JP6889101B2 - グルタミナーゼ阻害剤の結晶形態 - Google Patents
グルタミナーゼ阻害剤の結晶形態 Download PDFInfo
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- JP6889101B2 JP6889101B2 JP2017506401A JP2017506401A JP6889101B2 JP 6889101 B2 JP6889101 B2 JP 6889101B2 JP 2017506401 A JP2017506401 A JP 2017506401A JP 2017506401 A JP2017506401 A JP 2017506401A JP 6889101 B2 JP6889101 B2 JP 6889101B2
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Description
本願は、2014年8月7日に出願された米国仮特許出願第62/034,547号への優先権を主張し、この米国仮特許出願の内容は、本明細書中に参考として援用される。
グルタミンは、代謝性および非代謝性メカニズムを介してがん細胞の細胞生存、成長および増殖を支持する。活発に増殖する細胞において、グルタミンの代謝は、細胞に対するビルディングブロックおよびエネルギーの主要な供給源である。がん細胞が成長している培地からグルタミンが離脱すると、細胞は多くの場合成長を停止するか、または死亡する。がん細胞において、細胞により摂取されるグルタミンの大半は、酵素グルタミナーゼの作用を介してグルタメートに変換される。したがって、グルタミナーゼを介するグルタミンのグルタメートへの変換は、グルタミン代謝に対する制御ポイントである。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
式(I)
の構造を有する化合物の結晶塩。
(項目2)
前記塩が、塩酸塩、トルエンスルホン酸塩、硝酸塩、メタンスルホン酸塩または臭化水素酸塩である、項目1に記載の結晶塩。
(項目3)
前記塩が、塩酸塩である、項目2に記載の結晶塩。
(項目4)
2θ値16.70;17.26;21.09;22.69を有する、項目3に記載の結晶塩。
(項目5)
2θ値16.70;17.26;18.18;21.09;22.69;23.46;25.22;25.49;26.72を有する、項目4に記載の結晶塩。
(項目6)
2θ値9.53;11.63;16.70;17.26;18.18;19.10;19.80;21.09;22.16;22.69;23.46;24.63;25.22;25.49;25.91;26.72;28.45;29.38;31.39;31.82;34.91を有する、項目5に記載の結晶塩。
(項目7)
2θ値8.62;9.53;11.63;15.89;16.70;17.26;18.18;19.10;19.80;21.09;22.16;22.69;23.46;24.63;25.22;25.49;25.91;26.72;28.45;29.38;31.39;31.82;32.76;33.61;33.74;34.27;34.91;35.53;39.36;39.73を有する、項目6に記載の結晶塩。
(項目8)
図1に実質的に示されているXRDパターンを有する、項目7に記載の結晶塩。
(項目9)
2θ値8.34;18.83;21.10を有する、項目3に記載の結晶塩。
(項目10)
2θ値6.26;8.34;15.82;18.83;21.10;23.42;24.10;24.45;25.25;25.74を有する、項目9に記載の結晶塩。
(項目11)
2θ値6.26;8.34;11.02;12.58;14.80;15.61;15.82;17.58;18.20;18.83;19.81;20.00;21.10;22.58;23.42;24.10;24.45;25.25;25.74;26.36;27.83;28.70;29.84;30.46;31.81;32.38を有する、項目10に記載の結晶塩。
(項目12)
2θ値3.10;6.26;8.34;9.04;9.96;11.02;12.58;13.47;14.80;15.61;15.82;16.15;17.58;18.20;18.83;19.81;20.00;21.10;22.02;22.58;23.42;24.10;24.45;25.25;25.74;26.36;27.22;27.83;28.70;29.84;30.46;31.81;32.38;33.23;35.68;36.57;37.40;39.36;41.79を有する、項目11に記載の結晶塩。
(項目13)
図2に実質的に示されているXRDパターンを有する、項目12に記載の結晶塩。
(項目14)
式(I)
の構造を有する化合物の塩であって、
前記塩は、二塩酸塩である、塩。
(項目15)
項目1から14のいずれか一項に記載の塩と、1種または複数種の薬学的に許容される賦形剤とを含む、薬学的組成物。
(項目16)
項目1から14のいずれか一項に記載の塩または項目15に記載の薬学的組成物を投与することを含む、がんまたは免疫疾患もしくは神経疾患を処置または予防する方法。
(項目17)
前記がんは、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、副腎皮質癌、肛門がん、虫垂がん、非定型奇形腫様/ラブドイド腫瘍、基底細胞癌、胆管がん、膀胱がん、骨がん、脳腫瘍、星状細胞腫、脳および脊髄腫瘍、脳幹神経膠腫、中枢神経系非定型奇形腫様/ラブドイド腫瘍、中枢神経系胎児性腫瘍、乳がん、気管支腫瘍、バーキットリンパ腫、カルチノイド腫瘍、原発不明癌、中枢神経系がん、子宮頸がん、小児期がん、脊索腫、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、慢性骨髄増殖性障害、結腸がん、直腸結腸がん、頭蓋咽頭腫、皮膚T細胞リンパ腫、非浸潤性乳管癌(DCIS)、胎児性腫瘍、子宮内膜がん、上衣芽腫、上衣細胞腫、食道がん、感覚神経芽腫、ユーイング肉腫、頭蓋外胚細胞腫瘍、性腺外胚細胞腫瘍、肝外胆管がん、眼のがん、骨の線維性組織球腫、胆嚢がん、胃のがん、消化管カルチノイド腫瘍、消化管間質腫瘍(GIST)、胚細胞腫瘍、頭蓋外胚細胞腫瘍、性腺外胚細胞腫瘍、卵巣胚細胞腫瘍、妊娠性絨毛腫瘍、神経膠腫、有毛細胞白血病、頭頸部がん、心臓がん、肝細胞がん、組織球症、ランゲルハンス細胞がん、ホジキンリンパ腫、下咽頭がん、眼内黒色腫、島細胞腫瘍、カポジ肉腫、腎臓がん、ランゲルハンス細胞組織球症、喉頭がん、白血病、口唇および口腔がん、肝がん、上皮内小葉癌(LCIS)、肺がん、リンパ腫、AIDS関連リンパ腫、マクログロブリン血症、男性乳がん、髄芽腫、髄上皮腫、黒色腫、メルケル細胞癌、悪性中皮腫、原発不明の転移性頸部扁平上皮がん、NUT遺伝子を含む正中管癌、口のがん、多発性内分泌腫瘍症候群、多発性骨髄腫/形質細胞新生物、菌状息肉腫、骨髄異形成症候群、骨髄異形成/骨髄増殖性新生物、慢性骨髄性白血病(CML)、急性骨髄性白血病(AML)、骨髄腫、多発性骨髄腫、慢性骨髄増殖性障害、鼻腔がん、副鼻腔がん、鼻咽頭がん、神経芽細胞腫、非ホジキンリンパ腫、非小細胞肺がん、口腔のがん、口腔がん、口唇がん、中咽頭がん、骨肉腫、卵巣がん、膵がん、乳頭腫症、傍神経節腫、副鼻腔がん、鼻腔がん、副甲状腺がん、陰茎がん、咽頭がん、褐色細胞腫、中間型松果体実質腫瘍、松果体芽腫、下垂体腫瘍、形質細胞新生物、胸膜肺芽腫、乳がん、原発性中枢神経系(CNS)リンパ腫、前立腺がん、直腸がん、腎細胞がん、腎盂がん、尿管がん、移行性細胞がん、網膜芽腫、横紋筋肉腫、唾液腺がん、肉腫、セザリー症候群、皮膚がん、小細胞肺がん、小腸がん、軟部組織肉腫、扁平上皮癌、原発不明の頸部扁平上皮がん、転移性(metastatic)、胃がん、テント上原始神経外胚葉性腫瘍、T細胞リンパ腫、精巣がん、咽喉がん、胸腺腫、胸腺癌、甲状腺がん、腎孟および尿管の移行性細胞がん、妊娠性絨毛腫瘍、小児期の原発不明の稀ながん、尿道がん、子宮がん、子宮肉腫、ワルデンシュトレームマクログロブリン血症、またはウィルムス腫瘍を含む、項目16に記載の方法。
(項目18)
1種または複数種の化学療法剤を共投与することをさらに含む、項目16または項目17に記載の方法。
(項目19)
前記1種または複数種の化学療法剤が、アミノグルテチミド、アムサクリン、アナストロゾール、アスパラギナーゼ、カルメット−ゲラン桿菌ワクチン(bcg)、ビカルタミド、ブレオマイシン、ボルテゾミブ、ブセレリン、ブスルファン、カンプトテシン(campothecin)、カペシタビン、カルボプラチン、カルフィルゾミブ、カルムスチン、クロラ
ムブシル、クロロキン、シスプラチン、クラドリビン、クロドロネート、コルヒチン、シクロホスファミド、シプロテロン、シタラビン、ダカルバジン、ダクチノマイシン、ダウノルビシン、デメトキシビリジン、デキサメタゾン、ジクロロアセテート、ジエネストロール、ジエチルスチルベストロール、ドセタキセル、ドキソルビシン、エピルビシン、エストラジオール、エストラムスチン、エトポシド、エベロリムス、エキセメスタン、フィルグラスチム、フルダラビン、フルドロコルチゾン、フルオロウラシル、フルオキシメステロン、フルタミド、ゲムシタビン、ゲニステイン、ゴセレリン、ヒドロキシウレア、イダルビシン、イホスファミド、イマチニブ、インターフェロン、イリノテカン、レトロゾール、ロイコボリン、ロイプロリド、レバミソール、ロムスチン、ロニダミン、メクロレタミン、メドロキシプロゲステロン、メゲストロール、メルファラン、メルカプトプリン、メスナ、メトホルミン、メトトレキセート、マイトマイシン、ミトタン、ミトキサントロン、ニルタミド、ノコダゾール、オクトレオチド、オキサリプラチン、パクリタキセル、パミドロネート、ペントスタチン、ペリホシン、プリカマイシン、ポルフィマー、プロカルバジン、ラルチトレキセド、リツキシマブ、ソラフェニブ、ストレプトゾシン、スニチニブ、スラミン、タモキシフェン、テモゾロミド、テムシロリムス、テニポシド、テストステロン、チオグアニン、チオテパ、二塩化チタノセン、トポテカン、トラスツズマブ、トレチノイン、ビンブラスチン、ビンクリスチン、ビンデシン、ビノレルビン、MK2206、トラメチニブ、BEZ235、エルロチニブ、セルメチニブ、シロリムス、トラメチニブ、パゾパニブ、またはGSK1120212を含む、項目18に記載の方法。
(項目20)
がん処置の1種または複数種の非化学的方法を投与することをさらに含む、項目16から19のいずれか一項に記載の方法。
(項目21)
前記1種または複数種の非化学的方法が放射線治療を含む、項目20に記載の方法。
(項目22)
前記1種または複数種の非化学的方法が、手術、温熱切除、集束超音波治療、凍結治療、または前述の任意の組合せを含む、項目20に記載の方法。
(項目23)
1種または複数種の免疫調節剤を共投与することをさらに含む、項目16から22のいずれか一項に記載の方法。
(項目24)
前記免疫調節剤が、顆粒球コロニー刺激因子(G−CSF)、インターフェロン、イミキモド、IL−2、IL−7、IL−12、ケモカイン、合成シトシンリン酸グアノシン(CpG)オリゴデオキシヌクレオチド、グルカン、アプレミラスト、CC−122、CC−11006、CC−10015、レナリドミド、ポマリドミド、およびサリドマイド、またはサリドマイド類似体である、項目23に記載の方法。
(項目25)
式(I)
の構造を有する化合物の結晶塩を調製するための方法であって、
a)第1の有機溶媒中の式(I)の化合物の遊離塩基混合物を準備するステップと、
b)前記遊離塩基混合物を、前記式(I)の化合物の塩を含む混合物を形成するのに十分な条件下で、試薬溶液と接触させるステップであって、前記試薬溶液が、酸、および必要に応じて第2の有機溶媒を含む、ステップと、
c)前記式(I)の化合物の塩を含む前記混合物から前記式(I)の化合物の前記塩を結晶化するステップと
を含む、方法。
(項目26)
前記結晶塩が、塩酸塩、トルエンスルホン酸塩、硝酸塩、メタンスルホン酸塩、または臭化水素酸塩である、項目25に記載の方法。
(項目27)
前記第1の有機溶媒と、存在する場合前記第2の有機溶媒が、同じである、項目25に記載の方法。
(項目28)
前記第1の有機溶媒と、存在する場合前記第2の有機溶媒が、異なる、項目25に記載の方法。
(項目29)
前記第1の有機溶媒および前記第2の有機溶媒が、それぞれ独立して、エタノールおよび/またはアセトニトリルを含む、項目25から28のいずれか一項に記載の方法。
(項目30)
前記酸が、塩酸、p−トルエンスルホン酸、メタンスルホン酸、硝酸、または臭化水素酸である、項目25から29のいずれか一項に記載の方法。
(項目31)
ステップb)の前記酸が、前記遊離塩基混合物中の前記式(I)の化合物のモル量の約1.0〜約1.5倍であるモル量で前記試薬溶液中に存在する、項目25から30のいずれか一項に記載の方法。
(項目32)
前記式(I)の化合物の塩を含む前記混合物が溶液であり、前記混合物から前記式(I)の化合物の前記塩を結晶化する前記ステップが、前記式(I)の化合物の前記塩を溶液から沈殿させるために前記溶液を過飽和させるステップを含む、項目25から31のいずれか一項に記載の方法。
(項目33)
前記溶液を過飽和させる前記ステップが、貧溶媒をゆっくりと添加するステップ、前記溶液を冷却させるステップ、前記溶液の容量を減少させるステップ、またはこれらの任意の組合せを含む、項目32に記載の方法。
(項目34)
前記溶液を過飽和させる前記ステップが、前記溶液を周辺温度またはそれ未満に冷却するステップを含む、項目32に記載の方法。
(項目35)
前記結晶塩を単離するステップをさらに含む、項目25から34のいずれか一項に記載の方法。
(項目36)
前記結晶塩を単離するステップが、前記混合物から前記結晶化塩を濾過するステップを含む、項目35に記載の方法。
(項目37)
前記結晶塩を減圧下で乾燥させるステップをさらに含む、項目35または項目36に記載の方法。
(項目38)
前記結晶塩が、項目1から19のいずれか一項に記載の結晶塩である、項目25から37のいずれか一項に記載の方法。
(項目39)
式(I)
の構造を有する結晶化合物。
(項目40)
2θ値18.39;19.10;21.37;24.65を有する、項目39に記載の結晶化合物。
(項目41)
2θ値7.92;18.39;19.10;20.12;21.37;24.10;24.65;25.14を有する、項目40に記載の結晶化合物。
(項目42)
2θ値7.32;7.92;11.98;15.54;15.87;18.06;18.39;19.10;20.06;20.12;21.37;22.41;22.74;24.10;24.65;25.14;25.78;27.32を有する、項目41に記載の結晶化合物。
(項目43)
2θ値3.64;7.32;7.92;8.53;9.30;9.38;11.02;11.98;14.70;15.54;15.87;16.50;16.59;18.06;18.39;19.10;20.06;20.12;20.61;21.37;21.89;22.41;22.74;23.72;24.10;24.65;25.14;25.78;26.49;27.32;27.55;28.26;29.88;31.20;31.80;31.52;32.80;34.30;35.20;36.41;38.53;40.08;40.94;および43.86を有する、項目42に記載の結晶化合物。
(項目44)
図6に実質的に示されているXRDパターンを有する、項目43に記載の結晶化合物。
(項目45)
2θ値7.57;18.50;18.69を有する、項目39に記載の結晶化合物。
(項目46)
2θ値7.57;9.67;11.00;12.93;15.20;18.50;18.69;23.33;24.87を有する、項目45に記載の結晶化合物。
(項目47)
2θ値5.47;7.57;9.67;11.00;12.93;14.14;15.20;17.74;18.50;18.69;19.40;20.54;21.13;23.33;24.37;24.87;25.52を有する、項目46に記載の結晶化合物。
(項目48)
2θ値5.47;6.01;7.57;9.20;9.67;10.15;11.00;12.93;14.14;15.20;15.81;16.56;17.74;18.50;18.69;19.40;19.94;20.54;20.59;21.13;22.00;22.60;23.33;23.98;24.37;24.87;25.52;26.27;26.62;27.79;29.59;30.64;33.30;35.01;37.93;38.72を有する、項目47に記載の結晶化合物。
(項目49)
図7に実質的に示されているXRDパターンを有する、項目48に記載の結晶化合物。
特定の実施形態では、本発明は、式(I)の構造を有する化合物の結晶塩の調製のための方法であって、a)第1の有機溶媒中の式(I)の化合物の遊離塩基混合物を準備するステップと、b)式(I)の化合物の塩を含む混合物を形成するのに十分な条件下で、遊離塩基混合物を、酸および必要に応じて第2の有機溶媒を含む試薬溶液と接触させるステップと、c)式(I)の化合物の塩を含む混合物から式(I)の化合物の塩を結晶化するステップとを含む方法に関する。
グルタミンは、窒素、炭素、およびエネルギーの担体として重要な役割を果たす。グルタミンは肝臓のウレア合成のために、腎臓のアンモニア産生のために、糖新生のために、および多くの細胞用の呼吸の燃料として使用されている。グルタミンのグルタメートへの変換は、ミトコンドリア酵素、グルタミナーゼ(「GLS」)により開始される。2つの主要な形態の酵素、KタイプおよびLタイプが存在し、これらは、グルタミンに対するこれらのKm値およびグルタメートに対する応答により区別され、このKm値、すなわちミカエリス定数は、最大速度の半分に到達するのに必要とされる基質濃度である。「肝臓タイプ」またはGLS2としても公知のLタイプは、グルタミンに対して高いKmを有し、グルタメート耐性がある。「腎臓タイプ」またはGLS1としても公知のKタイプは、グルタミンに対して低いKmを有し、グルタメートにより阻害される。グルタミナーゼ(glutmainase)Cまたは「GAC」と呼ばれる代替のスプライス形態のGLS1が最近特定され、GLS1と同様の活性特徴を有する。特定の実施形態では、化合物は、GLS1、GLS2およびGACを選択的に阻害することができる。好ましい実施形態では、化合物はGLS1およびGACを選択的に阻害する。
a)本発明の結晶化合物または塩を含む薬学的製剤(例えば、1種または複数種の単一剤形)と、
b)例えば、上で考察した状態のいずれかを処置または予防するための、薬学的製剤の投与のための指示と
を含むキットを提供する。
特定の実施形態では、本発明は、式(I)の化合物の結晶化合物または塩と、1種または複数種の薬学的に許容される賦形剤とを含む薬学的組成物に関する。
湿潤剤、乳化剤および滑沢剤、例えば、ラウリル硫酸ナトリウムおよびステアリン酸マグネシウムなど、ならびに着色剤、剥離剤、コーティング剤、甘味剤、香味剤および香料、保存剤ならびに抗酸化剤もまた組成物中に存在することができる。
X線回折
大部分の粉末X線回折パターンは、Optix長ファインフォーカスソースを使用して生成したCu照射の入射ビームを使用して、PANalytical X’Pert PRO MPD回折計で収集した。楕円状傾斜多層膜鏡を使用して、検体を介しておよび検出器上へとCu Kα X線の焦点を合わせた。分析前、ケイ素検体(NIST SRM 640d)を分析して、Si 111ピークの観察された位置が、NISTで認証された位置と一致することを検証した。試料の検体を3μm厚のフィルムの間に挟み、透過幾何学で分析した。ビーム停止、短い抗散乱拡大、および抗散乱ナイフの縁を使用して、大気によって生成されたバックグランドを最小化した。入射および回析ビーム用のソーラースリットを使用して、軸発散からの広がりを最小化した。回折パターンを、検体から240mmに位置する走査型位置敏感型検出器(X’Celerator)およびData Collectorソフトウェアv.2.2bを使用して収集した。
TA Instruments Q2000示差走査熱量計を使用してDSCを実施した。NIST−トレーサブルインジウム金属を使用して温度較正を実施した。試料を、蓋をしたアルミニウムDSC皿に配置し、重量を正確に記録した。試料皿として構成された計量済アルミニウム皿をセルの基準側に配置した。使用した皿は、サーモグラムのコメントフィールドには「T0C」と略記されているTzero圧着パンであった。試料を、10℃/分で−30℃から250℃へ加熱した(サーモグラムの方法フィールドには「(−30)−250−10」と略記)。
TA Instruments 2050熱重量分析計を使用してTG分析を実施した。温度較正は、ニッケルおよびAlumel(商標)を使用して実施した。試料を白金皿内に配置し、TG炉に挿入した。窒素パージ下で炉を加熱した。試料を、10℃/分で、25℃から300℃へ加熱した(サーモグラムの方法フィールドには「00−300−10」と略記)。
CB−839結晶性遊離塩基、形態Aを以下の通り調製した:
化合物CB−839の塩の調製物
化合物アッセイ
化合物670を、インビトロ生化学的アッセイと細胞増殖アッセイの両方でアッセイした。アッセイの実験プロトコルおよび結果は、米国特許第8,604,016号、または代わりに米国特許出願公報第2014/0050699A1号に見出される。
本明細書中に記述されているすべての刊行物および特許は、それぞれ個々の刊行物または特許が具体的および個々に、参考として援用されていると示されているかのように、これらの全体が参考として本明細書に援用される。矛盾する場合、本明細書中のあらゆる定義を含めて、本出願が優先されるものとする。
本発明の具体的な実施形態が論じられているが、上記明細書は例証となるものであり、限定するものではない。本発明の多くの変化形が、本明細書および以下の特許請求の範囲を再検討した際に当業者には明らかとなろう。同等物の全範囲と共に特許請求の範囲を参照し、そしてこのような変化形と共に明細書を参照して、本発明の全範囲が判定されるべきである。
Claims (34)
- 2θ値16.70;17.26;18.18;21.09;22.69;23.46;25.22;25.49;および26.72を有する、請求項1に記載の結晶。
- 2θ値6.26;8.34;15.82;18.83;21.10;23.42;24.10;24.45;25.25;および25.74を有する、請求項1に記載の結晶。
- 請求項1から5のいずれか一項に記載の結晶と、1種または複数種の薬学的に許容される賦形剤とを含む、薬学的組成物。
- がんを処置または予防するための医薬の製造における、請求項1から5のいずれか一項に記載の結晶または請求項6に記載の薬学的組成物の使用。
- 前記がんは、副腎皮質癌、肛門がん、虫垂がん、胆管がん、膀胱がん、骨がん、脳および脊髄腫瘍、乳がん、結腸がん、胎児性腫瘍、食道がん、眼のがん、胆嚢がん、胃のがん、消化管間質腫瘍(GIST)、胚細胞腫瘍、頭頸部がん、心臓がん、腎臓がん、白血病、肝がん、肺がん、リンパ腫、悪性中皮腫、多発性内分泌腫瘍症候群、骨髄腫、卵巣がん、膵がん、副甲状腺がん、陰茎がん、下垂体腫瘍、前立腺がん、直腸がん、肉腫、皮膚がん、小腸がん、精巣がん、甲状腺がん、尿道がん、または子宮がんを含む、請求項7に記載の使用。
- 前記がんは、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、有毛細胞白血病、多発性骨髄腫、脳腫瘍、原発性中枢神経系(CNS)リンパ腫、バーキットリンパ腫、T細胞リンパ腫、ホジキンリンパ腫、AIDS関連リンパ腫、非ホジキンリンパ腫、子宮頸がん、子宮内膜がん、子宮肉腫、頭蓋外胚細胞腫瘍、性腺外胚細胞腫瘍、卵巣胚細胞腫瘍、眼内黒色腫、網膜芽腫、骨の線維性組織球腫、軟部組織肉腫、脳幹神経膠腫、肝細胞がん、下咽頭がん、中咽頭がん、喉頭がん、口腔のがん、口唇がん、ユーイング肉腫、カポジ肉腫、横紋筋肉腫、非小細胞肺がん、小細胞肺がん、ワルデンシュトレームマクログロブリン血症、または黒色腫を含む、請求項7に記載の使用。
- 前記がんは、肺がんである、請求項8に記載の使用。
- 前記がんは、乳がんである、請求項8に記載の使用。
- 前記がんは、多発性骨髄腫である、請求項9に記載の使用。
- 前記がんは、腎細胞がんである、請求項8に記載の使用。
- 前記医薬は、1種または複数種の化学療法剤との共投与のためのものである、請求項7から13のいずれか一項に記載の使用。
- 前記医薬は、1種または複数種の免疫調節剤との共投与のためのものである、請求項7から14のいずれか一項に記載の使用。
- 式(I)
の構造を有する化合物の塩酸塩の結晶を調製するための方法であって、
ここで、
(a)前記結晶が、2θ値16.70;17.26;21.09;22.69を有するか;または
(b)前記結晶が、2θ値8.34;18.83;21.10を有し、
ここで、前記2θ値は、Cu Kα照射を用いて測定された粉末X線回折パターンにおける値であり、
前記方法は、
a)第1の有機溶媒中の式(I)の化合物の遊離塩基混合物を準備するステップと、
b)前記遊離塩基混合物を、前記式(I)の化合物の塩酸塩を含む混合物を形成するのに十分な条件下で、試薬溶液と接触させるステップであって、前記試薬溶液が、塩酸、および必要に応じて第2の有機溶媒を含む、ステップと、
c)前記式(I)の化合物の塩酸塩を含む前記混合物から前記式(I)の化合物の塩酸塩を結晶化するステップと
を含む、方法。 - 以下:
(a)前記第1の有機溶媒と、存在する場合前記第2の有機溶媒が、同じである;
(b)前記第1の有機溶媒と、存在する場合前記第2の有機溶媒が、異なる;
(c)前記第1の有機溶媒および前記第2の有機溶媒が、それぞれ独立して、エタノールおよび/またはアセトニトリルを含む;
(d)ステップb)の塩酸が、前記遊離塩基混合物中の前記式(I)の化合物のモル量の1.0〜1.5倍であるモル量で前記試薬溶液中に存在する;あるいは
(e)前記式(I)の化合物の塩酸塩を含む前記混合物が溶液であり、前記混合物から前記式(I)の化合物の塩酸塩を結晶化する前記ステップが、前記式(I)の化合物の塩酸塩を溶液から沈殿させるために前記溶液を過飽和させるステップを含む;
のうちの一つまたは複数が適用される、請求項16に記載の方法。 - 前記結晶を単離するステップをさらに含む、請求項16または17に記載の方法。
- 前記結晶を単離するステップが、前記混合物から前記結晶化された塩を濾過するステップを含む、請求項18に記載の方法。
- 前記結晶を減圧下で乾燥させるステップをさらに含む、請求項18または請求項19に記載の方法。
- 2θ値7.92;18.39;19.10;20.12;21.37;24.10;24.65;25.14を有する、請求項21に記載の結晶。
- 2θ値7.57;9.67;11.00;12.93;15.20;18.50;18.69;23.33;24.87を有する、請求項21に記載の結晶。
- がんを処置または予防する方法における使用のための組成物であって、前記方法は、請求項1から5のいずれか一項に記載の結晶または請求項6に記載の薬学的組成物を投与することを含む、組成物。
- 前記がんは、副腎皮質癌、肛門がん、虫垂がん、胆管がん、膀胱がん、骨がん、脳および脊髄腫瘍、乳がん、結腸がん、胎児性腫瘍、食道がん、眼のがん、胆嚢がん、胃のがん、消化管間質腫瘍(GIST)、胚細胞腫瘍、頭頸部がん、心臓がん、腎臓がん、白血病、肝がん、肺がん、リンパ腫、悪性中皮腫、多発性内分泌腫瘍症候群、骨髄腫、卵巣がん、膵がん、副甲状腺がん、陰茎がん、下垂体腫瘍、前立腺がん、直腸がん、肉腫、皮膚がん、小腸がん、精巣がん、甲状腺がん、尿道がん、または子宮がんを含む、請求項26に記載の組成物。
- 前記がんは、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、有毛細胞白血病、多発性骨髄腫、脳腫瘍、原発性中枢神経系(CNS)リンパ腫、バーキットリンパ腫、T細胞リンパ腫、ホジキンリンパ腫、AIDS関連リンパ腫、非ホジキンリンパ腫、子宮頸がん、子宮内膜がん、子宮肉腫、頭蓋外胚細胞腫瘍、性腺外胚細胞腫瘍、卵巣胚細胞腫瘍、眼内黒色腫、網膜芽腫、骨の線維性組織球腫、軟部組織肉腫、脳幹神経膠腫、肝細胞がん、下咽頭がん、中咽頭がん、喉頭がん、口腔のがん、口唇がん、ユーイング肉腫、カポジ肉腫、横紋筋肉腫、非小細胞肺がん、小細胞肺がん、またはワルデンシュトレームマクログロブリン血症を含む、請求項26に記載の組成物。
- 前記がんは、肺がんである、請求項27に記載の組成物。
- 前記がんは、乳がんである、請求項27に記載の組成物。
- 前記がんは、多発性骨髄腫である、請求項28に記載の組成物。
- 前記がんは、腎細胞がんである、請求項27に記載の組成物。
- 前記方法は、1種または複数種の化学療法剤を共投与することをさらに含む、請求項26から32のいずれか一項に記載の組成物。
- 前記方法は、1種または複数種の免疫調節剤を共投与することをさらに含む、請求項26から33のいずれか一項に記載の組成物。
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