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3-O-aralkyl substituted 15-membered aza-lactone derivative and preparation method and application thereof

A technology of aralkyl derivatives, applied in the field of medicine, to achieve significant antibacterial activity and good antibacterial activity

Inactive Publication Date: 2021-08-24
PEOPLES HOSPITAL OF HENAN PROV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventors have found that there are few reports on the introduction of 4-aryl-1H-1,2,3-triazole side chains at the C-3 position, so the C-3 position is a very promising macrolide antibiotic. modification site

Method used

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  • 3-O-aralkyl substituted 15-membered aza-lactone derivative and preparation method and application thereof
  • 3-O-aralkyl substituted 15-membered aza-lactone derivative and preparation method and application thereof
  • 3-O-aralkyl substituted 15-membered aza-lactone derivative and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0109] 3-O-[2-(4-Phenyl-1H-1,2,3-triazol-1-yl)acetylhydrazino-formyl]-3-O-descladinose Azithromycin-11,12 - Preparation of cyclocarbonate (A1)

[0110] 1. Preparation of 3-O-desclardinose azithromycin

[0111] Azithromycin (20 g, 26.72 mmol) was dissolved in methanol (200 mL), then the pH of the solution was adjusted to about 1 with hydrochloric acid (1 M), and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane (200 mL), and the pH was adjusted to >7 with saturated sodium bicarbonate solution. Stand to separate the layers, wash the aqueous phase with dichloromethane (100 mL×2), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain a crude product, which was then subjected to column chromatography (dichloromethane:methanol:ammonia=20:1:0.1~15:1:0.1~10:1:0.1) to obtain a white Solid 10.54g, yi...

Embodiment 2

[0126] 3-O-[2-(4-p-Methylphenyl-1H-1,2,3-triazol-1-yl)acetylhydrazino-formyl]-3-O-declarinose Azithromycin- Preparation of 11,12-cyclocarbonate (A2)

[0127] A2 was prepared according to the preparation method of compound A1. White solid, melting point 143-145°C; 1 H NMR (600MHz, CDCl 3 ,δppm):8.18–8.04(m,1H),7.74–7.68(m,2H),7.21(d,J=7.8Hz,2H),6.36–6.21(m,1H),5.47(d,J=16.2 Hz, 1H), 5.24(d, J=16.2Hz, 1H), 5.16–4.81(m, 3H), 4.57(s, 1H), 4.45(d, J=6.8Hz, 1H), 3.76–3.63(m ,2H),3.50–3.38(m,2H),2.80–2.68(m,8H),2.37–2.34(m,4H),2.24(s,3H),2.19–2.08(m,2H),2.04–2.01 (m,2H),1.89–1.82(m,2H),1.77(d,J=8.9Hz,1H),1.58–1.52(m,2H),1.38(s,3H),1.25–1.21(m,8H ),1.15–1.02(m,9H),0.91–0.84(m,6H); MS(ESI)m / z calcd for C 43 h 68 N 7 o 12 [M+H] + :874.5,(C 43 h 69 N 7 o 12 ) 0.5 [M+2H] 2+ / 2:437.8,found:874.7,438.0.

Embodiment 3

[0129] 3-O-[2-(4-p-Ethylphenyl-1H-1,2,3-triazol-1-yl)acetylhydrazino-formyl]-3-O-descladinose Azithromycin- Preparation of 11,12-cyclocarbonate (A3)

[0130] A3 was prepared according to the preparation method of compound A1. White solid, melting point 150-152°C; 1 H NMR (600MHz, CDCl 3 ,δppm):8.15–8.02(m,1H),7.76–7.71(m,2H),7.23(d,J=7.9Hz,2H),6.26(s,1H),5.46(d,J=16.3Hz, 1H), 5.25(d, J=15.7Hz, 1H), 5.16–4.90(m, 2H), 4.57(s, 1H), 4.43(d, J=6.6Hz, 1H), 3.74–3.58(m, 4H ),3.42–3.37(m,1H),2.86–2.54(m,10H),2.35(d,J=10.7Hz,1H),2.24(s,3H),2.17–2.13(m,1H),2.10– 2.01(m,3H),1.86–1.80(m,2H),1.74(d,J=14.5Hz,1H),1.61–1.53(m,2H),1.46–1.38(m,3H),1.25–1.22( m,11H), 1.08(ddd,J=54.6,22.7,6.7Hz,9H),0.91–0.84(m,6H); MS(ESI)m / z calcd for C 44 h 70 N 7 o 12 [M+H] + :888.5,(C 44 h 71 N 7 o 12 ) 0.5 [M+2H] 2+ / 2:444.8,found:888.7,445.1.

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Abstract

The invention relates to the field of medicines, in particular to a 3-O-aralkyl substituted 15-membered aza lactone derivative and a preparation method and application thereof. The invention relates to a 3-O-aralkyl substituted 15-membered aza lactone derivative, and the derivative has a structure as shown in a general formula I, wherein R1 is selected from aryl or substituted aryl, and R2 is selected from hydrogen, acetyl or benzoyl. The 3-O-aralkyl substituted 15-membered aza-lactone derivative has remarkable antibacterial activity on various gram-positive bacteria and gram-negative bacteria, and particularly has good antibacterial activity on clinically separated enterococcus faecium drug-resistant bacteria, methicillin-resistant staphylococcus aureus and penicillin-resistant staphylococcus aureus, and the 3-O-aralkyl substituted 15-membered aza-lactone derivative has the advantages that the 3-O-aralkyl substituted 15-membered aza-lactone derivative has good antibacterial activity on various gram-positive bacteria and gram-negative bacteria, and can be used for preparing medicines for treating bacterial infection.

Description

technical field [0001] The invention relates to the field of medicine, in particular to 15-membered azalide derivatives substituted by 3-O-aralkyl groups and their preparation methods and applications. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Macrolide antibiotics usually contain a 14-, 15- or 16-membered lactone ring, which is connected to a sugar group through a glycosidic bond. Macrolide antibiotics are mainly used clinically to treat various infections caused by gram-positive bacteria, gram-negative bacteria, mycoplasma, chlamydia and rickettsia, so they are a type of clinical treatment of bacterial infections important drug. In addition, macrolide antibiotic...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H1/00A61K31/7056A61P31/04
CPCA61P31/04C07B2200/07C07H1/00C07H17/00
Inventor 秦银辉马培志滕月泰杨艳
Owner PEOPLES HOSPITAL OF HENAN PROV
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