JP2018184486A - N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド塩酸塩 - Google Patents
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド塩酸塩 Download PDFInfo
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- pyrimidin
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- benzamide
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Abstract
Description
本出願は、その医薬製剤の調製に適切である、安定した新規の塩形態のN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド、およびこれらの治療的使用に関する。
ヤヌスキナーゼ(JAK)に対する阻害が、過剰増殖性疾患の処置において評価されてきた。いくつかのJAK阻害剤が開発されてきた:ルキソリチニブ、トファシチニブ、バリシチニブ、レストールチニブ、パクリチニブ、フェドラチニブ、XL019、SB1518およびAZD1480が開発されている(Sonbol, Ther. Adv. Hematol.、4巻:15〜35頁、2013年)。化合物N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド(CYT−0387)はJAKキナーゼ阻害剤である。
本発明は、新規のCYT−0387形態を対象とする。
一態様では、本発明は、CYT−0387一塩酸塩無水形態I:
以下の説明は、例示的な組成物および方法、パラメータ等を記載する。しかし、このような説明は、本開示の範囲に対する限定であることを企図されず、その代わり例示的な実施形態の説明として提供されることを認識されたい。
れた場合物理的に不安定であることを示している。また、以下に記載の結果は、製造および/または貯蔵に適切な条件下で、CYT−0387二塩酸塩一水和物形態IIが二塩酸塩の熱力学的に安定した形態であることを示している。加えて、本出願は、没食子酸プロピル(フリーラジカルスカベンジャー酸化剤)の使用が水溶液中および錠剤製剤中でのCYT−0387二塩酸塩一水和物形態IIの酸化的分解を阻害または防止するのに有効であることを記載している。さらに、結果は、CYT−0387二塩酸塩一水和物形態IIが、CYT−0387二塩酸塩無水形態IおよびCYT−0387遊離塩基と比較してより高いバイオアベイラビリティーを呈することを示唆している。
れている。本明細書に記載の化合物が酸付加塩として得られる場合、その遊離塩基は、この酸塩の溶液を塩基性化することによって得ることができる。逆に、生成物が遊離塩基で
ある場合、付加塩、特に薬学的に許容される付加塩は、塩基化合物から酸付加塩を調製するための慣習的手順に従って、この遊離塩基を適切な有機溶媒に溶解し、その溶液を酸で処理することによって生成することができる。「処理」または「処理する」は、臨床結果を含めた有益なまたは所望の結果を得るための手法である。有益なまたは所望の臨床結果は、以下の1つまたは複数を含むことができる:a)疾患または状態の阻害(例えば、疾患もしくは状態から生じる1つもしくは複数の症状の低減、および/または疾患もしくは状態の程度の縮小);b)疾患または状態に関連する1つまたは複数の臨床症候の発症の緩徐または抑止(例えば、疾患もしくは状態の安定化、疾患もしくは状態の悪化もしくは進行の防止もしくは遅延、および/または疾患もしくは状態の拡大(例えば、転移)の防止もしくは遅延);ならびに/あるいはc)疾患の軽減、すなわち、臨床症候の退行を引き起こすこと(例えば、病状の緩和、疾患もしくは状態の部分的もしくは完全な寛解の提供、別の医薬品の効果の促進、疾患の進行の遅延、生活の質の向上、および/または延命)。
は疾患の進行の緩徐などの治療上の利益をもたらすのに十分な量を意味する。治療有効量は、対象、および処置されている疾患または状態、対象の体重および年齢、疾患または状態の重症度、ならびに投与方式に応じて変わり得るが、当業者によって容易に決定され得る。一実施形態では、本明細書中に記載されている化合物の治療有効量は、100mg、150mg、200mg、250mg、または300mgである。
本明細書に提供されている化合物は、通常、医薬組成物の形態で投与される。したがって、本明細書では、本明細書で開示されている式のいずれかの化合物または薬学的に許容されるその塩、異性体、プロドラッグ、もしくは溶媒和物の1つまたは複数、ならびに担体、アジュバントおよび賦形剤から選択される1つまたは複数の薬学的に許容されるビヒクルを含有する医薬組成物も提供される。適切な薬学的に許容されるビヒクルとして、例えば、不活性な固体希釈剤および充填剤、滅菌水溶液および様々な有機溶媒を含めた希釈剤、透過促進剤、可溶化剤およびアジュバントを挙げることができる。このような組成物は、薬学分野で周知の方式で調製される。例えば、Remington’s Pharmaceutical Sciences、Mace Publishing Co.、Philadelphia、Pa.、17版(1985年);およびModern Pharmaceutics、Marcel Dekker, Inc.3版(G.S. Banker & C.T. Rhodes編)を
参照。本明細書で使用される場合、「溶媒和物」は、溶媒と化合物の相互作用によって形成される。本明細書に記載される式のいずれかの化合物の塩の溶媒和物もまた提供される。これらの式のいずれかの化合物の水和物もまた提供される。また、「プロドラッグ」とは、ヒト身体への投与により、何らかの化学的または酵素的経路に従い生物活性のある親薬物に変換される薬物の生物活性のない誘導体として医薬品分野において定義されている。
用語「担体」は、化合物と共に投与される希釈剤または充填剤、崩壊剤、沈降防止剤、界面活性剤、流動促進剤、結合剤、滑沢剤、酸化防止剤、ならびに他の賦形剤およびビヒクルを指す。担体は一般に本明細書、またE.W. Martinによる「Remington's Pharmaceutical Sciences」に記載されている。担体の例として、限定されないが、モノステアリ
ン酸アルミニウム、ステアリン酸アルミニウム、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、クロスポビドン、イソステアリン酸グリセリル、モノス
テアリン酸グリセリル、ヒドロキシエチルセルロース、ヒドロキシエチルセルロース、ヒドロキシメチルセルロース、ヒドロキシオクタコサニルヒドロキシステアレート、ヒドロキシプロピルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ラクトース、ラクトース一水和物、ステアリン酸マグネシウム、マンニトール、微結晶性セルロース、ポロキサマー124、ポロキサマー181、ポロキサマー182、ポロキサマー188、ポロキサマー237、ポロキサマー407、ポビドン、二酸化ケイ素、コロイド状二酸化ケイ素、シリコーン、シリコーン接着剤4102、およびシリコーン乳濁液が挙げられる。しかし、本発明の開示に提供されている医薬組成物のために選択される担体、および組成物中のこのような担体の量は、製剤化の方法(例えば、乾式造粒製剤化、固体分散液製剤化)に応じて変わり得ることを理解されたい。
タルク、ならびにラウリン酸、オレイン酸、およびC8/C10脂肪酸を含む脂肪酸などの可溶化剤を挙げることができる。
グネシウム(stereate)である。
一部の実施形態では、本明細書に記載の医薬組成物は、単位剤形で製剤化される。用語「単位剤形」は、対象(例えば、ヒト対象および他の哺乳動物)に対する単位投与量として適切な物理的に別個の単位を指し、それぞれの単位は、適切な薬学的担体と一緒に、所望の治療効果をもたらすように計算された既定量の活性材料を含有する。
単位剤形を対象とする。一部の実施形態では、単位剤形は、約10mg〜約1000mg、約10mg〜約800mg、約10mg〜約700mg約10mg〜約500mg、約10mg〜約400mg、約10mg〜約300mg、約10mg〜約250mg、約10mg〜約200mg、約10mg〜約150mg、約10mg〜約100mg、約10mg〜約50mg、約50mg〜約1000mg、約50mg〜約800mg、約50mg〜約700mg約50mg〜約500mg、約50mg〜約400mg、約50mg〜約300mg、約50mg〜約250mg、約50mg〜約200mg、約50mg〜約150mg、約50mg〜約100mg、約100mg〜約1000mg、約100mg〜約800mg、約100mg〜約700mg約100mg〜約500mg、約100mg〜約400mg、約100mg〜約300mg、約100mg〜約250mg、約100mg〜約200mg、約150mg〜約300mg、約150mg〜約250mg、約150mg〜約200mg、約200mg〜約300mg、約200mg〜約250mg、または約200mg〜約300mgのCYT−0387遊離塩基に相当する量でCYT−0387二塩酸塩一水和物形態IIを含む。
む。さらに他の実施形態では、少なくとも2種の希釈剤は微結晶性セルロースおよびラクトースであり、少なくとも1種の崩壊剤はデンプングリコール酸ナトリウムであり、少なくとも1種の流動促進剤はコロイド状二酸化ケイ素であり、少なくとも1種の滑沢剤はステアリン酸マグネシウムであり、少なくとも1種の酸化防止剤は没食子酸プロピルである。またさらなる実施形態では、単位剤形は、約36%〜44%のCYT−0387二塩酸塩一水和物形態II;約30%〜38%の微結晶性セルロース;約14%〜20%のラクトース、約4%〜8%のデンプングリコール酸ナトリウム、約0.25%〜0.75%のコロイド状二酸化ケイ素、約1.2%〜1.8%のステアリン酸マグネシウム、および約0.1%〜0.5%の没食子酸プロピルを含む。
本明細書に記載の医薬組成物は、任意の慣習的方法、例えば、限定されないが、混合、溶解、造粒、糖衣錠の作製、粉砕、乳化、封入、エントラップ、溶融スピニング、スプレー乾燥、または凍結乾燥の方法を使用して製造することができる。
本出願の式の化合物または薬学的に許容されるその塩、異性体、プロドラッグ、もしくは溶媒和物、および適切なパッケージを含むキットもまた本明細書に提供されている。一実施形態では、キットは、使用するための指示書をさらに含む。一態様では、キットは、本明細書に記載の式の化合物または薬学的に許容されるその塩、異性体、プロドラッグ、もしくは溶媒和物、ならびに本明細書に記載の疾患または状態を含む適応症の処置に化合物を使用するためのラベルおよび/または指示書を含む。
本発明のCYT−0387形態は、JAKキナーゼ関連疾患、例えば、臓器移植を含む免疫学的および炎症性疾患;がんおよび骨髄増殖性疾患を含む過剰増殖性疾患;ウイルス性疾患;代謝性疾患;および血管系疾患などを含むキナーゼ関連疾患の処置に使用することができる。
病)、パジェット病、敗血症、結膜炎、鼻カタル(neranl catarrh)、慢性関節リウマ
チ、全身性全身性炎症反応症候群(SIRS)、多発性筋炎、皮膚筋炎(DM)、結節性多発動脈炎(Polaritis nodoa)(PN)、混合性結合組織疾患(MCTD)、シェーグレン症候群、クルーゾン症候群、軟骨無形成症、全身性エリテマトーデス、強皮症、血管炎、致死性骨異形成症、インスリン耐性、I型糖尿病ならびに糖尿病およびメタボリックシンドロームによる合併症が挙げられるが、これらに限定されない。
(inesothelioma);消化管:食道(扁平上皮癌、腺癌、平滑筋肉腫、リンパ腫)、胃(
癌、リンパ腫、平滑筋肉腫)、膵臓(管腺癌、インスリノーマ、グルカゴノーマ、ガストリノーマ、カルチノイド腫瘍、ビポーマ)、小腸(腺癌、リンパ腫、カルチノイド腫瘍、カポジ肉腫、平滑筋腫、血管腫、脂肪腫、神経線維腫、線維腫)、大腸(腺癌、管状腺腫、絨毛腺腫、過誤腫、平滑筋腫);泌尿生殖器:腎臓(腺癌、ウィルムス腫瘍[腎芽細胞腫]、リンパ腫、白血病)、膀胱および尿道(扁平上皮癌、移行上皮癌、腺癌)、前立腺(prostrate)(腺癌、肉腫)、精巣(精上皮腫、奇形腫、胎児性癌、奇形癌、絨毛癌、
肉腫、間質細胞癌、線維腫、線維腺腫、腺腫様腫瘍、脂肪腫);肝臓:肝癌(肝細胞癌)、胆管癌、肝芽腫、血管肉腫、肝細胞性腺腫、血管腫;骨:骨原性肉腫(骨肉腫)、線維肉腫、悪性線維性組織球腫、軟骨肉腫、ユーイング肉腫、悪性リンパ腫(細網肉腫)、多発性骨髄腫、悪性巨細胞腫脊索腫、骨軟骨腫(osteochronfrorna)(骨軟骨外骨腫症)、良性軟骨腫、軟骨芽細胞腫、軟骨粘液線維腫、類骨腫および巨細胞腫;神経系:頭蓋(骨腫、血管腫、肉芽腫、黄色腫、変形性骨炎(osteitis deformians))、髄膜(髄膜腫、髄膜肉腫、神経膠腫症)、脳(星状細胞腫、髄芽腫、神経膠腫、上衣細胞腫、胚細胞腫[松果体腫]、多形性神経膠芽細胞腫、乏突起細胞腫、シュワン細胞腫、網膜芽腫、先天性腫瘍)、脊髄神経線維腫、髄膜腫、神経膠腫、肉腫);婦人科系:子宮(子宮体癌)、子宮頚部(子宮頚癌、前腫瘍子宮頚部形成異常)、卵巣(卵巣癌[漿液性嚢胞腺癌、ムチン性嚢胞腺癌、分類不能癌]、顆粒膜包膜細胞腫、セルトリライディッヒ細胞腫瘍、未分化胚細胞腫、悪性奇形腫)、外陰部(扁平上皮癌、表皮内癌、腺癌、線維肉腫、黒色腫)、膣(明細胞癌、扁平上皮癌、ブドウ状肉腫[胎児型横紋筋肉腫])、卵管(癌腫);血液系:血液(骨髄性白血病[急性および慢性]、急性リンパ芽球性白血病、慢性リンパ球性白血病、多発性骨髄腫、骨髄異形成症候群)、ホジキン病、非ホジキンリンパ腫[悪性リンパ腫];皮膚:悪性黒色腫、基底細胞癌、扁平上皮癌、カポジ肉腫、異形成性母斑、脂肪腫、血管腫、皮膚線維腫、ケロイド、乾癬;副腎:神経芽細胞腫;および骨髄増殖性疾患、例えば、真性赤血球増加症(PV)、原発性骨髄線維症、血小板血症、本態性血小板血症(ET)、特発性骨髄化生(AMM)(また特発性骨髄線維症(IMF)とも呼ばれる)、慢性骨髄性白血病(CML)、全身性肥満細胞症(mastocystosis)(SM)、慢
性好中球性白血病(CNL)、骨髄異形成症候群(MDS)および全身性肥満細胞疾患(SMCD)が挙げられる。ある特定の実施形態では、骨髄線維症疾患は、真性赤血球増加症(PV)、原発性骨髄線維症、血小板血症、および本態性血小板血症(ET)から選択される。一実施形態では、本出願の医薬組成物は、骨髄増殖性疾患の処置に適切となり得、骨髄線維症疾患は、真性赤血球増加症(PV)、原発性骨髄線維症、血小板血症、および本態性血小板血症(ET)から選択される。一部の実施形態では、本出願の医薬組成物は、原発性骨髄線維症の処置に適切となり得る。
心筋梗塞、心臓、腎臓、肝臓および脳の虚血性疾患、ならびに肺動脈高血圧を含めた疾患を指す。
る効果を有する。
vitroでのコロニー形成、髄の細胞過多、髄外造血巣、巨脾症および肝肥大、ならびに血栓性および/または出血性の素因を含めた、一連の生物学的、病理学的および臨床的特徴を共有する万能性造血幹細胞のクローン障害の相互に関係する群である。骨髄増殖性腫瘍のリサーチおよび処置(IWG−MRT)のための国際ワーキンググループが確立されて、これらの状態の線引きおよび定義が行われ(例えば、Vannucchiら、CA Cancer
J. Clin.、2009年、59巻:171〜191頁を参照)、これらの疾患の定義は
、本明細書の目的に適用されるものとする。対象、とりわけMPNおよび特にPMFを示すヒト患者は、上述されたIWG−MRT基準を使用して当技術分野で識別可能である。
特定の形態のMPNに対して「危険がある」対象は、疾患の初期段階形態を有する対象であり、例えば、その遺伝マーカー、例えば、PV(>95%)、ET(60%)およびPMF(60%)に関連するJAK2V617Fアレルなどを有する対象を含み得る。対象はまた、すでに早期段階形態の症状を明らかにしている場合、MFNの形態に対して「危険がある」とも考えられる。したがって、MFNを示す対象は、ポスト−PVおよびポスト−ET(両方ともMPNの後に発症する)の危険がある。
i.サリドマイド、レナリドミド、ポマリドミド、およびCYT−0387以外のJAK2阻害剤から選択される薬物での、以前の治療;
ii.以下のうちの1つまたは両方から選択される臨床的判定基準:(1)脾臓のサイズが小さく、および(2)循環している芽球のパーセンテージが低い;
iii.以下の1つまたは複数から選択される生化学マーカー判定基準:(1)EGF、TNF−α、G−CSF、IFN−α、MIP−1β、HGF、MIG、およびVEGFから選択される少なくとも1種のタンパク質レベルの増加;(2)エオタキシンレベルの低下;ならびに(3)EPO、ヘプシジンおよびBMP−2から選択される少なくとも1種のタンパク質のレベルの変化。
阻害剤で処置されていた、または処置を受けている患者を含む。特にINCBO18424と命名されたJAK阻害剤、またはTG101348と命名されたJAK阻害剤で以前に処置した患者は、以前にこのような治療で処置されていない患者よりもCYT−0387治療に対して突出した脾臓応答を有することが判明した。好ましい実施形態では、CYT−0387治療のために選択される患者は、CYT−0387以外のJAK阻害剤による治療の対象下におかれることに加えて、輸血依存の患者でもある患者である。INCBO18424は、15または20mgのpo BIDの開始用量から、5mgBIDから25mgBIDへの用量漸増法で投与される。TG101348は、1日1回投与され、最大耐用量(MTD)は、680mg/日に決定されている。CYT−0387以外のJAK阻害剤は、任意のすべての他のJAK阻害剤を含み、特に、CYT−0387とは異なるJAK親和性、選択性または結合部位を有する、他のJAK阻害剤を含む。これらの特性は、その全体の開示が参照によって本明細書に組み込まれる、US7593820に記載されている、JAK2の結晶構造およびモデリング手法および活性アッセイを使用して決定することができる。それに続くCYT−0387治療がもたらすさらなる利益を得るため、患者は、他のJAK2阻害剤での処置を受けるか、またはCYT−0387治療開始に比べて、患者においてそのJA2阻害剤の効果が明らかとなるのに十分な時間枠で、このような薬物で処置されることになる。
(1)EGF、すなわち上皮成長因子、その成熟形態は、Swiss−Prot指定P01133を有する配列の残基971〜1023を含む;
(2)TNF−a、すなわち腫瘍壊死因子アルファ、その成熟および溶解形態は、Swiss−Prot指定P01375を有する配列の残基77〜233を含む;
(3)G−CSF、すなわち顆粒球コロニー刺激因子、その成熟形態は、Swiss−Prot指定P09919を有する配列の残基30〜207を含む;
(4)IFN−α、すなわちインターフェロンアルファ、その成熟形態が当技術分野で周知である、サブタイプのファミリーを含む;
(5)MIP−Iβ、すなわちマクロファージ炎症性タンパク質1−ベータ(C−Cモチーフケモカイン4、またはCCL4としても現在公知である)、その成熟形態は、Swiss−Prot指定PI3236を有する配列のいずれかの残基24〜92または26〜92を含む;
(6)HGF、すなわち肝細胞成長因子、その成熟形態は、Swiss−Prot指定P14210を有する配列に基づき、残基32〜494を有するアルファ鎖および残基495〜728を有するベータ鎖を含む;
(7)MIG、すなわちガンマインターフェロンにより誘発されるモノカイン(CXCL9としても現在公知である)は、走化性サイトカインのファミリーであり、その成熟形態は、Swiss−Prot指定Q07325を有する配列の残基23〜125を含む;
(8)VEGF、すなわち血管内皮成長因子A、その成熟形態は、Swiss−Prot指定PI5692を有する配列の残基27〜232を含む。
の前駆細胞である。芽球は通常成熟した血液細胞となる。循環している芽球の低いパーセンテージは、末梢血スメアの細胞形態分析ならびにマルチパラメータフローサイトメトリーおよび免疫組織化学法により測定される。予後の因子として、≧1%芽球が使用される。
R−4、TLR−5、TLR−6、TLR−7、TLR−8、TLR−9、TLR−10、TLR−11、TLR−12、および/またはTLR−13を含む)阻害剤、TK(チロシンキナーゼ)阻害剤、TPL2(セリン/スレオニンキナーゼ)阻害剤、NEK9阻害剤、Abl阻害剤、p38キナーゼ阻害剤、PYK阻害剤、PYK阻害剤、c−Kit阻害剤、NPM−ALK阻害剤、Flt−3阻害剤、c−Met阻害剤、KDR阻害剤、TIE−2阻害剤、VEGFR阻害剤、SRC阻害剤、HCK阻害剤、LYN阻害剤、FYN阻害剤、YES阻害剤、化学療法剤、免疫療法剤、放射線療法剤、抗腫瘍剤、抗がん剤、抗増殖性剤、抗線維化剤、抗血管新生剤、治療抗体、またはこれらの任意の組合せから選択することができる。一部の実施形態では、PI3K−δ阻害剤は、ChemDrawで命名した場合、(S)−2−(1−((9H−プリン−6−イル)アミノ)プロピル)−5−フルオロ−3−フェニルキナゾリン−4(3H)−オンであり(5−フルオロ−3−フェニル−2−[(1S)−1−(9H−プリン−6−イルアミノ)プロピル]キナゾリン−4(3H)−オンとも呼ぶことができる)、米国特許第7,932,260号に記載の方法で合成することができる。ある特定の実施形態では、SyK阻害剤は、ChemDrawで命名した場合、6−(1H−インダゾール−6−イル)−N−(4−モルホリノフェニル)イミダゾ[1,2−a]ピラジン−8−アミンであり(6−(1H−インダゾール−6−イル)−N−[4−(モルホリン−4−イル)フェニル]イミダゾ[1,2−a]ピラジン−8−アミンとも呼ぶことができる)、米国特許第8,450,321号に記載の方法で合成することができる。他の実施形態では、BTK阻害剤は、ChemDrawで命名した場合、(S)−6−アミノ−9−(1−(ブタ−2−イノイル)ピロリジン−3−イル)−7−(4−フェノキシフェニル)−7H−プリン−8(9H)−オンであり(6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オンでもあり得る)、米国特許第8,557,803号の方法で合成することができる。ある特定の実施形態では、MEK阻害剤はトラメチニブである。一部の実施形態では、EGFR阻害剤はエルロチニブである。一実施形態では、本出願の製剤は、PI3K阻害剤、MEK阻害剤、TBK阻害剤、EGFR阻害剤、またはこれらの組合せと組み合わせて使用することができる。追加の実施形態では、本出願の製剤は、トラメチニブと組み合わせて使用することができる。他の実施形態では、本出願の製剤は、エルロチニブと組み合わせて使用することができる。
(ヘキサメチルメラミンおよびチオテパ)、アルキルニトロソ尿素(BCNU)および類似体、ストレプトゾシン)、トラゼン−ダカルバジン(dacarbazinine)(DTIC);抗増殖/有糸分裂阻害性代謝拮抗剤、例えば葉酸類似体(メトトレキセート);白金配位錯体(シスプラチン、オキサリプラチン(oxiloplatinim)、カルボプラチン)、プロカルバジン、ヒドロキシ尿素、ミトタン、アミノグルテチミド;ホルモン、ホルモン類似体(エストロゲン、タモキシフェン、ゴセレリン、ビカルタミド、ニルタミド)およびアロマターゼ阻害剤(レトロゾール、アナストロゾール);抗凝固剤(ヘパリン、合成ヘパリン塩およびトロンビンの他の阻害剤);血栓溶解剤(例えば、組織プラスミノーゲン活性化因子、ストレプトキナーゼおよびウロキナーゼ)、アスピリン、ジピリダモール、チクロピジン、クロピドグレル;抗遊走(antimigratory)剤;抗分泌性剤(ブレフェルジン(breveldin));免疫抑制剤であるタクロリムス シロリムス アザチオプリン、ミコフェノレート;化合物(TNP−470、ゲニステイン)および成長因子阻害剤(血管内皮成長因子阻害剤、線維芽細胞成長因子阻害剤);アンジオテンシン受容体遮断剤、一酸化窒素供与体;アンチセンスオリゴヌクレオチド;抗体(トラスツズマブ、リツキシマブ);細胞周期阻害剤および分化誘発物質(トレチノイン);阻害剤、トポイソメラーゼ阻害剤(ドキソルビシン(アドリアマイシン)、ダウノルビシン、ダクチノマイシン、エニポシド(eniposide)、エピルビシン、エトポシド、イダルビシン、イリノテカンおよびミトキサントロン、トポテカン、イリノテカン、カンプトテシン(camptothesin))、コルチコステロイド(コルチゾン、デキサメタゾン、ヒドロコルチゾン、メチルプレドニゾロン(methylpednisolone)、プレドニゾンおよびプレドニゾロン(prenisolone));成長因子シグナル伝達キナーゼ阻害剤;機能障害誘発物質、毒素、例えばコレラ毒素、リシン、緑膿菌外毒素、百日咳菌のアデニル酸シクラーゼ毒素、またはジフテリア毒素、およびカスパーゼ活性化因子;ならびにクロマチン。
例えば、Agnew、Chem.Intl.Ed. Engl、33号:183〜186頁(1994年)参照;ダイネミシン(dynemicin)Aを含むダイネミシン;ビスフォスフォネート、例えばクロドロネート;エスペラマイシン;ならびにネオカルジノスタチンクロモフォアおよび関係する色素タンパク質エンジイン抗生物質発色団(chromomophore))、アクラシノマイシン、アクチノマイシン、アントラマイシン(authramycin)、アザセリン、ブレオマイシン、カクチノマイシン(cactinomycin)、カラビシン(carabicin)、カルミノマイシン(carrninomycin)、カルチノフィリン(carzinophilin)、クロモマイシン、ダクチノマイシン、ダウノルビシン、デトルビシン、6−ジアゾ−5−オキソ−L−ノルロイシン、ドキソルビシン(モルホリノ−ドキソルビシン、シアノモルホリノ−ドキソルビシン、2−ピロリノ−ドキソルビシンおよびデオキシドキソルビシンを含む)、エピルビシン、エソルビシン、イダルビシン、マルセロマイシン、マイトマイシン、例えばマイトマイシンC、ミコフェノール酸、ノガラマイシン、オリボマイシン、ペプロマイシン、ポトフィロマイシン(potfiromycin)、ピューロマイシン、ケラマイシン(quelamycin)、ロドルビシン(rodorubicin)、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシン;代謝拮抗物質、例えばメトトレキセートおよび5−フルオロウラシル(5−FU);葉酸類似体、例えばデモプテリン(demopterin)、メトトレキセート、プテロプテリン(pteropterin)、トリメトレキサート;プリン類似体、例えばフルダラビン、6−メルカプトプリン、チアミプリン、チオグアニン;ピリミジン類似体、例えばアンシタビン、アザシチジン、6−アザウリジン、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、フロクスウリジン;アンドロゲン、例えばカルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、メピチオスタン、テストラクトン;副腎皮質ホルモン抑制剤(anti−adrenals)、例えばアミノグルテチミド、ミトタン、トリロスタン;葉酸補充剤(replinisher)、例えばフォリン(frolinic)酸;アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;エニルウラシル;アムサクリン;ヘストラブシル(hestrabucil);ビサントレン;エダトレキセート(edatraxate);デフォファミン(defofamine);デメコルシン;ジアジクオン;エルホルムチン(elformthine);エリプチニウムアセタート;エポチロン;エトグルシド;硝酸ガリウム;ヒドロキシ尿素;レンチナン;ロイコボリン;ロニダミン;マイタンシノイド、例えばメイタンシンおよびアンサマイトシン;ミトグアゾン;ミトキサントロン;モピダモール;ニトラクリン;ペントスタチン;フェナメット;ピラルビシン;ロソキサントロン;フルオロピリミジン;フォリン酸;ポドフィリン酸;2−エチルヒドラジド;プロカルバジン;PSK(登録商標);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テヌアゾン酸;トリアジコン;2,2’,2’’−トリクロロトリエチルアミン(tricUorotriemylamine);トリコテセン(特に、T−2毒素、ベルカリン(verracurin)A、ロリジンAおよびアングイジン);ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン(gacytosine);アラビノシド(「Ara−C」);シクロホスファミド;チオテパ(thiopeta);タキソイド、例えば、パクリタキセル(TAXOL(登録商標))およびドセタキセル(TAXOTERE(登録商標));クロラムブシル;ゲムシタビン(Gemzar(登録商標));6−チオグアニン;メルカプトプリン;メトトレキセート;白金類似体、例えばシスプラチンおよびカルボプラチン;ビンブラスチン;白金;エトポシド(VP−16);イホスファミド;ミトキサントロン(mitroxantrone);ビンクリスチン(vancristine);ビノレルビン(Navelbine(登録商標));ノバントロン;テニポシド;エダトレキサート;ダウノマイシン;アミノプテリン;ゼローダ(xeoloda);イバンドロネート;CPT−11;トポイソメラーゼ阻害剤RFS2000;ジフルオロメチルオルニチン(DMFO);レチノイド、例えばレチノイン酸;カペシタビン;FOLFIRI(
フルオロウラシル、ロイコボリンおよびイリノテカン)、ならびに上記のもののいずれかの薬学的に許容される塩、酸または誘導体が挙げられる。本願では、1種または複数種の化学療法剤が使用されるか、または含まれる。例えば、ゲムシタビン、nab−パクリタキセル、ゲムシタビン/nab−パクリタキセル、カペシタビン、オキサリプラチン、およびカペシタビン/オキサリプラチンは、本出願の製剤と使用することができる。
and their inhibitors」(1999年)Nature Medicine 5巻:1359〜1364頁参照。
trile)(BAPN)などの化合物、ならびに、リシルオキシダーゼの阻害剤、ならびにコラーゲンの異常沈着に関連する疾患および状態の処置におけるそれらの使用に関する、1990年10月23日に発行された、Palfreymanらに対する「Inhibitors of lysyl oxidase」と題する米国特許第4,965,288号;様々な病理学的な線維性状態の処置のためにLOXを阻害する化合物に関する、1991年3月5日に発行された、Kaganらに対する「Anti−fibrotic
agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate」と題する米国特許第4,997,854号(これらは参考として本明細書に援用される)に開示の化合物が挙げられるが、これらに限定されない。さらなる例示的な阻害剤は、2−イソブチル−3−フルオロ−、クロロ−、またはブロモ−アリルアミンなどの化合物に関する、1990年7月24日に発行された、Palfreymanらに対する「Inhibitors of lysyl oxidase」と題する米国特許第4,943,593号;ならびに、例えば米国特許第5,021,456号;米国特許第5,5059,714号;米国特許第5,120,764号;米国特許第5,182,297号;米国特許第5,252,608号(2−(1−ナフチルオキシメチル(naphthyloxymemyl))−3−フルオロアリルアミンに関する);ならびに米国特許出願第2004/0248871号に記載されている(これらは参考として本明細書に援用される)。また、例示的な抗線維化剤として、リシルオキシダーゼの活性部位のカルボニル基と反応する第一級アミン、より具体的にはカルボニルと結合した後に共鳴によって安定化される生成物を生成するもの、例えば以下の第一級アミン:エミレンマミン(emylenemamine)、ヒドラジン、フェニルヒドラジンおよびそれらの誘導体、セミカルバジド、ならびに尿素誘導体、アミノニトリル、例えばベータ−アミノプロピオニトリル(BAPN)、または2−ニトロエチルアミン、不飽和もしくは飽和ハロアミン、例えば2−ブロモ−エチルアミン、2−クロロエチルアミン、2−トリフルオロエチルアミン、3−ブロモプロピルアミン、p−ハロベンジルアミン、セレノホモシステインラクトンが挙げられる。また、抗線維化剤は、細胞に貫入するかまたは貫入しない銅キレート剤である。例示的な化合物として、リシルオキシダーゼによってリシルおよびヒドロキシリシル残基の酸化的脱アミノ化に由来するアルデヒド誘導体を遮断する化合物などの間接的な阻害剤、例えばチオールアミン、特にD−ペニシラミンまたはその類似体、例えば2−アミノ−5−メルカプト−5−メチルヘキサン酸、D−2−アミノ−3−メチル−3−((2−アセトアミドエチル)ジチオ)ブタン酸、p−2−アミノ−3−メチル−3−((2−アミノエチル)ジチオ)ブタン酸、ナトリウム−4−((p−1−ジメチル−2−アミノ−2−カルボキシエチル)ジチオ)ブタンスルフレート(sulphurate)、2−アセトアミドエチル−2−アセトアミドエタンチオールスルファネート(sulphanate)、ナトリウム−4−メルカプトブタンスルフィネート(mercaptobutanesulphinate)三水和物が挙げられる。
romeximab)、エロツズマブ、エンシツキシマブ(ensituximab)、エルツマキソマブ(ertumaxomab)、エタラシズマブ(etaracizumab)、ファーレツズマブ(farietuzumab)、フィクラツズマブ(ficlatuzumab)、フィギツムマブ、フランボツマブ(flanvotumab)、フツキシマブ(futuximab)、ガニツマブ、ゲムツズマブ、ギレンツキシマブ(girentuximab)、グレンバツムマブ(glembatumumab)、イブリツモマブ、イゴボマブ(igovomab)、イマガツズマブ(imgatuzumab)、インダツキシマブ(indatuximab)、イノツズマブ、インテツムマブ(intetumumab)、イピリムマブ、イラツムマブ(iratumumab)、ラベツズマブ、レクサツムマブ、リンツズマブ、ロルボツズマブ(lorvotuzumab)、ルカツムマブ(lucatumumab)、マパツムマブ(mapatumumab)、マツズマブ、ミラツズマブ、ミンレツモマブ(minretumomab)、ミツモマブ(mitumomab)、モキセツモマブ(moxetumomab)、ナルナツマブ(narnatumab)、ナプツモマブ、ネシツムマブ、ニモツズマブ(nimotuzumab)、ノフェツモマブ(nofetumomabn)、オカラツズマブ(ocaratuzumab)、オファツムマブ、オララツマブ(olaratumab)、オナルツズマブ(onartuzumab)、オポルツズマブ(oportuzumab)、オレゴボマブ、パニツムマブ、パルサツズマブ(parsatuzumab)、パトリツマブ(patritumab)、ペムツモマブ(pemtumomab)、ペルツズマブ、ピンツモマブ(pintumomab)、プリツムマブ(pritumumab)、ラコツモマブ(racotumomab)、ラドレツマブ(radretumab)、リロツムマブ、リツキシマブ、ロバツムマブ(robatumumab)、サツモマブ(satumomab)、シブロツズマブ(sibrotuzumab)、シルツキシマブ、シムツズマブ(simtuzumab)、ソリトマブ(solitomab)、タカツズマブ(tacatuzumab)、タプリツモマブ(taplitumomab)、テナツモマブ(tenatumomab)、テプロツムマブ(teprotumumab)、ティガツズマブ、トシツモマブ、トラスツズマブ、ツコツズマブ(tucotuzumab)、ウブリツキシマブ(ublituximab)、ベルツズマブ、ボルセツズマブ(vorsetuzumab)、ボツムマブ(votumumab)、ザルツムマブ、オビヌツズマブ(obinutuzumab)、CC49および3F8が挙げられるが、これらに限定されない。例示的な治療用抗体は、さらに、放射性同位体粒子、例えばインジウムIn111、イットリウムY90、ヨウ素I−131で標識するか、またはそれらと組み合わせることができる。
07巻(1号)、265〜276頁に記載されている。
よびプレドニゾロン)、R−CHOP(リツキシマブとCHOP)、R−CVP(リツキシマブとCVP)、R−FCM(リツキシマブとFCM)、R−ICE(リツキシマブ−ICE)、ならびにR−MCP(R−MCP)が挙げられる。例えば、オキサリプラチンは、本出願の製剤と組み合わせて使用することができる。
作製の方法
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド(CYT−0387)は、米国特許第8,486,941号およびPCT出願WO2012/071612に記載の通り合成することができる。
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド(CYT−0387)二塩酸塩無水形態Iのメタノール中懸濁液に、モル過剰の水中塩酸を添加した。生じた固体を単離し、メタノールおよび水性の塩酸で洗浄して、CYT−0387二塩酸塩一水和物形態IIを生成した。
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド(CYT−0387)遊離塩基のメタノール中懸濁液に、モル過剰の濃塩酸を添加した。得られた懸濁液に、N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド(CYT−0387)二塩酸塩一水和物形態IIを任意選択で播種し、水を添加した。任意選択で播種したN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド(CYT−0387)二塩酸塩一水和物形態IIは、上に記載されている通り調製し得る。生じた固体を単離し、メタノールおよび水性の塩酸で洗浄して、CYT−0387二塩酸塩一水和物形態IIを生成した。
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド(CYT−0387)遊離塩基のメタノール中懸濁液に、1.0モル当量の濃塩酸を添加した。生じた固体を単離し、メタノールで洗浄して、CYT−0387一塩酸塩無水形態Iを生成した。
CYT−0387一塩酸塩無水形態Iの懸濁液を、水/THF(30%水;v/v)中で撹拌する。生じた固体を単離し、水/THF混合物で洗浄して、CYT−0387一塩酸塩無水形態IIIを生成した。
CYT−0387二塩酸塩一水和物形態IIの懸濁液をメタノール/水(30%水;v/v)中で撹拌する。生じた固体を単離し、メタノール/水混合物で洗浄して、CYT−0387一塩酸塩無水形態IIIを生成した。
Castle、DE、USA)を使用して評価した。約5〜10mgの固体試料を、各実験用のピンホールを開けた標準アルミニウム皿の中に配置し、50mL/minの窒素パージ下、10℃/minの速度で加熱した。データ分析を、Universal Analysis 2000バージョン4.7A(TA Instruments、New Castle、DE、USA)を使用して行った。融解熱分析を吸熱性融解ピークのシグモイド積分により行った。
CYT−0387二塩酸塩一水和物形態IIを、100mg、150mg、および200mgのCYT−0387遊離塩基に相当する量で含む錠剤は、本明細書に記載される方法により調製することができる。CYT−0387二塩酸塩一水和物形態IIを、100mg、150mg、200mg、250mg、および300mgのCYT−0387遊離塩基に相当する量で含む錠剤を調製した。以下の表4は、このような錠剤の製剤化を要約している。
により全部の分解生成物を判定することができなかったが、主要酸化分解生成物は観察されなかった(データは示されていない)。
0.5%または1.0%の没食子酸プロピルを有するCYT−0387形態IIの100mgの錠剤製剤と比較して、増加した安定性を呈したことを示した。25℃/60%RHでの研究の結果は、CYT−0387形態IIの分解がまた、0.2%、0.5%、および1.0%での没食子酸プロピルで減少したことを示した(データは示されていない)。25℃/60%RHでの分解プロファイルに対して観察された傾向は、40℃/75%RHで観察されたものと類似していた。すなわち、0%、0.5%、および1%没食子酸プロピルと比較して、錠剤製剤中のCYT−0387形態IIの増加した安定性が0.2%没食子酸プロピルにおいて観察された(データは示されていない)。これらを一緒に考えると、これらの結果は、これらの研究で試験した酸化防止剤およびそのパーセンテージの中で、0.2%での没食子酸プロピルが、CYT−0387二塩酸塩一水和物形態IIの安定性の最適な(optional)レベルを提供したことを示している。
CYT−0387二塩酸塩一水和物形態II(100、150、200、および300mgの遊離塩基に相当する用量)を含む錠剤、ならびにCYT−0387二塩酸塩無水形態I(300mgの遊離塩基に相当する用量)を含むカプセル剤を、健康な対象の第1相単回用量研究において評価した。
CYT−0387は、骨髄線維症を処置するための、現在調査中のヤヌスキナーゼ1および2(JAK1/JAK2)の選択的小分子阻害剤である。この研究は、ヒトにおける放射標識したCYT−0387の質量バランス/回復、代謝物プロファイル、薬物動態、および安全性を評価した。
5.8%;代謝物M19:5.2%;M5:2.7%;M28:2.5%;およびM20:2.3%)からなった。糞便に排泄された主構成成分は、CYT−0387(用量の12.6%)および他の代謝物(M21:用量の12.7%;共溶出するM19/M33:用量の7.1%)と共にM14(用量の21.4%)であった。糞便の中の残りの特定された10種の代謝物は、それぞれ用量の5%未満を占めた。尿の中で、代謝物M21は、主要の種(用量の11.5%)であり、低レベルの微量な代謝物が観察された。
CYT−0387は、ヤヌスキナーゼ1および2(JAK1/JAK2)の選択的小分子阻害剤であり、骨髄線維症を処置するために現在調査中である。骨髄線維症患者の第1/2相の研究において、300mgのCYT−0387カプセル剤1日1回が、好ましい利益:リスクプロファイルに基づく第3相用量として選択された。即時放出性錠剤製剤(CYT−0387錠剤)をさらなる臨床評価のために開発した。CYT−0387錠剤とカプセル剤との相対的バイオアベイラビリティーをこの研究で評価して、CYT−0387錠剤の第3相の用量を特定した。
本実施例は、M14(化合物3)、M8(化合物4)、M20(化合物12)、M21(化合物13)、化合物8および化合物10の調製について記載した。
l、1.1当量)、およびNMP(30mL)を充填した。得られた溶液を120℃で撹拌した。完了したら、反応物を冷却し、30mLの水性NaHCO3を添加した。得られたスラリーを濾過し、水ですすぎ、真空下、45℃で乾燥させて、以下の構造を有する4−(2−((4−(3−オキソモルホリノ)フェニル)アミノ)ピリミジン−4−イル)安息香酸(化合物3)を得た:
Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 5.2 Hz, 1H), 7.33 (d, J = 9.0 Hz, 2H), 4.19 (s, 2H), 3.98 (m, 2H), 3.71 (m, 2H)
(d, J = 8.4 Hz, 2H), 7.85 (d, J = 6.9 Hz, 2H), 7.51 (d, J = 4.8 Hz, 1H), 7.41 (bs, 1H), 7.32 (d, J = 8.9 Hz, 2H), 7.06 (bs, 1H), 4.19 (s, 2H), 3.98 (m, 2H), 3.85 (d, J = 5.8 Hz, 2H), 3.72 (m,
2H);HRMS(ESI+):C23H23N6O4[M+H]+の計算値:447.
18、実測値:447.19。
2H), 8.89 (d, J = 5.2 Hz, 1H), 9.39 (t, J = 5.5 Hz, 1H).
HRMS(ESI+):C13H10ClN4O[M+1]の計算値:273.15、実測値273.25。
J = 5.1 Hz, 1H), 8.24 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 5.2 Hz, 1H), 6.58
(d, J = 8.9 Hz, 2H), 5.20 (t, J = 5.8 Hz, 1H), 4.66 (t, J = 5.4 Hz, 1H), 4.35 (d, J = 5.4 Hz, 2H), 3.57 (q, J = 5.8 Hz, 2H),
3.08 (q, J = 5.8 Hz, 2H);HRMS(ESI+):C21H21N6O2[M+1]の計算値:389.17、実測値:389.27。
(d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 5.1 Hz, 1H), 6.56 (d, J = 8.4 Hz, 2H), 4.78 (bs, 2H), 4.36 (d, J = 6.4 Hz, 2H);HRMS(ESI+):C19H17N6Oの計算値[M+H]:345.15、実測値345.28。
1H), 8.57 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 8.1 Hz, 2H), (8.04,
J = 8.5 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 5.0 Hz, 1H), 4.36 (d, J = 5.3 Hz, 2H), 2.03
(s, 3H);HRMS(ESI+):C21H19N6O2[M+1]の計算値:387.16、実測値:387.28。
HRMS(ESI+):C23H21N6O3[M+1]の計算値:429.17、実測値:429.0。
この研究は、HepG2細胞、肝細胞癌細胞株中のヘプシジン産生に対するCYT−0387の効果を特徴付けた。骨形態形成タンパク質(BMP)は、構成的に活性のあるII型BMP受容体キナーゼ(BMPR−キナーゼ)とI型BMPR−キナーゼとの連結を促進することによって、肝細胞中のヘプシジンの転写誘導に関与していることが示されている(Andriopoulosら、Nat Genet、2009年、41巻(4号):482〜7頁;Zhaoら、J Clin Invest、2013年、123巻(6号):2337〜43頁)。これは、
結果としてI型BMPR−キナーゼのリン酸化および活性化を生じ、それに続くイフェクターSMADタンパク質(SMAD1/5/8)のダウンストリーム活性化、それに続くSMAD4と共同での核転送を生じる(Wrana、Cold Spring Harb Perspect Biol、
2013年、5:a011197)。
対する選択性を判定した。結果は表10に要約されており、CYT−0387は、ALK3と比較して、ALK2およびALK6に対してより高い親和性および阻害性活性を有することを示した。
転移性の非小細胞肺がん(NSCLC)または転移性の膵臓の管腺癌(PDA)の処置に対するCYT−0387製剤の効果を調べるために研究を行う。1つの研究では、白金ベースの化学療法に失敗した、転移性のカーステンラット肉腫ウイルス癌遺伝子ホモログ(KRAS)変異したNSCLCを有する患者に、28日間の少なくとも1回の処置サイクルの間、CYT−0387製剤を単独で、トラメチニブを単独で、またはCYT−0387とトラメチニブの組合せを投与する。CYT−0387製剤(CYT−0387二塩酸塩一水和物形態IIを錠剤フォーマットで含み得る)は、1日1回または2回、00mg、150mg、200mg、250mg、または300mgの用量で経口投与することができ、トラメチニブ(N−(3−{3−シクロプロピル−5−[(2−フルオロ−4−ヨードフェニル)アミノ]−6,8−ジメチル−2,4,7−トリオキソ−3,4,6,7−テトラヒドロピリド[4,3−d]ピリミジン−1(2H)−イル}フェニル)アセトアミドという化学名で言及することもできる)は、1日1回、0.5mg、1mg、または2mgの用量で経口投与することができる。研究には、KRAS−変異した転移性または再発性の非小細胞肺がんを有する患者が加わり、これらの患者は、RECIST v1.1、およびEastern Cooperative Oncology Group(ECOG)Performance Statusの0または1として測定可能病変を有し、白金ベースの化学療法での以前の処置、または2つのラインまでの以前の化学療法を受けたことがある。
(項1)
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド二塩酸塩一水和物形態II;
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド一塩酸塩無水形態I;および
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド一塩酸塩無水形態III
からなる群から選択される化合物。
(項2)
結晶形態である、上記項1に記載の化合物。
(項3)
前記結晶形態は、N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド二塩酸塩一水和物形態IIである、上記項1から2に記載の結晶形態。
(項4)
結晶が、T=100°Kにおいて、a=10.2837(6)Å、b=10.4981(6)Å、c=11.5143(7)Å、α=83.297(2)°、β=87.649(2)°、γ=67.445(2)°の単位格子パラメータ、および三斜晶P−1空間群を有する、上記項3に記載の結晶形態。
(項5)
図5に実質的に示されている粉末X線回折(XRPD)パターンによって特徴付けられる、上記項3に記載の結晶形態。
(項6)
約7.7°、19.3°、24.0°、25.7°、および29.6°2−θ±0.2°2−θにおいてピークを有する粉末X線回折(XRPD)パターンによって特徴付けられる、上記項3に記載の結晶形態。
(項7)
図8に実質的に示されている示差走査熱量測定(DSC)パターンによって特徴付けられる、上記項3に記載の結晶形態。
(項8)
図14に実質的に示されている動的蒸気吸着(DVS)パターンによって特徴付けられる、上記項3に記載の結晶形態。
(項9)
前記結晶形態は、結晶性のN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド一塩酸塩無水形態Iである、上記項2に記載の結晶形態。
(項10)
図6に実質的に示されている粉末X線回折(XRPD)パターンによって特徴付けられる、上記項9に記載の結晶形態。
(項11)
約13.5°、20.9°、26.1°、26.6°、および28.3°2−θ±0.2°2−θにおいてピークを有する粉末X線回折(「XRPD」)パターンによって特徴付けられる、上記項9に記載の結晶形態。
(項12)
図9に実質的に示されている示差走査熱量測定(DSC)パターンによって特徴付けられる、上記項9に記載の結晶形態。
(項13)
前記結晶形態は、結晶性のN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド一塩酸塩無水形態IIIである、上記項2に記載の結晶形態。
(項14)
図7に実質的に示されている粉末X線回折(XRPD)パターンによって特徴付けられる、上記項13に記載の結晶形態。
(項15)
約12.7°、14.6°、17.8°、19.7°、および23.3°2−θ±0.2°2−θにおいてピークを有する粉末X線回折(「PXRD」)パターンによって特徴付けられる、上記項13に記載の結晶形態。
(項16)
図10に実質的に示されている示差走査熱量測定(DSC)パターンによって特徴付けられる、上記項13に記載の結晶形態。
(項17)
上記項1から16のいずれかに記載の化合物を含む医薬組成物。
(項18)
上記項1に記載の化合物が、N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド二塩酸塩一水和物形態IIである、上記項17に記載の医薬組成物。
(項19)
N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド二塩酸塩一水和物形態IIが、50mg、100mg、150mg、または200mgの遊離塩基N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミドに相当する量で存在する、上記項17から18に記載の医薬組成物。
(項20)
錠剤の形態である、上記項17から19のいずれか一項に記載の医薬組成物。
(項21)
単回経口投与後、
260〜405ng/mLのN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミドの範囲のC max 、
2,057〜3,214ng・hr/mLのN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミドの範囲のAUC inf 、または
260〜405ng/mLのN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミドの範囲のC max と、2,057〜3,214ng・hr/mLのN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミドの範囲のAUC inf の両方
を提供する、上記項17から20のいずれかに記載の医薬組成物。
(項22)
単回経口投与後、300mgの遊離塩基N−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミドに相当する量でN−(シアノメチル)−4−(2−(4−モルホリノフェニルアミノ)ピリミジン−4−イル)ベンズアミド二塩酸塩無水形態Iを含む剤形と実質的に類似の薬物動態プロファイルを提供する、上記項21に記載の医薬組成物。
(項23)
必要とする対象に、有効量の上記項18に記載の医薬組成物を投与することを含む、ヤヌスキナーゼ(JAK)に関連する疾患の処置のための方法であって、前記疾患が、骨髄増殖性疾患が真性赤血球増加症(PV)、骨髄線維症、血小板血症、本態性血小板血症(ET)、特発性骨髄線維症、慢性骨髄性白血病、全身性肥満細胞症(SM)、慢性好中球性白血病(CNL)、骨髄異形成症候群(MDS)および全身性肥満細胞疾患(SMCD)からなる群から選択される上記項31の方法からなる群から選択される骨髄増殖性疾患である、方法。
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