JPH05117244A - New cyclobutane derivative - Google Patents

Abstract

PURPOSE:To obtain a new cyclobutane derivative, capable of exhibiting powerful antiviral action on viruses such as HBV, effective against hepatitis B or C viruses, etc., causing viral hepatitis or hepatic cancer and useful as an antiviral agent, a carcinostatic agent, etc. CONSTITUTION:A cyclobutane derivative expressed by formula I (B1 is nucleic acid base derivative; R1 is H or protecting group of OH) and its physiologically permissible salt and a cyclobutane derivative expressed by formula II (B2 is nucleic acid base derivative; R2 is H or protecting group of OH) and its physiologically permissible salt, e.g. 9-[(1beta,3beta)-3-(hydroxymethyl)-2- methylenecyclobutyl]adenine. The compound expressed by formula I is obtained by passing a compound expressed by formula 3 through respective compounds expressed by formulas 4, 5, 6 and 7. The compound expressed by formula II is obtained by passing the compound expressed by formula 3 through respective compounds expressed formulas 8, 9, 10 and 11.

Description

Detailed Description of the Invention

[0001]

The present invention relates to, for example, antiviral agents,
The present invention relates to a novel cyclobutane derivative expected as a drug such as an anticancer agent.

[0002]

2. Description of the Related Art Nucleic acid compounds are clinically used as effective medicines for cancers that repeat unregulated growth and viral infections that cause various diseases by growing only in cells. For example, as antiviral agents, acyclovir used for herpes simplex, azidothymidine used for treatment of AIDS (acquired immunodeficiency syndrome), DDI and the like are known. Further, as an anticancer agent, 5-fluorouracil used for the treatment of digestive organ cancer (esophageal cancer, gastric cancer, colon cancer) and breast cancer
(5-FU), cytosine arabinoside (Ara-C), which is used for the treatment of leukemia and malignant lymphoma, are known.

[0003]

However, the above-mentioned antiviral agents have a narrow application range for viruses, and there are some cases in which the dose and administration period are limited due to side effects such as bone marrow toxicity. Moreover, even the above-mentioned anticancer agents are still insufficient in drug efficacy, and show various side effects such as bone marrow toxicity and digestive organ symptoms. Therefore, development of new antiviral agents and anticancer agents is desired.

[0004]

The present invention has the general formula (1)

[0005]

[Chemical 3]

[Wherein B ₁ is a nucleobase derivative and R _{1 is}
Represents a hydrogen atom or a hydroxyl-protecting group] and physiologically acceptable salts of these compounds, and a general formula (2)

[0007]

[Chemical 4]

[In the formula, B ₂ is a nucleobase derivative, and R _{2 is}
Represents a hydrogen atom or a hydroxyl group-protecting group] and a physiologically acceptable salt of these compounds. In the general formulas (1) and (2), B
Examples of the nucleic acid base derivative include a purine base, a pyrimidine base, and those having a protecting group attached thereto. Purine bases include, for example, formulas

[0009]

[Chemical 5]

[Wherein X represents a hydrogen atom, an amino group and a halogen atom such as chlorine and fluorine, R ₃ represents an alkyl group having 1 to 20 carbon atoms such as a methyl group and an ethyl group,
A substituted or unsubstituted benzyl group such as benzyl group and 4-methoxybenzyl group, (C1-C4 alkoxy) C1-C4 alkyl group such as methoxyethyl group, and aryl group such as phenyl group]. Can be mentioned. Examples of the pyrimidine base include compounds of the formula

[0010]

[Chemical 6]

[Wherein R ₄ is a hydrogen atom, a methyl group, an ethyl group, a lower alkyl group having 1 to 4 carbon atoms such as a butyl group, a 2-bromovinyl group, a 2-iodovinyl group or the like].
A halogen-substituted vinyl group, or a halogen atom such as iodine, bromine, chlorine, or fluorine]. The protective group for the hydroxyl group in R ₁ and R ₂ is not particularly limited as long as it is generally used as a protective group, and an ester type protective group, an ether type protective group and the like can be used. Examples of the ester type protecting group include an acetyl group,
Examples thereof include an acyl group such as a benzoyl group and a substituted carbamoyl group such as a dimethylcarbamoyl group. Examples of the ether type protecting group include a substituted silyl group such as a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group, and a (C1-C4 alkoxy) such as a methoxymethyl group.
Examples thereof include a C1-C4 alkyl group, a cyclic acetal group such as a tetrahydropyranyl group, and a methyl group such as a benzyl group, a 4-methoxybenzyl group and a trityl group, which is substituted with one or more substituted or unsubstituted phenyl groups. ..

Further, physiologically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts,
Examples thereof include substituted ammonium salts, mineral acid salts such as hydrochloric acid, sulfuric acid and nitric acid, and organic acid salts such as acetic acid, fumaric acid, maleic acid, tartaric acid and methanesulfonic acid. Next, specific examples of the compound represented by formula (1) will be shown. The compounds shown here include all existing stereoisomers, optically active compounds, and racemates. Also, salt is not shown here.

1.9-[(1β, 3β) -3- (hydroxymethyl) -2-methylenecyclobutyl] adenine 2.9-[(1β, 3β) -3- (hydroxymethyl)
-2-Methylenecyclobutyl] guanine 3.9-[(1β, 3β) -3- (hydroxymethyl)
-2-Methylenecyclobutyl] hypoxanthine 4.2,6-diamino-9-[(1β, 3β) -3-
(Hydroxymethyl) -2-methylenecyclobutyl] purine 5.2-amino-6-chloro-9-[(1β, 3β)-
3- (Hydroxymethyl) -2-methylenecyclobutyl] purine 6.1-[(1β, 3β) -3- (hydroxymethyl)
2-Methylenecyclobutyl] cytosine 7.1-[(1β, 3β) -3- (hydroxymethyl)
2-Methylenecyclobutyl] thymine 8.1-[(1β, 3β) -3- (hydroxymethyl)
-2-Methylenecyclobutyl] uracil

9.5- (2-Bromovinyl) -1-
[(1β, 3β) -3- (Hydroxymethyl) -2-methylenecyclobutyl] uracil 10.5-Fluoro-1-[(1β, 3β) -3- (hydroxymethyl) -2-methylenecyclobutyl] uracil 11.9-[(1β, 2α) -3-methylene-2- (hydroxymethyl) cyclobutyl] adenine 12.9-[(1β, 2α) -3-methylene-2- (hydroxymethyl) cyclobutyl] guanine 13. 9-[(1β, 2α) -3-methylene-2- (hydroxymethyl) cyclobutyl] hypoxanthine 14.2,6-diamino-9-[(1β, 2α) -3-
Methylene-2- (hydroxymethyl) cyclobutyl] purine 15.2-amino-6-chloro-9-[(1β, 2α)
-3-Methylene-2- (hydroxymethyl) cyclobutyl] purine

16.1-[(1β, 2α) -3-methylene-2- (hydroxymethyl) cyclobutyl] cytosine 17.1-[(1β, 2α) -3-methylene-2- (hydroxymethyl) cyclobutyl] Thymine 18.1-[(1β, 2α) -3-methylene-2- (hydroxymethyl) cyclobutyl] uracil 19.5- (2-bromovinyl) -1-[(1β, 2
α) -3-Methylene-2- (hydroxymethyl) cyclobutyl] uracil 20.5-fluoro-1-[(1β, 2α) -3-methylene-2- (hydroxymethyl) cyclobutyl] uracil General formula of the compound of the present invention The compound represented by (1) is, for example, the reaction formula (1)

[0016]

[Chemical 7]

[Wherein B ₁ and B ₃ are nucleobase derivatives, and
₄ is a nucleobase derivative or a protected nucleobase derivative, R ₅ is a hydroxyl-protecting group, and Y is a leaving group such as chlorine, bromine, iodine, aryl sulfonate or alkyl sulfonate] Manufacturing method (M.Hon
jo, et al., Chem. Pharm. Bull. 37, 1413-1415 (1989))
It can be produced from the compound of the general formula (3) produced in (1) via the intermediate represented by the general formula (5). That is, a nucleobase derivative of the compound of the general formula (3) is introduced into the compound of the general formula (4) by introducing a protecting group, if necessary, and then the hydroxyl group at the 3-position is protected with a hydroxyl-protecting group, A compound of general formula (5) is obtained. Next, using a halogenating agent such as methyltriphenoxyphosphonium iodide or the like for the compound of the general formula (5), a solvent in which the compound (5) is dissolved, preferably a hydrocarbon solvent such as benzene or DMF.
In a polar solvent such as, from under ice cooling to the boiling point of the solvent used,
Preferably in the temperature range of 10 ° C to 50 ° C for 1 minute to 24
By reacting for a time, preferably 10 minutes to 5 hours, the compound of general formula (6) can be obtained.

The compound of the general formula (6) is a base, preferably sodium hydroxide, sodium hydride, potassium ter.
Using t-butoxide or the like, in a solvent in which the compound (6) is dissolved, preferably in a solvent such as pyridine or tert-butanol, from -20 ° C to the boiling point of the solvent used, preferably
The compound of the general formula (7) can be obtained by performing the reaction in the temperature range of 0 ° C. to 45 ° C. for 1 minute to 24 hours, preferably 10 minutes to 6 hours. The compound of the general formula (7) is deprotected by an appropriate method such as hydrolysis, solvolysis such as ammonolysis, or the like, by removing an existing protecting group,
It can be led to a compound represented by the general formula (1). Further, the compound represented by the general formula (2) of the present invention is
For example, reaction formula (2)

[0019]

[Chemical 8]

[Wherein B ₂ and B ₃ are nucleobase derivatives, B 2
₅ represents a nucleobase derivative or a protected nucleobase derivative, R ₆ represents a protective group for a hydroxyl group, and Z represents a leaving group such as chlorine, bromine, iodine, aryl sulfonate or alkyl sulfonate]. Similar to the compound of the formula (1), it can be produced from the compound of the general formula (3) via the intermediate represented by the general formula (9). That is, a nucleobase derivative of the compound of the general formula (3) is introduced into the compound of the general formula (8) by introducing a protecting group if necessary, and then the hydroxyl group at the 2-position is protected by using a protective group for the hydroxyl group. A compound of general formula (9) is obtained. Next, using a halogenating agent such as methyltriphenoxyphosphonium iodide for the 3-position hydroxyl group of the compound of the general formula (9), the compound (6)
The compound of the general formula (10) can be obtained in the same manner as in the production of. The compound of general formula (10) can be obtained by using a base, preferably potassium tert-butoxide, etc., to obtain the compound of general formula (11) in the same manner as in the production of compound (7). By deprotecting the compound of the general formula (11) by an appropriate method such as hydrolysis, solvolysis such as ammonolysis and the like, in the same manner as in the production of the compound (1), a compound of the general formula (11) The compound represented by 2) can be obtained.

[0021]

The compound of the present invention is shown to have a strong antiviral effect from the following experimental examples. Experimental Example The action against the hepatitis B virus (HBV), which is a DNA virus, was tested by the following method. (Method) (Cell line) The anti-HBV activity of the test compound is determined by the cell line HB611 (Proc. Natl. Acad. Sci.) Which continuously produces HBV particles.
Tested using USA, 84, 444-448 (1987). HB611 cells are Dr. Toshiki Tsurimoto (Associate Professor, Cell Engineering Center, Osaka University)
Established by 10% fetal bovine serum (Gipco
Dulbecco's modified Eagle medium (Gipco)
, Streptomycin 100 μg / ml, penicillin G 100
IU / ml, G418 200 μg / ml (all manufactured by Gipco) was added to the culture medium (hereinafter simply referred to as the culture medium), which was subcultured and used.

(Test method) The test is performed by Ueda et al. (Virolog
y, 169, 213-216 (1989)). HB611 cells were seeded on a 24-well plate (Corning) at 3 × 10 ⁴ cells / well for 2 days and precultured, and the culture solution was exchanged with a test substance-containing medium for 15 days. The culture medium (including the test substance) was replaced with a new one every 3 days during the culture period. After culturing, the cells were placed in Lysis buffer (10 mM Tris-HCl, pH7.4 / 5 mM Na ₂ ED).
It was dissolved with TA / 1% SDS / 0.1 mg / ml proteinase K), and total cell DNA was extracted and purified by the phenol-chloroform method / ethanol precipitation method. Next, the DNA was completely digested with the restriction enzyme Hind III (Takara Shuzo), and a portion (2-3 μg) was electrophoresed on a 1.5% agarose gel, followed by nylon membrane Hybond-N + (Amer.
Southern blot was performed using Sham). 32P-labeled HBV-DNA was used as a probe. The obtained autoradiogram was analyzed using a densitometer (Shimadzu, Chromatoscana S93
The presence or absence of activity was determined by measuring the band area derived from the intracellular HBV-DNA replication intermediate and the band area derived from the HBV-DNA integrated into the chromosome by scanning at 0). The results of the above experiments are shown in Table 1. Table 1. Anti-HBV action of the compound of the present invention

[0023]

[Table 1]

[0024]

[Effect] The compounds represented by the general formulas (1) and (2) of the present invention have a strong antiviral action against HBV, and are therefore effective against hepatitis B and C viruses causing viral hepatitis and liver cancer. Is expected to be. It is also expected as a carcinostatic agent. It is also expected to be effective against other viruses. When the compound of the present invention obtained as described above is used as an antiviral agent or an anticancer agent, it can be administered orally, intravenously, or transdermally. The dose varies depending on the patient's symptoms, age, and administration method, but is usually 0.1-500 mg / kg / day. The compound of the present invention is administered in the form of a preparation prepared by mixing with a suitable pharmaceutical carrier. The form of the formulation is tablets,
Granules, fine granules, powders, capsules, injections, creams, suppositories, etc. are used. The amount of the active ingredient contained in the preparation is about 0.01-99 %%.

[0025]

EXAMPLES Next, the production of the compound of the present invention will be described in detail with reference to examples. Example 1. N ⁶ -benzoyl-9-[(1β, 2α, 3β) -2,
Production of 3-bis (hydroxymethyl) cyclobutyl] adenine Document Description (M. Honjo, et al., Chem. Pharm. Bull. 37, 1
413-1415 (1989)) prepared by 9-[(1β, 2
α, 3β) -2,3-Bis (hydroxymethyl) cyclobutyl] adenine (613mg, 2.46mmol) in pyridine (25ml)
And benzoyl chloride (2 ml, 17.2 mmol) was added portionwise, and the mixture was stirred at room temperature for 3 hours. Water (2
ml), the solvent was distilled off, the residue was dissolved in benzene (50 ml), water (20 ml), saturated sodium carbonate solution (20 ml),
Wash with water (20 ml) and dry over anhydrous magnesium sulfate. The solvent was evaporated, the residue was azeotropically distilled twice with toluene (25 ml) to remove pyridine, and a caramel-like substance (1.61 g) was obtained. A portion of the product (1.51 g) was taken and pyridine (10 ml) and methanol (1
It is dissolved in a mixed solution of 0 ml), 2M sodium hydroxide solution (5 ml) is added while cooling with ice, and the mixture is left standing for 1 hour. After neutralizing with acetic acid, the solvent is distilled off and the residue is azeotropically distilled twice with toluene. The residue was dissolved in a small amount of ethanol and then subjected to silica gel column chromatography (Ф3.0x20cm), eluting with chloroform (0.6l) containing 0-20% ethanol to give N ⁶ -benzoyl-9.
-[(1β, 2α, 3β) -2,3-bis (hydroxymethyl) cyclobutyl] adenine (520 mg, 64%) is obtained. UV: absorption maximum (MeOH) 281 nm.

Example 2. N ⁶ -benzoyl-9-[(1β, 2α, 3β) -2-
Hydroxymethyl-3-triphenylmethoxymethyl)
Preparation of cyclobutyl] adenine N ⁶ -benzoyl-9-[(1β, 2α, 3β) -2,
3-bis (hydroxymethyl) cyclobutyl] adenine
Dissolve (1.25g, 3.54mmol) in pyridine (20ml), add triphenylmethane chloride (986mg, 3.54mmol) and add 1 at room temperature.
Leave it at night. After adding water (3 ml) and distilling off the solvent, the residue was dissolved in benzene (200 ml) and washed twice with water (100 ml),
Dry over anhydrous magnesium sulfate. After distilling off the solvent, the residue was azeotroped twice with toluene (25 ml) and dissolved in a small amount of chloroform, silica gel column chromatography (Φ3.6x50c).
m). Elution with chloroform containing 0-4.8% ethanol gave N ⁶ -benzoyl-9-[(1β, 2α, 3
β) -2-Hydroxymethyl-3-triphenylmethoxymethyl) cyclobutyl] adenine (462.8 mg, 22%) is obtained.

UV: absorption maximum (MeOH) 281 nm. ¹ H-NMR (CDCl ₃ ) δ; 2.1-2.9 (4
H, m), 3.26 (2H, m), 3.83 (2H,
t, J = 5.8 Hz), 4.37 (1H, t, J = 5.
9 Hz), 4.61 (1 H, m), 7.15-8.10
(20H, m), 8.02 (1H, s), 8.75 (1
H, s), 9.09 (1H, brs).

Example 3 N ⁶ -benzoyl-9-[(1β, 2α, 3β) -2-
Preparation of iodomethyl-3-triphenylmethoxymethyl) cyclobutyl] adenine N ⁶ -benzoyl-9-[(1β, 2α, 3β) -2-
Hydroxymethyl-3-triphenylmethoxymethyl)
Cyclobutyl] adenine (450mg, 0.76mmol) was added to DMF (20m
1), methyltriphenoxyphosphonium iodide (530 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After adding benzene (150 ml) to the reaction solution, it is washed successively with water (200 ml), 5% sodium thiosulfate solution (100 ml) and water (200 ml), and dried over anhydrous magnesium sulfate. Evaporate the solvent,
The residue was dissolved in a small amount of benzene, and then subjected to silica gel column chromatography (Ф2.2x20cm), eluting with benzene containing 0-50% ethyl acetate, and then with ethyl acetate and an equal volume solution of benzene (200 ml). ⁶ -benzoyl-9-
[(1β, 2α, 3β) -2-iodomethyl-3-triphenylmethoxymethyl) cyclobutyl] adenine (45
2.1 mg, 84.8%) is obtained.

UV: absorption maximum (MeOH) 281 nm. ¹ H-NMR (CDCl ₃ ) δ; 2.18 (1H,
m), 2.55 (2H, m), 3.0-3.5 (5H,
m), 4.62 (1H, q, J = 8.2Hz), 7.2
-8.05 (20H, m), 8.05 (1H, s),
8.76 (1H, s), 9.07 (1H, brs).

Example 4 N ⁶ -benzoyl-9-[(1β, 3β) -2-methylene-3-triphenylmethoxymethyl) cyclobutyl]
Production of adenine N ⁶ -benzoyl-9-[(1β, 2α, 3β) -2-
Iodomethyl-3-triphenylmethoxymethyl) cyclobutyl] adenine (444 mg, 0.63 mmol) was added to pyridine (10 m
l), tert-butanol (20 ml) and potassium tert-butoxide (637 mg, 5.7 mmol) were added and the mixture was stirred at room temperature for 1 hour.
Stir for hours. After neutralizing with acetic acid (20 drops) and distilling off the solvent,
The residue is dissolved in benzene (100 ml). The organic layer is water (50 ml)
After being washed twice with and dried over anhydrous magnesium sulfate, the solvent is distilled off. The residue was azeotroped twice with toluene (15 ml), dissolved in a small amount of benzene, and then subjected to silica gel column chromatography (Φ2.5x20 cm), eluting with benzene (450 ml) containing 0-67% ethyl acetate. N ⁶ -benzoyl-9-
[(1β, 3β) -2-methylene-3-triphenylmethoxymethyl) cyclobutyl] adenine (331.5 mg, 91.2
%).

UV: absorption maximum (MeOH) 281 nm. ¹ H-NMR (CDCl ₃ ) δ; 2.35 (1 H,
m), 2.81 (1H, m), 3.31 (1H, m),
3.40 (2H, m), 4.95 (1H, s), 5.1
6 (1H, s), 5.72 (1H, t, J = 8.4H
z), 7.2-8.1 (20H, m), 8.13 (1
H, s), 8.79 (1H, s), 9.11 (1H, b)
rs).

Example 5 Preparation of 9-[(1β, 3β) -2-methylene-3-triphenylmethoxymethyl) cyclobutyl] adenine N ⁶ -benzoyl-9-[(1β, 3β) -2-methylene-3 -Triphenylmethoxymethyl) cyclobutyl]
Adenine (126 mg, 0.22 mmol) was dissolved in methanol (5 ml), and 1N sodium methoxide-methanol solution (0.1
(ml) and stirred at 50 ° C for 6 hours. 1N hydrochloric acid (0.1m
l) Neutralize and evaporate the solvent, and the residue is chloroform (5 ml).
It is dissolved in water, washed twice with water (2 ml) and dried over anhydrous magnesium sulfate. The solution was concentrated to 3 ml and subjected to silica gel column chromatography (Ф2.3x8 cm), chloroform (100 ml), and then chloroform-ethanol (9:
The syrup obtained by elution with the solution (1) (100 ml) was crystallized from a small amount of methanol to give 9-[(1β, 3β)-
2-Methylene-3-triphenylmethoxymethyl) cyclobutyl] adenine (90.2 mg, 87.3%) is obtained. mp:
213-215 ° C. UV: absorption maximum (MeOH) 260
nm.

Example 6 Preparation of 9-[(1β, 3β) -2-methylene-3-hydroxymethyl) cyclobutyl] adenine 9-[(1β, 3β) -2-methylene-3-triphenylmethoxymethyl) cyclobutyl ] Adenine (190mg, 0.
40 mmol) was dissolved in methanol (15 ml) and 1N hydrochloric acid (1 m
Add l) and stir at 60 ° C for 1.5 hours. After cooling with ice, Amberlite IR400 (OAc type) (3 ml) was added and stirred for 10 minutes,
The resin is filtered off and the filtrate is concentrated. The residue was dissolved in chloroform (5 ml) and water (10 ml) to obtain an aqueous layer, chloroform.
After washing with (3 ml) and concentrating, 9-[(1β, 3β) -2-
Methylene-3-hydroxymethyl) cyclobutyl] adenine (68 mg, 73%) is obtained as white crystals.

Mp: 133-135 ° C. UV: absorption maximum (MeOH) 260 nm. MS: m / z 231, 214, 200. _{HR-MS: (C 11 H} 13 N 5 O) theory: m / z 231.1120 ^{Found: m / z 231.1127 1 H-} NMR (10% D 2 O / DMSO-d 6) δ;
2.42 (1H, q, J = 9.2 Hz), 2.63 (1
H, q, J = 9.8 Hz), 3.04 (1H, m),
3.68 (2H, d, J = 5.5Hz), 4.77 (1
H, s), 5.08 (1H, s), 5.51 (1H,
t, J = 8.5 Hz), 8.17 (1H, s), 8.2
4 (1H, s).

Example 7 N ⁶ -benzoyl-9-[(1β, 2α, 3β) -3-
Hydroxymethyl-2-triphenylmethoxymethyl)
Preparation of cyclobutyl] adenine The reaction and post-treatment of Example 2 are carried out and the product is subjected to silica gel column chromatography (Φ3.6 × 50 cm). Elute with chloroform containing 0-4.8% ethanol and add N 6 -benzoyl-9-[(1β, 2α, 3β) -3-hydroxymethyl-2-triphenylmethoxymethyl) cyclobutyl] adenine (589 mg, 28%). obtain. UV: absorption maximum (MeOH) 281 nm. ¹ H-NMR (CDCl ₁₃ ) δ; 2.33 (1H,
m), 2.50 (1H, m), 2.62 (1H, m),
2.74 (1H, dd, J = 5.0Hz, 6.5H
z), 3.32 (1H, dd, J = 6.6 Hz, 10.
0Hz), 3.43 (1H, dd, J = 5.1Hz, 1
0.0Hz), 3.74 (2H, m), 4.71 (1
H, q, J = 8.6 Hz), 7.2-8.05 (20
H, m), 7.97 (1H, s), 8.77 (1H,
s), 9.06 (1H, brs).

Example 8 N ⁶ -benzoyl-9-[(1β, 2α, 3β) -3-
Preparation of iodomethyl-2-triphenylmethoxymethyl) cyclobutyl] adenine N ⁶ -benzoyl-9-[(1β, 2α, 3β) -3-
Hydroxymethyl-2-triphenylmethoxymethyl)
Cyclobutyl] adenine (575mg, 0.97mmol) was added to DMF (25m
l), methyltriphenoxyphosphonium iodide (670 mg, 1.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was post-treated in the same manner as in Example 3 to give N ⁶ -benzoyl-9-[(1β, 2α, 3β) -3-iodomethyl-2-triphenylmethoxymethyl) cyclobutyl] adenine (568 mg, 83%). To get UV: absorption maximum (MeOH) 281 nm.

Example 9 N ⁶ -benzoyl-9-[(1β, 2α) -3-methylene-2-triphenylmethoxymethyl) cyclobutyl]
Production of adenine N ⁶ -benzoyl-9-[(1β, 2α, 3β) -3-
Iodomethyl-2-triphenylmethoxymethyl) cyclobutyl] adenine (547 mg, 0.78 mmol) was added to pyridine (10 m
l), dissolved in tert-butanol (25 ml) and potassium tert-butoxide (784 mg, 8.6 mmol), and added at room temperature to 1
Stir for hours. The reaction solution was post-treated in the same manner as in Example 4 to obtain N6-benzoyl-9-[(1β, 2α) -3-methylene-2-triphenylmethoxymethyl) cyclobutyl] adenine (416 mg, 93%). UV: absorption maximum (MeOH) 281 nm.

Example 10 Preparation of 9-[(1β, 2α) -3-methylene-2-triphenylmethoxymethyl) cyclobutyl] adenine N ⁶ -benzoyl-9-[(1β, 2α) -3-methylene-2 -Triphenylmethoxymethyl) cyclobutyl]
Adenine (396mg, 0.69mmol) was treated with 0.02M sodium methoxide-methanol solution (12ml) and stirred at 60 ° C for 4 hours. The reaction solution was post-treated in the same manner as in Example 5 and crystallized from methanol to give 9-[(1β, 2α) -3-methylene-2-triphenylmethoxymethyl) cyclobutyl] adenine (291 mg, 90%) as white. Obtained as crystals. mp: 196-198 ° C. UV: absorption maximum (MeOH) 260.5 nm.

Example 11 Preparation of 9-[(1β, 2α) -3-methylene-2-hydroxymethyl) cyclobutyl] adenine 9-[(1β, 2α) -3-methylene-2-triphenylmethoxymethyl) cyclobutyl ] Adenine (280 mg, 0.
59 mmol) was dissolved in methanol (20 ml) and 1N hydrochloric acid (1.5 ml) was added.
(ml) and stirred at 60 ° C for 1 hour. The reaction solution was post-treated in the same manner as in Example 6 to give 9-[(1β, 2α) -3-
Methylene-2-hydroxymethyl) cyclobutyl] adenine (108 mg, 79%) is obtained as white crystals. mp: 176-178 ° C. UV: absorption maximum (0.1 N hydrochloric acid) 259.5 nm, absorption maximum (water) 261 nm, absorption maximum (0.1 N sodium hydroxide) 261 nm. Elemental analysis: (C ₁₁ H ₁₃ N ₅ O) Theoretical value C: 57.13, H: 5.67, N: 30.2
8 Measured value C: 56.94, H: 5.64, N: 29.9
9. ¹ H-NMR (DMSO-d ₆ ) δ; 3.09 (1
H, q, J = 9.2 Hz), 3.37 (1 H, m),
3.67 (2H, m), 3.76 (1H, m), 4.7
7 (2H, m), 4.97 (1H, m), 5.02 (1
H, m), 7.15 (2H, brs), 8.14 (1
H, s), 8.25 (1H, s).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/53 7252-4C C07D 239/553 239/54 473/16 473/18 473/30 473 / 32 473/34 321 473/40 487/04 144 7019-4C 7038-4C C07D 239/55

Claims (2)

[Claims] 1. A general formula (1): A cyclobutane derivative represented by the formula: wherein B ₁ is a nucleobase derivative, and R ₁ represents a hydrogen atom or a hydroxyl-protecting group, and physiologically acceptable salts of these compounds. 2. A general formula (2): [Wherein B ₂ is a nucleobase derivative, and R ₂ represents a hydrogen atom or a hydroxyl-protecting group], and cyclobutane derivatives and physiologically acceptable salts of these compounds.