WO2017113526A1 - Applications de dérivé quinoxaline-1,4-dioxyde comme synergiste du sulfate de colistine - Google Patents

Applications de dérivé quinoxaline-1,4-dioxyde comme synergiste du sulfate de colistine Download PDF

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Publication number
WO2017113526A1
WO2017113526A1 PCT/CN2016/077920 CN2016077920W WO2017113526A1 WO 2017113526 A1 WO2017113526 A1 WO 2017113526A1 CN 2016077920 W CN2016077920 W CN 2016077920W WO 2017113526 A1 WO2017113526 A1 WO 2017113526A1
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Prior art keywords
quinoxaline
colistin sulfate
synergist
dioxide derivative
use according
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Ceased
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PCT/CN2016/077920
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English (en)
Chinese (zh)
Inventor
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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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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

Definitions

  • the invention belongs to the field of livestock and poultry medicine, and particularly relates to the application of quinoxaline-1,4-dioxide derivatives as a colistin sulfate synergist and a medicament for treating and preventing bacterial bacterial diarrhea in animals.
  • Colistin is produced by polymyxa and has strong antibacterial activity against Gram-negative bacteria.
  • the sensitive bacteria of colistin sulfate are Pseudomonas aeruginosa, Escherichia coli, Enterobacter, Klebsiella, Salmonella, Shigella, Pasteurella and Vibrio, which can be used for the treatment of leather.
  • Intestinal diseases caused by gram-negative bacteria and used as feed additives have obvious growth-promoting effects, and are widely used as feed additives in the feed industry to prevent livestock diseases, improve metabolism of livestock and poultry, improve survival rate and feed conversion ratio. .
  • the rational compatibility of colistin sulfate with other antibiotics can enhance the effect of the drug more than the use of colistin sulfate alone.
  • the commonly used compatibility reagents are bacitracin zinc, guitarmycin, and flavomycin. Wait for antibiotics. However, due to the toxicity of these antibiotics and the combined use of drug-resistant strains, some species are gradually being phased out in the EU and other regions. Therefore, in order to effectively improve the health status and growth rate of livestock and poultry, increase the feed conversion rate and improve the economic benefits of breeding, the development of new, safe and effective colistin sulfate compatibility reagent is to improve the colistin sulfate in livestock and poultry breeding. The key factors in the use of the effect.
  • the object of the present invention is to provide a novel, safe and effective synergistic synergist of colistin sulfate, which is suitable for replacing the commonly used antibiotics, such as zinc, guitarmycin, flavomycin, etc., with sulfuric acid and a drug-resistant strain.
  • the colistin combination is applied to the prevention and treatment of livestock diseases, that is, the application of the quinoxaline-1,4-dioxide derivative as a colistin sulfate synergist.
  • Colistin sulfate has antibacterial or bactericidal action against Gram-negative bacteria, and has a good effect in treating or controlling diarrhea caused by bacterial infection in animals, and is not easily absorbed and excreted in the digestive tract, and synergistic synergist The use will reduce the use of colistin sulfate to reduce the burden on the digestive tract of livestock and the pollution caused by the environment.
  • the colistin synergist provided by the present invention is a quinoxaline-1,4-dioxide derivative.
  • a series of quinoxaline-1,4-dioxide derivatives are disclosed as therapeutics and growth promoters for animals, as disclosed in U.S. Patent Nos. 3,344,022, 3,371,090, 1,344,022, 3,644,360, 4,148,642, 4,100,284, 4,303,657, 4,317,824, 4,343,942, 4,684,649.
  • Some quinoxaline derivatives are marketed in the United States and China for animal husbandry, but there is one General toxicity or tritoxicity and activity problems.
  • the inventors have disclosed a quinoxaline-1,4-dioxide derivative having a stronger antibacterial activity against low or no toxicity of livestock and poultry in the patent CN103145631A (China, Application Date, March 18, 2013). It is used for the treatment and prevention of animal diseases and as a feed additive for promoting animal growth. From the patented test data, it is known that the derivative of the quinoxaline-1,4-dioxide derivative described in the in vitro antibacterial experiment does not have antibacterial ability against Escherichia coli and Salmonella but against Staphylococcus aureus and the capsule of the gas-producing capsule. The bacteria have a strong inhibitory effect.
  • the present invention provides a quinoxaline-1,4-dioxide derivative, or a cis-trans isomer thereof, or a pharmaceutically acceptable salt thereof, and a solvate thereof as a synergist for colistin sulfate
  • the structure of the quinoxaline-1,4-dioxide derivative is as shown in the formula (I):
  • R 1 -R 5 are H, OH, NO 2 , O-CH 3 , C 1 -6 linear or branched alkane, Ph, CH 2 -Ph or halogen;
  • R 6 and R 7 are H, halogen or -O-CH 3 ;
  • the halogen is F, Cl, Br or I;
  • the phenyl group in the CH 2 -Ph and Ph means a benzene ring which is not substituted by any substituent.
  • the quinoxaline-1,4-dioxide derivative is preferably represented by the formula (II):
  • the inventors examined the minimum inhibitory concentration of colistin sulfate to Gram-negative bacteria in the presence of the quinoxaline-1,4-dioxide derivative by in vitro double-dilution method in an in vitro antibacterial test.
  • colistin sulfate enhances the bacteriostatic ability of sensitive or resistant Gram-negative bacteria by 2-4 fold.
  • the Gram-negative bacteria include Escherichia coli, Salmonella, Pseudomonas aeruginosa, Shigella, Klebsiella, Pasteurella, Proteus, Brucella, Serratia, and the like.
  • colistin sulfate can not only prevent livestock diseases, but also improve the metabolism of livestock and poultry, improve survival rate and feed conversion rate, and promote the growth of livestock and poultry.
  • Diarrhea is the most common disease in livestock and poultry, often caused by bacterial infection.
  • Colistin sulfate has a good effect in controlling diarrhea caused by bacterial infection in livestock and poultry. It is due to its antibacterial or bactericidal ability to the flora. Thereby improving the intestinal flora environment of livestock and poultry.
  • the use of the quinoxaline-1,4-dioxide derivative as a synergist for colistin sulfate is for the preparation of a drug resistant to colistin sulfate-resistant or resistant bacteria.
  • the use of the quinoxaline-1,4-dioxide derivative as a synergist for colistin sulfate is for the preparation of an animal feed additive.
  • the animal feed additive is an animal growth promoter.
  • the quinoxaline-1,4-dioxide derivative and colistin sulfate are orally administered to an animal at a therapeutic or prophylactic dose of colistin sulfate and quinoxaline-1,4-dioxide derivative. Things.
  • the oral form is oral administration or oral administration in an oral dosage form.
  • the oral dosage forms include tablets, capsules, powders, powders, suspensions, emulsions, solutions, granules, premixes and the like.
  • the quinoxaline-1,4-dioxide derivative can be used in combination with a colistin sulfate to control an animal diarrheal disease.
  • the quinoxaline-1,4-dioxide derivative can be prepared in combination with colistin sulfate to form a compound dosage form for controlling an animal diarrheal disease.
  • the animals include poultry and livestock, specifically chickens, ducks, geese, pigeons or baboons at various stages of growth and pigs, cattle, sheep, horses, rabbits, donkeys, deer, dogs, cats, foxes, foxes, ⁇ or ⁇ .
  • the therapeutic dose is the dose required to effectively control the condition of the animal and cure the disease without causing safety in the animal.
  • the prophylactic dose is the dose required to maintain an animal's ability to maintain a normal state of life during growth.
  • the therapeutic or prophylactic dose of the quinoxaline-1,4-dioxide derivative is from 1 to 500 mg/kg, preferably from 10 to 300 mg/kg, based on the animal body weight.
  • 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.
  • quinoxaline-1,4-dioxide provided by the present invention can be used as a novel effective and safe colistin synergist for the treatment of animal diseases.
  • R 1 -R 5 are H, OH, NO 2 , O-CH 3 , C 1 -6 linear or branched alkane, Ph, CH 2 -Ph or halogen; R 6 and R 7 are H, halogen Or O-CH 3 .
  • the halogen is F, Cl, Br or I;
  • the phenyl group in the CH 2 -Ph and Ph means a benzene ring which is not substituted by any substituent.
  • the preparation method of the above quinoxaline-1,4-dioxide derivative is the same as that disclosed in CN103145631A (China, Patent No. ZL201310087021.7, application date: March 18, 2013), so that the quinox can be obtained by referring to the patent preparation.
  • a porphyrin-1,4-dioxide derivative The reaction course is as follows: starting from 2-acetyl-3-methylquinoxaline-1,4-dioxide derivative with benzaldehyde derivative in methanol with sodium hydroxide as base in ice bath The reaction was monitored by TLC, and the reaction was carried to the end. The filtration was carried out as a work-up method, and the product was reacted with a 300-mesh silica gel column.
  • Tetrahydropyrrole (1 g, 15 mmol, 1 eq) and 100 mL of dichloromethane were added to a 250 mL eggplant-shaped flask and cooled to 0 ° C in an ice bath.
  • 2-Acetyl-3-methylquinoxaline-1,4-dioxide (3.27 g, 15 mmol, 1 eq) was added thereto while maintaining the temperature of the solution at 0 ° C, and 3-trifluoromethylbenzaldehyde was added ( 3.13 g, 18 mmol, 1.2 eq. was stirred for 20 min. EtOAc.
  • Example 2 Synergistic effect of quinoxaline-1,4-dioxide derivatives on colistin-sensitive Escherichia coli inhibitory activity.
  • the objective was to test the minimum inhibitory concentration of colistin sulfate to the corresponding strain in the case of containing 50.0 ppm of quinoxaline-1,4-dioxide derivative, and the results are shown in Table 2.
  • Table 2 all of the test strains were sensitive to colistin sulfate and all tested quinoxaline-1,4-dioxide derivatives had no inhibitory activity against the test strain.
  • the test group containing 50.0 ppm of quinoxaline-1,4-dioxide derivative showed a different degree of reduction in the minimum inhibitory concentration of the corresponding test strain, about 2-4 times (Table 3).
  • Example 3 Synergistic effect of quinoxaline-1,4-dioxide derivatives on the inhibitory activity of colistin sulfate-resistant Escherichia coli.
  • Example 4 Reversal of drug resistance of different concentrations of compound 030442 to different types of colistin sulfate resistant strains.
  • Example 7 Therapeutic effect of different doses of compound 030442 and colistin sulfate on artificial infection of pig Escherichia coli.
  • the first group was the non-administered challenge control group 1
  • the second group was the challenge control group 2 (colistin sulfate) given only colistin sulfate
  • the other test groups were challenged and given a fixed dose. Colistin sulfate and different doses of 003042.
  • control group 1 After artificial infection with the pathogenic Escherichia coli SGD strain, all of the test pigs that did not receive the challenge control group (control group 1) exhibited diarrhea, and 6 of them died during the test. All drug-administered groups had different degrees of protective effects against E. coli artificial infection (Table 10).
  • Example 8 Protective effect of quinoxaline-1,4-dioxide derivative 0023242 on chicken E. coli attack infection.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Zoology (AREA)
  • Animal Husbandry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des applications d'un dérivé quinoxaline-1,4-dioxyde en tant que synergiste du sulfate de colistine. Le dérivé quinoxaline-1,4-dioxyde est utilisé en tant que synergiste par collaboration du sulfate de colistine et le composé est utilisé conjointement avec le sulfate de colistine dans le traitement d'une maladie animale pour fournir une méthode de traitement des diarrhées infectieuses bactériennes chez les animaux. Le synergiste par collaboration du sulfate de colistine décrit dans la présente invention est apte à augmenter sensiblement les effets thérapeutiques du sulfate de colistine, est un nouveau synergiste par collaboration du sulfate de colistine non antibiotique très efficace et sûr, est applicable dans la prévention et le traitement de maladies pour l'élevage d'animaux, et augmente les avantages économiques pour le secteur agricole.
PCT/CN2016/077920 2015-12-29 2016-03-30 Applications de dérivé quinoxaline-1,4-dioxyde comme synergiste du sulfate de colistine Ceased WO2017113526A1 (fr)

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CN201511023319.7 2015-12-29
CN201511023319.7A CN106727576B (zh) 2015-12-29 2015-12-29 喹噁啉-1，4-二氧化物衍生物作为硫酸粘杆菌素增效剂的应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119752738A (zh) * 2025-03-05 2025-04-04 中国海洋大学 一种对虾肠道海泥黏着杆菌LvS229、益生菌制剂、饲料及应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4343942A (en) * 1966-11-08 1982-08-10 Research Corporation Quinoxaline derivatives
JPS60176550A (ja) * 1984-02-22 1985-09-10 Asahi Chem Ind Co Ltd 血液の免疫蛋白含有飼料
CN1197068A (zh) * 1997-04-21 1998-10-28 中国农业科学院中兽医研究所 3－甲基－2－苯乙烯酮基－喹恶啉－1,4－二氧化物的化合物及合成方法
CN1409638A (zh) * 1999-12-14 2003-04-09 旭化成株式会社 硫酸粘杆菌素颗粒
CN101473900A (zh) * 2008-10-27 2009-07-08 中谷集团农牧科技有限公司 仔猪断奶全价配合饲料
CN103145631A (zh) * 2013-03-18 2013-06-12 广州英赛特生物技术有限公司 抗菌性的喹噁啉-1,4-二氧化物的衍生物及其在动物生产中的应用

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
US4100284A (en) * 1977-01-18 1978-07-11 Pfizer Inc. 1,4-Dioxo- and 4-oxoquinoxaline-2-carboxaldehyde sulfonylhydrazones and certain derivatives thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4343942A (en) * 1966-11-08 1982-08-10 Research Corporation Quinoxaline derivatives
JPS60176550A (ja) * 1984-02-22 1985-09-10 Asahi Chem Ind Co Ltd 血液の免疫蛋白含有飼料
CN1197068A (zh) * 1997-04-21 1998-10-28 中国农业科学院中兽医研究所 3－甲基－2－苯乙烯酮基－喹恶啉－1,4－二氧化物的化合物及合成方法
CN1409638A (zh) * 1999-12-14 2003-04-09 旭化成株式会社 硫酸粘杆菌素颗粒
CN101473900A (zh) * 2008-10-27 2009-07-08 中谷集团农牧科技有限公司 仔猪断奶全价配合饲料
CN103145631A (zh) * 2013-03-18 2013-06-12 广州英赛特生物技术有限公司 抗菌性的喹噁啉-1,4-二氧化物的衍生物及其在动物生产中的应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119752738A (zh) * 2025-03-05 2025-04-04 中国海洋大学 一种对虾肠道海泥黏着杆菌LvS229、益生菌制剂、饲料及应用

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CN106727576B (zh) 2020-08-04

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