JP2631227B2 - 5'-benzyl-5-fluorouridine derivatives and intermediates thereof - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel 5′-benzyl-5-fluorouridine derivative and an intermediate for producing the derivative. The 5'-benzyl-5-fluorouridine derivative has an excellent anticancer effect and antiviral effect, and is useful as an antitumor agent and an antiviral agent.

Prior art and its problems 5-fluorouridine (hereinafter referred to as FUR) is 1959
It was first synthesized in 2000 and its excellent antineoplastic activity is already known (US Patent No. 2885398). However, it is problematic for clinical use due to its high toxicity.

Conventionally, many attempts have been made to solve the above problem by converting FUR into various derivatives, but useful derivatives have not yet been obtained (Japanese Patent Laid-Open No. 50-64).
280, 51-52183, 57-91997, 61-246196).

Means for Solving the Problem In view of such circumstances, the present inventors have considered that clinically useful FU
As a result of studying the derivative of R, a 5'-benzyl-5-fluorouridine derivative of the present invention which can achieve the above object and a useful intermediate for producing the derivative were found, and the present invention was completed. Reached.

The present invention relates to the following general formula (I) [In the formula, R ₁ represents a halogen atom, a lower alkoxy group or a lower alkyl group, and n represents an integer of 0 to 3. 5'-benzyl-5-fluorouridine derivative represented by the following general formula (II): [Wherein, R ₁ and n are the same as above, and R ₂ and R ₃ are the same or different and represent a lower alkyl group. ] Is provided.

The compound (I) of the present invention has lower toxicity than FUR,
It has strong antitumor and antiviral effects, and is useful as a medicine. Compound (II) is useful as an intermediate for producing compound (I).

In the general formulas (I) and (II), examples of the halogen atom include fluorine, chlorine, bromine, and iodine.
Examples of the lower alkoxy group include a linear or branched alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. As lower alkyl groups, methyl, ethyl, propyl, isopropyl, butyl, sec-
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms such as butyl, tert-butyl, pentyl and hexyl groups.

 The compound of the present invention is produced by the following method.

General formula Wherein R ₂ and R ₃ are the same as above. ] (Journal of Medical Chemistry (J.
Med.Chem.), 24 , 893-897, (1981)) Wherein R ₁ and n are the same as above. X represents a bromine atom or an iodine atom. With a substituted benzyl halide compound represented by the formula (I) in the presence of a base in a suitable solvent to obtain the intermediate (II) of the present invention,
The compound (I) of the present invention can be obtained by deprotecting the isoalkylidene group at the 2-position.

The above reaction for obtaining the intermediate (II) is performed in an organic solvent. The solvent used here is not particularly limited as long as it does not adversely affect the above reaction.Examples include aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, tetrahydrofuran, and ethers such as dioxane. , Aprotic polar solvents such as acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide and the like can be used singly or as a mixture of two or more.

As the base, various bases usually used in this type of reaction can be used, and examples thereof include alkali metal hydrides such as sodium hydride and potassium hydride, and alkali metal hydrides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide. Hydroxide, sodium methoxide, sodium ethoxide,
Alkali metal alkoxides such as potassium tert-butoxide, organic alkali metals such as butyl lithium, methyl lithium and potassium disilazide, silver oxide, silver nitrate and the like are preferably used.

The amount of the base to be used is generally about 1-10 mol, preferably about 2-4 mol, per 1 mol of compound of general formula (III). The amount of the substituted benzyl halide compound (IV) used is
It is generally about 1-10 mol, preferably about 1-4 mol, per 1 mol of compound (III).

Although the reaction temperature is not particularly limited, it is usually 0.
-100 ° C, preferably from room temperature to about 60 ° C, is advantageous for the progress of the reaction.

The reaction time varies depending on the type of solvent and base used, but is generally about 0.5 to 24 hours.

The above deprotection reaction is easily carried out in a suitable solvent by hydrolysis using an acid. The solvent used here is not particularly limited as long as it does not adversely affect the above reaction, and examples thereof include diethyl ether, tetrahydrofuran, ethers such as dioxane, methanol, ethanol, propanol, and butanol. , Alcohols, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane and the like, and water, etc., can be used alone or in combination.

As the acid, various acids used in this type of reaction can be used.For example, mineral acids such as hydrochloric acid and sulfuric acid, trifluoroacetic acid, acetic acid, formic acid, organic acids such as tosylic acid, Dowex-50W
Strongly acidic cation exchange resins such as (H ⁺ ) (Dow Chemicals) and CK-08P (H ⁺ ) (Mitsubishi Kasei) are preferably used.

The amount of the acid to be used is generally 0.01 mol per 1 mol of compound (II).
About 10 mol, preferably about 0.1 to 5 mol.

The compounds (I) and (I) of the present invention obtained by the above method
I) can be isolated and purified by ordinary separation and purification means such as recrystallization and silica gel column chromatography.

Examples Examples of the present invention will be described below, but the present invention is not limited thereto.

Example 1 5'-m-chlorobenzyl-5-fluorouridine (I
Preparation of -1) 2 ', 3'-isopropylidene-5-fluorouridine
1.0 g (3.3 mM) was dissolved in 6 ml of anhydrous tetrahydrofuran. 264 mg (6.6 mM) of 60% sodium hydride was added to the above solution, and the mixture was stirred at 60 ° C for 2 hours. After returning to room temperature, m-
A solution of 532 mg (3.3 mM) of chlorobenzyl chloride in 1 ml of anhydrous tetrahydrofuran was added dropwise, followed by 248 mg (1.65 mM) of sodium iodide and reacted at room temperature for 19 hours. The reaction solution was diluted with 20 ml of anhydrous tetrahydrofuran, neutralized with an ion exchange resin (WK-11, manufactured by Mitsubishi Kasei Co., Ltd.), and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography 30 g,
Elution with chloroform-methanol (50: 1) gave 1141 mg of 2 ', 3'-isopropylidene-5'-m-chlorobenzyl-5-fluorouridine (V-1) (yield 81).
%).

1130 mg (2.65 mM) of the obtained compound (V-1) was dissolved in 5 ml of chloroform, 1 ml of 90% -trifluoroacetic acid was added, and the mixture was reacted at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was subjected to silica gel column chromatography (20 g), the portion eluted with chloroform-methanol (20: 1) was concentrated under reduced pressure, the residue was recrystallized from ether, and collected by filtration. 892 mg of 5'-m-chlorobenzyl-5
-Fluorouridine (I-1) was obtained (yield 87%).

¹ H-NMR of compound (V-1) (solvent DMSO, internal standard TM
Table 1 shows the δ (ppm) value and yield (%) of S), and the δ of ¹ H-NMR (solvent DMSO, internal standard TMS) of compound (I-1).
Table II shows the (ppm) value, the yield (%) and the melting point (° C.).

Example 2 Preparation of 5'-p-methoxybenzyl-5-fluorouridine (I-10) 2 ', 3'-isopropylidene-5-fluorouridine
1.0 g (3.3 mM) was dissolved in 6 ml of anhydrous tetrahydrofuran. 264 mg (6.6 mM) of 60% sodium hydride was added to the above solution, and the mixture was stirred at 60 ° C for 2 hours. After returning to room temperature, p-
A solution in which 663 mg (3.3 mM) of methoxybenzyl bromide was dissolved in 1 ml of anhydrous tetrahydrofuran was added dropwise, followed by addition of 248 mg (1.65 mM) of sodium iodide, followed by a reaction at room temperature for 16 hours. After diluting the reaction solution with 20 ml of anhydrous tetrahydrofuran, an ion exchange resin (WK-11, manufactured by Mitsubishi Kasei)
And filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (30 g), and eluted with chloroform-methanol (50: 1) to give 1197
mg of 2 ', 3'-isopropylidene-5'-p-methoxybenzyl-5-fluorouridine (V-10) was obtained (86% yield).

1180 mg (2.79 mM) of the obtained compound (V-10) was dissolved in 3 ml of tetrahydrofuran, 3 ml of 1N hydrochloric acid-tetrahydrofuran (1: 1) was added, and the mixture was reacted at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was subjected to silica gel column chromatography (20 g), the portion eluted with chloroform-methanol (20: 1) was concentrated under reduced pressure, the residue was recrystallized from ether, and collected by filtration. Thus, 886 mg of 5'-p-methoxybenzyl-5-fluorouridine (I-10) was obtained (83% yield).

¹ H-NMR of compound (V-10) (solvent DMSO, internal standard TM
Table 1 shows the δ (ppm) value and yield (%) of S), and the δ of ¹ H-NMR (solvent DMSO, internal standard TMS) of compound (I-10).
Table II shows the (ppm) value, the yield (%) and the melting point (° C.).

Hereinafter, similarly, compounds (V-2) to (V-9),
(V-11) to (V-12) and compounds (I-2) to (I-
9), (I-11) to (I-12) were prepared, and their identification values are shown in Tables I and II, respectively.

Pharmacological Test 5 × 10 ⁶ mouse transplantable tumor sarcoma 180 cells were implanted subcutaneously on the back of male ICR / JCL mice (body weight 27-30 g). A sample was dissolved or suspended in a physiological saline solution containing 0.1% Tween 80, and this was added to a group of 7 mice.
A dose of 1/10 g of the mouse body weight was administered intraperitoneally three times in total on the first, fifth and ninth days after the tumor implantation.

The above-mentioned solution containing no specimen was administered to the control group in the same manner.

On day 12 after transplantation, for each sample administration group, the average tumor weight at each dose was measured, these were compared with the average tumor weight in the control group, and the tumor growth inhibition rate for the control group at each dose was determined. I asked.

 The results obtained are shown in Table III.

Continuation of the front page (72) Inventor Junji Uchida 463-10 Kagasuno, Kawauchi-machi, Tokushima City, Tokushima Prefecture (72) Inventor Viegiba. Konstanti 41-2 Shinkawaya, Kitajima-cho, Kitajima-cho, Itano-gun, Tokushima Prefecture (72) Inventor Yuji Yamada 4-2-8, Sumiyoshi, Tokushima-shi, Tokushima Prefecture (56) References JP-A-61-246196 (JP, A) 57-91997 (JP, A) JP-A-61-109720 (JP, A) JP-A-61-134397 (JP, A) Japanese Utility Model Application No. 57-142998 (JP, U) Japanese Utility Model Application No. 57-91994 (JP, A) U)

Claims (1)

(57) [Claims] (1) General formula [In the formula, R ₁ represents a halogen atom, a lower alkoxy group or a lower alkyl group, and n represents an integer of 0 to 3. 5'-benzyl-5-fluorouridine derivative represented by the formula: