JP7023933B2 - セコ-シクロプロパピロロインドール化合物、その抗体-薬物コンジュゲート、ならびに製造および使用方法 - Google Patents
セコ-シクロプロパピロロインドール化合物、その抗体-薬物コンジュゲート、ならびに製造および使用方法 Download PDFInfo
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- JP7023933B2 JP7023933B2 JP2019509530A JP2019509530A JP7023933B2 JP 7023933 B2 JP7023933 B2 JP 7023933B2 JP 2019509530 A JP2019509530 A JP 2019509530A JP 2019509530 A JP2019509530 A JP 2019509530A JP 7023933 B2 JP7023933 B2 JP 7023933B2
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6869—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
Description
本願は、35 U.S.C.§119(e)の下に、2016年8月19日付け出願の米国仮特許出願番号62/377,052の利益を主張するものであり;その内容を出典明示により本明細書に組み込むものとする。
[抗体]-[リンカー]-[薬物]
で表すことができる。
HalはClまたはBrであり;
R1は、
R2は、H、C1-C3アルキル、CO2H、CO2(C1-C3アルキル)、C(=O)NH2、C(=O)NH(C1-C3アルキル)、またはC(=O)N(C1-C3アルキル)2であり;
R3は、
R4、R4’、R5、R6、またはR7は、独立して、H、OMe、OH、6員のアリール(好ましくは、フェニル)基、5員または6員のヘテロアリール基、NH2、NHMe、NMe2、NH(C2-C4アルキル)、N(C2-C4アルキル)2、NHC(=O)X1、O(C2-C4アルキル)、O(CH2)0-2(C3-C6シクロアルキル)、O(CH2)0-2X1、または
ここで、C2-C4アルキル基は、置換されていなくても、またはOCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2で置換されてもよく、アリールまたはヘテロアリール基は、C1-C2アルキル、OH、NH2、NH(C1-C2アルキル)、N(C1-C2アルキル)2、F、Cl、Br、NO2、またはCNで置換されてもよい;
ただし、R4、R4’、R5、R6、およびR7のうち少なくとも1つはH以外の基であり;
R8およびR8’は、独立して、H、OH、O(C1-C3アルキル)、Cl、Br、F、O(CH2)2-4NH2、またはO(CH2)2-4OHであり;
R9は、H、C(=O)(C1-C3アルキル)、C(=O)NH2、C(=O)NH(C1-C3アルキル)、C(=O)(C1-C3アルキル)2、(CH2)2-4OH、(CH2)2-4O(C1-C3アルキル)、(CH2)2-4NH2、(CH2)2-4NH(C1-C3アルキル)、または(CH2)2-4N(C1-C3アルキル)2であり;
X1は、各々独立して、6員のアリール(好ましくは、フェニル)または5ないし6員のヘテロアリール基であって、置換されていないか、またはC1-C3アルキル、OH、O(C1-C3アルキル)、NH2、NH(C1-C3アルキル)、N(C1-C3アルキル)2、F、Cl、Br、NO2、またはCNで置換されており;
X2は、各々独立して、H、Me、またはC2-C4アルキル基であって、置換されていないか、またはOCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2で置換されてもよく;および
X3は、各々独立して、O、NH、N(C1-C3アルキル)、またはSである]
で示されるセコ-CPI化合物、またはその医薬的に許容される塩を提供する。
「抗体」は、全抗体、およびいずれかの抗原結合フラグメント(すなわち、「抗原結合部」)またはその単一鎖変種を意味する。全抗体は、ジスルフィド結合により相互に結合した、少なくとも2本の重鎖(H鎖)と2本の軽鎖(L鎖)とを含むタンパク質である。各重鎖は、重鎖可変領域(VH)と、3種のドメイン、CH1、CH2およびCH3を含む重鎖定常領域とを含む。各軽鎖は、軽鎖可変領域(VLまたはVK)と、1つの単一ドメイン、CLを含む軽鎖定常領域とを含む。VHおよびVL領域はさらに、相補性決定領域(CDR)と称される超可変領域と、保存性のより高い散在したフレームワーク領域(FR)に細分割することができる。VHおよびVLは、各々、3個のCDRと4個のFRとを含み、アミノ末端からカルボキシ末端の方向に、次の順序:FR1、CDR1、FR2、CDR2、FR3、CDR3、およびFR4で配列されている。可変領域は抗原と相互作用する結合ドメインを含有する。定常領域は、抗体の、宿主組織または因子(免疫系の種々の細胞(例えば、エフェクター細胞)および典型的な補体系の第一成分(Clq)を含む)との、結合を媒介してもよい。抗体が、抗原Xと、5x10-8M未満、より好ましくは6x10-9M未満、さらにより好ましくは3x10-9未満、その上より好ましくは2x10-9M未満のKDで、抗原Xと結合するならば、その抗体はその抗原Xに「特異的に結合する」と言える。抗体はキメラ、ヒト化と、または好ましくはヒトとすることができる。重鎖定常領域は、グリコシル化の型または程度に影響を及ぼし、抗体の半減期を延ばし、エフェクター細胞または補体系との相互作用を強化または軽減し、あるいは他のいくつかの特性を調整するように操作され得る。その工学操作は、1または複数のアミノ酸を置換、付加または欠失することにより、またはドメインをもう一つ別の免疫グロブリン型からのドメインと置換すること、あるいはそれらの組み合わせにより達成され得る。
式(I)およびこれらの可変基が存在する他の式において、文脈上、異なる好ましい実施態様または好ましい実施態様の組み合わせが適用され得ることが示されない限り、以下の好ましい実施態様が、個々に、または他の好ましい実施態様と組み合わせるかのいずれかで適用される。
(i)HalがClである。
(ii)R2がHである。
(iii)R3が、
(iv)R5が、OMe、OH、フェニル、NH2、NHMe、NMe2、NH(C2-C4アルキル)、N(C2-C4アルキル)2、NHC(=O)X1、O(C2-C4アルキル)、O(CH2)0-2(C3-C6シクロアルキル)、O(CH2)0-2X1、または式:
ここで、C2-C4アルキル基は、置換されていなくても、あるいはOCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2で置換されてもよく、フェニル基はC1-C2アルキル、OH、NH2、NH(C1-C2アルキル)、N(C1-C2アルキル)2、F、Cl、Br、NO2、またはCNで置換されてもよい;
(すなわち、R5はR4、R4’、R5、R6、またはR7の一つであり、H以外の基である)。
(v)R1が
(vi)R4、R4’、R5、R6、およびR7のうち3個未満は、より好ましくは2個未満は、H以外の基である。
(vii)X1中にあるアリールまたはヘテロアリール基は、フェニル、ピロリル、フラニル、チエニル、イミダゾリル、ピラゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリダジニル、またはピラジニルであり;より好ましくは、フェニル、特にNH2またはOHで置換されるフェニルである。
(viii)R1が、
概要
本発明のセコ-CPI化合物は、それ自体で治療薬として用いることができるが、コンジュゲートにて使用されるのが好ましい。より好ましくは、そのコンジュゲートの標的部分が抗体またはその抗原結合部であり、その抗原が腫瘍関連抗原、すなわち、腫瘍細胞により発現される抗原である。腫瘍関連抗原は、正常細胞と比べて、がん細胞によって独自に発現されるか、または過剰発現されることが好ましい。腫瘍関連抗原はがん細胞の表面に位置付けられるか、またはがん細胞によりその近辺に分泌されることが好ましい。
[D(XD)a(C)c(XZ)b]mZ
[式中、Zは標的部分であり、Dは本発明のセコ-CPI化合物であり、-(XD)a(C)c(XZ)b-は、ZとDを連結するために、総称して「リンカー部分」または「リンカー」と称される。リンカーの中で、CはDの意図する生物学的作用の部位で、またはその近辺で切断されるように設計された設計可能な基であり;XDおよびXZは、各々、DとCおよびCとZの間に間隔を設ける、スペーサー部分(または「スペーサー」)であり;a、bおよびcの下付き文字は、独立して、0または1である(すなわち、XD、XZ、およびCの存在は任意である)。下付き文字のmは1、2、3、4、5、6、7、8、9、または10(好ましくは、1、2、3、または4)である。D、XD、C、XZおよびZは、下記においてさらに十分に記載される。
好ましくは、標的とする部分Zは抗体である。便宜および簡潔のためであって、限定するものではなく、本明細書中で、Zおよびそのコンジュゲートに関する詳細な考察は、その文脈にて、抗体であると記載されているが、当業者であれば、変更すべきところは変更して、他の型のZがコンジュゲートし得ることを理解するであろう。例えば、標的とする部分としての葉酸とのコンジュゲートは、その表面に葉酸レセプターを有する細胞を標的としうる(Leamonら、Cancer Res. 2008, 68 (23), 9839)。同じ理由で、本明細書中の詳細な考察は、主に、ZがDに対して1:1の割合の単位で記載されている(m=1)。
上記されるように、リンカーは、3個までの因子:切断可能な基C、および任意のスペーサーXZおよびXDを含む。
ここで、下付き文字のgは0または1であり、下付き文字のhは1~24であり、好ましくは2~4である。これらのセグメントは、下記:
本発明のコンジュゲートは、好ましくは、Dおよびリンカー:(XD)a(C)c(XZ)b(ここで、XD、C、XZ、aおよびbは式(II)で定義されたとおりである)を含む化合物をまず調製し、式(III):
D-(XD)a(C)c(XZ)b-R31 (III)
[式中、R31は、Zにある補足的官能基と反応するのに適する官能基である]
で示される薬物-リンカーの化合物を形成することにより製造される。適切な基R31の例として、アミノ、アジド、チオール、シクロオクチン、
本発明のセコ-CPI化合物のADCは、セコ-CPI化合物にある官能基に結合したリンカーを含み、そのリンカーは抗体と結合している。当該分野にて知られるコンジュゲーション技法の多様性を鑑みて、本発明のセコ-CPI化合物は、抗体とのコンジュゲーションに適する多数の異なるセコ-CPI化合物-リンカー化合物を構成することができる。
Tは自己犠牲基であり;
tは0または1であり;
AAaおよび各AAbは、アラニン、β-アラニン、γ-アミノ酪酸、アルギニン、アスパラギン、アスパラギン酸、γ-カルボキシグルタミン酸、シトルリン、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、ノルロイシン、ノルバリン、オルニチン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、and バリンからなる群より独立して選択され;
uは0または1であり;
pは1、2、3、または4であり;
qは1、2、3、4、5、6、7、8、9、10、11、または12(好ましくは、2、3、4、または8)であり;
rは1、2、3、4、または5であり;
sは0または1であり;
vは0または1であり;
R31はH、
R1、R2、およびR3は、式(I)に関して、上記の「発明の概要」のセクションにて定義されるとおりである]
で示されうる。
R4、R5、R6、およびR7は、上記した「発明の概要」のセクションにおいて式(I)にて定義されるとおりであり;
R10は
R11、R12およびR13は、独立して、H、CH3、CH(CH3)2、CH2CO2H、CH2CH2CO2H、CH2C(=O)NH2、CH2CH2C(=O)NH2、(CH2)4NH2、(CH2)3NHC(=NH)NH2、または(CH2)3NHC(=O)NH2であり(すなわち、R11、R12、およびR13は、アミノ酸のグリシン、バリン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、リシン、アルギニン、およびシトルリンの側鎖残基に相当する);および
R14は
1の実施態様において、本発明のコンジュゲートは、(a)型のセコ-CPI-リンカー化合物より誘導され、式(IVa):
Abは抗体であり;
R40は、結合手、
mは1、2、3、または4であり;
vは0または1である:ただし、sが1で、R40が結合手の場合にのみ、vは0と、そしてvが0で、sが1である場合にのみ、R40は結合手とすることができ;
T、t、AAa、AAb、u、p、q、s、r、およびXAは、式(IIIa)に関して定義されるとおりであり;および
R1、R2、およびR3は、上記の「発明の概要」のセクションにて定義されるとおりである。
もう一つ別の態様において、本開示は、本発明の化合物、またはそのコンジュゲートの化合物が、医薬的に許容される担体または賦形剤と一緒に処方されて含む、医薬組成物を提供する。該医薬組成物は、所望により、抗体または他の薬物などの、1または複数の医薬的に活性なさらなる成分を含有してもよい。該医薬組成物は、もう一つ別の治療剤、特にもう一つ別の抗がん剤との併用療法にて投与され得る。
本発明の化合物またはそのコンジュゲートは、限定されないが、頭部、頚部、鼻腔、鼻洞、副鼻腔、鼻咽頭、口腔、中咽頭、喉頭、下咽頭、唾液腺、および傍神経節腫の腫瘍を含む、頭頸部がん;肝臓および胆管がん、特に肝細胞がん;腸がん、特に大腸がん;卵巣がん;小細胞および非小細胞肺がん(SCLCおよびNSCLC);繊維肉腫、悪性繊維性組織細胞腫、胚性横紋筋肉腫、骨髄肉腫、神経繊維肉腫、骨肉腫、滑膜肉腫、脂肪肉腫、および肺胞軟部肉腫などの乳がん肉腫;急性前骨髄性白血病(APL)、急性骨髄性白血病(AML)、急性リンパ芽球性白血病(ALL)、および慢性骨髄性白血病(CML)などの白血病;中枢神経系の新生物、特に脳がん;多発性骨髄腫(MM)、リンパ腫、例えばホジキンリンパ腫、リンパ球黄斑性リンパ腫、毛嚢リンパ腫、粘膜関連性リンパ組織リンパ腫、マントル細胞リンパ腫、B系列大細胞リンパ腫、バーキットリンパ腫、およびT細胞未分化大細胞リンパ腫を含む高増殖性疾患などの疾患を治療するために使用され得る。
臨床的に、本明細書に記載の方法の実施および組成物の使用は、がん性腫瘍の大きさまたは数の減少、および/または(適用される場合に)関連する徴候の減少をもたらすであろう。病理学的には、本明細書に記載の方法の実施および組成物の使用は、がん細胞増殖の阻害、がんまたは腫瘍の大きさの減少、さらなる転移の防止、および腫瘍血管新生の阻害などの病理学的に関連する応答を惹起するであろう。かかる疾患の治療方法は治療的に効果的な量の本発明の組み合わせを対象に投与することを含む。該方法は必要に応じて繰り返すことができる。
本発明の実施は、限定ではなく、例示として提供される、以下の実施例を参照することによりさらに理解され得る。
この一般的な操作は、リシンε-アミノ基と2-イミノチオランとの反応により、遊離チオール基を抗体に導入し、つづいて上記されるような、マレイミド含有の薬物-リンカー部分と反応させることを基礎とする。抗体を、最初に、50mM NaClおよび2mMジエチレントリアミン五酢酸(DTPA)含有の0.1Mリン酸緩衝液(pH8.0)に緩衝液交換に付し、5-10mg/mLに濃縮する。チオール化は2-イミノチオランの抗体への添加を通して達成される。2-イミノチオランの添加量は予備実験により決定され得、抗体ごとに変化する。予備実験では、漸増する量の2-イミノチオランを抗体に添加して滴定し、該抗体と一緒に室温(「RT」、約25℃)で1時間インキュベートした後、該抗体をSEPHADEX(登録商標)G-25カラムを用い、50mM HEPES、5mMグリシン、2mM DTPA、pH5.5中に脱塩し、ジチオジピリジン(DTDP)と反応させることによって、導入されたチオール基の数を迅速に測定する。チオール基とDTDPとの反応はチオピリジンの遊離をもたらし、それは324nmで分光学的にモニター観察され得る。典型的には、サンプルは、0.5-1.0mg/mLのプロトン濃度で使用される。280nmでの吸光度を用いてサンプル中のタンパク質の濃度を正確に測定することができ、次に各サンプル(0.9mL)のアリコートを0.1mL DTDP(エタノール中5mMストック溶液)と一緒に室温で10分間インキュベートした。緩衝液単独にDTDPを加えたブランクサンプルも並行してインキュベートされた。10分後、324nmでの吸光度を測定し、チオール基の数をチオピリジンについて19,800M-1での吸光係数を用いて定量した。
次の操作は、リンカーがアミンドナーとして作用しうるアミン基を有する際の、セコ-CPI-リンカー化合物のトランスグルタミナーゼ介在のコンジュゲーションに用いることができる。抗体は、トランスグルタミナーゼ反応性グルタミンを有する抗体、例えば、N297AまたはN297Q置換の抗体とすることができる。コンジュゲーションは、抗体:酵素のモル比を5:1として、組換え細菌性トランスグルタミナーゼによって実施される。該コンジュゲーションは、50mMトリス緩衝液、pH8.0中で標準的プロトコルを用い、37℃で一夜インキュベートして実施される。得られたコンジュゲートを、50mMトリス、pH8.0で予め平衡状態にしたプロテインA(Protein A)カラムで精製した。該コンジュゲートを0.1Mクエン酸ナトリウム緩衝液、pH3.5で溶出する。溶出したフラクションを1Mトリス、pH9.0を用いて中和する。該コンジュゲートは、20mg/mLソルビトール、10mg/mLグリシン、pH5.0にて処方され得る。
表IVは、種々のがん細胞株に対する増殖阻害効能およびCLogPを含め、本発明の化合物の特性を示す。増殖阻害は72時間のATP発光アッセイを用いて測定された(Chengら、US 8,394,922 B2(2013))。
この実施例および図1Aは化合物10の合成に関する。
化合物6a:1H NMR(500MHz、クロロホルム-d) δ 10.19(brs,1H)、8.06(d,J=2.2Hz,1H)、7.63(d,J=1.9Hz,1H)、7.52-7.47(m,2H)、7.44(t,J=7.4Hz,2H)、7.41-7.35(m,1H)、5.20(s,2H)、4.01(s,3H);13C NMR(126MHz、クロロホルム-d) δ 161.2、152.7、136.2、133.2、131.2、130.5、128.8、128.3、127.6、125.6、115.2、112.0、108.9、71.5、52.4;C17H14N2O5としての分析:計算値:327.1;測定値:327.3 [M+H]+
化合物6b:1H NMR(500MHz、クロロホルム-d) δ 9.38(brs,1H)、8.38(s,1H)、7.75(d,J=1.3Hz,1H)、7.57-7.51(m,2H)、7.51-7.42(m,3H)、7.38(d,J=2.0Hz,1H)、5.32(s,2H)、3.99(s,3H);13C NMR(126MHz、クロロホルム-d) δ 161.4、145.2、143.3、135.3、130.9、129.7、128.9、128.8、128.2、126.7、113.2、111.0、100.5、71.1、52.4;C17H14N2O5としての分析:計算値:327.1;測定値:327.3 [M+H]+
この実施例および図3Bはエステル12の調製に関する。
この実施例および図2は化合物16の製造に関する。
この実施例は、図2に示されるように、化合物18の製造に関する。
この実施例および図2はセコ-CPI化合物Ia-01の製造に関する。
この実施例および図3Aは化合物26の合成に関する。
この実施例および図3Bは化合物IIIa-03の製造に関する。
この実施例および図4は、セコ-CPI化合物Ia-21の製造に関する。
この実施例および図5はセコ-CPI-リンカー化合物IIIa-05の製造に関する。
図6は、セコ-CPI化合物Ia-15の合成についてのスキームを示す。使用の試薬、およびその使用のための条件は、当該分野において知られており、および/または上記の実施例において例示されている。表IXは化合物Ia-15について、同様にして製造された他の化合物についての分析データを示す。
図7は、セコ-CPI化合物Ia-18の合成についてのスキームを示す。使用の試薬、およびその使用のための条件は、当該分野において知られており、および/または上記の実施例において例示されている。表Xは化合物Ia-18について、同様にして製造された他の化合物についての分析データを示す。
図8は、セコ-CPI化合物Ib-01およびIb-02の合成についてのスキームを示す。使用の試薬、およびその使用のための条件は、当該分野において知られており、および/または上記の実施例において例示されている。Ib-01 [M+H]+=615.0;Ib-02 [M+H]+=659.4
図9は、セコ-CPI化合物Id-02の合成についてのスキームを示す。使用の試薬、およびその使用のための条件は、当該分野において知られており、および/または上記の実施例において例示されている。表XIは化合物Id-02および同様にして製造された他の化合物についての分析データを示す。
図10は、セコ-CPI化合物Ia-25の合成についてのスキームを示す。使用の試薬、およびその使用のための条件は、当該分野において知られており、および/または上記の実施例において例示されている。
図11は、セコ-CPI化合物Ia-27の合成についてのスキームを示す。使用の試薬、およびその使用のための条件は、当該分野において知られており、および/または上記の実施例において例示されている。化合物Ia-27についての質量スペクトルデータ:[M+H]+=588.1
図12は、セコ-CPI化合物Ia-29の合成についてのスキームを示す。使用の試薬、およびその使用のための条件は、当該分野において知られており、および/または上記の実施例において例示されている。化合物Ia-29についての質量スペクトルデータ:[M+H]+=574.1
セコ-CPI-リンカー化合物IIIa-01、IIIa-02、IIIa-03、およびIIIa-04を、上記した実施例1のマイケル付加反応と略同様にして、抗メソテリン抗体6A4(Terrettら、US 8,268,970 B2(2012))とコンジュゲートさせた。得られた抗体-薬物のコンジュゲートを、各々、6A4/IIIa-01 ADC、6A4/IIIa-02 ADC、6A4/IIIa-03 ADC、および6A4/IIIa-04 ADCと称した。
第1著者(または発明者)および本明細書よりも早い日付で、省略された形式で引用される次の参考文献についての十分な引用部を以下において提供する。これらの参考文献は、各々、あらゆる目的のために、出典明示により本明細書に組み込まれる。
Boger、US 6,548,530 B1(2003);
BogerおよびJohnson、Proc. Nat. Acad. Sci.(USA) 1995, 92, 3642;
Bogerら、J. Org. Chem. 1990, 55, 5823;
Bogerら、J. Am. Chem. Soc. 1997, 119, 4987;
Bogerら、Synthesis 1999, SI, 1505;
Bogerら、J. Org. Chem. 2000, 65, 4101;
Boydら、US 2008/0279868 A1(2008);
Chari ら、Cancer Res. 1995, 55, 4079;
Chenら、US 8,664,407 B2(2014);
Ducryら、Bioconjug. Chem. 2010, 21, 5;
Gangwarら、US 7,968,586 B2(2011);
Hurleyら、Science 1984, 226, 843;
Kobayashiら、Cancer Res. 1994, 54, 2404;
Lajinessら、J. Med. Chem. 2010, 53, 7731;
Liら、Cancer Res. 1992, 52, 4904;
NagamuraおよびSaito、Chem. Heterocyclic Compounds 1998, 34(12), 1386;
Nagamuraら、Chem. Pharm. Bull. 1996, 44(9), 1723;
Ngら、US 7,129,261 B2(2006);
Ngら、US 7,507,420 B2(2009);
Ngら、US 8,034,959 B2(2011);
Schramaら、Nature Rev. Drug Disc. 2006, 5, 147-159;
Sufiら、US 8461,117 B2(2013);
Tichenorら、J. Am. Chem. Soc. 2007, 129, 10858;
Tietzeら、ChemBioChem 2001, 2, 758;
Tietzeら、Bioorg. Med. Chem. 2008, 16, 6312;
Zhangら、US 8,852,599 B2(2014);
Zhaoら、US 7,655,660 B2(2010)
Claims (16)
- 構造式(I):
Halは、ClまたはBrであり;
R1は
R2は、H、C1-C3アルキル、CO2H、CO2(C1-C3アルキル)、C(=O)NH2、C(=O)NH(C1-C3アルキル)、またはC(=O)N(C1-C3アルキル)2であり;
R3は
R4、R4’、R5、R6、またはR7は、独立して、H、OMe、OH、6員のアリール基、5員または6員のヘテロアリール基、NH2、NHMe、NMe2、NH(C2-C4アルキル)、N(C2-C4アルキル)2、NHC(=O)X1、O(C2-C4アルキル)、O(CH2)0-2(C3-C6シクロアルキル)、O(CH2)0-2X1、または
ここで、C2-C4アルキル基は、置換されていないか、OCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2で置換されていてもよく、アリールまたはヘテロアリール基は、C1-C2アルキル、OH、NH2、NH(C1-C2アルキル)、N(C1-C2アルキル)2、F、Cl、Br、NO2、またはCNで置換されてもよい;
ただし、R4、R4’、R5、R6、およびR7のうち少なくとも1つはH以外の基であり;
R8およびR8’は、独立して、H、OH、O(C1-C3アルキル)、Cl、Br、F、O(CH2)2-4NH2、またはO(CH2)2-4OHであり;
R9は、H、C(=O)(C1-C3アルキル)、C(=O)NH2、C(=O)NH(C1-C3アルキル)、C(=O)(C1-C3アルキル)2、(CH2)2-4OH、(CH2)2-4O(C1-C3アルキル)、(CH2)2-4NH2、(CH2)2-4NH(C1-C3アルキル)、または(CH2)2-4N(C1-C3アルキル)2であり;
X1は、各々独立して、6員のアリール、または5ないし6員のヘテロアリール基であって、置換されていないか、C1-C3アルキル、OH、O(C1-C3アルキル)、NH2、NH(C1-C3アルキル)、N(C1-C3アルキル)2、F、Cl、Br、NO2、またはCNで置換されており;
X2は、各々独立して、H、Me、またはC2-C4アルキル基であって、置換されていないか、OCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2で置換されていてもよく;ならびに
X3は、各々独立して、O、NH、N(C1-C3アルキル)、またはSである]
で示される化合物またはその医薬的に許容される塩。 - R2がHであり、HalがClである、請求項1に記載の化合物。
- R1が、その対応するR1Hの化合物にて、0.300未満のCLogP値を有する、基である、請求項1に記載の化合物。
- 構造式(IIIa):
Tは、
の構造で示される基であり、ここで、星印(*)は、セコ-CPI化合物のフェノール性酸素と結合する末端を示し、波線
tは0または1であり;
AAaおよび各AAbは、アラニン、β-アラニン、γ-アミノ酪酸、アルギニン、アスパラギン、アスパラギン酸、γ-カルボキシグルタミン酸、シトルリン、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、ノルロイシン、ノルバリン、オルニチン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、およびバリンからなる群より独立して選択され;
uは0または1であり;
pは1、2、3、または4であり;
qは1、2、3、4、5、6、7、8、9、10、11、または12であり;
rは1、2、3、4、または5であり;
sは0または1であり;
vは0または1であり;
R31は、
ただし、sが1で、vが0の場合にのみ、R31はHとすることができ、そしてsが1で、R31がHである場合にのみ、vは0とすることができ;
HalはClまたはBrであり;
R1は
R2はH、C1-C3アルキル、CO2H、CO2(C1-C3アルキル)、C(=O)NH2、C(=O)NH(C1-C3アルキル)、またはC(=O)N(C1-C3アルキル)2であり;
R3は
R4、R4’、R5、R6、またはR7は、独立して、H、OMe、OH、6員のアリール基、5員または6員のヘテロアリール基、NH2、NHMe、NMe2、NH(C2-C4アルキル)、N(C2-C4アルキル)2、NHC(=O)X1、O(C2-C4アルキル)、O(CH2)0-2(C3-C6シクロアルキル)、O(CH2)0-2X1、または
ここで、C2-C4アルキル基は置換されていないか、またはOCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2で置換されていてもよく、アリールまたはヘテロアリール基は、C1-C2アルキル、OH、NH2、NH(C1-C2アルキル)、N(C1-C2アルキル)2、F、Cl、Br、NO2、またはCNで置換されていてもよい;
ただし、R4、R4’、R5、R6、およびR7のうち少なくとも1つはH以外の基であり;
R8およびR8’は、独立して、H、OH、O(C1-C3アルキル)、Cl、Br、F、O(CH2)2-4NH2、またはO(CH2)2-4OHであり;
R9は、H、C(=O)(C1-C3アルキル)、C(=O)NH2、C(=O)NH(C1-C3アルキル)、C(=O)(C1-C3アルキル)2、(CH2)2-4OH、(CH2)2-4O(C1-C3アルキル)、(CH2)2-4NH2、(CH2)2-4NH(C1-C3アルキル)、または(CH2)2-4N(C1-C3アルキル)2であり;
X1は、各々独立して、6員のアリール、または5ないし6員のヘテロアリール基であって、置換されていないか、またはC1-C3アルキル、OH、O(C1-C3アルキル)、NH2、NH(C1-C3アルキル)、N(C1-C3アルキル)2、F、Cl、Br、NO2、またはCNで置換されており;
X2は、各々独立して、H、Me、またはC2-C4アルキル基であって、置換されていないか、またはOCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2で置換されていてもよく;および
X3は、各々独立して、O、NH、N(C1-C3アルキル)、またはSである]
で示されるセコ-CPI-リンカー化合物またはその医薬的に許容される塩。 - 構造式(IVa):
Abは抗体であり;
R40は、結合手、
mは1、2、3、または4であり;
vは0または1である:ただし、sが1で、R40が結合手の場合にのみ、vは0とすることができ、そしてvが0で、sが1である場合にのみ、R40は結合手とすることができ;
Tは、
の構造で示される基であり、ここで、星印(*)は、セコ-CPI化合物のフェノール性酸素と結合する末端を示し、波線
tは0または1であり;
AAaおよび各AAbは、アラニン、β-アラニン、γ-アミノ酪酸、アルギニン、アスパラギン、アスパラギン酸、γ-カルボキシグルタミン酸、シトルリン、システイン、グルタミン酸、グルタミン、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、ノルロイシン、ノルバリン、オルニチン、フェニルアラニン、プロリン、セリン、スレオニン、トリプトファン、チロシン、およびバリンからなる群より独立して選択され;
uは0または1であり;
pは1、2、3、または4であり;
qは1、2、3、4、5、6、7、8、9、10、11、または12(好ましくは、2、3、4、または8)であり;
rは1、2、3、4、または5であり;
sは0または1であり;
HalはClまたはBrであり;
R1は
R2は、H、C1-C3アルキル、CO2H、CO2(C1-C3アルキル)、C(=O)NH2、C(=O)NH(C1-C3アルキル)、またはC(=O)N(C1-C3アルキル)2であり;
R3は
R4、R4’、R5、R6、またはR7は、独立して、H、OMe、OH、6員のアリール基、5員または6員のヘテロアリール基、NH2、NHMe、NMe2、NH(C2-C4アルキル)、N(C2-C4アルキル)2、NHC(=O)X1、O(C2-C4アルキル)、O(CH2)0-2(C3-C6シクロアルキル)、O(CH2)0-2X1、または
ここでC2-C4アルキル基は、置換されていなくても、OCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2によって置換されてもよく、アリールまたはヘテロアリール基はC1-C2アルキル、OH、NH2、NH(C1-C2アルキル)、N(C1-C2アルキル)2、F、Cl、Br、NO2、またはCNで置換されてもよい;
ただし、R4、R4’、R5、R6、およびR7のうち少なくとも1つはH以外の基であり;
R8およびR8’は、独立して、H、OH、O(C1-C3アルキル)、Cl、Br、F、O(CH2)2-4NH2、またはO(CH2)2-4OHであり;
R9は、H、C(=O)(C1-C3アルキル)、C(=O)NH2、C(=O)NH(C1-C3アルキル)、C(=O)(C1-C3アルキル)2、(CH2)2-4OH、(CH2)2-4O(C1-C3アルキル)、(CH2)2-4NH2、(CH2)2-4NH(C1-C3アルキル)、または(CH2)2-4N(C1-C3アルキル)2であり;
X1は、各々独立して、6員のアリールまたは5ないし6員のヘテロアリール基であって、置換されていないか、またはC1-C3アルキル、OH、O(C1-C3アルキル)、NH2、NH(C1-C3アルキル)、N(C1-C3アルキル)2、F、Cl、Br、NO2、またはCNで置換されており;
X2は、各々独立して、H、Me、またはC2-C4アルキル基であって、置換されていないか、OCH2CH2OH、OCH2CH2NH2、NHCH2CH2OH、NHCH2CH2NH2、OH、またはNH2で置換されていてもよく;および
X3は、各々独立して、O、NH、N(C1-C3アルキル)、またはSである]
で示される、抗体-薬物コンジュゲート、またはその医薬的に許容される塩。 - がんを治療するための、請求項1に記載の化合物、またはその抗体とのコンジュゲートを含む医薬組成物。
- 化合物が抗体とコンジュゲートしている、請求項14に記載の医薬組成物。
- がんが、肺がん、胃がん、卵巣がん、または結腸がんである、請求項14または15に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201662377052P | 2016-08-19 | 2016-08-19 | |
US62/377,052 | 2016-08-19 | ||
PCT/US2017/047465 WO2018035391A1 (en) | 2016-08-19 | 2017-08-18 | Seco-cyclopropapyrroloindole compounds, antibody-drug conjugates thereof, and methods of making and use |
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KR20210102334A (ko) | 2018-12-12 | 2021-08-19 | 브리스톨-마이어스 스큅 컴퍼니 | 트랜스글루타미나제 접합을 위해 변형된 항체, 그의 접합체, 및 방법 및 용도 |
WO2021055306A1 (en) | 2019-09-16 | 2021-03-25 | Bristol-Myers Squibb Company | Dual capture method for analysis of antibody-drug conjugates |
CA3234692A1 (en) * | 2021-09-30 | 2023-04-06 | Ajinomoto Co., Inc. | Conjugate of antibody and functional substance or salt thereof, and antibody derivative and compound used in production of the same or salts thereof |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011103557A1 (en) | 2010-02-22 | 2011-08-25 | Advanced Cancer Therapeutics, Llc | Small molecule inhibitors of pfkfb3 and glycolytic flux and their methods of use as anti-cancer therapeutics |
JP2013525347A (ja) | 2010-04-21 | 2013-06-20 | シンタルガ・ビーブイ | Cc−1065類似体の新規の複合体および二官能性リンカー |
JP2016520533A (ja) | 2013-03-19 | 2016-07-14 | ベイジン シェノゲン ファーマ グループ リミテッド | エストロゲン受容体関連疾患を処置するための抗体及び方法 |
Family Cites Families (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1981001145A1 (en) | 1979-10-18 | 1981-04-30 | Univ Illinois | Hydrolytic enzyme-activatible pro-drugs |
US4475196A (en) | 1981-03-06 | 1984-10-02 | Zor Clair G | Instrument for locating faults in aircraft passenger reading light and attendant call control system |
US4447233A (en) | 1981-04-10 | 1984-05-08 | Parker-Hannifin Corporation | Medication infusion pump |
US5144011A (en) | 1981-06-26 | 1992-09-01 | Boston University | Acidity-sensitive spacer molecule to control the release of pharmaceuticals from molecular carriers |
US4631190A (en) | 1981-06-26 | 1986-12-23 | Shen Wei C | Acidity-sensitive spacer molecule to control the release of pharmaceuticals from molecular carriers |
US4439196A (en) | 1982-03-18 | 1984-03-27 | Merck & Co., Inc. | Osmotic drug delivery system |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US4447224A (en) | 1982-09-20 | 1984-05-08 | Infusaid Corporation | Variable flow implantable infusion apparatus |
US4487603A (en) | 1982-11-26 | 1984-12-11 | Cordis Corporation | Implantable microinfusion pump system |
US4486194A (en) | 1983-06-08 | 1984-12-04 | James Ferrara | Therapeutic device for administering medicaments through the skin |
US4698420A (en) | 1985-02-25 | 1987-10-06 | Xoma Corporation | Antibody hybrid molecules and process for their preparation |
US4596556A (en) | 1985-03-25 | 1986-06-24 | Bioject, Inc. | Hypodermic injection apparatus |
US5374548A (en) | 1986-05-02 | 1994-12-20 | Genentech, Inc. | Methods and compositions for the attachment of proteins to liposomes using a glycophospholipid anchor |
MX9203291A (es) | 1985-06-26 | 1992-08-01 | Liposome Co Inc | Metodo para acoplamiento de liposomas. |
US4790824A (en) | 1987-06-19 | 1988-12-13 | Bioject, Inc. | Non-invasive hypodermic injection device |
US4941880A (en) | 1987-06-19 | 1990-07-17 | Bioject, Inc. | Pre-filled ampule and non-invasive hypodermic injection device assembly |
US5108921A (en) | 1989-04-03 | 1992-04-28 | Purdue Research Foundation | Method for enhanced transmembrane transport of exogenous molecules |
US5312335A (en) | 1989-11-09 | 1994-05-17 | Bioject Inc. | Needleless hypodermic injection device |
US5064413A (en) | 1989-11-09 | 1991-11-12 | Bioject, Inc. | Needleless hypodermic injection device |
US5091541A (en) * | 1990-02-01 | 1992-02-25 | Hoechst-Roussel Pharmaceuticals Inc. | Hexahydropyrrolo(2,3-B)indole carbamates, ureas, amides and related compounds |
US5383851A (en) | 1992-07-24 | 1995-01-24 | Bioject Inc. | Needleless hypodermic injection device |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
WO1997012862A1 (en) | 1995-10-03 | 1997-04-10 | The Scripps Research Institute | Cbi analogs of cc-1065 and the duocarmycins |
CA2290789A1 (en) | 1997-05-22 | 1998-11-26 | Dale L. Boger | Analogs of duocarmycin and cc-1065 |
US7425541B2 (en) | 1998-12-11 | 2008-09-16 | Medarex, Inc. | Enzyme-cleavable prodrug compounds |
KR100942863B1 (ko) | 1999-08-24 | 2010-02-17 | 메다렉스, 인코포레이티드 | 인간 씨티엘에이-4 항체 및 그의 용도 |
AU2001286727A1 (en) | 2000-08-24 | 2002-03-04 | Coulter Pharmaceutical, Inc. | Prodrugs activated by plasmin and their use in cancer chemotherapy |
CN101671335A (zh) | 2001-05-31 | 2010-03-17 | 梅达莱克斯公司 | 细胞毒素、其有用的前体药物、连接基团和稳定剂 |
AU2002316539C1 (en) | 2001-06-11 | 2008-10-30 | Medarex, Inc. | CD10-activated prodrug compounds |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
KR100668538B1 (ko) | 2002-01-09 | 2007-01-16 | 메다렉스, 인코포레이티드 | Cd30에 대한 인간 모노클로날 항체 |
US6756397B2 (en) | 2002-04-05 | 2004-06-29 | Immunogen, Inc. | Prodrugs of CC-1065 analogs |
JP4753867B2 (ja) | 2003-04-15 | 2011-08-24 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | ヒトil−18を含むコンジュゲートおよびその置換変異体 |
WO2005010048A2 (en) | 2003-07-22 | 2005-02-03 | Schering Aktiengesellschaft | Rg1 antibodies and uses thereof |
WO2005051976A2 (en) | 2003-11-20 | 2005-06-09 | Ansata Therapeutics, Inc. | Protein and peptide ligation processes and one-step purification processes |
CN102838675B (zh) | 2003-12-10 | 2014-07-30 | 梅达雷克斯有限责任公司 | Ip-10抗体及其用途 |
EP1718667B1 (en) | 2004-02-23 | 2013-01-09 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
US7691962B2 (en) | 2004-05-19 | 2010-04-06 | Medarex, Inc. | Chemical linkers and conjugates thereof |
BRPI0510909A2 (pt) | 2004-05-19 | 2008-12-16 | Medarex Inc | composto de ligaÇço fÁrmaco-ligante citotàxico, formulaÇço farmacÊutica, mÉtodo para matar uma cÉlula e mÉtodo para retardar ou interromper o crescimento de tumor |
CN101065151B (zh) | 2004-09-23 | 2014-12-10 | 健泰科生物技术公司 | 半胱氨酸改造的抗体和偶联物 |
KR101291640B1 (ko) | 2005-02-18 | 2013-08-05 | 메다렉스, 엘.엘.시. | 푸코실 잔기가 결핍된 전립선 특이적 막 항원(psma)에대한 단클론성 항체 |
CN101124249B (zh) | 2005-02-18 | 2011-06-29 | 米德列斯公司 | 抗前列腺特异性膜抗原(psma)的人单克隆抗体 |
US7714016B2 (en) | 2005-04-08 | 2010-05-11 | Medarex, Inc. | Cytotoxic compounds and conjugates with cleavable substrates |
AU2006244885B2 (en) | 2005-05-09 | 2011-03-31 | E. R. Squibb & Sons, L.L.C. | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
HUE026039T2 (en) | 2005-07-01 | 2016-05-30 | Squibb & Sons Llc | Human monoclonal antibodies programmed for death ligand 1 (PD-L1) |
PL3248613T3 (pl) | 2005-07-18 | 2022-04-19 | Seagen Inc. | Koniugaty β-glukuronid-linker-lek |
AU2006294554B2 (en) | 2005-09-26 | 2013-03-21 | E. R. Squibb & Sons, L.L.C. | Antibody-drug conjugates and methods of use |
CA2623236A1 (en) | 2005-09-26 | 2007-04-05 | Medarex, Inc. | Human monoclonal antibodies to cd70 |
ES2375843T3 (es) | 2005-10-26 | 2012-03-06 | Medarex, Inc. | Procedimientos y compuestos para la preparación de an�?logos de cc-1065. |
WO2007059404A2 (en) | 2005-11-10 | 2007-05-24 | Medarex, Inc. | Duocarmycin derivatives as novel cytotoxic compounds and conjugates |
PL1957539T3 (pl) | 2005-12-08 | 2013-08-30 | Squibb & Sons Llc | Ludzkie przeciwciała monoklonalne przeciwko białku kinazy tyrozynowej 7 (PTK7) i ich zastosowanie |
AU2006321553B2 (en) | 2005-12-08 | 2012-03-08 | E. R. Squibb & Sons, L.L.C. | Human monoclonal antibodies to O8E |
CA2638902C (en) | 2005-12-08 | 2014-09-23 | Medarex, Inc. | Human monoclonal antibodies to fucosyl-gm1 and methods for using anti-fucosyl-gm1 antibodies |
KR100869414B1 (ko) | 2005-12-13 | 2008-11-21 | 야마하 가부시키가이샤 | 건반식 음판 타악기용의 음판 및 그 제조방법, 음판타악기의 음원 유닛 및 건반식 타악기 |
WO2007103288A2 (en) * | 2006-03-02 | 2007-09-13 | Seattle Genetics, Inc. | Engineered antibody drug conjugates |
EP2035554B1 (en) | 2006-06-29 | 2013-04-24 | The Board of Trustees of The Leland Stanford Junior University | Cell-free synthesis of proteins containing unnatural amino acids |
JP2010500885A (ja) | 2006-08-18 | 2010-01-14 | ノボ ノルディスク ヘルス ケア アーゲー | 改善された特異性を有するトランスグルタミナーゼ変異体 |
CN101528914B (zh) | 2006-09-08 | 2014-12-03 | Ambrx公司 | 通过脊椎动物细胞位点特异性并入非天然氨基酸 |
SI2066351T1 (sl) | 2006-10-02 | 2016-02-29 | E.R. Squibb & Sons, L.L.C. | Humana protitelesa, ki vežejo cxcr4 in njihova uporaba |
US7935696B2 (en) * | 2006-10-27 | 2011-05-03 | Bristol-Myers Squibb Company | Heterocyclic amide compounds useful as kinase inhibitors |
KR20150067395A (ko) | 2006-12-01 | 2015-06-17 | 메다렉스, 엘.엘.시. | 씨디22에 결합하는 인간 항체 및 이의 용도 |
UY30776A1 (es) | 2006-12-21 | 2008-07-03 | Medarex Inc | Anticuerpos cd44 |
TWI412367B (zh) | 2006-12-28 | 2013-10-21 | Medarex Llc | 化學鏈接劑與可裂解基質以及其之綴合物 |
AR065404A1 (es) | 2007-02-21 | 2009-06-03 | Medarex Inc | Conjugados farmaco-ligando, los que se unen a citotoxinas potentes, composicion farmaceutica que los contienen y su uso para retardar o detener el crecimiento de un tumor en un mamifero |
BRPI0808014A2 (pt) | 2007-02-22 | 2014-06-17 | Novo Nordisk Healthcare Ag | Variantes de transglutaminase com especificidade melhorada |
US7691869B2 (en) * | 2007-03-30 | 2010-04-06 | King Pharmaceuticals Research And Development, Inc. | Pyrrolotriazolopyrimidine derivatives, pharmaceutical compositions containing them and methods of treating conditions and diseases mediated by the adenosine A2A receptor activity |
SI2178921T1 (sl) | 2007-07-17 | 2016-05-31 | E.R. Squibb & Sons, L.L.C. | Monoklonska protitelesa proti glipikan-3 |
WO2009026274A1 (en) | 2007-08-22 | 2009-02-26 | Medarex, Inc. | Site-specific attachment of drugs or other agents to engineered antibodies with c-terminal extensions |
EP2195017B1 (en) | 2007-10-01 | 2014-10-22 | Bristol-Myers Squibb Company | Human antibodies that bind mesothelin, and uses thereof |
US8940501B2 (en) | 2009-01-30 | 2015-01-27 | Whitehead Institute For Biomedical Research | Methods for ligation and uses thereof |
US8394922B2 (en) | 2009-08-03 | 2013-03-12 | Medarex, Inc. | Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof |
CA2930801C (en) | 2010-11-05 | 2019-05-28 | Rinat Neuroscience Corporation | Engineered polypeptide conjugates and methods for making thereof using transglutaminase |
US8852599B2 (en) | 2011-05-26 | 2014-10-07 | Bristol-Myers Squibb Company | Immunoconjugates, compositions for making them, and methods of making and use |
JP6182529B2 (ja) * | 2011-07-26 | 2017-08-16 | エリテックグループ・ベスローテン・フェンノートシャップElitechgroup B.V. | 副溝結合剤ホスホラミダイトおよび使用方法 |
CN102520153A (zh) * | 2011-12-15 | 2012-06-27 | 安徽师范大学 | 一种快速检测食品中的邻苯二甲酸二丁酯的方法 |
EP2836494B1 (en) * | 2012-04-05 | 2019-08-21 | Nerviano Medical Sciences S.r.l. | New alkylating agents |
LT2956173T (lt) | 2013-02-14 | 2017-06-26 | Bristol-Myers Squibb Company | Tubulizino junginiai, gavimo ir panaudojimo būdai |
US9765077B2 (en) * | 2015-05-29 | 2017-09-19 | University Of East Anglia | Synthesis of duocarmycin analogues |
-
2017
- 2017-08-18 KR KR1020197007464A patent/KR102493853B1/ko active IP Right Grant
- 2017-08-18 ES ES17758392T patent/ES2902179T3/es active Active
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011103557A1 (en) | 2010-02-22 | 2011-08-25 | Advanced Cancer Therapeutics, Llc | Small molecule inhibitors of pfkfb3 and glycolytic flux and their methods of use as anti-cancer therapeutics |
JP2013525347A (ja) | 2010-04-21 | 2013-06-20 | シンタルガ・ビーブイ | Cc−1065類似体の新規の複合体および二官能性リンカー |
JP2016520533A (ja) | 2013-03-19 | 2016-07-14 | ベイジン シェノゲン ファーマ グループ リミテッド | エストロゲン受容体関連疾患を処置するための抗体及び方法 |
Non-Patent Citations (2)
Title |
---|
STEPHENSON, M. J. et al.,The Journal of Organic Chemistry,2015年,Vol. 80,pp. 9454-9467 |
TICHENOR, M. S. et al.,Journal of the American Chemical Society,2007年,Vol. 129,pp. 10858-10869 |
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WO2018035391A1 (en) | 2018-02-22 |
US20180051031A1 (en) | 2018-02-22 |
KR20190039570A (ko) | 2019-04-12 |
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