JPS591726B2 - Method for producing a polymer compound with anticancer properties - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a novel polymer compound that exhibits long-lasting anticancer properties.

To be more specific, the present invention provides a formula force O...
(I) This invention relates to a method for producing a water-soluble polymer having an arabinofuranosylcytosine residue represented by -゜゜Re.

Arabinofuranosylcytosine C is known as an anticancer drug that is effective against leukemia, but when administered, it rapidly degrades in the body and loses its efficacy, so in order to maintain its efficacy over a long period of time, It has the inconvenience of having to be administered continuously through an intravenous drip or the like. On the other hand, as a means for sustaining the efficacy of pharmaceuticals, a method is known in which an active ingredient is bound to a suitable polymer and the polymer is gradually released within the body.

As for arabisofuranosylcytosine, a method has been proposed in which it is made into a polymer by reacting it with a polymer having a carboxyl group in the presence of carbodiimide.

However, this method has limitations on the introduction rate of arabinofuranosylcytosine, making it difficult to achieve an introduction rate of 60% by weight or more, and also limits the types of polymers that can be used. The disadvantage is that the polymer cannot be selected. In order to overcome the drawbacks of such conventional long-lasting derivatives of arabinofuranosylcytosine, the present inventors have conducted extensive research and have first produced a polymerizable derivative of arabinofuranosylcytosine, If this is polymerized alone or in combination with other copolymerizable monomers,
We have discovered that the introduction rate of active ingredients can be increased and controlled as desired, and based on this knowledge, we have accomplished the present invention. That is, the present invention provides 2 to 60 mol% of an arabinofuranosylcytosine derivative represented by the general formula (R in the formula is a hydrogen atom or a methyl group),
Provided is a method for producing a polymeric compound having anticancer properties, characterized by copolymerizing with 98 to 40 mol% of a monomer that produces a water-soluble polymer when polymerized alone. .

The arabinofuranosylcytosine derivative of the general formula () used in the method of the present invention is a novel compound that has not been described in any literature, and is obtained by reacting, for example, acrylic acid or methacrylic acid or a reactive derivative thereof with arabinofuranosylcytosine. Manufactured by Examples of monomers that produce water-soluble polymers when polymerized alone include N-vinylpyrrolidone, 2-vinylpyridine-N-oxide, 2-(methylsulfinyl)ethyl methacrylate, 2- (methylsulfinyl)ethyl acrylate,
At least one selected from acrylamide, hydroxylethyl methacrylate, and hydroxylethyl acrylate is used.

The arabinofuranosylcytosine derivative of the general formula () is used in an amount of 2 to 60 mol% of the total amount of monomers.

If this amount is less than 2 mol%, the anticancer effect will not be sufficient, and if it is more than 60 mol%, sufficient sustainability will not be exhibited. In order to suitably carry out the method of the present invention, a predetermined proportion of the arabinofuranosylcytosine derivative of the general formula () and the monomer that produces a water-soluble polymer when polymerized alone is mixed with a solvent such as water. , 20-70 for alcohol
% concentration, add a polymerization initiator, and react while heating.

In this case, it is advantageous to carry out the reaction in an inert atmosphere, such as argon, helium, nitrogen or the like. As the polymerization initiator, those commonly used in radical polymerization such as peroxides such as peracetic acid, benzoyl peroxide, and persulfates, azobisisobutyronitrile, and redox catalysts are used. The reaction temperature used is in the range of 40 to 100°C, and the reaction time varies depending on the monomers used, the polymerization initiator, and the reaction temperature, but is usually in the range of 30 minutes to 10 hours. After the reaction is completed, the product is separated from the reaction mixture by a reprecipitation method, purified, and then freeze-dried from the aqueous solution to obtain the desired polymer compound as a white flocculent material. This polymer compound is a water-soluble substance having an average molecular weight in the range of about 10,000 to 100,000. Since this polymer compound has the property of gradually releasing arabinofuranosylcytosine C in water, it is suitable as a long-lasting anticancer agent. Next, the present invention will be explained in more detail with reference to Reference Examples and Examples. Reference example 1 2.2t of arabinofuranosylcytosine C in 20ml of water
Dissolve and further add dioxane 6077!11.

Next, 2.8f of methacrylic anhydride was added to this mixture,
Stir at room temperature for 48 hours to complete the reaction. Next, the reaction mixture was concentrated under reduced pressure at room temperature, and the concentrated solution was added dropwise into n-hexane, and the precipitate deposited was filtered off. This precipitate is dissolved in 100 ml of water, passed through a cation exchange resin to remove impurities, and the resulting solution is freeze-dried. By recrystallizing the residue from a mixture of methanol and ether, N
-Methacryloyl-1,β,D-arabinofuranosylcytosine is obtained as white needle-like crystals with a melting point of 144-146°C. Reference example 2 Acrylic anhydride instead of methacrylic anhydride 2.87.
No. 37 was used and operated in exactly the same manner as in Reference Example 1, and the melting point was 121.
N-acryloyl- as white needle-like crystals at ~123°C
1,β,D-arabinofuranosylcytosine was obtained.

Example 1 13.47% of N-methacryloyl-1,β,D-arabinofuranosylcytosine obtained in Reference Example 1 and 6.37% of N-vinylpyrrolidone were mixed with 50% of water. 0.17 ammonium persulfate was added thereto, and the mixture was reacted at 70° C. for 5 hours in an argon atmosphere.

Concentrate the reaction mixture, pour the concentrate into ethanol,
The generated precipitate was collected by filtration, further purified by repeating dissolution in water and reprecipitation from ethanol, and then lyophilized from water to obtain a copolymer with an arabinofuranosylcytosine C content of approximately 43% by weight. Obtained as a white floc. The intrinsic viscosity of this product at 30° C. was 0.16, and the average molecular weight determined by a light scattering method was about 16,000.

Other physical properties of this product are as follows. Elemental analysis values: Ultraviolet absorption spectrum: Maximum solubility at 305, 250 nm: Soluble Water (1.2t/Me), Dimethyl sulfoxide Insoluble Ethanol Also, the infrared absorption spectrum of this product is shown in FIG.

Example 2 Using an equimolar mixture of N-acryloyl-1,β,D-arabinofuranosylcytosine obtained in Reference Example 2 and N-vinylpyrrolidone, arabino- A copolymer having a furanosylcytosine C content of about 50 mol% was obtained.

The average molecular weight of this product was about 25,000. Reference Example 3 Copolymer 27 obtained in Example 1 was adjusted to pH 7.

2 in 100 d of 0.01M phosphate buffer,
The release rate of arabinofuranosylcytosine C at 7°C was determined from the rate of decrease of the maximum point at 305 nm in the ultraviolet absorption spectrum.

The results are shown in FIG. 2 as a graph. As is clear from this graph, arabinofuranosylcytosine C is released at a rate of 2% per day, and this continues for more than two weeks.

[Brief explanation of drawings]

FIG. 1 is an infrared absorption spectrum diagram of the polymer compound obtained according to the present invention, and FIG. 2 is a graph showing the release rate of the active ingredient for the polymer compound.

Claims (1)

[Claims] 1 2 to 60 mol% of an arabinofuranosylcytosine derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R in the formula is a hydrogen atom or a methyl group);
A method for producing a polymer compound having anticancer properties, which comprises copolymerizing a monomer with 98 to 40 mol% of a monomer that produces a water-soluble polymer when polymerized alone. 2 Monomers that produce water-soluble polymers when polymerized alone are N-vinylpyrrolidone, 2-vinylpyridine-
Claim 1 is at least one selected from N-oxide, 2-(methylsulfinyl)ethyl methacrylate, 2-(methylsulfinyl)ethyl acrylate, acrylamide, hydroxylethyl methacrylate, and hydroxylethyl acrylate. the method of.