JP2655003B2 - 5-Substituted uridine derivatives and intermediates for producing the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a 5-substituted uridine derivative which is a novel substance and a 5′-trityl-5-substituted uridine derivative which is an intermediate for producing the derivative. The 5-substituted uridine derivative of the present invention has an excellent anticancer effect and is useful as an antitumor agent.

BACKGROUND ART 5-Fluorouridine (hereinafter abbreviated as FUR) was synthesized in 1959, and its excellent antineoplastic activity is already known (US Patent No. 2885398), but because of its high toxicity, There are problems with clinical use.

Conventionally, many attempts have been made to solve the above problem by converting FUR into various derivatives (Japanese Patent Application Laid-Open Nos. 50-64280, 51-52183, 57-91997, and 61-91997).
-246196), but a useful derivative has not yet been obtained.

Also, 5-trifluoromethyl-2 'represented by the following formula:
- deoxyuridine (hereinafter abbreviated as F ₃ TdR) Shows antitumor activity (Cancer Research Vol. 24, No. 19
79 (1964) [Cancer. Research 24, 1979, 1964]] and has a strong antiviral effect (Cancer Research, Vol. 30, 1549 (1970) [Cancer. Research 30,154
9,1970]). From such a point, various studies have been conducted on the usefulness of F ₃ TdR as a pharmaceutical, but a useful compound has not been obtained yet.

Object the present inventors and means for solving the problems in view of the above situation, compared to the FUR and F ₃ TdR, low toxicity, yet to develop a 5-substituted uridine derivatives with a higher antitumor effect As a result of intensive studies, it has been found that the 5-substituted uridine derivative of the present invention can achieve this object, and that the 5'-trityl-5-substituted uridine derivative is useful as an intermediate in the production of the 5-substituted uridine derivative. The inventors have found that the present invention has been completed.

That is, the present invention provides: [Wherein, X represents a fluorine atom or a trifluoromethyl group, and R ₁ and R ₂ represent (a) a general formula -OSi- (R ₄ )
(R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ are the same or different and each have an alkyl group having 1 to 10 carbon atoms, a general formula — (CH ₂ ) _n Ph
(In the formula, n represents 0 to 2, and Ph represents a phenyl group.)
A group represented by or formula _{-OSi- (R 7) (R 8} ) (OH)
(Wherein, R ₇ and R ₈ are the same or different and each represent a lower alkyl group). ) Group,
(B) a hydroxyl group, (c) an aminoacyloxy group in which an amino group may be substituted with a lower alkyl group or (d) a carboxylalkylcarbonyloxy group, and R ₃ is a group represented by the general formula -OSi- (R ₄ ) ( R ₅ ) (R ₆ ) wherein R ₄ , R ₅ and R ₆
Has the same meaning as described above. ), An aminoacyloxy group or a carboxylalkylcarbonyloxy group in which a hydrogen atom, a hydroxyl group, or an amino group may be substituted with a lower alkyl group. Provided that at least one of R ₁ R ₂ and R ₃ is a group —OSi— (R ₄ ) (R ₅ ) (R ₆ ) (wherein
R ₄ , R ₅ and R ₆ have the same meaning as described above. )
And when X is a fluorine atom, R ₃ is not a hydrogen atom] or a pharmaceutically acceptable salt thereof; [Wherein, X represents a fluorine atom or a trifluoromethyl group, and R ₂ ′ represents a hydroxyl group or a general formula -OSi- (R ₄ )
(R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ are the same or different and each have an alkyl group having 1 to 10 carbon atoms, a general formula — (CH ₂ ) _n Ph
(In the formula, n represents 0 to 2, and Ph represents a phenyl group.)
A group represented by or formula _{-OSi- (R 7) (R 8} ) (OH)
(Wherein, R ₇ and R ₈ are the same or different and each represent a lower alkyl group). And R ₃ ′ is a hydrogen atom, a hydroxyl group or a general formula -OSi-
(R ₄ ) (R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ have the same meaning as described above). Provided that at least one of R ₂ ′ and R ₃ ′ is a group —OSi— (R ₄ ) (R ₅ )
(R ₆ ) (wherein R ₄ , R ₅ and R ₆ have the same meanings as described above), and when X is a fluorine atom, R ₃ ′
Is not a hydrogen atom.] Is a 5-substituted-5'-trityluridine derivative represented by the formula:

The present invention also provides an antitumor agent comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the present invention provides a method for treating a tumor, which comprises administering an effective amount of the compound of the general formula (I) or a pharmaceutically acceptable salt thereof to a mammal.

FUR and F ₃ T
Compared with dR, it has lower toxicity, has a strong antitumor effect, and is useful as a medicine. Further, the 5'-trityl-5-substituted uridine derivative (II) is useful as an intermediate for producing the compound (I).

In the general formula (I), as the aminoacyloxy group in which the amino group represented by R ₁ , R ₂ and R ₃ may be substituted with a lower alkyl group, one or two hydrogen atoms on the nitrogen atom are included. Lower alkyl groups such as methyl, ethyl and propyl,
In particular, an acyloxy group having 2 to 6 carbon atoms in which one or two amino groups which may be substituted with a C _{1 to} C ₄ alkyl group are substituted,
Particularly an alkylcarbonyloxy group, specifically,
Glycyloxy, N, N-dimethylglycyloxy, alanyloxy, α-aminoisobutyryloxy, α-aminobutyryloxy, α-N, N-dimethylaminobutyryloxy, N, N-diethylalanyloxy, valyloxy , Leucyloxy, isoleucyloxy, ornithinyloxy, ridinyloxy, α, β-di (dimethylamino) propionyloxy group and the like. As the carboxylalkylcarbonyloxy group, those having 3 to 6 carbon atoms, such as a carboxylmethylcarbonyloxy group,
Examples thereof include a 2-carboxylethylcarbonyloxy group, a 2-carboxylpropylcarbonyloxy group, a 3-carboxylpropylcarbonyloxy group, and a 4-carboxylbutylcarbonyloxy group.

Examples of the alkyl group having 1 to 10 carbon atoms represented by R ₄ , R ₅ and R ₆ include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, n
Examples thereof include linear or branched alkyl groups such as eo-pentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, octyl, nonyl, and decyl groups. Also, R ₇ and
Examples of the lower alkyl group represented by R ₈ include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as ert-butyl, pentyl, neo-pentyl and hexyl groups.

In the above compound (I) of the present invention, X is a fluorine atom, and one or two of R ₁ , R ₂ and R ₃ are represented by the general formula —OSi
− (R ₄ ′) (R ₅ ′) (R ₆ ′) [wherein R ₄ ′, R ₅ ′ and
R ₆ 'is the same or different, an alkyl group, a benzyl group having 1 to 8 carbon atoms, 2-phenylethyl group or a group -OSi-
(R ₇ ) (R ₈ ) (OH) wherein R ₇ and R ₈ are the same or different and represent a lower alkyl group. The remaining one or two of R ₁ , R ₂ and R ₃ is a hydroxyl group, and an aminoalkylcarbonyloxy group or a carboxylalkylcarbonyloxy group in which the amino group may be substituted with a lower alkyl group. Are preferred. Among such preferred compounds, R ₁ is the group -OSi
− (R ₄ ′) (R ₅ ′) (R ₆ ′) [wherein R ₄ ′, R ₅ ′ and
R ₆ ′ is the same as above), and R ₂ and R ₃ are the same and a hydroxyl group,
A compound in which an amino group represents an aminoalkylcarbonyloxy group or a carboxylalkylcarbonyloxy group which may be substituted with a lower alkyl group, and R ₁ is a hydroxyl group, R ₂ and R ₃ are the same, and the above group —OSi- ( R ₄ ')
Compounds which are (R ₅ ′) (R ₆ ′), wherein R ₄ ′, R ₅ ′ and R ₆ ′ are as defined above, can be particularly mentioned.

In the general formula (I), X is a trifluoromethyl group, R ₃ is a hydrogen atom, and _one of R ₁ and R ₂ is a group —OSi- (R ₄ ′) (R ₅ ′) (R ₆ ′) [wherein R ₄ ′, R ₅ ′
And R ₆ ′ are the same or different and each are an alkyl group having 1 to 8 carbon atoms, a benzyl group, a 2-phenylethyl group or a group —OSi—
(R ₇ ) (R ₈ ) (OH) wherein R ₇ and R ₈ are the same or different and each represent a lower alkyl group. And R ₁ and
The other of R _{2 represents} a hydroxyl group, an amino group may be an aminoalkylcarbonyloxy group or a carboxyalkylcarbonyloxy group which may be substituted with a lower alkyl group, or
R ₁ and R ₂ both represent the above group —OSi— (R ₄ ′) (R ₅ ′)
(R ₆ ′) wherein R ₄ ′, R ₅ ′ and R ₆ ′ are the same as described above.
Are also preferred compounds of the present invention.

More preferred compounds of the present invention include the following (i) and (ii)
belongs to.

(I) In the general formula (I), X is a fluorine atom,
One or two of R ₁ , R ₂ and R ₃ are a tert-butyldimethylsilyloxy group, a dimethyloctylsilyloxy group or a benzyldimethylsilyloxy group, and one or more of the remaining R ₁ , R ₂ and R ₃ two are hydroxyl group, an amino group is optionally substituted Gurishiruokishi group or carboxyethyl carbonyloxy group by a lower alkyl group compound; (ii) in the general formula (I), X is trifluoromethyl group, R ₃ Is a hydrogen atom, and _one of R ₁ and R ₂ is tert.
-Butyldimethylsilyloxy group or benzyldimethylsilyloxy group, the other of R ₁ and R ₂ is a hydroxyl group, a glycyloxy group optionally substituted with an amino group with a lower alkyl group or a carboxylethylcarbonyloxy group, Or a compound in which both R ₁ and R ₂ are a tert-butyldimethylsilyloxy group or a benzyldimethylsilyloxy group.

As the more preferable compound of the present invention of the type (i), in particular, in the general formula (I), X is a fluorine atom, and R ₁ is a tert-butyldimethylsilyloxy group, a dimethyloctylsilyloxy group or a benzyldimethyl group. A silyloxy group, a compound in which R ₂ and R ₃ are the same and are a hydroxyl group, a glycyloxy group or a carboxyethylcarbonyloxy group in which the amino group may be substituted with a lower alkyl group, and R ₁ is a hydroxyl group, ₂ and R ₃ are the same and tert-
Examples of the compound include a butyldimethylsilyloxy group, a dimethyloctylsilyloxy group, and a benzyldimethylsilyloxy group.

Particularly preferred compounds of the general formula (I) are, for example, the following compounds.

5'-O-tert-butyldimethylsilyl-5-fluorouridine 2 ', 3'-bis (O-tert-butyldimethylsilyl)
-5-fluorouridine 5'-O-dimethyloctylsilyl-5-fluorouridine 5'-O-benzyldimethylsilyl-5-fluorouridine 5'-O-tert-butyldimethylsilyl-2 ', 3'-
Bis (O-dimethylglycyl) -5-fluorouridine 5'-O-tert-butyldimethylsilyl-2'-deoxy-5-trifluoromethyluridine 5'-O-tert-butyldimethylsilyl-2 ', 3 '-
Bis (O-2-carboxyethylcarbonyl) -5-fluorouridine Further, among the compounds (II) which are intermediates of the present invention, preferred are, for example, the following compounds.

2'-O-tert-butyldimethylsilyl-5'-O-
Triphenylmethyl-5-fluorouridine 3'-O-tert-butyldimethylsilyl-5'-O-
Triphenylmethyl-5-fluorouridine 2 ', 3'-bis (O-tert-butyldimethylsilyl-
5'-O-triphenylmethyl-5-fluorouridine 2'-O-benzyldimethylsilyl-5'-O-triphenylmethyl-5-fluorouridine 3'-O-tert-butyldimethylsilyl-5'-O −
Triphenylmethyl-2'-deoxy-5-trifluoromethyluridine The method for producing the compound of the present invention is described below.
The compound (I) of the present invention is produced by any of the following methods A, B and C.

Method A Compound (I) of the present invention can be prepared as shown in the following reaction formula.
It can be obtained by reacting compound (III) with a halogenosilyl compound represented by formula (IV) in a solvent in the presence of a basic catalyst.

Wherein X and R ₄ , R ₅ and R ₆ are the same as defined above, and X ₁
Is a halogen atom, R ₉ is a hydrogen atom or a hydroxyl group, R ₁₀ and R ₁₁ are a hydroxyl group or a general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ )
Wherein R ₄ , R ₅ and R ₆ are the same as defined above, and R ₁₂ is a hydrogen atom, a hydroxyl group or a general formula -OSi- (R ₄ )
(R ₅ ) (R ₆ ) wherein R ₄ , R ₅ and R ₆ are the same as defined above, and at least one of R ₁₀ , R ₁₁ and R ₁₂ is a group represented by the general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ are as defined above). However, when X is a fluorine atom, the case where R ₉ and R ₁₂ are a hydrogen atom is excluded. Specific examples of the halogen atom for X ₁ include chlorine,
It is each atom of bromine and iodine.

The solvent used here is not particularly limited as long as it does not adversely affect the above reaction, and conventionally known solvents can be widely used. For example, benzene, toluene, aromatic hydrocarbons such as xylene, ether, tetrahydrofuran, ethers such as dioxane, acetonitrile,
An aprotic solvent such as pyridine, dimethylformamide, dimethylsulfoxide and the like can be used alone or in combination of two or more.

As the basic catalyst, organic bases such as pyridine, dimethylaminopyridine, 2,6-lutidine, imidazole and triethylamine are preferably used.

The amount of the basic catalyst to be used is generally about 1 to 10 mol, preferably about 1.5 to 4 mol, per 1 mol of compound (III). The amount of the halogenosilyl compound represented by the general formula (IV) is usually per 1 mol of the compound (III).
It is about 0.5 to 10 mol, preferably about 0.8 to 3.1 mol.

The reaction temperature is preferably about 0 to 80 ° C, preferably about room temperature to about 50 ° C. The reaction time varies depending on the type of the solvent and the basic catalyst used, but is usually about 0.5 to 20 hours.

Method B General formula (II ') [Wherein, X represents a fluorine atom or a trifluoromethyl group, and R ₁₃ represents a hydroxyl group or a general formula -OSi- (R ₄ ) (R ₅ )
Represents a group represented by (R _6), R ₁₄ represents a group represented by a hydrogen atom, a hydroxyl group or the formula _{-OSi- (R 4) (R 5} ) (R 6), at least R ₁₃ and R ₁₄ One is the general formula -OSi-
It is a group represented by (R ₄ ), (R ₅ ), and (R ₆ ). However, the case where X is a fluorine atom and the case where R ₁₄ is a hydrogen atom are excluded. Here, R ₄ , R ₅ and R ₆ are the same as described above. The compound (I ″) of the present invention is produced by detritylation of the 5′-trityl-5-substituted uridine derivative represented by the following formula in the presence of an acid catalyst.

Wherein X, R ₁₃ and R ₁₄ are the same as above. As the solvent that can be used in this reaction, the same solvents as those described for Method A can be used. As the acid catalyst, organic carboxylic acids such as formic acid and acetic acid, and organic sulfonic acids such as tosylic acid are preferably used.

The amount of the acid catalyst to be used is generally about 0.01 to 10 mol, preferably about 0.05 to 10 mol, per 1 mol of the 5'-trityl-5-substituted uridine derivative (II ').

The reaction temperature is about 0 to 130 ° C, preferably room temperature to about 80 ° C. The reaction time varies depending on the type of solvent and base used, but is usually about 0.5 to 10 hours.

The 5′-trityl-5-substituted uridine derivative (II ′), which is an intermediate of the present invention, is represented by the following reaction formula:
It is produced by reacting a known compound, a 5'-trityl-5-substituted uridine derivative (V), with a halogenosilyl compound represented by the general formula (IV) in the presence of a basic catalyst.

Wherein R ₉ , X and X ₁ are the same as above. The reaction conditions such as the solvent, the basic catalyst, the reaction temperature, the reaction time, and the amount of the reactant used in this reaction are the same as those defined in Method A.

C method General formula [Wherein, X is the same as defined above, R ₁₅ and R ₁₆ are groups represented by the general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ), and the amino group is substituted with a lower alkyl group. Represents an aminoacyloxy group or a carboxylalkylcarbonyloxy group which may be substituted, R ₁₇ is a group represented by the general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ), and the amino group is substituted by a lower alkyl group Represents an aminoacyloxy group, a carboxylalkylcarbonyloxy group, or a hydrogen atom, wherein at least one of R ₁₅ , R ₁₆ and R _{17 is} a group represented by the general formula —OSi— (R ₄ ) (R ₅ ) (R ₆ ) And at least one of R ₁₅ , R ₁₆ and R ₁₇ is an aminoacyloxy group or a carboxylalkylcarbonyloxy group in which the amino group may be substituted with a lower alkyl group. However, when X is a fluorine atom, R ₁₇ is not a hydrogen atom. Also, R ₄ , R
₅ and R ₆ have the same meaning as described above. The compound of the present invention represented by the general formula produced by the method A or the method B Wherein X is the same as defined above, and R ₁₅ ′ and R ₁₆ ′ are
Hydroxyl group or the formula _{-OSi- (R 4) (R 5} ) a group represented by (R _6), R ₁₇ 'represents a hydrogen atom, a hydroxyl group or formula -OSi
— (R ₄ ) (R ₅ ) (R ₆ ), and
At least one of R ₁₅ ′, R ₁₆ ′ and R ₁₇ ′ has the general formula —OSi
— (R ₄ ) (R ₅ ) (R ₆ ), and R
₁₅ ', R _16' at least one of and R ₁₇ 'is a hydroxyl group. However, when X is a fluorine atom, R ₁₇ ′ is not a hydrogen atom. Further, R ₄ , R ₅ and R ₆ here are the same as described above. A compound represented by the following general formula (VIII) or a reactive derivative thereof or a compound represented by the general formula (IX) under the presence or absence of a condensing agent in the presence of a basic catalyst. It is produced by reacting an acid anhydride of a dicarboxylic acid. The compound represented by the general formula (VIII) or (IX) or a reactive derivative thereof is a compound represented by the formula (VII), wherein R ₁₅ ′, R ₁₆ ′ and R ₁₇ ′
Reacts with a hydroxyl group represented by at least one of the following.

R ₁₈ COOH (VIII) wherein R ₁₈ represents an aminoalkyl group in which the amino group may be substituted with a lower alkyl group, particularly a C ₁ -C ₅ aminoalkyl group. ] HOOC-R ₁₉ -COOH (IX) wherein, R ₁₉ represents an alkylene group, in particular C ₁ -C ₄ alkylene group. The reactive derivative of the carboxylic acid represented by the general formula (VIII) includes an acid halide, an acid anhydride and the like. The use of a condensing agent is not essential, but the reaction can proceed smoothly by using the condensing agent together. As a condensing agent
N, N-dicyclohexylcarboximide, 2-chloro-1-methylpyridinium tosylate and the like are used,
The amount of use is usually about 2 to 6 mol, preferably about 2 to 4 mol, per 1 mol of the compound of the general formula (VII).

Solvents that can be used in this reaction include methylene chloride,
Halogenated hydrocarbons such as 2-dichloroethane and chloroform, and ethers such as ether, tetrahydrofuran and dioxane can be used alone or in combination. As the basic catalyst, organic bases such as pyridine, dimethylaminopyridine, 2,6-lutidine, imidazole, triethylamine and the like are suitably used, and the amount of use is usually about 0.1 to 20 mol per 1 mol of compound (VII). And preferably about 5 to 10 mol.

The amount of the compounds represented by the general formulas (VIII) and (IX) to be used is generally about 1 to 6 mol, preferably about 2 to 4 mol, per 1 mol of the compound (VII). The reaction temperature is about 0 to 60 ° C, preferably about 0 to 30 ° C. The reaction time varies depending on the type of catalyst and basic catalyst used, but usually the reaction is completed in about 0.1 to 48 hours.

The thus obtained 5-substituted uridine derivative of the present invention can usually be easily separated and purified by known separation and purification means, for example, recrystallization, reprecipitation, column chromatography and the like.

The compound of the present invention can be used as it is as a therapeutic agent for malignant tumors, but can be derived into a pharmaceutically acceptable salt in order to increase water solubility for injection and the like, and to enhance its translocation into the body. As the pharmaceutically acceptable salt, in the compound of the present invention represented by the general formula (I), an acid component which forms a salt with an aminoacyloxy group optionally having an amino group substituted with a lower alkyl group; It is an alkali component capable of forming a salt with the carboxylalkylcarbonyloxy group portion of the compound, and is not particularly limited as long as it shows sufficient potency even when converted to a salt and is nontoxic or low toxic to living organisms. Specific examples of the acid component include hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, inorganic acids such as phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, formic acid, oxalic acid, succinic acid, ring acid, citric acid, Organic acids such as tartaric acid are exemplified. Specific examples of the alkali component include primary metals such as alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, piperidine, cyclohexylamine and triethylamine. Secondary and tertiary amines can be exemplified.

The above-mentioned salt can be prepared by subjecting the compound of the present invention represented by the general formula (I) to a method known in the art for producing a salt, for example,
It is obtained by reacting an acid or alkali component with a stoichiometric amount.

When the salt is soluble in the solvent, it can be produced by adding an insoluble solvent or by freeze-drying, or when the salt is sufficiently insoluble in the solvent, passing the produced salt. The salt obtained by the above method can be purified by MCI gel (manufactured by Mitsubishi Kasei Corporation, Japan) or the like.

Pharmaceutical administration forms when the compound of the present invention is used as a therapeutic agent for malignant tumors of mammals including humans include injection,
Parenteral preparations such as suppositories, eye drops and aerosols, tablets, coated tablets, powders, granules, capsules, liquid preparations and other oral preparations can be used, and oral preparations are generally preferred. The above-mentioned administration agent is formulated by a production method generally known in this field. When preparing a solid preparation for oral use, an excipient, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. are added to the component of the present invention, and then the mixture is prepared in a usual manner. Tablets, coated tablets, granules, powders, capsules and the like can be manufactured. When preparing an injection, the active ingredient of the present invention should be adjusted to pH
Additives, buffers, stabilizers, tonicity agents, local anesthetics and the like can be added to produce subcutaneous, intramuscular, and intravenous injections in a conventional manner. When preparing suppositories, a suppository can be produced by a conventional method after adding a base and, if necessary, a surfactant to the active ingredient of the present invention. Excipients used in oral solid preparations may be those generally used in this field, and specifically include lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, methylcellulose, glycerin , Sodium alginate, gum arabic, binders such as polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, ethyl cellulose, gum arabic, shellac, sucrose, water, ethanol, propanol, carboxymethyl cellulose, potassium phosphate, etc., as lubricants Magnesium stearate, talc and the like can be used, and other generally known additives such as a coloring agent and a disintegrant can also be used. As a base material for producing a suppository, for example, an oily base such as cocoa butter, polyethylene glycol, lanolin, fatty acid triglyceride, and Witepsol (registered trademark, Dynamite Nobel) can be used. Liquid preparations may be aqueous or oily suspensions, solutions, syrups and elixirs and are prepared according to the usual methods using conventional additives.

The amount of the compound (I) of the present invention in the pharmacological composition of the present invention varies depending on the dosage form, the solubility of the compound, the chemical properties, the administration route, the administration schedule, etc., but generally 10 to 15% w / w for an oral preparation.
In the case of parenteral injections, the concentration may be about 0.1 to 1 w / w%.

The dose of the compound (I) of the present invention is determined depending on the individual case in consideration of the symptoms, the age and sex of the administration subject, and the like. Dosing is divided into 4 times. In the case of injection, for example, in the case of intravenous administration, usually 2 ml (1 to 10 m
g) is diluted with physiological saline or glucose injection solution as needed, and administered gradually over 5 minutes. For suppositories,
Usually, for adults, about 1 to 300 mg once or twice a day, 6 to 1
The drug is inserted into the rectum at an interval of 2 hours.

Formulation examples are shown below. The compound No. of the compound (I) of the present invention used in the following formulation examples corresponds to the compound No. in the examples described later.

Formulation Example 1: Tablet Compound 1 50 g Lactose 200 g Corn starch 80 g Hydrolyzed starch 20 g Calcium stearate 10 g 360 g Compound 1, lactose, corn starch and hydrolyzed starch were mixed, and water was added to form an active paste. After drying at 45 ° C. overnight, it was sieved. Add calcium stearate to this and weigh 36 with a tableting machine.
Tablets of 0 mg, 10 mm in diameter were produced.

Formulation Example 2: Capsules Compound 4 25.0 g Lactose 150.0 g Maize starch 40.0 g Talc 5.0 g 200 mg of compound, lactose and corn starch in one capsule were mixed and pulverized. Talc was added and filled into hard gelatin capsules.

Formulation Example 3: Injection While stirring compound 40 (50 g) and glucose 400 g at room temperature sequentially, distilled water for injection was added to make a total volume of 10 liters.
The mixture was aseptically filled and filled into a 2 ml colorless ampoule, filled with nitrogen gas and ventilated to produce an injection of 10 ml per tube.

Examples Examples of the present invention are shown below.

Example 1 Preparation of 5'-O-tert-butyldimethylsilyl-5-fluorouridine (compound 1) 1.50 g (5.72 mmole) of 5-fluorouridine was added to 5 ml of N, N
-Dissolved in dimethylformamide. To the above solution, 520 mg (7.64 mmol) of imidazole and 633 mg (4.20 mmol) of tert-butyldimethylsilyl chloride were added, and the mixture was added at room temperature.
The reaction was performed for 15 hours. The reaction solution was ice-cooled, added with 40 ml of water, and extracted three times with 40 ml of ethyl acetate. Combine the organic layers,
After washing three times with 50 ml of water and three times with 50 ml of saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 20: 1), the eluate was concentrated, and the residue was recrystallized from ether to give 1.3 g of the title compound as white crystals (yield). 60%).

Example 2 (a) 5'-O-trityl-2'-O-tert-butyldimethylsilyl-5-fluorouridine (Compound A),
5'-O-trityl-3'-O-tert-butyldimethylsilyl-5-fluorouridine (compound B) and 5'-
Preparation of O-trityl 2 ', 3'-bis (O-tert-butyldimethylsilyl) -5-fluorouridine (Compound C) 5.0 g of 5'-O-trityl-5-fluorouridine (9.
99 mmol) was dissolved in 70 ml of N, N-dimethylformamide. 1.35 g (19.8 mmole) of imidazole and
1.78 g of tert-butyldimethylsilyl chloride (11.8 mmo
le), and reacted at room temperature for 12 hours. The reaction solution was ice-cooled, added with 30 ml of water, and extracted with 150 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 100: 1) to obtain 1.3 g (yield) of Compound C having an Rf value of 0.65 (chloroform: methanol = 50: 1). 0.90 g (yield 14.6%) of compound B having an Rf value of 0.50 (chloroform: methanol = 50: 1).
%) And an Rf value of 0.40 (chloroform: methanol = 50: 1)
0.75 g (yield 12.2%) of Compound A was obtained.

(B) 2'-O-tert-butyldimethylsilyl-5-
Fluorouridine (compound 2), 3'-O-tert-butyldimethylsilyl-5-fluorouridine (compound 3)
And production of 2 ', 3'-bis (O-tert-butyldimethylsilyl) -5-fluorouridine (compound 4) 5'-O-trityl-2'-O-tert obtained above
To 1.2 g (1.64 mmole) of -butyldimethylsilyl-5-fluorouridine (Compound A) was added 5 ml of an 80% aqueous acetic acid solution, and the mixture was stirred at 80 ° C for 1 hour. After the reaction, the reaction mixture was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform: methanol = 20: 1), the eluate was concentrated, and the obtained residue was recrystallized from ether to give 0.40 g of Compound 2. Obtained as white crystals (yield 64.9%).

Similarly, 5'-O-trityl-3'-O-tert-
From 0.80 g (1.09 mmole) of butyldimethylsilyl-5-fluorouridine (Compound B), 0.35 g of Compound 3 was obtained as white crystals (yield: 85.3%). Or 1.1 g (1.50 mm) of 5'-O-trityl-2 ', 3'-bis (O-tert-butyldimethylsilyl) -5-fluorouridine (compound C)
ole) to give 0.65 g of compound 4 as white crystals (yield)
88.3%).

Example 3 2 ', 3', 5'-tri (O-tert-butyldimethylsilyl) -5-fluorouridine (compound 5), 2 ', 5'-
Bis (O-tert-butyldimethylsilyl) -5-fluorouridine (compound 6) and 3 ', 5'-bis (O-rert
Preparation of -Butyldimethylsilyl) -5-fluorouridine (Compound 7) 2 g (7.63 mmole) of 5-fluorouridine was dissolved in 5 ml of N, N-dimethylformamide. To the above solution, 1.24 g (18.3 mmole) of imidazole and 2.98 g (19.1 mmole) of tert-butyldimethylsilyl chloride were added, and the mixture was stirred at room temperature for 10 hours. The reaction solution was cooled on ice, 60 ml of water was added, and then 30
Extracted with 0 ml of ethyl acetate. The extract was washed three times with 50 ml of a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (benzene: ether = 17: 1),
0.97 g (yield 21%) of compound 5 having an Rf value of 0.40 (benzene: ether = 17: 1), and 0.99 g (yield) of compound 7 having an Rf value of 0.30 (benzene: ether = 17: 1) 0.1 g (yield 2.7%) of compound 6 having an Rf value of 0.12 (benzene: ether = 17: 1).

Hereinafter, compounds 8 to 34 shown in Table I below were produced in the same manner.

The ¹ H-NMR (solvent D) of Compounds 1-34 of the present invention and Compounds A to C of the present invention are shown in Table I and Table II, respectively.
The δ (ppm) value and melting point (° C.) of MSO, internal standard TMS) are shown. In the following description, the value of the coupling constant J in the ¹ H-NMR spectrum data is expressed in Hz.

Example 4 Synthesis of 5'-O-tert-butyldimethylsilyl-5-trifluoromethyl-2'-deoxyuridine (Compound 35) 5-trifluoromethyl-2'-deoxyuridine 1.
0 g (3.6 mmole) was dissolved in 3 ml of N, N-dimethylformamide. 0.49 g of imidazole (7.2 mmol
e) and 0.64 g of tert-butyldimethylsilyl chloride
(4.3 mmole) was added and reacted at room temperature for 10 hours. Hereinafter, the same treatment as in Example 1 was carried out except that the developing solvent for silica gel column chromatography was chloroform: methanol = 30: 1, and 0.6 g of white crystals having a melting point of 199 to 200 ° C. (yield)
41%) of the title compound were obtained.

¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ values, ppm) 11.9 (1H, b , N-3H) 8.1 (1H, s, 6-H) 6.03 (1H, t, J = 6.8, 1'-H) 5.28 (1H, b, -OH) 4.00 to 4.28 (1H, b, 3'-H) 3.84 to 4.00 (1H, m, 4'-H) 3.68 to 3.84 (2H, m, 5 ' _{-CH 2) 2.00~2.32 (2H, m} , 2'-CH 2) 0.85 (9H, s, t-Bu) 0.05 (6H, s, -Si (CH 3) 2) example 5 3 ', 5' -Bis (O-tert-butyldimethylsilyl)
Synthesis of -5-trifluoromethyl-2'-deoxyuridine (Compound 36) 5-trifluoromethyl-2'-deoxyuridine 1.
0 g (3.6 mmole) was dissolved in 5 ml of N, N-dimethylformamide. To the above solution, imidazole 1.02g (15mmole)
And 1.14 g of tert-butyldimethylsilyl chloride (7.6
0 mmole) and reacted at room temperature for 18 hours. Thereafter, the same treatment as in Example 4 was carried out, and 1.6 g of white crystals having a melting point of 93 to 94 ° C. were obtained.
(88.5% yield) of the title compound was obtained.

¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ values, ppm) 11.9 (1H, b , N-3H) 8.1 (1H, s, 6-H) 6.03 (1H, t, J = 6.1, 1'-H) 4.20~4.44 (1H, b, 3'-H) 3.80~4.00 (1H, b, 4'-H) 3.60~3.80 (2H, b, 5'-CH 2) 2.04~2.36 (2H _{, m, 2'-CH 2)} 0.87,0.86 (18H, s, t-Bu) 0.08,0.05 (l2H, s, -Si (CH 3) 2) example 6 5'-O-trityl-3'O-tert-butyldimethylsilyl-5-trifluoromethyl-2'-deoxyuridine (compound D) and 3'-O-tert-butyldimethylsilyl-5-trifluoromethyl-2'-deoxyuridine (compound 37) Synthesis of 5'-O-trityl-5-trifluoromethyl-2 '
3.2 g (5.9 mmole) of deoxyuridine were dissolved in 5 ml of N, N-dimethylformamide. 0.82 g (12 mmole) of imidazole and 1.26 g (8.3 mmole) of tert-butyldimethylsilyl chloride were added to the above solution, and reacted at room temperature for 10 hours. Purification was performed in the same manner as in Example 4 to obtain 3.0 g (yield 94%) of compound D in an amorphous form.

¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ values, ppm) 11.9 (1H, b , N-3H) 8.16 (1H, s, 6-H) 7.36 (15H, m, Ph) 6.07 ( 1H, t, J = 7.0,1'-H) 4.20 to 4.48 (1H, m, 3'-H) 3.80 to 4.04 (1H, m, 4'-H) 3.00 to 3.40 (2H, m, 5'-H) _{CH 2) 2.08~2.44 (2H, m} , 2'-CH 2) 0.80 (9H, s, t-Bu) 0.03, -0.06 (6H, s, -Si (CH 3) 2) 5 obtained in the above '-O-trityl-3'-O-tert
-Butyldimethylsilyl-5-trifluoromethyl-
5% of 80% of 2'-deoxyuridine 2.9g (5.38mmole)
An aqueous acetic acid solution was added, and the mixture was stirred at 60 ° C for 1 hour. After the reaction, the mixture was extracted with saturated saline-ethyl acetate and dried over magnesium sulfate. Purification was performed in the same manner as in Example 4 to obtain 0.32 g (yield 16%) of compound 37 in an amorphous form.

¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ values, ppm) 11.8 (1H, b , N-3H) 8.67 (1H, s, 6-H) 6.05 (1H, t, J = 6.1, 1'-H) 5.26 (1H, b, -OH) 4.24 to 4.52 (1H, b, 3'-H) 3.72 to 3.88 (1H, m, 4'-H) 3.40 to 3.72 (2H, m, 5 ' _{-CH 2) 2.00~2.40 (2H, m} , 2'-CH 2) 0.87 (9H, s, t-Bu) 0.08 (6H, s, -Si (CH 3) 2) example 7 below, similar to the above Compound 38 was synthesized.

5'-O-triisopropylsilyl-5-trifluoromethyl-2'-deoxyuridine (compound 38) Melting point 171-171.5 ° C ¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ value, ppm) 11.9 (1H, b, N-3H) 8.06 (1H, s, 6-H) 6.02 (1H, t, J = 6.8,1'-H) 5.32 (1H, d, J = 4.4, -OH) 4.08 to 4.32 (1H, b, 3'-H ) 3.64~4.00 (3H, m, 4'-H, 5'-CH 2) 2.08~2.32 (2H, m, 2'-CH 2) 0.60~1.32 (21H, m , -Si (iso-Pr) ₃ ) Example 8 5'-O-tert-butyldimethylsilyl-2'3'-
Preparation of bis (O-dimethylglycyl) -5-fluorouridine (Compound 39) In 60 ml of a methylene chloride solution containing 2.5 g (6.65 mmole) of compound 1, 2.0 g (19.9 mmole) of dimethylglycine, N, N-
5.3 g (43.9 mmole) of dimethylaminopyridine and 6 g (20 mmol) of 2-chloro-1-methylpyridinium tosylate
e) was added and stirred at room temperature for 4 hours. After the reaction, ethyl acetate and water were added for extraction. The organic layer was washed with 0.1% cold dilute hydrochloric acid and dried over magnesium sulfate. After distilling off the organic layer,
3 g of compound 39 was obtained in amorphous form. (Yield 82.6%) ¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ value, ppm) 0.12 (6H, s) 0.90 (9H, s) 2.21 (6H, s) 2.26 (6H, s) 3.17 to 3.41 (4H, m) 3.87 (2H, m) 4.24 (1H, m) 5.37 (2H, m) 5.99 (1H, m) 7.98 (1H, d, J = 6.8) 11.96 (1H, br) 9 5'-O-tert-butyldimethylsilyl-2 ', 3'-
Preparation of bis (O-dimethylglycyl) -5-fluorouridine malate (Compound 40) and tosylate (Compound 41) Ether solution 2 containing 560 mg (1.0 mmole) of Compound 39
To 0 ml, 10 ml of an ether solution containing 287 mg (2.14 mmol) of L-malic acid was added,
Stir at room temperature for 1 hour. Remove the precipitated crystals and compound
800 mg of 40 was obtained (98% yield). Similarly, compound 39 was added to 200
mg (0.36 mmole) of ether solution containing 10 ml of tosylate 9
10 ml of an ether solution containing 6 mg (0.7 mmole) was added,
Stir for 30 minutes under ice cooling. Remove the precipitated crystals and compound
245 mg of 41 was obtained (95% yield).

Compound 40 Melting point 95-97 ° C ¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ value, ppm) 0.12 (6H, s) 0.90 (9H, s) 2.26 (6H, s) 2.32 (6H, s) ) 2.40 to 2.60 (4H, m) 3.20 to 3.52 (4H, m) 3.88 (2H, m) 4.08 to 4.32 (3H, m) 5.41 (2H, m) 6.00 (1H, m) 6.00 to 7.60 (6H, br 7.98 (1H, d, J = 6.9) 11.90 (1H, br) Compound 41 amorphous ¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ value, ppm) 0.18 (6H, s) 0.96 (9H, br) s) 2.33 (6H, s) 2.88 (6H, s) 2.93 (6H, s) 3.90 to 4.41 (7H, m) 5.51 (2H, m) 6.19 (1H, m) 7.11 to 7.21 (4H, m) 7.50 to 7.58 (4H, m) 7.99 (1H, d, J = 6.6) 10.04 (2H, br) 12.07 (1H, br) Example 10 5'-O- (2,3-dimethyl-2-butyl) dimethylsilyl- 2 ', 3'-bis (O-dimethylglycyl) -5
-Production of fluorouridine (compound 42) 763 mg (7.41 mmole) of dimethylglycine was added to 20 ml of a methylene chloride solution containing 1 g (2.47 mmole) of compound 14, N, N-
1.99 g (16.32 mmole) of dimethylaminopyridine and 2-
Chlor-1-methylpyridinium tosylate 2.23 g
(7.43 mmol) and stirred at room temperature for 2 hours. After the reaction, ethyl acetate and water are added for extraction. 0.1% of organic layer
After washing with cold diluted hydrochloric acid, it was dried with magnesium sulfate. After evaporating the organic layer, 1.24 g of Compound 42 was obtained in an amorphous form (88% yield).

¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ value, ppm) Compound 42 amorphous 0.15 (6H, s) 0.85 (6H, s) 0.86 (6H, d, J = 6.4) 1.40 to 1.80 (1H , m) 2.21 (6H, s) 2.26 (6H, s) 3.08 to 3.72 (4H, m) 3.86 (2H, m) 4.21 (1H, m) 5.36 (2H, m) 5.99 (1H, m) 7.94 (1H , d, J = 6.6) 11.98 (1H, br) Example 11 5'-O- (2,3-dimethyl-2-butyl) dimethylsilyl-2 ', 3'-bis (O-dimethylglycyl)- 5
Preparation of fluorouridine malate (compound 43) Ether solution 2 containing 0.5 g (0.87 mmole) of compound 42
5 ml of an ether solution containing 233 mg (1.74 mmole) of L-malic acid is added to 0 ml, and the mixture is stirred at room temperature for 1 hour. The precipitated crystals were collected to give 687 mg of compound 43 (yield 93.7
%).

Compound 43 amorphous ¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ value, ppm) 0.15 (6H, s) 0.85 (6H, s) 0.86 (6H, s) 1.40 to 1.80 (1H, m) 2.25 (6H, s) 2.31 (6H, s) 2.40 to 2.60 (4H, m) 3.20 to 3.72 (4H, m) 3.87 (2H, m) 4.04 to 4.32 (3H, m) 5.36 (2H, m) 5.98 (1H , m) 5.60-7.40 (7H, br) 7.96 (1H, d, J = 6.8) Example 12 5'-O-tert-butyldimethylsilyl-2 ', 3'-
Preparation of bis (O-2-carboxyethylcarbonyl) -5-fluorouridine (compound 44) 2.18 g (21.76 mmole) of succinic anhydride and N, N were added to 40 ml of a methylene chloride solution containing 2.0 g (5.44 mmole) of compound 1. −
Add 5.32 g (43.5 mmole) of dimethylaminopyridine and stir at room temperature for 8 hours. After the reaction, 10% aqueous citric acid solution and 500 ml of ether are added for extraction. The organic layer was washed with water and dried over magnesium sulfate. After evaporating the organic layer, the residue was recrystallized from n-pentane to obtain 2.5 g of a hygroscopic compound 44 (yield 7).
6.6%).

Compound 44 ¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ value, ppm) 0.11 (6H, s) 0.90 (9H, s) 3.33 to 3.49 (8H, m) 3.86 (2H, m) 4.18 ( 1H, m) 5.28 to 5.32 (2H, m) 6.02 (1H, m) 7.97 (1H, d, J = 6.8) 12.00 to 12.23 (3H, br) Example 13 5'-O-tert-butyldimethylsilyl- 2 ', 3'-
Production of bis (O-2-carboxyethylcarbonyl) -5-fluorouridine dipotassium salt (compound 45) 3.2 g (17.38 mm) of potassium 2-ethylhexanoate was added to 100 ml of an ethyl acetate solution containing 2.4 g (4.17 mmole) of compound 44.
ole) and stir at room temperature for 14 hours. The precipitated crystals were collected, purified on an MCI gel (50 g, H ₂ O → H ₂ O: CH ₃ CN = 1: 1, manufactured by Mitsubishi Kasei Corporation, Japan), and the eluted fraction was lyophilized. 560 mg of compound 45 was obtained (20.6% yield).

Compound 45 Melting point 195-197 ° C ¹ H-NMR (internal standard TMS, solvent D ₂ O, δ value, ppm) 0.18 (6H, s) 0.94 (9H, s) 2.41 to 2.70 (8H, m) 3.98 (2H, m) 4.40 (1H, m) 5.43 (2H, m) 6.17 (1H, m) 7.95 (1H, d, J = 5.9) Example 14 5'-O-tert-butyldimethylsilyl-3'-O-
Dimethylglycyl-5-trifluoromethyl-2'-deoxyuridine (compound 46) and 5'-O-tert-butyldimethylsilyl-3'-O-dimethylglycyl-5
Production of trifluoromethyl-2'-deoxyuridine malate (compound 47) Compounds 46 and 47 were produced in the same manner as in Examples 10 and 11.

Compound 46 amorphous ¹ H-NMR (internal standard TMS, solvent d ₆ -DMSO, δ value, ppm) 0.10 (6H, s) 0.89 (9H, s) 2.00 to 2.60 (2H, m) 2.29 (6H, s) 3.00 ~3.76 (3H, m) 3.76~4.00 ( 2H, m) 4.20 (1H, m) 5.21 (1H, m) 6.07 (1H, t, J = 2.9) 8.17 (1H, s) compound 47 amorphous ¹ H-NMR (Internal standard TMS, solvent D ₂ O, δ value, ppm) 0.06 (6H, s) 0.86 (9H, s) 2.20 to 2.60 (4H, m) 2.34 (6H, s) 3.37 (2H, s) 3.68 to 3.88 (2H, m) 4.00 to 4.28 (2H, m) 4.32 to 5.80 (4H, b) 5.21 (1H, m) 6.11 (1H, t, J = 3.7) 8.14 (1H, d, J = 0.9) Example 15 Preparation of 2 ', 3', 5'-tri (O-tert-butyldimethylsilyl) -5-trifluoromethyluridine (compound 48) 5-trifluoromethyluridine 596 mg (2.1 mmole)
Imidazole in 6 ml of N, N-dimethylformamide solution of 1.
14 g (16.7 mmole) and subsequently 1.27 g (8.4 mmole) of tert-butyldimethylchlorosilane are added, and the mixture is stirred at room temperature for 17 hours. When 30 ml of water was added to the reaction solution, ethyl acetate (30 ml ×
Extract in 3). The extract is washed with water (20 ml × 3) and saturated saline (20 ml × 1), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was subjected to silica gel column chromatography and eluted with 3% methanol / chloroform to give 1.28 g of compound 48.
Was obtained (93% yield).

Compound 48 amorphous ¹ H-NMR (internal standard TMS, solvent CDCl ₃ , δ value, ppm) 0.05, 0.09, 0.13, 0.16, 0.17 (18H, each s) 0.93, 0.97, 1.00 (27H, each s) 3.73 to 3.93 (2H, m) 4.08 to 4.23 (3H, m) 6.12 (1H, d, J = 5.7) 8.20 (1H, d, J = 1.1) 8.83 (1H, br) Example 16 2 ', 3', 5 ' Production of -tri (O-tert-butyldimethylsilyl) -5-fluorouridine (Compound 49) The same treatment as in Example 15 was carried out to obtain Compound 49.

Compound 49 amorphous ¹ H-NMR (internal standard TMS, solvent CDCl ₃ , δ value, ppm) 0.04,0.05 (12H, each s) 0.88, 0.89 (18H, each s) 2.33 (3H, s) 2.89 (6H, s ) 3.30 to 3.64 (2H, m) 4.05 to 4.38 (5H, m) 5.76 (1H, m) 7.16 (2H, m) 7.57 (2H, m) 8.02 (1H, d, J = 7.04) 10.02 (1H, br) 11.94 (1H, m) <Pharmacological test> 5 × 10 ⁶ mouse transplantable tumor sarcoma 180 cells were transplanted subcutaneously into the back of male ICR × JCL mice (weight 27 to 30 g). A sample was dissolved or suspended in a physiological saline solution containing 0.1% Tween 80, and the solution was added to a group of 7 mice at a rate of 0.1 ml / 10.
The mice were intraperitoneally administered at a dose of the body weight of the mouse three times in total on the first, fifth, and ninth days after the tumor implantation.

The above-mentioned solution containing no specimen was administered to the control group in the same manner.

On day 12 after transplantation, the average tumor weight at each dose was measured for each sample administration group, and these were compared with the average tumor weight in the control group to determine the tumor growth inhibition rate for the control group at each dose. Was.

 The results are shown in Table III.

As is clear from Table III, the compound (I) of the present invention
It can be seen that has higher antitumor activity and lower toxicity than FUR and F ₃ TdR.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Junji Uchida 463-10 Kagasuno, Kawauchi-cho, Tokushima City, Tokushima Prefecture Yuji Yamada 4-2-8 Sumiyoshi, Tokushima City, Tokushima Prefecture

Claims (12)

(57) [Claims] (1) General formula [In the formula, X represents a fluorine atom or a trifluoromethyl group, and R ₁ and R ₂ represent a general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ )
[In the formula, R ₄ , R ₅ and R ₆ are the same or different and are each an alkyl group having 1 to 10 carbon atoms, a general formula — (CH ₂ ) _n Ph (wherein n represents 0 to 2, group or formula Ph is represented by a phenyl _{group.) -OSi- (R 7) (} R
₈ ) A group represented by (OH) (wherein R ₇ and R ₈ are the same or different and each represents a lower alkyl group). Represents a aminoacyloxy group or a carboxylalkylcarbonyloxy group in which a hydroxyl group or an amino group may be substituted with a lower alkyl group, and R ₃ is a group represented by the general formula -OSi-
A group represented by (R ₄ ) (R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ are the same as defined above), a hydrogen atom, a hydroxyl group and an amino group are substituted with a lower alkyl group; Represents an aminoacyloxy group or a carboxylalkylcarbonyloxy group which may be substituted. Provided that at least one of R ₁ , R ₂ and R ₃ is represented by the general formula -OS
_{i- (R 4) (R 5} ) (R 6) ( wherein, R _4, R ₅ and R ₆ are the same) is a group represented by. When X is a fluorine atom, R ₃ is not a hydrogen atom. 5-
A substituted uridine derivative or a pharmaceutically acceptable salt thereof. 2. The general formula [Wherein, X represents a fluorine atom or a trifluoromethyl group, and R ₂ ′ represents a hydroxyl group or a general formula -OSi- (R ₄ ) (R ₅ )
(R ₆ ) (wherein, R ₄ , R ₅ and R ₆ are the same or different and each have an alkyl group having 1 to 10 carbon atoms, a general formula — (CH ₂ ) _n Ph, wherein n is 0 to 2 shows a, Ph is a group or formula represented by a phenyl _{group.) -OSi- (R 7) (} R
₈ ) A group represented by (OH) (wherein R ₇ and R ₈ are the same or different and each represents a lower alkyl group). R ₃ ′ represents a hydrogen atom, a hydroxyl group or a general formula —OSi— (R ₄ ) (R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ are as defined above) The same). Provided that at least one of R ₂ ′ and R ₃ ′ is a group —OSi— (R ₄ ) (R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ are the same as above); When X is a fluorine atom,
R ₃ 'is not a hydrogen atom. 5-substituted-
5'-trityl uridine derivative. 3. The compound according to claim 1, wherein X is a fluorine atom. 4. X is a fluorine atom and one of R ₁ , R ₂ and R ₃ is
One or two is a group —OSi— (R ₄ ′) (R ₅ ′) (R ₆ ′) [wherein R ₄ ′ and R ₅ ′
And R ₆ 'are the same or different and each have an alkyl group having 1 to 8 carbon atoms, a benzyl group, a 2-phenylethyl group or a group -OSi-
(R ₇ ) (R ₈ ) (OH) wherein R ₇ and R ₈ are the same or different and represent a lower alkyl group. Wherein R ₁ , R ₂ and R _{3 represent} one or two of the remaining ones being a hydroxyl group, an amino group optionally substituted with a lower alkyl group, an aminoalkylcarbonyloxy group or a carboxylalkylcarbonyloxy group. 2. The compound according to range 1, wherein 5. X is a trifluoromethyl group, R ₃ is a hydrogen atom, and _one of R ₁ and R ₂ is a group —OSi- (R ₄ ′) (R
₅ ') (R _6') wherein, R ₄ ', R _5' and R ₆ 'are the same or different and each an alkyl group having 1 to 8 carbon atoms, a benzyl group, 2
- phenylethyl group or a group _{-OSi- (R 7) (R 8} ) (OH)
Wherein R ₇ and R ₈ are the same or different and each represent a lower alkyl group. The other of R ₁ and R ₂ is a hydroxyl group, an amino group may be an aminoalkylcarbonyloxy group or a carboxyalkylcarbonyloxy group optionally substituted with a lower alkyl group, or both R ₁ and R ₂ There -OSi- the group _{(R 4 ') (R 5} ') (R 6 ') wherein, R _4', R ₅ '
And R ₆ ′ is the same as defined above. 6. X is a fluorine atom and one of R ₁ , R ₂ and R ₃ is
One or two is a tert-butyldimethylsilyloxy group, a dimethyloctylsilyloxy group or a benzyldimethylsilyloxy group, and one or two of the remaining R ₁ , R ₂ and R ₃ are
2. The compound according to claim 1, wherein one is a dihydroxyl group, and the amino group is a glycyloxy group or a carboxyethylcarbonyloxy group which may be substituted with a lower alkyl group. 7. X is a trifluoromethyl group, R ₃ is a hydrogen atom, one of R ₁ and R ₂ is a tert-butyldimethylsilyloxy group or a benzyldimethylsilyloxy group, and R ₁ and R The other of ₂ is a hydroxyl group, a glycyloxy group or an carboxyethylcarbonyloxy group in which an amino group may be substituted with a lower alkyl group, or both R ₁ and R ₂ are a tert-butyldimethylsilyloxy group or A benzyldimethylsilyloxy group;
Item. (8) 5'-O-tert-butyldimethylsilyl-
5-fluoro-uridine, 2 ', 3'-bis (O-tert-
Butyldimethylsilyl) -5-fluorouridine, 5 '
-O-dimethyloctylsilyl-5-fluorouridine, 5'-O-benzyldimethylsilyl-5-fluorouridine, 5'-O-tert-butyldimethylsilyl-
2 ', 3'-bis (O-dimethylglycyl) -5-fluorouridine, 5'-O-tert-butyldimethylsilyl-
Selected from the group consisting of 2'-deoxy-5-trifluoromethyluridine and 5'-O-tert-butyldimethylsilyl-2 ', 3'-bis (O-2-carboxyethylcarbonyl) -5-fluorouridine The compound according to claim 1. 9. The general formula [Wherein, R ₉ represents a hydrogen atom or a hydroxyl group, and X represents a fluorine atom or a trifluoromethyl group. However, when X is a fluorine atom, the case where R ₉ is a hydrogen atom is excluded. The compound represented by the general formula [In the formula, R ₄ , R ₅ and R ₆ are the same or different and are each an alkyl group having 1 to 10 carbon atoms, a general formula-(CH ₂ ) _n Ph (wherein n represents 0 to 2, Ph is or a group represented by the general formula represents a phenyl group.) -OSi- is _{(R 7) (R 8)} (OH) ( wherein, R ₇ and R ₈ are the same or different and a lower alkyl group) And X ₁ represents a halogen atom. A general formula characterized by reacting a halogenosilyl compound represented by the formula: [Wherein X is the same as defined above, and R ₁₀ and R ₁₁ are hydroxyl groups or a general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ R ₁₂ represents a hydrogen atom, a hydroxyl group or a general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ) wherein R ₄ , R ₅ and R ₆ represents a group represented by the same), at least one formula of R _10, R ₁₁ and _{R 12 -OSi- (R 4) (} R 5) (R 6) ( wherein, R ₄ , R ₅ and R ₆ are the same as defined above). However, the case where X is a fluorine atom and the case where R ₁₂ is a hydrogen atom are excluded. ] A method for producing a 5-substituted uridine derivative represented by the formula: 10. The general formula [Wherein, X represents a fluorine atom or a trifluoromethyl group, R ₁₃ represents a hydroxyl group or a general formula -OSi- (R ₄ ) (R ₅ )
(R ₆ ) [wherein, R ₄ , R ₅ and R ₆ are the same or different and each have an alkyl group having 1 to 10 carbon atoms, a general formula — (CH ₂ ) _n Ph (where n is 0 to And Ph represents a phenyl group) or a group represented by the general formula -OSi- (R ₇ )
And a group represented by (R ₈ ) (OH) (wherein R ₇ and R ₈ are the same or different and each represent a lower alkyl group). R ₁₄ is a hydrogen atom, a hydroxyl group or a general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ are the same as defined above) Wherein at least one of R ₁₃ and R ₁₄ is a group represented by the general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ), wherein R ₄ , R ₅ and R ₆ are as defined above. The same as the above). However, when X is a fluorine atom, R ₁₄ is not a hydrogen atom.] A general formula characterized in that a 5-substituted-5'-trityluridine derivative represented by the formula: is detritylated in the presence of an acid catalyst. [Wherein R _13, R ₁₄ and X are the same as those described above]. 11. The general formula [In the formula, X represents a fluorine atom or a trifluoromethyl group, and R ₁₅ ′ and R ₁₆ ′ represent a hydroxyl group or a general formula -OSi-
(R ₄ ) (R ₅ ) (R ₆ ) [wherein R ₄ , R ₅ and R ₆ are the same or different and each have an alkyl group having 1 to 10 carbon atoms, a general formula-(C
H ₂ ) _n Ph [wherein n represents 0 to 2 and Ph represents a phenyl group. Or a group represented by general formula] _{-OSi- (R 7) (R 8} )
(OH) wherein R ₇ and R ₈ are the same or different and each represents a lower alkyl group. R ₁₇ ′ is a hydrogen atom, a hydroxyl group or a general formula —OSi— (R ₄ ) (R ₅ ) (R ₆ ) (wherein R ₄ , R ₅ and R ₆ are as defined above) The same), R ₁₅ ′, R ₁₆ ′ and R ₁₆ ′
At least one formula _{17 '-OSi- (R 4) (} R 5) (R
₆ ) wherein R ₄ , R ₅ and R ₆ are as defined above, and at least one of R ₁₅ ′, R ₁₆ ′ and R ₁₇ ′ is a hydroxyl group. However, when X is a fluorine atom, R ₁₇ ′ is not a hydrogen atom, and a compound represented by the general formula R ₁₈ COOH (VIII) wherein R ₁₈ is an amino group substituted with a lower alkyl group Or a reactive derivative thereof, or a compound represented by the general formula HOOC-R ₁₉ -COOH (IX) wherein R ₁₉ represents an alkylene group. General formula characterized by reacting anhydride [Wherein X is the same as defined above, and R ₁₅ and R ₁₆ are represented by the general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ) wherein R ₄ , R ₅ and R ₆ are the same Or differently, an alkyl group having 1 to 10 carbon atoms, a general formula-(CH ₂ ) _n Ph wherein n represents 0 to 2 and Ph represents a phenyl group. Group or the formula _{-OSi- (R 7) (R 8} ) (OH) ( wherein, R ₇ and R ₈ are the same or different represents a lower alkyl group) represented by] a group represented by Show. Groups represented by], amino group represents an optionally substituted amino acyl group or a carboxyl alkylcarbonyloxy group with a lower alkyl group, R ₁₇ has the general formula _{-OSi- (R 4) (R 5} ) (R ₆ ) wherein R ₄ , R ₅ and R ₆ are the same as defined above, an aminoacyloxy group in which the amino group may be substituted with a lower alkyl group, a carboxylalkylcarbonyloxy group or a hydrogen atom. And at least one of R ₁₅ , R ₁₆ and R ₁₇ is a general formula —OSi— (R ₄ ) (R ₅ ) (R ₆ ), wherein R ₄ , R ₅ and R ₆ are as defined above. A group represented by R ₁₅ , R ₁₆ and
_At least one of R ₁₇ is an aminoacyloxy group or a carboxylalkylcarbonyloxy group in which the amino group may be substituted with a lower alkyl group. However, when X is a fluorine atom, R ₁₇ is not a hydrogen atom. ] A method for producing a 5-substituted uridine derivative represented by the formula: 12. The general formula [In the formula, X represents a fluorine atom or a trifluoromethyl group, and R ₁ and R ₂ represent a general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ )
[Wherein R ₄ R ₅ and R ₆ are the same or different and each have 1 carbon atom
To 10 alkyl groups, a group represented by the general formula — (CH ₂ ) _n Ph (wherein n represents 0 to 2 and Ph represents a phenyl group) or a general formula —OSi— (R ₇ )
And a group represented by (R ₈ ) (OH) (wherein R ₇ and R ₈ are the same or different and each represent a lower alkyl group). Groups represented by], a hydroxyl group, an amino group represents an optionally substituted amino acyl group or a carboxyl alkylcarbonyloxy group with a lower alkyl group, R ₃ is the formula _{-OSi- (R 4) (R 5} ) (R ₆ ) (where R ₄ , R
₅ and R ₆ are the same as defined above), an aminoacyloxy group or a carboxylalkylcarbonyloxy group in which a hydrogen atom, a hydroxyl group, or an amino group may be substituted with a lower alkyl group. However, at least one of R ₁ , R ₂ and R ₃ is represented by the general formula -OSi- (R ₄ ) (R ₅ ) (R ₆ ) (where R ₄ , R _4
5 and R ₆ are the same as defined above). Also,
When X is a fluorine atom, R ₃ is not a hydrogen atom.] Or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. .