JPS62258367A - 5-fluorouracil derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A 5-fluorouracil derivative shown by formula I (R is 0-10C unsubstituted or substituted alkylene; A is -NH- or -CO-; n is 0 or 1; Y is 1-10C unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroacryl, pyridinium ion containing halogen as pair ion or isocyanato). EXAMPLE:5-Fluoro-3,4-dihydro-2, 4-dioxo-N-( 2-thienyl )-1(2H)-pyrimidinecarboxa mide. USE:A carcinostatic agent or an intermediate derivative thereof. Having sufficient carcinostatic action, low toxicity and high purity. PREPARATION:5-Fluorouracil is reacted with an isocyanate shown by formula II to give a 5-fluorouracil derivative shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention is directed to a novel 5-5 drug useful as an anticancer agent or an intermediate thereof.
- Concerning fluorouracil derivatives.

(Prior art and its problems) Conventionally, 5-fluorouracil and its derivatives, such as 1-(2'-tetrahydrofuranyl)-5-fluorouracil and l-hexylcarbamoyl-5-fluorouracil, have been known as anticancer agents. .

However, since these compounds are toxic, they have a negative effect on living organisms, and when administered orally, they have drawbacks such as causing gastrointestinal disorders. For this reason, when administered as an anticancer agent, it is necessary to weaken the toxicity, and as the toxicity decreases, the anticancer effect also decreases, leading to problems such as the need to administer large amounts. Furthermore, it has been difficult to purify the desired product, and it has often been difficult to obtain a pure product.

An object of the present invention is to provide an anticancer agent that has sufficient anticancer activity, has low toxicity, and is a pure product.

(Means for Solving the Problems) That is, the present invention has the general formula (I) (wherein R is an unsubstituted or substituted alkylene group having 0 to 1 carbon atoms, and A is an atomic group consisting of -NH- and -co-). , n is O
or 1, and Y represents an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, a pyridinium ion or isocyanate group with a halogen as a counter ion)
The present invention provides a 5-fluorouracil derivative represented by the following formula and a method for producing the same.

The compound of the present invention is a novel compound that exhibits antitumor activity and is useful as an anticancer agent or an intermediate thereof.

The compound of the present invention is produced by the method shown below.

The first method is to prepare 5-fluorouracil and the corresponding isocyanate of the following formula: This is a method of reacting with the following reaction formula.

Examples of the isocyanate (■) used in this method include 2-chenyl isocyanate, 2-thiazolyl isocyanate, 2-chloroethyl isocyanate,
3-chloropropyl isocyanate, 5-bromopentyl isocyanate, 1-oxopyridin-3-yl isocyanate, 3-indolyl isocyanate, 3-indolylmethyl isocyanate, benzenecarboxamitomethyl isocyanate, 3-pyridine Carboxamitomethyl isocyanate, ethylene diisocyanate, 1.
3-trimethylene diisocyanate, 1,6-hexamethylene diisocyanate, 1゜10-decamethylene diisocyanate, 2-isocyanatoethylpyridinium chloride, 5-isocyanatopentylpyridinium bromide, 7-isocyanatoheptyl Trizinium iodide,
2-(3-phenylureido)ethyl isocyanate,
3-C3-(pyridin-3-yl)ureido]propyl isocyanate, 6-(3-(pyridin-2-yl)ureido)hexyl isocyanate, 6-(3-(
4-sulfamoylphenyl)ureido]hexyl isocyanate, 6- (3-(3-pyridinecarboxamide)ureido)hexyl isocyanate, 6- (3-
hexyl ureido) hexyl isocyaner small, 6- (
Examples include 3-(3-dimethylaminopropyl)ureido]hexyl isocyanate.

These isocyanates are commercially available or can be produced by an appropriate method and used as appropriate.

Suitable methods include, for example, a method for producing from the corresponding amine and dichlorocarbonyl, a method for producing from the corresponding carboxylic acid azide by the Curtius method, a method for producing from the corresponding amine and trichloromethyl chloroformate, a method for producing from the corresponding olefin and There are methods for producing it from isocyanic acid.

The molar ratio of 5-fluorouracil to isocyanate is preferably in the range of 1.5:1 to 1:1.5.

Examples of the reaction solvent include benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethyl acetate, chloroform, pyridine, and triethylamine.

The reaction can be carried out at a temperature in the range of 40 to 100°C, but the final temperature is preferably 80°C or higher to complete the reaction.

Although the reaction time varies depending on the reactivity of the isocyanate used, a range of 005 to 24 hours is appropriate.

A second method for obtaining the compounds of the present invention is to obtain 5-fluorouracil corresponding to the following formula % () (wherein R, A, n and Y are the same groups or numbers as in general formula (I). This is a method of reacting with a carboxylic acid azide represented by

Examples of the carboxylic acid azide (■) used in this method include 2-thenoyl azide, 2-thiazolylcarbonyl azide, 3-chloropropanoyl azide, 6-bromohexanoyl azide, 4-chlorobutanoyl azide, 1-oxo Pyridine-3-carbonyl azide, indole-3-carbonyl azide, indole-3-acetyl azide, benzenecarboxamide acetyl azide, 3
-Pyridinecarboxamide acetyl azide, butanedioyldiazide, pentanedioyldiazide, octanedioyldiazide, dodecanedioyldiazide, pyridinium-1-propanoylazide chloride, pyridinium-1-hexanoylazidobromide, pyridinium-1
-Octanoylazitoioside, 3-(3-phenylureido)propanoyl azide, 4-(3-(pyridin-3-yl)ureido]butanoyl azide, ?-(3-
(Pyridin-2-yl)ureido]heptanoyl azide, 7-(3-(4-sulfamoylphenyl)ureido)heptanoyl azide, ?-(3-(3-pyridinecarboxamide)ureido)heptanoyl azide, 7 −(
3-hexylureido)heptanoyl azide, 7-(
Examples include 3-(3-dimethylaminopropyl)ureido]heptanoyl azide.

These carboxylic acid azides can generally be produced from the corresponding carboxylic acids and acid hydrazides by conventional methods.

The molar ratio of 5-fluorouracil to carboxylic acid azide is preferably in the range of 1.5:1 to 1:1.5.

Examples of the reaction solvent include benzene, toluene, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethyl acetate, chloroform, pyridine, and triethylamine.

This reaction can be carried out at a temperature in the range of 40 to 100°C, but the final temperature is preferably 80°C or higher in order to complete the reaction.

The reaction time varies depending on the reactivity of the carboxylic azide used, but is suitably in the range of 0.5 to 24 hours.

A third method for obtaining the compound of the present invention is a 5-fluorouracil derivative containing an isocyanate group represented by the general formula (■): (wherein R represents the same group as in the general formula (I))
and the following formula: % formula % () (wherein Y represents the same group as in general formula (I),
Z represents -NH- or -NHNH-Co- group) to react with a compound represented by the general formula: (wherein R, Z and Y represent the same group as the above formula) 5 - A method for producing fluorouracil derivatives.

This can be expressed as a reaction formula as follows.

(IV) 0=old NH-R-NHCO-Z-Y 5 with incyanato group used in this reaction
-Fluorouracil derivative (IV) is the isocyanate Y-(A
), -R-NGO (VI), where Y is an isocyanato group (-N
GO) and n=o, and is easily available.

Compound (IV) is preferably used in a single, purified form, but it can be used unpurified or in the form of a reaction mixture.

The compound represented by the general formula (IX) used in this reaction is easily available, such as hexanamine, N,
N-dimethylpropanediamine, henzenethanamine, penzenamine, 2-aminopyridine, 3-aminopyridine, 2-aminothiazole, 2-aminodiazole, 4-aminebenzenesulfonamide, benzenecarbohydrazide, pyridine-2-carbo Examples include hydrazide, pyridine-3-carbohydrazide, and the like.

The molar ratio of the compound represented by -a2 (TV) and the compound represented by general formula (■) is 1.5:1 to 1:
A range of 1.5 is desirable. Examples of reaction solvents include benzene, toluene, tetrahydrofuran, dioxane,
Examples include acetonitrile, dimethylformamide, dimethylsulfoxide, ethyl acetate, chloroform, pyridine, and triethylamine.

This reaction can be carried out at a temperature range of 40 to 100°C.

The reaction time is the starting material compound (IV) and compound (IX).
Although it varies depending on the reactivity of the reaction time, a range of 0.5 to 24 hours is appropriate.

A fourth method for obtaining the compounds of the invention is a 5-5- This is a method for producing a 5-fluorouracil derivative represented by the general formula (I[[), which is characterized by reacting a fluorouracil derivative with pyridine, and the reaction formula is as follows.

0-Apricot-N H-R-X (XI) The 5-fluorouracil derivative (XI) used in this reaction is an isocyanate: Y-(A), 1-R-
NGO (VI) No Y is halogen (C1, Br or I
) and when n=o, it is a compound obtained by reaction with 5-fluorouracil and is easily available.

Although this compound (XI) is preferably used after being isolated and purified after production, it can also be used unpurified or as a reaction mixture.

The proportion of pyridine used is different from that of another raw material compound (XI).
It is sufficient if the molar ratio is 1 or more, and it may be used as a solvent for the reaction.

This reaction can be carried out at a temperature range of 30 to 100°C.

The reaction time varies depending on the reactivity of compound (XI) as a raw material, but is suitably in the range of 0.5 to 24 hours.

Next, a fifth method for obtaining the compound of the present invention will be explained.

This method uses 5-fluorouracil and a halogenoisocyanate: X-R-NGO (XII) (wherein R represents the same group as in general formula (I),
r or I (representing halogen) and 3 of pyridine
The pyridinium compound (I[[) is produced in one step from the components. This can be expressed as a reaction equation as follows.

The molar ratio of 5-fluorouracil and isocyanate (Xn) is preferably in the range of 1.5:I to 1:i,s.

The amount of pyridine may be at least 1 times the mole of the larger of the two components, and it is desirable to use it in excess as a reaction solvent.

The temperature range for the reaction is preferably 40 to 100°C.

The appropriate reaction time is 0.5 to 24 hours,
If the reaction time is less than 0.5 hours, the reaction rate of pyridine is so low that the pyridinium formation is incomplete, making it difficult to obtain a pure target product.

In the above five production methods, the residue obtained by distilling off the solvent from the final reaction product under reduced pressure or the residue precipitated by adding an appropriate poor solvent is processed by extraction, recrystallization, chromatography, etc. The desired product of the present invention can be obtained by purification according to the following methods.

The compounds targeted by the present invention are illustrated below.

5-Fluoro-3,4-dihydro-2,4-dioxo-
N-(2-chenyl)-1(2H)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(2-thiazolyl)-1<2H)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(I-oxopyridin-3-yl)-1(2H)-
Pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-N-(3-indolyl)-1
(2H)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(3-indolylmethyl)■(2U)-pyrimidinecarboxamide N-(benzenecarboxamide)methyl-5-fluoro-3,4-dihydro-2,4-dioxo1(2H)-pyrimidinecarboxamide 5-fluoro- 3,4-dihydro-2,4-dioxo-N-(3-pyridinecarboxamide)methyl-1(2H)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(2-(I-pyridinio)ethyl]-1(2H)
-pyrimidinecarboxamide chloride 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(3-(I-pyridinio)propyl)-1(2H)
-pyrimidinecarboxamide chloride 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(7-(I-pyridinio)hebutyl)-1(2H)
~Pyrimidine lupoxamide ioside 5-fluoro-3,4-dihydro-2,4-dioxo~
N=(2-isocyanatoethyl)-1(2fl)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-N-(3-incyanatopropyl)-1(2and)-pyrimidine Carboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(6-isocyanatoethyl)-1(2)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(3-phenylureido)hexyl-1(2H)
-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-N (6-(3-(3-pyridinyl)ureido]hexyl)-1(2H)-pyrimidinecarboxamide 5-fluoro-3,4 -dihydro-2,4-dioxo-
N [6-(3-(3-pyridyl)ureido]hexyl l -1(2H)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N (6-(3-(4-sulfamoylphenyl)ureido)hexyl l -1(2H)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N (6-(3-hexylureido)hexyl)-1(
2H)-pyrimidinecarboxamide 5-fluoro-3,
4-dihydro-2,4-dioxo-N (6-(3-(
3-dimethylaminopropyl)ureido]hexyl l-
1(2H)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(3-(2-thiazolyl)ureido]hexyl)-
1(2H)-pyrimidinecarboxamide N-(3-(2-diazolyl)ureido]hexyl-5
-Fluoro-3,4-dihydro-2,4-dioxo-1
(2H) -pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N (6-(3-(3-pyridinecarboxamide)ureido)hexyl)-1(2H)-pyrimidinecarboxamide 5-fluoro-3,4-dihydro-2,4-dioxo-
N (6-(3-(4-pyridinecarboxamide)ureido]hexyl)-1(2H)-pyrimidinecarboxamide The 5-fluorouracil derivatives that are the subject of the present invention are substances that exhibit antitumor activity, or Furthermore, it was found that the following modifications can be made into important intermediates that can lead to antitumor substances.The antitumor effects of these 5-fluoro derivatives are shown in Table 1. It is clear from Table 1 that mouse P-388Leukemia is significantly suppressed.

(Example) Next, the present invention will be explained in more detail with reference to Examples.

5-Fluoro-3,4-dihydro-2,4-dioxo-
N-(2-chenyl)-1(2-pyrimidinecarboxamide): 2-chenyl isocyanate 3.09 g (24.7 m
mol) and 5-fluorouracil 3.21 g (24,
7 mmol) in 50 ml of benzene and 20 ml of pyridine.
1 of a mixed solvent and stirred and refluxed at 80°C for 16 hours.

After cooling, the crystals were collected by filtration and washed with a mixed solvent of benzene:pyridine (3:2), followed by benzene:ethanol (3:2).
? After washing with M mixed solvent, vacuum drying, 5-fluoro-
5. 3,4-dihydro-2,4-dioxo-N-(2-chenyl)-1(28)-pyrimidinecarboxamide.
00 g (I9,6mm.

l) Obtained.

Yield 79.32 Melting point 166-175°C702()
)(em-') Elemental analysis: Actual value C42, 39, H2, 42, N 16
．． 50 (X) Calculated value (as CJbFNlosS)
: C42,35,H2,37°N 16.46 (χ
] SuJ111 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(I-oxopyridin-3-yl)-1(2H)-
Pyrimidine carboxamide: 3-(I-oxopyridyl)carbonyl azide 3.72 g (22.7 mmol)
and 5-fluorouracil 3.00g (23.1mn+o
1) was added to 45 ml of pyridine and reacted with stirring at 90°C for 1 hour. After cooling, the crystals were collected by filtration, washed with hot methanol, and dried in vacuum to give 5-fluoro-3゜4-dihydro-2.
, 4-dioxo-N-(I-oxopyridin-3-yl)-1(2H)-pyrimidinecarboxamide at 5.48
g (20.7 mmol) was obtained.

Yield 91χ Melting point 243-246°C IR,,, (KBr disk): 3460 (NH
), 3120°3080(-'), 1700~1
760 (>・0), 1280 (N-0).

1250 (n) (ell-heavy) Elemental analysis: Actual value C45,1?, H2,33,N2
1.23 (χ) Calculated value (as Ct.H, N40.F): C45,29,H2,2B.

N 21.13 (χ) Taitoyoban 1 5-Fluoro-3,4-dihydro-2,4-dioxo-
N-(3-indolyl)-1(2)-pyrimidinecarboxamide: 1.73 g of 3-indolylcarbonyl azide (9,2
9mmol1) and 5-fluorouracil 1.20g (9,
23 mmol) was taken in a mixed solvent of 15 ml of benzene and 3 ml of pyridine, and the mixture was stirred and refluxed at 80° C. for 24 hours.

After cooling, the crystals were collected by filtration, washed with benzene and then with hot methanol, and dried in vacuo to give 5-fluoro-3°4-dihydro-2,4-dioxo-N-(3-indolyl)-1(2
2.06 g (7,1
5 mmol) was obtained.

Yield 77χ Melting point 246-250°C (cm-') Elemental analysis: Actual value C53,99H2,'36. N 1
9.39 (χ) Calculated value (as CtJJ403F)
: C54,1? , H3, 15°N 19.44
(χ) Chestnut 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(3-indolylmethyl)-1(2)-pyrimidinecarboxamide: 6.90 g of 3-indolyl acetohydrazide (36,
Take 5 mmol) and 4.4 ml of concentrated hydrochloric acid in 800 ml of water, add sodium nitrite at 5-10°C, extract the purified acid azide with benzene, wash with water, dry with anhydrous sodium sulfate, and reduce the solution to about 100a+1. Concentrated. 50 ml of pyridine and 4.70 g (36.1 mmol) of 5-fluorouracil were added to the benzene solution of this acid azide, and the mixture was stirred and refluxed at 80° C. for 1 hour.

After cooling, the crystals are collected by filtration, washed with methanol, then dissolved in tetrahydrofuran, insoluble materials are removed, and concentrated under reduced pressure. The resulting crystals are washed with methanol, dried in vacuum, and 5-fluoro- 2.11 g (6,98 mmo
l) Obtained.

Yield 19χ Melting point 176-177°C IR,,X (KBr disk): 3440.33
00.3200 (NH).

HF 3120(7), 1740.1690-1720(>
・0), 1235 (-'>(cm-') Elemental analysis: Actual value C55, 29H3, 65, N 1B,
09 (X) Calculated value (CzHzFN403):
C55,59,H3,67°N 18.60 (χ) N-(benzenecarboxamitomethyl)-5-fluoro-3,4-dihydro-2,4-dioxo-1(2H)-
Pyrimidine lupoxamide: 7.30 g (35.8 mmol) of benzenecarboxamide acetyl azide and 5-
3.90 g (30.0 mmol) of fluorouracil was placed in a mixed solvent of 20 ml of benzene and 5 ml of pyridine, and the mixture was stirred and refluxed at 80° C. for 6 hours.

After cooling, the crystals were collected by filtration, washed with chloroform and then methanol, and dried in vacuum to give N-(benzenecarboxamitomethyl)-5-fluoro-3°4-dihydro-2,4.
6.77 g (22.1 mmol) of -dioxo-1(2H)-pyrimidinecarboxamide was obtained.

Yield 74
98, H3, 62°N 18.29 (χ) S'll1 5-Fluoro-3,4-dihydro-2,4-dioxo-
N-(2-(I-pyridinio)ethyl]-1(2H)
-pyrimidinecarboxamide chloride 2-chloroethyl isocyanate 4.71 g (44.6 mmol) and 5
- 5.80 g (44.6 mmol) of fluorouracil was taken in 50 ml of pyridine, and reacted with stirring at 90°C for 3.5 hours.

After cooling, the crystals were collected by filtration, washed with chloroform and methanol, and dried under vacuum to give 5-fluoro-3,4-dihydro-2,4-dioxo-N-[2-(I-pyridinio)].
2.38 g (7.56 mmol) of ethyl)-1(2H)-pyrimidinecarboxamide chloride was obtained.

Yield 17X Melting point 212-216℃TR,, (K
Br disk): 3430.3350.3270
(Ntl).

3100, 3045 (=//), 1700-174
0.1690(>・0)1260()) Ccm −
') Elemental analysis: Actual value C45, 33, H3, 98, N 17
．． 56 (χ) Calculated value (C, □H1□CIF NtO
s): C45,80°+13.84. N
17.80 (χ) 1'' di-5-fluoro-3,4-dihydro-2,4-dioxo-
N-(2-(I-pyridinio)ethyl]-1(2H)
- Pyrimidine carboxamide chloride. ! 2.00 g (8.49 mmol) of N-(2-chloroethyl)-5-fluoro-3°4-dihydro-2,4-dioxo-1(2H)-pyrimidinecarboxamide was placed in 10 ml of pyridine at 90°C for 6 hours. The reaction was stirred.

After cooling, the crystals were collected by filtration, washed with chloroform and methanol, and dried under vacuum to give 5-fluoro-3,4-dihydro-2,4-dioxo-N-[2-(I-pyridinio)].
1.36 g (4.32 mmol) of ethyl)-1(2H)-pyrimidinecarboxamide chloride was obtained.

Yield 51χ Melting point 213-216°C IR,,, (KBr disk): 3430.33
50.3270 (NH).

3100, 3045(7), 1700-1740.
1690 (>=0).

1260 (-/ ) (cm-') Elemental analysis: Actual value C45,53H4,07,N 17.
68 (χ) Calculated value (C+ zH+ zcIFN40+
): C45,80°H3,84,N 17.
80 (χ) Point 1 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(5-(I-pyridinio)pentyl]-1(2H)
-Pyrimidinecarboxamide bromide: 5-bromopentyl isocyanate3. OOg(I5,
6mm.

l) and 2.04 g of 5-fluorouracil (I5,'7
mmol) was taken in pyridine 25n+1, and the mixture was reacted with stirring while raising the temperature from 80°C to 100°C over 3 hours.

After cooling, the residue obtained by concentrating under reduced pressure was washed with chloroform and dried in vacuo to give 5-fluoro-3,4-dihydro-2,4-dioxo-N-[5-(I-pyridinio)].
3.68 g (9.17 m5+ol) of (pentyl)-1(2H)-pyrimidine carboxamide bromide was obtained.

Yield 59χ Melting point 132-135°C IR,,, (KBr disk): 3430.33
00 (NH), 3060 (7-).

2950.2860(C-)1), 1755.1720
．． 1675(>・0)l1245(=' ) (cl
ll-') Elemental analysis: Actual value C44,73, H4,57
, N 13.25 (X) Calculated value (C+sH+5Br
As FN403): C44,90°H4,52,
N 13.96 (I31m 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(3-(I-pyridinio)propyl]-1(2H)
-pyrimidinecarboxamide chloride 3-chloropropyl isocyanate 2.71 g (22,
7 mmol) and 5-fluorouracil 2.95 g (2
Take 2.7 mmol) in 20 ml of pyridine and add 90
The reaction was stirred at ℃ for 3 hours.

After cooling, benzene was added, the crystals were collected by filtration, washed with benzene and then with chloroform to give 5-fluoro3,4-dihydro-2,4-dioxo-N-(3-(I-pyridinio)).
2.82 g (8.58 mmol) of propyl-1(2)-pyrimidinecarboxamide chloride was obtained.

1710-1750.1640-1710 (>=O),
, 1245(7) (cm-') Elemental analysis: Actual value C
47,38,H4,,66,N 16.44 (χ)
Calculated value (as C+ J+ 4clFNmOz):
C47,50°H4,29,N 17.04 (χ)
5-Fluoro-3,4-dihydro-2,4-dioxo-
N-(6-(3-pyridyl)ureido]hexyl)-1
(2H)-pyrimidine lupoxamide: 1.29 g of 1.6-hexamethylene diisocyanate (
7.67 mmol) was taken in 20 ml of pyridine and 90
5-Fluorouracil at 1. OOg (7,69mm
After adding ol) little by little over 20 minutes, the mixture was stirred and reacted at 90°C for 1 hour.

After cooling, the residue obtained by concentrating under reduced pressure was dissolved in chloroform to remove insoluble materials. The solution of the derivative having an isocyanato group thus obtained was concentrated to about 10 ml,
0.72 g (7.65 mmol) of 3-aminopyridine was added and dissolved, followed by refluxing for 1 minute.

After cooling, the crystals were collected by filtration, washed with chloroform and hot acetonitrile, and dried in vacuum to give 5-fluoro-3,4-
dihydro-2,4-dioxo-N-(6-(3-(3-
1.41 g (3.59 mmol of pyridyl)ureido]hexyl)-1(2H)-pyrimidinecarboxamide
)Obtained.

Yield 47χ Melting point 180-183°C 1R,, (KBr disk): 3400.33
30 (NH), 3100 (-/).

2940, 2850 (C-11), 1740.169
5.1665 (>=O).

1230(') (cm-') Elemental analysis: Actual value C52,97,115,55,N2
1.48 (χ) Calculated value (C+7tl□IFN604
): C52,04°H5,39,N 21.
42m Dajong coal soil 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(6-(3-(2-pyridyl)ureido]hexyl)-1(2H)-pyrimidinecarboxamide 1.6-hexamethylene diisocyanate 2.59 g
(I5.4 mmol) was taken in 30 ml of pyridine,
2.00 g of 5-fluorouracil (I5,4
mmoL) was added little by little over 30 minutes, and the mixture was stirred and reacted at 90° C. for 1 hour.

After cooling, the residue obtained by concentrating under reduced pressure was dissolved in chloroform, insoluble materials were removed, and the filtrate was concentrated to 15 ml. 1.45 g of 2-aminopyridine (I5,4 mmol
) was added, stirred at room temperature for 10 minutes, and the precipitated crystals were removed.
After washing the crystals obtained by concentrating the filtrate with chloroform,
Vacuum dried, 5-fluoro-3,4-dihydro-2,4
1.81 g (4.61 mmol) of -dioxo-N-(6-(3-(2-pyridyl)ureido)hexyl)-1(2H)-pyrimidinecarboxamide was obtained.

Yield: 30 x Melting point: 177-181°C (R,,, (K
Br disk): 3450.3tLO, 3300
(NH).

3050 (I), 2940.2850 (C-H),
1740.1690°1675 (>=O), 123
0(I) (cm-') Elemental analysis: Actual value C52,33
, H5, 49, N 20.72 (χ) Calculated value (C+
Jz+FNbOa): C52,04°)15
．． 39. N 21.42 (χ) more than 1 tL1 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(6-(3-(4-sulfamoylphenyl)ureido]hexyl)-1(2H)- and rimidine carboxamide 1.6-hexamethylene diisocyanate 2.59 g (
5.4 mmol of 5-fluorouracil was added to 25 ml of benzene and refluxed. OOg(I5,4mm
A solution of ol) in pyridine (25 ml) was added dropwise over 20 minutes, and the mixture was stirred and refluxed for 1 hour.

After cooling, the residue obtained by concentrating under reduced pressure was dissolved in chloroform to remove insoluble materials. The filtrate was concentrated, and the residue was washed with hexane. 20 ml of tetrahydrofuran was added to the obtained crude product of the derivative containing an isocyanate group and dissolved, and 2.63 g (I5, 3 mmol) of sulfanilamide was obtained.
was added, and the mixture was refluxed for 1 hour. After cooling, the mixture was concentrated under reduced pressure, chloroform was added, and the crystals were collected by filtration and washed with chloroform and then acetone. Hot methanol was added to the crystals to dissolve them, insoluble materials were removed, the filtrate was concentrated and dried in vacuo, and 5-fluoro-3,4-dihydro-2,4-dioxo-N-(6
-(3-(4-sulfamoylphenyl)ureido]hexyl)-1(2H)-pyrimidinecarboxamide
．． 08g (2.30mmol) was obtained.

Yield 15! Melting point 181-184℃IR,,,(K
Br disk): 3400.3350.3260
(NH).

3130(=')+2960.2890(C-H
), 1750.1710°1685DJ), 134
0.1160 (Sow), 1240 (7) (aa
-') Elemental analysis: Actual value C46, 37, H5, 24, N
17.32 (χ) Calculated value (C+ allr*FN
bO*s): C45,95°H4,93,N
17.86 (χ) 5-Fluoro-3,4-dihydro-2,4-dioxo-
N-(6-(3-(3-dimethylaminopropyl)ureido]hexyl)-1(2H)-pyrimidinecarboxamide 1.6-hexamethylene diisocyaner) 2.59 g
(I5.4 mmol) was taken in 25 ml of pyridine,
5-fluorouracil at 90°C2. OOg(I5,4
mmol) was added little by little over 20 minutes, and the mixture was stirred and reacted at 90° C. for 1 hour.

After cooling, the residue obtained by concentrating under reduced pressure was dissolved in chloroform, insoluble materials were removed, and the filtrate was concentrated to about 10 ml. The resulting solution of the derivative having an isocyanato group was
, N-dimethyl-1,3-propanediamine 1.57g
(I5.4 mmol) was added, and the mixture was stirred and reacted at room temperature for 10 minutes. The solution was condensed under reduced pressure, chloroform was added to the resulting residue, and the separated viscous substance was washed with chloroform and dried in vacuo to give 5-fluoro-3,4-dihydro-2,
4.20 g (I0.5 ma + ol
)Obtained.

Yield: 68χ Melting point: 70-81°C ■ IR,,, (KBr disk): 3420 (NH
), 3120(7).

2960, 2880 (C-H), 1740.1690
(>-0)+1250(7) (cm-') Elemental analysis: Actual value C50,41, H7,06, N19
．． 36 (X) Calculated value (as C+JzJN604)
: C50,99°H7,30,N 20.99 (
χ〕 Inu charcoal top soil 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(6-(3-(3-pyridinecarboxamide)ureido)hexyl)-1(2H)-pyrimidinecarboxamide: 1.6-hexamethylene diisocyanate 2.59 g
(I5,4++u++ol) was taken in 25 ml of pyridine, and 2.00 g of 5-fluorouracil (I
5.4 mmol) was added little by little over 20 minutes, and then
The reaction was stirred at 0° C. for 1 hour.

After cooling, the residue obtained by concentrating under reduced pressure was dissolved in chloroform, insoluble materials were removed, and the filtrate was concentrated to about 10 ml. Add 3-pyridylcarbohydrazide to the filtrate2. lOg(
5.3 mmol) was added and the mixture was refluxed for 20 minutes.

After cooling, the crystals were collected by filtration, washed with chloroform, and dried under vacuum to give 5-fluoro-3,4-dihydro-2,4-dioxo-N-(6-(3-(3-pyridinecarboxamide)ureido). 2.05 g (4°71 mmol) of hexyl)-1(2 and)-pyrimidine carboxamide was obtained.

Yield 31χ Melting point 138-147°C HIRffi, (KBr disk): 32
00~3400(NH), 3100(=')+2
940.2860(C-t(), 1740,1700.
1660 (>=O).

1250(I) (Cm-') Elemental analysis: Actual value C50, 33, H5, 39, N 22
．． 88 (χ) Calculated value (as C+aHz□FN?O5): C50,82°H5,21,N 23.05
(χ) Husband 1 5-fluoro-3,4-dihydro-2,4-dioxo-
N-(6-(3-(4-pyridinecarboxamide)ureido)hexyl l-1(2H)-pyrimidinecarboxamide 1.6-hexamethylene diisocyanate 2.59 g
(I5.4 mmol) was taken in 25 ml of pyridine,
2.00 g of 5-fluorouracil (I5,4
mmol) was added little by little over 20 minutes, and the mixture was stirred and reacted at 90° C. for 1 hour.

After cooling, the residue obtained by concentrating under reduced pressure was dissolved in chloroform, insoluble materials were removed, and the filtrate was concentrated to about 10 ml. Add 2.10 g of 4-pyridylcarbohydrazide to the filtrate (
5.3 mmol) was added to the mixture, and the mixture was refluxed for 30 minutes. After cooling, the crystals are collected by filtration, washed with hot methanol, dissolved by adding hot pyridine, insoluble matter is removed, and the filtrate is concentrated under reduced pressure. The crystals obtained are washed with methanol and vacuum dried.
5-Fluoro-3,4-dihydro-2,4-dioxo-
1.56 g (3.58 ml) of N-(6-(3-(4-pyridinecarboxamide)ureido)hexyl)-1(2H)-pyrimidinecarboxamide was obtained.

Yield 23χ Melting point 185-197°C I IR,, (KBr disk): 3400,33
00 (NH), 3100 ('').

2940, 2860(c-)1), 1745. 1
700. 1670 (>=O).

1250 (I) (cm-') Elemental analysis: Actual value C50,72, H5,17, N23
．． 24 Cχ] Calculated value (as CIllH2□FN70s): C50,82°H5,21,N 23.
05 (χ) (Antitumor effect test) CDF or BDF, P-388 to mice (5 weeks old)
Mouse leukemia cells (1×10 6 cells/mouse) were intraperitoneally transplanted, and a predetermined amount of the compound of the present invention was continuously administered intracavitally for 5 days starting from the next day.

For the experimental group, 6 mice were used for each dose level, and for the control group, 30 to 33 mice were used. The antitumor activity was determined by the survival days ratio (T/C) expressed by the following formula, and the results are shown in Table 1.

[Acute toxicity test]

LD measured by administering the compounds obtained in each example to mice. was as shown in Table 2.

Table 2 (Effects of the Invention) According to the present invention, it is possible to provide an anticancer agent that has a sufficient anticancer effect and is less toxic.

Therefore, it does not have any adverse effects on living organisms, and in the case of oral administration, there are no disadvantages such as placing a burden on the digestive organs. Furthermore, when producing this anticancer drug, a purer target product can be obtained compared to the conventional production method.

Procedural amendment document January 22, 1988 Commissioner of the Patent Office Black 1) Akio Yu 1, Indication of the case 1986 Patent Application No. 74297 3, Relationship with the person making the amendment Patent applicant Address: Osaka, Osaka Prefecture, 530 3-6-32 Nakanoshima, Ichikita-ku (2
07) Chisso Co., Ltd. Representative Sadao Nogi 4, Detailed explanation of the invention column in the agent's specification
N-(6-(3-(quinolin-3-yl)ureido]hexyl)-1(2H)-pyrimidinecarboxamide: 1.6-hexamethylene diisocyanate 3.87 g
(23.0 mmol) was taken in 60 ml of pyridine,
2.98 g of 5-fluorouracil (22,
9 mmol) was added little by little over 30 minutes, and then heated to 90°C.
The mixture was stirred and reacted for 1 hour.

After cooling, the residue obtained by concentrating under reduced pressure was dissolved in chloroform, insoluble matter was removed, and the filtrate was concentrated to 30+d.

3.32 g (23.0 mmol) of 3-aminoquinoline was added to the solution of the derivative having an isocyanato group thus obtained.
) was added, stirred for 30 minutes under reflux, and the precipitated crystals were collected by filtration, washed with hot acetonitrile, and dried in vacuo to give 5-fluoro-3,4-dihydro-2,4-dioxo-N-(
6-C3-(quinolin-3-yl)ureido]hexyl)-1(2dan)-pyrimidinecarboxamide at 6.20
g (I4.0 mmol) was obtained.

Yield 61χ Melting point 190-195°C fR,,, (KBr disk): 3400.33
30 (NH), 3040 (・C-H), 1740.
1705.1680(>=O), 1260(・C-F
) (cm-') Elemental analysis: Actual value C57,30, H5,52, N 1B
, 40 (χ) Calculated value (as Cz+HzJNbOa): C57,01°H5,24,N 18.99
(χ) Daishi Gojo 1 5-Fluoro-3,4-dihydro-2,4-dioxo-
N-(6-(3-(benzothiazol-2-yl)ureido]hexyl)-1(2H)-pyrimidinecarboxamide: 1.6-hexamethylene diisocyanate 3.76 g
(22.4 mmol) in 60 ml of pyridine,
2.89 g of 5-fluorouracil (22,3
mmol) was added little by little over 30 minutes, and the mixture was stirred and reacted at 90° C. for 1 hour.

After cooling, the residue obtained by concentrating under reduced pressure was dissolved in chloroform, insoluble matter was removed, and the filtrate was concentrated to 30 ml. 3.35 g of 2-aminobenzothiazole (22,
3 mmol) was added, stirred for 1 hour under reflux, and the precipitated crystals were washed with methanol and dried in vacuo to give 5-fluoro-
3,4-dihydro-2,4-dioxo-N-(6-(3
-(benzothiazol-2-yl)ureido]hexyl)-1(2H)-pyrimidinecarboxamide 4.04
g (9.02 mmol) obtained. Yield 40χ Melting point 256-262°C IR,,, (KBr disk): 33B0.32
75 (NH), 3180°3050 (-C-H),
1750. 1720. 1690 (>fable 0),
1260 (・C-F) (aa-') Elemental analysis: Actual value C50, 68, ■4.96. N 1
9.00 (χ) Calculated value (as CtJg+FNh04S): C50,89゜n 4.72.N 1B
, 74 (χ) 1 fan ± 5-fluoro-3,4-dihydro-2,4-dioxo-
N-pyridiniomethyl-1(2H)-pyrimidinecarboxamide chloride: chloromethyl isocyaner) 10.6 g (I165s
ol) and 5-fluorouracil 7.56 g (58,2
- mol) in pyridine 100n+1 and under reflux,
The reaction was stirred for 15 minutes. After cooling, the crystals were collected by filtration, washed with pyridine and toluene, and dried in vacuo to give 5-fluoro-3,4-dihydro-2,4-dioxo-N-pyridiniomethyl-1(2H)-pyrimidifcal. 17.0 g (56.5 mmol) of xamide chloride was obtained.

Yield 97χ Melting point 171-177℃ IR,,, (KBr disk): 3300 (NH
), 3100.3055'(-C-11), 176
5.1730.1685(>=O), 1255(=C
-F) (am -') Elemental analysis: Actual value C43,72, H3,62, N IB
, 90 (χ) Calculated value (c, mountain. As FCIN, 02): C43,94°H3,35,N 18.63
(χ) Procedural amendment May 28, 1988 Director-General of the Patent Office Black 1) Mr. Akihiro 1, Indication of case 1985 Patent Application No. 074297 2, Title of the invention 5 - Fluorouracil derivative and its manufacturing method 3, Relationship with the case of the person making the amendment Patent applicant 3-6-32 Nakanoshima, Kita-ku, Osaka-shi, Osaka 530 (2)
07) Chisso Corporation representative Sadao Nogi 4, agent 6, “5-Fluorouracil” on page 3, line 6 of the amended statement of contents was changed to “5-fluorouracil”.
-Corrected to ``Fluorouracil''.

"Isocyanate" on page 1I, line 12 of the specification is corrected to "isocyanato."

Page 11, lines 18-19 of the specification, "The compound of the present invention is produced by the method shown below." was corrected to "The compound of the present invention is produced, for example, by the five methods shown below." do.

"Isocyanate" on page 18, line 9 of the specification is corrected to "isocyanato."

Claims (1)

[Claims] (i) General formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R is an unsubstituted or substituted alkylene group having 0 to 10 carbon atoms, and A is -NH- and - Atomic group consisting of CO-, n is 0
or 1, and Y represents an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, a pyridinium ion or isocyanato group with a halogen as a counter ion). The 5-fluorouracil derivatives shown. (ii) General formula (I) is a 5-
Fluorouracil derivatives: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, R, A, and n represent the same groups as the general formula (I)) Claim i Derivatives described in Section. (iii) 5-fluorouracil derivatives of general formula (I) in which Y is a pyridinium ion having a halogen as a counterion and n=0: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula , R represents the same group as the group shown in general formula (I), and X represents a halogen such as Cl, Br or I) according to claim 1. iv) General formula (I), Y is an isocyanato group,
A 5-fluorolaucyl derivative in which n=0: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R represents the same group as represented by the general formula (I)) Patent claim represented by The derivative according to the range item i. v) General formula (I), A is -NHCO-, -NHCO
NH-, or -NHCONHNHCO-, and n=1
and Y is an unsubstituted or substituted alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted heteroaryl group: ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (V) (Formula The derivative according to claim i, wherein R represents the same group as represented by general formula (I). (vi) General formula: ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R is an unsubstituted or substituted alkylene group having 0 to 10 carbon atoms, and A is an atomic group consisting of -NH- and -CO-. , n is 0
or 1, and Y represents an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, a pyridinium ion or isocyanato group with a halogen as a counter ion). In producing the 5-fluorouracil derivative shown, 5-fluorouracil and the general formula: Y-(A)n-R-NCO(VI) (wherein R, A, n and Y are the same as in formula (I) A method for producing a 5-fluorouracil derivative, which comprises reacting a 5-fluorouracil derivative with an isocyanate represented by a group or a number. (vii) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is an unsubstituted or substituted alkylene group having 0 to 10 carbon atoms, and A is an atomic group consisting of -NH- and -CO-. , n is 0
or 1, and Y represents an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, a pyridinium ion or isocyanato group with a halogen as a counter ion)
In producing the 5-fluorouracil derivative represented by 5-fluorouracil and the general formula: Y-(A)_n-R-CON_3(VII) (wherein R, A, n and Y are as in formula (I) A method for producing a 5-fluorouracil derivative, which comprises reacting a 5-fluorouracil derivative with a carboxylic acid azide represented by the same group or number. viii) the isocyanate is a diisocyanate of the general formula: OCN-R-NCO(VIII), in which R represents the same group as in formula (I);
The method described in section. ix) The following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) 5-fluorouracil derivative represented by (R in the formula represents an unsubstituted or substituted alkylene group having 0 to 10 carbon atoms) and the general formula: H-Z-Y(IX) (Y in the formula is an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, a pyridinium ion with a halogen as a counter ion) or represents an isocyanato group, Z is -N
General formula (X) characterized by reacting with a compound represented by H- or -NHNH-CO- group) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(X) (wherein R is the formula The groups in (IV) and also Y and Z
represents the same group as in formula (IX))
- A method for producing a fluorouracil derivative. x) The following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(X I) (In the formula, R represents an unsubstituted or substituted alkylene group having 0 to 10 carbon atoms, and X represents a halogen such as Cl, Br or I) The following formula is characterized by reacting a 5-fluorouracil derivative represented by pyridine with A method for producing a 5-fluorouracil derivative represented by (representing the same group as the group). xi) 5-fluorouracil and the following formula: The following formula is characterized by reacting a halogenoisocyanate and pyridine: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R and X are the same groups as shown in formula (XII) A method for producing a 5-fluorouracil derivative represented by