JPS6050191B2 - 5↓-Fluorouracil derivative - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula Two.

The present invention relates to a novel 5-fluorouracil derivative having H, O, and H°F(I).

In the above formula, R'' and R'' represent the same or different hydrogen atoms or lower alkoxy groups.

However, this excludes the case where both R'' and R'' are hydrogen atoms. In addition, R'' and R'' may be adjacent to form a lower alkylene dioxy group. The 5-fluorouracil derivative having the formula (1) is a novel compound and is a compound useful as a medicine that exhibits excellent anticancer activity.

In the general formula (1), R" and R" are the same or different hydrogen atoms; for example, methoxy, ethoxy,
It represents a linear or branched alkoxy group having 18 to 5 carbon atoms, such as n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-bentoxy, and isobentoxy. However, this excludes the case where both R' and R' are hydrogen atoms. Further, R" and R° are adjacent to each other to form an alkylenedioxy group having 18 to 3 carbon atoms, such as methylenedioxy, ethylenedioxy, ethylidenedioxy, and propylidenedioxy. Furthermore, suitable compounds include R", which is a methoxy group, R"
Examples include those in which 2 is a hydrogen atom, those in which R'' and R゜ are both methoxy groups, or those in which R1 and R2 form a methylenedioxy group. Conventionally, as 5-fluorouracil derivatives related to the present invention, For example, a patent application has been filed for 2-benzyloxy-5-fluoro?-pyrimidin-4-one (Japanese Patent Application Laid-Open No. 1361-1989).
7 eel).

The present inventors conducted research on the structure-activity relationship of 5-fluorouracil derivatives with the aim of developing anticancer drugs with fewer side effects, and as a result, a novel 5-fluorouracil derivative having the general formula (1) above was discovered. The present invention was completed by discovering that it exhibits stronger anticancer activity and lower toxicity than fluorouracil and its 2-benzyl derivative 7 derivatives. The novel compound according to the present invention can be produced by the method shown below. In the above formula, R' and R
” indicates the commercial meaning as described above, R3 indicates a lower alkyl group such as methyl, ethyl, n-propyl, or isopropyl, X indicates a halogen atom such as chlorine or bromine, and preferably R3 is It represents a methyl group, and X represents a chlorine atom.

The first step of method A is a step for producing a 5-fluorouracil derivative having the general formula (1), which is the target compound of the present invention, and is a step for producing a 5-fluorouracil derivative having the general formula (1), which is a compound of the general formula (■) produced from a dihalogen compound having the general formula (■). A compound having the general formula (wherein R1 and R2 have the same meanings as described above, and M represents an alkali metal atom such as sodium or potassium.

) is a step of heating and reacting with a substituted benzyl alcohol metal salt.

When carrying out the reaction in this step, the reaction is carried out using the general formula (■)
This is carried out by bringing a compound having the formula (■) into contact with a compound having the general formula (■) in the presence of a solvent and heating the mixture.

The solvent to be used is not particularly limited as long as it does not participate in this reaction, but aromatic hydrocarbons such as toluene and xylene, and ethers such as tetrahydrofuran and dioxane are suitable. The heating reaction temperature is not particularly limited, but it is usually carried out at around 60 to 140°C, and it is particularly preferable to heat to reflux around the boiling point of the solvent used. The reaction time varies mainly depending on the reaction temperature, but is about 3 minutes to 3 hours. At the end of the reaction, the target compound of this step (
1) is collected from the reaction mixture according to a conventional method.

For example, the solvent is distilled off from the reaction mixture under reduced pressure, and the residue is dissolved by adding an organic solvent such as penzene and water, and then the water layer is separated and the combined pH is around 8. A phosphate buffer such as sodium dihydrogen phosphate aqueous solution was added until the pH reached 4, and the pH was adjusted to around 4. The precipitated crystals were removed and washed with water. It can be obtained by drying.
The second step of Method B is a step of producing a compound having the general formula (■), in which the compound having the general formula (■) is heated and reacted with a substituted benzyl alcohol metal salt having the general formula (■).

The reaction conditions for the reaction in this step are the same as in the reaction in the first step described above, except that compound (■) is used in a 2 molar ratio to compound (■).

After the reaction is completed, the target compound (■) of this step is collected from the reaction mixture according to a conventional method. For example, the solvent is distilled off from the reaction mixture under reduced pressure, the residue is dissolved by adding a phosphate buffer such as an aqueous sodium dihydrogen phosphate solution and an organic solvent such as ethyl acetate, and then separated into organic solvents. The layer is separated, washed with saturated saline, dried, and then the solvent is distilled off under reduced pressure to obtain a trowel. The obtained product can be used in the next step reaction without purification.
The third step is a step for producing a 5-fluorouracil derivative having general formula (1), which is the object compound of the present invention, and is a step of heating and reacting a compound having general formula (■) with an aqueous alkali hydroxide solution.

When carrying out the reaction in this step, the reaction is carried out using the general formula (■)
This is carried out by contacting a compound having the following with an aqueous alkali hydroxide solution and heating it.

The alkali hydroxide used is sodium hydroxide,
Potassium hydroxide is preferred, and it is usually carried out using an aqueous solution thereof or a mixed solution of water and an alcohol such as methanol, ethanol, or n-propylene. There is no particular limitation on the heating reaction temperature, but it is usually 70 to 100
It is preferable to heat and reflux the temperature at around 0.degree. C., particularly around the boiling point of the solvent used. The reaction time varies mainly depending on the reaction temperature, but is about 5 to 2 times. After the reaction is completed, the target compound of this step is collected from the reaction mixture according to a conventional method.

For example, if necessary, alcohols are distilled off from the reaction mixture under reduced pressure, and the aqueous solution is washed with an organic solvent such as n-hexane to remove the aqueous layer. It can be obtained by adding a phosphate buffer such as an aqueous solution and carrying out activated carbon treatment, then further adding a phosphate buffer to adjust the pH to around 4, filtering out the precipitated crystals, washing with water, and drying. can. The fourth step of method C is a step of producing a compound having the general formula (■).
) (In the formula, R3 and M have the same meanings as described above.

) is a step of reacting with an alkali metal alkoxide having

The reaction conditions for the reaction in this step are known in the known literature [G. J. Dur
'R, J. Med. Chem. , vol. 8, p. 253 (19
This method is similar to the method for synthesizing 2-chloro-4-ethoxy-5-fluoropyrimidine described in 1965), in which the compound (■) is mixed with an alkali metal alkoxide (■) in the presence of the corresponding alcohol. This is done by making contact.

The fifth step is a step of producing a compound having the general formula (■), in which the compound having the general formula (■) is heated and reacted with a substituted benzyl alcohol metal salt having the general formula (■).

The reaction conditions for the reaction in this step are the same as those for the O reaction in the first step described above, and the post-treatment method is the same as in the reaction in the second step described above.

The sixth step is a step for producing a 5-fluorouracil derivative having the general formula (1), which is the object compound of the present invention, and is a step of heating and reacting the compound having the general formula (■) with an aqueous alkali hydroxide solution.

The reaction conditions and post-treatment method for this step are as described in the third section above.
The same is true for the reaction in the process.

The target compound obtained in the reaction steps of each of the above methods can be further purified, if necessary, by a conventional method, such as a recrystallization method or a reprecipitation method.

All of the 5-fluorouracil derivatives of the present invention having the general formula (1) exhibit remarkable anticancer effects in pharmacological tests.Next, the results of pharmacological tests regarding anticancer effects will be illustrated.

(1) Leukemia L-12W cells (1×1Cf') were transferred to BDF
Implant intraperitoneally into l mice.

(2) Administer once a day for 5 days starting from the day after L-12W cell transplantation.

(3) Production Example 1 Compound: 5-fluoro-2-piperonyloxy-pyrimidin-4-one.

(4) Production Example 2 Compound: 5-fluoro-2-(p-methoxybenzyloxy)-? -pyrimidine-4-one.

(5) 2-0-By-5-FU: 2benzyloxy-5
- Fluoro-pyrimidine-4-one.

(6) FT-207: N1-(tetrahydrofuryl)
-5-Fluorouracil. (7) 5-FU: 5-fluorouracil.

Therefore, the compound having the general formula (1) is useful as an anticancer agent for various cancer diseases.

Examples of the administration form include parenteral administration by intravenous injection, or oral administration by tablets, capsules, granules, powders, syrups, and the like. The dosage varies depending on symptoms, age, weight, etc., but the usual daily dose for adults is 5 to 50 m9/K when administered intravenously.
9, and in the case of oral administration, the daily dose is 200 to 2000.
fL9 and can be administered in 1 to 4 divided doses. Next, the present invention will be explained in more detail with reference to manufacturing examples.

Production Example 15-Fluoro-2-piperonyloxy-pyrimidin-4-one (a) Anhydrous dioxane 5 to 50 liters
5% oily sodium hydride 1.20f1 (28mm01
) was suspended, 4.55y of piperonyl alcohol (30 ml/ml) dissolved in 10 ml of anhydrous dioxane was added dropwise over 15 minutes at room temperature, and then heated under reflux for 30 minutes to precipitate a crystalline substance.

Once cooled, 2-chloro-5-fluoro-pyrimidine-4-one [G. J. DLlrr, J. Med.
Chem. , Vol. 8, p. 253 (1965)] 2.08y (14 mmol) was added and heated under reflux for 1 hour. After the reaction, the solvent was distilled off under reduced pressure to obtain a residue. Dissolve it in 50 ml of benzene and 50 ml of water and separate the layers.The organic layer is dissolved in 20 ml of 1N sodium monohydroxide.
After extraction again with 1 and 20 mL of water, each aqueous layer was extracted with 50 mL of water.
Wash twice with benzene from Step 1, combine the aqueous layers, and add 20% sodium dihydrogen phosphate aqueous solution (
(to the extent that it does not become cloudy) and then treated with activated carbon. Next, a total of 40 ml of a 20% aqueous sodium dihydrogen phosphate solution was added under ice cooling, and stirring was continued for 2 hours. The precipitated white crystals were collected, washed with water, and dried to give 3.121y.
The title compound is obtained. Melting point 154-156C Purple? ? Akira? ? ? S vector Nm (ε) (9600) Nuclear magnetic resonance vector di δ (DMSO-D6) 7.87
(Doublet, 1H, H at 6th position) 6.8-7.2 (Multiplet, 3
H, Elemental analysis value: Calculated value C, 5 as Cl2H9O4N2F
4.55; H, 3.43; N, lO. 6O; 2F, 7.
19. Analysis value C, 54.45; H, 3.35, N, lO
．． 72; F, 6.87 (b) Dioxane 100
1.60y of 55% oily sodium hydride was suspended in 1ml of the suspension, 6.10q of piperonyl alcohol dissolved in 10ml of anhydrous dioxane was added dropwise at room temperature, and heated under reflux for 3min. Afterwards, let it cool to room temperature.

Next, 2,4-dichloro-5-fluoropyrimidine [G
．． J. Dur'R, J. Med. Chem. , Volume 8, 2
53 pages (1965). [Synthesized according to the method of]2.46
Add V and heat to reflux for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 50 ml of a 20% aqueous potassium dihydrogen phosphate solution and 50 ml of ethyl acetate to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue were added 22.2 mt of 1N sodium monohydroxide and 22.2 ml of methanol, and the mixture was heated under reflux for 2 turns.

After the reaction was completed, methanol was distilled off under reduced pressure, and 10% of water was added.
Add m1, wash with 30 mL of n-hexane, and add 20 ml to the aqueous layer.
% potassium dihydrogen phosphate aqueous solution to the extent that it does not become cloudy, the pH is adjusted to around 8, and then treated with activated carbon. The obtained colorless aqueous solution is ice-cooled, and a 20% aqueous potassium dihydrogen phosphate solution is added thereto while stirring until no crystals are precipitated, and then stirring is continued for 2 hours. The precipitated crystals are collected, washed with water, and dried to obtain the title compound of 3.35y. Its properties were consistent with those shown in (a). :)2,4-
8.35y of dichloro-5-fluoropyrimidine is dissolved in 75mt of anhydrous methanol, cooled to around 0°C with a cryogen, and 25Tnt of Δ-sodium methoxide is added dropwise.

After stirring as it is for 2 hours, the solvent is distilled off under reduced pressure, water is added, and the mixture is left in the refrigerator for about 2 hours to precipitate crystals.
When this was taken out, washed with water, and dried, the melting point was 35% in quantitative yield.
A 2-chloro-5-fluoro-4-methoxypyrimidine having a temperature of ~36°C is obtained. Then 100m of anhydrous dioxane
3.23 f of oily sodium hydride was suspended at 55° C. in T, and 12.54 y of piperonyl alcohol dissolved in 20 ml of dioxane was added dropwise at room temperature.

Next, the three powders were heated under reflux, then allowed to cool to room temperature, the above 2-chloro-5-fluoro-4-methoxypyrimidine was added, and the mixture was heated under reflux for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and 150 ml of 20% potassium dihydrogen phosphate aqueous solution and 150 mL of ethyl acetate were added to the residue to separate the layers. After washing the organic layer with saturated brine, anhydrous magnesium sulfate was added. and evaporate the solvent under reduced pressure. On the resulting residue? 50ml of sodium monohydroxide and 100mt of methanol
and heated under reflux for 20 hours.

After the reaction, methanol was distilled off under reduced pressure, 10 ml of water was added to the residue, and the mixture was washed with 50 ml of n-hexane. A 20% aqueous potassium dihydrogen phosphate solution was added to the aqueous layer to adjust the pH to about 8. Treat with activated carbon. To the obtained aqueous solution was further added 20% potassium dihydrogen phosphate aqueous solution under ice-cooling until no crystals were precipitated, left as it was for 2 hours, the precipitated crystals were filtered out, washed with water, and dried to give 6.46 y. The target compound expressed as is obtained. Production Example 2 5-fluoro-2-(p-methoxybenzyloxy)-pyrimidin-4-one in 40 ml of anhydrous dioxane
Suspend 1.64y of 5% oily sodium hydride,
T! 6.22 q of p-methoxybenzyl alcohol dissolved in 0N anhydrous dioxane are added dropwise at room temperature.

After heating the 2-powder under reflux, it was allowed to cool to room temperature to form 2-chloro-5-fluoro? -pyrimidin-4-one 2.23y
and heated under reflux for 1.5 hours.

After the reaction is complete, the solvent is distilled off under reduced pressure and 20ml of water is added to the residue.
Add and dissolve 20 ml of n-hexane, separate the aqueous layer, wash twice with 20 ml of n-hexane, extract each organic layer with 10 ml of water, combine the aqueous layers, and cool on ice. Add 45ml of 20% sodium dihydrogen phosphate aqueous solution,
Leave it as is for 1 hour. After removing the precipitate and washing with water,
Recrystallize from ethanol (1:2) mixed solvent to obtain 3.1
The title compound 5y is obtained. After melting at a melting point of 118-119°C, it solidifies and melts again at a temperature of 183-19TC.

Ultraviolet absorption vector Nm (ε) Nuclear magnetic resonance vector Nm (DMSO-D6) 6.9~
7.6 (Multiple line, 4H, ▼-Vv?I3yc) So▼ゞ64d7 elemental analysis value: Cl2HllN2O3F・11
Calculated value as 4H20 C, 56.57; H, 4.55;
N, lO. 99; F, 7.45. Analysis value C, 56
．． 77; H, 4.4l; N, lO. 99: F, 7
．． 24 Production Example 3 2-(3,4-Dimethoxybenzyloxy)-5-fluoro-pyrimidine-4-one 50ml of anhydrous tetrahydrofuran to 55% oily hydrogenated) sodium 2.18y
(50rr1m0I) was suspended, and 3,4-dimethoxybenzyl alcohol 9.5f (60mm0l) was added.
Heat to reflux while stirring.

Since a crystalline substance precipitates, 50 ml of anhydrous tetrahydrofuran is further added and the mixture is heated under reflux for a total of 1 hour.・
Once released, 2-chloro5-fluoro? -Add 2.97y of pyrimidin-4-one (20ml) and heat under reflux for 8 hours. After the reaction, the solvent is distilled off under reduced pressure.
Add 5 ml of sodium dihydrogen phosphate aqueous solution to adjust the pH to about 9, and wash twice with 40 ml of benzene. The benzene layer was re-extracted with 20ml of 0.1N sodium monohydroxide,
The aqueous layers are combined, cooled in an ice bath, and 170 mt of a 20% aqueous sodium dihydrogen phosphate solution is added to adjust the pH to about 5.
After filtering out the precipitated crystals and washing them with water, the resulting crystals were suspended in about 400 ml of methanol to dissolve as much as possible, and then concentrated under reduced pressure to about 100 ml. After washing with water and drying, the title compound 3.818y is obtained as white crystals. Melting point 119
After melting at ~120°C, it solidifies and melts again at 184-195°C.

Ultraviolet absorption vector Nm (ε)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom or a lower alkoxy group. However, R^1 and 5-fluorouracil derivatives having R^2 (except when R^2 are both hydrogen atoms; R^1 and R^2 may be adjacent to each other to form a lower alkylenedioxy group).