Methods for treating diseases with compounds and their use

Abstract

This application provides a method for preventing or treating diabetic foot infection (DFI), or for alleviating DFI-related symptoms. The method comprises administering a topical therapeutic agent comprising a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof to a patient in need, wherein DFI is caused by a Gram-positive bacterial infection. TIFF2026521250000009.tif75170

Description

[Technical Field]

[0001] This application relates to the biomedical field, specifically to methods for preventing or treating diseases with compounds and the use thereof. [Background technology]

[0002] Diabetic foot infections (DFI) are one of the most serious complications in people with diabetes and are a leading cause of lower limb amputation in diabetic patients. Of the approximately 150 million people with diabetes worldwide, 15% to 20% may develop foot ulcers or gangrene during the course of the disease. The amputation rate due to diabetic foot infections is 15 times higher than in non-diabetic patients, and approximately 50% of annual amputations are in people with diabetes. Because diabetic foot ulcers are expensive to treat and their incidence is increasing significantly year by year in China, the medical and social problems caused by diabetic foot infections are beginning to attract the attention of many scholars in China. Treatment of diabetic foot infections is often hindered by local ischemia, and systemic administration of antibiotics often results in low plasma concentrations of antibiotics at the site of infection. This problem is particularly serious in cases of infections caused by drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, currently known treatments for diabetic foot infections include oral or injectable antibacterial agents (including antibiotics) such as cephalosporins, penicillins, and vancomycins, as well as anti-inflammatory drugs. However, these have drawbacks such as high toxicity and side effects, a high likelihood of drug resistance, and severe allergic reactions in some patients. Therefore, improving the treatment of diabetic foot infections is extremely urgent and important, especially when infection with certain drug-resistant bacteria occurs, and / or when the patient experiences severe local ischemia, and / or when bone tissue is affected. [Overview of the project]

[0003] The present invention provides a more practical and effective treatment method to overcome the shortcomings of prior art for treating diabetic foot infections.

[0004] In one embodiment, the present invention provides a method for preventing or treating diabetic foot infection (DFI) or alleviating DFI-related symptoms. The method comprises administering a topical therapeutic agent comprising a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof to a patient in need, wherein DFI is caused by a Gram-positive bacterial infection. TIFF2026521250000002.tif92170

[0005] In some embodiments, Gram-positive bacteria include drug-resistant strains.

[0006] In some embodiments, the topical treatment agent is an ointment.

[0007] 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.

[0008] In some embodiments, the topical therapeutic agent comprises 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 thereof.

[0009] In some embodiments, the amount used of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride is about 0.3% to about 0.7% of the total mass of the topical treatment.

[0010] In some embodiments, the amount of polyethylene glycol 400 used is approximately 55% to 60% of the total mass of the topical treatment.

[0011] In some embodiments, the amount of polyethylene glycol 3350 used is approximately 28% to 33% of the total mass of the topical treatment.

[0012] In some embodiments, the amount of propylene glycol used is about 8% to about 12% of the total mass of the topical treatment.

[0013] In some embodiments, the amount of solubilizer used is approximately 0.1% to 1% of the total mass.

[0014] In some embodiments, the amount of antioxidant used is approximately 0.5% to 1% of the total mass.

[0015] In some embodiments, the topical treatment consists of the following components: the amount of compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated is about 0.3% to about 0.7% of the total mass of the topical treatment, based on a total of 100% by mass; the amount of polyethylene glycol 400 is about 55% to about 60% of the total mass of the topical treatment; the amount of polyethylene glycol 3350 is about 28% to about 33% of the total mass of the topical treatment; the amount of propylene glycol is about 8% to about 12% of the total mass of the topical treatment; the amount of solubilizer is about 0.1% to about 1% of the total mass of the topical treatment; and the amount of antioxidant is about 0.5% to about 1% of the total mass of the topical treatment.

[0016] In some embodiments, this method involves administering a topical treatment to a patient in need at a frequency of administration selected from once every three days, once every two days, once a day, and twice a day.

[0017] In some embodiments, diabetic foot infections are caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcal infection.

[0018] In some embodiments, Staphylococcus aureus includes drug-resistant strains, and coagulase-negative staphylococci include drug-resistant strains.

[0019] In some embodiments, it further comprises administering to a patient in need an effective amount of another therapeutic agent.

[0020] According to another aspect, the present application provides the use of a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride thereof in the manufacture of a topical therapeutic agent. The topical therapeutic agent is used to prevent or treat diabetic foot infection (DFI) or relieve DFI-related symptoms, and DFI is caused by a Gram-positive bacterial infection. Here, the topical therapeutic agent comprises a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride thereof.

[0021] In some embodiments, the Gram-positive bacteria include drug-resistant strains.

[0022] In some embodiments, the topical therapeutic agent is an ointment.

[0023] In some embodiments, the topical therapeutic agent further comprises one or more of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, solubilizing agent, and antioxidant.

[0024] In some embodiments, the topical therapeutic agent consists of polyethylene glycol 400, polyethylene glycol 3350, propylene glycol, solubilizing agent, antioxidant, and a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride thereof.

[0025] In some embodiments, the amount of the compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuteride thereof used is from about 0.3% to about 0.7% of the total mass of the topical therapeutic agent.

[0026] In some embodiments, the amount of polyethylene glycol 400 used is approximately 55% to 60% of the total mass of the topical treatment.

[0027] In some embodiments, the amount of polyethylene glycol 3350 used is approximately 28% to 33% of the total mass of the topical treatment.

[0028] In some embodiments, the amount of propylene glycol used is about 8% to about 12% of the total mass of the topical treatment.

[0029] In some embodiments, the amount of solubilizer used is approximately 0.1% to 1% of the total mass.

[0030] In some embodiments, the amount of antioxidant used is approximately 0.5% to 1% of the total mass.

[0031] In some embodiments, the topical treatment consists of the following components: the amount of compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated is about 0.3% to about 0.7% of the total mass of the topical treatment, based on a total of 100% by mass; the amount of polyethylene glycol 400 is about 55% to about 60% of the total mass of the topical treatment; the amount of polyethylene glycol 3350 is about 28% to about 33% of the total mass of the topical treatment; the amount of propylene glycol is about 8% to about 12% of the total mass of the topical treatment; the amount of solubilizer is about 0.1% to about 1% of the total mass of the topical treatment; and the amount of antioxidant is about 0.5% to about 1% of the total mass of the topical treatment.

[0032] In some embodiments, the topical treatment is formulated to be administered to patients in need at a frequency selected from once every three days, once every two days, once a day, and twice a day.

[0033] In some embodiments, diabetic foot infections are caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcal infection.

[0034] In some embodiments, Staphylococcus aureus includes drug-resistant strains, and coagulase-negative staphylococci include drug-resistant strains.

[0035] In some embodiments, the topical treatment is formulated to be administered in combination with other treatments in effective amounts to patients who require it. [Modes for carrying out the invention]

[0036] Embodiments of the present invention will be described below with reference to specific examples. Those skilled in the art will readily understand other advantages and effects of the present invention from the information disclosed herein.

[0037] Definition of Terms In this application, the term “patients in need” may typically include 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” may, for example, be subjects with a confirmed specific disease, subjects receiving treatment related to a specific disease, or subjects with a tendency or risk of developing a specific disease.

[0038] In this application, the term “administration” typically refers to introducing a drug or a composition containing a drug (e.g., the therapeutic agent of this application) into a patient’s body via any introduction or delivery route. Any method known to those skilled in the art may be employed to bring cells, organs, or tissues into contact with the drug or its composition.

[0039] In this application, the term "therapeutic agent" usually refers to a compound, mixture of compounds, composition, biopolymer, or extract made from a biomaterial that, when administered appropriately to a patient, can induce a desired therapeutic effect, prevent the onset of a disease, or alleviate a related disease.

[0040] In this application, the term “pharmaceutically acceptable salt” usually refers to conventional acid addition salts or base addition salts that retain the biological efficacy and properties of the parent compound (e.g., the compound represented by formula (I)). Examples of 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, and trifluoroacetic acid. 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 those derived from organic bases such as primary amine salts, secondary amine salts, and tertiary amine salts. Chemical modification of (pharmaceutical) compounds into salts is a well-known technique among medicinal chemists to improve the physical and chemical stability, hygroscopicity, fluidity, and solubility of compounds. For example, see Ansel, H., et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., 1995.

[0041] In this application, the terms "solvated compound" and "solvate" are interchangeable and generally refer to an association or complex of one or more solvent molecules with the salt-type compound of this 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.

[0042] In this application, the term "prodrug" usually refers to a substance that, when administered to a patient, can be metabolized to form a compound having the structure of the compound of this application. The term "metabolite" usually refers to a substance obtained by metabolism when the compound of this application is administered to a patient. Prodrugs and metabolites contained in these derivatives are included within the scope of the present invention.

[0043] In this application, the terms "deuteride" and "deuterated compound" are interchangeable and generally refer to new compounds in which one or more hydrogen atoms in an organic compound are replaced by deuterium atoms.

[0044] In this application, the term "ointment" generally refers to a homogeneous, semi-solid topical preparation obtained by mixing a drug with an oily or water-soluble base. Depending on the dispersion state of the drug in the base, ointments are classified into solution-type ointments and suspension-type ointments. Solution-type ointments are ointments produced by dissolving or co-dissolving the drug in the base or base components, while suspension-type ointments are ointments produced by uniformly dispersing fine powder of the drug in the base. The ointments according to this application are generally used for topical and local treatment, but in some embodiments, the drug in the ointment (for example, the compound represented by formula (I) described in this application) can exert systemic pharmacological or therapeutic effects after transdermal absorption. In some embodiments, the base of the ointment form, as an excipient and drug carrier, has an important influence on the quality of the ointment and the release and absorption of the drug. Bases of ointment forms common in this art can be classified into oily bases, emulsion bases, and water-soluble bases. Using preparation methods and processes suitable for this field, the ointment formulation required for the therapeutic method of this invention can be obtained.

[0045] In this application, the term "selected from" generally refers to the selected subjects and all combinations thereof. For example, "(:) selected from A, B, and C" means all combinations of A, B, and C, such as A, B, C, A+B, A+C, B+C, or A+B+C.

[0046] In this application, the terms “effective dose” or “effective amount” are interchangeable and generally refer to an amount sufficient to achieve, or at least partially achieve, the desired therapeutic effect. When used in patients who require it, it generally refers to an amount sufficient to cure, or at least partially prevent, the disease and its complications in patients who are already ill. The effective dose for this use depends on the severity of the patient’s infection and the overall state of the patient’s immune system.

[0047] In this application, the term "combined administration" generally refers to the administration of the therapeutic agent described herein together with other therapeutic agents or drugs, either as a single formulation or as multiple independent formulations. Combined administration can be performed simultaneously or sequentially in any order, and is preferably performed, for example, over a period of time during which two (or all) active ingredients exert biological activity simultaneously. The therapeutic agent described herein and other therapeutic agents do not necessarily have to be administered via the same route of administration.

[0048] In this application, the terms “about” or “approximately” usually refer to being within the tolerance range of a particular value as determined by those skilled in the art, and this depends in part on how the value is measured or determined, i.e., the limits of the measuring system. For example, “about” or “approximately” may mean within or exceeding one standard deviation, according to the convention of the art. Alternatively, “about” or “approximately” may mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg may include any number between 2.7 mg and 3.3 mg (if 10%) or between 2.4 mg and 3.6 mg (if 20%). Furthermore, particularly with respect to biological systems or processes, this term may mean a value of up to one order of magnitude or a value of up to five times. Where specific values ​​or compositions are given in this specification and the appended claims, unless otherwise specified, the meaning of “about” or “approximately” should be assumed to be within the tolerance range of that specific value or composition.

[0049] Detailed description of the invention In one embodiment, the present invention provides a method for preventing or treating diabetic foot infection (DFI), or for alleviating DFI-related symptoms. The method comprises administering a topical therapeutic agent comprising a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof to a patient in need, wherein DFI is caused by a Gram-positive bacterial infection. In some embodiments, the Gram-positive bacteria may include drug-resistant strains.

[0050] In some embodiments, diabetic foot infections are caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcal infection. For example, Staphylococcus aureus may include drug-resistant strains, and coagulase-negative staphylococci may include drug-resistant strains. Specifically, coagulase-negative staphylococci may be selected from Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus xylosus, Staphylococcus haemolyticus, Staphylococcus capitis, Staphylococcus warneri, Staphylococcus simulans, Staphylococcus xylosus, and Staphylococcus simiae. In this application, drug-resistant strains may be resistant to rifamycin (e.g., rifampicin) alone, quinolone or quinolidinone alone, or both rifamycin and quinolidinone. For example, drug-resistant strains may be resistant to macrolides such as clarithromycin, azithromycin, and roxithromycin; nitroimidazoles such as metronidazole, ornidazole, pretomanid, and delamanid; aminoglycosides such as streptomycin and amikacin; β-lactams such as methicillin, ampicillin, and amoxicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; oxazolidons such as linezolid and tedizolid; nitrofurans such as furazolidone; polypeptides such as vancomycin and polymyxin; diallylquinolines such as bedaquiline; and other antibiotics such as clofazimine.

[0051] In some embodiments, the topical treatment agent may be an ointment.

[0052] 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. For example, the topical therapeutic agent comprises 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 thereof. Preferably, the solubilizer of the present application may include triethanolamine. Preferably, the antioxidant of the present application may include vitamin C, vitamin E, or a combination thereof.

[0053] In some embodiments, the amount used of the compound represented by formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides is about 0.3% to about 0.7% of the total mass of the topical treatment. For example, the amount used of the compound represented by formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides 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 mass of the topical treatment.

[0054] In some embodiments, the amount of polyethylene glycol 400 used is about 55% to about 60% of the total mass of the topical treatment. For example, the amount of polyethylene glycol 400 used is about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the total mass of the topical treatment.

[0055] In some embodiments, the amount of polyethylene glycol 3350 used is about 28% to about 33% of the total mass of the topical treatment. For example, the amount of polyethylene glycol 3350 used is about 28%, about 29%, about 30%, about 31%, about 32%, or about 33% of the total mass of the topical treatment.

[0056] In some embodiments, the amount of propylene glycol used is about 8% to about 12% of the total mass of the topical treatment. For example, the amount of propylene glycol used 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 mass of the topical treatment.

[0057] In some embodiments, the amount of solubilizer used is about 0.1% to about 1% of the total mass. For example, the amount of solubilizer used is about 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, or about 1.00% of the total mass.

[0058] In some embodiments, the amount of antioxidant used is about 0.5% to about 1% of the total mass. The amount of antioxidant used is about 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, or about 1.00% of the total mass.

[0059] Preferably, in some embodiments, the topical therapeutic agent comprises the following components: the amount of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated, relative to 100% by mass, is about 0.3% to about 0.7% of the total mass of the topical therapeutic agent (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. The amount of polyethylene glycol 400 used is approximately 55% to 60% of the total mass of the topical treatment (e.g., approximately 55%, 56%, 57%, 58%, 59%, or 60%), and the amount of polyethylene glycol 3350 used is approximately 28% to 33% of the total mass of the topical treatment (e.g., approximately 28%, 29%, 30%, 31%, 32%, or 33%), and the use of propylene glycol The amount of solubilizer used is approximately 8% to 12% of the total mass of the topical treatment (e.g., approximately 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, or 12.0%), and the amount of solubilizer used is approximately 0.1% to 1% of the total mass of the topical treatment (e.g., approximately 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, or The amounts of antioxidants used are approximately 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, or 1.00%, and the amount of antioxidants used is approximately 0.5% to 1% of the total mass of the topical treatment (e.g., approximately 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, or 1.00%).

[0060] In some embodiments, this method involves administering a topical treatment to a patient in need at a frequency of administration selected from once every three days, once every two days, once a day, and twice a day.

[0061] In some embodiments, this method further comprises administering an effective amount of another therapeutic agent to a patient in need. For example, this method further comprises administering an effective amount of another therapeutic agent to a patient by injection (e.g., intravenous, intramuscular, and / or subcutaneous injection), oral administration, intracavitary administration, intestinal administration, and / or transdermal absorption. For example, the other therapeutic agent may be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormonal agents, anti-inflammatory agents, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeabilizers, and muscle relaxants.

[0062] In another embodiment, 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 thereof in the manufacture of a topical therapeutic agent. The topical therapeutic agent is used to prevent or treat diabetic foot infection (DFI), or to alleviate DFI-related symptoms, DFI, which is caused by a Gram-positive bacterial infection. Herein, the topical therapeutic agent comprises a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof. In some embodiments, the Gram-positive bacteria include drug-resistant strains.

[0063] In some embodiments, diabetic foot infections are caused by Staphylococcus aureus infection and / or coagulase-negative staphylococcal infection. For example, Staphylococcus aureus may include drug-resistant strains, and coagulase-negative staphylococci may include drug-resistant strains. Specifically, coagulase-negative staphylococci may be selected from Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus xylosus, Staphylococcus haemolyticus, Staphylococcus capitis, Staphylococcus warneri, Staphylococcus simulans, Staphylococcus xylosus, and Staphylococcus simiae. In this application, drug-resistant strains may be resistant to rifamycin (e.g., rifampicin) alone, quinolone or quinolidinone alone, or both rifamycin and quinolidinone. For example, drug-resistant strains may be resistant to macrolides such as clarithromycin, azithromycin, and roxithromycin; nitroimidazoles such as metronidazole, ornidazole, pretomanid, and delamanid; aminoglycosides such as streptomycin and amikacin; β-lactams such as methicillin, ampicillin, and amoxicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; oxazolidons such as linezolid and tedizolid; nitrofurans such as furazolidone; polypeptides such as vancomycin and polymyxin; diallylquinolines such as bedaquiline; and other antibiotics such as clofazimine.

[0064] In some embodiments, the topical treatment agent may be an ointment.

[0065] 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. For example, the topical therapeutic agent comprises 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 thereof. Preferably, the solubilizer of the present application may include triethanolamine. Preferably, the antioxidant of the present application may include vitamin C, vitamin E, or a combination thereof.

[0066] In some embodiments, the amount used of the compound represented by formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides is about 0.3% to about 0.7% of the total mass of the topical treatment. For example, the amount used of the compound represented by formula (I) and / or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites, or deuterides 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 mass of the topical treatment.

[0067] In some embodiments, the amount of polyethylene glycol 400 used is about 55% to about 60% of the total mass of the topical treatment. For example, the amount of polyethylene glycol 400 used is about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the total mass of the topical treatment.

[0068] In some embodiments, the amount of polyethylene glycol 3350 used is about 28% to about 33% of the total mass of the topical treatment. For example, the amount of polyethylene glycol 3350 used is about 28%, about 29%, about 30%, about 31%, about 32%, or about 33% of the total mass of the topical treatment.

[0069] In some embodiments, the amount of propylene glycol used is about 8% to about 12% of the total mass of the topical treatment. For example, the amount of propylene glycol used 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 mass of the topical treatment.

[0070] In some embodiments, the amount of solubilizer used is about 0.1% to about 1% of the total mass. For example, the amount of solubilizer used is about 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, or about 1.00% of the total mass.

[0071] In some embodiments, the amount of antioxidant used is about 0.5% to about 1% of the total mass. The amount of antioxidant used is about 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, or about 1.00% of the total mass.

[0072] Preferably, in some embodiments, the topical therapeutic agent comprises the following components: the amount of the compound represented by formula (I) and / or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated, relative to 100% by mass, is about 0.3% to about 0.7% of the total mass of the topical therapeutic agent (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. The amount of polyethylene glycol 400 used is approximately 55% to 60% of the total mass of the topical treatment (e.g., approximately 55%, 56%, 57%, 58%, 59%, or 60%), and the amount of polyethylene glycol 3350 used is approximately 28% to 33% of the total mass of the topical treatment (e.g., approximately 28%, 29%, 30%, 31%, 32%, or 33%), and the use of propylene glycol The amount of solubilizer used is approximately 8% to 12% of the total mass of the topical treatment (e.g., approximately 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, or 12.0%), and the amount of solubilizer used is approximately 0.1% to 1% of the total mass of the topical treatment (e.g., approximately 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, or The amounts of antioxidants used are approximately 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, or 1.00%, and the amount of antioxidants used is approximately 0.5% to 1% of the total mass of the topical treatment (e.g., approximately 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, or 1.00%).

[0073] In some embodiments, the topical treatment is formulated to be administered to patients in need at a frequency selected from once every three days, once every two days, once a day, and twice a day.

[0074] In some embodiments, the topical treatment is formulated to be administered in combination with an effective amount of another treatment to patients who require it. For example, the topical treatment may be formulated to be administered in combination with an effective amount of another treatment to patients who require it, the other treatment may be administered to the patient by injection (e.g., intravenous, intramuscular, and / or subcutaneous), oral, intracavitary, intestinal, and / or transdermal absorption. For example, the other treatment may be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormones, anti-inflammatory agents, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeabilizers, and muscle relaxants.

[0075] While not limited by any theory, the following examples are merely for illustrative purposes to illustrate the method and use of the present invention and do not limit the scope of the present invention. [Examples]

[0076] Example 1 Measurement of the antimicrobial activity of the compound of formula (I) against biofilms of clinically isolated strains of diabetic foot infection (DFI). 1. Experimental Method Preparation of test strains: In this example, foot samples were collected from 49 patients with type II diabetes. From these samples, isolated strains were obtained by homogenization, application, and incubation at 37°C. Fungi, poorly growing strains, or strains that could not be isolated or purified were removed to obtain a total of 69 clinical strains. Of these, 55 strains were Gram-positive and 14 strains were Gram-negative. Among the Gram-positive strains, there were 43 Staphylococcus strains, 18 Staphylococcus aureus strains, 8 Staphylococcus epidermidis strains, and 5 Staphylococcus rugdunensis strains. In addition, one ATCC standard strain was used as a standard strain and quality control strain.

[0077] Biofilm preparation: Under sterile conditions, identified and proliferated single colonies were collected using an inoculation loop, and a bacterial suspension with a McFarland turbidity of 0.5 was prepared as the initial inoculum suspension. The initial inoculum suspension was diluted 1:200-fold, and 50 μL of the initial inoculum suspension was added to 10 mL of CAMHB medium. Using a pipette, 150 μL of the inoculum suspension was transferred to a CBD plate, and the inoculated CBD plate was incubated at 35±2°C for 16-20 hours.

[0078] Measurement of antimicrobial activity: Using standard broth dilution methods and literature-reported in vitro biofilm culture and drug susceptibility testing methods, the minimum inhibitory concentration (MIC) and minimum biofilm removal concentration (MBBC) for the compound of formula (I) and the control drug (see section 2 for details) against 69 clinically isolated strains of diabetic foot infections were evaluated.

[0079] 2.Result analysis Table 1-1 Summary of MIC and MBBC (μg / mL) results for compounds of formula (I) and control agents against DFI clinical isolates and biofilms (Gram-positive bacteria vs. Gram-negative bacteria) TIFF2026521250000003.tif61170

[0080] The results in Table 1-1 show that the compound of formula (I) has significantly superior antibacterial activity against Gram-positive bacterial isolates compared to Gram-negative bacteria. (1) Its MIC 50 and MIC 90 These values ​​are ≤0.015 μg / mL and 0.25 μg / mL, respectively, and linezolid (MIC), which is the first-line clinical drug. 50 and MIC 90 These are 2 μg / mL and 4 μg / mL respectively, and vancomycin (MIC 50 and MIC 90 Both are significantly superior to 2 μg / mL. (2) The MBBC results for the compound of formula (I) similarly demonstrate that it has superior bactericidal activity against in vitro biofilms of Gram-positive bacteria compared to Gram-negative bacteria, and its MBBC 50and MBBC 90 are 0.125 μg / mL and 16 μg / mL, respectively, and the clinically first-choice drug, linezolid (MBBC 50 and MBBC 90 are both > 128 μg / mL) and vancomycin (MBBC 50 and MBBC 90 are both significantly superior to (> 128 μg / mL).

[0081] Table 1-2 Summary of MIC (μg / mL) Results of Compounds of Formula (I) and Control Agents against DFI Clinically Isolated Strains (Representative Gram-Positive Bacteria) TIFF2026521250000004.tif60170

[0082] Table 1-3 Summary of MBBC (μg / mL) Results of Compounds of Formula (I) and Control Agents against Biofilms of DFI Clinically Isolated Strains (Representative Gram-Positive Bacteria) TIFF2026521250000005.tif58170

[0083] The results in Table 1-2 show that the compounds of formula (I) have good antibacterial activity against staphylococcus (including Staphylococcus aureus and Staphylococcus epidermidis) isolates. 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 compounds of formula (I) against staphylococcus and Staphylococcus aureus 50 are both ≤ 0.015 μg / mL, which are significantly superior to linezolid (MIC 50 are both 2 μg / mL) and vancomycin (MIC 50 are both 2 μg / mL). Also, their MIC 90 are both ≤ 0.015 μg / mL, which are significantly superior to linezolid (MIC 90 are both 4 μg / mL) and vancomycin (MIC 90 are both 2 μg / mL).

[0084] The results in Table 1-3 show that the compound of formula (I) has good bactericidal activity against in vitro biofilms of Staphylococcus aureus (including Staphylococcus aureus and Staphylococcus epidermidis). Their MBBC ranges are ≤0.015 to 1 μg / mL, 0.03 to 0.5 μg / mL, and ≤0.015 to 0.06 μg / mL, respectively, indicating the MBBC activity of the compound of formula (I) against Staphylococcus aureus and Staphylococcus aureus. 50 These are 0.06 μg / mL and 0.25 μg / mL, respectively, and linezolid (MBBC 50 These are both >128 μg / mL) and vancomycin (MBBC 50 All of these are significantly superior to those with >128 μg / mL. Furthermore, their MBBC 90 All of these are 0.5 μg / mL, and linezolid (MBBC 90 These are both >128 μg / mL) and vancomycin (MBBC 90 All of these are significantly superior to >128 μg / mL.

[0085] The results above suggest that, overall, the compound of formula (I) has excellent antibacterial and bactericidal activity against Gram-positive bacteria, as well as against isolates and in vitro biofilms of Staphylococcus aureus (including Staphylococcus epidermidis) among Gram-positive bacteria. Furthermore, its antibacterial and bactericidal activity is significantly superior to that of linezolid and vancomycin, which are first-line clinical drugs, suggesting potential clinical advantages in the treatment of diabetic foot infections.

[0086] Example 2 Drug efficacy evaluation using the treatment method described in this invention in a mouse model of Staphylococcus aureus skin infection. 1. Experimental Method In this example, in order to evaluate the antibacterial activity of the ointment containing the compound of formula (I) described in this application on the skin surface, a stable mouse skin infection model was constructed using S. aureus NRS 384. In this example, the following 6 groups were set: a control group (the end point of the experiment was 4 hours after infection), a solvent group, a Bactroban ointment group, and ointment groups containing the compound of formula (I) at low, medium, and high doses. Each of the above groups contained 8 animals, and the specific experimental design was as follows. TIFF2026521250000006.tif49170

[0087] 2. Result analysis 72 hours after infection, in a sterile environment, skin samples were collected from the mice in each treatment group, transferred to a 15 mL centrifuge tube containing 5 mL of sterile injection physiological saline, homogenized with a homogenizer for about 1 min, and then 200 μL of the homogenate was aspirated and diluted 10 0 to 10 -5 times with sterile injection physiological saline. 10 μL was taken for each dilution gradient, spotted on the plate, cultured overnight in an incubator at 35 ± 2 °C, and the CFU was counted the next day.

[0088] Table 2 Counting results of mouse skin bacteria TIFF2026521250000007.tif69170Remarks: ***: Compared with the model group, p < 0.001, indicating a very significant difference; *: Compared with the model group, 0.01 < p < 0.05, indicating a significant difference; one-way ANOVA was used.

[0089] The results of this efficacy test showed that the number of skin bacteria in mice treated with bactroban ointment (2% mupirocin) decreased by 2.119 log compared to the number of skin bacteria in the solvent group (9.154 ± 0.273 log), demonstrating good bactericidal activity. In mice treated with ointments containing the compound of formula (I) at concentrations of 0.5%, 0.05%, and 0.005%, the number of skin bacteria decreased by 4.718 log, 3.100 log, and 1.063 log, respectively. This indicates that the high-dose (0.5%) and medium-dose (0.05%) ointments showed good bactericidal effects in this skin infection model, with a very significant difference compared to the solvent group and superior to the bactroban ointment treatment group, further demonstrating the potential clinical benefits in the treatment of diabetic foot infections.

Claims

1. A method for preventing or treating diabetic foot infection (DFI), or for alleviating DFI-related symptoms, The present invention includes administering a topical therapeutic agent containing the compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof to a patient in need. The DFI is a method caused by Gram-positive bacterial infection.

2. The method according to claim 1, wherein the Gram-positive bacteria include drug-resistant strains.

3. The method according to claim 1 or 2, wherein the topical treatment agent is an ointment.

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 comprises 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 thereof.

6. The method according to any one of claims 1 to 5, wherein the amount used of the compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated 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 mass of the topical treatment 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 mass of the topical treatment agent.

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

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

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

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

13. The method according to any one of claims 1 to 12, comprising administering the topical therapeutic agent to the patient in need at a frequency of administration selected from once every three days, once every two 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 staphylococcal infection.

15. The method according to claim 14, wherein the Staphylococcus aureus includes a drug-resistant strain thereof, and the coagulase-negative staphylococcus includes a drug-resistant strain thereof.

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

17. The use of a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof in the manufacture of a topical therapeutic agent, The topical treatment is used to prevent or treat diabetic foot infection (DFI), or to alleviate DFI-related symptoms, wherein DFI is caused by a Gram-positive bacterial infection, and the topical treatment comprises a compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof.

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

19. The use according to claim 17 or 18, wherein the topical therapeutic agent is an ointment.

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 to 20, wherein the topical therapeutic agent comprises 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 thereof.

22. The use according to any one of claims 17 to 21, wherein the amount used of the compound represented by formula (I) and / or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite, or deuterated thereof 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 used is about 55% to about 60% of the total mass of the topical treatment agent.

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

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

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

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

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

29. The use according to any one of claims 17 to 28, wherein the topical treatment agent is formulated to be administered to patients in need at a frequency of administration selected from once every three days, once every two 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 staphylococcal infection.

31. The use according to claim 30, wherein the Staphylococcus aureus includes a drug-resistant strain thereof, and the coagulase-negative staphylococcus includes a drug-resistant strain thereof.

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

Images