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WO2023280327A1 - Utilisation d'un dérivé de cyclohexanetrione dans la préparation d'un médicament pour animaux - Google Patents

Utilisation d'un dérivé de cyclohexanetrione dans la préparation d'un médicament pour animaux Download PDF

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Publication number
WO2023280327A1
WO2023280327A1 PCT/CN2022/111827 CN2022111827W WO2023280327A1 WO 2023280327 A1 WO2023280327 A1 WO 2023280327A1 CN 2022111827 W CN2022111827 W CN 2022111827W WO 2023280327 A1 WO2023280327 A1 WO 2023280327A1
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Prior art keywords
cyclohexanetrione
animals
active ingredient
animal
infection
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Chinese (zh)
Inventor
彭险峰
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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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the technical field of medicines, in particular to the application of a cyclohexatrione derivative in the preparation of medicines for treating animal bacterial infectious diseases.
  • Clostridium perfringens is an important pathogen causing necrotic enteritis in poultry and red scour in piglets, and the disease has seriously affected the development of the breeding industry and caused great economic losses worldwide.
  • Clostridium perfringens will multiply in the intestinal tract of livestock and poultry, and produce toxins to damage the intestinal tract and cause intestinal inflammation.
  • 10 ml of Clostridium welchii vaccine type C is injected intramuscularly to pregnant sows one month before delivery and half a month after delivery, which can make the sows Strong immunity can be produced, and the protection of piglets can reach 100%.
  • the birth pens should be cleaned and strictly sterilized. Before the piglets eat milk, scrub the nipples of the sows with 0.1% potassium permanganate solution to reduce the incidence of infection. Take preventive drug treatment for newborn piglets, oral administration of oxytetracycline, tetracycline, streptomycin.
  • Endometritis is mucous, mucopurulent, and purulent inflammation of the uterine mucosa. It is the most common reproductive organ disease, mostly in cattle, horses, and pigs. The main cause of miscarriage.
  • the causes of the disease include: Escherichia coli, Streptococcus pyogenes, Staphylococcus aureus, Brucellosis, Corynebacterium, Pyogenic bacteria, Proteus Reinerii, Haemophilus and other pathogenic microorganisms infection; untimely mating and mating, disinfection during delivery Lack of strictness, improper midwifery, or surgical instrument damage to the reproductive tract during artificial insemination, causing birth canal and endometrial damage; secondary to tuberculosis, brucellosis, dystocia, retained placenta, uterine prolapse, incomplete uterine involution, miscarriage, postpartum lochia Do or stillbirth left in the womb and other diseases.
  • Antibiotic perfusion is a commonly used method of treatment. Because the pathogenic bacteria are very complex and most of them are mixed infections, drugs with a wide range of antibacterial agents are often used, such as tetracycline, chloramphenicol, gentamicin, kanamycin, erythromycin, gold, etc. Mycin, oxytetracycline, norfloxacin, furans.
  • Mastitis is an inflammation of mammary gland tissue caused by pathogenic bacteria. During the inflammatory process, mammary gland tissue is damaged and milk production decreases. It is one of the most serious diseases that cause economic losses in animal breeding. Intramammary infusion of antimicrobial agents is a common procedure for mastitis and clearance of breast infection. However, in clinical practice, the treatment effect of this method on dairy cow mastitis is not ideal, because the bacteria are resistant to antibacterial drugs and the distribution of drugs and pathogenic bacteria in the mammary gland is inconsistent after administration.
  • the purpose of the present invention is to provide a cyclohexatrione derivative, or at least one of its tautomers, solvates or pharmaceutically acceptable salts, in the preparation of animal medicines, wherein the medicine is used for For the treatment of bacterial infectious diseases in animals.
  • the present invention provides a cyclohexanetrione derivative with the structure shown in formula (I), or at least one of its tautomers, solvates or pharmaceutically acceptable salts in the preparation of animal medicines
  • said medicine is used for the treatment of animal bacterial infectious disease
  • R is methyl or ethyl.
  • the cyclohexanetrione derivatives provided by the present invention can be used to prepare medicaments for animals, and the cyclohexanetrione derivatives are toxic to animals.
  • Bacteria have a significant inhibitory effect, and the above-mentioned cyclohexatrione is further used in the treatment of pathogenic bacterial infectious diseases in animals. In the treatment of intestinal infection, birth canal infection, endometrium infection, breast infection and skin infection Has significant curative effect.
  • Some embodiments of the present invention provide a cyclohexanetrione derivative represented by formula (I), or at least one of its tautomers, solvates or pharmaceutically acceptable salts in the preparation of animal Application in medicine, wherein said medicine is used to treat bacterial infectious diseases in animals;
  • R is methyl or ethyl.
  • cyclohexanetrione derivatives provided by the present invention, or its tautomers, solvates or pharmaceutically acceptable salts are effective against animal pathogenic bacteria, such as Clostridium perfringens, Staphylococcus aureus, Agalactiae Coccus and Enterococcus faecalis have good antibacterial effects, and have shown significant therapeutic effects in animal bacterial infectious diseases.
  • Some embodiments of the present invention also provide an active ingredient comprising a cyclohexanetrione derivative with the structure shown in formula (I), or at least one of its tautomers, solvates or pharmaceutically acceptable salts
  • an active ingredient comprising a cyclohexanetrione derivative with the structure shown in formula (I), or at least one of its tautomers, solvates or pharmaceutically acceptable salts
  • R is methyl or ethyl.
  • the present invention provides a method for treating bacterial infectious diseases in animals, the method comprising administering to the animal a therapeutically effective amount of the cyclohexanetrione derivative of the present invention, or a tautomer thereof , a solvate or a pharmaceutically acceptable salt or a combination thereof, or a pharmaceutical composition comprising the same.
  • the cyclohexanetrione derivatives provided by the present invention are used to treat animal bacteria infectious disease.
  • the pharmaceutical composition of the present invention refers to a compound group comprising one or more than one compound as an active ingredient.
  • the pharmaceutical composition can be used for preparing medicine for animals, has significant inhibitory effect on animal pathogenic bacteria, and can be used for preparing medicine for treating infectious diseases of animal pathogenic bacteria.
  • the cyclohexanetrione derivative in the pharmaceutical composition of the present invention is the cyclohexanetrione derivative represented by the above formula (I), excluding other cyclohexanetrione derivatives or their salts and esters, Except for unavoidable small amounts of other cyclohexanetrione derivatives as impurities.
  • cyclohexanetrione derivatives involved in the present invention have enol structure and can exist in the form of tautomers, as shown in formula (II), these isomers are equivalent to cyclohexanetrione shown in formula (I) derivative;
  • cyclohexatrione derivatives of the present invention exist in free form or any other adducts that can be administered directly or indirectly according to the needs of organisms, such as solvates such as hydrates.
  • Solvate refers to the process of contacting the cyclohexatrione derivatives involved in the present invention with solvent molecules, external conditions and internal conditions cause the formation of chemical equivalent or non-chemical equivalent solvent molecules through non-covalent intermolecular forces eutectic associations.
  • Solvents for forming solvates include but are not limited to water, acetone, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, isopropanol and other solvents.
  • the solvate involved in the present invention is preferably a hydrate.
  • the pharmaceutically acceptable salts involved in the present invention are cyclohexanetrione derivatives and non-toxic organic bases and inorganic bases , salts formed from organic acids or inorganic acids, including but not limited to sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts or hydrochlorides of cyclohexanetrione derivatives.
  • pharmaceutically acceptable means that the substance or composition must be chemically or toxicologically appropriate in relation to the drug of composition or the farmed animal for consumption.
  • the pharmaceutical composition of the present invention also includes pharmaceutically acceptable excipients, and the pharmaceutically acceptable excipients are selected from pharmaceutically acceptable carriers, diluents, excipients, dispersants or suspending agents, surfactants, isotonic One or more of additives, thickeners, emulsifiers, preservatives, solid binders, lubricants and solvents.
  • Carrier refers to a pharmaceutically acceptable substance capable of carrying active ingredients, improving its dispersibility, and having good chemical stability and adsorption. Different carriers can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods .
  • Diluent refers to the substance that distributes the additive raw material evenly in the material, and dilutes the high-concentration additive raw material into a low-concentration premix or premix, which can separate trace components from each other and reduce the interaction between active components. To increase the stability of the active ingredient without affecting the physicochemical properties of the related substances.
  • the excipients are selected from the wetting agent that induces the inherent viscosity of the substance itself, the binder that binds the substance together, and the disintegrating agent that breaks the entire sheet of the substance into many fine particles, reducing the friction between particles
  • One or more of strong retention aids and anti-sticking agents to prevent materials from sticking including but not limited to magnesium stearate, talc, vegetable oil, magnesium lauryl sulfate, starch, starch slurry, water, inorganic salts, dextrin or powdered sugar.
  • the solvent refers to the solvent required to dissolve or disperse the solid, including but not limited to water, glycerol, ethanol.
  • the above-mentioned pharmaceutical excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, and partial glycerin of saturated vegetable fatty acids Esters mixtures, water, salts or electrolytes, sodium dihydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene- Blocking polymers, lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; Gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as
  • the active ingredient of the pharmaceutical composition includes a cyclohexanetrione derivative represented by formula (i), or a tautomer, solvate or pharmaceutically acceptable salt thereof;
  • the active ingredient of the pharmaceutical composition includes a cyclohexanetrione derivative represented by formula (ii), or a tautomer, solvate or pharmaceutically acceptable salt thereof;
  • the active ingredient of the pharmaceutical composition includes active ingredient A and active ingredient B;
  • the active ingredient A includes a cyclohexanetrione derivative represented by formula (i), or at least one of its tautomers, solvates or pharmaceutically acceptable salts;
  • the active ingredient B includes a cyclohexanetrione derivative shown in formula (ii), or at least one of its tautomers, solvates or pharmaceutically acceptable salts;
  • the active ingredient of the pharmaceutical composition includes the above two cyclohexanetrione derivatives shown in formula (i) and formula (ii), these two derivatives interact and coordinate, which is more conducive to the inhibition of animal pathogenic bacteria , which is conducive to improving the therapeutic effect.
  • the weight ratio of the active ingredient A to the active ingredient B in the pharmaceutical composition is 1:0.01-0.5.
  • the weight ratio of active ingredient A to active ingredient B in the pharmaceutical composition is typically but not limited to, for example, 1:0.01, 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45 and 1:0.5.
  • the ratio relationship is optimized, and the weight ratio of the active ingredient A to the active ingredient B in the pharmaceutical composition is 1:0.025-0.5.
  • the medicament for animals is used to treat bacterial infectious diseases in animals; giving a therapeutic dose of the medicament for animals of the present invention to sick animals can effectively treat bacterial infectious diseases in animals.
  • Bacterial infectious diseases in animals refer to the invasion of pathogenic bacteria into the animal body, the growth and reproduction in the body lead to the destruction of the normal function, metabolism and tissue structure of the body, causing damage to the local tissue and systemic inflammatory response, in which the local tissue specifically refers to the skin of the animal and mucosal surfaces.
  • the mucosal layer is composed of epithelial cells, lining the inner surface of tubular or luminal organs, under which are distributed blood vessels, nerve plexuses and lymph, and the surface is often moistened with mucus.
  • Tubular or luminal organs include, but are not limited to, the gut, mammary glands, uterus, and birth canal (including the endocervical canal, os, and vagina) of animals.
  • therapeutic dose means that, when administered to a diseased animal to treat a disease, that amount of the compound is sufficient to treat the disease and can vary with the compound, the disease and severity, and the condition, age, Changes in body weight and gender.
  • treatment refers to the administration of a therapeutic dose of the medicament for animals of the present invention to improve the disease or condition (i.e. slow down or prevent or alleviate the development of the disease or at least one clinical symptom thereof) to the sick animal; other embodiments Among them, treatment refers to giving a therapeutic dose of the animal medicine of the present invention to alleviate or improve at least one physical parameter, including physical parameters that may not be noticed by the patient; in other embodiments, treatment refers to the treatment of the diseased animal.
  • Animals are administered therapeutic doses of the medicament for animals of the present invention to modulate the disease or condition physically (e.g., stabilizing detectable symptoms) or physiologically (e.g., stabilizing physical parameters), or both; in other embodiments, the treatment refers to Administration of a therapeutic dose of the medicament for animals of the present invention to a diseased animal prevents or delays the onset, occurrence or worsening of a disease or condition.
  • the animal bacterial infectious disease includes one or more of animal intestinal infection, birth canal infection, endometrial infection, mammary gland infection, and skin infection.
  • the animal bacterial infectious disease includes one or more of intestinal dysentery, necrotic enteritis, endometritis, mastitis and pyoderma.
  • the pharmaceutical composition of the present invention is used in the preparation of medicaments for animals, and the medicaments for animals are used to treat intestinal bacterial infections in animals.
  • Bacterial infectious diseases in animal intestines are diseases caused by Gram-positive bacteria and/or pathogenic Gram-negative bacteria infecting the intestines; wherein, bacteria include but not limited to Clostridium perfringens, and/or pathogenic Gram-negative bacteria Escherichia coli, and/or enteric Salmonella; for example, red diarrhea in animals caused by Clostridium perfringens infection or necrotic enteritis in animals, such as necrotic enteritis in chickens and red diarrhea in pigs.
  • the pharmaceutical composition of the present invention is used in the preparation of medicaments for animals, and the medicaments for animals are used to treat bacterial infectious diseases on the endometrial surface of animals.
  • Bacterial infectious diseases of animal endometrium are diseases caused by Gram-positive bacteria infection and/or pathogenic Gram-negative bacteria infection of intestinal tract; wherein, bacteria include but not limited to Enterococcus faecalis, and/or pathogenic bacteria Escherichia coli, and/or Streptococcus, and/or Staphylococcus; for example, endometritis in animals caused by Streptococcus infection or endometritis in animals caused by Staphylococcus infection, such as endometritis in pigs.
  • the pharmaceutical composition of the present invention is used in the preparation of medicaments for animals, and the medicaments for animals are used to treat bacterial infectious diseases of animal mammary glands.
  • Bacterial infectious diseases of animal mammary glands are diseases caused by Gram-positive bacteria infection and/or pathogenic Gram-negative bacteria infection of the intestinal tract, among which bacteria include but not limited to Escherichia coli, environmental streptococcus, agalactiae coagulase, coagulase-negative staphylococcus, or Staphylococcus aureus; eg Streptococcus agalactiae and/or Staphylococcus aureus infection in animals such as mastitis in cows.
  • viviparous animals suffering from bacterial infectious diseases on the surface of the endometrium of animals or bacterial infectious diseases on the mammary glands of animals are viviparous animals.
  • the embryo absorbs nutrients and oxygen in the mother's blood through the placenta and umbilical cord during development, and at the same time sends metabolites into the mother's body.
  • Viviparous animals include but are not limited to pigs, beef cattle, dairy cows, rabbits, sheep, horses, donkeys, cats, dogs, foxes, mink or raccoon dogs.
  • the pharmaceutical composition of the present invention is used in the preparation of medicaments for animals, and the medicaments for animals are used to treat bacterial infectious diseases on animal skin.
  • Bacterial infectious diseases of animal skin are diseases caused by Gram-positive bacteria and/or Gram-negative bacteria infecting the skin; wherein, bacteria include but not limited to Staphylococcus aureus, and the above-mentioned bacterial infections can be secondary to animal skin Consequence of bacterial invasion following injury, eczema, or erythematous skin disease; for example, Staphylococcus aureus infection in animal skin diseases such as pyoderma in dogs.
  • the bacteria include one or more of Clostridium perfringens, Staphylococcus aureus, Streptococcus agalactiae, and Enterococcus faecalis.
  • the animal includes one or more of livestock, poultry, and pets.
  • Animals refer to wild animals and farmed animals that cannot convert inorganic substances into organic substances, but can only use organic substances as food, and perform life activities such as feeding, digestion, absorption, respiration, circulation, excretion, sensation, movement and reproduction.
  • the animals may be poultry, domestic animals or artificially raised pets.
  • livestock includes but not limited to pigs, beef cattle, dairy cows, rabbits, sheep, horses, donkeys, cats, dogs, foxes, mink or raccoon dogs; poultry includes but not limited to chickens, ducks, geese, pigeons or quails; pets include But not limited to cats, dogs, starlings or parrots.
  • the use method of the animal medicine involved in the present invention is described below.
  • the use method of the pharmaceutical composition of the present invention in the treatment of bacterial infectious diseases in animals is to give cyclohexatrione containing a therapeutic dose to the diseased part of the sick animal.
  • the pharmaceutical composition of the present invention can be manufactured according to those routine methods disclosed in the art.
  • a pharmaceutical composition is a specific target dosage form suitable for therapeutic purposes.
  • the cyclohexatrione derivative is mixed with a suitable pharmaceutical diluent, excipient or carrier selected according to the form of administration and conventional pharmaceutical practice, and administered in a topical dosage form via a suitable carrier.
  • the pharmaceutical composition is used for the treatment of bacterial infectious diseases in the intestinal tract of animals, and the administration dosage form includes but not limited to the oral enteric solution type of tablets, pills or capsules, and the breeders or veterinarians will contain the oral dosage form of the pharmaceutical composition of the present invention through gavage administered in oral form to diseased animals.
  • the pharmaceutical composition is used for the treatment of endometrium bacterial infectious diseases in animals, and the administration dosage form includes but not limited to cod liver oil suspension, oil injection, foaming agent or slow-release preparation infusion dosage form, and breeders or veterinarians will contain the present invention
  • the perfusate of the pharmaceutical composition is poured into the uterus.
  • the pharmaceutical composition is used to treat bacterial infectious diseases of the animal's birth canal or urethra
  • the dosage forms include but not limited to suppositories, and breeders or veterinarians insert the suppositories containing the pharmaceutical composition of the present invention into the birth canal or urethra of animals.
  • the pharmaceutical composition is used for the treatment of bacterial infectious diseases on the skin of animals, and the dosage form includes but not limited to emulsion, oil, ointment or gel, and the breeder or veterinarian evenly smears the drug containing the present invention on the infected skin part of the animal A topical dosage form of the composition.
  • the pharmaceutical composition is used in the treatment of bacterial infectious diseases of animal mammary glands.
  • the dosage forms include but not limited to injections of emulsion type, oil suspension type, and water suspension type.
  • the injection containing the pharmaceutical composition of the present invention is injected into the breast.
  • the dosing regimen of the pharmaceutical composition of the present invention will vary with known factors such as the pharmacokinetic profile of the particular agent and its mode and route of administration; the species, age and weight of the affected animal; the nature and nature of the symptoms and extent; type of concurrent treatment; frequency of treatment; route of administration and desired therapeutic effect.
  • a veterinarian can make the determination and prescribe an effective amount of medication to prevent, arrest, lessen or slow the progression of disease symptoms.
  • the daily oral dose of each active pharmaceutical ingredient used is in the range of 0.1-5 mg/kg body weight, preferably 3 mg/kg body weight.
  • the pharmaceutical composition of the present invention may be administered once a day, or may be administered two, three or four times a day.
  • composition of the present invention is prepared into a dosage unit form according to the formulation to maintain the dosage and dosage consistency.
  • Formulations suitable for administration may contain from 1 mg to 100 mg of the cyclohexanetrione derivative per unit dose.
  • the weight of the active ingredient is generally 0.5% to 95% of the total weight of the composition.
  • unit dose refers to a physically discrete unit of drug required for proper treatment of an organism.
  • Example 1 The cyclohexanetrione derivative provided in this example is hexahydrobeta acid (HHBA).
  • Example 2 The cyclohexanetrione derivative provided in this example is the free form of hexahydrolupulone (HHC).
  • Example 3 The cyclohexanetrione derivative provided in this example is hexahydrolupulone sodium salt (HHC-Na).
  • Example 4 The cyclohexanetrione derivative provided in this example is the free form of hexahydrolupulone (HHA).
  • Example 5 The cyclohexanetrione derivative provided in this example is a combination of HHC and HHA in a weight ratio of 1:0.5 (HHC-HHA (1:0.5)).
  • Example 6 The cyclohexanetrione derivative provided in this example is a combination of HHC and HHA in a weight ratio of 1:0.4 (HHC-HHA (1:0.4)).
  • Example 7 The cyclohexanetrione derivative provided in this example is a combination of HHC and HHA in a weight ratio of 1:0.25 (HHC-HHA (1:0.25)).
  • Example 8 The cyclohexanetrione derivative provided in this example is a combination of HHC and HHA in a weight ratio of 1:0.35 (HHC-HHA (1:0.35)).
  • Test Example 1 Study on antibacterial activity of cyclohexanetrione derivatives against animal pathogenic bacteria.
  • Clostridium perfringens type C was isolated from sick pigs diagnosed with endometritis and vaginitis, weaned pigs with swine dysentery, and chickens with necrotic enteritis (derived from weaned pigs with swine red dysentery) , Clostridium perfringens type A (derived from chickens suffering from chicken necrotic enteritis), Enterococcus faecalis (derived from sick pigs suffering from vaginitis), Staphylococcus aureus (derived from sick pigs suffering from endometritis ), Streptococcus agalactiae (derived from pigs suffering from endometritis), and the strains of Clostridium perfringens, Enterococcus faecalis, Streptococcus agalactiae and Staphylococcus aureus were inoculated on ordinary agar plates and without Strains of Strepto
  • Clostridium perfringens Pick several colonies of Clostridium perfringens and inoculate them into the medium for enrichment of Clostridium perfringens (medium formula (g/L): polyvalent peptone 15.0, soybean peptone 7.5, yeast powder 7.5, beef powder 7.5, ferric ammonium citrate 1.0, sodium metabisulfite 0.75, agar 20.0, pH value 7.6 ⁇ 0.1, 25°C), Enterococcus faecalis colonies were inoculated on Enterococcus agar (Enterococcus agar formula (g/L): monthly peptone 10.0, Maltose 20.0, yeast extract powder 10.0, sodium glycerophosphate 10.0, sodium chloride 5.0, lactose 1.0, bromocresol purple 0.015, sodium azide 0.4, TTC 0.1, agar 13.0, pH value 7.2 ⁇ 0.2, 25°C), dairy-free Streptococcus colonies were ino
  • test sample Get sterilized tube and add culture medium 2mL, test embodiment 1 ⁇ 7 (referred to as test sample) to the in vitro minimum inhibitory concentration (MIC) of pathogenic bacteria by test tube double dilution method and microplate reader detection means, the result is as shown in table 1 .
  • MIC in vitro minimum inhibitory concentration
  • mice were placed in an induction box for isoflurane induction anesthesia, a piece of dorsal fur was clipped to expose the skin, and a circular piece of skin was removed with a hand-held punch, leaving a wound with a central cavity on the back.
  • the wound was inoculated and infected with 10 ⁇ L of 2.5 ⁇ 10 7 CFU/mL Staphylococcus aureus suspension, the mice were placed in each recovery box marked with the mouse number, and the time of inoculation and the initial body weight of the mice were recorded. After the mice regained full consciousness, they were returned to their respective cages for 4 hours to monitor for postoperative or anesthesia complications.
  • the wound was treated with the formulation containing the cyclohexanetrione derivative of Example 2, Example 4, Example 5 or Example 8 at a concentration of 20 mg/g and 0.2 g of vehicle formulation
  • Local treatment was carried out, and the infected skin wound was treated again every 12 hours, for a total of 14 treatments, and the continuous monitoring and observation was carried out for seven days. Seven days later, mice were euthanized, and the original infected wound area was dissected and removed, tested for bacterial content by standard microbiology, and the harvested strain was confirmed to be S. aureus.
  • Table 2 The test results are shown in Table 2.
  • test group CFU/g reduce% vehicle 6481746 - HHC 271586 95.81 HHA 566504 91.26 HHC-HHA (1:0.5) 2658 99.95 HHC-HHA (1:0.35) 3396 99.94 HHC-HHA (1:0.25) 3407 99.95
  • the wounds of bacterial infection in mice are treated with the cyclohexatrione derivatives of the present invention, and the number of Staphylococcus aureus in the infected wound area is significantly reduced, which proves that the cyclohexatrione derivatives are effective on the skin of mice.
  • Infections were effectively treated, wherein the combination of HHC and HHA had more effective inhibitory activity against the infectious bacteria than HHA and HHC.
  • Test Example 3 The therapeutic effect of cyclohexanetrione derivatives on Clostridium perfringens infection.
  • the drug administration groups of the cyclohexatrione derivatives of Example 2, Example 4, Example 5 or Example 8 were respectively the 1st to 5th groups, and the test group without adding any antibacterial agent was used as the control group, wherein A part of the control group was orally challenged with Clostridium perfringens, and it was used as the non-administration challenge control group (the 6th group), and another part was not orally challenged with infection, and it was used as the non-administration and non-challenge control group (group 6). Group 7).
  • the control group without oral challenge and without adding antibacterial agents was isolated and housed alone.
  • Table 3 shows the experimental grouping of the protective effect of different cyclohexanone derivatives on the challenge infection of Clostridium perfringens.
  • Group I is the healthy group without drug administration
  • group II is the drug treatment group
  • group III, IV and V are treatment groups.
  • the test chickens in the challenge non-administration group and the challenge treatment group were orally administered with 10 9 CFU cultures of Clostridium perfringens type C resuspended in sterilized PBS for challenge infection twice, and the two challenge infection The interval time was 24 hours, and the broiler necrotic enteritis model was established.
  • broilers in the healthy group were orally administrated with 1 mL of sterilized PBS as a control treatment.
  • the broilers in each challenge treatment group were weighed and then fed with water containing the cyclohexatrione derivatives of 3 mg/kg of Example 2, Example 3 or Example 7 respectively. Suspension, administered once every 12 hours, continuous treatment for 3 days.
  • the challenge group without drug administration was given the same amount of vehicle according to body weight as a control.
  • the healthy group, the drug-challenging group and the drug-challenging treatment group were reared separately, and the healthy group and the drug-challenging group were not challenged, but they were fed with the same amount of vehicle according to their body weight every day as a control treatment.
  • the lesion score is divided into 5 grades from 0 to 4, specifically: a lesion score of 0 indicates a normal and healthy intestine without visible lesions; a lesion score of 1 indicates that the intestinal tract is thin or fragile, and the appearance is gray-white; A score of 2 indicates that the intestinal wall is obviously thinned or friable, with localized necrosis and a small amount of gas in the intestine; a lesion score of 3 indicates that the intestinal wall is significantly thinned or friable, with obvious necrotic lesions, the intestine is full of gas, and Punctate hemorrhage; a lesion score of 4 indicates severe generalized necrosis of the bowel, which is heavily gas-filled with significant hemorrhage. The results are shown in Table 6.
  • the intestinal lesion score of the broiler chickens in the healthy group was mostly 0 points, occasionally 1 point or 2 points; the intestinal lesion score of the broiler chickens in the challenge and non-administration group was mostly 3 to 4 points;
  • the combination of HHC-Na and HHC-HHA is superior to HHC in the treatment of challenged infected chickens. It can be seen that cyclohexatrione derivatives can effectively treat broiler necrosis caused by Clostridium perfringens infection. enteritis.
  • test drug of the test drug group (the first group, the second group, the third group) is successively the HHC of embodiment 2, the HHC-Na of embodiment 3 and the HHC-HHA (1:0.25) of Example 7, the IV group is the control group without administration.
  • the test cows collected milk samples twice before entering the dry period, the first milk sample was collected 1 day before the drug administration, and the second milk sample was collected before the dry milk drug was injected on the day of drug administration, and the interval between the two samples was 24 hours;
  • the first milk sample was collected at the first milking after calving at the end of the dry period, and the second milk sample was collected 24 hours later.
  • the first three handfuls of milk were discarded, and 10-20 mL of milk samples were collected in sterilized test tubes, stored at 4°C and subjected to bacteriological examination within 6 hours.
  • the detection of pathogenic bacteria in milk samples collected before administration and after calving of dairy cows in each test group was counted, and the infection rate of pathogenic bacteria in dairy cows in each test group was calculated and the drug treatment effect was evaluated.
  • the treatment effect is divided into: treatment failure, as long as there is a positive culture result in one sample of a pathogenic bacteria after treatment (the same as the bacteria isolated and cultured in the sample before treatment); The pathogens were not detected in the corresponding udder samples collected after parturition.
  • the cyclohexanetrione derivatives of the present invention have good antibacterial effects on Clostridium perfringens, Enterococcus faecalis, Streptococcus agalactiae and Staphylococcus aureus, and have good antibacterial effects on animal skin damage infection, Intestinal dysentery, necrotic enteritis, endometritis and mastitis have significant therapeutic effects, among which HCC and HHA interact and cooperate, which is more conducive to the inhibition of animal pathogenic bacteria, and has a more significant therapeutic effect.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne le domaine technique des médicaments, en particulier l'utilisation d'un dérivé de cyclohexanetrione dans la préparation d'un médicament pour animaux. Au moins le dérivé de cyclohexanetrione ou un tautomère, un solvate ou un sel de qualité pharmaceutique de celui-ci fourni par la présente invention peut être utilisé pour préparer un médicament pour animaux, le médicament pour animaux étant un médicament destiné à traiter des maladies infectieuses bactériennes chez des animaux. Le dérivé de cyclohexanetrione selon la présente invention présente un effet inhibiteur important sur les bactéries pathogènes chez les animaux, ainsi qu'un effet thérapeutique significatif sur les maladies infectieuses bactériennes chez les animaux.
PCT/CN2022/111827 2021-08-13 2022-08-11 Utilisation d'un dérivé de cyclohexanetrione dans la préparation d'un médicament pour animaux Ceased WO2023280327A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011883A1 (fr) * 1996-09-20 1998-03-26 Regents Of The University Of Minnesota Utilisation d'hexahydrolupulones comme agents antibacteriens
US5827895A (en) * 1996-02-27 1998-10-27 Regents Of The University Of Minnesota Hexahydrolupulones useful as anticancer agents
CN103980104A (zh) * 2014-02-19 2014-08-13 广州英赛特生物技术有限公司 六氢β-酸单酯、内络盐或单酯盐及其做为动物饲料添加剂的应用
CN104710307A (zh) * 2015-02-16 2015-06-17 广州英赛特生物技术有限公司 六氢β-酸双脂肪酸酯及其做作为动物饲料添加剂的应用
CN112500289A (zh) * 2020-11-20 2021-03-16 广州英赛特生物技术有限公司 六氢-β-酸组分化合物的前体化合物、饲用组合物及其应用
CN113476431A (zh) * 2021-08-13 2021-10-08 彭险峰 一种环三酮衍生物在制备动物用药中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2021014309A (es) * 2019-05-23 2022-03-11 Wisorig Tech Pte Limited Composicion para alimentos de animales que contiene los compuestos del componente hexahidro-?-acido y aplicacion de la misma.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827895A (en) * 1996-02-27 1998-10-27 Regents Of The University Of Minnesota Hexahydrolupulones useful as anticancer agents
WO1998011883A1 (fr) * 1996-09-20 1998-03-26 Regents Of The University Of Minnesota Utilisation d'hexahydrolupulones comme agents antibacteriens
CN103980104A (zh) * 2014-02-19 2014-08-13 广州英赛特生物技术有限公司 六氢β-酸单酯、内络盐或单酯盐及其做为动物饲料添加剂的应用
CN104710307A (zh) * 2015-02-16 2015-06-17 广州英赛特生物技术有限公司 六氢β-酸双脂肪酸酯及其做作为动物饲料添加剂的应用
CN112500289A (zh) * 2020-11-20 2021-03-16 广州英赛特生物技术有限公司 六氢-β-酸组分化合物的前体化合物、饲用组合物及其应用
CN113476431A (zh) * 2021-08-13 2021-10-08 彭险峰 一种环三酮衍生物在制备动物用药中的应用

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