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Pleuromutilin phosphate compounds, medicinal composition thereof, preparation method thereof and application thereof

A technology of pleuromutilin and phosphate esters, applied in the fields of pharmacology, drug synthesis and pharmacology, can solve the problems of first-pass metabolism and poor water solubility, and achieve the effect of reducing adverse effects and improving water solubility

Inactive Publication Date: 2010-03-17
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to develop pleuromutilin antibiotics that can be applied to human or animal systemic infections, the problems of first-pass metabolism and poor water solubility must be overcome

Method used

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  • Pleuromutilin phosphate compounds, medicinal composition thereof, preparation method thereof and application thereof
  • Pleuromutilin phosphate compounds, medicinal composition thereof, preparation method thereof and application thereof
  • Pleuromutilin phosphate compounds, medicinal composition thereof, preparation method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1: 14-[N-(4-methoxybenzoyl)]-carbamoylmutriptyline-11-dihydrogen phosphate (compound 1)

[0082] (a) Preparation of 14-[N-(4-methoxybenzoyl)]-carbamoylmutriptyline-11-dibenzyl phosphate

[0083]

[0084] Under nitrogen protection, 14-[N-(4-methoxybenzoyl)]-carbamylmutriptyline (200mg, 0.4mmol) and 1-hydrotetrazolium (140mg, 2.0mmol) were dissolved in In 10 mL of dry dichloromethane, stir at room temperature, add dibenzyl N, N'-diisopropyl phosphoramidite (695 mg, 2.0 mmol), continue the reaction for 2 hours, cool to -78 ° C, and add to the reaction A dry dichloromethane solution (5 mL) of m-chloroperoxybenzoic acid (500 mg, 2.0 mmol) was added dropwise to the solution, stirred for 30 minutes, then heated to -20°C and stirred for 1 hour. Slowly add 10% sodium bisulfite aqueous solution (20mL) dropwise to the reaction solution to quench the reaction, add dichloromethane (20mL), separate the layers, and use sodium bisulfite solution, saturated sodium carbonate ...

Embodiment 2

[0088] Example 2 14-[N-(4-methoxybenzoyl)]-carbamoylmutriptyline-11-disodium phosphate (compound 5)

[0089]

[0090] Example 1(b) compound (2g, 3.47mmol) and sodium acetate (0.57g, 6.93mmol) were stirred in water (20mL) until clarified, filtered, and the filtrate was lyophilized to obtain a white solid, which was recrystallized from ethanol and vacuum Drying gave the title compound (1.27 g, 59%). 1 H-NMR (D 2 O, ppm): δ7.96 (d, 2H), 7.15 (d, 2H), 6.43 (dd, 1H), 5.79 (d, 1H), 5.33 (dd, 2H), 4.41 (m, 1H), 3.95 (s,3H), 2.45(q,1H), 0.98-2.6(m,12H), 1.61(s,3H), 1.29(s,3H), 1.14(d,3H), 0.84(d,3H).

Embodiment 314

[0091] Example 314-[N-(4-methoxybenzoyl)]-carbamoyl-19,20-dihydromutriptyline-11-dihydrogen phosphate (compound 2)

[0092]

[0093] Example 1 (a) compound 14-[N-(4-methoxybenzoyl)]-carbamoyl-mutriptyline-11-dibenzyl phosphate (250mg, 0.33mmol) was dissolved in anhydrous methanol (20mL), add 35mg10%Pd / C, shake table catalytic reduction under 3atm hydrogen pressure for 5 hours. 20 / 45μm, the mobile phase was methanol: 0.25% trifluoroacetic acid aqueous solution = 20:80-50:50 gradient elution), and the title product (84.9 mg, 44.5%) was obtained as a white solid powder after lyophilization of the residual aqueous phase. 1 H-NMR (MeOD, ppm): δ7.86 (d, 2H), 7.01 (d, 2H), 5.72 (d, 1H), 4.31 (m, 1H), 3.83 (s, 3H), 2.54 (q, 1H), 0.88-2.4(m, 17H), 1.49(s, 3H), 1.12(s, 3H), 0.86(d, 3H), 0.75(d, 3H).

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Abstract

The invention belongs to the field of pharmaceutics, and provides pleuromutilin phosphate compounds shown as a right general formula (I), a medicinal composition thereof, a preparation method thereofand application thereof. The pleuromutilin phosphate compounds have good water solubility, quickly release parent medicaments in vivo after intravenous administration, achieve higher blood concentration, and have excellent anti-infectious activity, so the pleuromutilin phosphate compounds can be used for treating infectious diseases, particularly infectious diseases caused by multi-medicament andmedicament-resistant bacteria.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to the fields of drug synthesis and pharmacology. More specifically, it relates to a pleuromutilin compound containing a phosphate group, its pharmaceutical composition, its preparation method and its use in the preparation of anti-infective drugs. Background technique [0002] Worldwide emergence of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), drug-resistant Streptococcus pneumoniae (PRSP), multidrug-resistant Mycobacterium tuberculosis, and vancomycin-resistant enterococci (VRE) is the most difficult problem in the current clinical anti-infective treatment [Exp. Facing the challenges brought by multidrug-resistant bacteria, it is necessary to develop antibacterial drugs with new mechanisms of action. [0003] Pleuromutilin antibacterial drugs are a class of unique antibacterial drugs isolated from the fermentation broth of fungi Pleurotus mutilus...

Claims

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Application Information

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IPC IPC(8): C07F9/655A61K31/661A61P31/04
CPCC07F9/12C07D451/04C07F9/65182C07F9/6561C07F9/117C07D249/14A61P31/00A61P31/04C07F9/6518
Inventor 杨玉社姜智腾付利强蔡瞻李战晁阳嵇汝运
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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