JPH0340035B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, R ₁ is a hydrogen atom or a group

[Formula], R ₂ and R ₃ are the same or different, and are a hydrogen atom, a hydroxy group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms,
3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine represented by at least one atom or group selected from the group consisting of benzyloxy groups) The present invention relates to a derivative, a method for producing the same, and an antitumor agent containing the same. 2'-deoxy-5-fluorouridine (hereinafter
FUDR) and 5-fluorouracil (hereinafter referred to as 5-FU) are compounds used as anticancer agents, but the anticancer effects of these compounds are based on the cell-killing action of these compounds. (Remington's Pharmaceutical Sciences, 16th edition, page 1082, right column, 1980
Year). Therefore, these compounds act not only on cancer cells but also on normal cells, but the reason why these compounds are used as anticancer agents is because cancer cells divide at an extremely rapid rate.
This method takes advantage of the fact that, compared to normal cells that divide slowly, they are more strongly affected by the cell-killing effects of FUDR and 5-FU (ibid., loc. cit.). Currently, in order to obtain an anticancer effect in clinical treatment with anticancer drugs, it is necessary to administer the anticancer drug to the patient in an amount that causes toxicity (ibid. States・
Dispensatory, 27th edition, page 527, right column, 378
Page, left column, 1980, Cancer Medicine,
Page 675, left column, Lee and Huebiger,
Published in 1973). Therefore, of course, the main action, that is, the anticancer effect, is important for anticancer drugs, and its enhancement is desired, but the current goal is to reduce the toxicity of the anticancer drug, that is, to ensure its safety. It has also become an important issue that needs to be solved. However, since both the anticancer action and the toxicity of anticancer drugs are largely based on the cell-killing action that anticancer drugs have, it is possible to achieve the two objectives of strengthening anticancer action and reducing toxicity. It's not an easy thing to do. In particular, cells in the gastrointestinal tract and bone marrow, even if they become normal cells, are susceptible to the cytocidal effects of FUDR and 5-FU because they divide at a relatively rapid rate. It often manifests as a bone marrow disorder. Conventionally, many derivatives of FUDR have been synthesized, and the pharmacological activity of certain compounds among them has been reported. For example, British Patent Application Publication No. 2025401A describes a compound in which N at position 3 of FUDR is substituted with a specific benzoyl group, 3-(3,4-methylenedioxybenzoyl)-2'-deoxy-5 -Fluorouridine, etc. have been reported, and European Patent Application Publication No. 9882B1 describes 3',5'-di-O-acetyl-2'-deoxy-5-fluorouridine (hereinafter referred to as AcFUDR). 3-, which is a compound in which N at position 3 of ) is substituted with a specific benzoyl group.
(3-Methylbenzoyl)-3',5'-di-O-acetyl-2'-deoxy-5-fluorouridine and the like are described in detail along with experimental results of their anticancer activity and toxicity. Additionally, an experiment to synthesize 3-phenoxycarbonyl-3'-O-acetyl-5'-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine has been reported (Journal Ob.・Pharmaceutical Sciences, Volume 54, Pages 992, 994,
(1965). Generally, the dosage of an anticancer drug is extremely important because it is required to maximize its antitumor effect while minimizing toxicity. The relationship between the desired and undesired effects of a drug is known as the "therapeutic index."
(treatment of
Cancer, page 80, left column, Chapman &
Hall, published in 1982). Furthermore, the therapeutic coefficients of most anticancer drugs are generally low values, and in this sense, it is extremely important to consider the dosage of anticancer drugs (ibid., p. 80, right column). The present inventors have conducted research on various FUDR derivatives, including the above-mentioned known compounds, from the standpoint of evaluating the expression of antitumor effects and toxicity from the viewpoint of dosage, and have investigated the effects of these known compounds on various FUDR derivatives. We have been conducting extensive research on FUDR derivatives with the aim of increasing their anticancer effects and reducing their toxicity, but the 3' and 3'
It has been found that by substituting both hydrogen atoms in the 5'-position hydroxyl group with a specific phenoxycarbonyl group, a compound capable of solving the above problems can be obtained. The present invention was completed based on this knowledge. The present invention will be explained in detail below. The compounds provided by the present invention have the general formula (In the formula, R ₁ is a hydrogen atom or a group

[Formula], R ₂ and R ₃ are the same or different and at least one or more atoms selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group, a benzyloxy group, represents a group. ) expressed as 3′,
It is a 5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative,
As R ₁ , the base

[Formula] is preferred. Among R ₂ and R ₃ , halogen atoms include chlorine, bromine, iodine, and fluorine,
The alkyl group of the alkyl group and the alkoxy group may be linear or have a side chain, especially methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
Lower alkyl groups such as n-hexyl are preferred. In addition, when multiple alkoxy groups are substituted, adjacent alkoxy groups are combined,
It is also possible to form an alkyleneoxy group containing an oxygen atom as a heteroatom. Preferred examples of such alkyleneoxy groups include methylenedioxy group and ethylenedioxy group. Preferred examples of compounds of the invention include R ₁ of the formula

A compound represented by the formula, where R ₂ is a hydrogen atom and R ₃ is an alkoxy group,
In particular, compounds in which R ₃ is a propoxy group, as well as R ₂
and R ₃ are both alkoxy groups, especially,
Compounds in which R ₂ and R ₃ are both methoxy groups, and R ₂
Compounds in which R is a methoxy group and R ₃ is a propoxy group can be mentioned. The compound of the present invention represented by general formula (I) is
To FUDR, the general formula (R ₂ in the formula has the same meaning as above) or reacts FUDR with phosgene to the product obtained by the general formula (R ₂ in the formula has the same meaning as above) is reacted with the general formula (R ₂ in the formula has the same meaning as above), or the reaction product (Ia) obtained in this way is added to the reaction product (Ia) with the general formula (In the formula, R ₃ has the same meaning as above, and hal represents a halogen atom.) By reacting benzoyl halides represented by the formula, and subjecting the obtained compound to catalytic reduction, etc., as necessary. , general formula (R ₁ in the formula is a group

[Formula] is represented, and R ₂ and R ₃ have the same meanings as above. ) is expressed as
3',5'-di-O-phenoxycarbonyl-substituted-
It can be produced by producing a 2'-deoxy-5-fluorouridine derivative. These reactions are preferably carried out in an organic solvent in the presence of a base. Examples of preferred organic solvents include dioxane, acetone, acetonitrile,
Examples include chloroform, ethyl acetate, methylene chloride, tetrahydrofuran, pyridine, dimethylformamide, toluene, benzene, etc.
Examples of the base include organic bases such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N,N-dimethylaniline, and pyridine, and inorganic bases such as alkali carbonate, caustic alkali, and alkali acetate. In particular, pyridine is one of the solvents that can be advantageously used in the preparation of the compounds of the present invention since it is itself a base. The amount of base used is generally
It is sufficient to use 2 to 5 times the molar ratio of the raw materials used in the reaction, and there is no need to place any particular limitations on the molar ratio of the raw materials used in the reaction. In the reaction, it is preferable to use 2 to 2.5 times the molar amount of chloroformates relative to FUDR. Moreover, this reaction is completed in several minutes to 10 hours, usually 30 minutes to several hours. Other reactions are conveniently completed in a few hours to several tens of hours. The reaction between FUDR and phosgene can be carried out at -10° to room temperature. Although other reactions proceed at ice-cooling to room temperature, it is convenient to accelerate the reaction by heating to around the boiling point of the solvent, preferably around 80°C. In the compound represented by general formula (I), R ₁ is

3′,5′-di-O-phenoxycarbonyl-substituted-2′-deoxy- which is a group of [formula]
5-Fluorouridine derivatives are produced by, for example, reacting a compound represented by the general formula (Ia) with a benzoyl halide in which the symbol R ₃ in the general formula () is a benzyloxy group, and the product is obtained by catalytic reduction. It can be produced by removing the benzyl group by subjecting it to the following steps. For the catalytic reduction, it is sufficient to carry out the hydrogenation under mild conditions in the presence of a customary catalytic reduction catalyst by any commonly adopted means. Moreover, among the compounds represented by general formula (I),
3′,5′-di-O-phenoxycarbonyl-substituted-2′-deoxy-5-fluorouridine derivatives in which R ₂ is a hydroxy group, for example, in the general formula () or (), R ₂ is benzyloxy Starting from a compound as a group, a compound represented by general formula (Ia) or (Ib) is produced according to the above production method, and this is subjected to catalytic reduction etc. in the same manner as above. can do. The present invention will be explained below with reference to Examples. Example 1 50.0 g of 2'-deoxy-5-fluorouridine was dissolved in 150 ml of dry pyridine, and then 70.2 g of phenylchloroformate was added dropwise thereto. This was left at 70°C for 4 hours, and then gradually poured into about 300ml of ice water with stirring. Take the formed precipitate,
After drying, recrystallization from acetone-ethanol yielded 91.1 g of 3',5'-di-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine. Yield: 92.2%, melting point: 162-163℃, UV λ ^EtOH _nax nm: 264, NMR δ (ppm, DMSO- _d6 ): uridine moiety,
2.44−2.62 (2H, m, C ₂ ′−H), 4.40−4.56
(3H, m, C ₄ ′ _,5 ′−H), 5.28−5.38 (1H,
m, C ₃ ′-H), 6.18 (1H, bt, J=7Hz,
C ₁ '-H), 7.94 (1H, d, J = 7Hz, C ₆ -
H), 11.72 (disappeared with addition of 1H, bs, D ₂ O, −
NH-); substituent moiety at 3' and 5' positions, 7.14-
7.50 (10H, m, phenyl-H), elemental analysis value C ₂₃ H ₁₉ FN ₂ O ₉ Calculated value (%): C, 56.79; H, 3.94; N, 5.76 Actual value (%): C, 56.63 ; H, 3.65; N, 6.06 Example 2 Add 50 ml of acetone to 10 ml of phosgene under cooling (ice-salt).
ml, and then 2.46 g of 2'-deoxy-5-fluorouridine dissolved in 10 ml of acetone and 5 ml of triethylamine were added dropwise with stirring. The reaction mixture was left under stirring at room temperature for 17 hours. The reaction mixture was filtered, and 9.4 g of phenol and 20 g of triethylamine dissolved in 50 ml of acetone were added to the resulting liquid.
ml was added dropwise, and the mixture was further left at room temperature for 17 hours. The reaction mixture was filtered, and the solvent in the resulting liquid was distilled off under reduced pressure to obtain an oily residue. This was fractionated by silica gel column chromatography (solvent: chloroform), and the fraction with an Rf value of 0.1 was concentrated under reduced pressure to obtain crystals, washed with ether, dried, and recrystallized from acetone-ethanol.
1.18g of 3',5'-di-O-phenoxycarbonyl-
2'-deoxy-5-fluorouridine was obtained. Yield: 24.3%, melting point: 162-163°C, Example 3 2.00 g of 2'-deoxy-5-fluorouridine was dissolved in 40 ml of dry pyridine, and then 4-
3.90 g of chlorophenyl chloroformate was added dropwise. This was left at 70°C for 4 hours and then concentrated under reduced pressure. The residue thus obtained was dissolved in ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was fractionated by silica gel column chromatography (solvent: 2% methanol-chloroform), and the fractions were concentrated under reduced pressure to yield 2.41 g of 3',
5'-di-O-(4-chlorophenoxycarbonyl)
-2'-deoxy-5-fluorouridine was obtained as white crystals. Yield: 53.4%, melting point 96−100
℃, UV λ ^EtOH _nax nm: 266, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.46−2.70 (2H, m, C ₂ ′−H), 4.48−4.68
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.44 (1H,
m, C ₃ ′-H), 6.24 (1H, bt, J=7Hz,
C ₁ '-H), 8.04 (1H, d, J = 7Hz, C ₆ -
H), 11.50 (disappeared with addition of 1H, bs, D ₂ O, −
NH-); substituent moiety at 3' and 5' positions, 7.22-
7.56 (8H, m, phenyl-H), elemental analysis value C ₂₃ H ₁₇ Cl ₂ FN ₂ O ₉ Calculated value (%): C, 49.75; H, 3.09; N, 5.04 Actual value (%): C , 50.02; H, 3.07; N, 5.08 Examples 4 to 15 Reaction of 2'-deoxy-5-fluorouridine with chloroformates, treatment of the resulting reaction mixture, and fractionation by silica gel column chromatography Each operation in Example 3
The following 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivatives were prepared from the corresponding starting compounds according to the procedure described in the following. Name, yield, properties of the compound produced below,
The UV, NMR, and elemental analysis values are listed. Example 4 3',5'-di-O-(2-methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine,
Yield: 56.0%, melting point: 73-80℃, UV λ ^EtOH _nax nm: 263, 267, NMR δ (ppm, DMSO- _d6 ): uridine moiety,
2.42−2.58 (2H, m, C ₂ ′−H), 4.38−4.58
(3H, m, C ₄ ′ _,5 ′−H), 5.02−5.36 (1H,
m, C ₃ ′-H), 6.16 (1H, bt, J=7Hz,
C ₁ ′-H), 7.90 (1H, d, J=7Hz, C ₁ ′-
H), 7.90 (1H, d, J=7Hz, _C6 -H),
11.74 (1H, bs, disappeared upon addition of D ₂ O, -NH
-); substituent moieties at 3' and 5' positions, 2.10 and 2.16
(each, 3H, s), CH ₃ −), 7.02−7.30
(8H, m, phenyl-H), elemental analysis value C ₂₅ H ₂₃ FN ₂ O ₉ Calculated value (%): C, 58.37; H, 4.51; N, 5.45 Actual value (%): C, 58.18; H, 4.33; N, 5.57 Example 5 3',5'-di-O-(4-ethoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 97.7%, melting point: 119- 121℃, UV λ ^EtOH _nax nm: 270, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.42−2.62 (2H, m, C ₂ ′−H), 4.38−4.50
(3H, m, C ₄ ′ _,5 ′−H), 5.18−5.36 (1H,
m, C ₃ ′-H), 6.14 (1H, bt, J=7Hz,
C ₁ '-H), 7.90 (1H, d, J = 7Hz, C ₆ -
H), 11.78 (disappeared with addition of 1H, bs, D ₂ O, −
NH-); substituent moiety at 3' and 5' positions, 1.30
(6H, t, J=7Hz, C H ₃ CH ₂ O−X2),
3.96 (4H, q, J=7Hz, CH ₃ C H ₂ O−
X2), 6.76-7.22 (8H, m, phenyl-H), elemental analysis value C ₂₇ H ₂₇ FN ₂ O ₁₁ , calculated value (%): C, 56.45; H, 4.74; N, 4.88 Actual value (% ): C, 56.75; H, 4.90; N, 4.48 Example 6 3',5'-di-O-(4-tert-butylphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield : 46.3%, melting point: 184-185℃, UV λ ^EtOH _nax nm: 264, 268, NMR δ (ppm, DMSO- _d6 ): uridine moiety,
2.38−2.54 (2H, m, C ₂ ′−H), 4.30−4.50
(3H, m, C ₄ ′ _,5 ′−H), 5.14−5.30 (1H,
m, C ₃ ′-H), 6.08 (1H, bt, J=7Hz,
C ₁ '-H), 7.80 (1H, d, J = 7Hz, C ₆ -
H), 11.40 (disappeared with addition of 1H, bs, D ₂ O, −
NH−); substituent moiety at 3′ and 5′ positions, 1.26
(18H, s, (C H ₃ ) ₃ C−X2), 6.90−7.30
(8H, m, phenyl-H), elemental analysis value C ₃₁ H ₃₅ FN ₂ O ₉ Calculated value (%): C, 62.20; H, 5.89; N, 4.68 Actual value (%): C, 62.00; H, 5.87; N, 4.71 Example 7 3',5'-di-O-(4-bromophenoxycarbonyl)-2'-deoxy-5-fluorouridine,
Yield: 26.8%, melting point: 105-109℃, UV λ ^EtOH _nax nm: 266, NMR δ (ppm, DMSO- _d6 ): uridine moiety,
2.48−2.66 (2H, m, C ₂ ′−H), 4.40−4.62
(3H, m, _C4 '_,5' -H), 5.26-5.40 (1H,
m, C ₃ ′-H), 6.20 (1H, bt, J=7Hz,
C ₁ '-H), 7.96 (1H, d, J = 7Hz, C ₆ -
H), 11.64 (disappeared with addition of 1H, bs, D ₂ O, −
NH-); substituent moiety at 3' and 5' positions, 7.12-
7.64 (8H, m, phenyl-H), elemental analysis value C ₂₃ H ₁₇ Br ₂ FN ₂ O ₉ Calculated value (%): C, 42.88; H, 2.66; N, 4.35 Actual value (%): C , 42.79; H, 2.46; N, 4.37 Example 8 3',5'-di-O-(4-methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine,
Yield: 58.8%, melting point: 112-114℃, UV λ ^EtOH _nax nm: 266, 270, NMR δ (ppm, DMSO- _d6 ): uridine moiety,
2.52−2.68 (2H, m, C ₂ ′−H), 4.45−4.62
(3H, m, C ₄ ′ _,5 ′−H), 5.28−5.43 (1H,
m, C ₃ ′-H), 6.24 (1H, t, J=7Hz,
C ₁ '-H), 8.00 (1H, d, J = 7Hz, C ₆ -
H), 11.92 (1H, d, J=5Hz, disappeared by addition of D ₂ O, -NH-); substituent moiety at 3' and 5' positions, 2.32 ((6H, s, CH ₃ -X2), 7.01 −
7.32 (8H, m, phenyl-H), elemental analysis value C ₂₅ H ₂₃ FN ₂ O ₉ Calculated value (%): C, 58.37; H, 4.51; N, 5.45 Actual value (%): C, 57.97 ;H, 4.45;N, 5.43 Example 9 3',5'-di-O-(3-methylphenoxycarbonyl-2'-deoxy-5-fluorouridine,
Yield: 47.9%, melting point: 61-63℃, UV λ ^EtOH _nax nm: 264, 268, NMR δ (ppm, DMSO- _d6 ): uridine moiety,
2.44−2.64 (2H, m, C ₂ ′−H), 4.42−4.58
(3H, m, C ₄ ′ _,5 ′−H), 5.26−5.42 (1H,
m, C ₃ ′-H), 6.22 (1H, bt, J=7Hz,
C ₁ '-H), 8.00 (1H, d, J = 7Hz, C ₆ -
H), 11.90 (1H, d, J=5Hz, disappears with addition of D ₂ O, -NH-); substituent moieties at 3' and 5' positions, 2.30 and 2.34 (each, 3H, s, CH ₃ -) ,
6.96-7.40 (8H, m, phenyl-H), elemental analysis value C ₂₅ H ₂₃ FN ₂ O ₉ , calculated value (%): C, 58.37; H, 4.51; N, 5.45 Actual value (%): C , 58.40; H, 4.54; N, 5.52 Example 10 3',5'-di-O-(4-benzyloxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 66.3%, Powder, UV λ ^EtOH _nax nm: 269, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.46−2.62 (2H, m, C ₂ ′−H), 4.38−4.56
(3H, m, C ₄ ′ _,5 ′−H), 5.28−5.43 (1H,
m, C ₃ ′-H), 6.21 (1H, t, J=7Hz,
C ₁ '-H), 8.02 (1H, d, J = 7Hz, C ₆ -
H), 11.98 (disappeared with addition of 1H, bs, D ₂ O, -
NH-); substituent moiety at 3' and 5' positions, 5.11
(4H, s, _-CH2O -X2), 6.95-7.56
(18H, m, phenyl-H), elemental analysis value C ₃₇ H ₃₁ FN ₂ O ₁₁ Calculated value (%): C, 63.61; H, 4.47; N, 4.01 Actual value (%): C, 63.41; H, 4.50; N, 4.06 Example 11 3',5'-di-O-(3-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 56.3%, powder, UV λ ^EtOH _nax nm: 269, 276 (sh), NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.44−2.58 (2H, m, C ₂ ′−H), 4.44−4.52
(3H, m, C ₄ ′ _,5 ′−H), 5.24−5.36 (1H,
m, C ₃ ′-H), 6.16 (1H, bt, J=7Hz,
C ₁ '-H), 7.94 (1H, d, J = 7Hz, C ₆ -
H), 11.88 (disappeared with addition of 1H, bs, D ₂ O, −
NH−); substituent moiety at 3′ and 5′ positions, 3.70 and
3.74 (each, 3H, s, CH ₃ O−), 6.68−
7.34 (8H, m, phenyl-H), elemental analysis value C ₂₅ H ₂₃ FN ₂ O ₁₁ Calculated value (%): C, 54.95; H, 4.24; N, 5.13 Actual value (%): C, 55.11 ;H, 4.16;N, 5.08 Example 12 3',5'-di-O-(2-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 12.3%, powder, UV λ ^EtOH _nax nm: 269, 276 (sh), NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.40−2.60 (2H, m, C ₂ ′−H), 4.39−4.64
(3H, m, _C4 '_,5' -H), 5.24-5.40 (1H,
m, C ₃ ′-H), 6.24 (1H, bt, J=7Hz,
C ₁ '-H), 7.97 (1H, d, J = 7Hz, C ₆ -
H), 11.95 (disappeared with addition of 1H, bs, D ₂ O, −
NH−); substituent moiety at 3′ and 5′ positions, 3.78 and
3.82 (each, 3H, s, CH ₃ O−), 6.84−
7.40 (8H, m, phenyl-H), elemental analysis value C ₂₅ H ₂₃ FN ₂ O ₁₁・1/5CHCl ₃ Calculated value (%): C, 53.07; H, 4.10; N, 4.91 Actual value (% ): C, 53.15; H, 4.13; N, 5.06 Example 13 3',5'-di-O-(4-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 73.3 %, melting point: 189.5-191℃ UV λ ^EtOH _nax nm: 221.5, 269, NMR δ (ppm, DMSO-d ₆ ): uridine moiety,
2.44−2.65 (2H, m, C ₂ ′−H), 4.39−4.64
(3H, m, _C4 '_,5' -H), 5.24-5.45 (1H,
m, C ₃ ′-H), 6.24 (1H, bt, J=7Hz,
C ₁ '-H), 8.02 (1H, d, J = 7Hz, C ₆ -
H), 11.88 (disappeared with addition of 1H, bs, D ₂ O, −
NH-); substituent moiety at 3' and 5' positions, 3.79
(6H, s, CH ₃ O−X2), 6.86−7.15 (8H,
m, phenyl-H), elemental analysis value C ₂₅ H ₂₃ FN ₂ O ₁₁ Calculated value (%): C, 54.95; H, 4.24; N, 5.13 Actual value (%): C, 55.07; H, 4.22 ;N, 4.94 Example 14 3',5'-di-O-(4-ethylphenoxycarbonyl)-2'-deoxy-5-fluorouridine,
Yield: 36.8%, melting point: 129-131℃ UV λ ^EtOH _nax nm: 265, 269, NMR δ (ppm, DMSO- _d6 ): uridine moiety,
2.38−2.68 (6H, m, C ₂ ′−H and CH ₃ C H ₂ −
X2), 4.28−4.50 (3H, m, C ₄ ′ _,5 ′−H),
5.10−5.28 (1H, m, C ₃ ′−H), 6.06 (1H,
bt, J = 7Hz, C ₁ ′-H), 7.80 (1H, d,
J=7Hz, _C6 -H), 11.60(1H, bs, _D2O
Disappears upon addition, -NH-); Substituent moiety at 3' and 5' positions, 1.16 (6H, t, J=7Hz, C H ₃
CH ₂ −X2), CH ₂ overlaps with C ₂ ′ and −H, 6.86
-7.12 (8H, m, phenyl-H), elemental analysis value C ₂₇ H ₂₇ FN ₂ O ₉ Calculated value (%): C, 59.78; H, 5.02; N, 5.16 Actual value (%): C, 59.54; H, 4.74; N, 5.41 Example 15 3',5'-di-O-(4-n-butoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 85.0%, Melting point: 140-142℃, UV λ ^EtOH _nax nm: 270, NMR δ (ppm, DMSO- _d6 ): uridine moiety,
2.46−2.64 (2H, m, C ₂ ′−H), 4.46−4.56
(3H, m, _C4 '_,5' -H), 5.26-5.40 (1H,
m, C ₃ ′-H), 6.22 (1H, bt, J=7Hz,
C ₁ '-H), 8.00 (1H, d, J = 7Hz, C ₆ -
H), 11.90 (disappeared with addition of 1H, bs, D ₂ O, -
NH−); Substituent moiety at 3′ and 5′ positions, 0.94
(6H, t, J=6Hz, CH ₃ (CH ₂ ) ₂ CH ₂ O
−X2), 1.26−1.80 (8H, m, CH ₃ (CH ₂ )
₂ CH ₂ O−X2), 3.98 (4H, t, J=6Hz,
CH ₃ (CH ₂ ) ₂ CH ₂ O−X2), 6.86−7.28 (8H,
m, phenyl-H), elemental analysis value C ₃₁ H ₃₅ FN ₂ O ₁₁ Calculated value (%): C, 59.04; H, 5.59; N, 4.44 Actual value (%): C, 59.28; H, 5.52 ;N, 4.30 Example 16 3',5'-di-O-(4-chlorophenoxycarbonyl)-2'-deoxy-5-fluorouridine
Dissolve 1.00g in 10ml of dioxane, add 0.44g of benzoyl chloride and 0.87g of triethylamine.
Added ml. This was left at 70°C for 2 hours and then concentrated under reduced pressure. The resulting residue was dissolved in 30 ml of ethyl acetate.
The solution was washed with 20 ml of saturated brine three times, dried over magnesium sulfate, and concentrated under reduced pressure to obtain an oil. This was fractionated by silica gel column chromatography (3 x 30 cm, solvent: 1% methanol-chloroform), and the fractions were concentrated under reduced pressure to yield 1.16 g of 3-benzoyl-3',5'-di-O-
(4-chlorophenoxycarbonyl)-2'-deoxy-5-fluorouridine was obtained. yield:
85.2%, powder, UV λ ^EtOH _nax nm: 254, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.60−2.80 (2H, m, C ₂ ′−H), 4.52−4.64
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.48 (1H,
m, C ₃ ′-H), 6.28 (1H, bt, J=7Hz,
C ₁ '-H), 8.36 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3, 3' and 5' positions, 7.34-
8.20 (13H, m, phenyl-H), elemental analysis value C ₃₀ H ₂₁ Cl ₂ FN ₂ O ₁₀ , calculated value (%): C, 54.64; H, 3.21; N, 4.25 Actual value (%): C , 54.92; H, 2.97; N, 4.31 Examples 17 to 51 The reaction with benzoyl chloride, the treatment of the resulting reaction mixture, and the fractionation by silica gel column chromatography were carried out in accordance with Example 16. The following 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivatives were prepared from the corresponding starting compounds. Name, yield, properties of the compound produced below,
The UV, NMR, and elemental analysis values are listed. Example 17 3-benzoyl-3',5'-di-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 72.8%, powder, UV λ ^EtOH _nax nm: 254, NMR δ (ppm, _CDCl3 ): Uridine moiety, 2.46
−2.64 (2H, m, C ₂ ′−H), 4.42−4.67
(3H, m, C ₄ ′ _,5 ′−H), 5.27−5.44 (1H,
m, C ₃ ′-H), 6.39 (1H, bt, J=7Hz,
C ₁ '-H), 7.97 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 7.11-7.87
(15H, m, phenyl-H, phenyl- at position 3
(overlapping with H); 3-position substituent moiety, 3' and
Overlapping with phenyl-H at the 5′ position, elemental analysis value C ₃₀ H ₂₃ FN ₂ O ₁₀・1/5CHCl ₃ Calculated value (%): C, 59.04; H, 3.81; N, 4.56 Actual value (%) :C, 59.14;H, 3.66;N, 4.62 Example 18 3-(2-chlorobenzoyl)-3',5'-di-O
-Phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 46.4%, powder, UV λ ^EtOH _nax nm: 255, NMR δ (ppm, _CDCl3 ): uridine moiety, 2.49
−2.78 (2H, m, C ₂ ′−H), 4.35−4.60
(3H, m, C ₄ ′ _,5 ′−H), 5.18−5.36 (1H,
m, C ₃ ′-H), 6.27 (1H, bt, J=7Hz,
C ₁ '-H), 7.81 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 7.03-7.64
(14H, m, phenyl-H, phenyl- at position 3
(overlapping with H); 3-position substituent moiety, 3' and
Overlapping with phenyl-H at the 5' position, elemental analysis value C ₃₀ H ₂₂ ClFN ₂ O ₁₀ Calculated value (%): C, 57.65; H, 3.55; N, 4.48 Actual value (%): C, 57.39; H, 3.70; N, 4.48 Example 19 3-(2-methylbenzoyl)-3',5'-di-O
-Phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 47.2%, powder, UV λ ^EtOH _nax nm: 258, 276, NMR δ (ppm, DMSO-d ₆ ): uridine moiety,
2.44−2.74 (5H, m, C ₂ ′-H and CH ₃ −),
4.46−4.68 (3H, m, C ₄ ′ _,5 ′−H), 5.30−
5.46 (1H, m, C ₃ ′-H), 6.25 (1H, bt,
J=7Hz, _C1' -H), 8.34(1H, d, J=
7Hz, _C6 -H); substituent moieties at the 3' and 5' positions,
7.20−8.04 (14H, m, phenyl-H, 3rd position
(overlaps with phenyl-H); substituent part at position 3,
CH ₃ is the uridine moiety and phenyl-H is the 3′ and
Overlaps with phenyl-H at position 5′, elemental analysis value C ₃₁ H ₂₅ FN ₂ O ₁₀ Calculated value (%): C, 61.59; H, 4.17; N, 4.64 Actual value (%): C, 61.58; H, 4.31; N, 4.65 Example 20 3-(3-methylbenzoyl)-3',5'-di-O
-Phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 18.7%, powder, UV λ ^EtOH _nax nm: 258, NMR δ (ppm, _CDCl3 ): uridine moiety, 2.12
−2.77 (5H, m, C ₂ ′-H and CH ₃ −), 4.40
−4.65 (3H, m, C ₄ ′ _,5′ −H), 5.25−5.41
(1H, m, C ₃ ′-H), 6.37 (1H, bt, J=
7Hz, C ₁ ′-H), 7.12-7.78 (15H, m, C ₆
-H and phenyl-H); substituent moieties at the 3, 3' and 5' positions, overlap with the uridine moiety, elemental analysis value C ₃₁ H ₂₅ FN ₂ O ₁₀・1/10CHCl ₃ Calculated value (%): C, 60.59; H, 4.10; N, 4.54 Actual value (%): C, 60.41; H, 3.81; N, 4.68 Example 21 3-(4-methylbenzoyl)-3',5'-di-O
-Phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 68.3%, powder, UV λ ^EtOH _nax nm: 264, NMR δ (ppm, _CDCl3 ): uridine moiety, 2.25
−2.72 (5H, m, C ₂ ′-H and CH ₃ −), 4.36
−4.59 (3H, m, C ₄ ′ _,5′ −H), 5.20−5.33
(1H, m, C ₃ ′-H), 6.30 (1H, bt, J=
7Hz, C ₁ ′-H), 7.03-7.85 (15H, m, C ₆
-H and phenyl-H); substituent moieties at the 3, 3 _' and 5' positions, overlap with the uridine moiety, elemental analysis value C ₃₁ H ₂₅ FN ₂ O Calculated value (%): C, 61.59; H , 4.17; N, 4.64 Actual value (%): C, 61.65; H, 4.19; N, 4.74 Example 22 3-(2-ethylbenzoyl)-3',5'-di-O
-Phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 30.1%, powder, UV λ ^EtOH _nax nm: 256, NMR δ (ppm, DMSO-d ₆ ): uridine moiety,
Around 2.6 (2H, m, C ₂ ′-H), 4.39-4.51
(3H, m, C ₄ ′ _,5 ′−H), 5.19−5.37 (1H,
m, C ₃ ′-H), 6.11 (1H, bt, J=7Hz,
C ₁ '-H), 8.11 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 7.00-7.86
(14H, m, phenyl-H, phenyl- at position 3
overlaps with H); 3rd-position substituent part, 1.20 (3H,
t, J=7Hz, C H ₃ CH ₂ -), 2.96 (2H,
q, J=7Hz, _CH3CH2- ), _phenyl -H
overlaps with phenyl-H at the 3' and 5' positions, elemental analysis value C ₃₂ H ₂₇ FN ₂ O ₁₀ Calculated value (%): C, 62.14; H, 4.40; N, 4.53 Actual value (%): C, 62.59; H, 4.65; N, 4.78 Example 23 3-(4-methoxybenzoyl)-3',5'-di-
O-phenoxycarbonyl-2'-deoxy-5-
Fluorouridine, yield: 56.0%, powder, UV λ ^EtOH _nax nm: 286, NMR δ (ppm, _CDCl3 ): uridine moiety, 2.14
−2.82 (2H, m, C ₂ ′−H), 4.42−4.61
(3H, m, _C4 '_,5' -H), 5.27-5.40 (1H,
m, C ₃ ′-H), 6.42 (1H, bt, J=7Hz,
C ₁ '-H), 7.78 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 7.12-7.52
(10H, m, phenyl-H); 3rd-position substituent, 3.83 (3H, s, CH ₃ -), 6.95 (2H,
d, J=9Hz, C _3,5 −H), 7.93(2H, d,
J = 9Hz, C _2,6 -H), elemental analysis value C ₃₁ H ₂₅ FN ₂ O ₁₁ , calculated value (%): C, 60.00; H, 4.06; N, 4.52 Actual value (%): C, 60.14; H, 4.06; N, 4.58 Example 24 3-(4-n-propoxybenzoyl)-3',
5'-di-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 60.0%, powder, UV λ ^EtOH _nax nm: 287, NMR δ (ppm, DMSO- _d6 ): uridine part,
2.48−2.72 (2H, m, C ₂ ′−H), 4.38−4.56
(3H, m, C ₄ ′ _,5 ′−H), 5.22−5.34 (1H,
m, C ₃ ′-H), 6.14 (1H, bt, J=7Hz,
C ₁ '-H), 8.14 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 7.04-7.38
(10H, m, phenyl-H); 3rd-position substituent moiety, 0.96 (3H, t, J=7Hz, C H ₃
CH ₂ CH ₂ O−), 1.62−1.90 (2H, m,
CH ₃ C H ₂ CH ₂ O−), 3,98 (2H, t, J=
7Hz, CH ₃ CH ₂ CH ₂ O-), 6.94 (2H, d,
J = 9Hz, C _3,5 -H), 7.90 (2H, d, J =
9Hz, C _2,6 -H), elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₁ , calculated value (%): C, 61.11; H, 4.51; N, 4.32 Actual value (%): C, 61.01; H, 4.72; N, 4.37 Example 25 3-(3,4-methylenedioxybenzoyl)-
3',5'-di-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 60.0%,
Powder, UV λ ^EtOH _nax nm: 232, 277, 317, NMR δ (ppm, DMSO−d ₆ ): Uridine moiety,
2.50−2.72 (2H, m, C ₂ ′−H), 4.44−4.64
(3H, m, C ₄ ′ _,5 ′−H), 5.28−5.42 (1H,
m, C ₃ ′-H), 6.08-6.28 (3H, m, C ₁ ′-
H and -OCH ₂ O-) 8.20 (1H, d, J = 7
Hz, C ₆ -H); substituent moieties at the 3' and 5' positions,
7.12-7.48 (10H, m, phenyl-H); 3rd-position substituent moiety, OCH ₂ O- overlaps with uridine moiety, 7.02 (1H, d, J = 8Hz, C ₄ -
H), 7.58 (1H, d, J=2Hz, C2 _- H),
7.70 (1H, dd, J ₁ = 8Hz, J ₂ = 2Hz, C ₆ −
H), Elemental analysis value C ₃₁ H ₂₃ FN ₂ O ₁₂・1/5CHCl ₃ Calculated value (%): C, 56.92; H, 3.55; N, 4.25 Actual value (%): C, 57.23; H, 3.24; N, 4.05 Example 26 3-(2,3-dimethoxybenzoyl)-3',
5'-di-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 65.9%, powder, UV λ ^EtOH _nax nm: 266, 328, NMR δ (ppm, DMSO-d ₆ ) : Uridine part,
2.58−2.80 (2H, m, C ₂ ′−H), 4.48−4.72
(3H, m, C ₄ ′ _,5 ′−H), 5.36−5.54 (1H,
m, C ₃ ′-H), 6.30 (1H, bt, J=7Hz,
C ₁ '-H) 8.33 (1H, d, J = 6Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 7.04-7.67
(13H, m, phenyl-H, phenyl- at position 3
overlaps with H); substituent part at position 3, 3.79
3.94 (each, 3H, s, CH ₃ O−), phenyl
-H overlaps with phenyl-H at the 3' and 5' positions, elemental analysis value C ₃₂ H ₂₈ FN ₂ O ₁₂ Calculated value (%): C, 58.99; H, 4.33; N, 4.30 Actual value (% ): C, 59.33; H, 4.28; N, 4.39 Example 27 3-(3,5-dimethoxybenzoyl)-3',
5'-di-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 76.7%, powder, UV λ ^EtOH _nax nm: 274, 335, NMR δ (ppm, DMSO- _d6 ) : Uridine part,
2.58−2.78 (2H, m, C ₂ ′−H), 4.56−4.70
(3H, m, C ₄ ′ _,5 ′−H), 5.34−5.54 (1H,
m, C ₃ ′-H), 6.30 (1H, bt, J=7Hz,
C ₁ '-H), 8.35 (1H, d, J = 6Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 6.96-7.62
(13H, m, phenyl-H, phenyl- at position 3
overlaps with H); 3rd-position substituent part, 3.87 (6H,
s, CH ₃ O−X2), phenyl-H is 3′ and
Overlaps with phenyl-H at position 5′, elemental analysis value C ₃₂ H ₂₈ FN ₂ O ₁₂ Calculated value (%): C, 58.99; H, 4.33; N, 4.30 Actual value (%): C, 59.12; H, 4.21; N, 4.21 Example 28 3-(3-methylbenzoyl)-3',5'-di-O
-(3-methylphenoxycarbonyl-2'-deoxy-5-fluorouridine, yield: 87.8%, powder, UV λ ^EtOH _nax nm: 258, NMR δ (ppm, DMSO-d ₆ ): uridine moiety,
2.56−2.74 (2H, m, C ₂ ′−H), 4.48−4.64
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.44 (1H,
m, C ₃ ′-H), 6.20 (1H, bt, J=7Hz,
C ₁ '-H), 8.30 (1H, d, J = 7Hz, C ₆ -
H); 3′ and 5′ substituent moieties, 2.32 (6H,
s, _CH3 −X2), 7.00−7.94(12H, m,
phenyl-H, overlapped with phenyl-H at position 3);
Substituent moiety at position 3, 2.40 (3H, s, CH ₃
-), phenyl-H is phenyl- at the 3' and 5' positions.
Overlapping with H, elemental analysis value C ₃₃ H ₂₉ FN ₂ O _{As 10} , calculated value (%): C, 62.66; H, 4.62; N, 4.43 Actual value (%): C, 62.45; H, 4.52; N, 4.42 Example 29 3-(4-methoxybenzoyl)-3',5'-di-
O-(3-methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 76.3%,
Powder, UV λ ^EtOH _nax nm: 287, NMR δ (ppm, DMSO−d ₆ ): Uridine moiety,
2.53−2.73 (2H, m, C ₂ ′−H), 4.50−4.67
(3H, m, C ₄ ′ _,5 ′−H), 5.27−5.47 (1H,
m, C ₃ ′-H), 6.22 (1H, bt, J=7Hz,
C ₁ '-H), 8.23 (1H, d, J = 6Hz, C ₆ -
H); substituent moiety at 3' and 5' positions, 2.30 (6H,
s, _CH3 −X2), 6.92−8.14(12H, m,
phenyl-H, overlapped with phenyl-H at position 3);
Substituent moiety at position 3, 3.89 (3H, s, CH ₃ O
-), phenyl-H is phenyl- at the 3' and 5' positions.
Overlapping with H, elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₁ Calculated value (%): C, 61.11; H, 4.51; N, 4.32 Actual value (%): C, 60.77; H, 4.32; N, 4.36 Example 30 3-(2-chlorobenzoyl)-3',5'-di-O
-(3-methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 79.0%, powder, UV λ ^EtOH _nax nm: 256, NMR δ (ppm, DMSO-d ₆ ): Uridine moiety ,
2.58−2.71 (2H, m, C ₂ ′−H), 4.50−4.62
(3H, m, C ₄ ′ _,5 ′−H), 5.29−5.46 (1H,
m, C ₃ ′-H), 6.21 (1H, bt, J=7Hz,
C ₁ '-H), 8.12 (1H, d, J = 6Hz, C ₆ -
H); 3′ and 5′ substituent moieties, 2.32 (6H,
s, _CH3 −X2), 6.95−7.77(12H, m,
phenyl-H, overlapped with phenyl-H at position 3);
Substituent moiety at position 3, phenyl- at position 3' and 5'
Overlapping with H, elemental analysis value C ₃₂ H ₂₄ ClFN ₂ O As ₁₀ , calculated value (%): C, 59.04; H, 3.72; N, 4.30 Actual value (%): C, 58.66; H, 3.94; N, 4.20 Example 31 3-(4-fluorobenzoyl)-3',5'-di-
O-(3-methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 86.8%,
Powder, UV λ ^EtOH _nax nm: 256, NMR δ (ppm, DMSO−d ₆ ): Uridine moiety,
2.56−2.76 (2H, m, C ₂ ′−H), 4.53−4.68
(3H, m, C ₄ ′ _,5 ′−H), 5.32−5.48 (1H,
m, C ₃ ′-H), 6.26 (1H, bt, J=7Hz,
C ₁ ′-H), 6.96-8.42 (13H, m, C ₆ -H and
phenyl-H); substituent moiety at the 3′ and 5′ positions,
2.32 (6H, s, CH ₃ -X2), phenyl-H overlaps with uridine moiety; substituent moiety at position 3,
Overlaps with uridine moiety, elemental analysis value C ₃₂ H ₂₆ F ₂ N ₂ O ₁₀ Calculated value (%): C, 60.38; H, 4.12; N, 4.40 Actual value (%): C, 60.21; H, 4.00 ;N, 4.42 Example 32 3-(2-methoxybenzoyl)-3',5'-di-
O-(3-methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 69.0%,
Powder, UV λ ^EtOH _nax nm: 258, 321, NMR δ (ppm, DMSO−d ₆ ): Uridine moiety,
2.52−2.72 (2H, m, C ₂ ′−H), 4.46−4.60
(3H, m, C ₄ ′ _,5 ′−H), 5.28−5.46 (1H,
m, C ₃ ′-H), 6.22 (1H, bt, J=7Hz,
C ₁ '-H), 8.24 (1H, d, J = 6Hz, C ₆ -
H); 3′ and 5′ substituent moieties, 2.27 (6H,
s, _CH3 −X2), 6.92−8.08(12H, m,
phenyl-H, overlapped with phenyl-H at position 3);
Substituent moiety at position 3, 3.78 (3H, s, CH ₃ O
-), phenyl-H is phenyl- at the 3' and 5' positions.
Overlapping with H, elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₁ Calculated value (%): C, 61.11; H, 4.51; N, 4.32 Actual value (%): C, 61.30; H, 4.34; N, 4.40 Example 33 3-(4-chlorobenzoyl)-3',5'-di-O
-(4-Methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 63.7%, powder, UV λ ^EtOH _nax nm: 263, NMR δ (ppm, DMSO-d ₆ ): Uridine moiety ,
2.57−2.75 (2H, m, C ₂ ′−H), 4.47−4.71
(3H, m, C ₄ ′ _,5 ′−H), 5.33−5.50 (1H,
m, C ₃ ′-H), 6.26 (1H, bt, J=7Hz,
C ₁ ′-H), 7.00-8.39 (13H, m, C ₆ -H and
phenyl-H); substituent moiety at the 3′ and 5′ positions,
2.32 (6H, s, CH3 _- X2), phenyl-H overlaps with uridine moiety; substituent moiety at position 3,
Overlapping with uridine moiety, elemental analysis value C ₃₂ H ₂₆ ClFN ₂ O ₁₀・1/6CHCl ₃ Calculated value (%): C, 57.41; H, 3.91; N, 4.16 Actual value (%): C, 57.52; H, 3.98; N, 4.17 Example 34 3-(2-methylbenzoyl)-3',5'-di-O
-(4-Methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 63.2%, powder, UV λ ^EtOH _nax nm: 257, NMR δ (ppm, DMSO-d ₆ ): Uridine moiety ,
2.52−2.69 (5H, m, C ₂ ′-H and CH ₃ −),
4.46−4.60 (3H, m, C ₄ ′ _,5 ′−H), 5.26−
5.44 (1H, m, C ₃ ′-H), 6.20 (1H, bt,
J = 7Hz, C ₁ '-H), 8.23 (1H, d, J =
6Hz, _C6 -H); substituent moieties at the 3' and 5' positions,
2.30 (6H, s, _CH3 −X2), 7.00−7.96
(12H, m, phenyl-H, phenyl- at position 3
(overlapping H); 3rd-position substituent part, CH ₃ overlaps with uridine part, phenyl-H has 3′ and
Overlaps with phenyl-H at position 5′, elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₀ Calculated value (%): C, 62.66; H, 4.62; N, 4.43 Actual value (%): C, 62.28; H, 4.58; N, 4.46 Example 35 3-(4-methoxybenzoyl)-3',5'-di-
O-(4-methylphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 64.1%,
Powder, UV λ ^EtOH _nax nm: 286, NMR δ (ppm, DMSO−d ₆ ): Uridine moiety,
2.57−2.76 (2H, m, C ₂ ′−H), 4.51−4.69
(3H, m, C ₄ ′ _,5 ′−H), 5.35−5.48 (1H,
m, C ₃ ′-H), 6.28 (1H, bt, J=7Hz,
C ₁ '-H), 8.11 (1H, d, J = 6Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 2.31 (6H,
s, _CH3 −X2), 7.07−7.35(12H, m,
phenyl-H, overlapped with phenyl-H at position 3);
Substituent moiety at position 3, 3.92 (3H, s, CH ₃ O
-), phenyl-H is phenyl- at the 3' and 5' positions.
Overlapping with H, elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₁・1/11CHCl ₃ Calculated value (%): C, 60.27; H, 4.45; N, 4.25 Actual value (%): C, 60.63; H , 4.43; N, 4.22 Example 36 3-(4-n-propoxybenzoyl)-3′,
5'-di-O-(4-methylphenoxycarbonyl)
-2'-deoxy-5-fluorouridine, yield:
86.3%, powder, UV λ ^EtOH _nax nm: 289, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.54−2.72 (2H, m, C ₂ ′−H), 4.44−4.64
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.46 (1H,
m, C ₃ ′-H), 6.24 (1H, bt, J=7Hz,
C ₁ '-H), 8.27 (1H, d, J = 6Hz, C ₆ -
H); substituent moiety at 3' and 5' positions, 2.30 (6H,
s, _CH3 −X2), 7.02−8.12(12H, m,
phenyl-H, overlapped with phenyl-H at position 3);
Substituent part at position 3, 0.98 (3H, t, J=7
Hz _{, CH3CH2CH2O−} ), 1.64−1.87( _2H ,
m, CH ₃ C H ₂ CH ₂ O−), 4.08 (2H, t, J
= _7Hz , _CH3CH2CH2O- ), _phenyl -H
overlaps with phenyl-H at the 3' and 5' positions, elemental analysis value C ₃₅ H ₃₃ FN ₂ O ₁₁ Calculated value (%): C, 62.13; H, 4.92; N, 4.14 Actual value (%): C, 62.21; H, 4.86; N, 4.17 Example 37 3-(4-chlorobenzoyl)-3',5'-di-O
-(4-tert-butylphenoxycarbonyl)-
2'-deoxy-5-fluorouridine, yield:
51.1%, powder, UV λ ^EtOH _nax nm: 263, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
Around 2.7 (2H, m, C ₂ ′-H), 4.48-4.68
(3H, m, C ₄ ′ _,5 ′−H), 5.32−5.46 (1H,
m, C ₃ ′-H), 6.26 (1H, bt, J=7Hz,
C ₁ '-H), 8.34 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 1.30 (18H,
s, (C H ₃ ) ₃ C−X2), 7.10−7.50 (8H,
m, C _2,3,5,6 -HX2); 3-position substituent part,
7.68 (2H, d, J = 9Hz, C _3,5 -H), 8.18
(2H, d, J = 9Hz, C _2,6 −H), Elemental analysis value C ₃₈ H ₃₈ ClFN ₂ O ₁₀・1/10 CHCl ₃ Calculated value (%): C, 61.09; H, 5.13; N , 3.74 Actual value (%): C, 61.08; H, 4.98; N, 3.58 Example 38 3-(2-methylbenzoyl)-3',5'-di-O
-(4-tert-butylphenoxycarbonyl)-
2'-deoxy-5-fluorouridine, yield:
87.2%, powder, UV λ ^EtOH _nax nm: 256, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
Around 2.6 (2H, m, C ₂ ′-H), 4.46-4.66
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.46 (1H,
m, C ₃ ′-H), 6.24 (1H, bt, J=7Hz,
C ₁ '-H), 8.28 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 1.32 (18H,
s, (C H ₃ ) ₃ C−X2), 7.08−7.98 (12H,
m, phenyl-H, overlaps with phenyl-H at position 3); Substituent moiety at position 3, 2.64 (3H, s,
CH ₃ −), phenyl-H is at the 3′ and 5′ positions.
Overlapping with phenyl-H, elemental analysis value C ₃₉ H ₄₁ FN ₂ O ₁₀ Calculated value (%): C, 65.35; H, 5.77; N, 3.91 Actual value (%): C, 65.52; H, 5.91; N, 3.93 Example 39 3-(4-methoxybenzoyl)-3',5'-di-
O-(4-tert-butylphenoxycarbonyl)-
2'-deoxy-5-fluorouridine, yield:
81.7%, powder, UV λ ^EtOH _nax nm: 286, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
Around 2.6 (2H, m, C ₂ ′-H), 4.50-4.64
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.48 (1H,
m, C ₃ ′-H), 6.26 (1H, bt, J=7Hz,
C ₁ '-H), 8.30 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 1.30 (18H,
s, (C H ₃ ) ₃ C−X2), 7.06−7.50 (10H,
m, phenyl-H and 3-position _C3,5 -H); 3-position substituent moiety, 3.92 (3H, s, _CH3O- ),
8.06 (2H, d, J = 9Hz, C _2,6 −H), C _3,5
-H overlaps with phenyl-H at 3' and 5' positions, elemental analysis value C ₃₉ H ₄₁ FN ₂ O ₁₁ , calculated value (%): C, 63.93; H, 5.64; N, 3.82 Actual value (% ): C, 63.49; H, 6.18; N, 3.59 Example 40 3-(2-methylbenzoyl)-3',5'-di-O
-(2-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 84.0%,
Powder, UV λ ^EtOH _nax nm: 258, 275 (sh), NMR δ (ppm, _CDCl3 ): Uridine moiety, around 2.4 (2H, m, _C2' -H), 4.44-4.62 (3H,
m, C4 _{′ ,5′} −H), 5.26−5.40(1H, m,
C ₃ ′-H), 6.38 (1H, bt, J=7Hz, C ₁ ′-
H), 7.75 (1H, d, J=7Hz, _C6 -H);
Substituent moieties at 3' and 5' positions, 3.84 (6H, s,
CH ₃ O−X2), 6.84−7.68 (12H, m,
phenyl-H, overlapped with phenyl-H at position 3);
Substituent moiety at position 3, 2.69 (3H, s, CH ₃
-), phenyl-H is phenyl- at the 3' and 5' positions.
Overlapping with H, elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₂ Calculated value (%): C, 59.64; H, 4.40; N, 4.22 Actual value (%): C, 59.91; H, 4.49; N, 4.24 Example 41 3-(4-n-propoxybenzoyl)-3′,
5'-di-O-(2-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 60.4%, powder, UV λ ^EtOH _nax nm: 218, 277, 289, NMR δ ( ppm, DMSO- _d6 ): uridine moiety,
2.52−2.64 (2H, m, C ₂ ′−H), 4.45−4.62
(3H, m, C ₄ ′ _,5 ′−H), 5.26−5.43 (1H,
m, C ₃ ′-H), 6.23 (1H, t, J=7Hz,
C ₁ '-H), 8.25 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 3.81 (6H,
s, CH ₃ O−X2), 6.87−7.40 (10H, m,
phenyl-H and 3-position C _3,5 -H); 3-position substituent moiety, 0.97 (3H, t, J=7Hz, C H ₃
CH ₂ CH ₂ O−), 1.60−1.89 (2H, m,
CH ₃ C H ₂ CH ₂ O−), 4.09 (2H, t, J=7
Hz, CH ₃ CH ₂ CH ₂ O-), 8.05 (2H, d, J
=9Hz, C _2,6 -H), C _3,5 -H overlaps with phenyl-H at the 3' and 5' positions, elemental analysis value C ₃₅ H ₃₃ FN ₂ O ₁₃ , calculated value (%): C, 59.32; H, 4.69; N, 3.95 Actual value (%): C, 59.06; H, 4.64; N, 3.95 Example 42 3-(4-chlorobenzoyl)-3',5'-di-O
-(4-n-butoxyphenoxycarbonyl)-
2'-deoxy-5-fluorouridine, yield:
63.5%, powder, UV λ ^EtOH _nax nm: 217, 264, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.58−2.70 (2H, m, C ₂ ′−H), 4.50−4.62
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.42 (1H,
m, C ₃ ′-H), 6.24 (1H, bt, J=7Hz,
C ₁ '-H), 8.28 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 0.96 (6H,
t, J=6Hz, CH ₃ (CH ₂ ) ₂ CH ₂ O−×
2), 1.28−1.86 (8H, m, CH ₃ (CH ₂ )
₂ CH ₂ O−×2), 3.98 (4H, t, J=6Hz,
CH ₃ (CH ₂ ) ₂ CH ₂ O−×2), 6.90.−7.24
(8H, m, phenyl-H); 3-position substituent moiety, 7.66 (2H, d, J = 9Hz, C _3,5 -H),
8.16 (2H, d, J = 9Hz, C _2,6 -H), elemental analysis value C ₃₈ H ₃₈ ClFN ₂ O ₁₂ , calculated value (%): C, 59.34; H, 4.98; N, 3.64 Actual value (%): C, 59.66; H, 4.83; N, 3.66 Example 43 3-(2-methylbenzoyl)-3',5'-di-O
-(4-n-butoxyphenoxycarbonyl)-
2'-deoxy-5-fluorouridine, yield:
92.6%, powder, UV λ ^EtOH _nax nm: 223, 256, 276 (sh), NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
Around 2.6 (2H, m, C ₂ ′-H), 4.48-4.62
(3H, m, C ₄ ′ _,5 ′−H), 5.28−5.48 (1H,
m, C ₃ ′-H), 6.28 (1H, bt, J=7Hz,
C ₁ '-H), 8.30 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 0.94 (6H,
t, J=6Hz, CH ₃ (CH ₂ ) ₂ CH ₂ O−×
2), 1.26−1.84 (8H, m, CH ₃ (CH ₂ )
₂ CH ₂ O−×2), 3.98 (4H, t, J=6Hz,
CH ₃ (CH ₂ ) ₂ CH ₂ O−×2), 6.92−8.00
(12H, m, phenyl-H, phenyl- at position 3
overlaps with H); 3-position substituent part, 2.66 (3H,
s, CH ₃ −), phenyl-H at the 3′ and 5′ positions
Overlapping with phenyl-H, elemental analysis value C ₃₉ H ₄₁ FN ₂ O ₁₂ Calculated value (%): C, 62.56; H, 5.52; N, 3.74 Actual value (%): C, 62.39; H, 5.70; N, 3.51 Example 44 3-(4-methoxybenzoyl)-3',5'-di-
O-(4-n-butoxyphenoxycarbonyl)-
2'-deoxy-5-fluorouridine, yield:
51.6%, powder, UV λ ^EtOH _nax nm: 222, 284, NMR δ (ppm, _CDCl3 ): uridine moiety, 2.1−
2.7 (2H, m, C ₂ ′-H), 4.38-4.54 (3H,
m, C4 _{′ ,5′} −H), 5.20−5.36(1H, m,
C ₃ ′-H), 6.34 (1H, bt, J=7Hz, C ₁ ′-
H), 7.76 (1H, d, J=7Hz, _C6 -H);
Substituent moiety at 3′ and 5′ positions, 0.96 (6H, J=
6Hz, CH ₃ (CH ₂ ) ₂ CH ₂ O−×2), 1.28
−1.86 (8H, m, CH ₃ (CH ₂ ) ₂ CH ₂ O−×
2), 3.92 (4H, t, J=6Hz, CH ₃
(CH ₂ ) ₂ CH ₂ O−×2), 6.80−7.12 (10H,
m, phenyl-H and 3-position _C3,5 -H); 3-position substituent moiety, 3.82 (3H, s, _CH3O- ),
7.88 (2H, d, J = 9Hz, C _2,6 −H), C _3,5
-H overlaps with phenyl-H at the 3' and 5' positions, elemental analysis value C ₃₉ H ₄₁ FN ₂ O ₁₃ Calculated value (%): C, 61.25; H, 5.40; N, 3.66 Actual value (% ): C, 61.36; H, 5.26; N, 3.57 Example 45 3-benzoyl-3',5'-di-O-(4-ethoxyphenoxycarbonyl)-2'-deoxy-5
-Fluorouridine, yield: 66.6%, powder, UV λ ^EtOH _nax nm: 222, 254, 275 (sh), NMR δ (ppm, DMSO-d ₆ ): uridine moiety,
Around 2.6 (2H, m, C ₂ ′-H), 4.42-4.66
(3H, m, C ₄ ′ _,5 ′−H), 5.24−5.44 (1H,
m, C ₃ ′-H), 6.20 (1H, bt, J=7Hz,
C ₁ '-H), 8.26 (1H, d, J = 6Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 1.32 (6H,
t, J=7Hz, C H ₃ CH ₂ O−×2), 3.98
(4H, q, J=7Hz, CH ₃ CH ₂ O-×2),
6.84−8.10 (13H, m, phenyl-H, 3rd position
(overlaps with phenyl-): substituent part at position 3,
Overlapping with phenyl-H at 3' and 5' positions, elemental analysis value C ₃₄ H ₃₁ FN ₂ O ₁₂ Calculated value (%): C, 60.18; H, 4.60; N, 4.13 Actual value (%): C , 59.97; H, 4.34; N, 4.17 Example 46 3-(4-fluorobenzoyl)-3',5'-di-
O-(4-ethoxyphenoxycarbonyl)-2'-
Deoxy-5-fluorouridine, yield: 71.7
%, powder, UV λ ^EtOH _nax nm: 222, 256, 275 (sh), NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
Around 2.7 (2H, m, C ₂ ′-H), 4.48-4.64
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.48 (1H,
m, C ₃ ′-H), 6.26 (1H, bt, J=7Hz,
C ₁ '-H), 8.32 (1H, d, J = 7Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 1.32 (6H,
t, J=7Hz, C H ₃ CH ₂ O−×2), 4.04
(4H, q, J=7Hz, CH ₃ CH ₂ O-×2),
6.92−8.26 (12H, m, phenyl-H, 3rd position
(overlaps with phenyl-H); substituent part at position 3,
Overlapping with phenyl-H at 3' and 5' positions, elemental analysis value C ₃₄ H ₃₀ F ₂ N ₂ O ₁₂ Calculated value (%): C, 58.62; H, 4.34; N, 4.02 Actual value (%) :C, 58.68;H, 4.02;N, 3.87 Example 47 3-(4-methoxybenzoyl)-3',5'-di-
O-(4-ethoxyphenoxycarbonyl)-2'-
Deoxy-5-fluorouridine, yield: 52.7
%, powder, UV λ ^EtOH _nax nm: 222, 277, 283, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
Around 2.7 (2H, m, C ₂ ′-H), 4.48-4.64
(3H, m, C ₄ ′ _,5 ′−H), 5.30−5.44 (1H,
m, C ₃ ′-H), 6.24 (1H, bt, J=7Hz,
C ₁ '-H), 8.30 (1H, d, J = 6Hz, C ₆ -
H); Substituent moiety at 3' and 5' positions, 1.32 (6H,
t, J=7Hz, C H ₃ CH ₂ O−×2), 4.04
(4H, q, J=7Hz, CH ₃ CH ₂ O-×2),
6.90−7.24 (10H, m, phenyl-H and 3rd position
C _3,5 -H); 3-position substituent moiety, 3.90 (3H,
s, _CH3O− ), 8.06 (2H, d, J=9Hz,
C _2,6 -H), C _3,5 -H are phenyl at the 3' and 5' positions
Overlapping with -H, elemental analysis value C ₃₅ H ₃₃ FN ₂ O ₁₃・1/10CHCl ₃ Calculated value (%): C, 58.51; H, 4.63; N, 3.89 Actual value (%): C, 58.05; H, 4.46; N, 3.90 Example 48 3-(3-methylbenzoyl)-3',5'-di-O
-(4-benzyloxyphenoxycarbonyl)-
2'-deoxy-5-fluorouridine, yield:
87.7%, powder, UV λ ^EtOH _nax nm: 258, NMR δ (ppm, DMSO−d ₆ ): uridine moiety,
2.54−2.80 (2H, m, C ₂ ′−H), 4.42−4.70
(3H, m, C ₄ ′ _,5 ′−H), 5.32−5.48 (1H,
m, C ₃ ′-H), 6.12-6.40 (1H, m, C ₁ ′-
H), 6.93−8.40 (23H, m, C ₆ −H and
phenyl-H); substituent moiety at the 3′ and 5′ positions,
5.11 (4H, s, _-CH2O- ×2), phenyl-
H overlaps with uridine moiety); 3rd-position substituent moiety, 2.39 (3H, s, CH ₃ -), phenyl-
H overlaps with the uridine moiety, elemental analysis value C ₄₅ H ₃₇ FN ₂ O ₁₂ Calculated value (%): C, 66.17; H, 4.57; N, 3.43 Actual value (%): C, 66.00; H, 4.83 ;N, 3.67 Example 49 3-(4-bromobenzoyl)-3',5'-di-O
-(4-Methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 75%, powder, UV λ ^EtOH _nax nm: 219.5, 268, NMR δ (ppm, CDCl ₃ ): Uridine moiety , around 2.5 (2H, m, C ₂ ′-H), 4.41-4.64 (3H,
m, C4 _{′ ,5′} −H), 5.23−5.41(1H, m,
C ₃ ′-H), 6.38 (1H, bt, J=7Hz, C ₁ ′-
H), 7.82 (1H, d, J=6Hz, _C6 -H);
Substituent moieties at 3' and 5' positions, 3.81 (6H, s,
CH ₃ O−×2), 6.90 (4H, d, J=9Hz,
C _3,5 −H×2), 7.11 (4H, d, J=9Hz,
C _2,6 -H×2); 3rd-position substituent, 7.64
(2H, d, J = 9Hz, C _3,5 -H), 7.80
(2H, d, J = 9Hz, C _2,6 −H), elemental analysis value C ₃₂ H ₂₆ BrFN ₂ O ₁₂ , calculated value (%): C, 52.69; H, 3.59; N, 3.84 Actual value ( %): C, 52.61; H, 3.72; N, 3.83 Example 50 3-(4-methylbenzoyl)-3',5'-di-O
-(4-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 90%, powder, UV λ ^EtOH _nax nm: 216 (sh), 264.5, NMR δ (ppm, CDCl ₃ ) : Uridine moiety, around 2.5 (2H, m, C ₂ '-H), 4.38-4.66 (3H,
m, C4 _{′ ,5′} −H), 5.20−5.39(1H, m,
C ₃ ′-H), 6.35 (1H, bt, J=7Hz, C ₁ ′-
H), 7.75 (1H, d, J=6Hz, _C6 -H);
Substituent moieties at 3' and 5' positions, 3.77 (6H, s,
CH ₃ O−×2), 6.85 (4H, d, J=9Hz,
C _3,5 - H x 2), 6.96 - 7.16 (4H, m, C _2,6
-H×2); 3rd-position substituent group, 2.38 (3H,
s, CH ₃ −), 7.26 (2H, d, J=9Hz,
C _3,5 −H), 7.79 (2H, d, J=9Hz, C _2,6
-H), Elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₂ Calculated value (%): C, 59.64; H, 4.40; N, 4.22 Actual value (%): C, 59.75; H, 4.40; N, 4.15 Example 51 3-(2,3-dimethoxybenzoyl)-3′,
5'-di-O-(4-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine, yield: 98%, powder, UV λ ^EtOH _nax nm: 221, 267.5, 325, NMR δ ( ppm, _CDCl3 ): Uridine moiety, around 2.5 (2H, m, _C2' -H), 4.42-4.66 (3H,
m, _C4 ′ _,5′ −H), 5.28−5.42(1H, m,
C ₃ ′-H), 6.42 (1H, bt, J=7Hz, C ₁ ′-
H), 7.76 (1H, d, J=6Hz, _C6 -H);
Substituent moieties at 3' and 5' positions, 3.80 (6H, s,
CH ₃ O−×2), 6.90 (4H, d, J=9Hz,
C _3,5 −H×2), 7.02−7.30(6H, m,
phenyl-H and C _4,5 -H at position 3); substituent moiety at position 3, 3.86 (6H, s, CH ₃ O- x 2),
7.49−7.67 (1H, m, C ₆ −H), C _4,5 −H is
Overlapping with phenyl-H at 3' and 5' positions, elemental analysis value C ₃₄ H ₃₁ FN ₂ O ₁₄ Calculated value (%): C, 57.47; H, 4.40; N, 3.94 Actual value (%): C , 57.47; H, 4.40; N, 3.75 Example 52 1.50 g of 3',5'-di-O-(4-benzyloxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine and 4-n- Using 1.06 g of propoxybenzoyl chloride, 3-(4-n-propoxybenzoyl)-
1.30 g of 3',5'-di-O-(4-benzyloxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine was obtained. This was dissolved in 40 ml of methanol-acetone (3:1) solution, 0.4 ml of acetic acid was added, and the mixture was subjected to catalytic reduction using 5% palladium-carbon. After the reaction was completed, the catalyst was removed from the reaction mixture, and the liquid was concentrated under reduced pressure to obtain an oily residue. This was subjected to silica gel column chromatography (solvent: 1% methanol-chloroform).
The fractions were concentrated under reduced pressure to yield 410 mg of 3-(4-n-propoxybenzoyl)-3',5'-
Di-O-(4-hydroxyphenoxycarbonyl)
-2'-deoxy-5-fluorouridine was obtained. Yield: 40.2% powder, UV λ ^EtOH _nax nm: 222, 285, NMR δ (ppm, DMSO− _d6 ): uridine moiety,
2.55−2.75 (2H, m, C ₂ ′−H), 4.41−4.66
(3H, m, C ₄ ′ _,5 ′−H), 5.23−5.43 (1H,
m, C ₃ ′-H), 6.13-6.38 (1H, m, C ₁ ′-
H), 8.27 (1H, m, C ₆ -H); substituent moieties at 3' and 5' positions, 6.72-8.13 (12H, m,
phenyl-H, overlapped with phenyl-H at position 3),
9.52 (2H, m, HO-×2, disappeared by addition of D ₂ O); 3-position substituent moiety, 0.99 (3H, t,
J ₌ 7Hz, _CH3CH2CH2O- ), _1.60-1.95
(2H, m, CH ₃ C H ₂ CH ₂ O−), 4.09 (2H,
t, J=7Hz, CH ₃ CH ₂ CH ₂ O-),
phenyl-H overlaps with phenyl-H at the 3' and 5' positions, elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₃・1/10 CHCl ₃ , calculated value (%): C, 57.41; H, 4.24; N , 4.05 Actual value (%): C, 57.57; H, 4.19; N, 4.05 Examples 53 to 60 3',5'-di-O-phenoxycarbonyl-2'-
Deoxy-5-fluorouridine 2.00g and 4-n
-propoxybenzoyl chloride in various solvents in the presence of a base in the same manner as in Example 16 to obtain 3-(4-n-propoxybenzoyl chloride having physical properties consistent with those described in Example 24). )−
3',5'-di-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine was obtained. The reaction conditions and results are shown in Table 1.

[Table] Example 61 40 g of 3',5'-di-O-(4-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine was dissolved in 300 ml of dioxane, and 4-
22 g of n-propoxybenzoyl chloride and 50 ml of triethylamine were added. This was left under stirring at 80°C for 6 hours, and then concentrated under reduced pressure. The obtained residue was dissolved in 200 ml of ethyl acetate, and saturated brine was added.
The mixture was washed three times with 50 ml, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was washed with hot n-hexane and then recrystallized from ethyl acetate-ether-ethanol to give 42 g of 3-(4-n-propoxybenzoyl)-3',5'-di-O-(4 -methoxyphenoxycarbonyl)-2'-deoxy-
5-fluorouridine was obtained. Yield: 81%,
Melting point: 101-103℃, UV λ ^EtOH _nax nm: 222.5, 278 (sh), 283, 291 (sh)
, NMR δ (ppm, _CDCl3 ): Uridine moiety, around 2.4 (2H, m, _C2' -H), 4.30-4.58 (3H,
m, _C4 ′ _,5′ −H), 5.16−5.35(1H, m,
C ₃ ′-H), 6.32 (1H, bt, J=7Hz, C ₁ ′-
H), 7.77 (1H, d, J=6Hz, _C6 -H);
Substituent moieties at 3' and 5' positions, 3.72 (6H, s,
CH ₃ O−×2), 6.85 (4H, d, J=9Hz,
C _3,5 −H×2), 7.08 (4H, d, J=9Hz,
C _2,6 -H×2); Substituent part at position 3, 0.99
(3H, t, J=7Hz, CH ₃ CH ₂ CH ₂ O−),
1.50−1.96 (2H, m, CH ₃ CH ₂ CH ₂ O−),
3.93 (2H, t, J=7Hz, CH ₃ CH ₂ C H ₂ O
−), 6.90 (2H, d, J=9Hz, C _3,5 −H),
7.88 (2H, d, J = 9Hz, C _2,6 -H), elemental analysis value C ₃₅ H ₃₃ FN ₂ O ₁₃ , calculated value (%): C, 59.32; H, 4.69; N, 3.95 Actual value (%): C, 59.54; H, 4.75; N, 3.77 Example 62 3',5'-di-O-(4-methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine 10 g, 4 -Methoxybenzoyl chloride 4.8g
and Example 61 using 5.0 ml of triethylamine.
If you perform the same operation according to
-methoxybenzoyl)-3',5'-di-O-(4-
methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine was obtained. Yield: 77
%, melting point: 141.5-142.5℃, UV λ ^EtOH _nax nm: 222, 279 (sh), 283, NMR δ (ppm, _CDCl3 ): uridine moiety, around 2.5 (2H, m, _C2' -H), 4.36−4.60 (3H,
m, C ₄ ′ _,5 ′−H), 5.22−5.38(1H, m,
C ₃ ′-H), 6.35 (1H, bt, J=7Hz, C ₁ ′-
H), 7.77 (1H, d, J=6Hz, _C6 -H);
Substituent moieties at 3' and 5' positions, 3.76 (6H, s,
CH ₃ O−×2), 6.86 (4H, d, J=9Hz,
C _3,5 −H×2), 7.08 (4H, d, J=9Hz,
C _2,6 -H×2); 3-position substituent, 3.84
(3H, s, CH ₃ O−), 6.93 (2H, d, J=
9Hz, C _3,5 −H), 7.88 (2H, d, J=9
Hz, 3 _2,6 -H), elemental analysis value C ₃₃ H ₂₉ FN ₂ O ₁₃ Calculated value (%): C, 58.24; H, 4.29; N, 4.12 Actual value (%): C, 58.01; H, 4.32; N, 4.38 In order to investigate the pharmacological characteristics of the compound of the present invention produced in this way, the following tests for measuring antitumor activity and toxicity were conducted. In particular, in tests for measuring toxicity, the compounds of the present invention
Since it is a time-dependent antimetabolite like FUDR (Cancer Medicine; page 675, right column,
Page 676, right column, Lee and Huebiger,
(1973, Pharmacia, Vol. 9, p. 467, Pharmaceutical Society of Japan, 1973), taking into account cumulative toxicity, the toxicity that occurs after daily administration of the compound of the present invention for 7 to 10 days, that is, the occurrence of death and body weight. , bone marrow, and gastrointestinal tract toxicity were measured. Furthermore, various therapeutic coefficients were determined for the compounds of the present invention from these test results. In addition to FUDR, AcFUDR, and 5-FU, similar tests were also conducted on the following known compounds. A: 3-(3-methylbenzoyl)-3',5'-di-
O-acetyl-2'-deoxy-5-fluorouridine B: 3-(3,4-methylenedioxybenzoyl)
-3',5'-di-O-acetyl-2'-deoxy-5-fluorouridine C: 3-(3,4-methylenedioxybenzoyl)
-2'-deoxy-5-fluorouridine D: 3-phenoxycarbonyl-3'-O-acetone-5'-O-phenoxycarbonyl-2'-deoxy-5-fluorouridine 1 Antitumor in mice Tests to measure activity and toxicity (1) Tests in a system using polyethylene glycol as the administration solvent (a) Tests to measure antitumor activity Sarcoma 180 tumor cells (subcultured intraperitoneally in ICR male mice) )
Approximately 10 million cells were transplanted subcutaneously into the inguinal region of 5-week-old male ICR mice. After 24 hours, administration of compounds of the invention began. Administration was performed once a day for 7 days using an oral probe, and the weight of each animal was measured every day immediately before administration.
The compounds of the present invention are polyethylene glycol
Polyethylene glycol 400 alone was administered to the control group in the same volume of 0.1 ml/10 g to each animal. The dosage of the compounds of the present invention varies depending on the individual compound, but is generally between 2 mg/Kg and 128
mg/Kg range, and for the same compound,
The dose was varied over 3 to 6 steps, and one group of mice (consisting of 6 mice) was administered the compound of the invention at each dose step. In addition, 18 mice were used as a control group. On the 8th day after transplantation, the mouse was sacrificed by exsanguination under ether anesthesia, the tumor tissue was excised, and the tumor weight was immediately measured. Average tumor weight for each dose of each compound (this is defined as T)
The average tumor weight (this is referred to as C) in the control group and the control group was determined, and the values indicating T/C values of 0.70 and 0.50 were read from the dose-response curve. The results are shown in Table 2.

【table】

[Table] (b) Test for measuring toxicity Toxicity was measured by measuring the body weight and white blood cell count of the mice in the experiments (1) to (a) above. (i) Effect on body weight Animal body weights were measured daily from before the first administration until just before sacrifice on the 8th day. As a toxicity index, the dose at which the average body weight immediately before slaughter on day 8 was 96% of the average body weight before administration (BW ₉₆ %) was determined from a dose-response curve. Furthermore, in order to understand the relationship between antitumor activity and toxicity, the ratio of BW ₉₆ % to T/C: 0.70 (BW ₉₆ %/T/C) was used as the therapeutic coefficient.
C: 0.70) was calculated. The results are shown in Table 3.

【table】

[Table] (ii) Effect on white blood cell count The number of white blood cells in the blood collected at the time of slaughter on the 8th day was measured using the TOA automatic blood cell counter model.
Dose showing 30% of the white blood cell count of the control group (L/C: 0.30) measured using CC-108
was determined from a dose-response curve. Furthermore, in order to understand the relationship between antitumor activity and bone marrow toxicity, L/
The ratio of C: 0.30 and T/C: 0.70 (L/
C: 0.30/T/C: 0.70) was determined. The results are shown in Table 4.

【table】

[Table] (2) Test in a system using 5% acacia solution as the administration solvent (a) Test for measuring antitumor activity Polyethylene glycol 400, which was used as the administration solvent in (1)-(a) above, was added to 5% The same experiment as in (1)-(a) was conducted except that the acacia solution was used to test the antitumor activity of the compound of the present invention. The results are shown in Table 5.

【table】

[Table] (b) Toxicity measurement test A toxicity measurement test was conducted by measuring the body weight, white blood cell count, and degree of gastrointestinal disorder of the mice in the experiment (2)-(a) above. (i) Effect on body weight In the same manner as described in (1)-(b)-(i) above, BW ₉₆ % and therapeutic coefficient were determined.
BW ₉₆ %/T/C: 0.70 and BW ₉₆ %/
T/C: 0.50 was calculated. The results are shown in Table 6.

[Table] (ii) Effect on white blood cell count Using the same method as described in (1)-(b)-(ii) above, L/C: 0.30 and therapeutic coefficient L/C: 0.30/T/C. :0.70 and L/
C: 0.30/T/C: 0.50 was calculated. The results are shown in Table 7.

[Table] (iii) Effects on the gastrointestinal tract On the 8th day, the animals were subjected to laparotomy after tumor removal, and damage to the gastrointestinal tract was visually observed to determine the effects on the gastrointestinal tract according to the following criteria. . Gastrointestinal disorder index criteria Small intestine contents: Watery but mild: 1 point Watery, with almost no contents 2 points: Cecal stool condition; muddy but with a high water content 1 point: If the stool is watery and has little content 2 points: Condition of colon/rectal stool; Soft stool (stool just before defecation) 1 point: If the stool is diarrhea and contains content 2 points: Watery stool with almost no content case
3 points The sum of the indices related to the small intestine, cecum, colon, and rectum for each individual shall be the disability index for that individual. Therefore, the individual in which the most severe impairment was observed would receive an index of 7 points. In addition, the sum of the indices of all animals in each group was calculated, and the degree of disability for that group was determined as follows. In other words, when the total value is between 0 and 4 points, the degree of disability for that group is considered negative (-), between 5 and 9 points is considered a weak disability (±), and between 10 and 14 points is considered a slightly severe disability ( +), 15 to 19 points as a strong obstacle (),
A score of 20 or more was defined as an extremely severe disability (). The results are shown in Table 8 as the degree of gastrointestinal disorder at each dose of T/C: 0.30 (dose at which the tumor weight of the administration group is 30% of that of the control group), T/C: 0.50, and T/C 0.70.

[Table] 2 Tests to measure antitumor activity and toxicity in rats (1) Tests using oral administration (a) Tests to measure antitumor activity Five million Yoshida sarcoma cells (injected intraperitoneally into male Donriyu rats (subcultured) was subcutaneously transplanted into the inguinal region of a 6-week-old male rat (weighing 180 to 200 g). After 24 hours, administration of compounds of the invention began. Administration was performed once a day for 7 days using an oral probe, and the weight of each animal was measured every day immediately before administration. The compound of the invention is dissolved in polyethylene glycol 400,
In addition, the control group included polyethylene glycol
400 were administered in the same volume of 0.5ml/100g to each animal. Doses of the compounds of the invention ranged from 5 mg/Kg to 90 mg/Kg, with the same compound being administered in three steps, with one group of rats (consisting of 10 animals) receiving the same dose at each dose step. A compound of the invention was administered. Furthermore, 20 rats were used as a control group. On the 8th day after transplantation, the tumor tissue of the rat was excised under ether anesthesia, and the tumor weight was immediately measured. The antitumor activity of the compounds of the present invention was measured in the same manner as described in section 1-(1)-(a) above.

[Table] (b) Test for measuring toxicity Toxicity was measured by measuring the body weight of the rats in the experiments 2-(1) to (a) above. That is, the weight of the animals was measured every day from before the first administration of the compound of the present invention until immediately before sacrifice on the 8th day. Then, for each of the control group and each administration group, the average body weight before the first administration and immediately before sacrifice on the 8th day was determined, and the rate of change in body weight between the two time points was calculated. Next, calculate the rate of change in each dose group divided by the rate of change in the control group, plot these values and the dose of the compound of the present invention to create a dose-response curve, and from this curve, calculate the value of 0.90. Dose of the compound of the invention to be given (BW _0.90 )
was read and used as a toxicity index. In addition, in order to understand the relationship between antitumor activity and toxicity, BW _0.90 and T/
Ratio of C: 0.70 and T/C: 0.50 (BW _0.90 /T/C: 0.70 and BW _0.90 /T/
C: 0.50) was calculated. The results are shown in Table 10.

[Table] (2) Test using intraperitoneal administration system (a) Test for measuring antitumor activity Polyethylene glycol 400, which was used as the administration solvent in 2-(1)-(a) above, was mixed with 1% Tween-80-physiological The same experiment as in 2-(1)-(a) was conducted to measure the antitumor activity of the compound of the present invention by changing the administration route to a saline solution and intraperitoneal administration. The results are shown in Table 11.

【table】

[Table] (b) Toxicity measurement test A toxicity measurement test was conducted by measuring the body weight and degree of gastrointestinal disorder of the rats in the experiment 2-(2)-(a) above. (i) Effect on body weight In the same manner as described in 2-(1)-(b) above, BW _0.90 and therapeutic coefficient were determined.
BW _0.90 /T/C: 0.70 and BW _0.90 /T/
C: 0.50 was calculated. The results are shown in Table 12.

[Table] (ii) Effect on the gastrointestinal tract 1-(2)-(b) of the above test on mice
The effect of the compound of the present invention on the gastrointestinal tract was measured in the rats used in the experiment in 2-(2)-(a) above in the same manner as described in section -(iii). The compounds of the present invention to be tested are the same compounds listed in Tables 11 and 12. The test results show that none of the tested compounds of the present invention caused any damage to the gastrointestinal tract. That is, the compound of the present invention has T/C:
At each dose of 0.30, T/C: 0.50, and T/C: 0.70, the disability index was given a score of 0, which was equal to the control group. 3 Acute toxicity test The acute toxicity test of anticancer drugs with cumulative toxicity is as follows:
If the administration is not continued for at least 5 days,
Since no toxicity findings were obtained, in this study, the compound of the present invention was administered to mice for 7 days.
For rats, the administration was continued for 10 days, and the survival, body weight, and behavior of the animals were observed. Furthermore, the mice were continuously observed even after the end of the administration period. (1) Test on mice 5-week-old ICR male mice (6 mice per group)
Then, the compound of the present invention suspended in a 1% Tween 80 aqueous solution was orally administered using an oral probe.
Administration was performed once a day for 7 consecutive days.
Animals were observed over the course of several days. For compounds of the invention in which the symbols R ₁ and R ₂ in general formula (I) are both hydrogen, the dose is 196
Although the dose was increased to mg/Kg, no deaths were observed in these administration groups. Further, in the general formula (I), R ₁
is 3-methylbenzoyl or 4-n-propoxybenzoyl and R ₂ is hydrogen, no deaths occurred in the administration group where the dose was increased to 274 mg/Kg,
Only inhibition of weight gain in animals was observed. i.e. 196mg/Kg and 274mg/Kg
In the treated group, a weight loss of 5% to 17% was observed from day 7 to day 14 compared to the control group. In contrast, for known compound C, 157mg/
In the Kg-treated group, half of the animals died. (2) Test on rats 5%
The compound of the present invention suspended in aqueous acacia solution was orally administered for 10 consecutive days using an oral probe,
Animals were observed during the administration period. For compounds of the present invention in which the symbol R ₁ in general formula (I) is 4-methoxybenzoyl or 4-n-propoxybenzoyl and R ₂ is 4-methoxy, the dose is increased to 320 mg/Kg and administered. No deaths occurred in these treatment groups. 160mg/Kg and 320
In the mg/Kg administration group, no changes were observed other than suppression of animal weight gain (7% to 10% decrease compared to the control group). In contrast, for known compound A, 216mg/
Two of the 10 patients in the Kg administration group died. As described above, the results of tests in different tumor systems using mice and rats clearly demonstrate that the compounds of the present invention have useful antitumor activity. Furthermore, from the test results of the various toxicity measurements mentioned above and the various therapeutic index values obtained, the compound of the present invention can be used at doses that exhibit effective antitumor activity.
It can be clearly seen that the compound exhibits extremely low toxicity compared to known compounds. That is, the compound of the present invention has low general toxicity as shown by the results of the test for measuring the effect on body weight and the test for acute toxicity, and the result of the test for measuring the effect on white blood cell count shows that it has little harmful effect on the bone marrow and has low digestive effects. From the results of tests to measure effects on the gastrointestinal tract, it is clear that it is an antitumor agent with excellent pharmacological characteristics such as no harmful effects on the gastrointestinal tract. Preferred clinical dosages of the compounds of the invention range from 1 to 600 mg per adult per day. Regarding the dosage form and route of administration, intravenous, subcutaneous, or intramuscular administration is possible as an injection, but rectal administration via suppositories, or oral administration via tablets, capsules, liquids, etc. is preferred. be. For example, the preferred dosage form is 0.5 to 200 mg per unit dosage form.
Examples include tablets, capsules, liquids, suppositories, etc., containing the compound of the present invention as an active ingredient. These tablets and capsules may contain the following commonly used ingredients in addition to the active ingredient. That is, for example, excipients include lactose, corn starch, potato starch, various sucrose fatty acid esters, microcrystalline cellulose, polyethylene glycol 4000, etc.; binders include acacia, gelatin, hydroxypropyl cellulose,
Potato starch, etc.; as a lubricant, magnesium stearate, hydrogenated oil, talc, etc.; as a disintegrant, carboxymethyl cellulose calcium,
Low-substituted hydroxypropyl cellulose, corn starch, etc. are used. Although commonly used dissolving agents, suspending agents, etc. can be used for the liquid preparation, it is particularly preferable to use polyethylene glycol 200 to 600. As a base for suppositories, vitepsol, glycerin, cacao butter, lauric butter, glycerogelatin, polyethylene glycol, etc. can be used. Typical examples of formulations containing the compound of the present invention as a pharmaceutically active ingredient are shown below. Formulation Examples Capsules were produced by filling the compound of the present invention into capsules according to a conventional formulation method based on the following formulation. Formulation 1 (in 1 capsule) 3-(4-n-propoxybenzoyl)-3',5'-
Di-O-phenoxycarbonyl-2'-deoxy-
5-fluorouridine 100mg Lactose 69mg Magnesium stearate 1mg 170mg Formulation 2 (in 1 capsule) 3-(4-methoxybenzoyl)-3',5'-di-O
-(4-Methoxyphenoxycarbonyl)-2'-deoxy-5-fluorouridine 50mg Lactose 235mg Magnesium stearate 5mg 290mg Granulated using the compound of the present invention, excipients and binder according to the following recipe. After drying, the mixture was filled into capsules to produce capsules.

[Table] Suppositories were manufactured by a melting method using the compound of the present invention and a base according to the following formulation.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ represents a hydrogen atom or a group [Formula], and R ₂ and R ₃ are the same or different and are a hydrogen atom, a hydroxy group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, 1 an alkoxy group having ~4 carbon atoms,
Represents at least one atom or group selected from the group consisting of benzyloxy groups. ) A 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative. 2. The 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative according to claim 1, wherein _R1 is a hydrogen atom. 3. The 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative according to claim 1, wherein R ₁ is a group [Formula]. 4 3',5'- according to claim 1, wherein R ₂ is an alkoxy group having 1 to 4 carbon atoms.
Di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivatives. 5 3', 5'- according to claim 3, wherein R ₂ is an alkoxy group having 1 to 4 carbon atoms.
Di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivatives. 6 Claim 5 in which R ₂ is a methoxy group
3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivatives as described in 2. 7 _3′ ,5′- according to claim 3, wherein R 3 is an alkoxy group having 1 to 4 carbon atoms.
Di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivatives. 8. The 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative according to claim 7, wherein _R3 is a propoxy group. 9 3',5'-di-O-phenoxycarbonyl-substituted-2 according to claim 7, wherein R ₂ is an alkoxy group having 1 to 4 carbon atoms, which is the same as or different from R ₃ '-deoxy-5-fluorouridine derivative. 10 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5- according to claim 8, wherein R ₂ is a hydrogen atom and R ₃ is a 4-n-propoxy group. Fluorouridine derivative. 11. The 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative according to claim 9, wherein _R2 and _R3 are both 4-methoxy groups. 12 3' according to claim 9, wherein R ₂ is a 4-methoxy group and R ₃ is a 4-n-propoxy group;
5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative. 13 General formula (In the formula, R ₁ represents a hydrogen atom or a group [Formula], and R ₂ and R ₃ are the same or different and are a hydrogen atom, a hydroxy group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, 1 an alkoxy group having ~4 carbon atoms,
Represents at least one atom or group selected from the group consisting of benzyloxy groups. ) In producing the 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative, 2'-deoxy-5-fluorouridine is substituted with the general formula (R ₂ in the formula has the same meaning as above.) or by reacting 2'-deoxy-5-fluorouridine with phosgene, the product obtained by the general formula (R ₂ in the formula has the same meaning as above), or the reaction product thus obtained is reacted with the general formula (R ₃ in the formula has the same meaning as above, and hal represents a halogen atom.) 3',5'- A method for producing a di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine derivative. 14 Reaction of 2'-deoxy-5-fluorouridine with chloroformates or phosgene, reaction of products obtained by the reaction with phosgene with phenols, and reaction products obtained in this way with 3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy- according to claim 13, wherein the reaction with benzoyl halides is carried out in the presence of a base. A method for producing a 5-fluorouridine derivative. 15 General formula (In the formula, R ₁ represents a hydrogen atom or a group [Formula], R ₂ and R ₃ are the same or different, and are a hydrogen atom, a hydroxy group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, 1 an alkoxy group having ~4 carbon atoms,
3',5'-di-O-phenoxycarbonyl-substituted-2'-deoxy-5-fluorouridine represented by at least one atom or group selected from the group consisting of benzyloxy groups) An antitumor agent containing a derivative as an active ingredient. 16 Claim 1 in which R ₁ is a hydrogen atom
The antitumor agent according to item 5. 17. The antitumor agent according to claim 15, wherein R ₁ is a group [Formula]. 16. The antitumor agent according to claim 15, wherein 18 R ₂ is an alkoxy group having 1 to 4 carbon atoms. 18. The antitumor agent according to claim 17, wherein 19 R ₂ is an alkoxy group having 1 to 4 carbon atoms. 20. The antitumor agent according to claim 19, wherein _R2 is a methoxy group. 18. The antitumor agent according to claim 17, wherein 21 R ₃ is an alkoxy group having 1 to 4 carbon atoms. 22. The antitumor agent according to claim 21, wherein R ₃ is a propoxy group. 23. The antitumor agent according to claim 21, wherein _R2 is an alkoxy group having 1 to 4 carbon atoms, which is the same as or different from _R3 . 24. The antitumor agent according to claim 22, wherein _R2 is a hydrogen atom and _R3 is a 4-n-propoxy group. 25. The antitumor agent according to claim 23, wherein R ₂ and R ₃ are both 4-methoxy groups. 26. The antitumor agent according to claim 23, wherein _R2 is a 4-methoxy group and _R3 is a 4-n-propoxy group.