JP3115386B2 - Boron-containing uridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel boron-containing uridine derivative, and more particularly to a boron-containing uridine derivative which is used as a neutron capture agent in neutron capture therapy of various cancers or as a growth inhibitor for cancer cells. About.

[0002]

2. Description of the Related Art Until now, alkylating agents, antimetabolites, various anticancer antibiotics, plant alkaloids and the like have been put into practical use as anticancer agents, but all of these are basically cytotoxins. Yes, its anti-cancer mechanism is based on the difference in the growth rate between cancer cells and normal cells, so it is inevitable to damage the normal cells to some extent. there were.

[0003] Various attempts have been made to overcome this drawback. For example, as one example, BRM (Bi
(Biological Response Modifier) therapy has been proposed, but its effect is currently not satisfactory.

As another method, neutron capture therapy has been proposed. This and neutron capture therapy, the following equation between the natural and the boron atom having a mass number of 10 is a stable isotope contained about 20% in boron ⁽¹⁰ B) and the low energy thermal neutrons: ¹⁰ B ₅ + ¹ generated during the nuclear reaction shown in _{^{n 0 → 7 Li 3 + 4}} He 2 + 2.4MeV, a therapy that attempts to utilize the energy of 2.4MeV the destruction of cancer cells. That is, the compound containing ¹⁰ B a ⁽¹⁰ B carrier) are administered to a cancer patient, a ¹⁰ B carrier by irradiating a low energy thermal neutrons in after selectively taken up into cancer cells, cancer cells selectively It is a cure to get rid of it.

Examples of such neutron capture therapy include Hatanaka et al.'S attempt on brain tumors of mercaptoundecahydrododecaborate and Mishima et al.'S attempt on paraboronophenylalanine for malignant melanoma. (Yoshinori Yamamoto: Chemistry 46 10 pp. 24-27 1
991), but in order to further commercialize neutron capture therapy, there has been a strong demand for the development of a useful ¹⁰ B carrier applicable to a wider range of cancer types.

[0006]

Means for Solving the Problems The inventors of the present invention have been conducting research for the purpose of developing a useful and useful ¹⁰ B carrier having a wider range of application. The present inventors have found that a compound into which a boron atom has been introduced is incorporated into tumor cells at a high rate, is useful as a ¹⁰ B carrier, and has a growth inhibitory effect on cancer cells.

That is, the present invention provides the following general formula (I)

Embedded image (Wherein, X represents a hydrogen atom or a hydroxyl group, R represents a hydrogen atom, a lower alkyl group or a hydroxy-lower alkyl group) have a boron-containing uridine derivative and this is represented by
It is intended to provide a cell growth inhibitor as an active ingredient .

The boron-containing derivative of the present invention can be produced, for example, by any of the following methods.

Method 1: In formula (I), a compound in which R is a hydrogen atom (compound (Ia)) is first prepared according to the following reaction formula according to Robins et al. (Robins, MJ et al. Can. J. Chem.
vol. 60, p. 554 (1982)), in the presence of a palladium catalyst and copper iodide, iodinated uridine (compound (II) in which X ′ = OBz; compound (II) -1)) or iodinated deoxyuridine (compound (II) in which X ′ = H; compound (II-2))
Is reacted with trimethylsilylacetylene (IIIa) to obtain a corresponding trimethylsilylacetylene derivative (IVa), and then the obtained trimethylsilylacetylene derivative is detrimethylsilylated with tetrabutylammonium fluoride or the like to obtain a corresponding acetylene derivative (Va). Further, the obtained acetylene derivative is reacted with decaborane (VI) in the presence of a Lewis base to synthesize a protected benzoyl compound (VIIa) of the target compound, for example, by deprotection with sodium methoxide in methanol. be able to.

[0010]

Embedded image (Wherein Bz represents a benzoyl group, TMS represents a trimethylsilyl group, X represents a hydrogen atom or a hydroxyl group, and X ′ represents a hydrogen atom or a —OBz group). Compound (II) and compound (I
Examples of the palladium catalyst used in the reaction of IIa) include palladium chloride, palladium bromide, palladium acetate, palladium trifluoroacetate, palladium acetylacetonate, palladium bisbenzonitrile dichloride and the like. Examples of Lewis bases used in the reaction of compound (Va) with decaborane (VI) include propionitrile, diethyl sulfide and the like, and Heing et al. (Heying, TL et al .; Inorg. Chem. 1963,
2, p.1089) and Fine et al. (Fein, MM et al .; Inorg.
Chem. 1963, 2, p. 1111), and Lewis bases used for introducing decaborone into triple bonds.

Method 2: In formula (I), a compound wherein R is a hydroxy lower alkyl group and X is a hydroxyl group or a hydrogen atom (compound (Ib)) is prepared according to the following reaction formula:
Acyloxy lower alkyl acetylene (IIIb) is reacted with iodinated uridine (II-1) or iodinated deoxyuridine (II-2) in the presence of a palladium catalyst and copper iodide to form a corresponding acyloxy lower alkyl acetylene derivative (IVb) Then, the obtained acyloxy lower alkylacetylene derivative is reacted with decaborane (VI) in the presence of a Lewis base to give an acyl-protected compound (Vb) of the target compound
This can be synthesized, for example, by deprotection with sodium methoxide in methanol.

[0012]

Embedded image (In the formula, Ac represents an acyl group, L represents a lower alkylene group, and X, X ′ and Bz have the above-mentioned meanings.)

Method 3: Further, in the formula (I), a compound (compound (Ic)) in which R is a lower alkyl group and X is a hydroxyl group or a hydrogen atom is prepared according to the following reaction formula with a palladium catalyst and iodide. In the presence of copper, iodinated uridine (II-1) or iodinated deoxyuridine (II-2) was reacted with lower alkyl acetylene (IIIc) to give the corresponding lower alkyl acetylene derivative (IVc). It can be synthesized by reacting a lower alkylacetylene derivative with decaborane (VI) in the presence of a Lewis base to form a protected benzoyl compound (Vc) of the target compound, for example, by deprotection with sodium methoxide in methanol. .

[0014]

Embedded image (Wherein, Bz represents a benzoyl group, Q represents a lower alkyl group, and X and X ′ have the above-mentioned meanings)

The boron-containing uridine derivative (I) produced as described above is purified, if necessary, by a known purification means such as various column chromatography, liquid-liquid distribution, recrystallization, etc. A neutron capture agent or a cancer cell growth inhibitor can be obtained by combining with a carrier for neutrons. Of these, the neutron capture agent can be appropriately adjusted in its administration form depending on the type of the target cancer and its site, and an example of a preferable form is injection for local administration to or around a tumor site. And intravenous injections.

[0016]

The boron-containing uridine compound of the present invention has a uridine skeleton, which is a component of RNA, and is taken up by cancer cells with high cell proliferation regardless of the type of cancer. In addition, according to the ICP-AES method reported by the present inventors, the compound of the present invention is shown to be taken up into tumor cells at a high rate, so that it is advantageously used as a ¹⁰ B carrier in neutron capture therapy for various cancers. It is expected to be able to do.

Further, as described later in the Examples, the compound of the present invention itself has a growth inhibitory effect on cancer cells, and thus can be expected to have an effect as an anticancer agent in addition to neutron capture therapy. As described above, the mechanism of the action of the compound of the present invention to suppress the growth of cancer cells is not clear, but RNA incorporating the compound of the present invention instead of uridine does not perform its normal function. Conceivable. Therefore, if the compound of the present invention is a cancer type that is incorporated into RNA, the growth can be suppressed irrespective of the target, and not only that, but also acquired immunodeficiency syndrome (AIDS) caused by RNA virus. ) And adult T-cell leukemia (ATL).

[0018]

Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

EXAMPLES Example 1. 5-Carboranyluridine (in the formula (I), X = OH, R
(A) 2 ′, 3 ′, 5′-tris-O-benzoyl-5-
Preparation of [2- (trimethylsilyl) ethynyl] uridine (compound of formula (IVa) where X ′ = OBz) 2 ′, 3 ′, 5′-tris-O-benzoyl-5-iodo-
In a solution of 2.046 g (3.0 mmol) of uridine (II-1) in 30 ml of tetrahydrofuran (hereinafter abbreviated as THF), 53 mg (0.30 mmol) of palladium chloride, 158 mg (0.60 mmol) of triphenylphosphine and cuprous iodide 114 mg (0.60 mmol) was dissolved, and 1.2 ml of triethylamine and 0.85 ml (6.0 mmol) of trimethylsilylacetylene were added thereto, followed by stirring at 40 ° C. for 2 hours under an argon stream. The solvent was distilled off under reduced pressure,
The product was purified by a silica gel column (benzene: ethyl acetate = 5: 1) to give the title compound, 2 ′, 3 ′, 5′-tris-O-
Benzoyl-5- [2- (trimethylsilyl) ethynyl] uridine 1.47 g (2.25 mmol; yield 75)
%).

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3450, 3080, 2980,
2160,1720,1695,1460,1275,11
40,1100,850,715. ¹ in _{H-NMR (CDCl 3, 270MHz} , δpp
m): 8.24 (1H, s), 7.44 (1H, s), 7.3
2 to 8.14 (15H, m), 6.30 (1H, d, J = 5.
9Hz), 5.86 (1H, dd, J = 5.9, 3.7Hz),
5.74 (1H, dd, J = 5.9, 5.9 Hz), 4.76
. (3H, m), 0.18 (9H, m) MS (M + H): Calculated (as _{C 35 H 33 O 9 N 2} Si); m / z 65
3.1956, found; m / z 653.1973.

(B) 2 ', 3', 5'-tris-O-benzoyl-5- (ethynyl) uridine (in the formula (Va), X '=
Production of OBz compound) 2 ′, 3 ′, 5′-Tris-O-benzoyl-5- [2- (trimethylsilyl) ethynyl] obtained in (a) above
1.10 g (1.69 mmol) of uridine is added to THF 15
Then, 1.85 ml of a 1.1 M / THF solution of tetrabutylammonium fluoride was added dropwise thereto, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, the organic layer was extracted with dichloromethane, washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by a silica gel column (dichloromethane: ethyl acetate = 50: 1) to give a yield of 97%.
2 ′, 3 ′, 5′-Tris-O-benzoyl-5- (ethynyl) uridine which is a detrimethylsilyl derivative in%
4 mg (1.64 mmol) were obtained.

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3430, 3300, 3250,
3110,3090,1720,1450,1270,11
20,1090,710. ¹ H-NMR (in CDCl ₃ , 270 MHz, δpp
m): 8.24 (1H, brs), 7.79 (1H, s),
7.34 to 8.14 (15H, m), 6.34 (1H, d, J
= 5.9 Hz), 5.89 (1H, dd, J = 5.9, 4.0H)
z), 5.74 (1H, dd, J = 5.9, 5.9 Hz), 4.
83 (1H, dd, J = 14.0, 4.5 Hz), 4.75
(1H, m), 4.73 (1H, dd, J = 14.0,3.5H
z), 2.99 (1H, s). ¹³ C-NMR (270 MHz, δpp in CDCl ₃ )
m): 166.1, 165.3, 165.2, 160.9,
149.0, 143.2, 133.8, 133.7, 133.
5, 129.8, 129.7, 129.6, 129.0, 1
28.7, 128.5, 128.2, 100.3, 88.
1,82.3, 80.8, 73.9, 73.7, 7
. 1.2, 63.7 MS (M + H): Calculated (as _{C 32 H 25 O 9 N 2} ); m / z 581.1
560, found m / z: 581.1563.

(C) 2 ', 3', 5'-tris-O-benzoyl-5-carboranyluridine (in the formula (VIIa), X '
= OBz compound) 145m of the detrimethylsilyl derivative obtained in the above (b)
To 10 ml of a toluene solution of g (0.25 mmol) were added 37 mg (0.30 mmol) of decaborane and 0.36 ml (5.0 mmol) of propionitrile, and the mixture was refluxed for 18 hours under a stream of argon. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column (dichloromethane: ethanol = 10
0: 1) to give the title compound 2 ′,
117 mg of 3 ', 5'-tris-O-benzoyl-5-carboranyluridine was obtained.

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3450, 3250, 3100,
2610,1740,1690,1460,1275,11
30, 1100, 720. ¹ H-NMR (270 MHz, δpp in CDCl ₃ )
m): 8.50 (1H, brs), 7.76 (1H, s),
7.34 to 8.14 (15H, m), 6.19 (1H, d, J
= 5.9Hz) 5.93 (1H, dd, J = 5.5,4.0H)
z), 5.76 (1H, dd, J = 5.5, 5.5 Hz), 5.
61 (1H, brs), 4.81 (1H, dd, J = 11.
4.3.7 Hz), 4.77 (2H, m), 4.68 (1H, d
d, J = 11.4, 3.7 Hz), 1.0 to 3.0 (10H, b
r) ¹³ C-NMR (in CDCl ₃ , 270 MHz, δpp
m): 166.1, 165.4, 165.2, 160.3,
148.6, 142.6, 133.8, 133.7, 133.
4, 129.8, 129.7, 129.0, 128.5, 1
28.4, 128.4, 128.3, 128.0, 107.
8, 89.7, 80.7, 73.8, 71.1, 69.
. 2, 64.0,57.8 MS (M + H): Calculated (as _{C 32 H 35 O 9 N 2} B 10); m / z 70
1.3277, found; m / z 701.3370.

(D) Production of 5-carboranyl uridine 2 ', 3', 5'-Tris-O-benzoyl-5-carboranyl uridine 51 obtained according to the method of (c) above
0 mg (0.73 mmol) and 198 mg (3.67 mmol) of sodium methoxide in 20 ml of methanol
And stirred at room temperature for 3 hours. After the completion of the reaction, an ion exchange resin (Dowex 50W × 8, H ⁺ type) is added and p
After H was set to 6, it was filtered. The filtrate was concentrated under reduced pressure, and then subjected to a silica gel column (dichloromethane: ethanol = 15:
Purification was performed in 1) to give 235 mg (0.61 mmol) of the title compound, 5-carboranyluridine, as a white powder in a yield of 83%.

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3420, 3100, 2950,
2600,1700,1470,1300,1310. ¹ in _{H-NMR (CD 3 OD,} 270MHz, δpp
m): 8.49 (1H, s), 5.97 (1H, brs),
5.94 (1H, d, J = 4.8 Hz), 4.20 (1H, d
d, J = 4.8, 4.8 Hz), 4.15 (1H, dd, J =
4.8, 4.8 Hz), 4.07 (1H, m), 3.85 (1
H, dd, J = 11.7,2.6 Hz), 3.74 (1H, d
d, J = 11.7, 2.6 Hz). ¹³ C-NMR (270 MHz, δpp in CD ₃ OD)
m): 162.5, 151.0, 144.4, 108.0,
90.9, 86.7, 76.5, 72.3, 71.7,
62.0, 59.8. Melting point: 279-280 ° C

EXAMPLE 2 5-Carboranyl-2'-deoxyuridine (formula (I)
Wherein X = R = H): (a) 3 ′, 5′-bis-O-benzoyl-5- [2-
Preparation of (trimethylsilyl) ethynyl] -2′-deoxyuridine (compound of formula (IVa) where X ′ = H) 3 ′, 5′-bis-O-benzoyl-5-iodo-2′-deoxyuridine (II -b) 490 mg (0.87 mmol)
1), 15.4 mg of palladium chloride (0.087 mmol)
l), 45.6 mg of triphenylphosphine (0.17)
mmol) and cuprous iodide 33 mg (0.17 mm
ol) in 10 ml of THF solution.
25 ml (1.7 mmol) and 0.25 ml (1.74 mmol) of trimethylsilylacetylene were added, and reacted at 40 ° C. for 1 hour in an argon stream. After the reaction, the reaction was treated in the same manner as in Example 1 (a), and the title compound 3 ′, 5′-bis-O-benzoyl-5- [2-
(Trimethylsilyl) ethynyl] -2′-deoxyuridine (297 mg, 0.56 mmol) was obtained.

The physical properties of this compound are shown below. ¹ H-NMR (in CDCl ₃ , 270 MHz, δpp
m): 8.32 (1H, bs), 7.43 to 8.08 (10
H, m), 7.88 (1H, s), 6.37 (1H, dd, J =
8.5, 5.5 Hz), 5.60 (1 H, m), 4.83 (1
H, dd, J = 12.0, 3.5 Hz), 4.67 (1H, d
d, J = 12.0, 3.0 Hz), 4.59 (1H, m), 2.
78 (1H, ddd, J = 14.0, 5.5, 1.5 Hz),
2.28 (1H, ddd, J = 14.0, 8.5, 6.5H
z), 0.14 (9H, s) ¹³ C-NMR (270 MHz, δpp in CDCl ₃ )
m): 166.3, 166.2, 161.5, 149.6,
142.3, 133.9, 133.8, 130.0, 129.
8, 129.4, 129.2, 129.0, 128.8, 1
01.3, 100.1, 95.2, 86.2, 83.
5,75.3,64.6,38.8.

(B) 3 ', 5'-bis-O-benzoyl-
5-ethynyl-2′-deoxyuridine (in the formula (Va),
Production of compound wherein X '= H) 3', 5'-Bis-O-benzoyl-5- [2- (trimethylsilyl) ethynyl] -2'- obtained in above (a)
154 mg (0.29 mmol) of deoxyuridine was dissolved in acetonitrile (15 ml), and 121 mg (0.58 mmol) of tetraethylammonium bromide was added thereto.
l) and 33 mg (0.58 mmol) of potassium fluoride were added, and the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, the organic layer was extracted with dichloromethane, washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified by a silica gel column (n-hexane: ethyl acetate = 1: 1), and 3 ′, 5′-bis-O-benzoyl-5-ethynyl-2′-, which was a trimethylsilyl derivative in a yield of 90%, was obtained. 120 mg (0.26 mmol) of deoxyuridine were obtained.

The physical properties of this compound are shown below. ¹ H-NMR (in CDCl ₃ , 270 MHz, δpp
m): 9.00 (1H, bs), 7.91 (1H, s), 7.
44-8.09 (10H, m), 6.38 (1H, dd, J =
8.0, 5.5 Hz), 5.63 (1 H, m), 4.80 (1
H, dd, J = 12.0, 3.5 Hz), 4.71 (1H, d
d, J = 12.0, 3.0 Hz), 4.59 (1H, dd, J =
6.5, 3.0 Hz), 3.02 (1H, s), 2.80 (1
H, ddd, J = 14.0, 5.5, 1.5 Hz), 2.32
(1H, ddd, J = 14.0, 8.0, 6.5 Hz) ¹³ C-NMR (270 MHz, δpp in CDCl ₃ )
m): 166.1, 165.9, 160.8, 148.9,
142.7, 133.8, 133.6, 129.8, 129.
6, 129.1, 128.8, 128.6, 99.8, 8
5.9, 83.3, 82.1, 74.9, 74.0,
64.2, 38.7.

(C) 3 ', 5'-bis-O-benzoyl-
5-carboranyl-2'-deoxyuridine (formula (VII)
a) Production of a compound in which X ′ = H) a detrimethylsilyl compound obtained in the above (b), 3 ′, 5 ′
-Bis-O-benzoyl-5-ethynyl-2'-deoxyuridine 120 mg (0.26 mmol) and 38 mg (0.31 mmol) of decaborane in a toluene solution (10
0.18 ml (2.50 mmol) of propionitrile
l) was added, and the mixture was heated under reflux in an argon atmosphere for 17 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and the crude product was purified by a silica gel column (benzene: hexane = 9: 1), and the title compound 3 ′, 5 ′ was obtained in a yield of 55%. -Bis-O-benzoyl-5-carboranyl-
82 mg (0.14 mmol) of 2'-deoxyuridine were obtained.

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3425, 3200, 3100,
2600,1720,1680,1460,1260,11
00,710. ¹ H-NMR (in CDCl ₃ , 270 MHz, δpp
m): 8.90 (1H, bs), 7.43 to 8.08 (10
H, m), 7.95 (1H, s), 6.26 (1H, dd, J =
8.5, 5.4 Hz), 5.65 (1H, d, J = 6.0H)
z), 5.60 (1H, bs), 4.65 to 4.73 (3H,
m), 2.91 (1H, ddd, J = 14.0, 5.4, 1.5)
Hz), 2.38 (1H, ddd, J = 14.0, 8.5, 6.
0 Hz), 1.0-3.0 (10H, br) ¹³ C-NMR (270 MHz, δpp in CDCl ₃ )
m): 166.1, 165.9, 160.4, 148.8,
141.3, 133.8, 133.7, 129.8, 129.
6, 107.5, 86.9, 83.6, 74.9, 6
. 9.4, 64.5, 57.9, 39.0 MS (M + H): Calculated _{(C 25 H 31 O 7 N} 2 B 10); m / z 58
1.3062, found; m / z 581.3082.

(D) Production of 5-carboranyl-2'-deoxyuridine 2 ', 3', 5'- obtained according to the method of (c) above.
400 mg (0.68 mmol) of tris-O-benzoyl-5-carboranyl-2'-deoxyuridine and 185 mg (3.43 mmol) of sodium methoxide were dissolved in 20 ml of methanol and stirred at room temperature for 3 hours. After the reaction is completed, the ion exchange resin (Dowex 50W ×
(8, H ⁺ type) to adjust the pH to 6, followed by filtration. The filtrate was concentrated under reduced pressure, and then purified by a silica gel column (dichloromethane: ethanol = 15: 1) to give 230 mg (0.62 mmol) of the title compound, 5-carboranyl-2′-deoxyuridine, as a white powder in a yield of 91%. Obtained.

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3450, 3060, 2610,
1700, 1640, 1470, 1300, 1200. ¹ H-NMR (270 MHz, δpp in CD ₃ OD)
m): 8.45 (1H, s), 6.26 (1H, dd, J =
6.5, 6.5 Hz), 5.95 (1H, brs), 4.41
(1H, ddd, J = 5.7, 3.0, 3.0 Hz), 4.00
(1H, ddd, J = 3.0, 3.0, 3.0 Hz), 3.81
(1H, dd, J = 11.5, 3.0 Hz), 3.74 (1H, dd, J = 11.5, 3.0 Hz)
dd, J = 11.5, 3.0 Hz), 2.35 (1H, ddd,
J = 13.5, 6.5, 3.0 Hz), 2.20 (1H, dd)
d, J = 13.5, 6.5, 5.7 Hz. ¹³ C-NMR (270 MHz, δpp in CD ₃ OD)
m): 162.6, 150.8, 144.4, 107.8,
89.5, 87.5, 72.7, 72.4, 62.
7, 59.9, 42.1. Melting point: 185 to 187 ° C

EXAMPLE 3 5-Hydroxymethylcarboranyluridine (formula (I)
Wherein X = OH and R = —CH ₂ OH): (a) 2 ′, 3 ′, 5′-tris-O-benzoyl-5-
[3- (acetoxy) propynyl] uridine (formula (IV
b) in which L = methylene, X ′ = OBz, Ac = acetyl) 2 ′, 3 ′, 5′-Tris-O-benzoyl-5-iodo-
2.046 g (3.0 mmol) of uridine (II-1), palladium chloride / triphenylphosphine complex [PdCl
₂ (PPh ₃ ) ₂ ] 63 mg (0.09 mmol) and 114 mg (0.60 mmol) of cuprous iodide in THF
To 30 ml of the solution, 1.0 ml of triethylamine and 0.60 ml (6.0 mmol) of propargyl acetate were added, and the mixture was stirred at room temperature for 16 hours under an argon atmosphere.
After completion of the reaction, the crude product obtained by evaporating the solvent was purified by a silica gel column (n-hexane: ethyl acetate = 3: 2), and the title compound, 2 ′, 3 ′, was obtained in a yield of 62%. , 5'-
There was obtained 1.22 g (1.65 mmol) of tris-O-benzoyl-5- [3- (acetoxy) propynyl] uridine.

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3430, 3070, 1720,
1690,1450,1120,1100,1070,10
25. ¹ H-NMR (270 MHz, δpp in CDCl ₃ )
m): 8.50 (1H, s), 7.77 (1H, s), 7.3
2 to 8.14 (15H, m), 6.30 (1H, d, J = 5.
9Hz), 5.88 (1H, dd, J = 5.9, 4.0Hz),
5.75 (1H, dd, J = 5.9, 5.9 Hz), 4.75
(3H, m), 4.69 (1H, s), 4.68 (1H, s),
2.08 (3H, s) ¹³ C-NMR (270 MHz, δpp in CDCl ₃ )
m): 170.1, 166.0, 165.2, 161.0,
149.1, 143.2, 133.7, 133.6, 133.
3, 129.8, 129.7, 129.6, 129.0, 1
28.6, 128.4, 128.2, 100.2, 88.
4,87.8,80.7,76.8,73.9,7
. 1.7, 63.8,52.4, 20.5 MS ( M + H): Calculated (as _{C 35 H 29 O 11 N 2} ); m / z 653.1
772, found; m / z 653.1736.

(B) 2 ', 3', 5'-tris-O-benzoyl-5- (1-acetoxymethyl) carboranyluridine (in the formula (Vb), L = methylene, X '= OBz, Ac
= Acetyl compound) 163 mg (0.25 mmol) of 2 ', 3', 5'-tris-O-benzoyl-5- [3- (acetoxy) propynyl] uridine obtained in (a) above and decaborane 37
mg (0.30 mmol) in toluene solution (10 ml)
To the mixture was added 0.54 ml (5.0 mmol) of diethyl sulfide, and the mixture was refluxed for 4 hours under an argon atmosphere. The reaction solution was cooled to room temperature, and the crude product obtained by evaporating the solvent was purified by a silica gel column (n-hexane: ethyl acetate =
3: 1) to give the title compound 2 ′,
77 mg of 3 ', 5'-tris-O-benzoyl-5- (1-acetoxymethyl) carboranyluridine (0.10
mmol).

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3400,3240,3060,
2590,1720,1700,1620,1600,14
50, 1315, 1260, 1210, 1100, 1070,
1020,710. ¹ in _{H-NMR (CDCl 3, 270MHz} , δpp
m): 8.58 (1H, bs), 7.32 to 8.16 (15
H, m), 7.97 (1H, s), 6.30 (1H, d, J =
5.9Hz), 5.94 (1H, dd, J = 6.2, 4.0H)
z), 5.78 (1H, dd, J = 6.2, 6.2 Hz), 4.
83 (1H, dd, J = 11.4, 2.5 Hz), 4.78
(1H, m), 4.71 (1H, dd, J = 11.4, 4.0H
z), 4.46 (1H, d, J = 13.6 Hz), 4.38
(1H, d, J = 13.6 Hzs), 2.00 (3H, s),
1.0-3.0 (10H, br) ¹³ C-NMR (270 MHz, δpp in CDCl ₃ )
m): 169.5, 166.2, 165.5, 165.4,
159.1, 148.7, 147.0, 133.9, 133.
9, 133.7, 129.9, 129.9, 129.1, 1
28.8, 128.6, 128.6, 128.2, 105.
4,88.8,81.0,79.6,75.8,7
. 3.9, 71.2,64.1, 62.0, 20.2 MS (M + H): Calculated (as _{C 35 H 39 O 11 N 2} B 10); m / z 77
3.3485, found; m / z 773.3555.

(C) Production of 5-hydroxymethylcarboranyl uridine 2 ′, 3 ′, 5′-Tris-O-benzoyl-5- (1-acetoxymethyl) carbo obtained according to the method (b) above. Ranyl uridine 540 mg (0.70 mmol) and sodium methoxide 190 mg (3.52 mmol)
l) was dissolved in 20 ml of methanol and stirred at room temperature for 3 hours. After completion of the reaction, an ion exchange resin (Dowex 50)
(W × 8, H ⁺ type) to adjust the pH to 6, followed by filtration.
The filtrate is concentrated under reduced pressure and then purified by a silica gel column (dichloromethane: ethanol = 6: 1) to give the title compound, 5-hydroxymethylcarboranyl uridine in a yield of 89%.
260 mg (0.62 mmol) were obtained as a white powder.

The physical properties of this compound are shown below. IR (KBr, cm ^-1 ): 3420, 2600, 1690,
1460, 1300, 1110, 1080. ¹ H-NMR (270 MHz, δpp in CD ₃ OD)
m): 8.54 (1H, s), 5.94 (1H, d, J = 4.
5Hz), 4.22 (1H, dd, J = 4.5, 4.5Hz),
4.14 (1H, dd, J = 4.5, 4.5 Hz), 4.08
(1H, m), 3.93 (1H, d, J = 13.0), 3.87
(1H, dd, J = 12.0, 2.5 Hz), 3.86 (1H,
d, J = 13.0 Hz), 3.76 (1H, dd, J = 12.
0, 3.0 Hz) ¹³ C-NMR (270 MHz, δpp in CD ₃ OD)
m): 161.9, 151.2, 148.4, 105.6,
91.2, 86.7, 85.6, 77.3, 76.
4, 71.7, 64.1, 62.2. Melting point: 254 to 255 ° C

Example 4. Measurement of growth inhibitory activity The growth inhibitory activity of the compound of the present invention on various mouse malignant tumor cells was examined. The compound of the present invention, which is a sample, was placed in phosphate buffered saline (PBS) containing 75% ethanol at 9 × 1.
Dissolve at a concentration of 0 ^-2 M, store at -20 ° C, and use RPM
Diluted with I1640 medium. At this dilution concentration, the ethanol concentration is 0.085% or less, and does not affect cell growth. As mouse malignant tumor cells, murine leukemia cell lines P388 cells, L1210 cells and MBL-2 cells, and malignant melanoma cell lines B-16
Cells and MethA cells, which are sarcoma cell lines, were selected and used as test cells. These test cells are 5%
The cells were cultured in RPMI1640 medium containing fetal calf serum.

To measure the growth inhibitory activity, test cells were suspended at 2 × 10 ⁴ cells / ml in the same medium as described above, seeded on a 24-well tissue culture plate, and various concentrations of specimens were added thereto. In a carbon dioxide incubator, carbon dioxide concentration 5%, 37
After culturing at 3 ° C. for 3 days, the number of cells was measured with a Coulter counter after the completion of the culture, and the sample concentration (IC ₅₀ ) indicating 50% of the number of cells of the control was calculated.
As a control, one cultured without adding a sample at the same time was used. Table 1 shows the results.

[0043]

As is evident from the results, the compounds of the present invention exhibited a growth inhibitory activity against murine malignant tumor cells at an IC ₅₀ level of 10 ⁻⁵ M order. In addition,
A known uridine derivative, 5-boronouridine (Schi
nazi, RFand Prusoff, WH, J.Org.Chem., vol.1,50, p84
1 (1985)) was also measured for its growth inhibitory activity, but its IC ₅₀ was calculated to be 0.3 mM or more, indicating no growth inhibitory activity.

[0045]

EFFECTS OF THE INVENTION The boron-containing uridine derivative of the present invention has a high affinity for cancer cells and generates sufficient energy to destroy cancer cells when irradiated with neutrons. Useful as a ¹⁰ B carrier for neutron capture therapy. Further, since the compound of the present invention also has a cell growth inhibitory action, it is also useful for diseases caused by anticancer agents or RNA viruses. that's all

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields investigated (Int. Cl. ⁷ , DB name) C07H 23/00 A61K 31/7072 CA (STN) CAOLD (STN) CAPLUS (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The following general formula (I): (Wherein, X represents a hydrogen atom or a hydroxyl group, and R represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group). (2) The boron-containing uridine derivative according to claim 1,
Cell growth inhibitor as an active ingredient.