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WO2017113525A1 - Application de dérivés de n-benzylimidazolecarboxamide comme synergiste pour antibiotiques de type polymyxine - Google Patents

Application de dérivés de n-benzylimidazolecarboxamide comme synergiste pour antibiotiques de type polymyxine Download PDF

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Publication number
WO2017113525A1
WO2017113525A1 PCT/CN2016/077918 CN2016077918W WO2017113525A1 WO 2017113525 A1 WO2017113525 A1 WO 2017113525A1 CN 2016077918 W CN2016077918 W CN 2016077918W WO 2017113525 A1 WO2017113525 A1 WO 2017113525A1
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benzylmidamide
derivative
polymyxin
imidazole
use according
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彭险峰
覃宗华
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Guangzhou Insighter Biotechnology Co Ltd
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Guangzhou Insighter Biotechnology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/195—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the invention belongs to the field of biomedicine and relates to the application of N-benzylmidamide derivatives as synergistic synergists of polymyxin antibiotics, such as preparation of human drugs and application as an animal control agent and feed additive.
  • Polymyxin is an antibacterial polypeptide found in Bacillus polymyxa culture medium. It has five kinds of A, B, C, D, E, etc. It is similar in structure, and the antibacterial spectrum is similar to each other and has a wide range. It has a killing effect on Gram-negative bacteria in particular. Polymyxin B and polymyxin E (colistin sulfate) are commonly used in clinical practice. Due to its high toxicity, it is mainly used for local treatment of sensitive bacteria. Infection of Pseudomonas aeruginosa in eyes, ears, skin, mucosal infections and burns and oral administration for preoperative preparation of the intestines. As a feed additive application in the feed industry, it can prevent livestock diseases, improve the metabolism of livestock and poultry, and increase the survival rate and feed conversion rate to promote the growth of livestock and poultry.
  • One of the objects of the present invention is to provide a novel, safe and effective synergistic synergist for polymyxins.
  • the colistin synergist provided by the present invention is an N-benzylmidamide derivative.
  • the invention therefore provides for the use of a N-benzylmidamide derivative as a synergistic synergist for a polymyxin antibiotic having a structure as shown in formula (I):
  • the N- benzyl-imidazole derivatives R 1 is preferably H, R 2 is preferably halogen.
  • N- benzyl-imidazole derivatives R 1 is preferably H, R 2 is preferably Cl.
  • N-benzylmidamide derivative is preferably a compound of formula (II),
  • polymyxins of the present invention are selected from the group consisting of polymyxin A, polymyxin B, polymyxin C, polymyxin D or polymyxin E.
  • the N-benzylmidamide derivative provided by the invention has a remarkable synergistic effect on the inhibition of bacterial growth by colistin sulfate in an in vitro antibacterial test research process, and the minimum inhibitory concentration of colistin sulfate in the corresponding experiment There was a significant drop.
  • the test is separately in the culture When the N-benzylmidamide derivatives containing the same concentration of different structures were used, the minimum inhibitory concentration of polymyxin antibiotics on the corresponding sensitive strains in vitro, N-benzylmidamide derivatives showed obvious synergistic synergistic effect.
  • the minimum inhibitory concentration of the polymyxin antibiotic to the corresponding susceptible strain in the same concentration of the different concentration of the N-benzylmidamide derivative in the culture is tested, and the preferred test susceptible strain is Polymyxin-like antibiotic-sensitive E. coli.
  • synergistic effects of different concentrations of the same N-benzylmidamide derivative on polymyxin antibiotic resistant strains exhibit a dose effect.
  • the bacteria are Gram-negative bacteria, including Escherichia coli, Enterobacter, Pseudomonas aeruginosa, Shigella, Klebsiella, Salmonella, Clostridium perfringens, Staphylococcus aureus and the like.
  • a second object of the present invention is to provide the use of the N-benzylmidamide derivative as a polymyxin antibiotic synergist for the preparation of a medicament for antibacterial infection in animals, such as for preparation A drug that is resistant to polymyxin antibiotic-sensitive or resistant bacteria.
  • the common bacterial infection symptoms of animals are bacterial diarrhea caused by intestinal infection, which is characterized by diarrhea, loss of appetite, indigestion, mental dysfunction, body weight loss and death. Bacterial diarrhea is contagious and can affect the health of other livestock in the same group. Polymyxins have therapeutic and preventive effects on bacterial sputum in animals.
  • the polymyxin antibiotic synergist N-benzylmidamide derivative of the present invention is administered orally in an oral dosage form.
  • the oral dosage form comprises, in addition to the main drug component N-benzylimimidamide derivative, a pharmaceutically acceptable carrier, excipient, diluent, antioxidant, anti-caking agent, vehicle or a combination thereof.
  • the therapeutic oral dosage forms are tablets, capsules, granules, powders, oral liquids, powders, premixes and the like.
  • polymyxin antibiotic synergist of the present invention is prepared as a compound preparation in combination with a polymyxin antibiotic.
  • the compound preparation can be used orally, and contains a pharmaceutically acceptable carrier, an excipient, a diluent, an antioxidant, an anti-caking agent in addition to the N-benzylmidamide derivative and the polymyxin antibiotic. , solvent or a combination thereof.
  • the compound preparations are tablets, capsules, granules, powders, oral liquids, powders, premixes and the like.
  • the N-benzylmidamide derivative is used in a therapeutic dose of from 1 to 200 ppm, preferably from 10 to 200 ppm.
  • the N-benzylmidamide derivative is used as a polymyxin antibiotic synergist for anti-animal bacterial infection, and the animal is mainly poultry and livestock, specifically including chicken, duck, goose, pigeon, donkey, pig, Cow, sheep, horse, rabbit, donkey, dog, cat, fox, donkey or donkey.
  • a third object of the present invention is to provide the use of the N-benzylmidamide derivative as a polymyxin antibiotic synergist for the preparation of an animal growth promoter.
  • Polymyxin antibiotics have a significant effect on improving the performance of animals in the feed processing industry as an antibiotic animal growth promoter.
  • the N-benzylmidamide derivatives are compatible with polymyxin antibiotics. Synergistically enhances the effect of promoting animal growth performance.
  • the N-benzylmidamide derivative is formulated with a feed carrier, diluent, antioxidant, anti-caking agent, vehicle, or a combination thereof to produce a feed additive for growth promotion in an animal.
  • the N-benzylmidamide derivative and the polymyxin antibiotic are combined with a feeding carrier, diluent, antioxidant, anti-caking agent, vehicle, or a combination thereof to form a compound feed additive for use in The growth of animals.
  • the feed additive is a tablet, a powder, a powder, a granule, an oral solution, a capsule, a premix, and the like.
  • the feed additive provided by the present invention is added to the animal's daily ration in a separate form.
  • the feed additive, the feed additive, the carrier or the diluent provided by the present invention are prepared into an additive premixed feed, concentrated feed, compound feed, concentrate supplement feed, etc. in a certain ratio for the animal. edible.
  • the feed additive is used in the feed at a dose of N-benzylmidamide derivative in an amount of from 1 to 1000 ppm, preferably from 10 to 500 ppm.
  • N-benzylmidamide derivatives are used as synergistic synergists for polymyxins in animals for growth.
  • the animals are mainly poultry and livestock, including chickens, ducks, geese, pigeons, quails, pigs, and cattle. , sheep, horses, rabbits, donkeys, dogs, cats, foxes, baboons or baboons.
  • the present invention also provides a synergistic synergist of an N-benzylmidamide derivative as a polymyxin antibiotic for the preparation of a medicament for human infection against Gram-negative bacteria.
  • polymyxin antibiotics are highly toxic, and has adverse reactions such as nervous system toxicity and allergic reactions such as itching, fever and rash, which limits the clinical use and utilization rate of the drug.
  • the N-benzylmidamide derivative has synergistic effect on polymyxin antibiotics, and the combined use thereof can significantly reduce the dosage of polymyxin antibiotics and reduce the probability and intensity of toxic side reactions.
  • the N-benzylmidamide derivative of the present invention is combined with polymyxin antibiotics in the preparation of a compound therapeutic drug for human use Applications.
  • the compound therapeutic drug comprises one of N-benzylimimidamide derivative and polymyxin antibiotic and other medicinal excipients, and may be powder, granule, tablet, capsule, ointment, eye ointment, gel Agents, aerosols, films, oral liquids, eye drops, injections, suppositories, and the like.
  • the compound therapeutic drug can be used for treating diseases caused by Gram-negative bacteria infection such as gastrointestinal infection, sepsis, urinary tract infection, dysentery, whooping cough, respiratory tract infection, biliary tract infection, burn or traumatic wound infection caused by human bacteria.
  • the N-benzylmidamide derivative provided by the invention can be used as a novel effective and safe polymyxin antibiotic preparation for animal disease prevention and treatment, and as a synergistic agent to improve the growth of so-called antibiotic animals.
  • the use efficiency of the accelerator thereby improving the production performance of the animal improves the economic benefit of the feeding, and can reduce the dosage of the polymyxin antibiotic in the clinical use of the human medicine, thereby reducing the occurrence of toxic side reactions and improving the use efficiency of the medicine.
  • the invention also relates to methods and processes for the preparation, isolation, purification, and the like of the N-benzylmidamide derivatives.
  • any of the embodiments of any of the aspects of the invention may be combined with other embodiments as long as no contradiction occurs between them.
  • any of the technical features may be applied to the technical features in other embodiments as long as there is no contradiction between them.
  • C 1-4 straight or branched alkyl means methyl, ethyl, propyl, isopropyl, C 4 alkyl straight or branched An alkane group
  • C 1-4 straight or branched haloalkyl represents a methyl, ethyl, propyl, isopropyl, C 4 alkyl straight or branched alkane group and the alkane group is at least one halogen atom
  • OC 1-4 represents an alkoxy group
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a particular substituent.
  • a substituted group may have one or more substituents substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, The substituents may then be substituted at the same or different positions.
  • linking substituents are described.
  • the Markush variable recited for that group is understood to be a linking group.
  • the Markush group definition for the variable recites “alkyl”, it should be understood that the "alkyl” represents a linked alkylene group.
  • N-benzylmidamide derivatives of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined for formula (I).
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • Free 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (9.2 g, 50 mmol, 1 eq), 2-chloro-6-fluorobenzyl chloride (17.9 g, 100 mmol, 2 eq) and potassium carbonate (17.3 g, 125 mmol, 2.5 eq) was dissolved in 70 mL of N,N-dimethylformamide, and the reaction was stirred at 100 ° C for 15 h, and the reaction was monitored by TLC to the end.
  • reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(2-chloro-6fluorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester), which was directly used for the next reaction.
  • the product obtained in the first step 1-(2-chloro-6fluorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester, is dissolved in about 50 ml of aqueous ammonia, and stirred at 45 ° C overnight to obtain a white suspension. After filtration, the filter cake was washed with water (20 mL ⁇ 3), and dried under reduced pressure at 55 ° C to give 11.1 g of the product (1-(2-chloro-6-fluorobenzyl)-1H-imidazole-4,5-diamide). The total yield was 79.8%.
  • the reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(4-chlorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester).
  • the reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(3-chlorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester).
  • reaction solution was cooled to room temperature, added with 150 mL of water and ethyl acetate (100 mL) ⁇ 3), the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate, and evaporated.
  • (4-Fluorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester was used directly in the next reaction.
  • Free 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (6.0 g, 32.6 mmol, 1 eq), p-nitrobenzyl chloride (11.2 g, 65.2 mmol, 2 eq) and potassium carbonate (11.3 g, 81.5 mmol, 2.5 Eq) was dissolved in 50 mL of N,N-dimethylformamide, and the reaction was stirred at 120 ° C for 15 h, and the reaction was monitored by TLC to the end.
  • the reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(4-nitrobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester).
  • the product obtained in the first step is obtained by dissolving the product of 1-(4-nitrobenzyl)-1H-imidazole-4,5-dicarboxylate in about 50 ml of aqueous ammonia, and stirring at 45 ° C overnight to obtain a white suspension, which is filtered.
  • the filter cake was washed with water (20 mL ⁇ 3), and dried under reduced pressure at 55 ° C to give 4.8 g of the product (1-(4-nitrobenzyl)-1H-imidazole-4,5-diamide). The total yield was 50.5%.
  • Free 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (7.0 g, 38.0 mmol, 1 eq), p-methylbenzyl chloride (10.7 g, 76.0 mmol, 2 eq) and potassium carbonate (13.1 g, 95.0 mmol, 2.5 Eq) was dissolved in 50 mL of N,N-dimethylformamide, and the reaction was stirred at 120 ° C for 15 h, and the reaction was monitored by TLC to the end.
  • the reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(4-methylbenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester).
  • the product obtained in the first step is obtained by dissolving the product of 1-(4-methylbenzyl)-1H-imidazole-4,5-dicarboxylate in about 50 ml of aqueous ammonia, and stirring at 45 ° C overnight to obtain a white suspension, which is filtered. The filter cake was washed with water (20 mL ⁇ 3), and dried under reduced pressure at 55 ° C to give y. The total yield was 79%.
  • Free 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (7.0 g, 38.0 mmol, 1 eq), p-trifluoromethylbenzyl bromide (18.2 g, 76.0 mmol, 2 eq) and potassium carbonate (13.1 g, 95.0 mmol) , 2.5 eq) was sequentially dissolved in 50 mL of N,N-dimethylformamide, and the reaction was stirred at 120 ° C for 15 h, and the reaction was monitored by TLC to the end.
  • the reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(4-trifluoromethylbenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester).
  • the product obtained in the first step 1-(4-trifluoromethylbenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester, is dissolved in about 50 ml of aqueous ammonia, and stirred at 45 ° C overnight to obtain a white suspension. After filtration, the filter cake was washed with water (20 mL ⁇ 3), and dried under reduced pressure at 55 ° C to give the product (1-(4-trifluoromethylbenzyl)-1H-imidazole-4,5-diamide) 8.73 g. The total yield was 73%.
  • Free 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (9.2 g, 50 mmol, 1 eq), p-methoxybenzyl chloride (15.7 g, 100.0 mmol, 2 eq) and potassium carbonate (17.3 g, 125.0 mmol, 2.5 Eq) was dissolved in 70 mL of N,N-dimethylformamide, and the reaction was stirred at 120 ° C for 15 h, and the reaction was monitored by TLC to the end.
  • the reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(4-methoxybenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester).
  • the product obtained in the first step is obtained by dissolving the product of 1-(4-methoxybenzyl)-1H-imidazole-4,5-dicarboxylic acid in about 50 ml of aqueous ammonia, and stirring at 45 ° C overnight to obtain a white suspension.
  • the filter cake was washed with water (20 mL ⁇ 3), and dried under reduced pressure at 55 ° C to give the product (1-(4-methoxybenzyl)-1H-imidazole-4,5-diamide) 8.55 g.
  • the total yield was 62%.
  • Free 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (9.2 g, 50 mmol, 1 eq), 3,4-dichlorobenzyl bromide (24.0 g, 100.0 mmol, 2 eq) and potassium carbonate (17.3 g, 125.0 mmol, 2.5 eq) were sequentially dissolved in 70 mL of N,N-dimethylformamide, and the reaction was stirred at 110 ° C for 14 h, and the reaction was monitored by TLC to the end.
  • the reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(3,4-dichlorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester).
  • the product obtained in the first step 1-(3,4-dichlorobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester, is dissolved in about 50 ml of aqueous ammonia, and stirred at 45 ° C overnight to obtain a white suspension. After filtration, the filter cake was washed with water (20 mL ⁇ 3), and dried under reduced pressure at 55 ° C to give 11.1 g of the product (1-(3,4-dichlorobenzyl)-1H-imidazole-4,5-diamide). The total yield is 75%.
  • 3,5-Dinitrobenzoic acid (12 g, 56.6 mmol, 1 eq) was dissolved in 100 ml of tetrahydrofuran. After cooling to 0 ° C, sodium borohydride (4.3 g, 113.2 mmol, 2.0 eq) was added, and the reaction was stirred for 1 h, slowly added dropwise. Boron trifluoride.
  • 3,5-Dinitrobenzyl alcohol (2.4 g, 12.12 mmol, 1 eq) was dissolved in dry 50 mL dichloromethane, cooled to 0 ° C, triethylamine (4.9 g, 48.2 mmol, 4 eq) Sulfoxide (2.9 g, 24.2 mmol, 2 eq) was added dropwise, gradually warmed to reflux, reacted for 3 h, then the mixture was cooled and cooled to room temperature, and 50 mL of water was added dropwise to quench the reaction and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and evaporated, evaporated, evaporated, evaporated. Dinitrobenzyl chloride) 2.5 g, yield 95.3%.
  • the reaction mixture was cooled to room temperature, and 15 mL of water was added, and ethyl acetate (10 mL ⁇ 3) was added, and the ethyl acetate layer was combined, washed with water (10 mL ⁇ 3) and brine (10 mL ⁇ 2) and dried over anhydrous sodium sulfate.
  • the organic solvent was concentrated under reduced pressure to give the product as a colorless transparent liquid (1-(3,5-dinitrobenzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester).
  • the product obtained in the step 3 is obtained by dissolving dimethyl 1-(3,5-dinitrobenzyl)-1H-imidazole-4,5-dicarboxylate in about 25 ml of aqueous ammonia, and stirring at 45 ° C overnight to obtain a gray suspension. The mixture was filtered, washed with water (10 mL ⁇ 3), and dried under reduced pressure at 40 ° C to give 1.7 g of the product (1-(3,5-dinitrobenzyl)-1H-imidazole-4,5-diamide). The total yield in two steps was 75%.
  • the p-methylsulfonylbenzoic acid (12 g, 60.3 mmol, 1 eq) was dissolved in 100 ml of tetrahydrofuran, and the mixture was cooled to 0 ° C, then sodium borohydride (4.6 g, 120.6 mmol, 2.0 eq) was added, and the reaction was stirred for 1 h. Boron.
  • Free 1H-imidazole-4,5-dicarboxylic acid dimethyl ester (9.2 g, 50 mmol, 1 eq), p-methylsulfonylbenzyl chloride (20.5 g, 100 mmol, 2 eq) and potassium carbonate (17.3 g, 125.0 mmol, 2.5 eq
  • the solution was dissolved in 50 mL of N,N-dimethylformamide, and the reaction was stirred at 120 ° C for 20 h, and the reaction was monitored by TLC to the end.
  • reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate. Concentrated under reduced pressure to remove the organic solvent to give the product as a colorless transparent liquid ((1-(4-(methylsulfonyl)benzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl)) .
  • the product obtained in the step 3 (1-(4-(methylsulfonyl)benzyl)-1H-imidazole-4,5-dicarboxylic acid dimethyl ester is dissolved in about 50 ml of aqueous ammonia, and stirred at 45 ° C overnight to obtain a white suspension. The liquid was filtered, and the filter cake was washed with water (10 mL ⁇ 3), and dried under reduced pressure at 50 ° C to give the product ((1-(4-(methylsulfonyl)benzyl)-1H-imidazole-4,5-diamide) 6.6 g. The total yield of the last two steps was 41%.
  • Step 4 Preparation of methyl 1-(4-(4-chlorophenoxy)phenyl)-1H-imidazole-4,5-dicarboxylate
  • the reaction mixture was cooled to room temperature, and then added with 150 mL of water and ethyl acetate (100 mL ⁇ 3), and the ethyl acetate layer was combined, washed with water (100 mL ⁇ 3) and brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • Example 13 Synergistic effect of N-benzylmidamide derivatives on colistin-sensitive Escherichia coli inhibitory activity.
  • the concentration of the N-benzylmidamide derivative was fixed at 100.0 ppm, and the colistin sulfate was subjected to gradient dilution for the purpose of testing the derivative containing 100.0 ppm of N-benzylimidamide.
  • Example 14 Synergistic effect of N-benzylmidamide derivatives on colistin-sensitive Escherichia coli inhibitory activity.
  • MIC in vitro minimum inhibitory concentration
  • the minimum inhibitory concentration of colistin sulfate to the corresponding strain in the case of containing 100.0 ppm of N-benzylimimidamide derivative respectively (the combination of N-benzylmidamide derivative and colistin sulfate as test drug)
  • concentration of the N-benzylmidamide derivative was fixed at 100.0 ppm, and the colistin sulfate was subjected to a gradient dilution for the purpose of testing the coagulizin sulfate for the corresponding strain in the case of containing 100.0 ppm of the N-benzylimimidamide derivative.
  • Minimum inhibitory concentration The results are shown in Table 3.
  • test strains were sensitive to colistin sulfate and all the test N-benzylmidamide derivatives had no inhibitory activity against the test strain.
  • the test group containing 100.0 ppm of N-benzylimimidamide derivative showed a minimum reduction in the minimum inhibitory concentration of the corresponding test strain, about 2-4 times (Table 4).
  • E. coli 3Y-9 E. coli 2S-19 E. coli 5W-7 E. coli 3B-24 Colistin sulfate 2.0 2.0 1.0 2.0 15031 >800 >800 >800 >800 15037 >800 >800 >800 >800
  • Example 15 Reversal of drug resistance of different types of colistin sulfate resistant strains with different concentrations of N-benzylmidamide derivatives (15037).
  • Tests for different types of sulfuric acid by using the test tube double dilution method for colistin sulfate and N-benzylmidamide derivatives (15037)
  • the minimum inhibitory concentration of colistin-resistant Gram-negative bacteria resistant to colistin sulfate, MIC value greater than 4.0 ppm
  • the test also contained different concentrations of N-benzylmidamide in the culture medium.
  • the minimum inhibitory concentration of colistin sulfate to the corresponding strain in the derivative (15037).
  • Example 16 Synergistic application effect of N-benzylmidamide derivative and colistin sulfate in weaned piglets.
  • Example 17 Effect of synergistic application of N-benzylmidamide derivative (15037) and colistin sulfate in weaned piglets.
  • Example 18 Effect of synergistic application of different doses of N-benzylmidamide derivative (15037) and colistin sulfate in weaned piglets.
  • Example 19 The combined use of N-benzylmidamide derivative (15037) and colistin sulfate in chicken feed.
  • Example 20 The combined use effect of N-benzylmidamide derivative (15037) and colistin sulfate in meat duck feed.
  • Each test group contained 4 parallel test groups, 50 in each parallel test group, and added Lactobacillus sulfate in each group of feeds. Or / and N-benzylmidamide derivatives (15037). Cage in the trial period, free access to food and free drinking water. The trial period was 21 days. The test results showed that the N-benzylmidamide derivative (15037) and colistin sulfate showed synergistic effects on the weight gain and feed remuneration of the test ducks (Table 10).

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Abstract

La présente invention concerne l'application de dérivés de N-benzylimidazolecarboxamide comme synergiste pour des antibiotiques de type polymyxine. Des dérivés de N-benzylimidazolecarboxamide ont des effets synergiques pour des antibiotiques de type polymyxine dans la prévention et la lutte contre des maladies de bétail et de volaille et dans l'amélioration de croissance et de production de bétail et de volaille, et peuvent être utilisés dans le domaine de la prévention et la lutte contre des maladies de bétail et de volaille et pour favoriser la croissance de bétail et de volaille de façon à améliorer la performance de production animale et améliorer les bénéfices économiques d'élevage de bétail et de volaille. D'autre part, la combinaison de dérivés de N-benzylimidamide et d'antibiotiques de type polymyxine peut réduire la dose d'antibiotiques de type polymyxine de façon à réduire les effets secondaires et toxiques et améliorer l'efficacité d'utilisation et le cadre d'utilisation des antibiotiques de type polymyxine dans le domaine pharmaceutique humain.
PCT/CN2016/077918 2015-12-29 2016-03-30 Application de dérivés de n-benzylimidazolecarboxamide comme synergiste pour antibiotiques de type polymyxine Ceased WO2017113525A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023235376A1 (fr) * 2022-06-01 2023-12-07 Zoetis Services Llc Procédé de préparation de 1-(4-chlorobenzyl)-1h-imidazole-4,5-dicarboxamide

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CN111393300A (zh) * 2020-04-13 2020-07-10 南京工业大学 一种合成3,5-二硝基氯化苄的新方法
CN115779068A (zh) * 2022-12-29 2023-03-14 青岛农业大学 一种多粘菌素类抗生素用协同增效剂及其应用

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US4851424A (en) * 1986-06-06 1989-07-25 Ciba-Geigy Corporation 1-Phenyl-lower alkyl-imidazole 4- or 5-carboxamide compounds which are useful in the treatment of epilepsy
CN104672145A (zh) * 2015-03-09 2015-06-03 广州英赛特生物技术有限公司 咪唑双酰胺衍生物及其在制备抗球虫药物中的应用

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US4851424A (en) * 1986-06-06 1989-07-25 Ciba-Geigy Corporation 1-Phenyl-lower alkyl-imidazole 4- or 5-carboxamide compounds which are useful in the treatment of epilepsy
CN104672145A (zh) * 2015-03-09 2015-06-03 广州英赛特生物技术有限公司 咪唑双酰胺衍生物及其在制备抗球虫药物中的应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023235376A1 (fr) * 2022-06-01 2023-12-07 Zoetis Services Llc Procédé de préparation de 1-(4-chlorobenzyl)-1h-imidazole-4,5-dicarboxamide

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