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WO2018230479A1 - Dérivé d'éther de silyle en position 5' pour agent anticancéreux nucléosidique ou agent anti-viral - Google Patents

Dérivé d'éther de silyle en position 5' pour agent anticancéreux nucléosidique ou agent anti-viral Download PDF

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Publication number
WO2018230479A1
WO2018230479A1 PCT/JP2018/022132 JP2018022132W WO2018230479A1 WO 2018230479 A1 WO2018230479 A1 WO 2018230479A1 JP 2018022132 W JP2018022132 W JP 2018022132W WO 2018230479 A1 WO2018230479 A1 WO 2018230479A1
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compound
salt
agent
nucleoside
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Japanese (ja)
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孫市 酒向
晋平 杉山
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大原薬品工業株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Definitions

  • the present invention relates to the creation of compounds that have high stability against various hydrolytic metabolic enzymes and can be used as prodrugs of nucleoside anticancer agents or antiviral agents.
  • the anticancer nucleosides currently used in clinical practice include cytarabine, floxuridine, pentostatin, fludarabine, cladribine, gemcitabine, 5-azacytidine, 2'-deoxy-5-azacytidine, clofarabine, nelarabine, tri Examples include fluorothymidine.
  • These nucleosides are incorporated into DNA and RNA via a nucleic acid biosynthetic route in mitotic cancer cells to inhibit modification and elongation of DNA and RNA, and inhibit synthesis of the corresponding protein. Since it shows a cell killing action, it is used as a therapeutic agent for various cancers (Non-patent Document 1).
  • antiviral nucleosides in clinical use include zidovudine, lamivudine, stavudine, abacavir, emtricitabine, didanosine, zalcitabine, etc., but all of these nucleosides are used in virus-infected cells. Since it is incorporated into DNA or RNA via a nucleic acid biosynthesis route and inhibits reverse transcriptase involved in DNA or RNA synthesis and exhibits a cell killing action, it is used as an antiviral agent (Non-Patent Documents 2 to 3). ).
  • cytidine derivatives and adenosine derivatives have very low stability to hydrolytic metabolic enzymes present in blood or liver, ie cytidine deaminase or adenosine deaminase, and other nucleoside derivatives.
  • Some of these drugs have low oral absorbability and low cell membrane permeability, so the expected anticancer activity and antiviral activity cannot be obtained. In many cases, side effects are caused by administration of these large doses of drugs.
  • Non-Patent Documents 4 to 7 are examples of acetyl ester of the sugar moiety hydroxyl group of gemcitabine and 5′-position eridic ester (CP-4200) of azacitidine.
  • nucleoside anticancer agent or antiviral agent As a prodrug of a nucleoside anticancer agent or antiviral agent, it itself has high stability against various hydrolytic metabolic enzymes and is deprotected enzymatically or enzymatically in cells. Therefore, a derivative capable of easily releasing a nucleoside anticancer agent or antiviral agent is desired.
  • the subject of the present invention is a derivative of the 5′-hydroxyl moiety of a nucleoside anticancer agent or antiviral agent, which itself is against various hydrolytic metabolic enzymes such as cytidine deaminase, adenosine deaminase, esterase and the like.
  • a prodrug of a nucleoside anticancer agent or antiviral agent having a high stability and capable of gradually releasing the corresponding nucleoside anticancer agent or antiviral agent non-enzymatically under physiological conditions There is to provide as.
  • the present inventors have a high stability against hydrolytic metabolic enzymes such as cytidine deaminase, and can be administered orally in order to provide a drug that is further useful as a preventive or therapeutic agent for cancer or viral infection.
  • hydrolytic metabolic enzymes such as cytidine deaminase
  • the present inventors synthesized various 5′-position silyl ether derivatives of nucleoside anticancer agents or antiviral agents including 5-azacytidines, and investigated their chemical reactivity.
  • the 5'-position silyl ether derivative having a specific structure of a nucleoside anticancer agent or antiviral agent unexpectedly has high stability against various hydrolytic metabolic enzymes, but can be administered orally.
  • the present inventors have found that it has extremely excellent properties as a pharmaceutical that can be smoothly deprotected non-enzymatically and enter the nucleic acid biosynthetic route in cells. Further studies were made and the present invention was completed.
  • the nucleoside anticancer agent is cytarabine, floxuridine, pentostatin, fludarabine, cladribine, gemcitabine, clofarabine, nelarabine, trifluorothymidine, DFP-10917, cordycepin, 8-chloroactinomycin, RX-3117, triciribine,
  • [3] The compound or a salt thereof according to [1], wherein the antiviral agent is zidovudine, lamivudine, stavudine, abacavir, emtricitabine, didanosine or zalcitabine.
  • Compound is The compound according to [1] or a salt thereof.
  • R 1 , R 2 and R 3 may be the same or different and each may have a C 1 -C 6 alkyl group or phenyl C 1 -C 6 alkyl group or naphthyl C 1-
  • R 1 , R 2 and R 3 may be the same or different from each other, and are methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, pentyl group. Or a compound or a salt thereof according to any one of [1] to [4], which is a hexyl group. [7] Any of [1] to [4], wherein R 1 , R 2 and R 3 may be the same or different and each is a benzyl group, phenethyl group or naphthylmethyl group which may have a substituent. 2. The compound according to claim 1 or a salt thereof.
  • R 1 , R 2 and R 3 may be the same or different, and may be a methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group or benzyl group.
  • a nucleoside anticancer agent or an antiviral agent may be substituted with a trialkylsilyl halide, dialkylmonoarylalkylsilyl halide, monoalkyldiarylalkylsilyl halide, or triarylalkylsilyl halide, which may have a substituent, and dehydrohalogenated.
  • the method for producing a compound according to [1], comprising reacting in the presence of an agent.
  • the nucleoside anticancer agent or antiviral agent is a trialkylsilyl acylate or dialkyl monoarylalkylsilyl acylate or monoalkyldiarylalkylsilyl acylate or triarylalkylsilyl acylate which may have a substituent.
  • [11] [1]
  • a pharmaceutical composition comprising any one of [8] or a salt thereof.
  • the pharmaceutical composition according to [11] which is a growth inhibitor of cancer cells or virus-infected cells.
  • the pharmaceutical composition according to [11] which is a preventive or therapeutic agent for cancer or viral infection.
  • a method for inhibiting the growth of cancer cells or virus-infected cells in a mammal comprising administering to the mammal an effective amount of any one of [1] to [8] or a salt thereof.
  • a method for preventing or treating cancer or a viral infection in a mammal comprising administering an effective amount of any one of [1] to [8] or a salt thereof to the mammal.
  • the 5′-position silyl ether derivative of a nucleoside anticancer agent or antiviral agent is more lipophilic than the corresponding nucleoside anticancer agent or antiviral agent, and thus can be administered orally.
  • various hydrolytic metabolic enzymes carboxyesterase, cytidine deaminase, adenosine deaminase, etc.
  • It passes through the cell membrane of a virus-infected cell and is gradually hydrolyzed non-enzymatically in the cell membrane or in the cell under physiological conditions to efficiently release the corresponding nucleoside anticancer agent or antiviral agent.
  • nucleosides are incorporated into DNA or RNA via the nucleic acid biosynthesis route to inhibit modification or elongation of DNA or RNA, inhibit synthesis of the corresponding protein, or inhibit reverse transcriptase to kill. Since it is presumed to show cell action, it can be expected to function as a preventive or therapeutic agent for various cancers and viral infections.
  • the compound of the present invention or a salt thereof is a compound represented by the following formula (I).
  • D is the 5′-position of the nucleoside anticancer agent or antiviral agent
  • R 1 , R 2, and R 3 are each optionally substituted alkyl. Group or an arylalkyl group.
  • R 1 , R 2 and R 3 may be the same or different.
  • Nucleoside anticancer agents include cytarabine, floxuridine, pentostatin, fludarabine, cladribine, gemcitabine, clofalabine, and nearabine , Trifluorothymidine (TFT), DFP-10917, Cordycepin, 8-Chloro-adenosine, RX-3117, Triciribine, Forodesine, 5-Fluorodeoxy Examples include cytidine (5-Fluoro-2'-deoxycytidine), ribavirin, acadecine, etc. The chemical structures of these nucleoside anticancer agents are shown below as examples.
  • nucleoside antiviral agent examples include zidovudine, lamivudine, stavudine, abacavir, emtricitabine, didanosine, zalcitabine, and the like.
  • the chemical structure of the nucleoside antiviral agent is shown below.
  • Examples of the compound represented by the formula (I) of the present invention include the following formulas (i) to (xvi).
  • R 1 , R 2 and R 3 are each an alkyl group or an arylalkyl group which may have a substituent.
  • R 1 , R 2 and R 3 may be the same or different.
  • the “alkyl group optionally having substituent (s)” may or may not have a substituent.
  • the substituent may have 1 to 5, preferably 1 to 3 substituents at the substitutable position of the alkyl group, and when the number of substituents is 2 or more, each substituent may be the same or different.
  • Examples of the substituent include an alkyl group, a halogen atom, a cyano group, and a nitro group.
  • Preferred examples of the substituent are an alkyl group and a halogen atom.
  • alkyl group refers to a saturated aliphatic hydrocarbon group, for example, a linear or branched alkyl group having 1 to 20 carbon atoms or a cyclic alkyl group, unless otherwise specified.
  • linear or branched alkyl group include C 1 such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, pentyl group, and hexyl group.
  • heptyl group 1-methylhexyl group, 5-methylhexyl group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 4,4-dimethylpentyl group, 1-ethylpentyl group 2-ethylpentyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,3,3-trimethylbutyl group, 2,2,3-trimethylbutyl group, 2,3 , 3-trimethylbutyl group, 1-propylbutyl group, 1,1,2,2-tetramethylpropyl group, octyl group, 1-methylheptyl group, 3-methylheptyl group 6-methylheptyl group, 2-ethylhexyl group, 5,5-dimethylhexyl group, 2,4,4-trimethylpentyl group, 1-ethyl-1-methylpentyl group, nonyl group, 1-methyloctyl group,
  • Preferred examples of the C 1 -C 6 alkyl group are a methyl group and an ethyl group.
  • Examples of the cyclic alkyl group include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Preferred examples of the cyclic alkyl group are a cyclopentyl group and a cyclohexyl group.
  • the “arylalkyl group which may have a substituent” may or may not have a substituent.
  • the substituent may have 1 to 5, preferably 1 to 3 substituents at the substitutable position of the arylalkyl group. When the number of substituents is 2 or more, each substituent may be the same or different.
  • Examples of the substituent include an alkyl group, a halogen atom, a cyano group, and a nitro group. Preferred examples of the substituent are an alkyl group and a halogen atom.
  • Arylalkyl refers to an alkyl group substituted by an aryl. Preferred are a phenyl C 1 -C 6 alkyl group and a naphthyl C 1 -C 6 alkyl group. Examples of phenyl C 1 -C 6 alkyl groups are benzyl group, 1-phenylethyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group. Examples of the naphthyl C 1 -C 6 alkyl group include, but are not limited to, a naphthylmethyl group, a naphthylethyl group, and the like.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like, and preferred examples are a fluorine atom, a chlorine atom and a bromine atom.
  • a preferred combination of R 1, R 2 and R 3, R 1, R 2 and R 3 are each the same or different at best, a halogen atom optionally substituted C 1 have ⁇ C 6 alkyl group, or a halogen atom or a C 1 ⁇ C 6 alkyl-substituted phenyl C 1 optionally ⁇ C 6 alkyl group group.
  • R 1, R 2 and R 3 are each the same or different even if well, C 1 ⁇ C 6 alkyl group or a - optionally C 1 be substituted by a halogen atom C 6 alkyl group or a C 1 - C 6 alkyl group or a phenyl optionally substituted by a halogen atom C 1 A C 6 alkyl group.
  • R 1 is a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • R 2 is methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group , Isobutyl group, tert-butyl group, pentyl group, hexyl group or benzyl group
  • R 3 is methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group , A pentyl group, a hexyl group or a benzyl group.
  • the salt of the compound represented by the formula (I) of the present invention may be any salt as long as it is a pharmacologically acceptable salt.
  • the salt include inorganic acid salts (for example, hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic acid salts (for example, acetate, trifluoroacetate, succinate, And acid addition salts such as maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc. It is not limited to.
  • the compound represented by the formula (I) of the present invention may be a crystal, and may be a single crystal form or a mixture of a plurality of crystal forms.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • the compound represented by the formula (I) of the present invention may be a solvate (for example, a hydrate), and any of a solvate and a non-solvate (for example, a non-hydrate). Are also encompassed in compound (I).
  • the 5′-position silyl ether derivative of the nucleoside anticancer agent or antiviral agent of the present invention can be a prodrug of a nucleoside anticancer agent or antiviral agent.
  • Compound (I) of the present invention can be produced , for example, by the method shown below or a method analogous thereto (for example, Corey, EJ et al., J. Am. Chem. Soc., 94, 6190, 1972; Morita, T. et al., Tetrahedron Lett., 21, 835, 1980; see Kita, Y. et al., Tetrahedron Lett., 4311, 1979, etc. For reviews, see Lalonde, M .; Chan, TH Synthesis, 817-845, 1985, etc.).
  • compound (I) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, by reacting various nucleosides with a trialkylsilyl halide compound in an appropriate solvent in the presence of dehydrohalogen, or by reacting with a trialkylsilyl acylate compound in the presence of a base. 5'-position trialkylsilyl ether derivatives of nucleosides can be obtained.
  • silyl halide or silyl acylate compound is not particularly limited, and any of those used in the art can be used in the method of the present invention.
  • a trialkylsilyl halide compound, a monoalkyldiarylalkylsilyl halide compound, a dialkylmonoarylalkylsilyl halide, a triarylalkylsilyl halide compound, or the like can be used.
  • examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group. Can be used. Of these, a methyl group, an ethyl group, or a propyl group is preferable.
  • a benzyl group or the like can be used.
  • a chlorine atom which comprises a silyl halide compound
  • a chlorine atom a bromine atom, an iodine atom, etc.
  • a chlorine atom a chlorine atom
  • a bromine atom a bromine atom
  • an iodine atom etc.
  • examples of the silyl halide compound include trimethylsilyl chloride (sometimes referred to as trimethylchlorosilane; the same applies to the following compounds), triethylsilyl chloride, isopropyldimethylsilyl chloride, tert-butyldimethylsilyl chloride, and the like.
  • the kind of silyl acylate compound is not particularly limited, and any of those used in the art can be used in the method of the present invention.
  • a trialkylsilyl acylate compound for example, a trialkylsilyl acylate compound, a monoalkyldiarylalkylsilyl acylate compound, a dialkyl monoarylalkylsilyl acylate, a triarylalkylsilyl acylate compound, or the like can be used.
  • the silyl acylate compound has an alkyl group
  • examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a tert-butyl group.
  • the alkyl group examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a
  • silyl acylate compound has an arylalkyl group, a benzyl group or the like can be used. More specifically, as the silyl acylate compound, trimethylsilyl acetate, triethylsilyl acetate, isopropyldimethylsilyl acetate, tert-butyldimethylsilyl acetate, trimethylsilyl triflate, triethylsilyl triflate, isopropyldimethylsilyl triflate, tert-butyldimethyl Examples thereof include silyl triflate.
  • Examples of the dehydrohalogenating agent or base used include organic bases and inorganic bases.
  • Examples of organic bases include, but are not limited to, triethylamine, N, N-diisopropylethylamine. Imidazole, pyridine, 4-dimethylaminopyridine, n-butyllithium, potassium tert-butoxide and the like, and imidazole and triethylamine are preferred.
  • Examples of the inorganic base include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, and the like.
  • the equivalent of a raw material compound or more is preferable. Furthermore, a range of 1.0 to 10.0 equivalents can usually be exemplified with respect to 1 mol of the raw material compound, but a range of 1.0 to 6.0 equivalents is preferable, and 1.0 to 4.4 is more preferable. The range is preferably 0 equivalent.
  • reaction solvent From the viewpoint of smooth progress of the reaction, the reaction of the present invention is preferably carried out in the presence of a solvent.
  • the solvent in the reaction of the present invention may be any solvent as long as the reaction proceeds.
  • Examples of the solvent in the reaction of the present invention include amides (for example, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), N, N-diethylacetamide, N-methylpyrrolidone (NMP)).
  • Etc. preferably DMF, DMAC, NMP, more preferably DMF and sulfoxides (for example, dimethyl sulfoxide, etc.), but are not limited to these, as long as the reaction proceeds,
  • the amount of the solvent used in the reaction of the present invention can be appropriately adjusted by those skilled in the art.
  • reaction temperature The reaction temperature of the present invention is not particularly limited. In one embodiment, from the viewpoints of yield improvement, suppression of by-products and economic efficiency, etc., ⁇ 20 ° C. to 50 ° C. (ie, minus 20 ° C. to plus 50 ° C.), preferably ⁇ 10 ° C. to 30 ° C. A range of ° C. (that is, minus 10 ° C. to plus 30 ° C.) can be exemplified.
  • reaction time The reaction time of the present invention is not particularly limited. In one embodiment, from the viewpoint of improvement in yield, suppression of by-products and economic efficiency, etc., 0.5 hours to 120 hours, preferably 0.5 hours to 72 hours, more preferably 0.5 hours. A range of ⁇ 48 hours, more preferably 0.5 hours to 24 hours can be exemplified. However, the reaction time of the present invention can be appropriately adjusted by those skilled in the art.
  • composition of the present invention can be used as a pharmaceutical composition by mixing it with a pharmacologically acceptable carrier as it is or by a method known per se.
  • a pharmacologically acceptable carrier as it is or by a method known per se.
  • Monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc. Monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.
  • the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used.
  • preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • the dosage form of the pharmaceutical composition include tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, suspensions, sustained-release oral preparations, and the like. These can be safely administered orally.
  • a liquid agent is also possible, it is not restricted to this.
  • the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the compound (I) of the invention has many therapeutic and prophylactic uses.
  • the compounds (I) of the invention are each used for the corresponding nucleoside indication.
  • 5'-position silyl ether derivative of gemcitabine see formula (vi) in the above figure
  • non-small cell lung cancer pancreatic cancer
  • biliary tract cancer urothelial cancer
  • inoperable or recurrent breast cancer cancer chemistry Ovarian cancer, exacerbated after therapy, relapsed or refractory malignant lymphoma, etc.
  • cancer chemistry Ovarian cancer exacerbated after therapy, relapsed or refractory malignant lymphoma, etc.
  • the pharmaceutical composition used in the present invention is provided as a dosage form for oral administration.
  • the pharmaceutical compositions provided herein can be provided in solid, semi-solid or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual and sublingual administration.
  • Suitable oral dosage forms include tablets, capsules, pills, troches, medicinal candy, aroma preparations, cachets, pellets, drug-added chewing gum, granules, bulk powders, foamed formulations or non-foamed powders or granules, Examples include, but are not limited to, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs and syrups.
  • the pharmaceutical composition comprises binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, pigment migration inhibitors, sweeteners and flavoring agents,
  • One or more pharmaceutically acceptable carriers or excipients may be included without limitation.
  • the amount of compound (I) of the present invention within the pharmaceutical composition or dosage form is, for example, from about 1 mg to about 2,000 mg, from about 10 mg to about 2,000 mg, from about 20 mg to about 2,000 mg, from about 50 mg to about 1,000 mg, about It may range from 100 mg to about 500 mg, from about 150 mg to about 500 mg, or from about 150 mg to about 250 mg.
  • the effective dose is determined according to the nature of the cancer, the degree of progression of the cancer, the treatment policy, the degree of metastasis, the amount of the tumor, the body weight, age, sex, and the patient's (although it can be appropriately selected depending on genetic or racial background, the pharmaceutically effective amount is generally determined based on factors such as clinically observed symptoms and the degree of progression of cancer.
  • the daily dose is, for example, about 0.01 to about 10 mg / kg (about 0.5 mg to about 500 mg for a 60 kg adult), preferably about 0.05 to about 5 mg / kg when administered to a human. Preferably, it is about 0.1 to about 2 mg / kg. Administration may be performed once or divided into multiple times.
  • nucleosides having a cytosine skeleton were used.
  • 5′-position silyl ether derivatives (see formula (I)) were found to be very stable in the presence of cytidine deaminase in all cases. It was confirmed that it was difficult to undergo hydrolytic metabolism by the enzyme cytidine deaminase in the liver.
  • nucleosides having a hydroxyl group at the 5 'position for example, gemcitabine
  • the 5′-position silyl ether derivative of the nucleoside thus obtained (see formula (I)) is used in an environment close to physiological conditions (for example, at 37 ° C. in a phosphate buffered saline solution).
  • the stability was examined, among the derivatives according to the present invention, when the substituents (R 1 , R 2 and R 3 ) directly linked to the silyl group were appropriately selected, the derivatives were hydrolyzed at an appropriate speed and the corresponding nucleosides were obtained. Was confirmed to be efficiently given.
  • the 5′-position silyl ether derivative of the nucleoside according to the present invention having a high stability to the above-mentioned hydrolytic metabolic enzyme and an appropriate hydrolysis reactivity under physiological conditions (formula (I Can be prodrugs of the corresponding nucleosides.
  • room temperature means about 15-30 ° C.
  • 1 H-NMR and 13 C-NMR were measured using JEOL JNM-ECZ 400R and showed a chemical shift ⁇ (ppm) from tetramethylsilane as an internal standard.
  • Other symbols in the present specification have the following meanings. s: singlet, d: doublet, t: triplet, m: multiplet, br: broad, br s: broad singlet, J: binding constant Mass of each compound was measured using a Yamazen Smart Flash MS system apparatus. Value.
  • Nucleosides (1 mM) are dissolved or suspended in about 3 mL of anhydrous N, N-dimethylformamide (DMF) at room temperature, and this is mixed with imidazole (about 1.2 times mol with respect to the raw material) and the corresponding trialkylsilyl.
  • Halide (about 1.2 times mol with respect to the raw material) was added under cooling at 0 ° C., and then the mixture was stirred while gradually returning to room temperature until the raw material disappeared (about 0.5 to 17 hours).
  • the reaction mixture was poured into 50 mL of a mixture of ethyl acetate and saturated brine (2: 1), and extracted with ethyl acetate.
  • Nucleosides (1 mM) were dissolved or suspended in about 3 mL of anhydrous DMF at room temperature, and triethylamine (about 1.2 times mol to the raw material) and corresponding trialkylsilyl acylate (to the raw material, About 1.2 times mol) was added under cooling at 0 ° C., and then the mixture was stirred while gradually returning to room temperature until the raw materials disappeared (about 0.5 to 17 hours). The reaction mixture was poured into 50 mL of a mixture of ethyl acetate and saturated brine (2: 1), and extracted with ethyl acetate.
  • Nucleosides (1 mM) are dissolved or suspended in about 3 mL of anhydrous DMF at room temperature, and triethylamine (about 1.2 times mol to the raw material) and corresponding trialkylsilyl triflate (to the raw material, About 1.2-fold mol) was added under cooling at ⁇ 10 ° C., and the mixture was stirred while gradually returning to room temperature until the raw material disappeared (about 0.5 to 17 hours).
  • the reaction mixture was poured into 50 mL of a mixture of ethyl acetate and saturated brine (2: 1), and extracted with ethyl acetate.
  • a 5′-position silyl ether derivative (see formula (I)) of a nucleoside anticancer agent or antiviral agent is dissolved in 1 mL of acetonitrile, and 10 ⁇ L thereof is added to 1 mL of phosphate buffered saline. 10 ⁇ L of a cytidine deaminase phosphate buffered saline solution was added to the resulting solution and stirred at 37 ° C. for about 1 hour. 1 mL of acetonitrile was added to the reaction solution and centrifuged, and the supernatant was analyzed by HPLC.
  • Table 1 shows the analysis results for 5′-O-triethylsilyl-gemcitabine (Compound A) and 5′-O-isopropyldiethylsilyl-gemcitabine (Compound C).
  • Cytidine deaminase CDA (1-146aa), Human, His-tagged, Recombinant cytidine deaminase (ATGen) HPLC measurement conditions: Column: CAPCELL PAK ADME 4.6 mm ⁇ 150 mm, particle size: 3 ⁇ m
  • Elution: Eluent A 10 mM ammonium formate-containing purified water
  • Detector UV260nm
  • the 5′-position silyl ether derivative (see formula (I)) of the nucleoside anticancer agent or antiviral agent having a cytosine skeleton according to the present invention was very stable against cytidine deaminase. .
  • cytidine and gemcitabine disappeared completely under the reaction conditions described above.
  • a 5′-position silyl ether derivative of a nucleoside anticancer agent or antiviral agent for example, about 1 mg of 5′-O-triethylsilyl-gemcitabine (compound A) is dissolved in 1 mL of acetonitrile; 5 ⁇ L of the solution was added to 100 ⁇ L of 10 mM phosphate buffered saline solution and stirred at 37 ° C. As a result of HPLC analysis of the reaction product over time, the production of gemcitabine was confirmed, and the production of other decomposition products was not observed.
  • medical agent which can replace the nucleoside type

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Abstract

Le problème décrit par la présente invention concerne la fourniture d'un médicament qui remplace des agents anticancéreux nucléosidiques ou des agents anti-viraux cliniquement utilisés en tant que médicaments thérapeutiques pour le cancer ou l'infection virale, qui est hautement stable vis-à-vis de diverses enzymes métaboliques hydrolytiques, qui peut être pris par voie orale, et qui est incorporé dans les voies de biosynthèse d'ADN et d'ARN et produit un effet cytocide en effectuant une modification d'ADN ou d'ARN et une inhibition d'extension ou une inhibition de transcriptase inverse, ainsi qu'une une inhibition de synthèse de protéine. La solution selon l'invention porte sur un nouveau composé représenté par la formule (I). (Dans la formule : D représente la position 5' d'un agent anticancéreux nucléosidique ou d'un agent anti-viral ; et R1, R2 et R3 sont chacun éventuellement identiques ou différents, un groupe alkyle qui peut avoir un substituant, ou un groupe arylalkyle.)
PCT/JP2018/022132 2017-06-13 2018-06-11 Dérivé d'éther de silyle en position 5' pour agent anticancéreux nucléosidique ou agent anti-viral WO2018230479A1 (fr)

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WO2023022216A1 (fr) 2021-08-20 2023-02-23 塩野義製薬株式会社 Dérivés nucléosidiques et leurs promédicaments ayant une action inhibitrice de la croissance virale

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Publication number Priority date Publication date Assignee Title
WO2023022216A1 (fr) 2021-08-20 2023-02-23 塩野義製薬株式会社 Dérivés nucléosidiques et leurs promédicaments ayant une action inhibitrice de la croissance virale
KR20240050362A (ko) 2021-08-20 2024-04-18 시오노기 앤드 컴파니, 리미티드 바이러스 증식 억제 작용을 갖는 뉴클레오사이드 유도체 및 그들의 프로드러그

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