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WO2013137427A1 - Nouveau composé nucléosidique de type pyrimidine - Google Patents

Nouveau composé nucléosidique de type pyrimidine Download PDF

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Publication number
WO2013137427A1
WO2013137427A1 PCT/JP2013/057364 JP2013057364W WO2013137427A1 WO 2013137427 A1 WO2013137427 A1 WO 2013137427A1 JP 2013057364 W JP2013057364 W JP 2013057364W WO 2013137427 A1 WO2013137427 A1 WO 2013137427A1
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Prior art keywords
group
thio
ribofuranosyl
deoxy
fluorouracil
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PCT/JP2013/057364
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English (en)
Japanese (ja)
Inventor
由起 田中
野村　誠
裕美 数野
憩 小口
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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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a novel pyrimidine nucleoside compound having an excellent antitumor effect, particularly a 5-fluoro-4′-thio-2′-deoxypyrimidine nucleoside compound or a salt thereof.
  • nucleic acid biosynthesis is essential for cell growth, and so far, development of nucleic acid metabolism antagonists that inhibit nucleic acid metabolism has been vigorously conducted.
  • Patent Document 1 and Non-Patent Document 1 4′-thio-2′-deoxypyrimidine nucleosides as antiviral agents and antitumor agents, in particular, 4′-thio-2′-deoxyuridine and 4′-thio- Antiviral activity of 2′-deoxythymidine against herpes simplex virus type 1 (HSV1) and type 2 (HSV2), and human leukocyte L1210 cells, human endothelial tumor No. Reference is made to antitumor activity against two cells.
  • HSV1 herpes simplex virus type 1
  • HSV2 type 2
  • HSV2 human leukocyte L1210 cells
  • human endothelial tumor No Reference is made to antitumor activity against two cells.
  • Patent Documents 2 and 3 and Non-Patent Document 2 4′-thio-2′-deoxypyrimidine nucleoside as an antiviral agent, particularly 5- (2-chloroethyl) -4′-thio-2′-deoxy, among others.
  • HSV1 monologous virus type 1
  • HSV2 type 2
  • Non-Patent Document 3 5-fluoro-4′-thio-2′-deoxyuridine (1- [2′-deoxy-4′-thio-1- ⁇ -D) having a structure similar to that of the compound of the present invention is used. -Ribofuranosyl] -5-fluorouracil) is described for antitumor activity against L1210 cells.
  • An object of the present invention is to provide a novel pyrimidine nucleoside compound exhibiting a balance between antitumor effect and toxicity superior to existing pyrimidine nucleoside compounds.
  • a 1 and A 2 are the same or different and are a hydrogen atom, an alkyloxycarbonyl group optionally having substituent (s), a cycloalkyloxycarbonyl group optionally having substituent (s), substituted
  • An aryloxycarbonyl group which may have a group or an aralkyloxycarbonyl group which may have a substituent is shown.
  • a 1 and A 2 are not hydrogen atoms at the same time.
  • the pyrimidine nucleoside compound represented by these, or its salt is provided.
  • a 1 or A 2 when either A 1 or A 2 is a hydrogen atom, the other is a (C 1-10 alkyl) oxycarbonyl group (the alkyl group may have a halogen atom as a substituent). ), (C 3-7 cycloalkyl) oxycarbonyl group, (C 6-12 aryl) oxycarbonyl group (the aryl group may have a halogen atom or a C 1-6 alkoxy group as a substituent).
  • a 1 and A 2 are the same or different and each represents a (C 1-6 alkyl) oxycarbonyl group or a (C 3-7 cycloalkyl) oxycarbonyl group.
  • a 1 or A 2 when either A 1 or A 2 is a hydrogen atom, the other is an ethyloxycarbonyl group, n-butyloxycarbonyl group, n-hexyloxycarbonyl group, n-octyloxycarbonyl group, n- Decyloxycarbonyl group, isopropyloxycarbonyl group, pentan-3-yloxycarbonyl group, heptane-4-yloxycarbonyl group, 2-methylpropan-1-yloxycarbonyl group, 2,2-dimethylpropan-1-yl
  • An oxycarbonyl group (the alkyl group may have a chlorine atom as a substituent), a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, a chlorine atom as a substituent, or a methoxy group
  • a pyrimidine nucleoside compound or a salt thereof according to any of the following (1) to (32) is provided: (1) 1- [2′-Deoxy-3′-O-ethyloxycarbonyl-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (2) 1- [2′-Deoxy-3′-O- (n-butyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (3) 1- [2′-Deoxy-3′-O- (n-hexyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (4) 1- [2′- Deoxy-3'-O- (n-octyloxycarbonyl) -4'-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (5) 1- [2'-deoxy-3'-O- (n -
  • a pharmaceutical composition comprising an effective amount of any one of the above pyrimidine nucleoside compounds or salts thereof and a pharmaceutical carrier is provided.
  • an antitumor agent comprising an effective amount of any one of the above pyrimidine nucleoside compounds or salts thereof and a pharmaceutical carrier is provided.
  • any one of the above pyrimidine nucleoside compounds or salts thereof for producing an antitumor agent is provided.
  • any one of the above pyrimidine nucleoside compounds or salts thereof for use in the prevention and / or treatment of disease is provided.
  • any one of the above pyrimidine nucleoside compounds or salts thereof for use in the prevention and / or treatment of tumors is provided.
  • a method for preventing and / or treating a disease comprising administering to a patient an effective amount of any one of the above pyrimidine nucleoside compounds or salts thereof.
  • a method for preventing and / or treating a tumor comprising administering to a patient an effective amount of any one of the above pyrimidine nucleoside compounds or salts thereof.
  • novel pyrimidine nucleoside compound or a salt thereof of the present invention exhibits an excellent balance of antitumor effect and toxicity and is useful as an antitumor agent.
  • novel pyrimidine nucleoside compound or a salt thereof of the present invention is a compound represented by the above general formula (1).
  • examples of the “substituent” include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, a halogenoalkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, an aralkyl group, an alkenyl group, and an alkynyl group.
  • the “alkyloxycarbonyl group” of the “optionally substituted alkyloxycarbonyl group” represented by A 1 and A 2 is a linear or branched (C 1 -10 alkyl) oxycarbonyl group, methyloxycarbonyl group, ethyloxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, n-butyloxycarbonyl group, sec-butyloxycarbonyl group, tert-butyloxy Carbonyl group, n-pentyloxycarbonyl group, 1-methylbutyloxycarbonyl group, 2-methylbutyloxycarbonyl group, 3-methylbutyloxycarbonyl group, 1,1-dimethylpropyloxycarbonyl group, 1,2-dimethylpropyl Oxycarbonyl group, n-hexyloxycarboni Group, 1,1-dimethylbutyloxycarbonyl group, 1,1-dimethylpentyl
  • Examples of the “substituent” of the “optionally substituted alkyloxycarbonyl group” represented by A 1 and A 2 include the above substituents, preferably a halogen atom, more preferably a chlorine atom. It is. The number of substituents is 1 to 3.
  • an ethyloxycarbonyl group an isopropyloxycarbonyl group, an n-butyloxycarbonyl group, an n-hexyloxycarbonyl group, an n-octyloxycarbonyl group, n-decyloxycarbonyl group, pentan-3-yloxycarbonyl group, heptane-4-yloxycarbonyl group, 2-methylpropan-1-yloxycarbonyl group, 2,2-dimethylpropan-1-yloxycarbonyl group 2,2,2-trichloroethane-1-yloxycarbonyl group, particularly preferably isopropyloxycarbonyl group and 2,2-dimethylpropan-1-yloxycarbonyl group.
  • the “cycloalkyloxycarbonyl group” of the “cycloalkyloxycarbonyl group optionally having substituents” represented by A 1 and A 2 is (C 3-7 cycloalkyl) oxy
  • Preferred are a cyclopentyloxycarbonyl group and a cyclohexyloxycarbonyl group.
  • Examples of the “substituent” of the “cycloalkyloxycarbonyl group optionally having substituent (s)” represented by A 1 and A 2 include the above substituents.
  • the number of substituents is 1 to 3, preferably 1 or 2.
  • cycloalkyloxycarbonyl group which may have a substituent is a cyclopentyloxycarbonyl group or a cyclohexyloxycarbonyl group.
  • the “aryloxycarbonyl group” in the “aryloxycarbonyl group optionally having substituents” represented by A 1 and A 2 represents a C 6 -C 12 aryloxycarbonyl group.
  • a phenyloxycarbonyl group is preferred.
  • the “substituent” in the “aryloxycarbonyl group optionally having substituent (s)” represented by A 1 and A 2 is C 1 -C 6 alkoxy such as hydroxyl group, methoxy group, ethoxy group, isopropoxy group, etc.
  • the “aryloxycarbonyl group optionally having substituent (s)” is preferably a phenyloxycarbonyl group, a 4-chlorophenyloxycarbonyl group, or a 2-methoxyphenyloxycarbonyl group.
  • the “aralkyloxycarbonyl group” in the “aralkyloxycarbonyl group optionally having a substituent” represented by A 1 and A 2 is a (C 7 -C 10 aralkyl) oxycarbonyl group.
  • benzyloxycarbonyl group and phenethyloxycarbonyl group are exemplified.
  • a benzyloxycarbonyl group is preferred.
  • the “substituent” in the “aralkyloxycarbonyl group optionally having substituent (s)” represented by A 1 and A 2 is C 1 -C 6 alkoxy such as hydroxyl group, methoxy group, ethoxy group, isopropoxy group, etc.
  • Group, amino group, halogen atom such as chlorine, bromine and the like, cyano group, nitro group and the like are mentioned, preferably nitro group, and the number thereof is 1 to 3, preferably 1 or 2.
  • the “aralkyloxycarbonyl group optionally having substituent (s)” is preferably a benzyloxycarbonyl group or a 4-nitrobenzyloxycarbonyl group.
  • the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, but a fluorine atom, a chlorine atom or a bromine atom is preferable.
  • the alkyl group may be linear or branched, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl.
  • Groups, C 1-6 alkyl groups such as isopentyl group, hexyl group and the like.
  • the halogenoalkyl group may be linear or branched.
  • Examples thereof include C 1-6 halogenoalkyl groups such as ethyl group, monofluoro-n-propyl group, perfluoro-n-propyl group, perfluoroisopropyl group, and preferably C 1-3 halogenoalkyl group.
  • cycloalkyl group examples include C 3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkyl-alkyl groups include C 3-7 cycloalkyl substituted C 1-4 alkyl groups such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cycloheptylmethyl.
  • aralkyl group examples include C 7-13 aralkyl groups such as benzyl group, phenethyl group, naphthylmethyl group, and fluorenylmethyl group.
  • the alkenyl group may be linear, branched or cyclic, and means one having at least one double bond, for example, vinyl group, allyl group, 1-propenyl group, 2-methyl-2 -Propenyl group, isopropenyl group, 1-, 2- or 3-butenyl group, 2-, 3- or 4-pentenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 5- C 2-6 alkenyl groups such as a hexenyl group, 1-cyclopentenyl group, 1-cyclohexenyl group, 3-methyl-3-butenyl group and the like can be mentioned.
  • the alkynyl group may be linear, branched or cyclic, and means one having at least one triple bond, such as ethynyl group, 1- or 2-propynyl group, 1-, 2- or Examples thereof include C 2-6 alkynyl groups such as 3-butynyl group and 1-methyl-2-propynyl group.
  • the alkoxy group may be linear or branched, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, isopentyloxy And C 1-6 alkoxy groups such as a hexyloxy group.
  • the halogenoalkoxy group may be linear or branched, and examples thereof include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a fluoroethoxy group, and 1,1,1-trifluoro.
  • Examples thereof include C 1-6 halogenoalkoxy groups such as ethoxy group, monofluoro-n-propoxy group, perfluoro-n-propoxy group, perfluoro-isopropoxy group, preferably C 1-3 halogenoalkoxy group.
  • cycloalkoxy group examples include C 3-7 cycloalkoxy groups such as a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptyloxy group.
  • cycloalkylalkoxy group examples include C 3-7 cycloalkyl-substituted C 1-4 alkoxy groups such as a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, and a cycloheptylmethoxy group.
  • aralkyloxy group examples include C 7-13 aralkyloxy groups such as benzyloxy group, phenethyloxy group, naphthylmethyloxy group, and fluorenylmethyloxy group.
  • the alkylthio group may be linear or branched.
  • C 1-6 alkylthio such as methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, tert-butylthio group, n-pentylthio group, isopentylthio group, hexylthio group, etc.
  • C 1-6 alkylthio such as methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, tert-butylthio group, n-pentylthio group, isopentylthio group, hexylthio group, etc.
  • cycloalkylalkylthio group examples include C 3-7 cycloalkyl-substituted C 1-4 alkylthio groups such as a cyclopropylmethylthio group, a cyclobutylmethylthio group, a cyclopentylmethylthio group, a cyclohexylmethylthio group, and a cycloheptylmethylthio group.
  • the monoalkylamino group includes methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group.
  • an amino group mono-substituted by linear or branched C 1-6 alkyl such as a hexylamino group.
  • Dialkylamino groups include dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, isobutylamino, ditert-butylamino, di-n-pentylamino, di Examples thereof include an amino group disubstituted with a linear or branched C 1-6 alkyl such as an isopentylamino group and a dihexylamino group.
  • cycloalkylalkylamino group examples include C 3-7 cycloalkyl-substituted C 1-4 alkylamino such as cyclopropylmethylamino group, cyclobutylmethylamino group, cyclopentylmethylamino group, cyclohexylmethylamino group, and cycloheptylmethylamino group. Groups.
  • Acyl group means an alkylcarbonyl group or an arylcarbonyl group.
  • Alkylcarbonyl includes linear or branched groups such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl, etc. Examples include branched C 1-6 alkylcarbonyl.
  • Arylcarbonyl includes phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromancarbonyl, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyl, inda (C 6-13 aryl) carbonyl such as nylcarbonyl and phenanthrylcarbonyl.
  • Acyloxy group means an alkylcarbonyloxy group or an arylcarbonyloxy group.
  • alkylcarbonyloxy examples include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy And straight-chain or branched C 1-6 alkylcarbonyloxy such as hexylcarbonyloxy.
  • Arylcarbonyloxy includes phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4- (C 6-13 aryl) carbonyloxy such as dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy and phenanthrylcarbonyloxy.
  • the alkoxycarbonyl group may be linear or branched.
  • aralkyloxycarbonyl group examples include C 7-13 aralkyloxycarbonyl groups such as benzyloxycarbonyl group, phenethyloxycarbonyl group, naphthylmethyloxycarbonyl group, and fluorenylmethyloxycarbonyl group.
  • Saturated heterocyclic groups include morpholino group, 1-pyrrolidinyl group, piperidino group, piperazinyl group, 4-methyl-1-piperazinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, tetrahydrothiophenyl group, thiazolidinyl group, oxazolidinyl group Can be mentioned.
  • Unsaturated heterocyclic group means a monocyclic or polycyclic group comprising a 5- or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S. In the case of a polycyclic system, at least one ring may be a heteroaromatic ring.
  • Examples thereof include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, Examples thereof include an isoquinolyl group, a benzo [b] thienyl and benzoimidazolyl group, a benzothiazolyl group, and a benzoxazolyl group.
  • aromatic hydrocarbon group examples include a phenyl group, a toluyl group, a xylyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, a fluorenyl group, and a tetrahydronaphthyl group.
  • Saturated heterocyclic oxy groups include morpholinyloxy, 1-pyrrolidinyloxy, piperidino, piperazinyloxy, 4-methyl-1-piperazinyloxy, tetrahydrofuranyloxy, tetrahydropyrani
  • Examples include a ruoxy group, a tetrahydrothiophenyloxy group, a thiazolidinyloxy group, and an oxazolidinyloxy group.
  • the salt of the pyrimidine nucleoside compound of the present invention may be any pharmaceutically acceptable salt, for example, mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetic acid Organic acid salts such as salt, propionate, tartrate, fumarate, maleate, succinate, malate, citrate, methanesulfonate, p-toluenesulfonate, trifluoroacetate Can be formed.
  • the pyrimidine nucleoside compound of this invention may produce an optical isomer or a geometric isomer depending on the kind of substituent, this invention includes all of them. These isomers can be used either as a mixture or as a mixture.
  • the pyrimidine nucleoside compound of the present invention includes a solvate represented by a hydrate, an amorphous form, or a crystalline polymorph.
  • the pyrimidine nucleoside compound of the present invention or a salt thereof can be produced by various methods.
  • the compound (2) can be produced according to a generally known method (Patent Documents 1 and 2).
  • a modified derivative derived from the compound (2) can also be produced, for example, according to the following reaction process formulas 1-2.
  • Y is a protecting group for a hydroxyl group, and is not particularly limited as long as the protecting group can be removed under acidic or neutral conditions.
  • a trisubstituted silyl group such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, dimethyltexylsilyl group, tert-butyldiphenylsilyl group, triphenylmethyl group, 4-methoxytril
  • Examples thereof include a triarylmethyl group which may have a substituent such as a phenylmethyl group and a 4,4′-dimethoxyphenylmethyl group.
  • the protecting reagent used in this reaction is not particularly limited as long as it can selectively protect only the 5 ′ position and can be removed under acidic and neutral conditions, but BZ (Z represents a halogen atom) Or a tri-substituted halogenated silane such as trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, or dimethyltexylchlorosilane, or a triarylmethyl halide such as trityl chloride, monomethoxytrityl chloride, or dimethoxytrityl chloride. Is mentioned.
  • the solvent used in this reaction is not particularly limited as long as it does not participate in the reaction.
  • a base may be used as necessary.
  • Examples of the base include organic amines such as imidazole, 1-methylimidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like.
  • organic amines such as imidazole, 1-methylimidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like.
  • inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and the like, and only the base may be used as a solvent.
  • 1 to 20 moles, preferably 1 to 10 moles of the above-mentioned BZ is used with respect to 1 mole of the compound represented by the general formula
  • the reaction temperature is ⁇ 30 to 100 ° C., preferably ⁇ 10 to 60 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 24 hours.
  • the compound represented by the general formula (3) produced by this reaction can be isolated and purified as necessary, but can also be used in the next step without purification.
  • Step 2 the pyrimidine nucleoside compound represented by the general formula (3) or a salt thereof and A 1 -V (V represents a halogen, a p-nitrophenoxy group, or a 1-H-imidazol-1-yl group).
  • V represents a halogen, a p-nitrophenoxy group, or a 1-H-imidazol-1-yl group.
  • the compound represented by A 1 -V used in this reaction may be prepared according to a generally known method.
  • triphosgene has an alkyl alcohol which may have a corresponding substituent, an cycloalkyl alcohol which may have a substituent, an aryl alcohol which may have a substituent, or a substituent. It can also be obtained by reacting with a good aralkyl alcohol.
  • the compound represented by A 1 -V can be isolated and purified as necessary, but can also be used in this step without purification.
  • This reaction may be carried out according to a generally known method, but the solvent to be used is not particularly limited as long as it does not participate in the reaction.
  • dichloromethane chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, Toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination.
  • a base may be used as necessary.
  • Examples of the base include organic amines such as imidazole, 1-methylimidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like.
  • organic amines such as imidazole, 1-methylimidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like.
  • inorganic bases such as sodium hydrogen carbonate, sodium carbonate and potassium carbonate, and only the base may be used as a solvent.
  • a 1 -V is used in an amount of about 1 to 20 mol, preferably about 1 to 10 mol, and 1 to 100 mol of the base per 1 mol of the
  • the reaction temperature is ⁇ 30 to 100 ° C., preferably ⁇ 10 to 30 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 72 hours.
  • the compound represented by General formula (4) manufactured by this reaction can be isolated and purified as needed, it can also be used for the following process, without refine
  • the pyrimidine nucleoside compound represented by the general formula (4) is reacted with a deprotecting reagent to deprotect only the 5 ′ position, whereby the compound represented by the general formula (1a) can be produced.
  • the solvent used is not particularly limited as long as it does not participate in the reaction. For example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, water and the like can be mentioned, and these can be used alone or in combination.
  • the deprotection reagent to be used when a tri-substituted silyl group is used for Y, only Y can be removed and there is no particular limitation as long as it is usually used for deprotection of the silyl group.
  • Fluoride ion reagents such as ammonium fluoride, hydrogen fluoride, potassium fluoride, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or trifluoroacetic acid, acetic acid, propionic acid, formic acid, methanesulfone Examples include acids and organic acids such as p-toluenesulfonic acid.
  • the deprotecting reagent is used in an amount of about 0.5 to 200 mol, preferably about 1 to 100 mol, per 1 mol of the compound represented by the general formula (4).
  • the reaction temperature is ⁇ 30 to 150 ° C., preferably ⁇ 10 to 50 ° C., and the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
  • a pyrimidine nucleoside compound represented by the general formula (2) or a salt thereof is reacted with a compound represented by A 1 -V and A 2 -V to produce a compound represented by the general formula (1c). It is a process to do.
  • the compound represented by the general formula (1c) can be produced through the compound represented by the general formula (1b) in the same manner as in the second step.
  • the compound represented by the general formula (1c) can be produced through the compound represented by the general formula (1a) or (1b) in the same manner as in the second step.
  • the compound of the present invention and other compounds obtained as described above can form salts, particularly pharmaceutically acceptable salts, by a generally known method.
  • the compound of the present invention or a salt thereof, or another compound or a salt thereof can be isolated and purified by using generally known separation and purification means such as concentration, solvent extraction, filtration, recrystallization, various chromatography and the like.
  • the present invention provides a pharmaceutical composition containing an effective amount of at least one compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention When used as a medicine, it can be combined with a pharmaceutical carrier, and various administration forms can be adopted depending on the purpose of prevention or treatment. Examples of such forms include oral preparations, injections, and suppositories. Any of ointments, patches, and the like may be used, and oral preparations are preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
  • a pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, solubilizers, suspensions It is blended as an agent, isotonic agent, buffer, soothing agent and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary.
  • excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid
  • a binder water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc.
  • the disintegrating agent include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • Phosphate, borax, polyethylene glycol and the like, as the colorant, titanium oxide, iron oxide, white as the flavoring agent sugar, orange peel, citric acid can be exemplified tartaric acid.
  • 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 a conventional method.
  • 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.
  • a pH adjuster, buffer, stabilizer, tonicity 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 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 and glucose.
  • a formulation carrier known in the art such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and an interface such as Tween (registered trademark) as necessary are added to the compound of the present invention.
  • Tween registered trademark
  • 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, or a film or foam sheet made of cotton, suf, or chemical fiber is suitable.
  • the amount of the compound of the present invention or a salt thereof to be incorporated in each of the above dosage unit forms is not constant depending on the symptom of the patient to which the present invention is to be applied, or the dosage form thereof. It is desirable that the dosage is about 0.05 to 1000 mg for an agent, about 0.01 to 500 mg for an injection, and about 1 to 1000 mg for a suppository. Further, the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally, but is usually about 0.05 to 5000 mg per day for an adult, preferably The dose may be 0.1 to 1000 mg, and this is preferably administered once a day or divided into 2 to 4 times. In addition, in this invention, the compound represented by General formula (1) or its salt is used individually by 1 type or in combination of multiple types.
  • Diseases that can be treated by administering a drug containing the compound of the present invention include, for example, malignant tumors, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, Examples include lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, etc. .
  • the compound and antitumor agent of the present invention are useful for cancer / tumor prevention / treatment and / or recurrence prevention. Therefore, the present invention provides a preventive / therapeutic agent for cancer or tumor and a preventive agent for recurrence.
  • prevention of recurrence means prevention of recurrence of cancer or tumor after cancer or tumor tissue has once disappeared or cannot be recognized by surgery, radiation therapy, chemotherapy or the like.
  • In order to prevent recurrence of cancer or tumor usually about 0.05 to 5000 mg, preferably 0.1 to 1000 mg of the compound of the present invention may be administered per day for an adult.
  • the compound of the present invention is preferably administered once a day or divided into about 2 to 4 times a day.
  • the administration period for preventing recurrence is usually about 1 month to 1 year, especially about 3 months to 6 months. By continuing to take the compound of the present invention during this period, recurrence of cancer or tumor can be prevented.
  • the 1 H-NMR spectrum was measured using TMS (tetramethylsilane) as an internal standard, and showed a chemical shift with a ⁇ value (ppm). Chemical shifts show absorption patterns, coupling constants (J values), and proton numbers in parentheses.
  • Comparative Example 5 [2′-Deoxy-3′-O-ethyl-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil J. Org. Med. Chem. 1- [5′-O-monomethoxytrityl-2′-deoxy-4′-thio-1- ⁇ -] obtained by tritylation of 4′-Thio-FdUrd according to, 2010, 53, 4130.
  • D-arabinofuranosyl] -5-fluorouracil (hereinafter 5′-O-MMTr-4′-Thio-FdUrd) (400 mg) was dissolved in tetrahydrofuran (8.0 ml), and paraffin oil-containing 60% sodium hydride (119.7 mg) and iodoethane (1.16 g) were added, and the mixture was heated and stirred at 55 ° C. overnight. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the layers were separated.
  • Example 1 [5′-O-monomethoxytrityl-2′-deoxy-3′-O-ethyloxycarbonyl-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (1a) Shakaya, N .; et al. J. et al. Med. Chem.
  • 5′-O-MMTr-4′-Thio-FdUrd 400 mg was dissolved in dichloromethane (4.0 mL), cooled with ice, and then nitrogen atmosphere Lower pyridine (236 mg) and dimethylaminopyridine (46 mg) were added, and then ethyl chloroformate (162 mg) was added, followed by stirring at room temperature overnight.
  • Example 2 [5′-O-monomethoxytrityl-2′-deoxy-3′-O- (n-butyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (2a) 5′-O-MMTr-4′-Thio-FdUrd (400 mg) was treated in the same manner as Compound 1 using pyridine (236 mg), dimethylaminopyridine (46 mg) and chloroformate-n-butyl (305 mg). Compound 2a (308 mg, 65%) was obtained as a white foam.
  • Example 3 [5′-O-monomethoxytrityl-2′-deoxy-3′-O- (n-hexyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (3a )
  • 5'-O-MMTr-4'-Thio-FdUrd 350 mg
  • pyridine 207 mg
  • dimethylaminopyridine 40 mg
  • chloroformate-n-hexyl 172 mg
  • Example 4 1- [5′-O-monomethoxytrityl-2′-deoxy-3′-O- (n-octyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (4a) Using 5'-O-MMTr-4'-Thio-FdUrd (400 mg), pyridine (236 mg), dimethylaminopyridine (46 mg) and chloroformate-n-octyl (431 mg) in the same manner as in compound 1, 4a (325 mg, 63%) was obtained as a white foam.
  • Example 5 [5′-O-monomethoxytrityl-2′-deoxy-3′-O- (n-decyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (5a) Using 5'-O-MMTr-4'-Thio-FdUrd (400 mg), pyridine (236 mg), dimethylaminopyridine (46 mg) and chloroformate-n-decyl (494 mg) in the same manner as in compound 1, 5a (365 mg, 68%) was obtained as a white foam.
  • Example 6 [5′-O-monomethoxytrityl-2′-deoxy-3′-O-isopropyloxycarbonyl-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (6a) 5′-O-MMTr-4′-Thio-FdUrd (300 mg) was treated with Compound 6a (170 mg) in the same manner as Compound 1 using pyridine (177 mg), dimethylaminopyridine (34 mg) and isopropyl chloroformate (151 mg). 49%) as a white foam.
  • Example 7 3-pentyl chloroformate (7a) Triphosgene (16.6 g, 56.1 mmol) was dissolved in dichloromethane (100 mL), and 3-pentanol (18.4 mL, 170 mmol) was added dropwise at 0 ° C. under a nitrogen atmosphere. A dichloromethane solution (100 mL) of pyridine (15.1 mL) was added dropwise so that the internal temperature did not exceed 10 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was partitioned between dichloromethane and cold water, and the organic layer was washed with saturated brine and dried over calcium chloride.
  • Example 11 1- [5′-O-monomethoxytrityl-2′-deoxy-3′-O- (2,2-dimethylpropan-1-yloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-Fluorouracil (11a) Similar to Compound 1 using 5'-O-MMTr-4'-Thio-FdUrd (216 mg), pyridine (128 mg), dimethylaminopyridine (25 mg) and chloroformic acid-2,2-dimethylpropyl (134 mg) Compound 11a (191 mg, 73%) was obtained as a white foam.
  • Example 12 1- [5′-O-dimethoxytrityl-2′-deoxy-3′-O- (2,2,2-trichloroethane-1-yloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-Fluorouracil (12a) Shakaya, N .; et al. J. et al. Med. Chem.
  • Example 13 1- [5′-O-dimethoxytrityl-2′-deoxy-3′-O-phenyloxycarbonyl-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (13a) Using 5'-O-DMTr-4'-Thio-FdUrd (400 mg) with pyridine (224 mg), dimethylaminopyridine (43 mg) and phenyl chloroformate (166 mg), compound 13a (338 mg) was prepared in the same manner as compound 1. 70%) as a white foam.
  • Example 14 1- [5′-O-dimethoxytrityl-2′-deoxy-3′-O-benzyloxycarbonyl-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (14a)
  • Compound 14a (223 mg) was prepared in the same manner as Compound 1, except that pyridine (224 mg), dimethylaminopyridine (43 mg) and benzyl chloroformate (603 mg) were used against 5′-O-DMTr-4′-Thio-FdUrd (400 mg). 45%) as a white foam.
  • Example 15 1- [5′-O-dimethoxytrityl-2′-deoxy-3′-O- (4-nitrobenzyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil
  • 5′-O-DMTr-4′-Thio-FdUrd 400 mg was prepared by using pyridine (224 mg), dimethylaminopyridine (43 mg) and benzyl chloroformate (763 mg) in the same manner as in Compound 1, except that compound 15a (202 mg 38%) as a white foam.
  • Example 16 1- [5′-O-dimethoxytrityl-2′-deoxy-3′-O- (2-methylpropan-1-yloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5 Fluorouracil (16a) 5′-O-DMTr-4′-Thio-FdUrd (400 mg) was treated with pyridine (224 mg), dimethylaminopyridine (43 mg) and 2-methylpropyl chloroformate (193 mg) in the same manner as in compound 1. Compound 16a (214 mg, 45%) was obtained as a white foam.
  • Example 17 1- [5′-O-dimethoxytrityl-2′-deoxy-3′-O- (4-chlorophenyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (17a)
  • Compound 5'-O-DMTr-4'-Thio-FdUrd 400 mg was treated in the same manner as Compound 1 using pyridine (224 mg), dimethylaminopyridine (43 mg) and chloroformate-4-chlorophenyl (202 mg). 17a (354 mg, 70%) was obtained as a white foam.
  • Example 18 1- [5′-O-dimethoxytrityl-2′-deoxy-3′-O- (2-methoxyphenyloxycarbonyl) -4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (18a) 5′-O-DMTr-4′-Thio-FdUrd (400 mg) was treated with pyridine (224 mg), dimethylaminopyridine (43 mg) and 2-methoxyphenyl chloroformate (264 mg) in the same manner as in compound 1. Compound 18a (364 mg, 72%) was obtained as a white foam.
  • Example 19 [5′-O-isopropyloxycarbonyl-2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (19) 4′-Thio-FdUrd (200 mg) was dissolved in pyridine (4.0 mL), ice-cooled, dimethylaminopyridine (93 mg) was added under a nitrogen atmosphere, isopropyl chloroformate (205 mg) was added, and the mixture was stirred at room temperature overnight. did.
  • reaction mixture was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane ⁇ 9% methanol / chloroform) to give compound 19 (85 mg, 32%) as a white foam. Obtained.
  • Example 20 1- [5′-O-cyclopentyloxycarbonyl-2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (20)
  • Compound 20 (153 mg, 35%) was obtained as a white foam in the same manner as Compound 19 using dimethylaminopyridine (139 mg) and 9a (371 mg) against 4′-Thio-FdUrd (300 mg).
  • Example 21 1- [5′-O-cyclohexyloxycarbonyl-2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (21)
  • Compound 21 (187 mg, 50%) was obtained as a white foam in the same manner as Compound 19 using 4′-Thio-FdUrd (250 mg) with dimethylaminopyridine (116 mg) and 10a (310 mg).
  • Example 22 [5′-O- (2,2-Dimethylpropan-1-yloxycarbonyl) -2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (22) 4′-Thio-FdUrd (350 mg) was treated with dimethylaminopyridine (163 mg) and chloroformate-2,2-dimethylpropyl (501 mg), and compound 22 (101 mg, 20%) was treated in the same manner as compound 19 Obtained as a foam.
  • Example 23 [5′-O- (2,2,2-trichloroethane-1-yloxycarbonyl) -2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (23) 4'-Thio-FdUrd (400 mg) was treated with dimethylaminopyridine (186 mg) and chloroformate-2,2,2-trichloroethyl (483 mg) in the same manner as compound 19 but compound 23 (283 mg, 42%) was obtained as a white foam.
  • Example 24 [5′-O-phenyloxycarbonyl-2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (24)
  • Compound 24 (186 mg, 32%) was obtained as a white foam in the same manner as Compound 19 using dimethylaminopyridine (186 mg) and phenyl chloroformate (358 mg) against 4′-Thio-FdUrd (400 mg). .
  • Example 25 [5′-O-benzyloxycarbonyl-2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (25) 4′-Thio-FdUrd (400 mg) was treated with dimethylaminopyridine (186 mg) and benzyl chloroformate (1.03 g), and compound 25 (38 mg, 6.3%) was treated as a white foam in the same manner as compound 19. Obtained as material.
  • Example 26 1- [5′-O- (2-Methylpropan-1-yloxycarbonyl) -2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (26) 4′-Thio-FdUrd (400 mg) was treated with dimethylaminopyridine (186 mg) and 2-methylpropyl chloroformate (311 mg), and compound 26 (222 mg, 40%) in the form of a white foam in the same manner as compound 19. Obtained as material.
  • Example 27 1- [5′-O- (4-Chlorophenyloxycarbonyl) -2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (27) 4′-Thio-FdUrd (400 mg) was treated with dimethylaminopyridine (186 mg) and 4-chlorophenyl chloroformate (348 mg), and compound 27 (239 mg, 38%) was treated as a white foam in the same manner as compound 19. Got as.
  • Example 28 1- [5′-O- (2-methoxyphenyloxycarbonyl) -2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (28) 4′-Thio-FdUrd (400 mg) was treated with dimethylaminopyridine (186 mg) and 2-methoxyphenyl chloroformate (425 mg), and compound 28 (223 mg, 36%) as a white foam in the same manner as compound 19 Obtained as material.
  • Example 29 [3 ′, 5′-O-diisopropyloxycarbonyl-2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (29) 4′-Thio-FdUrd (350 mg) was dissolved in pyridine (10.0 mL), dimethylaminopyridine (162 mg) was added under a nitrogen atmosphere, isopropyl chloroformate (205 mg) was added, and the mixture was heated to 100 ° C. for 3 days. Stir overnight.
  • reaction mixture was concentrated to remove the solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer was washed with saturated brine, the solvent was then distilled off, and the residue was subjected to silica gel column chromatography (30% acetic acid). Purification by ethyl / hexane) gave compound 29 (66 mg, 11%) as a white foam.
  • Example 30 1- [3 ′, 5′-O-dicyclopentyloxycarbonyl-2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (30)
  • Compound 30 (267 mg, 48%) was obtained as a white foam in the same manner as Compound 29, using dimethylaminopyridine (139 mg) and 9a (1.35 g) against 4′-Thio-FdUrd (300 mg).
  • Example 31 1- [3 ′, 5′-O-dicyclohexyloxycarbonyl-2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil (31)
  • Compound 31 (127 mg, 26%) was obtained as a white foam in the same manner as Compound 29, using dimethylaminopyridine (116 mg) and 10a (775 mg) against 4′-Thio-FdUrd (250 mg).
  • Example 32 [3 ′, 5′-O-bis (2,2-dimethylpropan-1-yloxycarbonyl) -2′-deoxy-4′-thio-1- ⁇ -D-ribofuranosyl] -5-fluorouracil ( 32) 4′-Thio-FdUrd (350 mg) was treated with dimethylaminopyridine (163 mg) and chloroformate-2,2-dimethylpropyl (500 mg), and compound 32 (260 mg, 39%) was treated as white foam in the same manner as compound 29. Obtained as a substance.
  • Test example 1 Nude mouse subcutaneous tumor transplantation system, antitumor test in oral administration BALB / cA Jcl-nu mice (CLEA Japan, Inc.) human colon cancer strain KM20C subcultured into 2 mm square fragments, 6 or 7 weeks old BALB / cA Jcl-nu mice were implanted subcutaneously on the back.
  • BALB / cA Jcl-nu mice CLA Japan, Inc.
  • Vt 1/2 (Vl) ⁇ (Vs) 2 [wherein, Vt represents a tumor volume, Vl represents a tumor major axis, and Vs represents a tumor minor axis.
  • the compound of the present invention and Comparative Examples 1 to 5 were dissolved or suspended in 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The dose was set to a dose that was equimolar with 50 mg / kg / day of Comparative Example 1.
  • RTV relative tumor volume
  • IR tumor growth inhibition rate
  • IR (%) [1 ⁇ (RTVtest) / (RTVcont)] ⁇ 100 [Wherein, IR represents the tumor growth inhibition rate, RTVtest represents the average RTV value of the drug administration group, and RTVcont represents the average RTV value of the untreated group. ]
  • Test example 2 Nude mouse subcutaneous tumor transplantation system, calculation of therapeutic coefficient for oral administration BALB / cA Jcl-nu mouse (Nippon Claire Co., Ltd.) Human colon cancer strain KM20C subcultured into 2 mm square fragments, 6 or 7 weeks old BALB / cA Jcl-nu mice were implanted subcutaneously on the back. When the average tumor volume after grouping exceeds 100 mm 3 , measure the major axis and minor axis of the tumor, calculate the tumor volume according to the following formula, and then group the group so that there is no variation in the tumor volume of each group Performed (5 or 6 animals per group).
  • Vt 1/2 (Vl) ⁇ (Vs) 2
  • Vt represents the tumor volume
  • Vl represents the major axis of the tumor
  • Vs represents the minor axis of the tumor.
  • the compound of the present invention and Comparative Example 1 were each dissolved or suspended in a 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The dose was set to a dose that was equimolar with the 3.13, 6.25, 12.5, 25, 50, 100 and 200 mg / kg / day of Comparative Example 1.
  • RTV relative tumor volume
  • IR tumor growth inhibition rate
  • IR (%) [1 ⁇ (RTVtest) / (RTVcont)] ⁇ 100 [Wherein, IR represents the tumor growth inhibition rate, RTVtest represents the average RTV value of the drug administration group, and RTVcont represents the average RTV value of the untreated group. ]
  • the 50% tumor growth inhibition dose (ED50) was calculated from the tumor growth inhibition rate when each dose was administered.
  • the therapeutic index of the compound of the present invention was about twice or more when compared with Comparative Example 1, and it was revealed that the compound is more excellent in balance between effect and toxicity.
  • Test example 3 Nude mouse subcutaneous tumor transplantation system, life-prolonging effect in oral administration BALB / cA Jcl-nu mice (CLEA Japan, Inc.) human colon cancer strain KM20C subcultured into 2 mm square fragments, 6 or 7 weeks old BALB / CA Transplanted subcutaneously on the back of Jcl-nu mice.
  • the average tumor volume after grouping exceeds 100 mm 3 , measure the major axis and minor axis of the tumor, calculate the tumor volume according to the following formula, and then group the group so that there is no variation in the tumor volume of each group Performed (5 or 6 animals per group).
  • Vt 1/2 (Vl) ⁇ (Vs) 2
  • Vt represents the tumor volume
  • Vl represents the major axis of the tumor
  • Vs represents the minor axis of the tumor.
  • the compound of the present invention and Comparative Example 1 were dissolved or suspended in 0.5% hydroxypropylmethylcellulose aqueous solution, and orally administered once a day for 14 days once a day from the next day of grouping.
  • the dose was set to a dose that was equimolar with 100 mg / kg / day of Comparative Example 1.

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