CN112521382A - Aloe-emodin thiazolidinedione compound and preparation method and application thereof - Google Patents
Aloe-emodin thiazolidinedione compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN112521382A CN112521382A CN202011473961.6A CN202011473961A CN112521382A CN 112521382 A CN112521382 A CN 112521382A CN 202011473961 A CN202011473961 A CN 202011473961A CN 112521382 A CN112521382 A CN 112521382A
- Authority
- CN
- China
- Prior art keywords
- preparation
- aloe
- emodin
- compound
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to an aloe-emodin thiazolidinedione compound as well as a preparation method and application thereof, belonging to the technical field of chemical synthesis. The aloe-emodin thiazolidinedione compounds are shown as a general formula I, have 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, provide more efficient and safe candidate medicaments for clinical antimicrobial treatment, and are beneficial to 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 easily available, the synthetic route is short, and the application in the aspect of resisting infection is realizedHas important significance.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an aloe-emodin thiazolidinedione compound as well as a preparation method and application thereof.
Background
Aloe-emodin is one of the antimicrobial active components extracted from Chinese medicinal materials including radix et rhizoma Rhei, Aloe, folium sennae, etc. Researches show that the aloe-emodin compounds can interact with DNA and biological enzymes such as neuraminidase and pepsin, and further influence the life activities of cells. The structural modification by utilizing the structural advantages of the aloe-emodin dihydroxy anthraquinone is expected to obtain antimicrobial drug molecules with high potential.
Thiazolidinediones are important active fragments in the aspects of blood sugar reduction, antibacterial, antiviral, anti-inflammatory and anti-plasmodium drug molecule development and the like. Thiazolidinedione fragments contain N, S heteroatoms and one carbonyl group at each of the 2 and 4 positions and can bind to amino acid residues of the target protein via hydrogen bonds, and thiazolidinedione-modified drug molecules are also able to interact with DNA in an intercalated form, exhibiting inhibitory potential against microorganisms. Therefore, the utilization of the thiazolidinedione active segment to modify aloe-emodin and the change of the condensed group on the thiazolidinedione have important value for developing high-activity antimicrobial candidate drug molecules.
Disclosure of Invention
In view of the above, an object of the present invention is to provide aloe-emodin thiazolidinediones and pharmaceutically acceptable salts thereof; the second purpose of the invention is to provide a preparation method of aloe-emodin thiazolidinedione compounds and pharmaceutically acceptable salts thereof; the third purpose of the invention is to provide the application of the aloe-emodin thiazolidinedione 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 aloe-emodin thiazolidinedione compound and the pharmaceutically acceptable salts thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the aloe-emodin thiazolidinedione compound and the medicinal salt thereof have the structure shown as the general formula I:
in the formula: r is imidazolyl, thienyl, furyl, phenyl, p-methylphenyl, p-fluorophenyl, 2, 4-difluorophenyl, o-chlorophenyl, p-chlorophenyl, 2, 4-dichlorophenyl, pyridyl, pyrimidyl, indolyl, benzothienyl, benzofuryl, quinolyl, carbazolyl or naphthyl.
Preferably, R is furyl, thienyl, phenyl, p-methylphenyl, p-fluorophenyl, 2, 4-difluorophenyl, o-chlorophenyl, p-chlorophenyl, 2, 4-dichlorophenyl, pyridyl, N-ethylindolyl, N-hexylindolyl, N-allylindolyl, benzothienyl or naphthyl.
Preferably, it is any one of the following compounds:
preferably, the pharmaceutically acceptable salt is sodium salt, potassium salt, hydrochloride, nitrate or acetate.
2. The preparation method of the aloe-emodin thiazolidinedione compound and the pharmaceutically acceptable salt thereof comprises the following steps:
a. preparation of intermediate II: reacting thiourea serving as an initial raw material with chloroacetic acid by using water as a solvent to obtain an intermediate II;
b. preparation of intermediate III: indole-3-formaldehyde is used as a starting material, acetonitrile is used as a solvent, cesium carbonate is used as a base, and the starting material and the cesium carbonate react with a halogenated compound to obtain an intermediate III;
c. preparation of intermediate IV: taking the intermediate II as a starting material, taking piperidine as alkali, adding an aldehyde compound, and refluxing in ethanol to obtain an intermediate IV;
d. preparation of intermediate V: 1, 8-dihydroxy-3-hydroxymethyl anthraquinone is used as a starting material to react with thionyl chloride in N, N-dimethylformamide to obtain an intermediate V;
e. preparation of aloe-emodin thiazolidinediones of formula I: and (3) reacting the intermediate V and the intermediate IV by using acetonitrile as a solvent and triethylamine as alkali to obtain the aloe-emodin thiazolidinedione compound shown in the general formula I.
Preferably:
in the step a, the molar ratio of thiourea to chloroacetic acid is 1:1, and the reaction temperature is 100 ℃;
in the step b, the mol ratio of the indole-3-formaldehyde to the halogenated compound to the cesium carbonate is 1:1.2:1.5, and the reaction temperature is 80 ℃;
in the step c, the molar ratio of the intermediate II, the piperidine and the aldehyde compound is 1:1.5:1.5, and the reaction temperature is 80 ℃;
in the step d, the molar ratio of the 1, 8-dihydroxy-3-hydroxymethyl anthraquinone to the thionyl chloride is 1:27.5, and the reaction temperature is 0 ℃;
in the step e, the molar ratio of the intermediate V, the intermediate IV and triethylamine is 1:1.2:1, the base is triethylamine, and the reaction temperature is 80 ℃.
3. The aloe-emodin thiazolidinedione 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 ATCC25923, staphylococcus aureus ATCC29213, klebsiella pneumoniae, escherichia coli ATCC 25922, pseudomonas aeruginosa ATCC27853, or acinetobacter baumannii; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023 or Candida parapsilosis ATCC 20019.
4. A preparation containing the aloe-emodin thiazolidinedione compound and the pharmaceutically acceptable salts 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 aloe-emodin thiazolidinedione compounds and a preparation method and application thereof, the invention utilizes the principle of drug design split, a series of novel aloe-emodin thiazolidinedione compounds are designed and synthesized through aloe-emodin and thiazolidinedione, and the compounds are detected to have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923 and staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC 25922 and acinetobacter baumannii) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC90023 and candida parapsilosis ATCC22019) through in-vitro antimicrobial activity detection, can be used for preparing antibacterial and/or antifungal drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial treatment and being beneficial to 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 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.
Experimental example 1
Preparation of intermediate II
A500 mL round bottom flask was charged with thiourea (30.00g,0.39mol) and chloroacetic acid (37.24g,0.39mol), water (58mL) was used as a solvent, the reaction was stirred at 100 ℃ under reflux, and thin layer chromatography was used to follow the reaction to completion. Cooling to room temperature, adding 5-10 drops of water to precipitate a solid, performing suction filtration, washing filter residues for 2 times with water, drying and performing other post-treatments to obtain an intermediate II (33.95g,0.29mol), wherein the yield is as follows: 74.4 percent.
Experimental example 2
Preparation of intermediate III
Indole-3-carbaldehyde (1.00g,6.89mmol) and cesium carbonate (3.37g,10.34mmol) were charged in a 100mL round-bottomed flask, and the mixture was reacted with acetonitrile (30mL) at 80 ℃ under reflux for 2 hours, followed by cooling to room temperature and further addition of a halogenated compound (bromoethane (901mg,8.27mmol), bromohexane (1.37g,8.27mmol) and bromopropylene (1.00g,8.27mmol), respectively), followed by reaction with reflux at 80 ℃ for 3 hours. Thin layer chromatography followed to the end of the reaction, cooled to room temperature, and the solvent removed to give intermediate III-1(1.03g,5.97mmol), yield: 86.7 percent; intermediate III-2(1.38g,6.04mmol), yield: 87.7 percent; intermediate III-3(1.04g,5.63mmol), yield: 81.7 percent.
Experimental example 3
Preparation of intermediate IV
A100 mL round-bottomed flask was charged with intermediate II (1.00g,8.55mmol) and piperidine (1.09g,12.83mmol), and ethanol (30mL) was used as a solvent, followed by addition of an aldehyde compound (2-furfural (1.23g,12.83mmol), 2-thiophenecarboxaldehyde (1.44g,12.83mmol), benzaldehyde (1.36g,12.83mmol), p-tolualdehyde (1.54g,12.83mmol), p-fluorobenzaldehyde (1.59g,12.83mmol), 2, 4-difluorobenzaldehyde (1.59g,12.83mmol), o-chlorobenzaldehyde (1.59g,12.83mmol), p-chlorobenzaldehyde (1.80g,12.83mmol), 2, 4-dichlorobenzaldehyde (2.25g,12.83mmol), 4-pyridineformaldehyde (1.37g,12.83mmol), intermediate III-1(2.22g,12.83mmol), intermediate III-1 (2.83 mmol), intermediate III-2.83 mmol), 2.83 g, 2.83mmol), 2, 3.08 g, 3.08 mmol), 12.83mmol), 1-naphthaldehyde (2.00g,12.83mmol)), and the reaction was stirred at reflux at 80 ℃ for 3 h. Thin layer chromatography followed to the end of the reaction, cooled to room temperature, and the solvent removed to give intermediate IV-1(945mg,4.85mmol), yield: 56.7 percent; intermediate IV-2(861mg,4.08mmol), yield: 47.7 percent; intermediate IV-3(1.17g,5.70mmol), yield: 66.7 percent; intermediate IV-4(979mg,4.47mmol), yield: 52.3 percent; intermediate IV-5(772mg,3.46mmol), yield: 40.5 percent; intermediate IV-6(1.31g,5.45mmol), yield: 63.7 percent; intermediate IV-7(1.28g,5.36mmol), yield: 62.7 percent; intermediate IV-8(1.32g,5.51mmol), yield: 64.5 percent; intermediate IV-9(1.09g,3.98mmol), yield: 46.5 percent; intermediate IV-10(918mg,4.45mmol), yield: 52.1 percent; intermediate IV-11(1.13g,4.15mmol), yield: 48.5 percent; intermediate IV-12(2.05g,6.26mmol), yield: 73.2 percent; intermediate IV-13(1.41g,4.97mmol), yield: 58.1 percent; intermediate IV-14(1.45g,5.55mmol), yield: 64.9 percent; intermediate IV-15(996mg,3.91mmol), yield: 45.7 percent.
Experimental example 4
Preparation of intermediate V
A150 mL round-bottomed flask was charged with 1, 8-dihydroxy-3-hydroxymethylanthraquinone (2.7g,10mmol) and thionyl chloride (20mL,275mmol), and the reaction was stirred at 0 ℃ with N, N-dimethylformamide (200mL) as a solvent and followed by thin layer chromatography until the reaction was complete. Quenching with ice water, filtering, washing, recrystallizing and the like to obtain an intermediate V (1.76g) with the yield: 61.0 percent.
Experimental example 5
Preparation of Compound I-1
A100 mL round bottom flask was charged with intermediate V (200mg,0.69mmol), intermediate IV-1(162mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-1(152mg,0.34mmol) as a yellow solid. Yield: 49.0 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.93(bs,1H,OH),11.89(bs,1H,OH),8.11(s,1H),7.83(s,1H),7.81(d,J＝8.0Hz,1H),7.72(d,J＝7.1Hz,1H),7.62(s,1H),7.31(s,1H),7.19(s,1H),7.00(d,J＝7.7Hz,1H),6.78(s,1H),4.96(s,2H,CH2)ppm。
experimental example 6
Preparation of Compound I-2
A100 mL round bottom flask was charged with intermediate V (200mg,0.69mmol), intermediate IV-2(175mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to obtain compound I-2(127mg,0.27mmol) as a yellow solid. Yield: 39.7 percent; melting point: 191.8 to 192.6 ℃;1H NMR(600MHz,DMSO-d6)δ12.03(bs,1H,OH),11.83(bs,1H,OH),8.13(s,1H),7.83(s,1H),7.81(d,J＝7.9Hz,1H),7.71(d,J＝7.1Hz,1H),7.59(s,1H),7.31(s,1H),7.19(s,1H),7.00(d,J＝7.7Hz,1H),6.72(s,1H),4.94(s,2H,CH2)ppm。
experimental example 7
Preparation of Compound I-3
A100 mL round bottom flask was charged with intermediate V (200mg,0.69mmol), intermediate IV-3(170mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to obtain compound I-3(93mg,0.20mmol) as a yellow solid. Yield: 29.5 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.93(s,1H,OH),11.90(s,1H,OH),8.01(s,1H),7.82(m,2H),7.72(d,J＝7.6Hz,1H),7.66(t,J＝7.7Hz,2H),7.57(t,J＝7.7Hz,2H),7.52(t,J＝7.7Hz,1H),7.40(d,J＝7.9Hz,1H),7.34(s,1H),4.99(s,2H,CH2)ppm。
experimental example 8
Preparation of Compound I-4
In a 100mL round-bottom flask was addedIntermediate V (200mg,0.69mmol), intermediate IV-4(182mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, refluxing at 80 deg.C for 10h, and thin layer chromatography followed to completion of the reaction. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-4(72mg,0.15mmol) as a yellow solid. Yield: 20.1 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.92(d,J＝17.2Hz,2H,anthraquinone-1,8-(OH)2),7.76(s,1H),7.64(s,1H),7.56(d,J＝7.6Hz,1H),7.50(d,J＝8.0Hz,1H),7.35(m,3H),7.18(s,1H),6.64(s,2H,CH2),5.32(s,2H),2.09(s,3H,CH3)ppm。
experimental example 9
Preparation of Compound I-5
A100 mL round bottom flask was charged with intermediate V (200mg,0.69mmol), intermediate IV-5(185mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-5(88mg,0.18mmol) as a yellow solid. Yield: 20.5 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.90(d,J＝13.2Hz,2H，anthraquinone-1,8-(OH)2),8.02(s,1H,CH),7.82(t,J＝7.9Hz,1H,anthraquinone-6-H),7.74(m,3H,anthraquinone-5,7-H,phenyl-2-H),7.64(s,1H,anthraquinone-4-H),7.40(dd,J＝10.7,7.0Hz,3H,phenyl-3,5,6-H),7.33(s,1H,anthraquinone-2-H),4.98(s,2H,CH2)ppm。
experimental example 10
Preparation of Compound I-6
Add intermediate to 100mL round bottom flaskV (200mg,0.69mmol), intermediate IV-6(200mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, reflux at 80 ℃ for 10h, and thin layer chromatography followed to the end of the reaction. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-6(30mg,0.05mmol) as a yellow solid. Yield: 8.8 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.92(d,J＝11.1Hz,2H,anthraquinone-1,8-(OH)2),8.31(s,1H,CH),7.92(s,1H,2,4-difluorobenzaldehyde-5-H),7.82(m,1H,anthraquinone-5-H),7.73(d,J＝7.2Hz,1H,anthraquinone-6-H),7.68(d,1H,2,4-difluorobenzaldehyde-4-H),7.65(s,1H,anthraquinone-4-H),7.40(d,J＝7.3Hz,1H,anthraquinone-7-H),7.34(d,J＝14.4Hz,2H,anthraquinone-2-H,2,4-difluorobenzaldehyde-3-H),4.99(s,2H,CH2)ppm。
experimental example 11
Preparation of Compound I-7
A100 mL round bottom flask was charged with intermediate V (300mg,1.04mmol), intermediate IV-7(299mg,1.25mmol), triethylamine (105mg,1.04mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-7(221mg,0.45mmol) as a yellow solid. Yield: 43.2 percent; melting point: more than 250 ℃;1H NMR(600MHz,DMSO-d6)δ11.92(s,2H,anthraquinone-1,8-(OH)2),8.31(s,1H),8.01(s,1H),7.82(m,1H),7.73(d,J＝7.5Hz,1H),7.69(d,J＝8.6Hz,2H),7.63(d,J＝8.7Hz,2H),7.40(d,J＝8.3Hz,1H),7.34(s,1H),4.98(s,2H,CH2)ppm。
experimental example 12
Preparation of Compound I-8
A100 mL round bottom flask was charged with intermediate V (300mg,1.04mmol), intermediate IV-8(299mg,1.25mmol), triethylamine (105mg,1.04mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-8(208mg,0.42mmol) as a yellow solid. Yield: 40.6 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.92(d,J＝7.9Hz,2H),8.31(s,1H),8.10(s,1H),7.82(m,2H),7.73(d,J＝7.3Hz,1H),7.67(s,1H),7.55(s,1H),7.41(d,J＝8.0Hz,1H),7.36(s,1H),7.18(s,1H),4.99(s,2H,CH2)ppm。
experimental example 13
Preparation of Compound I-9
A100 mL round bottom flask was charged with intermediate V (200mg,0.69mmol), intermediate IV-9(227mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-9(50mg,0.05mmol) as a yellow solid. Yield: 13.8 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.91(d,J＝8.1Hz,2H,anthraquinone-1,8-(OH)2),8.02(s,1H,CH),7.87(s,1H,2,4-dichlorobenzaldehyde-3-H),7.82(t,J＝7.9Hz,1H,anthraquinone-5-H),7.72(d,J＝7.6Hz,1H,anthraquinone-6-H),7.64(d,J＝10.5Hz,3H,anthraquinone-4-H,2,4-dichlorobenzaldehyde-5-H,2,4-dichlorobenzaldehyde-6-H),7.39(d,J＝8.4Hz,1H,anthraquinone-7-H),7.35(s,1H,anthraquinone-2-H),4.98(s,2H,CH2)ppm。
experimental example 14
Preparation of Compound I-10
A100 mL round bottom flask was charged with intermediate V (200mg,0.69mmol), intermediate IV-10(171mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-10(75mg,0.16mmol) as a yellow solid. Yield: 23.2 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.92(d,J＝7.9Hz,2H),8.31(s,1H),8.10(s,1H),7.82(m,2H),7.73(d,J＝7.3Hz,1H),7.67(s,1H),7.55(s,1H),7.41(d,J＝8.0Hz,1H),7.36(s,1H),7.18(s,1H),4.99(s,2H,CH2)ppm。
experimental example 15
Preparation of Compound I-11
A100 mL round bottom flask was charged with intermediate V (200mg,0.69mmol), intermediate IV-11(226mg,0.83mmol), triethylamine (70mg,0.69mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-11(124mg,0.24mmol) as a yellow solid. Yield: 34.8 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.92(d,J＝20.5Hz,2H,anthraquinone-1,8-(OH)2),8.24(s,1H),7.96(m,2H),7.82(m,2H),7.72(d,J＝7.2Hz,1H),7.64(d,J＝6.8Hz,2H),7.40(d,J＝8.3Hz,1H),7.32(s,1H),7.26(d,J＝8.2Hz,1H),4.99(s,2H,CH2),4.39(m,2H,CH2CH3),1.09(t,J＝8.2Hz,3H,CH3)ppm。
experimental example 16
Preparation of Compound I-12
A100 mL round bottom flask was charged with intermediate V (600mg,2.08mmol), intermediate IV-12(819mg,2.50mmol), triethylamine (210mg,2.08mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-12(304mg,0.55mmol) as a yellow solid. Yield: 26.5 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.94(s,1H,anthraquinone-1-OH),11.90(s,1H,anthraquinone-8-OH),8.24(s,1H,indole-2-H),7.96(d,J＝7.9Hz,1H,indole-4-H),7.93(s,1H,CH),7.83–7.80(m,1H,anthraquinone-6-H),7.72(d,J＝7.2Hz,1H,anthraquinone-5-H),7.64(s,1H),7.40(d,J＝8.2Hz,1H),7.32(s,1H),7.25(m,2H),4.98(s,2H,CH2),4.35(m,2H,CH2(CH2)2CH3),1.99(dd,J＝13.0,6.8Hz,2H,CH2CH2CH2CH3),1.78(m,2H,(CH2)2CH2CH3),0.90(t,J＝7.3Hz,3H,(CH2)3CH3)ppm。
experimental example 17
Preparation of Compound I-13
A100 mL round bottom flask was charged with intermediate V (600mg,2.08mmol), intermediate IV-13(710mg,2.50mmol), triethylamine (210mg,2.08mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-13(396mg,0.74mmol) as a yellow solid. Yield: 35.5 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ1H NMR(600MHz,DMSO-d6)δ11.93(s,1H,OH),11.90(s,1H,OH),8.25(s,1H),7.97(d,J＝7.9Hz,1H),7.93(s,1H),7.82(t,J＝8.0Hz,1H),7.72(d,J＝7.5Hz,1H),7.64(d,J＝1.7Hz,1H),7.57(d,J＝8.2Hz,1H),7.40(d,J＝8.3Hz,1H),7.34–7.29(m,1H),7.26(t,J＝7.5Hz,1H),7.17(s,1H),6.05(m,1H),5.21(d,J＝10.4Hz,1H),5.12(d,J＝17.1Hz,1H),5.00(m,2H)ppm。
experimental example 18
Preparation of Compound I-14
A100 mL round bottom flask was charged with intermediate V (150mg,0.52mmol), intermediate IV-14(163mg,0.62mmol), triethylamine (53mg,0.52mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to give compound I-14(42mg,0.08mmol) as a yellow solid. Yield: 11.9 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.94(s,2H,anthraquinone-1,8-(OH)2),8.24(d,J＝15.5Hz,2H),8.17(d,J＝7.9Hz,1H),8.12(d,J＝7.8Hz,1H),7.82(t,J＝8.0Hz,1H),7.72(m,1H),7.66(d,J＝1.7Hz,1H),7.53(m,2H),7.40(d,J＝8.4Hz,1H),7.35(s,1H),5.01(s,2H,CH2)ppm。
experimental example 19
Preparation of Compound I-15
A100 mL round bottom flask was charged with intermediate V (300mg,1.04mmol), intermediate IV-15(318mg,1.25mmol), triethylamine (105mg,1.04mmol), acetonitrile (25mL) as solvent, refluxed at 80 ℃ for 10h, and followed by thin layer chromatography until the reaction was complete. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent, petroleum ether/dichloromethane (10/1-1/1, V/V)) to obtain compound I-15(239mg,0.47mmol) as a yellow solid. Yield: 45.3 percent; melting point:>250℃；1H NMR(600MHz,DMSO-d6)δ11.93(s,2H,anthraquinone-1,8-(OH)2),8.46(s,1H，-C＝CH-),8.27(s,1H,naphthalene-4-H),8.16(s,1H,naphthalene-5-H),8.07(t,2H,naphthalene-2,8-H),7.95(t,1H,anthraquinone-5-H),7.81(d,J＝12.8Hz,1H，naphthalene-7-H),7.73(d,J＝7.6Hz,2H，naphthalene-3-H,anthraquinone-6-H),7.66(s,1H,naphthalene-6-H),7.63(s,1H,anthraquinone-4-H),7.40(s,1H,anthraquinone-2-H),7.36(s,1H,anthraquinone-7-H),5.01(s,2H,CH2)ppm。
example 20
In vitro antimicrobial activity of aloe-emodin thiazolidinediones
The aloe-emodin thiazolidinediones prepared in examples 5 to 19 were assayed for their Minimum Inhibitory Concentrations (MICs) 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 ATCC27853, Escherichia coli ATCC 25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis ATCC20019) 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 and diluted to 1024. mu.g/mL with a culture medium, culturing at 35 deg.C for 24-72h, shaking the culture plate on a shaker, and detecting, the results are shown in tables 1-3.
TABLE 1 in vitro gram-positive activity data (MIC, mM) for Aloe-emodin thiazolidinedione compounds prepared in examples 5-19
As can be seen from Table 1, the aloe-emodin thiazolidinediones prepared in examples 5 to 19 of the present invention exhibit certain inhibitory effects on tested gram-positive bacteria, and the inhibitory activities of the benzene ring substituted compound I-3 and the benzothiophene substituted compound I-14 on Staphylococcus aureus ATCC25923 are superior to those of the reference drug norfloxacin; in particular, the compounds I-3 and I-4 showed excellent inhibitory activity against Staphylococcus aureus ATCC29213, which is 12 times that of the reference drug norfloxacin. This provides a certain basis for further antibacterial mechanism research.
TABLE 2 in vitro gram-negative activity data (MIC, mM) for Aloe-emodin thiazolidinedione compounds prepared in examples 5-19
TABLE 3 in vitro antifungal Activity data (MIC, mM) for Aloe-emodin thiazolidinediones prepared in examples 5-19
As can be seen from Table 2, the aloe-emodin thiazolidinediones prepared in examples 5-19 of the present invention exhibit some inhibitory effect on the gram-negative bacteria tested. The benzene ring substituted I-3 shows excellent inhibitory activity to Klebsiella pneumoniae, which is 6.5 times of the norfloxacin phase of the reference medicament; the MIC value of p-methylphenyl ring substituted compound I-4 to Pseudomonas aeruginosa ATCC27853 is 0.001mM, which is 13 times that of the reference drug norfloxacin.
As can be seen from Table 3, the benzene ring substituent I-3 of the aloe-emodin thiazolidinedione compounds prepared in examples 5-19 of the present invention has better inhibitory activity against Candida tropicalis than the reference drug fluconazole; various compounds such as I-1, I-2, I-3, I-4, I-5, I-6, I-8, I-14 and I-15 showed superior inhibitory activity to fluconazole against Candida parapsilosis ATCC 22019; in particular, all compounds showed superior inhibitory activity to candida albicans ATCC90023 than fluconazole.
Example 21
Pharmaceutical use of aloe-emodin thiazolidinedione compounds
According to the antimicrobial activity detection result, the aloe-emodin thiazolidinedione compound has better antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicines for clinical use. The medicines can be single preparations, for example, the medicines are prepared by aloe-emodin thiazolidinedione compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the aloe-emodin thiazolidinedione compound with one structure, the existing antibacterial and antifungal active ingredients (such as norfloxacin, sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials are prepared, or the aloe-emodin thiazolidinedione compounds with different structures and the pharmaceutically acceptable auxiliary materials are prepared. 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-2 tablets
Prescription: the tablet is prepared from 1000 tablets of compound I-210 g, 187g of lactose, 50g of corn starch, 3g of magnesium stearate and a proper amount of ethanol solution with the volume percentage concentration of 70%.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-2 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-2 capsules
Prescription: compound I-225 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) 2g, 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-2 into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, making into soft material with water, granulating 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-3 granules
Prescription: compound I-326 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound I-3, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-3 injection
Prescription: 1000mL of the compound I-310 g, 500mL of propylene glycol and 500mL of water for injection were prepared in total.
The preparation method comprises the following steps: weighing the compound I-3, 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-3.
5. Preparation of compound I-4 powder injection
The preparation method comprises the following steps: and subpackaging the sterile powder of the compound I-4 under the sterile condition to obtain the compound I-4.
6. Preparation of Compound I-4 eye drops
Prescription: 43.78 g of compound I, 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 I-4 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 hr.
7. Preparation of Compound I-4 Liniment
Prescription: compound I-44 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-4, 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-4
Prescription: the total amount of compound I-44 g, gelatin 14g, glycerin 70g, and distilled water was 100mL, and 100 tablets were prepared.
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-4, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-14 ointment
Prescription: 140.5-2 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-14, stirring, and cooling.
10. Preparation of compound I-14 and fluconazole compound powder injection
Prescription: compound I-1450 g, fluconazole 50g and sodium benzoate 1g, and 100 bottles are prepared.
The preparation method comprises the following steps: taking the compound I-14, 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-14.
11. Preparation of Compound I-14 Aerosol
Prescription: compound I-142.5 g, Span 203 g, talc (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.
The preparation method comprises the following steps: respectively drying the compound I-14, 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 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 aloe-emodin thiazolidinedione compound and the pharmaceutically acceptable salts thereof are characterized in that the structure is shown as a general formula I:
in the formula: r is imidazolyl, thienyl, furyl, phenyl, p-methylphenyl, p-fluorophenyl, 2, 4-difluorophenyl, o-chlorophenyl, p-chlorophenyl, 2, 4-dichlorophenyl, pyridyl, pyrimidyl, indolyl, benzothienyl, benzofuryl, quinolyl, carbazolyl or naphthyl.
2. The aloe-emodin thiazolidinediones and pharmaceutically acceptable salts thereof as set forth in claim 1,
r is furyl, thienyl, phenyl, p-methylphenyl, p-fluorophenyl, 2, 4-difluorophenyl, o-chlorophenyl, p-chlorophenyl, 2, 4-dichlorophenyl, pyridyl, N-ethylindolyl, N-hexylindolyl, N-allylindolyl, benzothienyl or naphthyl.
3. The aloe-emodin thiazolidinedione compound and the pharmaceutically acceptable salts thereof as set forth in claim 1, which is any one of the following compounds:
4. the aloe-emodin thiazolidinedione compound and pharmaceutically acceptable salts thereof as claimed in claim 1, wherein the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a hydrochloride salt, a nitrate salt, or an acetate salt.
5. A process for the preparation of aloe-emodin thiazolidinediones and pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 4, wherein the process is as follows:
a. preparation of intermediate II: reacting thiourea serving as an initial raw material with chloroacetic acid by using water as a solvent to obtain an intermediate II;
b. preparation of intermediate III: indole-3-formaldehyde is used as a starting material, acetonitrile is used as a solvent, cesium carbonate is used as a base, and the starting material and the cesium carbonate react with a halogenated compound to obtain an intermediate III;
c. preparation of intermediate IV: taking the intermediate II as a starting material, taking piperidine as alkali, adding an aldehyde compound, and refluxing in ethanol to obtain an intermediate IV;
d. preparation of intermediate V: 1, 8-dihydroxy-3-hydroxymethyl anthraquinone is used as a starting material to react with thionyl chloride in N, N-dimethylformamide to obtain an intermediate V;
e. preparation of aloe-emodin thiazolidinediones of formula I: and (3) reacting the intermediate V and the intermediate IV by using acetonitrile as a solvent and triethylamine as alkali to obtain the aloe-emodin thiazolidinedione compound shown in the general formula I.
6. The method of claim 5, wherein:
in the step a, the molar ratio of thiourea to chloroacetic acid is 1:1, and the reaction temperature is 100 ℃;
in the step b, the mol ratio of the indole-3-formaldehyde to the halogenated compound to the cesium carbonate is 1:1.2:1.5, and the reaction temperature is 80 ℃;
in the step c, the molar ratio of the intermediate II, the piperidine and the aldehyde compound is 1:1.5:1.5, and the reaction temperature is 80 ℃;
in the step d, the molar ratio of the 1, 8-dihydroxy-3-hydroxymethyl anthraquinone to the thionyl chloride is 1:27.5, and the reaction temperature is 0 ℃;
in the step e, the molar ratio of the intermediate V, the intermediate IV and triethylamine is 1:1.2:1, the base is triethylamine, and the reaction temperature is 80 ℃.
7. Use of aloe-emodin thiazolidinediones and their pharmaceutically acceptable salts according to any one of claims 1 to 4 in the preparation of antibacterial and/or antifungal medicaments.
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 ATCC 25922, pseudomonas aeruginosa ATCC27853, or acinetobacter baumannii; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023 or Candida parapsilosis ATCC 20019.
9. A formulation comprising the aloe-emodin thiazolidinediones as set forth in any one of claims 1 to 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 |
|---|---|---|---|
| CN202011473961.6A CN112521382A (en) | 2020-12-14 | 2020-12-14 | Aloe-emodin thiazolidinedione compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011473961.6A CN112521382A (en) | 2020-12-14 | 2020-12-14 | Aloe-emodin thiazolidinedione compound and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112521382A true CN112521382A (en) | 2021-03-19 |
Family
ID=74999853
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011473961.6A Pending CN112521382A (en) | 2020-12-14 | 2020-12-14 | Aloe-emodin thiazolidinedione compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112521382A (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000043006A1 (en) * | 1999-01-19 | 2000-07-27 | Sankyo Company, Limited | Inhibitor for nerve cell death due to glutamic acid cytotoxicity |
| WO2002062337A1 (en) * | 2000-12-18 | 2002-08-15 | Smithkline Beecham Corporation | Thiazolidinediones |
| EP1313471B1 (en) * | 2000-08-31 | 2007-04-11 | Ucb, S.A. | Benzylidene thiazolidinediones and their use as antimycotic agents |
| CN107629044A (en) * | 2017-10-25 | 2018-01-26 | 西南大学 | Naphthalimide aminothiazole class compound and its preparation method and application |
| CN108864072A (en) * | 2018-08-01 | 2018-11-23 | 西南大学 | Cumarin thiophene cyclohexadione compounds and its preparation method and application |
| CN109553579A (en) * | 2018-12-29 | 2019-04-02 | 西南大学 | The preparation method and applications of aloe-emodin azole compounds |
| CN109575007A (en) * | 2018-12-29 | 2019-04-05 | 西南大学 | Aminothiazole isatin class compound and its preparation method and application |
| CN111018853A (en) * | 2019-12-27 | 2020-04-17 | 西南大学 | Phenol berberine benzimidazole compound and preparation method and application thereof |
| CN111087388A (en) * | 2019-12-27 | 2020-05-01 | 西南大学 | Hydrazone group bridged naphthalimide imidazole compound and preparation method and application thereof |
| CN111518075A (en) * | 2020-04-17 | 2020-08-11 | 西南大学 | Naphthalimide piperazine triazole compound and preparation method and application thereof |
-
2020
- 2020-12-14 CN CN202011473961.6A patent/CN112521382A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000043006A1 (en) * | 1999-01-19 | 2000-07-27 | Sankyo Company, Limited | Inhibitor for nerve cell death due to glutamic acid cytotoxicity |
| EP1313471B1 (en) * | 2000-08-31 | 2007-04-11 | Ucb, S.A. | Benzylidene thiazolidinediones and their use as antimycotic agents |
| WO2002062337A1 (en) * | 2000-12-18 | 2002-08-15 | Smithkline Beecham Corporation | Thiazolidinediones |
| CN107629044A (en) * | 2017-10-25 | 2018-01-26 | 西南大学 | Naphthalimide aminothiazole class compound and its preparation method and application |
| CN108864072A (en) * | 2018-08-01 | 2018-11-23 | 西南大学 | Cumarin thiophene cyclohexadione compounds and its preparation method and application |
| CN109553579A (en) * | 2018-12-29 | 2019-04-02 | 西南大学 | The preparation method and applications of aloe-emodin azole compounds |
| CN109575007A (en) * | 2018-12-29 | 2019-04-05 | 西南大学 | Aminothiazole isatin class compound and its preparation method and application |
| CN111018853A (en) * | 2019-12-27 | 2020-04-17 | 西南大学 | Phenol berberine benzimidazole compound and preparation method and application thereof |
| CN111087388A (en) * | 2019-12-27 | 2020-05-01 | 西南大学 | Hydrazone group bridged naphthalimide imidazole compound and preparation method and application thereof |
| CN111518075A (en) * | 2020-04-17 | 2020-08-11 | 西南大学 | Naphthalimide piperazine triazole compound and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109942546B (en) | Quinolone pyrimidine compound and preparation method and application thereof | |
| CN107501178B (en) | Naphthalimide derivative and preparation method and application thereof | |
| CN110963996B (en) | Indanazolol compound containing acetophenone substituent, preparation method and medical application thereof | |
| MX2014015249A (en) | N-substituted second generation derivatives of antifungal antibiotic amphotericin b and methods of their preparation and application. | |
| CN109535176B (en) | Quinolone imidazole compound and preparation method and application thereof | |
| CN110452225B (en) | Triazole ethyl isatin derivative and preparation method and application thereof | |
| CN110330487B (en) | Quinazolinone thiazole compound and preparation method and application thereof | |
| CN108440518B (en) | 3- (2-aminothiazole) -7-substituted piperazine quinolone compound and preparation method and application thereof | |
| CN109734723B (en) | Ofloxacin thiazole analogue and preparation method and application thereof | |
| CN111518075B (en) | Naphthalimide piperazine triazole compound and preparation method and application thereof | |
| CN110283166B (en) | Ethoxy bridged thiazole coumarin compound and preparation method and application thereof | |
| CN109575007B (en) | Aminothiazole isatin compound and preparation method and application thereof | |
| CN108864072B (en) | Coumarin thiadione compound and preparation method and application thereof | |
| CN111087388A (en) | Hydrazone group bridged naphthalimide imidazole compound and preparation method and application thereof | |
| EP1311506A2 (en) | Chiral fluoroquinolizinone arginine salt forms | |
| CN111087392B (en) | Vinyl conjugated indolylaminothiazole compound and preparation method and application thereof | |
| CN113292476B (en) | Sulfaindole derivative and preparation method and application thereof | |
| CN110452224B (en) | Pyrimidineazolol compound and preparation method and application thereof | |
| CN112480105B (en) | Piperazine bridged naphthalimide aminothiazole oxime compound and preparation method and application thereof | |
| CN112521382A (en) | Aloe-emodin thiazolidinedione compound and preparation method and application thereof | |
| CN112661750B (en) | Ketene-bridged quinazolinone thiazole compound and preparation method and application thereof | |
| CN110396090B (en) | Imidazole alcohol tetrahydrocoptisane oxime conjugate and preparation method and application thereof | |
| CN109851611B (en) | Sulfadiazine compound and preparation method and application thereof | |
| CN110028455B (en) | Schiff base nitroimidazole compound and preparation method and application thereof | |
| CN108658971B (en) | tetrahydroberberine thiadione compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210319 |