JP2001064295A - New thietane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new thietane derivative useful as medicaments such as an antiviral agent and a carcinostatic agent. SOLUTION: This new derivative is represented by formula I (B is a nucleic- acid base residue; R1 and R2 are each H or a protective group for OH) and is e.g. 1,9-[2,3-bishydroxymethyl-thietan-1-yl]adenine. The compound of formula I is obtained by reacting a compound of formula II e.g. (2S,3R)-[(2,3)-bis(benzoyloxymethyl)]thietanesulfoxide, or the like} with a nucleic-acid base derivative and, if necessary, eliminating a protecting group when the resultant compound has the protecting group.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to novel nucleic acid derivatives expected as medicaments such as antiviral agents and anticancer agents,
It relates to its production method and its synthetic intermediate.

[0002]

2. Description of the Related Art Nucleic acid is a substance that controls genetic information of an organism and is very closely related to differentiation and proliferation. Therefore, natural or non-natural nucleic acid derivatives that control the proliferation of organisms (including viruses) are known. Many are known. In fact, some of them have been used clinically as medicaments effective for viral infections that grow only in cancer cells and human cells that repeat disorderly growth and cause various diseases. From the standpoint of antiviral agents, nucleic acids are mostly nucleic acid derivatives. For example, as antiviral agents, vidarabine, acyclovir, ganciclovir, azidothymidine, dideoxyinosine and the like are known.
As anticancer drugs, 5-fluorouracil (5-F
U), cytosine arabinoside (Ara-C) and the like are known.

[0003]

However, the above-mentioned antiviral agents have drawbacks such as a narrow range of application to viruses, and a limitation in the administration method due to factors such as solubility, oral absorbability, and metabolism. In addition, there are some cases in which the dose, administration period and the like are restricted by side effects such as bone marrow toxicity. On the other hand, acquired immunodeficiency disease (AIDS) with extremely poor prognosis,
There are many viral diseases without effective medicines and vaccines, such as human adult T-cell leukemia (ATL) and highly contagious cold syndrome. Therefore, development of new antiviral agents is strongly desired in the future. The effects of the above anticancer drugs,
In terms of side effects and the like, they are not always sufficient, and the development of new anticancer agents is desired.

[0004]

Means for Solving the Problems The present inventors have developed novel thietane derivatives represented by the general formula (1) and pharmacologically acceptable salts of these compounds, for example, antiviral agents,
The present inventors have found that the present invention is useful as a drug such as an anticancer drug, and have completed the present invention. That is, the present invention relates to the general formula (1)

[0005]

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(Wherein B is a nucleobase residue, R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group) and the pharmacological properties of these compounds Acceptable salt. General formula (2) (Wherein R ₁ and R ₂ each independently represent a hydrogen atom or a protecting group for a hydroxyl group), and are reacted with a nucleic acid base derivative. Wherein the protecting group of formula (1) is removed

[0007]

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(Wherein B is a nucleobase residue, and R ₁ and R ₂ each independently represent a hydrogen atom or a protecting group for a hydroxyl group). General formula (2)

[0009]

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(Wherein R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group). General formula (3)

[0011]

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(Wherein R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group).

[0013]

DETAILED DESCRIPTION OF THE INVENTION The present invention will be described in detail below.

In the general formula (1), examples of the nucleobase residue B include purine bases and pyrimidine bases, and those having a protecting group attached thereto. As the purine base, for example,

[0015]

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(Where Y represents a hydrogen atom, an amino group or a halogen atom such as chlorine, bromine or fluorine, and R ₃ represents an alkyl group having 1 to 20 carbon atoms such as a methyl group or an ethyl group, or a benzyl group. , 4-methoxybenzyl group and the like (C1-
C4 alkoxy) -substituted phenyl (C1-C4) alkyl group, aryl group such as phenyl group).

As the pyrimidine base, for example,

[0018]

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(Wherein R ₄ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group or a butyl group, a 2-halogen-substituted vinyl group such as a 2-iodovinyl group, iodine, A halogen atom such as chlorine or fluorine).

The protecting group for the hydroxyl group is not particularly limited as long as it is generally used as a protecting group. Ester type protecting groups, for example, acyl groups such as acetyl group and benzoyl group,
Or an ether-type protecting group, for example, a substituted silyl group such as a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group, a (C1-C4 alkoxy) C1-C4 alkyl group such as a methoxymethyl group, a tetrahydropyranyl group, etc. And a methyl group substituted by one or more substituted or unsubstituted phenyl groups such as a benzyl group, a 4-methoxybenzyl group, and a trityl group.

The pharmacologically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, substituted ammonium salts, and minerals such as hydrochloric acid, sulfuric acid and nitric acid. Organic acid salts such as acid salts, acetic acid, fumaric acid, maleic acid, tartaric acid and methanesulfonate.

Next, specific examples of the compound represented by the general formula (1) will be shown. The compounds shown here include all existing isomers, optically active isomers, and racemates. Salts are not shown here. 1,9- [2,3-bishydroxymethyl-thiethane-
1-yl] adenine 2,9- [2,3-bishydroxymethyl-thietane-
1-yl] guanine 3,2,6-diamino-9- [2,3-bishydroxymethyl-thietane-1-yl] purine 4,9- [2,3-bishydroxymethyl-thietane-
1-yl] hypoxanthine 5,2-amino-6-chloro-9- [2,3-bishydroxymethyl-thietane-1-yl] purine 6,1- [2,3-bishydroxymethyl-thietane-
1-yl] cytosine 7,1- [2,3-bishydroxymethyl-thietane-
1-yl] thymine 8,1- [2,3-bishydroxymethyl-thietane-
1-yl] uracil 9,5- (2-bromovinyl) -1- [2,3-bishydroxymethyl-thietane-1-yl] uracil 10,5-fluoro-1- [2,3-bishydroxymethyl- Thietane-1-yl] uracil

Purine base type compound represented by the general formula (1) of the present invention

[0024]

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(Wherein B is a nucleobase residue and R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group), a compound represented by the general formula (2) is used in the present invention. Can be obtained, for example, via an intermediate represented by the general formula (4) as in the following reaction formula (I). Here, TMS indicates trimethylsilyl. Also,
Tf indicates trifluoromethanesulfonyl.

[0026]

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Further, the pyrimidine base type compound represented by the general formula (1) of the present invention is prepared by converting the compound represented by the general formula (2) according to the method of the present invention, for example, as shown in the following reaction formula (II). It can be obtained via a compound represented by the general formula (5). However, the compound represented by the general formula (5) is also included in the compound represented by the general formula (1).

[0028]

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The compound represented by the general formula (4) is obtained by a glycosidation reaction of the compound represented by the general formula (2). Glycosidation reaction is usually performed on a compound represented by the general formula (2) in a solvent such as dichloromethane, acetonitrile, toluene or the like in a solvent such as TMSOTf @ trimethylsilyltrifluoromethanesulfonate (trimethylsilyl trifluoromethane).
G) In the presence of ア ミ ン and an organic amine such as triethylamine,
For example, the above-mentioned purine base or pyrimidine base and those having a protective group attached thereto are reacted. Where TM
S and Tf indicate the same as described above. TMSOTf is
Usually, 1 to 10 equivalents, preferably 1 to 8 equivalents, more preferably 1 to 7 equivalents are used. Triethylamine is used usually in 1 to 10 equivalents, preferably 1 to 8 equivalents, more preferably 1 to 7 equivalents (based on the number of equivalents of the silylated base used). The reaction time (relative to the number of equivalents of TMSOTf used) is usually from 30 minutes to 40 hours, preferably from 30 minutes to 10 hours. The temperature is usually -20C to 30C, preferably -15C to 25C.
° C.

Further, by reacting the compound represented by the general formula (4) in a sealed tube, the compound represented by the general formula (1) can be obtained. As the reaction solvent, lower alcohols such as methanol, ethanol and isopropyl alcohol, and ether solvents such as dioxane, tetrahydrofuran and dimethoxyethane are usually used. Preferred solvents include methanol. The temperature for cooling and stirring is usually -78 ° C to 0 ° C, preferably -78 ° C.
C. to -30C. The temperature for heating and stirring (sealing the tube) is usually 20 ° C to 130 ° C, preferably 60 ° C to 100 ° C.
° C. Further, the time for performing the sealed tube reaction is generally 10 hours to 72 hours, preferably 16 hours to 48 hours. After sealing, the tube is usually cooled to -78 ° C to -30 ° C and opened. After volatilizing the ammonia, purification is performed to obtain the general formula (1).

The compound represented by the general formula (2), which is used as a raw material for the reaction formulas (I) and (II), is obtained from the compound represented by the general formula (3) as shown in the following reaction formula (III). Can be manufactured.

[0032]

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That is, the compound represented by the general formula (2) is obtained by an oxidation reaction of the compound represented by the general formula (3).
The oxidation reaction generally uses a reagent that oxidizes sulfide to sulfoxide. For example, oxidizing agents such as sodium and potassium periodate, and metachloroperbenzoic acid are used. Halogen solvents such as chloroform and methylene chloride,
In a solvent such as an ether solvent such as THF or ether, or an aromatic hydrocarbon solvent such as benzene or toluene, the oxidizing agent is usually used in an amount of 1 to 1.5 equivalents, preferably 1 to 1.2 equivalents. Can be easily obtained. The reaction time is usually 5
Minutes to 30 hours, preferably 5 minutes to 16 hours, more preferably 10 minutes to 30 minutes. The reaction temperature is usually -78 ° C to 30 ° C, preferably -40 ° C.
２５25 ° C.

The compound represented by the general formula (3) can be synthesized, for example, from the compound represented by the general formula (6). That is, when the compound represented by the general formula (6) is reacted with sodium sulfide, lithium sulfide or a hydrate thereof in a solvent, a cyclization reaction occurs during the reaction, and the compound is represented by the general formula (3). The desired compound can be obtained. Here, Ms represents a mesyl group, that is, a methanesulfonyl group. Sodium sulfide and lithium sulfide are usually used in 1 to 3 equivalents, preferably 1 to 2 equivalents. Solvents used include lower alcohols such as methanol, ethanol and propanol, diethyl ether, and TH.
Ether solvents such as F and DMF are used. The reaction temperature is generally -30C to 130C, preferably 80C to 110C. The reaction time is generally from 5 minutes to 50 minutes.
Time, preferably 5 minutes to 2 hours.

[0035]

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[0036]

EXAMPLES The production of the compound of the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples. The compounds shown here are optically active substances.

Embodiment 1

[0038]

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(2S, 3R)-[(2,3) -bis (ben)
zoyloxymethyl)] thietane
Synthesis of (8) Dimesyl compound (7) (190.6 mg, 0.38 mmol)
Is dissolved in dimethylformamide (5 ml), sodium sulfide / 9-hydrate (1 eq, 91 mg) is added, and the mixture is heated and stirred at 100 ° C. for 10 minutes. After cooling the reaction solution to room temperature, it is poured into water and extracted with ethyl acetate (20 ml × 3). The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The resulting oil was purified by silica gel thin layer chromatography.
(Hexane / AcOEt = 3/1) to obtain the target compound (8) (37.4 mg, 29% yield). _[Α] ^D 19 +69.3 ° _{(c0.98, CHCl 3) IR (} neat) 1716cm -1 1 H-NMR (400MHz, CDCl 3) δ 3.08
(dd, J = 6.4, 9.3 Hz, 1H), 3.29 (t, J = 9.
3Hz, 1H), 3.48 (m, 1H), 3.91 (br.dt, J
= 5.9, 7.3 Hz, 1H), 4.45 (complex, 2
H), 4.50 (dd, J = 5.9, 11.2 Hz, 1H) 4.6
7 (dd, J = 7.3, 11.2 Hz, 1H), 7.40 (com
plex, 4H), 7.55 (complex, 2H), 8.0
2 (complex, 4H) ¹³ C-NMR (400 MHz) δ 23.93, 40.8
3, 41.95, 66.35, 68.19, 128.30 (×
2), 128.34,129.50 (× 3), 129.54 (×
2), 133.02, 133.07, 166.07, 166.2
2 FAB MS (positive) m / z 343 [M +
H] ⁺

Embodiment 2

[0041]

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(2S, 3R)-[(2,3) -bis (be
nzyloxymethyl)] Thietanes
Synthesis of ulfoxide (9) Compound (8) (254 mg, 0.74 mmol) was dissolved in anhydrous methylene chloride (5 ml), and cooled at −35 ° C. while cooling anhydrous metachloroperbenzoic acid (1.1 eq, 0.2 g). A methylene chloride (5 ml) solution was added dropwise little by little. 1
After stirring for 5 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to terminate the reaction.
The reaction solution was extracted using chloroform (20 ml ×
3). The chloroform layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (silica gel 50 cc, CHCl ₃ / MeOH = 50/1), and the target sulfoxide (9) (257.3 mg,
97%). IR (neat) γ _max 1716cm ^-1 , 1271c
^{m -1 1 H-NMR (400MHz} CDCl 3) δ 2.60
(m, 1H), 3.10 (t, J = 11.5 Hz, 1H), 3.24
(dd, J = 9.8, 12.7 Hz, 1H), 3.43 (ddd,
J = 2.0, 7.1, 12.7 Hz, 1H), 3.70 (comp
lex, 3H), 3.82 (m, 1H), 4.44 (comple
x, 3H), 4.52 (dd, J = 4.4, 11.7 Hz, 1H),
4.75 (complex, 3H), 4.95 (dd, J = 8.
3,12.7Hz, 1H), 7.45 (complex, 8H),
7.60 (complex, 4H), 8.05 (complex, 4H)
x, 8H) FAB MS (positive) m / z 359 [M +
H] ⁺

Embodiment 3

[0044]

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6-Chloro-9-[(2S, 3R)-
bis (benzoyloxymethyl) thie
Synthesis of tan-1-yl] purine (10) 6-chloropurine (3 eq, 0.158 g) was suspended in anhydrous toluene (4 ml) under a stream of argon, and triethylamine (7 eq, 0.33 ml) was added at room temperature. Dripping,
Further, trimethylsilyl triflate (7 eq, 0.4
3 ml) was added dropwise. After dissolution of 6-chloropurine, the reaction solution was ice-cooled and stirred for 15 minutes. Under an argon stream, the sulfoxide compound (120 mg, 0.34 mmol) was dissolved in anhydrous toluene (2 ml), added by cannulation (washed with 1 ml), and stirred for 30 minutes. Subsequently, the mixture was stirred at room temperature for 90 minutes. The reaction solution was poured into water and extracted with ethyl acetate (20 ml × 3 times). The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily substance was roughly separated by silica gel thin layer chromatography (CHCl ₃ / MeOH = 10/1) to obtain a coupling product (10) (α-form + β-form).
This was further purified by silica gel thin layer chromatography (he
xane / AcOEt = 2/1), and α- (1
0) (10 mg, 0.02 mmol), β- (10)
(27.7 mg, 0.06 mmol) were obtained. (Yield 22
%) Α- (10) [α ] D 19 -35.8 ° _{(c1.01, CHCl 3) IR (} neat) γ max 1719cm -1 1 H-NMR (400MHz, CDCl 3) δ 3.84
(m, 1H), 4.11 (m, 1H), 4.38 (complex,
2H), 4.71 (dd, J = 5.4, 11.7 Hz, 1H), 4.
85 (dd, J = 5.9, 11.7 Hz, 1H), 6.84 (d,
J = 7.8 Hz, 1H), 7.30 (complex, 2H),
7.50 (complex, 5H), 7.63 (m, 1H), 8.
10 (complex, 2H), 8.73 (s, 1H), 9.13
(s, 1H) β- (10 ) [α] D 19 +64.6 ° _{(c1.05, CHCl 3) IR (} neat) γ max 1722cm -1 1 H-NMR (400MHz, CDCl 3) δ 3.85
(m, 1H), 4.05 (m, 1H), 4.50 (dd, J = 4.6,
12.0Hz, 1H), 4.60 (complex, 2H), 4.
80 (dd, J = 5.6, 12.0 Hz, 1H), 6.71 (d,
J = 6.8 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 2
H), 7.50 (t, J = 7.8 Hz, 2H), 7.56 (m, 1
H), 7.64 (m, 1H), 7.82 (dd, J = 1.5, 7.8)
Hz, 2H), 8.08 (dd, J = 1.5, 7.8 Hz, 2H),
8.85 (s, 1H), 9.10 (s, 1H)

Embodiment 4

[0047]

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[0048]

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9-[(2S, 3R) -α-bis (hydr
oxymethyl) thietan-1-yl] ad
Synthesis of enine {α- (11)} α- (10) (4.6 mg) obtained in Example 3 was suspended in ethanol (3 ml) and placed in a sealed tube. This-
After cooling and stirring at 78 ° C., liquid ammonia was blown and sealed, and the mixture was heated and stirred at 70 ° C. for 39 hours. -78 ° C again
And opened. The mixture was allowed to naturally rise to room temperature, and after evaporating ammonia, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (CHCl ₃ / MeOH
= 4/1) to obtain α- (11) (1.8 mg, yield 73%). <Compound data> ¹ H-NMR (400 MHz, CD ₃ OD) δ 3.30
(complex, 2H), 3.64 (quint, J = 6.8
Hz, 1H), 3.74 (dd, J = 6.8, 11.2 Hz, 1
H), 3.82 (dd, J = 6.1, 11.2 Hz, 1H), 3.
93 (dd, J = 6.1, 11.2 Hz, 1H), 6.37 (d,
J = 7.6 Hz, 1H), 8.24 (s, 1H), 9.04 (s, 1
H) FAB MS (positive) m / z 268 [M +
H] ⁺

Embodiment 5

[0051]

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9-[(2S, 3R) -β-bis (hyd
roxymethyl) thietan-1-yl] a
Synthesis of denine {β- (11)} β- (10) (11.4 mg) obtained in Example 3 was dissolved in ethanol (3 ml) and placed in a sealed tube. This was cooled and stirred at −78 ° C., and after blowing liquid ammonia, sealed, and heated and stirred at 70 ° C. for 17 hours. -78 again
C. and opened. The mixture was allowed to naturally rise to room temperature, and after evaporating ammonia, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography (CHCl ₃ / MeO
H = 4/1), and the target product β- (11) (1.0 m
g, yield 16%). <Compound data> ¹ H-NMR (400 MHz, CD ₃ OD) δ 3.50
-3.85 (complex, 6H), 6.18 (d, J = 6.
8 Hz), 8.25 (s, 1H), 8.86 (s, 1H) FAB MS (positive) m / z 268 [M +
H] ⁺

[0053]

According to the present invention, for example, an antiviral agent,
New nucleic acid derivatives (new thietane derivatives and pharmacologically acceptable salts of these compounds) useful as medicaments such as anticancer agents are provided.

[0054]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/7076 A61K 31/7076 31/708 31/708 A61P 31/12 A61P 31/12 35/00 35 / 00

Claims (4)

[Claims] 1. The general formula (1) (Wherein B is a nucleobase residue, and R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group) and the pharmacologically acceptable of these compounds salt. 2. The general formula (2) (Wherein R ₁ and R ₂ each independently represent a hydrogen atom or a protecting group for a hydroxyl group), and are reacted with a nucleic acid base derivative. Wherein the protecting group of formula (1) is removed (Wherein B is a nucleobase residue, and R ₁ and R ₂ each independently represent a hydrogen atom or a protecting group for a hydroxyl group). 3. The general formula (2) (Wherein R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group). 4. The general formula (3) (Wherein R ₁ and R ₂ each independently represent a hydrogen atom or a hydroxyl-protecting group).