Matrine derivative, preparation method therefor, and use thereof

Abstract

The present application relates to the field of organic synthesis. Disclosed are a matrine derivative, a preparation method therefor, and a use thereof. By taking sophora acid methyl ester as a raw material, a nucleophilic substitution or nucleophilic addition reaction is carried out under an alkaline condition, to obtain a series of new matrine derivatives in one step. The matrine has certain insecticidal activity, but the insecticidal effect is not ideal; however, the activity of the matrine is multiplied by modifying the structure of the matrine and is obviously superior to that of the matrine before structural modification; in addition, some compounds also have an inhibitory effect on the activity of SIRT enzymes.

Description

Matrine derivative, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a matrine derivative and a preparation method and application thereof. Background Art

[0002] Matrine is a tetracyclic quinolidine alkaloid isolated from the roots of plants such as Sophora flavescens, Radix Sophorae flavescentis, and Sophora alopecuroides. It exhibits a wide range of biological properties, including anticancer, anti-inflammatory, antiviral, analgesic, and insecticidal activities. The traditional Chinese medicine compound Sophora flavescens injection was approved by the China Food and Drug Administration (CFDA) as an anticancer drug in 1995 and has been widely used in combination with anticancer drugs such as vinorelbine, cisplatin, and paclitaxel to treat non-small cell lung cancer, liver cancer, and gastric cancer. Matrine and its derivatives are registered as botanical pesticides in China for pest control and crop protection.

[0003] However, because it is extracted from traditional Chinese medicine, the cost is high, and its bioavailability and biological activity are poor, which hinders the market promotion and acceptance of matrine. Therefore, it is necessary to structurally modify the lead matrine and screen new highly active derivatives to comprehensively reduce costs and improve market competitiveness.

[0004] Summary of the Invention

[0005] The present invention aims to provide a matrine derivative and its preparation method and use. The matrine derivative not only has high insecticidal activity but also has an inhibitory effect on SIRT enzymes.

[0006] The present invention provides a matrine derivative having a structure shown in Formula I or its stereoisomers, cis-trans isomers, solvates, hydrates, pharmaceutically acceptable salts, or cocrystals:

[0007] Z is selected from alkyl, heteroalkyl, acyl, ester, sulfonyl, amide, and sulfonamide;

[0008] Ring A is a 3- to 6-membered ring, and is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted heterocycloalkyl;

[0009] Each occurrence of R is independently selected from hydrogen, halogen, cyano, =O, hydroxy, -NH2, carboxyl, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted C2-C10 Alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ester, acyl, amide, sulfinyl, sulfonyl, sulfonamide, sulfinamide, or any two R groups and the atoms connected thereto form a substituted or unsubstituted 3-12 membered hydrocarbon ring, or a substituted or unsubstituted 3-12 membered heterohydrocarbon ring;

[0010] n is selected from 1, 2, and 3.

[0011] Furthermore, R is selected from the following groups:

[0012] In the present invention, the matrine derivative is selected from the following compounds:

[0013] The numbers of the above compounds are only for the convenience of subsequent description.

[0014] In some specific embodiments of the present invention, the compound represented by formula I is selected from the following compounds:

[0015] In some specific embodiments of the present invention, the compound represented by formula I is selected from the following compounds:

[0016] The structures of the compounds of the present invention can be confirmed using conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed using conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data from a cultured single crystal using a Bruker D8 venture diffractometer, using Cu Kα radiation and a φ / ω scanning mode. After collecting relevant data, the crystal structure can be further analyzed using a direct method (Shelxs97) to confirm the absolute configuration.

[0017] In the technical solution of the present invention, the route for synthesizing the matrine derivatives of the present invention is as follows:

[0018] Z1 is selected from hydrogen, halogen, cyano, =0, hydroxy, -NH2, carboxyl, ester, acyl, amide, sulfinyl, sulfonyl, sulfonamide, and sulfinamide.

[0019] In some specific embodiments of the present invention, Z is selected from acyl, ester, and sulfonyl, and the base is an organic base; further, the organic base is selected from triethylamine, dimethylamine, aniline, and pyridine; further, the organic base is triethylamine.

[0020] In some specific embodiments of the present invention, Z is a C1-C6 alkyl group, and the base is an inorganic base; further, the inorganic base is selected from one or more of carbonates, acetates, phosphates, and organic bases;

[0021] Further, the base is selected from carbonate;

[0022] Furthermore, the base is selected from one or more of Li2CO3, Na2CO3, K2CO3, Ru2CO3, Cs2CO3 or hydrates thereof, preferably Na2CO3, K2CO3, Cs2CO3 and / or hydrates thereof.

[0023] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed herein, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0024] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0025] The present invention also provides the use of matrine derivatives in preparing insecticide products.

[0026] In some specific embodiments of the present invention, the insecticidal product is a product for controlling piercing-sucking pests.

[0027] Insects' feeding organs are called mouthparts, and common types include chewing and piercing-sucking. Piercing-sucking insects have needle-like mouthparts that pierce leaves, fruits, stems, roots, and other parts of the body. Through ducts within the mouthparts, they draw juices from plant tissues into their bodies. Common piercing-sucking pests include aphids, mites, whiteflies, planthoppers, leafhoppers, insects, thrips, spider mites, and scale insects. Damage to plants causes symptoms such as chlorotic spots, curled and wrinkled leaves, honeydew production, and poor growth.

[0028] Furthermore, the insecticide product is a product for preventing and controlling mites.

[0029] In the present invention, the insecticide product may be, but is not limited to, a systemic insecticide, a contact insecticide, and a fumigant.

[0030] The present invention provides the use of matrine derivatives in preparing products for treating and / or preventing at least one of tumors, neurodegenerative diseases and cardiovascular diseases.

[0031] The present invention provides the use of matrine derivatives in preparing products for inhibiting Sirt activity.

[0032] Furthermore, the product is a product that inhibits Sirt1 activity; furthermore, the product is a product that treats and / or prevents cancer.

[0033] Furthermore, the product is a product that inhibits Sirt2 activity; furthermore, the product is a product that treats and / or prevents nervous system diseases.

[0034] The Sirt protein family is a class of NAD+-dependent protein deacetylases and ADP-ribosyltransferases with highly conserved core regions. They regulate protein activity and gene expression by modulating protein acetylation / deacetylation. The Sirt protein family can be divided into seven distinct subtypes: Sirt1 to Sirt7. Sirt1, 2, 3, and 5 enzymes play distinct roles in tumorigenesis, central nervous system degenerative diseases, and cardiovascular disease. Sirt1 is overexpressed in human cancers and contributes to cancer cell drug resistance through multiple mechanisms. For example, altered Sirt1 expression in cancer cells contributes, in part, to resistance to cisplatin, an anticancer drug, by altering mitochondrial metabolism. Sirt5 may be a promising therapeutic target for cancer because it participates in numerous metabolic pathways. As a tumor suppressor, Sirt5 prevents the Warburg effect, increases protection against ROS, and reduces cell proliferation and metastasis. However, as an oncogene, it has the opposite effect, increasing resistance to chemotherapeutic drugs and / or radiation. Sirt2 is considered a promising target for the treatment of neurological diseases, and Sirt2 activity inhibitors can protect the damaged nervous system in major neurological diseases. Sirt3 regulates glucose and lipid metabolism, maintains myocardial ATP levels, protects the heart from metabolic disorders, and can protect cardiomyocytes from oxidative stress-mediated cell damage, preventing the development of cardiac hypertrophy, playing a key role in the prevention and treatment of cardiovascular disease.

[0035] The products of the present invention include but are not limited to medicines and functional foods.

[0036] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0037] "Cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent.

[0038] "Heterocycloalkyl" refers to a cycloalkyl group containing at least one heteroatom in the ring backbone.

[0039] Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.

[0040] "Ring" refers to any covalently closed structure, including, for example, a carbocyclic ring (e.g., an aryl or cycloalkyl group), a heterocyclic ring (e.g., a heteroaryl or heterocycloalkyl group), an aromatic group (e.g., an aryl or heteroaryl group), or a non-aromatic group (e.g., a cycloalkyl or heterocycloalkyl group). The "ring" herein may be a monocyclic ring or a polycyclic ring, and may be a fused ring, a spirocyclic ring, or a bridged ring.

[0041] Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0042] Typical heterocycloalkyl groups include, but are not limited to:

[0043] "Aryl" refers to a planar ring with a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.

[0044] Typical heteroaryl groups include, but are not limited to:

[0045] The alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl and the like described herein may be unsubstituted alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, or substituted alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl.

[0046] As used herein, “substituted” means that the group mentioned may be substituted by one or more additional groups, each of which is independently selected from the group consisting of alkyl, cycloalkyl, aryl, carboxyl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, alkylthio, aryloxy, O=, guanidino, cyano, nitro, acyl, halogen, haloalkyl, amino, and the like.

[0047] The beneficial effects of the present invention are as follows: the present invention provides a series of new matrine amide derivatives, and the results of biological activity tests thereof show that the insecticidal activity of the new derivatives is significantly better than that of matrine, and they can be used to prepare insecticides and other related products. DETAILED DESCRIPTION

[0048] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with embodiment.It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.In addition, unless otherwise clearly stated, all reagents adopted in the following examples are all commercially available, or can be synthesized according to this article or known methods, and for the reaction conditions not listed, they are also easily obtained by those skilled in the art.

[0049] Example 1 Synthesis of Intermediate 2a

[0050] Matrine (5.0 g, 20.1 mmol) was dissolved in 100.0 mL of 6N HCl and refluxed at 110°C. After 9 hours, the reaction was essentially complete as monitored by TLC. The reaction was stopped and stirred, solid sodium hydroxide was added to adjust the pH to 5-6, and the crude product was distilled under reduced pressure. The resulting crude solid was dissolved in dry methanol, the insoluble solid salts were filtered out, and the filtrate was distilled under reduced pressure to obtain 4.35 g (yield 86.9%) of intermediate 1a as a brown-yellow liquid. Intermediate 1a (2.00 g, 7.51 mmol) was dissolved in 50.0 mL of methanol solution, and dichlorothionyl (4.47 g, 2.67 mL, 37.57 mmol) was slowly added dropwise at 0°C. After the addition was complete, the reaction was moved to 45°C. After 2 hours, the reaction was essentially complete as monitored by TLC thin-layer chromatography. Stirring was stopped, and solid sodium bicarbonate was added to adjust the pH to neutral. The crude product was distilled under reduced pressure to obtain the product. The resulting crude solid product was dissolved in dry methanol, and the insoluble solid salts were filtered off. The filtrate was distilled under reduced pressure to remove the methanol, and the product was dissolved in water and freeze-dried to obtain 1.82 g (yield 86.5%) of the intermediate 2a as a white powdery solid.

[0051] Example 2 Synthesis of Intermediates 3a to 3e

[0052] (1) Synthesis of intermediate 3a

[0053] Dissolve 4-trifluoromethylnicotinic acid (200 mg, 1.05 mmol) in 5 mL of thionyl chloride and stir in an 80°C oil bath. After 1 hour, the reaction is complete as determined by TLC. Remove the thionyl chloride by distillation under reduced pressure to yield intermediate 3a, whose structural formula is as follows:

[0054] (2) Synthesis of intermediate 3b

[0055] 3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (200.0 mg, 0.66 mmol) was dissolved in 5 mL of thionyl chloride and stirred in an 80°C oil bath. After 1 hour, the reaction was complete as determined by TLC. The thionyl chloride was removed by distillation under reduced pressure to yield intermediate 3b, the structural formula of which is as follows:

[0056] (2) Synthesis of intermediate 3c

[0057] Dissolve 4-chlorobenzoic acid (200 mg, 1.28 mmol) in 5 mL of thionyl chloride and stir in an 80°C oil bath. After 1 hour, the reaction is complete as determined by TLC. Remove the thionyl chloride by distillation under reduced pressure to yield intermediate 3c, whose structural formula is as follows:

[0058] (3) Synthesis of intermediate 3d

[0059] Dissolve 2-thiophenecarboxylic acid (200 mg, 1.56 mmol) in 5 mL of thionyl chloride and stir in an 80°C oil bath. After 1 hour, the reaction is complete as determined by TLC. Remove the thionyl chloride by distillation under reduced pressure to yield intermediate 3d, whose structural formula is as follows:

[0060] (4) Synthesis of intermediate 3e

[0061] Dissolve 4-chloro-3-ethyl-1-methylpyrazole-5-carboxylic acid (200 mg, 1.06 mmol) in 5 mL of thionyl chloride and stir in an 80°C oil bath. After 1 hour, the reaction is complete as determined by TLC. Remove the thionyl chloride by distillation under reduced pressure to yield intermediate 3e, whose structural formula is as follows:

[0062] Example 3 Synthesis of Intermediates 4a to 4c

[0063] (1) Synthesis of intermediate 4a

[0064] BTC (166.17 mg, 0.56 mmol) was dissolved in 2 mL of dry dichloromethane. A dichloromethane solution of β-naphthylamine (200.00 mg, 1.40 mmol) and DIEA (36.19 mg, 0.28 mmol) was slowly added to the reaction flask at 0°C. After the addition was complete, the mixture was stirred at 0°C for 1 hour. The reaction was detected to be complete by TLC. The solvent and BTC were then removed by distillation under reduced pressure to obtain intermediate 4a, the structural formula of which is as follows:

[0065] (2) Synthesis of intermediate 4b

[0066] BTC (134.02 mg, 0.45 mmol) was dissolved in 2 mL of dry dichloromethane, and a dichloromethane solution of 4-trifluoromethoxyaniline (200.00 mg, 1.13 mmol) and DIEA (29.19 mg, 0.23 mmol) was slowly added at 0°C. After the addition was complete, the mixture was stirred at 0°C for 1 hour. After TLC detection, the reaction was complete, and the solvent and BTC were removed by distillation under reduced pressure to obtain intermediate 4b, the structural formula of which is as follows:

[0067] (3) Synthesis of intermediate 4c

[0068] 2-Amino-5-chlorobenzoic acid (2.00 g, 11.65 mmol) was dissolved in 15 mL of glacial acetic acid. NBS (2.49 g, 13.99 mmol) was slowly added at 0°C. After 2 h of reaction, the reaction was complete as determined by TLC. Ice water was added to precipitate the solid, which was filtered and dried to yield 2.23 g of Intermediate 2 as a brownish-yellow powder with a yield of 76.9%. Intermediate 2 (1.00 g, 4.02 mmol) was dissolved in 5 mL of thionyl chloride and stirred in an 80°C oil bath. After 1 h of reaction, the reaction was complete as determined by TLC. The thionyl chloride was removed by distillation under reduced pressure to yield Intermediate 3, which was used directly in the next reaction. Intermediate 3 (500 mg, 1.87 mmol) was dissolved in 5 mL of dichloromethane, and triethylamine (568.71 mg, 5.62 mmol) was added dropwise, followed by (1-cyclopropylethyl)amine hydrochloride (239.28 mg, 2.81 mmol). The reaction was allowed to proceed at room temperature for 3 h. After TLC analysis, the reaction was almost complete. The reaction was concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA=10:1→1:1) to obtain 398% brown powdery solid intermediate 4. BTC (77.03 mg, 0.25 mmol) was dissolved in 2 mL of dry dichloromethane, and a dichloromethane solution of intermediate 4 (200.00 mg, 0.63 mmol) and DIEA (16.77 mg, 0.13 mmol) was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 24 hours. The reaction was complete as determined by TLC. The solvent and BTC were then removed by distillation under reduced pressure to obtain intermediate 4c, whose structural formula is as follows:

[0069] Example 4 Synthesis of Intermediates 5a and 5b

[0070] (1) Synthesis of intermediate 5a

[0071] Ethyl chrysanthemate (2.00 g, 10.20 mmol) was dissolved in 20 mL of a 1:1 ethanol:water mixture and refluxed in an 85°C oil bath. Solid sodium hydroxide (2.35 g, 51.00 mmol) was added and allowed to react for 3 h. TLC confirmed the reaction was complete. The pH was adjusted to 4-5 with 6 mol / L HCl solution, concentrated under reduced pressure, dissolved in dichloromethane, and filtered to obtain 1.56 g (91.2% yield) of Intermediate 5. Intermediate 5 (200 mg, 1.19 mmol) was dissolved in 5 mL of thionyl chloride and stirred in an 80°C oil bath. After 1 h, the reaction was complete as determined by TLC. The thionyl chloride was removed by distillation under reduced pressure to obtain Intermediate 5a, whose structural formula is as follows:

[0072] (2) Synthesis of intermediate 5b

[0073] Dissolve 2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)cyclopropanecarboxylic acid (200 mg, 0.83 mmol) in 5 mL of thionyl chloride and stir in an 80°C oil bath. After 1 hour, the reaction was complete as determined by TLC. The thionyl chloride was removed by distillation under reduced pressure to yield intermediate 5b, the structural formula of which is as follows:

[0074] Example 5 Synthesis of Compounds I-1 to I-5

[0075] (1) Synthesis of Compound I-1

[0076] Intermediate 3b was dissolved in 2 mL of dry dichloromethane. Intermediate 2a (294.21 mg, 1.05 mmol) and TEA (318.74 mg, 3.15 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete as determined by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to yield 142.0 mg of I-1 (31.2% yield) as a light brown viscous liquid. 1 H NMR (400MHz, CDCl3) δ8.83(s,1H),8.80(d,J=5.1Hz,1H),7.56(d,J=5.2Hz,1H),3.70(s,3H),3.30(dd,J=13.6,9.1Hz,1H),2.97(dd,J=13.6,8.5 Hz,1H),2.82(t,J=9.9Hz,2H),2.43(td,J=7.1,2.4Hz,2H),2.00–1.67(m,13H),1.61–1.08(m,13H),0.95–0.81(m,2H).HRMS(AP-ESI):Calcd.For C 23 H 30 F3N3O3:454.2312(M+H) + .Found:454.2290. Its structural formula is as follows:

[0077] (2) Synthesis of Compound I-2

[0078] Intermediate 3b was dissolved in 2 mL of dry dichloromethane. Intermediate 2a (184.93 mg, 0.66 mmol) and TEA (194.28 mg, 1.92 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete as determined by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to yield 102.3 mg (27.5% yield) of I-2 as a pale yellow viscous liquid. 1 H NMR (400MHz, CDCl3) δ8.40(dd,J=4.7,1.5Hz,1H),7.90(dd,J=8.0,1.5Hz,1H),7.34(dd,J=8.0,4.7Hz,1H),6.62(s,1H),3.67(s,3H),2.76(d,J= 11.5Hz,2H),2.28(t,J=7.2Hz,2H),2.11–1.83(m,6H),1.75(d,J=13.8Hz,3H),1.62–1.13(m,15H),1.08–0.77(m,2H).HRMS(AP-ESI):Calcd.For C 25 H 31 BrClN5O3:564.1372(M+H) + .Found:564.0900. Its structural formula is as follows:

[0079] (3) Synthesis of Compound I-3

[0080] Intermediate 3c was dissolved in 2 mL of dry dichloromethane. Intermediate 2a (358.66 mg, 1.28 mmol) and TEA (388.60 mg, 3.84 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete as determined by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to yield 112.3 mg (21.0% yield) of I-3 as a pale yellow viscous liquid. 1H NMR (400MHz, CDCl3) δ7.41(d,J=8.5Hz,2H),7.37(d,J=8.6Hz,2H),3.68(s,3H),3.28(dd,J=13.0,8.0Hz,1H),2.76(dd,J=21.0,10.9Hz,2H),2.35( t,J=7.0Hz,2H),2.01(t,J=3.2Hz,2H),1.71(tdt,J=12.7,10.5,7.5Hz,1 3H), 1.41 (ddd, J=12.6, 10.7, 3.9Hz, 6H), 1.28 (s, 1H), 1.00–0.80 (m, 1H). 13 C NMR (101MHz, CDCl3) δ173.5,136.2,135.1,128.5,128.4,62.7,60.2,56.7,56.5 ,39.9,34.0,29.7,28.5,21.9,21.1,20.9,14.2,1.0.HRMS(AP-ESI):Calcd.For C 23 H 31 ClN2O3:419.2096(M+H) + .Found:419.2096. Its structural formula is as follows:

[0081] (4) Synthesis of Compound I-4

[0082] Intermediate 3d was dissolved in 2 mL of dry dichloromethane. Intermediate 2a (437.11 mg, 1.56 mmol) and TEA (473.57 mg, 4.68 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 215.2 mg (35.4% yield) of I-4 as a light brown viscous liquid. 1H NMR (400MHz, CDCl3) δ7.41(d,J=4.9Hz,1H),7.33(d,J=3.4Hz,1H),7.05–7.02(m ,1H),4.15–4.08(m,1H),3.88(dd,J=12.9,9.4Hz,1H),3.67(s,3H),3.60(dd,J= 13.1,7.3Hz,1H),2.80–2.70(m,2H),2.35(t,J=7.2Hz,2H),2.15–2.02(m,2H),1 .95–1.79(m,5H),1.76–1.53(m,8H),1.51–1.22(m,10H),0.89(d,J=7.2Hz,1H). Its structural formula is as follows:

[0083] (5) Synthesis of Compound I-5

[0084] Intermediate 3e was dissolved in 2 mL of dry dichloromethane. Intermediate 2a (297.01 mg, 1.06 mmol) and TEA (321.78 mg, 3.18 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 151.3 mg (31.7% yield) of I-5 as a light brown viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 4.61 (s, 1H), 3.80 (s, 3H), 3.67 (s, 3H), 3.57 (s, 1H), 3.36 (s, 1H), 2.63 (q, J = 7.6 Hz, 4H), 2.38 (dd, J = 15.0, 7.8 Hz, 2H), 2.11–1.69 (m, 9H), 1.64 (dd, J = 25.3, 16.2 Hz, 4H), 1.44 (dd, J = 13.9, 12.8 Hz, 5H), 1.25 (t, J = 7.6 Hz, 4H), 1.17–0.73 (m, 1H). Its structural formula is as follows:

[0085] Example 6 Synthesis of Compounds II-1 to II-3

[0086] (1) Synthesis of Compound II-1

[0087] Intermediate 4a was dissolved in 10 mL of dry dichloromethane. Intermediate 2a (292.28 mg, 1.40 mmol) and TEA (283.33 mg, 2.80 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete as determined by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 234.5 mg of II-1 as a brown viscous liquid (yield 44.3%). 1 H NMR(400MHz,d6-DMSO)δ8.71(s,1H),7.99(d,J=1.8Hz,1H),7.80–7.70(m,3H),7.57( dd,J=8.9,2.1Hz,1H),7.46–7.37(m,1H),7.37–7.24(m,1H),3.79(td,J=10.2,5.0Hz ,1H),3.60(t,J=6.8Hz,1H),3.56(s,3H),3.49(dd,J=13.6,6.1Hz,1H),2.68(dd,J=1 3.4,7.4Hz,2H),2.31(dd,J=14.6,7.2Hz,2H),2.07–1.91(m,2H),1.90–0.98(m,18H). 13 C NMR (101MHz, CDCl3) δ173.8,156.3,138.4,121.6,120.6,63.3,60.3,56.7,55.2,47.0 ,38.9,35.1,34.1,31.5,29.7,28.1,28.0,21.7,21.0,14.2.HRMS(AP-ESI):Calcd.For C 27 H 35 N3O3:450.2751(M+H) + .Found:564.2749. Its structural formula is as follows:

[0088] (2) Synthesis of Compound II-2

[0089] Intermediate 4b was dissolved in 10 mL of dry dichloromethane. Intermediate 2a (316.63 mg, 1.13 mmol) and TEA (228.69 mg, 2.26 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete as determined by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 201.2 mg of II-2 as a brown viscous liquid (yield 36.8%). 1H NMR(400MHz,d6-DMSO)δ8.66(s,1H),7.53(d,J=9.1Hz,2H),7.21(d,J=8.4Hz,2H),3.83–3.73(m,1H),3 .57(s,3H),3.42(dd,J=13.6,6.4Hz,1H),2.67(t,J=9.5Hz,2H),2.42–2.19(m,2H),2.10–1.11(m,19H). 13 C NMR(101MHz,d6-DMSO)δ173.84,156.3,142.7,140.7,121.5,120.8,63.3,56.7,54.4,51 .6,46.9,38.9,35.3,33.7,31.1,28.5,28.3,22.1,21.2,21.1.HRMS(AP-ESI):Calcd.For C 24 H 32 F3N3O4:484.2418(M+H) + .Found:484.2419. Its structural formula is as follows:

[0090] (3) Synthesis of Compound II-3

[0091] Intermediate 4c was dissolved in 10 mL of dry dichloromethane. Intermediate 2a (176.53 mg, 0.63 mmol) and TEA (127.50 mg, 1.26 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete as determined by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 140.1 mg of II-3 as a brown viscous liquid (yield 35.8%). 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.5 Hz, 1H), 7.53 (ddd, J = 7.4, 4.3, 2.7 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 3.68 (s, 3H), 3.38 (dd, J = 13.2, 6.8 Hz, 1H), 2.81 (s, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.22–1.40 (m, 30H), 1.33–1.23 (m, 6H). Its structural formula is as follows:

[0092] Example 7 Synthesis of Compounds III-1 to III-2

[0093] (1) Synthesis of Compound III-1

[0094] Intermediate 2a (200.00 mg, 0.71 mmol) and cesium carbonate (700.00 mg, 2.14 mmol) were dissolved in 10 mL of acetonitrile and stirred at room temperature for 30 minutes. 2-Chloro-5-chloromethylpyridine (231.69 mg, 1.43 mmol) was then added and allowed to react with stirring at room temperature. After 9 hours, the reaction was nearly complete as determined by TLC. The stirring reaction was stopped and the acetonitrile solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 60:1) to obtain 115.3 mg of III-1 as a brown viscous liquid (40.1% yield). 1 H NMR (400MHz, CDCl3) δ8.32(d,J=2.2Hz,1H),7.69(dd,J=8.2,2.3Hz,1H),7.29(d,J=8.1Hz,1H),4.07(d,J=13.8Hz,1H),3.65(s,3H),3 .14(d,J=13.8Hz,1H),2.64(s,5H),2.35–2.20(m,4H),1.96(ddd,J=34.5,25.0,10.0Hz,6H),1.83–1.62(m,12H),1.53–1.24(m,10H). 13 C NMR (101 MHz, CDCl3) δ 174.0, 151.3, 141.9, 138.2, 64.3, 57.5, 57.2, 56.3, 52.2, 51.5, 48.2, 37.8, 33.9, 28.1, 28.1, 27.1, 21.5, 21.2, 18.7. Its structural formula is as follows:

[0095] (2) Synthesis of Compound III-2

[0096] Intermediate 2a (200.00 mg, 0.71 mmol) and cesium carbonate (700.00 mg, 2.14 mmol) were dissolved in 10 mL of acetonitrile and stirred at room temperature for 30 minutes. 2-Chloro-5-chloromethylthiazole (239.89 mg, 1.43 mmol) was then added and allowed to react with stirring at room temperature. After 9 hours, the reaction was nearly complete as determined by TLC. The stirring reaction was stopped and the acetonitrile solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 60:1) to obtain 105.2 mg of III-2 as a brown viscous liquid (yield 36.0%). 1H NMR(400MHz, CDCl3)δ7.35(s,1H),4.10(d,J=14.5Hz,1H),3.68(s,3H),3.49(d,J=14.6Hz,1H),2.99–2.7 2(m,4H),2.38(dt,J=13.5,5.4Hz,3H),1.82(dddd,J=28.8,19.9,18.3,14.4Hz,15H),1.54–1.30(m,10H). 13 C NMR (101 MHz, CDCl3) δ 174.0, 173.1, 149.8, 139.2, 139.1, 138.9, 134.9, 124.2, 123.9, 64.3, 62.6, 57.5, 57.3, 52.9, 52.1, 51.5, 37.98, 34.0, 33.9, 28.4, 28.0, 27.2, 21.5, 21.3, 19.0. Its structural formula is as follows:

[0097] Example 8 Synthesis of Compounds IV-1 to IV-4

[0098] (1) Synthesis of Compound IV-1

[0099] Intermediate 2a (200.00 mg, 0.71 mmol) and triethylamine (236.00 mg, 0.535 mmol) were dissolved in 10 mL of DCM and stirred at room temperature for 30 minutes. 2,3,4,5,6-pentafluorobenzenesulfonyl chloride (285.00 mg, 1.07 mmol) was then added and allowed to react with stirring at room temperature. After 5 hours, the reaction was nearly complete as determined by TLC. The stirring reaction was stopped and the solvent, acetonitrile, was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 168.2 mg of IV-1 as a pale yellow powdery solid (yield 46.2%). 1 H NMR (400 MHz, CDCl3) δ 3.87 (s, 1H), 3.65 (s, 3H), 3.57 (t, J = 12.2 Hz, 1H), 3.14 (d, J = 7.3 Hz, 1H), 2.72 (s, 2H), 2.39–2.15 (m, 3H), 2.05–1.20 (m, 26H). The structural formula is as follows:

[0100] (2) Synthesis of Compound IV-2

[0101] Intermediate 2a (200.00 mg, 0.71 mmol) and triethylamine (236.00 mg, 0.535 mmol) were dissolved in 10 mL of DCM and stirred at room temperature for 30 minutes. 2-Naphthalenesulfonyl chloride (242.55 mg, 1.07 mmol) was then added and allowed to react with stirring at room temperature. After 5 hours, the reaction was nearly complete as determined by TLC. The stirring reaction was stopped and the solvent, acetonitrile, was distilled off under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 125.3 mg (yield 37.5%) of IV-2 as a pale yellow viscous liquid. 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.92 (ddd, J = 30.7, 16.9, 8.4 Hz, 5H), 7.67–7.57 (m, 2H), 3.73–3.60 (m, 3H), 3.58 (s, 3H), 3.37 (t, J = 11.8 Hz, 1H), 2.58 (dd, J = 29.1, 10.7 Hz, 3H), 2.33–2.10 (m, 4H), 2.06 (s, 3H), 1.99–1.76 (m, 8H), 1.70 (s, 3H), 1.63–1.22 (m, 12H). Its structural formula is as follows:

[0102] (3) Synthesis of Compound IV-3

[0103] Intermediate 2a (200.00 mg, 0.71 mmol) and triethylamine (236.00 mg, 0.535 mmol) were dissolved in 10 mL of DCM and stirred at room temperature for 30 minutes. 4-Isopropylbenzenesulfonyl chloride (234.00 mg, 1.07 mmol) was then added and allowed to react with stirring at room temperature. After 5 hours, the reaction was nearly complete as determined by TLC. The stirring reaction was stopped and the solvent, acetonitrile, was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 106.5 mg (yield 32.4%) of IV-3 as a pale yellow viscous liquid. 1H NMR (400MHz, CDCl3) δ7.78(d,J=8.3Hz,2H),7.34(d,J=8.3Hz,2H),3.66(s,3H),3.63–3.50(m,2H),3.30(t,J=11.7Hz,1H),2.99(dt,J= 13.8,6.9Hz,1H),2.64(dd,J=23.0,11.4Hz,2H),2.32–2.11(m,3H),2.04(d,J=20.8Hz,3H),1.96–1.76(m,8H),1.74–1.54(m,11H),1.43(ddd,J=17.7,15.0,8.8Hz,6H),1.30(s,4H),1.28(s,5H). Its structural formula is as follows:

[0104] (4) Synthesis of Compound IV-4

[0105] Intermediate 2a (200.00 mg, 0.71 mmol) and triethylamine (236.00 mg, 0.535 mmol) were dissolved in 10 mL of DCM and stirred at room temperature for 30 minutes. 3-Pyridinesulfonyl chloride (190.04 mg, 1.07 mmol) was then added and allowed to react with stirring at room temperature. After 5 hours, the reaction was nearly complete as determined by TLC. The stirring reaction was stopped and the solvent, acetonitrile, was distilled off under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 101.6 mg (yield 34.0%) of IV-4 as a pale yellow viscous liquid. 1 H NMR (400 MHz, CDCl3) δ9.08 (d, J = 1.9 Hz, 1H), 8.85–8.69 (m, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.1, 4.8 Hz, 1H), 4.11 (s, 3H), 3.59 (d, J = 55.8 Hz, 2H), 3.21 (dq, J = 68.3, 7.2 Hz, 2H), 2.60 (d, J = 48.3 Hz, 3H), 2.40–1.95 (m, 5H), 1.95–1.47 (m, 12H), 1.47–1.04 (m, 8H). Its structural formula is as follows:

[0106] Example 9 Synthesis of Compound V-1

[0107] Intermediate 2a (200.00 mg, 0.71 mmol) and triethylamine (236.00 mg, 0.535 mmol) were dissolved in 10 mL of DCM and stirred at room temperature for 30 minutes. p-Nitrophenyl chloroformate (215.67 mg, 1.07 mmol) was then added and allowed to react with stirring at room temperature. After 5 hours, the reaction was nearly complete as determined by TLC. The stirring reaction was stopped and the solvent, acetonitrile, was distilled off under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 125.3 mg of V-1 as a pale yellow viscous liquid (yield 39.6%). 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 9.1 Hz, 2H), 8.15 (d, J = 9.1 Hz, 2H), 7.26 (d, J = 9.1 Hz, 2H), 6.88 (d, J = 9.1 Hz, 2H), 4.08 (s, 1H), 3.70 (s, 3H), 2.76 (s, 4H), 2.51–2.28 (m, 2H), 2.13–1.66 (m, 11H), 1.65–1.39 (m, 8H), 1.37–1.13 (m, 2H), 1.13–0.82 (m, 1H). Its structural formula is as follows:

[0108] Example 10 Synthesis of Compounds VI-1 to VI-2

[0109] (1) Synthesis of Compound VI-1

[0110] Intermediate 5a was dissolved in 2 mL of dry dichloromethane. Intermediate 2a (333.44 mg, 1.19 mmol) and TEA (240.83 mg, 2.38 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 195.2 mg of VI-1 (38.1% yield), a pale yellow viscous liquid. 1H NMR (400MHz, CDCl3) δ4.93(d,J=6.5Hz,1H),3.67(s,3H),2.77–2.58(m,2H),2.35(t,J=7.5Hz,2H),2.10(ddd,J=42.6,25.2,16.9Hz,6H),1.73( s,6H),1.43(ddd,J=15.5,9.2,4.4Hz,9H),1.32(s,2H),1.28(s,6H),1.23–1.06(m,9H),0.88(dt,J=9.8,6.5Hz,4H).HRMS(AP-ESI):Calcd.For C 26 H 42 N2O3:431.3268(M+H) + .Found:431.3270. Its structural formula is as follows:

[0111] (2) Synthesis of Compound VI-2

[0112] Intermediate 5b was dissolved in 2 mL of dry dichloromethane. Intermediate 2a (184.93 mg, 0.83 mmol) and TEA (194.28 mg, 1.66 mmol) were added at room temperature. The reaction was stirred at room temperature. After 3 hours, the reaction was complete by TLC. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 200:1 → 100:1) to obtain 113.7 mg (yield 27.2%) of VI-2 as a pale yellow viscous liquid. 1 H NMR(400MHz, CDCl3) δ6.96(t,J=9.5Hz,1H),4.12(dt,J=31.8,15.9Hz,1H),3.67(s,3H),2.84(d,J=14.5Hz, 2H),2.34(t,J=6.7Hz,2H),2.22–2.12(m,2H),2.09–1.98(m,4H),1.96–1.83(m,4H),1.74(s,3H),1.67–1.49 (m,7H),1.47–1.42(m,2H),1.33(dd,J=8.6,5.6Hz,9H),1.28–1.25(m,1H),1.25(d,J=5.7Hz,2H),1.19(s,1H).HRMS(AP-ESI):Calcd.For C 26 H 42 N2O3:505.2439(M+H) + .Found:505.2441. Its structural formula is as follows:

[0113] Example 11 Synthesis of Compounds VII-1 to VII-4

[0114] (1) Synthesis of Compound VII-1

[0115] Intermediate 2a (500.0 mg, 1.78 mmol) was dissolved in 10 mL of acetonitrile and stirred at room temperature for 30 minutes. 4-Trifluoromethylbenzyl bromide (853.33 mg, 3.57 mmol) was then added and allowed to react with stirring at room temperature. After 4.5 hours, the reaction was nearly complete as determined by TLC. Stirring was discontinued and the acetonitrile solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 60:1) to obtain VII-1 as a pale yellow powder (270.2 mg, 41.6% yield). 1 H NMR (400MHz, d6-DMSO) δ7.67(d,J=6.5Hz,2H),7.54(d,J=7.1Hz,2H),4.08(d,J=14.0Hz,1H ),3.53(s,2H),3.33(s,3H),3.21(d,J=13.6Hz,1H),3.02–2.59(m,3H),2.34–0.58(m,19H). 13 C NMR (101MHz, CDCl3) δ174.0,145.0,128.9,128.6,125.7,125.1,125.1,123.0,64.4,57.6,57.3, 57.3,56.2,52.4,51.4,38.0,34.1,28.5,28.1,27.3,21.6,21.3,19.0.HRMS(AP-ESI):Calcd.For C 24 H 33 F3N2O2:439.2567(M+H) + .Found:439.2559. Its structural formula is as follows:

[0116] (2) Synthesis of Compound VII-2

[0117] Intermediate 2a (500.0 mg, 1.78 mmol) was dissolved in 10 mL of acetonitrile and stirred at room temperature for 30 minutes. 2-Nitrobenzyl bromide (771.23 mg, 3.57 mmol) was then added and allowed to react with stirring at room temperature. After 5 hours, the reaction was nearly complete as determined by TLC. Stirring was discontinued and the acetonitrile solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 60:1) to yield VII-2 as a brownish-red viscous liquid (256.8 mg, 34.74% yield). 1 H NMR (400MHz, d6-DMSO) δ7.85 (dd, J=8.0, 1.1Hz, 1H), 7.76 (d, J=7.0Hz, 1H), 7.68 (td, J=7.6 ,1.1Hz,1H),7.52–7.45(m,1H),4.20(d,J=15.5Hz,1H),3.52(s,3H),3.40(d,J=15.4Hz,1H) ,2.84(d,J=10.5Hz,1H),2.77–2.62(m,3H),2.20–2.12(m,2H),2.08(dd,J=11.3,3.8Hz,1H) ,1.97(s,1H),1.79(dt,J=28.7,12.8Hz,4H),1.62–1.20(m,13H).HRMS(AP-ESI):Calcd.For C 23 H 33 N3O4:416.2544(M+H) + .Found:416.2533. Its structural formula is as follows:

[0118] (3) Synthesis of Compound VII-3

[0119] Intermediate 2a (500.0 mg, 1.78 mmol) was dissolved in 10 mL of acetonitrile and stirred at room temperature for 30 minutes. Benzyl bromide (610.58 mg, 3.57 mmol) was then added and allowed to react with stirring at room temperature. After 4.5 hours, the reaction was nearly complete as determined by TLC. Stirring was discontinued and the acetonitrile solvent was removed under reduced pressure to afford the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 60:1) to afford VII-3 as a pale yellow powder (213.5 mg, 32.4% yield). 1H NMR (400MHz, CDCl3) δ7.42–7.29(m,H),7.26–7.19(m,1H),4.11(d,J=13.1Hz,1H),3.65(s,3H),3.13(d,J=13.3Hz,1H),2. 93–2.53(m,5H),2.33(dd,J=24.6,7.2Hz,5H),2.17–1.86(m,6H),1.45(ddd,J=30.0,20.8,11.8Hz,9H),0.95–0.78(m,7H). 13 C NMR (101MHz, CDCl3) δ173.6,149.5,136.2,132.7,130.39,127.1,124.1,64.4,60.1,57.5,57.4,57. 3,53.0,52.4,38.1,34.4,33.6,28.7,28.1,27.1,21.53,21.3,19.8,14.2.HRMS(AP-ESI):Calcd.For C 23 H 34 N2O2:371.2693(M+H) + .Found:371.2674. Its structural formula is as follows:

[0120] (4) Synthesis of Compound VII-4

[0121] Intermediate 2a (500.0 mg, 1.78 mmol) was dissolved in 10 mL of acetonitrile and stirred at room temperature for 30 minutes. 4-Chlorobenzyl iodide (899.35 mg, 3.57 mmol) was then added and allowed to react with stirring at room temperature. After 4.5 hours, the reaction was nearly complete as determined by TLC. Stirring was discontinued and the acetonitrile solvent was distilled off under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 200:1 → 60:1) to obtain VII-4 as a pale yellow powdery solid (289.3 mg, 40.2% yield). 1 H NMR (400 MHz, d6-DMSO) δ7.39 (d, J = 8.5 Hz, 4H), 4.05 (d, J = 40.3 Hz, 1H), 3.61–3.48 (m, 3H), 3.18 (s, 2H), 2.89 (d, J = 9.4 Hz, 2H), 2.74 (s, 1H), 2.60 (s, 1H), 2.33 (s, 3H), 2.01–1.81 (m, 3H), 1.82–0.96 (m, 13H). Its structural formula is as follows:

[0122] Test Example 1 Insecticidal activity of matrine derivatives against aphids

[0123] 1. Experimental Methods

[0124] (1) Take a broad bean leaf with stems, trim it into a suitable shape, place it in a moistened sponge, and then cover it with a box for later use. Place 10 wingless adult aphids (shinny black and large) on a 6-10 cm young broad bean leaf. Remove the adult aphids after 24 hours, and then incubate for another 48 hours before treating with the pesticide (ambient temperature around 25°C).

[0125] (2) Use the spray method and spray the pesticide according to different settings (as shown in Table 1) to moisten the entire broad bean plant. After spraying, use filter paper to absorb the excess filtrate and place a piece of filter paper at the root (to prevent the insects from falling into the water and drowning). Let it dry for a period of time and place it in an environment with suitable temperature and humidity (about 25°C) for cultivation.

[0126] (3) Investigation time and method: 48 hours after the application of the drug, gently poke the aphids with a brush. If the aphids do not move, they can be judged as dead.

[0127] (4) Calculation method: Based on the survey data, calculate the prevention effect of each treatment according to formulas ①, ② and ③, and retain the calculation results to two decimal places.

[0128] Table 1 Experimental design of the test agents with aphid-killing activity

[0129] 2. Experimental Results

[0130] As shown in Table 2, compounds I-4 and III-2 exhibited the best aphidicide activity. At a concentration of 2 mg / mL, the corrected lethality rates for aphids over 48 hours were 94.07% and 92.57%, respectively. These results demonstrate higher insecticidal activity than any other matrine derivative reported to date. Compound I-5 also exhibited significant insecticidal activity against aphids, achieving a corrected lethality rate of 73.3%.

[0131] Table 2 Results of 48h insecticidal activity test of matrine derivatives against broad bean aphids

[0132] The structures of compounds I-4, I-5 and III-2 were analyzed, and it was found that the introduction of a five-membered ring group at the secondary amine of the active skeleton 2a of matrine can greatly enhance the insecticidal activity of matrine against aphids. Compared with matrine, the insecticidal activity against aphids has been greatly improved by 3-4 times.

[0133] From the insecticidal activity data of amide series derivatives (Ⅰ-1~Ⅰ-5), urea series derivatives (Ⅱ-1~Ⅱ-3) and pyrethroid series derivatives (Ⅵ-1~Ⅵ-2), it can be seen that the introduction of a carbonyl group at the 16-N position has a greater effect on the activity of matrine derivatives. Among these series, the insecticidal activity is basically about twice that of matrine.

[0134] However, the activity data of the sulfonamide series derivatives (Ⅳ-1 to Ⅳ-4) show that the introduction of a sulfonyl group at the 16-N position has little effect on the insecticidal activity of matrine derivatives; and, based on the activity data of derivatives I-2, II-1 and IV-2, the introduction of a polycyclic structure at the secondary amine of the matrine active skeleton 2a will significantly reduce the insecticidal activity of matrine derivatives against broad bean aphids.

[0135] In addition, the activity of the pyrethroid derivative VI-1 is comparable to the insecticidal activity of matrine. We speculate that this is because pyrethroids themselves have a high degradation ability. In previous studies, the effect of pyrethroids themselves was slightly lower because of their own high degradation ability, which resulted in the degradation of pyrethroids before they had any insecticidal effect. The application of matrine derivative V-1 caused the broad bean plants to turn black and rot. Analysis showed that the reason may be that p-nitrophenoxy is an active leaving group in this compound, which is highly toxic to the plants after leaving.

[0136] Test Example 2 Insecticidal activity of matrine derivatives against Tetranychus cinnabarinus

[0137] 1. Experimental Methods

[0138] (1) Select broad bean leaves of uniform growth and use a hole punch to create leaf discs with a radius of 1-1.5 cm. Place three leaf discs per dish. Place filter paper in the dish, wet it, and then place the leaf discs on the filter paper. Set aside. Inoculate the prepared leaf discs with adult Tetranychus cinnabarinus mites reared indoors, 20 per dish. Record the base number before treatment.

[0139] (2) Use a spraying method. Use a spray bottle to allow the solution to settle on the leaf disc. After the leaf disc is dry, cover it with a culture dish. Keep the filter paper moist during the incubation process. After 3 days, investigate the mortality of spider mites.

[0140] (3) Investigation time and method: 72 hours after the drug application, use a brush to gently poke the cinnabarinus mite under a microscope. If the cinnabarinus mite does not move, it can be determined to be dead.

[0141] (4) The calculation method refers to Test Example 1.

[0142] Table 3 Experimental design of acaricide activity

[0143] 2. Experimental Results

[0144] The results, shown in Table 4, show that matrine derivative VII-3 exhibited the best acaricidal activity. At a concentration of 2 mg / mL, its adjusted lethality against T. cinnabarinus reached 98% over 72 hours. This is 20 times the adjusted lethality of matrine at the same concentration and higher than all currently reported matrine derivatives. A comparison with derivatives VII-1, VII-2, and VII-4 reveals that the addition of substituents to the benzene ring reduced their acaricidal activity against T. cinnabarinus.

[0145] Table 4 Results of the 72h acaricidal activity test of matrine derivatives against Tetranychus cinnabarinus

[0146] The present invention synthesized 21 matrine derivatives in multiple series, including amides, ureas, neonicotinoids, sulfonamides, carbamates and pyrethroids, and 1 H NMR, 13 The structures were determined by C NMR and HRMS, and the insecticidal activities of these new compounds against different types of pests were determined. It was finally found that compound I-4 and compound III-2 exhibited extremely high aphidicide activity, while VII-3 exhibited the best acaricide activity.

[0147] Experimental Example 3 Effects of Matrine Derivatives on Enzyme Activities Related to Tumors / Central Degenerative Diseases / Cardiovascular Diseases

[0148] 1. Experimental Methods

[0149] 1. Prepare 5mM and 0.5mM compound solutions

[0150] For a compound sample with a concentration of 10 mM, mix it with DMSO at a ratio of 1:1 and shake it with a vortex shaker to obtain a 5 mM compound solution. For a compound sample with a concentration of 5 mM, mix it with DMSO at a ratio of 1:10 and shake it with a vortex shaker to obtain a 0.5 mM compound solution.

[0151] For a sample concentration of 100 mM, mix the compound with DMSO at a ratio of 1:19 and shake well using a vortex shaker to obtain a 5 mM compound solution. For a positive compound with a concentration of 100 mM, use this method to prepare a 5 mM solution.

[0152] A 5 mM compound solution was mixed with DMSO at a ratio of 1:10 and mixed using a vortex shaker to obtain a 0.5 mM compound solution.

[0153] 2. Experimental steps

[0154] (1) Adding compounds: Based on the previous insecticidal activity screening, five compounds 1 (I-4), 2 (I-5), 3 (III-2), 4 (IV-2), 5 (VII-3) and 6 (matrine) were selected as comparison objects for enzyme activity detection. 1.2 μL of compound solution of different concentrations was added to a 96-well plate. Each concentration of compound had three replicate wells. The replicate wells corresponding to 100 μM were in rows A, B, and C, and the replicate wells corresponding to 10 μM were in rows D, E, and F. Row G was a blank well of 100 μM, and row H was a blank well of 10 μM, which was used to eliminate the error caused by the fluorescence of the compound itself. The positive compound for Sirt 5 was MLH-0719. There was no positive compound for Sirt1, Sirt2, and Sirt3, so no positive well was set. 1.2 μL of DMSO was added to the control well. The specific sequence is shown in Table 5, where the black box represents the area of ​​the 96-well plate, and the number in the 96-well plate is the number of the added sample.

[0155] Table 5 Order of compound addition in 96-well plate

[0156] (2) Add 38.5 μL of buffer. The buffers used for different enzyme systems are shown in Table 6. There are four types of enzymes used in this activity screening.

[0157] Table 6 Buffer and substrate conditions of different enzyme systems

[0158] (3) Add 10 μL of enzyme solution. For details of the enzyme solution, see Table 6. Incubate on a shaker for 10 min.

[0159] (4) Add NAD + 10 μL of the mixed solution with the substrate (for specific substrate conditions, see Table 6) was added and incubated for 2 h.

[0160] (5) Add 50 μL of terminator and incubate for 30 min.

[0161] (6) Data Processing: For each well, the inhibition rate of the compound in that well was calculated by subtracting the difference between the fluorescence intensity of the well and the blank fluorescence intensity from 100, multiplying the result by 100% and dividing the result by the average fluorescence intensity of the control and the blank fluorescence intensity (control value). After removing results with significant deviations, the average value was calculated.

[0162] 2. Experimental Results

[0163] The average inhibition rate of each sample on different enzymes is shown in Table 7:

[0164] Table 7

[0165] The six compounds showed no promoting or inhibiting activity against Sirt3 or Sirt5. However, among Sirt1 compounds, I-5 inhibited Sirt1 activity, with inhibition rates of 98.1% at 100 μM and 83.2% at 10 μM. Among Sirt2 compounds, III-2 inhibited Sirt2 activity, with inhibition rates of 92.5% at 100 μM and 34.8% at 10 μM, indicating its potential for the treatment of tumors and central nervous system degenerative diseases.

[0166] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Anyone skilled in the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by one of ordinary skill in the art without departing from the spirit and technical principles disclosed herein are intended to be covered by the claims of the present invention.

Claims

1. A matrine derivative, characterized in that: Having the structure shown in formula I or its stereoisomers or cis-trans isomers, solvates, hydrates or pharmaceutically acceptable salts or cocrystals: Z is selected from alkyl, heteroalkyl, acyl, ester, sulfonyl, amide, sulfonamide; Ring A is a 3- to 6-membered ring, and Ring A is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl; R is independently selected at each occurrence from hydrogen, halogen, cyano, =O, hydroxyl, -NH2, carboxyl, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, substituted or unsubstituted 3-12 membered cycloalkyl, substituted or unsubstituted 3-12 membered heterocycloalkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ester, acyl, amide, sulfinyl, sulfonyl, sulfonamide, sulfinamide, or any two R's and the atoms connected thereto form a substituted or unsubstituted 3-12-membered hydrocarbon ring, or a substituted or unsubstituted 3-12-membered heterohydrocarbon ring; n is selected from 1, 2, and 3.

2. The matrine derivative according to claim 1, characterized in that R is selected from the following groups:

3. The matrine derivative according to claim 1, characterized in that The compound represented by formula I is selected from the following compounds:

4. The matrine derivative according to claim 1, characterized in that The compound represented by formula I is selected from the following compounds:

5. The method for preparing the matrine derivative according to any one of claims 1 to 4, characterized in that: The synthetic route is as follows: Z1 is selected from hydrogen, halogen, cyano, =O, hydroxyl, -NH2, carboxyl, ester, acyl, amide, sulfinyl, sulfonyl, sulfonamide, sulfinamide.

6. The preparation method according to claim 5, characterized in that: The Z is selected from acyl, ester, and sulfonyl, and the base is an organic base; further, the organic base is selected from triethylamine, dimethylamine, aniline, and pyridine; further, the organic base is triethylamine; Or Z is a C1-C6 alkyl group, and the base is an inorganic base; further, the inorganic base is selected from one or more of carbonates, acetates, phosphates, and organic bases, preferably carbonates; further, the base is selected from one of Li2CO3, Na2CO3, K2CO3, Ru2CO3, Cs2CO3, or hydrates thereof. or several, preferably Na2CO3, K2CO3, Cs2CO3 and / or their hydrates.

7. Use of the matrine derivative according to any one of claims 1 to 4 in the preparation of insecticide products.

8. Use of the matrine derivative according to claim 3 in the preparation of a product for controlling piercing-sucking mouthpart pests.

9. Use of the matrine derivative according to claim 4 in the preparation of a product for controlling mites.

10. Use of the matrine derivative according to any one of claims 1 to 4 in the preparation of a product for inhibiting Sirt activity.

11. The use according to claim 11, characterized in that: The product is a product that inhibits the activity of Sirt1 and / or Sirt2.

12. Use of the matrine derivative according to any one of claims 1 to 4 in the preparation of a product for treating and / or preventing at least one of tumors, neurodegenerative diseases and cardiovascular diseases.

Images