JPS6030318B2 - Tetrahydrofurfuryl-5-halogenouracil derivative, its production method and antitumor agent containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel tetrahydrofurfuryl-5-halogenouracil derivative, a method for producing the same, and an antitumor agent containing the same.

The tetrahydrofurfuryl-5-halogenouracil derivative of the present invention is represented by the formula (wherein x represents a halogen atom and Y represents a hydrogen atom or a tetrahydrofurfuryl group).

The above compound of the present invention is a white crystal, and methanol,
It is soluble in chloroform, glacial acetic acid, pyridine, dimethyl sulfoxide, aqueous caustic soda, etc., but sparingly soluble in water, ethanol, acetone, ethyl acetate, aqueous hydrochloric acid, etc. The compounds of the present invention are derivatives of uracil and are useful as pharmaceuticals, particularly as antiviral and antitumor agents.

The biological activity of the compounds of the present invention is far superior to that of 5-halogenouracil and N,1-tetrahydrofurfuryluracil. For example, the compounds of the present invention are about 2 to 4 times superior to 5-fluorouracil and N,-tetrahydrofurfuryluracil in their cell proliferation inhibitory effects.
Furthermore, the compound of the present invention is superior to 5-fluorouracil and N,-tetrahydrofurfuryluracil in a survival test on gun-bearing rats. In addition, the compound of the present invention exhibited approximately 1/10 of the above-mentioned comparative compound in acute toxicity tests.
Shows low toxicity. The following tests were conducted to clarify the biological activity of the compounds of the present invention.

The rats used in the test were of the Donryu strain and weighed 100-1.
It is from the 50th evening. [1] Growth inhibition test for Yoshida sarcoma (solid) The tumor cells described above were transplanted subcutaneously into the left sore of rats, and after 2 days, they were injected with N. - Tetrahydrofurfuryl-5-fluorouracil was administered intraperitoneally at a dose of 30 9/k9.

On the 13th day, all the rats were killed with ants, the solid Hitomito was removed, and the average weight of the boil was measured.

For comparison, the average water weight of rats was measured using the same machine as above except that 5-fluorouracil and N,1-tetrahydrofurfuryluracil were used. For the control group, the average tumor weight of the rats was measured in the same manner except that physiological saline was administered instead of the drug. The results are shown in Table 1 as the ratio of the average weight of the drug administered group to the average weight of the weight of the control group. Table 1 From Table 1, N,1-tetrahydrofurfuryl of the present invention
It can be seen that 5-fluorouracil has an inhibitory effect on tumor cells about twice as much as 5-fluorouracil and about four times as much as N,-tetrahydrofurfuryluracil.

[2] Survival extension test for Nakki Yoshida (ascites type) cancer-bearing rats The tumor cells were transplanted intraperitoneally into the rats, and 24 hours later, N,1-tetrahydrofurfuryl was administered once a day for 7 consecutive days. 5-fluorouracil was administered intraperitoneally at a dose of 30 9/k9.

After completion of administration, observe the rats until they die, and record the average number of days they survive. The average survival days of rats were determined in the same manner as above except that 5-fluorouracil and N,-tetrahydrofurfuryluracil were used for comparison.
The mean survival days of the rats were examined in the same manner except that physiological saline was administered instead of the drug to the control group. The results are shown in Table 2. Table 2: Acute toxicity test N,-tetrahydrofurfuryl-5-fluorouracil and 5-fluorouracil were administered intraperitoneally to rats, and the LD rule was examined one week later.

The results are shown in Table 3. From Table 3, it can be seen that N,1-tetrahydrofurfuryl-5-fluorouracil has much lower toxicity than 5-fluorouracil.

The compounds of the present invention can be produced by various methods.

For example, it is produced by reacting 5-halogenouracil (D) with tetrahydrofurfuryl halide (dish). The reaction in this method is shown by the following reaction formula. (In the formula, X represents a halogen atom, Y represents a hydrogen atom or a tetrahydrofurfuryl group) 5-halogenouracil (b) used as a starting material in the above method is a known compound, specifically 5-fluorouracil , 5-chlorouracil, 5-bromouracil and 5-ioduracil.

Such 5-halogenouracil can be easily obtained, for example, by reaction of uracil with halogen gas, reaction of uracil with N-halogenosuccinimide, etc. Tetrahydrofurfuryl halide (m) used as the other starting material in this reaction is also a known compound, specifically tetrahydrofurfuryl fluoride, tetrahydrofurfuryl chloride, tetrahydrofurfuryl furomide, and Mention may be made of tetrahydrofurfuryl iodide.

Among these tetrahydrofurfuryl halides, tetrahydrofurfuryl furomide and tetrahydrofurfuryl iodide are preferred from the viewpoint of reactivity. In this reaction, the ratio of 5-halogenouracil and tetrahydrofurfuryl halide to be used may be determined as appropriate;
Since -halogenouracil is expensive, it is usually desirable to use about 1.1 to 1" molar amount of tetrahydrofurfurylide, preferably about 1.5 to 3 times the molar amount, relative to 5-halogenouracil. This reaction For example, it is preferable to use hydroxides or carbonates of alkali metals such as lithium, sodium, potassium, etc. as catalysts.Among them, carbonates of alkali metals, especially carbonates of alkali metals, are preferred from the viewpoint of ease of use and reaction yield. Sodium carbonate and potassium carbonate are preferred.The amount of the alkali metal hydroxide or carbonate used is 5
-Usually about 1 to 1 mol, preferably about 2 to 3 times the mol, relative to the halogenouracil.The reaction temperature and reaction time of this reaction are not particularly limited, but if the reaction temperature is too high, the reaction product may Because it may decompose and reduce the yield,
It is usually advantageous to operate at 50 to 200 oo. This reaction can be carried out in the presence of a solvent or without a solvent, but the use of a solvent is generally preferred since it can increase the reaction yield. Although various solvents can be used, polar solvents such as dimethylformamide and dimethyl sulfoxide are particularly preferred. In this reaction, together with the alkali metal hydroxide or carbonate, an alkali iodide,
In particular, the combined use of sodium iodide or potassium iodide is very advantageous because it can lower the reaction temperature, shorten the reaction time, and increase the reaction yield.

The amount of alkali iodide used can vary over a wide range, but since using a large amount will complicate the reaction process, it is usually preferable to use about 0.1 to equimolar amount to 5-halogenouracil. By the above reaction of the present invention, N,1-tetrahydrofurfuryl-5-halogenouracil (11a)
and N.・N3-bis(tetrahydrofurfuryl)-5
- A mixture of halogenouracil (11b) is obtained.

The formula for this reaction is as follows. (In the formula, X represents a halogen atom) Both compounds represented by (1-a) and (11b) are target compounds of the present invention.

Our research has revealed that compound (11b) is selectively converted to compound (1-a) by hydrolysis. Therefore, to obtain compound (1-a) in high yield,
After the reaction of compounds (0) and (m), it is preferable to hydrolyze them. Of course, compound (1-b) may be isolated from the reaction mixture of compounds (0) and (m) and then hydrolyzed, but in order to simplify the reaction process, it is preferable to directly hydrolyze the reaction mixture. It's advantageous. The hydrolysis reaction is expressed as follows.

The above hydrolysis of compound (11b) is usually carried out by a known method.

When a solvent is used in the reaction of compounds (0) and (m), it is preferable to hydrolyze the residue after distilling off the solvent. The hydrolysis reaction is carried out in a hydration solvent such as alcohol-water or acetone-water in the presence of an alkali metal, an alkali ± cervical metal hydroxide or carbonate, alkaline, preferably at pH 9 to 12, from room temperature to 100 qo. This can be easily carried out by reacting at a temperature for usually 0.5 to 2 hours.
The progress of the hydrolysis reaction can be easily determined by thin layer chromatography. The compound of the present invention can be easily purified by commonly known methods, such as extraction, concentration, recrystallization, column chromatography, and the like.

For example, compounds (11a) and (1-b) of the present invention are separated from a reaction mixture of compounds (0) and (m) in the following manner.

That is, after the completion of the reaction, insoluble matter is removed in an oven, and if a solvent is present, it is removed in an oven. The resulting concentrate is then subjected to column chromatography to obtain compounds (11a) and (1-b) separately in pure form. Compound (1-a
) can be separated more preferably by reacting compounds (0) and (m) and then hydrolyzing them.

That is, after the completion of hydrolysis, if there is a solvent, it is distilled off, the residue is dissolved in a small amount of water, and then n-hexane is added thereto,
The n-hexane soluble material is extracted and removed. A mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid is added to the extraction residue to adjust the pH to 3 to 7, preferably 6 to 6.5. Next, extract with an organic solvent such as chloroform or methylene chloride by a conventional method,
The obtained organic solvent layer is concentrated, and then the concentrate is recrystallized from alcohol such as ethanol. By the above method, pure compound (1-a) can be obtained in good yield.
The compounds of the invention can be mixed, for example, with suitable excipients to form anti-dead weight agents.

That is, the anti-dead weight agent of the present invention contains a pharmacologically effective amount of the tetrahydrofurfuryl-5-halogenouracil derivative of the present invention (1
) and excipients. The anti-tumor agent of the present invention can be formulated into various formulations depending on its administration route.

For example, oral preparations include tablets, capsules, granules,
Suspensions, syrups, etc. Parenterally administered drugs include injections,
It can be formulated into ointments, etc. for local administration such as suppositories, but
From the viewpoint of ease of formulation and stability, it is preferable to use it as a capsule, suppository, or ointment. Excipients used in the production of oral preparations such as tablets, capsules, jaw granules, and syrups include, for example, lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methylcellulose, carboxymethylcellulose,
Glycerin, sodium alginate, gum arabic, etc. can be mentioned.

The content of the active ingredient in the orally administered preparation is preferably 200 to 400 9% per formulation unit. Examples of base materials for producing suppositories include cocoa butter, Witepsol-W-3
5 (Witepsol-W35, oil and fat, Germany, Dynamite Nobel ■ product), etc. are suitable.

The active ingredient content per suppository is 500 to 1000.9
is preferred. The daily dosage of these oral preparations, suppositories, and other preparations intended for systemic administration is 800 to
9 of 1200 is appropriate. The base material of the ointment, which is a topical preparation, is an oily base material such as liquid paraffin, cetyl alcohol, white petrolatum, squalane, lanolin, cholesterol, etc., and the content of the active ingredient is 5 to 1 per skin t.
%. Examples are shown below to better understand the present invention.

Example 1 Dissolve 13 parts of 5-fluorouracil in 150 parts of dimethyl sulfoxide, add 33 parts of tetrahydrofurfurylfuromide and 28 parts of anhydrous potassium carbonate to 150 to 170 parts.
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After the reaction is complete, insoluble matter is removed from the furnace, and the furnace liquid is concentrated under reduced pressure to remove the solvent and
Remove unreacted substances. The residue was dissolved in 100 volumes of 80% ethanol and heated at 60° C. for 1 hour while maintaining pHIO to 11 with sodium hydroxide solution for hydrolysis. After the reaction, remove the alcohol and add 500 parts of water and 200 parts of n-hexane.
After adding acetic acid and shaking well, the n-hexane layer was removed, the pH was adjusted to 6.0 to 6.5 with diluted hydrochloric acid, and the mixture was extracted three times with 70% chloroform. The extracts are combined and concentrated, and the residue is recrystallized from ethanol to obtain white crystals of N,1-tetrahydrofurfuryl-5-fluorouracil. Yield 13.5% (63%) mp 170-171°C. Elemental analysis value (C9 days, as .N203F) HCN analysis value (%
) 5.16 50.43 13.30 Calculated value (%)
5.18 50.4713.08 Example 25-fluorouracil 13 was dissolved in dimethyl sulfoxide 150M, Taylor hydrofurfuryl furomide 33 was dissolved,
Anhydrous potassium carbonate 28% and sodium iodide 7.5%
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After the reaction is completed, insoluble materials are removed from the furnace, and the furnace solution is concentrated under reduced pressure to remove the solvent and unreacted materials. The obtained concentrate was subjected to column chromatography (silica gel, ethanol:chloroform=5
:1), separated by N, . 21.5 ml of N3-bis(tetrahydrofurfuryl)-5-fluorouracil is obtained as a colorless oil. Yield 72% Elemental analysis value (C,4
day, 9N204F・1/fine 20) HCN analysis value (
%) 6.61 55.21 9.01 Calculated value (%)
6.62 55.26 9.21 Example 35-fluorouracil 13 and tetrahydrofurfurylfuromide 33 are reacted in the same manner as in Example 2, and concentrated in the same manner.

The obtained concentrate was dissolved in an 80% aqueous ethanol solution and hydrolyzed by heating at 6,000 for 1 hour while maintaining the pHI at 0 to 11 with a sodium hydroxide solution. After the reaction, the alcohol was removed, 500 parts of water and 200 parts of n-hexane were added, and the mixture was shaken well. The n-hexane layer was removed and the pH was adjusted to 6.0 to 6.5 with dilute hydrochloric acid, and the pH was adjusted to 6.0 to 6.5 with 70 parts of chloroform. Extract times. The extracts are combined and concentrated, and the residue is recrystallized from ethanol to obtain white crystals of N,1-tetrahydrofurfury-5-fluorouracil. Yield 1
7.4th evening (81%) mp171-171.5qo Elemental analysis value (C9th, as .N203F) HCN analysis value (%
) 5.21 50.6013.06 Calculated value (%) 5
．． 18 50.4713.08 Example 3.8 ml of 45-furomouracil was dissolved in 50 ml of dimethyl sulfoxide, 4.9 ml of tetrahydrofurfuryl furomide,
Eight hours of anhydrous potassium carbonate and 0.8 hours of potassium iodide were added and stirred at 100 to 120 q○ for 1 hour.

After the reaction is completed, insoluble materials are removed from the furnace, and the furnace solution is concentrated under reduced pressure to remove the solvent and unreacted materials. Zanwan was dissolved in a 50% acetone aqueous solution and heated to 1.5% at 50°C while adding a potassium carbonate aqueous solution and maintaining the pH at 9 to 10. Insect time light worship and hydrolysis.
After the reaction, acetone was distilled off, and 50 parts of water and 3 parts of n-hexane were added.
After adding 0' and shaking well, remove the n-hexane layer.
Next, the pH is adjusted to 6.0 to 6.5 with diluted hydrochloric acid, and extracted three times with 30M chloroform. The chloroform extracts are combined and concentrated, and the residue is recrystallized from ethanol to obtain white crystals of N,1-tetrahydrofurfury-5-furomouracil. Yield 4.0 evening (72%) mpl94-1
95oo elemental analysis value (C9 days, as .N203Br)
HCN analysis value (%) 4.0139.0510.23 Calculated value (%) 4.0339.2910.18 Example 5
Dissolve 2.9 μl of 5-chlorouracil in 50 μl of dimethyl sulfoxide, add 4.9 μl of tetrahydrofurfuryl furomide, 8 μl of anhydrous potassium carbonate, and 0.8 μl of potassium iodide, and prepare at 100 to 120 q○. 1 Hataterama rope worship.

After the reaction is completed, the same procedure as in Example 4 is carried out to obtain white crystals of N,-tetrahydrofurfuryl-5-chlorouracil. Yield 3.5 evenings (75%) mp206-206.500
Elemental analysis value (C9 days, as .N203CI) HCN analysis value (%) 4.86 47.07 11.91 Calculated value (%) 4.81 46.87 12.02 Example 6
Dissolve 5.8 ml of 5-odouracil in 80 ml of dimethyl sulfoxide, add 4.9 ml of tetrahydrofurfuryl furomide, 8 ml of anhydrous potassium carbonate, and 0.8 ml of potassium iodide to give a solution of 60 to 70 ml. Worship at ℃ for 24 hours.

Claims (1)

[Claims] 1 Tetrahydrofurfuryl-5- represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. Halogenouracil derivative. 2. The tetrahydrofurfuryl-5-halogenouracil derivative according to claim 1, wherein Y is a hydrogen atom. 3. The tetrahydrofurfuryl-5-halogenouracil derivative according to claim 1, wherein Y is a tetrahydrofurfuryl group. 4 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a halogen atom) 5-halogenouracil and the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting tetrahydrofurfuryl halide represented by A method for producing a tetrahydrofurfuryl-5-halogenouracil derivative represented by 5. The manufacturing method according to claim 4, wherein the reaction is carried out in the presence of at least one alkaline substance selected from the group of alkali metal hydroxides and carbonates. 6. The production method according to claim 4 or 5, characterized in that the reaction is carried out in the presence of an alkali metal iodide. 7 5-halogenouracil and tetrahydrofurfuryl halide are reacted to obtain a mixture of N_1-tetrahydrofurfuryl-5-halogenouracil and N_1.N_3-bis(tetrahydrofurfuryl)-5-halogenouracil, and then The mixture is hydrolyzed to obtain the above N_
N_1-tetrahydrofurfuryl-5, which is characterized by converting 1.N_3-bis form into N_1-mono form.
- A method for producing halogenouracil. 8. The production method according to claim 7, wherein the reaction is carried out in the presence of at least one alkaline substance selected from the group of alkali metal hydroxides and carbonates. 9. The production method according to claim 7 or 8, characterized in that the reaction is carried out in the presence of an alkali metal iodide. 10. The production method according to any one of claims 4 to 9, wherein the tetrahydrofurfuryl halide is tetrahydrofurfuryl bromide or tetrahydrofurfuryl iodide. 11. The production method according to claim 5 or 8, wherein the alkaline substance is sodium carbonate or potassium carbonate. 12. The production method according to claim 6 or 9, wherein the alkali metal iodide is sodium iodide or potassium iodide. 13 Pharmacological properties of the tetrahydrofurfuryl-5-halogenouracil derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. An antitumor agent characterized by containing an effective amount and an excipient. 14. The antitumor agent according to claim 13, wherein 14 Y is a hydrogen atom. 15. The antitumor agent according to claim 13, wherein 15Y is a tetrahydrofurfuryl group.