Cyclohexalipopeptide compounds and pharmaceutical application thereof

A compound, lipopeptide technology, applied in the field of medicine

Inactive Publication Date: 2014-12-17
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Since the so-called semi-synthetic structural modification of the natural echinocandin is only for the replacement of its local groups, the semi-synthetic structurally modified cyclohexapeptide derivatives have great limitations in chemical structure sex

Method used

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  • Cyclohexalipopeptide compounds and pharmaceutical application thereof
  • Cyclohexalipopeptide compounds and pharmaceutical application thereof
  • Cyclohexalipopeptide compounds and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: dipeptide N-Boc-threo-pro-OMe (X 1 )Synthesis

[0058] 8.50g (51.3mmol) L-proline methyl ester (XI a ) hydrochloride was dissolved in 250mL dichloromethane, 35.8mL (205.2mmol) N,N-diisopropylethylamine (DIPEA) was added under ice-cooling, and stirred for 20min; N-Boc-threonine (1 a ) 11.25g (51.3mmol) and 1-hydroxy-benzo-triazole (HOBt) 9.7g (71.8mmol), stirred for 20min; then added EDC13.77g (71.8mmol) in batches, and continued the reaction in ice bath for 0.5h The ice bath was removed, and the reaction was stirred at 20°C for 24h. Stop the reaction, add 200 mL of 10% citric acid aqueous solution, separate the organic layer, wash with saturated sodium bicarbonate, water, and saturated brine successively, dry over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain a light yellow oil. Ethyl acetate was recrystallized to give threo-prodipeptide X as a white solid 1 15.2g, yield 89.74%. mp.59-61°C. MS (ESI + ) m / z: 353.83 (M+Na + , ...

Embodiment 2

[0059] Embodiment 2: dipeptide N-Boc-valerian-pro-OMe (X 2 )Synthesis

[0060] Same as X 1 Synthetic method, L-proline methyl ester (XI a ) with N-Boc-valine (1 b ) reaction to produce valerian-prodipeptide X 2 , yield 86.5%. MS (ESI + ) m / z: 351.87 (M+Na + , 100%). 1 H-NMR (CDCl 3 ) δ: 5.19 (d, 1H, J=9.13Hz, NH); 4.53 (m, 1H); 4.28 (m, 1H); 3.78 (m, 1H); 3.72 (s, 3H, OCH 3 ); 3.66 (m, 1H); 2.23 (m, 1H); 2.05~1.96 (m, 4H); 1.43 (s, 9H); 1.03 (d, 3H, J=6.77Hz); 0.94 (d, 3H, J=6.75Hz).

Embodiment 3

[0061] Example 3: Dipeptide N α -Boc-bird(N δ -Cbz)-4S-azido-pro-OMe (VII 1 )Synthesis

[0062] 4S-Azido-L-proline methyl ester (XI b ) 3.41g (20.05mmo) dissolved in 100mL dichloromethane, add N under ice bath α -Boc-N δ -Cbz-ornithine (3 a ) 7.34g (20.05mmol), HOBt4.52g (33.51mmol), EDC6.85g (35.74mmol) and DIPEA3.89mL (22.34mmol), react in ice bath for 30min, then raise the temperature to 25℃ and stir for 24h. To stop a reaction, press X 1 The same follow-up steps, get white solid preserved-bird dipeptide VII 1 9.67g, yield 93.07%. m.p.99-101°C. MS (ESI + ) m / z: 542.02 (M+Na + , 100%). 1 H-NMR (CDCl 3 ) δ: 7.30-7.40 (m, 5H); 5.22 (d, 1H, J=8.25Hz); 5.10 (s, 2H); 4.67 (dd, 1H, J 1 =4.63Hz,J 2 =8.88Hz); 4.40-4.42 (m, 1H); 4.22-4.26 (m, 1H); 4.08-4.20 (m, 1H); 3.73 (s, 3H); 3.50-3.55 (m, 1H); 3.30 (m, 1H); 2.40-2.48 (m, 1H); 2.15-2.22 (m, 1H); 1.55-1.90 (m, 4H); 1.42 (s, 9H).

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Abstract

The invention belongs to the technical field of medicine. The invention provides cyclohexalipopeptide compounds, whose chemical formula is represented by the formula (I), including optical isomer, raceme, cis-trans-isomer, and pharmaceutically acceptable salts. The invention also provides a preparation method of the compounds and an application of the compounds in preparation of antifungal drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new class of cyclohexapeptide compounds with antifungal activity and their application in the preparation of antifungal drugs. Background technique [0002] In recent years, with the rapid increase of AIDS patients with low immunity and immunodeficiency caused by the abuse of antibiotics, tumor radiotherapy and chemotherapy, and anti-rejection treatment of organ transplantation, deep fungal infections such as Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have increased significantly. On the rise, deep fungal infections have now become the leading cause of death from major diseases such as AIDS and tumors. Since deep mycoses mostly occur in patients with severe underlying disease, the mortality rate is very high. For example, the fatality rate of candidiasis is 40%, and that of invasive aspergillosis is as high as 50% to 100%. Therefore, ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/08A61P31/10C07K7/06
CPCY02P20/55
Inventor 姚建忠张万年陈海刘红明盛春泉缪震元
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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