Etilmicin derivative and preparation method thereof, pharmaceutical composition and application thereof

A technology of etimicin and derivatives is applied in the field of etimicin derivatives and preparation thereof, and achieves the effect of good resistance and significant resistance to drug-resistant bacteria

Inactive Publication Date: 2020-03-20
CHENGDU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to solve the problems faced by the existing antibiotic production field, and provide a kind of aminoglycoside molecular derivatives and its preparation method, as well as its pharmaceutical composition and application

Method used

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  • Etilmicin derivative and preparation method thereof, pharmaceutical composition and application thereof
  • Etilmicin derivative and preparation method thereof, pharmaceutical composition and application thereof
  • Etilmicin derivative and preparation method thereof, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of derivative A substituted with etimicin amino group (preparation scheme a)

[0041] 1. Preparation of Compound 2a

[0042] Steps: Dissolve 5.10 g of etimicin in 150 mL of methanol, add 2.14 g of DIPEA, stir at room temperature for 5 minutes, then dissolve 3.81 g of HONB-pNZ in 50 mL of THF, and add dropwise to the reaction system at room temperature; After completion, the mixture was stirred overnight at room temperature, and the solvent was evaporated under reduced pressure, followed by silica gel column chromatography to obtain compound 2a; it was a white solid with a mass of 2.84 g and a yield of 31.9%. 1 H NMR (600MHz, CDCl 3 ):δ0.99(m,1H),1.11(s,3H),1.13(t,3H),1.48(m,1H),1.69(m,2H),1.96(m,1H),2.18(d, 1H),2.42(d,1H),2.53(m,1H),2.60(s,3H),2.61(m,1H),2.71(m,1H),2.85(m,1H),2.89(m,2H ),3.11(m,2H),3.22(t,2H),3.27(t,2H),3.38(m,1H),3.42(d,1H),3.45(s,2H),3.50(m,1H) ,3.54(m,1H),3.75(m,2H),3.99(m,1H),4.89(d,2H),5.14(m,2H),5.22(m,2H),7.47(d,2H), 7.53(d,2H),8.1...

Embodiment 2

[0048] Preparation of derivatives B substituted with etimicin amino group (preparation scheme b)

[0049] Steps: Dissolve 2.31 g of etimicin in 50 mL of methanol, add 4.41 g of zinc acetate, and stir at room temperature for 10 minutes. After adding 2.04 g of acetic anhydride, the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and then separated by silica gel column chromatography to obtain Compound B with a mass of 1.79 g and a yield of 61.3%. 1 H NMR (600MHz,D 2 O): δ1.18(3H,s),1.32(m,1H),1.45(m,1H),1.66(m,3H),1.91(m,2H),1.94(m,6H),1.98(s ,3H),2.49(s,3H),2.59(d,1H),2.91(m,1H),3.19~3.30(m,4H),3.50(t,1H),3.59(t,1H),3.79( m,3H), 3.87(m,1H), 4.01(d,1H), 5.03(d,1H), 5.31(d,1H).ESIMS: Formula C 27 h 49 N 5 o 10 , found to be m / z 604.7 (M+H).

Embodiment 3

[0051] Preparation of derivative C substituted with etimicin amino group (preparation scheme c)

[0052] Steps: Dissolve 1.14 g of Compound B in 20 mL of methanol, add 1.04 g of acetic anhydride, and stir overnight at room temperature. The solvent was distilled off under reduced pressure, and then separated by silica gel column chromatography to obtain compound C with a mass of 1.10 g and a yield of 64.3%. 1 H NMR (600MHz,D 2 O): δ1.16(3H,s),1.46(m,1H),1.66(m,3H),1.89(m,1H),1.93(m,9H),1.98(s,3H),2.45(s ,3H),2.55(d,1H),3.24(m,3H),3.51(m,2H),3.66(m,2H),3.79(m,2H),3.88~3.97(m,2H),4.00( d,2H),5.02(d,1H),5.30(d,1H).ESIMS: Molecular formula C 29 h 51 N 5 o 11 , m / z 646.7 (M+H) was found.

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Abstract

The invention provides a glycoside molecular derivative as well as a preparation method and application thereof, and belongs to the technical field of aminoglycoside antibiotics. The invention provides an etimicin derivative, and the etimicin derivative is a compound represented by the following formula and a pharmaceutically acceptable salt or prodrug thereof, wherein R1 represents a hydrogen atom, an ethyl group or an acetyl group, R2 represents a hydrogen atom, an ethyl group or an acetyl group, R3 represents a hydrogen atom, an ethyl group or an acetyl group, R4 represents a hydrogen atom,an ethyl group or an acetyl group, and R5 represents a hydrogen atom, an ethyl group or an acetyl group; wherein at least one of R1, R2, R3 is an ethyl group or an acetyl group; when R1 is an ethyl group, at least one of R2 and R3 is an ethyl group or an acetyl group; when R1 is an acetyl group, R2 and R3 can be hydrogen at the same time. The derivative can be used as a new aminoglycoside antibiotics product with low toxicity and resistance to drug-resistant bacteria, has good resistance to drug-resistant bacteria, and has a significant effect on resisting drug-resistant bacteria. The formulais shown in the description.

Description

technical field [0001] The invention relates to aminoglycoside antibiotic derivatives, in particular to a class of etimicin derivatives and a preparation method thereof, as well as a pharmaceutical composition and application thereof. Background technique [0002] Antibiotics are an effective means of treating infectious diseases. Since the 1940s, a series of aminoglycoside antibiotics, such as streptomycin, gentamicin and kanamycin, have been widely used clinically and played an important role in the field of anti-infection therapy. For some aminoglycoside antibiotics, because of their broad-spectrum antibacterial properties, rapid bactericidal effect and synergistic effect with other antibiotics such as β-lactams, they are especially suitable for the treatment of some serious infections. [0003] In recent years, along with the long-term use of antibiotics, some bacterial strains have been induced to develop drug resistance, which has led to an increasingly serious global...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/236C07H1/00A61K31/7036A61P31/04
CPCC07H1/00C07H15/236
Inventor 陈仰邓盛齐刘瑜吕耷张晓游莉刘家健
Owner CHENGDU UNIV
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