JP2010529038A - 4−アミノキノリン−3−カルボニトリルを使用するイマチニブ耐性白血病の処置 - Google Patents
4−アミノキノリン−3−カルボニトリルを使用するイマチニブ耐性白血病の処置 Download PDFInfo
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- JP2010529038A JP2010529038A JP2010510505A JP2010510505A JP2010529038A JP 2010529038 A JP2010529038 A JP 2010529038A JP 2010510505 A JP2010510505 A JP 2010510505A JP 2010510505 A JP2010510505 A JP 2010510505A JP 2010529038 A JP2010529038 A JP 2010529038A
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- methoxy
- amino
- methoxyphenyl
- dichloro
- leukemia
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K31/33—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
本発明は、薬物耐性癌の処置のための方法に関する。特に、本発明は、イマチニブ耐性BcrAbl陽性白血病を処置するための方法に関する。
イマチニブは、商品名グリベック(GleevacおよびGlivec)の下で販売されており、多くの患者がほぼ90%の5年生存率を達成するのを助けることによって、慢性骨髄性白血病の処置をまず間違いなく変容させてきた。イマチニブ(商品名グリベック(GleevacおよびGlivec)の下で販売されている)に関する患者の部分集合は、チロシンキナーゼにおけるbcrabl変異がしばしば原因で、上記薬物に対する耐性を発生させる。イマチニブでの処置は、上記薬物が、上記チロシンキナーゼタンパク質「BcrAbl」(白血病に特徴的な異常な白血球の過剰増殖を駆動する以上タンパク質)をブロックするので、慢性骨髄性白血病(CML)を有する患者に、ほぼ90%の5年生存率を経験させることを可能にした。しかし、多くの患者は、最終的にはこの処置に対する耐性を発生させてしまう。なぜなら、彼らの癌細胞は、変異および適応することができ、彼らの疾患を再発させてしまうからである。
nは、1、2もしくは3であり;
Xは、NもしくはCHであるが、ただしXがNである場合、nは、2もしくは3であり;
Rは、1〜3個の炭素原子のアルキルであり;
R1は、2,4−ジクロロ−5−メトキシフェニル;2,4−ジクロロフェニル;3,4,5−トリメトキシフェニル;2−クロロ−5−メトキシフェニル;2−メチル−5−メトキシフェニル;2,4−ジメチルフェニル;2,4−ジメチル−5−メトキシフェニル;および2,4−ジクロロ−5−エトキシフェニルからなる群よりされ;そして
R2は、1〜2個の炭素原子のアルキルである。
XはNもしくはCHであり;
nは3であり;
R2およびRはメチルである。
nは、1、2もしくは3であり;
Xは、NもしくはCHであるが、ただしXがNである場合、nは、2もしくは3であり;
Rは、1〜3個の炭素原子のアルキルであり;
R1は、2,4−ジクロロ−5−メトキシフェニル;2,4−ジクロロフェニル;3,4,5−トリメトキシフェニル;2−クロロ−5−メトキシフェニル;2−メチル−5−メトキシフェニル;2,4−ジメチルフェニル;2,4−ジメチル−5−メトキシフェニル;および2,4−ジクロロ−5−エトキシフェニルからなる群より選択され;
R2は、1〜2個の炭素原子のアルキルである。
(一般的方法)
自動化された完全な血液数、鑑別数(異常の手動による確認を伴う)、骨髄形態、および細胞遺伝学を使用して、処置に対する応答を決定する。
イマチニブに対する耐性と関連することが公知の変異は、bcr/abl遺伝子に位置し、以下の通りである。ヌクレオチド位置およびヌクレオチド変化は、対応するアミノ酸変化が括弧に入れて示されかつ括弧に入れて続く:1052T>C(M351T);1075T>K(F359V);1187A>M(H396P);1295T>Y(I432T);1457T>C(F486S);730A>G(M244V);742C>S(L248V);749G>R(G250E);757T>C(Y253H);758A>T(Y253F);763G>R(E255K);787A>R(K263E);817T>A(L273M);944C>T(T315I);949T>C(F317L);および992A>G(N331S)。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[3−(4−メチル−1−ピペラジニル)プロポキシ]−3−キノリンカルボニトリル mp 116−120℃.;MS(ES) m/z 530.2, 532.2(M+1)。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−7−[3−(4−エチル−1−ピペラジニル)プロポキシ]−6−メトキシ−3−キノリンカルボニトリル; mp 102−104℃.;MS(ES) m/z 544.3, 546.4(M+1)。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[2−(4−メチル−1−ピペラジニル)エトキシ]−3−キノリンカルボニトリル mp 165−167℃.;MS(ES) m/z 516.0, 518.2(M+1)。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−7−[2−(4−エチル−1−ピペラジニル)エトキシ−]−6−メトキシ−3−キノリンカルボニトリル mp 101−105℃.; MS (ES) m/z 530.4, 532.4 (M+1)。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]−3−キノリンカルボニトリル mp 200−202℃.,MS 501.3(M+H)+, C25H26Cl2N4O3−0.8H2Oについての分析, 計測値:C,58.21; H,5.39; N,10.86, 実測値: C,58.19; H,5.23; N,10.67。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[2−(1−メチルピペリジン−4−イル)エトキシ]−3−キノリンカルボニトリル mp 190−191℃.,MS 515.19 (M+H)+, C26H28Cl2N4O3−1.0H2Oについての分析, 計算値:C,58.53; H,5.67; N,10.50, 実測値: C,58.65; H,5.57; N,10.34。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[3−(1−メチルピペリジン−4−イル)プロポキシ]キノリン−3−カルボニトリル mp 144−145℃.;質量分析 529.2 (ES+)。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−7−[(1−エチルピペリジン−4−イル)メトキシ]−6−メトキシキノリン−3−カルボニトリル mp 192−195℃.;質量分析 515.2 (ES+)。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[3−(4−メチルピペラジン−1−イル)プロポキシ]キノリン−3−カルボニトリル mp 137−138℃.,MS 542.0 (M−H)−, C27H31Cl2N5O3−−0.6H2Oについての分析, 計算値: C,58.40; H,5.84; N,12.61, 実測値: C,58.31; H,5.71; N,12.43。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]キノリン−3−カルボニトリル mp 182−186℃.,MS 513.0 (M−H)−, C26H28Cl2N4O3−−1.4H2Oについての分析 計算値: C,57.76; H,5.74; N,10.36, 実測値: C,57.65; H,5.43; N,10.15。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[3−(4−エチルピペラジン−1−イル)プロポキシ]キノリン−3−カルボニトリル mp 127−130℃., MS 558.3 (M+H)+, C28H33Cl2N5O3−−1.5H2Oについての分析, 計算値: C,57.44; H,6.20; N,11.96, 実測値: C,57.44; H,6.24; N,11.79。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[3−(1−メチルピペリジン−4−イル)プロポキシ]キノリン−3−カルボニトリル mp 148−151℃. 543.2(M+H)+, Analysis for C28H32Cl2N4O−3−−1.8H2O, 計算値: C,58.39; H,6.23; N,9.73, 実測値: C,58.40; H,6.16; N,9.64。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[2−(4−メチル−1−ピペラジニル)エトキシ]キノリン−3−カルボニトリル mp 141−143℃.,MS 530.2 (M+H)+, C26H29Cl2N5O3についての分析, 計算値: C,58.87; H,5.51; N,13.20, 実測値: C,58.48; H,5.45; N,12.95。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[2−(1−メチルピペリジン−4−イル)エトキシ]キノリン−3−カルボニトリル mp 174−176℃.,MS 529.1(M+H)+, C27H30Cl2N4O3についての分析, 計算値: C,61.25; H,5.71; N,10.58, 実測値: C,61.40; H,5.84; N,10.35。
4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[3−(4−プロピル−1−ピペラジニル)プロポキシ]−3−キノリンカルボニトリル 1℃.; MS (ES) m/z 558.2, 560.2 (M+1)。
4−[(2,4−ジクロロフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ−]−3−キノリンカルボニトリル mp 224−225℃.,MS 469.0 (ES−)。
6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]−4−[(3,4,5−トリメトキシフェニル)アミノ]キノリン−3−カルボニトリル mp>245℃.; HRMS (M+H)+ 計算値 493.24455, 実測値 493.24311。
4−[(2−クロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)m−エトキシ]キノリン−3−カルボニトリル mp 106−108℃., MS 467.2(ES+)。
6−メトキシ−4−[(5−メトキシ−2−メチルフェニル)アミノ]−7−[(1−メチルピペリジン−4−イル)m−エトキシ]キノリン−3−カルボニトリル mp>250℃.,MS 445.2 (ES−)。
4−[(2,4−ジメチルフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ−]キノリン−3−カルボニトリル mp 190−191℃.,MS 429.2 (ES−)。
6−メトキシ−4−[(5−メトキシ−2,4−ジメチルフェニル)アミノ]−7−[(1−メチルピペリジン−4−イル)メトキシ]キノリン−3−カルボニトリル mp 160−162℃.,MS 461.3 (ES+)。
4−[(2,4−ジクロロ−5−エトキシフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]キノリン−3−カルボニトリル
(実施例24)
BcrAbl陽性白血病に罹患しかつイマチニブでの処置に対して耐性のヒト患者の群を、SKI−606で、1週間〜1年超の間に及ぶ期間にわたって処置した。
表2は、表1で上記に記載される変異に対するさらなる応答者について集めた追跡データ、ならびにさらなるbcrabl変異に対する応答者および非応答者を表す。
Claims (25)
- イマチニブに耐性の被験体におけるBcrAbl陽性白血病を処置するための方法であって、該方法は、治療上有効な量の、以下の式の化合物またはその薬学的に受容可能な塩:
nは、1、2もしくは3であり;
Xは、NもしくはCHであるが、ただし、XがNである場合、nは2もしくは3であり;
Rは、1〜3個の炭素原子のアルキルであり;
R1は、2,4−ジクロロ−5−メトキシフェニル;2,4−ジクロロフェニル;3,4,5−トリメトキシフェニル;2−クロロ−5−メトキシフェニル;2−メチル−5−メトキシフェニル;2,4−ジメチルフェニル;2,4−ジメチル−5−メトキシフェニル;および2,4−ジクロロ−5−エトキシフェニルからなる群より選択され;そして
R2は、1〜2個の炭素原子のアルキルである、
方法。 - 前記化合物は、以下の式の化合物もしくはその薬学的に受容可能な塩である、請求項1に記載の方法:
nは、2〜3の整数であり;
Xは、NもしくはCHであり;
Rは、1〜3個の炭素原子のアルキルであり;
R1は、2,4−ジクロロ−5−メトキシフェニル;2,4−ジクロロフェニル;3,4,5−トリメトキシフェニル;2−クロロ−5−メトキシフェニル;2−メチル−5−メトキシフェニル;2,4−ジメチルフェニル;2,4−ジメチル−5−メトキシフェニル;および2,4−ジクロロ−5−エトキシフェニルからなる群より選択され;そして
R2は、1〜2個の炭素原子のアルキルである、
方法。 - 前記化合物は、以下の式の化合物もしくはその薬学的に受容可能な塩である、請求項1に記載の方法:
ここで、
Xは、NもしくはCHであり;
nは3であり;
R2およびRはメチルである、
方法。 - R2はメチルである、請求項1もしくは2に記載の方法。
- XはNである、請求項1〜3のいずれか1項に記載の方法。
- XはCHである、請求項1〜3のいずれか1項に記載の方法。
- 前記化合物は、4−[(2,4−ジクロロ−5−メトキシ−フェニル)アミノ]−6−メトキシ−7−[3−(4−メチル−1−ピペラジニル)プロポキシ]−3−キノリンカルボニトリルである、請求項1に記載の方法。
- 前記化合物は、4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−7−[3−(4−エチル−1−ピペラジニル)プロポキシ]−6−メトキシ−3−キノリンカルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[2−(4−メチル−1−ピペラジニル)エトキシ]−3−キノリンカルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−7−[2−(4−エチル−1−ピペラジニル)エトキシ]−6−メトキシ−3−キノリンカルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]−3−キノリンカルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[2−(1−メチルピペリジン−4−イル)エトキシ]−3−キノリンカルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[3−(1−メチルピペリジン−4−イル)プロポキシ]キノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−7−[(1−エチルピペリジン−4−イル)メトキシ]−6−メトキシキノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)−アミノ]−6−エトキシ−7−[3−(4−メチルピペラジン−1−イル)プロポキシ]キノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]キノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[3−(4−エチルピペラジン−1−イル)プロポキシ]キノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[3−(1−メチルピペリジン−4−イル)プロポキシ]キノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[2−(4−メチル−1−ピペラジニル)エトキシ]キノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−エトキシ−7−[2−(1−メチルピペリジン−4−イル)エトキシ]キノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[3−(4−プロピル−1−ピペラジニル)プロポキシ]−3−キノリンカルボニトリル;もしくはその薬学的に受容可能な塩である、請求項1に記載の方法。
- 前記化合物は、4−[(2,4−ジクロロフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]−3−キノリンカルボニトリル;6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]−4−[(3,4,5−トリメトキシフェニル)アミノ]キノリン−3−カルボニトリル;4−[(2−クロロ−5−メトキシフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]キノリン−3−カルボニトリル;6−メトキシ−4−[(5−メトキシ−2−メチルフェニル)アミノ]−7−[(1−メチルピペリジン−4−イル)−メトキシ]キノリン−3−カルボニトリル;4−[(2,4−ジメチルフェニル)アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]キノリン−3−カルボニトリル;6−メトキシ−4−[(5−メトキシ−2,4−ジメチルフェニル)アミノ]−7−[(1−メチルピペリジン−4−イル)メトキシ]キノリン−3−カルボニトリル;4−[(2,4−ジクロロ−5−エトキシフェニル)−アミノ]−6−メトキシ−7−[(1−メチルピペリジン−4−イル)メトキシ]キノリン−3−カルボニトリル;もしくはその薬学的に受容可能な塩である、請求項1に記載の方法。
- 前記白血病は、慢性骨髄性白血病である、請求項1〜9のいずれか1項に記載の方法。
- 前記白血病は、急性リンパ性白血病である、請求項1〜9のいずれか1項に記載の方法。
- 前記白血病は、1052T>C;1075T>G;1187A>C;1295T>C;1457T>C;730A>G;742C>G;749G>A;757T>C;758A>T;763G>A;787A>G;817T>A;944C>T;949T>C;および992A>Gからなる群より選択される、brlabl遺伝子における耐性関連核酸変異を有する、請求項1〜11のいずれか1項に記載の方法。
- 前記白血病は、M351T;F359V;H396P;I432T;F486S;M244V;L248V;G250E;Y253H;Y253F;E255K;K263E;L273M;T315I;F317L;およびN331Sからなる群より選択される、bcrablタンパク質における耐性関連アミノ酸変異を有する、請求項12に記載の方法。
- 前記被験体に投与される化合物は、SrcインヒビターおよびAblキナーゼインヒビターである、請求項1〜13のいずれか1項に記載の方法。
- 前記化合物は、BcrAbl陽性白血病を処置するために使用される1種以上の他の化合物と組み合わせて、被験体に投与される、請求項1〜14のいずれか1項に記載の方法。
- 前記1種以上の他の化合物は、グリベック(GLEEVEC)を含む、請求項15に記載の方法。
- イマチニブに耐性のBcrAbl陽性白血病を有する被験体の処置のための医薬の製造における、請求項1〜9のいずれか1項に記載の化合物の使用。
- 前記白血病は、慢性骨髄性白血病である、請求項17に記載の化合物の使用。
- 前記白血病は、急性リンパ性白血病である、請求項17に記載の化合物の使用。
- 前記白血病は、1052T>C;1075T>G;1187A>C;1295T>C;1457T>C;730A>G);742C>G;749G>A;757T>C;758A>T;763G>A;787A>G;817T>A;944C>T;949T>C;および992A>Gからなる群より選択される、bcrabl遺伝子における耐性関連核酸変異を有する、請求項17〜19のいずれか1項に記載の化合物の使用。
- 前記白血病は、M351T;F359V;H396P;I432T;F486S;M244V;L248V;G250E;Y253H;Y253F;E255K;K263E;L273M;T315I;F317L;およびN331Sからなる群より選択される、bcrablタンパク質における耐性関連アミノ酸変異を有する、請求項20に記載の化合物の使用。
- 前記被験体に投与される化合物は、SrcインヒビターおよびAblキナーゼインヒビターである、請求項17〜21のいずれか1項に記載の化合物の使用。
- 前記化合物は、BcrAbl陽性白血病を処置するための医薬の製造において、1種以上の他の化合物と組み合わせて使用される、請求項17〜22のいずれか1項に記載の化合物の使用。
- 前記1種以上の他の化合物は、グリベック(GLEEVEC)を含む、請求項23に記載の使用。
- イマチニブに耐性の被験体におけるBcrAbl陽性白血病を処置するための方法であって、該方法は、治療上有効な量の4−[(2,4−ジクロロ−5−メトキシ−フェニル)アミノ]−6−メトキシ−7−[3−(4−メチル−1−ピペラジニル)プロポキシ]−3−キノリンカルボニトリルを該被験体に投与する工程を包含し、ここで該被験体は、M351T;F359V;H396P;I432T;F486S;M244V;L248V;G250E;Y253H;Y253F;E255K;K263E;L273M;T315I;F317L;およびN331Sから選択される、Bcrablタンパク質における少なくとも1つの変異を有する、方法。
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TW200908982A (en) * | 2007-06-01 | 2009-03-01 | Wyeth Corp | Treatment of imatinib resistant leukemia |
CA2829131C (en) | 2011-03-04 | 2018-11-20 | Glaxosmithkline Intellectual Property (No.2) Limited | Amino-quinolines as kinase inhibitors |
TWI547494B (zh) | 2011-08-18 | 2016-09-01 | 葛蘭素史克智慧財產發展有限公司 | 作為激酶抑制劑之胺基喹唑啉類 |
TWI592417B (zh) | 2012-09-13 | 2017-07-21 | 葛蘭素史克智慧財產發展有限公司 | 胺基喹唑啉激酶抑制劑之前藥 |
TW201425307A (zh) | 2012-09-13 | 2014-07-01 | Glaxosmithkline Llc | 作為激酶抑制劑之胺基-喹啉類 |
CN105143208B (zh) | 2013-02-21 | 2017-09-26 | 葛兰素史密斯克莱知识产权发展有限公司 | 作为激酶抑制剂的喹唑啉 |
KR101733665B1 (ko) * | 2015-05-06 | 2017-05-10 | 재단법인 지능형 바이오 시스템 설계 및 합성 연구단 | 진세노사이드 F1 또는 Rg3을 유효성분으로 포함하는 글리벡 내성 백혈병 예방 또는 치료용 약학 조성물 |
KR20220052333A (ko) * | 2019-08-22 | 2022-04-27 | 바이오하벤 테라퓨틱스 리미티드 | 근위축성 측색 경화증 및 관련 장애의 치료를 위한 tdp-43에 결합하는 분자 |
CN115944636A (zh) * | 2022-11-01 | 2023-04-11 | 华南师范大学 | 博舒替尼在抑制i-motif结构上的应用 |
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US6002008A (en) | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
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IL156578A0 (en) * | 2001-01-25 | 2004-01-04 | Bristol Myers Squibb Co | A method for formulating an epothilone analog for pharmaceutical use and pharmaceutical preparations including an epothilone analog |
EP2290056A3 (en) | 2001-10-05 | 2011-06-01 | Novartis AG | Mutated Abl kinase domains |
TWI275390B (en) * | 2002-04-30 | 2007-03-11 | Wyeth Corp | Process for the preparation of 7-substituted-3- quinolinecarbonitriles |
US20050010780A1 (en) * | 2003-07-09 | 2005-01-13 | Kane John Richard | Method and apparatus for providing access to personal information |
JP2008539241A (ja) | 2005-04-25 | 2008-11-13 | ファイザー インコーポレイティッド | ミオスタチンに対する抗体 |
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TW200908982A (en) | 2007-06-01 | 2009-03-01 | Wyeth Corp | Treatment of imatinib resistant leukemia |
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