JPH032193A - 5-fluorouridine and 2'-deoxy-5-fluorouridine derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to novel 5-fluorouridine and 2'-deoxy-5-fluorouridine derivatives that have antitumor activity and are useful as pharmaceuticals. .

(Prior art) 5-Fluorouracil is an antitumor agent synthesized by Duschinsky in 1957. It has a wide antitumor spectrum and is used clinically, but its antitumor activity is insufficient and It is also highly toxic, so it is difficult to say that it is a satisfactory drug.

Therefore, in order to reduce the toxicity of 5-fluorouracil, 1-(2-tetrahydrofuryl)-5-fluorouracil (generic name: tegafur), l-hexylcarbamoyl-5-fluorouracil (generic name: carmofur), 5-fluorouracil, 'Deoxy-5-fluorouridine (-ship name: doxyfluridine) was discovered, but its antitumor effect is said to be inferior to that of 5-fluorouracil.

In addition, many attempts have been made to make various derivatives of 5-fluorouridine and 2'-deoxy-5-fluorouridine for the purpose of improving the antitumor effect (Japanese Patent Application Laid-open Nos. 77298-1982 and 92299-1989). No., JP-A-57-9
No. 1997, No. 91998, JP-A-58-49315
JP-A-61-134397, JP-A No. 196519, etc.), but nothing useful has yet been obtained.

(Problems to be Solved by the Invention) An object of the present invention is to develop novel 5-fluorouridine and 2'-deoxy-5-fluorouridine derivatives that have stronger antitumor activity than 5-fluorouracil and are less toxic. The goal is to provide the following.

(Means for Solving the Problems) As a result of intensive research to develop a compound that has stronger antitumor activity than 5-fluorouracil and is less toxic, the present inventors found that 5-fluorouridine and 2' It was discovered that N-acyl-aminocarboxylic acid esters of -deoxy-5-fluorouridine are suitable for the purpose, and the present invention was completed.

That is, the present invention relates to the general formula [wherein R' represents a hydrogen atom or an OR' group, R'', R
” and R4 are the same or different and each represents a hydrogen atom or a formula R'-NH-CH-(CH,l.-CO-(2) (in the formula, R6 represents an acyl group, R6 represents a hydrogen atom, the number of carbon atoms 1
~13 straight-chain or branched alkyl group, cycloalkyl group, aralkyl group, lower alkenyl group optionally substituted with halogen, or lower alkyl, lower alkenyl, or phenyl group optionally substituted with halogen; ,
n represents an integer of 0 to 6).

However, at least one of Rm, Ra and R4 is a group represented by formula (2), and.

R3 and R4 are not hydrogen atoms at the same time] and an antitumor agent containing the compound as an active ingredient.

The compound of the present invention also exists as a hydrate (l-hydrate, escaped hydrate, residual hydrate, etc.), and such compounds are also included in the present invention.

Examples of the acyl group represented by R1+ in formula (2) include formyl, acetyl, and propionyl.

Alkanoyl groups having 1 to 13 carbon atoms such as butyryl, isobutyryl, pentanoyl, hexanoyl, octanoyl, 2-propylpentanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl; phenylacetyl, 2-chlorophenylacetyl, 3-chlorophenylacetyl, 4-chlorophenyl Acetyl, 2-bromophenylacetyl, 3-bromophenylacetyl, 4-bromophenylacetyl, 2-fluorophenylacetyl,
3-fluorophenylacetyl, 4-fluorophenylacetyl, 2-methylphenylacetyl, 3-methylphenylacetyl, 4-methylphenylacetyl, 2-
Methoxyphenylacetyl, 3-methoxyphenylacetyl, 4-methoxyphenylacetyl, 2-nitrophenylacetyl, 3-nitrophenylacetyl, 4-nitrophenylacetyl, 1-naphthylacetyl, 2-naphthylacetyl, 2-phenylpropionyl, 3 -Aralkylcarbonyl groups such as phenylpropionyl, 2-phenylbutyryl, 3-phenylbutyryl, 4-phenylbutyryl; benzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2,4-dichloro Benzoyl, 3.4.5-1-dichlorobenzoyl, 2-bromobenzoyl, 3-bromobenzoyl, 4-
Promobenzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2.4-dimethylbenzoyl, 2.6-dimethylbenzoyl, 2-methoxy Benzoyl, 2.6-dimethoxybenzoyl, 3.4-dimethoxybenzoyl, 3-
Examples include aroyl groups such as cyanobenzoyl, 4-cyanobenzoyl, 2-acetylbenzoyl, 4-acetylbenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl, 1-naphthoyl, and 2-naphthoyl. Preferably R' is an alkanoyl group having 6 to 13 carbon atoms, especially a 2-propylpentanoyl group.

The linear or branched alkyl group having 1 to 13 carbon atoms represented by R6 in formula (2) includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, octyl, tridecyl, 11-methyldodecyl. etc. can be exemplified. Preferably R6 is a hydrogen atom.

Examples of the cycloalkyl group include cyclohexyl and cyclopentyl.

Examples of lower alkenyl groups optionally substituted with halogen include vinyl, 1-fluorovinyl, 2-fluorovinyl, 2.2-difluorovinyl, 2-bromovinyl, 2-
Examples include iodovinyl and allyl.

Examples of the aralkyl group include benzyl and 2-phenethyl.

Examples of the phenyl group optionally substituted with lower alkyl, lower alkenyl or halogen include phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,
2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl 42-tolyl, 3-tolyl,
Examples include 4-tolyl, 2.5-dimethylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl, and 4-vinylphenyl.

n is 0 to 6, preferably 0.

Among the compounds represented by the general formula (1), a compound in which R' is a hydrogen atom and R2 and R8 are the formula (2), and R1,
Compounds in which Rs and R4 are of formula (2) are preferred.

An example of manufacturing a compound represented by general formula (1) will be shown.

In general formula (1), R1 is a hydrogen atom or an OR' group,
The compound (1a) of the present invention, in which R8, R3, and R4 are groups represented by formula (2), can be produced using compound (3) as a starting material according to the following reaction scheme-8.

Reaction scheme-A>.

(In the formula, a', R' and n are the same as above, R1 represents a hydrogen atom or OR'', R7 represents a hydrogen atom or an OH group, R4m represents a group represented by formula (2)), that is, 5- Fluorouridine (3a) [in formula (3), R
7 represents an OH group] or 2'-deoxy-5-fluorouridine (3b) [a compound where R7 represents a hydrogen atom in formula (3)] in an appropriate solvent in the presence of a base and a condensing agent. The compound (la) of the present invention is obtained by carrying out an ester condensation reaction with the compound (2a).

The solvent used at this time is not limited as long as it does not affect the reaction, but specific examples include dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, and the like.

As the base, tertiary amines such as trialkylamine, pyridine, picoline, lutidine, and 4-(N,N-dimethylamino)pyridine can be used, and these can be used alone or in combination.

As a condensing agent, P-toluenesulfonyl chloride,
Triisopropylbenzenesulfonyl chloride, methanesulfonyl chloride, dicyclohexylcarbodiimide, thionyl chloride, phosphorus oxychloride, N-hydroxysuccinimide, and the like can be used.

The amount of each substance used in the reaction is 2 to 6 times the mole of compound (2a) and 2 times the mole of the base and condensing agent to compound (3).
6 The reaction temperature for using ~8 times the mole is usually under water cooling to around room temperature, and the reaction time for one reaction is usually 1 hour to 120 hours.

Moreover, in the general formula (1), R1 is an OH group, and R2 and R1 are groups represented by the formula (2).
b) and R2 and R3 are hydrogen atoms, and R4 is the formula (2
) The compound of the present invention (lb') represented by 1, for example, 5-
It can be produced according to the following reaction scheme-B using fluorouridine (3a) as a starting material.

<Reaction scheme-B> [In the formula, R4 & is the same as above, R8 represents a protecting group] That is, 5-fluorouridine (3a) is reacted with 1,3-dichlorotetraisopropyldisiloxane to form the compound (4 ) and then subjecting it to a protecting group introduction reaction to obtain a compound (5) in which a protecting group has been introduced at the 2' position. Compound (6) is obtained by subjecting compound (5) to a desilylation reaction.
Then, in the same manner as in Reaction Scheme-A, compound (2
Compound (7) is obtained by performing an ester condensation reaction with a).

Compound (7) is subjected to a deprotection reaction to form the compound (1) of the present invention.
b) can be produced.

In the above protecting group introduction reaction, examples of the protecting group represented by R8 include 2-tetrahydrofuranyl, 2-tetrahydropyranyl, 2-methoxy-2-methylethyl group, and the like. The reaction can be carried out using an acid catalyst in a suitable solvent or in the absence of a solvent.The reaction solvent is not limited as long as it does not affect the reaction, but specifically,
Dioxane, tetrahydrofuran, benzene, toluene, dichloromethane, chloroform, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, and the like can be used. As the acid catalyst, hydrogen chloride, sulfuric acid, nitric acid, phosphorous oxychloride, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, etc. can be used.The reaction temperature is not particularly limited, but is usually between water cooling and room temperature. The reaction time is usually around 0.
．． It takes about 5 to 48 hours. Further, the ester condensation reaction is carried out in the same manner as shown in Reaction Scheme-8 above. However, it is preferable that the amount of compound (2a), the base, and the condensing agent be 2 to 4.2 to 6.2 to 6 times the mole, respectively, and the reaction time be 1 to 72 hours.

Furthermore, the above deprotecting group reaction is carried out in a suitable solvent by a conventional method.
It can be carried out using an acid catalyst. The solvent used at this time is not limited as long as it does not affect the reaction, but examples include methanol, ethanol, isopropyl alcohol, dichloromethane, chloroform, etc., and these can be used alone or mixed with water. Examples of the acid catalyst include hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, etc. Although the reaction temperature is not particularly limited.

Usually under water cooling to around room temperature, reaction time usually 10 minutes to
It is 5 hours.

Furthermore, the compound (lb') of the present invention can be produced by subjecting compound (4) to an ester condensation reaction with compound (2a) and then carrying out a desilylation reaction.

The above ester condensation reaction is carried out in the same manner as shown in Reaction Scheme-8 above. However, it is preferable that the amount of compound (2a), the base and the condensing agent be 1 to 2 times, and 1 to 3.1 to 3 times the mole, respectively, and the reaction time be 1 to 72 hours.

The compounds (1b) and (lb') of the present invention have tautomeric relationships with formulas (lba) and (lb'a), respectively, as shown below, and exist as a mixture thereof.

[In the formula, R48 is the same as above] In addition, the compound of the present invention in which R3 is a hydrogen atom and R8 and R4 are a group represented by the formula (2) in the general formula (1) (
IC) can be produced according to the following reaction scheme -C using 1, for example, 5-fluorouridine (3a) as a starting material.

<Reaction scheme -〇> [In the formula, R4m is the same as above.] That is, 5-fluorouridine (3a) is reacted with 2,2-dimethoxypropane to form compound (9), and then compound (9) is converted to benzyl Compound (10) is produced by reacting with chloroformate. This is subjected to a reaction to remove the isopropylidene group to produce compound (11), which is then subjected to an ester condensation reaction with a compound represented by formula (2a), and the resulting compound (12) is catalytically reduced. The compound (lc) of the present invention is thereby obtained.

The above ester condensation reaction is carried out in the same manner as shown in the above reaction scheme-A. However, the compound represented by formula (2a), the base and the condensing agent are each 2 to 4.2 to 6.
．． It is preferable to make the amount 2 to 6 times the mole and to make the reaction time 1 hour to 72 hours.

In addition, the compounds of the present invention (ld, ld') in which R1 in general formula (1) is a hydrogen atom, one of R2 and R8 is a group represented by formula (2), and the other is a hydrogen atom, For example, 2'-deoxy-5-fluorouridine (3b
) can be produced according to the following reaction scheme using as a starting material.

[In the formula, R4'' is the same as above, Tr represents a triphenylmethyl group] That is, 2'-deoxy-5-fluorouridine (3b)
was reacted with triphenylmethyl chloride to form the compound (1
3), and when the obtained compound (13) is subjected to an ester condensation reaction with a compound represented by formula (2a), compound (14) is obtained.
). The compound (1d) of the present invention can be produced by subjecting the obtained compound (14) to a detritylation reaction.

The above ester condensation reaction is carried out in the same manner as shown in the above reaction scheme-A. However, the compound represented by formula (2a), the base and the condensing agent are each
It is preferable that the molar amount is 3.1 to 3 times the amount and the reaction time is 1 hour to 72 hours.

In addition, the compound (ld') of the present invention can be obtained by reacting compound (13) with benzyl chloroformate to produce compound (15), which is then subjected to a detritylation reaction, and the resulting compound (16) can be produced by performing an ester condensation reaction with a compound represented by formula (2a) to obtain compound (17), followed by catalytic reduction.

The above ester condensation reaction is carried out in the same manner as shown in the above reaction scheme -C.

(Effect of the invention) 5-fluorouridine and 2'-deoxy-5 of the present invention
- Fluorouridine derivatives have strong antitumor activity and low toxicity compared to 5-fluorouracil.

(Example) The compounds of the present invention will be explained in more detail by referring to Reference Examples, Examples, and Pharmacological Test Examples below.

Reference Example I Production of N-(2-n-propyl-〇-pentanoyl)glycine (2a) 6.93 g of glycine was dissolved in 63% of water, and under stirring under water cooling,
2-n-propyl-n-pentanoyl chloride 15g
and 36% sodium hydroxide solution 13- were alternately added dropwise. After the completion of the 0 dropwise addition, the reaction was stirred at room temperature for 3 hours, and then I
The pH was adjusted to about 2 with N hydrochloric acid, and the precipitated crystals were collected. This was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting crystals were recrystallized from hexane-ethyl acetate to yield 10.9 g of the target compound (yield: 59%) was obtained as colorless needles.

Reference Example 2 Production of 3',5'-0-(tetraisopropyldisiloxane-1,3-diyl)-5-fluoro-uridine (4) 5-fluorouridine log was dissolved in pyridine 300-, and the mixture was cooled with water and stirred. After 3 dropwise additions of 13.2 g of 1,3-dichlorotetraisopropyldisiloxane, the reaction was stirred at room temperature for 6 hours, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 220-chloroform,
Washed with water, IN-hydrochloric acid, and water. The chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain the target compound +2. xg (yield 54%) was obtained.

NMRfcDcm) δ: 9.87fLH, bS),
7.91flH, d).

5.75 (IH, d).

4, 35-4.15 (4H, ml.

4.0 (IH, ddl, 3.69flH, bd).

1.17-0.97f28H, ml.

Reference Example 3 Production of 3',5'-0-(tetraisopropyldisiloxane-1,3-diyl)2'-0-(2-tetrahydrofuranyl)-5-fluorouridine (5)3',5'- 0-(tetraisopropyldisiloxane-1,3-diyl)-5-fluorouridine 0.5g
and 2. Dissolve 0.17 g of 3-cyhtropin in 51 dl of methylene chloride, add 50 mg of pyridinium (p-toluenesulfothi), and stir the reaction at room temperature for 3.5 hours. After the reaction is complete, add 5 MI of ether, Wash with water,
The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography to obtain 0.46 g (yield: 79%) of the target compound.

Melting point 82-85°C CI-Mass (m/z) 589 (M”÷11.
505 Reference Example 4 Production of 2'-0-(2-tetrahydrofuranyl)-5-fluoro-uridine (6) 3', 5'-〇-(tetraisopropyldisiloxane-1,3-diyl-2'-0 12.4 g of -(2-tetrahydrofuranyl)-5-fluorouridine was dissolved in 100% of tetrahydrofuran, and 211 dl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution was added under stirring while cooling with water, and the mixture was stirred and reacted at room temperature for 40 minutes. After adding 3.7 g of sodium hydrogen carbonate and stirring at room temperature for 30 minutes, the seven-piece solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to separate the target compound into two stereoisomers. I got it as a body.

Thin layer chromatography analysis (CHCf2./M e
OH = 1/9), has a large Rf value (0,19), isomer yield 42% Melting point 93-96℃ CI-Mass (m/zl 347 (M'''+11.2
Yield of isomer with small 63Rf value (0,14) 52% Melting point 173-175℃ CI-Mass (m/zl 347 (M″″+11
．． 263 Reference Example 5 3',5'-bis-〇-[N-(2-n-pro-n-pentanoyl)glycyl]-2'0-(2-tetrahydrofuranyl)-5-fluorouridine (7) Production of 0.65 g of dicyclohexylcarbodiimide was added to a suspension of 0.64 g of N-(2-n-propyl-n-penctuyl)glycine in 35% of methylene chloride under water-cooling and stirring, followed by 15% of dicyclohexylcarbodiimide under water-cooling with stirring. Stirred for 6 minutes then 2'-0
Add 0.55 g of -(2-tetrahydrofuranyl)-5-fluorouridine (isomer with a small Rf value of Reference Example 4), 0.38 g of triethylamine, and 0.19 g of 4-(N,N-dimethylamino)pyridine, At room temperature, 1.5
The reaction was stirred for hours. After being left at room temperature overnight, the mixture was concentrated under reduced pressure, and 20 ml of ethyl acetate was added to the resulting residue, and the insoluble matter was removed in the oven. The residue obtained by concentrating the furnace liquid under reduced pressure was subjected to silica gel column chromatography to obtain 0.19 g of the target compound.
(yield: 17%).

NMR (CDC) δ: 9.38TIH, bS),
7.44+IH, d).

6.3 (IH, t), 6.26 (IH, t).

5.75TIH, d), 5.28 (IH, dddl.

4.6-4.3 (5H, ml.

4, 24-4.05 (4H, m).

3.78-3.65 (IH, nil.

3, 53-3.4 flH, ml.

2.27-2.1 (2H, ml.

1.9-1.1 (22H, ml.

0.89 (12H, tx41 Reference Example 6 Production of 2',3'-0-impropylidene-5-fluorouridine (9) 15 g of 5-fluorouridine in 750 ml of acetone, 2
．． 4. Add 1.1 g of 2-dimethoxypropane 7.5- and p-toluene chlorosulfonic acid, .l hydrate, and stir at room temperature.
The reaction was stirred for 5 hours. - After standing at room temperature overnight, 5 g of sodium hydrogen carbonate was added and stirred at room temperature for 2.5 hours. After removing the insoluble matter from the furnace, the crystals obtained by concentrating under reduced pressure were recrystallized from ethanol to obtain 15.7 g of the target compound (yield: 84%).
) was obtained as colorless needle crystals.

Reference example 7 5'-〇-benzyloxycarbonyl-2'3'-〇-
Preparation of isopropylidene-5-fluorouridine (10) 0.68 g of 2',3'-0-isopropylidene-5-fluorouridine and 0.3 g of 4-(N,N-dimethylamino)pyridine were mixed with 45-g of methylene chloride. After 0.35% of benzyl chloroformate was added dropwise under stirring while cooling with water, the mixture was stirred and reacted at room temperature for 9.5 hours. - After being left at room temperature overnight, the residue obtained by concentrating under reduced pressure was subjected to silica gel column chromatography to obtain 0.75 g (yield: 76%) of the target compound.

NMR (11, DC) δ: 8.25 (LH, bdl
, 7.48 (IH, d).

5.85 (IH, d), 5.18 (2! (, S14.
87-4.77 (2H, ml.

4, 45-4.35 (3H, m).

1.58+3H,S), 1.35(3H,Sl Reference Example 8 Production of 5'-〇-benzyloxycarbonyl-5-fluorouridine (11) 90% trifluoroacetic acid solution 3.1- was added under stirring under water cooling. 5
'-〇-benzyloxycarbonyl-2',3'-0
-Impropylidene-5-fluorouridine 0.71g
After dissolving, the mixture was stirred at room temperature for 1 hour. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography to obtain 0.54 g (yield: 84%) of the target compound.

Melting point 66-68℃ CI-Mass (m/zl 39? (M”+11
, 379. 267 Reference Example 9 5'-〇-benzyloxycarbonyl-2'3'-bis-〇-[N-(2-n-propyl-n-penctuyl)
Preparation of [glycyl]-5-fluorouridine (12) A suspension of 0.5 g of N-(2-n-propyl-〇-pentanoyl)glycine in 30 d of methylene chloride was added with 0.0 g of dicyclohexylcarbodiimide under stirring while cooling with water. After adding 51 g, the mixture was stirred for 10 minutes under water cooling.
-benzyloxycarbonyl-5-fluorouridine 0
．． 54 g, triethylamine 0.3 g and 4-(N
, N-dimethylamino)pyridine O (15 g) was added thereto, and the mixture was stirred and reacted at room temperature for 10 hours. Thereafter, treatment was performed according to the method of Reference Example 5 to obtain 0.62 g of the target compound (yield 60%).
) was obtained.

Melting point 75-77°C CI-Mass (m/zl 763(M”+11.
632 Reference Example 10 Production of 2'-deoxy-5'-0-trityl-5-fluorouridine (13) 0.25 g of 2'-deoxy-5-fluorouridine and 0.34 g of trityl chloride were dissolved in 2.5-pyridine. After one reaction of dissolving and stirring at 60° C. for 4 hours, the reaction solution was poured into 80° C. of ice water, and the precipitated crystals were collected in a furnace.

This was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography to obtain 0.28 g of the target compound (yield: 56%). ) was obtained.

Reference Example 11 Production of 2'-deoxy-3'-0-[N-(2-n-propyl-〇-pentanoyl)glycyl]-5'trityl-5-fluorouridine (14) N-(2-n-propyl) 0.11 g of dicyclohexylcarbodiimide was added to a suspension of 0.11 g of -〇-pentanoyl)glycine in 15 ml of methylene chloride while stirring under water cooling, and the mixture was stirred for 1 hour under water cooling. -5゛-
0.27 g of 〇-trityl-5-fluorouridine, 70n+g of triethylamine, and 34 mg of 4-(N,N-dimethylamino)pyridine were added, and the mixture was stirred and reacted at room temperature for 2 days. Thereafter, it was treated according to the method of Reference Example 5 to obtain 0.26 g (yield: 70%) of the target compound.

NMR (cnci's+δ: 8.5L (IH, di,
7.89 (11(,d).

7.57-7.21 (15H, ml.

6.29 (IH, ddl, 5.9 (IH, tl.

5.52 (IH, ddl, 4.18 (IH, dddl)
.

4.07i2H,d), 3.55(IH,dd), 3
．． 39 (IH, dd), 2.59 [IH, ddd).

2.35 (LH, ddd).

2.23-2.05 (LH, punishment.

1.73-1.19 (8H, ml.

o,9(6H,tx21 Example 1 2',3',5'-tris-0-[N-(2--
Production of N-(2-n-propyl-〇-pentanoyl)glycyl]-5-fluorouridine (1a) A suspension of 8.86 g of N-(2-n-propyl-〇-pentanoyl)glycine in 3801 dl of methylene chloride was stirred with water cooling. After adding 9.01 g of dicyclohexylcarbodiimide, the mixture was stirred for 50 minutes under water cooling. Next, 5-fluorouridine was added.
63 g, triethylamine 4.45 g and 4-(N,
N-dimethylamino) and 1.63 g of lysine, 4.45 g of triethylamine and 4-(N.

1.63 g of N-dimethylamino)pyridine was added, and the mixture was stirred and reacted at room temperature for 4 days. Thereafter, it was treated according to the method of Reference Example 5 to obtain 4.62 g (yield: 43%) of the target compound.

Melting point: 94-97°C Elemental analysis value (as CsJaJNsO+2・坏HzO)
Calculated value (%) e; 57.06 H; 7.74 N; 8.
53 Actual value (%) C: 57.09 H near, 72N: 8.
59 Example 2 2', 3', 5'-1-lis-〇-(benzoyl-D
Production of L-alanyl)-5-fluorouridine (la)) The target compound was obtained in the same manner as in Example 1 in a yield of 10%.

Melting point 87-89℃ FD-Mass (m/z) 788 (M”11.595
Example 3 2'-deoxy-3',5'-bis-〇-[N-(2-
Preparation of n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (1a) In a solution in which 2.04 g of N-(2-n-pro-n-pentanoyl)glycine was suspended in 110-methylene chloride, 2.09 g of dicyclohexylcarbodiimide under water cooling and stirring
After adding 0 and then 2', stirred for 20 minutes under water cooling.
1.25 g of -deoxy-5-fluorouridine, 1.23 g of triethylamine, and 0.62 g of 4-(N,N-dimethylamino)pyridine were added, and the mixture was stirred and reacted at room temperature for 1 day. Thereafter, the crystals obtained by treatment according to the method of Reference Example 5 were recrystallized from acetone-water to obtain the target compound 1.
38 g (44% yield) were obtained as colorless needles.

Melting point 191-192℃ CI-Mass (m/zl 613fM"+11.41
2 Example 4 3',5'-bis-〇-[N-(2-n-propyl-
Production of 3',5'-bis-〇-[N-(2-n-propyl-
0.5 g of fluorouridine (n-pentanoyl)glycyl]-2'0-(2-tetrahydrofuranyl)-5-fluorouridine was dissolved in 6 ml of ethanol, and pyridinium was dissolved under stirring at room temperature.
After adding p-toluenesulfonate 18B, the mixture was stirred and reacted at 55°C for 3.5 hours. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography to obtain 0.34 g (yield: 77%) of the target compound.

Melting point 91-94℃ Elemental analysis value (C, eH4sFN40+.・As genus HJ) Calculated value (%) C: 55.01 H; 7.24N; 8
．． 85 Actual value (%) C; 54.92 H near, 03N; 8.
68 Example 5 2',3'-bis-〇-[N-(2-n-propyl-
Production of 5'-〇-benzyloxycarbonyl-2'3'-bis-Q-[N-(2-n-propyl-n-pentanoyl)
After dissolving 0.62 g of [glycyl]-5-fluorouridine in 25-ethanol, 0.2 g of 5% palladium on carbon
was added and stirred for 50 minutes at room temperature and pressure in a hydrogen stream. After the catalyst was removed from the furnace, the residue obtained by concentrating under reduced pressure was subjected to silica gel column chromatography to obtain 0.36 g (yield: 68%) of the target compound.

Melting point 99-102°C Elemental analysis value (as CsJ4JN40.a-H-0) Calculated value (%) C; 53.85 H; 7.03 N: 8.6
6 Actual value (%) C: 53.72 H near, 2ON; 8.
3B Example 6 Preparation of 2'-deoxy-3'-0-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (1d) 2'-deoxy-3'-0- 0.24 g of [N-(2-n-propyl-n-pentanoyl)glycyl]-5'-trityl-5-fluorouridine was dissolved in 1.7 g of 50% trifluoroacetic acid solution and stirred for 15 minutes under water cooling. . The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography to obtain 0.12 g of the target compound (yield 78
%) was obtained.

NMR (C, DC mu DMSO-da) δ: 11.8
5flH, d).

8.27 (LH, tl.

8.22 flH, dl.

6.2flH, dd).

5, 4-5.23 (2H, ml.

4.09-4.0 (LH, ml.

3.85+2H,d).

3.68 (2H, S).

2.35-2.13 (3H, ml.

1.6-1.12 (8H, ml.

0.87 (6H, txzl) Pharmacological Test Example 1 2 x 10' KB cells were implanted in 9 microwells, and after 12 hours, the compounds of the present invention and 5-fluorouracil obtained in Examples 1 and 3 were added to 3 wells. /do
se) After culturing for 5 days, the number of cells was measured, and from the cell proliferation inhibition rate-concentration curve, the inhibition rate was 50%.
The cell growth inhibitory concentration (I Ca value) was determined. The results are shown in Table 1.

Table 1 Compound of Example 1 2.0 Compound of Example 3 1.8 5-Fluorouracil 17.7 Pharmacological Test Example 2 (Acute Toxicity) The compounds of the present invention obtained in Examples 1 and 3 were administered to 7-week-old BDF. ,
It was orally administered to female mice (10 mice per group), and the mice were determined to be alive or dead on the 21st day of administration, and the LDso value was determined from the mortality rate according to the Litchfield-Wilcochran method. The results are shown in Table 2.

Table 2 Compound of Example 1 Compound of Example 3 5-Fluorouracil 5000 or more 3000 or more Procedural amendment 1990

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) [In the formula, R^1 represents a hydrogen atom or an OR^4 group, and R^
2. R^3 and R^4 are the same or different and each has a hydrogen atom or formula ▲ Numerical formula, chemical formula, table, etc. ▼ (2) (In the formula, R^5 represents an acyl group, and R^6 represents hydrogen atom,
A straight or branched alkyl group having 1 to 13 carbon atoms, a cycloalkyl group, an aralkyl group, a lower alkenyl group optionally substituted with halogen,
or represents a phenyl group which may be substituted with lower alkyl, lower alkenyl or halogen, and n represents an integer of 0 to 6). However, at least one of R^2, R^3 and R^4 is a group represented by formula (2), and R^2 and R
^4 is never a hydrogen atom at the same time] A compound represented by the following. (2) An antitumor agent containing the compound according to claim 1 as an active ingredient.