JPS626714B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION Technical Field The present invention relates to 5-fluorouracil derivatives and methods for producing the same. The 5-fluorouracil derivative provided by the present invention is a new compound, has platelet aggregation inhibiting activity, and is useful as an agent for preventing cancer metastasis. It is also useful as an anticancer agent. Prior Art 5-fluorouracil is known to have excellent anticancer effects. On the other hand, 9,12,15-octadecatrienoic acid (α-linolenic acid) is abundantly contained in vegetable oils such as soybean oil, and is an essential fatty acid and an extremely important compound for humans. The present inventors synthesized various unsaturated higher fatty acid amides of 5-fluorouracil and studied their pharmacological activities, and as a result, they found that certain amides have excellent platelet aggregation inhibiting effects. OBJECTS OF THE INVENTION The object of the present invention is to provide novel 5-fluorouracil derivatives useful as platelet aggregation inhibitors. In recent years, it has been revealed that platelet aggregation is involved in cancer metastasis. Therefore, an object of the present invention is to provide 5-fluorouracil derivatives that are particularly useful as agents for preventing cancer metastasis. Also,
An object of the present invention is to provide 5-fluorouracil derivatives useful as anticancer agents. A further object of the present invention is to provide a method for producing a 5-fluorouracil derivative in which the acyl group of the triene higher fatty acid is substituted at the 1-position. DETAILED DESCRIPTION OF THE INVENTION The objects of the present invention are achieved by the configurations shown in the following sections. (1) General formula (In the formula, R represents an acyl group derived from a triene higher fatty acid.) A 5-fluorouracil derivative having the following formula. (2) A 5-fluorouracil derivative in which R in the above formula is an acyl group derived from a triene higher fatty acid having 14 to 24 carbon atoms. (3) A 5-fluorouracil derivative in which R in the above formula is an acyl group derived from 9,12,15-octadecatrienoic acid. (4) 5-fluorouracil and triene higher fatty acid are reacted in the presence of a condensing agent, or 5-fluorouracil and triene higher fatty acid are reacted in the presence of a condensing agent;
A method for producing a 5-fluorouracil derivative having the general formula [], which comprises reacting fluorouracil with a reactive derivative of a triene higher fatty acid. (5) The condensing agent is 2-chloro-1-methylpyridinium p-toluenesulfonate, 2-bromo-
The method according to item 4 above, which is 1-methylpyridinium iodide or N,N'-disuccinimidyl carbamate. (6) The method according to item 4 above, wherein the reactive derivative of triene higher fatty acid is a halide of triene higher fatty acid. (7) The method according to item 6 above, wherein the halide of the triene higher fatty acid is a chloride or bromide of the triene higher fatty acid. In the 5-fluorouracil derivative having the general formula [] provided by the present invention, R
The acyl group derived from a triene higher fatty acid as defined herein means a group obtained by removing the hydroxyl group from the carboxyl group of a higher fatty acid having three double bonds in its carbon chain. 14 to 24 as higher fatty acids
carbon atoms are preferred. The most preferred compound as a 5-fluorouracil derivative having the above formula [] is 1-(9,12,
15-octadecatrienoyl)-5-fluorouracil (1-α-linolenyl-5-fluorouracil) and 1-(8,11,14-eicosatrienoyl)-5-fluorouracil, but other examples include 1-( 11,14,17-eicosatrienoyl)-5-fluorouracil, 1-(6,9,12
-octadecatrienoyl)-5-fluorouracil, 1-(7,10,13-hexadecatrienoyl)-5-fluorouracil, and the like. The compound of the above formula [] of the present invention can be prepared by reacting a triene higher fatty acid with 5-fluorouracil in the presence of a condensing agent, or by reacting a reactive derivative of a triene higher fatty acid with 5-fluorouracil. can get. Examples of the condensing agent include 2-chloro-1-methylpyridinium p-toluenesulfonate, N,N'-disuccinimidyl carbamate, and the like. 2-chloro-1
-Methylpyridinium p-toluenesulfonate and 2-bromo-1-methylpyridinium iodide are usually used in the presence of a tertiary amine such as triethylamine or tributylamine. When using these condensing agents, aprotic solvents such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, and benzene are used. Reactive derivatives of triene higher fatty acids include acid halides, such as acid chlorides and acid bromides. When using the above-mentioned reactive derivatives, the solvent is not particularly limited, and organic solvents such as methylene chloride, chloroform, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, benzene, and toluene are widely used. The reaction is preferably carried out in an inert gun atmosphere such as nitrogen or argon. The reaction is usually carried out at -20°C to 120°C for about 0.5 to 10 hours. After the reaction is complete, the desired product is collected from the reaction mixture in a conventional manner. For example, the desired ester can be obtained as a pure product by filtering the reaction mixture, concentrating the liquid under reduced pressure, and subjecting the residue to column chromatography. The 5-fluorouracil derivative of the present invention is used as a platelet aggregation inhibitor, particularly as a cancer metastasis preventive agent or an anticancer agent, and the dosage is approximately 100 to 5000 mg per day for adults as the active ingredient, which may be administered in several doses if necessary. Oral administration is preferable, but intravenous injection is also possible. The compounds of the present invention can be mixed with pharmaceutical carriers or excipients in a conventional manner to form tablets, powders, capsules, etc.
Formulated into granules. Examples of carriers or excipients include calcium carbonate, calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate,
Examples include gum arabic. The tablets may be coated according to conventional methods. The compound of the present invention is
In addition to the solid formulations mentioned above, liquid formulations such as oily suspensions, syrups, and elixirs can also be used. Since the compound of the present invention has three double bonds in its molecule, α
-Tocopherol, 2,6-ditert-butyl-p-
Cresol (BHT) etc. can also be blended. Alternatively, the compound of the present invention can be stabilized by inclusion with cyclodextrin or the like. Next, the present invention will be explained in more detail with reference to Examples and Test Examples. Example 1 α-Linolenic acid (557 mg), 2-chloro-1-methylpyridinium p-toluenesulfonate (630 mg) and triethylamine (637
mg) and stir for 30 minutes. Add 5-
Add fluorouracil (260 mg), stir under ice cooling for 10 minutes, and react at room temperature for an additional 5 hours. The white precipitate formed is separated, the precipitate is washed with methylene chloride, and the liquid is concentrated under reduced pressure. The residue was washed with silica gel (25
g) subjected to column chromatography using
The solvent was distilled off from the methylene chloride-ethyl acetate (9:1) eluate to obtain oily 1-α-linolenyl-5-.
Fluorouracil (572 mg, yield 60%) was obtained.
The physicochemical data of this product are as follows. IR (CHCl ₃ ) ν _nax cm ^-1 : 1270, 1330, 1685,
1730 NMR ( _CDCl3 ) δ (ppm): 0.97 (3H, t, J=7.5Hz, _-CH2 - _CH3 ), 5.40
(6H, m, -CH=CH-), 8.33 (1H, d, J=
3.5Hz,

[Formula] Test Example Platelet Aggregation Inhibition Effect Collect 9 volumes of blood from the rabbit auricular vein using a syringe containing 3.8% sodium citrate solution (1 volume). The blood was centrifuged at 900 rpm for 10 minutes, and platelet-rich plasma (Platelet) was extracted from the supernatant.
Rich Plasma (hereinafter referred to as PRP) is obtained. Collect 3/4 of the supernatant and centrifuge at 3000 rpm for 15 minutes.
The supernatant contains platelet poor plasma (Platelet Poor).
Plasma (hereinafter referred to as PPP) is obtained. For the measurement of platelet aggregation ability, PRP was diluted with PPP and the platelet count was adjusted to approximately 500,000/μl. 250μ
1 of the adjusted PRP was placed in a cuvette and heated for 3 minutes in a 37°C constant temperature bath, followed by 25 μl of a solution of 1-α-linolenyl-5-fluorouracil (1.2×10 ^-2 M ethanol solution diluted with 0.05 M Tris buffer). Add 5
After incubation for a minute, 25 μl of a solution of arachidonic acid, an aggregation-inducing agent (3.2×10 ⁻¹ M ethanol solution diluted with Tris-buffered isotonic saline solution) was added, and the rate of inhibition of platelet aggregation was measured. The inhibition rate of 1-α-linolenyl-5-fluorouracil on platelet aggregation induced by arachidonic acid (3×10 ⁻⁴ M) was 23.1% at a dose of 8×10 ⁻⁵ M, 1×
It was 45.7% at the 10 ^-4 M dose. Effects of the Invention According to the present invention, a 5-fluorouracil derivative having a cancer metastasis preventive effect and an anticancer effect is provided. The above compounds of the present invention significantly suppress platelet aggregation induced by arachidonic acid. Since platelet aggregation is involved in cancer metastasis, the above compounds of the present invention can be used as agents for preventing cancer metastasis. Furthermore, since the compound of the present invention improves the bioability, particularly the absorption rate, of 5-fluorouracil, it is expected to be an excellent anticancer agent. Furthermore, according to the present invention, a method for producing the above-mentioned 5-fluorouracil derivative is provided.

Claims (1)

[Claims] 1. General formula (In the formula, R represents an acyl group derived from a triene higher fatty acid.) A 5-fluorouracil derivative having the following formula. 2. The 5-fluorouracil derivative according to claim 1, wherein R in the above formula is an acyl group derived from a triene higher fatty acid having 14 to 24 carbon atoms. 3. The 5-fluorouracil derivative according to claim 1, wherein R in the above formula is an acyl group derived from 9,12,15-octadecatrienoic acid. 4 General formula characterized by reacting 5-fluorouracil and triene higher fatty acid in the presence of a condensing agent, or reacting 5-fluorouracil and a reactive derivative of triene higher fatty acid (In the formula, R represents an acyl group derived from a triene higher fatty acid.) A method for producing a 5-fluorouracil derivative having the following. 5 The condensing agent is 2-chloro-1-methylpyridinium p-toluenesulfonate, 2-bromo-1-
Methylpyridinium iodide or N,
The method according to claim 4, which is N'-disuccinimidyl carbamate. 6. The method according to claim 4, wherein the reactive derivative of triene higher fatty acid is a halide of triene higher fatty acid. 7. The production method according to claim 6, wherein the halide of the triene higher fatty acid is a chloride or bromide of the triene higher fatty acid.