JPS6011703B2 - 5-fluoropyrimidin-4-one derivative and antitumor agent containing the same as an active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 5-fluoropyrimidin-4-one conductor and an antitumor agent containing the same as an active ingredient.

The 5-fluoropyrimidin-4-one derivative of the present invention has the general formula (wherein R is a straight or branched alkyl group having 4 to 18 carbon atoms, This is a novel compound represented by an alkenyl group, a tetrahydrofurfuryl group, an aryl group, or an aralkyl group.

Ever since Heidelberger et al. revealed that 5-fluorouracil has an anti-tumor effect on transplanted tumors (for example, Cancer Research, No. 1, No. 3).
05 pages, 195 Mother's Day), . It has been widely used clinically as an antitumor agent for many years.

However, 5-fluoruracil has a strong plexus effect, so continuous administration can cause loss of appetite, stomatitis, and nausea. Gastrointestinal disorders such as pupil vomiting, blood disorders such as decreased white blood cells and decreased platelets, liver disorders,
It cannot be administered for a long period of time because it causes side effects such as cognitive impairment, and therefore cannot exhibit sufficient therapeutic effects. As a result of intensive research to solve the above-mentioned drawbacks, the present inventor has discovered the following five features of the present invention.
It has been found that -fluoropyrimidine-4-one derivatives have extremely low toxicity and excellent anti-falconry effects.

The present invention was completed based on this new knowledge. The 5-fluoropyrimidin-4-one derivative '1'' of the present invention is, for example, 2,4-dichloro-5 represented by the formula
- A fluoropyrimidine is reacted with an alcoholate or a phenolate represented by the general formula ROM (wherein R is the same as above and M represents an alkali metal);
is the same as above), and then hydrolyzes it.

Moreover, the compound of the present invention is a 2-chloro-5-fluoropyrimidine-4 represented by the formula
It can also be produced by reacting -one with an alcoholate or a phenolate represented by ROM (in the formula, R and M are the same as above).

The above 2,4-dichloro-5-fluoropyrimidine (2) used as a starting material in the present invention is a known compound,
For example, Collection of Czechoslovak Chemical Communication, Volume 30, Page 1900, 1
968 King) etc. In addition, 2-chloro-5-fluoropyrimidin-4-one'4), which is another raw material of the present invention, is also a known compound, for example, Journal of Medicinal Chemistry, Vol. 8, p. 253, 1
963 King).

The alcoholate or phenolate represented by the general formula ROM used in the present invention is also a known compound, and examples of R include the various groups mentioned above, and examples of M include sodium, potassium, etc.

Such a ROM can be easily obtained, for example, by reacting an alcohol or phenol represented by ROH with an alkali metal compound such as metallic sodium, metallic potassium, sodium hydride, potassium hydride, or the like. In this case, if the alcohol or phenol is solid, it is preferably dissolved in anhydrous ethyl ether, dioxane, benzene, etc., and if the reaction is slow, the reaction is preferably carried out with flooding.
Specific examples of R in the general formula ROM include straight mirror or branched alkyl groups having 4 to 18 carbon atoms such as butyl, bentyl, hexyl, octyl, decyl, hexadecyl, octadecyl, etc.; vinyl, allyl, butenyl, hexenyl;
Straight-chain or branched alkenyl groups having 2 to 18 carbon atoms such as octenyl, 3,7-dimethyl-2,6-octadienyl, and 9-octadecenyl; Tetrahydrofurfuryl group; Aryl groups such as phenyl, tolyl, and xylyl: Aralkyl groups such as penzyl, phenethyl, phenylpropyl and the like can be mentioned. In the present invention, 2,4-dichloro-5-fluoropyrimidine [2' or 2-chloro-5]
-The reaction between fluoropyrimidin-4-one '41 and the compound represented by ROM (wherein R and M are the same as above) is preferably carried out in an anhydrous aprotic solvent such as benzene, toluene, dioxane, etc. It will be done. Further, the raw material alcohol or phenol used in manufacturing the ROM may be used as a solvent. The amount of ROM to be used is preferably about 2 to 3 times the molar amount of the pyrimidine derivative [21 or '41]. This reaction is usually about 50-2
It will be held at 00:00 ○. In the above, as starting material 2
When -chloro-5-fluoropyrimidin-4-one '4) is used, the object compound of the present invention [11] can be obtained directly. When 2,4-dichloro-5-fluoropyrimidine [2] is used as a starting material, the intermediate 2,4-disubstituted-5-fluoropyrimidine is first obtained by the above reaction, and then this is Hydrolysis yields the target compound {11. The hydrolysis reaction may be carried out after the intermediate '3' is isolated, or may be carried out without isolation. Intermediate {3} is separated from the reaction solution by conventional separation means such as extraction, distillation, recrystallization, etc. When hydrolysis is performed without isolation, it is preferable to remove the molten butter from the reaction solution in advance. The hydrolysis reaction may be carried out by a commonly known method,
For example, the substance to be hydrolyzed is first suspended or dissolved in water or a water-miscible solvent. Examples of solvents that are miscible with water include methanol, ethanol, and dioxane. Next, a basic substance is added to this suspension or solution and the mixture is generally heated to about 50 to 100°C. Examples of the basic substance include hydroxides and carbonates of alkali metals and alkali metals. From the above, 2,4-di-substituted-
Only the substituent at the 4-position of the leg of 5-fluoropyrimidine is selectively hydrolyzed to obtain the 5-fluoropyrimidin-4-one derivative '1 of the present invention. The progress of the reaction can be confirmed by thin layer chromatography. The compounds of the present invention obtained by any of the above methods are easily separated and recovered by commonly known methods. For example, after the reaction is completed, the solvent is removed by the reaction compound, diluted hydrochloric acid is added to adjust the pH to 4 to 6, and the mixture is then extracted with methylene chloride, chloroform, or the like. After concentrating the extract, the concentrate is recrystallized,
The compound of the present invention can be easily obtained by purification by conventional means such as column chromatography. The anti-tumor agent of the present invention contains a pharmacologically effective amount of the 5-fluoropyrimidine-4- of the present invention.
Contains an on derivative and an excipient.

The anti-tumor agent of the present invention can be formulated into various formulations depending on its administration route.

For example, oral preparations include capsules, soft capsules,
Tablets, cervical granules, sustained-release tablets, fine granules, syrups, etc.
For parenteral administration, it can be formulated into injections, suppositories, etc., and for topical administration, it can be formulated into ointments, etc. However, due to the difficulty of formulation, stability, and effectiveness, capsules, soft capsules, forehead granules, etc.
It is preferable to use it as sustained-release tablets or fine granules or suppositories. Capsules, tablets, forehead granules, sustained release forehead granules,
Examples of excipients used in manufacturing oral preparations such as granules and syrups include lactose, sucrose, starch,
Talc, magnesium stearate, crystalline cellulose,
Examples include methylcellulose, carboxymethylcellulose, glycerin, sodium alginate, gum arabic, and the like.

Examples of coating agents for sustained-release tablets include Ethocel (registered trademark, manufactured by The Dow Chemical Company, USA) and Oydragit (registered trademark, manufactured by Rohm and Haas Company, USA). Examples of excipients for European capsules include edible oils and fats with a melting point of 40°C or less, such as sesame oil, rapeseed oil, and medium-chain fatty oil, and if necessary, surfactants, suspending agents, silicon dioxide, etc. may be added. I can do it. The content of the active ingredient in such oral preparations is 2.
2 of 00 to 500 is preferable. Suitable bases for producing suppositories include, for example, cacao butter, Witepsol W-35 (registered trademark, product of Dynamite Nobel AG, Germany, fats and oils), and the like.

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% as the active ingredient.
~1500 legs is appropriate. Bases for ointments for topical administration include, for example, liquid paraffin, cetyl alcohol, stearyl alcohol, white petrolatum, squalane,
Using an oily base such as lanolin or cholesterol, the content of active ingredients is 5 to 1 skin t. %. Below, 5-fluoropyremidine-4 of the present invention
This figure shows an example of the production of a -one derivative, a formulation example of an anti-tumor agent containing a discussion conductor as an active ingredient, and an acute toxicity test and a pharmacological activity test of the anti-tumor agent.

Example 1 5.8% of sodium metal in 300% of anhydrous n-butanol
Add 16.7 g of 2,4-dichloro-5-fluoropyrimidine and reflux for 3 hours.

After the reaction, the solvent was concentrated, and the remaining bamboo was added with 35% of 2N-potassium hydroxide.
Add 0M and stir under reflux for 10 hours. Ether 1 after cooling
Extract twice with 0.00 [ml] to remove ether-soluble materials, and add dilute hydrochloric acid to the aqueous layer to adjust the pH to 4 to 5 and precipitate crystals. Recrystallization from ethanol yields 15.5 white crystals of 2-n-butoxy-5-fluoropyrimidine-14-one. Yield 83
．． 3%, melting point 127-129.5q0 elemental analysis value (C8
Day,. As N202F) C day N calculated value (%) 51
．． 61 5.95 15.05 Analysis value (%) 51.4
3 5.78 14.97 Example 2 Anhydrous ether 2
Dissolve 36.3 ml of n-hexadecanol in 00',
Add 3.3 liters of metallic sodium to this and reflux until dissolved.

Next, 2,4-dichloro-5-fluoropyrimidine 8.5
Add water and reflux for 3 hours. After the reaction, a small amount of water is added for washing, and the ether layer is concentrated to precipitate crystals. The obtained crystals were recrystallized from ethanol to form white crystals of 2,4-di(
n-hexadecyloxy)-5-fluoropyrimidine 18
．． Get 6 evenings. Yield 63.1%, melting point 62-630C Elemental analysis value (C36 days 67N202F) C days N
Calculated value (%) 74.69 11.67 4.84 Analysis value (%) 74.55 11.72 4.772.4
2.9 g of di-(n-hexadecyloxy)-5-fluoropyrimidine was dissolved in a solution containing 5 g of 2N potassium hydroxide and 25 g of ethanol and refluxed for 4 hours.

After the reaction, ethanol was distilled off, ether 50% was added, ether-soluble matter was removed, and the pH was adjusted to 4 to 5 with dilute hydrochloric acid to precipitate crystals. The obtained crystals were recrystallized from ethanol to obtain white crystals of 2-41n-hexadecyloxy-5-fluoropyrimidin-14-one. Yield 73.0% Melting point 97-98℃ Elemental analysis value (as C2 Rainbow 35N202F) C Day N calculation value (%) 67.76 9.95 7.20 Analysis value (%) 67.59 10.21 7. 45 Example 3
To a mixture of 28 parts of phenol and 200 parts of toluene, 6.9 parts of sodium metal was added and refluxed for 1 hour.

Next, 2,4-dichloro-5-fluoropyrimidine 16.
Add 7 hours of water and reflux for 4 hours. After the reaction was completed, 17.3 hours of 2-phenoxy-5-fluoropyrimidin-4-one was obtained as white crystals in the same manner as in Example 1. Yield 84.0%, melting point 224-224.5q0 elemental analysis (C, Niji 7N20
2F) C day N Calculated value (%) 58.26 3.42 13.59 Analytical value (%) 57.98 3.34 13.54 Example 4 Metallic sodium 5 in anhydrous n-butanol 300M
．． Add 14.9 μl of 2-chloro-5-fluoropyrimidine-4-one to dissolve, and then add 14.9 μl of 2-chloro-5-fluoropyrimidine-4-one to 140 ~
Heat and react at 150 qo for 5 hours.

After the reaction, the solvent is distilled off, and 50% of water is added to the residue, and the pH is adjusted to 4 to 5 with dilute hydrochloric acid to precipitate crystals. Recrystallization from ethanol gave 17.1 white crystals of 2-n-butoxy-5-fluorobyrimidin-4-one. Yield 91.9%, melting point 127-12 scale○ Elemental analysis value (C8 days, as .N202F) C day N calculated value (%) 51.61 5.95 15.05 Analysis value (%) 51.40 5 .80 15.00Example 5
Anhydrous sec-butanol 300', metallic sodium 5
．． 8 and 2-chloro-5-fluoropyrimidine-4
-On 14.9 pm was treated in the same manner as in Example 4.

The obtained crystals were recrystallized from ethanol-water to obtain 17.0 seconds of 2-sec-butoxy-5-fluoropyrimidin-4-one as white crystals. Yield 91.4%, melting point 104~
105°C Elemental analysis value (as C8HuN2QF) C day N Calculated value (%) 51.61 5.95 15.05 Analysis value (%) 51.43 5.80 15.21 Examples 6-9 Alcohol: n-bentanol; The corresponding target compound was obtained in the same manner as in Example 4 except that n-hexanol, n-decanol, and n-hexadecanol were used.

The physical properties and yield of the obtained compound are shown below. 21n
-bentyloxy-5-fluoropyrimidine-4-one mPI17-118qo Yield 90.3% Elemental analysis value (
C9 day, 3N202F) C day N calculated value (%)
53.99 6.55 13.99 Analysis value (%) 53
．． 91 6.63 13.792-n-hexyloxy-5-fluoropyrimidine-4-one mPI14-11
5q○ Yield 86.1% Elemental analysis value (C, P, 202
F) Day C N Calculated value (%) 56.06 7.06 13.08 Analysis value (%) 55.44 7.36 12.942-n
-Desyloxy-5-fluoropyrimidine-4-one mp
100~10ro Yield 84.3% Elemental analysis value (C, 4 days as 23N202F) C day N calculated value (%) 57.29 7.90 9.54 Analysis value (
%) 57.45 7.92 9.302-n-hexadecyloxy-5-fluoropyrimidin-4-one mP9
7-98℃ Yield 84.1% Elemental analysis value (as C2 mountain 3 mountain 202F) C Day N Calculated value (%) 67.76 9.957.20 Analysis value (%) 67.5010.037.41 Implemented Example 10 200 g of anhydrous toluene, 23.1 g of 3,7-dimethyl-2,6-octadiene-1-ol and 3 g of metallic sodium
．． Add 4 hours of water and heat at 40 to 50°C until the metallic sodium is dissolved, then add 7.4 hours of 2-chloro-5-fluoropyrimidin-4-one and reflux for 8 hours.

After the reaction, the solvent was removed, 30% of water was added to the residue, and the solution was purified with dilute hydrochloric acid.
Extract with 200 μg of chloroform and concentrate. The residue was purified by silica gel column chromatography to obtain 2-(3,7-dimethyl-2,6-octadiene-1-oxy)-5-fluoropyrimidine as a yellowish oil.
Obtain 4-one 8.39. Yield: 61.0% Elemental analysis value (
C, 4th, bu 202F, 1/4th 20) C day N
Calculated value (%) 62.09 7.26 10.34 Analysis value (%) 62.01 7.05 10.21 Example
11 100 parts of anhydrous toluene to 10 parts pendyl alcohol
Add 7.2 hours of sodium hydride and reflux for 1 hour, then add 14.9 hours of 2-chloro-5-fluoropyrimidin-4-one and heat in a sealed tube at 140-150°C for 6 hours. and react.

After the reaction, 17.2 hours of 2-benzyloxy-5-fluoropyrimidin-4-one was obtained as white crystals in the same manner as in Example 4. Yield 78.2%, melting point 146-147q0 Elemental analysis value (C, day 9N202F) C day N calculated value (%
) 60.00 4.12 12.72 Analysis value (%)
60.21 4.08 12.55 Example 12 Add 11.7 parts of metallic potassium to 200 parts of anhydrous toluene, add 28 parts of phenol and 100 parts of anhydrous toluene to a bottle, and dissolve the metallic potassium.

Next, 2-chloro-5-fluoropyrimidine-4-one 1
4. Add 9 evenings and pray for 8 hours for 100oo. After the reaction, 13.2 hours of white crystals of 2-phenoxy-5-fluoropyrimidin-4-one were obtained in the same manner as in Example 4. Yield 64
．． 1%, melting point 224-225℃ elemental analysis value (C, mountain 7N
(as 202F) C day N Calculated value (%) 58.26 3.42 13.59 Analytical value (%) 58.01 3.40 13.41 Example 13 Tetrahydrofurfuryl alcohol 40 minutes to 200 degrees of anhydrous toluene Add 7.2 quarts of sodium hydride and incubate for 1 hour at 75 to 80 qo, then add 2 chloride.
Add 14.9 g of 5-fluoropyrimidin-4-one and heat in a sealed tube at 148-15,000 for 5 hours to react.

After the reaction, white crystals of 2-tetrahydrofurfuryloxy-5-fluoropyrimidine-4-
Get on 15.4 evening. Yield 72.0%, melting point 89-9
1℃ Elemental analysis value (C9 day, as .N2QF) C day N Calculated value (%) 50.47 5.18 13.08 Analysis value (%) 50.19 5.11 13.22 Next, the antitumor of the present invention Examples of formulations of wound preparations are described below.

Formulation Example 1 6 parts of magnesium stearate and 44 parts of lactose were added and mixed well until homogeneous, then 50 parts of lactose and 100 parts of crystalline cellulose were added and mixed, and then 5 parts of 2-n-butoxy, which had been pulverized in advance, were added and mixed. -Fluoropyrimidine-4-
Add 200 g of onion and mix to make an adjusted powder.

The prepared powder is used to produce 400 capsules/cap using a capsule filling machine. Formulation Example 2 After uniformly mixing 3 parts of magnesium stearate, 10 parts of calcium carpoxymethylcellulose, and 44 parts of crystalline cellulose, and mixing with 250 parts of 2-pendyloxy-5-fluoropyrimidin-4-one, which had been pulverized in advance, and Rokuazusa. A slag is made using a slugging machine, the grains are made using an oscillator equipped with Japanese Pharmacopoeia no. Add magnesium oxide and prepare 9 uncoated tablets of 310 ml per tablet according to a conventional method.

This uncoated tablet can be coated with a bran coat or a film coat. Formulation Example 3 Pre-pulverized 2-n-butoxy-5-fluoropyrimidine-4-one (4k9), corn starch (3k9), lactose (1.5k9), and white rice bran (1.4k9) were placed in a fluid coating device and fluidized for 18 minutes.

Next, a solution of 200 mg of sodium carboxymethylcellulose dissolved in 15 mg of 30% methanol was made into a powder of 99 mg.
An amount equivalent to 10 tons of sodium carboxymethyl cellulose is spray-coated into a fluid powder per day to form a powder. After drying, size the pongee grains to yield 2-n per night.
-butoxy-5-fluoropyrimidin-4-one 400
A product containing 9 is produced. Formulation Example 4 Pre-pulverized 21n-butoxy-5-fluoropyrimidine-4-one 2k
9 was added to medium chain fatty acid triglyceride 3k9, mixed uniformly, and packed into 2-n-
Soft capsules containing 200 butoxy-5-fluoropyrimidin-4-ones are prepared.

Formulation Example 5 After mixing 2.5k9 of lactose, 1.45k9 of starch, and 5k9 of 2-benzyloxy-5-fluoropyrimidin-4-one, wet granulation was performed by adding 10% hydroxypropyl cellulose alcohol solution 500, followed by drying.
After grading, the particles were transferred to a fluid coating device, and a 10% solution of EthMel (Dow Chemical) was sprayed onto a 1:1 (weight ratio) mixed solution of methylene chloride and n-hexane in an amount equivalent to 100 tons of Ethcel per 900 particles. Produce persistent jaw grains.

The formulation releases 2-benzyloxy-5-fluoropyrimidin-4-one over one capsule hour when dissolution testing is performed. Formulation Example 6 After heating and dissolving Witepsol W351400 to 60 oz, add 750 oz of 2-benzyloxy-5-fluoropyrimidine-4-one, which has been crushed in advance, little by little, mix uniformly, cool to 40 qo, and use a suppository filling machine. Inject a specified amount into a plastic container, pass through a cooling tank at 15 to 20°C to cool and solidify, and then seal the injection part.
Make suppositories.

Formulation Example 7 100 parts of liquid paraffin, 50 parts of cetyl alcohol, and 797 parts of petrolatum were dissolved by heating at 80°C, and then 3 parts of cholesterol and 50 parts of crushed 2-benzyloxy-5-fluoropyrimidine-4-one were thoroughly stirred. While adding,
Next, leave it at room temperature and when it reaches an appropriate hardness, fill it into a container to prepare an ointment.

Next, the results of acute toxicity tests and anti-tumor field tests of the compounds of the present invention will be shown. (Acute toxicity test) The compound of the present invention was orally administered to mice;
LD5o after 3 weeks was calculated by the Litchfield-Wilcoxson method.

The results are shown in Table 1 below. Table 1 shows 5 for comparison.
- The results of measurements made in the same manner as above using fluorouracil are also listed. Table 1 Unit (phosphorus/&) (Anti-tumor field test) Ehrlitsu carcinoma and sarcoma 18 in mice
5 x 1 cells of No. 0 tumor cells were subcutaneously transplanted, and each compound of the present invention was orally administered once a day for 7 consecutive days starting 2 hours after transplantation, and the tumor weight was measured on the 10th day. Table 2 below shows the inhibition rate of each group relative to the seed field weight.

For comparison, Table 2 below also shows the results of measurements made in the same manner as above using 5-fluorouracil. Table 2

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is a straight chain or branched alkyl group having 4 to 18 carbon atoms, a straight chain or branched A 5-fluoropyrimidin-4-one derivative represented by a branched alkenyl group, a tetrahydrofurfuryl group, an aryl group or an aralkyl group. 2. The 5-fluoropyrimidin-4-one derivative according to claim 1, wherein R is a linear or branched alkyl group having 4 to 18 carbon atoms. 3. The 5-fluoropyrimidin-4-one derivative according to claim 1, wherein R is a linear or branched alkenyl group having 2 to 18 carbon atoms. 5-Fluoropyrimidin-4-one derivative according to claim 1, wherein 4R is a tetrahydrofurfuryl group. 5-Fluoropyrimidin-4-one derivative according to claim 1, wherein 5R is an aryl group. 5-Fluoropyrimidin-4-one derivative according to claim 1, wherein 6R is an aralkyl group. 7 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a straight chain or branched alkyl group having 4 to 18 carbon atoms, a straight chain or branched alkenyl group having 2 to 18 carbon atoms, An antitumor agent containing a pharmacologically effective amount of a 5-fluoropyrimidin-4-one derivative represented by a tetrahydrofurfuryl group, an aryl group, or an aralkyl group, and an excipient. 8. The antitumor agent according to claim 7, which is an orally administered agent in the form of a tablet, capsule, soft capsule, granule, sustained release granule, or fine granule. 9. The antitumor agent according to claim 8, which is an orally administered drug containing 200 to 500 mg of active ingredient per formulation unit. 10. The antitumor agent according to claim 7, which is in the form of a suppository. 11. The antitumor agent according to claim 10, which is a suppository containing 500 to 1000 mg of the active ingredient per formulation unit. 12. The antitumor agent according to claim 7, which is in the form of an ointment. 13. The antitumor agent according to claim 12, which is an ointment having an active ingredient concentration of 5 to 10% by weight.