JP6022657B2 - キナーゼカスケードを調節するための組成物および方法 - Google Patents
キナーゼカスケードを調節するための組成物および方法 Download PDFInfo
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- JP6022657B2 JP6022657B2 JP2015189232A JP2015189232A JP6022657B2 JP 6022657 B2 JP6022657 B2 JP 6022657B2 JP 2015189232 A JP2015189232 A JP 2015189232A JP 2015189232 A JP2015189232 A JP 2015189232A JP 6022657 B2 JP6022657 B2 JP 6022657B2
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Description
本願は、2006年12月28日に出願された米国仮特許出願第60/877,762号に対する優先権を主張する。この開示は、その全体が参考として援用される。
本発明は、実質的に純粋なN‐ベンジル‐2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトアミド(KX2‐391)、およびその塩の合成のための組成物およびプロセスに関する。本発明は、そのような組成物の使用の方法にも関する。
例えば、本発明は以下の項目を提供する。
(項目1)
HPLCによって判定される場合に98.0%を超える純度を持つ、KX2‐391、その塩、溶媒和物、水和物、またはプロドラッグを有する組成物。
(項目2)
前記KX2‐391は、99.0%の純度を持つ、項目1の組成物。
(項目3)
前記KX2‐391は、99.5%の純度を持つ、項目1の組成物。
(項目4)
前記KX2‐391は、99.6%の純度を持つ、項目1の組成物。
(項目5)
前記KX2‐391は、99.7%の純度を持つ、項目1の組成物。
(項目6)
前記組成物は、塩化エチル、エタノール、酢酸エチル、ヘプタン、アニソール、パラジウム、およびこれらの組み合わせから選択される、2%未満の不純物を含有する、項目1の組成物。
(項目7)
薬学的に許容される担体または賦形剤をさらに有する、項目1に記載の組成物。
(項目8)
プロテインキナーゼシグナル伝達カスケードの1つ以上の構成要素を調節するための薬剤の製造における、項目1〜項目7のいずれか1項に記載の組成物の使用。
(項目9)
キナーゼは、セリンキナーゼ、焦点接着キナーゼ、およびチロシンキナーゼから選択される、項目8に記載の使用。
(項目10)
前記チロシンキナーゼは、Srcファミリープロテインキナーゼである、項目9に記載の使用。
(項目11)
前記化合物は、経口的に投与されるものである、項目8に記載の使用。
(項目12)
前記化合物は、局所的に投与されるものである、項目8に記載の使用。
(項目13)
前記キナーゼカスケードの前記構成要素は、過剰増殖性疾患、癌、前癌状態、骨粗しょう症、心臓血管疾患、免疫系機能障害、2型糖尿病、肥満、眼疾患、黄斑浮腫、慢性神経因性疼痛、聴力損失、および移植拒絶反応から選択される病気または疾患の発現に関与する、項目8に記載の使用。
(項目14)
チロシンキナーゼ阻害によって調節される病気または疾患の治療または予防のための薬剤の製造における、項目1〜項目7のいずれか1項に記載の組成物の使用であって、項目1に記載の化合物、またはその塩、溶媒和物、水和物、あるいはプロドラッグと、少なくとも1つの薬学的に許容される賦形剤とを有する医薬組成物を、それを必要とする被験体に投与するステップを含む、該治療または予防は、項目1に記載の化合物、またはその塩、溶媒和物、水和物、あるいはプロドラッグと、少なくとも1つの薬学的に許容される賦形剤とを有する医薬組成物を、それを必要とする被験体に投与するステップを含むことを特徴とする、使用。
(項目15)
チロシンキナーゼ阻害によって調節される前記病気または疾患は、癌、前癌状態、過剰増殖性疾患、および微生物感染から選択される細胞増殖性疾患である、項目14に記載の使用。
(項目16)
前記微生物感染は、細菌、真菌、寄生虫、またはウイルス感染である、項目15に記載の使用。
(項目17)
前記細胞増殖性疾患は、乾癬、糖尿病性網膜症、および黄斑変性症から選択される過剰増殖性疾患である、項目15に記載の使用。
(項目18)
前記細胞増殖性疾患は癌である、項目15に記載の使用。
(項目19)
前記癌は固形腫瘍である、項目18に記載の使用。
(項目20)
前記癌は、肺、乳房、大腸、卵巣、脳、肝臓、膵臓、もしくは前立腺の癌、または悪性黒色腫、または黒色腫以外の皮膚癌である、項目18の使用。
(項目21)
前記癌は、乳癌、大腸癌、または肺癌である、項目20の使用。
(項目22)
前記癌は、血液腫瘍、血液悪性疾患、小児白血病、リンパ腫、多発性骨髄腫、ホジキン病、リンパ球または皮膚起源のリンパ腫、急性もしくは慢性白血病、リンパ芽球性白血病、急性骨髄性白血病、慢性骨髄性白血病、形質細胞腫、リンパ系腫瘍、またはAIDSに併う癌である、項目18の使用。
(項目23)
前記細胞増殖性疾患は、表皮嚢腫、皮様嚢腫、脂肪腫、腺腫、毛細血管腫、皮膚血管腫、リンパ管腫、母斑病変、奇形腫、腎腫、筋線維腫症、骨形成性腫瘍、または異形成腫瘤である、項目15の使用。
(項目24)
HPLCによって判定される場合98.0%を超える純度を持つ、KX2‐391.2HClを有する組成物。
便宜上、明細書、実施例、および付属の請求項において使用される特定の用語をここにまとめる。
4‐(2‐(4‐(4,4,5,5‐テトラメチル[1,3,2]ジオキサボロラン‐2‐イル)‐フェノキシ)エチル)モルホリンの合成:
この実施例で概説する合成は、中間スケール反応で使用されうる。少なくとも50gのバッチのKX2‐391の二塩酸塩の調製をスキーム1に示す。線形合成は6ステップで構成され、7番目のステップは試薬の1つである6‐フルオロピリジン‐3‐イルボロン酸(商業的にも入手可能である)の調製である。シークエンスの総収率は35%で、平均収率は83%、最も低い収率ステップの収率は68%であった。7つのステップのうち、クロマトグラフィーを必要としたものは1つだけであった。下記に示す手順は、70gスケールで実施した。
機械式攪拌装置、アダプター付き温度計、冷却器、および窒素流入口(冷却器の上部)を備えた5L容量の三つ口丸底フラスコに、1(140.7g、0.756モル)、4‐ブロモフェノール(130.6g、0.755モル)、無水K2CO3粉末(367.6g、2.66モル、3.5当量)、およびアセトニトリル(1.3L)を入れた。混合物を80℃で(一晩)激しく攪拌し(フラスコの底にブレードが触れるように)、その後DCM(500mL)およびヘプタン(200mL)で希釈して、セライトでろ過した。蒸発乾固(回転エバポレーター後、高真空)して、2を淡黄色の油として得た(216.00g、100%の収率、96.3%AUC、3.7%の未反応のブロモフェノールを含有)。この材料を、さらなる精製を行わずに使用することができた。
攪拌し冷却(ドライアイス‐アセトン浴)した無水[TBME](620mL、機械式攪拌装置、アダプター付き温度プローブ、および窒素流入口を備えた3L容量の三つ口丸底フラスコ中の)に、2MのBuLi(352mL、0.704モル、1.2当量)を(シリンジで)加えた。この急速に攪拌し冷却(<−75℃)した混合物に、3(102.2g、0.581モル)を含む無水TBME(100mL)の溶液を13分間にわたって加え、この間内部温度は−62℃に上昇した。反応物をさらに45分間攪拌し(温度を−62℃から−80℃の間に維持した)、その後、4ポーションのトリイソプロピルボラート(全量180g、0.957モル、1.65当量)を急速に連続添加した。添加終了時、内部温度は−33℃に上昇した。冷水浴でさらに45分間攪拌した後(内部温度は−33℃から−65℃に低下)、冷水浴を取り除き、50分間の間に攪拌混合物は自然に−22℃まで上昇した。15分間にわたって6℃まで昇温した(水浴で)後で、攪拌反応混合物を氷水浴内に静置し、窒素雰囲気下でNaOH(160g)を含む冷却水溶液(500mL)でクエンチした。添加が終了すると、内部温度は20℃であった。この混合物を室温で1.5時間攪拌した。水層を除去し、約350mLの濃HClでpH7の中性とした後、EtOAcで抽出した(3×1L)。ここでpHは8〜9であるため、約15mLの濃HClを使用して水層をpH7に調節し、酢酸エチルでさらに抽出した(2×1L)。集めたEtOAc抽出物を乾燥し(Na2SO4)、ろ過し、濃縮して約150mLの量にした。濃縮物を振り混ぜながら、ヘプタンをポーションで加え(全量は300mL)、生成物の沈殿/結晶化がもたらされた。ろ過、ヘプタンでの固体の洗浄(100mL、300mL、その後さらに300mL)、風乾によって、オフホワイトの固体として表題化合物を得て(68.6g、収率79〜90%*、LC純度96.4%、NMRでは、およそ5.5%w/wのヘプタンが示された)、これをさらなる精製を行わずに使用した。LC/MSは、これが下記の2つの構成要素の混合物であることを示しており、分子量が大きい構成成分の強度が大きかった(*注:反応物の収率は、ボロン酸が唯一の構成成分であると仮定すれば79%であり、環状ボレートが唯一の成分であると仮定すれば90%である)。
機械式攪拌装置、温度計およびアダプター、冷却器、ならびに窒素流入口(冷却器の上部に)を備えた2L容量の三つ口丸底フラスコに、2(110.7g、0.387モル)、4(71.05g、0.477モル、1.23当量)、およびDME(700mL)を入れた。得られた攪拌溶液を、攪拌溶液に窒素の急速気流を5分間通すことによって脱気し、その後、Na2CO3(121.06g、1.142モル、3当量)を含むH2Oの脱気溶液(250mL)および固形Pd(PPh3)4(19.8g、0.044当量)を加えた。最後の添加の直後に、反応混合物上部のヘッドスペースを窒素でパージし、その後混合物を80〜85℃(内部温度)で7時間攪拌し、次いで室温まで冷却した。水層がないため、上清をデカンテーションし、無機塩が残った(吸着水とともに)。無機塩が入った反応フラスコを50%のジクロロメタン/酢酸エチル(2×250mL)で洗浄し、洗浄液をデカンテーションした上清に加えた。これらの集めた有機物質を乾燥し(Na2SO4)、ろ過し、蒸発乾固して暗褐色の油とした(148g)。この油に、150gの50%ヘプタン/イソプロピルアルコール(IPA)を加え、振り混ぜて冷却した(氷水浴で)後、結晶化が始まった。さらなるヘプタン(50g)を加えて、得られた固体をろ過し、洗浄し、風乾して48gの淡褐色の固体を得た。ろ液を蒸発乾固した後、得られた混合物を100mLの50%ヘプタン/IPA中で振り混ぜ、その後さらにヘプタン(約100mL)を添加し、栓をして冷凍庫内に静置して結晶化させた。得られた固体を濾過し、ヘプタンで洗浄し、風乾して61gの粘着性の固体を得た。得られたろ液を蒸発させて油(34g)を得たが、これは、Ph3P=Oをはじめとする著しく極性の低い不純物を含有していたため、2NのHCl(240mL)およびEtOAc(220mL)の間にこれを分配した。底部の水層を除去して、K2CO3でpH7〜8に中性化しながらEtOAcとともに攪拌した。EtOAc層を乾燥し、ろ過し、蒸発乾固した(22g)。48g、61g、および22gのポーションについて、DCMに充填したシリカゲル(1.1Kg)でクロマトグラフィーを行った。DCM(400mL)、50%DCM/EtOAc(5L)、次いで漸増する量のMeOH/Et3N(1.5%MeOH/1%Et3Nから始まり、5%MeOH/3%Et3Nで終了)を含む50%DCM/EtOAc(8L)で溶出して、77.68gの粘調性の油(純度98.0%)を得て、これをヘプタン(300mL)中で振り混ぜるとすぐに結晶化した。ろ過、ヘプタンでの洗浄、および風乾によって75.55g(98.7%AUC)の固体5を得た。上記の34gのサンプルについて行ったようにそれらを洗浄し、その後蒸発結晶化することによって、Ph3P=Oを含む初期のクロマトグラフィー画分からさらなる純粋な5(全量で3.9g、98.6〜99.3%AUC)を得た。5の総収率は79.5g(68%)であった。
3L容量の三つ口丸底フラスコに、機械式攪拌装置、温度計およびアダプター、追加の漏斗、および窒素流入口(追加の漏斗の上部、バブラーで陽圧に)を取り付けた。バブラーを通過する窒素の急速気流下で、ストッパーを取り除き、フラスコにKHMDS(415.8g、2.08モル)、次いで無水THF(1L)を入れた。攪拌し冷却した(氷/メタノール浴、溶液の内部温度は−8℃であった)KHMDS/THF溶液に、MeCN(70g)を含むTHF(110mL)の溶液を22分間にわたって滴下しながら加え、その直後に5(79.06g、0.262モル)を含むTHF(400mL)の溶液を比較的急速(4分間)に加え、その後、反応混合物の内部温度は10℃に達した。引き続き冷却すると(1時間)、内部温度は−6℃となり、TLCでは、反応は完了したようであった。さらに30分後(内部温度は−3℃)、反応混合物を飽和食塩水(1L)でクエンチし、EtOAc(500mL)で希釈した。水層を除去した後、有機溶液を乾燥し(Na2SO4)、ろ過し、蒸発乾固(油になる)に続いて、IPA(150mL)に完全に溶解し、ヘプタン(300mL)で希釈し、種結晶(約100mgの粗製油をIPA(約150mg)に溶解することで調製した)を加え、ヘプタン(約2.5mL)で希釈し、一晩静置した。結晶固体を崩すように攪拌した後、固体をろ過し、250mLの2:1ヘプタン/IPAで洗浄した後ヘプタンで複数回洗浄し、風乾して64.38g(収率76%)の表題化合物6を結晶性褐色固体として得た(LC純度は99.3%)。純度が低い別の5.88gの材料をろ液から得た。
2L容量の1つ口の丸底フラスコに、6(64.00g、0.198モル)およびMeOH(360g)を入れた後で、ゆっくりと注意深くH2SO4(240g)を滴下しながら加え、得られた均一な溶液を反応が完了するまで(25時間で未反応の出発原料は0.8%)、3.5%のArCH2CO2Hとともに還流しながら(115℃の油浴)攪拌した。短時間の冷却後、MgSO4(75g)を加えて混合物を振り混ぜ、さらに45分間静置した(この時点の組成は、96.3%の生成物、0.8%の未反応の出発原料、および2.5%のArCH2CO2H)。次いで反応混合物を、急速に攪拌して冷却した(氷水浴)DCM(2L)およびK2CO3(450g)を含む水(600mL)の溶液の混合物にゆっくりと加えた。得られたエマルションを一晩静置した。有機溶液の透明部分を吸引し、残りの部分を水とDCMで繰り返し処理し、透明な有機物質を吸引したもとの部分と合わせる。集めた有機物質を乾燥し(Na2SO4)、ろ過し、約1.2Lの量に濃縮し、続いて300mLの5%EtOAc(ヘプタン中)、次にヘプタン(300mL)を加え、混合物を再度濃縮(回転エバポレーターで加熱して)してDCMを除去した。この時点で15mLのEtOAcを加えて、結晶化が始まるまで熱い混合物を振り混ぜ、結晶化がほぼ完了するまでひきつづき振り混ぜた後、静置して室温まで冷却して完全に結晶化させた。次に固体をろ過し、300mLの5%EtOAc(ヘプタン中)およびヘプタン(100mL)で洗浄した後で完全に風乾して、57.74g(82%収率)の7を淡黄色の固体として得た(98.9%AUC)。別の3.94gの他の物質が混入していない生成物(97.9%AUC)をろ液から得た(合計収率87%)。
1L容量の1つ口の丸底フラスコに、7(61.4g、0.172モル)、ベンジルアミン(55.6g、0.519モル、3当量)、および無水アニソール(300g)を入れ、反応が実質的に完了するまで還流しながら攪拌し(23時間、165℃油浴温度、内部温度は147℃であった)、ほぼ室温まで冷却した。反応混合物の1ポーション(1mL)をトルエン(1mL)で希釈すると、そのポーションの完全な結晶化がもたらされた。次にこの種を反応混合物に加え、反応混合物全体が単一のブロックに結晶化するまで静置した。トルエン(150mL)を加えて、混合物を振り混ぜて固体を崩した。ヘプタン/トルエン(1:1、100mL)を加えて、固体混合物をさらに崩した。最後に、ヘプタン(50mL、次に25mL)を加えて、より一層混合物を崩し、固体をろ過する前にさらに30分間静置した。固体のろ過、2:1トルエン/ヘプタン(300mL)、1:2トルエン/ヘプタン(300mL)、次いでヘプタン(2×300mL)での洗浄、その後乾燥(風乾、次に高真空)して、60.16g(収率81%)の表題生成物を白色固体として得た(≧98.9%AUC)。別の2.5gの純度が低い(97.4%)材料を母液から得た。
KX2‐391(遊離塩基、60.00g)を含む無水EtOH(600mL)の攪拌懸濁液に、170mLの2.5M HCl(エタノール中)を加えて、フラスコの側面を洗い流すために25mLのEtOHを加えた。得られた均一な溶液を室温で攪拌した後(20分間)、ほぼ乾燥するまで蒸発させた(泡立つまで)。EtOHでチェーシングした後(2×150mL)、残渣を再びEtOH(150mL)に取り、混合物が飽和したように見えるまでヘプタンをゆっくりと加えた(濁りが残るためには33mLが必要であった)。一晩攪拌後、2つの層が形成された。さらなるヘプタン(250mL)を添加後、やはり結晶化を誘発できなかったため、反応混合物を約200mLの量に濃縮したが、この時点で混合物は均一であった。この濃縮した均一な溶液を、非常に急速に攪拌した(機械的に)EtOAc(2L)に滴下しながら加えた。添加完了後、元のフラスコの25mLのEtOHすすぎ液と、添加用漏斗を急速に攪拌した混合物に加えた。急速な攪拌をさらに約1時間継続した後、混合物をろ過し、固体(部分的に粘着性)をEtOAc(300mL)で、次いでヘプタンで洗浄した。ヘプタンで洗浄を始めた途端に、固体の粘着性が増した。フリット付きブフナー漏斗とその内容物を覆い(ペーパータオル/ゴムバンド)、すばやく真空オーブン内に静置した。約45℃、真空で一晩置いた後、窒素雰囲気下で真空を開放し、生成物(泡状の固体)が入ったブフナー漏斗をただちにジップロックバックに入れ、窒素雰囲気下(グローブバッグ)で瓶に移し、泡状固体を粉末に崩した(へら)。高真空下(約45℃)における2晩目では、わずか1.3gのさらなる重量減少が起こった。高真空(約45℃)の3晩目でも一定の重量が実質的に得られ、重量のわずか0.2gが失われただけであった。材料の最終的な重量は68.05g(収率97%)で、0.29当量(4.8%w/w)のEtOAc、0.035当量(0.3%w/w)のEtOH、および0.03当量(0.6%w/w)のヘプタンを含有していた。純度は99.6%であった。
a.計算されたもの(%):C,60.03、H,6.54、N,7.65、Cl,12.91
b.観察されたもの(%):C,59.85/59.97、H,6.54/6.47、N,7.67/7.67、Cl,13.10/13.24
計算されたFW:534.63(1H NMRではH2Oのエビデンスが示されていないため、非常に吸湿性の高いこの粉末の取り扱い中に恐らく上昇した0.8H2Oを考慮していない)。
この実施例では、KX2‐391.2HClの少なくとも100gスケールでの調製のための合成経路の開発を説明する。この手順は、例えばキログラム量の材料を産生するために使用されうる。最終経路をスキーム1に示す。この経路は6つのステップであり、エーテル形成、鈴木カップリング、フッ化物置換、および酸触媒溶媒和化が含まれる。この手順を、105gのデモンストレーションバッチスケールでテストした。
実施例2でエーテル合成について説明した手順に対するいくつかの変更を開発した。アセトニトリル溶媒中でエーテル合成を行うとき、反応混合物は非常に濃いスラリーであり、攪拌が困難であった。従って、溶媒をジメチルホルムアミド(DMF)に変更し、これによってより扱いやすい白色の薄いスラリーが生成した。厳密な乾燥条件が不可欠でないことも決定した。例えば、0.3容の脱イオン(DI)水は、反応の純度または収率に不利な影響を与えない。反応溶媒をDMFに変えたため、ワークアップも変更した。変更したワークアップは、DI水での希釈およびMTBEでの抽出を伴うものとなった。残存する4‐ブロモフェノールを除去するために、水酸化ナトリウム水溶液で基本的な洗浄を行うのも好都合であった。
ボロン酸4の形成を、添加の順番および溶媒を変更することによっていくつかのやり方において改善した。最初の手順は、n‐BuLi溶液を含むヘキサンの冷MTBE溶液への添加を必要とした。次にアニオン性溶液を−75℃未満まで冷却し、5‐ブロモ‐2‐フルオロピリジンを含むMTBEの第2溶液をゆっくりと加えた。得られた混合物に、トリイソプロピルボラートをポーションで立て続けに加えた。このプロセスは、トリイソプロピルボラートを急速に加えるため、スケールアップに修正することはできなかった。この手順の開発は、発表済みの手順(Li,et al.,J.Org.Chem.2002,67,5394‐5397)に従うことによって先行していた。1つの改善は、5‐ブロモ‐2‐フルオロピリジンとトリイソプロピルボラートを、トルエンとTHFの溶液に予め混ぜておくことであった。混合物を−50〜−35℃に冷却し、次にn‐BuLi溶液を添加してアリールアニオンを形成した後で、これをトリイソプロピルボラートによってin situでクエンチして、アリールボラートを形成した。この手順は、発熱イベントを制御しただけでなく、前述のように−75℃未満よりも高い温度で実施された。反応の最中により高い温度が得られれば、ブロモブタンからのHBrの排除の競合的反応が認められると考えられた。n‐BuLiまたはアリールアニオンが副反応中の塩基であるかどうかは探索しなかった。単なる塩酸水溶液の代わりに、水酸化ナトリウム水溶液での抽出を加えることによってワークアップを変更した。水性抽出物を注意深く集め、これによって若干のpH調節が必要となったのみであった。
より小さいスケールのパラジウムカップリング反応の実施において、固体が反応装置のガラス壁上に形成されることに気付いた。固体は絶縁体として機能するであろうから、この反応をスケールアップすると反応装置の異常加熱をもたらす可能性がある。異常加熱を防ぐために2種類のアプローチを行った。反応物に加える水の量を2.3〜4.0容に増やし、反応をキログラムスケールで実施した場合には、閾値温度に達すれば加熱を制御するために、反応装置とマントルヒーターの間に追加の熱電対を使用した。カップリング反応は2バッチで完了し、合計5269gの4‐(2‐(4‐ブロモフェノキシ)エチル)モルホリンが5735gの4‐(2‐(4‐(6‐フルオロピリジン‐3‐イル)フェノキシ)エチル)モルホリンに変換され、バッチのHPLCによる純度は94.9および90.3(AUC%)であった。
パラジウムカップリング由来の粗生成物を、シリカゲルクロマトグラフィーで精製した。材料(5735g)を7つのカラムで精製して、化合物5を淡褐色の固体(4220g、HPLCで97.6AUC)として得て、パラジウムレベルは0.2wt%であった。毒性学のバッチでは、精製された化合物5の段階において、7および11ppmのパラジウムレベルが観察された。
スケールアップ可能なフッ化物置換反応の開発においていくつかの変更を行った。置換反応には、THFに含まれる溶液として商業的に入手できない、カリウムヘキサメチルジシラン(KHMDS)が必要であった。従って、反応には、固体から混合物を調製するステップが必要であった。この操作は、ラージスケール反応には望ましくないものであろう。3種類のカチオン(LiHMDS、KHMDS、およびNaHMDS)を評価した。LiHMDSは暗褐色の反応混合物をもたらし、変換は認められなかった。NaHMDSは、KHMDSと等しく機能した。NaHMDSのTHF溶液は容易に入手可能である。
ニトリル6の酸触媒加メタノール分解は典型的に、少量のカルボン酸7aをもたらした。恐らくは7aのソースである好都合な水を除去するために採ったアプローチは、メタノールと濃硫酸の反応混合物に発煙硫酸を加えることであった。濃硫酸は、通常は95〜98%溶液として供給される。発煙硫酸は、硫酸に含まれる2〜5%の水を除去する。濃硫酸と発煙硫酸の混合物を使用することで、6%未満のカルボン酸7aが副産物として常に生じ、これは水性ワークアップで容易に除去可能であった。
中間スケール反応で説明したアミド形成のための手順は、ラージスケールでも良好に機能した。メチルエステル7およびベンジルアミン(3当量)をアニソールに溶解し、150℃でほぼ2日間加熱した。しかし、中間スケールの手順を使用した生成物の単離は、固体の塊の生成物をもたらしうる。この問題を回避するため、抗溶媒を添加する前に、反応混合物を室温まで冷却せず、45〜50℃に冷却した。元の手順では抗溶媒としてトルエンおよびヘプタンを使用した。n‐ヘプタンを単独で使用すると、純分な純度が得られ、収率は81〜90%に増加した。さらに、ヘプタンの単一異性体の使用は、残存溶媒を十分に定量するのに不可欠であった。
KX2‐391.2HClが吸湿性であることから、再現性よくビス‐HCl塩を調整するためにさらなる注意を払った。無水エタノールに塩化アセチルを添加することにより、無水HCl溶液を含むエタノールを作製した。次に、窒素雰囲気下で、KX2‐391遊離塩基をこの溶液で処理した。続いて濃縮および共沸乾燥を用いた。しかし、KX2‐391.2HClの結晶化を再現性よく得ることはできなかった。複数種類の溶媒、例えばIPA(イソプロピルアルコール)、酢酸エチル/IPA、エタノール、プロパノール、およびブチルアルコール(表1)を使用した。表1の実験は、様々な結晶化および沈殿条件を探索するための最初の試みであった。報告した2つのロット(EおよびF)をもたらした最後の実験条件は、この情報に基づいて選択された。
試薬および溶媒は、商業的供給業者から受領した状態で使用した。反応の進行は、HPLC、GC/MS、または1H NMRでモニタリングした。薄層クロマトグラフィー(TLC)を、Analtechシリカゲルプレートを使用して行い、UV光(254nm)で可視化した。高圧液体クロマトグラフィー(HPLC)を、Agilent1100シリーズ機器で実施した。プロトンおよびカーボン核磁気共鳴スペクトルを、プロトンでは300MHzで、カーボンでは75MHzにおいてBruker AV300を使用して得た。プロトンおよびカーボンスペクトルでは、溶媒ピークを基準ピークとして使用した。
還流用冷却器および温度プローブを備えた50L容量のジャケット付き反応容器に、4‐(3‐クロロプロピル)モルホリン(2.44kg、0.54モル)、4‐ブロモフェノール(2.27kg、0.54モル、1.0当量)、粉末状炭酸カリウム(6.331kg、1.88モル、3.50当量)、およびDMF(12.2L)を入れて攪拌した。次に反応混合物を60〜65℃に加熱し、一晩攪拌した。17.5時間後、反応混合物を20〜25℃に冷却した。ワークアップ用の底部バルブを備えた別の反応容器に反応混合物を入れた。温度を20〜30℃の間に保ちながら、DI水(48.7L)を反応容器に入れた。相が分離した。水層をMTBEで抽出した(3×24.4L)。集めた有機物質に、DI水(18.3L)、次いで6Mの水酸化ナトリウム(18.2L)を加えた。2〜5分間混合物を攪拌し、相が分離した。有機相を水(24.4L)および食塩水(24.4L)で洗浄し、硫酸マグネシウムで乾燥し、ろ過し、濃縮して、3770gの黄色い油(89%粗収率、HPLCで99.4%AUC)を得た。
還流用冷却器および温度プローブを備えた72L容量の反応容器。反応容器に、5‐ブロモ−2‐フルオロピリジン(1.17L、0.568モル)、トルエン(18.2L)、およびトリイソプロピルボラート(3.13L、0.68モル、1.2当量)を入れて攪拌した。テトラヒドロフラン(4.4L)を反応容器に加えて、反応混合物を−35〜−50℃の間に冷却した。−35〜−45℃の温度を保ちながら、n‐ブチルリチウム(ヘキサンの2.5M溶液、5.44L、0.68モル、1.2当量)を慎重に反応容器に加えた。5時間後、反応が完了したと判断し、反応混合物を−15〜−20℃に昇温した。−15℃〜0℃の温度を保ちながら、反応物に2MのHCl(11.80L)を反応容器に加えた。18〜23℃で反応混合物を16時間攪拌し、相が分離した。次に有機物質を6Mの水酸化ナトリウム(6.0L)で抽出した。酸性および塩基性の水相を反応容器内で混合し、pHが7.5になるまで6MのHCl(2.5L)を加えた。次に塩化ナトリウム(6.0kg)を水相に加えた。次いで水相をTHFで抽出した(3×20L)。集めた有機物質を硫酸マグネシウムで乾燥し、濃縮して1300gの褐色固体(81%粗収率)を得た。
還流用冷却器、スパージチューブ、バブラー、および温度プローブを備えた72L容量の反応容器に、6‐フルオロピリジン−3‐イルホウ酸(2.84kg、1.24当量)、4‐(2‐(4‐ブロモフェノキシ)エチル)モルホリン(4.27kg、1.0当量)、およびDME(27L)を入れた。攪拌を始め、次に、炭酸ナトリウム(4.74kg、3.0当量)をDI水(17.1L)中の溶液として反応混合物に加えた。アルゴンを気泡化して反応混合物に50分間通した。アルゴン雰囲気下で、テトラキス(トリフェニルホスフィン)パラジウム(750g、0.04当量)を、DME(1.0L)中のスラリーとして反応混合物に加えた。反応混合物を75〜85℃に加熱し、一晩(17時間)加熱した。反応混合物を18〜22℃に冷却した。DI水(26.681kg)およびMTBE(26.681L)を反応容器に入れ、5分間攪拌した。相が分離し、水相をMTBE(2×26.7L)で抽出した。集めた有機物質を2MのHClで抽出した(1×15.0L、3×21.8L)。次に水相を反応容器に戻して、酢酸エチル(26.7L)を加えた。15〜25℃の温度を保ちながら、6M水酸化ナトリウム(26.7L)を使用してpHを6.2に調整した。相が分離し、水相を酢酸エチルで抽出した(2×26.7L)。集めた有機物質を硫酸マグネシウムで乾燥し、濃縮して4555gの残渣を得た(101%粗収率、HPLCで67.1%AUC)。
粗生成物(575g)を、メタノール/酢酸エチル/ヘプタン(30%酢酸エチル/ヘプタン、50%酢酸エチル/ヘプタン、75%酢酸エチル/ヘプタン、100%酢酸エチル、および5%メタノール/酢酸エチル)で溶離することによって、シリカゲルクロマトグラフィーで精製した。TLC(10%メタノール/ジクロロメタン、Rf=0.3)による純粋な画分の濃縮によって、420gの淡褐色の固体(73%回収、HPLCで>99.9%AUC)を得た。
5L容量のフラスコに、THF中のNaHMDS(2.0L、5.0当量)の1M溶液を入れ、−20〜−15℃に冷却した。−10℃未満の温度を保ちながら、フッ化物(119.7g、1.0当量)を含むTHF(500mL)を、20分間にわたってフラスコに入れた。−10℃未満の温度を保ちながら、アセトニトリル(82.5mL、4.0当量)を含むTHF(170mL)を20分間にわたってフラスコに加えた。次に反応混合物を1時間攪拌した。反応物に、食塩水(1.5L、12.6vol)を、10℃未満の温度を保てる速さで加えた。次に、溶液を室温まで昇温し、層を分離させた。混合物をセライトでろ過し、THFで洗浄した(1×200mL、1×100mL)。水相をトルエン(750mL)で抽出した。集めた有機物質を硫酸マグネシウムで乾燥し、ろ過し、トルエンで洗浄し(2×250mL)、乾燥するまで濃縮した。トルエン(1L)を加え、乾燥するまで溶液を再度濃縮して、169.8gの油を得た。MTBE(1190mL、7vol)を50℃で油に加え、15分間攪拌した。ヘプタン(850mL、5vol)を50℃で10分間にわたって加えた。次に、1.5時間で混合物を室温まで冷却し、2時間攪拌した。スラリーをろ過し、1:4MBTE/ヘプタン(2×100mL)で洗浄し、45℃のオーブン内で一晩乾燥して、102.3gのオフホワイトの固体を得た(80%収率、HPLCで98.8%AUC)。
攪拌子および熱電対を備えた3L容量のフラスコに、ニトリル6(101g)およびメタノール(1.01L、10vol)を入れた。60℃未満の温度を保ちながら、濃H2SO4(175mL、10.0当量)を15分間にわたって溶液に滴下しながら加えた。次いで、60℃未満の温度を保ちながら、30%発煙硫酸(124mL)を溶液に滴下しながら加えた。次に、マントルヒーターで溶液を還流加熱し、一晩攪拌した。反応が終了したと判断されたら、これを20℃に冷却した。2つめのフラスコ(22L容量)に、飽和重炭酸ナトリウム(10.7L)およびジクロロメタン(1.1L)を入れ、15℃に冷却した。20℃未満の温度を保ちながら、反応混合物を重炭酸ナトリウム/ジクロロメタン混合物に加えた。クエンチを15分間攪拌し、相が分離した。水相をジクロロメタンで抽出した(1×550mL、1×300mL)。集めた有機物質を硫酸マグネシウムで乾燥し、乾燥するまで濃縮して105gの橙色の固体を得た(94%粗収量、HPLCで97.7%AUC)。
エステル7(103g)、アニソール(513mL、5vol)、およびベンジルアミン(94mL、3.0当量)を、熱電対および攪拌翼を備えた3L容量のフラスコに入れた。次に、反応混合物を142℃に加熱し、2日間攪拌した。反応混合物を45〜50℃に冷却し、2時間攪拌した。混合物に、n‐ヘプタン(1.5L)を1時間にわたって滴下しながら加えた。3時間で溶液を室温に冷却した後、一晩攪拌した。得られたスラリーをろ過し、4:1アニソール/n‐ヘプタン(200mL)およびn‐ヘプタン(3×100mL)で洗浄した。オーブン内で一晩乾燥すると、得られた生成物は112.1gの褐色固体であった(90%収率、HPLCで99.6%AUC)。KX2‐391の1H NMRについては図5を参照されたい。
EtOH(1.0L)を2L容量のフラスコに入れ、塩化アセチル(62.5mL、3.0当量)をフラスコにゆっくりと加えて40分間攪拌した。温度を30℃に保ちながら、得られた溶液を30分間にわたってKX2‐391(100g)に加えた。溶液を質量270gまで濃縮した。急速に攪拌しながら、濃縮溶液を20分間にわたって酢酸エチル(2L)に加えた。混合物を一晩攪拌した後、窒素雰囲気下でろ過して、2つの識別可能な固体生成物、褐色固体(73.5g)および色の濃い固体(42.2g)を得た。固体を乾式ブレンドして、合計収率99%を得た。HPLC解析は99.0%の純度(AUC)を示していた。
本発明を、その詳細な説明とともに説明したが、これまでの説明は例示を目的とするものであって、添付の請求項の範囲によって定められる本発明の範囲を限定するものではない。その他の態様、利点、および変更は、下記の請求項の範囲内に含まれる。添付の請求項によって包含される本発明の範囲から逸脱せずに、その形態および詳細に各種の修正が加えられてよいことが当業者に理解されるであろう。
Claims (7)
- N‐ベンジル‐2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトアミドを調製するためのプロセスであって、
メチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートをベンジルアミンと反応させて、N‐ベンジル‐2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトアミドを得るステップ
を包含する、プロセス。 - (1)2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルをメチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートへ変換するステップ;および
(2)メチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートをベンジルアミンと反応させて、N‐ベンジル‐2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトアミドを得るステップ
を包含する、請求項1に記載のプロセス。 - (1)4‐(2‐(4‐(6‐フルオロピリジン‐3‐イル)フェノキシ)エチル)モルホリンをアセトニトリルと反応させて、2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルを得るステップ;
(2)2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルをメチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートへ変換するステップ;および
(3)メチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートをベンジルアミンと反応させて、N‐ベンジル‐2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトアミドを得るステップ
を包含する、請求項2に記載のプロセス。 - (1)4‐(2‐(4‐ブロモフェノキシ)エチル)モルホリンを6‐フルオロピリジン‐3‐イル‐3‐ボロン酸とカップリングさせて、4‐(2‐(4‐(6‐フルオロピリジン‐3‐イル)フェノキシ)エチル)モルホリンを得るステップ;
(2)4‐(2‐(4‐(6‐フルオロピリジン‐3‐イル)フェノキシ)エチル)モルホリンをアセトニトリルと反応させて、2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルを得るステップ;
(3)2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルをメチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートへ変換するステップ;および
(4)メチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートをベンジルアミンと反応させて、N‐ベンジル‐2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトアミドを得るステップ
を包含する、請求項3に記載のプロセス。 - (1)4‐(2‐クロロエチル)モルホリンを4‐ブロモフェノールと反応させて、4‐(2‐(4‐ブロモフェノキシ)エチル)モルホリンを得るステップ;
(2)4‐(2‐(4‐ブロモフェノキシ)エチル)モルホリンを6‐フルオロピリジン‐3‐イル‐3‐ボロン酸とカップリングさせて、4‐(2‐(4‐(6‐フルオロピリジン‐3‐イル)フェノキシ)エチル)モルホリンを得るステップ;
(3)4‐(2‐(4‐(6‐フルオロピリジン‐3‐イル)フェノキシ)エチル)モルホリンをアセトニトリルと反応させて、2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルを得るステップ;
(4)2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルをメチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートへと変換するステップ;および
(5)メチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートをベンジルアミンと反応させて、N‐ベンジル‐2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトアミドを得るステップ
を包含する、請求項1〜請求項4のいずれか一項に記載のプロセス。 - 2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)‐N‐ベンジルアセトアミドを塩酸溶液と接触させて、N‐ベンジル‐2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトアミド二塩酸塩を得るステップをさらに包含する、請求項1または請求項5に記載のプロセス。
- (1)4‐(2‐クロロエチル)モルホリンを4‐ブロモフェノールと反応させて、4‐(2‐(4‐ブロモフェノキシ)エチル)モルホリンを得るステップ;
(2)4‐(2‐(4‐ブロモフェノキシ)エチル)モルホリンを6‐フルオロピリジン‐3‐イル‐3‐ボロン酸とカップリングさせて、4‐(2‐(4‐(6‐フルオロピリジン‐3‐イル)フェノキシ)エチル)モルホリンを得るステップ;
(3)4‐(2‐(4‐(6‐フルオロピリジン‐3‐イル)フェノキシ)エチル)モルホリンをアセトニトリルと反応させて、2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルを得るステップ;
(4)2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセトニトリルをメチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートへと変換するステップ;
(5)メチル2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)アセタートをベンジルアミンと反応させて、2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)‐N‐ベンジルアセトアミドを得るステップ;および
(6)2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)‐N‐ベンジルアセトアミドを塩酸溶液と接触させて、2‐(5‐(4‐(2‐モルホリノエトキシ)フェニル)ピリジン‐2‐イル)‐N‐ベンジルアセトアミド二塩酸塩を得るステップ;
を包含する、請求項6に記載のプロセス。
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KR20180093945A (ko) * | 2015-12-18 | 2018-08-22 | 신퓨얼 아메리카스 코포레이션 | 필터 조립체 및 사용 방법 |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7300931B2 (en) * | 2004-12-28 | 2007-11-27 | Kinex Pharmaceuticals, Llc | Compositions for treating cell proliferation disorders |
US7968574B2 (en) | 2004-12-28 | 2011-06-28 | Kinex Pharmaceuticals, Llc | Biaryl compositions and methods for modulating a kinase cascade |
US20070202186A1 (en) | 2006-02-22 | 2007-08-30 | Iscience Interventional Corporation | Apparatus and formulations for suprachoroidal drug delivery |
AU2007265373B2 (en) * | 2006-06-29 | 2013-02-21 | Atnx Spv, Llc | Biaryl compositions and methods for modulating a kinase cascade |
US7935697B2 (en) * | 2006-12-28 | 2011-05-03 | Kinex Pharmaceuticals, Llc | Compositions for modulating a kinase cascade and methods of use thereof |
US7939529B2 (en) * | 2007-05-17 | 2011-05-10 | Kinex Pharmaceuticals, Llc | Process for the preparation of compositions for modulating a kinase cascade and methods of use thereof |
US20210198202A1 (en) * | 2006-12-28 | 2021-07-01 | Athenex, Inc. | Compositions for modulating a kinase cascade and methods of use thereof |
WO2008127727A1 (en) * | 2007-04-13 | 2008-10-23 | Kinex Pharmaceuticals, Llc | Biaryl compositions and methods for modulating a kinase cascade |
AU2014202221B2 (en) * | 2007-05-17 | 2016-06-23 | Atnx Spv, Llc | Process for the Preparation of Compositions for Modulating a Kinase Cascade and Methods of Use Thereof |
US8124605B2 (en) | 2007-07-06 | 2012-02-28 | Kinex Pharmaceuticals, Llc | Compositions and methods for modulating a kinase cascade |
CN105796568A (zh) | 2007-10-20 | 2016-07-27 | 阿西纳斯公司 | 用于调控激酶级联的药物组合物及其使用方法 |
WO2011129936A2 (en) | 2010-04-16 | 2011-10-20 | Kinex Pharmaceuticals, Llc | Compositions and methods for the prevention and treatment of cancer |
CN103327939B (zh) | 2010-10-15 | 2017-05-24 | 科尼尔赛德生物医学公司 | 用于进入眼睛的装置 |
CN102627663A (zh) * | 2012-03-23 | 2012-08-08 | 上海泰坦化学有限公司 | 含氟吡啶硼酸的制备方法 |
US9926273B2 (en) * | 2012-08-30 | 2018-03-27 | Athenex, Inc. | Composition and methods for modulating a kinase cascade |
KR20150083117A (ko) | 2012-11-08 | 2015-07-16 | 클리어사이드 바이오메디컬, 인코포레이드 | 인간 대상체에서 안구 질병을 치료하기 위한 방법 및 장치 |
JP6716139B2 (ja) | 2015-01-19 | 2020-07-01 | 学校法人慶應義塾 | 内耳性難聴治療薬 |
CN108697792A (zh) * | 2015-11-19 | 2018-10-23 | 珠海泰瑞尚生物医药科技有限公司 | 用于结合vegf的方法和组合物 |
CN106902358B (zh) | 2015-12-21 | 2020-07-10 | 广州市香雪制药股份有限公司 | 口服制剂及其制备方法 |
CA3062845A1 (en) | 2016-05-02 | 2017-11-09 | Clearside Biomedical, Inc. | Systems and methods for ocular drug delivery |
US10973681B2 (en) | 2016-08-12 | 2021-04-13 | Clearside Biomedical, Inc. | Devices and methods for adjusting the insertion depth of a needle for medicament delivery |
US10213435B2 (en) | 2016-08-12 | 2019-02-26 | Athenex, Inc. | Biaryl compositions and methods for modulating a kinase cascade |
CN106810490A (zh) * | 2017-02-06 | 2017-06-09 | 重庆泰润制药有限公司 | 一种二芳基化合物的晶型及其制备方法和应用 |
JP2020510042A (ja) | 2017-03-10 | 2020-04-02 | アセネックス インコーポレイテッド | 光線角化症を治療および/または予防する方法 |
CA3074831A1 (en) | 2017-09-07 | 2019-03-14 | Athenex HK Innovative Limited | Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide |
CN110034895B (zh) | 2018-01-12 | 2020-07-03 | 电信科学技术研究院有限公司 | 信息指示、确定方法及装置、计算机存储介质 |
CN109485599A (zh) * | 2019-01-16 | 2019-03-19 | 重庆迈德凯医药有限公司 | 一种Src酪氨酸激酶抑制剂晶型、其制备方法及药物组合物 |
CN113354575B (zh) * | 2021-06-07 | 2022-09-27 | 河南应用技术职业学院 | 一种特班布林的合成方法 |
EP4302831A1 (en) | 2022-07-04 | 2024-01-10 | Trifarma S.p.A. | Process for synthesis of tirbanibulin |
CN115010655A (zh) * | 2022-07-21 | 2022-09-06 | 重庆迈德凯医药有限公司 | 一种替尼布林的纯化方法 |
CN115073362A (zh) * | 2022-08-04 | 2022-09-20 | 重庆迈德凯医药有限公司 | 一种替尼布林的合成方法 |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1044222B (it) | 1972-05-23 | 1980-03-20 | Zambeletti Spa L | Bifenilil alcanoilaminopiridine ad attivita anti infiammatoria di lunga durata |
CA1261835A (en) | 1984-08-20 | 1989-09-26 | Masaaki Toda | (fused) benz(thio)amides |
US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
ZA985542B (en) | 1997-07-03 | 1999-04-07 | Smithkline Beecham Corp | Substituted benzanilides as CCR5 receptor ligands antiinflammatory agents and antiviral agents |
US20040214836A1 (en) | 1998-05-29 | 2004-10-28 | Cheresh David A. | Method of treatment of myocardial infarction |
US20030130209A1 (en) | 1999-12-22 | 2003-07-10 | Cheresh David A. | Method of treatment of myocardial infarction |
JP2001023259A (ja) | 1999-07-09 | 2001-01-26 | Sony Corp | 光磁気記録媒体およびその製造方法 |
US6844367B1 (en) | 1999-09-17 | 2005-01-18 | Millennium Pharmaceuticals, Inc. | Benzamides and related inhibitors of factor Xa |
KR100423899B1 (ko) | 2000-05-10 | 2004-03-24 | 주식회사 엘지생명과학 | 세포 증식 억제제로 유용한 1,1-디옥소이소티아졸리딘을갖는 인다졸 |
CA2441733A1 (en) | 2001-03-29 | 2002-10-10 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases |
DE10201764A1 (de) | 2002-01-18 | 2003-07-31 | Bayer Cropscience Ag | Substituierte 4-Aminopyridin-Derivate |
GB0206215D0 (en) | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
TWI319387B (en) | 2002-04-05 | 2010-01-11 | Astrazeneca Ab | Benzamide derivatives |
CA2484209C (en) | 2002-05-03 | 2013-06-11 | Exelixis, Inc. | Protein kinase modulators and methods of use |
AU2003254177A1 (en) | 2002-07-31 | 2004-02-16 | Smithkline Beecham Corporation | Substituted benzanilides as modulators of the ccr5 receptor |
US20040242572A1 (en) | 2002-08-24 | 2004-12-02 | Boehringer Ingelheim International Gmbh | New carboxamide compounds having melanin concentrating hormone antagonistic activity, pharmaceutical preparations comprising these compounds and process for their manufacture |
EP1575918A2 (en) | 2002-12-19 | 2005-09-21 | Neurogen Corporation | Substituted biaryl-4-carboxylic acid arylamide analogues as capsaicin receptor modulators |
WO2005013914A2 (en) | 2003-08-08 | 2005-02-17 | Vertex Pharmaceuticals Incorporated | Heteroarylaminosulfonylphenyl derivatives for use as sodium or calcium channel blockers in the treatment of pain |
WO2005014532A1 (en) | 2003-08-08 | 2005-02-17 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions and methods of use |
WO2005032493A2 (en) | 2003-10-07 | 2005-04-14 | Renovis, Inc. | Amide compounds as ion channel ligands and uses thereof |
US7300931B2 (en) * | 2004-12-28 | 2007-11-27 | Kinex Pharmaceuticals, Llc | Compositions for treating cell proliferation disorders |
US7968574B2 (en) | 2004-12-28 | 2011-06-28 | Kinex Pharmaceuticals, Llc | Biaryl compositions and methods for modulating a kinase cascade |
CA2602336A1 (en) * | 2005-03-31 | 2006-10-05 | Ucb Pharma S.A. | Compounds comprising an oxazole or thiazole moiety, processes for making them, and their uses |
CN101253152A (zh) | 2005-09-02 | 2008-08-27 | 安斯泰来制药株式会社 | 作为rock抑制剂的酰胺衍生物 |
AU2007265373B2 (en) * | 2006-06-29 | 2013-02-21 | Atnx Spv, Llc | Biaryl compositions and methods for modulating a kinase cascade |
AU2008254500B2 (en) * | 2007-05-17 | 2014-01-23 | Atnx Spv, Llc | Process for the preparation of compositions for modulating a kinase cascade and methods of use thereof |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20180093945A (ko) * | 2015-12-18 | 2018-08-22 | 신퓨얼 아메리카스 코포레이션 | 필터 조립체 및 사용 방법 |
KR102209639B1 (ko) * | 2015-12-18 | 2021-01-28 | 신퓨얼 아메리카스 코포레이션 | 필터 조립체 및 사용 방법 |
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AU2007340350B2 (en) | 2014-02-20 |
AU2007340350A2 (en) | 2009-09-17 |
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TW200827354A (en) | 2008-07-01 |
US20080221102A1 (en) | 2008-09-11 |
WO2008082637A1 (en) | 2008-07-10 |
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ES2559687T3 (es) | 2016-02-15 |
EP2114934B1 (en) | 2015-10-21 |
TWI457336B (zh) | 2014-10-21 |
CN102657656A (zh) | 2012-09-12 |
CA2673974C (en) | 2017-01-17 |
US7851470B2 (en) | 2010-12-14 |
CA2673974A1 (en) | 2008-07-10 |
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