Berberine derivative as well as preparation method and application thereof

Abstract

The invention provides a berberine derivative as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. According to the derivative, an acyl acetophenone substituent group is introduced to the 9 site of berberine, and a series of 9-site substituted berberine compounds are specifically designed and synthesized. In-vitro antimicrobial activity detection shows that the compounds have excellent inhibitory activity on gram-positive bacteria (staphylococcus aureus and methicillin-resistant staphylococcus aureus) and gram-negative bacteria (escherichia coli, shigella flexneri, shigella dysenteriae and vibrio parahaemolyticus), can be used for preparing antibacterial drugs, do not have obvious drug resistance, and can be used for preparing antibacterial drugs. And a more efficient and safer candidate drug can be provided for the treatment of clinical diarrhea related diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a berberine derivative and a preparation method thereof, and further relates to application of the compound as an antibacterial drug, particularly a diarrhea drug. BACKGROUND

[0002] Diarrhea is divided into acute and chronic, 80% of acute diarrhea is caused by intestinal infection, also known as infectious diarrhea, and main infection pathogens include bacteria, viruses, fungi, parasites, etc.

[0003] Berberine, also known as coptis, is an isoquinoline alkaloid extracted from coptis and Chinese cinnamon, etc. Its unique fused ring aromatic hydrocarbon structure can interact with many enzymes, proteins and other active sites in the body, thus showing multiple biological activities. At present, in clinical practice, berberine is generally used in the form of its hydrochloride to treat gastrointestinal infections, and has definite efficacy and good safety.

[0004] Berberine has a broad antibacterial spectrum, and can inhibit or kill various gram-positive bacteria, gram-negative bacteria, fungi, molds, viruses, protozoa and nematodes. As a broad-spectrum antibiotic, berberine has the antibacterial characteristics of high-concentration bactericidal and low-concentration bacteriostatic. Traditionally, berberine is considered to be a multi-target compound, which can act on multiple pathways of bacterial metabolism, interfere with the metabolism of sugar, fat, amino acid, nucleic acid and protein, destroy cell membrane and cell wall, and prevent the formation of bacterial biofilm, and make bacteria not easy to develop resistance to berberine. Moreover, berberine has poor water solubility and low oral exposure. After oral administration, the drug concentrates in the gastrointestinal tract to exert effect, and has good efficacy.

[0005] However, studies have shown that the antibacterial effect of berberine has limitations. The antibacterial activity of berberine is not strong against various diarrhea-causing bacteria such as Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Escherichia coli, Shigella flexneri, Shigella dysenteriae and Vibrio parahaemolyticus, and the efficacy of berberine against diarrhea caused by different bacteria also differs. SUMMARY

[0006] Therefore, the purpose of the present application is to provide a berberine derivative and a preparation method thereof, and application of the berberine derivative as an antibacterial drug, particularly a diarrhea drug. The present application improves the antibacterial activity of berberine against various diarrhea-causing bacteria (Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Escherichia coli, Shigella flexneri, Shigella dysenteriae and Vibrio parahaemolyticus) by modifying the structure of berberine, while maintaining the characteristics of oral non-absorption and concentration in the gastrointestinal tract, thereby improving the effect of berberine on treating bacterial infectious diarrhea.

[0007] To achieve the above purpose, the present application adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a berberine derivative having the structure of Formula I:

[0009] Formula I;

[0010] Wherein, R is selected from C1~C10 straight-chain alkyl, C3~C10 branched alkyl, C1~C10 alkoxy, C3~C10 carbocyclic, C4~C10 heterocyclic, C6~C10 aromatic or C5~C10 heteroaryl, -NR1R2.

[0011] R1 and R2 are each independently selected from C1-C10 straight-chain alkyl groups or C3-C10 branched alkyl groups; the substitution position of R is ortho, meta, or para.

[0012] Preferably, R is selected from C1-C6 straight-chain alkyl, C3-C6 branched alkyl, C1-C6 alkoxy, C3-C8 carbocyclic, C4-C8 heterocyclic, C6-C8 aromatic, or C5-C8 heteroaryl or -NR1R2.

[0013] Preferably, the position of R is aligned.

[0014] More preferably, the berberine derivative is selected from any one of the following formulas:

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021] .

[0022] More preferably, the berberine derivative is selected from any one of the following formulas:

[0023]

[0024] Preferably, the berberine derivative is selected from any one of the following formulas:

[0025] .

[0026] Secondly, the present invention provides a method for preparing the above-mentioned berberine derivative, comprising the following steps:

[0027] The compound shown in Formula A, the compound shown in Formula B, a basic substance, and an organic solvent are mixed and reacted to obtain a berberine derivative having the structure of Formula I.

[0028] Formula A; Formula B.

[0029] Preferably, the organic solvent is selected from any one or more of acetonitrile, DMF, DMSO or dioxane.

[0030] Preferably, the alkaline substance is selected from any one or more of potassium carbonate, cesium carbonate, or sodium carbonate.

[0031] Preferably, the reaction temperature is from room temperature to 80°C, and the reaction time is 1 to 16 hours, more preferably 4 to 12 hours, and even more preferably 6 to 8 hours. Room temperature refers to a temperature of 15 to 30°C, preferably 20 to 25°C.

[0032] Thirdly, the present invention provides an application of the above-mentioned berberine derivative in the preparation of antibacterial drugs.

[0033] Fourthly, the present invention provides an antibacterial drug comprising the berberine derivatives involved in the above-mentioned technical solutions and pharmaceutically acceptable excipients.

[0034] Preferably, the bacteria inhibited by the antibacterial drug include, but are not limited to, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Shigella flexneri, Shigella dysenteriae, or Vibrio parahaemolyticus.

[0035] Preferably, the minimum inhibitory concentration (MIC) of the antibacterial drug is 1~200 μg / mL.

[0036] Preferably, the antibacterial drug can be administered orally, including but not limited to oral administration.

[0037] In this invention, the antibacterial drug can be used specifically for diarrhea, but it should be noted that it is not intended for treatment.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0039] (1) The present invention provides a berberine derivative, which has significantly enhanced antibacterial activity against a variety of bacteria that cause diarrhea (such as Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Escherichia coli, Shigella flexneri, Shigella dysenteriae, Vibrio parahaemolyticus, etc.) and significantly improves the treatment effect of diarrhea.

[0040] (2) An acyl acetophenone substituent was introduced at the 9-position of berberine in this derivative, and a series of 9-position substituted berberine compounds were specifically designed and synthesized. These compounds were found to have excellent inhibitory activity against Gram-positive bacteria (Staphylococcus aureus, methicillin-resistant Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli, Shigella flexneri, Shigella dysenteriae, Vibrio parahaemolyticus) by in vitro antimicrobial activity tests. They can be used to prepare antibacterial drugs and have no obvious drug resistance. They can provide more efficient and safer candidate drugs for the treatment of clinical diarrhea-related diseases.

[0041] (3) The berberine derivatives provided by the present invention are easy to prepare from readily available raw materials and are easy to synthesize. They are of great significance in antibacterial applications, especially in the treatment of diarrhea. Detailed Implementation

[0042] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0043] To address the limitations of berberine's antibacterial effect in existing technologies, and the varying efficacy against diarrhea caused by different bacteria, this invention provides a berberine derivative having the structure of Formula I:

[0044] Formula I;

[0045] Wherein, R is selected from C1~C10 straight-chain alkyl (such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl), C3~C10 branched alkyl (such as isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl or tert-pentyl, etc.), C1~C10 alkoxy (such as methoxy, ethoxy, propoxy, butoxy or pentoxy, etc.), C3~C10 carbocyclic ring, 4~C10 heterocyclic ring, C6~C10 aromatic ring or substituted, or C5~C10 heteroaryl or -NR1R2.

[0046] R1 and R2 are each independently selected from straight-chain alkyl groups of C1 to C10 (such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl) or branched alkyl groups of C3 to C10 (such as isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, or tert-pentyl).

[0047] The substitution position of R is adjacent, intermediate, or anti-position, preferably anti-position.

[0048] In some embodiments of the present invention, the berberine derivative has the structure of Formula I, wherein R is selected from C1-C6 straight-chain alkyl, C3-C6 branched alkyl, C1-C6 alkoxy, C3-C8 carbocyclic, C4-C8 heterocyclic, C6-C8 aromatic, C5-C8 heteroaryl or -NR1R2.

[0049] In some specific embodiments of the present invention, the berberine derivative is preferably selected from any one of the following formulas:

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] .

[0057] In a further preferred embodiment of the present invention, the berberine derivative is selected from any one of the following formulas:

[0058] .

[0059] In a further preferred embodiment of the present invention, the berberine derivative is selected from any one of the following formulas:

[0060] .

[0061] The present invention preferably uses berberine derivatives with the above-described specific formulas 1 to 21 because they have superior antibacterial activity compared to other structures.

[0062] The present invention also provides a method for preparing the above-mentioned berberine derivative, comprising the following steps:

[0063] S1: Provides the compound shown in formula A;

[0064] S2: Mix and react the compound shown in Formula A, the compound shown in Formula B, the basic substance and the organic solvent to obtain a berberine derivative having the structure of Formula I;

[0065] Formula B.

[0066] According to the present invention, a compound of formula A is first provided.

[0067] In this invention, the compound represented by formula A is preferably obtained by high-temperature vacuum distillation of berberine, which can be carried out by means well known to those skilled in the art.

[0068] In some embodiments of the present invention, the compound represented by formula A is prepared according to the following method:

[0069] Berberine hydrochloride (50 g, 0.134 mol) was stirred in DMF (150 mL) solution at 150 °C for 5 h. After cooling to 60 °C, methyl tert-butyl ether (500 mL) was added, filtered, and dried to obtain red solid berberine hydrochloride A (35.44 g, 73.66%). LCMS (ES, m / z): [M-Cl]+=322.2.

[0070] After obtaining the compound shown in Formula A, according to the present invention, the compound shown in Formula A, the compound shown in Formula B, an alkaline substance and an organic solvent are mixed and reacted to obtain a berberine derivative having the structure of Formula I.

[0071] The organic solvent is selected from one or more of acetonitrile, DMF, DMSO, or dioxane; the alkaline substance is selected from one or more of potassium carbonate, cesium carbonate, or sodium carbonate. The reaction temperature is room temperature to 80°C, and the reaction time is 1 to 16 hours.

[0072] In some embodiments of the present invention, it is preferable to dissolve the compound of formula A and the basic substance in an organic solvent, and then add the compound of formula B to undergo an alkylation reaction to obtain a berberine derivative having the structure of formula I.

[0073] After the above reaction is completed, a post-processing step is preferably included. The post-processing step includes filtration, drying, etc.

[0074] The preparation method of the above-mentioned berberine derivatives provided by the present invention uses simple and readily available raw materials and is easy to synthesize, which is conducive to realizing large-scale or industrialized production.

[0075] The present invention also provides the application of the above-mentioned berberine derivative in the preparation of antibacterial drugs.

[0076] Specifically, the present invention provides an antibacterial drug comprising a berberine derivative and pharmaceutically acceptable excipients.

[0077] In this invention, the bacteria inhibited by the antibacterial drug include, but are not limited to, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Shigella flexneri, Shigella dysenteriae, or Vibrio parahaemolyticus.

[0078] According to the tests conducted on the above-mentioned bacteria, the minimum inhibitory concentration (MIC) of the antibacterial drug provided by the present invention is 1 ~ 200 μg / mL.

[0079] In this invention, the administration method of the antibacterial drug includes, but is not limited to, oral administration.

[0080] To further illustrate the present invention, the following embodiments will be described in detail.

[0081] All reagents used in the following examples are commercially available.

[0082] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).

[0083] NMR measurements were performed using a Bruker Avance NEO 300 and a Bruker Avance NEO 400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0084] LC-MS measurements were performed using a Shimadzu LC-MS 2020 (ESI) system.

[0085] The HPLC determination was performed using a Shimadzu LC-20-AD high-performance liquid chromatograph.

[0086] The thin-layer chromatography silica gel plates used are Merck GF254 silica gel plates. The specifications for thin-layer chromatography separation and purification of products are 1 mm and 20 × 20 cm.

[0087] Column chromatography typically uses 100-200 mesh silica gel as a carrier, manufactured by Chenghua Chemical (Shanghai) Co., Ltd.

[0088] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0089] Unless otherwise specified, all the following reactions are carried out under continuous magnetic stirring in an atmosphere of air, dry nitrogen or argon, using commercially available solvents, and the reaction temperatures are in degrees Celsius.

[0090] Preparation of intermediate formula A:

[0091]

[0092] Berberine hydrochloride (50 g, 0.134 mol) was stirred in DMF (150 mL) solution at 150 °C for 5 h. After cooling to 60 °C, methyl tert-butyl ether (500 mL) was added, filtered, and dried to obtain red solid berberine hydrochloride A (35.44 g, 73.66%). LCMS (ES, m / z): [M-Cl]+ = 322.2.

[0093] Example 1: Preparation of 10-methoxy-9-(2-oxo-2-phenoxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-chloride

[0094] ;

[0095] Berberine hydrochloride (1.00 g, 2.794 mmol), 2-bromoacetophenone (0.71 g, 3.073 mmol), and potassium carbonate (0.42 g, 3.073 mmol) were stirred in DMSO (5 mL) solution at 60 °C for 2 h. The mixture was filtered, and the filter cake was washed twice with water (10 mL), then slurried with methanol (10 mL), filtered, and dried to obtain a yellow solid, 10-methoxy-9-(2-oxo-2-phenoxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-chloride (0.64 g, 48.13%). LCMS (ES, m / z): [M-Cl] + =440.3.

[0096] 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.97 (s, 1H), 8.16-8.18 (d,1H), 7.97-8.01 (t, 3H), 7.81 (s, 1H), 7.69-7.73 (t, 1H), 7.56-7.60 (t, 2H), 7.11 (s, 1H), 6.18 (s, H), 5.90 (s, 2H), 4.95-4.98 (t, 2H), 3.95 (s, 3H), 3.21-3.24 (t, 2H).

[0097] Example 2: Preparation of 9-(2-(4-butylpiperidin-1-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride

[0098] ;

[0099] Step 1: Synthesis of 9-(2-ethoxy-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0100] ;

[0101] Berberine hydrochloride (0.50 g, 1.397 mmol) and potassium carbonate (0.58 g, 4.192 mmol) were stirred in DMSO (5 mL) solution at 80 °C for 0.5 h. Ethyl bromoacetate (0.47 g, 2.795 mmol) was added to the mixture. The mixture was stirred for another 2 h. 50 mL of petroleum ether was added to the mixture, and the mixture was filtered. The filter cake was dried to give 9-(2-ethoxy-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride. The crude product was used directly in the next reaction without purification.

[0102] Step 2: Synthesis of 9-(carboxymethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0103] ;

[0104] The 9-(2-ethoxy-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride obtained in the previous step was stirred in 2 M sodium hydroxide aqueous solution (2 mL) at 25 °C for 0.5 h. The pH was adjusted to 2-3 by adding 2 M dilute hydrochloric acid dropwise to the mixture. After filtration and drying of the filter cake, a yellow solid 9-(carboxymethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (0.32 g, 55.17%) was obtained. LCMS (ES, m / z): [M+H] + =380.2.

[0105] Step 3: Synthesis of 4-Butylpiperidine

[0106] ;

[0107] 0.30 g (1.243 mmol) of 4-butylpiperidine-1-carboxylic acid tert-butyl ester was stirred at 25 °C for 16 h in 4 M HCl-dioxane (3 mL) (1.5 mL). The resulting mixture was concentrated under reduced pressure to give 4-butylpiperidine. The crude product was used directly in the next reaction without purification.

[0108] Step 4: Synthesis of 9-(2-(4-butylpiperidin-1-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride

[0109] ;

[0110] The 4-butylpiperidine (0.18 g, 1.243 mmol), HATU (0.57 g, 1.491 mmol), and DIEA (0.40 g, 3.107 mmol) obtained in the previous step, along with 9-(carboxymethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (0.47 g, 1.119 mmol), were stirred in acetonitrile (3 mL) solution at 25 °C for 3 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with methanol / dichloromethane (1%–2%) to give a yellow solid 9-(2-(4-butylpiperidin-1-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride (28 mg, 4.18%). LCMS (ES, m / z): [M-Cl] + =503.0.

[0111] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.90 (s, 1H), 8.15-8.17 (d,1H), 7.94-7.96 (d, 1H), 7.79 (s, 1H), 7.10 (s, 1H), 7.10 (s, 1H), 5.23 (s,2H), 4.92-4.95 (t, 2H), 4.26-4.29 (d, 1H), 4.03 (s, 3H), 3.70-3.73 (d, 1H),3.19-3.22 (t, 2H), 2.95-3.01 (t, 1H), 1.65-1.72 (t, 2H), 1.46 (s, 2H), 1.23-1.26 (m, 6H), 1.01-1.10 (m, 2H), 0.86-0.88 (t, 3H).

[0112] Example 3: Preparation of 10-methoxy-9-(2-oxo-2-(p-tolyl)ethoxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride

[0113] ;

[0114] Berberine hydrochloride (0.50 g, 1.397 mmol), 2-bromo-4'-methylacetophenone (0.36 g, 1.677 mmol), and potassium carbonate (0.23 g, 2.096 mmol) were stirred in acetonitrile (4 mL) at 25 °C for 6 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid, 10-methoxy-9-(2-oxo-2-(p-tolyl)ethoxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride (520 mg, 82.02%), was obtained. LCMS (ES, m / z): [M-Cl] + =454.1.

[0115] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.96 (s, 1H), 8.16-8.18 (d,1H), 7.96-7.99 (d, 1H), 7.89-7.91 (d, 2H), 7.81 (s, 1H), 7.37-7.39 (d, 2H), 7.10 (s, 1H), 6.18 (s, 2H), 5.87 (s, 2H), 3.94 (s, 3H), 3.22 (t, 2H), 2.40 (s, 3H).

[0116] Example 4: Preparation of 9-(2-(4-ethylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 1)

[0117] ;

[0118] Berberine hydrochloride (0.50 g, 1.397 mmol), 2-bromo-1-(4-ethylphenyl)ethyl-1-one (0.38 g, 1.677 mmol), and potassium carbonate (0.23 g, 2.096 mmol) were stirred in acetonitrile (4 mL) at 25 °C for 6 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid 9-(2-(4-ethylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (520 mg, 80.00%) was obtained. LCMS (ES, m / z): [M-Cl] + =468.4.

[0119] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.97 (s, 1H), 8.16-8.18 (d,1H), 7.97-7.99 (d, 1H), 7.91-7.93 (d, 2H), 7.81 (s, 1H), 7.40-7.42 (d, 2H),7.10 (s, 1H), 6.18 (s, 2H), 5.87 (s, 2H), 4.96 (s, 2H), 3.95 (s, 3H), 3.21-3.24 (t, 2H), 2.69-2.71 (d, 2H), 1.19-1.22 (t, 3H).

[0120] Example 5: Preparation of 10-methoxy-9-(2-oxo-2-(4-propylphenyl)ethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (Formula 2)

[0121] ;

[0122] Step 1: Synthesis of 1-(4-propylphenyl)ethyl-1-one

[0123] ;

[0124] Pd(PPh3)4 (0.84 g, 1.005 mmol) was added to a mixture of 4-bromoacetophenone (2.00 g, 10.048 mmol), potassium phosphate (5.33 g, 10.048 mmol), pinacol 1-propanoate (1.88 g, 11.052 mmol), 1,4-dioxane (20 mL), and purified water (10 mL). The mixture was stirred at 80 °C for 24 h under nitrogen protection. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (5%) to give a colorless liquid 1-(4-propylphenyl)ethyl-1-one (0.54 g, 33.13%). LCMS (ES, m / z): [M+H] + =162.1.

[0125] Step 2: Synthesis of 2-bromo-1-(4-propylphenyl)ethyl-1-one

[0126] ;

[0127] 1-(4-propylphenyl)ethyl-1-one (0.54 g, 2.239 mmol) and 2-pyrrolidinedione hydrogen tribromide (1.98 g, 2.687 mmol) were stirred in methanol (5 mL) at 25 °C for 24 h. The resulting mixture was concentrated under reduced pressure, and ethyl acetate (5 mL) and saturated sodium bicarbonate aqueous solution (5 mL) were added to the residue. After standing and separation, the organic phase was concentrated under reduced pressure to give a pale yellow liquid, 2-bromo-1-(4-propylphenyl)ethyl-1-one (1.05 g, crude product). LCMS (ES, m / z): [M+H] + =242.9.

[0128] Step 3: Synthesis of 10-methoxy-9-(2-oxo-2-(4-propylphenyl)ethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride

[0129] ;

[0130] Berberine hydrochloride (0.20 g, 0.559 mmol), potassium carbonate (0.14 g, 0.838 mmol), and 2-bromo-1-(4-propylphenyl)ethyl-1-one (0.40 g, 1.677 mmol) were stirred in acetonitrile (3 mL) at 60 °C for 4 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid, 10-methoxy-9-(2-oxo-2-(4-propylphenyl)ethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (45 mg, 15.57%), was obtained. LCMS (ES, m / z): [M-Cl] + =482.3.

[0131] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.96 (s, 1H), 8.94 (s, 1H), 8.16 (d, 1H), 7.97 (d, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.38 (d, 2H), 7.10(s, 1H), 6.18 (s, 2H), 5.87 (s, 2H), 4.96 (t, 2H), 3.22 (t, 2H), 2.65 (t,2H), 1.59-1.65 (m, 2H), 0.89 (t, 3H).

[0132] Example 6: Preparation of 9-(2-(4-isopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 3)

[0133] ;

[0134] Step 1: Synthesis of 2-bromo-1-(4-isopropylphenyl)ethyl-1-one

[0135] ;

[0136] 4-Isopropylacetophenone (1.50 g, 9.246 mmol) and 2-pyrrolidone dihydrotribromide (5.50 g, 11.095 mmol) were stirred in methanol (5 mL) at 25 °C for 16 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (5%) to give a pale yellow liquid, 2-bromo-1-(4-isopropylphenyl)ethyl-1-one (2.34 g, crude product).

[0137] Step 2: Synthesis of 9-(2-(4-isopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0138] ;

[0139] Berberine hydrochloride (0.30 g, 0.838 mmol), potassium carbonate (0.17 g, 1.258 mmol), and 2-bromo-1-(4-isopropylphenyl)ethyl-1-one (0.30 g, 1.677 mmol) were stirred in acetonitrile (3 mL) at 60 °C for 16 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid 9-(2-(4-isopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (320 mg, 74.07%) was obtained. LCMS (ES, m / z): [M-Cl] + =482.3.

[0140] 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.96 (s, 1H), 8.16 (d, 1H), 7.97 (d, 1H), 7.92 (d, 2H), 7.82 (s, 1H), 7.43 (d, 1H), 7.10 (s, 1H), 6.18(s, 2H), 5.87 (s, 2H), 4.96 (t, 3H), 3.95 (s, 3H), 3.23 (t, 2H), 2.96-3.02(m, 1H), 1.22 (t, 6H).

[0141] Example 7: Preparation of 9-(2-(4-isobutylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 4)

[0142] ;

[0143] Step 1: Synthesis of 2-bromo-1-(4-isobutylphenyl)ethyl-1-one

[0144] ;

[0145] 4-Isobutylacetophenone (1.50 g, 8.510 mmol) and 2-pyrrolidone tribromide (4.64 g, 9.361 mmol) were stirred in methanol (15 mL) at 25 °C for 16 h. The resulting mixture was concentrated under reduced pressure, and ethyl acetate (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL) were added to the residue. After standing and separation, the organic phase was concentrated under reduced pressure to give a pale yellow liquid, 2-bromo-1-(4-isobutylphenyl)ethyl-1-one (1.99 g, crude product). LCMS (ES, m / z): [M+H] + =256.8.

[0146] Step 2: Synthesis of 9-(2-(4-isobutylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0147] ;

[0148] Berberine hydrochloride (0.30 g, 0.838 mmol), potassium carbonate (0.17 g, 1.258 mmol), and 2-bromo-1-(4-isobutylphenyl)ethyl-1-one (0.64 g, 2.515 mmol) were stirred in acetonitrile (3 mL) solution at 40 °C for 4 h. The mixture was filtered, and the filter cake was stirred in 20 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid 9-(2-(4-isobutylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (410 mg, 91.93%) was obtained. LCMS (ES, m / z): [M-Cl] + =496.3.

[0149] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.97 (s, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.91-7.99 (m, 2H), 7.82 (s, 1H), 7.35 (d, 2H), 7.10 (s, 1H),6.18 (s, 2H), 5.88 (s, 2H), 4.96 (t, 2H), 3.95 (s, 3H), 3.23 (t, 2H), 2.54(d, 2H), 1.85-1.92 (m, 1H), 0.86 (d, 6H).

[0150] Example 8: Preparation of 9-(2-(4-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (Formula 5)

[0151] ;

[0152] Step 1: Synthesis of 2-bromo-1-(4-cyclopropylphenyl)ethyl-1-one

[0153] ;

[0154] 1-(4-cyclopropylphenyl)ethyl ketone (0.50 g, 3.121 mmol) and 2-pyrrolidinedione hydrogen tribromide (1.55 g, 3.121 mmol) were stirred in methanol (5 mL) at 25 °C for 3 h. The resulting mixture was concentrated under reduced pressure, and ethyl acetate (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL) were added to the residue. The mixture was allowed to stand and separate into layers. The organic phase was concentrated under reduced pressure to give an orange liquid, 2-bromo-1-(4-cyclopropylphenyl)ethyl-1-one (0.73 g, crude product).

[0155] Step 2: Synthesis of 9-(2-(4-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0156] ;

[0157] Berberine hydrochloride (0.50 g, 1.397 mmol), potassium carbonate (0.15 g, 2.096 mmol), and 2-bromo-1-(4-cyclopropylphenyl)ethyl-1-one (0.34 g, 2.795 mmol) were stirred in acetonitrile (5 mL) solution at 60 °C for 3 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brownish-yellow solid, 9-(2-(4-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (340 mg, 94.30%), was obtained. LCMS (ES, m / z): [M-Cl] + =479.9.

[0158] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.96 (s, 1H), 8.18 (d, 1H), 7.98 (d, 1H), 7.88 (d, 2H), 7.81 (s, 1H), 7.26 (d, 1H), 7.10 (s, 1H), 6.18(s, 2H), 5.85 (s, 2H), 4.95 (t, 2H), 3.94 (s, 3H), 3.22 (t, 2H), 2.00-2.06(t, 1H), 1.04-1.09 (t, 2H), 0.77-0.81 (t, 2H).

[0159] Example 9: Preparation of 9-(2-([1,1'-biphenyl]-4-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 6)

[0160] ;

[0161] Step 1: Synthesis of 1-([1,1'-biphenyl]-4-yl)ethyl-1-one

[0162] ;

[0163] Pd(PPh3)4 (0.42 g, 0.502 mmol) was added to a mixture of 4-bromoacetophenone (1.00 g, 5.024 mmol), potassium carbonate (0.85 g, 6.029 mmol), phenylboronic acid (0.93 g, 7.536 mmol), 1,4-dioxane (10 mL), and purified water (5 mL). The mixture was stirred at 80 °C for 16 h under nitrogen protection. The resulting mixture was concentrated under reduced pressure, and 10 mL of petroleum ether was added and stirred for 0.5 h. The mixture was then filtered and dried to give a brown solid, 1-([1,1'-biphenyl]-4-yl)ethyl-1-one (0.77 g, 78.09%). LCMS (ES, m / z): [M+H] + =197.0.

[0164] Step 2: Synthesis of 1-([1,1'-biphenyl]-4-yl)-2-bromoethyl-1-one

[0165] ;

[0166] 1-([1,1'-biphenyl]-4-yl)ethyl-1-one (0.50 g, 2.548 mmol) and 2-pyrrolidinedione hydrogen tribromide (1.26 g, 2.548 mmol) were stirred in ethyl acetate (10 mL) at 50 °C for 5 h. The resulting mixture was concentrated under reduced pressure, and ethyl acetate (2 mL) and methanol (2 mL) were added to the residue. The mixture was stirred for 0.5 h, filtered, and dried to give a white solid 1-([1,1'-biphenyl]-4-yl)-2-bromoethyl-1-one (0.21 g, 29.96%). LCMS (ES, m / z): [M+H] + =275.0.

[0167] Step 3: Synthesis of 9-(2-([1,1'-biphenyl]-4-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride

[0168] ;

[0169] Berberine hydrochloride (0.20 g, 0.559 mmol), potassium carbonate (0.14 g, 0.838 mmol), and 1-([1,1'-biphenyl]-4-yl)-2-bromoethyl-1-one (0.21 g, 0.727 mmol) were stirred in acetonitrile (4 mL) solution at 60 °C for 3 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brown solid, 9-(2-([1,1'-biphenyl]-4-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (250 mg, 86.58%), was obtained. LCMS (ES, m / z): [M-Cl] + =516.2.

[0170] 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.97 (s, 1H), 8.20 (d, 2H), 8.10 (d, 2H), 8.00 (d, 1H), 7.90 (d, 2H), 7.82 (s, 1H), 7.78 (d, 1H), 7.53(t, 2H), 7.45 (t, 1H), 7.11 (s, 1H), 6.19 (s, 2H), 5.93 (s, 2H), 4.97 (t, 2H), 3.97 (s, 3H), 3.23 (t, 2H).

[0171] Example 10: Preparation of 9-(2-(4-(dimethylamino)phenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride (Formula 7)

[0172] ;

[0173] Berberine hydrochloride (1.00 g, 2.795 mmol), 2-bromo-1-(4-(dimethylamino)phenyl)acetone (1.02 g, 4.192 mmol), and potassium carbonate (0.58 g, 4.192 mmol) were stirred in acetonitrile (10 mL) at 40 °C for 16 h. The mixture was filtered, and the filter cake was stirred in 30 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid, 9-(2-(4-(dimethylamino)phenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (990 mg, 45.41%), was obtained. LCMS (ES, m / z): [M-Cl] + =483.3.

[0174] 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.95 (s, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.81 (t, 3H), 7.10 (s, 1H), 6.73 (d, 2H), 6.18 (s, 2H), 5.78(s, 2H), 4.95 (t, 2H), 3.96 (s, 3H), 3.22 (t, 2H), 3.03 (s, 6H).

[0175] Example 11: Preparation of 10-methoxy-9-(2-oxo-2-(m-tolyl)ethoxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride (Formula 8)

[0176] ;

[0177] Berberine hydrochloride (0.50 g, 1.397 mmol), 2-bromo-1-(3-methylphenyl)ethyl-1-one (0.36 g, 1.677 mmol), and potassium carbonate (0.29 g, 2.096 mmol) were stirred in acetonitrile (5 mL) at 60 °C for 1 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brown solid, 10-methoxy-9-(2-oxo-2-(m-tolyl)ethoxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolin-7-chloride (540 mg, 85.02%), was obtained. LCMS (ES, m / z): [M-Cl] + =453.9.

[0178] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.97 (s, 1H), 8.19 (d, 1H), 8.00 (d, 1H), 7.82 (d, 3H), 7.53 (d, 1H), 7.46 (t, 1H), 7.10 (s, 1H), 6.18(s, 2H), 5.88 (s, 2H), 4.96 (t, 2H), 3.95 (s, 3H), 3.23 (t, 2H), 2.39 (s,3H).

[0179] Example 12: Preparation of 9-(2-(3-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 9)

[0180] ;

[0181] Step 1: Synthesis of 2-bromo-1-(3-cyclopropylphenyl)ethyl-1-one

[0182] ;

[0183] 1-(3-cyclopropylphenyl)ethyl ketone (1.00 g, 6.241 mmol) and copper bromide (2.09 g, 9.362 mmol) were stirred in ethyl acetate (10 mL) at 50 °C for 16 h. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (4%–6%) to give a pale yellow liquid, 2-bromo-1-(3-cyclopropylphenyl)ethyl-1-one (0.20 g, 13.42%). LCMS (ES, m / z): [M+H] + =238.9 / 240.9.

[0184] Step 2: Synthesis of 9-(2-(3-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0185] ;

[0186] Berberine hydrochloride (0.20 g, 0.559 mmol), potassium carbonate (0.19 g, 1.397 mmol), and 2-bromo-1-(3-cyclopropylphenyl)ethyl-1-one (0.20 g, 0.838 mmol) were stirred in acetonitrile (4 mL) at 50 °C for 16 h. The mixture was filtered, and the filter cake was stirred with 4 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid, 9-(2-(3-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (230 mg, 85.82%), was obtained. LCMS (ES, m / z): [M-Cl] + =480.3.

[0187] 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.97 (s, 1H), 8.18 (d, 1H), 7.98 (d, 1H), 7.82 (s, 1H), 7.76 (d, 1H), 7.66 (s, 1H), 7.48–7.36 (m, 2H),7.11 (s, 1H), 6.18 (s, 2H), 5.88 (s, 2H), 4.96 (t, 2H), 3.95 (s, 3H), 3.23(t, 2H), 2.07–1.96 (m, 1H), 1.05–0.94 (m, 2H), 0.79–0.67 (m, 2H).

[0188] Example 13: Preparation of 9-(2-(3-ethylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 10)

[0189] ;

[0190] Step 1: Synthesis of 2-bromo-1-(3-ethylphenyl)ethyl-1-one

[0191] ;

[0192] 3-Ethylacetophenone (1.00 g, 6.747 mmol) and copper bromide (3.01 g, 13.494 mmol) were stirred in ethyl acetate (10 mL) at 80 °C for 5 h. The resulting mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (4%) to give an orange-red liquid, 2-bromo-1-(3-ethylphenyl)ethyl-1-one (1.17 g, 76.47%).

[0193] Step 2: Synthesis of 9-(2-(3-ethylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0194] ;

[0195] Berberine hydrochloride (0.20 g, 0.559 mmol), potassium carbonate (0.15 g, 0.839 mmol), and 2-bromo-1-(3-ethylphenyl)ethyl-1-one (0.25 g, 1.118 mmol) were stirred in acetonitrile (2 mL) at 25 °C for 16 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid, 9-(2-(3-ethylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (210 mg, 74.73%), was obtained. LCMS (ES, m / z): [M-Cl] + =468.3.

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.97 (s, 1H), 8.17 (d, 1H), 7.98 (d, 1H), 7.82 (d, 3H), 7.55 (d, 1H), 7.49 (d, 1H), 7.11 (s, 1H), 6.18(s, 2H), 5.88 (s, 2H), 4.96 (t, 2H), 3.96 (s, 3H), 3.23 (t, 2H), 2.66-2.72(m, 2H), 1.21 (t, 3H).

[0197] Example 14: Preparation of 9-(2-([1,1'-biphenyl]-3-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (Formula 11)

[0198] ;

[0199] Step 1: Synthesis of 1-([1,1'-biphenyl]-3-yl)-2-bromoethyl-1-one

[0200] ;

[0201] 3-Acetylbiphenyl (1.00 g, 5.096 mmol), NBS (1.09 g, 6.115 mmol), and p-toluenesulfonic acid (1.94 g, 10.191 mmol) were stirred in acetonitrile (10 mL) at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (5%–10%) to give a yellow liquid 1-([1,1'-biphenyl]-3-yl)-2-bromoethyl-1-one (0.90 g, 64.29%). LCMS (ES, m / z): [M+H] + =275.0 / 276.9.

[0202] Step 2: Synthesis of 9-(2-([1,1'-biphenyl]-3-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride

[0203] ;

[0204] Berberine hydrochloride (0.50 g, 1.397 mmol), potassium carbonate (0.48 g, 3.494 mmol), potassium iodide (0.23 g, 1.397 mmol), and 1-([1,1'-biphenyl]-3-yl)-2-bromoethyl-1-one (0.50 g, 1.817 mmol) were stirred in acetonitrile (5 mL) solution at 50 °C for 16 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brownish-yellow solid 9-(2-([1,1'-biphenyl]-3-yl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (400 mg, 55.56%) was obtained. LCMS(ES, m / z): [M-Cl] +=516.3.

[0205] 1 H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.96 (s, 1H), 8.26–8.14 (m, 2H), 8.00 (t, 3H), 7.82 (s, 1H), 7.75 (d, 2H), 7.68 (t, 1H), 7.51 (t, 2H), 7.43 (t, 1H), 7.11 (s, 1H), 6.18 (s, 2H), 5.98 (s, 2H), 5.02–4.86 (t, 2H), 3.97 (s, 3H), 3.27–3.16 (t, 2H).

[0206] Example 15: Preparation of 10-methoxy-9-(2-oxo-2-(o-tolyl)ethoxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride (Formula 12)

[0207] ;

[0208] Berberine hydrochloride (0.50 g, 1.397 mmol), 2-bromo-1-O-tolyl-acetone (0.36 g, 1.677 mmol), and potassium carbonate (0.23 g, 2.096 mmol) were stirred in acetonitrile (5 mL) at 60 °C for 3 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brown solid, 10-methoxy-9-(2-oxo-2-(o-tolyl)ethoxy)-5,6-dihydro-[1,3]dioxo[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (580 mg, 91.32%), was obtained. LCMS (ES, m / z): [M-Cl] + =454.0.

[0209] 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.95 (s, 1H), 8.19 (d, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.81 (s, 1H), 7.50 (t, 1H), 7.37 (t, 1H), 7.11(s, 1H), 6.18 (s, 2H), 5.72 (s, 2H), 4.93 (t, 2H), 3.98 (s, 3H), 3.22 (t,2H), 2.341 (s, 3H).

[0210] Example 16: Preparation of 9-(2-(2-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (Formula 13)

[0211] ;

[0212] Step 1: Synthesis of 1-(2-cyclopropylphenyl)ethyl-1-one

[0213] ;

[0214] Pd(PPh3)4 (0.87 g, 1.507 mmol) was added to a mixture of 2-bromoacetophenone (3.00 g, 15.072 mmol), potassium phosphate (8.00 g, 37.679 mmol), pinacol cyclopropylborate (3.04 g, 18.086 mmol), 1,4-dioxane (30 mL), and purified water (15 mL). The mixture was stirred at 80 °C for 24 h under nitrogen protection. The resulting mixture was extracted with ethyl acetate (30 mL), the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (7%) to give a yellow liquid 1-(2-cyclopropylphenyl)ethyl-1-one (0.70 g, 29.05%). LCMS (ES, m / z): [M+H] + =161.1.

[0215] Step 2: Synthesis of 2-bromo-1-(2-cyclopropylphenyl)ethyl-1-one

[0216] ;

[0217] 1-(2-cyclopropylphenyl)ethyl-1-one (0.70 g, 4.369 mmol) and 2-pyrrolidinedione hydrogen tribromide (1.71 g, 4.369 mmol) were stirred in methanol (10 mL) at 25 °C for 6 h. The resulting mixture was concentrated under reduced pressure, and ethyl acetate (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL) were added to the residue. The mixture was stirred for 0.5 h, allowed to stand, and allowed to separate into layers. The organic phase was concentrated under reduced pressure to give a pale yellow liquid, 2-bromo-1-(2-cyclopropylphenyl)ethyl-1-one (0.91 g, 87.50%). LCMS (ES, m / z): [M+H] + =240.8.

[0218] Step 3: Synthesis of 9-(2-(2-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0219] ;

[0220] Berberine hydrochloride (0.30 g, 0.838 mmol), potassium carbonate (0.17 g, 1.258 mmol), and 2-bromo-1-(2-cyclopropylphenyl)ethyl-1-one (0.30 g, 1.258 mmol) were stirred in acetonitrile (3 mL) at 60 °C for 4 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with methanol / dichloromethane (3%) to give a yellow solid 9-(2-(2-cyclopropylphenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (130 mg, 30.23%). LCMS (ES, m / z): [M-Cl] + =480.6.

[0221] 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.94 (s, 1H), 8.18 (d, 1H), 7.96 (d, 1H), 7.81 (s, 1H), 7.71 (d, 1H), 7.46 (t, 1H), 7.31 (t, 1H), 7.11 (s, 1H), 7.04 (d, 1H), 6.18 (s, 2H), 5.72 (s, 2H), 4.92 (t, 2H), 4.00 (s, 3H), 3.22 (t, 2H), 2.22-2.26 (m, 1H), 0.87-0.91(m, 2H), 0.62-0.66(m, 2H).

[0222] Example 17: Preparation of 10-methoxy-9-(2-(3-nitrophenyl)-2-oxoethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinolino-7-chloride (Formula 14)

[0223] ;

[0224] Berberine hydrochloride (0.20 g, 0.559 mmol), 2-bromo-3'-nitrophenyl ethyl ketone (0.15 g, 0.615 mmol), and potassium carbonate (0.12 g, 0.838 mmol) were stirred in acetonitrile (5 mL) at 60 °C for 3.5 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brown solid, 10-methoxy-9-(2-(3-nitrophenyl)-2-oxoethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (140 mg, 51.59%), was obtained. LCMS (ES, m / z): [M-Cl] + =453.9.

[0225] 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.97 (s, 1H), 8.71 (s, 1H), 8.54 (d, 1H), 8.45 (d, 1H), 8.20 (d, 1H), 7.99 (d, 1H), 7.90 (t, 1H), 7.82(s, 1H), 7.11 (s, 1H), 6.18 (s, 1H), 5.94 (s, 2H), 4.96 (t, 2H), 3.95 (s,3H), 3.32 (t, 2H), 2.08 (s, 2H).

[0226] Example 18: Preparation of 10-methoxy-9-(2-(2-nitrophenyl)-2-oxoethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (Formula 15)

[0227] ;

[0228] Berberine hydrochloride (0.20 g, 0.559 mmol), 2-bromo-2'-nitrophenyl ethyl ketone (0.15 g, 0.615 mmol), and potassium carbonate (0.12 g, 0.838 mmol) were stirred in acetonitrile (5 mL) at 60 °C for 1.5 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brown solid, 10-methoxy-9-(2-(2-nitrophenyl)-2-oxoethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (240 mg, 88.44%), was obtained. LCMS (ES, m / z): [M-Cl] + =453.9.

[0229] 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.96 (s, 1H), 8.22 (d, 2H), 8.03 (d, 1H), 7.96 (t, 1H), 7.86 (d, 1H), 7.84 (d, 1H), 7.80 (s, 1H), 7.11(s, 1H), 6.18 (s, 2H), 5.56 (s, 2H), 4.91 (t, 2H), 4.02 (s, 3H), 3.32 (t, 2H).

[0230] Example 19: Preparation of 9-(2-(3-fluorophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 17)

[0231] ;

[0232] Berberine hydrochloride (0.30 g, 0.838 mmol), 2-bromo-3'-fluoroacetophenone (0.27 g, 1.258 mmol), and potassium carbonate (0.17 g, 1.258 mmol) were stirred in acetonitrile (3 mL) solution at 60 °C for 2 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid 9-(2-(3-fluorophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (360 mg, 87.80%) was obtained. LCMS (ES, m / z): [M-Cl] + =458.1.

[0233] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.96 (s, 1H), 8.17 (d, 1H), 7.97 (d, 1H), 7.79-7.87 (m, 3H), 7.57-7.66 (m, 2H), 7.11 (s, 1H), 6.18 (s, 2H), 5.88 (s, 2H), 4.96 (t, 2H), 3.94 (s, 3H), 3.23 (t, 2H).

[0234] Example 20

[0235] Preparation of 9-(2-(3-cyanophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 18)

[0236] ;

[0237] Berberine hydrochloride (0.30 g, 0.838 mmol), 3-cyanobenzoylmethyl bromide (0.28 g, 1.258 mmol), and potassium carbonate (0.17 g, 1.258 mmol) were stirred in acetonitrile (6 mL) solution at 60 °C for 5 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brownish-yellow solid, 9-(2-(3-cyanophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (200 mg, 51.28%), was obtained. LCMS (ES, m / z): [M-Cl] + =465.0.

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.96 (s, 1H), 8.48 (s, 1H), 8.28 (d, 1H), 8.18 (d, 2H), 7.99 (d, 1H), 7.81 (t, 2H), 7.11 (s, 1H), 6.18(s, 2H), 5.91 (s, 2H), 4.95 (t, 2H), 3.94 (s, 3H), 3.23 (t, 2H).

[0239] Example 21: Preparation of 9-(2-(3-chlorophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 19)

[0240] ;

[0241] Berberine hydrochloride (0.30 g, 0.838 mmol), 2-bromo-3'-chloroacetophenone (0.29 g, 1.258 mmol), and potassium carbonate (0.17 g, 1.258 mmol) were stirred in acetonitrile (3 mL) solution at 60 °C for 2 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid 9-(2-(3-chlorophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (400 mg, 95.47%) was obtained. LCMS (ES, m / z): [M-Cl] + =474.2.

[0242] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.96 (s, 1H), 8.17 (d, 1H),7.95-8.03 (m, 3H), 7.78 (t, 2H), 7.64 (t, 1H), 7.11 (s, 1H), 6.18 (s, 2H), 5.88 (s, 2H), 4.95 (t, 2H), 3.95 (s, 3H), 3.22 (t, 2H).

[0243] Example 22: Preparation of 9-(2-(3-bromophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 20)

[0244] ;

[0245] Step 1: Synthesis of 2-bromo-1-(3-bromophenyl)ethyl-1-one

[0246] ;

[0247] 3-Bromoacetophenone (1.00 g, 5.024 mmol) and copper bromide (2.24 g, 10.048 mmol) were stirred in ethyl acetate (10 mL) at 55 °C for 6 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give an orange oil, 2-bromo-1-(3-bromophenyl)ethyl-1-one (1.36 g, 97.39%). LCMS (ES, m / z): [M-Cl] + =278.7.

[0248] Step 2: Synthesis of 9-(2-(3-bromophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride

[0249] ;

[0250] Berberine hydrochloride (0.40 g, 1.118 mmol), potassium carbonate (0.24 g, 1.677 mmol), and 2-bromo-1-(3-bromophenyl)ethyl-1-one (0.48 g, 1.677 mmol) were stirred in acetonitrile (4 mL) at 60 °C for 4 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brown solid, 9-(2-(3-bromophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (490 mg, 91.32%), was obtained. LCMS (ES, m / z): [M-Cl] + =518.1.

[0251] 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.96 (s, 1H), 8.17 (t, 2H), 8.00 (t, 2H), 7.91 (d, 1H), 7.82 (s, 1H), 7.55 (t, 1H), 7.11 (s, 1H), 6.18(s, 2H), 5.87 (s, 2H), 4.95 (t, 2H), 3.95 (s, 3H), 3.22 (t, 2H).

[0252] Example 23: Preparation of 9-(2-(4-bromophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinoline[3,2-a]isoquinoline-7-chloride (Formula 21)

[0253] ;

[0254] Berberine hydrochloride (0.50 g, 1.397 mmol), 2,4'-dibromoacetophenone (0.36 g, 2.096 mmol), and potassium carbonate (0.29 g, 2.096 mmol) were stirred in acetonitrile (5 mL) solution at 60 °C for 6 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a yellow solid 9-(2-(4-bromophenyl)-2-oxoethoxy)-10-methoxy-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (560 mg, 72.73%) was obtained. LCMS (ES, m / z): [M-Cl] + =520.0.

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.43 (s, 1H), 7.88 (t, 4H), 7.67 (d, 2H), 7.48 (s, 1H), 6.89 (s, 1H), 6.13 (s, 2H), 5.91 (s, 2H), 5.03(s, 2H), 4.02(s, 3H), 3.32(s, 2H).

[0256] Example 24: Preparation of 10-methoxy-9-(2-(4-nitrophenyl)-2-oxoethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquinolino[3,2-a]isoquinoline-7-chloride (Formula 16)

[0257] ;

[0258] Berberine hydrochloride (0.20 g, 0.559 mmol), 2-bromo-4'-nitrophenyl ethyl ketone (0.15 g, 0.615 mmol), and potassium carbonate (0.12 g, 0.838 mmol) were stirred in acetonitrile (5 mL) at 60 °C for 1.5 h. The mixture was filtered, and the filter cake was stirred with 10 mL of purified water at room temperature for 1 h. After filtration and drying, a brown solid, 10-methoxy-9-(2-(4-nitrophenyl)-2-oxoethoxy)-5,6-dihydro-[1,3]dioxacyclopenteno[4,5-g]isoquino[3,2-a]isoquinoline-7-chloride (240 mg, 88.44%), was obtained. LCMS (ES, m / z): [M-Cl] + =453.9.

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.97 (s, 1H), 8.41 (d, 2H), 8.26 (d, 2H), 8.20 (d, 1H), 7.98 (d, 1H), 7.82 (s, 1H), 7.11 (s, 1H), 6.18(s, 2H), 5.92 (s, 2H), 4.96 (t, 2H), 3.94 (s, 3H), 3.23 (t, 2H).

[0260] Experimental Example 1: In vitro antibacterial activity test

[0261] Detection Method: The serial dilution method according to the Clinical and Laboratory Standards Institute (CLSI) was used to determine the minimum inhibitory concentration (MIC) of the prepared berberine derivatives (Examples 1-23) and berberine alone (control) against Gram-positive bacteria (Staphylococcus aureus, methicillin-resistant Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli, Shigella flexneri, Shigella dysenteriae, Vibrio parahaemolyticus). The test compound was dissolved in a small amount of dimethyl sulfoxide, then diluted with water to prepare a solution with a concentration of 1.28 mg / mL, and then diluted with culture medium to 256 μg / mL. The solution was incubated at 35°C for 24-72 h. After thorough mixing on a shaker, the MIC (μg / mL) was measured at a wavelength of 490 nm. The experimental results are shown in Table 1.

[0262] Table 1

[0263]

[0264] As shown in Table 1, several compounds exhibited potent inhibitory activity against the tested bacteria. Against Staphylococcus aureus, the compounds provided in Examples 5, 7, 9, and 14 (corresponding to compounds of formulas 2, 4, 6, and 11, respectively) showed inhibitory activity of 1 μg / mL, which was 128 times stronger than berberine. Against methicillin-resistant Staphylococcus aureus, Shigella flexneri, and Shigella dysenteriae, the compounds provided in Examples 5, 7, and 9 (corresponding to compounds of formulas 2, 4, and 6, respectively) showed inhibitory activity of 1–2 μg / mL, which was 128 times stronger than berberine.

[0265] Experimental Example 2: Mouse Pharmacokinetic Experiment

[0266] (I) Research Objectives

[0267] The purpose of this study was to evaluate the pharmacokinetic behavior of the test substance in male CD-1 (ICR) mice after a single intravenous or gavage administration.

[0268] (II) Test Plan

[0269] 1. Test drugs

[0270] The compounds used in this experiment were derived from the compound of formula 2 provided in specific embodiment 5 of this invention and berberine alone.

[0271] 2. Experimental animals

[0272] CD-1 (ICR) mice, male, N=6, sourced from Beijing Vital River Co., Ltd. or other suppliers.

[0273] 3. Drug preparation and administration

[0274] Appropriate amounts of the compound were weighed and dissolved in their respective solvents (10% NMP / 10% polyoxyethylene castor oil EL / 80% water for the intravenous administration group; 0.5% sodium hydroxymethyl cellulose aqueous solution for the gavage group), and prepared into formulations of the target concentration by vortexing or sonication. Animals in the intravenous administration group were fasted, while animals in the gavage group were fasted overnight and resumed eating 4 hours after administration. The dose for the gavage group was 10 mg / kg, and the dose for the intravenous administration group was 2 mg / kg.

[0275] 4. Sample Collection

[0276] Whole blood samples (0.25 mL / time point) were collected at specified times via jugular vein puncture (or other suitable blood collection sites). Sampling time points for the intravenous administration group were 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h. Sampling time points for the gavage administration group were 0.25, 0.5, 1, 2, 4, 8, and 24 h.

[0277] After collection, all blood samples were transferred to commercially available tubes containing K2-EDTA and placed on wet ice. Within 60 minutes of blood collection, the supernatant plasma was centrifuged at 3200×g for 10 minutes at approximately 4°C and then quickly placed on dry ice. The samples were then stored at -60°C or lower for LC-MS / MS analysis.

[0278] 5. Sample processing

[0279] Take 5 μL of plasma sample, add 200 μL of acetonitrile containing internal standard, vortex mix at 1000 rpm for 5 min, and centrifuge at 3220×g, 4℃ for 10 min. Transfer 70 μL of supernatant to another clean 96-well plate for LC-MS / MS analysis.

[0280] (III) Test results: see Table 2.

[0281] Table 2

[0282]

[0283] As can be seen from Table 2, after oral administration, the compound of formula 2 provided in Example 5 had almost no in vivo exposure and a bioavailability of 0, proving that the compound is not absorbed after oral administration and can better concentrate in the gastrointestinal tract to exert its effects.

[0284] Based on the pharmacokinetic data of the compounds in the above specific embodiments, the compounds of the present invention are not absorbed after oral administration, and the systemic exposure is below the detection limit. They can better concentrate in the gastrointestinal tract to exert their effects, and have good safety.

[0285] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A berberine derivative, characterized in that, It has the structure of Formula I: Wherein, R is selected from C1~C10 straight-chain alkyl, C3~C10 branched alkyl, C1~C10 alkoxy, C3~C10 carbocyclic, C4~C10 heterocyclic, C6~C10 aromatic ring or substituted or unsubstituted C5~C10 heteroaryl, -NR1R2. R1 and R2 are each independently selected from C1~C10 straight-chain alkyl groups or C3~C10 branched-chain alkyl groups; The substitution position of R is adjacent, intermediate, or opposite.

2. The berberine derivative according to claim 1, characterized in that, The R is selected from C1-C6 straight-chain alkyl, C3-C6 branched alkyl, C1-C6 alkoxy, C3-C8 carbocyclic, C4-C8 heterocyclic, C6-C8 aromatic, or C5-C8 heteroaryl. The position of R is aligned.

3. The berberine derivative according to claim 1 or 2, characterized in that, The berberine derivative is selected from any one of the following formulas:

4. The berberine derivative according to claim 3, characterized in that, The berberine derivative is selected from any one of the following formulas:

5. The berberine derivative according to claim 4, characterized in that, The berberine derivative is selected from any one of the following formulas:

6. A method for preparing a berberine derivative as described in any one of claims 1 to 5, characterized in that, Includes the following steps: The compound shown in Formula A, the compound shown in Formula B, a basic substance, and an organic solvent are mixed and reacted to obtain a berberine derivative having the structure of Formula I.

7. The preparation method according to claim 6, characterized in that, The organic solvent is selected from any one or more of acetonitrile, DMF, DMSO or dioxane; The alkaline substance is selected from any one or more of potassium carbonate, cesium carbonate, or sodium carbonate; The reaction was carried out at a temperature of room temperature to 80°C for a time of 1 to 16 hours.

8. The use of the berberine derivative according to any one of claims 1 to 5 or the berberine derivative prepared according to the preparation method according to claim 6 or 7 in the preparation of antibacterial drugs.

9. An antibacterial drug, characterized in that, Including berberine derivatives and pharmaceutically acceptable excipients; The berberine derivative is the berberine derivative according to any one of claims 1 to 5 or the berberine derivative prepared by the preparation method according to claim 6 or 7.

10. The antibacterial drug according to claim 9, characterized in that, The bacteria inhibited by the antibacterial drug include, but are not limited to, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Shigella flexneri, Shigella dysenteriae, or Vibrio parahaemolyticus.

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