CN111518075B - Naphthalimide piperazine triazole compound and preparation method and application thereof - Google Patents
Naphthalimide piperazine triazole compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a naphthalimide piperazine triazole compound, and a preparation method and application thereof, and belongs to the technical field of chemical synthesis. The naphthalimide piperazine triazole compound 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, has an opportunity to provide more safe and efficient diversified candidate medicaments for clinical antimicrobial treatment, and is beneficial to solving clinical treatment problems such as increasingly severe 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 anti-infection aspect has important significance.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a naphthalimide piperazine triazole compound, and a preparation method and application thereof.
Background
The naphthalimide is an aromatic nitrogen-oxygen heterocyclic compound containing six-membered cyclic imide and naphthalene rings, has a larger electron-pushing conjugated system, and has a special structure favorable for intramolecular/intermolecular electron transfer, so that the special rigid fused ring structure is easy to interact with biological active sites such as enzymes, receptors, DNA and the like through various non-covalent bond interactions such as hydrogen bonds, hydrophobic interaction, pi-pi accumulation, electrostatic interaction and the like, thereby showing wide application potential. In recent years, especially in the field of pharmaceutical chemistry, the compounds show great development value and broad application prospects, and more research works are devoted to the research and development of drugs with naphthalimide as a basic skeleton, such as in the aspects of anti-tumor, anti-bacterial, anti-fungal, anti-viral, anti-inflammatory, anti-depression, medical diagnosis and the like. But the naphthalimide ring cannot be widely applied clinically due to the solubility, hepatotoxicity and other toxic and side effects, but the naphthalimide ring is easy to modify the structure and can conveniently introduce various functional groups, thereby playing an increasingly important role in the pharmaceutical field.
Disclosure of Invention
In view of the above, an object of the present invention is to provide naphthoylimine piperazine triazole compounds and pharmaceutically acceptable salts thereof; the invention also aims to provide a preparation method of the naphthalimide piperazine triazole compound and the pharmaceutically acceptable salt thereof; the third purpose of the invention is to provide the application of the naphthalimide piperazine triazole compound and the pharmaceutically acceptable salt thereof in preparing antibacterial and/or antifungal medicaments; the invention also aims to provide a preparation containing the naphthalimide piperazine triazole compound and a pharmaceutically acceptable salt thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the naphthalimide piperazine triazole compound and the pharmaceutically acceptable salt thereof is shown as the general formula I:
in the formula:
r is hydrogen, alkyl, aryl, halomethylene, alcoholic methylene, aldehyde group, sulfhydryl, alkynyl, alkenyl, cyano or ester group.
Preferably, R is hydrogen, ethyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, alkenyl, alkynyl, p-chlorophenyl, m-chlorophenyl, 2, 4-dichlorophenyl, p-fluorophenyl, m-fluorophenyl, 2, 4-difluorophenyl, cyano, hydroxyethyl, methoxyacyl or ethoxyacyl.
Preferably, it is any one of the following compounds:
preferably, the pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.
2. The preparation method of the naphthalimide piperazine triazole compound and the pharmaceutically acceptable salt thereof comprises the following steps:
a. preparation of intermediate II: 4-bromo-1, 8-naphthalic anhydride is used as an initial raw material, ethanol is used as a solvent, zinc acetate is used as a catalyst, and the mixture reacts with 4-amino-1, 2, 4-triazole to obtain an intermediate II;
b. preparation of intermediate III: taking the intermediate II as a starting material, taking ethylene glycol monomethyl ether as a solvent, and reacting with anhydrous piperazine to obtain an intermediate III;
c. the preparation method of the naphthalimide piperazine triazole compound shown in the general formula I comprises the step of reacting different halides with the intermediate III serving as a starting material, acetonitrile serving as a solvent and potassium carbonate serving as a catalyst to obtain the naphthalimide piperazine triazole compound shown in the general formula I.
In a preferred embodiment of the method of the invention,
in the step a, the reaction temperature is 80 ℃; the molar ratio of the 4-bromo-1, 8-naphthalic anhydride, 4-amino-1, 2, 4-triazole and zinc acetate is 1;
in the step b, the reaction temperature is 90 ℃; the molar ratio of the intermediate II to the anhydrous piperazine is 1;
in the step c, the reaction temperature is 80 ℃; the molar ratio of intermediate III, different halides and potassium carbonate is 1.07.
3. The naphthalimide piperazine triazole compound and the application of the medicinal salt thereof in preparing 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 ATCC25922, 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. The preparation of the naphthalimide piperazine triazole compound and the pharmaceutically acceptable salt thereof.
Preferably, the preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.
The invention has the beneficial effects that: the invention provides a naphthalimide piperazine triazole compound and a preparation method and application thereof, the invention utilizes a drug combination principle to introduce important antibacterial fragment 1,2, 4-triazole at N position of naphthalimide, and then introduces different substituents by piperazine bridging, a series of naphthalimide piperazine triazole compounds with novel structures are designed and synthesized, and the compounds are detected by in vitro antimicrobial activity to find that the compounds have certain inhibitory activity on one or more of gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli ATCC25922, pseudomonas aeruginosa ATCC27853, acinetobacter baumannii) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC90023, candida parapsilosis ATCC 20019), and can be used for preparing antibacterial and/or antifungal drugs, thereby providing more safe and efficient clinical antimicrobial therapy for more drugs, and being beneficial to solving the serious drug resistance of clinical and serious biological resistance of stubborn microorganisms. The preparation raw materials are simple, cheap and easy to obtain, the synthetic route is short, and the application in the anti-infection aspect has important significance.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter.
Detailed Description
The following embodiments of the present invention are provided by way of specific examples, and other advantages and effects of the present invention will be readily apparent to those skilled in the art from the disclosure herein. 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
A50 mL round-bottomed flask was charged with 4-bromo-1, 8-naphthalic anhydride (192.4 mg, 0.72mmol), 4-amino-1, 2, 4-triazole (90.8 mg, 1.08mmol), zinc acetate (12.8 mg, 0.07mmol) as a catalyst, ethanol (5 mL) as a solvent, and refluxed at 80 ℃ overnight. Pouring the reaction mixture into hydrochloric acid solution (10mL, 0.05mol/L), filtering to obtain a filter cake, and separatingThe filter cake was washed with water, ethanol and acetone, respectively. After drying, the mixture was subjected to column chromatography (developer: dichloromethane) to give intermediate II (222 mg) as a yellow solid in 90.0% yield. 1 H NMR(600MHz,DMSO-d6)δ8.89(s,3H,naphthalimide-H,triazole-H),8.53(d,J＝3.1Hz,1H,naphthalimide-H),8.32(d,J＝4.4Hz,1H,naphthalimide-H),7.70(d,J＝8.2Hz,1H,naphthalimide-H),6.97(s,1H,naphthalimide-H)ppm。
Experimental example 2
Preparation of intermediate III
A250 mL round bottom flask was charged with intermediate II (5.0 g,14.6 mmol) and anhydrous piperazine (3.8 g,43.8 mmol) in ethylene glycol monomethyl ether (100 mL) as a solvent, reacted at 90 deg.C, followed by thin layer chromatography until the reaction was complete, cooled to room temperature, and the solvent was removed to give intermediate III (4.2 g) as a golden yellow solid in 82.3% yield. 1 H NMR(600MHz,DMSO-d6)δ8.79(s,2H,triazole-H),8.59(d,J＝3.6Hz,1H,naphthalimide-H),8.56(d,J＝4.1Hz,1H,naphthalimide-H),8.49(d,J＝8.3Hz,1H,naphthalimide-H),7.90(d,J＝7.9Hz,1H,naphthalimide-H),7.44(d,J＝8.2Hz,1H,naphthalimide-H),4.23(s,1H,NH),3.37(s,4H,piperidine-H),2.97(s,4H,piperidine-H)ppm。
Experimental example 3
Preparation of Compound I-1
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromoethane (160mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and carrying out post-treatment such as column chromatography separation and drying to obtain the compound I-1 (353 mg), wherein the yield is as follows: 65.4 percent; a yellow solid; melting point: 155-156 ℃. 1 H NMR(600MHz,DMSO-d6)δ8.80(s,2H,triazole-H),8.58(d,J＝3.1Hz,1H,naphthalimide-H),8.57(d,J＝4.4Hz,1H,naphthalimide-H),8.49(d,J＝8.2Hz,1H,naphthalimide-H),7.89(s,1H,naphthalimide-H),7.41(d,J＝8.2Hz,1H,naphthalimide-H),2.71(t,4H,piperidine-H),2.50(t,4H,piperidine-H),2.48(s,2H,CH 2 CH 3 ),1.08(s,3H,CH 3 ).
Experimental example 4
Preparation of Compound I-2
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromohexane (230mg, 1.5 mmol), and potassium carbonate (0.82g, 5.6 mmol) in acetonitrile (15 mL), refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-2 (350 mg) with a yield: 57.9 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.65(d,J＝6.9Hz,1H,naphthalimide-H),8.58(d,J＝7.9Hz,1H,naphthalimide-H),8.54(d,J＝8.3Hz,1H,naphthalimide-H),8.31(s,2H,triazole-H),7.77(t,J＝7.6Hz,1H,naphthalimide-H),7.28(s,1H,naphthalimide-H),3.40(s,4H,piperidine-H),2.81(s,4H,piperidine-H),2.53–2.49(m,2H,CH 2 (CH 2 ) 4 CH 3 ),1.58(s,2H,CH 2 (CH 2 ) 3 CH 3 ),1.34(s,6H,(CH 2 ) 3 CH 3 ),0.91(s,3H,CH 3 )ppm。
experimental example 5
Preparation of Compound I-3
A50 mL round-bottom flask was charged with intermediate III (466 mg,1.4 mmol), octylbromide (290mg, 1.5 mmol), and potassium carbonate (0.82g, 5.6 mmol) in acetonitrile (15 mL), refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water,after column chromatography separation, drying and the like, compound I-3 (420 mg) was obtained, yield: 61.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.66(d,J＝6.9Hz,1H,naphthalimide-H),8.58(d,J＝7.9Hz,1H,naphthalimide-H),8.53(d,J＝8.3Hz,1H,naphthalimide-H),8.32(s,2H,triazole-H),7.77(t,J＝7.6Hz,1H,naphthalimide-H),7.28(s,1H,naphthalimide-H),3.41(s,4H,piperidine-H),2.80(s,4H,piperidine-H),2.53(m,2H,CH 2 (CH 2 ) 6 CH 3 ),1.58(m,2H,CH 2 (CH 2 ) 5 CH 3 ),1.34(m,10H,(CH 2 ) 5 CH 3 ),0.91(s,3H,CH 3 )ppm。
experimental example 6
Preparation of Compound I-4
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromodecane (332mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-4 (475 mg) with a yield: 65.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(400MHz,DMSO-d 6 )δ11.16(bs,1H,NNH),8.55(d,J＝8.3Hz,1H,naphthalimide-7-H),8.44(d,J＝8.2Hz,1H,naphthalimide-5-H),8.34(d,J＝7.7Hz,1H,naphthalimide-2-H),8.29(s,1H,CHN),7.65(t,J＝7.7Hz,1H,naphthalimide-6-H),7.19(d,J＝8.4Hz,1H,naphthalimide-3-H),4.81(bs,1H,OH),4.15(t,J＝12.4Hz,2H,NCH 2 CH 2 ),4.09(t,J＝12.4Hz,2H,CH 2 CH 2 OH),3.60(t,J＝11.5Hz,2H,CH 2 OH),2.65(t,J＝7.4Hz,2H,CH 2 CH 2 CH 2 CH 3 ),1.67(t,J＝11.0Hz,4H,NCH 2 CH 2 ,CH 2 CH 2 CH 2 CH 3 ),1.39(m,6H,NCH 2 CH 2 CH 2 CH 2 CH 3 ,CH 2 CH 2 CH 2 CH 3 ),0.93(m,6H,CH 3 )ppm。
experimental example 7
Preparation of Compound I-5
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromododecane (332mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-5 (475 mg) with a yield: 65.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.66(d,J＝7.2Hz,1H,naphthalimide-H),8.58(d,J＝8.2Hz,1H,naphthalimide-H),8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.31(s,2H,triazole-H),7.77(d,J＝8.3Hz,1H,naphthalimide-H),7.28(s,1H,naphthalimide-H),3.41(s,4H,piperidine-H),2.81(s,4H,piperidine-H),2.52(d,J＝7.6Hz,2H,CH 2 (CH 2 ) 12 CH 3 ),1.59–1.56(m,2H,CH 2 (CH 2 ) 11 CH 3 ),1.29(d,J＝18.5Hz,22H,(CH 2 ) 11 CH 3 ),0.89(s,3H,CH 3 )ppm。
experimental example 8
Preparation of Compound I-6
A50 mL round-bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromotetradecane (415mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-6 (475 mg) with a yield: 65.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.66(d,J＝7.2Hz,1H,naphthalimide-H),8.59(d,J＝8.2Hz,1H,naphthalimide-H),8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.31(s,2H,triazole-H),7.77(d,J＝8.3Hz,1H,naphthalimide-H)),7.28(s,1H,naphthalimide-H),3.41(s,4H,piperidine-H),2.81(s,4H,piperidine-H),2.53(d,J＝7.6Hz,2H,CH 2 (CH 2 ) 12 CH 3 ),1.59(m,2H,CH 2 (CH 2 ) 11 CH 3 ),1.29(d,J＝18.5Hz,18H,(CH 2 ) 9 CH 3 ),0.89(s,3H,CH 3 )ppm。
experimental example 9
Preparation of Compound I-7
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromohexadecane (457 mg,1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and carrying out post-treatment such as column chromatography separation and drying to obtain compound I-7 (461 mg), wherein the yield is as follows: 66.9 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.67–8.65(m,1H,naphthalimide-H),8.58(d,J＝8.2Hz,1H,naphthalimide-H),8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.31(s,2H,triazole-H),7.79–7.76(m,1H,naphthalimide-H),7.28(s,1H,naphthalimide-H),3.40(s,4H,piperidine-H),2.81(s,4H,piperidine-H),2.53–2.48(m,2H,CH 2 (CH 2 ) 14 CH 3 ),1.58(s,2H,CH 2 (CH 2 ) 13 CH 3 ),1.34(s,4H,CH 2 (CH 2 ) 11 CH 3 ),1.28(d,J＝20.2Hz,22H,(CH 2 ) 11 CH 3 ),0.88(t,J＝7.0Hz,3H,CH 3 )ppm。
experimental example 10
Preparation of Compound I-8
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromooctadecane (500mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-8 (390 mg) with a yield: 64.9 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.65(d,J＝7.1Hz,1H,naphthalimide-H),8.57(d,J＝8.2Hz,1H,naphthalimide-H),8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.31(s,2H,triazole-H),7.77(s,1H,naphthalimide-H),7.26(s,1H,naphthalimide-H),3.41(s,4H,piperidine-H),2.81(s,4H,piperidine-H),2.52(d,J＝7.6Hz,2H,CH 2 (CH 2 ) 16 CH 3 ),1.59–1.57(m,2H,CH 2 (CH 2 ) 15 CH 3 ),1.26(m,30H,(CH 2 ) 15 CH 3 ),0.88(s,3H,CH 3 )ppm。
experimental example 11
Preparation of Compound I-9
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromoethanol (186mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-9 (323 mg) with a yield: 66.9 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.66(d,J＝6.9Hz,1H,naphthalimide-H),8.60(d,J＝8.1Hz,1H,naphthalimide-H),8.53(d,J＝8.3Hz,1H,naphthalimide-H),8.32(s,2H,triazole-H),7.78(t,J＝7.6Hz,1H,naphthalimide-H),7.29(d,J＝8.2Hz),3.78(s,4H,piperidine-H),3.43(s,6H,piperidine-H,CH 2 CH 2 OH),2.99–2.97(t,2H,CH 2 CH 2 OH)ppm。
experimental example 12
Preparation of Compound I-10
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), methyl bromoacetate (230mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-10 (473 mg) with a yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.67(d,J＝7.3Hz,1H,naphthalimide-H),8.60(d,J＝8.1Hz,1H,naphthalimide-H),8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.32(s,2H,triazole-H),7.78(t,J＝7.9Hz,1H,naphthalimide-H),7.29(d,J＝8.2Hz,1H,naphthalimide-H),3.78(s,3H,CH 3 ),3.43(s,6H,NCH 2 CO,piperidine-H),2.99–2.97(m,4H,piperidine-H)ppm。
experimental example 13
Preparation of Compound I-11
A50 mL round-bottomed flask was charged with intermediate III (466 mg,1.4 mmol), ethyl bromoacetate (249mg, 1.5 mmol), and potassium carbonate (0.82g, 5.6 mmol) in acetonitrile (15 mL) at 80 ℃ under reflux for about 10h, followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and carrying out post-treatment such as column chromatography separation and drying to obtain the compound I-11 (315 mg) with yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,DMSO)δ8.79(s,2H,triazole-H),8.57(t,J＝8.2Hz,2H,naphthalimide-H),8.49(d,J＝8.2Hz,1H,naphthalimide-H),7.90(t,J＝7.9Hz,1H,naphthalimide-H),7.43(d,J＝8.2Hz,1H,naphthalimide-H),4.13(d,J＝7.1Hz,2H,NCH 2 CO),3.40(s,2H,OCH 2 CH 3 ),3.33(s,4H,piperidine-H),2.90–2.87(m,4H,piperidine-H),1.23(t,J＝7.1Hz,3H,CH 3 )ppm。
experimental example 14
Preparation of Compound I-12
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), bromopropene (182mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and carrying out post-treatment such as column chromatography separation and drying to obtain the compound I-12 (315 mg) with yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.66(d,J＝7.2Hz,1H,naphthalimide-H),8.58(d,J＝8.2Hz,1H,naphthalimide-H),8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.30(s,2H,triazole-H),7.79–7.75(m,1H,naphthalimide-H),7.29–7.27(m,1H,naphthalimide-H),5.94(ddt,J＝13.2,10.1,6.6Hz,1H,CH＝CH 2 ),5.31–5.23(m,2H,CH＝CH 2 ),3.41(s,4H,piperidine-H),3.19(d,J＝6.2Hz,2H),2.83(s,4H,piperidine-H)ppm。
experimental example 15
Preparation of Compound I-13
A50 mL round bottom flask was charged with intermediate III (466 mg, 1.4mmol), bromopropyne (179mg, 1.5mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-13 (315 mg) with a yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.67(d,J＝7.3Hz,1H,naphthalimide-H),8.59(d,J＝8.2Hz,1H,naphthalimide-H),8.56(d,J＝8.4Hz,1H,naphthalimide-H),8.31(s,2H,triazole-H),7.79(s,1H,naphthalimide-H),7.29(d,J＝8.2Hz,1H,naphthalimide-H),3.50(d,J＝2.3Hz,2H,CH 2 CCH),3.43(s,4H,piperidine-H),2.95–2.94(m,4H,piperidine-H),2.37(t,J＝2.2Hz,1H,CH)ppm。
experimental example 16
Preparation of Compound I-14
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), chloroacetonitrile (113mg, 1.5 mmol), and potassium carbonate (0.82g, 5.6 mmol) in acetonitrile (15 mL) at 80 ℃ under reflux for about 10h, followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and carrying out post-treatment such as column chromatography separation and drying to obtain compound I-14 (315 mg), wherein the yield is as follows: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,DMSO-d6)δ8.80(s,2H,triazole-H),8.59(t,J＝7.3Hz,2H,naphthalimide-H),8.49(d,J＝8.2Hz,1H,naphthalimide-H),7.92(s,1H,naphthalimide-H),7.44(d,J＝8.2Hz,1H,naphthalimide-H),3.91(s,2H,NCH 2 CN),3.36(s,4H,piperidine-H),2.86(d,J＝4.0Hz,4H,piperidine-H)ppm。
experimental example 17
Preparation of Compound I-15
A50 mL round bottom flask was charged with intermediate III (466 mg,1.4 mmol), p-chlorobenzyl chloride (242mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-15 (315 mg) with a yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.65(d,J＝6.6Hz,1H,naphthalimide-H),8.57(d,J＝8.2Hz,1H,naphthalimide-H),8.53(d,J＝7.8Hz,1H,naphthalimide-H),8.30(s,2H,triazole-H),7.77(s,1H,naphthalimide-H),7.33(d,4H,Ph-Cl-H),7.26(s,1H,naphthalimide-H),3.65(s,2H,NCH 2 Ph),3.39(s,4H,piperidine-H),2.80(s,4H,piperidine-H)ppm。
experimental example 18
Preparation of Compound I-16
A50 mL round-bottom flask was charged with intermediate III (466 mg,1.4 mmol), m-chlorobenzyl chloride (242mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-16 (315 mg) with a yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.65(dd,J＝7.3,0.9Hz,1H,naphthalimide-H),8.58(d,J＝8.2Hz,1H,naphthalimide-H),8.54(dd,J＝8.4,0.8Hz,1H,naphthalimide-H),8.30(s,2H,triazole-H),7.77(dd,J＝8.3,7.5Hz,1H,naphthalimide-H),7.41(s,1H,Ph-Cl-H),7.28(d,J＝1.8Hz,4H,naphthalimide-H,Ph-Cl-H),3.66(s,2H,NCH 2 Ph),3.40(s,4H,piperidine-H),2.81(s,4H,piperidine-H).
experimental example 19
Preparation of Compound I-17
A50 mL round-bottom flask was charged with intermediate III (466 mg,1.4 mmol), 2, 4-dichlorobenzyl chloride (293mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as a solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-17 (315 mg) with a yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.66(dd,J＝7.3,0.9Hz,1H,naphthalimide-H),8.58(d,J＝8.2Hz,1H,naphthalimide-H),8.55(dd,J＝8.4,0.9Hz,1H,naphthalimide-H),8.30(s,2H,triazole-H),7.78(dd,J＝8.3,7.5Hz,1H,naphthalimide-H),7.48(d,J＝8.1Hz,1H,Ph-Cl-H),7.41(d,J＝2.0Hz,1H,Ph-Cl-H),7.28–7.26(m,2H,naphthalimide-H,Ph-Cl-H),3.76(s,2H,NCH 2 Ph),3.39(s,4H,piperidine-H),2.87(s,4H,piperidine-H)ppm。
experimental example 20
Preparation of Compound I-18
A50 mL round bottom flask was charged with intermediate III (466mg, 1.4mmol), p-fluorobenzyl bromide (284mg, 1.5mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-18 (315 mg) with a yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.65(d,J＝7.3Hz,1H,naphthalimide-H),8.57(d,J＝8.2Hz,1H,naphthalimide-H),8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.30(s,2H,triazole-H),7.77(s,1H,naphthalimide-H),7.37(d,J＝5.8Hz,2H,Ph-F-H),7.26(s,1H,naphthalimide-H),7.04(s,2H,Ph-Cl-H),3.65(s,2H,NCH 2 Ph),3.39(s,4H,piperidine-H),2.80(s,4H,piperidine-H).
experimental example 21
Preparation of Compound I-19
A50 mL round bottom flask was charged with intermediate III (466 mg, 1.4mmol), m-fluorobenzyl bromide (284mg, 1.5mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, passing through a column layerAfter separation, drying and the like, compound I-19 (315 mg) was obtained, yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,DMSO-d6)δ8.80(s,2H,triazole-H),8.58–8.56(m,2H,naphthalimide-H),8.48(d,J＝8.2Hz,1H,naphthalimide-H),7.90–7.87(m,1H,naphthalimide-H),7.41(d,J＝3.7Hz,2H,naphthalimide-H,Ph-F-H),7.23(m,2H,Ph-F-H),7.12(m,1H,Ph-F-H),3.67(s,2H,NCH 2 Ph),2.74(s,4H),2.50(s,4H)ppm。
experimental example 22
Preparation of Compound I-20
A50 mL round-bottom flask was charged with intermediate III (466 mg,1.4 mmol), 2, 4-difluorobenzyl bromide (311mg, 1.5 mmol), potassium carbonate (0.82g, 5.6 mmol), acetonitrile (15 mL) as solvent, refluxed at 80 ℃ for about 10h, and followed by thin layer chromatography until the reaction was complete. Pouring the reaction solution into ice water, filtering, washing with ice water, and performing column chromatography separation, drying and other post-treatments to obtain a compound I-20 (315 mg) with a yield: 75.2 percent; a yellow solid; melting point:>250℃。 1 H NMR(600MHz,CDCl 3 )δ8.65(d,J＝7.3Hz,1H,naphthalimide-H),8.57(d,J＝8.2Hz,1H,naphthalimide-H),8.53(d,J＝8.4Hz,1H,naphthalimide-H),8.30(s,2H,triazole-H),7.77(s,1H,naphthalimide-H),7.42(d,J＝7.2Hz,1H,Ph-F-H),7.26(d,J＝8.3Hz,1H,naphthalimide-H),6.90(dd,J＝8.2,6.5Hz,1H,Ph-F-H),6.84(dd,J＝8.8,7.6Hz,1H,Ph-F-H),3.72(s,2H,NCH 2 Ph),3.39(s,4H,piperidine-H),2.84(s,4H,piperidine-H)ppm。
example 23
In vitro antimicrobial activity of naphthalimide piperazine triazole compound
The nadir inhibitory concentrations (MIC) of the naphthoylimine piperazine triazole compounds prepared in examples 2 to 22 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 ATCC25922, acinetobacter baumannii) and fungi (Candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC90023, and Candida parapsilosis ATCC 20019) were determined by 96-well microdilution method in accordance with the Clinical Laboratory Standards of the national Committee, CLSI, and the MIC results were determined by measuring the MIC concentrations of 1.28mg/mL of the naphthoylimine piperazine triazole compounds prepared in examples 2 to 22, diluting the test compounds with a small amount of dimethyl sulfoxide, adding water to a solution of a concentration of 128. Mu.g/mL, culturing at 35 ℃ for 24 to 72 hours, shaking the culture plates to a shaker sufficiently, and measuring the MIC results at 490nm of the wavelength of 1 to 3 nm of the Candida acinosa.
TABLE 1 in vitro gram-positive activity data (MIC, μ g/mL) for the naphthalimide piperazine triazole compounds prepared in examples 2-22
As can be seen from Table 1, the naphthalimide piperazine triazole compounds prepared in examples 2-22 of the invention have certain inhibitory effect on the tested gram-positive bacteria, and a part of compounds such as I-5 have moderate inhibitory activity on Staphylococcus aureus.
TABLE 2 in vitro gram negative bacteria resistance data (MIC, μ g/mL) for the naphthalimide piperazine triazole compounds prepared in examples 2-22
As can be seen from Table 2, the naphthalimide piperazine triazole compounds of examples 2-22 of the present invention showed certain inhibitory effect on the tested gram-negative bacteria. I-1 to I-4, I-6, I-7, I-12, I-13, I-15 to I-18 and I-20 show the inhibition activity on acinetobacter baumannii which is equivalent to that of the reference medicament norfloxacin.
TABLE 3 data on the antifungal Activity in vitro (MIC, μ g/mL) of the Naphthoimidopiperazine triazole Compounds prepared in examples 2-22
As can be seen from Table 3, the antifungal activity of the naphthalimide piperazine triazole compounds prepared in examples 2-22 of the present invention is generally superior to their antibacterial activity. MIC =4 μ g/mL for dodecyl substituted compound I-5 against candida parapsilosis ATCC22019, comparable to the reference drug fluconazole. The compound I-5 has good inhibition activity (MIC =4 mug/mL) on the aspergillus fumigatus, is 32 times that of the reference drug fluconazole, and is superior to the reference drug fluconazole; the 2, 4-dichlorophenyl substituted compound I-17 showed good activity against aspergillus fumigatus, with MIC =2 μ g/mL, 64 times that of the reference drug fluconazole; in particular, propargyl-substituted compound I-13, had 128-fold higher inhibitory activity against aspergillus fumigatus (MIC =1 μ g/mL) than the reference drug fluconazole.
Example 24
Pharmaceutical application of naphthalimide piperazine triazole compound
According to the antimicrobial activity detection result, the naphthalimide piperazine triazole compound has good antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicines for clinical use. The medicines can be single-component preparations, for example, the medicines are prepared from naphthalimide piperazine triazole compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound is prepared by the naphthalimide piperazine triazole 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, or the compound is prepared by a plurality of naphthalimide piperazine triazole compounds with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.
1. Preparation of Compound I-4 tablets
Prescription: the tablet is prepared from compound I-410g, lactose 187g, corn starch 50g, magnesium stearate 3g, and ethanol solution with volume percentage concentration of 70% in a proper amount, and is prepared into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-4 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10mg.
2. Preparation of Compound I-2 Capsule
Prescription: 2-25g of compound I, 12.5g of modified starch (120 meshes), 7.5g of microcrystalline cellulose (100 meshes), 2.5g of low-substituted hydroxypropyl cellulose (100 meshes), 2g of talcum powder (100 meshes), 1.25g of sweetener, 0.25g of orange essence, 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 I-2 into superfine powder, 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 25mg.
3. Preparation of Compound I-5 granules
Prescription: 26g of compound I-5, 120g of dextrin and 280g of sucrose.
The preparation method comprises the following steps: mixing compound I-5, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-17 injection
Prescription: compound I-17 (10 g), propylene glycol (500 mL), and water for injection (500 mL) were prepared in a total volume of 1000mL.
The preparation method comprises the following steps: weighing the compound I-17, 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-17.
5. Preparation of compound I-13 powder injection
The preparation method comprises the following steps: and subpackaging the sterile powder of the compound I-13 under the aseptic condition to obtain the compound I-13.
6. Preparation of Compound I-13 eye drops
Prescription: 3.78g of compound I-13, 0.9g of sodium chloride, a proper amount of boric acid buffer solution and distilled water are added to 1000mL.
The preparation method comprises the following steps: weighing the compound I-13 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-13 Liniment
Prescription: compound I-13 g, potassium soap 7.5g, camphor 5g, distilled water added to 100mL.
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-13, 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-13
Prescription: compound I-13 g, gelatin 14g, glycerin 70g, distilled water to 100mL, total 100.
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-13, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling for solidification.
9. Preparation of Compound I-13 ointment
Prescription: 0.5-2g of compound I-13, 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 100g.
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-13, stirring, and cooling.
10. Preparation of compound I-20 and fluconazole compound powder injection
Prescription: compound I-20 50g, fluconazole 50g and sodium benzoate 1g, and 100 bottles are prepared.
The preparation method comprises the following steps: taking the compound I-20, 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-20.
11. Preparation of Compound I-20 Aerosol
Prescription: compound I-20.5g, span20 3g, talc (100 mesh) 4g, trichlorofluoromethane to appropriate amount.
The preparation method comprises the following steps: respectively placing the compound I-20, the Span20 and the talcum powder in a vacuum drying oven for drying for several hours, placing in a dryer for cooling to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the trichloromonofluoromethane.
Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.
Claims (9)
1. The naphthalimide piperazine triazole compound or the pharmaceutically acceptable salt thereof is characterized in that the naphthalimide piperazine triazole compound is any one of the following compounds:
2. the naphthalimide piperazine triazole compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride, nitrate or acetate salt.
3. The method for preparing the naphthalimide piperazine triazole compound according to claim 1, wherein the method comprises the following steps:
a. preparation of intermediate II: 4-bromo-1, 8-naphthalic anhydride is used as an initial raw material, ethanol is used as a solvent, zinc acetate is used as a catalyst, and the mixture reacts with 4-amino-1, 2, 4-triazole to obtain an intermediate II;
b. preparation of intermediate III: taking the intermediate II as a starting material, taking ethylene glycol monomethyl ether as a solvent, and reacting with anhydrous piperazine to obtain an intermediate III;
c. the preparation of the naphthalimide piperazine triazole compound shown in the formula I-1-20 is carried out by taking the intermediate III as a starting material, acetonitrile as a solvent and potassium carbonate as a catalyst, and reacting with different halides to obtain the naphthalimide piperazine triazole compound shown in the formula I-1-20.
4. The method according to claim 3,
in the step a, the reaction temperature is 80 ℃; the molar ratio of the 4-bromo-1, 8-naphthalic anhydride, 4-amino-1, 2, 4-triazole and zinc acetate is 1;
in the step b, the reaction temperature is 90 ℃; the molar ratio of the intermediate II to the anhydrous piperazine is 1;
in the step c, the reaction temperature is 80 ℃; the molar ratio of intermediate III, different halides and potassium carbonate is 1.07.
5. Use of the naphthalimide piperazine triazole compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2 for preparing antibacterial and/or antifungal medicaments.
6. The use of claim 5, 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 20019.
7. The use of claim 6, wherein the bacteria is one or more of methicillin-resistant staphylococcus aureus, staphylococcus aureus ATCC25923, staphylococcus aureus ATCC29213, escherichia coli ATCC25922, or pseudomonas aeruginosa ATCC 27853; the fungus is Candida albicans ATCC90023.
8. A formulation comprising the naphthalimide piperazine triazole compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof.
9. The formulation of claim 8, 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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