JPS5843960A - 5-fluorouracil derivative, its preparation and carcinostatic agent - Google Patents

Abstract

NEW MATERIAL:The 5-fluorouracil derivative of formulaI(R1 and R2 are CH3 or C2H5; m is 1 or 2). EXAMPLE:1-(3,4-Dimethoxybenzylcarbamoyl)-5-fluorouracil. USE:Carcinostatic agent exhibiting higher carcinostatic activity than known 1-(4- methoxybenzylcarbamoyl)-5-fluorouracil, etc. PROCESS:The compound of formulaIis prepared, e.g. by reacting 5-fluorouracil with the isocyanate of formula II or by reacting an 5-fluorouracil with an isocyanate synthesized from a carboxylic acid and a diphenylphosphoric acid azide without isolating the isocyanate, in a solvent at room temperature -110 deg.C for 1-10hr.

Description

Detailed Description of the Invention The present invention provides 5-fluorouracil derivatives having excellent anticancer activity, more specifically, 5-fluorouracil derivatives having the general formula (wherein R+, Rg is methyl or ethyl group 1m is 1 or 2). The present invention relates to a 5-fluorouracil derivative, a method for producing the same, and an anticancer agent.

The present inventor first synthesized 1-alkylcarbamoyl-5-fluorouracil, and then synthesized 1-arafurekylcarbamoyl-5-fluorouracil by variously changing the carbamoyl group. (Unexamined Japanese Patent Publication No. 53-59680>,
at that time.

Substitutions on the aromatic ring were either unsubstituted or 1-substituted except for 2,5-dimethyl, and none showed excellent anticancer activity.

The present inventor further examined in detail the type, number, and position of substituents, and as a result, the present invention was determined to be two. The compound has been reached.

That is, it has been found that methyl, ethyl, propyl, ethoxy caponyl, etc. as a substituent do not improve the anticancer activity, but a methoxy group is good, and two methoxy groups are particularly useful for improving the anticancer activity.

The compound of the present invention can be obtained by reacting 5-fluorouracil with an isocyanate represented by the general formula (wherein R1, R2, m are expressed in general formula (1)) or corresponding to 1-chlorocarbonyl-5-fluorouracil. It can be synthesized by reacting amines.

The reaction between 5-fluorouracil and isocyanate can be carried out by dissolving or suspending 5-fluorouracil in an ordinary organic solvent and adding isocyanate thereto. Or.

The isocyanate synthesized from carboxylic acid and diphenylphosphoric azide may be reacted with 5-fluorouracil without isolation. The isocyanates used in this reaction include 3.4-dimethoxybenzyl isocyanate, 3.4-dimethoxybenzyl isocyanate, and 2.4-dimethoxybenzyl isocyanate.
-dimethoxybenzyl isocyanate, 3,4-dimethoxyphenethylisocyanate, 3-ethoxy-4-methoxybenzi(rei, chlorine anate, etc.) The solvent used in this reaction is pyridine.

Dimethylacetamide and the like are suitable. The temperature range is room temperature to 110°C, and the reaction time is 1 to 10 hours.

In the reaction between 1-chlorocarbonyl-5-fluorouracil and an amine, first, 5-fluorouracil is dissolved in a solvent, phosgene is applied to the mixture at a low temperature to synthesize 1-chlorocarbonyl-5-fluorouracil, and then the amine is added to the 1-chlorocarbonyl-5-fluorouracil. Add.

The reaction proceeds in 1-3 hours. At this time, it is desirable to add a dehydrochlorination agent such as triethylamine. If triethylamine hydrochloride is precipitated after the reaction, remove it by filtration. Which leakage or.

The above reaction solution of 5-fluorouracil and isocyanate is
The solvent is removed under reduced pressure, and when the residue is mixed with hydrochloric acid water and dichloromethane and stirred, the desired product precipitates as insoluble crystals, which can be obtained by filtration. It is also partially or completely dissolved in dichloromethane, so it must be dried.

The desired product can be obtained by concentration to dryness. If necessary, recrystallize with alcohol.

The compound obtained in this way has 2.3 at the 1st position.
-dimethoxybenzylcarbamoyl.

2.4-dimethoxybenzylcarbamoyl, 2゜5-dimethoxybenzylcarbamoyl, 2,6-dimethoxybenzylcarbamoyl, 3.4-dimethoxybenzylcarbamoyl, 3,5-dimethoxybenzylcarbamoyl,
2-Ethoxy-3-methoxy-benzylcarbamoyl'
, 3-ethoxy-2-methoxybenzylcarbamoyl.

2.3-jethoxybenzylcarbamoyl, 2-ethoxy-4-methoxybenzylcarbamoyl, 2-methoxy-4-ethoxybenzylcarbamoyl, 2,4-jethoxybenzylcarbamoyl, 2-ethoxy-5-methoxybenzylcarbamoyl, 2- Methoxy-5-ethoxybenzylcarbamoyl, 2,5-jethoxybenzylcarbamoyl, 2-ethoxy-6-methoxybenzylcarbamoyl, 2-methoxy-6-ethoxybenzylcarbamoyl, 2,6-jethoxybenzylcarbamoyl, 3
-ethoxy-4-methoxybenzylcarbamoyl, 3-
Methoxy-4-ethoxybenzylcarbamoyl, 3゜4
-Jethoxybenzylcarbamoyl, 3-ethoxy-5
-Methoxybenzylcarbamoyl.

3-Methoxy-5-ethoxybenzylcarbamo 471/
, 3,5-jethoxybenzylcarbamoyl, 2,3-
Dimethoxyphenethylcarbamoyl, 2,4-dimethoxyphenethylcarbamoyl, 2.5-dimethoxyphenethylcarbamoyl, 2,6-dimethoxyphenethylcarbamoyl, 3.4-dimethoxyphenethylcarbamoyl, 3.5-dimethoxyphenethylcarbamoyl, 3-ethoxy-4- Methoxyphenethylcarbamoyl, 3-methoxy-4-ethoxyphenethylcarbamoyl, 3,4
There are 5-fluorouracils having benzylcarbamoyl or phenethylcarbamoyl groups having two same or different alkoxy groups, such as -jethoxyphenethylcarbamoyl.

The compound thus obtained is 1 of the known comparative example 1.
-(4-Methoxybenzylcarbamoyl)-5-fluorouracil and 1-(4-ethoxycarbonyl-benzylcarbamoyl)-5-fluorouracil of Comparative Example 2 were compared for their anticancer activity.

10' Lewis Lang calsituma cells were intraperitoneally transplanted into 6 BDF mice per group, and 24 hours later, a predetermined amount of a 0.5% CMC suspension was orally administered three times every week. Seo calculated the life extension rate from the survival days using the following formula.

T: Days leading to death in treatment group C: Days leading to death in control group Table 1 Survival days extension rate (form) Example 1 14 62 1052 38
71 81 3 16 40 80 4 15 38 62 5 12 50 85 Comparative example 1 10 28 242 9
12-4 The results show that the compounds of Examples have much better anticancer activity than the compounds of Comparative Examples, especially Example 1 (7).
), 1-(3,4-dimethoxybenzylcarbamoyl)
-5-fluorouracil and then 1-(2,5
-dimethoxybenzylcarbamoyl)-5~fluorouracil was found to be excellent.

The anticancer agent of the present invention is available in capsules, 9 tablets, and fine granules.

Orally administered drugs such as syrups, injections, and suppositories.

It can be used as a parenteral agent such as a laxative.

These can be prepared using generally known methods and excipients. The daily dosage for adults is 100-70
0 cape, preferably 300 to 500 cape.

Example 1 40 ml of benzene, homoveratoric acid (3,4--,
'Methoxyphenylacetic acid) 3.9.2 f 10.0
2 mol) diphenyl phosphoric azide 5.69 (0,020
4, mol) triethylamine (2.021 F (0.02 mol)) was added one after another, and the temperature was gradually raised. Foaming was noticeable at 40°C, but the temperature was raised to 800°C over 1.5 hours. After cooling, benzene was distilled off under reduced pressure, 5-fluorouracil 2,6 f (0.02 mol) was added to the residual liquid, and the mixture was heated at 90°C.
Heat for 2 hours. Hydrochloric acid water 30s/and dichloromethane 3
The insoluble 5-70 lourasil was leaked out by applying 0 m of force, the dichloromethane layer was separated, and the dichloromethane layer was added with 20 m of hydrochloric acid.
When the mixture is added and stirred, white turbidity occurs, so this is leaked to obtain white crystals of 1-(3,4-dimethoxybenzylcarbamoyl)-5-fluorouracil, 2.92 f, melting point 1.
72°C was obtained. The dichloromethane layer was dried with sodium sulfate, then dried and recrystallized from methanol to obtain additional target compound 1.
．． 261F was obtained.

Example 2 2.5-dimethoxyphenylacetic acid 4.99 (0,02
5 mol), benzene 50 ml, diphenylphosphoric azide 7.02f (0,0255 mol), triethylamine 2.531! 1 (0,025 mol) were added one after another, the temperature was raised to 80°C over 2 hours, and the mixture was concentrated under reduced pressure. 3.25 g (0,025 mol) of 5-fluorouracil was added to the concentrate without isolating the produced irisyanate.
The whole solidifies when heated to 0°C for 1 hour. After cooling, 300 ml of dichloromethane and 100 g of hydrochloric acid were added to stir the whole mixture to obtain an insoluble material. This insoluble material was further washed with acid and recrystallized from methanol to obtain 1-"(2,5-dimethoxybenzylcarbamoyl)-5-fluorouracil 2.
．． 59. A melting point of 185°C was obtained. 1.2 g of the target product was also obtained from the dichloromethane layer.
NMR (CDCLs) 3.8 (3H,S,
0CHs), 3.87(3H,S,0CR1)4
．． 22 (2H, d, CH2) 6.8 (2H, s,
CgH2), 7.36 (IH,S.

CgH), 8.25 (IH, d, 5th position) (), 9.
5 (IH, s, NH), 11.8 (IH, s, 3rd position N
H) Example 3 3.44 s of 3.4-dimethoxyphenylpropionic acid,
Diphenyl phosphate azide 5g, triethylamine 2.1
g was reacted in benzene 40d in the same manner as in Example 1.

1.9 g of 1-(3,4-dimethoxyphenethylcarbamoyl)-5-fluorouracil having a melting point of 151°C was obtained.

Example 4 2.4-dimethoxyphenylacetic acid 3.929. 5.5 g of diphenylphosphoric acid azide and 2 g of triethylamine were reacted in 40 ml of benzene in the same manner as in Example 1, and the melting point was 1.
3.7 g of 1-(2,4-dimethoxybenzylcarbamoyl)-5-fluorouracil at 54°C was obtained.

Example 5 1.14 g of 5-fluorouracil was dissolved in 30 d of pyridine, 2.469 g of phosgene was blown into the solution at 5°C, and the mixture was left at room temperature for 1 hour. After adding 3.2 ml of triethylamine and stirring at room temperature for 1 hour, triethylamine hydrochloride leaked out, the leaked liquid was concentrated to dryness, and dichloromethane 100 ml was added.
-me, washed with hydrochloric acid water, dried, and concentrated to dryness.

Recrystallization from ethanol gave 2.3 g of 1-(4-ethoxy-3-methoxybenzylcarbamoyl)-5-fluorouracil with a melting point of 153°C. N M R (D M
S Ods ) 1.4-1.5 (3H, Ml, CH
s), 3.85 (3H, s.

0CHs), 4.04 (2H, q, 0CH2), 4.
44 (2H, d, CH2), 6.8 (2H, s, C6
H2).

7.2 (IH, s, C6H), 8.42 (IH, d, 6
position H), 9.2 (IH, m, NH) Example 6 l-(3,4-dimethoxybenzylcarbamoyl)-5
-Fluorouracil 10011F, Lactose 50 #.

A mixture of 50 drops of potato starch and 10 η of crystalline cellulose was packed into gelatin capsules to form 1-capsule.

Administer 3 capsules per day in divided doses after each meal.

Example 7 After heating Lytep Sol w35,5oo9 to 60°C, 100 g of 1-(2,5-dimethoxybenzylcarbamoyl)-5-fluorouracil was added little by little to make it uniform, then cooled to 40°C and filled into suppositories. Pour into a plastic container using a machine.

Cool to 15°C and make suppositories. Daily dosage/dose is 300
It is about ~500q.

Claims (1)

[Scope of Claims] A 5-fluorouracil derivative ((3) 1-(3,4-dimethoxybenzylcarbamoyl)) represented by the formula (wherein R,,R, is a methyl or ethyl group 1m is 1 or 2) 5-fluorouracil derivative (3) according to claim 1 which is -5-fluorouracil 5-fluorouracil derivative (3) according to claim 1 which is 1-(2,5-dimethoxybenzylcarbamoyl)-5-fluorouracil Fluorouracil derivative (4) Claim 1 which is 1-(3,4-dimethoxyphenethylcarbamoyl)-5-fluorouracil
5-fluorouracil derivative (5) as described in Claim 1, which is 1-(3-methoxy-4-ethoxybenzylcarbamoyl)-5-fluorouracil (6) 1-(2,4 5-fluorouracil derivative (7) according to claim 1, which is 5-fluorouracil (dimethoxybenzylcarbamoyl)-5-fluorouracil and the general formula 2) A patent for producing a 5-fluorouracil derivative (8) characterized by reacting an isocyanate prepared by 1-Chlorocarbonyl-5-fluorouracil and an amine of the general formula m is 1 or 2) (wherein R+, Rt, m
is as defined in the previous formula) (9) Method for producing a 5-fluorouracil derivative represented by the general formula (wherein R1, R2 are methyl or ethyl groups 2m is 1 or 2) -Anticancer agent containing fluorouracil derivative as active ingredient