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Methionine or oxidized methionine modified Clinafloxacin and application thereof

A technology for oxidizing methionine and methionine, which is applied in the fields of chemistry and pharmacy, can solve the problems of oxidation, low chemical stability, and not easy to accept, and achieves the effect of high chemical stability and meeting various needs.

Inactive Publication Date: 2012-08-15
金河牧星(重庆)生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the structure of this compound contains a methylthio group, and the sulfur atom is easily oxidized by a medium or strong oxidant, so the chemical stability is not high, and the compound has a certain bad smell, so it is not easy to be accepted by the crowd

Method used

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  • Methionine or oxidized methionine modified Clinafloxacin and application thereof
  • Methionine or oxidized methionine modified Clinafloxacin and application thereof
  • Methionine or oxidized methionine modified Clinafloxacin and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Example 1. Synthesis of compound IM1-1

[0015]

[0016] Add N-tert-butoxycarbonylmethionine (Boc-Met-OH), 1-hydroxybenzotriazole (HOBt) and an appropriate amount of tetrahydrofuran (THF) (subject to the complete dissolution of the raw materials) into the reaction flask, and stir to dissolve , Cooling in an ice bath, adding dicyclohexylcarbodiimide (DCC) and diisopropylethylenediamine (DIPEA), stirring in an ice bath for 30 minutes, adding clinfloxacin (CF) (CF, Boc-Met-OH, HOBt) The molar ratio of DCC and DIPEA is 10:12-14:12-15:12-15:15-20), and an appropriate amount of THF (subject to stirring) is added, the reaction is stirred at room temperature, and thin layer chromatography ( TLC) Monitor the progress of the reaction. After the reaction, the reaction solution was allowed to stand overnight at 4°C and filtered with suction. The filter cake was thoroughly washed with dichloromethane (DCM). The washing solution was combined with the filtrate, and the solvent was disti...

Embodiment 2

[0019] Example 2. Synthesis of compounds IM2-1 and IM2-2

[0020]

[0021] The raw material IM1-1 was added to the reaction flask, and then DCM was gradually added (subject to the complete dissolution of the raw materials), cooled in an ice bath, m-chloroperoxybenzoic acid (mCPBA) was added, and the reaction was stirred under temperature control, and the reaction progress was monitored by TLC. After the reaction is over, if a light yellow turbid liquid is obtained, add an appropriate amount of DCM to completely dissolve the solid; if a clear liquid is obtained, no additional DCM is required; then use 5% (w / w) Na 2 CO 3 Wash the solution and saturated brine, anhydrous Na 2 SO 4 Dry, filter, and distill the filtrate under reduced pressure to remove the solvent to obtain a crude product. The crude product is recrystallized with DCM-petroleum ether mixed solvent to obtain compound IM2-1 or IM2-2. Some synthetic experimental conditions and results are shown in Tables 2 to 3.

[0022] T...

Embodiment 3

[0028] Example 3. Synthesis of compounds TM1-1, TM1-2 and TM1-3

[0029]

[0030] Add raw materials IM1-1, IM2-1 or IM2-2 and appropriate amount of DCM (subject to complete dissolution of the raw materials) into the reaction flask, stir to dissolve, cool in an ice bath, slowly add TFA dropwise, stir the reaction in an ice bath, and monitor the reaction by TLC process. After the reaction, the TFA was removed as much as possible by distillation under reduced pressure. The residue was slowly added to the frozen ether, stirred, placed in the refrigerator to crystallize, the ether was aspirated, and the solid was washed with frozen ether and dried to obtain compounds TM1-1 and TM1- 2 or TM1-3. Some synthetic experimental conditions and results are shown in Tables 4-6.

[0031] Table 4 Synthesis conditions and results of compound TM1-1

[0032]

[0033] Table 5 Synthesis conditions and results of compound TM1-2

[0034]

[0035] Table 6 Synthesis conditions and results of compound TM1-3 ...

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Abstract

The invention discloses methionine or oxidized methionine modified Clinafloxacin, which refers to compounds shown in a formula I, wherein X is SO or SO2; Y is tert-butoxycarbonyl (Boc) or H.HZ, and HZ is HCl or trifluoroacetic acid (TFA); or X is S and Y is H.HCl. The compounds have certain bacteriostasis activity to gram-positive bacteria, such as Staphylococcus aureus, and gram-negative bacteria such as Escherichia coli, saimonella, and pseudomonas aeruginosa. The bacteriostasis activity to Staphylococcus aureus, pseudomonas aeruginosa and saimonella of the compounds TM2-1 (X is S and Y is H.HCl) and TM2-3 (X is SO2 and Y is H.HCl) is approximate to that of Clinafloxacin, and is superior to that of the known compound TM1-1 (X is S and Y is H.TFA). In the compound TM2-3 structure, S is in a maximum oxidation state, so that the compound TM2-3 is high in chemical stability. The Clinafloxacin derivatives can be used for preparing antibacterial medicaments, can provide more efficient and safe candidate medicaments for clinical treatment of infectious diseases, and meets various demands of clinical treatment.

Description

Technical field [0001] The invention belongs to the field of chemistry and pharmacy, and relates to a clinfloxacin derivative and its application in pharmacy. Background technique [0002] Clinafloxacin (Clinafloxacin), chemical name 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-chloro-1,4-dihydro-4-oxo-3 -Quinoline carboxylic acid is the fourth-generation quinolone antibacterial drug developed by Wamer-Lambert Pharmaceutical Company in the United States. Phase III clinical evaluation has been completed abroad. It used to have excellent broad-spectrum antibacterial activity, especially It has high activity against gram-positive bacteria, anaerobic bacteria and Mycoplasma pneumoniae and has attracted much attention. However, the development was stopped due to serious toxicity problems found in clinical use. In addition, clinfloxacin has poor solubility and unstable solution in pharmaceuticals. How to improve the solubility and stability of clinfloxacin while maintaining ex...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4709A61P31/04
CPCY02A50/30
Inventor 杨大成杨艳徐兴然陈力范莉肖国君赵爱珍
Owner 金河牧星(重庆)生物科技有限公司
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