JP6615746B2 - 腫瘍選択的併用療法 - Google Patents
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- JP6615746B2 JP6615746B2 JP2016507622A JP2016507622A JP6615746B2 JP 6615746 B2 JP6615746 B2 JP 6615746B2 JP 2016507622 A JP2016507622 A JP 2016507622A JP 2016507622 A JP2016507622 A JP 2016507622A JP 6615746 B2 JP6615746 B2 JP 6615746B2
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
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- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940086984 trisenox Drugs 0.000 description 1
- 229910052722 tritium Chemical group 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 1
- 229950011257 veliparib Drugs 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- 229940100445 wheat starch Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
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Description
本出願は、35 U.S.C. §119(e)の下で、2013年4月9日提出の米国仮特許出願第61/810,008号に対する優先権を主張し、これは参照により本明細書に組み入れられる。
本発明は、米国立衛生研究所により授与された契約番号CA102792の下で政府支援により行った。政府は本発明において一定の権利を有する。
がん処置における基本的挑戦は、がん細胞に対しては毒性であるが、健常細胞には毒性でない化合物の発見である。がんの顕著な特徴は急速かつ無制限の細胞分裂である。伝統的な化学療法剤の大部分は、細胞周期を撹乱することにより急速に分裂中の細胞を標的とし、細胞死を引き起こす。いくつかの健常組織はそれらの機能の一部として細胞分裂を必要とするため、抗増殖性細胞毒は健常細胞も死滅させ、重度の用量制限副作用を起こしうる。したがって、健常細胞とがん性細胞とをよりよく区別する、新しい治療法および新しい細胞標的を特定しなければならない。標的はがん患者のごく一部にのみ存在することもあり、それによりがんを処置するための個別の戦略を可能にする。
本発明は、がんおよびがん腫瘍細胞、例えば、NQO1のレベル上昇を有する腫瘍細胞を処置するための化合物、組成物および方法を提供する。本発明は、腫瘍選択的治療を提供するための、DNA修復阻害剤と組み合わせての、NQO1生体内活性化可能薬の投与を含む、新規併用療法も提供する。1つの態様において、塩基除去修復を阻害することは、膵臓がんなどのがんの腫瘍選択的治療のためのベータ-ラパコン媒介性細胞死を増強する。
[本発明1001]
がん性細胞を有する患者のがん細胞を死滅させるかまたはその成長を阻害するための、a)塩基除去修復(BER)酵素阻害剤、b)ポリ(ADP-リボシル)ポリメラーゼI(PARP1)阻害剤、またはc)AP塩基修飾薬と組み合わせての、NQO1生体内活性化可能薬の使用。
[本発明1002]
がん性細胞を有する患者のがん細胞を死滅させるかまたはその成長を阻害するための医薬製造のための、NQO1生体内活性化可能薬の第二の薬剤と組み合わせての使用であって、第二の薬剤はa)塩基除去修復(BER)酵素阻害剤、b)ポリ(ADP-リボシル)ポリメラーゼI(PARP1)阻害剤、またはc)AP塩基修飾薬であり、医薬は有効致死量または阻害量のNQO1生体内活性化可能薬および第二の薬剤を含む、使用。
[本発明1003]
がん細胞が塩基除去修復(BER)欠陥または欠陥のあるDNA修復プロセスによる脆弱性を有する、本発明1001の使用。
[本発明1004]
BER欠陥または脆弱性が欠陥レベルのX線クロス補足群1すなわちXRCC1遺伝子/タンパク質/酵素を含む、本発明1003の使用。
[本発明1005]
塩基除去修復(BER)酵素阻害剤との組み合わせである、本発明1001の使用。
[本発明1006]
ポリ(ADP-リボシル)ポリメラーゼI(PARP1)阻害剤との組み合わせである、本発明1001の使用。
[本発明1007]
AP塩基修飾薬との組み合わせである、本発明1001の使用。
[本発明1008]
NQO1生体内活性化可能薬がβ-ラパコンまたはDNQ化合物である、本発明1005の使用。
[本発明1009]
NQO1生体内活性化可能薬がβ-ラパコンまたはDNQ化合物である、本発明1006の使用。
[本発明1010]
NQO1生体内活性化可能薬がβ-ラパコンまたはDNQ化合物である、本発明1007の使用。
[本発明1011]
塩基除去修復(BER)酵素阻害剤またはAP塩基修飾薬がメトキシアミンである、本発明1001〜1005、1007〜1008または1010のいずれかの使用。
[本発明1012]
NQO1生体内活性化可能薬がdC3などのβ-ラパコンプロドラッグまたはそのベンゼン環類縁体である、本発明1001〜1010のいずれかの使用。
[本発明1013]
DNA損傷剤の投与をさらに含む、本発明1001〜1010のいずれかの使用。
[本発明1014]
さらなる化学療法剤または放射線療法をさらに含む、本発明1001〜1010のいずれかの使用。
[本発明1015]
がん細胞がNQO1レベルの上昇を有する、本発明1001〜1010のいずれかの使用。
[本発明1016]
がん細胞が固形腫瘍の形態である、本発明1015の使用。
[本発明1017]
がん細胞が非小細胞肺がん細胞、前立腺がん細胞、膵臓がん細胞、乳がん細胞、頭頸部がん細胞、または結腸がん細胞である、本発明1016の使用。
[本発明1018]
NQO1生体内活性化可能薬が図12に示す化合物である、本発明1001の使用。
[本発明1019]
NQO1生体内活性化可能薬が下記;またはその塩もしくは溶媒和物である、本発明1001の方法:
。
[本発明1020]
NQO1生体内活性化可能薬が下記;またはその塩もしくは溶媒和物である、本発明1011の方法:
。
[本発明1021]
NQO1生体内活性化可能薬がβ-ラパコンであり、かつ塩基除去修復酵素阻害剤がメトキシアミンである、本発明1001の使用。
[本発明1022]
NQO1生体内活性化可能薬がDNQまたはDNQ-87であり、かつ塩基除去修復酵素阻害剤がメトキシアミンである、本発明1001の使用。
[本発明1023]
がん細胞を死滅させるかまたはその成長を阻害する方法であって、がん細胞を有効致死量または阻害量のNQO1生体内活性化可能薬と塩基除去修復(BER)酵素阻害剤との組み合わせに接触させる段階を含み、それによりがん細胞を死滅させるかまたはその成長を阻害する、方法。
[本発明1024]
がん細胞を死滅させるかまたはその成長を阻害する方法であって、がん細胞を有効致死量または阻害量のNQO1生体内活性化可能薬とポリ(ADP-リボシル)ポリメラーゼI(PARP1)阻害剤との組み合わせに接触させる段階を含み、それによりがん細胞を死滅させるかまたはその成長を阻害する、方法。
[本発明1025]
がん細胞を死滅させるかまたはその成長を阻害する方法であって、がん細胞を有効致死量または阻害量のNQO1生体内活性化可能薬とAP塩基修飾薬との組み合わせに接触させる段階を含み、それによりがん細胞を死滅させるかまたはその成長を阻害する、方法。
腫瘍選択性はがんに対する有効な化学療法戦略の難題のままである。ほとんどの固形腫瘍におけるNAD(P)H:キノンオキシドレダクターゼ1(NQO1)のレベル上昇を特異的に利用するためのβ-ラパコンの最近の開発は、新規化学療法アプローチの代表例であるが、高い効力でプログラム壊死などの様々なメカニズムにより死滅させるさらなる治療法が必要とされている。デオキシニボキノン(DNQ)は広い範囲のがん細胞型(すなわち、乳がん、非小細胞肺がん、前立腺がん、膵臓がん)をNQO1依存的様式で、β-ラパコンに比べて大幅に改善された効力(20〜100倍)で死滅させる。DNQ致死性はNQO1依存性無益酸化還元サイクリングに頼っており、酸素を用い、高度に反応性の酸素種(ROS)、特にスーパーオキシドおよび過酸化水素を生成する。ROSレベルの上昇は高度のDNA損傷およびPARP-1過剰活性化を引き起こし、これは次いで、このクラスのNQO1「生体内活性化」薬物(例えば、β-ラパコンおよびDNQ)に特有のカルシウム依存性プログラム細胞壊死反応を刺激する、重度のNAD+/ATP欠乏を生じる。驚くことに、NQO1生体内活性化可能薬とDNA修復阻害剤との組み合わせは相乗的かつ腫瘍選択的療法を提供することが判明した。
DNQは、膵臓がんおよび非小細胞肺がんを含む広い範囲の治療が困難ながんに対する標的療法のために非常に有望な、広い治療ウィンドウを示す強力な化学療法剤である。がん化学療法におけるかなりの進歩にもかかわらず、ほとんどのがん化学療法剤の選択性の欠如は大きな制限因子のままである。ほとんどの固形腫瘍、特に非小細胞肺がん細胞(NSCLC)、前立腺がん、膵臓がんおよび乳がんで見られる、NAD(P)H:キノンオキシドレダクターゼ-1(NQO1、DT-ジアホラーゼ、EC 1.6.99.2)レベルの上昇は、本明細書に記載の治療的処置の標的を提供する。NQO1は、ほとんどのキノンを還元して安定なヒドロキノンを生成することが可能な、誘導性解毒第II相2電子オキシドレダクターゼである。ほとんどの場合に、グルタチオントランスフェラーゼが次いでヒドロキノンを解毒し、分泌のためにそれらをグルタチオンで抱合し、より毒性のセミキノンを効果的に回避する。
NQO1生体内活性化可能薬(NQO1の基質であるすべてのβ-ラパコンおよびDNQ誘導体)は、膨大なレベルの反応性酸素種を、NQO1依存的、腫瘍選択的様式で生成し、腫瘍特異的様式で用いられる、すべてのPARP1阻害剤、DNA二本鎖切断修復阻害剤、ならびに塩基除去修復阻害剤を含む、DNA損傷阻害剤の使用を可能にし、両方の薬剤の腫瘍選択的効果をもたらす。DNA修復阻害剤は、一般には、腫瘍選択性の欠如ゆえに失敗している。これらのNQO1生体内活性化可能薬は、DNA塩基損傷、一本鎖切断および二本鎖切断を含むDNA損傷の腫瘍選択的生成を引き起こすため、DNA修復阻害剤を用いて腫瘍選択的抗腫瘍活性を提供することができる。腫瘍選択的活性および反応には、解糖の劇的阻害ならびに他の腫瘍選択的代謝阻害が含まれる。
一般に、本明細書において用いられる用語および語句はそれらの技術分野において認められた意味を有し、これらは標準の教科書、参照文献および当業者には公知の文脈を参照することによって見出すことができる。そのような当技術分野において認められた意味は、Hawley's Condensed Chemical Dictionary 14th Edition, by R.J. Lewis, John Wiley & Sons, New York, N.Y., 2001などの技術辞書を参照することによって得てもよい。
基は末端基または架橋基であり得る。
*BSI-201は報告されたPARP1阻害剤であり、β-lapまたはDNQと相乗作用したが、PARP1ノックダウン細胞を用いて、本発明者らは、他のPARP1阻害剤では見られなかったさらなる相乗作用を認めた。さらに、それを加えても、他の阻害剤すべてのように、PARP1 PAR生成を防止することはなかった。本発明者らは、したがって、BSI-201はPARP1阻害剤ではなく、むしろDNA損傷剤であり、これは認められた相乗作用を説明するものであると結論付ける。
**PARP1阻害剤それぞれの様々な用量(μM)を、β-ラパコンまたはDNQの様々な用量と共に加えた。報告した感受性の値は、β-ラパコン(A549に対しては3μM、2μM Mia Paca2細胞)またはDNQ(A549細胞に対しては0.02μM、MiaPaca-2細胞に対しては0.025μM)いずれかの非毒性用量と各PARP1阻害剤の最適用量(すなわち、15μM)との組み合わせでの、A549 NSCLC細胞またはMiaPaCa-2膵臓がん細胞の生存率の変化を表す。10の値は1logの殺滅に等しく、100の値は2logの殺滅に等しく、他も同様である。PARP1阻害剤は100μMの高濃度まで非致死的であった。
本発明は、DNQ化合物、ベータ-ラパコンおよびその誘導体、ならびにがんの処置のための併用療法におけるNQO1生体内活性化可能薬の使用を提供する。DNQ化合物の例には式(I)の化合物、またはその塩もしくは溶媒和物が含まれる:
式中
R1、R2、R3、およびR4はそれぞれ独立に-Hまたは-X-Rであり;
各Xは独立に直接結合または架橋基であり、ここで架橋基は-O-、-S-、-NH-、-C(=O)-、-O-C(=O)-、-C(=O)-O-、-O-C(=O)-O-、または式-W-A-W-のリンカーであり、ここで
各Wは独立に-N(R')C(=O)-、-C(=O)N(R')-、-OC(=O)-、-C(=O)O-、-O-、-S-、-S(O)-、-S(O)2-、-N(R')-、-C(=O)-、-(CH2)n-、ここでnは1〜10であり、または直接結合であり、ここで各R'は独立にH、(C1-C6)アルキル、または窒素保護基であり;かつ
各Aは独立に(C1-C20)アルキル、(C2-C16)アルケニル、(C2-C16)アルキニル、(C3-C8)シクロアルキル、(C6-C10)アリール、-(OCH2-CH2)n-、ここでnは1〜約20であり、-C(O)NH(CH2)n-、ここでnは1〜約6であり、-OP(O)(OH)O-、-OP(O)(OH)O(CH2)n-、ここでnは1〜約6であり、または2つの炭素の間、もしくは炭素と酸素との間にシクロアルキル、複素環、もしくはアリールが割り込んだ、(C1-C20)アルキル、(C2-C16)アルケニル、(C2-C16)アルキニル、もしくは-(OCH2-CH2)n-であり;
各Rは独立にアルキル、アルケニル、アルキニル、ヘテロアルキル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、(シクロアルキル)アルキル、(ヘテロシクロアルキル)アルキル、(シクロアルキル)ヘテロアルキル、(ヘテロシクロアルキル)ヘテロアルキル、アリール、ヘテロアリール、(アリール)アルキル、(ヘテロアリール)アルキル、水素、ヒドロキシ、ヒドロキシアルキル、アルコキシ、(アルコキシ)アルキル、アルケニルオキシ、アルキニルオキシ、(シクロアルキル)アルコキシ、ヘテロシクロアルキルオキシ、アミノ、アルキルアミノ、アミノアルキル、アシルアミノ、アリールアミノ、スルホニルアミノ、スルフィニルアミノ、-CORx、-COORx、-CONHRx、-NHCORx、-NHCOORx、-NHCONHRx、-N3、-CN、-NC、-NCO、-NO2、-SH、-ハロ、アルコキシカルボニル、アルキルアミノカルボニル、スルホネート、スルホン酸、アルキルスルホニル、アルキルスルフィニル、アリールスルホニル、アリールスルフィニル、アミノスルホニル、RxS(O)Ry-、RxS(O)2Ry-、RxC(O)N(Rx)Ry-、RxSO2N(Rx)Ry-、RxN(Rx)C(O)Ry-、RxN(Rx)SO2Ry-、RxN(Rx)C(O)N(Rx)Ry-、カルボキシアルデヒド、アシル、アシルオキシ、-OPO3H2、-OPO3Z2であり、ここでZは無機カチオン、または糖であり;ここで各Rxは独立にH、OH、アルキルまたはアリールであり、かつ各Ryは独立に基Wであり;
ここで任意のアルキルまたはアリールは1つまたは複数のヒドロキシ、アミノ、シアノ、ニトロ、またはハロきで置換されていてもよい。
R1およびR2はメチルであり;R3は水素であり;かつR4は2-メチル-プロパンであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はブチルであり;
R1およびR4はメチルであり、かつR3は水素であり;かつR2はエチルであり;
R1およびR2はメチルであり、かつR3は水素であり;かつR4はエチルであり;
R1はメチルであり;R3は水素であり;R2はプロピルであり;かつR4はブチルであり;
R1およびR4はメチルであり;R2はプロピルであり、かつR3は水素であり;
R1はプロピルであり;R2およびR4はメチルであり、かつR3は水素であり;
R1およびR2はエチルであり;R3は水素であり;かつR2はメチルであり;
R1はプロピルであり;R2はメチルであり;R3は水素であり;かつR4はブチルであり;
R1およびR2はプロピルであり;R3は水素であり;かつR4はブチルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はC12アルキルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はtert-ブチルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はヒドロキシプロピルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4は3,3-diメチルブチル[-CH2CH2C(CH3)2CH3]であり;
R1およびR2はメチルであり;R3は水素であり;かつR4は3-メチブチル[-CH2CH2CH(CH3)CH3]であり;
R2およびR4はメチルであり;R3は水素であり;かつR1はエチルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はプロピルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はn-ペンチルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はn-ヘキシルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はイソプロピルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はシクロオクチルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はシクロプロピルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はメチルシクロプロピルであり;
R1およびR2はメチルであり;R3は水素であり;かつR4はエチルシクロプロピルであり;
R1はC12アルキルであり;R2およびR4はメチルであり;かつR3は水素であり;
R1およびR4はメチルであり;R3は水素であり;かつR2はC12アルキルであり;
R1、R2、およびR3はメチルであり;かつR4は-CH2OPO3Na2であり;
R1は-CH2OPO3Na2であり;R2およびR3はメチルであり;かつR4は水素であり;
R1およびR3はメチルであり;R2は-CH2OPO3Na2であり;かつR4は水素であり;
R1およびR2はメチルであり;R3は-CH2OPO3Na2であり;かつR4は水素であり;
R1およびR2はメチルであり;R3は-CH2CH2OPO3Na2であり;かつR4は水素であり;
R1、R2、およびR3はメチルであり;かつR4は-CH2OHであり;
R1は-CH2OHであり;R2およびR3はメチルであり;かつR4は水素であり;
R1およびR3はメチルであり;R2は-CH2OHであり;かつR4は水素であり;
R1およびR2はメチルであり;R3は-CH2OHであり;かつR4は水素であり;または
R1およびR2はメチルであり;R3は-CH2CH2OHであり;かつR4は水素である。本発明のさらなる特定の化合物および式は図11および12に例示する。
。特定の態様において、式Iの化合物は化合物9-253またはその塩もしくは溶媒和物である:
。特定の態様において、式Iの化合物は化合物9-251またはその塩もしくは溶媒和物である:
。特定の態様において、式Iの化合物は化合物10-41またはその塩もしくは溶媒和物である:
。特定の態様において、式Iの化合物は化合物109またはその塩もしくは溶媒和物である:
。特定の態様において、式Iの化合物は化合物107またはその塩もしくは溶媒和物である:
。特定の態様において、式Iの化合物は化合物9-281またはその塩もしくは溶媒和物である:
。特定の態様において、式Iの化合物は化合物9-249またはその塩もしくは溶媒和物である:
。特定の態様において、式Iの化合物は化合物9-255またはその塩もしくは溶媒和物である:
。特定の態様において、式Iの化合物は化合物9-257またはその塩もしくは溶媒和物である:
。
本発明は、本発明の化合物および組成物の作製法にも関する。化合物および組成物は、有機合成の任意の適用可能な技術によって調製することができる。多くのそのような技術は当技術分野において周知である。しかし、公知の技術の多くはCompendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971;Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974;Vol. 3, Louis S. Hegedus and Leroy Wade, 1977;Vol. 4, Leroy G. Wade, Jr., 1980;Vol. 5, Leroy G. Wade, Jr., 1984;およびVol. 6, Michael B. Smith;ならびにMarch's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed. byM.B. Smith and J. March (John Wiley & Sons, New York, 2001), Comprehensive Organic Synthesis; Selectivity, Strategy & Efficiency in Modern Organic Chemistry, in 9 Volumes, Barry M. Trost, Ed.-in-Chief (Pergamon Press, New York, 1993 printing) );Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Cary and Sundberg (1983);Protecting Groups in Organic Synthesis, Second Edition, Greene, T.W., and Wutz, P.G.M., John Wiley & Sons, New York;およびComprehensive Organic Transformations, Larock, R.C., Second Edition, John Wiley & Sons, New York (1999)などの標準の有機参考書に詳述されている。
本明細書に記載の化合物の薬学的に許容される塩は本発明の範囲内であり、所望の薬理活性を保持し、生物学的に有害でない(例えば、塩は過度に毒性、アレルギー性、または刺激性でなく、生物が利用可能である)、酸または塩基付加塩を含む。化合物が、例えば、アミノ基などの塩基性基を有する場合、薬学的に許容される塩は無機酸(塩酸、ヒドロホウ酸、硝酸、硫酸、およびリン酸などの)、有機酸(例えば、アルギネート、ギ酸、酢酸、安息香酸、グルコン酸、フマル酸、シュウ酸、酒石酸、乳酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ナフタレンスルホン酸、およびp-トルエンスルホン酸)または酸性アミノ酸(アスパラギン酸およびグルタミン酸などの)と形成されうる。本発明の化合物が、例えば、カルボン酸基などの酸性基を有する場合、アルカリおよびアルカリ土類金属(例えば、Na+、Li+、K+、Ca2+、Mg2+、Zn2+)などの金属、アンモニアもしくは有機アミン(例えば、ジシクロヘキシルアミン、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン)または塩基性アミノ酸(例えば、アルギニン、リジンおおびオルニチン)と塩を形成しうる。そのような塩は、化合物の単離および精製中にインサイチューで、または精製した化合物をその遊離塩基もしくは遊離酸の形で、それぞれ適切な酸もしくは塩基と別々に反応させ、そのようにして生成した塩を単離することによって調製することができる。
以下は、薬学的および薬理学的態様に関連する情報を記載し、当業者には入手可能な当技術分野における情報によってさらに補足される。厳密な製剤、投与経路および用量は、患者の状態を考慮して、個々の医師または臨床家が選択することができる(例えば、Fingl et al., in The Pharmacological Basis of Therapeutics, 1975, Ch. 1参照)。
リン酸緩衝化食塩水(PBS)中、pH7.4でのDNQの水溶性を、LC-MSで測定した。DNQをPBS中で30分間音波処理し、次いで溶解していない固体を0.45μmシリンジフィルターを通してのろ過により除去し、ろ液をLC-MSで分析した(λ=275nm、負モードでのESI-TOF)。最適音波処理時間は、DNQを1、5、10、および30分間音波処理することによって決定した。溶液中のDNQの濃度は1、5、および10分の間で実質的に増大したが、10分と30分との間ではわずかな差しかなかった。30分間の音波処理中、水浴は45℃まで加温した(試料はろ過の前に室温まで冷却した)。較正曲線は、DNQをメタノール中に500μMの濃度まで溶解し、この保存液の水:メタノール=80:20の希釈液を作製することにより、1〜100μMまで生成した。較正曲線(UV吸光度による尺度)はこの範囲全体で直線で;1μMはほぼ検出限界であった。DNQのPBS中の溶解度は115μMと測定された。溶液は非常に薄い黄色であった。
本明細書に記載の活性成分(例えば、式(I)の化合物)は他の活性成分との組み合わせで用いることもできる。そのような組み合わせは、処置する状態、成分の交差反応性および組み合わせの薬物特性(pharmaco-property)に基づいて選択される。例えば、がんを処置する場合、組成物を他の抗がん化合物(パクリタキセルまたはラパマイシンなどの)と組み合わせることができる。
がん療法は、化学物質および放射線に基づく処置の両方との様々な併用療法も含みうる。併用化学療法には、シスプラチン、エトポシド、イリノテカン、kアンプトスター(camptostar)、トポテカン、パクリタキセル、ドセタキセル、エポシロン、タキソテール、タモキシフェン、5-フルオロウラシル、メトキシトレキセート(methoxtrexate)、テモゾロミド、シクロホスファミド、SCH 66336、R115777、L778,123、BMS 214662、イレッサ(商標)(ゲフィチニブ)、タルセバ(商標)(塩酸エルロチニブ)、EGFRに対する抗体、グリベック(商標)(イマチニブ)、イントロン、ara-C、アドリアマイシン、シトキサン、ゲムシタビン、ウラシル マスタード、クロルメチン、イホスファミド、メルファラン、クロラムブシル、ピポブロマン、トリエチレンメラミン、トリエチレンチオホスホルアミン(triethylenethiophosphoramine)、ブスルファン、カルムスチン、ロムスチン、ストレプトゾシン、ダカルバジン、フロクスウリジン、シタラビン、6-メルカプトプリン、6-チオグアニン、リン酸フルダラビン、ペントスタチン(pentostatine)、ビンブラスチン、ビンクリスチン、ビンデシン、ブレオマイシン、ドキソルビシン、ダクチノマイシン、ダウノルビシン、エピルビシン、イダルビシン、ミトラマイシン、デオキシコホルマイシン、マイトマイシン-C、L-アスパラギナーゼ、テニポシド、17α-エチニルエストラジオール、ジエチルスチルベストロール、テストステロン、プレドニゾン、フルオキシメステロン、プロピオン酸ドロモスタノロン、テストラクトン、酢酸メゲストロール、メチルプレドニゾロン、メチルテストステロン、プレドニゾロン、トリアムシノロン、クロロトリアニセン、ヒドロキシプロゲステロン、アミノグルテチミド、エストラムスチン、酢酸メドロキシプロゲステロン、ロイプロリド、フルタミド、トレミフェン、ゴセレリン、カルボプラチン、ヒドロキシ尿素、アムサクリン、プロカルバジン、ミトタン、ミトキサントロン、レバミゾール、ナベルベン(navelbene)、アナストラゾール(anastrazole)、レトラゾール(letrazole)、カペシタビン、レロキサフィン(reloxafine)、ドロロキサフィン(droloxafine)、ヘキサメチルメラミン、アバスチン、ハーセプチン、ベキサール、ゼバリン、トリセノックス、ゼローダ、ビノレルビン、ポルフィマー、アービタックス(商標)(セツキシマブ)、リポソーム製剤、チオテパ、アルトレタミン、メルファラン、トラスツズマブ、レロゾール(lerozole)、フルベストラント、エキセメスタン、フルベストラント、イホスフォミド(ifosfomide)、リツキシマブ、C225、キャンパス、カルボプラチン、プロカルバジン、メクロレタミン、シクロホスファミド、カンプトテシン、イホスファミド、メルファラン、クロラムブシル、ブスルファン、ニトロソ尿素、ダクチノマイシン、ダウノルビシン、ドキソルビシン、ブレオマイシン、プリコマイシン(plicomycin)、マイトマイシン、エトポシド(VP 16)、タモキシフェン、ラロキシフェン、エストロゲン受容体結合剤、パクリタキセル、ゲムシタビン、ナベルビン、ファルネシル-タンパク質トランスフェラーゼ阻害剤、、トランス白金製剤(transplatinum)、5-フルオロウラシル、ビンクリスチン、ビンブラスチンおよびメトトレキサート、または前述の任意の類縁体もしくは誘導体変種などの化学療法剤の使用を含む。
DNA損傷を引き起こし、広く用いられている他の因子には、ガンマ線、X線、および/または放射性同位体の腫瘍細胞への指向送達として一般に公知のものが含まれる。マイクロ波およびUV照射などの、DNA損傷因子の他の形態も企図される。おそらく、これらの因子はすべて、DNA、DNAの前駆体、DNAの複製および修復、ならびに染色体の組み立ておよび維持における広範囲の損傷に影響をおよぼす。X線の線量範囲は、長期間(例えば、3〜4週間)のためには50〜200レントゲンの1日線量から2000〜6000レントゲンの1回線量までの範囲である。放射性同位体の線量範囲は大きく変動し、同位体の半減期、放出される放射線の強さおよび種類、ならびに新生物細胞による取り込みに依存する。「接触した」および「曝露した」なる用語は、細胞に適用する場合、本明細書において、それにより治療用コンストラクトおよび化学療法剤または放射線療法剤が標的細胞に送達される、または標的細胞に直接並置されるプロセスを記載するために用いられる。細胞死滅または静止を達成するために、両方の薬剤を細胞に、細胞を死滅させる、またはその分裂を防止するのに有効な組み合わせ量で送達する。
免疫療法は、一般には、がん細胞を標的とし、これらを破壊するための免疫エフェクター細胞および分子の使用に頼っている。免疫エフェクターは、例えば、腫瘍細胞の表面上のあるマーカーに特異的な抗体であり得る。抗体は単独で治療のエフェクターとしてはたらいてもよく、または細胞死滅に実際に影響をおよぼすために他の細胞を動員してもよい。抗体は薬物または毒素(化学療法剤、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)にコンジュゲートし、単に標的指向剤としてはたらいてもよい。または、エフェクターは、腫瘍細胞標的と、直接的または間接的のいずれかで相互作用する表面分子を有するリンパ球であってもよい。様々なエフェクター細胞には、細胞毒性T細胞およびNK細胞が含まれる。
さらにもう1つの態様において、第2の処置は、治療用ポリヌクレオチドを第1の化学療法剤の前、後、または同時に投与する第2の遺伝子療法である。遺伝子産物をコードするベクターと共に化学療法剤を送達することで、標的組織に対して組み合わせの抗過剰増殖効果がある。
がんを有する人の約60%が、ある種の手術を受けることになり、それには予防的、診断的もしくは病期分類、治癒的、および緩和的手術が含まれる。治癒的手術は、本発明の処置、化学療法、放射線療法、ホルモン療法、遺伝子療法、免疫療法および/または代替療法などの他の治療と共に使用し得るがん処置である。治癒的手術は、がん性組織の全て、または一部を物理的に除去し、切り出し、かつ/または破壊する切除術を含む。腫瘍切除術とは、腫瘍の少なくとも一部の物理的除去を意味する。腫瘍切除術に加えて、手術による処置には、レーザー手術、冷凍手術、電気手術、および顕微鏡制御下での手術(モース術)が含まれる。本発明は表在性がん、前がん、または付随的な量の正常組織の除去とともに用い得ることが、さらに企図される。
A549=ヒト肺胞基底上皮腺がん細胞
ATP=アデノシン三リン酸
β-lap=β-ラパコン
DHE=ジヒドロエチジウム
DNQ=デオキシニボキノン
DNQd=デオキシニボキノンの任意の類縁体または誘導体
ELISA=酵素結合免疫吸着検定法
h=時間
H596=[NCI-H596] ヒト肺腺扁平上皮癌細胞株
HT1080=霊長類線維肉腫細胞株
LD50=死亡を引き起こす確立50%を有する致死用量
LD90=死亡を引き起こす確立90%を有する致死用量
LD100=死亡を引き起こす確立100%を有する致死用量
MCF-7=ヒト乳腺癌細胞株
MDA-MB-231=ヒト乳がん細胞株
MIA-PaCa2=膵臓がん細胞株
mins=分
NADH=ニコチンアミドアデニンジヌクレオチド
NQO1=NAD(P)H:キノンオキシドレダクターゼ1
NSCLC=非小細胞肺がん細胞
OCR=酸素消費速度
p53=腫瘍抑制タンパク質
PC-3=ヒト前立腺がん細胞株
ROS=反応性酸素種
±SE=標準誤差
siRNA=低分子干渉リボ核酸
shRNA=低分子ヘアピン型リボ核酸
μM=マイクロモル濃度
nM=ナノモル濃度
μmol=マイクロモル
DNA塩基除去(BER)またはSSB修復プロセスをPARP1阻害剤で阻止することにより、膵臓がんなどのNQO1+過剰発現がんに対するNQO1生体内活性化可能薬の有効性を劇的に高め、その必要な用量を著しく下げることができる。これらの方法を示すために、インビトロでNQO1+対NQO1-またはshRNAノックダウン膵臓がん細胞に対し、BERまたはSSB修復の阻害がNQO1生体内活性化可能薬と相乗作用することを機構的に示すための実験を行った。加えて、インビボでNQO1生体内活性化可能薬の有効性を増強するためにMeOXまたはPARP1阻害剤を最適化するための実験も行った。したがって、DNA修復阻害剤(例えば、BERおよびPARP1阻害剤)を用いての併用療法を、腫瘍特異的アプローチとして用いることができる。
IB-DNQ(DNQ-87;図12)はβ-ラパコンよりもはるかに低い用量、および親DNQ化合物と同等の用量で作用する。図13に示すとおり、これは乳がん細胞に対してNQO1依存的様式で、ならびに三重陰性乳がん細胞に対して有効である。β-ラパコン(β-lap)とは異なり、DNQ87の有効性はNQO1依存的様式で増大し、治療ウィンドウはより大きい(図14)。図15に示すとおり、DNQ87は細胞死を引き起こし、これはジクマロール、カタラーゼ、およびBAPTA-AM(カルシウムキレート化剤)によって、上位からこの順に阻止され得(A)、NQO1生体内活性化可能薬によって引き起こされる細胞死の提唱される経路と一致する(B)。(C)DNQ87曝露によって引き起こされるPARP1過剰活性化を、PAR-PARP1形成によって測定し、μ-カルパイン媒介性p53切断(C)および細胞死中のPARP1の約60kDaのタンパク質分解性断片への非定型的切断(D)によって強調された。ガンマ-H2AX、ATMのser1981でのリン酸化、およびDNA-PKcsのThr1892部位でのリン酸化によりモニターして、DNQ87は遅延様式でDNA損傷(DNA二本鎖切断)も引き起こした(図16)。これらのデータは、DSB修復阻害剤を用いてDNQ87致死性を増強し得ることも示している。重要なことに、アルカリ性溶出は広範なDNA塩基損傷およびDNA一本鎖切断を示すが、中性コメット検定により評価した同じ細胞はDNA損傷を示さない。
NOD/SCID:100万個の3LL-Luc細胞を各マウスに注射し、2日後にIVを開始した。
*パイロット実験により、NOD/SCID、iv、1日おきに1×、5回注射における新しい実質的MTDが示される。
以下の製剤は、本明細書に記載の式の化合物(例えば、DNQもしくはDNQ化合物、またはβ-Lapもしくはβ-Lap誘導体)、本明細書に具体的に開示される化合物、その薬学的に許容される塩もしくは溶媒和物、または本明細書に記載の化合物の組み合わせ(以下「化合物X」と呼ぶ)の治療的または予防的投与のために使用しうる代表的な薬学的剤形を例示する。
Claims (9)
- NQO1生体内活性化可能薬がDNQである、請求項1記載の薬学的組成物。
- NQO1生体内活性化可能薬がDNQ-87である、請求項1記載の薬学的組成物。
- DNA損傷剤の投与をさらに含む、請求項1〜3のいずれか一項記載の薬学的組成物。
- さらなる化学療法剤または放射線療法と組み合わせて使用するための、請求項1〜4のいずれか一項記載の薬学的組成物。
- がん細胞がNQO1レベルの上昇を有する、請求項1〜5のいずれか一項記載の薬学的組成物。
- がん細胞が固形腫瘍の形態である、請求項6記載の薬学的組成物。
- がん細胞が非小細胞肺がん細胞、前立腺がん細胞、膵臓がん細胞、乳がん細胞、頭頸部がん細胞、または結腸がん細胞である、請求項7記載の薬学的組成物。
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Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4906562A (en) * | 1984-12-21 | 1990-03-06 | Oncogen | Monocolonal antibodies and antigen for human non-small cell lung carcinomas |
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US6833373B1 (en) | 1998-12-23 | 2004-12-21 | G.D. Searle & Co. | Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
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US6635677B2 (en) | 1999-08-13 | 2003-10-21 | Case Western Reserve University | Methoxyamine combinations in the treatment of cancer |
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AU2003226408B2 (en) * | 2002-04-15 | 2007-06-14 | Sloan-Kettering Institute For Cancer Research | Combination therapy for the treatment of cancer |
AU2003228666A1 (en) * | 2002-04-23 | 2003-11-10 | Case Western Reserve University | Lapachone delivery systems, compositions and uses related thereto |
JP2006522088A (ja) | 2003-03-31 | 2006-09-28 | ファイザー・インク | ポリ(adp−リボース)ポリメラーゼの三環系阻害剤の塩 |
US8614228B2 (en) * | 2004-08-11 | 2013-12-24 | Arqule, Inc. | Quinone prodrug compositions and methods of use |
WO2006024545A1 (en) * | 2004-09-03 | 2006-03-09 | Stichting Voor De Technische Wetenschappen | Fused bicyclic natural compounds and their use as inhibitors of parp and parp-mediated inflammatory processes |
EP1986641A1 (en) * | 2006-02-09 | 2008-11-05 | Spectrum Pharmaceuticals, Inc. | Bladder cancer treatment involving determination of tumor enzyme level |
US8017618B2 (en) | 2006-12-29 | 2011-09-13 | Tracon Pharmaceuticals, Inc. | Antifolate agent combinations in the treatment of cancer |
EP2217227B1 (en) | 2007-11-12 | 2013-08-21 | BiPar Sciences, Inc. | Treatment of breast cancer with 4-iodo-3-nitrobenzamide in combination with anti-tumor agents |
US20090275608A1 (en) * | 2008-02-04 | 2009-11-05 | Bipar Sciences, Inc. | Methods of diagnosing and treating parp-mediated diseases |
NZ601788A (en) * | 2010-03-01 | 2014-11-28 | Myrexis Inc | Inhibitors of nicotinamide phosphoribosyltransferase and therapeutic uses thereof |
WO2011130689A1 (en) | 2010-04-15 | 2011-10-20 | Tracon Pharmaceuticals, Inc. | Potentiation of anti-cancer activity through combination therapy with ber pathway inhibitors |
US9081428B2 (en) * | 2010-04-23 | 2015-07-14 | Psion Inc. | Apparatus and method for impact resistant touchscreen display module |
EP2975399B1 (en) * | 2010-09-15 | 2022-05-11 | Almac Diagnostic Services Limited | Molecular diagnostic test for cancer |
PL2619331T3 (pl) | 2010-09-22 | 2018-10-31 | The Board Of Regents Of The University Of Texas System | Sposoby leczenia nowotworu obejmujące ukierunkowanie na nqo1 |
US20120142650A1 (en) * | 2010-12-07 | 2012-06-07 | John Hollingsworth | Method for treating lung disease |
US20120208767A1 (en) * | 2011-02-14 | 2012-08-16 | University Of Maryland, Baltimore | Method to Detect or Treat Painful Bladder Syndrome based on Relation to Quinone Oxidoreductase 1 |
EP3498998A1 (en) * | 2011-09-12 | 2019-06-19 | Cummins Emission Solutions, Inc. | Exhaust gas aftertreatment device |
TR201810152T4 (tr) | 2011-10-14 | 2018-08-27 | The Board Of Regents Of The Universty Of Texas System | Bileşikler ve anti-tümör nqo1 substratları. |
PL2984184T3 (pl) * | 2013-04-09 | 2021-06-14 | The Board Of Trustees Of The University Of Illinois | Stosowanie DNQ lub DNQ-87 w połączeniu z inhibitorem PARP1 do leczenia nowotworu |
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JP2019163309A (ja) * | 2013-04-09 | 2019-09-26 | ザ ボード オブ トラスティーズ オブ ザ ユニバーシティ オブ イリノイ | 腫瘍選択的併用療法 |
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MX2015014282A (es) | 2016-07-20 |
JP2019163309A (ja) | 2019-09-26 |
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CN111481551B (zh) | 2023-06-09 |
CN111481551A (zh) | 2020-08-04 |
AU2020202453A1 (en) | 2020-05-28 |
EP2984184B1 (en) | 2020-11-25 |
AU2014251043A1 (en) | 2015-11-05 |
CA2909091A1 (en) | 2014-10-16 |
MX2021000828A (es) | 2021-03-25 |
JP2016516775A (ja) | 2016-06-09 |
ZA201507755B (en) | 2019-11-27 |
ES2853973T3 (es) | 2021-09-20 |
US10576096B2 (en) | 2020-03-03 |
EP2984184A1 (en) | 2016-02-17 |
AU2014251043B2 (en) | 2020-01-16 |
WO2014168991A1 (en) | 2014-10-16 |
HUE052930T2 (hu) | 2021-05-28 |
JP6719620B2 (ja) | 2020-07-08 |
CA2909091C (en) | 2021-11-02 |
PT2984184T (pt) | 2021-02-24 |
US20180099002A1 (en) | 2018-04-12 |
CN105658809B (zh) | 2020-03-27 |
PL2984184T3 (pl) | 2021-06-14 |
DK2984184T3 (da) | 2021-03-01 |
US20160030457A1 (en) | 2016-02-04 |
AU2020202453B2 (en) | 2022-04-14 |
EP2984184A4 (en) | 2016-11-30 |
US10272099B2 (en) | 2019-04-30 |
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