WO2017010835A1 - Use of radotinib for prevention or treatment of viral respiratory disease - Google Patents

Use of radotinib for prevention or treatment of viral respiratory disease Download PDF

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WO2017010835A1
WO2017010835A1 PCT/KR2016/007719 KR2016007719W WO2017010835A1 WO 2017010835 A1 WO2017010835 A1 WO 2017010835A1 KR 2016007719 W KR2016007719 W KR 2016007719W WO 2017010835 A1 WO2017010835 A1 WO 2017010835A1
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radotinib
cov
treatment
prevention
present
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PCT/KR2016/007719
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French (fr)
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Dong Yeon Kim
Man Seong Park
Dae Jin Cho
Gong Yeal Lee
Hong Youb Kim
Hea Un Lee
Choong Am Ahn
Hye Jin BANG
Song Ei SONG
Jong Seong Park
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Il-Yang Pharm. Co., Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to use of radotinib which has antiviral activity against coronaviruses, specifically for the prevention or treatment of respiratory disease caused by Middle East respiratory syndrome coronavirus (MERS-CoV).
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • Coronaviruses are enveloped, positive-sense single strand RNA viruses and have 25-32 kb of genome size, and so they belong to a relatively large virus among RNA viruses known up to now. Because spike proteins ⁇ which are club-shaped bumps ⁇ are embedded in a membrane, the name "coronavirus” is derived from the Latin corona , meaning halo or crown and refers to the characteristic appearance.
  • coronaviruses have been found in various birds and mammals such as bat, cat, dog, cow, pig and mouse. Coronaviruses are divided into four (4) groups (Alpha-, Beta-, Gamma- and Deltacoronavirus). Alphacoronavirus and Betacoronavirus groups primarily infect mammals, and Gammacoronavirus and Deltacoronavirus groups are discovered from birds. It has been known that coronaviruses cause various diseases such as gastrointestinal diseases and respiratory diseases.
  • SARS coronavirus causing severe acute respiratory syndrome, was first discovered in 2003. According to a report of the World Health Organization (WHO), there were 8,273 patients and 775 deaths (fatality rate: about 10%) all over the world in 2002 and 2003. There were additional cases and deaths until 2004.
  • WHO World Health Organization
  • HCV-EMC coronavirus
  • this novel coronavirus was classified by the name of "Middle East respiratory syndrome-coronavirus (MERS-CoV)" by the Coronavirus Study Group of the International Committee on Taxonomy of Viruses. Because the genetic sequencing of this virus is similar to Pipistrellus Bat CoV-HKU5 and HKU4 found in bats, it was assumed that bats are most probable infection source. However, recently the article published in The Lancet Infectious Diseases reported that all of 50 sera from Omani dromedary camels had protein-specific antibodies against MERS-CoV spike. However, in the Canary islands 15 of 105 camels showed an antibody-positive reaction.
  • MERS-CoV Middle East respiratory syndrome-coronavirus
  • MERS-CoV is a novel virus which is considerably different from SARS-CoV in terms of molecular genetics.
  • MERS-CoV shows a low nucleotide identity of about 55% with SARS-CoV, and these two viruses show evolutionary differences from each other in a phylogenetic analysis.
  • SARS-CoV belongs to the B group of Betacoronavirus
  • MERS-CoV belongs to the C group of Betacoronavirus.
  • SARS-CoV, and HcoV-HKU1 and HCoV-OC43 which are human coronaviruses, had been known.
  • SARS-CoV and MERS-CoV are different in a route to enter into cells.
  • SARS-CoV uses ACE2 receptors distributed on ciliated cells of the human respiratory tract
  • MERS-CoV uses dipeptidyl peptidase 4 (DDP4, also known as CD26) expressed in non-ciliated cells. Both receptors are mainly distributed on the human lower respiratory tract rather than the upper respiratory tract.
  • DDP4 dipeptidyl peptidase 4
  • MERS-CoV and SARS-CoV show high fatality rates, they must be transmitted via large droplets after progression to pneumonia. As a result, it is believed that they are less contagious as compared with disease spread via aerosol such as influenza or measles.
  • aerosol such as influenza or measles.
  • MERS MERS
  • the major clinical symptoms of MERS are those of pneumonia such as fever (87%), cough (89%), shortness of breath and the like, and vomiting and diarrhea (35%) also occur in some patients. Renal failure has also been reported in patients having lowered immune function, and fatality rate (34.5%) is very high. Because many cases occurred in the Middle East region (Saudi Arabia, Vietnamese, etc.), it is assumed that this is an infection region, but the precise infection route is still unclear. There was no evidence of the disease widely spreading between humans, but it has been confirmed that transmission can occur when family members or medical personnel are in close contact with patients. It is assumed that the incubation period is 9 to 12 days, but varies considerably depending on patients. Middle East Journal of Management (MEJM, February 2008) reported that the incubation period is 1.9 to 14.7 days (average 5.2 days).
  • the present invention is intended to provide an antiviral agent showing potent antiviral activity against coronaviruses.
  • the present invention provides a therapeutic composition for the prevention or treatment of respiratory disease caused by coronavirus, comprising radotinib (Chemical Formula 1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • composition of the present invention comprises radotinib or a pharmaceutically acceptable salt thereof as an active ingredient, and can be used for the prevention or treatment of disease caused by coronavirus.
  • the present invention provides a receptor tyrosine kinase inhibitor for the prevention or treatment of viral respiratory disease, and specifically use of radotinib or a pharmaceutically acceptable salt thereof.
  • use of radotinib for inhibiting replication, infection, or both replication and infection of coronavirus is provided.
  • the present invention provides use of a receptor tyrosine kinase inhibitor such as radotinib for the prevention or treatment of viral respiratory disease in an animal, more preferably a mammal, and still more preferably a human.
  • radotinib refers to 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(3-methylpyrazin-2-yl)-pyrimidin-2-ylamino)benzamide represented by the above Chemical Formula 1.
  • Korean Patent No. 10-0674813 discloses that the compound of Chemical Formula 1 has excellent anticancer effect on various cancers such as lung cancer, gastric cancer, colon cancer, pancreatic cancer, hepatoma, prostatic cancer, breast cancer, chronic or acute leukemia, hematologic malignancy, brain tumor, bladder cancer, rectal cancer, cervical cancer, lymphoma, etc.
  • respiratory viruses such as coronavirus, adenovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, etc.
  • the compound of the present invention may be used as itself or in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the salt is physiologically acceptable and normally causes no allergic or other similar adverse reactions when administered to a human.
  • the salt is preferably an acid addition salt formed from a pharmaceutically acceptable free acid.
  • the acid addition salt may be formed from the compound of the present invention and an inorganic or organic acid which includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, ascorbic acid, citric acid, malonic acid, fumaric acid, maleic acid, lactic acid, salicylic acid, sulfamic acid or tartaric acid.
  • These salts may be prepared by a method known in the art ⁇ for example, by treating the compound of the present invention with an appropriate acid in the presence of an appropriate solvent.
  • the compound of the present invention may be in the form of crystalline form or solvate (e.g., hydrate), and both forms are within the scope of the present invention.
  • solvate refers to complexes in various stoichiometry formed by a solute (in the present invention, the compound of the present invention) and a solvent. Such solvents should not impede the biological activity of the solute.
  • the solvent may be water, ethanol, methanol, ethyl acetate or acetone.
  • a pharmaceutically acceptable salt of the compound of Chemical Formula 1 includes both solvated form and non-solvated form.
  • the present invention provides a method for the prevention of coronavirus infection in mammals, which comprises administering a therapeutically effective amount of the compound of Chemical Formula 1 or a pharmaceutically acceptable derivative thereof to mammals.
  • the present invention mainly states the treatment of the infection by coronavirus, specifically human coronavirus
  • the present invention is useful for the treatment of animal or human infected by Coronaviridae, more spefically Betacoronavirus, and still more specifically Middle East respiratory syndrome-coronavirus (MERS-CoV).
  • MERS-CoV Middle East respiratory syndrome-coronavirus
  • composition of the present invention may be provided in the form of a pharmaceutical composition.
  • the pharmaceutical composition according to the present invention may comprise a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof alone or in combination, along with one or more pharmaceutically acceptable carriers.
  • the carrier may be a pharmaceutically acceptable inert carrier.
  • pharmaceutically effective amount refers to an amount required to show the desired effect as compared with a negative control group, and preferably it refers to an amount sufficient for the prevention or treatment of viral respiratory disease.
  • the therapeutic dose may be 50 mg to 2,000 mg/day, and more preferably 100 mg to 1,000 mg/day, depending on the seriousness of status and whether radotinib is administered alone or in combination with another drug(s).
  • the pharmaceutical composition may be administered via oral or parenteral route once a day or dividedly.
  • the pharmaceutically effective amount may be properly changed depending on the particular disease and severity thereof, age, body weight, physical conditions and sex of patients, administration route, treatment period, or other various factors.
  • compositions are physiologically acceptable and is nontoxic without causing allergic or other similar adverse reactions, such as gastroenteric trouble or dizziness, when administered to a human.
  • the composition of the present invention may be prepared into various formulations depending on administration routes along with a pharmaceutically acceptable carrier according to methods known in the art.
  • the administration route includes oral and parenteral routes, but is not limited thereto. Examples of the parenteral administration route include transdermal, intranasal, intraabdominal, intramuscular, subcutaneous and intravenous routes.
  • the pharmaceutical composition of the present invention may be formulated into powder, granule, tablet, pill, sugar-coated tablet, capsule, liquid, gel, syrup, suspension, wafer, or the like together with an adequate carrier for oral administration according to a method known in the art.
  • the carrier may include a filler such as sugar including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, etc., starch including corn starch, wheat starch, rice starch, potato starch, etc., celluloses including cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, etc., gelatin, polyvinylpyrrolidone, or the like.
  • a disintegrating agent such as crosslinked polyvinylpyrrolidone, agar, alginic acid, sodium alginate, etc. may be added.
  • the pharmaceutical composition may additionally include an anticoagulant, a lubricant, a wetting agent, a fragrance, an emulsifier, an antiseptic, or the like.
  • the pharmaceutical composition of the present invention may be formulated into an injection, a transdermal system or a nasal inhaler together with an adequate carrier for parenteral administration according to a method known in the art.
  • the injection should be sterilized and be protected from contamination by microorganisms such as bacteria and fungi.
  • an adequate carrier include, but are not limited to, a solvent or a suspension medium such as water, ethanol, polyol (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), a mixture thereof and/or vegetable oil.
  • the carrier may be Hank's balanced salt solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, sterile water for injection, or isotonic solution such as 10% ethanol, 40% propylene glycol and 5% dextrose.
  • the injection may further include various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, etc. for protection from contamination by microorganisms.
  • the injection may include an isotonic agent such as sugar or sodium chloride in most cases.
  • the compound of the present invention may be conveniently delivered in the form of a pressurized pack or an aerosol spray delivered from a nebulizer by the use of an adequate propellant compound ⁇ e.g. dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other appropriate gases.
  • a pressurized aerosol may be equipped with a valve for delivering a unit dosage.
  • a capsule or a cartridge used in the inhaler or insufflator may be formulated to include a powder mixture of proper powder matrix.
  • composition of the present invention provides the use of the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof in inhibiting replication or infection of coronavirus.
  • composition may be administered in combination with one or more drugs having antiviral activity to prevent or treat viral respiratory disease.
  • composition may be administered in combination with one or more drugs having antiviral effect such as antibiotics, interferon and ribavirin to prevent or treat viral respiratory disease.
  • drugs having antiviral effect such as antibiotics, interferon and ribavirin to prevent or treat viral respiratory disease.
  • the efficacy of antiviral agents was evaluated to ascertain the antiviral activity of the compound of Chemical Formula 1 on respiratory disease caused by coronavirus.
  • ribavirin ⁇ which is a control drug
  • radotinib showed a decrease of RNA copy number as compared with the control group at most of the treated concentrations.
  • the present invention provides a composition for the prevention or treatment of respiratory disease caused by coronavirus, comprising radotinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a composition for the prevention or treatment of viral respiratory disease, comprising 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(3-methylpyrazin-2-yl)-pyrimidin-2-ylamino)benzamide represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a composition for the prevention or treatment of respiratory disease caused by MERS-CoV.
  • the present invention provides a composition for the prevention or treatment of viral respiratory disease, comprising radotinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the composition of the present invention can be effectively used in the prevention or treatment of respiratory disease caused by Middle East respiratory syndrome-coronavirus (MERS-CoV).
  • MERS-CoV Middle East respiratory syndrome-coronavirus
  • Figure 1 shows the results of analyzing virus genome titer at 12 and 24 hours after infection in which MERS-CoV was first treated with the compound of the present invention and then infected cells.
  • Figure 2 shows the results of analyzing virus genome titer at 8 and 24 hours after incubation in which cells were first infected with MERS-CoV and then transferred to cell culture media containing various concentrations of the compound of the present invention.
  • Example 1 MERS-CoV (strain isolated in Korea, P4) was treated with radotinib before cell infection in order to evaluate its efficacy on inhibiting virus infection by directly acting on the virus envelope protein.
  • Radotinib was diluted into the concentrations of 200 ⁇ M, 50 ⁇ M, 12.5 ⁇ M, 3.13 ⁇ M and 0.0 ⁇ M (control group in which radotinib is not treated), and MERS-CoV (10 4 PFU) was then treated with radotinib at a 37°C, 5% CO 2 incubator for 1 hour. After treatment, Vero cell line was infected with MERS-CoV for 1 hour and washed with PBS. At 12 and 24 hours after virus infection, cell supernatants were collected to extract RNA. qRT-PCR was carried out by the use of the extracted RNA to evaluate antiviral efficacy by comparing RNA copy number.
  • Example 1 virus was first treated with radotinib and then inoculated into cells, and the drug was not added to a culture medium. As such, Example 1 only confirmed the inhibitory effect on viral entry into cells. That is, because radotinib was not included in a cell culture medium, virus inhibitory effect could hardly be expected to continue any longer. In this case, the numerical difference of some viruses ⁇ which manage to invade cells despite the drug's inhibitory effect ⁇ can be shown at the initial stage. However, although very small numbers of viruses are entered into cells due to the drug's inhibitory effect, they can exponentially replicate by lapse of time, so that RNA copy number can be expected to be similar to that of the control group. Therefore, in the case that after inhibition against viral entry into cells the drug was not added to a culture medium as in the experimentation of Example 1, it was confirmed that there is no difference in the RNA copy number of viruses according to the concentrations of the drug at 24 hours after infection.
  • Example 2 cells were first infected with MERS-CoV (strain isolated in Korea, P4), and radotinib was added to cell culture media in order to evaluate the efficacy of antiviral agents in which the inhibitory efficacy against infection and replication of viruses released from the infected cells is compared with the control drug, ribavirin.
  • MERS-CoV strain isolated in Korea, P4
  • radotinib was added to cell culture media in order to evaluate the efficacy of antiviral agents in which the inhibitory efficacy against infection and replication of viruses released from the infected cells is compared with the control drug, ribavirin.
  • Vero cell line was infected with MERS-CoV (MOI 0.01) at 37°C for 1 hour. After washing cells with PBS, cell culture media containing each concentration (50 ⁇ M, 12.5 ⁇ M, 3.13 ⁇ M and 0.0 ⁇ M) of radotinib were added, and cells were incubated at a 37°C, 5% CO 2 incubator. At the predetermined time of 8 and 24 hours, cell supernatants were collected to extract RNA. qRT-PCR was carried out by the use of the extracted RNA to evaluate antiviral efficacy by comparing RNA copy number.
  • MERS-CoV MOI 0.01
  • RNA copy number in the supernatants obtained at 8 and 24 hours after virus infection decreased by 50% or more.
  • RNA copy number in the supernatant obtained 24 hours after virus infection of the radotinib-treated test group was compared with the radotinib-nontreated control group, RNA copy number decreased by a minimum of 56% to a maximum of 71% based on orf1a gene, and decreased by a minimum of 66% to a maximum of 78% based on upE gene.
  • the present invention is illustrated by exemplary embodiments. However, a person skilled in the art would appreciate that various modifications and alterations are possible, without departing from the scope and sprit of the invention disclosed herein.
  • the present invention can be developed as an antiviral agent for the prevention or treatment of viral respiratory disease by providing a composition comprising radotinib or a pharmaceutically acceptable salt thereof as an active ingredient.

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Abstract

The present invention relates to a novel use of a compound of Chemical Formula 1 (radotinib) in the prevention or treatment of viral respiratory disease. According to the present invention, a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof can be used for the prevention, alleviation or treatment of coronavirus infection. Specifically, the present invention can be used as a useful antiviral agent for the prevention or treatment of disease caused by infection of Middle East respiratory syndrome-coronavirus (MERS-CoV).

Description

USE OF RADOTINIB FOR PREVENTION OR TREATMENT OF VIRAL RESPIRATORY DISEASE
The present invention relates to use of radotinib which has antiviral activity against coronaviruses, specifically for the prevention or treatment of respiratory disease caused by Middle East respiratory syndrome coronavirus (MERS-CoV).
Coronaviruses are enveloped, positive-sense single strand RNA viruses and have 25-32 kb of genome size, and so they belong to a relatively large virus among RNA viruses known up to now. Because spike proteins―which are club-shaped bumps―are embedded in a membrane, the name "coronavirus" is derived from the Latin corona, meaning halo or crown and refers to the characteristic appearance.
After the first discovery from chickens in 1937, coronaviruses have been found in various birds and mammals such as bat, cat, dog, cow, pig and mouse. Coronaviruses are divided into four (4) groups (Alpha-, Beta-, Gamma- and Deltacoronavirus). Alphacoronavirus and Betacoronavirus groups primarily infect mammals, and Gammacoronavirus and Deltacoronavirus groups are discovered from birds. It has been known that coronaviruses cause various diseases such as gastrointestinal diseases and respiratory diseases.
Human coronaviruses―which infect human beings―are HCoV-229E and HCoV-OC43, discovered in the 1960s, and HCoV-NL63 (2004) and HCoV-HKU1 (2005), discovered after the severe acute respiratory syndrome (SARS) pandemic. It is known that they generally relate to upper respiratory tract infections, but may cause serious lung diseases in patients with immune deficiencies. It has been reported that coronavirus infection is increased primarily in the winter and early spring seasons, and it has been known that coronaviruses cause a significant percentage of common colds in human adults. SARS coronavirus (SARS-CoV), causing severe acute respiratory syndrome, was first discovered in 2003. According to a report of the World Health Organization (WHO), there were 8,273 patients and 775 deaths (fatality rate: about 10%) all over the world in 2002 and 2003. There were additional cases and deaths until 2004.
In September 2012, severe respiratory disease patients showing respiratory symptoms such as hyperthermia, cough, dyspnea and the like which are similar with SARS occurred, and a pathogen causing this disease was identified as a new type of coronavirus (HCoV-EMC) which is different from known viruses.
In May 2013, this novel coronavirus was classified by the name of "Middle East respiratory syndrome-coronavirus (MERS-CoV)" by the Coronavirus Study Group of the International Committee on Taxonomy of Viruses. Because the genetic sequencing of this virus is similar to Pipistrellus Bat CoV-HKU5 and HKU4 found in bats, it was assumed that bats are most probable infection source. However, recently the article published in The Lancet Infectious Diseases reported that all of 50 sera from Omani dromedary camels had protein-specific antibodies against MERS-CoV spike. However, in the Canary islands 15 of 105 camels showed an antibody-positive reaction.
Although virus itself was not found, such study results mean that those camels were infected by the MERS virus or a similar virus at some time, and it is highly likely that camels are a host of the virus.
The first identified case of infection by MERS-CoV occurred in Saudi Arabia in September 2012. And then, there were 808 cases and 313 deaths (fatality rate: 34.5%) officially reported to the WHO by June 2014.
At the time of initial occurrence in patients in which infection by MERS-CoV was diagnosed definitely, the clinical symptoms of patients are very similar to those of SARS. Therefore, there was a concern that MERS-CoV has considerable association with SARS-CoV. However, after analysis of the whole genome, it turned out that MERS-CoV is a novel virus which is considerably different from SARS-CoV in terms of molecular genetics.
First of all, MERS-CoV shows a low nucleotide identity of about 55% with SARS-CoV, and these two viruses show evolutionary differences from each other in a phylogenetic analysis. SARS-CoV belongs to the B group of Betacoronavirus, and MERS-CoV belongs to the C group of Betacoronavirus. As those belonging to Betacoronavirus group, SARS-CoV, and HcoV-HKU1 and HCoV-OC43, which are human coronaviruses, had been known.
In addition, SARS-CoV and MERS-CoV are different in a route to enter into cells. SARS-CoV uses ACE2 receptors distributed on ciliated cells of the human respiratory tract, and MERS-CoV uses dipeptidyl peptidase 4 (DDP4, also known as CD26) expressed in non-ciliated cells. Both receptors are mainly distributed on the human lower respiratory tract rather than the upper respiratory tract. In addition, although MERS-CoV and SARS-CoV show high fatality rates, they must be transmitted via large droplets after progression to pneumonia. As a result, it is believed that they are less contagious as compared with disease spread via aerosol such as influenza or measles. However, in the case of outbreak of SARS patients, when closely exposed to SARS patients or under the circumstance of evoking aerosolization of respirable droplets, their contagiousness can be quite high. As such, it can be said that the risk of infection is still high.
What is a first infection source of MERS-CoV and how it was transmitted to human beings and caused a disease are still unknown. However, in two (2) cases of confirmed patients with novel coronavirus infection, the patients visited a farm and contacted animals. This shows a possibility of zooanthroponosis.
The major clinical symptoms of MERS are those of pneumonia such as fever (87%), cough (89%), shortness of breath and the like, and vomiting and diarrhea (35%) also occur in some patients. Renal failure has also been reported in patients having lowered immune function, and fatality rate (34.5%) is very high. Because many cases occurred in the Middle East region (Saudi Arabia, Qatar, etc.), it is assumed that this is an infection region, but the precise infection route is still unclear. There was no evidence of the disease widely spreading between humans, but it has been confirmed that transmission can occur when family members or medical personnel are in close contact with patients. It is assumed that the incubation period is 9 to 12 days, but varies considerably depending on patients. Middle East Journal of Management (MEJM, February 2008) reported that the incubation period is 1.9 to 14.7 days (average 5.2 days).
Up to now, there has been no medicament with a treatment effect on MERS-CoV and vaccine. Accordingly, there is no specific method for prevention and treatment other than avoiding contact with a patient suspicious of viral infection and paying close attention to personal hygiene. At present, antibiotics, ribavirin, interferon and serum of patients have been used for the treatment of MERS-CoV infection, but those therapeutic agents did not show specific effects.
Therefore, there is an urgent need for developing an alternative medicament for the prevention and treatment of MERS-CoV.
The present invention is intended to provide an antiviral agent showing potent antiviral activity against coronaviruses.
The present invention provides a therapeutic composition for the prevention or treatment of respiratory disease caused by coronavirus, comprising radotinib (Chemical Formula 1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]
Figure PCTKR2016007719-appb-I000001
Hereinafter, the present invention is explained in more detail.
The composition of the present invention comprises radotinib or a pharmaceutically acceptable salt thereof as an active ingredient, and can be used for the prevention or treatment of disease caused by coronavirus.
The present invention provides a receptor tyrosine kinase inhibitor for the prevention or treatment of viral respiratory disease, and specifically use of radotinib or a pharmaceutically acceptable salt thereof. In one non-limiting embodiment of the present invention, use of radotinib for inhibiting replication, infection, or both replication and infection of coronavirus is provided. The present invention provides use of a receptor tyrosine kinase inhibitor such as radotinib for the prevention or treatment of viral respiratory disease in an animal, more preferably a mammal, and still more preferably a human.
Herein, the term "radotinib" refers to 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(3-methylpyrazin-2-yl)-pyrimidin-2-ylamino)benzamide represented by the above Chemical Formula 1.
It has been known that the compound of Chemical Formula 1 inhibits one or more tyrosine kinases―for example, c-Abl, Bcr-Abl, and a receptor tyrosine kinase such as PDGFR, Flt3, VEGF-R, EGF-R and c-Kit. In addition, Korean Patent No. 10-0674813 discloses that the compound of Chemical Formula 1 has excellent anticancer effect on various cancers such as lung cancer, gastric cancer, colon cancer, pancreatic cancer, hepatoma, prostatic cancer, breast cancer, chronic or acute leukemia, hematologic malignancy, brain tumor, bladder cancer, rectal cancer, cervical cancer, lymphoma, etc. However, there is no report about the effect on viral respiratory diseases caused by respiratory viruses such as coronavirus, adenovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, etc.
The compound of the present invention may be used as itself or in the form of a pharmaceutically acceptable salt. Herein the term "pharmaceutically acceptable" means that the salt is physiologically acceptable and normally causes no allergic or other similar adverse reactions when administered to a human. The salt is preferably an acid addition salt formed from a pharmaceutically acceptable free acid. The acid addition salt may be formed from the compound of the present invention and an inorganic or organic acid which includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, ascorbic acid, citric acid, malonic acid, fumaric acid, maleic acid, lactic acid, salicylic acid, sulfamic acid or tartaric acid. These salts may be prepared by a method known in the art―for example, by treating the compound of the present invention with an appropriate acid in the presence of an appropriate solvent.
The compound of the present invention may be in the form of crystalline form or solvate (e.g., hydrate), and both forms are within the scope of the present invention. The term "solvate" refers to complexes in various stoichiometry formed by a solute (in the present invention, the compound of the present invention) and a solvent. Such solvents should not impede the biological activity of the solute. For example, the solvent may be water, ethanol, methanol, ethyl acetate or acetone.
A pharmaceutically acceptable salt of the compound of Chemical Formula 1 includes both solvated form and non-solvated form.
The present invention provides a method for the prevention of coronavirus infection in mammals, which comprises administering a therapeutically effective amount of the compound of Chemical Formula 1 or a pharmaceutically acceptable derivative thereof to mammals.
Although the present invention mainly states the treatment of the infection by coronavirus, specifically human coronavirus, the present invention is useful for the treatment of animal or human infected by Coronaviridae, more spefically Betacoronavirus, and still more specifically Middle East respiratory syndrome-coronavirus (MERS-CoV).
In addition, a composition of the present invention may be provided in the form of a pharmaceutical composition. The pharmaceutical composition according to the present invention may comprise a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof alone or in combination, along with one or more pharmaceutically acceptable carriers. Preferably, the carrier may be a pharmaceutically acceptable inert carrier. Herein the term "pharmaceutically effective amount" refers to an amount required to show the desired effect as compared with a negative control group, and preferably it refers to an amount sufficient for the prevention or treatment of viral respiratory disease. In the case that the patient is a human, the therapeutic dose may be 50 mg to 2,000 mg/day, and more preferably 100 mg to 1,000 mg/day, depending on the seriousness of status and whether radotinib is administered alone or in combination with another drug(s). The pharmaceutical composition may be administered via oral or parenteral route once a day or dividedly. However, the pharmaceutically effective amount may be properly changed depending on the particular disease and severity thereof, age, body weight, physical conditions and sex of patients, administration route, treatment period, or other various factors.
Herein the expression "pharmaceutically acceptable" means that the composition is physiologically acceptable and is nontoxic without causing allergic or other similar adverse reactions, such as gastroenteric trouble or dizziness, when administered to a human. The composition of the present invention may be prepared into various formulations depending on administration routes along with a pharmaceutically acceptable carrier according to methods known in the art. The administration route includes oral and parenteral routes, but is not limited thereto. Examples of the parenteral administration route include transdermal, intranasal, intraabdominal, intramuscular, subcutaneous and intravenous routes.
For oral administration, the pharmaceutical composition of the present invention may be formulated into powder, granule, tablet, pill, sugar-coated tablet, capsule, liquid, gel, syrup, suspension, wafer, or the like together with an adequate carrier for oral administration according to a method known in the art. Examples of the carrier may include a filler such as sugar including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, etc., starch including corn starch, wheat starch, rice starch, potato starch, etc., celluloses including cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, etc., gelatin, polyvinylpyrrolidone, or the like. In addition, a disintegrating agent such as crosslinked polyvinylpyrrolidone, agar, alginic acid, sodium alginate, etc. may be added. Furthermore, the pharmaceutical composition may additionally include an anticoagulant, a lubricant, a wetting agent, a fragrance, an emulsifier, an antiseptic, or the like.
For parenteral administration, the pharmaceutical composition of the present invention may be formulated into an injection, a transdermal system or a nasal inhaler together with an adequate carrier for parenteral administration according to a method known in the art. The injection should be sterilized and be protected from contamination by microorganisms such as bacteria and fungi. In the case of injection, examples of an adequate carrier include, but are not limited to, a solvent or a suspension medium such as water, ethanol, polyol (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), a mixture thereof and/or vegetable oil. More preferably, the carrier may be Hank's balanced salt solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, sterile water for injection, or isotonic solution such as 10% ethanol, 40% propylene glycol and 5% dextrose. The injection may further include various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, thimerosal, etc. for protection from contamination by microorganisms. In addition, the injection may include an isotonic agent such as sugar or sodium chloride in most cases.
These formulations are described in the publication (Remington's Pharmaceutical Sciences, 15th Edition, 1975, Mack Publishing Company, Easton, Pennsylvania), which is well known in the pharmaceutical chemistry field.
In the case of an inhaler, the compound of the present invention may be conveniently delivered in the form of a pressurized pack or an aerosol spray delivered from a nebulizer by the use of an adequate propellant compound―e.g. dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other appropriate gases. A pressurized aerosol may be equipped with a valve for delivering a unit dosage. For example, a capsule or a cartridge used in the inhaler or insufflator may be formulated to include a powder mixture of proper powder matrix.
Other pharmaceutically acceptable carriers may refer to the following publication (Remington's Pharmaceutical Sciences, 19th Edition, 1995, Mack Publishing Company, Easton, Pennsylvania).
The composition of the present invention provides the use of the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof in inhibiting replication or infection of coronavirus.
The composition may be administered in combination with one or more drugs having antiviral activity to prevent or treat viral respiratory disease.
The composition may be administered in combination with one or more drugs having antiviral effect such as antibiotics, interferon and ribavirin to prevent or treat viral respiratory disease.
In the Examples of the instant specification, the efficacy of antiviral agents was evaluated to ascertain the antiviral activity of the compound of Chemical Formula 1 on respiratory disease caused by coronavirus. Under the condition of treating ribavirin―which is a control drug, there was no virus inhibitory effect according to concentrations. However, as can be seen from Figures 1 and 2, radotinib showed a decrease of RNA copy number as compared with the control group at most of the treated concentrations. As a result, it was confirmed that radotinib has antiviral activity against MERS-CoV.
Therefore, the present invention provides a composition for the prevention or treatment of respiratory disease caused by coronavirus, comprising radotinib or a pharmaceutically acceptable salt thereof as an active ingredient. In addition, the present invention provides a composition for the prevention or treatment of viral respiratory disease, comprising 4-methyl-N-[3-(4-methylimidazol-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(3-methylpyrazin-2-yl)-pyrimidin-2-ylamino)benzamide represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
More preferably, the present invention provides a composition for the prevention or treatment of respiratory disease caused by MERS-CoV.
The above explanation does not limit the claimed scope in any way, and the combination of the mentioned characteristics is not absolutely necessary for the solution of the present invention.
The present invention provides a composition for the prevention or treatment of viral respiratory disease, comprising radotinib or a pharmaceutically acceptable salt thereof as an active ingredient. The composition of the present invention can be effectively used in the prevention or treatment of respiratory disease caused by Middle East respiratory syndrome-coronavirus (MERS-CoV).
Figure 1 shows the results of analyzing virus genome titer at 12 and 24 hours after infection in which MERS-CoV was first treated with the compound of the present invention and then infected cells.
Figure 2 shows the results of analyzing virus genome titer at 8 and 24 hours after incubation in which cells were first infected with MERS-CoV and then transferred to cell culture media containing various concentrations of the compound of the present invention.
Hereinafter, the present invention is explained in more detail with the following examples. However, the following examples are only intended to facilitate understanding of the present invention, and the protection scope of the present invention is not limited thereto.
Example 1
In Example 1, MERS-CoV (strain isolated in Korea, P4) was treated with radotinib before cell infection in order to evaluate its efficacy on inhibiting virus infection by directly acting on the virus envelope protein.
1) Virus
- MERS-CoV, strain isolated in Korea (P4)
- Virus titer: 1 × 105 PFU/ml
- Virus inoculation titer: MOI 0.01 (3 × 103 PFU/ml)
2) Cell strain - Vero cells (24-well plate)
3) Methods
Radotinib was diluted into the concentrations of 200 μM, 50 μM, 12.5 μM, 3.13 μM and 0.0 μM (control group in which radotinib is not treated), and MERS-CoV (104 PFU) was then treated with radotinib at a 37°C, 5% CO2 incubator for 1 hour. After treatment, Vero cell line was infected with MERS-CoV for 1 hour and washed with PBS. At 12 and 24 hours after virus infection, cell supernatants were collected to extract RNA. qRT-PCR was carried out by the use of the extracted RNA to evaluate antiviral efficacy by comparing RNA copy number.
As a result, as can be seen from Figure 1, all test groups (200 μM, 50 μM and 3.13 μM-treated groups) except for 12.5 μM-treated group showed a decrease of RNA copy number.
In Example 1, virus was first treated with radotinib and then inoculated into cells, and the drug was not added to a culture medium. As such, Example 1 only confirmed the inhibitory effect on viral entry into cells. That is, because radotinib was not included in a cell culture medium, virus inhibitory effect could hardly be expected to continue any longer. In this case, the numerical difference of some viruses―which manage to invade cells despite the drug's inhibitory effect―can be shown at the initial stage. However, although very small numbers of viruses are entered into cells due to the drug's inhibitory effect, they can exponentially replicate by lapse of time, so that RNA copy number can be expected to be similar to that of the control group. Therefore, in the case that after inhibition against viral entry into cells the drug was not added to a culture medium as in the experimentation of Example 1, it was confirmed that there is no difference in the RNA copy number of viruses according to the concentrations of the drug at 24 hours after infection.
Example 2
In Example 2, cells were first infected with MERS-CoV (strain isolated in Korea, P4), and radotinib was added to cell culture media in order to evaluate the efficacy of antiviral agents in which the inhibitory efficacy against infection and replication of viruses released from the infected cells is compared with the control drug, ribavirin.
1) Virus
- MERS-CoV, strain isolated in Korea (P4)
- Virus titer: 1 × 105 PFU/ml
- Virus inoculation titer: MOI 0.01 (3 × 103 PFU/ml)
2) Cell strain - Vero cells (24-well plate)
3) Methods
Vero cell line was infected with MERS-CoV (MOI 0.01) at 37°C for 1 hour. After washing cells with PBS, cell culture media containing each concentration (50 μM, 12.5 μM, 3.13 μM and 0.0 μM) of radotinib were added, and cells were incubated at a 37°C, 5% CO2 incubator. At the predetermined time of 8 and 24 hours, cell supernatants were collected to extract RNA. qRT-PCR was carried out by the use of the extracted RNA to evaluate antiviral efficacy by comparing RNA copy number.
As a result, as can be seen from Figure 2, in the radotinib-treated test group the RNA copy number in the supernatants obtained at 8 and 24 hours after virus infection decreased by 50% or more. Specifically, in the results in which the RNA copy number in the supernatant obtained 24 hours after virus infection of the radotinib-treated test group was compared with the radotinib-nontreated control group, RNA copy number decreased by a minimum of 56% to a maximum of 71% based on orf1a gene, and decreased by a minimum of 66% to a maximum of 78% based on upE gene. On the contrary, in the case of the ribavirin-treated test group, the decrease of the RNA copy number was not observed at 8 hours after virus infection, and the RNA copy number in only the 12.5 μM-treated group at 24 hours after virus infection was decreased by 29% based on orf1a gene.
To sum up the test results, there was little virus inhibitory effect depending on concentrations in the ribavirin-treated conditions. However, at most of the concentration conditions in which radotinib was treated the patterns of decreasing RNA copy number were shown, as compared with the control group. As such, it was confirmed that radotinib has antiviral activity against MERS-CoV.
The present invention is illustrated by exemplary embodiments. However, a person skilled in the art would appreciate that various modifications and alterations are possible, without departing from the scope and sprit of the invention disclosed herein. In addition, the present invention can be developed as an antiviral agent for the prevention or treatment of viral respiratory disease by providing a composition comprising radotinib or a pharmaceutically acceptable salt thereof as an active ingredient.

Claims (9)

  1. A pharmaceutical composition for the prevention or treatment of viral respiratory disease of a subject, comprising radotinib or a pharmaceutically acceptable salt thereof as an active ingredient.
  2. The pharmaceutical composition according to Claim 1, wherein the radotinib is a compound of the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:
    [Chemical Formula 1]
    Figure PCTKR2016007719-appb-I000002
  3. The pharmaceutical composition according to Claim 1, wherein the viral respiratory disease is a disease caused by infection of coronavirus.
  4. The pharmaceutical composition according to Claim 1, wherein the viral respiratory disease is a disease caused by infection of Middle East respiratory syndrome-coronavirus (MERS-CoV).
  5. The pharmaceutical composition according to Claim 1, wherein the subject is an animal.
  6. The pharmaceutical composition according to Claim 5, wherein the animal is a mammal.
  7. The pharmaceutical composition according to Claim 6, wherein the mammal is a human.
  8. The pharmaceutical composition according to Claim 1, which further comprises one or more therapeutic agents selected from the group consisting of an antibiotic, interferon and ribavirin.
  9. The pharmaceutical composition according to Claim 1, which further comprises a pharmaceutically acceptable inert carrier.
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