JPS6260400B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to dihydrouridine derivatives and their uses, and more particularly, trans-6-alkoxy-5-fluoro-5,6-dihydro-5'-O-
Acyluridine and its use as an antitumor agent. Certain dihydrouridines are classified as
It is described in Publication No. 18945. As a result of intensive research to develop new dihydrouridine derivatives, the present inventors succeeded in producing and separating a new derivative not disclosed in the publication and stereoisomers of known and new dihydrouridine derivatives. Furthermore, it was discovered that these new isomers have superior antitumor activity compared to tegafur and the like, which have been conventionally used as antitumor agents, leading to the completion of the present invention. That is, the gist of the present invention is that the formula: [In the formula, R ₁ represents an aliphatic acyl group or aromatic acyl group having 2 to 10 carbon atoms, and R ₂ represents a saturated or unsaturated alkyl group having 1 to 20 carbon atoms. ] An antitumor agent containing trans-6-alkoxy-5-fluoro-5,6-dihydro-5'-O-acyluridine and the compound [ ] as active ingredients. In the formula [], the bond at the 5th and 6th positions and...
... merely represents the trans form, and the compound [ ] includes the d- and l- forms as well as the cerami form. The chemical stability of the alkyl group of the alkoxy group ( _-OR2 ) at the 6-position on the pyridine core of formula [] increases as the number of carbon atoms increases. The preferred number of carbon atoms is 1-20. Specific examples of saturated alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,
Examples include nonyl, decyl, dodecyl, hexadecyl, octadecyl, etc., which may be linear or branched. Specific examples of the unsaturated alkyl group include corresponding unsaturated groups. The acyl group (R ₁ ) at the 5' position on the ribose is determined by the selection of the starting material, but preferably has 2 to 10 carbon atoms. Specific examples include acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl,
Examples include decanoyl, benzoyl, naphthoyl, and the like. The compound [] of the present invention has the formula: [In the formula, R ₁ has the same meaning as above. ] January 1982 using the compound shown as the starting material.
It can be produced by the production method described in the specification attached to the patent application filed on the 27th (title of invention: Process for producing uridine derivatives and uridine derivatives), and can be obtained by separating stereoisomers by column chromatography. can. The compound [ ] of the present invention has excellent effects on various tumors, especially solid cancers such as gastrointestinal cancer, lung cancer, and breast cancer. The compound [ ] of the present invention has 2' and 3' hydroxyl groups and is therefore easily soluble in water. When formulated into an antitumor agent, it is mixed with known pharmacologically acceptable carriers, excipients, diluents, etc., if desired, and manufactured into various dosage forms by per se known formulation methods. Administration can be safely carried out either orally or parenterally. The dosage must be determined according to the doctor's prescription depending on the type of tumor, patient's condition, etc., but it is usually 5 to 300 mg for adult patients.
It is administered at a rate of mg/Kg/day, preferably 10-200 mg/Kg/day. Moreover, the daily dose can be administered once or in several divided doses. Furthermore, the compound of the present invention [ ] can also be used in combination with known antitumor agents. Next, the present invention will be specifically explained with reference to Examples. Example 1 3.0 g of 5'-O-acetyluridine was dissolved in 100 ml of glacial acetic acid in a 200 ml Diflon (trademark, Daikin Industries, Ltd.) resin flask equipped with a stirrer, cooler, gas inlet and thermometer. Then, add fluorine/nitrogen mixed gas (fluorine 20%) to this at room temperature.
was blown for 1 hour at a flow rate of 50 ml/min. Thin layer chromatography (silica gel plate 60F254 (Merck) 5 x 10 cm; chloroform: methanol =
5:1) to confirm that the starting material was consumed,
From the disappearance of ultraviolet absorption, 5 is a 5/6-saturated compound.
-Fluoro-6-acetoxy-5'-O-acetyluridine was observed to be produced. 50 ml of the glacial acetic acid solution was dried under reduced pressure at room temperature to obtain 1.5 g of amorphous 5-fluoro-6-acetoxy-5'-O-acetyluridine. ¹ H−NMR (d ₄ −
MeOH; TMSi external standard) δ = 2.12ppm
(OCOCH ₃ ). Add 50 ml of methanol to the remaining 50 ml of glacial acetic acid solution, let it stand for 3 days, dry it under reduced pressure at room temperature, and apply it to thin layer chromatography analysis (using the same plate and developing solution as above). After development, plate at 200°C. When heated for 1 hour and irradiated with ultraviolet rays to measure spot positions, the presence of isomers with Rf of 0.57, 0.55, and 0.51 was confirmed. The resulting reaction solution containing 5'-O-acetyl-5-fluoro-6-methoxy-5,6-dihydrouridine was concentrated, and the residue was subjected to column chromatography [Silica gel (Merck & Co., Ltd.) 70
~230 meshes, 30 cm x 9.6 cm ² ; Solvent: methylene chloride/methanol = 10/1 (volume)], developed at a flow rate of 1 ml/min, took 8 g of each fraction, and combined fractions containing the same components. About 375 mg of cis isomer and about 200 mg of trans isomer were obtained. Table 1 shows the Rf of the trans isomer and the results of ¹⁹ F-NMR (d ₄ -MeOH, trifluoroacetic acid external standard). Example 2 5'-O-acetyl-5-fluoro-6-acetoxy-5,6- prepared in a similar manner to Example 1
After adding 50 ml of n-hexanol to 50 ml of a glacial acetic acid solution of dihydrouridine and stirring at 40°C for 3 days, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography. ^19F -NMR analysis ( _d4-
δ in MeOH; trifluoroacetic acid external standard)
= 5′-O-acetyl-5 with isomers showing chemical shifts of 115.2ppm, 129.4ppm and 130.4ppm
1.5 g of -fluoro-6-hexanoxy-5,6-dihydrouridine was obtained. This was separated by column chromatography in the same manner as in Example 1 to obtain the trans isomer. Rf and ¹⁹ F− of this isomer
The NMR results are shown in Table 1. Example 3 In a flask similar to Example 1, 3.0 g of 5'-O-hexanoyl uridine was dissolved in 100 ml of glacial acetic acid, and a fluorine/nitrogen mixed gas (fluorine 2%) was added to this at room temperature.
was blown for 1 hour at a flow rate of 60 ml/min. Example 1
Consumption of the starting material and production of a 5,6-saturated compound were confirmed using the same procedure as above. 50 ml of the glacial acetic acid solution was dried under reduced pressure at room temperature to obtain 1.6 g of 5'-O-hexanoyl-5-fluoro-6-acetoxy-5,6-dihydrouridine. ^1H -NMR ( _d4 -MeOH;
TMSi external standard) δ = 2.12 ppm (OCOCH ₃ ). Add 50 ml of n-butanol to the remaining 50 ml of glacial acetic acid, stir for 3 days, distill off the solvent, and perform column chromatography (silica gel (Merck) 70-230 mesh; chloroform:methanol = 10:1) to 5'-O-hexanoyl-5-fluoro-6- with isomers that are 0.70, 0.65 and 0.62
1.3 g of butoxy-5,6-dihydrouridine was obtained. This was separated by column chromatography in the same manner as in Example 1 to obtain the trans isomer. Table 1 shows the Rf and ¹⁹ F-NMR results of this isomer. Example 4 The procedure of Example 1 was repeated using 5'-O-isobutyryl uridine as the starting material and butanol instead of methanol to prepare trans-6-
Butoxy-5-fluoro-5'-O-isobutyryl-5,6-dihydrouridine was obtained. The Rf and ¹⁹ F-NMR results of this isomer are shown in Table 1. Example 5 The procedure of Example 1 was repeated except that butanol was used instead of methanol to prepare 5'-O-acetyl-
trans-6-butoxy-5-fluoro-5,6-
Dihydrolaucil was obtained. The Rf and ¹⁹ F-NMR results of this isomer are shown in Table 1. Example 6 Transplantation 7 of mice transplanted with S-180A experimental tumor
Ascites (0.05ml/animal) was collected from experimental animals (JCL-
ICR mouse (Clea Japan Co., Ltd.), 1 group 5
) was inoculated intraperitoneally. The compound obtained in Example 5 and a control drug (tegafur) were suspended in physiological saline containing 1.5% CMC to a predetermined concentration. The above suspension (0.2 ml/20 g) was intraperitoneally administered once a day for 4 consecutive days starting 24 hours after tumor cell inoculation, while the same amount of physiological saline containing 1.5% CMC was intraperitoneally administered to the control group. administered. Seven days after inoculation, the amount of ascitic fluid was measured, and a portion of it was taken into a hematocrit tube and centrifuged at 10,000 rpm.
Calculated using TPCV (Total Packed Cell Volume). Ratio of TPCV between drug administration group and control group (T/C
%) was calculated, and T/C=100-66 was set as -, 65-41 as +, 40-11 as ++, and 10-0 as +++. The results are shown in Table 2. In addition, similar experiments were conducted by administering the drug orally instead of intraperitoneally. Same result as second
Shown in the table.

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【table】

Claims (1)

[Claims] 1 Formula: [In the formula, R ₁ represents an aliphatic acyl group or aromatic acyl group having 2 to 10 carbon atoms, and R ₂ represents a saturated or unsaturated alkyl group having 1 to 20 carbon atoms. ] trans-6-alkoxy-5-fluoro-5,6-dihydro-5'-O-acyluridine. 2 formula: [In the formula, R ₁ represents an aliphatic acyl group or aromatic acyl group having 2 to 10 carbon atoms, and R ₂ represents a saturated or unsaturated alkyl group having 1 to 20 carbon atoms. ] An antitumor agent containing trans-6-alkoxy-5-fluoro-5,6-dihydro-5'-O-acyluridine as an active ingredient.