JPH0344378A - Production of 5-fluorouracil derivative and polymer thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is H or CH3). EXAMPLE:1-Acryloyloxyethylcarbamoyl-5-fluorouracil. USE:A medicine and monomer for producing 5-fluorouracil derivative-based homopolymers or copolymers, excellent in antitumor activity, having high polymerization activity and useful as an antitumor agent for various malignant tumors. PREPARATION:A propionyl halide expressed by formula II (X and X' are halogen) is esterified with ethanolamine expressed by formula VI in a solvent according to a conventional method to form a compound expressed by formula III, which is subsequently reacted with phosgene and converted into an isocyanate to afford a compound expressed by formula IV. The resultant compound expressed by formula IV is then subjected to dehydrohalogenating reaction in the coexistence of a reaction initiator and a dehydrohalogenating agent in a solvent to produce a compound expressed by formula V, which is subsequently reacted with a compound expressed by formula VII in the presence of a polymerization inhibitor in a solvent to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel 5-fluorouracil derivative and a method for producing a 5-fluorouracil polymer using the same as a monomer.

(Prior art) 5-fluorouracil has been known to significantly inhibit nucleic acid biosynthesis and inhibit cell proliferation by 1111%, and has antitumor effects against various malignant tumors such as liver cancer, breast cancer, and gastrointestinal cancer. It is widely used as an agent.

However, its antitumor activity in clinical settings is not necessarily as good as that obtained in experimental tumors;
In addition, even in relatively small amounts, they exhibit serious side effects such as nausea, vomiting, and decreased white blood cells, and they are also highly toxic.

In order to solve these problems, research has been conducted on 5-fluorouracil derivatives. For example, 1 hexyl carba
Derivatives such as moyl-5-fluorouracil have been developed, but they do not have sufficient antitumor activity and are transient, requiring many administrations, resulting in burden on patients and side effects.
These derivatives are not sufficient in terms of acute toxicity, and there is a need for the development of newer derivatives.

On the other hand, methods of administering polymerized 5-fluorouracil as a means of sustaining antitumor activity and reducing side effects and toxicity are known, and various studies are being conducted. For example, sugar furanose rings with acrylic acid residues and N-
(Copolymers of 5-fluorouracil and acrylamide having a 3-(dimethylvinylsilyl)propyl core group are known, but there are only a few types of them, and the former dimethyl silicone type has a bulky structure. Therefore, the development of new polymers using monomers with high polymerization activity is desired because it is difficult to obtain homopolymers.

(Problems to be Solved by the Invention) As a result of intensive research in response to these demands, the present inventors found that a novel 5-fluorouracil having a (meth)acryloyloxyethylcarbamoyl group at the 1-position has high polymerization activity and is homogeneous. We discovered that polymers or copolymers with other vinyl group-containing compounds are suitable as base materials, and that they have excellent antitumor activity either by themselves or when made into polymers. Based on this knowledge, we developed this book. The invention was completed.

(Means for Solving the Problems) Thus, according to the present invention, as the first invention, the following formula (I
) 5-fluorouracil derivatives are provided.

(In the formula, R represents a hydrogen atom or a methyl group.) In addition, as a second invention, the 5-fluorouracil derivative represented by the above formula (I), or the derivative and a vinyl group-containing compound are combined in the presence of a polymerization initiator. Provided is a method for producing a 5-fluorouracil-based polymer, which comprises subpolymerizing the 5-fluorouracil polymer.

The 5-fluorouracil derivative of the present invention is a novel compound that has not been described in any literature, and can be obtained, for example, according to the following reaction method.

(It) (III) H2 CC0CHzCHJCO (V) (I) (In the formula, R represents a hydrogen atom or a methyl group, and X and X' represent a halogen atom.) First, propionyl halide represented by the above formula (n) A propiokyloxyethyleneamine represented by the above formula (I[[) can be obtained by esterifying the compound with ethanolamine in a suitable solvent according to a conventional method. Specific examples of the solvent include benzene, toluene, xylene, dioxane, tetrahydrofuran, dichloromethane, chloroform, tetrahydrofuran, ethylene glycol monomethyl ether, and the like.

The reaction temperature is usually O~200''C1, preferably 20~12
0″C1 reaction time is 0.2 to 10 hours, preferably 0.2 to 10 hours.
5 to 5 hours.

Next, phosgene is added to the reaction system to cause an isocyanation reaction, thereby obtaining propionyloxyethyl isocyanate represented by the above formula (TV).

The reaction temperature is usually -20~200''C1, preferably 0~1
The 20''C1 reaction time is usually 0.1 to 10 hours, preferably 0.5 to 2 hours.

Next, the obtained propionyloxyethyl isocyanate is subjected to a dehydrohalogenation reaction in an appropriate solvent in the coexistence of a reaction initiator and a dehydrohalogenating agent, resulting in the (meth) compound represented by the above formula (V). Acryloyloxyethyl isocyanate is obtained.

Specific examples of solvents include quinoline, pyridine, benzene,
Examples include toluene and xylene.

Specific examples of the reaction initiator include anthraquinone, naphthoquinone, and 9,10-phenanthroquinone.

Specific examples of dehydrohalogenating agents include quinoline, pyridine, piperidine, 1,5-diazabicyclo[4,3,0
]Nonene-5,1,8-diazabicyclo[5,4,Ol
Examples include undecene-7.

The reaction temperature is usually 20-300'C1, preferably 100'C1
~200°02 reaction time is usually 0.5 to 10 hours, preferably 1 to 4 hours.

The formula (I) is then reacted with (meth)acryloyloxyethyl isocyanate and 5-fluorouracil in an appropriate solvent in the presence of a polymerization inhibitor.
A 5-fluorouracil derivative represented by can be obtained.

Specific examples of the solvent include pyridine, quinoline, hexane, benzene, toluene, xylene, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, dichloromethane, dichloroethane, and the like.

Specific examples of polymerization inhibitors include hydroquinone, 2.5-dibutylhydroquinone, tert-butylcatechol, 4,4'-dioxydiphenyl, phenyl-α-naphthylagon, N,N'-diphenyl-P-phenylenecyamine. , aldol-α-funatiruahin, 2-mercaptobenzimidazur, and the like.

The reaction temperature is usually O~100''C2, preferably 10~6
The 0''C2 reaction time is usually 0.1 to 20 hours, preferably 1 to 6 hours.

The 5-fluorouracil derivative of the present invention thus obtained has excellent antitumor activity and high polymerization activity, so it is suitable as a monomer for forming a homopolymer or a copolymer with other vinyl group-containing compounds. be.

Any vinyl group-containing compound used as a comonomer may be used as long as it is copolymerizable with the 5-fluorouracil derivative, and specific examples thereof include, for example,
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; Dazole, 2-
Nitrogen-containing vinyl compounds such as vinylpyridine, 4-vinylpyridine, N-vinylpyrrolidone; 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, and diethyl 5-noethyl methacrylate; Saturated carboxylic acid amides; Styrenic compounds such as styrene, vinyltoluene and α-methylstyrene; Ethylenically unsaturated monoolefins such as ethylene, propylene and butylene; Diolefins such as butadiene, isoprene and piperylene; Vinyl chloride, vinylidene chloride, Hinyl halides such as vinyl fluoride;
Vinyl esters such as vinyl acetate and vinyl propionate; vinyl ethers such as vinyl methyl ether and vinyl ethyl ether; and vinyl ketones such as vinyl methyl ketone and methyl isopropenyl ketone.

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

Polymerization is carried out using the 5-fluorouracil derivative, or the same and another vinyl group-containing compound in a suitable solvent in the presence of a polymerization initiator according to a conventional method.

Specific examples of the solvent used include methylene chloride, chloroform, methanol, ethanol, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, p-dichlorobenzene, dimethylformamide, diethylformamide, acetonitrile, propionitrile, Examples include butyronitrile and benzonitrile.

Specific examples of the polymerization initiator include azobis compounds such as α,α'-azobisisobutyronitrile, α,α-ab-α-ethylbutyronitrile, cumene hydroperoxide, and t-butyl hydroperoxide. Examples include radical polymerization initiators such as organic peroxides such as benzoyl peroxide, diisopropyl peroxydicarbonate, and t-butyl peroxybivalate, and redox catalysts, as well as anionic polymerization initiators such as butyl lithium. Examples include agents.

The amount of such polymerization initiator used is usually 10% of the monomer component.
The amount is 0.01 to 10 parts by weight, preferably 0.05 to 5 parts by weight.

Polymerization temperature is usually -40~200''C1, preferably 30~
100'C, and the time is 1 to 100 hours, preferably 10 to 40 hours.

The homopolymer or copolymer thus obtained has a number average molecular weight of about 11,000 to several hundred thousand.

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.

(Effects of the Invention) Thus, according to the present invention, it is possible to obtain a 5-fluorouracil derivative having excellent antitumor activity and high polymerization activity, and furthermore, it is possible to easily obtain a 5-fluorouracil-based polymer by using it as a monomer. .

(Example) The present invention will be described in more detail with reference to Examples below. Note that the percentages in the examples are based on weight unless otherwise specified.

Example 1 (I) Synthesis of 3-chloropropionyloxyethyl isocyanate ester Ethanolamine hydrochloride 185111R under nitrogen atmosphere
Add 50mfi of toluene to 101 and heat to 90°C.
3-chloropropionyl chloride 185mmo there
1 was added dropwise, and the mixture was stirred under reflux for 2.5 hours.

Then, the temperature was returned to room temperature, and 185 mm of phosgene dimer was added.
After adding 1 and heating to 100"C, 110 mmol of phosgene dimer was added. Toluene was distilled off and vacuum distillation was performed to obtain 25.9 g of 3-chloropropionyloxyethyl isocyanate (yield: 79 %) obtained.

(2) Synthesis of acryloyloxyethyl isocyanate ester Under nitrogen atmosphere, 3-chloropropionyloxyethyl isocyanate 145 mn+ol, quinoline 17.
4mjl! and 1.16 mmol of anthraquinone
After stirring at 60°C for 2 hours, vacuum distillation was performed to obtain 14.3 g (yield: 70%) of acryloyloxyethyl isocyanate.

(3) I-acryloyloxyethylcarbamoyl-5
- Synthesis and physical properties of fluorouracil under nitrogen atmosphere, 5
-Fluorouracil 0.43 + amo I% hydroquinone 0.02 mw + of, pyridine 0.5 ml and acryloyloxyethyl isocyanate 0.43
After stirring mmol at room temperature for 3 hours, pyridine was distilled off, and 1N hydrochloric acid and ethyl acetate were added to separate the layers. The oil layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain l-acryloyloxyethylcarbamoyl-
5-fluorouracil 9 (I8 mg (yield 79%)) was obtained.

The physical property values are shown below.

Melting point 140-142°C NMR [(CTo) 2SO, CDCl,, CCf!
,,, 100MHz]: δ (ppm) 3.66 (q
, 2H, J=6Hz, Hd, He) IR (Nujol)
:ci-' 3330 (-CONH-) 1730 (
-QC-)1690 (-CONH-) Example 2 Under nitrogen atmosphere, 1-acryloyloxyethylcarbamoyl-5-fluorouracil 7,54 mmol and α
, α'-azobisisobutyronitrile 0.42 mmol
was added to 60mj2 of methylene chloride and heated under reflux for several hours, and the precipitate was filtered and washed with methanol, resulting in poly-1-acryloyloxyethylcarbamoyl-5-
378 mg (yield 18%) of fluorouracil was obtained. The intrinsic viscosity of this peach (23°C5 dimethyl sulfoxide was 0.38).

Example 3 The procedure of Example 2 was carried out using the predetermined amounts of 1-acryloyloxyethylcarbamoyl-5-fluorouracil, comonomer, and methylene chloride shown in Table 1, except for heating and refluxing for the predetermined time. A copolymer having the composition shown in Table i was obtained. Conversion rate (%) is the first
Shown in the table. However, as a polymerization initiator, α,α'-azobisophthyronitrile should be used at a concentration of 0 per 1 mmol of all monomer components.
．． 005+wmol was used.

*1: 1-acryloyloxyethylcarbamoyl-5
-Fluorouracil: comonomer 〇 composition ratio was calculated by elemental analysis.

*2: 1-acryloyloxyethylcarbamoyl-5
- Conversion rate (%) relative to fluorouracil is shown.

From Examples 2 and 3, the 5-fluorouracil derivative of the present invention has high polymerization activity and is a 7-fluorouracil derivative that forms a homopolymer or a copolymer with other vinyl group-containing compounds.
It can be seen that it is excellent as

Test Example 1 6 L-1210 mouse leukemia cells IXIO/mouse were intraperitoneally transplanted into a male BDF strain mouse (5 weeks old), and 1-acryloyloxyethylcarbamoyl obtained in Example 1 above was implanted. -5-Fluorouracil 100 mg/K
G was orally administered once a day for 5 consecutive days starting from the day after the next day.

The antitumor activity is determined by the survival rate (IL
(abbreviated as S), ILS=37%
Met.

Life extension rate (ILS%) - Experimental example 2 - Test example except that 30 mg/Kg of acryloyloxyethylcarbamoyl-5-fluorouracil and a 5-fluorouracil-based polymer made from the comonomers shown in Table 2 were administered intracavitally. The same procedure as in 1 was performed to determine antitumor activity.

The results are shown in Table 2.

Table *4: 1-Acryloyloxyethylcarbamoyl-5
- Fluorouracil: The &I ratio of the comonomer was calculated by elemental analysis.

Test Examples 1 and 2 show that the 5-fluorouracil polymer obtained by the method of the present invention has high antitumor activity.

Claims (1)

[Claims] 1. A 5-fluorouracil derivative represented by the following formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (In the formula, R represents a hydrogen atom or a methyl group.) 2. The 5-fluorouracil derivative according to claim 1, or the derivative and a vinyl group-containing compound. A method for producing a 5-fluorouracil polymer, which comprises polymerizing in the presence of a polymerization initiator.