JPS6081197A - 5-fluorouridine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A high-molecular weight 5-fluorouridine derivative of formula I (n>=2) and a salt thereof. USE:A carcinostatic agent having improved prolonged release properties of the 5- fluorouridine and low toxicity. PREPARATION:Divinyl ether-maleic anhydride copolymer of formula II is reacted with 5-fluorouridine of formula III in the presence of an organic solvent, e.g. N-methylpyrrolidone, and the resultant reaction product is then hydrolyzed. Substances other than the aimed substance are then removed by ultrafiltration, etc., and the resultant reaction product is freeze-dried, etc. to afford the aimed compound of formula I . The content of the 5-fluorouridine in the resultant high- molecular weight derivative is preferably 5-40wt%.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a 5-fluorouridine derivative, which is a novel compound, and a method for producing the same, and more specifically, a high molecular weight 5-fluorouridine derivative with low toxicity and excellent anticancer effect, and a method for producing the same. It is related to.

Some nucleic acid derivatives have excellent anticancer effects, especially 5-fluorouranol and its related compounds against solid tumors, and 1-β-D-arabinofuranosiltone against leukemia. The effect is remarkable,
These are widely used clinically.

However, these anticancer active substances 1 have excellent anticancer effects and at the same time are strong against normal cells.
Therefore, when using it, it is necessary to be careful about side effects, and therefore, complicated methods such as applying a small amount of force many times are used.

By the way, when the anticancer active substance, which is a low molecular compound as described above, is bound to a high molecular compound, the anticancer active substance is gradually released in the body and its concentration is kept constant.
It is expected that the distribution of oxda itself in the body will change, reducing its toxicity and increasing its anticancer effect.

In view of these circumstances, the present inventors have conducted extensive research on polymer compounds to which 5-fluorouridine, which has anticancer activity, is bound.As a result, the divinyl ether-maleic anhydride copolymer itself is excellent. It has an anticancer effect and has many acid anhydride structures in the molecule, so it easily reacts with the hydroxyl group in the 5-fluorouridine to form an ester bond. We have discovered that 5-fluorouridine, which is released gradually under mild conditions, is extremely excellent as a carrier for 5-fluorouridine, which is an anticancer active substance, and based on this knowledge, we have completed the present invention. reached.

That is, the present invention provides 5-fluorouridine compounds and their salts -7j with a general formula % (wherein n is an integer of 2 or more) with a high molecular weight of J<, and the presence of an organic solvent. Below, a vinyl ether-maleic anhydride copolymer represented by the general formula ((n in the formula is the same as above) is reacted with 5-fluorouridine represented by the formula, and then hydrolyzed to 1) A polymer represented by general formula (1) in item 11 [1:
The present invention provides a method for producing 5-fluorouridine derivatives and salts thereof.

The divinyl needle-maleic anhydride copolymer used in the present invention is a compound represented by the general formula (1),
It is obtained by copolymerizing divinyl ether and maleic anhydride according to a known method.

The hydrolyzate of divinyl ether-maleic anhydride copolymer itself has excellent anticancer effects against various tumors, especially those with a molecular weight of 100,000 or less, especially 3 or less. 11j is extremely low, and LDlo is also ro.
Omg/Kg or more, which is good.

Moreover, since the copolymer has many acid anhydride structures in its molecule, it can easily react with the hydroxyl group in 5-fluorouridine to form an ester bond.

The 5-fluorouridine used in the present invention has the formula (Il
13 The polymer of the present invention, which is a nucleic acid derivative represented by 5-fluorouridine+A and which does not have an excellent anticancer effect on solid tumors, is an organic compound such as N-methylpyrrolidone. Divinyl ether-maleic anhydride copolymer and 5-fluorouridine were reacted in the presence of a solvent and a catalyst such as triethylamine, and then hydrolyzed, and then anything other than the target product was removed by ultrafiltration etc. It can then be obtained by freeze-drying or the like. If desired, after the above hydrolysis, the salt may be converted into a pharmacologically acceptable salt such as sodium salt, potassium salt, calcium salt, or magnesium salt, and then subjected to ultrafiltration, freeze-drying, etc. It can also be extracted as salt.

The content E11 of 5-fluorouridine in the high molecular weight 5-fluorouridine derivative thus obtained is preferably in the range of 5 to 40% by weight.

In the high molecular weight 5-fluorouridine derivative of the present invention, the free carboxyl group acts as a catalyst to gradually cleave the ester bond even under mild conditions, and 5-fluorouridine is slowly released.

The polymeric 1115-fluorouridine derivative of the present invention is a novel compound, which has excellent sustained release properties of 5-fluorouridine, which is an anticancer active substance, and is low in weight. Due to the synergistic effect with the copolymer, 5-
It has a greater anticancer effect than when fluorouridine is used alone.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Note that the divinyl ether-maleic anhydride co-i1 combination is abbreviated as DIVEMA.

Example 1]) IVkMA (molecule fl'; 28,800)
20 (J mj) was added to 4 me of N-methylpyrrolidone (in a vessel, 240 my of 5-fluorouridine and 70.10 m of triethylamine were added, and the mixture was reacted by stirring at room temperature for 40 hours. After adding sodium bicarbonate to adjust the pH to 8, the mixture was left to stand for 2 hours.

Then, after adjusting the pH to 3 by adding IN hydrochloric acid, it was ultrafiltered using a diaflow membrane (YLA-S) to remove unreacted substances, organic solvents, and salts, and then freeze-dried! Target object:
Obtained 302 mg as a white powder. UV of this thing
Based on the absorption amount (λITIax-267-5rlm), the 5-fluorouridine content was 31.7% by weight. The infrared absorption spectrum of this product is shown in FIG.

Example 2 D Engineering VE MA (molecular weight 28,800) 50
0 mg of 11-methylpyrrolidone was dissolved in OmI2 of 11-methylpyrrolidone, 5-fluorouridine I o o my and 13+++ g of triethylamine were added, and the mixture was stirred and reacted at room temperature for 40 hours.

The reaction mixture was treated in the same manner as in Example 1 to obtain the desired product 7.
04 I ↓j +nf/. The 5-fluorouridine content of this product was 14.5% by weight. .

Reference Example 1 1 mg of the 5-fluorouridine-DIVKMA conjugate obtained in Example 1 was dissolved in 1 ml of physiological saline and kept at 37°C. A portion of the reaction solution was taken out at regular intervals and the amount of 5-fluorouridine released was determined using high performance liquid chromatography.1. The results are shown in FIG.

As is clear from the figure, the release of 5-fluorouridine was extremely slow, and it was found that about 55% of 5-fluorouridine was released in one week.

Reference Example 2 DiVEMA molecule -11 or 28.80 (1,5-fluorouridine (hrur+) has 3 abundances of 13 or 13, respectively)
3 wt%, 20 wt%, 15 wt% ir IJ R-
D ] VEM A conjugate was investigated for its anticancer properties.

That is, 74 L of CDE' at 8-10 weeks of age, 1
(Transfer 11 cells to 41 (t), and after 24 hours,
RD] Vli: A predetermined amount of the MA conjugate dissolved in physiological saline containing 2% sodium bicarbonate was injected into the abdominal cavity once.

The anticancer activity was evaluated using the following formula: % formula % () where T: Median number of days of survival in the treatment group C: Number of days of survival in the control group Based on the survival rate indicated by the median value and the proportion of surviving mice of 30 or more. went. The results are shown in the table below.

[Brief explanation of the drawing]

FIG. 1 is an infrared absorption spectrum diagram of the compound of the present invention, and FIG. 2 is a graph showing the amount of 5-fluorouridino released from the compound of the present invention over time.

Claims (1)

[Scope of Claims] 1. A polymer JIi represented by the general formula (in the formula, n is an integer of 2 or more): 5-fluorouridine derivatives and salts thereof. 2 In the presence of an organic solvent, a divinyl ether-maleic anhydride copolymer represented by the general formula (n in the formula is an integer of 2 or more) is reacted with 5-fluorouridine represented by the formula, and then hydrolyzed. A method for producing a high molecular weight 5-fluorouridine derivative represented by the general formula (in which n is the same as above) and salts thereof, which is then converted into a salt as desired.