JP5474043B2 - (+)−2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンを含む固形物形態、その組成物およびその使用 - Google Patents
(+)−2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンを含む固形物形態、その組成物およびその使用 Download PDFInfo
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Description
本明細書で提供されるのは、(+)−2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンを含む固形物形態、上記固形物形態を含む組成物、上記固形物形態を製造する方法および様々な疾患および/または障害の治療のためのその使用方法である。
腫瘍壊死因子α(TNF−α)は、免疫賦活剤に応答して単核食細胞によって主として放出されるサイトカインである。TNF−αは、分化、動員、増殖、およびタンパク質分解など、大部分の細胞の過程を促進することができる。低レベルで、TNF−αは、感染性媒介物、腫瘍および組織損傷に対する保護を与える。しかし、TNF−αはまた、多くの疾患においてある種の役割を果たしている。患者に投与するとき、TNF−αは、炎症、発熱、心血管の影響、出血、凝固、および急性感染およびショック状態の間に見られるものと類似の急性期反応を引き起こすまたは悪化させる。増強されたまたは調節されないTNF−α産生は、例えば、固形腫瘍および血液性腫瘍などの癌;うっ血性心不全などの心疾患;ならびにウイルス性疾患、遺伝病、炎症性疾患、アレルギー性疾患、および自己免疫疾患などの、多数の疾患および医学上の状態に関与しているとされてきた。
本明細書で使用される場合、「化合物A」という用語は、カラムが150mm×4.6mm Ultron Chiral ES−OVSキラルHPLCカラム(Agilent Technology)であり、溶離液がpH3.5の15:85エタノール:20mM KH2PO4であり、観測波長が240nmであるとき、約25.4分でHPLCカラムから得られる鏡像異性体として純粋な(+)−2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンを意味する。化合物Aの1H NMRスペクトルは実質的に以下の通りである:δ (CDCl3); 1.47 (t, 3H); 2.26 (s, 3H); 2.87 (s, 3H); 3.68-3.75 (dd, 1H); 3.85 (s, 3H); 4.07-4.15 (q, 2H); 4.51-4.61 (dd, 1H); 5.84-5.90 (dd, 1H); 6.82-8.77 (m, 6H); 9.46 (s, 1H).化合物Aの13C NMRスペクトルは実質的に以下の通りである:δ (DMSO-d6); 14.66; 24.92; 41.61; 48.53; 54.46; 55.91; 64.51; 111.44; 112.40; 115.10; 118.20; 120.28; 124.94; 129.22; 131.02; 136.09; 137.60; 148.62; 149.74; 167.46; 169.14; 169.48.メタノールに溶解した化合物Aは、偏光面を(+)方向に回転させる。
本発明は、その(−)鏡像異性体が実質的にない、2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンの(+)鏡像異性体である立体異性体として純粋な化合物A、ならびに使用する新規な方法および立体異性体として純粋な化合物Aおよび/または化合物Aを含む固形物形態を含む組成物に関する。例えば、本発明は、化合物Aのin vitroおよびin vivoでの使用、化合物Aの医薬組成物への取り込みおよび様々な疾患および障害の治療および予防に有用な単回投与製剤を包含する。TNF−αレベルの低減またはPDE4の阻害によって寛解する疾患および障害は、当技術分野で周知であり、本明細書に記載されている。本発明の具体的な方法はTNF−α阻害薬として用いた化合物に伴う有害作用を低減するまたは回避する。本発明の他の具体的な方法は、ラセミ体の2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンの使用に伴う有害作用を低減するまたは回避する。
本明細書におけるいくつかの実施形態は、上記で示した化学構造を有する化合物Aを含む固形物形態を提供する。ラセミ体の2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンは、参照により本明細書に組み込まれる米国特許第6,020,358号の方法を用いて容易に調製される。2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンの(+)鏡像異性体である化合物Aは、参照により本明細書に組み込まれる米国特許第6,962,940号に記載の方法を含めた当業者に明らかである任意の方法に従って調製することができる。
本明細書におけるいくつかの実施形態は、化合物Aの形態A結晶形を提供する。いくつかの実施形態において、化合物Aの形態Aは、それだけには限らないが、アセトン、エタノール、およびそれらの混合物を含む溶媒系を含めた、様々な溶媒から得ることができる。いくつかの実施形態において、形態Aは、高速冷却結晶化方法を用いて得ることができる。
本明細書におけるいくつかの実施形態は、化合物Aの形態B結晶形を提供する。いくつかの実施形態において、化合物Aの形態Bは、それだけには限らないが、2−プロパノール、アセトン、アセトニトリル、エタノール、酢酸エチル、ヘプタン、メタノール、メチルエチルケトン、メチルt−ブチルエーテル、塩化メチレン、n−ブタノール、酢酸n−ブチル、テトラヒドロフラン、トルエン、水およびそれらの2つ以上を含む混合物を含む溶媒系を含めた、様々な溶媒から得ることができる。例えば、いくつかの実施形態では、形態Bは、エタノール:水1:1を含む溶媒系から結晶化することによって得ることができ、例えば、約25℃でエタノール:水1:1の溶媒系を蒸発し、その後形態Bを単離するステップを含む方法によって得ることができる。例えば、いくつかの実施形態では、形態Bは、アセトン:エタノール1:1を含む溶媒系から結晶化することによって得ることができ、例えば、アセトン:エタノール1:1で約25℃で約2日間化合物Aを含む固形物形態をスラリー化し、その後形態Bを単離するステップを含む方法によって得ることができる。
本明細書におけるいくつかの実施形態は、化合物Aの形態C結晶形を提供する。いくつかの実施形態において、化合物Aの形態Cは、それだけには限らないが、アセトン、アセトニトリル、エタノール、ヘプタン、メタノール、メチルエチルケトン、テトラヒドロフラン、トルエン、水、およびそれらの2つ以上を含む混合物を含む溶媒系を含めた、様々な溶媒系から得ることができる。例えば、いくつかの実施形態では、形態Cは、トルエンを含む溶媒系から結晶化することによって得ることができ、例えば、貧溶媒としてトルエンを使用し、その後形態Cを単離するステップを含む方法によって得ることができる。
本明細書におけるいくつかの実施形態は、化合物Aの形態D結晶形を提供する。いくつかの実施形態において、化合物Aの形態Dは、それだけには限らないが、塩化メチレンを含む溶媒系を含めた、様々な溶媒から得ることができる。例えば、いくつかの実施形態では、形態Dは、塩化メチレンを含む溶媒系から結晶化することによって得ることができ、例えば、塩化メチレンを蒸発し、その後形態Dを単離するステップを含む方法によって得ることができる。
本明細書におけるいくつかの実施形態は、化合物Aの形態E結晶形を提供する。いくつかの実施形態において、化合物Aの形態Eは、それだけには限らないが、アセトン、アセトニトリル、ヘプタン、塩化メチレン、およびそれら2つ以上を含む混合物を含む溶媒系を含めた、様々な溶媒から得ることができる。例えば、いくつかの実施形態では、形態Eは、アセトニトリルを含む溶媒系から結晶化することによって得ることができ、例えば、アセトニトリルを蒸発し、その後形態Eを単離するステップを含む方法によって得ることができる。
本明細書におけるいくつかの実施形態は、化合物Aの形態F結晶形を提供する。いくつかの実施形態において、化合物Aの形態Fは、それだけには限らないが、アセトン、エタノール、水、およびそれら2つ以上を含む混合物を含む溶媒系を含めた、様々な溶媒から得ることができる。例えば、いくつかの実施形態では、形態Fは、エタノールおよび/または水を含む溶媒系から結晶化することによって得ることができ、例えば、化合物Aを含む固形物形態をエタノールおよび/または水を含む溶媒系に接触させ、その後形態Fを単離するステップを含む方法によって得ることができる。
本明細書におけるいくつかの実施形態は、化合物Aの形態G結晶形を提供する。いくつかの実施形態において、化合物Aの形態Gは、それだけには限らないが、酢酸エチルを含む溶媒系を含めた、様々な溶媒から得ることができる。例えば、いくつかの実施形態では、形態Gは、酢酸エチルを含む溶媒系から結晶化することによって得ることができ、例えば、化合物Aを含む固形物形態を酢酸エチルを含む溶媒系に接触させ、その後形態Gを単離するステップを含む方法によって得ることができる。
本発明は、患者におけるTNF−αレベルの低減によって寛解する疾患または障害を治療する、予防するまたは管理する方法であって、例えば、本明細書で提供される、化合物Aの形態A、化合物Aの形態B、化合物Aの形態C、化合物Aの形態D、化合物Aの形態E、化合物Aの形態F、化合物Aの形態G、または化合物Aの非晶質の形態など、化合物Aを含む1種または複数の固形物形態の治療上有効量または予防上有効量を、かかる治療、予防または管理を必要とする患者に投与するステップを含む方法を包含する。
ミン錯体;ポルフィマーナトリウム;ポルフィロマイシン;プレドニゾン;プロピルビスアクリドン;プロスタグランジンJ2;プロテアソーム阻害薬;タンパク質Aに基づく免疫モジュレーター;プロテインキナーゼC阻害薬;微細藻類のプロテインキナーゼC阻害薬;プロテインチロシンホスファターゼ阻害薬;プリンヌクレオシドホスホリラーゼ阻害薬;プルプリン;ピラゾロアクリジン;ピリドキシル化ヘモグロビンポリオキシエチレン複合体;rafアンタゴニスト;ラルチトレキセド;ラモセトロン;rasファルネシルプロテイントランスフェラーゼ阻害薬;ras阻害薬;ras−GAP阻害薬;脱メチル化レテリプチン;エチドロン酸レニウムRe 186;リゾキシン;リボザイム;RIIレチンアミド;ログレチミド;ロヒツキン(rohitukine);ロムルチド;ロキニメックス;ルビギノンB1;ルボキシル;サフィンゴール;サイントピン;SarCNU;サルコフイトールA;サルグラモスチム;Sdi1模倣体;セムスチン;老化由来阻害薬1;センスオリゴヌクレオチド;シグナル伝達阻害薬;シグナル伝達モジュレーター;単鎖抗原結合タンパク質;シゾフィラン;ソブゾキサン;ナトリウムボロカプタート(sodium borocaptate);フェニル酢酸ナトリウム;ソルベロール(solverol);ソマトメジン結合タンパク質;ソネルミン(sonermin);スパルフォシン酸;スピカマイシンD;スピロムスチン;スプレノペンチン;スポンギスタチン1;スクアラミン;幹細胞阻害薬;幹細胞分裂阻害薬;スチピアミド;ストロメライシン阻害薬;スルフィノシン;超活性血管作用性小腸ペプチドアンタゴニスト;スラジスタ(suradista);スラミン;スウェインソニン;合成グリコサミノグリカン;タリムスチン;タモキシフェンメチオジド;タウロムスチン;タザロテン;テコガランナトリウム;テガフール;テルラピリリウム(tellurapyrylium);テロメラーゼ阻害薬;テモポルフィン;テモゾロミド;テニポシド;テトラクロロデカオキシド;テトラゾミン;タリブラスチン;チオコラリン;トロンボポエチン;トロンボポエチン模倣体;サイマルファシン;サイモポエチン受容体アゴニスト;チモトリナン;甲状腺刺激ホルモン;スズエチルエチオプルプリン;チラパザミン;二塩化チタノセン;トプセンチン;トレミフェン;全能性幹細胞因子;翻訳阻害薬;トレチノイン;トリアセチルウリジン;トリシリビン;トリメトレキサート;トリプトレリン;トロピセトロン;ツロステリド;チロシンキナーゼ阻害薬;チロホスチン;UBC阻害薬;ウベニメクス;尿生殖洞由来増殖抑制因子;ウロキナーゼ受容体アンタゴニスト;バプレオチド;バリオリンB;ベクター系、赤血球遺伝子療法;ベラレソール;ベラミン;ベルジン(verdin);ベルテポルフィン;ビノレルビン;ビンキサルチン(vinxaltine);バイタクシン;ボロゾール;ザノテロン;ゼニプラチン;ジラスコルブ;およびジノスタチンスチマラマーが含まれる。
化合物Aを含む1種または複数の固形物形態を含む医薬組成物および単回投与製剤は、本明細書で提供される。また、本明細書で提供されるのは、化合物Aを含む1種または複数の固形物形態を含む医薬組成物および単回投与製剤を調製する方法である。例えば、いくつかの実施形態では、本明細書で提供される固形物形態を含む個別の剤形または本明細書で提供される固形物形態を用いて調製された個別の剤形は、経口、(直腸、経鼻、または経膣を含めた)粘膜、(皮下、筋肉内、ボーラス注入、動脈内、または静脈内を含めた)非経口、舌下、経皮、口腔、または局所投与に適し得る。
経口投与に適している本発明の医薬組成物は、それだけには限らないが、錠剤(例えば、咀嚼可能な錠剤)、カプレット、カプセル剤、および液体(例えば、味付きのシロップ剤)などの分離した剤形として提供することができる。かかる剤形は、あらかじめ定めた量の有効成分を含み、当業者に周知の薬学の方法によって調製することができる。一般に、Remington’s Pharmaceutical Sciences、第18版、Mack Publishing、Easton PA(1990年)を参照のこと。
本明細書で提供される化合物Aを含む固形物形態は、制御放出手段によってまたは当業者によく知られている送達デバイスによって投与することができる。例としては、それだけには限らないが、米国特許第3,845,770号;第3,916,899号;第3,536,809号;第3,598,123号;および第4,008,719号、第5,674,533号、第5,059,595号、第5,591,767号、第5,120,548号、第5,073,543号、第5,639,476号、第5,354,556号、および第5,733,566号に記載されているものが含まれ、そのそれぞれが参照により本明細書に組み込まれる。かかる剤形は、割合を変えて所望の放出プロファイルを提供するための、例えば、ヒドロプロピルメチルセルロース、他のポリマーマトリックス、ゲル剤、透過膜、浸透圧系、多層コーティング、微小粒子、リポソーム、ミクロスフェア、またはそれらの組合せを用いて1種または複数の有効成分の緩徐放出または制御放出を提供することができる。本明細書に記載したものを含めて、当業者に知られている適当な制御放出配合物は、本発明の有効成分と共に用いるために容易に選択することができる。したがって、本発明は、それだけには限らないが、制御放出のために適合されている、錠剤、カプセル剤、ゲルキャップおよびカプレットなどの経口投与に適した単回投与製剤を包含する。
非経口剤形は、皮下、(ボーラス注入を含めた)静脈内、筋肉内、および動脈内を含むがそれだけには限らない様々な経路によって、患者に投与することができる。これらの投与によって、通常、汚染物に対する患者の自然防御を回避するため、非経口剤形は、好ましくは、無菌であるまたは患者に投与する前に減菌することができる。非経口剤形の例には、それだけには限らないが、注射にすぐに使用できる液剤、薬学的に許容される注射用ビヒクルにすぐに溶解または懸濁できる乾燥製品、注射にすぐに使用できる懸濁剤、および乳剤が含まれる。
本発明の経皮、局所、および粘膜剤形には、それだけには限らないが、点眼剤、スプレー剤、エアゾール剤、クリーム剤、ローション剤、軟膏剤、ゲル剤、液剤、乳剤、懸濁剤、または当業者に知られている他の形態が含まれる。例えば、Remington’s Pharmaceutical Sciences、第16版および第18版、Mack Publishing、Easton PA(1980年および1990年);およびIntroduction to Pharmaceutical Dosage Forms、第4版、Lea & Febiger、Philadelphia(1985年)を参照のこと。口腔内の粘膜組織を治療するのに適した剤形は、洗口剤としてまたは経口ゲル剤として配合することができる。さらに、経皮剤形には、皮膚に適用することができるおよびある特定の期間装着して有効成分の所望の量を浸透させることが可能である「リザーバータイプ」または「マトリックスタイプ」のパッチが含まれる。
保湿剤または湿潤剤は、望むなら、医薬組成物および剤形に加えることもできる。かかる追加成分の例は、当技術分野でよく知られている。例えば、Remington’s Pharmaceutical Sciences、第16版および第18版、Mack Publishing、Easton PA(1980年および1990年)を参照のこと。
本発明は、医師によって用いられるとき、適当な量の有効成分の患者への投与を単純化することができるキットを包含する。
本出願は、下記明細書で提供される実施例を含めた、米国特許第6,962,940号(2005年11月8日発行)の全体を参照により組み込む。
1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチルアミン(1.0g、3.7mmol)および3−アセトアミドフタル無水物(751mg、3.66mmol)の酢酸(20mL)中の撹拌した溶液を還流下で15時間加熱した。溶媒を真空中で除去してオイルを生成した。得られたオイルのクロマトグラフィーにより、生成物を黄色の固形物として得た(1.0g、収率59%):融点、144℃;1H NMR (CDCl3) δ: 1.47 (t, J=7.0 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CH), 3.85 (s, 3H, CH3), 4.11 (q, J=7 Hz, 2H, CH2), 5.87 (dd, J=4.3, 10.5 Hz, 1H, NCH), 6.82-6.86 (m, 1H, Ar), 7.09-7.11 (m, 2H, Ar), 7.47 (d, J= 7 Hz, 1H, Ar), 7.64 (t, J= 8 Hz, 1H, Ar), 8.74 (d, J= 8 Hz, 1H, Ar), 9.49 (br s, 1H, NH); 13C NMR (CDCl3) δ: 14.61, 24.85, 41.54, 48.44, 54.34, 55.85, 64.43, 111.37, 112.34, 115.04, 118.11, 120.21, 124.85, 129.17, 130.96, 136.01, 137.52, 148.54, 149.65, 167.38, 169.09, 169.40; 元素分析C22H24NO7Sの計算値: C, 57.38; H, 5.25; N, 6.08. 実測値: C, 57.31; H, 5.34; N, 5.83.
3−アミノフタル酸の調製
10%Pd/C(2.5g)、3−ニトロフタル酸(75.0g、355mmol)およびエタノール(1.5L)を、窒素雰囲気中で2.5L Parr水素添加装置に充填した。水素を反応容器に55psiまで充填した。50〜55psiの水素圧力を維持しながら、混合物を13時間振り混ぜた。水素を放出し、混合物を窒素で3回パージした。懸濁液をセライト層でろ過し、メタノールですすいだ。ろ液を真空中で濃縮した。得られた固形物をエーテル中で再びスラリー化し、真空ろ過によって単離した。固形物を真空中で一定の重量まで乾燥し、3−アミノフタル酸54g(収率84%)を黄色の生成物として得た。1H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (br, s, 2H); 13C-NMR (DMSO-d6) δ: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
1Lの3口丸底フラスコは、機械式撹拌機、温度計、および冷却器を装備させ、3−アミノフタル酸(108g、596mmol)および無水酢酸(550mL)で充填した。反応混合物を3時間加熱還流し、約25℃まで冷却し、さらに0〜5℃まで追加で1時間冷却した。結晶性固体を真空ろ過によって収集し、エーテルで洗浄した。固形生成物を真空中で周囲温度で一定の重量まで乾燥し、3−アセトアミドフタル無水物75g(収率61%)を白色の生成物として得た。1H-NMR (CDCl3) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).
3Lの3口丸底フラスコは、機械式撹拌機、温度計、および冷却器を装備させ、2−(3−エトキシ−4−メトキシフェニル)−1−(メチルスルホニル)−エト−2−イルアミン(137.0g、500mmol)、N−アセチル−L−ロイシン(52g、300mmol)、およびメタノール(1.0L)を充填した。撹拌したスラリーを1時間加熱還流した。撹拌した混合物を周囲温度まで放冷し、追加で3時間周囲温度で撹拌を続けた。スラリーをろ過し、メタノール(250L)で洗浄した。固形物を風乾し、次いで、真空中で周囲温度で一定の重量まで乾燥し、粗生成物(85.8%ee)109.5g(収率98%)を得た。粗固形物(55.0g)およびメタノール(440mL)を1時間還流させ、室温まで冷却し、追加の3時間周囲温度で撹拌した。スラリーをろ過し、フィルターケークをメタノール(200mL)で洗浄した。固形物を風乾し、次いで真空中で30℃で一定の重量まで乾燥し、(S)−2−(3−エトキシ−4−メトキシフェニル)−1−(メチルスルホニル)−エト−2−イルアミン−N−アセチル−L−ロイシン塩(98.4%ee)49.6g(90%回収)を得た。キラルHPLC(Agilent Technologies社からの1/99 EtOH/20mM KH2PO4、pH7.0、Ultron Chiral ES−OVS、150mm×4.6mm、0.5mL/分、240nm):18.4分(S−異性体、99.2%)、25.5分(R−異性体、0.8%)。
500mLの3口丸底フラスコは、機械式撹拌機、温度計、および冷却器を装備させた。反応容器を(S)−2−(3−エトキシ−4−メトキシフェニル)−1−(メチルスルホニル)−エト−2−イルアミンN−アセチル−L−ロイシン塩(25g、56mmol、98%ee)、3−アセトアミドフタル無水物(12.1g、58.8mmol)、および氷酢酸(250mL)で充填した。混合物を終夜還流し、次いで、<50℃まで冷却した。溶媒を真空中で除去し、残留物を酢酸エチルに溶解した。得られた溶液を水(250mL×2)、飽和の水性NaHCO3(250mL×2)、食塩水(250mL×2)で洗浄し、硫酸ナトリウムで乾燥した。溶媒を真空中で蒸発させ、残留物をエタノール(150mL)およびアセトン(75mL)を含む2成分の溶媒から再結晶化した。固形物を真空ろ過によって単離し、エタノール(100mL×2)で洗浄した。生成物を真空中で60℃で一定の重量まで乾燥し、S−{2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセトアミドイソインドリン−1,3−ジオン}19.4g(収率75%)を98%eeで得た。キラルHPLC(Agilent Technology社からの15/85 EtOH/20mM KH2PO4、pH5、Ultron Chiral ES−OVS、150mm×4.6mm、0.4mL/分、240nm): 25.4分(S−異性体、98.7%)、29.5分(R−異性体、1.2%)。1H-NMR (CDCl3) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H); 13C-NMR (DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
ヒト全血LPS誘発TNF−αアッセイ
新たに採取した全血をPBMCの代わりに用いたことを除いて、ヒトの全血によるLPS誘発TNF−α産生を阻害する化合物の能力を、基本的に、ヒトPBMCにおけるLPS誘発TNF−αアッセイについて以下に記載された通り測定した(Mullerら、1999年、Bioorg.&Med.Chem.Lett.、9巻:1625〜1630頁)。化合物Aのヒト全血LPS誘発TNF−αIC50=294nM。
化合物を前述した方法に従って本動物モデルで試験した(Corralら、1996年、Mol.Med.、2巻:506〜515頁)。化合物AのマウスLPS誘発血清TNF−α阻害(ED50、mg/kg、p.o.)=0.05。
リポ多糖類(LPS)は、TNF−αを含めた多くの炎症誘発性サイトカインの産生を誘発する、大腸菌(E.coli)などのグラム陰性菌によって産生される内毒素である。末梢血液単核細胞(PBMC)中で、LPSに応答して産生されたTNF−αは、総PBMCのおよそ5〜20%を含む単球に由来する。化合物を、前述したヒトのPBMCから得られたLPS誘発TNF−α産生を阻害する能力について試験した(Mullerら、1996年、J.Med.Chem.、39巻:3238頁)。正常なドナーから得られたPBMCをFicoll Hypaque(Pharmacia、Piscataway、NJ、USA)密度遠心法によって得た。細胞を10%AB±ヒト血清(Gemini Bio−products、Woodland、CA、USA)、2mM L−グルタミン、100U/mlペニシリン、および100μg/mlストレプトマイシン(Life Technologies)を補充したRPMI(Life Technologies、Grand Island、NY、USA)中で培養した。
炎症性疾患の経過中、TNF−α産生は、しばしば細菌由来のLPSによってではなくサイトカインIL−1βによって刺激される。化合物を、ヒトのPBMCから得られたIL−1β誘発TNF−α産生を阻害する能力について、PBMCを発生源である白血球ユニット(Sera−Tec Biologicals、North Brunswick、NJ、USA)からFicoll−Paque Plus(Amersham Pharmacia、Piscataway、NJ、USA)の遠心によって単離し、熱失活した10%ウシ胎児血清(Hyclone)、2mM L−グルタミン、100U/mlペニシリン、および100mg/mlストレプトマイシン(完全培地)を含むRPMI−1640培地中(BioWhittaker、Walkersville、Maryland、USA)、96ウェル組織培養プレートに3×105細胞/ウェルで播種し、CO2 5%で加湿した培養器中に37℃で1時間最終DMSO濃度0.1%で10μM、2μM、0.4μM、0.08μM、0.016μM、0.0032μM、0.00064μM、および0μMの化合物でデュプリケートで前処理し、次いで、50ng/mlの組換え型ヒトIL−1β(Endogen)で18時間で刺激した以外、LPS誘発TNF−α産生について前述した通り試験した。化合物AのIL−β誘導TNF−αIC50=83nM。
PDE1、2、3、5、および6酵素アッセイ
化合物のPDE4に対する特異性をウシのPDE1、ヒト血小板から得られたヒトのPDE2、PDE3、およびPDE5(Hidaka and Asano、1976年、Biochem.Biophys.Acta、429巻:485頁、およびNicholsenら、1991年、Trends Pharmaco.Sci.、12巻:19頁)、ならびにウシ網膜かん体外節の分節から得られたPDE6(Baehrら、1979年、J.Biol.Chem.、254巻:11669頁、およびGillespieら、1989年、Mol.Pharm.、36巻:773頁)に対して単一の濃度(10μM)で試験することによって検定した。結果を表1に示す。
PDE7は、主にT細胞中および骨格筋に発現するcAMP選択的PDEである。IL−2およびIFN−γなどのT細胞由来サイトカインは、PDE7阻害によって潜在的に調節可能である。PDE7を、前述した通り陰イオン交換クロマトグラフィーによってHut78ヒトT細胞から精製した(Bloom and Beavo、1996年、Proc.Natl.Acad.Sci.USA、93巻:14188〜14192頁)。化合物を、PDE4について表1で記載した通り10nM cAMPの存在下でPDE7調製に対して試験した。
PDE4(U937細胞由来)酵素アッセイ
PDE4酵素を、前述した通りゲルろ過クロマトグラフィーによってU937ヒト単核球細胞から精製した(Mullerら、1998年、Bioorg.&Med.Chem.Lett.8巻:2669〜2674頁)。ホスホジエステラーゼ反応を、pH7.5の50mMトリスHCl、5mM MgCl2、1μM cAMP、10nM[3H]−cAMP中で30℃で30分間行い、煮沸することによって停止させ、1mg/mlヘビ毒で処理し、記載された通りAG−IXSイオン交換樹脂(BioRad)を用いて分離した(Mullerら、1998年、Bioorg.&Med.Chem.Lett.8巻:2669〜2674頁)。反応は、利用可能な基質を15%未満消費した。結果を表1に示す。
SEB誘発IL−2およびIFN−γ産生
ブドウ球菌エンテロトキシンB(SEB)は、グラム陽性菌の黄色ブドウ球菌(Staphylococcus aureus)に由来するスーパー抗原である。SEBは、特定のT細胞受容体Vβ鎖を発現するT細胞に特異的な都合がよい生理的刺激をもたらす。(およそ50%のT細胞からなる)ヒトPBMCを、前述した通り発生源である白血球ユニットから単離し、完全培地中、96ウェル組織培養プレートに3×105細胞/ウェルで播種し、CO2 5%で加湿した培養器中に37℃で1時間最終DMSO濃度0.1%で10μM、2μM、0.4μM、0.08μM、0.016μM、0.0032μM、0.00064μM、および0μMの化合物でデュプリケートで前処理し、次いで、100ng/ml SEB(Sigma Chemical Co.、St.Louis、MO、USA)で18時間刺激した。IL−2およびIFN−γレベルをELISA(R&D Systems、Minneapolis、MN、USA)によって測定した。化合物AのIL−2 IC50=291nM。化合物AのIFN−γ IC50=46nM。
PGE2誘発cAMP上昇
プロスタグランジンE2(PGE2)は、単球、T細胞および他の白血球上でプロスタノイド受容体に結合し、その結果、細胞内cAMPレベルを上昇させ、細胞応答の阻害をもたらす。PGE2およびPDE4阻害薬の組合せは、これらの細胞タイプ中のcAMPレベルを相乗的に上昇させ、PGE2の存在下でPDE4阻害薬よって引き起こされるPBMC中のcAMPの上昇は、このPDE4阻害薬の阻害活性に比例する。細胞内cAMPをヒトのPBMC中で以下のように測定した。PBMCを、前述した通り単離し、RPMI−1640中の1ウェル当たり1×106細胞で96ウェルプレートに播種した。細胞を、デュプリケートでCO2 5%で加湿した培養器中に37℃で1時間DMSO最終濃度2%で100μM、10μM、1μM、0.1μM、0.01μM、および0μMの化合物で前処理した。次いで、細胞をPGE2(10μM)(Sigma)で1時間刺激した。細胞を0.1N最終濃度のHClで溶解してホスホジエステラーゼ活性を阻害し、プレートを−20℃で凍結した。生成されたcAMPをcAMP(低pH)イムノアッセイキット(R&D Systems)を用いて測定した。ラセミ体のPBMCのcAMP EC50は3.09μMである。化合物AのPBMC cAMP EC50は1.58μMである。
N−ホルミル−メチオニン−ロイシン−フェニルアラニン(fMLF)は、好中球を活性化させて速やかに脱顆粒し、移動し、内皮細胞に付着し、ロイコトリエンLTB4を放出する細菌由来ペプチドであり、アラキドン酸代謝の生成物およびそれ自体好中球の化学誘引物質である。化合物を、以下の修正を加えて、前述した通り(Hatzelmann and Schudt、2001年、J.Pharm.Exp.Ther.、297巻:267〜279頁)fMLF誘発好中球LTB4産生を遮断する能力について試験した。好中球を、前述した通り単離し、pH7.2の10mM HEPESを含む、カルシウムまたはマグネシウム(BioWhittaker)を含まないリン酸緩衝食塩水に再懸濁し、1.7×106細胞/ウェルの濃度で96ウェル組織培養プレート中に播種した。細胞を50μMチメロサール(Sigma)/1mM CaCl2/1mM MgCl2で15分間37℃でCO25%で処理し、次いで、最終DMSO濃度0.01%で1000nM、200nM、40nM、8nM、1.6nM、0.32nM、0.064nMおよび0nMの化合物で10分間デュプリケートで処理した。好中球を1μM fMLFで30分間刺激し、次いで、メタノール(最終濃度20%)を加えて溶解し、ドライアイス/イソプロパノール浴で10分間凍結した。LTB4含有量を競合的なLTB4 ELISA(R&D Systems)によって測定するまで、ライセートを−70℃で貯蔵した。結果を表2に示す。
ザイモサンA、または加熱殺菌された酵母サッカロマイセス−セレビシエ(Saccharomyces cerevisiae)は、好中球表面で接着分子Mac−1に結合し、食作用、細胞活性化およびIL−8産生を誘発する。ザイモサン誘発IL−8産生を、以下の修正を加えて前述した通り(Auら、1998年、Brit.J.Pharm.、123巻:1260〜1266頁)測定した。ヒト好中球を、前述した通り精製し、完全培地中で3×105細胞/ウェルで96ウェル組織培養プレート中に播種し、最終DMSO濃度0.1%で10μM、2μM、0.4μM、0.08μM、0.016μM、0.0032μM、0.00064μM、および0μMの化合物で1時間37℃でCO25%でデュプリケートで処理した。次いで、好中球を、オプソニン化されていない煮沸されたザイモサンA(Sigma)で2.5×105粒子/ウェルで18時間刺激した。上澄みを収集し、ELISA(R&D Systems)によってIL−8について試験した。結果を表2に示す。
好中球上のCD18/CD11b(Mac−1)発現を、以下の修正を加えて前述した通り(Derianら、1995年、J.Immunol.、154巻:308〜317頁)測定した。好中球を、前述した通り単離し、次いで、完全培地中で1×106細胞/mlで再懸濁し、最終DMSO濃度0.1%で10μM、1μM、0.1μM、0.01μM、および0μMの化合物で10分間37℃でCO25%でデュプリケートで前処理した。次いで、細胞を30nM fMLFで30分間刺激し、次いで、4℃まで冷却した。細胞を、Fc受容体を遮断するためにウサギIgG(Jackson ImmunoResearch Labs、West Grove、PA、USA)(10μg/1×106細胞)で処理し、CD18−FITCおよびCD11b−PE(Becton Dickinson)で染色し、FACSCaliburのフローサイトメトリー法によって分析した。刺激のないCD18/CD11b発現(平均蛍光)をすべてのサンプルから差し引いて阻害曲線を得、IC50値を算出した。結果を表2に示す。
ヒト臍静脈内皮細胞(HUVEC)を、以下の修正を加えて前述した通り(Derianら、1995年、J.Immunol.、154巻:308〜317頁)、好中球の接着のための基質として用いた。HUVEC細胞を、Anthrogenesis社(Cedar Knolls、NJ、USA)から入手し、好中球をサイトカラシンBで処理しなかった。細胞を、最終DMSO濃度0.1%で10μM、1μM、0.1μM、0.01μM、0.001μMおよび0μMの化合物で10分間デュプリケートで処理し、500nM fMLFで30分間刺激し、PBSでデュプリケートで洗浄してから、FLX800プレートリーダー(Bio−Tek Instruments、Winooski、VT、USA)で蛍光を測定した。結果を表2に示す。
平衡溶解度をpH7.4の水性緩衝液中で測定した。pH7.4の緩衝液を0.07M NaH2PO4溶液のpHを10N NaOHで7.4に調整することによって調製した。溶液のイオン強度は0.15であった。少なくとも粉末1mgを緩衝液1mlと合わせて>1mg/mlの混合物を作製した。これらのサンプルを>2時間振り混ぜ、室温で終夜静置した。次いで、サンプルを、まずサンプルで飽和させた0.45μmNylonシリンジフィルターでろ過した。ろ液を連続してデュプリケートでサンプリングした。ろ液を50%メタノールで調製した標準に対してHPLCによってアッセイした。化合物Aは、ラセミ混合物よりも3.5倍大きい水の溶解性を有する。測定された溶解性 化合物A=0.012mg/mL;ラセミ混合物=0.0034mg/mL。
覚醒フェレットモデルを用いて、経口(p.o.)経路で投与したとき、PDE4阻害薬の抗炎症作用、催吐作用および挙動の影響を調査している。これらの実験から、各PDE4阻害薬の治療係数(TI)は決定することができる。TIは、催吐エピソードおよび挙動の変化を引き起こすための閾値用量を、抗炎症用量(LPS誘発好中球増加症の50%阻害を引き起こす用量)で除することによって算出されている。
雄フェレット(Mustela Pulorius Euro、体重1〜2kg)。フェレットは、Bury Green FarmまたはMisay Consultancyによって供給された。輸送後、動物をホールディング室で7日間以上置いて順応させた。食餌は、自由に与える、食物をペレット化したSDS diet Cと1週間に3回与えるWhiskers(商標)キャットフードから構成された。水は、低温殺菌された動物用飲料水であり、毎日交換した。
PDE4阻害薬を、最初に1〜10g/kgの用量で経口投与(p.o.)したが、続いて、TIが10またはそれよりも高いかどうかを確立するために30mg/kgまで経口投与し、かつ/または好中球増加症の50%阻害を引き起こす最小限の用量を確立するために低用量で経口投与した。フェレットは、終夜絶食させたが、水を自由に利用できるようにさせた。動物に、咽頭の奥を通り抜けて食道に通す15cmの投薬用針を用いてビヒクルまたはPDE4阻害薬を経口で投与した。投与後、動物は、Perspexドアが付いたホールディングケージに戻して観察され、水を自由に利用できるようにさせた。投与後、動物を絶えず観察し、いかなる嘔吐または挙動の変化も記録した。動物は、p.o.投与の60〜90分後食物を利用できるようにさせた。
化合物またはビヒクル対照によるp.o.投与の30分後、フェレットを密封したPerspex容器に入れ、LPS(100μg/ml)のエアゾール剤に10分間曝露した。LPSのエアゾール剤をネビュライザー(DeVilbiss、USA)によって生成し、これをPerspex曝露チャンバー内に向けた。10分の曝露時間の後、動物をホールディングケージに戻して、水を自由に利用させ、その後の段階で、食物を自由に利用できるようにさせた。観察は、p.o.投与後少なくとも2.5時間続け、催吐エピソードおよび挙動の変化を記録した。
LPS曝露の6時間後、動物を、腹腔内に投与した過量のペントバルビトンナトリウムによって死亡させた。次いで、気管をポリプロピレン管を用いてカニューレ処置し、肺を20mlのヘパリン化(10ユニット/ml)リン酸緩衝食塩水(PBS)でデュプリケートで洗浄した。
末端の血液サンプル(10ml)を経胸壁心臓穿刺によって除去した。血液を2,500rpmで15分間回転させ、血漿を除去し−20℃で貯蔵した。脳も除去し化合物含有量の分析のために−20℃で凍結した。
気管支肺胞洗浄検査(BAL)サンプルを1,500rpmで5分間遠心した。上澄みを除去し、得られた細胞ペレットを1mlのPBSに再懸濁した。再懸濁した液体の細胞スメアを調製し、リーシュマン染色で染色して異なる細胞計数を可能にした。総細胞数を残りの再懸濁したサンプルを用いてカウントした。これにより、BAL中の好中球の総数を決定した。
1.LPS誘発肺好中球増加症の%阻害。
2.催吐エピソード−嘔吐およびレッチングの数をカウントした。
3.挙動の変化−以下の挙動の影響を示した。すなわち、流涎、あえぎ呼吸、マウスクロウイング、伏せ姿勢(flattened posture)、運動失調、アーチ型の背中および後退り(backward walking)である。挙動の変化を重症度評価(軽度、中等度または重度)を適用することによって半定量化した。
4.TIを、肺好中球増加症を50%以上まで抑制することが判明した最低用量で除した、催吐エピソードを引き起こさないことが判明した最高用量として算出した。
PDE4のp.o.投与後、フェレットを少なくとも2時間観察し、催吐エピソード(嘔吐およびレッチング)および挙動の変化を記録した。
これらの実験から、治療係数(TI)を、各化合物について催吐エピソードを誘発する閾値用量を肺好中球増加症を阻害するED50値で除することによって決定した。TI算出を表4にまとめて示す。化合物Aは、TIが12であり、1mg/kgの抗炎症用量で催吐エピソードを引き起こさなかった。
化合物Aは、ヒト細胞モデルにおける炎症誘発性サイトカイン産生をダウンレギュレートする新規な経口剤である。化合物Aにより、TNF−α、IL−12およびIFN−γ産生を低下することならびにIL−10の産生を上昇することが示されている。
乾癬は、免疫調節性化合物による潜在的な療法を可能にするサイトカインおよびケモカインの調節不全に強く関連している。この第2相、非盲検、一群、パイロット試験を、重度のプラーク型乾癬患者における化合物Aの生物活性を評価するために設計した。臨床成績の追加の評価を実施して重度のプラーク型乾癬を治療する化合物Aの潜在的な効力を評価した。
この第2相、多施設、ランダム化、二重盲検、プラセボ対照、平行群、用量−比較試験によって、全身治療の候補者である中等度から重度のプラーク型乾癬を伴う対象において化合物Aの有効性および安全性を評価した。
5.12.1.実験方法論
溶解性試験。化合物Aの秤量したサンプル(約100mg)を試験溶媒約2mLで処理した。使用した溶媒は、試薬またはHPLC用であった。得られた混合物を少なくとも24時間約25℃でかき混ぜた。すべての固形物を目視検査によって溶解したとき、推定される溶解性を算出した。溶液を生成するために用いた溶媒の総体積に基づいたこれらの実験から溶解性を推定した。実際の溶解性は、大量の溶媒の使用または溶解のゆっくりとした速度によって算出したものよりも高くなり得る。実験中に溶解が起こらなかった場合、溶解性を重量的に測定した。体積既知のろ液を蒸発乾固し、残留物の重量を測定した。
固形物形態スクリーニングに記載した通りに生成したサンプルを、通常、粉末X線回折(XRPD)によって分析した。XRPDをThermo ARL X’TRA(商標)粉末X線回折計で1.54ÅのCu Kα放射線を用いて実施した。装置は、ファインフォーカス型X線管を装備させた。X線発生装置の電圧およびアンペア数を、それぞれ45kVおよび40mAに設定した。ダイバージェンススライスを4mmおよび2mmに設定し、測定スライスを0.5mmおよび0.2mmに設定した。回折した放射線をペルティエ冷却Si(Li)固体検出器によって検出した。通常、2.40°/分(0.5秒/0.02°ステップ)で1.5°2θ〜40°2θまでの1θ−2θ連続スキャンを使用した。焼結アルミナ標準を用いてピーク位置を確認した。一般に、XRPDピークの位置は、測定ごとに約±0.2°2θで個別に変わることが予想された。一般に、当技術分野で理解されるように、第1のパターンの特徴的なピークが第2のパターンの特徴的なピークとほぼ同じ位置に位置する場合、2つのXRPDパターンは互いに一致する。当技術分野で理解されるように、2つのXRPDパターンが一致するか否かまたは2つのXRPDパターンの個別のピークが一致するか否かを決定することは、それだけには限らないが、とりわけ、好ましい配向、相の不純物、結晶化度の程度、粒度、回折計装置一式の違い、XRPDデータ収集パラメーターの変動、および/またはXRPDデータ処理のばらつきなどの個別の変数およびパラメーターを考慮する必要があり得る。2つのパターンが一致するか否かの決定は、眼および/またはコンピュータ分析によって実施することができる。これらの方法およびパラメーターを用いて収集したおよび分析したXRPDパターンの例を、本明細書で、例えば、図1、図5、図9、図13、図17、図21および図25として提供する。
固形物形態スクリーニング試験中に調製された化合物Aを含む固形物形態には、形態A、B、C、D、E、F、Gおよび非晶質の形態が含まれた。形態A、B、C、D、E、FおよびGのそれぞれについての代表的なXRPDパターン、DSCプロット、TGAプロットおよびDVSプロットを本明細書で図1〜図28として提供する。
表13は、0サイズカプセル剤中で、化合物Aを含む固形物形態200mg、すなわち、約40重量パーセントを含む単回投与単位のためのバッチ配合物および単回用量配合物を図示する。
表14は、化合物Aを含む固形物形態100mgを含むバッチ配合物および単回投与単位配合物を図示する。
Claims (29)
- 実質的に純粋な形態Bの結晶であり、2θで10.1°、13.5°、20.7°および26.9°のピークを含む粉末X線回折パターンを有する、式(I)の化合物
の鏡像異性体として純粋な固形結晶形態。 - 2θで12.4°、15.7°、18.1°および24.7°のピークをさらに含む粉末X線回折パターンを有する、請求項1に記載の固形結晶形態。
- 2θで16.3°、22.5°、26.2°および29.1°のピークをさらに含む粉末X線回折パターンを有する、請求項2に記載の結晶形態。
- 図5に示す粉末X線回折パターンを有する、請求項1に記載の結晶形態。
- 実質的に純粋な形態Bの結晶であり、154℃の開始温度による吸熱イベントを含む示差走査熱量測定プロットを有する、式(I)の化合物
の鏡像異性体として純粋な固形結晶形態。 - 図6に示す示差走査熱量測定プロットを有する、請求項5に記載の結晶形態。
- 25℃から140℃まで加熱したとき1%未満の質量損失を含む熱重量分析プロットを有する、請求項5に記載の結晶形態。
- 質量損失が0.25%未満である、請求項7に記載の結晶形態。
- 図7に示す熱重量分析プロットを有する、請求項1または5に記載の結晶形態。
- 相対湿度0%から95%までの相対湿度の増加を受けたとき1%未満の質量の増加を示す、請求項1または5に記載の結晶形態。
- 質量増加が0.6%である、請求項10に記載の結晶形態。
- 図8に示す動的蒸気収着を有する、請求項1または5のいずれか一項に記載の結晶形態。
- 4週間40℃および相対湿度75%への曝露に対して安定である、請求項1または5に記載の結晶形態。
- 請求項1〜13のいずれか一項に記載の結晶形態を10mg〜200mg含む、経口投与に適した医薬組成物。
- 前記医薬組成物が、前記結晶形態を10mg〜100mg含む、請求項14に記載の医薬組成物。
- 前記医薬組成物が、カプセル形態である、請求項14に記載の医薬組成物。
- 前記カプセルが、前記結晶形態を10mg含む、請求項16に記載の医薬組成物。
- 前記カプセルが、前記結晶形態を20mg含む、請求項16に記載の医薬組成物。
- 前記カプセルが、前記結晶形態を25mg含む、請求項16に記載の医薬組成物。
- 前記カプセルが、前記結晶形態を50mg含む、請求項16に記載の医薬組成物。
- 前記医薬組成物が、錠剤形態である、請求項14に記載の医薬組成物。
- 前記錠剤が、前記結晶形態を10mg含む、請求項21に記載の医薬組成物。
- 前記錠剤が、前記結晶形態を20mg含む、請求項21に記載の医薬組成物。
- 前記錠剤が、前記結晶形態を25mg含む、請求項21に記載の医薬組成物。
- 前記錠剤が、前記結晶形態を50mg含む、請求項21に記載の医薬組成物。
- 前記医薬組成物が、乾癬、乾癬性関節炎、関節リウマチまたはベーチェット病の治療に用いられる、請求項14に記載の医薬組成物。
- 前記医薬組成物が、乾癬の治療に用いられる、請求項14に記載の医薬組成物。
- 前記医薬組成物が、乾癬性関節炎の治療に用いられる、請求項14に記載の医薬組成物。
- 前記医薬組成物が、ベーチェット病の治療に用いられる、請求項14に記載の医薬組成物。
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PCT/US2008/004021 WO2009120167A1 (en) | 2008-03-27 | 2008-03-27 | Solid forms comprising (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, compositions thereof, and uses thereof |
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JP (1) | JP5474043B2 (ja) |
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CN (1) | CN102046167A (ja) |
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ES (1) | ES2476252T3 (ja) |
HR (1) | HRP20140609T1 (ja) |
IL (3) | IL208216A0 (ja) |
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JP2014114308A (ja) * | 2014-01-31 | 2014-06-26 | Celgene Corp | (+)−2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンを含む固形物形態、その組成物およびその使用 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2014114308A (ja) * | 2014-01-31 | 2014-06-26 | Celgene Corp | (+)−2−[1−(3−エトキシ−4−メトキシフェニル)−2−メチルスルホニルエチル]−4−アセチルアミノイソインドリン−1,3−ジオンを含む固形物形態、その組成物およびその使用 |
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RU2471782C2 (ru) | 2013-01-10 |
MX359839B (es) | 2018-10-12 |
DK2276483T3 (da) | 2014-06-10 |
BRPI0822398B8 (pt) | 2018-05-29 |
KR20140142323A (ko) | 2014-12-11 |
ZA201006663B (en) | 2012-02-29 |
BRPI0822398B1 (pt) | 2018-01-16 |
EP2695616A1 (en) | 2014-02-12 |
KR20100132045A (ko) | 2010-12-16 |
AU2008353468A1 (en) | 2009-10-01 |
CN102046167A (zh) | 2011-05-04 |
HRP20140609T1 (hr) | 2014-08-15 |
AU2008353468B2 (en) | 2015-08-06 |
BRPI0822398A2 (pt) | 2014-11-18 |
WO2009120167A1 (en) | 2009-10-01 |
IL208216A0 (en) | 2010-12-30 |
EP2276483A1 (en) | 2011-01-26 |
EP2276483B1 (en) | 2014-05-07 |
JP2011515463A (ja) | 2011-05-19 |
NZ588104A (en) | 2012-11-30 |
IL247411A0 (en) | 2016-11-30 |
SI2276483T1 (sl) | 2014-08-29 |
IL227991A0 (en) | 2013-09-30 |
KR20150038547A (ko) | 2015-04-08 |
PL2276483T3 (pl) | 2014-09-30 |
MX2010010454A (es) | 2010-12-20 |
CY1115361T1 (el) | 2017-01-04 |
ES2476252T3 (es) | 2014-07-14 |
RU2010143907A (ru) | 2012-05-10 |
PT2276483E (pt) | 2014-07-25 |
CA2718601A1 (en) | 2009-10-01 |
NO2015017I1 (no) | 2015-07-27 |
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