Preparation method and application of aryl bisphosphonate derivative

A technology of aryl geminal diphosphoric acid and derivatives, which is applied in the fields of medicinal chemistry and drug therapy, and achieves the effects of good inhibitory activity and clear efficacy.

Inactive Publication Date: 2018-06-29
SICHUAN UNIV
View PDF2 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are also a variety of MBL inhibitors reported, most of the MBL inhibitors exert their inhibitory effect by chelating the Zn ion at the active site of MBL, such as the thiol energy of Captopril (an

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method and application of aryl bisphosphonate derivative
  • Preparation method and application of aryl bisphosphonate derivative
  • Preparation method and application of aryl bisphosphonate derivative

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0032] Example 1

[0033] Synthesis of compound 1

[0034]

[0035] Add 0.3mmol of 2-phenylpyridine and 0.36mmol of tetraethyl methylene diphosphate to a dry 15ml sealed tube, and the catalyst dichloro (pentamethylcyclopentadienyl) rhodium(III) dimer (CAS No. 12354-85-7) 5% mol, silver sulfate 10% mol and solvent DCE 3ml, stir at 80℃ for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, column chromatography, DCM / MeOH (80:1) to obtain a yellow oil product with a yield of 93%.

[0036] 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (d, J = 4.5 Hz, 1H), 8.03 (d, J = 7.5Hz, 1H), 7.77 (td, J = 7.7, 1.4 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.48 –7.34 (m, 3H), 7.32 – 7.20 (m, 1H), 5.09 (t, J = 25.7 Hz, 1H), 4.29 – 3.87 (m,8H), 1.21 (t, J = 7.0 Hz, 6H), 1.15 (t, J = 7.0 Hz, 6H). 13 C NMR (150 MHz, CDCl 3 ) δ 159.09, 149.10, 140.62, 136.57, 131.20, 130.36, 128.31, 128.07, 127.66, 124.55, 121.94, 63.31, 63.26, 62.74, 62.69, 39.78 (t, J =130.65Hz), 16.25, 16.21...

Example Embodiment

[0037] Example 2

[0038] Synthesis of compound 2

[0039]

[0040] Add 0.3 mmol of o-methyl 2-phenylpyridine and 0.36 mmol of tetraethyl methylene diphosphate to a dry 15ml sealed tube, and the catalyst dichloro (pentamethylcyclopentadienyl) rhodium(III) Dimer (CAS No. 12354-85-7) 5% mol, silver sulfate 10% mol and solvent DCE 3ml, stirred at 80°C for 12 hours. After the completion of the reaction, it was concentrated under reduced pressure, column chromatography, DCM / MeOH (80:1) was used to obtain 98.4 mg of yellow oily product with a yield of 72%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (d, J =4.5 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.75 (dd, J = 10.8, 4.5 Hz, 1H), 7.39(d, J = 7.7 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.21 (d, J = 7.5 Hz, 1H), 4.04(ddt, J = 23.8, 16.1, 8.0 Hz, 8H), 3.72 (t, J = 25.4 Hz, 1H), 2.02 (s, 3H), 1.24 (t, J = 5.8 Hz, 6H), 1.18 (t, J = 7.0 Hz, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ158.25, 149.60, 136.73, 136.12, 129.48, 127.83, 127.77, 127.74, 125.57,122.14, 112.4...

Example Embodiment

[0041] Example 3

[0042] Synthesis of compound 3

[0043]

[0044] Add 0.3mmol of o-methoxy 2-phenylpyridine and 0.36mmol of tetraethyl methylene diphosphate to a dry 15ml sealed tube, and the catalyst dichloro (pentamethylcyclopentadienyl) rhodium (III) ) Dimer (CAS No. 12354-85-7) 5% mol, silver sulfate 10% mol and solvent DCE 3ml, stirred at 80°C for 12 hours. After the reaction was completed, concentrated under reduced pressure, column chromatography, DCM / MeOH (80:1) to obtain a yellow oil product 96.2mg, a yield of 68%,. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.65(d, J = 4.4 Hz, 1H), 7.85 (t, J = 7.4 Hz, 1H), 7.45 – 7.31 (m, 4H), 7.08 (d, J = 7.5 Hz, 1H), 3.85 (ddd, J = 24.3, 15.2, 7.5 Hz, 8H), 3.67 (s, 3H), 1.12(t, J = 7.0 Hz, 6H), 1.02 (t, J = 7.0 Hz, 6H); 13 C NMR (100 MHz, CDCL 3 ) δ157.40, 149.08, 136.03, 129.78, 129.70, 128.99, 126.72, 122.17, 119.23,110.29, 63.39, 62.78, 55.76, 40.89 (t, J = 136.80 Hz), 16.32; 31 P NMR (162MHz, DMSO- d 6 ) δ 18.69.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

(The formula I is as shown in the description.) The invention provides a preparation process and application of an aryl bisphosphonate derivative with the structure as shown in the formula (I) or physiologically acceptable salt as well as a pharmaceutical composition comprising the derivative. The pharmacodynamic test proves that the compound provided by the invention has high inhibition activityon beta-lactamase, in particular the compounds 46 and 50 have the most excellent inhibition activity which is obviously better than that of the currently reported beta-lactamase micromolecular inhibitors such as captopril. The substituted aryl bisphosphonate derivative has specific medicine effect and provides new pharmacy choice for the clinic.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and drug therapy, in particular to aryl geminal diphosphoric acid derivatives which can be used as β-lactamase inhibitors, as well as their pharmaceutical composition and medical application. Background technique [0002] β-lactam antibiotics are currently the most widely used antibiotics clinically (such as cephalosporins, carbapenems, etc.), with good clinical efficacy, low toxicity, and wide indications (for Gram-positive bacteria and Gram-positive bacteria and Lambert-negative bacteria have good antibacterial effect) and other advantages. β-lactam antibiotics mainly inhibit the catalytic activity of bacterial cell wall mucopeptide synthase (ie, penicillin-binding protein, PBP for short), thereby preventing the synthesis of cell wall mucopeptides, which in turn leads to bacterial cell wall defects, cell swelling, and lysis. However, nowadays, β-lactam antibiotic-resistant "super" bacteria w...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07F9/58C07F9/62C07F9/576C07F9/6512C07F9/6503C07F9/40C07F9/6558A61K31/675A61K31/683A61P31/04
CPCC07F9/62C07F9/4056C07F9/5765C07F9/65583C07F9/65586
Inventor 吴勇李国菠海俐张晨刘莎于竹君
Owner SICHUAN UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap