WO2023143397A1 - 一种环烷氨基烷氧基取代的芳基并吡喃酮类化合物及其用途 - Google Patents

一种环烷氨基烷氧基取代的芳基并吡喃酮类化合物及其用途 Download PDF

Info

Publication number
WO2023143397A1
WO2023143397A1 PCT/CN2023/073234 CN2023073234W WO2023143397A1 WO 2023143397 A1 WO2023143397 A1 WO 2023143397A1 CN 2023073234 W CN2023073234 W CN 2023073234W WO 2023143397 A1 WO2023143397 A1 WO 2023143397A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
compound
alkyl
unsubstituted
Prior art date
Application number
PCT/CN2023/073234
Other languages
English (en)
French (fr)
Inventor
黄成钢
崔晓兰
谢阳
田小亭
郭珊珊
李志雄
高英杰
Original Assignee
中国科学院上海药物研究所
中国中医科学院中药研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院上海药物研究所, 中国中医科学院中药研究所 filed Critical 中国科学院上海药物研究所
Publication of WO2023143397A1 publication Critical patent/WO2023143397A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present invention also relates to the use of the compound and its pharmaceutically acceptable salts, solvates, and stereoisomers including mixtures in various proportions, especially the use in the preparation of antiviral drugs.
  • a series of antiviral drugs have been developed in this field, such as Baloxavir marboxil, Peramivir, Laninamivir octanoate, Oseltamivir, Oseltamivir, etc. Phosphate), Zanamivir, Rimantadine, Amantadine, etc., but there are no effective drugs for respiratory viruses such as parainfluenza virus, respiratory syncytial virus, adenovirus, and coronavirus.
  • Broad-spectrum antiviral drugs such as ribavirin or interferon, are needed.
  • lopinavir/ritonavir chloroquine phosphate, arbidol, darunavir, hydroxychloroquine, etc.
  • Favipiravir Remdesivir and other drugs.
  • the above-mentioned antiviral drugs still have many deficiencies in therapeutic effect and application safety, therefore, there is still a need to develop new antiviral therapeutic drugs in this field.
  • the object of the present invention is to provide an isoflavone derivative and a pharmaceutically acceptable salt thereof.
  • the first aspect of the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof,
  • X 1 and X 2 are each independently selected from the following group: O, NR 7 ; wherein, said R 7 is selected from the following group: hydrogen, alkyl, substituted alkyl, arylalkyl, substituted aryl Alkyl, cycloalkyl, substituted cycloalkyl;
  • X 3 is selected from the following group: O, NR 8 ; wherein, the R 8 is selected from the following group: hydrogen, alkyl;
  • R 1a , R 1b , and R 1c are each independently selected from the group consisting of hydrogen, hydroxyl, and alkoxy;
  • R is selected from the group consisting of substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 3a and R 3b are each independently selected from the following group: hydrogen, alkyl, halogen;
  • R 4a and R 4b are each independently selected from the following group: hydrogen, alkyl, halogen;
  • R is selected from the group consisting of hydrogen or alkoxy
  • R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, aminoalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 2 -C 6 acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted carbamoyl, or (CH 2 ) t R 7 ; where t is 1, 2, 3, 4 , 5 or 6; wherein, the R 7 is selected from the group consisting of C 2 -C 6 acyl, C 2 -C 6 amido, aryl, heteroaryl, cycloalkyl, heterocyclyl, NR 8 COR 9 ;
  • the R is selected from the following group: hydrogen, alkyl; R is selected from the following group: alkyl, aryl, heteroaryl, cycloalky
  • Ring A is a substituted or unsubstituted cycloalkyl group
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • each substitution means that the hydrogen atom on the group is replaced by one or more substituents selected from the following group: cyano, halogen, alkyl, hydroxyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl base;
  • the alkyl group is a C 1 -C 6 alkyl group
  • the aryl group is a C 6 -C 10 aryl group
  • the cycloalkyl group is a C 3 -C 8 cycloalkyl group
  • the alkoxy group C 1 -C 6 alkoxy
  • alkenyl is C 2 -C 6 alkenyl
  • alkynyl is C 2 -C 6 alkynyl
  • heteroaryl is 5-12 members (preferably 5- 7-membered) heteroaryl.
  • X 1 is O;
  • X2 is O.
  • said R 7 is selected from the group consisting of hydrogen and alkyl.
  • X 3 is O.
  • R 1a , R 1b , and R 1c are each independently selected from hydrogen.
  • R 2 is substituted or unsubstituted aryl, preferably substituted or unsubstituted phenyl.
  • R 3a and R 3b are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and halogen.
  • R 4a and R 4b are each independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and halogen.
  • R 5 is selected from hydrogen or C 1 -C 4 alkoxy.
  • R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, aminoalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted heterocyclic group, substituted or unsubstituted C 2 -C 6 acyl group, or (CH 2 ) t R 7 ; wherein, t is 1, 2, 3, 4, 5 or 6; R 7 is selected from the following group: C 2 -C 6 acyl, C 2 -C 6 amido, aryl NR 8 COR 9 , the R 8 is selected from the group consisting of hydrogen and alkyl; R 9 is selected from the group consisting of alkyl and aryl.
  • ring A is a substituted or unsubstituted C 3 -C 7 cycloalkyl group, preferably a C 3 -C 6 cycloalkyl group.
  • n 1, 2, 3 or 4.
  • said R 6 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl.
  • said R 6 is selected from the group consisting of hydrogen and unsubstituted alkyl.
  • the compound of formula I has the structure shown in formula II,
  • R 9a , R 9b , R 9c are each independently selected from the following group: hydrogen, hydroxyl, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , C 6 -C 10 aryl, 5-12 membered heteroaryl;
  • R 10a , R 10b , R 10c , R 10d , R 10e are each independently selected from the following group: hydrogen, hydroxyl, C 1 -C 6 alkoxy, halogen, cyano;
  • n 1, 2, 3, 4 or 5.
  • the compound of formula II is selected from the following group:
  • the compound of formula I has the structure shown in formula III,
  • R 11a , R 11b , and R 11c are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy C 6 -C 10 aryl, 5-12 membered heteroaryl;
  • R is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, aminoalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Substituted C 2 -C 6 acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted carbamoyl, or (CH 2 ) t R 7 ; where t is 1, 2, 3, 4, 5 or 6; wherein, the R 7 is selected from the group consisting of C 2 -C 6 acyl, C 2 -C 6 amido, aryl, heteroaryl, cycloalkyl, heterocyclyl, NR 8 COR 9 ; Said R is selected from the following group: hydrogen, alkyl; R is selected from the following group: alkyl, aryl, heteroaryl, cycloalky
  • R 13a , R 13b , R 13c , R 13d , R 13e are each independently selected from the group consisting of hydrogen, hydroxyl, alkoxy, halogen, cyano.
  • the compound of formula III is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof; and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof, the drug described in the second aspect of the present invention
  • the use of the composition is for the preparation of a pharmaceutical composition
  • X 1 and X 2 are each independently selected from the following group: O, NR 7 ; wherein, the R 7 is selected from the following group: hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl radical, cycloalkyl, substituted cycloalkyl;
  • X 3 is selected from the following group: O, NR 8 ; wherein, the R 8 is selected from the following group: hydrogen, alkyl;
  • R 1a , R 1b , and R 1c are each independently selected from the group consisting of hydrogen, hydroxyl, and alkoxy;
  • R is selected from the group consisting of substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 3a and R 3b are each independently selected from the following group: hydrogen, alkyl, halogen;
  • R 4a and R 4b are each independently selected from the following group: hydrogen, alkyl, halogen;
  • R is selected from the group consisting of hydrogen or alkoxy
  • R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, aminoalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C 2 -C 6 acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted carbamoyl, or (CH 2 ) t R 7 ; wherein, t is 1, 2, 3, 4, 5 or 6; wherein, the R 7 is selected from the group consisting of C 2 -C 6 acyl, C 2 -C 6 amido, aryl, heteroaryl, cycloalkyl , heterocyclyl, NR 8 COR 9 ; the R 8 is selected from the following group: hydrogen, alkyl; R 9 is selected from the following group: alkyl, aryl, heteroaryl, cycloal
  • Ring A is a substituted or unsubstituted cycloalkyl group
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • each substitution means that the hydrogen atom on the group is replaced by one or more substituents selected from the following group: cyano, halogen, alkyl, hydroxyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl base;
  • composition for being selected from the purposes of following group:
  • the virus is selected from the group consisting of influenza virus, respiratory syncytial virus, coronavirus (such as SARS-COV-2 virus), and parainfluenza virus.
  • the infection is a virus infection.
  • the virus is selected from the group consisting of influenza virus, respiratory syncytial virus, coronavirus (such as SARS-COV-2 virus), and parainfluenza virus.
  • Figure 1 shows a line graph of the drug efficacy test results of compound 4 against the novel coronavirus.
  • Fig. 2 is the cell membrane chromatogram of the compound of the present invention.
  • Figure 3 is a diagram of the calcium imaging results of compound 4 in ACE2-293T cells.
  • Figure 4 shows the bar graph of the effect of Compound 4 on the INF- ⁇ content in the lung tissue of a mouse pneumonia model infected with influenza virus FM1.
  • Figure 5 shows the effect of compound 4 on the TNF- ⁇ content in the lung tissue of the mouse pneumonia model infected with influenza virus FM1 A histogram of the impact.
  • Figure 6 shows the bar graph of the effect of compound 4 on the IL-1 content in the lung tissue of a mouse pneumonia model infected with human coronavirus 229E.
  • Figure 7 shows the bar graph of the effect of compound 4 on the IL-10 content in the lung tissue of a mouse pneumonia model infected with human coronavirus 229E.
  • the inventor unexpectedly found that the compound of the present invention has excellent effects in treating diseases caused by various viral infections, and thus conducted comparative experiments on the compound of the present invention and various known antiviral drugs.
  • the present invention has been accomplished on this basis.
  • substituted refers to any substituent mentioned in the description of the present invention, including but not limited to, halogen, nitro, cyano, carboxyl, oxo, alkyl, substituted alkyl, cycloalkyl, Substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, Hydroxy, Alkoxy, Aryloxy, Alkanoyloxy, Aroyloxy, Amino, Alkanoylamino, Aroylamino, Arylalkylacylamino, Heteroarylalkylacylamino, Aminoalkylacylamino , alkylaminoalkylacylamino, dialkylaminoalkylacylamino, alkylamino, arylamino, arylalkylamino
  • halogen refers to fluorine, chlorine, bromine, iodine.
  • alkyl refers to a linear or branched unsubstituted hydrocarbon group having 1-20 carbon atoms, preferably 1-7 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and the like.
  • substituted alkyl refers to an alkyl group substituted by 1 to 4 substituents such as: halogen, nitro, cyano, carboxyl, oxo, alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines (wherein the two Each amino substituent is selected from the group consisting of alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkyls
  • alkenyl refers to a straight or branched chain hydrocarbon group having 2-20 carbon atoms, preferably 2-15 carbon atoms, most preferably 2-8 carbon atoms, and having 1-4 double bonds.
  • substituted alkenyl refers to an alkenyl group substituted by 1-2 substituents such as: halogen, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted Heteroaryl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines (two of the Amino substituents are selected from alkyl, aryl or arylalkyl).
  • alkynyl refers to a straight or branched chain hydrocarbon group having 2-20 carbon atoms, preferably 2-15 carbon atoms, most preferably 2-8 carbon atoms, and having 1-4 triple bonds.
  • substituted alkynyl refers to an alkynyl group substituted with a substituent such as halo, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines (wherein the two amino substituents selected from alkyl, aryl or arylalkyl).
  • a substituent such as halo, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines (wherein the two amino substituents selected from alkyl, aryl
  • aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6-12 carbon atoms in the ring portion.
  • Aryl includes bicyclic groups that include rings fused to saturated or partially unsaturated aromatic rings, or aromatic carbocyclic or heterocyclic rings.
  • Typical aryl groups include, but are not limited to, the following groups: benzene, naphthalene, anthracene, biphenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.
  • substituted aryl refers to an aryl group substituted by 1 to 4 substituents such as: halogen, halogen, nitro, cyano, ureido, carboxyl, trifluoromethoxy, trifluoro Methyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocycle, substituted heterocycle, hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino , Disubstituted amines (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alk
  • cycloalkyl refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group, which can be optionally substituted by one or more of the substituents described herein, which have 3- 30 carbon atoms make a monocyclic ring, or 7-12 carbon atoms make a bicyclic ring.
  • Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3 -alkenyl, cyclohexyl, 1-cyclohex-1-enyl, cycloheptyl, cyclooctyl.
  • Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane.
  • heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic ring group, which may be, for example, 4-7 membered Monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic ring systems having at least one heteroatom in at least one ring containing carbon atoms.
  • Each ring of the heteroatom-containing heterocyclic group may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms.
  • the "heterocyclyl” can be optionally substituted by one or more substituents described in this application.
  • heterocyclyl examples include but are not limited to pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, Lino, thiomorpholino, piperazinyl, homopiperazinyl, epoxypropylene, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1. 0]heptyl, azabicyclo[2.2.2]hexyl, N-pyridylurea, pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.
  • heteroaryl refers to a monovalent aromatic group of 5-, 6-, 7-, 8, 9 or 10-membered rings and includes fused systems of 5-20 atoms containing one or more Heteroatoms from nitrogen, oxygen, phosphorus and sulfur may be optionally substituted with one or more of the substituents described herein.
  • heteroaryl include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, thiazolyl , quinolinyl, indolyl, etc.
  • sulfonamido refers to a -SO2NH2 group.
  • substituted carbamoyl means that amides, sulfonamides or carbamates respectively have at least one hydrogen selected from the group consisting of alkyl, substituted alkyl, chain alkenyl, substituted Alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl.
  • acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention.
  • Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, acid sulfate, isonicotinate, lactate , salicylate, acid citrate, succinate, maleate, fumarate, gluconate, formate, mesylate and pamolate.
  • Acceptable salt may refer to the inclusion of another molecule such as maleate or other counterion. The counterion stabilizes the charge in the parent compound.
  • An "acceptable salt” can have more than one charged atom, and multiple charged atoms can have multiple counterions.
  • the desired “acceptable salt” can be prepared by suitable methods, for example, by treating the free base with the following mineral acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or with the following Organic acids: acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, pyranosidic acids such as glucuronic or galacturonic acids, alpha-hydroxy acids such as Citric or tartaric acid, amino acids such as glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid.
  • mineral acids hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
  • Organic acids acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid,
  • the desired "acceptable salt” can be prepared by suitable methods, for example, by treating the free acid with an inorganic or organic base such as an amine, an alkali metal hydroxide or an alkaline earth metal hydroxide wait.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, salts of primary, secondary and tertiary amines, and salts of cyclic amines such as piperidine, morpholine and piperazine, and salts derived from sodium, calcium, potassium , magnesium, manganese, iron, copper, zinc, aluminum and lithium derived inorganic salts.
  • a solvate refers to a combination or complex of one or more solvent molecules with a compound of the invention.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and ethanolamine.
  • the compounds of the present invention may exist in unsolvated form or in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., so the present invention shall include both solvated and unsolvated forms.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and hindered isomers, and mixtures thereof such as racemic mixtures, will form part of the present invention.
  • the stereochemistry of any particular chiral atom is not determined, all stereoisomers are contemplated.
  • the invention relates to all geometric and positional isomers.
  • the compounds of the present invention can be different tautomeric forms exist and all such forms are included within the scope of the present invention. All stereoisomers of the compounds of the invention are intended to be included in admixture or in pure or substantially pure form. Resolution may be by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.
  • the compounds of the present invention may be used alone or in combination with other therapeutic agents.
  • Combination therapy may provide a synergistic effect, ie, the effect achieved when the active ingredients are used together is greater than the sum of the effects of the compounds when used separately.
  • the combination therapy can be administered on a simultaneous or sequential schedule.
  • the combination may be administered in two or more uses.
  • the compounds may be administered together in a single pharmaceutical combination, or separately, and when administered separately, simultaneously or sequentially in any order.
  • the compounds of the invention may be administered by any route appropriate to the condition being treated. Suitable routes include, but are not limited to, oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal), vaginal, intraperitoneal, intrapulmonary and intranasal. It is understood that the preferred route may vary due to, for example, the condition of the patient.
  • parenteral including subcutaneous, intramuscular, intravenous, intraarterial, intradermal
  • vaginal intraperitoneal
  • intrapulmonary and intranasal it is understood that the preferred route may vary due to, for example, the condition of the patient.
  • the compound When the compound is administered orally, it can be formulated into pills, capsules, tablets and the like with pharmaceutically acceptable carriers or excipients.
  • the compound When the compound is formulated parenterally, it can be formulated with a pharmaceutically acceptable parenteral carrier.
  • the present invention can administer the compound in any convenient preparation form, and the "preparation" referred to in the present invention refers to a dosage form containing the compound of general formula I of the present invention that is beneficial to administration (drug delivery), such as: but not limited to, aqueous solution injection, Powder injections, pills, powders, tablets, patches, suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powder sprays, sustained-release and controlled-release preparations, etc.
  • drug delivery such as: but not limited to, aqueous solution injection, Powder injections, pills, powders, tablets, patches, suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powder sprays, sustained-release and controlled-release preparations, etc.
  • These pharmaceutical excipients can be conventionally used in various preparations, such as: but not limited to, isotonic agents, buffers, flavoring agents, excipients, fillers, binders, disintegrants and lubricants, etc. ; It can also be selected for use in order to be compatible with the substance, such as: emulsifier, solubilizer, bacteriostat, analgesic and antioxidant, etc., this type of adjuvant can effectively improve the stability of the compound contained in the composition and solubility or change the release rate and absorption rate of the compound, etc., thereby improving the metabolism of the compound of the present invention in vivo, thereby enhancing the administration effect.
  • excipients that can be used to achieve specific administration purposes or methods such as sustained-release administration, controlled-release administration, and pulse administration, such as, but not limited to, gelatin, albumin, chitosan , polyether and polyester polymer materials, such as: but not limited to, polyethylene glycol, polyurethane, polycarbonate and its copolymers.
  • sustained-release administration controlled-release administration
  • pulse administration such as, but not limited to, gelatin, albumin, chitosan , polyether and polyester polymer materials, such as: but not limited to, polyethylene glycol, polyurethane, polycarbonate and its copolymers.
  • the main manifestations of the so-called "beneficial to drug administration” are: but not limited to improving the therapeutic effect, improving bioavailability, and reducing side effects use and improve patient compliance.
  • Step 1 Add compound 7-hydroxyisoflavone (0.040mol), anhydrous acetone 400mL, 1,2-dibromoethane (0.403mol) and potassium carbonate (0.080mol) into a 1L round bottom flask, heat to reflux overnight. TLC traced the end of the reaction, spin-dried the solvent, added 10 mL of water and 300 mL of ethyl acetate, separated the organic layer, dried over anhydrous Na 2 SO 4 , concentrated the organic layer to dryness, and performed silica gel column chromatography to obtain a white solid 7-(2 -Bromoethoxy) isoflavone 12.98g, yield 94%.
  • Step 2 Add compound 7-(2-bromoethoxy) isoflavone (0.5mmol), CH 3 CN 27mL and cyclopropylamine (1.0mmol) successively in a 50mL round bottom flask, add K 2 CO 3 (1.0 mmol), heated to reflux overnight, TLC traced the end of the reaction.
  • Spin to dry the solvent add 50mL water and 100mL ethyl acetate, divide The organic layer was taken out, dried over anhydrous Na 2 SO 4 , the organic layer was concentrated to dryness, and subjected to silica gel column chromatography to obtain the target compound with a yield of 53%.
  • Example 13 Therapeutic effect of compounds of the present invention on mouse pneumonia model infected with H1N1 influenza virus FM1 strain
  • Ribavirin Granules Production unit: Sichuan Baili Pharmaceutical Co., Ltd. Indications: This product is suitable for viral pneumonia and bronchitis caused by respiratory syncytial virus, and skin herpes virus infection. Main ingredient: Ribavirin. Properties: White or off-white soluble granules. Specifications: 50mg/bag, 18 bags/box. Usage and dosage: take orally, 150mg once, 3 times a day. Storage conditions: airtight, keep in a dry place.
  • mice Take the ICR mice and divide them randomly according to their body weight: normal control group, model control group, ribavirin control group, compound 4, compound F1, compound F2, and compound F3. 10 only.
  • the mice were lightly anesthetized with ether, and infected with 15 LD 50 H1N1 influenza virus liquid FM1 strain nasally, 30 ⁇ l each.
  • administration was started, and 0.2ml/10g was administered by intragastric administration each time, once a day, for 4 consecutive days.
  • the normal control group and the model control group were intragastrically administered with distilled water under the same conditions.
  • the animals were dissected, the lungs were weighed, and the lung index and lung index inhibition rate were calculated. The results were statistically analyzed using the t-test for comparison between groups.
  • Lung index (%) lung wet weight (g) ⁇ 100/body weight (g)
  • compound 4 is stronger than that of compound F1, indicating that the 7-position substituent has a very important impact on the anti-influenza virus drug effect of this type of isoflavone derivatives; and compound 4 is more effective than compound F2 and compound F3. Strong, indicating that the position and structure of the substituent have a very important impact on the anti-influenza virus efficacy of this type of isoflavone derivatives.
  • Embodiment 14 Compound of the present invention is to influenza A H1N1 influenza virus FM1 strain, PR8 infection mouse pneumonia The therapeutic effect of the model
  • mice Take the ICR mice, and divide them randomly according to their body weight: normal control group, model control group, oseltamivir control group, compound 4, compound F4, compound F5, compound 5, compound 7 and two dosage groups for each drug.
  • Group 10 Except for the normal control group, the mice were lightly anesthetized with ether, and infected with 15 LD 50 H1N1 influenza virus liquid (FM1/PR8 strain), 30 ⁇ l each. On the day of infection, administration was started, and 0.2ml/10g was administered by intragastric administration each time, once a day, for 4 consecutive days.
  • the normal control group and the model control group were intragastrically administered with distilled water under the same conditions. On the 5th day, after weighing, the animals were dissected, the lungs were weighed, and the lung index and lung index inhibition rate were calculated. The results were statistically analyzed using the t-test for comparison between groups.
  • Lung index (%) lung wet weight (g) ⁇ 100/body weight (g)
  • results in table 2 show: after adopting influenza A H1N1 influenza virus FM1 strain virus to infect mice, the lung index of mice obviously increases, compares with normal control group and has significant difference (P ⁇ 0.01); Days later, Compound 4 could significantly reduce the lung index after infection in mice at a dose of 40 mg/kg/d, which was significantly different from that of the model control group (P ⁇ 0.01), and the lung index inhibition rate was 54.04%; Compound 7's 40 mg/kg The /d dose tended to decrease the lung index. However, compound F4, compound F5, and compound 5 had no effect on reducing the lung index of mice after infection.
  • Compound F4, compound F5, compound 5, and compound 7 are all decreasing in efficacy relative to compound 4, wherein compound F4 and compound F5 are metabolites of compound 4 in vivo, and compound 5 is the 7-position 2-(1-methyl Cyclopropylamino) ethoxy substituent derivatives, compound 7 are 7-position 2-(cyclohexylamino) ethoxy substituent derivatives, prove that 7-position 2-(cyclopropylamino) ethoxy substituents are for The efficacy of such isoflavone derivatives has a very important influence.
  • mice were infected with the PR8 strain of influenza A H1N1 virus the lung index of the mice was significantly increased, which was significantly different from that of the normal control group (P ⁇ 0.01);
  • Compound 4 can significantly reduce the lung index of mice after infection at a dose of 15 mg/kg/d, which is significantly different from that of the model control group (P ⁇ 0.01), and the lung index inhibition rate is 60.27%; the dose of 27.5 mg/kg/d
  • the inhibition rate of oseltamivir was 58.89%.
  • Example 15 Therapeutic effect of compounds of the present invention on human coronavirus 229E infected mouse pneumonia model
  • Test drugs compound 4, compound F1, compound F2, compound F3.
  • HCV-229E human coronavirus 229E
  • Human coronavirus 229E (HCoV-229E)
  • Human embryonic lung fibroblasts MRC5 were purchased from Beijing Bei Na Chuanglian Institute of Biotechnology, passaged in our laboratory, and stored in liquid nitrogen for future use.
  • TCID50 50% cytopathic concentration
  • mice divide them randomly into normal control group, model control group, chloroquine phosphate control group, compound 4, compound F1, compound F2, compound F3 two dosage groups for each drug according to body weight, 10 in each group, male and female Half and half. Except for the normal control group, mice in other groups were lightly anesthetized with ether and infected with 100TCID 50 HCoV-229E nasal drops, 50 ⁇ l/mouse, once every other day, and infected twice in total. On the day of the initial infection, each dose Group administration, once a day, for 4 consecutive days. After weighing the body weight one day after the last administration, the lungs were dissected and weighed, and the lung index and inhibition rate of the mice were calculated.
  • Table 4 The compound of the present invention is to the impact of human coronavirus 229E infection mouse pneumonia model
  • compound 4 is stronger than that of compound F1, indicating that the 7-position substituent has a very important effect on the anti-coronavirus drug effect of this type of isoflavone derivatives; and compound 4 is more effective than compound F2 and compound F3 Stronger, indicating that the position and structure of the substituent have a very important impact on the anti-coronavirus efficacy of this type of isoflavone derivatives.
  • test reagents test instruments and test methods are the same as above.
  • the results in Table 5 show: after adopting the human coronavirus 229E to infect the mice, the lung index of the mice was significantly increased, which was significantly different from that of the normal control group (P ⁇ 0.01); The doses of 30mg/kg/d, 15mg/kg/d, and 7.5mg/kg/d can significantly reduce the lung index of mice after infection, and there are significant differences compared with the model control group (P ⁇ 0.01, P ⁇ 0.05).
  • the lung index inhibition rates were 86.46%, 76.52%, and 44.34% respectively; the dose of 15mg/kg/d of compound 7 could reduce the Compared with the model control group, there was a significant difference (P ⁇ 0.05), and the inhibition rate was 41.56%.
  • Compound F4, compound F5, and compound 5 had no effect on reducing the lung index of mice after infection.
  • the efficacy of compound F4, compound F5, compound 5, and compound 7 are all decreasing relative to compound 4, proving that the 7-position 2-(cyclopropylamino)ethoxy substituent has anti-coronavirus efficacy for such isoflavone derivatives have a very important influence.
  • Example 17 Therapeutic Effect of Compound 4 on Human Coronavirus OC43 Infected Mouse Pneumonia Model
  • test reagents test instruments and test methods are the same as above.
  • mice after adopting the human coronavirus OC43 virus to infect the mice, the lung index of the mice was significantly increased, which was significantly different from that of the normal control group (P ⁇ 0.01); The 15mg/kg/d dose can significantly reduce the lung index of mice after infection, and there is a significant difference compared with the model control group (P ⁇ 0.05), and the lung index inhibition rate is 47.43%; 90mg/kg/d dose of phosphoric acid The inhibition rate of chloroquine was 42.72%.
  • Example 18 Effects of compound 4 of the present invention on a mouse model of pneumonia infected with parainfluenza virus
  • Ribavirin Granules Production unit Sichuan Baili Pharmaceutical Co., Ltd.
  • Indications This product is suitable for For viral pneumonia and bronchitis caused by respiratory syncytial virus, skin herpes virus infection.
  • Main ingredient Ribavirin.
  • Properties White or off-white soluble granules. Specifications: 50mg/bag, 18 bags/box. Usage and dosage: take orally, 150mg once, 3 times a day. Storage conditions: airtight, keep in a dry place.
  • Virus strain parainfluenza virus, purchased from ATCC in the United States, and stored at -80°C by our laboratory.
  • mice Take 60 ICR mice, SPF grade, weighing 13-15g, and divide them randomly into 6 groups according to body weight: normal control group, model control group, ribavirin group, compound 4 three dose groups, 10 mice in each group, male and female Half and half. Except for the normal control group, mice in other groups were lightly anesthetized with ether, and were intranasally infected with 100 TCID 50 parainfluenza virus Sendai strain, 45 ⁇ l each. The mice in each group were given corresponding drugs after infection, and the normal control group and model control group were given distilled water under the same conditions for 4 consecutive days. On the 5th day, the mice were weighed and the lung tissue was separated and the lung weight was measured.
  • Lung index lung weight ⁇ 100/body weight
  • Table 7 show: after adopting parainfluenza virus to infect the mice, the lung index of the mice in the model control group increased significantly, which was significantly different from that in the normal control group (P ⁇ 0.01); The index decreased significantly, and there was a significant difference compared with the model control group (P ⁇ 0.05).
  • the three dose groups had a good dose-effect correlation, and the inhibition rate of the compound 4 high-dose group was 46.39%.
  • Example 19 Anti-new coronavirus (SARS-CoV-2) effect of compound 4 of the present invention in vitro
  • VeroE6 cells preserved by the virus room of the State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health.
  • CPE cytopathic changes
  • SHIMADZU LC-2040C 3D high performance liquid chromatography Japan; Sartorius 1712 electronic analytical balance; Fulham FCR1002-UF ultrapure water preparation machine (Qingdao Fulham Technology Co., Ltd.); SHZ-D (III) cycle Water vacuum pump (Gongyi Yingyu Yuhua Instrument Factory); SB-5200DTD ultrasonic cleaner (Ningbo Xinzhi Biotechnology Co., Ltd.); pipette (Eppendorf, Germany).
  • the 293T cell line with high expression of ACE2 receptor was constructed in the laboratory.
  • Methanol was chromatographically pure, water was ultrapure water, and other reagents were analytically pure.
  • ACE2-293T/CMC cell membrane chromatography column (10 ⁇ 2.0mm), the mobile phase is water, the flow rate is 0.2mL/min, the column temperature is 37°C, the injection volume is 10 ⁇ L, and DAD detection. Positive control: chloroquine phosphate.
  • the cell membrane chromatogram of the compound of the present invention is shown in FIG. 2 .
  • Test method Intracellular Ca2+ flow change detection: insert the cells into a 96-well plate, discard the medium after overnight, wash with CIB, add Fluo-3, and incubate the AM incubation solution in the incubator for 40 minutes, discard the incubation solution, Wash with CIB, discard the CIB under a fluorescence microscope, add drugs to each well in turn, observe the changes in the fluorescence intensity of the cells before and after adding the drugs, observe under the fluorescence microscope for 2 minutes, and add drugs to stimulate 10 seconds after the start of photographing and observation.
  • Test results Changes in intracellular Ca 2+ flux: Compound 4 can stimulate ACE2-293T cells to mobilize calcium at 10 ⁇ g/mL. With the increase of administration concentration, the degree of intracellular calcium fluctuation in ACE2-293T cells increases in a dose-dependent manner.
  • the calcium imaging results of compound 4 in ACE2-293T cells are shown in Figure 3.
  • Example 21 Effect of Compound 4 on the Content of Inflammatory Factors in the Lung Tissue of Mice Infected with Influenza Virus
  • Test method detection of inflammatory factors in mouse lung tissue (Elisa method)
  • Tissue homogenate sample After the lung tissue was weighed from the mouse, the lung tissue of the mouse was collected and stored at -4°C. After weighing 50 mg of lung tissue and adding 500 ⁇ L of normal saline, use an ultrasonic cell disruptor to homogenize the tissue, and use a low-temperature high-speed centrifuge to centrifuge at -4 °C at 1000 x g for 10 minutes. After aspirating the supernatant, aliquot it and store it in a -80°C refrigerator for future use. Avoid repeated freeze-thaw cycles.
  • Sample preparation The sample is diluted 2 times with diluent for detection, that is, 50 ⁇ L serum + 50 ⁇ L diluent.
  • Fig. 4 and Fig. 5 show that after the mice were infected with the influenza virus H1N1/FM1 strain, the contents of IFN- ⁇ and TNF-a in the lung tissue of the mice increased, which was significantly different from that of the normal control group (p ⁇ 0.01); After compound 4 was administered for 4 days, it could significantly reduce the contents of IFN- ⁇ and TNF-a in the lung tissue of infected mice, which was significantly different from that of the model control group (p ⁇ 0.01).
  • Example 22 Effect of Compound 4 on the Content of Inflammatory Factors in the Lung Tissue of Mice Infected with Coronavirus 229E
  • Lung tissue samples the therapeutic effect of compound 4 on a mouse model of pneumonia infected with human coronavirus 229E
  • Fig. 6 and Fig. 7 show that after adopting human coronavirus 229E to infect mice, the levels of IL-1 and IL-10 in the lung tissue of the mice increased, which was significantly different from that of the normal control group (p ⁇ 0.01); Compound 4 After 4 days of administration, it can significantly reduce the content of IL-1 and IL-10 in the lung tissue of infected mice, which is significantly different from that of the model control group (p ⁇ 0.01).
  • Example 23 Therapeutic effect of compounds of the present invention on human coronavirus 229E infected mouse pneumonia model
  • HCV-229E human coronavirus 229E
  • Human coronavirus 229E (HCoV-229E)
  • Human embryonic lung fibroblasts MRC5 were purchased from Beijing Bei Na Chuanglian Institute of Biotechnology, passaged in our laboratory, and stored in liquid nitrogen for future use.
  • TCID 50 50% cytopathic concentration
  • mice Take BALB/c mice and randomly divide them into normal control group, model control group, chloroquine phosphate control group, compound 4, compound 9, compound 10, and compound 11, each drug dose group, 10 mice in each group, male and female Half and half. Except for the normal control group, mice in other groups were lightly anesthetized with ether and infected with 100TCID 50 HCoV-229E nasal drops, 50 ⁇ l/mouse, once every other day, and infected twice in total. On the day of the first infection, each administration group was administered once a day for 4 consecutive days. After weighing the body weight one day after the last administration, the lungs were dissected and weighed, and the lung index and inhibition rate of the mice were calculated.
  • Lung index lung wet weight (g) ⁇ 100/body weight (g)
  • Table 10 The compound of the present invention is to the impact of human coronavirus 229E infection mouse pneumonia model
  • Ribavirin Granules Production unit Sichuan Baili Pharmaceutical Co., Ltd.
  • Indications This product is suitable for viral pneumonia and bronchitis caused by respiratory syncytial virus, and skin herpes virus infection.
  • Main ingredient Ribavirin.
  • Properties White or off-white soluble granules. Specifications: 50mg/bag, 18 bags/box. Usage and dosage: take orally, 150mg once, 3 times a day. Storage conditions: airtight, keep in a dry place.
  • Virus strain parainfluenza virus, purchased from ATCC in the United States, and stored at -80°C by our laboratory.
  • mice Take 150 ICR mice, SPF grade, weighing 13-15g, and divide them randomly into 15 groups according to body weight: normal control group, model control group, ribavirin group, compound 4, compound 9, compound 10, compound 11, compound 12.
  • Compound 2 has two dosage groups, 10 rats in each group, half male and half male. Except for the normal control group, mice in other groups were lightly anesthetized with ether, and were intranasally infected with 100 TCID 50 parainfluenza virus Sendai strain, 45 ⁇ l each. The mice in each group were given corresponding drugs after infection, and the normal control group and model control group were given distilled water under the same conditions for 4 consecutive days. On the 5th day, the mice were weighed and the lung tissue was separated and the lung weight was measured.
  • Lung index lung weight g ⁇ 100 / body weight g
  • Oseltamivir Phosphate Capsules (Tamiflu) Production Unit Hofme Roche Co., Ltd., Basel, Switzerland.
  • mice were randomly divided into 9 groups according to their body weight: normal control group, model control group, oseltamivir phosphate control group, compound 9, compound 12, and compound 2, each in 2 dose groups, with 10 mice in each group. Except for the normal control group, the mice were lightly anesthetized with ether, and infected with 15 LD 50 H1N1/PR8 influenza virus drops, 30 ⁇ l each. On the day of infection, administration was started, and 0.2ml/10g was administered by intragastric administration each time, once a day, for 4 consecutive days. The normal control group and the model control group were intragastrically administered with distilled water under the same conditions. On the 5th day, after weighing, the animals were dissected, the lungs were weighed, and the lung index and lung index inhibition rate were calculated. The results were statistically analyzed using the t-test for comparison between groups.
  • Lung index (%) lung wet weight (g) ⁇ 100/body weight (g)
  • mice after using human coronavirus 229E to infect mice, the lung index of the model control group mice significantly increased, which was significantly different from that of the normal control group (P ⁇ 0.05); the 15mg/kg/d of compound 12, 7.5 The lung index of the mice in the mg/kg/d dose group decreased significantly, and there was a significant difference compared with the model control group (P ⁇ 0.01, P ⁇ 0.05).
  • Embodiment 27 Mouse acute toxicity test of compound 4
  • mice with a body weight of 17-21g, were randomly divided into 7 groups according to fasting body weight: normal control group and 475, 633, 844, 1125, 1500, 2000 mg test substance/kg of the test drug (compound 4) 6 There are 10 dose groups in each group, half male and half male. After fasting for about 15 hours, each administration group was intragastrically administered once, with an administration volume of 40ml/kg, and the control group was intragastrically administered an equal volume of 0.5% sodium carboxymethylcellulose solution once/day, and continuous observation after administration Animal death within 14 days.
  • Compound 4 was administered to animals at doses of 475, 633, 844, 1125, 1500, and 2000 mg of test article/kg, once a day, and the main observed toxic reaction was acute death.
  • 1125mg test product/kg and above dose group occurred animal death after administration, 844mg test product/kg and below dose group did not appear animal death, animal death all occurred within 4 days after the drug, and the death peak was 24-24 after the drug. Within 48 hours.
  • the mortality rates of the animals in the above six dosage groups were 0%, 0%, 0%, 20%, 80% and 100%, respectively.
  • the LD 50 calculated by the Bliss method is 1299.054 mg of the test product/kg, and the 95% credible limit is 1152.937-1463.820 mg of the test product/kg; the maximum non-lethal dose is 844 mg of the test product/kg; The maximum no adverse reaction dose is 475mg test article/kg.
  • Embodiment 28 Mouse acute toxicity test of compound 12
  • ICR mice body weight 17-21g, were randomly divided into 3 groups according to fasting body weight: normal control group and test drug (compound 12) 2000mg, 4000mg test substance/kg dose group, 10 in each group, male and female Half and half. After about 15 hours of fasting, each administration group was intragastrically administered once, with an administration volume of 40ml/kg, and the control group was intragastrically administered an equal volume of 0.5% sodium carboxymethylcellulose solution once/day, and observed continuously for 14 hours after administration. Days of animal death.
  • Compound 12 was administered to animals with 2000, 4000 mg test product/kg dose, 1 time/day orally administered to animals, observed immediately after administration, and thereafter until the end of the observation period of 14 days, the general conditions, activities, gait, breathing, eating, No abnormalities were found in drinking water, stool, and fur. No animal died during the experiment.
  • the pharmacodynamic ratio of compound 4 was modified from the precursor 7-hydroxyl
  • the drug effect of isoflavones is stronger, but the drug effect of 7-hydroxy isoflavones is not very strong, indicating that the 7-position transformation strategy of the present invention about 7-hydroxy isoflavones has a very important impact on the antiviral drug effects of such isoflavone derivatives effect; while compound 4 is better than compound F2 (7-glycosidation strategy derivatives), compound F4 (7-position alkoxyalkoxy derivatives) and compound F5 (7-position amidoalkoxy derivatives) have stronger drug efficacy, indicating that compound 4 obtained through the transformation strategy of cycloalkylaminoalkoxy group has anti- Viruses work better.
  • Compound 4 has stronger antiviral efficacy than compound 5 and compound 7, indicating that the 7-position 2-(cyclopropylamino)ethoxy substituent derivative has better effect. It shows that the position and structure of the substituent have a very important impact on the antiviral efficacy of the 7-hydroxyisoflavone derivatives, and the experiment proves that the antiviral efficacy of the 7-position introducing 2-(cyclopropylamino)ethoxy substituent is the best. good.
  • Compound 9 and Compound 12 derived from Compound 4 also have strong drug effects, but Compound 10 and Compound 11 derived from Compound 4 have poor drug effects, indicating that cyclopropanyl and R in the general formula (I) 6
  • the structure of has a very important influence on the antiviral efficacy.
  • derivatives in which R 6 is an alkyl group or a substituted alkyl group have strong pharmacological activity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了通式I所示的一种新化合物及其药学上可接受的盐、溶剂化物以及包括其各种比例混合物在内的立体异构体以及含有所述化合物的药物组合物，R1a、R1b、R1c、R2、R3a、R3b、R4a、R4b、R5、R6、X1、X2、X3、A环等具有在说明书中给出的含义。本发明还涉及此类化合物的制备方法，并且还涉及该类化合物其药学上可接受的盐、溶剂化物、各种比例混合物在内的立体异构体的用途，特别是在制备抗病毒类药物中的用途。

Description

一种环烷氨基烷氧基取代的芳基并吡喃酮类化合物及其用途 技术领域
本发明一种新化合物及其药学上可接受的盐、溶剂化物、各种比例混合物在内的立体异构体以及含有所述化合物的药物组合物。本发明还涉及该类化合物其药学上可接受的盐、溶剂化物、各种比例混合物在内的立体异构体的用途，特别是在制备抗病毒药物中的用途。
背景技术
本领域已开发了一系列抗病毒药物，例如针对流感病毒的药物巴洛沙韦(Baloxavir marboxil)、帕拉米韦(Peramivir)、拉尼米韦(Laninamivir octanoate)、奥司他韦、(Oseltamivir phosphate)、扎那米韦(Zanamivir)、金刚乙胺(Rimantadine)、金刚烷胺(Amantadine)等，但针对副流感病毒、呼吸道合胞病毒、腺病毒、冠状病毒等呼吸道病毒尚无有效药物，需要采用广谱抗病毒药物，如利巴韦林，或者干扰素等。同时，针对新型冠状病毒肺炎常用洛匹那韦/利托那韦(lopinavir /ritonavir)、磷酸氯喹(chloroquine phosphate)、阿比多尔(arbidol)、达芦那韦(darunavir)、羟氯喹(hydroxychloroquine)、法匹拉韦(favipiravir)、瑞德西韦(remdesivir)等药物。上述抗病毒药物在治疗效果和使用安全性上仍有诸多不足，因此，本领域仍然需要开发新型的抗病毒治疗药物。
发明内容
本发明的目的在于提供一种异黄酮类衍生物及其药学上可接受的盐。
本发明的第一方面，提供一种式I所示的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物，
其中，X1、X2各自独立地选自下组：O、NR7；其中，所述的R7选自下组：氢、烷基、取代的烷基、芳基烷基、取代的芳基烷基、环烷基、取代的环烷基；
X3选自下组：O、NR8；其中，所述R8选自下组：氢、烷基；
R1a、R1b、R1c各自独立地选自下组：氢、羟基、烷氧基；
R2选自下组：取代或未取代的芳基，或取代或未取代的杂芳基；
R3a、R3b各自独立地选自下组：氢、烷基、卤素；
R4a、R4b各自独立地选自下组：氢、烷基、卤素；
R5选自下组：氢或烷氧基；
R6选自下组：氢、取代或未取代的烷基、取代或未取代的芳基烷基、氨基烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的C2-C6酰基、取代或未取代的烷氧基羰基、取代或未取代的氨基甲酰基，或(CH2)tR7；其中，t为1、2、3、4、5或6；其中，所述R7选自下组：C2-C6酰基、C2-C6酰胺基、芳基、杂芳基、环烷基、杂环基、NR8COR9；所述R8选自下组：氢、烷基；R9选自下组：烷基、芳基、杂芳基、环烷基、杂环基；
A环为取代或未取代的环烷基；
n为1、2、3、4、5、6、7、8、9或10；
其中，各个取代指基团上的氢原子被一个或多个选自下组的取代基替代：氰基、卤素、烷基、羟基、烷氧基、烯基、炔基、芳基、杂芳基；
并且，所述式I化合物不包括
上述各式中，除非特别说明，烷基为C1-C6的烷基、芳基为C6-C10的芳基、环烷基为C3-C8的环烷基、烷氧基为C1-C6的烷氧基、烯基为C2-C6的烯基、炔基为C2-C6的炔基、杂芳基为5-12元(较佳地为5-7元)的杂芳基。
在另一优选例中，X1为O；并且/或者
X2为O。
在另一优选例中，所述的R7选自下组：氢、烷基。
在另一优选例中，X3为O。
在另一优选例中，R1a、R1b、R1c各自独立地选自氢。
在另一优选例中，R2为取代或未取代的芳基，优选为取代或未取代的苯基。
在另一优选例中，R3a、R3b各自独立地选自下组：氢、C1-C4的烷基、卤素。
在另一优选例中，R4a、R4b各自独立地选自下组：氢、C1-C4的烷基、卤素。
在另一优选例中，R5选自氢或C1-C4烷氧基。
在另一优选例中，R6选自下组：氢、取代或未取代的烷基、取代或未取代的芳基烷基、氨基烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的C2-C6酰基、或(CH2)tR7；其中，t为1、2、3、4、5或6；R7选自下组：C2-C6酰基、C2-C6酰胺基、芳基NR8COR9，所述R8选自下组：氢、烷基；R9选自下组：烷基、芳基。
在另一优选例中，A环为取代或未取代的C3-C7环烷基，优选为C3-C6环烷基。
在另一优选例中，n为1、2、3或4。
在另一优选例中，所述的R6选自下组：氢、取代或未取代的烷基。
在另一优选例中，所说的R6选自下组：氢、未取代的烷基。
在另一优选例中，所述式I化合物具有式II所示的结构，
其中，R9a、R9b、R9c各自独立地选自下组：氢、羟基、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-12元杂芳基；
R10a、R10b、R10c、R10d、R10e各自独立地选自下组：氢、羟基、C1-C6烷氧基、卤素、氰基；
m为1、2、3、4或5。
在另一优选例中，式II所述化合物选自下组：
在另一优选例中，所述式I化合物具有式III所示的结构，
R11a、R11b、R11c各自独立地选自下组：氢、羟基、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6的烷氧基C6-C10芳基、5-12元杂芳基；
R12选自下组：取代或未取代的烷基、取代或未取代的芳基烷基、氨基烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的C2-C6酰基、取代或未取代的烷氧基羰基、取代或未取代的氨基甲酰基，或(CH2)tR7；其中，t为1、2、3、4、5或6；其中，所述R7选自下组：C2-C6酰基、C2-C6酰胺基、芳基、杂芳基、环烷基、杂环基、NR8COR9；所述R8选自下组：氢、烷基；R9选自下组：烷基、芳基、杂芳基、环烷基、杂环基；
R13a、R13b、R13c、R13d、R13e各自独立地选自下组：氢、羟基、烷氧基、卤素、 氰基。
在另一优选例中，式III所述化合物选自下组：

本发明的第二方面，提供一种药物组合物，所述药物组合物包含第一方面所述的化合物、或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体；以及药学上可接受的载体。
本发明的第三方面，提供一种式I化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物，本发明第二方面所述的药物组合物的用途，所述用途为用于制备药物组合物；
X1、X2各自独立地选自下组：O、NR7；其中，所述的R7选自下组：氢、烷基、取代的烷基、芳基烷基、取代的芳基烷基、环烷基、取代的环烷基；
X3选自下组：O、NR8；其中，所述R8选自下组：氢、烷基；
R1a、R1b、R1c各自独立地选自下组：氢、羟基、烷氧基；
R2选自下组：取代或未取代的芳基，或取代或未取代的杂芳基；
R3a、R3b各自独立地选自下组：氢、烷基、卤素；
R4a、R4b各自独立地选自下组：氢、烷基、卤素；
R5选自下组：氢或烷氧基；
R6选自下组：氢、取代或未取代的烷基、取代或未取代的芳基烷基、氨基烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的C2-C6酰基、取代或未取代的烷氧基羰基、取代或未取代的氨基甲酰基，或(CH2)tR7；其中， t为1、2、3、4、5或6；其中，所述R7选自下组：C2-C6酰基、C2-C6酰胺基、芳基、杂芳基、环烷基、杂环基、NR8COR9；所述R8选自下组：氢、烷基；R9选自下组：烷基、芳基、杂芳基、环烷基、杂环基；
A环为取代或未取代的环烷基；
n为1、2、3、4、5、6、7、8、9或10；
其中，各个取代指基团上的氢原子被一个或多个选自下组的取代基替代：氰基、卤素、烷基、羟基、烷氧基、烯基、炔基、芳基、杂芳基；
且所述的药物组合物用于选自下组的用途：
(1)改善，缓解或逆转由病毒感染引发的疾病或病症；
(2)作为SARS-Cov-2病毒ACE-2受体拮抗剂；
(3)作为感染后炎性细胞因子抑制剂。
在另一优选例中，所述的病毒选自下组：流感病毒、呼吸道合胞病毒、冠状病毒(如SARS-COV-2病毒)、副流感病毒。
在另一优选例中，所述的感染为病毒感染。
在另一优选例中，所述的病毒选自下组：流感病毒、呼吸道合胞病毒、冠状病毒(如SARS-COV-2病毒)、副流感病毒。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了化合物4对新型冠状病毒药效检测结果的折线图。
图2为本发明化合物的细胞膜色谱图。
图3为化合物4在ACE2-293T细胞中的钙成像结果图。
图4显示了化合物4对流感病毒FM1感染小鼠肺炎模型肺组织中INF-β含量的影响的柱状图。
图5显示了化合物4对流感病毒FM1感染小鼠肺炎模型肺组织中TNF-α含量 的影响的柱状图。
图6显示了化合物4对人冠状病毒229E感染小鼠肺炎模型肺组织IL-1含量的影响的柱状图。
图7显示了化合物4对人冠状病毒229E感染小鼠肺炎模型肺组织IL-10含量的影响的柱状图。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现本发明化合物在治疗多种病毒感染导致的疾病中具有优异的效果，从而对本发明化合物和多种已知抗病毒药物进行了对比实验。在此基础上完成了本发明。
定义
下面是本说明书中所用术语的定义。除非另外指出，本文所提供的基团或术语的初始定义适用于本书明说中单独地或作为其他基团的一部分的基团或者术语。
术语“取代的”是指本发明说明书中提到的任一取代基，包括但不限于，卤素、硝基、氰基、羧基、氧代基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷酰基氨基、芳酰基氨基、芳基烷基酰基氨基、杂芳基烷基酰基氨基、氨基烷基酰基氨基、烷基氨基烷基酰基氨基、二烷基氨基烷基酰基氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基、取代的烷酰基、芳酰基、杂芳酰基、羧基、烷氧基羰基、芳氧基羰基、烷氨基羰基、芳氨基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、取代的烷基氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。
术语“卤素”或“卤”是指氟、氯、溴、碘。
术语“烷基”是指直链或者支链未取代的具有1-20个碳原子、优选1-7个碳原子的烃基团。“烷基”的实例包括但是不要局限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-丁基等等。
术语“取代的烷基”是指由1-4个取代基取代的烷基，所述的取代基诸如：卤素、硝基、氰基、羧基、氧代基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。
术语“链烯基”是指具有2-20个碳原子、优选2-15个碳原子、最优选2-8个碳原子，且具有1-4个双键的直链或支链烃基团。
术语“取代的链烯基”是指由1-2个取代基取代的链烯基，所述取代基例如：卤素、硝基、氰基、芳基、取代的芳基、杂芳基、取代的杂芳基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)。
术语“炔基”是指具有2-20个碳原子、优选2-15个碳原子、最优选2-8个碳原子，且具有1-4个三键的直链或支链烃基团。
术语“取代的炔基”是指由以下取代基取代的炔基，所述取代基例如：卤素、硝基、氰基、芳基、取代的芳基、杂芳基、取代的杂芳基、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)。
术语“芳基”是指在环部分中具有6-12个碳原子的单环或双环芳烃基团。芳基包括二环基团，该二环将基团中包括稠合至饱和的或部分不饱和的芳族环，或者芳族碳环或杂环的环。通常芳基基团包括但是不局限于以下的基团：苯、萘、蒽、联苯基、1,2-二氢萘、1,2,3,4-四氢萘基等等。
术语“取代的芳基”是指由1-4个取代基取代的芳基，所述取代基例如：卤素、卤素、硝基、氰基、脲基、羧基、三氟甲氧基、三氟甲基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺 (其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)，烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。
术语“环烷基”是指非芳族的、饱和的或部分不饱和的环烃基团，所述环烷基可以任意地被一个或多个本申请所述的取代基取代，其具有3-30个碳原子成为单环的环，或者7-12个碳原子成为二环的环。单环环烷基的实例包括但是不局限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、环庚基、环辛基。示例性的成桥二环环烷基包括但是不局限于二环[2.2.1]庚烷、二环[2.2.2]辛烷、二环[3.2.2]壬烷。
术语“杂环”、“杂环的”和“杂环基”是指任选取代的、完全饱和的或不饱和的、芳族或非芳族环基团，例如它可以是4-7元单环、7-11元双环或10-15元三环体系，其在至少一个含碳原子的环中具有至少一个杂原子。含杂原子的杂环基的每个环可以具有1、2或3个选自氮原子、氧原子和硫原子的杂原子。所述“杂环基”可以任意地被一个或多个本申请所述的取代基取代，“杂环基”的实例包括但是不局限于吡咯烷基、四氢呋喃基、四氢吡喃基、吗啉代、硫吗啉代、哌嗪基、高哌嗪基、环氧丙烷基、咪唑烷基、3-氮杂二环[3.1.0]己烷基、3-氮杂二环[4.1.0]庚烷基、氮杂二环[2.2.2]己烷基、N-吡啶基脲、嘧啶酮基和1,1-二氧代-硫吗啉基。
术语“杂芳基”是指5-、6-、7-、8、9或10-元环的一价芳香基团，并且包括5-20个原子的稠合系统，含有一个或多个选自氮、氧、磷和硫的杂原子，可以任意地被一个或多个本申请所述的取代基取代。“杂芳基”的实例包括但是不局限于吡啶基、咪唑基、咪唑并吡啶基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、噻唑基、喹啉基、吲哚基等等。
术语“氧代基”代表二价基＝O。
术语“氨基甲酰基”是指-OC(＝O)NH2基团。
术语“酰胺”是指-C(＝O)NH2基团。
术语“磺酰胺基”是指-SO2NH2基团。
术语“取代的氨基甲酰基”、“取代的酰胺”、“取代的磺酰胺基”是指酰胺、磺酰胺或氨基甲酸酯分别至少有一个氢被选自烷基、取代的烷基、链烯基、取代的 链烯基、环烷基、取代的环烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基的基团所取代。
术语“可接受的盐”，是指本发明化合物的药学上可接受有机或无机盐。示例性的盐包括但是不局限于硫酸盐、枸橼酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、酸式硫酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式枸橼酸盐、琥珀酸盐、马来酸盐、延胡索酸盐、葡萄糖酸盐、甲酸盐、甲磺酸盐和巴莫酸盐。“可接受的盐”可涉及包括另一分子例如马来酸盐或其他平衡离子。平衡离子在母体化合物中稳定电荷。“可接受的盐”可以有多于一个的荷电原子，多个荷电原子可具有多个平衡离子。
如果本发明化合物是碱，需要的“可接受的盐”可通过适宜的方法制备，例如，用以下的无机酸处理该游离碱：盐酸、氢溴酸、硫酸、硝酸、磷酸；或者用如下的有机酸：乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、水杨酸、吡喃糖苷基酸如葡萄糖醛酸或半乳糖醛酸、α-羟基酸如枸橼酸或酒石酸、氨基酸如谷氨酸、芳香族酸如苯甲酸或肉桂酸、磺酸如甲磺酸或对甲苯磺酸。
如果本发明化合物是酸，需要的“可接受的盐”可通过适宜的方法制备，例如，用如下的无机碱或者有机碱处理该游离酸：胺、碱金属氢氧化物或碱土金属氢氧化物等。适宜的盐的示例性的示例包括但是不限于由氨基酸得到的有机盐，伯、仲、叔胺盐，以及环状胺例如哌啶、吗啉和哌嗪的盐，以及由钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到的无机盐。
溶剂合物是指一个或多个溶剂分子与本发明化合物的结合物或络合物。形成溶剂合物的溶剂的示例包括但是不局限于水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和乙醇胺。本发明化合物可以以非溶剂化形式存在，也可以与药学上可接受的溶剂如水、乙醇等以溶剂化形式存在，所以本发明将包括溶剂化和非溶剂化的形式。
本发明的化合物可以含有不对称中心或手性中心，并且因此存在不同的立体异构体形式。本发明化合物的所有立体异构体形式，包括但不局限于，非对映体、对映体和位阻异构体，以及它们的混合物例如外消旋混合物，将形成本发明的一部分。在本文中，当任何特定手性原子的立体化学未确定时，所有立体异构体均被考虑。此外，本发明涉及所有的几何和位置异构体。本发明化合物可以以不同 的互变异构体形式存在，并且所有这些形式均包括在本发明范围内。本发明化合物的所有立体异构体预期包括混合物形式或纯的或基本上纯的形式。可以通过物理方法例如分步结晶、非对映体衍生物的分离或结晶、或者通过手性柱层析分离来拆分。
本发明的化合物可以单独使用，或者与其他治疗剂联合使用。联合治疗可以提供协同作用，即当活性成分一起使用时达到的效果，大于分别使用所述化合物所产生效果的加和。
所述联合治疗可以以同时或连续的方案施用。当连续施用时，所述组合可以以两种或多种用法来施用。化合物可以再单一的药物组合中一起施用，或分开施用，且当分开施用时，可以同时地或以任意次序先后地进行。
本发明化合物可以通过适宜所治疗病况的任何途径施用。适宜的途径包括但是不局限于口腔、胃肠外(包括皮下、肌内、静脉内、动脉内、皮内)、阴道、腹膜内、肺内和鼻内。应当理解，优选的途径可以因例如病人的病况变化。当所述化合物经口施用时，可以将其与药学上可接受的载体或赋形剂配制成丸剂、胶囊剂、片剂等。当所述化合物配制成胃肠外时，其可以与药学上可接受的胃肠外载体配制。
本发明可以以任意方便的制剂形式施用化合物，本发明所称的“制剂”是指含有本发明通式I化合物的有利于给药(drug delivery)的剂型，如：但不仅限于，水溶液注射剂、粉针剂、丸剂、散剂、片剂、贴剂、栓剂、乳剂、霜剂、凝胶剂、颗粒剂、胶囊剂、气雾剂、喷雾剂、粉雾剂、缓释剂和控释剂等。这些药用辅料既可以是各种制剂中常规使用的，如：但不仅限于，等渗剂、缓冲液、矫味剂、赋形剂、填充剂、粘合剂、崩解剂和润滑剂等；也可以是为了与所述物质相适应而选择使用的，如：乳化剂、增溶剂、抑菌剂、止痛剂和抗氧剂等，这类辅料能有效提高组合物所含化合物的稳定性和溶解性或改变化合物的释放速率和吸收速率等，从而改善本发明化合物在生物体内的代谢，进而增强给药效果。此外，还可以为实现特定的给药目的或方式，如：缓释给药、控释给药和脉冲给药等，而使用的辅料，如：但不仅限于，明胶、白蛋白、壳聚糖、聚醚和聚酯类高分子材料，如：但不仅限于，聚乙二醇、聚氨酯、聚碳酸酯及其共聚物等。所称的“有利于给药”的主要表现有：但不仅限于提高治疗效果、提高生物利用度、降低毒副作 用和提高患者顺应性等。
在以下实施例中，仅以阐明本发明方法的方式给出本发明的部分实施例。然而，这些实施例不以任何方式限制本发明的范围，在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。也就是，结合所列举的实施方案来描述本发明时，应当理解为其无意将本发明限制为那些实施方案。相反，本发明意欲包括所有的变化、改良和等价形式。本领域技术人员会认识到与本申请所述的那些类似或等同的许多方法和物质，它们可以用于实现本发明。
在下文描述的实施例中，除非另外说明，所有温度均以摄氏度给出。除非另外说明，试剂从商业供应商购置或者定制，例如国药、韶远、安耐吉、TCI、Sigma等等。
实施例1 化合物1的合成
在50mL的圆底烧瓶中，称取底物(0.5mmol)，溶于27mL乙腈中，加入有机胺(5.0mmol)，加入K2CO3(1.0mmol)，加热回流过夜，TLC追踪反应结束。旋干溶剂，加入50mL水和100mL乙酸乙酯，分出有机层，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率38％。
实施例2 化合物2的合成
在50mL的圆底烧瓶中，称取底物(0.5mmol)，溶于27mL乙腈中，加入有机胺(5.0mmol)，加入K2CO3(1.0mmol)，加热回流过夜，TLC追踪反应结束。旋干溶剂，加入50mL水和100mL乙酸乙酯，分出有机层，无水Na2SO4干燥，有 机层并浓缩至干，硅胶柱层析，得到目标化合物，产率44％。
1H NMR(500MHz,CDCl3)δ8.23(d,J＝8.9Hz,1H),7.97(s,1H),7.58(dt,J＝3.1,1.8Hz,2H),7.53–7.34(m,3H),6.98(dt,J＝28.2,14.1Hz,1H),6.90(d,J＝2.3Hz,1H),4.47–4.06(m,2H),4.03–3.59(m,2H),2.86–2.72(m,1H),2.66–2.47(m,2H),1.18(t,J＝7.4Hz,3H),1.04–0.74(m,4H).
13C NMR(126MHz,DMSO)δ174.65,163.09,159.02,157.43,153.50,130.10,126.95,124.09,123.36,117.55,115.10,113.63,101.04,68.31,55.17,47.62,40.02,39.85,39.69,39.52,39.35,39.19,39.02,30.04,6.20.
实施例3 化合物3的合成
在50mL的圆底烧瓶中，称取底物(0.5mmol)，溶于27mL乙腈中，加入有机胺(5.0mmol)，加入K2CO3(1.0mmol)，加热回流过夜，TLC追踪反应结束。旋干溶剂，加入50mL水和100mL乙酸乙酯，分出有机层，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率42％。
实施例4 化合物4的合成
第1步：在1L的圆底烧瓶中加入化合物7-羟基异黄酮(0.040mol)，无水丙酮400mL，1,2-二溴乙烷(0.403mol)和碳酸钾(0.080mol)，加热回流过夜。TLC追踪反应结束，旋干溶剂，加入10mL水和300mL乙酸乙酯，分出有机层，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得白色固体7-(2-溴乙氧基)异黄酮12.98g，产率94％。
第2步：在50mL的圆底烧瓶中依次加入化合物7-(2-溴乙氧基)异黄酮(0.5mmol)，CH3CN 27mL和环丙胺(1.0mmol)，加入K2CO3(1.0mmol)，加热回流过夜，TLC追踪反应结束。旋干溶剂，加入50mL水和100mL乙酸乙酯，分 出有机层，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率53％。
1HNMR(400MHz,DMSO)δ8.46(s,1H),8.04(d,J＝8.8Hz,1H),7.64–7.35(m,5H),7.16(s,1H),7.09(d,J＝8.8Hz,1H),4.17(t,J＝5.4Hz,2H),2.99(t,J＝5.3Hz,2H),2.23–2.09(m,1H),0.46–0.18(m,4H).
13CNMR(101MHz,DMSO)δ174.4,163.1,157.4,154.1,132.0,128.9,128.1,127.8,127.0,123.8,117.6,115.1,101.1,68.3,47.6,30.0,6.2.
HRMS(ESI):m/z，calcd for[M+H]+:322.1438；found:322.1439.
实施例5 化合物5的合成
在50mL的圆底烧瓶中依次加入化合物7-(2-溴乙氧基)异黄酮(0.5mmol)，CH3CN 27mL和1-甲基-环丙胺(1.0mmol)，加入K2CO3(1.0mmol)，加热回流过夜，TLC追踪反应结束。旋干溶剂，加入50mL水和100mL乙酸乙酯，分出有机层，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率37％。
1H NMR(500MHz,CDCl3)δ8.20(d,J＝8.9Hz,1H),7.93(s,1H),7.63–7.49(m,2H),7.47–7.40(m,2H),7.40–7.33(m,1H),6.99(dd,J＝8.9,2.4Hz,1H),6.85(d,J＝2.3Hz,1H),4.14(t,J＝5.3Hz,2H),3.13(t,J＝5.3Hz,2H),1.32(s,3H),0.71–0.57(m,2H),0.48–0.36(m,2H).
13C NMR(126MHz,CDCl3)δ175.73,163.36,157.97,152.80,132.06,129.09,128.58,128.22,127.91,125.38,118.61,115.00,100.81,68.75,44.82),34.98,22.10,14.60.
HRMS(ESI):m/z[M+H]+calcd forC21H22NO3 +:326.1600；found:336.1529。
实施例6 化合物6的合成
在50mL的圆底烧瓶中，称取底物(0.5mmol)，溶于27mL乙腈中，加入有机 胺(5.0mmol)，加入K2CO3(1.0mmol)，加热回流过夜，TLC追踪反应结束。旋干溶剂，加入50mL水和100mL乙酸乙酯，分出有机层，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率32％。
实施例7 化合物7的合成
在50mL的圆底烧瓶中依次加入化合物7-(2-溴乙氧基)异黄酮(0.5mmol)，CH3CN 27mL和环己胺(1.0mmol)，加入K2CO3(1.0mmol)，加热回流过夜，TLC追踪反应结束。旋干溶剂，加入50mL水和100mL乙酸乙酯，分出有机层，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率45％。
1H NMR(400MHz,DMSO)δ8.46(s,1H),8.03(d,J＝8.9Hz,1H),7.72–7.30(m,5H),7.17(s,1H),7.09(d,J＝8.9Hz,1H),4.16(t,J＝5.4Hz,2H),2.95(t,J＝5.4Hz,2H),2.43(t,J＝10.0Hz,1H),2.33(d,J＝65.9Hz,1H),1.88–1.49(m,5H),1.26–0.98(m,5H).
13C NMR(101MHz,DMSO)δ174.4,163.1,157.4,154.2,132.0,128.9,128.1,127.8,127.0,123.8,117.6,115.2,101.1,68.6,56.0,44.7,32.6,25.8,24.4.
HRMS(ESI):m/z[M+H]+calcd forC23H26NO3 +:364.1907；found:364.1909.
实施例8 化合物8的合成
在50mL的圆底烧瓶中，称取底物(0.5mmol)，溶于27mL乙腈中，加入有机胺(5.0mmol)，加入K2CO3(1.0mmol)，加热回流过夜，TLC追踪反应结束。旋干溶剂，加入50mL水和100mL乙酸乙酯，分出有机层，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率32％。
实施例9 化合物9的合成
在50mL的圆底烧瓶中依次加入化合物4(2mmol)，溶解于20ml甲醇中，再加入多聚甲醛(20mmol)、氰基硼氢化钠(10mmol)以及乙酸(4mmol)，室温搅拌过夜，TLC追踪反应结束。旋干溶剂，加入饱和碳酸钠溶液100ml和200mL乙酸乙酯，分出有机层，饱和氯化钠洗涤，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率72％。
1H NMR(500MHz,CDCl3)δ8.22(d,J＝5.7Hz,1H),7.86(d,J＝91.6Hz,1H),7.43(dd,J＝82.0,59.1Hz,5H),7.03(s,1H),6.88(s,1H),4.22(s,2H),3.04(s,2H),2.50(s,3H),1.78(s,1H),0.51(d,J＝16.3Hz,4H).
13C NMR(126MHz,CDCl3)δ175.63,163.31,157.91,152.67,132.02,129.01,128.49,128.13,127.77,125.26,118.46,115.03,100.76,66.55,56.67,43.70,38.66,6.91..
HRMS(ESI):m/z[M+H]+calcd forC21H22NO3 +:336.16；found:336.1672.
实施例10 化合物10的合成
在50mL的圆底烧瓶中依次加入化合物4(2mmol)，溶解于20ml吡啶中，再加入乙酸酐(20mmol)，室温搅拌过夜，TLC追踪反应结束。旋干溶剂，加入1M盐酸100ml和200mL乙酸乙酯，分出有机层，1M盐酸洗涤，饱和碳酸氢钠洗涤洗涤，饱和氯化钠洗涤，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率81％。
1H NMR(500MHz,CDCl3)δ8.25(t,J＝29.2Hz,1H),7.96(s,1H),7.55(t,J＝18.2Hz,2H),7.45(t,J＝7.4Hz,2H),7.39(t,J＝7.3Hz,1H),6.98(dt,J＝21.9,10.9Hz,1H),6.90(d,J＝1.9Hz,1H),4.47–4.11(m,2H),3.78(dt,J＝30.5,5.4Hz,2H),2.99–2.63(m,1H),2.35–1.98(m,3H),1.09–0.68(m,4H).
13C NMR(126MHz,CDCl3)δ175.63,174.16,163.08,157.95,152.76,131.98,129.02,128.51,128.16,127.87,125.29,118.59,114.91,100.72,66.40,46.77,32.17,22.82,9.79.
实施例11 化合物11的合成
在50mL的圆底烧瓶中依次加入化合物4(2mmol)，溶解于20ml吡啶中，再加入丙酸酐(20mmol)，室温搅拌过夜，TLC追踪反应结束。旋干溶剂，加入1M盐酸100ml和200mL乙酸乙酯，分出有机层，1M盐酸洗涤，饱和碳酸氢钠洗涤洗涤，饱和氯化钠洗涤，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率83％。
1H NMR(500MHz,CDCl3)δ8.23(d,J＝8.9Hz,1H),7.97(s,1H),7.58(dt,J＝3.1,1.8Hz,2H),7.53–7.34(m,3H),6.98(dt,J＝28.2,14.1Hz,1H),6.90(d,J＝2.3Hz,1H),4.47–4.06(m,2H),4.03–3.59(m,2H),2.86–2.72(m,1H),2.66–2.47(m,2H),1.18(t,J＝7.4Hz,3H),1.04–0.74(m,4H).
13C NMR(126MHz,CDCl3)δ177.35,175.70,163.17,158.02,152.79,132.03,129.07,128.56,128.21,127.93,125.36,118.62,114.97,100.75,66.53,47.02,31.41,27.56,9.73,9.23.
实施例12 化合物12的合成
在50mL的圆底烧瓶中依次加入化合物4(2mmol)，溶解于20ml甲醇中，再加入丙酮(20mmol)、氰基硼氢化钠(10mmol)以及乙酸(4mmol)，室温搅拌过夜，TLC追踪反应结束。旋干溶剂，加入饱和碳酸钠溶液100ml和200mL乙酸乙酯，分出有机层，饱和氯化钠洗涤，无水Na2SO4干燥，有机层并浓缩至干，硅胶柱层析，得到目标化合物，产率75％。
1H NMR(500MHz,CDCl3)δ8.21(d,J＝8.9Hz,1H),7.95(s,1H),7.60–7.52(m,2H),7.44(dd,J＝10.2,4.7Hz,2H),7.41–7.35(m,1H),6.99(dd,J＝8.9,2.3Hz,1H), 6.86(d,J＝1.6Hz,1H),4.15(s,2H),3.14(s,1H),3.03(s,2H),1.98(s,1H),1.10(s,6H),0.49(d,J＝37.0Hz,4H).
1H NMR(500MHz,MeOD)δ8.25(s,1H),8.13(d,J＝9.3Hz,1H),7.58–7.52(m,2H),7.44(t,J＝7.4Hz,2H),7.41–7.36(m,1H),7.11–7.06(m,2H),4.25(t,J＝6.1Hz,2H),3.22–3.13(m,1H),3.07(t,J＝6.1Hz,2H),2.11–1.92(m,1H),1.14(d,J＝6.7Hz,6H),0.59–0.52(m,2H),0.49–0.43(m,2H).
13C NMR(126MHz,CDCl3)δ175.71,163.51,158.03,152.69,132.10,129.08,128.55,128.17,127.84,125.33,118.44,115.09,100.76,68.10,53.25,49.13,34.54,18.97,7.23.
HRMS(ESI):m/z[M+H]+calcd forC23H26NO3 +:364.1913；found:364.1906.
下文表中或者图中出现的化学结构如下所示：

实施例13：本发明化合物对甲型H1N1流感病毒FM1株感染小鼠肺炎模型的治疗作用
1试验材料
1.1受试药物：化合物4、化合物F1、化合物F2、化合物F3
1.2阳性对照药
利巴韦林颗粒：生产单位：四川百利药业有限责任公司。适应症：本品适用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎，皮肤疱疹病毒感染。主要成分：利巴韦林。性状：白色或类白色可溶颗粒。规格：50mg/袋，18袋/盒。用法用量：口服，一次150mg，一日3次。储存条件：密闭，在干燥处保存。
1.3试验动物
1.4病毒株
1.5试验仪器
2试验方法
2.1剂量设计及配制
受试药物
利巴韦林颗粒
2.2造模及给药
取ICR小鼠，按体重等级随机分为：正常对照组、模型对照组、利巴韦林对照组、化合物4、化合物F1、化合物F2、化合物F3每个药物均为二个剂量组，每组10只。除正常对照组外，将小鼠用乙醚轻度麻醉，以15个LD50H1N1流感病毒液FM1株滴鼻感染，每只30μl。感染当天开始给药，每次按0.2ml/10g灌胃，每天1次，连续4天，正常对照组和模型对照组在同等条件下蒸馏水灌胃。第5天称重后解剖，称肺重，计算肺指数及肺指数抑制率。结果采用组间比较t检验进行统计学处理。
肺指数(％)＝肺湿重(g)×100/体重(g)
3试验结果
表1 本发明化合物对流感病毒H1N1/FM1株感染小鼠肺炎模型的治疗作用
注：与正常组比较##P<0.01；与模型对照组比较，*P<0.05
表1结果显示：采用甲型H1N1流感病毒FM1株病毒感染小鼠后，小鼠肺指数明显增高，与正常对照组比较具有显著性差异(P<0.01)；感染当天开始给予化合物4、化合物F1、化合物F2、化合物F3治疗4天后，化合物4的50mg/kg/d剂量组可明显降低小鼠感染后肺指数，与模型对照组比较有显著性差异(P<0.05)；化合物F1的50mg/kg有降低肺指数趋势；化合物F2、化合物F3对小鼠肺指数无明显影响。化合物4的药效比化合物F1药效更强，说明7位取代基对于此类异黄酮衍生物的抗流感病毒药效具有很重要的影响；而化合物4比化合物F2、化合物F3的药效更强，说明取代基的位置以及结构对于此类异黄酮衍生物的抗流感病毒药效具有很重要的影响。
实施例14：本发明化合物对甲型H1N1流感病毒FM1株、PR8感染小鼠肺炎 模型的治疗作用
1试验材料
1.1受试药物：化合物4、化合物F4、化合物F5、化合物5、化合物7
1.2阳性对照药
磷酸奥司他韦胶囊(达菲) 生产单位：瑞士巴塞尔豪夫迈·罗氏有限公司。适应症：用于成人和1岁及1岁以上儿童的甲型和乙型流感的治疗；用于成人和13岁及13岁以上青少年的甲型和乙型流感的预防。主要成分：磷酸奥司他韦。性状：本品为灰色和淡黄色胶囊，内容物为白色至黄白色粉末，可含有块状物。规格：以奥司他韦计，75mg/粒，10粒/盒。用法用量：口服，成人和13岁及13岁以上青少年，每次75mg，每日2次，共5天。储存条件：密封保存。
1.3试验动物
1.4病毒株
1.5试验仪器
2试验方法
2.1剂量设计及配制
受试药物
磷酸奥司他韦胶囊
2.2试验步骤
取ICR小鼠，按体重等级随机分为：正常对照组、模型对照组、奥司他韦对照组、化合物4、化合物F4、化合物F5、化合物5、化合物7每个药物二个剂量组，每组10只。除正常对照组外，将小鼠用乙醚轻度麻醉，以15个LD50H1N1流感病毒液(FM1/PR8株)滴鼻感染，每只30μl。感染当天开始给药，每次按0.2ml/10g灌胃，每天1次，连续4天，正常对照组和模型对照组在同等条件下蒸馏水灌胃。第5天称重后解剖，称肺重，计算肺指数及肺指数抑制率。结果采用组间比较t检验进行统计学处理。
肺指数(％)＝肺湿重(g)×100/体重(g)
3试验结果
表2 本发明化合物对流感病毒H1N1/FM1株感染小鼠肺炎模型的治疗作用

注：与正常组比较##P<0.01；与模型对照组比较，**P<0.01，*P<0.05
表2结果显示：采用甲型H1N1流感病毒FM1株病毒感染小鼠后，小鼠肺指数明显增高，与正常对照组比较具有显著性差异(P<0.01)；感染当天开始给予本发明化合物治疗4天后，化合物4在40mg/kg/d剂量可明显降低小鼠感染后肺指数，与模型对照组比较有显著性差异(P<0.01)，肺指数抑制率为54.04％；化合物7的40mg/kg/d剂量有降低肺指数的趋势。但是，化合物F4、化合物F5、化合物5对感染后小鼠肺指数无降低作用。化合物F4、化合物F5、化合物5、化合物7相对于化合物4的药效都在下降，其中，化合物F4、化合物F5为化合物4在生物体内的代谢物，化合物5为7位2-(1-甲基环丙胺基)乙氧基取代基衍生物、化合物7为7位2-(环己胺基)乙氧基取代基衍生物，证明7位2-(环丙胺基)乙氧基取代基对于此类异黄酮衍生物的药效具有很重要的影响作用。
表3 本发明化合物4对流感病毒H1N1/PR8株感染小鼠肺炎模型的治疗作用

注：与正常组比较##P<0.01；与模型对照组比较，*P<0.05，**P<0.01
表3结果显示：采用甲型H1N1流感病毒PR8株感染小鼠后，小鼠肺指数明显增高，与正常对照组比较具有显著性差异(P<0.01)；感染当天开始给予化合物4治疗4天后，化合物4在15mg/kg/d剂量可明显降低小鼠感染后肺指数，与模型对照组比较有显著性差异(P<0.01)，肺指数抑制率为60.27％；27.5mg/kg/d剂量的奥司他韦抑制率为58.89％。
实施例15：本发明化合物对人类冠状病毒229E感染小鼠肺炎模型的治疗作用
1试验材料
1.1受试药物：化合物4、化合物F1、化合物F2、化合物F3。
1.2阳性药物：磷酸氯喹片，四川升和药业股份有限公司。规格：0.25g/片，用法用量：0.5g/60kg/d，口服。
1.3实验动物
1.4毒株及细胞：人冠状病毒229E(HCoV-229E)，由中国医学科学院医药生物技术研究所提供，本实验室传代，-80℃冰箱保存备用。人胚肺成纤维细胞MRC5，购自北京北纳创联生物技术研究院，本实验室传代，液氮保存备用。
1.5试验仪器

2试验方法
2.1药物剂量设计及配制
受试药物
磷酸氯喹片
2.2病毒传代
取已长成单层MRC-5细胞的25cm2培养瓶，弃掉培养液，用细胞维持液冲洗细胞面3遍后，加入细胞维持液5ml，再加入HCoV-229E病毒液200μl，置37℃5％CO2培养箱中培养72～96h，每日倒置显微镜下观察细胞病变情况，直至80％细胞出现明显病变(CPE)后，将细胞培养瓶置于-80℃低温冰箱冻存，病毒液反复冻融3次后，用于病毒滴度测定。
2.3病毒滴度测定
取已长成单层MRC5细胞的96孔板，弃掉培养液，用细胞维持液冲洗细胞3遍后，按10倍倍比(10-1～10-8)稀释接种不同滴度的HCoV-229E病毒液，共8个稀释度，100μl/孔，每个稀释度做4个复孔，同时设正常细胞对照。96孔板置37℃、5％CO2培养箱中培养72～96h，每日倒置显微镜下观察细胞病变情况，并记录各孔的细胞病变情况。按Reed-Muench法计算50％细胞病变浓度(TCID50)。
2.4人冠状病毒肺炎小鼠模型构建及给药
取BALB/c小鼠，按体重随机分为正常对照组，模型对照组，磷酸氯喹对照组，化合物4、化合物F1、化合物F2、化合物F3每个药物二个剂量组，每组10只，雌雄各半。除正常对照组外，其他各组小鼠乙醚轻度麻醉后，用100TCID50HCoV-229E滴鼻感染，50μl/只，隔日1次，共感染2次。初次感染当天，各给药 组给药，每天1次，连续4天。末次给药后一天称量体重后，解剖取肺并称量肺重，计算小鼠肺指数及抑制率。
3试验结果
表4 本发明化合物对人冠状病毒229E感染小鼠肺炎模型的影响
注：与正常对照组比较##P<0.01；与模型对照组比较**P<0.01。
表4结果显示：采用人冠状病毒229E感染小鼠后，模型对照组小鼠肺指数显著增加，与正常对照组比较有显著性差异(P<0.01)；化合物4在50mg/kg、40mg/kg剂量组小鼠肺指数显著降低，与模型对照组比较有显著性差异(P<0.05)，抑制率分别为41.00％、41.85％。化合物F1、化合物F2、化合物F3对小鼠肺指数无明显影响。化合物4的药效比化合物F1药效更强，说明7位取代基对于此类异黄酮衍生物的抗冠状病毒药效具有很重要的影响作用；而化合物4比化合物F2、化合物F3的药效更强，说明取代基的位置以及结构对于此类异黄酮衍生物的抗冠状病毒药效具有很重要的影响。
实施例16：本发明化合物对冠状病毒229E感染小鼠肺炎模型的影响
试验试剂、试验仪器、试验方法同上。
受试样品：化合物4、化合物F4、化合物F5、化合物5、化合物7
动物合格证：BALB/c小鼠1100112011066562881/718
表5 本发明化合物对冠状病毒229E感染肺炎小鼠模型的影响
注：与正常对照组比较##P<0.01；与模型对照组比较**P<0.01、*P<0.05
表5结果显示：采用人冠状病毒229E感染小鼠后，小鼠肺指数明显增高，与正常对照组比较具有显著性差异(P<0.01)；感染当天开始给予本发明化合物治疗4天后，化合物4在30mg/kg/d、15mg/kg/d、7.5mg/kg/d剂量可明显降低小鼠感染后肺指数，与模型对照组比较均有显著性差异(P<0.01、P<0.05)，肺指数抑制率分别为86.46％、76.52％、44.34％；化合物7的15mg/kg/d剂量可降低肺 指数，与模型对照组比较有显著性差异(P<0.05)，抑制率为41.56％；化合物F4、化合物F5、化合物5对小鼠感染后肺指数无降低作用。化合物F4、化合物F5、化合物5、化合物7相对于化合物4的药效都在下降，证明7位2-(环丙胺基)乙氧基取代基对于此类异黄酮衍生物的抗冠状病毒药效具有很重要的影响作用。
实施例17：化合物4对人类冠状病毒OC43感染小鼠肺炎模型的治疗作用
试验试剂、试验仪器、试验方法同上。
受试样品：化合物4
动物合格证：BALB/c小鼠110011211110038632
表6 本发明化合物4对人冠状病毒OC43感染小鼠肺炎模型的影响
注：与正常对照组比较##P<0.01；与模型对照组比较**P<0.01。
表6结果显示：采用人冠状病毒OC43病毒感染小鼠后，小鼠肺指数明显增高，与正常对照组比较具有显著性差异(P<0.01)；感染当天开始给予化合物4治疗4天后，化合物4在15mg/kg/d剂量可明显降低小鼠感染后肺指数，与模型对照组比较均有显著性差异(P<0.05)，肺指数抑制率为在47.43％；90mg/kg/d剂量的磷酸氯喹抑制率为42.72％。
实施例18：本发明化合物4对副流感病毒感染小鼠肺炎模型的影响
1试验材料
1.1受试药物：化合物4
1.2利巴韦林颗粒 生产单位：四川百利药业有限责任公司。适应症：本品适 用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎，皮肤疱疹病毒感染。主要成分：利巴韦林。性状：白色或类白色可溶颗粒。规格：50mg/袋，18袋/盒。用法用量：口服，一次150mg，一日3次。储存条件：密闭，在干燥处保存。
1.3试验动物
1.4病毒株：副流感病毒，购自美国ATCC，由本研究室-80℃保存。
1.5试验仪器
2试验方法
2.1剂量设计及配制
受试药物
利巴韦林颗粒

2.2造模及给药
取ICR小鼠60只，SPF级，体重13～15g，按体重随机分为6组：正常对照组、模型对照组、利巴韦林组、化合物4三个剂量组，每组10只，雌雄各半。除正常对照组外，其他各组小鼠乙醚轻度麻醉后，滴鼻感染100TCID50副流感病毒仙台株，每只45μl。各组小鼠于感染后给予相应的药物，正常对照组、模型对照组在同等条件下给予蒸馏水，连续给药4天。第5天，小鼠称重后分离肺组织后称量肺重。
肺指数＝肺重×100/体重，
表7 化合物4对副流感病毒感染小鼠肺炎模型的影响
注：与正常对照组比较##P<0.01；与模型对照组比较*P<0.05
表7结果显示：采用副流感病毒感染小鼠后，模型对照组小鼠肺指数显著增加，与正常对照组比较有显著性差异(P<0.01)；化合物4的15mg/kg剂量组小鼠肺指数显著降低，与模型对照组比较有显著性差异(P<0.05)，三个剂量组有良好的量效相关性，化合物4高剂量组抑制率为46.39％。
实施例19：本发明化合物4在体外抗新型冠状病毒(SARS-CoV-2)作用
1试验材料
1.1受试药物：化合物4
1.2细胞株：VeroE6细胞，由广州呼吸健康研究院呼吸疾病国家重点实验室病毒室保存。
1.3病毒株：SARS-CoV-2,滴度为TCID50＝10-6/100μL，由广州海关技术中心卫生检疫研究所国家生物安全检测重点实验室(P3实验室)-80℃保存；使用病毒滴度为100TCID50。
2试验方法
2.1样品准备
药物名称、实验浓度和分组
2.2受试药物抗病毒实验
①无菌96孔培养板，每孔加入100μL浓度为2×105cells/mL VeroE6细胞，37℃5％CO2培养24小时；
②培养板实验组和病毒对照组加入100TCID50病毒液100μL/孔，37℃，5％CO2培养箱吸附2h；
③2h后，弃去96孔培养板中细胞培养液；受试药物稀释成表1中的各个浓度，每个浓度3个复孔，100μl/孔加入上述药液；
④同时设立细胞对照、空白对照(溶剂对照)和病毒对照(阴性对照)；
⑤细胞37℃,5％C02孵箱孵育3～4天；
⑥光学显微镜下观察细胞病变(CPE)，细胞出现病变程度按以下6级标准记录：“-”无病变出现；“±”为细胞病变少于10％；“+”为细胞病变约25％；“++”为细胞病变约50％；“+++”为约75％的细胞出现病变：“++++”为75％以上病变。采用Reed-Muench法或GraphPad Prism5.0计算半数有效浓度(IC50)。判断药效标准：具有50％的抑制病毒CPE的浓度视为有效浓度。
3试验结果
通过观察细胞病变(CPE)并记录实验结果，采用Reed-Muench法或GraphPad Prism5.0计算半数有效浓度(IC50)，实验结果如下
表8 化合物4抗新型冠状病毒药效结果
化合物4对新型冠状病毒药效检测结果如图1所示。
表8结果显示：药物化合物4在体外对新型冠状病毒(SARS-CoV-2)感染Vero E6细胞致细胞病变有抑制作用。
实施例20：本发明化合物4体外抗SARS-Cov-2作用机制研究
1.与293T细胞ACE2受体结合作用
试验目的：观察受试样品与ACE-2受体的结合作用，寻找可能的作用机制。
仪器与材料
受试药物：化合物4、化合物F1、化合物F2、化合物F3
SHIMADZU LC-2040C 3D高效液相色谱仪(日本)；Sartorius 1712型电子分析天平；富勒姆FCR1002-UF超纯水制备机(青岛富勒姆科技有限公司)；SHZ-D(Ⅲ)型循环水真空泵(巩义市英峪予华仪器厂)；SB-5200DTD超声波清洗仪(宁波新芝生物科技股份有限公司)；移液器(德国Eppendorf)。
ACE2受体高表达的293T细胞系实验室构建。
甲醇为色谱纯，水为超纯水，其它试剂均为分析纯。
试验方法
样品与293T细胞ACE2受体结合作用
样品制备
精密称取本发明化合物4、化合物F1、化合物F2、化合物F3各5mg，用色谱纯甲醇使其充分溶解，转移至10mL量瓶中，定容，得到浓度为0.5mg/mL的 本发明化合物系列药品储备液，避光冷藏备用；用时稀释至所需浓度，储备液每周新鲜配制。
CMC色谱条件
ACE2-293T/CMC细胞膜色谱柱(10×2.0mm)，流动相为水，流速0.2mL/min，柱温为37℃，进样量为10μL，DAD检测。阳性对照：磷酸氯喹。
试验结果
本发明化合物的细胞膜色谱图如图2所示。
表9 样品和磷酸氯喹的KD值
2.化合物4对ACE2-293T细胞功能学影响评价
试验方法：胞内Ca2+流变化检测：将细胞接入96孔板，过夜后，弃去培养基，用CIB清洗，加入Fluo-3，AM孵育液在培养箱内孵育40min后，弃孵育液，用CIB清洗，于荧光显微镜下，弃CIB后每孔依次加药，观察加药前后细胞荧光强度变化，在荧光显微镜下持续观察2min，开始拍照观察后10s时加药刺激。
试验结果：胞内Ca2+流变化：化合物4在10μg/mL下可刺激ACE2-293T细胞发生钙动员，随着给药浓度的增加，ACE2-293T细胞内钙波动程度呈剂量依赖性增强。化合物4在ACE2-293T细胞中的钙成像结果图如图3所示。
实施例21：化合物4对流感病毒感染小鼠肺脏组织中炎性因子含量的影响
肺组织样本：化合物4对流感病毒H1N1/FM1株感染小鼠肺炎模型的治疗作用
试验方法：小鼠肺组织中炎性因子检测(Elisa法)
组织匀浆液样本：小鼠取肺组织称重后，收集小鼠肺组织，-4℃保存。称量50mg肺组织加入500μL生理盐水后，使用超声细胞破碎仪匀浆组织，使用低温高速离心机-4℃1000x g离心10分钟。吸取上清液之后分装，保存于-80℃冰箱贮存备用。避免反复冻融。
样本准备工作：样本用稀释剂2倍稀释后进行检测，即50μL血清+50μL稀释剂。
从已平衡至室温的密封袋中取出微孔板，分别将不同浓度标准品，实验样本或 者质控品加入相应孔中，每孔100μL。用封板胶纸封住反应孔，室温孵育2小时。用洗液洗板，重复操作4次。最后一次洗板结束，将板倒置，在吸水纸拍干所有残留液体；在每个微孔内加入100μL酶标检测抗体。用封板胶纸封住反应孔，室温孵育2小时。重复第4步洗板操作，在每个微孔内加入100μL显色底物，室温孵育30分钟。注意避光。在每个微孔内加入100μL终止液后30分钟内，使用酶标仪测量450nm的吸光度值。计算结果。
图4、图5结果显示：采用流感病毒H1N1/FM1株感染小鼠后，小鼠肺组织中IFN-β及TNF-a含量增高，与正常对照组比较有显著性差异(p<0.01)；化合物4给药4天后，可明显降低感染后小鼠肺组织中IFN-β及TNF-a含量，与模型对照组比较有显著性差异(p<0.01)。
实施例22：化合物4对冠状病毒229E感染小鼠肺脏组织中炎性因子含量的影响
肺组织样本：化合物4对人冠状病毒229E感染小鼠肺炎模型的治疗作用
图6、图7结果显示：采用人冠状病毒229E感染小鼠后，小鼠肺组织中IL-1及IL-10含量增高，与正常对照组比较有显著性差异(p<0.01)；化合物4给药4天后，可明显降低感染后小鼠肺组织中IL-1及IL-10含量，与模型对照组比较有显著性差异(p<0.01)。
实施例23 本发明化合物对人类冠状病毒229E感染小鼠肺炎模型的治疗作用
1试验材料
1.1受试药物：化合物4、化合物9、化合物10、化合物11、化合物F1。
1.2阳性药物：磷酸氯喹片，四川升和药业股份有限公司。规格：0.25g/片，用法用量：0.5g/60kg/d，口服。
1.3实验动物

1.4毒株及细胞：人冠状病毒229E(HCoV-229E)，由中国医学科学院医药生物技术研究所提供，本实验室传代，-80℃冰箱保存备用。人胚肺成纤维细胞MRC5，购自北京北纳创联生物技术研究院，本实验室传代，液氮保存备用。
1.5试验仪器
2试验方法
2.1药物剂量设计及配制
受试药物
磷酸氯喹片
2.2病毒传代
取已长成单层MRC-5细胞的25cm2培养瓶，弃掉培养液，用细胞维持液冲洗 细胞面3遍后，加入细胞维持液5ml，再加入HCoV-229E病毒液200μl，置37℃5％CO2培养箱中培养72～96h，每日倒置显微镜下观察细胞病变情况，直至80％细胞出现明显病变(CPE)后，将细胞培养瓶置于-80℃低温冰箱冻存，病毒液反复冻融3次后，用于病毒滴度测定。
2.3病毒滴度测定
取已长成单层MRC5细胞的96孔板，弃掉培养液，用细胞维持液冲洗细胞3遍后，按10倍倍比(10-1～10-8)稀释接种不同滴度的HCoV-229E病毒液，共8个稀释度，100μl/孔，每个稀释度做4个复孔，同时设正常细胞对照。96孔板置37℃、5％CO2培养箱中培养72～96h，每日倒置显微镜下观察细胞病变情况，并记录各孔的细胞病变情况。按Reed-Muench法计算50％细胞病变浓度(TCID50)。
2.4人冠状病毒肺炎小鼠模型构建及给药
取BALB/c小鼠，按体重随机分为正常对照组，模型对照组，磷酸氯喹对照组，化合物4、化合物9、化合物10、化合物11每个药物1个剂量组，每组10只，雌雄各半。除正常对照组外，其他各组小鼠乙醚轻度麻醉后，用100TCID50HCoV-229E滴鼻感染，50μl/只，隔日1次，共感染2次。初次感染当天，各给药组给药，每天1次，连续4天。末次给药后一天称量体重后，解剖取肺并称量肺重，计算小鼠肺指数及抑制率。
肺指数＝肺湿重(g)×100/体重(g)
3试验结果
表10 本发明化合物对人冠状病毒229E感染小鼠肺炎模型的影响

注：与正常对照组比较#P<0.05；与模型对照组比较*P<0.05
表10结果显示：采用人冠状病毒229E感染小鼠后，模型对照组小鼠肺指数显著增加，与正常对照组比较有显著性差异(P<0.05)；化合物4、化合物9的7.5mg/kg/d剂量组小鼠肺指数显著降低，与模型对照组比较有显著性差异(P<0.05)。
实施例24 本发明化合物对副流感病毒感染小鼠肺炎模型的影响
1试验材料
1.1受试药物：化合物4、化合物9、化合物10、化合物11、化合物12、化合物2。
1.2利巴韦林颗粒 生产单位：四川百利药业有限责任公司。适应症：本品适用于呼吸道合胞病毒引起的病毒性肺炎与支气管炎，皮肤疱疹病毒感染。主要成分：利巴韦林。性状：白色或类白色可溶颗粒。规格：50mg/袋，18袋/盒。用法用量：口服，一次150mg，一日3次。储存条件：密闭，在干燥处保存。
1.3试验动物
1.4病毒株：副流感病毒，购自美国ATCC，由本研究室-80℃保存。
1.5试验仪器

1.6试验场所：中国中医科学院中药研究所ABSL-2实验室
2试验方法
2.1剂量设计及配制
受试药物
利巴韦林颗粒
2.2造模及给药
取ICR小鼠150只，SPF级，体重13～15g，按体重随机分为15组：正常对照组、模型对照组、利巴韦林组、化合物4、化合物9、化合物10、化合物11、化合物12、化合物2均为二个剂量组，每组10只，雌雄各半。除正常对照组外，其他各组小鼠乙醚轻度麻醉后，滴鼻感染100TCID50副流感病毒仙台株，每只45μl。各组小鼠于感染后给予相应的药物，正常对照组、模型对照组在同等条件下给予蒸馏水，连续给药4天。第5天，小鼠称重后分离肺组织后称量肺重。
肺指数＝肺重g×100/体重g
表11 本发明化合物对副流感病毒感染小鼠肺炎模型的影响
注：与正常对照组比较#P<0.05；与模型对照组比较*P<0.05
表11结果显示：采用副流感病毒感染小鼠后，模型对照组小鼠肺指数显著增加，与正常对照组比较有显著性差异(P<0.01)；化合物4、化合物9、化合物12的15mg/kg/d、7.5mg/kg/d剂量组小鼠肺指数显著降低，与模型对照组比较有显著性差异(P<0.05)。
实施例25 本发明化合物对甲型流感病毒H1N1/PR8、H1N1/FM1感染小鼠肺炎模型的治疗作用
1试验材料
1.1受试药物：化合物9、化合物12、化合物2。
1.2阳性对照药
磷酸奥司他韦胶囊(达菲) 生产单位：瑞士巴塞尔豪夫迈·罗氏有限公司。适应症：用于成人和1岁及1岁以上儿童的甲型和乙型流感的治疗；用于成人和13岁及13岁以上青少年的甲型和乙型流感的预防。主要成分：磷酸奥司他韦。 性状：本品为灰色和淡黄色胶囊，内容物为白色至黄白色粉末，可含有块状物。规格：以奥司他韦计，75mg/粒，10粒/盒。用法用量：口服，成人和13岁及13岁以上青少年，每次75mg，每日2次，共5天。储存条件：密封保存。
1.3试验动物
1.4病毒株
1.5试验仪器
1.6试验场所：中国中医科学院中药研究所ABSL-2实验室
2试验方法
2.1剂量设计及配制
受试药物
磷酸奥司他韦胶囊
2.2试验步骤
取ICR小鼠，按体重等级随机分9组：正常对照组、模型对照组、磷酸奥司他韦对照组、化合物9、化合物12、化合物2药物均为2个剂量组，每组10只。除正常对照组外，将小鼠用乙醚轻度麻醉，以15个LD50H1N1/PR8流感病毒液滴鼻感染，每只30μl。感染当天开始给药，每次按0.2ml/10g灌胃，每天1次，连续4天，正常对照组和模型对照组在同等条件下蒸馏水灌胃。第5天称重后解剖，称肺重，计算肺指数及肺指数抑制率。结果采用组间比较t检验进行统计学处理。
肺指数(％)＝肺湿重(g)×100/体重(g)
3试验结果
表12 本发明化合物对流感病毒H1N1/PR8株感染小鼠肺炎模型的治疗作用

注：与正常组比较##P<0.01；与模型对照组比较，**P<0.01，*P<0.05
表12结果显示：采用甲型H1N1/PR8流感病毒感染小鼠后，小鼠肺指数明显增高，与正常对照组比较具有显著性差异(P<0.01)；感染当天开始给予化合物9、化合物12、化合物2治疗4天后肺指数显著降低，与模型对照组比较有显著性差异(P<0.01)。
表13 本发明化合物对流感病毒H1N1/FM1株感染小鼠肺炎模型的治疗作用
注：与正常组比较##P<0.01；与模型对照组比较，**P<0.01，*P<0.05
表13结果显示：采用甲型H1N1/FM1流感病毒感染小鼠后，小鼠肺指数明显增高，与正常对照组比较具有显著性差异(P<0.01)；感染当天开始给予化合物9、化合物12、化合物2治疗4天后肺指数显著降低，与模型对照组比较有显著性差异(P<0.01)。
实施例26：化合物12对人冠状病毒229E感染小鼠肺炎模型的治疗作用
实验材料、实验方法同实施例23。
表14 化合物12对人冠状病毒229E感染小鼠肺炎模型的影响
注：与正常对照组比较#P<0.05；与模型对照组比较*P<0.05
表14结果显示：采用人冠状病毒229E感染小鼠后，模型对照组小鼠肺指数显著增加，与正常对照组比较有显著性差异(P<0.05)；化合物12的15mg/kg/d、7.5mg/kg/d剂量组小鼠肺指数显著降低，与模型对照组比较有显著性差异(P<0.01、P<0.05)。
实施例27：化合物4的小鼠急性毒性试验
1.试验方法
70只ICR小鼠，体重17-21g，按禁食体重随机分为7组：正常对照组和受试药物(化合物4)的475、633、844、1125、1500、2000mg供试品/kg 6个剂量组，每组10只，雌雄各半。禁食约15h后，各给药组均灌胃给药1次，给药体积40ml/kg，对照组1次/日灌胃等体积0.5％羧甲基纤维素钠溶液，给药后连续观察14天内动物的死亡情况。
给药后即刻观察动物是否出现毒性反应，毒性症状及其程度，毒性出现和消失的时间，记录不良反应情况，对死亡动物进行大体剖检，包括动物皮毛、眼、耳、口、鼻、生殖孔、肛门及其黏膜的观察。
2.实验结果
2.1小鼠死亡率和不良反应观察
化合物4以475、633、844、1125、1500、2000mg供试品/kg剂量，1次/日灌胃给予动物，可观察到的主要毒性反应为急性死亡。
1125mg供试品/kg及以上剂量组在给药后出现动物死亡，844mg供试品/kg及以下剂量组未出现动物死亡，动物死亡均在药后4d内发生，死亡高峰在药后24-48h内。上述6个剂量组动物的死亡率分别为0％、0％、0％、20％、80％和100％。
2.2除急性死亡外，其它肉眼可见的不良反应主要表现为自发活动减少、静卧、 共济失调、震颤、惊厥、俯卧、正位反射消失和竖毛；633、844、1125、1500、2000mg供试品/kg剂量组均有上述指征不同程度的改变，发生率分别为40％、60％、80％、100％和100％，发生在药后60min-5d内。475mg供试品/kg剂量组未见肉眼可见的不良反应。此后直至观察期14天结束，动物的一般情况、活动、步态、呼吸、进食、饮水、二便、皮毛等均未见异常。
综上所述：采用Bliss法计算得出LD50为1299.054mg供试品/kg，95％可信限为1152.937～1463.820mg供试品/kg；最大无致死剂量为844mg供试品/kg；最大无不良反应剂量为475mg供试品/kg。
实施例28：化合物12的小鼠急性毒性试验
1.试验方法
30只ICR小鼠，体重17-21g，按禁食体重随机分为3组：正常对照组和受试药物(化合物12)的2000mg、4000mg供试品/kg剂量组，每组10只，雌雄各半。禁食约15h后，各给药组灌胃给药1次，给药体积40ml/kg，对照组1次/日灌胃等体积0.5％羧甲基纤维素钠溶液，给药后连续观察14天内动物的死亡情况。
给药后即刻观察动物是否出现毒性反应，毒性症状及其程度，毒性出现和消失的时间，记录不良反应情况，对死亡动物进行大体剖检，包括动物皮毛、眼、耳、口、鼻、生殖孔、肛门及其黏膜的观察。
2.实验结果
化合物12以2000、4000mg供试品/kg剂量，1次/日灌胃给予动物，给药后即刻观察，此后直至观察期14天结束，动物的一般情况、活动、步态、呼吸、进食、饮水、二便、皮毛等均未见异常。实验期间无动物死亡。
结合以上实施例，关于本发明化合物对流感病毒H1N1/FM1株感染小鼠肺炎模型的治疗作用以及对人冠状病毒229E感染小鼠肺炎模型的影响，化合物4的药效比改造前体7-羟基异黄酮药效更强，7-羟基异黄酮的药效不是很强，说明本发明关于7-羟基异黄酮的7位改造策略对于此类异黄酮衍生物的抗病毒药效具有很重要的影响作用；而化合物4比化合物F2(7位糖苷化策略衍生物)、化合物 F4(7位烷氧烷氧基衍生物)、化合物F5(7位酰胺基烷氧基衍生物)的药效更强，说明经环烷氨基烷氧基策略的改造策略得到的化合物4的抗病毒效果更好。化合物4比化合物5、化合物7的抗病毒药效都更强，说明7位2-(环丙胺基)乙氧基取代基衍生物效果更好。说明取代基的位置以及结构对于7-羟基异黄酮衍生物的抗病毒药效具有很重要的影响，而且实验证明7位引入2-(环丙胺基)乙氧基取代基的抗病毒药效最好。由化合物4衍生得到的化合物9、化合物12也具有很强的药效，但是由化合物4衍生得到的化合物10、化合物11的药效较差，说明环丙烷基与通式(I)中R6的结构对于抗病毒药效具有很重要的影响。在保留环丙胺基取代基的情况下，R6为烷基或者取代烷基的衍生物具有很强的药理活性。同时，前期毒理学研究结果显示，化合物4小鼠急性毒性实验的LD50为1299.054mg，化合物12最大可灌胃给药的浓度为4000mg/kg，动物无死亡发生，表明化合物12与化合物4相比，化合物12的安全窗更大，药效更好，说明R6为烷基或者取代烷基的衍生物不仅保持更好的药理活性，而且安全性更高。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I所示的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物，
    X1、X2各自独立地选自下组：O、NR7；其中，所述的R7选自下组：氢、烷基、取代的烷基、芳基烷基、取代的芳基烷基、环烷基、取代的环烷基；
    X3选自下组：O、NR8；其中，所述R8选自下组：氢、烷基；
    R1a、R1b、R1c各自独立地选自下组：氢、羟基、烷氧基；
    R2选自下组：取代或未取代的芳基，或取代或未取代的杂芳基；
    R3a、R3b各自独立地选自下组：氢、烷基、卤素；
    R4a、R4b各自独立地选自下组：氢、烷基、卤素；
    R5选自下组：氢或烷氧基；
    R6选自下组：氢、取代或未取代的烷基、取代或未取代的芳基烷基、氨基烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的C2-C6酰基、取代或未取代的烷氧基羰基、取代或未取代的氨基甲酰基，或(CH2)tR7；其中，t为1、2、3、4、5或6；其中，所述R7选自下组：C2-C6酰基、C2-C6酰胺基、芳基、杂芳基、环烷基、杂环基、NR8COR9；所述R8选自下组：氢、烷基；R9选自下组：烷基、芳基、杂芳基、环烷基、杂环基；
    A环为取代或未取代的环烷基；
    n为1、2、3、4、5、6、7、8、9或10；
    其中，各个取代指基团上的氢原子被一个或多个选自下组的取代基替代：氰基、卤素、烷基、羟基、烷氧基、烯基、炔基、芳基、杂芳基；
    并且，所述式I化合物不包括
    上述各式中，除非特别说明，烷基为C1-C6的烷基、芳基为C6-C10的芳基、环烷基为C3-C8的环烷基、烷氧基为C1-C6的烷氧基、烯基为C2-C6的烯基、炔基为C2-C6的炔基、杂芳基为5-12元(较佳地为5-7元)的杂芳基。
  2. 如权利要求1所述的化合物，其特征在于，X1为O；并且/或者
    X2为O。
    在另一优选例中，所述的R7选自下组：氢、烷基。
    在另一优选例中，X3为O。
    在另一优选例中，R1a、R1b、R1c各自独立地选自氢。
  3. 如权利要求1所述的化合物，其特征在于，R2为取代或未取代的芳基，优选为取代或未取代的苯基。
    在另一优选例中，R3a、R3b各自独立地选自下组：氢、C1-C4的烷基、卤素。
    在另一优选例中，R4a、R4b各自独立地选自下组：氢、C1-C4的烷基、卤素。
    在另一优选例中，R5选自下组：氢或C1-C4烷氧基。
    在另一优选例中，R6选自下组：氢、取代或未取代的烷基、取代或未取代的芳基烷基、氨基烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的C2-C6酰基、或(CH2)tR7；其中，t为1、2、3、4、5或6；R7选自下组：C2-C6酰基、C2-C6酰胺基、芳基、NR8COR9，所述R8选自下组：氢、烷基；R9选自下组：烷基、芳基。
    在另一优选例中，A环为取代或未取代的C3-C7环烷基，优选为C3-C6环烷基。
    在另一优选例中，n为1、2、3或4。
    在另一优选例中，所述的R6选自下组：氢、取代或未取代的烷基。
    在另一优选例中，所说的R6选自下组：氢、未取代的烷基。
  4. 如权利要求1所述的化合物，其特征在于，所述式I化合物具有式II所示的结构，
    R9a、R9b、R9c各自独立地选自下组：氢、羟基、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、5-12元杂芳基；
    R10a、R10b、R10c、R10d、R10e各自独立地选自下组：氢、羟基、C1-C6烷氧基、卤素、氰基；
    m为1、2、3、4或5。
  5. 如权利要求4所述的化合物，其特征在于，式II所述化合物选自下组：

  6. 如权利要求1所述的化合物，其特征在于，所述式I化合物具有式III所示的结构，
    R11a、R11b、R11c各自独立地选自下组：氢、羟基、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6的烷氧基C6-C10芳基、5-12元杂芳基；
    R12选自下组：取代或未取代的烷基、取代或未取代的芳基烷基、氨基烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的C2-C6酰基、取代或未取代的烷氧基羰基、取代或未取代的氨基甲酰基，或(CH2)tR7；其中，t为1、2、3、4、5或6；其中，所述R7选自下组：C2-C6酰基、C2-C6酰胺基、芳基、杂芳基、环烷基、杂环基、NR8COR9；所述R8选自下组：氢、烷基；R9选自下组：烷基、芳基、杂芳基、环烷基、杂环基；
    R13a、R13b、R13c、R13d、R13e各自独立地选自下组：氢、羟基、烷氧基、卤素、氰基。
  7. 根据权利要求6所述的化合物，其特征在于，式III所述化合物选自下组：

  8. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-7任一项所述的化合物、或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体；以及药学上可接受的载体。
  9. 式I所示的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物，或权利要求8所述的药物组合物的用途，其特征在于，用于制备药物组合物；
    X1、X2各自独立地选自下组：O、NR7；其中，所述的R7选自下组：氢、烷基、取代的烷基、芳基烷基、取代的芳基烷基、环烷基、取代的环烷基；
    X3选自下组：O、NR8；其中，所述R8选自下组：氢、烷基；
    R1a、R1b、R1c各自独立地选自下组：氢、羟基、烷氧基；
    R2选自下组：取代或未取代的芳基，或取代或未取代的杂芳基；
    R3a、R3b各自独立地选自下组：氢、烷基、卤素；
    R4a、R4b各自独立地选自下组：氢、烷基、卤素；
    R5选自下组：氢或烷氧基；
    R6选自下组：氢、取代或未取代的烷基、取代或未取代的芳基烷基、氨基烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的C2-C6酰基、取代或未取代的烷氧基羰基、取代或未取代的氨基甲酰基，或(CH2)tR7；其中，t为1、2、3、4、5或6；其中，所述R7选自下组：C2-C6酰基、C2-C6酰胺基、芳基、杂芳基、环烷基、杂环基、NR8COR9；所述R8选自下组：氢、烷基；R9选自下组：烷基、芳基、杂芳基、环烷基、杂环基；
    A环为取代或未取代的环烷基；
    n为1、2、3、4、5、6、7、8、9或10；
    其中，各个取代指基团上的氢原子被一个或多个选自下组的取代基替代：氰基、卤素、烷基、羟基、烷氧基、烯基、炔基、芳基、杂芳基；
    且所述的药物组合物用于选自下组的用途：
    (1)改善，缓解或逆转由病毒感染引发的疾病或病症；
    (2)作为SARS-Cov-2病毒ACE-2受体拮抗剂；
    (3)作为感染后炎性细胞因子抑制剂。
  10. 如权利要求9所述的用途，其特征在于，所述的病毒选自下组：流感病毒、呼吸道合胞病毒、冠状病毒(如SARS-COV-2病毒)、副流感病毒。
    在另一优选例中，所述的感染为病毒感染。
    在另一优选例中，所述的病毒选自下组：流感病毒、呼吸道合胞病毒、冠状病毒(如SARS-COV-2病毒)、副流感病毒。
PCT/CN2023/073234 2022-01-28 2023-01-19 一种环烷氨基烷氧基取代的芳基并吡喃酮类化合物及其用途 WO2023143397A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210107552.7A CN116554137A (zh) 2022-01-28 2022-01-28 一种环烷氨基烷氧基取代的芳基并吡喃酮类化合物及其用途
CN202210107552.7 2022-01-28

Publications (1)

Publication Number Publication Date
WO2023143397A1 true WO2023143397A1 (zh) 2023-08-03

Family

ID=87470793

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/073234 WO2023143397A1 (zh) 2022-01-28 2023-01-19 一种环烷氨基烷氧基取代的芳基并吡喃酮类化合物及其用途

Country Status (2)

Country Link
CN (1) CN116554137A (zh)
WO (1) WO2023143397A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090215767A1 (en) * 2008-02-26 2009-08-27 Cherng-Chyi Tzeng Isoflavone derivatives and pharmaceutical compositions comprising the same
CN101723926A (zh) * 2008-10-10 2010-06-09 四川省中医药科学院 一种异黄酮衍生物及其制备方法和用途
CN102617536A (zh) * 2011-01-27 2012-08-01 上海瑞广生化科技开发有限公司 异黄酮类化合物,其制备方法及其在制备抗病毒或抗肿瘤药物中的应用
CN105377253A (zh) * 2013-07-16 2016-03-02 奇尼塔公司 抗病毒化合物、医药组合物和其使用方法
WO2016073947A1 (en) * 2014-11-07 2016-05-12 Kineta, Inc. Anti-viral compounds, pharmaceutical compositions, and methods of use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090215767A1 (en) * 2008-02-26 2009-08-27 Cherng-Chyi Tzeng Isoflavone derivatives and pharmaceutical compositions comprising the same
CN101723926A (zh) * 2008-10-10 2010-06-09 四川省中医药科学院 一种异黄酮衍生物及其制备方法和用途
CN102617536A (zh) * 2011-01-27 2012-08-01 上海瑞广生化科技开发有限公司 异黄酮类化合物,其制备方法及其在制备抗病毒或抗肿瘤药物中的应用
CN105377253A (zh) * 2013-07-16 2016-03-02 奇尼塔公司 抗病毒化合物、医药组合物和其使用方法
WO2016073947A1 (en) * 2014-11-07 2016-05-12 Kineta, Inc. Anti-viral compounds, pharmaceutical compositions, and methods of use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WANG DONGMEI; HU MIN; LI XINPENG; ZHANG DAN; CHEN CHENGJUAN; FU JUNMIN; SHAO SHUAI; SHI GAONA; ZHOU YU; WU SONG; ZHANG TIANTAI: "Design, synthesis, and evaluation of isoflavone analogs as multifunctional agents for the treatment of Alzheimer's disease", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 168, 1 January 1900 (1900-01-01), AMSTERDAM, NL , pages 207 - 220, XP085627792, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2019.02.053 *

Also Published As

Publication number Publication date
CN116554137A (zh) 2023-08-08

Similar Documents

Publication Publication Date Title
CN111848616B (zh) 吡啶酮衍生物及其用于制备抗流感病毒药物的用途
KR101473028B1 (ko) 인플루엔자 치료제
US9284304B2 (en) Substituted pyrimidines as toll-like receptor modulators
DK2776416T3 (en) Pharmaceutical compounds
WO2014165128A2 (en) Hepatitis b antiviral agents
KR102145649B1 (ko) 구아니디노벤조산 에스테르 화합물
TW202204337A (zh) 截短側耳素類之醫療用途
JP2020196704A (ja) インフルエンザウイルス感染症またはコロナウイルス感染症の予防および／または治療剤
JP2023162363A (ja) 広域スペクトルの抗ウイルス組成物及び方法
WO2022169891A1 (en) Compounds, compositions, and methods of using the same
WO2023143397A1 (zh) 一种环烷氨基烷氧基取代的芳基并吡喃酮类化合物及其用途
CN111303147A (zh) 吡啶酮衍生物、其组合物及作为抗流感病毒药物的应用
JP6377139B2 (ja) ウイルス感染症およびさらなる疾患の処置のためのピリドン誘導体
TW202102502A (zh) 作為流感病毒複製抑制劑之稠合多環吡啶酮化合物
AU2019376684A1 (en) Novel compounds for the treatment of respiratory diseases
WO2023011443A1 (zh) 用于治疗或预防冠状病毒感染的3cl蛋白酶小分子抑制剂及其用途
CN115160301A (zh) 一种山荷叶素衍生物、其制备方法及用途
KR20220097446A (ko) 약학적 화합물
WO2024078618A1 (zh) 一种含氰基取代的多肽类化合物的晶型及其制备方法
WO2023070373A1 (zh) 一类多环聚酮化合物在制备抗新型冠状病毒药物中的应用
AU2014262658A1 (en) Furanone compounds as kinase inhibitors
US20230364074A1 (en) Compounds and Compositions for Disrupting Programmed Ribosomal Frameshifting
WO2016107542A1 (zh) 吡咯酰胺类化合物及其制备方法与用途
JP2021508341A (ja) 医薬化合物
WO2023064368A1 (en) Novel rhodanine derivatives and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23746276

Country of ref document: EP

Kind code of ref document: A1