Novel antibacterial lipopeptide compound and preparation method and application thereof

A technology of compound and lipopeptide, which is applied in the field of preparation of the lipopeptide compound, can solve the problem of little effect on drug-resistant pathogenic bacteria

Pending Publication Date: 2019-12-17
美国蓝博药业公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In order to solve the problem that existing antibiotics have little effect on drug-resistant pathogenic bacteria, the object of the present invention is to provide a lipopeptide compound, which has inhibitory effects on vancomycin-resistant microorganisms, penicillin-resistant microorganisms and methicillin-resistant bacteria

Method used

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  • Novel antibacterial lipopeptide compound and preparation method and application thereof
  • Novel antibacterial lipopeptide compound and preparation method and application thereof
  • Novel antibacterial lipopeptide compound and preparation method and application thereof

Examples

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preparation example Construction

[0151] 4. Preparation of intermediate (Inter-I)

[0152] The preparation of the intermediate (Inter-I) can start from daptomycin, first with di-tert-butyl dicarbonate, (Boc) 2 O reacts to add a tert-butoxycarbonyl protecting group (Boc) to the amino group of ornithine ， The amino group on the aniline is then alkylated using a reductive amination reaction. Reagents for reductive amination can be an aldehyde plus sodium cyanoborohydride. Acetaldehyde, formaldehyde, and propionaldehyde are used in these reactions to convert anilines to phNHEt, phNHMe, and phNHPr groups, respectively.

[0153] Specifically, daptomycin (1) reacts with di-tert-butyl dicarbonate and triethylamine, and a tert-butoxycarbonyl protecting group (Boc) is added to the amino group of ornithine to generate daptomycin-Boc (2 ).

[0154]

[0155]

[0156] Daptomycin-Boc(2) reacts with formaldehyde, acetaldehyde or propionaldehyde in the presence of sodium cyanoborohydride at room temperature to perfor...

Embodiment 1

[0205] The preparation of embodiment 1 Inter-IA

[0206]

[0207] Step 1. Boc protection of ornithine amino group to generate daptomycin-Boc

[0208] A mixture of daptomycin (1.0 g) and water (6 mL) was stirred at room temperature for 1 hour and the solid gradually dissolved. To this solution was added triethylamine (600 uL) followed by a solution of di-tert-butyl dicarbonate (500 mg) in dimethyl sulfoxide (DMSO, 2 mL). The resulting suspension became a pale yellow solution after being vigorously stirred for 1 hour, and liquid-mass analysis showed that daptomycin was completely converted into daptomycin-Boc. Positive-order ESIMS: m / z 1720.7(MH)+, with daptomycin-Boc(C 77 h 110 N 17 O28) was consistent with theoretical mass (Scheme A2). The reaction mixture was extracted with ethyl acetate (5 mL) to remove unreacted reagents, the aqueous layer was acidified with acetic acid (800 uL), then extracted twice with n-butanol (2 x 5 mL). The combined n-butanol solutions were ...

Embodiment 2

[0211] The preparation of embodiment 2 Inter-IB

[0212]

[0213] To a solution of daptomycin-Boc (500 mg) in methanol (5 mL) was added acetic acid (360 uL), followed by 37% aqueous formaldehyde (900 uL). The resulting mixture was stirred at room temperature for 5 minutes, then mixed with a solution of sodium cyanoborohydride (360 mg) in methanol (2 mL). The reaction solution was stirred at room temperature for 20 minutes and the product was purified by HPLC (Scheme B1). The peak at 16 minutes was collected and evaporated in vacuo to give Inter-IB as a yellow powder (255 mg). Negative polarity ESIMS: m / z1732.6(M-H) - , with Inter-IB(C 78 h 110 N 17 o 28 ) are consistent with the theoretical mass (Scheme A1-Neg).

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Abstract

The invention discloses a novel antibacterial lipopeptide compound and a medicinal salt thereof. The structural general formula is as shown in the specification. The efficacy of the novel antibacterial lipopeptide compound is obviously superior to efficacy of daptomycin, and the anti-methicillin-resistant staphylococcus aureus (MRSA) activity of the compounds RP005 and RP012 is about ten times greater than anti-methicillin-resistant staphylococcus aureus (MRSA) activity of daptomycin. The RP005 and RP012 also simultaneously show the anti-vancomycin resistant enterococcus (VRE) activity ten times greater than anti-vancomycin resistant enterococcus (VRE) activity of daptomycin. The novel antibacterial lipopeptide compound can be used for treating infection caused by gram-positive bacteria.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a lipopeptide compound having an inhibitory effect on vancomycin-resistant microorganisms, penicillin-resistant microorganisms and methicillin bacteria, and also relates to a preparation method and application of the lipopeptide compound. Background technique [0002] The increasing resistance of pathogenic bacteria to antibiotics is a major problem threatening public health. In recent years, infections caused by drug-resistant Gram-positive and drug-resistant Gram-negative pathogens have been increasing, which requires the research on new antibiotics to be greatly strengthened. Daptomycin is a relatively new antibacterial drug used to treat serious systemic infections caused by Gram-positive bacteria, including drug-resistant strains (see Kline, M., Mason, E., Jr., Kaplan S. ., Lamberth, L., and Johnson, G., Comparative in-vitro activity of LY146032 and eight other...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08A61K38/10A61P31/04
CPCC07K7/08A61P31/04A61K38/00
Inventor 何海音
Owner 美国蓝博药业公司
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