JP2013032293A - 5-FLUOROURACIL COMPOUND HAVING HUMAN dUTPase-INHIBITING ACTIVITY OR SALT THEREOF - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which has excellent dUTPase-inhibiting activity and is useful as an anti-tumor agent, an efficacy potentiator for anti-tumor agents or the like.SOLUTION: The 5-fluorouracil compound is represented by general formula (I) (wherein n denotes a number of 1 to 3; X represents an oxygen atom, a sulfur atom, a 2-6C alkenylene group, or the like; Y represents a 1-8C alkylene group; Z represents -SONRR, -NRSO-Rand the like; Rand Reach represents a hydrogen atom, a 1-6C alkyl group or aralkyl group or a group forming a saturated heterocyclic group together with an adjacent nitrogen atom; Rrepresents a hydrogen atom or a 1-6C alkyl group; Rrepresents an aromatic hydrocarbon group or an unsaturated heterocyclic group; and Rrepresents a methyl group). Also the salt thereof is provided.

Description

  The present invention relates to a novel 5-fluorouracil compound or a salt thereof which has excellent human dUTPase inhibitory activity and is useful as a disease related to dUTPase, such as an antitumor drug, an antitumor drug effect enhancer and the like.

  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 anticancer drug (Non-patent Document 3), an antimalarial drug (Patent Document 1 and Non-patent Document 4), an antituberculosis drug (Non-patent Document 5), an anti-pylori drug (Patent Document 2), trypanosoma and leash. Antiparasitic drugs such as mania (Non-Patent Document 6), and anti-herpesviruses such as human herpes simplex virus, cytomegalovirus, Epstein-Barr virus (Non-patent document 7) and anti-vaccinia viruses (Non-patent document 8) It has been suggested that it can be a target for viral drugs.

As described above, dUTPase is attracting attention as a target for therapeutic agents for various diseases, and dUTPase inhibitors are also widely studied.
As dUTPase inhibitors, for example, triphosphate mimic type low molecular weight compounds (for example, Patent Document 3, Non-Patent Document 9 and the like), 5′-O-substituted phenyl-deoxyuridine compounds (Non-Patent Document 10) are known. Yes.

International Publication No. 2005/065689 Pamphlet International Publication No. 2003/089461 Pamphlet International Publication No. 1995/15332 Pamphlet

Structure, 4, 1077-1092 (1996) Acta Biochim. Pol., 44, 159-171 (1997) Curr. Protein Pept. Sci., 2, 361-370 (2001) Structure, 13, 329-338 (2005) J. Mol. Biol., 341, 503-517 (2004) Bioorg. Med. Chem. Lett., 16, 3809-3812 (2006) Curr. Protein Pept. Sci., 2, 3711-380 (2001) Acta Crystallogr. D. Biol. Crystallogr, 63, 571-580 (2007) Mol. Pharmacol., 29, 288-292 (1986) Nucleosides Nucleotides & Nucleic acids, 20, 1691-1704 (2001)

However, none of these compounds have sufficient inhibitory activity against human dUTPase and are not compounds used as pharmaceuticals.
Accordingly, an object of the present invention is to provide a compound or a salt thereof having excellent dUTPase inhibitory activity and useful as an antitumor drug, an antitumor drug effect enhancer and the like.

  As a result of intensive studies to solve the above problems, the present inventors have found that a 5-fluorouracil compound having a sulfonamide structure or a pyrrolidin-1-yl-carbonyl structure at the N-1 position of the 5-fluorouracil ring or a salt thereof. Has been found to have excellent dUTPase inhibitory activity and is useful as an antitumor drug, an antitumor drug effect enhancer, etc., and has completed the present invention.

  That is, the present invention provides the following formula (I)

[In general formula (I), n shows the number of 1-3,
X is a bond, an oxygen atom, a sulfur atom, an alkenylene group having 2 to 6 carbon atoms, a divalent aromatic hydrocarbon group which may have a substituent, or a divalent which may have a substituent. A saturated or unsaturated heterocyclic group of
Y represents a bond or a linear or branched alkylene group having 1 to 8 carbon atoms;
Z represents —SO ₂ NR ¹ R ² , —NR ³ SO ₂ —R ⁴ , or the following formula:

R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aralkyl group which may have a substituent, or together with an adjacent nitrogen atom. , A group that forms an optionally substituted heterocyclic group,
R ³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
R ⁴ represents an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group which may have a substituent,
R ⁵ represents a methyl group which may have a substituent. ]
The 5-fluorouracil compound represented by these, or its salt is provided.

  The present invention also provides a pharmaceutical composition containing a 5-fluorouracil compound represented by the formula (I) or a salt thereof.

  The novel 5-fluorouracil compound or a salt thereof of the present invention has excellent dUTPase inhibitory activity, and is useful as a disease related to dUTPase, for example, an antitumor drug, an antitumor drug effect enhancer, and the like.

The novel 5-fluorouracil compound of the present invention is represented by the above general formula (I) and has a feature that it has a sulfonamide structure or a pyrrolidin-1-yl-carbonyl structure at the N-1 position of the 5-fluorouracil ring.
In International Publication No. 2005065689 (Patent Document 1), as a terminal of a 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. However, a compound having a sulfonamide bond of the compound of the present invention is not disclosed. In addition, as shown in Test Examples described later, a compound having a trityl group as a terminal of the uracil ring N-1 substituent showed almost no human dUTPase inhibitory activity.
Japanese Patent Application Laid-Open No. 2002-284686 discloses a uracil compound having a sulfonamide bond via a hydroxamic acid residue as a uracil ring N-1 substituent. That is, it differs from the compound of the present invention in that the alkylene chain bonded to the N-1 position of the uracil ring has a hydroxamic acid group as a substituent. Moreover, although it has been described that it has an MMP inhibitory action, there is no mention of dUTPase inhibitory activity.

  In the present specification, the “aromatic hydrocarbon group” is preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as a phenyl group and a naphthyl group, and more preferably a phenyl group in terms of dUTPase inhibitory activity. .

  The “saturated or unsaturated heterocyclic group” is a monocyclic or bicyclic saturated or unsaturated heterocyclic group having one or two oxygen atoms, nitrogen atoms or sulfur atoms. Preferably, for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperidinyl 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, pyridazyl group, indolyl group, isoindolyl group, indazolyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, benzofuranyl group, dihydrobenzofuranyl Group, benzoy Dazoriru group, benzoxazole group, benzothiazolyl group, purinyl group, a quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinyl group, tetrahydrofuryl group, tetrahydropyridinyl group, and the like. Among these, a 5-membered to 7-membered saturated or unsaturated heterocyclic group having one oxygen atom or one nitrogen atom is preferable. From the viewpoint of dUTPase inhibitory activity, a tetrahydrofuryl group, a tetrahydropyryl group, and a pyridyl group are preferable. More preferred.

  The “saturated heterocyclic group” is preferably a monocyclic saturated heterocyclic group having one or two of an oxygen atom, a nitrogen atom, and a sulfur atom, such as a pyrrolidinyl group, piperidinyl group, piperazinyl. Group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperidinyl group and the like.

  Examples of the “aralkyl group” include an alkyl group substituted with an aromatic hydrocarbon group having 6 to 10 carbon atoms, specifically, an alkyl group having 1 to 6 carbon atoms substituted with a phenyl group, or a naphthyl group. Examples include substituted alkyl groups having 1 to 6 carbon atoms.

  Examples of the group (substituent) that can be substituted with the aromatic hydrocarbon group, saturated or unsaturated heterocyclic group and aralkyl group include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, and a halogenoalkyl group. Group, cycloalkyl group, cycloalkyl-alkyl group, aralkyl group, alkenyl group, alkoxy group, halogenoalkoxy group, alkynylalkoxy group, cycloalkoxy group, cycloalkyl-alkoxy group, aralkyloxy group, alkylthio group, cycloalkyl-alkylthio Groups, amino groups, mono- or dialkylamino groups, cycloalkyl-alkylamino groups, acyl groups, acyloxy groups, oxo groups, saturated or unsaturated heterocyclic groups, aromatic hydrocarbon groups, saturated heterocyclic oxy groups and the like. When the substituent is present, the number is typical. Is 1 to 3.

In the above substituent, examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
In the above substituent, 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, and a trifluoromethyl group.

In the above substituent, 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.
In the above-mentioned substituent, the cycloalkyl-alkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with cycloalkyl having 3 to 7 carbon atoms, such as cyclopropylmethyl group, cyclopropylethyl group, cyclohexane A butylmethyl group, a cyclopentylmethyl group, etc. are mentioned.

  In the above substituent, 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, a benzyl group, A phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, etc. are mentioned.

  In the above substituent, 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.

  In the above substituents, the alkoxy group, halogenoalkoxy group, and alkynylalkoxy group are each preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, and the halogen atom is substituted for these alkoxy groups. Or an alkoxy group substituted with an alkynyl group having 2 to 6 carbon atoms, and a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, a 1-methylpropoxy group, an n-butoxy group, s-butoxy group, isobutoxy group, 2-methyl-butoxy group, neopentyloxy group, pentan-2-yloxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 1,1- Difluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroe Xyl group, 1,1,2,2-tetrafluoroethoxy group, perfluoroethoxy group, 3-fluoro-2- (fluoromethyl) -propoxy group, 1,3-difluoropropan-2-yloxy group, 2,2 , 3,3,3-pentafluoro-1-propoxy group, but-3-in-2-yloxy group, and the like.

In the above substituent, the cycloalkoxy group is preferably a C3-C7 cycloalkoxy group, and examples thereof include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
In the above-mentioned substituent, the cycloalkyl-alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms substituted with cycloalkyl having 3 to 7 carbon atoms, and includes a cyclopropylmethoxy group, a cyclopropylethoxy group, a cyclo A butylmethoxy group, a cyclopentylmethoxy group, a (1-methylcyclopropyl) methoxy group and the like can be mentioned.
In the above substituent, 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.
In the substituent, the alkylthio group is preferably a thio group having an alkyl group having 1 to 6 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, and an n-propylthio group.
In the above substituent, the cycloalkyl-alkylthio group is preferably an alkylthio group having 1 to 6 carbon atoms substituted with cycloalkyl having 3 to 7 carbon atoms, such as a cyclopropylmethylthio group, a cyclopropylethylthio group, A cyclobutylmethylthio group, a cyclopentylmethylthio group, etc. are mentioned.

In the above substituent, 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.
In the above substituent, 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. .
In the above-mentioned substituent, the acyl group has 1 to 6 carbon atoms having a straight chain or branched chain such as formyl group, acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, isovaleryl group, and pivaloyl group. An acyl group, a benzoyl group, and the like.
In the above-mentioned substituent, the acyloxy group includes straight or branched carbon such as acetoxy group, propionyloxy group, n-butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, and pivaloyloxy group. Examples include an acyloxy group of 1 to 6 and a benzoyloxy group.

  In the above-mentioned substituent, 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. Or an unsaturated heterocyclic group such as pyrrolidinyl, piperidinyl, piperazinyl, hexamethyleneimino, morpholino, thiomorpholino, homopiperidinyl, tetrahydrofuryl, tetrahydropyryl, imidazolyl, thienyl, furyl Group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolinyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, pyridazyl group, indolyl group, isoindolyl group, indazolyl group, methylenedioxy Phenyl group, ethyl Dioxy phenyl group, benzofuranyl group, dihydrobenzofuranyl group, benzimidazolyl group, benzoxazole group, benzothiazolyl group, purinyl group, a quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinyl group, and the like.

In the above substituent, the aromatic hydrocarbon group preferably represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.
In the above substituent, the saturated heterocyclic oxy group represents an oxy group having the saturated heterocyclic group, and examples thereof include a tetrahydrofuryloxy group and a tetrahydropyryloxy group.

  In the general formula (I), n represents a number of 1 to 3, but 1 or 3 is preferable in terms of dUTPase inhibitory activity.

  In general formula (I), X has a bond, an oxygen atom, a sulfur atom, an alkenylene group having 2 to 6 carbon atoms, a divalent aromatic hydrocarbon group which may have a substituent, or a substituent. A divalent saturated or unsaturated heterocyclic group which may be present;

In X, the bond is preferably a single bond.
In X, examples of the “alkenylene group having 2 to 6 carbon atoms” include the alkenylene group described above, but an alkenylene group having 2 to 4 carbon atoms is preferable, and a vinylene group is more preferable.

  “Aromatic hydrocarbon group” of “a divalent aromatic hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated heterocyclic group which may have a substituent” in X As the “saturated or unsaturated heterocyclic group”, the same aromatic hydrocarbon group and the same as the saturated or unsaturated heterocyclic group described above may be mentioned, but a phenylene group or a pyridinediyl group is particularly preferable. preferable.

  X is preferably a bond, an oxygen atom, a sulfur atom, a vinylene group, a phenylene group, or a pyridinediyl group from the viewpoint of dUTPase inhibitory activity, and particularly preferably an oxygen atom or a vinylene group.

  In general formula (I), Y represents a bond or a linear or branched alkylene group having 1 to 8 carbon atoms which may have a cycloalkylidene structure having 3 to 6 carbon atoms on one carbon atom. And a bond or a linear or branched alkylene group having 1 to 8 carbon atoms is preferable.

  Here, as the “linear or branched alkylene group having 1 to 8 carbon atoms”, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, propylene group, butylene group Dimethyltrimethylene group, dimethyltetramethylene group, ethyltrimethylene group, diethyltetramethylene group and the like.

In general formula (I), when X represents a bond, (CH ₂ ) _n —XY represents an alkylene group having 3 to 6 carbon atoms, and a trimethylene group or a pentamethylene group is preferable.

Examples of Y include a bond or a linear or branched alkylene group having 1 to 8 carbon atoms in terms of dUTPase inhibitory activity, and examples thereof include an ethylene group and a trimethylene group (provided that X represents a bond). In this case, (CH ₂ ) _n —X—Y represents a trimethylene group or a pentamethylene group.

In the general formula (I), Z represents —SO ₂ NR ¹ R ² or —NR ³ SO ₂ —R ⁴ , or the following formula.

In Z, R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aralkyl group which may have a substituent, or an adjacent nitrogen atom The group which together forms the saturated heterocyclic group which may have a substituent is shown.

In R ¹ and R ² , the “C 1-6 alkyl group” represents a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, Examples include isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like.

In R ¹ and R ² , “aralkyl group” of “optionally substituted aralkyl group” is substituted with an aromatic hydrocarbon group optionally having 6 to 14 carbon atoms. The linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and examples thereof include a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, and the like, and a benzyl group is preferable.

  In the linear or branched alkyl group having 1 to 6 carbon atoms substituted with the aromatic hydrocarbon group which may have a substituent having 6 to 14 carbon atoms constituting the “aralkyl group”, When the alkyl group has a substituent, examples of the substituent include a hydroxyl group; a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a 2-methylpropyl group, an n-butyl group, and an n-pentyl group. An alkyl group having 1 to 6 carbon atoms; a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group; a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, and the like C1-C6 alkylthio group; halogen atom, methoxy group, ethoxy group, isobutoxy group, cyclobutoxy group, cyclopentyloxy group, cyclopro Have a substituent such as Rumetokishi group include unsaturated heterocyclic groups such as an aromatic hydrocarbon group or thienyl group, which may have one or two of these identical or different from each other. In addition, when the two substituents are alkyl groups having 1 to 6 carbon atoms, the carbon atoms of the alkyl group may form a cycloalkylidene structure.

  Moreover, the C1-C6 linear or branched alkyl group substituted by the aromatic hydrocarbon group which may have a C6-C14 substituent which comprises the said "aralkyl group". In the case where the aromatic hydrocarbon group has a substituent, examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; hydroxyl group, halogen atom, ethynyl group and vinyl group A linear or branched alkoxy group having 1 to 6 carbon atoms which may have a substituent of 3 to 7 carbon atoms such as cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, etc. Cycloalkoxy group; cyclopropylmethoxy group, cyclopropylethoxy group, cyclobutylmethoxy group, cyclopentylmethoxy group, (1-methylcyclopropyl) methoxy A cycloalkyl-alkoxy group having 3 to 7 carbon atoms such as a group; a saturated heterocyclic oxy group such as tetrahydrofuran-3-yloxy group, tetrahydro-2H-pyran-4-yloxy group, a cyclopropylmethylthio group, a cyclobutylthio group, C3-C7 cycloalkyl-alkylthio groups, such as a cyclobutylmethylthio group and a cyclopentylthio group, are mentioned, You may have either 1-2 of these.

In the general formula (I), “saturated heterocyclic group” of “saturated heterocyclic group optionally having substituents” which R ¹ and R ² may be formed together with the adjacent nitrogen atom As for, the above-mentioned saturated heterocyclic group is mentioned.
In the general formula (I), as the “substituent” of the “saturated heterocyclic group optionally having substituent (s)” that R ¹ and R ² may be formed together with the adjacent nitrogen atom, , And the above substituents.

That is, R ¹ is preferably a hydrogen atom in terms of dUTPase inhibitory activity, and R ² is preferably a benzyl group which may have a substituent in terms of dUTPase inhibitory activity. [When the methylene group of the benzyl group has a substituent, the substituent includes a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and an alkyl group having 1 to 6 carbon atoms. Alkylthio group, optionally substituted aromatic hydrocarbon group or unsaturated heterocyclic group may be the same or different and may have 1 or 2 (the two substituents have carbon number). In the case of 1 to 6 alkyl groups, carbon atoms of the alkyl group may form a cycloalkylidene structure.) When the phenyl group of the benzyl group has a substituent, Halogen atom A linear or branched alkoxy group having 1 to 6 carbon atoms which may have a group, a cycloalkoxy group having 3 to 7 carbon atoms, a cycloalkyl-alkoxy group having 3 to 7 carbon atoms, or 3 carbon atoms It may have 1 to 2 of any of -7 cycloalkyl-alkylthio groups and saturated heterocyclic oxy groups. ].

In Z, R ³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and examples of the “alkyl group having 1 to 6 carbon atoms” include the same groups as the alkyl groups in R ¹ and R ² . Among these, a hydrogen atom is preferable in terms of dUTPase inhibitory activity.

In Z, R ⁴ represents an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group which may have a substituent.
In R ⁴ , the “aromatic hydrocarbon group” of the “aromatic hydrocarbon group optionally having substituent (s)” is exemplified by the above aromatic hydrocarbon group, and in terms of dUTPase inhibitory activity, phenyl Groups are preferred.
In R ⁴ , the “substituent” of the “aromatic hydrocarbon group which may have a substituent” includes the above-mentioned “substituent”, and may have 1 to 6 carbon atoms which may be halogen-substituted. An alkoxy group having 3 to 7 carbon atoms and a cycloalkyl-alkoxy group having 3 to 7 carbon atoms are preferable, and a cyclopropylmethoxy group, a 2,2-difluoroethoxy group, and a cyclopentyloxy group are more preferable.

In R ⁴ , the “unsaturated heterocyclic group” of the “unsaturated heterocyclic group optionally having substituent (s)” is exemplified by the above unsaturated heterocyclic group.
In R ⁴ , examples of the “substituent” of the “unsaturated heterocyclic group optionally having substituent (s)” include the above-mentioned substituents.
In R ⁵ , the “substituent” of the “methyl group having a substituent” includes the above-mentioned “substituent”, and an aromatic hydrocarbon group and a hydroxyl group are preferable, and a phenyl group and a hydroxyl group are preferable. The aromatic hydrocarbon group may further have a substituent, preferably a halogen atom, and particularly preferably a fluorine atom.

  Pharmaceutically acceptable salts of the compound represented by formula (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid. Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, glutamic acid Salt, ammonium salt with inorganic base such as sodium, potassium, magnesium, calcium and aluminum, organic base such as methylamine, ethylamine, meglumine and ethanolamine, or basic amino acid such as lysine, arginine and ornithine . The compounds of the present invention include optical isomers and hydrates.

  The 5-fluorouracil compound of the present invention can be produced according to the following reaction process formula.

[Wherein, R ^a is ^a linear or branched alkyl group having 1 to 6 carbon atoms which may have ^a substituent, a cycloalkyl group having 3 to 7 carbon atoms, or a cycloalkyl group having 3 to 7 carbon atoms. -Represents either an alkyl group or a saturated heterocyclic group, and Lg represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group. ]

[A-1]
(a) In this step, a readily available 3-cyanophenol (1) and an alkyl halide, alkyl mesylate, alkyl tosylate, or alkyl trifluoromethanesulfonate represented by the general formula (2) are present in the presence of a base. By reacting, the compound represented by the general formula (4) can be produced.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but diethyl ether, tetrahydrofuran (hereinafter THF), dioxane, acetone, dimethoxyethane, acetonitrile, N, N-dimethylformamide (hereinafter DMF). N, N-dimethylacetamide (hereinafter referred to as DMA), dimethyl sulfoxide (hereinafter referred to as DMSO) and the like are exemplified, and DMF is preferred.
Examples of the base used include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, Organic amines such as collidine are exemplified, and potassium carbonate is preferred. The number of equivalents is 0.8 to 10 equivalents, preferably 1.0 to 5.0 equivalents.
The number of equivalents of the general formula (2) is 0.8 to 10 equivalents, preferably 1.0 to 5.0 equivalents. The reaction temperature is 20 to 150 ° C, preferably 50 to 130 ° C. The reaction time is 0.5 to 24 hours, preferably 1.0 to 12 hours.

(b) In this step, the compound represented by the general formula (4) is obtained by condensing the readily available 3-cyanophenol (1) and the alcohol represented by the general formula (3) by Mitsunobu reaction. It can also be manufactured.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but dichloromethane, 1,2-dichloroethane (hereinafter referred to as DCE), benzene, xylene, toluene, ethyl acetate, propyl acetate, butyl acetate, diethyl Examples include ether, THF, dioxane, acetone, dimethoxyethane, acetonitrile, DMF and the like, preferably THF.
The reagent used in the Mitsunobu reaction is not particularly limited as long as it is a reagent that can be usually used in the Mitsunobu reaction. However, diazots such as diethyl azodicarboxylate (hereinafter DEAD) and diisopropyl azodicarboxylate (hereinafter DIAD) are used. Lower alkyl azodicarboxylates or azo compounds such as azodicarbonyl such as 1,1 '-(azodicarbonyl) dipiperidine and triarylphosphine such as triphenylphosphine or tri-nphosphine such as tri-n-butylphosphine A combination of lower alkyl phosphine and the like. A combination of DEAD and triphenylphosphine is preferable.
The number of equivalents of the general formula (3), di-lower alkylazodicarboxylate or azo compound, triarylphosphine or tri-lower alkylphosphine is 0.8 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents. The reaction temperature is -20 ° C to 120 ° C, preferably 0-60 ° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 6.0 hours.

[A-2]
In this step, the compound represented by the general formula (5) can be produced by reacting the cyano compound represented by the general formula (4) with a generally known reducing agent.
Examples of the reaction solvent used include methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, dimethoxyethane, diethylene glycol dimethyl ether, diisopropyl ether, diethyl ether, THF, dioxane and the like, depending on the type of reduction reaction used. Preferably, it is THF.
Examples of reducing agents used include lithium aluminum hydride (LAH), lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, magnesium aluminum hydride, magnesium aluminum hydride chloride, Examples include sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, or catalytic reduction using a catalyst such as palladium / carbon, palladium hydroxide, platinum, preferably LAH It is. The number of equivalents is 0.5 to 5.0 equivalents, preferably 0.8 to 2.0 equivalents. The reaction temperature is 0 to 100 ° C, preferably 20 to 60 ° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 6.0 hours.

[Wherein, R ^a and Lg are the same as defined above, R ^b represents a hydrogen atom or a halogen atom, and R ^c and R ^d are each independently a linear or branched group optionally having a substituent. And an alkyl group having 1 to 6 carbon atoms, Hal represents a halogen atom. ]

[B-1]
In this step, a carboxy group of a readily available compound (6) is esterified with an alcohol compound (7) by a generally known method, and then the general formula (A) is used in the same manner as in the step [A-1]. 8) can be produced.

[B-2]
In this step, the compound represented by the general formula (9) can be produced by reacting the compound represented by the general formula (8) with a generally known reducing agent.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl ether, diisopropyl ether, THF, dioxane and the like, and preferably THF.
The reducing agent used is LAH, lithium diethoxyaluminum hydride, lithium triethoxyaluminum hydride, lithium tri-t-butoxyaluminum hydride, magnesium aluminum hydride, magnesium aluminum hydride chloride, sodium aluminum hydride, hydrogenated Examples include sodium triethoxyaluminum, sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride (hereinafter referred to as DIBAL), lithium borohydride, and the like, preferably lithium borohydride. The number of equivalents is 0.8 to 10 equivalents, preferably 1.0 to 5.0 equivalents. The reaction temperature is from 0 ° C. to the boiling point of the solvent, preferably the boiling point of the solvent. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.

[B-3]
In this step, the aldehyde compound represented by the general formula (10) can be produced by reacting the compound represented by the general formula (9) with a generally known oxidizing agent.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, carbon tetrachloride, DCE, chlorobenzene, toluene, xylene, and the like, preferably dichloromethane.
Oxidizing agents used include chromic anhydride, pyridine and acetic anhydride complex reagents, chromium-based oxidizing agents such as pyridium chlorochromate and pyridium dichromate, high-valent iodine oxidizing agents such as Dess-Martin reagent, DMSO and anhydrous DMSO-based oxidizing agent, manganese (IV) oxide used in combination with acetic acid, oxalyl chloride, dicyclohexylcarbodiimide (DCC), or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC / HCl) 2,2,6,6-tetramethylpiperidine-1-oxyl radical, and preferably manganese (IV) oxide. The number of equivalents is 0.8-30 equivalents, preferably 1.0-20 equivalents. The reaction temperature is -20 to 150 ° C, preferably 0 to 100 ° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
When R ^b is a hydrogen atom, a compound represented by the general formula (10) can be produced by a method similar to [A-1] using 3-hydroxybenzaldehyde that is readily available as a starting material. it can. Furthermore, the nitrile compound represented by the general formula (4) can be produced by a generally known reduction reaction, for example, DIBAL reduction method, to produce the compound represented by the general formula (10).

[B-4]
In this step, the compound represented by the general formula (10) is reacted with 2-methyl-2-propanesulfinamide, which can be easily obtained, under acidic conditions to represent the general formula (11). Compounds can be produced.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but examples include diethyl ether, diisopropyl ether, THF, dioxane, dichloromethane, chloroform, carbon tetrachloride, toluene, xylene, and the like. Toluene.
Examples of the acid used include hydrochloric acid, magnesium sulfate, p-toluenesulfonic acid, and Lewis acids such as titanium tetraisopropoxide and titanium tetraethoxide, with titanium tetraisopropoxide being preferred. The number of equivalents of 2-methyl-2-propanesulfinamide and titanium tetraisopropoxide is 0.8 to 10 equivalents, preferably 1.0 to 3.0 equivalents. The reaction temperature is 20 to 150 ° C, preferably 50 to 120 ° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 6.0 hours.

[B-5]
In this step, the compound represented by the general formula (11) is reacted with a Grignard reagent (12) represented by R ^d MgHal or an organolithium reagent (13) represented by R ^d Li to obtain a compound represented by the general formula ( 14) can be produced diastereoselectively.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, THF, dimethoxyethane, dioxane, dichloromethane, chloroform, four Examples include carbon chloride, toluene, xylene and the like. The equivalent of Grignard reagent or organolithium reagent is 0.8 to 20 equivalents, preferably 1.0 to 10 equivalents. The reaction temperature is −100 ° C. to 100 ° C., preferably −78 ° C. to 50 ° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.

[B-6]
In this step, the compound represented by the general formula (15) can be produced by treating the compound represented by the general formula (14) with an acid.
The solvent to be used is not particularly limited as long as it does not affect the reaction, but alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and dioxane, ethyl acetate, etc. Exemplified and preferred is methanol.
Examples of the acid to be used include hydrochloric acid, sulfuric acid, phosphoric acid and the like, preferably hydrochloric acid. The equivalent number is 0.1 to 10 equivalents, preferably 1.0 to 2.0 equivalents. The reaction temperature is -20 ° C to 100 ° C, preferably 0 to 50 ° C. The reaction time is 0.01 to 24 hours, preferably 0.1 to 1.0 hours.
In the case where R ^d is a hydrogen atom, the compound represented by the general formula (9) is azidated by a generally known method and then treated with a generally known reducing agent (for example, LAH) to obtain a compound represented by the general formula The compound represented by (15) can also be produced. Furthermore, when the compound represented by the general formula (15) is obtained as a racemate, the compound represented by the general formula (10) is converted into an alcohol compound by the same method as in Step B-5, and is generally known. The compound represented by the general formula (15) can also be produced by azidation by the above method and then reducing by a generally known method.

[Wherein, R ^a and R ^b are the same as defined above, and R ^e and R ^f are the same or different and each represents a hydrogen atom or a linear or branched C 1-6 which may have a substituent. Indicates an alkyl group. ]

[C-1]
In this step, a compound represented by the general formula (17) is obtained by reacting a readily available compound (16) with any amine represented by the general formula (5) or (15) in the presence of a base. Can be manufactured.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but examples include acetone, THF, diethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride, DMF, DMA, acetonitrile, and the like. Preferably, it is dichloromethane.
Examples of the base to be used include inorganic bases such as sodium bicarbonate, sodium carbonate and potassium carbonate, and organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine and collidine. Is triethylamine. The number of equivalents of base and amine is 0.5 to 10 equivalents, preferably 0.7 to 5.0 equivalents. The reaction temperature is -20 ° C to 100 ° C, preferably 0 to 50 ° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 6.0 hours.

[C-2]
In this step, after reacting the chloro compound represented by the general formula (17) with an acetoxylation reagent by a generally known method, the alcohol compound represented by the general formula (18) by a generally known deacetylation method. Can be manufactured.

[C-3]
In this step, the compound represented by the general formula (18) is methoxymethylated (MOMated) by a generally known method, followed by Lewis acid treatment, and then commercially available 5-fluoro-2, A compound represented by the general formula (19) can be produced by reacting with 4-bis (trimethylsilyloxy) pyrimidine.
The solvent used for the Lewis acid treatment is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, carbon tetrachloride, DCE, toluene, xylene, and the like, preferably dichloromethane. Examples of the Lewis acid include boron trichloride (hereinafter referred to as BCl ₃ ), boron trifluoride, boron tribromide, and the like, preferably BCl ₃ . The number of equivalents is 0.01 to 10 equivalents, preferably 0.2 to 0.5 equivalents. The reaction temperature is −20 to 100 ° C., preferably 0 to 50 ° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 5.0 hours.
The solvent used in the reaction with 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is not particularly limited as long as it does not affect the reaction, but dichloromethane, chloroform, carbon tetrachloride, DCE, Toluene, xylene and the like are exemplified, and DCE or toluene is preferred. The number of equivalents of 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is 0.8 to 10 equivalents, preferably 0.9 to 5.0 equivalents. The equivalent number of iodine is 0.001 to 1.0 equivalent, preferably 0.05 to 0.5 equivalent. The reaction temperature is 20 to 150 ° C, preferably 50 to 100 ° C. The reaction time is 0.1 to 120 hours, preferably 0.5 to 100 hours.

[Wherein, R ^a , R ^b , R ^e , R ^f are as defined above, Pg represents a protecting group for a nitrogen atom on the sulfonamide group, E represents a bond or a vinylene group (provided that E represents a bond) In this case, CH ₂ -E- (CH ₂ ) m represents an n-propylene group or n-pentylene group), m represents an integer of 1 to 3, and Bz represents a benzoyl group. ]

[D-1]
In this step, the nitrogen atom on the sulfonamide group of the compound represented by the general formula (20) is protected with a protecting group such as a methoxymethyl group or a tert-butoxycarbonyl group by a generally known method, and then the step [ The compound represented by the general formula (21) can be produced by the same method as in C-2].

[D-2]
In this step, an alcohol compound represented by the general formula (21) is obtained by the same method as in the step [B-3], and then reacted with a Horner-Wadsworth-Emmons reagent. ) 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 benzene, toluene, diethyl ether, diisopropyl ether, THF, diglyme, dimethoxyethane, DMSO, etc., preferably THF. .
Horner-Wadsworth-Emmons reagent is triethylphosphonoacetate, eg sodium hydride, sodium amide, lithium diisopropylamide Prepare by treatment with a base such as sodium methoxide. The number of equivalents of base is 0.1 to 10 equivalents, preferably 0.8 to 2.0 equivalents. The reaction temperature is -20 ° C to 100 ° C, preferably 0 to 70 ° C. The reaction time is 0.05 to 12 hours, preferably 0.1 to 2.0 hours.
The number of equivalents of Horner-Wadsworth-Emmons reagent is 0.1-10 equivalents, preferably 0.3-5.0 equivalents. The reaction temperature is 0 ° C to 150 ° C, preferably 10 ° C to 100 ° C. The reaction time is 0.05 to 12 hours, preferably 0.1 to 4.0 hours.

[D-3]
In this step, the compound represented by the general formula (22) can be produced from the compound represented by the general formula (22) by a generally known reduction method, preferably the DIBAL reduction method.

[D-4]
In this step, the compound represented by the general formula (24) can be produced from the compound represented by the general formula (23) by a generally known catalytic reduction method.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, dimethoxyethane, diethylene glycol dimethyl ether, diisopropyl ether, diethyl ether, THF, Examples include dioxane, ethyl acetate, butyl acetate and the like, preferably methanol or ethyl acetate.
Examples of the catalyst used include 5 to 10% palladium / carbon, palladium hydroxide, platinum, Raney nickel, platinum oxide, and rhodium-aluminum oxide, and preferably 5 to 10% palladium / carbon. The number of equivalents is 0.001 to 10 equivalents, preferably 0.01 to 5.0 equivalents. The reaction temperature is 0 to 100 ° C, preferably 20 to 60 ° C. The reaction time is 0.1 to 24 hours, preferably 0.2 to 6.0 hours.

[D-5]
In this step, 3-benzoyl 5-fluoropyrimidine-2,4 (1H, 3H) -dione obtained according to the method described in the literature (Bioorg. Med. Chem. Lett., 12, 1395-1397 (2002)) The Mitsunobu reaction of (25) and any alcohol compound represented by the general formula (21), (23), (24) in the same manner as in the step [A-1] (b) yields the general formula ( 26) can be produced.

[D-6]
In this step, the compound represented by the general formula (27) can be produced by debenzoylating and depgrating the compound represented by the general formula (26) by a generally known deprotection method.

[Wherein, Hal, R ^a , R ^b , ^Re and R ^f are as defined above, and Ar represents a divalent aromatic hydrocarbon group or a divalent unsaturated heterocyclic group. ]

[E-1]
In this step, the compound represented by the general formula (28) is reacted with any amine represented by the general formula (5) or (15) in the same manner as in the step [C-1]. The compound represented by (29) can be produced.

[E-2]
In this step, the compound represented by the general formula (29) and the commercially available 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine are reacted in the presence of iodine to represent the general formula (30). Compounds can be produced.
The solvent to be used is not particularly limited as long as it does not affect the reaction, but DCE, THF, dioxane, acetonitrile, toluene and the like are exemplified, and DCE or toluene is preferable.
The number of equivalents of 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine is 0.5 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents. The number of equivalents of iodine is 0.01 to 1.0 equivalent, preferably 0.1 to 0.5 equivalent.
The reaction temperature is 10 to 100 ° C, preferably 70 to 95 ° C. The reaction time is 0.1 to 120 hours, preferably 0.5 to 100 hours.

[Wherein R ^e , R ^f and m are as defined above. R ^g and R ^h are the same or different and are a hydrogen atom, a halogen atom, a benzoyloxy group, a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, and a carbon number of 3 A cycloalkyl group having ˜7, a linear or branched alkoxy group having 1 to 6 carbon atoms which may have a substituent, a cycloalkoxy group having 3 to 7 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms Represents an alkyl-alkoxy group, Ar ′ represents an aromatic hydrocarbon group or an unsaturated heterocyclic group, Cbz represents a benzyloxycarbonyl group, and MOM represents a methoxymethyl group. ]

[F-1]
In this step, an amino alcohol compound represented by the general formula (31) that can be easily obtained is converted to Cbz of the amino group by a generally known method, and then converted to MOM by a generally known method. 32) can be produced.
For example, when m = 2, the amino alcohol compound represented by the general formula (31) is ethyl 3-amino-obtained by the method described in J. Med. Chem., 34, 633-642 (1991). When 3-methylbutanoate can be prepared by reduction with LAH, and m = 3 and R ^e and R ^f are methyl groups, J. Am. Chem. Soc., 77, 1079-1083 ( 1955).

[F-2]
In this step, the compound represented by the general formula (32) has a substituent that can be easily obtained after de-Cbzation by a generally known method, for example, by reacting palladium-carbon in a hydrogen atmosphere. And may be produced according to a method described in J. Pesticide. Chem., 13, 107-115 (1988)) under basic conditions. Can be produced.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but dichloromethane, DMF, ethyl acetate, THF, dioxane, diethyl ether, acetonitrile and the like are exemplified, and dichloromethane is preferable.
The number of equivalents of the optionally substituted arylsulfonyl chloride is 0.9 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents.
Examples of the base used include organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and 1,8-diazabicyclo [5.4.0] -7-undecene (hereinafter DBU). And is preferably triethylamine. The number of equivalents is 0.9 to 10 equivalents, preferably 1.0 to 3.0 equivalents.
The reaction temperature is 0-60 ° C, preferably 0-30 ° C. The reaction time is 0.1 to 100 hours, preferably 1.0 to 72 hours.
When R ^g or R ^h is a benzoyloxy group, it can be converted into various functional groups by a generally known method.

[F-3]
In this step, the compound represented by the general formula (34) can be produced by reacting the compound represented by the general formula (33) in the same manner as in [C-3].

[In the formula, Ar ′, R ^e , R ^f , R ^g and R ^h are as defined above. ]

[G-1]
In this step, for example, the compound represented by the general formula (35) that can be easily obtained according to the method described in Tetrahedron Lett., 38, 1241-1244 (1997) and a readily available substituent are included. Arylsulfonyl chloride (which can be produced according to the method described in J. Pesticide. Chem., 13, 107-115 (1988)) in the same manner as [F-2]. The compound represented by the general formula (36) can be produced.
When R ^g or R ^h is a benzoyloxy group, it can be converted into various functional groups by a generally known method.

[G-2]
In this step, the methyl group of the compound represented by the general formula (36) is converted to a commonly known brominating agent such as sodium bromate and sodium bisulfite, or N-bromosuccinimide and azobisisobutyronitrile (AIBN). After the reaction and bromination, the compound represented by the general formula (37) can be produced by the same method as [E-2].

[G-3]
In this step, the hydroxyl group of 6- (hydroxymethyl) nicotinonitrile (38) obtained by the method described in JP-A-2006-508054 is converted to a protecting group, preferably tert-butyldimethylsilyl ( Hereinafter, after reacting a compound introduced with a TBS) group with a methylating agent that can be prepared from cerium chloride and methyllithium, the easily substituted substituent is obtained in the same manner as in [F-2]. The compound represented by the general formula (39) can be produced by reacting with a good arylsulfonyl chloride.
Examples of the reaction solvent used for methylation include THF, dioxane, diethyl ether and the like, preferably THF and diethyl ether. The number of equivalents of cerium chloride is 1.0 to 5.0 equivalents, preferably 2.0 to 4.0 equivalents. The number of equivalents of methyllithium is 1.0 to 5.0 equivalents, preferably 2.0 to 4.0 equivalents.
The reaction temperature for methylation is −100 to 40 ° C., preferably −78 to 30 ° C. The reaction time is 0.5 to 5.0 hours, preferably 2.0 to 3.0 hours.
When R ^g or R ^h is a benzoyloxy group, it can be converted into various functional groups by a generally known method.

[G-4]
In this step, the TBS group of the compound represented by the general formula (39) is removed, and the resulting hydroxyl group is brominated by a generally known method such as triphenylphosphine and carbon tetrabromide, and then [E-2] A compound represented by the general formula (40) can be produced by the same method.

[In the formula, R ⁱ , R ^j and R ^k are the same or different and have a hydrogen atom, a hydroxyl group, a halogen atom, an aromatic hydrocarbon group which may have a substituent or a substituent. Or an unsaturated heterocyclic group. ]

[H-1]
In this step, 4- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 () obtained by the method described in the literature (Med. Chem. Res., 10, 390-403 (2001)). A compound represented by the general formula (42) can be produced by condensing 2H) -yl) butanoic acid (41) with a readily available pyrrolidine derivative.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, toluene, dichloromethane, acetonitrile, THF, and the like, preferably dichloromethane. Examples of the condensing agent to be used include DCC and EDC / HCl, and examples of the condensing aid include 1-hydroxybenzotriazole (hereinafter HOBt), and a combination of EDC / HCl and HOBt is preferable. The number of equivalents is 0.8 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents. The equivalence number of an amine compound is 0.8-5.0 equivalent, Preferably it is 1.0-3.0 equivalent. The reaction temperature is 0-100 ° C, preferably 10-40 ° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 4.0 hours.

  As described above, 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.

As shown in the examples described later, the 5-fluorouracil compound or a salt thereof of the present invention has an excellent dUTPase inhibitory activity, and thus is useful as a pharmaceutical represented by an antitumor drug.
When the 5-fluorouracil compound or a salt thereof of the present invention is contained in a pharmaceutical composition, it can be combined with a pharmaceutical carrier as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment. Examples include oral preparations, injections, suppositories, ointments, patches, and the like, with oral preparations being preferred. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

  As 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.

  When preparing an oral solid preparation, after adding an excipient, and if 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.

  Examples of the excipient include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid.

  As binders, water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, α-starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned.

Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, 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.

  When preparing an oral liquid preparation, a liquid preparation, a syrup, an elixir and the like can be produced by a conventional method by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like to the compound of the present invention. In this case, the flavoring / flavoring agent may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin. If necessary, 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.

  When preparing an injection, 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. Can be manufactured. In this case, examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.

  When preparing a suppository, 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.

  When preparing an ointment, 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. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.

  When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method. As the support, 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.
In addition, 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. It is about 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into 2 to 3 times a day.
Diseases that can be treated by administering a drug containing the compound of the present invention include malignant tumors, malaria, tuberculosis and the like. For example, in the case of malignant tumors, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal 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 tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple Examples include myeloma, skin cancer, and brain tumor. It can also be used as an anti-pylori drug, an antiparasitic drug, or an antiviral drug.

  Reference Examples, Examples, Test Examples and Formulation Examples are shown below to explain the present invention in more detail, but the present invention is not limited to these Examples.

Reference Example 1 Synthesis of (3- (cyclopropylmethoxy) phenyl) methanamine

  3-Cyanophenol (12.4 g) is dissolved in N, N-dimethylformamide (DMF, 100 mL), potassium carbonate (30.5 g), potassium iodide (1.74 g), (chloromethyl) cyclopropane (10.2 mL) ) Was added and stirred at 90 ° C. for 4 hours. Water (130 mL) was added to the reaction mixture, and the mixture was extracted with toluene (130 mL). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Dissolve the residue in tetrahydrofuran (hereinafter THF, 60 mL), slowly add dropwise a solution of lithium aluminum hydride (LAH) in THF (2.4 M, 68 mL) at 0 ° C, and then add the reaction solution at 45 ° C for 4 hours. Stir. Water (10 mL), aqueous sodium hydroxide (1.0 M, 10 mL), and water (5.0 mL) were slowly added to the reaction solution at 0 ° C. The resulting precipitate was filtered off, washed with 10% methanol / THF (400 mL), and the combined filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (18.1 g) as a crude product.

Reference example 2
Synthesis of (R) -1- (3- (cyclopentyloxy) phenyl) ethanamine hydrochloride

  3-hydroxybenzaldehyde (12.2 g) was dissolved in DMF (120 mL), bromocyclopentane (32.8 mL), potassium carbonate (27.6 g), and potassium iodide (1.66 g) were added, and the mixture was stirred at 120 ° C. for 3.5 hours. The reaction mixture was allowed to cool, water (120 mL) was added, and the mixture was extracted with toluene (120 mL). The organic layer was washed with water (120 mL), aqueous sodium hydroxide solution (1.0 M, 120 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Dissolve the residue in toluene (250 mL), add (S)-(-)-2-methyl-2-propanesulfinamide (13.3 g) and titanium tetraisopropoxide (44.4 mL), and stir at 70 ° C. for 6 hours. did. The reaction mixture was allowed to cool, and saturated aqueous sodium hydrogen carbonate solution (130 mL) was added. The resulting precipitate was filtered off, washed with ethyl acetate (200 mL × 4), and the combined filtrate was concentrated under reduced pressure. To the residue was added saturated brine (200 mL), and the mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A portion (1.47 g) of the residue (29.3 g) was dissolved in THF (7.5 mL), and methylmagnesium bromide in diethyl ether (3.0 M, 3.33 mL) was added dropwise at 0 ° C. Stir for hours. A saturated aqueous ammonium chloride solution (6.0 mL) was added to the reaction solution at 0 ° C. over 5 minutes, and the mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (6.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40% ethyl acetate / hexane). The obtained compound (1.09 g) was dissolved in methanol (10 mL), hydrochloric acid-dioxane solution (4.0 M, 1.1 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and azeotroped with toluene (5.0 mL x 3) to give the title compound (845 mg).

Reference Example 3
Synthesis of (R) -1- (3-((R) -tetrahydrofuran-3-yloxy) phenyl) ethanamine hydrochloride

  3-Hydroxybenzaldehyde (1.3 g), triphenylphosphine (3.6 g), (S)-(+)-tetrahydro-3-furanol (1.2 mL) was dissolved in THF (20 mL), and diethylazodicarboxylate ( A toluene solution (2.2 M, 6.2 mL) of DEAD) was slowly added dropwise at 0 ° C., followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (20 mL) was added, and the organic layer was washed with aqueous sodium hydroxide solution (1.0 M, 5.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in toluene (6.5 mL), and (S)-(-)-2-methyl-2-propanesulfinamide (330 mg) and titanium tetraisopropoxide (1.1 mL) were added at 75 ° C. Stir for 6 hours. The reaction mixture was allowed to cool, and saturated aqueous sodium hydrogen carbonate solution (10 mL) was added. The resulting precipitate was filtered off, washed with ethyl acetate (20 mL × 4), and the combined filtrate was concentrated under reduced pressure. To the residue was added saturated brine (30 mL), and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (7.5 mL), methylmagnesium bromide in diethyl ether (3.0 M, 1.7 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 2 hr. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution at 0 ° C. over 10 minutes, and the mixture was extracted with ethyl acetate (15 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 chromatography (100% ethyl acetate). The obtained compound was dissolved in methanol (5.0 mL), hydrochloric acid-dioxane solution (4.0 M, 470 μL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and azeotroped with toluene (4.0 mL x 3) to give the title compound (244 mg).

Reference example 4
Synthesis of (3- (cyclopropylmethoxy) -4-fluorophenyl) methanamine

  4-Fluoro-3-hydroxybenzoic acid (15.0 g) is dissolved in DMF (200 mL), and (chloromethyl) cyclopropane (18.0 mL), potassium carbonate (29.2 g), and potassium iodide (1.6 g) are added. Stir at 90 ° C. for 6 hours. The reaction mixture was allowed to cool, water (120 mL) was added, and the mixture was extracted with toluene (120 mL). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in toluene (65 mL), a hexane solution (1.0 M, 130 mL) of diisobutylaluminum hydride (hereinafter DIBAL) was added dropwise at 0 ° C., and the reaction solution was stirred at 0 ° C. for 2 hours. Water (10 mL) and aqueous sodium hydroxide solution (1.0 M, 10 mL) were slowly added to the reaction solution. The resulting precipitate was filtered off, washed with ethyl acetate (100 mL × 5), and the combined filtrate was concentrated under reduced pressure. Water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (40% ethyl acetate / hexane). The obtained compound was dissolved in THF (75 mL), diphenylphosphoryl azide (12.9 mL), 1,8-diazabicyclo [5.4.0] -7-undecene (hereinafter DBU) (9.4 mL) was added dropwise at room temperature, Stir at room temperature for 1 hour. Saturated brine (100 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (100 mL x 2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). The obtained compound was dissolved in THF (80 mL), and a THF solution of LAH (2.4 M, 40 mL) was slowly added dropwise at 0 ° C., followed by stirring at 0 ° C. for 1 hour. Water (5.0 mL) and aqueous sodium hydroxide solution (1.0 M, 5.0 mL) were slowly added dropwise to the reaction solution at 0 ° C. The precipitate was filtered off, washed with 10% methanol / THF (200 mL), and the combined filtrate was concentrated under reduced pressure. To the residue is added saturated brine (100 mL), and the mixture is extracted with ethyl acetate (150 mL) .The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (10.5 g) as a crude product. It was.

Reference Example 5
Synthesis of (R) -1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethanamine hydrochloride

  4-Fluoro-3-hydroxybenzoic acid (12.0 g) was dissolved in ethanol (200 mL), sulfuric acid (3.5 mL) was added, and the mixture was heated to reflux at 105 ° C. for 4 hr. The reaction solution was allowed to cool and then concentrated under reduced pressure. Water (100 mL) and sodium carbonate (18.0 g) were added to the residue, and the aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene (15 mL x 2), dissolved in DMF (100 mL), (chloromethyl) cyclopropane (6.9 mL), potassium carbonate (19.8 g), and potassium iodide (1.2 g) were added. The mixture was further stirred at 90 ° C. for 3.5 hours. The reaction mixture was allowed to cool, water (200 mL) was added, and the mixture was extracted with toluene (100 mL x 2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (75 mL), a THF solution of lithium borohydride (2.0 M, 54 mL) was added dropwise at room temperature, and the mixture was heated to reflux at 80 ° C. for 3.5 hours. The reaction mixture was allowed to cool, water (200 mL) was added dropwise at 0 ° C., and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (250 mL), manganese dioxide (86 g) was added at room temperature, and the mixture was heated to reflux at 45 ° C. for 6 hours. The reaction mixture was allowed to cool, insoluble material was filtered off, washed with chloroform (100 mL x 4), and the combined filtrate was concentrated. Dissolve the residue in toluene (150 mL), add (S)-(-)-2-methyl-2-propanesulfinamide (8.5 g) and titanium tetraisopropoxide (28.4 mL), and stir at 75 ° C. for 6 hours. did. The reaction mixture was allowed to cool, and saturated aqueous sodium hydrogen carbonate solution (150 mL) was added. The resulting precipitate was removed by filtration, washed with ethyl acetate (200 mL × 6), and the combined filtrate was concentrated under reduced pressure. To the residue was added saturated brine (150 mL), and the mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (85 mL), methylmagnesium bromide in diethyl ether (3.0 M, 42 mL) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 2 hr. A saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution at 0 ° C. over 10 minutes, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in methanol (70 mL), hydrochloric acid-dioxane solution (4.0 M, 13 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene (40 mL x 3) to obtain the title compound (9.09 g).

Reference Example 6
Synthesis of (R) -1- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-methylpropan-1-amine hydrochloride

  4-Fluoro-3-hydroxybenzoic acid (1.2 g) was dissolved in ethanol (20 mL), sulfuric acid (350 μL) was added, and the mixture was heated to reflux at 105 ° C. for 4 hours. The reaction solution was allowed to cool and then concentrated under reduced pressure. Water (10 mL) and sodium carbonate (1.8 g) were added to the residue, and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene (4.0 mL x 2), dissolved in DMF (50 mL), (chloromethyl) cyclopropane (762 μL), potassium carbonate (2.1 g), and potassium iodide (133 mg) were added. The mixture was stirred at 90 ° C for 3.5 hours. The reaction mixture was allowed to cool, water (20 mL) was added, and the mixture was extracted with toluene (20 mL x 2). 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 THF (8.0 mL), a THF solution of lithium borohydride (2.0 M, 7.5 mL) was added dropwise at room temperature, and the mixture was heated to reflux at 75 ° C. for 3.5 hours. The reaction mixture was allowed to cool, water (20 mL) was added dropwise at 0 ° C., and the aqueous layer was extracted with ethyl acetate (20 mL × 2). 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 (25 mL), manganese dioxide (8.6 g) was added at room temperature, and the mixture was heated to reflux at 45 ° C. for 6 hours. The reaction mixture was allowed to cool, insoluble material was filtered off, washed with chloroform (20 mL x 4), and the combined filtrate was concentrated. Dissolve the residue in toluene (17.5 mL), add (R)-(+)-2-methyl-2-propanesulfinamide (985 mg) and titanium tetraisopropoxide (3.3 mL), and stir at 75 ° C. for 6 hours. did. After allowing to cool, saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The resulting precipitate was filtered off and washed with ethyl acetate (20 mL x 6). The combined filtrate was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (85 mL), and a THF solution of isopropyl lithium (0.7 M, 12 mL) was added dropwise at −78 ° C., followed by stirring at −78 ° C. for 45 minutes. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture at −78 ° C., and the aqueous layer was extracted with ethyl acetate (20 mL × 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in methanol (7.0 mL), hydrochloric acid-dioxane solution (4.0 M, 470 μL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene (10 mL x 3) to obtain the title compound (425 mg).

  The amines shown in the following table were synthesized according to any of Reference Examples 2, 3, 5, and 6.

Reference Example 31
Synthesis of N- (3- (cyclopropylmethoxy) benzyl) -3- (methoxymethoxy) propane-1-sulfonamide

(3- (Cyclopropylmethoxy) phenyl) methanamine (10.0 g) obtained in Reference Example 1 was dissolved in dichloromethane (50 mL), triethylamine (11.9 g), 3-chloropropanesulfonyl chloride (10.6 g) at 0 ° C. And stirred at room temperature for 12 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (50 mL). The organic layer was washed with dilute hydrochloric acid (1.0 M, 100 mL) and saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (100 mL), sodium acetate (10.2 g) and sodium iodide (18.6 g) were added, and the mixture was stirred at 80 ° C. for 8 hr. The reaction mixture was allowed to cool, water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in 5-10% hydrochloric acid / methanol solution (100 mL) and heated to reflux at 80 ° C. for 1 hour. The reaction solution was allowed to cool and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (66% ethyl acetate / hexane). The obtained compound was dissolved in dichloromethane (80 mL), N, N-diisopropylethylamine (14.1 mL) and chloromethyl methyl ether (4.1 mL) were added, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (50 mL). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate / hexane) to give the title compound (11.5 g).
The compounds shown in the following table were synthesized according to the method of Reference Example 31 using any of the amines obtained in Reference Examples 2 to 30.

Reference Example 61
Synthesis of (R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -3-hydroxy-N- (methoxymethyl) propane-1-sulfonamide

  (R) -1- [3- (cyclopropylmethoxy) -4-fluorophenyl] ethanamine hydrochloride (1.20 g) obtained in Reference Example 5 was dissolved in dichloromethane (7.5 mL), triethylamine (1.6 mL), 3-Chloropropanesulfonyl chloride (550 μL) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate / hexane). The obtained compound was dissolved in dichloromethane (7.0 mL), N, N-diisopropylethylamine (5.0 mL) and chloromethyl methyl ether (1.5 mL) were added, and the mixture was stirred at 40 ° C. for 6 hr. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (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 (20% ethyl acetate / hexane). The obtained compound was dissolved in DMF (8.0 mL), sodium acetate (887 mg) and sodium iodide (1.62 g) were added, and the mixture was stirred at 80 ° C. for 8 hr. The reaction mixture was allowed to cool, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). 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 purified by silica gel column chromatography (66% ethyl acetate / hexane) to give the title compound (932 mg).

Reference Example 62
Synthesis of (R, E) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -5-hydroxy-N- (methoxymethyl) pent-3-ene-1-sulfonamide

(R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -3-hydroxy-N- (methoxymethyl) propane-1-sulfonamide obtained by Reference Example 61 ( 844 mg) was dissolved in dichloromethane (10 mL), Dess-Martin reagent (1.4 g) was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution (20 mL) and a saturated aqueous sodium thiosulfate solution (20 mL) were added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene (15 mL x 2) and then dissolved in THF (2.5 mL).
To a THF suspension (5.0 mL) of sodium hydride (55%, 150 mg) was added triethylphosphonoacetate (695 μL) at 0 ° C., and the mixture was stirred at room temperature for 15 minutes. A THF solution of the residue azeotroped with toluene was added to the reaction solution at 0 ° C, and the mixture was stirred at 70 ° C for 1 hour. The reaction mixture was allowed to cool, saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 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 (33% ethyl acetate / hexane). The obtained compound was dissolved in THF (8.0 mL), a DIBAL THF solution (1.0 M, 4.0 mL) was added at -78 ° C, and the mixture was stirred at -78 ° C for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). 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 (50% ethyl acetate / hexane) to give the title compound (330 mg).

Reference Example 63
Synthesis of (R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -5-hydroxy-N- (methoxymethyl) pentane-1-sulfonamide

  (R, E) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -5-hydroxy-N- (methoxymethyl) pent-3-ene obtained in Reference Example 62 -1-sulfonamide (296 mg) was dissolved in ethyl acetate (5.0 mL), 10% palladium-carbon (170 mg) was added, and the reaction solution was stirred at room temperature for 2 hours in a hydrogen atmosphere. The insoluble material was filtered off using celite, washed with ethyl acetate (100 mL), and the combined filtrate was concentrated under reduced pressure to give the title compound (208 mg) as a crude product.

  The compounds shown in the following table were synthesized according to any one of Reference Examples 61 to 63 using amines of Reference Examples 1, 2, 8, 11, and 19.

Reference Example 76
Synthesis of (R) -4- (bromomethyl) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) benzenesulfonamide

  (R) -1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethanamine hydrochloride (393 mg) obtained in Reference Example 5 was dissolved in dichloromethane (3.0 mL), and triethylamine (670 μL) was dissolved. 4- (Bromomethyl) benzenesulfonyl chloride (450 mg) was added at 0 ° C., and the mixture was stirred for 2 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give the title compound (308 mg).

  The compounds shown in the following table were synthesized according to the method of Reference Example 76 using the amines of Reference Examples 2, 8, 11, and 19.

Reference Example 81
Synthesis of benzyl 5- (methoxymethoxy) -2-methylpentan-2-ylcarbamate

  4-Amino-4-methylpentan-1-ol (6.7 g) obtained by the method described in the literature (J. Am. Chem. Soc., 77, 1079-1083 (1955)) was added to dichloromethane (100 mL). After dissolution, N-carbobenzoxyoxysuccinimide (18 g) was added and stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure, water (200 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate / hexane). The obtained colorless oily substance (7.9 g) was dissolved in dichloromethane (100 mL), N, N-diisopropylethylamine (19 mL) and chloromethyl methyl ether (6.0 mL) were added, and the mixture was stirred at room temperature for 3 hr. A saturated aqueous ammonium chloride solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with a saturated aqueous ammonium chloride solution (150 mL x 3) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the title compound (7.8 g) as a colorless oil. The benzyloxycarbonyl group was expressed as Cbz.

Reference Example 82
Synthesis of 3- (cyclopropylmethoxy) -N- (5- (methoxymethoxy) -2-methylpentan-2-yl) benzenesulfonamide

  Dissolve benzyl 5- (methoxymethoxy) -2-methylpentan-2-ylcarbamate (242 mg) obtained in Reference Example 81 in methanol (5.0 mL), add 10% palladium-carbon (250 mg), and add hydrogen. The reaction was stirred at room temperature for 1 hour under atmosphere. The insoluble material was filtered off using celite, washed with methanol (20 mL), and the combined filtrate was concentrated. The residue was dissolved in dichloromethane (3.0 mL), triethylamine (170 μL), and 3-benzoyloxybenzenesulfonyl chloride (297) obtained by the method described in the literature (J. Pesticide Chem., 13, 107-115 (1988)). mg) was added and stirred at room temperature for 2 hours. Water (7.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 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 (30% ethyl acetate / hexane). The obtained colorless oily substance (165 mg) was dissolved in a methanol solution of methylamine (40%, 3.0 mL) and stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue was dissolved in DMF (3.0 mL), potassium carbonate (102 mg), potassium iodide (6.0 mg), (chloromethyl) cyclopropane (34 μL) were added, and the mixture was stirred at 90 ° C. for 14 hours. did. The reaction mixture was allowed to cool, water (10 mL) was added, 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 (30% ethyl acetate / hexane) to give the title compound (124 mg) as a colorless oil.

Reference Example 83
Synthesis of 3- (2,2-difluoroethoxy) -N- (5- (methoxymethoxy) -2-methylpentan-2-yl) benzenesulfonamide

  From the benzyl 5- (methoxymethoxy) -2-methylpentan-2-ylcarbamate (628 mg) obtained in Reference Example 81, according to the method of Reference Example 82, the title compound (367 mg) was obtained as a pale yellow gum. Obtained as material.

Reference Example 84
Synthesis of 3- (cyclopentyloxy) -N- (5- (methoxymethoxy) -2-methylpentan-2-yl) benzenesulfonamide

  From the benzyl 5- (methoxymethoxy) -2-methylpentan-2-ylcarbamate (628 mg) obtained in Reference Example 81, according to the method of Reference Example 82, the title compound (379 mg) was pale yellow gum. Obtained as material.

Reference Example 85
Synthesis of N- (2- (4- (bromomethyl) phenyl) propan-2-yl) -3- (cyclopropylmethoxy) benzenesulfonamide

  2-p-Tolylpropan-2-amine (298 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)) was dissolved in dichloromethane (5.0 mL) and triethylamine (420 μL ), 3-benzoyloxybenzenesulfonyl chloride (445 mg) obtained by the method described in the literature (J. Pesticide Chem., 13, 107-115 (1988)) was added and stirred at room temperature for 16 hours. Water (15 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 (20% ethyl acetate / hexane). The obtained colorless gum (316 mg) was dissolved in a methanol solution of methylamine (40%, 4.0 mL) and stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, the residue was azeotroped with toluene (5.0 mL), and then dissolved in DMF (5.0 mL), and potassium carbonate (213 mg), potassium iodide (13 mg), (chloromethyl) cyclohexane. Propane (78 μL) was added and stirred at 90 ° C. for 16 hours. The reaction mixture was allowed to cool, water (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with water (15 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 (20% ethyl acetate / hexane). The obtained colorless solid (233 mg) was dissolved in carbon tetrachloride (6.0 mL), and N-bromosuccinimide (125 mg) and azobisisobutyronitrile (hereinafter AIBN, 3.0 mg) were added. Heated to reflux for hours. The insoluble material was removed by filtration, washed with chloroform (30 mL), and the combined filtrate was concentrated. To the residue was added saturated brine (10 mL), and the mixture was extracted with 50% ethyl acetate / hexane (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (255 mg) as a crude product.

Reference Example 86
Synthesis of N- (2- (4- (bromomethyl) phenyl) propan-2-yl) -3- (2,2-difluoroethoxy) benzenesulfonamide

  From 2-p-tolylpropan-2-amine (414 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)), according to the method of Reference Example 85, the title compound ( 540 mg) was obtained as a colorless solid.

Reference Example 87
Synthesis of N- (2- (4- (bromomethyl) phenyl) propan-2-yl) -3- (cyclopentyloxy) benzenesulfonamide

  From 2-p-tolylpropan-2-amine (414 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)), according to the method of Reference Example 85, the title compound ( 549 mg) was obtained as a colorless solid.

Reference Example 88
Synthesis of N- (2- (6- (bromomethyl) pyridin-3-yl) propan-2-yl) -3- (cyclopropylmethoxy) benzenesulfonamide

  6- (Hydroxymethyl) nicotinonitrile (1.59 g) obtained by the method described in JP-A-2006-508054 was dissolved in DMF (30 mL), and imidazole (2.1 g), tert-butyldimethylsilyl chloride (2.33 g) was added and stirred at room temperature for 1.5 hours. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with 50% ethyl acetate / hexane (60 mL). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane). The obtained colorless solid (1.99 g) was azeotroped with toluene (10 mL × 3).

  Cerium chloride (1.48 g) was suspended in THF (12 mL) and stirred vigorously at room temperature for 2 hours. The reaction solution was sonicated for 5 minutes, cooled to −78 ° C., methyl lithium in diethyl ether (1.09 M, 5.5 mL) was slowly added dropwise, and the reaction solution was stirred at −78 ° C. for 30 minutes. A part (497 mg) of the colorless solid azeotroped with toluene was dissolved in THF (2.0 mL), slowly added to the reaction solution at −78 ° C., and stirred at room temperature for 2 hours. Saturated aqueous ammonia (5.0 mL) was added to the reaction mixture, and the mixture was vigorously stirred at room temperature for 30 min. The insoluble material was filtered off using celite, washed with THF (100 mL), and the combined filtrate was concentrated. Water (20 mL) was added to the residue, and the mixture was extracted with chloroform (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 (6.0 mL), and triethylamine (420 μL), 3-benzoyloxybenzenesulfonyl chloride obtained by the method described in the literature (J. Pesticide. Chem., 13, 107-115 (1988)) ( 593 mg) was added and stirred at room temperature for 3 days. 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 saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained pale orange oily substance (700 mg) was dissolved in a methanol solution of methylamine (40%, 3.0 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (60% ethyl acetate / hexane). The obtained pale yellow oily substance (522 mg) was dissolved in DMF (12 mL), and potassium carbonate (332 mg), potassium iodide (20 mg), (chloromethyl) cyclopropane (122 μL) were added, and 90 ° C was added. For 18 hours. The reaction mixture was allowed to cool, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with water (25 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol / chloroform) to give a desilylated product (254 mg). The desilylated product (249 mg) was dissolved in THF (3.0 mL), triphenylphosphine (182 mg) and carbon tetrabromide (230 mg) were 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 (60% ethyl acetate / hexane) to give the title compound (226 mg) as a purple gum.

Reference Example 89
Synthesis of N- (2- (6- (bromomethyl) pyridin-3-yl) propan-2-yl) -3- (2,2-difluoroethoxy) benzenesulfonamide

  According to the method of Reference Example 88, the title compound (143 mg) was obtained as a purple oily substance from 6- (hydroxymethyl) nicotinonitrile (372 mg) obtained by the method described in JP-A-2006-508054. .

Reference Example 90
Synthesis of N- (2- (6- (bromomethyl) pyridin-3-yl) propan-2-yl) -3- (cyclopentyloxy) benzenesulfonamide

  According to the method of Reference Example 88, the title compound (139 mg) was obtained as a purple foam from 6- (hydroxymethyl) nicotinonitrile (377 mg) obtained by the method described in JP-A-2006-508054. It was.

Example 1
Of N- (3- (cyclopropylmethoxy) benzyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide Composition

N- (3- (cyclopropylmethoxy) benzyl) -3- (methoxymethoxy) propane-1-sulfonamide (588 mg) obtained in Reference Example 31 was dissolved in dichloromethane (5.0 mL), and boron trichloride ( Thereafter, a dichloromethane solution (1.0 M, 561 μL) of BCl ₃ ) was added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (hereinafter DCE, 3.0 mL).

  Dissolve commercially available 5-fluoro-2,4-bis (trimethylsilyloxy) pyrimidine (657 mg) in DCE (2.0 mL), add the remaining DCE (3.0 mL) solution, and iodine (60 mg) at 95 ° C. Heated to reflux for 3.5 hours. The reaction mixture was allowed to cool, water (30 mL) and saturated aqueous sodium thiosulfate solution (2.0 mL) were added, and the mixture was extracted with 10% methanol / chloroform (20 mL x 3). The combined organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (90% ethyl acetate / hexane) to give the title compound (305 mg, yield 41%) as a colorless foam.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.32-0.39 (2H, m), 0.61-0.68 (2H, m), 1.20-1.31 (1H, m), 2.00-2.17 (2H, m), 3.02 (2H, t, J = 7.0 Hz), 3.65 (2H, t, J = 6.2 Hz), 3.81 (2H, d, J = 7.0 Hz), 4.26 (2H, d, J = 5.7 Hz), 4.64 (1H , brs), 5.09 (2H, s), 6.83-6.89 (3H, m), 7.29-7.35 (2H, m)

Example 2 to Example 30
The following compounds were synthesized from the compounds obtained in Reference Examples 32 to 60 according to the method of Example 1. The results are shown in the table below.

Example 2
(R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy Propane-1-sulfonamide Example 3
3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N-((R) -1- (3-((R) -tetrahydrofuran- 3-yloxy) phenyl) ethyl) propane-1-sulfonamide Example 4
N- (3- (cyclopropylmethoxy) -4-fluorobenzyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1 -Sulfonamide Example 5
(R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H ) -Yl) methoxy) propane-1-sulfonamide Example 6
(R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-methylpropyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) -yl) methoxy) propane-1-sulfonamide Example 7
(R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) propyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H ) -Yl) methoxy) propane-1-sulfonamide Example 8
(R) -N- (1- (3- (cyclopropylmethoxy) phenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) Methoxy) propane-1-sulfonamide Example 9
(R) -N- (1- (3- (cyclopentyloxy) -4-fluorophenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -Yl) methoxy) propane-1-sulfonamide Example 10
N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-methylpropyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H ) -Yl) methoxy) propane-1-sulfonamide Example 11
(R) -N- (1- (3- (cyclopropylmethoxy) phenyl) propyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) Methoxy) propane-1-sulfonamide Example 12
(R) -N- (1- (3- (cyclopentylmethoxy) phenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy Propane-1-sulfonamide Example 13
(R) -3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3- (1,1,2, 2-Tetrafluoroethoxy) phenyl) ethyl) propane-1-sulfonamide Example 14
(R) -3-((5-Fluoro2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3- (2,2,2-tri Fluoroethoxy) phenyl) ethyl) propane-1-sulfonamide Example 15
(R) -N- (1- (3- (1,3-Difluoropropan-2-yloxy) phenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine- 1 (2H) -yl) methoxy) propane-1-sulfonamide Example 16
(R) -3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3-isobutoxyphenyl) ethyl) propane -1-sulfonamide Example 17
3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N-((R) -1- (3-((S) -2- Methylbutoxy) phenyl) ethyl) propane-1-sulfonamide Example 18
(R) -3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3-((1-methylcyclopropyl ) Methoxy) phenyl) ethyl) propane-1-sulfonamide Example 19
(R) -N- (1- (3- (2,2-difluoroethoxy) phenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -Yl) methoxy) propane-1-sulfonamide Example 20
N-((R) -1- (3-((S) -but-3-in-2-yloxy) phenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4- Dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide Example 21
N-((R) -1- (3-((R) -but-3-in-2-yloxy) phenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4- Dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide Example 22
(R) -3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3- (2-fluoroethoxy) phenyl ) Ethyl) propane-1-sulfonamide Example 23
N-((R) -1- (3- (R) -sec-butoxyphenyl) ethyl-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl ) Methoxy) propane-1-sulfonamide Example 24
N-((R) -1- (3- (S) -sec-butoxyphenyl) ethyl-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl ) Methoxy) propane-1-sulfonamide Example 25
3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N-((R) -1- (3-((S) -pentane- 2-yloxy) phenyl) ethyl) propane-1-sulfonamide Example 26
3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N-((R) -1- (3-((R) -pentane- 2-yloxy) phenyl) ethyl) propane-1-sulfonamide Example 27
(R) -3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3- (2,2,3, 3,3-Pentafluoropropoxy) phenyl) ethyl) propane-1-sulfonamide Example 28
(R) -3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N- (1- (3- (tetrahydro-2H-pyran- 4-yloxy) phenyl) ethyl) propane-1-sulfonamide Example 29
3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -N-((R) -1- (3-((R) -tetrahydrofuran- 3-yloxy) phenyl) ethyl) propane-1-sulfonamide Example 30
(R) -N- (1- (3- (2-cyclopropylethoxy) phenyl) ethyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H)- Yl) methoxy) propane-1-sulfonamide

Example 31
(R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -3- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) Synthesis of -yl) propane-1-sulfonamide

  (R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -3-hydroxy-N- (methoxymethyl) propane-1-sulfonamide obtained by Reference Example 61 ( 230 mg) was dissolved in THF (4.5 mL) and obtained according to the method described in triphenylphosphine (189 mg), literature (Bioorg. Med. Chem. Lett., 12, 1395-1397 (2002)) 3-Benzoyl 5-fluoropyrimidine-2,4 (1H, 3H) -dione (162 mg) was added, and the mixture was stirred at room temperature for 5 minutes. To the reaction solution, a toluene solution of DEAD (2.2 M, 330 μL) was slowly added dropwise and stirred at room temperature for 4 hours. The reaction mixture 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%, 4.0 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 (90% ethyl acetate / hexane). The obtained compound was dissolved in dioxane (1.5 mL), hydrochloric acid-dioxane solution (4.0 M, 500 μL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution (4.0 mL) at 0 ° C., and extracted with ethyl acetate (15 mL × 2) and 10% methanol / chloroform (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 (100% ethyl acetate) to give the title compound (17 mg, yield 6%).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.32-0.38 (2H, m), 0.60-0.67 (2H, m), 1.22-1.30 (1H, m), 1.51 (3H, d, J = 6.8 Hz ), 1.97-2.05 (2H, m), 2.63-2.75 (2H, m), 3.63-3.80 (2H, m), 3.88 (2H, d, J = 7.0 Hz), 4.51-4.58 (1H, m), 5.54 (1H, brs), 6.86-7.09 (3H, m), 7.32 (1H, d, J = 5.4 Hz)

Example 32 to Example 45
The following compounds were synthesized from the compounds obtained in Reference Examples 62 to 75 according to the method of Example 31. The results are shown in the table below.

Example 32
(R, E) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 ( 2H) -yl) pent-3-ene-1-sulfonamide Example 33
(R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -Yl) pentane-1-sulfonamide Example 34
(E) -N- (3- (cyclopropylmethoxy) benzyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) pent-3-ene- 1-sulfonamide Example 35
N- (3- (cyclopropylmethoxy) benzyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) pentane-1-sulfonamide Example 36
(R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) propane- 1-sulfonamide Example 37
(R, E) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) Pent-3-ene-1-sulfonamide Example 38
(R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) pentane- 1-sulfonamide Example 39
(R) -N- (1- (3- (cyclopropylmethoxy) phenyl) ethyl) -3- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) propane -1-sulfonamide Example 40
(R, E) -N- (1- (3- (cyclopropylmethoxy) phenyl) ethyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl Pent-3-ene-1-sulfonamide Example 41
(R) -N- (1- (3- (cyclopropylmethoxy) phenyl) ethyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) pentane -1-sulfonamide Example 42
(R) -N- (1- (3- (cyclopropylmethoxy) phenyl) propyl) -3- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) propane -1-sulfonamide Example 43
(R) -N- (1- (3- (2,2-difluoroethoxy) phenyl) ethyl) -3- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H)- Yl) propane-1-sulfonamide Example 44
(R, E) -N- (1- (3- (2,2-difluoroethoxy) phenyl) ethyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H ) -Yl) pent-3-ene-1-sulfonamide Example 45
(R) -N- (1- (3- (2,2-difluoroethoxy) phenyl) ethyl) -5- (5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H)- Yl) pentane-1-sulfonamide

Example 46
(R) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) -4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H ) -Yl) methyl) benzenesulfonamide

  ((R) -4- (bromomethyl) -N- (1- (3- (cyclopropylmethoxy) -4-fluorophenyl) ethyl) benzenesulfonamide (120 mg) obtained according to Reference Example 76 and commercially available 5 -Fluoro-2,4-bis (trimethylsilyloxy) pyrimidine (112 mg) was dissolved in DCE (1.5 mL), iodine (13 mg) was added at room temperature, and the mixture was refluxed with heating at 95 ° C. for 4 hours. After cooling, water (10 mL) and saturated aqueous sodium thiosulfate solution (1.0 mL) were added, and the mixture was extracted with 10% methanol / chloroform (10 mL x 3) The organic layer was washed with saturated brine (10 mL), The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (90% ethyl acetate / hexane) to give the title compound (44.2 mg, yield 33%) as a foam.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.32-0.36 (2H, m), 0.59-0.62 (2H, m), 1.14-1.38 (4H, m), 3.76 (2H, d, J = 7.0 Hz), 4.33 (1H, quin, J = 7.6 Hz), 4.86 (2H, s), 6.65 (1H, brs), 6.89-6.96 (2H, m), 7.38 (2H, d, J = 8.3 Hz) , 7.62 (2H, d, J = 8.3 Hz), 8.14-8.20 (2H, m), 11.88 (1H, brs)

Example 47 to Example 50
The following compounds were synthesized from the compounds obtained in Reference Examples 77 to 80 according to the method of Example 46. The results are shown in the table below.

Example 47
(R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl ) Benzenesulfonamide Example 48
(R) -N- (1- (3- (cyclopropylmethoxy) phenyl) ethyl) -4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) Methyl) benzenesulfonamide Example 49
(R) -N- (1- (3- (cyclopropylmethoxy) phenyl) propyl) -4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) Methyl) benzenesulfonamide Example 50
(R) -N- (1- (3- (2,2-difluoroethoxy) phenyl) ethyl) -4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -Il) methyl) benzenesulfonamide

Example 51 to Example 53
The following compounds were synthesized from the compounds obtained in Reference Examples 82 to 84 in accordance with the method of Example 1. The results are shown in the table below.

Example 51
3- (Cyclopropylmethoxy) -N- (5-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -2-methylpentan-2-yl ) Benzenesulfonamide Example 52
3- (2,2-difluoroethoxy) -N- (5-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -2-methylpentane- 2-yl) benzenesulfonamide Example 53
3- (cyclopentyloxy) -N- (5-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) -2-methylpentan-2-yl) Benzenesulfonamide

Example 54 to Example 56
The following compounds were synthesized from the compounds obtained in Reference Examples 85 to 87 according to the method of Example 46. The results are shown in the table below.

Example 54
3- (Cyclopropylmethoxy) -N- (2- (4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) phenyl) propane-2- Yl) benzenesulfonamide Example 55
3- (2,2-difluoroethoxy) -N- (2- (4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) phenyl) propane -2-yl) benzenesulfonamide Example 56
3- (Cyclopentyloxy) -N- (2- (4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) phenyl) propan-2-yl ) Benzenesulfonamide

Example 57 to Example 59
The following compounds were synthesized from the compounds obtained in Reference Examples 88 to 90 according to the method of Example 46. The results are shown in the table below.

Example 57
3- (cyclopropylmethoxy) -N- (2- (6-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) pyridin-3-yl) Propan-2-yl) benzenesulfonamide Example 58
3- (2,2-difluoroethoxy) -N- (2- (6-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) pyridine-3 -Yl) propan-2-yl) benzenesulfonamide Example 59
3- (Cyclopentyloxy) -N- (2- (6-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) pyridin-3-yl) propane -2-yl) benzenesulfonamide

Example 60
(S) -5-Fluoro-1- (4- (2- (hydroxydiphenylmethyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

  4- (5-Fluoro-2,4-dioxo-3,4-dihydropyrimidine-1 (2H)-obtained by the method described in the literature (Med. Chem. Res., 10, 390-403 (2001)) Yl) butanoic acid (25 mg) in dichloromethane (2.5 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC / HCl, 34 mg), 1-hydroxybenzo Triazole (hereinafter HOBt, 23 mg) and easily available (S) -diphenyl (pyrrolidin-2-yl) methanol (56 mg) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (90% ethyl acetate / hexane) to give the title compound (23 mg, yield 46%) as a foam.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.83-0.90 (1H, m), 1.55-1.70 (3H, m), 1.96-2.11 (2H, m), 2.44-2.48 (2H, m), 3.06 -3.12 (1H, m), 3.33-3.42 (1H, m), 4.32-4.44 (2H, m), 5.21-5.25 (1H, m), 6.73 (1H, brs), 7.26-7.33 (9H, m) , 7.40-7.43 (2H, m), 7.62 (1H, brs)

  The following compounds were synthesized according to the method of Example 60. The results are shown in the table below.

Example 61
(S) -1- (4- (2- (bis (4-fluorophenyl) (hydroxy) methyl) pyrrolidin-1-yl) -4-oxobutyl) -5-fluoropyrimidine-2,4 (1H, 3H) -Zeon

Comparative Example 1
1-((2-trityloxy) ethoxy) methyl) pyrimidine-2,4- (1H, 3H) -dione

  It was synthesized by the method described in International Publication WO2005-065689 (Patent Document 1).

Comparative Example 2
4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -N-hydroxy-2- (N-methyl-4-phenoxyphenylsulfonamido) butanamide

  It was synthesized by the method described in JP-A-2002-284686.

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).
1 μM dUTP (containing 588 Bq / mL [5- ³ H] dUTP) 0.02 mL, 0.2 M Tris buffer (pH 7.4) 0.05 mL, 16 mM magnesium chloride 0.05 mL, 20 mM 2-mercaptoethanol 0.02 mL, 0.02 mL of 1% fetal bovine serum-derived albumin aqueous solution, 0.02 mL of purified compound solution or 0.02 mL of purified water expressed using E. coli as a control, and 0.02 mL of purified human dUTPase solution at 37 ° C The reaction was allowed for 15 minutes. Immediately after the reaction, the reaction was stopped by heating at 100 ° C. for 1 minute, followed by centrifugation at 15000 rpm for 2 minutes. After centrifugation, a part (150 μL) of the obtained supernatant was analyzed with a high performance liquid chromatograph (Shimadzu, Prominence) using an Atlantis dC18 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 at a flow rate of 0.8 mL / min Elution was performed with a 30-minute concentration gradient from a 4: 6 mixture of mM tetrabutylammonium and 30% methanol to mobile phase B. [5- ³ H] dUMP (RT 10.2 min) radioactivity was measured.
The inhibitory activity of the test compound was determined by the following formula, 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 30 as IC ₅₀ (μM).

  The table below shows human dUTPase inhibitory activity data.

Claims (6)

Formula (I)

(In general formula (I), n represents a number of 1 to 3,
X is a bond, an oxygen atom, a sulfur atom, an alkenylene group having 2 to 6 carbon atoms, a divalent aromatic hydrocarbon group which may have a substituent, or a divalent which may have a substituent. A saturated or unsaturated heterocyclic group of
Y represents a bond or a linear or branched alkylene group having 1 to 8 carbon atoms;
Z represents —SO ₂ NR ¹ R ² , —NR ³ SO ₂ —R ⁴ , or the following formula:

R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an aralkyl group which may have a substituent, or together with an adjacent nitrogen atom. , A group forming a saturated heterocyclic group which may have a substituent,
R ³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
R ⁴ represents an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group which may have a substituent,
R ⁵ represents a methyl group which may have a substituent. )
The 5-fluorouracil compound or its salt represented by these.   2. X represents a bond, an oxygen atom, a sulfur atom, a vinylene group, a phenylene group or a pyridinediyl group, and Y represents a bond or a linear or branched alkylene group having 1 to 8 carbon atoms. 5-fluorouracil compound or a salt thereof. Z represents —SO ₂ NR ¹ R ² , R ¹ is a hydrogen atom, and R ² may have a substituent (when the methylene group of the benzyl group has a substituent, As a substituent, the alkyl group having 1 to 6 carbon atoms may be the same or different and may have 1 or 2 (when the two substituents are alkyl groups having 1 to 6 carbon atoms, The carbon atoms of the alkyl group may form a cycloalkylidene structure.) When the phenyl group of the benzyl group has a substituent, the substituent has a halogen atom or a substituent. A linear or branched alkoxy group having 1 to 6 carbon atoms, a cycloalkoxy group having 3 to 7 carbon atoms, a cycloalkyl-alkoxy group having 3 to 7 carbon atoms, or a saturated heterocyclic oxy group. 1 or 2 may be present). 5-fluorouracil or a salt thereof, wherein. n represents 1 or 3, X represents an oxygen atom or vinylene group, Y represents a bond, an ethylene group, or a trimethylene group (provided that when X represents a bond, (CH ₂ ) _n —X—Y A methylene group or a pentamethylene group), Z is —SO ₂ NR ¹ R ² , R ¹ is a hydrogen atom, and R ² may have a substituent (the benzyl group). When the methylene group of the group has a substituent, the substituent may have 1 to 2 alkyl groups having 1 to 6 carbon atoms, which are the same or different (the two substituents are In the case of an alkyl group having 1 to 6 carbon atoms, carbon atoms of the alkyl group may form a cycloalkylidene structure.) When the phenyl group of the benzyl group has a substituent, the substitution As a group, a halogen atom, a straight chain which may have a substituent Or a branched alkoxy group having 1 to 6 carbon atoms, a cycloalkoxy group having 3 to 7 carbon atoms, a cycloalkyl-alkoxy group having 3 to 7 carbon atoms and a saturated heterocyclic oxy group. The 5-fluorouracil compound or a salt thereof according to any one of claims 1 to 3, which may be present.   The pharmaceutical composition containing the 5-fluorouracil compound or its salt of any one of Claims 1-4.   The human dUTPase inhibitor containing the 5-fluorouracil compound or its salt of any one of Claims 1-4.