JP2011195452A - New uracil compound having amide structure or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an uracil compound having an excellent deoxyuridine triphosphatase (dUTPase)-inhibiting activity and useful as an antitumor medicine and the like, or a salt thereof.SOLUTION: There is provided the uracil compound represented by formula (I) (wherein, X is a 1C to 6C alkylene or a 2C to 6C alkenylene; the methylene of the alkylene chain adjacent to an amide structure may be substituted with an unsaturated heterocyclic group; Rand Rare each identically or differently H, a 1C to 6C alkyl or an aralkyl which may have one or more substituents, or exhibit a nitrogen-containing saturated heterocyclic group which may have one or more substituents, together with the adjacent nitrogen atom), or a salt thereof.

Description

  The present invention relates to a novel uracil compound or a salt thereof having excellent human deoxyuridine triphosphatase inhibitory activity and useful as a therapeutic agent for diseases related to deoxyuridine triphosphatase, such as an antitumor agent.

  Deoxyuridine triphosphatase (hereinafter also referred to as dUTPase (EC3.6.1.23)) is a preventive DNA repair enzyme. It is an enzyme that specifically recognizes only deoxyuridine triphosphate (hereinafter referred to as dUTP) among natural nucleic acid triphosphates and decomposes it into deoxyuridine monophosphate (hereinafter referred to as dUMP) and pyrophosphate (Non-patent Document 1) (1) reduce the amount of dUTP pool in the cell to avoid accidental incorporation of uracil into DNA instead of thymine, (2) important de novo for supplying thymine in DNA It is thought to be responsible for two reactions: supplying the substrate dUMP of thymidylate synthase responsible for the pathway (Non-patent Document 2).

  dUTPase is known to be essential for cell survival in both prokaryotes and eukaryotes. Therefore, this enzyme is an antitumor drug (Non-Patent Documents 3 and 4), an antimalarial drug (Patent Documents 1 and 5), an antituberculosis drug (Non-Patent Document 6), and an anti-pylori drug (Patent Document 2). , Anti-parasitic drugs such as trypanosoma and leishmania (non-patent document 7), and herpesviruses such as human herpes simplex virus, cytomegalovirus, Epstein-Barr virus (non-patent document 8) and vaccinia virus (non-patent document 9) It has been suggested that it can be a target for antiviral drugs such as

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 10 and the like), 5′-O-substituted phenyl-deoxyuridine compounds (Non-Patent Document 11) are known. Yes. However, none of these compounds have sufficient inhibitory activity against human dUTPase and are not compounds used as pharmaceuticals.
Therefore, development of a dUTPase inhibitor having a superior human dUTPase inhibitory activity and useful as a therapeutic agent for a disease related to dUTPase, such as an antitumor agent, is strongly desired.
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) Cancer Reseach, 60, 3493-3503, July 1 (2000) 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)

  An object of the present invention is to provide a uracil compound having an amide structure or a salt thereof, which has excellent dUTPase inhibitory activity and is useful as an antitumor agent or the like.

  As a result of intensive studies to solve the above problems, the present inventors have found that a uracil compound having an amide structure at the N-1 position of the uracil ring or a salt thereof has an excellent dUTPase inhibitory activity, an antitumor agent, etc. It was found useful as a pharmaceutical product of the present invention, and the present invention was completed.

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

[In General Formula (I), X represents an alkylene group having 1 to 6 carbon atoms or an alkenylene group having 2 to 6 carbon atoms, and the methylene group in the alkylene chain adjacent to the amide structure is an unsaturated heterocyclic group. May be substituted;
R ¹ and R ² are the same or different and are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group which may have a substituent (however, an aromatic hydrocarbon group constituting the aralkyl group). the two substituents bonded to the α-position carbon atom are simultaneously an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group, or a saturated or unsaturated heterocyclic group). Or it shows the nitrogen-containing saturated heterocyclic ring which may have a substituent together with the adjacent nitrogen atom. ]
The uracil compound represented by these, or its salt is provided.

The present invention also provides a pharmaceutical composition containing a uracil compound represented by the formula (I) or a salt thereof.
Moreover, this invention provides the human dUTPase inhibitor containing the uracil compound or its salt represented by a formula (I).

  The novel uracil compound or a salt thereof of the present invention has excellent human dUTPase inhibitory activity and is useful as a disease associated with dUTPase, such as an antitumor agent.

The novel uracil compound of the present invention is represented by the above general formula (I), and has a feature that the uracil ring N-1 position substituent has an amide structure.
International Publication No. 2005065689 (Patent Document 1) discloses that a uracil ring N-1 substituent has an amide structure, and the terminal of the uracil ring N-1 position is a trityl group, a triphenylsilyl group, or the like. A uracil compound having a substituent (-E (R ⁶ ) (R ⁷ ) (R ⁸ ) group) is disclosed, and has been described as exhibiting dUTPase inhibitory activity and useful as an antimalarial drug. However, as shown in Test Examples described later, a compound having a trityl group as the terminal of the uracil ring N-1 position substituent hardly showed human dUTPase inhibitory activity.

  In the present specification, examples of the “substituent” include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, a halogenoalkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, an aralkyl group, an alkenyl group, and an alkynyl group. , Alkoxy group, halogenoalkoxy group, cycloalkoxy group, cycloalkyl-alkoxy group, aralkyloxy group, alkylthio group, cycloalkyl-alkylthio group, amino group, mono- or dialkylamino group, cycloalkyl-alkylamino group, acyl group, An acyloxy group, an oxo group, a saturated or unsaturated heterocyclic group, an aromatic hydrocarbon group, a saturated heterocyclic oxy group, and the like. When the substituent is present, the number is typically 1 to 3 is there.

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 alkynyl group is a hydrocarbon group containing a carbon-carbon triple bond, preferably having 2 to 6 carbon atoms, and examples thereof include an ethynyl group and a propargyl group.

  In the above substituent, the alkoxy group and the halogenoalkoxy group preferably represent a linear or branched alkoxy group having 1 to 6 carbon atoms, or a group obtained by substituting the halogen atom for these alkoxy groups. , Methoxy group, ethoxy group, n-propoxy group, isopropoxy group, 1-methylpropoxy group, n-butoxy group, isobutoxy group, 2-methyl-butoxy group, neopentyloxy group, pentan-2-yloxy group, fluoro Methoxy group, difluoromethoxy group, trifluoromethoxy group, 1,1-difluoroethoxy group, 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2-tetrafluoroethoxy Group, perfluoroethoxy group, 3-fluoro-2- (fluoromethyl) -propoxy group, 1,3 Difluoro-2-yloxy group, 2,2,3,3,3-pentafluoro-1-propoxy 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, etc. are 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 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, pyridazinyl group, indolyl group, isoindolyl group, indazolyl group, methylenedioxy Phenyl group, ethyl Nji oxyphenyl 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 is a monocyclic saturated heterocyclic group having one or two oxygen atoms, nitrogen atoms or sulfur atoms, for example, pyrrolidinyl group, piperidinyl group, An oxy group having a piperazinyl group, a hexamethyleneimino group, a morpholino group, a thiomorpholino group, a homopiperidinyl group or the like, and includes a tetrahydrofuryloxy group and a tetrahydropyryloxy group.

  In the general formula (I), the “C1-C6 alkylene group” represented by X is preferably a linear or branched alkylene group having 1 to 6 carbon atoms, such as a methylene group, an ethylene group, Examples include trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, propylene group, butylene group, dimethyltrimethylene group, dimethyltetramethylene group, and ethyltrimethylene group.

  In the general formula (I), the “unsaturated heterocyclic group” in which the methylene group in the alkylene chain adjacent to the amide structure represented by X may be substituted is the same as the above “substituent”. An unsaturated heterocyclic group is exemplified, and a monocyclic unsaturated heterocyclic group having one or two oxygen atoms, nitrogen atoms, and sulfur atoms is preferable, and in terms of human dUTPase inhibitory action, A furyl group and a thiazolyl group are more preferable.

  That is, when X is an “alkylene group having 1 to 6 carbon atoms”, X is a methylene group in the alkylene chain adjacent to the trimethylene group, tetramethylene group, or amide structure in terms of human dUTPase inhibitory action. An alkylene group having 2 to 4 carbon atoms which may be substituted with a furyl group or a thiazolyl group is preferable, and a trimethylene group, a tetramethylene group, or the following formula (II)

Or the following formula (III)

Is more preferable.

  Examples of the “C2-C6 alkenylene group” represented by X include vinylene group, propenylene group, butadienylene group and the like, and propenylene group is preferable.

  The “methylene group having 1 to 6 carbon atoms or alkenylene group having 2 to 6 carbon atoms” represented by X is particularly preferably a trimethylene group from the viewpoint of human dUTPase inhibitory action.

The “C 1-6 alkyl group” represented by R ¹ and R ² is preferably a linear or branched alkyl group having 1-6 carbon atoms, such as a methyl group, an ethyl group, and n-propyl. Group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like. Among these, a C1-C3 alkyl group is preferable and a methyl group and an isopropyl group are more preferable.

The “aralkyl group” of the “aralkyl group optionally having substituents” represented by R ¹ and R ² is 1 to 6 carbon atoms substituted with an aromatic hydrocarbon group having 6 to 14 carbon atoms. These linear or branched alkyl groups are preferred, and specific examples include benzyl group, phenylethyl group, phenylpropyl group, naphthylmethyl group, naphthylethyl group, and the like, and phenylethyl group is preferred.

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 (however, the aromatic carbon atom constituting the aralkyl group). Except when the two substituents bonded to the α-position carbon atom of the hydrogen group are simultaneously an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group, or a saturated or unsaturated heterocyclic group. ” R ¹ is particularly preferably a hydrogen atom; an alkyl group having 1 to 3 carbon atoms such as a methyl group or an isopropyl group from the viewpoint of human dUTPase inhibitory action. R ² represents the following formula (IV) from the viewpoint of human dUTPase inhibitory action.

[In Formula (IV), R ³ and R ⁴ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
R ⁵ and R ⁶ are the same or different and represent a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, or an optionally substituted aromatic hydrocarbon group (provided that R ⁵ and R 6 ⁶ is simultaneously an alkyl group having 1 to 6 carbon atoms or an aromatic hydrocarbon group which may have a substituent.), Or together with the adjacent carbon atom, cycloalkylidene Showing the structure,
Y ¹ and Y ² are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted alkoxy group having 1 to 6 carbon atoms. ]
A substituted phenylethyl group represented by

In formula (IV), examples of the “alkyl group having 1 to 6 carbon atoms” represented by R ³ and R ⁴ include the same alkyl groups as the above “substituent”, and a methyl group is preferable.
That is, R ³ and R ⁴ are particularly preferably a hydrogen atom and a methyl group from the viewpoint of human dUTPase inhibitory action.

Examples of the “alkyl group having 1 to 6 carbon atoms” represented by R ⁵ and R ⁶ include the same alkyl group as the above “substituent”, and an ethyl group is preferable.
The “aromatic hydrocarbon group” of the “optionally substituted aromatic hydrocarbon group” represented by R ⁵ and R ⁶ is the same aromatic hydrocarbon group as the above “substituent”. And a phenyl group is preferable.
Examples of the “substituent” of the “aromatic hydrocarbon group which may have a substituent” represented by R ⁵ and R ⁶ include the same substituents as described above. And a cycloalkyl-alkoxy group such as a cyclopropyl-methoxy group is preferred.

That is, R ⁵ and R ⁶ are the same or different and represent a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, or an aromatic hydrocarbon group which may have a substituent (provided that R ⁵ and R ⁶ is an alkyl group having 1 to 6 carbon atoms, or have a substituent unless also an aromatic hydrocarbon group.) when simultaneously as the R ⁵ and R ^6, human dUTPase From the viewpoint of inhibitory action, a hydroxyl group, an ethyl group, a methoxyphenyl group, a cyclopropylmethoxyphenyl group, and a phenyl group are particularly preferable.

The “cycloalkylidene structure” which may be formed by R ⁵ and R ⁶ is preferably a cycloalkylidene structure having 3 to 6 carbon atoms, specifically, cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexyl. Silidene is mentioned, and cyclopropylidene and cyclopentylidene are preferred in terms of human dUTPase inhibitory action.

Examples of the “halogen atom” represented by Y ¹ and Y ² include the same halogen atoms as the above-mentioned “substituent”, preferably a chlorine atom and a fluorine atom, and particularly preferably a fluorine atom.
The “alkoxy group having 1 to 6 carbon atoms” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by Y ¹ and Y ² is the same as the above “substituent”. An alkoxy group is mentioned, A methoxy group is preferable.
Examples of the “substituent” of the “optionally substituted alkoxy group having 1 to 6 carbon atoms” represented by Y ¹ and Y ² include the same substituents as the above “substituent”. A cycloalkyl group having 3 to 7 carbon atoms is preferred, and a cyclopropyl group is more preferred.

In the general formula (I), the “nitrogen-containing saturated heterocycle” of the “nitrogen-containing saturated heterocycle which may have a substituent” includes an oxygen atom, a nitrogen atom, a sulfur atom in addition to the adjacent nitrogen atom 5-7 membered monocyclic saturated heterocyclic ring which may have one or two of any of the above, for example, pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thio Examples thereof include a morpholino group and a homopiperidinyl group, and a pyrrolidinyl group is preferable.
That is, in the general formula (I), the “nitrogen-containing saturated heterocyclic ring which may have a substituent” is preferably a pyrrolidinyl group which may have a substituent. Of these, the following formula (IV)

[In the formula (V), R ⁷ , R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a hydroxyl group, a halogen atom, an aromatic hydrocarbon group or a substituent which may have a substituent. The unsaturated heterocyclic group which may have is shown. ]
The pyrrolidinyl group represented by these is preferable.

Examples of the “halogen atom” represented by R ⁷ , R ⁸ and R ⁹ include the same halogen atom as the above “substituent”, and a fluorine atom is preferred from the viewpoint of human dUTPase inhibitory action.
The “aromatic heterocyclic group” of the “optionally substituted aromatic hydrocarbon group” represented by R ⁷ , R ⁸ and R ⁹ is the same aromatic heterocycle as the above “substituent”. Examples thereof include a cyclic group, and a phenyl group is preferred from the viewpoint of human dUTPase inhibitory action.
Examples of the “substituent” of the “optionally substituted aromatic hydrocarbon group” represented by R ⁷ , R ⁸ and R ⁹ include the same substituents as the above “substituent”. A halogen atom and an alkoxy group having 1 to 6 carbon atoms are preferable, and a chlorine atom, a fluorine atom, and a methoxy group are more preferable from the viewpoint of human dUTPase inhibitory action.
The “unsaturated heterocyclic group” of the “unsaturated heterocyclic group optionally having substituent (s)” represented by R ⁷ , R ⁸ and R ⁹ is the same as the above-mentioned “unsaturated heterocyclic group”. Examples thereof include a cyclic group, and a thienyl group is preferable from the viewpoint of human dUTPase inhibitory action.
Examples of the “substituent” of the “unsaturated heterocyclic group optionally having substituent (s)” represented by R ⁷ , R ⁸ and R ⁹ include the same substituents as the above “substituent”. A C1-C6 alkyl group is preferable and a methyl group is more preferable at the point of human dUTPase inhibitory action.

The uracil N-1 position compound of the present invention can be produced according to the following reaction process formula.
[Process A]

[Wherein, X ¹ is an alkylene group having 1 to 6 carbon atoms or an alkenylene group having 2 to 6 carbon atoms, A is an unsaturated heterocyclic group, Rb is a protecting group for a carboxyl group, Hal is a halogen atom, and TMS is a trimethylsilyl group. Indicates. ]
The compound represented by the general formula (3) is described, for example, in the method described in J. Med. Chem., 8, 187-189 (1965), in the Russian Journal of Bioorganic Chemistry, 26, 662-668 (2005). However, it can also be produced by the following production method [A-1] [A-2].

[A-1]
In this step, a compound represented by the general formula (1) that can be easily obtained, for example, ethyl-4-bromocrotonate and obtained by the method described in Nucleosides & Nucleotides, 4, 565-585 (1985) 2 By reacting 1,4-bis (trimethylsilyloxy) pyrimidine in the presence of iodine, a compound represented by the general formula (2) can be produced.

  In Step A-1, the reaction solvent is not particularly limited as long as it does not affect the reaction, but acetone, tetrahydrofuran (hereinafter also referred to as THF), dialkyl ether (hereinafter, alkyl is ethyl, propyl). ), Dioxane, dichloromethane, 1,2-dichloroethane, acetonitrile, propionitrile, toluene and the like, preferably 1,2-dichloroethane. The number of equivalents of 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.

[A-2]
In this step, the compound represented by the general formula (3) can be produced by hydrolyzing the ester compound represented by the general formula (2) by a generally known method.
[A-3]
In this step, the compound represented by the general formula (5) is obtained by reacting 2,4-bis (trimethylsilyloxy) pyrimidine with a compound represented by the general formula (4) that is readily available in the presence of a catalyst. Can be manufactured.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but dichloromethane, chloroform, carbon tetrachloride, dichloroethane, toluene, xylene and the like are exemplified, and dichloroethane is preferable. The number of equivalents of 2,4-bis (trimethylsilyloxy) pyrimidine is 0.8 to 10 equivalents, preferably 1.0 to 5.0 equivalents. The catalyst is preferably iodine, and the equivalent number is 0.001 to 0.8 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.
[A-4]
In this step, the compound represented by the general formula (6) can be produced by hydrolyzing the ester compound represented by the general formula (5) by a generally known method.
[Process B]

[Wherein R ³ , R ⁴ and Rb are as defined above, Ar ¹ and Ar ² represent an aromatic hydrocarbon group or an unsaturated heterocyclic group which may have a substituent, and Ra represents an amino group Indicates a protecting group. ]

[B-1]
In this step, a compound represented by the general formula (8) is reacted with a readily available compound represented by the general formula (7) by reacting the corresponding Grignard reagent (where Ar ¹ and Ar ² are The same).

  In Step B-1, the reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, dialkyl ether, toluene, dichloromethane, and the like, and preferably THF. The number of equivalents of Grignard reagent is 2.0 to 10 equivalents, preferably 4.0 to 5.0 equivalents. The reaction temperature is -90 to 200 ° C, preferably 0 to 90 ° C. The reaction time is 0.5 to 48 hours, preferably 2.0 to 5.0 hours.

[B-2]
In this step, the compound represented by the general formula (9) can be produced by deprotecting the protecting group of the amine compound represented by the general formula (8) by a generally known method.

[B-3]
In this step, for example, a known compound represented by the general formula (10) obtained according to the method described in the literature (J. Org. Chem., 70, 1188-1197 (2005)) After treating with reaction conditions to obtain an aldehyde compound, by reacting with a Grignard reagent represented by Ar ¹ MgHal (Hal represents a halogen atom) in the same manner as in Step B-1, general formula (11) Can be produced.

  Examples of the oxidation reaction include Swern oxidation using dimethyl sulfoxide (hereinafter also referred to as DMSO) and oxalyl chloride, oxidation using DMSO and carbodiimide, Dess-Martin oxidation using Dess-Martin periodinane, etc., preferably DMSO. And oxidation using carbodiimides. Examples of carbodiimides to be used include dicyclohexylcarbodiimide (hereinafter also referred to as DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (hereinafter also referred to as EDC / HCl), and preferably EDC / HCl. It is. The number of equivalents is 1.0 to 10 equivalents, preferably 1.1 to 5.0 equivalents. The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, dialkyl ether, toluene, dichloromethane, acetonitrile, and the like, preferably toluene. The reaction temperature is -78 to 200 ° C, preferably 10 to 30 ° C. The reaction time is 0.1 to 48 hours, preferably 0.5 to 1.5 hours.

[B-4]
In this step, the compound represented by the general formula (11) is converted into a ketone compound by the same method as B-3, and then Ar ² MgHal (Hal represents a halogen atom) by the same method as B-1. The compound represented by the general formula (9) can be produced by reacting with the Grignard reagent represented by the formula (2) and further deprotecting by a generally known method in the same manner as B-2.

[B-5]
In this step, the compound represented by the general formula (12) can be produced by reacting the compound represented by the general formula (9) with triphosgene in the presence of a base.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include dimethoxyethane, diethylene glycol dimethyl ether, diisopropyl ether, diethyl ether, THF, dioxane, ethyl acetate, butyl acetate and the like. is there. 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 triethylamine is preferred. The number of equivalents of triphosgene is 0.8 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents. The reaction temperature is 0 ° 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.

[B-6]
In this step, the compound represented by the general formula (13) can be produced by reacting the compound represented by the general formula (12) with 50-80% hydrogen fluoride / pyridine.
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, toluene, xylene, and the like, preferably dichloromethane. The number of equivalents of 50-80% hydrofluoric acid / pyridine is 0.8 to 100 equivalents, preferably 1.0 to 50 equivalents. The reaction temperature is -20 ° C to 100 ° C, preferably 0 to 50 ° C. The reaction time is 0.5 to 48 hours, preferably 1.0 to 24 hours.

[Process C]

[Wherein R ¹ , R ³ , R ⁴ , Ar ¹ , Rb are as defined above, Rc represents a protecting group for a hydroxyl group, and Ms represents a methanesulfonyl group. ]

[C-1]
In this step, the hydroxyl group of the readily available compound (14) is protected by a generally known method, and then reacted with a Grignard reagent in the same manner as in B-1, thereby expressing the compound represented by the general formula (15). Can be produced.

[C-2]
In this step, after deprotecting Rc of the compound represented by the general formula (15) by a generally known method, the compound represented by the general formula (16) is reacted with methanesulfonyl chloride in the presence of a base. Can be manufactured.

[C-3]
In this step, the compound represented by the general formula (17) can be produced by reacting the compound represented by the general formula (16) with an amine compound (R ¹ NH ₂ ) such as methylamine.

  The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, dialkyl ether, toluene, dichloromethane, etc., preferably THF. The number of equivalents of methylamine is 0.1 to 10,000 equivalents, preferably 1.0 to 1000 equivalents. The reaction temperature is -90 to 200 ° C, preferably 30 to 90 ° C. The reaction time is 0.5 to 48 hours, preferably 1.0 to 10 hours.

[Process D]

[Wherein R ¹ , R ⁵ , R ⁶ and Ar ¹ are as defined above. ]

[D-1]
In this step, the compound represented by the general formula (19) can be produced by condensing the amine compound (R ¹ NH ₂ ) with a readily available compound (18) under basic conditions.

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 DMF. 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 number of equivalents of the amine compound (R ¹ NH ₂ ) is 0.8 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents. Examples of the base to be used include organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and preferably triethylamine. The number of equivalents is 0.8 to 10 equivalents, preferably 1.0 to 4.0 equivalents. 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.

[D-2]
In this step, the compound represented by the general formula (20) can be produced by reacting the compound represented by the general formula (19) 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 THF, dioxane, dialkyl ether, toluene, dichloromethane, etc., preferably THF. Examples of the reducing agent to be used include diisobutylaluminum hydride, lithium aluminum hydride and the like, preferably lithium aluminum hydride. The number of equivalents is 0.1 to 10 equivalents, preferably 1.0 to 4.0 equivalents. The reaction temperature is -90 to 200 ° C, preferably 0 to 90 ° C. The reaction time is 0.5 to 48 hours, preferably 2.0 to 10 hours.

[Process E]

[Wherein Y ¹ , Y ² and R ⁵ are as defined above. ]

[E-1]
In this step, the compound represented by the general formula (21) is condensed with N, O-dimethylhydroxylamine hydrochloride in the presence of a base in the same manner as in D-1, thereby being represented by the general formula (22). Can be produced.

[E-2]
In this step, the compound represented by the general formula (23) is reacted with the Grignard reagent represented by R ⁵ MgHal in the same manner as in B-2 to thereby convert the compound represented by the general formula (23). Can be synthesized.

[E-3]
In this step, the compound represented by the general formula (24) can be produced by reacting the compound represented by the general formula (23) with methyltriphenylphosphonium bromide under basic conditions.

  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 THF. Examples of the base used include bis (trimethylsilyl) amide sodium salt (hereinafter referred to as NaHMDS), metal hydride salts such as n-butyllithium, sec-butyllithium, sodium hydride, potassium hydride, etc., preferably NaHMDS. . The number of equivalents is 0.8 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents. The number of equivalents of methyltriphenylphosphonium bromide is 0.9 to 5.0 equivalents, preferably 1.0 to 1.5 equivalents. The reaction temperature is −100 to 100 ° C., preferably −78 to 40 ° C. The reaction time is 0.5 to 24 hours, preferably 1.0 to 5.0 hours.

[E-4]
In this step, the compound represented by the general formula (25) can be produced by reacting the compound represented by the general formula (24) with AD-mix or osmium tetroxide.
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, water, alkyl alcohol, etc., preferably tert-butanol / water (1 / 1) It is a solution. The reaction temperature is 0-100 ° C, preferably 0-10 ° C. The reaction time is 0.5 to 24 hours, preferably 1.0 to 5.0 hours.

[E-5]
In this step, after the compound represented by the general formula (25) is methanesulfonylated by a generally known method, the compound represented by the general formula (26) is reacted with a generally known azido reagent. Can be manufactured.

  The reaction solvent used for the azidation is not particularly limited as long as it does not affect the reaction, and examples thereof include DMF, THF, dioxane, acetonitrile, toluene, dichloromethane and the like, preferably DMF. Examples of the azidation reagent to be used include sodium azide and lithium azide, and sodium azide is preferred. The number of equivalents is 1.0 to 10 equivalents, preferably 1.2 to 6.0 equivalents. The reaction temperature is 10 to 120 ° C, preferably 50 to 100 ° C. The reaction time is 1.0 to 24 hours, preferably 1.5 to 12 hours.

[E-6]
In this step, a compound represented by the general formula (27) can be produced by performing a reduction reaction of the compound represented by the general formula (26) using a metal catalyst in a hydrogen atmosphere.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, methanol, ethanol, ethyl acetate, and the like, preferably ethyl acetate. Examples of the metal catalyst to be used include various palladium catalysts and rhodium catalysts, and palladium-carbon is preferable. The reaction temperature is 0-100 ° C, preferably 10-30 ° C. The reaction time is 0.1 to 10 hours, preferably 0.5 to 1.0 hours.

[E-7]
In this step, the compound represented by the general formula (28) can be produced by reacting the compound represented by the general formula (27) with an alkyl chloroformate under basic conditions.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include THF, dioxane, dialkyl ether, toluene, dichloromethane, acetonitrile and the like, and acetonitrile is preferable. Examples of the base to be used include organic amines such as triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and preferably triethylamine. The number of equivalents is 1.0 to 10 equivalents, preferably 1.1 to 2.0 equivalents. The number of equivalents of methyl chloroformate is 0.8 to 10 equivalents, preferably 0.9 to 1.3 equivalents. The reaction temperature is -90 to 200 ° C, preferably 10 to 30 ° C. The reaction time is 0.5 to 48 hours, preferably 1.0 to 5.0 hours.

[E-8]
In this step, the compound represented by the general formula (29) can be produced by reacting the compound represented by the general formula (28) 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 THF, dioxane, dialkyl ether, toluene, dichloromethane, etc., preferably THF. Examples of the reducing agent to be used include diisobutylaluminum hydride, lithium aluminum hydride and the like, preferably lithium aluminum hydride. The number of equivalents is 0.1 to 10 equivalents, preferably 1.0 to 4.0 equivalents. The reaction temperature is -90 to 200 ° C, preferably 0 to 90 ° C. The reaction time is 0.5 to 48 hours, preferably 2.0 to 10 hours.

[Process F]

[Wherein R ¹ , R ² , A, X ¹ , X are as defined above. ]

[F-1]
In this step, the compound represented by the general formula (3) or the general formula (6) is converted into an amine compound (general formula (9), (13), (17), (20), (29) Or a readily available amine compound) is subjected to a condensation reaction in the same manner as in D-1, to produce a compound represented by general formula (I).

  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 below-mentioned Examples, the uracil compound or a salt thereof of the present invention has an excellent human dUTPase inhibitory activity, and thus is useful as a pharmaceutical represented by an antitumor drug or the like.

  When the uracil compound of the present invention or a salt thereof is contained in a pharmaceutical composition, it can be combined with a pharmaceutical carrier as necessary, and various administration forms can be employed depending on the purpose of prevention or treatment. For example, oral agents, injections, suppositories, ointments, patches and the like can be mentioned, and oral agents are preferred. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

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, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple Examples include myeloma, skin cancer, and brain tumor.

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

The raw material of the manufacturing method of the uracil compound shown in an Example can be manufactured by the following reference examples 1-8, for example.
Reference example 1
Synthesis of (E) -4- (2,4-dioxo-3,4-dihydromyrimidin-1 (2H) -yl) but-2-enoic acid

Easily available (E) -ethyl 4-bromobut-2-enoate (541 μL) is dissolved in 1,2-dichloroethane (DCE, 10 mL), and the literature (Nucleosides & Nucleotides, 4, 565-585 ( 1985)) 2,4-bis (trimethylsilyloxy) pyrimidine (1.0 g) and iodine (102 mg) obtained by the method described above were added and heated to reflux at 93 ° C. for 3 hours. The reaction mixture was allowed to cool, water (10 mL), saturated aqueous sodium thiosulfate solution (1.0 mL) were added, and the mixture was extracted with 10% methanol / chloroform (20 mL). 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 (2% methanol / chloroform). The obtained compound was dissolved in aqueous sodium hydroxide solution (2.0 M, 4.0 mL) and stirred at 50 ° C. for 3 hours. After allowing the reaction solution to cool, a strongly acidic cation exchange resin (Diaion PK212, H ⁺ form) was added until the pH reached 2.0, and then the resin was filtered off, and water (100 mL x 2), methanol (100 The filtrate was washed with mL x 2) and the combined filtrate was concentrated under reduced pressure. The residue was azeotroped with ethanol (20 mL x 3) to give the title compound (310 mg) as a white solid.

Reference example 2
Synthesis of 2-amino-1,1-bis (3-methoxyphenyl) -2-methylpropan-1-ol hydrochloride

  Methyl 2- (tert-butoxycarbonylamino) -2-methylpropanoate (500 mg) obtained by the method described in the literature (Bioorg. Med. Chem. Lett., 17, 2456-2458 (2007)) was converted to tetrahydrofuran. (THF, 10 mL), a THF solution of 3-methoxyphenylmagnesium bromide (1.0 M, 10 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the solution was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound was dissolved in hydrochloric acid-dioxane solution (4.0 M, 10 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene (20 mL x 3) to give the title compound (118 mg) as a white solid.

Reference example 3
Synthesis of (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -1- (methylamino) butan-2-ol

Easily available 4-fluoro-3-hydroxybenzoic acid (4.7 g) was dissolved in ethanol (80 mL), sulfuric acid (1.0 mL) was added, and the mixture was heated to reflux at 90 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was neutralized with sodium bicarbonate. Ethyl acetate (50 mL) was added for liquid separation, and the organic layer was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (hereinafter DMF, 30 mL), potassium carbonate (8.0 g), chloromethylcyclopropane (2.9 mL), sodium iodide (432 mg) were added, and 90 ° C was added. For 4 hours. Toluene (20 mL) and water (20 mL) are added to the reaction mixture, and the mixture is separated.The organic layer is washed with water (20 mL), aqueous sodium hydroxide (1.0 M, 20 mL), and saturated brine (20 mL). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (10 mL) and water (10 mL), aqueous sodium hydroxide solution (4.0 M, 22 mL) was added, and the mixture was stirred at 50 ° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, acidified with dilute hydrochloric acid (1.0 M, 100 ml), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in DMF (80 mL), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (hereinafter referred to as EDC · HCl, 8.0 g), 1-hydroxybenzotriazole (hereinafter referred to as HOBt, 5.0). g), N, O-dimethylhydroxylamine hydrochloride (3.3 g), and triethylamine (4.9 mL) were added, and the mixture was stirred at room temperature for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained compound was dissolved in THF (70 mL), and a THF solution of ethylmagnesium bromide (1.0 M, 60 mL) was added dropwise at 0 ° C., followed by stirring at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the mixture was separated. The organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane) to obtain a ketone body (4.98 g).
Methyltriphenylphosphonium bromide (10.8 g) was suspended in THF (80 mL), and a solution of bis (trimethylsilyl) amide sodium salt (hereinafter NaHMDS) in THF (1.0 M, 30 mL) was added at 0 ° C. Stir for minutes. The mixture was cooled to −78 ° C., the ketone body (4.98 g) obtained in the previous reaction was added, and the mixture was stirred at room temperature for 3 hours. Acetic acid (2.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was suspended in a 10% ethyl acetate / hexane solution, insolubles were filtered off, washed with a 10% ethyl acetate / hexane solution (50 ml), and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% ethyl acetate / hexane). The obtained compound was dissolved in tert-butanol (90 mL) and water (90 mL), AD-mixα (30 g) was added at 0 ° C., and the mixture was stirred at the same temperature for 3 hr. Saturated aqueous sodium hydrogen sulfite solution was added to the reaction mixture at 0 ° C. until insoluble matter disappeared, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (50 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (33% ethyl acetate / hexane). The obtained diol (5.27 g, 1.77 g) was dissolved in dichloromethane (30 mL), triethylamine (1.4 mL) and methanesulfonyl chloride (579 μL) were added, and the mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction solution, and the mixture was separated. The organic layer was washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (30 mL), sodium azide (2.2 g) was added, and the mixture was stirred at 80 ° C. for 12 hr. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane). The obtained compound was dissolved in methanol (20 mL), 10% palladium-carbon (2.0 g) was added, and the mixture was stirred at room temperature for 1 hr in a hydrogen atmosphere. The insoluble material was filtered off using celite, washed with methanol (30 ml), and the combined filtrate was concentrated under reduced pressure. The residue was dissolved in acetonitrile (20 mL), triethylamine (1.25 mL) and methyl chloroformate (348 μL) were added, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane).
A solution of lithium aluminum hydride (LAH) in THF (2.4 M, 3.37 mL) in THF (6.0 mL) was dissolved in THF (6.0 mL), and the carbamate obtained in the previous reaction (840 mg in 1.1 g) was cooled with ice. A THF (2.0 mL) solution was added dropwise, and the mixture was heated to reflux at 80 ° C. for 10 hours. A small amount of water was slowly added at room temperature, the resulting solid was filtered off, washed with THF (50 ml), and the combined filtrate was concentrated under reduced pressure to give the title compound (650 mg) as a colorless oil. .

Reference example 4
Synthesis of N-methyl-1- (1-phenylcyclopropyl) methanamine

  Easily available 1-phenylcyclopropanecarboxylic acid (2.95 g) is dissolved in DMF (120 mL) and EDC-HCl (5.2 g), HOBt (3.2 g), methylamine in methanol (40%, 1.94). mL) was added and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained amide compound (1.1 g out of 2.9 g) was dissolved in THF (60 mL), and a THF solution of LAH (2.4 M, 7.9 mL) was added dropwise at 0 ° C., and the mixture was heated to reflux at 80 ° C. for 12 hours. . Water (4.0 mL) was slowly added dropwise to the reaction solution at 0 ° C. The resulting precipitate was filtered off, washed with THF (60 mL), and the combined filtrate was concentrated under reduced pressure to give the title compound (1.0 g) as a colorless oil.

Reference Example 5
Synthesis of N-((1-phenylcyclopropyl) methyl) propan-2-amine

  The title compound (900 mg) was obtained as a colorless oil by synthesis from readily available 1-phenylcyclopropanecarboxylic acid (2.0 g) and isopropylamine (1.2 mL) according to the method of Reference Example 4. Obtained.

Reference Example 6
Synthesis of N-methyl-1- (1-phenylcyclopentyl) methanamine

  The title compound (800 mg) was obtained as a colorless oil by synthesizing from readily available 1-phenylcyclopentanecarboxylic acid (2.0 g) according to the method of Reference Example 4.

Reference Example 7
Synthesis of 2-amino-1- (3- (cyclopropylmethoxy) phenyl) -2-methyl-1-phenylpropan-1-ol hydrochloride

Tert-butyl 1-hydroxy-2-methylpropan-2-ylcarbamate (800 mg) obtained by the method described in the literature (J. Org. Chem., 70, 1188-1197 (2005)) was dissolved in toluene (7.7 mL). ), Dimethyl sulfoxide (11.5 mL), EDC · HCl (2.43 g), pyridine (0.31 mL) and trifluoroacetic acid (0.16 mL) were added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was azeotroped 3 times with toluene (10 mL) and dissolved in THF (10 mL). Phenylmagnesium bromide (1.0 M, 10.6 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane). Dissolve the compound obtained in toluene (5.1 mL) and dimethyl sulfoxide (7.6 mL), add EDC / HCl (1.63 g), pyridine (0.21 mL), trifluoroacetic acid (0.10 mL), and stir at room temperature for 30 minutes. did. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene (10 mL) three times.
Magnesium (166 mg) is suspended in THF (3.0 mL), iodine (2.0 mg) is added, and the readily available 3-bromophenol from literature (Eur. J. org. Chem., 4, 916-923 ( 2006)), a solution of 3-bromo-cyclopropylmethoxybenzene (773 mg) obtained in accordance with the method described in THF (3.0 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The supernatant was added dropwise to a THF (6.0 mL) solution of the ketone body obtained in the previous reaction under ice-cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane). The obtained compound was dissolved in a dioxane solution (4.0 M, 5.0 mL) of hydrogen chloride and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene (10 mL x 3) to give the title compound (50 mg) as a white solid.

Reference Example 8
Synthesis of (R) -2- (methylamino) -1,1-diphenylpropan-1-ol

  Easily available methyl D-lactate (1.0 g) was dissolved in DMF (30 mL), imidazole (980 mg) and tert-butyldimethylsilyl chloride (1.73 g) were added, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane). The obtained compound was dissolved in THF (30 mL), and a THF solution of phenylmagnesium bromide (1.0 M, 24.6 mL) was added dropwise under ice cooling, followed by stirring at room temperature for 2 hours. Aqueous ammonium chloride solution (30 mL) was added to the reaction solution and the phases were separated, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate / hexane). The obtained compound was dissolved in THF (10 mL), tetrabutylammonium fluoride THF solution (1.0 M, 20 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (30% hexane / ethyl acetate). The obtained diol (1.0 mg, 250 mg) was dissolved in dichloromethane (5.0 mL), triethylamine (228 μL) and methanesulfonyl chloride (102 μL) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the mixture was separated. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (4.0 mL), 40% aqueous methylamine solution (4.0 mL) was added, and the mixture was stirred at 60 ° C. for 4 hours in a glass sealed tube. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene (10 mL x 3) to give a crude product (200 mg) of the title compound as a colorless oil.

Reference Example 9
Synthesis of (R) -2-amino-1,1-bis (4-fluorophenyl) -3-methylbutan-1-ol

  Easily available L-valine ethyl ester hydrochloride (1.0 g) was added to a THF solution of 4-fluorophenylmagnesium bromide (1.0 M, 45 mL) at 0 ° C. and heated to reflux at 80 ° C. for 15 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture at 0 ° C., and the mixture 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 purified by amino silica gel column chromatography (30% ethyl acetate / hexane) to give the title compound (255 mg).

Reference Example 10
Synthesis of (R) -1-fluoro-1,1-bis (4-fluorophenyl) -3-methylbutan-2-amine

  (R) -2-amino-1,1-bis (4-fluorophenyl) -3-methylbutan-1-ol (366 mg) obtained in Reference Example 9 was dissolved in THF (6.0 mL), and triethylamine ( 388 μL) and a THF solution (4.0 mL) of triphosgene (436 mg) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (10% methanol / chloroform). The obtained compound was dissolved in dichloromethane (1.0 mL), added to hydrogen fluoride-pyridine (70%, 8.0 mL) at 0 ° C., and stirred at room temperature for 24 hours. Aqueous ammonia (2.0 M, 10 mL) was added to the reaction mixture at 0 ° C., and the mixture was extracted with dichloromethane (20 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 amino silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (295 mg).

Reference Example 11
Synthesis of 2-amino-2-methyl-1,1-di (thiophen-2-yl) propan-1-ol

  The title compound (75) was synthesized from readily available 2-aminoisobutyric acid methyl ester hydrochloride (500 mg) and 2-thienylmagnesium bromide (18 mL) according to the method of Reference Example 9. mg) was obtained as a white solid.

Reference Example 12
Synthesis of 5-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) furan-2-carboxylic acid

Easily available methyl 5- (chloromethyl) -1-furoate (1.2 g) is dissolved in DCE (5.0 mL) and obtained by the method described in the literature (Nucleosides & Nucleotides, 4, 565-585 (1985)). The obtained 2,4-bis (trimethylsilyloxy) pyrimidine (2.6 g), tetra-n-butylammonium iodide (500 mg) and iodine (300 mg) were added, and the mixture was heated to reflux at 95 ° C. for 15 hours. The reaction mixture was allowed to cool, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 5). 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 column chromatography (100% ethyl acetate). The obtained compound was dissolved in aqueous sodium hydroxide solution (1.0 M, 10 mL) and stirred at room temperature for 1 hour. After adding Diaion PK212 (H ⁺ form) to the reaction solution until the pH of the reaction solution reached 2.0, the resin was filtered off and washed with water (100 mL x 2) and methanol (100 mL x 2). The combined filtrate was concentrated under reduced pressure. The residue was azeotroped with ethanol (20 mL x 3) to obtain the title compound (560 mg).

Reference Example 13
Synthesis of 4-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) thiazole-2-carboxylic acid

  Reference was made from 4- (chloromethyl) thiazole-2-carboxylic acid ethyl ester (1.14 g) obtained according to the method described in the literature (J. Am. Chem. Soc. 123, 5249-5259. (2001)). The title compound (530 mg) was obtained by synthesis according to the method of Example 12.

Example 1
Synthesis of (S) -1- (4- (2- (hydroxydiphenylmethyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) butano obtained by the method described in the literature (J. Med. Chem., 8, 187-189 (1965)) Dissolve ic acid (40 mg) in DMF (2.0 mL) and add EDC-HCl (56 mg), HOBt (35 mg), and (S) -diphenyl (pyrrolidin-2-yl) methanol ( 56 mg) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol / chloroform) to give the title compound (62 mg, yield 65%) as a foam.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.00-1.09 (1H, m), 1.54-1.65 (1H, m), 1.90-2.09 (4H, m), 2.19-2.40 (2H, m), 3.01 -3.11 (1H, m), 3.35-3.44 (1H, m), 3.50-3.60 (1H, m), 3.67-3.77 (1H, m), 5.13 (1H, dd, J = 8.4, 5.7 Hz), 5.69 (1H, dd, J = 7.8 Hz, 1.9 Hz), 6.70 (1H, s), 7.14 (1H, d, J = 7.8 Hz), 7.21-7.42 (10H, m), 8.68 (1H, brs)

Examples 2-19
The following compounds were obtained by the method described in the literature (J. Med. Chem., 8, 187-189 (1965)) 4- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H)- I) Butanoic acid and each amine were synthesized according to the method of Example 1 (in Examples 2 and 8, triethylamine (40 μL) was added). The results are shown in the table below.

Example 2
(S) -1- (4- (2-Benzhydrylpyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 3
(S) -1- (4- (2- (Fluorodiphenylmethyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 4
4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -N- (1-hydroxy-1,1-bis (3-methoxyphenyl) -2-methylpropane-2- Yl) butanamide

Example 5
4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -N-methyl-N-((1-phenylcyclopropyl) methyl) butanamide

Example 6
4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -N-isopropyl-N-((1-phenylcyclopropyl) methyl) butanamide

Example 7
4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -N-methyl-N-((1-phenylcyclopentyl) methyl) butanamide

Example 8
N- (1- (3- (cyclopropylmethoxy) phenyl) -1-hydroxy-2-methyl-1-phenylpropan-2-yl) -4- (2,4-dioxo-3,4-dihydropyrimidine- 1 (2H) -yl) butanamide

Example 9
(R) -4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -N- (1-hydroxy-1,1-diphenylpropan-2-yl) -N-methyl Butanamide

Example 10
(S) -N- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -4- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H) -Il) -N-methylbutanamide

Example 11
(S) -1- (4- (2- (Bis (4-fluorophenyl) (hydroxy) methyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 12
(S) -1- (4- (2- (bis (4-chlorophenyl) (hydroxy) methyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 13
(S) -1- (4- (2- (hydroxybis (3-methylthiophen-2-yl) methyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 14
(S) -1- (4- (2- (hydroxybis (3-methoxyphenyl) methyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 15
(S) -1- (4- (2- (hydroxydithiophen-3-ylmethyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 16
(S) -1- (4- (2- (Bis (3-fluorophenyl) (hydroxy) methyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 17
(S) -1- (4- (2- (hydroxybis (2-methoxyphenyl) methyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

Example 18
4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -N- (2,2-diphenylethyl) -N-methylbutanamide

Example 19
4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) -N- (1-hydroxy-2-methyl-1,1-diphenylpropan-2-yl) butanamide

Example 20
(S) -1- (4- (2- (hydroxydiphenylmethyl) pyrrolidin-1-yl) -4-oxobutyl) pyrimidine-2,4 (1H, 3H) -dione

  In the above table, the amines used in Examples 2-3 and 20 were readily available, and the amines used in Examples 4-10 were obtained according to Reference Examples 2-8, respectively. Examples 11 to 17 are described in the literature (Tetrahedron Asymmetry, 14 (1), 95-100 (2003)), and Example 18 is a literature (J. Med. Chem., 67, 5028-5031 (2002)). The described method, Example 19, used an amine obtained according to the method described in the literature (J. Am. Chem. Soc., 75, 2959-2962 (1953)).

Example 21
(S) -N- (2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -2-hydroxybutyl) -5- (2,4-dioxo-3,4-dihydropyrimidine-1 (2H) Of (-yl) -N-methylpentanamide

  5- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) pentanoic obtained by the method described in the literature (Russian Journal of Bioorganic Chemistry, 26, 662-668 (2005)) Acid (100 mg) and (S) -2- (3- (cyclopropylmethoxy) -4-fluorophenyl) -1- (methylamino) butan-2-ol (126 mg) obtained in Reference Example 3 Synthesis was performed according to the method of Example 1 to obtain the title compound (120 mg, yield 55%) as a gum-like substance.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.30-0,34 (2H, m), 0.55-0.67 (5H, m), 1.11-2.00 (7H, m), 2.22 (2H, t, J = 6.8 Hz), 2.63 (1H, s), 2.80 (2H, s), 3.40-3.80 (4H, m), 3.87 (2H, d, J = 7.0 Hz), 5.36 (1H, brs), 5.54 ( 1H, d, J = 7.8 Hz), 6.91-7.19 (3H, m), 7.58-7.63 (1H, m), 11.2 (1H, brs)

Example 22
Synthesis of (S, E) -1- (4- (2- (hydroxydiphenylmethyl) pyrrolidin-1-yl) -4-oxobut-2-enyl) pyrimidine-2,4 (1H, 3H) -dione

  4- (2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) butanoic acid (50 mg) obtained according to Reference Example 1 and (S) -2- Synthesis was performed from (fluorodiphenylmethyl) pyrrolidine (70 mg) according to the method of Example 1, and the title compound (74 mg, yield 69%) was obtained as a white foam.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.79-0.89 (1H, m), 1.51-1.56 (1H, m), 1.97-2.15 (2H, m), 2.98-3.07 (1H, m), 3.37 -3.46 (1H, m), 4.48 (2H, d, J = 5.1 Hz), 5.25 (1H, dd, J = 3.8, 8.4 Hz), 5.74 (1H, d, J = 6.5 Hz), 6.20 (1H, d, J = 15 Hz), 6.82 (1H, m), 7.11 (1H, d, J = 8.1 Hz), 7.20-7.39 (10H, m), 8.48 (1H, brs)

Example 23
(R) -N- (1,1-bis (4-fluorophenyl) -1-hydroxy-3-methylbutan-2-yl) -5-((2,4-dioxo-3,4-dihydropyrimidine-1 Synthesis of (2H) -yl) methyl) furan-2-carboxamide

  5-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) furan-2-carboxylic acid (30 mg) obtained in Reference Example 12 was added to dichloromethane (2.0 mL). Suspended, EDC · HCl (37 mg), HOBt (26 mg) and (R) -2-amino-1,1-bis (4-fluorophenyl) -3-methylbutane-1- All (43.7 mg) was added at room temperature and stirred for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (24 mg, yield 37%).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.95 (3H, d, J = 6.8 Hz), 1.85-1.94 (2H, m), 3.76 (1H, brs), 4.76 (2H, s), 5.02 (1H, dd, J = 10.3, 2.2 Hz), 5.64 (1H, d, J = 7.8 Hz), 6.40 (1H, d, J = 3.5 Hz), 6.81- 6.97 (5H, m), 7.12 (1H, d, J = 7.8 Hz), 7.40-7.48 (4H, m)

Example 24
(R) -5-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) -N- [1-fluoro-1,1-bis (4-fluorophenyl)- Synthesis of 3-methylbutan-2-yl] furan-2-carboxamide

  5-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) furan-2-carboxylic acid (40 mg) obtained by Reference Example 12 and Reference Example 10 The title compound (52) was synthesized from (R) -1-fluoro-1,1-bis (4-fluorophenyl) -3-methylbutan-2-amine (60 mg) according to the method of Example 23. mg, yield 59%).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90-1.02 (6H, m), 1.89-2.02 (1H, m), 3.42-3.51 (1H, m), 4.89 (2H, s), 5.05-5.23 (1H, m), 5.73 (1H, d, J = 8.1 Hz), 6.42-6.46 (2H, m), 6.94-7.10 (4H, m), 7.18 (1H, d, J = 7.8 Hz), 7.36- 7.48 (3H, m)

Example 25
(R) -N- (1,1-bis (4-fluorophenyl) -1-hydroxy-3-methylbutan-2-yl) -4-((2,4-dioxo-3,4-dihydropyrimidine-1 Synthesis of (2H) -yl) methyl) thiazole-2-carboxamide

  4-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) thiazole-2-carboxylic acid (40 mg) obtained by Reference Example 13 and Reference Example 9 The title compound (34) was synthesized from (R) -2-amino-1,1-bis (4-fluorophenyl) -3-methylbutan-1-ol (56 mg) according to the method of Example 23. mg, yield 40%).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.86 (3H, d, J = 7.0 Hz), 0.95 (3H, d, J = 6.8 Hz), 1.85-1.94 (1H, m), 4.93 (2H, s), 4.98 (1H, dd, J = 10.5, 2.4 Hz), 5.67 (1H, d, J = 7.6 Hz), 6.84-7.06 (5H, m), 7.32 (1H, d, J = 7.8 Hz), 7.39-7.63 (4H, m)

Example 26
5-((2,4-Dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) -N- (1-hydroxy-2-methyl-1,1-di (thiophen-2-yl) Synthesis of propan-2-yl) furan-2-carboxamide

  5-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methyl) furan-2-carboxylic acid (15 mg) obtained by Reference Example 12 and Reference Example 11 By synthesizing from 2-amino-2-methyl-1,1-di (thiophen-2-yl) propan-1-ol (43 mg) according to the method of Example 23, the title compound (20 mg, Yield 66%) was obtained.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.54 (6H, s), 4.99 (2H, s), 5.70 (1H, d, J = 8.1 Hz), 6.64 (1H, d, J = 3.5 Hz ), 6.96-7.02 (3H, m), 7.21-7.23 (2H, m), 7.30-7.33 (2H, m), 7.64 (1H, d, J = 8.1 Hz)

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

  The compound is described in International Publication No. 2005-065689 as a compound having the strongest human deoxyuridine triphosphatase (hereinafter referred to as dUTPase) inhibitory activity, and described in International Publication No. WO2005-065689 to compare the activity with the compound of the present invention. The method was synthesized.

The inhibitory activity against human dUTPase Test Example 1 Human dUTPase inhibitory activity present compound, the following methods [5- ³ H] deoxyuridine triphosphate ^{(hereinafter, [5- 3 H] dUTP)} [5- 3 H] from It was determined by measuring the production of deoxyuridine monophosphate (hereinafter referred to as [5- ³ H] dUMP).
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 in a 100 ° C. water bath 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 8 as IC ₅₀ (μM).

  The table below shows human dUTPase inhibitory activity data.

Claims (7)

Formula (I)

[In General Formula (I), X represents an alkylene group having 1 to 6 carbon atoms or an alkenylene group having 2 to 6 carbon atoms, and the methylene group in the alkylene chain adjacent to the amide structure is an unsaturated heterocyclic group. May be substituted;
R ¹ and R ² are the same or different and are a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aralkyl group which may have a substituent (however, an aromatic hydrocarbon group constituting the aralkyl group). the two substituents bonded to the α-position carbon atom are simultaneously an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon group, or a saturated or unsaturated heterocyclic group). Or it shows the nitrogen-containing saturated heterocyclic ring which may have a substituent together with the adjacent nitrogen atom. ]
Or a salt thereof. X represents an alkylene group having 2 to 4 carbon atoms or a propenylene group, and a methylene group in the alkylene chain adjacent to the amide structure may be substituted with a furyl group or a thiazolyl group;
R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
R ² is an aralkyl group which may have a substituent (provided that two substituents bonded to the α-position carbon atom of the aromatic hydrocarbon group constituting the aralkyl group are simultaneously an alkyl group, an alkenyl group, an alkynyl group, A group, an aromatic hydrocarbon group or a saturated or unsaturated heterocyclic group), or R ¹ and R ² together with the adjacent nitrogen atom are The uracil compound or its salt of Claim 1 which shows the pyrrolidinyl group which may have. X is a trimethylene group, a tetramethylene group, a propenylene group, or the following formula (II)

Or the following formula (III)

Represents a group represented by
R ¹ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms;
R ² represents the following formula (IV)

[In formula (IV), R < ³ > and R < ⁴ > are the same or different, and show a hydrogen atom or a C1-C6 alkyl group;
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, or an aromatic hydrocarbon group which may have a substituent (provided that R ⁵ and R ⁶ are simultaneously an alkyl group having 1 to 6 carbon atoms, or an aromatic hydrocarbon group which may have a substituent.), Or together with adjacent carbon atoms Having a cycloalkylidene structure,
Y ¹ and Y ² are the same or different and each represents a hydrogen atom, a halogen atom or an optionally substituted alkoxy group having 1 to 6 carbon atoms. Or a substituted phenylethyl group represented by:
R ¹ and R ² together with the adjacent nitrogen atom are represented by the following formula (V)

[In the formula (V), R ⁷ , R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a hydroxyl group, a halogen atom, an aromatic hydrocarbon group or a substituent which may have a substituent. The unsaturated heterocyclic group which may have is shown. ]
The uracil compound or its salt of Claim 1 or 2 which shows the substituted pyrrolidinyl group represented by these. The uracil compound or a salt thereof according to any one of claims 1 to 3, wherein R ¹ represents a hydrogen atom, a methyl group or an isopropyl group. R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a methyl group;
R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a hydroxyl group, an ethyl group or a phenyl group optionally having an alkoxy group having 1 to 6 carbon atoms; or an adjacent carbon atom and Taken together show C3-C7 cycloalkylidene structure;
Y ¹ and Y ² are the same or different and each represents a hydrogen atom, a chlorine atom, a fluorine atom or a methoxy group which may have a cycloalkyl group having 3 to 7 carbon atoms;
R ⁷ , R ⁸ and R ⁹ are the same or different and are a hydrogen atom, a hydroxyl group, a fluorine atom, a halogen atom as a substituent or a phenyl group or carbon which may have an alkoxy group having 1 to 6 carbon atoms. The uracil compound or its salt of Claim 3 or 4 which shows the thienyl group which may have a C1-C6 alkyl group.   The pharmaceutical composition containing the uracil compound or its salt of any one of Claims 1-5.   The human dUTPase inhibitor containing the uracil compound or its salt of any one of Claims 1-5.