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WO2010023946A1 - Nouvel uracile comportant un hétérocycle azoté ou l'un de ses sels - Google Patents

Nouvel uracile comportant un hétérocycle azoté ou l'un de ses sels Download PDF

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Publication number
WO2010023946A1
WO2010023946A1 PCT/JP2009/004229 JP2009004229W WO2010023946A1 WO 2010023946 A1 WO2010023946 A1 WO 2010023946A1 JP 2009004229 W JP2009004229 W JP 2009004229W WO 2010023946 A1 WO2010023946 A1 WO 2010023946A1
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Inventor
正哲 福岡
達史 横川
成司 宮原
均 宮腰
稚子 矢野
淳子 田口
弥生 高尾
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Taiho Pharmaceutical Co Ltd
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Taiho Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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 novel uracil compound or a salt thereof having excellent human deoxyuridine triphosphatase inhibitory activity and useful as a therapeutic agent for diseases related to deoxyuridine triphosphatase, such as an antitumor agent.
  • Deoxyuridine triphosphatase (hereinafter also referred to as dUTPase (EC3.6.1.23)) is a preventive DNA repair enzyme. It is an enzyme that specifically recognizes only deoxyuridine triphosphate (hereinafter referred to as dUTP) among natural nucleic acid triphosphates and decomposes it into deoxyuridine monophosphate (hereinafter referred to as dUMP) and pyrophosphate (Non-patent Document 1) , (1) reduce the amount of dUTP pool in the cell to avoid accidental incorporation of uracil into DNA instead of thymine, (2) important de novo for supplying thymine in DNA It is thought to be responsible for two reactions: supplying the substrate dUMP of thymidylate synthase responsible for the pathway (Non-patent Document 2).
  • DUTPase is known to be essential for cell survival in both prokaryotes and eukaryotes. Therefore, this enzyme is an antitumor drug (Non-Patent Documents 3 and 4), an antimalarial drug (Patent Documents 1 and 5), an antituberculosis drug (Non-Patent Document 6), and an anti-pylori drug (Patent Document 2).
  • Anti-parasitic drugs such as trypanosoma and leishmania (non-patent document 7), and herpesviruses such as human herpes simplex virus, cytomegalovirus, Epstein-Barr virus (non-patent document 8) and vaccinia virus (non-patent document 9). It has been suggested that it can be a target for antiviral drugs such as
  • dUTPase is attracting attention as a target for therapeutic agents for various diseases, and dUTPase inhibitors are also widely studied.
  • dUTPase inhibitors for example, triphosphate mimic type low molecular weight compounds (for example, Patent Document 3, Non-Patent Document 10 and the like), 5′-O-substituted phenyl-deoxyuridine compounds (Non-Patent Document 11) are known. Yes. However, none of these compounds have sufficient inhibitory activity against human dUTPase and are not compounds used as pharmaceuticals. Therefore, development of a dUTPase inhibitor having a superior human dUTPase inhibitory activity and useful as a therapeutic agent for a disease related to dUTPase, such as an antitumor agent, is strongly desired.
  • An object of the present invention is to provide a uracil compound having a nitrogen-containing heterocyclic ring or a salt thereof, which has excellent human dUTPase inhibitory activity and is useful as an antitumor agent or the like.
  • a uracil compound having a nitrogen-containing heterocycle in the uracil ring N-1 side chain or a salt thereof has excellent human dUTPase inhibitory activity.
  • the present invention was completed by discovering that it is useful as a medicine such as an antitumor drug.
  • X represents a divalent hydrocarbon group which may have a hetero atom between carbon atoms or at the terminal
  • Y represents a hydrogen atom or a fluorine atom
  • A represents a nitrogen-containing unsaturated heterocyclic group which may have a substituent
  • R 1 and R 2 are the same or different and are a hydrogen atom, a cyano group, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted carbon atom having 2 to An alkenyl group having 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms which may have a substituent, a monoalkylaminocarbonyl group, a dialkylaminocarbonyl group, an aryl group, an unsaturated heterocyclic group, or a substituent.
  • the aralkyl group which may be sufficient is shown.
  • the uracil compound represented by these, or its salt is provided.
  • the present invention also provides a pharmaceutical composition containing a uracil compound represented by the formula (I) or a salt thereof. Moreover, this invention provides the human dUTPase inhibitor containing the uracil compound or its salt represented by a formula (I). The present invention also provides use of the uracil compound represented by the formula (I) or a salt thereof for producing a human dUTPase inhibitor. The present invention also provides a method for inhibiting human dUTPase, comprising administering a compound represented by formula (I) or a salt thereof.
  • novel uracil compound or a salt thereof of the present invention has excellent human dUTPase inhibitory activity, and is useful as a drug for diseases related to dUTPase, such as antitumor drugs.
  • the novel uracil compound of the present invention is represented by the above general formula (I) and has a feature that the uracil ring N-1 substituent has a nitrogen-containing heterocyclic structure.
  • Patent Document 1 as a terminal of the uracil ring N-1 position substituent, a substituent such as a trityl group or a triphenylsilyl group (-E (R 6 ) (R 7 ) (R 8 A uracil compound having a) group) is disclosed, which shows dUTPase inhibitory activity and is useful as an antimalarial drug.
  • a compound having a nitrogen-containing unsaturated heterocyclic structure of the compound of the present invention is not disclosed. Further, as shown in Test Examples described later, compounds having a trityl group at the terminal of the uracil ring N-1 position substituent showed almost no human dUTPase inhibitory activity.
  • examples of the “substituent” include a halogen atom, hydroxyl group, cyano group, nitro group, alkyl group, halogenoalkyl group, alkoxyalkyl group, cycloalkyl group, cycloalkyl-alkyl group, aralkyl group, alkenyl group.
  • examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
  • the alkyl group and the halogenoalkyl group preferably represent a linear or branched alkyl group having 1 to 6 carbon atoms or a group obtained by substituting the halogen atom for the alkyl group, Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a monofluoromethyl group, a trifluoromethyl group, and a 2,2-difluoroethyl group.
  • the alkoxyalkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with linear or branched alkoxy having 1 to 6 carbon atoms, such as a methoxymethyl group or ethoxymethyl group. Group, methoxyethyl group and the like.
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • the cycloalkyl-alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with cycloalkyl having 3 to 7 carbon atoms, and includes a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropyl group, A butylmethyl group, a cyclopentylmethyl group, etc. are mentioned.
  • the aralkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms substituted with an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as a benzyl group, A phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, etc. are mentioned.
  • the alkenyl group includes a carbon-carbon double bond, preferably a hydrocarbon group having 2 to 6 carbon atoms, and includes a vinyl group, an allyl group, a methylvinyl group, a propenyl group, a butenyl group, A pentenyl group, a hexenyl group, etc. are mentioned.
  • the alkynyl group is a hydrocarbon group containing a carbon-carbon triple bond, preferably 2 to 6 carbon atoms, and examples thereof include an ethynyl group and a propargyl group.
  • the alkoxy group and the halogenoalkoxy group preferably represent a linear or branched alkoxy group having 1 to 6 carbon atoms, or a group in which the above halogen atom is substituted for these alkoxy groups.
  • Methoxy group, ethoxy group, n-propoxy group isopropoxy group, 1-methylpropoxy group, n-butoxy group, sec-butoxy group, isobutoxy group, 2-methyl-butoxy group, neopentyloxy group, pentane-2 -Yloxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 1,1-difluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2, 2-tetrafluoroethoxy group, perfluoroethoxy group, 3-fluoro-2- (fluoromethyl) -propyl Epoxy group, 1,3-difluoro-2-yloxy group, 2,2,3,3,3-pentafluoro-1-propoxy group and the like.
  • the cycloalkoxy group is preferably a cycloalkoxy group having 3 to 7 carbon atoms, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
  • the cycloalkyl-alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms substituted by cycloalkyl having 3 to 7 carbon atoms, such as cyclopropylmethoxy group, 1-methylcyclopropylmethoxy group.
  • the aralkyloxy group is preferably an oxy group having the aralkyl group, and examples thereof include a benzyloxy group, a phenylethoxy group, a phenylpropoxy group, a naphthylmethoxy group, and a naphthylethoxy group.
  • the mono- or dialkylamino group represents an amino group mono- or di-substituted by the alkyl group, and includes a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, and a methylethylamino group. Etc.
  • the cycloalkyl-alkylamino group represents an alkylamino group substituted with the above cycloalkyl group, and examples thereof include a cyclopropylmethylamino group, a cyclobutylmethylamino group, and a cyclopentylmethylamino group.
  • examples of the cycloalkylidene structure include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene.
  • the acyl group includes a straight or branched carbon number of 1 to 6 such as formyl group, acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, isovaleryl group, and pivaloyl group.
  • the acyloxy group includes straight or branched carbon such as acetoxy group, propionyloxy group, n-butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, etc. Examples thereof include an acyloxy group of 1 to 6 and a benzoyloxy group.
  • the saturated or unsaturated heterocyclic group is preferably a monocyclic or bicyclic saturated group having preferably one or two oxygen atoms, nitrogen atoms and sulfur atoms.
  • an unsaturated heterocyclic group for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperidinyl group, tetrahydrofuryl group, tetrahydropyryl group, imidazolyl group, thienyl group, furyl Group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, pyridaziny
  • the aryl group is preferably an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.
  • the saturated heterocyclic oxy group is a monocyclic saturated heterocyclic group having one or two oxygen atoms, nitrogen atoms or sulfur atoms, for example, pyrrolidinyl group, piperidinyl group, An oxy group having a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperidinyl group or the like, such as a tetrahydrofuryloxy group or a tetrahydropyryloxy group.
  • the “divalent hydrocarbon group optionally having a heteroatom between carbon atoms or terminals” represented by X has a heteroatom between carbon atoms or terminals.
  • Aryl-alkyl groups are preferred.
  • examples of the “heteroatom” include an oxygen atom, a nitrogen atom, and a sulfur atom.
  • the “heteroatom” that may be present between carbon atoms or at the terminal of an alkylene group having 1 to 6 carbon atoms Is preferably an oxygen atom, and a heteroatom which may be present between or at the terminals of a divalent alkyl-aryl-alkyl group having 6 to 20 carbon atoms is preferably an oxygen atom or a sulfur atom.
  • C 1-6 alkylene group is preferably a linear or branched C 1-6 alkylene group, for example, methylene, ethylene, trimethylene, tetra Examples include methylene group, pentamethylene group, hexamethylene group, propylene group, butylene group, dimethyltrimethylene group, dimethyltetramethylene group, and ethyltrimethylene group.
  • a linear alkylene group having 2 to 3 carbon atoms and a branched alkylene group having 4 to 6 carbon atoms are preferable, and an ethylene group, a trimethylene group, and a dimethyltrimethylene group are more preferable.
  • examples of the “divalent aryl group having 6 to 14 carbon atoms” include a phenylene group and a naphthylene group, and a phenylene group is preferable. Of these, a 1,3-phenylene group is particularly preferred.
  • the divalent alkyl-aryl-alkyl group having 6 to 20 carbon atoms is preferably a C 1-6 alkyl-C 6-10 aryl-C 1-6 alkyl group.
  • examples of the C 6-10 aryl group include a phenylene group and a naphthylene group, but a phenylene group is preferable, and a 1,2-phenylene group is particularly preferable.
  • alkyl-aryl-alkyl group examples include the following general formula (II)
  • Z represents an oxygen atom or a sulfur atom
  • R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • the Z terminal in Formula (II) is the same as in Formula (I)).
  • It binds to a methylene group
  • the carbon terminal in formula (II) binds to A in formula (I).
  • the group represented by these is preferable.
  • examples of the alkyl group having 1 to 6 carbon atoms represented by R 3 include the same alkyl groups as the above-mentioned “substituent”, but an alkyl group having 1 to 3 carbon atoms is preferable.
  • a methyl group is more preferable.
  • X is an ethylene group, a trimethylene group, and the following formulas (IV) to (VII) in terms of human dUTPase inhibitory action.
  • the oxygen end in formula (IV) is bonded to the methylene group in formula (I), the methylene end in formula (IV) is bonded to A in formula (I), and the methylene group in formula (VII)
  • the terminal is bonded to the methylene group in formula (I), and the dimethylmethylene terminal in formula (VII) is bonded to A in formula (I).
  • any group selected from the group represented by formula (II) and the group represented by formula (II) is preferable.
  • an ethylene group, a trimethylene group or a group represented by the formula (IV) is particularly preferable.
  • Y is a fluorine atom
  • a trimethylene group or a group represented by the formula (IV) is particularly preferable.
  • the “nitrogen-containing unsaturated heterocyclic group” of the “nitrogen-containing unsaturated heterocyclic group which may have a substituent” represented by A includes at least one in the ring structure.
  • An unsaturated heterocyclic group containing a nitrogen atom for example, imidazolyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, Examples include a pyridazinyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzimidazolyl group, a benzoxazole group, a benzothiazolyl group, a purinyl group, a quinolyl group, an is
  • a 3- to 6-membered nitrogen-containing unsaturated heterocyclic group is preferred, a 5-membered nitrogen-containing unsaturated heterocyclic group is more preferred, and a pyrrolyl group, pyrazolinyl group, triazolyl group, or tetrazolyl group is more preferred.
  • any one of the nitrogen-containing unsaturated heterocyclic groups selected from the following is preferable, and any nitrogen-containing unsaturated heterocyclic group selected from the formulas (X) to (XII) or the formula (XV) is particularly preferable.
  • Y is a fluorine atom
  • a nitrogen-containing unsaturated heterocyclic group represented by the formula (XII) is particularly preferable.
  • the “alkyl group having 1 to 6 carbon atoms” is linear or branched.
  • An alkyl group having 1 to 6 carbon atoms is preferable, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, etc.
  • An alkyl group having 1 to 3 carbon atoms is preferable, a methyl group or an ethyl group is more preferable, and a methyl group is more preferable.
  • the “substituent” that the alkyl group having 1 to 6 carbon atoms may have is preferably a halogen atom, a hydroxyl group, or an alkoxy group having 1 to 6 carbon atoms. More preferred are groups, methoxy groups and ethoxy groups.
  • the “optionally substituted alkyl group having 1 to 6 carbon atoms” represented by R 1 and R 2 includes a methyl group, a monofluoromethyl group, a difluoroethyl group, a methoxymethyl group, an ethoxy group.
  • a methyl group, a methoxyethyl group and an ethoxyethyl group are preferred.
  • the “alkenyl group having 2 to 6 carbon atoms” may be, for example, the above “substituent”. Although the same alkenyl group is mentioned, a vinyl group is preferable and unsubstituted is preferable.
  • the “alkynyl group having 2 to 6 carbon atoms” represented by R 1 and R 2 includes, for example, the above “substituent” and although the same alkynyl group is mentioned, an ethynyl group is preferable and unsubstituted is preferable.
  • Examples of the “monoalkylaminocarbonyl group” represented by R 1 and R 2 include a carbonyl group having a monoalkylamino group similar to the above “substituent”.
  • dialkylaminocarbonyl group represented by R 1 and R 2 include a carbonyl group having a dialkylamino group similar to the above “substituent”, and a dimethylaminocarbonyl group is preferred.
  • Examples of the “aryl group” represented by R 1 and R 2 include aryl groups having 6 to 14 carbon atoms such as a phenyl group and a naphthyl group.
  • Examples of the “unsaturated heterocyclic group” represented by R 1 and R 2 include unsaturated heterocyclic groups similar to the above “substituent”, but a thiazolyl group is preferred.
  • the “aralkyl group optionally having substituent (s)” represented by R 1 and R 2 is, for example, an aralkyl group having 7 to 24 carbon atoms, such as a C 6-10 aryl-C 1-6 alkyl group. More preferred is a phenyl-C 1-6 alkyl group. Specifically, a benzyl group which may have a substituent and a phenylethyl group which may have a substituent are preferable.
  • R 6 and R 7 are the same or different and each represents a hydrogen atom or a phenyl group
  • R 8 and R 9 are the same or different and each represents a hydrogen atom or (This represents an optionally substituted alkoxy group having 1 to 6 carbon atoms.)
  • the benzyl group represented by these is preferable.
  • the “substituent” as the “substituent” as described above for the “alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 Although the same alkoxy group is mentioned, a methoxy group is preferable.
  • the “substituent” in the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 is preferably a cycloalkyl group, more preferably a cyclopropyl group. .
  • R 6 and R 7 are the same or different.
  • R 8 and R 9 are the same or different and represent a hydrogen atom, a halogen atom
  • a good phenyl group or a thienyl group optionally having a substituent. Is preferred.
  • Examples of the “alkyl group having 1 to 6 carbon atoms” represented by R 4 and R 5 include the same alkyl groups as the above “substituent”, but a methyl group is preferred.
  • Examples of the “alkyl group having 1 to 6 carbon atoms” represented by R 6 and R 7 include the same alkyl groups as described above, preferably a methyl group, an ethyl group and an isopropyl group, more preferably an ethyl group. preferable.
  • the substituent of the “optionally substituted phenyl group” represented by R 6 and R 7 is preferably a halogen atom, an alkoxy group having 1 to 6 carbon atoms, a fluorine atom, a chlorine atom, a methoxy group Is more preferable.
  • halogen atom represented by R 8 and R 9 include the same halogen atoms as the above “substituent”, but a chlorine atom and a fluorine atom are more preferable.
  • alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 include, for example, the above “substituent” and Although the same alkoxy group is mentioned, a linear or branched alkoxy group having 1 to 6 carbon atoms is preferable, and a methoxy group, an ethoxy group, an isobutoxy group, and a sec-butoxy group are more preferable.
  • Examples of the “substituent” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by R 8 and R 9 include the same substituents as the above “substituent”.
  • a halogen atom and a cycloalkyl group having 3 to 7 carbon atoms are preferable, and a fluorine atom, a cyclopropyl group, a 1-methylcyclopropyl group, a cyclobutyl group, and a cycloalkylidenyl group are more preferable.
  • the cycloalkylidenyl group preferably has a cycloalkylidene structure having 3 to 6 carbon atoms. Specific examples include cyclopropylidene, cyclobutylidene, cyclopentylidene, and cyclohexylidene, which inhibit human dUTPase inhibition. From the viewpoint of action, cyclopropylidene is preferred.
  • Examples of the “C3-C7 cycloalkoxy group optionally having an oxygen atom between carbon atoms” represented by R 8 and R 9 include, for example, the above-mentioned “substituent” cycloalkoxy group and saturated complex Although the same group as a ring oxy group is mentioned, A cyclobutyloxy group, a cyclopentyloxy group, a tetrahydrofuryloxy group, and a tetrahydropyryloxy group are preferable.
  • Examples of the substituent of the “optionally substituted phenyl group” represented by R 8 and R 9 include the same halogen atoms as the above “substituent”, but a fluorine atom and a chlorine atom are more preferable. . Examples of the substituent of the “optionally substituted thienyl group” represented by R 8 and R 9 include the same substituents as the above “substituent”.
  • R 4 and R 5 are preferably a hydrogen atom and a methyl group, and particularly preferably a hydrogen atom, from the viewpoint of human dUTPase inhibitory action.
  • R 6 is preferably a hydrogen atom or a hydroxyl group from the viewpoint of human dUTPase inhibitory action
  • R 7 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a fluorine as a substituent from the viewpoint of human dUTPase inhibitory action.
  • a phenyl group optionally having an atom, a chlorine atom, or an alkoxy group having 1 to 6 carbon atoms is particularly preferred.
  • R 8 and R 9 have a hydrogen atom, a fluorine atom, a chlorine atom, a halogen atom as a substituent, a cycloalkyl group having 3 to 7 carbon atoms or a cycloalkylidenyl group from the viewpoint of human dUTPase inhibitory action.
  • Preferred phenyl group or thienyl group is preferable.
  • R 1 is a hydrogen atom, a cyano group, a methyl group, a monofluoromethyl group, a difluoroethyl group, a vinyl group, an ethynyl group, or a methoxy group.
  • a dimethyl ether group, a dimethylaminocarbonyl group or a phenyl group, wherein R 2 is a hydrogen atom, a phenyl group, a benzyl group (n 0) represented by the general formula (III), or a general formula (III).
  • a phenylethyl group (n 1), or a thiazolyl group.
  • the uracil N-1 compound of the present invention can be produced according to the following reaction process formula. [Process A]
  • the hydroxyl group of the compound represented by the general formula (1) that can be easily obtained or obtained by a known method is methanesulfonylated by a generally known method, and then reacted with an azido reagent.
  • a compound represented by the general formula (2) can be produced.
  • the reaction solvent used for azidation is not particularly limited as long as it does not affect the reaction, but N, N-dimethylformamide (hereinafter DMF), tetrahydrofuran (hereinafter THF), dioxane, acetonitrile, toluene, dichloromethane, etc. And is preferably DMF.
  • Examples of the azidation reagent to be used include sodium azide and lithium azide, and sodium azide is preferred.
  • the number of equivalents is 0.8 to 10 equivalents, preferably 1.0 to 6.0 equivalents.
  • the reaction temperature is 10 to 120 ° C, preferably 50 to 100 ° C.
  • the reaction time is 1.0 to 24 hours, preferably 3.0 to 12 hours.
  • the compound represented by the general formula (3) can be produced by reacting the compound represented by the general formula (2) with triphenylphosphine in the presence of water and then treating with hydrochloric acid.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, THF, dioxane, acetonitrile and the like, preferably THF.
  • the number of equivalents of triphenylphosphine used is 1.0 to 5.0 equivalents, preferably 1.1 to 2.0 equivalents.
  • the reaction temperature is 0 to 120 ° C, preferably 10 to 60 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1.0 to 3.0 hours.
  • Examples of the base to be used include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and preferably triethylamine.
  • the number of equivalents is 1.0 to 10 equivalents, preferably 1.1 to 3.0 equivalents.
  • the reaction temperature is -78 to 50 ° C, preferably -40 to 30 ° C.
  • the reaction time is 1.0 to 24 hours, preferably 2.0 to 3.0 hours.
  • the compound represented by the general formula (5) can be produced by reacting the compound represented by the general formula (4) with a generally known acid.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include ethyl acetate, dioxane, water, methanol, ethanol and the like, and dioxane is preferable.
  • the acid to be used include inorganic acids such as hydrogen chloride, hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid, and hydrogen chloride is preferable.
  • the number of equivalents is 0.5-1000 equivalents, preferably 1.0-100 equivalents.
  • the reaction temperature is 0 to 100 ° C., preferably 10 to 30 ° C.
  • the reaction time is 0.1 to 5.0 hours, preferably 0.5 to 1.0 hours.
  • 2,4-bis (trimethylsilyloxy) pyrimidine can be produced by the method described in Nucleosides & Nucleotides, 4, 565-585 (1985), and 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is easy Is available.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but acetone, THF, diethyl ether, dioxane, 1,2-dichloromethane, dichloroethane and the like are exemplified, and 1,2-dichloroethane is preferable. It is.
  • the number of equivalents of 2,4-bis (trimethylsilyloxy) pyrimidine or 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents.
  • the Lewis acid used include boron trichloride (hereinafter referred to as BCl 3 ), boron tribromide, trimethylsilyl iodide, and the like, and BCl 3 is preferred.
  • the number of equivalents is 0.1 to 2.0 equivalents, preferably 0.2 to 0.4 equivalents.
  • the number of equivalents of iodine is 0.001 to 0.5 equivalents, preferably 0.1 to 0.2 equivalents.
  • the reaction temperature is 50 to 120 ° C, preferably 60 to 100 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1.0 to 10 hours.
  • the compound represented by the general formula (6) obtained by a generally known method is activated with a base and reacted with a readily available chloroformate to represent the compound represented by the general formula (7).
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, THF, dioxane, diethyl ether, etc., preferably THF.
  • Examples of the base to be used include metal hydride, n-butyllithium, sec-butyllithium, tert-butyllithium and the like, preferably n-butyllithium.
  • the number of equivalents is 0.8 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents.
  • the number of equivalents of chloroformate is 0.8 to 2.0 equivalents, preferably 1.0 to 1.2 equivalents.
  • the reaction temperature is ⁇ 100 to 100 ° C., preferably ⁇ 78 to 0 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1.0 to 5.0 hours.
  • Examples of the reagent used in the Mitsunobu reaction include diisopropyl azodicarboxylate, diethyl azodicarboxylate, and the like, and preferably diisopropyl azodicarboxylate.
  • the number of equivalents is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents.
  • the number of equivalents of triphenylphosphine is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents.
  • the number of equivalents of the compound represented by the general formula (1) is 1.0 to 3.0 equivalents, preferably 1.5 to 2.0 equivalents.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, acetone, toluene and the like, preferably THF.
  • the reaction temperature is 0 to 100 ° C., preferably 10 to 30 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.2 to 3.0 hours.
  • Step B-1 the compound represented by the general formula (10) obtained by a known method is converted into the same method as in Step A-1, the method described in Tetrahedron Lett., 48, 7109-7172 (2007), or diphenylphosphoryl.
  • an azide compound represented by the general formula (11) can be produced.
  • R 8 is a halogen atom and R 9 is an optionally substituted alkoxy group having 1 to 6 carbon atoms, for example, easily available 4-fluoro-3-hydroxybenzoic acid is used as a starting material.
  • a compound represented by the general formula (10) can be obtained by using a Grignard reaction or the like.
  • Step B-2 the compound represented by the general formula (11) and the alkyne compound (5) or (8) produced in Step A are reacted in the presence of a ruthenium catalyst and cyclized, and then a protected carboxyl group.
  • the compound of the present invention represented by the general formula (12) can be produced by converting (R 1 ) as necessary.
  • the reaction solvent used in the cyclization reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, dichloromethane, acetonitrile, THF, dioxane and the like, and dioxane is preferable.
  • ruthenium catalyst As the ruthenium catalyst to be used, various organic ruthenium catalysts such as chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II), pentamethylcyclopentadienylbis (triphenylphosphine) ruthenium (II) chloride, etc. Illustrative examples include chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II). The number of equivalents is 0.001 to 0.5 equivalents, preferably 0.01 to 0.3 equivalents.
  • the reaction temperature is 0 to 100 ° C., preferably 20 to 90 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1.0 to 5.0 hours.
  • R 1 , R 4 to R 9 , X, Rc, and n are as defined above, and Rh represents a protecting group for a hydroxyl group.
  • Step C-2 the compound represented by the general formula (13) and the compound represented by the general formula (11) are subjected to a cyclization reaction in the same manner as in Step B-2 to thereby represent the compound represented by the general formula (14). Can be produced.
  • the compound represented by the general formula (15) can be produced by converting the protected carboxyl group of the compound represented by the general formula (14).
  • the protected carboxyl group is reduced by a generally known method to obtain a hydroxylmethyl group
  • an alkylation reaction or a halogen substitution reaction can be performed.
  • a vinyl form can be produced by reacting with methyltriphenylphosphonium bromide under basic conditions, and Eur. J. Org.
  • An ethynyl compound can also be produced by reacting dimethyl 1-diazo-2-oxopropylphosphonate obtained by the method described in Chem., 5, 821-832 (2003) in the presence of a base.
  • an amide body can also be manufactured by deprotecting a carboxyl group and condensing with various amines by a conventionally well-known method.
  • R 4 to R 9 , X, Rh, and n are as defined above.
  • reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, acetonitrile, DMF, ethanol, methanol, n-butanol, and the like. Is n-butanol.
  • Examples of the base to be used include potassium carbonate, cesium carbonate, sodium hydrogen carbonate and the like, and potassium carbonate is preferable.
  • the number of equivalents is 0.1 to 3.0 equivalents, preferably 0.12 to 2.0 equivalents.
  • the number of equivalents of acetohydrazide is 0.1 to 20 equivalents, preferably 0.2 to 10 equivalents.
  • the reaction temperature is -78 to 200 ° C, preferably 120 to 160 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1.0 to 5.0 hours.
  • reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, acetonitrile, DMF, and the like, preferably DMF.
  • Examples of the base to be used include metal hydride, n-butyl lithium, bis (trimethylsilyl) amide sodium salt (hereinafter referred to as NaHMDS), and sodium hydride is preferred.
  • the number of equivalents is 0.8 to 3.0 equivalents, preferably 1.0 to 1.2 equivalents.
  • the number of equivalents of the mesyl compound of the general formula (10) is 0.5 to 2.0 equivalents, preferably 0.7 to 1.2 equivalents.
  • the reaction temperature is -78 to 100 ° C, preferably 0 to 60 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1.0 to 10 hours.
  • R 4 to R 9 , X, Rh, and n are as defined above.
  • Examples of the base used include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and imidazole, and triethylamine is preferable.
  • the number of equivalents is 0.8 to 5.0 equivalents, preferably 1.0 to 1.2 equivalents.
  • the reaction solvent used in this step is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, ethanol, methanol, DMF and the like, preferably ethanol. is there.
  • Examples of the acid to be used include acetic acid, sulfuric acid, methanesulfonic acid, hydrochloric acid and the like, and acetic acid is preferable.
  • the number of equivalents is 1.0 to 10 equivalents, preferably 2.0 to 5.0 equivalents.
  • the reaction temperature is -90 to 200 ° C, preferably 10 to 100 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.5 to 9.0 hours.
  • R 1 , R 4 to R 9 , X, Rh, and n are as defined above.
  • R 4 to R 9 , X, Rh, and n are as defined above, Rn represents an amino-protecting group, and m represents an integer of 1-6. ]
  • the number of equivalents is 0.5 to 10 equivalents, preferably 0.8 to 5.0 equivalents.
  • the reaction solvent used in the reaction with triphosgene is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, toluene, dichloromethane, DMF, and the like, preferably toluene.
  • the reaction temperature is -90 to 200 ° C, preferably -78 to 10 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.2 to 5.0 hours.
  • Examples of the base used in the reaction with the compound represented by the general formula (25) include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, imidazole, and the like. Is triethylamine.
  • the number of equivalents is 0.2 to 10 equivalents, preferably 0.5 to 5.0 equivalents.
  • the reaction solvent used in the reaction with the compound represented by the general formula (25) is not particularly limited as long as it does not affect the reaction, but THF, dioxane, diethyl ether, toluene, dichloromethane, DMF, acetonitrile Etc., and preferably a mixed solvent of toluene and acetonitrile.
  • the reaction temperature is -90 to 200 ° C, preferably 0 to 70 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.2 to 10 hours.
  • the compound represented by the general formula (27) can be produced by reacting the compound represented by the general formula (26) under basic conditions.
  • the base to be used include sodium hydroxide and potassium hydroxide, and sodium hydroxide is preferable.
  • the number of equivalents is 0.2 to 100 equivalents, preferably 1.0 to 50 equivalents.
  • the reaction solvent to be used include water, methanol, ethanol, n-propanol, n-butanol, THF, dioxane and the like, and a mixed solvent of water and dioxane is preferable.
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 120 ° C.
  • the reaction time is 0.1 to 48 hours, preferably 0.2 to 10 hours.
  • the amino group of the uracil ring of the compound represented by the general formula (31) is protected by a generally known method, and then reacted with an azide reagent in the presence of triphenylphosphine and dialkyl azodicarboxylate.
  • the compound of the present invention represented by the general formula (32) can be produced by removing the amino-protecting group by a generally known method.
  • the reaction solvent used for the reaction with the azidation reagent is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, diethyl ether, DMF, toluene, dichloromethane and the like, preferably THF. is there.
  • Examples of the azodicarboxylic acid ester used include diethyl azodicarboxylate and diisopropyl azodicarboxylate, with diisopropyl azodicarboxylate being preferred.
  • the number of equivalents is 0.9 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents.
  • Examples of the azide reagent used include azido acid, sodium azide, potassium azide, trimethylsilyl azide and the like, and trimethylsilyl azide is preferred.
  • the number of equivalents is 0.8 to 5.0 equivalents, preferably 1.0 to 4.0 equivalents.
  • the number of equivalents of triphenylphosphine is 0.8 to 5.0 equivalents, preferably 1.0 to 4.0 equivalents.
  • the reaction temperature is 0 to 100 ° C., preferably 10 to 60 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 5.0 to 24 hours.
  • the compound represented by the general formula (38) can be produced by reacting the compound represented by the general formula (37) in the same manner as in Step A-5.
  • the compound represented by the general formula (39) can be easily obtained or acetylene which can be obtained by a known method, for example, the method described in J. Org. Chem., 53, 2489-2496 (1988).
  • the compound of the present invention represented by the general formula (40) can be produced.
  • the reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, THF, dioxane, DMF, and the like, preferably toluene or DMF.
  • the number of equivalents of the acetylene compound is 0.8 to 100 equivalents, preferably 1.0 to 50 equivalents.
  • the reaction temperature is 0 to 200 ° C, preferably 20 to 160 ° C.
  • the reaction time is 0.1 to 120 hours, preferably 0.5 to 100 hours.
  • the compound of the present invention and the synthetic intermediate thus produced can be usually isolated and purified by known separation and purification means such as recrystallization, crystallization, distillation, column chromatography and the like.
  • the compounds of the present invention and synthetic intermediates can usually form pharmacologically acceptable salts by known methods, and can be converted into each other.
  • the uracil compound or salt thereof of the present invention has excellent human dUTPase inhibitory activity, and thus is useful as a pharmaceutical represented by an antitumor drug and the like.
  • uracil compound of the present invention or a salt thereof When the uracil compound of the present invention or a salt thereof is contained in a pharmaceutical composition, it can be combined with a pharmaceutical carrier as necessary, and various administration forms can be employed depending on the purpose of prevention or treatment. For example, oral agents, injections, suppositories, ointments, patches and the like can be mentioned, and oral agents are preferred. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
  • the pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, colorants in solid preparations; solvents, dissolution aids, suspensions in liquid preparations. It is blended as a turbidity agent, tonicity agent, buffering agent, soothing agent and the like. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.
  • a binder, a disintegrating agent, a lubricant, a coloring agent, a corrigent / flavoring agent, etc. to the compound of the present invention, a tablet is prepared by a conventional method. Coated tablets, granules, powders, capsules and the like can be produced.
  • excipient examples include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid.
  • binder examples include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, ⁇ -starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned.
  • disintegrant examples include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.
  • Examples of the colorant include titanium oxide and iron oxide.
  • Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
  • an oral solution, syrup, elixir and the like can be produced by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like to the compound of the present invention by conventional methods.
  • the flavoring / flavoring agent may be those listed above
  • examples of the buffer include sodium citrate
  • examples of the stabilizer include tragacanth, gum arabic, and gelatin.
  • an enteric coating or a coating can be applied to the oral preparation by a known method for the purpose of sustaining the effect. Examples of such a coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.
  • a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods.
  • the pH adjuster and buffer in this case include sodium citrate, sodium acetate, and sodium phosphate.
  • the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • local anesthetics include procaine hydrochloride and lidocaine hydrochloride.
  • isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.
  • a formulation carrier known in the art such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., and an interface such as Tween 80 (registered trademark), if necessary, are added to the compound of the present invention. After adding an activator etc., it can manufacture by a conventional method.
  • bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention are blended as necessary, and mixed and formulated by a conventional method.
  • the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
  • the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.
  • the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method.
  • a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.
  • the amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which the compound is to be applied or the dosage form thereof, but is generally about an oral dosage form per dosage unit form. 0.05 to 1000 mg, about 0.01 to 500 mg for injections, and about 1 to 1000 mg for suppositories.
  • the daily dose of the drug having the above-mentioned dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally.
  • the dose is about 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into about 2 to 3 times a day.
  • Diseases that can be treated by administering the pharmaceutical composition containing the compound of the present invention include malignant tumors, malaria, tuberculosis, etc.
  • malignant tumors in the case of malignant tumors, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectum Cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular cancer, bone / soft tissue sarcoma, leukemia, malignant lymphoma, Examples include multiple myeloma, skin cancer, brain tumor and the like.
  • antitumor agent that can be used in combination is not particularly limited, but antitumor agents having an inhibitory action on thymidylate synthetase, such as antimetabolite such as 5-Fu and antifolate, are preferable.
  • the compound of the present invention can be used as an anti-pylori drug, an antiparasitic drug, or an antiviral drug.
  • the obtained compound was suspended in a hydrogen chloride-dioxane solution (4.0 M, 40 mL) and heated to reflux at 100 ° C. for 30 minutes. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL ⁇ 5) to give the title compound (1.9 g) as a pale yellow solid.
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the obtained compound was dissolved in DCE (5.0 mL), and 2,4-bis (trimethylsilyloxy) pyrimidine (531 mg) obtained by the method described in the literature (Nucleosides & Nucleotides, 4, 565-585 (1985)) and Iodine (40 mg) was added, and the mixture was heated to reflux at 93 ° C. for 3 hours.
  • the reaction mixture was allowed to cool, and water (10 mL) and saturated aqueous sodium thiosulfate solution (1.0 mL) were added to separate the layers.
  • the obtained compound was dissolved in THF (30 mL), TBAF in THF (1.0 M, 46 mL) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
  • the resulting compound was dissolved in dichloromethane (20 mL).
  • Triethylamine (2.18 mL) and methanesulfonyl chloride (975 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated.
  • the obtained compound was dissolved in THF (30 mL), water (3.0 mL) and triphenylphosphine (2.26 g) were added, and the mixture was stirred at 50 ° C. for 2 hr.
  • the reaction mixture was concentrated under reduced pressure, chloroform (50 mL) was added to the residue, and the mixture was extracted with 1N hydrochloric acid (50 mL ⁇ 2).
  • the aqueous layer was concentrated under reduced pressure and azeotroped with toluene (10 mL ⁇ 3).
  • the obtained compound was suspended in a hydrogen chloride-dioxane solution (4.0 M, 4.0 mL) and stirred at room temperature for 2 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to obtain the title compound (410 mg) as a pale yellow solid.
  • silyl compound (1.05 g of 3.95 g) was dissolved in THF (10 mL), and a hexane solution of n-butyllithium (2.77 M, 1.13 mL) was added dropwise at -78 ° C. Stir for hours.
  • Methyl chloroformate (242 ⁇ L) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (5.0 mL) was added to the reaction solution to separate the layers.
  • the title compound (2.1 g) was obtained as a colorless oil by synthesis from easily available 4-pentyn-1-ol (1.5 g) according to the method of Reference Example 8.
  • Methyl 5- (methoxymethoxy) pent-2-inoate (15 g) obtained in Reference Example 10 was dissolved in dichloromethane (70 mL), and a dichloromethane solution (1.0 M, 16.9 mL) of BCl 3 was added under ice cooling at room temperature. Stir for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCE (100 mL), and 2,4-bis (trimethylsilyloxy) pyrimidine ( 21.6 g) and iodine (1.2 g) were added, and the mixture was heated to reflux at 93 ° C. for 3 hours.
  • the reaction mixture was allowed to cool, water (60 mL) and saturated aqueous sodium thiosulfate solution (10 mL) were added for liquid separation, and the aqueous layer was extracted with 10% methanol / chloroform (100 mL). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol / chloroform) to obtain the title compound (6.1 g) as a foam.
  • the obtained compound was dissolved in a methanol solution of methylamine (40%, 7.0 mL) and stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (75% ethyl acetate / hexane) to give the title compound (1.3 g) as a white solid.
  • the obtained compound (500 mg of 3.25 g) was dissolved in dichloromethane (10 mL), triethylamine (540 ⁇ L) and methanesulfonyl chloride (242 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added for liquid separation. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (10 mL), sodium azide (423 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr.
  • Reference Examples 15 to 27 were synthesized from the respective raw materials shown in the following table according to the method of Reference Example 14.
  • ethyl 2- (3- (cyclopropylmethoxy) phenyl) acetate (1.0 g out of 1.2 g) was dissolved in ethanol (2.0 mL) and water (1.6 mL), and an aqueous sodium hydroxide solution (4.0 M, 3.2 mL) was added and the mixture was stirred at 50 ° C. for 3 hours.
  • Hydrochloric acid (2.0 M, 10 mL) was added to the reaction solution to make it acidic, and the reaction solution was concentrated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL).
  • the residue was purified by silica gel column chromatography (17% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (6.0 mL), and a THF solution (1.0 M, 1.7 mL) of bis (trimethylsilyl) amide sodium salt (hereinafter NaHMDS) was added dropwise at ⁇ 78 ° C., followed by stirring at ⁇ 78 ° C. for 1.5 hours. did.
  • a solution of methyl iodide (490 ⁇ L) in THF (1.0 mL) was added dropwise to the reaction solution, and the mixture was stirred at ⁇ 78 ° C. for 2 hours.
  • a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at room temperature, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (14% ethyl acetate / hexane). The obtained compound was dissolved in THF (2.0 mL), a THF solution (2.0 M, 1.2 mL) of lithium borohydride was added, and the mixture was stirred at room temperature for 12 hours. To the reaction solution was added saturated brine (10 mL) under ice-cooling, and the mixture was extracted with ethyl acetate (10 mL ⁇ 2).
  • the title compound (190 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 28 from readily available 2- (3-hydroxyphenyl) acetic acid (1.0 g).
  • the title compound (151 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 28 from readily available 2- (3-hydroxyphenyl) acetic acid (2.0 g).
  • a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at room temperature, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound (260 mg of 300 mg) was dissolved in dichloromethane (3.0 mL), triethylamine (262 ⁇ L) and methanesulfonyl chloride (117 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers.
  • N, O-dimethylhydroxylamine hydrochloride (3.3 g) and triethylamine (4.9 mL) were added, and the mixture was stirred at room temperature for 3 hours.
  • the obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 22 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with water (50 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to ⁇ 78 ° C., the ketone body (4.98 g) obtained in the previous reaction was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (2.0 mL) was added and the mixture was concentrated under reduced pressure. The residue was suspended in 10% ethyl acetate / hexane (80 mL).
  • the reaction solution was concentrated under reduced pressure, the residue was suspended in 10% ethyl acetate / hexane (100 mL), insolubles were filtered off, washed with 10% ethyl acetate / hexane (100 mL), and the combined filtrate was reduced in vacuo. Concentrated. The residue was purified by silica gel column chromatography (4% ethyl acetate / hexane). The obtained compound was dissolved in ethanol (10 mL) and water (10 mL), aqueous sodium hydroxide solution (4.0 M, 22 mL) was added, and the mixture was stirred at 50 ° C. for 3 hr.
  • the reaction mixture was concentrated under reduced pressure, acidified with dilute hydrochloric acid (1.0 M, 100 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Dissolve the residue in DMF (80 mL), add EDCHCl (8.0 g) and HOBt (5.0 g), add N, O-dimethylhydroxylamine hydrochloride (3.3 g) and triethylamine (4.9 mL), and Stir for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 25 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the phases were separated.
  • the organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to ⁇ 78 ° C., and the ketone body (4.98 g) obtained in the previous reaction was added, followed by stirring at room temperature for 3 hours. Acetic acid (2.0 mL) was added, and the mixture was concentrated under reduced pressure.
  • the obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 25 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution and the phases were separated, and the organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), a THF solution of NaHMDS (1.0 M, 30 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to ⁇ 78 ° C., and the ketone body (4.98 g) obtained in the previous reaction was added, followed by stirring at room temperature for 3 hours. Acetic acid (2.0 mL) was added and the mixture was concentrated under reduced pressure. The residue was suspended in 10% ethyl acetate / hexane (80 mL).
  • silyl compound (1.55 g out of 5.2 g) was dissolved in THF (25 mL), and a THF solution of 4-fluorophenylmagnesium bromide (1.0 M, 28 mL) was added dropwise at 0 ° C. Stir for hours.
  • a saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (20 mL), a TBAF solution in THF (1.0 M, 20 mL) was added, and the mixture was stirred at room temperature for 2 hr.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
  • the resulting diol (1.0 g out of 1.3 g) was dissolved in dichloromethane (20 mL), triethylamine (831 ⁇ L) and methanesulfonyl chloride (371 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (40 mL), sodium azide (1.0 g) was added, and the mixture was stirred at 70 ° C. for 12 hr. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (300 mg) as a pale yellow oil.
  • the azide forms shown in the following table are based on easily available 2-hydroxyethyl acetate, and using a readily available Grignard reagent or a Grignard reagent that can be prepared from a readily available bromo form by a generally known method. Synthesized according to the method of Reference Example 61.
  • the title compound (710 mg) was obtained as a pale yellow oily substance by synthesis according to the method of Reference Example 65 from readily available 2- (hydroxymethyl) phenol (700 mg).
  • Aqueous ammonium chloride solution (10 mL) was added to the reaction solution and the phases were separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (14% ethyl acetate / hexane). The obtained compound was dissolved in methanol (3.0 mL), 10% palladium-carbon (700 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hr. The insoluble material was removed by filtration, washed with methanol (20 mL), and the combined filtrate was concentrated under reduced pressure.
  • a THF solution (2.4 M, 11.6 mL) of lithium aluminum hydride (hereinafter referred to as LAH) was dissolved in THF (20 mL), and the residue obtained from the previous reaction (2.2 g out of 5.7 g, 2.2 g) of THF (under ice cooling) 5.0 mL) solution was added dropwise and stirred at room temperature for 3 hours.
  • Water (5.0 mL) was slowly added to the reaction solution at 0 ° C., and the resulting solid was filtered off, washed with ethyl acetate (50 mL) and THF (50 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was azeotroped with toluene (10 mL ⁇ 3), dissolved in chloroform (100 mL), manganese dioxide (7.0 g) was added, and the mixture was heated to reflux at 80 ° C. for 2 hours.
  • the insoluble material was filtered off using celite, washed with chloroform (200 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was azeotroped with toluene (5.0 mL ⁇ 2).
  • the obtained compound was dissolved in acetone (12 mL), 12N hydrochloric acid (6.0 mL) was added, and the mixture was stirred for 10 min.
  • the reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution (20 mL) and concentrated under reduced pressure.
  • Chloroform (20 mL) and water (10 mL) were added to the residue and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was dissolved in ethanol (20 mL), sodium borohydride (383 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hr.
  • a saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution, and the mixture was partitioned. The organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (4.0 mL), sodium azide (277 mg) was added, and the mixture was stirred at 50 ° C. for 3 hr. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (310 mg) as a pale yellow oil.
  • 2,2-diphenylethanol 500 mg was dissolved in THF (20 mL), triphenylphosphine (656 mg) and azodicarboxylate diisopropyltoluene solution (1.9 M, 1.32 mL) were added, and the mixture was stirred at room temperature for 5 minutes.
  • Diphenylphosphoryl azide (538 ⁇ L) was added dropwise to the reaction solution, and the mixture was stirred at 50 ° C. for 12 hours.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane) to give the title compound (300 mg) as a pale yellow oil.
  • the obtained compound was dissolved in THF (10 mL), and a THF solution of methylmagnesium bromide (1.0 M, 10 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours.
  • a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • Methyltriphenylphosphonium bromide (2.86 g) was suspended in THF (30 mL), a NaHMDS THF solution (1.0 M, 8.0 mL) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The mixture was cooled to ⁇ 78 ° C., the ketone body (550 mg) obtained in the previous reaction was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was suspended in a 10% ethyl acetate / hexane solution (50 mL).
  • a sodium hydroxide aqueous solution (3.0 M, 1.75 mL) was added to the reaction solution at 0 ° C., and the mixture was stirred for 5 minutes, 30% aqueous hydrogen peroxide (1.75 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • a saturated aqueous sodium hydrogen sulfite solution (2.0 mL) was added to the reaction mixture at 0 ° C., and the mixture was acidified with hydrochloric acid (1.0 M, 5.0 mL), and extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution (2.0 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in DMF (2.0 mL), sodium azide (138 mg) was added, and the mixture was stirred at 90 ° C. for 48 hr.
  • Water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5.0 mL).
  • the organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (52 mg) as a pale yellow oil.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane).
  • the obtained compound (1.0 g out of 1.1 g) was dissolved in THF (7.0 mL), a THF solution of lithium borohydride (2.0 M, 1.48 mL) was added, and the mixture was heated to reflux at 80 ° C. for 5 hours.
  • the reaction mixture was allowed to cool, saturated brine (10 mL) was added, and the mixture was separated.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (840 mg) as a colorless oil.
  • the obtained compound was dissolved in THF (1.3 mL), a THF solution of TBAF (1.0 M, 1.31 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give the title compound (180 mg) as a colorless oil.
  • the residue was purified by silica gel column chromatography (25% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (1.5 mL), a TBAF solution in THF (1.0 M, 1.5 mL) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform) to give the title compound (190 mg) as a colorless oil.
  • the obtained compound was dissolved in ethyl acetate (3.0 mL), 10% palladium-carbon (1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hr.
  • the solid was filtered off using celite, washed with ethyl acetate (20 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was azeotroped with toluene (3 mL ⁇ 3), dissolved in THF (1.23 mL), TBAF in THF (1.0 M, 1.23 mL) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (190 mg) as a colorless oil.
  • a part (150 mg) of the obtained compound (650 mg) was suspended in methanol (600 ⁇ L) and water (100 ⁇ L), an aqueous sodium hydroxide solution (4.0 M, 203 ⁇ L) was added, and the mixture was stirred at 50 ° C. for 2 hours.
  • the reaction mixture was allowed to cool, acidified with hydrochloric acid (1.0 M, 1.0 mL), and separated by adding ethyl acetate (5.0 mL) and water (3.0 mL).
  • the aqueous layer was extracted with ethyl acetate (3.0 mL).
  • the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the obtained compound (100 mg) was dissolved in THF (500 ⁇ L), a THF solution of TBAF (1.0 M, 500 ⁇ L) was added, and the mixture was stirred for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (70 mg) as a colorless oil.
  • Methyl 5- (methoxymethoxy) pent-2-inoate (1.53 g) obtained in Reference Example 10 and (S) -1-azido-2- (3- (cyclopropylmethoxy)- 4-Fluorophenyl) butan-2-ol (2.07 g) was dissolved in toluene (40 mL), and chloro (pentamethylcyclopentadienyl) (cyclooctadiene) ruthenium (II) (281 mg) was added at 80 ° C. Stir for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (25 mL), a solution of lithium borohydride in THF (2.0 M, 8.8 mL) was added, and the mixture was stirred at 80 ° C. for 10 hr. To the reaction solution was added saturated brine (30 mL) at 0 ° C., and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2.5% methanol / chloroform).
  • the obtained diol (1.73 g, 400 mg) was dissolved in dichloromethane (4.0 mL), triethylamine (198 ⁇ L) and methanesulfonyl chloride (80 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction solution to separate the layers.
  • the organic layer was washed with water (5.0 mL) and saturated brine (5.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in THF (2.0 mL), TBAF in THF (1.0 M, 5.0 mL) was added, and the mixture was stirred at 50 ° C.
  • the reaction solution was allowed to cool, and ethyl acetate (20 mL), hexane (20 mL) and water (20 mL) were added to separate the layers. The organic layer was dried over anhydrous magnesium sulfate and dried under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane). The obtained regioisomer mixture (279 mg) was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / ethyl acetate) to give the title compound (188 mg) as a colorless oil.
  • the obtained monoalcohol was dissolved in THF (20 mL), carbon tetrabromide (3.29 g) and triphenylphosphine (2.6 g) were added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was concentrated under reduced pressure, and hexane (10 mL) and ethyl acetate (1.0 mL) were added to the residue.
  • the resulting solid was removed by filtration, washed with 10% ethyl acetate / hexane (30 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the obtained trimethylsilyl compound was dissolved in ethanol (4.0 mL), sodium hydroxide (420 mg) was added, and the mixture was stirred at room temperature for 3 hours.
  • the reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (20 mL).
  • the organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (3% ethyl acetate / hexane) to give the title compound (660 mg) as a pale yellow oil.
  • the obtained compound (890 mg) was dissolved in DMF (10 mL), sodium acetate (900 mg) and sodium iodide (549 mg) were added, and the mixture was stirred at 90 ° C. for 12 hours. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution and the phases were separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane).
  • the obtained compound (198 mg) was dissolved in a methanol solution of methylamine (40%, 2.0 mL) and stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane).
  • the obtained compound (140 mg) was dissolved in dimethyl sulfoxide (2.0 mL) and toluene (1.0 mL), EDC / HCl (270 mg), pyridine (38 ⁇ L), trifluoroacetic acid (20 ⁇ L) were added, and the mixture was stirred at room temperature for 1 hour. did.
  • the reaction mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane) to give the title compound (80 mg) as a pale yellow oil.
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the obtained compound was dissolved in methanol (20 mL), 10% palladium-carbon (2.0 g) was added, and the mixture was stirred at room temperature for 2 hr in a hydrogen atmosphere.
  • the insoluble material was removed by filtration, washed with methanol (50 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was dissolved in ethanol (1.6 mL) and water (1.6 mL), aqueous sodium hydroxide solution (4.0 M, 3.2 mL) was added, and the mixture was stirred at 50 ° C. for 2 hr.
  • the residue was purified by silica gel column chromatography (2% ethyl acetate / hexane).
  • the obtained compound was dissolved in THF (1.5 mL) and water (300 ⁇ L), acetic acid (300 ⁇ L) was added, and the mixture was stirred at room temperature for 3.5 hours.
  • the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution (5.0 mL) and extracted with ethyl acetate (10 mL).
  • the organic layer was washed with saturated brine (5.0 mL) and dried over anhydrous magnesium sulfate.
  • the residue was purified by silica gel column chromatography (2.5% ethyl acetate / hexane) to give the title compound (96 mg) as a colorless oil.
  • the obtained pale yellow oily substance (345 mg) was dissolved in DMF (6.0 mL), imidazole (371 mg) and tert-butyldimethylsilyl chloride (411 mg) were added, and the mixture was stirred at room temperature for 1 hour.
  • Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL).
  • the organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (15% ethyl acetate / hexane).
  • the obtained orange oily substance (153 mg) was dissolved in THF (1.0 mL), a THF solution of TBAF (1.0 M, 0.465 mL) was added, and the mixture was stirred at room temperature for 30 minutes and at 50 ° C. for 30 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (110 mg) as a pale yellow oil.
  • the reaction mixture was concentrated under reduced pressure, water (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% ethyl acetate / hexane). The obtained compound was dissolved in a hydrogen chloride-dioxane solution (4.0 M, 3.0 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and azeotroped with toluene (2.0 mL ⁇ 3).
  • the obtained compound was dissolved in THF (1.0 mL), a TBAF solution in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to give the title compound (71 mg) as a colorless oil.
  • 2,2-bis4-chlorophenyl) ethanamine (320 mg) obtained by the method described in the literature (J. Am. Chem. Soc., 105, 3183-3188 (1983)) was dissolved in toluene (6.5 mL), Triethylamine (335 ⁇ L) was added and cooled to 0 ° C. Triphosgene (132 mg) was added to the reaction mixture, followed by stirring at 0 ° C. for 1.5 hours. The resulting precipitate was filtered off, washed with toluene (10 mL ⁇ 5), and the combined filtrate was concentrated under reduced pressure. The residue was dissolved in toluene (6.0 mL).
  • the residue was purified by amino silica gel column chromatography (70% ethyl acetate / hexane). A part (513 mg) of the obtained compound (1.29 g) was dissolved in acetonitrile (6.5 mL), triethylamine (251 ⁇ L) and a toluene solution of the residue were added, and the mixture was stirred at 50 ° C. for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (60% ethyl acetate / hexane).
  • the obtained compound (179 mg) was dissolved in dioxane (2.5 mL), an aqueous sodium hydroxide solution (4.0 M, 2.5 mL) was added, and the mixture was heated to reflux at 100 ° C. for 5 hr.
  • the reaction mixture was allowed to cool, neutralized with hydrochloric acid (6.0 M, 1.7 mL), and extracted with ethyl acetate (15 mL ⁇ 2).
  • the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (60% ethyl acetate / hexane).
  • the obtained compound 120 mg was dissolved in dichloromethane (2.0 mL), and triethylamine (53 ⁇ L), N, N-dimethylamino-4-pyridine (4.6 mg) and di-tert-butyl dicarbonate (62 mg) were added. Stir at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate / hexane).
  • the obtained compound (131 mg) was dissolved in THF (1.0 mL), TBAF in THF (1.0 M, 270 ⁇ L) was added, and the mixture was stirred at 50 ° C. for 1.5 hr.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (77 mg) as a foam.
  • the obtained colorless foam (3.90 g) was dissolved in DMF (60 mL), sodium azide (1.07 g) was added, and the mixture was stirred at 70 ° C. for 2 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL ⁇ 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.28 g) as a colorless oil.
  • the obtained pale yellow gum (2.27 g) was dissolved in DMF (20 mL), potassium carbonate (2.0 g) and thioacetic acid (680 ⁇ L) were added, and the mixture was stirred at room temperature for 30 minutes.
  • Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL ⁇ 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in methanol (12 mL) and THF (3.0 mL), sodium methoxide (443 mg) was added, and the mixture was stirred at room temperature for 30 min.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (12 mL), N, N-diisopropylethylamine (2.14 mL) and chloromethyl methyl ether (780 ⁇ L) were added, and the mixture was stirred at room temperature for 5 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL).
  • the reaction mixture was allowed to cool, saturated aqueous sodium sulfite solution (10 mL) and water (50 mL) were added, and the mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (70% ethyl acetate / hexane). The obtained pale yellow gum (381 mg) was dissolved in THF (4.0 mL), TBAF in THF (1.0 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / chloroform).
  • the obtained colorless gum-like substance (200 mg) was dissolved in pyridine (4.0 mL), methanesulfonyl chloride (63 ⁇ L) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (5.0 mL ⁇ 1) and purified by silica gel column chromatography (3% methanol / chloroform).
  • the obtained pale yellow gum (221 mg) was dissolved in DMF (4.0 mL), sodium azide (117 mg) was added, and the mixture was stirred at 55 ° C. for 16 hr.
  • the obtained colorless oily substance (5.62 g, 1.74 g) was dissolved in THF (5.0 mL), TBAF in THF (1.0 M, 5.0 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane).
  • the obtained colorless oily substance (393 mg of 771 mg) was dissolved in toluene (4.0 mL) and DMSO (4.0 mL), and pyridine (243 ⁇ L), trifluoroacetic acid (111 ⁇ L) and EDC ⁇ HCl (1.15 g) were added. Stir at room temperature for 1 hour.
  • the obtained colorless gum-like substance (220 mg) was dissolved in methanol (3.0 mL), sodium methoxide (61 mg) was added, and the mixture was stirred at 45 ° C. for 12 hours. After neutralization with hydrochloric acid (6.0 M, about 9 drops), the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (5.0 mL) and purified by silica gel column chromatography (4% methanol / chloroform). The resulting colorless gum (148 mg) was dissolved in pyridine (3.0 mL), methanesulfonyl chloride (44 ⁇ L) was added, and the mixture was stirred at room temperature for 3.5 hours.
  • Examples 2 to 118 were synthesized according to the method of Example 1 from alkynes and azides shown in the following table, respectively.
  • Example 8 3- (3- (1- (2- (cyclopentyloxy) phenethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 31 (4- (1-((S) -2-hydroxy-2- (3-((R) -tetrahydrofuran-3-yloxy) phenyl) butyl) -1H-1,2,3-triazole-5- Yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 40 1- (3- (1- (2,2-bis (4-fluorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H , 3H) -Dione
  • Example 46 (2-((1- (3- (cyclopropylmethoxy) -4-fluorophenethyl) -1H-1,2,3-triazol-5-yl) methoxy) ethyl) pyrimidine-2,4 (1H, 3H) -Dione
  • Example 50 (3- (1-phenethyl-1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 54 (4- (1- (2-methoxyphenethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 60 (2- (1- (2,2-bis (4-fluorophenyl) -2-hydroxyethyl l) -1H-1,2,3-triazol-5-yl) ethyl) pyrimidine-2,4 ( 1H, 3H) -Dione
  • Example 64 (3- (1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -Dione
  • Example 65 (4- (1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H) -Dione
  • Example 66 1- (3- (1- (2,2-bis (4-chloro-3-methoxyphenyl) -2-hydroxyethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2 , 4 (1H, 3H) -Dione
  • Example 80 (3- (1- (2- (biphenyl-2-yl) ethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H, 3H) -dione
  • Example 82 1- (3- (1- (2-hydroxy-2,2-bis (3-methoxyphenethyl) ethyl) -1H-1,2,3-triazol-5-yl) propyl) pyrimidine-2,4 (1H , 3H) -Dione
  • Example 100 1-((2- (1- (3- (cyclopropylmethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) ethoxy) methyl) -5-fluoropyrimidine-2,4 (1H, 3H) -Dione
  • Example 102 (4- (1- (3- (cyclopentyloxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) -5-fluoropyrimidine-2,4 (1H, 3H) -dione
  • Example 104 (4- (1- (3- (2,2-difluoroethoxy) phenethyl) -1H-1,2,3-triazol-5-yl) butyl) -5-fluoropyrimidine-2,4 (1H, 3H) -Dione
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform).
  • the obtained compound was dissolved in a methanol solution of methylamine (40%, 5.0 mL) and stirred at room temperature for 30 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform) to give the title compound (110 mg, yield 49%) as a foam.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3% methanol / chloroform).
  • the obtained methyl ester compound (500 mg out of 1.2 g) was dissolved in THF (4.0 mL), a THF solution of lithium borohydride (2.0 M, 1.38 mL) was added, and the mixture was stirred at 50 ° C. for 3 hours.
  • Saturated brine (10 mL) was added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give the title compound (120 mg, yield 25%) as a foam.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform).
  • the obtained methyl ester (5.8 g) was dissolved in methanol (7.0 mL) and water (5.0 mL), an aqueous sodium hydroxide solution (4.0 M, 8.1 mL) was added, and the mixture was stirred at 50 ° C. for 4 hr.
  • strongly acidic cation exchange resin (DIAIONPK212, H + form) was added to acidify the reaction solution, the resin was filtered off, washed with methanol (50 mL) and water (50 mL), and the combined filtrate was concentrated under reduced pressure.
  • the residue was azeotroped with toluene (20 mL ⁇ 4).
  • Example 128 1- (2,2-bis (4-chlorophenyl) -2-hydroxyethyl) -5- (3- (2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) propyl) -N Of 2-methyll-1H-1,2,3-triazole-4-carboxamide
  • Examples 130 and 131 1- (4- (1- (3- (cyclopropylmethoxy) phenethyl) -4-methyl-1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H)- Dione and 1- (4- (1- (3- (cyclopropylmethoxy) phenethyl) -4-methyl-1H-1,2,3-triazol-5-yl) butyl) pyrimidine-2,4 (1H, 3H ) -Dione synthesis
  • Example 130 54 mg, 39% yield
  • Example 131 40 mg, 29% yield
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1.5% methanol / chloroform).
  • the obtained compound was dissolved in a methanol solution of methylamine (40%, 3.0 mL) and stirred at room temperature for 30 minutes.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2.5% methanol / chloroform) to give the title compound (150 mg, yield 51%) as a colorless gum.
  • Example 138 1- (3- (4- (2,2-bis (4-chlorophenyl) ethyl) -5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) propyl) pyrimidine- Synthesis of 2,4 (1H, 3H) -dione
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (70% ethyl acetate / hexane).
  • the obtained compound was dissolved in a methanol solution of methylamine (40%, 1.5 mL) and stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (2.0 mL ⁇ 2).
  • the residue was dissolved in a hydrogen chloride-dioxane solution (4.0 M, 1.5 mL) and stirred at room temperature for 1 hour.
  • reaction solution was concentrated under reduced pressure, and the residue was azeotroped with toluene (2.0 mL ⁇ 3) and purified by silica gel column chromatography (8% methanol / chloroform) to give the title compound (48 mg, 66% yield). Obtained as a foam.
  • Examples 140-142 The following compounds are readily available from the compounds of Reference Examples 104 to 106 or from acetylene compounds obtained by the method described in the literature (Example 140: J. Org. Chem., 53, 2489-2496 (1988)). Synthesized according to the method of Example 139.
  • Example 140 1-((2- (2- (5- (thiazol-2-yl)-(1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H , 3H) -Dione
  • Examples 143 and 144 1-((2- (2- (5-phenyl-1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione and 1 Synthesis of-((2- (2- (4-phenyl-1H-1,2,3-triazol-1-yl) ethyl) benzyloxy) methyl) pyrimidine-2,4- (1H, 3H) -dione
  • the compound is described in International Publication No. 2005-065689 as a compound having the strongest human deoxyuridine triphosphatase (hereinafter referred to as dUTPase) inhibitory activity, and described in International Publication No. WO2005-065689 in order to compare the activity with the compound of the present invention.
  • the method was synthesized.
  • the inhibitory activity against human dUTPase Test Example 1 Human dUTPase inhibitory activity present compound, the following methods [5- 3 H] deoxyuridine triphosphate (hereinafter, [5- 3 H] dUTP) [5- 3 H] from It was determined by measuring the production of deoxyuridine monophosphate (hereinafter referred to as [5- 3 H] dUMP).
  • the reaction was stopped by heating in a water bath at 100 ° C. for 1 minute, followed by centrifugation at 15000 rpm for 2 minutes. After centrifugation, a part of the obtained supernatant (150 ⁇ L) was analyzed with a high performance liquid chromatograph (Shimadzu Corporation, Prominence) using an AtlantisdC18 column (Waters, 4.6 ⁇ 250 mm).
  • Mobile phase A (10 mM potassium dihydrogen phosphate (pH 6.7), 10 mM tetrabutylammonium, 0.25% methanol) and mobile phase B (50 mM potassium dihydrogen phosphate (pH 6.7), 5.6 mM at a flow rate of 0.8 mL / min Elution was performed with a 30-minute concentration gradient from a 4: 6 mixture of tetrabutylammonium, 30% methanol) to mobile phase B.
  • the scintillator (Perkin Elmer, Ultima-FloAP) was mixed with the eluent at a ratio of 1: 2, and [5- 3 H] dUMP (RT10.2min) generated by RadiomaticFlowScintillationAnalyzer (PerkinElmer, 525TR) Radioactivity was measured.
  • the inhibitory activity of the test compound was determined by the following equation, and the concentration of the test solution that inhibits the amount of [5- 3 H] dUMP produced by human dUTPase by 50% is shown in Table 47 as IC 50 ( ⁇ M).
  • the following table shows human dUTPase inhibitory activity data.

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Abstract

La présente invention concerne un uracile comportant un hétérocycle azoté, de formule (I), présentant une excellente activité inhibitrice de la dUTPase humaine et pouvant être employé en tant qu'agent antitumoral, etc., ou un sel dudit uracile. [Dans la formule, X représente un hydrocarbure divalent pouvant comporter un hétéroatome entre les atomes de carbone ou en extrémité ; Y représente H ou F ; A représente un hétérocycle insaturé azoté (substitué) ; et R1 et R2 représentent indépendamment H ou un groupement CN, alkyle en C1-4 (substitué), alcényle ou alcynyle en C2-4 (substitué), un groupement mono- ou di-alkylaminocarbonyle, un groupement aryle, un hétérocycle insaturé ou un groupement arylalkyle (substitué).]
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US20160002204A1 (en) * 2014-07-03 2016-01-07 Board Of Regents, The University Of Texas System Gls1 inhibitors for treating disease
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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11884652B2 (en) * 2020-06-29 2024-01-30 Boehringer Ingelheim International Gmbh Tetrazole derivatives as TRPA1 inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54130586A (en) * 1978-03-09 1979-10-09 Elkawi Ag 55fluorouracil derivative*its manufacture and drug containing it

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54130586A (en) * 1978-03-09 1979-10-09 Elkawi Ag 55fluorouracil derivative*its manufacture and drug containing it

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BRZEZINSKI, B. ET AL.: "Influence of intermolecular hydrogen bonds on the geometry of the photodimerization of 1,1'-trimethylene- bis(5R,5R')uracils", JOURNAL OF MOLECULAR STRUCTURE, vol. 245, no. 1-2, 1991, pages 13 - 19 *
GENESTE, H. ET AL.: "Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: 1H-Pyrimidin-2-one derivatives", BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 16, no. 3, 2006, pages 490 - 494 *
GOLANKIEWICZ, K. ET AL.: "Non-bonding base-base interaction in nucleic acids. I. Synthesis and properties of several 1,1'-polymethylenebispyrimidines", BULLETIN DE L'ACADEMIE POLONAISE DES SCIENCES, SERIE DES SCIENCES CHIMIQUES, vol. 18, no. 8, 1970, pages 449 - 454 *
HUANG, S.Q. ET AL.: "Study on porphyrins: Synthesis and antitumor activity of porphyrin- fluorouracil compounds", ACTA PHARMACEUTICA SINICA, vol. 26, no. 6, 1991, pages 415 - 419 *
KORONIAK, H. ET AL.: "The structural study of internal [2 + 2] photodimers of the derivatives of l,l'-trimethylen-bis(5-fluoro) uracil", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 146, no. 3, 1987, pages 1270 - 1276 *
LIU, Y. ET AL.: "Syntheses of pyridylporphyrin-5- fluorouracil compounds", CHINESE JOURNAL OF APPLIED CHEMISTRY, vol. 22, no. 2, 2005, pages 219 - 221 *
MCCORMICK, J.E. ET AL.: "N,N'-transphthaloylation in a monoprotected diamine", SYNTHESIS, no. 6, 2006, pages 983 - 988 *
MCELHINNEY, R.S. ET AL.: "Nucleoside analogs: 8. Some isomers of B.3839, the original 5-fluorouracil/nitrosourea molecular combination, and their effect on colon, breast and lung tumors in mice", ANTI-CANCER DRUG DESIGN, vol. 4, no. 1, 1989, pages 1 - 20 *

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