JP6161592B2 - オーリスタチンチラミンリン酸塩およびオーリスタチンアミノキノリン誘導体ならびにそのプロドラッグ - Google Patents
オーリスタチンチラミンリン酸塩およびオーリスタチンアミノキノリン誘導体ならびにそのプロドラッグ Download PDFInfo
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Description
本出願は、その全開示を本明細書に参照により組み入れる、2011年3月30日出願の米国仮特許出願第61/469,428号の優先権を主張する。
本発明は、米国保健社会福祉省、国立癌研究所、癌治療・診断部門より与えられた助成金R01 CA 90441−01−05、2R56 CA 090441−06A1、および5−R01 CA 90441−07−08からの政府支援で行われた。政府は本発明において特定の権利を有する。
1、ドラスタチン10
b、R1=CO2CH3、R2=Ph、R3=H、オーリスタチンPHE
c、R1=CH3、R2=(S)−OH、R3=Ph、オーリスタチンE
により表され、式中、Rは:
および
からなる群から選択される。
である。
である。
であり、式中、R3およびR4は独立して、リチウム(Li+)、ナトリウム(Na+)、カリウム(K+)、水素(H)、モルホリン、キニン、トリス(ヒドロキシメチル)アミノメタン(TRIS)、セリン、ニトロアルギニンおよびリンカー単位からなる群から選択される。
により表され、式中、Rは:
および
からなる群から選択される。
AaWwYy
を有する。
である。
である。
N−Boc−ドラプロインおよびDov−Val−Dil.TFAを前述したように合成した。1、2試薬および無水溶媒をAcros Organics(Fisher Scientific)、Sigma−Aldrich Chemical Company、およびLancaster Synthesisから購入し、そのまま用いた。ジイソプロピルエチルアミン(DIEA)を水酸化カリウムで再蒸留した。ジベンジルホスファイトを使用前に再蒸留した(0.1mmHgで沸点160℃)。薄層クロマトグラフィーには、Analtech Silia Gel GHLF Uniplateを用い、短波UV照射および過マンガン酸塩溶液の使用、その後の加熱で視覚化した。水溶液の溶媒抽出物を硫酸マグネシウムで乾燥させた。カラムクロマトグラフィーには、E.Merck(ドイツ、ダルムシュタット)からのシリカゲル(230〜400メッシュ ASTM)を用いた。イオン交換クロマトグラフィーのため、Dowex 50W×8−400水素型樹脂(Sigma−Aldrich)を使用前にMeOH、塩酸(1M)、および脱イオンH2Oで洗浄した。カチオン型の樹脂を対応する塩基の水溶液(1M)、その後の脱イオンH2Oの溶出により調製した。
3の合成をスキーム1に示すように行った。γ−アミノ酸Boc−Dap(6)1のチラミンとの、1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩(EDCI)および1−ヒドロキシベンゾトリアゾール(HOBT)の存在下での反応は、保護アミド7aをもたらした。Boc基のブロモトリメチルシラン(TMSBr)での除去は、臭化水素塩(7b)を生成し、これをEDCIおよびHOBTの存在下でDov−Val−Dil.TFA(8)2と縮合させ、親オーリスタチンチラミド(9)を得た。9の1Hおよび13C NMRスペクトルにおけるシグナルの倍加は、2つの異性体の存在、ドラスタチン10に類似し、Dil−Dap結合でのシス−トランス異性から得られる配座異性体によるパターンを示した。2
b癌細胞株は順に:マウスリンパ球性白血病(P388);肺(NCI−H460);結腸(KM20L2);前立腺(DU−145);膵臓(BXPC−3);乳(MCF−7);CNS(SF−268)。
(1)(a)Pettit,G.R.;Singh,S.B.;Herald,D.L.;Lloyd−Williams,P.;Kantoci,D.;Burkett,D.D.;Barkoczy,J.;Hogan,F.;Wardlaw,T.R.J.Org.Chem.1994,59,6287−6295.(b)Pettit,G.R.;Grealish,M.P.J.Org.Chem.2001,66,8640−8642.(c)Mordant,C.;Reymond,S.;Tone,H.;Lavergne,D.;Touati,R.;Ben Hassine,B.;Ratovelomanana−Vidal,V;Genet,J.−P.Tetrahedron 2007,63,6115−6123.
(2)Pettit,G.R.;Srirangam,J.K.;Singh,S.B.;Williams,M.D.;Herald,D.L.;Barkoczy,J.;Kantoci,D.;Hogan,F.J.Chem.Soc.,Perkin Trans.1 1996,859−863.
(3)Egan,T.J.;Hunter,R.;Kaschula,C.H.;Marques,H.M.;Misplon,A.;Walden,J.J.Med.Chem.2000,43,283−291.
(4)(a)Schulman,S.G.;Abate,K.;Kovi,P.J.;Capomacchia,A.C.;Jackman,D.Anal.Chim.Acta 1973,65,59−67.(b)Abernethy,J.L.;Kilday,W.J.Org.Chem.1960,25,1924−1928.
(5)(a)Pozdnev,V.F.Int.J.Peptide Protein Res.1994,36−48.(b)Furlong,S.T.;Mauger,R.C.;Strimpler,A.M.;Liu,Y.−P.;Morris,F.X.;Edwards,P.D.Bioorg.Med.Chem.2002,10,3637−3647.
(6)(a)Olah,G.A.;Nojima,M.;Kerekes,I.Synthesis 1973,487−488.(b)Bertho,J.−N.;Loffet,A.;Pinel,C.;Reuther,F.;Sennyey,G.Tetrahedron Lett.1991,32,1303−1306.
(7)(a)Carpino,L.A.;Mansour,E.−S.M.E.;Sadat−Aalee,D.J.Org.Chem.1991,56,2611−2614.(b)Wenschuh,H.;Beyermann,M.;El−Faham,A.;Ghassemi,S.;Carpino,L.A.;Bienert,M.J.Chem.Soc.,Chem.Commun.1995,669−670.(c)Carpino,L.A.;Beyermann,M.;Wenschuh,H.;Bienert,M.Acc.Chem.Res.1996,29,268−274.
(8)(a)Pettit,G.R.In Progress in the Chemistry of Organic Natural Products;Herz,W.;Kirby,G.W.;Moore,R.E.;Stglich,W.;Tamm,C.,Eds.;Springer:Vienna,1997;Vol.70,1−79.(b)Pettit,G.R.;Srirangam,J.K.;Barkoczy,J.;Williams,M.D.;Durkin,K.P.M.;Boyd,M.R.;Bai,R.;Hamel,E.;Schmidt,J.M.;Chapuis,J.−C.Anti−Cancer Drug Des.1995,10,529−544.
(9)Pettit,G.R.Dolastatin anticancer drugs.In International Oncology Updates:Murine anticancer compounds in the era of targeted therapies,Chabner,B.;Cortes−Funes,H.,Eds.;Permanyer Publications:Barcelona,2009.
Claims (17)
- 式(I):
R1およびR2はHまたはメチルであり、
R3 は、リチウム(Li+)、ナトリウム(Na+)、カリウム(K+)および水素(H)からなる群から選択され、R 4 はリチウム(Li + )、ナトリウム(Na + )、カリウム(K + )、モルホリン、キニン、トリス(ヒドロキシメチル)アミノメタン(TRIS)、セリンおよびニトロアルギニンからなる群から選択され、
各R5はHである、化合物。 - R3およびR4がナトリウム(Na + )である、請求項1に記載の化合物。
- R1がメチルであり、R2がメチルである、請求項1または2に記載の化合物。
- 請求項1〜3のいずれか1項に記載の化合物および医薬的に許容可能な担体を含み、
前記化合物が、請求項2または請求項2を引用する請求項3の化合物の場合、R 3 およびR 4 は、ナトリウム(Na + )であり、それ以外の場合、R 3 およびR 4 は、ナトリウム(Na + )またはカリウム(K + )である、医薬組成物。 - 請求項1〜3のいずれか1項に記載の化合物および医薬的に許容可能な担体の組み合わせを含み、
前記化合物が、請求項2または請求項2を引用する請求項3の化合物の場合、R 3 およびR 4 は、ナトリウム(Na + )であり、それ以外の場合、R 3 およびR 4 は、ナトリウム(Na + )またはカリウム(K + )である、医薬組成物。 - 治療に効果的な量の、チューブリン形成阻害剤、トポイソメラーゼ阻害剤、およびDNA結合剤からなる群から選択される化学療法剤をさらに含む、請求項4または請求項5に記載の医薬組成物。
- 請求項1〜3のいずれか1項に記載の化合物、またはその医薬的に許容可能な溶媒和を含み、
前記化合物が、請求項2または請求項2を引用する請求項3の化合物の場合、R 3 およびR 4 は、ナトリウム(Na + )であり、それ以外の場合、R 3 およびR 4 は、ナトリウム(Na + )またはカリウム(K + )である、腫瘍細胞もしくは癌細胞の殺傷またはその増殖の阻害用医薬組成物。 - 請求項1〜3のいずれか1項に記載の化合物、またはその医薬的に許容可能な溶媒和を含み、
前記化合物が、請求項2または請求項2を引用する請求項3の化合物の場合、R 3 およびR 4 は、ナトリウム(Na + )であり、それ以外の場合、R 3 およびR 4 は、ナトリウム(Na + )またはカリウム(K + )である、患者における癌の治療用医薬組成物。 - 前記医薬組成物が医薬的に許容可能な担体を含む、請求項7または8に記載の医薬組成物。
- 前記医薬組成物が静脈内投与されるものである、請求項7または8に記載の医薬組成物。
- 前記医薬組成物が単位用量注射可能形態に製剤される、請求項10に記載の医薬組成物。
- 細胞培地における細胞を請求項1〜3のいずれか1項に記載の化合物と接触させるステップ、およびこれにより該細胞の増殖が阻害される、該化合物の細胞毒性活性を測定するステップを含み、
前記化合物が、請求項2または請求項2を引用する請求項3の化合物の場合、R 3 およびR 4 は、ナトリウム(Na + )であり、それ以外の場合、R 3 およびR 4 は、ナトリウム(Na + )またはカリウム(K + )である、化合物による細胞増殖の阻害の測定方法。 - 前記細胞を6時間〜5日間の期間培養するステップをさらに含む、請求項12に記載の方法。
- 腫瘍関連抗原に特異的な抗体、および任意で化学療法剤と複合させた請求項1〜3のいずれか1項に記載の化合物を含み、
前記化合物が、請求項2または請求項2を引用する請求項3の化合物の場合、R 3 およびR 4 は、ナトリウム(Na + )であり、それ以外の場合、R 3 およびR 4 は、ナトリウム(Na + )またはカリウム(K + )である、腫瘍関連抗原を過剰発現する腫瘍細胞の成長の阻害用医薬組成物。 - 前記腫瘍細胞が乳、卵巣、胃、子宮内膜、唾液腺、肺、腎臓、結腸、大腸、甲状腺、膵臓、前立腺および膀胱癌からなる群から選択される癌に関連する、請求項14に記載の医薬組成物。
- 請求項1〜3のいずれか1項に記載の化合物の、癌を治療するための薬剤の製造における、使用であって、
前記化合物が、請求項2または請求項2を引用する請求項3の化合物の場合、R 3 およびR 4 は、ナトリウム(Na + )であり、それ以外の場合、R 3 およびR 4 は、ナトリウム(Na + )またはカリウム(K + )である、使用。 - 請求項1〜3のいずれか1項に記載の化合物、容器、および該化合物を少なくとも1つの腫瘍関連抗原の過剰発現により特徴づけられる癌を治療するのに用いることができることを示す添付文書またはラベルを含む、製品であって、
前記化合物が、請求項2または請求項2を引用する請求項3の化合物の場合、R 3 およびR 4 は、ナトリウム(Na + )であり、それ以外の場合、R 3 およびR 4 は、ナトリウム(Na + )またはカリウム(K + )である、製品。
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EP3327027B9 (en) | 2011-11-17 | 2021-07-07 | Pfizer Inc. | Cytotoxic peptides and antibody drug conjugates thereof |
US10226535B2 (en) | 2012-12-10 | 2019-03-12 | Mersana Therapeutics, Inc. | Auristatin compounds and conjugates thereof |
SG11201507619PA (en) | 2013-03-15 | 2015-10-29 | Ct For Drug Res And Dev | Cytotoxic and anti-mitotic compounds, and methods of using the same |
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WO2015095952A1 (en) | 2013-12-27 | 2015-07-02 | The Centre For Drug Research And Development | Var2csa-drug conjugates |
WO2015095953A1 (en) | 2013-12-27 | 2015-07-02 | The Centre For Drug Research And Development | Sulfonamide-containing linkage systems for drug conjugates |
CN107001415B (zh) * | 2014-09-17 | 2021-06-18 | 酵活有限公司 | 细胞毒性和抗有丝分裂化合物、及其使用方法 |
WO2016130969A1 (en) | 2015-02-13 | 2016-08-18 | George Robert Pettit | Silstatin compounds |
CN105949277B (zh) * | 2015-05-05 | 2019-03-01 | 成都永泰诺科技有限公司 | 一种抗肿瘤化合物及其用途 |
US10435435B2 (en) * | 2015-07-24 | 2019-10-08 | The Arizona Board Of Regents On Behalf Of Arizona State University | Quinstatin compounds |
WO2017161206A1 (en) | 2016-03-16 | 2017-09-21 | Halozyme, Inc. | Conjugates containing conditionally active antibodies or antigen-binding fragments thereof, and methods of use |
US10517958B2 (en) | 2016-10-04 | 2019-12-31 | Zymeworks Inc. | Compositions and methods for the treatment of platinum-drug resistant cancer |
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US9539342B2 (en) | 2017-01-10 |
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