JP7432590B2 - 選択的cdk9阻害剤としての酒石酸塩及びその結晶形 - Google Patents
選択的cdk9阻害剤としての酒石酸塩及びその結晶形 Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Description
(1)3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミドと、溶媒としてある一定量のジメチルスルホキシドを混合し、加熱して溶解させ、第一混合物を得ること;
(2)第一混合物に、ある一定量の酒石酸及び水を加え、反応させて、第二混合物を得ること;ならびに
(3)第二混合物に、ある一定量の水混和性溶媒を加え、反応させて、3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩を得ること、得られるものは、酒石酸塩のA型結晶である。
「がん」という用語は、以下のがんを含むが、これらに限定されない:白血病、乳癌、卵巣癌、子宮頸癌、前立腺癌、精巣癌、食道癌、胃癌、皮膚癌、肺癌、骨癌、結腸癌、膵癌、甲状腺癌、胆道癌、咽喉癌、***癌、舌癌、口腔癌、咽喉癌、小腸癌、結腸直腸癌、大腸癌、直腸癌、脳及び中枢神経系癌、悪性神経膠腫、膀胱癌、肝臓癌、腎臓癌、リンパ腫など。
3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩(LS007の名称を使用)の塩形成性
1.1塩形成の高処理スクリーニング
LS007のpKa値及び異なるpHでの溶解度に基づき、pKa値が約3以下の酸を塩形成スクリーニングの酸として使用することが可能であると決定することができる。したがって、本発明者らは、塩酸、硫酸、アスパラギン酸、マレイン酸、リン酸、グルタミン酸、酒石酸、及びフマル酸を含む8種の酸を選択した。
1)酸の0.02MのTHF溶液を調製する、ただし、グルタミン酸、硫酸、及びリン酸は水溶液である;
2)LS007の0.01MのTHF/MeOH(1:1)溶液を調製する;
3)塩酸1mL、硫酸0.25mL、アスパラギン酸0.5mL、マレイン酸0.5mL、リン酸0.5mL、グルタミン酸0.5mL、酒石酸0.5mL、及びフマル酸0.5mLを加え、ついでそれぞれにLS007の溶液1mLを加える;ならびに
4)ボルテックス後、40℃の油浴で1時間反応させ、室温で有機溶媒をエバポレートし、最後に50℃で減圧乾燥させる。
3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩の結晶形
LS007酒石酸塩の結晶多型問題について、この試験では、異なる結晶化条件及び実験的アプローチを用いることにより、化合物LS007酒石酸塩の可能な結晶形を系統的にスクリーニングした。約300通りの結晶化実験を通じて、LS007酒石酸塩は、2種の異なる結晶形、それぞれ、A型結晶及びB型結晶で存在する可能性があることがわかった。さらなる特性決定から、異なる結晶形の間に物理化学的特性の顕著な差異はないことが明らかとなった。結晶形間の変換実験では、A型がより安定な結晶形であり、ある一定の条件下でB型はA型結晶に変換可能であることがわかった。
柱状結晶、薬物は溶融して分解し、分解ピーク温度は236.8℃である。これは、非吸湿性である(80%湿度において、吸湿性重量増加は0.22%)。通常の貯蔵湿度の範囲内において、湿度の変動幅は小さい。物理及び化学特性は、比較的理想的であり、試料は、最良の結晶化度を有し、流動性はB型のものよりも大きく、薬物形成能はB型のものよりも良好である。そのうえ、平衡溶解度は、種々の模擬in vivo条件(pH=2.0、4.6、6.8)下でB型のものより大きい。
顆粒状結晶、薬物は溶融して分解し、分解ピーク温度は240.5℃である。これは、非吸湿性である(80%湿度において、吸湿性重量増加は0.11%)。通常の貯蔵湿度の範囲内において、湿度の変動幅は小さい。B型は、50℃での懸濁実験において、溶媒としてNM:H2O(1:1)を用いた場合に得ることができる。
Claims (10)
- 式II:
により表されるとおりの構造を有する、3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩のA型結晶であって、2θ値が7.3、9.6、11.0、15.3、18.1、18.9、23.8、24.5、26.2、26.7、及び27.1の位置に出るピークを持つX線粉末回折パターン、ラマンシフト値が1613cm-1、1597cm-1、1571cm-1、1543cm-1、1389cm-1、827cm-1、及び543cm-1の位置に出るピークを持つラマンスペクトル、ならびに238.6℃に鋭い吸熱ピークを持つDSCサーモグラムを有することを特徴とする、前記酒石酸塩のA型結晶。 - 請求項1に記載の3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩のA型結晶及び1種または複数の薬学上許容される賦形剤を含む、医薬配合物。
- 請求項1に記載の3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩のA型結晶の調製法であって、以下の工程:
(1)3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド遊離塩基に、前記遊離塩基の4~8倍の量でジメチルスルホキシドを加え、完全に溶解するまで加熱し、前記液体が熱いまま濾過して、第一混合物を得ること;
(2)前記第一混合物に、ある一定量の酒石酸及び水を加え、60±2℃に加熱し、温度を一定に保ち、反応させて、第二混合物を得ること;ならびに
(3)前記第二混合物に、ある一定量のアルコールを加え、温度を保ったまま反応させ、系の温度を25±5℃に下げて、3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩のA型結晶を得ること、を含む、前記方法。 - 前記アルコールは、エタノールである、請求項3に記載の方法。
- 前記第二混合物は、酒石酸と3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミドを、モル比1.1~1.3:1で混合することにより得られる、請求項3に記載の方法。
- 増殖性障害により引き起こされる疾患または症状の治療用医薬の調製における、請求項1に記載の3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩のA型結晶の使用。
- 前記増殖性障害により引き起こされる疾患または症状は、がんである、請求項6に記載の使用。
- 前記がんは、白血病である、請求項7に記載の使用。
- 前記白血病が、急性骨髄性白血病である、請求項8に記載の使用。
- タンパク質キナーゼの阻害用医薬の調製における、請求項1に記載の3-(5-フルオロ-4-(4-メチル-2-(メチルアミノ)チアゾール-5-イル)ピリミジン-2-イルアミノ)-ベンゼンスルホンアミド酒石酸塩のA型結晶の使用。
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