JP2008517018A - 固相ペプチド合成のための方法 - Google Patents
固相ペプチド合成のための方法 Download PDFInfo
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- JP2008517018A JP2008517018A JP2007537195A JP2007537195A JP2008517018A JP 2008517018 A JP2008517018 A JP 2008517018A JP 2007537195 A JP2007537195 A JP 2007537195A JP 2007537195 A JP2007537195 A JP 2007537195A JP 2008517018 A JP2008517018 A JP 2008517018A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/815—Protease inhibitors from leeches, e.g. hirudin, eglin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
- C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier
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Abstract
Description
1996, Chem. Pharm. Bull. 44:1344-1350 1999, Eur. J. Biochem. 265:598-605 Giraud et al., 1999, J. Peptide Science 5:457-461 Atherton et al., 1988, Tetrahedron 44:843-857
1.A=P−X1−Tyr(R9)−X2−、ここで、X1は、任意に、0乃至200、好ましくは1乃至100、最も好ましくは2乃至50アミノ酸の個々のアミノ酸側鎖上に保護基を具備したペプチジル部位であり、X2は、単一の、任意に側鎖又はC−末端を保護され、−O−又は−NH−を介して固相に結合されたアミノ酸残基であり、好ましくは、X2はTrp、Cys又はArgではなく、PはH(即ち−NH2を与える)又は保護基であり、好ましくはその保護基は直交性の保護基であるか下で定義されるような強酸性条件下で除去可能な保護基であり、より好ましくはその保護基はBoc、Fmoc、Dde、Nps、Alloc、Zからなる群より選択される保護基である。
3.A=P−X1−Asp(R4)−Phe−Glu(R5)−Glu(R6)−Ile−Pro−Glu(R7)−Glu(R8)−Tyr(R9)−Leu−O又はP−X1−Asp(R4)−Phe−Glu(R5)−Glu(R6)−Ile−Pro−Glu(R7)−Glu(R8)−Tyr(R9)−X2
4.A=P−X1−[Gly]0-3−Asn(R3)−Gly−Asp(R4)−Phe−Glu(R5)−Glu(R6)−Ile−Pro−Glu(R7)−Glu(R8)−Tyr(R9)−Leu−O又はP−X1− −[Gly]0-3−Asn(R3)−Gly−Asp(R4)−Phe−Glu(R5)−Glu(R6)−Ile−Pro−Glu(R7)−Glu(R8)−Tyr(R9)−X2
5.A=P−X1−Arg(R2)−Pro−Gly−Gly−Gly−Asn(R3)−Gly−Asp(R4)−Phe−Glu(R5)−Glu(R6)−Ile−Pro−Glu(R7)−Glu(R8)−Tyr(R9)−Leu−O−又はP−X1−Arg(R2)−Pro−Gly−Gly−Gly−Asn(R3)−Gly−Asp(R4)−Phe−Glu(R5)−Glu(R6)−Ile−Pro−Glu(R7)−Glu(R8)−Tyr(R9)−X2
P、X1、X2の定義は、A及び生成するペプチド−固相共役体についての全てのこれらの可能な態様に対して、構成的に適用される。
を示すのにちょうど最適な距離及び間隔にあり、例えば、ジケトピペラジン形成への前触れであるサイクリックな配置を避けると推測される。
素早く単純なサイズ基準の分離を実質的に可能にするため、本定義により‘不溶性’に含まれる。より好ましい意味では、‘不溶性’は、ペプチド合成のための所定の溶媒系において、一方の相は完全な固体の懸濁された相である二相系を指す。
また、ここで、R’’’は固相であり、R’’1、R’’2、R’’3 は、独立に、水素、4−若しくは4’−(C1−C4アルキル)又は4−若しくは4’−(C1−C4アルコキシ)であり、R’’1、R’’2 の一方のみが水素であってもよいという条件付きで同じ又は異なっていてもよく、R’’2 は、任意に、R’’1 がHであるという条件付きで2−Clであってもよく、さらに及び最も好ましくは、式IIのハンドル又はリンカーは2−クロロ−トリチル、4−メトキシ−トリチル、4,4’−ジメトキシトリチル、4−メチルトリチルからなる群より選択される、
b.又は式III、
c.又は式IV、
1.Boc−D−Phe−Pro−Arg(Pbf)−Pro−Gly−Gly−Gly−Gly−Asn(Trt)−Gly−Asp(tBu)−Phe−Glu(tBu)Glu(tBu)−Ile−Pro−Glu(tBu)−Glu(tBu)−Tyr(tBu)−Leu−O−2−CTC(欧州特許第489070号明細書に記載の保護されたヒルログ−8、カルボキシ末端において2−CTC樹脂へとエステル結合で共役)の合成
全ての試薬は、EMD Biosciences(Madison, WI/U.S.A.; Novabiochem-brand)から入手された。Fmoc−Leu−OHによってあらかじめローディングされたポリスチレン系2−ClTrt(CTC)樹脂(Cbl Patras, ギリシア)は、基質高分子に関しては100乃至200メッシュであり、あらかじめローディングされた最終的なCTC樹脂生成物に関しては60乃至200メッシュであった。ローディング密度は、約0.60mmol/gであった。個々のアミノ酸は、Fmocアミノ酸か、又は、D−Pheの場合には容易にBoc保護されたBoc−D−Pheかの、何れかとして入手された。カップリングは、ジクロロメタン/N−メチルピロリドン(NMP)中、Hunig塩基(ジイソプロピル−エチルアミン、DIEA)の存在下で、TCTUを用いて実施された。2.5当量が用いられたFmoc−Arg(Pbf)のカップリングを除いて、通常は、1.5当量のFmoc又はBoc保護されたアミノ酸が使用された。同様に、Fmoc−Arg(Pbf)の場合は、60分(30℃において)の標準的なカップリング反応時間が、90分に延長された。カップリング効率の工程管理は、Kaiser試験又はクロラニル試験によって達成された。
実験1で生成された48.3gの樹脂(約100mlの膨潤した樹脂)からの切断は、それぞれ、15℃におけるジクロロメタン中の2%(w/w)TFA、1%(w/w)トリエチルシラン(TES)の3サイクルによって成し遂げられた。反応は、窒素バブリングによって攪拌され;反応の色はサイクル毎に黄色/橙色から茶色系に変化した。各サイクルの後、切断反応は、全反応液を希ピリジン(ピリジン/エタノール 1:9(v/v))中へと注ぐことによって直接的にクエンチされた。樹脂は、その後、フリットを用いた濾過によって除去され、次のサイクルに供された。全ての濾液は、溜められ、真空下(RotaVap)で橙色の半液体へと濃縮され、DCMで洗浄され、400mlの再蒸留水中で再び懸濁され、室温で攪拌され、濾過され、水を用いて洗浄され、乾燥された。収量は、分析品質(〜90%純度)のわずかに黄色の粉末の28.8gであった。生成物は、HPLC及びLC−MSによって分析された。
包括的な脱保護は、切断カクテル(‘CC’)によって希釈されたDCM、DCM:‘CC’=1:10(v/v)、中で実施された。‘CC’は、混合比(%w/w)89:2.5:2.5:5.0:1.0のTFA/チオアニソール/フェノール/水/TESから調合された。実験2からの1gの乾燥生成物は、先に述べたように‘CC’を用いて希釈されたDCM10mlに溶解され、室温で5時間攪拌された。生成物は、その後、50mlのメチル−tertブチルエーテル(MTBE、Fluka Chemie, Buchs/スイス)を添加し攪拌しながら水浴中で30分間0℃へと反応を冷却し、その間に形成された塩析沈殿物を濾過することによって回収された。濾過ケークは、MTBEを用いて数回すすがれ、その後室温で乾燥され、HPLCによって決定された約55%の純度の粗生成物0.8gを生成する。第2及び第3工程を併せた総収率は、約55%である。
Claims (7)
- 式Iの2−クロロ−トリチルハンドルを具備したペプチド−樹脂共役体であって、
- 前記固相は高分子であり、700より小さなメッシュサイズ(US Bureau of Standards)を有しており、好ましくは50乃至600メッシュのメッシュサイズを有している請求項1に記載の共役体。
- R2はペンタメチルジヒドロベンゾフラニル、アダマンチルオキシ−カルボニル又はイソボルニルオキシカルボニルであり、R9はtert.ブチル又はその誘導体であり、R3乃至R8は酸置換活性な保護基であることを特徴とする請求項1に記載の共役体。
- R2はPbfであり、R4乃至R9は酸置換活性な保護基であって、少なくとも50%のトリフルオロアセティックをそのため又はその上に必要とすることを特徴とする請求項3に記載の共役体。
- R3はトリチルであり、R4,R5,R6,R7及びR8は第3級ブチルであることを特徴とする請求項4に記載の共役体。
- R9は第3級ブチルであることを特徴とする請求項5に記載の共役体。
- N−末端のBoc基は、強酸性条件下で除去可能な別の保護基によって置換されることを特徴とする請求項1に記載の共役体。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP04024812 | 2004-10-19 | ||
EP04024812.2 | 2004-10-19 | ||
PCT/EP2005/011226 WO2006045503A1 (en) | 2004-10-19 | 2005-10-19 | Method for solid phase peptide synthesis |
Publications (3)
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JP2008517018A true JP2008517018A (ja) | 2008-05-22 |
JP2008517018A5 JP2008517018A5 (ja) | 2008-12-04 |
JP4903709B2 JP4903709B2 (ja) | 2012-03-28 |
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JP2007537195A Active JP4903709B2 (ja) | 2004-10-19 | 2005-10-19 | 固相ペプチド合成のための方法 |
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US (2) | USRE46830E1 (ja) |
EP (1) | EP1737889B1 (ja) |
JP (1) | JP4903709B2 (ja) |
CN (2) | CN102225966B (ja) |
AT (1) | ATE480561T1 (ja) |
DE (1) | DE602005023429D1 (ja) |
DK (1) | DK1737889T3 (ja) |
ES (1) | ES2352204T3 (ja) |
IL (1) | IL182698A (ja) |
PT (1) | PT1737889E (ja) |
WO (1) | WO2006045503A1 (ja) |
Cited By (3)
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JP2014162722A (ja) * | 2013-02-21 | 2014-09-08 | Chemical And Biopharmaceutical Labolatories Of Patra Sa | 側鎖結合を介する固相ペプチド合成 |
US10183966B2 (en) | 2013-02-21 | 2019-01-22 | Chemical & Biopharmaceutical Laboratories Of Patras S.A. | Solid phase peptide synthesis via side chain attachment |
JP2020138975A (ja) * | 2020-05-18 | 2020-09-03 | ケミカル アンド バイオファーマシューティカル ラボラトリーズ オブ パトラ エス.エー. | 側鎖結合を介する固相ペプチド合成 |
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JP2014162722A (ja) * | 2013-02-21 | 2014-09-08 | Chemical And Biopharmaceutical Labolatories Of Patra Sa | 側鎖結合を介する固相ペプチド合成 |
US10183966B2 (en) | 2013-02-21 | 2019-01-22 | Chemical & Biopharmaceutical Laboratories Of Patras S.A. | Solid phase peptide synthesis via side chain attachment |
JP2020138975A (ja) * | 2020-05-18 | 2020-09-03 | ケミカル アンド バイオファーマシューティカル ラボラトリーズ オブ パトラ エス.エー. | 側鎖結合を介する固相ペプチド合成 |
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ES2352204T3 (es) | 2011-02-16 |
DE602005023429D1 (de) | 2010-10-21 |
CN101094867A (zh) | 2007-12-26 |
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ATE480561T1 (de) | 2010-09-15 |
PT1737889E (pt) | 2010-12-13 |
EP1737889B1 (en) | 2010-09-08 |
EP1737889A1 (en) | 2007-01-03 |
US20080287648A1 (en) | 2008-11-20 |
DK1737889T3 (da) | 2011-01-03 |
IL182698A0 (en) | 2007-09-20 |
JP4903709B2 (ja) | 2012-03-28 |
WO2006045503A1 (en) | 2006-05-04 |
CN102225966B (zh) | 2012-12-26 |
CN102225966A (zh) | 2011-10-26 |
US7939629B2 (en) | 2011-05-10 |
USRE46830E1 (en) | 2018-05-08 |
CN101094867B (zh) | 2011-08-24 |
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