JP4789414B2 - 可溶化トポイソメラーゼ毒性剤 - Google Patents
可溶化トポイソメラーゼ毒性剤 Download PDFInfo
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- JP4789414B2 JP4789414B2 JP2003552222A JP2003552222A JP4789414B2 JP 4789414 B2 JP4789414 B2 JP 4789414B2 JP 2003552222 A JP2003552222 A JP 2003552222A JP 2003552222 A JP2003552222 A JP 2003552222A JP 4789414 B2 JP4789414 B2 JP 4789414B2
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- 238000007918 intramuscular administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
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- 238000002372 labelling Methods 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
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- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
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- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
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- 125000003367 polycyclic group Chemical group 0.000 description 1
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- 150000003077 polyols Chemical class 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
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- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 229940023144 sodium glycolate Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
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- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 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
- 210000001541 thymus gland Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- 229960002622 triacetin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Paper (AREA)
Description
DNA−トポイソメラーゼは、細胞の核に存在している酵素であり、この場所では、それらは、DNA鎖の破断および再結合を触媒し、DNAの位相幾何学的な状態を制御する。最近の研究はまた、トポイソメラーゼがRNA転写中のテンプレートスーパーコイリングにも関与していることを示唆している。2種類の主な哺乳動物トポイソメラーゼが存在している。DNA−トポイソメラーゼ−Iは、過渡的な一本鎖破断−結合サイクルを実行することにより、二本鎖DNAの位相幾何学的な状態の変化を触媒する。対照的に、哺乳動物トポイソメラーゼIIは、過渡的な酵素架橋二本鎖破断を引き起こすことに続いて、ストランドパッシングおよびリシーリングにより、DNAのトポロジーを変える。哺乳動物トポイソメラーゼIIは、さらに、IIα型およびIIβ型に分類される。トポイソメラーゼ毒である試薬に付随した抗腫瘍活性は、それらが酵素−DNA開裂可能錯体を安定化する能力に関連している。この酵素−DNA錯体の薬剤誘発安定化は、この酵素を細胞毒へと効果的に変換する。
出願人は、溶解性が改良されトポイソメラーゼIおよび/またはトポイソメラーゼIIIに対して阻害活性も有する化合物を発見した。従って、本発明は、式Iの化合物またはそれらの薬学的に受容可能な塩である本発明の化合物を提供する:
AおよびBは、別個に、NまたはCHである;
Wは、NまたはCHである;
R3およびR4は、それぞれ別個に、H、(C1〜C6)アルキルまたは置換(C1〜C6)アルキルであるか、またはR3およびR4は、一緒になって、=O、=S、=NHまたは=N−R2である;
YおよびZは、別個に、ヒドロキシ、(C1〜C6)アルコキシ、置換(C1〜C6)アルコキシ、(C1〜C6)アルカノイルオキシ、置換(C1〜C6)アルカノイルオキシ、−O−P(=O)(OH)2または−O−C(=O)NRcRdである;またはYおよびZは、それらが結合する環原子と一緒になって、5個〜7個の環原子を備えたアルキレンジオキシ環を形成する;
R1は、1個またはそれ以上(例えば、1個、2個、3個または4個)の可溶化基Rzで置換された(C1〜C6)アルキルである;
R2は、(C1〜C6)アルキルまたは置換(C1〜C6)アルキルである;そして
RcおよびRdは、それぞれ別個に、(C1〜C6)アルキルまたは置換(C1〜C6)アルキルである;またはRcおよびRdは、それらが結合する窒素と一緒になって、N’−{(C1〜C6)アルキル}ピペラジノ環、ピロリジノ環またはピペリジノ環を形成し、該環は、必要に応じて、1個またはそれ以上のアリール、ヘテロアリールまたは複素環で置換できる。
特に明記しない限り、以下の定義を使用する。
先に記述されたように、T7発現系を使用して、E.Coliにおいて、ヒトトポイソメラーゼIを発現し、そして組換え融合タンパク質として単離した(Makhey,D.ら、Bioorg.Med.Chem.,2000,8,1−11を参照)。先に報告されたようにして、子ウシ胸腺から、DNAトポイソメラーゼIを精製した(Maniatis,T.,ら、J.Molecular Cloning,a Laboratory Manual,Cold Spring Harbor Laboratory,Cold Spring Harbor,New York,149−185)。記述されたように、アルカリ溶解方法に続いて、フェノール除タンパクおよびCsCl/エチジウム等密度遠心分離により、プラスミドYepGも精製した(Maniatis,T.;Fritsch,E.F.;Sambrook,J.Molecular Cloning,a Laboratory Manual;Cold Spring Harbor Laboratory:Cold Spring Harbor,NY 1982;pp149−185を参照)。先に記述されたように、制限酵素での消化に続いて、Klenowポリメラーゼでのエンドフィリング(end−filling)により、このブラスミドのエンドラベリング(end−labeling)を達成した(Liu,L.F.;Rowe,T.C.;Yang,L.;Tewey,K.M.;Chen,G.L.,J.Biol.Chem.1983,258,15365を参照)。先に記述されたように、開裂アッセイを実行した(B.Gattoら、Cancer Res.,1996,56,2795−2800を参照)。この薬剤およびDNAを、トポイソメラーゼIの存在下にて、37℃で、30分間インキュベートした。これらのゲルの展開後、典型的には、24時間の露出を使用して、DNA断片化の範囲を概略するオートラジオグラムを得た。トポイソメラーゼI媒介DNA開裂値は、REC(Relative Effective Concentration)、すなわち、2,3−ジメトキシ−8,9−メチレンジオキシベンゾ[i]フェナントリジンに対する濃度として報告し、その値は、任意に、1.0であると想定され、これらは、ヒトトポイソメラーゼIの存在下にて、このプラスミドDNAに対して、同じ開裂を生じることができる。相対的効力は、約10%のDNA断片化を誘発するのに必要な薬剤の相対量に基づいている。アッセイは、Dr.L.F.Liu(Department of Pharmacology,The University of Medicine and Dentistry of New Jersey,Robert Wood Johnson Medical School,Piscataway,New Jersey)の指示の下で、実行する。
この細胞毒性は、MTT−マイクロタイタープレートテトラゾリウム細胞毒性アッセイ(MTA)を使用して、決定する。Chen A.Y.ら、Cancer Res.1993,53,1332;Mosmann,T.J.,J.Immunol.Methods 1983,65,55;およびCarmichael,J.ら、Cancer Res.1987,47,936を参照。ヒトリンパ芽球RPMI 8402およびそのカンプトセシン耐性変異株細胞系であるCPT−K5は、Dr.Toshiwo Andohにより提供された(Anchi Cancer Research Institute,Nagoya,Japan)(Andoh,T.;Okada,K,Adv.in Pharmacology 1994,29B,93を参照)。ヒトU−937骨髄白血病細胞およびU−937/CR細胞は、Rubinら、J.Biol.Chem.,1994,269,2433−2439により記述された。この細胞毒性アッセイは、200mLの成長培地にて、2000個の細胞/ウェルを使い、96ウェルマイクロタイタープレートを使用することにより、実行する。細胞は、37℃で、5%CO2にて、懸濁液中で成長し、そしてRPMI培地(これは、10%熱不活性化ウシ胎児血清、L−グルタミン(2mM)、ペニシリン(100U/mL)およびストレプトマイシン(0.1mg/mL)で捕捉した)にて、通常の継代で維持する。IC50を決定するには、細胞は、3〜4日間にわたって、種々の濃度の薬剤に継続的に晒し、MTTアッセイは、4日目の最後で実行した。各アッセイは、任意の薬剤を含まない対照と共に実行する。全てのアッセイは、6個の複製ウェルにて、少なくとも2回実行する。全てアッセイは、Dr.L.F.Liu(Department of Pharmacology,The University of Medicine and Dentistry of New Jersey,Robert Wood Johnson Medical School,Piscataway,New Jersey)の指示の下で、実行する。
以下は、代表的な医薬剤形を示し、これらは、ヒトにおける治療用途または予防用途のための式Iの化合物(「化合物X」)を含有する。
(i)錠剤1 mg/錠剤
「化合物X」 100.0
ラクトース 77.5
ポビドン 15.0
クロスカルメロースナトリウム 12.0
微結晶セルロース 92.5
ステアリン酸マグネシウム 3.0
300.0
(ii)錠剤2 mg/錠剤
「化合物X」 20.0
微結晶セルロース 410.0
デンプン 50.0
グリコール酸ナトリウムデンプン 15.0
ステアリン酸マグネシウム 5.0
500.0
(iii)カプセル mg/カプセル
「化合物X」 10.0
コロイド状二酸化ケイ素 1.5
ラクトース 465.5
予めゼラチン化したデンプン 120.0
ステアリン酸マグネシウム 3.0
600.0
(iv)注射1(1mg/ml) mg/ml
「化合物X」(遊離酸形状) 1.0
二塩基性リン酸ナトリウム 12.0
一塩基性リン酸ナトリウム 0.7
塩化ナトリウム 4.5
1.0N水酸化ナトリウム溶液
(7.0〜7.5にpH調節した) q.s.
注射用の水 q.s.ad 1mL
(v)注射2(10mg/ml) mg/ml
「化合物X」(遊離酸形状) 1.0
一塩基性リン酸ナトリウム 0.3
二塩基性リン酸ナトリウム 1.0
ポリエチレングリコール400 200.0
01N水酸化ナトリウム溶液
(7.0〜7.5にpH調節した) q.s.
注射用の水 q.s.ad 1mL
(vi)注射3(1mg/ml) mg/ml
「化合物X」(遊離塩基形状) 1.0
クエン酸 0.1%
D5W q.s.ad 1mL
(vii)エアロゾル mg/can
「化合物X」 20.0
オレイン酸 10.0
トリクロロモノフルオロメタン 5,000.0
ジクロロジフルオロメタン 10,000.0
ジクロロテトラフルオロエタン 5,000 。
上記処方は、医薬分野で周知の通常の手順により、得られる。
Claims (10)
- Yが、−OCH3である、請求項1に記載の化合物。
- Zが、(C1〜C6)アルコキシである、請求項1〜2のいずれか1項に記載の化合物。
- Zが、OCH3である、請求項1〜2のいずれか1項に記載の化合物。
- R1が、1個またはそれ以上のNRaRb基で置換された(C1〜C6)アルキルである、請求項1〜4のいずれか1項に記載の化合物。
- R1が、1個のNRaRb基で置換されている、請求項1〜4のいずれか1項に記載の化合物。
- R1が、1個またはそれ以上のNH2基で置換された(C1〜C6)アルキルである、請求項1〜4のいずれか1項に記載の化合物。
- R1が、1個〜2個のNH2基で置換された(C1〜C6)アルキルである、請求項1〜4のいずれか1項に記載の化合物。
- R1が、1個の置換NH2基である、請求項1〜4のいずれか1項に記載の化合物。
- 化合物13−{2−(ジメチルアミノ)−エチル}−2,3−ジメトキシ−13H−8,10−ジオキサ−6,13−ジアザ−シクロペンタ[b]クリセン−12−オン、またはそれらの薬学的に受容可能な塩。
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EP (1) | EP1453507B1 (ja) |
JP (1) | JP4789414B2 (ja) |
KR (1) | KR20040088466A (ja) |
AT (1) | ATE424200T1 (ja) |
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ATE390923T1 (de) * | 2001-11-14 | 2008-04-15 | Univ Rutgers | Topoisomerase-giftmittel |
MXPA04004606A (es) * | 2001-11-14 | 2004-09-10 | Univ Rutgers | Venenos de topoisomerasa solubilizados. |
WO2003041653A2 (en) * | 2001-11-14 | 2003-05-22 | Rutgers, The State University | Cytotoxic agents |
AU2002365161B2 (en) * | 2001-11-14 | 2008-07-03 | Rutgers, The State University | Solubilized topoisomerase poison agents |
AU2003265406A1 (en) * | 2002-08-09 | 2004-02-25 | Edmond J. Lavoie | Nitro and amino substituted topoisomerase agents |
AU2003265405A1 (en) * | 2002-08-09 | 2004-02-25 | Edmond J. Lavoie | Nitro and amino substituted heterocycles as topoisomerase i targeting agents |
US6992089B2 (en) * | 2002-08-09 | 2006-01-31 | Rutgers, The University Of New Jersey | Nitro and amino substituted topoisomerase agents |
CA2510337C (en) * | 2002-11-12 | 2013-01-08 | Rutgers, The State University Of New Jersey | Topoisomerase-targeting agents |
JP2006528691A (ja) | 2003-05-12 | 2006-12-21 | パーデュー・リサーチ・ファウンデーション | 細胞傷害性インデノおよびイソインドロイソキノロン |
US7495100B2 (en) | 2004-05-07 | 2009-02-24 | Purdue Research Foundation | Synthesis of indenoisoquinolines |
EP2403856B1 (en) | 2009-03-06 | 2012-12-19 | Rutgers, The State University of New Jersey | Methylenedioxybenzo [i]phenanthridine derivatives used to treat cancer |
WO2010127363A1 (en) | 2009-05-01 | 2010-11-04 | Rutgers, The State University Of New Jersey | Toposiomerase inhibitors |
CN102993094B (zh) * | 2011-09-08 | 2014-07-23 | 中国石油大学(北京) | 一种四氢喹啉衍生物的合成方法 |
JP2019515025A (ja) | 2016-04-04 | 2019-06-06 | ラトガース ザ ステイト ユニバーシティー オブ ニュージャージー | トポイソメラーゼ毒 |
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AU2003265405A1 (en) * | 2002-08-09 | 2004-02-25 | Edmond J. Lavoie | Nitro and amino substituted heterocycles as topoisomerase i targeting agents |
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WO2003051289A2 (en) | 2003-06-26 |
EP1453507B1 (en) | 2009-03-04 |
US20100240664A1 (en) | 2010-09-23 |
CA2467279A1 (en) | 2003-06-26 |
US6987109B2 (en) | 2006-01-17 |
MXPA04004607A (es) | 2004-09-10 |
DE60231426D1 (de) | 2009-04-16 |
KR20040088466A (ko) | 2004-10-16 |
WO2003051289A3 (en) | 2003-12-11 |
EP1453507A2 (en) | 2004-09-08 |
AU2002365161B2 (en) | 2008-07-03 |
US20060058306A1 (en) | 2006-03-16 |
AU2002365161A1 (en) | 2003-06-30 |
JP2005511762A (ja) | 2005-04-28 |
US20050009826A1 (en) | 2005-01-13 |
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