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Application of n-benzyl imidamide derivatives as synergistic agents of polymyxin antibiotics

A technology of benzyl imidamide and polymyxin, which is applied in the field of biomedicine and can solve problems such as environmental pollution

Active Publication Date: 2020-08-04
GUANGZHOU INSIGHER BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In production practice, a variety of drugs have been used in combination with polymyxin antibiotics in order to increase the efficacy of drugs. Experiments have proved that the therapeutic effects of these compatible drugs combined with polymyxin antibiotics are actually their inhibition of different infection strains. Combined results of effects without any synergistic effect on polymyxin antibiotics
In addition, these compatible drugs are either antibacterial agents or bactericides or chemical reagents with certain toxicity. Long-term combined use may cause new multidrug-resistant strains or cause serious pollution to the environment. Some compatible drugs have been approved by the European Union. Prohibited as a feed additive

Method used

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  • Application of n-benzyl imidamide derivatives as synergistic agents of polymyxin antibiotics
  • Application of n-benzyl imidamide derivatives as synergistic agents of polymyxin antibiotics
  • Application of n-benzyl imidamide derivatives as synergistic agents of polymyxin antibiotics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 Preparation of 1-(2-chloro-6-fluorobenzyl)-1H-imidazole-4,5-diamide (15031)

[0053]

[0054] Step 1: Preparation of dimethyl 1-(2-chloro-6-fluorobenzyl)-1H-imidazole-4,5-dicarboxylate

[0055] Free dimethyl 1H-imidazole-4,5-dicarboxylate (9.2g, 50mmol, 1eq), 2-chloro-6-fluorobenzyl chloride (17.9g, 100mmol, 2eq) and potassium carbonate (17.3g, 125mmol, 2.5eq) were successively dissolved in 70mL N,N-dimethylformamide, stirred and reacted at 100°C for 15h, and monitored by TLC until the end point. The reaction solution was cooled to room temperature, 150 mL of water was added, extracted with ethyl acetate (100 mL×3), the ethyl acetate layers were combined, washed with water (100 mL×3) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to remove the organic solvent to obtain a colorless transparent liquid (dimethyl 1-(2-chloro-6-fluorobenzyl)-1H-imidazole-4,5-dicarboxylate), which is directly used in t...

Embodiment 2

[0059] Example 2 Preparation of 1-(4-chlorobenzyl)-1H-imidazole-4,5-diamide (15037)

[0060]

[0061] Step 1: Preparation of dimethyl 1-(4-chlorobenzyl)-1H-imidazole-4,5-dicarboxylate

[0062] Free dimethyl 1H-imidazole-4,5-dicarboxylate (7.6g, 41mmol, 1eq), p-chlorobenzyl chloride (13.2g, 82mmol, 2eq) and potassium carbonate (14.2g, 103mmol, 2.5eq) were sequentially dissolved In 50mL of N,N-dimethylformamide, the reaction was stirred at 90°C for 16h, and the reaction was monitored by TLC until the end point. The reaction solution was cooled to room temperature, 150 mL of water was added, extracted with ethyl acetate (100 mL×3), the ethyl acetate layers were combined, washed with water (100 mL×3) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. Concentration under reduced pressure to remove the organic solvent gave the product as a colorless transparent liquid (1-(4-chlorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester), which was directly...

Embodiment 3

[0066] Example 3 Preparation of 1-(3-chlorobenzyl)-1H-imidazole-4,5-diamide (15041)

[0067]

[0068] Step 1: Preparation of dimethyl 1-(3-chlorobenzyl)-1H-imidazole-4,5-dicarboxylate

[0069] Free dimethyl 1H-imidazole-4,5-dicarboxylate (5.0 g, 27 mmol, 1 eq), 3-chlorobenzyl bromide (11.5 g, 56 mmol, 2 eq) and potassium carbonate (9.3 g, 67.5 mmol, 2.5 eq) Dissolve in 50mL N,N-dimethylformamide successively, stir and react at 90°C for 10h, and monitor the reaction to the end by TLC. The reaction solution was cooled to room temperature, 150 mL of water was added, extracted with ethyl acetate (100 mL×3), the ethyl acetate layers were combined, washed with water (100 mL×3) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. The organic solvent was removed by concentration under reduced pressure to obtain a colorless transparent liquid (1-(3-chlorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester), which was directly used in the next reaction.

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Abstract

The present invention discloses the application of N-benzylimidazolecarboxamide derivatives as synergist for polymyxin antibiotics. N-benzylimidazolecarboxamide derivatives have synergistic effects for polymyxin antibiotics in the prevention and control of livestock and poultry diseases and in the improvement of the growth and production of livestock and poultry, and can be used in the field of the prevention and control of livestock and poultry diseases and the promotion of livestock and poultry growth to improve animal production performance and thus enhance the economic benefits of livestock and poultry farming. On the other hand, the combination of N-benzylimidamide derivatives and polymyxin antibiotics can reduce the dose of polymyxin antibiotics so as to reduce toxic and side effect and improve the use efficiency and use scope of polymyxin antibiotics in human pharmaceutic field.

Description

Technical field: [0001] The invention belongs to the field of biomedicine, and relates to the application of N-benzyl imidamide derivatives as synergists of polymyxin antibiotics, such as the preparation of human medicines and their application as animal disease prevention and control medicines and feed additives. Background technique: [0002] Polymyxin is an antibacterial polypeptide found in the culture medium of Bacillus polymyxa. There are five kinds of A, B, C, D, E, etc., which have similar structures, similar antibacterial spectrum and wide range. , especially for Gram-negative bacteria, polymyxin B and polymyxin E (colistin sulfate) are commonly used clinically. Due to their high toxicity, they are mainly used for local treatment of infections caused by sensitive bacteria. Eye, ear, skin, mucous membrane infection and Pseudomonas aeruginosa infection in burns, as well as oral administration for intestinal preoperative preparation. It is used as a feed additive in t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4174C07D233/64A61P31/04A61P3/00A61P1/12A23K20/137A23K20/195
CPCC07D233/64A23K20/137A23K20/195A61K9/08A61K9/20A61K31/4174
Inventor 彭险峰覃宗华
Owner GUANGZHOU INSIGHER BIOTECHNOLOGY CO LTD
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