JP2022504765A - ジヒドロイミダゾピラジノン化合物、該化合物を含む組成物およびその使用 - Google Patents
ジヒドロイミダゾピラジノン化合物、該化合物を含む組成物およびその使用 Download PDFInfo
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- JP2022504765A JP2022504765A JP2021520119A JP2021520119A JP2022504765A JP 2022504765 A JP2022504765 A JP 2022504765A JP 2021520119 A JP2021520119 A JP 2021520119A JP 2021520119 A JP2021520119 A JP 2021520119A JP 2022504765 A JP2022504765 A JP 2022504765A
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Abstract
Description
本発明の第1の態様では、式(I)で表れる化合物、或いはその互変異性体、立体異性体、プロドラッグ、結晶、薬学的に許容される塩、水和物または溶媒和物を提供する。
Y1、Y2、Y3、Y4、Y5、Y6およびY7は、それぞれ独立して、水素、重水素、ハロゲン、またはトリフルオロメチルから選択され;
R1、R2、R3、R4、R5およびR6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およびX3は、それぞれ独立してCH3、CD3、CHD2またはCH2Dから選択され;
追加の条件は、前記化合物が少なくても1つの重水素原子を含むことである。
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。
一実施形態において、本発明は、式(I)で表われる化合物、或いはその互変異性体、立体異性体、プロドラッグ、結晶形、薬学的に許容される塩、水和物または溶媒和物に関する。
Y1、Y2、Y3、Y4、Y5、Y6およびY7は、それぞれ独立して、水素、重水素、ハロゲン、またはトリフルオロメチルから選択され;
R1、R2、R3、R4、R5およびR6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およびX3は、それぞれ独立してCH3、CD3、CHD2またはCH2Dから選択され;
追加の条件は、前記化合物が少なくても1つの重水素原子を含むことである。
R1、R2、R3およびR4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およびX3は、それぞれ独立してCH3、CD3、CHD2またはCH2Dから選択され;
追加の条件は、前記化合物が少なくても1つの重水素原子を含むことである。
R1、R2、R3およびR4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およびX3は、それぞれ独立してCH3、CD3、CHD2またはCH2Dから選択され;
追加の条件は、前記化合物が少なくても1つの重水素原子を含むことである。
R1、R2、R3およびR4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およびX3は、それぞれ独立してCH3、CD3、CHD2またはCH2Dから選択され;
追加の条件は、前記化合物が少なくても1つの重水素原子を含むことである。
本発明の化合物(その塩を含む)は、既知の有機合成技術で調製され、以下のスキームのような様々な可能な合成経路のいずれかに従って合成することができる。本発明の化合物を調製する反応は、有機合成分野の技術者によって容易に選択される適切な溶媒中で実施される。適切な溶媒は、反応が行われる温度(例えば、溶媒の凍結温度から沸点までの範囲の温度)で、出発物質(反応物)、中間体または生成物と実質的に反応しない。所望の反応は、1種の溶媒または2種以上の溶媒の混合物中で実施しても良い。当業者は、特定の反応工程に応じて、特定の反応工程用の溶媒を選択することができる。
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)および医薬上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。
本発明は、癌の併用療法に使用するための、式(I)~(IV)で表われる化合物またはその薬学的に許容される塩と、他の治療薬とを提供する。
他の治療薬には、以下の1つまたは複数が含まれる。
(i)腫瘍医学で使用される抗増殖剤・抗腫瘍剤およびそれらの組み合わせ、例えば、アルキル化剤(例えば、シスプラチン、オキサリプラチン、カルボプラチン、シクロホスファミド、ナイトロジェンマスタード、メルファラン(melphalan)、クロラムブシル、ブスルファン、テモゾロミドおよびニトロソウレア);代謝拮抗剤(例えば、5-フルオロウラシルやテガフールなどのフルオロピリミジン、ラルチトレキサート、メトトレキサート、シトシンアラビノシド、ヒドロキシ尿素のようなゲムシタビンおよび葉酸拮抗薬);抗腫瘍抗生物質(例えば、アドリアマイシン、ブレオマイシン、ドキソルビシン、ダウノマイシン、エピルビシン、イダルビシン、マイトマイシン-C、ダクチノマイシン、ミトラマイシンのようなアントラサイクリン);有糸分裂阻害剤(例えば、ビンクリスチン、ビンブラスチン、ビンデシン、ビノレルビンのようなビンカアルカロイド、およびタキソール、タキソテール、ポロキナーゼ(polokinase)阻害剤などのタキソイド);ならびに、トポイソメラーゼ阻害剤(例えば、エトポシド、テニポシド、アムサクリン、トポテカン、カンプトテシンのようなエピポドフィロトキシン);
(ii)抗ホルモン剤、例えは、抗エストロゲン剤(例えば、タモキシフェン、フルベストラント、トレミフェン、ラロキシフェン、ドロロキシフェンおよびヨードキシフェン)、抗アンドロゲン剤(例えば、ビカルタミド、フルタミド、ニルタミドおよび酢酸シプロテロン)、LHRHアンタゴニストまたはLHRHアゴニスト(例えば、ゴセレリン、リュープロレリンおよびブセレリン)、プロゲストゲン(例えば酢酸メゲストロール)、アロマターゼ阻害剤(例えば、アナストロゾール、レトロゾール、ボラゾール(virazole)およびエキセメスタン)、ならびに5αリダクターゼ阻害剤(例えばフィナステリド);
(iii)成長因子の機能およびそれらの下流のシグナル伝達経路の阻害剤:
Sternらのレビュー(Critical Reviews in Oncology/Haematology,2005,54,pp11-29)に記載された任意の成長因子または成長因子受容体標的のAbモジュレーターを含み;このような標的の小分子阻害剤をさらに含み、例えばキナーゼ阻害剤(例として、抗erbB2抗体トラスツズマブ[Hercepitn(商標)]、抗EGFR抗体パニツムマブ、抗EGFR抗体セツキシマブ[エルビタックス、C225]およびチロシンキナーゼ阻害剤が挙げられる)を含み、これらのチロシンキナーゼ阻害剤は、例えば上皮成長因子ファミリー受容体(EGFR/erbB1)チロシンキナーゼ阻害剤(例えば、ゲフィチニブまたはエルロチニブ)、erbB2チロシンキナーゼ阻害剤(例えばラパチニブ)、および混合erb1/2阻害剤(例えばアファタニブ)などのerbB受容体ファミリーの阻害剤を含み;同様の戦略は、他のタイプの成長因子およびそれらの受容体にも利用可能であり、例えば、肝細胞成長因子ファミリーまたはそれらの受容体(c-metおよびRonを含む)の阻害剤;インスリンおよびインスリン成長因子ファミリーまたはそれらの受容体(IGFR、IR)の阻害剤、血小板由来成長因子ファミリーまたはそれらの受容体(PDGFR)の阻害剤、および例えばc-kit、AnLKおよびCSF-1Rなどの他の受容体チロシンキナーゼによって媒介されるシグナル伝達の阻害剤;
上記以外のセリン/スレオニンキナーゼの阻害剤、例えば、ベムラフェニブなどのraf阻害剤、セルメチニブ(AZD6244ARRY-142886)、コビメチニブまたはGDC-0623(例えばWO2015/0832840を参照)などのMEK阻害剤、イマチニブまたはニロチニブなどのAbl阻害剤、イブルチニブなどのBtk阻害剤、フォスタマチニブなどのSyk阻害剤、オーロラキナーゼ阻害剤(例えばAZD1152)、JAK、STATおよびIRAK4などの他のser/thrキナーゼの阻害剤、およびサイクリン依存性キナーゼ阻害剤を含み;
(iv)DNA損傷シグナル伝達経路のモジュレーター、例えば、PARP阻害剤(例えば、オラパリブ)、ATR阻害剤またはATM阻害剤;
(v)アポトーシスおよび細胞死経路のモジュレーター、例えば、Bclファミリーモジュレーター(例えば、ABT-263/Navitoclax、ABT-199);
(vi)抗血管新生剤、例えば、血管内皮増殖因子の効果を阻害するもの[例えば、抗血管内皮細胞増殖因子抗体ベバシズマブ(Avastin(商標))、および例えばVEGF受容体チロシンキナーゼ阻害剤、例えはソラフェニブ、アキシチニブ、パゾパニブ、スニチニブ、バンデタニブ(および他のメカニズムで作用する化合物(例えば、リノミド、インテグリンανβ3機能の阻害剤およびアンギオスタチン))];
(vii)血管崩壊剤、例えば、コンブレタスタチンA4;
(viii)抗浸潤剤、例えばダサチニブ(J.Med.Chem.,2004,47,6658-6661)およびボスチニブ(SKI-606)のようなc-Srcキナーゼファミリー阻害剤、ならびにマリマスタットのようなメタロプロテイナーゼ阻害剤、ウロキナーゼプラスミノーゲンアクチベーター受容体機能の阻害剤またはヘパラナーゼに対する抗体];
(ix)免疫療法アプローチ:例えば、インターロイキン2、インターロイキン4または顆粒球-マクロファージコロニー刺激因子などのサイトカインによるトランスフェクションのような患者の腫瘍細胞の免疫原性を高めるex-vivoおよびin-vivoアプローチ、T細胞アネルギーを減少させるアプローチ、サイトカインをトランスフェクトした樹状細胞などのトランスフェクトした免疫細胞を使用するアプローチ、サイトカインをトランスフェクトした腫瘍細胞株を使用するアプローチ、および抗イディオタイプ抗体を使用するアプローチを含む。具体的な例としては、PD-1(例えばBMS-936558)、PDL-1またはCTLA4(例えばイピリムマブ、トレメリムマブ)を標的とするモノクローナル抗体が挙げられ;
(x)アンチセンスまたはRNAiに基づく治療法、例えば、記載された標的に関する治療法。
(xi)遺伝子治療法アプローチ:例えば、異常な遺伝子(例えば異常なp53または異常なBRCA1またはBRCA2)を置き換えるアプローチ;例えばシトシンデアミナーゼ、チミジンキナーゼまたは細菌ニトロレダクターゼを使用するアプローチのようなGDEPT(遺伝子指向酵素プロドラッグ療法)アプローチ;および、化学療法または放射線療法に対する患者の耐性を高めるアプローチ(例えば多剤耐性遺伝子治療法)を含む。
以下、特定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。
-15℃で、イソブチリルクロリド(14.96g,110mol)の無水THF(20mL)溶液を、化合物1(21.8g,99.54mmol)およびN-メチルモルホリン(11.2g,110mmol)の無水THF(100mL)溶液にゆっくりと滴下した後、-15℃でさらに20min反応させた。
NaBH4(12.00g,318mmol)のH2O(20mL)溶液を、上記の反応液にゆっくりと添加した後、-15℃で45min反応させた。EtOAc(700mL)を加えて反応液を希釈し、希塩酸(2M)で系を中性に調節し、有機層を分離し、飽和食塩水(100mL)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=20%)によって精製して、62.83%の収率で13gの淡黄色の油状物を得た。1H NMR(300 MHz,CDCl3) δ 5.19(s,1H),3.83-3.60(m,3H),3.59-3.44(m,2H),3.35(s,3H),2.96(s,1H),1.43(s,9H).
氷浴中で、MSCl(2.27g,19.83mmol)の無水DCM(20mL)溶液を、化合物2(3.4g,16.58mmol)およびTEA(2.06g,20.4mmol)の無水DCM(100mL)溶液にゆっくりと加え、室温で反応液を撹拌して2.5h反応させた。水(30mL)で反応をクエンチし、有機層を分離し、炭酸水素ナトリウムの飽和水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮して得られた淡黄色の油状物をそのまま次の工程に使用した。收率:100%。
氷浴中で、NaH(6.42g,160.5mmol)を、化合物4(15g,107.04mmol)の無水DMF(75mL)溶液に加え、30min撹拌した後、SEMCl(28.47mL,160.56mmol)を反応液に加え、室温で反応を一晩撹拌した。水(100mL)で反応をクエンチし、酢酸エチル(200mL×3)で抽出し、有機層を合わせ、飽和食塩水(100mL×4)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=10%)によって精製して、58.9%の収率で17gの淡黄色の油状物を得た。1H NMR(500 MHz,CDCl3) δ 7.26(d,J=1.0Hz,1H),7.20(d,J=1.0Hz,1H),5.79(s,2H),4.42(q,J=7.1Hz,2H),3.58-3.54(m,2H),1.43(t,J=7.1Hz,3H),0.94-0.90(m,2H),-0.03(s,9H).
氷浴中で、化合物5(6.8g,25.18mmol)の無水DMF(30mL)と無水DCM(30mL)との混合溶液に、NBS(4.93g,27.70mmol)を数回分けて加え、室温で24h反応させた。水(100mL)で反応をクエンチし、減圧下でDCMを除去し、酢酸エチル(150mL×3)で抽出し、有機層を合わせ、飽和食塩水(100mL×4)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=10%)によって精製して、57%の収率で5gの淡黄色の油状物を得た。1H NMR(400 MHz,DMSO-d6) δ 7.82(d,J=14.5Hz,1H),5.66(s,2H),4.30 (q,J=7.1Hz,2H),3.58-3.44(m,2H),1.30(t,J=7.1Hz,3H),0.89-0.74(m,2H),-0.06(s,9H).
窒素ガス保護下で、X-phos(410mg)およびPd2(dba)3CHCl3(370mg)を、化合物6(5.00g,14.36mmol)、B2(pin)2(4.36g)および酢酸カリウム(4.20g)の無水ジオキサン(60mL)溶液に加え、80℃に加熱し、一晩反応させた。室温に冷却し、セライトで濾過し、ジオキサンでフィルターケーキを洗浄した。減圧下で濾液を濃縮し、得られた淡黄色の油状物をそのまま次の工程に使用した。
上記の化合物7を、ジオキサン(90mL)と水(15mL)との混合溶媒に加え、化合物2,4-ジクロロ-5-メチルピリミジン(2.60g,15.80mmol)およびCs2CO3(9.34g,28.72mmol)をさらに加え、大気を窒素に置き換え、窒素ガス保護下でPd(PPh3)4(1.00g)を反応液に添加し、85℃で2.5h反応させた。室温に冷却し、セライトで濾過し、濾液を減圧してジオキサンを除去し、50mLの水で反応をクエンチし、酢酸エチル(200mL×3)で抽出し、有機層を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=5%)によって精製して、65.4%の収率で3.72gの淡黄色の固体を得た。LC-MS(APCI):m/z=397.0(M+1)+。1H NMR(300 MHz,CDCl3) δ 8.42(s,1H),8.13(s,1H),5.82(s,2H),4.45(q,J=7.1Hz,2H),3.71-3.50(m,2H),2.70(s,3H),1.45(t,J=7.1Hz,3H),0.98-0.91(m,2H),-0.01(s,9H).
TFA(13.0mL)を化合物8(3.7g,9.34mmol)のDCM(13mL)溶液に加え、室温で一晩反応させた。減圧下で反応液を除去し、飽和炭酸水素ナトリウム溶液(30mL)を添加し、2h撹拌した。固体を濾過し、水で洗浄し、真空で固体を乾燥して、91.0%の収率で2.25gの淡黄色の固体を得た。LC-MS(APCI):m/z=267.1(M+1)+。1H NMR(300 MHz,DMSO-d6) δ 13.96(s,1H),8.59(s,1H),8.11(s,1H),4.34(q,J=7.1Hz,2H),2.59(s,3H),1.32(t,J=7.1Hz,3H).
Cs2CO3(2.70,8.28mmol(2-3eq))を、化合物9(1.10g,4.14mmol,1eq.)および化合物3(3.0-4eq)の無水DMF(15mL)溶液に加え、窒素保護下、100℃で、反応液を20h反応した。室温に冷却し、水(30mL)で反応をクエンチし、酢酸エチル(50mL×4)で抽出し、有機層を合わせ、飽和食塩水(30mL×4)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=20%)によって精製して、40.0%の収率で820mgの淡黄色の固体を得た。LC-MS (APCI): m/z=454.1(M+1)+,1H NMR(300 MHz,CDCl3) δ 8.39(s,1H),7.95(s,1H),5.09(d,J=8.8Hz,1H),4.70(dd,J=13.4,4.3Hz,1H),4.60-4.33(m,3H),4.22(s,1H),3.49(dd,J=6.8,3.3Hz,2H),3.37(s,3H),2.69(s,3H),1.45(t,J=7.1Hz,3H),1.30(s,9H).
HCl(15mL)のジオキサン溶液を、化合物10(770mg,1.70mmol)に加え、室温で一晩撹拌し、固体を濾過し、酢酸エチル(15mL)で洗浄し、固体を真空乾燥した。そのまま次の工程に使用した。LC-MS(APCI):m/z=354.1(M+1)+。
上記の化合物11をMeOH/NH3(30mL,7N)の溶液に加え、室温で一晩撹拌した。減圧下で反応液を濃縮させ、濃縮液をカラムクロマトグラフィー(DCM/MeOH=5%)によって精製して、465mgの淡黄色の固体を得た。2つの工程の収率:87.4%。LC-MS(APCI):m/z=308.0(M+1)+。
氷浴中で、NaH(2.67g,66.75mol)を化合物12(12.18g,63.69mmol)の無水THF(200mL)溶液に加え、滴下完了後、室温でさらに30min反応させた。
氷浴中で、重水素化ヨードメタン(8.70g,60.00mmol)の無水THF(20mL)溶液を、上記の反応液にゆっくり加え、室温で3h反応した。水(200mL)で反応をクエンチした。減圧下でTHFを除去し、EtOAc(700mL)を加えて反応液を希釈し、希塩酸(2M)で系を中性に調節し、有機層を分離し、飽和食塩水(100mL)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=20%)によって精製して、20.1%の収率で3.1gの淡黄色の油状物を得た。
氷浴中で、MsCl(1.40g)の無水DCM(10mL)溶液を、化合物13(2.1g,10.24mmol)およびTEA(1.27g)の無水DCM(70mL)溶液にゆっくりと加え、室温で反応液を撹拌し、2.5h反応させた。水(30mL)で反応をクエンチし、有機層を分離し、炭酸水素ナトリウムの飽和水溶液で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮して得られた淡黄色の油状物をそのまま次の工程に使用した。收率:100%。
Cs2CO3(3.05g,9.38mmol)を、化合物9(1.00g,3.75mmol,1eq.)および上記の化合物14(10.24mmol)の無水DMF(15mL)溶液に加え、窒素ガス保護下、100℃で反応液を20h反応させた。室温に冷却し、水(30mL)で反応をクエンチし、酢酸エチル(50mL×4)で抽出し、有機層を合わせ、飽和食塩水(30mL×4)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=20%)によって精製して、44.4%の収率で760mgの淡黄色の固体を得た。LC-MS(APCI):m/z=457.1(M+1)+。
HCl(15mL)のジオキサン溶液を化合物15(760mg,1.66mol)に加え、室温で一晩撹拌し、固体を濾過し、酢酸エチル(15mL)で洗浄し、固体を真空乾燥した。そのまま次の工程に使用した。LC-MS(APCI):m/z=357.1(M+1)+。
上記の化合物16をMeOH/NH3(30mL,7N)の溶液に加え、室温で一晩撹拌した。減圧下で反応液を濃縮させ、濃縮液をカラムクロマトグラフィー(DCM/MeOH=5%)によって精製して、530mgの淡黄色の固体を得た。2つの工程の収率:100%。LC-MS(APCI):m/z=311.1(M+1)+。
氷浴中で、化合物3,4-ジフルオロ安息香酸メチル(2.00g,11.62mmol)の無水THF(10mL)溶液を、LiAlD4(490mg,11.62mmol)の無水THF(40mL)溶液にゆっくりと滴下し、滴下完了後、室温でさらに60min反応させた。氷浴中で、上記の反応液に重水(3mL)を添加し、さらに30min撹拌した。セライトで濾過し、THFでフィルターケーキを洗浄し、無水硫酸ナトリウムで濾液を乾燥させ、減圧下で濃縮して淡黄色の液体を得た。そのまま次の工程に使用した。
HBr(33%,10mL)を上記の化合物(3,4-ジフルオロフェニル)メタン-d2-オールに加え、反応液を還流して1h反応させた。室温に冷却し、DCM(50mL×2)で抽出し、有機層を飽和食塩水(50mL)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=1%)によって精製して、80%の収率で1.7gの淡黄色の液体を得た。1H NMR(300MHz,CDCl3) δ 7.26-7.17(m,1H),7.15-7.08(m,2H).
重水素化ヨードメタン(2.90g,20.0mmol)を、化合物5-ニトロ-1H-ピラゾール(1.13g,10.00mmol)およびK2CO3(4.14g,30.00mmol)の無水DMF(40mL)溶液に加え、窒素ガス保護下、45℃で反応液を24h反応させた。室温に冷却し、水(100mL)で反応をクエンチし、酢酸エチル(150mL×3)で抽出した。有機層を合わせ、飽和食塩水(100mL×3)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(PE/EtOAc=35%)によって精製して100mgの淡黄色の油状物を得た。
5%のPt-C(50mg)を、化合物1-(メチル-d3)-5-ニトロ-1H-ピラゾール(100mg)の無水メタノールに加え、水素ガス雰囲気で4h反応させた。反応液をセライトで濾過し、減圧下で濾液を濃縮させ、濃縮液をカラムクロマトグラフィー(DCM/MeOH=10%)によって精製して70mgの淡黄色の固体を得た。1H NMR(500MHz,DMSO-d6) δ 6.96(d,J=1.7Hz,1H),5.22(d,J=1.8Hz,1H),5.08(s,2H).
室温で化合物B-2(460mg,2.22mmol)を、化合物A-1(456mg,1.48mmol)およびNaH(152mg,3.82mmol)の無水DMF(10mL)溶液に加え、室温で2.5h反応させた。水(30mL)で反応をクエンチし、酢酸エチル(50mL×3)で抽出し、有機層を合わせ、飽和食塩水(30mL×3)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(ジクロロメタン/メタノール=4%)によって精製して、96.75%の収率で620mgの淡黄色の固体を得た。LC-MS (APCI): m/z=434.2(M+1)+。1H NMR(500MHz,CDCl3) δ 8.42(d,J=0.5Hz,1H),7.94(s,1H),7.25-7.19(m,1H),7.18-7.08(m,2H),5.33(d,J=15.0Hz,1H),4.42(dd,J=13.2,1.0Hz,1H),4.28-4.17(m,2H),3.85-3.78(m,1H),3.38(dd,J=9.4,4.9Hz,1H),3.31-3.25(m,4H),2.76(s,3H).
窒素ガス保護下で、XantPhos-Pd-G2(15mg,0.015mmol)を、化合物D-1(120mg,0.27mmol)、化合物C-1(64mg,0.64mmol)およびCs2CO3(190mg,0.58mmol)の無水ジオキサン(8mL)溶液に加え、100℃で一晩反応させた。室温に冷却し、セライトで濾過し、減圧下で濾液を濃縮させ、DCM(200mL)を添加し、飽和食塩水(50mL×3)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(ジクロロメタン/メタノール=5%)によって精製して、92.9%の収率で125mgの褐色の固体を得た。純度:96.78%(HPLC);LC-MS (APCI): m/z=498.3(M+1)+。1H NMR(300MHz,DMSO-d6) δ 9.20(s,1H),8.30(s,1H),7.92(s,1H),7.50-7.34(m,2H),7.31(d,J=1.9Hz,1H),7.25(d,J=4.2Hz,1H),6.28(d,J=1.8Hz,1H),5.06(d,J=15.4Hz,1H),4.56-4.29(m,3H),4.10-3.93(m,1H),3.42-3.34(m,2H),3.16(s,3H),2.49(s,3H).
室温で、化合物B-1(205mg,0.98mmol)を、化合物A-1(200mg,0.65mmol)およびNaH(65mg,1.63mmol)の無水DMF(8mL)溶液に加え、室温で2.5h反応させた。水(30mL)で反応をクエンチし、酢酸エチル(50mL×3)で抽出し、有機層を合わせ、飽和食塩水(30mL×3)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(ジクロロメタン/メタノール=4%)によって精製して、67.2%の収率で190mgの淡黄色の固体を得た。LC-MS(APCI):m/z=436.2(M+1)+。
窒素ガス保護下で、XantPhos-Pd-G2(10mg)を、化合物D-2(95mg,0.22mmol)、化合物C-2(50mg,0.54mmol)およびCs2CO3(142mg,0.44mmol)の無水ジオキサン(6mL)溶液に加え、100℃で一晩反応させた。室温に冷却し、セライトで濾過し、減圧下で濾液を濃縮させ、DCM(100mL)を添加し、飽和食塩水(25mL×3)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(ジクロロメタン/メタノール=6%)によって精製して、83.2%の収率で90mgの褐色の固体を得た。純度:98.69%(HPLC);LC-MS(APCI):m/z=497.2(M+1)+。1H NMR(300MHz,DMSO-d6) δ 9.20(s,1H),8.30(s,1H),7.92(s,1H),7.51-7.34(m,2H),7.33-7.29(m,1H),7.29-7.17(m,1H),6.28(d,J=1.8Hz,1H),4.58-4.33(m,2H),4.07-3.92(m,1H),3.68(s,3H),3.41-3.36(m,1H),3.31-3.25(m,1H),3.16(s,3H),2.49(s,3H).
室温で、化合物B-2(536mg,2.59mmol)を、化合物A-2(530mg,1.72mmol)およびNaH(172mg,4.30mmol)の無水DMF(10mL)溶液に加え、室温で2.5h反応させた。水(30mL)で反応をクエンチし、酢酸エチル(50mL×3)で抽出し、有機層を合わせ、飽和食塩水(30mL×3)で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(ジクロロメタン/メタノール=4%)によって精製して、87.8%の収率で660mgの淡黄色の固体を得た。LC-MS(APCI):m/z=437.1(M+1)+。
窒素ガス保護下で、XantPhos-Pd-G2(44mg)を、化合物D-3(220mg,0.50mmol)、化合物C-2(121.4mg,1.25mmol)およびCs2CO3(325mg,1.00mmol)の無水ジオキサン(10mL)溶液に加え、100℃で一晩反応させた。室温に冷却し、セライトで濾過し、減圧下で濾液を濃縮させ、DCM(200mL)を添加し、飽和食塩水(50mL×3)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(ジクロロメタン/メタノール=5%)によって精製して、褐色の固体として205mgのラセミ化合物I-4を得た。LC-MS(APCI):m/z=498.3(M+1)+。
キラルカラムによってラセミ化合物I-4を分割して、化合物I-4-1および化合物I-4-2を得た。
窒素ガス保護下で、XantPhos-Pd-G2(44mg)を、化合物D-3(220mg,0.50mmol)、化合物C-1(125mg,1.25mmol)およびCs2CO3(325mg,1.00mmol)の無水ジオキサン(10mL)溶液に加え、100℃で一晩反応させた。室温に冷却し、セライトで濾過し、減圧下で濾液を濃縮させ、DCM(200mL)を添加し、飽和食塩水(50mL×3)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で濃縮させ、濃縮液をカラムクロマトグラフィー(ジクロロメタン/メタノール=5%)によって精製して、褐色の固体として225mgのラセミ化合物I-5を得た。LC-MS(APCI):m/z=501.3(M+1)+。
キラルカラムによってラセミ化合物I-5を分割して、化合物I-5-1および化合物I-5-2を得た。
(1)代謝安定性の評価
ミクロソーム実験:ヒト肝臓ミクロソーム: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)。
表1
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。
試薬および材料:
ERK2キナーゼ(Promega、カタログ番号V1961)、RET(V804M)、Active(Signalchem、カタログ番号R02-12GG)、ADP-Glo TMキット(Promega、カタログ番号V9102)、GDC-0994(MCE、カタログ番号HY-15947)、ATP(Promega、カタログ番号V910B)、DMSO(Sigma、カタログ番号D8418)、DTT(Invitrogen、カタログ番号P2325)、384ウェルプレート(Greiner、カタログ番号784075)、ポリプロピレン製384ウェルプレート(Labcyte、カタログ番号P-05525-BC)、ポリプロピレン製96ウェルプレート(Nunc、カタログ番号249944)、プレートシェーカー(Thermo、カタログ番号4625-1 CECN/THZ Q)、遠心分離機(Eppendorf、カタログ番号5810R)、マルチラベルプレートリーダーEnvision 2104 multi-label Reader(PerkinElmer、カタログ番号74785)、Echo acoustic dispenser(Labcyte、カタログ番号550)。
化合物の調製:試験化合物をDMSOに溶解して、10mMのストック溶液を調製した。次に、ストック溶液を3倍の勾配で10回希釈した。薬物を添加する場合、緩衝液で10倍希釈した。
表2:
対数増殖期の細胞を採取し、トリパンブルー色素排除法で細胞生存率を検出し、細胞生存率が90%以上であることを確保した。細胞濃度を調整し、150μLの細胞懸濁液を96ウェルプレートに加え、37℃、5%CO2で16時間インキュベートした。試験する薬物の最大濃度は10μMであり、3倍の勾配希釈で10濃度に希釈した。96ウェルプレートの各ウェルに50μLの薬物溶液をデュープリケート(in duplicate)で加え、インキュベーションを4時間続けた。培地を除去した後、0.2mlの細胞溶解溶液および1mlのPMSFを各ウェルに加え、氷上で30分間インキュベートし、4℃で10分間遠心分離して細胞溶解溶液を得た。PathScan(登録商標)Phospho-p90RSK(Thr359)サンドイッチELISAキット(CST、カタログ番号91959C)を使用して、本発明の化合物のphospho-p90RSKに対する阻害率を検出し、各ウェルに100μLの細胞溶解液を添加し、4℃で一晩インキュベートした。プレートを洗浄し、100μLの再構成検出抗体(reconstituted Detection Antibody)を加え、37℃で1時間インキュベートした。プレートを洗浄し、100μLの西洋ワサビペルオキシダーゼ(HRP)標識二次抗体(reconstituted HRP-Linked secondary antibody)を加え、37℃で30分間インキュベートした。プレートを洗浄し、100μLのTMB発色液(TMB Substrate)を添加し、25℃で30分間インキュベートした後、100μLのSTOP Solutionを添加し、EnVision(Perkin Elmer 2104)で蛍光値を検出し、さまざまな濃度の化合物の影響下での阻害率を算出した。IC50の計算は、Prism Graphpad8.0ソフトウェアを使用して実行された。
表3:
Claims (13)
- 式(I)で表われる化合物、或いはその互変異性体、立体異性体、プロドラッグ、結晶、薬学的に許容される塩、水和物または溶媒和物であって、
Y1、Y2、Y3、Y4、Y5、Y6およびY7は、それぞれ独立して、水素、重水素、ハロゲン、またはトリフルオロメチルから選択され;
R1、R2、R3、R4、R5およびR6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およびX3は、それぞれ独立してCH3、CD3、CHD2またはCH2Dから選択され;
追加の条件は、前記化合物が少なくても1つの重水素原子を含むことである、
式(I)で表われる化合物、或いはその互変異性体、立体異性体、プロドラッグ、結晶、薬学的に許容される塩、水和物または溶媒和物。 - R3およびR4が水素である、
請求項1~4のいずれか1項に記載の化合物。 - X2がCH3である、
請求項1~5のいずれか1項に記載の化合物。 - R1およびR2がそれぞれ独立して水素である、
請求項1~6のいずれか1項に記載の化合物。 - X1がCD3である、
請求項1~7のいずれか1項に記載の化合物。 - X2がCD3である、
請求項1~8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1~10のいずれか1項に記載の化合物、或いはその互変異性体、立体異性体、プロドラッグ、結晶、薬学的に許容される塩、水和物または溶媒和物と
を含む、医薬組成物であって、
好ましくは、他の治療剤をさらに含み、
好ましくは、前記の他の治療剤がMEK阻害剤から選択される、医薬組成物。 - RAS/RAF/MEK/ERKキナーゼ、ERKキナーゼ、KARSキナーゼ、またはBRAF変異型キナーゼから選択されるキナーゼによって調節される増殖性疾患を治療および/または予防する医薬品の調製における、請求項1~10のいずれか1項に記載の化合物或いはその互変異性体、立体異性体、プロドラッグ、結晶、薬学的に許容される塩、水和物または溶媒和物、若しくは請求項11に記載の医薬組成物の使用であって、
好ましくは、前記のERKキナーゼがERK2キナーゼであり、
好ましくは、前記のBRAF変異型キナーゼがBRAF V600E変異型キナーゼである、前記の使用。 - 前記の増殖性疾患が非小細胞肺癌、膵臓癌、または結腸直腸癌から選択される、
請求項12に記載の使用。
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