Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/04—Ortho- or peri-condensed ring systems
  • C07D221/06—Ring systems of three rings
  • C07D221/10—Aza-phenanthrenes
  • C07D221/12—Phenanthridines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to anti-coronavirus drugs.
• Coronaviruses are viruses that originally cause cold symptoms in humans, and four types of coronaviruses are known, and 10 to 15% of colds are caused by these viruses. In addition, previously known coronaviruses cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) with high fatality rates. There are about 8,000 SARS patients with a fatality rate of about 10% and about 2,500 MERS patients with a fatality rate of about 35%. Coronaviruses are positive-strand RNA viruses having an envelope with a diameter of about 100 nm. SARS-CoV is classified as a second-class pathogen, and MERS-CoV is classified as a third-class pathogen.
• SARS-CoV is classified as a second-class pathogen
• MERS-CoV is classified as a third-class pathogen.
• Paxlobide is a combination drug of nilmatrelvir, a low-molecular-weight compound that inhibits the function of the main protease required for viral replication, and ritonavir, which acts as a booster to maintain its blood concentration.
• these drugs have some drawbacks such as side effects such as teratogenicity and problems in combination with other drugs. Therefore, it is of great importance to identify and develop novel agents with selective and potent antiviral effects against SARS-CoV-2.
• Patent Document 1 phenanthridinone derivatives are effective against human hepatitis C virus and have filed a patent application (Patent Document 1).
• Patent Document 1 no relationship between phenanthridinone derivatives and anti-coronavirus activity has been reported so far.
• An object of the present invention is to provide an antiviral drug that is effective against coronaviruses such as SARS-CoV-2.
• the present inventors have established an anti-coronavirus assay system for drugs and screened various drugs.
• the anti-coronavirus effect against coronavirus was recognized, and the present invention was completed.
• R 1 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 4 -C 6 cycloalkynyl, heterocyclyl , aryl, arylalkyl, arylalkenyl, heteroaryl and heteroarylalkyl, each of which is independently unsubstituted or one or more of halogen, hydroxyl, NH2 , NO2 , C( O ) Z (Z is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl , C3 - C6 cycloalkyl , C3 - C6 cycloalkenyl, C4- C6 cycloalky
• R 7 and R 8 are NH 2 , NH-C(O)Z (Z is C 1 -C 8 alkyl, heterocyclyl or NH-(C 1 -C 8 alkyl); groups are unsubstituted or substituted by one or more hydroxyl or NH2 ), N( R10 )( R11 ) ( R10 and R11 are each independently C 1 - C8 alkyl or arylalkyl, said group being unsubstituted or having one or more of hydroxyl, O-( C1 - C8 alkyl), NH2 , N( CH3 ) 2 or substituted by CONH 2 ) or NH(R 10 ) (R 10 is C 1 -C 8 alkyl, arylalkyl or heterocyclyl, said group being unsubstituted or one or more hydroxyl, O—(C 1 )
• R 8 is NH(R 10 ) (where R 10 is C 2 -C 5 alkyl substituted with 1 or 2 hydroxyls) or NH—C(O)Z (where Z is substituted with 1 hydroxyl) (1), a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
• R 1 is C 3 -C 7 alkyl, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof .
• the anti-coronavirus drug according to (8) above which is used for prevention or treatment of COVID-19.
• (10) Use of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof according to any one of (1) to (6) above in the manufacture of an anti-coronavirus drug.
• (11) The use according to (10) above, wherein the anti-coronavirus drug is an anti-SARS-CoV-2 drug.
• the anti-coronavirus drug is used for the prevention or treatment of COVID-19.
• an antiviral drug effective against coronaviruses such as SARS-CoV-2 can be provided.
• alkyl means a straight or branched chain aliphatic hydrocarbon group containing the specified number of carbon atoms.
• C 1 -C 8 alkyl means a straight or branched saturated hydrocarbon chain containing at least 1 and at most 8 carbon atoms.
• Suitable alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n -octyl and the like.
• alkenyl means a group in which one or more C-C single bonds of the above alkyl are replaced with double bonds.
• Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 -methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-pentenyl, 1-hexenyl, n-heptenyl, 1-octenyl and the like.
• alkynyl means a group in which one or more C-C single bonds of the alkyl are substituted with triple bonds.
• Suitable alkynyls include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 1-hexynyl , 1-heptynyl, 1-octynyl and the like.
• cycloalkyl means a cycloaliphatic alkyl containing the specified number of carbon atoms.
• C3 - C6 cycloalkyl means a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms.
• Suitable cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• cycloalkenyl means a group in which one or more C-C single bonds of the cycloalkyl are replaced with double bonds.
• Suitable cycloalkenyls include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
• cycloalkynyl means a group in which one or more C-C single bonds of the cycloalkyl are replaced with triple bonds.
• Suitable cycloalkynyls include, but are not limited to, cyclobutynyl, cyclopentynyl, cyclohexynyl, and the like.
• heterocyclyl means that one or more carbon atoms of said cycloalkyl, cycloalkenyl or cycloalkynyl are each independently selected from nitrogen (N), sulfur (S) and oxygen (O) It means a group substituted with a heteroatom.
• N or S includes substitution of N-oxides or S by oxides or dioxides, respectively.
• Suitable heterocyclyls include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, and the like. can be mentioned.
• aryl means an aromatic ring group having 6 to 15 carbon atoms. Suitable aryl include, but are not limited to, phenyl, naphthyl, anthryl (anthracenyl), and the like.
• arylalkyl means a group in which one hydrogen atom of the alkyl is substituted with the aryl.
• Suitable arylalkyls include, but are not limited to, benzyl, 1-phenethyl, 2-phenethyl and the like.
• arylalkenyl means a group in which one hydrogen atom of the alkenyl is substituted with the aryl. Suitable arylalkenyls include, but are not limited to, styryl, and the like.
• heteroaryl means that one or more carbon atoms of said aryl have been replaced with heteroatoms each independently selected from nitrogen (N), sulfur (S) and oxygen (O) means the base.
• N nitrogen
• S sulfur
• O oxygen
• substitution by N or S includes substitution of N-oxides or S by oxides or dioxides, respectively.
• Suitable heteroaryl include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, Examples include isoquinolinyl, indolyl, and the like.
• heteroarylalkyl means a group in which one hydrogen atom of the above alkyl is substituted with the above heteroaryl.
• Each of the groups described above are independently unsubstituted or contain one or more halogen, hydroxyl, NH2 , NO2 , C(O)Z, where Z is hydrogen, hydroxyl, C1 - C 8 alkyl, C2 - C8 alkenyl, C2- C8 alkynyl, C3 - C6 cycloalkyl, C3 - C6 cycloalkenyl, C4 - C6 cycloalkynyl, heterocyclyl, NH2 or NH-(C 1 - C8 alkyl)), NH-C(O)Z (where Z is hydrogen, hydroxyl, C1- C8 alkyl, C2 - C8 alkenyl, C2 - C8 alkynyl, C3 - C6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 4 -C 6 cycloalkynyl, heterocyclyl, NH 2 or NH-(C
• halogen or halo means fluorine, chlorine, bromine or iodine.
• the "salt" is preferably a pharmaceutically acceptable salt.
• the counter ion of the compound represented by formula (I) includes, but is not limited to, cations such as sodium ion, potassium ion, calcium ion and magnesium ion, or chloride ion and bromide ion.
• solvates of the compound represented by formula (I) or salts thereof include hydrates.
• the compound represented by Formula (I), its salt, or solvate thereof may be a deuterium conversion product in which 1 H is converted to 2 H(D). Such compounds are also included in the present invention.
• prodrug means any compound of formula (I) that, when administered to a biological system, results in a spontaneous chemical reaction or by a catalyzed enzymatic or metabolic reaction. indicates a compound.
• Groups constituting prodrugs used for hydroxyl or amino groups include, for example, C 2-7 -acyl group, C 1-6 -alkoxy(C 2-7 -acyl) group, C 1-6 -alkoxycarbonyl (C 2-7 -acyl) group, C 1-6 -alkoxycarbonyl group, C 1-6 -alkoxy(C 2-7 -alkoxycarbonyl) group, (C 2-7 -acyloxy)methyl group, 1-( C 2-7 -acyloxy)ethyl group, (C 2-7 -alkoxycarbonyl)oxymethyl group, 1-[(C 2-7 -alkoxycarbonyl)oxy]ethyl group and the like, and C 2-7 -acyl C 1-6 -alkoxycarbonyl
• Groups constituting prodrugs used in carboxyl groups include, for example, C 1-6 -alkyl groups, C 1-6 -alkoxy-C 1-6 -alkyl groups, (C 2-7 -acyloxy)methyl groups , 1-(C 2-7 -acyloxy)ethyl group, (C 2-7 -alkoxycarbonyl)oxymethyl group, 1-[(C 2-7 -alkoxycarbonyl)oxy]ethyl group and the like, and C 1 -6 -alkyl groups, C 1-6 -alkoxy-C 1-6 -alkyl groups are preferred.
• the compounds represented by formula (I), their pharmaceutically acceptable salts, their solvates, or their prodrugs also include stereoisomers such as racemates and optically active isomers.
• R 1 is preferably C 3 -C 7 alkyl, more preferably C 4 alkyl and R 3 is preferably 1,1,1,3,3,3 -hexafluoro-2-hydroxypropan-2-yl.
• R 7 and R 8 is NH 2 , NH-C(O)Z (Z is C 1 -C 8 alkyl, heterocyclyl or NH-(C 1 - C 8 alkyl), said groups being unsubstituted or substituted by one or more hydroxyl or NH 2 ), N(R 10 )(R 11 ) (R 10 and R 11 are each independently C 1 -C 8 alkyl or arylalkyl, said groups being unsubstituted or one or more of hydroxyl, O--(C 1 -C 8 alkyl), NH 2 , N( CH3 ) 2 or CONH2 ) or NH( R10 ) ( R10 is C1 - C8 alkyl, arylalkyl or heterocyclyl, said group being unsubstituted or substituted by one or more hydroxyl, O-( C1 - C8 alkyl), NH2 , N( CH3 ) 2
• R1 is C3 - C7 alkyl
• R3 is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl
• R2 , R4 , R5 , R 6 and R 9 are hydrogen
• at least one of R 7 and R 8 is NH 2 , NH-C(O)Z (Z is C 1 -C 8 alkyl, heterocyclyl or NH-(C 1 -C 8 alkyl) and said groups are unsubstituted or substituted by one or more hydroxyl or NH2 )
• N(R 10 )(R 11 ) R 10 and R 11 are each independently is C 1 -C 8 alkyl or arylalkyl, said group being unsubstituted or one or more of hydroxyl, O--(C 1 -C 8 alkyl), NH 2 , N( CH 3 ) 2 or CONH 2 ) or
• R1 is C4 alkyl
• R3 is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl
• R2 , R4 , R5 , R6 and R 9 is hydrogen
• at least one of R 7 and R 8 is NH 2 , NH—C(O)Z, where Z is C 1 -C 8 alkyl, heterocyclyl or NH—(C 1 -C 8 alkyl)
• Said groups are unsubstituted or substituted with one or more hydroxyl or NH2 ), N( R10 )( R11 ) ( R10 and R11 are each independently C 1 -C 8 alkyl or arylalkyl, said group being unsubstituted or having one or more hydroxyl, O--(C 1 -C 8 alkyl), NH 2 , N(CH 3 ) 2 or CONH 2 ) or NH(R 10 ) (where R 10 is C 1 -
• R1 is C4 alkyl
• R3 is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl
• R2 , R4 , R5 , R6 , R 7 and R 9 are hydrogen
• R 8 is NH(R 10 ) (R 10 is C 2 -C 3 alkyl substituted with 1 or 2 hydroxyls, such as CH 2 CH 2 OH, CH 2 CH(OH) CH2OH ).
• R1 is C4 alkyl
• R3 is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl
• R8 is NH 2
• R 2 , R 4 , R 5 , R 6 , R 7 and R 9 are hydrogen (NR-31-5)
• N-(p-nitrobenzoyl)-substituted product (NR-31-3).
• N,N-dimethylacetamide, cesium carbonate, palladium(II) acetate, and tricyclohexylphosphine tetrafluoroborate were added in order, and the mixture was stirred under heating.
• -Nitrophenanthridinone derivative (NR-31-4) is obtained.
• a 9-nitrophenanthridinone derivative (NR-31-5 ) can be obtained.
• the 9-aminophenanthridinone derivative (NR-31-5) can be converted into various N-substituted compounds by modifying it by N-alkylation, N-acylation and the like.
• p-fluorobenzoyl chloride is used in place of p-nitrobenzoyl chloride to obtain a 9-fluorophenanthridinone derivative, followed by 3-amino-1,2-propanediol or the like. It can be converted into various N-substituted forms by reacting with amine compounds.
• 8-aminophenanthridinone derivatives can be obtained, which are N-alkylated, N-acyl It can be converted into various N-substituted forms by modification such as conversion.
• a commonly used method such as column chromatography using silica gel as a carrier, methanol, ethanol, chloroform, dimethyl sulfoxide, n-hexane-ethyl acetate, water, etc. Crystal method can be used.
• Elution solvents for column chromatography include methanol, ethanol, chloroform, acetone, hexane, dichloromethane, ethyl acetate, and mixed solvents thereof.
• the above compound can be formulated as an anti-coronavirus drug in combination with a conventional pharmaceutical carrier.
• the dosage form is not particularly limited, and may be appropriately selected and used as necessary, including tablets, capsules, granules, fine granules, powders, sustained-release preparations, liquids, suspensions, emulsions, and syrups. , oral agents such as elixirs, and parenteral agents such as injections and suppositories.
• Oral preparations are manufactured by conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, inorganic salts, and the like.
• binders, disintegrants, surfactants, lubricants, fluidity promoters, corrigents, coloring agents, perfumes, and the like can be added as appropriate.
• binders examples include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, and macrogol.
• disintegrants include starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, low-substituted hydroxypropylcellulose and the like.
• surfactants include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid esters, polysorbate 80, and the like.
• lubricants examples include talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.
• Fluidity promoters include, for example, light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.
• Injections are prepared according to a conventional method, and diluents such as distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc., can be generally used. . Further, if necessary, bactericides, antiseptics, stabilizers, tonicity agents, soothing agents and the like may be added. In addition, from the viewpoint of stability, injections can also be frozen after being filled in vials or the like, and water is removed by a normal freeze-drying technique, and a liquid preparation can be reprepared from the freeze-dried product immediately before use. The proportion of the compound of formula (I) in the injection may vary between 5 and 50% by weight, but is not limited thereto.
• parenteral agents include suppositories for rectal administration, etc., and are manufactured according to conventional methods.
• the formulated anti-coronavirus drug differs depending on the dosage form, administration route, etc., it can be administered, for example, 1 to 4 times a day for a period of 1 week to 3 months.
• the weight of the compound of formula (I) is usually 0.1 to 6000 mg for an adult, although this varies depending on the patient's age, body weight and degree of disease. , preferably 100 to 2000 mg, in several divided doses per day.
• the weight of the compound of formula (I) for adults is usually 0.1 to 0.1, although it varies depending on the patient's age, body weight and degree of disease. It is suitable to administer 6000 mg, preferably 100-2000 mg, by intravenous injection, intravenous drip infusion, subcutaneous injection or intramuscular injection.
• the anti-coronavirus drug of the present invention exhibits antiviral activity against coronaviruses that cause COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), etc. is used for the prevention or treatment of coronavirus infections in In the present invention, treatment also includes prevention of exacerbation.
• SARS severe acute respiratory syndrome
• MERS Middle East respiratory syndrome
• the compound represented by formula (I) can be contained as the sole active ingredient in the pharmaceutical composition, or can contain other active ingredients.
• the compound of formula (I) may also be used in combination with other agents effective against coronavirus infections such as SARS-CoV-2. These may be administered separately during the course of treatment, or combined with the compounds of formula (I) above in a single dosage form such as a tablet, intravenous solution, or capsule.
• agents include, for example, remdesivir and the like.
• Coronaviruses are known to infect various animals, and SARS-CoV is also known to infect various animals across species barriers. Therefore, the therapeutic target of the anti-coronavirus drug of the present invention is not limited to humans, and various animals such as pets (e.g., dogs and cats), pigs, camels, bats, palm civets, tigers, ferrets, golden hamsters, minks, and sparrows. encompasses
• Anti-SARS-CoV-2 effect (assay with HEK293T/ACE2 cells) (1) Determination of cell viability (absorbance) HEK293T/ACE2 cells (2 ⁇ 10 4 cells/well) were seeded in microplates with 100 ⁇ L of cell culture medium. After culturing for 24 hours, 50 ⁇ L of various drugs obtained by diluting the drug stock solution to 4 times the final concentration were added to each well, and SARS-CoV-2 (WK-521) (obtained from the National Institute of Infectious Diseases) was added. 50 ⁇ L of virus solution was added at a multiplicity of infection (MOI) of 0.1 (infection plate).
• MOI multiplicity of infection
• Table 3 shows the evaluation results of the anti-SARS-CoV-2 effects of various phenanthridinone derivatives.
• IC50 50% inhibitory concentration (drug concentration that reduces virus production and replication by 50%)
• IC90 90% inhibitory concentration (drug concentration that reduces virus production and replication by 90%)
• CC50 50% toxic concentration (concentration of drug that reduces the number of viable cells by 50%)
• IC50 and IC90 show the results of qPCR measurement, and CC50 shows the results of cell viability determination (absorbance).
• Table 3 shows that phenanthridinone derivatives have anti-SARS-CoV-2 effects.
• Example 2 Anti-SARS-CoV effect IC 50 and IC 90 were obtained in the same manner as in Example 1, except that SARS-CoV (SARS-CoV-HKU-39849) was used instead of SARS-CoV-2. rice field. Table 4 shows the evaluation results of the anti-SARS-CoV effects of various phenanthridinone derivatives.
• Example 3 Anti-MERS-CoV effect IC 50 and IC 90 were obtained in the same manner as in Example 1, except that MERS-CoV (MERS-CoV-EMC/2012) was used instead of SARS-CoV-2. rice field. Table 5 shows the evaluation results of the anti-MERS-CoV effects of various phenanthridinone derivatives.
• MOI at infection
• Anti-SARS-CoV-2 efficacy and cytotoxicity of drugs were determined by comparing viable cell numbers in infected and uninfected cells, respectively, with those in the absence of drug. Table 6 shows the evaluation results of the effect of NR-31 on each SARS-CoV-2 strain.
• EC 50 50% effective concentration (concentration of drug that inhibits cell death induced by SARS-CoV-2 infection by 50%)
• CC50 50% toxic concentration (concentration of drug that reduces the number of viable cells by 50%)
• the phenanthridinone derivative was synthesized as follows.
• the residue was dissolved in cyclopentyl methyl ether and treated with hydrochloric acid for deprotection.
• the reaction solution was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with ethyl acetate.
• the organic layer was washed with city water and saturated brine in that order.
• the organic layer was dried over sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated. Purification of the residue gave NR-30.

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• 2022
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