WO2024254840A1 - 化合物治疗疾病的方法及其用途 - Google Patents

化合物治疗疾病的方法及其用途 Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutic agent
pharmaceutically acceptable
formula
compound
prodrug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/100594
Other languages
English (en)
French (fr)
Inventor
马振坤
陈静
耿国柱
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TenNor Therapeutics (Suzhou) Ltd
Original Assignee
TenNor Therapeutics (Suzhou) Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by TenNor Therapeutics (Suzhou) Ltd filed Critical TenNor Therapeutics (Suzhou) Ltd
Priority to PCT/CN2023/100594 priority Critical patent/WO2024254840A1/zh
Publication of WO2024254840A1 publication Critical patent/WO2024254840A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • 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

本申请提供了一种预防或治疗急性细菌性皮肤和皮肤结构感染（ABSSSI）、或者减轻所述ABSSSI相关病症的方法，所述方法包括持续7天以内向有需要的患者静脉输注治疗剂，每次所述静脉输注的治疗剂包含约10mg至约500mg式（I）所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物，

Description

化合物治疗疾病的方法及其用途 技术领域
本申请涉及生物医药领域，具体的涉及一种化合物预防或治疗疾病的方法及其用途。
背景技术
急性细菌性皮肤和皮肤结构感染(ABSSSI)是全球范围内最常被诊断的皮肤感染类疾病，其包括蜂窝组织炎、伤口感染以及包括福尼尔(Fournier’s)坏疽在内的严重皮肤脓肿。目前ABSSSI的流行率和对治疗选择的需求处在上升阶段。一方面，致病细菌对抗生素的耐药逐渐增多，使得抗生素经验性治疗愈发地困难，并且疾病临床的多样性也使得医生和治疗机构难以选择最合适的治疗方法。另一方面，在实践过程中的大量临床数据表明，有相当一部分患者在接受了不恰当的抗生素治疗后，将极大可能延长住院时间，增加发病和死亡的风险。另外，ABSSSI常常伴随着的高频率的并发症(如，糖尿病或肥胖症)等危险因素都使得适当的抗生素选择具有高度挑战性。
发明内容
本发明申请的目的是提供了一种更切实有效的治疗方法，使患者在短期的抗菌治疗下即可治愈或减轻ABSSSI相关疾病病症。
一方面，本申请提供预防或治疗急性细菌性皮肤和皮肤结构感染(ABSSSI)、或者减轻所述ABSSSI相关病症的方法，所述方法包括持续7天以内向有需要的患者静脉输注治疗剂，每次所述静脉输注的治疗剂包含约10mg至约500mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物，
在一些实施方案中，所述方法包括每间隔约8小时至每间隔约24小时向所述有需要的患者静脉输注所述治疗剂。
在一些实施方案中，所述方法包括每间隔约12小时向所述有需要的患者静脉输注所述治疗剂。
在一些实施方案中，所述静脉输注的单次输注时间为约20分钟至约3小时。
在一些实施方案中，所述静脉输注的单次输注时间为约60分钟。
在一些实施方案中，每次所述静脉输注的治疗剂包含约100mg至约400mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
在一些实施方案中，每次所述静脉输注的治疗剂包含约200mg至约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
在一些实施方案中，每次所述静脉输注的治疗剂包含约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
在一些实施方案中，所述治疗剂还包含选自其他药物、药学上可接受的载体、溶剂和缓冲液的其他组分。
在一些实施方案中，所述其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物彼此不混合。
在一些实施方案中，所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物相互混合。
在一些实施方案中，所述急性细菌性皮肤和皮肤结构感染由革兰氏阳性菌感染引起。
在一些实施方案中，所述急性细菌性皮肤和皮肤结构感染由金黄色葡萄球菌感染和/或凝 固酶阴性葡萄球菌感染引起。
在一些实施方案中，所述革兰氏阳性菌包含其耐药菌株。
在一些实施方案中，所述金黄色葡萄球包含其耐药菌株，且所述凝固酶阴性葡萄球菌包含其耐药菌株。
在一些实施方案中，所述方法还包括向所述有需要的患者施用有效量的其他治疗剂。
另一方面，本申请提供式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物在制备静脉输注治疗剂中的用途，所述治疗剂用于预防或治疗急性细菌性皮肤和皮肤结构感染(ABSSSI)或者减轻所述ABSSSI相关病症，且所述治疗剂单次输注的剂量包含约10mg至约500mg的式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物，以及所述治疗剂被配制成适于持续7天以内向有需要的患者进行静脉输注。
在一些实施方案中，所述治疗剂被配制成适于每间隔约8小时至每间隔约24小时向所述有需要的患者进行静脉输注。
在一些实施方案中，所述治疗剂被配制成适于每间隔约12小时向所述有需要的患者进行静脉输注。
在一些实施方案中，所述治疗剂被配制成适于每次以约20分钟至约3小时的静脉输注时间施用于所述有需要的患者。
在一些实施方案中，所述治疗剂被配制成适于每次以约60分钟的静脉输注时间施用于所述有需要的患者。
在一些实施方案中，所述治疗剂在单次所述静脉输注中包含约100mg至约400mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
在一些实施方案中，所述治疗剂在单次所述静脉输注中包含约200mg至约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
在一些实施方案中，所述治疗剂在单次所述静脉输注中包含约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
在一些实施方案中，所述治疗剂还包含选自其他药物、药学上可接受的载体、溶剂和缓冲液的其他组分。
在一些实施方案中，所述其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物彼此不混合。
在一些实施方案中，所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上 可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物相互混合。
在一些实施方案中，所述急性细菌性皮肤和皮肤结构感染由革兰氏阳性菌感染引起。
在一些实施方案中，所述革兰氏阳性菌包含其耐药菌株。
在一些实施方案中，所述急性细菌性皮肤和皮肤结构感染由金黄色葡萄球菌感染和/或凝固酶阴性葡萄球菌感染引起。
在一些实施方案中，所述金黄色葡萄球包含其耐药菌株，且所述凝固酶阴性葡萄球菌包含其耐药菌株。
在一些实施方案中，所述治疗剂被配制成适于与有效量的其他治疗剂共同施用于所述有需要的患者。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中，术语“有需要的患者”通常可包括接受预防性或治疗性治疗的人类患者和其它哺乳动物对象包括但不限于非人类灵长类动物、实验动物如兔子、犬类、大鼠和小鼠、以及其它动物。这些“有需要的患者”示例性地可以是患有确诊的特定疾病的对象、正在接受特定疾病相关治疗的对象、有发展成特定疾病的趋势或风险的对象等。
在本申请中，术语“治疗剂”通常是指当适当施用患者时能够诱导所需治疗效果、预防产生某种病症、或使相关病症减轻的化合物、化合物的混合物、组合物、生物大分子或由生物材料制成的提取物。
在本申请中，术语“药学上可接受的盐”通常是指保留母体化合物(例如，式(I)所示的化合物)的生物学效能和性质的常规酸-或碱-加成盐。仅作为示例，酸-加成盐可以由适合的非毒性的有机或无机酸形成，样品酸-加成盐包括从无机酸诸如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、磷酸和硝酸等衍生的那些，和从有机酸诸如对-甲苯磺酸、萘磺酸、萘二磺酸、甲磺酸、乙磺酸、三氟乙酸等衍生的那些；碱-加成盐包括从无机碱衍生出的诸如钠盐、钾盐、锂盐、铵盐、钙盐和镁盐，和从有机碱衍生的诸如伯胺、仲胺和叔胺的盐。将(药物)化合物化学修饰成盐对于药物化学家是众所周知的技术，以获得化合物的改进的物理和化学稳定性、 吸湿性、流动性和溶解度。参见，例如，Ansel，H.，等，Pharmaceutical Dosage Forms and Drug Delivery Systems，6th ed.，1995。
在本申请中，术语“溶剂化物”和“溶剂合物”可互换使用，其通常是指一个或多个溶剂分子与本申请的盐型化合物的缔合物或复合物。形成溶剂合物的溶剂的例子包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”通常是指其中的溶剂分子是水的复合物。
在本申请中，术语“前药”通常是指该前药物质在对患者施用并且之后可以代谢形成具有本申请化合物结构的物质；术语“代谢产物”通常是指本申请的化合物在对患者施用并且之后代谢得到的物质，这类衍生物所包含的前药和代谢产物包括在本申请发明的范围内。
在本申请中，术语“氘代物”和“氘代化合物”可互换使用，其通常是指有机化合物中的一个或多个氢原子被氘原子取代后获得的新化合物。
在本申请中，术语“药物”通常是指具有所需生物学效力的分子。药物可以是预防性或治疗性的。药物可以包括不限于：蛋白分子，包括但不限于肽，多肽，蛋白质，包括翻译后修饰的蛋白质、融合蛋白、抗体等；小分子，包括无机或有机化合物；核酸分子，包括但不限于双链或单链DNA、或双链或单链RNA(如反义(分子)、RNAi等)、内含子序列、三螺旋核酸分子和适体；或疫苗(如，利斯特和非利斯特疫苗)。药物可获自任何已知的生物(包括但不限于：动物、植物、细菌、真菌和原生动物或病毒)或合成分子库。
在本申请中，术语“药学上可接受的载体”通常是指不干扰活性成分的生物活性的有效性的一种或多种非毒性材料。这类制剂常规地可以含有盐、缓冲剂、防腐剂、相容的载体、以及任选地其他治疗剂。这类药学上可接受的制剂还可以包含适于给予人的相容的固体或液体填料、稀释剂或包封物质。可以用于在此所述的配制品中的其他设想的载体、赋形剂、和/或添加剂，可包括，例如调味剂、抗微生物剂、增甜剂、抗氧化剂、抗静电剂、脂质、蛋白质赋形剂(如血清白蛋白、明胶、酪蛋白)、成盐平衡离子(如钠)等等。适合用于在此所述的配制品中的这些和另外已知的药物载体、赋形剂和/或添加剂是本领域中已知的，例如，“雷明顿药物科学与实践(Remington:The Science&Practice of Pharmacy)”，第21版，利平科特威廉斯与威尔金斯出版公司(Lippincott Williams&Wilkins)(2005)以及“医师案头参考(Physician’sDesk Reference)”，第60版，医药经济出版社(Medical Economics)，蒙特维尔(Montvale)，新泽西(2005)中所列出的。可以常规地选择对于所希望或所要求的给予方式、溶解度和/或稳定性来决定合适的药学上可接受的载体。
在本申请中，术语“混合”通常是指将在相同的区域中一种或多种化合物、细胞、分子等组合在一起的过程。这可以例如在试管、培养皿或允许混合一种或多种化合物、细胞或分子的任意容器中进行。
在本申请中，术语“施用”通常是指通过任意引入或递送途径将所述药物或包含所述药物的组合物(例如，本申请提供的治疗剂)引入患者的身体中。可以采用本领域技术人员已知的用于使细胞、器官或组织与所述药物或其组合物接触的任何方法。
在本申请中，术语“包含”通常是指包括明确指定的特征，但不排除其他要素。术语“以上”、“以下”或“以内”通常是指不包含本数的情况。
在本申请中，术语“选自”通常是指包括选择的对象以及其所有组合。例如“选自(：)A、B和C”意指包括A、B和C的所有组合，例如，A、B、C、A+B、A+C、B+C或A+B+C。
在本申请中，术语“有效量”或“有效剂量”可互换地使用，通常是指足够获得或至少部分获得预期疗效的量，当用于有需要的患者时，其通常是指足够使一个已经患病的病人治愈或至少部分阻止该病及其并发症的量。对于这种用途有效的量将依赖于所述病人感染的严重程度和病人自身免疫系统的整体状态。
在本申请中，术语“共同施用”通常是指本申请所述的治疗剂与其他治疗剂或药物作为一个单一制剂或作为多个独立制剂的施用。共同施用可以是同时进行的或以任何顺序相继进行的，例如，可优选在两种(或所有)药物活性成分同时发挥其生物活性时持续一定的时间段。所述本申请的治疗剂和其他治疗剂不一定由相同的施用途径施用。
在本申请中，术语“约”或“大约”通常由本领域普通技术人员确定的针对特定值的可接受误差范围内，其部分取决于怎样测量或确定该值，即，测量系统的限制。例如，“约”或“大约”可意指按照本领域的实践在1或超过1个标准偏差内。或者，“约”或“大约”可意指至多10％或20％的范围(即，±10％或±20％)。例如，约3mg可包括2.7mg和3.3mg之间(对于10％)或2.4mg和3.6mg之间(对于20％)的任何数量。此外，特别是关于生物学系统或过程，该术语可意指至多一个数量级的值或至多5倍的值。当具体的值或组合物在本说明书和所附权利要求书中提供时，除了另外说明，“约”或“大约”的含义应假定在对于该具体的值或组合物可接受的误差范围内。
发明详述
一方面，本申请提供预防或治疗急性细菌性皮肤和皮肤结构感染(ABSSSI)、或者减轻 所述ABSSSI相关病症的方法，所述方法包括持续7天以内向有需要的患者静脉输注治疗剂，每次所述静脉输注的治疗剂包含约10mg至约500mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。例如，所述方法可包括持续1天、持续2天、持续3天、持续4天、持续5天或持续6天向所述有需要的患者静脉输注所述治疗剂。例如，所述治疗剂所包含的式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物可约为：10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、410mg、420mg、430mg、440mg、450mg、460mg、470mg、480mg、490mg或500mg。更进一步地，在一些实施方案中，所述治疗剂可包含约100mg至约400mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。例如，所述治疗剂所包含的式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物可约为：100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg或400mg。在一些实施方案中，所述治疗剂可包含约200mg至约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。例如，所述治疗剂所包含的式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物可约为：200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg或300mg。示例性地，所述治疗剂可包含约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
在一些实施方案中，所述方法包括每间隔约8小时至每间隔约24小时向所述有需要的患者静脉输注所述治疗剂。例如，所述方法包括以任选自下列所述的时间间隔向所述有需要的患者静脉输注所述治疗剂：约每8小时、约每9小时、约每10小时、约每11小时、约每12小时、约每13小时、约每14小时、约每15小时、约每16小时、约每17小时、约每18小时、约每19小时、约每20小时、约每21小时、约每22小时、约每23小时和约每24小时。在本申请所述的持续7天以内向所述有需要的患者静脉输注所述治疗剂的期间，可保持以相同的时间间隔进行所述输注，也可根据所述患者的实际需求或遵照医嘱改变输注的时间间隔。例如，所述方法包括每间隔约12小时向所述有需要的患者静脉输注所述治疗剂。
在一些实施方案中，所述静脉输注的单次输注时间为约20分钟至约3小时。例如，所述静脉输注可持续的单次输注时间可约为：20分钟、30分钟、40分钟、50分钟、60分钟(1小时)、70分钟、80分钟、90分钟、100分钟、110分钟、120分钟(2小时)、130分钟、140分钟、150分钟、160分钟、170分钟或180分钟(3小时)。更进一步地，在一些实施方案中，所述单次静脉输注可持续60±10分钟。例如，所述静脉输注可持续的单次输注时间可约为：50分钟、51分钟、52分钟、53分钟、54分钟、55分钟、56分钟、57分钟、58分钟、59分钟、60分钟、61分钟、62分钟、63分钟、64分钟、65分钟、66分钟、67分钟、68分钟、69分钟或70分钟。例如，所述静脉输注的单次输注时间为约60分钟。
在一些实施方案中，所述治疗剂还包含选自其他药物、药学上可接受的载体、溶剂和缓冲液的其他组分。例如，所述其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物彼此不混合。例如，所述彼此不混合可指其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物均分别放置在不同的容器和/或装置中。例如，所述彼此不混合可指所述治疗剂中放置所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物的容器或装置，和放置其他组分的容器或装置均分别置于不同的储存空间和/或不同的储存条件下。例如，所述彼此不混合可指其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物分别在各自放置的容器和/或装置中以特定计量单位分装保存。例如，所述彼此不混合可指其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物仅在使用所述治疗剂前进行混合，该混合过程可包括使用包含或不包含在所述治疗剂中的混合装置、将其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物转移到放置另一组分的容器或装置中进行混合，和/或将其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物均转移到另外的容器或装置中进行混合。
在一些实施方案中，所述治疗剂包含选自其他药物、药学上可接受的载体、溶剂和缓冲液的其他组分，且所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物相互混合。例如，所述相互混合可指所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物被混合放置在同一容器或装置中。例如，所述相互混合可指所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物混合后以特定计量单位分装保存在同一个或不同容器或装 置中。例如，所述相互混合可指所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物混合后，在所述治疗剂被使用前仍需要进一步充分混合(例如需要用力摇匀使其充分混合)。
在一些实施方案中，所述急性细菌性皮肤和皮肤结构感染由革兰氏阳性菌感染引起。例如，所述革兰氏阳性菌还可包含其耐药菌株。在一些实施方案中，所述急性细菌性皮肤和皮肤结构感染由金黄色葡萄球菌感染和/或凝固酶阴性葡萄球菌感染引起。例如，所述金黄色葡萄球还可包含其耐药菌株，且所述凝固酶阴性葡萄球菌还可包含其耐药菌株。具体地，所述凝固酶阴性葡萄球菌可选自表皮葡萄球菌、腐生葡萄球菌、木葡萄球菌、溶血葡萄球菌、头状葡萄球菌、华纳葡萄球菌、模仿葡萄球菌、木糖葡萄球菌和猿类葡萄球菌。在本申请中，所述耐药菌株可以是抗利福霉素(例如，利福平)单耐药的、抗喹诺酮或喹嗪酮单耐药的、或者抗利福霉素和喹嗪酮双耐药的。例如，所述耐药菌株还可以是对其他抗生素耐药的，其中包括对大环内酯类药物如克拉霉素、阿奇霉素、罗红霉素等耐药；对硝基咪唑类药物如甲硝唑、奥硝唑、普瑞玛尼、德拉马尼等耐药；对氨基糖苷类药物如链霉素、阿米卡星等耐药；对β-内酰胺类药物如甲氧西林、氨苄西林、阿莫西林等耐药；对四环素类药物如四环素、替加环素、米诺环素等耐药；对恶唑烷酮类药物如利奈唑胺、特地唑胺等耐药；对硝基呋喃类药物如呋喃唑酮等耐药；对多肽类药物如万古霉素、多粘菌素等耐药；对二芳基喹啉类药物如贝达喹啉耐药以及氯法齐明耐药等。
在一些实施方案中，所述方法还包括向所述有需要的患者施用有效量的其他治疗剂。例如，所述方法还包括通过注射给药(例如，静脉注射、肌肉注射和/或皮下注射)、口服给药、腔内给药、肠内给药和/或透皮吸收向所述患者施用有效量的其他治疗剂。例如，所述其他治疗剂可选自抗菌剂、麻醉剂、镇痛药、镇静药、激素药、抗炎药、抗凝剂、血小板聚集抑制剂、退热剂、细胞膜渗透剂和肌松药等。
另一方面，本申请提供式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物在制备静脉输注治疗剂中的用途，所述治疗剂用于预防或治疗急性细菌性皮肤和皮肤结构感染(ABSSSI)或者减轻所述ABSSSI相关病症，且所述治疗剂单次输注的剂量包含约10mg至约500mg的式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物，以及所述治疗剂被配制成适于持续7天以内向有需要的患者进行静脉输注。例如，所述治疗剂被配制成适于持续1天、持续2天、持续3天、持续4天、持续5天或持续6天向所述有需要的患者静脉输注所述治疗剂。例如，所述治疗剂所包含的式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢 产物或氘代物可约为：10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、410mg、420mg、430mg、440mg、450mg、460mg、470mg、480mg、490mg或500mg。更进一步地，在一些实施方案中，所述治疗剂可包含约100mg至约400mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。例如，所述治疗剂所包含的式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物可约为：100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg或400mg。在一些实施方案中，所述治疗剂可包含约200mg至约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。例如，所述治疗剂所包含的式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物可约为：200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg或300mg。示例性地，所述治疗剂可包含约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
在一些实施方案中，所述治疗剂被配制成适于每间隔约8小时至每间隔约24小时向所述有需要的患者进行静脉输注。例如，所述治疗剂被配制成适于以任选自下列所述的时间间隔向所述有需要的患者进行静脉输注：约每8小时、约每9小时、约每10小时、约每11小时、约每12小时、约每13小时、约每14小时、约每15小时、约每16小时、约每17小时、约每18小时、约每19小时、约每20小时、约每21小时、约每22小时、约每23小时和约每24小时。在本申请所述的治疗剂被持续7天以内向所述有需要的患者进行静脉输注的期间，所述治疗剂可被配制成适于以相同的所述时间间隔进行静脉输注，也可根据所述患者的实际需求或遵照医嘱配制适于不同输注时间间隔的治疗剂。例如，所述治疗剂被配制成适于以每间隔约12小时向所述有需要的患者进行静脉输注。
在一些实施方案中，所述治疗剂被配制成适于每次以约20分钟至约3小时的静脉输注时间施用于所述有需要的患者。例如，所述治疗剂被配制成适于以任选自下列所述的单次输注时间施用于所述有需要的患者：约20分钟、约30分钟、约40分钟、约50分钟、约60分钟(1小时)、约70分钟、约80分钟、约90分钟、约100分钟、约110分钟、约120分钟(2 小时)、约130分钟、约140分钟、约150分钟、约160分钟、约170分钟和约180分钟(3小时)。更进一步地，在一些实施方案中，所述治疗剂被配制成适于以60±10分钟的单次输注时间施用于所述有需要的患者。例如，所述治疗剂被配制成适于以任选自下列所述的单次输注时间施用于所述有需要的患者：50分钟、51分钟、52分钟、53分钟、54分钟、55分钟、56分钟、57分钟、58分钟、59分钟、60分钟、61分钟、62分钟、63分钟、64分钟、65分钟、66分钟、67分钟、68分钟、69分钟或70分钟。例如，所述治疗剂被配制成适于每次以约60分钟的静脉输注时间施用于所述有需要的患者。
在一些实施方案中，所述治疗剂还包含选自其他药物、药学上可接受的载体、溶剂和缓冲液的其他组分。例如，所述其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物彼此不混合。例如，所述彼此不混合可指其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物均分别放置在不同的容器和/或装置中。例如，所述彼此不混合可指所述治疗剂中放置所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物的容器或装置，和放置其他组分的容器或装置均分别置于不同的储存空间和/或不同的储存条件下。例如，所述彼此不混合可指其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物分别在各自放置的容器和/或装置中以特定计量单位分装保存。例如，所述彼此不混合可指其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物仅在使用所述治疗剂前进行混合，该混合过程可包括使用包含或不包含在所述治疗剂中的混合装置、将其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物转移到放置另一组分的容器或装置中进行混合，和/或将其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物均转移到另外的容器或装置中进行混合。
在一些实施方案中，所述治疗剂包含选自其他药物、药学上可接受的载体、溶剂和缓冲液的其他组分，且所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物相互混合。例如，所述相互混合可指所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物被混合放置在同一容器或装置中。例如，所述相互混合可指所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物混合后以特定计量单位分装保存在同一个或不同容器或装置中。例如，所述相互混合可指所述其他组分的一种或一种以上与所述式(I)化合物和/或其 药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物混合后，在所述治疗剂被使用前仍需要进一步充分混合(例如需要用力摇匀使其充分混合)。
在一些实施方案中，所述急性细菌性皮肤和皮肤结构感染由革兰氏阳性菌感染引起。例如，所述革兰氏阳性菌还可包含其耐药菌株。在一些实施方案中，所述急性细菌性皮肤和皮肤结构感染由金黄色葡萄球菌感染和/或凝固酶阴性葡萄球菌感染引起。例如，所述金黄色葡萄球还可包含其耐药菌株，且所述凝固酶阴性葡萄球菌还可包含其耐药菌株。具体地，所述凝固酶阴性葡萄球菌可选自表皮葡萄球菌、腐生葡萄球菌、木葡萄球菌、溶血葡萄球菌、头状葡萄球菌、华纳葡萄球菌、模仿葡萄球菌、木糖葡萄球菌和猿类葡萄球菌。在本申请中，所述耐药菌株可以是抗利福霉素(例如，利福平)单耐药的、抗喹诺酮或喹嗪酮单耐药的、或者抗利福霉素和喹嗪酮双耐药的。例如，所述耐药菌株还可以是对其他抗生素耐药的，其中包括对大环内酯类药物如克拉霉素、阿奇霉素、罗红霉素等耐药；对硝基咪唑类药物如甲硝唑、奥硝唑、普瑞玛尼、德拉马尼等耐药；对氨基糖苷类药物如链霉素、阿米卡星等耐药；对β-内酰胺类药物如甲氧西林、氨苄西林、阿莫西林等耐药；对四环素类药物如四环素、替加环素、米诺环素等耐药；对恶唑烷酮类药物如利奈唑胺、特地唑胺等耐药；对硝基呋喃类药物如呋喃唑酮等耐药；对多肽类药物如万古霉素、多粘菌素等耐药；对二芳基喹啉类药物如贝达喹啉耐药以及氯法齐明耐药等。
在一些实施方案中，所述治疗剂被配制成适于与有效量的其他治疗剂共同施用于所述有需要的患者。例如，所述治疗剂可被配制成适于与有效量的其他治疗剂共同施用于所述有需要的患者，其中，所述其他治疗剂可通过注射给药(例如，静脉注射、肌肉注射和/或皮下注射)、口服给药、腔内给药、肠内给药和/或透皮吸收施用于所述患者。例如，所述其他治疗剂可选自抗菌剂、麻醉剂、镇痛药、镇静药、激素药、抗炎药、抗凝剂、血小板聚集抑制剂、退热剂、细胞膜渗透剂和肌松药等。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的方法和用途等，而不用于限制本申请发明的范围。
实施例
实施例1
本申请治疗方法的有效性分析
1.实验方法
本实施例将符合条件的患者随机分配到以下2个治疗组中的一个：(1)A组：接受至少 3天、每间隔12小时(q12h)、每次约60分钟的静脉输注，每次输注的治疗剂包含300mg式(I)化合物，并在首次给药后48小时至72小时的早期评估(EA)时间窗后，根据临床判断受试患者将停止治疗、继续接受该静脉输注治疗(静脉治疗最长不超过14天)或转为接受对革兰氏阳性微生物有活性的系统性抗菌药的口服治疗(需判断是否满足转换标准)；(2)B组：接受至少3天、每间隔12小时(q12h)、每次约60分钟的静脉输注，每次输注的治疗剂配制剂量为15mg/kg的万古霉素，并在首次给药后48小时至72小时的早期评估(EA)时间窗后，根据临床判断受试患者将停止治疗、继续接受该静脉输注治疗(静脉治疗最长不超过14天)或转为接受对革兰氏阳性微生物有活性的系统性抗菌药的口服治疗(需判断是否满足转换标准)。然后在按照如下表定义所划分的ITT、mITT和micro-ITT人群中，比较接受式(I)化合物静脉输注治疗的受试者和接受万古霉素静脉输注治疗的受试者分别的EA访视时的早期临床应答(百分比)。
2.实验结果及分析
表1早期评估访视时的早期临床应答(ITT/mITT/micro-ITT人群)

注：
CI＝置信区间；n＝各人群中的应答者数量；N＝各人群中的总受试者数量，百分比计
算公式为100×(n/N)。
a：使用精确(Clopper-Pearson)置信限计算应答率的95％CI。
b：式(I)化合物应答率减去万古霉素应答率的差值，该差值的CI基于Miettinen-
Nurminen方法。
表1的结果显示，在式(I)化合物治疗组和万古霉素治疗组中，ITT人群应答率分别为76.3％和67.5％，mITT人群应答率分别为76.9％和67.5％，micro-ITT人群应答率分别为80.4％和65.5％，可见式(I)化合物的治疗效果优于万古霉素。
表2按基线病原体分类的早期评估访视时的早期临床应答(micro-ITT人群)

注：
N＝micro-ITT人群中的受试者数量，N1＝micro-ITT人群中具有特定基线病原体的受试
者数量，n＝特定类别中的应答者数量，百分比计算公式为100×(n/N1)。
计数方法：在超过一份标本中具有相同病原体的受试者在该病原体中计数一次。从血液和原发ABSSSI培养物中鉴定出相同病原体的受试者仅计数一次。同时存在MRSA和MSSA、CRSA或CSSA、RRSA和RSSA的受试者在整个金黄色葡萄球菌行中计数一次。应答均基于EA访视时的早期临床应答。
表2的结果表明，式(I)化合物的治疗组受试者针对常见耐药菌种的应答率均高于万古霉素治疗组。

Claims (32)

  1. 预防或治疗急性细菌性皮肤和皮肤结构感染(ABSSSI)、或者减轻所述ABSSSI相关病症的方法，所述方法包括持续7天以内向有需要的患者静脉输注治疗剂，每次所述静脉输注的治疗剂包含约10mg至约500mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物，
  2. 根据权利要求1所述的方法，所述方法包括每间隔约8小时至每间隔约24小时向所述有需要的患者静脉输注所述治疗剂。
  3. 根据权利要求1-2中任一项所述的方法，所述方法包括每间隔约12小时向所述有需要的患者静脉输注所述治疗剂。
  4. 根据权利要求1-3中任一项所述的方法，所述静脉输注的单次输注时间为约20分钟至约3小时。
  5. 根据权利要求1-4中任一项所述的方法，所述静脉输注的单次输注时间为约60分钟。
  6. 根据权利要求1-5中任一项所述的方法，每次所述静脉输注的治疗剂包含约100mg至约400mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
  7. 根据权利要求1-6中任一项所述的方法，每次所述静脉输注的治疗剂包含约200mg至约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
  8. 根据权利要求1-7中任一项所述的方法，每次所述静脉输注的治疗剂包含约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
  9. 根据权利要求1-8中任一项所述的方法，所述治疗剂还包含选自其他药物、药学上可接受的载体、溶剂和缓冲液的其他组分。
  10. 根据权利要求9所述的方法，所述其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物彼此不混合。
  11. 根据权利要求9所述的方法，所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物相互混合。
  12. 根据权利要求1-11中任一项所述的方法，所述急性细菌性皮肤和皮肤结构感染由革兰氏阳性菌感染引起。
  13. 根据权利要求1-12中任一项所述的方法，所述急性细菌性皮肤和皮肤结构感染由金黄色葡萄球菌感染和/或凝固酶阴性葡萄球菌感染引起。
  14. 根据权利要求12所述的方法，所述革兰氏阳性菌包含其耐药菌株。
  15. 根据权利要求13所述的方法，所述金黄色葡萄球包含其耐药菌株，且所述凝固酶阴性葡萄球菌包含其耐药菌株。
  16. 根据权利要求1-15中任一项所述的方法，所述方法还包括向所述有需要的患者施用有效量的其他治疗剂。
  17. 式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物在制备静脉输注治疗剂中的用途，所述治疗剂用于预防或治疗急性细菌性皮肤和皮肤结构感染(ABSSSI)或者减轻所述ABSSSI相关病症，且所述治疗剂单次输注的剂量包含约10mg至约500mg的式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物，以及所述治疗剂被配制成适于持续7天以内向有需要的患者进行静脉输注。
  18. 根据权利要求17所述的用途，所述治疗剂被配制成适于每间隔约8小时至每间隔约24小时向所述有需要的患者进行静脉输注。
  19. 根据权利要求17-18中任一项所述的用途，所述治疗剂被配制成适于每间隔约12小时向所述有需要的患者进行静脉输注。
  20. 根据权利要求17-19中任一项所述的用途，所述治疗剂被配制成适于每次以约20分钟至约3小时的静脉输注时间施用于所述有需要的患者。
  21. 根据权利要求17-20中任一项所述的用途，所述治疗剂被配制成适于每次以约60分钟的静脉输注时间施用于所述有需要的患者。
  22. 根据权利要求17-21中任一项所述的用途，所述治疗剂在单次所述静脉输注中包含约100mg至约400mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
  23. 根据权利要求17-22中任一项所述的用途，所述治疗剂在单次所述静脉输注中包含约200mg至约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
  24. 根据权利要求17-23中任一项所述的用途，所述治疗剂在单次所述静脉输注中包含约300mg式(I)所示的化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物。
  25. 根据权利要求17-24中任一项所述的用途，所述治疗剂还包含选自其他药物、药学上可接受的载体、溶剂和缓冲液的其他组分。
  26. 根据权利要求25所述的用途，所述其他组分与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物彼此不混合。
  27. 根据权利要求25所述的用途，所述其他组分的一种或一种以上与所述式(I)化合物和/或其药学上可接受的盐、水合物、溶剂化物、前药、代谢产物或氘代物相互混合。
  28. 根据权利要求17-27中任一项所述的用途，所述急性细菌性皮肤和皮肤结构感染由革兰氏阳性菌感染引起。
  29. 根据权利要求28所述的用途，所述革兰氏阳性菌包含其耐药菌株。
  30. 根据权利要求17-29中任一项所述的用途，所述急性细菌性皮肤和皮肤结构感染由金黄色葡萄球菌感染和/或凝固酶阴性葡萄球菌感染引起。
  31. 根据权利要求30所述的用途，所述金黄色葡萄球包含其耐药菌株，且所述凝固酶阴性葡萄球菌包含其耐药菌株。
  32. 根据权利要求17-31中任一项所述的用途，所述治疗剂被配制成适于与有效量的其他治疗剂共同施用于所述有需要的患者。
PCT/CN2023/100594 2023-06-16 2023-06-16 化合物治疗疾病的方法及其用途 Ceased WO2024254840A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2023/100594 WO2024254840A1 (zh) 2023-06-16 2023-06-16 化合物治疗疾病的方法及其用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2023/100594 WO2024254840A1 (zh) 2023-06-16 2023-06-16 化合物治疗疾病的方法及其用途

Publications (1)

Publication Number Publication Date
WO2024254840A1 true WO2024254840A1 (zh) 2024-12-19

Family

ID=93851184

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/100594 Ceased WO2024254840A1 (zh) 2023-06-16 2023-06-16 化合物治疗疾病的方法及其用途

Country Status (1)

Country Link
WO (1) WO2024254840A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101031572A (zh) * 2004-07-22 2007-09-05 坎布里制药公司 (r/s)利福霉素衍生物，它们的制备和药物组合物
CN109464673A (zh) * 2019-01-08 2019-03-15 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子及其盐的应用和制剂
CN109529045A (zh) * 2019-01-08 2019-03-29 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子及其药学上可接受的盐的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101031572A (zh) * 2004-07-22 2007-09-05 坎布里制药公司 (r/s)利福霉素衍生物，它们的制备和药物组合物
CN109464673A (zh) * 2019-01-08 2019-03-15 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子及其盐的应用和制剂
CN109529045A (zh) * 2019-01-08 2019-03-29 丹诺医药(苏州）有限公司 利福霉素-喹嗪酮偶联分子及其药学上可接受的盐的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
WANG MIN, YUAN MING-MING, LI SHU-JUN, LI HE-PING, ZHANG QING-YE, ZHANG YU-QIN: "Study on the distribution and resistance of bacterial strains isolated from adult with bacterial dermatic infection", JOURNAL OF PATHOGEN BIOLOGY, vol. 15, no. 7, 30 July 2020 (2020-07-30), CN , pages 846 - 849, XP093248303, ISSN: 1673-5234, DOI: １０．１３３５０／ｊ． *
ZHANG WENTAO, YANG WEIJIANG, LUO JIEFU, YANG TAO, CHEN JINYI, TAN YANG, LI JING, LEI XIA: "Analysis of pathogenic bacteria distribution and drug resistance in patients with dermatological infection", CHONGQING MEDICAL JOURNAL, vol. 50, no. 10, 9 December 2020 (2020-12-09), CN , pages 1663 - 1667, XP093248296, ISSN: 1671-8348, DOI: １０．３９６９／ｊ *
ZHENKUN MA, ANTHONY SIMON LYNCH: "Development of a Dual-Acting Antibacterial Agent (TNP-2092) for the Treatment of Persistent Bacterial Infections", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 14, 28 July 2016 (2016-07-28), US , pages 6645 - 6657, XP055718162, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b00485 *

Similar Documents

Publication Publication Date Title
US20240226119A9 (en) Minocycline compounds and methods of use thereof
JP7232128B2 (ja) 抗菌剤及び抗炎症剤を含む眼内投与のための医薬組成物
AU2012207698A1 (en) Injectable compositions for mastitis comprising an NSAID and an antibiotic in a non-aqueous solvent
UA82359C2 (uk) Композиція (варіанти) і спосіб лікування мікробних і паразитних інфекцій у великої рогатої худоби і інших тварин
WO2016131100A1 (en) Methods of treating infectious diseases
EP4192247A1 (en) Antibacterial compositions and methods for fabricating thereof
AU2018298043A1 (en) Novel secnidazole soft gelatin capsule formulations and uses thereof
WO2024254841A1 (zh) 化合物治疗疾病的方法及其用途
US20200170990A1 (en) Method for treating schnitzler's syndrome
BRPI0918593B1 (pt) composição farmacêutica para uso no tratamento de infecções sexualmente transmitidas
WO2024221162A1 (zh) 化合物预防关节假体周围感染的方法
WO2024221160A1 (zh) 化合物治疗关节假体周围感染的方法
Sykes et al. Antimicrobial Therapy in Dogs and Cats
RU2195937C1 (ru) Комбинированный противотуберкулезный препарат (ризобутол)
AU2015268626B2 (en) Injectable compositions for mastitis comprising an NSAID and an antibiotic in a non-aqueous solvent
BR112012006250B1 (pt) composições para tratar infecções bacterianas usando ceftaroline
US20200330441A1 (en) Pediatric oral suspension formulations of amoxicillin and clavulanate potassium and methods for using same
WO2024243773A1 (zh) 关节腔给药方法及其用途
JP5322649B2 (ja) セフキノム組成物およびその使用方法
CN113456641B (zh) 一种化合物在制备抗真菌药物中的应用
TW202606673A (zh) Ｋｉｆ１８ａ抑制劑治療乳腺癌的用途
CN118697738A (zh) 药物及其用途
US20160193144A1 (en) Intraocular lens comprising pharmaceutical compositions and methods for fabricating thereof
CN121287624A (zh) 一种利奈唑胺脂质体吸入制剂及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23941075

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23941075

Country of ref document: EP

Kind code of ref document: A1