JP6317742B2 - キノン化合物及びがんの治療のためのその使用 - Google Patents
キノン化合物及びがんの治療のためのその使用 Download PDFInfo
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- JP6317742B2 JP6317742B2 JP2015524762A JP2015524762A JP6317742B2 JP 6317742 B2 JP6317742 B2 JP 6317742B2 JP 2015524762 A JP2015524762 A JP 2015524762A JP 2015524762 A JP2015524762 A JP 2015524762A JP 6317742 B2 JP6317742 B2 JP 6317742B2
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- NYDXNILOWQXUOF-GXKRWWSZSA-L pemetrexed disodium Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-GXKRWWSZSA-L 0.000 description 1
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- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
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- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 238000012956 testing procedure Methods 0.000 description 1
- QIWDGSYHBCMXSI-UHFFFAOYSA-J tetrasodium;(2-methyl-4-phosphonatooxynaphthalen-1-yl) phosphate;hexahydrate Chemical compound O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].C1=CC=CC2=C(OP([O-])([O-])=O)C(C)=CC(OP([O-])([O-])=O)=C21 QIWDGSYHBCMXSI-UHFFFAOYSA-J 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 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
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Images
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
- C07D203/14—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom with carbocyclic rings directly attached to the ring nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Description
n=2、3、4、5、6又は7であり、
R1は、水素、エタノイル、プロパノイル、ブタノイル、又は1つ以上のC1〜10アルキル、C1〜10アルコキシ、ヒドロキシ、ハロゲン、ニトロ又はアミノ基で場合により置換されたベンゾイルであり、
R2は、メチル、エチル、又は1つ以上のC1〜10アルキル、C1〜10アルコキシ、ヒドロキシ、ハロゲン、ニトロ又はアミノ基で場合により置換されたフェニルである)
によって表される化合物並びにその塩及び/又は溶媒和物、並びにそのような化合物を用いた治療の方法に関する。
n=3、4、5、6又は7であり、
R1は、水素、エタノイル、プロパノイル、ブタノイル、又は1つ以上のC1〜10アルキル、C1〜10アルコキシ、ヒドロキシ、ハロゲン、ニトロ又はアミノ基で場合により置換されたベンゾイルであり、
R2は、メチル、エチル、又は1つ以上のC1〜10アルキル、C1〜10アルコキシ、ヒドロキシ、ハロゲン、ニトロ又はアミノ基で場合により置換されたフェニルである)
によって表される化合物又はその塩及び/若しくは溶媒和物を提供する。
本発明の化合物、医薬組成物及び医学的使用は、DT-ジアホラーゼ(DTD)、すなわち当技術分野においては別名NQO1及びNAD(P)H:キノン受容体オキシドレダクターゼ1(EC1.6.99.2)としても公知の酵素を過剰発現するがんの治療にとりわけ適している。いかなる特定の理論にも拘束されることを望むものではないが、DTDを過剰発現するがん細胞は、比較的不活性なキノンプロドラッグをがん細胞内での酵素的二電子還元により選択的に活性化させて強力なDNA架橋剤であるヒドロキノンを生成し、これががん細胞に対して細胞傷害性を有することになると一般に考えられている。この治療的用途の選択性は、DTDが正常細胞と比較して種々のヒト腫瘍において過剰発現されることから達成でき、そのような腫瘍としては、脳のがん、白血病、非小細胞肺がん、結腸がん、CNSがん、メラノーマ、卵巣がん、腎臓がん、前立腺がん及び乳がんが挙げられる(Zappaら、J.Histochem.Cytochem.、49、1187〜1188ページ、2001、Tudorら、Anti-Cancer Drugs、16、381〜391ページ、2005、Dansonら、Annals of Oncology、22、1653〜1660ページ、2011)。がん細胞によるDTDの過剰発現は、細胞の野生型表現型の結果であることが一般に好ましい。代替的又は追加的に、DTDの過剰発現は、DTDをコードする核酸を用いて標的がん細胞を形質転換させることによって生じさせてもよい(Dansonら、上記文献を参照のこと)。
本明細書において開示する、がんの治療のための本発明の化合物は、単独で投与してもよいが、一般には、本化合物を、1種以上の薬学的に許容される担体、アジュバント、賦形剤、希釈剤、充填剤、緩衝液、安定化剤、保存剤、滑沢剤、又は当業者に周知の他の材料、及び、他の治療的又は予防的な薬剤を場合により追加で含む医薬組成物の形態で提供することが好ましい。医薬組成物の成分の例は、Remington's Pharmaceutical Sciences、第20版、2000、Lippincott、Williams & Wilkins発行に記載されている。
がんの治療(treatment cancer)のための本明細書において開示する薬剤を含む組成物は、標準的な化学療法薬投与法と組み合わせて、又は放射線療法と共に、本明細書に記載の方法で使用してもよい。他の化学療法剤の例としては、アムサクリン(Amsidine)、ブレオマイシン、ブスルファン、カペシタビン(Xeloda)、カルボプラチン、カルムスチン(BCNU)、クロラムブシル(Leukeran)、シスプラチン(シスプラチナム)、クラドリビン(Leustat)、クロファラビン(Evoltra)、塩化コバルト、クリサンタスパーゼ(Erwinase)、シクロホスファミド、シタラビン(ARA-C)、ダカルバジン(DTIC)、ダクチノマイシン(アクチノマイシンD)、ダウノルビシン、ドセタキセル(Taxotere)、ドキソルビシン、エピルビシン、エトポシド(Vepesid、VP-16)、フルダラビン(Fludara)、フルオロウラシル(5-FU)、ゲムシタビン(Gemzar)、ヒドロキシウレア(ヒドロキシカルバミド、Hydrea)、イダルビシン(Zavedos)、イホスファミド(Mitoxana)、イリノテカン(CPT-11、Campto)、ロイコボリン(フォリン酸)、リポソーム化ドキソルビシン(Caelyx、Myocet)、リポソーム化ダウノルビシン(DaunoXome(登録商標))、ロムスチン、メルファラン、メルカプトプリン、メスナ、メトトレキセート、マイトマイシン、ミトキサントロン、オキサリプラチン(Eloxatin)、パクリタキセル(Taxol)、ペメトレキセド(Alimta)、ペントスタチン(Nipent)、プロカルバジン、ラルチトレキセド(Tomudex(登録商標))、ストレプトゾシン(Zanosar(登録商標))、テガフールウラシル(Uftoral)、テモゾロミド(Temodal)、テニポシド(Vumon)、チオテパ、チオグアニン(6-TG)(Lanvis)、トポテカン(Hycamtin)、トレオスルファン、ビンブラスチン(Velbe)、ビンクリスチン(Oncovin)、ビンデシン(Eldisine)及びビノレルビン(Navelbine)が挙げられる。好ましくは、他の治療剤は、相加又は相乗効果をもたらすように選択される。
in vivoでの投与は、治療過程の全体を通して、単回用量の形態で、又は持続的に、又は間欠的に(例えば、適切な間隔をおいて分割用量の形態で)、行うことができる。投与の最も有効な手段及び用量を決定する方法は、当業者に周知であり、治療に使用される製剤、治療の目的、治療しようとする標的細胞、及び治療しようとする対象によって変更されると予想される。単回又は複数回投与は、治療担当医が選択した用量レベル及びパターンで実行することができる。
Es5の合成
Rf0.52(SiO2、Hex:EtOAc=3:1)。
融点80〜82℃(文献では81〜82℃(Reedら、JACS、120(38)、9729〜9734ページ、1998)。
1H NMR (400MHz, CDCl3) 2.12 (3H, s, CH3), 3.72 (3H, s, OCH3), 3.75 (3H, s, OCH3), 6.60 (1H, s, ArH), 7.10 (1H, s, ArH) ppm.
Rf0.52(SiO2、Hex:EtOAc=1:1)。
1H NMR (400MHz, CDCl3) 2.15 (3H, s, CH3), 2.55 (1H, br s, OH), 6.68 (3H, s, OCH3), 3.78 (3H, s, OCH3), 4.45 (2H, s, CH2), 6.62 (1H, s, ArH), 6.68 (1H, s, ArH) ppm.
Rf0.61(SiO2、Hex:EtOAc=1:1)。
1H NMR (400MHz, CDCl3) 2.08 (3H, s, CH3), 2.18 (3H, s, CH3), 3.72 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.90 (2H, s, CH2), 6.62 (1H, s, ArH), 6.78 (1H, s, ArH) ppm.
Rf0.36(SiO2、Hex:EtOAc=1:1)。
1H NMR (400MHz, CDCl3) 1.98 (2H, m. CH2), 2.10 (3H, s, CH3), 2.24 (3H, s, CH3), 2.68 (2H, m, CH2), 3.82 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.15 (2H, m, CH2), 6.66 (1H, s, ArH), 6.70 (1H, s, ArH) ppm.
13C NMR (400MHz, CDCl3) 14.1, 16.1, 21.0, 26.7, 28.9, 32.3, 55.9, 56.1, 64.3, 112.8, 113.8, 124.9, 127.4, 151.2, 151.4, 171.22.
Rf0.69(SiO2、Hex:EtOAc=1:1)。
1H NMR(400MHz,CDCl3)
Rf0.52(SiO2、Hex:EtOAc=1:1)。
1H NMR(400MHz,CDCl3)
RH1、MeDZQ及びすべてのエステルを、先行技術のプロトコール(Kidscan laboratories)に従って合成し、テスト用にDMSO中の10mMストック溶液として仕上げた。表1は、一部のエステルの構造、及び、トリス緩衝液中でのそれらの半減期を、MDA468及びMDA NQ01細胞株に対するそれらのIC50値に加えて示すものである。
エステル及びその加水分解生成物の安定性を、溶液中で測定した。[50μM Es5、トリス緩衝液(0.1mol dm-3)中、pH7.4]。サンプルは、決まった時間間隔をおいて24時間まで採取し、HPLCによって分析した。検出波長は、330nmであった。クロマトグラフ分析は、30:70のMeOH:トリス緩衝液(0.1mol dm-3、pH7.4)を1ml/分で用いたイソクラチック溶出によって実行した。薬物のクロマトグラフ分離は、内径250mm×4.6mmのHypersil ODSカラムを用いて行われた。
本発明の化合物、例えばEs5及び4-61は、DT-ジアホラーゼを発現する細胞に対して優れた選択性を示す。選択性は、RH1が示すものを超えることがわかった。IC50値は、MTTアッセイを用いて測定した。
エステラーゼ及び細胞抽出物によるEs5の切断及びその活性化を調べた。Es5は、水性緩衝液中では安定であるが、血清中ではゆっくり加水分解された(t1/2=100分)。ブタエステラーゼを用いた実験により、エステラーゼはEs5を速やかに切断してEs5加水分解生成物にすることが示されたが、これは、ブタの脳抽出物を使用した際に繰り返された結果である。DT-ジアホラーゼを発現するMDA468 NQ01細胞株由来の細胞抽出物はこのエステルを速やかに切断したが、一方、DT-ジアホラーゼ欠失(DT-diaphorase null)MDA468細胞株由来の抽出物は、はるかに遅い速度でエステルを切断した。これは、DT-ジアホラーゼを発現する細胞又は腫瘍における活性化の方がより大きい可能性があることを示している。
2種の細胞株MDA NQ01及びMDA468の細胞溶解物由来のエステラーゼによるEs5の分解について調べた。Es5は、MDA NQ01細胞株抽出物中では不安定でありアルコール4.61に分解され、室温ではおよそ160分の半減期を呈した。DTD欠失細胞株MDA468においては、親分子からそのアルコールへの分解は、かなり遅い速度で生じた。
Martinら(Journal of Experimental Medicine.、182、1545〜1556ページ、1995)に記載されている方法に基づいて、本発明の化合物が原因で生じるアポトーシスの誘導を決定した。アポトーシスをアネキシンV結合により測定したところ、DT-ジアホラーゼを発現する細胞においては2時間以内にプログラム細胞死の誘導が生じるのに対し、DT-ジアホラーゼ欠失MDA468細胞においてはこの時点では細胞死がみられないことが示された。アポトーシスレベルの低下は、この細胞株においては4時間後にみられる。これは、Es5が、DT-ジアホラーゼを発現する細胞と発現しない細胞とに対して異なる効果を及ぼすことを示すものである。
DNA損傷については、コメットアッセイを用いて測定し、MDA468 NQ01及びDT-ジアホラーゼ欠失MDA468細胞株を処理した後のEs5がコメットの頭部及び尾部の強度に及ぼす効果を調べた。この実験から、どちらの細胞株についても、H2O2を添加することによりDNA鎖切断が生じ、その結果、頭部と比較して尾部でのDNAの蓄積が増加することが示された。DT-ジアホラーゼを発現する細胞株(NQ01)を10nMのEs5で2時間処理すると、H2O2単独で処理した場合と比較して、頭部におけるDNAの割合が増加した。このことから、DNAはEs5によって架橋されていることが示された。DT-ジアホラーゼ欠失細胞株をEs5で処理した場合には、尾部の強度は低下しなかった。このことは、DT-ジアホラーゼによる活性化がなされなければEs5はDNA架橋剤ではないということを示しており、これが、提唱されるEs5の作用機序である。6時間のインキュベーションを行ったところ、DT-ジアホラーゼ欠失細胞株において架橋が認められた。いかなる特定の理論にも拘束されることを望むものではないが、本発明者らは、これは、DT-ジアホラーゼがあることで起きる二電子還元ではなく、異なる機序、例えば一電子還元が2回行われることによって生じるものであるに違いないと考えている。
表3は、Es5(4.65)の特徴のRH1との比較を示すものであり、それらとシスプラチナム、ドセタキセル、塩化コバルト、エピルビシン、ara-C及びマイトマイシンCとの組合せ指数を記載したものである。比較のために記すと、MMC+塩化コバルトのIC50での組合せ指数は、MDA468では0.443、NQ01細胞では0.239である。表3からわかるように、Es5とシスプラチナムの組合せは、どちらの細胞株においても相乗作用を実証しており、Es5と塩化コバルトの組合せは、どちらの細胞株においても強い相乗作用を実証している。Es5とドセタキセルの組合せは、NQ01に関しては相加作用を示すがMDA468に関しては中等度に阻害効果を示すのに対し、Es5とマイトマイシンCの組合せは、NQ01に関しては相加作用を示し、MDA468に関してはわずかな拮抗作用を示す。
3種のがん細胞株H460、MDA-MB-468-NQ01及びMDA-MB-468-MOCKに対するEs5(4.65)の活性をin vivoで評価した。ここで用いたのは、in vivo中空繊維アッセイ(HFA:hollow fibre assay)であり、繊維は、腹腔内(i.p.)部位及び皮下(s.c.)部位の両方に埋め込んだ。Es5及び対照物質のドキソルビシンを、腹腔内注射(i.p.)による複数回用量として、Es5は0.5mg/kg/日、ドキソルビシンは2.5mg/kg/日で第3日、第4日、第5日及び第6日に投与した。
Es5(4.65)は、多少ボルテックスしながら生理食塩溶液に溶解した。
図1及び図2は、本試験について得られた結果を示すものであり、データは、対応したs.c.又はi.p.非処置対照に対する細胞生存率(%)として表してある。図1には、各細胞株についてグループ化したデータを示してあり、図2には、これを各処置について示してある。
Claims (24)
- n=3である、請求項1又は2に記載の化合物。
- R1が、水素又はエタノイルである、請求項1から3のいずれか一項に記載の化合物。
- 酢酸3-(2,5-ビスアジリジン-1-イル-4-メチル-3,6-ジオキソシクロヘキサ-1,4-ジエニル)-プロピルエステル又は2,5-ビスアジリジン-1-イル-3-(3-ヒドロキシプロピル)-6-メチル-1,4-ベンゾキノン又はその塩若しくは溶媒和物である、請求項1から4のいずれか一項に記載の化合物。
- 請求項1から5のいずれか一項に記載の化合物を含む医薬組成物。
- 1種以上のさらなる治療剤をさらに含む、請求項6に記載の医薬組成物。
- 前記さらなる治療剤が、がんの治療において使用するためのものである、請求項7に記載の医薬組成物。
- 前記さらなる治療剤が、シスプラチナム、ドセタキセル及びマイトマイシンCから選択される、請求項7又は8に記載の医薬組成物。
- 前記さらなる治療剤がシスプラチナムである、請求項7又は8に記載の医薬組成物。
- 前記さらなる治療剤が、ドセタキセル又はマイトマイシンCである、請求項7又は8に記載の医薬組成物。
- 治療方法において使用するための、請求項6から11のいずれか一項に記載の組成物。
- がんを治療する方法において使用するための、請求項6から11のいずれか一項に記載の組成物。
- 前記がんの細胞がDT-ジアホラーゼを過剰発現する、請求項13に記載の、がんを治療する方法において使用するための組成物。
- 前記化合物が、DT-ジアホラーゼによる酵素的還元を受けてヒドロキシキノンを生成する、請求項13又は14に記載の、がんを治療する方法において使用するための組成物。
- 前記がんが、脳のがん、白血病、非小細胞肺がん、結腸がん、CNSがん、メラノーマ、卵巣がん、腎臓がん、前立腺がん又は乳がんである、請求項13から15のいずれか一項に記載の、がんを治療する方法において使用するための組成物。
- 前記方法が、患者からがん細胞のサンプルを得るステップ、前記がん細胞がDT-ジアホラーゼを過剰発現するかどうかを決定するステップ、及び、前記がん細胞がDT-ジアホラーゼを実際に過剰発現する場合には、式Iによって表される化合物で前記患者を治療するステップを含む、請求項13から16のいずれか一項に記載の、がんを治療する方法において使用するための組成物。
- がんを治療する方法において使用するための請求項1から5のいずれか一項に記載の化合物を含む医薬組成物であって、前記方法が、シスプラチナム、ドセタキセル及びマイトマイシンCから選択されるさらなる治療剤での治療を含む、医薬組成物。
- 前記さらなる治療剤がシスプラチナムである、請求項18に記載の、がんを治療する方法において使用するための医薬組成物。
- 前記さらなる治療剤がドセタキセル又はマイトマイシンCである、請求項18に記載の、がんを治療する方法において使用するための医薬組成物。
- 前記がんの細胞が、DT-ジアホラーゼを過剰発現する、請求項18から20のいずれか一項に記載の、がんを治療する方法において使用するための医薬組成物。
- 前記化合物が、DT-ジアホラーゼによる酵素的還元を受けてヒドロキシキノンを生成する、請求項18から21のいずれか一項に記載の、がんを治療する方法において使用するための医薬組成物。
- 前記がんが、脳のがん、白血病、非小細胞肺がん、結腸がん、CNSがん、メラノーマ、卵巣がん、腎臓がん、前立腺がん又は乳がんである、請求項18から22のいずれか一項に記載の、がんを治療する方法において使用するための医薬組成物。
- 前記方法が、患者からがん細胞のサンプルを得るステップ、前記がん細胞がDT-ジアホラーゼを過剰発現するかどうかを決定するステップ、及び、前記がん細胞がDT-ジアホラーゼを実際に過剰発現する場合には、式Iによって表される化合物とさらなる治療剤とで前記患者を治療するステップを含む、請求項18から23のいずれか一項に記載の、がんを治療する方法において使用するための医薬組成物。
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HK1209111A1 (zh) | 2016-03-24 |
MX2015000969A (es) | 2015-09-23 |
BR112015001837A2 (pt) | 2017-07-04 |
GB201213486D0 (en) | 2012-09-12 |
IN2015DN01223A (ja) | 2015-06-26 |
RU2688675C2 (ru) | 2019-05-22 |
AU2013298653A1 (en) | 2015-02-19 |
US20150210639A1 (en) | 2015-07-30 |
CA2880021C (en) | 2020-01-14 |
ES2662917T3 (es) | 2018-04-10 |
JP2015524815A (ja) | 2015-08-27 |
KR20150036215A (ko) | 2015-04-07 |
BR112015001837B1 (pt) | 2021-11-16 |
GB2519004B (en) | 2016-03-30 |
NO2882743T3 (ja) | 2018-05-12 |
CN104583200A (zh) | 2015-04-29 |
EP2882743B1 (en) | 2017-12-13 |
KR102142164B1 (ko) | 2020-08-06 |
CA2880021A1 (en) | 2014-02-06 |
EP2882743A1 (en) | 2015-06-17 |
RU2015105036A (ru) | 2016-09-20 |
DK2882743T3 (en) | 2018-03-12 |
AU2013298653B2 (en) | 2017-10-19 |
WO2014020012A1 (en) | 2014-02-06 |
US9266829B2 (en) | 2016-02-23 |
GB2519004A (en) | 2015-04-08 |
MX361650B (es) | 2018-12-13 |
CN104583200B (zh) | 2017-07-25 |
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