CN111018853A - Phenol berberine benzimidazole compound and preparation method and application thereof - Google Patents
Phenol berberine benzimidazole compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a phenol berberine benzimidazole compound and a preparation method and application thereof, belonging to the technical field of chemical synthesis, wherein the phenol berberine benzimidazole compound is shown as a general formula I, has certain inhibitory activity on one or more of gram-positive bacteria, gram-negative bacteria and/or fungi, and can be used for preparing antibacterial and/or antifungal medicaments, thereby having the opportunity of providing more safe and efficient diversified candidate medicaments for clinical antimicrobial treatment. The preparation raw materials are simple, cheap and easy to obtain, the synthetic route is short, and the application in the anti-infection aspect has important significance.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a phenol berberine benzimidazole compound as well as a preparation method and application thereof.
Background
Benzimidazole rings have attracted much attention as key bioactive components of various antiparasitic, anticancer, anti-inflammatory, and antiulcer drugs. Benzimidazole is an important heterocyclic compound similar to purine structure and can inhibit the synthesis of nucleic acid and protein, thereby inhibiting the growth of bacterial colonies. Therefore, the drug developed based on benzimidazole has great application value in the antibacterial field.
Disclosure of Invention
In view of the above, an object of the present invention is to provide phenolic berberine benzimidazole compounds and pharmaceutically acceptable salts thereof; the second object of the present invention is to provide a process for preparing a phenolic berberine benzimidazole compound and pharmaceutically acceptable salts thereof; the third purpose of the invention is to provide the application of the phenol berberine benzimidazole compound and the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments; the fourth purpose of the invention is to provide a preparation containing the phenol berberine benzimidazole compound and the medicinal salt thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the phenol berberine benzimidazole compound and the medicinal salt thereof is shown as the general formula I:
in the formula (I), the compound is shown in the specification,
R1is hydrogen, alkyl, methoxy, halogen, cyano, nitro, trifluoromethyl, alkenyl, alkynyl, aryl, hydroxyalkyl, carboxyl, ester, acyl or mercapto;
R2is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, cyano, hydroxyalkyl, amino, carboxyl, ester, acyl or heterocyclyl;
n is an integer of 0 to 18.
Preferably, the first and second liquid crystal materials are,
R1is hydrogen, chlorine, bromine, methyl or methoxy;
R2is hydrogen, methyl, alkenyl, alkynyl, hydroxymethyl, cyclopropyl, cyclohexyl, N-dimethylAmino, morpholinyl, 2-chlorophenyl, 2, 4-dichlorophenyl, 3, 4-dichlorophenyl, 2, 4-difluorophenyl, 2-fluorophenyl, N-diacetamido, N-diisopropylamido, pyrrolamido, morpholinoamido or tert-butylcarbonyl;
n is 0, 1,2, 3,4, 5, 7 or 9.
Preferably, it is any one of the following compounds:
preferably, the pharmaceutically acceptable salt is hydrochloride, bromate, iodate, sulfate, nitrate, trifluoroacetate or acetate.
2. The preparation method of the phenol berberine benzimidazole compound and the pharmaceutically acceptable salt thereof comprises the following steps:
a. preparation of intermediate II: distilling berberine at 190 deg.C under reduced pressure to obtain berberrubine II;
b. preparation of intermediate III: dissolving the intermediate II and hexamethylenetetramine in trifluoroacetic acid to perform formylation reaction to obtain an intermediate III;
c. preparing an intermediate IV-1-23: dissolving o-phenylenediamine in N, N-dimethylformamide, and reacting with a halogenated compound under the action of potassium carbonate to obtain an intermediate IV-1-23;
d. preparation of phenolic berberine benzimidazole compounds of general formula I-1: reacting the intermediate III with o-phenylenediamine in the presence of sodium metabisulfite as a catalyst and N, N-dimethylformamide as a solvent to obtain a phenol berberine benzimidazole compound shown as a general formula I-1;
e. the preparation method of the phenolic berberine benzimidazole compound shown in the general formula I-2-4 comprises the following steps: taking N, N-dimethylformamide as a solvent, and reacting the intermediate III with 4-chloro-1, 2-o-phenylenediamine, 4-bromo-1, 2-o-phenylenediamine and 4-methyl-1, 2-o-phenylenediamine respectively to prepare a phenol berberine benzimidazole compound shown in a general formula I-2-4;
f. preparation of phenolic berberine benzimidazole compounds of general formula I-5: reacting the intermediate III with 4-methoxy-1, 2-o-phenylenediamine in the presence of potassium hydrogen persulfate serving as a catalyst and N, N-dimethylformamide serving as a solvent to obtain a phenol berberine benzimidazole compound shown as a general formula I-5;
g. preparation of phenolic berberine benzimidazole compounds represented by general formulas I-6-28: and (3) reacting the intermediate III with the intermediates IV-1-23 by using sodium metabisulfite as a catalyst and N, N-dimethylformamide as a solvent to obtain the phenol berberine benzimidazole compound shown in the general formula I-6-28.
Preferably, the first and second liquid crystal materials are,
in the step a, the time of the reduced pressure distillation is 40 min;
in the step b, the mass ratio of the intermediate II to the hexamethylene tetramine is 1: 1.2; the formylation reaction specifically uses trifluoroacetic acid as a solvent and reacts for 6h at 120 ℃;
in the step c, the mass ratio of the o-phenylenediamine to the halogenated compound to the potassium carbonate is 2:1.5: 1.5; the reaction is specifically carried out by taking N, N-dimethylformamide as a solvent, and stirring at room temperature for reaction for 4-10 h;
in the step d, the mass ratio of the intermediate III, o-phenylenediamine and sodium metabisulfite is 1:1:2, and the reaction specifically comprises the following steps: reacting for 5-8h at 110 ℃;
in the step e, the mass ratio of the intermediate III to the 4-chloro-1, 2-o-phenylenediamine, 4-bromo-1, 2-o-phenylenediamine or 4-methyl-1, 2-o-phenylenediamine is 1:2, and the reaction specifically comprises the following steps: reacting for 5-8h at 110 ℃;
in the step f, the mass ratio of the intermediate III, the 4-methoxy-1, 2-o-phenylenediamine and the potassium hydrogen persulfate is 1:2:2, and the reaction specifically comprises the following steps: reacting for 5-8h at 110 ℃;
in the step g, the mass ratio of the intermediate III, the intermediates IV-1 to IV-23 and the sodium metabisulfite is 1:2:2, and the reaction specifically comprises the following steps: reacting at 110 ℃ for 5-8 h.
3. The application of the phenol berberine benzimidazole compound and the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments.
Preferably, the bacteria is one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC29213, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922 or acinetobacter baumannii; the fungi is one or more of Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023 or Candida parapsilosis ATCC 22019.
4. A preparation containing the phenol berberine benzimidazole compound and the medicinal salt thereof.
Preferably, the preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.
The invention has the beneficial effects that: the invention provides a phenol berberine benzimidazole compound and a preparation method and application thereof, the invention utilizes the principle of drug design split, benzimidazole compounds are introduced on 12 th position of berberine, a series of phenol berberine benzimidazole compounds are designed and synthesized, the compounds are detected by in vitro antimicrobial activity to find that the compounds have certain inhibitory activity to gram positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC 29213), gram negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922, Acinetobacter baumannii) and fungi (candida tropicalis, aspergillus fumigatus, candida albicans ATCC90023, candida parapsilosis ATCC 22019), and can be used for preparing antibacterial and/or antifungal drugs, and the norfloxacin antibacterial composition has no obvious drug resistance, can be used together with norfloxacin to more efficiently inhibit the growth of bacteria, provides more efficient and safe candidate drugs for clinical antibacterial treatment, and is helpful for solving the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly-appeared harmful microorganisms and the like. The preparation raw materials are simple, cheap and easy to obtain, the synthetic route is short, and the application in the anti-infection aspect has important significance.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter.
Drawings
For the purposes of promoting a better understanding of the objects, aspects and advantages of the invention, reference will now be made to the following detailed description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a graph showing the results of the test of the inhibitory effect of compound I-20, norfloxacin and the combination of compound I-20 and norfloxacin on Staphylococcus aureus ATCC 29213.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Example 1 preparation of intermediate II
Berberine (15g,40.3mmol) was distilled at 190 deg.C under reduced pressure for 40min to give 11g of Berberrubine II in 78.6% yield.
Example 2 preparation of intermediate III
A50 mL round-bottomed flask was charged with intermediate II (1.50g,4.20mmol) and hexamethylenetetramine (706mg, 5.04mmol), and reacted at 120 ℃ for 6 hours using trifluoroacetic acid (10mL) as a solvent. The mixture was cooled to room temperature, 10% hydrochloric acid solution was added thereto, stirred for 20min, then neutralized with saturated sodium bicarbonate solution, suction filtered, and the resulting solid was further purified by silica gel column chromatography (eluent: dichloromethane/methanol, 25/1-20/1, V/V) to give 898mg of compound III as a yellow solid in yield: 55.4 percent; melting point: 241 ℃ and 243 ℃;1H NMR(600MHz,CD3OD)δ＝9.82(s,1H,Ber-8-H),8.76(s,1H,CHO),8.15(s,1H,Ber-13-H),7.56(s,1H,Ber-1-H),6.97(s,1H,Ber-4-H),6.13(s,2H,OCH2O),6.04(s,1H,Ber-11-H),4.10(s,3H,OCH3),3.34–3.32(m,2H,Ber-6-2H),3.27–3.23(m,2H,Ber-5-2H)ppm。
example 3 preparation of intermediates IV-1 to 23:
o-phenylenediamine (27mmol), potassium carbonate (20.25mmol) and a halogenated compound (20.25mmol) were reacted in N, N-dimethylformamide (45mL) with stirring at room temperature for 4-10 h. Washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase is washed 2-3 times with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to give compound IV, yield: 31.2 to 69.1 percent.
Example 4 preparation of compound I-1:
intermediate III (750mg, 2.10mmol), o-phenylenediamine (231mg, 2.10mmol) and sodium metabisulphite (798mg, 4.20mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 738mg of compound I-1 as a yellow solid, yield: 80.2%, melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ＝10.03(s,1H,Ber-8-H),9.25(dr,1H,OH),8.66(s,1H,Ber-13-H),7.95(s,1H,Ber-1-H),7.89(s,3H,Ber-4-H,Bim-4-H,Bim-7-H),7.53(s,2H,Ber-5-H,Bim-6-H),7.09(s,1H,Ber-11-H),6.16(s,2H,OCH2O),4.93(s,2H,Ber-6-2H),4.17(s,3H,OCH3),3.21(s,2H,Ber-5-2H)ppm。
example 5, preparation of compound I-2:
intermediate III (250mg, 0.65mmol) and 4-chloro-1, 2-o-phenylenediamine (185mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 158mg of compound I-2 as a yellow solid in yield: 46.9%, melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ＝10.01(s,1H,Ber-8-H),9.57(s,1H Ber-13-H),8.69(s,1H,Ber-1-H),7.85(s,1H,Bim-4-H),7.81(d,J＝8.5Hz,1H,Bim-6-H),7.71(s,1H,Ber-11-H),7.44(d,J＝8.3Hz,1H,Bim-7-H),7.07(s,1H,Ber-2-H),6.17(s,2H,OCH2O),4.96–4.90(m,2H,Ber-6-2H),4.17(s,3H,OCH3),3.26–3.18(m,2H,Ber-5-2H)ppm。
example 6 preparation of compound I-3:
intermediate III (300mg, 0.78mmol) and 4-bromo-1, 2-o-phenylenediamine (244mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 320mg of compound I-3 as a brown solid in yield: 61.1%, melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ＝10.00(s,1H,Ber-8-H),9.56(s,1H,Ber-13-H),8.69(s,1H,Ber-1-H),7.96(d,J＝8.3Hz,1H,Bim-4H),7.75(d,J＝8.5Hz,1H,Bim-6H),7.71(s,1H,Ber-11-H),7.54(d,J＝8.2Hz,1H,Bim-7-H),7.06(s,1H,Ber-2-H),6.17(s,2H,OCH2O),4.92(d,J＝5.7Hz,2H,Ber-6-2H),4.17(s,3H,OCH3),3.24–3.18(m,2H,Ber-5-2H)ppm。
example 7, preparation of Compound I-4:
intermediate III (300mg, 0.78mmol) and 4-methyl-1, 2-o-phenylenediamine (209mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 269mg of compound I-4 as a brown solid in yield: 69.5%, melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ＝10.07(s,1H,Ber-8-H),8.95(s,1H,Ber-13-H),8.68(s,1H,Ber-1-H),8.03(s,1H,Bim-4-H),7.81(d,J＝8.3Hz,1H,Bim-6-H),7.72(s,1H,Ber-11-H),7.43(d,J＝8.3Hz,1H,Bim-7-H),7.08(s,1H,Ber-2-H),6.16(s,2H,OCH2O),4.98–4.92(m,2H,Ber-6-2H),4.17(s,3H,OCH3),3.24–3.18(m,2H,Ber-5-2H),2.55(s,3H,CH3)ppm。
example 8, preparation of compound I-5:
intermediate III (350mg, 0.98mmol), 4-methoxy-1, 2-o-phenylenediamine (271mg, 1.96mmol) and oxone (612mg, 1.98mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 172mg of brown solid compound I-5, yield: 37.6%, melting point:>250℃；1H NMR(400MHz,DMSO-d6)δ＝9.82(s,1H,Ber-8-H),9.49(s,1H,Ber-13-H),8.08(s,1H,Ber-1-H),7.53(d,J＝8.7Hz,1H,Bim-7-H),7.44(s,1H,Ber-4-H),7.11(s,1H,Bim-4-H),7.03(s,1H,Ber-11-H),6.86(dd,J＝8.7,1.9Hz,1H,Bim-6-H),6.16(s,2H,OCH2O),4.69(s,2H,Ber-6-2H),3.97(s,3H,Bim-5-OCH3),3.84(s,3H,OCH3),3.14(s,2H,Ber-5-2H)ppm。
example 9, preparation of Compound I-6:
intermediate III (400mg, 1.04mmol), intermediate IV-1(283mg, 2.08mmol) and sodium metabisulfite (395mg, 2.08mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. ObtainedWashing the organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 260mg of compound I-6 as a yellow solid, yield: 49.8%, melting point:>250℃；1H NMR(600MHz,CD3OD)δ＝10.12(s,1H,Ber-8-H),8.52(s,1H,Ber-13-H),8.36(s,1H,Ber-1-H),8.16(d,J＝6.7Hz,1H,Bim-4-H),8.02(dd,J＝6.2,1.8Hz,1H,Bim-7-H),7.87–7.78(m,2H,Bim-5-H,Bim-6-H),7.64(s,1H,Ber-4-H),6.98(s,1H,Ber-11-H),6.06(s,2H,OCH2O),5.00(s,2H,Ber-6-2H),4.54(s,2H,CH2CH3),4.19(s,3H,OCH3),3.31(s,2H,Ber-5-2H),1.51(t,J＝6.1Hz,3H,CH2CH3)ppm。
example 10, preparation of compound I-7:
intermediate III (250mg, 0.65mmol), intermediate IV-2(214mg, 1.30mmol) and sodium metabisulphite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 238mg of compound I-7 as a yellow solid in yield: 69.0%, melting point:>250℃；1H NMR(600MHz,CD3OD)δ＝10.12(s,1H,Ber-8-H),8.53(s,1H,Ber-13-H),8.32(s,1H,Ber-1-H),8.14(d,J＝8.2Hz,1H,Bim-4-H),8.02(d,J＝8.6Hz,1H,Bim-7-H),7.86–7.80(m,2H,Bim-5-H,Bim-6-H),7.63(s,1H,Ber-4-H),6.98(s,1H,Ber-11-H),6.07(s,2H,OCH2O),5.00(s,2H,Ber-6-2H),4.48(s,2H,CH2(CH2)2CH3),4.18(s,3H,OCH3),3.31(s,2H,Ber-6-5H),1.89(s,2H,CH2CH2CH2CH3),1.32–1.26(m,2H,(CH2)2CH2CH3),0.80(t,J＝7.1Hz,3H,(CH2)3CH3)ppm。
example 11, preparation of Compound I-8:
intermediate III (250mg, 0.65mmol), intermediate IV-3(232mg, 1.30mmol) and sodium metabisulfite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 238mg of compound I-8 as a yellow solid in yield: 71.9%, melting point: 209-211 ℃;1H NMR(600MHz,CD3OD)δ＝9.42(s,1H,Ber-8-H),7.88(s,1H,Ber-13-H),7.75(d,J＝7.7Hz,1H,Ber-1-H),7.62(d,J＝10.5Hz,2H,Bim-4-H,Bim-7-H),7.37(dt,J＝15.3,7.0Hz,2H,Bim-5-H,Bim-6-H),7.10(s,1H,Ber-4-H),6.83(s,1H,Ber-11-H),5.96(s,2H,OCH2O),4.65(t,J＝5.7Hz,2H,Ber-6-2H),4.21(t,J＝7.1Hz,2H,CH2(CH2)3CH3),3.93(s,3H,OCH),3.17–3.10(m,2H,Ber-6-5H),1.70(dd,J＝14.3,7.3Hz,2H,CH2CH2(CH2)2CH3),1.09–0.95(m,4H,CH2CH2(CH2)2CH3),0.63(t,J＝7.0Hz,3H,(CH2)4CH3)ppm。
example 12, preparation of compound I-9:
intermediate III (400mg, 1.04mmol), intermediate IV-4(283mg, 2.08mmol) and sodium metabisulfite (395mg, 2.08mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After the reaction was complete, the mixture was cooled to room temperature and dichloromethane (3X 50 m) was addedL), and extracting. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 252mg of compound I-9 as a yellow solid, yield: 43.6%, melting point: 215-217 ℃;1H NMR(600MHz,CD3OD)δ＝10.09(s,1H,Ber-8-H),8.48(s,1H,Ber-13-H),8.29(s,1H,Ber-1-H),8.08(d,J＝8.0Hz,1H,Bim-4-H),8.00(d,J＝7.3Hz,1H,Bim-7-H),7.80–7.73(m,2H,Bim-5-H,Bim-6-H),7.58(s,1H,Ber-4-H),6.98(s,1H,Ber-11-H),6.06(s,2H,OCH2O),5.02–4.96(m,2H,Ber-6-2H),4.45(t,J＝7.2Hz,2H,CH2(CH2)4CH3),4.17(s,3H,OCH3),3.32–3.27(m,2H,Ber-5-2H),1.91–1.84(m,2H,CH2CH2(CH2)3CH3),1.22–1.08(m,6H,(CH2)2(CH2)3CH3),0.75(t,J＝6.7Hz,3H,(CH2)5CH3)ppm。
example 13, preparation of compound I-10:
intermediate III (300mg, 0.78mmol), intermediate IV-5(344mg, 1.56mmol) and sodium metabisulphite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 396mg of compound I-10 as a yellow solid in yield: 86.8%, melting point: 229 ℃ and 231 ℃;1H NMR(600MHz,CD3OD)δ＝9.57(s,1H,Ber-8-H),7.99(d,J＝7.0Hz,1H,Ber-13-H),7.83–7.76(m,2H,Bim-4-H,Ber-1-H),7.68(d,J＝7.9Hz,1H,Bim-7-H),7.42(dt,J＝14.9,7.2Hz,2H,Bim-5-H,Bim-6-H),7.16(s,1H,Ber-4-H),6.87(s,1H,Ber-11-H),5.99(s,2H,OCH2O),4.74(t,J＝5.9Hz,2H,Ber-6-2H),4.28(t,J＝6.9Hz,2H,CH2(CH2)6CH3),3.99(s,3H,OCH3),3.22–3.15(m,2H,Ber-6-2H),1.30(ddd,J＝14.5,12.8,6.1Hz,2H,CH2CH2(CH2)5CH3),1.09(dt,J＝14.1,6.9Hz,2H,(CH2)2CH2(CH2)4CH3),1.00(s,8H,(CH2)3(CH2)4CH3),0.77(t,J＝7.3Hz,3H,(CH2)7CH3)ppm。
example 14, preparation of Compound I-11:
intermediate III (250mg, 0.65mmol), intermediate IV-6(323mg, 1.30mmol) and sodium metabisulfite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 245mg of compound I-11 as a yellow solid in yield: 65.2%, melting point: 217 ℃ to 219 ℃;1H NMR(600MHz,CD3OD)δ＝9.88(s,1H,Ber-8-H),8.13(d,J＝1.8Hz,2H,Ber-13-H,Ber-1-H),7.84(d,J＝7.8Hz,1H,Bim-4-H),7.76(d,J＝7.9Hz,1H,Bim-7-H),7.48(dt,J＝21.8,7.3Hz,2H,Bim-5-H,Bim-6-H),7.25(s,1H,Ber-4-H),6.91(s,1H,Ber-11-H),6.01(s,2H,OCH2O),4.89(s,2H,Ber-6-2H),4.31(t,J＝6.9Hz,2H,CH2(CH2)8CH3),4.09(s,3H,OCH3),3.25–3.18(m,2H,Ber-5-2H),1.73(d,J＝11.2Hz,2H,CH2CH2(CH2)7CH3),1.21(dq,J＝14.2,7.1Hz,2H,(CH2)2CH2(CH2)6CH3),1.12(dd,J＝14.8,6.8Hz,2H,(CH2)3CH2(CH2)5CH3),1.05(d,J＝14.3Hz,2H,(CH2)4CH2(CH2)4CH3),0.99(d,J＝21.6Hz,8H,(CH2)5(CH2)4CH3),0.84(t,J＝7.3Hz,3H,(CH2)9CH3)ppm。
example 15, preparation of Compound I-12:
intermediate III (300mg, 0.78mmol), intermediate IV-7(231mg, 1.56mmol) and sodium metabisulfite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 195mg of compound I-12 as a yellow solid in yield: 57.4%, melting point: 220 ℃ and 222 ℃;1H NMR(600MHz,CD3OD)δ＝9.94(s,1H,Ber-8-H),8.25(d,J＝10.7Hz,2H,Ber-13-H,Ber-1-H),7.89–7.81(m,2H,Bim-4-H,Bim-7-H),7.62–7.58(m,2H,Bim-5-H,Bim-6-H),7.42(s,1H,Ber-4-H),6.85(s,1H,Ber-11-H),6.00(ddd,J＝15.7,10.2,4.9Hz,1H,CH＝CH2),5.94(s,2H,OCH2O),5.22(d,J＝10.6Hz,1H,CH＝CH2),5.10(d,J＝17.2Hz,1H,CH＝CH2),4.95(d,J＝4.1Hz,2H,CH2),4.85(t,J＝6.1Hz,2H,Ber-6-2H),4.01(s,3H,OCH3),3.19–3.15(m,2H,Ber-5-2H)ppm。
example 16, preparation of compound I-13:
intermediate III (250mg, 0.65mmol), intermediate IV-8(190mg, 1.30mmol) and sodium metabisulfite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After the reaction is finished, the reaction solution is added,the mixture was cooled to room temperature, dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 215mg of compound I-13 as a yellow solid in yield: 65.0%, melting point: 190 ℃ and 192 ℃;1H NMR(600MHz,CD3OD)δ＝10.09(s,1H,Ber-8-H),8.48(d,J＝9.1Hz,2H,Ber-13-H,Ber-1-H),8.14(d,J＝7.2Hz,1H,Bim-4-H),8.02(d,J＝7.1Hz,1H,Bim-7-H),7.79(p,J＝7.3Hz,2H,Bim-5-H,Bim-6-H),7.61(s,1H,Ber-4-H),6.98(s,1H,Ber-11-H),6.07(s,2H,OCH2O),5.29(d,J＝2.2Hz,2H,CH2),4.99(t,J＝6.2Hz,2H,Ber-6-2H),4.20(s,3H,OCH3),3.32–3.29(m,2H,Ber-5-2H),3.19(s,1H,C≡CH)ppm。
example 17, preparation of compound I-14:
intermediate III (300mg, 0.78mmol), intermediate IV-9(237mg, 1.56mmol) and sodium metabisulphite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 15/1-10/1, V/V) afforded 155mg of compound I-14 as a yellow solid in yield: 38.6%, melting point: 211-213 ℃;1H NMR(600MHz,CD3OD)δ＝10.07(s,1H,Ber-8-H),8.66(s,1H,Ber-13-H),8.30(s,1H,Ber-1-H),8.14(dd,J＝9.9,4.0Hz,1H,Bim-4-H),8.03–7.97(m,1H,Bim-7-H),7.80(dd,J＝5.7,3.6Hz,2H,Bim-5-H,Bim-6-H),7.56(s,1H,Ber-4-H),6.95(s,1H,Ber-11-H),6.03(s,2H,OCH2O),4.99–4.93(m,2H,Ber-6-2H),4.62(s,2H,CH2CH2OH),4.15(s,3H,OCH3),4.00–3.96(m,2H,CH2CH2OH),3.28–3.25(m,2H,Ber-5-2H)ppm。
example 18, preparation of compound I-15:
intermediate III (250mg, 0.65mmol)), intermediate IV-10(211mg, 1.30mmol) and sodium metabisulfite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 78mg of compound I-15 as a yellow solid in yield: 24.4%, melting point: 223 ℃ to 225 ℃;1H NMR(600MHz,CD3OD)δ＝9.46(s,1H,Ber-8-H),7.87(s,1H,Ber-13-H),7.77(d,J＝7.9Hz,1H,Ber-1-H),7.71(d,J＝6.7Hz,2H,Bim-4-H,Bim-7-H),7.39(dt,J＝21.5,7.4Hz,2H,Bim-5-H,Bim-6-H),7.12(s,1H,Ber-4-H),6.85(s,1H,Ber-11-H),5.97(s,2H,OCH2O),4.67(t,J＝5.8Hz,2H,Ber-6-2H),4.12(d,J＝6.7Hz,2H,CH2),3.94(s,3H,OCH3),3.18–3.12(m,2H,Ber-5-2H),0.71(d,J＝14.7Hz,1H,cyclopropane-CH),0.36(d,J＝7.9Hz,2H,cyclopropane-CH2),0.06(d,J＝4.7Hz,2H,cyclopropane-CH2)ppm。
example 19, preparation of compound I-16:
intermediate III (250mg, 0.65mmol)), intermediate IV-11(266mg, 1.30mmol) and sodium metabisulfite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 90mg of a yellow solidBody compound I-16, yield: 25.9%, melting point: 225 ℃ and 227 ℃;1H NMR(600MHz,CD3OD)δ＝9.54(s,1H,Ber-8-H),7.88(d,J＝3.3Hz,1H,Ber-13-H,),7.77(d,J＝5.0Hz,2H,Ber-1-H,Bim-4-H),7.66(d,J＝7.8Hz,1H,Bim-7-H),7.39(dt,J＝20.8,7.0Hz,2H,Bim-5-H,Bim-6-H),7.12–7.07(m,1H,Ber-4-H),6.86–6.79(m,1H,Ber-11-H),6.01–5.92(m,2H,OCH2O),4.71(s,2H,CH2),4.10(t,J＝9.4Hz,2H,Ber-6-2H),3.97(s,3H,OCH3),3.16(s,2H,Ber-5-2H),1.78–1.69(m,1H,cyclohexane-CH),1.47(s,3H,cyclohexane-CH2),1.35(d,J＝12.2Hz,2H,cyclohexane-CH2),0.97(s,3H,cyclohexane-CH2),0.70(d,J＝10.3Hz,2H,cyclohexane-CH2)ppm。
example 20, preparation of compound I-17:
intermediate III (250mg, 0.65mmol), intermediate IV-12(233mg, 1.30mmol) and sodium metabisulfite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 8 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 15/1-10/1, V/V) afforded 67mg of compound I-17 as a yellow solid in yield: 20.2%, melting point: 217 ℃ to 219 ℃;1H NMR(600MHz,CD3OD)δ＝9.41(s,1H,Ber-8-H),7.95(s,1H,Ber-13-H),7.77(d,J＝7.7Hz,1H,Bim-4-H),7.70(s,1H,Ber-1-H),7.66(d,J＝7.8Hz,1H,Bim-7-H),7.38(dd,J＝14.7,7.7Hz,2H,Bim-5-H,Bim-6-H),7.15(s,1H,Ber-4-H),6.85(s,1H,Ber-11-H),5.98(s,2H,OCH2O),4.65(s,2H,CH2CH2N(CH3)2),4.35(t,J＝6.6Hz,2H,Ber-6-2H),3.95(s,3H,OCH3),3.18–3.11(m,2H,Ber-5-2H),2.69(t,J＝6.5Hz,2H,CH2CH2N(CH3)2),1.29(s,3H,CH2CH2N(CH3)2),0.65(t,J＝7.1Hz,3H,CH2CH2N(CH3)2)ppm。
example 21 preparation of compound I-18:
intermediate III (250mg, 0.65mmol), intermediate IV-13(288mg, 1.30mmol) and sodium metabisulfite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 8 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 15/1-10/1, V/V) afforded 95mg of compound I-18 as a yellow solid in yield: 26.5%, melting point: 215-217 ℃;1H NMR(400MHz,CD3OD)δ＝10.06(s,1H,Ber-8-H),8.55(s,1H,Ber-13-H)),8.28(s,1H,Ber-1-H),8.22(d,J＝7.4Hz,1H,Bim-4-H),8.01–7.97(m,1H,Bim-7-H),7.83–7.74(m,2H,Bim-5-H,Bim-6-H),7.60(s,1H,Ber-4-H),6.94(s,1H,Ber-11-H),6.03(s,2H,OCH2O),4.95(d,J＝5.8Hz,2H,CH2CH2),4.64–4.54(m,2H,Ber-6-2H),4.19(s,3H,OCH3),3.91(d,J＝11.9Hz,2H,CH2CH2),3.74(t,J＝12.2Hz,2H,morpholine-CH2),3.26(s,2H,Ber-5-2H),3.20–3.13(m,2H,morpholine-CH2),3.02(t,J＝10.7Hz,2H,morpholine-CH2),2.29(s,2H,morpholine-CH2)。
example 22, preparation of compound I-19:
intermediate III (250mg, 0.65mmol), intermediate IV-14(303mg, 1.3mmol) and sodium metabisulfite (247mg, 1.30mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. For the organic phase obtainedWashing with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 280mg of compound I-19 as a yellow solid in yield: 76.5%, melting point: 215-217 ℃;1H NMR(600MHz,DMSO-d6)δ10.08(s,1H,Ber-8-H),8.28(s,2H,Ber-13-H,Ber-1-H),7.96(d,J＝7.0Hz,1H,Bim-4-H),7.83(d,J＝7.0Hz,1H,Bim-7-H),7.61(s,1H,Ber-4-H),7.55(s,2H,Bim-5-H,Bim-6-H)),7.22(d,J＝8.4Hz,2H,Ph-3-H,Ph-4-H),7.10(d,J＝8.3Hz,2H,Ph-6-H,Ph-5-H),7.06(s,1H,Ber-11-H),6.13(s,2H,OCH2O),5.57(s,2H,CH2),4.92(s,2H,Ber-6-2H),3.93(s,3H,OCH3),3.25–3.14(m,2H,Ber-5-2H)ppm。
example 23, preparation of compound I-20:
intermediate III (300mg, 0.78mmol), intermediate IV-15(417mg, 1.56mmol) and sodium metabisulfite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 204mg of compound I-20 as a yellow solid in yield: 41.5%, melting point: 190 ℃ and 192 ℃;1H NMR(600MHz,CD3OD)δ＝10.04(s,1H,Ber-8-H),8.40(s,1H,Ber-13-H),8.10(ddd,J＝8.6,6.9,2.7Hz,2H,Bim-4-H,Bim-7-H),7.90(s,1H,Ber-1-H),7.88–7.82(m,2H,Bim-5-H,Bim-6-H),7.46(s,1H,Ber-4-H),7.27(d,J＝1.7Hz,1H,Ph-3-H),7.17(d,J＝8.4Hz,1H,Ph-5-H),7.13(dd,J＝8.3,1.7Hz,1H,Ph-6-H),6.96(s,1H,Ber-11-H),6.10(s,2H,OCH2O),5.78(s,2H,CH2),4.93(s,2H,Ber-5-2H,CD3OD-H2O),4.09(s,3H,OCH3),3.34–3.32(m,2H,Ber-6-2H),3.29(t,J＝6.1Hz,2H,Ber-5-2H)ppm。
example 24, preparation of compound I-21:
intermediate III (400mg, 1.04mmol), intermediate IV-16(556mg, 2.08mmol) and sodium metabisulfite (395mg, 2.08mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 278mg of compound I-21 as a yellow solid, yield: 41.2%, melting point: 201-203 ℃;1H NMR(600MHz,CD3OD)δ＝9.95(s,1H,Ber-8-H),8.15(s,1H,Ber-13-H),7.94(d,J＝7.7Hz,1H,Bim-4-H),7.86(d,J＝7.8Hz,1H,Bim-7-H),7.73(s,1H,Ber-1-H),7.63–7.54(m,2H,Bim-5-H,Bim-6-H),7.24(d,J＝8.3Hz,1H,Ph-5-H),7.10(s,1H,Ber-4-H),6.98(s,1H,Ph-2-H),6.94(s,1H,Ph-6-H),6.92(s,1H,Ber-11-H),6.06(s,2H,OCH2O),5.47(s,2H,CH2),4.92(d,J＝6.1Hz,2H,Ber-6-2H),4.03(s,3H,OCH3),3.27–3.23(m,2H,Ber-5-2H)ppm。
example 25, preparation of compound I-22:
intermediate III (300mg, 0.78mmol), intermediate IV-17(322mg, 1.56mmol) and sodium metabisulphite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 300mg of compound I-22 as a yellow solid in yield: 81.5%, melting point: 190 ℃ and 192 ℃;1H NMR(600MHz,CD3OD)δ＝9.97(s,1H,Ber-8-H),8.22(s,1H,Ber-13-H),7.94(s,2H,Ber-1-H,Bim-4-H),7.87–7.84(m,1H,Bim-7-H),7.59(p,J＝6.6Hz,2H,Bim-5-H,Bim-6-H),7.26(s,1H,Ber-4-H),7.07(dd,J＝14.7,8.3Hz,1H,Ph-3-H),6.95(s,1H,Ber-11-H),6.83(t,J＝7.4Hz,1H,Ph-5-H),6.79–6.72(m,1H,Ph-6-H),6.06(s,2H,OCH2O),5.59(s,2H,CH2),4.93(d,J＝6.2Hz,2H,Ber-6-2H,OCH3),4.04(s,3H,OCH3),3.25(t,J＝6.1Hz,2H,Ber-5-2H)。
example 26, preparation of compound I-23:
intermediate III (300mg, 0.78mmol), intermediate IV-18(337mg, 1.56mmol) and sodium metabisulphite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 230mg of compound I-23 as a yellow solid in yield: 50.8%, melting point: 211-213 ℃;1H NMR(600MHz,CD3OD)δ＝10.05(s,1H,Ber-8-H),8.41(s,1H,Ber-13-H),8.12(d,J＝7.5Hz,1H,Bim-4-H),8.08–8.03(m,1H,Bim-7-H),8.01(s,1H,Ber-1-H),7.82(p,J＝7.4Hz,2H,Bim-5-H,Bim-6-H),7.50(s,1H,Ber-4-H),7.23–7.13(m,2H,Ph-3-H,Ph-4-H),7.00(t,J＝7.5Hz,1H,Ph-6-H),6.97(s,1H,Ber-11-H),6.95–6.90(m,1H,Ph-5-H),6.08(s,2H,OCH2O),5.79(s,2H,CH2),4.96(s,12H,Ber-6-2H,CD3OD-H2O),4.07(s,3H,OCH3),3.36–3.20(m,2H,Ber-5-2H)ppm。
example 27, preparation of compound I-24:
intermediate III (250mg, 0.65mmol), intermediate IV-19(190 mg)1.30mmol) and sodium metabisulphite (247mg, 1.30mmol) in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-20/1, V/V) afforded 257mg of compound I-24 as a yellow solid in yield: 67.5%, melting point:>250℃；1H NMR(600MHz,CD3OD)δ＝10.01(s,1H,Ber-8-H),8.30(d,J＝12.9Hz,2H,Ber-13-H,Ber-1-H),7.97–7.93(m,1H,Bim-4-H),7.80(d,J＝7.6Hz,1H,Bim-7-H),7.69(d,J＝6.4Hz,2H,Bim-5-H,Bim-6-H),7.57(s,1H,Ber-4-H),6.90(s,1H,Ber-11-H),6.02(s,2H,OCH2O),5.45(s,2H,CH2),4.92(s,2H,Ber-6-2H,CD3OD-H2O),4.11(s,3H,OCH3),3.44–3.37(m,2H,CON(CH2CH3)2),3.22–3.19(m,2H,Ber-5-2H),1.32(t,J＝7.3Hz,2H,CON(CH2CH3)2),1.15–1.10(m,3H,CON(CH2CH3)2),0.98(dd,J＝6.1,3.7Hz,3H,CON(CH2CH3)2)。
example 28, preparation of compound I-25:
intermediate III (300mg, 0.78mmol), intermediate IV-20(249mg, 1.56mmol) and sodium metabisulfite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 25/1-19/1, V/V) afforded 278mg of compound I-25 as a yellow solid, yield: 61.5%, melting point:>250℃；1H NMR(400MHz,CD3OD)δ＝10.06(s,1H,Ber-8-H),8.45(s,1H,Ber-13-H),8.30(s,1H,Ber-1-H),8.01(dd,J＝6.4,2.9Hz,1H,Bim-4-H),7.87(dd,J＝6.4,3.0Hz,1H,Bim-7-H),7.82–7.76(m,2H,Bim-5-H,Bim-6-H),7.62(s,1H,Ber-4-H),6.93(s,1H,Ber-11-H),6.03(s,2H,OCH2O),5.50(s,2H,CH2),4.95(s,2H,Ber-6-2H,CD3OD-H2O),4.14(s,3H,OCH3),4.05–3.97(m,1H,CON(CH(CH3)2)2),3.56–3.47(m,1H,CON(CH(CH3)2)2),3.25(s,2H,Ber-5-2H),1.09(d,J＝79.6Hz,12H,CON(CH(CH3)2)2)ppm。
example 29, preparation of compound I-26:
intermediate III (300mg, 0.78mmol), intermediate IV-21(367mg, 1.56mmol) and sodium metabisulfite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification using silica gel column chromatography (300-400 mesh) (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 331mg of compound I-26 as a yellow solid, yield: 77.2%, melting point: 232 ℃ and 234 ℃;1H NMR(600MHz,CD3OD)δ9.52(s,1H,Ber-8-H),8.12(s,1H,Ber-13-H),7.79–7.68(m,2H,Bim-4-H,Bim-7-H),7.49(s,1H,Ber-1-H),7.37(dd,J＝16.8,7.1Hz,2H,Bim-5-H,Bim-6-H),7.29(s,1H,Ber-4-H),6.79(s,1H,Ber-11-H),5.96(s,2H,OCH2O),4.94(s,2H,Ber-6-2H),4.68(s,2H,CH2),3.88(s,3H,OCH3),3.43(s,2H,pyrrole-CH2),3.31(s,2H,pyrrole-CH2),3.07(s,2H,Ber-5-2H),1.93(d,J＝6.0Hz,2H,pyrrole-CH2),1.85–1.77(m,2H,pyrrole-CH2)ppm。
example 30, preparation of compound I-27:
intermediate III (300mg, 0.78mmol), intermediate IV-22(367mg, 1.56mmol) and sodium metabisulfite (297mg, 1.56mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 386mg of compound I-27 as a yellow solid in yield: 87.5%, melting point: 238-241 ℃ of temperature;1H NMR(400MHz,DMSO-d6)δ＝9.63(s,1H,Ber-8-H),8.12(s,1H,Ber-13-H),7.77(dd,J＝5.3,3.7Hz,1H,Bim-4-H),7.67(s,1H,Ber-1-H),7.58–7.52(m,1H,Bim-7-H),7.37–7.29(m,2H,Bim-5-H,Bim-6-H),7.27(s,1H,Ber-4-H),7.00(s,1H,Ber-11-H),6.07(s,2H,OCH2O),5.15(s,2H,Ber-6-2H),4.80–4.69(m,2H,CH2),3.86(s,3H,OCH3),3.48(d,J＝10.7Hz,4H,morpholine-4H),3.39(d,J＝7.1Hz,4H,morpholine-4H),3.14–3.06(m,2H,Ber-5-2H)ppm。
example 31, preparation of compound I-28:
intermediate III (400mg, 1.04mmol), intermediate IV-23(462mg, 2.08mmol) and sodium metabisulfite (395mg, 2.08mmol) were reacted in N, N-dimethylformamide at 110 ℃ for 6 h. After completion of the reaction, the mixture was cooled to room temperature, and dichloromethane (3X 50mL) was added and extracted. Washing the obtained organic phase with saturated sodium chloride solution for 2-3 times, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude product. Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol, 20/1-15/1, V/V) afforded 499mg of yellow solid compound I-28, yield: 86.8%, melting point: 220 ℃ and 222 ℃;1H NMR(600MHz,CD3OD)δ＝10.07(s,1H,Ber-8-H),8.41(s,1H,Ber-13-H),8.23(s,1H,Ber-1-H),8.05–7.95(m,1H,Bim-4-H),7.91(d,J＝1.7Hz,1H,Bim-7-H),7.82–7.75(m,2H,Bim-5-H,Bim-6-H),7.54(s,1H,Ber-4-H),6.94(s,1H,Ber-11-H),5.28(t,J＝21.6Hz,2H,CH2),4.95(s,2H,Ber-6-2H),4.14(s,3H,OCH3),3.26(d,J＝5.2Hz,2H,Ber-5-2H),1.35(s,9H,C(CH3)3)ppm。
note: ber is benzene, Bim is benzimidazole, and Ph is a benzene ring.
Example 32 in vitro antimicrobial Activity of phenolic Berberine benzimidazole Compounds
The phenolic berberine benzimidazole compounds prepared in examples 4-31 were tested for their Minimal Inhibitory Concentrations (MIC) against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Acinetobacter baumannii) and fungi (Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis ATCC 22019) by a multiple dilution method of Clinical Laboratory Standards (CLSI) prepared by the American national Committee, the Minimum Inhibitory Concentrations (MIC) of the phenolic berberine benzimidazole compounds were determined, the test compounds were dissolved in a small amount of dimethyl sulfoxide, diluted with water to a solution having a concentration of 1.28mg/mL, and diluted with a culture medium to 256. mu.g/mL, after incubation at 35 ℃ for 24-72 hours, the plates were shaken well on a shaker and MIC was measured at 490nm, the results are shown in tables 1-3.
TABLE 1 in vitro gram-positive activity (MIC, mM) of phenolic berberine benzimidazole compounds prepared in examples 4-31
As can be seen from Table 1, the compounds of the present invention showed a certain inhibitory effect on gram-positive bacteria tested, the inhibitory activity of alkane compounds was relatively good, and the 2, 4-dichlorobenzyl substituted compound (compound I-20) had good inhibitory activity against MRSA and Staphylococcus aureus ATCC29213 with MIC values of 0.006mM, respectively.
TABLE 2 phenolic berberine benzimidazole compounds prepared in examples 4-31 have in vitro anti-gram negative bacterial activity (MIC, mM)
As can be seen from Table 2, the compounds of the present invention showed a certain inhibitory effect on the tested gram-negative bacteria, the MIC values of n-butyl derivative I-8 in the alkyl substituted compound were 0.014 to 0.029mM for the tested Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Escherichia coli ATCC 25922 and Acinetobacter baumannii, and the MIC values of methylene cyclopropane substituted compound I-15 for Escherichia coli and Pseudomonas aeruginosa were 0.015 mM and 0.004mM, respectively, which are significantly superior to those of the reference drug norfloxacin (the MIC values were 0.050mM and 0.006mM, respectively). The inhibitory activity of the 2, 4-dichlorobenzyl substituted compound (compound I-20) on acinetobacter baumannii is 2 times that of norfloxacin.
TABLE 3 in vitro antifungal Activity data (MIC, mM) for phenolic berberine benzimidazole compounds prepared in examples 4-31
As can be seen from Table 3, the compounds of the invention show a certain inhibitory effect on the fungi tested. The series of compounds have stronger inhibition activity on aspergillus fumigatus, and the activity of part of compounds is obviously superior to that of a reference drug fluconazole. MIC values of the compounds I-4 and I-6 to Candida parapsilosis ATCC 22019 reached 0.002mM and 0.004mM, respectively.
Example 33
The Minimal Inhibitory Concentrations (MICs) of the 2, 4-dichlorobenzyl-substituted phenol berberine benzimidazole compound (compound I-20) prepared in example 23 and the reference drug norfloxacin against bacteria (MRSA, staphylococcus aureus ATCC29213, pseudomonas aeruginosa, acinetobacter baumannii, enterococcus faecalis, escherichia coli) were examined by a checkerboard titration method, and the interaction was judged by calculating Fractional inhibitory concentration index (FIC), where MIC of the drug a when the drug a was used in combination/MIC of the drug a when the drug a was used alone + MIC of the drug b when the drug b was used alone/MIC of the drug b when the drug b was used alone, the FIC index was not more than 0.5 as a synergistic effect, 0.5 to 1 as an additive effect, >1 and <2 as an unrelated effect, and not less than 2 as an antagonistic effect, and the results are shown in table 4.
TABLE 4 data (MIC, μ g/mL) for the combination of phenolic berberine benzimidazole compound and norfloxacin prepared in example 23
RD: reference drug norfloxacin.
The 2, 4-dichlorobenzyl substituted phenol berberine benzimidazole compound (compound I-20) prepared in example 23, norfloxacin, and the combination of compound I-20 and norfloxacin were tested for their inhibitory effects on staphylococcus aureus ATCC29213, respectively, and the test results are shown in fig. 1, and it can be seen from fig. 1 that, after 16 generations of culture, staphylococcus aureus ATCC29213 was more resistant to the reference drug norfloxacin than compound I-20 and the combination of compound norfloxacin.
EXAMPLE 34 pharmaceutical use of phenolic Berberine benzimidazole Compounds
According to the antimicrobial activity detection result, the phenol berberine benzimidazole compound has good antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicines for clinical use. The medicines can be single-ingredient preparations, for example, the medicines are prepared from phenol berberine benzimidazole compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound preparation is prepared by phenolic berberine benzimidazole compounds with one structure, existing antibacterial and antifungal active ingredients (such as sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or is prepared by several phenolic berberine benzimidazole compounds with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.
1. Preparation of Compound I-4 tablets
Prescription: the tablet is prepared from the following components of compound I-410 g, corn starch 50g, lactose 187g, magnesium stearate 3.0g, and a proper amount of ethanol solution with the volume percentage concentration of 70%, and is prepared into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-4 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.
2. Preparation of Compound I-6 Capsule
Prescription: compound I-625 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2.0g, sweetening agent 1.25g, orange essence 0.25g, proper amount of pigment and water, and prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound I-6, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, granulating with water, sieving with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into capsule; each tablet weighs 50mg, and the content of active ingredient is 25 mg.
3. Preparation of Compound I-9 granules
Prescription: compound I-926 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound I-9, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-20 injection
Prescription: compound I-2010 g, propylene glycol 500mL, water for injection 500mL, made up to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-20, adding propylene glycol and injection water, stirring for dissolving, adding 1g of activated carbon, fully stirring, standing for 15 minutes, filtering with a 5-micron titanium rod for decarbonization, sequentially fine-filtering with microporous filter membranes with the pore diameters of 0.45 micron and 0.22 micron, finally encapsulating in a 10mL ampoule, and sterilizing with 100 ℃ circulating steam for 45 minutes to obtain the compound I-20.
5. Preparation of compound I-8 powder injection
The preparation method comprises the following steps: and subpackaging the intermediate I-8 sterile powder under the aseptic condition to obtain the compound.
6. Preparation of Compound I-15 eye drops
Prescription: compound I-153.78 g, sodium chloride 0.9g, appropriate amount of boric acid buffer solution, and distilled water to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-15 and sodium chloride, adding into 500mL of distilled water, dissolving completely, adjusting pH to 6.5 with boric acid buffer solution, adding distilled water to 1000mL, stirring well, filtering with microporous membrane, filling, sealing, and sterilizing with 100 deg.C flowing steam for 1 hr.
7. Preparation of Compound I-16 Liniment
Prescription: compound I-164 g, potassium soap 7.5g, camphor 5g, distilled water to 100 mL.
The preparation method comprises the following steps: dissolving camphor with 95 percent ethanol solution by volume percentage for later use; heating potassium soap to liquefy, weighing compound I-16, adding potassium soap solution and Camphora ethanol solution under stirring, gradually adding distilled water, emulsifying completely, and adding distilled water to full volume.
8. Preparation of suppository of compound I-8
Prescription: 100 metric copies of compound I-84 g, 14g of gelatin, 70g of glycerol and 100mL of distilled water.
The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound I-8, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-4 ointment
Prescription: 40.5-2 g of compound I, 6-8 g of hexadecanol, 8-10 g of white vaseline, 8-19 g of liquid paraffin, 2-5 g of monoglyceride, 2-5 g of polyoxyethylene (40) stearate, 5-10 g of glycerol, 0.1g of ethylparaben and distilled water added to 100 g.
The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely dissolve, mixing, and keeping the temperature at 80 deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85 deg.C for dissolving, adding oil phase under stirring, emulsifying, adding compound I-4, stirring, and cooling.
10. Preparation of compound I-6 and fluconazole compound powder injection
Prescription: the total amount of the compound I-650 g, fluconazole 50g and sodium benzoate 1g is 100 bottles.
The preparation method comprises the following steps: taking the compound I-5, the fluconazole and the sodium benzoate according to the prescription amount, uniformly mixing in a sterile state, and subpackaging 100 bottles to obtain the compound I-5.
11. Preparation of Compound I-9 Aerosol
Prescription: compound I-92.5 g, Span 203 g, talcum powder (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.
The preparation method comprises the following steps: respectively placing the compound I-9, the Span20 and the talcum powder in a vacuum drying oven for drying for a plurality of hours, placing in a dryer for cooling to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the trichloromonofluoromethane.
Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.
Claims (10)
1. The phenol berberine benzimidazole compound and the medicinal salt thereof are characterized in that the structure is shown as the general formula I:
in the formula (I), the compound is shown in the specification,
R1is hydrogen, alkyl, methoxy, halogen, cyano, nitro, trifluoromethyl, alkenyl, alkynyl, aryl, hydroxyalkyl, carboxyl, ester, acyl or mercapto;
R2is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, cyano, hydroxyalkyl, amino, carboxyl, ester, acyl or heterocyclyl;
n is an integer of 0 to 18.
2. The phenolic berberine benzimidazole compound of claim 1, and pharmaceutically acceptable salts thereof,
R1is hydrogen, chlorine, bromine, methyl or methoxy;
R2is hydrogen, methyl, alkenyl, alkynyl, hydroxymethyl, cyclopropyl, cyclohexyl, N-dimethylamino, morpholinyl, 2-chlorophenyl, 2, 4-dichlorophenyl, 3, 4-dichlorophenyl, 2, 4-difluorophenyl, 2-fluorophenyl, N-diacetamido, N-diisopropylamido, pyrrylamido, morpholinoamido or tert-butylcarbonyl;
n is 0, 1,2, 3,4, 5, 7 or 9.
3. The phenolic berberine benzimidazole compound of claim 1, or a pharmaceutically acceptable salt thereof, that is any one of the following compounds:
4. the phenolic berberine benzimidazole compound of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, a bromate, an iodate, a sulfate, a nitrate, a trifluoroacetate or an acetate salt thereof.
5. A process for the preparation of a phenolic berberine benzimidazole compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein the process comprises:
a. preparation of intermediate II: distilling berberine at 190 deg.C under reduced pressure to obtain berberrubine II;
b. preparation of intermediate III: dissolving the intermediate II and hexamethylenetetramine in trifluoroacetic acid to perform formylation reaction to obtain an intermediate III;
c. preparing an intermediate IV-1-23: dissolving o-phenylenediamine in N, N-dimethylformamide, and reacting with a halogenated compound under the action of potassium carbonate to obtain an intermediate IV-1-23;
d. preparation of phenolic berberine benzimidazole compounds of general formula I-1: reacting the intermediate III with o-phenylenediamine in the presence of sodium metabisulfite as a catalyst and N, N-dimethylformamide as a solvent to obtain a phenol berberine benzimidazole compound shown as a general formula I-1;
e. the preparation method of the phenolic berberine benzimidazole compound shown in the general formula I-2-4 comprises the following steps: taking N, N-dimethylformamide as a solvent, and reacting the intermediate III with 4-chloro-1, 2-o-phenylenediamine, 4-bromo-1, 2-o-phenylenediamine and 4-methyl-1, 2-o-phenylenediamine respectively to prepare a phenol berberine benzimidazole compound shown in a general formula I-2-4;
f. preparation of phenolic berberine benzimidazole compounds of general formula I-5: reacting the intermediate III with 4-methoxy-1, 2-o-phenylenediamine in the presence of potassium hydrogen persulfate serving as a catalyst and N, N-dimethylformamide serving as a solvent to obtain a phenol berberine benzimidazole compound shown as a general formula I-5;
g. preparation of phenolic berberine benzimidazole compounds represented by general formulas I-6-28: and (3) reacting the intermediate III with the intermediates IV-1-23 by using sodium metabisulfite as a catalyst and N, N-dimethylformamide as a solvent to obtain the phenol berberine benzimidazole compound shown in the general formula I-6-28.
6. The method of claim 5,
in the step a, the time of the reduced pressure distillation is 40 min;
in the step b, the mass ratio of the intermediate II to the hexamethylene tetramine is 1: 1.2; the formylation reaction specifically uses trifluoroacetic acid as a solvent and reacts for 6h at 120 ℃;
in the step c, the mass ratio of the o-phenylenediamine to the halogenated compound to the potassium carbonate is 2:1.5: 1.5; the reaction is specifically carried out by taking N, N-dimethylformamide as a solvent, and stirring at room temperature for reaction for 4-10 h;
in the step d, the mass ratio of the intermediate III, o-phenylenediamine and sodium metabisulfite is 1:1:2, and the reaction specifically comprises the following steps: reacting for 5-8h at 110 ℃;
in the step e, the mass ratio of the intermediate III to the 4-chloro-1, 2-o-phenylenediamine, 4-bromo-1, 2-o-phenylenediamine or 4-methyl-1, 2-o-phenylenediamine is 1:2, and the reaction specifically comprises the following steps: reacting for 5-8h at 110 ℃;
in the step f, the mass ratio of the intermediate III, the 4-methoxy-1, 2-o-phenylenediamine and the potassium hydrogen persulfate is 1:2:2, and the reaction specifically comprises the following steps: reacting for 5-8h at 110 ℃;
in the step g, the mass ratio of the intermediate III, the intermediates IV-1 to IV-23 and the sodium metabisulfite is 1:2:2, and the reaction specifically comprises the following steps: reacting at 110 ℃ for 5-8 h.
7. Use of the phenolic berberine benzimidazole compound of any one of claims 1-4, and pharmaceutically acceptable salts thereof, for the preparation of an antibacterial and/or antifungal medicament.
8. The use of claim 7, wherein the bacteria is one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC29213, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922, or acinetobacter baumannii; the fungi is one or more of Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023 or Candida parapsilosis ATCC 22019.
9. A preparation comprising the phenolic berberine benzimidazole compound of any one of claims 1-4, and pharmaceutically acceptable salts thereof.
10. The preparation of claim 9, wherein the preparation is one of a tablet, a capsule, a granule, an injection, a powder injection, an eye drop, a liniment, a suppository, an ointment or an aerosol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911381997.9A CN111018853A (en) | 2019-12-27 | 2019-12-27 | Phenol berberine benzimidazole compound and preparation method and application thereof |
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| CN112521382A (en) * | 2020-12-14 | 2021-03-19 | 西南大学 | Aloe-emodin thiazolidinedione compound and preparation method and application thereof |
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