WO2024259930A1 - Composé phosphonate et son utilisation médicale - Google Patents

Composé phosphonate et son utilisation médicale Download PDF

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Publication number
WO2024259930A1
WO2024259930A1 PCT/CN2023/141023 CN2023141023W WO2024259930A1 WO 2024259930 A1 WO2024259930 A1 WO 2024259930A1 CN 2023141023 W CN2023141023 W CN 2023141023W WO 2024259930 A1 WO2024259930 A1 WO 2024259930A1
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virus
compound
substituted
reaction
unsubstituted
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WO2024259930A9 (fr
Inventor
吕佳声
张启国
周天伦
孔宪起
陈大为
张文宏
万延民
陈刚
叶祥胜
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Risen Shanghai Pharma Engineering Co Ltd
Risen Suzhou Pharma Tech Co Ltd
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Risen Shanghai Pharma Engineering Co Ltd
Risen Suzhou Pharma Tech Co Ltd
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    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems

Definitions

  • the present invention relates to a phosphonate compound or a pharmaceutically acceptable salt or ester thereof, and use thereof in preparing a medicine for treating, inhibiting or preventing a virus infection disease or a cell proliferation disease.
  • Cidofovir is an acyclic nucleoside phosphonate (ANP) analog, which is essentially a nucleoside monophosphate analog with the advantage of metabolic stability.
  • NBP nucleoside phosphonate
  • Current studies have shown that cidofovir has broad-spectrum activity against all DNA viruses, including adenovirus, polyomavirus, papillomavirus and poxvirus.
  • poxviruses vaccinia, smallpox, cowpox, monkeypox, camelpox, molluscum contagiosum and sheeppox virus (orf) [De Clercq, Antiviral Research 2002, 55, 2002, 113].
  • Monkeypox is a viral zoonosis that causes symptoms in humans similar to those seen in smallpox patients in the past. While smallpox no longer exists in the world after it was eradicated in 1980, monkeypox still occurs in parts of Africa. Monkeypox occurs in monkeys in the rainforests of central and western Africa, and can also infect other animals and occasionally humans. The clinical manifestations are similar to smallpox, but the condition is milder. The disease is caused by the monkeypox virus, which can be transmitted from animals to humans through direct close contact, and can also be spread from person to person. The 2022 monkeypox outbreak was first discovered in the UK on May 7, 2022 local time. On May 20, local time, with more than 100 confirmed and suspected cases of monkeypox in Europe.
  • cidofovir Since the phosphonate part of cidofovir is negatively charged at physiological pH, cidofovir cannot pass through lipid-rich cell membranes, which hinders its antiviral activity and bioavailability [De Clercq, Antiviral Research 2002, 55, 2002, 113]. Cidofovir can also cause renal insufficiency [De Clercq & Holy, Nat. Rev. Drug Discov. 2005, 4, 928-940]. In order to reduce the nephrotoxicity of cidofovir, researchers synthesized cyclic cidofovir (cHPMPC) [Bischofberger et al. Antimicrob. Agents Chemother. 1994, 38, 2387-2391].
  • cHPMPC cyclic cidofovir
  • the main technical problem solved by the present application is to provide a phosphonate prodrug, which can have at least one or more of the following effects:
  • the present invention provides a phosphonate compound represented by formula (I) or a pharmaceutically acceptable salt or ester thereof:
  • X is selected from -OR 6 , or X and R 3 are combined to form a chemical bond;
  • R1 is selected from H or C4-C30 carbonyl
  • the C4-C30 carbonyl includes substituted or unsubstituted hydrocarbylcarbonyl, substituted or unsubstituted arylcarbonyl or heterocyclic carbonyl and substituted or unsubstituted hydrocarbyloxycarbonyl
  • the carbon number of the C4-C30 carbonyl is 4 to 30, which can be 4 to 10, 10 to 30 or 20 to 30, and specifically can be 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30;
  • R 2 and R 6 are independently selected from H, wherein R 7 is selected from substituted or unsubstituted C15-C30 hydrocarbon groups, specifically C16, C17, C18, C19, C20 alkyl groups, and the hydrocarbon group may be a straight-chain hydrocarbon group or a branched hydrocarbon group, especially a straight-chain hydrocarbon group;
  • R3 is selected from: H, formyl, C4-C30 carbonyl, wherein the C4-C30 carbonyl includes substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl or heterocyclic carbonyl, and substituted or unsubstituted alkoxycarbonyl, and the carbonyl has no more than 30 carbon atoms, or an amino acid residue;
  • R 4 and R 5 are independently selected from hydrogen (H) or deuterium (D);
  • R 1 , R 2 , R 3 , and R 6 are not H at the same time, and the compound is not brincidofovir; when X and R 3 are combined to form a chemical bond, R 1 and R 2 are not H at the same time.
  • R 1 is selected from substituted or unsubstituted arylcarbonyl, especially substituted or unsubstituted phenylcarbonyl; C1-C6 alkylcarbonyl, especially C1-C4 alkylcarbonyl; and
  • R2 is Wherein R7 is selected from substituted or unsubstituted C15-C20, especially C16-C20 straight chain hydrocarbon groups.
  • R 1 , R 3 , and R 6 are not H at the same time; when X and R 3 are combined to form a chemical bond, R 1 is not H.
  • R 1 is selected from H; substituted or unsubstituted arylcarbonyl, especially substituted or unsubstituted phenylcarbonyl; CH 3 OCH 2 CH 2 Ocarbonyl; C1-C5 alkyloxycarbonyl; CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 Ocarbonyl; CH 3 CH 2 CH 2 COOCH(CH 3 )Ocarbonyl; substituted or unsubstituted heteroarylalkyloxycarbonyl, especially substituted or unsubstituted five-membered ring carbonate C1-C2 alkoxycarbonyl, such as substituted or unsubstituted heteroarylalkyloxycarbonyl, (CH 3 ) 2 CHCOOCH(CH 3 )Ocarbonyl, CH 3 COOCH(CH 3 )Ocarbonyl;
  • R3 is selected from H ; formyl, substituted or unsubstituted arylcarbonyl, especially substituted or unsubstituted phenylcarbonyl; C1-C5 alkyloxycarbonyl ; CH3OCH2CH2OCH2CH2OCH2CH2Ocarbonyl; C1- C8 alkylcarbonyl; ( CH3 ) 2CHCOOCH ( CH3 ) Ocarbonyl ; substituted or unsubstituted heteroarylalkyloxycarbonyl, especially substituted or unsubstituted Substituted five-membered ring carbonate group C1-C2 alkoxycarbonyl, such as (CH 3 ) 2 CHCOOCH(CH 3 )Ocarbonyl; and
  • X is a hydroxyl group.
  • the above compound is a compound represented by (IIIa) or (IIIb):
  • R 3 is H
  • R3 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the above compound is a compound represented by formula (IV):
  • R 1 , R 3 , and R 6 are not H at the same time; when X and R 3 are combined to form a chemical bond, R 1 is not H.
  • the above compound is a compound represented by (IVa) or (IVb):
  • R1 is selected from substituted or unsubstituted hydrocarbon carbonyl groups, specifically, including the groups shown below:
  • R1 is selected from substituted or unsubstituted arylcarbonyl or heterocyclic carbonyl, specifically, including the following groups:
  • Y is selected from H, F, Cl, Br, Me, -OMe, -OEt, -CF3 or -CN.
  • R1 is selected from substituted or unsubstituted hydrocarbonoxycarbonyl groups, specifically, including the following groups:
  • R7 includes the following groups:
  • R 3 includes the following groups
  • R3 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R3 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compounds include the compounds shown in Table 1a and Table 1b below:
  • viral infections include hepatitis B virus (HBV), new coronavirus (SARS-COV-2), human immunodeficiency virus (HIV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex virus (HSV), BK virus, JC virus, Epstein-Barr virus (EBV), Ebola virus, polyomavirus, papillomavirus, orthopoxvirus, hepatitis C virus (HCV), respiratory syncytial virus (RSV), dengue virus, influenza virus, adenovirus, parainfluenza virus and/or infection caused by rhinovirus.
  • HBV hepatitis B virus
  • SARS-COV-2 new coronavirus
  • HCV human immunodeficiency virus
  • VZV varicella zoster virus
  • CMV herpes simplex virus
  • BK virus BK virus
  • JC virus herpes simplex virus
  • EBV Epstein-Barr virus
  • orthopoxviruses include severe and mild smallpox viruses, monkeypox virus, cowpox virus, camelpox virus, molluscum contagiosum, sheeppox virus, aractuba virus (ARAV), BeAn 58058 virus (BAV), cantagalo orthopoxvirus (CTGV), mousepox virus, elephantpox virus, vaccinia virus (VV), rabbitpox virus, raccoonpox virus, skunkpox virus, gerbilpox virus and volepox virus.
  • the compounds disclosed in the present application can be used to prepare drugs for treating, inhibiting or preventing diseases caused by monkeypox virus or smallpox virus infection in mammals.
  • the compounds provided in the present application can be used to prepare drugs for treating, inhibiting or preventing diseases caused by viral infection.
  • diseases caused by viral infection include diseases caused by DNA virus infection, specifically, the diseases are selected from retinitis, pneumonia, cystitis, proteinopathy, etc.
  • the cells provided herein can also be used to prepare drugs for treating, inhibiting or preventing cell proliferation-induced diseases.
  • the cell proliferation-induced disease is a tumor or cancer, specifically, the tumor or cancer is selected from multiple myeloma (MM), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), solid tumors, refractory solid tumors, non-Hodgkin's lymphoma, hematological tumors, neuroblastoma, colorectal cancer, cervical cancer, lung cancer, leukemia, breast cancer, pancreatic cancer, B-cell malignancies, metastatic tumors and colon cancer.
  • MM myeloma
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • solid tumors refractory solid tumors
  • non-Hodgkin's lymphoma hematological tumors
  • neuroblastoma colorectal cancer
  • cervical cancer lung cancer
  • leukemia breast cancer
  • the present application also provides a pharmaceutical composition, comprising one or more of the above compounds and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable carrier includes one or more of creams, emulsions, gels, liposomes and nanoparticles;
  • the pharmaceutically acceptable excipient includes one or more of binders, fillers, disintegrants, lubricants and glidants.
  • the above pharmaceutical composition is suitable for oral administration or injection administration.
  • the present application also provides a kit, which includes any one or more of the above-mentioned compounds or pharmaceutically acceptable salts or esters or any one or more of the pharmaceutical compositions.
  • the specific compounds or pharmaceutically acceptable salts or esters thereof provided in the present application, or pharmaceutical compositions containing the same, can effectively treat, inhibit or prevent viral infections and/or cell proliferation diseases in mammals, especially smallpox and monkeypox, and have at least one or more of the effects of changing the pharmacokinetic properties in the body, adjusting the absorption and distribution of the drug in the body, improving the stability and solubility of the drug, reducing toxicity and adverse reactions, improving the transport and distribution to specific parts, improving the sustained release effect, and prolonging the duration of action.
  • FIG1 is a graph showing the inhibitory activity-drug concentration curve of the test compound.
  • FIG. 2 shows a death curve diagram of a surrogate endpoint of mouse death, wherein FIG. 2a is a graph of body weight change, and FIG. 2b is a surrogate endpoint death curve.
  • FIG. 3 shows a graph of the actual mortality of mice, wherein FIG. 3a is a graph of weight changes, and FIG. 3b is an actual mortality curve.
  • the words “comprising”, “having” and synonyms are inclusive and open-ended and do not exclude additional unlisted elements or processing steps.
  • the term “about” or “approximately” is used to indicate that the value includes the error caused by the instruments and methods used in determining the value.
  • pharmaceutically acceptable refers to drugs, medicines, inert ingredients, etc. described by the term, which are suitable for contact with the tissues of humans and lower animals without abnormal toxicity, incompatibility, instability, irritation, allergic reaction, etc., commensurate with a reasonable benefit/risk ratio. It is preferably a compound, composition, and preparation, etc. listed in the pharmacopoeia or other recognized pharmacopoeia for use in animals, more particularly in humans.
  • a "pharmaceutically acceptable salt” of a compound refers to a salt of a compound that is pharmaceutically acceptable. Desirable salts of compounds (basic, acidic or charged functional groups) can retain or improve the biological activity and properties of the parent compound as defined herein and are not biologically undesirable.
  • esters refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • prodrug refers to an agent that is directly or indirectly converted into an active form in vitro or in vivo (see, for example, RB Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), “Design of Prodrugs”. 360pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), “Prodrugs: Challenges and Rewards, XVIII, 1470p. Springer).
  • Prodrugs can be used to change the biodistribution of a particular drug (for example, so that the agent does not normally enter the protease reaction site) or pharmacokinetics.
  • a variety of groups such as esters, ethers, phosphates/salts, etc. have been used to modify compounds to form prodrugs.
  • the prodrug When the prodrug is administered to a subject, the group is cleaved off enzymatically or non-enzymatically, reduced, oxidatively or hydrolytically, or otherwise releases the active compound.
  • prodrugs include pharmaceutically acceptable salts, or pharmaceutically acceptable solvates, and any crystalline forms of the above. Prodrugs are generally (although not necessarily) pharmaceutically inactive, until it is converted into active form.
  • substituted or “substituted” as used in the present invention includes an implicit condition, that is, such substitution changes with the valence of the substituted atom and the substituent, and the substitution produces a stable compound (for example, the compound cannot spontaneously undergo rearrangement, cyclization, elimination, etc.).
  • substituted includes all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. The substituent can be one or more.
  • substituted means that when the above groups are substituted at one or more positions, the substituents include acylamino (including carbamoyl and ureido), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxyl, carboxyl, aminocarbonyl, mono- and dialkylaminocarbonyl, cyano, azido, halogen (F, Cl, Br and I), hydroxy, nitro, trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl, thiocarboxylate, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, lower alkoxy, aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsul
  • alkyloxy refers to -ORb , where Rb is a hydrocarbon.
  • C15-C30 hydrocarbon group means having 15 to 30 carbon atoms in the hydrocarbon structure, specifically, the number of carbon atoms can be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and the term "C1-C16 hydrocarbon group” means having 1 to 16 carbon atoms in the hydrocarbon structure, specifically, the number of carbon atoms can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16.
  • aryl or “aryl ring” used in the present invention refers to an aromatic group having "4n+2" ( ⁇ ) electrons in a conjugated monocyclic or polycyclic system (condensed or non-condensed), and having 6 to 14 ring atoms, wherein n is an integer from 1 to 3.
  • the polycyclic system includes at least one aromatic ring.
  • the aryl group can be directly connected or connected through a C1-C3 alkyl group (also referred to as an arylalkyl group or an aralkyl group).
  • aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthenyl, fluorenyl, phenanthrenyl, anthracenyl, etc.
  • aryl includes unsubstituted aryl and substituted aryl.
  • heteroaryl or “heteroaryl ring” as used herein refers to an aromatic group having "4n+2" ( ⁇ ) electrons in a conjugated monocyclic or polycyclic system (fused or non-fused), wherein n is an integer from 1 to 3 and includes one to six heteroatoms (e.g., N, O, S, P) or a group including heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO2 , SO, SO2 , etc.).
  • the polycyclic system includes at least one heteroaromatic ring.
  • the heteroaryl group can be directly attached or attached through a C1-C3 alkyl group (also known as heteroarylalkyl or heteroaralkyl).
  • the heteroaryl group can be attached to carbon or to a heteroatom (e.g., through a nitrogen atom).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl; isoxazolyl, Thiazolyl, oxazolyl, isothiazolyl, pyrrolidinyl, quinolyl, isoquinolyl, indolyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, pteridinyl, furanyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quina
  • heteroaryl includes unsubstituted heteroaryl and substituted heteroaryl.
  • C5-Cn heteroaryl wherein n is an integer from 6 to 15, refers to a heteroaryl group having from 5 to the indicated "n" atoms in the ring structure, including at least one heterocyclic group or atom as defined above.
  • the present invention provides a phosphonate compound, or a pharmaceutically acceptable salt or ester thereof, for use in the preparation of a medicament for treating, inhibiting or preventing a viral infection or a cell proliferation disease, wherein the phosphonate compound is selected from but not limited to the compounds listed in Table 1a and Table 1b.
  • amino acid residue refers to the major portion of an amino acid after removal of the carboxyl group.
  • amino acid generally refers to an organic compound that contains both a carboxylic acid group and an amino group.
  • amino acid includes “natural” and “unnatural” amino acids.
  • amino acid includes O-alkylated or N-alkylated amino acids, as well as amino acids with nitrogen-, sulfur- or oxygen-containing side chains (e.g., Lys, Cys or Ser), wherein the nitrogen, sulfur or oxygen atom may or may not be acylated or alkylated.
  • the amino acid may be an L-amino acid, a D-amino acid or a mixed L- and D-amino acid, including (but not limited to) a racemic mixture.
  • natural amino acid and equivalent expressions used in the present invention refer to L-amino acids that are usually found in naturally occurring proteins.
  • natural amino acids include, but are not limited to, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), ⁇ -alanine ( ⁇ -Ala) and ⁇ -aminobutyric acid (GABA), etc.
  • non-natural amino acid refers to any derivative of a natural amino acid, including D-amino acids and their derivatives, as well as ⁇ - and ⁇ -amino acid derivatives. It should be noted that certain non-natural amino acids (e.g., hydroxyproline) in the present invention may exist in certain biological tissues or specific proteins in nature. Amino acids with many different protecting groups suitable for direct use in solid phase peptide synthesis are commercially available.
  • unnatural amino acids and amino acid derivatives can be used according to the present invention (common abbreviations are in parentheses): 2-aminoadipic acid (Aad), 3-aminoadipic acid ( ⁇ -Aad), 2-aminobutyric acid (2-Abu), ⁇ , ⁇ -dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid ( ⁇ -Aib), 2-amino-thiazoline-4-carboxylic acid, 5-aminopentanoic acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-amino
  • the present invention provides methods for treating mammalian diseases associated with viral infection, inappropriate cell proliferation, etc. These methods specifically comprise administering to a human or other mammal in need of treatment a therapeutically effective amount of a compound of the present invention.
  • the compounds provided herein can be used to prepare a drug that can be used to treat, inhibit or prevent viral infection or viral infection-induced diseases.
  • the compounds provided herein and their pharmaceutically acceptable salts or esters are used to prepare drugs for treating smallpox virus infection or diseases caused by smallpox virus.
  • the compounds provided herein and their pharmaceutically acceptable salts or esters are used to prepare drugs for treating monkeypox virus infection or diseases caused by monkeypox virus.
  • the compounds provided herein have good effects in treating, inhibiting or preventing viral infections and diseases caused by viral infections. At the same time, the applicant has found that the compounds provided herein also have good effects in treating cancer or tumors.
  • the compounds provided herein and their pharmaceutically acceptable salts or esters can be used to prepare drugs, which can be used to treat, inhibit or prevent tumors or cancers caused by cell proliferation.
  • the drug provided herein further comprises at least one pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is selected from creams, emulsions, gels, liposomes or nanoparticles.
  • the compound or medicine provided by the present invention can be applied to the subject in any appropriate manner known in the art.
  • Suitable routes of administration include, but are not limited to, oral; parenteral, such as intramuscular, intravenous, subcutaneous (such as injection or implantation), intraperitoneal, intracisternal, intraarticular, intracerebral (intracerebral parenchyma and intraventricular); nasal; vaginal; sublingual; intraocular; rectal; topical (such as transdermal); oral and inhaled.
  • the accumulation injection method generally administered subcutaneously or intramuscularly can also be used to release the compound or medicine disclosed in the present application within a limited time period.
  • the medicine is an injectable preparation.
  • the medicine is formulated for oral administration to the subject.
  • kits containing antiviral infection compounds or drugs are generally in the form of a physical structure that contains various components and can be used, for example, to implement the methods provided herein.
  • the kit can include one or more compounds or drugs disclosed herein (e.g., provided in a sterile container), which can be in the form of a pharmaceutical composition suitable for administration to a subject.
  • the compound can be in a ready-to-use form (e.g., tablet or capsule) or in a form that requires, for example,
  • the kit may be provided in the form of a reconstructed or diluted (e.g., powder) before administration.
  • the kit may also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc., packaged together with the compound or packaged separately.
  • a diluent e.g., sterile water
  • the kit may contain several therapeutic agents independently, or they may have been combined in the kit.
  • Each component of the kit may be packaged in a separate container, and all the various containers may be in a single package.
  • the kit of the present invention may be designed to appropriately maintain the conditions required for the components contained therein (e.g., refrigerated or frozen).
  • the medicaments or pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • the method of such preparation comprises the steps of combining a compound described herein ("active ingredient") with a carrier and/or one or more other auxiliary ingredients, and then, if necessary and/or desired, forming and/or packaging the product into a desired single-dose unit or multiple-dose units.
  • a "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient.
  • the amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to a subject and/or a convenient fraction of such a dose, such as half or one-third of such a dose.
  • the compounds provided by the present invention can be synthesized according to the following general formula, wherein all reagents used to prepare the compounds of the present invention are commercially available or prepared according to preparation methods disclosed in the literature.
  • Compound A is used as a starting material, and under the action of a condensation agent 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (PYBOP), it undergoes cyclization and condensation reaction with different alcohols to obtain compound B; under the action of a base such as potassium carbonate, the amino group on compound B reacts with an acyl chloride to obtain compound C, which is then hydrolyzed with a sodium hydroxide solution and acidified to obtain compound D;
  • a condensation agent 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate PYBOP
  • PYBOP condensation agent 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate
  • Step A Sodium hydride (4.91 g, 122.82 mmol, 1.5 eq.) and DMF (150 mL) were added to the reaction flask. Under ice-water bath stirring, a DMF solution of 1,3-propylene glycol (28.04 g, 368.45 mmol, 26.63 mL, 4.5eq.; dissolved in 150mL DMF). After the addition is complete, stir at room temperature for 10 minutes. Slowly drop 1-bromohexadecane (25g, 81.88mmol, 1.0eq.) into the reaction system. After the addition is complete, stir at 95°C for 5 hours.
  • Step B Add [rac-(1S)-1-[(4-amino-2-oxopyrimidin-1-yl)methyl]-2-hydroxyethoxy]methylphosphonic acid (1.5 g, 5.37 mmol, 1 eq.), DMF (25 mL) and DIPEA (10 mL) to the reaction flask. Stir the reaction at 45°C for 2 hours.
  • Step C Add intermediate 1 (100 mg, 0.18 mmol, 1 eq.) and sodium hydroxide aqueous solution (0.5 M, 3.68 mmol, 10 eq.) to the reaction flask. Stir the reaction for 4 hours at room temperature. The reaction system becomes clear. In an ice-water bath, slowly add 1N HCl solution dropwise to adjust the pH to about 1. A large amount of solid precipitates, which is filtered and dried in vacuo to obtain intermediate 2 (50 mg, yield 47.09%).
  • Step A Add intermediate 2 (600 mg, 1.07 mmol, 1.0 eq.), DMF (10 mL) and triethylamine (5 mL) to a reaction flask, stir at room temperature for half an hour, concentrate to remove the solvent, add DMF (10 mL), 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene (545 mg, 1.6 mmol, 1.5 eq.) and triethylamine (325 mg, 3.2 mmol, 3.0 eq.). Stir at room temperature for one hour, concentrate to remove the solvent. Add DMF (20 mL) to the residue and prepare the intermediate 2-1 reaction reagent (46 mg/mL) for standby use.
  • Step B Add intermediate 1 (110 mg, 202.33 ⁇ mol, 1 eq.), DIPEA (78.45 mg, 606.98 ⁇ mol, 3 eq.), 2-methoxyethyl (4-nitrophenyl) carbonate (97.6 mg, 404.65 ⁇ mol, 2 eq.) and DMF (2 mL) to the reaction flask. Stir the reaction at 50 °C for 16 hours. TLC column chromatography detected that the reaction raw materials were completely consumed.
  • Step C Add 3-1 (80 mg, 123.89 ⁇ mol, 1 eq.) and THF (4 mL) to the reaction flask, add sodium hydroxide aqueous solution (0.5 mol/L, 743.31 ⁇ L, 3 eq.), and stir at room temperature for one hour.
  • LC-MS monitored the complete consumption of the reaction raw materials, and adjusted the pH of the reaction system to 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions, and then concentrated to remove most of the solvent.
  • Step B Add intermediate 1 (102 mg, 187.61 ⁇ mol, 1 eq.), DIPEA (72.74 mg, 562.84 ⁇ mol, 3 eq.) and DMF (2 mL) to the reaction flask. Add a solution of n-pentyl chloroformate (56.51 mg, 375.22 ⁇ mol, 2 eq.) in DMF (0.5 mL) dropwise to the reaction system under stirring, and stir at 50°C for 16 hours. TLC column chromatography detected that the reaction raw materials were completely consumed.
  • Step C Add 4-1 (64 mg, 97.29 ⁇ mol, 1 eq.) and THF (3 mL) to the reaction flask, add sodium hydroxide aqueous solution (0.5 mol/L, 486.46 ⁇ L, 2.5 eq.), and stir at room temperature for one hour.
  • LC-MS monitoring shows that the reaction raw materials have been consumed. Adjust the pH of the reaction system to 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions, and then concentrate to remove most of the solvent.
  • Step A Compound 5b (84 mg, 0.12 mmol, 1.0 eq.) DMF (4 mL) and NaH (47.98 mg, 1.20 mmol, 60% purity, 10.0 eq.). Stir at room temperature for 20 minutes. 4-nitrophenyl-4-chlorobenzoate (66.7 mg, 0.239 mmol, 2.1 eq.) DMF (0.5 mL) solution was added dropwise to the reaction. Stir the reaction at room temperature for 3 hours, add ethyl acetate (25 mL) to dilute, and add 1N HCl dropwise to quench the reaction at low temperature to ensure that the pH of the aqueous phase is 1-2.
  • Step B n-pentanol (0.5 g, 3.32 mmol, 1 eq.) and DCM (20 mL) were added to the reaction flask, and pyridine (0.31 g, 3.98 mmol, 1.2 eq.) was added dropwise under ice bath conditions. A solution of 4-nitrophenyl phosgene (0.46 g, 3.32 mmol, 1 eq.) in DCM (15 mL) was added dropwise, and the reaction was stirred at room temperature for 2 hours after the addition. TLC monitored the complete consumption of the reaction raw materials, and water (30 mL) was added, and dichloromethane was extracted and washed (30 mL*2).
  • Step B Add intermediate 1 (150 mg, 275.90 ⁇ mol, 1 eq.), dichloromethane (6 mL), and DIPEA to the reaction flask. (106.97 mg, 827.70 ⁇ mol, 144.17 ⁇ L, 3 eq.), DMAP (16.85 mg, 137.95 ⁇ mol, 0.5 eq.) and CbzCl (141.20 mg, 827.70 ⁇ mol, 116.50 ⁇ L, 3 eq.). The reaction was stirred at room temperature for 16 hours.
  • Step C Add 9-1 (30 mg, 44.26 ⁇ mol, 1 eq.), tetrahydrofuran (2 mL) and 0.5 M NaOH aqueous solution (0.5 M, 619.65 ⁇ L, 7 eq.) to the reaction flask. Stir at room temperature for 1 hour and directly concentrate to obtain product 9-2 (30.7 mg, yield 99.94%).
  • Step D Add 2-(2-(2-methoxymethoxy)ethoxy)ethanol-1-ol (2.0 g, 12.18 mmol, 1 eq.) and DCM (20 mL) into a reaction flask, add triethylamine (1.85 g, 18.27 mmol, 1.5 eq.), add 4-nitrophenylphosgene (2.46 g, 12.18 mmol, 1 eq.) in DCM (15 mL) dropwise under ice bath conditions, and stir the reaction at room temperature for 16 hours. The reaction raw materials were consumed as monitored by TLC, and water (100 mL) was added, and the mixture was washed with dichloromethane (30 mL*2).
  • reaction was stirred at 0°C for 20 min, and then a solution of 2-(2-(2-methoxymethoxy)ethoxy)ethyl(4-nitrophenyl)carbonate (378.61 mg, 1.15 mmol, 2 eq.) in DMF (1 mL) was added dropwise. After the addition, the reaction was stirred at room temperature for 16 hours. TLC monitoring showed that most of the raw materials were consumed. Under ice-water bath conditions, the reaction system was adjusted to pH 2 with 1 mol/L hydrochloric acid aqueous solution, water (50 mL) was added, and ethyl acetate was extracted and washed (20 mL*4).
  • Step A Add 4-(nitro)phenol (2.51 g, 18.01 mmol, 1.1 eq.), dichloromethane (80 mL), benzoic acid (2 g, 16.38 mmol, 1.0 eq.) and DCC (4.05 g, 19.65 mmol, 1.2 eq.) to the reaction flask. React at room temperature for 16 hours under stirring. Filter to remove solids, concentrate the mother liquor to remove dichloromethane, add ethyl acetate (100 mL) and water (70 mL) to the residue, extract and wash the layers, and wash the organic layer with brine (70 mL).
  • Step B Add 9-2 (0.2 g, 0.287 mmol, 1 eq.) and tetrahydrofuran (5 mL) to the reaction flask. Add LiHMDs (1 M, 1.15 mL, 4 eq.) dropwise under ice-water bath conditions, stir for 20 minutes after the addition is complete. Add a tetrahydrofuran solution of (4-nitrophenyl) benzoate (0.21 g, 0.862 mmol, 3.0 eq. dissolved in 1 mL tetrahydrofuran) dropwise to the reaction system. React at room temperature for 4 hours under stirring.
  • Step C Add 10-1 (140 mg, 0.175 mmol, 1 eq.), tetrahydrofuran (20 mL), methanol (5 mL) and Pd/C (25 mg) to the reaction flask. React at room temperature for 16 hours under hydrogen atmosphere, filter to remove palladium carbon, concentrate the mother liquor and purify it by preparative column to obtain compound 10b (23 mg, yield 19.55%).
  • Step D Nonanoic acid (1.0 g, 6.32 mmol, 1 eq.), 4-nitrophenol (879.11 mg, 6.32 mmol, 1 eq.) and DCM (30 mL) were added to the reaction flask, and N,N'-dicyclohexylcarbodiimide (1.56 g, 7.58 mmol, 1.2 eq.) was added, and the reaction was stirred at room temperature for 6 hours. TLC monitoring showed that most of the reaction materials were consumed, and water (60 mL) was added, and dichloromethane was added.
  • Step B Add 2-(2-(2-methoxymethoxy)ethoxy)ethanol-1-ol (2.0 g, 12.18 mmol, 1 eq.) and DCM (20 mL) into a reaction flask, add triethylamine (1.85 g, 18.27 mmol, 1.5 eq.), add 4-nitrophenylphosgene (2.46 g, 12.18 mmol, 1 eq.) in DCM (15 mL) dropwise under ice bath conditions, and stir the reaction at room temperature for 16 hours. After TLC monitoring, the reaction raw materials were consumed, water (100 mL) was added, and dichloromethane was extracted and washed (30 mL*2).
  • Step C Add 12-1 (110 mg, 149.89 ⁇ mol, 1 eq.) and THF (5 mL) to the reaction flask, add sodium hydroxide aqueous solution (0.5 mol/L, 749.45 ⁇ L, 2.5 eq.), and stir at room temperature for one hour.
  • Step D 12-2 (235 mg, 312.55 ⁇ mol, 1 eq.) and DMF (4 mL) were added to the reaction flask, and NaH (100.02 mg, 2.50 mmol, 60% purity, 8 eq.) was added under ice bath, and the reaction was stirred at 0°C for 20 min. Then, a solution of 2-(2-(2-methoxymethoxy)ethoxy)ethyl(4-nitrophenyl)carbonate (205.85 mg, 625.10 ⁇ mol, 2 eq.) in DMF (1 mL) was added dropwise, and the reaction was stirred at 50°C for 2 hours. TLC monitoring showed that most of the raw materials were consumed.
  • Step A Methanol (0.5 g, 315.6 mmol, 1.0 eq.), dichloromethane (40 mL), (4-nitrophenyl) carbonyl chloride (3.15 g, 15.6 mmol, 1.0 eq.) and DIPEA (3.03 g, 23.41 mmol, 1.5 eq.) were added to the reaction flask. The reaction was stirred at room temperature for 4 hours. The solvent was removed by concentration, and ethyl acetate (30 mL) and water (20 mL) were added to extract and separate the layers. The organic layer was washed with saturated brine (30 mL).
  • Step D Add 9-2 (150 mg, 215.57 ⁇ mol, 1 eq.) and THF (2 mL) to the reaction flask, add LiHMDS (1 M, 862.29 ⁇ L, 4 eq.) dropwise under ice bath, stir and react at 0°C for 20 min, then add 4-nitrophenylpentyl carbonate (163.78 mg, 646.72 ⁇ mol, 3 eq.) in THF (0.5 mL) dropwise, and stir and react at room temperature for 16 hours. LC-MS monitoring showed that most of the reaction raw materials were consumed. The reaction system was adjusted to pH 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions.
  • Step C 4-nitrophenol (2.0 g, 14.38 mmol, 1 eq.) and Py (4 mL) were added to the reaction flask, and acetic anhydride (2.20 g, 21.57 mmol, 1.5 eq.) was added dropwise under ice bath conditions. The reaction was stirred at room temperature for 16 hours after the addition was completed. TLC monitoring showed that the reaction raw materials were completely consumed. Under ice water bath conditions, 1 mol/L hydrochloric acid aqueous solution was used to adjust the reaction system to a weak acidity. Water (80 mL) and dichloromethane were added for extraction and washing (30 mL*2). The organic layer was washed once with saturated brine (60 mL).
  • the intermediate 2 (90 mg, 160.23 ⁇ mol, 1 eq.) and DMF (2 mL) were added to the reaction flask, and NaH (51.27 mg, 1.28 mmol, 60% purity, 8 eq.) was added under ice bath, and the reaction was stirred at 0°C for 20 min, and then a solution of 4-nitrophenyl acetate (116.10 mg, 640.92 ⁇ mol, 4 eq.) in DMF (0.5 mL) was added dropwise, and the reaction was stirred at 50°C for 2 hours after the addition.
  • reaction system was adjusted to pH 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions, water (50 mL) was added, and ethyl acetate was extracted and washed (20 mL*4), and the organic layer was washed once with saturated brine (60 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by preparative plate to obtain compound 16b (16.6 mg, yield 15.56%).
  • Step A Add intermediate 2 (120 mg, 0.213 mmol, 1 eq.), DMF (5 mL), ethyl 1-(4-nitrophenoxy)carbonyloxybutyrate (95.26 mg, 0.32 mmol, 1.5 eq.) and DIPEA (110.44 mg, 0.85 mmol, 1 eq.) to the reaction flask. Stir the reaction at 80°C for 1 hour. Add ethyl acetate (50 mL) to dilute, add 1N HCl dropwise at low temperature to quench the reaction, and ensure that the pH of the aqueous phase is 1-2.
  • Step B Nicotinic acid (500 mg, 4.06 mmol, 1 eq.), 4-nitrophenol (677.98 mg, 4.87 mmol, 1.2 eq.) and DCM (30 mL) were added to the reaction flask, and N, N'-dicyclohexylcarbodiimide (1.01 g, 4.87 mmol, 1.2 eq.) was added, and the reaction was stirred at room temperature for 16 hours. TLC monitoring showed that the reaction raw materials were completely consumed, and water (70 mL) was added, and dichloromethane was extracted and washed (30 mL*2).
  • Step C Add 20-1 (120 mg, 184.97 ⁇ mol, 1 eq.) and THF (5 mL) to the reaction flask, add sodium hydroxide aqueous solution (0.5 mol/L, 739.86 ⁇ L, 2 eq.), and stir at room temperature for one hour.
  • Step A Compound 5b (87 mg, 0.124 mmol, 1.0 eq.) DMF (3 mL) and NaH (50 mg, 1.24 mmol, 60% purity, 10.0 eq.) were added to the reaction flask. Stir at room temperature for 20 minutes. 4-Nitrophenyl-4-butyrate (52 mg, 0.248 mmol, 2.0 eq.) DMF (0.5 mL) solution was added dropwise to the reaction. Stir the reaction at room temperature for 3 hours, add ethyl acetate (25 mL) to dilute, and add 1N HCl dropwise to quench the reaction at low temperature to ensure that the pH of the aqueous phase is 1-2.
  • Step A 4-(Hydroxymethyl)phenol (2.82 g, 22.70 mmol, 1 eq.), dichloromethane (100 mL), n-butyric acid (2 g, 22.70 mmol, 1.0 eq.), EDCI (5.22 g, 27.24 mmol, 1.2 eq.) and DMAP (277.33 mg, 2.27 mmol, 0.1 eq.). The reaction was carried out at room temperature for 16 hours under stirring conditions.
  • Step B Add [4-(Hydroxymethyl)phenyl]butyrate (2g, 10.30mmol, 1eq.), dichloromethane (30mL), (4-nitrophenyl)carbonyl chloride (2.08g, 10.3mmol, 1.1eq.) and DIPEA (2g, 15.45mmol, 1.5eq.) to the reaction flask. React at room temperature for 4 hours under stirring. Concentrate to remove the solvent, add ethyl acetate (30mL) and water (20mL) to extract and wash the layers, and wash the organic layer with saturated brine (30mL).
  • Step C Add intermediate 2 (30 mg, 0.053 mmol, 1 eq.), DMF (3 mL), [4-[(4-nitrophenoxy)carbonylmethyl]phenyl]butyrate (28.79 mg, 0.080 mmol, 1.5 eq.) and DIPEA (27.61 mg, 0.21 mmol, 1 eq.) to the reaction flask. Stir the reaction at 80 °C for 16 hours. Add ethyl acetate (25 mL) to dilute, add 1N HCl dropwise at low temperature to quench the reaction, and ensure that the pH of the aqueous phase is 1-2.
  • Step B Add ethanol (457.11 mg, 9.92 mmol, 2 eq.) and DCM (10 mL) to the reaction flask, add triethylamine (753.04 mg, 7.44 mmol, 1.5 eq.), add 4-nitrophenylphosgene (1.0 g, 4.96 mmol, 1 eq.) in DCM (10 mL) dropwise under ice bath conditions, and stir and react at room temperature for 16 hours.
  • Step C Add 23-1 (75 mg, 121.81 ⁇ mol, 1 eq.) and THF (4 mL) to the reaction flask, add sodium hydroxide aqueous solution (0.5 mol/L, 609.03 ⁇ L, 2.5 eq.), and stir at room temperature for one hour.
  • LC-MS monitored the complete consumption of the reaction raw materials, and adjusted the reaction system pH to 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions, and then concentrated to remove most of the solvent .
  • the crude product was then separated and purified by reverse phase preparative column (acetonitrile, water, ammonium acetate system), and lyophilized to obtain compound 23b (39.1 mg, yield 50.53%).
  • Step C Add intermediate 2 (100 mg, 0.053 mmol, 1 eq.), DMF (3 mL), (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl (4-nitrophenyl) carbonate (105.11 mg, 0.356 mmol, 2.0 eq.) and DIPEA (92.04 mg, 0.712 mmol, 4 eq.) to the reaction flask. Stir the reaction at 80 °C for 7 hours, and then stir the reaction at 50 °C for 16 hours. Add ethyl acetate (25 mL) to dilute, add 1N HCl dropwise at low temperature to quench the reaction, and ensure that the pH of the aqueous phase is 1-2.
  • Step A Add 1-butyric acid (600 mg, 6.81 mmol, 1 eq.), water (20 mL) and sodium hydroxide (272 mg, 6.81 mmol, 1 eq.) to the reaction flask. Stir the reaction at room temperature for 10 minutes, and the system becomes clear. Add silver nitrate (1.16 g, 6.81 mmol, 1 eq.) and stir at room temperature for 30 minutes. A large amount of solid is generated, which is filtered and vacuum dried to obtain the product 1-butyric acid silver (1.1 g, 82.85%).
  • Step C Add intermediate 2 (120 mg, 0.213 mmol, 1 eq.), DMF (5 mL), ethyl 1-(4-nitrophenoxy)carbonyloxybutyrate (95.26 mg, 0.32 mmol, 1.5 eq.) and DIPEA (110.44 mg, 0.85 mmol, 1 eq.) to the reaction flask. Stir the reaction at 80 °C for 1 hour. Add ethyl acetate (50 mL) to dilute, add 1N HCl dropwise at low temperature to quench the reaction, and ensure that the pH of the aqueous phase is 1-2.
  • Step C Add isobutyric acid (1.0 g, 11.35 mmol, 1 eq.) and H 2 O (10 mL) to a reaction flask, and dropwise add an aqueous solution (10 mL) of NaOH (454.0 mg, 11.35 mmol, 1 eq.) under ice bath conditions, and stir and react at room temperature for half an hour. Then dropwise add an aqueous solution (10 mL) of AgNO 3 (1.93 g, 11.35 mmol, 1 eq.), and stir and react at room temperature for another hour. The reaction solution is directly filtered, and the filter cake is washed with a small amount of water and dried to obtain the product (isobutyryloxy)silver (1.2 g, yield 54.23%).
  • Step D 1-iodoethyl (4-nitrophenyl) carbonate (1.3 g, 3.86 mmol, 1 eq.), (isobutyryloxy)silver (902.33 mg, 4.63 mmol, 1.2 eq.) and toluene (50 mL) were added to the reaction flask, and the reaction solution was stirred at 50° C. for 16 hours.
  • Step E In a reaction flask, intermediate 2 (110 mg, 195.84 ⁇ mol, 1 eq.), DIPEA (101.24 mg, 783.35 ⁇ mol, 4 eq.) and DMF (3 mL) were added, and then a solution of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyrate (87.33 mg, 293.76 ⁇ mol, 1.5 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred at 80° C. for 1 h. Hours. LC-MS monitored the complete consumption of the reaction raw materials.
  • reaction system was adjusted to pH 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions. Water (50 mL) was added, and ethyl acetate was extracted and washed (20 mL*4). The organic layer was washed once with saturated brine (60 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by reverse phase preparative column (acetonitrile, water, ammonium acetate system) and freeze-dried to obtain compound 26b (45.5 mg, yield 32.28%).
  • Step E Intermediate 2 (120 mg, 213.64 ⁇ mol, 1 eq.), DIPEA (110.44 mg, 854.56 ⁇ mol, 4 eq.) and DMF (3 mL) were added to a reaction flask, and then a solution of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)acetate (86.27 mg, 320.46 ⁇ mol, 1.5 eq.) in DMF (1 mL) was added dropwise. The mixture was stirred at 80°C for 1 hour. LC-MS monitored that the reaction raw materials were consumed. The reaction system was adjusted to pH 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions.
  • the animal is administered a measured volume of dosing solution by oral administration.
  • blood samples are collected at specific time points (e.g., 0.5, 1, 2, 4, 8, 24, 32, and 48 hours).
  • the blood samples are converted into plasma samples using standard techniques.
  • LC-MS/MS analysis is performed to obtain the concentration of the test compound and Brincidofovir (BCV, comparison compound) in plasma.
  • Compound 2b and the control compound were orally administered to ICR male mice at an equimolar amount of 20 mg/kg.
  • the experimental method was as described above.
  • the obtained pharmacokinetic parameters are shown in Table 2.
  • the remaining compounds and comparative examples were orally administered to ICR male mice at an equimolar amount of 40 mg/kg.
  • the experimental method was as described above.
  • the obtained pharmacokinetic parameters are shown in Table 3.
  • Vero cells (ATCC CRL-1587) were inoculated in 96-well plates in a medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin in MEM (Gibco Cat#41500034), and an infection dose of 0.05 PFU/cell of vaccinia virus, Tiantan strain was added.
  • Virus inhibition activity (%) (number of virus plaques in the drug group/number of virus plaques in the control group) ⁇ 100.
  • mice 60 male Balb/c nude mice were randomly divided into 5 groups, namely blank control group, BCV administration group, compound 15b administration group, HPMPA prodrug 3b administration group and HPMPA prodrug 6b administration group.
  • the experimental mice were inoculated with vaccinia virus on D1 of the experiment, and then gavaged with the corresponding drugs on D2, D4 and D6 of the experiment (the blank control group was only given the same volume of solvent), and the three administration doses were 20 mg/kg, 5 mg/kg and 5 mg/kg respectively.
  • the weight changes of the animals before and after administration were recorded during the experiment to evaluate the protective effect of the test substance on the animals, and blood and tissues were taken for standby use.
  • mice in the blank control group gradually reached the surrogate endpoint from D3, a large number of mice reached the surrogate endpoint on D6 and D7, and all mice reached the surrogate endpoint on D8; the BCV administration group failed to improve the situation of mice reaching the surrogate endpoint, and all mice in this group also reached the surrogate endpoint on D8; while the situation of the compound 15b administration group was significantly improved.
  • the efficacy of compound 15b is better than BCV. It can delay the virus-induced weight loss in mice and even restore the weight growth of mice. It can also reduce the death of mice caused by the virus.

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Abstract

L'invention concerne un composé phosphonate ou un sel ou ester pharmaceutiquement acceptable de celui-ci, et son utilisation dans la préparation d'un médicament pour le traitement, l'inhibition ou la prévention d'une maladie provoquée par une infection virale ou une prolifération cellulaire, en particulier pour le traitement, l'inhibition ou la prévention d'une infection par le virus de la variole du singe ou d'une maladie provoquée par celui-ci chez des mammifères, tels que l'être humain.
PCT/CN2023/141023 2022-06-24 2023-12-22 Composé phosphonate et son utilisation médicale Pending WO2024259930A1 (fr)

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