JPS60239472A - 5-fluorouracil derivative and medicinal pharmaceutical containing same as active constituent - Google Patents

Abstract

NEW MATERIAL:A 5-fluorouracil derivative of the formula (R is acyl derived from pentaenoic higher fatty acid or hexaenoic higher fatty acid). EXAMPLE:1-(5,8,11,14,17-Eicosapentaenoyloxymethyl)-5-fluorouracil. USE:Useful as a carcinostatic agent and inhibitor for blood platelet agglutination with antitumor action and low toxicity, and administered orally in the form of a capsule or tablet, etc. or parenterally in the form of a suppository, etc. PREPARATION:A pentaenoic higher fatty acid or hexaenoic higher fatty acid of the 1-hydroxymethyl derivative of 5-fluorouracil is reacted with ethyl chloroformate (ClCO2C2H5) in the presence of a base to give a solution of a mixed acid anhydride, which is then reacted with a reaction mixture obtained by reacting 5-fluorouracil with formalin in the presence of a base to afford the aimed compound of the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION 1. Background of the Invention Technical Field The present invention relates to a 5-fluorouracil derivative and a pharmaceutical preparation containing the same as an active ingredient.

1. The 5-fluorouracil derivative provided by the present invention is a new compound and has a strong anticancer effect.

Furthermore, the 5-fluorouracil derivative of the present invention has a strong ability to inhibit platelet aggregation. It also has an effect.

Prior art 5.8,11.14.17-eicosapentaenoic acid or 4,7.1 (1,13,16,19-docosahexaenoic acid) is known to be an essential fatty acid contained in fish oil.

5-Fluorouracil is used clinically as an anticancer drug, but it has the problems of high toxicity and a narrow effective blood concentration range. As a result of synthesizing esters of fatty acids or hexaene higher fatty acids and conducting intensive research on their pharmacological activities, the present inventors discovered that they have excellent anticancer and platelet aggregation inhibitory effects, leading to the completion of the present invention. Ta.

(1)Object of the Invention The object of the present invention is to provide a novel 5-fluorouracil derivative. Furthermore, it is an object of the present invention to provide an anticancer agent and a platelet aggregation inhibitor containing the derivative as an active ingredient.

Detailed description of the m1 invention The object of the present invention is achieved by the configuration shown below.

That is, the present invention provides 5-
It is a fluorouracil derivative.

Further, the present invention provides a method of formula 5 represented by the general formula (wherein R is an acyl group derived from pentaene higher fatty acid or hexaene higher fatty acid).
-An anticancer agent containing a fluorouracil derivative as an active ingredient.

Furthermore, the present invention provides a 5-
An containing fluorouracil derivative as an active ingredient
It is a platelet aggregation inhibitor.

In the above general formula, R is 5.8,11.14.17-eicosapentaenoic acid or 4,7,1+1,13
, 16.

Preferably, it is an acyl group derived from 19-docosahexaenoic acid.

The 5-fluorouracil derivative represented by the above formula of the present invention combines the above higher fatty acid and ethyl chloroformate (C6CO2C
2H5) in the presence of a base, and a solution of the mixed acid anhydride obtained by reacting 5-fluorouracil<5-FU)2 with formalin in the presence of a base. .

As a base, triethylamine, tributylamine,
Tertiary amines such as dimethylaminopyridine are preferably used.

The 5-fluorouracil derivative of the present invention exhibits antitumor effects equivalent to or better than 5-fluorouracil used clinically in animal tests, and has lower toxicity than 5-fluorouracil. Furthermore, the 5-fluorouracil derivative of the present invention is also characterized in that it has a strong platelet aggregation inhibitory effect that is not found in 5-FU.

The 5-fluorouracil derivative of the present invention can be used as an anticancer agent.
It is also usefully used as a platelet aggregation inhibitor. The dosage is preferably about 0.1 to 3 f per day for adults.

The 5-fluorouracil derivative of the present invention can be administered orally in the form of capsules, tablets, granules, syrups, etc., or parenterally in the form of injections, suppositories, etc., in a conventional manner.

Next, the present invention will be explained in more detail with reference to Production Examples and Test Examples, but the present invention is not limited thereto.

Example-1 5,8.11.14.17-eicosapentaene ill in argon stream 3. (124r was dissolved in 200Tnt of anhydrous tetrahydrofuran, ethyl chloroformate 1 and ossr were added under water cooling, and after 15 minutes, triethylamine 1.
112ff:m down. Stir for an additional hour to prepare a mixed acid anhydride solution. Into the solution of the mixed acid anhydride, 1.31 dt of 5-fluorouracil and 1.3 dt of 37-thiformin were added.
After heating at -50 DEG C. for 5 hours, a solution of the residue obtained by azeotropically distilling water with benzene in 20 d of condensed dimethylformamide was added under water cooling, and then 2.024 t'ft of triethylamine was added thereto.

The mixture was stirred at room temperature for 24 hours. The resulting precipitate was filtered off and the resulting filtrate was concentrated. The residue was dissolved in 50° of water and IN-
After adjusting the pH to 4 with oxalic acid, the mixture was extracted with ether, washed with water, dried with sodium sulfate, and concentrated under reduced pressure to obtain a residue of 3.885'. This was subjected to silica gel chromatography and methylene chloride-ethyl acetate (
4:1) i@ output part was further subjected to gel chromatography, and the target 1-(5,8,11,14,17
-nicosapentaenoyloxymethyl) -5-,;
y fluorouracil 1.72f was obtained. The physicochemical data of this product are as follows.

IR(CDCL,)shi:&x: 1715,1675
．． 1260,112ONMR(CDCL,') δ(p
pm) 20, 97 (3H, t, J=7.5Hz
), 2.40 (2H, t, J=7.6Hz), 5.
64 (2H, s), 7.62 (I H, d, J=
5.4Hz)1i1ASS(m/z): 444
(Molecular ion beak) Example 2 In an argon stream, dissolve 4.7.10,13,16.19-docosahexaenoic acid 1.9711' in 100 ml of anhydrous tetrahydrofuric acid, and add ethyl chloroformate under water cooling. 651 IQ was added, and after 15 minutes, triethylamine 607 ■ was added dropwise. Stir for an additional hour to prepare m* of mixed acid anhydride. 5-fluorouracil 780yQ and 37% forbulin 1.11n were added to the mixed acid anhydride solution.
After heating t at 50°C for 5 hours, the residue obtained by azeotropically distilling water with benzene was mixed with anhydrous dimethylformamide 15*4
Add molten tL dissolved in water while cooling with water, and then add 1.214f of triethylamine. The mixture was stirred at room temperature for 24 hours. The resulting white precipitate was filtered off, the precipitate was washed with tetrahydrofuran, and the resulting filtrate was concentrated under reduced pressure. Residue whole water 5
After adjusting the pH to 4 with IN-1z acid, extraction with ether, washing with water, drying with Glauber's salt, and condensation under reduced pressure left a residue 2.
84t was obtained. This was subjected to silica gel chromatography, and the methylene chloride-ethyl acetate (4:1) eluate was further subjected to gel chromatography.
,7,10,13,16,19-docosahexenoyloxymethyl)-5-fluorouracil 1.215ft-
Obtained. The physicochemical data of this product are as follows.

IR (CDCL,) ShuX: 1715, 1670.1
265,1125NMR (CDCL3) δ (ppm)
: 0.97 (3H, t, J = 7.6Hz),
2.07 (2H, m), 5.65 (2H, s), 7.6
1 (IH.

d, J=5.4Hz) MASS (m/z): 470 (molecular ion beak) [Test example] 1. Antitumor effect CDF, P388 cells 1 x 1 in mice (male, 5 weeks old)
0 cells/mouse are implanted intraperitoneally. 1-(5,8,11,14,17-nicosaintaenoyloxymethyl)-5-fluorouracil obtained in Example 1, or 1-(4,7°10.13 obtained in Example 2) ,1
6. A suspension of 19-docosahexenoyloxymethyl)-5-fluorouracil in 0,5 ticaldexymethylcellulose the next day! 1 l is administered intraperitoneally once a day for 5 consecutive days to measure survival rate. Life extension rate (ILS%)
The results of the comparison with 5-fluorouracil (5-FU) are shown in the table, where the median survival time of the control group is -100.

(Itako Ii, h) It is clear from Table A, 1-(5゜8.11) according to the present invention.
．． 14.17-nicosapentaenoyloxymethyl)
-5-fluorouracil and 1-(4°7.10,1
3,16.19-docosahexenoyloxymethyl)-
5-Fluorouracil has shown antitumor activity equal to or higher than that of 5-FH. Ma7'C15-FU is 30'
At lf/kg/day, the number of survival days of mice is shorter than that of controls in which the above anticancer drug is not administered due to the 1g effect;
,17-nicosapentaenoyloxymethyl)-5-
Fluorouracil and 1-(4,7,10,13,
16,19-docosahexenoyloxymethyl)-5-
Fluorouracil is ILS (I) even at 7 oz/day to 9/day
were 36°30, respectively, and it became clear that the toxicity was lower than that of 5-FU.

2. Platelet aggregation 1+11 action 3.8 Collect 9 volumes of blood from the rabbit carotid artery using a syringe containing sodium citrate (1 volume). The blood is centrifuged to obtain platelet-rich plasma (PRP: 400,000 cells/μt). Using the PRP, the platelet aggregation inhibitory effect of the compound of the present invention was measured using arachidonic acid or collagen as an aggregation-inducing agent. Arachidonic acid (80
1 −(μm)-induced platelet aggregation
The 50% inhibitory concentration (IC5,) of 5,8,11,14゜17-nicosapentaenoylodimethyl)-5-fluorouracil is 1.2X10-4M, 1-(4
,7,10,13゜16.19-docosahexenoyloxymethyl)-5 5-fluorouracil IC5oIt'J, 5.4x
lOM whereas 5-FUtj:1xlo-'M
Even if more than 50 doses were administered, it could not be suppressed by 50%.

The IC5o of 1-(5,8,11,14,17-nicosapentaenoyloxymethyl)-5-fluorouracil against platelet aggregation induced by collagen (25μf/1nl) was 7.1 x 10-'M. , 1-
(4,7°10,], 3.16.19-docosahexenoyloxymethyl)-5-fluorouracil IC5o
is 9. OX was 10-5M, whereas 5-FU's concentration of C58 was 1X10M or more, demonstrating that the compound of the present invention has a strong platelet aggregation inhibiting effect.

3. Acute toxicity 1-(5,8,11,14,17-nicosapentaenoyloxymethyl)-5-fluorouracil and 1-(4,7,10,13,16,19-docosahe) As a result of investigating the acute toxicity of intraperitoneal administration of 5-fluorouracil (xenoyloxymethyl)-5-fluorouracil using ICR mice (male, 7 weeks old), the LD of 5-fluorouracil was investigated.
5° value is 235 tIg/Ig, whereas the T)5o value of the compound according to the present invention is as much as 500 tIg/Ig/9, which confirms the high safety of the compound according to the present invention. Ta.

■0 Effect of the invention According to the invention, 5, represented by the general formula % (wherein R is an acyl group derived from a pentaene fatty acid or a hexaene higher fatty acid),
- Fluorouracil derivatives are provided.

The derivative according to the present invention has a strong anticancer effect and an inhibitory effect on platelet aggregation.

Furthermore, in recent years, results have been obtained suggesting that platelet aggregation is involved in cancer metastasis. Therefore, the platelet aggregation inhibitor using the 5-fluorouracil derivative of the present invention can also be used as a cancer metastasis preventive agent. Therefore, the 5-fluorouracil derivative of the present invention has both anticancer action and cancer metastasis preventive action, and has low toxicity, so it can be effectively used for cancer treatment.

Furthermore, the platelet aggregation inhibitor using the 5-fluorouracil derivative of the present invention can also be effectively used for preventing coagulation of collected blood.

Patent applicant: Chill Seven Co., Ltd.

Claims (1)

[Scope of Claims] (1) 5- represented by the general formula (wherein R is an acyl group derived from a pentaene higher fatty acid or a hexaene higher fatty acid)
The 5-fluorouracil derivative according to claim 1, which is an acyl group derived from a fluorouracil-derived acid. (3) The 5-fluorouracil derivative according to claim 1, wherein R is an acyl group derived from 4,7,10,13,16.19-docosahexaenoic acid. (4) 5- represented by the general formula (wherein R is an acyl group derived from a pentaene higher fatty acid or a hexaene higher fatty acid)
Formula W containing a fluorouracil derivative as an active ingredient
J agent. (5) The anticancer agent according to claim 4, wherein R is an acyl group derived from 5.8.11.14.17-eicosapentaenoic acid. (6) The anticancer agent according to claim 4, wherein R is an acyl group derived from 4,7,10.13,16.19-docosahexaenoic acid. (wherein R is an acyl group derived from pentaene higher fatty acid or hexaene lower fatty acid)
A platelet aggregation inhibitor containing a fluorouracil derivative as an active ingredient. (8) The platelet aggregation inhibitor according to claim 7, wherein R is an acyl group derived from 5,8,11,14.17-dicosa (ntanoic acid). (9) R is 4,7 , 10, 13, 16. The platelet aggregation inhibitor according to claim 7-4, which is an acyl group derived from 19-docosahexaenoic acid.