JPS6010036B2 - 5-Fluorouracil derivative and its production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 5-fluorouracil derivatives having excellent anticancer activity.
In the formula, R is a hydrogen atom, a lower alkyl group, an alkoxy group,
or represents an alkoxycarbonyl group, and n is 1 or 2.

) and a method for producing the same.

The 5-fluorouracil derivative of the present invention is further developed based on the knowledge of anticancer active compounds discovered by the present inventors, such as 1-alkylcarbamoy-5-fluorouracil and 1-phenylcarbamoy-5-fluorouracil. It was devised as a result of research and is a compound with excellent anticancer activity.

The 5-fluorouracil derivative of the present invention comprises 5-fluorouracil and the general formula (b) (wherein R and n are as defined in the general formula (1)).

) can be produced by reacting with isocyanatomethylcyclohexanes represented by:

Furthermore, 1-chlorocarbonyl-5-fluorouracil and general formula (m) (wherein R and n are as defined in general formula (1)).

) It can also be produced by reacting with aminomethylcyclohexanes represented by:

The reaction between 5-fluorouracil and the isocyanatomethylcyclohexanes represented by the general formula (D) can be carried out by dissolving or suspending 5-fluorouracil in an organic solvent and adding the above-mentioned isocyanate thereto. can.

The isocyanatomethylcyclohexanes used in this reaction include, for example, isocyanatomethylcyclohexane,
1-isocyanatomethyl-4-methylcyclohexane,
Examples include 1-isocyanatomethyl-4-methoxycyclohexane, 1-isocyanatomethyl-4-ethoxycarbonylcyclohexane, and 1-isocyanatomethyl-2,5-dimethoxycyclohexane. Further, suitable reaction solvents used in this reaction include dimethylformamide, dimethylacetamide, dimethylsulfoxide, pyridine, picolines, and lutidines. The reaction temperature may be about 0°C to 100°C, and the reaction time may be 1 hour to 2 hours. After the reaction is complete,
The solvent and excess substituted methyl isocyanate are distilled off from the reaction solution, the residue is extracted with a solvent, and the extraction solvent is distilled off to obtain a 5-fluorouracil derivative, which is the target compound. If necessary, a pure target compound can be obtained by purification by a method such as recrystallization. The reaction between 1-chlorocarbonyl-5-fluorouracil and aminomethylcyclohexane represented by general formula (m) can also be carried out in the above reaction solvent.

1-Chlorocarbonyl-5-fluoro.

Uracil can be synthesized by reacting 5-fluorouracil with phosgene in a solvent. The aminomethylcyclohexanes used in the production of the compounds of the present invention include aminomethylcyclohexane, 1-aminomethyl-4-methylcyclohexane, 1-aminomethyl-4-toxycyclohexane, 1-aminomethyl-
Examples include 4-ethoxycarbonylcyclohexane and 1-aminomethyl-2,5-dimethylcyclohexane.

Stereoisomers exist in those having substituents. Generally, when synthesized by catalytic hydrogenation of penzylamines, cis-
Many substituted products are obtained, and when this is heated with acid or alkali, the proportion of trans-substituted products increases. This reaction was carried out using amines containing many cis-substituted compounds, except for special cases. A simple method for synthesizing the compounds of the present invention is as follows:
- First, 1-chlorocarbonyl-5-fluorouracil is synthesized by adding a slight excess of phosgene to fluorouracil in a solvent at low temperature in the presence of a deoxidizing agent. A total addition and reaction time of 0.5 to 1 hour is sufficient. Without isolating 1-chlorocarbonyl-5-fluorouracil, an equivalent amount of aminomethylcyclohexane is added to the reaction solution simultaneously or sequentially with a deoxidizing agent.

The reaction proceeds easily at low to room temperature, and the product can be confirmed by thin layer chromatography. 80~ in about 1-2 hours
90% reaction progresses. Suitable solvents used in the reaction include dimethylformamide, dimethylacetamide, dimethylsulfoxide, pyridine, picolines, lutidines, and the like in which 5-fluorouracil is dissolved. In the reaction of 5-fluorouracil and phosgene as a deoxidizing agent,
Dimethylaniline, triethylamine, pyridine, etc. are suitable, and if a basic solvent such as pyridine or picoline is used, there is no need to add anything else. On the other hand, for the latter reaction, that is, the reaction between 1-chlorocarponyl-5-fluorouracil and aminomethylcyclohexanes, a strong base such as triethylamine is preferred. For example, if triethylamine hydrochloride is precipitated, the reaction solution is filtered to remove it, and the filtrate is concentrated to dryness under reduced pressure.

To this residue, a water-insoluble solvent such as chloroform, dichloromethane, ethyl acetate, etc. is added to dissolve most of the residue, which is washed with dilute hydrochloric acid and water, and unreacted substances are removed to the aqueous layer. After drying the solvent layer, it is decolorized with activated carbon, evaporated to dryness, and recrystallized from an appropriate solvent. 1- obtained here
[N-(substituted cyclohexylmethyl)carbamoyl]-
Table 1 shows the melting points, n, and m'r data of 5-fluorouracils. All the compounds of the present invention have excellent anticancer activity, and the compounds of the present invention have excellent anticancer activity. We measured the life extension rate, which is used as an indicator.

Experimental example: Method for measuring life extension rate Lymphocytic leukemia Hitomi cells L were added to 6 BDF mice per group.
-1210 was implanted intraperitoneally, and 24 hours later, a predetermined amount of a 0.5% CMC suspension of the specimen was administered by intraperitoneal injection (IP) or oral administration once a day for 5 days. (p.o.
) and the life extension rate was calculated using the following formula.

Life extension rate (Mountain S%) = End' x 100 T: Days leading to death in treatment group C: Number of days leading to death in control group As a result, any of the above compounds j. p. , p. o.

Both have an ILS of 10-30% at a dose of 9/k9 of 30.
It was found that a dose of 100w9/k9 had an anticancer activity of 30 to 60%. The present invention will be specifically explained by the following examples.

Example 1 (Synthesis of Compound No. 3) 6.5 g of 5-fluorouracil is dissolved in 200 g of pyridine and cooled on ice to 5-7°C.

Add to this 4.6' of trichloromethyl chloride formmate.
Phosgene generated by contacting activated carbon was cooled with dry ice-methanol and added dropwise. Yellow crystals were formed in the reaction solution. To this, a solution of 7.16 g of 1-aminomethyl-4-methoxycyclohexane dissolved in 20 pyridine was added dropwise at 5-10 qC, and then 25 qC of triethylamine was added dropwise at the same temperature, and the mixture was incubated at room temperature for 1 hour. . After the reaction was completed, triethylamine hydrochloride was removed by filtration, and the filtrate solution was concentrated under reduced pressure. 250 μg of chloroform was added to the residue, and the mixture was extracted and washed with water acidified with hydrochloric acid. Next, the chloroform layer was extracted and washed twice with 150 liters of water, dried with molasses, and the chloroform was distilled off.13. A residue of batter was obtained. After washing this residue with a small amount of ethanol,
Recrystallization from ethanol gave 10.6 g of target product 1-[N-(4-methoxycyclohexylmethyl)-carbamoyl]-5-fluorouracil. The melting point of this thing is 13
6 to 137q0, and the yield of the target compound based on 5-fluorouracil was 70.8%. Example 25
- Dissolve 6.5 g of fluorouracil in 200 g of pyridine, and add 1-isocyanatomethyl-4-methoxysyl to this.

12.7 g of hexane was added and heated, and the reaction was carried out at 100° C. for 2 hours. After standing overnight at room temperature, the solvent and excess isocyanate were removed under reduced pressure to obtain a residue. This residue was treated in the same manner as in Example 1 to give 1-[N-(4-methoxycyclohexylmethyl)rubamoyl]-5-fluorouracil 10. Gained shipboard. Yield 70%. Example
3 (Synthesis of Compound No. 4) 5-fluorouracil6. Dissolve the mustache in 200M pyridine and cool on ice to 5-7°C.

Phosgene, which was generated by contacting activated carbon with 4.6 parts of trichloromethyl chloroformate, was cooled with dry ice and methanol and added dropwise thereto.

Yellow crystals were formed in the reaction solution. To this, transformer 1-
A solution of 9.26 g of aminomethyl-4-ethoxycarbonylcyclohexane dissolved in 25 g of triethylamine was added to
The mixture was added dropwise at 11 mm and reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was treated in the same machine as in Example 1.
1-[N-(4-ethoxycarbonylcyclohexylmethyl)-carbamoyl]-5-fluorouracil 10.
5g was obtained. The melting point of this product is 27 ○ (decomposition), and the yield of the target compound based on 5-fluorouracil is 6
It was 1.5%. Examples 4 to 6 The following reactions were carried out in the same manner as in Example 1 to obtain the target compounds as follows.

Compound 1 1-(N-cyclohexylmethylcarbamoyl)-5-fluorouracil Yield 48% Melting point 171-1720 Compound 2 1-[N-(4-methylcyclohexylmethyl)-carbamoyl]-5-fluorouracil Yield 77% Melting point 155. 5-156q○ Compound 5 1-[N-(2,5-dimethylcyclohexylmethyl)-carbamoyl]-5-fluorouracil Yield 49% Melting point 154-155°C

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom, a lower alkyl group, an alkoxy group, or an alkoxycarbonyl group, and n is 1 or 2. 5-fluorouracil derivative represented by ). 2. The 5-fluorouracil derivative according to claim 1, which is 1-[N-(cyclohexylmethyl)carbamoyl]-5-fluorouracil. 3. The 5-fluorouracil derivative according to claim 1, which is 1-[N-(4-methylcyclohexylmethyl)carbamoyl]-5-fluorouracil. 4 1-[N-(4-methoxycyclohexylmethyl)
The 5-fluorouracil derivative according to claim 1, which is [carbamoyl]-5-fluorouracil. 5. The 5-fluorouracil derivative according to claim 1, which is 1-[N-(4-ethoxycarbonylcyclohexylmethyl)carbamoyl]-5-fluorouracil. 6. The 5-fluorouracil derivative according to claim 1, which is 1-[N-(2,5-dimethylcyclohexylmethyl)carbamoyl]-5-fluorouracil. 7 5-Fluorouracil and the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents a hydrogen atom, a lower alkyl group, an alkoxy group, or an alkoxycarbonyl group, and n is 1 or 2.) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R and n are as defined in the previous formula.) 5 - A method for producing a fluorouracil derivative. 8 1-Chlorocarbonyl-5-fluorouracil and the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents a hydrogen atom, lower alkyl group, alkoxy group, or alkoxycarbonyl group, and n is 1 or 2. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ that are characterized by reacting with aminomethylcyclohexanes represented by ) (in the formula, R and n are as defined in the previous formula. ) A method for producing a 5-fluorouracil derivative represented by