WO2022253159A1 - 5-硝基-8-羟基喹啉的应用 - Google Patents

5-硝基-8-羟基喹啉的应用 Download PDF

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Publication number
WO2022253159A1
WO2022253159A1 PCT/CN2022/095861 CN2022095861W WO2022253159A1 WO 2022253159 A1 WO2022253159 A1 WO 2022253159A1 CN 2022095861 W CN2022095861 W CN 2022095861W WO 2022253159 A1 WO2022253159 A1 WO 2022253159A1
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WIPO (PCT)
Prior art keywords
human papillomavirus
hydroxyquinoline
nitro
virus
pharmaceutically acceptable
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
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PCT/CN2022/095861
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English (en)
French (fr)
Inventor
邓一军
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.)
Jiangsu Yahong Meditech Co Ltd
Asieris Pharmaceuticals Shanghai Co Ltd
Original Assignee
Jiangsu Yahong Meditech Co Ltd
Asieris Pharmaceuticals Shanghai Co Ltd
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Publication date
Application filed by Jiangsu Yahong Meditech Co Ltd, Asieris Pharmaceuticals Shanghai Co Ltd filed Critical Jiangsu Yahong Meditech Co Ltd
Priority to US18/561,801 priority Critical patent/US20240238269A1/en
Priority to BR112023022649A priority patent/BR112023022649A2/pt
Priority to CA3219273A priority patent/CA3219273A1/en
Priority to EP22815205.4A priority patent/EP4349335A4/en
Priority to JP2023572619A priority patent/JP2024519988A/ja
Priority to KR1020237044054A priority patent/KR20240016311A/ko
Priority to CN202280018341.4A priority patent/CN116940360B/zh
Priority to MX2023013970A priority patent/MX2023013970A/es
Priority to AU2022284147A priority patent/AU2022284147A1/en
Publication of WO2022253159A1 publication Critical patent/WO2022253159A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
    • A61L2/16—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using chemical substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
    • A61L2/16—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using chemical substances
    • A61L2/18—Liquid substances
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2101/00—Chemical composition of materials used in disinfecting, sterilising or deodorising
    • A61L2101/32—Organic compounds

Definitions

  • the present disclosure relates to the fields of organic chemistry, medicine, antiviral therapy. In particular, it relates to the use of 5-nitro-8-hydroxyquinoline.
  • HPV Human papillomavirus
  • Papillomaviridae which is a very common type of virus in the world.
  • HPV members have mucosal epithelial and skin epithelial tropism. In addition to causing genital warts and other reproductive tract diseases, they can also cause cervical cancer, penile cancer, anal cancer, oral cancer, throat cancer, tonsil cancer, esophageal cancer, etc. various malignant tumors.
  • cervical cancer penile cancer
  • anal cancer oral cancer
  • throat cancer tonsil cancer
  • esophageal cancer etc. various malignant tumors.
  • There are more than 100 types of human papillomaviruses at least ten of which can cause cancer. It is the most important type of human tumor virus.
  • the virus has a high infection rate and strong pathogenicity, which is very harmful to the crowd, especially women, and has attracted extensive attention from the medical circles at home and abroad.
  • preventive multivalent vaccines HPV6, 11, 16, 18, etc.
  • HPV6 preventive multivalent vaccines
  • the development of effective drugs targeting multiple types of HPV can provide new methods for the clinical treatment and prevention of HPV-related diseases including malignant tumors.
  • the technical problem to be solved in this disclosure is to provide 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotope derivative or its prodrug in the preparation of antiviral drugs application, especially in the preparation of anti-human papillomavirus (HPV) medicaments.
  • HPV anti-human papillomavirus
  • the present disclosure provides a kind of 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotope derivative or its prodrug in the preparation of antiviral drugs Applications.
  • the antiviral drug is for use in mammals, preferably humans.
  • the virus is human papillomavirus; preferably human papillomavirus 6 (Human Papillomavirus 6, HPV6), human papillomavirus 11 (Human Papillomavirus 11, HPV11), human papillomavirus 16 (Human Papillomavirus 16, HPV16) and one or more of Human Papillomavirus 18 (HPV18).
  • human papillomavirus 6 Human Papillomavirus 6, HPV6
  • human papillomavirus 11 Human Papillomavirus 11, HPV11
  • human papillomavirus 16 Human Papillomavirus 16, HPV16
  • HPV18 Human Papillomavirus 18
  • the present disclosure provides 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotope derivative or its prodrug for treating viral infection .
  • the present disclosure provides a 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof or a precursor thereof for treating viral infections in mammals. medicine.
  • the mammal is preferably human.
  • the virus is human papillomavirus; preferably human papillomavirus 6 (Human Papillomavirus 6, HPV6), human papillomavirus 11 (Human Papillomavirus 11, HPV11), human papillomavirus 16 (Human Papillomavirus 16, HPV16) and one or more of Human Papillomavirus 18 (HPV18).
  • human papillomavirus 6 Human Papillomavirus 6, HPV6
  • human papillomavirus 11 Human Papillomavirus 11, HPV11
  • human papillomavirus 16 Human Papillomavirus 16, HPV16
  • HPV18 Human Papillomavirus 18
  • the present disclosure provides a method for treating viral infection, comprising the steps of: administering to a subject a therapeutically effective amount of 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal Forms, their solvates, their isotopic derivatives or their prodrugs.
  • the present disclosure provides a method for treating viral infection in mammals, comprising the steps of administering to a subject a therapeutically effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, or Crystal forms, solvates thereof, isotopic derivatives thereof or prodrugs thereof.
  • the mammal is preferably human.
  • the virus is human papillomavirus; preferably human papillomavirus 6 (Human Papillomavirus 6, HPV6), human papillomavirus 11 (Human Papillomavirus 11, HPV11), human papillomavirus 16 (Human Papillomavirus 16, HPV16) and one or more of Human Papillomavirus 18 (HPV18).
  • human papillomavirus 6 Human Papillomavirus 6, HPV6
  • human papillomavirus 11 Human Papillomavirus 11, HPV11
  • human papillomavirus 16 Human Papillomavirus 16, HPV16
  • HPV18 Human Papillomavirus 18
  • the present disclosure provides a pharmaceutical composition for treating viral infections, which comprises 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form, its solvate, and its isotopic derivatives Or its prodrug, and pharmaceutically acceptable excipients.
  • the present disclosure provides a pharmaceutical composition for treating viral infection in mammals, which comprises 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotope derivative Drugs or their prodrugs, and pharmaceutically acceptable excipients.
  • the virus is human papillomavirus; preferably human papillomavirus 6 (Human Papillomavirus 6, HPV6), human papillomavirus 11 (Human Papillomavirus 11, HPV11), human papillomavirus 16 (Human Papillomavirus 16, HPV16) and one or more of Human Papillomavirus 18 (HPV18).
  • human papillomavirus 6 Human Papillomavirus 6, HPV6
  • human papillomavirus 11 Human Papillomavirus 11, HPV11
  • human papillomavirus 16 Human Papillomavirus 16, HPV16
  • HPV18 Human Papillomavirus 18
  • the present disclosure provides a non-therapeutic method.
  • a method for in vitro disinfection includes the steps of: contacting the environment or object to be treated with an effective amount of 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form , its solvates, and its isotopic derivatives.
  • the positive progress effect of the present disclosure is: the present disclosure provides 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotopic derivatives or its prodrugs in terms of antiviral application, especially in the application of anti-human papilloma virus (HPV).
  • HPV anti-human papilloma virus
  • Nitroxoline the chemical name is 5-nitro-8-hydroxyquinoline, and the CAS number is 4008-48-4.
  • any compound selected from the following in the preparation of antiviral drugs 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form, its solvate, Its isotopic derivatives and its prodrugs.
  • any compound selected from the following in the preparation of a drug against human papillomavirus infection 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal Forms, their solvates, their isotopic derivatives, and their prodrugs.
  • a 5-nitro-8-hydroxyquinoline a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof for use in preventing Or treatment against human papillomavirus infection.
  • 5-nitro-8-hydroxyquinoline is provided as a pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts may be acid addition salts or base addition salts.
  • the acid can be an inorganic acid, including but not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; or can be an organic acid, including but not limited to: citric acid, maleic acid, oxalic acid, formic acid, acetic acid , propionic acid, valeric acid, glycolic acid, benzoic acid, fumaric acid, trifluoroacetic acid, succinic acid, tartaric acid, lactic acid, glutamic acid, aspartic acid, salicylic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid acid, p-benzenesulfonic acid.
  • the base can be an inorganic base, including but not limited to: sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; or can be an organic base, including but not limited to: ammonium hydroxide, triethyl Amines, N,N-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, arginine, or lysine; or may be an alkali metal salt, including but not limited to: lithium, potassium, and sodium salts (for example: sodium dihydrogen phosphate and disodium hydrogen phosphate); or may be Alkaline earth metal salts, including but not limited to: barium, calcium and magnesium salts; or can be transition metal salts, including but not limited to zinc salts.
  • inorganic base including but not limited to: sodium hydroxide, potassium hydroxide,
  • pharmaceutically acceptable refers to its use in the preparation of pharmaceutical compositions that are generally safe, non-toxic, biologically acceptable and acceptable as Drugs for mammals (eg humans).
  • 5-nitro-8-hydroxyquinoline may be provided in its crystalline form.
  • 5-nitro-8-hydroxyquinoline is provided in the form of a solvate thereof.
  • solvate means the form of 5-nitro-8-hydroxyquinoline with a suitable solvent.
  • the solvent is water.
  • the solvent is a pharmaceutically acceptable organic solvent.
  • 5-nitro-8-hydroxyquinoline is provided as an isotopic derivative thereof.
  • isotopically derivative refers to a compound that differs from 5-nitro-8-hydroxyquinoline only by the presence of one or more isotopically enriched atoms. For example, with its structure, only “deuterium” or “tritium” is substituted for hydrogen, and/or, 11 C, 13 C or 14 C is substituted for carbon, while the rest is unchanged.
  • 5-nitro-8-hydroxyquinoline is provided as a prodrug thereof.
  • prodrug refers to a derivative of 5-nitro-8-hydroxyquinoline that contains a bioreactive functional group such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the derivative or otherwise way to react to provide 5-nitro-8-hydroxyquinoline.
  • the prodrug of 5-nitro-8-hydroxyquinoline is (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropionylpyrrolidine- 2-Carboxylate, its structural formula is as follows:
  • the prodrug of 5-nitro-8-hydroxyquinoline can be formulated according to the methods disclosed in WO2021/238978.
  • an antiviral drug refers to any compound capable of inhibiting (or reducing, hindering, interfering, inactivating, killing) viral activity, vitality, replication, proliferation, growth, infectivity, or virulence in vivo or in vitro or composition.
  • antiviral drugs are used to prevent, treat, and improve virus-related diseases or symptoms in subjects.
  • antiviral drugs are used to prevent, treat, and improve human papillomavirus-related diseases or symptoms in subjects.
  • HPV Human papillomavirus
  • Papillomavirus A genus of the family Papovaviridae belongs to the Papillomavirus A genus of the family Papovaviridae.
  • HPV is a spherical DNA virus.
  • more than 130 different types of HPV have been isolated, which can be divided into:
  • High-risk mucosal types HPV16, 18, 30, 31, 33, 35, 53, 39, etc.
  • the antiviral drugs of the present disclosure are used for mucosal (high, low risk) human papillomavirus-related diseases or symptoms; mention may be made of: HPV6, 11, 13, 16, 18, 30, 31, 32, 33, 34, 35, 39, 40, 42, 43, 44, 53, 54.
  • the HPV is particularly selected from any one or combination of the following: human papillomavirus 6 (Human Papillomavirus 6, HPV6), human papillomavirus 11 (Human Papillomavirus 11, HPV11), human Papillomavirus 16 (Human Papillomavirus 16, HPV16) and Human Papillomavirus 18 (Human Papillomavirus18, HPV18).
  • human papillomavirus 6 Human Papillomavirus 6, HPV6
  • human papillomavirus 11 Human Papillomavirus 11, HPV11
  • human Papillomavirus 16 Human Papillomavirus 16, HPV16
  • Human Papillomavirus 18 Human Papillomavirus18, HPV18.
  • the present disclosure provides a method of preventing or treating a viral infection in a subject.
  • the method for preventing a viral infection in a subject comprises (or consists of): administering to the subject a prophylactically effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable Salts, crystal forms thereof, solvates thereof, isotopic derivatives thereof or prodrugs thereof.
  • the method of treating a viral infection in a subject comprises (or consists of): administering to the subject a therapeutically effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable Salts, crystal forms thereof, solvates thereof, isotopic derivatives thereof or prodrugs thereof.
  • administering when applied to an animal, human, subject, cell, tissue, organ, or biological fluid, refers to the interaction of an exogenous drug (such as a compound of the present disclosure), therapeutic agent, or composition with an animal, human, Exposure of subjects, cells, tissues, organs or biological fluids.
  • subject refers to mammals including, for example, camels, donkeys, zebras, cows, pigs, horses, goats, sheep, cats, dogs, rats, rabbits, guinea pigs, mice, primates.
  • the subject is a human.
  • the subject is a human who is exposed to, susceptible to, suspected of having, or has had a viral infection.
  • Having had should be understood in the broadest sense and also includes having a statistically significantly higher probability of having a viral infection than a control at a set significance level.
  • p is set at, for example but not limited to, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, 0.0001, or even lower.
  • two individuals or groups are considered to be statistically significantly different when the resulting p-value is less than a specified p-value when compared between them.
  • a subject is susceptible to, potentially exposed to, or exposed to a viral infection.
  • the subject is suspected of having or has had a viral infection.
  • treating refers to eliminating disease, arresting disease progression, slowing disease progression, reducing the duration of one or more symptoms associated with disease, amelioration or reversal of at least one measurable parameter associated with disease, or increasing the risk of disease. Survival of subjects with disease.
  • prevention refers to preventive measures against causative factors (such as exposure to viruses), which may be measures against the environment, or measures against the subject.
  • prevention is the treatment of an uninfected subject, environment or object by means of a compound or pharmaceutical composition of the present disclosure to prevent infection, reduce the risk of infection, reduce the probability of infection, delay the onset of symptoms of infection, or Seizures etc.
  • the term "effective amount” refers to the amount of a compound or pharmaceutical composition of the present disclosure that elicits a desired effect in a subject, environment or object.
  • a "therapeutically effective amount” is an amount sufficient to treat a disease state or symptom, especially a state or symptom associated with a viral infection state, or to prevent, delay or reverse a viral infection or other undesirable symptoms.
  • a “prophylactically effective amount” is an amount that, when administered to a subject, environment or object, will have a predetermined prophylactic effect.
  • the therapeutic or prophylactic effect does not necessarily occur after administration of one dose, but may occur after administration of a series of doses.
  • the selection of an effective amount can be determined by one skilled in the art based on consideration of a variety of factors, such as via clinical trials, including the activity of the disclosed compounds, the rate of metabolism of the particular compound used , the disease to be treated, the symptoms involved, the route of administration, the time of administration, the severity of the disease, the weight of the patient, the immune status of the patient, other drugs (compounds and/or materials) used in combination with the specific compound used, and Other factors known to those skilled in the art. Those skilled in the art can readily determine the required effective amount. Effective amounts can be derived from dose-response curves derived from animal model test systems and are allowed to be determined according to the judgment of the physician and each patient's circumstances. Among them, the relationship between the doses of animals and humans is described in Freireich et al. 1966, Cancer Chemother Rep 50: 219, and the body surface area can be approximately determined by the patient's height and weight.
  • a suitable daily dose of a compound of the present disclosure will be that amount of the compound effective to produce a prophylactic or therapeutic effect.
  • the effective amount of the disclosed compound can be 0.01 mg/kg to 500 mg/kg, preferably 1 mg/kg to 200 mg/kg, more preferably 10 mg/kg to 100 mg/kg; specifically 0.01, 0.05, 0.1, 0.5 , 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400 , 450, 500mg/kg, and the range between any two points above.
  • the daily dose of a compound of the present disclosure may, if desired, be administered at appropriate intervals throughout the day as two, three, four, five, six or more sub-doses administered separately; optionally, the sub-doses are Dosage in unit dosage form.
  • the pharmaceutical composition or compound provided in the present disclosure can be administered according to conventional clinical treatment methods, for example, for viral infection, it can be directly infused and applied to the infected site for administration; the dosage can be used according to the dosage determined by medical workers.
  • compositions or compounds provided herein are formulated for vaginal administration.
  • unit dosage refers to a physically discrete unit suitable as a unit dosage for administration to a subject, environment or object.
  • Each unit contains a predetermined amount of a compound of the present disclosure, or a composition thereof.
  • unit doses described in the present disclosure are expressed in volume and are selected from the group consisting of: 0.1ml, 0.15ml, 0.2ml, 0.5ml, 1.0ml, 1.5ml, 2.0ml, 2.5ml, 3.0ml , 4.0ml, 5.0ml, 10.0ml, 20.0ml, 30.0ml, 40.0ml, 50.0ml, 60.0ml, 70.0ml, 80.0ml, 90.0ml, 100.0ml, 150ml, 200ml, 250.00ml, and any two of the above between ranges.
  • the unit dose when administered vaginally to a human subject, is preferably in the range of 1 ml to 100 ml, such as 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 ml, and any two of the above range between.
  • the unit dose When administered subcutaneously to a human subject, the unit dose is preferably in the range of 0.5 ml to 1.0 ml.
  • the unit dose When administered intravenously to a human subject, the unit dose is preferably in the range of 30.0 ml to 1000 ml.
  • unit doses are expressed by volume, this does not mean that the disclosed compounds or compositions thereof can only be liquid formulations.
  • the unit dose volume may represent the volume of the dry or lyophilized powder when reconstituted as a liquid.
  • the subject is administered a compound of the present disclosure or a composition thereof at the following frequency: 1 to 4 times every 4 years, 1 to 3 times every 3 years, 1 to 2 times every 2 years, every year 1 time, 2 times a year, 3 times a year, 4 times a year, 5 times a year, 6 times a year, 1 time a month, 2 times a month, 3 times a month, 4 times a month, 5 times a month, every month 6 times, 7 times a month, 8 times a month, 1 time a week, 2 times a week, 3 times a week, 4 times a week, 5 times a week, 6 times a week, 1 time every three days, 2 times every three days, 3 times every three days, 1 time every 2 days, 2 times every 2 days, 1 time a day, 2 times a day.
  • the frequency of administration of a compound of the present disclosure, or a composition thereof may be the same or different.
  • the time interval between each administration is the same or different.
  • administration of a compound of the present disclosure or a composition thereof is systemic (also systemic) or local.
  • a compound of the present disclosure, or a composition thereof is administered by parenteral (eg, intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal) injection.
  • parenteral eg, intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal
  • a compound of the present disclosure or a composition thereof is administered intramuscularly.
  • the disclosed compounds or compositions thereof are delivered intradermally (eg, without mechanical means to disrupt the epithelial cell barrier).
  • the disclosed compounds or compositions thereof are administered rectally, vaginally.
  • the compounds of the present disclosure are used for non-therapeutic use.
  • a disinfectant (or disinfectant composition) is provided, which comprises an effective amount of 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, its crystal form, its solvate, its isotope derivative or its prodrug.
  • the antiseptic composition may also include one or more pharmaceutically acceptable adjuvants, which include conventional diluents, excipients, fillers, binders, etc. Agents, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants or synergists, etc.
  • aqueous and non-aqueous carriers examples include: water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol) or mixtures thereof, oils (such as olive oil, organic esters ).
  • the disinfectant composition can be prepared in the form of sprays, detergents, lotions, and culture media.
  • disinfectant especially refers to any virus activity that can inhibit (or reduce, block, interfere, inactivate, kill) in vitro (such as in the environment, objects, and its surface, etc.), A compound (or composition) of viability, replication, proliferation, growth, infectivity, or virulence.
  • the disinfectants (or disinfecting compositions) of the present disclosure are used to disinfect environments, areas, objects, samples, surfaces, containers, or food that are infected or contaminated by viruses.
  • a method of disinfection or antiviral suitable for treating an environment, area, item, sample, surface, container, or food product exposed to or threatened by a pathogen is provided.
  • a method of sanitizing by contacting an environment, area, item, sample, surface, container, or food with an effective amount of a compound of the present disclosure or a composition thereof.
  • the disclosed compounds or compositions thereof are applicable to various surfaces (especially hard surfaces where these viruses can remain active for a relatively long period of time), as well as commercial and public settings (such as hospitals, outpatient clinics, etc.) department, hotel) virus.
  • a compound of the present disclosure or a composition thereof is used as an additive.
  • an “effective amount” is that required or sufficient to inhibit (or reduce, impede, interfere with, inactivate, kill) the activity, vigor, replication, proliferation, growth, infectivity, or virulence of a virus quantity.
  • an effective amount of a compound of the disclosure is an amount that produces a statistically significant reduction in viral load, viral transmissibility, or viral viability in the environment.
  • a pharmaceutical composition comprising a compound of the present disclosure and optionally a pharmaceutically acceptable excipient.
  • Suitable pharmaceutically acceptable excipients are described in Remington Pharmaceutical Sciences by E.W. Martin.
  • the pharmaceutical composition includes one or more pharmaceutically acceptable excipients, which include conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, and agent, absorption enhancer, surfactant, adsorption carrier, lubricant or synergist, etc.
  • pharmaceutically acceptable excipients include conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, and agent, absorption enhancer, surfactant, adsorption carrier, lubricant or synergist, etc.
  • the difference from the pharmaceutical composition in liquid form lies in the difference in water content and/or the difference in the buffer environment.
  • the pharmaceutical composition of the present disclosure can be administered in the form of injections, suppositories, tablets, pills, capsules, suspensions, emulsions, sprays, disinfectants, and detergents.
  • the pharmaceutical composition may be in a form suitable for oral administration, such as tablet, troche, aqueous or oil suspension, dispersible powder or granules, emulsion, capsule, or syrup.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives.
  • Excipients suitable for the manufacture of tablets may be inert excipients (such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate); granulating agents and disintegrants (such as microcrystalline cellulose, croscarboxymethyl sodium cellulose, corn starch, or alginic acid); binders (such as starch, gelatin, polyvinylpyrrolidone, or acacia); and lubricants (such as magnesium stearate, stearic acid, or talc).
  • excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate
  • granulating agents and disintegrants such as microcrystalline cellulose, croscarboxymethyl sodium cellulose, corn starch, or alginic acid
  • binders such as starch, gelatin, polyvinylpyrrolidone, or acacia
  • lubricants such as magnesium stearate, stearic acid, or talc
  • aqueous suspensions contain a compound of the present disclosure and excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents (such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia); dispersing or wetting agents, which can be Naturally occurring phospholipids such as lecithin, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, polyethylene oxide sorbitan monooleate, or polyethylene oxide sorbitan monooleate).
  • Aqueous suspensions may also contain preservatives (eg, ethyl paraben or n-propyl paraben), coloring agents, flavoring agents.
  • oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as peanut, olive, sesame or coconut oil, or mineral oil.
  • Oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil (eg olive or peanut oil, or mineral oil).
  • Suitable emulsifiers may be naturally occurring phospholipids (such as soy lecithin).
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds.
  • a continuous intravenous delivery device can be used.
  • suppository forms for vaginal or rectal administration are provided.
  • These pharmaceutical compositions can be prepared by mixing a compound of the present disclosure with a non-irritating excipient (solid at ordinary temperatures, but liquid in the vagina or rectum).
  • a non-irritating excipient solid at ordinary temperatures, but liquid in the vagina or rectum.
  • Such compositions include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, or fatty acid esters of polyethylene glycols.
  • kits for implementing the above prevention or treatment, disinfection method which comprises at least one container, and the container independently comprises: the compound of the present disclosure or its composition.
  • the composition and/or amount in different containers may be the same or different.
  • the disclosed compounds or compositions thereof are formulated in sterile liquids and contained in sterile containers (eg, tubes, bottles, ampoules, syringes).
  • sterile containers eg, tubes, bottles, ampoules, syringes.
  • the disclosed compound or composition thereof is contained in a container in the form of dry powder or lyophilized powder. Just before use, reconstitute into liquid form.
  • the kit of the present disclosure further comprises one or a combination thereof selected from the following: needles, water for injection, and instructions for use.
  • Human papillomavirus 6 Human Papillomavirus 6, HPV6;
  • Human papillomavirus 11 Human papillomavirus 11, HPV11;
  • Human papillomavirus 16 Human papillomavirus 16, HPV16
  • Human papillomavirus 18 Human papillomavirus 18, HPV18;
  • SARS-CoV-2 Novel coronavirus
  • CHIKV Chikungunya Virus
  • Dengue Virus 2 Dengue Virus 2
  • MERS-CoV Middle East Respiratory Syndrome Coronavirus
  • RVFV Rift Valley Fever Virus
  • Tacaribe Virus TCRV
  • wt-cottontail rabbit papillomavirus (wt-CRPV);
  • mE8-cottontail rabbit papillomavirus (mE8-CRPV);
  • Murine Papillomavirus (MmuPV1).
  • Embodiment 1 prepares 5-nitro-8-hydroxyquinoline
  • the 5-nitro-8-hydroxyquinoline in the present disclosure is not limited by the preparation method, and can be obtained according to any preparation method disclosed in the prior art, or commercially available products can be used.
  • Embodiment 2 prepares the prodrug of 5-nitro-8-hydroxyquinoline
  • the evaluation system included a plasmid expressing the viral helicase E1 and the origin of replication binding protein E2, a plasmid containing the expression of the NanoLuc gene driven by the TK promoter (Promega), and the origin of replication sequences of the human papillomavirus strains listed below.
  • the cooperative binding and unwinding activity of E1 and E2 expressed by the plasmid drives the replication of the reporter plasmid, resulting in more than 100-fold increase in NanoLuc activity compared to E1 or E2 alone.
  • the replication origin sequence positions of the three NanoLuc reporter plasmids are 7825-7993:1-99, 7662-7901:1-99 and 7740-7837:1-102, respectively for HPV11 (NCBI accession number HE611260.1), HPV16 ( KP212151.1) and HPV18 (KC470230.1).
  • the sequence positions of the El open reading frame (ORF) corresponding to HPV11, HPV16 and HPV18 are the sequence parts of 832-2781, 864-2813 and 914-2887 in the same sequence, respectively.
  • the sequence positions of the E2 open reading frames (ORFs) corresponding to HPV11, HPV16 and HPV18 are the sequence parts of 2723-3826, 2755-3852 and 2817-3908 in the same sequence, respectively.
  • the test of HPV6 adopts the test method similar to the aforementioned HPV11, HPV16, and HPV18.
  • the cells for transient transfection were C-33A cells (ATCC HTB-31), and the medium was DMEM supplemented with Earle's salt, L-glutamine and 2% fetal bovine serum.
  • the NanoLuc expression plasmid (5 ng/well) and the E1 and E2 expression plasmids of the homologous virus were co-transfected with Lipofectamine LTX and PlusReagent (Invitrogen, Thermo Fisher Scientific Company). After incubation for 1 hour, the transfected cells were seeded into wells containing 5-fold diluted test drug and positive control drug 9-(2-phosphonomethoxyethoxy)guanine (PMEG) (Sigma-Aldrich) middle.
  • PMEG 9-(2-phosphonomethoxyethoxy)guanine
  • Transfected cells were also inoculated into duplicate dishes of the same dilution of the test drug to assess cytotoxicity. All transfected monolayers were incubated at 37°C for 48 hours.
  • the NanoLuc activity expressed by the reporter plasmid was detected with Nano-Glo reagent (Promega Company), the cell viability in the cytotoxicity plate was measured with CellTiter-Glo reagent (Promega Company), and the luminescence intensity was quantified on a microplate reader.
  • the concentration of the compound that reduces the reporter plasmid copy number by 50% (EC 50 ), 90% (EC 90 ) was identified from the experimental data.
  • the prodrug prepared in Example 2 was administered to animals (dogs), and it was detected in circulating samples that it was converted into the active form 5-nitro-8-hydroxyquinoline. Therefore, the prodrug and 5-nitro-8-hydroxyquinoline are equivalent in anti-HPV effect.

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Abstract

提供了一种5-硝基-8-羟基喹啉的应用。特别提供了一种5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药在制备抗病毒药物中的应用。所述5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药在抗人乳头状瘤病毒方面具有显著的活性。

Description

5-硝基-8-羟基喹啉的应用
本申请要求2021年05月31日中国专利申请(申请号2021106017773)的优先权。
技术领域
本公开涉及有机化学、医学、抗病毒治疗领域。具体而言，涉及5-硝基-8-羟基喹啉的应用。
背景技术
人乳头状瘤病毒(HPV)是属于乳头状瘤病毒科的一种DNA病毒，为世界范围内极为常见的一类病毒。HPV成员具有粘膜上皮和皮肤上皮嗜性，除了可以导致生殖器疣等多种生殖道疾病外，其还可以引起包括宫颈癌、阴茎癌、肛门癌、口腔癌、咽喉癌、扁桃体癌、食道癌等在内的多种恶性肿瘤。人乳头瘤病毒有100多种类型，其中至少有十多种类型可引起癌症，是人类肿瘤病毒中最重要的一类病毒。该病毒感染率高，致病性较强，对人群尤其是妇女危害很大，引起了国内外医学界的广泛重视。目前临床上已有预防性的多价疫苗(HPV6，11，16，18等)可以预防多种病毒类型感染，但对于已感染的病人使用预防疫苗没有显著治疗效果。开发具有靶向多种类型HPV的有效药物，能为临床上治疗和预防包括恶性肿瘤在内的人乳头状瘤病毒相关疾病提供新的方法。
目前，本领域仍需要针对HPV的有效药物。
发明内容
本公开所要解决的技术问题是提供5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药在制备抗病毒药物中的应用，尤其是在制备抗人乳头状瘤病毒(HPV)药物中的应用。
本公开通过以下技术方案解决上述技术问题：
第一方面，本公开提供一种5-硝基-8-羟基喹啉、其药学上可接受 的盐、其晶型、其溶剂化物、其同位素衍生物或其前药在制备抗病毒药物中的应用。
优选地，所述抗病毒药物用于哺乳动物，优选为人。
优选地，所述病毒为人乳头瘤病毒；优选为人乳头瘤病毒6(Human Papillomavirus 6，HPV6)、人乳头瘤病毒11(Human Papillomavirus 11，HPV11)、人乳头瘤病毒16(Human Papillomavirus 16，HPV16)和人乳头瘤病毒18(Human Papillomavirus 18，HPV18)中的一种或多种。
第二方面，本公开提供一种用于治疗病毒感染的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药。
优选地，本公开提供一种用于治疗哺乳动物病毒感染的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药。其中，所述哺乳动物优选为人。
优选地，所述病毒为人乳头瘤病毒；优选为人乳头瘤病毒6(Human Papillomavirus 6，HPV6)、人乳头瘤病毒11(Human Papillomavirus 11，HPV11)、人乳头瘤病毒16(Human Papillomavirus 16，HPV16)和人乳头瘤病毒18(Human Papillomavirus 18，HPV18)中的一种或多种。
第三方面，本公开提供一种治疗病毒感染的方法，其包括如下步骤：向受试者施用治疗有效量的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药。
优选地，本公开提供一种治疗哺乳动物病毒感染的方法，其包括如下步骤：向受试者施用治疗有效量的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药。其中，所述哺乳动物优选为人。
优选地，所述病毒为人乳头瘤病毒；优选为人乳头瘤病毒6(Human Papillomavirus 6，HPV6)、人乳头瘤病毒11(Human Papillomavirus 11，HPV11)、人乳头瘤病毒16(Human Papillomavirus 16，HPV16)和人乳头瘤病毒18(Human Papillomavirus 18，HPV18)中的一种或多种。
第四方面，本公开提供一种治疗病毒感染的药物组合物，其包含5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药，以及药学上可接受的辅料。
优选地，本公开提供一种治疗哺乳动物病毒感染的药物组合物，其包含5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药，以及药学上可接受的辅料。
优选地，所述病毒为人乳头瘤病毒；优选为人乳头瘤病毒6(Human Papillomavirus 6，HPV6)、人乳头瘤病毒11(Human Papillomavirus 11，HPV11)、人乳头瘤病毒16(Human Papillomavirus 16，HPV16)和人乳头瘤病毒18(Human Papillomavirus 18，HPV18)中的一种或多种。
第五方面，本公开提供一种非治疗方法。具体而言，提供一种体外消毒的方法，其包括如下步骤：使待处理的环境或物体接触有效量的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物。
本公开的积极进步效果在于：本公开提供5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药在抗病毒方面的应用，尤其是在抗人乳头状瘤病毒(HPV)方面的应用。
具体实施方式
5-硝基-8-羟基喹啉及其用途
硝羟喹啉(Nitroxoline)，化学名为5-硝基-8-羟基喹啉，CAS号为4008-48-4。
根据一些实施方案，提供了选自以下的任一化合物在制备抗病毒药物中的用途：5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物、其前药。
在一些实施方案中，提供了选自以下的任一化合物在制备抗人乳头瘤病毒感染的药物中的用途：5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物、其前药。
在一些实施方案中，提供了一种5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药，其用于预防或治疗抗人乳头瘤病毒感染。
在一些实施方案中，5-硝基-8-羟基喹啉以其药学上可接受的盐的形式而提供。药学上可接受的盐可以为酸加成盐或碱加成盐。在一些 实施方案中，酸可以为无机酸，包括但不限于：盐酸、硫酸、磷酸、氢溴酸；或可以为有机酸，包括但不限于：柠檬酸、马来酸、草酸、甲酸、乙酸、丙酸、戊酸、乙醇酸、苯甲酸、富马酸、三氟乙酸、琥珀酸、酒石酸、乳酸、谷氨酸、天门冬氨酸、水杨酸、丙酮酸、甲磺酸、苯磺酸、对苯磺酸。在一些实施方案中，碱可以为无机碱，包括但不限于：氢氧化钠、氢氧化钾、氢氧化镁、氢氧化钙；或可以为有机碱，包括但不限于：氢氧化铵、三乙胺、N,N-二苄基乙二胺、氯普鲁卡因、胆碱、氨、二乙醇胺和其他羟基烷基胺、乙二胺、N-甲基葡糖胺、普鲁卡因、N-苄基苯乙胺、精氨酸或赖氨酸；或可以为碱金属盐，包括但不限于：锂、钾和钠盐(例如：磷酸二氢钠和磷酸氢二钠)；或可以为碱土金属盐，包括但不限于：钡、钙和镁盐；或可以为过渡金属盐，包括但不限于锌盐。
术语“药学上可接受的”指的是其用于制备药物组合物，所述药物组合物一般是安全的，无毒的，在生物学方面满足需要并且所述药物组合物可以被接受并作为哺乳动物(例如人)的药物。
在一些实施方案中，5-硝基-8-羟基喹啉可以是其晶型的形式而提供。
在另一些实施方案中，5-硝基-8-羟基喹啉以其溶剂化物的形式而提供。
术语“溶剂化物”表示5-硝基-8-羟基喹啉与适宜的溶剂形成的物质。在具体的实施方案中，所述溶剂为水。在其他具体的实施方案中，所述溶剂为药学上可接受的有机溶剂。
在另一些实施方案中，5-硝基-8-羟基喹啉以其同位素衍生物的形式而提供。
术语“同位素衍生物”指的是与5-硝基-8-羟基喹啉的不同之处仅在于存在一种或多种同位素富集原子的化合物。例如，具有其结构，仅用“氘”或“氚”代替氢，和/或，用 11C、 13C或 14C代替碳，而其余部分不改变。
在另一些实施方案中，5-硝基-8-羟基喹啉以其前药的形式而提供。术语“前药”指的是包含生物反应官能团的5-硝基-8-羟基喹啉的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从衍生物上 裂解或以其他方式发生反应以提供5-硝基-8-羟基喹啉。
在一些具体的实施方案中，5-硝基-8-羟基喹啉的前药是(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯，其结构式如下：
Figure PCTCN2022095861-appb-000001
(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯可通过WO2020/063824实施例20的制备方法制得。
在一些实施方案中，5-硝基-8-羟基喹啉的前药可以按照WO2021/238978所公开的方法进行制剂。
在本公开中，抗病毒药物是指任何能够在体内或体外抑制(或降低、阻碍、干扰、失活、杀灭)病毒活性、活力、复制、增殖、生长、传染性、或毒力的化合物或组合物。
在本公开中，抗病毒药物用于预防、治疗、改善受试者中病毒相关的疾病或症状。
在本公开中，抗病毒药物用于预防、治疗、改善受试者中人乳头瘤病毒相关的疾病或症状。
人乳头瘤病毒(HPV)属于乳多空病毒科乳头瘤空泡病毒A属。HPV是球形DNA病毒。HPV目前已分离出130多种不同的型别，根据侵犯的组织部位不同可分为：
(1)皮肤低危型，HPV1、2、3、4、7、10、12、15等；
(2)皮肤高危型，HPV5、8、14、17、20、36、38等；
(3)黏膜低危型，HPV6、11、13、32、34、40、42、43、44、54等；
(4)黏膜高危型，HPV16、18、30、31、33、35、53、39等。
在一些实施方案中，本公开的抗病毒药物用于黏膜型(高、低危) 人乳头瘤病毒相关的疾病或症状；可以提及：HPV6、11、13、16、18、30、31、32、33、34、35、39、40、42、43、44、53、54。
在一些具体的实施方案中，所述HPV尤其选自以下的任一项或其组合：人乳头瘤病毒6(Human Papillomavirus 6，HPV6)、人乳头瘤病毒11(Human Papillomavirus 11，HPV11)、人乳头瘤病毒16(Human Papillomavirus 16，HPV16)和人乳头瘤病毒18(Human Papillomavirus18，HPV18)。
在本公开中，当提及“本公开的化合物”时，是指5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药。
预防或治疗方法
本公开提供了一种预防或治疗受试者中病毒感染的方法。
在一些实施方案中，预防受试者中病毒感染的方法包括步骤(或由其组成)：向受试者施用预防有效量的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药。
在一些实施方案中，治疗受试者中病毒感染的方法包括步骤(或由其组成)：向受试者施用治疗有效量的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药。
“施用”，当其应用于动物、人、受试者、细胞、组织、器官或生物流体时，是指外源性药物(如本公开的化合物)、治疗剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。
术语“受试者”是指哺乳动物，包括例如骆驼、驴、斑马、牛、猪、马、山羊、绵羊、猫、狗、大鼠、兔、豚鼠、小鼠、灵长动物。
在一些具体的实施方案中，受试者为人。
在一些具体的实施方案中，受试者为暴露于、易感于、疑似患有、已经患有病毒感染的人。
“已经患有”应当做最广泛地理解，也包括在设定的显著水平处患有病毒感染的概率在统计学上显著高于对照。对于统计学上的“显著”，p设定为例如但不限于0.5、0.1、0.05、0.01、0.005、0.001、0.0005、0.0001、甚至更低。例如，当两个个体或群体之间进行比较时，所得p值小于设定的特定p值时，则认为两个个体或群体存在统计学上的显 著差异。
在预防方法中，受试者易感于、潜在暴露于、或暴露于病毒感染。
在治疗方法中，受试者疑似患有或已经患有病毒感染。
术语“治疗”指的是消除疾病，阻止疾病进展，减缓疾病进展，减少与疾病相关的一种或多种症状的持续时间，至少一个与疾病相关的可测量参数的改善或逆转，或者增加患有疾病的受试者的存活率。
术语“预防”指的是针对致病因素(如暴露于病毒)的预防措施，可以是针对环境的措施、或针对受试者的措施。在具体的实施方案中，预防是借助本公开的化合物或药物组合物，对尚未感染的受试者、环境或物体进行处理以防止感染、降低感染风险、降低感染概率、推迟感染的症状出现或发作等。
术语“有效量”是指本公开的化合物或药物组合物在受试者、环境或物体中引发期望效果的量。
在一些实施方案中，“治疗有效量”是足以治疗疾病状态或症状、尤其与病毒感染状态相关的状态或症状，或者阻碍、延迟或逆转病毒感染或其他不理想症状的量。
在一些实施方案中，“预防有效量”是当给予受试者、环境或物体时，将具有预定的预防效应的量。
治疗或预防的效果未必在给予一个剂量之后便发生，可能在给予一系列剂量之后发生。
在具体的实施方案中，本领域技术人员可以基于对多种因素的考虑(例如经由临床试验)来确定有效量的选择，所述因素包括本公开的化合物的活性、所用的具体化合物的代谢速率、待治疗的疾病、所涉及的症状、施用途径、施用时间、疾病的严重程度、患者的体重、患者的免疫状态、与所用的具体化合物组合使用的其他药物(化合物和/或材料)、和本领域技术人员已知的其他因素。本领域技术人员可容易地确定所需的有效量。有效量，可以从来源于动物模型测试系统的剂量-应答曲线而得到，并允许根据医生的判断和每位患者的情况来决定。其中，动物和人的用药量的相互关系描述于Freireich等人1966，Cancer Chemother Rep 50：219，且人体表面积可以近似地由患者的身高和体重确定。
一般而言，本公开的化合物的合适的日剂量将是有效产生预防或治疗作用的化合物量。
本公开的化合物的有效量可为0.01mg/kg至500mg/kg，优选为1mg/kg至200mg/kg，更优选为10mg/kg至100mg/kg；具体可以提及0.01、0.05、0.1、0.5、1、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、450、500mg/kg，以及上述任意两点之间的范围。
如果需要的话，本公开的化合物的日剂量可以在一天中以分开施用的二、三、四、五、六或更多个亚剂量以适宜的时间间隔施用；任选地，所述亚剂量是单位剂型的剂量。
本公开提供的药物组合物或化合物可以按照常规临床治疗方法给药，例如对于病毒感染，可以直接灌注、施加至受感染部位而给药；给药剂量可按照医疗工作者确定的剂量进行使用。
在具体的实施方案中，本公开提供的药物组合物或化合物制备成阴道施用的剂型。
虽然本公开的化合物可以单独施用，但允许以药物组合物的形式施用所述化合物。
本公开中所用术语“单位剂量”，是指在实体上呈分离的单位，适合作为施用于受试者、环境或物体的单位剂量。各个单位含有预定量的本公开的化合物或其组合物。
在一些实施方式中，本公开中所述的单位剂量以体积的形式表示，并且选自：0.1ml、0.15ml、0.2ml、0.5ml、1.0ml、1.5ml、2.0ml、2.5ml、3.0ml、4.0ml、5.0ml、10.0ml、20.0ml、30.0ml、40.0ml、50.0ml、60.0ml、70.0ml、80.0ml、90.0ml、100.0ml，150ml，200ml，250.00ml，以及上述任意两点之间的范围。
技术人员理解，过大或过小的单位剂量导致临床操作不便。例如，当阴道施用于人类受试者时，单位剂量优选在1ml至100ml范围内，例如1、10、20、30、40、50、60、70、80、90、100ml，以及上述任意两点之间的范围。当皮下施用于人类受试者时，单位剂量优选在0.5ml至1.0ml范围内。当静脉注射于人类受试者时，单位剂量优选在30.0ml至1000ml范围内。
此处应当理解的是，单位剂量虽然以体积进行表示，但这并不意味着本公开的化合物或其组合物只能是液体制剂。当制备成固体(干粉或冻干粉)制剂时，单位剂量的体积可以代表干粉或冻干粉重新配制为液体时的体积。
一些实施方案中，按照以下的频率向所述受试者施用本公开的化合物或其组合物：每4年1至4次、每3年1至3次、每2年1至2次、每年1次、每年2次、每年3次、每年4次、每年5次、每年6次、每月1次、每月2次、每月3次、每月4次、每月5次、每月6次、每月7次、每月8次、每周1次、每周2次、每周3次、每周4次、每周5次、每周6次、每三天1次、每三天2次、每三天3次、每两天1次、每两天2次、每天1次、每天2次。
一些实施方案中，本公开的化合物或其组合物的施用频率可以相同或不同。
一些实施方案中，每次施用之间的时间间隔是相同的或不同的。
在一些实施方式中，本公开的化合物或其组合物的施用是系统性的(也作全身性)或局部的。
在一些实施方式中，通过胃肠道外(如肌肉内、腹腔内、静脉内、皮下、皮内)注射来施用本公开的化合物或其组合物。
在一些实施方式中，本公开的化合物或其组合物是通过肌肉内施用。
在其它实施方式中，本公开的化合物或其组合物是经皮内传输(例如不以机械装置来破坏上皮细胞障壁的方式)。
在另一些实施方式中，本公开的化合物或其组合物是通过直肠、阴道的途径而施用。
消毒组合物和消毒方法
在另一些实施方案中，本公开的化合物用于非治疗用途。
提供一种消毒剂(或消毒组合物)，其包含有效量的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药。
在具体的实施方案中，消毒组合物还可包括一种或多种药学上可接受的辅料，所述药学上可接受的辅料包括药学领域常规的稀释剂、 赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂或增效剂等。
可用于本公开消毒组合物中的合适的水性和非水性载体的示例包括：水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇)或其混合物、油(如橄榄油、有机酯类)。
消毒组合物可以制备成喷雾剂、洗涤剂、洗剂、培养介质的形式。
在本公开中，消毒剂(或消毒组合物)尤其是指任何能够在体外(例如环境中、物体、及其表面等)抑制(或降低、阻碍、干扰、失活、杀灭)病毒活性、活力、复制、增殖、生长、传染性、或毒力的化合物(或组合物)。
本公开的消毒剂(或消毒组合物)用于消毒被病毒感染或污染的环境、区域、物品、样品、表面、容器、或食品。
在一些实施方案中，提供一种消毒方法或抗病毒方法，其适合用于处理暴露于病原体或受病原体威胁的环境、区域、物品、样品、表面、容器、或食品。
根据一些实施方案，提供了一种消毒的方法，使环境、区域、物品、样品、表面、容器、或食品接触有效量的本公开的化合物或其组合物。
在一些实施方案中，本公开的化合物或其组合物适用于各种表面(特别是这些病毒能在相对长的一段时间内保持活性的硬质表面)、以及商业和公共环境(例如医院、门诊部、旅馆)的病毒。
在一些实施方案中，本公开的化合物或其组合物作为添加剂使用。
对于“消毒”应用，“有效量”是抑制(或降低、阻碍、干扰、失活、杀灭)病毒的活性、活力、复制、增殖、生长、传染性、或毒力所需的或者足够的量。在一个示例中，本公开化合物的有效量是能够将环境中的病毒载量、病毒传播能力、或病毒活力产生统计学上显著性降低的量。
药物组合物
根据一些实施方案，提供了一种药物组合物，其包含本公开的化合物以及任选地药学上可接受的辅料。适宜的药学上可接受的辅料描述于E.W.Martin的Remington Pharmaceutical Sciences中。
在具体的实施方案中，所述药物组合物包括一种或多种药学上可接受的辅料，其包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂或增效剂等。
技术人员能够理解的是，当药物组合物是干粉或冻干粉形式时，和液体形式的药物组合物区别在于含水量的不同和/或缓冲环境的不同。
在具体的实施方案中，本公开药物组合物可以制成注射剂、栓剂、片剂、丸剂、胶囊、悬浮剂、乳剂、喷雾剂、消毒液、洗涤剂的形式施用。
在一些实施方案中，药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、水或油混悬液、可分散粉末或颗粒、乳液、胶囊，或糖浆剂。可按照本领域任何已知制备药物组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂。适宜制备片剂的赋形剂可以是惰性赋形剂(如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠)；造粒剂和崩解剂(例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸)；粘合剂(例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶)；和润滑剂(例如硬脂酸镁、硬脂酸或滑石粉)。
在一些实施方案中，水混悬液含有本公开的化合物和适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂(例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶)；分散剂或湿润剂，可以是天然产生的磷脂例(如卵磷脂、聚氧乙烯硬脂酸酯、或环氧乙烷与长链脂肪醇的缩合产物、聚环氧乙烷山梨醇单油酸酯、或聚环氧乙烷脱水山梨醇单油酸酯)。水混悬液也可以含有防腐剂(例如尼泊金乙酯或尼泊金正丙酯)、着色剂、矫味剂。
在一些实施方案中，油混悬液可通过使活性成分悬浮于植物油(如花生油、橄榄油、芝麻油或椰子油，或矿物油)中配制而成。油混悬液可含有增稠剂(例如蜂蜡、硬石蜡或鲸蜡醇)。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油(例如橄榄油或花生油，或矿物油)。适宜的乳化剂可以是天然产 生的磷脂(例如大豆卵磷脂)。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递送装置。
在一些具体的实施方案中，提供用于阴道或直肠给药的栓剂形式。可通过将本公开化合物与无刺激性赋形剂(在常温下为固体，但在阴道或直肠中为液体)混合来制备这些药物组合物。此类组合物包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇、或聚乙二醇的脂肪酸酯。
药盒
根据本公开的另一方面，提供了一种用于实施上述预防或治疗、消毒方法的药盒，其包含至少一个容器，所述容器独立地包含：本公开的化合物或其组合物。不同容器中的组成和/或量可以相同，也可以不同。
在一些实施方式中，本公开的化合物或其组合物配制于无菌液体内，并且装在无菌容器(如管、瓶、安瓿、注射器)内。
在另一些实施方式中，本公开的化合物或其组合物以干粉或冻干粉的形式装在容器内。临用前，配制成液体形式。
在一个示例性实施方式中，本公开的药盒还包含选自以下的一项或其组合：针头、注射用水、使用说明书。
本说明书中，当描述数值范围时，所用的表述“…至…”、“范围之内”或“范围之间”包含端点值。这种表述是一种简写的方式，范围内的每一个整数或小数视为明确得到指明。
本说明书中，当描述数值时(除非另有指明)，应当包含统计学上的误差、操作引入的误差。误差程度取决于具体情况，例如当涉及施用量时，涉及称量误差、制剂过程中引入的误差等；如150ml，可以理解为150ml±称量误差。
除非另有说明，本文所使用的冠词“一”、“一个(种)”旨在包括 “至少一个”或“一个或多个”。
下面通过实施例的方式进一步说明本公开，但并不因此将本公开限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下述效果例中，各病毒的中文名称及拉丁文学名如下：
人乳头瘤病毒6(Human Papillomavirus 6，HPV6)；
人乳头瘤病毒11(Human Papillomavirus 11，HPV11)；
人乳头瘤病毒16(Human Papillomavirus 16，HPV16)；
人乳头瘤病毒18(Human Papillomavirus 18，HPV18)；
新型冠状病毒(SARS-CoV-2)；
基孔肯雅病毒(Chikungunya Virus,CHIKV)；
登革病毒2(Dengue Virus 2)；
甲型流感病毒H1N1亚型(Influenza A H1N1)；
中东呼吸综合症冠状病毒(MERS-CoV)；
裂谷热病毒(Rift Valley Fever Virus,RVFV)；
塔卡里伯病毒(Tacaribe Virus,TCRV)；
wt-棉尾兔乳头瘤病毒(wt-CRPV)；
mE8-棉尾兔乳头瘤病毒(mE8-CRPV)；
鼠乳头瘤病毒(MmuPV1)。
实施例1.制备5-硝基-8-羟基喹啉
本公开中的5-硝基-8-羟基喹啉不受制备方法的限制，按任何现有技术中公开的制备方法获得、或者可用市售产品。
实施例2.制备5-硝基-8-羟基喹啉的前药
根据WO/2020/063824实施例20公开的方法，制备5-硝基-8-羟基喹啉的前药(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯。
效果例1
测试5-硝基-8-羟基喹啉对人乳头状瘤病毒(HPV)的抗病毒活力， 采用瞬时转染实验来评估。
该评估系统包括表达病毒解旋酶E1和复制起点结合蛋白E2的质粒、含有由TK启动子(Promega公司)驱动NanoLuc基因表达的质粒以及下面列出的人乳头状瘤病毒株的复制起点序列。与单独使用E1或E2相比，通过质粒表达的E1和E2的协同结合和解旋活性驱动报告质粒的复制，使得NanoLuc活性提高了100倍以上。3个NanoLuc报告质粒的复制起点序列位置为7825-7993:1-99、7662-7901:1-99和7740-7837:1-102，分别用于HPV11(NCBI登录号HE611260.1)、HPV16(KP212151.1)和HPV18(KC470230.1)。对应于HPV11、HPV16和HPV18的E1开放阅读框(ORF)序列位置分别为相同序列中的832-2781、864-2813和914-2887的序列部分。对应于HPV11、HPV16和HPV18的E2开放阅读框(ORF)序列位置分别为相同序列中的2723-3826、2755-3852和2817-3908的序列部分。HPV6的测试采用与前述HPV11、HPV16、HPV18类似的测试方法。
进行瞬时转染的细胞为C–33A细胞(ATCC HTB-31)，培养基为DMEM并添加Earle’s盐补充、L-谷氨酰胺和2％胎牛血清。实验中，用Lipofectamine LTX和PlusReagent(Invitrogen，Thermo Fisher Scientific公司)共转染NanoLuc表达质粒(5ng/孔)与同源病毒的E1和E2表达质粒。孵育1小时后，将转染的细胞接种到含有稀释5倍的试验药物和阳性对照药物9-(2-膦酰甲氧基乙氧基)鸟嘌呤(PMEG)(Sigma-Aldrich公司)的孔中。转染后的细胞同时也被接种到相同稀释度的实验药物的重复培养皿中，以评估细胞毒性。所有转染的单层细胞均在37℃孵育48小时。用Nano-Glo试剂(Promega公司)检测报告质粒表达的NanoLuc活性，用CellTiter-Glo试剂(Promega公司)测定细胞毒板中的细胞活力，并在酶标仪上定量发光强度。从实验数据中鉴定使报告质粒复制数减少50％(EC 50)、90％(EC 90)时的化合物浓度。
具体操作方法，见参考文献(Beadle,J.et al.Synthesis and Antiviral Evaluation of Octadecyloxyethyl Benzyl 9-[(2–Phosphonomethoxy)ethyl]guanine(ODE-Bn-PMEG),a Potent Inhibitor of Transient HPV DNA Amplification.J Med Chem.2016，59(23):10470-8；Kachaeva,M.et al. In vitro activity of novel 1,3-oxazole derivatives against HPV.Ibnosina J Med Biomed Sci.2017；9(4):111-8)。
具体测试结果，见表1和表2。结果显示5-硝基-8-羟基喹啉的抗病毒活性优于阳性对照药物。
效果例2
采用同效果例1类似的方法测试5-硝基-8-羟基喹啉对新型冠状病毒、基孔肯雅病毒、登革病毒2、甲型流感病毒H1N1亚型、中东呼吸综合症冠状病毒、裂谷热病毒、塔卡里伯病毒、人类冠状病毒(α)、人类冠状病毒(β)、单纯疱疹病毒1、单纯疱疹病毒2、水痘带状疱疹病毒、人乳头瘤病毒11、人乳头瘤病毒16、人乳头瘤病毒18、人乳头瘤病毒6的抗病毒活性，测试结果见表2。
当SI 50值>10时，判定化合物对病毒有活性。结果显示5-硝基-8-羟基喹啉对HPV有特异性抑制活性，而对其他病毒未观察到这种活性。
效果例3(前药)
根据WO 2021/238978中测试例4的方法，将实施例2制备的前药施用至动物(犬)体内，在循环样本中检测到其转换成活性形式5-硝基-8-羟基喹啉。因此，前药和5-硝基-8-羟基喹啉在抗HPV效果上具有等效性。
表1.阳性对照药物对HPV的活性数据
Figure PCTCN2022095861-appb-000002
Figure PCTCN2022095861-appb-000003

Claims (8)

  1. 选自以下的任一项在制备抗病毒药物中的用途：
    5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物、其前药；
    所述病毒为人乳头瘤病毒。
  2. 根据权利要求1所述的用途，所述抗病毒药物用于哺乳动物，优选为人。
  3. 根据权利要求1或2所述的用途，所述病毒选自以下的任一项或其组合：人乳头瘤病毒6(Human Papillomavirus 6，HPV6)、人乳头瘤病毒11(Human Papillomavirus 11，HPV11)、人乳头瘤病毒16(Human Papillomavirus 16，HPV16)和人乳头瘤病毒18(Human Papillomavirus 18，HPV18)。
  4. 根据权利要求1至3中任一项所述的用途，其中：
    所述前药是(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯。
  5. 一种预防或治疗病毒感染的方法，其包括如下步骤：
    向受试者施用预防有效量或治疗有效量的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物或其前药；
    所述病毒为人乳头瘤病毒；
    所述受试者是哺乳动物，优选人。
  6. 一种体外消毒的方法，其包括如下步骤：
    使待处理的环境或物体接触有效量的5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物。
  7. 根据权利要求5或6所述的方法，所述病毒选自以下的任一项或其组合：人乳头瘤病毒6(Human Papillomavirus 6，HPV6)、人乳头 瘤病毒11(Human Papillomavirus 11，HPV11)、人乳头瘤病毒16(Human Papillomavirus 16，HPV16)和人乳头瘤病毒18(Human Papillomavirus 18，HPV18)。
  8. 一种治疗病毒感染的药物组合物，其包含：
    -药学上可接受的辅料、以及
    -选自以下的任一项：5-硝基-8-羟基喹啉、其药学上可接受的盐、其晶型、其溶剂化物、其同位素衍生物、其前药；
    所述病毒是人乳头瘤病毒；
    优选地，所述病毒选自以下的任一项或其组合：人乳头瘤病毒6(Human Papillomavirus 6，HPV6)、人乳头瘤病毒11(Human Papillomavirus 11，HPV11)、人乳头瘤病毒16(Human Papillomavirus 16，HPV16)和人乳头瘤病毒18(Human Papillomavirus 18，HPV18)；
    优选地，所述前药是(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯。
PCT/CN2022/095861 2021-05-31 2022-05-30 5-硝基-8-羟基喹啉的应用 Ceased WO2022253159A1 (zh)

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