CARBAMATE-SUBSTITUTED STYRYL SULFONE COMPOUNDS, PREPARATION METHOD AND USE THEREOF

Abstract

Carbamate-substituted styryl sulfone compounds have a structure of general formula (I). The compounds not only has a significantly enhanced acetylcholinesterase inhibitory activity compared with carbamates as positive drugs, but also has a significantly enhanced therapeutic effect on Parkinson's disease compared with caffeic acid phenethyl ester compounds having similar structures.

##STR00001##

Claims

1. A compound of general formula I or pharmaceutically acceptable salts thereof: ##STR00036## wherein, at least one of R.sub.1 and R.sub.2 is independently selected from: carbamoyloxy unsubstituted or substituted by one or two R.sub.3; the other one of R.sub.1 and R.sub.2 is independently selected from: carbamoyloxy unsubstituted or substituted by one or two R.sub.3, C.sub.1-6 alkoxy unsubstituted or substituted by one to six halogen, —N(R.sub.4).sub.2 or —OR.sub.5, C.sub.1-6 alkylacyloxy or C.sub.7-10 arylacyloxy unsubstituted or substituted by one to six halogen, —N(R.sub.4).sub.2 or —OR.sub.5, sulfonyloxy substituted by C.sub.1-3 alkyl or C.sub.6-8 aryl, —OSi(R.sub.6).sub.3, and —OH; W is C.sub.1-6 alkylene or C.sub.2-6 alkenylene unsubstituted or substituted by one to three halogen, nitro, C.sub.1-6 alkyl, —N(R.sub.4).sub.2 or —OR.sub.5; each R is independently selected from halogen, nitro, —OR.sub.7, —N(R.sub.4).sub.2, and C.sub.1-6 alkyl, C.sub.6-10 aryl or C.sub.5-9 heteroaryl, unsubstituted or substituted by one to six halogen, nitro, —N(R.sub.4).sub.2 or —OR.sub.5; n is an integer from 0 to 5; wherein, each R.sub.3 is independently selected from: C.sub.1-6 saturated alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.6-10 aryl, C.sub.5-9 heteroaryl, C.sub.1-6 alkylacyl or C.sub.7-10 arylacyl, unsubstituted or substituted by one to six halogen, nitro, —N(R.sub.4).sub.2 or —OR.sub.5; sulfonyl substituted by C.sub.1-3 alkyl or C.sub.6-8 aryl; or two R.sub.3 together with the nitrogen atom to which they are attached form a 5- to 7-membered nitrogen-containing saturated heterocyclyl (for example, 1-pyrrolidinyl, 1-piperidyl, 4-morpholinyl or 1-piperazinyl) unsubstituted or substituted by one or two R.sub.6; each R.sub.4 is independently —H or C.sub.1-6 saturated alkyl; each R.sub.5 is independently selected from —H, C.sub.1-6 saturated alkyl, C.sub.2-4 alkenyl, C.sub.6-10 aryl, and C.sub.5-9 heteroaryl; each R.sub.6 is independently selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.6-8 aryl, unsubstituted or substituted by one to six halogen; each R.sub.7 is independently selected from H; C.sub.1-6 saturated alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.6-10 aryl, C.sub.5-9 heteroaryl, C.sub.1-6 alkylacyl or C.sub.7-10 arylacyl, unsubstituted or substituted by one to six halogen, N(R.sub.4).sub.2 or OR.sub.5; sulfonyl substituted by C.sub.1-3 alkyl or C.sub.6-8 aryl; and Si(R.sub.6).sub.3.

2. The compound or pharmaceutically acceptable salts thereof according to claim 1, characterized in that: at least one of R.sub.1 and R.sub.2 is independently selected from carbamoyloxy unsubstituted or substituted by one or two R.sub.3; the other one of R.sub.1 and R.sub.2 is independently selected from: carbamoyloxy unsubstituted or substituted by one or two R.sub.3, C.sub.1-6 alkoxy unsubstituted or substituted by one to six halogen or OR.sub.5, C.sub.1-6 alkylacyloxy unsubstituted or substituted by —N(R.sub.4).sub.2 or —OR.sub.5, sulfonyloxy substituted by C.sub.1-3 alkyl or C.sub.6-8 aryl, and —OSi(R.sub.6).sub.3.

3. The compound or pharmaceutically acceptable salts thereof according to claim 1, characterized in that: W is C.sub.1-6 alkylene or C.sub.2-6 alkenylene unsubstituted or substituted by one or two halogen, nitro, C.sub.1-6 alkyl or —OR.sub.5.

4. The compound or pharmaceutically acceptable salts thereof according to claim 1, characterized in that: each R is independently selected from halogen, nitro, —OR.sub.7, —N(R.sub.4).sub.2, and C.sub.1-6 alkyl or C.sub.6-10 aryl unsubstituted or substituted by one to six halogen, nitro or —OR.sub.5.

5. The compound or pharmaceutically acceptable salts thereof according to claim 1, characterized in that: n is an integer from 0 to 3.

6. The compound or pharmaceutically acceptable salts thereof according to claim 1, characterized in that: at least one of R.sub.1 and R.sub.2 is independently selected from carbamoyloxy unsubstituted or substituted by one or two R.sub.3; the other one of R.sub.1 and R.sub.2 is independently selected from: carbamoyloxy unsubstituted or substituted by one or two R.sub.3, C.sub.1-6 alkoxy unsubstituted or substituted by one to six halogen or OR.sub.5, C.sub.1-6 alkylacyloxy unsubstituted or substituted by —N(R.sub.4).sub.2 or —OR.sub.5, sulfonyloxy substituted by C.sub.1-3 alkyl or C.sub.6-8 aryl, and —OSi(R.sub.6).sub.3; W is C.sub.1-6 alkylene or C.sub.2-6 alkenylene unsubstituted or substituted by one or two halogen, nitro, C.sub.1-6 alkyl or —OR.sub.5; each R is independently selected from halogen, nitro, —OR.sub.7, —N(R.sub.4).sub.2, and C.sub.1-6 alkyl or C.sub.6-10 aryl unsubstituted or substituted by one to six halogen, nitro or —OR.sub.5; n is an integer from 0 to 3; wherein each R.sub.3 is independently selected from: C.sub.1-6 saturated alkyl, C.sub.6-10 aryl or C.sub.5-9 heteroaryl, unsubstituted or substituted by one to six halogen, nitro, —N(R.sub.4).sub.2 or —OR.sub.5; and sulfonyl substituted by C.sub.1-3 alkyl or C.sub.6-8 aryl.

7. A method for preparing a compound of general formula I according to claim 1, comprising: a) reacting a compound of general formula II with solid phosgene under an alkaline condition to produce a compound of general formula III; ##STR00037## b) reacting the compound of general formula III with NH.sub.3, R.sub.3NH.sub.2 or (R.sub.3).sub.2NH to produce the compound of general formula I, and ##STR00038## c) optionally, converting the compound of general formula I into its pharmaceutically acceptable salt; wherein at least one of R.sub.a and R.sub.b is independently —OH; the other one of R.sub.a and R.sub.b is independently selected from: —OH, C.sub.1-6 alkoxy unsubstituted or substituted by one to six halogen, —N(R.sub.4).sub.2 or —OR.sub.5, C.sub.1-6 alkylacyloxy or C.sub.7-10 arylacyloxy unsubstituted or substituted by one to six halogen, —N(R.sub.4).sub.2 or —OR.sub.5, sulfonyloxy substituted by C.sub.1-3 alkyl or C.sub.6-8 aryl, and —OSi(R.sub.6).sub.3; at least one of R.sub.c and R.sub.d is independently —OCOCl; the other one of R.sub.c and R.sub.d is independently selected from —OCOCl, C.sub.1-6 alkoxy unsubstituted or substituted by one to six halogen, —N(R.sub.4).sub.2 or —OR.sub.5, C.sub.1-6 alkylacyloxy or C.sub.7-10 arylacyloxy unsubstituted or substituted by one to six halogen, —N(R.sub.4).sub.2 or —OR.sub.5, sulfonyloxy substituted by C.sub.1-3alkyl or C.sub.6-8aryl, —OSi(R.sub.6).sub.3, and —OH; wherein the definitions for W, R, n, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as recited in any of claims 1 to 6.

8. A pharmaceutical composition, comprising a compound of general formula I or pharmaceutically acceptable salts thereof according to claim 1, as well as at least one pharmaceutically acceptable carrier.

9. (canceled)

10. A method for treating Parkinson's disease, comprising administrating a compound of general formula I or pharmaceutically acceptable salts thereof according to claim 1 or a pharmaceutical composition according to claim 8 to a patient in need thereof.

11. The compound or pharmaceutically acceptable salts thereof according to claim 1, wherein at least one of R.sub.1 and R.sub.2 is independently selected from carbamoyloxy, N-methylcarbamoyloxy, N,N-dimethylcarbamoyloxy, N,N-diethylcarbamoyloxy, N-methyl-N-ethylcarbamoyloxy, N-methyl-N-(2-methoxyethyl)carbamoyloxy, N-(5-methyl-2-nitroanilino)carbamoyloxy, N-(2-methyl-5-nitroanilino)carbamoyloxy, N-(p-methoxyphenyl)carbamoyloxy, N-(p-methylaminophenyl)carbamoyloxy, N-methyl-N-phenylcarbamoyloxy, N-methyl-N-p-chlorophenylcarbamoyloxy, N-methyl-N-p-bromophenylcarbamoyloxy, N-methyl-N-p-iodophenylcarbamoyloxy, N-thienylcarbamoyloxy, N-furylcarbamoyloxy, N-methyl-N-mesylcarbamoyloxy, and N-methyl-N-p-tosylcarbamoyloxy; the other one of R.sub.1 and R.sub.2 is independently selected from carbamoyloxy, N-methylcarbamoyloxy, N,N-dimethylcarbamoyloxy, N,N-diethylcarbamoyloxy, N-methyl-N-ethylcarbamoyloxy, N-methyl-N-(2-methoxyethyl)carbamoyloxy, N-(5-methyl-2-nitroanilino)carbamoyloxy, N-(2-methyl-5-nitroanilino)carbamoyloxy, N-(p-methoxyphenyl)carbamoyloxy, N-(p-methylaminophenyl)carbamoyloxy, N-methyl-N-phenylcarbamoyloxy, N-methyl-N-p-chlorophenylcarbamoyloxy, N-methyl-N-p-bromophenylcarbamoyloxy, N-methyl-N-p-iodophenylcarbamoyloxy, N-thienylcarbamoyloxy, N-furylcarbamoyloxy, N-methyl-N-mesylcarbamoyloxy, and N-methyl-N-p-tosylcarbamoyloxy, or selected from methoxy, ethoxy, t-butoxy, trifluoromethoxy, 2,3-dibromobutoxy, 2-methoxyethoxy, 2-benzyloxyethoxy, acetyloxy, propionyloxy, pivaloyloxy, methoxyacetyloxy, 4-methoxybutyryloxy, 3-aminopropionyloxy, 2-aminopropionyloxy, mesyloxy, ethylsulfonyloxy, p-tosyloxy, trimethylsiloxy, triphenylsiloxy, chloromethyl(dimethyl)siloxy, and dimethoxy(phenyl)siloxy.

12. The compound or pharmaceutically acceptable salts thereof according to claim 1, wherein W is selected from —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —CH(F)—, —CH(Cl)—, —CH(Br)—, —CF.sub.2—, —CH(Cl)CH.sub.2—, —CH.sub.2CH(Cl)—, —CH(Cl)CH(Cl)—, —CH.sub.2CH(Cl)CH.sub.2—, —CH(NO.sub.2)—, —CH.sub.2CH(NO.sub.2)—, —CH.sub.2CH(NO.sub.2)CH.sub.2—, —CH(CH.sub.3)—, —CH(CH.sub.3)CH.sub.2—, —CH(OCH.sub.3)—, —CH.sub.2CH(OCH.sub.2CH.sub.3)CH(OCH.sub.2CH.sub.3)—, —CH.sub.2CH(OCH.sub.2C.sub.6H.sub.5)CH.sub.2—, —CH.sub.2CH(OH)—, —CH═CH—, —CH.sub.2CH═CHCH.sub.2—, —CH═CHCH.sub.2—, —CH═C(CH.sub.3)—, and —CH(Cl)CH═CHCH.sub.2—.

13. The compound or pharmaceutically acceptable salts thereof according to claim 1, wherein each R is independently selected from fluoro, chloro, bromo, iodo, nitro, hydroxy, methoxy, ethoxy, isopropoxy, t-butoxy, 2,2,2-trifluoroethoxy, 2-methylaminoethoxy, N,N-dimethylaminomethoxy, allyloxy, phenoxy, benzyloxy, p-methylaminobenzyloxy, 3,4-dimethoxybenzyloxy, formyloxy, acetyloxy, dimethylaminoacetyloxy, benzoyloxy, phenylacetyloxy, p-methoxyphenylacetyloxy, trimethylsiloxy, triphenylsiloxy, chloromethyl(dimethyl)siloxy, dimethoxy(phenyl)siloxy, amino, methylamino, ethylamino, diisopropylamino, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, phenyl, benzyl, phenethyl, p-chlorophenyl, p-nitrophenyl, and 3,4-dimethoxyphenyl.

14. The compound or pharmaceutically acceptable salts thereof according to claim 5, wherein each R.sub.3 is independently selected from: C.sub.1-6 saturated alkyl, C.sub.6-10 aryl or C.sub.5-9 heteroaryl, unsubstituted or substituted by one to six halogen, nitro, —N(R.sub.4).sub.2 or —OR.sub.5; and sulfonyl substituted by C.sub.1-3alkyl or C.sub.6-8 aryl.

15. The compound or pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is selected from the following compounds: ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043##

16. The method for preparing the compound of general formula I according to claim 7, wherein the base used in said a) is a moderately alkaline or weakly alkaline inorganic or organic base, wherein the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium acetate, and cesium carbonate; and the organic base is selected from pyridine, triethylamine, 4-dimethylaminopyridine, DBU (1,8-diazabicycloundec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), and MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene).

17. The method for preparing the compound of general formula I according to claim 7, wherein the base or no base is used in said b), and when a base is used, the base is a moderately alkaline or weakly alkaline inorganic or organic base, wherein the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium acetate, and cesium carbonate; and the organic base is selected from pyridine, triethylamine, 4-dimethylaminopyridine, DBU (1,8-diazabicycloundec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), and MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene).

Description

DESCRIPTION OF EMBODIMENTS

[0058] In order to further illustrate the invention, a series of Examples are provided below. These Examples are completely illustrative, and only used to describe the invention in detail and should not be construed as limiting the invention. Unless otherwise specified, in the following Examples, the expression “the solvent is subjected to rotary evaporation under reduced pressure” generally refers to “the solvent is evaporated to dryness with a rotary evaporator under the condition of reduced pressure by a water pump.”

[0059] The starting materials in the invention can be synthesized by the method in CN104230770B or according to methods known in the art, or can be directly purchased from reagent companies such as J&K Scientific Co., Ltd., Aladdin Reagent (Shanghai) Co., Ltd., and Beijing Ouhe Technology Co., Ltd.

Example 1: Preparation of (E)-4-{2-[(4-trifluoromethylphenyl)mesyl]ethenyl}-1,2-phenylenebis(diethylcarbamate) (Compound B1-1)

Step 1. Preparation of (E)-4-{2-[(4-trifluoromethylphenyl)mesyl]ethenyl}-1,2-phenylenebischloroformate (Compound B1-1-a)

[0060] ##STR00010##

[0061] The solid phosgene (475 mg, 1.6 mmol) was dissolved in dichloromethane (10 mL), cooled to 0° C. in an ice-water bath, and a solution of (E)-4-{2-[(4-trifluoromethylphenyl)mesyl]ethenyl}benzene-1,2-diol (860 mg, 2.4 mmol) in dichloromethane (20 mL) was slowly dropwise added over 30 min. After stirring for 15 min, a solution of pyridine (0.40 mL, 5.0 mmol) in dichloromethane (5 mL) was slowly dropwise added over 15 min. In the process of the above dropwise addition, the temperature of the reaction solution should be controlled to be no higher than 5° C. After the dropwise addition was completed, the reaction solution was allowed to be naturally warmed to room temperature, and reacted under stirring for 2 h. The reaction solution was washed with pre-cooled water (25 mL×3 times), dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain Compound B1-1-a, as a yellowish oily liquid, which can be used in the next step without purification.

Step 2. Preparation of (E)-4-{2-[(4-trifluoromethylphenyl)mesyl]ethenyl}-1,2-phenylenebis(diethylcarbamate) (Compound B1-1)

[0062] ##STR00011##

[0063] Compound B1-1-a obtained in step 1 was dissolved in tetrahydrofuran (5 mL), and added to a solution of diethylamine (0.52 mL, 5.0 mmol) in tetrahydrofuran (10 mL) at 0-5° C. The reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed under TLC monitoring, 30 mL of water was added, and extracted with diethyl ether (25 mL×3 times). The organic phases were combined, successively washed with 0.01 mol/L aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution (each 50 mL), dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate system, v/v=9:1), to give a beige white solid product, i.e., Compound B1-1 (606 mg, yield: 45% over two steps).

[0064] Melting point: 107-109° C.

[0065] .sup.1H NMR (CDCl.sub.3) δ:1.19 (t, 12H, J=8.1 Hz, NCH.sub.2CH.sub.3), 3.23 (q, 8H, J=8.1 Hz, NCH.sub.2CH.sub.3), 4.65 (s, 2H, SO.sub.2CH.sub.2), 7.06-7.17 (m, 3H, CH═CHSO.sub.2, ArH), 7.35-7.41 (m, 3H, ArH), 7.52 (m, 2H, ArH), 7.88 (d, 1H, J=15.0 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:12.7 (NCH.sub.2CH.sub.3*4), 42.4 (NCH.sub.2CH.sub.3*4), 62.8 (SO.sub.2CH.sub.2), 118.7 (CH═CHSO.sub.2), 120.6 (ArC), 121.7 (ArC), 124.2 (CF.sub.3), 125.8 (ArC), 126.1 (ArC*2), 128.8 (ArC*2), 129.5 (ArC), 130.1 (ArC), 132.0 (ArC), 134.5 (CH═CHSO.sub.2), 143.6 (ArC), 145.1 (ArC), 154.3 (NCOO), 154.8 (NCOO); HRMS-EI(M+):C.sub.26H.sub.31F.sub.3N.sub.2O.sub.6S, calcd: 556.1855, found: 556.1865.

Example 2: Preparation of (E)-4-[2-(3-phenylpropylsulfonyl)ethenyl]-1,2-phenylenebis(diethylcarbamate) (Compound C1-1)

[0066] ##STR00012##

[0067] With (E)-4-{2-[(3-phenylpropyl)sulfonyl]ethenyl}benzene-1,2-diol as starting material and in accordance with the preparation method in Example 1, Compound C1-1 was prepared by two steps, as a light yellow solid (yield: 42% over two steps).

[0068] Melting point: 96-99° C.

[0069] .sup.1H NMR (CDCl.sub.3) δ:1.26 (m, 12H, NCH.sub.2CH.sub.3), 2.19 (tt, 2H, J=7.6, 5.4 Hz, SO.sub.2CH.sub.2CH.sub.2CH.sub.2), 2.81 (t, 2H, J=7.6 Hz, SO.sub.2CH.sub.2CH.sub.2CH.sub.2), 3.06 (t, 2H, J=5.4 Hz, SO.sub.2CH.sub.2CH.sub.2CH.sub.2), 3.43 (m, 8H, NCH.sub.2CH.sub.3), 6.77 (d, 1H, J=15.4 Hz, CH═CHSO.sub.2), 7.20-7.42 (m, 8H, ArH), 7.54 (d, 1H, J=15.4 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:13.3 (NCH.sub.2{right arrow over (C)}H.sub.3*2), 14.1 (NCH.sub.2CH.sub.3*2), 24.2 (SO.sub.2CH.sub.2CH.sub.2CH.sub.2), 34.2 (SO.sub.2CH.sub.2CH.sub.2CH.sub.2), 42.0 (NCH.sub.2CH.sub.3*2), 42.4 (NCH.sub.2CH.sub.3*2), 54.4 (SO.sub.2CH.sub.2CH.sub.2CH.sub.2), 123.4 (ArC), 124.3 (ArC), 125.0 (CH═CHSO.sub.2), 126.5 (ArC), 126.6 (ArC), 128.5 (ArC*2), 128.7 (ArC*2), 130.1 (ArC), 139.9 (CH═CHSO.sub.2), 143.6 (ArC), 143.9 (ArC), 146.0 (ArC), 152.8 (NCOO), 153.0 (NCOO); HRMS-EI(M+):C.sub.27H.sub.36N.sub.2O.sub.6S, calcd: 516.2294, found: 516.2282.

Example 3: Preparation of (E)-4-{2-[(4-chlorophenyl)mesyl]ethenyl}-1,2-phenylenebis(diethylcarbamate) (Compound D1-1)

[0070] ##STR00013##

[0071] With (E)-4-{2-[(4-chlorophenyl)mesyl]ethenyl}benzene-1,2-diol as starting material and in accordance with the preparation method in Example 1, Compound D1-1 was prepared by two steps, as a light yellow solid (yield: 53% over two steps).

[0072] Melting point: 108-110° C.

[0073] .sup.1H NMR (CDCl.sub.3) δ:1.28 (m, 12H, NCH.sub.2CH.sub.3), 3.46 (m, 8H, NCH.sub.2CH.sub.3), 4.31 (s, 2H, SO.sub.2CH.sub.2), 6.71 (d, 1H, J=15.4 Hz, CH═CHSO.sub.2), 7.32-7.45 (m, 8H, CH═CHSO.sub.2, ArH); .sup.13C NMR (CDCl.sub.3) δ:13.3 (NCH.sub.2CH.sub.3), 14.2 (NCH.sub.2CH.sub.3), 42.0 (NCH.sub.2CH.sub.3), 42.4 (NCH.sub.2CH.sub.3), 61.2 (SO.sub.2CH.sub.2), 123.5 (ArC), 124.1 (CH═CHSO.sub.2), 124.4 (ArC), 126.5 (ArC), 129.2 (ArC*2), 130.0 (ArC), 132.3 (ArC*2), 134.9 (ArC), 135.3 (CH═CHSO.sub.2), 144.0 (ArC), 144.7 (ArC), 146.1 (ArC), 152.8 (NCOO), 153.0 (NCOO); HRMS-EI(M+):C.sub.25H.sub.31ClN.sub.2O.sub.6S, calcd: 522.1591, found: 522.1585.

Example 4: Preparation of (E)-4-{2-[(4-t-butylphenyl)mesyl]ethenyl}-1,2-phenylenebis(diethylcarbamate) (Compound G1-1)

[0074] ##STR00014##

[0075] With (E)-4-{2-[(4-t-butylphenyl)mesyl]ethenyl}benzene-1,2-diol as starting material and in accordance with the preparation method in Example 1, Compound G1-1 was prepared by two steps, as a white solid (yield: 56% over two steps).

[0076] Melting point: 95-98° C.

[0077] .sup.1H NMR (CDCl.sub.3) δ: 1.23 (m, 12H, NCH.sub.2CH.sub.3), 1.36 (m, 9H, t-Bu), 3.42 (m, 8H, NCH.sub.2CH.sub.3), 4.30 (s, 2H, SO.sub.2CH.sub.2), 6.70 (d, 1H, J=15.5 Hz, CH═CHSO.sub.2), 7.24-7.33 (m, 5H, ArH), 7.40 (d, 1H, J=15.5 Hz, CH═CHSO.sub.2), 7.45 (d, 2H, J=7.6 Hz, ArH); .sup.13C NMR (CDCl.sub.3) δ: 13.3 (NCH.sub.2CH.sub.3), 14.1 (NCH.sub.2CH.sub.3), 31.3 (C(CH.sub.3).sub.3), 34.7 (C(CH.sub.3).sub.3), 42.0 (NCH.sub.2CH.sub.3), 42.4 (NCH.sub.2CH.sub.3), 61.6 (SO.sub.2CH.sub.2), 123.4 (ArC), 124.3 (ArC), 124.6 (ArC), 124.9 (CH═CHSO.sub.2), 125.9 (ArC*2), 126.4 (ArC), 130.2 (ArC), 130.6 (ArC*2), 143.9 (ArC), 144.1 (CH═CHSO.sub.2), 145.9 (ArC), 152.0 (t-Bu-ArC), 152.8 (NCOO), 153.0 (NCOO); HRMS-EI(M+):C.sub.29H.sub.40N.sub.2O.sub.6S, calcd: 544.2607, found: 544.2604.

Example 5: Preparation of (E)-4-{2-[2-chloro-2-(4-chloro-3-nitrophenyl)ethylsulfonyl]ethenyl}-2-hydroxyphenyl-N-methylcarbamate (Compound E2-2)

Step 1. Preparation of (E)-4-{2-[2-chloro-2-(4-chloro-3-nitrophenyl)ethylsulfonyl]ethenyl}-2-hydroxyphenylchloroformate (Compound E2-2-a)

[0078] ##STR00015##

[0079] The solid phosgene (237 mg, 0.8 mmol) was dissolved in dichloromethane (10 mL), cooled to 0° C. in an ice-water bath, and a solution of (E)-4-{2-[2-chloro-2-(4-chloro-3-nitrophenyl)ethylsulfonyl]ethenyl}benzene-1,2-diol (1003 mg, 2.4 mmol) in dichloromethane (20 mL) was slowly dropwise added over 30 min. After stirring for 15 min, a solution of pyridine (0.20 mL, 2.5 mmol) in dichloromethane (5 mL) was slowly dropwise added over 15 min. In the process of the above dropwise addition, the temperature of the reaction solution should be controlled to be no higher than 5° C. After the dropwise addition was completed, the reaction solution was allowed to be naturally warmed to room temperature, and reacted under stirring for 2 h. The reaction solution was washed with pre-cooled water (25 mL×3 times), dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain Compound E2-2-a, as a yellow oily liquid, which can be used in the next step without purification.

Step 2. Preparation of (E)-4-{2-[2-chloro-2-(4-chloro-3-nitrophenyl)ethylsulfonyl]ethenyl}-2-hydroxyphenyl-N-methylcarbamate (Compound E2-2)

[0080] ##STR00016##

[0081] Compound E2-2-a obtained in step 1 was dissolved in tetrahydrofuran (5 mL), and added to a solution of methylamine (2 M solution in tetrahydrofuran, 1.25 mL, 2.5 mmol) in tetrahydrofuran (10 mL) at 0-5° C. The reaction was slowly warmed to room temperature and stirred overnight. After the reaction was completed under TLC monitoring, 30 mL of water was added, and extracted with diethyl ether (25 mL×3 times). The organic phases were combined, successively washed with 0.01 mol/L aqueous hydrochloric acid solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution (each 50 mL), dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate system, v/v=15:2), to give a light yellow solid product, i.e., Compound E2-2 (403 mg, yield: 35% over two steps).

[0082] Melting point: 211-213° C.

[0083] .sup.1H NMR (CDCl.sub.3) δ:2.89 (s, 3H, NHCH.sub.3), 3.85 (dd, 1H, J=12.5, 7.0 Hz, SO.sub.2CH.sub.2), 4.11 (dd, 1H, J=12.5, 7.0 Hz, SO.sub.2CH.sub.2), 4.82 (brs, 1H, CONH), 5.67 (m, 1H, CHCl), 6.87 (d, 1H, J=7.5 Hz, ArH), 6.95-7.33 (m, 6H, CH═CHSO.sub.2, ArOH, ArH), 7.41 (d, 1H, J=7.4 Hz, ArH), 7.63 (d, 1H, J=15.5 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:27.5 (NHCH.sub.3), 49.3 (CHCl), 62.5 (SO.sub.2CH.sub.2), 115.2 (ArC), 120.9 (CH═CHSO.sub.2), 121.6 (ArC), 122.7 (ArC), 126.1 (ArC), 125.9 (ArC), 128.7 (ArC), 130.2 (ArC), 130.8 (ArC), 134.9 (ArC), 139.3 (ArC—OCO), 142.5 (ArC—NO.sub.2), 143.8 (CH═CHSO.sub.2), 149.1 (ArC—OH), 155.2 (NCOO); HRMS-EI(M+):C.sub.18H.sub.16Cl.sub.2N.sub.2O.sub.7S, calcd: 474.0055, found: 474.0072.

Example 6: Preparation of (E)-2-methoxy-4-{2-[(3,4,5-trimethoxyphenyl)mesyl]ethenyl}-phenyl-N,N-diphenylcarbamate (Compound K3-3)

[0084] ##STR00017##

[0085] With (E)-2-methoxy-4-{2-[(3,4,5-trimethoxyphenyl)mesyl]ethenyl}phenol as starting material and in accordance with the preparation method in Example 5, Compound K3-3 was prepared by two steps, as a beige white solid product (yield: 51% over two steps).

[0086] Melting point: 195-197° C.

[0087] .sup.1H NMR (CDCl.sub.3) δ:3.85 (m, 12H, OCH.sub.3), 4.66 (s, 2H, SO.sub.2CH.sub.2), 6.75-7.21 (m, 6H, CH═CHSO.sub.2, ArH), 7.35-7.51 (m, 10H, N—ArH), 7.90 (d, 1H, J=15.5 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:56.0 (OCH.sub.3*2), 56.2 (OCH.sub.3), 59.3 (SO.sub.2CH.sub.2), 60.7 (OCH.sub.3), 108.9 (ArC*2), 111.4 (ArC), 120.5 (CH═CHSO.sub.2), 122.3 (ArC), 122.6 (ArC), 126.9 (ArC*4), 127.2 (ArC), 128.1 (ArC*2), 129.9 (ArC), 130.2 (ArC*4), 137.1 (ArC), 137.5 (CH═CHSO.sub.2), 141.2 (ArC*2), 144.6 (ArC), 149.9 (ArC*2), 150.7 (ArC), 154.7 (NCOO); HRMS-EI(M+):C.sub.32H.sub.31NO.sub.8S, calcd: 589.1770, found: 589.1761.

Example 7: Preparation of 4-{(E)-2-[(E)-3-(4-allyloxyphenyl)prop-1-en-1-yl]sulfonylethenyl}-2-(N,N-diallylcarbamoyloxy)phenyl acetate (Compound K1-4)

[0088] ##STR00018##

[0089] With 4-{(E)-2-[(E)-3-(4-allyloxyphenyl)prop-1-en-1-yl]sulfonylethenyl}-2-hydroxyphenyl acetate as starting material and in accordance with the preparation method in Example 5, Compound K1-4 was prepared by two steps, as a white solid (yield: 38% over two steps).

[0090] Melting point: 146-149° C.

[0091] .sup.1H NMR (CDCl.sub.3) δ:2.54 (s, 3H, CH.sub.3CO), 3.42 (m, 2H, CH.sub.2Ar), 3.66 (d, 4H, J=6.1 Hz, CH.sub.2═CHCH.sub.2N), 4.63 (d, 2H, J=6.0 Hz, CH.sub.2═CHCH.sub.2O), 5.19-5.53 (m, 6H, CH.sub.2═CHCH.sub.2N, CH.sub.2═CHCH.sub.2O), 5.89-6.05 (m, 3H, CH.sub.2═CHCH.sub.2N, CH.sub.2═CHCH.sub.2O), 6.36 (d, 1H, J=15.2 Hz, SO.sub.2CH═CHCH.sub.2), 6.73-7.30 (m, 8H, ArCH═CHSO.sub.2, ArH), 7.46 (dt, 1H, j=15.1 Hz, 6.2 Hz, SO.sub.2CH═CHCH.sub.2), 8.05 (d, 1H, J=15.3 Hz, ArCH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:20.3 (CH.sub.3CO), 38.1 (CH.sub.2Ar), 49.8 (CH.sub.2═CHCH.sub.2N*2), 68.5 (CH.sub.2═CHCH.sub.2O), 115.0 (ArC*2), 117.5 (CH.sub.2═CHCH.sub.2N*2), 117.9 (CH.sub.2═CHCH.sub.2O), 122.1 (ArC), 122.6 (ArC), 124.7 (ArC), 126.1 (ArCH═CHSO.sub.2), 129.1 (ArC*2), 130.8 (ArC), 132.7 (CH.sub.2═CHCH.sub.2N*2), 133.1 (CH.sub.2═CHCH.sub.2O), 133.9 (ArCH═CHSO.sub.2), 135.0 (ArC), 137.4 (SO.sub.2CH═CHCH.sub.2), 142.1 (ArC), 142.9 (ArC), 143.3 (SO.sub.2CH═CHCH.sub.2), 153.6 (NCOO), 157.4 (ArC), 168.6 (CH.sub.3COO); HRMS-EI(M+):C.sub.29H.sub.31NO.sub.7S, calcd: 537.1821, found: 537.1804.

Example 8: Preparation of 4-{(E)-1-[(E)-3-(chloromethyldimethylsiloxy)-4-(N,N-dimethylcarbamoyloxy)styrylsulfonyl]prop-1-en-2-yl}phenyl-2-(4-methoxyphenyl) acetate (Compound P1-7)

[0092] ##STR00019##

[0093] With 4-{(E)-1-[(E)-3-(chloromethyldimethylsiloxy)-4-hydroxystyrylsulfonyl]prop-1-en-2-yl}phenyl-2-(4-methoxyphenyl) acetate as starting material and in accordance with the preparation method in Example 5, Compound P1-7 was prepared by two steps, as a white solid (yield: 43% over two steps).

[0094] Melting point: 123-125° C.

[0095] .sup.1H NMR (CDCl.sub.3) δ:0.13 (s, 6H, SiCH.sub.3*2), 2.24 (s, 3H, CH.sub.3C═CH), 2.72 (s, 2H, ClCH.sub.2Si), 3.15 (s 3H, CH.sub.3N), 3.27 (s 3H, CH.sub.3N), 3.81 (s, 3H, OCH.sub.3), 4.11 (s, 2H, OCOCH.sub.2), 6.75 (SO.sub.2CH═C), 6.85-7.05 (m, 6H, CH═CHSO.sub.2, ArH), 7.20-7.32 (m, 6H, ArH), 8.08 (CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:−1.8 (SiCH.sub.3*2), 15.3 (CH.sub.3C═CH), 29.8 (ClCH.sub.2Si), 36.8 (NCH.sub.3*2), 41.2 (OCOCH.sub.2), 55.3 (OCH.sub.3), 114.4 (ArC*2), 116.7 (ArC), 121.0 (ArC), 121.3 (ArC*2), 121.5 (ArC), 124.9 (CH═CHSO.sub.2), 126.7 (ArC), 126.9 (ArC*2), 128.7 (SO.sub.2CH═C), 130.0 (ArC), 130.5 (ArC*2), 131.7 (CH═CHSO.sub.2), 137.6 (ArC), 142.2 (ArC), 147.8 (ArC), 148.8 (CH.sub.3C═CH), 150.9 (ArC), 154.8 (NCOO), 158.0 (ArC), 169.7 (OCOCH.sub.2); HRMS-EI(M+):C.sub.32H.sub.36ClNO.sub.8SSi, calcd: 657.1619, found: 657.1633.

Example 9: Preparation of (E)-4-{2-[3-(4-benzyloxy-3-hydroxyphenyl)-2,3-diethoxypropyl]sulfonylethenyl}-2-[N-(4-methylaminophenyl)carbamoyloxy]phenyl acetate (Compound H2-4)

[0096] ##STR00020##

[0097] With (E)-4-{2-[3-(4-benzyloxy-3-hydroxyphenyl)-2,3-diethoxypropyl]sulfonylethenyl}-2-hydroxyphenyl acetate as starting material and in accordance with the preparation method in Example 5, Compound H2-4 was prepared by two steps, as a light yellow solid (yield: 18% over two steps).

[0098] Melting point: 182-183° C.

[0099] .sup.1H NMR (CDCl.sub.3) δ:1.19 (m, 6H, OCH.sub.2CH.sub.3*2), 2.49 (s, 3H, CH.sub.3CO), 2.70 (s, 3H, CH.sub.3NH), 3.03 (m, 2H, OCH.sub.2CH.sub.3), 3.40 (m, 1H, SO.sub.2CH.sub.2), 3.62 (m, 1H, SO.sub.2CH.sub.2), 3.81 (dq, 1H, J=12.5, 8.1 Hz, OCH.sub.2CH.sub.3), 4.19 (dq, 1H, J=12.5, 8.1 Hz, OCH.sub.2CH.sub.3), 4.30 (brs, 1H, CH.sub.3NH), 4.55 (m, 1H, SO.sub.2CH.sub.2CH), 4.72 (m, 1H, OCHAr), 5.22 (m, 2H, OCH.sub.2Ph), 5.90 (brs, 1H, Ar—OH), 6.48 (d, 2H, J=7.5 Hz, ArH), 6.68-6.81 (m, 3H, NHCOO, ArH), 6.98-7.09 (m, 2H, ArH), 7.16 (d, 1H, J=15.3 Hz, CH═CHSO.sub.2), 7.25-7.45 (m, 9H, ArH), 8.11 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:15.3 (OCH.sub.2CH.sub.3), 15.4 (OCH.sub.2CH.sub.3), 20.5 (CH.sub.3CO), 29.8 (CH.sub.3NH), 50.7 (SO.sub.2CH.sub.2), 64.8 (OCH.sub.2CH.sub.3), 65.2 (OCH.sub.2CH.sub.3), 70.7 (OCH.sub.2Ph), 71.9 (SO.sub.2CH.sub.2CH), 81.5 (OCHAr), 114.9 (ArC), 115.8 (ArC), 116.9 (CH═CHSO.sub.2), 117.1 (ArC*2), 119.9 (ArC), 121.9 (ArC), 122.3 (ArC), 122.8 (ArC*2), 125.3 (ArC), 127.6 (ArC*2), 127.8 (ArC), 128.5 (ArC*2), 129.8 (ArC), 133.0 (ArC), 133.3 (ArC), 134.2 (CH═CHSO.sub.2), 135.1 (ArC), 142.3 (ArC), 143.2 (ArC), 146.1 (ArC), 146.2 (ArC), 151.6 (ArC), 154.1 (NHCOO), 168.6 (CH.sub.3CO); HRMS-EI(M+):C.sub.38H.sub.42N.sub.2O.sub.10S, calcd: 718.2560, found: 718.2537.

Example 10: Preparation of (E)-2-[(methylamino)methoxy]-4-{2-[1-(4′-nitro-[1,1′-biphenyl]-4-yl)ethylsulfonyl]ethenyl}phenylcarbamate (Compound M1-3)

[0100] ##STR00021##

[0101] With (E)-2-[(methylamino)methoxy]-4-{2-[1-(4′-nitro-[1,1′-biphenyl]-4-yl)ethylsulfonyl]ethenyl}phenol as starting material and in accordance with the preparation method in Example 5, Compound M1-3 was prepared by two steps, as a yellow solid (yield: 33% over two steps).

[0102] Melting point: 256-258° C.

[0103] .sup.1H NMR (CDCl.sub.3) δ:1.12 (brs, 1H, CH.sub.3NH), 1.73 (d, 3H, J=6.8 Hz, CHCH.sub.3), 2.44 (s, 3H, CH.sub.3NH), 4.39 (q, 1H, J=6.8 Hz, CHCH.sub.3), 4.89 (brs, 2H, NH.sub.2COO), 5.02 (d, 1H, J=12.5 Hz, NHCH.sub.2O), 5.53 (d, 1H, J=12.5 Hz, NHCH.sub.2O), 6.88 (d, 1H, J=7.6 Hz, ArH), 7.12-7.33 (m, 5H, CH═CHSO.sub.2, ArH), 7.61 (d, 2H, J=7.6 Hz, ArH), 7.68 (m, 4H, ArH), 8.12 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:15.3 (CH.sub.3CH), 35.0 (CH.sub.3NH), 67.5 (CH.sub.3CH), 82.1 (NHCH.sub.2O), 113.8 (ArC), 122.6 (ArC), 123.9 (ArC), 124.6 (CH═CHSO.sub.2), 126.7 (ArC*2), 128.2 (ArC*2), 128.9 (ArC*2), 129.5 (ArC*2), 130.9 (ArC), 134.7 (ArC), 136.0 (ArC), 137.5 (ArC), 138.5 (CH═CHSO.sub.2), 138.9 (ArC), 142.7 (ArC), 148.5 (ArC), 156.1 (NH.sub.2COO); HRMS-EI(M+):C.sub.25H.sub.25N.sub.3O.sub.7S, calcd: 511.1413, found: 511.1418.

Example 11: Preparation of (E)-5-{2-[(4-[pyridin-2-yl-oxy]phenyl)difluoromethylsulfonyl]ethenyl}-2-[N-(2,2,2-trifluoroacetyl)carbamoyloxy]phenyl-2,2,3,3,3-pentafluoropropionate (Compound L1-4)

[0104] ##STR00022##

[0105] With (E)-5-{2-[(4-[pyridin-2-yl-oxy]phenyl)difluoromethylsulfonyl]ethenyl}-2-hydroxyphenyl-2,2,3,3,3-pentafluoropropionate as starting material and in accordance with the preparation method in Example 5, Compound L1-4 was prepared by two steps, as a light yellow solid (yield: 40% over two steps).

[0106] Melting point: 153-156° C.

[0107] .sup.1H NMR (CDCl.sub.3) δ:6.36 (brs, 1H, CF.sub.3CONH), 6.79-6.91 (m, 2H, ArH), 7.03-7.09 (m, 3H, ArH), 7.16 (d, 1H, J=15.1 Hz, CH═CHSO.sub.2), 7.23-7.32 (m, 1H, ArH), 7.33-7.54 (m, 4H, ArH), 8.09 (d, 1H, J=15.1 Hz, CH═CHSO.sub.2), 8.79 (d, 1H, J=5.0 Hz, ArH); .sup.13C NMR (CDCl.sub.3) δ:9.3 (CF.sub.3CF.sub.2CO), 23.9 (CF.sub.3CO), 27.2 (CF.sub.3CF.sub.2CO), 58.5 (SO.sub.2CF.sub.2), 112.9 (ArC), 119.1 (CH═CHSO.sub.2), 120.4 (ArC), 120.9 (ArC), 121.5 (ArC*2), 123.8 (ArC), 125.2 (ArC), 126.9 (ArC), 129.5 (ArC*2), 130.7 (ArC), 134.6 (CH═CHSO.sub.2), 139.4 (ArC), 141.8 (ArC), 143.6 (ArC), 147.7 (ArC), 151.9 (NHCOO), 153.0 (ArC), 162.8 (ArC), 169.1 (CF.sub.3CO), 172.8 (CF.sub.3CF.sub.2CO); HRMS-EI(M+):C.sub.26H.sub.14F.sub.10N.sub.2O.sub.8S, calcd: 704.0311, found: 704.0336.

Example 12: Preparation of (E)-2-(2,3-dibromobutoxy)-4-{2-[4-(2,2,2-trifluoroethoxy)phenylethylsulfonyl]ethenyl}phenyl-N-(thien-3-yl)carbamate (Compound K1-3)

[0108] ##STR00023##

[0109] With (E)-2-(2,3-dibromobutoxy)-4-{2-[4-(2,2,2-trifluoroethoxy)phenylethylsulfonyl]ethenyl}phenol as starting material and in accordance with the preparation method in Example 5, Compound K1-3 was prepared by two steps, as an orange-yellow solid (yield: 25% over two steps).

[0110] Melting point: 110-113° C.

[0111] .sup.1H NMR (CDCl.sub.3) δ:1.79 (d, 3H, J=7.0 Hz, CH.sub.3CHBr), 3.09-3.28 (m, 4H, SO.sub.2CH.sub.2CH.sub.2), 4.17 (m, 1H, OCH.sub.2CHBr), 4.25-4.35 (m, 3H, CF.sub.3CH.sub.2O, CH.sub.3CHBr), 4.65 (m, 1H, OCH.sub.2CHBr), 4.97 (m, 1H, OCH.sub.2CHBr), 6.12 (s, 1H, ArH), 6.45 (m, 1H, ArH), 6.63 (brs, 1H, NHCOO), 6.85 (m, 2H, ArH), 7.01 (d, 1H, J=7.6 Hz, ArH), 7.15-7.29 (m, 5H, CH═CHSO.sub.2, ArH), 7.41 (d, 1H, J=7.5 Hz, ArH), 8.11 (d, 1H, J=15.4 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:14.7 (CF.sub.3), 23.0 (CH.sub.3CHBr), 30.1 (SO.sub.2CH.sub.2CH.sub.2), 49.5 (CH.sub.3CHBr), 52.6 (SO.sub.2CH.sub.2CH.sub.2), 60.2 (OCH.sub.2CHBr), 64.2 (OCH.sub.2CF.sub.3), 70.1 (OCH.sub.2CHBr), 105.7 (ArC), 113.8 (ArC), 114.7 (ArC*2), 120.3 (CH═CHSO.sub.2), 122.6 (ArC), 123.4 (ArC), 124.1 (ArC), 126.8 (ArC), 129.5 (ArC*2), 130.4 (ArC), 130.8 (ArC), 133.1 (ArC), 136.0 (CH═CHSO.sub.2), 144.4 (ArC), 149.2 (ArC), 154.1 (NHCOO), 157.1 (ArC); HRMS-EI(M+):C.sub.27H.sub.26Br.sub.2F.sub.3NO.sub.6S.sub.2, calcd: 740.9500, found: 740.9495.

Example 13: Preparation of (E)-2-[N-(2-methoxyethyl)-N-methylcarbamoyloxy]-4-{2-[3-(5-methylfur-2-yl)phenylethylsulfonyl]ethenyl}phenyl acetate (Compound J1-4)

[0112] ##STR00024##

[0113] With (E)-2-hydroxy-4-{2-[3-(5-methylfur-2-yl)phenylethylsulfonyl]ethenyl}phenyl acetate as starting material and in accordance with the preparation method in Example 5, Compound J1-4 was prepared by two steps, as a light yellow solid (yield: 43% over two steps).

[0114] Melting point: 191-193° C.

[0115] .sup.1H NMR (CDCl.sub.3) δ:2.34 (furan-CH.sub.3), 2.52 (CH.sub.3CO), 3.13 (m, 5H, SO.sub.2CH.sub.2CH.sub.2, CH.sub.3N), 3.36 (CH.sub.3O), 3.60 (t, 2H, J=4.0 Hz, CH.sub.2NCH.sub.3), 3.75 (m, 4H, CH.sub.3OCH.sub.2, SO.sub.2CH.sub.2CH.sub.2), 6.10 (d, 1H, J=7.5 Hz, ArH), 6.84 (d, 1H, J=7.5 Hz, ArH), 6.96 (d, 1H, J=7.4 Hz, ArH), 7.08 (d, 1H, J=15.1 Hz, CH═CHSO.sub.2), 7.15-7.32 (m, 3H, ArH), 7.42 (t, 1H, J=7.5 Hz, ArH), 7.55 (m, 2H, ArH), 8.10 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:13.5 (furan-CH.sub.3), 20.7 (CH.sub.3CO), 30.2 (SO.sub.2CH.sub.2CH.sub.2), 42.7 (CH.sub.3N), 49.8 (CH.sub.2NCH.sub.3), 53.1 (SO.sub.2CH.sub.2CH.sub.2), 58.2 (CH.sub.3O), 72.7 (CH.sub.3OCH.sub.2), 107.1 (ArC), 108.5 (ArC), 120.4 (CH═CHSO.sub.2), 121.9 (ArC), 122.5 (ArC), 122.8 (ArC), 124.8 (ArC), 127.1 (ArC), 127.9 (ArC), 129.6 (ArC), 130.0 (ArC), 130.9 (ArC), 135.9 (CH═CHSO.sub.2), 138.0 (ArC), 142.1 (ArC), 143.2 (ArC), 150.9 (ArC), 152.6 (ArC), 154.5 (NCOO), 168.8 (CH.sub.3COO); HRMS-EI(M+):C.sub.28H.sub.31NO.sub.8S, calcd: 541.1770, found: 541.1793.

Example 14: Preparation of (E)-2-(2-benzyloxyethoxy)-4-{2-[4-(N,N-diisopropylamino)phenylethylsulfonyl]ethenyl}phenyl-N-(4-iodophenyl)-N-methylcarbamate (Compound A1-3)

[0116] ##STR00025##

[0117] With (E)-2-(2-benzyloxyethoxy)-4-{2-[4-(N,N-diisopropylamino)phenylethylsulfonyl]ethenyl}phenol as starting material and in accordance with the preparation method in Example 5, Compound A1-3 was prepared by two steps, as an orange-red solid (yield: 31% over two steps).

[0118] Melting point: 170-172° C.

[0119] .sup.1H NMR (CDCl.sub.3) δ: 1.32 (m, 12H, CH(CH.sub.3).sub.2*2), 3.02 (t, 2H, J=8.3 Hz, SO.sub.2CH.sub.2CH.sub.2), 3.77 (t, 2H, J=8.3 Hz, SO.sub.2CH.sub.2CH.sub.2), 3.84 (m, 5H, BzOCH.sub.2, NCH.sub.3), 4.18 (t, 2H, J=7.2 Hz, CH.sub.2OAr), 4.47 (m, 4H, PhCH.sub.2O, CH(CH.sub.3).sub.2*2), 6.67 (d, 2H, J=7.4 Hz, ArH), 7.02 (d, 2H, J=7.5 Hz, ArH), 7.06-7.21 (m, 6H, CH═CHSO.sub.2, ArH), 7.35 (m, 5H, ArH), 7.52 (d, 2H, J=7.5 Hz, ArH), 8.12 (d, 1H, J=15.3 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ: 20.9 (CH(CH.sub.3).sub.2*2), 30.3 (SO.sub.2CH.sub.2CH.sub.2), 35.1 (NCH.sub.3), 48.9 (CH(CH.sub.3).sub.2*2), 52.8 (SO.sub.2CH.sub.2CH.sub.2), 69.3 (CH.sub.2OAr), 70.2 (BzOCH.sub.2), 73.0 (PhCH.sub.2O), 88.2 (I—ArC), 114.1 (ArC), 118.1 (ArC*2), 119.7 (CH═CHSO.sub.2), 120.6 (ArC*2), 122.8 (ArC), 123.0 (ArC), 127.9 (ArC*2), 128.1 (ArC), 128.8 (ArC*2), 129.9 (ArC*2), 130.2 (ArC), 131.1 (ArC), 136.0 (CH═CHSO.sub.2), 136.8 (ArC*2), 138.1 (ArC), 143.9 (ArC), 144.7 (ArC), 147.6 (ArC), 149.3 (ArC), 155.4 (NCOO); HRMS-EI(M+):C.sub.39H.sub.45IN.sub.2O.sub.6S, calcd: 796.2043, found: 796.2048.

Example 15: Preparation of (E)-4-{2-[2-(3′,4′-dimethoxy-[1,1′-biphenyl]-4-yl)-2-nitroethylsulfonyl]ethenyl}-1,2-phenylenebis(N-ethyl-N-methylcarbamate) (Compound M1-1)

[0120] ##STR00026##

[0121] With (E)-4-{2-[2-(3′,4′-dimethoxy-[1,1′-biphenyl]-4-yl)-2-nitroethylsulfonyl]ethenyl}benzene-1,2-diol as starting material and in accordance with the preparation method in Example 1, Compound M1-1 was prepared by two steps, as a white solid (yield: 67% over two steps).

[0122] Melting point: 159-161° C.

[0123] .sup.1H NMR (CDCl.sub.3) δ:1.22 (t, 6H, J=8.0 Hz, NCH.sub.2CH.sub.3*2), 3.16 (s, 6H, NCH.sub.3*2), 3.38-3.55 (m, 4H, SO.sub.2CH.sub.aH.sub.bCH, NCH.sub.aH.sub.bCH.sub.3*2), 3.72 (m, 1H, SO.sub.2CH.sub.aH.sub.bCH), 3.85 (s, 3H, OCH.sub.3), 3.91 (s, 3H, OCH.sub.3), 4.06 (m, 1H, NCH.sub.aH.sub.bCH.sub.3), 4.20 (m, 1H, NCH.sub.aH.sub.bCH.sub.3), 7.02 (d, 1H, J=7.6 Hz, ArH), 7.15-7.33 (m, 6H, CH═CHSO.sub.2, ArH), 7.46 (m, 2H, ArH), 7.58 (d, 2H, J=7.5 Hz, ArH), 8.10 (d, 1H, J=15.3 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:12.0 (NCH.sub.2CH.sub.3*2), 32.3 (CHNO.sub.2), 36.1 (NCH.sub.3*2), 46.3 (NCH.sub.2CH.sub.3*2), 54.3 (SO.sub.2CH.sub.2), 56.5 (OCH.sub.3*2), 112.0 (ArC), 113.5 (ArC), 117.6 (CH═CHSO.sub.2), 119.0 (ArC), 121.6 (ArC), 123.1 (ArC), 126.1 (ArC), 126.8 (ArC*2), 128.2 (ArC*2), 128.9 (ArC), 134.1 (ArC), 136.2 (CH═CHSO.sub.2), 138.3 (ArC), 141.9 (ArC), 143.2 (ArC), 144.7 (ArC), 150.6 (ArC), 151.1 (ArC), 154.7 (NCOO), 154.9 (NCOO); HRMS-EI(M+):C.sub.32H.sub.37N.sub.3O.sub.10S, calcd: 655.2200, found: 655.2174.

Example 16: Preparation of (E)-4-{1-amino-2-[4-t-butoxy-3-(N-methyl-N-phenylcarbamoyloxy)styrylsulfonyl]ethyl}phenyl-2-(4-methoxyphenyl)acetate (Compound P1-3)

[0124] ##STR00027##

[0125] With (E)-4-{1-amino-2-[4-t-butoxy-3-hydroxystyrylsulfonyl]ethyl}phenyl-2-(4-methoxyphenyl)acetate as starting material and in accordance with the preparation method in Example 5, Compound P1-3 was prepared by two steps, as a beige yellow solid (yield: 58% over two steps).

[0126] Melting point: 146-149° C.

[0127] .sup.1H NMR (CDCl.sub.3) δ:1.36 (brs, 11H, NH.sub.2, OC(CH.sub.3).sub.3), 3.69 (m, 2H, SO.sub.2CH.sub.aH.sub.b, OCOCH.sub.aH.sub.b), 3.81 (s, 3H, OCH.sub.3), 3.98 (s, 3H, NCH.sub.3), 4.11 (m, 2H, SO.sub.2CH.sub.aH.sub.b, OCOCH.sub.aH.sub.b), 4.59 (m, 1H, NH.sub.2CH), 6.84 (d, 2H, J=7.5 Hz, ArH), 6.93 (d, 2H, J=7.4 Hz, ArH), 7.10 (d, 1H, J=7.5 Hz, ArH), 7.18 (m, 3H, CH═CHSO.sub.2, ArH), 7.30-7.42 (m, 5H, ArH), 7.55 (d, 2H, J=7.6 Hz, ArH), 7.73 (m, 2H, ArH), 8.09 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:28.2 (OC(CH.sub.3).sub.3), 34.9 (NCH.sub.3), 42.3 (OCOCH.sub.2), 52.9 (SO.sub.2CH.sub.2), 54.6 (NH.sub.2CH), 55.8 (OCH.sub.3), 81.5 (OC(CH.sub.3).sub.3), 112.7 (ArC*2), 116.9 (CH═CHSO.sub.2), 120.3 (ArC), 121.9 (ArC*2), 122.2 (ArC*2), 123.5 (ArC), 125.3 (ArC*2), 127.1 (ArC), 128.2 (ArC*2), 128.9 (ArC), 129.7 (ArC*2), 130.8 (ArC*2), 134.9 (CH═CHSO.sub.2), 137.8 (ArC), 142.5 (ArC), 143.1 (ArC), 145.9 (ArC), 151.0 (ArC), 154.7 (NCOO), 158.3 (ArC), 170.1 (OCOCH.sub.2); HRMS-EI(M+):C.sub.37H.sub.40N.sub.2O.sub.8S, calcd: 672.2505, found: 672.2501.

Example 17: Preparation of (E)-4-{2-[4-(4-dimethylaminobenzyl)phenylbromomethylsulfonyl]ethenyl}-2-[2-(4-dimethylaminophenyl)acetyl]phenyl-2-trifluoromethylpyrrolidine-1-carboxylate (Compound M1-5)

[0128] ##STR00028##

[0129] With (E)-5-{2-[4-(4-dimethylaminobenzyl)phenylbromomethylsulfonyl]ethenyl}-2-hydroxyphenyl-2-(4-dimethylaminophenyl)acetate as starting material and in accordance with the preparation method in Example 5, Compound M1-5 was prepared by two steps, as a light yellow solid (yield: 44% over two steps).

[0130] Melting point: 213-215° C.

[0131] .sup.1H NMR (CDCl.sub.3) δ:1.73-2.01 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2), 2.98 (s, 12H, NCH.sub.3*4), 3.16 (m, 1H, NCH.sub.aH.sub.b), 3.55 (m, 1H, NCH.sub.aH.sub.b), 3.68 (m, 2H, NCHCF.sub.3, CH.sub.aH.sub.bCOO), 3.83 (s, 2H, PhCH.sub.2Ph), 4.25 (d, 1H, J=12.5 Hz, CH.sub.aH.sub.bCOO), 6.58 (m, 5H, CHBr, ArH), 6.83 (d, 1H, J=7.5 Hz, ArH), 6.91 (d, 2H, J=7.4 Hz, ArH), 7.13 (d, 1H, J=15.0 Hz, CH═CHSO.sub.2), 7.22 (m, 3H, ArH), 7.38 (m, 3H, ArH), 7.63 (d, 2H, J=7.4 Hz, ArH), 8.12 (d, 1H, J=15.1 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:17.6 (CF.sub.3), 24.9 (NCH.sub.2CH.sub.2), 35.1 (NCH.sub.2CH.sub.2CH.sub.2), 40.5 (CH.sub.2COO), 41.2 (NCH.sub.3*4), 41.9 (PhCH.sub.2Ph), 47.0 (NCH.sub.2), 56.4 (NCHCF.sub.3), 61.5 (CHBr), 114.0 (ArC*2), 114.5 (ArC*2), 117.6 (CH═CHSO.sub.2), 120.9 (ArC), 121.7 (ArC), 125.0 (ArC), 126.3 (ArC), 128.1 (ArC*2), 129.6 (ArC*2), 129.8 (ArC*2), 129.9 (ArC*2), 130.7 (ArC), 131.5 (ArC), 132.5 (ArC), 135.0 (CH═CHSO.sub.2), 140.2 (ArC), 142.3 (ArC), 144.0 (ArC), 151.1 (ArC*2), 155.3 (NCOO), 170.4 (CH.sub.2COO); HRMS-EI(M+):C.sub.40H.sub.41BrF.sub.3N.sub.3O.sub.6S, calcd: 827.1852, found: 827.1829.

Example 18: Preparation of (E)-4-{2-[4-(diethylphenylsiloxy)phenylchloromesyl]ethenyl}-2-(3-chloro-2-methoxybenzoyloxy)phenyl-2,6-dimethylmorpholine-4-carboxylate (Compound R1-5)

[0132] ##STR00029##

[0133] With (E)-5-{2-[4-(diethylphenylsiloxy)phenylchloromesyl]ethenyl}-2-hydroxyphenyl-3-chloro-2-methoxybenzoate as starting material and in accordance with the preparation method in Example 5, Compound R1-5 was prepared by two steps, as a yellow solid (yield: 37% over two steps).

[0134] Melting point: 167-170° C.

[0135] .sup.1H NMR (CDCl.sub.3) δ:0.78 (m, 4H, SiCH.sub.2*2), 1.02 (t, 6H, J=7.9 Hz, SiCH.sub.2CH.sub.3*2), 1.25 (d, 3H, J=6.8 Hz, CHCH.sub.3), 1.34 (d, 3H, J=6.8 Hz, CHCH.sub.3), 3.32 (dd, 1H, J=12.5, 6.9 Hz, NCH.sub.aH.sub.b), 3.41 (dd, 1H, J=12.5, 6.9 Hz, NCH.sub.aH.sub.b), 3.63 (s, 3H, OCH.sub.3), 3.72 (m, 2H, OCHCH.sub.3*2), 3.99 (dd, 1H, J=12.5, 6.9 Hz, NCH.sub.aH.sub.b), 4.08 (dd, 1H, J=12.5, 6.9 Hz, NCH.sub.aH.sub.b), 6.29 (s, 1H, ClCH), 7.15 (m, 4H, CH═CHSO.sub.2, ArH), 7.24-7.43 (m, 8H, ArH), 7.55 (d, 2H, J=7.6 Hz, ArH), 7.61 (dd, 1H, J=7.5, 1.7 Hz, ArH), 7.73 (dd, 1H, J=7.3, 2.0 Hz, ArH), 8.10 (d, 1H, J=15.0 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:6.9 (SiCH.sub.2CH.sub.3*2), 11.2 (SiCH.sub.2CH.sub.3*2), 18.9 (OCHCH.sub.3*2), 52.1 (NCH.sub.2*2), 62.8 (OCH.sub.3), 71.4 (OCHCH.sub.3*2), 79.5 (ClCH), 120.1 (ArC), 121.5 (ArC*2), 121.8 (ArC), 123.5 (ArC), 124.6 (ArC), 124.9 (ArC), 125.3 (ArC), 125.8 (CH═CHSO.sub.2), 126.1 (ArC*2), 127.9 (ArC), 130.2 (ArC*2), 130.4 (ArC), 131.1 (ArC), 132.5 (ArC), 134.1 (ArC), 134.6 (ArC*2), 140.2 (ArC), 142.3 (ArC), 144.0 (ArC), 152.8 (ArC), 154.0 (NCOO), 155.7 (CH═CHSO.sub.2), 159.2 (ArC), 167.3 (ArCOO); HRMS-EI(M+):C.sub.40H.sub.43Cl.sub.2NO.sub.9SSi, calcd: 811.1805, found: 811.1788.

Example 19: Preparation of (E)-2-[N-(3-methyl-4-nitrobenzoyl)carbamoyloxy]-4-{2-[(perfluorophenyl)mesyl]ethenyl}phenyl acetate (Compound D5-4)

[0136] ##STR00030##

[0137] With (E)-2-hydroxy-4-{2-[(perfluorophenyl)mesyl]ethenyl}phenyl acetate as starting material and in accordance with the preparation method in Example 5, Compound D5-4 was prepared by two steps, as a yellow solid (yield: 42% over two steps).

[0138] Melting point: 264-267° C.

[0139] .sup.1H NMR (CDCl.sub.3) δ:2.32 (s, 3H, Ph-CH.sub.3), 2.54 (s, 3H, CH.sub.3CO), 4.69 (s, 2H, SO.sub.2CH.sub.2), 5.50 (brs, 1H, CONH), 7.01 (d, 1H, J=7.5 Hz, ArH), 7.09 (s, 1H, ArH), 7.18 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2), 7.23 (d, 1H, J=7.5 Hz, ArH), 7.49 (m, 2H, ArH), 7.58 (dd, 1H, J=7.5, 2.0 Hz, ArH), 8.13 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:19.9 (Ph-CH.sub.3), 20.8 (CH.sub.3CO), 56.1 (SO.sub.2CH.sub.2), 105.3 (ArC), 118.6 (CH═CHSO.sub.2), 122.3 (ArC), 123.1 (ArC), 125.2 (ArC), 127.6 (ArC), 129.1 (ArC), 130.4 (ArC), 130.6 (ArC), 133.5 (ArC), 134.8 (CH═CHSO.sub.2), 136.7 (ArC), 137.8 (ArC), 138.8 (ArC), 141.7 (ArC), 142.2 (ArC*2), 143.1 (ArC), 144.0 (ArC), 145.8 (ArC), 152.4 (NHCOO), 165.7 (CONHCOO), 169.1 (CH.sub.3CO); HRMS-EI(M+):C.sub.26H.sub.17F.sub.5N.sub.2O.sub.9S, calcd: 628.0575, found: 628.0553.

Example 20: Preparation of (E)-4-{[4-(ethylsulfonyloxy)-3-(N-methyl-N-mesylaminomesyloxy)styrylsulfonyl]methyl}phenylesilate (Compound S1-6)

[0140] ##STR00031##

[0141] With (E)-4-{[4-(ethylsulfonyloxy)-3-hydroxystyrylsulfonyl]methyl}phenylesilate as starting material and in accordance with the preparation method in Example 5, Compound S1-6 was prepared by two steps, as a light yellow solid (yield: 29% over two steps).

[0142] Melting point: 255-257° C.

[0143] .sup.1H NMR (CDCl.sub.3) δ:1.41 (t, 3H, J=8.1 Hz, CH.sub.3CH.sub.2SO.sub.2), 1.53 (t, 3H, J=8.0 Hz, CH.sub.3CH.sub.2SO.sub.2), 2.75 (s, 3H, CH.sub.3N), 2.92 (s, 3H, CH.sub.3SO.sub.2), 3.07 (q, 4H, J=8.0 Hz, CH.sub.3CH.sub.2SO.sub.2*2), 4.68 (s, 2H, SO.sub.2CH.sub.2Ph), 7.15 (d, 1H, J=15.1 Hz, CH═CHSO.sub.2), 7.25 (m, 2H, ArH), 7.38 (d, 1H, J=7.6 Hz, ArH), 7.44 (d, 2H, J=7.5 Hz, ArH), 7.67 (d, 2H, J=7.4 Hz, ArH), 8.10 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:8.5 (CH.sub.3CH.sub.2SO.sub.2*2), 31.5 (CH.sub.3N), 42.3 (CH.sub.3SO.sub.2), 45.7 (CH.sub.3CH.sub.2SO.sub.2*2), 59.3 (SO.sub.2CH.sub.2Ph), 118.8 (CH═CHSO.sub.2), 120.6 (ArC), 122.3 (ArC), 123.5 (ArC*2), 125.0 (ArC), 126.9 (ArC), 127.6 (ArC*2), 128.1 (ArC), 134.8 (CH═CHSO.sub.2), 141.5 (ArC), 146.3 (ArC), 148.6 (ArC), 150.2 (NCOO); HRMS-EI(M+):C.sub.22H.sub.27NO.sub.12S.sub.4, calcd: 625.0416, found: 625.0404.

Example 21: Preparation of (E)-2-(N-methyl-N-p-tosylcarbamoyloxy)-4-{2-[(4-p-tosyloxyphenyl)mesyl]ethenyl}phenyl p-toluenesulfonate (Compound S6-6)

[0144] ##STR00032##

[0145] With (E)-2-hydroxy-4-{2-[(4-p-tosyloxyphenyl)mesyl]ethenyl}phenyl p-toluenesulfonate as starting material and in accordance with the preparation method in Example 5, Compound S6-6 was prepared by two steps, as a beige white solid product (yield: 47% over two steps).

[0146] Melting point: 271-274° C.

[0147] .sup.1H NMR (CDCl.sub.3) δ:2.42 (s, 9H, CH.sub.3Ph*3), 3.03 (s, 3H, CH.sub.3N), 4.68 (s, 2H, SO.sub.2CH.sub.2Ph), 7.11 (m, 1H, ArH), 7.15-7.23 (m, 4H, CH═CHSO.sub.2, ArH), 7.26-7.35 (m, 5H, ArH), 7.48 (m, 4H, ArH), 7.73 (m, 4H, ArH), 8.01 (d, 2H, J=7.6 Hz, ArH), 8.11 (d, 1H, J=15.3 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:21.5 (CH.sub.3Ph*3), 32.6 (CH.sub.3N), 59.5 (SO.sub.2CH.sub.2Ph), 119.3 (CH═CHSO.sub.2), 121.3 (ArC), 122.0 (ArC), 124.1 (ArC), 124.6 (ArC*2), 126.5 (ArC), 127.9 (ArC*2), 128.6 (ArC*2), 128.8 (ArC*2), 128.9 (ArC), 129.3 (ArC*2), 129.5 (ArC*2), 130.1 (ArC*4), 134.6 (CH═CHSO.sub.2), 136.3 (ArC), 136.8 (ArC), 137.2 (ArC), 140.4 (ArC*2), 142.1 (ArC), 143.0 (ArC), 144.5 (ArC), 146.9 (ArC), 149.9 (NCOO); HRMS-EI(M+):C.sub.38H.sub.35NO.sub.12S.sub.4, calcd: 825.1042, found: 825.1019.

Example 22: Preparation of (E)-4-{2-[4-(dimethylamino)-4-(4-(N,N-dimethylglycyloxy)phenyl)butylsulfonyl]ethenyl}-2-(N-methyl-N-phenylcarbamoyloxy)phenyl-4-(p-methylphenyl)piperazine-1-carboxylate (Compound P1-1)

[0148] ##STR00033##

[0149] With (E)-4-{4-[(3,4-dihydroxystyryl)sulfonyl]-1-(dimethylamino)butyl}phenyl-N,N-dimethylglycinate as starting material and in accordance with the preparation method in Example 5, (E)-4-{2-[4-(dimethylamino)-4-(4-(N,N-dimethylglycyloxy)phenyl)butylsulfonyl]ethenyl}-2-hydroxyphenyl-4-(p-methylphenyl)piperazine-1-carboxylate (Compound P1-1-a) was prepared by two steps (yield: 26% over two steps); then using Compound P1-1-a as starting material and in accordance with the preparation method in Example 5, Compound P1-1 was prepared by two steps, as a light yellow solid (yield: 43% over two steps).

[0150] Melting point: 271-274° C.

[0151] .sup.1H NMR (CDCl.sub.3) δ:1.44 (m, 1H, NCHCH.sub.aH.sub.b), 1.77 (m, 1H, SO.sub.2CH.sub.2CH.sub.aH.sub.b), 2.03 (m, 1H, SO.sub.2CH.sub.2CH.sub.aH.sub.b), 2.24 (s, 3H, CHNCH.sub.3), 2.27 (s, 3H, CHNCH.sub.3), 2.32 (s, 3H, CH.sub.3Ph), 2.39 (s, 3H, CH.sub.3NCH.sub.2), 2.48 (s, 3H, CH.sub.3NCH.sub.2), 2.85 (m, 1H, SO.sub.2CH.sub.aH.sub.b), 2.99-3.08 (m, 3H, NCHCH.sub.aH.sub.b, CH.sub.aH.sub.bNCO, SO.sub.2CH.sub.aH.sub.b), 3.18-3.30 (m, 3H, ArNCH.sub.aH.sub.b*2, COCH.sub.aH.sub.bN), 3.39-3.43 (m, 2H, ArCHN, CH.sub.aH.sub.bNCO), 3.59 (s, 3H, PhNCH.sub.3), 3.72 (m, 2H, ArNCH.sub.aH.sub.b, COCH.sub.aH.sub.bN), 3.88 (m, 1H, CH.sub.aH.sub.bNCO), 4.17 (m, 1H, ArNCH.sub.aH.sub.b), 4.33 (m, 1H, CH.sub.aH.sub.bNCO), 6.63 (d, 2H, J=7.5 Hz, ArH), 6.95 (d, 2H, J=7.5 Hz, ArH), 7.03 (m, 0.3H, ArH), 7.05 (s, 1H, ArH), 7.16 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2), 7.22 (m, 1H, ArH), 7.31-7.37 (m, 3H, ArH), 7.40 (d, 2H, J=7.4 Hz, ArH), 7.49 (dd, 2H, J=7.5, 2.0 Hz, ArH), 8.15 (d, 1H, J=15.2 Hz, CH═CHSO.sub.2); .sup.13C NMR (CDCl.sub.3) δ:18.9 (SO.sub.2CH.sub.2CH.sub.2), 21.0 (CH.sub.3Ph), 32.6 (CH.sub.2CHN), 35.7 (PhNCH.sub.3), 42.7 (CHN(CH.sub.3).sub.2), 45.8 (CON(CH.sub.2).sub.2), 46.5 (ArN(CH.sub.2).sub.2), 47.2 (CH.sub.2N(CH.sub.3).sub.2), 55.1 (SO.sub.2CH.sub.2), 60.6 (COCH.sub.2N), 72.1 (ArCHN), 112.9 (ArC*2), 119.3 (CH═CHSO.sub.2), 120.8 (ArC), 121.5 (ArC), 121.8 (ArC*2), 122.3 (ArC*2), 125.0 (ArC), 125.5 (ArC), 127.3 (ArC), 128.6 (ArC*2), 129.1 (ArC), 129.4 (ArC*2), 130.1 (ArC*2), 135.6 (CH═CHSO.sub.2), 137.5 (ArC), 140.1 (ArC), 141.3 (ArC), 143.2 (ArC), 149.0 (ArC), 149.5 (ArC), 152.3 (CH.sub.2NCOO), 154.7 (CH.sub.3NCOO), 168.3 (CH.sub.2COO); HRMS-EI(M+):C.sub.44H.sub.53N.sub.5O.sub.8S, calcd: 811.3615, found: 811.3652.

##STR00034##

Example 23: Evaluation of the Inhibitory Activity of the Target Compounds on the Damage from Parkinson's Disease in Fetal Rat Midbrain Neurons (Using the Survival Rate of Primary Midbrain Neurons Induced by MPP+ as the Evaluation Indicator)

[0152] 1. Experiment Principle

[0153] The main pathological feature of Parkinson's disease (PD) lies in the degeneration and loss of dopaminergic neuron in the substantia nigra-striatum of the midbrain. 1-Methyl-4-phenylpyridinium (MPP+) has a high affinity to dopamine carriers and a selective toxicity on dopaminergic neurons. Thus, MPP+ is one of the most ideal classic neurotoxins for establishing PD cell models. The primary cell culture of fetal rat midbrain is often used to establish PD cell models in recent years. Although it is more cumbersome and has higher technical requirements than cell line culture, it is closer to the pathological characteristics of PD. Thus, a PD cell model is established using neurons from the primary cell culture of fetal rat midbrain under MPP+ induction, to evaluate the protective effect of target compounds on the model neurons.

[0154] 2. Experiment Method

[0155] The midbrain was separated from a fetal rat of a 15-day-pregnant SD rat and cut into pieces, then subjected to trypsin digestion, pipetting, screen filtration, and resuspension steps, and inoculated in a 24-well cell culture plate pre-coated with poly-D-lysine. 12 hours after culture, cytarabine was added to inhibit the growth of glial cells. On the 5.sup.th day of neuron growth, the toxin MPP+ can be added to make a PD cell model. When detecting the activity of a target compound, the target compound was pre-incubated with midbrain neurons for 3 h, then MPP+ was added, and after 48 h co-incubation the neuronal viability was detected by CCK-8 method and the neuronal survival rate was calculated to evaluate the inhibitory activity of the target compound on the midbrain neuronal PD damage. The experiment included blank control group, MPP+ model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G), and target compound group (prepared according to Examples 1-22 in the invention).

[0156] Among them, the prototype control group has a structure formula as follows:

##STR00035##

[0157] 3. Experiment Results

[0158] The effect of each group on the primary midbrain neuron damage induced by MPP+ is shown in the table below:

TABLE-US-00001 Changes and statistical difference (P value) Con. Survival rate Compared with the Compared with the Compared with the Group (μM) (%) model group positive group* prototype group** Blank control group / .sup. 100 ± 1.53 / / / MPP.sup.+ model group / 48.92 ± 2.19 / / / Positive control group 5 54.97 ± 3.78 Increased, P < 0.05 / / 10 67.08 ± 2.98 Increased, P < 0.01 / / 20 82.56 ± 2.13 Increased, P < 0.01 / / Prototype control group 3B 5 65.94 ± 1.47 Increased, P < 0.01 Increased, P < 0.01 / 10 76.41 ± 6.54 Increased, P < 0.01 Increased, P < 0.05 / 20 84.92 ± 2.65 Increased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3C 5 61.33 ± 3.22 Increased, P < 0.01 Increased, P < 0.05 / 10 75.69 ± 1.98 Increased, P < 0.01 Increased, P < 0.01 / 20 74.25 ± 4.55 Increased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3D 5 69.54 ± 5.21 Increased, P < 0.01 Increased, P < 0.01 / 10  84.1 ± 1.87 Increased, P < 0.01 Increased, P < 0.01 / 20 91.49 ± 2.32 Increased, P < 0.01 Increased, P < 0.01 / Prototype control group 3G 5 51.38 ± 3.54 Equivalent, P > 0.05 Equivalent, P > 0.05 / 10 68.41 ± 1.89 Increased, P < 0.01 Equivalent, P > 0.05 / 20 71.18 ± 3.75 Increased, P < 0.01 Decreased, P < 0.01 / Group B1-1 5 78.46 ± 4.12 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 10 89.74 ± 2.89 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 20 93.85 ± 1.59 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group C1-1 5 69.54 ± 3.89 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 10 82.15 ± 3.07 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 20 90.33 ± 2.17 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group D1-1 5 80.31 ± 2.67 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 10 94.56 ± 3.76 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 20 97.95 ± 1.32 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group G1-1 5 78.53 ± 3.59 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 10 85.94 ± 2.67 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 20 91.44 ± 1.59 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group E2-2 5 58.13 ± 4.27 Increased, P < 0.01 Equivalent, P > 0.05 / 10 69.29 ± 2.33 Increased, P < 0.01 Equivalent, P > 0.05 / 20 86.12 ± 2.06 Increased, P < 0.01 Increased, P < 0.05 / Group K3-3 5 62.51 ± 3.58 Increased, P < 0.01 Equivalent, P < 0.05 / 10 75.46 ± 2.37 Increased, P < 0.01 Increased, P < 0.01 / 20 88.45 ± 1.73 Increased, P < 0.01 Increased, P < 0.01 / Group K1-4 5 76.71 ± 3.17 Increased, P < 0.01 Increased, P < 0.01 / 10 87.13 ± 2.56 Increased, P < 0.01 Increased, P < 0.01 / 20 93.22 ± 1.81 Increased, P < 0.01 Increased, P < 0.01 / Group P1-7 5 79.23 ± 3.72 Increased, P < 0.01 Increased, P < 0.01 / 10 86.63 ± 2.93 Increased, P < 0.01 Increased, P < 0.01 / 20 91.17 ± 2.08 Increased, P < 0.01 Increased, P < 0.01 / Group H2-4 5 68.95 ± 4.31 Increased, P < 0.01 Increased, P < 0.01 / 10 81.53 ± 3.24 Increased, P < 0.01 Increased, P < 0.01 / 20 89.37 ± 1.65 Increased, P < 0.01 Increased, P < 0.01 / Group M1-3 5 76.51 ± 4.82 Increased, P < 0.01 Increased, P < 0.01 / 10 85.29 ± 2.97 Increased, P < 0.01 Increased, P < 0.01 / 20 93.26 ± 2.26 Increased, P < 0.01 Increased, P < 0.01 / Group L1-4 5 67.49 ± 3.52 Increased, P < 0.01 Increased, P < 0.01 / 10 75.37 ± 2.59 Increased, P < 0.01 Increased, P < 0.01 / 20 86.18 ± 1.86 Increased, P < 0.01 Increased, P < 0.05 / Group K1-3 5 65.39 ± 4.31 Increased, P < 0.01 Increased, P < 0.01 / 10 72.08 ± 2.77 Increased, P < 0.01 Increased, P < 0.05 / 20 83.19 ± 1.76 Increased, P < 0.01 Equivalent, P > 0.05 / Group J1-4 5 75.23 ± 3.29 Increased, P < 0.01 Increased, P < 0.01 / 10 84.79 ± 2.27 Increased, P < 0.01 Increased, P < 0.01 / 20 90.34 ± 2.60 Increased, P < 0.01 Increased, P < 0.01 / Group A1-3 5 74.32 ± 3.75 Increased, P < 0.01 Increased, P < 0.01 / 10 89.74 ± 1.95 Increased, P < 0.01 Increased, P < 0.01 / 20 94.07 ± 1.87 Increased, P < 0.01 Increased, P < 0.01 / Group M1-1 5 82.36 ± 2.54 Increased, P < 0.01 Increased, P < 0.01 / 10 89.93 ± 3.67 Increased, P < 0.01 Increased, P < 0.01 / 20 95.07 ± 1.94 Increased, P < 0.01 Increased, P < 0.01 / Group P1-3 5 71.02 ± 3.56 Increased, P < 0.01 Increased, P < 0.01 / 10 85.24 ± 2.94 Increased, P < 0.01 Increased, P < 0.01 / 20 93.66 ± 3.08 Increased, P < 0.01 Increased, P < 0.01 / Group M1-5 5 68.16 ± 4.31 Increased, P < 0.01 Increased, P < 0.01 / 10 78.24 ± 3.76 Increased, P < 0.01 Increased, P < 0.01 / 20 86.91 ± 3.08 Increased, P < 0.01 Increased, P < 0.05 / Group R1-5 5 72.28 ± 2.94 Increased, P < 0.01 Increased, P < 0.01 / 10 82.51 ± 2.83 Increased, P < 0.01 Increased, P < 0.01 / 20 90.17 ± 1.76 Increased, P < 0.01 Increased, P < 0.01 / Group D5-4 5 60.45 ± 3.19 Increased, P < 0.01 Equivalent, P > 0.05 / 10 73.18 ± 4.53 Increased, P < 0.01 Increased, P < 0.05 / 20 87.46 ± 2.16 Increased, P < 0.01 Increased, P < 0.01 / Group S1-6 5 80.25 ± 5.19 Increased, P < 0.01 Increased, P < 0.01 / 10 87.53 ± 3.61 Increased, P < 0.01 Increased, P < 0.01 / 20 93.29 ± 3.07 Increased, P < 0.01 Increased, P < 0.01 / Group S6-6 5 71.96 ± 2.47 Increased, P < 0.01 Increased, P < 0.01 / 10 83.16 ± 4.07 Increased, P < 0.01 Increased, P < 0.01 / 20 91.72 ± 3.18 Increased, P < 0.01 Increased, P < 0.01 / Group P1-1 5 75.35 ± 3.12 Increased, P < 0.01 Increased, P < 0.01 / 10 86.59 ± 2.39 Increased, P < 0.01 Increased, P < 0.01 / 20 92.17 ± 3.05 Increased, P < 0.01 Increased, P < 0.01 / *Comparison with the data of the positive drug control group at an equal concentration **Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0159] It can be seen that compared with the model group, all the compounds showed a statistically significant increase in the survival rate, demonstrating that these compounds have a definite protective effect on the primary midbrain neuron damage induced by MPP+. Compared with the positive control CAPE, most of the compounds had a relatively significant or significant increase in the survival rate, demonstrating that the protective effect on the primary midbrain neuron damage inducted by MPP+ of these compounds were stronger than that of the positive control CAPE. The survival rates of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were significantly increased compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D), and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the protective effect on the primary midbrain neuron damage induced by MPP+ of these compounds was significantly enhanced.

Example 24: Evaluation of the Inhibitory Activity of the Target Compounds on the Inflammatory Response in Glial Cells (Inhibition of the NO Release of Primary Glial Cells Induced by LPS, Using the NO Content in the Cell Culture Medium as the Evaluation Indicator)

[0160] 1. Experiment Principle

[0161] Lipopolysaccharide (LPS) is a main component of the cell wall of Gram-negative bacteria. It is a potent inflammatory factor that can directly activate gliocytes, and the activated gliocytes secrete a large amount of inflammation mediators such as tumor necrosis factor, interleukin, and nitric oxide, thus causing inflammatory reactions and oxidative stress reactions and eventually leading to neuronal denaturation and death. In recent years, the targeted injection of LPS into rat substantia nigra or striatum to induce neuroinflammation can successfully establish PD models, which can simulate most of the clinical manifestations and pathological features of PD, and are used for the study on the neuroinflammation mechanism associated with PD. LPS-induced primary glial cell PD inflammation model is suitable for the preliminary anti-neuroinflammation screening for neuroprotective agents. LPS is used to directly activate primary glial cells to simulate the pathogenesis mechanism of neuroinflammation, and the inhibitory activity of the target compounds on the inflammatory response of primary glial cells can be investigated.

[0162] 2. Experiment Method

[0163] The materials were taken from the brain tissue of fetal rat, for primary glial cell culture. At 7 to 10 days of the culture, LPS was added for the activation of nitric oxide (NO) release in glial cells. When a target compound was added, the reduction value for NO content in the cell culture medium was measured, to evaluate the anti-neuroinflammation activity of the compound. The experiment included blank control group, LPS model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, the structures of which compounds are shown as above), and target compound group.

[0164] 3. Experiment Results

[0165] The inhibitory effect of each group on the NO release of primary glial cells induced by LPS is shown in the table below:

TABLE-US-00002 Changes and statistical difference (P value)** Con. NO inhibition Compared with the Compared with the Group* (μM) (%) positive group prototype group Positive control group 2 31.52 ± 5.43 / / 5 45.23 ± 3.85 / / 10 77.08 ± 4.37 / / Prototype control group 3B 5 17.18 ± 4.56 Decreased, P < 0.05 / 10 38.58 ± 2.13 Decreased, P < 0.05 / 20 92.02 ± 3.01 / / Prototype control group 3C 5  9.24 ± 4.88 Decreased, P < 0.05 / 10 24.56 ± 3.09 Decreased, P < 0.05 / 20 45.76 ± 5.25 / / Prototype control group 3D 2 23.48 ± 8.05 Equivalent, P > 0.05 / 5 34.65 ± 4.89 Decreased, P < 0.05 / 10 74.72 ± 3.32 Equivalent, P > 0.05 / Prototype control group 3G 5 41.20 ± 3.01 Equivalent, P > 0.05 / 10 59.56 ± 2.44 Decreased, P < 0.05 / 20 85.78 ± 3.88 / / Group B1-1 5 21.58 ± 2.18 Decreased, P < 0.05 Equivalent, P > 0.05 10 42.75 ± 3.56 Decreased, P < 0.05 Equivalent, P > 0.05 20 97.65 ± 2.04 / Increased, P < 0.05 Group C1-1 5 17.58 ± 3.24 Decreased, P < 0.05 Increased, P < 0.05 10 32.75 ± 5.25 Decreased, P < 0.05 Increased, P < 0.05 20 59.45 ± 4.33 / Increased, P < 0.05 Group D1-1 2 24.78 ± 4.08 Equivalent, P > 0.05 Equivalent, P > 0.05 5 61.38 ± 2.77 Increased, P < 0.05 Increased, P < 0.05 10 84.54 ± 7.56 Equivalent, P > 0.05 Increased, P < 0.05 Group G1-1 2 27.20 ± 3.98 Equivalent, P > 0.05 / 5 64.23 ± 3.25 Increased, P < 0.05 Increased, P < 0.05 10 85.77 ± 5.01 Increased, P < 0.05 Increased, P < 0.05 Group E2-2 5 20.27 ± 4.73 Decreased, P < 0.05 / 10 36.78 ± 6.11 Decreased, P < 0.05 / 20 68.93 ± 3.75 / / Group K3-3 5 17.58 ± 3.24 Decreased, P < 0.05 / 10 40.62 ± 3.11 Decreased, P < 0.05 / 20 72.48 ± 6.08 / / Group K1-4 2 30.18 ± 4.01 Equivalent, P > 0.05 / 5 53.48 ± 5.52 Increased, P < 0.05 / 10 77.41 ± 5.09 Equivalent, P > 0.05 / Group P1-7 5 21.26 ± 4.43 Decreased, P < 0.05 / 10 41.22 ± 1.95 Decreased, P < 0.05 / 20 70.95 ± 3.67 / / Group H2-4 2 32.18 ± 4.49 Equivalent, P > 0.05 / 5 50.08 ± 5.37 Equivalent, P > 0.05 / 10 85.41 ± 4.90 Increased, P < 0.05 / Group M1-3 2 23.93 ± 4.67 Decreased, P < 0.05 / 5 47.42 ± 4.43 Equivalent, P > 0.05 / 10 73.41 ± 4.83 Equivalent, P > 0.05 / Group L1-4 2 26.73 ± 6.93 Equivalent, P > 0.05 / 5 50.92 ± 3.72 Increased, P < 0.05 / 10 72.27 ± 4.80 Equivalent, P > 0.05 / Group K1-3 5 33.26 ± 6.71 Decreased, P < 0.05 / 10 54.19 ± 4.06 Decreased, P < 0.05 / 20 81.36 ± 4.29 / / Group J1-4 2 24.81 ± 5.02 Equivalent, P > 0.05 / 5 40.92 ± 3.94 Equivalent, P > 0.05 / 10 69.67 ± 5.85 Equivalent, P > 0.05 / Group A1-3 5 19.58 ± 3.67 Decreased, P < 0.05 / 10 43.17 ± 2.36 Decreased, P < 0.05 / 20 62.09 ± 4.73 / / Group M1-1 2 38.26 ± 3.42 Increased, P < 0.05 / 5 52.92 ± 5.36 Increased, P < 0.05 / 10 82.67 ± 2.47 Increased, P < 0.05 / Group P1-3 5 25.78 ± 4.25 Decreased, P < 0.05 / 10 41.96 ± 5.34 Decreased, P < 0.05 / 20 58.23 ± 3.66 / / Group M1-5 5 21.19 ± 3.12 Decreased, P < 0.05 / 10 45.63 ± 4.28 Decreased, P < 0.05 / 20 66.73 ± 4.02 / / Group R1-5 5 23.78 ± 4.32 Decreased, P < 0.05 / 10 48.55 ± 3.68 Decreased, P < 0.05 / 20 73.61 ± 3.92 / / Group D5-4 2 24.26 ± 2.82 Decreased, P < 0.05 / 10 80.67 ± 4.06 Equivalent, P > 0.05 / Group S1-6 2 23.19 ± 1.87 Decreased, P < 0.05 / 5 37.18 ± 3.41 Decreased, P < 0.05 / 10 76.67 ± 3.56 Equivalent, P > 0.05 / Group S6-6 5 30.18 ± 2.97 Decreased, P < 0.05 / 10 59.23 ± 3.49 Decreased, P < 0.05 / 20 85.10 ± 4.41 / / Group P1-1 2 25.85 ± 3.54 Equivalent, P > 0.05 / 5 39.98 ± 2.66 Decreased, P < 0.05 / 10 78.38 ± 3.96 Equivalent, P > 0.05 / *The test results of the blank control group and the LPS model group were only used as calculation basis, and did not shown as the inhibition rate. **Only the comparison with the positive group or prototype group at an equal concentration was conducted for the comparison for the Changes; only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0166] It can be seen that every concentration group for all the compounds had a certain NO inhibitory rate, demonstrating that these compounds have a definite inhibitory effect on the NO release of primary glial cells induced by LPS. Among them, part of compounds had a higher inhibitory rate than the positive control group at an equal concentration, demonstrating that the inhibitory effect on the NO release of primary glial cells induced by LPS of these compounds were stronger than that of the positive control CAPE. The four groups of compounds B1-1, C1-1, D1-1, and G1-1 had a equivalent or higher inhibitory rate compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, respectively, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect on the NO release of primary glial cells induced by LPS has a certain enhancement.

Example 25: Evaluation of the Neuroprotective Activity of the Target Compounds in the Parkinson's Disease Model Mouse (Using the Midbrain p-α-s as the Evaluation Indicator)

[0167] 1. Experiment Principle

[0168] Neurotoxins can be used to establish PD animal models. Currently, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the sole synthetic toxin which is recognized to induce PD symptoms in human and non-human primates and in mice. Using MPTP subacute modeling method, C57BL/6J male mice were intraperitoneally injected with MPTP 30 mg/kg, once a day for 5 consecutive days. The experiment animals were divided into blank control group, MPTP model group, and compound treatment group. For the MPTP model group and compound treatment group, the compound was administrated by gavage for 21 consecutive days after the completion of modeling; for the MPTP model group, the normal saline was administrated by gavage for 21 consecutive days after the completion of modeling; and for the blank control group, the normal saline was first intraperitoneally injected for 5 days, and then administrated by gavage for 21 days.

[0169] Alpha-synuclein is an “unfolded protein” in its natural state. It exists in a monomeric form, and participates in the physiological functions such as the release of neurotransmitters, the establishment of synaptic junctions, and the regulation of synaptic plasticity. Under pathological conditions, more than 90% of alpha-synuclein is phosphorylated at serine of position 129 and converted into phosphorylated alpha-synuclein (p-α-s), thereby forming Lewy bodies. The formation of Lewy bodies is one of the main pathological manifestations and pathological mechanisms for Parkinson's disease, and plays an important role in the formation and development of PD. The detection of the p-α-s expression in the midbrain and substantia nigra of PD model mice can evaluate the neuroprotective activity of the compound.

[0170] 2. Experiment Method

[0171] Half of experiment mice in each group were taken to extract the total midbrain protein, and the change in the midbrain P-α-s protein expression was determined by western-blotting using GAPDH as the internal reference. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0172] 3. Experiment Results

[0173] The effect of each group on the change in the midbrain p-α-s protein expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00003 Changes and statistical difference (P value) Expression Compared with the Compared with the Compared with the Group (p-α-s/GAPDH) model group positive group prototype group* Blank control group 0.50 ± 0.08 / / / MPTP model group 1.66 ± 0.10 / / / Positive control group 0.54 ± 0.12 Decreased, P < 0.01 / / Prototype control group 3B 0.93 ± 0.04 Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3C 0.92 ± 0.13 Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3D 0.49 ± 0.12 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3G 0.61 ± 0.08 Decreased, P < 0.01 Equivalent, P > 0.05 / Group B1-1 0.23 ± 0.12 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group C1-1 0.63 ± 0.06 Decreased, P < 0.01 Equivalent, P > 0.05 Decreased, P < 0.01 Group D1-1 0.42 ± 0.10 Decreased, P < 0.01 Equivalent, P > 0.05 Equivalent, P > 0.05 Group G1-1 0.34 ± 0.09 Decreased, P < 0.01 Decreased, P < 0.05 Decreased, P < 0.01 Group E2-2 0.45 ± 0.07 Decreased, P < 0.01 Equivalent, P > 0.05 / Group K3-3 0.62 ± 0.11 Decreased, P < 0.01 Equivalent, P > 0.05 / Group K1-4 0.45 ± 0.12 Decreased, P < 0.01 Equivalent, P > 0.05 / Group P1-7 0.27 ± 0.08 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4 0.53 ± 0.13 Decreased, P < 0.01 Equivalent, P > 0.05 / Group M1-3 0.42 ± 0.05 Decreased, P < 0.01 Equivalent, P > 0.05 / Group L1-4 0.38 ± 0.08 Decreased, P < 0.01 Decreased, P < 0.05 / Group K1-3 0.34 ± 0.10 Decreased, P < 0.01 Decreased, P < 0.05 / Group J1-4 0.47 ± 0.11 Decreased, P < 0.01 Equivalent, P > 0.05 / Group A1-3 0.56 ± 0.12 Decreased, P < 0.01 Equivalent, P > 0.05 / Group M1-1 0.27 ± 0.08 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-3 0.31 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5 0.24 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 0.46 ± 0.11 Decreased, P < 0.01 Equivalent, P > 0.05 / Group D5-4 0.64 ± 0.12 Decreased, P < 0.01 Equivalent, P > 0.05 / Group S1-6 0.34 ± 0.09 Decreased, P < 0.01 Decreased, P < 0.05 / Group S6-6 0.28 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-1 0.48 ± 0.12 Decreased, P < 0.01 Equivalent, P > 0.05 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0174] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in terms of the p-α-s protein expression, demonstrating that these compounds have a definite inhibitory effect on the increase of midbrain p-α-s protein expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, all the compounds were equivalent in terms of the p-α-s protein expression or had a relatively significant or significant decrease in terms of the p-α-s protein expression, demonstrating that the inhibitory effect of these compounds on the increase of midbrain p-α-s protein expression in the Parkinson's disease model mouse were comparable to or even stronger than that of the positive control CAPE. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were equivalent or significantly lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of midbrain p-α-s protein expression in the Parkinson's disease model was significantly enhanced.

Example 26: Evaluation of the Neuroprotective Activity of the Target Compounds in the Parkinson's Disease Model Mouse (Using the Substantia Nigra p-α-s as the Evaluation Indicator)

[0175] 1. Experiment Principle

[0176] Identical to that of Example 25.

[0177] 2. Experiment Method

[0178] Half of experiment mice in each group were taken to separate the midbrain after perfusion and fixation. The tissue was trimmed, and the substantia nigra-striatum area was taken to prepare paraffin sections. The p-α-s immunofluorescence staining was performed in the brain sections of mice in each group. The p-α-s expression was observed for the statistics of the change in terms of the p-α-s protein expression. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0179] 3. Experiment Results

[0180] The effect of each group on the change in the substantia nigra p-α-s protein expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00004 Expression* Changes and statistical difference (P value) (Immunofluorescence Compared with Compared with the Compared with the Group intensity %) the model group positive group prototype group** Blank control group 100.00 ± 5.46  / / / MPTP model group 346.25 ± 5.24  / / / Positive control group 202.07 ± 8.34  Decreased, P < 0.01 / / Prototype control group 3B 236.55 ± 13.78 Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3C 132.98 ± 7.78  Decreased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3D 104.89 ± 7.56  Decreased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3G 203.66 ± 8.37  Decreased, P < 0.01 Equivalent, P > 0.05 / Group B1-1 82.54 ± 9.34 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group C1-1 123.59 ± 8.25  Decreased, P < 0.01 Decreased, P < 0.01 Equivalent, P > 0.05 Group D1-1 42.52 ± 5.43 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group G1-1 77.36 ± 9.15 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group E2-2 128.26 ± 11.62 Decreased, P < 0.01 Decreased, P < 0.01 / Group K3-3 180.11 ± 13.51 Decreased, P < 0.01 Decreased, P < 0.05 / Group K1-4 106.95 ± 9.27  Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-7 61.28 ± 5.36 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4 136.53 ± 8.94  Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-3 79.17 ± 5.10 Decreased, P < 0.01 Decreased, P < 0.01 / Group L1-4 58.37 ± 6.11 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-3 90.04 ± 7.43 Decreased, P < 0.01 Decreased, P < 0.01 / Group J1-4 116.95 ± 8.06  Decreased, P < 0.01 Decreased, P < 0.01 / Group A1-3 134.19 ± 11.28 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-1 95.64 ± 9.25 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-3 48.33 ± 5.37 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5 67.90 ± 3.29 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 125.28 ± 9.35  Decreased, P < 0.01 Decreased, P < 0.01 / Group D5-4 186.19 ± 11.02 Decreased, P < 0.01 Decreased, P < 0.05 / Group S1-6 101.02 ± 5.94  Decreased, P < 0.01 Decreased, P < 0.01 / Group S6-6 72.57 ± 6.63 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-1 182.99 ± 12.70 Decreased, P < 0.01 Decreased, P < 0.05 / *Expression was expressed in the percentage for the immunofluorescence intensity of each group in the mean immunofluorescence intensity of blank control group. **Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0181] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in terms of the p-α-s protein expression, demonstrating that these compounds have a definite inhibitory effect on the increase of substantia nigra p-α-s protein expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, most of the compounds had a significant decrease in terms of the p-α-s protein expression, demonstrating that the inhibitory effect of these compounds on the increase of substantia nigra p-α-s protein expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were equivalent or significantly lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of substantia nigra p-α-s protein expression in the Parkinson's disease model was significantly enhanced.

Example 27: Evaluation of the Neuroprotective Activity of the Target Compounds in the Parkinson's Disease Model Mouse (Using the Midbrain TH as the Evaluation Indicator)

[0182] 1. Experiment Principle

[0183] The principle and establishment method of PD model mice are identical to those of Example 25.

[0184] The main cause of PD lies in the pathological changes in the substantia nigra-striatum projection system of the brain and the progressive degeneration and loss of dopaminergic neurons. Tyrosine hydroxylase (TH) is the first enzyme in the biosynthesis of catecholamine neurotransmitters, as well as the first rate-limiting enzyme in the dopamine synthesis. It plays an important role in the synthesis and metabolism of the neurotransmitter DA. The TH in PD animal models and patients has a wide range of abnormal changes, from the gene expression to the enzyme protein content and enzyme activity. The detection of the TH expression in the midbrain and substantia nigra of PD model mice can be used to evaluate the neuroprotective activity of the compound.

[0185] 2. Experiment Method

[0186] Half of experiment mice in each group were taken to extract the total midbrain protein, and the change in the midbrain TH was determined by western-blotting using GAPDH as the internal reference. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0187] 3. Experiment Results

[0188] The effect of each group on the change in the midbrain TH expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00005 Changes and statistical difference (P value) Expression Compared with the Compared with the Compared with the Group (TH/GAPDH) model group positive group prototype group* Blank control group 1.29 ± 0.03 / / / MPTP model group 0.44 ± 0.03 / / / Positive control group 0.85 ± 0.04 Increased, P < 0.01 / / Prototype control group 3B 0.53 ± 0.03 Increased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3C 0.63 ± 0.03 Increased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3D 0.93 ± 0.06 Increased, P < 0.01 Increased, P < 0.05 / Prototype control group 3G 0.45 ± 0.05 Increased, P < 0.01 Decreased, P < 0.01 / Group B1-1 0.92 ± 0.02 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group C1-1 1.20 ± 0.06 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group D1-1 1.27 ± 0.05 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group G1-1 0.70 ± 0.03 Increased, P < 0.01 Decreased, P < 0.01 Increased, P < 0.01 Group E2-2 0.97 ± 0.03 Increased, P < 0.01 Increased, P < 0.01 / Group K3-3 1.15 ± 0.05 Increased, P < 0.01 Increased, P < 0.01 / Group K1-4 0.74 ± 0.08 Increased, P < 0.01 Equivalent, P > 0.05 / Group P1-7 0.88 ± 0.06 Increased, P < 0.01 Equivalent, P > 0.05 / Group H2-4 1.02 ± 0.04 Increased, P < 0.01 Increased, P < 0.01 / Group M1-3 0.84 ± 0.06 Increased, P < 0.01 Equivalent, P > 0.05 / Group L1-4 0.79 ± 0.04 Increased, P < 0.01 Decreased, P < 0.05 / Group K1-3 0.91 ± 0.04 Increased, P < 0.01 Increased, P < 0.05 / Group J1-4 0.89 ± 0.04 Increased, P < 0.01 Equivalent, P > 0.05 / Group A1-3 0.93 ± 0.07 Increased, P < 0.01 Increased, P < 0.05 / Group M1-1 1.35 ± 0.04 Increased, P < 0.01 Increased, P < 0.01 / Group P1-3 0.77 ± 0.03 Increased, P < 0.01 Decreased, P < 0.05 / Group M1-5 0.83 ± 0.06 Increased, P < 0.01 Equivalent, P > 0.05 / Group R1-5 0.94 ± 0.03 Increased, P < 0.01 Increased, P < 0.01 / Group D5-4 1.19 ± 0.05 Increased, P < 0.01 Increased, P < 0.01 / Group S1-6 0.91 ± 0.06 Increased, P < 0.01 Equivalent, P > 0.05 / Group S6-6 1.07 ± 0.06 Increased, P < 0.01 Increased, P < 0.01 / Group P1-1 0.88 ± 0.04 Increased, P < 0.01 Equivalent, P > 0.05 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0189] It can be seen that compared with the model group, all the compounds showed a statistically significant increase in the TH expression, demonstrating that these compounds have a definite protective effect on the midbrain TH expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, most of the compounds were equivalent in the TH expression or had a relatively significant or significant increase in the TH expression, demonstrating that the protective effect of these compounds on the midbrain TH expression in the Parkinson's disease model mouse were comparable to or even stronger than that of the positive control CAPE. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were significantly higher compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the protective effect of these compounds on the midbrain TH expression in the Parkinson's disease model was significantly enhanced.

Example 28: Evaluation of the Neuroprotective Activity of the Target Compounds in the Parkinson's Disease Model Mouse (Using the Substantia Nigra TH as the Evaluation Indicator)

[0190] 1. Experiment Principle

[0191] Identical to that of Example 27.

[0192] 2. Experiment Method

[0193] Half of experiment mice in each group were taken to separate the midbrain after perfusion and fixation. The tissue was trimmed, and the substantia nigra-striatum area was taken to prepare paraffin sections. The TH immunofluorescence staining was performed in the brain sections of mice in each group. The TH expression was observed for the statistics of the change in the number of neurons with TH positive expression. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0194] 3. Experiment Results

[0195] The effect of each group on the change in the substantia nigra TH expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00006 Expression* Changes and statistical difference (P value) (Immunofluorescence Compared with Compared with the Compared with the Group intensity %) the model group positive group prototype group** Blank control group 100.00 ± 2.32  / / / MPTP model group 57.57 ± 7.70 / / / Positive control group 79.21 ± 6.59 Increased, P < 0.01 / / Prototype control group 3B 83.18 ± 5.87 Increased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3C 74.63 ± 9.15 Increased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3D 87.38 ± 4.01 Increased, P < 0.01 Increased, P < 0.05 / Prototype control group 3G 76.08 ± 7.08 Increased, P < 0.01 Equivalent, P > 0.05 / Group B1-1 95.86 ± 4.43 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group C1-1 96.58 ± 6.15 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group D1-1 99.19 ± 3.67 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group G1-1 77.13 ± 7.40 Increased, P < 0.01 Equivalent, P > 0.05 Equivalent, P > 0.05 Group E2-2 93.12 ± 4.56 Increased, P < 0.01 Increased, P < 0.01 / Group K3-3 98.53 ± 3.08 Increased, P < 0.01 Increased, P < 0.01 / Group K1-4 74.20 ± 6.58 Increased, P < 0.01 Equivalent, P > 0.05 / Group P1-7 88.07 ± 5.03 Increased, P < 0.01 Increased, P < 0.05 / Group H2-4 95.20 ± 6.06 Increased, P < 0.01 Increased, P < 0.01 / Group M1-3 84.07 ± 3.19 Increased, P < 0.01 Equivalent, P > 0.05 / Group L1-4 83.22 ± 5.98 Increased, P < 0.01 Equivalent, P > 0.05 / Group K1-3 87.28 ± 4.11 Increased, P < 0.01 Increased, P < 0.05 / Group J1-4 88.65 ± 5.41 Increased, P < 0.01 Increased, P < 0.05 / Group A1-3 89.68 ± 5.69 Increased, P < 0.01 Increased, P < 0.05 / Group M1-1 101.36 ± 5.21  Increased, P < 0.01 Increased, P < 0.01 / Group P1-3 79.20 ± 6.53 Increased, P < 0.01 Equivalent, P > 0.05 / Group M1-5 87.24 ± 2.97 Increased, P < 0.01 Increased, P < 0.05 / Group R1-5 92.45 ± 3.93 Increased, P < 0.01 Increased, P < 0.01 / Group D5-4 99.86 ± 6.27 Increased, P < 0.01 Increased, P < 0.01 / Group S1-6 87.73 ± 3.49 Increased, P < 0.01 Increased, P < 0.05 / Group S6-6 96.01 ± 7.32 Increased, P < 0.01 Increased, P < 0.01 / Group P1-1 88.13 ± 3.43 Increased, P < 0.01 Increased, P < 0.05 / *Expression was expressed in the percentage for the immunofluorescence intensity of each group in the mean immunofluorescence intensity of blank control group. **Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0196] It can be seen that compared with the model group, all the compounds showed a statistically significant increase in the TH expression, demonstrating that these compounds have a definite protective effect on the substantia nigra TH expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, all the compounds were equivalent in the TH expression or had a relatively significant or significant increase in the TH expression, demonstrating that the protective effect of these compounds on the substantia nigra TH expression in the Parkinson's disease model mouse were comparable to or even stronger than that of the positive control CAPE. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were equivalent or significantly higher compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the protective effect of these compounds on the substantia nigra TH expression in the Parkinson's disease model was significantly enhanced.

Example 29: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Activation of p38 MAPK Phosphorylation, Using Midbrain Pp38 as the Evaluation Indicator)

[0197] 1. Experiment Principle

[0198] The p38 mitogen-activated protein kinase (p38 MAPK) is expressed in both neurons and glial cells, and is the intersection point of neuron-glial cell network information regulations. The activation of p38 signaling pathway is an important initiator of neuronal degeneration, which continuously induces the apoptosis of dopaminergic neurons in multiple ways. It has become a research hotspot for the treatment of PD. Studies have shown that the protective mechanism of CAPE against the death of primary cultured cerebellar granule neurons induced by glutamate lies in inhibiting the activation of p38 phosphorylation and in turn inhibiting the activation of the caspase 3 apoptotic pathway to prevent neuronal apoptosis. Therefore, the MPTP-induced PD mouse model can be used to investigate the inhibitory effect of the target compounds on the activation of p38 phosphorylation on the overall animal level.

[0199] 2. Experiment Method

[0200] Half of experiment mice in each group were taken to extract the total midbrain protein, and the change in the midbrain phosphorylated p38 protein expression was determined by western-blotting using GAPDH as the internal reference. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0201] 3. Experiment Results

[0202] The effect of each group on the change in the midbrain pp38 protein expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00007 Changes and statistical difference (P value) Expression Compared with the Compared with the Compared with the Group (pp38/GAPDH) model group positive group prototype group* Blank control group 0.24 ± 0.03 / / / MPTP model group 1.73 ± 0.15 / / / Positive control group 0.58 ± 0.12 Decreased, P < 0.01 / / Prototype control group 3B 1.18 ± 0.08 Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3C 0.85 ± 0.22 Decreased, P < 0.01 Increased, P < 0.05 / Prototype control group 3D 1.00 ± 0.11 Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3G 0.69 ± 0.22 Decreased, P < 0.01 Equivalent, P > 0.05 / Group B1-1 0.37 ± 0.12 Decreased, P < 0.01 Decreased, P < 0.05 Decreased, P < 0.01 Group C1-1 0.63 ± 0.06 Decreased, P < 0.01 Equivalent, P > 0.05 Equivalent, P > 0.05 Group D1-1 0.50 ± 0.13 Decreased, P < 0.01 Equivalent, P > 0.05 Decreased, P < 0.01 Group G1-1 0.33 ± 0.07 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group E2-2 0.43 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.05 / Group K3-3 0.55 ± 0.08 Decreased, P < 0.01 Equivalent, P > 0.05 / Group K1-4 0.44 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.05 / Group P1-7 0.40 ± 0.04 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4 0.43 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.05 / Group M1-3 0.42 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.05 / Group L1-4 0.28 ± 0.04 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-3 0.35 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.01 / Group J1-4 0.41 ± 0.08 Decreased, P < 0.01 Decreased, P < 0.05 / Group A1-3 0.27 ± 0.08 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-1 0.40 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.05 / Group P1-3 0.33 ± 0.07 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5 0.29 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 0.44 ± 0.07 Decreased, P < 0.01 Decreased, P < 0.05 / Group D5-4 0.61 ± 0.07 Decreased, P < 0.01 Equivalent, P > 0.05 / Group S1-6 0.21 ± 0.04 Decreased, P < 0.01 Decreased, P < 0.01 / Group S6-6 0.27 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-1 0.50 ± 0.09 Decreased, P < 0.01 Equivalent, P > 0.05 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0203] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in the pp38 protein expression, demonstrating that these compounds have a definite inhibitory effect on the increase of midbrain pp38 protein expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, all the compounds were equivalent in the pp38 protein expression or had a relatively significant or significant decrease in the pp38 protein expression, demonstrating that the inhibitory effect of these compounds on the increase of midbrain pp38 protein expression in the Parkinson's disease model mouse were comparable to or even stronger than that of the positive control CAPE. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were equivalent or significantly lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of midbrain pp38 protein expression in the Parkinson's disease model was significantly enhanced.

Example 30: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Activation of p38 MAPK Phosphorylation, Using Substantia Nigra Pp38 as the Evaluation Indicator)

[0204] 1. Experiment Principle

[0205] Identical to that of Example 29.

[0206] 2. Experiment Method

[0207] Half of experiment mice in each group were taken to separate the midbrain after perfusion and fixation. The tissue was trimmed, and the substantia nigra-striatum area was taken to prepare paraffin sections. The double immunofluorescence staining for TH and phosphorylated p38 was performed to observe the coexpression of TH and phosphorylated p38, for the statistics of the change in the phosphorylated p38 protein expression. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0208] 3. Experiment Results

[0209] The effect of each group on the change in the substantia nigra pp38 protein expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00008 Expression* Changes and statistical difference (P value) (Immunofluorescence Compared with the Compared with the Compared with the Group intensity %) model group positive group prototype group** Blank control group 100.00 ± 8.25  / / / MPTP model group 255.23 ± 26.39 / / / Positive control group 139.72 ± 25.32 Decreased, P < 0.01 / / Prototype control group 3B 134.70 ± 31.07 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3C 138.79 ± 27.44 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3D 114.68 ± 21.42 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3G 118.25 ± 10.60 Decreased, P < 0.01 Equivalent, P > 0.05 / Group B1-1  76.35 ± 21.90 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group C1-1 108.71 ± 12.51 Decreased, P < 0.01 Decreased, P < 0.05 Equivalent, P > 0.05 Group D1-1  57.50 ± 15.33 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group G1-1 82.16 ± 8.10 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group E2-2  96.01 ± 10.37 Decreased, P < 0.01 Decreased, P < 0.01 / Group K3-3 111.17 ± 9.62  Decreased, P < 0.01 Decreased, P < 0.05 / Group K1-4 100.80 ± 5.48  Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-7  77.29 ± 13.06 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4 103.17 ± 12.58 Decreased, P < 0.01 Decreased, P < 0.05 / Group M1-3 100.22 ± 14.12 Decreased, P < 0.01 Decreased, P < 0.05 / Group L1-4  62.93 ± 17.51 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-3  73.08 ± 18.10 Decreased, P < 0.01 Decreased, P < 0.01 / Group J1-4 100.62 ± 13.35 Decreased, P < 0.01 Decreased, P < 0.05 / Group A1-3  58.19 ± 12.07 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-1 98.35 ± 6.93 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-3 81.90 ± 9.52 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5  87.45 ± 11.05 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 101.93 ± 7.44  Decreased, P < 0.01 Decreased, P < 0.01 / Group D5-4 103.25 ± 15.27 Decreased, P < 0.01 Decreased, P < 0.05 / Group S1-6 45.83 ± 9.29 Decreased, P < 0.01 Decreased, P < 0.01 / Group S6-6 105.30 ± 10.08 Decreased, P < 0.01 Decreased, P < 0.05 / Group P1-1 99.55 ± 8.46 Decreased, P < 0.01 Decreased, P < 0.01 / *Expression was expressed in the percentage for the immunofluorescence intensity of each group in the mean immunofluorescence intensity of blank control group. **Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0210] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in the pp38 protein expression, demonstrating that these compounds have a definite inhibitory effect on the increase of substantia nigra pp38 protein expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, all the compounds had a relatively significant or significant decrease in the pp38 protein expression, demonstrating that the inhibitory effect of these compounds on the increase of substantia nigra pp38 protein expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were equivalent or significantly lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of substantia nigra pp38 protein expression in the Parkinson's disease model was significantly enhanced.

Example 31: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Glial Cell Activation, Using Midbrain CD11b as the Evaluation Indicator)

[0211] 1. Experiment Principle

[0212] More and more evidences show that the glial cells play an important role in supporting the neuron development and maintaining the immune homeostasis of the central nervous system. Neuron-glial cell network homeostasis disorder is an important factor for the selective and progressive death of substantia nigra dopaminergic neurons in PD. In the neurotoxic effect of MPTP, the excessive activations of microglial cells and astrocytes produce a variety of inflammatory cytokines and reactive oxygen species (ROS). These inflammatory factors and ROS amplify their respective toxicities and mediate malignant feedback loop, causing a cascade inflammation response and aggravating the pathological process of PD. CD11b and GFAP are the marker proteins for activations of microglial cells and astrocytes, respectively. Therefore, the effect of the target compounds on the activations of the microglial cells and astrocytes in the substantia nigra, hippocampus, and midbrain areas of MPTP-induced PD mice can be investigated, to explore the mechanism of the anti-PD effect of the target compounds by inhibiting the neuroinflammation.

[0213] 2. Experiment Method

[0214] Half of experiment mice in each group were taken to extract the total midbrain protein, and the change in the midbrain P-α-s protein expression was determined by western-blotting using CD11b as the internal reference. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D), and 3G, whose structures are shown as above), and target compound group.

[0215] 3. Experiment Results

[0216] The effect of each group on the change in the midbrain CD11b protein expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00009 Changes and statistical difference (P value) Expression Compared with the Compared with the Compared with the Group (CD11b/GAPDH) model group positive group prototype group* Blank control group 0.76 ± 0.02 / / / MPTP model group 1.85 ± 0.05 / / / Positive control group 1.28 ± 0.10 Decreased, P < 0.01 / / Prototype control group 3B 1.31 ± 0.10 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3C 1.02 ± 0.13 Decreased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3D 1.30 ± 0.10 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3G 0.67 ± 0.12 Decreased, P < 0.01 Decreased, P < 0.01 / Group B1-1 0.41 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group C1-1 1.11 ± 0.08 Decreased, P < 0.01 Decreased, P < 0.05 Equivalent, P > 0.05 Group D1-1 0.33 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group G1-1 0.50 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.05 Group E2-2 1.17 ± 0.06 Decreased, P < 0.01 Equivalent, P > 0.05 / Group K3-3 1.15 ± 0.07 Decreased, P < 0.01 Decreased, P < 0.05 / Group K1-4 1.09 ± 0.10 Decreased, P < 0.01 Decreased, P < 0.05 / Group P1-7 0.39 ± 0.03 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4 0.69 ± 0.04 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-3 0.84 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.01 / Group L1-4 1.09 ± 0.09 Decreased, P < 0.01 Decreased, P < 0.05 / Group K1-3 1.01 ± 0.08 Decreased, P < 0.01 Decreased, P < 0.01 / Group J1-4 0.75 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.01 / Group A1-3 1.12 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.05 / Group M1-1 0.46 ± 0.04 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-3 1.09 ± 0.08 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5 0.83 ± 0.07 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 1.25 ± 0.08 Decreased, P < 0.01 Equivalent, P > 0.05 / Group D5-4 1.11 ± 0.10 Decreased, P < 0.01 Decreased, P < 0.05 / Group S1-6 0.43 ± 0.05 Decreased, P < 0.01 Decreased, P < 0.01 / Group S6-6 0.62 ± 0.04 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-1 0.70 ± 0.06 Decreased, P < 0.01 Decreased, P < 0.01 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0217] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in the CD11b protein expression, demonstrating that these compounds have a definite inhibitory effect on the increase of midbrain CD11b protein expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, most of the compounds had a relatively significant or significant decrease in the CD11b protein expression, demonstrating that the inhibitory effect of these compounds on the increase of midbrain CD11b protein expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were equivalent or lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D), and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of midbrain CD11b protein expression in the Parkinson's disease model was significantly enhanced.

Example 32: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Glial Cell Activation, Using Substantia Nigra CD11b as the Evaluation Indicator)

[0218] 1. Experiment Principle

[0219] Identical to that of Example 31.

[0220] 2. Experiment Method

[0221] Half of experiment mice in each group were taken to separate the midbrain after perfusion and fixation. The tissue was trimmed, and the substantia nigra area was taken to prepare paraffin sections. The CD11b immunohistochemical staining was performed for the statistics of the change in the number of microglial cells with CD11b positive expression. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0222] 3. Experiment Results

[0223] The effect of each group on the change in the number of substantia nigra microglial cells with CD11b positive expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00010 Changes and statistical difference (P value) Positive cell Compared with the Compared with the Compared with the Group number model group positive group prototype group* Blank control group 10 ± 2 / / / MPTP model group 145 ± 11 / / / Positive control group 49 ± 7 Decreased, P < 0.01 / / Prototype control group 3B 44 ± 5 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3C 70 ± 6 Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3D 39 ± 4 Decreased, P < 0.01 Decreased, P < 0.05 / Prototype control group 3G 52 ± 5 Decreased, P < 0.01 Equivalent, P > 0.05 / Group B1-1 32 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group C1-1 27 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group D1-1 15 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group G1-1 36 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group E2-2 40 ± 5 Decreased, P < 0.01 Decreased, P < 0.05 / Group K3-3 39 ± 3 Decreased, P < 0.01 Decreased, P < 0.05 / Group K1-4 30 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-7 15 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4 29 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-3 33 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group L1-4 35 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-3 32 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group J1-4 24 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group A1-3 38 ± 4 Decreased, P < 0.01 Decreased, P < 0.05 / Group M1-1 20 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-3 31 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5 28 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 39 ± 6 Decreased, P < 0.01 Decreased, P < 0.05 / Group D5-4 41 ± 3 Decreased, P < 0.01 Decreased, P < 0.05 / Group S1-6 18 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group S6-6 19 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-1 26 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0224] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in the number of microglial cells with CD11b positive expression, demonstrating that these compounds have a definite inhibitory effect on the increase of number of substantia nigra microglial cells with CD11b positive expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, all the compounds had a relatively significant or significant decrease in the number of microglial cells with CD11b positive expression, demonstrating that the inhibitory effect of these compounds on the increase of number of substantia nigra microglial cells with CD11b positive expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE. The numbers of positive cells of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were significantly lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D), and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of number of substantia nigra microglial cells with CD11b positive expression in the Parkinson's disease model mouse was significantly enhanced.

Example 33: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Glial Cell Activation, Using Hippocampus CD11b as the Evaluation Indicator)

[0225] 1. Experiment Principle

[0226] Identical to that of Example 35.

[0227] 2. Experiment Method

[0228] Half of experiment mice in each group were taken to separate the midbrain after perfusion and fixation. The tissue was trimmed, and the hippocampus area was taken to prepare paraffin sections. The CD11b immunohistochemical staining was performed for the statistics of the change in the number of microglial cells with CD11b positive expression. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0229] 3. Experiment Results

[0230] The effect of each group on the change in the number of hippocampus microglial cell with CD11b positive expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00011 Changes and statistical difference (P value) Positive cell Compared with the Compared with the Compared with the Group number model group positive group prototype group* Blank control group  4 ± 1 / / / MPTP model group 52 ± 3 / / / Positive control group 24 ± 2 Decreased, P < 0.01 / / Prototype control group 3B 16 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3C 20 ± 3 Decreased, P < 0.01 Decreased, P < 0.05 / Prototype control group 3D 18 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3G 18 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group B1-1  9 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group C1-1  7 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group D1-1  7 ± 1 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group G1-1  6 ± 1 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group E2-2 15 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group K3-3 18 ± 1 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-4 13 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-7  8 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4  7 ± 1 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-3 12 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group L1-4 15 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-3 16 ± 1 Decreased, P < 0.01 Decreased, P < 0.01 / Group J1-4 10 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group A1-3 14 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-1  5 ± 1 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-3 16 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5 11 ± 1 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 17 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group D5-4 12 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group S1-6  8 ± 1 Decreased, P < 0.01 Decreased, P < 0.01 / Group S6-6  9 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-1  7 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0231] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in the number of microglial cells with CD11b positive expression, demonstrating that these compounds have a definite inhibitory effect on the increase of number of hippocampus microglial cell with CD11b positive expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, all the compounds had a significant decrease in the number of microglial cells with CD11b positive expression, demonstrating that the inhibitory effect of these compounds on the increase of number of hippocampus microglial cell with CD11b positive expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE. The numbers of positive cells of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were significantly lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of number of hippocampus microglial cell with CD11b positive expression in the Parkinson's disease model mouse was significantly enhanced.

Example 34: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Glial Cell Activation, Using Substantia Nigra GFAP as the Evaluation Indicator)

[0232] 1. Experiment Principle

[0233] Identical to that of Example 31.

[0234] 2. Experiment Method

[0235] Half of experiment mice in each group were taken to separate the midbrain after perfusion and fixation. The tissue was trimmed, and the substantia nigra area was taken to prepare paraffin sections. The GFAP immunohistochemical staining was performed for the statistics of the change in the number of astrocytes with GFAP positive expression. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0236] 3. Experiment Results

[0237] The effect of each group on the change in the number of substantia nigra astrocyte with GFAP positive expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00012 Changes and statistical difference (P value) Positive cell Compared with the Compared with the Compared with the Group number model group positive group prototype group* Blank control group 62 ± 5 / / / MPTP model group 275 ± 12 / / / Positive control group 132 ± 8  Decreased, P < 0.01 / / Prototype control group 3B 121 ± 10 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3C 121 ± 13 Decreased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3D 110 ± 9  Decreased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3G 130 ± 6  Decreased, P < 0.01 Equivalent, P > 0.05 / Group B1-1 88 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group C1-1 56 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group D1-1 64 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group G1-1 76 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group E2-2 102 ± 5  Decreased, P < 0.01 Decreased, P < 0.01 / Group K3-3 96 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-4 112 ± 4  Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-7 73 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4 93 ± 6 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-3 110 ± 5  Decreased, P < 0.01 Decreased, P < 0.01 / Group L1-4 98 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-3 86 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group J1-4 77 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group A1-3 105 ± 6  Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-1 59 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-3 69 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5 81 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 90 ± 6 Decreased, P < 0.01 Decreased, P < 0.01 / Group D5-4 97 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group S1-6 67 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group S6-6 78 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-1 73 ± 6 Decreased, P < 0.01 Decreased, P < 0.01 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0238] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in the number of astrocytes with GFAP positive expression, demonstrating that these compounds have a definite inhibitory effect on the increase of number of substantia nigra astrocyte with GFAP positive expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, all the compounds had a significant decrease in the number of astrocytes with GFAP positive expression, demonstrating that the inhibitory effect of these compounds on the increase of number of substantia nigra astrocyte with GFAP positive expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE. The numbers of positive cells of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were significantly lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of number of substantia nigra astrocyte with GFAP positive expression in the Parkinson's disease model mouse was significantly enhanced.

Example 35: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Glial Cell Activation, Using Hippocampus GFAP as the Evaluation Indicator)

[0239] 1. Experiment Principle

[0240] Identical to that of Example 31.

[0241] 2. Experiment Method

[0242] Half of experiment mice in each group were taken to separate the midbrain after perfusion and fixation. The tissue was trimmed, and the hippocampus area was taken to prepare paraffin sections. The GFAP immunohistochemical staining was performed for the statistics of the change in the number of astrocytes with GFAP positive expression. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0243] 3. Experiment Results

[0244] The effect of each group on the change in the number of hippocampus astrocytes with GFAP positive expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00013 Changes and statistical difference (P value) Positive cell Compared with the Compared with the Compared with the Group number model group positive group prototype group* Blank control group 64 ± 3 / / / MPTP model group 175 ± 10 / / / Positive control group 86 ± 2 Decreased, P < 0.01 / / Prototype control group 3B 118 ± 8  Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3C 147 ± 4  Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3D 106 ± 6  Decreased, P < 0.01 Increased, P < 0.01 / Prototype control group 3G 130 ± 6  Decreased, P < 0.01 Increased, P < 0.01 / Group B1-1 64 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group C1-1 78 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group D1-1 58 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group G1-1 66 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 Decreased, P < 0.01 Group E2-2 50 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group K3-3 69 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-4 71 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-7 49 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group H2-4 61 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-3 57 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group L1-4 76 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group K1-3 65 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group J1-4 79 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group A1-3 55 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-1 51 ± 5 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-3 74 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group M1-5 67 ± 6 Decreased, P < 0.01 Decreased, P < 0.01 / Group R1-5 80 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group D5-4 59 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / Group S1-6 61 ± 4 Decreased, P < 0.01 Decreased, P < 0.01 / Group S6-6 58 ± 2 Decreased, P < 0.01 Decreased, P < 0.01 / Group P1-1 72 ± 3 Decreased, P < 0.01 Decreased, P < 0.01 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0245] It can be seen that compared with the model group, all the compounds showed a statistically significant decrease in the number of astrocytes with GFAP positive expression, demonstrating that these compounds have a definite inhibitory effect on the increase of number of hippocampus astrocytes with GFAP positive expression in the Parkinson's disease model mouse. Compared with the positive control CAPE, all the compounds had a significant decrease in the number of astrocytes with GFAP positive expression, demonstrating that the inhibitory effect of these compounds on the increase of number of hippocampus astrocytes with GFAP positive expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE. The numbers of positive cells of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were significantly lower compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the inhibitory effect of these compounds on the increase of number of hippocampus astrocytes with GFAP positive expression in the Parkinson's disease model mouse was significantly enhanced.

Example 36: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Oxidative Stress Damage, Using HO-1 as the Evaluation Indicator)

[0246] 1. Experiment Principle

[0247] Oxidative stress is an important pathogenic mechanism of PD. Dopaminergic neurons are more sensitive to oxidative stress and are more susceptible to oxidative stress damage. Heme oxygenase (HO-1), a phase II enzyme, is also a well-known antioxidase. It plays an important protective role by catalyzing the conversion of free radicals into non-toxic products and increasing their water solubility to facilitate the elimination of free radicals, and maintain the redox balance in the body. It plays an important role in the process of protecting cells against oxidative stress damage. The activation of p38 protein phosphorylation has a negative regulatory effect on phase II enzymes. Studies have found that in PD mouse models and cell models, the expression of NADPH oxidase is down-regulated by inhibiting the activation of p38, which can up-regulate the expression of HO-1 and resist oxidative damage. Using HO-1 as an indicator, the inhibitory effect of the target compounds on MPTP-induced oxidative stress damage in PD mice can be investigated.

[0248] 2. Experiment Method

[0249] HO-1 is expressed in astrocytes, microglial cells, and neurons. The total proteins of the midbrain tissue of mice in each experiment group were extracted, to determine the expression of phase II enzyme HO-1 in the midbrain of mice by western blot using GAPDH as the internal reference. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), and target compound group.

[0250] 3. Experiment Results

[0251] The effect of each group on the change in the midbrain HO-1 expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00014 Changes and statistical difference (P value) Expression Compared with the Compared with the Compared with the Group (HO-1/GAPDH) model group positive group prototype group* Blank control group 0.76 ± 0.06 / / / MPTP model group 0.48 ± 0.03 / / / Positive control group 0.52 ± 0.07 Equivalent, P > 0.05 / / Prototype control group 3B 0.56 ± 0.03 Increased, P < 0.01 Equivalent, P > 0.05 / Prototype control group 3C 0.44 ± 0.05 Equivalent, P > 0.05 Equivalent, P > 0.05 / Prototype control group 3D 1.03 ± 0.20 Increased, P < 0.01 Increased, P < 0.01 / Prototype control group 3G 0.51 ± 0.07 Equivalent, P > 0.05 Equivalent, P > 0.05 / Group B1-1 0.90 ± 0.10 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group C1-1 0.88 ± 0.09 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group D1-1 1.63 ± 0.12 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group G1-1 1.35 ± 0.10 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group E2-2 1.58 ± 0.08 Increased, P < 0.01 Increased, P < 0.01 / Group K3-3 0.69 ± 0.07 Increased, P < 0.01 Increased, P < 0.01 / Group K1-4 1.02 ± 0.09 Increased, P < 0.01 Increased, P < 0.01 / Group P1-7 0.71 ± 0.09 Increased, P < 0.01 Increased, P < 0.01 / Group H2-4 0.95 ± 0.10 Increased, P < 0.01 Increased, P < 0.01 / Group M1-3 0.80 ± 0.09 Increased, P < 0.01 Increased, P < 0.01 / Group L1-4 1.13 ± 0.12 Increased, P < 0.01 Increased, P < 0.01 / Group K1-3 0.83 ± 0.08 Increased, P < 0.01 Increased, P < 0.01 / Group J1-4 1.25 ± 0.06 Increased, P < 0.01 Increased, P < 0.01 / Group A1-3 0.66 ± 0.05 Increased, P < 0.01 Increased, P < 0.01 / Group M1-1 1.29 ± 0.07 Increased, P < 0.01 Increased, P < 0.01 / Group P1-3 0.77 ± 0.10 Increased, P < 0.01 Increased, P < 0.01 / Group M1-5 0.96 ± 0.08 Increased, P < 0.01 Increased, P < 0.01 / Group R1-5 0.87 ± 0.06 Increased, P < 0.01 Increased, P < 0.01 / Group D5-4 0.93 ± 0.10 Increased, P < 0.01 Increased, P < 0.01 / Group S1-6 0.85 ± 0.06 Increased, P < 0.01 Increased, P < 0.01 / Group S6-6 1.08 ± 0.11 Increased, P < 0.01 Increased, P < 0.01 / Group P1-1 1.17 ± 0.05 Increased, P < 0.01 Increased, P < 0.01 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0252] It can be seen that compared with the model group, all the compounds showed a statistically significant increase in terms of the HO-1 expression, demonstrating that these compounds have a definite up-regulation effect on the midbrain HO-1 expression in the Parkinson's disease model mouse, and were beneficial for the resistance against oxidative damage. Compared with the positive control CAPE, all the compounds had a significant increase in the HO-1 expression, demonstrating that the up-regulation effects of these compounds on the midbrain HO-1 expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE, and have better resistance against oxidative damage. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were significantly higher compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D, and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the up-regulation effect of these compounds on the midbrain HO-1 expression in the Parkinson's disease model was significantly enhanced.

Example 37: Study on the Neuroprotection Mechanism of the Target Compounds in the Parkinson's Disease Model Mouse (i.e., the Inhibitory Effect on the Oxidative Stress Damage, Using GCLC as the Evaluation Indicator)

[0253] 1. Experiment Principle

[0254] Oxidative stress is an important pathogenic mechanism of PD. Dopaminergic neurons are more sensitive to oxidative stress and are more susceptible to oxidative stress damage. Glutathione (GSH) is an important antioxidant substance in the cell, and glutamate cysteine ligase (GCL) is the rate-limiting enzyme for GSH synthesis, which is composed of catalytic subunit (GCLC) and regulatory subunit (GCLM). The increase of GCLC expression can promote the synthesis of GSH and enhance the ability of tissue cells against oxidative stress. GCL, a phase II enzyme, plays an important protective role by catalyzing the conversion of free radicals into non-toxic products and increasing their water solubility to facilitate the elimination of free radicals, and maintain the redox balance in the body. It plays an important role in the process of protecting cells against oxidative stress damage. The activation of p38 protein phosphorylation has a negative regulatory effect on phase II enzymes. Studies have found that in PD mouse models and cell models, the expression of NADPH oxidase is down-regulated by inhibiting the activation of p38, which can up-regulate the expression of GCLC and resist oxidative damage. Using GCLC as an indicator, the inhibitory effect of the target compounds on MPTP-induced oxidative stress damage in PD mice can be investigated.

[0255] 2. Experiment Method

[0256] GCLC is expressed in astrocytes, microglial cells, and neurons. The total proteins of the midbrain tissue of mice in each experiment group were extracted, to determine the expression of phase II enzyme GCLC in the midbrain of mice by western blot using GAPDH as the internal reference. The experiment included blank control group, MPTP model group, positive control group (caffeic acid phenethyl ester, CAPE), prototype control group (styryl sulfone compounds 3B, 3C, 3D), and 3G, whose structures are shown as above), and target compound group.

[0257] 3. Experiment Results

[0258] The effect of each group on the change in the midbrain GCLC expression in the Parkinson's disease model mouse is shown in the table below:

TABLE-US-00015 Changes and statistical difference (P value) Expression Compared with the Compared with the Compared with the Group (GCLC/GAPDH) model group positive group prototype group* Blank control group 1.26 ± 0.12 / / / MPTP model group 0.37 ± 0.04 / / / Positive control group 0.77 ± 0.06 Increased, P < 0.01 / / Prototype control group 3B 0.33 ± 0.04 Equivalent, P > 0.05 Decreased, P < 0.01 / Prototype control group 3C 0.34 ± 0.05 Equivalent, P > 0.05 Decreased, P < 0.01 / Prototype control group 3D 0.53 ± 0.04 Increased, P < 0.01 Decreased, P < 0.01 / Prototype control group 3G 0.57 ± 0.09 Increased, P < 0.01 Decreased, P < 0.01 / Group B1-1 1.17 ± 0.06 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group C1-1 1.34 ± 0.08 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group D1-1 1.29 ± 0.05 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group G1-1 1.05 ± 0.04 Increased, P < 0.01 Increased, P < 0.01 Increased, P < 0.01 Group E2-2 1.48 ± 0.11 Increased, P < 0.01 Increased, P < 0.01 / Group K3-3 0.86 ± 0.04 Increased, P < 0.01 Increased, P < 0.05 / Group K1-4 1.10 ± 0.07 Increased, P < 0.01 Increased, P < 0.01 / Group P1-7 0.87 ± 0.08 Increased, P < 0.01 Increased, P < 0.05 / Group H2-4 1.21 ± 0.08 Increased, P < 0.01 Increased, P < 0.01 / Group M1-3 0.82 ± 0.07 Increased, P < 0.01 Increased, P < 0.05 / Group L1-4 0.96 ± 0.10 Increased, P < 0.01 Increased, P < 0.01 / Group K1-3 1.13 ± 0.08 Increased, P < 0.01 Increased, P < 0.01 / Group J1-4 1.24 ± 0.10 Increased, P < 0.01 Increased, P < 0.01 / Group A1-3 0.84 ± 0.04 Increased, P < 0.01 Increased, P < 0.05 / Group M1-1 1.30 ± 0.09 Increased, P < 0.01 Increased, P < 0.01 / Group P1-3 0.91 ± 0.11 Increased, P < 0.01 Increased, P < 0.05 / Group M1-5 1.35 ± 0.08 Increased, P < 0.01 Increased, P < 0.01 / Group R1-5 1.02 ± 0.09 Increased, P < 0.01 Increased, P < 0.01 / Group D5-4 0.97 ± 0.07 Increased, P < 0.01 Increased, P < 0.01 / Group S1-6 1.44 ± 0.13 Increased, P < 0.01 Increased, P < 0.01 / Group S6-6 1.29 ± 0.08 Increased, P < 0.01 Increased, P < 0.01 / Group P1-1 0.98 ± 0.06 Increased, P < 0.01 Increased, P < 0.01 / *Only four groups of compounds (B1-1, C1-1, D1-1, and G1-1) were compared with the prototype compounds of corresponding structures (i.e., styryl sulfones 3B, 3C, 3D, and 3G)

[0259] It can be seen that compared with the model group, all the compounds showed a statistically significant increase in terms of the GCLC expression, demonstrating that these compounds have a definite up-regulation effect on the midbrain GCLC expression in the Parkinson's disease model mouse, and were beneficial for the resistance of oxidative damage. Compared with the positive control CAPE, all the compounds had a relatively significant or significant increase in the GCLC expression, demonstrating that the up-regulation effects of these compounds on the midbrain GCLC expression in the Parkinson's disease model mouse were stronger than that of the positive control CAPE, and have better resistance against oxidative damage. The expressions of the four groups of compounds B1-1, C1-1, D1-1, and G1-1 were significantly higher compared with those of the styryl sulfone prototype compounds 3B, 3C, 3D), and 3G, demonstrating that compared with the prototype compounds without the introduction of carbamate functional group, the up-regulation effects of these compounds on the midbrain GCLC expression in the Parkinson's disease model was significantly enhanced.

Example 38: Evaluation of the Inhibitory Activity of the Target Compounds on Cholinesterase (Using IC50 Value of Acetylcholinesterase as the Evaluation Indicator)

[0260] 1. Experiment Principle

[0261] The central cholinergic system is an important part of the central nervous system. Acetylcholine (ACh) and butyrylcholine (BCh) are important neurotransmitters synthesized and secreted by central cholinergic neurons, which specifically act on various types of cholinergic receptors and play an important role in regulating synaptic plasticity and learning and memory functions. Therefore, the dysfunction of metabolic function such as neurotransmitter synthesis, release, and uptake or the destroying of cholinergic receptors and post-receptor signaling can lead to the hypofunction of the learning and memory function. Studies have shown that the activity of choline transferase decreases in the cortex such as frontal lobe, temporal lobe, parietal lobe, and right hippocampus of PD patient, and cholinergic neuron damage may be the main biochemical mechanism of PD cognitive dysfunction and dementia. By evaluating the inhibitory activities of the target compounds on the two cholinesterases, their potential therapeutic effect on PD cognitive dysfunction and dementia can be evaluated.

[0262] 2. Experiment Method

[0263] The modified Ellman method was used to determine the inhibitory activity on acetylcholinesterase. The principle lies in that acetylthiocholine iodide is decomposed under the action of acetylcholinesterase (AchE) to generate thiocholine. The thiocholine is quickly reacted with DTNB as the colour-developing agent to generate a yellow substance with light absorption at 405 nm. To a 96-well microplate, 50 μl of enzyme reaction buffer, 125 μl of DTNB (3 mM), 25 μl of test sample or positive control drug, and 25 μl of AchE (0.2 U/ml) were successively added. After incubation at room temperature for 5 min, 25 μl of ATCI (15 mM) was added. After incubation at room temperature for 8 min, the absorbance value was determined at 405 nm with a microplate reader. A blank control group without enzyme (25 μl PBS instead of the sample to be tested) was also established. The inhibition percentage was calculated based on the measurement results, using the negative logarithm of the molar concentration of the corresponding compound as the abscissa and the enzyme inhibition rate as the ordinate to obtain a linear equation. When the inhibition rate is 50%, the molar concentration of the compound, i.e., the IC.sub.50 value of the compound, was calculated. The experiment included blank control group, CAPE control group, prototype control group (styryl sulfone compounds 3B, 3C, 3D, and 3G, whose structures are shown as above), positive drug control group (Rivastigmine), and target compound group.

[0264] 3. Experiment Results

[0265] The inhibitory effect of each group on the acetylcholinesterase is shown in the table below:

TABLE-US-00016 Group IC.sub.50 (μM) CAPE control group >100 Prototype control group 3B >100 Prototype control group 3C >100 Prototype control group 3D >100 Prototype control group 3G >100 Positive drug control group 53.38 ± 3.14 Group B1-1 13.34 ± 2.85 Group C1-1 14.66 ± 3.51 Group D1-1  4.16 ± 1.07 Group G1-1 10.76 ± 2.13 Group E2-2 51.28 ± 3.94 Group K3-3 38.26 ± 2.79 Group K1-4 16.89 ± 1.22 Group P1-7 21.38 ± 2.07 Group H2-4 11.25 ± 1.34 Group M1-3 17.56 ± 2.19 Group L1-4  9.48 ± 1.34 Group K1-3 22.31 ± 3.17 Group J1-4  8.54 ± 1.65 Group A1-3 25.16 ± 3.34 Group M1-1  6.60 ± 0.71 Group P1-3 14.39 ± 2.04 Group M1-5 31.27 ± 4.63 Group R1-5 27.51 ± 3.49 Group D5-4 20.77 ± 3.12 Group S1-6 13.64 ± 2.16 Group S6-6 15.56 ± 3.07 Group P1-1 11.27 ± 1.48

[0266] It can be seen that all the compounds have IC.sub.50 values of less than 100 μM, demonstrating that these compounds have a definite inhibitory effect on acetylcholinesterase; while the IC.sub.50 values in the CAPE control group and prototype control group were both greater than 100 μM, demonstrating that these compounds do not have a definite inhibitory effect. The inhibitory effect of the designed compound on acetylcholinesterase is derived from the newly introduced carbamate functional group. Compared with the positive control drug group, all the compounds have lower IC.sub.50 values, demonstrating that the inhibitory effect of these compounds on acetylcholinesterase is stronger than that of the positive control drug.