JP2018531993A - Alkおよびsrpk阻害剤ならびに使用方法 - Google Patents
Alkおよびsrpk阻害剤ならびに使用方法 Download PDFInfo
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- JP2018531993A JP2018531993A JP2018534509A JP2018534509A JP2018531993A JP 2018531993 A JP2018531993 A JP 2018531993A JP 2018534509 A JP2018534509 A JP 2018534509A JP 2018534509 A JP2018534509 A JP 2018534509A JP 2018531993 A JP2018531993 A JP 2018531993A
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- alkyl
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Abstract
Description
本出願は、2015年9月23日出願の米国仮出願第62/222,504号および2016年6月29日出願の米国仮出願第62/356,066号の恩典および優先権を主張するものであり、いずれの内容もその全体が参照により本明細書に組み入れられる。
本発明は、米国国立衛生研究所が授与した助成金番号R01 CA136851およびR01 CA172592に基づく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。
未分化リンパ腫キナーゼ(ALK)は、インスリン受容体スーパーファミリーにおける受容体チロシンキナーゼである。ALKは、脳の発達において重要な役割を果たし、神経系内の特定のニューロンに対して効果を発揮する。転座または点変異によるALKの異常発現および過剰活性化が、多種多様ながん、例えば炎症性筋線維芽細胞性腫瘍、びまん性大細胞型B細胞リンパ腫、扁平上皮がん、および非小細胞肺がんにおいて発がん性であることが示された。ALK再編成を伴う肺がんはALKチロシンキナーゼ阻害に対する感受性が高く、このことは、当該のがんがALKキナーゼ活性に大きく依存していることを強調するものである。したがって、ALKは、診断剤または治療剤の設計および開発のための魅力的な標的として広く認識されている。例えば、ALK阻害剤クリゾチニブが、ALK再編成を伴う進行NSCLCを有する患者を処置するために、FDAによって承認された。しかし、ALK再編成NSCLCにおける高い奏効率にもかかわらず、大部分の患者は処置の1年後にクリゾチニブに対する耐性を発生させる。特に、中枢神経系(CNS)が最も一般的な再発部位の1つである。
本出願は、ALK活性を阻害可能な、本明細書に定義される式(I)または(Ia)の化合物に関する。本出願は、活性化ALKが役割を果たす疾患を処置または予防することを必要とする対象においてそれを行う方法であって、該対象に治療有効量の本明細書に定義される式(I)もしくは(Ia)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体を投与することによる方法を特徴とする。
式中、R1、R2、R3、R4、R5、R6、m、およびnはそれぞれ本明細書において以下で詳細に記載される。
式中、R1、R2、R3、R4、R5、R6'、m、およびnはそれぞれ本明細書において以下で詳細に記載される。
本出願の化合物
本出願の第1の局面は、式(I)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体に関する:
式中、
各R1は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R2はHまたは(C1〜C3)アルキルであり;
R3はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
R4はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
各R5は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R6はCN、COOH、N((C1〜C6)アルキル)-(CH2)1〜4-N((C1〜C6)アルキル)2、少なくとも1個のOHで置換された(C1〜C6)アルキル、(C2〜C6)アルケニル、C6〜C10アリール、5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリール、または5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該(C2〜C6)アルケニル、アリール、ヘテロアリール、およびヘテロシクリルはそれぞれ1個または複数個のQ-Tで置換されていてもよく;
Qは結合または(C1〜C6)アルキルリンカーであり;
Tは(C1〜C6)アルキル、(C1〜C6)アルキルアミノ、ジ(C1〜C6)アルキルアミノ、アミノ、アミノカルボニル、(C1〜C6)アルキルアミノカルボニル、ジ(C1〜C6)アルキルアミノカルボニル、OH、S(O)qF、または5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、R6が(C2〜C6)アルケニルである場合、Tは(C1〜C6)アルキルではなく;
qは1または2であり;
mは0、1、2、または3であり; かつ
nは1、2、または3である。
式中、n1は0、1、または2であり、R1、R2、R3、R4、R5、R6、Q、T、およびmはそれぞれ本明細書において上記式(I)に定義の通りである。
式中、R5およびR6はそれぞれ本明細書において上記式(I)に定義の通りである。
変異ALK(例えばALK G1202R)を阻害するための;
変異ALK(例えばALK G1202R)が役割を果たす疾患または障害(例えばがん)を処置または予防するための;
がんの処置または予防のために変異ALK(例えばALK G1202R)の阻害を必要とすると同定された対象においてがんを処置または予防するための;
ALK標的治療、例えばアレクチニブ(AF802)、セリチニブ(LDK378)、ブリガチニブ(AP26113)、クリゾチニブ(ザーコリ)、および/またはPF-06463922による治療に耐性がある疾患または障害(例えばがん)を処置または予防するための;
がん細胞が変異ALK(例えばALK G1202R)を含むがんを処置または予防するための;
SRPK(例えばSRPK1および/またはSRPK2)を阻害するための;
VEGF媒介血管新生を制御する(例えば阻害する)ための;
VEGF媒介血管新生が役割を果たす疾患または障害(例えばAMDまたは血管新生依存性がん)を処置または予防するための;
(例えばAMDの処置または予防のためにVEGF媒介血管新生の制御(例えば阻害)を必要とすると同定された対象において)AMDを処置または予防するための; あるいは
(例えば血管新生依存性がんの処置または予防のためにVEGF媒介血管新生の制御を必要とすると同定された対象において)血管新生依存性がん(例えば腫瘍性がん)を処置または予防するための、
式(Ia)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体に関する:
式中、
各R1は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R2はHまたは(C1〜C3)アルキルであり;
R3はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
R4はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
各R5は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R6'はCN、COOH、N((C1〜C6)アルキル)-(CH2)1〜4-N((C1〜C6)アルキル)2、少なくとも1個のOHで置換された(C1〜C6)アルキル、(C2〜C6)アルケニル、C6〜C10アリール、5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリール、または5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該(C2〜C6)アルケニル、アリール、ヘテロアリール、およびヘテロシクリルはそれぞれ1個または複数個のQ-Tで置換されていてもよく;
Qは結合または(C1〜C6)アルキルリンカーであり;
Tは(C1〜C6)アルキル、(C1〜C6)アルキルアミノ、ジ(C1〜C6)アルキルアミノ、アミノ、アミノカルボニル、(C1〜C6)アルキルアミノカルボニル、ジ(C1〜C6)アルキルアミノカルボニル、OH、S(O)qF、または5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、R6'が(C2〜C6)アルケニルである場合、Tは(C1〜C6)アルキルではなく;
qは1または2であり;
mは0、1、2、または3であり; かつ
nは1、2、または3である。
変異ALK(例えばALK G1202R)を阻害する;
変異ALK(例えばALK G1202R)が役割を果たす疾患または障害(例えばがん)を処置または予防する;
がんの処置または予防のために変異ALK(例えばALK G1202R)の阻害を必要とすると同定された対象においてがんを処置または予防する;
ALK標的治療、例えばアレクチニブ(AF802)、セリチニブ(LDK378)、ブリガチニブ(AP26113)、クリゾチニブ(ザーコリ)、および/またはPF-06463922による治療に耐性がある疾患または障害(例えばがん)を処置または予防する;
がん細胞が変異ALK(例えばALK G1202R)を含むがんを処置または予防する;
SRPK(例えばSRPK1および/またはSRPK2)を阻害する;
VEGF媒介血管新生を制御する(例えば阻害する);
VEGF媒介血管新生が役割を果たす疾患または障害(例えばAMDまたは血管新生依存性がん)を処置または予防する;
(例えばAMDの処置または予防のためにVEGF媒介血管新生の制御(例えば阻害)を必要とすると同定された対象において)AMDを処置または予防する; あるいは
(例えば血管新生依存性がんの処置または予防のためにVEGF媒介血管新生の制御を必要とすると同定された対象において)血管新生依存性がん(例えば腫瘍性がん)を処置または予防する、方法であって、
それを必要とする対象に有効量の式(Ia)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体を投与する段階を含む方法に関する。
変異ALK(例えばALK G1202R)を阻害するための;
変異ALK(例えばALK G1202R)が役割を果たす疾患または障害(例えばがん)を処置または予防するための;
がんの処置または予防のために変異ALK(例えばALK G1202R)の阻害を必要とすると同定された対象においてがんを処置または予防するための;
ALK標的治療、例えばアレクチニブ(AF802)、セリチニブ(LDK378)、ブリガチニブ(AP26113)、クリゾチニブ(ザーコリ)、および/またはPF-06463922による治療に耐性がある疾患または障害(例えばがん)を処置または予防するための;
がん細胞が変異ALK(例えばALK G1202R)を含むがんを処置または予防するための;
SRPK(例えばSRPK1および/またはSRPK2)を阻害するための;
VEGF媒介血管新生を制御する(例えば阻害する)ための;
VEGF媒介血管新生が役割を果たす疾患または障害(例えばAMDまたは血管新生依存性がん)を処置または予防するための;
(例えばAMDの処置または予防のためにVEGF媒介血管新生の制御(例えば阻害)を必要とすると同定された対象において)AMDを処置または予防するための; あるいは
(例えば血管新生依存性がんの処置または予防のためにVEGF媒介血管新生の制御を必要とすると同定された対象において)血管新生依存性がん(例えば腫瘍性がん)を処置または予防するための、
下記構造
の式(Ia)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体に関する。
の式(Ia)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体に関する。
変異ALK(例えばALK G1202R)を阻害する;
変異ALK(例えばALK G1202R)が役割を果たす疾患または障害(例えばがん)を処置または予防する;
がんの処置または予防のために変異ALK(例えばALK G1202R)の阻害を必要とすると同定された対象においてがんを処置または予防する;
ALK標的治療、例えばアレクチニブ(AF802)、セリチニブ(LDK378)、ブリガチニブ(AP26113)、クリゾチニブ(ザーコリ)、および/またはPF-06463922による治療に耐性がある疾患または障害(例えばがん)を処置または予防する;
がん細胞が変異ALK(例えばALK G1202R)を含むがんを処置または予防する;
SRPK(例えばSRPK1および/またはSRPK2)を阻害する;
VEGF媒介血管新生を制御する(例えば阻害する);
VEGF媒介血管新生が役割を果たす疾患または障害(例えばAMDまたは血管新生依存性がん)を処置または予防する;
(例えばAMDの処置または予防のためにVEGF媒介血管新生の制御(例えば阻害)を必要とすると同定された対象において)AMDを処置または予防する; あるいは
(例えば血管新生依存性がんの処置または予防のためにVEGF媒介血管新生の制御を必要とすると同定された対象において)血管新生依存性がん(例えば腫瘍性がん)を処置または予防する、方法であって、
それを必要とする対象に有効量の下記構造
の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体を投与する段階を含む方法に関する。
の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体を投与する段階を含む方法に関する。
本出願を記述するために使用される様々な用語の定義を以下に列挙する。これらの定義は、特定の事例に別途限定されない限り、本明細書および特許請求の範囲の全体を通じて使用されるように、個々にまたはより大きな群の一部として、用語に適用される。
本出願の化合物は、標準的化学反応を含む種々の方法によって作製することができる。本出願の合成方法は多種多様な官能基を許容しうるものであり、したがって様々な置換出発原料を使用することができる。本方法は一般に、プロセス全体の最後またはその近くで所望の最終化合物を与えるが、特定の場合では、該化合物をその薬学的に許容される塩、エステル、またはプロドラッグにさらに変換することが望ましいことがある。好適な合成経路を以下のスキームに示す。
式(I)の化合物を調製する一般的様式を一般的スキームAに例示する。化合物37-bと化合物Aとを好適な溶媒、例えば1,4-ジオキサン中で鈴木カップリングを通じて反応させて式(I)の化合物を得る。
化合物37-bと化合物Bとを好適な溶媒、例えば1,4-ジオキサン中で鈴木カップリングを通じて反応させて化合物40を得る。化合物40は、式(I)の他の化合物を調製するための中間体として使用可能である。
a) Pd(Dppf)Cl2 6mol%、t-BuXphos 8mol%、2M Na2CO3水溶液5当量、1,4-ジオキサン 100℃、1時間、次にLiOH 2当量、H2O、室温
b) ジメチルアミンHCl 1.2当量、HATU 2当量、DIEA 5当量、DMF 54%
スキーム1は化合物6への合成経路を示す。出発原料化合物37(市販)を鈴木カップリング条件、続いてエステル加水分解に供してカルボン酸化合物38を得る。次に化合物38とジメチルアミンHClおよびHATUとを反応させて化合物6を得る。
a) Pd2(dba)3 6mol%、トリ(o-トリル)9mol%、NaOt-bu 8当量、1,4-ジオキサン 110℃、2時間、48%
化合物37を所望のアミンを使用するBuchwald-Hartwigカップリング条件に供することで、アルキル複素環置換基を有する化合物を調製する(スキーム2)。
a) Pd(OAc)2 5mol%、PPh3 12mol%、CuI 11mol%、Et2NH、90℃、4時間、次にTBAF 3当量、THF、4時間
b) TMS-N3 1.5当量、CuI 5mol%、DMF、MeOH、100℃、4時間、36%
スキーム3は、化合物13、および同様の構造を有する本出願の化合物を調製するための合成経路を示す。
a) Pd(Dppf)Cl2 6mol%、t-BuXphos 8mol%、2M Na2CO3水溶液5当量 1,4-ジオキサン100℃、1時間
b) ad-mixβ 5mol%、t-BuOH、H2O、0℃〜室温、12時間、51%
c) OSO4 1mol%、オキソン4当量、室温、6時間、82%
スキーム4は、化合物22および24、ならびに同様の構造を有する本出願の化合物を調製するための合成経路を示す。
増殖阻害アッセイ
本出願の化合物を、固定濃度または一連の濃度での増殖阻害アッセイにおいて、形質導入していないかあるいは野生型ALKまたは1つもしくは複数の変異(例えば本明細書に記載の変異)を含むALKを形質導入した様々な細胞(例えばBa/F3細胞、またはNSCLCなどの腫瘍細胞株)中で試験する。細胞を該化合物で異なった期間処理した後、生細胞の割合をMTSアッセイによって確定する。次に、必要であればIC50またはEC50を計算する。
本出願の化合物で処理された細胞からの細胞溶解液をタンパク質含有量に関して均一化し、ランニングバッファーと共にゲル上に添加する。タンパク質をゲルから膜に移し、膜をタンパク質(例えばALK)に対する一次抗体でプローブする。二次抗体を加え、洗浄後、タンパク質の量を、例えばHRP基質試薬のシグナル強度をイメージャで検出することで確定する。
別の局面では、本出願は、キナーゼ(例えばSRPK(例えばSRPK1および/もしくはSRPK2)、ALK、または変異ALK(例えばALK G1202R))を本明細書に開示される化合物(例えば、本明細書に開示される式I、Ia、II、IIa、もしくはIIbのいずれかの化合物、または任意の特定の化合物、例えば化合物6〜38)、あるいはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、または互変異性体で阻害する方法を提供する。いくつかの態様では、ALKは、C1156Y、F1174L、L1196M、L1152R、1151 Tins、G1202R、G1269A、およびS1206Yより選択される1つまたは複数の変異を含む。さらなる態様では、変異ALKは少なくとも変異G1202Rを含む。
別の局面では、本出願は、本明細書に開示される化合物またはその薬学的に許容されるエステル、塩、もしくはプロドラッグを薬学的に許容される担体と共に含む、薬学的組成物を提供する。
すべての反応を、0.25mm E. Merckプレコーティングシリカゲルプレート(60 F254)を用いる薄層クロマトグラフィー(TLC)、ならびにSunFire(商標)C18カラム(4.6x50mm、粒径5μm)を使用するWaters LCMSシステム(Waters 2489紫外可視検出器、Waters 3100質量検出器、Waters 515 HPLCポンプ、Waters 2545バイナリーグラジエントモジュール、Waters試薬マネージャー、Waters 2767試料マネージャー)によってモニタリングした: 溶媒勾配 = 0分で100% A、5分で1% A; 溶媒A = 水中0.035% TFA; 溶媒B = CH3CN中0.035% TFA; 流量: 2.5mL/分。反応生成物の精製を、CombiFlash(登録商標)RfをTeledyne Isco RediSep(登録商標)Rf High Performance GoldまたはSilicycle SiliaSep(商標)High Performanceカラム(4g、12g、24g、40g、80g、または120g)と共に使用するフラッシュクロマトグラフィーによって行った。
atm 雰囲気
br ブロード
DIPEA N,N-ジイソプロピルエチルアミン
DMF N,N-ジメチルホルムアミド
DMSO ジメチルスルホキシド
DIEA ジイソプロピルエチルアミン
EtOAc 酢酸エチル
HCl 塩酸
h 時間
HATU ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム3-オキシドヘキサフルオロ-ホスフェート
HPLC 高速液体クロマトグラフィー
LCMS 液体クロマトグラフィー質量分析
m 多重項
MeOH メタノール
MHz メガヘルツ
min 分
MS 質量分析
NMR 核磁気共鳴
Pd2(dba)3 トリス(ジベンジリデンアセトン)ジパラジウム(0)
Pd(dppf)Cl2 ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド
ppm 百万分率
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
TBAF フッ化テトラ-n-ブチルアンモニウム
Xphos 2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピルビフェニル
9-エチル-6,6-ジメチル-8-(1-メチル-1H-ピラゾール-4-イル)-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル(化合物7)の合成
1-メチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール(34mg、0.16mmol)および37(60mg、0.13mmol)を1,4-ジオキサン(5mL)および2M飽和Na2CO3水溶液(0.17mL、0.34mmol)に溶解させ、徹底的に脱気した。Pd(dppf)Cl2(6mg、0.008mmol)およびt-ブチルXPhos(4mg、0.005mmol)を加え、混合物を密封バイアル中で100℃に加熱した。1時間攪拌後、LC-MS分析は反応が完了したことを示した。反応混合物をセライトを通じて濾過し、30→100% CH3CN/0.035% TFA入りのH2Oの勾配を使用する逆相HPLCで精製して、所望の化合物をベージュ色固体として得た。
8-(4-(ジメチルアミノ)ピペリジン-1-イル)-9-エチル-6,6-ジメチル-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル(化合物17)の合成
N,N-ジメチルピペリジン-4-アミン(30mg、0.15mmol)、NaOt-Bu(70mg、0.73mmol)、および37(40mg、0.09mmol)を1,4-ジオキサン(3mL)に溶解させ、混合物を徹底的に脱気した。Pd2(dba)3(5mg、0.05mmol)およびトリ(o-トリル)(3mg、0.09mmol)を加えた。混合物を110℃に4時間加熱した。LC-MS分析は所望の生成物への変換を示した。混合物を濾過し、10→60% CH3CN/0.035% TFA入りのH2Oの勾配を使用する逆相HPLCで精製して、所望の化合物を褐色固体(18mg、収率45%)として得た。
9-エチル-6,6-ジメチル-11-オキソ-8-(1H-1,2,3-トリアゾール-5-イル)-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル(化合物13)の合成
エチニルトリメチルシラン(70μL、0.5mmol)および37(200mg、0.45mmol)をジエチルアミン(2mL)に溶解させた。トリフェニルホスフィン(15mg、0.054mmol)およびCuI(10mg、0.05mmol)を加え、溶液を脱気した。Pd(OAc)2(5mg、0.022mmol)を加え、混合物を90℃に4時間加熱した。混合物をセライトを通じて濾過し、40→100% CH3CN/0.035% TFA入りのH2Oの勾配を使用する逆相HPLCで精製して、所望の化合物を白色固体(131mg、収率70%)として得た。この材料をTHF(5mL)に溶解させ、THF中TBAF 1M(0.95mL、0.95mmol)を加えた。混合物を室温で5時間攪拌した。反応液を水で反応停止させ、EtOAc(3X50mL)で抽出し、ブラインで洗浄し、MgSO4で乾燥させ、濃縮してアルキンを白色固体として定量的収率で得た。アルキン39(50mg、0.15mmol)およびCuI(3mg、0.007mmol)の9:1 DMF/MeOH混合物(1mL)中溶液にTMS-アジド(30μL、0.22mmol)を加え、100℃で4時間攪拌した。混合物をセライトを通じて濾過し、40→100% CH3CN/0.035% TFA入りのH2Oの勾配を使用する逆相HPLCで精製して、所望の化合物を白色固体(20mg、収率36%)として得た。
9-エチル-6,6-ジメチル-11-オキソ-8-ビニル-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル(40)
化合物7を調製するために使用した手順を使用して化合物40(32mg、収率68%)を調製した。
(R)-8-(1,2-ジヒドロキシエチル)-9-エチル-6,6-ジメチル-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル(化合物22)
AD-mixβ(206mg)および化合物40(50mg、0.15mmol)をH2O(3mL)およびt-BuOHの0℃溶液に溶解させた。混合物を室温にゆっくりと昇温させ、室温で12時間攪拌した。LC-MS分析は出発原料から所望の生成物への完全な変換を示した。反応混合物を濾過し、20→70% CH3CN/0.035% TFA入りのH2Oの勾配を使用する逆相HPLCで精製して、所望の化合物を白色固体(28mg、収率51%)として得た。
本出願の化合物の合成
実施例1〜4において概説した手順に従って以下の表1の化合物を合成した。
生化学試験
増殖および増殖阻害をMTSアッセイにより評価し、アッセイを既に確立された方法に従って行った(Zhou et al., Nature 2009)。MTSアッセイは、細胞培地に可溶性でありかつ分光測定で検出可能であるホルマザン生成物にMTSを細胞によって生体内還元することに基づく、生細胞の数を確定するための比色法である。活性化ALKおよび異なるALK二次変異のBa/F3細胞を72時間の処理に供し、実験当たりの使用細胞数を経験的にかつ既に確立された様式で(Zhou et al., Nature 2009)確定した。すべての実験点を6個のウェル中で設定し、すべての実験を少なくとも3回繰り返した。データをWindows用GraphPad Prismバージョン5.0(GraphPad Software; www.graphpad.com)を使用してグラフで示した。非線形回帰モデルを使用して曲線をS字形用量反応にフィッティングした。
臨床的ALK阻害剤との比較でのALK変異体に対する活性
本出願の化合物を、臨床的ALK阻害剤と共に、最も一般的な二次ALK変異体のパネルに対して試験した。EML4-ALKWTもしくは二次変異体形質転換Ba/F3細胞、または細胞毒性対照としての非形質導入Ba/F3を、用量漸増MTSアッセイにおいてALK阻害剤で処理し、72時間後に生存率に関して評価した。平均IC50値(nM)(n=3)を表2に示す。表2に示すように、G1202R変異体は全臨床病期のALK阻害剤に対する耐性を付与する。対照的に、化合物6は、G1202R変異体および報告されている最も一般的な変異体に対する強力な活性を示す。
G1202R変異ALKに対する本出願の化合物の活性
本出願の化合物を一点阻害アッセイにおいてBa/F3細胞に対して試験した。EML4-ALKWTもしくはEML4-ALKG1202R形質転換Ba/F3細胞または非形質導入Ba/F3対照を単一用量(1μM)の本出願の化合物で処理した。72時間後、各化合物の未処理対照に対する生存率パーセントをMTSアッセイによって確定した。結果を表3に示す。
ALK変異体に対する本出願の化合物の活性
一点阻害アッセイにおいて非形質導入Ba/F3細胞の強力な阻害を示すことなくG1202R変異体の強力な阻害を示した化合物を、最も一般的な二次ALK変異体のパネルに対して試験した。本出願の化合物をEML4-ALKWTまたは二次変異体形質転換Ba/F3細胞中での用量漸増MTSアッセイにおいてBa/F3細胞に対して試験した。非形質導入Ba/F3対照を細胞毒性対照として使用した。72時間後に細胞の生存率を確定し、IC50(nM)を表4に示した。
ALK変異体を有する細胞の増殖の本出願の化合物による阻害
本出願の化合物、ならびに臨床病期ALK阻害剤アレクチニブ、セリチニブ(LDK378)、AP26113(ブリガチニブ)、およびクリゾチニブ(ザーコリ)の阻害活性を、NSCLC由来の細胞株(H3122、DFCI76、およびDFCI114)ならびに神経芽腫由来の細胞株(Kelly、LAN-1、SH-SY5Y(F1174L)、SK-N-SH(F1174L)、LAN-5(R1275Q)、SMS-KCNR(R1275Q)、CHLA-20(R1275Q)、SK-N-BE2(wt)、SK-N-FI(wt)、およびSK-N-AS(wt))のパネルにおける異なるALK変異体に対して試験した(表5ならびに図4A、図4B、および図5)。
本出願の化合物のKINOMESCAN(商標)解析
本出願の化合物のキナーゼ選択性を、456種のキナーゼのパネル(カリフォルニア州サンジエゴ、Ambit Biosciences)にわたってKINOMESCAN(商標)の方法論を使用して評価した。化合物6および32を濃度1μMでスクリーニングした。両化合物はアレクチニブよりもわずかに選択性が低かった。化合物6は化合物32よりも選択性が高く、マッピングされた相互作用はS-スコア(1) = 0.06で34個対39個であった。このことは、神経芽腫細胞株に対する細胞毒性の増加を説明しうる(図3)。化合物6を使用した用量反応解析は、10μM未満でのCSNK2A1の阻害、IC50 = 14nMでのIRAK1の阻害、IC50 = 465nMでのIRAK 4の阻害、IC50 = 14nMでのCLK4の阻害、IC50 = 3nMでのRETの阻害、IC50 = 13nMでのRET V804Lの阻害、およびIC50 = 12nMでのRET V804Mの阻害を明らかにした。化合物32を使用した用量反応解析は、10μM未満でのCSNK2A1の阻害、IC50 = 15nMでのIRAK1の阻害、IC50 = 234nMでのIRAK 4の阻害、IC50 = 4nMでのCLK4の阻害、IC50 = 2nMでのRETの阻害、IC50 = 9nMでのRET V804Lの阻害、およびIC50 = 23nMでのRET V804Mの阻害を明らかにした。
本出願の化合物の薬物動態およびCNSバイオアベイラビリティ
化合物6のマウス薬物動態プロファイルは、経口量10mg/kgの後で良好な経口バイオアベイラビリティ(87 %F)、半減期1.69時間、および血漿曝露量64,635(分*ng/mL、AUClast)を示した(表7)。さらに、経口量10mg/kgの2時間後に、化合物6は血漿曝露量0.34μMおよび脳曝露量0.03μMを示した。これは脳/血漿濃度比0.1に等しい。化合物6と比較すると、化合物32は、経口量10mg/kgの後でより低い経口バイオアベイラビリティ(26 %F)、半減期4.7時間、および血漿曝露量109,909(分*ng/mL、AUClast)を示した(表8)。さらに、経口量10mg/kgの2時間後に、化合物32は血漿曝露量0.21μMおよび脳曝露量0.03μMを示した。これは脳/血漿濃度比0.14に等しい。
分子モデリング
ALKとアレクチニブとの共結晶構造(PDB: 3AOX)に基づく分子モデリング試験(Sakamoto, H. et al., Cancer Cell 2011, 19, 679)を行うことで、本出願の化合物によるALKおよび/またはALK変異体の阻害の構造-活性関係を評価した。モデリングは、化合物6がアレクチニブと同じ骨格ヒンジ接触を作り出すが、化合物6がR1120のグアニジン部分とジメチルアセトアミド基のカルボニル基との間で2つのさらなる水素結合相互作用を形成することを示した(図1A)。さらに、G1202R変異体中で、化合物6はR1202のグアニジン部分とピラゾール環の窒素との間でさらなる水素結合相互作用を形成する(図1B)。モデリング試験では、化合物6のカルボニルアミドがR1120のグアニジン部分と相互作用するためには、ピラゾール環とジメチルアセトアミド部分との間のメチレンスペーサーが好ましいと予測された。
IC50(nM)として測定された本出願の化合物のSRPK1阻害活性を表9に示す。
当業者は、単なる日常的実験を使用することで、本明細書に具体的に記載される特定の態様の数多くの等価物を認識するかまたは確認可能であるであろう。そのような等価物は以下の特許請求の範囲に包含されるように意図されている。
Claims (55)
- 式(I)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体:
式中、
各R1は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R2はHまたは(C1〜C3)アルキルであり;
R3はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
R4はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
各R5は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R6はCN、COOH、N((C1〜C6)アルキル)-(CH2)1〜4-N((C1〜C6)アルキル)2、少なくとも1個のOHで置換された(C1〜C6)アルキル、(C2〜C6)アルケニル、C6〜C10アリール、5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリール、または5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該(C2〜C6)アルケニル、アリール、ヘテロアリール、およびヘテロシクリルはそれぞれ1個または複数個のQ-Tで置換されていてもよく;
Qは結合または(C1〜C6)アルキルリンカーであり;
Tは(C1〜C6)アルキル、(C1〜C6)アルキルアミノ、ジ(C1〜C6)アルキルアミノ、アミノ、アミノカルボニル、(C1〜C6)アルキルアミノカルボニル、ジ(C1〜C6)アルキルアミノカルボニル、OH、S(O)qF、または5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、R6が(C2〜C6)アルケニルである場合、Tは(C1〜C6)アルキルではなく;
qは1または2であり;
mは0、1、2、または3であり; かつ
nは1、2、または3である。 - nが1である、請求項1に記載の化合物。
- R5が(C1〜C6)アルキルである、請求項2に記載の化合物。
- R5がエチルである、請求項3に記載の化合物。
- R6がCN、COOH、N((C1〜C6)アルキル)-(CH2)1〜4-N((C1〜C6)アルキル)2、少なくとも1個のOHで置換された(C1〜C6)アルキル、C6〜C10アリール、5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリール、または5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該アリール、ヘテロアリール、およびヘテロシクリルがそれぞれ1個または複数個のQ-Tで置換されていてもよい、請求項1に記載の化合物。
- R6が5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリールまたは5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該ヘテロアリールおよびヘテロシクリルがそれぞれ1個または複数個のQ-Tで置換されていてもよい、請求項5に記載の化合物。
- R6が5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリールであり、該ヘテロアリールが1個または複数個のQ-Tで置換されていてもよい、請求項6に記載の化合物。
- R6が、1個または複数個のQ-Tで置換されていてもよい、フラニル、チオフェニル、ピラゾリル、イソオキサゾリル、またはトリアゾリルである、請求項7に記載の化合物。
- R6が、1個または複数個のQ-Tで置換されていてもよいC6〜C10アリールである、請求項5に記載の化合物。
- mが0である、請求項1に記載の化合物。
- R2がHである、請求項1に記載の化合物。
- R3およびR4がそれぞれ(C1〜C6)アルキルである、請求項1に記載の化合物。
- R3およびR4がそれぞれメチルである、請求項11に記載の化合物。
- 請求項1〜15のいずれか一項に記載の化合物と薬学的に許容される担体とを含む、薬学的組成物。
- キナーゼを阻害する方法であって、それを必要とする対象に有効量の請求項1〜15のいずれか一項に記載の化合物を投与する段階を含む方法。
- キナーゼがALKおよび/または変異ALKである、請求項17に記載の方法。
- キナーゼがSRPK 1および/またはSRPK2である、請求項17に記載の方法。
- キナーゼが役割を果たす疾患または障害を処置または予防する方法であって、それを必要とする対象に有効量の請求項1〜15のいずれか一項に記載の化合物を投与する段階を含む方法。
- 疾患または障害がALK標的治療に耐性がある、請求項20に記載の方法。
- VEGF媒介血管新生を制御する方法であって、それを必要とする対象に有効量の請求項1〜15のいずれか一項に記載の化合物を投与する段階を含む方法。
- VEGF媒介血管新生が役割を果たす疾患または障害を処置または予防する方法であって、それを必要とする対象に有効量の請求項1〜15のいずれか一項に記載の化合物を投与する段階を含む方法。
- 加齢黄斑変性を処置または予防する方法であって、それを必要とする対象に有効量の請求項1〜15のいずれか一項に記載の化合物を投与する段階を含む方法。
- 変異ALKを阻害するための;
変異ALKが役割を果たす疾患または障害を処置または予防するための;
がんの処置または予防のために変異ALKの阻害を必要とすると同定された対象においてがんを処置または予防するための;
ALK標的治療に耐性がある疾患または障害を処置または予防するための;
がん細胞が変異ALKを含むがんを処置または予防するための;
SRPKを阻害するための;
VEGF媒介血管新生を制御するための;
VEGF媒介血管新生が役割を果たす疾患または障害を処置または予防するための;
AMDを処置または予防するための; あるいは
血管新生依存性がんを処置または予防するための、
式(Ia)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体:
式中、
各R1は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R2はHまたは(C1〜C3)アルキルであり;
R3はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
R4はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
各R5は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R6'はCN、COOH、N((C1〜C6)アルキル)-(CH2)1〜4-N((C1〜C6)アルキル)2、少なくとも1個のOHで置換された(C1〜C6)アルキル、(C2〜C6)アルケニル、C6〜C10アリール、5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリール、または5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該(C2〜C6)アルケニル、アリール、ヘテロアリール、およびヘテロシクリルはそれぞれ1個または複数個のQ-Tで置換されていてもよく;
Qは結合または(C1〜C6)アルキルリンカーであり;
Tは(C1〜C6)アルキル、(C1〜C6)アルキルアミノ、ジ(C1〜C6)アルキルアミノ、アミノ、アミノカルボニル、(C1〜C6)アルキルアミノカルボニル、ジ(C1〜C6)アルキルアミノカルボニル、OH、S(O)qF、または5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、R6'が(C2〜C6)アルケニルである場合、Tは(C1〜C6)アルキルではなく;
qは1または2であり;
mは0、1、2、または3であり; かつ
nは1、2、または3である。 - nが1である、請求項25に記載の化合物。
- R5が(C1〜C6)アルキルである、請求項25に記載の化合物。
- R5がエチルである、請求項27に記載の化合物。
- R6'がCN、COOH、N((C1〜C6)アルキル)-(CH2)1〜4-N((C1〜C6)アルキル)2、少なくとも1個のOHで置換された(C1〜C6)アルキル、C6〜C10アリール、5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリール、または5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該アリール、ヘテロアリール、およびヘテロシクリルがそれぞれ1個または複数個のQ-Tで置換されていてもよい、請求項25に記載の化合物。
- R6'が5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリールまたは5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該ヘテロアリールおよびヘテロシクリルがそれぞれ1個または複数個のQ-Tで置換されていてもよい、請求項29に記載の化合物。
- R6'が5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリールであり、該ヘテロアリールが1個または複数個のQ-Tで置換されていてもよい、請求項30に記載の化合物。
- R6'が、1個または複数個のQ-Tで置換されていてもよい、フラニル、チオフェニル、ピラゾリル、イソオキサゾリル、またはトリアゾリルである、請求項31に記載の化合物。
- R6'が、1個または複数個のQ-Tで置換されていてもよいC6〜C10アリールである、請求項29に記載の化合物。
- 加齢黄斑変性を処置または予防するための、請求項25に記載の化合物。
- SRPKを阻害するための、請求項25に記載の化合物。
- 変異ALKを阻害する; 変異ALKが役割を果たす疾患または障害を処置または予防する; がんの処置または予防のために変異ALKの阻害を必要とすると同定された対象においてがんを処置または予防する; ALK標的治療に耐性がある疾患または障害を処置または予防する; がん細胞が変異ALKを含むがんを処置または予防する; SRPKを阻害する; VEGF媒介血管新生を制御する; VEGF媒介血管新生が役割を果たす疾患または障害を処置または予防する; AMDを処置または予防する; あるいは血管新生依存性がんを処置または予防する方法であって、それを必要とする対象に有効量の式(Ia)の化合物、またはその薬学的に許容される塩、水和物、溶媒和物、プロドラッグ、立体異性体、もしくは互変異性体を投与する段階を含む方法:
式中、
各R1は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R2はHまたは(C1〜C3)アルキルであり;
R3はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
R4はH、(C1〜C6)アルキル、または(C1〜C6)ハロアルキルであり;
各R5は独立して(C1〜C6)アルキル、(C1〜C6)ハロアルキル、(C1〜C6)アルコキシ、(C1〜C6)ハロアルコキシ、ハロゲン、NO2、NH2、OH、またはCNであり;
R6'はCN、COOH、N((C1〜C6)アルキル)-(CH2)1〜4-N((C1〜C6)アルキル)2、少なくとも1個のOHで置換された(C1〜C6)アルキル、(C2〜C6)アルケニル、C6〜C10アリール、5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリール、または5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該(C2〜C6)アルケニル、アリール、ヘテロアリール、およびヘテロシクリルはそれぞれ1個または複数個のQ-Tで置換されていてもよく;
Qは結合または(C1〜C6)アルキルリンカーであり;
Tは(C1〜C6)アルキル、(C1〜C6)アルキルアミノ、ジ(C1〜C6)アルキルアミノ、アミノ、アミノカルボニル、(C1〜C6)アルキルアミノカルボニル、ジ(C1〜C6)アルキルアミノカルボニル、OH、S(O)qF、または5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、R6'が(C2〜C6)アルケニルである場合、Tは(C1〜C6)アルキルではなく;
qは1または2であり;
mは0、1、2、または3であり; かつ
nは1、2、または3である。 - nが1である、請求項39に記載の方法。
- R5が(C1〜C6)アルキルである、請求項39に記載の方法。
- R5がエチルである、請求項41に記載の方法。
- R6'がCN、COOH、N((C1〜C6)アルキル)-(CH2)1〜4-N((C1〜C6)アルキル)2、少なくとも1個のOHで置換された(C1〜C6)アルキル、C6〜C10アリール、5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリール、または5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該アリール、ヘテロアリール、およびヘテロシクリルがそれぞれ1個または複数個のQ-Tで置換されていてもよい、請求項39に記載の方法。
- R6'が5員環もしくは6員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリールまたは5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロシクリルであり、該ヘテロアリールおよびヘテロシクリルがそれぞれ1個または複数個のQ-Tで置換されていてもよい、請求項43に記載の方法。
- R6'が5員環とN、O、およびSより選択される1〜3個のヘテロ原子とを含むヘテロアリールであり、該ヘテロアリールが1個または複数個のQ-Tで置換されていてもよい、請求項44に記載の方法。
- R6'が、1個または複数個のQ-Tで置換されていてもよい、フラニル、チオフェニル、ピラゾリル、イソオキサゾリル、またはトリアゾリルである、請求項45に記載の方法。
- R6'が、1個または複数個のQ-Tで置換されていてもよいC6〜C10アリールである、請求項43に記載の方法。
- 加齢黄斑変性を処置または予防する方法である、請求項39に記載の方法。
- SRPKを阻害する方法である、請求項39に記載の方法。
- 加齢黄斑変性を処置または予防する方法である、請求項50に記載の方法。
- SRPKを阻害する方法である、請求項50に記載の方法。
- SRPKタンパク質を標識する方法であって、該SRPKタンパク質と請求項1〜15のいずれか一項に記載の化合物とを相互作用させる段階を含む方法。
- SRPKタンパク質がSRPK1である、請求項53に記載の方法。
- SRPK1がアミノ酸残基Y227において標識される、請求項54に記載の方法。
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