JP2015024981A - Novel pyrimidine nucleoside compounds or salts thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide novel pyrimidine nucleoside compounds that exhibit an excellent balance between antitumor effect and toxicity compared to existing pyrimidine nucleoside compounds.SOLUTION: The present invention provides pyrimidine nucleoside compounds represented by the general formula (1) in the figure or salts thereof.

Description

  The present invention relates to a novel pyrimidine nucleoside compound having an excellent antitumor effect, particularly a 5-fluoro-4'-thio-2'-deoxypyrimidine nucleoside compound or a salt thereof.

  Cancers characterized by abnormal cell proliferation are still difficult to treat, and the development of effective therapeutic agents is desired. Nucleic acid biosynthesis is essential for cell growth, and so far, development of nucleic acid metabolism antagonists that inhibit nucleic acid metabolism has been vigorously conducted.

  The following reports have been made on nucleic acid nucleosides in which the sugar portion of the nucleoside is converted to a thiosugar.

  In Patent Document 1 and Non-Patent Document 1, 4′-thio-2′-deoxypyrimidine nucleosides as antiviral agents and antitumor agents, in particular 4′-thio-2′-deoxyuridine and 4′-thio- Antiviral activity of 2′-deoxythymidine against herpes simplex virus type 1 (HSV1) and type 2 (HSV2), and human leukocyte L1210 cells, human endothelial tumor No. Reference is made to antitumor activity against two cells.

  In Patent Documents 2 and 3 and Non-Patent Document 2, 4′-thio-2′-deoxypyrimidine nucleoside as an antiviral agent, in particular, 5- (2-chloroethyl) -4′-thio-2′-deoxy, among others. Uridine, E-5- (2-bromovinyl) -4'-thio-2'-deoxyuridine, 5-nitro-4'-thio-2'-deoxyuridine, 5-bromo-4'-thio-2'- Deoxyuridine, 5-iodo-4′-thio-2′-deoxyuridine, 5-ethynyl-4′-thio-2′-deoxyuridine, 5-ethyl-4′-thio-2′-deoxyuridine, 5- Trifluromethyl-4′-thio-2′-deoxyuridine and 4′-thio-2′-deoxythymidine against herpes simplex virus type 1 (HSV1) and type 2 (HSV2) HSV activity and mentions for anti-VZV activity against varicella-zoster (VZV).

  Particularly in Non-Patent Document 3, 5-fluoro-4′-thio-2′-deoxyuridine (1- [2′-deoxy-4′-thio-1-β-D) having a structure similar to that of the compound of the present invention. -Ribofuranosyl] -5-fluorouracil) is described for antitumor activity against L1210 cells.

International Publication No. WO91 / 04033 International Publication No. WO91 / 01326 International Publication No. WO91 / 04982

Secrist, J, III. et al. , J .; Med. Chem. , 34, 2361-2366 (1991) Rahim, S .; G. et al. , J .; Med. Chem. 39, 789-795 (1996) Hui, Y .; et al. , Nucleosides & Nucleotides. , 12 (2), 139-147 (1993)

  An object of the present invention is to provide a novel pyrimidine nucleoside compound that exhibits an excellent balance between antitumor effect and toxicity compared to existing pyrimidine nucleoside compounds.

  As a result of intensive studies to solve the above problems, the present inventors have found that a novel pyrimidine nucleoside compound represented by the following general formula (1) or a salt thereof is excellent in antitumor effect and toxicity in oral administration. The present invention was completed by finding that it shows a balance.

  That is, the present invention provides the following pyrimidine nucleoside compounds or salts thereof, pharmaceutical compositions and antitumor agents.

  Item 1. The following general formula (1)

[In the formula, ^one of A ¹ and A ² represents a hydrogen atom or a group represented by R ¹ —CO— and the other represents a group represented by R ² —CO—, or one represents a hydrogen atom or A group represented by R ³ — (O—CH ₂ ) _m — and the other represents a group represented by R ⁴ — (O—CH ₂ ) _n —, or one represented by R ¹ —CO—. And the other is a group represented by R ³ — (O—CH ₂ ) _m —, provided that n = 1 when one of A ¹ and A ² is hydrogen,
R ¹ and R ² may be the same or different and each may have a linear or branched alkyl group having 1 to 6 carbon atoms, or may have a substituent group having 3 to 7 carbon atoms. A cyclic alkyl group or an aryl group having 6 to 14 carbon atoms which may have a substituent,
m is 0 or 1,
n is 0 or 1;
R ³ and R ⁴ are the same or different and are aralkyl groups having 7 to 15 carbon atoms which may have a substituent. ]
The pyrimidine nucleoside compound represented by these, or its salt.
Item 2. When A ¹ is a group represented by R ² —CO— and A ² is a hydrogen atom,
R ² is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent or a cyclic alkyl group having 3 to 7 carbon atoms which may have a substituent,
When A ¹ is a hydrogen atom and A ² is a group represented by R ² —CO—,
R ² has a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, a cyclic alkyl group having 3 to 7 carbon atoms which may have a substituent, or a substituent. An aryl group having 6 to 14 carbon atoms,
When A ¹ is a group represented by R ¹ —CO— and A ² is a group represented by R ² —CO—,
R ¹ and R ² are the same or different and each is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent,
When A ¹ is a group represented by R ⁴ — (O—CH ₂ ) _n — and A ² is a hydrogen atom,
n is 0 or 1;
R ⁴ is an optionally substituted aralkyl group having 7 to 15 carbon atoms, and A ¹ is a group represented by R ³ — (O—CH ₂ ) _m —, wherein A ² is R ^When it is a group represented by 4- (O—CH ₂ ) _n —,
m is 0,
n is 0,
R ³ and R ⁴ are the same or different and are an aralkyl group having 7 to 15 carbon atoms which may have a substituent,
Item 4. A pyrimidine nucleoside compound or a salt thereof according to Item 1.

Item 3. R ¹ and R ² are the same or different and are each a linear or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, or an aryl group having 6 to 14 carbon atoms, Item 3. The pyrimidine nucleoside compound or a salt thereof according to Item 1 or 2, wherein R ³ and R ⁴ are the same or different and are an aralkyl group having 7 to 15 carbon atoms which may have a halogen atom as a substituent.

Item 4. R ¹ and R ² are the same or different and are a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclohexyl group or a phenyl group, and R ³ and R ⁴ are the same or different and are a benzyl group, 4 Item 4. The pyrimidine nucleoside compound or a salt thereof according to any one of Items 1 to 3, which is a chlorobenzyl group, a 3,4-dichlorobenzyl group, or a 4-bromobenzyl group.

Item 5. The pyrimidine nucleoside compound or salt thereof according to any one of the following (1) to (16):
(1) 1- [2′-Deoxy-3′-O-cyclohexanecarbonyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (2) 1- [2′-deoxy-3′- O-propionyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (3) 1- [2′-deoxy-3′-O-isobutyryl-4′-thio-1-β-D- Ribofuranosyl] -5-fluorouracil (4) 1- [5′-O-cyclohexanecarbonyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (5) 1- [5 ′ —O-cyclopropanecarbonyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (6) 1- [5′-O-benzoyl-2′-deoxy-4′- Thio-1-β-D-ribofuranosyl -5-fluorouracil (7) 1- [5'-O-propionyl-2'-deoxy-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (8) 1- [2'-deoxy- 3 ′, 5′-O-di-acetyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (9) 1- [2′-deoxy-3 ′, 5′-O-di- Isobutyryl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (10) 1- [2′-deoxy-3 ′, 5′-O-di-propionyl-4′-thio-1-β -D-ribofuranosyl] -5-fluorouracil (11) 1- [2'-deoxy-3'-O-benzyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (12) 1- [ 2′-deoxy-3 ′, 5′-O-dibenzyl-4′-thio-1-β-D Ribofuranosyl] -5-fluorouracil (13) 1- [2′-deoxy-3′-O-benzyloxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (14) 1- [2 '-Deoxy-3'-O- (4-chlorobenzyl) oxymethyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (15) 1- [2'-deoxy-3'-O -(3,4-Dichlorobenzyl) oxymethyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (16) 1- [2'-deoxy-3'-O- (4-bromobenzyl) ) Oxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil Item 6. A pharmaceutical composition comprising an effective amount of the pyrimidine nucleoside compound or a salt thereof according to any one of Items 1 to 5, and a pharmaceutical carrier.

  Item 7. Item 6. An antitumor agent comprising an effective amount of the pyrimidine nucleoside compound or a salt thereof according to any one of Items 1 to 5 and a pharmaceutical carrier.

  The novel pyrimidine nucleoside compound or a salt thereof of the present invention has an excellent balance between antitumor effect and toxicity and is useful as an antitumor agent.

The survival rate at the time of administration of each compound is shown.

1. The pyrimidine nucleoside compound or salt thereof of the present invention The novel pyrimidine nucleoside compound or salt thereof of the present invention is a compound represented by the above general formula (1).

In the present specification, examples of the “substituent” include a halogen atom, a hydroxyl group, a cyano group, a nitro group, and an alkyl group (however, R ¹ or R ² may have a substituent having 1 to 6 carbon atoms). Except for a substituent which is an alkyl group in the case of a linear or branched alkyl group), halogenoalkyl group, cycloalkyl group, cycloalkyl-alkyl group, aralkyl group, alkenyl group, 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, acyloxy group, oxo group, Carboxyl group, alkoxycarbonyl group, aralkyloxyca Examples thereof include a bonyl group, a carbamoyl group, a saturated or unsaturated heterocyclic group, an aromatic hydrocarbon group, and a saturated heterocyclic oxy group. When the substituent is present, the number is typically one or two. Or three.

  In the present specification, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and the halogen atom is preferably a chlorine atom or a bromine atom.

The alkyl group may be linear or branched, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl. C _1-6 alkyl groups such as a group, isopentyl group, and hexyl group.

The halogenoalkyl group is a linear or branched alkyl group having 1 to 13 carbon atoms and having 1 to 13 carbon atoms. Examples of the halogenoalkyl group include a fluoromethyl group, a difluoromethyl group, and a trifluoro group. Halogeno C _1-6 alkyl such as methyl group, trichloromethyl group, fluoroethyl group, 1,1,1-trifluoroethyl group, monofluoro-n-propyl group, perfluoro-n-propyl group, perfluoroisopropyl group A group, preferably a halogeno C _1-3 alkyl group.

Specific examples of the cycloalkyl group include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Examples of the cycloalkyl-alkyl group include C _3-7 cycloalkyl-substituted C _1-4 alkyl groups such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a cycloheptylmethyl group.

Examples of the aralkyl group include C _7-13 aralkyl groups such as benzyl group, phenethyl group, naphthylmethyl group, and fluorenylmethyl group.

The alkenyl group may be linear, branched or cyclic, and means an unsaturated hydrocarbon group having at least one double bond. Examples of the alkenyl group include a vinyl group, an allyl group, 1- Propenyl group, 2-methyl-2-propenyl group, isopropenyl group, 1-, 2- or 3-butenyl group, 2-, 3- or 4-pentenyl group, 2-methyl-2-butenyl group, 3-methyl Examples thereof include C _2-6 alkenyl groups such as 2-butenyl group, 5-hexenyl group, 1-cyclopentenyl group, 1-cyclohexenyl group, and 3-methyl-3-butenyl group.

The alkynyl group may be linear, branched or cyclic, and means an unsaturated hydrocarbon group having at least one triple bond. Examples of the alkynyl group include ethynyl group, 1- or 2-propynyl. C _2-6 alkynyl groups such as a group, 1-, 2- or 3-butynyl group, 1-methyl-2-propynyl group and the like.

The alkoxy group may be linear or branched, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, isopentyloxy And C _1-6 alkoxy groups such as a hexyloxy group.

The halogenoalkoxy group is a linear or branched alkoxy group having 1 to 13 carbon atoms and having 1 to 13 carbon atoms. Examples of the halogenoalkoxy group include a fluoromethoxy group, a difluoromethoxy group, and a trifluoro group. Halogeno C _1- such as methoxy group, trichloromethoxy group, fluoroethoxy group, 1,1,1-trifluoroethoxy group, monofluoro-n-propoxy group, perfluoro-n-propoxy group, perfluoro-isopropoxy group Examples include ₆ alkoxy groups, preferably halogeno C _1-3 alkoxy groups.

Examples of the cycloalkoxy group include C _3-7 cycloalkoxy groups such as a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptyloxy group.

Examples of the cycloalkylalkoxy group include C _3-7 cycloalkyl-substituted C _1-4 alkoxy groups such as a cyclopropylmethoxy group, a cyclobutylmethoxy group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, and a cycloheptylmethoxy group.

Examples of the aralkyloxy group include C _7-13 aralkyloxy groups such as benzyloxy group, phenethyloxy group, naphthylmethyloxy group, and fluorenylmethyloxy group.

The alkylthio group may be linear or branched, for example, methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, tert-butylthio group, n - pentylthio group, isopentylthio group and a C _1-6 alkylthio group such as a hexylthio group.

Examples of the cycloalkyl-alkylthio group include C _3-7 cycloalkyl-substituted C _1-4 alkylthio groups such as a cyclopropylmethylthio group, a cyclobutylmethylthio group, a cyclopentylmethylthio group, a cyclohexylmethylthio group, and a cycloheptylmethylthio group.

The monoalkylamino group includes methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group. And an amino group mono-substituted by a linear or branched C _1-6 alkyl group such as a hexylamino group.

Dialkylamino groups include dimethylamino group, diethylamino group, di-n-propylamino group, diisopropylamino group, di-n-butylamino group, isobutylamino group, ditert-butylamino group, di-n-pentylamino group, di- Examples thereof include an amino group disubstituted with a linear or branched C _1-6 alkyl group such as an isopentylamino group and a dihexylamino group.

Examples of the cycloalkyl-alkylamino group include C _3-7 cycloalkyl-substituted C _1-4 alkyl such as cyclopropylmethylamino group, cyclobutylmethylamino group, cyclopentylmethylamino group, cyclohexylmethylamino group, and cycloheptylmethylamino group. An amino group is mentioned.

  An acyl group means an alkylcarbonyl group or an arylcarbonyl group.

Examples of the alkylcarbonyl group include straight-chain such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl or the like. A branched (C _1-6 alkyl) carbonyl group may be mentioned.

As the arylcarbonyl group, phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromancarbonyl, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyl, (C _6-13 aryl) carbonyl groups such as indanylcarbonyl and phenanthrylcarbonyl.

  An acyloxy group means an alkylcarbonyloxy group or an arylcarbonyloxy group.

Examples of the alkylcarbonyloxy group include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyl Examples thereof include a linear or branched (C _1-6 alkyl) carbonyloxy group such as oxy and hexylcarbonyloxy.

As the arylcarbonyloxy group, phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4 -(C _6-13 aryl) carbonyloxy groups such as dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy and phenanthrylcarbonyloxy.

The alkoxycarbonyl group may be linear or branched, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl And (C _1-6 alkoxy) carbonyl groups such as pentyloxycarbonyl group, isopentyloxycarbonyl group and hexyloxycarbonyl group.

Examples of the aralkyloxycarbonyl group include (C _7-13 aralkyl) oxycarbonyl groups such as benzyloxycarbonyl group, phenethyloxycarbonyl group, naphthylmethyloxycarbonyl group, and fluorenylmethyloxycarbonyl group.

  The saturated heterocyclic group means a 5- or 6-membered monocyclic saturated heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S. Examples of the saturated heterocyclic group include Morpholino group, 1-pyrrolidinyl group, piperidino group, piperazinyl group, 4-methyl-1-piperazinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, tetrahydrothiophenyl group, thiazolidinyl group and oxazolidinyl group.

  An unsaturated heterocyclic group means a monocyclic or polycyclic group consisting of 5 or 6 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; As the unsaturated heterocyclic group, in the case of a polycyclic system, at least one ring may be a heteroaromatic ring. Specific examples include furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, indolyl group, quinolyl group, Examples thereof include an isoquinolyl group, a benzo [b] thienyl and benzoimidazolyl group, a benzothiazolyl group, and a benzoxazolyl group.

  Examples of the aromatic hydrocarbon group include phenyl group, toluyl group, xylyl group, naphthyl group, anthracenyl group, phenanthryl group, fluorenyl group, and tetrahydronaphthyl group.

  Saturated heterocyclic oxy group means a 5- or 6-membered monocyclic saturated heterocyclic oxy group containing 1 to 3 heteroatoms selected from N, O and S. As a saturated heterocyclic oxy group, Is, for example, morpholinyloxy group, 1-pyrrolidinyloxy group, piperidino group, piperazinyloxy group, 4-methyl-1-piperazinyloxy group, tetrahydrofuranyloxy group, tetrahydropyranyloxy group, Examples include a tetrahydrothiophenyloxy group, a thiazolidinyloxy group, and an oxazolidinyloxy group.

In the general formula (1), the “straight chain having 1 to 6 carbon atoms” of “a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent” represented by R ¹ and R ² Examples of the “branched alkyl group” include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, n-pentyl group, n- A hexyl group etc. are mentioned. Preferably, they are a methyl group, an ethyl group, or an isopropyl group.

  Examples of the “substituent” in the “straight or branched alkyl group having 1 to 6 carbon atoms which may have a substituent” include the above-mentioned substituents. Typically one, two or three.

  The “linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent” is preferably a methyl group, an ethyl group, or an isopropyl group.

In the general formula (1), examples of the “cyclic alkyl group having 3 to 7 carbon atoms” of the “cyclic alkyl group having 3 to 7 carbon atoms which may have a substituent” represented by R ¹ and R ² include, for example, , Cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like. Preferably, it is a cyclopropyl group or a cyclohexyl group.

  Examples of the “substituent” of the “cyclic alkyl group having 3 to 7 carbon atoms which may have a substituent” include the above-mentioned substituents. When the substituent is present, the number is typically 1 The number is 2, 2 or 3.

  The “cyclic alkyl group having 3 to 7 carbon atoms which may have a substituent” is preferably a cyclopropyl group or a cyclohexyl group.

In the general formula (1), examples of the “aryl group having 6 to 14 carbon atoms” of the “optionally substituted aryl group having 6 to 14 carbon atoms” represented by R ¹ and R ² include, for example, phenyl Group, naphthyl group and the like. Preferably, it is a phenyl group.

  Examples of the “substituent” in the “aryl group having 6 to 14 carbon atoms which may have a substituent” include the above-mentioned substituents. When the substituent is present, the number is typically 1 Two or three.

  The “aryl group having 6 to 14 carbon atoms which may have a substituent” is preferably a phenyl group.

In the general formula (1), the “aralkyl group having 7 to 15 carbon atoms” of the “aralkyl group having 7 to 15 carbon atoms which may have a substituent” represented by R ³ and R ⁴ includes, for example, benzyl Group, phenethyl group, benzhydryl group, naphthylmethyl group and the like. Preferably, it is a benzyl group.

  The “substituent” of the “aralkyl group having 7 to 15 carbon atoms which may have a substituent” is exemplified by the above-mentioned substituent, and when the substituent is present, the number is typically 1 Two or three. A preferred substituent is a halogen atom, more preferably a chlorine atom or a bromine atom, and still more preferably a chlorine atom. When the substituent is a chlorine atom, the number is preferably 1 or 2, and more preferably 1. When the substituent is a bromine atom, the number is preferably one.

  The “aralkyl group having 7 to 15 carbon atoms which may have a substituent” is preferably a benzyl group, a 4-chlorobenzyl group, a 3,4-dichlorobenzyl group or a 4-bromobenzyl group.

A ¹ and A ² in the general formula (1) are preferably a group in which A ¹ is represented by R ² —CO— and A ² is a hydrogen atom; A ¹ is a hydrogen atom. And A ² is a group represented by R ² —CO—; A ¹ is a group represented by R ¹ —CO—, and A ² is a group represented by R ² —CO—. In some cases; A ¹ is a group represented by R ⁴ — (O—CH ₂ ) _n — and A ² is a hydrogen atom; or A ¹ is R ³ — (O—CH ₂ ) _m. This is the case where A ² is a group represented by R ⁴ — (O—CH ₂ ) _n —.

When A ¹ is a group represented by R ² —CO— and A ² is a hydrogen atom, R ² is preferably a straight chain having 1 to 6 carbon atoms which may have a substituent. Or a cyclic alkyl group having 3 to 7 carbon atoms which may have a linear or branched alkyl group or a substituent. More preferably, R ² is a linear or branched alkyl group having 1 to 6 carbon atoms or a cyclic alkyl group having 3 to 7 carbon atoms. More preferably, R ² is an ethyl group, an isopropyl group, or a cyclohexyl group.

When A ¹ is a hydrogen atom and A ² is a group represented by R ² —CO—, R ² is preferably a straight chain having 1 to 6 carbon atoms which may have a substituent. Or a branched alkyl group, a cyclic alkyl group having 3 to 7 carbon atoms which may have a substituent, or an aryl group having 6 to 14 carbon atoms which may have a substituent. More preferably, R ² is a linear or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, or an aryl group having 6 to 14 carbon atoms. More preferably, R ² is an ethyl group, a cyclopropyl group, a cyclohexyl group or a phenyl group.

When A ¹ is a group represented by R ¹ —CO— and A ² is a group represented by R ² —CO—, R ¹ and R ² are preferably the same or different, A linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, and more preferably, R ¹ and R ² are the same or different, and are straight chain having 1 to 6 carbon atoms. Or a branched alkyl group. More preferably, R ¹ and R ² are the same or different and are a methyl group, an ethyl group, or an isopropyl group. Most preferably, R ¹ and R ² are the same and are a methyl group, an ethyl group, or an isopropyl group.

When A ¹ is a group represented by R ⁴ — (O—CH ₂ ) _n —, A ² is a hydrogen atom, and n is 0, R ⁴ is preferably a substituent. An aralkyl group having 7 to 15 carbon atoms which may be present. More preferably, R ⁴ is an aralkyl group having 7 to 15 carbon atoms. More preferably, R ⁴ is a benzyl group.

When A ¹ is a group represented by R ⁴ — (O—CH ₂ ) _n — and A ² is a hydrogen atom and n is 1, R ⁴ preferably has a substituent. Or an aralkyl group having 7 to 15 carbon atoms. More preferably, R ⁴ is an aralkyl group having 7 to 15 carbon atoms or an aralkyl group having 7 to 15 carbon atoms which may have a halogen atom as a substituent. More preferably, R ⁴ is a benzyl group or a benzyl group which may have a halogen atom as a substituent. More preferably, R ⁴ is a benzyl group, a 4-chlorobenzyl group, a 3,4-dichlorobenzyl group, or a 4-bromobenzyl group.

When A ¹ is a group represented by R ³ — (O—CH ₂ ) _m — and A ² is a group represented by R ⁴ — (O—CH ₂ ) _n —, R ³ and R ⁴ is preferably the same or different and is an aralkyl group having 7 to 15 carbon atoms which may have a substituent. More preferably, R ³ and R ⁴ are the same or different and are aralkyl groups having 7 to 15 carbon atoms. More preferably, R ³ and R ⁴ are both benzyl groups. m and n are preferably 0.

Preferable specific compounds of the present invention include pyrimidine nucleoside compounds described in the following (1) to (16).
(1) 1- [2′-Deoxy-3′-O-cyclohexanecarbonyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (2) 1- [2′-deoxy-3′- O-propionyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (3) 1- [2′-deoxy-3′-O-isobutyryl-4′-thio-1-β-D- Ribofuranosyl] -5-fluorouracil (4) 1- [5′-O-cyclohexanecarbonyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (5) 1- [5 ′ —O-cyclopropanecarbonyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (6) 1- [5′-O-benzoyl-2′-deoxy-4′- Thio-1-β-D-ribofuranosyl -5-fluorouracil (7) 1- [5'-O-propionyl-2'-deoxy-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (8) 1- [2'-deoxy- 3 ′, 5′-O-di-acetyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (9) 1- [2′-deoxy-3 ′, 5′-O-di- Isobutyryl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (10) 1- [2′-deoxy-3 ′, 5′-O-di-propionyl-4′-thio-1-β -D-ribofuranosyl] -5-fluorouracil (11) 1- [2'-deoxy-3'-O-benzyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (12) 1- [ 2′-deoxy-3 ′, 5′-O-dibenzyl-4′-thio-1-β-D Ribofuranosyl] -5-fluorouracil (13) 1- [2′-deoxy-3′-O-benzyloxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (14) 1- [2 '-Deoxy-3'-O- (4-chlorobenzyl) oxymethyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (15) 1- [2'-deoxy-3'-O -(3,4-Dichlorobenzyl) oxymethyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (16) 1- [2'-deoxy-3'-O- (4-bromobenzyl) ) Oxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil The salt of the pyrimidine nucleoside compound of the present invention may be any pharmaceutically acceptable salt, for example, Acid salts, hydrobromides, sulfates, nitrates, phosphates and other mineral salts, acetates, propionates, tartrate, fumarate, maleate, succinate, malate, citric acid Organic acid salts such as acid salts, methanesulfonic acid salts, p-toluenesulfonic acid salts, and trifluoroacetic acid salts can be formed. Moreover, although the pyrimidine nucleoside compound of this invention may produce an optical isomer or a geometric isomer depending on the kind of substituent, this invention includes all of them. These isomers can be used either as a mixture or as a mixture. Furthermore, the pyrimidine nucleoside compound of the present invention includes a solvate represented by a hydrate, an amorphous form, or a crystalline polymorph.
2. Process for Producing Pyrimidine Nucleoside Compound of the Present Invention or a Salt thereof The pyrimidine nucleoside compound of the present invention or a salt thereof can be produced by various methods, for example, according to the following.
I. Preparation of the compound A ¹ -Z or A ² -Z

[V represents an aralkyl group having 7 to 15 carbon atoms which may have a substituent. ]
According to the reaction process formula 1, A ¹ and A ² in the general formula (1) are either a hydrogen atom or a group represented by R ³ — (O—CH ₂ ) _m — and the other is R ⁴ — ( A group represented by O—CH ₂ ) _n — or a group represented by one of R ¹ —CO— and the other represented by R ³ — (O—CH ₂ ) _m —. In the case where m or n is 1, A ¹ -Z or A ² -Z (Z represents a halogen atom) used for the production of the pyrimidine nucleoside compound of the present invention or a salt thereof can be produced.
(Process 1)
In this step, the alcohol moiety of the aralkyl alcohol represented by the general formula (AR1) can be reacted with methylthiomethyl chloride in the presence of a base to produce a compound represented by the general formula (AR2). The compound represented by the general formula (AR2) can be produced according to a generally known method (for example, Tetrahedron Lett., 1975, 3269). The compound represented by the general formula (AR2) produced by this reaction can be isolated and purified as necessary, but can also be used in the next step without purification.
(Process 2)
In this step, the compound represented by the general formula (AR2) can be reacted with sulfuryl chloride to produce the compound represented by the general formula (AR3) (that is, A ¹ -Z or A ² -Z). The compound represented by the general formula (AR3) can be produced according to a generally known method (for example, Synthesis, 1983, 762). The compound represented by the general formula (AR3) produced by this reaction can be isolated and purified as necessary, but can also be used in the next step without purification.
II. Process for producing pyrimidine nucleoside compound or salt thereof of the present invention

(A ¹ and A ² each represents a hydrogen atom or a group represented by R ¹ —CO— and the other represents a group represented by R ² —CO—, or one of them represents a hydrogen atom or R ³ —. A group represented by (O—CH ₂ ) _m — and the other represents a group represented by R ⁴ — (O—CH ₂ ) _n —, or one represented by R ¹ —CO—. And the other is a group represented by R ³ — (O—CH ₂ ) _m —, where n is 1 when one of A ¹ and A ² is hydrogen.)
By this reaction process formula 2, the pyrimidine nucleoside compound of the present invention or a salt thereof can be produced.

Hereinafter, in each reaction process formula, Y is a protecting group for a hydroxyl group, and is not particularly limited as long as the protecting group can be removed under acidic or neutral conditions, and those commonly used as a protecting group for a nucleoside. Illustrated. Preferably, tri-substituted silyl groups such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, dimethyltexylsilyl group, tert-butyldiphenylsilyl group, triphenylmethyl group, 4-methoxytril. Examples thereof include a triarylmethyl group which may have a substituent such as a phenylmethyl group and a 4,4′-dimethoxyphenylmethyl group.
(Process 3)
In this step, a known pyrimidine nucleoside compound represented by the general formula (2) or a salt thereof is reacted with a hydroxyl-protecting reagent to selectively protect only the 5 ′ position, and represented by the general formula (3). Can be produced.

  The compound represented by General formula (2) can be normally manufactured according to a well-known method (patent document 1, 2).

  The compound represented by the general formula (3) can be produced according to a generally known method (for example, J. Med. Chem., 2010, 53, 4130, Carbohydrate Res, 2007, 259).

The protecting reagent used in this reaction is not particularly limited as long as it can selectively protect only the 5 ′ position and can be removed under acidic and neutral conditions, but YZ (Z represents a halogen atom). Or a tri-substituted halogenated silane such as trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, or dimethyltexylchlorosilane, or a triarylmethyl halide such as trityl chloride, monomethoxytrityl chloride, or dimethoxytrityl chloride. Is mentioned. The solvent used in this reaction is not particularly limited as long as it does not participate in the reaction. For example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N, N-dimethylformamide, N , N-dimethylacetamide, dimethyl sulfoxide and the like, and these can be used alone or in combination. In the reaction, a base may be used as necessary. Examples of the base include organic amines such as imidazole, 1-methylimidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like. And inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and the like, and only the base may be used as a solvent. In this reaction, the above YZ is used in an amount of about 1 to 20 mol, preferably about 1 to 10 mol, and the base is 1 to 100 mol with respect to 1 mol of the compound represented by the general formula (2). The amount is preferably about 1 to 20 mol. The reaction temperature is −30 to 100 ° C., preferably −10 to 60 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 hour to 24 hours. The compound represented by the general formula (3) produced by this reaction can be isolated and purified as necessary, but can also be used in the next step without purification.
(Process 4)
In this step, the pyrimidine nucleoside compound represented by the general formula (3) or a salt thereof and A ¹ -Z (Z represents a halogen atom) or A ¹ -O-A ¹ is reacted in the presence of a base, and the general formula ( The compound represented by 4) can be produced. When A ¹ is a group represented by R ¹ —CO— or a group represented by R ² —CO—, examples of A ¹ -Z include acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride and the like. As the acid chloride, A ¹ -O-A ¹ , for example, acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, and valeric anhydride can be used. When A ¹ is a group represented by R ³ — (O—CH ₂ ) _m — or a group represented by R ⁴ — (O—CH ₂ ) _n — and m or n is 0, For example, when ^1- Z is a benzylating agent, and m or n is 1, AR3 produced by, for example, reaction process formula 1 can be used as A ¹ -Z.

The solvent used in this reaction is not particularly limited as long as it does not participate in the reaction. For example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N, N-dimethylformamide, N , N-dimethylacetamide, dimethyl sulfoxide and the like, and these can be used alone or in combination. In the reaction, a base may be used as necessary. Examples of the base include organic amines such as imidazole, 1-methylimidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like. And inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and the like, and only the base may be used as a solvent. In this reaction,
(1) A ¹ is a group represented by R ¹ —CO— or a group represented by R ² —CO—;
The above A ¹ -Z or A ¹ -O-A ¹ is used in an amount of about ¹ to 20 mol, preferably about ¹ to 2 mol, per 1 mol of the compound represented by the general formula (3), and the base is used. About 0.5 to 100 mol, preferably about 1 to 10 mol is used. The reaction temperature is −30 to 100 ° C., preferably 0 to 30 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 24 hours.
(2) A ¹ is a group represented by R ³ — (O—CH ₂ ) _m — or R ⁴ — (O—CH ₂ ) _n —, and m or n is 0;
The A ¹ -Z is used in an amount of about ¹ to 20 mol, preferably about 1 to 1.2 mol, and the base is used in an amount of 0.5 to 100 mol per 1 mol of the compound represented by the general formula (3). The amount is preferably about 1 to 10 mol. The reaction temperature is −30 to 100 ° C., preferably 0 to 30 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 24 hours.
(3) A ¹ is a group represented by R ³ — (O—CH ₂ ) _m — or R ⁴ — (O—CH ₂ ) _n —, and m or n is 1;
The A ¹ -Z is used in an amount of about 1 to 20 mol, preferably about 1 to 10 mol, and the base is about 1 to 100 mol, preferably 1 mol of the compound represented by the general formula (3). Can be used in an amount of about 1 to 20 moles. The reaction temperature is −30 to 100 ° C., preferably −10 to 60 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 hour to 24 hours.

The compound represented by the general formula (4) produced by this reaction can be isolated and purified as necessary, but can also be used in the next step without purification.
(Process 5)
In this step, the pyrimidine nucleoside compound represented by the general formula (4) is reacted with a deprotecting reagent to deprotect only the 5 ′ position, whereby the present compound represented by the general formula (1a) can be produced. . The solvent used is not particularly limited as long as it does not participate in the reaction. For example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, water and the like can be mentioned, and these can be used alone or in combination. The deprotection reagent used is not particularly limited as long as it can remove only Y when a tri-substituted silyl group is used for Y and is usually used for deprotection of a silyl group. Fluoride ion reagents such as ammonium fluoride, hydrogen fluoride, potassium fluoride, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or trifluoroacetic acid, acetic acid, propionic acid, formic acid, methanesulfone Examples include acids and organic acids such as p-toluenesulfonic acid. When a triarylmethyl group is used for Y, there is no particular limitation as long as only Y can be removed, and examples thereof include the mineral acids and organic acids described above. These acids may be used by mixing with water. good. In this reaction, the deprotecting reagent is used in an amount of about 0.5 to 200 mol, preferably about 1 to 100 mol, per 1 mol of the compound represented by the general formula (4). The reaction temperature is −30 to 150 ° C., preferably −10 to 50 ° C., and the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours.
(Step 6)
In this step, the pyrimidine nucleoside compound represented by the general formula (2) or a salt thereof and A ² —Z (Z represents a halogen atom) or A ² —O—A ² are reacted in the presence of a base, and the general formula ( The compound of the present invention represented by 1b) can be produced. A ² is a group represented by R ¹ —CO or R ¹ —CO—, or a group represented by R ¹ — (O—CH ₂ ) _m — or R ¹ — (O—CH ₂ ) _n —. . This step can be performed in the same manner as step 4.
(Step 7)
In this step, when A ¹ and A ² are the same, the pyrimidine nucleoside compound represented by the general formula (2) or a salt thereof and A ¹ -Z (Z represents a halogen atom) or A ¹ -OA ^The compound of the present invention represented by the general formula (1) can be produced by reacting ¹ in the presence of a base. A ¹ and A ² are the same or different and are a group represented by R ¹ —CO or R ¹ —CO—, or R ¹ — (O—CH ₂ ) _m — or R ¹ — (O—CH _2). ) A group represented by _n- . This step can be performed in the same manner as step 4. In Step 7, it is preferable to increase the molar amount of A ¹ —Z or A ¹ —O—A ¹ compared to Step 6 to increase the reaction time and to increase the reaction temperature. For example, in step 6, A ¹ -Z or A ¹ -O-A ¹ is preferably 1 mol, the reaction time is 1 to 2 hours, and the reaction temperature is 0 ° C, whereas in step 7, A ^1- Z or A ¹ —O—A ¹ is 2 mol, the reaction time is 12 to 24 hours, and the reaction temperature is 25 to 30 ° C.
(Process 8)
In this step, when A ¹ and A ² are different from each other, the present compound represented by the general formula (1b) and A ¹ -Z (Z represents a halogen atom) or A ¹ -O-A ¹ is present as a base. The compound of the present invention represented by the general formula (1) can be produced by the reaction below. A ¹ is as defined in step 7.
This step can be performed in the same manner as step 4.
(Step 9)
In this step, the compound of the present invention represented by the general formula (1a) and A ² —Z (Z represents a halogen atom) or A ² —O—A ² are reacted in the presence of a base, and the general formula (1) The represented compounds of the invention can be prepared. A ² is as defined in step 6. This step can be performed in the same manner as step 4.

The Scheme 2, may include a step of deprotecting steps and N ^3-position protecting the N ³ position as necessary. One of A ¹ and A ² is a hydrogen atom or a group represented by R ³ — (O—CH ₂ ) _m —, and the other is a group represented by R ⁴ — (O—CH ₂ ) _n —, Alternatively, when n is 1 (provided that one of A ¹ and A ² is hydrogen, n = 1), it is preferable to include these steps.

The step of protecting the N ³ position can be performed before step 3, for example. That is, a known pyrimidine nucleoside compound represented by the general formula (2) or a salt thereof is reacted with an amino group protecting reagent to selectively produce a compound in which only the N ³ position is protected.

A compound in which only the N ³ position is selectively protected can be produced according to a generally known method (for example, J. Med. Chem., 1989, 32, 136). The protecting reagent used in this reaction is not particularly limited as long as it can protect the amino group and can be removed under basic conditions, but acetyl chloride represented by XZ (Z represents a halogen atom), Examples include halogenated acyl groups such as propionyl chloride, butyryl chloride, pentanoyl chloride, isovaleryl chloride and heptanoyl chloride, and halogenated aryl oil groups such as benzoyl chloride, toluoyl chloride and naphthoyl chloride. The solvent used in this reaction is not particularly limited as long as it does not participate in the reaction. For example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N, N-dimethylformamide, N , N-dimethylacetamide, dimethyl sulfoxide and the like, and these can be used alone or in combination. In the reaction, a base may be used as necessary. Examples of the base include organic amines such as imidazole, 1-methylimidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like. And inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate and the like, and only the base may be used as a solvent. In this reaction, with respect to 1 mol of the compound represented by the general formula (2), the above XZ is used in an amount of about 1 to 20 mol, preferably about 1 to 10 mol, and the base is used in an amount of 1 to 100 mol. The amount is preferably about 1 to 20 mol. The reaction temperature is −30 to 100 ° C., preferably −10 to 60 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 hour to 24 hours. The compound produced by this reaction can be isolated and purified as necessary, but can also be used in the next step without purification.

Deprotecting the N ³ position may be included prior to performing step 5 The compound represented by e.g. N ^3-position is protected formula (4).

That is, a compound obtained by reacting a known pyrimidine nucleoside compound represented by the general formula (4) in which the N ³ position is protected with a deprotecting reagent to deprotect only the N ³ position (that is, in the general formula (4) Known pyrimidine nucleoside compounds) can be produced.

The solvent used is not particularly limited as long as it does not participate in the reaction. For example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, water and the like can be mentioned, and these can be used alone or in combination. The deprotection reagent to be used is not particularly limited as long as only X can be selectively removed. For example, organic bases such as ammonia and methylamine, sodium methoxide, sodium ethoxy, potassium carbonate, sodium carbonate hydrogenation Examples thereof include inorganic bases such as sodium. In this reaction, the deprotecting reagent is used in an amount of about 0.5 to 200 mol, preferably 1 to 100, per 1 mol of the known pyrimidine nucleoside compound represented by the general formula (4) in which the N ³ position is protected. Use about molar amount. The reaction temperature is −30 to 150 ° C., preferably −10 to 50 ° C., and the reaction time is 0.1 to 100 hours, preferably 0.5 to 24 hours. The compound produced by the reaction and deprotected only at the N ³ position (that is, a known pyrimidine nucleoside compound represented by the general formula (4)) can be isolated and purified as necessary. It can also be used in the process.

  The compound of the present invention and the other compounds obtained as described above can form a salt, particularly a pharmaceutically acceptable salt, by a generally known method.

The compound of the present invention or a salt thereof, or another compound or a salt thereof can be isolated and purified by using a generally known separation and purification means such as concentration, solvent extraction, filtration, recrystallization, various chromatography and the like.
3. The use method of the pyrimidine nucleoside compound of this invention, or its salt This invention is a pharmaceutical composition containing the effective amount of the at least 1 sort (s) of this invention represented by General formula (1), or its pharmaceutically acceptable salt. Is to provide.

  When the compound of the present invention is used as a medicine, it can be combined with a pharmaceutical carrier, and various administration forms can be adopted depending on the purpose of prevention or treatment. Examples of such forms include oral preparations, injections, and suppositories. Any of ointments, patches, and the like may be used, and oral preparations are preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

  As a pharmaceutical carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, solubilizers, suspensions It is blended as an agent, isotonic agent, buffer, soothing agent and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary.

  When preparing an oral solid preparation, after adding an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. to the compound of the present invention, if necessary, a tablet by a conventional method, Coated tablets, granules, powders, capsules and the like can be produced. Such additives may be those commonly used in the art. For example, excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid As a binder, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. are used. Examples of the disintegrating agent include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Phosphate, borax, polyethylene glycol and the like, as the colorant, titanium oxide, iron oxide, white as the flavoring agent sugar, orange peel, citric acid, can be exemplified tartaric acid.

  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 and flavoring agents may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  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 and glucose.

  When preparing a suppository, a formulation carrier known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and an interface such as Tween (registered trademark) as necessary are added to the compound of the present invention. 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, or a film or foam sheet made of cotton, suf, or chemical fiber is suitable.

  The amount of the compound of the present invention or a salt thereof to be incorporated in each of the above dosage unit forms is not constant depending on the symptom of the patient to which the present invention is to be applied, or the dosage form thereof. About 0.05 to 1000 mg for an agent, about 0.01 to 500 mg for an injection, and about 1 to 1000 mg for a suppository are desirable. 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, but is usually about 0.05 to 5000 mg per day for an adult, preferably It may be 0.1-1000 mg, and it is preferable to administer this once a day or divided into 2-4 times. In addition, in this invention, the compound represented by General formula (1) or its salt is used individually by 1 type or in combination of multiple types.

  Diseases that can be treated by administering a drug containing the compound of the present invention include, for example, malignant tumors, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, Examples include lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, etc. .

  The compound and antitumor agent of the present invention are useful for prevention / treatment of cancer or tumor and / or prevention of recurrence. Therefore, the present invention provides a preventive / therapeutic agent for cancer or tumor and a preventive agent for recurrence. Here, prevention of recurrence means prevention of recurrence of cancer or tumor after cancer or tumor tissue has once disappeared or cannot be recognized by surgery, radiation therapy, chemotherapy or the like. In order to prevent recurrence of cancer or tumor, about 0.05 to 5000 mg, preferably 0.1 to 1000 mg of the compound of the present invention is usually administered per day for an adult. The compound of the present invention is preferably administered once a day or divided into about 2 to 4 times a day. The administration period for preventing recurrence is usually about 1 month to 1 year, especially about 3 months to 6 months. By continuing to take the compound of the present invention during this period, recurrence of cancer or tumor can be prevented.

Hereinafter, the present invention will be described in more detail with reference to Comparative Examples, Examples, Pharmacological Test Examples and Preparation Examples. However, the present invention is not limited to these examples. The ¹ H-NMR spectrum was measured using TMS (tetramethylsilane) as an internal standard, and showed a chemical shift with a δ value (ppm). Chemical shifts show the absorption pattern, coupling constant (J value), and proton number in parentheses.

The following symbols are used for the absorption pattern. s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, m = multiplet, br = broad, brs = broad singlet.
Moreover, the following symbols are used regarding the structural formula of the compound. Me = methyl, Et = ethyl.
Example 1
Synthesis of 1- [2′-deoxy-3′-O-cyclohexanecarbonyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (1)
(1) Synthesis of 1- [5′-O-tert-butyldimethylsilyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (1a) 4′-Thio-FdUrd (440 mg) was dissolved in pyridine (5.0 mL), and 4- (N, N-dimethylamino) pyridine (10 mg) and t-butyldimethylsilyl chloride (300 mg) were added under ice-cooling at 0 ° C. and overnight at room temperature. Stirring was performed. Methanol (0.4 mL) was added, stirred for 1 hour, and concentrated to distill off the solvent, followed by liquid separation extraction with ethyl acetate and distilled water, and the organic layer was concentrated to distill off the solvent. The residue was purified by suspension washing with 50% ethyl acetate / heptane and then collected by filtration to give compound 1a (600 mg, 95%) as a white solid. Physical property values are shown below.
¹ H-NMR (DMSO-d ₆ ) δ 11.9 (1H, brs), 8.20 (1H, d, J = 4.0 Hz), 6.22 (1H, dd, J = 8.0 & 8.0 Hz) ), 5.31 (1H, d, J = 3.7 Hz), 4.32 (1H, m), 3.79 (2H, m), 3.31 (1H, m), 2.20 (2H, m), 0.88 (9H, s), 0.12 (6H, s); ESI-MS m / z 375 (M-H) ^- .
(2) Synthesis of Compound 1 Compound 1a (185 mg) was dissolved in pyridine (2.0 mL), 4- (N, N-dimethylamino) pyridine (6 mg) and cyclohexanecarbonyl chloride (101 mg) were added, and the mixture was ice-cooled. Stir for 1 hour. After stopping the reaction by adding methanol (0.5 mL), the reaction solution was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (40% ethyl acetate / hexane). The obtained compound was dissolved in ethanol (3.0 mL), (±) -10-camphorsulfonic acid (130 mg) was added, and the mixture was stirred with heating at 70 ° C. for 2 hr. After completion of the reaction, the solvent was distilled off, followed by liquid separation washing with ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the solvent was distilled off after concentration to dryness to give Compound 1 (121 mg, 88%) as a white solid Got as. The physical property values are shown in Table 1.
Example 2
Synthesis of 1- [2′-deoxy-3′-O-propionyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (2) To 4- (N, Using N-dimethylamino) pyridine (11 mg), propionyl chloride (52 mg), and (±) -10-camphorsulfonic acid (130 mg) (139 mg), compound 2 (105 mg, 83%) was prepared in the same manner as compound 1. Obtained as a white solid. The physical property values are shown in Table 1.
Example 3
Synthesis of 1- [2′-deoxy-3′-O-isobutyryl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (3) To 4- (N, N-dimethylamino) pyridine (15 mg), isobutyryl chloride (79 mg), and (±) -10-camphorsulfonic acid (185 mg) were used in the same manner as Compound 1 to give Compound 3 (159 mg, 90%) in white Obtained as a solid. The physical property values are shown in Table 1.
Example 4
Synthesis of 1- [5′-O-cyclohexanecarbonyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (4) 4′-Thio-FdUrd (269 mg) was converted to pyridine ( 5.0 mL), cyclohexanecarbonyl chloride (180 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and hydrochloric acid are added for liquid separation washing, the organic layer is concentrated and the solvent is distilled off. Then, the suspension is washed with 50% ethyl acetate / heptane, and the suspension is collected by filtration and dried to give a compound. 4 (306 mg, 80%) was obtained as a white solid. The physical property values are shown in Table 1.
Example 5
Synthesis of 1- [5′-O-cyclopropanecarbonyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (5) 4′-Thio-FdUrd (240 mg) was converted to pyridine (5.0 mL), cyclopropanecarbonyl chloride (110 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and hydrochloric acid are added for liquid separation washing, the organic layer is concentrated and the solvent is distilled off. Then, the suspension is washed with 50% ethyl acetate / heptane, and the suspension is collected by filtration and dried to give a compound. 5 (208 mg, 65%) was obtained as a white solid. The physical property values are shown in Table 1.
Example 6
Synthesis of 1- [5′-O-benzoyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (6) 4′-Thio-FdUrd (200 mg) was converted to pyridine (5 0.0 mL), benzoyl chloride (129 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and hydrochloric acid are added for liquid separation washing, the organic layer is concentrated and the solvent is distilled off. Then, the suspension is washed with 50% ethyl acetate / heptane, and the suspension is collected by filtration and dried to give a compound. 6 (196 mg, 70%) was obtained as a white solid. The physical property values are shown in Table 1.
Example 7
Synthesis of 1- [5′-O-propionyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (7) 4′-Thio-FdUrd (240 mg) was converted to pyridine (5 0.0 mL), propionyl chloride (102 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and hydrochloric acid are added for liquid separation washing, the organic layer is concentrated and the solvent is distilled off. Then, the suspension is washed with 50% ethyl acetate / heptane, and the suspension is collected by filtration and dried to give a compound. 7 (178 mg, 61%) was obtained as a white solid. The physical property values are shown in Table 1.
Example 8
Synthesis of 1- [2′-deoxy-3 ′, 5′-O-di-acetyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (8) 4′-Thio-FdUrd (203 mg ) Was dissolved in pyridine (5.0 mL), 4- (N, N-dimethylamino) pyridine (180 mg) and acetic anhydride (316 mg) were added under ice-cooling at 0 ° C., and the mixture was stirred at room temperature for 3 hours. . Methanol (2.0 mL) was added and the mixture was stirred for 1 hour and concentrated to evaporate the solvent. Ethyl acetate and 1N aqueous hydrochloric acid were added to separate and wash, and then the organic layer was concentrated. The residue was subjected to silica gel column chromatography. Purification by (50% ethyl acetate / chloroform) gave compound 8 (249 mg, 93%) as a white solid. The physical property values are shown in Table 1.
Example 9
Synthesis of 1- [2′-deoxy-3 ′, 5′-O-di-isobutyryl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (9) 4′-Thio-FdUrd (200 mg ) Was dissolved in pyridine (5.0 mL), and 4- (N, N-dimethylamino) pyridine (186 mg) and isobutyric anhydride (482 mg) were added under ice-cooling at 0 ° C., followed by stirring at room temperature for 3 hours. It was. Methanol (2.0 mL) was added and the mixture was stirred for 1 hour and concentrated to evaporate the solvent. Ethyl acetate and 1N aqueous hydrochloric acid were added to separate and wash, and then the organic layer was concentrated. The residue was subjected to silica gel column chromatography. Purification by (50% ethyl acetate / chloroform) gave compound 9 (270 mg, 88%) as a white solid. The physical property values are shown in Table 1.
Example 10
Synthesis of 1- [2′-deoxy-3 ′, 5′-O-di-propionyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (10) 4′-Thio-FdUrd (202 mg ) Was dissolved in pyridine (5.0 mL), and 4- (N, N-dimethylamino) pyridine (180 mg) and propionic anhydride (200 mg) were added under ice-cooling at 0 ° C., followed by stirring at room temperature for 3 hours. It was. Methanol (2.0 mL) was added and the mixture was stirred for 1 hour and concentrated to evaporate the solvent. Ethyl acetate and 1N aqueous hydrochloric acid were added to separate and wash, and then the organic layer was concentrated. The residue was subjected to silica gel column chromatography. Purification by (50% ethyl acetate / chloroform) gave compound 10 (262 mg, 91%) as a white solid. The physical property values are shown in Table 1.
Example 11
Synthesis of 1- [2′-deoxy-3′-O-benzyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (11) Shakaya, N .; et al. , J .; Med. Chem. , 53 (10) 4130-4140 (2010), 1- [5′-O-dimethoxytrityl-2′-deoxy-4′-thio-] obtained by tritylation of 4′-Thio-FdUrd 1-β-D-ribofuranosyl] -5-fluorouracil (hereinafter 5′-O-DMTr-4′-Thio-FdUrd) (4.12 g) was dissolved in tetrahydrofuran (40 mL), and paraffin was added at 0 ° C. with ice cooling. Oil-containing 60% sodium hydride (1.27 g) and benzyl bromide (1.1 mL) were added, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate was added and the mixture was stirred for 1 hour and concentrated to distill off the solvent, followed by liquid separation extraction with ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was concentrated to distill off the solvent. Ethyl acetate (10 mL), ethanol (70 mL), and 1N hydrochloric acid water (10 mL) were added to the residue, and the mixture was stirred at 60 ° C. for 2 hours. After cooling, 2N-caustic soda water (6 mL) was added, and the suspension formed after the reaction was stopped was collected by filtration and dried to obtain Compound 11 (2.1 g, 80%) as a white solid. The physical property values are shown in Table 1.
Example 12
Synthesis of 1- [2′-deoxy-3 ′, 5′-O-dibenzyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (12) Compound 11 (1.0 g) was added to tetrahydrofuran ( 50 mL), paraffin oil-containing 60% sodium hydride (520 mg) and benzyl bromide (3.5 mL) were added, and the mixture was stirred at 60 ° C. overnight. Acetic acid (1 mL) and distilled water were added to stop the reaction, and the mixture was concentrated to distill off the solvent. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to carry out liquid separation extraction, and the organic layer was washed with saturated brine. Concentrated and evaporated. The residue was purified by silica gel column chromatography (20% chloroform / ethyl acetate) to give Compound 12 (970 mg, 75%) as a white solid. The physical property values are shown in Table 1.
Example 13
Synthesis of 1- [2′-deoxy-3′-O-benzyloxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (13)
(1) Synthesis of N ³ -toluoyl-1- [5′-O-tert-butyldiphenylsilyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (T) Junichi Y. et al. , J .; Med. Chem. , 32 (1) 136-139 (1989), N ³ -toluoyl-1- [2′-deoxy-4′-thio-1-β-- obtained by toluoylating 4′-Thio-FdUrd D-ribofuranosyl] -5-fluorouracil (hereinafter N ³ -toylyl-4′-Thio-FdUrd) (1.05 g) was dissolved in N, N-dimethylformamide (11 mL), and imidazole (469 mg) and t-butyl were dissolved. Diphenylsilyl chloride (788 mg) was added and stirred overnight at room temperature. Methanol (2 mL) was added to stop the reaction, and then toluene and distilled water were added to perform liquid separation extraction. The organic layer was washed again with distilled water and then concentrated to distill off the solvent. The residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give Compound T (1.24 g, 73%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 8.34 (1H, d, J = 7.0 Hz), 7.97 (2H, d, J = 8.4 Hz), 7.68-7.38 (12H M), 6.15 (1H, dd, J = 6.8 & 5.7 Hz), 5.37 (1H, d, J = 4.1 Hz), 4.41 (1H, m), 4.10-3 .81 (2H, m), 3.42 (1H, m), 2.41 (3H, s), 2.26 (2H, m), 1.02 (9H, s).
(2) N ³ -toluoyl-1- [5′-O-tert-butyldiphenylsilyl-2′-deoxy-3′-O-benzyloxymethyl-4′-thio-1-β-D-ribofuranosyl]- Synthesis of 5-fluorouracil (13a) Compound T (250 mg) was dissolved in tetrahydrofuran (5.0 mL), and diisopropylethylamine (417 mg), benzyloxymethyl chloride (253 mg), and tetrabutylammonium iodide (29.8 mg) were added. And stirred at 70 ° C. overnight. After cooling, ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, followed by liquid separation washing, followed by concentration and evaporation of the solvent. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give compound 13a ( 288 mg, 95%) was obtained as an oil.
¹ H-NMR (DMSO-d ₆ ) δ 8.36 (1H, d, J = 7.0 Hz), 7.98 (2H, d, J = 8.4 Hz), 7.66-7.21 (17H M), 6.18 (1H, dd, J = 7.8 & 6.8 Hz), 4.77 (2H, s), 4.49 (3H, m), 4.01-3.59 (3H, m ), 2.47 (5H, m), 0.99 (9H, s).
(3) Synthesis of Compound 13 Compound 13a (288 mg) was dissolved in tetrahydrofuran (1.0 mL) and methanol (3.0 mL), 7N-ammonia / methanol solution (3.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. went. After the reaction solution was concentrated and the solvent was distilled off, the residue was dissolved in tetrahydrofuran (4.0 mL), 1N-tetrabutylammonium / tetrahydrofuran solution (0.85 mL) was added, and the mixture was stirred at room temperature for 1 hour. . The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (70% ethyl acetate / hexane solution) to give Compound 13 (12 mg, 8%) as a foam. The physical property values are shown in Table 1.
Example 14
Synthesis of 1- [2′-deoxy-3′-O- (4-chlorobenzyl) oxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (14)
(1) Synthesis of (4-chlorobenzyl) chloromethyl ether (14a) J. et al. et al. Tetrahedron Lett. , 3269 (1975), (4-chlorobenzyl) methylthiomethyl ether (3.16 g) obtained by methylthiomethylation of commercially available 4-chlorobenzyl alcohol was dissolved in dichloromethane (50 mL), and sulfuryl chloride ( 2.11 g) was added and stirred at room temperature for 30 minutes. The reaction solution was concentrated and the solvent was distilled off to obtain Compound 14a (2.95 g, 99%) as a liquid substance.
¹ H-NMR (CDCl 3) δ 7.32 (4H, m), 5.52 (2H, s), 4.70 (2H, s).
(2) N ³ -toluoyl-1- [5′-O-tert-butyldiphenylsilyl-2′-deoxy-3′-O- (4-chlorobenzyl) oxymethyl-4′-thio-1-β- Synthesis of D-ribofuranosyl] -5-fluorouracil (14b) Using compound 14a (555 mg), diisopropylethylamine (602 mg), and tetrabutylammonium iodide (42.9 mg) for compound T (360 mg), similar to compound 13a Thus, compound 14b (435 mg, 97%) was obtained.
¹ H-NMR (DMSO-d ₆ ) δ 8.36 (1H, d, J = 7.0 Hz), 7.98 (2H, d, J = 8.1 Hz), 7.65-7.27 (16H M), 6.19 (1H, dd, J = 7.6 & 7.3 Hz), 4.80 (2H, s), 4.48 (3H, m), 4.06-3.60 (3H, m ), 2.41 (5H, m), 0.99 (9H, s).
(3) Synthesis of Compound 14 To Compound 14b (225 mg), 7N-ammonia / methanol solution (3.0 mL) and 1N-tetrabutylammonium / tetrahydrofuran solution (1.00 mL) were used in the same manner as Compound 13. Compound 14 (21 mg, 17%) was obtained as a white solid. The physical property values are shown in Table 1.
Example 15
Synthesis of 1- [2′-deoxy-3′-O- (3,4-dichlorobenzyl) oxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (15)
(1) Synthesis of (3,4-dichlorobenzyl) chloromethyl ether (15a) J. et al. et al. Tetrahedron Lett. , 3269 (1975), (3,4-dichlorobenzyl) methylthiomethyl ether (4.97 g) obtained by methylthiomethylation of commercially available 3,4-dichlorobenzyl alcohol was dissolved in dichloromethane (80 mL). Compound 15a (4.70 g, 99%) was obtained as a liquid substance in the same manner as Compound 14a using sulfuryl chloride (2.83 g).
¹ H-NMR (CDCl 3) δ 7.45 (2H, m), 7.17 (1H, m), 5.52 (2H, s), 4.69 (2H, s).
(2) N ³ -toluoyl-1- [5′-O-tert-butyldiphenylsilyl-2′-deoxy-3′-O- (3,4-dichlorobenzyl) oxymethyl-4′-thio-1- Synthesis of β-D-ribofuranosyl] -5-fluorouracil (15b) Compound T (306 mg) was dissolved in tetrahydrofuran (3.0 mL), compound 15a (557 mg), diisopropylethylamine (640 mg), tetrabutylammonium iodide (36 Compound 15b (395 mg, 99%) was obtained in the same manner as Compound 13a.
¹ H-NMR (DMSO-d ₆ ) δ 8.37 (1H, d, J = 7.0 Hz), 7.97 (2H, d, J = 8.1 Hz), 7.66-7.26 (15H , M), 6.19 (1H, m), 4.83 (2H, s), 4.56 (3H, m), 4.04-3.60 (3H, m), 2.43 (5H, m), 0.99 (9H, s).
(3) Synthesis of Compound 15 To Compound 15b (395 mg), 7N-ammonia / methanol solution (3.0 mL) and 1N-tetrabutylammonium / tetrahydrofuran solution (0.80 mL) were used in the same manner as Compound 13. Compound 15 (44 mg, 20%) was obtained as a white solid. The physical property values are shown in Table 1.
Example 16
Synthesis of 1- [2′-deoxy-3′-O- (4-bromobenzyl) oxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (16)
(1) Synthesis of (4-bromobenzyl) chloromethyl ether (16a) J. et al. et al. Tetrahedron Lett. , 3269 (1975), and (4-bromobenzyl) methylthiomethyl ether (4.67 g) obtained by methylthiomethylation of commercially available 4-bromobenzyl alcohol was dissolved in dichloromethane (80 mL), and sulfuryl chloride ( 2.55 g) was used to give compound 16a (4.40 g, 99%) as a liquid substance in the same manner as compound 14a.
¹ H-NMR (CDCl 3) δ 7.46 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 5.45 (2H, s), 4.67 (2H, s).
(2) N ³ -toluoyl-1- [5′-O-tert-butyldiphenylsilyl-2′-deoxy-3′-O- (4-bromobenzyl) oxymethyl-4′-thio-1-β- Synthesis of D-ribofuranosyl] -5-fluorouracil (16b) Compound T (280 mg) was dissolved in tetrahydrofuran (3.0 mL), compound 16a (532 mg), diisopropylethylamine (584 mg), tetrabutylammonium iodide (33.4 mg). ) To give Compound 16b (369 mg, 99%) in the same manner as Compound 13a.
¹ H-NMR (DMSO-d ₆ ) δ 8.37 (1H, d, J = 7.3 Hz), 7.98 (2H, d, J = 8.1 Hz), 7.65-7.27 (16H , M), 6.19 (1H, dd, J = 7.3 & 7.0 Hz), 4.81 (2H, s), 4.52 (3H, m), 4.02-3.59 (3H, m ), 2.43 (5H, m), 1.00 (9H, s).
(3) Synthesis of Compound 16 To Compound 16b (369 mg), 7N-ammonia / methanol solution (4.0 mL) and 1N-tetrabutylammonium / tetrahydrofuran solution (0.9 mL) were used in the same manner as Compound 13. Compound 16 (44 mg, 20%) was obtained as a white solid. The physical property values are shown in Table 1.
Comparative Example 1
Synthesis of 1- [2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (hereinafter 4′-Thio-FdUrd) (17) according to the method of Japanese Patent No. 3205852 Synthesized. The physical property values are shown in Table 1.
Comparative Example 2
Synthesis of 1- [2′-deoxy-3′-O-cyclopentylaminocarbonyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (18) Horton, D. et al . et al. , Carbohydr. Res. , 342 (2), 259-267 (2007), 1- [5′-O- (t-butyldiphenylsilyl) -2′-deoxy obtained by silylation of 4′-Thio-FdUrd -4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (hereinafter 5′-O-TBDPS-4′-Thio-FdUrd) (3.39 g) was dissolved in pyridine (70.0 mL). , Cyclopentyl isocyanate (6.02 g) was added and the mixture was stirred with heating at 100 ° C. for 3 days. After concentrating the reaction solution and distilling off the solvent, the residue was dissolved in tetrahydrofuran (hereinafter referred to as THF) (20.0 ml), and a 1.0 M tetrabutylammonium fluoride / THF solution (13.5 ml) was added. Stir at room temperature for 2 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (80% ethyl acetate / chloroform) to obtain Compound 18 (1.76 g, 70%) as a white foam. The physical property values are shown in Table 1.
Comparative Example 3
Synthesis of 1- [2′-deoxy-3′-O-cyclohexylaminocarbonyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (19) 5′-O-TBDPS-4′-Thio -FdUrd (4.72 g) and cyclohexyl isocyanate (9.40 g) and 1.0 M-tetrabutylammonium fluoride / THF solution (18.8 ml) were used in the same manner as for compound 18 to give compound 19 (3. (09 g, 85%) was obtained as a white foam. The physical property values are shown in Table 1.
Comparative Example 4
1- [2′-deoxy-3′-O- (2,2-dimethylaminopropan-1-ylaminocarbonyl) -4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (20) Synthesis 3,3-dimethylbutyric acid (6.49 g) was dissolved in toluene (30 ml), diphenylphosphoryl azide (15.3 g) and triethylamine (14.1 g) were added, and the mixture was heated and stirred at 100 ° C. for 3 hours. Thereafter, 5′-O-TBDPS-4′-Thio-FdUrd (3.50 g) and pyridine (30 ml) were added, and the mixture was further stirred at 100 ° C. overnight. After the reaction solution was concentrated and the solvent was distilled off, the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in THF (50.0 ml), 1.0M-tetrabutylammonium fluoride / THF solution (16.9 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (80% ethyl acetate / chloroform) to obtain Compound 20 (2.12 g, 81%) as a white foam. The physical property values are shown in Table 1.
Comparative Example 5
Synthesis of 1- [2′-deoxy-3′-O-ethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (21) Shakaya, N .; et al. , J .; Med. Chem. , 53 (10), 4130-4140 (2010), 1- [5′-O-monomethoxytrityl-2′-deoxy-4′- obtained by tritylation of 4′-Thio-FdUrd Thio-1-β-D-ribofuranosyl] -5-fluorouracil (400 mg) is dissolved in tetrahydrofuran (8.0 ml), and paraffin oil-containing 60% sodium hydride (119.7 mg) and iodoethane (1.16 g) are added. And stirred at 55 ° C. overnight. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the layers were separated. The organic layer was concentrated, the solvent was distilled off, and the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane). The obtained compound was dissolved in 80% aqueous trifluoroacetic acid solution (6.0 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (80% ethyl acetate / chloroform) to obtain Compound 21 (119 mg, 55%) as a white foam. The physical property values are shown in Table 1.

Test example 1
Nude mouse subcutaneous tumor transplantation system, antitumor test in oral administration BALB / cA Jcl-nu mice (CLEA Japan, Inc.) human colon cancer strain KM20C subcultured into 2 mm square fragments, 6 or 7 weeks old BALB / cA Jcl-nu mice were implanted subcutaneously on the back. When the average tumor volume after grouping exceeds 100 mm ³ , measure the major axis and minor axis of the tumor, calculate the tumor volume according to the following formula, and then group the group so that there is no variation in the tumor volume of each group Performed (5 or 6 animals per group).
(Formula 1) Vt = 1/2 (Vl) × (Vs) ²
[In the formula, Vt represents the tumor volume, Vl represents the major axis of the tumor, and Vs represents the minor axis of the tumor. ]
The compounds of the present invention and the compounds of Comparative Examples 1 to 5 were dissolved or suspended in a 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The dose was set to a dose that was equimolar with 50 mg / kg / day of Comparative Example 1.

15 days after the grouping, the major axis and the minor axis of the subcutaneously transplanted tumor of each group of mice were measured, and the tumor volume ratio (relative tumor volume, RTV) and tumor growth inhibition rate (IR) were calculated from the following formulae. The antitumor effect was determined by calculation. The test results are shown in Table 2.
(Formula 2) RTV = Vt1 / Vt2
[In the formula, RTV represents the tumor volume ratio, Vt1 represents the tumor volume on the date of determination, and Vt2 represents the tumor volume on the grouping date. ]
(Formula 3) IR (%) = [1- (RTVtest) / (RTVcont)] × 100
[Wherein, IR represents the tumor growth inhibition rate, RTVtest represents the average RTV value of the drug administration group, and RTVcont represents the average RTV value of the untreated group. ]

From the results in Table 2, it was revealed that the tumor growth inhibitory rate of the compound of the present invention is equal to or higher than that of the compound of Comparative Example 1, and has an excellent antitumor effect. Moreover, it became clear that this invention compound has the outstanding antitumor effect also compared with the compound of Comparative Examples 2-5.
Test example 2
Nude mouse subcutaneous tumor transplantation system, calculation of therapeutic coefficient for oral administration BALB / cA Jcl-nu mouse (CLEA Japan) subcultured human colon cancer strain KM20C into 2 mm square fragments, 6 or 7 weeks old BALB / cA Jcl-nu mice were implanted subcutaneously on the back. When the average tumor volume after grouping exceeds 100 mm ³ , measure the major axis and minor axis of the tumor, calculate the tumor volume according to the following formula, and then group the group so that there is no variation in the tumor volume of each group Performed (5 or 6 animals per group).
(Formula 1) Vt = 1/2 (Vl) × (Vs) ²
[In the formula, Vt represents the tumor volume, Vl represents the major axis of the tumor, and Vs represents the minor axis of the tumor. ]
The compound of the present invention and the compound of Comparative Example 1 were each dissolved or suspended in a 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The dose was set to a dose that was equimolar with the 3.13, 6.25, 12.5, 25, 50, 100 and 200 mg / kg / day of Comparative Example 1.

15 days after the grouping, the major axis and the minor axis of the subcutaneously transplanted tumor of each group of mice were measured, and the tumor volume ratio (relative tumor volume, RTV) and tumor growth inhibition rate (IR) were calculated from the following formulae. The antitumor effect was determined by calculation. Furthermore, even after the determination of the antitumor effect, the animals were observed for life and death in the period from the grouping to 29 days later.
(Formula 2) RTV = Vt1 / Vt2
[In the formula, RTV represents the tumor volume ratio, Vt1 represents the tumor volume on the date of determination, and Vt2 represents the tumor volume on the grouping date. ]
(Formula 3) IR (%) = [1- (RTVtest) / (RTVcont)] × 100
[Wherein, IR represents the tumor growth inhibition rate, RTVtest represents the average RTV value of the drug administration group, and RTVcont represents the average RTV value of the untreated group. ]
The 50% tumor growth inhibitory dose (ED50) was calculated from the tumor growth inhibitory rate when each dose was administered.

In addition, the therapeutic index was calculated from the following formula, with the dose at which no death occurred during the period from the grouping to 29 days after, as the MTD of each compound.
(Formula 4) Treatment coefficient = MTD / ED50
The test results are shown in Table 3.

As shown in the results of Table 3, the therapeutic index of the compound of the present invention is about twice or more when compared with the compound of Comparative Example 1, and it is clear that the compound has a better balance between efficacy and toxicity. became.
Test example 3
Nude mouse subcutaneous tumor transplantation system, life-prolonging effect in oral administration BALB / cA Jcl-nu mouse (Japan Claire Co., Ltd.) human colon cancer strain KM20C subcultured into 2 mm square fragments, 6 or 7 weeks old BALB / CA Jcl-nu mice were implanted subcutaneously on the back. When the average tumor volume after grouping exceeds 100 mm ³ , measure the major axis and minor axis of the tumor, calculate the tumor volume according to the following formula, and then group the group so that there is no variation in the tumor volume of each group Performed (5 or 6 animals per group).
(Formula 1) Vt = 1/2 (Vl) × (Vs) ²
[In the formula, Vt represents the tumor volume, Vl represents the major axis of the tumor, and Vs represents the minor axis of the tumor. ]
The compound of the present invention and the compound of Comparative Example 1 were each dissolved or suspended in a 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The dose was set to a dose that was equimolar with 100 mg / kg / day of Comparative Example 1.

The life and death of the mice at the time of administration of each compound from 29 days after grouping were confirmed. The survival rate at the time of administration of each compound was calculated from the following formula, and the test results are shown in FIG.
(Formula 2) Survival rate (%) = number of surviving animals / number of animals per group × 100
In the results of FIG. 1, in the group administered with the compound of Comparative Example 1, animals that die after 17 days (3 days after the end of administration) after grouping were observed, and on the 19th day (6 days after the end of administration) after grouping. All patients died by day). On the other hand, in the groups administered with the compounds of Examples 2, 3, 6, 7, 11, 12 and 14, all cases were confirmed to be alive until 29 days after the grouping. From the above results, it was revealed that the compound of the present invention is a compound that provides an excellent life prolonging effect as compared with the compound of Comparative Example 1.

Claims (7)

The following general formula (1)
[In the formula, ^one of A ¹ and A ² represents a hydrogen atom or a group represented by R ¹ —CO— and the other represents a group represented by R ² —CO—, or one represents a hydrogen atom or A group represented by R ³ — (O—CH ₂ ) _m — and the other represents a group represented by R ⁴ — (O—CH ₂ ) _n —, or one represented by R ¹ —CO—. And the other is a group represented by R ³ — (O—CH ₂ ) _m —, provided that n = 1 when one of A ¹ and A ² is hydrogen,
R ¹ and R ² may be the same or different and each may have a linear or branched alkyl group having 1 to 6 carbon atoms, or may have a substituent group having 3 to 7 carbon atoms. A cyclic alkyl group or an aryl group having 6 to 14 carbon atoms which may have a substituent,
m is 0 or 1,
n is 0 or 1;
R ³ and R ⁴ are the same or different and are aralkyl groups having 7 to 15 carbon atoms which may have a substituent. ]
The pyrimidine nucleoside compound represented by these, or its salt. When A ¹ is a group represented by R ² —CO— and A ² is a hydrogen atom,
R ² is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent or a cyclic alkyl group having 3 to 7 carbon atoms which may have a substituent,
When A ¹ is a hydrogen atom and A ² is a group represented by R ² —CO—,
R ² has a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent, a cyclic alkyl group having 3 to 7 carbon atoms which may have a substituent, or a substituent. An aryl group having 6 to 14 carbon atoms,
When A ¹ is a group represented by R ¹ —CO— and A ² is a group represented by R ² —CO—,
R ¹ and R ² are the same or different and each is a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent,
When A ¹ is a group represented by R ⁴ — (O—CH ₂ ) _n — and A ² is a hydrogen atom,
n is 0 or 1;
R ⁴ is an optionally substituted aralkyl group having 7 to 15 carbon atoms, and A ¹ is a group represented by R ³ — (O—CH ₂ ) _m —, wherein A ² is R ^When it is a group represented by 4- (O—CH ₂ ) _n —,
m is 0,
n is 0,
R ³ and R ⁴ are the same or different and are an aralkyl group having 7 to 15 carbon atoms which may have a substituent,
The pyrimidine nucleoside compound or a salt thereof according to claim 1. R ¹ and R ² are the same or different and are each a linear or branched alkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 7 carbon atoms, or an aryl group having 6 to 14 carbon atoms,
R ³ and R ⁴ are the same or different and are an aralkyl group having 7 to 15 carbon atoms which may have a halogen atom as a substituent.
The pyrimidine nucleoside compound or a salt thereof according to claim 1 or 2. R ¹ and R ² are the same or different and are a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a cyclohexyl group, or a phenyl group;
R ³ and R ⁴ are the same or different and are a benzyl group, a 4-chlorobenzyl group, a 3,4-dichlorobenzyl group, or a 4-bromobenzyl group.
The pyrimidine nucleoside compound or a salt thereof according to any one of claims 1 to 3. The pyrimidine nucleoside compound or salt thereof according to any one of the following (1) to (16):
(1) 1- [2′-Deoxy-3′-O-cyclohexanecarbonyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (2) 1- [2′-deoxy-3′- O-propionyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (3) 1- [2′-deoxy-3′-O-isobutyryl-4′-thio-1-β-D- Ribofuranosyl] -5-fluorouracil (4) 1- [5′-O-cyclohexanecarbonyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (5) 1- [5 ′ —O-cyclopropanecarbonyl-2′-deoxy-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (6) 1- [5′-O-benzoyl-2′-deoxy-4′- Thio-1-β-D-ribofuranosyl -5-fluorouracil (7) 1- [5'-O-propionyl-2'-deoxy-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (8) 1- [2'-deoxy- 3 ′, 5′-O-di-acetyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (9) 1- [2′-deoxy-3 ′, 5′-O-di- Isobutyryl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (10) 1- [2′-deoxy-3 ′, 5′-O-di-propionyl-4′-thio-1-β -D-ribofuranosyl] -5-fluorouracil (11) 1- [2'-deoxy-3'-O-benzyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (12) 1- [ 2′-deoxy-3 ′, 5′-O-dibenzyl-4′-thio-1-β-D Ribofuranosyl] -5-fluorouracil (13) 1- [2′-deoxy-3′-O-benzyloxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil (14) 1- [2 '-Deoxy-3'-O- (4-chlorobenzyl) oxymethyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (15) 1- [2'-deoxy-3'-O -(3,4-Dichlorobenzyl) oxymethyl-4'-thio-1-β-D-ribofuranosyl] -5-fluorouracil (16) 1- [2'-deoxy-3'-O- (4-bromobenzyl) ) Oxymethyl-4′-thio-1-β-D-ribofuranosyl] -5-fluorouracil   A pharmaceutical composition comprising an effective amount of the pyrimidine nucleoside compound or a salt thereof according to any one of claims 1 to 5 and a pharmaceutical carrier.   An antitumor agent comprising an effective amount of the pyrimidine nucleoside compound or a salt thereof according to any one of claims 1 to 5 and a pharmaceutical carrier.