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Antibacterial cyclic lipopeptides

A cyclolipopeptide and cycloalkynyl technology, applied in the field of antibacterial agents, can solve the problems of non-natural amino acid substitution of daptomycin and inability to generate

Active Publication Date: 2019-03-15
VERSITECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Indeed, these methods described above do not generate analogs containing modifications at positions Trp1, Thr4, Gly5, Orn6, and Kyn13 of daptomycin, and do not substitute unnatural amino acids for residues of daptomycin

Method used

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  • Antibacterial cyclic lipopeptides
  • Antibacterial cyclic lipopeptides
  • Antibacterial cyclic lipopeptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0235] Embodiment 1. Synthesis of compound 1

[0236] Synthesis of linear peptide resin-Gly-Asp(tBu)-DAla-Asp(tBu)-Orn(Boc)-Gly-Thr[O- meKyn-mGlu(tBu)-DSer(tBu)]-Asp(tBu)-DAsn(Trt)-Trp(Boc)-C 9 h 19 . The peptide was cleaved from 2-chlorotrityl resin under mild conditions (TFE / AcOH / DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU / DCM. The solution was then concentrated and then treated with a cocktail containing 95% TFA and 2.5% water for 10 minutes. The crude product was purified by preparative RP-HPLC to afford the methylated Kyn-containing daptomycin analog Compound 1. [M+H] + Calculated 1635.7, [M+H] + The measured value is 1635.7, [M+2H] 2+ 818.1.

[0237]

Embodiment 2

[0238] Embodiment 2. Synthesis of compound 2

[0239] The linear peptide resin-Gly-Asp(tBu)-DAla-Asp(tBu)-Orn(Boc)-Gly-Thr[O- Kyn-mGlu(tBu)-DSer(tBu)]-Asp(tBu)-DAsn(Trt)-meTrp-C 9 h 19 . The peptide was cleaved from 2-chlorotrityl resin under mild conditions (TFE / AcOH / DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU / DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water for 10 minutes. The crude product was purified by preparative RP-HPLC to yield the methylated TRP-containing daptomycin analog Compound 2. [M+H] + Calculated 1635.7, [M+H] + The measured value is 1635.6, [M+2H] 2+ 818.0.

[0240]

Embodiment 3

[0241] Embodiment 3. Synthesis of compound 3

[0242] Synthesis of linear peptide resin-Gly-Asp(tBu)-DAla-Asp(tBu)-Orn(Boc)-Gly-Thr[O- Kyn-mGlu(tBu)-DSer(tBu)]-Asp(tBu)-DAsn(Trt)-2Nal-C 9 h 19 . The peptide was cleaved from 2-chlorotrityl resin under mild conditions (TFE / AcOH / DCM). After drying, the peptide was cyclized for an additional 4 hours using HATU / DCM. The solution was then concentrated and then treated with a mixture containing 95% TFA and 2.5% water for 10 minutes. The crude product was purified by preparative RP-HPLC to give compound 3, a daptomycin analog containing 2-naphthyl Ala. [M+H] + Calculated value 1630.8, [M+H] + The measured value is 1630.8, [M+2H] 2+ 815.4.

[0243]

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Abstract

Cyclic lipopeptides having one or more modifications relative to daptomycin, and methods of making them are provided. The cyclic lipopeptides can be used as antibacterial agents. The daptomycin analogues are generated by chemical synthesis, which makes introduction of an unnatural amino acid and any modification into daptomycin possible. Pharmaceutical compositions and method of use thereof for the disclosed daptomycin analogues are also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit and priority of U.S. Utility Model Application 15 / 093950, filed April 8, 2016, and U.S. Provisional Application 62 / 438,138, filed December 22, 2016, and each is hereby incorporated by reference in its entirety Specifically incorporated into this article. field of invention [0003] The invention belongs to the field of antibacterial agents, especially antibacterial cyclolipopeptides. Background of the invention [0004] Despite the variety of antimicrobial agents currently available, there remains a need for improved antibiotics. One reason is that antibiotics are not effective against different pathogenic organisms. In addition, pathogenic organisms are known to develop resistance to antibiotics that were once effective against that organism. This situation is exacerbated by individual patients who often have severe reactions to specific antibiotics due to hypersensitivity and / or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64A61K38/12A61P31/04
CPCA61K38/00C07K7/08C07K7/56A61K2039/6018A61P31/04
Inventor 李学臣周凯仪
Owner VERSITECH LTD
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