CN112209881B - Emodin oxazole compound and preparation method and application thereof - Google Patents
Emodin oxazole compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an emodin oxazole compound and a preparation method and application thereof, belonging to the technical field of chemical synthesis. The emodin oxazole alcohol compound is shown in general formulas I-VII, has certain inhibitory activity on one or more of gram-positive bacteria, gram-negative bacteria and fungi, can be used for preparing antibacterial and/or antifungal medicaments, provides more efficient and safe candidate medicaments for clinical antimicrobial treatment, and is beneficial to solving 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 aspect of infection resistance is of great significance.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an emodin oxazole compound, and a preparation method and application thereof.
Background
The development of antibacterial drugs designed from natural products with abundant content and low toxicity is a research focus in recent years, such as coumarin and berberine. However, rhubarb, which has a wide range of biological activities, is a main ingredient of Chinese herbal medicines, and research in the antibacterial field is very rare. Some researches show that the derivatives of emodin can inhibit the replication of DNA by causing the permeability of bacterial cell membranes to increase, leading nucleotides and other important substances in bacterial cells to leak out, inhibiting the metabolic activity of microorganisms or damaging the structure of bacterial DNA, thereby inhibiting the growth and the reproduction of bacteria, such as emodin, aloe-emodin and tetracycline antibacterial drugs. This has therefore prompted us to develop emodin antibacterial compounds with potential multi-targets. Researches show that the planar rigid structure of emodin causes poor water solubility, and the application of emodin in the field of medicines is severely limited. However, reports show that water-soluble groups are introduced into the emodin derivative, so that the bioavailability of the emodin derivative is improved, and the bioactivity of the emodin derivative can be further improved.
Piperazine is an important nitrogen heterocycle, and exists in many clinical medicines, such as antibacterial drugs linezolid and ciprofloxacin, probably because two secondary nitrogen atoms of a polar piperazine ring not only can improve the water solubility of a drug molecule through forming a hydrogen bond, but also plays an important role in the bioavailability of a compound, and is also helpful for improving the binding affinity of a bioactive molecule and enhancing the bioactivity of the bioactive molecule. In addition, the particularity of the piperazine structure enables the piperazine structure to be widely applied to developers of new drugs. Therefore, linking the oxazolol structure with emodin via piperazine is desirable to develop better antibacterial compounds.
Hydroxyethyl is an important structural fragment widely existing in a plurality of active molecules, plays a positive role in changing the biological activity of drug molecules, is beneficial to improving the water solubility of the compound, and can form hydrogen bonds with drug resistance mutation regions of bacteria so as to overcome drug resistance to a certain extent. Azoles are important five-membered aromatic heterocyclic compounds, have high electrical property, are beneficial to the azole derivatives to interact with the active sites of organisms through a plurality of non-covalent bonds such as coordination bonds, hydrogen bonds, pi-pi accumulation and the like, and improve the physicochemical and pharmacokinetic properties of drug molecules, thereby improving the bioavailability and the drug selectivity and being widely applied in the medicine development. At present, many azoles alcohol drugs formed by combining hydroxyethyl and azole are widely used in clinical treatment of various diseases, such as metronidazole, secnidazole and ornidazole which are long-term used in clinical treatment of infectious diseases caused by anaerobic bacteria, and antifungal fluconazole. Therefore, the oxazolol fragment shows wide application potential and great development value in the antimicrobial field, and becomes one of the hot spots of medicinal chemistry research.
Disclosure of Invention
In view of the above, an object of the present invention is to provide emodin halohydrin compounds and pharmaceutically acceptable salts thereof; the second object of the present invention is to provide a process for preparing an emodin oxazolol compound and a pharmaceutically acceptable salt thereof; the third purpose of the invention is to provide the application of the emodin oxazole 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 emodin oxazole compound and the medicinal salt thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
1. emodin oxazole compound and its medicinal salt, the structure is shown in general formula I-VII:
in the formula (I), the compound is shown in the specification,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Hydrogen, alkyl, halogen, aldehyde group, methoxy, trifluoromethyl, nitro or cyano;
x, Y, Z is a CH or N atom.
Preferably, the first and second electrodes are formed of a metal,
R 1 、R 2 、R 3 is hydrogen or alkyl;
R 4 、R 5 、R 6 hydrogen, alkyl, halogen, aldehyde, nitro or cyano;
R 7 、R 8 、R 9 、R 10 、R 11 is hydrogen, halogen, trifluoromethyl or nitro;
R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Is hydrogen or halogen;
x, Y, Z is a CH or N atom.
Preferably, it is any one of the following compounds:
preferably, the pharmaceutically acceptable salt is a hydrochloride, nitrate or acetate salt.
2. The preparation method of the emodin azole alcohol compound and the pharmaceutically acceptable salt thereof comprises the following steps:
a. preparation of intermediate VIII: the aloe-emodin and thionyl chloride are subjected to halogenation reaction at room temperature to obtain an intermediate VIII;
b. preparation of intermediate IX: carrying out nucleophilic substitution reaction on the intermediate VIII and piperazine to obtain an intermediate IX;
c. preparation of intermediate X: carrying out nucleophilic substitution reaction on the intermediate IX and epoxy chloropropane under the action of potassium carbonate to obtain an intermediate X;
d. preparation of emodin oxazolol compounds of general formulae I-VI: carrying out ring-opening reaction on the intermediate X and an azole compound under the conditions that acetonitrile is used as a solvent and potassium carbonate is used as a base to obtain an emodin azole alcohol compound shown in general formulas I-VI;
e. preparation of emodin oxazolol compound of general formula VII: and (3) carrying out ring-opening reaction on the intermediate X and the carbazole compound under the condition that acetonitrile is used as a solvent and cesium carbonate is used as alkali to obtain the emodin oxazole compound shown in the general formula VII.
Preferably, the first and second electrodes are formed of a metal,
in the step a, the molar ratio of the aloe-emodin to the thionyl chloride is 1: 27.5; the halogenation reaction specifically comprises the following steps: reacting for 8 hours at room temperature by taking N, N-dimethylformamide as a solvent;
in the step b, the molar ratio of the intermediate VIII to the piperazine is 1: 5; the nucleophilic substitution reaction is specifically as follows: reacting for 8 hours at room temperature by taking dichloromethane as a solvent;
in the step c, the molar ratio of the intermediate IX, the potassium carbonate and the epichlorohydrin is 1:1.5: 1.5; the nucleophilic substitution reaction specifically comprises the following steps: reacting for 24 hours at room temperature by taking acetonitrile as a solvent;
in the step d, the molar ratio of the intermediate X, the potassium carbonate and the azole compound is 1:1.5: 1.2; the ring-opening reaction is specifically as follows: reacting for 12 hours at 80 ℃;
in the step e, the molar ratio of the intermediate X, cesium carbonate and the carbazole compound is 1:1.5: 1.2; the ring-opening reaction is specifically as follows: the reaction was carried out at 80 ℃ for 12 h.
3. The emodin oxazole compound and the medicinal salt thereof are applied to the preparation of antibacterial and/or antifungal medicaments.
Preferably, the bacteria are one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922, or acinetobacter baumannii; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC 90023 or Candida parapsilosis ATCC 22019.
4. A preparation containing the emodin oxazole 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 emodin azole alcohol compounds and a preparation method and application thereof, the invention utilizes the drug design split principle to synthesize a series of novel emodin azole alcohol compounds through piperazine bridging emodin and azole alcohol design, the compounds are detected by in vitro antimicrobial activity to find that the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923 and staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa, Pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922 and Acinetobacter baumannii) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC 90023 and candida parapsilosis ATCC 22019), and can be used for preparing antibacterial and/or antifungal drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial therapy and being beneficial to solving the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly emerged 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 aspect of infection resistance is of great 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.
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 VIII
A150 mL round bottom flask was charged with 1, 8-dihydroxy-3-hydroxymethylanthraquinone (2.7g, 10mmol) and thionyl chloride (20mL, 275mmol), and N, N-dimethylformamide (200mL) was used as a solvent, and the reaction was stirred at room temperature for 8h and followed by thin layer chromatography until the end of the reaction. Quenching with ice water, filtering, washing, recrystallizing and performing other post-treatments to obtain an intermediate VIII (1.76 g); yield: 61.0 percent.
Example 2 preparation of intermediate IX
Piperazine (889mg,10.32mmol) was added to dichloromethane (20mL), intermediate VIII (596mg,2.06mmol) was added to dichloromethane (20mL), dichloromethane containing intermediate VIII was added dropwise to piperazine-containing dichloromethane with stirring at room temperature, reaction was carried out for 8h, and the reaction was followed by thin layer chromatography. After the reaction is finished, the reaction mixture isThe extract, dried over anhydrous sodium sulfate and purified by column chromatography to give a purple solid (296 mg); yield: 42.4 percent; melting point: 229 ℃ and 231 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.93(s,2H,anthraquinone-1.8-OH),7.81(t,J＝7.9Hz,1H,anthraquinone-6-H),7.72(d,J＝7.4Hz,1H,anthraquinone-5-H),7.70(s,1H,anthraquinone-4-H),7.39(d,J＝8.3Hz,1H,anthraquinone-7-H),7.31(s,1H,anthraquinone-2-H),3.60(s,2H,CH 2 ),2.47–2.38(m,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 3 preparation of intermediate X
Intermediate IX (2.00g,5.91mmol) and potassium carbonate (1.23g,8.87mmol) were added to acetonitrile (80mL) and the reaction stirred at room temperature for 0.5h, epichlorohydrin (820mg,8.87mmol) was added and stirring continued for 24 h. Tracking the reaction by thin-layer chromatography, and after the reaction is finished, carrying out reduced pressure concentration, extraction and column chromatography purification on the system to obtain a yellow solid (512 mg); yield: 21.4 percent; melting point: 189-191 deg.C; 1 H NMR(600MHz,DMSO-d 6 )δ11.92(s,2H,anthraquinone-1,8-OH),7.81(t,J＝7.8Hz,1H,anthraquinone-5-H),7.72(d,J＝7.4Hz,1H,anthraquinone-6-H),7.69(s,1H,anthraquinone-4-H),7.39(d,J＝8.5Hz,1H,anthraquinone-7-H),7.30(s,1H,anthraquinone-2-H),3.82(s,1H),3.64(dd,J＝11.0,4.0Hz,1H),3.59(s,2H,anthraquinone-CH 2 -piperazine),3.53(dd,J＝11.0,5.5Hz,1H),2.63(d,J＝23.1Hz,2H),2.49–2.27(m,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 4 preparation of Compound I-1
N-methyl-2-mercaptoimidazole (137mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracing the reaction by thin layer chromatographyAfter the reaction was completed, the mixture obtained by the reaction was concentrated, extracted and purified by column chromatography to obtain a yellow solid (89 mg); yield: 17.5 percent; melting point: 234 ℃ and 235 ℃; 1 H NMR(600MHz,CDCl 3 )δ12.03(s,2H,anthraquinone-1,8-OH),7.80(d,J＝7.3Hz,1H,anthraquinone-5-H),7.77(s,1H,anthraquinone-4-H),7.66(t,J＝7.9Hz,1H,anthraquinone-6-H),7.29(d,J＝6.6Hz,2H,anthraquinone-7-H,imidazole-5-H),6.97(s,1H,anthraquinone-2-H),6.89(s,1H,imidazole-4-H),4.12–4.04(m,2H,CH(OH)-CH 2 ),3.70(d,J＝5.2Hz,2H,CH(OH)-CH 2 -S),3.61(s,3H,N-CH 3 ),3.58(s,2H,anthraquinone-CH 2 -piperazine),3.29–3.25(m,1H,piperazine-CH 2 -CH(OH)),3.10(dd,J＝14.0,6.7Hz,1H,piperazine-CH 2 -CH(OH)),2.65(d,J＝16.1Hz,4H,piperazine-3,5-CH 2 ),2.56(d,J＝6.1Hz,4H,piperazine-2,6-CH 2 )ppm。
example 5 preparation of Compound I-2
1-methyl-5-mercapto-1H-tetrazole (139mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) are added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5H. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking the reaction by thin-layer chromatography, and after the reaction is finished, performing reduced pressure concentration, extraction and column chromatography purification on a mixture obtained by the reaction to obtain a red solid (79 mg); yield: 15.5 percent; melting point: 106-107 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ7.77(t,J＝7.8Hz,1H,anthraquinone-6-H),7.65(d,J＝7.3Hz,1H,anthraquinone-5-H),7.61(s,1H,anthraquinone-4-H),7.34(d,J＝8.2Hz,1H,anthraquinone-7-H),7.24(s,1H,anthraquinone-2-H),5.15(s,1H,CHOH),4.03(t,J＝5.9Hz,1H,CH(OH)),3.56(s,2H,anthraquinone-CH 2 -piperazine),3.54–3.50(m,2H,CH(OH)-CH 2 -S),3.28–3.23(m,2H,piperazine-CH 2 -CH(OH)),2.59(s,4H,piperazine-2,6-CH 2 ),2.41(d,J＝5.8Hz,4H,piperazine-3,5-CH 2 )ppm。
example 6 preparation of Compound II
3-mercapto-1, 2, 4-triazole (121mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking the reaction by thin-layer chromatography, and after the reaction is finished, concentrating the obtained mixture under reduced pressure, extracting and purifying by column chromatography to obtain a yellow solid (78 mg); yield: 15.8 percent; melting point: 234 ℃ and 235 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ8.50(s,1H,triazole-5-H),7.80(t,J＝7.9Hz,1H,anthraquinone-6-H),7.71(d,J＝7.4Hz,1H,anthraquinone-5-H),7.68(s,1H,anthraquinone-4-H),7.38(d,J＝8.3Hz,1H,anthraquinone-7-H),7.31(s,1H,anthraquinone-2-H),5.76–5.64(m,1H,CH(OH)),5.09(s,1H,CH(OH)),4.87(s,2H,CH 2 -S-triazole),4.31–4.10(m,2H,anthraquinone-CH 2 -piperazine),4.07–3.95(m,2H,piperazine-CH 2 ),3.68–3.48(m,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 7 preparation of Compound III-1
5-Methyltetrazole (101mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the mixture obtained by the reaction by reduced pressure concentration, extraction and column chromatography to obtain a yellow solid (89 mg); yield: 18.7 percent; melting point: 138 ℃ and 139 ℃; 1 H NMR(600MHz,CDCl 3 )δ12.04(s,2H,anthraquinone-1,8-OH),7.82(d,J＝7.1Hz,1H,anthraquinone-5-H),7.78(s,1H,anthraquinone-4-H),7.68(t,J＝7.9Hz,1H,anthraquinone-6-H),7.30(s,1H,anthraquinone-2-H),7.28(d,J＝8.8Hz,1H,anthraquinone-7-H),4.50–4.43(m,1H,CHOH-CH 2 -tetrazole),4.22(dd,J＝14.3,6.1Hz,1H,CHOH-CH 2 -tetrazole),3.80–3.63(m,2H,CHOH-CH 2 -tetrazole),3.58(s,2H,anthraquinone-CH 2 -piperazine),2.72(s,2H,piperazine-CH 2 -CHOH),2.63(d,J＝8.5Hz,4H,piperazine-2,6-CH 2 ),2.58–2.43(m,7H,CH 3, piperazine-3,5-CH 2 )ppm。
example 8 preparation of Compound III-2
1,2, 4-triazole (83mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the obtained mixture by vacuum concentration, extraction and column chromatography to obtain yellow solid (87 mg); yield: 18.8 percent; melting point: 165-166 ℃; 1 H NMR(600MHz,CDCl 3 )δ8.34(s,1H,triazole-3-H),8.10(s,1H,triazole-5-H),8.09(s,1H,anthraquinone-5-H),7.90(s,1H,anthraquinone-4-H),7.85(d,J＝9.2Hz,2H,anthraquinone-2,7-H),7.78–7.71(m,1H,anthraquinone-6-H),4.36(d,J＝3.9Hz,1H,CHOH),4.29(dd,J＝14.1,3.6Hz,2H,CHOH-CH 2 -triazole),4.25(d,J＝14.3Hz,1H,CHOH),4.13(dd,J＝14.1,6.5Hz,2H,anthraquinone-CH 2 -piperazine),4.08(dd,J＝14.1,6.4Hz,1H,piperazine-CH 2 -CHOH),4.00(d,J＝4.2Hz,1H,piperazine-CH 2 -CHOH),2.75–1.97(m,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 9 preparation of Compound IV-1
2-methyl-5-nitroimidazole (152mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and reducing the obtained mixtureConcentrating under reduced pressure, extracting and purifying by column chromatography to obtain yellow solid (124 mg); yield: 23.8 percent; melting point: 105 ℃ to 106 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.91(s,2H,anthraquinone-1,8-OH),8.21(s,1H,imidazole-4-H),7.83–7.79(m,1H,anthraquinone-6-H),7.72(d,J＝7.4Hz,1H,anrhraquinone-5-H),7.69(s,1H,anthraquinone-4-H),7.38(d,J＝8.3Hz,1H,anthraquinone-7-H),7.30(s,1H,anthraquinone-2-H),5.10(s,1H,CHOH),4.11(dd,J＝13.9,2.3Hz,1H,CHOH),3.94(s,1H,CHOH-CH 2 -imidazole),3.88(dd,J＝13.9,7.8Hz,1H,CHOH-CH 2 -imidazole),3.60(s,2H,anthraquinone-CH 2 -piperazine),3.39(s,2H,CH 2 -CHOH),2.44(s,8H,piperazine-2,3,5,6-CH 2 ),2.37(s,3H,CH 3 )ppm。
example 10 preparation of Compound IV-2
4-Nitroimidazole (135mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the obtained mixture by vacuum concentration, extraction and column chromatography to obtain yellow solid (98 mg); yield: 19.3 percent; melting point: 204 ℃ and 205 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.95(s,2H,anthraquinone-1,8-OH),8.31(s,1H,imidazole-2-H),7.82(t,J＝7.9Hz,1H,anthraquinone-6-H),7.77(s,1H,imidazole-5-H),7.73(d,J＝7.4Hz,1H,anthraquinone-5-H),7.70(s,1H,anthraquinone-4-H),7.40(d,J＝8.0Hz,1H,anthraquinone-7-H),7.32(s,1H-anthraquinone-2-H),5.32(s,1H,CHOH),5.13(s,1H,CHOH),4.18(d,J＝10.8Hz,2H,CHOH-CH 2 -imidazole),3.96(s,2H,anthraquinone-CH 2 -piperazine),3.76(d,J＝11.3Hz,2H,piperazine-CH 2 -CHOH),2.40–2.31(m,8H,piprazine-2,3,5,6-CH 2 )ppm。
example 11 preparation of Compound IV-3
4, 5-dicyanoimidazole (142mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature, intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the mixture obtained by the reaction by reduced pressure concentration, extraction and column chromatography to obtain yellow solid (106 mg); yield: 20.8 percent; melting point: 165-166 ℃; 1 H NMR(600MHz,CDCl 3 )δ12.07(s,2H,anthraquinone-1,8-OH),7.99(s,1H,imidazole-2-H),7.83(d,J＝7.4Hz,1H,anthraquinone-5-H),7.80(s,1H,anthraquinone-4-H),7.68(t,1H,anthraquinone-6-H),7.30(d,J＝8.0Hz,2H anthraquinone-7-H,anthraquinone-2-H),4.16–4.12(m,1H,CHOH),4.08(dt,J＝10.5,5.3Hz,1H,CHOH),3.94(dd,J＝10.2,5.3Hz,2H,CHOH-CH 2 -imidazole),3.77(dd,J＝11.4,3.9Hz,2H,anthraquinone-CH 2 -piperazine),2.76(s,2H,piperazine-CH 2 -CHOH),2.61–2.53(m,8H piprazine-2,3,5,6-CH 2 )ppm。
example 12 preparation of Compound IV-4
2-butyl-4-chloro-5-imidazolidinal (227mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the mixture obtained by the reaction by reduced pressure concentration, extraction and column chromatography to obtain a yellow solid (198 mg); yield: 34.1 percent; melting point:>250℃； 1 H NMR(600MHz,DMSO-d 6 )δ11.90(s,2H,anthraquinone-1,8-OH),9.63(s,1H,CHO),7.80(t,J＝7.9Hz,1H,anthraquinone-6-H),7.69(d,J＝7.4Hz,1H,anthraquinone-5-H),7.66(s,1H anthraquinone-4-H),7.37(d,J＝8.3Hz,1H,anthraquinone-7-H),7.29(s,1H,anthraquinone-2-H),5.00(s,1H,CHOH),4.48(d,J＝11.9Hz,1H,CHOH),3.97–3.80(m,2H,CHOH-CH 2 -imidazole),3.59(s,2H,anthraquinone-CH 2 -piperazine),3.33(s,2H,piperazine-CH 2 -CHOH),2.72(d,J＝7.7Hz,2H,imidazole-4-CH 2 -CH 2 ),2.48–2.31(m,8H,piprazine-2,3,5,6-H),1.64(dd,J＝14.5,7.3Hz,2H,imidazole-4-CH 2 -CH 2 ),1.37–1.30(m,2H,imidazole-4-CH 2 -CH 2 -CH 2 ),0.90(t,J＝7.3Hz,3H,CH 2 -CH 3 )ppm。
example 13 preparation of Compound V-1
Benzimidazole (142mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the obtained mixture by vacuum concentration, extraction and column chromatography to obtain yellow solid (57 mg); yield: 11.1 percent; melting point: 167-168 ℃ of reaction; 1 H NMR(600MHz,CDCl 3 )δ12.09(s,1H,anthraquinone-8-OH),12.04(s,1H,anthraquinone-1-OH),7.84(s,1H,benzimidazole-2-H),7.83(s,1H,anthraquinone-5-H),7.81(s,1H,anthraquinone-4-H),7.79(d,1H,anthraquinone-6-H),7.68(t,J＝7.9Hz,2H,benzimidazole-5,6-H),7.33(s,1H,anthraquinone-2-H),7.30(d,J＝8.1Hz,2H,anthraquinone-2-H,benzimidazole-4-H),7.26(s,1H,benzimidazole-7-H),3.61(d,J＝4.1Hz,2H,CHOH),3.49(s,2H,anthraquinone-CH 2 -piperazine),2.79–2.77(m,2H,CHOH-CH 2 -benzimidazole),2.58(s,8H,piprazine-2,3,5,6-H)ppm。
example 14 preparation of Compound V-2
6-Nitrobenzimidazole (196mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography to reverseUpon completion, the reaction mixture was concentrated under reduced pressure, extracted and purified by column chromatography to give a yellow solid (63 mg); yield: 11.3 percent; melting point: 207 ℃ and 209 ℃; 1 H NMR(600MHz,CDCl 3 )δ12.08(s,1H,anthraquinone-8-OH),12.05(s,1H,anthraquinone-1-OH),8.76(s,1H,benzimidazole-7-H),8.71(s,1H,benzimidazole-2-H),8.31(d,J＝11.4Hz,1H,benzimidazole-5-H),8.25(d,J＝11.2Hz,1H,benzimidazole-4-H),8.20(d,J＝9.1Hz,1H,anthraquinone-5-H),7.80(s,1H,anthraquinone-4-H),7.69(t,J＝7.8Hz,1H,anthraquinone-6-H),7.54(d,J＝9.0Hz,1H,anthraquinone-7-H),7.31(s,1H,anthraquinone-2-H),6.63(d,J＝17.2Hz,1H,CHOH),5.32(d,J＝30.3Hz,1H,CHOH),4.41–4.31(m,2H,CHOH-CH 2 -benzimidazole),4.17(d,J＝14.4Hz,2H,piperazine-CH 2 -CHOH),3.60(s,2H,anthraquinone-CH 2 -piperazine),2.55(s,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 15 preparation of Compound V-3
2-Chlorobenzimidazole (183mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the obtained mixture by vacuum concentration, extraction and column chromatography to obtain yellow solid (75 mg); yield: 13.7 percent; melting point: 246-247 ℃; 1 H NMR(600MHz,CDCl 3 )δ11.97(d,J＝26.9Hz,2H,anthraquinone-1,8-OH),7.77–7.73(m,1H,anthraquinone-6-H),7.71(d,J＝4.1Hz,1H,anthraquinone-5-H),7.60(dd,J＝13.3,5.9Hz,2H,benzimidazole-4,7-H),7.40–7.34(s,1H,anthraquinone-4-H),7.21(d,J＝4.8Hz,2H,benzimidazole-5,6-H),7.18(d,1H,anthraquinone-7-H),6.98(s,1H,anthraquinone-2-H),4.17(ddd,J＝20.4,12.1,5.2Hz,2H,CHOH-CH 2 -bemzimidazole),4.10–4.06(m,1H,CHOH),3.50(d,J＝2.7Hz,2H,CHOH),2.64(s,2H,piperazine-CH 2 -CHOH),2.42(dd,J＝20.4,5.3Hz,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 16 preparation of Compound V-4
2-Trifluoromethylbenzimidazole (223mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the obtained mixture by vacuum concentration, extraction and column chromatography to obtain yellow solid (78 mg); yield: 13.5 percent; melting point: 210 ℃ and 211 ℃; 1 H NMR(600MHz,CDCl 3 )δ11.95(d,J＝26.7Hz,2H,anthraquinone-1,8-OH),7.76(d,J＝7.8Hz,1H,anthraquinone-5-H),7.72(d,J＝7.0Hz,1H,anthraquinone-6-H),7.69(s,1H,anthraquinone-4-H),7.58(d,J＝7.1Hz,2H,benzimidazole-4,7-H),7.33(d,J＝7.2Hz,1H,benzimidazole-5-H),7.28(d,J＝7.1Hz,1H,benzimidazole-6-H),7.20(s,2H,anthraquinone-2,6-H),4.30(d,J＝14.8Hz,1H,CHOH),4.25–4.20(m,1H,CHOH-CH 2 -imidazole),4.04(s,1H,CHOH-CH 2 -imidazole),3.48(s,2H,anthraquinone-CH 2 -piperazine),2.61(s,2H,piperazine-CH 2 -CHOH),2.40(d,J＝21.8Hz,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 17 preparation of Compound V-5
6-chloro-2-trifluoromethylbenzimidazole (264mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cool to room temperature and add intermediate X (394mg,1.0mmol) and continue stirring at 80 deg.C for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the mixture obtained by the reaction by reduced pressure concentration, extraction and column chromatography to obtain a yellow solid (78 mg); yield: 12.7 percent; melting point:>250℃； 1 H NMR(600MHz,CDCl 3 )δ12.05(d,J＝12.1Hz,2H,anthraquinone-1,8-OH),7.83(d,J＝7.3Hz,1H,anthraquinone-5-H),7.79(s,1H,benzimidazole-7-H),7.74(dd,J＝5.0,3.4Hz,2H,benzimidazole-4-H,anthraquinone-4-H),7.70–7.67(m,1H,anthraquinone-6-H),7.32(d,J＝2.3Hz,1H,benzimidazole-5-H),7.30(d,J＝2.0Hz,1H,anthraquinone-7-H),7.28(s,1H,anthraquinone-2-H),5.35(t,J＝4.7Hz,1H,CHOH),4.31(dt,J＝15.8,10.6Hz,4H,CHOH-CH 2 -imidazole,anthraquinone-CH 2 -piperazine),3.63(s,2H,piperazine-CH 2 -CHOH),2.78(d,J＝82.6Hz,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 18 preparation of Compound VI
4-Hydroxycarbazole (275mg,1.2mmol) and potassium carbonate (207mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cool to room temperature and add intermediate X (394mg,1.0mmol) and continue stirring at 80 deg.C for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the mixture obtained by the reaction by reduced pressure concentration, extraction and column chromatography to obtain a yellow solid (89 mg); yield: 15.4 percent; melting point: 225 ℃ and 267 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.21(s,1H,NH),8.23(d,J＝7.7Hz,1H,carbazole-5-H),7.78(t,J＝7.9Hz,1H,anthraquinone-6-H),7.68(d,J＝7.3Hz,1H,anthraquinone-5-H),7.65(s,1H,anthraquinone-4-H),7.43(d,J＝8.0Hz,1H,carbazole-8-H),7.36–7.31(m,2H,carbazole-7-H,carbazole-2-H),7.29–7.26(m,2H,anthraquinone-2-H,carbazole-1-H),7.13(t,J＝7.4Hz,1H,carbazole-6-H),7.06(d,J＝8.0Hz,1H,carbazole-3-H),6.67(d,J＝7.9Hz,1H,anthraquinone-7-H),4.98(s,1H,CH(OH)),4.14(dd,J＝19.1,14.5Hz,3H,CH(OH),CH 2 -O-carbazole),3.57(s,2H,anthraquinone-CH 2 -piperazine),2.67(dd,J＝12.6,5.1Hz,2H,piperazine-CH 2 ),2.61–2.54(m,4H,piperazine-2,6-CH 2 ),2.46(s,4H,piperazine-3,5-CH 2 )ppm。
example 19 preparation of Compound VII-1
2-Bromocarbazole (295mg,1.2mmol) and cesium carbonate (488mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cooled to room temperature and intermediate X (394mg,1.0mmol) was added and stirring continued at 80 ℃ for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the obtained mixture by vacuum concentration, extraction and column chromatography to obtain yellow solid (76 mg); yield: 11.9 percent; melting point: 204 ℃ and 206 ℃; 1 H NMR(600MHz,DMSO-d 6 )δ11.92(s,2H,anthraquinone-1,8-OH),8.13(d,J＝7.7Hz,1H,carbazole-5-H),8.07(d,J＝8.2Hz,1H,carbazole-4-H),7.87(s,1H,carbazole-8-H),7.80(t,J＝7.9Hz,1H,anthraquinone-6-H),7.71(d,J＝7.4Hz,1H,anthraquinone-5-H),7.68(s,1H,anthraquinone-4-H),7.63(d,J＝8.2Hz,1H,carbazole-1-H),7.46(t,J＝7.5Hz,1H,carbazole-7-H),7.38(d,J＝8.3Hz,1H,carbazole-3-H),7.31(s,1H,anthraquinone-7-H),7.29(s,1H,anthraquinone-2-H),7.20(t,J＝7.4Hz,1H,carbazole-6-H),5.00(s,1H,CHOH),4.45(d,J＝12.0Hz,1H,CHOH-CH 2 -imidazole),4.28(dd,J＝14.8,6.1Hz,1H,CHOH-CH 2 -imidazole),4.03(s,1H,CHOH),3.62(s,2H,anthraquinone-CH 2 -piperazine),2.62(s,2H,piperazine-CH 2 ),2.49–2.28(m,8H,piperazine-2,3,5,6-H)ppm。
example 20 preparation of Compound VII-2
3-Bromocarbazole (295mg,1.2mmol) and cesium carbonate (488mg,1.5mmol) were added to acetonitrile (25mL) and stirred at 80 ℃ for 0.5 h. Cool to room temperature and add intermediate X (394mg,1.0mmol) and continue stirring at 80 deg.C for 12 h. Tracking by thin layer chromatography until the reaction is finished, and purifying the mixture obtained by the reaction by vacuum concentration, extraction and column chromatography to obtain a yellow solid (88 mg); yield: 13.8 percent; melting point: 184 ℃ and 185 ℃; 1 H NMR(600MHz,CDCl 3 )δ12.08(s,1H,anthraquinone-8-OH),12.02(s,1H,anthraquinone-1-OH),8.04(d,J＝7.7Hz,1H,carbazole-5-H),7.91(d,J＝8.2Hz,1H,anthraquinone-5-H),7.82(d,J＝7.5Hz,1H,carbazole-8-H),7.78(s,1H,carbazole-4-H),7.67(dd,J＝9.0,6.8Hz,2H,anthraquinone-6-H,carbazole-7-H),7.47(s,1H,anthraquinone-4-H),7.46(d,J＝8.7Hz,1H,carbazole-2-H),7.33(dd,J＝8.9,0.6Hz,2H,carbazole-1,6-H),7.30(s,1H,anthraquinone-7-H),7.29(s,1H,anthraquinone-2-H),4.33(ddd,J＝20.7,15.2,5.0Hz,3H,CHOH-CH 2 -carbazole),4.22(s,1H,CHOH),3.57(s,2H,anthraquinone-CH 2 -piperazine),2.69(s,2H,piperazine-CH 2 ),2.50(d,J＝8.0Hz,8H,piperazine-2,3,5,6-CH 2 )ppm。
example 21 in vitro antimicrobial Activity of emodin Azolol Compounds
The intermediates prepared in examples 2 to 3 and the emodin enol compounds prepared in examples 4 to 20 were tested for their Minimal Inhibitory Concentrations (MIC) against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC 90023, Candida parapsilosis ATCC 22019) by a 96-well microdilution method in accordance with the Clinical Laboratory Standards Institute (CLSI) set by the American national Committee, and the test compounds were dissolved in a small amount of dimethyl sulfoxide, diluting with water to obtain 1.28mg/mL solution, diluting with the culture medium to 128. mu.g/mL, culturing at 35 deg.C for 24-72h, shaking the culture plate on a shaker, and determining MIC at 490nm, the results are shown in tables 1-3.
TABLE 1 in vitro gram-positive activity data (MIC, μ g/mL) for intermediates prepared in examples 2-3 and emodin oxazolol compounds prepared in examples 4-20
TABLE 2 in vitro gram-negative activity data (MIC, μ g/mL) of the intermediates prepared in examples 2 to 3 and emodin oxazolol compounds prepared in examples 4 to 20
As can be seen from tables 1 and 2, the intermediates prepared in examples 2 to 3 of the present invention and the emodin halohydrin compounds prepared in examples 4 to 20 showed good inhibitory effects on the tested bacteria, and in particular, 2-bromocarbazol-modified emodin VII-1 showed good activity against gram-positive bacteria, and the minimum inhibitory concentration especially on drug-resistant MRSA, staphylococcus aureus and staphylococcus aureus ATCC 25923 was better than or equal to that of the reference drug norfloxacin.
TABLE 3 in vitro antifungal Activity data (MIC, μ g/mL) for the intermediates prepared in examples 2-3 and the emodin oxazolol compounds prepared in examples 4-20
As can be seen from Table 3, the intermediate prepared in examples 2-3 and the emodin halohydrin compounds prepared in examples 4-20 of the invention show excellent inhibitory effect on the tested fungi, and the antifungal activity of the compounds VII-1-2 is 4-16 mug/mL, which is 1-4 times that of the reference drug fluconazole.
Example 22 pharmaceutical use of emodin Azolol Compound
According to the antimicrobial activity detection result, the emodin oxazole 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, prepared by emodin halohydrin compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, prepared from emodin azole alcohol 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 prepared from several emodin azole alcohol 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 II tablets
Prescription: 10g of compound II, 50g of corn starch, 187g of lactose, 3.0g of magnesium stearate and a proper amount of ethanol solution with the volume percentage concentration of 70 percent, and the total amount of the compound II is prepared into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound II with lactose and corn starch, making soft mass with 70% ethanol solution, sieving, granulating, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.
2. Preparation of Compound III-1 Capsule
Prescription: the formula comprises, by weight, compound III-125 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, a proper amount of pigment and a proper amount of water, and the granules are prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound III-1, 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 V-5 granules
Prescription: compound V-526 g, dextrin 120g and cane sugar 280 g.
The preparation method comprises the following steps: mixing compound V-5, dextrin and sucrose, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of compound IV-4 injection
Prescription: 1000mL of the compound IV-410 g, 500mL of propylene glycol and 500mL of water for injection.
The preparation method comprises the following steps: weighing compound IV-4, adding propylene glycol and water for injection, stirring for dissolving, adding 1g of activated carbon, stirring thoroughly, standing for 15min, filtering with 5 μm titanium rod to remove carbon, sequentially fine-filtering with microporous membrane with pore diameter of 0.45 μm and 0.22 μm, packaging in 10mL ampoule, and sterilizing with 100 deg.C flowing steam for 45 min.
5. Preparation of intermediate VII-1 powder injection
The preparation method comprises the following steps: and (3) subpackaging the intermediate VII-1 sterile powder under the aseptic condition to obtain the compound.
6. Preparation of Compound II eye drops
Prescription: 3.78g of compound II, 0.9g of sodium chloride, a proper amount of boric acid buffer solution and distilled water are added to 1000 mL.
The preparation method comprises the following steps: weighing the compound II 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, bottling, sealing, and sterilizing with 100 deg.C flowing steam for 1 h.
7. Preparation of compound V-3 liniment
Prescription: compound V-34 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 V-3, 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 II
Prescription: 4g of compound II, 14g of gelatin, 70g of glycerol and 100 metric copies of distilled water are added to 100 mL.
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 II, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-1 ointment
Prescription: 10.5-2 g of compound I, 6-8g of hexadecanol, 8-10g of white vaseline, 8-19g of liquid paraffin, 2-5g of monoglyceride, 2-5g of polyoxyethylene (40) stearate, 5-10g 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-1, stirring, and cooling.
10. Preparation of compound VII-1 and fluconazole compound powder injection
Prescription: 100 bottles of compound VII-150 g, fluconazole 50g and sodium benzoate 1 g.
The preparation method comprises the following steps: taking the compound VII-1, 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 VII-1.
11. Preparation of Compound VII-2 Aerosol
Prescription: compound VII-22.5 g, Span 203 g, talcum powder (100 mesh) 4g, trichloromonofluoromethane added to appropriate amount.
The preparation method comprises the following steps: respectively drying the compound VII-2, the Span20 and the talcum powder in a vacuum drying oven for several hours, cooling in a drier 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 compound VII-2.
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 emodin oxazolol compound and the medicinal salt thereof are characterized in that the structure of the emodin oxazolol compound is shown in general formulas I-VII:
in the formula (I), the compound is shown in the specification,
R 1 、R 2 、R 3 is hydrogen, methyl or n-butyl;
R 4 、R 5 、R 6 hydrogen, methyl, n-butyl, halogen, aldehyde group, nitro or cyano;
R 7 、R 8 、R 9 、R 10 、R 11 is hydrogen, halogen, trifluoromethyl or nitro;
R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 、R 24 、R 25 and R 26 Is hydrogen or halogen;
x, Y, Z is a CH or N atom.
2. The emodin halohydrin compound and pharmaceutically acceptable salts thereof according to claim 1, wherein the emodin halohydrin compound is any one of the following compounds:
3. the emodin halohydrin compound and pharmaceutically acceptable salts thereof of claim 1, wherein the pharmaceutically acceptable salts are hydrochloride, nitrate or acetate salts.
4. A method for producing an emodin halohydrin compound and pharmaceutically acceptable salts thereof according to any one of claims 1 to 3, characterized in that the method comprises:
a. preparation of intermediate VIII: performing halogenation reaction on the aloe-emodin and thionyl chloride at room temperature to obtain an intermediate VIII;
b. preparation of intermediate IX: carrying out nucleophilic substitution reaction on the intermediate VIII and piperazine to obtain an intermediate IX;
c. preparation of intermediate X: the intermediate IX is subjected to nucleophilic substitution reaction with epichlorohydrin under the action of potassium carbonate to obtain an intermediate X;
d. preparation of emodin oxazolol compounds of general formulae I-VI: carrying out ring-opening reaction on the intermediate X and an azole compound under the conditions that acetonitrile is used as a solvent and potassium carbonate is used as a base to obtain an emodin azole alcohol compound shown in general formulas I-VI;
e. preparation of emodin oxazolol compound of general formula VII: and (3) carrying out ring-opening reaction on the intermediate X and the carbazole compound under the condition that acetonitrile is used as a solvent and cesium carbonate is used as alkali to obtain the emodin oxazole compound shown in the general formula VII.
5. The production method according to claim 4,
in the step a, the molar ratio of the aloe-emodin to the thionyl chloride is 1: 27.5; the halogenation reaction is specifically as follows: reacting for 8 hours at room temperature by taking N, N-dimethylformamide as a solvent;
in the step b, the molar ratio of the intermediate VIII to the piperazine is 1: 5; the nucleophilic substitution reaction is specifically as follows: reacting for 8 hours at room temperature by taking dichloromethane as a solvent;
in the step c, the molar ratio of the intermediate IX, the potassium carbonate and the epichlorohydrin is 1:1.5: 1.5; the nucleophilic substitution reaction is specifically as follows: reacting for 24 hours at room temperature by taking acetonitrile as a solvent;
in the step d, the molar ratio of the intermediate X, the potassium carbonate and the azole compound is 1:1.5: 1.2; the ring-opening reaction is specifically as follows: reacting for 12 hours at 80 ℃;
in the step e, the molar ratio of the intermediate X, cesium carbonate and the carbazole compound is 1:1.5: 1.2; the ring-opening reaction is specifically as follows: the reaction was carried out at 80 ℃ for 12 h.
6. Use of the emodin halohydrin compounds and pharmaceutically acceptable salts thereof of any one of claims 1 to 3 in the preparation of antibacterial and/or antifungal medicaments.
7. The use of claim 6, wherein the bacteria is one or more of enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa or acinetobacter baumannii; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 22019.
8. The use of claim 7, wherein the bacteria is one or more of methicillin-resistant staphylococcus aureus, staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213, pseudomonas aeruginosa ATCC 27853, or escherichia coli ATCC 25922; the fungus is Candida albicans ATCC 90023.
9. A preparation comprising the emodin azole alcohol compound according to any one of claims 1 to 3 and a pharmaceutically acceptable salt thereof.
10. The formulation of claim 9, wherein the formulation is one of a tablet, a capsule, a granule, an injection, an eye drop, a liniment, a suppository, an ointment, or an aerosol.
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