Method of treating disease using compound, and use of compound

Abstract

Provided in the present application is a method of preventing or treating diabetic foot infection (DFI) or alleviating a DFI-related disorder. The method comprises administering a topical therapeutic agent to a patient in need thereof, wherein the topical therapeutic agent contains a compound as shown in formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated compound thereof, and the DFI is caused by Gram-positive bacterial infection.

Description

Methods and uses of compounds for treating diseases Technical Field

[0001] The present invention relates to the field of biomedicine, and more particularly to a method for preventing or treating a disease using a compound and its use. Background Art

[0002] Diabetic foot infection (DFI) is a serious complication of diabetes and the leading cause of lower limb amputations in diabetic patients. Of the approximately 150 million people with diabetes worldwide, 15% to 20% may develop foot ulcers or gangrene during their disease course. The amputation rate for diabetic foot disease is 15 times higher than that of non-diabetic patients, and approximately 50% of annual amputations occur in patients with diabetes. The cost of treating DFIs is enormous, and their incidence in China is increasing significantly year by year. Consequently, the medical and social challenges posed by DFIs have begun to attract significant attention in China. Treatment of DFIs is often hampered by local ischemia, and systemic administration of antibiotics can sometimes only achieve low plasma levels of antibiotics at the site of infection. This problem is particularly acute in cases where the infection is caused by drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, currently available treatments for diabetic foot infections typically utilize oral or injectable antibiotics and anti-inflammatory drugs such as cephalosporins, penicillins, and vancomycin. These drugs have drawbacks such as significant toxic side effects, a high risk of developing drug resistance, and severe allergic reactions in some patients. Therefore, improving the treatment of diabetic foot infections, particularly in cases of infection with specific drug-resistant bacteria and / or when patients experience severe ischemia and / or bone tissue damage, is of particular urgency and importance.

[0003] Summary of the Invention

[0004] In order to solve the difficulties in the existing technology for treating diabetic foot infection, the present invention provides a more practical and effective treatment method.

[0005] In one aspect, the present application provides a method for preventing or treating diabetic foot infection (DFI), or alleviating symptoms associated with the DFI, comprising administering a topical therapeutic agent to a patient in need thereof, wherein the topical therapeutic agent comprises a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof, and the DFI is caused by Gram-positive bacterial infection.

[0006] In some embodiments, the Gram-positive bacteria include drug-resistant strains thereof.

[0007] In some embodiments, the topical therapeutic agent is an ointment formulation.

[0008] In some embodiments, the topical therapeutic agent further comprises one or more of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizer, and an antioxidant.

[0009] In some embodiments, the topical therapeutic agent consists of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizer, an antioxidant, and a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

[0010] In some embodiments, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product is about 0.3% to about 0.7% of the total weight of the topical therapeutic agent.

[0011] In some embodiments, the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent.

[0012] In some embodiments, the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent.

[0013] In some embodiments, the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent.

[0014] In some embodiments, the solubilizer is used in an amount of about 0.1% to about 1% of the total mass.

[0015] In some embodiments, the antioxidant is used in an amount of about 0.5% to about 1% by weight of the total weight.

[0016] In some embodiments, the topical therapeutic agent is composed of the following components: based on the total weight percentage being 100%, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof is about 0.3% to about 0.7% of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent, the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent, the amount of the solubilizer is about 0.1% to about 1% of the total weight of the topical therapeutic agent, and the amount of the antioxidant is about 0.5% to about 1% of the total weight of the topical therapeutic agent.

[0017] In some embodiments, the method comprises administering the topical therapeutic agent to the patient in need thereof at a dosing frequency selected from once every 3 days, once every 2 days, once daily, and twice daily.

[0018] In some embodiments, the diabetic foot infection is caused by Staphylococcus aureus infection and / or coagulase-negative Staphylococcus infection.

[0019] In some embodiments, the Staphylococcus aureus comprises a drug-resistant strain thereof, and the coagulase-negative Staphylococcus comprises a drug-resistant strain thereof.

[0020] In some embodiments, the method further comprises administering to the patient in need thereof an effective amount of an additional therapeutic agent.

[0021] On the other hand, the present application provides the use of a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof in the preparation of a topical therapeutic agent, wherein the topical therapeutic agent is used to prevent or treat diabetic foot infection (DFI) or alleviate the DFI-related symptoms, and the DFI is caused by Gram-positive bacterial infection; wherein the topical therapeutic agent comprises a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

[0022] In some embodiments, the Gram-positive bacteria include drug-resistant strains thereof.

[0023] In some embodiments, the topical therapeutic agent is an ointment formulation.

[0024] In some embodiments, the topical therapeutic agent further comprises one or more of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizer, and an antioxidant.

[0025] In some embodiments, the topical therapeutic agent consists of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizer, an antioxidant, and a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

[0026] In some embodiments, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product is about 0.3% to about 0.7% of the total weight of the topical therapeutic agent.

[0027] In some embodiments, the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent.

[0028] In some embodiments, the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent.

[0029] In some embodiments, the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent.

[0030] In some embodiments, the solubilizer is used in an amount of about 0.1% to about 1% of the total mass.

[0031] In some embodiments, the antioxidant is used in an amount of about 0.5% to about 1% by weight of the total weight.

[0032] In some embodiments, the topical therapeutic agent is composed of the following components: based on the total weight percentage being 100%, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof is about 0.3% to about 0.7% of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent, the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent, the amount of the solubilizer is about 0.1% to about 1% of the total weight of the topical therapeutic agent, and the amount of the antioxidant is about 0.5% to about 1% of the total weight of the topical therapeutic agent.

[0033] In some embodiments, the topical therapeutic agent is formulated for administration to a patient in need thereof at a dosing frequency selected from the group consisting of once every 3 days, once every 2 days, once a day, and twice a day.

[0034] In some embodiments, the diabetic foot infection is caused by Staphylococcus aureus infection and / or coagulase-negative Staphylococcus infection.

[0035] In some embodiments, the Staphylococcus aureus comprises a drug-resistant strain thereof, and the coagulase-negative Staphylococcus comprises a drug-resistant strain thereof.

[0036] In some embodiments, the topical therapeutic agent is formulated to be co-administered to the patient in need thereof with an effective amount of another therapeutic agent. DETAILED DESCRIPTION

[0037] The following describes the implementation of the present invention through specific embodiments. People familiar with this technology can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0038] Definition of terms

[0039] In this application, the term "patient in need thereof" generally includes human patients and other mammalian subjects receiving prophylactic or therapeutic treatment, including but not limited to non-human primates, experimental animals such as rabbits, dogs, rats and mice, and other animals. These "patients in need thereof" can be, for example, subjects with a confirmed specific disease, subjects receiving treatment related to a specific disease, subjects with a tendency or risk of developing a specific disease, etc.

[0040] In this application, the term "administer" generally refers to introducing the drug or a composition comprising the drug (e.g., a therapeutic agent of the present application) into the patient's body by any introduction or delivery route. Any method known to those skilled in the art for contacting cells, organs, or tissues with the drug or its composition can be used.

[0041] In this application, the term "therapeutic agent" generally refers to a compound, a mixture of compounds, a composition, a biomacromolecule or an extract made from a biological material that can induce a desired therapeutic effect, prevent a certain disease, or alleviate a related disease when properly administered to a patient.

[0042] In this application, the term "pharmaceutically acceptable salt" generally refers to conventional acid- or base-addition salts that retain the biological efficacy and properties of the parent compound (e.g., the compound shown in formula (I)). By way of example only, acid-addition salts can be formed from suitable non-toxic organic or inorganic acids, sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.; base-addition salts include those derived from inorganic bases such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts and magnesium salts, and salts derived from organic bases such as primary, secondary and tertiary amines. Chemically modifying (drug) compounds into salts is a well-known technique for pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, fluidity and solubility of the compounds. See, e.g., Ansel, H., et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., 1995.

[0043] In this application, the terms "solvate" and "solvate" are used interchangeably and generally refer to an association or complex of one or more solvent molecules with the salt-type compound of the present application. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" generally refers to a complex in which the solvent molecule is water.

[0044] In the present application, the term "prodrug" generally refers to the prodrug substance that can be metabolized to form a substance having the structure of the compound of the present application after being administered to a patient; the term "metabolite" generally refers to the substance obtained by the metabolism of the compound of the present application after being administered to a patient, and the prodrugs and metabolites contained in such derivatives are included in the scope of the invention of the present application.

[0045] In this application, the terms "deuterated compound" and "deuterated compound" are used interchangeably, and generally refer to a new compound obtained by replacing one or more hydrogen atoms in an organic compound with a deuterium atom.

[0046] In this application, the term "ointment preparation" generally refers to a uniform semi-solid topical preparation made by mixing a drug with an oily or water-soluble matrix. Due to the different dispersion states of the drug in the matrix, it can be divided into solution-type ointments and suspension-type ointments. Solvent-type ointments are ointment formulations made by dissolving or co-dissolving the drug in the matrix or matrix components, while suspension-type ointments are ointment formulations made by uniformly dispersing the drug powder in the matrix. The ointment preparations provided in this application are generally used for external use and local treatment. In certain embodiments, the drug in the ointment preparation (e.g., the compound of formula (I) described in this application) can exert a systemic pharmacological or therapeutic effect after transdermal absorption. In certain embodiments, the matrix of the ointment formulation serves as an excipient and drug carrier, which can have a significant impact on the quality of the ointment and the release and absorption of the drug. The matrices of ointment formulations commonly used in the art can be divided into oily matrices, emulsion matrices, and water-soluble matrices. The ointment formulation required for the treatment method of this application can be obtained using preparation methods and processes suitable in the art.

[0047] In this application, the term "selected from" generally refers to the selected objects and all combinations thereof. For example, "selected from (:) A, B and C" means all combinations of A, B and C, for example, A, B, C, A+B, A+C, B+C or A+B+C.

[0048] In this application, the terms "effective amount" or "effective dose" are used interchangeably and generally refer to an amount sufficient to achieve or at least partially achieve the desired therapeutic effect. When used in a patient in need, it generally refers to an amount sufficient to cure a patient already suffering from a disease or at least partially prevent the disease and its complications. The effective amount for this use will depend on the severity of the patient's infection and the overall state of the patient's own immune system.

[0049] In this application, the term "co-administration" generally refers to the administration of a therapeutic agent described herein with another therapeutic agent or drug as a single formulation or as multiple independent formulations. Co-administration can be simultaneous or sequential in any order, for example, preferably for a period of time while two (or all) active pharmaceutical ingredients simultaneously exert their biological activities. The therapeutic agent described herein and the other therapeutic agent are not necessarily administered by the same route of administration.

[0050] In this application, the term "about" or "approximately" is generally within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "approximately" can mean within 1 or more than 1 standard deviation according to the practice in the art. Alternatively, "about" or "approximately" can mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can include any amount between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). In addition, particularly with respect to biological systems or processes, the term can mean a value of up to one order of magnitude or a value of up to 5 times. When a specific value or composition is provided in this specification and the appended claims, unless otherwise indicated, the meaning of "about" or "approximately" should be assumed to be within an acceptable error range for that specific value or composition.

[0051] Detailed Description of the Invention

[0052] In one aspect, the present application provides a method for preventing or treating diabetic foot infection (DFI), or alleviating a condition associated with the DFI, comprising administering a topical therapeutic agent to a patient in need thereof, the topical therapeutic agent comprising a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated form thereof, wherein the DFI is caused by Gram-positive bacterial infection. In some embodiments, the Gram-positive bacteria may include drug-resistant strains thereof.

[0053] In some embodiments, the diabetic foot infection is caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcus infection. For example, the Staphylococcus aureus may also include its resistant strains, and the coagulase-negative staphylococcus may also include its resistant strains. Specifically, the coagulase-negative staphylococcus may be selected from Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus xylinus, Staphylococcus haemolyticus, Staphylococcus capitis, Staphylococcus warneri, Staphylococcus mimicus, Staphylococcus xylosus and Staphylococcus apes. In the present application, the resistant strain may be rifamycin (e.g., rifampicin) single-drug resistant, quinolone-resistant or quinolizinone-resistant or rifamycin- and quinolizinone-resistant. For example, the resistant strains may also be resistant to other antibiotics, including resistance to macrolides such as clarithromycin, azithromycin, and roxithromycin; resistance to nitroimidazoles such as metronidazole, ornidazole, premanide, and delamanide; resistance to aminoglycosides such as streptomycin and amikacin; resistance to β-lactams such as methicillin, ampicillin, and amoxicillin; resistance to tetracyclines such as tetracycline, tigecycline, and minocycline; resistance to oxazolidinones such as linezolid and tedizolid; resistance to nitrofurans such as furazolidone; resistance to polypeptides such as vancomycin and polymyxins; resistance to diarylquinolines such as bedaquiline and clofazimine, etc.

[0054] In some embodiments, the topical therapeutic agent may be an ointment formulation.

[0055] In some embodiments, the topical therapeutic agent further comprises one or more of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizing agent, and an antioxidant. For example, the topical therapeutic agent is composed of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizing agent, an antioxidant, and a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated compound thereof. Preferably, the solubilizing agent described herein may include triethanolamine. Preferably, the antioxidant described herein may include vitamin C, vitamin E, or a combination thereof.

[0056] In some embodiments, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance is about 0.3% to about 0.7% of the total weight of the topical therapeutic agent. For example, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance is about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65% or about 0.70% of the total weight of the topical therapeutic agent.

[0057] In some embodiments, the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent. For example, the amount of polyethylene glycol 400 is about 55%, about 56%, about 57%, about 58%, about 59% or about 60% of the total weight of the topical therapeutic agent.

[0058] In some embodiments, the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent. For example, the amount of polyethylene glycol 3350 is about 28%, about 29%, about 30%, about 31%, about 32%, or about 33% of the total weight of the topical therapeutic agent.

[0059] In some embodiments, the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent. For example, the amount of propylene glycol is about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, or about 12.0% of the total weight of the topical therapeutic agent.

[0060] In some embodiments, the solubilizing agent is used in an amount of about 0.1% to about 1% of the total mass. For example, the solubilizing agent is used in an amount of about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95% or about 1.00% of the total mass.

[0061] In some embodiments, the antioxidant is used in an amount of about 0.5% to about 1% of the total mass. For example, the antioxidant is used in an amount of about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95% or about 1.00% of the total mass.

[0062] Preferably, in some embodiments, the topical therapeutic agent is composed of the following components: based on the total weight percentage being 100%, the amount of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof accounts for about 0.3% to about 0.7% (e.g., about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.75%, about 0.80%, about 0.90%, about 10.10%, about 10.20%, about 10.30%, about 10.40%, about 10.50%, about 10.60%, about 10.70%, about 10.80%, about 10.90%, about 10.10%, about 10. 65% or about 0.70%), the amount of polyethylene glycol 400 is about 55% to about 60% (e.g., about 55%, about 56%, about 57%, about 58%, about 59% or about 60%) of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 3350 is about 28% to about 33% (e.g., about 28%, about 29%, about 30%, about 31%, about 32% or about 33%) of the total weight of the topical therapeutic agent, the amount of propylene glycol is about 8% to about 10% of the total weight of the topical therapeutic agent, The solubilizing agent is used in an amount of about 0.1% to about 1% (e.g., about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, about 10.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about .60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95% or about 1.00%), and the amount of the antioxidant is about 0.5% to about 1% (e.g., about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95% or about 1.00%) of the total weight of the topical therapeutic agent.

[0063] In some embodiments, the method comprises administering the topical therapeutic agent to the patient in need thereof at a dosing frequency selected from once every 3 days, once every 2 days, once daily, and twice daily.

[0064] In some embodiments, the method further comprises administering an effective amount of other therapeutic agents to the patient in need. For example, the method further comprises administering an effective amount of other therapeutic agents to the patient by injection (e.g., intravenous injection, intramuscular injection and / or subcutaneous injection), oral administration, intracavitary administration, enteral administration and / or transdermal absorption. For example, the other therapeutic agents may be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormones, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeation agents and muscle relaxants, etc.

[0065] In another aspect, the present application provides the use of a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated product thereof in the preparation of a topical therapeutic agent for preventing or treating diabetic foot infection (DFI) or alleviating DFI-related conditions, wherein the DFI is caused by Gram-positive bacteria; wherein the topical therapeutic agent comprises a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated product thereof. In some embodiments, the Gram-positive bacteria include drug-resistant strains thereof.

[0066] In some embodiments, the diabetic foot infection is caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcus infection. For example, the Staphylococcus aureus may also include its resistant strains, and the coagulase-negative staphylococcus may also include its resistant strains. Specifically, the coagulase-negative staphylococcus may be selected from Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus xylinus, Staphylococcus haemolyticus, Staphylococcus capitis, Staphylococcus warneri, Staphylococcus mimicus, Staphylococcus xylosus and Staphylococcus apes. In the present application, the resistant strain may be rifamycin (e.g., rifampicin) single-drug resistant, quinolone-resistant or quinolizinone-resistant or rifamycin- and quinolizinone-resistant. For example, the resistant strains may also be resistant to other antibiotics, including resistance to macrolides such as clarithromycin, azithromycin, and roxithromycin; resistance to nitroimidazoles such as metronidazole, ornidazole, premanide, and delamanide; resistance to aminoglycosides such as streptomycin and amikacin; resistance to β-lactams such as methicillin, ampicillin, and amoxicillin; resistance to tetracyclines such as tetracycline, tigecycline, and minocycline; resistance to oxazolidinones such as linezolid and tedizolid; resistance to nitrofurans such as furazolidone; resistance to polypeptides such as vancomycin and polymyxins; resistance to diarylquinolines such as bedaquiline and clofazimine, etc.

[0067] In some embodiments, the topical therapeutic agent may be an ointment formulation.

[0068] In some embodiments, the topical therapeutic agent further comprises one or more of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizing agent, and an antioxidant. For example, the topical therapeutic agent is composed of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizing agent, an antioxidant, and a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated compound thereof. Preferably, the solubilizing agent described herein may include triethanolamine. Preferably, the antioxidant described herein may include vitamin C, vitamin E, or a combination thereof.

[0069] In some embodiments, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance is about 0.3% to about 0.7% of the total weight of the topical therapeutic agent. For example, the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance is about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65% or about 0.70% of the total weight of the topical therapeutic agent.

[0070] In some embodiments, the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent. For example, the amount of polyethylene glycol 400 is about 55%, about 56%, about 57%, about 58%, about 59% or about 60% of the total weight of the topical therapeutic agent.

[0071] In some embodiments, the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent. For example, the amount of polyethylene glycol 3350 is about 28%, about 29%, about 30%, about 31%, about 32%, or about 33% of the total weight of the topical therapeutic agent.

[0072] In some embodiments, the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent. For example, the amount of propylene glycol is about 8.0%, about 8.5%, about 9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, or about 12.0% of the total weight of the topical therapeutic agent.

[0073] In some embodiments, the solubilizing agent is used in an amount of about 0.1% to about 1% of the total mass. For example, the solubilizing agent is used in an amount of about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95% or about 1.00% of the total mass.

[0074] In some embodiments, the antioxidant is used in an amount of about 0.5% to about 1% of the total mass. For example, the antioxidant is used in an amount of about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95% or about 1.00% of the total mass.

[0075] Preferably, in some embodiments, the topical therapeutic agent is composed of the following components: based on the total weight percentage being 100%, the amount of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof accounts for about 0.3% to about 0.7% (e.g., about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.75%, about 0.80%, about 0.90%, about 10.10%, about 10.20%, about 10.30%, about 10.40%, about 10.50%, about 10.60%, about 10.70%, about 10.80%, about 10.90%, about 10.10%, about 10. 65% or about 0.70%), the amount of polyethylene glycol 400 is about 55% to about 60% (e.g., about 55%, about 56%, about 57%, about 58%, about 59% or about 60%) of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 3350 is about 28% to about 33% (e.g., about 28%, about 29%, about 30%, about 31%, about 32% or about 33%) of the total weight of the topical therapeutic agent, the amount of propylene glycol is about 8% to about 10% of the total weight of the topical therapeutic agent, The solubilizing agent is used in an amount of about 0.1% to about 1% (e.g., about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, about 10.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about 15.10%, about .60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95% or about 1.00%), and the amount of the antioxidant is about 0.5% to about 1% (e.g., about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95% or about 1.00%) of the total weight of the topical therapeutic agent.

[0076] In some embodiments, the topical therapeutic agent is formulated for administration to a patient in need thereof at a dosing frequency selected from the group consisting of once every 3 days, once every 2 days, once a day, and twice a day.

[0077] In some embodiments, the topical therapeutic agent is formulated to be suitable for co-administration with an effective amount of other therapeutic agents to the patient in need. For example, the topical therapeutic agent can be formulated to be suitable for co-administration with an effective amount of other therapeutic agents to the patient in need, wherein the other therapeutic agents can be administered by injection (e.g., intravenous injection, intramuscular injection and / or subcutaneous injection), oral administration, intracavitary administration, enteral administration and / or transdermal absorption to the patient. For example, the other therapeutic agents can be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormones, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeation agents and muscle relaxants, etc.

[0078] Without intending to be bound by any theory, the following embodiments are merely intended to illustrate the methods and uses of the present application and are not intended to limit the scope of the present invention.

[0079] Example

[0080] Example 1

[0081] Determination of the antibacterial activity of the compound of formula (I) against biofilms of clinically isolated strains of diabetic foot infection (DFI)

[0082] 1. Experimental Methods

[0083] Preparation of Test Strains: In this example, foot specimens were collected from 49 patients with type II diabetes. From these specimens, strains were isolated by homogenization, plating, and culturing at 37°C. After removing fungi, strains with poor growth, or strains that could not be isolated and purified, a total of 69 clinical strains were obtained, including 55 Gram-positive bacteria and 14 Gram-negative bacteria. Among the Gram-positive bacteria, 43 were Staphylococci, 18 were Staphylococcus aureus, 8 were Staphylococcus epidermidis, and 5 were Staphylococcus lugdunensis. An ATCC standard strain was also used as a standard and quality control strain.

[0084] Biofilm Preparation: In a sterile environment, use an inoculating loop to pick a single, identified and revived colony and prepare a suspension with a 0.5 McFarland turbidity unit (MTU) as the initial inoculum. Dilute this suspension 1:200 by adding 50 μL of the initial inoculum to 10 mL of CAMHB medium. Pipette 150 μL of the suspension onto a CBD plate. Incubate the plate in a 35 ± 2°C incubator for 16–20 hours.

[0085] Antibacterial activity assay: The minimum inhibitory concentration (MIC) and minimum biofilm clearing concentration (MBBC) of the compound of formula (I) and a control drug (see 2 for details) against 69 clinical strains of diabetic foot infection isolated from the clinic were evaluated using the standard broth dilution method and in vitro biofilm culture and drug sensitivity methods reported in the literature.

[0086] 2. Results Analysis

[0087] Table 1-1 Summary of MIC and MBBC (μg / mL) results of compounds of formula (I) and control drugs against DFI clinical isolates (Gram-positive bacteria vs. Gram-negative bacteria)

[0088] The results in Table 1-1 show that the compound of formula (I) has significantly better antibacterial activity against Gram-positive bacterial isolates than against Gram-negative bacteria. (1) Its MIC 50 and MIC 90 The MICs were ≤0.015 μg / mL and 0.25 μg / mL, respectively, and were significantly better than the first-line clinical drug linezolid (MIC 50 and MIC 90 2 μg / mL and 4 μg / mL, respectively) and vancomycin (MIC 50 and MIC 90 (2) The MBBC results of the compound of formula (I) also showed that it had better bactericidal activity against Gram-positive bacterial biofilms in vitro than Gram-negative bacteria. 50 and MBBC 90 The results were 0.125 μg / mL and 16 μg / mL respectively, which were significantly better than the first-line clinical drug linezolid (MBBC 50 and MBBC 90 >128 μg / mL) and vancomycin (MBBC 50 and MBBC 90 All >128 μg / mL).

[0089] Table 1-2 Summary of MIC (μg / mL) of the compound of formula (I) and the control drug against DFI clinical isolates (representative Gram-positive bacteria)

[0090] Table 1-3 Summary of MBBC (μg / mL) results of compounds of formula (I) and control drugs against biofilms of DFI clinical isolates (representative Gram-positive bacteria)

[0091] The results in Table 1-2 show that the compound of formula (I) has good antibacterial activity against Staphylococcus (including Staphylococcus aureus and Staphylococcus epidermidis) isolates, and their MIC ranges are ≤0.015-0.25 μg / mL, ≤0.015-0.03 μg / mL and ≤0.015-0.03 μg / mL, respectively. The MIC of the compound of formula (I) against Staphylococcus and Staphylococcus aureus is ≤0.015-0.25 μg / mL, ≤0.015-0.03 μg / mL and ≤0.015-0.03 μg / mL, respectively. 50All were ≤0.015μg / mL, which was significantly better than linezolid (MIC 50 both 2 μg / mL) and vancomycin (MIC 50 2 μg / mL); their MIC 90 All were ≤0.015μg / mL, which was significantly better than linezolid (MIC 90 both 4 μg / mL) and vancomycin (MIC 90 Both were 2 μg / mL).

[0092] The results in Tables 1-3 show that the compound of formula (I) has good bactericidal activity against in vitro biofilms of Staphylococci (including Staphylococcus aureus and Staphylococcus epidermidis), and their MBBC ranges are ≤0.015-1 μg / mL, 0.03-0.5 μg / mL and ≤0.015-0.06 μg / mL, respectively. The MBBC of the compound of formula (I) against Staphylococci and Staphylococcus aureus is ≤0.015-1 μg / mL, 0.03-0.5 μg / mL and ≤0.015-0.06 μg / mL. 50 0.06μg / mL and 0.25μg / mL respectively, which were significantly better than linezolid (MBBC 50 Both >128 μg / mL) and vancomycin (MBBC 50 All were >128μg / mL); their MBBC 90 Both were 0.5 μg / mL, which was significantly better than linezolid (MBBC 90 Both >128 μg / mL) and vancomycin (MBBC 90 All were >128 μg / mL).

[0093] The above results generally indicate that the compound of formula (I) has excellent antibacterial and bactericidal activity against Gram-positive bacteria and staphylococcal isolates (including Staphylococcus aureus and Staphylococcus epidermidis) among Gram-positive bacteria and in vitro biofilms, and the antibacterial and bactericidal activities are significantly better than those of the clinical first-line drugs linezolid and vancomycin, and it has potential clinical advantages in the treatment of diabetic foot infections.

[0094] Example 2

[0095] Pharmacodynamic evaluation of the therapeutic method of this application in a mouse Staphylococcus aureus skin infection model

[0096] 1. Experimental Methods

[0097] In this example, S. aureus NRS 384 was used to construct a stable mouse skin infection model to evaluate the antibacterial activity of the ointment containing the compound of formula (I) described in this application on the skin surface. A total of 6 groups were set up in this example, namely: blank control group (with 4 hours after infection as the experimental endpoint), solvent group, Bactroban ointment group, and ointment groups containing low, medium, and high doses of the compound of formula (I). Each of the above groups had 8 animals, and the specific experimental settings were as follows:

[0098] 2. Result analysis

[0099] At 72 hours after infection, mouse skin samples were taken from animals in each treatment group under aseptic operation conditions and placed in a 15 mL centrifuge tube containing 5 mL of sterile injectable saline. A homogenizer was used for homogenization for about 1 minute, and 200 μL of the homogenate was taken and diluted 10 0 ~10 -5 times with sterile injectable saline. 10 μL was taken from each dilution gradient and spotted on a plate, and then placed in an incubator at 35±2 °C for overnight culture. The next day, CFU counting was performed.

[0100] Table 2 Results of counting the bacterial load on mouse skin Note: *** Compared with the model group, p < 0.001, with extremely significant difference; * compared with the model group, 0.01 < p < 0.05, with significant difference; one-way ANOVA analysis method was used.

[0101] The results of this efficacy experiment showed that compared with the skin bacterial load of 9.154±0.273 log in the solvent group, the skin bacterial load of mice treated with Bactroban ointment (2% mupirocin) decreased by 2.119 log values, indicating its good bactericidal effect; for mice treated with the ointment containing 0.5%, 0.05%, and 0.005% of the compound of formula (I), their skin bacterial loads decreased by 4.718 log values, 3.100 log values, and 1.063 log values respectively, indicating that the ointments in the high-dose group (0.5%) and the medium-dose group (0.05%) showed good bactericidal effects in this skin infection model, with extremely significant differences compared with the animals in the solvent group, and were superior to the Bactroban ointment treatment group, further proving its potential clinical advantages for the treatment of diabetic foot infections.

Claims

1. A method for preventing or treating diabetic foot infection (DFI), or alleviating a condition associated with the DFI, the method comprising administering a topical therapeutic agent to a patient in need thereof, the topical therapeutic agent comprising a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof, and the DFI is caused by infection with Gram-positive bacteria, 2. The method according to claim 1, wherein the Gram-positive bacteria comprise drug-resistant strains.

3. The method according to any one of claims 1-2, wherein the external therapeutic agent is an ointment preparation.

4. The method according to any one of claims 1 to 3, wherein the topical therapeutic agent further comprises one or more of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizer and an antioxidant.

5. The method according to any one of claims 1 to 4, wherein the topical therapeutic agent is composed of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizer, an antioxidant, and a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

6. The method according to any one of claims 1 to 5, wherein the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof is about 0.3% to about 0.7% of the total mass of the topical therapeutic agent.

7. The method according to any one of claims 1 to 6, wherein the amount of polyethylene glycol 400 used is about 55% to about 60% of the total weight of the topical therapeutic agent.

8. The method according to any one of claims 1 to 7, wherein the amount of polyethylene glycol 3350 used is about 28% to about 33% of the total weight of the topical therapeutic agent.

9. The method according to any one of claims 1 to 8, wherein the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent.

10. The method according to any one of claims 1 to 9, wherein the solubilizing agent is used in an amount of about 0.1% to about 1% of the total mass.

11. The method according to any one of claims 1 to 10, wherein the antioxidant is used in an amount of about 0.5% to about 1% of the total weight.

12. The method according to any one of claims 1 to 11, wherein the topical therapeutic agent is composed of the following components: Taking the total weight percentage as 100%, the amount of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product is about 0.3% to about 0.7% of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent, the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent, the amount of the solubilizer is about 0.1% to about 1% of the total weight of the topical therapeutic agent, and the amount of the antioxidant is about 0.5% to about 1% of the total weight of the topical therapeutic agent.

13. The method according to any one of claims 1-12, comprising administering the topical therapeutic agent to the patient in need thereof at a dosing frequency selected from: once every 3 days, once every 2 days, once a day, and twice a day.

14. The method according to any one of claims 1 to 13, wherein the diabetic foot infection is caused by Staphylococcus aureus infection and / or coagulase-negative Staphylococcus infection. 15 . The method according to claim 14 , wherein the Staphylococcus aureus comprises drug-resistant strains thereof, and the coagulase-negative Staphylococcus comprises drug-resistant strains thereof.

16. The method of any one of claims 1-15, further comprising administering to the patient in need thereof an effective amount of an additional therapeutic agent.

17. Use of a compound of formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof in the preparation of an external therapeutic agent for preventing or treating diabetic foot infection (DFI) or alleviating symptoms associated with the DFI, wherein the DFI is caused by Gram-positive bacterial infection; wherein: The topical therapeutic agent comprises the compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

18. The use according to claim 17, wherein the Gram-positive bacteria comprises drug-resistant strains thereof.

19. The use according to any one of claims 17-18, wherein the external therapeutic agent is an ointment preparation.

20. The use according to any one of claims 17 to 19, wherein the topical therapeutic agent further comprises one or more of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizer and an antioxidant.

21. The use according to any one of claims 17-20, wherein the topical therapeutic agent is composed of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, a solubilizer, an antioxidant, and a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

22. The use according to any one of claims 17 to 21, wherein the amount of the compound of formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product is about 0.3% to about 0.7% of the total mass of the topical therapeutic agent.

23. The use according to any one of claims 17 to 22, wherein the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent.

24. The use according to any one of claims 17 to 23, wherein the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent.

25. The use according to any one of claims 17 to 24, wherein the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent.

26. The use according to any one of claims 17 to 25, wherein the solubilizer is used in an amount of about 0.1% to about 1% of the total mass.

27. The use according to any one of claims 17 to 26, wherein the antioxidant is used in an amount of about 0.5% to about 1% of the total mass.

28. The use according to any one of claims 17 to 27, wherein the topical therapeutic agent is composed of the following components: Taking the total weight percentage as 100%, the amount of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product is about 0.3% to about 0.7% of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 400 is about 55% to about 60% of the total weight of the topical therapeutic agent, the amount of polyethylene glycol 3350 is about 28% to about 33% of the total weight of the topical therapeutic agent, the amount of propylene glycol is about 8% to about 12% of the total weight of the topical therapeutic agent, the amount of the solubilizer is about 0.1% to about 1% of the total weight of the topical therapeutic agent, and the amount of the antioxidant is about 0.5% to about 1% of the total weight of the topical therapeutic agent.

29. The use according to any one of claims 17-28, wherein the topical therapeutic agent is formulated to be suitable for administration to a patient in need thereof at a dosing frequency selected from the following: once every 3 days, once every 2 days, once a day, and twice a day.

30. The use according to any one of claims 17 to 29, wherein the diabetic foot infection is caused by Staphylococcus aureus infection and / or coagulase-negative Staphylococcus infection.

31. The use according to claim 30, wherein the Staphylococcus aureus comprises drug-resistant strains thereof, and the coagulase-negative Staphylococcus comprises drug-resistant strains thereof.

32. The use according to any one of claims 17-31, wherein the topical therapeutic agent is formulated to be co-administered with an effective amount of another therapeutic agent to the patient in need thereof.

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