JPH0639497B2 - Method for producing 5-fluorouracil-based polymer - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a 5-fluorouracil-based polymer, and more specifically, to polymerize a 5-fluorouracil derivative or a vinyl group-containing compound with the derivative. The present invention relates to a method for producing a characteristic 5-fluorouracil polymer.

(Prior Art) Conventionally, 5-fluorouracil has been known to significantly inhibit nucleic acid biosynthesis and prevent tumor cell growth,
It is widely used as an antitumor agent against various malignant tumors such as liver cancer, breast cancer and gastrointestinal cancer.

However, its antitumor activity is not always as clinically superior as that obtained with experimental tumors, and
Since a comparatively small amount shows serious side effects such as nausea, vomiting, and leukopenia, and is highly toxic, the administration of
It requires careful attention, and complicated methods such as multiple administrations in small doses are taken. However, such an administration method increases the burden on the patient, and
There were problems such as side effects and the possibility of acute toxicity.

As a method for solving these problems, recently, if 5-fluorouracil is polymerized, it is gradually released in the body, its blood concentration is kept constant, and the duration of antitumor activity is improved. It has been found that its distribution in the body changes and side effects and toxicity are reduced, and based on that knowledge, studies on the polymerization of 5-fluorouracil have been actively conducted.
For example, a sugar furanose ring to which an acrylic acid residue is bound or N
Copolymers of 5-fluorouracil having an [-(3- (dimethylvinylsilyl) propyl] amide group and acrylamide are known, but the types thereof are few,
Also, the former dimethyl silicon type has a bulky structure, so it is difficult to obtain a homopolymer.
Development of a novel polymer using a monomer having high polymerization activity is desired.

(Problems to be Solved by the Invention) The inventors of the present invention have conducted earnest researches on such a demand, and as a result, 5-fluorouracil having a (meth) acryloyloxymethyl group at the 1-position has high polymerization activity. It has been found that the polymer can be easily polymerized with a vinyl group-containing compound to form a polymer, and that the polymer has excellent antitumor activity, and the present invention has been completed based on this finding.

(Means for Solving Problems) Thus, according to the present invention, the following formula (I)
Provided is a method for producing a 5-fluorouracil-based polymer, which comprises polymerizing a fluorouracil derivative or the derivative and a vinyl group-containing compound in the presence of a polymerization initiator.

(In the formula, R represents a hydrogen atom or a methyl group.) The monomer used in the present invention is a 5-fluorouracil derivative in which a (meth) acryloyloxymethyl group is bonded to the 1-position represented by the formula (I). Is.
The 5-fluorouracil derivative is a novel compound and can be obtained, for example, according to the following reaction formula.

(In the formula, R represents a hydrogen atom or a methyl group.) First, 5-fluorouracil and formalin are reacted by a conventional method to obtain 1,3-dihydroxymethyl-5-fluorouracil represented by the formula (II).

Separately, (meth) acrylic acid and thiophenol are reacted in a suitable solvent to obtain 3-phenylthiocarboxylic acid represented by the formula (III).

Next, the obtained 1,3-dihydroxymethyl-5-fluorouracil and 3-phenylthiocarboxylic acid are condensed in a suitable solvent in the presence of a condensing agent and a base to give the above formula (I
1- (3-phenylthiocarboxymethyl) -5-fluorouracil represented by V) is obtained.

In this reaction, most of 3-phenylthiocarboxylic acid reacts with the 1-position of 1,3-dihydroxymethyl-5-fluorouracil, and the hydroxymethyl group at the 3-position is removed as formalin. At this time, a small amount of 3-phenylthiocarboxylic acid reacted at the 3-position or the 1,3-position is produced, but these can be easily separated by a usual means such as column chromatography.

Specific examples of the solvent include acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, diethylformamide, methanol, ethanol, ethylene glycol, dichloromethane, chloroform, dichloroethane and the like.

Specific examples of the condensing agent include dicyclohexylcarbodiimide, diphenylcarbodiimide, hexamethylenecarbodiimide and the like.

Specific examples of the base include pyridine, quinoline, trimethylamine, triethylamine, tributylamine, ethyldiisopropylamine and the like.

The reaction conditions are not particularly limited, but usually the reaction temperature is 0 to
The reaction time is 30 ° C, preferably 5 to 25 ° C, and the reaction time is 5 to 30 hours, preferably 10 to 25 hours.

And 1- (3-phenylthiocarboxymethyl)-
The 5-fluorouracil derivative represented by the above formula (I) can be obtained by converting 5-fluorouracil into a sulfoxide with an oxidizing agent in a suitable solvent and then heating.

Specific examples of the solvent include methanol, ethanol, propanol, tert-butanol, ethylene glycol and the like.

Specific examples of the oxidizing agent include sodium periodate, hydrogen peroxide, peracetic acid, acyl sulfate, chromic acid, hydroperoxide, m-chloroperbenzoic acid and the like.

The 5-fluorouracil derivative is a (meth) acrylic acid halide and 1,3-dihydroxymethyl-5-
It can also be obtained by reacting with fluorouracil by a conventional method.

The polymer obtained in the present invention is a homopolymer obtained by polymerizing only the 5-fluorouracil derivative, or
It is a copolymer obtained by copolymerizing the derivative and a vinyl group-containing compound.

The vinyl group-containing compound used as a comonomer may be any as long as it can be copolymerized with the 5-fluorouracil derivative, and specific examples thereof include:
Unsaturated nitriles such as acrylonitrile, methacrylonitrile, α-acetoxyacrylonitrile, α-chloroacrylonitrile; unsaturated carboxylic acids such as acrylic acid, methacrylic acid, crotonic acid, itaconic acid, maleic acid, fumaric acid, citraconic acid; vinylimidazole , 2-
Nitrogen-containing vinyl compounds such as vinyl pyridine, 4-vinyl pyridine and N-vinyl pyrrolidone; methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate, methacryl Unsaturated carboxylic acid esters such as propyl acid, butyl methacrylate, 2-ethylhexyl methacrylate, dimethylaminoethyl methacrylate, diethylaminoethyl methacrylate; styrene compounds such as styrene, vinyltoluene, α-methylstyrene; ethylene, propylene, Ethylenically unsaturated monoolefins such as butylene; Diolefins such as butadiene, isoprene and piperylene; Vinyl halides such as vinyl chloride, vinylidene chloride and vinyl fluoride;
Examples thereof include vinyl esters such as vinyl acetate and vinyl propionate; vinyl ethers such as vinyl methyl ether and vinyl ethyl ether; vinyl ketones such as vinyl methyl ketone and methyl isopropenyl ketone.

The charging ratio of the monomers to be used is arbitrarily selected according to the antitumor activity of the desired polymer, the administration method, the administration form, the application site, etc., but usually, the 5-fluorouracil derivative is 1 to 100 mol%, vinyl. Group-containing compound 99
To 0 mol%, preferably 2 to 100 mol% of 5-fluorouracil derivative, 98 to 0 mol% of vinyl group-containing compound
Is.

Polymerization is carried out by a conventional method in the presence of a polymerization initiator in a suitable solvent of 5-fluorouracil or another compound containing vinyl group. Specific examples of the solvent used include benzene, toluene, xylene, p-dichlorobenzene, dimethylformamide, diethylformamide, acetonitrile, propionitrile, butyronitrile, benzonitrile and the like.

Specific examples of the polymerization initiator include azobis compounds such as α · α′-azobisisobutyronitrile and α · α′-azo-α-ethylbutyronitrile, quinumehydroperoxide and t-butylhydro. Organic peroxides such as peroxides, benzoyl peroxide, diisopropyl peroxydicarbonate, and t-butyl peroxybivalate, and radical polymerization initiators such as redox catalysts are exemplified, and other anions such as butyl lithium. A polymerization initiator may be used. The amount of such a polymerization initiator used is usually 0.05 to 10 parts by weight, preferably 0.1 to 100 parts by weight, per 100 parts by weight of the monomer component.
5 parts by weight.

The polymerization temperature is usually -40 to 200 ° C, preferably 30 to 1
00 ° C., the time is 1 to 100 hours, preferably 10
~ 40 hours.

The homopolymer or copolymer thus obtained is a polymer having a number average molecular weight of about 1,000 to several hundreds of thousands.

The polymer of the present invention obtained as described above has excellent antitumor activity and is useful as an antitumor agent against various malignant tumors.

(Effect of the invention) Thus, according to the present invention, a homopolymer or a copolymer with a vinyl group-containing compound can be easily obtained by using a 5-fluorouracil derivative having a high polymerization activity.

(Example) Hereinafter, the present invention will be described more specifically with reference to Examples.

Reference Example 1 (1) Synthesis of 1,3-dihydroxymethyl-5-fluorouracil 100 mmol 5-fluorouracil and 35% formalin 2
After stirring 20 mmol with 60 mmol for 30 minutes, water was distilled off under reduced pressure to obtain 100 mmol of oily 1,3-dihydroxymer-5-fluorouracil (yield 100%).

(2) Synthesis of 3-phenylthiopropionic acid 150 mmol of acrylic acid and 115 mmol of thiophenol were added to 100 ml of chloroform, 130 mmol of triethylamine was added dropwise in an ice bath, and the mixture was stirred for 1 hour and then overnight at room temperature. Chloroform was added to the new one and 1N
After washing twice with hydrochloric acid and once with saturated saline, the chloroform layer was dried over anhydrous sodium sulfate, and after that, chloroform was distilled off under reduced pressure to obtain 100 mmol of 3-phenylthiopropionic acid (yield 67%). Obtained.

(3) 1- (3-phenylthiopropionyl oxymer)
Synthesis of 5-fluorouracil Dissolve 115 mmol of 3-phenylthiopropionic acid in 150 ml of dimethylformamide, add 100 mmol of 1,3-dihydroxymethyl-5-fluorouracil, 110 mmol of dicyclohexylcarbodiimide and 1 mmol of 4-dimethylaminopyridine, and stir at room temperature overnight. did. Pass the insoluble matter, add methylene chloride to the solution, and add 2 with 1N hydrochloric acid.
After washing once with saturated saline and once with methylene chloride, the methylene chloride layer was dried over anhydrous sodium sulfate, and methylene chloride was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1),
When recrystallized with methylene chloride-hexane, 1- (3
32 mmol (yield 33%) of -phenylthiopropionyloxymethyl) -5-fluorouracil was obtained.

(4) Synthesis of 1- [3- (benzenesulfonyl) propionyloxymethyl] -5-fluorouracil 1- (3-phenylthiopropionyloxymethyl)-
5-fluorouracil (32.7 mmol) in methanol (70 ml)
Dissolved in water and added with sodium periodate (40.4 mmol) in an ice bath, and then stirred at room temperature for a whole day and night, and added methylene chloride,
It was washed twice with a 20% aqueous sodium hydrogen sulfite solution, and the methylene chloride layer was dried over anhydrous sodium sulfate. After the
Methylene chloride was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride: methanol =
20: 1), the amorphous 1- [3-
(Benzenesulfonyl) propionyloxymethyl]-
31 mmol (yield 96%) of 5-fluorouracil was obtained.

(5) Synthesis and physical properties of 1-acryloyloxymethyl-5-fluorouracil 31-mmol of 1- [3- (benzenesulfonyl) propionyloxymethyl] -5-fluorouracil was heated under reflux in 100 ml of acetonitrile for 26 hours, and then under reduced pressure. Acetonitrile was distilled off, and Rf value = by silica gel column chromatography (ethyl acetate: hexane = 1: 1).
A 0.35 portion was collected and recrystallized from methylene chloride-hexane to give 1-acryloyloxymethyl-
16 mmol of 5-fluorouracil (yield 52%) was obtained.

The physical property values are shown below.

m. p. 107-109 ° C NMR (DMSO, CDCl ₃ , CCl ₄ ): δ (ppm) 5.71 (s, 2H, d, e) 5.90-6.15 (m, 2H, a, b) 5.50 (dd, 1H, Jbc = 15Hz, Jac = 4Hz, c) 7.74 (d, 1H, J = 7Hz, f) 11.74 (b, 1H, g) IR (nujol) (cm ^-1 ) Reference Example 2 0.523 mmol of 1,3-dihydroxymethyl-5-fluorouracil was dissolved in 1 ml of acetonitrile, 0.575 mmol of acrylic acid chloride was added, and 0.627 mmol of ethyldiisopropylamine was added dropwise. Then 35
The mixture was stirred for 8 hours at 0 ° C., 1N hydrochloric acid and 5 ml of methylene chloride were added for liquid separation, the aqueous layer was removed, 5 ml of 1N hydrochloric acid was added again for liquid separation, and the methylene chloride layer was dried over anhydrous magnesium sulfate. After that, methylene chloride was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1) to fractionate an Rf value = 0.35 and recrystallized from methylene chloride-hexane. I did 1
0.148 mmol (yield 28.3%) of -acryloyloxymethyl-5-fluorouracil was obtained.

Reference Example 3 1,3-Dihydroxymethyl-5-fluorouracil 5
0 mmol and 50 mmol of methacrylic acid chloride were dissolved in 70 ml of acetonitrile, 100 mmol of ethyldiisopropylamine was added dropwise in the presence of hydroquinone, and the mixture was stirred at 35 ° C. for a whole day and night, and then the same procedure as in Example 2 was repeated to perform silica gel column chromatography (ethyl acetate: hexane). = 1:
In 1), the Rf value = 0.40 was collected and methylene chloride-
When recrystallized from hexane, 20 mmol of 1-methacryloyloxymethyl-5-fluorouracil (yield 3
9%) was obtained.

The physical property values are shown below.

m. p. 116-117 ° C NMR (CDCl ₃ , CCl ₄ ): δ (ppm) 1.96 (s, 3H, c) 5.72 (s, 3H, a, d, e) 6.22 (s, 1H, b) 7.69 (d, J = 7Hz, 1H, f) 9.59 (b, 1H, g) IR (nujol) (cm ^-1 ) Example 1 1-acryloyloxymethyl-5-fluorouracil 1.66 mmol and azobisisobutyronitrile 0.08
After adding 3 mmol to 53 ml of benzene, it was freeze-deaerated three times with dry ice-acetone. Next, after heating under reflux for 2 hours in a nitrogen atmosphere, the precipitate was filtered and washed with methylene chloride, and poly-1-acryloyloxymethyl-5-fluorouracil 258 mg (yield 72
%)was gotten.

The physical property values are shown below.

・ Intrinsic viscosity in dimethyl sulfoxide solution at 23 ° C [η] = 0.315 ・ IR (KBr) 1660 cm ^-1 1720 cm ^-1 Example 2 Predetermined amount of 1-acryloyloxymethyl- shown in Table 1
6 × 1 of 5-fluorouracil, acrylonitrile, and azobis (isobutyronitrile) per 1 mmol of all monomer components
After adding 0 ⁻⁴ mmol to 3 ml of benzene, it was freeze-deaerated 5 times with dry ice-acetone. Then, the mixture was heated under reflux in a nitrogen atmosphere for a predetermined time, and then the precipitate was filtered and washed with methylene chloride to obtain a copolymer of 1-acryloyloxymethyl-5-fluorouracil and acrylonitrile.

The physical property values are shown below.

Example 3 Predetermined amount of 1-acryloyloxymethyl- shown in Table 2
5-fluorouracil, acrylic acid, and azobisisobutyronitrile were added at 8 × 10 ⁻³ per 1 mmol of all monomer components.
After adding mmol to 3 ml of benzene, it was freeze-deaerated 5 times with dry ice-acetone. Next, after heating and refluxing for a predetermined time in a nitrogen atmosphere, the precipitate was filtered and washed with methylene chloride, and 1-acryloyloxymethyl-
A copolymer of 5-fluorouracil and acrylic acid was obtained.

The physical property values are shown below.

Example 4 Predetermined amount of 1-acryloyloxymethyl- shown in Table 3
8-fluorouracil, vinylimidazole, and azobisisobutyronitrile were added in 8 × per 1 mmol of all monomer components.
After 10 ⁻³ mmol was added to 3 ml of benzene, it was freeze-deaerated 5 times with dry ice-acetone. Next, the mixture was heated under reflux in a nitrogen atmosphere for a predetermined time, and then the precipitate was filtered and washed with methylene chloride to obtain a copolymer of 1-acryloyloxymethyl-5-fluorouracil and vinylimidazole.

The physical property values are shown below.

Test Example 1 Antitumor Effect Male BDF ₁ strain mice (5 weeks old) were intraperitoneally transplanted with 1 × 10 ⁶ L-1210 mouse leukemia cells / mouse, and 100 mg of the compound of the present invention obtained in the previous example / Kg was intraperitoneally administered once a day for 5 consecutive days from the day after the next day. The determination of antitumor activity was performed by the life extension rate (hereinafter abbreviated as ILS) represented by the following formula.

The results are summarized in Table 4.

Claims (1)

[Claims] 1. A 5-fluorouracil derivative represented by the following formula (I), or the derivative and a vinyl group-containing compound are polymerized in the presence of a polymerization initiator.
-Method for producing fluorouracil-based polymer. (In the formula, R represents a hydrogen atom or a methyl group.)