JP7176798B2 - インダゾールキナーゼ阻害剤及びその使用 - Google Patents
インダゾールキナーゼ阻害剤及びその使用 Download PDFInfo
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- JP7176798B2 JP7176798B2 JP2021523586A JP2021523586A JP7176798B2 JP 7176798 B2 JP7176798 B2 JP 7176798B2 JP 2021523586 A JP2021523586 A JP 2021523586A JP 2021523586 A JP2021523586 A JP 2021523586A JP 7176798 B2 JP7176798 B2 JP 7176798B2
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Description
Xは-(CH=CH)m-であり、ここで、mは0又は1であり、
Yは-NH-又は-(CH2)n-からなる群から選択され、ここでnは0~3の整数であり、
R1は、1個~3個の独立したR4基で任意に置換されたフェニル、1個~3個の独立したR4基で任意に置換されたピリジニル、1個~3個の独立したR4基で任意に置換されたピラゾリル、及び1個~3個の独立したR4基で任意に置換されたピリミジニルからなる群から選択され、
R2は、水素及びC1~6アルキルからなる群から選択され、
R3は、1個又は2個の独立したR5基で任意に置換されたC1~6アルキル、C1~6アルキルアミノ、並びに1個~3個の独立したR4基で任意に置換されたフェニル、1個~3個の独立したR4基で任意に置換されたナフチル、1個~3個の独立したR4基で任意に置換されたピリジニル、1~3個の独立したR4基で任意に置換されたピペラジニル、及び1~3個の独立したR4基で任意に置換されたピペリジルからなる群から選択され、
R4は、ハロゲン、アミノ、C1~6アルキル、C3~6シクロアルキル、C1~6ハロアルキル、C1~6アルコキシ、C1~6ヒドロキシアルキル、C1~6アルキルアミノ、C2~6アルキルアミド、(4-メチルピペラジン-1-イル)メチル、モルホリノメチル、モルホリニル、4-メチルピペラジン-1-イル、4-ピペリジル、及び4-テトラヒドロピラニルからなる群から独立して選択され、
R5は、アミノ、ヒドロキシル、及びC1~6アルキルチオからなる群から独立して選択される)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、選択的な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):
Xは-(CH=CH)m-であり、ここで、mは0又は1であり、mが0の場合、Xは直接結合を表し、
Yは、-NH-又は-(CH2)n-からなる群から選択され、ここで、nは0~3の整数であり、nが0の場合、Yは直接結合を表し、
R1は、1個~3個の独立したR4基で任意に置換されたアリール基及びヘテロアリール基からなる群から選択され、
R2は、水素及びC1~6アルキルからなる群から選択され、
R3は、1個~2個の独立したR5基で任意に置換されたC1~6アルキル、C1~6アルキルアミノ、並びに1個~3個の独立したR4基で任意に置換されたアリール基、ヘテロアリール基及びヘテロシクリル基からなる群から選択され、
R4は、ハロゲン、アミノ、C1~6アルキル、C3~6シクロアルキル、C1~6ハロアルキル、C1~6アルコキシ、C1~6ヒドロキシアルキル、C1~6アルキルアミノ、C2~6アルキルアミド、(4-メチルピペラジン-1-イル)メチル、モルホリノメチル、モルホリニル、4-メチルピペラジン-1-イル、4-ピペリジル、及び4-テトラヒドロピラニルからなる群から独立して選択され、
R5は、アミノ、ヒドロキシル、及びC1~6アルキルチオからなる群から独立して選択される)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新規キナーゼ阻害剤を提供する。
本発明はまた、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。
本発明のキナーゼ阻害剤は、細胞若しくは被験体においてcKIT(特に突然変異型cKIT/T670I)、FLT3(突然変異型FLT3-ITDを含む)、PDGFRα、PDGFRβ、及び/又はVEGFR2のキナーゼ活性を低下若しくは阻害するために使用される、及び/又は被験体においてcKIT(特に突然変異型cKIT/T670I)、FLT3(突然変異型FLT3-ITDを含む)、PDGFRα、PDGFRβ、及び/又はVEGFR2の活性に関連する障害を未然防止若しくは処置するために使用される、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、又は医薬組成物を含む。
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。
N-(5-(1H-インダゾール-6-イル)-4-メチルチアゾール-2-イル)-2-(4-メチルピペラジン-1-イル)アセトアミド(0.6g)を50mL容の丸底フラスコに添加し、次いで、N,N-ジメチルホルムアミド(10mL)、ヨウ素(0.8g)及び水酸化カリウム(0.4g)を添加した。反応系を、気体アルゴン保護下、室温で8時間撹拌した。反応後、系内の溶媒を減圧下での蒸留により乾燥させ、得られたものを水で希釈し、水相を酢酸エチルで抽出し、有機相を水及び飽和食塩水でそれぞれ洗浄し、次いで無水硫酸ナトリウムで乾燥させた。有機相を濾過し、減圧下での蒸留により乾燥させて、粗生成物を得た。粗生成物を加圧シリカゲルカラムクロマトグラフィーにより精製して、純粋な生成物を得た。MS(ESI)m/z(M+1)+:497.06。
癌細胞の成長に対する本発明の化合物の効果を試験することにより(表2)、癌細胞の増殖に対する本明細書中の化合物の阻害効果及び癌細胞の増殖を阻害する際のそれらの選択性を更に評価した。
本実施例では、TEL-cKIT/T670I-BaF3及びGIST-T1-T670Iのマウスモデルにおける化合物9の実験結果をそれぞれ試験した。
(1)4週齢~6週齢のBalb/c雌性マウスをBeijing Weitong Lihua Experimental Animal Co., Ltd.から購入し、SPFレベルの実験室で飼育した。飲料水及び寝わらをオートクレーブ滅菌した。マウスに対する全ての操作を無菌条件下で行った。
(2)0日目に、約5×106のTEL-cKIT/T670I-BaF3細胞又は5×106のGIST-T1-T670I細胞を、それぞれ、全てのマウスの左背部に皮下注射した。
(3)TEL-cKIT/T670I-BaF3のマウスモデルでは、6日目から開始して、対応するマウスにメチルセルロース(HKI)ビヒクル(マウス5匹);マウスの体重で10mg/kg、20mg/kg、40mg/kg、100mg/kgの用量の化合物9(各5匹のマウス);マウスの体重で40mg/kgの用量のスニチニブ(中国のMedChemExpressから購入)(マウス5匹)を毎日経口投与した。GIST-T1-T670Iのマウスモデルでは、15日目から開始して、対応するマウスにメチルセルロース(HKI)ビヒクル(マウス5匹);マウスの体重で20mg/kg、30mg/kg、40mg/kgの用量の化合物9(各5匹のマウス);マウスの体重で40mg/kgの用量のスニチニブ(マウス5匹)を毎日経口投与した。
(4)6日目(TEL-cKIT/T670I-BaF3のマウスモデル)及び15日目(GIST-T1-T670Iのマウスモデル)から開始して、皮下腫瘍の長さ/幅をノギスで毎日測定し、マウスの体重を毎日記録して、マウスの体重に対する化合物9の効果をそれぞれ判定した。
(5)腫瘍体積の計算方法:長さ×幅×幅/2mm3を用いて、内皮下腫瘍の成長傾向を計算した。
本発明は、細胞若しくは被験体におけるcKIT(特に突然変異型cKIT/T670I)、FLT3(突然変異型FLT3-ITDを含む)、PDGFRα、PDGFRβ、及び/又はVEGFR2のキナーゼ活性の低下若しくは阻害において使用することができる、及び/又は被験体におけるcKIT(特に突然変異型cKIT/T670I)、FLT3(突然変異型FLT3-ITDを含む)、PDGFRα、PDGFRβ、及び/又はVEGFR2の活性に関連する障害の未然防止若しくは処置において使用することができる新規キナーゼ阻害剤化合物を提供する。したがって、該新規キナーゼ阻害剤化合物を対応する薬物として調製することができ、産業上の利用可能性がある。
Claims (19)
- 式(I):
Xは-(CH=CH)m-であり、ここで、mは0又は1であり、
Yは-NH-又は-(CH2)n-からなる群から選択され、ここでnは0~3の整数であり、
R1は、1個~3個の独立したR4基で任意に置換されたフェニル、1個~3個の独立したR4基で任意に置換されたピリジニル、1個~3個の独立したR4基で任意に置換されたピラゾリル、及び1個~3個の独立したR4基で任意に置換されたピリミジニルからなる群から選択され、
R2は、水素及びC1~6アルキルからなる群から選択され、
R3は、1個又は2個の独立したR5基で任意に置換されたC1~6アルキル、C1~6アルキルアミノ、並びに1個~3個の独立したR4基で任意に置換されたフェニル、1個~3個の独立したR4基で任意に置換されたナフチル、1個~3個の独立したR4基で任意に置換されたピリジニル、1~3個の独立したR4基で任意に置換されたピペラジニル、及び1~3個の独立したR4基で任意に置換されたピペリジルからなる群から選択され、
R4は、ハロゲン、アミノ、C1~6アルキル、C3~6シクロアルキル、C1~6ハロアルキル、C1~6アルコキシ、C1~6ヒドロキシアルキル、C1~6アルキルアミノ、C2~6アルキルアミド、(4-メチルピペラジン-1-イル)メチル、モルホリノメチル、モルホリニル、4-メチルピペラジン-1-イル、4-ピペリジル、及び4-テトラヒドロピラニルからなる群から独立して選択され、
R5は、アミノ、ヒドロキシル、及びC1~6アルキルチオからなる群から独立して選択される)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、cKIT、FLT3、PDGFRα、PDGFRβ、及び/又はVEGFR2のキナーゼ活性を阻害するためのキナーゼ阻害剤。 - Xは-(CH=CH)-である、請求項1に記載のキナーゼ阻害剤。
- Yは直接結合又は-CH2-である、請求項1に記載のキナーゼ阻害剤。
- R1は、1個~3個の独立したR4基で任意に置換されたフェニル基、ピリジニル基、ピラゾリル基、及びピリミジニル基からなる群から選択され、R4はハロゲン、アミノ、C1~6アルキル、C1~6ハロアルキル、C1~6アルコキシ、及び(4-メチルピペラジン-1-イル)メチルからなる群から独立して選択される、請求項1に記載のキナーゼ阻害剤。
- R1は、メチル、アミノ又はハロゲンで任意に置換されたフェニル基、2-ピリジニル基、3-ピリジニル基、4-ピラゾリル基、及び5-ピリミジニル基からなる群から選択される、請求項4に記載のキナーゼ阻害剤。
- R2は水素又はメチルである、請求項1に記載のキナーゼ阻害剤。
- R3は、1個又は2個の独立したR5基で任意に置換されたC1~6アルキル、C1~6アルキルアミノ、並びに1個~3個の独立したR4基で任意に置換されたフェニル基、ナフチル基、ピリジニル基、ピペラジニル基及びピペリジル基からなる群から選択され、R4は、ハロゲン、アミノ、C1~6アルキル、C1~6ハロアルキル、C1~6アルコキシ、及び(4-メチルピペラジン-1-イル)メチルからなる群から独立して選択され、R5は、アミノ、ヒドロキシル、及びメチルチオからなる群から独立して選択される、請求項1に記載のキナーゼ阻害剤。
- R3は、アミノ、ヒドロキシ又はメチルチオで任意に置換されたC1~6アルキル;ジメチルアミノ;メチルで任意に置換されたN-ピペラジニル;ハロゲン、トリフルオロメチル又はメトキシで任意に置換されたフェニル;ナフチル;4-ピリジニル;3-ピペリジル;及びメチルで任意に置換された4-ピペリジルからなる群から選択される、請求項7に記載のキナーゼ阻害剤。
- Yが直接結合である場合、R3は、アミノ、ヒドロキシ又はメチルチオで任意に置換されたC1~6アルキル、及び4-ピリジニルからなる群から選択され、Yが-CH2-である場合、R3は、メトキシで任意に置換されたフェニル、メチルで任意に置換されたN-ピペラジニル、及びメチルで任意に置換された4-ピペリジルからなる群から選択される、請求項1に記載のキナーゼ阻害剤。
- 請求項1~10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、cKIT、FLT3、PDGFRα、PDGFRβ、及び/又はVEGFR2の活性に関連する疾患、障害又は疾病の処置又は未然防止のための医薬組成物。
- cKIT、FLT3、PDGFRα、PDGFRβ、及び/又はVEGFR2のキナーゼ活性を阻害するための薬物の調製における、請求項1~10のいずれか一項に記載のキナーゼ阻害剤の使用。
- 突然変異型cKIT/T670Iのキナーゼ活性を阻害するための薬物の調製における、請求項1~10のいずれか一項に記載のキナーゼ阻害剤の使用。
- cKIT、FLT3、PDGFRα、PDGFRβ、及び/又はVEGFR2の活性に関連する疾患、障害又は疾病の処置又は未然防止のための薬物の調製における、請求項1~10のいずれか一項に記載のキナーゼ阻害剤の使用。
- 突然変異型cKIT/T670Iの活性に関連する疾患、障害又は疾病の処置又は未然防止のための薬物の調製における、請求項1~10のいずれか一項に記載のキナーゼ阻害剤の使用。
- 前記疾患、障害又は疾病は、cKIT-T670I突然変異型消化管間質腫瘍である、請求項15に記載の使用。
- 突然変異型cKIT/T670Iのキナーゼ活性を阻害するための、請求項1~10のいずれか一項に記載のキナーゼ阻害剤。
- cKIT、FLT3、PDGFRα、PDGFRβ、及び/又はVEGFR2の活性に関連する疾患、障害又は疾病の処置又は未然防止のための、請求項1~10のいずれか一項に記載のキナーゼ阻害剤。
- 前記疾患、障害又は疾病はcKIT-T670I突然変異型消化管間質腫瘍である、請求項18に記載のPDGFRキナーゼ阻害剤。
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