JPH0597887A - New 2'-deoxy-5-fluorouridine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as an antitumor agent. CONSTITUTION:A compound expressed by formula I [R<1> is group obtained by removing one carboxyl group at the alpha-position from the C-terminal of a (protected)amino acid, dipeptide or tripeptide; R<2> and R<3> are H, (substituted) lower alkanoyl, group, etc., obtained by removing one OH group of carboxyl group from the (protected)amino acid], e.g. 3-[(t-butoxycarbonyl) aminoethylcarbonyloxymethyl]-5'-O-(t-butyldimethylsilyl)-3'-O-(4-chlor obenzyl)-2'- deoxy-5-fluorouridine. The compound expressed by formula I is obtained by reacting a compound expressed by formula II (R<21> is H, OH-protecting group, etc.) with a carboxylic acid ester compound expressed by the formula X-CH2 OCO-R<11> (R<11> is group obtained by removing one carboxyl group at the ex-position from the C-terminal of the (protected)amino acid, dipeptide or tripeptide; X is reactive residue].

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel 2'-deoxy-5
-A fluorouridine derivative or a pharmaceutically acceptable salt thereof.

[0002]

BACKGROUND OF THE INVENTION 5-Fluorodeoxyuridine (5-F
UdR) is known to have an antitumor effect,
Since the compound has the drawbacks of being highly toxic and having a narrow safety margin, various 5-fluorodeoxyuridine derivatives such as 3- (4-chlorobenzyloxymethyl) -2'-deoxy have been developed in order to improve these points. -5-Fluorouridine (JP-A-1-275596) and the like are being studied.

[0003]

DISCLOSURE OF THE INVENTION The present invention is to provide a novel 2'-deoxy-5-fluorouridine derivative useful as an antitumor agent having a wide safety margin.

[0004]

The present invention relates to a 2'-deoxy-5-fluorouridine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a process for producing the same.

[Chemical 2] [In the formula, R ¹ is an amino acid whose terminal amino group, imino group or carboxyl group may be protected, a group obtained by removing one carboxyl group at the α-position from the C-terminal of a dipeptide or tripeptide, R ² and R ^{2 3} is a hydrogen atom, a lower alkanoyl group which may be substituted with a carboxyl group or a lower alkoxy group, a group obtained by removing one hydroxyl group of a carboxyl group from an amino acid whose terminal amino group or imino group may be protected, A lower alkoxy-lower alkyl group, a benzyl group whose benzene ring may be substituted with a halogen atom or a trihalogenomethyl group, a phenoxycarbonyl group whose benzene ring may be substituted with a lower alkoxy group, (In the formula, Y ¹ and Y ² are each a phenoxy group which may be substituted with a halogen atom or a trihalogenomethyl group, or a phenylthio group.)

The object compound (I) of the present invention and a pharmacologically acceptable salt thereof have excellent antitumor activity and high therapeutic index, and are useful as antitumor agents. is there.

In the object compound (I) of the present invention, R ¹
Specific examples of the group obtained by removing the α-carboxyl group from the C-terminal of the amino acid, dipeptide or tripeptide of
For example, glycine, alanine, isoleucine, leucine,
Valine, glutamic acid, methionine, phenylalanine, proline, β-alanine, arginine, ornithine, serine, threonine, aspartic acid, asparagine, glutamine, cystine, cysteine, tyrosine, histidine, tryptophan, natural amino acids such as lysine or its enantiomer, Or L- or D-amino acids of synthetic origin such as ε-aminocaproic acid, thioproline, α-aminoisobutanoic acid, piperidylcarboxylic acid, or glycylglycine, valylglycine, methionylglycine,
The above-mentioned natural amino acids such as prolylglycine, glycylproline, glycylphenylalanine, glycylvaline, alanylproline, valylproline and phenylalanylvaline, or dipeptides composed of antipodes thereof, or the above-mentioned glycylalanylproline etc. Α from the C-terminal of a tripeptide composed of a natural amino acid or its antipode
Group excluding the carboxyl group at the position.

Specific examples of R ² and R ³ are hydrogen atom; linear or branched alkanoyl group having 2 to 6 carbon atoms such as acetyl group and isovaleryl group; carboxypropionyl group, methoxyacetyl group and methoxy group. Carboxyl group such as butyryl group and the like or alkanoyl group having 2 to 6 carbon atoms which is substituted with alkoxy group having 1 to 6 carbon atoms; natural amino acid such as glycyl group, valyl group and prolyl group or a carboxyl group from its enantiomer A group excluding one hydroxy group; an alkoxy-alkyl group having 2 to 12 carbon atoms such as an ethoxymethyl group; a halogen atom such as a benzyl group, a fluorobenzyl group, a chlorobenzyl group, a trifluoromethylbenzyl group or a trihalogenomethyl group A benzyl group which may be substituted with phenoxycarbonyl group,
A phenoxycarbonyl group which may be substituted with a lower alkoxy group such as a methoxyphenyloxycarbonyl group;
Such as diphenoxyphosphoryl group, bis (fluorophenoxy) phosphoryl group, bis (chlorophenoxy) phosphoryl group, bis [(trifluoromethyl) phenoxy] phosphoryl group, bis (chlorophenylthio) phosphoryl group (In the formula, each of Y ¹ and Y ² is a phenoxy group or a phenylthio group which may be substituted with a halogen atom or a trihalogenomethyl group).

In the above compound (I) of the present invention,
When R ¹ , R ² or R ³ contains an amino group, an imino group or a carboxyl group, these groups may be protected, and examples of the protecting group for the amino group or imino group include a lower alkyl group. (Eg, methyl group), lower alkanoyl group (eg, acetyl group), phenyl lower alkyl group (eg, benzyl group), lower alkoxycarbonyl group (eg, t-butoxycarbonyl group),
Examples thereof include a substituted or unsubstituted benzyloxycarbonyl group (eg, benzyloxycarbonyl group, p-methoxybenzylcarbonyl group). Examples of the protective group for the carboxyl group include a lower alkyl group (eg t-butyl group) and a diphenyl lower alkyl group (eg benzhydryl group).

According to the present invention, the object compound (I) can be produced by various methods as described below. (I) General formula (II):

[Chemical 3] [Wherein R ²¹ is a hydrogen atom, a protective group for a hydroxyl group, an optionally protected carboxyl group or a lower alkanoyl group optionally substituted with a lower alkoxy group, a terminal amino group or an imino group is protected, Is a group obtained by removing one hydroxyl group of a carboxyl group from an amino acid, a lower alkoxy-lower alkyl group, a benzyl group whose benzene ring may be substituted with a halogen or a trihalogenomethyl group, and a benzene ring which is a lower alkoxy group. A phenoxycarbonyl group which may be substituted, And Y ¹ , Y ² and R ³ have the same meanings as described above] and a compound represented by the general formula (III): X-CH ₂ OCO-R ¹¹ (III) [wherein R ¹¹ is a terminal An amino group, an imino group, or an amino acid which may have a protected carboxyl group, a group obtained by removing one α-position carboxyl group from the C-terminus of a dipeptide or tripeptide, and X is a reactive residue]
By reacting with a camponic acid ester compound represented by the general formula (Ia):

[Chemical 4] [In the formula, R ¹¹ , R ²¹ and R ³ are the same as defined above]
Or by subjecting the compound to a peptide chain extension reaction, or

(Ii) General formula (IV):

[Chemical 5] [Wherein R ¹¹ and R ³ have the same meanings as described above] and a compound represented by the general formula (V): R ²¹ ′ OH (V) [wherein R ²¹ ′ is a hydrogen atom or a hydroxyl group-protecting group] Compounds (Ib) having the same meaning as R ²¹ except for the above are condensed with a reactive derivative thereof to give compound (Ib):

[Chemical 6] [Wherein R ¹¹ , R ²¹ 'and R ³ have the same meanings as described above]
Or the compound (Ib) is optionally subjected to a peptide chain elongation reaction, or

(Iii) General formula (VI):

[Chemical 7] [Wherein R ²² is a hydrogen atom, a protective group for a hydroxyl group, an optionally protected carboxyl group or a lower alkanoyl group optionally substituted with a lower alkoxy group, a terminal amino group or an imino group is protected, , A group obtained by removing one hydroxyl group of a carboxyl group from amino acid, a lower alkoxy-lower alkyl group, a benzyl group whose benzene ring may be substituted with a halogen atom or a trihalogenomethyl group, and a lower alkoxy group having a benzene ring. A phenoxycarbonyl group optionally substituted with, And Y ¹ , Y ² and R ¹¹ have the same meanings as defined above] and a compound represented by the general formula (VII): R ³¹ OH (VII) [wherein R ³¹ is an optionally protected carboxyl group] Group or a lower alkanoyl group which may be substituted with a lower alkoxy group, a group obtained by removing one hydroxyl group of a carboxyl group from an amino acid which may have a terminal amino group or imino group protected, a lower alkoxy-lower alkyl group, A benzyl group whose benzene ring may be substituted with a halogen atom or a trihalogenomethyl group, a phenoxycarbonyl group whose benzene ring may be substituted with a lower alkoxy group, (Wherein Y ¹ and Y ² have the same meanings as defined above) and are condensed with a compound represented by the formula (Ic):

[Chemical 8] [Wherein R ¹¹ , R ²² and R ³¹ have the same meanings as described above]
To obtain the compound (Ic), if desired.
Are simultaneously subjected to a peptide chain extension reaction, and if desired, the protecting group is removed from the product to give the desired compound (I).
Can also be manufactured.

In the above method of the present invention, as the carboxylic acid ester compound (III), a compound in which the reactive residue (X) is a halogen atom such as chlorine atom, iodine atom or bromine atom is preferably used. it can.

Examples of the reactive derivative of compound (V) and compound (VII) include acid halides, acid halides such as acid chlorides, active esters, alkyl halides and active halides such as aralkyl halides.

The above methods (i) to (iii) are usually carried out under the following conditions. [Method (i)] The reaction of the compound (II) with the carboxylic acid ester compound (III) can be carried out in a suitable solvent in the presence or absence of a deoxidizing agent. As the solvent, for example, acetone or acetonitrile can be preferably used. As the deoxidizing agent, both conventional inorganic and organic bases can be used, and for example, alkali metal carbonate or the like can be preferably used. This reaction suitably proceeds at room temperature to under heating, for example, 10 to 60 ° C.

[Methods (ii) and (iii)] The condensation reaction of compound (IV) with compound (V) and compound (VI) with compound (VII) is carried out in a suitable solvent in the presence of a condensing agent. be able to. As the solvent, for example, acetonitrile, tetrahydrofuran, dimethylformamide or the like can be used. Examples of the condensing agent include dicyclohexylcarbodiimide and carbonyldiimidazole. This reaction is carried out under cooling to heating, for example, 0
Suitably proceeds at ~ 80 ° C.

On the other hand, the condensation reaction between the compound (IV) and the reactive derivative of the compound (V) and the compound (VI) and the reactive derivative of the compound (VII) is carried out without a solvent or in the presence of a deoxidizing agent in a suitable solvent. It can be carried out underneath or in the absence. As the solvent, for example, pyridine, acetonitrile, tetrahydrofuran, etc. can all be preferably used. Examples of the deoxidizing agent include organic bases such as pyridine and triethylamine. This reaction is cooling ~
It proceeds suitably under heating, for example, at 0 to 60 ° C.

When the compound (Ia), the compound (Ib) or the compound (Ic) is extended with a peptide chain, it can be easily carried out according to a usual peptide synthesis reaction. Further, when the product obtained as described above is a compound having a protected amino group or imino group, the removal of the protecting group can be easily carried out according to a conventional method depending on the kind of the protecting group. ..

The object compound (I) of the present invention can be used for medicinal use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmacologically acceptable salt include, for example, hydrochloride, hydrobromide, sulfate, sulfite,
Inorganic acid addition salts such as phosphates and nitrates, organic acids such as methanesulfonate, p-toluenesulfonate, fumarate, maleate, tartrate, phthalate, citrate and ascorbate Examples thereof include alkali metal salts such as addition salts, sodium salts and potassium salts.

The object compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be administered by a conventional method such as tablets, capsules and powders. , And can be appropriately used as a pharmaceutical preparation such as an injection.

The dose of the objective compound (I) of the present invention and a pharmacologically acceptable salt thereof varies depending on the age, body weight, condition or degree of disease of the patient, but usually the daily dose is A suitable dose is 0.4 to 40 mg / kg for oral administration and 0.2 to 20 mg / kg for parenteral administration.

The starting compound (II) of the present invention can be prepared, for example, by the general formula (VIII):

[Chemical 9][In the formula, R^{twenty one}Is as defined above]
And general formula (IX): X¹-R³  [In the formula, X¹Is a reactive residue, R³Has the same meaning as above]
In a suitable solvent with a compound represented by
It can be produced by reacting in the presence of potassium oxide).
It

[0022]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Reference Examples.

[0023]Example 1  (1) N- (t-butoxycarbonyl) in 50 ml of acetone
2.3) and β-alanine chloromethyl ester
Add 2 g of sodium iodide and stir at room temperature for 30 minutes
It 5'-O- (t-butyldimethylsilyl) was added to the reaction mixture.
) -3'-O- (4-chlorobenzyl) -2'-deo
2.0 g of xy-5-fluorouridine and potassium carbonate
3 g of aluminum is added and stirred at room temperature for 6 hours. Filter the reaction solution
And concentrate the filtrate under reduced pressure. Ethyl acetate and the residue
After adding water and shaking, the organic layer is separated. Dry the organic layer
After that, it is filtered, and the solvent is distilled off from the filtrate under reduced pressure. The residue
Silica gel column chromatography (solvent: ethyl acetate
(Chloroform / chloroform / n-hexane)
3-[(t-butoxycarbonyl) aminoethylcalcyl
Bonyloxymethyl] -5'-O- (t-butyl dimethyl)
Rusilyl) -3'-O- (4-chlorobenzyl) -2 '
-Colorless caramel of deoxy-5-fluorouridine
2.6 g are obtained. (2) 2.4 g of this product is dissolved in 10 ml of dioxane,
Add 10 ml of 6.5N hydrogen chloride dioxane solution at room temperature
Stir for 40 minutes. The reaction solution is stirred in 300 ml of ether.
Add dropwise with stirring. The precipitated powder should be filtered, washed and dried.
With 3- (aminoethylcarbonyloxymethyl)
-3'-O- (4-chlorobenzyl) -2'-deoxy
-5 g of 5-fluorouridine hydrochloride amorphous powder
To get NMR (DMSO-d₆) Δ: 2.22 (1H, m),
2.38 (1H, m), 2.72 and 3.01 (respectively
2H, t, J = 7 Hz), 3.4 to 3.8 (2H,
m), 4.08 (1H, m), 4.21 (1H, m),
4.54 (2H, s), 5.34 (1H, t, J = 5.3.
4 Hz), 5.83 (2H, s), 6.17 (1H, d)
d, J = 6, 6 Hz), 7.39 and 7.41 (respectively
2H, dd, J = 2.4, 8.8 Hz, 8.01 (3
H, br-s), 8.40 (1H, d, J = 7Hz)

[0024]Examples 2 to 17  The corresponding starting compound was treated as in Example 1 and the following Table 1
~ To obtain the compounds listed in Table 6.

[Table 1]

[0025]

[Table 2]

[0026]

[Table 3]

[0027]

[Table 4]

[0028]

[Table 5]

[0029]

[Table 6]

[0030]Example 18  A) 3'-O- (4-chlorobenzyl) -2'-deoxy
1.45 g of ci-5-fluorouridine (Reference Example 26-
(Compound of (3)), N- (t-butoxycarbonyl)-
Glycine chloromethyl ester 1.34 g, sodium iodide
Example using 1.2 g of lithium and 1.65 g of potassium carbonate
By performing a reaction treatment in the same manner as in 1- (1), 3-
[(T-butoxycarbonyl) aminomethylcarbonyl
Oxymethyl] -3'-O- (4-chlorobenzyl)-
Colorless caramel of 2'-deoxy-5-fluorouridine
1.79 g are obtained. NMR (CDCl₃) Δ: 1.44 (9H, s), 2.
18 (1H, m), 2.25 (1H, br), 2.53
(1H, ddd, J = 2.5, 5.9, 13.7H
z), 3.84 to 4.0 (2H, m), 3.93 (2
H, d, J = 5.4 Hz), 4.20 (1H, d, J =
2.4 Hz), 4.26 (1H, dd, J = 2.9,
5.9 Hz), 4.47 (1H, d, J = 11.7H)
z), 4.56 (1H, d, J = 11.7 Hz), 4.
98 (1H, br), 6.04 (2H, s), 6.30
(1H, dd, J = 5.9, 6.4Hz), 7.26
(2H, d, J = 8.3 Hz), 7.34 (2H, d,
J = 8.3 Hz), 8.06 (1H, d, J = 5.9H)
z)

B) 1.74 g of this product was added to 20 ml of dioxane.
And then treated in the same manner as in Example 1- (2) to give 3- (aminomethylcarbonyloxymethyl)-
3'-O- (4-chlorobenzyl) -2'-deoxy-
Amorphous powder of 5-fluorouridine hydrochloride 1.40 g
To get NMR (DMSO-d ₆ ) δ: 2.16 to 2.49 (2
H, m), 3.64 (2H, br), 3.84 (2H,
s), 4.09 (1H, m), 4.22 (1H, m),
4.54 (2H, s), 5.32 (1H, br), 5.
93 (2H, s), 6.17 (1H, dd, J = 5.
9,6.4 Hz), 7.37 (2H, dd, J = 2.
4, 8.8 Hz), 7.44 (2H, dd, J = 2.
4, 8.8 Hz), 8.42 (1H, d, J = 7H
z), 8.44 (3H, br-s)

[0032]Examples 19A-23A  The corresponding starting compound was treated as in Example 18-A),
The compounds described in Tables 7 to 9 below are obtained.

[Table 7]

[0033]

[Table 8]

[0034]

[Table 9]

[0035]Examples 19B-23B  The corresponding starting compound was treated as in Example 18-B),
The compounds shown in Tables 10 and 11 below are obtained.

[Table 10]

[0036]

[Table 11]

[0037]Example 24  (1) 3'-O- (4-trifluoromethylbenzyl)
-2'-deoxy-5-fluorouridine (reference example below)
29- (3) compound) 1.21 g, N- (t-butoki)
Cycarbonyl) -D-valine chloromethyl ester 1.
57 g, potassium carbonate 4 g and sodium iodide 1.
Using 1 g, the reaction treatment was carried out in the same manner as in Example 18-A).
With 3- [N- (t-butoxycarbonyl) -D-
Valyloxymethyl] -3'-O- (4-trifluoro
Methylbenzyl) -2'-deoxy-5-fluorouri
1.55 g of a colorless caramel of gin is obtained. NMR (CDCl₃) Δ: 0.88 (3H, d, J =
6.8Hz), 0.95 (3H, d, J = 6.8H
z), 1.44 (9H, s), 2.1 to 2.33 (3
H, m), 2.55 (1H, ddd, J = 2.4, 5.
9, 13.7 Hz), 3.83 (1H, m), 4.00
(1H, m), 4.2-4.3 (3H, m), 4.57
(1H, d, J = 12.2 Hz), 4.65 (1H,
d, J = 12.2 Hz), 5.00 (1H, br),
6.01 (2H, s), 6.31 (1H, m), 7.4
5 (2H, d, J = 8.3 Hz), 7.63 (2H,
d, J = 6.8 Hz), 8.07 (1H, d, J = 6.
4Hz) (2) To 1.5 ml of this product in 20 ml of acetonitrile solution
N- (t-butoxycarbonyl) -sarco under ice-cooling stirring
Syn. 0.92 g, dicyclohexylcarbodiimide 1.
20 g and dimethylaminopyridine 0.1 g are added. Room
After stirring overnight at warm temperature, the insoluble matter is filtered off. Concentrate the filtrate under reduced pressure
The residue is subjected to silica gel column chromatography (solvent:
3 by purifying with ethyl acetate / n-hexane)
-[N- (t-butoxycarbonyl) -D-valyloxy
Cimethyl] -5'-O- [N- (t-butoxycarbonyl
) -Sarcosyl] -3'-O- (4-trifluorome
Cylbenzyl) -2'-deoxy-5-fluorourigi
1.90 g of a colorless caramel-like substance are obtained. NMR (CDCl₃) Δ: 0.88 (3H, d, J =
6.8 Hz), 0.96 (3H, d, J = 6.8H)
z), 1.44 (18H, s), 2.10 (2H,
m), 2.56 (1H, m), 2.96 (3H, s),
3.9-4.5 (7H for all), 4.59 (2H,
s), 5.0 (1H, br-d), 6.02 (2H, d
× 2-like), 6.26 (1H, t-like),
7.44 (2H, d, J = 8.3Hz), 7.63 (2
H, d, J = 8.3 Hz), 7.73 (1H, d, J =
(6.3 Hz) (3) Using 1.85 g of this product in the same manner as in Example 1- (2)
By reaction treatment, 3- (D-valyloxymethyi)
) -5'-O-sarcosyl-3'-O- (4-trif
Luoromethylbenzyl) -2'-deoxy-5-fluor
1.35 g of amorphous powder of lauridine dihydrochloride are obtained. NMR (DMSO-d₆) Δ: 0.94 (3H, d, J
= 6.8 Hz), 0.95 (3H, d, J = 6.8H)
z), 2.17 (1H, m), 2.4 (2H, m),
2.57 (3H, s), 3.91 (1H, br-s),
4.00 (2H, br-s), 4.27 (1H, m),
4.35 (1H, m), 4.43 (2H, m), 4.6
9 (2H, s), 5.87 (1H, d, J = 9.8H
z), 5.98 (1H, d, J = 9.8Hz), 6.2
1 (1H, t-like), 8.25 (1H, d, J =
6.8 Hz), 8.65 (3H, br-s), 9.55
(2H, br-s)

[0038]Examples 25-39  In place of the compound of Example 24- (1),
Of the compounds of Examples 24- (2) and 24- (3).
By carrying out the same reaction treatment, the following Tables 12 to 16 and
And the compounds described in Tables 17 to 21 are obtained.

[Table 12]

[0039]

[Table 13]

[0040]

[Table 14]

[0041]

[Table 15]

[0042]

[Table 16]

[0043]

[Table 17]

[0044]

[Table 18]

[0045]

[Table 19]

[0046]

[Table 20]

[0047]

[Table 21]

[0048]Example 40  (A) N- (t-butoxycarbonyl) glycine 300
mg, dicyclohexylcarbodiimide 420 mg and
And 1-hydroxybenzotriazole 230 mg
Add to 15 ml of trinitrile and stir at room temperature for 3.5 hours.
A reaction solution is obtained (reaction solution A). On the other hand, 3'-O- (4-
Lolobenzyl) -3- (glycyloxymethyl) -2 '
-Deoxy-5-fluoro-uridine hydrochloride (Example
18- (B) of the target compound) 700 mg and triethi
Add 160 mg of luamine to 15 ml of acetonitrile
After stirring, the reaction solution A was added to the solution and stirred at room temperature for 4 hours.
Stir. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue
Ethyl acetate is added to and the insoluble matter is filtered off. Concentrate the filtrate
The residue on silica gel column chromatography (dissolution
Medium: chloroform / ethyl acetate)
3- [N- (t-butoxycarbonyl) glycylglycy
Luoxymethyl] -3'-O- (4-chlorobenzyl)
-Colorless caramel of 2'-deoxy-5-fluorouridine
693 mg of syrup is obtained. NMR (CDCl₃) Δ: 1.45 (9H, s), 2.
18 (1H, ddd, J = 5.6, 7.6, 13.7H
z), 2.53 (1H, ddd, J = 2.9, 5.9,
13.7 Hz), 2.99 (1H, br), 3.8 (1
H, m), 3.84 (2H, d, J = 5.9Hz),
3.97 (1H, dd, J = 2.4, 11.7), 4.
07 (2H, d, J = 5.4Hz), 4.20 (1H,
d, J = 2.4 Hz), 4.27 (1H, m), 4.4
7 (1H, d, J = 11.7Hz), 4.55 (1H,
d, J = 11.7 Hz), 5.26 (1H, br),
6.03 (2H, s), 6.28 (1H, t, J = 5.
9 Hz), 6.76 (1H, br), 7.25 (2H,
d, J = 8.8 Hz), 7.33 (2H, dd, J =
2.4, 8.8 Hz), 8.08 (1H, d, J = 5.
9 Hz) (B) Dissolve 650 mg of this product in 15 ml of dioxane,
10 ml of 6.5N hydrogen chloride dioxane solution was added to the solution.
By performing the same process as in Example 1- (2),
3'-O- (4-chlorobenzyl) -3- (glycylg
Lysyloxymethyl) -2'-deoxy-5-fluoro
560 mg of amorphous powder of uridine hydrochloride is obtained. NMR (DMSO-d₆) Δ: 2.19 to 2.41 (2
H, m), 3.62 (4H, m), 3.99 (2H,
d, J = 5.4 Hz), 4.09 (1H, d, J = 2.
4Hz), 4.22 (1H, m), 4.55 (2H,
s), 5.36 (1H, br), 5.85 (2H,
s), 6.17 (1H, dd, J = 5.9, 7.3H)
z), 7.37 (2H, dd, J = 2.4, 8.8H
z), 7.44 (2H, dd, J = 2.4, 8.8H
z), 8.20 (3H, br), 8.41 (1H, d,
J = 7.3 Hz), 8.91 (1H, t, J = 5.9H)
z)

[0049]Examples 41-50  Example 40- (A) and 4 using corresponding raw material compounds
0- (B) was treated in the same manner as
Compounds described in Tables 22 to 25 and 26 to 29
To get

[Table 22]

[0050]

[Table 23]

[0051]

[Table 24]

[0052]

[Table 25]

[0053]

[Table 26]

[0054]

[Table 27]

[0055]

[Table 28]

[0056]

[Table 29]

[0057]Example 51  (A) 3 ', 5'-O-bis (ethoxymethyl) -2'
-Deoxy-5-fluorouridine (Reference Example 30-
(Compound of (3)) 725 mg, N- (carbobenzylo
Xy) -L-prolinkrol methyl ester 1.19
g, sodium iodide 750 mg, potassium carbonate 1.3
Example 1- (1) using 8 g and 40 ml of acetone
3- [N- (benzyl
Oxycarbonyl) -L-prolyloxymethyl]-
3 ', 5'-O-bis (ethoxymethyl) -2'-deo
1.08 g of a colorless oily substance of xy-5-fluorouridine was added.
obtain. NMR (CDCl₃) Δ: 1.22, 1.25 (3 for each)
H, t, J = 7 Hz), 1.7 to 2.3 (5 H, m),
2.35-2.6 (1H, m), 3.3-3.7 (2
H, m), 3.61, 3.62 (2H, q, J = 7 respectively)
Hz), 3.73, 3.90 (each 1H, dd, J =
2.5, 11.5 Hz), 4.21 (1H, brm),
4.25-4.45 (2H, m), 4.72, 4.76
(2H, s each), 5.14 (2H, m), 5.99
(2H, m), 6.33 (1H, dd, J = 6,6H
z), 7.15 to 7.4 (5H, m), 8.07 (1
(H, d, J = 6.5Hz) (B) This product 990mg, 10% palladium carbon
20 ml of formic acid and 560 mg of formic acid under stirring.
The reaction was stirred for 30 minutes then filtered and the insoluble material was washed with ethyl acetate.
Wash sequentially. Combine the filtrate and washings, and then add sodium bicarbonate.
It is washed with aqueous sodium chloride solution and then with saturated saline. Separate the organic layer
It was dried over anhydrous magnesium sulfate and filtered.
Add 180 mg of fumaric acid to the liquid. Concentrate the reaction solution under reduced pressure
The resulting residue was dissolved in a small amount of water and then freeze-dried.
L-prolyloxymethyl-3 ', 5'-O-bis (e
Toxoxymethyl) -2'-deoxy-5-fluorouridy
792 mg of pale yellow caramel-like fumarate
It NMR (DMSO-d₆) Δ: 1.13 (6H, t, J
= 7 Hz), 1.7 to 2.1 (3H, m), 2.1 to
2.4 (3H, m), 3.1 to 3.35 (2H, m),
3.0-3.8 (3H, br), 3.54 (4H, q,
J = 7 Hz), 3.66, 3.75 (each 1H, m),
4.10, 4.29 (1H, m each), 4.41 (1
H, m), 4.69 (4H, s), 5.94 (2H,
s), 6.15 (1H, m), 6.63 (2H, s),
8.18 (1H, d, J = 7Hz)

[0058]Examples 52-53  Using corresponding raw material compounds, Examples 51- (A) and 5
By carrying out the reaction treatment in the same manner as in 1- (B),
The compounds shown in Tables 30 and 31 are obtained.

[Table 30]

[0059]

[Table 31]

[0060]Example 54  (A) 5'-O- (t-butyldimethylsilyl) -2 '
-Deoxy-5-fluorouridine (Reference Example 26-
(Compound of (1)) 1.44 g, N-acetyl-L-pro
Lincolyl methyl ester 1.44 g, sodium iodide
Example 1-using 1.60 g of magnesium and 5 g of potassium carbonate
By performing the reaction treatment in the same manner as in (1), 3- (N-acetate
Cyl-L-prolyloxymethyl) -5'-O- (t-
Butyldimethylsilyl) -2'-deoxy-5-fluor
2.1 g of colorless caramel of loridine are obtained. NMR (CDCl₃) Δ: 0.12, 0.13 (3H ×
2, s × 2), 0.92 (9H, s), 1.9 to 2.3.
(5H, m), 2.08 (3H, s), 2.42 (1
H, m), 2.59 (1H, d, J = 3.9 Hz),
3.4-3.7 (2H, m), 3.84, 3.96 (1
H × 2, dd × 2, J = 2, 11 Hz), 4.06 (1
H, m), 4.49 (2H, m), 5.97, 6.06
(1H × 2, d × 2, J = 9.3 Hz), 6.36 (1
H, t-like), 8.11 (1H, d, J = 6.4)
Hz) (B) Dissolve this product 2.0 in 40 ml of tetrahydrofuran.
And, with stirring, 2.5 ml of diisopropylethylamine
And 850 mg of ethoxymethyl chloride were added and mixed
The material is heated under reflux overnight. The solvent was distilled off under reduced pressure, and the residue
Ethyl acetate and water are added to and the organic layer is separated after stirring. Existence
The organic layer was washed with saturated saline and dried over magnesium sulfate.
Filter and evaporate the solvent. The residue is purified by silica gel column chromatography.
By matography (solvent: chloroform / methanol)
By purifying, 3- (N-acetyl-L-prolyl)
Luoxymethyl) -3'-O-ethoxymethyl-5'-
O- (t-butyldimethylsilyl) -2'-deoxy-
1.98 g of a colorless caramel-like substance of 5-fluorouridine
obtain. NMR (CDCl₃) Δ: 0.14 (6H, s), 0.
92 (9H, s), 1.22 (3H, t, J = 6.8H
z), 1.8 to 2.3 (8H, s + m), 2.50 (1
H, ddd, J = 3.9, 6.4, 13.7 Hz),
3.50 (2H, m), 3.61 (2H, q, J = 6.
8 Hz, 3.81, 3.98 (1H × 2, dd × 2,
J = 2.0, 11.7 Hz), 4.12, 4.34,
4.51 (1H × 3, m), 4.72 (2H, s),
6.03 (2H, m), 6.30 (1H, m), 8.1
0, 8.15 (1H, d, J = 6.4Hz) (C) 1.95 g of this product was added to 60 ml of tetrahydrofuran.
Dissolve, 1.2 g of acetic acid and tetrabutylammonium under ice cooling
Add 3.5 g of nium fluoride. Mixture at room temperature
After stirring for 5 hours, add 50 ml of methanol and concentrate under reduced pressure.
Contract. Silica gel column chromatography of the residue
Purification with (solvent: chloroform / methanol)
From 3- (N-acetyl-L-prolyloxymethyl)
-3'-O-ethoxymethyl-2'-deoxy-5-fu
1.54 g of a colorless caramelized product of luoururidine is obtained. NMR (CDCl₃) Δ: 1.21 (3H, t, J =
6.8 Hz), 1.9, 2.08 (3H, s), 1.9
~ 2.5 (7H, m), 3.5 (2H, m), 3.61
(2H, q, J = 6.8Hz), 3.89 (2H,
m), 4.13 (1H, m), 4.43 (2H, m),
4.73 (2H, s), 5.96, 6.05 (2H, d
× 2, J = 9.8 Hz), 6.28 (1H, t-lik)
e), 8.25, 8.33 (1H, d, J = 6.3H)
z)

[0061]Examples 55-59  Corresponding raw material compounds were prepared in the same manner as in Example 54-A.
2 and the compounds listed in Table 33 are obtained.

[Table 32]

[0062]

[Table 33]

The corresponding starting compounds were treated in the same manner as in Example 54-B to give compounds shown in Tables 34 and 35 below.

[Table 34]

[0064]

[Table 35]

The corresponding starting compounds were treated in the same manner as in Example 54-C to give compounds shown in Tables 36 and 37 below.

[Table 36]

[0066]

[Table 37]

The corresponding starting compounds were treated in the same manner as in Example 52-B to give compounds shown in Tables 38 and 39 below.

[Table 38]

[0068]

[Table 39]

[0069]Example 60  (A) 5'-O- (t-butyldimethylsilyl) -2 '
-Deoxy-5-fluorouridine-3'-O-bis
(4-Fluorophenyl) phosphate (Reference Example 31-
(Compound of (A)) 2.43 g, N- (t-butoxycal
Bonyl) -L-prolinkrol methyl ester 1.58
g, sodium iodide 1.5 g and potassium carbonate 3 g
By carrying out a reaction treatment in the same manner as in Example 1- (1).
3- [N- (t-butoxycarbonyl) -L-prolyl
Luoxymethyl] -5'-O- (t-butyldimethylsi
Ryl) -2'-deoxy-5-fluorouridine-3 '
-Colorless bis (4-fluorophenyl) phosphate
3.07 g of lamels are obtained. NMR (CDCl₃) Δ: 0.11, 0.12 (3 for each)
H, s), 0.91 (9H, s), 1.42 (9H,
s), 1.7 to 2.4 (5H, m), 2.57 (1H,
dd, J = 6,15 Hz), 3.2 to 3.65 (2H,
m), 3.80, 3.90 (1H, d, J = 12H respectively)
z), 4.1 to 4.4 (2H, m), 5.13 (1H,
dd, J = 5, 5 Hz), 5.98, 6.00 (1 for each)
H, d, J = 16 Hz), 6.38 (1H, ddd, J
= 1.5, 6, 7 Hz), 6.9 to 7.3 (8H,
m), 7.98 (1H, d, J = 6.5 Hz) (B) 2.93 g of this product was dissolved in 20 ml of dioxane,
10 ml of 7.5N hydrogen chloride dioxane solution was added to the solution.
In the following, reaction treatment is carried out in the same manner as in Example 1- (2).
From 3-L-prolyloxymethyl-2'-deoxy-
5-fluorouridine-3'-bis (4-fluorophene
2.0 g of amorphous powder of (nyl) phosphate hydrochloride was obtained.
It NMR (DMSO-d₆) Δ: 1.75 to 2.4 (4
H, m), 2.3 to 2.6 (2H, m), 3.0 to 3.
4 (2H, m), 3.5 to 3.8 (2H, brm),
4.17 (1H, ddd, J = 3, 3, 3 Hz), 4.
41 (1H, dd, J = 6.5, 8.5Hz), 5.3
0 (1H, m), 5.50 (1H, brm), 5.9
3, 5.94 (each 1H, d, J = 11Hz), 6.2
0 (1H, dd, J = 6, 7 Hz), 7.0 to 7.4
(8H, m), 8.37 (1H, d, J = 7Hz),
9.7 (2H, br)

[0070]Examples 61-65  Corresponding raw material compounds were used in the same manner as in Example 60, and are listed in Tables 40 to 40 below.
The compounds listed in Table 41 and Tables 42-43 are obtained.

[Table 40]

[0071]

[Table 41]

[0072]

[Table 42]

[0073]

[Table 43]

[0074]Example 66  (A) Di (4-chlorophenyl) phosphorochloride
To 10 ml of tetrahydrofuran solution containing 1.03 g of ice
5'-O- (t-butyldimethylsilyl) -3 under stirring
-[N- (t-butoxycarbonyl) -L-valyloxy
Cimethyl] -2'-deoxy-5-fluorouridine
(Compound of Reference Example 32) 1.20 g of pyridine solution 20
Add ml dropwise. After stirring the mixture at room temperature for 7 hours, methanol was added.
(10 ml) is added, and the mixture is concentrated under reduced pressure. Ethyl acetate
Dissolved in dilute hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and
And sequentially wash with saturated saline. Dried over magnesium sulfate
After filtration, the obtained filtrate is concentrated under reduced pressure. Siri the residue
Kagel column chromatography (solvent: ethyl acetate /
5'-O- (t- by purifying with n-hexane)
Butyldimethylsilyl) -3- [N- (t-butoxyca)
Lubonyl) -L-valyloxymethyl] -2'-deoxy
Ci-5-fluorouridine-3'-O-bis (4-chloro
1.23 colorless caramelized substance of phenyl) phosphate
get g. NMR (CDCl₃) Δ: 0.11, 0.12 (6H,
s), 0.89, 0.96 (3H × 2, d, J = 6.8)
Hz), 0.91 (9H, s), 1.44 (9H, s)
s), 2.18 (2H, m), 2.61 (1H, dd-
like), 3.79, 3.91 (1H × 2, dd-l
ike), 4.27 (2H, m), 4.99 (1H, b
rd-like), 5.14 (1H, t-like)
e) 5.97, 6.06 (1H × 2, d, J = 9H
z), 6.39 (1H, t-like), 7.15 (4
H, m), 7.31 (4H, m), 7.99 (1H,
(d, J = 5.9 Hz) (B) 1.1 g of this product was dissolved in 5 ml of dioxane,
5 ml of 5N hydrogen chloride dioxane solution was added, and
By treating in the same manner as 1- (2), 3-L-variable
Luoxymethyl-2'-deoxy-5-fluorourigi
-3'-O-bis (4-chlorophenyl) phosphate
Obtained 720 mg of amorphous powder of sodium chloride. NMR (DMSO-d₆) Δ: 0.94 (6H, d-1
ike, J = 7.3 Hz), 2.16 (1H, m),
2.5 (2H, m), 3.64 (2H, br), 3.9
3 (1H, d, J = 4.4Hz), 4.18 (1H,
m), 5.34 (1H, m), 5.52 (1H, b
r), 5.88 (1H, d, J = 9.8 Hz), 5.9
5 (1H, d, J = 9.8Hz), 6.20 (1H, t
-Like), 7.33 (4H, d, J = 8Hz),
7.52 (4H, d, J = 8Hz), 8.39 (1H,
d, J = 6.8 Hz), 8.56 (3H, br-s)

[0075]Examples 67-69  Corresponding raw material compounds were prepared in the same manner as in Example 66 and are listed in Tables 44 to 44 below.
The compounds listed in Table 45 and Tables 46-47 are obtained.

[Table 44]

[0076]

[Table 45]

[0077]

[Table 46]

[0078]

[Table 47]

[0079]Example 70  (A) 5'-O- (t-butyldimethylsilyl) -3-
[N- (t-butoxycarbonyl) -L-valyloxy
Methyl] -2'-deoxy-5-fluorouridine (see
Compound of Consideration Example 32) 15 ml of pyridine solution of 1.54 g
Under ice cooling, S, S-di (4-chlorophenyl) phosphor
Rodiothioate monocyclohexyl ammonium 1.
72 g, 2,4,6-triisopropylbenzenesulfon
25 ml of a pyridine solution of 1.72 g of aluminum chloride was added dropwise.
Down. After dropping, stir overnight at room temperature and concentrate the reaction mixture under reduced pressure.
Contract. Chloroform and water were added to the residue and stirred to form an organic layer.
Was collected, washed successively with dilute hydrochloric acid, water and saturated saline, and then
Dry with magnesium acidate. The solvent was distilled off under reduced pressure and the residue
Silica gel column chromatography of the residue (solvent: acetic acid
5'-O by purification with ethyl / n-hexane)
-(T-butyldimethylsilyl) -3'-O- [S, S
-Di (4-chlorophenyl) phosphorodithioate]
-3- [N- (t-butoxycarbonyl) -L-valyl
Oxymethyl] -2'-deoxy-5-fluorourigi
This gives 1.30 g of a colorless caramel-like substance. NMR (CDCl₃) Δ: 0.12 (SH, s), 0.
13 (3H, s), 0.90 (3H, d, J = 7.3H
z), 0.92 (9H, s), 0.96 (3H, d, J
= 7.3 Hz), 1.45 (9H, s), 2.13 (2
H, m), 2.50 (1H, dd), 3.77 (1H,
dd, J = 2.0, 11.7 Hz), 3.88 (1H,
dd, J = 2.0, 11.7 Hz), 4.19 (1H,
m), 4.30 (1H, m), 5.00 (1H, br-
d), 5.14 (1H, dd-like), 5.99.
(1H, d, J = 9.8Hz), 6.06 (1H, d,
J = 9.8 Hz), 6.35 (1H, t-like),
7.35 to 7.50 (8H, m), 7.99 (1H,
(d, J = 5.9 Hz) (B) 1.24 g of this product is dissolved in 5 ml of dioxane,
Add 10 ml of 6.5N hydrogen chloride dioxane solution,
By treating in the same manner as in Example 1- (2), 3'-
O- [S, S-di (4-chlorophenyl) phosphology
Thioate] -3-L-valyloxymethyl-2'-de
Amorphous powder of oxy-5-fluorouridine hydrochloride 8
30 mg are obtained. NMR (DMSO-d₆) Δ: 0.96 (6H, d, J
= 6.8 Hz), 2.17 (1 H, m), 2.45 (2
H, m), 3.64 (2H, br), 3.95 (1H,
d, J = 4.4 Hz), 4.09 (1H, m), 5.3
1 (1H, br-m), 5.47 (1H, br), 5.
90 (1H, d, J = 9.8Hz), 5.96 (1H,
d, J = 9.8 Hz), 6.17 (1H, t-lik)
e), 7.55 (8H, m), 8.37 (1H, d, J
= 6.8 Hz), 8.56 (3H, br-s)

[0080]Examples 71-72  Corresponding raw material compounds are shown in Examples 1- (1) and 1- (2).
The same reaction treatment was performed to obtain the compounds shown in Table 48 and Table 49 below.
Get the compound.

[Table 48]

[0081]

[Table 49]

[0082]Example 73  (A) N- (t-butoxycarbonyl) -L-barlink
A solution of 1.59 g of loromethyl ester in 20 ml of acetone
Sodium iodide 900 mg was added to the mixture and the mixture was stirred at room temperature.
Stir for 2.5 hours. Powdered potassium carbonate was added to the resulting mixture.
2 g and 5'-O- (4-chlorobenzyl) -2'-de
Oxy-5-fluorouridine (of Reference Example 33- (3))
Compound) 1.12 g acetone 10 ml solution was added
It Allow the reaction to stand at ambient temperature for 20 hours and then at 50 ° C for 1 hour
Stir for a while. Then, the reaction treatment was carried out in the same manner as in Example 1- (1).
3- [N- (t-butoxycarbonyl) -L-valyl
Oxymethyl] -5'-O- (4-chlorobenzyl)-
Colorless caramel of 2'-deoxy-5-fluorouridine
1.560 g of solid are obtained. NMR (CDCl₃) Δ: 0.87, 0.94 (3 for each)
H, d, J = 7 Hz), 1.43 (9H, s), 1.9
5 to 2.2 (1H, m), 2.15 (1H, ddd, J
= 6,7,13.5 Hz), 2.38 (1H, ddd,
J = 3.5, 7, 13.5 Hz), 2.38 (1H,
d, J = 4 Hz), 3.68, 3.81 (1H, d respectively)
d, J = 2.5, 10 Hz), 4.12 (1H, dd
d, J = 2.5, 2.5, 2.5 Hz), 4.23 (1
H, dd, J = 5, 9 Hz), 4.4 to 4.6 (1H,
m), 4.52-4.56 (each 1H, d, J = 11H
z), 5.03 (1H, brd, J = 9Hz), 5.9
8, 5.99 (each 1H, d, J = 10Hz), 6.3
6 (1H, dd, J = 7, 7 Hz), 7.26, 7.3
3 (2H, d, J = 8.5Hz each), 8.03 (1
(H, d, J = 6.5 Hz) (B) Reaction of 1.51 g of this product in the same manner as in Example 1- (2)
Treated with 3-L-valyloxymethyl-5'-O- (4
-Chlorobenzyl) -2'-deoxy-5-fluoro
1.305 g of white powder of lysine / hydrochloride was obtained. m. p. 105 ° C or higher (gradual decomposition) NMR (DMSO-d₆) Δ: 0.94, 0.95 (each
3H, d, J = 7 Hz), 2.0 to 2.3 (3H,
m), 3.65 (1H, dd, J = 4, 10.5H)
z), 3.73 (1H, dd, J = 3, 10.5H)
z), 3.91 (1H, d, J = 7Hz), 3.97.
(1H, ddd, J = 3, 3, 4Hz), 4.27 (1
H, brm), 4.55 (2H, s), 5.50 (1
H, brm), 5.87-5.93 (1H, d, J respectively)
= 10 Hz), 6.17 (1H, dd, J = 5, 6.5)
Hz), 7.37, 7.42 (2H, ddd, J = respectively)
2,2,9Hz), 8.12 (1H, d, J = 7H
z), 8.60 (3H, brs)

[0083]Example 74  (A) 2'-deoxy-5-fluorouridine 3.69
g in the same manner as in Example 1- (1) to give 3- [N- (t
-Butoxycarbonyl) -L-prolyloxymethyl]
White powder of 2'-deoxy-5-fluorouridine
4.27 g are obtained. m. p. 127.5-129 ° C NMR (CDCl₃) Δ: 1.43 (9H, s), 1.
8-2.5 (6H, m), 2.81, 2.99 (1H,
dd, J = 4, 4 Hz), 2.92, 3.14 (1H,
d, J = 4 Hz), 3.2 to 3.6 (2H, m), 3.
7-4.0 (2H, m), 4.05 (1H, m), 4.
1 to 4.3 (1H, m), 4.4 to 4.6 (1H,
m), 4.8 to 6.1 (2H, m), 6.30 (1H,
m), 8.18 (1H, d, J = 6.5 Hz) (B) 1.89 g of this product was treated in the same manner as in Reference Example 31- (A).
In addition, 3- [N- (t-butoxycarbonyl) -L-p
Loryloxymethyl] -2'-deoxy-5-fluoro
Uridine-5'-O-bis (4-fluorophenyl) pho
1.639 g of a white foam of sulphate are obtained. NMR (CDCl₃) Δ: 1.42 (9H, s), 1.
7-2.6 (6H, m), 2.9, 3.15 (1H, b
r), 3.2 to 3.65 (2H, m), 4.0 to 4.6
(5H, m), 5.98 (2H, m), 6.28 (1
H, dd, J = 6,7 Hz), 6.85 to 7.25 (8
H, m), 7.65 (1H, d, J = 6.5 Hz) (C) 2.07 g of this product is treated in the same manner as in Example 1- (2).
And 3-L-prolyloxymethyl-2'-deoxy-
5-fluorouridine-5'-bis (4-fluorophene
1.705 g of a white powder of (nil) phosphate hydrochloride.
obtain. m. p. 90 ° C or higher (gradual decomposition) NMR (DMSO-d₆) Δ: 1.8 to 2.4 (6H,
m), 3.21 (2H, m), 4.02 (1H, dd
d, J = 3, 3, 3 Hz), 4.25 (1 H, m),
4.3-4.6 (3H, m), 5.61 (1H, d, J
= 4 Hz), 5.93, 5.94 (1H, d, J = respectively)
10Hz), 6.22 (1H, dd, J = 6,7H
z), 7.1 to 7.35 (8H, m), 8.05 (1
H, d, J = 7 Hz), 9.6 (2H, br)

[0084]Example 75  (A) 2'-deoxy-5-fluorouridine 3.65
g was reacted in the same manner as in Example 1- (1) to give 3- [N-
(Benzyloxycarbonyl) -D-valyloxymethyl
] 2'-deoxy-5-fluorouridine white
5.22 g of regular powder are obtained. NMR (CDCl₃) Δ: 0.88, 0.96 (3 for each)
H, d, J = 6.8 Hz), 2.1 to 2.3 (2H,
m), 2.40, 2.64 (1H, m each), 2.76
(1H, d, J = 3.9 Hz) 3.8, 3.9, 4.
03, 4.27, 4.53 (each 1H, m), 5.09
(2H, s), 5.36 (1H, d, J = 9.3H
z), 6.00 (2H, s), 6.29 (1H, t-1)
ike), 7.3 (5H, m), 8.13 (1H, d,
J = 6.4 Hz) (B) This product 2.20 g, ethoxymethyl chloride 450
mg, triethylamine 875 mg with tetrahydrofuran
It is dissolved in 70 ml of water and stirred overnight under reflux with heating. Reaction liquid
Is concentrated, chloroform and water are added to the residue, and the mixture is stirred. Existence
The organic layer was separated, dried and the solvent was distilled off.
Silica gel column chromatography (solvent: ethyl acetate
3- [N- (beta)
N-dioxycarbonyl) -D-valyloxymethyl]
-5'-O-ethoxymethyl-2'-deoxy-5-f
920 mg of a colorless caramelized product of luoururidine are obtained. NMR (CDCl₃) Δ: 0.89, 0.96 (3 for each)
H, d, J = 6.8 Hz), 1.24 (3H, t, J =
6.8 Hz), 2.18 (3 H, m), 2.43 (1
H, m), 3.61 (2H, q, J = 6.8Hz),
3.74, 3.89 (1H, dd, J = 2.9, 1 respectively)
1Hz), 4.14 (1H, m), 4.33 (1H, d
d, J = 4.4, 9.3 Hz), 4.51 (1H,
m), 4.76 (2H, s), 5.10 (2H, s),
5.28 (1H, br-d), 6.01 (2H, s),
6.35 (1H, m), 7.35 (5H, s), 8.0
7 (1H, d, J = 6.4 Hz) (C) 0.88 g of this product was treated in the same manner as in Example 51- (B).
And 3-D-valyloxymethyl-5'-O-etoki
Cymethyl-2'-deoxy-5-fluorouridine
0.68 g of colorless and amorphous malate powder is obtained. NMR (DMSO-d₆) Δ: 0.85, 0.87 (each
3H, d, J = 5.4 Hz), 1.34 (3H, t,
J = 7.3 Hz), 1.9-2.2 (3H, m), 3.
5 to 3.7 (5H, m), 3.94, 4.27 (1 for each)
H, m), 4.67 (2H, s), 5.80, 5.90.
(Each 1H, d, J = 10Hz), 6.18 (1H,
m), 6.56 (2H, s), 6.94 (5H, b
r), 8.15 (1H, d, J = 6.8Hz)

[0085]Example 76  (A) 2'-deoxy-5-fluorouridine 3.00
g, N- (t-butoxycarbonyl) -L-valincro
Romethyl ester 4.86 g, sodium iodide 4.1
2 g, potassium carbonate 8.42 g and acetone 100 m
l was treated as in Example 1- (1) to give 3- [N- (t
-Butoxycarbonyl) -L-valyloxymethyl]-
2'-deoxy-5-fluorouridine colorless foam
5.37 g are obtained. NMR (CDCl₃) Δ: 0.88 (3H, d, J =
6.8Hz), 0.95 (3H, d, J = 6.8H
z), 2.1 (1H, br-m), 2.2-2.5 (2
H, m), 2.66 (1H, br-t-like, J =
4.2 Hz), 2.73 (1H, d, J = 3.9H)
z), 3.8 to 4.0 (2H, m), 4.06 (1H,
d-like, J = 2.9 Hz), 4.2 (1H,
m), 4.57 (1H, m), 5.06 (1H, br-
d, J = 9.3 Hz), 6.00 (2H, s), 8.1
6 (1H, d, J = 6.4 Hz) (B) 1.40 g of this product, 1 g of acetic anhydride, tetrahydric anhydride
40 ml of lofran and 36 m of dimethylaminopyridine
g was treated in the same manner as in Example 24- (1) to give 3 ', 5'-.
O-bis (acetyl) -3- [N- (t-butoxyl
Bonyl) -L-valyloxymethyl] -2'-deoxy
-5-Fluorouridine colorless caramelized substance 1.513
get g. NMR (CDCl₃) Δ: 0.89, 0.96 (3 for each)
H, d, J = 7 Hz), 1.44 (9H, s), 2.1
2, 2.15 (each 3H, s), 2.0 to 2.3 (2
H, m), 2.57 (1H, ddd, J = 2.5, 6,
14 Hz), 4.1 to 4.3 (2H, m), 4.33
(1H, dd, J = 3, 13Hz), 4.41 (1H,
dd, J = 4, 13 Hz), 5.00 (1H, br
m), 5.22 (1H, dd, J = 2.5, 2.5, 5
Hz), 5.98, 6.04 (1H, d, J = 10 respectively)
Hz), 6.31 (1H, ddd, J = 1.5, 6, 7
Hz), 7.70 (1 H, d, J = 6 Hz) (C) 1.49 g of this product, 15 ml of anhydrous dioxane and
10 ml of 7.5N hydrogen chloride dioxane solution was used in Example 1-
The same process as in (2) was performed to obtain 3 ', 5'-O-bis (acetyl group).
) -3-L-Valyloxymethyl-2'-deoxy-
White powder of 5-fluorouridine hydrochloride 1.182 g
To get m. p. 90 ° C or higher (gradual decomposition) NMR (DMSO-d₆) Δ: 0.94, 0.95 (each
3H, d, J = 7Hz), 2.05, 2.07 (each)
3H, s), 2.0 to 2.7 (3H, m), 3.91.
(1H, d, J = 5Hz), 4.1 to 4.4 (3H,
m), 5.20 (1H, ddd, J = 3, 3, 6H
z), 5.88, 5.95 (1H, d, J = 10H respectively)
z), 6.19 (1H, dd, J = 7, 7 Hz), 8.
19 (1H, d, J = 7Hz), 8.62 (3H, br
s)

[0086]Examples 77-79  Example 76-Compound of (A) and corresponding starting material compound
Process as in 24- (1) and Example 1- (2).
Therefore, the following Table 50 to Table 51 and Table 52 to
The compounds listed in Table 53 are obtained.

[Table 50]

[0087]

[Table 51]

[0088]

[Table 52]

[0089]

[Table 53]

[0090]Example 80  3 ', 5'-O-bis (methoxyacetyl) -2'-de
Oxy-5-fluorouridine (Compound of Reference Example 34)
1.25 g, sodium iodide 1.50 g, acetone 4
0 ml, N- (t-butoxycarbonyl) -L-valine
Chloromethyl ester 1.30 g and potassium carbonate 5
g in the same manner as in Example 1- (1) to give 3- [N- (t
-Butoxycarbonyl) -L-valyloxymethyl]-
3 ', 5'-O-bis (methoxyacetyl) -2'-de
Oxy-5-fluorouridine pale yellow caramel
1.42 g are obtained. NMR (CDCl₃) Δ: 1.42 (9H, s), 1.
49 (6H, s), 2.2-2.5 (2H, m), 3.
44, 3.47 (3H × 2, s × 2), 4.09, 4.
12 (2H × 2, s × 2), 4.32 (1H, m),
4.34, 4.57 (1H × 2, dd × 2, J = 3.
4, 13.2 Hz), 4.9 (1H, br-s), 5.
33 (1H, d, J = 5.9 Hz), 6.02 (2H,
s-like), 6.42 (1H, m), 7.85 (1
(H, d, J = 6.4 Hz) (B) 1.40 g of this product, 5 ml of dioxane and water chloride
5 ml of a dioxane solution was treated in the same manner as in Example 1- (2).
Therefore, 3-L-valyloxymethyl-3 ', 5'-O-
Bis (methoxyacetyl) -2'-deoxy-5-fur
1.193 g of white powder of ourouridine hydrochloride is obtained. m. p. 75 ° C- (gradual decomposition) NMR (DMSO-d₆) Δ: 1.46 (6H, s),
2.3-2.5 (2H, m), 3.32, 3.33 (3
H × 2, s × 2), 4.11 (4H, s), 4.2-
4.4 (3H, m), 5.31 (1H, m), 5.92
(2H, s-like), 6.21 (1H, t-like)
e), 8.18 (1H, d, J = 6.8 Hz), 8.7
5 (3H, br-s)

[0091]Example 81  (A) 2'-deoxy-5-fluorouridine 1.72
g, Nt-butoxycarbonyl-α-t-butyl-L
-Glutamic acid / γ-chloromethyl ester 3.52
g, sodium iodide 3.0 g and acetone 70 ml
In the same manner as in Example 1- (1),
[Nt-butoxycarbonyl-α-t-butyl-L-
Glutaminyloxymethyl] -2'-deoxy-5-fu
2.205 g of luoururidine caramel are obtained. NMR (CDCl₃) Δ: 1.43, 1.46 (9 each)
H, s), 1.67, 2.60 (1H, brs each),
1.8-2.7 (6H, m), 3.89, 3.98 (each
1H, brd), 4.05 (1H, dd, J = 3.
3,3 Hz), 4.0 to 4.25 (1 H, m), 4.5
8 (1H, brm), 5.15 (1H, brd, J = 8
Hz), 5.97, 5.98 (1H, d, J = 10 respectively)
Hz), 6.31 (1H, dd, J = 5, 6.5H
z), 8.11 (1H, d, J = 6 Hz) (B) 2.19 g of this product, 15 ml of anhydrous dioxane and
15 ml of 7.5N hydrogen chloride dioxane solution was used in Example 1-
Treated in the same manner as in (2), 3- (L-glutaminyl-γ-
Oxymethyl) -2'-deoxy-5-fluorourigi
This gives 1.910 g of white powder of hydrochloride. NMR (DMSO-d₆) Δ: 1.8 to 2.25 (5
H, m), 2.3 to 2.7 (1H, m), 3.4 to 3.
7 (2H, m), 3.83 (1H, ddd, J = 3
3,3 Hz), 3.7 to 3.95 (1 H, m), 4.2
8 (1H, m), 5.0 (2H, br), 5.81 (2
H, s), 6.16 (1H, dd, J = 5,6Hz),
8.42 (1H, d, J = 7Hz), 8.52 (4H,
brs)

[0092]Example 82  (A) 3- [N- (t-butoxycarbonyl) -L-p
Loryloxymethyl] -2'-deoxy-5-fluoro
2.0 g of uridine (compound of Example 74- (A))
Dissolve with 50 ml of lysine, phenylchloroformate
Add 2.2 ml. After reacting at room temperature for 1.5 hours, under reduced pressure
Concentrate with. Ethyl acetate and water were added to the residue, and after stirring,
The machine layer is separated, washed with water, dried, and concentrated. Silica residue
Gel column chromatography (solvent: ethyl acetate / n
-[N- (t-
Butoxycarbonyl) -L-prolyloxymethyl]-
3 ', 5'-O-bis (phenoxycarbonyl) -2'
-Colorless caramel of deoxy-5-fluorouridine
2.76 g are obtained. NMR (CDCl₃) Δ: 1.44 (9H, s), 1.
8-2.3 (5H, m), 2.68 (1H, m), 3.
45 (2H, m), 3.95, 4.3 (1H, respectively)
m), 4.3 to 4.6 (2H, m), 5.3 (1H, b)
rd), 6.01 (2H, m), 6.44 (1H,
m), 7.2-7.4 (10H, m), 7.8 (1H,
(d, J = 5.9 Hz) (B) 1.75 g of this product was reacted in the same manner as in Example 1- (2).
Treated to give 3-L-prolyloxymethyl-3 ', 5'
-O-bis (phenoxycarbonyl) -2'-deoxy
White powder of -5-fluorouridine hydrochloride 1.35 g
To get NMR (DMSO-d₆) Δ: 1.9 to 2.3 (4H,
m), 2.61 (2H, m), 3.20 (2H, b
r), 4.4 to 4.5 (4H, m), 5.3 (1H,
m), 5.96 (2H, s), 6.29 (1H, t-1)
ike), 7.2-7.5 (10H, m), 8.25
(1H, d, J = 6.8Hz), 9.67 (2H, br
-S)

[0093]Example 83  (A) 3- [N- (t-butoxycarbonyl) -L-p
Loryloxymethyl] -2'-deoxy-5-fluoro
Uridine (compound of Example 74- (A)) and corresponding raw material
The compound was treated in the same manner as in Example 82- (A) to give 3-
[N- (t-butoxycarbonyl) -L-prolyloxy
Cimethyl] -3 ', 5'-O-bis (4-methoxyphen)
Nyloxycarbonyl) -2'-deoxy-5-fluor
A colorless caramel-like substance of lauridine was obtained with a yield of 92.9%.
It NMR (CDCl₃) Δ: 1.43 (9H, s), 1.
8-2.4 (5H, m), 2.73 (1H, m), 3.
5 (2H, m), 3.80, 3.81 (3H, respectively)
s), 4.24, 4.50 (each 1H, m), 4.55
(2H, m), 5.35 (1H, m), 6.01 (2
H, m), 6.47 (1H, m), 6.90 (4H,
m), 7.10 (4H, m), 7.75 (1H, d, J
= 5.9 Hz) (B) This product was treated in the same manner as in Example 82- (B).
3-L-prolyloxymethyl-3 ', 5'-O-bis
(4-Methoxyphenyloxycarbonyl) -2'-de
Oxy-5-fluorouridine hydrochloride colorless colorless powder
The powder is obtained with a yield of 89.2%. NMR (DMSO-d₆) Δ: 1.9 to 2.3 (4H,
m), 2.60 (2H, m), 3.21 (2H, m),
3.75, 3.76 (3H, s each), 4.4-4.5
(4H, m), 5.34 (1H, m), 5.96 (2
H, s), 6.29 (1H, t-like), 6.9-.
7.2 (8H, m), 8.24 (1H, d, J = 6.8
Hz), 9.2 (2H, br)

[Production of Raw Material Compound]Reference example 1  N- (t-butoxycarbonyl) -β-alanine 3.7
8 g, tetrabutyl ammonium sulfate 680 m
g and 6.72 g of sodium hydrogen carbonate with 30 ml of water
Dissolve in a mixture with 30 ml of methylene chloride and add to the solution.
Methyl chloride of romethoxysulfonyl chloride 3.96 g
5 ml of the solution was added dropwise under stirring and ice cooling, and the mixture was stirred at the same temperature for 1 hour.
Stir. Separate the organic layer from the reaction mixture, wash, dry, and reduce.
By distilling off the solvent under pressure, N- (t-butoxyca
Lubonyl) -β-alanine chloromethyl ester colorless
4.21 g of oil is obtained. NMR (CDCl₃) Δ: 1.44 (9H, s), 2.
61 (2H, t), 3.43 (2H, q), 4.9 (1
H, br), 5.71 (2H, s)

[0095]Reference Examples 2-25  The corresponding raw material compounds were treated in the same manner as in Reference Example 1 and the results shown in Table 54 below.
~ Obtain the compounds in Table 57.

[Table 54]

[0096]

[Table 55]

[0097]

[Table 56]

[0098]

[Table 57]

[0099]Reference example 26  (1) 5.0 g of 2'-deoxy-5-fluorouridine
2.1 g of imidazole and 1 g of dimethylformamide
Dissolve in 00 ml and cool to -50 ° C. Same temperature as the solution
4.5 g of t-butyldimethylsilyl chloride
100 ml of tylformamide solution was added dropwise with stirring, and -2
React at 5 ° C for 5 hours. 300m of methanol in the reaction solution
l is added and left at room temperature overnight, then concentrated under reduced pressure. Residue
200 ml of chloroform and saturated sodium bicarbonate
A 50 ml aqueous solution is added and shaken, and then the organic layer is separated.
The organic layer was washed, dried and filtered, and the filtrate was dissolved under reduced pressure.
The medium is distilled off. Silica gel column chromatograph of the residue
(Solvent: ethyl acetate / toluene / n-hexane)
By refining, 5'-O- (t-butyldimethylsi
Ryl) -2'-deoxy-5-fluorouridine white
5.8 g of powder are obtained. m. p. 199.5-201 ° C FABMS (m / z): 361 (MH⁺) (2) 5.8 g of this product and 6 g of potassium hydroxide
Mixing 200 ml of sun, 70 ml of toluene and 1 ml of water
Add to the solution and stir for 3 hours. P-chlorobenzyl in the solution
After adding 5 g of iodide and stirring at room temperature for 20 hours, the reaction solution was
Concentrate under reduced pressure. To the residue 300 ml ether and water
After adding 50 ml and stirring and neutralizing with 10% hydrochloric acid,
Separate the layers. The organic layer is washed, dried and filtered to obtain a filtrate.
The solvent is distilled off under reduced pressure. The residue is a silica gel column
Chromatography (solvent: ethyl acetate / chloroform
5'-O- (t
-Butyldimethylsilyl) -3'-O- (4-chlorobe
) -2'-Deoxy-5-fluorouridine 7.
7 g are obtained. m. p. 70-72 ° C FABMS (m / z): 486 (MH⁺) (3) 5'-O- (t-butyldimethylsilyl) -3 '
-O- (4-chlorobenzyl) -2'-deoxy-5-
Fluorouridine (Compound of Reference Example 26- (2)) 4.
Add 85 g to 150 ml of 67% acetic acid and stir overnight at room temperature
It The solvent was distilled off from the reaction solution under reduced pressure, and the residue was washed,
Recrystallize from ethyl acetate / isopropyl ether mixture
Thereby, 3'-O- (4-chlorobenzyl) -2 '
Colorless needle-like crystals of -deoxy-5-fluorouridine 3.
4 g are obtained. m. p. 201-202 ° C FABMS (m / z): 371 (MH⁺)

[0100]Reference Examples 27 to 29  Corresponding raw material compounds were used in Reference Examples 26- (1), (2) and
Treated in the same manner as (3) to obtain the compounds shown in Table 58 below.
It

[Table 58]

[0101]Reference Example 30  (1) 2'-deoxy-5-fluorouridine 4.92
g, pivalic acid chloromethyl ester 4.55 g and
13.82 g of potassium carbonate was added in the same manner as in Example 1- (1).
By carrying out the reaction treatment, 3- (t-butylcarbonylo)
Xymethyl) -2'-deoxy-5-fluorouridine
To obtain 6.35 g of a colorless caramel-like substance. FABMS (m
/ Z): 361 (MH⁺) (2) 6.32 g of this product, ethoxymethyl chloride 6.6
2 g and 13.57 g of diisopropylethylamine
Dissolved in 250 ml of tetrahydrofuran, and carried out later
By processing in the same manner as in Example 54-B, 3 ', 5'-O
-Bis (ethoxymethyl) -3- (t-butylcarbonyl)
Luoxymethyl) -2'-deoxy-5-fluorouri
6.59 g of a colorless oil of gin are obtained. FABMS (m / z): 477 (MH⁺) (3) Dissolve 4.05 g of this product in 10% ammonia-methanol
Dissolve in 80 ml of liquid and stir overnight at room temperature. Concentrated under reduced pressure
Shrink, add ethyl acetate and saturated saline to the residue, and after stirring
Separate the layers. After washing with saturated saline solution, magnesium sulfate
And filtered, and the filtrate is concentrated under reduced pressure. Siri the residue
Kagel column chromatography (solvent: chloroform
/ Ethyl acetate / n-hexane).
3 ', 5'-O-bis (ethoxymethyl) -2'-deo
2.40 g of white powder of xy-5-fluorouridine was obtained.
It m. p. 106-107.5 ° C FABMS (m / z): 363 (MH⁺)

[0102]Reference example 31  A) 5'-O- (t-butyldimethylsilyl) -2'-
Deoxy-5-fluorouridine (1.80 g) in pyridine
Dissolve in 12 ml and add di (4-fluorophenyl) to the solution.
Solution of 2.28 g of phosphorochloridate in pyridine
10 ml is added dropwise with stirring under ice cooling. After stirring at room temperature for 4 hours,
Add 10 ml of methanol and concentrate under reduced pressure. Vinegar on the residue
Ethyl acid and water were added, and the organic layer was separated after stirring, water,
With diluted hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated saline
Wash, filter and then concentrate the filtrate. Silica residue
Gel column chromatography (solvent: chloroform /
5'-O- (t-
Butyldimethylsilyl) -2'-deoxy-5-fluor
Lauridine-3'-O-bis (4-fluorophenyl)
2.63 g of a white powder of phosphate are obtained. m. p. 139.5-140 ° C (ethyl acetate / isopro
Pyrether) FABMS (m / z): 629 (MH⁺) B) 1.89 g of this product was dissolved in 40 ml of methanol, and p
-Add 1.14 g of toluenesulfonic acid monohydrate, and add
Stir for 2 hours at warm temperature. Sodium hydrogen carbonate in the mixture
Add 0.6 g and 2 ml of water and stir for 30 minutes, then concentrate the reaction mixture.
Contract. Ethyl acetate and water were added to the residue, and after stirring,
Separate the layers. Saturated with saturated sodium bicarbonate solution
After washing with brine, drying over magnesium sulfate, filtration,
Concentrate to dryness. The residue in 100 ml of tetrahydrofuran
Dissolve in the solution and add N-methyl-N- (t-butoxycal
Bonyl) glycine 1.42 g, dicyclohexylcarbo
1.55 g of diimide, 15 mg of dimethylaminopyridine
And stir overnight at room temperature. Methanol 10 in the reaction solution
Add ml and concentrate under reduced pressure. Add ethyl acetate to the residue.
Then, the insoluble matter is filtered off. The filtrate is concentrated and the residue is silica gel.
Column chromatography (solvent: chloroform / acetic acid
5'-O- [N- (t
-Butoxycarbonyl) -N-methylglycyl] -2 '
-Deoxy-5-fluorouridine-3'-O-bis
Amorphous powder of (4-fluorophenyl) phosphate
2.1 g are obtained. FABMS (m / z): 686 (MH⁺)

[0103]Reference Example 32  5'-O- (t-butyldimethylsilyl) -2'-deo
3.7 g of xy-5-fluorouridine (Reference Example 26-
(Compound of (1)), N- (t-butoxycarbonyl)-
L-valine / chloromethyl ester 4.07 g, iodinated
Using 4.6 g of sodium and 8 g of potassium carbonate,
By treating in the same manner as in Example 1- (1), 5'-O
-(T-butyldimethylsilyl) -3- [N- (t-but
Toxycarbonyl) -L-valyloxymethyl] -2 '
-Colorless caramel of deoxy-5-fluorouridine
3.98 g are obtained. NMR (CDCl₃) Δ: 0.13 (3H, s), 0.
14 (3H, s), 0.93 (3H, s), 0.87
(3H, d), 0.95 (3H, d), 1.44 (9
H, s), 2.1 to 2.5 (4H, m), 3.85 (1
H, dd), 3.96 (1H, dd), 4.07 (1
H, m), 4.26 (1H, m), 4.51 (1H,
m), 5.03 (1H, br), 5.98 (1H, br)
d), 6.04 (1H, d), 6.36 (1H, m),
8.12 (1H, d)

[0104]Reference Example 33  (1) 2'-deoxy-5-fluorouridine 4.92
g, t-butyldimethylsilyl chloride 9.0 g and
Imidazole (8.1 g) was added in the same manner as in Reference Example 26- (1).
The 3 ', 5'-O-bis (t-bu
Tyldimethylsilyl) -2'-deoxy-5-fluoro
9.35 g of a white powder of uridine are obtained. m. p. 58 ~
62 ° C (2) 9.30 g of this product was added to a 90% methanol aqueous solution 200
Dissolved in ml, 800 mg of 10-camphorsulfonic acid
And stir at room temperature for 6 hours. Sodium bicarbonate 3
g is added and the solvent is distilled off under reduced pressure. Add ethyl acetate to the residue.
After washing the organic layer with saturated saline solution, dry it with magnesium sulfate.
Dry and filter. By concentrating the filtrate under reduced pressure,
3'-O- (t-butyldimethylsilyl) -2'-deo
3.83 g of white powder of xy-5-fluorouridine was obtained.
It m. p. 164-168 ° C (3) Using 3.8 g of this product, Reference Examples 26- (2) and 2
By carrying out the reaction treatment in the same manner as in 6- (3), 5'-O
-(4-chlorobenzyl) -2'-deoxy-5-fur
3.30 g of colorless acicular crystals of olouridine are obtained. m. p. 133.5-34 ° C

[0105]Reference Example 34  1.23 g of 2'-deoxy-5-fluorouridine,
Toxic acetic acid 1.80 g, dicyclohexylcarbodiimi
4.12 g and 20 mg of dimethylaminopyridine
By using the same method as in Reference Example 31-B.
3 ', 5'-O-bis (methoxyacetyl) -2'-de
Oxy-5-fluorouridine colorless caramel.
90 g are obtained. FABMS (m / z): 391 (MH⁺)

[0106]

The object of the present invention, 2'-deoxy-
The 5-fluorouridine derivative (I) and a pharmacologically acceptable salt thereof show an excellent antitumor effect on various tumors (eg, solid tumor, ascites liver cancer, leukemia, etc.), and warm-blooded animals affected by them Can effectively prolong the survival time and / or effectively suppress the growth of tumor cells. For example, when sarcoma 180, which is an experimental tumor of a mouse, is used to examine the effect of suppressing tumor cell growth, 3- (glycyloxymethyl) -3′-O, which is the object of the present invention, is examined.
-(4-chlorobenzyl) -5'-O- (N, N-dimethylaminoacetyl) -2'-deoxy-5-fluorouridine (compound of Example 35- (B)) and 3-
6.25 mg / kg of (D-prolyloxymethyl) -3'-O- (4-trifluorobenzyl) -2'-deoxy-5-fluorouridine (compound of Example 16) was given 5 times per day. Those administered orally for consecutive days suppressed the growth of sarcoma 180 cells by 50% or more as compared with the case where the sample non-administration group was used as a control. In addition, the above two test compounds have low toxicity, for example, 200 mg / kg in mice.
No deaths were observed even after 5 days from oral administration.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yukio Akaike 710 Azuma Higashiarai, Omiya City, Saitama Prefecture 50-11-402

Claims (2)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R ¹ is an amino acid whose terminal amino group, imino group or carboxyl group may be protected, a group obtained by removing one carboxyl group at the α-position from the C-terminal of a dipeptide or tripeptide, R ² and R ^{2 3} is a hydrogen atom, a lower alkanoyl group which may be substituted with a carboxyl group or a lower alkoxy group, a group obtained by removing one hydroxyl group of a carboxyl group from an amino acid whose terminal amino group or imino group may be protected, A lower alkoxy-lower alkyl group, a benzyl group whose benzene ring may be substituted with a halogen atom or a trihalogenomethyl group, a phenoxycarbonyl group whose benzene ring may be substituted with a lower alkoxy group, (In the formula, Y ¹ and Y ² are each a phenoxy group which may be substituted with a halogen atom or a trihalogenomethyl group, or a phenylthio group.)
The 2'-deoxy-5-fluorouridine derivative represented by or a pharmacologically acceptable salt thereof. 2. A natural amino acid or an antipode thereof, or a dipeptide or tripeptide composed of a natural amino acid or its antipode, wherein R ¹ may have a terminal amino group, imino group or carboxyl group protected. The 2'-deoxy-5-fluoro group according to claim 1, which is a group obtained by removing one carboxyl group at the α-position from the C-terminal of thioproline, ε-aminocaproic acid, α-aminoisobutanoic acid or piperidylcarboxylic acid. A uridine derivative or a pharmaceutically acceptable salt thereof.