JPH0344397A - 5'-substituted-5-fluorouridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is H, lower alkyl or aralkyl; R<2> is lower alkyl or aralkyl or R<1> and R<2>, together with the adjacent C and O atoms, may form tetrahydrofuranyl or tetrahydropyranyl). EXAMPLE:5'-(Tetrahydropyran-2-yl)-5-fluorouridine. USE:Useful as an antitumor agent having excellent carcinostatic action. PREPARATION:5-Fluorouridine is used as a starting raw material and OH groups at the 2'- and 3'-positions thereof are protected. The resultant compound expressed by formula II (R<3> and R<4> are protecting groups of OH groups) is then reacted with an acetal compound expressed by formula III or enol ether compound expressed by formula IV (R<5> is H, lower alkyl, allyl or aralkyl; R<2> and R<5> may be mutually linked to form dihydropyran or dihydrofuran) in the presence of an acid in a suitable organic solvent to afford a compound expressed by formula V. The protecting groups at the 2'- and 3'-positions are subsequently removed.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel 5-monosubstituted-5-fluorouridine derivatives, more specifically, novel 5'-monosubstituted-5-fluorouridine derivatives which have excellent anticancer activity and are useful as antitumor agents. The present invention relates to substituted-5-fluorouridine derivatives.

Conventional technology 5-Fluorouridine (hereinafter referred to as FUR) was developed in 1959.
It was first discovered in 2013, and its excellent anti-malignant tumor activity is already known (US Pat. No. 2,885,398). However, there were clinical problems in terms of toxicity, and this was considered a development issue. Many attempts have been made to solve the above problems by converting FUR into various derivatives, but a compound with excellent efficacy and satisfactory toxicity has not yet been obtained.

Problems to be Solved by the Invention An object of the present invention is to provide a FUR derivative that has excellent efficacy and is satisfactory in terms of toxicity.

In view of this situation, the present inventors have developed a clinically effective FUR.
As a result of studying the derivatives of
The present invention has now been completed.

Means for solving the problem The 5'-substituted-5-fluorouridine derivatives of the present invention are
The following general formula (I) HOOH [wherein, R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group, R2 represents a lower alkyl group or an aralkyl group, and R1 and R2 represent an adjacent carbon atom and an oxygen atom] - A lahydrofuranyl group or a tetrahydropyranyl group may be formed. ].

Compound (I) of the present invention has lower toxicity than FUR, has a strong antitumor effect, and is useful as a medicine.

In the above general formula (I), the lower alkyl group represented by R1 or R2 is a straight carbon number group such as methyl, ethyl, propyl, isopropyl, butyl, 5eC-butyl, tert-butyl, pentyl, hexyl group, etc. Mention may be made of chain or branched alkyl groups.

As an aralkyl group, one or several aromatic substituents,
For example, an alkyl group having 1 to 5 carbon atoms, preferably 1 to 3 carbon atoms, substituted with a phenyl group or a naphthyl group, such as benzyl, 2-phenylethyl, 3-phenylpropyl, α-
Examples include naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, and the like. The aromatic group itself may also be substituted with 1@ or several alkyl or alkoxy groups having 1 to 3 carbon atoms; examples of aralkyl groups in this case include 4-methylbenzyl, 2 .4.6-) Limethylbenzyl, 3,4.5-trimethylbenzyl, 4
-methoxybenzyl, 4-methoxyphenyldiphenylmethyl and the like. Preferably it is a benzyl group.
The method for producing the compound of the present invention will be explained below.

First, using 5-fluorouridine as a starting material, the hydroxyl groups at the 2' and 3' positions are subjected to a conventional acylation reaction or nitrophenyl chloroformate to form a cyclic carbonyl group using a method described in the literature [R., L. , Rechinger
(R, L, Letsinger) et al. Journal of Organic Chemistry (J, Org, Che
m, ), 32.296 (1967)], and the compound is protected according to the following general formula (II[)].

[In the formula, R3 and R4 represent a hydroxyl group-protecting group.

Next, the compound of general formula (III) is converted into an acetal compound or general formula represented by the general formula R1 R20-CH-OR2(IV) [wherein R1 and R2 are the same as above] % formula % () [In the formula, R2 is the same as above. R5 represents a hydrogen atom, a lower alkyl group, an allyl group or an aralkyl group. R2 and R5 may be combined with each other to form dihydropyran or dihydrofuran. A compound of the following general formula (II) is obtained by reacting with the enol ether compound represented by the following formula (II) in a suitable organic solvent in the presence of an acid.

] The compound (I) of the present invention can be obtained by isolating the compound (II) or removing the protecting groups at the 2'-position and the 3'-position without isolating the compound (II).

The organic solvent used in the reaction to obtain compound (II) is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, and tetrahydrofuran. , ethers such as dioxane, halogenated hydrocarbons such as dichloromethane and chloroform, acetonitrile,
Conventionally known aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide can be used alone or in combination.

As the acid used in the reaction to obtain compound (I[), various acids commonly used in this type of reaction can be used, such as mineral acids such as hydrochloric acid and sulfuric acid, acetic acid, trifluoroacetic acid, tosylic acid, etc. organic acids, Lewis acids such as zinc chloride, aluminum chloride, strong acid cation exchange resins such as Dowex-50W (H'') [Dow Chemicals], etc. are preferably used.The amount of acid used is , compound 1 of general formula (m)
Usually about 0.01 to 10 mol, preferably 0
．． It is about 0.01 to 3 moles.

The amount of acetal compound (TV) used is compound (III)
Usually about 1 to 20 moles per mole, preferably 2 to 1
It is about 0 mole.

The reaction temperature is not particularly limited, but is usually 0 to 1.
A temperature of about 00°C, preferably from room temperature to about 60°C, is advantageous for the reaction to proceed. The reaction time varies depending on the solvent used, the type of acid, and the reaction temperature, but is generally about 1 to 24 hours.

The deprotection reaction of the 2'- and 3-position protecting groups of compound (II) is easily carried out by a solvation reaction using a base. The solvent used here includes the solvent used in the solvation reaction, such as methanol, ethanol, propatool, a protic polar solvent such as water, or a solvent that does not adversely affect the reaction, such as diethyl ether, tetrahydrofuran, A mixture of a plurality of ethers such as dioxane, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc. can be used. As bases, the species commonly used in this type of deprotection reaction are L, hydroxyl, and sodium oxide. Inorganic salts such as potassium, potassium carbonate, ammonia, and sodium carbonate, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, and organic bases such as pyridine, imidazole, trialkylamines, dialkylamines, and monoalkylamines are used.

The amount of base used in the deprotection reaction is based on the general formula (II
) is about 1 to 20 mol per mol of the compound. The reaction temperature is from 0°C to the reflux temperature of the solvent, preferably from 15 to
A temperature of about 40°C is best. The reaction time is about 1 to 24 hours, preferably about 1 to 8 hours.

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

In the above general formulas (n) and (III), as a protecting group for the hydroxyl group at the 2'-position and 3-position represented by R3R4 (7P1-)
Alkanoyl groups such as acetyl, propionyl, butyryl or isobutyryl groups, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl groups that can be deprotected. , an acyloxyacyl group such as acetyloxymethylcarbonyl, propionyloxymethylcarbonyl or acetyloxyethylcarbonyl group, an acyl group such as an aroyl group having a substituent such as p-chlorobenzoyl, p-methylbenzoyl, p-nitrobenzoyl group, etc. Alternatively, it is desirable to use a cyclic carbonyl group in which R3 and R4 are combined.

Next, examples of the present invention will be shown, but the present invention is not limited thereto.

Reference Example 1 [Manufacture of 5-fluorouridine-2=,3' cyclic carbonate] 5.00 g of 5-fluorouridine (19.0 mmo
Add 5. p-nitrophenyl chloroformate to 50 ml of pyridine solution of 1) under water cooling. 38g (26.7mmol
) and 0.5 g of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 25 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was poured into 150 ml of cold 5% hydrochloric acid, saturated with sodium chloride, and then extracted with ethyl acetate (100 ml x 3). The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel (200 g) column chromatography. 4.20 g of the target product is obtained from the ethyl acetate extract (yield 76%).

IH-NMR (DMS O-d6) δ (ppm) value 12.03 (LH, br, 3-NH) 8.17 (LH, d, J-7,03, C6-H) 5.9
7 (LH, m, C1'-H) 5.22-5.84 (3H, m, 02', C3-H, 5
--0H)4.15~4.50(311,m,C",C
'-H) Example 1 [5'-(tetrahydropyran-2-
Production of 5-fluorouridine-2",3"-cyclic carbonate) in 20 ml of anhydrous dioxane was added 3, 4-dihydro-2H-pyran 4.4 g (52.3 mmo 1) of dioxane 20
ml solution, then para-toluenesulfonic acid 100mg
was added and stirred at room temperature for 2 hours. After adding triethylamine (150 mg) to the reaction solution, it was concentrated under reduced pressure. The residue was subjected to silica gel (100 g) column chromatography, and 5'-(tetrahydropyran-2-yl)-5-fluorouridine-2'3'-cyclic carbonate (compound 1.5 g of (1)-1) was obtained.

The obtained compound (II-1) was mixed with pyridine-water (1:1
) Dissolve in 20ml of mixed solution and reflux for 20 minutes 1 f
--Gyote Wiζ68shi) Saved 2 ships 1. -1 Keiban ζ
,★1 Su-manyo, real name-2no 11 Kageru (100
g) Subjected to column chromatography. Chloroform-
A fraction of methanol (9:1) was concentrated under reduced pressure, and the residue was crystallized with ether to obtain 645m of the title compound (I-1).
I got g.

The δ (ppm) values of 1H-NMR (solvent DMSO1 internal standard TMS) of compound (II-1) are shown in Table 1.
I-1) IH-NMR (solvent DMSO, internal standard TM
Table 2 shows the δ (ppm) value, yield (%) and melting point (°C) of S).

Example 2 [5”-(1-benzyloxypropyl)-
Production of 5-fluorouridine (compound l-2)] 5-fluorouridine-2-,3''-cyclic carbonate) 3.0 g (10.4 mmo 1) and propionaldehyde dibenzyl acetal 16.0 g (6
300 mq of pyridium p-toluenesulfonate was added to a solution of 2.5 mmol 1) in anhydrous dioxane (40 ml), and the mixture was stirred at 50°C for 1.5 hours. After adding 1 ml of triethylamine to the reaction solution, it was concentrated under reduced pressure. The residue was subjected to silica gel (40 g) column chromatography,
By concentrating the eluate of chloroform-methanol (49:1) under reduced pressure, 5=-(1-benzyloxypropyl)-5-fluorouridine-2'3--cyclic carbonate (compound It-2) was obtained. Obtained. Dissolve this in 100ml of pyridine-water (1:1) mixture,
Heat to reflux for minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel (50 g) column chromatography. The eluate of chloroform-methanol (97:3) was concentrated under reduced pressure, and the residue was crystallized from ether to obtain 2.22 g of the title compound (I-2).

6 (ppm) value of lH-NMR (solvent DMSO1 internal standard TMS) of compound (I-2), yield (%) and melting point (
°C) are shown in Table 2.

Example 3 [Production of 5=-(1-benzyloxy-2,2-dimethyl-propyl)-5-fluorouridine (compound l-3)] 5-fluorouridine-2'3'-cyclic carbonate 3. 0g (10,4mmo 1) and pivalaldehyde dibenzyl acetal 16.0g (56,
Add 100 mg of para-toluenesulfonic acid to a solution of 3 mmol 1) in anhydrous dioxane (30 ml), and add 100 mg of para-toluenesulfonic acid to a solution of 1)
Time reacted. After adding 0.4 ml of triethylamine to the reaction solution, it was concentrated under reduced pressure, and the resulting residue was soaked in silica gel (5 ml).
0 g) was subjected to column chromatography. The crude product obtained by concentrating the hexane-ethyl acetate (1:1) eluate under reduced pressure was dissolved in a pyridine-water (1:1) mixture,
Heated under reflux for 40 minutes. The reaction solution was concentrated, the resulting residue was subjected to silica gel (50 g) column chromatography, the chloroform-methanol (97:3) eluate was concentrated under reduced pressure, and the residue was recrystallized from hexane-ether to give the title product. 683 mg of compound (■-3) was obtained.

LH-NMR (solvent DMSO1 internal standard TMS) δ (ppm) value, yield (%) and melting point (
℃) are shown in Table 2.

Example 4 Compounds (II-4), (II-5) and compounds (I-4) and (I-5) were produced in the same manner. These identified values are shown in Tables 1 and 2, respectively.

Pharmacological Test Mouse Reimplantation Tumor Sarcoma 180 cells (5 x 106 cells) were subcutaneously transplanted into the back of male IOR/JCL mice (body weight 27-30 g). The samples were dissolved or suspended in physiological saline containing 0.1% Tween 80, and one group was divided into 7
The drug was intraperitoneally administered to each mouse at a dose of 0.1 ml/10 g mouse body weight three times on the 1st, 5th, and 9th day after tumor implantation.

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

On the 12th day after transplantation, the average tumor weight at each dose was measured for each specimen, and these were compared with the average weight in the control group to determine the tumor growth inhibition rate at each dose relative to the control group.

The results obtained are shown in Table 3.

The number of dead sections in the table represents the mortality of mice that died within 12 days after tumor implantation.

Claims (1)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 represents a hydrogen atom, a lower alkyl group, or an aralkyl group, and R^2 represents a lower alkyl group or an aralkyl group, or R^ 1 and R^2 may form a tetrahydrofuranyl group or a tetrahydropyranyl group together with adjacent carbon atoms and oxygen atoms. ] A 5'-substituted-5-fluorouridine derivative.