JP6401250B2 - 7−(6−(2−ヒドロキシプロパン−2−イル)ピリジン−3−イル)−1−((trans)−4−メトキシシクロヘキシル)−3,4−ジヒドロピラジノ[2,3−b]ピラジン−2(1H)−オン、その固体形態の医薬組成物、及びその使用方法 - Google Patents
7−(6−(2−ヒドロキシプロパン−2−イル)ピリジン−3−イル)−1−((trans)−4−メトキシシクロヘキシル)−3,4−ジヒドロピラジノ[2,3−b]ピラジン−2(1H)−オン、その固体形態の医薬組成物、及びその使用方法 Download PDFInfo
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- JP6401250B2 JP6401250B2 JP2016516763A JP2016516763A JP6401250B2 JP 6401250 B2 JP6401250 B2 JP 6401250B2 JP 2016516763 A JP2016516763 A JP 2016516763A JP 2016516763 A JP2016516763 A JP 2016516763A JP 6401250 B2 JP6401250 B2 JP 6401250B2
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- methoxycyclohexyl
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Description
本出願は、その内容全体が引用により本明細書中に組み込まれる、2013年5月29日に出願された米国仮特許出願第61/828,506号の利益を主張する。
異常なタンパク質リン酸化と疾患の原因又は結果との関係は、20年以上にわたって知られている。したがって、タンパク質キナーゼは、非常に重要な薬物標的群となっている。Cohenの文献、Nature, 1: 309-315(2002)を参照されたい。様々なタンパク質キナーゼ阻害剤が、癌、慢性炎症性疾患、糖尿病、及び脳卒中などの多種多様な疾患を治療する際に臨床的に使用されている。Cohenの文献、Eur. J. Biochem., 268: 5001-5010(2001)、疾患治療用のタンパク質キナーゼ阻害剤:有望性及び問題点(Protein Kinase Inhibitors for the Treatment of Disease: The Promise and the Problems)、実験薬理学の手引き(Handbook of Experimental Pharmacology)、Springer Berlin Heidelberg, 167(2005)を参照されたい。
本明細書に提供されるのは、7-(6-(2-ヒドロキシプロパン-2-イル)ピリジン-3-イル)-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オン、又はその医薬として許容し得る塩、アイソトポログ、代謝物、もしくは固体形態の組成物である。一実施態様において、該固体形態は、結晶性である。別の実施態様において、該固体形態は、7-(6-(2-ヒドロキシプロパン-2-イル)ピリジン-3-イル)-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オンの単一成分結晶性形態である。また別の実施態様において、該固体形態は、7-(6-(2-ヒドロキシプロパン-2-イル)ピリジン-3-イル)-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オンの結晶性形態Aである。
(5.1 定義)
本明細書に示される開示を理解しやすくするために、いくつかの用語を以下で定義する。
一実施態様において、本明細書に提供されるのは、化合物Aの固体形態又はその医薬として許容し得る塩である。ある実施態様において、該固体形態は、結晶性である。ある実施態様において、該固体形態は、単一成分固体形態である。ある実施態様において、該固体形態は、無水物である。
ある実施態様において、本明細書に提供されるのは、化合物Aを調製する方法であって:(1)エチル-2-(3,5-ジブロモピラジン-2-イルアミノ)アセテートをtrans-4-メトキシシクロヘキシルアミン塩酸塩及び1-メチル-2-ピロリジンと接触させ、DIPEAを添加して、エチル 2-((5-ブロモ-3-(((trans)-4-メトキシシクロヘキシル)アミノ)ピラジン-2-イル)アミノ)アセテートを生じさせること;(2)エチル 2-((5-ブロモ-3-(((trans)-4-メトキシシクロヘキシル)アミノ)ピラジン-2-イル)アミノ)アセテートを、酸(例えば、リン酸溶液)と接触させて、7-ブロモ-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オンを生じさせること;及び(3) 7-ブロモ-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オンを2-(5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2イル)ピリジン-2-イル)プロパン-2-オール及びPdCl2(Amphos)2と接触させることを含む、方法である。
一実施態様において、本明細書に提供されるのは、化合物A及び1以上の医薬として許容し得る賦形剤又は担体を含む医薬組成物である。一実施態様において、本明細書に提供される医薬組成物は、化合物Aの形態A及び1以上の医薬として許容し得る賦形剤又は担体を含む。一実施態様において、本明細書に提供される医薬組成物は、化合物Aの形態B(水和物)及び1以上の医薬として許容し得る賦形剤又は担体を含む。一実施態様において、本明細書に提供される医薬組成物は、化合物Aの形態C(無水物)及び1以上の医薬として許容し得る賦形剤又は担体を含む。一実施態様において、本明細書に提供される医薬組成物は、化合物Aの形態D(メタノール溶媒和物)及び1以上の医薬として許容し得る賦形剤又は担体を含む。一実施態様において、本明細書に提供される医薬組成物は、化合物Aの形態E(p-キシレン溶媒和物)及び1以上の医薬として許容し得る賦形剤又は担体を含む。一実施態様において、本明細書に提供される医薬組成物は、非晶質化合物A及び1以上の医薬として許容し得る賦形剤又は担体を含む。
化合物Aの固体形態(例えば、形態A、形態B、形態C、形態D、形態E、又は非晶質)、化合物Aのアイソトポログ、化合物Aの代謝物(例えば、O-デスメチル化合物A)、及び本明細書に提供される医薬組成物は、対象における疾患、例えば、増殖性疾患を治療又は予防するための医薬品としての有用性を有する。さらに、化合物Aの固体形態(例えば、形態A、形態B、形態C、形態D、形態E、又は非晶質)、化合物Aのアイソトポログ、化合物Aの代謝物(例えば、O-デスメチル化合物A)、及び本明細書に提供される医薬組成物は、癌、炎症性疾患、免疫学的疾患、神経変性疾患、糖尿病、肥満、神経学的障害、加齢関連疾患、及び/又は心血管疾患に関与するものを含む、キナーゼ(例えば、タンパク質キナーゼ)に対して活性がある。理論によって限定されるものではないが、化合物Aの固体形態(例えば、形態A、形態B、形態C、形態D、形態E、又は非晶質)、化合物Aのアイソトポログ、化合物Aの代謝物(例えば、O-デスメチル化合物A)、及び本明細書に提供される医薬組成物は、疾患及び疾病の病因に関与するキナーゼを調節する(例えば、阻害する)その能力のために、疾患及び疾病を治療又は予防する際に有効であると考えられる。したがって、本明細書に提供されるのは、本明細書に示されるこれらの疾患の治療又は予防を含む、化合物Aの固体形態(例えば、形態A、形態B、形態C、形態D、形態E、又は非晶質)、化合物Aのアイソトポログ、化合物Aの代謝物(例えば、O-デスメチル化合物A)、及び本明細書に提供される医薬組成物の使用である。ある実施態様において、本明細書に提供される方法は、化合物Aの固体形態(例えば、形態A、形態B、形態C、形態D、形態E、もしくは非晶質)、化合物Aのアイソトポログ、化合物Aの代謝物(例えば、O-デスメチル化合物A)、又は本明細書に提供される医薬組成物を投与することを含み、ここで、化合物Aの固体形態(例えば、形態A、形態B、形態C、形態D、形態E、もしくは非晶質)、化合物Aのアイソトポログ、化合物Aの代謝物(例えば、O-デスメチル化合物A)、又は本明細書に提供される医薬組成物は、本明細書に提供されるキットの一部である。
Chem-4D Draw(ChemInnovation Software社、San Diego, CA)、ChemDraw Ultra(Cambridgesoft, Cambridge, MA)、又はACD/Name(Advanced Chemistry Development社、Toronto, Ontario)を用いて、化学構造に名前を付けた。
ACN アセトニトリル
Amphos ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン
BHT ブチル化ヒドロキシトルエン
Boc tert-ブトキシカルボニル
dba ジベンジリデンアセトン
DCM ジクロロメタン
DIBE ジイソブチルヘキサヒドロフタレート
DIPEA N,N-ジイソプロピルエチルアミン
DIPE ジイソプロピルエーテル
DME ジメトキシエタン
DMAP 4-ジメチルアミノピリジン
DMSO ジメチルスルホキシド
dppf 1,1'-ビス(ジフェニルホスフィノ)フェロセン
DSC 示差走査熱量測定
ESI エレクトロスプレーイオン化
EtOAc 酢酸エチル
DVS 動的水蒸気収着
HPLC 高速液体クロマトグラフィー
IPA イソプロピルアルコール
IPAc 酢酸イソプロピル
MeOAc 酢酸メチル
MIBK メチルイソブチルケトン
mp 融点
MS 質量分析
MTBE メチル tert-ブチルエーテル
NBS N-ブロモスクシンイミド
NMR 核磁気共鳴
NMP N-メチル-2-ピロリジノン
PEG ポリエチレングリコール
PFL 遮光
REF 冷蔵
RTmp又はRT 室温
TEA トリエチルアミン
TFA トリフルオロ酢酸
TGA 熱重量分析
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
TMS トリメチルシリル
XRPD X線粉末回折
(6.1.1 特徴付けの方法)
(6.1.1.1 X線粉末回折(XRPD))
固体形態スクリーンで生成された固体試料は全て、XRPDで分析された。XRPD分析は、Bruker AXS C2 GADDS又はBruker AXS D8 Advance X線粉末回折計で実施された。
変調DSCデータを、50ポジションオートサンプラーを備えたTA Instruments Q2000で収集した。サファイアを用いて熱容量の較正を実施し、認定インジウムを用いてエネルギーと温度の較正を実施した。通常、ピンホールの開いたアルミニウムパン中の3〜1.5mgの各試料を2℃/分で-80℃から300℃に加熱した。50mL/分での乾燥窒素のパージを試料にわたって維持した。2℃/分の基調加熱速度と60秒毎(期間)の±1.272℃(大きさ)の温度変調パラメータとを用いて、温度変調DSCを実施した。機器制御ソフトウェアは、Advantage for Q Series v2.8.0.392及びThermal Advantage v4.8.3であり、データは、Universal Analysis v4.4Aを用いて解析した。
TGAデータを、34ポジションオートサンプラーを備えたMettler TGA/SDTA 851eで収集した。この機器を、認定インジウムを用いて温度較正した。通常、5〜15mgの各試料を予め計量済みのアルミニウムるつぼに充填し、10℃/分で周囲温度から350℃に加熱した。50ml/分での窒素パージを試料にわたって維持した。機器制御及びデータ解析ソフトウェアは、STARe v9.20であった。
試料を、画像取込用のデジタルビデオカメラを備えたLeica LM/DM偏光顕微鏡で調べた。少量の各試料をガラススライド上に置き、浸漬油中で標本化し、ガラススリップで覆い、個々の粒子を可能な限り分離した。試料を、適切な倍率、及びλ疑似カラーフィルターに連結された部分偏光を用いて観察した。
収着等温線を、DVS Intrinsic Controlソフトウェアv1.0.0.30によって制御されるSMS DVS Intrinsic水分収着分析計を用いて取得した。試料温度を、機器制御により、25℃に維持した。湿度は、総流量200mL/分で乾燥窒素と湿潤窒素の流れを混合することにより制御した。相対湿度は、試料の近くに位置する較正済Rotronicプローブ(1.0〜100%RHのダイナミックレンジ)で測定した。%RHの関数としての試料の重量変化(質量緩和)は、微量天秤(精度±0.005mg)で常にモニタリングした。通常、5〜20mgの試料を、周囲条件下、風袋計量したメッシュステンレススチールバスケットに入れた。試料を40%RH及び25℃(典型的な室内条件)で充填及び脱充填した。標準的な等温線を、25℃で、10%RH間隔で、0〜90%RH範囲にわたって実施した。データ解析を、DVS Analysis Suite v6.0.0.7を用いて、Microsoft Excelで行った。
多形体スクリーンで使用される溶媒は、HPLC等級又は試薬等級のどちらかであり、これには、トルエン、MTBE(メチル tert-ブチルエーテル)、DIPE(ジイソプロピルエーテル)、THF(テトラヒドロフラン)、DME(ジメトキシエタン)、IPAc(酢酸イソプロピル)、EtOAc(酢酸エチル)、MIBK(メチルイソブチルケトン)、アセトン、IPA(イソプロピルアルコール)、エタノール、ACN(アセトニトリル)、ニトロメタン、p-キシレン、p-キシレン/アセトン(例えば、50:50)、p-キシレン/MTBE(例えば、50:50)、又はIPA:水(例えば、95:5)が含まれた。
非晶質化合物A(実験当たり〜10mg)を明記された溶媒で処理した。溶液を室温でゆっくりと蒸発させ、残留固体をXRPDで分析した。懸濁液を加熱/冷却サイクル(50℃/室温、8時間サイクル)に16時間供し;その後、溶媒を蒸発させ、残留固体をXRPDで分析した。
(6.1.3.1 XRPD、TGA、及びDSCによる特徴付け)
形態Aは、図1に示すような結晶性XRPDパターン及び図2に示すような不規則な平板状晶癖を有する。化合物Aの形態AのXRPDパターンは、形態Aが結晶性であることを示している。結晶性形態AのいくつかのXRPDピークを表2にまとめる。
形態Aの吸湿性を水分吸着及び脱離により決定した。形態Aの水分収着/脱離挙動をDVSより決定した。結果を図4にまとめる。形態Aは、0〜80%相対湿度で有意な吸水を示さなかった(<0.1%w/w)。これは、形態Aが吸湿性でないことを示している。完全な水分吸着/脱離サイクルを経た後、試料のXRPDディフラクトグラムは、該材料が最初の形態Aから変化していないことを示した。特徴付けの結果に基づき、形態Aは、無水かつ非吸湿性の結晶性材料であることが分かった。
(調製1:)
化合物AをIPA及び水(3×:5×容量)中のBHT(0.001当量)と合わせた。該混合物を65℃に加熱し、この温度を維持しながら、65℃に加熱した水(5×容量)を添加した。65℃に加熱した水中の少量の表題化合物(0.02当量)を添加した。該混合物を2時間保持し、4時間かけて室温に冷却し、さらに2時間撹拌した。得られた固体を濾過により回収し、水中の20%IPAで洗浄し、乾燥させると、化合物Aが白色〜黄色の固体として得られた。
化合物AをMeOAc(25×容量)中のBHT(0.02当量)と合わせ、55℃に加熱した。該溶液を25℃に冷却し、MeOAc中の少量の表題化合物(0.02当量)を添加した。該スラリーを1時間保持し、低容量になるまで真空下で蒸留し、n-ヘプタン(10×容量)で処理した。該スラリーを2時間保持し、得られた固体を濾過により回収し、n-ヘプタン中の50%MeOAcで洗浄し、乾燥させると、化合物Aが白色〜黄色の固体として得られた。
化合物AをBHT(0.02当量)、及びMeOAcと合わせ、55℃に加熱すると、透明な溶液が形成された。該溶液を熱い間に濾過し、30℃に冷却し、MeOAc中の少量の表題化合物(0.02当量)を添加した。該スラリーを少なくとも1時間撹拌し、低容量になるまで真空下で蒸留し、n-ヘプタンで処理した。得られた固体を濾過により回収し、n-ヘプタン中のMeOAcの1:1混合物で洗浄し、乾燥させると、化合物Aが白色〜黄色の固体として得られた。
化合物A(形態A)と化合物A(ピナコール共結晶)の1:1 wt/wt混合物を、周囲温度で4日間撹拌しながら、IPA(6×容量)で処理した。固体を濾過により回収し、減圧下、40〜50℃で乾燥させると、化合物A(形態A)が黄色の固体として得られた。195℃のDSC吸熱。XRPDディフラクトグラム(最大ピーク±0.5°) 2θ角度(°): 8.0、9.0、12.0、13.0、16.5、17.5、18.2、21.5、22.5、25.0、26.5。
化合物AをBHT(0.02当量)及び5%水性THF(5×容量)と合わせると、透明な溶液が形成された。該溶液を任意に活性炭で4時間処理した。該溶液を濾過し、酢酸イソプロピル(3×容量)で処理し、溶液温度が80℃に達するまで、大気圧下、酢酸イソプロピルを添加して、一定容量で蒸留した。該溶液を75℃に冷却し、酢酸イソプロピル中の少量の表題化合物(0.02当量)で処理し、スラリーを2時間保持した。該スラリーを、スラリー温度が88℃に達するまで、大気圧下、酢酸イソプロピルを添加して、一定容量で蒸留した。該スラリーを80〜85℃に冷却し、2時間保持し、4時間かけて25℃に冷却し、少なくとも8時間保持した。得られた固体を濾過により回収し、酢酸イソプロピルで洗浄し、乾燥させると、形態Aが白色〜黄色の固体として得られた。或いは、濾過及び酢酸イソプロピルの添加後、一定容量での蒸留を、減圧下、反応混合物を40℃に保持しながら、酢酸イソプロピル(3.5×容量)が添加されてしまうまで実施することができる。その後、40℃の溶液を、酢酸イソプロピル中の少量の表題化合物(0.02当量)で処理し、2時間保持し、追加分の酢酸イソプロピル(10×容量)を添加して、一定容量で、真空下40℃で蒸留する。該スラリーを40℃で2時間熟成させ、2時間かけて25℃に冷却し、少なくとも8時間保持し、固体を濾過により回収し、酢酸イソプロピルで洗浄し、乾燥させると、形態Aが白色〜黄色の固体として得られる。
化合物A、ピナコール(2.4当量)、及びTHF(5×容量)を合わせ、45〜50℃に加熱し、トルエン(1×容量)を添加した。該溶液を、減圧(300〜350トール)下、40〜45℃の温度を保持して、4×容量まで蒸留した。該溶液を冷却し、トルエン(5×容量)を添加しながら、減圧(300〜350トール)下、トルエン中15%THFが達成されるまで、溶媒を連続的に除去した。このバッチに、ピナコール共結晶(0.02当量)を25℃で種晶添加し、該バッチを72時間保持した。固体を濾過し、THF/トルエンですすぎ、真空下、45〜50℃で乾燥させると、化合物Aピナコール共結晶が得られた(1H NMRにより、71%収率、20wt%ピナコール)。119.0℃でのDSC融解。XRPDディフラクトグラム(最大ピーク±0.5°) 2θ角度(°): 5.0、6.0、12.5、14.0、15.0、15.5、17.5、18.5、22.5。
化合物AをIPA及び水(3×:5×容量)中のBHT(0.001当量)と合わせた。該混合物を55℃に加熱し、水(5×容量)を添加した。水中の少量の表題化合物(0.02当量)を添加した。該混合物を1時間かけて室温に冷却し、室温でさらに48時間撹拌した。得られた固体を濾過により回収し、水中の20%IPAで洗浄し、乾燥させると、化合物Aの水和物がピンク色の固体として得られた。該固体は、111.3℃のDSC吸熱、164.9℃の発熱、及び201.6℃の吸熱を有していた。TGA分析により、6.4%の重量損失及び50℃の開始温度が示された。XRPDディフラクトグラム(最大ピーク±0.5°) 2θ角度(°): 6.0、7.0、8.0、10.0、12.0、14.0、17.0、18.0、20.0、20.5、22.5、24.5。
(調製1:)
化合物AをMeOH(10×容量)中のBHT(0.001当量)と合わせた。該混合物を低容量(5×)になるまで蒸留し、さらに50mLの蒸留液が回収されるまで、IPAを添加して、さらに蒸留し、該溶液を室温に冷却した。得られた固体を濾過により回収し、IPA(2×容量)で洗浄し、乾燥させると、化合物Aがオフホワイト色の固体として得られた。該固体のDSC分析により、161℃の吸熱及び200℃の吸熱が示された。XRPDディフラクトグラム(最大ピーク±0.5°) 2θ角度(°): 6.5、9.0、10.0、14.5、16.5、19.0、23.0、23.5。
化合物A(ピナコール共結晶)及びBHT(0.01×wt)をIPA(8×容量)で処理し、周囲温度で4日間撹拌した。該固体を濾過により回収し、IPAで洗浄し、減圧下、40〜50℃で乾燥させると、化合物A(形態C)が固体として得られた。該固体のDSC分析により、160℃での吸熱及び発熱並びに200℃での吸熱が示された。XRPDディフラクトグラム(最大ピーク±0.5°) 2θ角度(°): 6.5、9.0、10.0、14.5、16.5、19.0、23.0、23.5。
化合物AをMeOH(20×容量)中のBHT(0.001当量)と合わせ、65℃に加熱した。該溶液を室温に冷却し、さらに18時間撹拌した。得られた固体を濾過により回収し、洗浄し、40〜45℃で乾燥させると、化合物Aがピンク色の固体として得られた。該固体は、98.3℃のDSC吸熱、159.3℃の発熱、及び200.6℃の吸熱を有していた。TGA分析により、7.4%の重量損失及び80℃の開始温度が示された。XRPDディフラクトグラム(最大ピーク±0.5°) 2θ角度(°): 6.0、7.5、8.0、9.0、10.0、12.5、14.5、16.5、19.0、19.5、20.5、23.0。
化合物Aの形態EのXRPDパターン、晶癖、TGA、SDTA、TGA-MS、HPLC、及びMSを図15〜20に示す。形態Eは、p-キシレン中でのスラリー変換実験、アセトン/p-キシレン(50/50)中での熱濾過実験、及びMTBE/p-キシレン(50/50)中での蒸発実験:を含む、少なくとも3つの実験で調製した。さらなる分析に使用される試料は、p-キシレン中でのスラリー変換実験で調製した。
(6.2.1 化合物Aの大規模合成)
(6.2.1.1 合成1)
化合物Aの代謝物を次のように調製した:
(6.3.1 14C濃縮された化合物Aの合成)
14C放射性標識された化合物Aを次のように調製した。
13C標識された化合物Aを次のように調製した。
13C5標識された化合物Aの代謝物を次のように調製した。
重水素濃縮された化合物Aは、次のように調製することができる。
化合物Aの重水素濃縮代謝物は、次のように調製することができる。
(6.4.1 錠剤)
化合物Aを、約5mg、20mg、及び50mgの化合物Aを活性医薬成分として含有する錠剤として製剤化した。該錠剤製剤中で使用された賦形剤及び担体を、その意図される機能と併せて、表6にまとめる。
錠剤を0.5〜2.2kgの範囲のバッチサイズで生産した。まず、化合物Aの形態Aを、Globepharma製の4〜8クォートのビンビレンダーを用いて、結合剤、希釈剤(複数可)、並びに/又は崩壊剤(例えば、ラクトース一水和物(NF)、クロスカルメロースナトリウム(NF)、及び/もしくは微結晶性セルロース(NF))と混合/ブレンドした。その後、該混合物を18メッシュスクリーンで篩にかけた。篩にかけた混合物を、Globepharma製の4〜8クォートのビンビレンダーを用いて、さらに混合/ブレンドした。滑沢剤(複数可)(例えば、ステアリン酸(NF)及び/又はステアリン酸マグネシウム(NF))を30メッシュスクリーンで篩にかけた後、次に、滑沢剤(複数可)を混合物に添加した。その後、得られた混合物を、Globepharma製の4〜8クォートのビンビレンダーを用いて、混合/ブレンドした。その後、該混合物を回転式錠剤プレスで圧縮して錠剤にし、その後、Ohara 8"パン中でコーティングした。このように生産された錠剤を、その粉末特性、錠剤特性、医療品光安定性/短期安定性、及び製造プロセスについて評価した。
表17.錠剤製剤IX
表22.錠剤製剤X(50mg)の錠剤短期安定性
表24.錠剤製剤X(5mg)の錠剤短期安定性
表26.錠剤製剤XII(50mg)
表29. 50mg錠及び20mg錠の製剤化のプロセスパラメータ(ブレンディング/圧縮)
表33.錠剤製剤XVI(15mg)
溶液を、適量の50:50(v:v) EtOH:PEG 400、[14C]-化合物A、及び化合物Aを用いて調製して、28.6mg/mLの最終濃度を達成した。該溶液のアリコートを、用量投与用の白色のSize 00 Capsugel(登録商標) V Caps Plus Hypromelloseカプセルに移した。予備的安定性データは、冷蔵条件で保管し、遮光した場合、該インプロセスバルク溶液が少なくとも48時間安定であることを示した。
(6.5.1 健康な男性成人対象における錠剤及びカプセル剤製剤の単回経口投与後の化合物Aの薬物動態を評価するための第1相非盲検無作為化交差試験)
本明細書に提供される特定の製剤を第1相非盲検無作為化交差試験で評価した。この試験には、スクリーニング段階、3つの治療及び試料収集期間、及び再診(follow-up visit)が含まれた。
表36.薬物動態パラメータ(幾何平均(幾何CV%))
表37
本研究の主要な目的は:[14C]-化合物A溶液のマイクロトレーサーを含有する化合物Aカプセル剤の単回20mg経口投与後の健康な男性対象における化合物Aの生体変換及び排泄を特徴付けること(パート1)、並びに化合物A錠剤の単回経口20-mg投与後の化合物Aの薬物動態(PK)に対する高脂肪食の効果を評価すること(パート2)である。
処置B:絶食又は摂食条件下での化合物A錠剤の単回20-mg経口投与。
Claims (16)
- 有効量の7-(6-(2-ヒドロキシプロパン-2-イル)ピリジン-3-イル)-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オン、又はその医薬として許容し得る塩、アイソトポログ、もしくは固体形態、約30〜60重量%のラクトース一水和物、約20〜40重量%の低水分等級の微結晶性セルロース、約1〜5重量%のクロスカルメロースナトリウム、及び約0.5〜3重量%のステアリン酸マグネシウムを含む医薬組成物。
- 微結晶性セルロースとして約20〜40重量%のAVICEL PH 112(登録商標)を含む、請求項1記載の医薬組成物。
- 約31重量%のAVICEL PH 112(登録商標)を含む、請求項2記載の医薬組成物。
- 前記クロスカルメロースナトリウムがAC-DI-SOL(登録商標)である、請求項1記載の医薬組成物。
- 約1〜5重量%のAC-DI-SOL(登録商標)を含む、請求項4記載の医薬組成物。
- 約10〜20重量%の7-(6-(2-ヒドロキシプロパン-2-イル)ピリジン-3-イル)-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オン、又はその医薬として許容し得る塩、アイソトポログ、もしくは固体形態を含む、請求項1記載の医薬組成物。
- 約15重量%の7-(6-(2-ヒドロキシプロパン-2-イル)ピリジン-3-イル)-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オン、又はその医薬として許容し得る塩、アイソトポログ、もしくは固体形態を含む、請求項6記載の医薬組成物。
- 約8.3、13.2及び18.2°2θにピークを含むX線粉末回折パターンを有する7-(6-(2-ヒドロキシプロパン-2-イル)ピリジン-3-イル)-1-((trans)-4-メトキシシクロヘキシル)-3,4-ジヒドロピラジノ[2,3-b]ピラジン-2(1H)-オンの結晶形態を含む、請求項6記載の医薬組成物。
- 約1重量%のステアリン酸マグネシウムを含む、請求項1記載の医薬組成物。
- 錠剤として製剤化される、請求項1記載の医薬組成物。
- 前記錠剤がフィルムコーティングされている、請求項10記載の医薬組成物。
- 前記フィルムコーティングが前記錠剤の約4重量%である、請求項11記載の医薬組成物。
- 癌、炎症性疾患、免疫学的疾患、神経変性疾患、糖尿病、肥満、神経学的障害、加齢関連疾患、心血管疾患、又はキナーゼ経路の阻害によって治療可能もしくは予防可能な疾患を治療又は予防するための、請求項1記載の医薬組成物。
- 前記キナーゼ経路がTORキナーゼ経路である、請求項13記載の医薬組成物。
- 固形腫瘍を有する対象において、完全応答、部分応答、又は安定疾患の固形腫瘍の応答評価基準(RECIST 1.1)を達成するための、請求項1記載の医薬組成物。
- NHLの国際ワークショップ基準(IWC)によって決定される完全寛解、部分寛解、又は安定疾患をもたらすための、多発性骨髄腫の国際統一応答基準(IURC)によって特徴付けられる治療応答を誘導するための、東部共同腫瘍学グループのパフォーマンスステータス(ECOG)を改善するための、又はGBMの神経腫瘍学応答評価(RANO)ワーキンググループで評価される治療応答を誘導するための、請求項1記載の医薬組成物。
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JP2016523225A (ja) | 2016-08-08 |
CA2912627A1 (en) | 2014-12-04 |
US9604939B2 (en) | 2017-03-28 |
EP3003313A1 (en) | 2016-04-13 |
CN109503591B (zh) | 2022-03-01 |
HK1248225A1 (zh) | 2018-10-12 |
MX2015015880A (es) | 2016-05-31 |
CN107474051B (zh) | 2020-10-30 |
CA2912627C (en) | 2022-03-15 |
WO2014193912A1 (en) | 2014-12-04 |
HK1223286A1 (zh) | 2017-07-28 |
CN109503591A (zh) | 2019-03-22 |
CN105407892A (zh) | 2016-03-16 |
CA3143529A1 (en) | 2014-12-04 |
US9974786B2 (en) | 2018-05-22 |
US10052323B2 (en) | 2018-08-21 |
CN113831345A (zh) | 2021-12-24 |
CN107474051A (zh) | 2017-12-15 |
US20180071287A1 (en) | 2018-03-15 |
US20170182042A1 (en) | 2017-06-29 |
NZ629486A (en) | 2017-11-24 |
US20140356430A1 (en) | 2014-12-04 |
CN105407892B (zh) | 2019-05-07 |
US20180200252A1 (en) | 2018-07-19 |
US9795603B2 (en) | 2017-10-24 |
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