5-FLUOROURACIL DERIVATIVES, PHARMACEUTICAL COMPOSITION AND USE

Abstract: A novel 5-fluorouracil derivative of the formula: wherein R¹ is a fluorine-containing C₁-C₁₀ organic group which optionally contains sulfur, oxygen and/or nitrogen, which is useful as a carcinostatic substance, which has high carconostatic activity but less toxicity against digestive tract and causes less automatic imbalance than other known 5-fluorouracil derivatives, a pharmaceutical composition containing the above 5-fluorouracil derivative as active ingredient, and use of the above 5-fluorouracil derivative in the preparation of a carcinostatic medicament are disclosed.

Description: BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to novel 5-fluorouracil derivatives, which are useful as carcinostatic substances. Description of the Prior Arts 5-Fluorouracil is known as a antimetabolite having a broad-spectrum antitumor activity and used in clinical therapy. However, it is highly toxic when orally administered and particularly accompanied with side effects such as disorders in gastrointestinal. To solve such drawbacks of 5-fluorouracil, many derivatives of 5-fluorouracil have been proposed. One of early developed derivatives is 1-(2-tetrahydrofuryl)-5-fluorouracil. Although this compound is less toxic, its carcinostatic activity is weak so that it is not yet good carcinostatic substance (cf. "Gan to Kagakuryouhou" (Cancer and Chemotherapy), 8 , No. 11, 1811 (1981)). To maintain the strong activity on one hand and to decrease the toxicity of 5-fluorouracil on the other hand, studies on the derivatives of 5-fluorouracil have been made. As a result, for example, 1-hexylcarbamoyl-5-fluorouracil was developed. This derivative is more suitable than the previous derivatives for oral administration, since it has stronger carcinostatic activity and lower toxicity against the gastrointestinal. However, since metabolites produced from 1-hexylcarbamoyl-5-fluorouracil by oxidation of the hexyl group in a liver causes autonomic imbalances such as frequency of feces, heat sensation and pollakiuria which are not found in the use of other 5-fluorouracil derivatives, practically this derivative should be used together with a tranquilizer (cf. Pharmacia, 16 , No. 6, 524-527 (1980)). GB-B-1524640 discloses 1-carbamoyl 5-fluorouracil derivatives represented by the general formula wherein R is an alkyl group containing from 3 - 8 carbon atoms. Such derivatives are disclosed as being useful in the treatment of tumors. SUMMARY OF THE INVENTION One object of the present invention is to provide novel 5-fluorouracil derivatives which are useful as carcinostatic substances having high activity but less toxicity. Another object of the present invention is to provide novel 5-fluorouracil derivatives which cause less side effects such as disorders in the digestive tracts and autonomic imbalance. Accordingly, the present invention provides a novel derivative of the formula: wherein R¹ is a group of the formula: -(CH₂) h -CH(R²)-CF₃ wherein R² is hydrogen or a C₁-C₄ aliphatic group, and h is an integer of 0 to 4; a group of the formula: -CH₂-(CR³₂) i -CHF₂ wherein R³ is hydrogen or fluorine, and i is an integer of 0 to 5; or a group of the formula: -(CH₂) j -CHF(R⁴) wherein R⁴ is hydrogen or methyl, and j is an integer of 1 to 4 since they have large therapeutic indexes (TI) and/or causes less autonomic imbalance. Preferred examples of the group R¹ are -CH₂CF₃, -(CH₂)₂CF₃, -(CH₂)₃CF₃, -(CH₂)₄CF₃, -(CH₂)₅CF₃, -CH₂CH(CH₃)CF₃, -CH₂CH(C₂H₅)CF₃, -CH₂CH(C₃H₇)CF₃, -CH₂CH(C₄H₉)CF₃, -(CH₂)₂CH(CH₃)CF₃, -CH₂CHF₂, -(CH₂)₂CHF₂, -(CH₂)₃CHF₂, -(CH₂)₄CHF₂, -(CH₂)₅CHF₂, -(CH₂)₄CH₂F and -(CH₂)₄CHFCH₃. Among them, -(CH₂)₂CF₃, -(CH₂)₃CF₃, -CH₂CH(CH₃)CF₃, -(CH₂)₂CH(CH₃)CF₃ and -(CH₂)₅CHF₂ are more preferred. The 5-fluorouracil derivative (I) of the present invention may be prepared by following method (i) or (ii): Method (i) : 5-Fluorouracil is successively reacted with phosgene (COCl₂) and a fluorine-containing amine of the formula: NH₂R¹ (II) wherein R¹ is the same as defined above as follows: wherein R¹ is the same as defined above. The first reaction of 5-fluorouracil with phosgene is effected by dissolving 5-fluorouracil in an organic base (e.g. pyridine, triethylamine and methylmorpholine) and blowing 1.2 to 2 equivalents of phosgene in the solution of 5-fluorouracil with cooling at -10 to +10°C. The second reaction with the fluorine-containing amine is effected by adding 1 to 1.5 equivalents of said amine to the reaction mixture of 5-fluorouracil and phosgene at -10 to +10°C. The fluorine-containing amine (II) may be prepared by, for example, converting a hydroxyl group and chlorine of a compound having the hydroxyl group and chlorine to fluorine and the amine group, respectively (cf. Bull. Chem. Soc. Jpn, 51 , 1267 (1978) and Angew. Chem. Int. Ed., 7 , 919 (1968)), or reducing a fluorine-containing primary amide with sodium borohydride or lithium aluminum hydride (cf. Tetrahedron Lett., 1969 , 4555). Method (ii) : A fluorine-containing carboxylic acid of the formula: R¹COOH (III) wherein R¹ is the same as defined above is reacted with diphenylphosphoryl azide to obtain an isocyanate of the formula: OCN-R¹ (IV) wherein R¹ is the same as defined above and reacting the isocyanate (IV) with 5-fluorouracil to obtain the 5-fluorouracil derivative (I) of the present invention. The fluorine-containing carboxylic acid (III) can be prepared by the method described in J. Am. Chem. Soc., 76 3722 (1954). When the fluorine-containing carboxylic acid (III), diphenylphosphoryl azide and 5-fluorouracil are mixed and heated in an organic solvent, the above two reactions proceed successively, it is not necessary to carry out these reactions stepwise. Examples of the organic solvent are pyridine, triethylamine, dimethylacetamide, dimethylformamide and mixtures thereof. Usually, the reaction temperature is from 10 to 110°C, and the reaction time is from 1 to 10 hours. The fluorine-containing carboxylic acid is used in an amount of 1 to 1.5 moles per mole of 5-fluorouracil, and diphenylphosphoryl azide is used in an amount of 1 to 1.5 moles per mole of 5-fluorouracil. The present invention will be illustrated by following examples. Examples 1-13 To a cold solution of 5-fluorouracil (2.6 g, 0.02 mole) in pyridine (50 ml) at -3 to +2°C, phosgene which was generated by dropping trichloromethyl chloroformate onto activated carbon (4 g, 0.02 mole) was introduced. After purging unreacted phosgene by blowing nitrogen in the mixture, a fluorine-containing amine shown in Table 1 (0.02 mole) was added to the mixture cooled at -5°C and stirred at the same temperature for one hour and then at room temperature for 30 minutes. After concentrating the reaction mixture under reduced pressure, ethyl acetate (200 ml) and 1N hydrochloric acid (50 ml) were added and stirred. Materials precipitated were filtrated off. The filtrate (the ethyl acetate phase) was recovered and evaporated to dryness under reduced pressure followed by purification by column chromatography using silica gel. The kind of the fluorine-containing amine used, the R¹ group contained in the product, a yield of the prosuct, results of ¹H- and ¹⁹F-NMR analyses of the product, ILS (%) and TI are shown in Table 1. The ILS and TI have common meanings in this field and are measured according to the methods described in Chem. Pharm. Bull., 26 , No. 1, 161-165 (1978) in which used were BDF type mice (female) (5 mice per group, an average weight of 16±2 g) inplanted by 1 x 10⁵ celles of lymphocytic leukemia L-1210 (National Cancer Institute type) and the product was orally administered. Examples 14-17 To a mixture of dimethylformamide (15 ml), 5-fluorouracil (1 g, 7.7 mmol), diphenylphosphoryl azide (2.2 g, 8 mmol) and triethylamine (5.1 g, 50 mmol), a fluorine-containing carboxylic acid shown in Table 2 (8 mmol) was added and reacted at 80°C for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. To the concentrated mixture, ethyl acetate (100 ml) and 1N hydrochloric acid (50 ml) were added and stirred. Materials precipitated were filtrated off. The filtrate (the ethyl acetate phase) was recovered and evaporated to dryness under reduced pressure followed by purification by column chromatography using silica gel with a mixed solvent of chloroform and ethanol in a volum ratio of 10:1. The kind of the fluoring-containing carboxylic acid, the R¹ group contained in the product, a yield of the product, results of ¹H- and ¹⁹F-NMR analyses of the product, ILS (%) and TI are shown in Table 2. As a solvent in the NMR analyses of the compounds, CDCl₃ was used in Examples 6, 8, 10, 11, 13, 16 and 17, and (CD₃)₂SO was used in other Examples. In ¹⁹F-NMR, trifluoroacetic acid was an external standard. For evaluation of suppression of autonomic imbalance by the compound of the present invention, according to the description of "Rinsho-yakuri" (Clinical pharmacology), 11 , No. 1, 17 and 27 (1980), (1) action on neutrons in a pretaminar part of the optic nerve which is a center for regulation of body temperature of rats and outside said part (a degree of caumesthesia) and (2) action on bladder movement of cats (frequency of uresiesthesia) were examined. From the results of these examinations, the compound having the R¹ group selected from the group consisting of -(CH₂)₂-CF₃, -(CH₂)₃CF₃, -CH₂CH(CH₃)CF₃, -(CH₂)₂CH(CH₃)CF₃ and -(CH₂)₄CHF₂ are found to have better effects. Comparative Examples 1 and 2 With a compound (I) wherein R¹ is -(CH₂)₅CH₃ (Comparative Example 1) or -CH₂(CF₂)₂CF₃ (Comparative Example 2), ILS and TI were measured. The results are shown in Table 3.

Claims: A 5-fluorouracil derivative of the formula: wherein R¹ is a group of the formula: -(CH₂) h -CH(R²)-CF₃ wherein R² is hydrogen or a C₁-C₄ aliphatic group, and h is an integer of 0 to 4; a group of the formula: -CH₂-(CR³₂) i -CHF₂ wherein R³ is hydrogen or fluorine, and i is an integer of 0 to 5; or a group of the formula: -(CH₂) j -CHF(R⁴) wherein R⁴ is hydrogen or methyl, and j is an integer of 1 to 4. The 5-fluorouracil derivative according to claim 1, wherein R¹ is -CH₂CF₃, -(CH₂)₂CF₃, -(CH₂)₃CF₃, -(CH₂)₄CF₃, -(CH₂)₅CF₃, -CH₂CH(CH₃)CF₃, -CH₂CH(C₂H₅)CF₃, -CH₂CH(C₃H₇)CF₃, -CH₂CH(C₄H₉)CF₃ or -(CH₂)₂CH(CH₃)CF₃. The 5-fluorouracil derivative according to claim 2, wherein R¹ is -(CH₂)₂CF₃, -(CH₂)₃CF₃, -CH₂CH(CH₃)CF₃ or -(CH₂)₂CH(CH₃)CF₃. The 5-fluorouracil derivative according to claim 1, wherein R¹ is -CH₂CHF₂, -(CH₂)₂CHF₂, -(CH₂)₃CHF₂, -(CH₂)₄CHF₂ or -(CH₂)₅CHF₂. The 5-fluorouracil derivative according to claim 4, wherein R¹ is -(CH₂)₅CHF₂. The 5-fluorouracil derivative according to claim 1, wherein R¹ is -(CH₂)₄CH₂F or -(CH₂)₄CHFCH₃. Pharmaceutical composition comprising the 5-fluorouracil derivative according to any of the preceding claims as active ingredient, and a pharmaceutically acceptable carrier. Use of any of the compounds according to claims 1 to 6 in the preparation of a carcinostatic medicament.

Inventors: IWAI, HIROYUKI, KAWANO, TOSHIHIKO, SHIMOKAWA, KAZUHIRO, YAMAMOTO, YOSHIHIRO, YOSHIZAWA, TORU
Applicants: DAIKIN INDUSTRIES, LIMITED
Application year: 1987
Main classification: C07D239
IPC codes: C07D239