CN116621897B - Scopolamine derivatives, preparation method and medical application thereof - Google Patents

Scopolamine derivatives, preparation method and medical application thereof Download PDF

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CN116621897B
CN116621897B CN202310514275.6A CN202310514275A CN116621897B CN 116621897 B CN116621897 B CN 116621897B CN 202310514275 A CN202310514275 A CN 202310514275A CN 116621897 B CN116621897 B CN 116621897B
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CN116621897A (en
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夏元铮
殷勇
张尧尧
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention belongs to the technical field of medicines. The invention discloses scopolamine derivatives with good anti-gout activity, a preparation method and medical application thereof, and relates to 3-C substituted coumarin derivatives shown in structural general formulas (I), (II) and (III). The activity screening test proves that the compound has an inhibiting effect on the NO content in cells, has good anti-gout activity, has a prospect of being developed into a medicine for treating gout, and has the advantages of simple steps, mild conditions and strong operability and controllability. The prior art does not disclose the derivatives of the invention, the preparation method and the medical application thereof.

Description

Scopolamine derivatives, preparation method and medical application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to scopolamine derivatives, a preparation method and medical application thereof.
Background
Gout is a metabolic disease caused by purine metabolic disorder, the concentration of blood uric acid is increased, sodium urate crystals are deposited on the bones and joints of lower limbs, the disease is manifested by red, swelling, heat, pain and unfavorable joint movement, and the serious patient is joint deformity and dysfunction and has the characteristic of repeated attack. Gout can also lead to the worsening of coronary heart disease, diabetes, hypertension and other diseases. Up to now, no good medicine for treating gout exists. The gout patients in China are over 8000 ten thousands of people, and the annual growth rate of 9.7% per year is rapidly increasing. Gout is a second most metabolic disease in China after diabetes mellitus, and is a non-negligible health warning.
Many research reports suggest coumarin parent nuclei as potential candidates for the development of anti-inflammatory drugs. Various plant components such as umbelliferone, scopoletin, and more plant components derived from coumarin parent nucleus were found to have potent anti-inflammatory and antioxidant activity. The anti-inflammatory activity of coumarin derivatives has been reported, and the relation between (SAR) structure and activity has been explored, and a large number of coumarin derivatives have been designed, synthesized and evaluated for anti-inflammatory activity.
The invention aims to provide scopolamine derivatives with anti-gout activity and a preparation method thereof. The scopolamine derivatives provided by the invention provide preliminary pharmacological experimental research on the research on anti-gout drugs by MTT cytotoxicity experiments and in-cell NO release inhibition experiments, hyperuricemia model mouse experiments, gouty arthritis rat model experiments, rat joint synovium HE staining and joint synovium tissue ELISA experiments (IL-1 beta and TNF-alpha), are expected to become candidate drugs for treating gout and hyperuricemia, and have good application prospects.
Disclosure of Invention
The invention aims to: it is an object of the present invention to provide a class of scopolamine derivatives.
It is another object of the present invention to provide a process for the preparation of the scopolamine derivatives described above.
It is a further object of the present invention to provide a medical use of the scopolamine derivatives described above.
The technical scheme is as follows: in order to achieve the aim of the invention, the invention provides a preparation method of scopolamine derivatives shown in structural formulas (I), (II) and (III), and pharmacological activity research is carried out through MTT cytotoxicity experiment and in-cell NO release inhibition experiment, hyperuricemia model mouse experiment, gouty arthritis rat model experiment, rat joint synovium HE staining and ELISA experiment (IL-1 beta and TNF-alpha), so that scopolamine derivative 16 has good pharmacological activity.
The scopolamine derivatives provided by the invention are represented by structural general formulas (I), (II) and (III):
In the general structural formula (I), the substituent R 1 is selected from C 1-C4 alkoxy or C 6-C8 aromatic alkyl or C 1-C3 chain alkyl;
In the general structural formula (II), the substituent R 2 is selected from C 4-C7 aliphatic hydrocarbon group, C 3-C7 cycloaliphatic hydrocarbon group or C 6-C8 aromatic hydrocarbon group;
In the general structural formula (III), the substituent R 3 is selected from C 1-C4 alkoxy, C 6-C8 aromatic hydrocarbon, halogen substituted C 1-C4 aliphatic hydrocarbon, halogen substituted C 1-C4 alkoxy, C 1-C10 aliphatic hydrocarbon or C 1-C7 amino.
Preferably, the method comprises the steps of,
Compound 1: r 1 =2 ',4' -diOMe; compound 2: r 1 =2 ',5' -diOMe;
Compound 3: r 1 =3 ',4' -diOMe; compound 4: r 1 =4' -Me;
compound 5: r 1 =4' -Ph;
Preferably, the method comprises the steps of,
Compound 6: r 2＝-CH(CH3)CH2CH3; compound 7: r 2 = -cyclobutyl;
compound 8: r 2 = -cyclohexyl compound 9: r 2 = -Ph;
Preferably, the method comprises the steps of,
Preferably, the derivative is selected from any one of the following compounds:
the preparation method of the scopolamine derivative comprises the following steps: acylation reaction, knoevenagel condensation reaction and nucleophilic substitution reaction.
The preparation method of scopolamine derivatives provided by the invention comprises the following operation steps:
step a, D-glucose and acetic anhydride are subjected to acylation reaction to obtain an intermediate IV shown in the following structural formula;
Step b, reacting the intermediate IV with HBr to obtain an intermediate V shown in the following structural formula;
preparation of a compound of the general structural formula (I):
Step c, reacting Mirabilic acid and 2, 4-dihydroxybenzaldehyde under the catalysis of sodium acetate to obtain an intermediate VI shown in the following structural formula;
Step d, reacting the intermediate VI with different R 1 substituent compounds to obtain an intermediate VII shown in the following structural formula;
Step e, reacting the intermediate VII with the intermediate V to obtain a compound with a structural general formula (I);
Preparation of a compound of the general structural formula (II):
step f, reacting 2, 4-dihydroxybenzaldehyde with ethyl acetoacetate to obtain an intermediate VIII shown in the following structural formula;
step g, reacting the intermediate VIII with different R 2 substituent compounds to obtain an intermediate IX shown in the following structural formula;
Step h, reacting the intermediate IX with the intermediate V to obtain a compound with a structural general formula (II);
preparation of a compound of the general structural formula (III):
Step i, reacting the intermediate VIII with different R 3 substituent compounds to obtain an intermediate X shown in the following structural formula;
step j, reacting the intermediate X with the intermediate V to obtain a compound with a structural general formula (III);
Preferably, the reaction conditions in step a comprise: perchloric acid is used as a catalyst under the ice bath condition.
More preferably, step a comprises: firstly, dissolving perchloric acid (0.14 eq) into acetic anhydride (5 eq), uniformly stirring, then adding D-glucose powder (1 eq) into the mixture, and then carrying out reaction under ice bath condition, and detecting the reaction progress by TLC; after the completion of the reaction, an intermediate was obtained by a method of recrystallization using ethanol.
Preferably, the reaction conditions in step b comprise: HBr is used as a catalyst under ice bath condition.
More preferably, step b comprises: firstly, dissolving an intermediate IV (1 eq) into a proper amount of anhydrous dichloromethane, adding HBr (8 eq) into the mixture after the mixture is uniformly stirred, carrying out a reaction under the ice bath condition, monitoring the reaction progress in real time by developing sulfuric acid and ethanol, extracting water and ethyl acetate after the reaction is finished, concentrating the mixture under reduced pressure to obtain oily liquid, and standing the oily liquid at normal temperature for 20min to precipitate crystals, thus obtaining an intermediate V.
Preferably, the reaction conditions in step c comprise: sodium acetate is used as a catalyst for reaction at normal temperature.
More preferably, step c comprises: firstly, 2, 4-dihydroxybenzaldehyde (1 eq) and Mi's acid (3 eq) are dissolved in purified water, and after being stirred uniformly, a proper amount of sodium acetate is added into the mixture, and then the reaction is carried out under normal temperature. White solid is separated out in the reaction process, TLC detects the reaction progress, and after the reaction is finished, the intermediate VI is obtained through suction filtration and washing by purified water.
Preferably, the reaction conditions in step d comprise: HATU and DIPEA are used as catalysts for reaction at normal temperature.
More preferably, step d comprises: intermediate VI (1 eq) is first dissolved in anhydrous dichloro, stirred well and HATU (3 eq) and DIPEA (5 eq) are then added to it, after which the reaction is carried out for 10min at ambient temperature. Then adding different R 1 substituent compounds (1.5 eq) into the reaction system, reacting at normal temperature, detecting the reaction progress by TLC, obtaining an organic layer by using a method of extracting dichloromethane and water after the reaction is finished, obtaining a crude product by decompressing and concentrating, and purifying by column chromatography to obtain an intermediate compound VII.
Preferably, the reaction conditions in step f comprise: PIPERIDINE is used as a catalyst for reaction at 80-85 ℃.
More preferably, step f comprises: firstly, respectively and sequentially adding 2, 4-dihydroxybenzaldehyde (1 eq) and ethyl acetoacetate (3 eq) into a proper amount of ethanol solution, fully dissolving, then adding PIPERIDINE (0.005 eq) into a reaction system, reacting at 80-85 ℃, detecting the reaction progress by TLC, and obtaining an intermediate VIII by adopting an ethanol recrystallization method after the reaction is completed.
Preferably, the reaction conditions in step g/i comprise: pyrrolidine is used as a catalyst for reaction at 80 ℃.
More preferably, step g/i comprises: firstly, dissolving intermediate VIII (1 eq) in a proper amount of ethanol, setting the temperature in a parallel reactor at 80 ℃ and 600rpm, adding Pyrrolidine (0.0056 eq) into a reaction system after the intermediate VIII (1 eq) is fully dissolved, adding different R 2/R3 substituent compounds (2 eq) into the system for reaction after the ethanol is refluxed for 10min, detecting the reaction progress by TLC, obtaining an organic layer by a methylene dichloride extraction method after the reaction is finished, obtaining a crude product by decompression concentration, and purifying by column chromatography to obtain an intermediate compound IX/X.
Preferably, the reaction conditions in step e/h/j comprise: ag 2 O is used as a catalyst, sodium methoxide is used as alkali, cation exchange resin is used as a blending agent, and the reaction is carried out at normal temperature.
More preferably, step e/h/j comprises: firstly, intermediate VII/IX/X (1 eq) and intermediate V (4 eq) are dissolved in a proper amount of acetonitrile solution, ag 2 O (1 eq) is added after full stirring, reaction is carried out for 6 hours at normal temperature, TLC detects the reaction progress, after the reaction is detected, dichloromethane is used for extracting and spin-drying the system, proper amount of methanol is used for dissolution, sodium methoxide is added into the reaction system after full dissolution, and reaction is carried out for 1 hour at normal temperature. Adding cation exchange resin into the reaction system for blending, filtering to remove the resin, extracting with an organic solvent, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain scopolamine derivative compounds 1-35.
The invention provides application of scopolamine derivatives in preparing medicines for treating gout.
Pharmacological activity research of the target scopolamine derivatives is based on MTT cytotoxicity experiments and NO release inhibition experiments in cells, hyperuricemia model mouse experiments, gouty arthritis rat model experiments, rat joint synovium HE staining and joint synovium tissue ELISA experiments (IL-1 beta and TNF-alpha). The scopolamine derivative 16 has better anti-gout activity on MSU induced gouty arthritis rats.
In light of the foregoing, many other modifications, substitutions and alterations are also possible in accordance with the ordinary skill and knowledge of one skilled in the art without departing from the spirit and scope of the present invention.
The foregoing is further supplemented by the following examples, which should not be construed as limiting the scope of the invention to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: the scopolamine derivatives provided by the invention are applied to medicines for resisting hyperuricemia or gout, have side effects smaller than those of allopurinol which is a positive medicine, and provide a new choice for medicines for treating gout.
Drawings
FIG. 1 shows the effect of scopoletin derivative 16 on serum indicators of hyperuricemia in mice due to potassium oxazinate and hypoxanthine;
FIG. 2 is a graph of swelling of scopolamine derivatives 16 on MSU-induced gouty arthritis in a rat model experiment;
FIG. 3 is a plot of swelling rate of scopolamine derivatives 16 versus MSU-induced gouty arthritis in a rat model experiment;
FIG. 4 is a graph of scopolamine derivatives 16 staining MSU-induced gouty arthritis rat joint synovium HE;
FIG. 5 is the effect of scopolamine derivatives 16 on IL-1. Beta. And TNF-. Alpha.levels in MSU-induced gouty arthritis rat joint synovial tissue.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings.
The invention is better illustrated by the following examples. The present invention is not limited by the following examples.
The process flow is as follows:
example 1
Synthesis of Compound 1
(1) Synthesis of intermediate IV
Firstly, dissolving 0.8ml of perchloric acid into 50ml of acetic anhydride, uniformly stirring, then adding 100 mmolD-glucose powder into the mixture, then carrying out reaction for 10 hours under ice bath conditions, and detecting the reaction progress by TLC; after the reaction is completed, intermediate IV is obtained by a recrystallization method using ethanol.
(2) Synthesis of intermediate V
Firstly, 50mmol of intermediate IV is dissolved into 20ml of anhydrous dichloromethane, 10ml of HBr is added into the solution after the solution is uniformly stirred, the reaction is carried out for 12 hours under the ice bath condition, the reaction progress is monitored in real time by color development of sulfuric acid ethanol, after the reaction is finished, water and ethyl acetate are extracted, the solution is concentrated under reduced pressure to obtain oily liquid, and the oily liquid is placed at normal temperature for 20min to separate out crystals, thus obtaining an intermediate V.
(3) Synthesis of intermediate VI
Firstly, 50mmold of 2, 4-dihydroxybenzaldehyde and 150mmol of Mi's acid are dissolved in purified water, and after being stirred uniformly, a proper amount of sodium acetate is added into the mixture, and the reaction is carried out for 12 hours at normal temperature. White solid is separated out in the reaction process, TLC detects the reaction progress, and after the reaction is finished, the intermediate VI is obtained through suction filtration and washing by purified water.
(4) Synthesis of intermediate VII
5Mmol of intermediate VI is first dissolved in 20ml of anhydrous dichloro, after stirring thoroughly and homogeneously, 15mmol of HATU and 25mmol of DIPEA are added thereto, and then the reaction is carried out at room temperature for 10min. Then adding 7.5mmol of R 1 substituent compound (2, 4-dimethoxy aniline) into the reaction system, reacting at normal temperature, detecting the reaction progress by TLC, obtaining an organic layer by using a method of extracting dichloromethane and water after the reaction is finished, obtaining a crude product by decompressing and concentrating, and purifying by column chromatography to obtain an intermediate compound VII.
(5) Synthesis of Compound 1
Dissolving 5mmol of intermediate compound VII and 20mmol of intermediate V in 30ml of acetonitrile solution, adding 5mmol of Ag 2 O after full stirring, reacting for 6 hours at normal temperature, detecting the reaction progress by TLC, extracting and spin-drying a system by using dichloromethane after the detection reaction is finished, dissolving by using 20ml of methanol, adding sodium methoxide into the reaction system after full dissolution, and reacting for 1 hour at normal temperature. Cation exchange resin is added into the reaction system for blending, then the resin is removed by filtration, the mixture is extracted by an organic solvent, a crude product is obtained by decompression concentration, and the final product compound 1 is purified and separated by column chromatography. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ10.93(s,1H),8.98(s,1H),8.33(d,J＝8.9Hz,1H),7.97(d,J＝8.8Hz,1H),7.19(d,J＝2.2Hz,1H),7.12(dd,J＝8.7,2.3Hz,1H),6.68(d,J＝2.6Hz,1H),6.55(dd,J＝8.9,2.6Hz,1H),5.44(d,J＝4.6Hz,1H),5.17(d,J＝3.8Hz,1H),5.13(d,J＝7.3Hz,1H),5.10(d,J＝5.2Hz,1H),4.62(t,J＝4.8Hz,1H),3.89(s,3H),3.76(s,3H),3.71(dd,J＝9.6,4.7Hz,1H),3.48(q,J＝5.5Hz,2H),3.33–3.27(m,2H),3.19(dt,J＝13.3,6.7Hz,1H).13C NMR(125MHz,DMSO)δ162.71,161.89,159.29,156.85,156.26,150.19,148.61,132.17,121.29,120.96,115.88,115.30,113.69,104.74,103.17,100.33,99.26,77.65,76.93,73.57,70.05,61.08,56.64,55.81.HRMS(ESI)m/z:526.1323[M+Na]+(calcd for 526.1320,C24H25NNaO11).
Example 2:
Synthesis of Compound 2
Referring to example 1, step 4 was performed using 2, 5-dimethoxyaniline instead of 2, 4-dimethoxyaniline, and the other conditions were the same as in example 1. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ11.14(s,1H),9.01(s,1H),8.15(d,J＝3.0Hz,1H),7.98(d,J＝8.8Hz,1H),7.19(d,J＝2.0Hz,1H),7.13(dd,J＝8.7,2.2Hz,1H),7.02(d,J＝9.0Hz,1H),6.66(dd,J＝8.9,3.0Hz,1H),5.45(d,J＝4.5Hz,1H),5.16(d,J＝3.9Hz,1H),5.14(d,J＝7.2Hz,1H),5.09(d,J＝5.2Hz,1H),4.61(t,J＝5.2Hz,1H),3.85(s,3H),3.72(s,3H),3.69(dd,J＝11.5Hz,1H),3.48(q,J＝9.7,7.9Hz,2H),3.32–3.28(m,2H),3.19(td,1H).13C NMR(150MHz,DMSO)δ162.41,161.41,159.51,155.92,153.12,148.65,142.71,131.85,128.14,115.25,114.91,113.22,111.68,107.75,106.74,102.72,99.84,77.20,76.46,73.11,69.59,60.62,56.59,55.36.HRMS(ESI)m/z:526.1322[M+Na]+(calcd for 526.1320,C24H25NNaO11).
Example 3:
Synthesis of Compound 3
Referring to example 1, step 4 was performed using 3, 4-dimethoxyaniline instead of 2, 4-dimethoxyaniline, and the other conditions were the same as in example 1. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ10.49(s,1H),8.90(s,1H),7.95(d,J＝8.8Hz,1H),7.38(d,J＝2.4Hz,1H),7.28(dd,J＝8.7,2.4Hz,1H),7.20(d,J＝2.1Hz,1H),7.13(dd,J＝8.7,2.3Hz,1H),6.95(d,J＝8.8Hz,1H),5.43(d,J＝4.7Hz,1H),5.13(t,J＝6.2Hz,2H),5.07(d,J＝5.3Hz,1H),4.59(t,J＝5.5Hz,1H),3.78(s,3H),3.75(s,3H),3.72(dd,J＝9.8,5.2Hz,1H),3.47(q,2H),3.31–3.29(m,2H),3.19(td,J＝11.1,5.6Hz,1H).13C NMR(125MHz,DMSO)δ162.16,161.00,159.57,155.72,148.70,147.67,145.56,131.55,131.47,116.19,114.81,113.09,112.07,111.97,105.00,102.73,99.83,77.16,76.46,73.07,69.58,60.62,55.71,55.50.HRMS(ESI)m/z:526.1321[M+Na]+(calcd for 526.1320,C24H25NNaO11).
Example 4:
Synthesis of Compound 4
Referring to example 1, step 4 replaced 2, 4-dimethoxyaniline with 4-methylphenylamine, and the other conditions were the same as in example 1. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ10.57(s,1H),8.91(s,1H),7.96(d,J＝8.8Hz,1H),7.60(d,J＝8.4Hz,2H),7.21–7.17(m,3H),7.13(dd,J＝8.7,2.3Hz,1H),5.45(d,J＝3.5Hz,1H),5.17(s,1H),5.13(d,J＝7.3Hz,1H),5.09(d,J＝4.6Hz,1H),4.61(t,J＝5.0Hz,1H),3.71(dd,J＝9.7,4.8Hz,1H),3.46(dd,J＝7.7Hz,2H),3.17(d,J＝3.3Hz,3H),2.29(s,3H).13C NMR(125MHz,DMSO)δ162.66,161.52,160.24,156.23,148.24,135.96,133.74,132.08,129.87(2C),120.31(2C),116.71,115.27,113.57,103.20,100.29,77.64,76.94,73.55,70.04,61.08,49.07.HRMS(ESI)m/z:480.1265[M+Na]+(calcd for 480.1265,C23H23NNaO9).
Example 5:
synthesis of Compound 5
Referring to example 1, step 4 replaced 2, 4-dimethoxyaniline with p-phenylphenylamine under the same conditions as in example 1. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ10.73(s,1H),8.94(s,1H),7.98(d,J＝8.8Hz,1H),7.83(d,J＝8.5Hz,2H),7.73–7.66(m,4H),7.46(t,J＝7.6Hz,2H),7.35(t,J＝7.3Hz,1H),7.21(d,1H),7.14(dd,J＝8.7,2.1Hz,1H),5.45(d,1H),5.13(q,3H),4.62(s,1H),3.72(d,J＝9.7Hz,1H),3.48(d,J＝7.7Hz,2H),3.22–3.16(m,3H).13C NMR(125MHz,DMSO)δ162.25,160.98,160.07,155.80,147.88,139.49,137.43,135.84,131.65,128.92(2C),127.16(2C),126.31(2C),120.29(2C),116.23,114.82,113.08(2C),102.75,99.84,77.17,76.46,73.08,69.57,60.60.HRMS(ESI)m/z:542.1418[M+Na]+(calcd for 542.1422,C28H25NNaO9).
Example 6:
Synthesis of Compound 6
(1) Synthesis of intermediate V
Referring to example 1, steps 1 and 2.
(2) Synthesis of intermediate VIII
Firstly, 100mmol of 2, 4-dihydroxybenzaldehyde and 300mmol of ethyl acetoacetate are respectively and sequentially added into 200ml of ethanol solution, after the mixture is fully dissolved, 1ml of PIPERIDINE is added into a reaction system, the reaction is carried out at 80 ℃, the TLC detects the reaction progress, and after the reaction is completed, an ethanol recrystallization method is adopted to obtain an intermediate VIII.
(3) Synthesis of intermediate IX
Dissolving 5mmol of intermediate VIII in 20ml of ethanol, setting the temperature in a parallel reactor to be 80 ℃ and 600rpm, adding 100ul Pyrrolidine into a reaction system after the intermediate VIII is fully dissolved, adding 10mmol of R 2 substituent compound (2-methyl butyraldehyde) into the system after the ethanol is refluxed for 10min for reaction, detecting the reaction progress by TLC, obtaining an organic layer by a dichloromethane extraction method after the reaction is finished, obtaining a crude product by decompression concentration, purifying by column chromatography, and obtaining an intermediate compound IX
(4) Synthesis of Compound 6
Referring to example 1, step 5 uses intermediate compound IX instead of intermediate compound VII, and the other conditions are the same as in example 1 to obtain compound 6. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ8.70–8.60(m,1H),7.90(dd,J＝10.6,8.8Hz,1H),7.12(d,J＝2.2Hz,1H),7.08(d,J＝8.6Hz,1H),7.06–6.85(m,2H),5.43(s,1H),5.13–5.09(m,3H),4.60(t,1H),3.70(dd,1H),3.47(q,J＝8.3Hz,2H),3.30–3.27(m,2H),3.21(td,1H),1.24(s,2H),1.06(d,J＝6.7Hz,1H),0.89–0.82(m,6H).13C NMR(125MHz,DMSO)δ187.33,159.19,156.92,154.44,148.06,132.28,126.89,114.96,114.88,113.35,113.19,103.16,100.28,77.64,76.93,73.54,70.04,61.07,38.21,28.73,19.22,11.98.HRMS(ESI)m/z:457.1470[M+Na]+(calcd for457.1469,C22H26NaO9).
Example 7:
Synthesis of Compound 7
Referring to example 6, step 3 replaced 2-methylbutyraldehyde with cyclobutylbenzaldehyde, and the other conditions were the same as in example 6. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ8.63(d,J＝5.8Hz,1H),7.90(dd,J＝8.7,2.6Hz,1H),7.11(dd,J＝4.1,2.3Hz,1H),7.09–7.06(m,1H),7.05–6.99(m,1H),6.76–6.66(m,1H),5.43(d,J＝4.5Hz,1H),5.15(d,J＝4.5Hz,1H),5.11(d,1H),5.08(d,J＝5.3Hz,1H),4.59(t,1H),3.50–3.40(m,2H),3.23(d,J＝1.8Hz,2H),3.19–3.14(m,2H),3.04–2.93(m,1H),1.86–1.58(m,7H).13C NMR(125MHz,DMSO)δ189.07,162.89,159.19,159.16,157.01,148.11,148.00,132.56,121.80,114.96,113.21,103.08,100.23,77.64,76.93,73.54,70.04,40.48,38.65,28.89,24.39,18.19.HRMS(ESI)m/z:455.1311[M+Na]+(calcd for 455.1313,C22H24NaO9).
Example 8:
Synthesis of Compound 8
Referring to example 6, step 3 replaced 2-methylbutyraldehyde with cyclohexylbenzaldehyde, and the other conditions were the same as in example 6. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ8.62(d,J＝19.2Hz,1H),7.88(dd,J＝10.9,8.8Hz,1H),7.11(d,J＝2.2Hz,1H),7.09–7.06(m,1H),7.04–6.90(m,2H),5.44(d,J＝4.7Hz,1H),5.15(d,J＝4.4Hz,1H),5.10(d,J＝7.2Hz,1H),5.08(d,J＝5.3Hz,1H),4.60(t,J＝5.5Hz,1H),3.70(dd,1H),3.46(q,J＝7.2Hz,2H),3.33–3.26(m,2H),3.13(td,J＝4.3Hz,1H),1.81–1.58(m,7H),1.31–1.13(m,4H).13C NMR(125MHz,DMSO)δ187.33,162.86,159.18,157.00,154.10,147.91,132.53,125.99,121.88,114.94,113.19,103.09,100.28,77.64,76.92,73.54,70.04,61.08,41.41,31.67(2C),25.65(3C).HRMS(ESI)m/z:483.1627[M+Na]+(calcd for 483.1626,C24H28NaO9).
Example 9:
Synthesis of Compound 9
Referring to example 6, step 3 replaced 2-methylbutanal with benzaldehyde, and the other conditions were the same as in example 6. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ8.71(s,1H),7.91(d,J＝8.8Hz,1H),7.79–7.74(m,4H),7.47(dd,J＝4.9,1.9Hz,3H),7.15(d,J＝2.3Hz,1H),7.10(dd,J＝8.7,2.4Hz,1H),5.46(d,J＝4.6Hz,1H),5.17(d,J＝4.5Hz,1H),5.13(d,J＝7.2Hz,1H),5.09(s,1H),4.62(t,J＝5.5Hz,1H),3.72(dd,J＝9.6,4.7,4.2Hz,1H),3.48(q,2H),3.33–3.26(m,2H),3.19(td,J＝3.8Hz,1H).13C NMR(125MHz,DMSO)δ187.15,162.79,159.31,156.98,148.22,143.86,135.01,132.37,131.25,129.55(2C),129.09(2C),125.19,122.44,114.95,113.40,103.18,100.25,77.64,76.93,73.55,70.03,61.07.HRMS(ESI)m/z:477.1158[M+Na]+(calcd for 477.1156,C24H22NaO9).
Example 10:
Synthesis of Compound 10
(1) Synthesis of intermediate V
Referring to example 6, step 1.
(2) Synthesis of intermediate VIII
Referring to example 6, step 2.
(3) Synthesis of intermediate X
Referring to example 6, step 3. The R 3 substituent compound (2-methoxybenzaldehyde) is substituted for the R 2 substituent compound (2-methyl butyraldehyde) to obtain an intermediate compound X.
(3) Synthesis of Compound 10
Referring to example 1, step 5 uses intermediate compound X instead of intermediate compound VII, and the other conditions are the same as in example 1 to obtain compound 10. The thin layer of the GF254nm silica gel plate spreads to form a point, and the ultraviolet lamp UV254nm is a dark spot .1H NMR(600MHz,DMSO-d6)δ8.71(s,1H),7.98(d,J＝15.9Hz,1H),7.91(d,J＝8.7Hz,1H),7.82(d,J＝16.0Hz,1H),7.73(dd,J＝7.8,1.7Hz,1H),7.49–7.43(m,1H),7.13(d,J＝8.4Hz,2H),7.09(dd,J＝8.7,2.3Hz,1H),7.04(t,J＝7.3Hz,1H),5.44(d,J＝4.8Hz,1H),5.15(d,J＝4.5Hz,1H),5.12(d,J＝7.2Hz,1H),5.08(d,J＝5.3Hz,1H),4.60(t,J＝5.5Hz,1H),3.89(s,3H),3.71(dd,J＝9.6,5.2Hz,1H),3.47(q,2H),3.32–3.27(m,2H),3.18(td,1H).13C NMR(150MHz,DMSO)δ186.59,162.34,158.87,158.39,156.53,147.81,137.97,132.46,131.94,128.49,124.74,122.86,122.02,120.86,114.47,112.96,111.93,102.70,99.80,77.18,76.47,73.08,69.57,60.60,55.74.HRMS(ESI)m/z:507.1264[M+Na]+(calcd for507.1262,C25H24NaO10).
Example 11
Synthesis of Compound 11
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 3-methoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.69(s,1H),7.90(dd,J＝8.7,4.1Hz,1H),7.73(q,2H),7.38(t,J＝7.9Hz,1H),7.33(d,J＝7.6Hz,1H),7.30(s,1H),7.14(d,J＝2.3Hz,1H),7.09(dd,1H),7.04(dd,J＝8.6,2.8Hz,1H),5.45(d,J＝4.8Hz,1H),5.16(d,J＝4.3Hz,1H),5.12(d,J＝7.3Hz,1H),5.09(d,J＝5.2Hz,1H),4.61(t,J＝5.5Hz,1H),3.80(s,3H),3.72(dd,J＝9.8,5.1Hz,1H),3.47(q,J＝7.1Hz,2H),3.32–3.28(m,2H),3.19(td,J＝9.1,5.4Hz,1H).13C NMR(150MHz,DMSO)δ186.87,162.33,159.66,158.81,156.51,147.63,143.43,135.99,131.90,130.13,125.09,122.09,120.88,116.62,114.50,113.79,112.94,102.75,99.82,77.19,76.48,73.10,69.59,60.63,55.26.HRMS(ESI)m/z:507.1264[M+Na]+(calcd for 507.1262,C25H24NaO10).
Example 12
Synthesis of Compound 12
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 4-methoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.67(s,1H),7.89(d,J＝8.8Hz,1H),7.75–7.70(m,3H),7.63(d,J＝15.8Hz,1H),7.14(d,J＝2.3Hz,1H),7.09(dd,J＝8.7,2.4Hz,1H),7.03(d,J＝8.8Hz,2H),5.44(d,J＝4.6Hz,1H),5.15(d,J＝4.5Hz,1H),5.11(d,J＝7.2Hz,1H),5.08(d,J＝5.3Hz,1H),4.60(t,J＝5.5Hz,1H),3.82(s,3H),3.71(dd,J＝9.5,5.1Hz,1H),3.47(q,2H),3.32–3.28(m,2H),3.18(td,1H).13C NMR(150MHz,DMSO)δ186.53,162.20,161.52,158.85,156.41,147.35,143.65,131.78,130.59(2C),127.14,122.27,122.26,114.60(2C),114.43,112.97,102.71,99.81,77.17,76.47,73.09,69.58,60.61,55.42.HRMS(ESI)m/z:507.1263[M+Na]+(calcd for 507.1262,C25H24NaO10).
Example 13
Synthesis of Compound 13
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2, 3-dimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.72(s,1H),7.93(d,J＝3.6Hz,1H),7.91(d,J＝3.5Hz,1H),7.83(d,J＝16.0Hz,1H),7.35(dd,J＝6.2,3.2Hz,1H),7.18–7.16(m,2H),7.14(d,J＝2.3Hz,1H),7.09(dd,J＝8.6,2.4Hz,1H),5.44(d,J＝4.8Hz,1H),5.16(d,J＝4.4Hz,1H),5.12(d,J＝7.1Hz,1H),5.08(d,J＝5.3Hz,1H),4.60(t,J＝5.6Hz,1H),3.84(s,3H),3.80(s,3H),3.75(dd,J＝7.1Hz,1H),3.47(q,J＝6.2Hz,2H),3.30–3.26(m,2H),3.17(dt,J＝8.7,4.4Hz,1H).13C NMR(150MHz,DMSO)δ186.54,162.41,158.90,156.58,152.87,148.34,148.00,137.32,132.00,128.09,125.70,124.53,121.91,119.10,115.18,114.51,112.95,102.72,99.80,77.18,76.47,73.08,69.57,60.96,60.61,55.86.HRMS(ESI)m/z:537.1369[M+Na]+(calcd for537.1367,C26H26NaO11).
Example 14
Synthesis of Compound 14
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2, 4-dimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.67(s,1H),7.93(d,J＝15.9Hz,1H),7.90(d,J＝8.7Hz,1H),7.69(q,2H),7.13(d,J＝2.3Hz,1H),7.08(dd,J＝8.7,2.4Hz,1H),6.66–6.63(m,2H),5.44(d,J＝4.7Hz,1H),5.15(d,J＝4.4Hz,1H),5.11(d,J＝7.1Hz,1H),5.08(d,J＝5.3Hz,1H),4.60(t,J＝5.6Hz,1H),3.89(s,3H),3.84(s,3H),3.71(dd,J＝9.7,5.1Hz,1H),3.47(q,J＝5.6Hz,2H),3.31–3.27(m,2H),3.18(td,J＝8.8,5.2Hz,1H).13C NMR(150MHz,DMSO)δ186.40,163.25,162.19,160.13,158.87,156.41,147.39,138.45,131.80,130.23,122.32,122.01,115.84,114.40,112.98,106.55,102.69,99.81,98.42,77.18,76.47,73.08,69.57,60.60,55.85,55.58.HRMS(ESI)m/z:537.1365[M+Na]+(calcd for 537.1367,C26H26NaO11).
Example 15
Synthesis of Compound 15
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2, 5-dimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.69(s,1H),7.92(q,2H),7.79(d,J＝15.9Hz,1H),7.27(d,1H),7.13(d,J＝2.4Hz,1H),7.09(dd,J＝8.7,2.4Hz,1H),7.06(d,J＝2.2Hz,2H),5.44(d,J＝4.8Hz,1H),5.16(d,J＝4.6Hz,1H),5.12(d,J＝7.2Hz,1H),5.08(d,J＝5.3Hz,1H),4.61(t,J＝5.5Hz,1H),3.84(s,3H),3.76(s,3H),3.71(dd,J＝9.6,5.1Hz,1H),3.47(q,J＝5.8Hz,2H),3.30–3.26(m,2H),3.18(td,J＝8.4,5.0Hz,1H).13C NMR(150MHz,DMSO)δ186.81,162.32,158.79,156.49,153.19,152.88,147.64,137.86,131.90,125.19,123.44,122.18,118.02,114.47,113.17,112.98,112.94,102.74,99.81,77.19,76.47,73.10,69.59,60.62,56.16,55.61.HRMS(ESI)m/z:537.1367[M+Na]+(calcd for 537.1367,C26H26NaO11).
Example 16
Synthesis of Compound 16
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2, 6-dimethoxybenzaldehyde under the same conditions as in example 10. GF 254 nm silica gel sheet thin layer was spread into a spot, and UV lamp UV 254 nm was a dark spot .1H NMR(600MHz,DMSO-d6)δ8.66(s,1H),8.10(q,J＝16.0Hz,2H),7.91(d,J＝8.6Hz,1H),7.40(t,J＝8.4Hz,1H),7.11(d,J＝2.3Hz,1H),7.08(dd,J＝8.6,2.4Hz,1H),6.74(d,J＝8.5Hz,2H),5.44(dd,1H),5.11(dd,J＝7.2Hz,3H),4.61(t,1H),3.88(s,6H),3.71(dd,1H),3.47(q,2H),3.31–3.26(m,2H),3.18(td,J＝8.4Hz,1H).13C NMR(150MHz,DMSO)δ187.48,162.23,160.06(2C),158.87,156.49,147.61,134.11,132.55,131.92,126.63,122.39,114.40,113.02,111.60,104.24(2C),102.71,99.86,77.21,76.48,73.11,69.60,60.62,48.61(2C).HRMS(ESI)m/z:537.1370[M+Na]+(calcd for 537.1367,C26H26NaO11). example 17
Synthesis of Compound 17
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 3, 4-dimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.62(s,1H),7.88(d,J＝8.7Hz,1H),7.70(d,J＝15.7Hz,1H),7.58(d,J＝15.8Hz,1H),7.34(d,J＝6.8Hz,2H),7.13(d,J＝2.3Hz,1H),7.08(dd,J＝8.7,2.4Hz,1H),7.04(d,J＝8.9Hz,1H),5.45(d,J＝4.8Hz,1H),5.16(d,J＝4.6Hz,1H),5.11(d,J＝7.2Hz,1H),5.09(d,J＝5.3Hz,1H),4.62(t,J＝5.5Hz,1H),3.82(s,6H),3.71(dd,J＝9.6,5.2Hz,1H),3.47(q,J＝8.4Hz,2H),3.34–3.28(m,2H),3.18(td,J＝8.8,5.3Hz,1H).13C NMR(150MHz,DMSO)δ186.96,162.15,158.82,156.37,151.44,149.00,147.03,144.37,131.74,127.34,123.24,122.57,122.56,114.46,112.98,111.80,111.10,102.79,99.85,77.21,76.49,73.13,69.63,60.66,55.67,55.64.HRMS(ESI)m/z:537.1365[M+Na]+(calcd for537.1367,C26H26NaO11).
Example 18
Synthesis of Compound 18
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 3, 5-dimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.67(s,1H),7.89(d,J＝8.7Hz,1H),7.68(q,2H),7.14(d,J＝2.3Hz,1H),7.09(dd,J＝8.7,2.4Hz,1H),6.92(d,J＝2.3Hz,2H),6.60(t,J＝2.3Hz,1H),5.45(d,J＝4.7Hz,1H),5.16(d,J＝4.4Hz,1H),5.12(d,J＝7.2Hz,1H),5.09(d,J＝5.3Hz,1H),4.61(t,J＝5.5Hz,1H),3.79(s,6H),3.71(dd,J＝9.6,5.1Hz,1H),3.47(q,J＝5.9Hz,2H),3.31–3.27(m,2H),3.19(td,J＝6.4,2.6Hz,1H).13C NMR(150MHz,DMSO)δ187.10,162.29,160.78(2C),158.76,156.47,147.46,143.59,136.53,131.86,125.38,122.22,114.49,112.93,106.51(2C),102.85,102.78,99.82,77.19,76.48,73.11,69.60,60.63,55.43(2C).HRMS(ESI)m/z:537.1367[M+Na]+(calcd for 537.1367,C26H26NaO11).
Example 19
Synthesis of Compound 19
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2,3, 4-trimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.69(s,1H),7.91(d,J＝8.7Hz,1H),7.84(d,J＝15.9Hz,1H),7.76(d,J＝15.9Hz,1H),7.51(d,J＝8.9Hz,1H),7.13(d,J＝2.3Hz,1H),7.09(dd,J＝8.7,2.3Hz,1H),6.93(d,J＝8.9Hz,1H),5.45(d,J＝4.3Hz,1H),5.16(d,J＝4.5Hz,1H),5.12(d,J＝7.1Hz,1H),5.09(d,J＝5.2Hz,1H),4.61(t,J＝5.5Hz,1H),3.86(s,6H),3.77(s,3H),3.72(dd,1H),3.47(q,J＝6.7Hz,2H),3.31–3.29(m,2H),3.18(td,1H).13C NMR(150MHz,DMSO)δ186.44,162.30,158.92,156.50,155.92,153.23,147.67,141.89,138.12,131.90,123.80,123.36,122.16,120.92,114.48,112.99,108.61,102.72,99.83,77.20,76.48,73.10,69.60,61.45,60.63,60.50,56.09.HRMS(ESI)m/z:567.1471[M+Na]+(calcd for 567.1473,C27H28NaO12).
Example 20
Synthesis of Compound 20
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2,4, 5-trimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ8.62(s,1H),7.95(d,J＝15.8Hz,1H),7.88(d,J＝8.7Hz,1H),7.63(d,J＝15.8Hz,1H),7.25(s,1H),7.12(s,1H),7.08(dd,J＝8.7,2.3Hz,1H),6.75(s,1H),5.43(d,J＝13.9Hz,1H),5.20(d,J＝17.3Hz,1H),5.11(d,J＝7.1Hz,2H),4.59(t,J＝15.6Hz,1H),3.89(s,3H),3.87(s,3H),3.77(s,3H),3.72(dd,J＝9.9Hz,1H),3.48(q,2H),3.29–3.26(m,2H),3.18(td,J＝8.5Hz,1H).13C NMR(125MHz,DMSO)δ186.66,162.11,158.74,156.30,154.58,153.06,146.92,143.04,138.47,131.68,122.65,121.97,114.39,114.17,112.93,111.41,102.74,99.87,97.69,77.19,76.47,73.11,69.62,60.64,56.41,56.24,55.89.HRMS(ESI)m/z:567.1474[M+Na]+(calcd for 567.1473,C27H28NaO12).
Example 21
Synthesis of Compound 21
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2,4, 6-trimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.62(s,1H),8.06(d,J＝15.9Hz,1H),7.98(d,J＝15.9Hz,1H),7.90(d,J＝8.7Hz,1H),7.10(d,J＝2.4Hz,1H),7.07(dd,J＝8.7,2.3Hz,1H),6.31(s,2H),5.44(d,J＝4.8Hz,1H),5.15(d,J＝4.6Hz,1H),5.10(d,J＝7.2Hz,1H),5.08(d,J＝5.3Hz,1H),4.61(t,J＝5.5Hz,1H),3.89(s,6H),3.86(s,3H),3.71(dd,J＝9.8,5.2Hz,1H),3.46(q,2H),3.31–3.29(m,2H),3.18(td,J＝8.6,5.2Hz,1H).13C NMR(150MHz,DMSO)δ187.21,163.54,162.08,161.52(2C),158.85,156.36,147.13,134.65,131.76,123.46,122.72,114.32,113.04,105.24,102.68,99.86,91.09(2C),77.21,76.48,73.11,69.60,60.62,56.08(2C),55.63.HRMS(ESI)m/z:567.1474[M+Na]+(calcd for 567.1473,C27H28NaO12).
Example 22
Synthesis of Compound 22
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 3,4, 5-trimethoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.62(s,1H),7.88(d,J＝8.7Hz,1H),7.68(d,J＝15.8Hz,1H),7.60(d,J＝15.8Hz,1H),7.13(d,J＝2.3Hz,1H),7.10(s,2H),7.08(d,J＝2.3Hz,1H),5.45(d,J＝4.7Hz,1H),5.16(d,J＝4.5Hz,1H),5.11(d,J＝7.1Hz,1H),5.09(d,J＝5.3Hz,1H),4.61(t,J＝5.4Hz,1H),3.83(s,6H),3.71(s,3H),3.70(dd,1H),3.47(q,J＝5.7Hz,2H),3.31–3.28(m,2H),3.17(td,J＝8.7,5.2Hz,1H).13C NMR(150MHz,DMSO)δ187.36,162.16,158.71,156.36,153.15(2C),147.00,144.33,139.92,131.73,130.11,124.24,122.57,114.47,112.92,106.30(2C),102.80,99.82,77.20,76.48,73.11,69.61,60.64,60.20,56.07(2C).HRMS(ESI)m/z:567.1472[M+Na]+(calcd for 567.1473,C27H28NaO12).
Example 23
Synthesis of Compound 23
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2-fluorobenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ8.74(s,1H),7.92(d,J＝9.3Hz,1H),7.86(d,J＝13.0Hz,1H),7.84(s,1H),7.77(d,J＝16.0Hz,1H),7.52(q,J＝7.1Hz,1H),7.33(q,J＝7.9,7.5Hz,2H),7.14(s,1H),7.10(d,J＝11.0Hz,1H),5.44(d,1H),5.16(d,J＝28.6Hz,2H),5.11(d,1H),4.61(t,1H),3.71(dd,J＝9.3Hz,1H),3.47(q,2H),3.30–3.27(m,2H),3.19(td,J＝8.3Hz,1H).13C NMR(125MHz,DMSO)δ186.42,162.50,159.97,158.86,156.62,148.21,134.91,134.89,132.05,129.67,127.15,125.17,121.60,116.32,116.14,114.54,112.93,102.73,99.82,77.17,76.46,73.08,69.57,60.60.HRMS(ESI)m/z:495.1060[M+Na]+(calcd for 495.1062,C24H21FNaO9).
Example 24
Synthesis of Compound 24
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 4-fluorobenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),9.17(d,J＝8.7Hz,1H),9.11(d,J＝5.6Hz,1H),9.09(d,J＝5.5Hz,1H),9.00(d,J＝6.4Hz,2H),8.58(t,J＝8.7Hz,2H),8.41(d,J＝2.4Hz,1H),8.36(dd,J＝8.8,2.3Hz,1H),6.70(d,J＝4.4Hz,1H),6.42(d,1H),6.38(d,J＝7.2Hz,1H),6.35(d,J＝5.3Hz,1H),5.86(t,1H),4.98(dd,J＝10.6,4.2Hz,1H),4.73(q,J＝6.9Hz,2H),4.49–4.43(m,2H),4.36(td,1H).13C NMR(125MHz,DMSO)δ186.65,164.44,162.46,162.33,158.77,156.48,147.66,142.18,131.87,130.99,130.93,124.64,121.97,116.20,116.02,114.48,112.91,102.74,99.83,77.16,76.46,73.08,69.58,60.60.HRMS(ESI)m/z:495.1064[M+Na]+(calcd for495.1062,C24H21FNaO9).
Example 25
Synthesis of Compound 25
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2, 5-dichlorobenzaldehyde, and the other conditions were the same as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.76(s,1H),7.97(s,1H),7.91(d,J＝8.6Hz,1H),7.85(d,J＝6.8Hz,2H),7.60(d,J＝8.0Hz,1H),7.54(d,J＝8.6Hz,1H),7.14(s,1H),7.10(d,J＝8.4Hz,1H),5.46(d,J＝4.7Hz,1H),5.17(d,J＝4.4Hz,1H),5.13(d,J＝7.1Hz,1H),5.10(d,J＝5.3Hz,1H),4.61(t,J＝5.5Hz,1H),3.72(dd,J＝10.0,5.2Hz,1H),3.47(q,J＝7.8Hz,2H),3.33–3.29(m,2H),3.19(td,J＝8.8,4.1Hz,1H).13C NMR(150MHz,DMSO)δ186.24,162.64,158.69,156.69,148.39,135.94,134.17,132.83,132.54,132.15,131.80,131.53,128.83,127.60,121.53,114.65,112.86,102.78,99.80,77.20,76.48,73.10,69.59,60.63.HRMS(ESI)m/z:545.0375[M+Na]+(calcd for 545.0377,C24H20Cl2NaO9).
Example 26
Synthesis of Compound 26
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 3, 5-dibromo-4-methoxybenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(500MHz,DMSO-d6)δ8.68(s,1H),8.09(s,2H),7.89(d,J＝8.8Hz,1H),7.72(d,J＝15.9Hz,1H),7.62(d,J＝10.8Hz,1H),7.14(d,J＝2.3Hz,1H),7.10(dd,J＝8.4,2.3Hz,1H),5.43(d,J＝4.6Hz,1H),5.13(d,J＝3.6Hz,1H),5.10(d,J＝5.5Hz,1H),5.07(d,J＝5.0Hz,1H),4.59(t,J＝5.4Hz,1H),3.84(s,3H),3.70(dd,J＝7.0Hz,1H),3.47(q,2H),3.32–3.27(m,2H),3.13(td,1H).13C NMR(125MHz,DMSO)δ186.74,162.38,158.57,156.48,154.82,147.64,139.73,133.98,132.62(2C),131.88,126.66,121.97,118.12(2C),114.52,112.84,102.78,99.84,77.17,76.46,73.09,69.60,60.63(2C).HRMS(E SI)m/z:664.9450[M+Na]+(calcd for 664.9454,C25H22Br2NaO10).
Example 27
Synthesis of Compound 27
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 3-fluorobenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.71(s,1H),7.90(d,J＝8.7Hz,1H),7.76(q,2H),7.61(t,2H),7.51(q,J＝7.8Hz,1H),7.30(t,J＝7.1Hz,1H),7.15(d,J＝2.3Hz,1H),7.10(d,1H),5.45(d,J＝4.9Hz,1H),5.16(d,J＝4.3Hz,1H),5.12(d,J＝7.2Hz,1H),5.09(d,J＝5.4Hz,1H),4.61(t,J＝5.4Hz,1H),3.71(dd,J＝9.7,5.2Hz,1H),3.47(q,2H),3.29–3.25(m,2H),3.17(td,J＝5.1Hz,1H).13C NMR(150MHz,DMSO)δ186.81,163.28,162.41,161.66,158.76,156.56,147.85,141.84,131.96,131.10,131.05,126.20,121.92,117.48,114.82,114.54,112.92,102.76,99.80,77.19,76.47,73.09,69.58,60.62.HRMS(ESI)m/z:495.1062[M+Na]+(calcd for 495.1062,C24H21FNaO9).
Example 28
Synthesis of Compound 28
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 2-chloro-6-fluorobenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.77(s,1H),8.03(d,J＝16.2Hz,1H),7.94(d,J＝8.7Hz,1H),7.81(d,J＝16.1Hz,1H),7.53–7.50(m,1H),7.48(d,J＝6.7Hz,1H),7.39(dd,J＝10.6,8.1Hz,1H),7.14(d,J＝2.3Hz,1H),7.09(dd,J＝8.7,2.4Hz,1H),5.50(d,J＝4.8Hz,1H),5.25(d,1H),5.12(d,J＝7.2Hz,2H),4.64(d,J＝5.6Hz,1H),3.71(dd,J＝9.8Hz,1H),3.47(q,J＝8.1Hz,2H),3.32–3.28(m,2H),3.20(td,J＝11.4Hz,1H).13C NMR(150MHz,DMSO)δ186.39,162.70,160.56,159.06,156.82,148.82,132.30,132.07,131.11,131.02,126.45,121.27,121.13,115.76,115.61,114.63,113.01,102.74,99.82,77.22,76.48,73.11,68.83,60.71.HRMS(ESI)m/z:529.0675[M+Na]+(calcd for 529.0672,C24H20ClFNaO9).
Example 29
Synthesis of Compound 29
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with o-trifluoromethylbenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.78(s,1H),8.05(d,J＝7.9Hz,1H),7.93(d,J＝8.7Hz,1H),7.91(d,J＝2.2Hz,1H),7.89(s,1H),7.85(d,J＝7.9Hz,1H),7.81(t,J＝7.5Hz,1H),7.68(t,J＝7.6Hz,1H),7.15(d,J＝2.3Hz,1H),7.10(dd,J＝8.6,2.4Hz,1H),5.45(d,1H),5.19(d,J＝9.7Hz,1H),5.13(d,J＝7.1Hz,1H),5.10(d,J＝5.7Hz,1H),4.60(t,1H),3.70(dd,J＝9.7,5.1Hz,1H),3.47(d,J＝6.2Hz,2H),3.29–3.24(m,2H),3.19(td,J＝8.6Hz,1H).13C NMR(151MHz,DMSO)δ186.10,162.65,158.90,156.74,148.57,136.56,133.27,132.88,132.20,130.64,128.90,128.33,126.37,125.07,123.26,121.44,114.65,112.92,102.76,99.79,77.19,76.46,73.09,69.57,60.61.HRMS(ESI)m/z:545.1030[M+Na]+(calcd for 545.1030,C25H21F3NaO9).
Example 30
Synthesis of Compound 30
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 4-methylbenzaldehyde, and the other conditions were the same as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.69(s,1H),7.90(d,J＝8.7Hz,1H),7.72(s,2H),7.65(d,J＝8.1Hz,2H),7.29(d,J＝7.9Hz,2H),7.14(d,J＝2.3Hz,1H),7.09(dd,J＝8.7,2.3Hz,1H),5.44(d,1H),5.12(d,J＝7.1Hz,3H),4.60(t,1H),3.71(dd,1H),3.47(q,J＝8.6Hz,2H),3.30–3.26(m,2H),3.18(td,1H),2.35(s,3H).13C NMR(150MHz,DMSO)δ186.64,162.28,158.84,156.48,147.60,143.57,140.93,131.86,131.84,129.71(2C),128.69(2C),123.69,122.08,114.46,112.95,102.71,99.79,77.17,76.46,73.08,69.57,60.60,21.11.HRMS(ESI)m/z:491.1314[M+Na]+(calcd for491.1313,C25H24NaO9).
Example 31
Synthesis of Compound 31
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 4-phenylbenzaldehyde, and the other conditions were the same as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.72(s,1H),7.92(d,J＝8.7Hz,1H),7.85(d,J＝8.1Hz,2H),7.80(q,J＝12.8,7.9Hz,4H),7.74(d,J＝7.6Hz,2H),7.50(t,J＝7.6Hz,2H),7.41(t,J＝7.4Hz,1H),7.15(d,J＝2.3Hz,1H),7.10(dd,J＝8.7,2.3Hz,1H),5.41(d,J＝9.6Hz,1H),5.19(d,J＝5.2Hz,2H),5.13(d,J＝7.0Hz,1H),4.62(t,1H),3.72(dd,J＝10.0Hz,1H),3.45(q,2H),3.32–3.26(m,2H),3.19(td,J＝8.7Hz,1H).13C NMR(150MHz,DMSO)δ186.60,162.36,158.88,156.54,147.77,142.93,142.24,139.15,133.70,131.93,129.33(2C),129.07(2C),128.08,127.26(2C),126.75(2C),124.62,122.02,114.50,112.97,102.74,99.82,77.19,76.48,73.10,69.58,60.62.HRMS(ESI)m/z:553.1468[M+Na]+(calcd for 553.1469,C30H26NaO9).
Example 32
Synthesis of Compound 32
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 3, 5-di-t-butylbenzaldehyde, and the other conditions were the same as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.64(s,1H),7.90(d,J＝8.6Hz,1H),7.77(d,J＝15.9Hz,1H),7.69(d,J＝15.9Hz,1H),7.57(s,2H),7.50(s,1H),7.13(d,J＝2.3Hz,1H),7.09(dd,J＝8.6,2.4Hz,1H),5.45(d,J＝4.7Hz,1H),5.16(d,J＝4.5Hz,1H),5.12(d,J＝7.2Hz,1H),5.09(d,J＝5.3Hz,1H),4.61(t,J＝5.5Hz,1H),3.71(dd,J＝9.4,5.2Hz,1H),3.44(q,J＝12.6,5.6Hz,2H),3.31–3.27(m,2H),3.18(dt,J＝8.1,4.4Hz,1H),1.32(s,18H).13C NMR(150MHz,DMSO)δ187.29,162.19,158.85,156.40,151.11(2C),147.15,144.98,133.95,131.77,124.80,124.35,122.93(2C),122.49,114.44,112.96,102.78,99.83,77.19,76.48,73.11,69.60,60.63,35.06(2C),31.11(6C).HRMS(ESI)m/z:589.2408[M+Na]+(calcd for 589.2408,C32H38NaO9).
Example 33
Synthesis of Compound 33
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with N, N-dimethyl-4-aminobenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.62(s,1H),7.88(d,J＝8.7Hz,1H),7.68(d,J＝15.6Hz,1H),7.58(d,J＝8.5Hz,2H),7.50(d,J＝15.6Hz,1H),7.12(d,J＝2.3Hz,1H),7.08(dd,J＝8.7,2.3Hz,1H),6.76(d,J＝8.7Hz,2H),5.44(d,1H),5.22(d,2H),5.10(d,J＝7.2Hz,1H),4.62(q,1H),3.71(dd,J＝9.3Hz,1H),3.47(q,2H),3.32–3.25(m,2H),3.18(td,J＝8.2Hz,1H),3.01(s,6H).13C NMR(150MHz,DMSO)δ185.94,162.01,158.93,156.27,152.16,146.79,145.08,131.62,130.67(2C),122.68,121.76,118.82(2C),114.35,113.04,111.87,102.69,99.83,77.19,76.48,73.10,69.59,60.61,54.92,48.60.HRMS(ESI)m/z:498.1757[M+H]+(calcd for 498.1759,C26H28NO8).
Example 34
Synthesis of Compound 34
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with N, N-diethyl-4-aminobenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.62(s,1H),7.88(d,J＝8.7Hz,1H),7.66(d,J＝15.5Hz,1H),7.55(d,J＝8.6Hz,2H),7.47(d,J＝15.5Hz,1H),7.12(d,J＝2.3Hz,1H),7.07(dd,J＝8.7,2.3Hz,1H),6.72(d,J＝8.6Hz,2H),5.44(d,J＝4.7Hz,1H),5.15(d,J＝4.5Hz,1H),5.10(d,J＝7.2Hz,1H),5.08(d,J＝5.3Hz,1H),4.61(t,J＝5.6Hz,1H),3.71(dd,J＝9.7,5.4Hz,1H),3.47(q,2H),3.44(q,J＝6.9,5.1Hz,4H),3.32–3.30(m,2H),3.20(td,1H),1.12(t,J＝7.0Hz,6H).13C NMR(150MHz,DMSO)δ185.91,161.98,158.95,156.26,149.73,146.74,145.15,131.61(2C),131.08,122.74,121.01,118.21,114.34,113.07(2C),111.30,102.69,99.84,77.18,76.48,73.10,69.59,60.62,48.60(2C),12.47(2C).HRMS(ESI)m/z:526.2071[M+H]+(calcd for 526.2072,C28H32NO9).
Example 35
Synthesis of Compound 35
Referring to example 10, step 3 replaced 2-methoxybenzaldehyde with 4-isobutylbenzaldehyde under the same conditions as in example 10. The thin layer of GF 254 nm silica gel plate is unfolded to form a point, and the thin layer is dark spots under the UV 254 nm of an ultraviolet lamp .1H NMR(600MHz,DMSO-d6)δ8.70(s,1H),7.90(d,J＝8.6Hz,1H),7.72(s,2H),7.67(d,J＝8.2Hz,2H),7.26(d,J＝7.8Hz,2H),7.14(d,J＝2.3Hz,1H),7.09(dd,J＝8.7,2.3Hz,1H),5.44(d,J＝4.8Hz,1H),5.16(d,J＝4.5Hz,1H),5.12(d,J＝7.1Hz,1H),5.09(d,J＝5.2Hz,1H),4.60(t,1H),3.70(dd,J＝5.8Hz,1H),3.44(q,2H),3.30–3.29(m,2H),3.18(td,J＝11.8,4.5Hz,1H),2.48(d,2H),1.87(dt,J＝13.5,6.7Hz,1H),0.87(d,J＝6.6Hz,6H).13C NMR(150MHz,DMSO)δ186.67,162.29,158.84,156.48,147.62,144.56,143.58,132.16,131.86,129.70(2C),128.58(2C),123.84,122.08,114.46,112.95,102.72,99.79,77.17,76.47,73.08,69.56,60.60,44.46,29.58,22.13(2C).HRMS(ESI)m/z:511.1963[M+H]+(calcd for 511.1963,C28H31O9).
Example 36
Toxicity test of scopolamine derivatives on RAW264.7 cells
Experimental principle: MTT is a yellow compound that can be reduced by some dehydrogenases present in mitochondria in living cells to a water-insoluble, crystalline, blue-violet compound Formazan. Formazan can be dissolved by dimethyl sulfoxide (DMSO), and the dissolution product has maximum absorption near 570nm, and the absorbance value at 570nm is measured by using a microplate reader. The higher absorbance indicates better cell proliferation, and the lower absorbance indicates higher cytotoxicity of the test substance.
The experimental method comprises the following steps: RAW264.7 cells are subjected to cell subculture, cell inoculation and cell administration, and after the administration is completed for 24 hours, the operation is carried out according to the instructions of the MTT cell proliferation and cytotoxicity detection kit. The effect of drug on RAW264.7 cell viability can be calculated from OD values between the different groups. Cell viability = OD value of each of the different concentration experimental groups/OD value of the control group x100%; cell death rate = 1-cell survival rate;
Experimental results: as shown in Table 1, most of the compounds did not cause cell death at 10. Mu. Mol/L, but the cell viability of compounds 22, 23, 29, 32 and 35 was 60% or less at 10. Mu. Mol/L, indicating that these compounds were strongly cytotoxic. Is not suitable for screening anti-inflammatory drugs.
Table 1: MTT cytotoxicity assay results
Example 37
Experiment of influence of scopolamine derivatives on NO content in RAW264.7 cells
Experimental principle: endogenous NO has an inhibitory effect on inflammation in the early stage of inflammation, and further exacerbation of inflammation is caused by iNOS-induced NO in the late stage of inflammation. RAW 264.7 macrophages promote expression of iNOS under the stimulation of LPS, and generate a large amount of NO, and when the NO is continuously accumulated and the concentration reaches a threshold concentration, NF- κB channels are further activated to release cytokines such as IL-6, TNF-alpha and the like. NO exhibits instability in cells, which is mainly present in the supernatant of the cell culture broth and is converted to nitrous acid and NO 2- ions in a short time. The concentration of NO and the concentration of NO 2- ions are linearly related.
The experimental method comprises the following steps: the concentration of NO 2- is measured by using the Griess reagent method to measure the absorbance at 540nm, and then the concentration of NO is deduced.
Experimental results: as shown in Table 2, most of the compounds decreased intracellular NO content at 10. Mu. Mol/L concentration, and especially compounds 10, 15, 16, 19, 26, 27 and 34, were effective in inhibiting NO production while ensuring NO cytotoxicity, and thus could be used as active drugs for animal level screening.
Table 2: results of NO inhibition test in cells
Example 38
Influence of scopoletin derivatives on serum indicators of hyperuricemia in mice caused by potassium oxazinate and hypoxanthine
Experimental principle: the KM mice can raise uric acid in the mice after being subjected to intraperitoneal injection of potassium oxazinate and gastric lavage administration of hypoxanthine, can reduce serum uric acid level in the mice after being subjected to positive medicine administration, and can rapidly detect uric acid reducing effect of the compound by further administering scopolamine derivatives through a hyperuricemia mouse model.
The experimental method comprises the following steps: male Kunming mice were 88, 18-22g in body weight, 6 weeks old. After one week of adaptive feeding, the animals were randomly divided into 11 groups: (1) normal group, (2) model group, (3) positive control group: allopurinol 10mg/kg, (4) positive control group: 10mg/kg of benzbromarone and 40mg/kg of scopolamine derivatives 10,15,16,19,26,27,34. The normal group mice were lavaged and injected with 0.5% CMC-Na solution intraperitoneally, the remaining groups of mice were intraperitoneally injected with 300mg/kg of potassium oxazinate, 300mg/kg of gastric hypoxanthine, and after 1h, the normal group and model group mice were lavaged with 0.5% CMC-Na solution, and the remaining groups of mice were given by lavaging, and the molding was continued for 7 days. The eyes were taken 1h after the administration of the drug, blood was taken from the eyes, urine was taken from the bladders, and uric acid, creatinine and urea nitrogen levels in the serum and urine of the mice were measured according to the kit method.
Experimental results: as shown in Table 3 and FIG. 1, the scopolamine derivatives 16 and 27 can inhibit the increase of serum uric acid of mice caused by potassium oxazinate and hypoxanthine after gastric lavage administration, and each dosage group can reduce serum creatinine and urea nitrogen level; the effect is equivalent to that of the positive medicine allopurinol, but the scopolamine derivative 27 shows a certain toxicity in a KM mouse, so that the scopolamine derivative 16 is selected in the subsequent experiments.
Table 3: influence of scopoletin derivatives on serum indicators of hyperuricemia in mice caused by potassium oxazinate and hypoxanthine
Example 39
Experiment of influence of scopolamine derivative 16 on gouty arthritis in SD rats
(1) Swelling of joints
Experimental principle: the MSU crystal is used for inducing the SD rat to generate inflammation, the ankle circumference of the rat is measured by a line binding method, and the ankle circumferences before molding, during molding, 24h and 48h are measured respectively to judge the swelling degree.
The experimental method comprises the following steps: preparation of MSU crystals: 1g of uric acid is heated and dissolved in 194ml of pure water, 6ml of 1M/L NaOH solution is added, after complete dissolution, 1M/L HCl is added to adjust the pH to be 7, standing overnight and naturally cooling are carried out, white crystals at the bottom of a beaker can be seen the next day, a solid is obtained through suction filtration, and the solid is dried in an oven for standby. And (3) molding: SPF-grade male SD rats 18 were divided into 6 groups of 3 by body weight, each group being divided into a control group, a model group, an indomethacin group, a low dose compound group, a medium dose compound group and a high dose compound group. Experiments were started after one week of feeding to accommodate them. According to the weight administration amount of the rats, the administration volume is 10ul/g, the control group and the model group are administrated by intragastric administration of 0.5% CMC-Na, the positive drug is administrated by intragastric administration of 6mg/kg indomethacin, the other three groups are respectively administrated by intragastric administration of 10mg/kg, 20mg/kg and 40mg/kg of compound 16 for 5 days, after the administration is completed for 1h on the third day, each group is injected with 200ul of MSU suspension of 25mg/ml in ankle joint cavity at right side of the rats, and the control group is injected with 200ul of physiological saline.
Experimental results: as shown in fig. 2,3 and table 4, with the time extension, the joints of the other groups except the normal group are swollen to different degrees after sodium urate crystals are injected, the model group is obvious, the swelling degree of the joints of each dosing group is related to the dosing dose, and the swelling degree is lower as the dosing dose is larger.
TABLE 4 Effect of scopoletin derivative 16 on sodium urate Crystal (MSU) induced gouty joint swelling in rats
(2) Pain gouty arthritis rat joint synovium HE staining experiment
Experimental principle: the model SD rat in example 39 was treated, and its arthritic synovial membrane was cut into HE-stained sections to determine its tissue condition.
The experimental method comprises the following steps: preparing chloral hydrate, injecting chloral hydrate into abdominal cavity according to rat body weight after molding for 48h to anesthetize, removing cervical vertebra, killing, shearing the right leg by scissors, peeling the hair layer by layer to strip muscle tissue, carefully fixing the film attached to joint cavity by forceps, shearing the film into two parts by scissors, and immersing one part in formalin to prepare HE slice.
Experimental results: as shown in fig. 4, rat joint synovial HE staining showed that scopolamine derivatives 16 can reduce inflammatory infiltrates in a dose-dependent manner, and has a repairing effect on damage caused by MSU to joints.
(3) ELISA experiment of joint synovium of rat with gouty arthritis
Experimental principle: ELISA is based on the property that antigens and antibodies can specifically bind, and on the basis that specific enzymes and antigens or antibodies can undergo enzymatic reactions with enzyme substrates to produce colored substances after binding. The method is sensitive and has strong specificity, and is often used for detecting antigens or antibodies in scientific research.
The experimental method comprises the following steps: taking part of the joint synovium in example 42, putting the part into an EP tube of 2ml, adding steel balls and Western and IP lysate, grinding for 5min in a tissue grinder, repeating for 2 times, removing the steel balls by using a magnet, firstly adjusting a centrifugal machine to a specified temperature, putting the EP tube into a temperature of 4 ℃, 12000rpm, centrifuging for 10min, taking the supernatant to obtain synovium lysate, and measuring the content of TNF-alpha and IL-1 beta according to an ELISA kit specification.
Experimental results: as shown in fig. 5, the IL-1 β and TNF- α levels were significantly elevated in the MSU compared to the blank group, indicating that SD rats stimulated by MSU promoted the production of inflammatory factors IL-1 β and TNF- α at the joint synovium; compared with the model group, the positive drug indometacin can obviously reduce the IL-1 beta and TNF-alpha levels in the joint synovium; IL-1 beta and TNF-alpha levels were also reduced following treatment of the scopolamine derivatives 16 at each dose, indicating that scopolamine derivatives 16 were able to inhibit inflammatory factor production in an in vivo model.
The measurement result shows that the scopolamine derivative 16 has better anti-arthritis activity.
The above embodiments are only for describing the technical solution of the present invention, and are not limited thereto; although the invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will appreciate that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; these modifications and substitutions do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention, and the scope of protection of the present invention should not be limited to the above specific embodiments.

Claims (11)

1. Scopoletin derivatives have the following structural general formula:
In the general structural formula (I), the substituent R 1 is selected from C 1-C4 alkoxy or C 6-C8 aromatic alkyl or C 1-C3 chain alkyl;
In the general structural formula (II), the substituent R 2 is selected from C 4-C7 aliphatic hydrocarbon group, C 3-C7 cycloaliphatic hydrocarbon group or C 6-C8 aromatic hydrocarbon group;
In the general structural formula (III), the substituent R 3 is selected from C 1-C4 alkoxy, C 6-C8 aromatic hydrocarbon, halogen substituted C 1-C4 aliphatic hydrocarbon, halogen substituted C 1-C4 alkoxy and C 1-C10 aliphatic hydrocarbon C 1-C7 amino.
2. A scopolamine derivative according to claim 1, wherein in the general structural formula (I), the substituent R1 is selected from a C 6-C8 aromatic hydrocarbon group or a C 1-C3 chain hydrocarbon group; in the general structural formula (II), the substituent R 2 is selected from C 4-C7 aliphatic hydrocarbon group, C 3-C7 cycloaliphatic hydrocarbon group or C 6-C8 aromatic hydrocarbon group; in the general structural formula (III), the substituent R 3 is selected from C 1-C4 alkoxy, C 6-C8 aromatic hydrocarbon, halogen substituted C 1-C4 aliphatic hydrocarbon, halogen substituted C 1-C4 alkoxy and C 1-C10 aliphatic hydrocarbon C 1-C7 amino.
3. Scopolamine derivatives, characterized in that the derivatives are selected from any one of the following compounds:
4. A process for the preparation of scopolamine derivatives according to claim 1 or 2, characterised in that it comprises the steps of:
step a, D-glucose and acetic anhydride are subjected to acylation reaction to obtain an intermediate IV shown in the following structural formula;
Step b, reacting the intermediate IV with HBr to obtain an intermediate V shown in the following structural formula;
preparation of a compound of the general structural formula (I):
Step c, reacting Mirabilic acid and 2, 4-dihydroxybenzaldehyde under the catalysis of sodium acetate to obtain an intermediate VI shown in the following structural formula;
Step d, reacting the intermediate VI with different R 1 substituent compounds to obtain an intermediate VII shown in the following structural formula;
Step e, reacting the intermediate VII with the intermediate V to obtain a compound with a structural general formula (I);
Preparation of a compound of the general structural formula (II):
step f, reacting 2, 4-dihydroxybenzaldehyde with ethyl acetoacetate to obtain an intermediate VIII shown in the following structural formula;
step g, reacting the intermediate VIII with different R 2 substituent compounds to obtain an intermediate IX shown in the following structural formula;
Step h, reacting the intermediate IX with the intermediate V to obtain a compound with a structural general formula (II);
preparation of a compound of the general structural formula (III):
Step i, reacting the intermediate VIII with different R 3 substituent compounds to obtain an intermediate X shown in the following structural formula;
step j, reacting the intermediate X with the intermediate V to obtain a compound with a structural general formula (III);
5. A method of preparing as claimed in claim 3, wherein step a comprises: firstly, dissolving perchloric acid into acetic anhydride, uniformly stirring, then adding D-glucose powder into the mixture, and reacting under the ice bath condition; after the reaction is completed, intermediate IV is obtained by a recrystallization method using ethanol.
6. A method of preparing as claimed in claim 3, wherein step b comprises: dissolving the intermediate IV into a proper amount of anhydrous dichloromethane, adding HBr into the mixture after stirring uniformly, reacting under ice bath condition, extracting water and ethyl acetate after the reaction is finished, concentrating under reduced pressure to obtain oily liquid, and standing at normal temperature for a period of time to precipitate crystals to obtain an intermediate V.
7. A process according to claim 3, wherein step c comprises dissolving 2, 4-dihydroxybenzaldehyde and milbezier acid in purified water, stirring uniformly, adding a proper amount of sodium acetate, reacting at room temperature, filtering, and washing with purified water to obtain intermediate vi.
8. A method of preparing as claimed in claim 3, wherein step d comprises: dissolving the intermediate VI in a proper amount of anhydrous dichloro, fully and uniformly stirring, adding HATU and DIPEA into the mixture, and then carrying out reaction at normal temperature; then adding different R 1 substituent compounds into a reaction system, reacting at normal temperature, extracting with dichloromethane and water to obtain an organic layer, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain an intermediate compound VII; or, step f includes: respectively and sequentially adding 2, 4-dihydroxybenzaldehyde and ethyl acetoacetate into a proper amount of ethanol solution, fully dissolving, adding PIPERIDINE into a reaction system, reacting at 80-85 ℃, and obtaining an intermediate VIII by adopting an ethanol recrystallization method after the reaction is completed.
9. A method of preparation according to claim 3, wherein step g/i comprises: dissolving intermediate VIII in proper amount of ethanol, adding Pyrrolidine into a reaction system after the intermediate VIII is fully dissolved, adding different R 2/R3 substituent compounds into the system after the ethanol is refluxed for a period of time to react, obtaining an organic layer by using a dichloromethane extraction method, obtaining a crude product by decompressing and concentrating, and purifying by using column chromatography to obtain an intermediate compound IX/X.
10. A method of preparing according to claim 3, wherein step e/h/j comprises: dissolving an intermediate VII/IX/X and an intermediate V in a proper amount of acetonitrile solution, fully stirring, adding Ag 2 O, reacting at normal temperature, extracting and spin-drying a system by using dichloromethane, dissolving by using a proper amount of methanol, adding sodium methoxide into a reaction system after fully dissolving, and reacting for a period of time at normal temperature; adding cation exchange resin into the reaction system for blending, filtering to remove the resin, extracting with an organic solvent, concentrating under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain scopolamine derivative compounds 1-35.
11. Use of a scopolamine derivative according to any one of claims 1-2 in the manufacture of a medicament for the treatment of gout.
CN202310514275.6A 2023-05-08 Scopolamine derivatives, preparation method and medical application thereof Active CN116621897B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016060714A1 (en) * 2014-10-13 2016-04-21 American Sterilizer Company Biological indicator
CN112755041A (en) * 2021-02-09 2021-05-07 中国药科大学 Application of coumarin derivative in preparation of medicine for preventing and/or treating gout

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016060714A1 (en) * 2014-10-13 2016-04-21 American Sterilizer Company Biological indicator
CN112755041A (en) * 2021-02-09 2021-05-07 中国药科大学 Application of coumarin derivative in preparation of medicine for preventing and/or treating gout

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