JP6559719B2 - (s)−6−((1−アセチルピペリジン−4−イル)アミノ)−n−(3−(3、4−ジヒドロイソキノリン−2(1h)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミドの結晶塩 - Google Patents
(s)−6−((1−アセチルピペリジン−4−イル)アミノ)−n−(3−(3、4−ジヒドロイソキノリン−2(1h)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミドの結晶塩 Download PDFInfo
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- JP6559719B2 JP6559719B2 JP2016575040A JP2016575040A JP6559719B2 JP 6559719 B2 JP6559719 B2 JP 6559719B2 JP 2016575040 A JP2016575040 A JP 2016575040A JP 2016575040 A JP2016575040 A JP 2016575040A JP 6559719 B2 JP6559719 B2 JP 6559719B2
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Description
によって表される。
[1](S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミドのコハク酸塩の結晶形。
[2]CuK α 放射線を用いて測定された際に、約4.5、8.2、9.0、10.4、13.5、15.8、16.4、17.3、17.7、18.1、18.8、19.6、20.8、21.9、22.7、23.3、24.0、24.7、26.4、28.2および29.6度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、[1]に記載の結晶形。
[3]CuK α 放射線を用いて測定された際に、約4.5、8.2、10.4、13.5、15.8、16.4、17.3、17.7、18.1、18.8、19.6、20.8、21.9、23.3および24.0度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、[1]に記載の結晶形。
[4]CuK α 放射線を用いて測定された際に、約4.5、8.2、10.4、13.5、15.8、16.4、17.7、18.1、18.8、20.8、21.9、23.3および24.0度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、[1]に記載の結晶形。
[5]CuK α 放射線を用いて測定された際に、約4.5、10.4、17.7、18.1、20.8および24.0度2θの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、[1]に記載の結晶形。
[6]図1に実質的に従った粉末X線回折(XRPD)パターンによって特徴付けられる、[2]〜[5]のいずれかに記載の結晶形。
[7](S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミドの安息香酸塩の結晶形。
[8]CuK α 放射線を用いて測定された際に、約4.3、7.7、9.2、10.9、12.8、14.2、15.6、16.6、16.9、18.1、18.6、21.5、22.1、23.4、24.0、24.2、25.1、25.9、27.1、28.8および30.7度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、[7]に記載の結晶形。
[9]CuK α 放射線を用いて測定された際に、約4.3、7.7、9.2、10.9、12.8、14.2、15.6、16.6、16.9、18.1、18.6、22.1、24.0、24.2、25.9、27.1および28.8度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、[7]に記載の結晶形。
[10]CuK α 放射線を用いて測定された際に、約4.3、7.7、15.6、16.6、16.9、18.1、18.6、22.1、24.0、27.1および28.8度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、[7]に記載の結晶形。
[11]CuK α 放射線を用いて測定された際に、約4.3、7.7、18.1、18.6、22.1および24.0度2θの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、[7]に記載の結晶形。
[12]図2に実質的に従った粉末X線回折(XRPD)パターンによって特徴付けられる、[8]〜[11]のいずれかに記載の結晶形。
[13][1]〜[6]のいずれかに記載の結晶形および薬学的に許容可能な担体を含んでなる、医薬組成物。
[14][7]〜[12]のいずれかに記載の結晶形および薬学的に許容可能な担体を含んでなる、医薬組成物。
[15]経口投与用に適用される、[13]に記載の組成物。
[16]錠剤またはカプセルの形態である、[15]に記載の組成物。
[17]経口投与用に適用される、[14]に記載の組成物。
[18]錠剤またはカプセルの形態である、[17]に記載の組成物。
[19]その治療を必要とするヒトにおいて癌を治療する方法であって、該ヒトに[1]〜[6]のいずれかに記載の結晶形の有効量を投与することを含んでなる、方法。
[20]その治療を必要とするヒトにおいて癌を治療する方法であって、該ヒトに[7]〜[12]のいずれかに記載の結晶形の有効量を投与することを含んでなる、方法。
[21]その治療を必要とするヒトにおいて癌を治療する方法であって、該ヒトに[13]、[15]または[16]に記載の組成物の有効量を投与することを含んでなる、方法。
[22]その治療を必要とするヒトにおいて癌を治療する方法であって、該ヒトに[14]、[17]または[18]に記載の組成物の有効量を投与することを含んでなる、方法。
[23]前記癌が、造血癌、肺癌、前立腺癌、黒色腫および膵臓癌からなる群から選択される、[19]〜[22]のいずれかに記載の方法。
[24]療法に用いるための、[1]〜[12]のいずれかに記載の結晶形。
[25]PRMT5−媒介疾患の治療に用いるための、[1]〜[12]のいずれかに記載の結晶形。
[26]癌の治療に用いるための、[1]〜[12]のいずれかに記載の結晶形。
[27]前記癌が、造血癌、肺癌、前立腺癌、黒色腫および膵臓癌からなる群から選択される、[26]に記載の結晶形。
さらなる詳述なしに、当業者は、前述の記載を用いて本発明を最大限利用できると信じられている。以下の実施例は、従って、いかなる方法においても本発明の範囲の制限としてではなく、単なる例証として解釈されるべきである。
(a)tert−ブチル(1−アセチルピペリジン−4−イル)カルバミン酸塩
ジクロロメタン(3000mL)中の、tert−ブチルピペリジン−4−イルカルバミン酸塩(200g、1mol)、およびトリエチルアミン(150g、1.5mol)の溶液に、温度を0℃に維持しながら、1時間かけて、無水酢酸(102g、1mol)を滴下して添加した。添加後、混合物を0℃でもう2時間撹拌し、この時間でTLCが、反応が完了したことを示した。溶液を、水(1L)の添加によってクエンチした。有機層を回収し、重炭酸ナトリウム水溶液(1L)で洗浄し、硫酸ナトリウムで乾燥し、濃縮し、粗製産物を得た。4つのバッチを平行して運転し、670g重量の組み合わさった粗製産物を製造した。
メタノール(1000mL)中の、tert−ブチル(1−アセチルピペリジン−4−イル)カルバミン酸(330g、1.36mol)溶液に、0℃の温度を維持して30分間かけて、塩酸(メタノール中4M、300mL)を添加した。添加後、混合物を、0℃でもう2時間撹拌し、次いで、濃縮して、粗製産物を得た。2つのバッチを平行して運転し、310g重量の組み合わさった粗製産物を製造した。
水(500mL)中の(Z)−1、4−ジエトキシ−1、4−ジオキソブト−2−エン−2−オレートナトリウム(55.0g、262mmol)溶液に、酢酸ホルムアミジン(27.3g、262mmol)および水酸化ナトリウム(10.5g)を添加した。添加後、得られた混合物を、16時間、25℃で撹拌し、次いで、濃縮し、次いで、pH=1まで、添加した含水塩酸(1N)で酸性化した。得られた固体をろ過によって回収し、水およびエーテルで洗浄し、6−ヒドロキシピリミジン−4−カルボン酸(6.0g、収率:16.3%)を得た。
酢酸エチル(3000mL)中の6−ヒドロキシピリミジン−4−カルボン酸(300g、2.14mol)の撹拌した混合物に、反応温度を30℃未満に維持して、塩化オキサリル(1356g、10.68mol)をゆっくりと滴下した。添加後、混合物を、30分間、20℃で撹拌し、次いで、2mLのN、N−ジメチルホルムアミドを混合物に添加した。混合物を、次いで16時間、80℃で撹拌し、濃縮して黒い固体として粗製産物を得た。3つのバッチを平行して運転し、787g重量の組み合わさった粗製産物を製造した。
0℃での、テトラヒドロフラン(100mL)中の、1、2、3、4−テトラヒドロイソキノリン(10g、0.15mol)溶液に、フッ化カリウム(22g、0.3mmol)を添加した。1時間後、(S)−オキシラン−2−イルメチル3−スルホン酸ニトロベンゼン(21.4g、0.17mmol)を添加し、得られた溶液を、16時間、22℃で撹拌した。固体を、ろ過によって除去し、テトラヒドロフランで洗浄した。溶液を、次いで濃縮した(15g、収率53%)。
−78℃での、エタノール(100mL)中の、(R)−2−(オキシラン−2−イルメチル)−1、2、3、4−テトラヒドロイソキノリン(15g、0.08mol)溶液に、アンモニアガスをゆっくりと泡立てながら通気した。反応混合物を、次いで密封し、3時間、80℃で加熱した。反応混合物を、次いで濃縮した(15g、収率92%)。
ジクロロメタン(3500mL)中の、(S)−1−アミノ−3−(3、4−ジヒドロイソキノリン−2(1H)−イル)プロパン−2−オール(247g、1.20mol)とトリエチルアミン(250g、2.5mol)の撹拌した混合物に、6−クロロピリミジン−4−塩化カルボニル(100mLのジクロロメタン中190g)を1時間かけて、−60℃で、ゆっくりと添加した。添加後、混合物を10℃まであたためた。撹拌を1時間継続し、この時間でTLCが、反応が完了したことを示した。反応物を、水(1.5L)の添加によってクエンチした。有機相を回収し、硫酸ナトリウムで乾燥し、蒸発させた。残渣を、フラッシュクロマトグラフィーで精製して(酢酸エチル〜ジクロロメタン:メタノール=10:1)、淡い黄色い固体として所望の産物を得た。4つのバッチを平行して運転し、800g重量、収率49%の組み合わさった粗製産物を製造した。
イソプロパノール(2000mL)中の、(S)−6−クロロ−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミド(190g、0.55mmol)、1−(4−アミノピペリジン−1−イル)エタノン(78g)、およびトリエチルアミン(100g、1mol)の溶液を、16時間、60℃で撹拌した。混合物を濃縮し、残渣を、フラッシュクロマトグラフィーによって精製し、所望の産物を得た。4つのバッチを平行して運転し、482g重量の組み合わさった粗製産物を製造した。この材料を、分取HPLCでさらに精製し、標題の化合物(325g、純度98%超、遊離塩基形態)を得た。
(a)小規模
酢酸エチル(0.5mL)を、(S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミド(非晶質遊離塩基)(19.9mg)に添加した。懸濁液に、コハク酸(メタノール中1M溶液、1.0当量)を添加し、懸濁液の温度を、48時間、40℃〜5℃の間で循環させた。結晶塩を遠心力ろ過によって単離し、固体をXPRDで分析した。
イソプロパノール(5.0mL)を、(S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミド(非晶質遊離塩基)(361.3mg)に添加した。懸濁液を40℃に加熱し、コハク酸(メタノール中1M溶液、1.0当量)を添加した。懸濁液に、コハク酸塩の種(上記の方法(a)によって調製された)を添加し、懸濁液の温度を、16時間、40℃〜5℃の間で循環させた。結晶コハク酸塩を真空下で単離し、15分間空気乾燥し、4時間、40℃で、真空オーブンで乾燥した。結晶コハク酸塩の収率は、68.6%(312.9mg)であった。コハク酸塩の化学量論は、1HNMRによって、およそ1:1((S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミド:コハク酸)であると決定された。
開放容器中25℃/60%RHで、開放容器中40℃/75%RHで、および閉鎖容器中50℃/大気条件で、4週間後、≦0.4%の分解。開放容器中25℃/60%RHで、開放容器中40℃/75%RHで、および閉鎖容器中50℃/大気条件で、6週間後、XPRD分析によって、物理的変化は検出されなかった。形態変化はXPRD分析により観察されずに、1xICH固形で光分解によるおよそ1.4%の分解。
(a)小規模
メチルtert−ブチルエーテル(0.5mL)を、(S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミド(非晶質遊離塩基)(21.5mg)に添加した。懸濁液に安息香酸(テトラヒドロフラン中3M溶液、1.0当量)を添加し、懸濁液の温度を、48時間、40℃〜5℃で循環した。結晶塩を、遠心力ろ過によって単離し、固体を、XPRD分析によって分析した。
イソプロパノール(3.5mL)を、(S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミド(非晶質遊離塩基)(349.9mg)に添加した。懸濁液を、40℃に加熱し、安息香酸(テトラヒドロフラン中3M溶液、1.0当量)を添加した。懸濁液に、安息香酸塩の種(上記の方法(a)によって調製された)を添加し、懸濁液の温度を、16時間、40℃〜5℃で循環した。結晶安息香酸塩を真空下で単離し、15分間空気で乾燥し、4時間、40℃で、真空オーブンで乾燥した。結晶安息香酸塩の収率は、68.6%(305.3mg)であった。安息香酸塩の化学量論は、1HNMRにより、およそ1:1((S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミド:安息香酸)であると決定された。
開放容器中25℃/60%RHで、開放容器中40℃/75%RHで、および閉鎖容器中50°C/大気条件で、2週間後、XPRD分析によって、物理的変化は検出されなかった。形態変化はXPRD分析により観察されずに、1xICH固形で光分解によるおよそ1.6%の分解。
Claims (10)
- (S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミドのコハク酸塩の結晶形。
- CuKα放射線を用いて測定された際に、約4.5、8.2、9.0、10.4、13.5、15.8、16.4、17.3、17.7、18.1、18.8、19.6、20.8、21.9、22.7、23.3、24.0、24.7、26.4、28.2および29.6度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、請求項1に記載の結晶形。
- CuKα放射線を用いて測定された際に、約4.5、8.2、10.4、13.5、15.8、16.4、17.3、17.7、18.1、18.8、19.6、20.8、21.9、23.3および24.0度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、請求項1に記載の結晶形。
- CuKα放射線を用いて測定された際に、約4.5、8.2、10.4、13.5、15.8、16.4、17.7、18.1、18.8、20.8、21.9、23.3および24.0度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、請求項1に記載の結晶形。
- CuKα放射線を用いて測定された際に、約4.5、10.4、17.7、18.1、20.8および24.0度2θの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、請求項1に記載の結晶形。
- (S)−6−((1−アセチルピペリジン−4−イル)アミノ)−N−(3−(3、4−ジヒドロイソキノリン−2(1H)−イル)−2−ヒドロキシプロピル)ピリミジン−4−カルボキサミドの安息香酸塩の結晶形。
- CuKα放射線を用いて測定された際に、約4.3、7.7、9.2、10.9、12.8、14.2、15.6、16.6、16.9、18.1、18.6、21.5、22.1、23.4、24.0、24.2、25.1、25.9、27.1、28.8および30.7度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、請求項6に記載の結晶形。
- CuKα放射線を用いて測定された際に、約4.3、7.7、9.2、10.9、12.8、14.2、15.6、16.6、16.9、18.1、18.6、22.1、24.0、24.2、25.9、27.1および28.8度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、請求項6に記載の結晶形。
- CuKα放射線を用いて測定された際に、約4.3、7.7、15.6、16.6、16.9、18.1、18.6、22.1、24.0、27.1および28.8度2θからなる群から選択される少なくとも3つの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、請求項6に記載の結晶形。
- CuKα放射線を用いて測定された際に、約4.3、7.7、18.1、18.6、22.1および24.0度2θの回折角度を含んでなる粉末X線回折(XRPD)パターンによって特徴付けられる、請求項6に記載の結晶形。
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