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WO1998039352A1 - Novel bicyclonucleoside and oligonucleotide analogues - Google Patents

Novel bicyclonucleoside and oligonucleotide analogues Download PDF

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Publication number
WO1998039352A1
WO1998039352A1 PCT/JP1998/000945 JP9800945W WO9839352A1 WO 1998039352 A1 WO1998039352 A1 WO 1998039352A1 JP 9800945 W JP9800945 W JP 9800945W WO 9839352 A1 WO9839352 A1 WO 9839352A1
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French (fr)
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Takeshi Imanishi
Satoshi Obika
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Priority to AU61209/98A priority Critical patent/AU720472B2/en
Priority to CA002283509A priority patent/CA2283509C/en
Priority to EP98905804.5A priority patent/EP1013661B2/en
Priority to AT98905804T priority patent/ATE541576T2/de
Priority to DK98905804.5T priority patent/DK1013661T4/en
Application filed by Individual filed Critical Individual
Priority to US09/380,638 priority patent/US6268490B1/en
Priority to US13/533,781 priority patent/USRE44779E1/en
Priority to DE98905804T priority patent/DE98905804T1/de
Priority to ES98905804T priority patent/ES2380354T5/es
Publication of WO1998039352A1 publication Critical patent/WO1998039352A1/ja
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Definitions

  • the present invention relates to novel nucleoside and nucleotide analogs, and more particularly to nucleotide analogs suitable for antisense molecules.
  • Antisense oligonucleotides are one of the most promising fields in recent years as pharmaceuticals, as they specifically regulate the expression of unwanted genes.
  • the antisense method is based on the concept of controlling the flow of so-called centralola dogma using DNA ⁇ RNA ⁇ protein using an antisense oligonucleotide.
  • nucleic acid derivatives and analogs have been synthesized and studied. For example, phosphorothioate in which the oxygen atom on the phosphorus atom has been replaced by an ⁇ atom, methylphosphonate in which the methyl group has been replaced by a methyl group, and more recently, those in which the phosphorus atom has been replaced by a carbon atom, and also the structure of the sugar moiety Some have been synthesized, and others have been modified with modified nucleobases. In any case, derivatives and analogs that are sufficiently satisfactory in terms of stability in vivo, ease of synthesis, and sequence specificity (selective control of specific gene expression only) Is currently not available.
  • the inventors of the present invention designed a nucleic acid analog having a sugar moiety conformation immobilized thereon, which is considered to be useful in the antisense method, and designed a nucleoside analog having a unit structure thereof. The synthesis was performed, and it was confirmed that the oligonucleotide analogs prepared using this were extremely useful as antisense molecules.
  • FIG. 1 is a chart showing a time-dependent change in ultraviolet absorption (260 nm) when a natural oligonucleotide is decomposed with exonuclease.
  • FIG. 2 is a chart showing the change over time in the ultraviolet absorption (260 nm) when the oligonucleotide (X 2) of the present invention is decomposed with exonuclease.
  • nucleoside analog of the present invention can be represented by the following general formula (I)
  • B is pyrimidine or purine nucleobase or an analog thereof, and X and Y are the same or different and are hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group, or an acyl group. Or a silyl group], or an amidite derivative thereof.
  • the alkyl group refers to a linear or branched alkyl group having 1 to 20 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, and a t-alkyl group. Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • the alkenyl group refers to a linear or branched alkenyl group having 2 to 20 carbon atoms, and examples thereof include a vinyl group, an aryl group, a butenyl group, a pentenyl group, a geranyl group, and a farnesyl group. .
  • the alkynyl group refers to a linear or branched alkynyl group having 2 to 20 carbon atoms, and includes, for example, an ethynyl group, a propynyl group, a butynyl group and the like.
  • the cycloalkyl group refers to a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexyl group, and a cyclooctyl group.
  • Heterocyclic groups in which one or more arbitrary methylene on the ring of the cycloalkyl group is substituted with an oxygen atom, a sulfur atom, or a nitrogen atom substituted with an alkyl group are also included, and examples include a tetrahydroviranyl group.
  • the aryl group means a monovalent substituent obtained by removing one hydrogen atom from an aromatic heterocyclic group or an aromatic hydrocarbon group, and preferably, by removing one hydrogen atom from an aromatic hydrocarbon group.
  • a monovalent substituent means, for example, a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, a phananthryl group and the like.
  • the carbon atom on the ring of the aryl group may be substituted by one or more groups such as a halogen atom, a lower alkyl group, a hydroxyl group, an alkoxy group, an amino group, a nitro group and a trifluoromethyl group.
  • substituents include a halogen atom, a hydroxyl group, an amino group, an alkoxy group, an aryloxy group and the like.
  • An aralkyl group is a group in which an alkyl group is bonded to an aralkyl group, and the aralkyl group may be substituted.
  • An aralkyl group which may be substituted is a group in which an aralkyl group is bonded to an aralkyl group, wherein at least one hydrogen atom of an aryl group and an alkyl group is substituted with the following substituent. Means a good group.
  • substituent include an acyl group, an amino group, an aryl group, an alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyl group, a nitro group, and a halogen atom.
  • the amino group may or may not be substituted.
  • the substituted amino group include an alkylamino group, an arylamino group, and an acylamino group.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, i-pro Examples include a oxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, a pentyloxy group, a hexyloxy group, and a phenoxy group.
  • Halogen atoms include fluorine, chlorine, bromine and iodine.
  • aralkyl group examples include, for example, a trityl group, a benzyl group, a phenethyl group, a tritylmethyl group, a diphenylmethyl group, a naphthylmethyl group, and a 4,4′-dimethoxytrityl (DMTr) group. Is the DMT r group.
  • acetyl group examples include an acetyl group, a formyl group, a propionyl group, a benzoyl group, and a benzyloxycarbonyl group.
  • silyl group examples include a trialkylsilyl group, and preferably a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, and the like. Preferably it is a trimethylsilyl group.
  • the nucleotide analog of the present invention has the general formula (la)
  • ⁇ is a pyrimidine or purine nucleobase or an analog thereof
  • BB are the same or different and is a pyrimidine or purine nucleic acid base or their analogues
  • R represents hydrogen, hydroxyl, Ri halogen or alkoxy groups der
  • WW 2 are the same or different and are hydrogen, an alkyl group , An alkenyl group, an alkynyl group, a cycloalkyl group, an aralkyl group, an aryl group, an acyl group, a silyl group or a natural nucleoside via a phosphoric acid residue or a phosphoric diester bond, a synthetic nucleoside, or an oligo containing these nucleosides a nucleotide or Helsingborg nucleotide
  • n 1 or n 2 are the same or different, is an integer of 0-5 0
  • N 3 is an integer of 1 to 5 0, where, n When 1 and / or n 2 is 2 or more, B 1 and B may not be the same, and R may not be the same.
  • the pyrimidine or purine nucleobase is thymine, peracyl, cytosine, adenine, guanine and derivatives thereof.
  • nucleond analog and nucleotide analog of the present invention can be synthesized as follows ( (1) Synthesis of nucleoside analog) O— 98/39352
  • the second method is based on D-ribose [3] AGM Barrett et al., J. Org. Chem., 55, 3853 (1990); 4) GH Jones et al., Ibid., 44, 1309 (1979) )], Via compound 13. That is, compound 13 is converted into compound 16 in three steps, and the ring-closing reaction under basic conditions yields the target methylglycol. The sil compound 17 was obtained. Substitution of the OMe group at position 1 of this compound with various natural nucleobases or non-natural nucleobase analogs is possible by various methods already developed. For example, methods such as the following compounds 17 to 20 can be used.
  • a third method is to use diacetone D-glucose, which is obtained from D-glucose in one step and is commercially available, as a starting material.
  • Reference 5 Compound 31 is prepared according to RD Youssefyeh, JPH Verheyden and JG Moffatt., J. Org. Chem., 44, 1301-1309 (1979). Then, as shown in the following formula, compound 31 was stepwise protected with two kinds of primary hydroxyl groups with t-butyldiphenylsilyl group and P-toluenesulfonyl group, and acetylated to give compound 34.
  • Compound 8 is reacted with 2-cyanoethyl-N, N, ⁇ ', N * -tetraisopropylphosphoramidite to obtain an amide 21 and then combined with a natural nucleoside amidite to form an automatic DNA synthesizer. Is used to synthesize various oligonucleotide analogs.
  • the synthesized crude product is purified using Oligopak and reversed-phase chromatography columns, and the purity of the purified product is confirmed by HPLC analysis.
  • One or more monomer units of compound 8 can be present in the oligonucleotide analog. In addition, it may be present at two or more positions in the oligonucleotide analog in an isolated state via one or more natural nucleotides. According to the present invention, it is possible to synthesize an antisense molecule in which the nucleotide analog (nucleoside analog) of the present invention is introduced at a required position in a required number (length). The total length of the oligonucleotide analog is 2 to 50, preferably 10 to 30, nucleoside units.
  • oligonucleotide analogs are not easily degraded by various nucleases, and can exist in the living body for a long time after administration to the living body. For example, they form stable duplexes with messenger RNA to inhibit the biosynthesis of pathogenic proteins, or form triplexes with double-stranded DNA in the genome to form messenger RNAs. Inhibits transcription to It will also be able to control the growth of infected viruses. From these facts, the oligonucleotide analogs (antisense molecules) using the nucleoside analogs of the present invention can be used as pharmaceuticals for treating diseases by inhibiting the function of specific genes, such as antitumor agents and antiviral agents. Is expected to be useful.
  • the antisense molecule using the nucleotide (nucleotide) analog of the present invention may be formulated into a parenteral administration preparation by combining conventional auxiliaries such as a buffer and / or a stabilizer, or a ribosome preparation. Can be.
  • a common pharmaceutical carrier can be compounded to prepare an ointment, cream, solution, salve or the like.
  • Compound 3 White powder rap 119-120 ° C.
  • Methyl 5-0-(t-butyldiphenylsilyl) synthesis of 1-3-0,4-C-methylene-1 / 3-D-ribofuranoside (18)
  • Triethylamine (3.71 ml, 26.6 mraol) and t-butyl were added to a methylene chloride solution (50 ml) of compound 31 (2.50 g, 8.08 mmol) prepared according to the above reference 5) under a nitrogen stream and ice cooling.
  • Diphenylsilyl chloride (6.94 ml, 26.7 mmol) was added, and the mixture was stirred at room temperature for 10.5 hours. After adding a saturated aqueous solution of sodium bicarbonate to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over sodium sulfate.
  • triethylamine (395 ⁇ , 2.83 mmol) and p-toluenesulfonyl chloride (139.2) were added to a solution of 32 (250 mg, 0.456 mmol) in methylene chloride. mg, 0.730 mmol) and 4-dimethylaminopyridine (8.92 mg, 0.0730 mmol), and the mixture was stirred at room temperature for 15.5 hours. After adding a saturated aqueous solution of sodium bicarbonate to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate.
  • acetic anhydride (6.0 ml, 63.6 mmol) and concentrated sulfuric acid (56 jul, 1.10 mol) were added to an acetic acid solution (56 ml) of 34 (3.70 g, 5.27 mmol), and the mixture was stirred at room temperature for 2 hours. did. After the reaction solution was poured into ice water (300 ml) and stirred for 30 minutes, saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate.
  • tetrabutylammonium fluoride (1.0 M in THF, 379 ⁇ , 0.379 raol) was added to a solution of 37 (188.7 mg, 0.316 mmol) in tetrahydrofuran (1 ml), and the mixture was stirred at room temperature for 2.5 hours. did.
  • the reaction solution was evaporated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (AcOEt-hexane, 1: 1 ⁇ 1: 0) to give a white powder (38) (94.6 mg, 0.262 mg). Ol, 83%).
  • the oligomer was cleaved from the support by treatment with concentrated aqueous ammonia according to a conventional method, the cyanoethyl group on the phosphorus atom was removed, and the protecting groups of adenine, guanine and cytosine were removed.
  • the resulting 5 '— 0— DMT r-oligonucleotide analog was purified on reverse phase column chromatography (Millipore, Oligo-Pak TM SP) by removing the DMT r group with 5 ml of trifluoroacetic acid.
  • the target oligonucleotide analog was obtained.
  • the various oligonucleotide analogs synthesized in Example 2 were used as antisense strands, and the melting temperature (Tm value) of annealed natural strands of DNA or RNA was measured to determine the melting temperature (Tm value) of the present invention.
  • Tm value melting temperature
  • the final concentrations were NaC 110 Om.
  • a nitrogen stream was passed through the cell chamber of the spectrophotometer (Shimadzu UV-2100PC) to prevent dew condensation, the sample solution was gradually cooled to 5 ° C, and kept at 5 ° C for another 20 minutes before measuring. It has started.
  • the sample temperature was increased by 0.2 ° C per minute to 90 ° C, and ultraviolet absorption at 260 nm was measured at 0.1 ° C intervals.
  • the cell was used with a lid, and the measurement was performed with one drop of mineral oil added to the surface of the sample solution.
  • oligomers in which one or two units (X) of the nucleoside analog (general formula (la)) of the present invention were introduced into a natural DNA chain, hybridized with a complementary DNA oligomer. 2 to 7 degrees (approximately 2 times per modified residue) as compared to the natural chain as assessed by Tm value, and as high as 11 degrees for all T substituted with X (X6) did.
  • the increase in the Tm value of the oligomer introduced with one or two oligomers was 410 to 10 degrees (4 to 6 degrees per modified residue) compared to the natural chain.
  • a buffer solution of snake venom phosphodiesterase (0.003 U / ml, 400 1) was mixed with the buffer solution of the oligonucleotide kept at C (10 M, 400 H). The mixed solution was placed in a quartz cell (800 il) maintained at 37 ° C, and the increase in ultraviolet absorption (260 nm) due to the decomposition of the oligonucleotide was measured over time using SHIMADZU UV-2100PC.
  • the buffer composition used was 0.1 mM Tris-HCl (pH 8.6), 0.1 mM NaCl, and 14 mM MgCl 2, and was sufficiently degassed before measurement.
  • FIG. 1 naturally chain
  • FIG. 2 X 2
  • the UV absorption value of the natural chain became constant at about 30 minutes after the start of the oxygen reaction, and became constant at about 90 minutes for X2.
  • this analog provides an oligonucleotide analog antisense molecule that is not easily hydrolyzed by an enzyme in a living body, has high binding ability to a sense strand, and is easy to synthesize.
  • Sequence type nucleotide, nucleotide analog
  • Sequence type nucleotide, nucleotide analog Number of strands: single strand
  • Sequence type nucleotide, nucleotide analog Number of strands: single strand
  • Sequence type nucleotide, nucleotide analog Number of strands: single strand
  • Sequence type nucleotide, nucleotide analog
  • Sequence type nucleotide, nucleotide analog
  • Sequence type nucleotide, nucleotide analog
  • Sequence type nucleotide, nucleotide analog Number of strands: single strand

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Description

明 細 書 新規ビシクロヌクレオシド及びォリゴヌクレオチド類縁体
[技術分野]
本発明は新規なヌクレオシド類縁体とヌクレオチド類縁体に関し、 更に詳細に はアンチセンス分子に適したヌクレオチド類縁体に関するものである。
[背景技術]
1 9 7 8年にアンチセンス分子がィンフルェンザウィルスの感染を阻害したと の報告が初めて成された。 以後、 ガン遺伝子発現や A I D S感染を阻害したとの 報告もなされている。 アンチセンスオリゴヌクレオチドが望ましくない遺伝子の 発現を特異的に制御することから、 医薬品として近年、 最も期待されている分野 の一つである。
アンチセンス法とは、 D N A→R N A→タンパク質という、 いわゆるセントラ ノレドグマの一連の流れをアンチセンスオリゴヌクレオチドを用いて制御しようと いう概念に基づいている。
しかしながら、 天然型オリゴヌクレオチドをアンチセンス分子としてこの方法に 適用した場合、 生体内の各種ヌクレア一ゼにより分解を受けたり、 細胞膜透過性 が高くないなどの問題が生じた。 そのため、 様々な核酸誘導体や類縁体が数多く 合成され、 研究が重ねられてきた。 例えば、 リン原子上の酸素原子をィォゥ原子 に置換したホスホロチォエート、 メチル基に置換したメチルホスホネート、 また 最近になっては、 リン原子も炭素原子で置換したもの、 さらには糖部の構造を変 換したもの、 核酸塩基を修飾したものなども合成されている。 しカヽし、 いずれの 場合も、 生体内での安定性、 合成の容易さ、 配列特異性 （特定の遺伝子発現のみ を選択的に制御する） などの点で十分に満足のいく誘導体や類縁体が得られてい ないのが現状である。
生体内でヌクレアーゼによる分解を受けにく く、 高い親和力で標的のメ ッセン ジャー R N Aに結合し、 その特異性に優れ、 よって特定の遺伝子の発現を効率よ く制御することのできるアンチセンス用の分子の創製が望まれている。
[発明の開示] 本発明の発明者らは、 アンチセンス法において有用と考えられる、 核酸におけ る糖部のコンホメーションの固定化を施したした核酸類縁体を設計し、 その単位 構造となるヌクレオシド類縁体の合成を行い、 これを用いて調製したオリゴヌク レオチド類縁体にアンチセンス分子として極めて有用であることを確認した。
[図面の簡単な説明]
第 1図は、 天然型のオリゴヌクレオチドをェキソヌクレアーゼで分解した時の 紫外部吸収 （2 6 0 n m) の経時変化を示すチャートである。
第 2図は、 本発明のオリゴヌクレオチド （X 2 ) をェキソヌクレアーゼで分解 した時の紫外部吸収 （2 6 0 n m) の経時的変化を示すチヤ一トである。
以下に本発明の詳細を説明する。
本発明のヌクレオシド類縁体の構造は下記の一般式 （ I ) で表すことができる
Figure imgf000004_0001
[式中、 Bはピリ ミジンもしくはプリン核酸塩基又はそれらの類縁体であり、 X及び Yは同一もしくは異なり、 水素、 アルキル基、 アルケニル基、 アルキニル 基、 シクロアルキル基、 ァラルキル基、 ァリール基、 ァシル基、 又はシリル基で ある] で表わされるヌクレオシド類縁体もしくはそれらのアミダイ ト誘導体であ
O o
アルキル基とは炭素数 1一 2 0の直鎖または分枝鎖状のアルキル基を示し、 例 えば、 メチル基、 ェチル基、 n—プロピル基、 i—プロピル基、 n—ブチル基、 t—ブチル基、 ペンチル基、 へキシル基、 ヘプチル基、 ォクチル基、 ノニル基、 デシル基等があげられる。 アルケニル基とは、 炭素数 2— 2 0の直鎖または分枝鎖状のアルケニル基を示 し、 例えば、 ビニル基、 ァリル基、 ブテニル基、 ペンテニル基、 ゲラニル基、 ファ ルネシル基等があげられる。
アルキニル基とは、 炭素数 2— 2 0の直鎖または分枝鎖状のアルキニル基を示 し、 例えば、 ェチニル基、 プロピニル基、 プチニル基等があげられる。
シクロアルキル基とは、 炭素数 3— 8のシクロアルキル基を示し、 例えば、 シ クロプロピル基、 シクロブチル基、 シクロペンチル基、 シクロへキシル基、 シク 口へプチル基、 シクロォクチル基等があげられる。 シクロアルキル基の環上の 1 つ以上の任意のメチレンが酸素原子や硫黄原子あるいはアルキル基で置換された 窒素原子に置換された複素環基も含まれ、 例えばテトラヒ ドロビラニル基などが あげられる。
ァリール基とは、 芳香族複素環基又は芳香族炭化水素基、 から水素原子 1個を 除いた 1価の置換基を意味し、 好ましくは、 芳香族炭化水素基から水素原子 1個 を除いた 1価の置換基を意味し、 例えば、 フエニル基、 トリル基、 キシリル基、 ビフヱニル基、 ナフチル基、 アントリル基、 フヱナントリル基等である。 また、 ァリール基の環上の炭素原子はハロゲン原子、 低級アルキル基、 水酸基、 アルコ キシ基、 アミノ基、 ニトロ基、 トリフルォロメチル基等の 1種以上の基によって 置換されていてもよい。 置換基としてはハロゲン原子、 水酸基、 アミノ基、 アル コキシ基、 ァリールォキシ基等があげられる。
ァラルキル基とは、 ァリール基にアルキル基が結合した基で、 ァラルキル基は 置換されていてもよい。 置換されていてもよいァラルキル基とはァリール基にァ ルキル基が結合した基で、 ァリ一ル基及びアルキル基の任意の 1つ以上の水素原 子が以下の置換基で置換されていてもよい基を意味する。 ここで置換基として は、 ァシル基、 アミノ基、 ァリール基、 アルキル基、 シクロアルキル基、 アルコ キシ基、 水酸基、 ニトロ基、 ハロゲン原子等がある。
ァミノ基は置換されていてもいなくてもよいが、 置換されているァミノ基の例 としてはアルキルアミノ基、 ァリールアミノ基、 ァシルァミノ基等がある。 アル コキシ基の例としては、 メ トキシ基、 エトキン基、 n—プロポキシ基、 i—プロ ポキシ基、 n—ブトキシ基、 i一ブトキン基、 s—ブトキシ基、 t一ブトキシ基、 ペンチルォキシ基、 へキシルォキシ基、 フヱノキシ基等がある。 ハロゲン原子と してはフッ素、 塩素、 臭素、 ヨウ素がある。
ァラルキル基の好ましい例としては、 例えばトリチル基、 ベンジル基、 フエネ チル基、 トリチルメチル基、 ジフヱニルメチル基、 ナフチルメチル基、 4 , 4 '一 ジメ トキシトリチル （D MT r ) 基等があるが、 特に好ましいのは D M T r基で ある。
ァシル基としては、 ァセチル基、 ホルミル基、 プロピオニル基、 ベンゾィル基、 ベンジルォキシカルボニル基等があげられる。 シリル基の例としては、 卜リアル キルシリル基があげられるが、 好ましくは、 トリメチルシリル基、 トリェチルシ リル基、 トリイソプロビルシリル基、 t—ブチルジメチルシリル基、 t—ブチル ジフエニルシリル基等があげられ、 更に好ましくはトリメチルシリル基である。 また、 本発明のヌクレオチド類縁体は、 一般式 （ l a )
Figure imgf000006_0001
[式中、 Βはピリ ミジンもしくはプリン核酸塩基又はそれらの類縁体である] で 表される構造を 1または 2以上有するオリゴヌクレオチドまたはポリヌクレオチ ド類縁体、 または、 一般式 （Π)
Figure imgf000007_0001
II
[式中、 B Bは同一または異なり、 ピリ ミジンもしくはプリン核酸塩基又は それらの類縁体であり、 Rは水素、 水酸基、 ハロゲン、 またはアルコキシ基であ り、 W W2は同一または異なり、 水素、 アルキル基、 アルケニル基、 アルキニ ル基、 シクロアルキル基、 ァラルキル基、 ァリール基、 ァシル基、 シリル基また はリン酸残基もしくはリン酸ジエステル結合を介した天然型ヌクレオシド、 合成 ヌクレオシドまたはこれらヌクレオンドを含むォリゴヌクレオチドもしくはボリ ヌクレオチドであり、 n 1または n 2は同一または異なり、 0〜 5 0の整数である
(ただし、 n 1または n 2が同時にゼロになることはない。 また、 n 2の全てが同 時にゼロになることはない。 ） 、 n 3は 1〜5 0の整数である、 ただし、 n 1およ び または n 2が 2以上の場合には B 1と Bは同一でなくてもよく、 Rも同一でな くてもよい] で表されるオリゴヌクレオチドもしくはポリヌクレオチド類縁体で あ 。
本発明における、 ピリ ミジンもしくはプリン核酸塩基とは、 チミン、 ゥラシル、 シ トシン、 アデニン、 グァニン及びそれらの誘導体である。
本発明のヌクレオンド類縁体及びヌクレオチド類縁体は次のように合成できる ( ( 1 ) ヌクレオシド類縁体の合成 O— 98/39352
Figure imgf000008_0001
Figure imgf000008_0002
roヽ y
Figure imgf000008_0003
a
ゥリジンから文献 [1) J. A. Secrist et al. , J. Am. Chem. So ， 101, 155 4 (1979); 2) G. H. Jones et al. , J. Org. Chem. , 44, 1309 (1979)] に従い 合成した化合物 1をトシルクロリ ド （Ts C 1 ) で 2個ある第一級アルコールの 一方のみをトシル化して化合物 2に導き、 酸加水分解して卜リオール体 3とした c 化合物 3はベンズアルデヒ ドと酸触媒下で縮合反応を行いベンジリデン化合物 4 として、 このものを四塩化チタン （T i C 14) 存在下にナトリゥムシァノボ口 ヒ ドリ ド （Na BH3CN) で還元すると化合物 5が得られた。 本化合物をテ卜 ラヒ ドロフラン （THF) 中でナトリウムへキサメチルジシラジド （N a HMD S) と反応させたところ、 ビシクロ化合物 6 (化合物 I ： Β-ゥラシル （U) , χ = Η, Υ =ベンジル） が得られた。 化合物 6をパラジウム炭素触媒下で接触 還元すると、 ジオール化合物 7 (化合物 （ I ) ； B = U, X = Y = H) が得られ、 更に、 4、 4' ージメ 卜キシ卜リチルク口リ ド （DMT r C 1 ) 処理すると卜リ チル体 8 (化合物 I ； B = U. X = DMT r, Y = H) が得られた。 化合物 6、 7及び 8は様々な化合物 Iの原料として利用することができる。
ゥリジン以外の天然 ·非天然を問わず様々な核酸塩基を有する化合物 （ I ) は 3通りの方法で合成することができる。
その一つは、 化合物 8からの変換である。 すなわち、 化合物 8をァセチル化し て化合物 9とした後、 1、 2、 4一トリァゾールと反応して化合物 10に導き、 加水分解すると化合物 11 (化合物 （I ) : B =シ トシン （C) . X = DMT r, Y = H) が得られた。 オリゴヌクレオチド合成の原料となる化合物 12 (化合物 ( I) ； B-ベンゾイルントシン （CBz)， X = DMT r, Y = H) は化合物 1 1のベンゾィル化で容易に得られる。
Figure imgf000009_0001
第二の方法は D—リボースから文献 [3) A. G. M. Barrett et al. , J. Org. Ch em. , 55, 3853(1990); 4) G. H. Jones et al. , ibid. , 44, 1309 (1979)] に従つ て容易に得られる化合物 13を経由する方法である。 すなわち、 化合物 13を 3 工程で化合物 16に導き、 塩基性条件下に閉環反応すると、 目的のメチルグリコ シル化合物 1 7が得られた。 本化合物の 1位 O M e基を天然の様々な核酸塩基や 非天然の核酸塩基類縁体に置換するには、 既に開発された種々の方法により可能 である。 例えば、 下式化合物 1 7から化合物 2 0のような方法が使用できる。
Figure imgf000011_0001
Me 2)
Figure imgf000011_0002
Figure imgf000011_0003
20 Wひ ·98/39352 さらに、 第三の方法としては、 D-グルコースから 1工程で得られ、 しかも市 販品であるジアセトン D-グルコースを出発原料とする方法である。 文献 5) R. D. Youssefyeh, J. P. H. Verheyden and J. G. Moffatt. , J. Org. Chem. , 44, 1301-1309 (1979) に従って化合物 31を調製する。 次いで、 化合物 31を下記 の式に示した通り、 2種の 1級水酸基を t-ブチルジフエニルシリル基、 P-トル エンスルホニル基で段階的に保護し、 ァセチル化処理して化合物 34に導いた。
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
化合物 34にトリメチルシリル化して活性化したチミン （2TMS · T) 、 ベ ンゾィルアデニン （2TMS . ABz) 、 イソプチリルグァニン （3TMS * GiBu) を別々に縮合させ、 下記の式に示すように、 化合物 5、 10、 14をそれぞれ高 収率で得た。 ついで、 これら縮合体は脱ァセチル化 （化合物 36、 41、 45) 、 5員環形成 （化合物 37、 42、 46) 、 脱シリル化 （化合物 38、 43、 47) 、 更に脱べンジル化して目的の化合物 39へと誘導した。
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
38: B= 39a: B=T 43: B=A Bz 39b: B=ABz 47: B=G iBu 39c: B=G旧 u ( 2 ) オリゴヌクレオチド類縁体の合成
化合物 8に 2—シァノエェチルー N, N, Ν' , N* ーテトライソプロピルホ スホロアミダイ トを作用させ、 ァミダイ 卜体 2 1を得、 このものと天然ヌクレオ シドアミダイ ト体とを組み合わせて、 D N A自動合成機を用いて種々のオリゴヌ クレオチド類縁体を合成する。 合成した粗生成物はオリゴパック、 逆相クロマト カラムを用いて精製し、 精製物の純度を H P L Cで分析することにより確認する
天 «ヌクレオシド
アミダイト オリゴヌクレオテド
Figure imgf000014_0001
CN
21
化合物 8のモノマーュニッ トは、 オリゴヌクレオチド類縁体の中に 1つ以上存 在させることができる。 また、 オリゴヌクレオチド類縁体の中の 2ケ所以上の位 置に、 1または 2以上の天然ヌクレオチドを介して隔離された状態で存在させて も良い。 本発明に依れば、 本発明のヌクレオチド類縁体 （ヌクレオシド類縁体） を必要な位置に必要な数 （長さ） で導入したアンチセンス分子を合成することが できる。 オリゴヌクレオチド類縁体全体の長さとしてヌクレオシド単位が 2〜5 0、 好ましくは 1 0〜3 0個である。
このようなオリゴヌクレオチド類縁体 （アンチセンス分子） は、 各種ヌクレア5 ーゼに対して分解されにく く、 生体への投与後、 長時間生体内に存在することが できる。 そして、 例えば、 メ ッセンジャー R N Aと安定な二重鎖を形成して病因 となるタンパク質の生合成を阻害したり、 ゲノム中の二重鎖 D N Aとの間で三重 鎖を形成して、 メ ッセンジャー R N Aへの転写を阻害する。 また、 感染したウイ ルスの増殖を抑えることも可能となる。 これらのことから、 本発明のヌクレオシド類縁体を用いたオリゴヌクレオチド 類縁体 （アンチセンス分子） は、 抗腫瘍剤、 抗ウィルス剤をはじめとした、 特定 遺伝子の働きを阻害して疾病を治療する医薬品としての有用性が期待される。 本発明のヌクレオチド （ヌクレオチド） 類縁体を用いたアンチセンス分子は、 例 えば、 緩衝剤および/または安定剤等の慣用の助剤を配合して非経口投与製剤と したり、 リボソーム製剤とすることができる。 また、 局所用の製剤としては、 慣 用の医薬用担体を配合して軟膏、 クリーム、 液剤、 または膏薬等に調剤できる。 ' 本発明のヌクレオシド類縁体ならびにヌクレオチド類縁体の合成を実施例およ び製造例により、 さらに詳しく説明する。 実施例では、 塩基としてゥラシルを主 として使用しているが、 他のプリン核酸塩基も同様に使用できる。
[実施例 1] ヌクレオシド類縁体の合成
(1) 2'. 3' -0-シクロへキシリデン -4'- (P-トルエンスルホニルォキシ
メチル） ゥリジン（2)の合成
窒素気流下、 文献既知化合物 1 ( 956 mg, 2.70 匪 ol ) の無水ピリジン溶液 ( 13.5 ml ) に室温で p -トルエンスルホニルクロリ ド （771 mg, 4.05 raraol)を 加え、 60 でで 5時間撹拌した。
反応溶液に飽和重曹水を加えた後、 ベンゼンで 3回抽出した。 有機層を飽和食 塩水で 1回洗浄後、 無水 MgS04 にて乾燥した。 溶媒を減圧留去し、 ベンゼンで 3回共沸し、 得られた粗成績体をシリカゲルカラムクロマトグラフィー （CHC13: MeOH = 15:1) により精製後、 ベンゼン一へキサンにて再沈澱し、 白色粉末とし て化合物 2 (808 mg, 1.59 ramol, 59%) を得た。
化合物 2 : 白色粉末 rap 104-106 °C (ベンゼン一へキサン）. IR (KBr): 33 26. 2929. 2850, 1628. 1577, 1544, 1437, 1311, 1244 era—1. !H-NMR (d6-acet one): δ 1.45-1.67 (瓶 m), 2.45 (3H, s), 3.71 (2H, ABq, J = 12 Hz), 4. 20 (2H, ABq, J = 11 Hz), 4.92 (1H， d, J' = 6 Hz), 5.05, 5.06 (1H, dd， J = 4, 6 Hz), 5.60 (1H, d, J = 7 Hz), 5.75 (1H, d, J = 4 Hz), 7.48 (2H, d, J = 8 Hz), 7.77 (1H, d, J = 8 Hz), 7.81 (2H, d, J = 8 Hz), 10.10 (1H, s, ). 13C-NMR (de-acetone): δ 21.5, 24.1, 24.5, 25.5, 34.8, 36.9, 63.5, 69.7, 82.5, 84.7, 87.8, 92.9, 102.9, 115.4， 128.8， 130.8, 133.9, 1 42.7, 145.9, 151.3, 163.5. ass(EI): m/z 481(M+- H20).
Anal. Calcd for C23H28N209S- 1/3 H20: C， 53.69; H, 5.61; N, 5.44; S, 6. 22. Found: C, 53.99 ;H, 5.48 :N, 5.42 :S, 6.10.
(2) 4'—(p-トルエンスルホニルォキシメチル）ゥリジン（3)の合成
化合物 2 (107 mg( 0.21 随 ol)を TFA— H2O (98:2, 1 ml) 中室温で 10 分 間撹拌した。 反応溶液を減圧留去し、 EtOHを加えて 3回共沸した。 得られた粗成 繽体をシリカゲルカラムクロマ卜グラフィ一（CHCl3:MeOH = 10:1)により精製し、 化合物 3(85. O mg, 0.20 随 ol, 94%)を得た。
化合物 3 : 白色粉末 rap 119-120 °C. IR v (KBr): 3227, 3060, 2932, 2837, 1709, 1508, 1464, 1252, 978, 835, 763. 556 era—1. ^-NMR (d6 - acetone) : 5 2.31 (3H, s), 2.84 (3H, s), 3.71 (2H, s), 4.13, 4.20 (2H, ABq, J = 11 Hz), 4.28, 4.31 (1H, dd, J' = 9, 6 Hz), 4.36 (1H, d, J' = 6 Hz), 5.54 (1 H, d, J' = 8 Hz), 5.75 (1H, d, J = 7 Hz), 7.32 (2H, d, J = 8 Hz), 7.67 (2H, d, J = 8 Hz), 7.70 (1H, d, J' = 8 Hz), 10.14 (1H, s). 13C-NMR (de- acetone)： δ 21.5, 63.7, 70.8, 72.7, 74.6, 86.8, 88.8, 103.1, 128.8, 130. 7. 133.9, 141.7, 145.8, 151.8, 163.9. Mass (EI): m/z 256 (M+- OTs) . (3) 2', 3'- O-ベンジリデン一 4' _(p-トルエンスルホニルォキシメチル） ゥリジン （4) の合成
窒素気流下、 化合物 3 (400 mg, 0.93 圆 ol) にべンズアルデヒ ド （2.4 ml, excess), 塩化亜鉛 （670 mg, 5.0 mmol)を加え室温にて 5時間撹拌した。 反応を 飽和重曹水により止め、 クロ口ホルムで抽出し、 飽和重曹水、 水、 飽和食塩水で 洗浄した。 有機層を無水硫酸ナトリウムで乾燥し、 溶媒留去後シリカゲルカラム クロマトグラフィー（CHC13 ： eOH = 40： 1) により精製し、 化合物 4 (380 rag, 0.74 ramol, 80¾ を得た。
化合物 4: 白色粉末. mp 99-102 。C (CH2C12-へキサン）. [«]□ 23- 26.7 ° (c = 1.0, CHC13). IR v (KBr)： 3059, 1691, 1460, 1362, 1269, 1218, 1177 cm-1. !H-NMR (CDC13) δ： 2.41 (3H, s), 3.25 (1H, br), 3.79 (2H, ra), 4.19 (2H, s), 5.09 (1H, d, J = 7 Hz), 5.28 (1H, dd, J = 3, 7 Hz), 5.60 (1H, d , J = 4 Hz), 5.73 (1H， d , J = 8 Hz), 5.94 (1H, s), 7.24 (1H, d, J = 8 H z), 7.38 (2H, d, J = 9 Hz), 7.42 (5H, br), 7.69 (2H, d, J = 9 Hz), 9.11 (1H, br). 13C-NMR ( CDC13): δ 21.6, 63.5, 68.3, 77.2. 82.8, 84.2, 87.7, 94.9, 102.6, 107.5, 126.5, 127.9, 128.5, 129.7, 132.2, 135.0, 143.0, 14 5.0, 150.4, 163.5.
Anal. Calcd for C24H24N209S'l/3 H20: C, 55.17; H, 4.76; N, 5.36; S， 6. 14. Found: 55.19 ;H, 4.66; N， 5.29; S， 5.98.
(4) 3'一 0—ベンジル一 4'—(p -トルエンスルホニルォキシメチル）
ゥリジン （5) の合成
窒素気流下、 化合物 4 (150 mg, 0.29 mraol)のァセトニトリル溶液 （3 ml)に シァノ水素化ホウ素ナトリウム （92 mg, 1.5 mmol)を室温にて加えた。 その後、 四塩化チタン （0.16 ml, 1.5 mmol)を氷冷下で滴下し室温にて 15 時間撹拌した。 反応液をクロ口ホルムに希釈して飽和重曹水、 水、 飽和食塩水で洗浄したのち有 機層を無水硫酸ナトリゥムで乾燥し、 溶媒留去後シリ力ゲル力ラムクロマトグラ フィー（CHC13 ： MeOH = 25:1)により精製し、 化合物 5 (112 mg, 0.22 mmol. 75¾) を得た。
化合物 5 : 無色結晶. mp 195-197°C (AcOEt-へキサン）. [a]o 23 -14.6° (c = 1.0, CHC13). I v (KBr)： 3033, 2885, 2820, 1726, 1470, 1361, 1274, 1175, 1119 cm-1. !H-NMR (CDC13) δ 2.40 (3H, s)， 3.59-3.77 (3H, m), 4. 10, 4.24 (2H, AB, J = 11 Hz), 4.32 (1H, d, J = 6 Hz), 4.56 (2H, m), 4.69 (1H, d, J = 11 Hz), 5.52 (1H, d , J = 6 Hz), 5.67 (1H, d . J = 8 Hz). 7.24 -7.29 (7H, m), 7.48 (1H, d, J = 8 Hz), 7.70 (2H, d, J = 9 Hz), 9.91 (1H, s). 13C-霞 (CDC13): δ 21.6, 63.2, 69.2, 73.6, 74.6, 78.1, 86.6, 92.9, 102.5. 127.9, 128.2, 128.3, 128.6. 129.9, 132.3, 136.9, 142.4, 145.2, 1 50.7, 163.8.
Anal. Calcd for C24H26N209S ： C, 55.59; H, 5.05; N, 5.40; S, 6.18.
Found: C, 55.41;H, 5.02; N, 5.32; S, 6.15. (5) 3'— 0—ベンジル一 2'—0, 4'— C—メチレンゥリ ジン （6) の合成 窒素気流下、 化合物 5 (80 mg, 0.16 mraol)の無水 T H F溶液 （1.5 ml) に室 温で NaHMDS (3.2 raraol) の無水ベンゼン懸濁液 （0.7 ml) を加え、 室温で 20 時 間撹拌した。 反応溶液に飽和重曹水を加え、 CHC13 にて抽出した。 有機層を飽和 食塩水で洗浄した後、 無水硫酸ナトリウムにて乾燥した。 溶媒を減圧留去し、 得 られた粗成績体をシリカゲルカラムクロマトグラフィー （CHC13 ： MeOH = 10:1) にて精製後、 MeOHにて再結晶し、 化合物 6 (41 mg, 0.10 raraol, 61%) を得た。 化合物 6 : 無色結晶. rap 217-219 °C (MeOH). [a]D 23+108.4 。 (c = 0.3, M eOH). IR v (KBr)： 3059, 2951, 1688, 1459, 1271. 1053 cm—1. 'H-N R (de - D MS0) δ： 3.75, 3.85 (2H, AB, J = 8 Hz), 3.77 (2H, d, J = 5 Hz), 3.92 (1H, s)， 4.44 (1H, s), 4.60 (2H, s), 5.39 (1H, t , J = 5 Hz), 5.48 (1H, s), 7. 31 (5H, ra)， 7.72 (1H, d, J = 8 Hz), 11.37 (1H, s). 13C-NMR (d6-DMS0): δ 56.0, 71.1, 71.6, 75.8, 76.5, 86.5, 88.3, 100.9, 127.4, 127.6, 128.2, 1 37.9, 139.0, 150.0, 163.3. Mass(EI): m/z 346 (M+, 1.1).
Anal. Calcd. for C17H18N206 ： C, 58.96; H, 5.24; N, 8.09.
Found: C, 58.67; H, 5.23; N, 8.05.
(6) 2'— O, 4'— C—メチレンゥリジン （7) の合成
化合物 6 (25 rag, 0.072 匪 ol)のメタノール溶液 (2.5 ml)に 10% Pd-C (25 mg) を加え、 水素気流下、 常圧にて 15 時間撹拌した。 反応液を濾過し、 溶媒留去後、 シリカゲルカラムクロマトグラフィ一 （CHC13： MeOH = 10:1 then 5:1) にて精 製し、 7 (18.3 rag, quant.)を得た。
化合物 7 : 無色結晶. mp 239-243 °C (MeOH). [a]o 23+92.2 ° (c = 0.3, Me OH). IR v (KBr)： 3331, 3091, 3059, 2961, 1689, 1463, 1272. 1049 cm"1. !H-NM (CD30D) δ： 3.76, 3.96 (2H, AB, J = 8 Hz), 3.90 (2H, s), 4.04 (1H, s), 4.28 (1H, s), 5.55 (1H, s), 5.69 (1H, d, J = 8 Hz), 7.88 (1H, d. J = 8 Hz).
Anal. Calcd. for d。1^ 2N206 ： C, 46.88; H, 4.72; N, 10.93.
Found: C, 46.74; H. 4.70; N, 10.84. (7) 5'—0—（4, 4' _ジメ トキシトリチル）一 2'— 0, 4'— C—メチレン ゥリジン （8) の合成
化合物 7 (140 mg, 0.53 ramol) に無水ピリジンを加えて 3回共沸した後、 無 水ピリジン溶液 （1.5 ml) とし、 窒素気流下、 室温で 4 , 4 '—ジメ トキシトリチ ルクロリ ド （210 rag, 0.63 隱 ol)、 DMAP (6.5 mg, 0.053 隱 ol)を加え室温 で 5時間撹拌した。 反応溶液に飽和重曹水を加えた後、 CH2C12 で抽出した。 有 機層を水、 飽和食塩水で洗浄後、 無水硫酸ナトリウムにて乾燥した。 溶媒を減圧 留去し、 得られた粗成績体をシリ力ゲル力ラムクロマトグラフィ一（CHC13 ： MeOH = 40:1)により精製し、 化合物 8 (230 mg, 0.34 mmol, 66¾)を得た。
化合物 8 : 白色粉末. mp 117-120 °C (CHC13). [«]D 23+17.2 ° (c = 1.0, CHCU). IR v (KBr): 3393， 3101, 2885, 1689, 1464, 1272， 1047 cm-1.1H-N MR (CDCI3) δ 2.59 (1H, br), 3.56 (2H. q, J = 7. 11 Hz), 3.87 (1H, d， J = 7 Hz), 4.26 (1H, s), 4.47 (1H, s), 5.60 (1H, d, J = 9 Hz), 5.63 (1H, s), 5.84 (4H, d, J = 9 Hz), 7.22-7.45 (9H, ra), 7.93 (1H, d, J = 9 Hz). [実施例 2] ヌクレオシド類縁体の合成
(1) メチル =5— 0— ( t—ブチルジフヱニルシリル） 一4—ヒ ドロキシ
メチル一 2, 3— 0—イソプロピリデン一 /3— D—リボフラノシド (14) の合成
窒素気流下、 文献既知化合物 13 (2.0()8,8.54匪01)の無水じ^12じ 12溶液（40 ml)に氷冷下で Et3N(2.62ral, 18.8mmol)、 tーブチルジフエニルシリノレクロリ ド（4. 88ml， 18.8mmol)を加え、 室温で 13時間撹拌した。 反応溶液に飽和重曹水を加え た後、 AcOEtで 3回抽出した。 有機層を飽和食塩水で 1回洗浄後、 無水 Na2S04に て乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲルカラムクロマト グラフィ一 （へキサン： AcOEt=5:l)により精製し、 無色油状物質 14 (2.82g, 5.9 8mmol， 70%)を得た。
[α]ο17-16.2° (c=0.52,CHCl3) IRレ （KBr) :3510, 3061, 2938, 2852, 1465, 110 3cm—
^-NMR (CDC 13) δ ： 1.09(9H,s), 1.28(3H, s), 1.49(3H，s), 3.22(3H, s), 3.67, 3.76(2H, AB, J=llHz), 3.88, 3.93(2H, AB, J=llHz), 4.49(1H, d, J=6Hz), 4.57C1H, d, J=6Hz), 4.93(1H, s), 7.38-7.43C6H, m). 7.67(4H, d， J=7Hz).
13C— NMR (CDC ") 5 c : 19. % 24.4, 25.9, 26.9, 55.0, 62.9, 64.8, 82.2, 85.9, 88.7, 108.6, 112.6, 127.8, 129.9, 133.0, 135.7.
Anal. Calcd for C26H3606Si · 1/4 H20： C, 65.45; H， 7.71. Found :C, 65.43; H, 7.59.
(2) メチル =5—0— ( t—ブチルジフヱニルシリル） 一2, 3—0—
ィソプロピリデン一 4— (p— トルエンスルホニルォキシメチル） —^—リボフラノシド （15) の合成
窒素気流下、 化合物（2.13g,4.51mmol)の無水 CH2C12溶液 （15ml)に室温で Et3N (3.92g, 28.0匪 ol)、p—トルエンスルホニルクロリ ド（1.34g, 7.22ramol)、 4ージメ チルァミノピリジン（90mg, 0.72mmol)を加え、 室温で 17時間撹拌した。 反応溶 液に飽和重曹水を加えた後、 AcOEtで 3回抽出した。 有機層を飽和食塩水で 1回 洗浄後、 無水 Na2S04にて乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリ 力ゲルカラムクロマトグラフィ一 （へキサン： AcOEt=10:l)により精製し、 無色 油状物質 15 (2.76g, 4.42隱 ol, 98%)を得た。
[α]ο17-3.82° (c=0.56,CHCl3) IR （KBr) :2934, 2852, 1369, 1104cm-1.
1H— NMR (CDC ") δ ： 1.02(9H,s), 1.20(3H, s), 1.32(3H, s), 2.4K3H, s), 3.09(3H, s), 3.51,3.77(2H. AB, J=10Hz)( 4.34(1H, d, J=6Hz), 4.25, 4.39(2H, AB, J=9Hz), 4.47(1H, d, J=6Hz), 4.77(1H, s), 7.28, 7.8K4H, AB, J=9Hz), 7.39-7. 44(6H,ra), 7.62-7.65(4H, m), 7.8K2H, d, J=9Hz).
13C 匪 R (CDC ") (5 c ： 19.2, 21.6, 24.5, 25.8, 26.8, 54.9, 62.7, 68.8, 81.9, 85.6, 87.5, 108.7. 112.8, 127.7, 127.8, 128.2, 129.6, 129.9, 132.9, 135.6, 144.4.
Anal. Calcd for C33H4208SSi:C, 63.23; H, 6.75;S， 5.11. Found :C, 62.99; H.6.5 3; S, 5.13.
(3) メチル =5— 0— ( t—ブチルジフヱニルシリル） 一 4一 （p— トルエン スルホニルォキシメチル） 一 3— D—リボフラノシド （16) の合成 化合物 15 (645rag, 1.03ramol)の THF- H20[llml, 8:3(v/v)]溶液に室温でトリフロ 口酢酸（14ml)を加え、 室温で 20分撹拌した。 溶媒を減圧留去し、 得られた粗成 績体をシリカゲルカラムクロマ卜グラフィー （hexane:AcOEt=5:l)により精製し、 無色油状物質 16 (464mg, 0.79ramol, 77%)を得た。
[ ] D1 7 - 35.8° (c=1.90,CHCl3) IRレ （KBr) :3499， 3051, 2931. 2840, 1594, 146 8, 1362, 1109cm-1.
'H-N R (CDC 13) δ 1.02(9Η( s), 2.42(3Η, s), 3.16(3Η, s), 3.54. 3.70(2Η, ΑΒ, J=10Hz), 3.97(1Η, d, J=5Hz), 4.18(1Η, d, J=5Hz), 4.26, 4.39(2H, AB, J=10Hz), 4.73C1H, s), 7.30(2H, d, J=8Hz)( 7.36-7.44(6H, m), 7.59-7.66(4H, m), 7.78(2H, d, J=8Hz).
13C-NMR(CDC 13)5c : 19.2, 21.6, 26.7. 55.2, 66.5, 69.6, 74.0, 75.2, 76.5, 84.8, 107.5, 127.7, 128.0, 129.8， 132.6, 132.7. 132.8, 135.5, 135.6, 144.9.
Anal. Calcd for C30H38SSi08'l/4 H20:C, 60.94; H, 6.56. Found :C, 60.94; H, 6.4 3.
(4) メチル =5—0— ( t—ブチルジフエニルシリル） 一2— 0, 4 -C- メチレン一 yS— D—リボフラノシド （17) 及び
メチル =5— 0— （ t—プチルジフエニルシリル） 一3— 0, 4 -C- メチレン一 /3— D—リボフラノシド （18) の合成
窒素気流下、 化合物 16 (194mg,0.33隱 ol)の無水 THF溶液 （4ral)に室温で NaHMDS(3.30匪 ol)の benzene懸濁液 (1.6ml)を加え、 室温で 1時間撹拌した。 反 応溶液に飽和重曹水を加えた後、 反応溶媒を留去し、 AcOEtで 3回抽出した。 有 機層を飽和食塩水で 1回洗浄後、 無水 Na2S04にて乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲルカラムクロマ卜グラフィ ー （へキサン： Ac0Et=5: 1)により精製し、 無色油状物質 17 (48mg,0.116mmol,35¾ 及び無色油状物質 1 8 (59mg, 0.142raraol, 43¾)を得た。
化合物 17 :IRリ（KBr):3438, 3064, 1103, 1036cm—
1H— NMR (CDC 13) δ ： 1.08(9H,s), 2.04(lH,br s), 3.39(3H, s), 3.65, 3.98(2H, AB, J=8Hz), 3.95, 4.02(2H, AB, J=12Hz), 4.02(lH,s), 4.30(1H, s), 4.79 (lH,s)， 7.38-7.46(6H, m), 7.65-7.69(4H, m).
13C-NMR (CDC 1 3) (5 : 19.2, 26.7, 55.0, 60.7. 71.2, 73.1, 79.9, 85.5, 104.3, 127.8, 129.9. 130.0, 132.9, 135.6, 135.7.
Anal. Calcd for C23Il3005Si'l/4 H20:C.65.68; H, 7.34. Found :C, 65.98; H, 7.23. 化合物 1 8 :IRレ （KBr):3456, 3058, 2938, 2852, 1467, 1108cm-1.
^-NMR (CDC 1 3) δ ： 1.10(9H. s), 3.26C3H, s), 3.71(2H,s), 4.02(1H, d, J=6Hz), 4.35, 4.95(2H, d, J=7Hz), 5. Ol(lH.s), 5.1K1H, d, J=6Hz), 7.38-7.4 4(6H, m), 7.66(4H, d, J=7Hz).
13C-NMR (CDC 1 3) 。 ： 19.3, 26.8, 55.4, 63.7, 75.1, 77.9, 84.5, 86.3， 111.9, 127.8, 128.0, 129.9, 132.9, 133.0, 135.6, 135.8. 135.9. Anal. Calcd for C23H3005Si.l/4 H20:C, 65.91; H, 7.34. Found :C.66.07; H, 7.14. (5) メチル = 3—O—ァセチルー 5—O— ( t—ブチルジフヱ二ルシリ
ル） 一 2— 0, 4— C—メチレン一^一 D—リボフラノシド （ 1 9 ) の合成
窒素気流下、 化合物 1 7 (704mg, 1.70議 ol)の無水ピリジン溶液 （10ml)に室温 で無水酢酸（0.38ml, 4.08關 ol)、 4ージメチルァミノピリジン（21mg, 0.170園 ol)を 加え、 室温で 3時間撹拌した。 反応溶液に飽和重曹水を加えた後、 AcOEtで 3回 抽出した。 有機層を飽和食塩水で 1回洗浄後、 無水 Na2S04にて乾燥した。 溶媒を 減圧留去し、 得られた粗成績体をシリカゲルカラムクロマトグラフィー （へキサ ン ： Ac0Et=7:l)により精製し、 無色油状物質 19 (665mg, 1.46隱 ol,86¾)を得た。
[ ] D17— 34.3° (c=0.93, CHC13) IRレ （KBr):3438, 3064, 2934, 1749, 1468, 110 3, 1036cm一1.
'H-NMR (CD C ") δ ： 0.99(9H,s), 1.97C3H, s), 3.34(3H, s), 3.69.3.8 6(2H, AB, J=8Hz), 3.86(2H, s), 4.17(1H, s), 4.77C1H, s), 5.06(1H, s), 7.28-7.3 9(6H, ra), 7.58-7.63(4H, m).
13C— NMR (CDC 1 3) (5 : 19.3, 20.9, 26.7, 55.0, 60.3, 72.0, 73.6, 78.3, 85.3, 104.4, 127.7. 129.8, 133.0, 135.6, 169.8. Anal. Calcd for C25H3206Si- 1/4 H20:C, 65.12; H, 7.10. Found :C, 65.27;H, 7.00. (6) 5'— 0— (t—プチルジフヱニルシリル） 一2' -0, 4' — C—メチ レン一 5—メチルゥリジン （20) の合成
窒素気流下、 化合物 19 (109.2g.0.239mraol)の無水 CH3CN溶液 （2ml)に室 温で 0, 0'—ビストリメチルシリルチミン（154mg， 0.598mmol)を加えた後、 氷冷 下で卜リメチルシリルトリフルォロメタンスルホネ一卜（0.82ml, 8.74匪 ol)の 1, 1ージクロロェタン（0.31ral)溶液を加え、 室温で 18時間撹拌した。 反応溶液を CH2C 12で希釈し、 飽和重曹水を加えた後、 AcOEtで 3回抽出した。 有機層を 飽和食塩水で 1回洗浄後、 無水 Na2S04にて乾燥した。 溶媒を減圧留去し、 得られ た粗成績体をシリカゲルカラムクロマトグラフィ一 （へキサン： Ac0Et=3:l)によ り精製し、 無色油状物質 20 (87.7mg, 0.173隨 ol' 70¾)を得た。
IRレ （KBr):3048, 2935, 2852. 1749, 1466, 1369, 1234, 1108, 1040cm-1.
1H— NMR (CDC 13) δ 1.06(9H, s), 1.94(3H. s), 2.98(1H, br s), 3.63. 4.00(2H, AB, J=10Hz), 3.72(1H, d, J=7Hz), 3.82-3.84(2H, m), 4.30(1H, s), 5.25 (lH,s), 7.40-7.46(6H, m), 7.60(4H, d, J=6Hz), 7.66(1H. s), 9.68(lH,br s).
[実施例 3] ヌクレオシド類縁体の合成 （別法）
(1) 3— 0—ベンジルー 5— 0— t一ブチルジフヱニルシリル一 4— (ヒ ドロ キシメチル） 一 1, 2— 0—イソプロピリデン一 一 D—エリス口ベント フラノース （32) の合成
窒素気流下、 氷冷下で前記文献 5) に従って調整した化合物 31(2.50 g, 8.0 8 mmol) の塩化メチレン溶液 （50 ml) に、 卜リェチルァミ ン （3.71 ml, 26.6 m raol)、 t-ブチルジフヱニルシリルクロリ ド （6.94 ml, 26.7 mmol) を加え、 室温 で 10.5 時間撹拌した。 反応溶液に飽和重曹水を加えた後、 酢酸ェチルで抽出し た。 有機層を飽和食塩水で洗浄後、 硫酸ナトリウムで乾燥した。 溶媒を減圧留去 し、 得られた粗成績体をシリカゲルカラムクロマトグラフィー （AcOEt-へキサン， 1:4 → 1:3) により精製し、 白色固体 （32) (2.97 g, 5.41 mmol, 67 ¾) を 得た。
mp. 98 - 99 °C (へキサン） . [a] D 20 + 54.8 ° (c = 1.12. アセトン）. IR レ max (Or) ： 3553, 2936. 1463, 1379, 1107 cm 1. 'H-N R (CDC13) δ： 1.13 (9Η, s), 1.50 (3H, s), 1.78 (3H, s)， 2.56 (1H, t, J = 7 Hz), 3.82, 3.92 (2H, AB, J = 11 Hz), 3.94 (2H, t, J = 6 Hz), 4.57 (1H, d. J = 5 Hz), 4. 64, 4.95 (2H, AB, J = 12 Hz), 4.83 (III, dd, J = 4, 5 Hz), 5.95 (1H， d, J = 4 Hz), 7.44-7.55 (11H, m), 7.72-7.78 (4H, ra). 13C-讓 (CDC13) < 19. 2, 26.2, 26.5, 26.8, 63.2, 65.4, 72.5, 77.9, 79.1, 87.4, 104.4, 113.7. 1 27.6, 127.7, 128.0, 128.5, 129.5, 129.7, 132.9, 133.1, 134.7, 135.5, 137. 2.
Anal. Calcd for C32H4006Si ： C, 70.04; H, 7.38. Found ： C, 70.19; H, 7.3 5.
(2) 3—0—ベンジル一 5—O— ( t _プチルジフエ二ルンリル） 一4— (p — トルエンスルホニルォキシメチル） 一 1, 2— <¾— D—エリス口ベント フラノース （33) の合成
窒素気流下、 氷冷下で 32(250 mg, 0.456 mmol) の塩化メチレン溶液に、 ト リエチルアミ ン （395 ρΛ, 2.83 mmol), p-トルエンスルホニルクロリ ド （139.2 mg, 0.730 mmol) 及び 4 -ジメチルアミノピリジン （8.92 mg, 0.0730 mmol) を 加え、 室温で 15.5 時間撹拌した。 反応溶液に飽和重曹水を加えた後、 酢酸ェチ ルで抽出した。 有機層を飽和食塩水で洗浄後、 硫酸ナトリウムにて乾燥した。 溶 媒を減圧留去し、 得られた粗成績体をシリカゲルカラムクロマトグラフィー （Ac OEt-へキサン， 1:6) により精製し、 淡黄色油状物質 （33) (310.6 mg, 0.442 mmol, 97 ¾) を得た。
[ ] D20 + 16.0 ° (c = 0.44, アセトン）. IR max (KBr) ： 2935, 1595, 146
2, 1363. 1174. 1106 cm"1. ^-NMR (CDC13) δ： 1.08 (9Η, s), 1.40 (3H, s), 1.46 (3H, s). 2.48 (3H, s), 3.68, 3.83 (2H, AB, J = 11 Hz) ， 4.45 (2H, dd, J = 4. 5 Hz), 4.64, 4.81 (2H, AB, J = 12 Hz), 4.68 (1H, dd, J = 4, 5 Hz), 5.81 (1H, d, J = 4 Hz), 7.32 (2H, d, J = 8 Hz). 7.42-7.72 (15H， m), 7.82, (2H, d， J = 8 Hz), 7.66 (4H, m), 7.72 (2H, d, J = 8 Hz). 13C-讀 (CDC13) 5c: 19.1, 21.5, 26.1, 26.4. 26.7, 64. , 70.0, 72.5. 78.1, 78.9, 85.4, 104.2, 113.6, 127.3, 127.7, 127.9, 128.0, 128.4. 129.6. 129.7. 12 9.8, 132.7, 132.8, 135.5, 137.2, 144.4. MS (EI) m/z ： 646 ( +-t-Bu). Hi gh-HS (EI) ： Calcd for C35H3708SSi (M+-t-Bu) ： 645.1978. Found ： 645.19
69.
(3) 1, 2—ジ一 O—ァセチル一 3—0—ベンジルー 5—0— t—ブチルジ フエニルシリル一4_ (p—トルエンスルホニルォキシメチル） — α— および一 ;9— D—リボフラノース （34) の合成
窒素気流下、 34 (3.70 g, 5.27 mmol) の酢酸溶液 （56 ml) に無水酢酸 （6. 0 ml, 63.6 mmol) 及び濃硫酸 （56 jul, 1.10 mol) を加え、 室温で 2 時間撹 拌した。 反応溶液を氷水 （300 ml) にあけて 30 分間撹拌した後、 飽和食塩水を 加え、 酢酸ェチルで抽出した後、 有機層を硫酸マグネシウムにて乾燥した。 溶媒 を留去して得られた粗成績体をシリカゲルカラムクロマトグラフィー （AcOEt-へ キサン， 2:1) により精製し、 黄色油状物質 （34) (3.36 g, 4.53 匪 ol, 86 ¾) を α ： ;3 = 1:4 の混合物として得た。
IR レ max (KBr) ： 2934, 2863, 1751. 1365, 1217, 1106 cm"1. 'H-NMR (CDC13) [/3体] δ： 1.02 (9H( s), 1.77 (3H, s), 1.98 (3H, s), 2.39 (3H, s), 3.61, 3.76 (2H, AB, J = 11 Hz), 4.21-4.58 (5H, m), 5.26 (1H, d, J = 5 Hz). 5. 94 (1H, s), 7.15-7.59 (13H, in), 7.58-7.66 (4H, ra), 7.72 (2H, d, J = 8 Hz) . [ 体] d: 1.02 (9H, s), 1.98 (3H, s), 2.36 (3H, s), 3.48. 3.58 (2H, AB, J = 11 Hz), 4.21-4.58 (5H, m)， 5.12 (1H, dd, J = 5, 6 Hz), 6.33 (1H, d, J = 5 Hz), 7.15-7.59 (13H, m), 7.58-7.66 (4H, m), 7.72 (2H. d, J = 8 Hz) • 13C -腿 (CDC13) ( c : 14.2, 19.3, 20.5, 20.8, 21.6, 26.7, 26.8, 60.3, 6 4.8, 69.1, 73.6, 74.1, 78.6, 85.3, 97.4, 127.4, 127.6, 127.7, 127.8, 127. 9, 128.0, 128.2, 128.3, 128.4, 129.5, 129.6, 1289.8. 129.9, 132.4, 132.8, 132.9, 135.4, 135.5, 135.6. 136.9, 144.5, 168.7， 169.4. High-MS(FAB) ： Calcd for 。！ 0SSiNa (M++Na) ： 769.2479, Found ： 769.2484.
(4) 2' —0—ァセチル一 3' —0—ベンジル一 5' — 0— t—ブチルジフエ ニルシリルー 4' — P— トルエンスルホニルォキシメチル一 5—メチルゥ リジン （35) の合成
窒素気流下、 氷冷下で 34(L88g, 2.52 mraol) の 1, 2-ジクロロエタン溶液 (26 ml) に 2TMS.T (1.04 g, 4.03議 ol) 及びトリメチルシリルトリフルォロメ タンスルホナート （730 β\, 4.03 ramol) を加え、 室温で 17 時間撹拌した。 反 応溶液に飽和重曹水を加え、 セライ 卜濾過した後、 母液をクロ口ホルムで抽出し た。 有機層を飽和食塩水で洗浄後、 硫酸ナトリウムにて乾燥した。 溶媒を減圧留 去して得られた粗成績体をシリカゲルカラムクロマトグラフィー （AcOEt-へキサ ン， 2:3) により精製し、 白色粉末 （35) (2.00 g, 2.44 mmol, 97 ) を得た。 mp. 70 - 71.5 °C. C«] D24 + 4.58 ° (c = 1.25, アセトン）. IR レ max (KBr) ： 3059, 2934, 1694, 1465， 1368, 704 cm-1. -匿 (CDC13) δ 1.18 (9Η, s) , 1.63 (3H, d, J = 1 Hz), 2.10 (3H, s) , 2.42 (3H, s) , 3.73, 3.86 (2H, AB, J = 11 Hz), 4.12, 4.20 (2H, AB, J = 11 Hz), 4.44, 4.57 (2H, AB, J = 11 Hz) , 4.45 (1H, d, J = 6 Hz), 5.38 (1H, t, J = 6 Hz), 6.02 (1H, d, J = 6 Hz), 7.21-7.60 (13H， m), 7.62-7.69 (7H, m), 8.91 (1H, br s). 13C -賺 (CDCI3) δ 11.9, 19.3. 20.6, 21.6, 27.0, 65.3, 68.6, 74.1. 74.8, 77.2, 77.3, 86.0, 86.4, 111.6, 127.9, 128.0, 128.2, 128.5, 129.7, 130.1. 130. 2, 131.8, 132.3, 132.5, 135.3, 135.5, 135.6. 136.8, 144.9, 150.2, 163.4, 170.2. MS (FAB) m/z ： 813 (M++H).
Anal. Calcd for C43H48 2O10SSi-2H20: C, 60.83; H, 6.17; N, 3.30. Found ： C, 60.55; H, 5.78; N, 3.22.
(5) 3' —0—ベンジルー 5' —O— t—ブチルジフヱニルシリル一 4' - p —トルエンスルホニルォキシメチル一 5—メチルゥリジン （36) の合成 氷冷下、 35 (250 mg, 0.308 mmol) のメチルアルコール溶液 （4 ml) に炭酸 カリウム （12.75 rag, 0.0923 mmol) 及び水 （0.5 ml) を加え、 室温で 22 時間 撹拌した。 氷冷下、 反応溶液に酢酸を加えて中和した後、 溶媒を減圧留去した。 残渣に水を加えた後、 酢酸ェチルで抽出した。 有機層を飽和食塩水で洗浄した後、 硫酸ナトリウムで乾燥した。 溶媒を減圧留去した後、 得られた粗成績体をシリカ ゲルカラムクロマトグラフィー （AcOEt-へキサン， 3:2) により精製し、 白色粉 末 （36) (216.7 rag, 0.283 mmol, 92 ¾) を得た。
rap. 74 ― 77 °C. [ ] D 23 + 5.15 ° (c = 1.23, CHC13). IR レ max (KBr) ： 30 48, 2934, 1695, 1363, 1181, 1108. 977, 819, 704 cm- 1. 1H-NMR (CDC13) d: 1.05 (9H, s), 1.65 (3H, d, J = 1 Hz), 2.39 (3H， s), 3.04 (1H, br d, J = 9 Hz), 3.72 (2H, s), 4.17 (2H, s), 4.18 (1H, d, J = 5 Hz), 4.24-4.32 (1H, m), 4.54, 4.62 (2H, AB, J = 11 Hz), 5.62 (1H, d, J = 6 Hz), 7.19-7.69 (20H, ra), 8.46 (1H, br s). 13C-NMR (CDC13) δ 12.1, 19.4. 26.9, 58.8. 7 2.0, 72.2. 75.8, 76.7, 87.4, 88.8, 110.4, 127.7, 12.79, 128.1, 128.2, 12 8.5, 128.7, 129.8, 130.0, 130.1, 132.2, 134.3, 135.3, 135.5, 136.8, 149. 8, 163.9. MS (FAB) m/z ： 771 (M++H).
Anal. Calcd for C41H46N209SSi: C, 63.41; H, 6.16; N, 3.51; S, 3.95.
Found ： C, 63.87; H, 6.01; N, 3.63; S, 4.16.
(6) 3' —O—ベンジルー 5' —O— tーブチルジフエニルシリル一 2' — 0, 4' —C—メチレン一 5—メチルゥリ ジン （37) の合成
窒素気流下、 氷冷下で 36 (1.86 g, 2.42 mraol) のテトラヒ ドロフラン溶液 (30 ml) にナトリウムビス （卜リメチルシリル） アミ ド （1.0 M in THF, 8.47 m 1, 8.47 mmol) を加え、 室温で 1 時間撹拌した。 反応溶液に飽和重曹水 （14 ml) を加えた後、 溶媒を減圧留去した。 残渣に水を加え、 クロ口ホルムで抽出した。 有機層を飽和食塩水で洗浄した後、 硫酸ナトリウムにて乾燥した。 溶媒を減圧留 去し、 得られた粗成績体をシリカゲルカラムクロマトグラフィー （AcOEt-へキサ ン， 2:3) により精製し、 白色粉末 （37) (1.42 g, 2.37 mmol, 98 ¾) を得た。 mp. 70.5- 72 °C. [ ] D 22 + 52.47 ° (c = 1.025， ァセトン）. IR リ max (KBr) ： 2936, 1694, 1465, 1275, 1106, 1055, 809. 704 cm-1. ^- HR (CDC13) δ : 1.21 (9H, s). 1.76 (3H, s), 3.88， 4.07 (2H, AB, J = 8 Hz), 4.07, 4.15 (2H, AB, J = 11 Hz), 4.16 (1H, s), 4.66, 4.80 (2H, AB, J = 11 Hz), 4.76 (1H, s), 7.34-7.79 (16H, ra), 10.0 (1H, br s). MS (FAB) m/z ： 599 (M++H). Anal. Calcd for C34H38N20eSi'2H20: C, 64.33; H, 6.03; N, 4.41. Found ： C, 64.58; H, 6.15; N, 4.28.
(7) 3' —0—ベンジル一 2' -0, 4' —C—メチレン一 5—メチルゥリジ ン （38) の合成
窒素気流下、 37 (188.7 mg, 0.316mmol) のテトラヒ ドロフラン溶液 （1 ml) に、 テトラプチルアンモニゥムフルオリ ド （1.0 M in THF, 379 βΐ, 0.379 ra ol) を加え、 室温で 2.5 時間撹拌した。 反応溶液を減圧留去して得られた粗成 績体をシリカゲルカラムクロマトグラフィー （AcOEt-へキサン， 1:1→1:0) によ り精製し、 白色粉末 （38) (94.6 mg, 0.262隨 ol, 83 %) を得た。
IR max (KBr) ： 3424, 3183, 3063, 2950, 1691, 1463, 1273, 1057, 734cm-1. •H-NMR (CDC13) δ： 1.90 (3Η, d, J = 1 Hz), 3.83, 4.05 (2H. AB, J = 8 Hz) ， 3.93, 4.02 (2H， AB, J = 12 Hz), 3.94 (1H, s)， 4.53 (1H, s), 4.56, 4.58 (2H, AB, J = 12 Hz), 5.65 (1H, s), 7.32 (5H, s), 7.44 (1H, d， J = 1 Hz). High - MS (EI) ：
Calcd for C18H20N06 (M+) ： 360.1321, Found ： 360.1312. (8) 2'— 0. 4' —C—メチレン一 5—メチレンゥリジン （39 a) の合成 化合物 38 (86.5 mg, 0.240 mraol) のメチルアルコール溶液 （4 ml) に 20 % Pd(0H)2-C (86.5 mg) を加え、 水素気流下常圧にて 14.5 時間撹拌した。 反応溶 液を濾過した後、 溶媒を減圧留去して無色結晶 （39) (62.5 mg, 0.230 mmol, 96 ¾) を得た。
nip. 194- 195 °C. [a] D 20 + 53.7 ° (c =1.02, EtOH). IR レ max (KBr) ： 332 3, 3163, 3027, 2889, 2826, 1689, 1471. 1276, 1057 cm— 1. »H-NMR (CD30D) δ： 1.89 (3H, q, J = 1 Hz), 3.74, 3.95 (2H, AB, J = 8 Hz), 3.90 (1H, s),
4.07 (1H, s), 4.26 (1H, s), 5.53 (1H, s) , 7.74 (1H, d, J = 1 Hz). 13C - 隱 (CD30D) dc: 12.6, 57.6, 70.3, 72.4, 80.8, 88.3， 90.4, 110.7, 136.8,
151.8, 166.5.
[実施例 4 ]
(1) 2' — O—ァセチルー 3' —O—ベンジル一 5' — O— t—ブチルジフエ ニルシリル一 4' — p— トルエンスルホニルォキンメチル一Νβ —べンゾ ィルアデノシン （40) の合成
文献 6) (H. Vorbrggen, K. Krolikiewicz and B. Bennua, Chem. , Ber. , 114, 1234-1255 (1981)) に従って調整した 2TMS-ABz (128.7 rag. 0.336 mmol) に窒 素気流下、 室温で 34 (250 mg, 0.336 mmol) の 1, 2-ジクロロエタン溶液 （5.0 ml) 及び卜リメチルシリルトリフルォロメタンスルホナー ト （6.7〃 1, 0.0336 mmol) を加え、 26 時間加熱還流した。 反応溶液に飽和重曹水を加えた後、 塩化 メチレンで 3 回抽出した。 有機層を飽和食塩水で洗浄後、 硫酸ナトリウムにて 乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲルカラムクロマトグ ラフィー （CHC13- MeOH. 30:1) により精製し、 白色粉末 （40) (234.5 mg, 0. 253 mmol, 75 ¾) を得た。
mp. 77-78 。C (AcOEt / へキサン）. [な] D 24 _ 13.2 ° (c = 1.00. CHC13). IR umax (KBr) ： 3058, 2934, 1749, 1703. 1606, 1105 cnr1. 'H-NM (CDC13) 6 : 0.99 (9H, s). 2.04 (3H, s), 2.38 (3H, s), 3.74, 3.85 (2Π, AB, J = 1 1 Hz), 4.31, 4.43 (2H, AB, J = 11 Hz), 4.52. 4.58 (2H, AB, J = 11 Hz) , 4.81 (1H, d, J = 6 Hz), 5.94 (10, d, J = 6 Hz), 6.04 (1H, d, J = 5 Hz), 7.18 一 7.61 (20H, m), 7.69 (2H, d, J = 8 Hz), 7.99 (1H, s), 8.01 (2H. d, J = 7 Hz), 8.56 (1H, s), 8.99 (1H, br s). 13C-隱 (CDC13) <5c: 19.1, 20. 5， 21.5, 26.7, 64.1, 68.4, 74.0, 74.6. 77.9, 86.57, 86.64, 123.4, 127.7, 127.8, 127.9, 128.1, 128.5, 128.8， 129.6, 129.9, 132.0. 132.3, 132.6, 1 32.7, 133.5, 135.4, 135.5, 136.8, 142.0, 144.7, 149.6, 151.2, 152.6, 164. 5, 169.8. MS (FAB) m/z ： 926 (M++H) .
(2) 3' —O—べンジルー 5' — O— t—ブチルジフヱニルシリル一 4' - p —トルエンスルホニルォキシメチル一Νβ —ベンゾィルアデノシン （41) の合成
化合物 40(167.9 mg, 0.182 mmol) のメチルアルコール溶液 （3.0 ml) に室 温で炭酸カリウム （15.0 mg, 0.109 mmol) を加えた後、 室温で 15 分撹拌した。 反応溶液に濃塩酸を加えて溶液を中和した後、 塩化メチレンで 3 回抽出した。 有機層を飽和食塩水で洗浄後、 硫酸ナトリウムにて乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲルカラムクロマトグラフィー （CHCl3-MeOH, 30:1) により精製し、 白色粉末 （41) (140.5 mg, 0.160 mmol, 88 ¾) を得た。
mp. 82- 83 °C (AcOEt—へキサン）. [a] D 25 — 6.02 。 （c = 0.96, CHC13). IB リ max (KBr) ： 3306, 3066. 2935. 2859, 1701. 1611 cm 1. ^- HR (CDC13) δ : 0.98 (9H, s), 2.37 (3H, s), 3.76 (2H, s), 4.39, 4.45 (1H, AB, J = 11 Hz), 4.54 (1H, d, J = 6 Hz), 4.67, 4.76 (2H， AB, J = 11 Hz), 4.85 (1H, dd, J = 5, 6 Hz), 5.79 (1H, d, J = 5 Hz), 7.20 - 7.58 (21H, m), 7.73 (2H, d， J = 8 Hz), 7.80 (1H, s)， 7.96 (2H, d, J = 8 Hz), 8.49 (1H, s), 9.18
(1H, br s). 13C-NME (CDC13) 5c: 19.1, 21.6. 26.8. 64.4. 68.9, 74.1, 74.
6， 79.2, 86.8, 89.8. 123.1, 127.7, 127.8, 128.0, 128.2. 128.4. 128.6. 12 8.8, 129.7, 130.0, 132.1, 132.5, 132.6, 132.8, 133.4, 135.4. 135.5, 136.
8, 142.1, 144.8, 149.4, 152.3, 164.5.
(3) 3' —O—ベンジル一 5' —O— t—ブチルジフエニルシリル一 2' — 0， 4' — C—メチレン一 Νβ —ベンジルアデノシン （42) の合成 窒素気流下、 41(210.5 mg, 0.238 mmol) のテトラヒ ドロフラン溶液 （8· 0 m 1) に室温でナトリウムビス （トリメチルシリル） ァミ ド （1.0 M in THF, 0.58 ml, 0.572 mmol) を加えた後、 室温で 3 時間撹拌した。 反応溶液に飽和重曹水 を加えた後、 塩化メチレンで 3 回抽出した。 有機層を飽和食塩水で洗浄後、 硫 酸ナトリウムにて乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲル カラムクロマトグラフィー （CHC13- MeOH, 30:1) により精製し、 白色粉末 （42) (169.5 rag, 0.238 mmol, quant. ) を得た。
mp. 80- 81 °C. IR レ max (KBr) ： 3259, 3064, 2932, 2858. 1703, 1607 cm"1. Ή-NMR (CDC13) δ ： 1.07 (9H, s), 3.95, 4.10 (2H, AB, J = 8 Hz), 4.02 (2 H， d， J = 8 Hz), 4.56, 4.64 (2H, AB, J = 12 Hz), 4.26 (1H， s) , 4.86 (1H, s), 6.14 (1H, s), 7.26 ― 7.70 (18H, m), 8.04 (2H, d, J = 7 Hz), 8.22 (1 H, s), 8.78 (1H, s), 9.18 (1H, br s). 13C-NMR (CDC13) (5c: 19.2, 26.5, 2 6.8, 29.7, 59.2, 72.4, 72.6. 76.5, 76.8, 86.7, 88.6, 123.4, 127.7, 127.8. 127.9, 128.1, 128.4, 128.8, 129.5, 130.0， 132.4, 132.5, 132.8. 133.5, 1 34.8, 135.2, 135.5, 135.6, 136.8. 140.4, 152.7.
(4) 3' —O—ベンジル一 2' -O, 4' — C—メチレン一 N6 —ベンゾィル アデノシン （43) の合成
化合物 42 (173.6 mg, 0.244 mmol) のテトラヒ ドロフラン溶液 （7.0 ml) に 室温でテトラプチルアンモニゥムフルオリ ド （1.0 M in THF, 1.0 ml, 1.0 mmol) を加え、 室温で 25 分撹拌した。 反応溶液を減圧留去して得られた粗成績体を シリカゲルカラムクロマトグラフィー （CHC13- MeOH, 15:1) により精製し、 白色 粉末 （43) (115.4 mg, 0.244 mmol, quant. ) を得た。
mp. 154 一 155 °C (Et20). IR レ max (KBr) ： 3339, 2944, 1701, 1611 cm—1. 1 H-NMR (CDCI3) δ： 3.91, 4.13 (2H, AB, J = 8 Hz), 3.93, 4.01 (2H, AB, J = 12 Hz), 4.38 (1H, s), 4.64 (1H, s), 4.85 (1H, s), 6.08 (1H, s), 7.29 (1 H, s), 7.51 (2H, d, J = 8 Hz), 7.58 (1H, d, J = 7 Hz), 8.05 (2H, d, J = 7 Hz), 8.14 (1H, s), 8.75 (1H， s), 9.50 (1H, br s). 13C-NMR (CDC13) δ c: 57.1, 2.4, 77.0, 77.1, 86.9, 88.6, 122.9, 127.6, 128.0, 128.1, 128.4. 128.7, 132.8, 133.5, 136.9. 140.5, 149.8, 150.5, 152.8, 165.0.
[実施例 5]
(1) 2' —0—ァセチル一 3' — 0—ベンジル一 5' — 0— t—ブチルジフエ ニルシリル一 4' — p— トルエンスルホニルォキシメチル一 N2 —イソブ チリルグアノシン （44) の合成
前記の文献 6) に従って調整した 3TMS* Gi Bu (146.8 rag, 0.336 mmol) に窒 素気流下、 室温で 4 (250 mg, 0.336 mraol) の 1, 2-ジクロロェタン溶液 （5.0 ml) 及びトリメチルシリルトリフルォロメタンスルホナート （6.7 βΐ, 0.0336 mmol) を加え、 15 時間加熱還流した。 反応溶液に飽和重曹水を加えた後、 塩化 メチレンで 3 回抽出した。 有機層を飽和食塩水で洗浄後、 硫酸ナトリウムにて 乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲルカラムクロマトグ ラフィー （CHCl3-MeOH, 30:1) により精製し、 白色粉末 （44) (213.6 mg, 0.2 35 mmol, 70 ¾) を得た。
mp. 96一 97 °C (AcOEt—へキサン）. [a] D 24 -11.09 。 (c = 0.97, CHC13). I R ymax (KBr) ： 3152. 3065, 2934, 1746, 1681, 1606 cm— Ή-NMR (CDC13) d: 0.96 (9H, s), 1.10 (3H, d, J = 9 Hz), 1.13 (3H, d, J = 9 Hz), 1.98 (3H, s), 2.36 (3H, s), 2.48 (1H, m), 3.65, 3.72 (2H, AB, J = 11 Hz), 4.2 3, 4.43 (2H, AB, J = 11 Hz), 4.47 (2H, s), 4.63 (1H, d, J = 6 Hz), 5.74 (1H, t, J = 6 Hz), 5.96 (1H, d, J = 6 Hz), 7.14 ― 7.68 (20H, m), 9.15 (1 H, s)， 12.20 (1H, s). 13C-NMR (CDC13) (5c: 19.1, 19.3, 19.4. 20.8， 21.9, 27.0, 27.2, 36.5, 64.5, 68.9, 74.4, 74.9. 76.7, 86.1, 86.7, 122.0. 127. 6, 127.7, 127.9, 128.1, 128.3, 128.4, 128.8, 130.1, 130.4, 132.3, 132.7, 132.9, 135.7, 135.8, 137.3. 137.8, 145.2, 147.8, 148.5, 156.2, 170.2， 1 78.8.
(2) 3' — O—ベンジルー 5' —O— t—プチルジフエニルシリル一 4' - p ― トルエンスルホニルォキシメチル一 N2 —ィソブチリルグアノシン (45) の合成
化合物 44 (137.0 mg, 0.151 mmol) のメチルアルコール溶液 （3.0 ml) に室 温で炭酸カリウム （15.8 mg, 0.113 ramol) を加えた後、 室温で 45 分撹拌した。 反応溶液に濃塩酸を加えて溶液を中和した後、 塩化メチレンで 3 回抽出した。 有機層を飽和食塩水で洗浄後、 硫酸ナトリウムにて乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲルカラムクロマトグラフィー （CHC13- MeOH, 30:1) により精製し、 白色粉末 45 (83.4 mg, 0.097 mmol, 64 %) を得た。
mp. 102 一 103 。C (AcOEt—へキサン）. [a] D 25 - 2.00 ° (c = 0.40, CHC13). IR レ max (KBr) ： 3166, 2932, 1684, 1607 cm— 1. !H-NMR (CDC13) δ： 0.90 (9H, s), 1.09 (3H, d, J = 7 Hz), 1.13 (3H, d, J = 7 Hz). 2.30 (1H, m), 2. 37 (3H, s), 3.71, 3.76 (2H, AB, J = 11 Hz), 4.32, 4.48 (2H, AB, J = 11 H z), 4.35 (1H, d， J = 6 Hz), 4.63, 4.90 (2H, AB, J = 12 Hz), 4.96 (1H, t， J = 6 Hz), 5.67 (1H, d, J = 7 Hz), 7.17 ― 7.71 (20H, m), 8.82 (1H, s)， 12.05 (1H, br s).13C-N R (CDC13) <5c: 18.7, 19.0, 21.6, 26.5, 36.2. 63.5, 69.1, 73.7, 74.3, 78.8. 86.2, 89.5, 127.7, 127.8, 128.0, 128.1, 128.5, 129.7, 130.0, 132.0, 132.6, 132.7, 135.3. 135.4, 137.4, 138.2, 144.8, 14 6.9, 155.5, 178.5.
(3) 3' —0—ベンジルー 5' — 0— t—ブチルジフエニルシリル一 2' — 0, 4' — C—メチレン一 N2 —イソプチリルグアノシン （46) の合成 窒素気流下、 45 (92.1 mg, 0.102 mmol) のテトラヒドロフラン溶液 （3.0 m 1) に室温でナトリウムビス （トリメチルシリル） ァミ ド （1.0 M in THF, 0.31 ml, 0.315 mmol) を加えた後、 室温で 3 時間撹拌した。 反応溶液に飽和重曹水 を加えた後、 塩化メチレンで 3 回抽出した。 有機層を飽和食塩水で洗浄後、 硫 酸ナトリウムにて乾燥した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲル カラムクロマトグラフィー （CHC13- MeOH, 25:1) により精製し、 白色粉末 （46) (31.4 mg, 0.160 mmol, 44 %) を得た。
mp. 99 - 100 °C. IR max (KBr) ： 3162, 3068, 2932, 1683, 1610 cm"1. Ή- 隱 (CDC13) δ： 1.06 (9Η, s), 1.25 (3H, d, J = 7 Hz), 1.27 (3H, d, J = 7 Hz), 2.64 (1H, m), 3.83, 4.01 (2H, AB, J = 8 Hz). 3.97 (2H， d, J = 7 H z), 4.18 (1H， s)， 4.51 (1H, s), 4.54 (2H, d, J = 2 Hz), 5.77 (1H, s), 7. 17-7.42 (5H, πθ, 7.64 - 7.72 (雇, m), 7.84 (1H, s). 9.03 (1H, s), 12.08 (1H, br s). 13C-NMR (CDC13) <5c: 18.9, 19.0. 19.1, 26.5, 26.7. 36.4, 59. 1. 72.4, 72.5, 76.8, 77.5, 86.3, 88.3, 121.7, 127.6. 127.7， 127.8, 127.9, 128.1. 128.4, 129.6, 130.0, 132.36, 132.42, 134.8, 135.45, 135.54, 135.
8, 136.8. 146.8, 147.7, 155.4, 178.6.
(4) 3' —0—ベンジル 1—2' -0, 4' — C—メチレン一 N2 —イソプチ
リルグアノシン （47) の合成
化合物 46 (41.3 nig, 0.060 mmol) のテトラヒ ドロフラン溶液 （3.0 ml) に 室温でテトラプチルアンモニゥムフルオリ ド （1.0 M in THF, 0.90 ml, 0.90 mm ol) を加えた後、 室温で 1 時間撹拌した。 反応溶液を減圧留去して得られた粗 成績体をシリカゲルカラムクロマトグラフィー （AcOH- EtOH, 20:1) により精製 し、 白色粉末 （47) (27.1 mg, 0.060 mmol, quant. ) を得た。
mp. 228 - 229 °C (Et20). [a] D25 + 32.90 。 （c = 0.875. CHC13). IR max (KBr) ： 3162, 2934, 1683, 1608 cm"1. Ή-NMR (CDC") δ： 1.24 (3H. d, J = 7 Hz), 1.26 (3H, d, J = 7 Hz), 2.76 (1H， m), 3.83, 4.03 (2H, AB, J = 8 Hz), 3.92. 4.02 (2H, AB, J = 13 Hz), 4.33 (1H, s), 4.55 (1H, s), 4.62 (2H, s), 5.80 (1H, s). 7.25 (5H. s), 7.91 (1H, s), 9.85 (1H, s), 12.05 (1H, s). 13C-薩 (CDC13) (5c: 19.19, 19.25, 36.4, 57.4, 72.5, 77.0, 77.5. 86.5, 88.8, 121.0, 127.8, 128.1, 128.2. 128.3, 128.4, 128.6, 137.1, 137. 5, 147.5, 148.2, 155.7, 179.9.
[実施例 6] オリゴヌクレオチド類縁体の合成
天; »ヌクレオシド
アミダイト
«■«オリゴヌクレオチド ¾ΒΛ*
Figure imgf000034_0001
21
Figure imgf000035_0001
(1) 3'—0— [2—シァノエ卜キシ （ジイソプロピルァミノ） ホスフイノ]— 5'— 0— (4, 4'—ジメ トキシトリチル）一 2'— 0, 4'—メタノ
ゥリジン （21) の合成
化合物 8 (200 mg, 0.31 mmol)、 ジイソプロピルアンモニゥム テトラゾリ ド （39.6 mg, 0.23 mmol)を無水 CH3CN で 3回共沸した後、 無水 CH3CN - 無水 THF溶液 （3:1, 4 ml)とし、 窒素気流下 2—シァノエチル N, N, N' , N'—テトラ イソプロピル ホスホロジアミダイ ト （0.12 ml, 0.37 ramol)を加え、 室温で 90 分間撹拌した。 溶媒を減圧留去し、 得られた粗成績体をシリカゲルカラムクロマ トグラフィー （AcOEt：へキサン： Et3N = 75:25:1) により精製後、 AcOEt-へキ サンにて再沈澱し、 アミダイ 卜体 21 (181 mg. 0.25 mmol, 81¾) を得た。
mp71- 74。C (AcOEt-へキサン）. 31P-隱 (CDC13): δ 149.6, 149.5, 149.4, 149.3. 149.2.
(2) オリゴヌクレオチド類縁体の一般合成 ォリゴマーの合成は Pharmacia社 製 DN A合成装置 Gene Assembler Plusにより 0.2 ； amolスケールで行った。 溶 媒、 試薬、 ホスホロアミダイ トの濃度は天然 DNA合成の場合と同じである。 3' -水酸基が CPG支持体に結合した 5'-0— DMTr-チミジン （0.2 zmol) の DMT r 基をトリクロロ酢酸によって脱保護し、 その 5'-水酸基に天然 DNA合成用の 4 種の核酸塩基からなるアミダイ トおよび化合物 21を用いて縮合反応を繰り返し 行い、 それぞれの配列のオリゴヌクレオチド類縁体を合成した。 合成サイクルは 下記の通りである。
合成サイクル （0.2 ^mol scale)
1) detritylation 1% CC13C00H in CH2C1CH2C1( 6 sec
2) coupling 0.1 phosphoramidite (25 equiv. ), 0.5 M lH-tetrazole (500 equiv. ) in MeCN, 2 min
3) capping 3% 4-(dimethylaraino)pyridine, 10¾ Ac20,
in MeCN, 18 sec
4) oxidation 0.01 M I2 in 2, 4, 6-collidine/H20/MeCN(l:5:ll),
6 sec
合成後は、 常法に従って、 濃アンモニア水処理によりオリゴマーを支持体から 切り出すとともに、 リン原子上の保護基シァノエチル基をはずし、 さらにはアデ ニン、 グァニン、 シトシンの保護基をはずした。
得られた 5' — 0— DMT r化されたオリゴヌクレオチド類縁体は、 逆相カラ ムクロマト （Millipore, Oligo-Pak™ SP) 上でトリフルォロ酢酸 5 m 1により DMT r基をはずし、 引き続き精製を行い、 目的のオリゴヌクレオチド類縁体を 得た。
本一般合成法に従って、 以下のォリゴヌクレオチド類縁体を合成した。
(2) 5' - GCGXTTTTTGCT - 3' (XT5)
収量 0.06 mol (30¾ yield)
(3) 5 GCGTTXTTTGCT - 3' (T 2 XT3)
収量 0.05 〃mol (25¾ yield)
(4) 5 GCGTTTXTTGCT- 3' (T3 XT2)
収量 0.03 1 (15% yield)
(5) 5' 一 GCGTTTTTXGCT - 3' (T 5 X)
収量 0.06 fiml (30% yield)
(6) 5' GCGXXTTTTGCT - 3' (X2T4)
収量 0.06 βαοΐ (30¾ yield)
(7) 5' GCGTTXXTTGCT- 3' (T 2 X 2T 2)
収量 0.05 raol (25% yield)
(8) 5' GCGTTTTXXGCT - 3' (T4 X 2)
収量 0.06 〃mol (30¾ yield)
(9) 5' GCGXXXXXXGCT- 3' (X 6) 収量 0.06 raol (30¾ yield)
(10) 5' - GTTTTTTTTTXXC - 3' (X 2) 収量 0.07 ϊϋοΐ (35¾ yield)
[実験例 1] 融解温度 （Tm) の測定
実施例 2で合成した種々のオリゴヌクレオチド類縁体をアンチセンス鎖とし、 天然の DN Aあるいは RN Aからなるセンス鎖とをァニーリング処理したものの 融解温度 （Tm値） を測定することにより、 本発明のオリゴヌクレオチド類縁体 の相補 DN Aおよび RN Aに対するハイプリッ ド形成能を調べた。
終濃度をそれぞれ、 N a C 1 10 Om . リン酸ナトリウム緩衝液 （ p H 7. 2) 1 OmM、 アンチセンス鎖 4〃M、 センス鎖 4 /Mとしたサンプル溶液 （5 Ο Ο βΙ) を沸騰水中に浴し、 10時間をかけてゆっく り室温まで冷却した。 分 光光度計 （島津 UV-2100PC) のセル室内に結露防止のために窒素気流を通し、 サ ンプル溶液を 5°Cまで徐々に冷却し、 さらに 20分間 5°Cに保った後、 測定を開 始した。 サンプル温度は 90°Cまで毎分 0.2°Cずつ上昇させ、 0. 1°C間隔で 2 60 nmにおける紫外線吸収を測定した。 なお、 温度上昇とともにサンプル濃度 が変化するのを防ぐため、 セルは蓋付きのものを用い、 サンプル溶液表面に鉱油 を 1滴添加して測定した。
結果は、 下記の表に示した。 アンチセンスオリゴヌクレオチド類縁体の相補 DNA及び RNAに対する 融解温度 （Tm値） アンチセンス分子 相補 DNAa>との Tm 相補 RNAb>との Tm
(△Tm/raod. ) (△Tm/mod. )
5' -GCGTTTTTTGCT-3' (天然） 47°C 45°C
5' -GCGXTTTTTGCT-3* (XT5) 50°C (+3°C) 49°C (+4°C)
5' -GCGTTXTTTGCT-3' (T2XT3) 49°C (+2°C) 49°C (+4°C)
5' - GCGTTTXTTGCT- 3' (T3XT2) 49°C (+2°C) 50°C (+5°C)
5' -GCGTTTTTXGCT-3* (T5X) 52°C (+4°C) 51°C (+6°C)
5' -GCGXXTTTTGCT-3* (X2T4) 51。C (+2°C) 53°C (+4°C)
5' -GCGTTXXTTGCT-3' (T2X2T2) 49°C (+1°C) 53°C (+4。C) 5' -GCGTTTTXXGCT-3' (T4X2) 54°C (+3.5°C) 55°C (+5°C)
5' -GCGXXXXXXGCT-3* (X6) 58°C (+1.8°C) 71°C (+4.3°C) a): 3' -CGCAAAAAACGA-5' . b): 3' -r(CGCAAAAAACGA).
表から明らかなように、 天然 DNA鎖中に本発明のヌクレオシド類縁体 （一般式 ( l a) ) のュニッ 卜 （X) が 1個あるいは 2個導入したオリゴマーでは、 相補 DNAオリゴマーとのハイプリ ド形成能が、 Tm値で評価して天然鎖よりも 2— 7度 (1修飾残基当たり 2度程度） 上昇し、 Tをすベて Xで置換した （X6) におい ては 1 1度も上昇した。 一方、 相補 RMに対するハイプリッ ド形成能を評価した ところ、 1個あるいは 2個導入したオリゴマ一では天然鎖よりも 4一 10度 （1 修飾残基当たり 4度から 6度） の Tm値の上昇が認められ、 しかも （X6) にお いては相補 RNAに対するハイブリツ ド形成能が更に強まり、 Tm値が 25度以上 (1修飾残基当たり 4度） も上昇が認められた。 このように、 天然鎖よりも Tm 値がかくも上昇する類縁体の例がなく、 また DNAよりも RNAに対する親和性が高 いことは、 本発明のビシクロオリゴヌクレオシド類縁体を構成単位としたオリゴ ヌクレオチド類縁体がァンチセンス分子として極めて高い性能と医薬品素材とし ての有用性を有していることを意味していると言える。
[実験例 2] ヌクレアーゼ酵素耐性の測定
15分間 3了。 Cに保ったオリゴヌクレオチドのバッファ一溶液（10〃M, 400 H) に蛇毒ホスホジエステラーゼのバッファー溶液 （0.003U/ml, 400 1)を混合した。 混合溶液を 37°Cに保った石英セル（800 il)に入れ、 オリゴヌクレオチドの分解 による紫外部吸収（260nm)の増加を SHIMADZU UV- 2100PCを用いて経時的に測定し た。 用いたバッファーの組成は Tris- HCl(pH8.6)0. lM、NaCl 0. lM、MgCl214mMであ り測定前に十分に脱気した。
半減期（t1/2)の測定
測定開始時（t=0)及び紫外部吸収が認められなくなった点の UV吸収の平均値 を示す時間を半減期 （t1/2)とした。
ォリゴヌクレオチド配列 t1/2 (秒） 5' -GTTTTTTTTTTTC-3' (天然型） 260
5' - GTTTTTTTTT- XX- C- 3' ( X 2 ) 850
また、 紫外部吸収の経時変化を示すチャートを図 1 (天然鎖） 及び図 2 ( X 2 ) に示した。 天然鎖は酸素反応開始後、 約 3 0分で紫外部吸収値が一定となり、 X 2では約 9 0分で一定となつた。
[産業上の利用可能性]
この類縁体の使用により、 生体内で酵素の加水分解を受けにく く、 センス鎖との 結合能が高く、 しかも合成が容易であるオリゴヌクレオチド類縁体アンチセンス 分子が提供される。
[配列表]
出願人の氏名 ：今西武
発明の名称：新規ビシクロヌクレオシド及びォリゴヌクレオチド類縁体 整理番号：
出願番号：
出願日 ：平成 10年 3月 曰
優先権番号：特願平 9一 53409号
優先日 ：平成 9年 3月 7曰
配列の数： 10 配列番号： 1
配列の長さ ： 12
配列の型： ヌクレオチド
鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' 一 GCGTTTTTTGCT - 3' 配列番号： 2
配列の長さ ： 12
配列の型： ヌクレオチド、 ヌクレオチド類縁体
鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' 一 GCGXTTTTTGCT - 3' 配列番号： 3
配列の長さ ： 12 配列の型： ヌクレオチド、 ヌクレオチド類縁体 鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' -GCGTTXTTTGCT-3' 配列番号： 4
配列の長さ ： 12
配列の型： ヌクレオチド、 ヌクレオチド類縁体 鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' -GCGTTTXTTGCT-3' 配列番号： 5
配列の長さ ： 12
配列の型： ヌクレオチド、 ヌクレオチド類縁体 鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' 一 GCGTTTTTXGCT - 3' 配列番号： 6
配列の長さ ： 12
配列の型： ヌクレオチド、 ヌクレオチド類縁体 鎖の数： 1本鎖
トポロジー：直鎖状
配列： W098/39352 PC雷 98/00945
5' 一 GCGXXTTTTGCT - 3' 配列番号： 7
配列の長さ ： 12
配列の型： ヌクレオチド、 ヌクレオチド類縁体
鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' - GCGTTXXTTGCT - 3' 配列番号： 8
配列の長さ ： 12
配列の型： ヌクレオチド、 ヌクレオチド類縁体
鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' 一 GCGTTTTXXGCT - 3' 配列番号： 9
配列の長さ ： 12
配列の型： ヌクレオチド、 ヌクレオチド類縁体
鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' -GCGXXXXXXGCT-3' 配列番号： 10
配列の長さ ： 13 配列の型： ヌクレオチド、 ヌクレオチド類縁体 鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' -GTTTTTTTTTTTC-3' 配列番号： 11
配列の長さ ： 13
配列の型： ヌクレオチド、 ヌクレオチド類縁体 鎖の数： 1本鎖
トポロジー：直鎖状
配列：
5' -GTTTTTTTTXXTC-3'

Claims

請求の範囲 一般式 （ I )
Figure imgf000045_0001
[式中、 Bはピリ ミジンもしくはプリン核酸塩基又はそれらの類縁体であり、 X及び Yは同一もしくは異なり、 水素、 アルキル基、 アルケニル基、 アルキニル 基、 シクロアルキル基、 ァラルキル基、 ァリール基、 ァシル基、 又はシリル基] で表わされるヌクレオシド類縁体もしくはそのァミダイ ト誘導体。
2. X、 Yがともに水素である請求項 1記載のヌクレオシド類縁体。
3. が 4, 4' -ジメ トキシトリチル （DMT r ) で、 Yが 2—シァノエトキシ (ジイソプロピルアミノ） ホスフイノ基 （アミダイ ト基） である請求項 1記載の モノヌクレオシドアミダイ ト誘導体。
4. 一般式 （ I a )
Figure imgf000045_0002
( Ι ) [式中、 Bはピリ ミジンもしくはプリン核酸塩基又はそれらの類縁体である] で 表される構造を 1または 2以上有するオリゴヌクレオチドまたはポリヌクレオチ ド類縁体。
5. —般式 （II)
Figure imgf000046_0001
( II )
[式中、 B '、 Bは同一または異なり、 ピリ ミジンもしくはプリン核酸塩基又は それらの類縁体であり、 Rは水素、 水酸基、 ハロゲン、 またはアルコキシ基であ り、 、 W2は同一または異なり、 水素、 アルキル基、 アルケニル基、 アルキニ ル基、 シクロアルキル基、 ァラルキル基、 ァリール基、 ァシル基、 シリル基また はリン酸残基もしくはリン酸ジエステル結合を介した天然型ヌクレオシド、 及び その類縁体またはこれらヌクレオシドを含むオリゴヌクレオチドもしくはポリヌ クレオチドであり、 n 1または n 2は同一または異なり、 0から 5 0の整数である (ただし、 n lまたは n 2が同時にゼロになることはない。 また n 2のすべてがゼ 口になることはない。 ） 、 n 3は 1〜5 0の整数である、 ただし、 n 1および Zま たは n 2が 2以上の場合には B 1と Bは同一でなくてもよく、 Rも同一でなくても よい] で表されるオリゴヌクレオチドもしくはポリヌクレオチド類縁体。
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