JP6067943B1 - プラジエノライドピリジン化合物及び使用の方法 - Google Patents
プラジエノライドピリジン化合物及び使用の方法 Download PDFInfo
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- JP6067943B1 JP6067943B1 JP2016526218A JP2016526218A JP6067943B1 JP 6067943 B1 JP6067943 B1 JP 6067943B1 JP 2016526218 A JP2016526218 A JP 2016526218A JP 2016526218 A JP2016526218 A JP 2016526218A JP 6067943 B1 JP6067943 B1 JP 6067943B1
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
Description
本明細書で使用される場合、以下の定義は、特に指示されていない限り適用される。
特に規定がない限り、本明細書に描かれている化合物としては、本明細書に描かれている化合物の混合物、及びその構造の鏡像異性体、ジアステレオマー、及び幾何学的(又は立体構造)形態のいずれか、例えば各不斉中心についてのR及びS立体配置、(Z)及び(E)二重結合異性体、並びに(Z)及び(E)立体構造異性体を挙げることができる。特に規定がない限り、互変異性形態と同時に存在する本明細書で描かれている化合物は、本発明の範囲内にある。さらに、特に規定がない限り、本明細書で描かれている構造は、1つ又は複数の同位体的に富化されている原子の存在下でのみ異なる化合物を含むことも意図されている。例えば、水素を重水素又はトリチウムに置換すること、又は炭素を13C−又は14C−富化炭素に置換すること以外は本発明の構造を有する化合物は、本発明の範囲内にある。このような化合物は、例えば、生物学的アッセイで分析ツール又はプローブとして有用であることができる。
並びにその医薬上許容しうる塩である。
本発明の化合物は、医薬上許容しうる担体と組み合わせて、その医薬製剤を提供することができる。担体及び製剤の特定の選択は、組成物が意図される投与の特定の経路による。
本発明の化合物は、SF3B1を標的にする薬剤に応答性のあるものを含めた様々の種類のがんを治療するために使用されうる。上述のとおり、プラジエノライドBの抗腫瘍活性が、そのSF3b複合体の標的に結合されること、遺伝子発現のパターンのスプライシング及び改変を阻害することとして報告されている。(Kotakeら、「Splicing factor SF3b as a target of the antitumor natural product pladienolide」、Nature Chemical Biology 2007、3巻、570〜575頁)。スプライソソーム遺伝子、例えばスプライシング因子3Bサブユニット1(SF3B1)タンパク質における突然変異は、いくつかのがん、例えば血液悪性腫瘍及び固形腫瘍と関係づけられることが知られている。Scottら、「Acquired mutations that affect pre−mRNA splicing in hematologic malignancies and solid tumors」、JNCI 105、20、1540〜1549頁。
全般:
Biotage EmrysのLiberator又はInitiatorのマイクロ波を使用して、マイクロ波加熱を行った。Isco Rf200dを使用して、カラムクロマトグラフィーを実行した。Buchiのロータリーエバポレーター又はGenevac遠心分離エバポレーターのいずれかを使用して、溶媒除去を実行した。酸性移動相条件下でWatersの自動精製装置及び19×100mm XTerra5ミクロンMS C18カラムを使用して、分取LC/MSを行った。Varian400MHz分光測定装置を使用して、NMRスペクトルを記録した。
MeOH:メタノール
DMF:ジメチルホルムアミド
KHMDS:カリウムビス(トリメチルシリル)アミド
LCMS:液体クロマトグラフィー−質量分光測定装置
TBSCl:tert−ブチルジメチルシリルクロリド
THF:テトラヒドロフラン
TLC:薄層クロマトグラフィー
移動相:A(H2O中の0.1%ギ酸)及びB(アセトニトリル中の0.1%ギ酸)。
勾配:1.8分でB 5%→95%。
カラム:AcquityBEH C18カラム(1.7um、2.1×50mm)。
化合物を、96ウエルプレートに供給し、三重で試験した。DMSO中の化合物の10mM保存溶液4マイクロリットルを、3つのウエル各々に分配した。プレートを、分析の日まで−20℃で又は未満で保存した。メタノール(HPLCグレード)及び0.1N HCl(EMDカタログHX0603A−6)を、希釈のために使用した。アセトニトリル(HPLCグレード)、水(ミリ−Q(Milli−Q)でろ過された)、トリフルオロ酢酸(分光用グレード)及び0.2Mリン酸緩衝液(Wako、カタログ番号163−14471)を使用して、2つの分析方法のための移動相を調製した。
細胞生存能力アッセイプロトコール
細胞(ATCCから得られているWiDr及びPanc05.04)を、96ウエルプレートに、細胞2000個/100μL/ウエルで播種し、一夜インキュベートした。消耗された培地を除去し、9つの異なる濃度の化合物を含有する新鮮な培地(100μL/ウエル)を添加し、化合物保存溶液から得られるDMSO濃度を0.1%に調節した。各化合物処置を、各濃度で二重に又は三重に行った。
Ti>/=Tzの濃度について、[(Ti−Tz)/(C−Tz)]×100
Ti<Tzの濃度について、[(Ti−Tz)/Tz]×100。
*時間ゼロ(Tz)、対照成長(C)、及び化合物の存在下での試験成長(Ti)
成長阻害率/生存率を、化合物濃度に対してプロットし、Emaxを決定した。
介在配列の欠失を有するアデノウイルス2型構築物(Ad2)のビオチンで標識されているプレmRNA(Berg,M.G.ら、2012 Mol. Cell Bio.、32(7):1271〜83頁)を、インビトロ転写により調製した。Exon1 (41ヌクレオチド)、イントロン(231ヌクレオチド)、及びExon2(72ヌクレオチド)を含有するAd2構築物を、遺伝子合成により産生させ、ジーンウィズ(Genewiz)(登録商標)(South Plainfield、New Jersey)によるpGEM(登録商標)−3Zベクター(Promega)のEcoRI及びXbaI部位にクローン化した。その後、プラスミドを、XbaI消化により直線化し、精製した。製造業者の指示により、それぞれ、MEGAスクリプト(script)(登録商標)T7転写キット(インビトロゲン(Invitrogen)(商標)、ライフ テクノロジーズ(Life Technologies)(商標)、Grand Island、New York)及びMEGAクリア(clear)(商標)転写クリーンアップキット(インビトロゲン(商標)、ライフ テクノロジーズ(商標)、Grand Island、New York)を使用して、転写プレ−mRNAのインビトロ転写及び精製を行った。ビオチン−16−UTP(Roche Diagnostics Corporation、Indianapolis、Indiana)対冷UTPの比は、スプライシングされているAd2mRNA当たりおよそ2つのビオチン分子を組み込むのに1:13であった。
データを下の表3で報告する。Emaxは、試験した用量範囲での化合物に対する最大達成可能な応答を指し、負の値は、細胞致死性を示す。大きな負のEmax値は、特定の化合物について細胞致死性が大きいことを示す。例えば、突然変異体SF3B1細胞株であるPanc05.04細胞では、大きな負のEmax値は、化合物1が、化合物2より大きな細胞致死性を有したことを示す。
マウスでの薬物動態学的(PK)研究
化合物2を、CD−1マウスに5mg/kgIV(静脈内)又は10mg/kgPO(経口投与)で投与した。投与後、血液試料を、5匹のマウスから、尾静脈からの連続放血を介して予め決定されている時点で採取した。血液を、投与後0.083(0.167POのみ)、0.5、1、2、4、6、8及び24時間に採取した。血液採取後30分以内に、血液試料を5000RPMで5分間遠心分離して、血漿を採取した。抽出後、試料をLCMSを使用して分析した。PKパラメーターはWinNonlin v6.3における非コンパートメント分析を使用して計算した。
化合物2の効力をマウスの異種移植モデルで試験した。Nalm−6SF3B1K700E同質遺伝子細胞(ヒトのプレB−細胞株、10×106細胞)をメスのCB17−SCIDマウスの側腹部に皮下移植した。マウスを化合物2(10%エタノール、5%TWEEN−80、85%生理食塩水)又は溶媒対照で処置した。マウスに、図2で示されている量で、14日間、毎日経口で投与(QD×14PO)し、マウスが以下の終点のいずれかに達するまで観察した:1)週3回測定した過剰な腫瘍体積(楕円の式:(長さ×幅2)/2を使用することにより計算される腫瘍体積);又は2)なんらかの健康上の問題、例えば麻痺又は過剰な体重減少の発生。全ての動物研究は、H3 Biomedicine Guide for the Care and Use of Laboratory Animalsに従って実行した。
Nalm−6マウスの異種移植モデルで、化合物2の薬物動態学(PK)/薬力学(PD)も分析した。Nalm−6 SF3B1K700E同質遺伝子細胞(ヒトのプレB−細胞株、10×106細胞)を、メスのCB17−SCIDマウスの側腹部に皮下移植した。マウスに、単一の経口用量の10mg/kgの化合物2(10%エタノール、5%TWEEN−80、85%生理食塩水)を投与し、分析のために、投与の後の所定時間に腫瘍を採取した。
化合物2の存在下でのPanc05.04がん細胞(SF3B1MUT)(SF3B1におけるQ699H及びK700E突然変異)の生存能力を評価するために、384ウエルプレート中にウエル当たり750個の細胞を播種し、72時間、37℃で、図4に示した濃度の化合物2で処置した。生存性又はアポトーシス細胞の相対数は、セルタイター−グロ(登録商標)発光性細胞生存性アッセイ(Promega)を使用して発光により測定した。
nカウンター(nCounter)(登録商標)分析システム(NanoString Techologies, Inc.、Seattle、Washington)を使用して、E7107及び化合物2についての選択的スプライシングの調節を決定した。Nalm−6同質遺伝子細胞を、10×GI50で、6時間、化合物2又はE7107(Eisai, Inc.から得られる)で処置した。リボピュア(商標)RNA精製キット(アンビオン(登録商標))を使用して、RNAを単離し、分析に使用した。スーパースクリプト(登録商標)ビロ(VILO)(商標)cDNA合成キット(インビトロゲン(商標))の指示によりRNAをレトロ転写し、0.04μlのcDNAを、qPCR用に使用した。
化合物1を、CD−1マウスに5mg/kgIV又は12mg/kgPOで投与した。投与後、5匹のマウスから尾静脈からの連続放血を介して予め決定されている時点で血液試料を採取した。血液は、投与後0.083(0.167POのみ)、0.5、1、2、4、6、8及び24時間に採取した。血液採取30分以内に、血液試料を5000RPMで5分間遠心分離して、血漿を採取した。抽出後、試料を、LCMSを使用して分析した。PKパラメーターを、WinNonlin v6.3における非コンパートメント分析を使用して計算した。
化合物1の効力をマウスの異種移植モデルで試験した。Nalm−6SF3B1K700E同質遺伝子細胞(ヒトのプレB−細胞株、10×106細胞)をメスのCB17−SCIDマウスの側腹部に皮下で移植した。マウスを、化合物1(10%エタノール、5%TWEEN−80、85%生理食塩水)又は溶媒対照で処置した。マウスに、7.5mg/kg又は10mg/kgの化合物1又は溶媒を、14日間、毎日経口で投与(QD×14PO)し、マウスが以下の終点のいずれかに達するまで観察した:1)週3回測定されている過剰な腫瘍体積(楕円の式:(長さ×幅2)/2を使用して計算される腫瘍体積);又は2)なんらかの健康上の問題、例えば麻痺又は過剰な体重減少の発生。全ての動物研究は、H3 Biomedicine Guide for the Care and Use of Laboratory Animalsに従って実行した。
Nalm−6マウスの異種移植モデルで、化合物1の薬物動態学的(PK)/薬力学的(PD)も分析した。Nalm−6 SF3B1K700E同質遺伝子細胞(ヒトのプレB−細胞株、10×106細胞)を、メスのCB17−SCIDマウスの側腹部に皮下で移植した。マウスに、単一の経口用量の化合物1(10%エタノール、5%TWEEN−80、85%生理食塩水)を投与し、分析のために、投与の後の所定時間に腫瘍を採取した。
CD−1マウスに化合物3を5.964mg/kgIV又は13.307mg/kgPOで投与した。投与後、5匹のマウスから、尾静脈からの連続放血を介して予め決定されている時点で血液試料を採取した。血液を、投与後0.083(0.167POのみ)、0.5、1、2、4、6、8及び24時間で採取した。血液採取後30分以内に、血液試料を5000RPMで5分間遠心分離して、血漿を採取した。抽出後、試料を、LCMSを使用して分析した。PKパラメーターを、WinNonlin v6.3における非コンパートメント分析を使用して計算した。
化合物4を、CD−1マウスに5mg/kgIV又は10mg/kgPOで投与した。投与後、5匹のマウスから、尾静脈からの連続放血を介して予め決定されている時点で血液試料を採取した。血液を、投与後0.083(0.167POのみ)、0.5、1、2、4、6、8及び24時間で採取した。血液採取後30分以内に、血液試料を5000RPMで5分間遠心分離して、血漿を採取した。抽出後、試料を、LCMSを使用して分析した。PKパラメーターを、WinNonlin v6.3における非コンパートメント分析を使用して計算した。
Claims (51)
- 前記化合物が、立体異性的に純粋である、請求項1に記載の化合物。
- 請求項1〜6のいずれか一項に記載の化合物又はその医薬上許容しうる塩を含む医薬組成物。
- 前記組成物が、静脈内、経口、皮下、又は筋肉内投与のために製剤化されている、請求項7に記載の医薬組成物。
- 前記組成物が、経口投与のために製剤化されている、請求項8に記載の医薬組成物。
- 骨髄異形成症候群、慢性リンパ性白血病、急性リンパ芽球性白血病、慢性骨髄単球性白血病、急性骨髄性白血病、結腸がん、膵臓がん、子宮内膜がん、卵巣がん、乳がん、ブドウ膜黒色腫、胃がん、胆管細胞がん及び肺がんから選択されるがんの治療における使用のための、請求項7〜9のいずれか一項に記載の医薬組成物。
- 前記がんが、結腸がんである、請求項10に記載の医薬組成物。
- 前記がんが、膵臓がんである、請求項10に記載の医薬組成物。
- 前記がんが、骨髄異形成症候群、慢性リンパ性白血病、急性リンパ芽球性白血病、慢性骨髄単球性白血病及び急性骨髄性白血病から選択される、請求項10に記載の医薬組成物。
- 前記がんが、骨髄異形成症候群である、請求項13に記載の医薬組成物。
- 前記がんが、慢性骨髄単球性白血病である、請求項13に記載の医薬組成物。
- 前記がんが、急性骨髄性白血病である、請求項13に記載の医薬組成物。
- 前記がんが、スプライソソーム遺伝子又はタンパク質における1つ又は複数の突然変異について陽性である、請求項10〜16のいずれか一項に記載の医薬組成物。
- 前記スプライソソーム遺伝子又はタンパク質が、スプライシング因子3Bサブユニット1、U2核内低分子RNA補助因子1、セリン/アルギニン富化スプライシング因子2、プレ−mRNA−プロセシング-スプライシング因子8、U2核内低分子RNA補助因子2、スプライシング因子1、スプライシング因子3aサブユニット1、PRP40プレ−mRNAプロセシング因子40相同体B、RNA結合モチーフタンパク質10、ポリ(rC)結合タンパク質1、クルックドネック プレ−mRNAスプライシング因子1、DEAH(Asp−Glu−Ala−His)ボックスヘリカーゼ9、ペプチジル−プロリル シス−トランスイソメラーゼ−様2、RNA結合モチーフタンパク質22、核内低分子リボヌクレオプロテインSmD3、プロバブル ATP−依存性RNAヘリカーゼDDX5、プレ−mRNA−スプライシング因子 ATP−依存性RNAヘリカーゼDHX15及びポリアデニレート−結合タンパク質1から選択される、請求項17に記載の医薬組成物。
- 前記スプライソソーム遺伝子又はタンパク質が、スプライシング因子3Bサブユニット1である、請求項18に記載の医薬組成物。
- がんを治療するための医薬の製造における請求項1〜6のいずれか一項に記載の化合物又はその医薬上許容しうる塩の使用であって、前記がんが、骨髄異形成症候群、慢性リンパ性白血病、急性リンパ芽球性白血病、慢性骨髄単球性白血病、急性骨髄性白血病、結腸がん、膵臓がん、子宮内膜がん、卵巣がん、乳がん、ブドウ膜黒色腫、胃がん、胆管細胞がん及び肺がんから選択される、使用。
- 前記がんが、結腸がんである、請求項20に記載の使用。
- 前記がんが、膵臓がんである、請求項20に記載の使用。
- 前記がんが、骨髄異形成症候群、慢性リンパ性白血病、急性リンパ芽球性白血病、慢性骨髄単球性白血病及び急性骨髄性白血病から選択される、請求項20に記載の使用。
- 前記がんが、骨髄異形成症候群である、請求項23に記載の使用。
- 前記がんが、慢性骨髄単球性白血病である、請求項23に記載の使用。
- 前記がんが、急性骨髄性白血病である、請求項23に記載の使用。
- 前記がんが、スプライソソーム遺伝子又はタンパク質における1つ又は複数の突然変異について陽性である、請求項20〜26のいずれか一項に記載の使用。
- 前記スプライソソーム遺伝子又はタンパク質が、スプライシング因子3Bサブユニット1である、請求項27に記載の使用。
- 前記組成物が、静脈内、経口、皮下、又は筋肉内投与のために製剤化されている、請求項29に記載の医薬組成物。
- 前記組成物が、経口投与のために製剤化されている、請求項30に記載の医薬組成物。
- 骨髄異形成症候群、慢性リンパ性白血病、急性リンパ芽球性白血病、慢性骨髄単球性白血病、急性骨髄性白血病、結腸がん、膵臓がん、子宮内膜がん、卵巣がん、乳がん、ブドウ膜黒色腫、胃がん、胆管細胞がん及び肺がんから選択されるがんの治療における使用のための、請求項29〜31のいずれか一項に記載の医薬組成物。
- 前記がんが、結腸がんである、請求項32に記載の医薬組成物。
- 前記がんが、膵臓がんである、請求項32に記載の医薬組成物。
- 前記がんが、骨髄異形成症候群、慢性リンパ性白血病、急性リンパ芽球性白血病、慢性骨髄単球性白血病及び急性骨髄性白血病から選択される、請求項32に記載の医薬組成物。
- 前記がんが、骨髄異形成症候群である、請求項32に記載の医薬組成物。
- 前記がんが、慢性骨髄単球性白血病である、請求項32に記載の医薬組成物。
- 前記がんが、急性骨髄性白血病である、請求項32に記載の医薬組成物。
- 前記がんが、スプライソソーム遺伝子又はタンパク質における1つ又は複数の突然変異について陽性である、請求項32〜38のいずれか一項に記載の医薬組成物。
- 前記スプライソソーム遺伝子又はタンパク質が、スプライシング因子3Bサブユニット1、U2核内低分子RNA補助因子1、セリン/アルギニン富化スプライシング因子2、プレ−mRNA−プロセシング-スプライシング因子8、U2核内低分子RNA補助因子2、スプライシング因子1、スプライシング因子3aサブユニット1、PRP40プレ−mRNAプロセシング因子40相同体B、RNA結合モチーフタンパク質10、ポリ(rC)結合タンパク質1、クルックドネック プレ−mRNAスプライシング因子1、DEAH(Asp−Glu−Ala−His)ボックスヘリカーゼ9、ペプチジル−プロリル シス−トランスイソメラーゼ−様2、RNA結合モチーフタンパク質22、核内低分子リボヌクレオプロテインSmD3、プロバブルATP−依存性RNAヘリカーゼDDX5、プレ−mRNA−スプライシング因子 ATP−依存性RNAヘリカーゼDHX15及びポリアデニレート−結合タンパク質1から選択される、請求項39に記載の医薬組成物。
- 前記スプライソソーム遺伝子又はタンパク質が、スプライシング因子3Bサブユニット1である、請求項40に記載の医薬組成物。
- がんを治療するための医薬の製造における請求項2に記載の化合物又はその医薬上許容しうる塩の使用であって、前記がんが、骨髄異形成症候群、慢性リンパ性白血病、急性リンパ芽球性白血病、慢性骨髄単球性白血病、急性骨髄性白血病、結腸がん、膵臓がん、子宮内膜がん、卵巣がん、乳がん、ブドウ膜黒色腫、胃がん、胆管細胞がん及び肺がんから選択される、使用。
- 前記がんが、結腸がんである、請求項42に記載の使用。
- 前記がんが、膵臓がんである、請求項42に記載の使用。
- 前記がんが、骨髄異形成症候群、慢性リンパ性白血病、急性リンパ芽球性白血病、慢性骨髄単球性白血病及び急性骨髄性白血病から選択される、請求項42に記載の使用。
- 前記がんが、骨髄異形成症候群である、請求項45に記載の使用。
- 前記がんが、慢性骨髄単球性白血病である、請求項45に記載の使用。
- 前記がんが、急性骨髄性白血病である、請求項45に記載の使用。
- 前記がんが、スプライソソーム遺伝子又はタンパク質における1つ又は複数の突然変異について陽性である、請求項42〜48のいずれか一項に記載の使用。
- 前記スプライソソーム遺伝子又はタンパク質が、スプライシング因子3Bサブユニット1、U2核内低分子RNA補助因子1、セリン/アルギニン富化スプライシング因子2、プレ−mRNA−プロセシング-スプライシング因子8、U2核内低分子RNA補助因子2、スプライシング因子1、スプライシング因子3aサブユニット1、PRP40プレ−mRNAプロセシング因子40相同体B、RNA結合モチーフタンパク質10、ポリ(rC)結合タンパク質1、クルックドネック プレ−mRNAスプライシング因子1、DEAH(Asp−Glu−Ala−His)ボックスヘリカーゼ9、ペプチジル−プロリル シス−トランスイソメラーゼ−様2、RNA結合モチーフタンパク質22、核内低分子リボヌクレオプロテインSmD3、プロバブルATP−依存性RNAヘリカーゼDDX5、プレ−mRNA−スプライシング因子 ATP−依存性RNAヘリカーゼDHX15及びポリアデニレート−結合タンパク質1から選択される、請求項49に記載の使用。
- 前記スプライソソーム遺伝子又はタンパク質が、スプライシング因子3Bサブユニット1である、請求項50に記載の使用。
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WO2022263702A1 (es) * | 2021-06-18 | 2022-12-22 | Universidad de Córdoba | Compuesto para el tratamiento del glioblastoma |
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