CN112250690B

CN112250690B - Sulfonyl fangchinoline compounds and preparation method and application thereof

Info

Publication number: CN112250690B
Application number: CN202011018556.5A
Authority: CN
Inventors: 刘玉法; 吕绪涛; 高修正; 闫新华
Original assignee: Shandong Normal University
Current assignee: Shandong Normal University
Priority date: 2020-09-24
Filing date: 2020-09-24
Publication date: 2022-07-15
Anticipated expiration: 2040-09-24
Also published as: CN112250690A

Abstract

The invention discloses a sulfonyl fangchinuoThe lindrine compound has a structure shown in a formula (I) or a formula (I'):

Description

Sulfonyl fangchinoline compounds and preparation method and application thereof

Technical Field

The invention relates to the field of medicines, and in particular relates to a sulfonyl fangchinoline compound and a preparation method and application thereof.

Background

The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Uric acid is a final product of purine metabolized by XOD, and the production, absorption, decomposition and excretion of uric acid in a human body are in steady balance, so that once one part in the process is disordered, the steady balance of uric acid in the body is abnormal, and hyperuricemia is caused.

XOD plays a key role in uric acid synthesis, inhibits the activity of XOD, can reduce the generation of uric acid in vivo and further reduce the concentration of uric acid in serum, and therefore, the inhibition of the activity of XOD becomes an important strategy for developing a drug for treating hyperuricemia. With the progress of research, a plurality of XOD inhibitors are widely applied clinically and have better effects to a certain extent. Allopurinol, approved by the FDA in the united states in 1966, is widely used for a considerable period of time as the earliest and most widely used inhibitor of XOD in clinical practice. Allopurinol is an isomer of hypoxanthine and competes with hypoxanthine for binding to the active site of XOD, the center of tear pterin, thereby preventing the eventual metabolism of hypoxanthine to uric acid. However, clinical data reports show that allopurinol is easy to cause serious adverse reactions of skin, such as allergic rash, severe erythema multiforme, exfoliative and purpuric lesions, and the like, and long-term taking of a large amount of allopurinol can cause blood system diseases such as leucopenia and thrombopenia and agranulocytosis, and secondary infection or visceral organ failure can be caused to endanger life in serious cases. The side effects of allopurinol class and the higher effective dosage limit the clinical application of allopurinol. Febuxostat and topiroxostat are novel nonpurine XOD inhibitors approved by the US FDA to be marketed in 2009 and 2013 respectively, compared with allopurinol, the selectivity and the activity of the inhibitors on XOD are improved, and the inhibitors are mainly suitable for patients with hyperuricemia who are sensitive to allopurinol or have impaired renal function. However, febuxostat and topiroxostat have common adverse reactions such as liver dysfunction, headache, diarrhea, vomiting, joint pain and the like, and the XOD inhibitor is mainly metabolized by the liver, so that the use of patients with liver dysfunction is forbidden, and therefore, the application range of the XOD inhibitor is small.

Therefore, there is a great need to develop XOD inhibitors with high activity.

Disclosure of Invention

The invention aims to overcome the defects and provide a sulfonyl fangchinoline compound and a preparation method thereof. The invention also aims to provide the application of the sulfonyl fangchinoline compound in XOD inhibitor drugs.

Specifically, the technical scheme of the invention is as follows:

in a first aspect of the invention, the invention provides a sulfonyl fangchinoline compound, which has a structure shown in formula (I) or formula (I'):

wherein R is selected from alkyl, aryl, benzyl, heterocyclic radical, substituted alkyl, substituted aryl, substituted benzyl, substituted heterocyclic radical; wherein, the substituent group of the substituted alkyl is halogen or nitryl, the substituent group of the substituted aromatic alkyl, the substituent group of the substituted benzyl and the substituent group of the substituted heterocyclic radical are one or more of halogen, alkyl and nitryl; y is selected from 1 molecule of inorganic acid and organic acid or 2 molecules of inorganic acid and organic acid.

The substituted hydrocarbon group in the present invention may be a mono-substituted hydrocarbon group, or may be a poly-substituted hydrocarbon group such as a di-substituted hydrocarbon group or a tri-substituted hydrocarbon group. The substituted aryl can be a mono-substituted aryl, and can also be a polysubstituted aryl such as a di-substituted aryl, a tri-substituted aryl and the like. The substituted benzyl can be mono-substituted benzyl, and can also be multi-substituted benzyl such as di-substituted benzyl, tri-substituted benzyl and the like. The substituted heterocyclic group described in the present invention may be a mono-substituted heterocyclic group, or may be a polysubstituted heterocyclic group such as a di-substituted heterocyclic group, a tri-substituted heterocyclic group, etc.

Preferably, the hydrocarbyl group is C_1-8An alkyl group; the substituted hydrocarbon radical being halogen-substituted C_1-8An alkyl group.

Preferably, the hydrocarbyl group is methyl, ethyl, n-propyl, isopropyl, cyclopropylalkyl, n-butyl, iso-n-butyl, n-hexylalkyl or n-octylalkyl.

Preferably, the substituted hydrocarbyl is chloromethyl, bromomethyl, trichloromethyl, 2-chloroethyl, or 2-bromoethyl.

Preferably, the arene is phenyl or naphthyl.

Preferably, the substituted aromatic hydrocarbon group is an o-chlorophenyl group, an m-chlorophenyl group, a p-chlorophenyl group, a 3, 4-dichlorophenyl group, an o-bromophenyl group, an m-bromophenyl group, a p-bromophenyl group, a 3, 4-dibromophenyl group, an o-fluorophenyl group, an m-fluorophenyl group, a p-fluorophenyl group, a 3, 4-difluorophenyl group, a p-methylphenyl group or a p-nitrophenyl group.

Preferably, the substituted benzyl group is an o-chlorobenzyl group, an m-chlorobenzyl group, a p-chlorobenzyl group, a 3, 4-dichlorobenzyl group, an o-bromobenzyl group, an m-bromobenzyl group, a p-bromobenzyl group, a 3, 4-dibromobenzyl group, an o-fluorobenzyl group, an m-fluorobenzyl group, a p-fluorobenzyl group or a 3, 4-difluorobenzyl group.

Preferably, the heterocyclic group is thienyl or pyridyl.

Preferably, the substituted heterocyclyl is 5-chlorothienyl, 5-bromothienyl or 1, 2-dimethyl-1H-imidazolyl.

Preferably, the mineral acid is hydrochloric acid, hydrobromic acid or hydroiodic acid.

Preferably, the organic acid is formic acid, acetic acid, propionic acid, malonic acid, 1, 4-succinic acid, benzoic acid, nicotinic acid, fumaric acid, malic acid, maleic acid, gluconic acid, or citric acid.

Preferably, Y is 1 molecule of acetic acid, 2 molecules of hydrochloric acid, or 2 molecules of hydrobromic acid.

Preferably, the compounds of formula (I) or formula (Γ) of the present invention have the structure shown in table 1 below:

TABLE 1

In the second aspect of the invention, the invention provides a preparation method of sulfonyl fangchinoline compounds, which takes fangchinoline as an initial reactant and RSO₂(ii) reacting X to produce a compound of formula (I), or to obtain a compound of formula (I) and further adding Y to produce a compound of formula (I'), wherein X is halo and R, Y is as described above.

The reaction principle for preparing the compound of formula (I) is shown in formula (II):

wherein X is halogen selected from Cl and Br; r is as defined hereinbefore.

Preferably, the method comprises: dissolving fangchinoline in a solvent, adding an alkaline substance in an inert atmosphere, uniformly mixing, and adding RSO at-20-60 DEG C₂And (2) reacting for 0.1-12 h, keeping the solution alkaline (pH 7.0-14) in the reaction process, detecting the reaction by chromatography, standing to room temperature after the reaction is finished, and preparing the compound shown in the formula (I) by separation and purification, or further adding Y to neutralize to be neutral, and separating and purifying to prepare the compound shown in the formula (I').

Preferably, the solvent is selected from one or more of water, methanol, ethanol, propanol, butanol, pentanol, glycerol, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, 1, 4-dioxane, 1, 2-dichloroethane, tetrahydrofuran, N-Dimethylformamide (DMF), ethyl acetate, and dimethyl sulfoxide (DMSO).

Preferably, the solvent is used in an amount such that each mole of fangchinoline base is dissolved in 5-100L of solvent.

Preferably, the alkaline substance is selected from gamma-Al₂O₃-Na、γ-Al₂O₃-K、γ-Al₂O₃-NaOH-Na、γ-Al₂O₃-NaOH-K、γ-Al₂O₃-KOH-Na、γ-Al₂O₃-one or more of KOH-K, sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium amide, sodium metal, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium oxide, potassium oxide, calcium oxide, potassium carbonate, sodium carbonate, ammonia, ethylamine, diethylamine, triethylamine, methylamine, dimethylamine, trimethylamine, pyridine, and piperidine.

Preferably, the fangchinoline and RSO₂X and the molar ratio of the alkaline substances is 1: 0.1-10: 0.01-10, preferably 1: 1.0-1.2: 0.6-3.0.

Preferably, the separation and purification method is selected from a combination of one or more of filtration, resin treatment, water washing, distillation, crystallization, extraction, activated carbon treatment, molecular sieve treatment and chromatography.

The separation and purification method of the invention can be as follows: for example, after detecting all reactions of fangchinoline base by TLC, heating to room temperature, adding water, extracting with dichloromethane, chloroform, acetone or ethyl acetate for 1 to multiple times { e.g. 3 times such as [ (50-300) mL × 3] }, tracing the reaction and the separation and purification process of the product by TLC, recovering the extract, drying the obtained solid substance at 50-60 ℃ for 4-6 hours to obtain the target product.

For example, the reaction of fangchinoline is detected by TLC, the reaction solution is concentrated and chromatographed (e.g. purified by neutral alumina column), and the eluent is dichloromethane and methanol (120: 1-50: 1).

For example, detecting all reactions of fangchinoline in TLC, concentrating the reaction solution, crystallizing in a cold well at 0 deg.C, rapidly filtering, and drying.

In a third aspect of the present invention, the present invention provides a pharmaceutical composition comprising the sulfonyl fangchinoline compound described above.

In a fourth aspect of the present invention, the present invention provides a pharmaceutical preparation, comprising the sulfonyl fangchinoline compound and a pharmaceutically acceptable adjuvant and/or carrier.

The administration form of the pharmaceutical preparation of the present invention may be a liquid form or a solid form. The liquid dosage forms can be true solutions, colloids, microparticles, emulsions, suspensions, etc. The solid dosage form can be tablet, capsule, pill, powder, granule, suppository, lyophilized powder, etc.

The auxiliary materials of the invention include but are not limited to: binders (e.g., syrup, sorbitol, etc.), fillers (e.g., corn starch, lactose, etc.), lubricants (e.g., magnesium stearate, polyethylene glycol, etc.), disintegrants (e.g., potato starch, etc.), and the like.

Vectors of the present invention include, but are not limited to: ion exchanger, aluminum oxide, aluminum stearate, lecithin, human serum albumin, phosphate, glycerol, sorbitan esters, potassium sorbate, water, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, and the like. The carrier may be present in the pharmaceutical composition in an amount of 1% to 98% by weight, typically about 80% by weight.

In a fifth aspect of the present invention, the present invention provides an application of the sulfonyl fangchinoline compound, the pharmaceutical composition or the pharmaceutical preparation in an XOD inhibitor.

In a sixth aspect of the invention, the invention provides an application of the sulfonyl fangchinoline compound, the pharmaceutical composition or the pharmaceutical preparation in preparation of a drug for treating hyperuricemia.

The invention has the beneficial effects that:

the sulfonyl fangchinoline compound has a dibenzylisoquinoline parent nucleus structure and also has a sulfonyl group-containing characteristic, so that the sulfonyl fangchinoline compound has good inhibition activity on XOD (X-ray diffraction), the inhibition rate of the sulfonyl fangchinoline compound on XOD (X-ray diffraction) is generally higher than 80% at 1.56-6.25 mu M, and the activity of the sulfonyl fangchinoline compound is far higher than that of allopurinol used in clinical application and is about 2-6 times of that of allopurinol.

Detailed Description

It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.

Example 1

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 3mL of dichloromethane and two necks filled with argon were addedThe flask was placed in a cold well controlled to 0 deg.C, 66.5mg (about 0.72mmol) triethylamine dissolved in 2mL dichloromethane was added under magnetic stirring, after mixing for 1h, 31.0mg (about 0.27mmol) methanesulfonyl chloride was added and the reaction was followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, the eluent is dichloromethane and methanol (eluting by 120:1 and 80:1 respectively), and the white powdery product 117.5mg (about 0.17mmol), the melting point: 208.1-209.9 ℃ and the yield is 94.4 percent. And (3) analyzing and characterizing products:¹H NMR(400MHz,CDCl₃)δ7.40(dd,J＝8.2,1.9Hz,1H),7.15(dd,J＝8.2,2.5Hz,1H),6.85(d,J＝7.7Hz,2H),6.81(dd,J＝8.3,2.5Hz,1H),6.56(s,1H),6.46(s,1H),6.40(s,1H),6.33(dd,J＝8.3,2.0Hz,1H),6.04(s,1H),3.92(s,3H),3.78(s,3H),3.70(dd,J＝22.5,12.4Hz,2H),3.52(dd,J＝16.1,12.9Hz,2H),3.43–3.36(m,3H),2.99(tdd,J＝18.0,13.2,6.7Hz,6H),2.87(d,J＝8.4Hz,3H),2.81(dd,J＝13.8,6.1Hz,2H),2.69(d,J＝9.0Hz,3H),2.60–2.45(m,2H),2.30(s,3H)；¹³C NMR(101MHz,CDCl₃)δ154.05,150.13,149.26,148.93,148.67,147.04,142.47,134.36,133.63,132.65,130.52,127.64,127.09,125.34,123.40,122.98,122.30,122.05,121.91,115.88,112.33,111.54,106.14,64.38,61.37,56.10,56.01,55.80,45.84,44.89,43.77,42.29,41.83,41.37,39.53,39.12,23.39,22.12；HRMS(ESI):calcd for C₃₈H₄₂N₂O₈S m/z:686.2662，found:687.2711[M+H]⁺. Compound 1 in table 1.

Example 2

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 3mL of chloroform, and the resulting solution was placed in a two-necked flask filled with argon, and placed in a cold well controlled to-20 ℃, and 5.0mg of NaH (about 0.20mmol) dissolved in 2mL of chloroform was added thereto under magnetic stirring, and after mixing for 1 hour, 23.2mg (about 0.18mmol) of ethylsulfonyl chloride was added to the resulting mixture to react, and the reaction was followed by TLC. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using dichloromethane to methanol (120:1, 80:1, respectively) as eluent, and then separated and purified to obtain 113.6mg (about 0.162mmol) of a white powdery product, melting point: 205.5-207.2 ℃ and the yield is 90.0 percent. And (3) product analysis and characterization:¹H NMR(400MHz,CDCl₃)δ7.36(dd,J＝8.2,1.9Hz,1H),7.14(dd,J＝8.2,2.4Hz,1H),6.82(dt,J＝8.3,5.3Hz,3H),6.51(d,J＝16.7Hz,2H),6.42–6.30(m,2H),6.04(s,1H),3.92(s,3H),3.88–3.81(m,1H),3.81–3.73(m,3H),3.69(s,1H),3.62–3.41(m,3H),3.37(d,J＝11.3Hz,3H),3.31–3.11(m,2H),3.08–2.64(m,10H),2.59(s,3H),2.47(ddd,J＝36.1,25.3,16.1Hz,2H),2.35–2.23(m,3H),1.26(t,J＝7.4Hz,3H)；¹³C NMR(101MHz,CDCl₃)δ153.58,150.32,149.36,148.89,148.10,146.92,142.25,135.08,134.46,132.51,132.40,130.42,128.47,128.30,127.70,123.67,122.78,122.12,121.94,121.41,115.79,112.60,111.39,106.14,63.94,61.37,56.08,56.06,55.86,46.42,46.02,45.14,43.71,42.46,42.30,41.47,38.94,24.77,22.14；HRMS(ESI):calcd for C₃₉H₄₄N₂O₈S m/z:700.2818,found:701.2892[M+H]⁺. Compound 2 in table 1.

Example 3

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 10mL of dichloromethane, and the mixture was placed in a two-necked flask filled with argon and cooled to 0 ℃ in a cold well, and 62.0mg (about 0.72mmol) of piperidine dissolved in 2mL of dichloromethane was added with stirring, and after mixing for 1 hour, 25.6mg (about 0.20mmol) of n-propylsulfonyl chloride was added and the reaction was followed by TLC. After the reaction is finished, the reaction solution is concentrated to 1/3 of the volume of the original solution, crystallized in a cold well at 0 ℃ for more than 4h, quickly filtered, and dried in vacuum at the temperature of less than 50 ℃ to obtain 115.9mg (about 0.162mmol) of a white powdery product, the melting point: 204.9-206.5 ℃ and the yield is 90.0 percent. And (3) product analysis and characterization:¹H NMR(400MHz,CDCl₃)δ7.29(dd,J＝8.2,1.9Hz,1H),7.06(dd,J＝8.1,2.4Hz,1H),6.74(dt,J＝8.3,5.4Hz,3H),6.43(d,J＝14.0Hz,2H),6.36–6.19(m,2H),5.96(s,1H),3.84(s,3H),3.76(dd,J＝11.1,5.3Hz,0H),3.73–3.65(m,3H),3.62(d,J＝9.7Hz,0H),3.40(ddd,J＝11.9,9.6,5.7Hz,1H),3.26(d,J＝14.9Hz,3H),2.93–2.74(m,2H),2.70–2.59(m,1H),2.57–2.45(m,1H),2.23(d,J＝16.7Hz,1H),1.76–1.57(m,1H),0.89(t,J＝7.5Hz,1H)；¹³C NMR(101MHz,CDCl₃)δ153.60,150.38,149.37,148.97,148.10,146.92,142.25,135.16,134.52,132.46,130.42,128.42,127.63,123.67,122.78,122.15,121.95,121.55,115.84,112.60,111.38,106.14,64.04,61.39,56.09,56.08 55.87,53.46,45.19,43.74,42.41,41.52,39.23,29.72,24.73,22.11,17.16,12.91；HRMS(ESI):calcd for C₄₀H₄₆N₂O₈S m/z:714.2975，found:715.3008[M+H]⁺. Compound 3 in table 1.

Example 4

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 10mL of DMF solvent, and the mixture was placed in a two-necked flask filled with argon, and cooled in a cold well controlled to 10 ℃, and 66.5mg (about 0.72mmol) of triethylamine dissolved in 3mL of DMF solvent was added under magnetic stirring, and after mixing for 1 hour, 31.2mg (about 0.20mmol) of n-butylsulfonyl chloride was added to react, and the reaction was followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, the eluent is dichloromethane and methanol (the eluent is respectively 120:1 and 80: 1), and the white powdery product is obtained after separation and purification, wherein the white powdery product is 120.8mg (about 0.166mmol), the melting point: 203.3-205.1 ℃ and the yield is 92.2 percent. And (3) analyzing and characterizing products:¹H NMR(400MHz,CDCl₃)δ7.29(d,J＝8.0Hz,1H),7.06(d,J＝7.8Hz,1H),6.82–6.71(m,3H),6.43(d,J＝16.6Hz,2H),6.34–6.22(m,2H),5.95(s,1H),3.84(s,3H),3.78(dd,J＝11.0,4.8Hz,1H),3.67(d,J＝11.1Hz,3H),3.62(d,J＝9.8Hz,1H),3.46–3.36(m,2H),3.28(s,3H),2.95–2.78(m,6H),2.7–2.60(m,2H),2.53(s,3H),2.49–2.30(m,2H),2.21(s,3H),1.62(dt,J＝30.1,15.2Hz,2H),1.36–1.12(m,4H),0.81(t,J＝7.2Hz,3H)；¹³C NMR(101MHz,CDCl₃)δ153.64,150.37,149.36,148.97,148.12,146.93,142.26,135.11,134.54,132.55,130.40,128.44,128.20,127.70,123.67,122.81,122.13,121.93，121.57,115.87,112.60,111.41,106.14,64.06,61.39,56.07,56.07,55.87,51.63,45.17,43.75,42.48,42.31,41.55,39.19,25.28,24.67,22.09,21.50,13.58；HRMS(ESI):calcd for C₄₁H₄₈N₂O₈S m/z:728.3131，found:729.3204[M+H]⁺. Compound 6 in table 1.

Example 5

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 5mL tetrahydrofuran solvent, adding into two-neck flask filled with argon, placing in cold well controlled to 5 deg.C, and magnetically stirringNext, 66.5mg (about 0.72mmol) of triethylamine dissolved in 2mL of tetrahydrofuran was added, and after mixing for 1 hour, 35.1mg (about 0.20mmol) of benzenesulfonyl chloride was added for reaction, followed by TLC. After the reaction is finished, the reaction solution is concentrated to 1/3 of the volume of the original solution, crystallized in a cold well at 0 ℃ for more than 4h, quickly filtered, and dried in vacuum at the temperature of less than 50 ℃ to obtain 117.3mg (about 0.157mmol) of a white powdery product, and the melting point: 202.2-204.1 ℃ and the yield is 87.2 percent. And (3) analyzing and characterizing products:¹H NMR(400MHz,CDCl₃)δ7.66(dd,J＝15.5,7.8Hz,4H),7.47(t,J＝7.4Hz,2H),7.33(d,J＝8.1Hz,1H),7.16(dd,J＝8.1,1.4Hz,1H),6.88(s,2H),6.78–6.72(m,1H),6.51–6.44(m,2H),6.32–6.20(m,2H),3.93(s,3H),3.69(dd,J＝15.9,7.6Hz,2H),3.52(dd,J＝19.7,9.0Hz,2H),3.44(s,3H),3.27(d,J＝12.0Hz,3H),3.26–3.12(m,2H),2.97–2.87(m,4H),2.74(dd,J＝16.4,7.2Hz,2H),2.63(d,J＝6.5Hz,4H),2.47(dd,J＝17.6,12.5Hz,2H),2.29(s,3H)；¹³C NMR(101MHz,CDCl₃)δ153.75,150.99,149.31,148.87,147.75,147.12,142.39,137.39,135.25,135.03,134.60,133.56,132.52,130.25,128.58,128.36,128.19,128.11,123.77,122.85,121.69,121.03,116.08,112.70,111.52,106.00,63.87,61.37,56.13,55.78,55.69,45.08,43.85,42.39,42.03,39.77,24.30,22.04；HRMS(ESI):calcd for C₄₃H₄₄N₂O₈S m/z:748.2852，found:749.2864[M+H]⁺. Compound 15 in table 1.

Example 6

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 5mL of DMSO solvent, and the resulting solution was placed in a two-necked flask filled with argon, and placed in a cold well controlled to 25 ℃, and 42.5mg (about 0.72mmol) of trimethylamine dissolved in 2mL of DMSO solvent was added under magnetic stirring, and after mixing for 1 hour, 38.0mg (about 0.20mmol) of p-toluenesulfonyl chloride was added for reaction, and the reaction was followed by TLC. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using methylene chloride and methanol (120:1, 80:1, respectively) as eluent, and then separated and purified to obtain 119.5mg (about 0.157mmol) of a white powdery product, melting point: 201.7-203.6 ℃ and the yield is 87.2%. And (3) analyzing and characterizing products:¹H NMR(400MHz,CDCl₃)δ7.53(d,J＝8.1Hz,2H),7.36–7.20(m,4H),7.15(dd,J＝8.0,1.9Hz,1H),6.87(s,2H),6.75(dd,J＝8.2,1.9Hz,1H),6.46(d,J＝8.7Hz,2H),6.32–6.22(m,2H),3.92(s,3H),3.77–3.51(m,4H),3.47(s,3H),3.28(s,3H),2.97–2.69(m,8H),2.64(s,3H),2.54(d,J＝13.7Hz,2H),2.47(s,3H),2.28(s,3H)；¹³C NMR(101MHz,CDCl₃)δ153.73,151.10,149.25,148.83,147.78,147.10,144.42,142.40,135.23,134.99,134.58,134.37,132.61,132.35,130.08,129.13,128.65,128.21,127.64,123.62,122.88,121.65,121.58，120.98,116.15,115.94,112.74,111.50,106.09,64.06,61.40,56.11,55.78,55.72,45.08,43.84,42.48,42.29,41.91,39.62,24.32,22.06,21.83；HRMS(ESI):calcd for C₄₄H₄₆N₂O₈S m/z:762.2975，found:763.3008[M+H]⁺. Compound 16 in table 1.

Example 7

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 10mL of toluene solvent, and the resulting solution was placed in a two-necked flask filled with argon, and placed in a cold well controlled to 0 ℃, and 5.5mg (about 0.21mmol) of sodium metal dissolved in 5mL of toluene solvent was added under magnetic stirring, and after mixing for 1 hour, 44.2mg (about 0.20mmol) of 4-nitrobenzenesulfonyl chloride was added for reaction, and the reaction was followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, the eluent is dichloromethane: methanol (which is respectively eluted by 120:1 and 80: 1), and the separation and purification are carried out to obtain 117.2mg (about 0.148mmol) of a light yellow powdery product, the melting point: 202.6-204.4 ℃ and the yield is 82.2 percent. And (3) product analysis and characterization:¹H NMR(400MHz,CDCl₃)δ8.22(d,J＝8.8Hz,3H),7.76(d,J＝8.8Hz,2H),7.20–7.15(m,1H),7.04(dd,J＝8.1,2.5Hz,1H),6.78(s,2H),6.68(dd,J＝8.3,2.5Hz,1H),6.38(d,J＝20.5Hz,2H),6.25–6.17(m,2H),3.85(s,3H),3.61–3.54(m,2H),3.38(s,3H),3.23(s,3H),3.16–2.61(m,10H),2.57(s,3H),2.48–2.36(m,2H),2.19(s,3H)；¹³C NMR(101MHz,CDCl₃)δ153.65,150.49,150.43,149.38,148.54,147.73,147.11,142.84,141.92,135.11,134.24,133.11,132.54,130.09,129.77,128.64,128.40,127.80,123.87,123.69,122.80,122.01,121.81,120.30,115.80,112.78,111.52,106.16,64.04,61.33,56.12,55.76,45.07,43.76,42.57,42.35,41.95,38.15,25.08,22.15；HRMS(ESI):calcd for C₄₃H₄₃N₃O₁₀S m/z:793.2669，found:794.2656[M+H]⁺. Compound 17 in table 1.

Example 8

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 10mL of ethanol, and the mixture was placed in a two-necked flask filled with argon, and placed in a cold well controlled to-5 ℃, and 24.5mg (about 0.36mmol) of sodium ethoxide dissolved in 5mL of ethanol was added under magnetic stirring, and after mixing for 1 hour, 42.0mg (about 0.20mmol) of 4-chlorobenzenesulfonyl chloride was added, and the reaction was followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, and the eluent is dichloromethane: methanol (which is respectively eluted by 120:1 and 80: 1), and the mixture is separated and purified to obtain 114.2mg (about 0.146mmol) of a light yellow powdery product, the melting point: 215.3-217.1 ℃ and the yield is 81.1 percent. And (3) product analysis and characterization:¹H NMR(400MHz,CDCl₃)δ7.52(d,J＝8.6Hz,2H),7.47–7.27(m,4H),7.11(dd,J＝8.1,2.4Hz,1H),6.79(s,2H),6.68(dd,J＝8.2,2.4Hz,1H),6.37(d,J＝12.4Hz,2H),6.26–6.18(m,2H),3.86(s,3H),3.62–3.54(m,2H),3.45(s,3H),3.33(ddd,J＝23.1,12.3,8.9Hz,2H),3.21(s,3H),2.92–2.62(m,8H),2.57(s,3H),2.49–2.37(m,2H),2.20(s,3H)；¹³C NMR(101MHz,CDCl₃)δ153.64,150.93,149.42,148.61,147.68,147.10,142.23,140.15,135.93,135.10,134.40,132.60,130.30,130.05,129.34,128.92,128.50,128.37,128.21,128.02,123.80,122.77,121.87,120.41,115.80,112.79,111.49,106.13,63.96,61.37,56.07,55.79,53.54,45.08,43.84,42.54,42.34,42.04,39.15,24.58,22.12；HRMS(ESI):calcd for C₄₃H₄₃ClN₂O₈S m/z:782.2829，found:783.2862[M+H]⁺. Compound 20 in table 1.

Example 9

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 10mL of t-butanol solvent, and the solution was put into a two-necked flask filled with argon, and placed in a cold well controlled to-5 ℃, and 35.0mg (about 0.36mmol) of sodium t-butoxide dissolved in 5mL of t-butanol was added under magnetic stirring, and after mixing for 1 hour, 50.7mg (about 0.20mmol) of 2-bromobenzenesulfonyl chloride was added for reaction, and the reaction was followed by TLC. After the reaction is finished, concentrating the reaction solution, purifying the reaction solution by a neutral alumina column, and eluting the eluent by dichloromethane, methanol (A), (B)Elution was carried out at 120:1 and 80:1, respectively), followed by separation and purification to obtain 123.6mg (about 0.149mmol) of a white powdery product, melting point: 216.3-218.5 ℃ and the yield is 82.8 percent. And (3) product analysis and characterization:¹H NMR(400MHz,CDCl₃)δ7.79(t,J＝1.6Hz,1H),7.70(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.38–7.16(m,3H),7.10(dd,J＝8.1,2.5Hz,1H),6.83–6.77(m,2H),6.66(dd,J＝8.3,2.5Hz,1H),6.38(d,J＝7.2Hz,2H),6.25(s,1H),6.17(dd,J＝8.3,2.0Hz,1H),3.83(d,J＝9.4Hz,3H),3.65(dd,J＝11.1,5.4Hz,1H),3.57(d,J＝9.9Hz,1H),3.45(s,3H),3.43–3.31(m,2H),3.20(s,3H),2.96–2.59(m,8H),2.55(s,3H),2.43(dd,J＝30.0,9.4Hz,2H),2.20(s,3H)；¹³C NMR(101MHz,CDCl₃)δ153.77,150.96,149.26,148.70,147.61,147.12,142.29,139.25,136.62,135.06,134.51,132.69,131.39,130.17,128.53,128.32,127.98,127.22,123.98,122.85,122.46,121.77,120.61,116.26,112.81,111.47,106.22,63.74,61.38,56.11,55.80,46.14,45.02,43.80,42.37,39.64,24.33,22.00；HRMS(ESI):calcd for C₄₃H₄₃BrN₂O₈S m/z:826.1923,found:827.1965[M+H]⁺. Compound 22 in table 1.

Example 10

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 3mL of dichloromethane, adding into a two-neck flask filled with argon, placing in a cold well controlled to-5 deg.C, adding gamma-Al under magnetic stirring₂O₃Na 20.0mg, mixed for 1h, and then added with 50.7mg (ca. 0.20mmol) of 3-bromobenzenesulfonyl chloride to react, followed by TLC. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using dichloromethane to methanol (100: 1, 60:1 elution, respectively), and the mixture was separated and purified to obtain 128.0mg (about 0.155mmol) of a white powder product, melting point: 215.8-217.7 ℃ and the yield is 86.1 percent. And (3) analyzing and characterizing products:¹H NMR(400MHz,CDCl₃)δ7.79(t,J＝1.6Hz,1H),7.70(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.38–7.16(m,3H),7.10(dd,J＝8.1,2.5Hz,1H),6.83–6.77(m,2H),6.66(dd,J＝8.3,2.5Hz,1H),6.38(d,J＝7.2Hz,2H),6.25(s,1H),6.17(dd,J＝8.3,2.0Hz,1H),3.83(d,J＝9.4Hz,3H),3.65(dd,J＝11.1,5.4Hz,1H),3.57(d,J＝9.9Hz,1H),3.45(s,3H),3.43–3.31(m,2H),3.20(s,3H),2.96–2.59(m,8H),2.55(s,3H),2.43(dd,J＝30.0,9.4Hz,2H),2.20(s,3H)；¹³C NMR(101MHz,CDCl₃)δ153.77,150.96,149.26,148.70,147.61,147.12,142.29,139.25,136.62,135.06,134.51,132.69,131.39,130.17,128.53,128.32,127.98,127.22,123.98,122.85,122.46,121.77,120.61,116.26,112.81,111.47,106.22,63.74,61.38,56.11,55.80,46.14,45.02,43.80,42.37,39.64,24.33,22.00；HRMS(ESI):calcd for C₄₃H₄₃BrN₂O₈S m/z:826.1923found:827.1844[M+H]⁺. Compound 23 in table 1.

Example 11

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 3mL of dichloromethane, adding into a two-neck flask filled with argon, placing in a cold well controlled to-5 deg.C, adding gamma-Al under magnetic stirring₂O₃-K20.0 mg, after mixing for 1h, 38.8mg (ca. 0.20mmol) of 2-fluorobenzenesulfonyl chloride are added for reaction, and the reaction is followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, the eluent is dichloromethane and methanol (eluting by 100:1 and 60:1 respectively), and the white powdery product 117.4mg (about 0.153mmol), the melting point: 205.1-207.2 ℃ and the yield is 85.0 percent. And (3) analyzing and characterizing products:¹H NMR(400MHz,CDCl₃)δ7.66–7.43(m,2H),7.15(ddd,J＝27.5,17.5,8.3Hz,4H),6.77(d,J＝7.8Hz,2H),6.67(dd,J＝8.2,2.0Hz,1H),6.41(d,J＝3.2Hz,2H),6.18(d,J＝12.3Hz,2H),5.27(s,1H),3.83(s,3H),3.65–3.53(m,2H),3.42(dd,J＝19.0,9.5Hz,2H),3.35–3.28(m,3H),3.22(s,3H),3.17–2.55(m,8H),2.52(s,3H),2.38(dd,J＝35.6,30.4Hz,2H),2.22(d,J＝16.2Hz,3H)；¹³C NMR(101MHz,CDCl₃)δ160.96,158.37,153.80,150.52,149.29,148.93,147.91,147.10,142.35,135.91,135.00,134.68,132.65,132.53,131.06,130.26,128.46,128.22,127.69,125.95,123.71,122.9,121.71,120.96,117.15,116.94,116.14,112.77,111.52,105.83,63.91,61.34,56.12,55.79,55.56,45.03,43.76,42.39,42.29,41.72,39.88,24.14,22.00；HRMS(ESI):calcd for C₄₃H₄₃FN₂O₈S m/z:766.2724，found:767.2717[M+H]⁺. Compound 26 in table 1.

Example 12

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 3mL piperidine solvent, adding into a two-necked flask filled with argon, placing in a cold well controlled to-5 deg.C, adding gamma-Al under magnetic stirring₂O₃NaOH-Na 20.0mg, mixed for 1h, and reacted by adding 38.8mg (about 0.20mmol) of 4-fluorobenzenesulfonyl chloride, followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, the eluent is dichloromethane and methanol (eluting by 100:1 and 60:1 respectively), and the white powdery product 122.9mg (about 0.16mmol), the melting point: 206.0-207.7 ℃ and the yield is 88.9 percent. And (3) product analysis and characterization:¹H NMR(400MHz,CDCl₃)δ7.63(d,J＝6.8Hz,2H),7.40–7.07(m,5H),6.86(s,2H),6.75(d,J＝7.8Hz,1H),6.49(s,2H),6.26(d,J＝13.2Hz,2H),3.91(s,3H),3.67(t,J＝10.0Hz,2H),3.48(d,J＝10.5Hz,2H),3.38(s,3H),3.30(s,3H),2.79(ddd,J＝33.4,22.7,13.2Hz,8H),2.60(s,3H),2.57–2.34(m,2H),2.28(s,3H)；¹³C NMR(101MHz,CDCl₃)δ166.95,153.77,150.89,149.39,148.74,147.81,147.14,142.32,134.98,134.45,133.49,132.61,131.43,130.22,128.31,128.11,127.74,123.84,122.82,121.85,120.72,116.02,115.96,115.79,112.73,111.52,106.04,63.98,61.35,56.13,55.77,45.05,43.85,42.39,42.09,39.20,24.49,22.08；

HRMS(ESI):calcd for C₄₃H₄₃FN₂O₈S m/z:766.2724，found:767.2717[M+H]⁺. Compound 28 in table 1.

Example 13

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 3mL of dichloromethane, adding into a two-neck flask filled with argon, placing in a cold well controlled to 0 deg.C, adding gamma-Al under magnetic stirring₂O₃22.0mg of-NaOH-K, and after mixing for 1 hour, 36.4mg (about 0.20mmol) of 2-thiophenesulfonyl chloride was added thereto and the reaction was followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, the eluent is dichloromethane and methanol (the eluent is respectively 100:1 and 50:1), and the white powdery product 111.5mg (0.148mmol), the melting point: 202.5-204.2 ℃ and the yield is 82.2 percent. Product separationAnalysis and characterization:¹H NMR(400MHz,CDCl₃)δ7.56(d,J＝4.9Hz,1H),7.38(d,J＝3.8Hz,1H),7.26(dd,J＝8.1,1.7Hz,1H),7.07(dd,J＝8.1,2.4Hz,1H),7.01–6.96(m,1H),6.78(d,J＝8.0Hz,2H),6.68(dd,J＝8.2,2.4Hz,1H),6.42(t,J＝9.4Hz,2H),6.28–6.16(m,2H),5.37(s,1H),3.83(d,J＝9.1Hz,3H),3.70–3.59(m,2H),3.43(d,J＝11.3Hz,3H),3.36(dd,J＝27.5,17.6Hz,2H),3.22(s,3H),2.75(ddd,5.8Hz,8H),2.54(d,J＝9.2Hz,3H),2.49–2.30(m,2H),2.26–2.18(m,3H)；¹³C NMR(101MHz,CDCl₃)δ153.74,150.97,149.34,149.15,148.97,147.83,147.09,142.37,137.00,135.16,134.63,133.66,132.65,130.27,128.55,127.96,127.91,127.05,123.79,122.83,121.79,121.24,116.06,112.64,111.49,105.85,64.06,61.37,56.13,55.81,55.79,45.16,43.82,42.56,42.31,41.94,40.33,24.16,22.06；HRMS(ESI):calcd for C₄₁H₄₂N₂O₈S₂m/z:754.2383，found:755.2459[M+H]⁺. Compound 43 in table 1.

Example 14

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 3mL of dichloromethane, and the mixture was placed in a two-necked flask filled with argon, and cooled in a cold well controlled to 0 ℃, and 66.5mg (about 0.72mmol) of triethylamine dissolved in 2mL of dichloromethane was added under magnetic stirring, and after mixing for 1 hour, 35.4mg (about 0.20mmol) of 3-pyridinesulfonyl chloride was added to carry out a reaction, and the reaction was followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, the eluent is dichloromethane and methanol (the eluent is respectively 100:1 and 50:1), and the white powdery product is obtained by separation and purification, wherein the white powdery product is 108.0mg (about 0.144mmol), the melting point: 207.2-208.9 ℃ and the yield is 80.0 percent. And (3) analyzing and characterizing products:¹H NMR(400MHz,CDCl₃)δ8.77(dd,J＝10.1,3.3Hz,2H),7.84(d,J＝8.1Hz,1H),7.31(dd,J＝8.0,3.5Hz,2H),7.19(s,1H),7.10(dd,J＝8.1,2.3Hz,1H),6.79(s,2H),6.69(dd,J＝8.2,2.3Hz,1H),6.41(d,J＝16.1Hz,2H),6.27–6.17(m,2H),3.86(s,3H),3.75–3.60(m,2H),3.40(s,3H),3.34(s,3H),2.96–2.76(m,6H),2.68(d,J＝12.2Hz,2H),2.59(s,3H),2.49–2.35(m,2H),2.21(s,3H)；¹³C NMR(101MHz,CDCl₃)δ153.77,150.36,149.28,148.84,147.83,147.11,142.15,136.06,135.09,134.42,134.03,132.95,132.60,130.37,128.62,127.93,127.71,123.84,123.28,122.81,121.87,121.08,115.94,112.68,111.47,105.92,63.80,61.33,56.12,55.81,55.56,53.49,50.82,43.68,42.30,41.87,39.89,24.21,22.09；HRMS(ESI):calcd for C₄₂H₄₃N₃O₈S m/z:749.2804，found:750.2824[M+H]⁺. Compound 47 in table 1.

Example 15

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 3mL of dichloromethane, and the solution was placed in a two-necked flask filled with argon, and cooled in a cold well controlled to 0 ℃, 66.5mg (about 0.72mmol) of triethylamine dissolved in 2mL of dichloromethane was added under magnetic stirring, and after mixing for 1 hour, 31.0mg (about 0.27mmol) of methanesulfonyl chloride was added, and the reaction was followed by TLC. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using dichloromethane to methanol (120:1, 60:1 elution, respectively), and then separated and purified to obtain 110.0mg (about 0.16mmol) of a white powder product, melting point: 208.0-209.7 ℃. Slowly adding 36% HCl into the product under stirring at a temperature controlled below 60 ℃, stopping adding hydrochloric acid until the pH value of the solution is 7.0, continuously stirring for reacting for 2h, and performing vacuum drying at 60 ℃ for 6h to obtain 113.9mg (about 0.15mmol) of a white powdery product, wherein the yield is 83.3%, and the melting point of the target product is as follows: 253.2-255.1 ℃, and the product analysis and characterization:¹H NMR(400MHz,CD₃OD)δ8.17(br,1H),8.01(br,1H),7.39(dd,J＝8.2,1.9Hz,1H),7.14(dd,J＝8.2,2.5Hz,1H),6.84(d,J＝7.7Hz,2H),6.80(dd,J＝8.3,2.5Hz,1H),6.55(s,1H),6.45(s,1H),6.39(s,1H),6.32(dd,J＝8.3,2.0Hz,1H),6.03(s,1H),3.91(s,3H),3.77(s,3H),3.61(dd,J＝22.5,12.4Hz,2H),3.49(dd,J＝16.1,12.9Hz,2H),3.42–3.36(m,3H),2.98(tdd,J＝18.0,13.2,6.7Hz,6H),2.86(d,J＝8.4Hz,3H),2.65(dd,J＝13.8,6.1Hz,2H),2.71(d,J＝9.0Hz,3H),2.40–2.55(m,2H),2.31(s,3H)；¹³C NMR(101MHz,CD₃OD)δ155.25,151.34,150.45,150.12,149.87,148.24,143.67,135.55,134.82,133.84,131.71,128.83,128.28,124.45,124.59,124.17,123.49,123.24,123.09,116.07,113.52,112.73,107.33,72.20,73.57,69.56,67.01,57.29,49.76,48.47,46.03,45.97,43.02,42.56,40.72,40.31,22.58,21.31；HRMS(ESI):calcd for C₃₈H₄₂N₂O₈S[M-2HCl]m/z:686.2662，found:687.2732[M-2HCl+H]⁺. Compound 48 in table 1.

Example 16

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 3mL of chloroform, and the resulting solution was placed in a two-necked flask filled with argon, and placed in a cold well controlled to-20 ℃, and 5.0mg of NaH (about 0.20mmol) dissolved in 2mL of chloroform was added thereto under magnetic stirring, and after mixing for 1 hour, 23.2mg (about 0.18mmol) of ethylsulfonyl chloride was added to the resulting mixture to react, and the reaction was followed by TLC. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using dichloromethane to methanol (120:1, 60:1 elution, respectively), and then separated and purified to obtain 116.2mg (about 0.166mmol) of a white powder product, melting point: 205.7-207.6 ℃. Slowly adding 36% HCl into the product under stirring at a temperature controlled below 60 ℃, stopping adding hydrochloric acid when the pH value of the solution is 7.0, continuously stirring for reaction for 2 hours, and performing vacuum drying at 60 ℃ for 6 hours to obtain a white powdery product 123.8mg (about 0.16mmol), wherein the yield is 88.8%, and the melting point of the target product is as follows: 252.7-254.4 ℃, and the product analysis and characterization:¹H NMR(400MHz,CD₃OD)δ8.15(br,1H),7.99(br,1H),7.35(dd,J＝8.2,1.9Hz,1H),7.13(dd,J＝8.2,2.4Hz,1H),6.81(dt,J＝8.3,5.3Hz,3H),6.50(d,J＝16.7Hz,2H),6.41–6.29(m,2H),6.03(s,1H),3.91(s,3H),3.87–3.80(m,1H),3.80–3.72(m,3H),3.68(s,1H),3.61–3.40(m,3H),3.36(d,J＝11.3Hz,3H),2.99–2.89(m,2H),2.87–2.63(m,8H),2.59(s,3H),2.46(ddd,J＝36.1,25.3,16.1Hz,2H),2.34–2.22(m,3H),1.25(t,J＝7.4Hz,3H)；¹³C NMR(101MHz,CD₃OD)δ155.12,151.52,150.77,150.17,149.54,148.47,143.69,136.56,135.96,133.97,133.94,131.90,129.79,129.77,129.31,125.14,124.25,123.62,122.47,122.91,116.24,114.10,112.79,107.62,70.85,57.27,49.31,48.77,47.90,47.52,46.60,43.81,42.95,40.33,24.24,21.62；HRMS(ESI):calcd for C₃₉H₄₄N₂O₈S[M-2HCl]m/z:700.2818,found:701.2876[M-2HCl+H]⁺. The product of interest is compound 49 in table 1.

Example 17

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 5mL tetrahydrofuran solvent, into a two-necked flask filled with argon, placed in a cold well controlled to 5 ℃, and under magnetic stirring, 66.5mg (about 0.72mmol) of triethylamine dissolved in 2mL tetrahydrofuran was added, and after mixing for 1 hour, 35.1mg (about 0.20mmol) of benzenesulfonyl chloride was added for reaction, and the reaction was followed by TLC. After the reaction is finished, the reaction solution is concentrated to 1/3 of the volume of the original solution, crystallized in a cold well at 0 ℃ for more than 4h, quickly filtered, and dried in vacuum at the temperature of less than 50 ℃ to obtain 116.0mg (about 0.155mmol) of a white powdery product, the melting point: 202.3-204.2 ℃. Slowly adding 36% HCl into the product under stirring at a temperature controlled below 50 ℃, stopping adding hydrochloric acid until the pH value of the solution is 7.0, continuously stirring for reacting for 2h, and performing vacuum drying at 50 ℃ for 6h to obtain a white powdery product 123.2mg (about 0.15mmol), wherein the yield is 83.2%, and the melting point of the target product is as follows: 255.3-257.1 ℃. And (3) product analysis and characterization:¹H NMR(400MHz,CD₃OD)δ8.11(br,1H),7.94(br,1H),7.65(dd,J＝15.5,7.8Hz,4H),7.46(t,J＝7.4Hz,2H),7.32(d,J＝8.1Hz,1H),7.15(dd,J＝8.1,1.4Hz,1H),6.87(s,2H),6.77–6.72(m,1H),6.50–6.45(m,2H),6.31–6.20(m,2H),3.92(s,3H),3.68(dd,J＝15.9,7.6Hz,2H),3.51(dd,J＝19.7,9.0Hz,2H),3.43(s,3H),3.26(d,J＝12.0Hz,3H),3.25–3.12(m,2H),3.12–2.97(m,4H),2.73(dd,J＝16.4,7.2Hz,2H),2.69(d,J＝6.5Hz,4H),2.45(dd,J＝17.6,12.5Hz,2H),2.28(s,3H)；¹³C NMR(101MHz,CD₃OD)δ154.80,152.04,150.36,149.92,148.90,148.17,143.44,138.43,136.30,136.08,135.65,134.61,133.57,131.30,129.563,129.41,129.24,129.16,124.82,123.90,122.74,122.05,117.13,113.75,112.57,107.05,74.92,72.42,67.18,66.82,56.74,49.45,48.57,46.13,43.08,40.82,23.35,21.09；HRMS(ESI):calcd for C₄₃H₄₄N₂O₈S[M-2HCl]m/z:748.2852，found:749.2897[M-2HCl+H]⁺. Compound 62 in table 1.

Example 18

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 10mL of tert-butanol solvent, adding into a two-necked flask filled with argon, placing in a cold well controlled to-10 deg.C, adding 35.0mg (about 0.36mmol) of sodium tert-butoxide dissolved in 5mL of tert-butanol under magnetic stirring, mixing for 1h, adding 50.7mg (about 0.20mmol) of 3-bromobenzeneSulfonyl chloride reaction, TLC followed reaction. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using dichloromethane to methanol (120:1, 60:1 elution, respectively), and then separated and purified to obtain 134.6mg (about 0.16mmol) of a white powder product, melting point: 216.5-218.2 deg.C, slowly adding 36% HCl into the product under stirring at 50 deg.C or below until the pH value of the solution is 7.0, stopping adding hydrochloric acid, stirring for reaction for 2 hr, and vacuum drying at 50 deg.C for 6 hr to obtain white powder product 144.1mg (about 0.16mmol) with yield of 88.8%. And (3) product analysis and characterization:¹H NMR(400MHz,CD₃OD)δ8.97(br,1H),8.78(br,1H),7.78(t,J＝1.6Hz,1H),7.69(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.37–7.15(m,3H),7.09(dd,J＝8.1,2.5Hz,1H),6.82–6.77(m,2H),6.65(dd,J＝8.3,2.5Hz,1H),6.37(d,J＝7.2Hz,2H),6.24(s,1H),6.16(dd,J＝8.3,2.0Hz,1H),3.82(d,J＝9.4Hz,3H),3.64(dd,J＝11.1,5.4Hz,1H),3.56(d,J＝9.9Hz,1H),3.44(s,3H),3.42–3.31(m,2H),3.19(s,3H),2.75–2.59(m,8H),2.57(s,3H),2.42(dd,J＝30.0,9.4Hz,2H),2.21(s,3H)；¹³C NMR(101MHz,CD₃OD)δ154.79,151.98,150.28,149.72,148.63,148.14,143.31,140.27,137.64,136.08,135.53,133.71,132.41,131.19,129.55,129.35,129.00,128.24,125.01,123.87,123.48,122.79,121.63,117.28,113.83,112.49,107.24,72.13,71.82,69.16,67.70,49.85,48.59,47.16,46.04,40.66,23.35,21.02；HRMS(ESI):calcd for C₄₃H₄₃BrN₂O₈S[M-2HCl]m/z:826.1923,found:827.1957[M-2HCl+H]⁺. Compound 70 in table 1.

Example 19

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 3mL chloroform, adding into a two-neck flask filled with argon, placing in a cold well controlled to 0 deg.C, adding gamma-Al under magnetic stirring₂O₃NaOH-K22.0 mg, mixed for 1h, added 36.4mg (ca. 0.20mmol) of 2-thiophenesulfonyl chloride and followed by TLC. After the reaction is finished, the reaction solution is concentrated and purified by a neutral alumina column, the eluent is dichloromethane and methanol (the eluent is respectively 100:1 and 50:1), and the white powdery product 113.2mg (0.15mmol), the melting point: 202.7-204.5 ℃. The product isSlowly adding 36% HCl under stirring and temperature controlled below 50 ℃, stopping adding hydrochloric acid until the pH value of the solution is 7.0, continuing stirring for reaction for 2h, and vacuum-drying at 50 ℃ for 6h to obtain 124.2mg (about 0.15mmol) of a white powdery product, wherein the yield is 83.3%, and the melting point of a target product is as follows: 244.5-247.4 ℃. And (3) analyzing and characterizing products:¹H NMR(400MHz,CD₃OD)δ8.23(br,1H),7.93(br,1H),7.55(d,J＝4.9Hz,1H),7.37(d,J＝3.8Hz,1H),7.25(dd,J＝8.1,1.7Hz,1H),7.06(dd,J＝8.1,2.4Hz,1H),7.00–6.96(m,1H),6.77(d,J＝8.0Hz,2H),6.67(dd,J＝8.2,2.4Hz,1H),6.41(t,J＝9.4Hz,2H),6.27–6.16(m,2H),5.36(s,1H),3.82(d,J＝9.1Hz,3H),3.69–3.59(m,2H),3.42(d,J＝11.3Hz,3H),3.35(dd,J＝27.5,17.6Hz,2H),3.21(s,3H),2.67(ddd,5.8Hz,8H),2.53(d,J＝9.2Hz,3H),2.48–2.30(m,2H),2.29–2.21(m,3H)；¹³C NMR(101MHz,CD₃OD)δ154.75,151.98,150.35,150.16,149.98,148.84,148.11,143.38,138.01,136.17,135.64,134.67,133.66,131.28,129.56,128.97,128.92,128.06,124.80,123.84,122.80,122.25,117.07,113.65,112.50,106.86,75.54,74.02,72.80,71.17,65.07,62.38,50.23,49.57,43.32,42.95,41.34,23.17,21.07；HRMS(ESI):calcd for C₄₁H₄₂N₂O₈S₂[M-2HCl]m/z:754.2383，found:755.2447[M-2HCl+H]⁺. Compound 90 in table 1.

Example 20

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 3mL of DMF solvent, and the mixture was placed in a two-necked flask filled with argon and cooled to 5 ℃, 66.5mg (about 0.72mmol) of triethylamine dissolved in 2mL of DMF solvent was added with magnetic stirring, and after mixing for 1 hour, 31.0mg (about 0.27mmol) of methanesulfonyl chloride was added, and the reaction was followed by TLC. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using dichloromethane to methanol (120:1, 60:1 elution, respectively), and the mixture was separated and purified to obtain 109.9mg (about 0.16mmol) of a white powder product, melting point: 208.3-209.9 deg.C, slowly adding 60% propionic acid under stirring at 50 deg.C or below until pH of the solution is 7.0, stopping adding propionic acid, stirring for reaction for 2 hr, vacuum drying at 50 deg.C for 6 hr to obtain 121.7mg (about 0.16mmol) of white powder product with yield of 88.9%, melting point of the target product: 245.5-247.3 ℃. And (3) analyzing and characterizing products:¹H NMR(400MHz,CD₃OD)δ8.27(br,1H),7.41(dd,J＝8.2,1.9Hz,1H),7.16(dd,J＝8.2,2.5Hz,1H),6.86(d,J＝7.7Hz,2H),6.82(dd,J＝8.3,2.5Hz,1H),6.57(s,1H),6.47(s,1H),6.41(s,1H),6.34(dd,J＝8.3,2.0Hz,1H),6.05(s,1H),3.93(s,3H),3.79(s,3H),3.71(dd,J＝22.5,12.4Hz,2H),3.42(dd,J＝16.1,12.9Hz,2H),3.42–3.36(m,3H),2.73(m,2H),2.30(tdd,J＝18.0,13.2,6.7Hz,6H),2.88(d,J＝8.4Hz,3H),2.82(dd,J＝13.8,6.1Hz,2H),2.70(d,J＝9.0Hz,3H),2.61–2.45(m,2H),2.31(s,3H),2.05(s,3H)；¹³C NMR(101MHz,CD₃OD)δ173.35,153.06,149.14,148.27,147.94,147.68,146.05,141.48,133.37,132.64,131.66,129.53,126.65,126.10,124.35,122.41,121.99,121.31,121.06,120.92,114.89,111.34,110.55,105.15,69.39,65.38,62.02,61.81,55.11,52.85,51.90,42.78,41.30,40.84,40.38,38.54,38.13,34.27,22.40,21.30,21.13；HRMS(ESI):calcd for C₃₈H₄₂N₂O₈S[M-C₃H₆O₂]m/z:686.2685，found:687.2735[M-C₃H₆O₂+H]⁺. Compound 95 in table 1.

Example 21

Dissolving 100.0mg fangchinoline (about 0.18mmol) in 3mL DMSO solvent, adding into two-necked flask filled with argon, placing in cold well controlled to-5 deg.C, adding gamma-Al under magnetic stirring₂O₃Na 20.0mg, mixed for 1h, and then added with 50.7mg (about 0.20mmol) of 3-bromobenzenesulfonyl chloride for reaction, followed by TLC. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using dichloromethane to methanol (100: 1, 60:1 elution, respectively), and the mixture was separated and purified to obtain 132.4mg (about 0.16mmol) of a white powder product, melting point: 215.5-217.2 ℃, slowly adding 50% fumaric acid (dissolved by DMSO solvent in advance) into the product under stirring at the temperature below 60 ℃, stopping adding the fumaric acid when the pH value of the solution is 7.0, continuing stirring for reaction for 2h, and drying in vacuum at 50 ℃ for 6h to obtain 141.6mg (about 0.15mmol) of a white powdery product, wherein the yield is 83.3%, and the melting point of the target product is as follows: 244.5-247.4 ℃. And (3) product analysis and characterization:¹H NMR(400MHz,CD₃OD)δ10.76(br,1H),8.01(br,1H),7.78(t,J＝1.6Hz,1H),7.69(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.37–7.16(m,3H),7.09(dd,J＝8.1,2.5Hz,1H),6.82–6.77(m,2H),6.65(dd,J＝8.3,2.5Hz,1H),6.37(d,J＝7.2Hz,2H),6.24(s,1H),6.16(dd,J＝8.3,2.0Hz,1H),5.91(d,J＝8.77,1H),5.54(d,J＝8.77,1H),3.82(d,J＝9.4Hz,3H),3.64(dd,J＝11.1,5.4Hz,1H),3.56(d,J＝9.9Hz,1H),3.44(s,3H),3.42–3.31(m,2H),3.19(s,3H),2.75–2.59(m,8H),2.57(s,3H),2.42(dd,J＝30.0,9.4Hz,2H),2.22(s,3H)；¹³C NMR(101MHz,CD₃OD)δ179.05,172.87,154.90,151.99,150.29,149.73,148.64,148.15,143.42,140.28,137.65,136.09,135.54,133.82,132.52,131.20,129.58,129.35,129.01,128.25,125.01,123.88,123.49,122.90,121.64,117.29,113.84,112.60,107.25,67.37,66.65,64.77,62.51,61.14,60.83,57.17,56.05,53.83,52.50,40.67,23.37,22.03；HRMS(ESI):calcd for C₄₃H₄₃N₂O₈SBr[M-C₄H₄O₄]m/z:826.1923found:827.1857[M-C₄H₄O₄+H]⁺. Compound 117 in table 1.

Example 22

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 3mL of dichloromethane, and the resulting solution was placed in a two-necked flask filled with argon, and placed in a cold well controlled to 0 ℃, and 66.5mg (about 0.72mmol) of triethylamine dissolved in 2mL of dichloromethane was added thereto under magnetic stirring, and after mixing for 1 hour, 35.4mg (about 0.20mmol) of 3-pyridinesulfonyl chloride was added to carry out a reaction, and the reaction was followed by TLC. After the reaction, the reaction mixture was concentrated and purified by a neutral alumina column using dichloromethane to methanol (100: 1, 50:1 elution, respectively), and the mixture was separated and purified to obtain 112.3mg (about 0.15mmol) of a white powdery product, melting point: 207.1-208.7 ℃, slowly adding 60% acetic acid into the product under stirring and temperature control below 50 ℃, stopping adding the acetic acid when the pH value of the solution is 7.0, continuing stirring for reaction for 2h, and performing vacuum drying at 50 ℃ for 6h to obtain 1303.5mg (about 0.15mmol) of a white powdery product, wherein the yield is 83.4%, the melting point of the target product is: 247.7-249.3 deg.C. And (3) product analysis and characterization:¹H NMR(400MHz,CD₃OD)δ8.75(dd,J＝10.1,3.3Hz,2H),8.02(br,1H),7.82(d,J＝8.1Hz,1H),7.29(dd,J＝8.0,3.5Hz,2H),7.17(s,1H),7.08(dd,J＝8.1,2.3Hz,1H),6.77(s,2H),6.68(dd,J＝8.2,2.3Hz,1H),6.39(d,J＝16.1Hz,2H),6.25–6.17(m,2H),3.84(s,3H),3.73–3.60(m,2H),3.38(s,3H),3.35(s,3H),2.74–2.66(m,6H),2.62(d,J＝12.2Hz,2H),2.57(s,3H),2.47–2.35(m,2H),2.29(s,3H),2.23(s,3H)；¹³C NMR(101MHz,CD₃OD)δ171.91,152.79,149.38,148.30,147.86,146.85,146.13,141.17,135.08,134.11,133.44,133.05,131.97,131.62,129.39,127.64,126.95,126.73,122.86,122.30,121.83,120.89,120.10,114.96,111.70,110.49,104.94,62.82,61.83,60.58,60.35,59.51,58.84,55.14,52.70,51.32,40.89,38.91,25.31,23.73,22.11；HRMS(ESI):calcd for C₄₂H₄₃N₃O₈S[M-2C₂H₄O₂]m/z:749.2804，found:750.2852[M-2C₂H₄O₂+H]⁺. Compound 137 in table 1.

Example 23

100.0mg of fangchinoline (about 0.18mmol) was dissolved in 3mL of dichloromethane, and the resulting solution was placed in a two-necked flask filled with argon, and placed in a cold well controlled to 10 ℃, and 66.5mg (about 0.72mmol) of triethylamine dissolved in 2mL of dichloromethane was added under magnetic stirring, and after mixing for 1 hour, 45.2mg (about 0.20mmol) of 2-naphthalenesulfonyl chloride was added and reacted for 2 hours, followed by heating to 60 ℃ and reaction by TLC. After the reaction, the reaction solution was concentrated and purified by a neutral alumina column using dichloromethane and methanol (120:1, 80:1, respectively), and the mixture was separated and purified to obtain 118.0mg (about 0.148mmol) of a pale yellow powder product in 82.2% yield. And (3) analyzing and characterizing products:¹H NMR(400MHz,CDCl₃)δ8.20(s,1H),8.02–7.75(m,4H),7.69(t,J＝7.5Hz,1H),7.56(dd,J＝15.4,8.1Hz,2H),6.85–6.73(m,3H),6.61(d,J＝7.4Hz,1H),6.54(dd,J＝8.2,2.1Hz,1H),6.30(d,J＝23.5Hz,2H),6.21(s,1H),6.03(d,J＝8.2Hz,1H),4.40(s,1H),3.84(s,3H),3.53(d,J＝10.0Hz,1H),3.45(d,J＝10.1Hz,3H),3.33(ddd,J＝21.6,20.7,10.6Hz,2H),3.19(d,J＝14.4Hz,3H),2.94–2.68(m,6H),2.53(s,3H),2.51–2.31(m,4H),2.20(d,J＝12.1Hz,3H)；¹³C NMR(101MHz,CDCl₃)δ153.47,151.48,149.29,148.57,147.57,147.12,142.42,135.28,134.63,134.59,134.47,132.42,131.87,129.97,129.52,128.73,128.08,127.79,127.59,123.85,122.83,121.50,120.04,115.89,112.84,111.47,106.42,63.42,61.42,56.12,56.59,55.77,44.96,43.91,42.41,42.32,42.23,39.05,24.34,22.05；HRMS(ESI):calcd for C₄₇H₄₆N₂O₈S m/z:798.2975,found:799.3029[M+H]⁺. Compound 138 in table 1.

Other compounds can be obtained by similar preparation methods (including purification methods) to the above examples.

Example 24 in vitro inhibition of XOD Activity

Phosphate buffer (PBS, 10mM, pH 7.4), XOD (92U/L) and xanthine (0.5mM) were prepared first and then stored at 4 ℃ for later use. Next, compounds 1-140 were accurately weighed and the stock solution was made up to 200 μ M concentration, and the compounds to be tested were further diluted to different concentrations (50, 25, 12.5, 6.25, 3.125, 1.5625 μ M) with PBS. Both blank and positive controls were set, with PBS and allopurinol (guangzhoukang and pharmaceutical co., ltd.) replacing the test compounds, respectively. The reaction was performed in 96-well microplates containing 200 μ Ι _ of reaction mixture per well, with 3 replicates per concentration setting. First, 100. mu.L of test compounds at various concentrations were mixed with 50. mu.L XOD (Shanghai-derived leaf Biotechnology Co., Ltd.) and equilibrated at 37 ℃ for 5min in an incubator, and then 50. mu.L of xanthine (Shanghai-derived leaf Biotechnology Co., Ltd.) was added to initiate a reaction, and the reaction was incubated at 37 ℃ for 30min in the incubator. After the reaction was completed, the OD value of each well was measured by a microplate reader, and data was analyzed using Microsoft Excel 2013, and the OD value changes of the blank group and the test compound group were calculated from the inhibition (%) and IC was calculated using GraphPad Prism 7.0₅₀Values to evaluate XOD inhibitory activity of test compounds.

Calculating the formula: inhibition ratio (%) ═ (OD)_blank-OD_compound)/OD_blank×100％

OD_blankDenotes the OD value, OD, of the blank group_compoundThe OD values of the test compound groups are shown.

The results of the in vitro inhibition of XOD activity are summarized in Table 2.

TABLE 2 inhibition of XOD Activity IC by Sulfonyl fangchinoline Compounds₅₀Value of

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An application of sulfonyl fangchinoline compound in preparing XOD inhibitor;

wherein the sulfonyl fangchinoline compound has a structure shown in a formula (I) or a formula (I'):

wherein R is selected from alkyl, substituted aryl, substituted benzyl, heterocyclic radical and substituted heterocyclic radical; wherein the alkyl is methyl, the substituted alkyl is chloromethyl, bromomethyl or trichloromethyl, the substituted aryl is o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, 3, 4-dichlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, 3, 4-dibromophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl or 3, 4-difluorophenyl, the substituted benzyl is m-fluorobenzyl, the heterocyclic group is thienyl or pyridyl, and the substituted heterocyclic group is 5-chlorothienyl, 5-bromothienyl or 1, 2-dimethyl-1H-imidazolyl; y is selected from 1 molecule of inorganic acid and organic acid or 2 molecules of inorganic acid and organic acid.

2. Use according to claim 1, characterized in that the mineral acid is hydrochloric acid, hydrobromic acid or hydroiodic acid.

3. Use according to claim 1, characterized in that the organic acid is formic acid, acetic acid, propionic acid, malonic acid, 1, 4-butanedioic acid, benzoic acid, nicotinic acid, fumaric acid, malic acid, maleic acid, gluconic acid or citric acid.

4. Use according to claim 1, characterized in that Y is 1 molecule of acetic acid, 2 molecules of hydrochloric acid or 2 molecules of hydrobromic acid.

5. A preparation method of sulfonyl fangchinoline compounds is characterized in that fangchinoline is used as an initial reactant and RSO₂Preparing a compound of formula (I) after X reacts, or further adding Y to obtain a compound of formula (I) to prepare a compound of formula (I'), wherein X is halogen, and R is selected from alkyl, substituted aryl, substituted benzyl, heterocyclic group and substituted heterocyclic group; wherein the alkyl is methyl, the substituted alkyl is chloromethyl, bromomethyl or trichloromethyl, the substituted aromatic alkyl is o-chlorophenyl, m-chlorophenyl, 3, 4-dichlorophenyl, p-bromophenyl, 3, 4-dibromophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl or 3, 4-difluorophenyl, the substituted benzyl is m-fluorobenzyl, the heterocyclic group is thienyl, and the substituted heterocyclic group is 5-chlorothienyl, 5-bromothienyl or 1, 2-dimethyl-1H-imidazolyl; y is selected from 1 molecule of inorganic acid, organic acid or 2 molecules of inorganic acid and organic acid;

6. the method for preparing a sulfonyl fangchinoline compound as claimed in claim 5, wherein the method comprises: dissolving fangchinoline in a solvent, adding an alkaline substance in an inert atmosphere, uniformly mixing, and performing reaction at-20-60 DEG CAddition of RSO₂And (3) reacting for 0.1-12 h, keeping the solution alkaline in the reaction process, detecting the reaction by using a chromatography method until the reaction is finished, standing to room temperature, and preparing the compound shown in the formula (I) by separation and purification, or further adding Y to neutralize to be neutral, and separating and purifying to prepare the compound shown in the formula (I').

7. The method according to claim 6, wherein the solvent is one or more selected from the group consisting of water, methanol, ethanol, propanol, butanol, pentanol, glycerol, dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, 1, 4-dioxane, 1, 2-dichloroethane, tetrahydrofuran, N-dimethylformamide, ethyl acetate, and dimethyl sulfoxide.

8. The method for producing a sulfonyl fangchinoline compound according to claim 6, wherein the solvent is used in an amount such that fangchinoline is dissolved in 5 to 100L of the solvent per mole of fangchinoline.

9. The method for producing a sulfonyl fangchinoline compound according to claim 6, wherein the basic substance is γ -Al₂O₃-Na、γ-Al₂O₃-K、γ-Al₂O₃-NaOH-Na、γ-Al₂O₃-NaOH-K、γ-Al₂O₃-KOH-Na、γ-Al₂O₃-one or more of KOH-K, sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium amide, sodium metal, sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium oxide, potassium oxide, calcium oxide, potassium carbonate, sodium carbonate, ammonia, ethylamine, diethylamine, triethylamine, methylamine, dimethylamine, trimethylamine, pyridine, and piperidine.

10. The method for preparing a sulfonyl fangchinoline compound as claimed in claim 6, wherein fangchinoline and RSO are used as raw materials₂The molar ratio of X to the alkaline substance is 1: 0.1-10: 0.01-10.

11. The method for preparing a sulfonyl fangchinoline compound as claimed in claim 10, wherein the fangchinoline and RSO are₂The molar ratio of X to the alkaline substance is 1: 1.0-1.2: 0.6-3.0.