WO2021235392A1 - 抗ＳＡＲＳ－ＣｏＶ－２薬 - Google Patents

抗ＳＡＲＳ－ＣｏＶ－２薬 Download PDF

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WO2021235392A1
WO2021235392A1 PCT/JP2021/018617 JP2021018617W WO2021235392A1 WO 2021235392 A1 WO2021235392 A1 WO 2021235392A1 JP 2021018617 W JP2021018617 W JP 2021018617W WO 2021235392 A1 WO2021235392 A1 WO 2021235392A1
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alkyl
cycloalkyl
cycloalkenyl
alkynyl
cycloalkynyl
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French (fr)
Japanese (ja)
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昌範 馬場
実佳 岡本
政明 外山
祐一 橋本
宏正 橋本
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Oncolys Biopharma Inc
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Oncolys Biopharma Inc
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Priority to US17/926,101 priority Critical patent/US20230192622A1/en
Priority to EP21808187.5A priority patent/EP4154884A4/en
Priority to JP2022524462A priority patent/JP7765835B2/ja
Publication of WO2021235392A1 publication Critical patent/WO2021235392A1/ja
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    • 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
    • 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
    • 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
    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems

Definitions

  • the present invention relates to an anti-SARS-CoV-2 drug.
  • Coronavirus is originally a virus that causes the symptoms of colds in humans, and four types of coronaviruses are known, and 10 to 15% of colds are caused by these viruses.
  • coronaviruses that cause the highly lethal severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) have been known so far.
  • the number of SARS patients is about 8,000, the case fatality rate is about 10%, the number of MARS patients is about 2,500, and the case fatality rate is about 35%.
  • Coronavirus is a + chain RNA virus having an envelope with a diameter of about 100 nm, and SARS-CoV is classified as a second-class pathogen and MERS-CoV is classified as a third-class pathogen.
  • SARS-CoV-2 is currently also called a new type coronavirus, and the infectious disease caused by the virus is named COVID-19 by WHO.
  • COVID-19 the infectious disease caused by the virus
  • WHO World Health Organization
  • remdesivir which has been clinically tested as an anti-Ebola drug, was approved as a special case on May 7, 2020, and clinical trials for COVID-19 are being conducted for the anti-influenza drug favipiravir and the like.
  • Patent Document 1 a phenanthridinone derivative is effective against human hepatitis C virus, and have filed a patent application (Patent Document 1).
  • Patent Document 1 the relationship between phenanthridinone derivatives and anti-SARS-CoV-2 activity has never been reported.
  • An object of the present invention is to provide an effective antiviral drug for SARS-CoV-2.
  • the present inventors have established an anti-SARS-CoV-2 assay system for drugs in order to solve the above-mentioned problems, and as a result of proceeding with screening for various drugs, the present inventors have selected anti-anti-SARS-CoV-2 assays for specific phenanthridinone derivatives. The effect of SARS-CoV-2 was recognized, and the present invention was completed.
  • Aryl, Arylalkyl, Arylalkenyl, Heteroaryl and Heteroarylalkyl (the above groups are independently unsubstituted or one or more halogens, hydroxyls, NH 2 , NO 2 , C ( O) Z (Z is hydrogen, hydroxyl, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkenyl, C 4 to C 6 cycloalkynyl or NH 2 ), C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkenyl, C 4 ⁇ C 6 cycloalkynyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroary
  • C 4 to C 6 cycloalkynyl heterocyclyl, aryl, arylalkyl, arylalkenyl, heteroaryl and heteroarylalkyl (each of the above groups is independently unsubstituted or one or more halogens, Hydroxyl, NH 2 , NO 2 , C (O) Z (Z is water) Element, hydroxyl, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkenyl, C 4 to C 6 cycloalkynyl or NH 2 ), NH-C (O) Z (Z is hydrogen, hydroxyl, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 3 to C 6 cycloalkyl, C 3 ⁇ C 6 cycloalkenyl, C 4 ⁇
  • the cycloalkyl, heterocyclyl or aryl condensing with each is independently unsubstituted or one or more halogens, hydroxyls, NH 2 , NO 2 , C (O) Z (Z is hydrogen, hydroxyl, C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkenyl, C 4 to C 6 cycloalkynyl or NH 2 ) , C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkenyl, C 4 to C 6 cycloalkynyl, heterocyclyl, aryl, Arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, Q- (C 1 to C 8
  • Cycloalkyls, heterocyclyls or aryls are independently unsubstituted or one or more halogens, hydroxyls, NH 2 , NO 2 , C (O) Z (Z is hydrogen, hydroxyl, C 1).
  • C 8 alkyl C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkenyl, C 4 to C 6 cycloalkynyl or NH 2 ), C 1 to C 8 alkyl, C 2 to C 8 alkenyl, C 2 to C 8 alkynyl, C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkenyl, C 4 to C 6 cycloalkynyl, heterocyclyl, aryl, arylalkyl , Arylalkenyl, Heteroaryl, Heteroarylalkyl, Q- (C 1 to C 8 alkyl), Q- (C 2 to C 8 alkenyl), Q- (C 2 to C 8 alkynyl), Q- (C 3 to C 6 cycloalkyl), Q- (C 3 to C 6 cycloalkenyl), Q- (C 3 to
  • FIG. 1 outlines the anti-SARS-CoV-2 assay performed in the examples.
  • FIG. 2 shows the cell change (cell death) induced by SARS-CoV-2 infection and the effect of the phenanthridinone derivative (HA-719) on it.
  • FIG. 3 shows the relationship between the concentration of the phenanthridinone derivative (HA-719, KZ32, YN029) and the number of non-virus-infected cells and the number of viable cells 3 days after culturing the infected cells.
  • FIG. 4 shows the 1 H-NMR spectrum of NR-04.
  • FIG. 5 shows the 1 H-NMR spectrum of NR-32.
  • FIG. 6 shows the 1 H-NMR spectrum of NR-51.
  • FIG. 7 shows the 1 H-NMR spectrum of NR-19.
  • alkyl means a linear or branched aliphatic hydrocarbon group containing a specific number of carbon atoms.
  • C 1 to C 8 alkyl means a straight or branched saturated hydrocarbon chain containing at least one and at most eight carbon atoms.
  • Suitable alkyls are, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n. -Can be mentioned as octyl.
  • alkenyl means a group in which one or more C-C single bonds of the alkyl are substituted with double bonds. Suitable alkenyls are, but are not limited to, for example 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 can be mentioned.
  • alkynyl means a group in which one or more C-C single bonds of the alkyl are substituted with triple bonds.
  • Suitable alkynyls are, but are not limited to, for example, 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 an alicyclic alkyl containing a specific number of carbon atoms.
  • C 3 to C 6 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 substituted 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 substituted with triple bonds.
  • Suitable cycloalkynyls include, but are not limited to, cyclobutynyl, cyclopentynyl, cyclohexynyl and the like.
  • heterocyclyl one or more carbon atoms of the cycloalkyl, cycloalkenyl or cycloalkynyl are independently selected from nitrogen (N), sulfur (S) and oxygen (O), respectively.
  • N nitrogen
  • S sulfur
  • O oxygen
  • N nitrogen
  • S sulfur
  • O oxygen
  • Suitable heterocyclyls include, but are not limited to, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, tioxanyl, piperazinyl and the like. Can be mentioned.
  • aryl means an aromatic ring group having 6 to 15 carbon atoms. Suitable aryls include, but are not limited to, phenyl, naphthyl, anthryl (anthrasenyl) and the like.
  • arylalkyl means a group in which one of the hydrogen atoms 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 of the hydrogen atoms of the alkenyl is substituted with the aryl.
  • Suitable aryl alkenyls include, but are not limited to, styryl and the like.
  • heteroaryl means that one or more carbon atoms of the aryl are each independently replaced with a heteroatom selected from nitrogen (N), sulfur (S) and oxygen (O). Means the group.
  • N nitrogen
  • S sulfur
  • O oxygen
  • the substitution with N or S includes the substitution with N-oxide or S oxide or dioxide, respectively.
  • Suitable heteroaryls are, but are not limited to, for example, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridadinyl, pyrazinyl, pyrimidinyl, quinolinyl, etc. Isoquinolinyl, indrill and the like can be mentioned.
  • heteroarylalkyl means a group in which one of the hydrogen atoms of the alkyl is substituted with the heteroaryl.
  • the groups described above are independent, unsubstituted, or one or more halogens, hydroxyls, NH 2 , NO 2 , C (O) Z (Z is hydrogen, hydroxyl, C 1 to C).
  • halogen or halo means fluorine, chlorine, bromine or iodine.
  • salt is preferably a pharmaceutically acceptable salt.
  • the counter ion of the compound represented by the formula (I) is not limited, but is, for example, a cation such as sodium ion, potassium ion, calcium ion, magnesium ion, or chloride ion or bromide ion.
  • R 1 is preferably C 3 to 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 3 is preferably 1,1, 1, 3, 3, 3 -Hexafluoro-2-hydroxypropan-2-yl.
  • the compounds in which the two groups R 4 and R 5 and / or the two groups R 7 and R 8 are methylenedioxy, and R 2 and R 4 to Compounds in which at least one of R 9 is a group selected from methoxyl, hydroxyl and halogen are also preferred compounds.
  • At least one of R 7 and R 8, hydroxyl, O- (C 1 ⁇ C 8 alkyl), or alkyl portion is substituted with a hydroxyl O- (C 1 ⁇ C 8 alkyl) (for example, OCH 2 CH 2 OH, OCH 2 C (CH 3 ) 2 OH, OCH 2 CH 2 CH 2 OH, OCH 2 CH 2 CH 2 CH 2 OH, OCH 2 CH 2 CH 2 CH 2 OH, OCH 2 CH (OH) CH 2 OH) compounds are preferred.
  • Patent Document 1 International Publication No. 2011/093483
  • Yuko Nishiyama "Physiologically active substances using a phenanthridinone skeleton as an alternative to the steroid skeleton. Creation of compounds ”(URL: http://doi.org/10.15083/00073871), and compounds not specifically described in the relevant document are also described in the relevant document. Can be manufactured according to the above.
  • a commonly used method for example, column chromatography using silica gel or the like as a carrier or recrystallization using methanol, ethanol, chloroform, dimethylsulfoxide, n-hexane-ethyl acetate, water or the like is used.
  • the crystallization method may be used.
  • the elution solvent for column chromatography include methanol, ethanol, chloroform, acetone, hexane, dichloromethane, ethyl acetate, and a mixed solvent thereof.
  • the above compound can be formulated as an anti-SARS-CoV-2 drug in combination with a conventional pharmaceutical carrier.
  • the dosage form is not particularly limited and is appropriately selected and used as necessary, and is used as tablets, capsules, granules, fine granules, powders, sustained release preparations, liquids, suspensions, emulsions and syrups.
  • Oral agents such as elixirs, parenteral agents such as injections and suppositories.
  • Oral preparations are conventionally produced using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, inorganic salts and the like.
  • a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance and the like can be appropriately added.
  • binder examples include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol and the like.
  • disintegrant examples include starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and the like.
  • surfactant examples include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80 and the like.
  • lubricant examples include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol and the like.
  • fluidity accelerator examples include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like.
  • the injection is produced according to a conventional method, and generally distilled water for injection, physiological saline, aqueous glucose solution, olive oil, sesame oil, lacquer oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be used as the diluent. .. Further, if necessary, a bactericide, a preservative, a stabilizer, an tonicity agent, a painless agent and the like may be added. Further, from the viewpoint of stability, the injection can be filled in a vial or the like and then frozen, water is removed by a usual freeze-drying technique, and the 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 from 5 to 50% by weight, but is not limited thereto.
  • parenteral preparations examples include suppositories for intrarectal administration, which are manufactured according to a conventional method.
  • the formulated anti-SARS-CoV-2 drug varies depending on the dosage form, administration route, etc., but for example, it is possible to administer 1 to 4 times a day for a period of 1 week to 3 months.
  • the weight of the compound of the above formula (I) is, for example, 0.1 to 1000 mg. , It is preferable to take 1 to 500 mg in several divided doses a day.
  • the weight of the compound of the above formula (I) is, for example, 0.1 to. It is appropriate to administer 1000 mg, preferably 1 to 500 mg, by intravenous injection, intravenous drip infusion, subcutaneous injection, or intramuscular injection.
  • the compound represented by the above formula (I) may be used in combination with another drug effective against SARS-CoV-2 infection. They are administered separately in the course of treatment or combined with the compound of formula (I) above in a single dosage form such as tablets, intravenous solutions, or capsules. Examples of such other drugs include remdesivir, favipiravir and the like.
  • Example 1 Anti-SARS-CoV-2 effect (assay with VeroE6 / TMPRSS2 cells)
  • the outline of the anti-SARS-CoV-2 assay is shown in FIG.
  • MOI multiplicity of infection
  • FIG. 2 shows the changes in cells (cell death) induced by SARS-CoV-2 infection observed under a microscope and the effects of the phenanthridinone derivative (HA-719) on them.
  • FIG. 3 shows the relationship between the concentration of the phenanthridinone derivative (HA-719, KZ32, YN029) and the number of non-virus-infected cells and the number of viable cells 3 days after culturing the infected cells.
  • the vertical axis of FIG. 3 shows the number of non-virus-infected cells and the number of viable cells 3 days after culturing the infected cells.
  • the horizontal axis shows the concentration of the drug.
  • the number of living cells is expressed as 100% in the absence of the drug (0). As the concentration of the drug increases, the number of viable cells of the infected cells increases, indicating that these drugs have an anti-SARS-CoV-2 effect.
  • Table 1 shows the anti-SARS-CoV-2 effects of various phenanthridinone derivatives.
  • EC 50 50% effective concentration (concentration of drug that suppresses cell death induced by SARS-CoV-2 infection by 50%)
  • CC 50 50% toxic concentration (concentration of drug that reduces the number of living cells by 50%)
  • Table 4 shows the evaluation results of the anti-SARS-CoV-2 effect of various phenanthridinone derivatives.
  • IC 50 50% inhibitory concentration (concentration of drug that reduces virus production / replication by 50%)
  • IC 90 90% inhibitory concentration (concentration of drug that reduces virus production / replication by 90%)
  • CC 50 50% toxic concentration (concentration of drug that reduces the number of living cells by 50%)
  • IC 50 and IC 90 show the results of qPCR measurement, and CC 50 shows the results of cell viability determination (absorbance).
  • the phenanthridinone derivative was synthesized as follows.
  • NR-04-a 95.0 g, 624 mmol was charged in N, N-dimethylformamide (1.14 L).
  • 2- (benzyloxy) ethylmethane sulfonate 169 g, 734 mmol
  • potassium carbonate 152 g, 1.10 mol
  • potassium iodide 24.4 g, 147 mmol
  • the reaction mixture was stirred at 70 ° C. for 1 hour, N, N-dimethylformamide (100 mL) was added, and the mixture was stirred at 85 ° C. for 2 hours.
  • MTBE (1.00 L) and city water (2.00 L) were added to separate the liquids.
  • the aqueous layer was extracted with MTBE, and the organic layers were collectively washed with 0.5N aqueous sodium hydroxide solution, city water, and saturated brine in that order.
  • the organic layer was dried over sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated to obtain an intermediate.
  • the entire amount of the intermediate was charged in methanol (800 mL).
  • An aqueous solution (800 mL) of lithium hydroxide monohydrate (42.0 g, 1.00 mol) was added to the reaction solution, and the mixture was stirred for 2 hours.
  • the solvent was distilled off, city water was added, and the pH was adjusted to 2 with hydrochloric acid.
  • NR-04-b (92.9 g, 341 mmol) was charged in dichloromethane (527 mL). The reaction solution was immersed in a water bath, and oxalyl chloride (298 mL, 3.41 mol) and N, N-dimethylformamide (0.528 mL, 6.82 mmol) were added. The acid chloride was obtained by stirring at room temperature for 3 hours and distilling off the solvent.
  • NR-04-1 (46.6 g, 67.4 mmol) was charged in N, N-dimethylacetamide (438 mL).
  • Cesium carbonate (98.8 g, 303 mmol), palladium (II) acetate (3.03 g, 13.5 mmol) and tricyclohexylphosphine tetrafluoroborate (6.21 g, 16.9 mmol) were added in this order to the reaction mixture, and the mixture was stirred at 100 ° C. for 3 hours. bottom. It was cooled to room temperature and filtered through cerite. The filtrate was poured into city water, adjusted to pH 3-4 with hydrochloric acid, and then extracted with MTBE.
  • NR-04-2 (25.0 g, 44.1 mmol) was charged in tetrahydrofuran (375 mL).
  • 5% Palladium-carbon (18.8 g, 4.41 mmol, 50% wet product) was added to the reaction mixture, the inside of the system was replaced with hydrogen, and the mixture was stirred at room temperature for 23 hours.
  • 5% palladium-carbon (10.0 g, 2.35 mmol, 50% wet product) was added to the reaction solution, and the mixture was further stirred at room temperature for 66 hours.
  • the 1 H-NMR spectrum of NR-04 is shown in FIG.

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WO2024237331A1 (ja) * 2023-05-17 2024-11-21 オンコリスバイオファーマ株式会社 フェナントリジノン誘導体のコリン塩

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WO2024237331A1 (ja) * 2023-05-17 2024-11-21 オンコリスバイオファーマ株式会社 フェナントリジノン誘導体のコリン塩

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