WO2024259934A9 - Analogue nucléosidique et son application médicale - Google Patents

Analogue nucléosidique et son application médicale Download PDF

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Publication number
WO2024259934A9
WO2024259934A9 PCT/CN2023/141230 CN2023141230W WO2024259934A9 WO 2024259934 A9 WO2024259934 A9 WO 2024259934A9 CN 2023141230 W CN2023141230 W CN 2023141230W WO 2024259934 A9 WO2024259934 A9 WO 2024259934A9
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Prior art keywords
virus
compound
substituted
carbonyl
unsubstituted
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Chinese (zh)
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WO2024259934A1 (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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Publication of WO2024259934A1 publication Critical patent/WO2024259934A1/fr
Publication of WO2024259934A9 publication Critical patent/WO2024259934A9/fr
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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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a nucleoside analog or a pharmaceutically acceptable salt or ester thereof, and use thereof in preparing a drug for treating, inhibiting or preventing a viral infection disease or a cell proliferation disease.
  • viruses can be divided into DNA viruses, RNA viruses, etc.
  • the design and discovery of new antiviral drugs are generally directed against viral or cellular targets. Drugs that inhibit viral proteins may be virus-specific and more susceptible to resistance.
  • 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.
  • Monkeypox is a viral zoonosis that causes symptoms in humans similar to those seen in smallpox patients in the past. However, since smallpox was eradicated from the world in 1980, smallpox no longer exists, while monkeypox is still sporadic 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, a double-stranded DNA virus with a relatively stable structure and a low mutation rate.
  • the virus can be transmitted from animals to humans through direct close contact, and can also be transmitted from person to person.
  • the main technical problem solved by the present application is to provide a nucleoside analog compound, which can have at least one or more of the following effects:
  • the present invention provides a nucleoside analogue represented by formula (I) or a pharmaceutically acceptable salt or ester thereof:
  • X is selected from -OR 4 , 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 hydrocarbon carbonyl, substituted or unsubstituted aryl carbonyl or heterocyclic carbonyl, and substituted or unsubstituted hydrocarbon oxycarbonyl
  • the carbonyl has a carbon number of 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 1 , R 2 , R 3 , and R 4 are not H at the same time; 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 , R 3 , and R 4 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 present invention provides compounds represented by formula (IIIa) and formula (IIIb):
  • R 1 , R 3 , and R 4 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 present invention provides a compound represented by formula (IVa) or (IVb):
  • R 1 or R 3 is as defined above.
  • R 1 and R 3 are independently selected from formyl, C1-C3 alkylcarbonyl, (CH 3 ) 2 CHCOOCH(CH 3 )C(O)-, CH 3 COOCH(CH 3 )C(O)-; and X is H.
  • R 1 and R 3 are independently selected from C1-C3 alkylcarbonyl, and X is H.
  • R1 is selected from substituted or unsubstituted arylcarbonyl or heterocyclic carbonyl, including the groups shown below:
  • Y is selected from H, F, Cl, Br, Me, -OMe, -OEt, -CF3 or -CN.
  • R1 is selected from substituted or unsubstituted alkyloxycarbonyl groups, including the groups shown below:
  • R 5 includes the following groups:
  • R 3 includes the following groups:
  • the compounds of the present invention include the compounds shown in the following Table 1a and Table 1b:
  • 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), BeAn58058 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 provided in the present application 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 preferably refers to compounds, compositions and preparations, etc. listed in the pharmacopoeia or other recognized pharmacopoeias 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.
  • the compounds disclosed herein exist as a prodrug.
  • prodrug refers to a pharmaceutical agent that is directly or indirectly converted into an active form in vitro or in vivo (see, for example, R.B. 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 alter the biodistribution (e.g., so that the agent does not normally enter the protease reaction site) or pharmacokinetics of a particular drug.
  • a variety of groups such as esters, ethers, phosphates/salts, etc. have been used to modify compounds to form prodrugs.
  • 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.
  • prodrug includes pharmaceutically acceptable salts, or pharmaceutically acceptable solvates, and any crystalline forms of the above. Prodrugs are generally (although not necessarily) pharmaceutically inactive until they are converted to an active form.
  • substituted or “substituted” as used in the present invention includes the implicit condition that 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, 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, alkylsulfinyl, sulfony
  • hydrocarbyloxy refers to -OR b , where R b is a hydrocarbyl.
  • 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 called 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, triazine, isoindolyl, pteridinyl, furanyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quin
  • heteroaryl includes unsubstituted heteroaryl and substituted heteroaryl.
  • C5-Cn heteroaryl wherein n is an integer from 6 to 15, means a heteroaryl having from 5 to "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 1.
  • 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 amine 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.
  • the present invention also provides a kit comprising an antiviral infection compound or drug.
  • the kit is generally in the form of a physical structure that accommodates various components, and can be used, for example, to implement the method provided herein.
  • the kit may include one or more compounds or drugs disclosed in the present invention (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject.
  • the compound may be provided in a ready-to-use form (e.g., tablet or capsule) or in a form that requires, for example, reconstruction or dilution (e.g., powder) before administration.
  • the kit may also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc. that is 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 encapsulated 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., refrigeration or freezing).
  • 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 Add diethoxymethanol phosphate (20 g, 118.96 mmol, 1.0 eq.), dichloromethane (400 mL) and triethylamine (14.44 g, 142.75 mmol, 1.2 eq.) to the reaction flask. After cooling to -60 °C, slowly drop trifluoromethanesulfonic anhydride (38.6 g, 136.80 mmol, 23.02 mL, 1.15 eq.) into the reaction system and stir for half an hour. Slowly warm to room temperature and stir for 1 hour.
  • Step C Add compound b (5 g, 11.07 mmol, 1.0 eq.) and tetrahydrofuran (100 mL) to the reaction flask. Cool to -60 °C, slowly add LiHMDs (1.0 M, 33.22 mL, 3.0 eq.). After stirring at -60 °C for 15 minutes, slowly add diethoxy methyl trifluoromethanesulfonate solution (8.30 g dissolved in 20 mL tetrahydrofuran, 28.79 mmol, 2.6 eq.). Warm to room temperature and stir for 16 hours.
  • LiHMDs 1.0 M, 33.22 mL, 3.0 eq.
  • Step E Add d (0.8 g, 2.23 mmol, 1 eq.), acetonitrile (10 mL) and TMSBr (1.36 g, 8.91 mmol, 1.18 mL, 4.0 eq.) to a reaction flask, stir at room temperature for 16 hours, concentrate to remove the reaction solvent, add water to the residue, and freeze-dry to obtain product e (675 mg, yield: 99.10%).
  • Step F Add e (0.2 g, 0.66 mmol, 1 eq.), DMF (10 mL), and DIPEA (1 mL) to the reaction flask. Stir the reaction at 45°C for 2 hours. Concentrate and remove the solvent to obtain a residue, add DMF (10 mL), 2-(octadecyloxy)ethane-1-ol (0.31 g, 0.99 mmol, 1.5 eq.), DIPEA (0.51 g, 3.96 mmol, 0.69 mL, 6.0 eq.) and pyBOP (1.03 g, 1.98 mmol, 3.0 eq.).
  • Step G Add f (70 mg, 0.12 mmol, 1 eq.) and sodium hydroxide aqueous solution (0.5 M, 1.2 mmol, 5.0 eq.) to the reaction flask. Stir the reaction at room temperature for 48 hours. 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 1 (65 mg, yield 84.56%).
  • Step A Add intermediate 1 (50 mg, 0.083 mmol, 1.0 eq.), DMF (3 mL) and NaH (33.35 mg, 0.833 mmol, 60% purity, 10.0 eq.) to the reaction flask. Stir at room temperature for 20 minutes. 4-nitrophenylbutyrate (34.22 mg, 0.208 mmol, 2.5 eq.) DMF (0.5 mL) solution was added dropwise to the reaction. Stir at room temperature for 3 hours, then heated to 50 ° C for 2 hours.
  • Step A 4-nitrophenol (2.0 g, 14.38 mmol, 1 eq.) and Py (4 mL) were added to the reaction flask, acetic anhydride (2.20 g, 21.57 mmol, 1.5 eq.) was added dropwise under ice bath conditions, and the reaction was stirred at room temperature for 16 hours.
  • the intermediate 1 (100 mg, 166.74 ⁇ mol, 1 eq.) and DMF (2 mL) were added to the reaction flask, and NaH (53.36 mg, 1.33 mmol, 60% purity, 8 eq.) was added under ice bath, and the reaction was stirred at 0°C for 20 min, and then a DMF (1 mL) solution of 4-nitrophenyl acetate (120.82 mg, 666.96 ⁇ mol, 4 eq.) was added dropwise, and the reaction was stirred at 50°C for 2 hours after the addition.
  • Step A 2-(octadecyloxy)ethyl hydrogen (((S)-1-(6-amino-9H-purin-9-yl)-3-hydroxypropyl-2-yl)oxy)methyl)phosphonate (30 mg, 0.05 mmol, 1 eq.) and formic acid (4 mL) were added to a reaction flask. The mixture was stirred at 60°C for 16 hours, and the formic acid was removed by concentration. Methanol (5 mL) was added to the residual crude product, and the mixture was stirred for 30 minutes. The solid was filtered to obtain a solid. After the solid was dispersed in water, it was lyophilized to obtain compound 3b (20 mg, yield 59.88%).
  • Step A Add intermediate 1 (80 mg, 133.39 ⁇ mol, 1 eq.), DIPEA (68.96 mg, 533.56 ⁇ mol, 4 eq.) and DMF (2 mL) into a reaction flask, and then add dropwise a solution of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)isobutyrate (79.30 mg, 266.78 ⁇ mol, 2 eq.) in DMF (1 mL). After the addition is completed, stir the reaction at 80°C for 6 hours. LC-MS monitoring showed that the reaction raw materials were basically consumed.
  • 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). 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 lyophilized to obtain compound 4b (20 mg, yield 18.83%).
  • Step A Intermediate 1 (100 mg, 166.74 ⁇ mol, 1 eq.), DIPEA (86.20 mg, 666.96 ⁇ mol, 4 eq.) and DMF (4 mL) were added to a reaction flask, and then a solution of ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)acetate (67.33 mg, 250.11 ⁇ mol, 1.5 eq.) in DMF (1 mL) was added dropwise. The mixture was stirred at 80°C for 5 hours. LC-MS monitoring showed that the reaction raw materials were basically consumed. The reaction system was adjusted to pH 2 with 1 mol/L hydrochloric acid aqueous solution under ice-water bath conditions.
  • Step A Add intermediate 1 (200 mg, 0.34 mmol, 1 eq.) and formic acid (10 mL) to the reaction flask. Stir the reaction at 60°C for 16 hours, concentrate to remove formic acid, add methanol (5 mL) and acetonitrile (5 mL) to the residual crude product, stir for 10 minutes, filter to obtain a solid, disperse the solid in methanol (15 mL), continue stirring for 10 minutes, and filter to obtain a solid. After the solid is dispersed in water, freeze-dried to obtain compound 6b (150 mg, yield 69.87%).
  • Step C Add 1-1 (5 g, 11.07 mmol, 1.0 eq.) and tetrahydrofuran (100 mL) to the reaction flask. Cool to -60 °C, slowly add LiHMDs (1.0 M, 33.22 mL, 3.0 eq.). After stirring at -60 °C for 15 minutes, slowly add diethoxy methyl trifluoromethanesulfonate solution (8.30 g dissolved in 20 mL tetrahydrofuran, 28.79 mmol, 2.6 eq.). Warm to room temperature and stir for 16 hours.
  • LiHMDs 1.0 M, 33.22 mL, 3.0 eq.
  • Step E 1-3 (0.8 g, 2.23 mmol, 1 eq.), acetonitrile (10 mL) and TMSBr (1.36 g, 8.91 mmol, 1.18 mL, 4.0 eq.) were added to a reaction flask, stirred at room temperature for 16 hours, concentrated to remove the reaction solvent, added water to the residue, and freeze-dried to obtain product 1-4 (675 mg, yield: 99.10%).
  • Step F 1-4 (0.2 g, 0.66 mmol, 1 eq.), DMF (10 mL), and DIPEA (1 mL) were added to the reaction flask. The reaction was stirred at 45°C for 2 hours. The solvent was removed by concentration to obtain a residue, and DMF (10 mL), 2-(octadecyloxy)ethane-1-ol (0.31 g, 0.99 mmol, 1.5 eq.), DIPEA (0.51 g, 3.96 mmol, 0.69 mL, 6.0 eq.) and pyBOP (1.03 g, 1.98 mmol, 3.0 eq.) were added.
  • Step G Add 1-5 (70 mg, 0.12 mmol, 1 eq.) and sodium hydroxide aqueous solution (0.5 M, 1.2 mmol, 5.0 eq.) to the reaction flask. Stir the reaction for 48 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 Comparative Example 1 (65 mg, yield 84.56%).
  • Steps A-E are the same as those of Comparative Example 1
  • Step F Add 2-1 (0.675 g, 2.23 mmol, 1 eq.), DMF (25 mL), and DIPEA (3 mL) to the reaction flask. Stir the reaction at 45°C for 2 hours. Concentrate and remove the solvent to obtain a residue, add DMF (25 mL), 3-(hexadecyloxy)propanol (1 g, 3.34 mmol, 1.5 eq.), DIPEA (1.73 g, 13.36 mmol, 2.33 mL, 6.0 eq.) and pyBOP (3.48 g, 6.68 mmol, 3.0 eq.).
  • Step G Add 2-2 (150 mg, 0.26 mmol, 1 eq.) and sodium hydroxide aqueous solution (0.5 M, 2.64 mmol, 5.0 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 the product comparative example 2 (80 mg, yield 51.29%).
  • 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 the parent drug in the comparative example in plasma.
  • 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 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.
  • the results of the in vitro test are shown in FIG1 .
  • the inhibitory activities of BCV and BCV prodrug 15b are similar, while the inhibitory activities of the present compound 3b and compound 6b are similar, about 10-30 times that of BCV, with EC50 values of 0.068 ⁇ M and 0.165 ⁇ M, respectively.
  • mice 60 male Balb/c nude mice were randomly divided into 5 groups, namely blank control group, BCV administration group, BCV prodrug 15b administration group, compound 3b administration group and compound 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 3b and compound 6b administration groups was significantly improved, among which compound 3b had the best effect, and only one mouse reached the surrogate endpoint on D14.
  • the therapeutic effects of compound 3b and compound 6b are better than BCV. They can delay the virus-induced weight loss in mice, and even restore the weight growth of mice, and can also reduce the death of mice caused by the virus.

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Abstract

Analogue de nucléoside, ou sel ou ester pharmaceutiquement acceptable de celui-ci, à utiliser dans la préparation d'un médicament pour traiter, inhiber ou prévenir une maladie provoquée par une infection virale ou une prolifération cellulaire, et en particulier qui permet traiter, inhiber ou prévenir une infection par la variole du singe ou une maladie provoquée par une infection par la variole du singe chez un mammifère, notamment les êtres humains.
PCT/CN2023/141230 2022-06-24 2023-12-22 Analogue nucléosidique et son application médicale Pending WO2024259934A1 (fr)

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ES2600792T3 (es) * 2006-05-03 2017-02-10 Chimerix, Inc. Alcoxialquilésteres metabólicamente estables de fosfonatos, fosfonatos nucleosídicos y fosfatos nucleosídicos antivirales o antiproliferativos
WO2011053812A1 (fr) * 2009-10-30 2011-05-05 Chimerix, Inc. Procédés de traitement de maladies associées à des virus
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