Use of 5-nitro-8-hydroxyquinoline

Abstract

The use of 5-nitro-8-hydroxyquinoline is provided. Specifically, the use of 5-nitro-8-hydroxyquinoline, its pharma- ceutically acceptable salt, its crystalline form, its solvate, its isotopic derivative or its prodrug in the preparation of an antiviral drug is provided. 5-nitro-8-hydroxyquinoline, its pharma- ceutically acceptable salt, its crystalline form, its solvate, its isotopic derivative or its prodrug has remarkable activity in the fight against human papillomavirus.

Description

[Technical Field]

[0001] The present application claims priority from Chinese Patent Application No. 2021106017773 filed on May 31, 2021.

[0002] The present disclosure relates to the fields of organic chemistry, pharmaceuticals and antiviral therapy. Specifically, the present application relates to the use of 5-nitro-8-hydroxyquinoline. [Background Art]

[0003] Human papillomavirus (HPV) is a DNA virus belonging to the family Papillomaviridae, and is a very common virus worldwide. Members of HPV have tropism for mucosal epithelium and cutaneous epithelium. In addition to various genital system diseases such as genital warts, HPV can also cause various malignant tumors including cervical cancer, penile cancer, anal cancer, oral cancer, pharyngeal and laryngeal cancer, tonsillar cancer, esophageal cancer and the like. There are more than 100 types of human papillomavirus, and at least 12 types thereof can cause cancer, so HPV has become the most important type of human tumor virus. Human papillomavirus has a high infection rate and strong pathogenicity, is very harmful to populations, especially women, and has attracted great attention from medical associations at home and abroad. Currently, clinically, there are prophylactic multivalent HPV vaccines (such as HPV 6, 11, 16, 18) that can prevent infection by multiple types of the virus, but the use of the prophylactic vaccine in infected patients does not produce significant therapeutic effects. The development of effective drugs targeting multiple types of HPV can provide new approaches for the clinical treatment and prevention of HPV-related diseases including malignant tumors.

[0004] Currently, effective drugs against HPV are still needed in the art. [Prior Art Literature] [Patent Literature]

[0005] [Patent Document 1] WO2020 / 063824 [Patent Document 2] WO2021 / 238978 [Non-patent literature]

[0006] [Non-Patent Document 1] Freireich et al., 1966, Cancer Chemother Rep 50:219 [Non-Patent Document 2] Remington Pharmaceutical Sciences by EW Martin [Non-Patent Document 3] 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 [Non-Patent Document 4] 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 [Overview of the project] [Problems that the invention aims to solve]

[0007] The technical problem addressed in this disclosure is to provide the use of 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salts, its crystalline form, its solvates, its isotopic derivatives, or its prodrugs in the preparation of antiviral drugs, particularly in the preparation of anti-human papillomavirus (HPV) drugs. [Means for solving the problem]

[0008] This disclosure addresses the above technical challenges through the following technical solutions.

[0009] In a first aspect, the disclosure provides the use of 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salts, its crystalline form, its solvates, its isotopic derivatives, or its prodrugs in the preparation of antiviral agents.

[0010] Preferably, antiviral drugs are intended for use in mammals, preferably humans.

[0011] 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).

[0012] In a second aspect, the Disclosure provides 5-nitro-8-hydroxyquinoline, pharmaceutically acceptable salts thereof, crystalline forms thereof, solvates thereof, isotopic derivatives thereof, or prodrugs thereof for use in the treatment of viral infections.

[0013] Preferably, the present disclosure provides 5-nitro-8-hydroxyquinoline, pharmaceutically acceptable salts thereof, crystalline forms thereof, solvates thereof, isotopic derivatives thereof, or prodrugs thereof for use in the treatment of viral infections in mammals. The mammal is preferably human.

[0014] 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).

[0015] In a third aspect, the present disclosure provides a method for treating a viral infection, comprising the step of administering to a subject a therapeutically 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.

[0016] Preferably, the present disclosure provides a method for treating a viral infection in a mammal, comprising the step of administering to a subject a therapeutically 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, wherein the mammal is preferably a human.

[0017] 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).

[0018] In a fourth aspect, the present disclosure provides a pharmaceutical composition for treating a 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.

[0019] Preferably, the present disclosure provides a pharmaceutical composition for treating a viral infection in a mammal, 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.

[0020] 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).

[0021] In a fifth aspect, the present disclosure provides a non-therapeutic method. Specifically, the present disclosure provides an in vitro disinfection method comprising the step of contacting an environment or an object to be treated with an effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, or an isotopic derivative thereof.

[0022] The positive constructive and innovative effect of the present disclosure lies in that the present disclosure provides the use 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 in the fight against viruses, particularly in the fight against human papillomavirus (HPV).

Mode for Carrying Out the Invention

[0023] 5-Nitro-8-hydroxyquinoline and Use Thereof Nitroxoline has the chemical name 5-nitro-8-hydroxyquinoline and CAS number 4008-48-4.

[0024] According to some embodiments, there is provided use of any compound selected from 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, and a prodrug thereof in the preparation of an antiviral drug.

[0025] In some embodiments, there is provided use of any compound selected from 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, a crystalline form thereof, a solvate thereof, an isotopic derivative thereof, and a prodrug thereof in the preparation of a drug against human papillomavirus infection.

[0026] In some embodiments, there is provided 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 treating human papillomavirus infection.

[0027] In some embodiments, 5-nitro-8-hydroxyquinoline is provided in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt may be an acid addition salt or a base addition salt. In some embodiments, the acid may be an inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, or 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, pyruvate, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. In some embodiments, the base may include, but is not limited to, an inorganic base containing sodium hydroxide, potassium hydroxide, magnesium hydroxide, or calcium hydroxide; it may also include, but is not limited to, an organic base containing ammonium hydroxide, triethylamine, N,N-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucosamine, procaine, N-benzylphenethylamine, arginine, or lysine; it may also include, but is not limited to, an alkali metal salt containing, but is not limited to, a salt of lithium, potassium, and sodium (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate); it may also include, but is not limited to, an alkaline earth metal salt containing, but is not limited to, a zinc salt; and it may also include, but is not limited to, a transition metal salt.

[0028] The term "pharmaceutically acceptable," when used in the preparation of a pharmaceutical composition, means that the pharmaceutical composition is generally safe and non-toxic, meets biological needs, and is acceptable and functional as a drug for use in mammals (e.g., humans).

[0029] In some embodiments, 5-nitro-8-hydroxyquinoline can be provided in crystalline form.

[0030] In other embodiments, 5-nitro-8-hydroxyquinoline is provided in the form of its solvate.

[0031] The term "solvate" refers to a substance formed by 5-nitro-8-hydroxyquinoline and a suitable solvent. In certain embodiments, the solvent is water. In other specific embodiments, the solvent is a pharmaceutically acceptable organic solvent.

[0032] In some other embodiments, 5-nitro-8-hydroxyquinoline is provided in the form of its isotopic derivatives.

[0033] The term "isotope derivative" refers to a compound that has one or more isotopic enriched atoms compared to 5-nitro-8-hydroxyquinoline. For example, the compound has the structure of 5-nitro-8-hydroxyquinoline, but the hydrogen is substituted with "deuterium" or "tritium", and / or the carbon is 11 C, 13 C or 14 It is replaced with C, but the rest of the part remains unchanged.

[0034] In some other embodiments, 5-nitro-8-hydroxyquinoline is provided in the form of its prodrug. The term “prodrug” refers to a derivative of 5-nitro-8-hydroxyquinoline that contains a biologically reactive functional group so that the biologically reactive functional group can be cleaved from the derivative or otherwise reacted under biological conditions (in vitro or in vivo) to provide 5-nitro-8-hydroxyquinoline.

[0035] In some specific embodiments, the prodrug of 5-nitro-8-hydroxyquinoline has the following structural formula [ka] It is (S)-(5-nitroquinoline-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate having the following properties:

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

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

[0038] In this disclosure, antiviral agent means any compound or composition that can inhibit (or reduce, impair, interfere with, inactivate, or kill) the activity, viability, replication, proliferation, growth, infectivity, or pathogenicity of a virus in vivo or in vitro.

[0039] In this disclosure, antiviral agents are used to prevent, treat, or induce remission of a target virus-related disease or symptom.

[0040] In this disclosure, antiviral agents are used to prevent, treat, or induce remission of a target human papillomavirus-related disease or condition.

[0041] Human papillomavirus (HPV) belongs to the genus Alphapapillomavirus of the family Papovaviridae. HPV is a spherical DNA virus. Currently, more than 130 different types of HPV have been isolated and can be classified into the following types according to the infected tissue and site: (1) Low-risk skin types, HPV1, 2, 3, 4, 7, 10, 12, 15, etc. (2) High-risk skin types, such as HPV 5, 8, 14, 17, 20, 36, 38; (3) Low-risk mucosal types, HPV6, 11, 13, 32, 34, 40, 42, 43, 44, 54, etc. (4) High-risk mucosal types, such as HPV 16, 18, 30, 31, 33, 35, 53, 39, etc.

[0042] In some embodiments, the antiviral agents of this disclosure are for use for mucosal (high-risk and low-risk) human papillomavirus-related diseases or conditions, including HPV6, 11, 13, 16, 18, 30, 31, 32, 33, 34, 35, 39, 40, 42, 43, 44, 53, and 54.

[0043] In some specific embodiments, the HPV is selected from the group consisting of, among other things, human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16), human papillomavirus 18 (HPV18), or combinations thereof.

[0044] In this disclosure, when "compounds of the disclosure" refers to 5-nitro-8-hydroxyquinoline, its pharmaceutically acceptable salts, its crystalline form, its solvates, its isotopic derivatives, or its prodrugs.

[0045] Prevention or treatment methods This disclosure provides a method for preventing or treating a target virus infection.

[0046] In some embodiments, a method for preventing infection of a target virus comprises or consists of administering a preventive amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, its crystalline form, its solvate, its isotopic derivative, or its prodrug to the target.

[0047] In some embodiments, a method for treating a target viral infection comprises or consists of administering a therapeutically effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, its crystalline form, its solvate, its isotopic derivative, or its prodrug to the target.

[0048] When applied to animals, humans, subjects, cells, tissues, organs, or bodily fluids, “administering” or “administration” means bringing an exogenous drug (e.g., a compound of the Disclosure), therapeutic agent, or composition into contact with an animal, human, subject, cell, tissue, organ, or bodily fluid.

[0049] The term "subject" refers to mammals, including, for example, camels, donkeys, zebras, cows, pigs, horses, goats, sheep, cats, dogs, rats, rabbits, guinea pigs, mice, and primates.

[0050] In some specific embodiments, the subject is human.

[0051] In some specific embodiments, the subject is exposed to, susceptible to, suspected of being infected with, or already infected with a virus.

[0052] "Already infected" should be understood in a broad sense, including the fact that the probability of having a viral infection is statistically higher than that of a control at a given significant threshold. For "statistically significant," p is set to, for example, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, 0.0001 or even lower, but not limited to these. For example, if a comparison is made between two individuals or groups and the resulting p-value is lower than a given specific p-value, the two individuals or groups are considered to have a statistically significant difference.

[0053] In prevention methods, the target group is those who are susceptible to viral infection, those who may be exposed to viral infection, or those who have been exposed to viral infection.

[0054] In terms of treatment methods, the subjects are those suspected of having a viral infection or who have already been infected with a viral infection.

[0055] The term “treating” or “treatment” refers to eliminating a disease, preventing its progression, slowing its progression, reducing the duration of one or more symptoms associated with the disease, improving or reversing at least one measurable parameter associated with the disease, or extending the survival of a patient with the disease.

[0056] The terms “preventing” or “prevention” refer to preventive measures against exposure to pathogenic factors, such as viruses, and may be taken against the environment or subject. In certain embodiments, preventing or prevention involves treating an uninfected subject, environment, or object with the compounds or pharmaceutical compositions of this disclosure to prevent infection, reduce the risk of infection, reduce the probability of infection, delay the appearance or onset of infectious symptoms, etc.

[0057] The term "effective amount" refers to the amount of the compound or pharmaceutical composition of this disclosure that induces the desired effect in a subject, environment, or target product.

[0058] In some embodiments, “therapeutic dose” is an amount sufficient to treat a disease state or symptoms associated with a viral infection, in particular, or to block, delay, or reverse a viral infection or other undesirable symptoms.

[0059] In some embodiments, the "preventive effective dose" is the amount that, when administered to a subject, environment, or target product, produces a predetermined preventive effect.

[0060] Therapeutic or preventive effects do not necessarily occur at the time of a single dose, but may occur after a series of doses have been administered.

[0061] In certain embodiments, a person skilled in the art can determine the selection of an effective dose based on consideration of various factors (e.g., through clinical trials), including the activity of the compound of this disclosure, the metabolic rate of the specific compound used, the disease being treated, the symptoms involved, the route of administration, the time of administration, the severity of the disease, the patient's body weight, the patient's immune status, other drugs (compounds and / or materials) used in combination with the specific compound used, and other factors known to a person skilled in the art. A person skilled in the art can easily determine the required effective dose. The effective dose can be obtained from dose-response curves derived from animal model test systems and can be determined according to the physician's opinion and the circumstances of each patient. The correlation between animal doses and human doses is described in Freireich et al., 1966, Cancer Chemother Rep 50:219, and the surface area of ​​the human body can be roughly determined by the patient's height and body weight.

[0062] Generally, an appropriate daily dose of the compounds disclosed herein is the amount of the compound that effectively exerts a preventive or therapeutic effect.

[0063] The effective amount of the compound disclosed herein may 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, and specifically, ranges 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 any two of the above values.

[0064] If necessary, the daily dose of the compounds disclosed herein may be administered separately in two, three, four, five, six or more subdoses at appropriate time intervals throughout the day, and optionally, the subdoses may be doses of the unit dosage form.

[0065] The pharmaceutical compositions or compounds provided by this disclosure can be administered, for example, according to conventional clinical treatment methods for viral infections, and can be administered directly by perfusion or application to the site of infection, and the dose used for administration may be a dose determined by a medical professional.

[0066] In certain embodiments, the pharmaceutical composition or compound provided by this disclosure is prepared in a dosage form for intravaginal administration.

[0067] The compounds of this disclosure may be administered alone, but they may also be administered in the form of a pharmaceutical composition.

[0068] As used in this disclosure, the term "unit dose" refers to a physically distinct unit suitable for administration to a subject, environment, or target substance. Each unit contains a predetermined amount of the compound or composition thereof of this disclosure.

[0069] In some embodiments, the unit doses described herein are expressed in volume and are 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 values.

[0070] Those skilled in the art will understand that excessively high or low unit doses can lead to clinical problems. For example, when administered intravaginally to human subjects, 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 any two of the above values. When administered subcutaneously to human subjects, the unit dose is preferably in the range of 0.5 ml to 1.0 ml. When administered intravenously to human subjects, the unit dose is preferably in the range of 30.0 ml to 1000 ml.

[0071] While unit doses are expressed in volume, this should be understood not to mean that the compounds or compositions thereof of this disclosure are formulated only in liquid form. When prepared as a solid (powder or lyophilized powder) formulation, the volume of the unit dose represents the volume of the reconstituted liquid prepared from the powder or lyophilized powder.

[0072] In some embodiments, the compounds or compositions thereof of the Disclosure are administered to subjects at frequencies of 1 to 4 times every 4 years, 1 to 3 times every 3 years, 1 to 2 times every 2 years, once a year, twice a year, three times a year, four times a year, five times a year, six times a year, once a month, twice a month, three times a month, four times a month, five times a month, six times a month, seven times a month, eight times a month, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, once every three days, twice every three days, three times every three days, once every two days, twice every two days, once a day, and twice a day.

[0073] In some embodiments, the administration frequency of the compounds or compositions thereof of this disclosure may be the same or different.

[0074] In some embodiments, the time intervals between each dose may be the same or different.

[0075] In some embodiments, the administration of the compounds or compositions thereof of this disclosure is systemic or topical.

[0076] In some embodiments, the compounds or compositions thereof of the Disclosure are administered by parenteral injection (e.g., intramuscular, intraperitoneal, intravenous, subcutaneous, or intradermal).

[0077] In some embodiments, the compounds or compositions thereof of this disclosure are administered intramuscularly.

[0078] In other embodiments, the compounds or compositions of the Disclosure are delivered transdermally (for example, in a manner that does not disrupt the epithelial cell barrier by mechanical devices).

[0079] In some other embodiments, the compounds or compositions thereof of the Disclosure are administered via the rectal or vaginal route.

[0080] Disinfectant composition and disinfection method In some other embodiments, the compounds of this disclosure are intended for non-therapeutic use.

[0081] A disinfectant (or disinfectant composition) is provided comprising an effective amount of 5-nitro-8-hydroxyquinoline, a pharmaceutically acceptable salt thereof, its crystalline form, its solvate, its isotopic derivative, or its prodrug.

[0082] In certain embodiments, the disinfectant composition may further include one or more pharmaceutically acceptable excipients, such as diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbents, lubricants, or synergists, which are common in the pharmaceutical field.

[0083] Examples of suitable aqueous or non-aqueous carriers useful for the disinfectant compositions of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol) or mixtures thereof, and oils (e.g., olive oil, organic esters).

[0084] Disinfectant compositions can be prepared in the form of sprays, detergents, lotions, or culture media.

[0085] In this disclosure, disinfectant (or disinfectant composition) means, in particular, any compound (or composition) that can inhibit (or reduce, impair, interfere with, inactivate, or kill) the activity, viability, replication, proliferation, growth, infectivity or pathogenicity of a virus in vitro (e.g., in the environment, on an object and on its surface).

[0086] The disinfectants (or disinfectant compositions) of this disclosure are intended for use in disinfecting environments, areas, articles, samples, surfaces, containers, or food that are infected or contaminated with viruses.

[0087] In some embodiments, a disinfection or antiviral method is provided that is suitable for treating environments, areas, articles, samples, surfaces, containers, or food that have been exposed to or threatened by a pathogen.

[0088] According to some embodiments, a disinfection method is provided which involves bringing an environment, area, article, sample, surface, container, or food into contact with an effective amount of the compound or composition thereof of the present disclosure.

[0089] In some embodiments, the compounds or compositions thereof of this disclosure are suitable for viruses in various surfaces (in particular, hard surfaces on which these viruses can remain active for a relatively long period of time) and in commercial and public environments (e.g., hospitals, clinics, hotels).

[0090] In some embodiments, the compounds or compositions thereof of this disclosure are used as additives.

[0091] For disinfection purposes, the "effective amount" is the amount required or sufficient to inhibit (or reduce, impair, interfere with, inactivate, or kill) the activity, viability, replication, proliferation, growth, infectivity, or pathogenicity of a virus. In one example, the effective amount of the compound disclosed herein is the amount that can statistically significantly reduce the viral load, viral transmissibility, or viral viability in the environment.

[0092] Pharmaceutical composition According to some embodiments, pharmaceutical compositions comprising the compounds of the present disclosure and optionally pharmaceutically acceptable excipients are provided. Suitable pharmaceutically acceptable excipients are described in Remington Pharmaceutical Sciences by E.W. Martin.

[0093] In certain embodiments, the pharmaceutical composition includes one or more pharmaceutically acceptable excipients, such as diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbents, lubricants, or synergists, which are conventional in the field of pharmaceuticals.

[0094] Those skilled in the art will understand that, when a pharmaceutical composition is in the form of a powder or lyophilized powder, the difference between a pharmaceutical composition in powder form and a pharmaceutical composition in liquid form lies in the water content and / or the buffer environment.

[0095] In certain embodiments, the pharmaceutical compositions of the present disclosure can be prepared in the form of injections, suppositories, tablets, pills, capsules, suspensions, emulsions, sprays, detergents, and lotions for administration.

[0096] In some embodiments, the pharmaceutical composition may be in a form suitable for oral administration, such as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, capsules, or syrups. The oral composition may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more components selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives. Suitable excipients for preparing tablets may be inactive excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulators and disintegrants, such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone, or gum arabic; and lubricants, such as magnesium stearate, stearic acid, or talc.

[0097] In some embodiments, the aqueous suspension comprises the compounds of the Disclosure and excipients suitable for the preparation of the aqueous suspension. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersing or wetting agents, which may be naturally occurring phospholipids, such as lecithin, polyoxyethylene stearate, or polyethylene oxide sorbitol monooleate or polyethylene oxide sorbitan monooleate, which are condensation products of ethylene oxide and long-chain fatty alcohols. The aqueous suspension may also contain preservatives (e.g., ethylparaben or propylparaben), colorants, and flavorings.

[0098] In some embodiments, the oily suspension can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oil. The oily suspension may contain a thickening agent, such as beeswax, solid paraffin, or cetyl alcohol.

[0099] The pharmaceutical compositions of this disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil. A suitable emulsifier may be a naturally occurring phospholipid, such as soy lecithin. Such preparations may also contain buffers, preservatives, colorants, and antioxidants.

[0100] The pharmaceutical compositions of this disclosure may be in the form of sterile aqueous solutions for injection. Acceptable solvents that can be used are water, Ringer's solution, and isotonic saline. The injection solution or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of this disclosure. A continuous intravenous drug delivery device can be used to maintain this constant concentration.

[0101] In some specific embodiments, the form of suppositories for vaginal or rectal administration is provided. These pharmaceutical compositions can be prepared by mixing the compounds of the Disclosure with non-irritating excipients (which are solid at room temperature but liquid in the vagina or rectum). Such compositions include cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycol of various molecular weights, or fatty acid esters of polyethylene glycol.

[0102] kit In another aspect of the present disclosure, a kit is provided for carrying out the above-described prevention, treatment, or disinfection method, comprising at least one container independently containing the compounds or compositions thereof of the present disclosure. The compositions and / or quantities in the different containers may be the same or different.

[0103] In some embodiments, the compounds or compositions thereof of the present disclosure are formulated into a sterile solution and contained in a sterile container (e.g., tubes, vials, ampoules, and syringes).

[0104] In some other embodiments, the compounds or compositions thereof of the Disclosure are contained in a container in the form of a powder or lyophilized powder, which is reconstituted into a liquid form immediately before use.

[0105] In exemplary embodiments, the kit of the present disclosure further includes a needle, water for injection, and instructions for use, or a combination thereof.

[0106] In this specification, when describing a numerical range, the expressions "~(to)", "within the range", or "between the range" are used to include the endpoint value. This expression is an abbreviation that is considered to uniquely represent each integer or decimal within the range.

[0107] In this specification, when numerical values ​​are given, statistical errors and errors introduced by the process should be taken into consideration unless otherwise specified. The degree of error depends on the specific circumstances. For example, with respect to dosage, errors due to weighing operations and errors introduced in the formulation process, etc., may be considered as 150 ml ± 10%.

[0108] Unless otherwise specified, the articles “a, an” and “the” used herein are intended to include “at least one” or “one or more.” [Examples]

[0109] The present disclosure will be further illustrated below by examples, but will not be limited to the scope of these examples. Experimental methods will follow conventional methods and conditions, or methods and conditions suggested in the product description, without specifying any particular conditions in the examples.

[0110] In the following examples of effects, the names of the viruses and their Latin names are as follows: Human papillomavirus 6 (HPV6); Human papillomavirus 11 (HPV11); Human papillomavirus 16 (HPV16); Human papillomavirus 18 (HPV18); Novel coronavirus (SARS-CoV-2); Chikungunya virus (CHIKV); Dengue virus 2; Influenza A H1N1; Middle East Respiratory Syndrome Coronavirus (MERS-CoV); Rift Valley fever virus (RVFV); Takaribe virus (TCRV); wt-cotton rabbit papillomavirus (wt-CRPV); mE8-Cottontail Rabbit Papillomavirus (mE8-CRPV); Mouse papillomavirus (MmuPV1).

[0111] (Example 1: Preparation of 5-nitro-8-hydroxyquinoline) The 5-nitro-8-hydroxyquinoline of this disclosure is not limited by the method of preparation, and may be obtained by any preparation method disclosed in the prior art, or a commercially available product may be used.

[0112] (Example 2: Preparation of a prodrug of 5-nitro-8-hydroxyquinoline) (S)-(5-nitroquinoline-8-yloxy)methyl1-isopropionylpyrrolidine-2-carboxylate, a prodrug of 5-nitro-8-hydroxyquinoline, was prepared according to the method disclosed in Example 20 of WO2020 / 063824.

[0113] (Example of effect 1) The antiviral activity of 5-nitro-8-hydroxyquinoline against human papillomavirus (HPV) was tested and evaluated using a transient transfection assay.

[0114] This evaluation system included plasmids expressing viral helicase E1 and origin-of-replication (ORP) binding protein E2, the NanoLuc gene (Promega) whose expression is driven by a TK promoter, and plasmids containing the origin-of-replication sequences of the human papillomavirus strains listed below. Compared to the use of E1 or E2 alone, the synergistic binding and helicase activity of E1 and E2 expressed from the plasmids drove the replication of the reporter plasmid, resulting in a more than 100-fold increase in NanoLuc activity. The origin-of-replication sequence locations for the three NanoLuc reporter plasmids were 7825-7993:1-99, 7662-7901:1-99, and 7740-7837:1-102 for HPV11 (NCBI accession number HE611260.1), HPV16 (KP212151.1), and HPV18 (KC470230.1), respectively. The E1 open reading frame (ORF) sequences corresponding to HPV11, HPV16, and HPV18 were located at 832-2781, 864-2813, and 914-2887, respectively, within the same sequence. The E2 open reading frame (ORF) sequences corresponding to HPV11, HPV16, and HPV18 were located at 2723-3826, 2755-3852, and 2817-3908, respectively, within the same sequence. Testing for HPV6 was performed using the same test methods as for HPV11, HPV16, and HPV18.

[0115] The cells used for transient transfection were C-33A cells (ATCC HTB-31) in DMEM medium supplemented with Earl's salt, L-glutamine, and 2% fetal bovine serum. In the experiment, NanoLuc expression plasmid (5 ng / well) was co-transfected with homologous virus E1 and E2 expression plasmids using Lipofectamine LTX and PlusReagent (Invitrogen, Thermo Fisher Scientific). After 1 hour incubation, the transfected cells were inoculated into wells containing a 5-fold dilution of the test reagent and the positive control 9-[(2-phosphonomethoxy)ethyl]guanine (PMEG) (Sigma-Aldrich). The transfected cells were also inoculated into double dishes containing the same dilution of the test reagent to evaluate cytotoxicity. All transfected cell monolayers were incubated at 37°C for 48 hours. NanoLuc activity expressed by the reporter plasmid was detected using Nano-Glo reagent (Promega), and cell viability in cytotoxic plates was measured using CellTiter-Glo reagent (Promega). Fluorescence intensity was quantified using a microplate reader. The reporter plasmid copy number was 50% (EC2). 50 ), 90% (EC 90 The concentrations of the compounds that decreased were identified from the experimental data.

[0116] The detailed methods were as described in the 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).

[0117] Detailed test results are shown in Tables 1 and 2. The results showed that the antiviral activity of 5-nitro-8-hydroxyquinoline was better than that of the positive control drug.

[0118] (Example of effect 2) The antiviral activity of 5-nitro-8-hydroxyquinoline against novel coronaviruses, chikungunya virus, dengue virus 2, influenza A H1N1, Middle East Respiratory Syndrome coronavirus, Rift Valley fever virus, Takaribe virus, human coronavirus (α), human coronavirus (β), herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, human papillomavirus 11, human papillomavirus 16, human papillomavirus 18, and human papillomavirus 6 was tested using the same method as used in Efficacy Example 1. The test results are shown in Tables 2.

[0119] SI 50 If the value > 10, the compound was determined to be active against the virus. The results showed that 5-nitro-8-hydroxyquinoline had specific inhibitory activity against HPV, and this activity was not observed against other viruses.

[0120] (Example of effect 3 (prodrug)) According to the method of Test Example 4 in WO2021 / 238978, the prodrug prepared in Example 2 was administered to animals (dogs), 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 were equivalent in their anti-HPV effects.

[0121] [Table 1]

[0122] [Table 2]

Claims

1. In the preparation of antiviral drugs, the following: 5-Nitro-8-hydroxyquinoline, pharmaceutically acceptable salts of 5-nitro-8-hydroxyquinoline, Crystals of 5-nitro-8-hydroxyquinoline, 5-nitro-8-hydroxyquinoline solvate, Isotope derivatives of 5-nitro-8-hydroxyquinoline, and 5-nitro-8-hydroxyquinoline prodrug Any one of the uses selected from, The virus is the human papillomavirus. The prodrug used is (S)-(5-nitroquinoline-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate.

2. The use according to claim 1, wherein the antiviral agent is for use in mammals.

3. The use according to claim 1, wherein the antiviral agent is for use in humans.

4. The use according to any one of claims 1 to 3, wherein the virus is selected from the group consisting of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16), human papillomavirus 18 (HPV18), or a combination thereof.

5. An in vitro method for inhibiting or killing a virus, 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 of 5-nitro-8-hydroxyquinoline, crystals of 5-nitro-8-hydroxyquinoline, a solvate of 5-nitro-8-hydroxyquinoline, or an isotopic derivative of 5-nitro-8-hydroxyquinoline, How to determine that the virus is the human papillomavirus.

6. The method according to claim 5, wherein the virus is selected from the group consisting of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16), human papillomavirus 18 (HPV18), or a combination thereof.

7. - Pharmaceutically acceptable excipients, and - One of the following selected from: 5-nitro-8-hydroxyquinoline, pharmaceutically acceptable salts of 5-nitro-8-hydroxyquinoline, crystals of 5-nitro-8-hydroxyquinoline, solvates of 5-nitro-8-hydroxyquinoline, isotopic derivatives of 5-nitro-8-hydroxyquinoline, or prodrugs of 5-nitro-8-hydroxyquinoline. A pharmaceutical composition for treating viral infections, comprising: The virus is the human papillomavirus. A pharmaceutical composition in which the prodrug is (S)-(5-nitroquinoline-8-yloxy)methyl 1-isopropionylpyrrolidine-2-carboxylate.

8. The pharmaceutical composition according to claim 7, wherein the virus is selected from the group consisting of human papillomavirus 6 (HPV6), human papillomavirus 11 (HPV11), human papillomavirus 16 (HPV16), human papillomavirus 18 (HPV18), or a combination thereof.

Images