122.89，122.68，119.92，114.39，112.47，58.71，55.64，41.33，40.25，24.44。
Example 5
Anti-influenza virus neuraminidase activity of 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine and salts thereof
1. Principle of experiment
The compound MUNANA is a specific substrate of neuraminidase, metabolites generated under the action of neuraminidase can generate 450nm fluorescence under the irradiation and excitation of 360nm, and the change of fluorescence intensity can sensitively reflect neuraminidase activity. The enzymes are all from A/PR/8/34 (H)1N1) A viral strain.
2. Experimental methods
In an enzyme reaction system, a sample with a certain concentration and influenza virus neuraminidase NA are suspended in a reaction buffer solution (pH6.5), a fluorescent substrate MUNANA is added to start the reaction system, and after incubation for 40 minutes at 37 ℃, a reaction termination solution is added to terminate the reaction. The fluorescence intensity values were determined under the parameters of an excitation wavelength of 360nm and an emission wavelength of 450 nm. The inhibition rate of the compound on the NA activity can be calculated according to the reduction of the fluorescence intensity.
3. Detecting a sample: EXAMPLES Compounds
4. Active results
The inhibition of neuraminidase by the compounds of the examples at a concentration of 40.0. mu.g/mL in the reaction system is shown in Table 1:
TABLE 16 inhibitory Activity of- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-aroyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine on neuraminidase
The 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine has good activity of resisting influenza virus neuraminidase and can be used for preparing influenza virus neuraminidase inhibitors.
Claims (5)
1. A class of 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazines having a chemical structural formula I and pharmaceutically acceptable salts thereof:
wherein R is selected from: hydrogen, C1～C2Alkyl, hydroxy, methoxy, ethoxy, fluoro, chloro, bromo or iodo.
2. The 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine of claim 1 selected from the group consisting of:
6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-benzoyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine, 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7- (4-chlorobenzoyl) -6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine or 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7- (4-methoxybenzoyl) -6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine.
3. The process for the preparation of 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine according to claim 1, wherein 4- [ (4-dimethylaminophenyl) methyleneamino ] -3- (6-methylpyridin-3-yl) -1H-1 by reacting 4-amino-3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione with 4-dimethylaminophenyl-7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3, 4] thiadiazine as a starting material, 2, 4-triazole-5 (4H) -thioketone, and then 6- (4-dimethylaminophenyl) -3- (6-methylpyridine-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine (I) is prepared by cyclization; the preparation reaction is as follows:
wherein R is as defined in claim 1.
4. The use of 6- (4-dimethylaminophenyl) -3- (6-methylpyridin-3-yl) -7-arylformyl-6, 7-dihydro-5H- [1,2,4] triazolo [3,4-b ] [1,3,4] thiadiazine according to claim 1 or 2, and pharmaceutically acceptable salts thereof for the preparation of influenza virus neuraminidase inhibitors.
5. A pharmaceutical composition comprising a compound of claim 1 or 2 and a pharmaceutically acceptable carrier.
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Effective date of registration: 20230626 Address after: No. 424, Phase I Complex Building, Changsha E Center, No. 18, Xiangtai Road, Liuyang Economic and Technological Development Zone, Changsha, Hunan 410000 Patentee after: Hunan Xianshi Pharmaceutical Co.,Ltd. Address before: H Hunan University, No.1 Lushan South Road, Changsha City, Hunan Province Patentee before: HUNAN University |