Use of 5-nitro-8-hydroxyquinoline

Abstract

Provided is an application related to 5-nitro-8-hydroxyquinoline. In particular, provided is an application of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof or a prodrug thereof in the preparation of an antiviral drug. The 5-nitro-8-hydroxyquinoline, the pharmaceutically acceptable salt thereof, the crystal form thereof, the solvate thereof, the isotopic derivative thereof or the prodrug thereof has significant activity against human papillomavirus.

Description

[0001] This application claims priority to Chinese patent application (application number 2021106017773) filed on May 31, 2021. TECHNICAL FIELD

[0002] The present disclosure relates to the fields of organic chemistry, medicine, and antiviral therapy. In particular, it relates to the use of 5-nitro-8-hydroxyquinoline. BACKGROUND

[0003] Human papillomavirus (HPV) is a DNA virus belonging to the Papillomaviridae family, and is a very common virus worldwide. HPV members have a mucosal epithelium and skin epithelium tropism, and in addition to causing various diseases of the genital tract such as genital warts, they can also cause various malignancies including cervical cancer, penile cancer, anal cancer, oral cancer, throat cancer, tonsil cancer, esophageal cancer, etc. There are more than 100 types of human papillomavirus, at least more than ten of which can cause cancer, and they are the most important class of human tumor viruses. The virus has a high infection rate and strong pathogenicity, and poses a great threat to the population, especially women, and has attracted widespread attention from the medical community at home and abroad. At present, there are prophylactic multivalent vaccines (HPV6, 11, 16, 18, etc.) that can prevent infection with multiple virus types in clinical practice, but the use of prophylactic vaccines for infected patients has no significant therapeutic effect. The development of effective drugs targeting multiple types of HPV can provide new methods for the clinical treatment and prevention of human papillomavirus-related diseases, including malignancies.

[0004] At present, there is still a need in the art for effective drugs against HPV. SUMMARY

[0005] The technical problem to be solved by the present disclosure is to provide the use of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof in the preparation of an antiviral drug, especially in the preparation of an anti-human papillomavirus (HPV) drug.

[0006] The present disclosure solves the above technical problem by the following technical solution:

[0007] In a first aspect, the present disclosure provides the use of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof in the preparation of an antiviral drug.

[0008] Preferably, the antiviral drug is for use in a mammal, preferably a human.

[0009] Preferably, the virus is a human papillomavirus; preferably one or more of Human Papillomavirus 6 (HPV6), Human Papillomavirus 11 (HPV11), Human Papillomavirus 16 (HPV16) and Human Papillomavirus 18 (HPV18).

[0010] In a second aspect, the present disclosure provides 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 treating a viral infection.

[0011] Preferably, the present disclosure provides 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 treating a viral infection in a mammal. Preferably, the mammal is a human.

[0012] Preferably, the virus is a human papillomavirus; preferably one or more of Human Papillomavirus 6 (HPV6), Human Papillomavirus 11 (HPV11), Human Papillomavirus 16 (HPV16) and Human Papillomavirus 18 (HPV18).

[0013] In a third aspect, the present disclosure provides a method of treating a viral infection, comprising the step of administering to a subject a therapeutically effective amount of 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.

[0014] Preferably, the present disclosure provides a method of treating a viral infection in a mammal, comprising the step of administering to a subject a therapeutically effective amount of 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. Preferably, the mammal is a human.

[0015] Preferably, the virus is human papillomavirus; preferably one or more of Human Papillomavirus 6 (HPV6), Human Papillomavirus 11 (HPV11), Human Papillomavirus 16 (HPV16), and Human Papillomavirus 18 (HPV18).

[0016] In a fourth aspect, the present disclosure provides a pharmaceutical composition for treating viral infection, comprising 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.

[0017] In a fourth aspect, the present disclosure provides a pharmaceutical composition for treating viral infection, comprising 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.

[0018] Preferably, the virus is human papillomavirus; preferably one or more of Human Papillomavirus 6 (HPV6), Human Papillomavirus 11 (HPV11), Human Papillomavirus 16 (HPV16), and Human Papillomavirus 18 (HPV18).

[0019] In a fifth aspect, the present disclosure provides a non-therapeutic method. Specifically, a method for disinfecting in vitro is provided, comprising the step of contacting an environment or object to be treated with an effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof.

[0020] The positive progress effect of the present disclosure is that the present disclosure provides the application of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof in antiviral, especially in anti-human papillomavirus (HPV). DETAILED DESCRIPTION

[0021] 5-nitro-8-hydroxyquinoline and uses thereof

[0022] Nitroxoline, chemical name 5-nitro-8-hydroxyquinoline, CAS No. 4008-48-4.

[0023] According to some embodiments, there is provided use of any one of the compounds selected from the group consisting of 5-nitro-8-hydroxyquinoline, pharmaceutically acceptable salts thereof, crystal forms thereof, solvates thereof, isotopic derivatives thereof, prodrugs thereof, in the preparation of an antiviral medicament.

[0024] In some embodiments, there is provided use of any one of the compounds selected from the group consisting of 5-nitro-8-hydroxyquinoline, pharmaceutically acceptable salts thereof, crystal forms thereof, solvates thereof, isotopic derivatives thereof, prodrugs thereof, in the preparation of a medicament for the treatment of human papillomavirus infection.

[0025] In some embodiments, there is provided a 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof, for use in the prevention or treatment of human papillomavirus infection.

[0026] In some embodiments, the 5-nitro-8-hydroxyquinoline is provided in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt can be an acid addition salt or a base addition salt. In some embodiments, 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, p-toluenesulfonic acid. In some embodiments, 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, triethylamine, N,N-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, arginine or lysine; or can 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 can be an alkaline earth metal salt, including but not limited to: barium, calcium and magnesium salts; or can be a transition metal salt, including but not limited to zinc salt.

[0027] The term "pharmaceutically acceptable" refers to its use in preparing a pharmaceutical composition that is generally safe, non-toxic, biologically acceptable and that can be administered to a mammal (e.g. a human) as a pharmaceutical.

[0028] In some embodiments, the 5-nitro-8-hydroxyquinoline can be provided in the form of a crystal form thereof.

[0029] In other embodiments, the 5-nitro-8-hydroxyquinoline is provided in the form of a solvate thereof.

[0030] The term "solvate" means a 5-nitro-8-hydroxyquinoline formed with a suitable solvent. In particular embodiments, the solvent is water. In other particular embodiments, the solvent is a pharmaceutically acceptable organic solvent.

[0031] In other embodiments, 5-nitro-8-hydroxyquinoline is provided in the form of an isotopically-labeled derivative thereof.

[0032] The term "isotopically-labeled derivative" means a compound which differs from 5-nitro-8-hydroxyquinoline only in the presence of one or more isotopically-enriched atoms. For example, a compound having the structure of 5-nitro-8-hydroxyquinoline, only with "deuterium" or "tritium" instead of hydrogen, and / or, with 11 C, 13 C or 14 C instead of carbon, and the rest unchanged.

[0033] In other embodiments, 5-nitro-8-hydroxyquinoline is provided in the form of a prodrug thereof. The term "prodrug" means a derivative of 5-nitro-8-hydroxyquinoline which contains a bioreactive functional group such that under biological conditions (in vitro or in vivo) the bioreactive functional group is cleaved or otherwise reacts to provide 5-nitro-8-hydroxyquinoline.

[0034] In some particular embodiments, the prodrug of 5-nitro-8-hydroxyquinoline is (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropylcarbonylpyrrolidine-2-carboxylate, which has the following structure:

[0035]

[0036] (S)-(5-nitroquinolin-8-yloxy)methyl 1-isopropylcarbonylpyrrolidine-2-carboxylate can be prepared by the preparation method of WO2020 / 063824 Example 20.

[0037] In some embodiments, the prodrug of 5-nitro-8-hydroxyquinoline can be formulated according to the method disclosed in WO2021 / 238978.

[0038] In the present disclosure, an antiviral agent refers to any compound or composition that can inhibit (or reduce, hinder, interfere with, inactivate, kill) viral activity, viability, replication, proliferation, growth, infectivity, or virulence in vivo or in vitro.

[0039] In the present disclosure, an antiviral agent is used to prevent, treat, ameliorate a viral-related disease or symptom in a subject.

[0040] In the present disclosure, an antiviral agent is used to prevent, treat, ameliorate a human papillomavirus-related disease or symptom in a subject.

[0041] Human papillomavirus (HPV) belongs to the Papillomaviridae family of the Papillomavirus genus. HPV is a spherical DNA virus. More than 130 different types of HPV have been isolated, which can be divided into:

[0042] (1) low-risk skin types, HPV1, 2, 3, 4, 7, 10, 12, 15, etc.;

[0043] (2) high-risk skin types, HPV5, 8, 14, 17, 20, 36, 38, etc.;

[0044] (3) low-risk mucosal types, HPV6, 11, 13, 32, 34, 40, 42, 43, 44, 54, etc.;

[0045] (4) high-risk mucosal types, HPV16, 18, 30, 31, 33, 35, 53, 39, etc.

[0046] In some embodiments, the antiviral drug of the present disclosure is used for mucosal (high, low-risk) human papillomavirus-related diseases or symptoms; mention can be made of: HPV6, 11, 13, 16, 18, 30, 31, 32, 33, 34, 35, 39, 40, 42, 43, 44, 53, 54.

[0047] In some specific embodiments, the HPV is especially selected from any one or a combination of the following: Human Papillomavirus 6 (HPV6), Human Papillomavirus 11 (HPV11), Human Papillomavirus 16 (HPV16), and Human Papillomavirus 18 (HPV18).

[0048] In the present disclosure, when referring to “the compound of the present disclosure”, it refers to 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof.

[0049] Prevention or treatment method

[0050] The present disclosure provides a method for preventing or treating viral infection in a subject.

[0051] In some embodiments, the method for preventing viral infection in a subject comprises (or consists of) the step of: administering to the subject a prophylactically effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof.

[0052] In some embodiments, the method of treating a viral infection in a subject comprises (or consists of) the step of administering to the subject a therapeutically effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof.

[0053] "Administering", when applied to an animal, human, subject, cell, tissue, organ, or biological fluid, means the contact of an exogenous drug (such as a compound of the disclosure), therapeutic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid.

[0054] The term "subject" refers to a mammal, including, for example, a camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, rabbit, guinea pig, mouse, primate.

[0055] In some specific embodiments, the subject is a human.

[0056] In some specific embodiments, the subject is a human exposed to, susceptible to, suspected of having, or already having a viral infection.

[0057] "Already having" is to be construed most broadly, and also includes a probability of having a viral infection at a set significant level that is statistically significantly higher than a control. For statistical "significance", p is set to, 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. For example, when a comparison is made between two individuals or populations, a statistically significant difference exists between the two individuals or populations when the resulting p-value is less than a set p-value.

[0058] In prophylactic methods, the subject is susceptible to, potentially exposed to, or exposed to a viral infection.

[0059] In therapeutic methods, the subject is suspected of having or already has a viral infection.

[0060] The term "treatment" refers to eliminating the disease, arresting the development of the disease, slowing the progression of the disease, reducing the duration of one or more symptoms associated with the disease, an improvement or reversal of at least one measurable parameter associated with the disease, or increasing the survival rate of a subject having the disease.

[0061] The term "prevention" refers to prophylactic measures against a causative agent (such as exposure to a virus), which can be measures against the environment, or measures against the subject. In specific embodiments, prevention is the treatment of a subject, environment, or object that has not yet been infected with a compound or pharmaceutical composition of the disclosure to prevent infection, reduce the risk of infection, reduce the probability of infection, delay the appearance or onset of symptoms of infection, and the like.

[0062] The term "effective amount" means the amount of a compound or pharmaceutical composition of the present disclosure that will elicit the desired effect in a subject, environment, or object.

[0063] In some embodiments, a "therapeutically effective amount" is an amount that is sufficient to treat a disease state or symptoms, particularly a state or symptoms associated with a viral infection state, or to impede, delay, or reverse a viral infection or other undesirable symptoms.

[0064] In some embodiments, a "prophylactically effective amount" is an amount that will have the intended prophylactic effect when administered to a subject, environment, or object.

[0065] The effects of treatment or prevention do not necessarily occur immediately after administration of one dose, and can occur after administration of a series of doses.

[0066] In particular embodiments, the selection of an effective amount can be determined by those of skill in the art based on a variety of factors (e.g., via clinical trials), including the activity of the compound of the present disclosure, the rate of metabolism of the particular compound employed, the disease being treated, the disorder being treated, the route of administration, the time period of administration, the severity of the disease, the body weight of the patient, the immunological status of the patient, other drugs (compounds and / or materials) being used in combination with the particular compound employed, and other factors that are known to those of skill in the art. The effective amount needed will be readily determined by those of skill in the art. Effective amounts, can be found from dose-response curves derived from animal model test systems, and determined in accordance with the judgment of the clinician and the circumstances of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al. 1966, Cancer Chemother Rep 50:219, and the human surface area can be estimated from the patient's height and weight.

[0067] In general, a suitable daily dose of a compound of the present disclosure will be that amount of the compound that is effective to produce the therapeutic or prophylactic effect.

[0068] An effective amount of a compound of the present disclosure 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; particular mention can be made of 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, 500 mg / kg, and ranges between any of the aforementioned values.

[0069] If desired, the daily dosage of a compound of the present disclosure can be administered in two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, with unit dosage forms being employed in such sub-doses.

[0070] The pharmaceutical compositions or compounds provided by the present disclosure can be administered according to conventional clinical techniques, for example, for viral infections, can be administered by direct infusion, application to the infected site; the dosage can be used according to the dosage determined by the medical worker.

[0071] In specific embodiments, the pharmaceutical compositions or compounds provided by the present disclosure are prepared into a vaginal administration dosage form.

[0072] Although the compounds of the present disclosure can be administered alone, it is permissible to administer the compounds in the form of a pharmaceutical composition.

[0073] The term "unit dose" as used in the present disclosure refers to physically discrete unit suitable as unitary dosages to be administered to a subject, environment or object. Each unit contains a predetermined quantity of a compound of the present disclosure or a composition thereof.

[0074] In some embodiments, the unit dose described in the present disclosure is expressed in the form of volume, and is selected from the group consisting of: 0.1 ml, 0.15 ml, 0.2 ml, 0.5 ml, 1.0 ml, 1.5 ml, 2.0 ml, 2.5 ml, 3.0 ml, 4.0 ml, 5.0 ml, 10.0 ml, 20.0 ml, 30.0 ml, 40.0 ml, 50.0 ml, 60.0 ml, 70.0 ml, 80.0 ml, 90.0 ml, 100.0 ml, 150 ml, 200 ml, 250.00 ml, and a range between any two of the above.

[0075] The skilled person understands that too large or too small unit doses result in inconvenient clinical handling. For example, when vaginally administered to a human subject, the unit dose is preferably in the range of 1 ml to 100 ml, for example 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 ml, and a range between any two of the above. When subcutaneously administered to a human subject, the unit dose is preferably in the range of 0.5 ml to 1.0 ml. When intravenously administered to a human subject, the unit dose is preferably in the range of 30.0 ml to 1000 ml.

[0076] It should be understood here that although the unit dose is expressed in volume, this does not mean that the compound of the present disclosure or a composition thereof can only be a liquid preparation. When prepared into a solid (dry powder or lyophilized powder) preparation, the volume of the unit dose can represent the volume when the dry powder or lyophilized powder is reconstituted into a liquid.

[0077] In some embodiments, the compound of the disclosure or a composition thereof is administered to the subject at a frequency of 1 to 4 times per 4 years, 1 to 3 times per 3 years, 1 to 2 times per 2 years, 1 time per year, 2 times per year, 3 times per year, 4 times per year, 5 times per year, 6 times per year, 1 time per month, 2 times per month, 3 times per month, 4 times per month, 5 times per month, 6 times per month, 7 times per month, 8 times per month, 1 time per week, 2 times per week, 3 times per week, 4 times per week, 5 times per week, 6 times per week, 1 time per three days, 2 times per three days, 3 times per three days, 1 time per two days, 2 times per two days, 1 time per day, 2 times per day.

[0078] In some embodiments, the frequency of administration of the compound of the disclosure or a composition thereof can be the same or different.

[0079] In some embodiments, the time interval between each administration is the same or different.

[0080] In some embodiments, the administration of the compound of the disclosure or a composition thereof is systemic (also known as systemic) or local.

[0081] In some embodiments, the compound of the disclosure or a composition thereof is administered by parenteral injection (e.g., intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal).

[0082] In some embodiments, the compound of the disclosure or a composition thereof is administered intramuscularly.

[0083] In other embodiments, the compound of the disclosure or a composition thereof is delivered transdermally (e.g., without the use of mechanical devices to disrupt the epithelial cell barrier).

[0084] In yet other embodiments, the compound of the disclosure or a composition thereof is administered by the rectal, vaginal route.

[0085] Disinfecting composition and disinfecting method

[0086] In yet other embodiments, the compound of the disclosure is used for non-therapeutic purposes.

[0087] A disinfectant (or disinfecting composition) is provided, which comprises an effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystal form thereof, a solvate thereof, an isotopic derivative thereof, or a prodrug thereof.

[0088] In specific embodiments, the disinfecting composition can further include one or more pharmaceutically acceptable excipients, including diluents, excipients, fillers, binders, humectants, disintegrants, absorption promoters, surfactants, adsorptive carriers, lubricants, or synergists, etc. that are conventional in the pharmaceutical art.

[0089] Examples of suitable aqueous and nonaqueous carriers that can be employed in the sanitizing compositions of the present disclosure include: water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol) or mixtures thereof, oils (such as olive oil, organic esters).

[0090] The sanitizing compositions can be prepared in the form of a spray, a wash, a lotion, a culture medium.

[0091] In the present disclosure, sanitizing agent (or sanitizing composition) refers to, inter alia, any compound (or composition) capable of inhibiting (or reducing, hindering, interfering with, inactivating, killing) viral activity, viability, replication, proliferation, growth, infectivity, or virulence in vitro (e.g., in the environment, on an object, on a surface thereof, etc.).

[0092] The sanitizing agent (or sanitizing composition) of the present disclosure is used for sanitizing an environment, area, object, sample, surface, container, or food item infected or contaminated with a virus.

[0093] In some embodiments, there is provided a method of sanitization or antiviral method suitable for treating an environment, area, object, sample, surface, container, or food item exposed to or threatened by a pathogen.

[0094] According to some embodiments, there is provided a method of sanitization by contacting an environment, area, object, sample, surface, container, or food item with an effective amount of a compound of the present disclosure or a composition thereof.

[0095] In some embodiments, the compounds of the present disclosure or a composition thereof are suitable for use against viruses on various surfaces (particularly hard surfaces on which these viruses can remain active for a relatively long period of time), as well as in commercial and public environments (e.g., hospitals, clinics, hotels).

[0096] In some embodiments, the compounds of the present disclosure or a composition thereof are used as an additive.

[0097] For "sanitizing" applications, an "effective amount" is an amount required or sufficient to inhibit (or reduce, hinder, interfere with, inactivate, kill) viral activity, viability, replication, proliferation, growth, infectivity, or virulence. In one example, an effective amount of a compound of the present disclosure is an amount capable of producing a statistically significant reduction in viral load, viral transmission ability, or viral viability in an environment.

[0098] Pharmaceutical compositions

[0099] According to some embodiments, there is provided 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.

[0100] In specific embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, including diluents, excipients, fillers, binders, humectants, disintegrants, absorption accelerators, surfactants, adsorptive carriers, lubricants, or synergists, etc. that are conventional in the pharmaceutical art.

[0101] The skilled artisan will appreciate that when the pharmaceutical composition is in the form of a dry or lyophilized powder, it differs from a pharmaceutical composition in liquid form in the amount of water present and / or in the buffer environment.

[0102] In specific embodiments, the pharmaceutical composition of the present disclosure can be administered in the form of an injection, suppository, tablet, pill, capsule, suspension, emulsion, spray, antiseptic, or detergent.

[0103] In some embodiments, the pharmaceutical composition can be in a form suitable for oral use, for example, as tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, capsules, or syrups. The oral compositions can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the following: sweetening agents, flavoring agents, coloring agents and preserving agents. Suitable excipients for use in the preparation of tablets can be inert excipients (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate); granulating and disintegrating agents (for example, microcrystalline cellulose, sodium starch glycolate, corn starch or alginic acid); binding agents (for example, starch, gelatin or acacia); and lubricating agents (for example, magnesium stearate, stearic acid or talc).

[0104] In some embodiments, the aqueous suspension contains the compound of the present disclosure and an excipient suitable for the manufacture of an aqueous suspension. Such excipients are suspending agents (for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum acacia); dispersing or wetting agents, which can be naturally occurring phosphatides (for example, lecithin, polyoxyethylene stearates, or condensation products of ethylene oxide with long chain aliphatic alcohols, polyoxyethylene sorbitol monooleate, or polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain preservatives (for example, nipagin or nipasol), colorants, flavoring agents.

[0105] In some embodiments, the oil suspension can be prepared by suspending the active ingredient in a vegetable oil (for example, peanut oil, olive oil, sesame oil or coconut oil, or mineral oil). The oil suspension can contain a thickening agent (for example, beeswax, hard fat or cetyl alcohol).

[0106] The pharmaceutical compositions of the present disclosure can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil (such as olive oil or peanut oil, or a mineral oil). Suitable emulsors can be naturally-occurring phospholipids (such as soybean phospholipids). Such formulations can also contain a demulcent, preservative, colorant, and antioxidant.

[0107] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The injectable solutions or microemulsions can be introduced into a patient's blood stream by local bolus injection. Alternatively, the solutions and microemulsions are preferably administered in such a way about to maintain a constant circulating concentration of the compound of the present disclosure. To maintain such a constant concentration, a continuous intravenous delivery device can be used.

[0108] In some specific embodiments, suppositories for vaginal or rectal administration are provided. These pharmaceutical compositions can be prepared by mixing the compound of the present disclosure with a non-irritative excipient, which is solid at ordinary temperatures but liquid at body temperature and in the vaginal or rectal cavity. Such compositions include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, or fatty acid esters of polyethylene glycols.

[0109] Kit

[0110] According to another aspect of the present disclosure, there is provided a kit for practicing the above-mentioned prophylactic or therapeutic, disinfection method, comprising at least one container, which independently contains: a compound of the present disclosure or a composition thereof. The components and / or amounts in different containers can be the same or different.

[0111] In some embodiments, the compound of the present disclosure or a composition thereof is formulated in a sterile liquid and contained in a sterile container (such as a tube, bottle, ampoule, syringe).

[0112] In other embodiments, the compound of the present disclosure or a composition thereof is contained in a container in the form of a dry powder or a lyophilized powder. Before use, it is formulated into a liquid form.

[0113] In an exemplary embodiment, the kit of the present disclosure further comprises one or a combination selected from the following: a needle, water for injection, an instruction manual.

[0114] In the present specification, when describing a numerical range, the expressions "to", "within the range of" or "between the range of" are used, which include the end point values. This expression is a way of abbreviation, and each integer or decimal number within the range is considered to be explicitly indicated.

[0115] In the present specification, when describing numerical values (unless otherwise specified), statistical errors, errors introduced by operations should be included. The degree of error depends on the specific circumstances, for example, when referring to the amount of administration, referring to weighing errors, errors introduced during the preparation process, etc.; such as 150 ml, it can be understood as 150 ml ± weighing error.

[0116] Unless otherwise specified, the articles "a", "an" used herein are intended to include "at least one" or "one or more".

[0117] The present disclosure will be further illustrated by the following examples, but the present disclosure is not limited in the scope of the examples described. The experimental methods in the following examples without specific conditions are selected according to conventional methods and conditions, or according to the instructions of the commodity.

[0118] In the following effect examples, the Chinese name and Latin name of each virus are as follows:

[0119] Human Papillomavirus 6 (HPV6);

[0120] Human Papillomavirus 11 (HPV11);

[0121] Human Papillomavirus 16 (HPV16);

[0122] Human Papillomavirus 18 (HPV18);

[0123] Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2);

[0124] Chikungunya Virus (CHIKV);

[0125] Dengue Virus 2;

[0126] Influenza A H1N1;

[0127] Middle East Respiratory Syndrome Coronavirus (MERS-CoV);

[0128] Rift Valley Fever Virus (RVFV);

[0129] Tacaribe Virus (TCRV);

[0130] wt-cottontail rabbit papillomavirus (wt-CRPV);

[0131] mE8-cottontail rabbit papillomavirus (mE8-CRPV);

[0132] murine papillomavirus (MmuPV1).

[0133] Example 1. Preparation of 5-nitro-8-hydroxyquinoline

[0134] The 5-nitro-8-hydroxyquinoline in the present disclosure is not limited by the method of preparation, obtained by any method of preparation disclosed in the prior art, or available as a commercial product.

[0135] Example 2. Preparation of prodrug of 5-nitro-8-hydroxyquinoline

[0136] The prodrug of 5-nitro-8-hydroxyquinoline, (S)-(5-nitroquinolin-8-yloxy)methyl 1- isopropionylpyrrolidine-2-carboxylate, was prepared according to the method disclosed in Example 20 of WO / 2020 / 063824.

[0137] Example 1

[0138] The antiviral activity of 5-nitro-8-hydroxyquinoline against human papillomavirus (HPV) was tested using a transient transfection assay for evaluation.

[0139] The evaluation system includes plasmids expressing viral helicase El and replication origin binding protein E2, a plasmid containing a NanoLuc gene expressed driven by a TK promoter (Promega Corporation), and the replication origin sequences of the human papillomavirus strains listed below. The synergistic binding and helicase activity of El and E2 expressed by the plasmids drives the replication of the reporter plasmid, resulting in more than 100-fold increase in NanoLuc activity compared to using El or E2 alone. The replication origin sequence positions of the 3 NanoLuc reporter plasmids are 7825-7993:1-99, 7662-7901:1-99, and 7740-7837:1-102, for HPV11 (NCBI Accession No. HE611260.1), HPV16 (KP212151.1), and HPV18 (KC470230.1), respectively. The El open reading frame (ORF) sequence positions corresponding to HPV11, HPV16, and HPV18 are the sequence portions of 832-2781, 864-2813, and 914-2887 in the same sequences, respectively. The E2 open reading frame (ORF) sequence positions corresponding to HPV11, HPV16, and HPV18 are the sequence portions of 2723-3826, 2755-3852, and 2817-3908 in the same sequences, respectively. The test for HPV6 uses a similar test method as the aforementioned HPV11, HPV16, HPV18.

[0140] The cells for transient transfection were C-33A cells (ATCC HTB-31) and the culture medium was DMEM supplemented with Earle’s salts, L-glutamine and 2% fetal bovine serum. In the experiment, Lipofectamine LTX and Plus Reagent (Invitrogen, Thermo Fisher Scientific) were used to co-transfect NanoLuc expression plasmid (5 ng / well) with E1 and E2 expression plasmids of the homologous virus. After 1 hour of incubation, the transfected cells were seeded into the wells containing 5-fold diluted test drugs and positive control drug 9-(2-phosphonomethoxyethoxy) guanine (PMEG) (Sigma-Aldrich). The transfected cells were also seeded into duplicate culture dishes of the same dilution of the test drugs to evaluate cytotoxicity. All the transfected monolayer cells were incubated at 37°C for 48 hours. NanoLuc activity expressed by the reporter plasmid was detected with Nano-Glo reagent (Promega), and cell viability in the cytotoxicity plate was determined with CellTiter-Glo reagent (Promega), and the luminescence intensity was quantified on a microplate reader. The compound concentrations that reduced the number of reporter plasmid copies by 50% (EC 50 ), 90% (EC 90 ) were identified from the experimental data.

[0141] For specific methods, see references (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).

[0142] For specific test results, see Tables 1 and 2. The results show that the antiviral activity of 5-nitro-8-hydroxyquinoline is better than that of the positive control drug.

[0143] Example 2

[0144] The anti-viral activity of 5-nitro-8-hydroxyquinoline against novel coronavirus, chikungunya virus, dengue virus 2, influenza A virus subtype H1N1, Middle East respiratory syndrome coronavirus, Rift Valley fever virus, Tacaribe virus, human coronavirus (alpha), human coronavirus (beta), herpes simplex virus 1, herpes simplex virus 2, varicella zoster virus, human papillomavirus 11, human papillomavirus 16, human papillomavirus 18, human papillomavirus 6 was tested using a similar method as in Example 1, and the test results are shown in Table 2.

[0145] When SI 50 When the value > 10, the compound is determined to have activity against the virus. The results show that 5-nitro-8-hydroxyquinoline has specific inhibitory activity against HPV, and such activity is not observed against other viruses.

[0146] Example 3 (prodrug)

[0147] According to the method of Test Example 4 in WO 2021 / 238978, the prodrug prepared in Example 2 was administered to an animal (dog) in vivo, and its conversion to the active form 5-nitro-8-hydroxyquinoline was detected in the circulating sample. Therefore, the prodrug and 5-nitro-8-hydroxyquinoline are equivalent in terms of anti-HPV effect.

[0148] Table 1. Activity data of positive control drugs against HPV

[0149]

[0150]

Claims

1. Use in the preparation of antiviral drugs, selected from any of the following: 5-Nitro-8-hydroxyquinoline, its pharmaceutically acceptable salt, and its prodrug; The prodrug is (S)-(5-nitroquinoline-8-yloxy)methyl-1-isopropionylpyrrolidine-2-carboxylic acid ester; The virus is a human papillomavirus, selected from any one or a combination of the following: human papillomavirus 6, human papillomavirus 11, human papillomavirus 16 and human papillomavirus 18.

2. The use according to claim 1, wherein the antiviral drug is used in mammals.

3. The use according to claim 2, wherein the mammal is a human.

4. The use according to any one of claims 1 to 3, wherein the medicament further comprises pharmaceutically acceptable excipients.