WO2024254840A1 - Procédé et utilisation d'un composé pour le traitement de maladies - Google Patents

Procédé et utilisation d'un composé pour le traitement de maladies Download PDF

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Publication number
WO2024254840A1
WO2024254840A1 PCT/CN2023/100594 CN2023100594W WO2024254840A1 WO 2024254840 A1 WO2024254840 A1 WO 2024254840A1 CN 2023100594 W CN2023100594 W CN 2023100594W WO 2024254840 A1 WO2024254840 A1 WO 2024254840A1
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Prior art keywords
therapeutic agent
pharmaceutically acceptable
formula
compound
prodrug
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PCT/CN2023/100594
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English (en)
Chinese (zh)
Inventor
马振坤
陈静
耿国柱
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TenNor Therapeutics (Suzhou) Ltd
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TenNor Therapeutics (Suzhou) Ltd
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Priority to PCT/CN2023/100594 priority Critical patent/WO2024254840A1/fr
Publication of WO2024254840A1 publication Critical patent/WO2024254840A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present application relates to the field of biomedicine, and specifically to a method for preventing or treating a disease with a compound and its use.
  • ABSSSI Acute bacterial skin and skin structure infections
  • the purpose of the present invention is to provide a more effective treatment method, which can cure or alleviate ABSSSI-related disease symptoms in patients with short-term antibacterial treatment.
  • the present application provides a method for preventing or treating acute bacterial skin and skin structure infections (ABSSSI), or alleviating the ABSSSI-related symptoms, the method comprising intravenously infusing a therapeutic agent to a patient in need thereof for no more than 7 days, wherein each intravenous infusion of the therapeutic agent comprises about 10 mg to about 500 mg of a compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof,
  • the method comprises intravenously infusing the therapeutic agent to the patient in need thereof at intervals of about 8 hours to about 24 hours.
  • the method comprises administering the therapeutic agent to the patient in need thereof at intervals of about 12 hours intravenously.
  • the intravenous infusion is administered over a single infusion period of about 20 minutes to about 3 hours.
  • the intravenous infusion is administered over a single infusion time of about 60 minutes.
  • each intravenous infusion of the therapeutic agent comprises about 100 mg to about 400 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.
  • each intravenous infusion of the therapeutic agent comprises about 200 mg to about 300 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.
  • each intravenous infusion of the therapeutic agent comprises about 300 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.
  • the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers.
  • the other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product are not mixed with each other.
  • one or more of the other components are mixed with the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.
  • the acute bacterial skin and skin structure infection is caused by a Gram-positive bacterial infection.
  • the acute bacterial skin and skin structure infection is caused by Staphylococcus aureus infection and/or Infection caused by enzyme-negative staphylococci.
  • the Gram-positive bacteria include drug-resistant strains thereof.
  • the Staphylococcus aureus comprises a drug-resistant strain thereof, and the coagulase-negative Staphylococcus comprises a drug-resistant strain thereof.
  • the method further comprises administering to the patient in need thereof an effective amount of an additional therapeutic agent.
  • the present application provides a use of a compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof in the preparation of an intravenous infusion therapeutic agent, wherein the therapeutic agent is used to prevent or treat acute bacterial skin and skin structure infection (ABSSSI) or alleviate the ABSSSI-related symptoms, and a single infusion dose of the therapeutic agent contains about 10 mg to about 500 mg of a compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof, and the therapeutic agent is formulated for intravenous infusion into a patient in need thereof for up to 7 days.
  • ABSSSSI acute bacterial skin and skin structure infection
  • the therapeutic agent is formulated for intravenous infusion into the patient in need thereof at intervals of about 8 hours to about 24 hours.
  • the therapeutic agent is formulated for intravenous infusion into the patient in need thereof at intervals of about 12 hours.
  • the therapeutic agent is formulated to be administered to the patient in need thereof by intravenous infusion over a period of about 20 minutes to about 3 hours per administration.
  • the therapeutic agent is formulated to be administered to the patient in need thereof as an intravenous infusion over a period of about 60 minutes per administration.
  • the therapeutic agent comprises about 100 mg to about 400 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof in a single intravenous infusion.
  • the therapeutic agent comprises about 200 mg to about 300 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof in a single intravenous infusion.
  • the therapeutic agent comprises about 300 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof in a single intravenous infusion.
  • the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers.
  • the other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product are not mixed with each other.
  • one or more of the other components are combined with the compound of formula (I) and/or its pharmaceutically Acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances are mixed with each other.
  • the acute bacterial skin and skin structure infection is caused by a Gram-positive bacterial infection.
  • the Gram-positive bacteria include drug-resistant strains thereof.
  • the acute bacterial skin and skin structure infection is caused by Staphylococcus aureus infection and/or a coagulase-negative Staphylococcus infection.
  • the Staphylococcus aureus comprises a drug-resistant strain thereof, and the coagulase-negative Staphylococcus comprises a drug-resistant strain thereof.
  • the therapeutic agent is formulated to be co-administered with an effective amount of another therapeutic agent to the patient in need thereof.
  • the term "patient in need” generally includes human patients and other mammalian subjects receiving preventive 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” can be exemplarily subjects with confirmed specific diseases, subjects receiving treatment related to specific diseases, subjects with a tendency or risk of developing specific diseases, etc.
  • therapeutic agent generally refers to a compound, a mixture of compounds, a composition, a biomacromolecule or an extract made from biological materials that can induce a desired therapeutic effect, prevent a certain disease, or alleviate a related disease when properly administered to a patient.
  • 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)).
  • 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, aminosulfonic 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
  • solvate and “solvate” are used interchangeably and generally refer to an association or complex of one or more solvent molecules and a salt-type compound of the present application.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate generally refers to a complex in which the solvent molecule is water.
  • 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
  • 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.
  • deuterated substance and “deuterated compound” are used interchangeably, and generally refer to a new compound obtained after one or more hydrogen atoms in an organic compound are replaced by deuterium atoms.
  • the term "drug” generally refers to a molecule with a desired biological effect.
  • the drug can be preventive or therapeutic.
  • the drug may include, but is not limited to: protein molecules, including but not limited to peptides, polypeptides, proteins, including post-translationally modified proteins, fusion proteins, antibodies, etc.; small molecules, including inorganic or organic compounds; nucleic acid molecules, including but not limited to double-stranded or single-stranded DNA, or double-stranded or single-stranded RNA (such as antisense (molecules), RNAi, etc.), intron sequences, triple-helix nucleic acid molecules and aptamers; or vaccines (such as Lister and non-Lister vaccines).
  • the drug can be obtained from any known organism (including but not limited to: animals, plants, bacteria, fungi and protozoa or viruses) or synthetic molecule libraries.
  • the term "pharmaceutically acceptable carrier” generally refers to one or more non-toxic materials that do not interfere with the effectiveness of the biological activity of the active ingredient.
  • Such preparations can conventionally contain salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents.
  • Such pharmaceutically acceptable preparations can also include compatible solid or liquid fillers, diluents or encapsulated materials suitable for administration to people.
  • Other envisioned carriers, excipients, and/or additives that can be used in the formulations described herein may include, for example, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids, protein excipients (such as serum albumin, gelatin, casein), salt-forming counterions (such as sodium), etc.
  • Suitable pharmaceutically acceptable carriers can be routinely selected for the desired or required mode of administration, solubility and/or stability.
  • mixing generally refers to the process of combining one or more compounds, cells, molecules, etc. in the same area. This can be done, for example, in a test tube, a petri dish, or any container that allows mixing of one or more compounds, cells or molecules.
  • administering generally refers to introducing the drug or a composition comprising the drug (e.g., a therapeutic agent provided herein) 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.
  • selected from generally refers to including selected objects and all combinations thereof.
  • selected from (:) A, B and C means including all combinations of A, B and C, for example, A, B, C, A+B, A+C, B+C or A+B+C.
  • the term "effective amount” or “effective dose” is used interchangeably, generally refers to an amount sufficient to obtain or at least partially obtain the desired therapeutic effect, and when used for a patient in need, it generally refers to an amount sufficient to cure an already sick patient 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.
  • co-administration generally refers to the administration of the therapeutic agent described herein with other therapeutic agents or drugs as a single formulation or as multiple independent formulations. Co-administration can be performed simultaneously or sequentially in any order, for example, it can be preferably continued for a certain period of time when two (or all) active pharmaceutical ingredients exert their biological activities simultaneously.
  • the therapeutic agent of the present application and other therapeutic agents are not necessarily administered by the same route of administration.
  • the term "about” or “approximately” is generally within an acceptable error range for a particular value 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.
  • “about” or “approximately” may mean within 1 or more than 1 standard deviation according to the practice of the art.
  • “about” or “approximately” may mean a range of up to 10% or 20% (i.e., ⁇ 10% or ⁇ 20%).
  • about 3 mg may include any amount between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%).
  • the term may mean a value of up to one order of magnitude or a value of up to 5 times.
  • the present application provides a method for preventing or treating acute bacterial skin and skin structure infections (ABSSSI), or for reducing
  • ABSSSI-related disorders comprises intravenously infusing a therapeutic agent to a patient in need for no more than 7 days, wherein each intravenous infusion of the therapeutic agent comprises about 10 mg to about 500 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof.
  • the method may comprise intravenously infusing the therapeutic agent to the patient in need for 1 day, 2 days, 3 days, 4 days, 5 days or 6 days.
  • the therapeutic agent may contain about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,
  • the therapeutic agent may include about 100 mg to about 400 mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.
  • the therapeutic agent may contain about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg of the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.
  • the therapeutic agent may include about 200 mg to about 300 mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.
  • the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance contained in the therapeutic agent may be about: 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg or 300 mg.
  • the therapeutic agent may include about 300 mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.
  • the method includes intravenously infusing the therapeutic agent to the patient in need at intervals of about 8 hours to about 24 hours.
  • the method includes intravenously infusing the therapeutic agent to the patient in need at intervals selected from the following: about every 8 hours, about every 9 hours, about every 10 hours, about every 11 hours, about every 12 hours, about every 13 hours, about every 14 hours, about every 15 hours, about every 16 hours, about every 17 hours, about every 18 hours, about every 19 hours, about every 20 hours, about every 21 hours, about every 22 hours, about every 23 hours and about every 24 hours.
  • the infusion can be maintained at the same time interval, or the time interval of infusion can be changed according to the actual needs of the patient or in accordance with the doctor's advice.
  • the method includes intravenously infusing the therapeutic agent to the patient in need at intervals of about 12 hours.
  • the single infusion time of the intravenous infusion is about 20 minutes to about 3 hours.
  • the sustainable single infusion time of the intravenous infusion can be about: 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes (1 hour), 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes (2 hours), 130 minutes, 140 minutes, 150 minutes, 160 minutes, 170 minutes or 180 minutes (3 hours).
  • the single intravenous infusion can be sustainable for 60 ⁇ 10 minutes.
  • the single infusion time that the intravenous infusion can last is about: 50 minutes, 51 minutes, 52 minutes, 53 minutes, 54 minutes, 55 minutes, 56 minutes, 57 minutes, 58 minutes, 59 minutes, 60 minutes, 61 minutes, 62 minutes, 63 minutes, 64 minutes, 65 minutes, 66 minutes, 67 minutes, 68 minutes, 69 minutes or 70 minutes.
  • the single infusion time of the intravenous infusion is about 60 minutes.
  • the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers.
  • the other components and the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances do not mix with each other.
  • the non-mixing with each other may refer to that the other components and the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances are placed in different containers and/or devices respectively.
  • the non-mixing with each other may refer to that the container or device in which the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances are placed in the therapeutic agent, and the containers or devices in which the other components are placed are placed in different storage spaces and/or different storage conditions respectively.
  • the term "non-mixing" may refer to that other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance are separately packaged and stored in specific measurement units in containers and/or devices respectively placed therein.
  • non-mixing may refer to that other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance are mixed only before using the therapeutic agent, and the mixing process may include using a mixing device included or not included in the therapeutic agent, transferring other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance to a container or device where another component is placed for mixing, and/or transferring other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance to another container or device for mixing.
  • the therapeutic agent comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers, and one or more of the other components are mixed with the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances.
  • the mutual mixing may refer to one or more of the other components being mixed with the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances and placed in the same container or device.
  • the mutual mixing may refer to one or more of the other components being mixed with the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances and then being stored in the same or different containers or devices in specific measurement units.
  • the mutual mixing may mean that after one or more of the other components are mixed with the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product, further sufficient mixing (for example, vigorous shaking is required to fully mix) is required before the therapeutic agent is used.
  • the acute bacterial skin and skin structure infection is caused by Gram-positive bacteria infection.
  • the Gram-positive bacteria may also include resistant strains thereof.
  • the acute bacterial skin and skin structure infection is caused by Staphylococcus aureus infection and/or coagulase-negative Staphylococcus infection.
  • the Staphylococcus aureus may also include resistant strains thereof, and the coagulase-negative Staphylococcus may also include resistant strains thereof.
  • 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.
  • the resistant strain may be single-resistant to rifamycin (e.g., rifampicin), single-resistant to quinolone or quinolones, or double-resistant to rifamycin and quinolones.
  • the resistant strains may also be resistant to other antibiotics, including resistance to macrolide drugs such as clarithromycin, azithromycin, roxithromycin, etc.; resistance to nitroimidazole drugs such as metronidazole, ornidazole, premanid, delamanid, etc.; resistance to aminoglycoside drugs such as streptomycin, amikacin, etc.; resistance to ⁇ -lactam drugs such as methicillin, ampicillin, amoxicillin, etc.; resistance to tetracycline drugs such as tetracycline, tigecycline, minocycline, etc.; resistance to oxazolidinone drugs such as linezolid, tedizolid, etc.; resistance to nitrofuran drugs such as furazolidone, etc.; resistance to polypeptide drugs such as vancomycin, polymyxin, etc.; resistance to diarylquinoline drugs such as bedaquiline and clofazimine, etc.
  • macrolide drugs such as clarithro
  • the method further comprises administering an effective amount of other therapeutic agents to the patient in need.
  • 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.
  • the other therapeutic agents can be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormone drugs, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeation agents and muscle relaxants, etc.
  • the present application provides a compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof for use in the preparation of an intravenous infusion therapeutic agent, wherein the therapeutic agent is used to prevent or treat acute bacterial skin and skin structure infection (ABSSSI) or alleviate the ABSSSI-related conditions, and the single infusion dose of the therapeutic agent contains about 10 mg to about 500 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof, and the therapeutic agent is formulated to be suitable for intravenous infusion to a patient in need for up to 7 days.
  • ABSSSSI acute bacterial skin and skin structure infection
  • the therapeutic agent is formulated to be suitable for intravenous infusion of the therapeutic agent to the patient in need for 1 day, 2 days, 3 days, 4 days, 5 days or 6 days.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof contained in the therapeutic agent is suitable for intravenous infusion to the patient in need for up to 7 days.
  • the product or deuterated substance may be about: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg , 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg or 500mg.
  • the therapeutic agent may comprise about 100mg to about 400mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.
  • the therapeutic agent may contain about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg of the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.
  • the therapeutic agent may include about 200 mg to about 300 mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.
  • the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance contained in the therapeutic agent may be about: 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg or 300 mg.
  • the therapeutic agent may include about 300 mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.
  • the therapeutic agent is formulated to be suitable for intravenous infusion to the patient in need every interval of about 8 hours to every interval of about 24 hours.
  • the therapeutic agent is formulated to be suitable for intravenous infusion to the patient in need at an optional time interval described below: about every 8 hours, about every 9 hours, about every 10 hours, about every 11 hours, about every 12 hours, about every 13 hours, about every 14 hours, about every 15 hours, about every 16 hours, about every 17 hours, about every 18 hours, about every 19 hours, about every 20 hours, about every 21 hours, about every 22 hours, about every 23 hours and about every 24 hours.
  • the therapeutic agent can be formulated to be suitable for intravenous infusion at the same time interval, and the therapeutic agent suitable for different infusion time intervals can also be prepared according to the actual needs of the patient or in accordance with the doctor's advice.
  • the therapeutic agent is formulated for intravenous infusion into the patient in need thereof at intervals of about 12 hours.
  • the therapeutic agent is formulated to be suitable for administration to the patient in need thereof with an intravenous infusion time of about 20 minutes to about 3 hours each time.
  • the therapeutic agent is formulated to be suitable for administration to the patient in need thereof with a single infusion time selected from the following: about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes (1 hour), about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes (2 Hours), about 130 minutes, about 140 minutes, about 150 minutes, about 160 minutes, about 170 minutes and about 180 minutes (3 hours).
  • the therapeutic agent is formulated to be suitable for being administered to the patient in need with a single infusion time of 60 ⁇ 10 minutes.
  • the therapeutic agent is formulated to be suitable for being administered to the patient in need with a single infusion time optionally selected from the following: 50 minutes, 51 minutes, 52 minutes, 53 minutes, 54 minutes, 55 minutes, 56 minutes, 57 minutes, 58 minutes, 59 minutes, 60 minutes, 61 minutes, 62 minutes, 63 minutes, 64 minutes, 65 minutes, 66 minutes, 67 minutes, 68 minutes, 69 minutes or 70 minutes.
  • the therapeutic agent is formulated to be suitable for being administered to the patient in need with an intravenous infusion time of about 60 minutes each time.
  • the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers.
  • the other components and the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances do not mix with each other.
  • the non-mixing with each other may refer to that the other components and the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances are placed in different containers and/or devices respectively.
  • the non-mixing with each other may refer to that the container or device in which the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances are placed in the therapeutic agent, and the containers or devices in which the other components are placed are placed in different storage spaces and/or different storage conditions respectively.
  • the term "non-mixing" may refer to that other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance are separately packaged and stored in specific measurement units in containers and/or devices respectively placed therein.
  • non-mixing may refer to that other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance are mixed only before using the therapeutic agent, and the mixing process may include using a mixing device included or not included in the therapeutic agent, transferring other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance to a container or device where another component is placed for mixing, and/or transferring other components and the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance to another container or device for mixing.
  • the therapeutic agent comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers, and one or more of the other components are mixed with the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances.
  • the mutual mixing may refer to one or more of the other components being mixed with the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances and placed in the same container or device.
  • the mutual mixing may refer to one or more of the other components being mixed with the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances and then stored in the same or different containers or devices in specific measurement units.
  • the mutual mixing may refer to one or more of the other components being mixed with the compound of formula (I) and/or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, metabolites or deuterated substances and then stored in the same or different containers or devices in specific measurement units.
  • the acute bacterial skin and skin structure infection is caused by Gram-positive bacteria infection.
  • the Gram-positive bacteria may also include resistant strains thereof.
  • the acute bacterial skin and skin structure infection is caused by Staphylococcus aureus infection and/or coagulase-negative Staphylococcus infection.
  • the Staphylococcus aureus may also include resistant strains thereof, and the coagulase-negative Staphylococcus may also include resistant strains thereof.
  • 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.
  • the resistant strain may be single-resistant to rifamycin (e.g., rifampicin), single-resistant to quinolone or quinolones, or double-resistant to rifamycin and quinolones.
  • the resistant strains may also be resistant to other antibiotics, including resistance to macrolide drugs such as clarithromycin, azithromycin, roxithromycin, etc.; resistance to nitroimidazole drugs such as metronidazole, ornidazole, premanid, delamanid, etc.; resistance to aminoglycoside drugs such as streptomycin, amikacin, etc.; resistance to ⁇ -lactam drugs such as methicillin, ampicillin, amoxicillin, etc.; resistance to tetracycline drugs such as tetracycline, tigecycline, minocycline, etc.; resistance to oxazolidinone drugs such as linezolid, tedizolid, etc.; resistance to nitrofuran drugs such as furazolidone, etc.; resistance to polypeptide drugs such as vancomycin, polymyxin, etc.; resistance to diarylquinoline drugs such as bedaquiline and clofazimine, etc.
  • macrolide drugs such as clarithro
  • the therapeutic agent is formulated to be suitable for co-administration with an effective amount of other therapeutic agents to the patient in need.
  • the 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 agent 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.
  • the other therapeutic agent can be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormone drugs, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeation agents and muscle relaxants, etc.
  • eligible patients were randomly assigned to one of the following two treatment groups: (1) Group A: patients who received at least The patients were treated with intravenous infusions of 3 days, 12 hours apart (q12h), and about 60 minutes each time. Each infusion contained 300 mg of the compound of formula (I). After an early assessment (EA) window of 48 to 72 hours after the first dose, the patients were clinically judged to stop treatment, continue the intravenous infusion treatment (up to 14 days of intravenous treatment), or switch to oral treatment with systemic antibacterial drugs active against Gram-positive microorganisms (it is necessary to determine whether the conversion criteria are met).
  • EA early assessment
  • Group B The patients were treated with intravenous infusions of 15 mg/kg of vancomycin, 12 hours apart (q12h), and about 60 minutes each time for at least 3 days. After an early assessment (EA) window of 48 to 72 hours after the first dose, the patients were clinically judged to stop treatment, continue the intravenous infusion treatment (up to 14 days of intravenous treatment), or switch to oral treatment with systemic antibacterial drugs active against Gram-positive microorganisms (it is necessary to determine whether the conversion criteria are met).
  • EA early assessment
  • Enumeration Methodology Subjects with the same pathogen in more than one specimen were counted once for that pathogen. Subjects with the same pathogen identified from blood and primary ABSSSI culture were counted only once. Subjects with coexisting MRSA and MSSA, CRSA, or CSSA, RRSA, and RSSA were counted once for the entire S. aureus row. Responses were based on early clinical response at the EA visit.

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

Abstract

La présente invention concerne une méthode de prévention ou de traitement d'infections bactériennes aiguës de la peau et des structures cutanées (ABSSSI), ou de soulagement d'affections liées à des ABSSSI. Le procédé comprend l'administration d'un agent thérapeutique par perfusion intraveineuse chez un patient que le nécessite pendant jusqu'à 7 jours consécutifs, l'agent thérapeutique pour chaque perfusion intraveineuse comprenant environ 10 mg à environ 500 mg d'un composé tel que représenté dans la formule (I) et/ou un hydrate, un solvate, un promédicament, un métabolite, une substance deutérée ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/100594 2023-06-16 2023-06-16 Procédé et utilisation d'un composé pour le traitement de maladies Ceased WO2024254840A1 (fr)

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