CN112480105A - Piperazine bridged naphthalimide aminothiazole oxime compound and preparation method and application thereof - Google Patents
Piperazine bridged naphthalimide aminothiazole oxime compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to piperazine bridged naphthalimide aminothiazole oxime compounds and a preparation method and application thereof, belonging to the technical field of chemical synthesis. The piperazine bridged naphthalimide aminothiazole oxime compound is shown as a general formula I, has certain inhibitory activity on one or more of gram-positive bacteria, gram-negative bacteria and fungi, can be used for preparing antibacterial and/or antifungal medicaments, provides more efficient and safe candidate medicaments for clinical antimicrobial treatment, and is beneficial to solving the problems of increasingly serious drug resistance, stubborn pathogenic microorganisms andthe new occurrence of harmful microorganisms and other clinical treatment problems. The preparation raw materials are simple, cheap and easy to obtain, the synthetic route is short, and the application in the aspect of infection resistance is of great significance.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to piperazine bridged naphthalimide aminothiazole oximes and a preparation method and application thereof.
Background
Naphthalimides are aromatic nitrogen-oxygen heterocyclic compounds of six-membered cyclic imide condensed naphthalene, and have larger conjugated systems and strong intramolecular electron transfer capacity, so that the special rigid condensed ring structure is easy to react with ions, small molecules and biological macromolecules through various non-covalent bond actions such as hydrogen bonds, hydrophobic action, pi-pi accumulation, electrostatic interaction and the like, and shows broad spectrum. In recent years, the method has great development value and wide application prospect particularly in the field of pharmaceutical chemistry, so that more and more research works are devoted to the research and development of the drug taking naphthalimide as a basic skeleton, such as the aspects of anti-tumor, anti-bacterial, anti-fungal, anti-viral, anti-inflammatory, anti-depression, medical diagnosis and the like. The naphthalimide ring is easy to carry out structural modification and can conveniently introduce various functional groups, and along with the increasing serious drug resistance of antimicrobial drugs, the development of the pharmaceutical application of the naphthalimide novel compound shows more and more important significance for overcoming the drug resistance.
Disclosure of Invention
One of the purposes of the invention is to provide piperazine bridged naphthalimide aminothiazole oxime compounds and pharmaceutically acceptable salts thereof; the second purpose of the invention is to provide a preparation method of piperazine bridged naphthalimide aminothiazole oxime compound and a medicinal salt thereof; the invention also aims to provide application of the piperazine bridged naphthalimide aminothiazole oxime compound and the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments; the invention also aims to provide a preparation containing the piperazine bridged naphthalimide aminothiazole oxime compound and a pharmaceutically acceptable salt thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the piperazine bridged naphthalimide aminothiazole oxime compound and the medicinal salt thereof have the structures shown as a general formula I:
in the formula:
R1is alkyl, cycloalkyl, hydroxy, alkoxy, hydroxyalkyl, hydroxyalkylamino, N-dimethylethyl, cyanoalkyl, carboxylic acid alkyl, amido, amino, aminoalkyl or heterocyclyl;
R2is an alkyl group.
Preferably, R1Is methyl, N-butyl, N-hexyl, dodecyl, cyclopropyl, cyclopentyl, cyclohexyl, hydroxyl, ethoxy, hydroxyethyl, hydroxyethylamino, 1, 3-dihydroxypropyl, N-dimethylethyl, cyanoethyl, acetoxy, propionyloxy, acetamido, amino, aminoethyl, aminobutyl, aminohexyl, thiazolyl or triazolyl;
R2is methyl.
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 piperazine bridged naphthalimide aminothiazole oxime compound and the medicinal 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, and the initial raw material and the ethanol react with an amino compound to obtain an intermediate II;
b. preparation of intermediate III: taking the intermediate II as an initial raw material, taking ethylene glycol monomethyl ether as a solvent, and reacting with anhydrous piperazine to obtain an intermediate III;
c. preparation of piperazine bridged naphthalimide aminothiazole oximes of the general formula I: and (3) taking the intermediate III as a starting material, triethylamine as an alkali and ethanol as a solvent to react with 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester to obtain the piperazine bridged naphthalimide aminothiazole oxime compound shown in the general formula I.
Preferably, the first and second liquid crystal materials are,
in the step a, the molar ratio of the 4-bromo-1, 8-naphthalic anhydride to the amino compound is 1:1.2, and the reaction temperature is 80 ℃;
in the step b, the molar ratio of the intermediate II to the anhydrous piperazine is 1:3, and the reaction temperature is 120 ℃;
in the step c, the molar ratio of the intermediate III, the 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thio benzothiazole ester and the triethylamine is 1:1:1, and the reaction temperature is 25 ℃.
3. The piperazine bridged naphthalimide aminothiazole oxime 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 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 containing the piperazine bridged naphthalimide aminothiazole oxime compound and the medicinal salt thereof.
Preferably, the preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.
The invention has the beneficial effects that: the invention provides piperazine bridged naphthalimide aminothiazole oxime compounds and a preparation method and application thereof, the invention utilizes a drug design split principle to design and synthesize a series of novel piperazine bridged naphthalimide aminothiazole oxime compounds through piperazine bridged naphthalimide and drug effect fragment aminothiazole oxime, and the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923 and staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922 and acinetobacter baumannii) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC90023 and candida parapsilosis ATCC 22019) 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
A100 mL round-bottomed flask was charged with 4-bromo-1, 8-naphthalic anhydride (2.00g,7.22mmol), ethanol (30mL) as a solvent, and then an amino compound (methylamine (269mg,8.66mmol), N-butylamine (633mg,8.66mmol), N-hexylamine (876mg,8.66mmol), dodecylamine (1.61g,8.66mmol), cyclopropylamine (494mg,8.66mmol), cyclopentylamine (737mg,8.66mmol), cyclohexylamine (859mg,8.66mmol), hydroxylamine (286mg,8.66mmol), ethoxyamine (529mg,8.66mmol), ethanolamine (529mg,8.66mmol), 2-hydroxyethylhydrazine (659mg,8.66mmol), 2-amino-1, 3-propanediol (789mg,8.66mmol), N-dimethylethylenediamine (763mg,8.66mmol), ethylcyanamide (485mg,8.66mmol), glycine (650.66 mmol), 8.66mmol) and ethanol (30mL) were added, Alanine (772mg,8.66mmol), acethydrazide (642mg,8.66mmol), hydrazine hydrate (434mg,8.66mmol), ethylenediamine (520mg,8.66mmol), 1, 4-butanediamine (763mg,8.66mmol), 1, 6-hexanediamine (1.01g,8.66mmol), 2-aminothiazole (867mg,8.66mmol) and 4-amino-1, 2, 4-triazole (728mg,8.66mmol), and the reaction was stirred at 80 ℃ for 2 hours. Thin layer chromatography followed to the end of the reaction, cooled to room temperature, and the solvent removed to give intermediate II-1(1.81g,6.26mmol), yield: 86.7 percent; II-2(2.05g,6.19mmol), yield: 85.7 percent; II-3(2.25g,6.26mmol), yield: 86.7 percent; II-4(2.63g,5.94mmol), yield: 82.3 percent; II-5(2.06g,6.53mmol), yield: 90.5 percent; II-6(2.07g,6.04mmol), yield: 83.7 percent; II-7(2.13g,5.97mmol), yield: 82.7 percent; II-8(1.99g,6.82mmol), yield: 94.5 percent; II-9(1.99g,6.25mmol), yield: 86.5 percent; II-10(1.96g,6.14mmol), yield: 85.1 percent; II-11(2.30g,6.90mmol), yield: 95.5 percent; II-12(2.45g,7.02mmol), yield: 97.2 percent; II-13(2.20g,6.36mmol), yield: 88.1 percent; II-14(2.02g,6.42mmol), yield: 88.9 percent; II-15(2.30g,6.91mmol), yield: 95.7 percent; II-16(2.20g,6.33mmol), yield: 87.7 percent; II-17(2.06g,6.20mmol), yield: 85.9 percent; II-18(1.84g,6.33mmol), yield: 87.7 percent; II-19(1.96g,6.16mmol), yield: 85.3 percent; II-20(2.27g,6.56mmol), yield: 90.8 percent; II-21(2.34g,6.27mmol), yield: 86.8 percent; II-22(2.15g,6.01mmol), yield: 83.3 percent; II-23(2.34g,6.84mmol), yield: 94.7 percent.
Experimental example 2
Preparation of intermediate III
A100 mL round-bottomed flask was charged with intermediate II (intermediate II-1(1.00g,3.46mmol), intermediate II-2(1.15g,3.46mmol), intermediate II-3(1.24g,3.46mmol), intermediate II-4(1.53g,3.46mmol), intermediate II-5(1.09g,3.46mmol), intermediate II-6(1.19g,3.46mmol), intermediate II-7(1.24g,3.46mmol), intermediate II-8(1.07g,3.46mmol), intermediate II-9(1.10g,3.46mmol), intermediate II-10(1.10g,3.46mmol), intermediate II-11(1.16g,3.46mmol), intermediate II-12(1.21g,3.46mmol), intermediate II-13(1.20g,3.46mmol), intermediate II-14(1.09g,3.46mmol), intermediate II-15.46 g, 15.46 mmol), 3.46mmol), intermediate II-17(1.15g,3.46mmol), intermediate II-18(1.00g,3.46mmol), intermediate II-19(1.10g,3.46mmol), intermediate II-20(1.20g,3.46mmol), intermediate II-21(1.29g,3.46mmol), intermediate II-22(1.24g,3.46mmol), intermediate II-23(1.18g,3.46mmol), ethylene glycol monomethyl ether (10mL) as solvent, anhydrous piperazine (894mg,10.38mmol) added, and the reaction was stirred at 120 ℃ under reflux for 1.5 hours. Thin layer chromatography followed to the end of the reaction, cooled to room temperature, and the solvent removed to give intermediate III-1(681mg,2.31mmol), yield: 66.7 percent; III-2(650mg,1.93mmol), yield: 55.7 percent; III-3(829mg,2.27mmol), yield: 65.7 percent; III-4(1.12g,2.50mmol), yield: 72.3 percent; III-5(783mg,2.44mmol), yield: 70.5 percent; III-6(769mg,2.20mmol), yield: 63.7 percent; III-7(913mg,2.52mmol), yield: 72.7 percent; III-8(663mg,2.23mmol), yield: 64.5 percent; III-9(759mg,2.34mmol), yield: 67.5 percent; III-10(844mg,2.60mmol), yield: 75.1 percent; III-11(841mg,2.47mmol), yield: 71.5 percent; III-12(825mg,2.33mmol), yield: 67.2 percent; III-13(829mg,2.36mmol), yield: 68.1 percent; III-14(763mg,2.38mmol), yield: 68.9 percent; III-15(771mg,2.27mmol), yield: 65.7 percent; III-16(827mg,2.34mmol), yield: 67.7 percent; III-17(888mg,2.63mmol), yield: 75.9 percent; III-18(693mg,2.34mmol), yield: 67.7 percent; III-19(842mg,2.60mmol), yield: 75.2 percent; III-20(739mg,2.10mmol), yield: 60.8 percent; III-21(878mg,2.31mmol), yield: 66.8 percent; III-22(797mg,2.19mmol), yield: 63.3 percent; III-23(899mg,2.58mmol), yield: 74.7 percent.
Experimental example 3
Preparation of Compound I-1
Adding intermediate III-1(300mg,1.03mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (361mg,1.03mmol) and triethylamine (104mg,1.03mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by using ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-1(211mg,0.44mmol), wherein the yield is as follows: 42.9 percent; a yellow solid; melting point: 221.5-222.3 ℃.1H NMR(600MHz,DMSO-d6)δ8.51(d,J＝6.8Hz,1H,naphthalimide-H),8.46(d,J＝4.2Hz,1H,naphthalimide-H),8.38(d,J＝6.5Hz,1H,naphthalimide-H),7.96(d,J＝4.2Hz,1H,naphthalimide-H),7.80(s,1H,thiazole-H),7.36(d,J＝6.5Hz,1H,naphthalimide-H),7.23(s,2H,NH2),3.90(s,3H,NOCH3),3.37(s,3H,CH3),2.89(s,4H,piperazine-H),2.73(s,4H,piperazine-H)ppm。
Experimental example 4
Preparation of Compound I-2
Adding intermediate III-2(300mg,0.89mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (312mg,0.89mmol) and triethylamine (90mg,0.89mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-2(224mg,0.43mmol), wherein the yield is as follows: 48.5 percent; a yellow solid; melting point: 224.8-225.1 ℃.1H NMR(600MHz,DMSO-d6)δ8.51(d,J＝8.1Hz,1H,naphthalimide-H),8.47(d,J＝6.6Hz,1H,naphthalimide-H),8.39(d,J＝7.9Hz,1H,naphthalimide-H),7.81(t,J＝7.7Hz,1H,naphthalimide-H),7.36(d,J＝8.0Hz,1H,naphthalimide-H),7.24(s,2H,NH2),6.91(s,1H,thiazole-H),4.02(t,J＝7.1Hz,2H,NCH2(CH2)2CH3),3.91(s,4H,piperazine-H),3.57(m,2H,piperazine-H),3.33(s,3H,NOCH3),3.21(m,2H,piperazine-H),1.59(m,2H,CH2CH2CH3),1.34(m,2H,CH2CH3),0.92(t,J＝7.1Hz,3H,CH2CH3)ppm。
Experimental example 5
Preparation of Compound I-3
A100 mL round bottom flask was charged with intermediate III-3(300mg,0.82mmol), 2- (2-amino-4-thia-neOxazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (288mg,0.82mmol), triethylamine (83mg,0.82mmol), ethanol (20mL) as a solvent, reacting at 25 ℃ for 15h, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-3(236mg,0.43mmol), yield: 52.4 percent; a yellow solid; melting point: 211.8-212.3 ℃.1H NMR(600MHz,DMSO-d6)δ8.52(d,J＝8.4Hz,1H,naphthalimide-H),8.48(d,J＝7.2Hz,1H,naphthalimide-H),8.40(d,J＝8.1Hz,1H,naphthalimide-H),7.82(t,J＝7.8Hz,1H,naphthalimide-H),7.38(d,J＝8.1Hz,1H,naphthalimide-H),7.23(s,2H,NH2),6.90(s,1H,thiazole-H),4.02(t,J＝7.1Hz,2H,NCH2(CH2)4CH3),3.90(s,4H,piperazine-H),3.56(m,2H,piperazine-H),3.32(s,3H,NOCH3),3.21(m,2H,piperazine-H),1.61(m,2H,CH2(CH2)3CH3),1.30(m,6H,(CH2)3CH3),0.85(t,J＝6.7Hz,3H,(CH2)5CH3)ppm。
Experimental example 6
Preparation of Compound I-4
Adding intermediate III-4(300mg,0.67mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (234mg,0.67mmol) and triethylamine (68mg,0.67mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-4(183mg,0.29mmol), wherein the yield is as follows: 42.6 percent; a yellow solid; melting point: 201.3-201.7 ℃.1H NMR(600MHz,DMSO-d6)δ8.52(d,J＝8.4Hz,1H,naphthalimide-H),8.48(d,J＝7.2Hz,1H,naphthalimide-H),8.40(d,J＝8.1Hz,1H,naphthalimide-H),7.82(t,J＝7.8Hz,1H,naphthalimide-H),7.38(d,J＝8.1Hz,1H,naphthalimide-H),7.23(s,2H,NH2),6.90(s,1H,thiazole-H),3.90(s,4H,piperazine-H),3.58(t,J＝7.1Hz,2H,NCH2(CH2)10CH3),3.56(m,2H,piperazine-H),3.32(s,3H,NOCH3),3.21(m,2H,piperazine-H),1.67(m,2H,CH2(CH2)9CH3),1.26(m,18H,(CH2)9CH3),0.85(t,J＝6.7Hz,3H,(CH2)11CH3)ppm。
Experimental example 7
Preparation of Compound I-5
Adding intermediate III-5(300mg,0.93mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (327mg,0.93mmol) and triethylamine (94mg,0.93mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-5(208mg,0.41mmol), wherein the yield is as follows: 44.3 percent; a yellow solid; melting point: 234.3-234.9 ℃.1H NMR(600MHz,DMSO-d6)δ8.47(d,J＝8.4Hz,1H,naphthalimide-H),8.41(d,J＝7.2Hz,1H,naphthalimide-H),8.34(d,J＝8.0Hz,1H,naphthalimide-H),7.78(t,J＝7.8Hz,1H,naphthalimide-H),7.34(d,J＝8.1Hz,1H,naphthalimide-H),7.24(s,2H,NH2),6.91(s,1H,thiazole-H),3.91(s,4H,piperazine-H),3.57(m,2H,piperazine-H),3.34(s,3H,NOCH3),3.19(m,2H,piperazine-H),2.75(m,1H,cyclopropane-H),1.08(q,J＝6.8Hz,2H,cyclopropane-H),0.76(d,J＝7.3Hz,2H,cyclopropane-H)ppm。
Experimental example 8
Preparation of Compound I-6
A100 mL round-bottom flask was charged with intermediate III-6(300mg,0.86mmol), thiobenzothiazole 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetate (301mg,0.86mmol), triethylamine (87mg,0.86mmol), ethanol (20mL) as a solvent, reacted at 25 ℃ for 15h, followed by thin layer chromatography until the reaction was completeCooled to room temperature, and the solvent was removed to give compound I-6(238mg,0.45mmol), yield: 52.1 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.49(d,J＝8.4Hz,1H,naphthalimide-H),8.46(d,J＝7.2Hz,1H,naphthalimide-H),8.38(d,J＝8.0Hz,1H,naphthalimide-H),7.80(t,J＝7.8Hz,1H,naphthalimide-H),7.35(d,J＝8.1Hz,1H,naphthalimide-H),7.24(s,2H,NH2),6.91(s,1H,thiazole-H),5.45(m,1H,cyclopentane-H),3.91(s,4H,piperazine-H),3.57(m,2H,piperazine-H),3.33(s,3H,NOCH3),3.21(m,2H,piperazine-H),2.11(m,2H,cyclopentane-H),1.98(m,2H,cyclopentane-H),1.84(m,2H,cyclopentane-H),1.62(m,2H,cyclopentane-H)ppm。
experimental example 9
Preparation of Compound I-7
Adding intermediate III-7(300mg,0.83mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (289mg,0.83mmol) and triethylamine (84mg,0.83mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-7(252mg,0.46mmol), wherein the yield is as follows: 55.6 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.50(d,J＝8.4Hz,1H,naphthalimide-H),8.46(d,J＝7.2Hz,1H,naphthalimide-H),8.38(d,J＝7.9Hz,1H,naphthalimide-H),7.81(t,J＝7.8Hz,1H,naphthalimide-H),7.37(d,J＝8.0Hz,1H,naphthalimide-H),7.24(s,2H,NH2),6.90(s,1H,thiazole-H),4.88(m,1H,cyclohexane-H),3.90(s,4H,piperazine-H),3.57(m,2H,piperazine-H),3.33(s,3H,NOCH3),3.20(m,2H,piperazine-H),2.44(m,2H,cyclohexane-H),1.83(m,2H,cyclohexane-H),1.65(m,2H,cyclohexane-H),1.35(m,2H,cyclohexane-H),1.20(m,2H,cyclohexane-H)ppm。
experimental example 10
Preparation of Compound I-8
Adding intermediate III-8(300mg,1.01mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (354mg,1.01mmol) and triethylamine (102mg,1.01mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-8(273mg,0.57mmol), wherein the yield is as follows: 56.2 percent; a yellow solid; melting point: 211.1-211.5 ℃.1H NMR(600MHz,DMSO-d6)δ11.58(s,1H,OH),8.50(d,J＝8.4Hz,1H,naphthalimide-H),8.46(d,J＝7.2Hz,1H,naphthalimide-H),8.38(d,J＝7.9Hz,1H,naphthalimide-H),7.81(t,J＝7.8Hz,1H,naphthalimide-H),7.37(d,J＝8.0Hz,1H,naphthalimide-H),7.24(s,2H,NH2),6.90(s,1H,thiazole-H),3.90(s,4H,piperazine-H),3.57(m,2H,piperazine-H),3.33(s,3H,NOCH3),3.20(m,2H,piperazine-H)ppm。
Experimental example 11
Preparation of Compound I-9
Adding intermediate III-9(300mg,0.92mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (323mg,0.92mmol) and triethylamine (93mg,0.92mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-9(231mg,0.46mmol), wherein the yield is as follows: 49.5 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.54(d,J＝14.6Hz,1H,naphthalimide-H),8.47(d,J＝7.1Hz,1H,naphthalimide-H),8.40(d,J＝14.8Hz,1H,naphthalimide-H),7.83(t,J＝7.8Hz,1H,naphthalimide-H),7.37(d,J＝8.1Hz,1H,naphthalimide-H),7.23(s,2H,NH2),6.90(s,1H,thiazole-H),4.19(m,2H,CH2CH3),3.90(s,4H,piperazine-H),3.57(m,2H,piperazine-H),3.31(s,3H,NOCH3),3.22(m,2H,piperazine-H),1.32(t,J＝7.0Hz,3H,CH2CH3)ppm。
experimental example 12
Preparation of Compound I-10
Adding intermediate III-10(300mg,0.92mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (323mg,0.92mmol) and triethylamine (93mg,0.92mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-10(274mg,0.54mmol), wherein the yield is as follows: 58.7 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.54(d,J＝14.6Hz,1H,naphthalimide-H),8.47(d,J＝7.1Hz,1H,naphthalimide-H),8.40(d,J＝14.8Hz,1H,naphthalimide-H),7.83(t,J＝7.8Hz,1H,naphthalimide-H),7.37(d,J＝8.1Hz,1H,naphthalimide-H),7.23(s,2H,NH2),6.90(s,1H,thiazole-H),4.80(bs,1H,OH),4.13(t,J＝6.5Hz,2H,CH2CH2OH),3.90(s,4H,piperazine-H),3.60(t,J＝5.4Hz,2H,CH2OH),3.57(m,2H,piperazine-H),3.31(s,3H,NOCH3),3.22(m,2H,piperazine-H)ppm。
experimental example 13
Preparation of Compound I-11
Adding intermediate III-11(300mg,0.88mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (308mg,0.88mmol) and triethylamine (89mg,0.88mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-11(244mg,0.47mmol), wherein the yield is as follows: 53.1 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.53(d,J＝8.4Hz,1H,naphthalimide-H),8.48(d,J＝6.9Hz,1H,naphthalimide-H),8.41(d,J＝15.8Hz,1H,naphthalimide-H),7.83(t,J＝7.8Hz,1H,naphthalimide-H),7.38(d,J＝8.1Hz,1H,naphthalimide-H),7.24(s,2H,NH2),6.91(s,1H,thiazole-H),6.28(t,J＝6.2Hz,1H,NNH),4.66(t,J＝5.3Hz,1H,OH),3.91(s,4H,piperazine-H),3.60(m,4H,CH2CH2OH),3.34(s,3H,NOCH3),3.23(m,2H,piperazine-H),3.04(m,2H,piperazine-H)ppm。
experimental example 14
Preparation of Compound I-12
Adding intermediate III-12(300mg,0.85mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (296mg,0.85mmol) and triethylamine (86mg,0.85mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-12(274mg,0.51mmol), wherein the yield is as follows: 59.8 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.52(d,J＝8.4Hz,1H,naphthalimide-H),8.47(d,J＝7.0Hz,1H,naphthalimide-H),8.39(d,J＝7.9Hz,1H,naphthalimide-H),7.82(t,J＝7.7Hz,1H,naphthalimide-H),7.38(d,J＝7.7Hz,1H,naphthalimide-H),7.23(s,2H,NH2),6.90(s,1H,thiazole-H),5.22(m,1H,NCH(CH2OH)2),4.75(bs,2H,OH),3.94(d,J＝5.8Hz,2H,CH2OH),3.90(s,4H,piperazine-H),3.83(d,J＝6.1Hz,2H,CH2OH),3.57(m,2H,piperazine-H),3.33(s,3H,NOCH3),3.21(m,2H,piperazine-H)ppm。
experimental example 15
Preparation of Compound I-13
A100 mL round bottom flask was charged with intermediate III-13(300mg,0.85mmol)2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thio-benzothiazole ester (296mg,0.85mmol), triethylamine (86mg,0.85mmol), ethanol (20mL) is used as a solvent, the reaction is carried out for 15h at 25 ℃, thin layer chromatography is used for tracking until the reaction is finished, the reaction is cooled to room temperature, the solvent is removed to obtain a compound I-13(283mg,0.53mmol), and the yield: 62.3 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.50(d,J＝8.4Hz,1H,naphthalimide-H),8.45(d,J＝7.2Hz,1H,naphthalimide-H),8.37(d,J＝8.0Hz,1H,naphthalimide-H),7.80(t,J＝7.8Hz,1H,naphthalimide-H),7.35(d,J＝8.1Hz,1H,naphthalimide-H),7.25(s,2H,NH2),6.91(s,1H,thiazole-H),4.13(t,J＝6.7Hz,2H,CH2CH2N(CH3)2),3.91(s,4H,piperazine-H),3.56(m,2H,piperazine-H),3.35(s,3H,NOCH3),3.21(m,2H,piperazine-H),2.51(t,J＝6.7Hz,2H,CH2CH2N(CH3)2),2.21(s,6H,CH2CH2N(CH3)2)ppm。
experimental example 16
Preparation of Compound I-14
Adding intermediate III-14(300mg,0.94mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (329mg,0.94mmol) and triethylamine (95mg,0.94mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by using ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-14(261mg,0.52mmol), wherein the yield is as follows: 55.2 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.54(d,J＝12.8Hz,1H,naphthalimide-H),8.47(d,J＝11.5Hz,1H,naphthalimide-H),8.39(d,J＝8.0Hz,1H,naphthalimide-H),7.82(t,J＝7.8Hz,1H,naphthalimide-H),7.38(d,J＝8.0Hz,1H,naphthalimide-H),7.23(s,2H,NH2),6.91(s,1H,thiazole-H),4.60(s,2H,CH2CN),3.90(s,4H,piperazine-H),3.58(m,2H,piperazine-H),3.33(s,3H,NOCH3),3.23(m,2H,piperazine-H)ppm。
experimental example 17
Preparation of Compound I-15
Adding intermediate III-15(300mg,0.88mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (310mg,0.88mmol) and triethylamine (89mg,0.88mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-15(235mg,0.45mmol), wherein the yield is as follows: 51.2 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.53(d,J＝6.7Hz,1H,naphthalimide-H),8.49(d,J＝5.5Hz,1H,naphthalimide-H),8.41(d,J＝6.7Hz,1H,naphthalimide-H),7.83(t,J＝6.7Hz,1H,naphthalimide-H),7.38(d,J＝7.4Hz,1H,naphthalimide-H),7.23(s,2H,NH2),6.90(s,1H,thiazole-H),4.25(s,3H,NOCH3),3.90(s,4H,piperazine-H),3.57(t,2H,CH2COOH),2.76(s,4H,piperazine-H)ppm。
experimental example 18
Preparation of Compound I-16
Adding intermediate III-16(300mg,0.85mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thio-benzothiazole ester (298mg,0.85mmol) and triethylamine (86mg,0.85mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-16(227mg,0.42mmol), and obtaining the yield: 49.9 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.53(d,J＝6.7Hz,1H,naphthalimide-H),8.49(d,J＝5.5Hz,1H,naphthalimide-H),8.41(d,J＝6.7Hz,1H,naphthalimide-H),7.83(t,J＝6.7Hz,1H,naphthalimide-H),7.38(d,J＝7.4Hz,1H,naphthalimide-H),7.23(s,2H,NH2),6.90(s,1H,thiazole-H),4.25(s,3H,NOCH3),3.90(s,4H,piperazine-H),3.57(t,2H,CH2CH2COOH),2.76(s,4H,piperazine-H),2.56(t,2H,CH2CH2COOH)ppm。
experimental example 19
Preparation of Compound I-17
Adding intermediate III-17(300mg,0.89mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (312mg,0.89mmol) and triethylamine (90mg,0.89mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-17(224mg,0.43mmol), wherein the yield is as follows: 48.3 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ10.63(s,1H,NHCOCH3),8.57(d,J＝8.1Hz,1H,naphthalimide-H),8.50(d,J＝7.1Hz,1H,naphthalimide-H),8.43(d,J＝8.0Hz,1H,naphthalimide-H),7.84(t,J＝7.8Hz,1H,naphthalimide-H),7.39(d,J＝8.1Hz,1H,naphthalimide-H),7.26(s,2H,NH2),6.92(s,1H,thiazole-H),3.91(s,4H,piperazine-H),3.58(m,2H,piperazine-H),3.37(s,3H,NOCH3),3.24(m,2H,piperazine-H),2.09(s,3H,NHCOCH3)ppm。
experimental example 20
Preparation of Compound I-18
Adding intermediate III-18(300mg,1.01mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (354mg,1.01mmol) and triethylamine (102mg,1.01mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-18(306mg,0.64mmol), wherein the yield is as follows:63.2 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.50(d,J＝7.2Hz,1H,naphthalimide-H),8.42(d,J＝8.1Hz,1H,naphthalimide-H),7.83(t,J＝7.8Hz,1H,naphthalimide-H),7.38(d,J＝8.1Hz,1H,naphthalimide-H),7.22(s,2H,NH2),6.90(s,1H,thiazole-H),5.76(s,2H,NNH2),4.03(m,2H,piperazine-H),3.57(s,4H,piperazine-H),3.32(s,3H,NOCH3),3.24(m,2H,piperazine-H)ppm。
experimental example 21
Preparation of Compound I-19
Adding intermediate III-19(300mg,0.93mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (324mg,0.93mmol) and triethylamine (94mg,0.93mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-19(223mg,0.44mmol), wherein the yield is as follows: 47.4%; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.50(d,J＝7.2Hz,1H,naphthalimide-H),8.42(d,J＝8.1Hz,1H,naphthalimide-H),7.83(t,J＝7.8Hz,1H,naphthalimide-H),7.38(d,J＝8.1Hz,1H,naphthalimide-H),7.22(s,2H,NH2),6.90(s,1H,thiazole-H),4.03(m,2H,piperazine-H),3.57(s,4H,piperazine-H),3.38(t,2H,NCH2CH2NH2),3.32(s,3H,NOCH3),3.24(m,2H,piperazine-H),2.80(m,2H,NCH2CH2NH2),2.24(s,2H,NCH2CH2NH2)ppm。
experimental example 22
Preparation of Compound I-20
Adding intermediate III-20(300mg,0.85mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (298mg,0.85mmol) and triethylamine (86mg,0.85mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by taking ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-20(224mg,0.42mmol), wherein the yield is as follows: 49.2 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.50(d,J＝7.2Hz,1H,naphthalimide-H),8.42(d,J＝8.1Hz,1H,naphthalimide-H),7.83(t,J＝7.8Hz,1H,naphthalimide-H),7.38(d,J＝8.1Hz,1H,naphthalimide-H),7.22(s,2H,NH2),6.90(s,1H,thiazole-H),4.03(m,2H,piperazine-H),3.57(s,4H,piperazine-H),3.38(t,2H,NCH2(CH2)3NH2),3.32(s,3H,NOCH3),3.24(m,2H,piperazine-H),2.80(m,2H,N(CH2)3CH2NH2),1.65(m,4H,NCH2(CH2)2CH2NH2),1.50(s,2H,N(CH2)4NH2)ppm。
experimental example 23
Preparation of Compound I-21
Adding intermediate III-21(300mg,0.79mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester (277mg,0.79mmol) and triethylamine (80mg,0.79mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by using ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain compound I-21(213mg,0.38mmol), wherein the yield is as follows: 47.9 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.54(d,J＝8.4Hz,1H,naphthalimide-H),8.50(d,J＝7.2Hz,1H,naphthalimide-H),8.42(d,J＝8.1Hz,1H,naphthalimide-H),7.83(t,J＝7.8Hz,1H,naphthalimide-H),7.38(d,J＝8.1Hz,1H,naphthalimide-H),7.22(s,2H,NH2),6.90(s,1H,thiazole-H),4.03(m,2H,piperazine-H),3.57(s,4H,piperazine-H),3.38(t,2H,NCH2(CH2)5NH2),3.32(s,3H,NOCH3),3.24(m,2H,piperazine-H),2.69(m,2H,N(CH2)5CH2NH2),1.70(m,8H,NCH2(CH2)4CH2NH2),1.50(s,2H,N(CH2)6NH2)ppm。
experimental example 24
Preparation of Compound I-22
Adding intermediate III-22(300mg,0.82mmol), 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thio-benzothiazole ester (287mg,0.82mmol) and triethylamine (83mg,0.82mmol) into a 100mL round-bottom flask, reacting for 15h at 25 ℃ by using ethanol (20mL) as a solvent, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, removing the solvent to obtain a compound I-22(263mg,0.48mmol), wherein the yield is as follows: 58.7 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.60(d,J＝8.5Hz,1H,naphthalimide-H),8.50(d,J＝7.2Hz,1H,naphthalimide-H),8.43(d,J＝8.0Hz,1H,naphthalimide-H),7.98(d,J＝3.0Hz,1H,naphthalimide-H),7.90(d,J＝3.0Hz,1H,thiazole-H),7.86(t,J＝7.8Hz,1H,naphthalimide-H),7.41(d,J＝8.1Hz,1H,thiazole-H),7.24(s,2H,NH2),6.92(s,1H,thiazole-H),3.91(s,4H,piperazine-H),3.59(m,2H,piperazine-H),3.33(s,3H,NOCH3),3.27(m,2H,piperazine-H)ppm。
experimental example 25
Preparation of Compound I-23
A100 mL round-bottomed flask was charged with intermediate III-23(300mg,0.86mmol), thiobenzothiazole 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetate (301mg,0.86mmol), triethylamine (87mg,0.86mmol), and ethanol (20 m)L) as solvent, reacted at 25 ℃ for 15h, followed by thin layer chromatography until the reaction is complete, cooled to room temperature, and the solvent removed to afford compound I-23(244mg,0.46mmol), yield: 53.4 percent; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6)δ8.81(s,2H,triazole-H),8.66(d,J＝8.4Hz,1H,naphthalimide-H),8.58(d,J＝7.2Hz,1H,naphthalimide-H),8.50(d,J＝8.0Hz,1H,naphthalimide-H),7.90(t,J＝7.8Hz,1H,naphthalimide-H),7.45(d,J＝8.1Hz,1H,naphthalimide-H),7.26(s,2H,NH2),6.92(s,1H,thiazole-H),3.91(s,4H,piperazine-H),3.60(m,2H,piperazine-H),3.36(s,3H,NOCH3),3.29(m,2H,piperazine-H)ppm。
example 26
In vitro antimicrobial activity of piperazine bridged naphthalimide aminothiazole oximes
The piperazine-bridged, naphthalimide aminothiazole oxime compounds prepared in examples 3-25 were tested for their Minimal Inhibitory Concentrations (MIC) against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), 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, Candida parapsilosis ATCC20019) by a 96-well microdilution method in accordance with the Clinical Laboratory Standards Institute (CLSI) set by the national Committee, the Compound to be tested was 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 24-72 hr, 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 piperazine bridged naphthalimide aminothiazole oximes prepared in examples 3-25
As can be seen from Table 1, the piperazine bridged naphthalimide aminothiazole oximes prepared in examples 3-25 of the present invention, the compound shows certain inhibition effect on tested gram-positive bacteria, the inhibition activity of partial compounds such as I-1, I-10, I-11, I-12, I-18, I-20, I-21, I-22 and I-23 on MRSA is better than that of a reference medicament norfloxacin, the inhibition activity of I-1, I-8, I-9, I-14, I-16, I-17, I-19 and I-21 on enterococcus faecalis better than that of a reference medicament norfloxacin, and the inhibition activity of I-3, I-4, I-14, I-17 and I-21 on staphylococcus aureus is better than that of a reference medicament. And secondly, the inhibitory activity of I-23 on staphylococcus aureus ATCC29213 is superior to that of a reference drug norfloxacin, which provides a certain foundation for further antibacterial mechanism research.
TABLE 2 in vitro gram negative activity data (MIC, mM) for piperazine bridged naphthalimide aminothiazole oximes prepared in examples 3-25
As can be seen from Table 2, the piperazine-bridged naphthalimide aminothiazole oximes prepared in examples 3-25 of the present invention show certain inhibitory effect on tested gram-negative bacteria. In particular, I-1, I-13 and I-21 all showed superior inhibitory activity against Klebsiella pneumoniae compared to the reference drugs norfloxacin, I-11, I-12, I-13, I-18, the I-20 and the I-21 show the inhibition activity on Escherichia coli superior to that of norfloxacin serving as a reference medicament, the I-10, the I-13, the I-15, the I-21 and the I-23 show the inhibition activity on pseudomonas aeruginosa superior to that of norfloxacin serving as a reference medicament, the I-21 shows the inhibition activity on pseudomonas aeruginosa ATCC27853 superior to that of norfloxacin serving as a reference medicament, the I-13 shows the inhibition activity on Escherichia coli ATCC25922 superior to that of norfloxacin serving as a reference medicament, and all the compounds show the superior inhibition activity on acinetobacter baumannii.
TABLE 3 in vitro antifungal Activity data (MIC, mM) for piperazine bridged Nafimidothiazole oximes prepared in examples 3-25
As can be seen from Table 3, the piperazine bridged naphthalimide aminothiazole oximes prepared in examples 3-25 of the present invention, I-6, I-7 and I-21, showed superior inhibitory activity against Candida albicans than the reference drug fluconazole, and all the compounds showed excellent inhibitory activity against Aspergillus fumigatus.
Example 27
Pharmaceutical application of piperazine bridged naphthalimide aminothiazole oxime compound
According to the antimicrobial activity detection result, the piperazine bridged naphthalimide aminothiazole oxime compound has better antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicaments for clinical use. The medicaments can be single-component preparations, for example, the medicaments are prepared from piperazine bridged naphthalimide aminothiazole oxime compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound is prepared by piperazine bridged naphthalimide aminothiazole oxime 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 is prepared by a plurality of piperazine bridged naphthalimide aminothiazole oxime 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-13 tablets
Prescription: the tablet is prepared from compound I-1310 g, lactose 187g, corn starch 50g, magnesium stearate 3g, and an appropriate amount of ethanol solution with volume percentage concentration of 70% into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-13 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-13 Capsule
Prescription: compound I-1325 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 the prepared granules are 1000 granules.
The preparation method comprises the following steps: micronizing compound I-13 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-15 granules
Prescription: 1526 g of compound I, 120g of dextrin and 280g of sucrose.
The preparation method comprises the following steps: mixing compound I-15, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-15 injection
Prescription: compound I-1510 g, propylene glycol 500mL, water for injection 500mL, made up to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-15, 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-15.
5. Preparation of compound I-22 powder injection
The preparation method comprises the following steps: and subpackaging the compound I-22 sterile powder under the aseptic condition to obtain the compound I-22.
6. Preparation of Compound I-22 eye drops
Prescription: compound I-223.78 g, sodium chloride 0.9g, appropriate amount of boric acid buffer solution, and distilled water to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-22 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-22 Liniment
Prescription: compound I-224 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-22, 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-22
Prescription: 100 metric pills of compound I-224 g, 14g of gelatin, 70g of glycerol and 100mL of distilled water.
The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound I-22, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-23 ointment
Prescription: compound I-230.5-2 g, cetyl alcohol 6-8g, white vaseline 8-10g, liquid paraffin 8-19g, monoglyceride 2-5g, polyoxyethylene (40) stearate 2-5g, glycerol 5-10g, ethylparaben 0.1g, distilled water 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-23, stirring, and cooling.
10. Preparation of compound I-23 and fluconazole compound powder injection
Prescription: compound I-2350 g, fluconazole 50g and sodium benzoate 1g, and 100 bottles are prepared.
The preparation method comprises the following steps: taking the compound I-23, 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-23.
11. Preparation of Compound I-23 Aerosol
Prescription: compound I-232.5 g, Span 203 g, talcum powder (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.
The preparation method comprises the following steps: respectively drying the compound I-23, 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 piperazine bridged naphthalimide aminothiazole oxime compound and the medicinal salt thereof are characterized in that the structure is shown as the general formula I:
in the formula:
R1is alkyl, cycloalkyl, hydroxy, alkoxy, hydroxyalkyl, hydroxyalkylamino, N-dimethylethyl, cyanoalkyl, carboxylic acid alkyl, amido, amino, aminoalkyl or heterocyclyl;
R2is an alkaneAnd (4) a base.
2. The piperazine bridged naphthalimide aminothiazole oxime compound of claim 1 and its pharmaceutically acceptable salts,
R1is methyl, N-butyl, N-hexyl, dodecyl, cyclopropyl, cyclopentyl, cyclohexyl, hydroxyl, ethoxy, hydroxyethyl, hydroxyethylamino, 1, 3-dihydroxypropyl, N-dimethylethyl, cyanoethyl, acetoxy, propionyloxy, acetamido, amino, aminoethyl, aminobutyl, aminohexyl, thiazolyl or triazolyl;
R2is methyl.
3. The piperazine-bridged naphthalimide aminothiazole oximes and their pharmaceutically acceptable salts according to claim 1, which are any one of the following compounds:
4. the piperazine bridged naphthalimide aminothiazole oxime compound of claim 1 wherein said pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.
5. A process for the preparation of piperazine bridged naphthalimide aminothiazole oximes and their pharmaceutically acceptable salts according to any of claims 1 to 4, characterized by 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, and the initial raw material and the ethanol react with an amino compound to obtain an intermediate II;
b. preparation of intermediate III: taking the intermediate II as an initial raw material, taking ethylene glycol monomethyl ether as a solvent, and reacting with anhydrous piperazine to obtain an intermediate III;
c. preparation of piperazine bridged naphthalimide aminothiazole oximes of the general formula I: and (3) taking the intermediate III as a starting material, triethylamine as an alkali and ethanol as a solvent to react with 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thiobenzothiazole ester to obtain the piperazine bridged naphthalimide aminothiazole oxime compound shown in the general formula I.
6. The method of claim 5,
in the step a, the molar ratio of the 4-bromo-1, 8-naphthalic anhydride to the amino compound is 1:1.2, and the reaction temperature is 80 ℃;
in the step b, the molar ratio of the intermediate II to the anhydrous piperazine is 1:3, and the reaction temperature is 120 ℃;
in the step c, the molar ratio of the intermediate III, the 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid thio benzothiazole ester and the triethylamine is 1:1:1, and the reaction temperature is 25 ℃.
7. Use of the piperazine bridged naphthalimide aminothiazole oximes and their pharmaceutically acceptable salts according to any of claims 1 to 4 for 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 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.
9. A formulation comprising a piperazine bridged naphthalimide aminothiazole oxime compound according to 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.
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| CN114874142A (en) * | 2022-06-27 | 2022-08-09 | 河南省人民医院 | Fluorescent probe based on 1, 8-naphthalimide derivative and preparation method and application thereof |
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