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WO2023054759A1 - Dérivé de 2-aminoquinazoline et composition antivirale le comprenant - Google Patents

Dérivé de 2-aminoquinazoline et composition antivirale le comprenant Download PDF

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Publication number
WO2023054759A1
WO2023054759A1 PCT/KR2021/013418 KR2021013418W WO2023054759A1 WO 2023054759 A1 WO2023054759 A1 WO 2023054759A1 KR 2021013418 W KR2021013418 W KR 2021013418W WO 2023054759 A1 WO2023054759 A1 WO 2023054759A1
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Prior art keywords
group
amino
substituted
formula
alkyl group
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PCT/KR2021/013418
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English (en)
Korean (ko)
Inventor
김형래
김승택
권선오
전상은
진영희
송종환
김범태
박철민
이지혜
이준영
신영섭
민정선
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Korea Research Institute of Chemical Technology KRICT
Korea Institute of Oriental Medicine KIOM
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Korea Research Institute of Chemical Technology KRICT
Korea Institute of Oriental Medicine KIOM
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Priority to PCT/KR2021/013418 priority Critical patent/WO2023054759A1/fr
Publication of WO2023054759A1 publication Critical patent/WO2023054759A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without further substituents on alkyl

Definitions

  • the present invention relates to a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof and an antiviral pharmaceutical composition containing the same as an active ingredient.
  • Coronavirus Infectious Disease-19 is a respiratory syndrome caused by SARS-CoV-2 infection, starting in Wuhan City, Hubei Province, China in December 2019, and spreading rapidly worldwide, The rapid increase in the number of deaths is causing a great social problem.
  • the SARS-CoV-2 pathogen is an RNA virus belonging to the Coronaviridae, which has been associated with SARS-CoV, the pathogen of Severe Acute Respiratory Syndrome (SARS) in 2002 and Middle East Respiratory Syndrome (MERS) in 2015. It is very closely related to the MERS coronavirus (MERS-CoV), the pathogen of SARS-CoV-2 and SARS-CoV bind to the ACE2 (Angiotensin Converting Enzyme2) receptor, and MERS-CoV utilizes DPP4 (Dipeptidyl Peptidase4; CD26) as a receptor.
  • SARS Severe Acute Respiratory Syndrome
  • MERS Middle East Respiratory Syndrome
  • SARS-CoV-2 and SARS-CoV spike proteins have a very similar shape (Walls et al., 2020, Structure, Function and antigenicity of the SARS-CoV-2 spike SARS -It was found that CoV-2 also attaches strongly to the surface of host cells through the ACE2 receptor, and the molecular structure of the spike protein and ACE2 complex was recently revealed (Zhou et al., 2020 A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature.;Yan et al., 2020, Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2.Science, DOI: 10.1126/science.abb2762).
  • SARS-CoV-2 transmits and spreads more rapidly than SARS-CoV, which is why SARS-CoV-2 binds more strongly to ACE2 in host cells and makes parts of the spike protein more easily cut by protein scissors. It is presumed that this is because it is deformed.
  • the present inventors have completed the present invention by finding that 2-aminoquinazoline derivatives introduced with various substituents are compounds having an inhibitory effect on COVID-19.
  • An object of the present invention is to provide a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
  • an object of the present invention is to provide an antiviral pharmaceutical composition comprising a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
  • an object of the present invention is to provide a health food composition for preventing and improving viral infection, which includes a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
  • the present invention provides an antiviral pharmaceutical composition
  • an antiviral pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for COVID-19 coronavirus antivirus.
  • composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more known antiviral agents.
  • the present invention relates to a compound according to Formula 1; Or it provides a health food composition for preventing and improving viral infection comprising a food chemically acceptable salt thereof as an active ingredient.
  • composition containing a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to the present invention has an excellent anti-proliferation activity against SARS-CoV-2 infected with Vero cell lines and It can be used as a virus treatment because of its low toxicity, and in particular, it can be used as a treatment for COVID-19 (Coronavirus Infectious Disease-19).
  • the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
  • alkyl or “alkyl group” refers to an aliphatic hydrocarbon radical and includes both straight-chain and branched-chain hydrocarbon radicals.
  • C 1 ⁇ C 6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like are all included.
  • alkene or “alkenyl group” refers to a group in which at least two carbon atoms contain at least one carbon-carbon double bond
  • alkyne or “alkynyl group” refers to a group in which at least two carbon atoms contain at least one carbon-carbon double bond.
  • heterocycle or “heterocyclic group” includes one or more heteroatoms, includes at least one of a single ring and multiple rings, and includes heteroaliphatic and heteroaromatic rings, unless otherwise specified. It may also be formed by combining adjacent functional groups.
  • aryl or “aryl group” refers to one or more hydrocarbon rings having a covalent pi electron system, and includes, for example, phenyl, naphthyl, biphenyl, and the like.
  • halogen refers to elements belonging to group 17 of the periodic table, and may be specifically fluorine, chlorine, bromine, and iodine.
  • alkoxy or “alkoxy group” means a radical in which the hydrogen atom of a hydroxy group is substituted with an alkyl, unless otherwise defined, and for example, C 1 to C 6 alkoxy is methoxy, ethoxy, propoxy, n- Butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy and the like are all included.
  • hydroxyl group means -OH.
  • amino group means -NH 2 .
  • benzyloxy group means a monovalent atomic group consisting of an oxy group and a benzyl group, that is, -O-CH 2 -C 6 H 5 .
  • substitution means that one hydrogen atom is substituted, for example, when substituted with a hydroxyl group, -CH 3 is substituted with -CH 2 OH.
  • the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
  • R 4 may be absent
  • R 1a is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group; Or a substituted or unsubstituted C 2 ⁇ C 6 alkenyl group,
  • alkenyl group of C 2 ⁇ C 6 when substituted, it is substituted with a hydroxyl group, an amino group, a halogen atom or an acetoxy group,
  • R 1b is a C 1 ⁇ C 6 alkyl group; Or a substituted or unsubstituted C 6 ⁇ C 10 aryl group,
  • R 1c is a hydroxyl group; C 1 ⁇ C 6 alkanoyloxy group; benzyloxy group; or NR a R b ;
  • R 1d and R 1e are each independently hydrogen; sodium; Or a C 1 ⁇ C 6 alkyl group,
  • n is an integer from 0 to 3;
  • R 2 is hydrogen, a C 3 ⁇ C 6 cycloalkyl group; -(X) n -C 6 ⁇ C 10 An aryl group,
  • R 1 and R 2 together may form a ring
  • R 3a is a C 1 ⁇ C 6 alkanoyloxy group, o is 1 or 2;
  • R 5 is hydrogen; halogen; cyano group; nitro group; hydroxy group; amino group; C 1 ⁇ C 6 Alkyl group; C 2 ⁇ C 6 Alkenyl group; A C 2 ⁇ C 6 alkynyl group; A C 1 ⁇ C 6 alkoxy group; C 1 ⁇ C 6 alkanoyloxy group; C 3 ⁇ C 6 Cycloalkyl group; C 6 ⁇ C 10 aryl group; A C 2 ⁇ C 10 heterocyclic group containing at least one heteroatom selected from O, N, and S; NR e R f ; And, when a is 1 or more, a plurality of R 5 are the same as or different from each other,
  • a is an integer from 0 to 4.
  • R a , R b , R c , R d , R e and R f are each independently hydrogen; Or a C 1 ⁇ C 3 alkyl group;
  • the term 'ring' herein refers to a fused ring composed of an aliphatic ring having 3 to 20 carbon atoms, an aromatic ring having 6 to 20 carbon atoms, a heterocyclic ring having 2 to 20 carbon atoms, or a combination thereof, and includes a saturated or unsaturated ring.
  • the present invention includes a compound in which Formula 1 is represented by Formula 2 below.
  • R 1 , R 3 , R 4 , R 5 and a are the same as defined above,
  • b is an integer from 0 to 5.
  • the present invention includes a compound represented by any one of the following formulas 3 to 5 in the formula (1).
  • R 1 , R 5 , R 6 , a and b are the same as defined above,
  • R 7 is a C 1 ⁇ C 6 alkyl group; or a tert-butanoyloxymethoxy group.
  • R 1a is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group; or a substituted or unsubstituted C 2 ⁇ C 6 alkenyl group, where, when the C 1 ⁇ C 6 alkyl group is substituted, a C 1 ⁇ C 3 alkoxy group; substituted with a hydroxy group, an amino group, a halogen or an acetoxy group,
  • alkenyl group of C 2 ⁇ C 6 when substituted, it is substituted with a hydroxyl group, an amino group, a halogen or an acetoxy group.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be any one of the following compounds.
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be any one of the following compounds.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof may have a substituent containing an asymmetric atom, in which case the compound of Formula 1 or a salt thereof is (R), (S), or racemic (RS) may exist as optical isomers. Therefore, unless otherwise indicated, the compound of Formula 1 or a pharmaceutically acceptable salt thereof includes all optical isomers such as (R), (S), or racemic (RS) forms.
  • the compound of Formula 1 of the present invention may be in the form of a pharmaceutically acceptable salt.
  • Such salts include conventional acid addition salts, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxy acid.
  • organic acids such as camphorsulfonic acid, capric acid, myristic acid, hypric acid or orotic acid.
  • the salt is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, calcium carbonate, potassium t-butoxide, sodium ethoxide, triethylamine, ammonia, guanidine, ethylenediamine, ethanolamine, diethanol amines, triethanolamine, piperazine, morpholine, or salts derived from dicyclohexylamine.
  • a pharmaceutically acceptable salt of the compound of Formula 1 can be prepared from the compound of Formula 1 by a conventional method.
  • such salts can be prepared by reacting a compound of Formula 1 in free acid/base form with a stoichiometric amount or excess of the desired salt-forming inorganic acid, inorganic salt, organic acid or organic salt in a suitable solvent or various combinations of solvents.
  • the present invention provides an antiviral pharmaceutical composition
  • an antiviral pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier such as a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent, and may be formulated into tablets, capsules, powders, granules, and suspensions according to conventional methods. It may be formulated into oral preparations such as emulsions or syrups or preparations for parenteral administration such as injections. The formulation may be formulated in a variety of forms, for example single dose or multiple dose dosage forms.
  • a pharmaceutically acceptable carrier such as a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent
  • composition of the present invention may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration.
  • Compositions of the present invention are preferably administered orally.
  • the composition of the present invention may be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions.
  • carriers such as lactose and corn starch and lubricants such as magnesium stearate may usually be added.
  • lactose and/or dried corn starch may be used as diluents.
  • the active ingredient may be combined with emulsifying and/or suspending agents.
  • compositions according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4.
  • a pharmaceutically acceptable carrier such as saline having a pH of 7.4. The solution can be introduced into the patient's intramuscular bloodstream by local bolus injection.
  • a pharmaceutical composition according to the present invention can be administered in a therapeutically effective amount. Therefore, the compound of formula 1 contained in the pharmaceutical composition; Or a pharmaceutically acceptable salt thereof may be administered to the patient in an effective amount of about 10 mg/kg to about 500 mg/kg per day. Of course, the dose may be changed according to the patient's age, body weight, sensitivity, symptoms or efficacy of the compound.
  • the present invention also provides a therapeutically effective amount of the compound of Formula 1; Or a method for preventing or treating a virus, preferably a coronavirus, more preferably COVID-19, comprising administering a pharmaceutically acceptable salt thereof to a mammal, including a human.
  • a virus preferably a coronavirus, more preferably COVID-19
  • composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more antiviral agents.
  • the present invention also relates to a compound of Formula 1 for the preparation of a drug for preventing or treating a virus; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a treatment for coronavirus, particularly COVID-19, comprising a 2-aminoquinazoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. it's about
  • the 2-Aminoquinazoline derivative of Chemical Formula 1 effectively inhibits SARS-CoV-2 in a drug efficacy test using Vero cells infected with SARS-CoV-2 and is expected to have a therapeutic effect on coronavirus due to its low cytotoxicity. It was confirmed that it can be used, and in particular, it was confirmed that it can be used as a treatment for COVID-19.
  • the therapeutic agent or pharmaceutical composition for COVID-19 containing the compound of Formula 1 according to the present invention as an active ingredient is added to the compound of Formula 1 with a conventional non-toxic pharmaceutically acceptable carrier, reinforcing agent or excipient, etc. in the pharmaceutical field.
  • Oral administration preparations such as tablets, capsules, troches, solutions, suspensions, etc. can be formulated in conventional preparations.
  • a pharmaceutical composition may be provided by using the compound of Formula 1 according to the present invention as an active ingredient and further including other antiviral agents.
  • it can be provided as a conventional preparation in the pharmaceutical field by adding the compound of Formula 1, other antiviral agents and pharmaceutically acceptable carriers to a COVID-19 treatment or pharmaceutical composition.
  • the dosage of the compound of Formula 1 may vary depending on the patient's age, weight, sex, dosage form, health condition and disease degree, and is generally 10 to 4,000 mg/day, and may be divided and administered once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist.
  • the present invention is a compound of Formula 1; Or it provides a health food composition for preventing and improving viral infection comprising a food chemically acceptable salt thereof as an active ingredient.
  • the compound represented by Formula 1 according to the present invention may be prepared by reacting as shown in Reaction Scheme 1 below, but is not limited thereto.
  • R 5 , R 6 , a and b have the same definition as above.
  • Comp 1 (29.1 mmol, 1 eq) and urea (582.8 mmol, 20 eq) were placed in a 100 mL round bottom flask and heated at 150 °C for 2 hours. After the reaction was completed, the mixture was cooled at room temperature, 60 mL of water was added thereto, and the mixture was heated at 100° C. for 1 hour. Cooling the reactants precipitates a white solid. After filtering the white solid, it was washed with water and hexane and dried to obtain Comp 2 (yield: about 90%). Comp 2 was used in the next step without further purification.
  • the compound represented by Formula 1 according to the present invention may be prepared by reacting as in Scheme 2-1 below, but is not limited thereto.
  • the compound represented by Formula 1 according to the present invention may be prepared by reacting as in Scheme 2-3 below, but is not limited thereto.
  • R 1a , R 5 , R 6 , a and b have the same definitions as above.
  • Synthesis Examples 1, 2-1, 2-2, 2-3, and 2-4 are examples of the compound synthesis method according to the present invention, and include modification of some reagents, solvents, and chemical reaction sequences.
  • Example 1-1 7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one
  • Example 1-1 0.6 mmol, 200 mg
  • potassium carbonate (0.72 mmol, 99.5 mg)
  • dimethylacetamide (6 mL)
  • iodomethyl pivalate 0.9 mmol, 140 ⁇ L
  • work-up was performed with water and EA, and the organic layer was dried in MgSO 4 , filtered, and evaporated to obtain a crude product. .
  • the crude product was purified with silica to obtain a product.
  • Example 2-4 The reaction was carried out in the same manner as in Example 2-1, but using 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one (Example 1-44). Thus, ((2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4-yl)oxy)methyl pivalate (Example 2-4) was obtained.
  • Example 1-1 compound (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (2.94 mmol, 1000 mg) was added to 100 mL RBF, sodium eye Sodium iodide (1.76 mmol, 264 mg) and cesium carbonate (8.82 mmol, 2874 mg) were added, sealed, and nitrogen substitution was performed. After adding DMAc (29.4 mL) and stirring, di-tert-butyl chloromethyl phosphate (7.35 mmol, 1.73 mL) was added and heated to 60 ° C.
  • Example 1-1 (7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (10 mmol, 3 g) was added to 250 mL RBF. After adding acetic anhydride (100 mL) and stirring, TEA (30 mmoL, 4 mL) was slowly added dropwise. The reaction proceeded by heating the reactant to 85 ° C. After the reaction is completed, work-up is performed with brine and EA, and the organic layer is dried with MgSO 4 , filtered, and evaporated to obtain a crude product.
  • Example 2-11 3-acetyl-7-chloro-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one
  • Example 1-1 7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one
  • formic acid 100 ⁇ L
  • acetic anhydride 500 ⁇ L
  • work-up is performed using sodium bicarbonate and EA.
  • the organic layer is dried over MgSO4, filtered, and evaporated to obtain a crude product.
  • Example 1-1 (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (200 mg, 0.587 mmol) was mixed with dichloromethane (3 mL) and triethylamine (164 mL. 1.174 mmL) and acetoxyacetyl chloride (195 mL, 1.761 mmol) was added. The reaction mixture was stirred at 40 ° C for 2.5 hours, and when the reaction was complete, it was diluted with dichloromethane (20 mL) and washed with water (20 mL).
  • Example 1-1 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one) was used to obtain 7-chloro-2-((3,5-dichlorophenyl)amino)-3-methylquinazolin-4(3H)-one (Example 2-27).
  • Example 1-1 (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (500 mg, 1.468 mmol) was mixed with dichloromethane (12 mL) and triethylamine (307 mL, 2.20 mmol) and dimethylaminopyridine (18 mg, 0.147 mmol) and methanesulfonyl chloride (136 mL, 1.762 mmol) were added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours.
  • 2-Amino-4-chloro-N-(2-(dimethylamino)ethyl)benzamide (0.2 g, 0.7 mmol) and 1,3-dichloro-5-isothiocyanatobenzene in DMF (6 mL) (0.143 g, 0.7 mmol) and a mixture of CuBr (0.05 g, 0.35 mmol) and triethylamine (0.05 mL, 0.36 mmol) was refluxed at 80 oC for 8 hours.
  • Vero cells used in the present invention were purchased from the American Type Culture Collection (ATCC, CCL-81; Manassas, VA) and used, 10% heat inactivated fetal bovine serum and 1 ⁇ antibiotic-antimycotic , Gibco/Thermo Fisher Scientific, Waltham, MA) containing Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea) and incubated at 37°C under 5% carbon dioxide.
  • ATCC American Type Culture Collection
  • CCL-81 Manassas, VA
  • DMEM Dulbecco's modified Eagle's medium
  • SARS-CoV-2 Korean isolate (MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15]) was obtained from the Korea Centers for Disease Control and Prevention, National Institutes of Health , and proliferated in Vero cells according to the method presented in Kim et al., 2016 doi: 10.1093/cid/ciw239. All experiments using MERS-CoV were performed at the Pasteur Institute in Korea, which followed the enhanced Biosafety Level 3 (BL-3) containment procedures of the National Institutes of Health approved by the Korea Centers for Disease Control and Prevention.
  • BL-3 Biosafety Level 3
  • Chloroquine diphosphate (CQ; C6628), lopinavir (LPV; GP6351), and Remdesivir were purchased from SelleckChem (Houston, TX) and Glentham Life Science (UK), respectively.
  • the anti-SARS-CoV-2 spike antibody used as the primary antibody was manufactured by Sino Biological Inc. (Beijing, China).
  • Alexa Fluor 488 goat anti-rabbit IgG as a secondary antibody and Hoechst 33342 as a nuclear chromosome were purchased from Molecular Probes/Thermo Fisher Scientific (Waltham, MA).
  • PFA Paraformaldehyde
  • aqueous solution and normal goat serum were obtained from Electron Microscopy Sciences (Hatfield, PA) and Vector Laboratories, Inc, respectively. (Burlingame, CA).
  • cells infected with SARS-CoV-2 express viral proteins, it can be measured using antibodies that specifically bind to viral proteins.
  • cells were stained using an antibody that binds to the spike protein of SARS-CoV-2, and infected cells were imaged through a microscope.
  • the infection rate (number of cells expressing SARS-CoV-2 spike protein/total number of cells) was measured with an internally developed Image Mining 3.0 (IM 3.0) plug-in.
  • infected cells treated with dimethyl sulfoxide (DMSO) were used as negative controls, and three compounds (CQ, LPV, Remdesivir) known to have antiviral activity against SARS-CoV-2 was used as a positive control to optimize the image-based assay.
  • DMSO dimethyl sulfoxide
  • Vero cells were plated at 1.2 ⁇ 10 4 cells per well in Opti-PROTM SFM containing 4 mM L-Glutamine and 1 ⁇ Antibiotic-Antimycotic in black, 384-well, microclear plates (Clear plates, Greiner bio-one, Kremsmunster, Austria). After 24 hours, small molecule compounds were added to each well using an automated liquid handling system (Apricot Designs, Covina, Calif.) prior to virus infection. The final concentration of the test compound was 2.5 to 28.2 ⁇ M, and the concentration of DMSO was maintained at 0.5%. The compound-treated group was transferred to a BL-3 containment room and infected with SARS-CoV-2 at an MOI of 0.0625.
  • the fixed cells were stained using Alexa Fluor 488 goat anti-rabbit IgG and Hoechst 33342. After fixation and staining of infected cells, they were imaged on a fluorescence imaging system (Perkin Elmer Operetta, 20 ⁇ , Waltham, MA) at 20 ⁇ magnification.
  • the infection rate for SARS-CoV-2 of the cells treated with the small molecule compound was converted into the negative control group (0% infection inhibition rate) and the positive control group (100% infection inhibition rate) on each plate, resulting in an inhibitory effect of 90% or more A low-molecular-weight compound was identified.
  • the inhibitory effect of viral infection according to the concentration of the compound can be seen through a concentration-response curve experiment.
  • the highest concentration of the test compound is 5 mM, diluted 2 times with DMSO, and serially diluted up to 10 steps. This is treated with cells prepared in the same way as in 1-5 above.
  • the highest concentration of the final concentration of the test compound was 25 ⁇ M, and the concentration of DMSO was maintained at 0.5%.
  • the compound-treated group was moved to a BL-3 containment room and infected with SARS-CoV-2 at an MOI of 0.0625. 24 hours after infection, the infection rate was imaged and converted in the same manner as in 1-5 above.
  • Example 1-1 0.269 >25 92.9
  • Example 1-2 0.403 >25 62.085
  • Example 1-3 5.13 >25 4.87
  • Example 1-4 2.064 >25 12.113
  • Example 1-5 0.328 >25 76.3
  • Example 1-6 0.272 >25 92
  • Examples 1-7 0.254 >25 98.241
  • Examples 1-8 >25 >25 One Examples 1-9 >25 >25 One Examples 1-10 4.877 12.9 2.64
  • Example 1-11 >25 >25 One Examples 1-12 0.41 >25 60.94
  • Examples 1-13 0.511 >25 48.93
  • Examples 1-14 1.513 >25 16.52
  • Examples 1-15 >25 >25 One Examples 1-16 >25 >25 >25 One Examples 1-17 >25 >25 One Examples 1-18 0.362 >25 71
  • Examples 1-19 0.991 >25 25.22
  • Examples 1-20 >25 >25 >25 68.67
  • Examples 1-22 0.89 >25 28.1
  • Examples 1-24 0.308 14.046 45.55
  • the compound according to one aspect of the present invention has excellent antiviral inhibitory activity against SARS-CoV-2, it can be seen that it can be used as a treatment for COVID-19 (coronavirus infection-19). there is.
  • the present invention is useful in the field of medicine and medicine through antiviral effects through a novel pharmaceutical composition of a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.

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Abstract

La présente invention concerne un dérivé de 2-aminoquinazoline ou un sel pharmaceutiquement acceptable de celui-ci et, plus spécifiquement, un composé représenté par la formule chimique 1 ou un sel pharmaceutiquement acceptable de celui-ci, et une composition pharmaceutique antivirale le comprenant en tant que principe actif. [formule chimique 1]
PCT/KR2021/013418 2021-09-30 2021-09-30 Dérivé de 2-aminoquinazoline et composition antivirale le comprenant Ceased WO2023054759A1 (fr)

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US12030904B2 (en) 2020-08-24 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
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US12030904B2 (en) 2020-08-24 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12473314B2 (en) 2020-08-24 2025-11-18 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12208110B2 (en) 2020-10-16 2025-01-28 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12091420B2 (en) 2022-08-05 2024-09-17 Gilead Sciences, Inc. SARS-COV2 main protease inhibitors
US12410183B2 (en) 2022-08-05 2025-09-09 Gilead Sciences, Inc. Sars-cov2 main protease inhibitors

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