JP2021510717A - キナーゼ活性を阻害するためのジフェニルアミノピリミジン系化合物 - Google Patents
キナーゼ活性を阻害するためのジフェニルアミノピリミジン系化合物 Download PDFInfo
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- JP2021510717A JP2021510717A JP2020539273A JP2020539273A JP2021510717A JP 2021510717 A JP2021510717 A JP 2021510717A JP 2020539273 A JP2020539273 A JP 2020539273A JP 2020539273 A JP2020539273 A JP 2020539273A JP 2021510717 A JP2021510717 A JP 2021510717A
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Abstract
Description
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8およびY9は、それぞれ独立して水素または重水素から選択され;
X1、X2、X3およびX4は、それぞれ独立してCH3、CD3、CHD2およびCH2Dからなる群から選択され;
X1、X2、X3およびX4がそれぞれCH3である場合、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8およびY9のうちの少なくとも1つは重水素である。
用語および定義
本明細書において、特に明記しない限り、「重水素化」とは、化合物または基における1つまたは複数の水素が重水素で置換されていることを意味する。「重水素化」は、重水素によって一置換、二置換、多置換、または完全に置換されていてもよい。「1つ以上の重水素で置換された」および「重水素で1回以上置換された」という用語は互換的に使用できる。
本発明は、式(I)で表れる化合物,或いはその薬学的に許容される塩、プロドラッグ、水和物または溶媒和物、結晶形、N−オキシドおよび様々なジアステレオ異性体を提供する。
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8およびY9は、それぞれ独立して水素または重水素から選択され;
X1、X2、X3およびX4は、それぞれ独立してCH3、CD3、CHD2およびCH2Dからなる群から選択され;
X1、X2、X3およびX4はそれぞれCH3である場合、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8およびY9のうちの少なくとも1つは重水素である。
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、Y5、X1、X2、X3およびX4は、上記で定義されたとおりである。
他の様態では、本発明は、本発明の化合物(「活性成分」とも呼ばれる)および薬学的に許容される賦形剤を含む医薬組成物を提供する。一部の実施形態において、前記の医薬組成物は、有効量の活性成分を含む。一部の実施形態において、前記の医薬組成物は、治療有効量の活性成分を含む。一部の実施形態において、前記の医薬組成物は、予防有効量の活性成分を含む。
本発明の化合物は、JAK2タンパク質チロシンキナーゼに対する阻害効果を示し、且つ化合物は、単独で、または他の活性剤(例えば、下記の化学療法剤またはタンパク質治療薬)と併用して、様々な疾患を治療するために使用される、これらの疾患は、例えば、骨髄組織の増殖性疾患、増殖性糖尿病性網膜症、および固形腫瘍や他の種類の癌を含む血管の形成に関連する疾患、眼の疾患、炎症、乾癬、およびウイルス感染が含まれるが、これらに限定されない。治療できる癌の種類として、消化器/消化器癌、結腸癌、肝臓癌、皮膚癌、乳癌、卵巣癌、前立腺癌、リンパ腫、白血病(急性骨髄性白血病および慢性骨髄性白血病を含む)、腎臓癌、肺癌、筋肉癌、骨癌、膀胱癌または脳癌が含まれる、これらに限定されない。
本発明の化合物は、抗炎症剤、抗ヒスタミン剤、化学療法剤、免疫調節剤、治療用抗体、またはチロシンキナーゼ阻害剤などのプロテインキナーゼ阻害剤とともに、治療を必要とする被験者に投与される。化学療法剤には、メトトレキサートなどの代謝拮抗剤、シスプラチン/カルボプラチンなどのDNA架橋剤;canbusilなどのアルキル化剤;ダクチノマイシンなどのトポイソメラーゼI阻害剤;タキソール(パクリタキソール)などの微小管阻害剤が含まれるが、これらに限定されない。他の化学療法剤としては、例えば、ビンカアルカロイド、マイトマイシン抗生物質、ブレオマイシン抗生物質、葉酸拮抗薬、コルヒチン、demecoline、エトポシド、タキサン、アントラサイクリン系抗生物質、ドキソルビシン、ダウノルビシン、カルミノマイシン、エピルビシン、イダルビシン、ミトキサントロン、4−ジメトキシ−ダノマイシン、11−デオキシダウノルビシン、13−デオキシダウノルビシン、アドリアマイシン−14−ベンゾエート、アドリアマイシン−14−オクタノエート、アドリアマイシン−14−ナフチルアセテート、アムサクリン、カルムスチン、シクロホスファミド、シタラビン、エトポシド、ロバスタチン、メルファラン、トポテカン、オキサラプラチン、クロラムブシル、メトトレキサート、ロムスチン、チオグアニン、アスパラギナーゼ、ビンブラスチン、ビンデシン、タモキシフェンまたはメクロレタミンが含まれる。治療用抗体には、トラスツズマブなどのHER2タンパク質に対する抗体、血管内皮増殖因子を標的とするベバシズマブおよび上皮増殖因子を標的とするOSI−774などの増殖因子または増殖因子受容体に対する抗体;Vitaxin(MEDI−522とも呼ばれる)などのインテグリン受容体に対する抗体が含まれるが、これらに限定されない。本発明の組成物および方法に適する抗癌剤の種類は、1)微小管阻害剤(例えば、ビンクリスチン、ビンブラスチン、およびビンデシンなど)を含むアルカロイド、微小管安定剤(例えば、パクリタキセル[タキソール])およびドセタキセル、タキソテールなど)、ならびにエピポドフィロトキシン(例えば、エトポシド[VP−16]およびテニポシド[VM−26]など)などのトポイソメラーゼ阻害剤およびトポイソメラーゼIを標的とする活性剤(例えば、カンプトテシンおよびイシリノテカン[CPT−11]など)を含むクロマチン機能阻害剤;2)メクロレタミン(例えば、ナイトロジェンマスタード、クロラムブシル、シクロホスファミド、イホスファミド、およびブスルファン[busulfan]など)、ニトロソ尿素(例えば、カルムスチン、ロムスチン、およびセムスチンなど)を含む共有DNA結合剤[アルキル化剤]、および他のアルキル化剤(例えば、ダカルバジン、ヘキサメチロールメラミン、チオテパ、およびmitocycinなど);3)核酸阻害剤(例えば、アクチノマイシンD[dactinomycin D]など)、アントラサイクリン類(例えば、ダウノルビシン[ダウノマイシンおよびセルビジン]、ドキソルビシン[アドリアマイシン]およびイダルビシン[デメトキシダウノルビシン]など)、アントラキノン(例えば、[ミトキサントロン]などのアントラサイクリン系抗生物質類似物)、ブレオマイシン(bleomycin)など、およびプリカマイシン(ミトラマイシン)などを含む非共有DNA結合剤[抗腫瘍抗生物質];4)葉酸拮抗薬(例えば、メトトレキサート、フォレックス、メトトレキサートナトリウムなど)、プリン代謝拮抗薬(例えば、6−メルカプトプリン[6−MP、メルカプトプリン]、6−チオグアニン[6−TG]、アザチオプリン、アシクロビル、ガンシクロビル、クロロデオキシアデノシン、2−クロロデオキシアデノシン[CdA]および2’−デオキシコホルマイシン[ペントスタチン]など)、ピリミジン拮抗薬(例えば、フルオロピリミジン[5−フルオロウラシル(Adrucil)、5−フルオロデオキシウリジン(FdUrd)(フルオロウリジン)]など)およびシトシンアラビノシド(例えば、サイトサル[ara−C]およびフルダラビンなど)を含む代謝拮抗薬;5)L−アスパラギナーゼを含む酵素;6)抗エストロゲン剤(例えば、タモキシフェンなど)などのグルココルチコイド、非ステロイド性抗アンドロゲン剤(例えば、フルタミドなど)、およびアロマターゼ阻害剤(例えば、アナストロゾール[アリミデックス]など)を含むホルモン;7)白金化合物(例えば、シスプラチンおよびカルボプラチンなど);8)抗癌剤、毒素および/または放射性核種と結合したモノクローナル抗体など;9)生物学的応答修飾物質(例えば、インターフェロン[例えば、IFN−αなど]およびインターロイキン[例えば、IL−2など]など);10)養子免疫療法;11)造血成長因子;12)腫瘍細胞の分化を誘導する活性剤(例えば、オールトランスレチノイン酸など);13)遺伝子治療技術;14)アンチセンス療法技術;15)腫瘍ワクチン;16)転移腫瘍に対する治療法(例えば、バチミスタットなど);および17)血管新生阻害剤が含まれるが、これらに限定されない。
以下、具体的な実施形態によって本発明をさらに説明する。これらの実施例は、本発明を説明するためのみに使用され、本発明の範囲を限定するものではないことを理解しべきである。以下の実施例において、特定の条件を明記しない実験方法は、一般に、通常の条件または製造業者が推奨する条件に従う。特に明記しない限り、部およびパーセンテージは、重量部および重量パーセントである。
マグネチックスターラーを備えた250mLの一つ口フラスコに、化合物1(10.0 g,45.12mmol)およびTHF(100mL)を順次に加え、攪拌して溶液を形成し、氷水浴でtert−ブチルアミン(9.9g,135.37mmol)のTHF溶液(20mL)をゆっくり滴下した後、氷水浴を取り外し、窒素雰囲気下、室温で反応を1時間攪拌した。有機溶媒を減圧下で蒸発させ,水(50mL)を添加し、ジクロロメタン(50ml×3)で抽出し、有機相を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、シリカゲルカラムクロマトグラフィーで分離し、81.6%の収率で白色固体9.5gを得た。LC−MS(APCI):m/z=259.1(M+1)+。1H NMR(500mHz,CDCl3) δ ppm:8.75(t,J=2.0Hz,1H),8.40(dd,J=8.0Hz,J=2.0Hz,1H),8.24(dd,J=8.0Hz,J=2.0Hz,1H),7.73(t,J=8.0Hz,1H),4.99(s,1H),1.27(s,9H).
マグネチックスターラーおよび冷却管を備えた100mLの一つ口フラスコに、エタノール/水混合液(60mL,2/1)および化合物3(3.0g,11.66mmol)を加え、撹拌しながら、還元鉄粉(6.51g,116.6mmol)および塩化アンモニウム(3.12g,58.3mmol)を添加し、窒素雰囲気下で85℃に昇温し、この温度を保持して1時間反応させた。
室温まで冷却し、不溶性の固体を濾別し、有機溶媒を減圧下で蒸発させ、飽和NaHCO3水液(5mL)を添加し、酢酸エチル(50ml×3)で抽出し、有機相を合わせ、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して95.79%の収率で白色固体2.55gを得た。LC−MS(APCI):m/z=229.1(M+1)+。
室温で、マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物5(1.0g,6.13mmol)およびメタノール/水混合液(15mL,1/1)を順次に加え、攪拌して溶液を形成し、化合物4(1.26g,5.52mmol)を添加し、窒素雰囲気下で反応混合物を45℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、大量の白色固体が析出し、濾過し、濾過ケーキをメタノール/水(3.4mL/4.0mL)で洗浄し、吸引乾燥し、50℃で真空乾燥して、60.17%の収率で白色固体1.31gを得た。LC−MS(APCI):m/z=354.1(M+1)+. 1H NMR(500mHz,DMSO−D6) δ ppm:9.11(s,1H),8.11−8.09(m,2H),7.88−7.86(m,1H),7.55−7.52(m,3H),2.18(s,3H),1.12(s,9H).
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物7(300mg,2.16mmol)およびDMF(6ml)を順次に加え、攪拌して溶液を形成し、炭酸カリウム(894mg,6.47mmol)および化合物8(827mg,4.31mmol)を添加し、窒素雰囲気下で反応混合物を80℃に昇温し、この温度を保持して攪拌しながら4時間反応させた。室温まで冷却し、水30mLを添加し、酢酸エチル(30ml×3)で抽出し、有機相を合わせ、水(60mL×3)で洗浄し、飽和食塩水(30mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮してシリカゲルカラムで分離して、83.4%の収率で白色固体450mgを得た。LC−MS(APCI):m/z=250.0および252.0(M+1)+.
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物9(450mg,1.8mmol)およびDMF(6ml)を順次に加え、攪拌して溶液を形成し、炭酸カリウム(746mg,5.4mmol)およびピロリジン(256mg,3.6mmol)を添加し、窒素雰囲気下で反応混合物を80℃に昇温し、この温度を保持して攪拌しながら4時間反応させた。室温まで冷却し、水30mLを添加し、酢酸エチル(30ml×3)で抽出し、有機相を合わせ、水(60mL×3)で洗浄し、飽和食塩水(30mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルカラムで分離して、57.8%の収率で黄色油状物250mgを得た。LC−MS(APCI):m/z=241(M+1)+.
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物10(250mg,1.04mmol)およびメタノール(10mL)を加え、攪拌して溶液を形成し、Pd/C(25mg,10%)を加え、水素バルーン下、真空にして水素ガスで3回置換し、水素雰囲気下で一晩反応させた。触媒を濾別し、メタノール(3mL)で濾過ケーキを洗浄し、濾液を合わせ、濃縮して98.6%の収率で黄色油状物220mgを得た。LC−MS(APCI):m/z=211.1(M+1)+.
マグネチックスターラーおよび冷却管を備えた25mLの一つ口フラスコに、化合物6(200mg,0.56mmol)、化合物11(107mg,0.51mmol)およびエチレングリコールモノメチルエーテル(6mL)を加え、攪拌して溶液を形成し、塩化水素のイソプロパノール溶液(1.41mmol,0.28mL,5M)を滴下し、窒素雰囲気下、120℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、水(10mL)および飽和炭酸水素ナトリウム(5mL)を添加し、ジクロロメタン(15ml×3)で抽出し、有機相を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、残留物をシリカゲルカラムで分離して、50.3%の収率で白色固体150mgを得た。LC−MS(APCI):m/z=529.2(M+1)+. 1H NMR(500mHz,CDCl3) δ ppm:8.11(s,1H),7.92−7.89(m,2H),7.57(d,J=8.0Hz,1H),7.41−7.38(m,3H),6.91(d,J=8.0Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J=6.0Hz,2H),2.94(t,J=6.0Hz,2H),2.13(s,3H),1.22(s,9H).
マグネチックスターラーを備えた20mLのマイクロ波反応チューブに、化合物12(1.0g,7.93mmol)、Pd/C(200mg,10%)および重水(15mL)を加え、水素ガスを2分間バブリングし、マイクロ波反応チューブを密封し、マイクロ波反応装置に設置し、180℃に昇温し、1時間反応させた。室温まで冷却し、触媒を濾別し、酢酸エチル(30ml×3)で抽出し、有機相を合わせ、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルカラムで分離して、67.8%の収率で白色固体700mgを得た。LC−MS(APCI):m/z=131.1(M+1)+。1H NMR(300mHz,DMSO−d6) δ ppm:11.00(s,1H),10.58(s,1H).
マグネチックスターラーを備えた50mLの三つ口フラスコに、化合物13(360mg,2.77mmol)およびオキシ塩化リン(5mL,)を順次に加え、窒素雰囲気下で110℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。未反応のオキシ塩化リンを減圧下で蒸発させ、残留物を酢酸エチル(40mL)に溶解し、飽和炭酸水素ナトリウム水溶液(10mL)を添加し、5分間撹拌し、層状に分離させ、有機相を無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルカラムで分離して、86.5%の収率で白色固体400mgを得た。LC−MS(APCI):m/z=168.1(M+1)+。
室温で、マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物14(400mg,2.39mmol)およびMeOD/重水混合液(10mL,1/1)を順次に加え、攪拌して溶液を形成し、化合物4(382mg,1.68mmol)を添加し、窒素雰囲気下で反応混合物を45℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、大量の白色固体が析出し、濾過し、濾過ケーキをMeOD/重水(2mL/2mL)で洗浄し、吸引乾燥し、50℃で真空乾燥して、46.7%の収率で白色固体400mgを得た。LC−MS(APCI):m/z=358.1(M+1)+. 1H NMR(400mHz,DMSO−D6) δ/ppm:9.11(s,1H),8.11−8.09(m,1H),7.88−7.86(m,1H),7.55−7.52(m,3H),1.12(s,9H).
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物7(1.0g,7.19mmol)、化合物16(1.58g,9.35mmol)およびDMF(20ml)を順次に加え、撹拌しながら、Cs2CO3(炭酸セシウム,7.0g,21.6mmol)を添加し、窒素雰囲気下で反応混合物を100℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、水30mLを添加し、酢酸エチル(30ml×3)で抽出し、有機相を合わせ、水(60mL×3)で洗浄し、飽和食塩水(30mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルカラムで分離して、70.4%の収率で白色固体1.2gを得た。LC−MS(APCI):m/z=237.1 (M+1)+. 1H NMR(300mHz,CDCl3) δ ppm:8.20(d,J=9.0Hz,2H),6.98(d,J=9.0Hz,2H),4.21(t,J=6.0Hz,2H),2.96(t,J=6.0Hz,2H),2.67−2.64(m,4H),1.88−1.82(m,4H).
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物17(250mg,1.04mmol)およびメタノール(10mL)を加え、攪拌して溶液を形成し、Pd/C(25mg,10%)を添加し、水素バルーン下、真空にして水素ガスで3回置換し、水素雰囲気下で一晩反応させた。触媒を濾別し、メタノール(3mL)で濾過ケーキを洗浄し、濾液を合わせ、濃縮して、98.6%の収率で黄色油状物220mgを得た。LC−MS(APCI):m/z=207.1(M+1)+.
マグネチックスターラーおよび冷却管を備えた25mLの一つ口フラスコに、化合物15(200mg,0.56mmol)、化合物18(107mg,0.51mmol)およびエチレングリコールモノメチルエーテル(6mL)を加え、攪拌して溶液を形成し、塩化水素のイソプロパノール溶液(1.41mmol,0.28mL,5M)を滴下し、窒素雰囲気下、120℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、水(10mL)および飽和炭酸水素ナトリウム(5mL)を添加し、ジクロロメタン(15ml×3)で抽出し、有機相を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、残留物をシリカゲルカラムで分離して、50.3%の収率で白色固体150mgを得た。LC−MS(APCI):m/z=529.2(M+1)+. 1H NMR(500mHz,CDCl3) δ/ppm:8.11(s,1H),7.90(dd,J=8.0Hz,J=1.0Hz,1H),7.57(d,J=8.0Hz,1H),7.41−7.38(m,3H),6.91(d,J=8.0Hz,1H),6.81(s,1H),6.44(s,1H),4.75(s,1H),4.13(t,J=6.0Hz,2H),2.94(t,J=6.0Hz,2H),2.69−2.64(m,4H),1.85−1.81(m,4H),1.22(s,9H).
マグネチックスターラーおよび冷却管を備えた100mLの三つ口フラスコに、化合物19(4.0g,62.39mmol)およびジエチルエーテル(40mL)を順次に加え、窒素雰囲気下、−10℃まで冷却し、この温度を保持して臭化メチルマグネシウム(20.80mL,62.39mmol,3M)をゆっくり滴下した後、ゆっくりと室温に昇温し、さらに2時間加熱還流した。室温まで冷却し、氷水浴で飽和NH4Cl水溶液(10mL)を滴下して反応をクエンチし、10分間撹拌し、層状に分離させ、水層をジエチルエーテル(20mL×2)で抽出し、有機相を合わせ、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下、室温で注意深く蒸留して、33.99%の収率で無色液体1.7gを得た。そのまま次の工程で用いた。
氷水浴で濃硫酸(10g)を水(10g)にゆっくり滴下し、温度を5℃以下に制御し、濃硫酸(1.52g,23.33mmol)をバッチでゆっくりと加え、攪拌して溶液を形成し、化合物20(1.7g,21.21mmol)を添加し、窒素雰囲気下、室温で攪拌しながら一晩反応させた。ジエチルエーテル(20mL)を添加し、静置して層状に分離させ、上部の有機相を分離し、下層を再びジエチルエーテル(20mL)で抽出し、有機相を合わせ、飽和NaHCO3(5mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、室温で溶媒を注意深く蒸発させ、53.80%の収率で黄色液体1.2gを得た。そのまま次の工程で用いた。
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物21(1.2g,11.41mmol)およびメタノール(20mL)を加え、攪拌して溶液を形成し、Pd/C(120mg,10%)を添加し、水素バルーン下、真空にして水素ガスで3回置換し、水素雰囲気下で一晩反応させた。触媒を濾別し、塩化水素のイソプロパノール溶液(5M)をゆっくり滴下し、pH〜2に調整し、10分間撹拌し、溶媒を減圧下で蒸発させて、79.23%の収率で黄色固体1.04gを得た。そのまま次の工程で用いた。
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物1(2.0g,9.02mmol)およびTHF(30mL)を順次に加え、攪拌して溶液を形成し、氷水浴で化合物22(1.04g,9.02mmol)およびトリエチルアミン(3.65g,36.08mmol)をゆっくり滴下した後、氷水浴を取り外し、窒素雰囲気下、室温で反応を1時間攪拌した。有機溶媒を減圧下で蒸発させ、水(50mL)を添加し、ジクロロメタン(50ml×3)で抽出し、有機相を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、シリカゲルカラムクロマトグラフィーで分離して、29.34%の収率で白色固体700mgを得た。LC−MS(APCI):m/z=265.1(M+1)+。1H NMR(500mHz,CDCl3) δ 8.75(t,J=2.0Hz,1H),8.40(dd,J=8.0Hz,J=2.0Hz,1H),8.24(dd,J=8.0Hz,J=2.0Hz,1H),7.73(t,J=8.0Hz,1H),4.99(s,1H),1.27(s,3H).
マグネチックスターラーおよび冷却管を備えた50mLの一つ口フラスコに、エタノール/水混合液(15mL,2/1)および化合物23(300mg,1.17mmol)を加え、撹拌しながら、還元鉄粉(651mg,11.67mmol)および塩化アンモニウム(0.31mg,5.83mmol)を添加し、窒素雰囲気下で85℃に昇温し、この温度を保持して1時間反応させた。室温まで冷却し、不溶性の固体を濾別し、有機溶媒を減圧下で蒸発させ、飽和NaHCO3水溶液(5mL)を添加し、酢酸エチル(20ml×3)で抽出し、有機相を合わせ、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、95.79%の収率で白色固体250mgを得た。LC−MS(APCI):m/z=235.1(M+1)+。
室温で、マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物24(200mg,1.23mmol)およびメタノール/水混合液(15mL,1/1)を順次に加え、攪拌して溶液を形成し、化合物5(250mg,1.10mmol)を添加し、窒素雰囲気下で反応混合物を45℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、大量の白色固体が析出し、濾過し、濾過ケーキをメタノール/水(3.4mL/4.0mL)で洗浄し、吸引乾燥し、50℃で真空乾燥して、52.83%の収率で白色固体230mgを得た。LC−MS(APCI):m/z=361.1(M+1)+.1H NMR(500mHz,DMSO−d6) δ9.11(s,1H),8.11−8.09(m,2H),7.88−7.86(m,1H),7.55−7.52(m,3H),2.18(s,3H),1.12(s,3H).
マグネチックスターラーおよび冷却管を備えた25mLの一つ口フラスコに、化合物25(200mg,0.56mmol)、化合物18(107mg,0.51mmol)およびエチレングリコールモノメチルエーテル(6mL)を加え、攪拌して溶液を形成し、塩化水素のイソプロパノール溶液(1.41mmol,0.28mL,5M)を滴下し、窒素雰囲気下で120℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、水(10mL)および飽和炭酸水素ナトリウム(5mL)を添加してジクロロメタン(15ml×3)で抽出し、有機相を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、残留物をシリカゲルカラムで分離して、50.3%の収率で白色固体150mgを得た。LC−MS(APCI):m/z=531.2(M+1)+. 1H NMR(300mHz,CDCl3) δ8.11(s,1H),7.92−7.89(m,2H),7.57(d,J=8.1Hz,1H),7.41−7.38(m,3H),6.91(d,J=8.1Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J=6.0Hz,2H),2.94(t,J=6.0Hz,2H),2.69−2.64(m,4H),2.13(s,3H),1.85−1.81(m,4H),1.22(s,3H).
マグネチックスターラーおよび冷却管を備えた100mLの三つ口フラスコに、マグネシウム粉末(1.80g,74.87mmol)を加え、真空にして窒素ガスで3回置換し、窒素雰囲気下でジエチルエーテル(30mL)およびCD3I(10.0g,68.96mmol)を添加した後、2時間加熱還流した。−10℃まで冷却し、化合物19(4.0g,62.39mmol)のジエチルエーテル溶液(10mL)を滴下した後、ゆっくりと室温に昇温し、さらに2時間加熱還流した。室温まで冷却し、氷水浴で飽和NH4Cl水溶液(10mL)を滴下して反応をクエンチし、10分間撹拌し、層状に分離させ、水層をジエチルエーテル(20mLx2)で抽出し、有機相を合わせ、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下、室温で注意深く蒸留して、33.99%の収率で無色液体1.7gを得た。そのまま次の工程で用いた。
氷水浴で濃硫酸(10g)を水(10g)にゆっくり滴下し、温度を5℃以下に制御し、濃硫酸(1.52g,23.33mmol)をバッチでゆっくりと加え、攪拌して溶液を形成し、化合物28(1.7g,21.21mmol)を添加し、窒素雰囲気下、室温で攪拌しながら一晩反応させた。ジエチルエーテル(20mL)を添加し、静置して層状に分離させ、上部の有機相を分離し、下層を再びジエチルエーテル(20mL)で抽出し、有機相を合わせ、飽和NaHCO3(5mL)で洗浄し、無水硫酸ナトリウムで乾燥させ、室温で溶媒を注意深く蒸発させ、53.80%の収率で黄色液体1.2gを得た。そのまま次の工程で用いた。
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物29(1.2g,11.41mmol)およびメタノール(20mL)を加え、攪拌して溶液を形成し、Pd/C(120mg,10%)を添加し、水素バルーン下、真空にして水素ガスで3回置換し、水素雰囲気下で一晩反応させた。触媒を濾別し、塩化水素のイソプロパノール溶液(5M)をゆっくり滴下し、pH値を約2に調整し、10分間撹拌し、溶媒を減圧下で蒸発させ、79.23%の収率で黄色固体1.04gを得た。そのまま次の工程で用いた。
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物1(2.0g,9.02mmol)およびTHF(30mL)を順次に加え、攪拌して溶液を形成し、氷水浴で化合物30(1.04g,9.02mmol)およびトリエチルアミン(3.65g,36.08mmol)をゆっくり滴下した後、氷水浴を取り外し、窒素雰囲気下、室温で反応を1時間攪拌した。有機溶媒を減圧下で蒸発させ、水(50mL)を添加し、ジクロロメタン(50ml×3)で抽出し、有機相を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、シリカゲルカラムクロマトグラフィーで分離して、29.34%の収率で白色固体700mgを得た。LC−MS(APCI):m/z=268.1(M+1)+。1H NMR(500mHz,CDCl3) δ8.75(t,J=2.0Hz,1H),8.40(dd,J=8.0Hz,J=2.0Hz,1H),8.24(dd,J=8.0Hz,J=2.0Hz,1H),7.73(t,J=8.0Hz,1H),4.99(s,1H).
マグネチックスターラーおよび冷却管を備えた50mLの一つ口フラスコに、エタノール/水混合液(15mL,2/1)および化合物31(300mg,1.17mmol)を加え、撹拌しながら、還元鉄粉(651mg,11.67mmol)および塩化アンモニウム(0.31mg,5.83mmol)を添加し、窒素雰囲気下で85℃に昇温し、この温度を保持して1時間反応させた。室温まで冷却し、不溶性の固体を濾別し、有機溶媒を減圧下で蒸発させ、飽和NaHCO3水溶液(5mL)を添加して酢酸エチル(20ml×3)で抽出し、有機相を合わせ、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、95.79%の収率で白色固体250mgを得た。LC−MS(APCI):m/z=238.1(M+1)+。
室温で、マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物32(200mg,1.23mmol)およびメタノール/水混合液(15mL,1/1)を順次に加え、攪拌して溶液を形成し、化合物5(250mg,1.10mmol)を添加し、窒素雰囲気下で反応混合物を45℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、大量の白色固体が析出し、濾過し、濾過ケーキをメタノール/水(3.4mL/4.0mL)で洗浄し、吸引乾燥し、50℃で真空乾燥して、52.83%の収率で白色固体230mgを得た。LC−MS(APCI):m/z=364.1(M+1)+. 1H NMR(500mHz,DMSO−d6) δ9.11(s,1H),8.11−8.09(m,2H),7.88−7.86(m,1H),7.55−7.52(m,3H),2.18(s,3H).
マグネチックスターラーおよび冷却管を備えた25mLの一つ口フラスコに、化合物33(200mg,0.56mmol)、化合物18(107mg,0.51mmol)およびエチレングリコールモノメチルエーテル(6mL)を加え、攪拌して溶液を形成し、塩化水素のイソプロパノール溶液(1.41mmol,0.28mL,5M)を滴下し、窒素雰囲気下、120℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、水(10mL)および飽和炭酸水素ナトリウム(5mL)を添加してジクロロメタン(15ml×3)で抽出し、有機相を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、残留物をシリカゲルカラムで分離して、50.3%の収率で白色固体150mgを得た。LC−MS(APCI):m/z=534.2(M+1)+. 1H NMR(300mHz,CDCl3) δ8.11(s,1H),7.92−7.89(m,2H),7.57(d,J=8.1Hz,1H),7.41−7.38(m,3H),6.91(d,J=8.1Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J=6.0Hz,2H),2.94(t,J=6.0Hz,2H),2.69−2.64(m,4H),2.13(s,3H),1.85−1.81(m,4H).
マグネチックスターラーを備えた50mLの三つ口フラスコに、NaH(595mg,14.88mmol,60%)を加え、真空にして窒素ガスで3回置換し、窒素雰囲気下で無水THF(20mL)を添加し、氷水浴で2−エタノールアミン(909mg,14.88mmol)の無水THF(2mL)溶液を滴下し、反応を10分間攪拌し、さらに化合物34(2.0g,14.17mmol)の無水THF(3mL)溶液を滴下した後、氷水浴を取り外し、室温で反応を2時間撹拌した。飽和酢酸エチル水溶液(50mL)を添加して反応をクエンチし、濾過し、濾液を無水硫酸ナトリウムで乾燥させ、濾過し、濃縮してシリカゲルカラムにより分離して、61.69%の収率で黄色油状物1.6gを得た。LC−MS(APCI):m/z=183.1(M+1)+。1H NMR(300mHz,CDCl3) δ8.21(d,J=9.3Hz,2H),6.97(d,J=9.3Hz,2H),4.09(t,J=5.1Hz,2H),3.15(t,J=5.1Hz,2H).
氷水浴で、マグネチックスターラーおよび冷却管を備えた50mLの一つ口フラスコに、臭化水素酸水溶液(7.57g,93.57mmol,48%)および濃硫酸(3.67g)を加え、均一に攪拌し、化合物37(3.0g,37.43mmol)を滴下した後、反応混合物を90℃に昇温させ、この温度を保持して2時間撹拌しながら反応させた。室温まで冷却し、酢酸エチル(20mL×2)で抽出し、有機相を合わせ、無水硫酸ナトリウムで乾燥させ、濃縮し、シリカゲルカラムにより分離して、17.89%の収率で無水油状物1.5gを得た。
マグネチックスターラーおよび冷却管を備えた50mLの一つ口フラスコに、化合物36(420mg,2.31mmol)、化合物38(640mg,2.86mmol)およびアセトニトリル(15mL)を加え、攪拌して溶液を形成し、ヨウ化カリウム(76mg,0.46mmol)および炭酸カリウム(382mg,2.77mmol)を添加し、窒素雰囲気下で反応混合物を加熱還流させ、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、溶媒を減圧下で蒸発させ、水(15mL)および酢酸エチル(20mL)を添加して有機層を分離し、酢酸エチル(20mL×2)で水層を抽出し、有機相を合わせ、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルカラムにより分離して、44.2%の収率で黄色油状物250mgを得た。LC−MS(APCI):m/z= 245.1(M+1)+。1H NMR(300mHz,CDCl3) δ8.20(d,J=9.0Hz,2H),6.98(d,J=9.0Hz,2H),4.21(t,J=6.0Hz,2H),2.96(t,J=6.0Hz,2H)。
マグネチックスターラーを備えた50mLの一つ口フラスコに、化合物39(250mg,1.04mmol)およびメタノール(10mL)を加え、攪拌して溶液を形成し、Pd/C(25mg,10%)を添加し、水素バルーン下、真空にして水素ガスで3回置換し、水素雰囲気下で一晩反応させた。触媒を濾別し、メタノール(3mL)で濾過ケーキを洗浄し、濾液を合わせ、濃縮して、98.6%の収率で黄色油状物220mgを得た。LC−MS(APCI):m/z=215.1(M+1)+.
マグネチックスターラーおよび冷却管を備えた25mLの一つ口フラスコに、化合物40(200mg,0.56mmol)、化合物6(107mg,0.51mmol)およびエチレングリコールモノメチルエーテル(6mL)を加え、攪拌して溶液を形成し、塩化水素のイソプロパノール溶液(1.41mmol,0.28mL,5M)を滴下し、窒素雰囲気下、120℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、水(10mL)および飽和炭酸水素ナトリウム(5mL)を添加してジクロロメタン(15ml×3)で抽出し、有機相を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、残留物をシリカゲルカラムで分離して、50.3%の収率で白色固体150mgを得た。LC−MS(APCI):m/z=533.2(M+1)+. 1H NMR(500mHz,CDCl3) δ8.11(s,1H),7.92−7.89(m,2H),7.57(d,J=8.0Hz,1H),7.41−7.38(m,3H),6.91(d,J=8.0Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J=5.5Hz,2H),2.94(t,J=5.5Hz,2H),2.13(s,3H),1.22(s,9H).
(1)キナーゼ阻害効果
試薬および材料:
JAK2,JAK2/V617F,ATP(Sigma,カタログ番号A7699−1G),DMSO (Sigma,カタログ番号D2650),96ウェルプレート(Corning,カタログ番号3365),384ウェルプレート(Greiner,カタログ番号784076),HTRF Kinase TKキット(Cisbio),5×キナーゼ緩衝液A(Life Technologies,カタログ番号PV3186),キナーゼトレーサー199(Life Technologies,カタログ番号PV5830),LanthaScreen(登録商標)Eu−anti−GST抗体(Life Technologies,カタログ番号PV5594)。
化合物の製剤:試験化合物をDMSOに溶解して、20mMストック溶液を調製した。その後、DMSOで3倍勾配希釈で10回希釈した。使用時は緩衝液で10倍に希釈した。
BaF3−EpoR−JAK2、BaF3−EpoR−JAK2/V617F細胞の活性に対する実施例化合物の阻害効果を測定した。
ミクロソーム実験:ヒト肝臓ミクロソーム:0.5mg/mL,Xenotech;ラット肝臓ミクロソーム:0.5mg/mL,Xenotech;マウス肝臓ミクロソーム:0.5mg/mL,Xenotech;補酵素(NADPH/NADH):1mM,Sigma Life Science;塩化マグネシウム:5mM、100mMのリン酸塩緩衝液(pH7.4)。
6匹のSprague−Dawleyラット(オス、7−8週齢、体重約210g)を2グループに分け、各グループ3匹ずつ、それぞれに、経静脈または経口(経静脈3mg/kg、経口10mg/kg)で単回投与量の化合物を投与し、その薬物動態学の差異を比較した。
マグネチックスターラーおよび冷却管を備えた25mLの一つ口フラスコに、化合物25(200mg,0.56mmol)、化合物18(107mg,0.51mmol)およびエチレングリコールモノメチルエーテル(6mL)を加え、攪拌して溶液を形成し、塩化水素のイソプロパノール溶液(1.41mmol,0.28mL,5M)を滴下し、窒素雰囲気下で120℃に昇温し、この温度を保持して攪拌しながら一晩反応させた。室温まで冷却し、水(10mL)および飽和炭酸水素ナトリウム(5mL)を添加してジクロロメタン(15ml×3)で抽出し、有機相を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、残留物をシリカゲルカラムで分離して、50.3%の収率で白色固体150mgを得た。LC−MS(APCI):m/z=531.2(M+1)+. 1H NMR(300mHz,CDCl3) δ8.11(s,1H),7.92−7.89(m,2H),7.57(d,J=8.1Hz,1H),7.41−7.38(m,3H),6.91(d,J=8.1Hz,1H),6.81(s,1H),6.44(s,1H),4.60(s,1H),4.13(t,J=6.0Hz,2H),2.94(t,J=6.0Hz,2H),2.69−2.64(m,4H),2.13(s,3H),1.85−1.81(m,4H),1.22(s,3H).
Claims (17)
- 式(I)で表れる化合物、或いはその薬学的に許容される塩、プロドラッグ、水和物または溶媒和物、結晶形、N−オキシドおよび様々なジアステレオ異性体であって、
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8およびY9は、それぞれ独立して水素または重水素から選択され;
X1、X2、X3およびX4は、それぞれ独立してCH3、CD3、CHD2およびCH2Dからなる群から選択され;
X1、X2、X3およびX4はそれぞれCH3である場合、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8およびY9のうちの少なくとも1つは重水素である、
式(I)で表れる化合物、或いはその薬学的に許容される塩、プロドラッグ、水和物または溶媒和物、結晶形、N−オキシドおよび様々なジアステレオ異性体。 - R5、R6、R7、R8、R9、R10、R11、R12は水素である、
請求項2に記載の化合物。 - X2はCH3である、
請求項2または3に記載の化合物。 - Y5は水素であり、且つX4はCH3である、
請求項2〜4のいずれか1項に記載の化合物。 - X1およびX3はCH3である、
請求項2〜5のいずれか1項に記載の化合物。 - R1、R2、R3およびR4は重水素である、
請求項1〜6のいずれか1項に記載の化合物。 - 薬学的に許容される賦形剤と
請求項1〜8のいずれか1項に記載の化合物、或いはその薬学的に許容される塩、プロドラッグ、水和物または溶媒和物、結晶形、N−オキシドおよび様々なジアステレオ異性体と
を含む、医薬組成物。 - 少なくとも部分的にJAK2によって媒介される疾患を治療する薬物の調製における、請求項1〜8のいずれか1項に記載の化合物、或いはその薬学的に許容される塩、プロドラッグ、水和物または溶媒和物、結晶形、N−オキシドおよび様々なジアステレオ異性体、もしくは請求項9に記載の医薬組成物の使用の方法。
- 少なくとも部分的にJAK2/V617Fによって媒介される疾患を治療する薬物の調製における、請求項1〜8のいずれか1項に記載の化合物、或いはその薬学的に許容される塩、プロドラッグ、水和物または溶媒和物、結晶形、N−オキシドおよび様々なジアステレオ異性体、もしくは請求項9に記載の医薬組成物の使用の方法。
- 前記の疾患は、骨髄組織の増殖性疾患、真性多血症、特発性血小板増加症、骨髄線維症、骨髄に関連するいかなる他の疾患、増殖性糖尿病性網膜症、癌、眼疾患、炎症、乾癬、血管新生に関連するいかなる疾患、またはウイルス感染である、
請求項10または11に記載の方法。 - 前記の疾患は真性多血症である、
請求項12に記載の方法。 - 前記の疾患は特発性血小板増加症である、
請求項12に記載の方法。 - 前記の疾患は骨髄化生を伴った骨髄線維症である、
請求項12に記載の方法。 - 前記の疾患は骨髄に関連するいかなる疾患である、
請求項12に記載の方法。 - 前記の疾患は、心血管疾患、血液疾患、慢性骨髄性白血病、骨髄増殖性疾患からなる群から選択される、
請求項12に記載の方法。
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