JP2018501261A - Ras阻害インデニルアセトアミド化合物、組成物、およびその使用 - Google Patents
Ras阻害インデニルアセトアミド化合物、組成物、およびその使用 Download PDFInfo
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- JP2018501261A JP2018501261A JP2017533503A JP2017533503A JP2018501261A JP 2018501261 A JP2018501261 A JP 2018501261A JP 2017533503 A JP2017533503 A JP 2017533503A JP 2017533503 A JP2017533503 A JP 2017533503A JP 2018501261 A JP2018501261 A JP 2018501261A
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- methyl
- acetamide
- inden
- hydroxy
- dimethoxybenzylidene
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Images
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- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
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- C07C309/63—Esters of sulfonic acids
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
Description
本発明は、NIH/NCI補助金番号CA155638およびCA148817のもとの一部支援により行われた。したがって、米国政府は、本発明において一定の権利を有する。
をさらに提供する。
をin vivoまたはin vitroで投与をすることを含み、
を投与することを含み、
をin vivoまたはin vitroで投与することを含み、
を投与することを含み、
本実施例は、本発明の一実施形態による化合物:054、055、056、057、および058の合成を例示する。
(実施例2)
(実施例4)
(実施例5)
(実施例6)
(実施例7)
Claims (19)
- 式Iの化合物:
RおよびR0は、独立して、水素またはヒドロキシルであり;nは、0、1、または2であり;
R1、R2、R3、およびR4のうちの3つは水素であり、1つはハロゲン、アルキル、もしくはアルコキシであるか、またはR1、R2、R3、およびR4のうちの2つは水素であり、2つはアルコキシであり;
R5およびR6は一緒になって、炭素−炭素結合を形成し;R7は、水素であり;R8は、アルキルであり;
YおよびY’は一緒になって、酸素であり;
Xは、NR’R”であり、式中、R’は、ハロゲン、アルキル、ハロアルキル、シアノ、シアノアルキル、ニトロ、ヒドロキシル、アルコキシ、ホルミルオキシ、ヒドロキシアルキル、アルデヒド、アミノ、アルキルアミノ、ジアルキルアミノ、アミノアルキル、アルキルアミノアルキル、メルカプト、およびアルキルメルカプト、アジド、ならびにアルキルスルホニル、アルキルスルフィニル、アルキルスルフィニルオキシ、アルキルスルホニルオキシ、アルキルカルボニルオキシ、カルバメート、カルバミド、アルコキシカルボニル、アルキルアミノカルボニル、アミノカルボニル、およびスルホンアミドから選択される置換もしくは非置換の基のうちの1つまたは複数で置換されたアリールであるか、またはいずれか2つの置換された位置は、アルキレンジオキシ基によって占有されていてもよく;R”は、水素であり;
Eは、置換アリールである);あるいは
その薬学的に許容される塩もしくはそのプロドラッグ、または対応するZもしくはE異性体。 - Eが、ハロゲン、アルキル、ハロアルキル、シアノ、シアノアルキル、ニトロ、ヒドロキシル、アルコキシ、ホルミルオキシ、ヒドロキシアルキル、アルデヒド、アミノ、アルキルアミノ、ジアルキルアミノ、アミノアルキル、アルキルアミノアルキル、メルカプト、アルキルメルカプト、アジド、ならびにアルキルスルホニル、アルキルスルフィニル、アルキルスルフィニルオキシ、アルキルスルホニルオキシ、アルキルカルボニルオキシ、カルバメート、カルバミド、アルコキシカルボニル、アルキルアミノカルボニル、アミノカルボニル、およびスルホンアミドから選択される置換もしくは非置換の基のうちの1つまたは複数で置換されたアリールであるか、またはいずれか2つの置換された位置は、アルキレンジオキシ基によって占有されていてもよい、請求項1に記載の化合物、その薬学的に許容される塩もしくはプロドラッグ、または対応するZもしくはE異性体。
- 式(II):
RおよびR0は、独立して、水素またはヒドロキシルであり;nは、0、1、または2であり;
YおよびY’は一緒になって、酸素であり;
R1、R2、R3、およびR4のうちの3つは水素であり、1つはハロゲン、アルキル、もしくはアルコキシであるか、またはR1、R2、R3、およびR4のうちの2つは水素であり、2つはアルコキシであり;
R7は、水素であり、R8は、アルキルであり;
R12、R13、R14、R15、およびR16のうちの少なくとも1つは、独立して、ハロゲン、アルキル、ハロアルキル、シアノ、シアノアルキル、ニトロ、ヒドロキシル、アルコキシ、ホルミルオキシ、ヒドロキシアルキル、アルデヒド、アミノ、アルキルアミノ、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノ、メルカプト、アルキルメルカプト、アジド、ならびにアルキルスルホニル、アルキルスルフィニル、アルキルスルフィニルオキシ、アルキルスルホニルオキシ、アルキルカルボニルオキシ、カルバメート、カルバミド、アルコキシカルボニル、アルキルアミノカルボニル、アミノカルボニル、およびスルホンアミドから選択される置換もしくは非置換の基から選択され、またはR12、R13、R14、R15、およびR16のうちのいずれか2つは、アルキレンジオキシ基を形成し;
Xは、NR’R”であり、式中R”は、水素であり;R’は、ハロゲン、アルキル、ハロアルキル、シアノ、シアノアルキル、ニトロ、ヒドロキシル、アルコキシ、ホルミルオキシ、ヒドロキシアルキル、アルデヒド、アミノ、アルキルアミノ、ジアルキルアミノ、アミノアルキル、アルキルアミノアルキル、メルカプト、およびアルキルメルカプト、アジド、ならびにアルキルスルホニル、アルキルスルフィニル、アルキルスルフィニルオキシ、アルキルスルホニルオキシ、アルキルカルボニルオキシ、カルバメート、カルバミド、アルコキシカルボニル、アルキルアミノカルボニル、アミノカルボニル、およびスルホンアミドから選択される置換もしくは非置換の基のうちの1つまたは複数で置換されたアリールであるか、またはいずれか2つの置換された位置は、アルキレンジオキシ基で占有されていてもよい)、
を有する、請求項1または2に記載の化合物、あるいはその薬学的に許容される塩もしくはプロドラッグ、または対応するZもしくはE異性体。 - R’が、ハロゲン、アルキル、ハロアルキル、シアノ、シアノアルキル、ニトロ、ヒドロキシル、アルコキシ、ホルミルオキシ、ヒドロキシアルキル、アルデヒド、アミノ、アルキルアミノ、ジアルキルアミノ、アミノアルキル、アルキルアミノアルキル、メルカプト、およびアルキルメルカプト、アジド、ならびにアルキルスルホニル、アルキルスルフィニル、アルキルスルフィニルオキシ、アルキルスルホニルオキシ、アルキルカルボニルオキシ、カルバメート、カルバミド、アルコキシカルボニル、アルキルアミノカルボニル、アミノカルボニル、およびスルホンアミドから選択される置換または非置換の基のうちの1つまたは複数で置換されたフェニルまたはビフェニルであるか、あるいはいずれか2つの置換された位置は、アルキレンジオキシ基によって占有されていてもよく;R12、R13、R14、R15、およびR16のうちの少なくとも1つは、独立して、ハロゲン、アルキル、ハロアルキル、シアノ(cycno)、シアノアルキル、ニトロ、ヒドロキシル、アルコキシ、ホルミルオキシ、ヒドロキシアルキル、アルデヒド、アミノ、アルキルアミノ、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノ、メルカプト、アルキルメルカプト、アジド、ならびにアルキルスルホニル、アルキルスルフィニル、アルキルスルフィニルオキシ、アルキルスルホニルオキシ、アルキルカルボニルオキシ、カルバメート、カルバミド、アルコキシカルボニル、アルキルアミノカルボニル、アミノカルボニル、およびスルホンアミドから選択される置換もしくは非置換の基から選択され、または、R12、R13、R14、R15、およびR16のうちのいずれか2つは、アルキレンジオキシ基を形成する、請求項3に記載の化合物、その薬学的に許容される塩もしくはプロドラッグ、または対応するZもしくはE異性体。
- R’が、ハロゲン、アルキル、トリフルオロメチル、およびアルコキシのうちの1つまたは複数で置換されたフェニルであり;R12、R13、R14、R15、およびR16のうちの1つまたは複数が独立して、ハロゲン、アルキル、ホルミルオキシ、アルキルカルボニルオキシ、ならびにアルキルスルホニル、アルキルスルフィニル、アルキルスルフィニルオキシ、アルキルスルホニルオキシ、カルバメート、カルバミド、アルコキシカルボニル、アルキルアミノカルボニル、アミノカルボニル、およびスルホンアミドから選択される置換または非置換の基から選択される、請求項3または4に記載の化合物、その薬学的に許容される塩もしくはプロドラッグ、または対応するZもしくはE異性体。
- (Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(036)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(037)、
(Z)−N−(3,4−ジメチルフェニル)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)アセトアミド(038)、
(Z)−N−(3,4−ジメチルフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(039)、
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(p−トリル)アセトアミド(040)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(p−トリル)アセトアミド(041)、
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(o−トリル)アセトアミド(042)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(o−トリル)アセトアミド(043)、
(Z)−2−(1−(4−ヒドロキシ−3−メトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(046)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3−メトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(047)、
(Z)−2−(1−(4−ヒドロキシ−3−メトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(048)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3−メトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(049)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(7−メチルナフタレン−2−イル)アセトアミド(050)、
(Z)−4−((5−フルオロ−2−メチル−3−(2−オキソ−2−(m−トリルアミノ)エチル)−1H−インデン−1−イリデン)メチル)−2,6−ジメトキシフェニルエチルカルバメート(051)、
(Z)−4−((5−フルオロ−2−メチル−3−(2−オキソ−2−(m−トリルアミノ)エチル)−1H−インデン−1−イリデン)メチル)−2,6−ジメトキシフェニルメタンスルホネート(052)、
(Z)−2−(5−フルオロ−1−(4−アセトキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(053)、および
(Z)−N−(4−(tert−ブチル)フェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(059)から選択される、請求項1または2に記載の化合物、あるいはその薬学的に許容される塩もしくはプロドラッグ、またはその対応するE異性体。 - 請求項1から6のいずれか一項に記載の化合物、その薬学的に許容される塩もしくはプロドラッグ、またはその対応するZもしくはE異性体、および薬学的に許容される担体を含む医薬組成物。
- 式Iの化合物、その薬学的に許容される塩もしくはプロドラッグ、またはその対応するZもしくはE異性体以外の少なくとも1種の追加の治療剤をさらに含む、請求項7に記載の医薬組成物。
- ヒトまたは非ヒト哺乳動物Ras媒介性生物学的プロセスを阻害する方法であって、Ras阻害量の少なくとも1種の請求項1から6のいずれか一項に記載の化合物、その薬学的に許容される塩またはプロドラッグをin vivoまたはin vitroで投与することを含み、前記化合物、あるいはその薬学的に許容される塩もしくはプロドラッグ、またはZもしくはE異性体は、単独で、あるいは前記化合物、またはその薬学的に許容される塩もしくはプロドラッグ、またはZもしくはE異性体以外の少なくとも1種の追加の治療剤と組み合わせて投与される、方法。
- 1つまたは複数のRas媒介性生物学的プロセスを阻害することによって処置可能な疾患または状態を有するヒトまたは非ヒト哺乳動物患者を治療的または予防的に処置する方法であって、それを必要とする患者に、治療有効量または予防有効量の少なくとも1種の請求項1から6のいずれか一項に記載のras阻害性化合物、その薬学的に許容される塩またはプロドラッグを投与することを含み、前記化合物、あるいはその薬学的に許容される塩もしくはプロドラッグ、またはZもしくはE異性体は、単独で、あるいは前記化合物、またはその薬学的に許容される塩もしくはプロドラッグ、またはZもしくはE異性体以外の少なくとも1種の追加の治療剤と組み合わせて投与される、方法。
- ヒトまたは非ヒト哺乳動物Ras媒介性生物学的プロセスを阻害する方法であって、Ras阻害量の
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(036)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(037)、
(Z)−N−(3,4−ジメチルフェニル)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)アセトアミド(038)、
(Z)−N−(3,4−ジメチルフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(039)、
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(p−トリル)アセトアミド(040)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(p−トリル)アセトアミド(041)、
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(o−トリル)アセトアミド(042)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(o−トリル)アセトアミド(043)、
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(044)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(045)、
(Z)−2−(1−(4−ヒドロキシ−3−メトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(046)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3−メトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(047)、
(Z)−2−(1−(4−ヒドロキシ−3−メトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(048)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3−メトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(049)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(7−メチルナフタレン−2−イル)アセトアミド(050)、
(Z)−4−((5−フルオロ−2−メチル−3−(2−オキソ−2−(m−トリルアミノ)エチル)−1H−インデン−1−イリデン)メチル)−2,6−ジメトキシフェニルエチルカルバメート(051)、
(Z)−4−((5−フルオロ−2−メチル−3−(2−オキソ−2−(m−トリルアミノ)エチル)−1H−インデン−1−イリデン)メチル)−2,6−ジメトキシフェニルメタンスルホネート(052)、
(Z)−2−(5−フルオロ−1−(4−アセトキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(053)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(4−フルオロフェニル)アセトアミド(054)、
(Z)−N−(4−クロロフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(055)、
(Z)−N−(3,4−ジクロロフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(056)、
(Z)−N−(4−ブロモフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(057)、
(Z)−N−(3−ブロモフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(058)、および
(Z)−N−(4−(tert−ブチル)フェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(059)から選択される少なくとも1種の化合物、あるいは
その薬学的に許容される塩もしくはプロドラッグ、またはその対応するE異性体をin vivoまたはin vitroで投与することを含み、
前記化合物、その薬学的に許容される塩もしくはプロドラッグ、またはそのE異性体は、単独で、または前記化合物、その薬学的に許容される塩、プロドラッグ、もしくはE異性体以外の少なくとも1種の追加の治療剤と組み合わせて投与される、方法。 - 1つまたは複数のRas媒介性生物学的プロセスを阻害することによって処置可能な疾患または状態を有するヒトまたは非ヒト哺乳動物患者を治療的または予防的に処置する方法であって、それを必要とする患者に、治療有効量または予防有効量の
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(036)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(037)、
(Z)−N−(3,4−ジメチルフェニル)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)アセトアミド(038)、
(Z)−N−(3,4−ジメチルフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(039)、
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(p−トリル)アセトアミド(040)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(p−トリル)アセトアミド(041)、
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(o−トリル)アセトアミド(042)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(o−トリル)アセトアミド(043)、
(Z)−2−(1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(044)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(045)、
(Z)−2−(1−(4−ヒドロキシ−3−メトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(046)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3−メトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(047)、
(Z)−2−(1−(4−ヒドロキシ−3−メトキシベンジリデン)−5−メトキシ−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(048)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3−メトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(3−メトキシフェニル)アセトアミド(049)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(7−メチルナフタレン−2−イル)アセトアミド(050)、
(Z)−4−((5−フルオロ−2−メチル−3−(2−オキソ−2−(m−トリルアミノ)エチル)−1H−インデン−1−イリデン)メチル)−2,6−ジメトキシフェニルエチルカルバメート(051)、
(Z)−4−((5−フルオロ−2−メチル−3−(2−オキソ−2−(m−トリルアミノ)エチル)−1H−インデン−1−イリデン)メチル)−2,6−ジメトキシフェニルメタンスルホネート(052)、
(Z)−2−(5−フルオロ−1−(4−アセトキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(m−トリル)アセトアミド(053)、
(Z)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)−N−(4−フルオロフェニル)アセトアミド(054)、
(Z)−N−(4−クロロフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(055)、
(Z)−N−(3,4−ジクロロフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(056)、
(Z)−N−(4−ブロモフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(057)、
(Z)−N−(3−ブロモフェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(058)、および
(Z)−N−(4−(tert−ブチル)フェニル)−2−(5−フルオロ−1−(4−ヒドロキシ−3,5−ジメトキシベンジリデン)−2−メチル−1H−インデン−3−イル)アセトアミド(059)から選択される少なくとも1種のras阻害性化合物、あるいは
その薬学的に許容される塩もしくはプロドラッグ、またはその対応するE異性体を投与することを含み、
前記化合物、その薬学的に許容される塩もしくはプロドラッグ、またはそのE異性体は、単独で、または前記化合物、その薬学的に許容される塩、プロドラッグ、もしくはE異性体以外の少なくとも1種の追加の治療剤と組み合わせて投与される、方法。 - 前記Ras媒介性生物学的プロセスが、腫瘍細胞の成長、増殖、生存、転移、薬物耐性、および放射線耐性から選択される、請求項9から12のいずれか一項に記載の方法。
- 前記Ras媒介性生物学的プロセスが、がんである、請求項13に記載の方法。
- 前記がんが、膵臓がん、肺がん、直腸結腸がん、黒色腫、卵巣がん、腎臓がん、前立腺がん、頭頸部がん、内分泌性がん、子宮がん、乳がん、肉腫がん、胃がん、肝臓がん、食道がん、中枢神経系がん、脳がん、肝臓がん、生殖細胞系がん、リンパ腫、および白血病から選択される、請求項13または14に記載の方法。
- 前記がんが、膵臓がん、直腸結腸がん、および肺がんから選択される、請求項14または15に記載の方法。
- 前記がんが、薬物耐性または放射線耐性である、請求項14から16のいずれか一項に記載の方法。
- 前記患者が、異常、変異型、もしくは過活性ras遺伝子もしくはRasタンパク質、または異常なRas媒介性生物学的プロセスについての前記患者の組織、血液、または腫瘍のアッセイを利用することによって予め選択される、請求項9から17のいずれか一項に記載の方法。
- 前記患者の組織、血液、または腫瘍が、異常、変異型、もしくは過活性ras遺伝子もしくはRasタンパク質、または異常なRas媒介性生物学的プロセスを含有する、請求項9から18のいずれか一項に記載の方法。
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