CN114702436B - Application of piperlonguminine compound in preparation of medicines for treating schistosomiasis japonica and pharmaceutical composition - Google Patents

Application of piperlonguminine compound in preparation of medicines for treating schistosomiasis japonica and pharmaceutical composition Download PDF

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CN114702436B
CN114702436B CN202210360760.8A CN202210360760A CN114702436B CN 114702436 B CN114702436 B CN 114702436B CN 202210360760 A CN202210360760 A CN 202210360760A CN 114702436 B CN114702436 B CN 114702436B
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piperlonguminine
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钱益平
申昌德
黄丽娜
仲鑫
路东亮
邓修龙
李勋
范小林
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Gannan Normal University
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Abstract

The invention provides application of piperlonguminine compounds in preparation of medicines for treating schistosomiasis japonica and a pharmaceutical composition, and belongs to the technical field of medicine treatment. The invention introduces different substituent groups at alpha position of Michael double bond of piperlonguminine, the obtained piperlonguminine compound has high-efficiency therapeutic activity on schistosome, and 72h in vitro anti-schistosome IC of the piperlonguminine compound 50 The value is 1-5 times of that of piperlonguminine, wherein the IC of 72h in vitro anti-Japanese blood fluke activity of the compound 9 50 The value is equivalent to that of praziquantel as a positive control of clinical medicines.

Description

Application of piperlonguminine compound in preparation of medicines for treating schistosomiasis japonica and pharmaceutical composition
Technical Field
The invention relates to the technical field of drug treatment, in particular to application of piperlonguminine compounds in preparation of drugs for treating schistosomiasis japonica and a pharmaceutical composition.
Background
Schistosomiasis japonica is widely popular in southern China, and is the schistosomiasis japonica with the most serious harm to human health and the greatest prevention and treatment difficulty in the world. Due to the lack of vaccines, chemotherapy is currently the primary means of schistosomiasis japonica prevention. Praziquantel is the only drug recommended by the world health organization to treat schistosomiasis japonica, and long-term large-scale repeated application can induce schistosoma japonicum to generate resistance. Meanwhile, compared with the rapid development of new medicines for other diseases, the development of new medicines for treating the schistosomiasis japonica is relatively seriously lagged, and no new clinical medicines are currently available. Therefore, the development of a novel effective and safe drug for treating the schistosomiasis japonica has extremely important practical significance for the schistosomiasis japonica prevention and treatment work.
Disclosure of Invention
The invention aims to provide an application of piperlonguminine compounds in preparing medicines for treating schistosomiasis japonica and a pharmaceutical composition, wherein the piperlonguminine compounds have high-efficiency therapeutic activity on schistosoma japonica.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides application of piperlonguminine compounds in preparation of medicines for treating schistosomiasis japonica, wherein the piperlonguminine compounds have a structure shown in a formula I:
Figure BDA0003583609560000011
in the formula I, R 1 ～R 5 Independently comprises H, OH, CH 3 、OCH 3 、NH 2 、F、Cl、Br、I、CN、NO 2 、CF 3 、OCF 3 C1-C6 alkyl, ester, ether or haloalkyl;
x includes H, CH 3 、OCH 3 、F、Cl、Br、CF 3 C1-C4 alkyl, haloalkyl or substituted phenyl; y comprisesCl or Br; n=0, 1, 2 or 3.
Preferably, the piperlonguminine compound is
Figure BDA0003583609560000021
Preferably, the preparation method of the piperlonguminine compound comprises the following steps:
when X is H, mixing substituted benzene acrylic acid, oxalyl chloride and a first solvent, and performing an acyl chlorination reaction to obtain a benzene acrylic chloride compound;
mixing the phenyl acryloyl chloride compound with a lithium lactam salt solution, and performing a first nucleophilic substitution reaction to obtain a piperlonguminine compound;
when X is not H, mixing substituted benzene acrylic acid, pivaloyl chloride, triethylamine and a second solvent, and carrying out acidolysis reaction to obtain an anhydride compound;
mixing the anhydride compound with a lithium lactam salt solution, and performing a second nucleophilic substitution reaction to obtain a piperlonguminine compound;
the substituted benzene acrylic acid has a structure shown in a formula 1; the lactam in the lithium lactam salt solution has a structure shown in a formula 2;
Figure BDA0003583609560000031
in formula 1, R 1 ～R 5 Independently comprises H, OH, CH 3 、OCH 3 、NH 2 、F、Cl、Br、I、CN、NO 2 、CF 3 、OCF 3 C1-C6 alkyl, ester, ether or haloalkyl; x includes H, CH 3 、OCH 3 、F、Cl、Br、CF 3 C1-C4 alkyl, haloalkyl or substituted phenyl;
in formula 2, Y includes Cl or Br; n=0, 1, 2 or 3.
Preferably, when X is H, the molar ratio of the substituted benzene acrylic acid to the oxalyl chloride is 1 (1-20), the temperature of the acyl chlorination reaction is 0-40 ℃ and the time is 0.5-5H.
Preferably, when X is H, the molar ratio of the benzoyl chloride compound to the lithium lactam salt in the lithium lactam salt solution is (1-3): 1; the first nucleophilic substitution reaction process comprises: after reacting for 0.5-2 h at-78 ℃, reacting for 4-24 h at room temperature.
Preferably, the preparation method of the lithium lactam salt in the lithium lactam salt solution comprises the following steps: mixing lactam and lithium diisopropylamide in an inert gas atmosphere, and reacting at-78 ℃ to-40 ℃ for 0.5-2 hours to obtain lactam lithium salt; the molar ratio of the lactam to the lithium diisopropylamide is 1 (1-3).
Preferably, when X is not H, the molar ratio of the substituted benzene acrylic acid to the pivaloyl chloride to the triethylamine is 1 (1-3) (0.1-0.5); the acidolysis reaction is carried out at the temperature of 0-40 ℃ for 0.5-8 h.
Preferably, when X is not H, the molar ratio of the acid anhydride compound to the lithium lactam salt in the lithium lactam salt solution is (1-3): 1; the process of the second nucleophilic substitution reaction comprises: after 0.5 to 2 hours of reaction at the temperature of minus 78 ℃, the reaction is carried out for 4 to 24 hours at room temperature.
Preferably, the effective dosage of the piperlonguminine compound is 2.5-20 mu M.
The invention provides a pharmaceutical composition for treating schistosomiasis japonica, which comprises piperlonguminine compounds and pharmaceutically acceptable auxiliary materials.
The invention provides an application of piperlonguminine compounds in preparing medicines for treating schistosomiasis japonica, wherein alpha-position of Michael double bond of the piperlonguminine compounds contains different substituents, so that the electrophilic capability of Michael acceptors in the compounds can be effectively improved, the piperlonguminine compounds are easier to interact with schistosoma japonicum in vivo oxidation-reduction balance enzymes, thus interfering the schistosoma japonicum in vivo oxidation-reduction balance and promoting schistosoma japonicum death, thus having high-efficiency therapeutic activity on schistosomiasis japonica, and 72h in vitro anti-schistosomiasis japonica activity LC of the piperlonguminine compounds 50 The value is 1-5 times of that of piperlonguminine, wherein the compound 9 has the activity LC of resisting Japanese blood fluke in vitro for 72 hours 50 The value is equivalent to that of praziquantel as a positive control of clinical medicines.
Drawings
FIG. 1 is a graph showing the activities of piperlonguminine compounds 1 (A), 2 (B), 3 (C) and 4 (D) against Schistosoma japonicum;
FIG. 2 is a graph showing the activities of piperlonguminine compounds 5 (A), 6 (B), 7 (C) and 8 (D) against Schistosoma japonicum;
FIG. 3 is a graph showing the activities of piperlonguminine compounds 9 (A), 10 (B), 11 (C) and PZQ (D) against Japanese blood fluke.
Detailed Description
The invention provides application of piperlonguminine compounds in preparation of medicines for treating schistosomiasis japonica, wherein the piperlonguminine compounds have a structure shown in a formula I:
Figure BDA0003583609560000041
in the formula I, R 1 ～R 5 Independently comprises H, OH, CH 3 、OCH 3 、NH 2 、F、Cl、Br、I、CN、NO 2 、CF 3 、OCF 3 C1-C6 alkyl, ester, ether or haloalkyl;
x includes H, CH 3 、OCH 3 、F、Cl、Br、CF 3 C1-C4 alkyl, haloalkyl or substituted phenyl; y comprises Cl or Br; n=0, 1, 2 or 3.
In the invention, the piperlonguminine compound is preferably
Figure BDA0003583609560000042
Figure BDA0003583609560000051
In the invention, the preparation method of the piperlonguminine compound preferably comprises the following steps:
when X is H, mixing substituted benzene acrylic acid, oxalyl chloride and a first solvent, and performing an acyl chlorination reaction to obtain a benzene acrylic chloride compound;
mixing the phenyl acryloyl chloride compound with a lithium lactam salt solution, and performing a first nucleophilic substitution reaction to obtain a piperlonguminine compound;
when X is not H, mixing substituted benzene acrylic acid, pivaloyl chloride, triethylamine and a second solvent, and carrying out acidolysis reaction to obtain an anhydride compound;
mixing the anhydride compound with a lithium lactam salt solution, and performing a second nucleophilic substitution reaction to obtain a piperlonguminine compound;
the substituted benzene acrylic acid has a structure shown in a formula 1; the lactam in the lithium lactam salt solution has a structure shown in a formula 2;
Figure BDA0003583609560000052
in formula 1, R 1 ～R 5 Independently comprises H, OH, CH 3 、OCH 3 、NH 2 、F、Cl、Br、I、CN、NO 2 、CF 3 、OCF 3 C1-C6 alkyl, ester, ether or haloalkyl; x includes H, CH 3 、OCH 3 、F、Cl、Br、CF 3 C1-C4 alkyl, haloalkyl or substituted phenyl;
in formula 2, Y includes Cl or Br; n=0, 1, 2 or 3.
In the present invention, the preparation materials are commercially available as known to those skilled in the art unless otherwise specified.
In the invention, when X is H, the preparation reaction formula of the piperlonguminine compound with the structure shown in the formula I is as follows:
Figure BDA0003583609560000061
in the invention, the substituted benzene acrylic acid, oxalyl chloride and a first solvent are preferably mixed for acyl chlorination reaction to obtain the benzene acrylic chloride compound.
In the present invention, the substituted benzene acrylic acid has a structure represented by formula 1:
Figure BDA0003583609560000062
in formula 1, R 1 ～R 5 Independently comprises H, OH, CH 3 、OCH 3 、NH 2 、F、Cl、Br、I、CN、NO 2 、CF 3 、OCF 3 C1-C6 alkyl, ester, ether or haloalkyl; x includes H, CH 3 、OCH 3 、F、Cl、Br、CF 3 C1-C4 alkyl, haloalkyl or substituted phenyl.
The source of the substituted benzene acrylic acid is not particularly limited, and the substituted benzene acrylic acid can be commercially available or prepared according to a process well known in the art; the method for preparing the substituted benzene acrylic acid is not particularly limited, and the substituted benzene acrylic acid with the structure of formula 1 can be synthesized correspondingly according to the known method in the art.
In the present invention, the substituted benzene acrylic acid is preferably prepared according to the following reaction formula:
Figure BDA0003583609560000063
the specific reaction process of the substituted benzene acrylic acid preferably comprises the following steps: according to the mol ratio of 1 (1) - (3), the substituted benzaldehyde and carboxylic acid compound
Figure BDA0003583609560000064
Mixing, adding 0.1-1 equivalent of alkali, reacting for 2-10 hours at room temperature-150 ℃ under the protection of nitrogen, adding dilute hydrochloric acid for precipitation, and recrystallizing the obtained solid to obtain the substituted benzene acrylic acid. In the present invention, the base preferably includes DMAP, triethylamine, pyridine, potassium carbonate, sodium carbonate, or triphenyl phosphate. When x=br or Cl, the carboxylic acid compound can also be prepared by using N-bromosuccinimide or N-chlorosuccinimide instead of the carboxylic acid compound according to the above conditions.
In the present invention, the molar ratio of the substituted benzene acrylic acid to the oxalyl chloride is preferably 1 (1-20), more preferably 1 (7.375-14.75), still more preferably 1 (10.325-11.8), and the first solvent is preferably anhydrous dichloromethane; the amount of the first solvent is not particularly limited, and the reaction can be ensured to be carried out smoothly.
In the present invention, the mixing of the substituted benzene acrylic acid, the oxalyl chloride and the first solvent includes mixing the substituted benzene acrylic acid and the first solvent, and adding the oxalyl chloride dropwise to the obtained solution.
In the present invention, the temperature of the acid chloride reaction is preferably 0 to 40 ℃, more preferably 30 to 35 ℃, and the time is preferably 0.5 to 5 hours, more preferably 2 to 4 hours, and still more preferably 3 to 3.5 hours.
After the acyl chlorination reaction is completed, the method preferably carries out reduced pressure distillation on the obtained product to obtain the phenylacryloyl chloride compound; the reduced pressure distillation is not particularly limited, and may be performed according to a process well known in the art.
After obtaining the benzoyl chloride compound, the invention preferably mixes the benzoyl chloride compound with a lithium lactam salt solution to perform a first nucleophilic substitution reaction to obtain the piperlonguminine compound.
In the present invention, the preparation method of the lithium lactam salt in the lithium lactam salt solution preferably comprises the following steps: mixing lactam and lithium diisopropylamide in an inert gas atmosphere, and reacting at-78 to-40 ℃ for 0.5-2 h to obtain lactam lithium salt; more preferably 45 to 60 minutes.
In the present invention, the inert gas atmosphere is preferably a nitrogen atmosphere.
In the present invention, the lactam has a structure represented by formula 2:
Figure BDA0003583609560000071
in formula 2, Y includes Cl or Br; n=0, 1, 2 or 3.
In the present invention, the lactam is prepared according to the following reaction formula:
Figure BDA0003583609560000072
the preparation process of the lactam comprises the following steps: mixing cyclic amide with n carbon number, phosphorus pentachloride and bromine (molar ratio is 1 (2-10)), reacting for 1h at-20-5 ℃, and then reacting for 6-24 h at 20-80 ℃; after the reaction is completed, cooling to room temperature, adding 50-250 mL of ice water, adding alkali (sodium hydroxide or potassium hydroxide), and adjusting the pH of the solution to be neutral; extracting and separating an organic phase by using dichloromethane or ethyl acetate, concentrating the organic phase, and purifying and separating by using column chromatography to obtain dihalolactam; in an inert gas atmosphere, reacting dihalolactam, lithium carbonate and lithium chloride (molar ratio of dihalolactam, lithium carbonate and lithium chloride is 1 (1.2-3): (1.2-3)) for 2-12 h at 50-140 ℃, filtering, separating to obtain a crude product, and purifying by column chromatography to obtain the lactam with the structure shown in formula 2.
In the present invention, the molar ratio of the lactam to lithium diisopropylamide is preferably 1 (1 to 3), more preferably 1 (1.1 to 2.55), and still more preferably 1 (1.5 to 2). In the present invention, the mixing of the lactam with lithium diisopropylamide further comprises adding anhydrous tetrahydrofuran, preferably dissolving the lactam in anhydrous tetrahydrofuran, and adding lithium diisopropylamide to the resulting solution; the dosage of the anhydrous tetrahydrofuran is not particularly limited, and the reaction can be ensured to be carried out smoothly. The concentration of the lithium lactam salt in the lithium lactam salt solution is not particularly limited, and the lithium lactam salt can be adjusted according to actual requirements.
In the present invention, the molar ratio of the benzoyl chloride compound to the lithium lactam salt in the lithium lactam salt solution is preferably (1-3): 1, more preferably 2:1; the process of the first nucleophilic substitution reaction preferably includes: after 0.5 to 2 hours at-78 ℃, the reaction is carried out for 4 to 24 hours at room temperature, more preferably for 1 hour at-78 ℃ and then for 12 to 20 hours at room temperature. More preferably 15 to 16 hours.
After the first nucleophilic substitution reaction is completed, preferably, the method comprises the steps of adding saturated ammonium chloride solution into the obtained product to quench the reaction, and sequentially carrying out dichloromethane extraction, anhydrous sodium sulfate drying, suction filtration, concentration and column chromatography on the obtained product to obtain the piperlonguminine compound. The process of the suction filtration, concentration and column chromatography is not particularly limited, and may be carried out according to a method known in the art.
In the invention, when X is not H, the preparation reaction formula of the piperlonguminine compound with the structure shown in the formula I is as follows:
Figure BDA0003583609560000081
preferably, the acid anhydride compound is obtained by mixing the substituted benzene acrylic acid, pivaloyl chloride, triethylamine and the second solvent and performing acidolysis reaction. In the invention, the molar ratio of the substituted benzene acrylic acid, the pivaloyl chloride and the triethylamine is preferably 1 (1-3): 0.1-0.5, more preferably 1 (1.1-2.2): 0.12-0.24; the second solvent is preferably anhydrous dichloromethane; the amount of the second solvent is not particularly limited, and the reaction can be ensured to be carried out smoothly.
In the present invention, the mixing of the substituted benzene acrylic acid, pivaloyl chloride, triethylamine and the second solvent preferably includes mixing the substituted benzene acrylic acid and pivaloyl chloride, followed by dropwise addition of pivaloyl chloride and triethylamine.
In the present invention, the acidolysis reaction is preferably carried out under reflux conditions; the acidolysis reaction is preferably carried out at a temperature of 0 to 40 ℃, more preferably 20 to 35 ℃, and for a time of 0.5 to 8 hours, more preferably 4 to 6 hours.
After completion of the acidolysis reaction, the present invention preferably does not perform any treatment, and the obtained acid anhydride compound is directly subjected to a subsequent reaction.
After the acid anhydride compound is obtained, the acid anhydride compound is preferably mixed with a lithium lactam salt solution, and a second nucleophilic substitution reaction is carried out to obtain the piperlonguminine compound. In the present invention, the preparation process of the lithium lactam salt solution is the same as that when X is H, and will not be described herein.
In the present invention, the molar ratio of the acid anhydride compound to the lithium lactam salt in the lithium lactam salt solution is preferably (1 to 3): 1, more preferably 2:1; the process of the second nucleophilic substitution reaction preferably includes: after 0.5 to 2 hours at-78 ℃, the reaction is carried out for 4 to 24 hours, more preferably 12 hours, at room temperature.
After the second nucleophilic substitution reaction is completed, preferably, the method comprises the steps of adding saturated ammonium chloride solution into the obtained product to quench the reaction, and sequentially carrying out dichloromethane extraction, anhydrous sodium sulfate drying, suction filtration, concentration and column chromatography on the obtained product to obtain the piperlonguminine compound. The process of the suction filtration, concentration and column chromatography is not particularly limited, and may be carried out according to a method known in the art.
In the invention, the in vitro use concentration of the piperlonguminine compound is preferably 2.5-20 mu M.
The invention provides a pharmaceutical composition for treating schistosomiasis japonica, which comprises piperlonguminine compounds and pharmaceutically acceptable auxiliary materials. The pharmaceutically acceptable auxiliary materials are not particularly limited, and the corresponding auxiliary materials are well known in the art.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examples, synthesis of the lactams and substituted benzene acrylic acids used:
1. synthesis of lactams
1) First lactam:
Figure BDA0003583609560000091
synthesis of 3, 3-dichloro-2-piperidone:
5g (50.4 mmol) of 2-piperidone and 50mL of chloroform were added to a 100mL round bottom flask, 31.6g (152 mmol) of phosphorus pentachloride was added in portions at 0℃and reacted for 15min, and then heated to 60℃for reactionShould be 12h. After the reaction was completed, the mixture was cooled to room temperature, added to 250mL of ice water, pH was adjusted to neutrality with sodium hydroxide solution, an organic phase was obtained by extraction with methylene chloride, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 5.47g of a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.78(s,1H),3.41(td,J＝6.2,2.3Hz,2H),2.87-2.64(m,2H),2.16-1.85(m,2H). 13 C NMR(101MHz,Chloroform-d)δ165.85,82.14,43.64,42.43,20.14.
Figure BDA0003583609560000101
Synthesis of 3-chloro-5, 6-dihydro-2 (1H) -one:
2.7g (16 mmol) of 3, 3-dichloro-2-piperidone, 2.4g (32.5 mmol) of anhydrous lithium carbonate and 1.4g (33.0 mmol) of anhydrous lithium chloride were successively added to a 50mL round bottom flask containing 8.5mL of anhydrous N, N-dimethylformamide under nitrogen atmosphere, and reacted at 120℃for 8 hours. After completion of the reaction, the mixture was cooled to room temperature, distilled under reduced pressure, and the residue was dissolved in chloroform, filtered, and the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain 1.08g of an off-white solid. 1 H NMR(400MHz,Chloroform-d)δ7.19(s,N-H),6.76(t,J＝4.6Hz,1H),3.46(td,J＝7.1,2.7Hz,2H),2.46(td,J＝7.1,4.6Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ162.47,137.31,127.39,39.74,25.24.
2) Second lactam:
Figure BDA0003583609560000102
synthesis of 3, 3-dibromo-2-piperidone:
9.907g (100 mmol) of valerolactam and 200mL of methylene chloride were put into a 500mL two-necked flask, 41.65g (200 mmol) of phosphorus pentachloride was added in portions, and the mixture was stirred at 0℃for 10min; 1.1g (3.4 mmol) of zinc iodide was added thereto and the mixture was reacted for 1 hour. Bromine in dichloromethane was added dropwise and reacted overnight. After completion of the reaction, 500mL of ice water was added, pH was adjusted to neutrality, extraction was performed with methylene chloride, drying was performed with anhydrous sodium sulfate, concentration was performed, and chloroform recrystallization was performed to obtain 5.69g of pale yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.04(s,1H),6.82(s,1H),3.48(d,J＝2.8Hz,2H),2.42(d,J＝4.6Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ166.11,59.00,46.42,42.74,21.34.
Figure BDA0003583609560000111
Synthesis of 3-bromo-5, 6-dihydro-2 (1H) -one:
5.058g (20 mmol) of 3, 3-dibromo-2-piperidone, 1.581g (37.3 mmol) of anhydrous lithium chloride and 2.766g (37.3 mmol) of anhydrous lithium carbonate are added into a 100mL round bottom flask, the protection of nitrogen is achieved, 28.5mL of anhydrous N, N-dimethylformamide is added, and the mixture is heated to 130 ℃ for reaction for 8 hours; after the reaction was completed, it was cooled to room temperature, N-dimethylformamide was distilled off under reduced pressure, the solid was washed with an appropriate amount of chloroform, and filtered, and the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a gray viscous solid, and 150mL of ethyl acetate/methanol (15:1) was added to the solid, heated under reflux for 3 hours, and then concentrated, and column chromatography was carried out to obtain 1.45g of pale yellow solid. 1 H NMR(400MHz,Chloroform-d)δ6.77(s,1H),3.48-3.29(m,2H),2.66-2.55(m,2H),2.17-1.92(m,2H),1.68(td,J＝4.5,2.5Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ161.99,141.98,118.36,39.99,26.53.
3) Third lactam:
Figure BDA0003583609560000112
synthesis of 3, 3-dichloro-2-caprolactam
11.3g (100 mmol) of caprolactam and 100mL of chloroform were added to a 100mL round bottom flask, thoroughly dissolved with vigorous stirring, and cooled to 0deg.C; 62.4g (300 mmol) of phosphorus pentachloride was added in portions, reacted at 0℃for 30min with stirring, and then heated to 60℃for 8h. After the reaction is completed, cooling to room temperature, adding 250mL of ice water, and adjusting the pH to be neutral by sodium hydroxide; the organic phase was concentrated by extraction with methylene chloride and separated by column chromatography to give 5.96g of pale yellow solid. 1 H NMR(400MHz,Chloroform-d)δ6.77(s,1H),3.48-3.29(m,2H),2.66-2.55(m,2H),2.17-1.92(m,2H),1.68(td,J＝4.5,2.5Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ168.55,90.01,43.88,42.47,29.79,28.58,26.42.
Figure BDA0003583609560000113
Synthesis of 3-chloro-6, 7-dihydro-1H-azepin-2 (5H) -one:
into a 50mL two-necked flask, 5.26g (29 mmol) of 3, 3-dichloro-2-piperidone, 1.24g (29.2 mmol) of anhydrous lithium chloride and 2.17g (29.2 mmol) of anhydrous lithium carbonate were charged under nitrogen; then, 8.5mL of anhydrous N, N-dimethylformamide is added, and the mixture is heated to 120 ℃ for reaction for 8 hours; after the reaction is completed, cooling to room temperature, decompressing and distilling out N, N-dimethylformamide, dissolving solid by using chloroform, filtering, washing solid by using a proper amount of chloroform, merging organic phases, washing by using saturated saline water and drying by using anhydrous sodium sulfate; finally, filtration, concentration and column chromatography gave 2.27g of an off-white solid. 1 H NMR(400MHz,Chloroform-d)δ7.94(s,1H,N-H),6.60(t,J＝6.7Hz,1H),3.25(q,J＝6.0Hz,2H),2.35(q,J＝7.1Hz,2H),1.92(dd,J＝7.2,4.8Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ168.08,135.84,127.50,40.15,29.03,25.83.
Synthesis of substituted benzene acrylic acid:
1)
Figure BDA0003583609560000121
synthesis of 4-methoxyphenylacrylic acid (first substituted phenylacrylic acid):
10mmol of p-methoxybenzaldehyde is weighed and added into a 50mL round bottom flask containing 5mL of toluene, 0.12mL of aniline and 1.5mL of pyridine are added dropwise, the mixture is reacted for 8 hours at 110 ℃, after the reaction is finished, the mixture is cooled to room temperature, concentrated hydrochloric acid is added for acidification, a large amount of white crystals are separated out, the mixture is filtered, and ethanol is recrystallized, so that 1.13g of white solid is obtained. 1 H NMR(400MHz,DMSO-d 6 )δ7.68(d,J＝15.6Hz,1H),7.51(d,J＝8.8Hz,2H),7.34(d,J＝15.6Hz,1H),6.87(d,J＝8.8Hz,2H),3.81(s,3H)。
2)
Figure BDA0003583609560000122
Synthesis of 3 (E) -2-bromo-3- (3, 4, 5-trimethoxyphenyl) acrylic acid (second substituted benzene acrylic acid)
In a 100mL two-necked flask, 1.74g (5 mmol) of ethoxyformylmethylene triphenylphosphine, 0.98g (5.5 mmol) of N-bromosuccinimide and 20mL of anhydrous dichloromethane were sequentially added, and reacted at-20℃for 1 hour; 1.73g (12.5 mmol) of potassium carbonate and 0.98g (5 mmol) of 3,4, 5-trimethoxybenzaldehyde were added and reacted at room temperature for 72 hours; 10mL of water was added to quench the reaction, and the mixture was dried by extraction with methylene chloride, filtered, concentrated and purified by column chromatography to give 1.54g of a white solid. The white solid was dissolved in 40mL of tetrahydrofuran, 30mL of 2M sodium hydroxide solution was added, stirred at room temperature for 12 hours, after the reaction was completed, the pH was adjusted to 1, suction filtration and ethanol recrystallization were performed to obtain 0.61g of a white solid. 1 HNMR(400MHz,DMSO-d 6 )δ8.20(s,1H),7.34(s,2H),3.81(s,6H),3.72(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ164.58,153.00,140.26,139.69,129.07,113.50,108.50,60.56,56.43.
3)
Figure BDA0003583609560000131
Synthesis of 3 (E) -2- (4-methoxyphenyl) -3- (3, 4, 5-trimethoxyphenyl) acrylic acid (third substituted phenylacrylic acid)
Into a 25mL two-necked flask, 0.39g (2 mmol) of 3,4, 5-trimethoxybenzaldehyde, 0.66g (4 mmol) of 4-methoxyphenylacetic acid, 4mL of acetic anhydride and 1mL of triethylamine were added, the mixture was heated to 120℃for reaction for 12 hours, cooled to room temperature, 5mL of concentrated hydrochloric acid was added to precipitate a solid, suction filtration and methanol recrystallization were carried out to obtain 0.51g of a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.67(s,1H),7.12(d,J＝8.6Hz,2H),7.00(d,J＝8.7Hz,2H),6.43(s,2H),3.76(s,3H),3.61(s,3H),3.48(s,6H). 13 C NMR(101MHz,Chloroform-d)δ173.78,163.97,157.46,144.13,143.35,137.24,136.03,135.02,133.78,119.32,113.21,65.21,60.53,60.41.
4)
Figure BDA0003583609560000132
Synthesis of 3 (E) -2-trifluoromethyl-3- (3, 4, 5-trimethoxyphenyl) acrylic acid (fourth substituted benzene acrylic acid)
Into a 25mL round bottom flask at zero temperature was charged 0.3g (1.5 mmol), 0.128g (1 mmol) 3, 3-trifluoropropionic acid and 5mL anhydrous tetrahydrofuran, stirredAfter 10min, adding 0.17mL of titanium tetrachloride, heating to react for 0.5h, and adding 0.6mL of triethylamine; after the reaction is completed, adding 10mL of water to quench the reaction, extracting with methylene dichloride, and drying with anhydrous sodium sulfate; filtration, concentration and column chromatography separation gave 0.12g of yellow solid. 1 H NMR(400MHz,Chloroform-d)δ8.15(s,1H),6.71(s,2H),3.92(s,3H),3.88(s,6H). 13 C NMR(101MHz,Chloroform-d)δ168.31,152.91,150.47,140.49,127.08,123.11,120.47,120.38,120.15,107.71,107.69,107.66,61.01,56.21.
Example 1
Figure BDA0003583609560000133
Synthesis of Piperlonguminine (Compound 1):
into a 50mL round bottom flask, 20mL of anhydrous dichloromethane and 0.95g (4 mmol) of 3,4, 5-trimethoxy benzene acrylic acid (second substituted benzene acrylic acid) were added, 5mL (59 mmol) of oxalyl chloride was added dropwise, and after reaction for 5h at 30 ℃, reduced pressure distillation was performed to obtain 3,4, 5-trimethoxy benzene acryloyl chloride;
0.19g (2 mmol) of 5, 6-dihydropyridin-2 (1H) -one (first lactam) was dissolved in 10mL of anhydrous tetrahydrofuran under nitrogen and cooled to-78 ℃; then 1.3mL (2.2 mmol) of lithium diisopropylamide is slowly added for reaction at-78 ℃ for 45min to obtain a lithium lactam salt solution; adding 4mmol of 3,4, 5-trimethoxy benzene acryloyl chloride, continuously reacting for 1h at-78 ℃, and then heating to room temperature for reacting for 12h; after the reaction, 10mL of saturated ammonium chloride solution is added to quench the reaction, dichloromethane extraction, anhydrous sodium sulfate drying, suction filtration, concentration and column chromatography separation are carried out, and white solid (compound 1) is obtained.
1 H NMR(400MHz,Chloroform-d)δ7.70(s,1H),7.45(d,J＝15.5Hz,1H),6.97-6.92(m,1H),6.80(s,1H),6.06(dt,J＝9.7,1.8Hz,1H),4.06(t,J＝6.5Hz,2H),3.89(s,6H),3.88(s,3H),2.50(tdd,J＝6.3,4.2,1.8Hz,2H). 13 C NMR(100MHz,Chloroform-d)δ168.78,165.77,153.28,145.45,143.69,139.94,130.58,125.75,121.03,105.45,60.88,56.11,41.58,24.74.HPLC-MS:Calcd.for:C 17 H 20 NO 5 + [M+H] + 318.1336,found:318.13426,error:2.077ppm.
Example 2
Figure BDA0003583609560000141
Synthesis of Compound 2
10mL of anhydrous methylene chloride and 0.95g (4 mmol) of 3,4, 5-trimethoxy benzene acrylic acid (second substituted benzene acrylic acid) were added into a 25mL round bottom flask, 2.5mL (29.5 mmol) of oxalyl chloride was added dropwise under stirring, reflux was carried out at 40 ℃ for 4 hours, and then reduced pressure distillation was carried out to obtain 3,4, 5-trimethoxy benzene acryloyl chloride;
0.26g (2 mmol) of 3-chloro-5, 6-dihydro-2 (1H) -one (first lactam) was dissolved in 5mL of anhydrous tetrahydrofuran under nitrogen and cooled to-78 ℃; then 2.6mL (4.4 mmol) of lithium diisopropylamide is slowly added for reaction for 45min to obtain a lithium lactam salt solution, 4 mmole of 3,4, 5-trimethoxy-benzoyl chloride is added for continuous reaction for 2h at minus 78 ℃, and then the temperature is raised to room temperature for reaction for 16h; after the completion of the reaction, the reaction was quenched by adding 10mL of saturated ammonium chloride solution, extracted with methylene chloride, dried over anhydrous sodium sulfate, suction-filtered, concentrated, and separated by column chromatography to give 0.11g of a yellow solid (compound 2).
1 H NMR(400MHz,Chloroform-d)δ7.72(d,J＝15.5Hz,1H),7.43(d,J＝15.5Hz,1H),7.10(t,J＝4.6Hz,1H),6.80(s,2H),4.10(t,J＝6.5Hz,2H),3.89(d,J＝5.7Hz,9H),2.58(q,J＝6.4Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.50,161.40,153.37,145.01,141.16,140.19,130.35,128.20,120.20,105.59,60.99,56.22,41.81,25.31.HPLC-MS:Calcd.for:C 17 H 18 NO 5 Cl[M+Na+CH 3 OH] + 406.10279,found:406.10424,error:3.571ppm.
Example 3
Figure BDA0003583609560000151
Synthesis of Compound 3
Into a 50mL round bottom flask were added 20mL of anhydrous methylene chloride and 0.95g (4 mmol) of 3,4, 5-trimethoxy benzene acrylic acid (second substituted benzene acrylic acid), 4mL (47.2 mmol) of oxalyl chloride was added dropwise with stirring, reflux was conducted at 35℃for 3 hours, and then distillation was conducted under reduced pressure to obtain 3,4, 5-trimethoxy benzene acrylic acid chloride;
under nitrogen protection, 0.35g (2 mmol) of 3-bromo-5, 6-dihydro-2 (1H) -one (second lactam) and 5mL of anhydrous tetrahydrofuran were added and cooled to-78 ℃; then slowly adding 1.3mL (2.2 mmol) of lithium diisopropylamide, reacting for 45min to obtain a lactam lithium salt solution, adding 4mmol of 3,4, 5-trimethoxy-benzoyl chloride, continuously reacting for 2h at-78 ℃, and then heating to room temperature for reacting for 12h; after the completion of the reaction, the reaction was quenched by adding 10mL of saturated ammonium chloride solution, extracted with methylene chloride, dried over anhydrous sodium sulfate, suction-filtered, concentrated, and separated by column chromatography to give 0.195g of a white solid (compound 3).
1 H NMR(400MHz,Chloroform-d)δ7.73(d,J＝15.5Hz,1H),7.44(d,J＝15.5Hz,1H),7.38(t,J＝4.6Hz,1H),6.82(s,2H),4.12(t,J＝6.5Hz,2H),3.91(s,6H),3.89(s,3H),2.56(td,J＝6.4,4.7Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.60,161.11,153.36,145.97,144.99,140.18,130.36,120.23,119.09,105.61,60.99,56.24,41.91,26.72.HPLC-MS:Calcd.for:C 17 H 18 NO 5 Br[M+Na] + 418.02606,found:418.02695,error:2.129ppm.
Example 4
Figure BDA0003583609560000152
Synthesis of Compound 4
A25 mL two-necked flask was charged with 0.1g (0.315 mmol) of piperlonguminine prepared in example 1 and 0.2g (0.79 mmol) of I 2 And 3.2mL of a mixture of carbon tetrachloride and pyridine (1:1), stirring overnight at room temperature in the absence of light, after the completion of the reaction, adding 10mL of a saturated ammonium chloride solution, extracting with methylene chloride, combining the organic phases, washing with a saturated sodium bisulfite solution, drying over anhydrous sodium sulfate, filtering, concentrating, and separating by column chromatography to obtain 0.07g of a yellow solid (compound 4).
1 H NMR(400MHz,Chloroform-d)δ7.71-7.65(m,2H),7.41(d,J＝15.5Hz,1H),6.80(s,2H),4.11(t,J＝6.5Hz,2H),3.89(s,6H),3.88(s,3H),2.50(td,J＝6.4,4.7Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ168.90,161.45,154.62,153.50,140.39,130.52,120.45,105.87,96.86,61.11,56.41,42.25,28.67.HPLC-MS:m/z calcd.for C 17 H 18 NO 5 I[M+Na] + :466.01219；found:466.01175,error＝-0.944ppm.
Example 5
Figure BDA0003583609560000161
Synthesis of Compound 5
15mL of anhydrous dichloromethane and 0.95g (4 mmol) of 3,4, 5-trimethoxy benzene acrylic acid (second substituted benzene acrylic acid) are uniformly mixed, 3.5mL (41.3 mmol) of oxalyl chloride is added dropwise, reflux is carried out for 3.5h at 35 ℃ and reduced pressure distillation is carried out, thus obtaining 3,4, 5-trimethoxy benzene acrylic acid chloride;
0.26g (2 mmol) of 3-chloro-6, 7-dihydro-1H-azepin-2 (5H) -one (third lactam) and 5mL of anhydrous tetrahydrofuran were added under nitrogen and cooled to-78 ℃; then slowly adding 1.3mL (2.2 mmol) of lithium diisopropylamide, and reacting for 45min to obtain a lithium lactam salt solution; adding 4mmol of 3,4, 5-trimethoxy benzene acryloyl chloride, continuously reacting for 1.5 hours at the temperature of minus 78 ℃, and then heating to room temperature for reacting for 16 hours; after the completion of the reaction, the reaction was quenched by adding 10mL of a saturated ammonium chloride solution, extracted with methylene chloride, dried by adding anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 0.088g of a white solid (compound 5).
1 H NMR(400MHz,Chloroform-d)δ7.62(d,J＝15.9Hz,1H),6.76(s,2H),6.36(d,J＝15.9Hz,1H),4.26(t,J＝6.1Hz,2H),3.89(d,J＝3.9Hz,9H),3.62(t,J＝6.2Hz,2H),1.91(tdd,J＝9.8,4.6,2.5Hz,4H). 13 C NMR(101MHz,Chloroform-d)δ166.86,153.44,144.86,140.21,129.82,117.15,105.28,63.64,60.94,56.16,44.47,29.21,26.20.HPLC-MS:Calcd.for:C 18 H 20 NO 5 Cl[M+Na+CH 3 OH] + 420.11844,found:420.12034,error:4.523ppm.
Example 6
Figure BDA0003583609560000162
Synthesis of Compound 6
10mL of anhydrous dichloromethane and 0.59g (4 mmol) of benzene acrylic acid were added into a 25mL round bottom flask, followed by dropwise addition of 2.5mL (29.5 mmol) of oxalyl chloride, stirring at 30℃for 4h under reflux, and then concentration under reduced pressure to obtain benzene acryloyl chloride;
0.26g (2 mmol) of 3-chloro-5, 6-dihydro-2 (1H) -one (first lactam) was dissolved in 5mL of anhydrous tetrahydrofuran under nitrogen and cooled to-78 ℃; then 1.95mL (3.3 mmol) of lithium diisopropylamide is slowly added for reaction for 30min to obtain a lithium lactam salt solution; adding 4mmol of benzoyl chloride, continuously reacting for 2 hours, heating to room temperature, and stirring for 24 hours; after the completion of the reaction, the reaction was quenched by adding 10mL of saturated ammonium chloride solution, extracted with methylene chloride, dried over anhydrous sodium sulfate, suction-filtered, concentrated, and separated by column chromatography to give 0.16g of a yellow solid (compound 6).
1 HNMR(400MHz,Chloroform-d)δ7.69(d,J＝15.6Hz,1H),7.50-7.48(m,2H),7.42(d,J＝15.6Hz,1H),7.28-7.26(m,3H),6.99(t,J＝4.6Hz,1H),4.00(t,J＝6.5Hz,2H),2.48(td,J＝6.5,4.6Hz,2H). 13 CNMR(101MHz,Chloroform-d)δ168.68,161.53,144.74,141.24,134.94,130.44,128.93,128.55,128.33,121.26,41.84,25.43.HPLC-MS:Calcd.for:C 14 H 12 NO 2 Cl[M+Na] + 284.04488.found:284.04554,error:2.324ppm.
Example 7
Figure BDA0003583609560000171
Synthesis of Compound 7->
Into a 25mL round bottom flask was added 10mL of anhydrous dichloromethane and 0.71g (4 mmol) of p-methoxyphenylacrylic acid (first phenylacetic acid), and the mixture was sufficiently dissolved by vigorous stirring; 2.5mL (29.5 mmol) of oxalyl chloride was added dropwise, and the mixture was refluxed at 40℃for 5 hours under a magnetic stirrer and distilled under reduced pressure to give p-methoxyphenylacryloyl chloride;
0.26g (2 mmol) of 3-chloro-5, 6-dihydro-2 (1H) -one (first lactam) was dissolved in 5mL of anhydrous tetrahydrofuran under nitrogen and cooled to-78 ℃; then slowly adding 1.3mL (2.2 mmol) of lithium diisopropylamide for reaction for 60min to obtain a lithium lactam salt solution, adding 4mmol of p-methoxy-benzoyl chloride, continuously reacting at-78 ℃ for 1.5h, and then heating to room temperature for reaction for 20h; after the completion of the reaction, the reaction was quenched by adding 10mL of a saturated ammonium chloride solution, extracted with methylene chloride, dried by adding anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 0.16g of a yellow solid (compound 7).
1 H NMR(400MHz,Chloroform-d)δ7.79(d,J＝15.6Hz,1H),7.58-7.54(m,2H),7.44(d,J＝15.5Hz,1H),7.10(t,J＝4.6Hz,1H),6.93-6.89(m,2H),4.11(t,J＝6.5Hz,2H),3.85(s,3H),2.59(td,J＝6.5,4.7Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ168.73,161.49,161.41,144.65,140.96,130.18,128.30,127.61,118.65,114.25,55.40,41.71,25.33.HPLC-MS:Calcd.for:C 15 H 14 NO 3 Cl[M+Na] + 314.05544,found:314.05673,error:4.108ppm.
Example 8
Figure BDA0003583609560000181
Synthesis of Compound 8
Into a 25mL round bottom flask was charged 10mL of anhydrous dichloromethane and 0.83g (4 mmol) of p-acetoxy benzene acrylic acid; 4mL (47.2 mmol) of oxalyl chloride was added dropwise under stirring, and the mixture was refluxed at 40℃for 3.5h; distilling under reduced pressure to obtain p-acetoxy benzene acryloyl chloride;
0.26g (2 mmol) of 3-chloro-5, 6-dihydro-2 (1H) -one (first lactam) was dissolved in 5mL of anhydrous tetrahydrofuran under nitrogen and cooled to-45 ℃; then 3mL (5.1 mmol) of lithium diisopropylamide is slowly added for reaction for 100min to obtain a lactam lithium salt solution, 4mmol of p-acetoxy-benzoyl chloride is added for continuous reaction for 1h at minus 78 ℃, and the temperature is raised to room temperature for reaction for 15h; after the completion of the reaction, the reaction was quenched by adding 10mL of a saturated ammonium chloride solution, extracted with methylene chloride, dried by adding anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 0.127g of a white solid (compound 8).
1 H NMR(400MHz,Chloroform-d)δ7.76(d,J＝15.6Hz,1H),7.62–7.59(m,2H),7.48(d,J＝15.6Hz,1H),7.13-7.08(m,3H),4.11(t,J＝6.5Hz,2H),2.59–2.55(m,2H),2.31(s,3H). 13 C NMR(101MHz,Chloroform-d)δ169.16,168.43,161.43,152.10,143.46,141.14,132.58,129.57,128.22,122.06,121.29,41.73,25.31,21.16.HPLC-MS:m/z calcd.for C 16 H 14 NO 4 Cl[M+H] + :320.06841,found:320.06765,error＝-2.374ppm.
Example 9
Figure BDA0003583609560000182
Synthesis of Compound 9
Into a 50mL round bottom flask was charged 20mL of anhydrous dichloromethane and 0.31g (1 mmol) of 3 (E) -2-trifluoromethyl-3- (3, 4, 5-trimethoxyphenyl) acrylic acid (fourth substituted benzene acrylic acid); 0.13mL (1.1 mmol) of pivaloyl chloride and 0.12g (0.12 mmol) of triethylamine were added dropwise under stirring, and the mixture was refluxed at 35℃for 4 hours to give an acid anhydride;
0.065g (0.5 mmol) of 3-chloro-5, 6-dihydro-2 (1H) -one (first lactam) was dissolved in 5mL of anhydrous tetrahydrofuran under nitrogen and cooled to-78 ℃; then 0.33mL (0.55 mmol) of lithium diisopropylamide is slowly added for reaction for 60min to obtain a lithium lactam salt solution, the 1mmol of anhydride is added for continuous reaction for 1h at minus 78 ℃, and the temperature is raised to room temperature for reaction for 24h; after the completion of the reaction, the reaction was quenched by adding 10mL of a saturated ammonium chloride solution, extracted with methylene chloride, dried by adding anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 0.081g of a yellow solid (Compound 9).
1 H NMR(400MHz,Chloroform-d)δ8.15(s,1H),6.71(s,2H),3.92(s,3H),3.88(s,6H). 13 C NMR(101MHz,Chloroform-d)δ167.16,167.13,160.47,152.95,141.64,140.01,139.97,139.93,139.90,139.75,128.26,127.93,127.40,127.35,122.82,120.10,107.18,107.15,107.12,60.89,56.13,42.43,25.05.HPLC-MS:m/z calcd.for C 18 H 17 NO 5 F 3 Cl[M-H] - :418.06746,found:418.06696,error＝-1.196ppm.
Example 10
Figure BDA0003583609560000191
Synthesis of Compound 10
Into a 50mL round bottom flask was charged 10mL anhydrous tetrahydrofuran and 0.32g (1 mmol) 3 (E) -2-bromo-3- (3, 4, 5-trimethoxyphenyl) acrylic acid (second substituted benzene acrylic acid); 0.26mL (2.2 mmol) of pivaloyl chloride and 0.24g (0.24 mmol) of triethylamine were added dropwise with stirring, and the mixture was refluxed at 20℃for 5 hours; obtaining anhydride;
0.13g (1.0 mmol) of 3-chloro-5, 6-dihydro-2 (1H) -one (first lactam) was dissolved in 10mL of anhydrous tetrahydrofuran under nitrogen and cooled to-78 ℃; adding 0.66mL (1.1 mmol) of lithium diisopropylamide for reaction for 60min to obtain a lithium lactam salt solution, adding the 1mmol of anhydride, continuing to react for 1.5h at the temperature of minus 78 ℃, and then heating to room temperature for reaction for 12h; after the completion of the reaction, the reaction was quenched by adding 10mL of a saturated ammonium chloride solution, extracted with methylene chloride, dried by adding anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 0.040g of a white solid (compound 10).
1 H NMR(400MHz,Chloroform-d)δ7.40(s,1H),7.12(t,J＝4.6Hz,1H),7.06(s,2H),4.00(t,J＝6.4Hz,2H),3.88(s,3H),3.88(s,6H),2.65(td,J＝6.4,4.9Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ169.71,160.15,152.85,141.25,139.43,135.85,128.99,127.53,114.76,107.42,60.90,56.20,43.54,25.26.HPLC-MS:m/z calcd.for C 17 H 17 NO 5 ClBr[M+Na] + :451.98708,found:451.98667,error＝-0.907ppm.
Example 11
Figure BDA0003583609560000201
Synthesis of Compound 11
Into a 50mL round bottom flask was charged 15mL of anhydrous tetrahydrofuran and 0.34g (1 mmol) of 3 (E) -2- (4-methoxyphenyl) -3- (3, 4, 5-trimethoxyphenyl) acrylic acid (third substituted phenylacrylic acid); 0.26mL (2.2 mmol) of pivaloyl chloride and 0.36g (0.36 mmol) of triethylamine were added dropwise under stirring, and the mixture was refluxed at 35℃for 6 hours to give the corresponding acid anhydride;
0.065g (0.5 mmol) of 3-chloro-5, 6-dihydro-2 (1H) -one (first lactam) was dissolved in 10mL of anhydrous tetrahydrofuran under nitrogen and cooled to-78 ℃; then 0.66mL (1.1 mmol) of lithium diisopropylamide is slowly added for reaction for 60min to obtain a lithium lactam salt solution, the 1mmol of anhydride is added for continuous reaction for 1.2h at minus 78 ℃, and the temperature is raised to room temperature for reaction for 16h; after the completion of the reaction, the reaction was quenched by adding 10mL of saturated ammonium chloride solution, extracted with methylene chloride, dried over anhydrous sodium sulfate, suction-filtered, concentrated, and separated by column chromatography to give 0.029g of a yellow solid (compound 11).
1 H NMR(400MHz,Chloroform-d)δ7.30-7.27(m,2H),6.97(t,J＝4.6Hz,1H),6.89(s,1H),6.87-6.84(m,2H),6.33(s,2H),3.97(t,J＝6.4Hz,2H),3.80(s,3H),3.78(s,3H),3.57(s,6H),2.56(q,J＝6.3Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ174.71,160.49,159.50,152.70,140.69,138.43,137.37,134.15,131.55,130.55,127.80,113.95,107.53,60.97,55.86,55.42,43.38,25.37.HPLC-MS:m/z calcd.for C 24 H 24 NO 6 Cl[M+Na] + :480.11844,found:480.11742,error＝-2.124ppm.
Example 12
Test of in vitro anti-Japanese blood fluke Activity of Compounds 1-11:
the medium containing 10% (volume fraction) of newborn calf serum was pre-added to a 24-well plate and placed in a medium containing 5% CO 2 Is preheated in an incubator at 37 ℃. Fresh adults with better activity are selected and randomly distributed into a preheated 24-well plate, 5 pairs of Japanese blood flukes are added to each well, different concentrations of compounds are added, and different parameters (such as activity, swelling and curling) are monitored through a microscope at regular intervals.
Meanwhile, 3 groups of controls were set: the blank control group is a culture medium containing only 10% of new born calf serum; the negative control group is a culture medium containing 10% of new born calf serum of DMSO, the concentration of DMSO is 1% (volume fraction), and the culture medium is the highest using concentration of DMSO diluted compound in the experimental group; the positive control group was PZQ (praziquantel).
The piperlonguminine compound is used in the culture medium at the concentration of 1-40 mu M. Each experiment was repeated 2 times and the results obtained are shown in figures 1 to 3. Meanwhile, the results show that the blank control group and the negative control group have no death of the schistosome of the Japanese, namely the death rate is 0 percent.
FIG. 1 is a graph showing the activities of piperlonguminine compounds 1 (A), 2 (B), 3 (C) and 4 (D) against Schistosoma japonicum; as can be seen from FIG. 1, piperlonguminine (1) 2.5 μM48 h can cause the death of Japanese blood fluke, 10 μM 60h can cause the death of 60% of Japanese blood fluke, and 20 μM 60h can cause the death of 100% of Japanese blood fluke (A in FIG. 1). 25. Mu.M 36h of the compound resulted in 60% of the Japanese blood flukes dying and 10. Mu.M 72h resulted in 100% of the Japanese blood flukes dying (FIG. 1B). The compound 310. Mu.M for 24h resulted in 50% of the Japanese blood flukes dying and 20. Mu.M for 36h resulted in 100% of the Japanese blood flukes dying (C in FIG. 1). The compound 410. Mu.M for 36h resulted in 50% of the Japanese blood flukes dying and 20. Mu.M for 72h resulted in 90% of the Japanese blood flukes dying (D in FIG. 1).
FIG. 2 is a graph showing the activities of piperlonguminine compounds 5 (A), 6 (B), 7 (C) and 8 (D) against Schistosoma japonicum; as can be seen from FIG. 2, the compound 510. Mu.M 36h resulted in 50% of the Japanese blood fluke death, and 20. Mu.M 36h resulted in 100% of the Japanese blood fluke death (A in FIG. 2). Compound 6. Mu.M for 72h resulted in 100% of the death of Schistosoma japonicum, and 20. Mu.M for 24h resulted in 100% of the death of Schistosoma japonicum (B in FIG. 2). Compound 7, 10 μm 24h resulted in 50% of schistosoma japonicum death, and 20 μm 36h resulted in 100% of schistosoma japonicum death (C in fig. 2). Compound 8.5. Mu.M 36h resulted in 50% of Japanese blood fluke death and 20. Mu.M 36h resulted in 100% of Japanese blood fluke death (D in FIG. 2).
FIG. 3 is a graph showing the activities of piperlonguminine compounds 9 (A), 10 (B), 11 (C) and PZQ (D) against Japanese blood fluke; as can be seen from FIG. 3, compound 9 5. Mu.M for 24 hours resulted in 60% of Japanese blood fluke death, and 10. Mu.M for 36 hours resulted in 100% of Japanese blood fluke death (A in FIG. 3); 10. Mu.M for 24h of the compound resulted in 50% of the death of Schistosoma japonicum, and 20. Mu.M for 60h resulted in 90% of the death of Schistosoma japonicum (FIG. 3B); compound 11, 10 μm, 36h resulted in 75% of schistosoma japonicum death, and 20, 48h resulted in 90% of schistosoma japonicum death (C in fig. 3); the positive control praziquantel, 2.5. Mu.M for 48 hours resulted in 100% of the Japanese blood flukes dying, and 5. Mu.M for 6 hours resulted in 90% of the Japanese blood flukes dying (D in FIG. 3).
As shown in figures 1-3, piperlonguminine compounds can effectively cause schistosoma japonicum death within the range of 2.5-20 uM.
Piperlonguminine compound and positive control praziquantel, in the dosage range, LC for 72 hr to resist Japanese blood fluke 50 The values are shown in Table 1.
TABLE 1 Piper longum alkaloid compounds and positive controlsPraziquantel 72h LC 50 Value of
Figure BDA0003583609560000221
As can be seen from table 1, the anti-schistosome activity of compound 9 was substantially equivalent to that of the positive control praziquantel in the range of the dosage used.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (10)

1. The application of piperlonguminine compounds in preparing medicines for treating schistosomiasis japonica is characterized in that the piperlonguminine compounds have a structure shown in a formula I:
Figure QLYQS_1
in the formula I, R 1 ～R 5 Independently selected from H, OH, OCH 3 、NH 2 、F、Cl、Br、I、CN、NO 2 、CF 3 、OCF 3 C1-C6 alkyl; x is selected from H, OCH 3 、F、Cl、Br、CF 3 C1-C4 alkyl; y is selected from Cl or Br; n=2;
alternatively, the compound of formula I is of the structure:
Figure QLYQS_2
2. the use according to claim 1, wherein the piperlonguminine compound is:
Figure QLYQS_3
3. the use according to claim 1 or 2, wherein the preparation method of piperlonguminine compound comprises the following steps:
when X is H, mixing substituted benzene acrylic acid, oxalyl chloride and a first solvent, and performing an acyl chlorination reaction to obtain a benzene acrylic chloride compound;
mixing the phenyl acryloyl chloride compound with a lithium lactam salt solution, and performing a first nucleophilic substitution reaction to obtain a piperlonguminine compound;
when X is not H, mixing substituted benzene acrylic acid, pivaloyl chloride, triethylamine and a second solvent, and carrying out acidolysis reaction to obtain an anhydride compound;
mixing the anhydride compound with a lithium lactam salt solution, and performing a second nucleophilic substitution reaction to obtain a piperlonguminine compound;
the substituted benzene acrylic acid has a structure shown in a formula 1; the lactam in the lithium lactam salt solution has a structure shown in a formula 2;
Figure QLYQS_4
4. the method according to claim 3, wherein when X is H, the molar ratio of the substituted benzene acrylic acid to the oxalyl chloride is 1 (1-20), the temperature of the acyl chloride reaction is 0-40 ℃ and the time is 0.5-5H.
5. The use according to claim 4, wherein when X is H, the molar ratio of the benzoyl chloride compound to the lithium lactam salt in the lithium lactam salt solution is (1-3): 1; the first nucleophilic substitution reaction process comprises: after reacting for 0.5-2 h at-78 ℃, reacting for 4-24 h at room temperature.
6. The use according to claim 5, wherein the preparation method of the lithium lactam salt in the lithium lactam salt solution comprises the following steps: mixing lactam and lithium diisopropylamide in an inert gas atmosphere, and reacting at-78 to-40 ℃ for 0.5-2 h to obtain lactam lithium salt; the molar ratio of the lactam to the lithium diisopropylamide is 1 (1-3).
7. The use according to claim 3, wherein when X is not H, the molar ratio of substituted benzene acrylic acid, pivaloyl chloride and triethylamine is 1 (1-3): 0.1-0.5; the acidolysis reaction is carried out at the temperature of 0-40 ℃ for 0.5-8 h.
8. The use according to claim 7, wherein when X is not H, the molar ratio of the acid anhydride compound to the lithium lactam salt in the lithium lactam salt solution is (1-3): 1; the process of the second nucleophilic substitution reaction comprises: after 0.5 to 2 hours of reaction at the temperature of minus 78 ℃, the reaction is carried out for 4 to 24 hours at room temperature.
9. The use according to claim 1, wherein the piperlonguminine compound is used in vitro at a concentration of 2.5 to 20 μm.
10. The application of a pharmaceutical composition in preparing medicines for treating Japanese hemostix is characterized in that the pharmaceutical composition comprises the piperlonguminine compound as claimed in claim 1 and pharmaceutically acceptable auxiliary materials.
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