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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
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 old drug for lowering blood pressure, which was found to be an MBL inhibitor). Chelates Zn ions at the active sites of various MBL subtypes, but so far there is no MBL inhibitor that has entered clinical trials

Method used

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  • 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

Embodiment 1

[0033] Synthesis of compound 1

[0034]

[0035] Add 0.3mmol of 2-phenylpyridine and 0.36mmol of tetraethyl methylene diphosphate to a dry sealed tube of 15ml, 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, it was concentrated under reduced pressure, column chromatography, DCM / MeOH (80:1) to obtain a yellow oily product, and the yield was 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 ( J =130.65Hz),16.25, 16.21, 16.17, 16.13; 31 P NMR (162 MHz, CDCl 3 ) δ 19.45.

Embodiment 2

[0038] Synthesis of compound 2

[0039]

[0040] Add 0.3mmol of o-methyl 2-phenylpyridine and 0.36mmol of tetraethyl methylene diphosphate to a dry sealed tube of 15ml, 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 completion of the reaction, concentrated under reduced pressure, column chromatography, DCM / MeOH (80:1) to obtain 98.4 mg of yellow oil product, yield 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, 112.47, 63.38, 62.79, 62.74, 41.45 ...

Embodiment 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 completion of the reaction, concentrated under reduced pressure, column chromatography, DCM / MeOH (80:1) to obtain 96.2 mg of yellow oil product, yield 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 ( J = 136.80 Hz), 16.32; 31 P NMR (162MHz, DMSO- d 6 ) δ 18.69.

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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

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Application Information

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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
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