JP7330542B2 - キノリン構造を有するpan-KITキナーゼ阻害剤及びその適用 - Google Patents
キノリン構造を有するpan-KITキナーゼ阻害剤及びその適用 Download PDFInfo
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- JP7330542B2 JP7330542B2 JP2021533277A JP2021533277A JP7330542B2 JP 7330542 B2 JP7330542 B2 JP 7330542B2 JP 2021533277 A JP2021533277 A JP 2021533277A JP 2021533277 A JP2021533277 A JP 2021533277A JP 7330542 B2 JP7330542 B2 JP 7330542B2
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 238000003963 x-ray microscopy Methods 0.000 description 1
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Description
Aはアリール又は6員ヘテロシクリルから選択され、
nは1~3から選択される整数であり、
R1は、水素、ハロ、C1~6アルキル、C1~6ハロアルキル、C1~6アルコキシ、及びシアノから選択され、
R2及びR3はそれぞれ独立して、水素、ハロ、C1~6アルキル、C1~6ハロアルキル、C1~6アルコキシから選択されるか、又はR2及びR3は共にフェニル若しくは5員ヘテロシクリルを形成する)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグを含む、選択的キナーゼ阻害剤を提供する。
特段の規定がない限り、本明細書で使用される全ての技術用語及び科学用語は、特許請求の範囲に記載の主題が属する技術分野における当業者によって通常理解されるのと同じ意味を有する。
本発明は、式(I):
Aはアリール又は6員ヘテロシクリルから選択され、
nは1~3から選択される整数であり、
R1は、水素、ハロ、C1~6アルキル、C1~6ハロアルキル、C1~6アルコキシ、及びシアノから選択され、
R2及びR3はそれぞれ独立して、水素、ハロ、C1~6アルキル、C1~6ハロアルキル、C1~6アルコキシから選択されるか、又はR2及びR3は共にフェニル若しくは5員ヘテロシクリルを形成する)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグを含む、選択的キナーゼ阻害剤を提供する。
本出願はまた、少なくとも1つの式(I)の化合物、又は該化合物の薬学的に許容可能な塩、溶媒和物、エステル、酸、薬学的に活性な代謝物若しくはプロドラッグと、薬学的に許容可能な担体又は賦形剤と、任意に他の治療剤とを含む医薬組成物を提供する。
式(I)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグ、又はそれを含む医薬組成物は、チロシンキナーゼKIT(野生型若しくは様々な変異型、又はそれらの組合せ)の活性を阻害するために使用され得る。式(I)の化合物、又はその薬学的に許容可能な塩、溶媒和物、エステル、酸、代謝物若しくはプロドラッグ、又はその医薬組成物は、固形腫瘍(良性又は特に悪性のタイプを含む)、特に肉腫、消化管間質腫瘍(GIST)、結腸直腸癌、急性骨髄芽球性白血病(AML)、慢性骨髄性白血病(CML)、新生物(neoplasia)、甲状腺癌、全身性肥満細胞症、好酸球増多症候群、線維症、エリテマトーデス、移植片対宿主病、神経線維腫症、肺高血圧症、アルツハイマー病、精上皮腫、未分化胚細胞腫、肥満細胞腫、肺癌、気管支癌、精巣上皮内腫瘍、黒色腫、乳癌、神経芽細胞腫、甲状腺乳頭癌/甲状腺濾胞癌、悪性リンパ腫、非ホジキンリンパ腫、多発性内分泌腫瘍2型、褐色細胞腫、甲状腺癌、副甲状腺過形成/副甲状腺腫、結腸癌、結腸直腸腺腫、卵巣癌、前立腺癌、神経膠芽腫、脳腫瘍、悪性神経膠腫、膵臓癌、悪性胸膜内皮腫、血管芽細胞腫、血管腫、腎臓癌、肝臓癌、副腎癌、膀胱癌、胃癌、直腸癌、膣癌、子宮頸癌、子宮内膜癌、多発性骨髄腫、頭頸部腫瘍、並びに他の増殖性の病態等、又はそれらの組合せからなる群から選択される1つ以上の疾患の治療、予防又は改善のために使用され得る。消化管間質腫瘍(GIST)、結腸直腸癌、急性骨髄芽球性白血病(AML)、慢性骨髄性白血病(CML)、甲状腺癌等、又はそれらの組合せの治療に特に好ましい。
式(I)の化合物を、当業者に既知の標準的な合成技術を使用して、又は当該技術分野で既知の方法を本明細書に記載される方法と組み合わせて使用して合成することができる。また、本明細書に提示される溶媒、温度、及び他の反応条件は、当業者に応じて変化し得る。更なるガイドとして、以下の合成方法も利用することができる。
本明細書で提供される化合物を、癌細胞の成長に対するそれらの効果を試験することにより、癌細胞の増殖に対するそれらの阻害効果について更に評価した。本実施例では、以下の細胞を使用した:初代マウスB細胞BaF3(ATCCから購入)、ヒト消化管間質腫瘍細胞株のGIST-T1細胞(野生型KIT遺伝子を発現)(Cosmo Bio Co., Ltd.(日本)から購入)。本発明者らの研究室は、更に以下を構築して使用した:マウスTel-Kit-BaF3(KIT野生型キナーゼを安定して発現)、マウスTel-Kit/T670I-BaF3(KIT T670I変異型キナーゼを安定して発現)、マウスTel-Kit/V559A-BaF3(KIT V559A変異型キナーゼを安定して発現)、マウスTel-Kit/V559D-BaF3(KIT V559D変異型キナーゼを安定して発現)、マウスTel-Kit/V559G-BaF3(KIT V559G変異型キナーゼを安定して発現)、マウスTel-Kit/V560D-BaF3(KIT V560D変異型キナーゼを安定して発現)、マウスTel-Kit/L576P-BaF3(KIT L576P変異型キナーゼを安定して発現)、マウスTel-Kit/V654A-BaF3(KIT V654A変異型キナーゼを安定して発現)、マウスTel-Kit/V654A/V559D-BaF3(KIT V654A V559D変異型キナーゼを安定して発現)、マウスTel-Kit/T670E-BaF3(KIT T670E変異型キナーゼを安定して発現)、マウスTel-Kit/T670I/V559D-BaF3(KIT T670I V559D変異型キナーゼを安定して発現)、マウスTel-Kit/S709F-BaF3(KIT S709F変異型キナーゼを安定して発現)、マウスTel-Kit/D816E-BaF3(KIT D816E変異型キナーゼを安定して発現)、マウスTel-Kit/D816H-BaF3(KIT D816H変異型キナーゼを安定して発現)、マウスTel-Kit/D820E-BaF3(KIT D820E変異型キナーゼを安定して発現)、マウスTel-Kit/D820G-BaF3(KIT D820G変異型キナーゼを安定して発現)、マウスTel-Kit/D820Y-BaF3(KIT D820Y変異型キナーゼを安定して発現)、マウスTel-Kit/N822K-BaF3(KIT N822K変異型キナーゼを安定して発現)、マウスTel-Kit/Y823D-BaF3(KIT Y823D変異型キナーゼを安定して発現)、マウスTel-Kit/A829P-BaF3(KIT A829P変異型キナーゼを安定して発現)、ヒト消化管間質腫瘍細胞株のGIST-T1-T670I細胞(KIT-T670I変異遺伝子を発現)。上記の細胞株を、PCRを介してヒトKITの配列及びKITの様々な変異型キナーゼ領域をそれぞれ増幅すること、N末端TELフラグメント及び/又はNPMフラグメント及び/又はTPRフラグメント(Clontechから購入)を有するMSCV-Puroベクターにフラグメントをそれぞれ挿入すること、レトロウイルスを用いてマウスBaF3細胞をベクターでトランスフェクトし、安定的にトランスフェクトされた細胞を取得すること、成長因子IL-3を除去すること、それによって最終的に移入されたタンパク質KIT又はKITの様々な変異型に依存する細胞株を取得することにより構築した。GIST-T1-T670I(C-KIT-T670I変異遺伝子を発現)細胞株は、本発明者らの研究室によって、CRISPR Design Tool(ウェブサイト:crispr.mit.edu、Zhang Feng Lab)によりKIT遺伝子のT670周辺の領域を標的とするsgRNAを設計すること、それをpSpCas9(BB)-2A-Puroベクターにクローニングすること、得られたベクター及びT670に近いT670I部位変異を有する一本鎖オリゴヌクレオチドを用いて細胞を同時トランスフェクトすること、得られたものを抗生物質スクリーニングに供し、続いて希釈し、96ウェルプレートで単細胞培養すること、サンガーシーケンシングによる配列検出により細胞の部位T670を検証することにより構築した。
本実施例では化合物1及び化合物2をそれぞれ、TEL-cKIT/T670I-BaF3、TEL-cKIT/Y823D-BaF3、TEL-cKIT/D820G-BaF3、及びGIST-T1-T670Iのマウスモデルで試験した。
Claims (10)
- 野生型KIT及び/又は変異型KITチロシンキナーゼの活性を阻害するためのキナーゼ阻害剤であって、式(I):
(式中、Yは、
であり、
Aはフェニルであり、
nは1であり、
R1は、水素、ハロ、C1~6アルキル、C1~6ハロアルキル、及びC1~6アルコキシから選択され、
R2及びR3はそれぞれ独立して、水素、ハロ、C1~6アルキル、C1~6ハロアルキル、C1~6アルコキシから選択されるか、又はR2及びR3は共にフェニル若しくは5員ヘテロシクリルを形成する)の化合物、又はその薬学的に許容可能な塩若しくは溶媒和物を含む、キナーゼ阻害剤。 - R1が、水素、フルオロ、クロロ、メチル、エチル、又はプロピルから選択され、R2及びR3がそれぞれ独立して、水素、フルオロ、クロロ、メチル、エチル、プロピル、トリフルオロメチル、ジフルオロメチル、トリフルオロエチル、メトキシ、エトキシ、プロポキシから選択されるか、又はR2及びR3が共にフェニル若しくはジオキソランを形成する、請求項1に記載のキナーゼ阻害剤。
- 前記式(I)の化合物が、式(Ia):
- 請求項1~4のいずれか一項に記載のキナーゼ阻害剤と、薬学的に許容可能な担体又は賦形剤と、任意に他の治療剤とを含む、野生型KIT及び/又は変異型KITチロシンキナーゼの活性を阻害するための医薬組成物。
- 野生型KIT及び/又は変異型KITキナーゼの活性によって調節されるか若しくは影響を受ける、又は野生型KIT及び/又は変異型KITキナーゼの活性が関係している疾患、障害又は病態の治療、予防又は改善のための、請求項5に記載の医薬組成物。
- 前記疾患、障害又は病態が、以下の増殖性疾患:固形腫瘍、肉腫、消化管間質腫瘍、結腸直腸癌、急性骨髄芽球性白血病、慢性骨髄性白血病、甲状腺癌、全身性肥満細胞症、好酸球増多症候群、線維症、エリテマトーデス、移植片対宿主病、神経線維腫症、肺高血圧症、アルツハイマー病、精上皮腫、未分化胚細胞腫、肥満細胞腫、肺癌、気管支癌、精巣上皮内腫瘍、黒色腫、乳癌、神経芽細胞腫、甲状腺乳頭癌/甲状腺濾胞癌、悪性リンパ腫、非ホジキンリンパ腫、多発性内分泌腫瘍2型、褐色細胞腫、甲状腺癌、副甲状腺過形成/副甲状腺腫、結腸癌、結腸直腸腺腫、卵巣癌、前立腺癌、神経膠芽腫、脳腫瘍、悪性神経膠腫、膵臓癌、悪性胸膜内皮腫、血管芽細胞腫、血管腫、腎臓癌、肝臓癌、副腎癌、膀胱癌、胃癌、直腸癌、膣癌、子宮頸癌、子宮内膜癌、多発性骨髄腫、頭頸部腫瘍、及び新生物、又はそれらの組合せから選択される、請求項6に記載の医薬組成物。
- 前記疾患、障害又は病態が、以下の自己免疫疾患:関節炎、リウマチ性関節炎、骨関節炎、狼瘡、リウマチ様関節炎、炎症性腸疾患、乾癬性関節炎、骨関節炎、スティル病、若年性関節炎、糖尿病、重症筋無力症、橋本甲状腺炎、オード甲状腺炎、グレーブス病、シェーグレン症候群、多発性硬化症、ギランバレー症候群、急性散在性脳脊髄炎、アジソン病、眼球クローヌス・ミオクローヌス運動失調、強直性脊椎炎、抗リン脂質抗体症候群、再生不良性貧血、自己免疫性肝炎、セリアック病、グッドパスチャー症候群、特発性血小板減少性紫斑病、視神経炎、強皮症、原発性胆汁性肝硬変、ライター症候群、高安動脈炎、側頭動脈炎、温式自己免疫性溶血性貧血、ウェゲナー肉芽腫症、乾癬、汎発性脱毛症、ベーチェット病、慢性疲労、家族性自律神経失調症、子宮内膜症、間質性膀胱炎、神経筋緊張症、強皮症、外陰部痛、又はそれらの組合せから選択される、請求項6に記載の医薬組成物。
- 前記疾患、障害又は病態が、以下の血液悪性腫瘍:骨髄腫、急性リンパ性白血病、急性骨髄芽球性白血病、急性前骨髄球性白血病、慢性リンパ性白血病、慢性骨髄芽球性白血病、慢性好中球性白血病、急性未分化白血病、未分化大細胞リンパ腫、成人T細胞急性リンパ芽球性白血病、三血球系脊髄形成異常を伴う急性骨髄芽球性白血病、混合系統白血病、骨髄異形成症候群、骨髄増殖性疾患、多発性骨髄腫、骨髄性肉腫、又はそれらの組合せから選択される、請求項6に記載の医薬組成物。
- 前記疾患、障害又は病態が、KIT変異に関連する消化管間質腫瘍である、請求項6に記載の医薬組成物。
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