A method for preparing a 7-sulfonated derivative of zebulin

Abstract

This invention relates to a method for preparing a 7-sulfonated derivative of zebulin, comprising the following steps: in an organic solvent, zebulin reacts with sulfonyl chloride to obtain a 7-sulfonated derivative of zebulin with the structure of Formula I.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a method for preparing a 7-sulfonated derivative of zelanolin. Background Technology

[0002] Zekranlin is a drug developed by Estee East Pharmaceutical Co., Ltd. in South Korea for the treatment of gastritis and peptic ulcers. This invention obtains a series of 7-sulfonated derivatives by sulfonating its 7-hydroxyl group. The flavonoid structure is the backbone for the pharmacological action of Zekranlin. This invention introduces an aromatic ring (or heteroaromatic ring) sulfonyl pharmacophore at the 7-position, significantly enhancing the anti-inflammatory activity of Zekranlin. This invention provides a method for preparing the above-mentioned 7-sulfonated derivatives of Zekranlin. Summary of the Invention

[0003] This invention provides a method for preparing a 7-sulfonated derivative of zebulinerin with a structure of Formula I, characterized by comprising the following steps:

[0004]

[0005] In organic solvents, zeolite and sulfonyl chloride The reaction yields a 7-sulfonated derivative of zelandrin with the structure of Formula I; wherein ring A is selected from 5-6-membered heterocyclic groups or 6-10-membered aryl groups optionally substituted with one or more R1 groups; wherein R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, nitro, cyano, amino, hydroxyl, and C1-C6 alkoxycarbonyl.

[0006] The organic solvent is preferably one or more of the following: dichloromethane, chloroform, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane, acetone, etc.

[0007] In the above preparation method, it is preferable to add an alkaline reagent during the reaction. The alkaline reagent includes organic bases and inorganic bases. The alkaline reagent is further preferably one or a mixture of several of the following: alkali metal carbonates (such as Li2CO3, Na2CO3, K2CO3), triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP (dimethylaminopyridine), and 2,6-dimethylpyridine.

[0008] Another embodiment of the present invention provides a method for preparing a 7-sulfonated derivative of zebulinen with the structure of Formula I above, characterized in that the 5-6 membered heterocyclic group is selected from pyridinyl, thiopheneyl, furanyl, pyranyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, triazolyl; the 6-10 membered aryl group is selected from phenyl, naphthyl; the C1-C6 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylpropyl, 2-methylpentyl ... The C1-C6 alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and cyclopropoxy; the C1-C6 haloalkyl group is selected from trifluoromethyl, trichloromethyl, tribromomethyl, difluoromethyl, monofluoromethyl, and hexafluoroethyl; the C1-C6 haloalkoxy group is selected from trifluoromethoxy, difluoromethoxy, monofluoromethoxy, and hexafluoroethoxy; the C1-C6 alkoxycarbonyl group is selected from methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl; and the halogen is selected from fluorine, chlorine, bromine, and iodine.

[0009] Another embodiment of the present invention provides a method for preparing a 7-sulfonated derivative of zebulinen with the structure of Formula I described above, characterized in that ring A is selected from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 3-cyanophenyl, 4-cyanophenyl, phenyl, 3-pyridyl, 2-thienyl, 4-tert-butylphenyl.

[0010] The application of the 7-position sulfonated derivative of zelandrin with the formula I prepared by the above-described preparation method of the present invention in the preparation of anti-inflammatory drugs.

[0011] The 5-6 membered heterocyclic group of this invention is selected from 5-6 membered heterocyclic groups containing 1-3 heteroatoms, wherein the heteroatoms are selected from N, O, and S; the 5-6 membered heterocyclic group is further preferably pyridyl, thiophenyl, furanyl, pyranyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, or triazolyl. The 6-10 membered aryl group is selected from phenyl and naphthyl. The C1-C6 alkyl group refers to a straight-chain, branched, or cycloalkyl group containing 1 to 6 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 3-methylpentyl, or 2,3-dimethylpropyl. The C1-C6 alkoxy group refers to a straight-chain, branched, or cycloalkoxy group containing 1 to 6 carbon atoms, preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or cyclopropoxy. The C1-C6 haloalkyl group refers to a straight-chain, branched, or cycloalkyl group containing 1 to 6 carbon atoms substituted with one or more halogens, preferably trifluoromethyl, trichloromethyl, tribromomethyl, difluoromethyl, monofluoromethyl, or hexafluoroethyl. The C1-C6 haloalkoxy group refers to a straight-chain, branched, or cycloalkoxy group containing 1 to 6 carbon atoms substituted with one or more halogens, preferably trifluoromethoxy, difluoromethoxy, monofluoromethoxy, or hexafluoroethoxy. The C1-C6 alkoxycarbonyl group refers to a straight-chain, branched, or cycloalkoxycarbonyl group containing 1 to 6 carbon atoms, preferably methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl. The "halogen" is preferably fluorine, chlorine, bromine, or iodine.

[0012] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0013] Compared with existing technologies, the advantages of this invention are as follows: This invention provides a method for preparing a 7-sulfonated derivative of zebulinen, which involves simple preparation steps, mild reaction conditions, and high yield. Furthermore, the 7-sulfonated derivative of zebulinen prepared by this invention has a novel structure and excellent pharmacological activity. Attached Figure Description

[0014] Figure 1 This is the standard curve of nitric oxide;

[0015] Figure 2 This is a graph showing the release of nitric oxide from the control group, model group, and individual test groups.

[0016] Figure 3 This is the standard curve diagram of IL-6;

[0017] Figure 4This is a graph showing the IL-6 release levels in the control group, model group, and individual test groups. Detailed Implementation

[0018] To facilitate a further understanding of the present invention, the following embodiments are provided for more detailed description. However, these embodiments are only for a better understanding of the invention and are not intended to limit the scope or implementation principles of the invention. The implementation of the present invention is not limited to the following.

[0019] Example 1: Preparation of Zelinlanin Derivatives 1-31

[0020] Synthetic compound 1

[0021] Add 0.14 mmol of zeolite to a 100 mL three-necked flask, add 50 mL of chloroform to dissolve it, add K2CO3 (0.22 mmol) and 2-toluenesulfonyl chloride (0.22 mmol), heat to reflux temperature, reflux for 3 h, and TLC to detect complete reaction. Add appropriate amount of water to quench reaction, extract with chloroform, dry the organic layer with anhydrous sodium sulfate, filter, concentrate and separate by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain compound 1 (65.6 mg).

[0022] Synthetic compound 2

[0023] 0.1 mmol of zeolite was dissolved in 40 mL of dichloromethane, and triethylamine (0.2 mmol), 3-toluenesulfonyl chloride (0.2 mmol), and a catalytic amount of DMAP were added. After reacting at 30 °C for 5 h, the reaction was detected by TLC to be complete. The reaction was quenched with an appropriate amount of water, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain compound 2 (47.4 mg).

[0024] Synthetic compound 3

[0025] Dissolve 0.1 mmol of zeolite in 30 mL of acetone, add pyridine (0.3 mmol) and 4-toluenesulfonyl chloride (0.2 mmol), react overnight at room temperature, and detect complete reaction by TLC. Quench reaction with appropriate amount of water, extract with dichloromethane, dry organic layer with anhydrous sodium sulfate, filter, concentrate and separate by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain compound 3 (47.3 mg).

[0026] Following a similar method to the synthesis of compounds 1, 2, and 3 described above, using zeylanin in organic solvents (dichloromethane, chloroform, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane)

[0027] The reaction of one or more of dimethylaniline, DMAP (dimethylaminopyridine), and 2,6-dimethylpyridine (at room temperature to reflux temperature) yields the corresponding zebulin derivatives (compounds 4-31) in the yields shown in the table below.

[0028]

[0029]

[0030]

[0031] The NMR and MS data of compounds 1-31 are as follows:

[0032] The structural characterization data of compound 1 are as follows: 1 H NMR(400MHZ,CHCl3)δ12.99(s,1H),7.91(d,J=7.87Hz,1H),7.55(q,J=8.35Hz,2H),7.43(d,J=7.58Hz,1H),7.31(q, J=7.21Hz,2H),7.09(s,1H),6.99(d,J=8.44Hz,1H),6.63(s,1H),3.99(d,J=8.34Hz,6H),3.66(s,3H),2.85(s,3H); 13 C NMR(101MHz,CHCl3)δ183.01,165.07,154.08,152.70,151.03,149.41,146.75,139.55,136.32,134.48,13 2.78,130.21,126.11,123.18,120.46,111.21,110.10,108.75,104.26,102.23,60.79,56.18,20.60; HRMS m / z:499.09452[M+H] + .

[0033] The structural characterization data of compound 2 are as follows: 1H NMR(400MHZ,CHCl3)δ13.00(s,1H),7.82(s,1H),7.77(d,J=7.80Hz,1H),7.52(q,J=7.26Hz,2H),7.44(t,J=7.72Hz,1H),7.35(s,1 H),7.26(d,J=0.60Hz,1H),7.10(s,1H),6.99(d,J=8.20Hz,1H),6.64(s,1H),3.99(d,J=8.88Hz,6H),3.71(s,3H),2.45(s,3H).13C NMR(101MHz,CHCl3)δ183.03,154.16,146.84,139.61,135.40,129.05,128.71,125.6 0,120.47,123.19,111.22,110.20,108.77,104.29,102.16,60.85,56.20,21.35; HRMS m / z:499.09842[M+H] + .

[0034] The structural characterization data of compound 3 are as follows: 1 H NMR(400MHZ,CHCl3)δ12.98(s,1H),7.85(d,J=7.91Hz,2H),7.53(d,J=8.54Hz,1H),7.35(d,J=6.97Hz,3 H),7.11(s,1H),6.99(d,J=8.48Hz,1H),6.64(s,1H),3.99(d,J=8.98Hz,6H),3.72(s,3H),2.46(s,3H); 13 C NMR(101MHz,CHCl3)δ183.02,165.08,154.14,152.72,151.10,149.44,146.96,145.83,136.36,132.6 3,129.85,128.51,123.20,120.47,111.23,110.17,108.78,104.28,102.12,60.90,56.19,21.81; HRMS m / z:499.10611[M+H] + .

[0035] The structural characterization data of compound 4 are as follows: 1H NMR(400MHZ,CHCl3)δ12.96(s,1H),7.89(d,J=7.85Hz,1H),7.64(q,J=7.83Hz,1H),7.53(q,J=8.46Hz,1H),7 .34(s,1H),7.10(d,J=9.51Hz,2H),7.02(m,J=7.72Hz,2H),6.63(s,1H),3.99(d,J=9.22Hz,9H),3.76(s,3H); 13 CNMR(101MHz,CHCl3)δ183.02,165.06,158.20,154.07,152.69,151.11,149.42,147.57,136.47,13 1.48,123.24,120.45,120.14,112.57,111.21,109.99,108.78,104.27,102.41,60.98,56.25; HRMS m / z:515.10078[M+H] + .

[0036] The structural characterization data of compound 5 are as follows: 1 H NMR(400MHZ,CHCl3)δ12.98(s,1H),7.89(d,J=8.26Hz,2H),7.53(q,J=8.47Hz,1H),7.35(s,1H),7 .11(s,1H),7.00(d,J=8.24Hz,2H),6.63(s,1H),3.99(d,J=9.00Hz,6H),3.89(s,3H),3.74(s,3H); 13 CNMR(101MHz,CHCl3)δ183.00,165.05,164.43,154.12,152.71,151.10,149.42,147.03,136 .38,130.81,126.80,123.17,120.46,114.40,60.94,56.18,55.77,29.71,29.33,14.14; HRMS m / z:515.10089[M+H] + .

[0037] The structural characterization data of compound 6 are as follows: 1H NMR(400MHZ,CHCl3)δ13.01(s,1H),7.99(d,J=7.92Hz,2H),7.75(q,J=7.92Hz,2H),7.53(q,J=7.36Hz,2H),7.42(q, J=7.64Hz,1H),7.35(s,1H),7.08(s,1H),6.99(d,J=8.44Hz,1H),6.64(s,1H),3.99(d,J=7.44Hz,6H),3.73(s,3H); 13 C NMR(101MHz,CHCl3)δ182.99,165.14,154.22,152.75,151.09,149.43,147.19,136.35,136.22,13 1.66,128.36,126.32,123.14,120.43,111.23,110.34,108.76,104.28,102.60,60.90,56.17; HRMS m / z:445.22787[M+H] + .

[0038] The structural characterization data of compound 7 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.04(s,1H),7.91(d,J=7.76Hz,1H),7.86(s,1H),7.63(q,J=8.00Hz,1H),7.55(q,J=8. 52Hz,2H),7.35(s,1H),7.06(s,1H),7.00(d,J=8.48Hz,1H),6.65(s,1H),3.99(d,J=7.40Hz,6H),3.73(s,3H); 13 CNMR(101MHz,CHCl3)δ182.97,165.17,154.30,152.79,151.08,149.46,149.24,146.39,137.59,136.28,13 0.90,127.06,126.79,123.10,121.12,120.50,111.24,110.44,108.77,104.31,102.20,60.81,56.18; HRMS m / z:445.22797[M+H] + .

[0039] The structural characterization data of compound 8 are as follows: 1H NMR(400MHZ,CHCl3)δ13.04(s,1H),8.05(d,J=8.11Hz,2H),7.53(d,J=8.46Hz,1H),7.39(q,J=8.36Hz,2 H),7.35(s,1H),7.06(s,1H),6.99(d,J=8.47Hz,1H),6.65(s,1H),3.99(d,J=7.14Hz,6H),3.73(s,3H); 13 C NMR(101MHz,CHCl3)δ182.96,165.13,154.25,153.54,152.79,151.07,149.45,146.48,136.24,133.88,130.8 0,123.08,120.81,120.49,111.23,110.38,108.76,104.28,102.19,60.81,56.17,121.46,118.87,29.71; HRMS m / z:569.07306[M+H] + .

[0040] The structural characterization data of compound 9 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.00(s,1H),8.12(d,J=7.96Hz,1H),8.00(d,J=7.83Hz,1H),7.83(q,J=7.64Hz,1H),7.71(q,J=7. 70Hz,1H),7.54(d,J=8.47Hz,1H),7.35(s,1H),7.10(s,1H),6.99(d,J=8.31Hz,1H),3.99(d,J=8.21Hz,6H),3.66(s,3H); 13 C NMR(101MHz,CHCl3)δ182.98,165.18,154.29,152.77,151.12,149.44,146.66,136.27,134.53,134.31,132.39 ,132.23,128.72,128.66,123.09,123.70,120.50,111.23,110.39,108.75,104.27,102.78,60.80,56.18; HRMS m / z:553.06445[M+H] + .

[0041] The structural characterization data of compound 10 are as follows: 1H NMR(400MHZ,CHCl3)δ13.05(s,1H),8.30(s,1H),8.15(d,J=7.85Hz,1H),7.97(q,J=7.76Hz,1H),7.73(q,J=7.84Hz,1H),7 .54(d,J=8.36Hz,1H),7.35(s,1H),7.07(s,1H),7.00(d,J=8.40Hz,1H),6.65(s,1H),3.99(d,J=8.21Hz,6H),3.66(s,3H); 13 C NMR(101MHz,CHCl3)δ182.97,165.19,154.30,152.81,151.10,149.47,146.30,137.03,136.19,131.63 ,131.11,129.99,125.73,123.09,120.51,111.25,110.48,108.79,104.33,102.32,60.77,56.18; HRMS m / z:553.07703[M+H] + .

[0042] The structural characterization data of compound 11 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.06(s,1H),8.13(d,J=8.11Hz,2H),7.85(d,J=8.12Hz,2H),7.54(q,J=8.47Hz,1 H),7.35(s,1H),7.06(s,1H),7.00(d,J=8.44Hz,1H),6.65(s,1H),3.99(d,J=6.73Hz,6H),3.72(s,3H); 13 C NMR (101MHz, CHCl3) δ149.47,146.38,129.05,126.37,123.08,120.51,111.25,108.77,104.33,102.14,60.85,56.19; HRMS m / z:553.07373[M+H] + .

[0043] The structural characterization data of compound 12 are as follows: 1H NMR(400MHZ,CHCl3)δ13.00(s,1H),7.86(t,J=7.18Hz 1H),7.71(q,J=6.66Hz,1H),7.54(d,J=8.40Hz,1H),7.32(q,J=6.66Hz,3H),7.11 (s,1H),6.99(d,J=8.42Hz,1H),6.64(s,1H),3.99(d,J=8.41Hz,6H),3.76(s,3H); 13 CNMR(101MHz,CHCl3)δ183.00,165.16,154.24,152.75,151.11,149.43,146.69,56.20,61.01,102.63, 104.30,108.77,110.37,111.22,117.42,117.63,120.50,123.13,124.34,131.07,136.38,137.04; HRMS m / z:503.06891[M+H] + .

[0044] The structural characterization data of compound 13 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.04(s,1H),7.77(d,J=7.81Hz,1H),7.71(d,J=7.71Hz,1H),7.56(q,J=8.49Hz,2H),7.41(t,J=8.30Hz 1H),7.35(s,1H),7.08(s,1H),7.00(d,J=8.51Hz 1H),6.65(s,1H),3.99(d,J=8.45Hz,6H),3.74(s,3H). 13 C NMR (101MHz, CHCl3) δ182.99,165.17,154.26,131.06,124.33,121.83,120.51,116.02,111.24,108.80,104.33,102.16,60.89,56.18; HRMS m / z:503.08005[M+H] + .

[0045] The structural characterization data of compound 14 are as follows: 1H NMR(400MHZ,CHCl3)δ13.02(s,1H),8.00(q,J=4.21Hz,1H),7.54(d,J=8.40Hz,1H),7.35(s,1H),7.23(d,J=8.20Hz 1H),7.08(s,1H),7.00(d,J=8.48Hz 1H),6.65(s,1H),3.99(d,J=8.45Hz,6H),3.74(s,3H); 13 C NMR(101MHz,CHCl3)δ182.98,165.14,154.25,152.79,151.12,149.46,146.66,136.28,131.44 ,123.13,120.49,116.75,116.52,111.24,110.33,108.78,104.30,102.22,60.91,56.19; HRMS m / z:503.07880[M+H] + .

[0046] The structural characterization data of compound 15 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.00(s,1H),8.00(d,J=7.93Hz,1H),7.63(m,J=7.16Hz,2H),7.53(d,J=8.43Hz,1H),7.41(t,J=7.50Hz 1H),7.34(s,1H),7.07(s,1H),6.99(d,J=8.51Hz 1H),6.63(s,1H),3.99(d,J=7.62Hz,6H),3.74(s,3H); 13 C NMR(101MHz,CHCl3)δ182.99,165.14,154.27,152.74,151.07,149.42,146.81.136.39,135. 27,134.32,133.85,132.22,131.85,126.96,123.14,120.49,111.21,110.33,108.77,104.29 102.66,61.08,56.19; HRMS m / z:519.04724[M+H] + .

[0047] The structural characterization data of compound 16 are as follows: 1H NMR(400MHZ,CHCl3)δ13.04(s,1H),8.00(s,1H),7.86(d,J=7.80Hz,1H),7.68(d,J=8.4Hz,1H ),7.52(m,J=5.41Hz,2H),7.34(d,J=7.64Hz,1H),7.26(s,1H),7.07(s,1H),6.99(q,J=7.60Hz 1H),6.65(s,1H),3.99(d,J=8.76Hz,6H),3.74(s,3H); 13 C NMR(101MHz,CHCl3)δ183.00,165.17,154.26,152.78,151.09,149.45,146.46,137.35,136.27,135.46,134.7 2,130.45,128.50,126.55,123.12,120.51,111.24,110.41,108.77,104.33,102.22,60.88,56.18,29.72; HRMS m / z:519.04755[M+H] + .

[0048] The structural characterization data of compound 17 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.03(s,1H),7.91(d,J=7.80Hz,2H),7.54(d,J=8.36Hz,3H),7.35(s, 1H),7.07(s,1H),7.00(d,J=8.44Hz,1H),6.65(s,1H),3.99(d,J=8.28Hz,6H),3.74(s,3H); 13 C NMR(101MHz,CHCl3)δ182.97,165.14,154.26,152.77,151.11,149.44,146.60,141.44,136.25,13 4.11,129.90,129.59,123.10,120.50,111.22,110.36,108.74,104.31,102.18,60.93,56.19; HRMS m / z:519.04773[M+H] + .

[0049] The structural characterization data of compound 5-18 are as follows: 1H NMR(400MHZ,CHCl3)δ13.00(s,1H),8.03(d,J=7.7Hz,1H),7.87(d,J=7.80Hz,1H),7.49(M,J=7.94Hz,3 H),7.34(s,1H),7.06(s,1H),6.99(d,J=8.36Hz,1H),6.64(s,1H),3.99(d,J=7.40Hz,6H),3.74(s,3H); 13 C NMR(101MHz,CHCl3)δ182.99,165.13,154.27,152.73,151.05,149.41,146.79,136.39,136.22,135.78,13 5.14,132.10,127.56,123.13,121.60,120.49,111.21,110.32,108.76,104.29,102.65,61.14,56.18; HRMS m / z:564.99518[M+H] + .

[0050] The structural characterization data of compound 19 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.05(s,1H),8.16(s,1H),7.90(d,J=7.96Hz,1H),7.83(d,J=7.96Hz,1H),7.54(d,J=8.40Hz 1H),7.45(t,J=7.96Hz 1H),7.35(s,1H),7.07(s,1H),7.00(s,J=8.48Hz,1H),6.65(s,1H),3.99(d,J=8.80Hz,6H),3.75(s,3H); 13 C NMR (101MHz, CHCl3) δ130.63,126.97,123.10,120.51,111.24,110.41,108.77,104.32,102.23,60.88,56.20; HRMS m / z:564.98511[M+H] + .

[0051] The structural characterization data of compound 20 are as follows: 1H NMR(400MHZ,CHCl3)δ13.04(s,1H),7.84(d,J=7.75Hz 2H),7.71(d,J=7.61Hz,2H),7.54(d,J=8.44Hz,1H),7.35(s,1H),7.07(s,1H),7.00(d,J=8.43 Hz,1H),6.65(s,1H),7.00(s,J=8.48Hz,1H),6.65(s,1H),3.99(d,J=8.21Hz,6H),3.74(s,3H); 13 C NMR(101MHz,CHCl3)δ182.97,165.14,154.26,152.78,151.10,149.45,146.59,136.25,134.70,13 2.57,130.04,129.90,123.11,120.50,111.24,110.36,108.76,104.31,102.15,60.92,56.20; HRMS m / z:564.99500[M+H] + .

[0052] The structural characterization data of compound 21 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.05(s,1H),8.12(d,J=7.72Hz,1H),7.92(d,J=7.79Hz,2H),7.86(t,J=7.57Hz,1H),7.76(t,J=7.57Hz,1 H),7.54(d,J=8.38Hz,1H),7.36(s,1H),7.11(s,1H),7.00(d,J=8.30Hz,1H),6.66(s,1H),3.99(d,J=7.91Hz,6H),3.74(s,3H); 13 C NMR(101MHz,CHCl3)δ183.00,165.27,154.38,151.18,149.45,146.62,136.24,135.46,13 2.35,131.78,129.53,125.07,123.07,120.55,111.23,108.77,104.32,61.10,56.19; HRMS m / z:530.07159[M+H] + .

[0053] The structural characterization data of compound 22 are as follows: 1H NMR(400MHZ,CHCl3)δ13.07(s,1H),8.86(s,1H),8.55(d,J=8.20Hz,2H),8.28(d,J=7.78Hz,1H),7.80(t,J=8.05Hz,1H),7 .55(d,J=8.51Hz,1H),7.36(s,1H),7.11(s,1H),7.00(d,J=8.39Hz,1H),6.66(s,1H),3.99(d,J=9.10Hz,6H),3.75(s,3H); 13 C NMR(101MHz,CHCl3)δ182.94,165.28,154.37,152.85,151.18,149.48,137.75,133.88 ,130.54,128.95,123.94,120.56,111.26,108.80,104.36,102.38,60.95,56.21; HRMS m / z:530.07164[M+H] + .

[0054] The structural characterization data of compound 23 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.07(s,1H),8.41(d,J=8.11Hz 2H),8.18(d,J=8.20Hz,2H),7.54(d,J=8.09Hz,1H),7.35(s,1H),7.08(s,1H ),7.00(d,J=8.42Hz,1H),6.66(s,1H),3.99(d,J=7.29Hz,6H),3.72(s,3H); 13 C NMR(101MHz,CHCl3)δ182.97,165.14,154.26,152.77,151.11,149.44,146.60,141.44,136.25,13 4.11,129.90,129.59,123.10,120.50,111.22,110.36,108.74,104.31,102.18,60.93,56.19; HRMS m / z:530.07166[M+H] + .

[0055] The structural characterization data of compound 24 are as follows: 1H NMR(400MHZ,CHCl3)δ13.00(s,1H),8.04(d,J=7.94Hz,1H),7.76(s,2H),7.64(q,J=4.47Hz,1H),7.53(d ,J=8.42Hz,1H),7.34(s,1H),7.05(s,1H),6.99(d,J=8.44Hz,1H),3.98(d,J=8.45Hz,8H),3.73(s,2H); 13 C NMR(101MHz,CHCl3)δ183.00,166.81,165.11,154.30,152.74,151.10,149.44,147.01,136.46,134.27,133.3 2,130.92,130.28,129.76,123.17,120.48,111.23,110.30,108.81,104.31,102.44,60.97,56.19,53.33; HRMS m / z:563.98109[M+H] + .

[0056] The structural characterization data of compound 25 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.03(s,1H),8.22(d,J=7.79Hz,2H),8.05(d,J=7.81Hz,2H),7.54(q,J=8.57Hz,1 H),7.35(s,1H),7.08(s,1H),7.00(d,J=8.40Hz,1H),6.65(s,1H),3.99(d,J=8.94Hz,9H),3.70(s,3H); 13 C NMR(101MHz,CHCl3)δ182.97,165.23,154.26,152.78,149.44,146.54,139.49,130.29,128.5 3,123.11,120.52,135.48,111.23,110.40,108.76,104.32,102.20,60.88,56.19,52.86; HRMS m / z:543.08360[M+H] + .

[0057] The structural characterization data of compound 26 are as follows: 1H NMR(400MHZ,CHCl3)δ13.07(s,1H),8.28(s,1H),8.19(d,J=8.02Hz,1H),7.98(q,J=7.69Hz,1H),7.73(q,J=7.83Hz,1H),7 .54(d,J=8.26Hz,1H),7.35(s,1H),7.08(s,1H),7.00(d,J=8.48Hz,1H),6.66(s,1H),3.99(d,J=8.58Hz,6H),3.73(s,3H); 13 C NMR(101MHz,CHCl3)δ182.94,165.27,154.35,152.83,151.16,149.46,146.17,137.55,137.42,132.36,13 2.06,130.27,123.03,120.56,116.70,113.92,111.24,110.58,108.76,104.36,102.32,60.92,56.20; HRMS m / z:508.06812[M+H] + .

[0058] The structural characterization data of compound 27 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.07(s,1H),8.01(d,J=7.89Hz,2H),7.87(d,J=7.97Hz,2H),7.54(q,J=8.48Hz,1 H),7.34(s,1H),7.06(s,1H),7.00(d,J=8.45Hz,1H),6.65(s,1H),3.99(d,J=7.28Hz,6H),3.71(s,3H); 13 C NMR(101MHz,CHCl3)δ182.92,165.23,154.35,152.85,151.13,149.46,146.24,139.87,136.05,132.89 ,129.11,123.00,120.53,118.25,116.92,111.24.110.54,108.75,104.33,102.25,60.90,56.20; HRMS m / z:508.06709[M+H] + .

[0059] The structural characterization data of compound 28 are as follows: 1H NMR(400MHZ,CHCl3)δ13.00(s,1H),7.98(d,J=7.79Hz,2H),7.70(d,J=7.43Hz,1H),7.56(m,J=5.61Hz,3 H),7.35(s,1H),7.10(s,1H),6.99(d,J=8.24Hz,1H),6.64(s,1H),3.99(d,J=8.87Hz,6H),3.70(s,3H); 13 C NMR(101MHz,CHCl3)δ183.02,165.10,154.17,152.73,151.08,149.43,146.80,136.36,135.70,134.6 1,129.23,128.47,123.17,120.48,111.22,110.24,108.76,104.29,102.18,60.86,56.19,2.12; HRMS m / z:485.0936[M+H] + .

[0060] The structural characterization data of compound 29 are as follows: 1 H NMR (400MHZ, CHCl3) δ13.05 (s, 1H), 9.16 (s, 1H), 8.91 (d, J = 4.41Hz, 1H), 8.25 (d, J = 7.55Hz, 1H), 7.53 (q, J = 5. 20Hz,2H),7.35(s,1H),7.10(s,1H),7.00(d,J=8.24Hz,1H),6.65(s,1H),3.99(d,J=8.67Hz,6H),3.72(s,3H); 13 CNMR(101MHz,CHCl3)δ182.95,165.21,154.91,154.31,152.82,151.13,149.46,149.09,146.2 7,136.10,123.72,123.06,120.53,111.25,110.52,108.79,104.33,102.34,60.88,56.20; HRMS m / z:485.0827[M+H] + .

[0061] The structural characterization data of compound 30 are as follows: 1H NMR(400MHZ,CHCl3)δ13.01(s,1H),7.77(d,J=4.86Hz,2H),7.54(d,J=8.49Hz,1H),7.35(s,1H),7.15(d ,J=4.23Hz,1H),7.10(s,1H),7.00(d,J=8.46Hz,1H),6.65(s,1H),3.99(d,J=8.56Hz,6H),3.78(s,3H); 13 C NMR(101MHz,CHCl3)δ183.01,165.15,154.20,152.77,149.45,146.77,136.48,135.72,13 5.16,127.69,123.16,120.50,111.23,110.36,108.80,104.31,102.18,61.05,56.20; HRMS m / z:491.04691[M+H] + .

[0062] The structural characterization data of compound 31 are as follows: 1 H NMR(400MHZ,CHCl3)δ13.00(s,1H),7.91(d,J=7.92Hz,2H),7.58(d,J=7.88Hz,2H),7.53(d,J=8.48Hz,1H),7. 35(s,1H),7.09(s,1H),6.99(d,J=8.48Hz,1H),6.64(s,1H),3.99(d,J=7.53Hz,6H),3.70(s,3H),1.35(s,9H); 13 CNMR(101MHz,CHCl3)δ183.03,165.04,158.74,154.10,152.71,151.04,149.43,146.85,136.39,132.68,128. 35,126.27,123.19,120.45,111.21,110.15,108.76,104.25,102.08,60.77,56.18,35.42,31.01,29.71; HRMS m / z:541.15295[M+H] + .

[0063] Example 2

[0064] This invention establishes an inflammation model by inducing cells with LPS. Figure 2This invention discloses that the derivatives of zebulin 1-31 and zebulin, at a concentration of 100 μM, significantly reduced nitric oxide release levels in RAW164.7 cells. Compared to the model group (LPS), compounds 1-31 reduced nitric oxide release levels by more than 50% at a concentration of 100 μM. At a concentration of 100 μM, zebulin showed activity comparable to compound 14 (J14) (not shown in the figure). Here, the applicant only lists the inhibitory effects of compounds 7 (labeled J7 in the figure), 9 (labeled J9 in the figure), 11 (labeled J11 in the figure), 12 (labeled J12 in the figure), 13 (labeled J13 in the figure), 14 (labeled J14 in the figure), 22 (labeled J22 in the figure), and 26 (labeled J26 in the figure) on nitric oxide release levels, with specific experimental details as follows:

[0065] An inflammation model was established by inducing cell division with LPS. RAW164.7 cells were treated with different concentrations (0, 25, 50, 100, 150, 200 μM). The changes in nitric oxide content in cell supernatant at different concentrations of eight compounds were measured using a nitric oxide kit. Standard curves were obtained as follows: Figure 2 Since absorbance is directly proportional to the amount of nitric oxide released, the amount of nitric oxide released can be inferred from absorbance.

[0066] Example 3

[0067] This invention relates to zebulin derivatives 1-31 and the inhibitory effect of zebulin on IL-6 release levels.

[0068] The applicant only listed the inhibitory effects of compounds 7 (labeled J7 in the figure), 9 (labeled J9 in the figure), 11 (labeled J11 in the figure), 12 (labeled J12 in the figure), 13 (labeled J13 in the figure), 14 (labeled J14 in the figure), 22 (labeled J22 in the figure), and 26 (labeled J26 in the figure) on IL-6 release levels. The specific experimental results are as follows:

[0069] After establishing the inflammation model, eight compounds (7, 9, 11, 12, 13, 14, 22, and 26) were applied to the cells at drug concentrations of 50 μmol and 100 μmol. The IL-6 content in the cell supernatant was measured using an ELISA kit, and a standard curve was plotted as shown below. Figure 3 Since absorbance is directly proportional to the amount of IL-6 released, the amount of IL-6 released can be inferred from absorbance. At a concentration of 100 μM, zebulin showed activity comparable to compound 14 (J14) (not shown in the figure).

[0070] Depend on Figure 4The activity results showed that, compared with the LPS group, the amount of IL-6 released by compounds 7, 9, 11, 12, 13, 14, 22, and 26 decreased with increasing drug concentration, indicating that all compounds had anti-inflammatory effects.

Claims

1. A method for preparing a 7-sulfonated derivative of zebulinerin with a structure of Formula I, characterized in that... Includes the following steps: In organic solvents, zeolite and sulfonyl chloride The reaction yields a 7-sulfonated derivative of zelandrin with the structure of Formula I; wherein ring A is selected from 5-6-membered heterocyclic groups or 6-10-membered aryl groups optionally substituted with one or more R1 groups; wherein R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, nitro, cyano, amino, hydroxy, and C1-C6 alkoxycarbonyl. The 5-6 membered heterocyclic group is selected from pyridinyl, thiopheneyl, furanyl, pyranyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, and triazolyl; the 6-10 membered aryl group is selected from phenyl and naphthyl.

2. The preparation method according to claim 1, characterized in that... The C1-C6 alkyl groups are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 3-methylpentyl, and 2,3-dimethylpropyl; the C1-C6 alkoxy groups are selected from methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and cyclopropoxy; the C1-C6 haloalkyl groups are selected from trifluoromethyl, trichloromethyl, tribromomethyl, difluoromethyl, monofluoromethyl, and hexafluoroethyl; the C1-C6 haloalkoxy groups are selected from trifluoromethoxy, difluoromethoxy, monofluoromethoxy, and hexafluoroethoxy; the C1-C6 alkoxycarbonyl groups are selected from methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl; and the halogens are selected from fluorine, chlorine, bromine, and iodine.

3. The preparation method according to claim 1, characterized in that... The A ring is selected from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 3-cyanophenyl, 4-cyanophenyl, phenyl, 3-pyridyl, 2-thiophenyl, 4-tert-butylphenyl.

4. The preparation method according to claim 1, characterized in that... The organic solvent is selected from one or more of dichloromethane, chloroform, acetonitrile, benzene, toluene, THF, diethyl ether, ethylene glycol dimethyl ether, DMF, dioxane, and acetone.

5. The preparation method according to any one of claims 1-4, characterized in that... An alkaline reagent is added to the reaction, wherein the alkaline reagent is selected from organic bases and inorganic bases.

6. The preparation method according to claim 5, characterized in that... The alkaline reagent is selected from one or a mixture of several of the following: alkali metal carbonates, triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, dimethylaminopyridine, and 2,6-dimethylpyridine.

7. The preparation method according to claim 6, characterized in that... The alkali metal carbonate is selected from one or more of Li2CO3, Na2CO3, and K2CO3.

8. The use of the 7-sulfonated derivative of zelanin of Formula I prepared by the method of claim 1, or a pharmaceutically acceptable salt thereof, in the preparation of anti-inflammatory drugs.

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