JP2009001543A - 5−[3−(3−ヒドロキシフェノキシ)アゼチジン−1−イル]−5−メチル−2,2−ジフェニルヘキサンアミド塩酸塩 - Google Patents
5−[3−(3−ヒドロキシフェノキシ)アゼチジン−1−イル]−5−メチル−2,2−ジフェニルヘキサンアミド塩酸塩 Download PDFInfo
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- JP2009001543A JP2009001543A JP2008065066A JP2008065066A JP2009001543A JP 2009001543 A JP2009001543 A JP 2009001543A JP 2008065066 A JP2008065066 A JP 2008065066A JP 2008065066 A JP2008065066 A JP 2008065066A JP 2009001543 A JP2009001543 A JP 2009001543A
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- asthma
- bronchitis
- bronchiectasis
- azetidin
- compound
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Abstract
【解決手段】5−[3−(3−ヒドロキシフェノキシ)アゼチジン−1−イル]−5−メチル−2,2−ジフェニルヘキサンアミド塩酸塩。該化合物またはそれらの誘導体を有効量含む医薬組成物。該医薬品は、気管支収縮、末梢気道閉塞、肺気腫、慢性閉塞性肺疾患(COPD)、成人呼吸窮迫症候群(ARDS)、慢性/急性気管支炎、喘息、気管支拡張症等からなる疾患、障害、および病態の治療に有用である。
【選択図】なし
Description
・治療が必要な患者に本発明の塩酸塩と治療剤とのこうした組合せを同時に投与し、その際、こうした成分は、前記患者に実質上同時に前記成分を放出する単一剤形に一緒に製剤化される、
・治療が必要な患者に本発明の塩酸塩と治療剤とのこうした組合せを実質上同時に投与し、その際、こうした成分は、個々の剤形に互いに別個に製剤化され、これらが前記患者によって実質上同時に摂取されると、前記成分は前記患者に実質上同時に放出される、
・治療が必要な患者に本発明の塩酸塩と治療剤とのこうした組合せを順次投与し、その際、こうした成分は、個々の剤形に互いに別個に製剤化され、これらが各投与間の有意な時間間隔をおいて前記患者によって連続的に摂取されると、前記成分は前記患者に実質上異なる時間に放出される、
・治療が必要な患者に本発明の塩酸塩と治療剤とのこうした組合せを順次投与し、その際、こうした成分は、制御された方法で前記成分を放出する単一剤形に一緒に製剤化されると、それらは前記患者によって同時および/または異なる時間に、同時に、連続的に、および/または重複して投与される、
ここでは、各器官は、同じまたは異なる経路によって投与され得る。
(a)5−リポキシゲナーゼ(5−LO)阻害剤または5−リポキシゲナーゼ活性化タンパク質(FLAP)拮抗薬、
(b)LTB4、LTC4、LTD4、およびLTE4の拮抗薬を包含するロイコトリエン拮抗薬(LTRA)、
(c)H1およびH3拮抗薬を包含するヒスタミン受容体拮抗薬、
(d)うっ血除去薬使用のためのα1およびα2−アドレナリン受容体作動性血管収縮性交感神経様作用薬、
(e)短時間または長時間作用性β2作動薬、
(f)PDE阻害剤、例えば、PDE3、PDE4、およびPDE5阻害剤、
(g)テオフィリン、
(h)クロモグリク酸ナトリウム、
(i)COX阻害剤、非選択的および選択的COX−1またはCOX−2阻害剤(NSAID)、
(j)経口および吸入グルココルチコステロイド、
(k)内因性炎症性要素に対して活性なモノクローナル抗体、
(l)抗腫瘍壊死因子(抗TNF−α)薬剤、
(m)VLA−4拮抗薬を包含する接着分子阻害剤、
(n)キニン−B1およびB2受容体拮抗薬、
(o)免疫抑制剤、
(p)マトリクスメタロプロテアーゼ(MMP)の阻害剤、
(q)タキキニンNK1、NK2、およびNK3受容体拮抗薬、
(r)エラスターゼ阻害剤、
(s)アデノシンA2a受容体作動薬、
(t)ウロキナーゼ阻害剤、
(u)ドーパミン受容体に作用する化合物、例えば、D2作動薬、
(v)NFκB経路のモジュレーター、例えば、IKK阻害剤、
(w)p38MAPキナーゼまたはsykキナーゼなどのサイトカインシグナル伝達経路のモジュレーター、
(x)粘液溶解薬または鎮咳薬として分類することができる薬剤、
(y)抗生物質、
(z)HDAC阻害剤、
(aa)PI3キナーゼ阻害剤、ならびに
(bb)CXCR2拮抗薬
が挙げられるが、それらだけに限らない。
− H3拮抗薬、
− β2作動薬、
− PDE4阻害剤、
− ステロイド、特に副腎皮質ステロイド、
− アデノシンA2a受容体作動薬、
− p38MAPキナーゼまたはsykキナーゼなどのサイトカインシグナル伝達経路のモジュレーター、または
− LTB4、LTC4、LTD4、およびLTE4の拮抗薬を包含するロイコトリエン拮抗薬(LTRA)
との組合せが好ましい。
− 副腎皮質ステロイド、具体的には、プレドニゾン、プレドニゾロン、フルニソリド、トリアムシノロンアセトニド、ジプロピオン酸ベクロメタゾン、ブデソニド、プロピオン酸フルチカゾン、シクレソニド、およびフロ酸モメタゾンを包含する全身性副作用を低減した吸入副腎皮質ステロイド、または
− 具体的には、サルブタモール、テルブタリン、バンブテロール、フェノテロール、サルメテロール、ホルモテロール、ツロブテロール、およびそれらの塩を包含するβ2作動薬
との組合せがさらに好ましい。
・慢性または急性の気管支収縮、慢性気管支炎、末梢気道閉塞、および肺気腫、
・すべてのタイプ、病因、または病原の閉塞性または炎症性気道疾患、具体的には、慢性好酸球性肺炎、慢性閉塞性肺疾患(COPD)、慢性気管支炎を包含するCOPD、COPDに関連するまたは関連しない肺気腫または呼吸困難、不可逆的進行性気道閉塞を特徴とするCOPD、成人呼吸窮迫症候群(ARDS)、他の薬物治療の結果生じる気道反応亢進の悪化、および肺高血圧症に関連する気道疾患からなる群から選択されるメンバーである閉塞性または炎症性気道疾患、
・すべてのタイプ、病因、または病原の気管支炎、具体的には、急性気管支炎、急性喉頭気管気管支炎、アラキジン酸の気管支炎、カタル性気管支炎、クループ性気管支炎、乾性気管支炎、感染性の喘息性気管支炎、増殖性気管支炎、ブドウ球菌または連鎖球菌性気管支炎、および小胞性気管支炎からなる群から選択されるメンバーである気管支炎、
・すべてのタイプ、病因、または病原の喘息、具体的には、アトピー性喘息、非アトピー性喘息、アレルギー性喘息、アトピー性気管支IgE媒介喘息、気管支喘息、本態性喘息、真性喘息、病態生理学的障害によって引き起こされる内因性喘息、環境要因によって引き起こされる外因性喘息、未知または不顕性原因の本態性喘息、非アトピー性喘息、気管支炎性喘息、気腫性喘息、運動誘発性喘息、アレルゲン誘発性喘息、冷風誘発性喘息、職業性喘息、細菌、真菌、原生動物、またはウイルス感染によって引き起こされる感染性喘息、非アレルギー性喘息、初発喘息、喘鳴幼児症候群(wheezy infant syndrome)、および細気管支炎からなる群から選択されるメンバーである喘息、
・急性肺障害、
・すべてのタイプ、病因、または病原の気管支拡張症、具体的には、円柱状気管支拡張症、嚢胞状気管支拡張症、紡錘状気管支拡張症、毛細管気管支拡張症、嚢状気管支拡張症、乾性気管支拡張症、および濾胞性気管支拡張症からなる群から選択されるメンバーである気管支拡張症。
粉末X線回折パターンを、自動試料交換器、θ−θゴニオメータ、自動ビーム発散スリット、およびPSD Vantec−1検出器を取り付けたBruker−AXS Ltd.のD4粉末X線回折計を使用して測定した。サンプルを低バックグラウンドシリコンウェーハ標本マウント上に載置して分析準備をした。X線管を40kV/35mAで操作して、標本を、CuのKα1X線(波長=1.5406Å)で照射しながら回転させた。分析を、2°〜55°の2θ範囲にわたって0.018°ステップにつき0.2秒間の連続モード設定で作動するゴニオメータを用いて実施した。測定パターンを図1に示す。得られた粉末X線回折パターンの強度およびピーク位置(角2θ誤差は±0.1度)を、表1に示す。
実施例1の結晶構造を、Bruker SMART APEX単結晶X線回折計およびMoのKα線を使用して、単結晶X線回折で室温にて決定した。強度をいくつかの一連の露光から積分し(参照:SMART v5.622(コントロール)およびSAINT v6.02(集積)ソフトウェア、Bruker AXS Inc.、マディソン、ウィスコンシン州、1994年)、ここでは、各露光をωで0.3°にわたり、露光時間は30秒であり、合計データセットは、半球を超える範囲となった。データは、マルチスキャン方法を使用して、吸収に関して補正した(参照:SADABS、面積検出器データのスケーリングおよび補正のためのプログラム、G.M.Sheldrick、University of Gottingen、1997年(R.H.Blessing、Acta Cryst.、1995年、A51、33〜38頁の方法に基づく))。結晶構造は、SHELXS−97(参照:SHELXS−97、結晶構造解明のためのプログラム。G.M.Sheldrick、University of Gottingen、ドイツ、1997年、リリース97−2)を使用して、空間群P212121において直接法によってうまく解明され、SHELXL−97(参照:SHELXL−97、結晶構造解明のためのプログラム。G.M.Sheldrick、University of Gottingen、ドイツ、1997年、リリース97−2)を使用して、最小二乗法によって精密化した。
2θ角および相対強度を、Accelrys MS Modelling(商標)の「反射粉末回析(Reflex Powder Diffraction)」モジュール[バージョン3.0]を使用して、実施例1の単結晶構造から算出した。
関連するシミュレーションパラメータは、
波長=1.5406Å(CuのKα)
偏光因子=0.5
疑似フォークトプロフィール(U=0.01、V=−0.001、W=0.002)
とした。
1HNMR(400MHz,CDCl3)δ:1.10(s,6H)、1.22〜1.34(m,2H)、2.42〜2.55(m,2H)、3.28〜3.40(m,2H)、3.65〜3.88(m,2H)、4.70〜4.80(m,1H)、5.55〜5.70(brs,2H)、6.23〜6.36(m,2H)、6.45〜6.53(m,1H)、7.03〜7.12(m,1H)、7.19〜7.39(m,10H);LRMS ESI m/z 445[M+H]+
1HNMR(300MHz,CDCl3)δ:0.98(s,6H)、1.35〜1.44(m,2H)、2.41〜2.52(m,2H)、3.18〜3.26(m,2H)、3.48〜3.57(m,2H)、4.65〜4.74(m,1H)、6.26〜6.29(m,1H)、6.32〜6.37(m,1H)、6.43〜6.47(m,1H)、7.12(t,J 8.2Hz,1H)、7.25〜7.44(m,10H)
1HNMR(400MHz,CDCl3)δ:0.90〜1.03(m,6H)、1.31〜1.44(m,2H)、2.41〜2.56(m,2H)、3.07〜3.24(m,2H)、3.42〜3.54(m,2H)、3.77(s,3H)、4.63〜4.74(m,1H)、6.28〜6.38(m,2H)、6.48〜6.55(m,1H)、7.26〜7.49(m,11H);LRMS APCI m/z 441[M+H]+
1HNMR(300MHz,d6−dmso)δ:2.07〜2.16(m,2H)、2.69〜2.77(m,2H)、3.70〜3.78(m,1H)、3.72(s,3H)、3.94〜4.00(m,1H)、4.21〜4.29(m,1H)、4.42〜4.45(m,1H)、4.92〜5.00(m,1H)、6.36〜6.42(m,2H)、6.54〜6.59(m,1H)、7.16〜7.23(m,1H)、7.30〜7.40(m,2H)、7.41〜7.46(m,8H)
rt=室温
Me=メチル
Ph=フェニル
SM=出発材料
h=時間
mins=分
d=日
抗力アッセイ
M3の効力を、NFATベータラクタマーゼ遺伝子でトランスフェクトしたCHO−K1細胞において決定する。ヒトムスカリンM3受容体を組換え発現するCHO(チャイニーズハムスター卵巣)細胞を、NFAT_β−Lac_Zeoプラスミドでトランスフェクトした。細胞をGlutamax−1を有するDMEMにおいて成長させ、10%FCS(牛胎児血清;Sigma F−7524)、1nMピルビン酸ナトリウム(Sigma S−8636)、NEAA(非必須アミノ酸;Invitrogen 11140−035)、および200μg/mlのZeocin(Invitrogen R250−01)を含有する25mMのHEPES(Life Technologies 32430−027)を補足した。
5%CO2含有大気中37℃で5分間、細胞と共にインキュベートされた酵素不含細胞解離溶液(Life technologies 13151−014)を使用して細胞が密集度80〜90%に達したときに、細胞をアッセイ用に採取する。分離した細胞を温めた成長培地に収集し、2000rpmで10分間遠心分離機にかけ、PBS(リン酸緩衝溶液;Life Technologies 14190−094)で洗浄し、先に記載したように再度遠心分離機にかける。細胞を、成長培地(上述した通りの組成物)において2×105細胞/mlで再懸濁する。この細胞懸濁液20μlを、384ウエルのブラッククリアボトムプレート(Greiner Bio One 781091−PFI)それぞれに添加する。使用したアッセイ緩衝液は、0.05%プルロニックF−127(Sigma 9003−11−6)および2.5%DMSOを補足したPBSである。ムスカリンM3受容体シグナル伝達を、37℃/5%CO2で4時間細胞と共にインキュベートした80nMカルバミルコリン(Aldrich N240−9)を使用して刺激し、インキュベーション期間の最後にTecan SpectraFluor+プレートリーダーを使用して監視する(λ−励起405nm、発光450nmおよび503nm)。試験する化合物を、4時間のインキュベーション期間の初めにアッセイに添加し、化合物活性をカルバミルコリン誘発シグナルの濃度依存性阻害として測定する。阻害曲線をプロットし、IC50値を4パラメータのシグモイドフィットを使用して生成し、Cheng−Prusoff補正およびアッセイのカルバミルコリンに関するKD値を使用してKi値に変換する。
体重350〜450gの雄のDunkin−Hartleyモルモットを、CO2濃度を増加させて選別し、続いて大静脈から放血させる。気管を喉頭から胸腔内の入口点(entry point)まで切り出し、次いで室温において新鮮な酸素化改良クレブス緩衝液(10μMプロプラノロール、10μMグアネチジン、および3μMインドメタシンを含有するクレブス)に入れた。気管筋の対側の軟骨を切り離して、気管を開く。およそ3〜5個の軟骨輪の幅の片に切断する。フォーストランスデューサに取り付けるためにこの片の一端の軟骨に綿糸を取り付け、器官槽中に組織を固定するのに綿糸の輪をもう一端に作製する。各片を、通気した温かい(37℃)改良クレブスを満たした5mlの器官槽に載置する。ポンプの流速を1.0ml/分に設定し、組織を絶え間なく洗浄する。組織を初張力1000mg下に配置する。15分および30分後に組織を再度伸張し、次いでさらに30〜45分間平衡に放置する。
雄のDunkin−Hartleyモルモット(体重350〜450g)から気管を取り外し、付着結合組織を除去した後、気管筋の対側の軟骨を切開し、気管片を3〜5個の軟骨輪の幅に整える。気管片を、5mlの組織浴において同長性(isometric)ストレインゲージと固定された組織用フックとの間に筋肉を水平にして初張力1g下で吊し、3μMインドメタシンおよび10μMグアネチジンを含有する(95%O2/5%CO2)クレブス液を満たした温かい槽(37℃)に浸す。組織を平行な白金線電極間(間隔約1cm)に配置する。新鮮なクレブス液(上記組成物)の1ml/分の一定な流れを、ぜん動ポンプを使用して組織浴全体に維持する。平衡期間開始から15分および30分で再度1gの張力をかけながら、組織を1時間平衡に放置する。平衡終了時、組織を次のパラメータ:10V、10Hz、0.1ミリ秒パルス幅、2分毎に10秒連発を使用して、電場刺激(EFS)にかける。各組織において、電圧応答曲線を10v〜30Vの範囲にわたって作図して(他のすべての刺激パラメータは一定に維持)、ちょうど最大な刺激を決定する。これらの刺激パラメータを使用すると、EFS応答は、1μMテトロドトキシンまたは1μMアトロピンによる遮断で確認されるように、神経媒介が100%、コリン作動性が100%である。次いで、応答が再現可能になるまで、組織を2分間隔で繰り返し刺激する。ぜん動ポンプを20分停止させた後、試験化合物を添加し、平均単収縮をコントロール応答として最後の10分間にわたって記録する。試験化合物を組織浴に添加し、各組織に単一濃度の化合物を受けさせ、2時間平衡に放置する。添加2時間後、EFS応答の阻害を記録し、同じ動物の気管片に関する一連の化合物濃度を使用して、IC50曲線を作図する。次いで、組織を急速洗浄し、クレブス液による1ml/分の灌流を回復させる。組織をさらに16時間刺激し、EFS応答の回復を記録する。16時間終了時、10μMヒスタミンを浴槽に添加して、組織の生存度を確認する。拮抗薬のちょうど最大の濃度(阻害が>70%であるが100%未満の応答を生じる試験濃度)を、IC50曲線から特定し、誘発された阻害が25%回復する時間(T25)を、この濃度を受ける組織において計算する。化合物を一般にn=2〜5にて試験して、作用持続時間を推定する。
Claims (11)
- 5−[3−(3−ヒドロキシフェノキシ)アゼチジン−1−イル]−5−メチル−2,2−ジフェニルヘキサンアミド塩酸塩。
- 5−[3−(3−ヒドロキシフェノキシ)アゼチジン−1−イル]−5−メチル−2,2−ジフェニルヘキサンアミド塩酸塩の非溶媒和結晶形。
- 請求項1から3のいずれか一項に記載の化合物またはそれらの誘導体を少なくとも有効量含む医薬組成物。
- 医薬品として使用するための、請求項1から3のいずれか一項に記載の化合物またはその誘導体もしくは組成物。
- ・慢性または急性の気管支収縮、慢性気管支炎、末梢気道閉塞、および肺気腫、
・すべてのタイプ、病因、または病原の閉塞性または炎症性気道疾患、特に、慢性好酸球性肺炎、慢性閉塞性肺疾患(COPD)、慢性気管支炎を包含するCOPD、COPDに関連するまたは関連しない肺気腫または呼吸困難、不可逆的進行性気道閉塞を特徴とするCOPD、成人呼吸窮迫症候群(ARDS)、他の薬物治療の結果生じる気道反応亢進の悪化、および肺高血圧症に関連する気道疾患からなる群から選択されるメンバーである閉塞性または炎症性気道疾患、
・すべてのタイプ、病因、または病原の気管支炎、特に、急性気管支炎、急性喉頭気管気管支炎、アラキジン酸性気管支炎、カタル性気管支炎、クループ性気管支炎、乾性気管支炎、感染性喘息性気管支炎、増殖性気管支炎、ブドウ球菌または連鎖球菌性気管支炎、および小胞性気管支炎からなる群から選択されるメンバーである気管支炎、
・すべてのタイプ、病因、または病原の喘息、特に、アトピー性喘息、非アトピー性喘息、アレルギー性喘息、アトピー性気管支IgE媒介喘息、気管支喘息、本態性喘息、真性喘息、病態生理学的障害によって引き起こされる内因性喘息、環境要因によって引き起こされる外因性喘息、未知または不顕性原因の本態性喘息、非アトピー性喘息、気管支炎性喘息、気腫性喘息、運動誘発性喘息、アレルゲン誘発性喘息、冷風誘発性喘息、職業性喘息、細菌、真菌、原生動物、またはウイルス感染によって引き起こされる感染性喘息、非アレルギー性喘息、初発喘息、喘鳴幼児症候群、および細気管支炎からなる群から選択されるメンバーである喘息、
・急性肺障害、
・すべてのタイプ、病因、または病原の気管支拡張症、特に、円柱状気管支拡張症、嚢胞状気管支拡張症、紡錘状気管支拡張症、毛細管気管支拡張症、嚢状気管支拡張症、乾性気管支拡張症、および濾胞性気管支拡張症からなる群から選択されるメンバーである気管支拡張症
からなる群から選択される疾患、障害、および病態の治療に使用される、請求項1から3のいずれか一項に記載の化合物またはその誘導体もしくは組成物。 - M3拮抗薬活性を有する薬物の製造のための、請求項1から3のいずれか一項に記載の化合物またはその誘導体もしくは組成物の使用。
- 請求項6に記載する群から選択される疾患、障害、および病態の治療用薬物の製造のための、請求項1から3のいずれか一項に記載の化合物またはその誘導体もしくは組成物の使用。
- 有効量の請求項1から3のいずれか一項に記載の化合物またはその誘導体もしくは組成物でヒトを包含する哺乳動物を治療することを包含する、M3拮抗薬で前記哺乳動物を治療する方法。
- 疾患、障害、または病態が、請求項7に記載する群から選択される、請求項9に記載の方法。
- 請求項1から3のいずれか一項に記載の化合物またはその誘導体と、
(a)5−リポキシゲナーゼ(5−LO)阻害剤または5−リポキシゲナーゼ活性化タンパク質(FLAP)拮抗薬、
(b)LTB4、LTC4、LTD4、およびLTE4の拮抗薬を包含するロイコトリエン拮抗薬(LTRA)、
(c)H1およびH3拮抗薬を包含するヒスタミン受容体拮抗薬、
(d)うっ血除去薬使用のためのα1およびβ2−アドレナリン受容体作動性血管収縮性交感神経様作用薬、
(e)短時間または長時間作用性β2作動薬、
(f)PDE阻害剤、例えば、PDE3、PDE4、およびPDE5阻害剤、
(g)テオフィリン、
(h)クロモグリク酸ナトリウム、
(i)COX阻害剤、非選択的および選択的COX−1またはCOX−2阻害剤(NSAID)、
(j)経口および吸入グルココルチコステロイド、
(k)内因性炎症性要素に対して活性なモノクローナル抗体、
(l)抗腫瘍壊死因子(抗TNF−α)薬剤、
(m)VLA−4拮抗薬を包含する接着分子阻害剤、
(n)キニン−B1およびB2受容体拮抗薬、
(o)免疫抑制剤、
(p)マトリクスメタロプロテアーゼ(MMP)の阻害剤、
(q)タキキニンNK1、NK2、およびNK3受容体拮抗薬、
(r)エラスターゼ阻害剤、
(s)アデノシンA2a受容体作動薬、
(t)ウロキナーゼ阻害剤、
(u)ドーパミン受容体に作用する化合物、例えば、D2作動薬、
(v)NFκB経路のモジュレーター、例えば、IKK阻害剤、
(w)p38MAPキナーゼまたはsykキナーゼなどのサイトカインシグナル伝達経路のモジュレーター、
(x)粘液溶解薬または鎮咳薬として分類することができる薬剤、
(y)抗生物質、
(z)HDAC阻害剤、
(aa)PI3キナーゼ阻害剤、ならびに
(bb)CXCR2拮抗薬
から選択される治療剤との組合せ。
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US89516307P | 2007-03-16 | 2007-03-16 |
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JP4277051B2 JP4277051B2 (ja) | 2009-06-10 |
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US (1) | US8263583B2 (ja) |
EP (1) | EP2125714B1 (ja) |
JP (1) | JP4277051B2 (ja) |
KR (1) | KR101120227B1 (ja) |
CN (2) | CN101641327A (ja) |
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BR (1) | BRPI0808413A2 (ja) |
CA (1) | CA2678683C (ja) |
CY (1) | CY1111701T1 (ja) |
DK (1) | DK2125714T3 (ja) |
ES (1) | ES2364727T3 (ja) |
HK (1) | HK1189591A1 (ja) |
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PL (1) | PL2125714T3 (ja) |
PT (1) | PT2125714E (ja) |
RU (1) | RU2422439C2 (ja) |
SI (1) | SI2125714T1 (ja) |
TW (1) | TWI348907B (ja) |
WO (1) | WO2008135819A1 (ja) |
ZA (1) | ZA200906462B (ja) |
Families Citing this family (10)
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CN102712674A (zh) | 2009-11-23 | 2012-10-03 | 帕拉丁科技公司 | 黑皮质素-1受体-特异性的线性肽 |
EA021897B1 (ru) | 2009-11-23 | 2015-09-30 | Палатин Текнолоджиз, Инк. | Циклические пептиды, специфичные к рецептору меланокортина-1 |
EP2578570A1 (en) | 2011-10-07 | 2013-04-10 | Almirall, S.A. | Novel process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(r)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one via novel intermediates of synthesis. |
EP2641900A1 (en) | 2012-03-20 | 2013-09-25 | Almirall, S.A. | Novel polymorphic Crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one, heminapadisylate as agonist of the ß2 adrenergic receptor. |
EP3596046A1 (en) | 2017-03-15 | 2020-01-22 | Mylan Laboratories Ltd. | Novel polymorphs of (5-[3-(3-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide hydrochloride |
CN114732910A (zh) | 2017-10-05 | 2022-07-12 | 弗尔康医疗公司 | P38激酶抑制剂降低dux4和下游基因表达以用于治疗fshd |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
WO2020261160A1 (en) * | 2019-06-25 | 2020-12-30 | Mylan Laboratories Limited | Methods and intermediates for preparing hydrochloride salt of 5-[3-(3-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide |
WO2021260441A1 (en) * | 2020-06-26 | 2021-12-30 | Mylan Pharma Uk Limited | Formulations including 5-[3-(3-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide |
CN113577059B (zh) * | 2021-08-02 | 2022-05-20 | 山东大学齐鲁医院(青岛) | 一种用于小儿哮喘的活性药物 |
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DE69720518T2 (de) * | 1996-12-02 | 2004-02-26 | Kyorin Pharmaceutical Co., Ltd. | Neue derivate von n-substituierten pyrrolidin derivaten und deren herstellungsverfahren |
JPH11100366A (ja) | 1997-09-29 | 1999-04-13 | Kyorin Pharmaceut Co Ltd | 新規n−置換環状アミン誘導体及びその製造法 |
CN101268046B (zh) * | 2005-09-21 | 2012-07-25 | 辉瑞有限公司 | 作为毒蕈碱性受体拮抗剂的碳酰胺衍生物 |
US20100160279A1 (en) * | 2006-09-22 | 2010-06-24 | Pfizer Inc | Azetidine Derivatives as Muscarinic Receptor Antagonists |
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