JP5868596B2 - 特定の化学的実体、組成物および方法 - Google Patents
特定の化学的実体、組成物および方法 Download PDFInfo
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- JP5868596B2 JP5868596B2 JP2010541560A JP2010541560A JP5868596B2 JP 5868596 B2 JP5868596 B2 JP 5868596B2 JP 2010541560 A JP2010541560 A JP 2010541560A JP 2010541560 A JP2010541560 A JP 2010541560A JP 5868596 B2 JP5868596 B2 JP 5868596B2
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Description
細胞の活性は、細胞内事象を刺激または阻害する外部シグナルによって制御され得る。細胞内反応を誘発するための刺激性または阻害性シグナルが細胞内におよび細胞内で伝達される過程は、シグナル伝達と呼ばれる。過去数十年にわたり、シグナル伝達事象のカスケードが解明され、様々な生物学的反応において中心的な役割を担うことが見出されてきた。シグナル伝達経路の様々な成分の欠陥は、数々の形態の癌、炎症性障害、代謝性障害、血管および神経疾患を含む膨大な数の疾患の原因であることが見出されている(非特許文献1)。
一態様では、本発明は、以下の式Iの化合物または薬学的に許容されるその塩を提供し、式中、
Bは、式IIの部分であり、
Xは、存在しないか、または−(CH(R9))z−であり、zは整数1であり、
Yは、存在しないか、または−N(R9)−であり、
R1は、水素、アルキル、アルケニル、アルキニル、アルコキシ、アミド、アルコキシカルボニル、スルホンアミド、ハロ、シアノまたはニトロであり、
R2は、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミノ、ハロ、シアノ、ヒドロキシまたはニトロであり、
R3は、水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アルコキシ、アミド、アミノ、アルコキシカルボニルスルホンアミド、ハロ、シアノ、ヒドロキシまたはニトロであり、
R5、R6、R7およびR8は、独立に、水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル(hetercycloalkyl)、アルコキシ、アミド、アミノ、アシル、アシルオキシ、スルホンアミド、ハロ、シアノ、ヒドロキシまたはニトロであり、
R9の各存在は、独立に、水素、アルキル、シクロアルキルまたはヘテロシクロアルキルである。
Bは、アルキル、アミノ、ヘテロアルキルまたは式IIの部分であり、
Xは、存在しないか、または−(CH(R9))z−であり、zは、独立に、1、2、3または4の整数であり、
Yは、存在しないか、−O−、−S−、−S(=O)−、−S(=O)2−、−N(R9)−、−C(=O)−(CHR9)z−、−C(=O)−、−N(R9)(C=O)−、−N(R9)(C=O)NH−または−N(R9)C(R9)2−であり、
R1は、水素、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、ホスフェート、尿素またはカーボネートであり、
R2は、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、ホスフェート、尿素またはカーボネートであり、
R3は、水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、アリール、ヘテロアリールまたはニトロであり、
R5、R6、R7およびR8は、独立に、水素、C1〜C4アルキル、C2〜C5アルケニル、C2〜C5アルキニル、C3〜C5シクロアルキル、C1〜C4ヘテロアルキル、C1〜C4アルコキシ、C1〜C4アミド、アミノ、アシル、C1〜C4アシルオキシ、アルコキシカルボニル,C1〜C4スルホンアミド、ハロ、シアノ、ヒドロキシまたはニトロであり、
R9の各存在は、独立に、水素、C1〜C10アルキル、C3〜C7シクロアルキル、ヘテロシクロアルキルまたはC2〜C10ヘテロアルキルである。
Bが、式IIの部分であり、
Wcが、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルであり、qが、0、1、2、3または4の整数であり、
Xが、存在しないか、または−(CH(R9))z−であり、zが、整数1であり、
Yが、存在しないか、または−N(R9)−であり、
Yが存在しない場合、Wdは、
R1が、水素、アルキル、アルケニル、アルキニル、アルコキシ、アミド、アルコキシカルボニル、スルホンアミド、ハロ、シアノまたはニトロであり、
R2が、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミノ、ハロ、シアノ、ヒドロキシまたはニトロであり、
R3が、水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アルコキシ、アミド、アミノ、アルコキシカルボニルスルホンアミド、ハロ、シアノ、ヒドロキシまたはニトロであり、
R9が、各場合、独立に、水素、C1〜C10アルキル、シクロアルキルまたはヘテロシクロアルキル(hetercyclooalkyl)であり、R12が、H、アルキル、アルキニル、アルケニル、ハロ、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルである、式Iの構造を有する化合物および薬学的に許容されるその塩が提供される。
Bが、アルキル、アミノ、ヘテロアルキルまたは式IIの部分であり、
Wcが、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルであり、qが、0、1、2、3または4の整数であり、
Xが、存在しないか、または−(CH(R9))z−であり、zが、1、2、3または4の整数であり、
Yが、存在しないか、−N(R9)−または−N(R9)−CH(R9)−であり、
Wdが、
R1が、水素、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、ホスフェート、尿素またはカーボネートであり、
R2が、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロまたはホスフェートであり、
R3が、水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、アリールまたはヘテロアリールであり、
R9が、各場合、独立に、水素、C1〜C10アルキル、C3〜C7シクロアルキル、ヘテロシクロアルキルまたはC2〜C10ヘテロアルキルであり、
R12が、H、アルキル、アルキニル、アルケニル、ハロ、アリール、ヘテロアリール、ヘテロシクロアルキル、シクロアルキル、シアノ、アミノ、カルボン酸、アルコキシカルボニルまたはアミドである、式Iの構造を有する化合物および薬学的に許容されるその塩が提供される。
本発明は、例えば以下の項目を提供する。
(項目1)
式Iの化合物
または薬学的に許容されるその塩[式中、
Bは、式IIの部分であり、
式中、W c は、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルであり、
qは、0、1、2、3または4の整数であり、
Xは、存在しないか、または−(CH(R 9 )) z −であり、zは、整数1であり、
Yは、存在しないか、または−N(R 9 )−であり、
Yが存在しない場合、Wdは、
であり、またはYが存在する場合、Wdは、
であり、
R 1 は、水素、アルキル、アルケニル、アルキニル、アルコキシ、アミド、アルコキシカルボニル、スルホンアミド、ハロ、シアノまたはニトロであり、
R 2 は、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミノ、ハロ、シアノ、ヒドロキシまたはニトロであり、
R 3 は、水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アルコキシ、アミド、アミノ、アルコキシカルボニルスルホンアミド、ハロ、シアノ、ヒドロキシまたはニトロであり、
R 9 の各存在は、独立に、水素、アルキルまたはヘテロシクロアルキルであり、
R 12 は、H、アルキル、アルキニル、アルケニル、ハロ、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルである]。
(項目2)
式Iの化合物
または薬学的に許容されるその塩[式中、
Bは、アルキル、アミノ、ヘテロアルキルまたは式IIの部分であり、
式中、W c は、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルであり、
qは、0、1、2、3または4の整数であり、
Xは、存在しないか、または−(CH(R 9 )) z −であり、zは、1、2、3または4の整数であり、
Yは、存在しないか、−N(R 9 )−または−N(R 9 )−CH(R 9 )−であり、
Wdは、
であり、
R 1 は、水素、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、ホスフェート、尿素またはカーボネートであり、
R 2 は、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロまたはホスフェートであり、
R 3 は、水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、アリールまたはヘテロアリールであり、
R 9 の各存在は、独立に、水素、C 1 〜C 10 アルキル、C 3 〜C 7 シクロアルキル、ヘテロシクロアルキルまたはC 2 〜C 10 ヘテロアルキルであり、
R 12 は、H、アルキル、アルキニル、アルケニル、ハロ、アリール、ヘテロアリール、ヘテロシクロアルキル、シクロアルキル、シアノ、アミノ、カルボン酸、アルコキシカルボニルまたはアミドである]。
(項目3)
R 3 が、−H、−CH 3 、−CH 2 CH 3 、−CF 3 、−Clまたは−Fである、項目1または2に記載の化合物。
(項目4)
R 3 が、−CH 3 、−Clまたは−Fである、項目1または2に記載の化合物。
(項目5)
Bが式IIの部分である、項目2に記載の化合物
[式中、W c は、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルであり、
qは、0、1、2、3または4の整数である]。
(項目6)
Bがヘテロシクロアルキルである、項目1または2に記載の化合物。
(項目7)
Bが単環式ヘテロアリールである、項目1または2に記載の化合物。
(項目8)
Bが置換フェニルである、項目1または2に記載の化合物。
(項目9)
Bが置換アルキルである、項目2に記載の化合物。
(項目10)
Bが−(CH 2 ) 2 −NR a R a であり、各R a が、独立に、水素、アルキル、フルオロアルキル、カルボシクリル、カルボシクリルアルキル、アリール、アラルキル、ヘテロシクロアルキル、ヘテロシクロアルキルアルキル、ヘテロアリールまたはヘテロアリールアルキルであり、あるいは−NR a R a が、一緒に組み合わさって環状部分を形成する、項目9に記載の化合物。
(項目11)
R 1 が、H、−F、−Cl、−CN、−CH 3 、イソプロピル、−CF 3 、−OCH 3 、ニトロまたはホスフェートである、項目1または2に記載の化合物。
(項目12)
R 1 がホスフェートである、項目2に記載の化合物。
(項目13)
R 2 が、ハロ、ヒドロキシ、シアノまたはニトロであり、qが1である、項目1または2に記載の化合物。
(項目14)
R 2 がホスフェートであり、qが1である、項目2に記載の化合物。
(項目15)
R 2 が、アルキルまたはハロであり、qが、1または2である、項目1または2に記載の化合物。
(項目16)
Xが、−CH 2 −、−CH(CH 2 CH 3 )または−CH(CH 3 )−である、項目1または2に記載の化合物。
(項目17)
X−Yが、−CH 2 −N(CH 3 )、−CH 2 −N(CH 2 CH 3 )、−CH(CH 2 CH 3 )−NH−または−CH(CH 3 )−NH−である、項目1または2に記載の化合物。
(項目18)
Yが、N(CH 2 CH 3 )CH 2 −またはN(CH 3 )CH 2 −である、項目2に記載の化合物。
(項目19)
R 12 が単環式ヘテロアリールである、項目1または2に記載の化合物。
(項目20)
R 12 が二環式ヘテロアリールである、項目1または2に記載の化合物。
(項目21)
R 12 がヘテロシクロアルキルである、項目1または2に記載の化合物。
(項目22)
式IV−Aの構造を有する、項目1に記載の化合物。
(項目23)
式V−Aの構造を有する、項目1に記載の化合物。
(項目24)
式IV−Aの構造を有する、項目2に記載の化合物。
(項目25)
式V−Aの構造を有する、項目2に記載の化合物。
(項目26)
式VI−Aの構造を有する、項目2に記載の化合物。
(項目27)
薬学的に許容される賦形剤および項目1に記載の化合物を含む組成物。
(項目28)
液体、固体、半固体、ゲルまたはエアゾール形態である、項目27に記載の組成物。
(項目29)
薬学的に許容される賦形剤および項目2に記載の化合物を含む組成物。
(項目30)
液体、固体、半固体、ゲルまたはエアゾール形態である、項目29に記載の組成物。
(項目31)
ホスファチジルイノシトール−3キナーゼ(PI3キナーゼ)を、有効量の項目1または2に記載の化合物と接触させるステップを含む、PI3キナーゼを阻害する方法。
(項目32)
前記接触ステップが、前記PI3キナーゼを含有する細胞を接触させることを含む、項目31に記載の方法。
(項目33)
前記阻害が、呼吸器疾患に罹患している対象で行われ、前記化合物が、式IV−Aの構造を有する、項目31に記載の方法
[式中、R 12 は、置換フェニルである]。
(項目34)
前記阻害が、関節リウマチまたは呼吸器疾患に罹患している対象で行われ、前記化合物が、式IV−Aの構造を有する、項目31に記載の方法
[式中、R 12 は、二環式ヘテロアリールである]。
(項目35)
第2の治療剤を前記対象に投与するステップを含む、項目31に記載の方法。
(項目36)
望ましくない免疫反応を現している疾患を治療する方法であって、該望ましくない免疫反応を緩和するのに有効な量で、項目1または2に記載の1つまたは複数の化合物を、該治療を必要としている対象に投与するステップを含む、方法。
(項目37)
1つまたは複数の化合物が、試験動物に約30mg/kg BID未満の量で投与される場合に抗TNP IgG3の産生を少なくとも約5分の1に低減することで明らかにされるように、T細胞独立性B細胞活性化を阻害する、項目36に記載の方法。
(項目38)
前記疾患が、対象の関節の腫れまたは疼痛に関連する、項目36に記載の方法。
(項目39)
前記投与が、17日後に関節の平均直径を少なくとも約10%低減すること、および/または7日間の治療後に足首の直径を少なくとも5%低減することで明らかなように、1つまたは複数の関節リウマチの症候を緩和するのに有効である、項目36に記載の方法。
(項目40)
前記望ましくない免疫反応が、抗タイプIIコラーゲン抗体の生成の強化によって明らかである、項目36に記載の方法。
(項目41)
1つまたは複数の化合物が、血清抗タイプIIコラーゲンレベルを約10mg/kg未満のED50に低減する、項目40に記載の方法。
(項目42)
前記疾患が自己免疫疾患である、項目36に記載の方法。
(項目43)
前記対象に、IgEの産生を阻害する薬剤を投与するステップを含む、項目36に記載の方法。
本明細書に列挙されているあらゆる刊行物、特許文書および特許出願文書は、あたかもそれぞれ個々の刊行物、特許文書および特許出願文書が、参考として具体的に個々に援用されることを示すのと同程度に、参考として本明細書に援用される。
本発明の好ましい実施形態を本明細書に示し、記載しているが、かかる実施形態は例示のみによって提供されることが、当業者には明らかとなろう。今回、数々の変動、変化および置換は、本発明から逸脱せずに当業者に明らかとなろう。本明細書に記載の本発明の実施形態の様々な代替が、本発明の実施において使用できることを理解されたい。添付の特許請求の範囲は、本発明の範囲を定義するものであり、これらの特許請求の範囲およびそれらの等価物の範囲に含まれる方法および構造は、それによって包含されることを企図する。
Wdは、ヘテロシクロアルキル、アリールまたはヘテロアリールであり、
Bは、アルキル、アミノ、ヘテロアルキルまたは式IIの部分であり、
qは、0、1、2、3または4の整数であり、
Xは、存在しないか、または−(CH(R9))z−であり、zは、1、2、3または4の整数であり、
Yは、存在しないか、−O−、−S−、−S(=O)−、−S(=O)2−、−N(R9)−、−C(=O)−(CHR9)z−、−C(=O)−、−N(R9)−C(=O)−または−N(R9)−C(=O)NH−、−N(R9)C(R9)2−または−C(=O)−(CHR9)z−であり、
R1は、水素、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、ホスフェート、尿素またはカーボネートであり、
R2は、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、ホスフェート、尿素またはカーボネートであり、
R3は、水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アルコキシ、アミド、アミノ、アシル、アシルオキシ、アルコキシカルボニル、スルホンアミド、ハロ、シアノ、ヒドロキシ、ニトロ、アリールまたはヘテロアリールであり、
R5、R6、R7およびR8は、独立に、水素、C1〜C4アルキル、C2〜C5アルケニル、C2〜C5アルキニル、C3〜C5シクロアルキル、C1〜C4ヘテロアルキル、C1〜C4アルコキシ、C1〜C4アミド、アミノ、アシル、C1〜C4アシルオキシ、C1〜C4スルホンアミド、ハロ、シアノ、ヒドロキシまたはニトロであり、
R9の各存在は、独立に、水素、C1〜C10アルキル、C3〜C7シクロアルキル、ヘテロシクロアルキルまたはC2〜C10ヘテロアルキルである。
R11は、H、アルキル、ハロ、アミノ、アミド、ヒドロキシまたはアルコキシであり、
R12は、H、アルキル、シアノ、アルキニル、アルケニル、ハロ、アリール、ヘテロアリール、ヘテロシクロアルキル、シクロアルキル、アミノ、カルボン酸、アルコキシカルボニルまたはアミドである。
R11は、アミノであり、R12は、H、アルキル、アルキニル、アルケニル、ハロ、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルである。
R11は、アミノであり、R12は、H、アルキル、アルキニル、アルケニル、ハロ、アリール、ヘテロアリール、ヘテロシクロアルキルまたはシクロアルキルである。
本発明は、本発明の1つまたは複数の化合物を含む医薬組成物を提供する。
幾つかの実施形態では、本発明は、本発明の化合物および経口投与に適した医薬賦形剤を含有する、経口投与のための医薬組成物を提供する。
幾つかの実施形態では、本発明は、本発明の化合物および注射に適した医薬賦形剤を含有する、注射のための医薬組成物を提供する。組成物中の成分および薬剤の量は、本明細書に記載の通りである。
幾つかの実施形態では、本発明は、本発明の化合物および経皮送達に適した医薬賦形剤を含有する、経皮送達のための医薬組成物を提供する。
吸入または吹送のための組成物には、薬学的に許容される水性もしくは有機溶媒またはそれらの混合物中の溶液剤および懸濁剤、ならびに散剤が含まれる。液体または固体組成物は、前述の適切な薬学的に許容される賦形剤を含有することができる。好ましくは、組成物は、局所性または全身性作用のために、経口または鼻による呼吸経路によって投与される。好ましくは薬学的に許容される溶媒中の組成物は、不活性なガスを使用することによってネブライザ投与することができる。ネブライザ投与される溶液剤は、ネブライザデバイスまたはフェイスマスクテントに取り付けることができるネブライザデバイス、または間欠的陽圧呼吸機から直接吸入することができる。溶液剤、懸濁剤または散剤組成物は、適切なやり方で製剤を送達するデバイスから、好ましくは経口または経鼻投与することができる。
医薬組成物はまた、本明細書に記載の組成物および舌下、経頬、直腸、骨内、眼内、鼻腔内、硬膜外または髄腔内投与に適した1つまたは複数の薬学的に許容される賦形剤から調製することができる。かかる医薬組成物の調製は、当技術分野で周知である。例えば、それらの全体が参照によって全て本明細書に組み込まれる、Anderson、Philip O.;Knoben、James E.;Troutman、William G、編集、Handbook of Clinical Drug Data、Tenth Edition、McGraw−Hill、2002年;PrattおよびTaylor、編集、Principles of Drug Action、Third Edition、Churchill Livingston、New York、1990年;Katzung、編集、Basic and Clinical Pharmacology、Ninth Edition、McGraw Hill、20037ybg;GoodmanおよびGilman、編集、The Pharmacological Basis of Therapeutics、Tenth Edition、McGraw Hill、2001年;Remingtons Pharmaceutical Sciences、20th Ed.、Lippincott Williams & Wilkins.、2000年;Martindale、The Extra Pharmacopoeia、Thirty−Second Edition(The Pharmaceutical Press、London、1999年)参照。
本発明はまた、それに限定されるものではないが、1種または複数種のPI3キナーゼの機能低下に関連する疾患を含む病状を治療するために、本発明の化合物または医薬組成物を使用する方法を提供する。p110δキナーゼ活性によって媒介される状態および障害の詳説は、その全体があらゆる目的で参照によって本明細書に組み込まれるSaduら、WO01/81346に提示されている。
本発明はまた、他の経路、または同じ経路の他の成分、または重複している標的酵素の組を調節することが知られている薬剤を、本発明の化合物または薬学的に許容される塩、エステル、プロドラッグ、溶媒和物、水和物もしくはその誘導体と組み合わせて使用する併用療法のための方法を提供する。一態様では、かかる療法は、相乗的または付加的治療効果を得るために、それに限定されるものではないが、対象化合物と化学療法剤、治療抗体および放射線治療の組合せを含む。
スキーム12.3−((4−アミノ−3−(3−ヒドロキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)−8−メチル−2−o−トリルイソキノリン−1(2H)−オン(化合物1613)の合成
スキーム13.方法Bによる3−((4−アミノ−3−(3−ヒドロキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)−8−メチル−2−o−トリルイソキノリン−1(2H)−オン(化合物1613)の合成を記載する。
スキーム14.(R)−3−((4−アミノ−3−(3−ヒドロキシブト−1−イニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)−8−メチル−2−o−トリルイソキノリン−1(2H)−オン(化合物1802)の合成を記載する。
スキーム15.3−((6−アミノ−9H−プリン−9−イル)メチル)−8−メチル−2−o−トリルイソキノリン−1(2H)−オン(化合物1902)の合成を記載する。
スキーム16.3−((4−アミノ−3−(3−ヒドロキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)−2−イソプロピル−8−メチルイソキノリン−1(2H)−オン(化合物2010)の合成を記載する。
スキーム17:8−メチル−3−((メチル(9H−プリン−6−イル)アミノ)メチル)−2−o−トリルイソキノリン−1(2H)−オン(化合物4004)の合成を記載する。
スキーム18:3−(1−(9H−プリン−6−イルアミノ)エチル)−8−メチル−2−o−トリルイソキノリン−1(2H)−オン(化合物4106)の合成を記載する。
スキーム19.3−(4−アミノ−1−((8−メチル−1−オキソ−2−o−トリル−1,2−ジヒドロイソキノリン−3−イル)メチル)−1H−ピラゾロ[3,4−d]ピリミジン−3−イル)−5−フルオロフェニルリン酸二水素(化合物4303)の合成を記載する。
クラスIのPI3−Kは、購入することができ(p110α/p85α、p110β/p85α、p110δ/p85αはUpstateから、p110γはSigmaから)、または過去に記載の通り発現させることができる(Knightら、2004年)。IC50値は、脂質キナーゼ活性のための標準のTLCアッセイ(以下に記載)またはハイスループット膜捕捉アッセイのいずれかを使用して測定される。キナーゼの反応は、キナーゼ、阻害剤(2%DMSO最終濃度)、バッファー(25mMのHEPES、pH7.4、10mMのMgCl2)および新しく超音波処理したホスファチジルイノシトール(100μg/ml)を含有する反応混合物を調製することによって実施される。反応は、10μCiのγ−32P−ATPを含有するATPを添加して、最終濃度10〜100μMにすることによって開始し、室温に5分間静置して進行させる。次いでTLC分析のために、1NのHCl105μlに次いでCHCl3:MeOH(1:1)160μlを添加することによって、反応を完了させる。二相混合物をボルテックスし、手短に遠心分離にかけ、CHCl3で事前にコーティングしたゲル搭載ピペットチップを使用して、有機相を新しい管に移す。この抽出物を、TLCプレート上にスポットし、n−プロパノール:1M酢酸の65:35溶液中で3〜4時間展開する。次いでTLCプレートを乾燥させ、リン酸イメージャー(phosphorimager)スクリーン(Storm、Amersham)に曝露させ、定量化する。各化合物について、キナーゼ活性を、試験した最高濃度(一般に200μM)からの2倍希釈である10〜12の阻害剤濃度で測定する。著しい活性を示す化合物について、IC50の決定を2〜4回反復し、報告値をこれらの独立な測定の平均値とする。
Ablキナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、200μMのATP(2.5μCiのγ−32P−ATP)およびBSA0.5mg/mLを含むアッセイにおいて、組換え完全長AblまたはAbl(T315I)(Upstate)に対して3重にアッセイすることができる。最適化Ablペプチド基質EAIYAAPFAKKKを、ホスホアクセプター(phosphoacceptor)(200μM)として使用する。反応を、リン酸セルロースシート上にスポットすることによって完了させ、それを0.5%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
Hckキナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、200μMのATP(2.5μCiのγ−32P−ATP)およびBSA0.5mg/mLを含むアッセイにおいて、組換え完全長Hckに対して3重にアッセイすることができる。最適化Srcファミリーキナーゼペプチド基質EIYGEFKKKを、ホスホアクセプター(200μM)として使用する。反応を、リン酸セルロースシート上にスポットすることによって完了させ、それを0.5%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
IR受容体キナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、10mMのMnCl2、200μMのATP(2.5μCiのγ−32P−ATP)およびBSA0.5mg/mLを含むアッセイにおいて、組換えインスリン受容体キナーゼドメイン(Upstate)に対して3重にアッセイすることができる。ポリE−Y(Sigma、2mg/mL)を基質として使用する。反応を、ニトロセルロース上にスポットすることによって完了させ、それを1MのNaCl/1%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
Srcキナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、200μMのATP(2.5μCiのγ−32P−ATP)およびBSA0.5mg/mLを含むアッセイにおいて、組換え完全長SrcまたはSrc(T338I)に対して3重にアッセイすることができる。最適化Srcファミリーキナーゼペプチド基質EIYGEFKKKを、ホスホアクセプター(200μM)として使用する。反応を、リン酸セルロースシート上にスポットすることによって完了させ、それを0.5%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
DNAKキナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順に従って測定することができる。DNA−PKは、Promegaから購入することができ、DNA−PKアッセイ系(Promega)を使用して、製造者の指示に従ってアッセイすることができる。
mTorに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、50mMのHEPES、pH7.5、1mMのEGTA、10mMのMgCl2、2.5mM、0.01%Tween、10μMのATP(2.5μCiのγ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えmTOR(Invitrogen)に対して試験することができる。ラット組換えPHAS−1/4EBP1(Calbiochem、2mg/mL)を基質として使用する。反応を、ニトロセルロース上にスポットすることによって完了させ、それを1MのNaCl/1%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
VEGF受容体に対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、0.1%のBME、10μMのATP(2.5μCiのμ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えKDR受容体キナーゼドメイン(Invitrogen)に対して試験することができる。ポリE−Y(Sigma、2mg/mL)を基質として使用する。反応を、ニトロセルロース上にスポットすることによって完了させ、それを1MのNaCl/1%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
EphB4に対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、0.1%のBME、10μMのATP(2.5μCiのμ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えEphrin受容体B4キナーゼドメイン(Invitrogen)に対して試験することができる。ポリE−Y(Sigma、2mg/mL)を基質として使用する。反応を、ニトロセルロース上にスポットすることによって完了させ、それを1MのNaCl/1%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
EGFRキナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、0.1%のBME、10μMのATP(2.5μCiのμ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えEGF受容体キナーゼドメイン(Invitrogen)に対して試験することができる。ポリE−Y(Sigma、2mg/mL)を基質として使用する。反応を、ニトロセルロース上にスポットすることによって完了させ、それを1MのNaCl/1%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
KITキナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、1mMのDTT、10mMのMnCl2、10μMのATP(2.5μCiのμ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えKITキナーゼドメイン(Invitrogen)に対して試験することができる。ポリE−Y(Sigma、2mg/mL)を基質として使用する。反応を、ニトロセルロース上にスポットすることによって完了させ、それを1MのNaCl/1%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
RETキナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、2.5mMのDTT、10μMのATP(2.5μCiのμ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えRETキナーゼドメイン(Invitrogen)に対して試験することができる。最適化Ablペプチド基質EAIYAAPFAKKKを、ホスホアクセプター(200μM)として使用する。反応を、リン酸セルロースシート上にスポットすることによって完了させ、それを0.5%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
PDGFRキナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、2.5mMのDTT、10μMのATP(2.5μCiのμ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えPDG受容体キナーゼドメイン(Invitrogen)に対して試験することができる。最適化Ablペプチド基質EAIYAAPFAKKKを、ホスホアクセプター(200μM)として使用する。反応を、リン酸セルロースシート上にスポットすることによって完了させ、それを0.5%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
FLT−3キナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、2.5mMのDTT、10μMのATP(2.5μCiのμ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えFLT−3キナーゼドメイン(Invitrogen)に対して試験することができる。最適化Ablペプチド基質EAIYAAPFAKKKを、ホスホアクセプター(200μM)として使用する。反応を、リン酸セルロースシート上にスポットすることによって完了させ、それを0.5%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
TIE2キナーゼに対する本発明の1つまたは複数の化合物の交差活性またはその欠如は、当技術分野で公知の任意の手順または以下に開示の方法に従って測定することができる。本明細書に記載の化合物を、25mMのHEPES、pH7.4、10mMのMgCl2、2mMのDTT、10mMのMnCl2、10μMのATP(2.5μCiのγ−32P−ATP)およびBSA3μg/mLを含むアッセイにおいて、組換えTIE2キナーゼドメイン(Invitrogen)に対して試験することができる。ポリE−Y(Sigma、2mg/mL)を基質として使用する。反応を、ニトロセルロース上にスポットすることによって完了させ、それを1MのNaCl/1%リン酸で洗浄する(約6回、それぞれ5〜10分)。シートを乾燥させ、移行した放射能を、リン酸イメージングによって定量化する。
B細胞の活性化および増殖を阻害する1つまたは複数の対象化合物の能力を、当技術分野で公知の標準の手順に従って決定する。例えば、生存細胞の代謝活性を測定するインビトロ細胞増殖アッセイを確立する。アッセイは、Alamar Blue還元を使用して、96ウェルマイクロタイタープレートで実施する。Balb/c脾臓B細胞を、Ficoll−Paque(商標)PLUS勾配で精製し、その後MACS B細胞単離キット(Miletenyi)を使用して磁気細胞を分離する。細胞を、B細胞培地(RPMI+10%FBS+Penn/Strep+50uMのbME+5mMのHEPES)中、90ulとして細胞50,000個/ウェルで蒔く。本明細書に開示の化合物を、B細胞培地で希釈し、体積10ulで添加する。プレートを、37Cおよび5%CO2(最終濃度0.2%DMSO)で30分間インキュベートする。次いで、LPS10ug/mlまたはF(ab’)2Donkey抗マウスIgM5ug/mlのいずれかと、2ng/mlの組換えマウスIL4を含有するB細胞刺激カクテル50ulを、B細胞培地に添加する。プレートを、37℃および5%CO2で72時間インキュベートする。体積15uLのAlamar Blue試薬を各ウェルに添加し、プレートを37Cおよび5%CO2で5時間インキュベートする。Alamar Blue蛍光物質(fluoresce)を、560Ex/590Emで読み取り、IC50またはEC50値を、GraphPad Prism 5を使用して算出する。
腫瘍細胞系の増殖を阻害する1つまたは複数の対象化合物の能力を、当技術分野で公知の標準の手順に従って決定する。例えば、生存細胞の代謝活性を測定するために、インビトロ細胞増殖アッセイを実施することができる。アッセイは、Alamar Blue還元を使用して、96ウェルマイクロタイタープレートで実施する。ヒト腫瘍細胞系を、ATCC(例えば、MCF7、U−87MG、MDA−MB−468、PC−3)から得、T75フラスコ中で増殖集密させ、0.25%トリプシンでトリプシン処理し、腫瘍細胞培地(DMEM+10%FBS)で1回洗浄し、腫瘍細胞培地中、90ulとして細胞5,000個/ウェルで蒔く。本明細書に開示の化合物を、腫瘍細胞培地で希釈し、体積10ulで添加する。プレートを、37Cおよび5%CO2で72時間インキュベートする。体積10uLのAlamar Blue試薬を各ウェルに添加し、プレートを37Cおよび5%CO2で3時間インキュベートする。Alamar Blue蛍光物質を、560Ex/590Emで読み取り、IC50値を、GraphPad Prism 5を使用して算出する。
本明細書に記載の化合物を、ヒトおよびマウス腫瘍モデルのパネルで評価することができる。
1.臨床から得る卵巣癌モデル
この腫瘍モデルは、卵巣癌患者の腫瘍生検から確立する。腫瘍生検を、患者から取り出す。
A2780Taxは、パクリタキセルに耐性のあるヒト卵巣癌モデルである。これは、細胞をパクリタキセルおよびベラパミル、MDR拮抗薬(reversal agent)と共にインキュベートすることによって、感受性患者A2780系から得る。その耐性機構は、非MDR関連であることが示されており、βチューブリンタンパク質をコードする遺伝子における突然変異に起因するものである。
HCT116/VM46は、感受性HCT116親系から発症したMDR耐性結腸癌である。ヌードマウスでインビボ増殖したHCT116/VM46は、パクリタキセルに対して一貫して高い耐性を示している。
M5076は、本質的にインビボでパクリタキセルに不応性であるマウス線維肉腫である。
1つまたは複数の対象化合物の安定性を、当技術分野で公知の標準手順に従って決定する。例えば、1つまたは複数の対象化合物の安定性は、インビトロアッセイによって確立される。特に、肝臓からのマウス、ラットまたはヒトミクロソームと反応する場合の、1つまたは複数の対象化合物の安定性を測定するインビトロミクロソーム安定性アッセイが確立される。ミクロソームと化合物の反応は、1.5mLのエッペンドルフ管中で実施される。各管に、10.0mg/mlのNADPH0.1μL;20.0mg/mlのマウス、ラットまたはヒト肝臓ミクロソーム75μL;0.2Mリン酸緩衝液0.4μLおよびddH2O425μLを入れる。陰性対照(NADPHなし)の管に、20.0mg/mlのマウス、ラットまたはヒト肝臓ミクロソーム75μL;0.2Mリン酸緩衝液0.4μLおよびddH2O525μLを入れる。反応は、10.0mMの試験化合物1.0μLを添加することによって開始する。反応管を、37℃でインキュベートする。反応の0、5、10、15、30および60分において、冷却メタノール300μLを入れた新しいエッペンドルフ管に、サンプル100μLを収集する。サンプルを15,000rpmで遠心分離にかけて、タンパク質を除去する。遠心分離にかけたサンプルの上清を、新しい管に移す。ミクロソームと反応した後の安定な化合物の上清中濃度を、液体クロマトグラフィー/質量分析(LC−MS)によって測定する。
血漿中の1つまたは複数の対象化合物の安定性を、当技術分野で公知の標準手順に従って決定する。例えば、Rapid Commun. Mass Spectrom.、10巻:1019〜1026頁参照。以下の手順は、ヒトの血漿を使用するHPLC−MS/MSアッセイであり、サル、イヌ、ラットおよびマウスを含む他の種も利用可能である。冷凍したヘパリン化ヒト血漿を冷却水浴中で解凍し、使用前に10分間、4℃において2000rpmでスピンする。原液400μMからの対象化合物を、事前に温めた一定分量の血漿に添加して、試験化合物5μMおよび0.5%DMSOを含有する最終アッセイ体積400μL(または半減期の決定のために800μL)を得る。反応物を、37℃で0分および60分間、または半減期の決定のために37Cで0、15、30、45および60分間、振とうしながらインキュベートする。インキュベーション混合物50μLを氷冷アセトニトリル200μLに移すことによって反応を停止し、5分間振とうすることによって混合する。サンプルを6000×gで15分間、4℃において遠心分離にかけ、上清120μLを取り出して清浄な管に入れる。次いでサンプルを蒸発乾固させ、HPLC−MS/MSによる分析のために提示する。
1つまたは複数の対象化合物の化学安定性は、当技術分野で公知の標準の手順に従って決定する。以下に、対象化合物の化学安定性を確定するための例示的手順を詳説する。化学安定性のアッセイに使用される初期(default)バッファーは、pH7.4のリン酸緩衝食塩水(PBS)であるが、他の適切なバッファーを使用することができる。原液100μMからの対象化合物を、一定分量のPBSに添加して(二重に)、試験化合物5μMおよび1%DMSOを含有する最終アッセイ体積400μLを得る(半減期の決定のためには、サンプル総体積700μLを調製する)。反応物を、37℃で0分および24時間、振とうしながらインキュベートし、半減期の決定のために、サンプルを0、2、4、6および24時間インキュベートする。インキュベーション混合物100μLを氷冷アセトニトリル100μLにすぐに添加することによって反応を停止し、5分間ボルテックスする。次いでサンプルを、HPLC−MS/MSによる分析まで−20℃で保存する。所望の場合、問題とする対象化合物は24時間にわたってかなり加水分解されるので、対照化合物またはクロラムブシルなどの参照化合物(5μM)を、この化合物と同時に試験する。サンプルを、(RP)HPLC−MS/MSによって、選択された反応モニタリング(SRM)を使用して分析する。HPLC条件は、オートサンプラーを備えたバイナリLCポンプ、C12、2×20mmのミックスモードカラムおよび勾配プログラムからなる。分析物に対応するピーク領域を、HPLC−MS/MSによって記録する。24時間後に残っている親化合物対時間0における残量の比をパーセントで表し、化学安定性として報告する。半減期の決定の場合、半減期は、残っている化合物(%)対時間の対数曲線の最初の線形範囲の傾斜から推定し、一次速度則を推測する。
それに限定されるものではないが、L6筋芽細胞、B−ALL細胞、B細胞、T細胞、白血病細胞、骨髄細胞、p190形質導入細胞、philladelphiaクロモソーム陽性細胞(Ph+)およびマウス胎児線維芽細胞を含むAkt/mTOR経路の成分を含む細胞を、一般に、ウシ胎児血清および/または抗生物質を補充したDMEMなどの細胞増殖培地中で増殖させ、培養密度まで増殖させる。
PI3K/Akt/mTorシグナル伝達は、phosflow法(Methods Enzymol.2007年;434:131〜54頁)を使用して血球中で測定する。この方法の利点は、それが生来単一細胞アッセイであり、したがって集団平均ではなく細胞の異種性を検出し得ることである。これによって、他のマーカーによって定義された様々な集団におけるシグナル伝達状態を同時に区別(dinstinction)することができる。Phosflowは、かなり定量的でもある。本明細書に開示の1つまたは複数の化合物の効果を試験するために、未分化脾細胞または末梢血単核細胞を抗CD3で刺激して、T細胞受容体シグナル伝達を開始する。次いで細胞を固定し、表面マーカーおよび細胞内リンタンパク質のために染色する。本明細書に開示の阻害剤は、Akt−S473およびS6の抗CD3媒介性リン酸化を阻害する一方、ラパマイシンはS6リン酸化を阻害し、試験条件下でAktリン酸化を強化すると予期される。
p190BCR−Ablレトロウイルスで新しく形質転換したマウスの骨髄細胞(本明細書では、p190形質導入細胞と呼ぶ)を、約7日間、約30%血清中組換えヒトIL−7を含むM3630メチルセルロース培地中、様々な薬物の組合せの存在下で蒔き、形成したコロニーの数を、顕微鏡下で目視検査によって計数する。
レシピエントである雌マウスに、γ源からそれぞれ約5Gyで、約4時間離して2回の投与で致死的放射線を照射する。2回目の放射線投与の約1時間後、マウスに約1×106個の白血病細胞(例えば、Ph+ヒトもしくはマウス細胞、またはp190形質導入骨髄細胞)を静脈注射する。これらの細胞を、3〜5週齢のドナーマウスからの放射線防護線量の約5×106個の正常な骨髄細胞と一緒に投与する。レシピエントに、水に入れた抗生物質を与え、毎日モニターする。約14日後に罹患したマウスを安楽死させ、リンパ器官を分析のために回収する。キナーゼ阻害剤の処理は、白血病細胞注射の約10日後に開始し、マウスが罹患するまでまたは移植後最大約35日まで、毎日継続する。阻害剤は、経口洗浄によって与える。
B細胞におけるPI3Kシグナル伝達に対抗する阻害性受容体FcγRIIbをもたないマウスは、高い浸透度の狼瘡を発症する。FcγRIIbノックアウトマウス(R2KO、Jackson Labs)は、幾人かの狼瘡の患者がFcγRIIbの発現または機能の低下を示す場合、ヒト疾患の有効なモデルとみなされる(S. BollandおよびJ.V. Ravtech 2000年、Immunity 12巻:277〜285頁)。
雌のレシピエントマウスに、γ線源から致死的放射線を照射する。放射線投与の約1時間後、初期継代のp190形質導入培養物から約1×106個の白血病細胞をマウスに注射する(例えば、Cancer Genet Cytogenet.2005年8月、161巻(1号):51〜6頁に記載の通り)。これらの細胞は、3〜5週齢のドナーマウスからの、放射線防護線量の約5×106個の正常な骨髄細胞と一緒に投与される。レシピエントに、抗体を水に入れて与え、毎日モニターする。約14日後に罹患したマウスを安楽死させ、フローサイトメトリーおよび/または磁気濃縮(magnetic enrichment)のために、リンパ器官を回収する。処理は、およそ10日目に開始し、マウスが罹患するまでまたは移植後最長約35日後まで、毎日継続する。薬物を強制経口(p.o.)によって与える。パイロット実験では、治癒性はないが、白血病の発症を約1週間以下遅延する用量の化学治療剤を同定し、対照をビヒクル処理し、またはこのモデルにおける白血病誘発を遅延するが治癒しないことが既に示されている化学療法剤(例えば、イマチニブ約70mg/kg毎日2回)で処理する。第1相では、eGFPを発現するp190細胞を使用し、死後分析は、骨髄、脾臓およびリンパ節(LN)における白血病細胞のパーセンテージのフローサイトメトリーによる計数に限定される。第2相では、ヒトCD4の無尾形態を発現するp190細胞を使用し、死後分析は、hCD4+脾臓からの細胞を磁気分類し、その後非常に重要なシグナル伝達エンドポイントであるpAkt−T308およびS473;pS6およびp4EBP−1の免疫ブロット分析を行うことを含む。免疫ブロット検出のための対照として、分類した細胞を、溶解前の本開示の阻害剤のキナーゼ阻害剤の存在下、またはそれなしにインキュベートする。場合によって「phosflow」を使用して、事前の分類なしに、hCD4依存性細胞におけるpAkt−S473およびpS6−S235/236を検出する。これらのシグナル伝達試験は、例えば薬物処理したマウスが35日目の時点で臨床的白血病を発症していなかった場合に特に有用である。生存についてのカプラン−マイヤープロットを作成し、当技術分野で公知の方法に従って統計的分析を実施する。p190細胞からの結果を、別個に累積的に分析する。
T細胞独立性抗体産生を抑制する本発明の化合物の作用を試験するために、TNP−Ficoll B細胞活性化アッセイを本明細書に記載の通り使用した。本発明の化合物を、適切なビヒクル(例えば、5%1−メチル−2−ピロリジノン、85%ポリエチレングリコール400、10%solutor)に溶解した。化合物は、4〜10週齢のマウスにTNP−Ficoll処理する約1時間前に経口投与した。B細胞活性化に対する化合物の作用を研究するために、マウスの組を以下の表に従って群に分けた。
自己免疫疾患である関節炎に対する本発明の化合物の作用を研究するために、コラーゲン誘発性発症型関節炎モデルを使用した。雌のLewisラットに、0日目にコラーゲンを注射した。ウシタイプIIコラーゲンを、0.01N酢酸中4mg/ml溶液として調製した。等体積のコラーゲンおよびフロイント不完全アジュバントを、乳化材料のビーズが水中でその形態を保持するまで手動で混合することによって、乳化させた。各げっ歯類に、それぞれの注射時間において混合物300μlを注射し、背部の3つの皮下部位にわたって展開した。
0=正常
1=滑膜/関節周囲組織における炎症細胞の最小限の浸潤
2=軽度の浸潤
3=中等度の浮腫を伴う中等度の浸潤
4=顕著な浮腫を伴う顕著な浸潤
5=重症の浮腫を伴う重症の浸潤
足首パンヌス
0=正常
1=軟骨および軟骨下骨におけるパンヌスの最小限の浸潤
2=軽度の浸潤(辺縁帯において脛骨または足根骨の<1/4)
3=中等度の浸潤(辺縁帯において脛骨または小足根骨の1/4〜1/3が罹患)
4=顕著な浸潤(辺縁帯において脛骨または足根骨の1/2〜3/4が罹患)
5=重症の浸潤(辺縁帯において脛骨または足根骨の>3/4が罹患、全体構造の重症の捻挫)
膝パンヌス
0=正常
1=軟骨および軟骨下骨におけるパンヌスの最小限の浸潤
2=軽度の浸潤(脛骨または大腿骨の表面または軟骨領域の最大1/4にわたって拡大)
3=中等度の浸潤(脛骨または大腿骨の表面または軟骨領域の>1/4かつ<1/2にわたって拡大)
4=顕著な浸潤(脛骨または大腿骨表面の1/2〜3/4にわたって拡大)
5=重症の浸潤(表面の>3/4に拡大)
軟骨損傷(足首、小足根骨重視)
0=正常
1=最小限=明らかな軟骨細胞喪失またはコラーゲン破壊がない、トルイジンブルー染色の最小限から軽度の喪失
2=軽度=限局性の軽度(表在性)軟骨細胞喪失および/またはコラーゲン破壊がある、トルイジンブルー染色の軽度喪失
3=中等度=多源性であり中等度の(中間帯域までの深度)軟骨細胞喪失および/またはコラーゲン破壊があり、小足根骨が1/2〜3/4の深度まで罹患した、トルイジンブルー染色の中等度の喪失
4=顕著=多源性であり顕著な(深部帯域までの深度)軟骨細胞喪失および/またはコラーゲン破壊があり、1つまたは複数の小足根骨が軟骨の全層喪失を有する、トルイジンブルー染色の顕著な喪失
5=重症=多源性であり重症の(タイドマークまでの深度)軟骨細胞喪失および/またはコラーゲン破壊がある、トルイジンブルー染色の重症のびまん性喪失
軟骨損傷(膝、大腿骨顆重視)
0=正常
1=最小限=明らかな軟骨細胞喪失またはコラーゲン破壊がない、トルイジンブルー染色の最小限から軽度の喪失
2=軽度=限局性の軽度(表在性)軟骨細胞喪失および/またはコラーゲン破壊がある、トルイジンブルー染色の軽度喪失
3=中等度=多源性からびまん性の中等度の(中間帯域までの深度)軟骨細胞喪失および/またはコラーゲン破壊がある、トルイジンブルー染色の中等度の喪失
4=顕著=多源性からびまん性の顕著な(深部帯域までの深度)軟骨細胞喪失および/またはコラーゲン破壊があり、あるいは一方の大腿骨表面が完全にまたはほぼ完全に喪失している、トルイジンブルー染色の顕著な喪失
5=重症=両方の大腿骨および/または脛骨に多源性であり重症の(タイドマークまでの深度)軟骨細胞喪失および/またはコラーゲン破壊がある、トルイジンブルー染色の重症のびまん性喪失
骨吸収(足首)
0=正常
1=最小限=低倍率では容易に明らかにならない小領域の再吸収、まれに破骨細胞
2=軽度=低倍率では容易に明らかにならないより多数の領域の再吸収、より多数の破骨細胞、辺縁帯において再吸収された脛骨または足根骨<1/4
3=中等度=皮質の全層欠陥のない髄質骨梁および皮質骨の明らかな再吸収、幾らかの髄質骨梁の喪失、低倍率で明らかな病変、より多数の破骨細胞、辺縁帯において脛骨または足根骨の1/4〜1/3が罹患
4=顕著=皮質骨の全層欠陥、しばしば残りの皮質表面のプロファイルの捻挫を伴う、髄様骨の顕著な喪失、多数の破骨細胞、辺縁帯において脛骨または足根骨の1/2〜3/4が罹患
5=重症=皮質骨の全層欠陥、しばしば残りの皮質表面のプロファイルの捻挫を伴う、髄様骨の顕著な喪失、多数の破骨細胞、辺縁帯において脛骨または足根骨の>3/4が罹患、全体構造の重症の捻挫
骨吸収(膝)
0=正常
1=最小限=低倍率では容易に明らかにならない小領域の再吸収、まれに破骨細胞
2=軽度=より多数の領域の再吸収、脛骨または大腿骨表面(内側または外側)の1/4に及ぶ軟骨下骨の明らかな喪失
3=中等度=脛骨または大腿骨表面(内側または外側)の>1/4かつ<1/2に及ぶ軟骨下骨の明らかな再吸収
4=顕著=脛骨または大腿骨表面(内側または外側)の≧1/2かつ<3/4に及ぶ軟骨下骨の明らかな再吸収
5=重症=脛骨または大腿骨表面(内側または外側)の>3/4に及ぶ破壊による全体の関節の捻挫
身体/足の重量の統計的分析、足のAUCパラメータおよび病理組織学的パラメータを、スチューデントのt試験または他の適切な試験(ANOVAと事後試験)を使用して、有意水準5%の有意性の組を用いて評価した。足の重量およびAUCの阻害パーセントを、以下の式を使用して算出した。
%阻害=A−B/A×100
A=平均疾患対照−平均正常
B=平均処理−平均正常
図3に示した結果は、試験条件下での、ラット発症型タイプIIコラーゲン誘発性関節炎モデルにおける平均足首直径に対する、12時間間隔での10、30および60mg/kgの用量の化合物#53の経時的作用を示す。ビヒクルのみの対照またはメトトレキサート対照に対して、本発明の化合物は、関節炎誘発性の足首直径増大の有意な経時的低減を示した。
ラットにおいて7日で確立されたタイプIIコラーゲン誘発性関節炎の炎症、軟骨破壊および骨再吸収を阻害する、本発明の化合物の用量反応性の有効性を調べるために、化合物を6日間毎日または毎日2回、経口投与した。
ラットの髄腔内カテーテル法
イソフルランで麻酔したLewisラット(200〜250g)に、髄腔内(IT)カテーテルを移植した。6日の回復期間後、感覚障害または運動障害を有すると思われた動物(総数の5%未満)を除く全ての動物を実験に使用した。IT投与について、薬物または食塩水10μlに次いで等張食塩水10μlを、カテーテルを介して注射した。
アジュバントによる関節炎および薬物処理
Lewisラットを、カテーテル移植の数日後0日目に、尾の付け根に完全フロイントアジュバント(CFA)0.1mlで免疫を付与した(n=6/群)。薬物(例えば、本発明の1つもしくは複数の化合物またはビヒクル)処理を、一般に8日目に開始し、20日目まで毎日継続した。関節炎の臨床徴候は、一般に10日目に始まり、足の膨張を水置換性プレチスモメトリー(plethysmometry)によって1日置きに決定した。
本発明の化合物の薬物動態を研究するために、4〜10週齢のマウスの組を以下の表に従って群に分ける。
baseotestアッセイは、Orpegen Pharma Basotest試薬キットを使用して実施する。ヘパリン化全血を、試験化合物または溶媒で、37Cにおいて20分間事前インキュベートする。次いで血液を、アッセイキット刺激バッファー(反応のための一次細胞に対する)に次いでアレルゲン(イエダニ抽出物または草抽出物)で、20分間インキュベートする。脱顆粒過程は、血液サンプルを氷上でインキュベートすることによって停止する。次いで、細胞を抗IgE−PEで標識化して、好塩基性顆粒球を検出し、抗gp53−FITCで標識化して、gp53(活性化した好塩基球上で発現する糖タンパク質)を検出する。染色後、溶解溶液を添加することによって赤血球を溶解する。細胞を洗浄し、フローサイトメトリーによって分析する。化合物7および53は、このアッセイで試験した場合、マイクロモル以下の範囲の好塩基性顆粒球のアレルゲン誘発性活性化を阻害する。
本発明の化合物は、IgE産生または活性を阻害する薬剤と併用投与される場合、相乗的または付加的有効性を示すことができる。IgE産生を阻害する薬剤には、例えば、TEI−9874、2−(4−(6−シクロヘキシルオキシ−2−ナフチルオキシ)フェニルアセトアミド)安息香酸、ラパマイシン、ラパマイシン類似体(即ちラパログ)、TORC1阻害剤、TORC2阻害剤ならびにmTORC1およびmTORC2を阻害する任意の他の化合物の1つまたは複数が含まれる。IgE産生を阻害する薬剤には、例えば、オマリズマブおよびTNX−901などの抗IgE抗体が含まれる。
マウスを安楽死させ、脾臓を取り出し、ナイロンメッシュを介して分散させて、単一細胞懸濁液を生成する。脾細胞を洗浄し(浸透圧ショックによって赤血球を除去した後)、抗CD43および抗Mac−1抗体結合マイクロビーズ(Miltenyi Biotec)でインキュベートする。ビーズに結合した細胞を、磁気細胞分類デバイスを使用して、未結合細胞から分離する。磁化カラムによって望ましくない細胞を保持し、静止B細胞を流水式で収集する。精製したB細胞に、リポ多糖または抗CD40抗体およびインターロイキン4で刺激を与える。刺激を受けたB細胞を、ビヒクルのみで、または化合物53などの本発明のPI3Kδ阻害剤で、ラパマイシン、ラパログまたはmTORC1/C2阻害剤などのmTOR阻害剤を伴って、またはそれなしに処理する。結果は、mTOR阻害剤(例えばラパマイシン)のみの存在下で、IgGおよびIgE反応に対する実質的効果が殆どないか全くないことを示すと予期される。しかし、PI3KδおよびmTOR阻害剤の存在下では、B細胞は、ビヒクルのみで処理したB細胞と比較してIgG反応の低減を示し、B細胞は、PI3Kδ阻害剤のみで処理したB細胞と比較してIgE反応の低減を示すことが予期される。
マウスを、TNP−FicollまたはTNP−KHLで免疫付与し、ビヒクル、PI3Kδ阻害剤、例えば本発明の化合物53、mTOR阻害剤、例えばラパマイシン、またはラパマイシンなどのmTOR阻害剤と組み合わせたPI3Kδ阻害剤で処理する。抗原特異的血清IgEを、ELISAによって、TNP−BSAでコーティングしたプレートおよびアイソタイプの特異的標識化抗体を使用して測定する。mTOR阻害剤のみで処理したマウスは、ビヒクル対照と比較して、抗原特異的IgG3反応に対して殆どまたは全く実質的効果を示さず、IgE反応の統計的に有意な増大を全く示さないと予期される。また、PI3Kδ阻害剤およびmTOR阻害剤の両方で処理したマウスは、ビヒクルのみで処理したマウスと比較して、抗原特異的IgG3反応の低減を示すと予期される。さらに、PI3Kδ阻害剤およびmTOR阻害剤の両方で処理したマウスは、PI3Kδ阻害剤のみで処理したマウスと比較して、IgE反応の低減を示す。
雌のLewisラットを麻酔し、調製したコラーゲン注射を与え、前述の通り0日目に投与する。6日目に動物を麻酔し、第2のコラーゲン注射を与える。正常な(疾患前)右および左足首関節のノギス測定を、9日目に実施する。10〜11日目に関節炎が一般に生じ、ラットを処理群に無作為化する。無作為化は、足首関節腫脹が明らかに確立し、両側性疾患の十分な証拠が見られた後に実施する。
Claims (27)
- 式Iの化合物
Bは、式IIの部分であり、
qは、0、1、2、3または4の整数であり、
Xは、存在しないか、または−(CH(R9))z−であり、かつzは、1の整数であり、
Yは、−N(R9)−であり、
Wdは、
R1は、水素、アルキル、またはハロであり、
R2は、アルキル、またはハロであり、
R3は、水素、またはアルキルであり、かつ
R9の各存在は、独立に、水素、またはアルキルであり;
ここで、該アルキル、アリール、及びシクロアルキルは、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヒドロキシ、ハロ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ニトロ、トリメチルシラニル、−ORa、−SRa、−OC(O)−Ra、−N(Ra)2、−C(O)Ra、−C(O)ORa、−OC(O)N(Ra)2、−C(O)N(Ra)2、−N(Ra)C(O)ORa、−N(Ra)C(O)Ra、−N(Ra)C(O)N(Ra)2、−N(Ra)C(NRa)N(Ra)2、−N(Ra)S(O)tRa、−S(O)tORa、−S(O)tN(Ra)2、またはPO3(Ra)2(式中、各Raは、独立に、水素、アルキル、フルオロアルキル、カルボシクリル、カルボシクリルアルキル、アリール、アラルキル、ヘテロシクロアルキル、ヘテロシクロアルキルアルキル、ヘテロアリールまたはヘテロアリールアルキルであり、かつtは、1または2である)から選択される1つまたは複数の置換基によって、場合によって置換されており、
該ヘテロアリールは、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヒドロキシ、ハロ、シアノ、ニトロ、オキソ、チオキソ、トリメチルシラニル、−OR a 、−SR a 、−OC(O)−R a 、−N(R a ) 2 、−C(O)R a 、−C(O)OR a 、−C(O)N(R a ) 2 、−N(R a )C(O)OR a 、−N(R a )C(O)R a 、−N(R a )S(O) t R a 、−S(O) t OR a 、−S(O) t N(R a ) 2 またはPO 3 (R a ) 2 (各R a は、独立に、水素、アルキル、フルオロアルキル、カルボシクリル、カルボシクリルアルキル、アリール、アラルキル、ヘテロシクロアルキル、ヘテロシクロアルキルアルキル、ヘテロアリールまたはヘテロアリールアルキルであり、tは、1または2である)から選択される1つまたは複数の置換基によって、場合によって置換されており、
該ヘテロシクロアルキルは、アルキル、ヘテロアルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、ヒドロキシ、ハロ、シアノ、ニトロ、オキソ、チオキソ、トリメチルシラニル、−OR a 、−SR a 、−OC(O)−R a 、−N(R a ) 2 、−C(O)R a 、−C(O)OR a 、−C(O)N(R a ) 2 、−N(R a )C(O)OR a 、−N(R a )C(O)R a 、−N(R a )S(O) t R a 、−S(O) t OR a 、−S(O) t N(R a ) 2 またはPO 3 (R a ) 2 (各R a は、独立に、水素、アルキル、フルオロアルキル、カルボシクリル、カルボシクリルアルキル、アリール、アラルキル、ヘテロシクロアルキル、ヘテロアリールまたはヘテロアリールアルキルであり、tは、1または2である)から選択される1つまたは複数の置換基によって、場合によって置換されている]。 - qが0である、請求項1記載の化合物または薬学的に許容されるその塩。
- R1がハロである、請求項2記載の化合物または薬学的に許容されるその塩。
- R1がC1〜C6アルキルである、請求項2記載の化合物または薬学的に許容されるその塩。
- R1がメチルである、請求項4記載の化合物または薬学的に許容されるその塩。
- R3がC1〜C6アルキルである、請求項1記載の化合物または薬学的に許容されるその塩。
- R3がメチルである、請求項6記載の化合物または薬学的に許容されるその塩。
- R9が水素である、請求項1記載の化合物または薬学的に許容されるその塩。
- Xが、−CH2−、−CH(CH2CH3)−または−CH(CH3)−である、請求項1記載の化合物または薬学的に許容されるその塩。
- X−Yが、−CH2−N(CH3)−、−CH2−N(CH2CH3)−、−CH(CH2CH3)−NH−または−CH(CH3)−NH−である、請求項1記載の化合物または薬学的に許容されるその塩。
- 下記化合物
- 下記化合物
- 薬学的に許容される賦形剤および請求項1〜12のいずれか一項記載の化合物または薬学的に許容されるその塩を含む、組成物。
- 液体、固体、半固体、ゲルまたはエアゾール形態である、請求項13記載の組成物。
- ホスファチジルイノシトール−3キナーゼ(PI3キナーゼ)を阻害するための組成物であって、有効量の請求項1〜12のいずれか一項記載の化合物または薬学的に許容されるその塩を含む、前記組成物。
- 前記PI3キナーゼを含有する細胞と接触されることを特徴とする、請求項15記載の組成物。
- 前記細胞が、T細胞、B細胞、肥満細胞、樹状細胞および好中球から選択される、請求項16記載の組成物。
- 前記阻害が、癌、骨疾患、炎症性疾患、免疫疾患、神経疾患、代謝性障害、呼吸器疾患、血栓症または心疾患に罹患している対象で行われる、請求項16記載の組成物。
- 前記阻害が、癌に罹患している対象で行われる、請求項18記載の組成物。
- 前記癌が、リンパ腫または白血病である、請求項18記載の組成物。
- 前記白血病が、急性骨髄性白血病(AML)、急性リンパ性白血病、慢性リンパ性白血病(CLL)、慢性骨髄性白血病(CML)、有毛細胞白血病、脊髄形成異常症、骨髄増殖性疾患、肥満細胞症、多発性骨髄腫(MM)または骨髄異形成症候群(MDS)である、請求項20記載の組成物。
- 前記リンパ腫が、びまん性大型B細胞リンパ腫、B細胞免疫芽細胞リンパ腫、小型非切れ込み核細胞性リンパ腫、ヒト白血球ウイルス−タイプ1(HTLV−1)白血病/リンパ腫、成人T細胞リンパ腫、ホジキン疾患または非ホジキンリンパ腫である、請求項20記載の組成物。
- 前記疾患が、炎症性疾患または免疫疾患であり、該炎症性疾患または免疫疾患が、喘息、肺気腫、アレルギー、皮膚炎、関節リウマチ、乾癬、紅斑性狼瘡、移植片対宿主病、炎症性腸疾患、湿疹、強皮症、クローン病または多発性硬化症である、請求項18記載の組成物。
- 疾患を治療するための請求項1〜12のいずれか一項記載の化合物を含む組成物であって、該疾患が、癌、骨疾患、炎症性疾患、免疫疾患、神経疾患、代謝性障害、呼吸器疾患、血栓症または心疾患である、前記組成物。
- 前記疾患が癌である、請求項24記載の組成物。
- 前記疾患が炎症性疾患である、請求項24記載の組成物。
- 疾患を治療するための薬剤の製造における請求項1〜12のいずれか一項記載の化合物の使用であって、該疾患が、癌、骨疾患、炎症性疾患、免疫疾患、神経疾患、代謝性障害、呼吸器疾患、血栓症または心疾患である、前記使用。
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