JP2018150376A - オキシトシン/バソプレッシンV1aレセプターのアンタゴニストとしてのピロリジン誘導体 - Google Patents
オキシトシン/バソプレッシンV1aレセプターのアンタゴニストとしてのピロリジン誘導体 Download PDFInfo
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- JP2018150376A JP2018150376A JP2018108155A JP2018108155A JP2018150376A JP 2018150376 A JP2018150376 A JP 2018150376A JP 2018108155 A JP2018108155 A JP 2018108155A JP 2018108155 A JP2018108155 A JP 2018108155A JP 2018150376 A JP2018150376 A JP 2018150376A
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Abstract
Description
b)有機溶媒中で1%アルコールにより精製する。
c)有機溶媒中で2%アルコールにより精製する。
b)トルエン中にて1%メタノールで精製する。
c)トルエン中にて2%メタノールで精製する。
本発明は、(3Z,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムと、(3E,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムと、を含む粗製の異性体混合物として得られる、(3Z,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムの合成および精製に関する。
上述のプロトコルに従って得られた粗製の異性体混合物の乾式フラッシュクロマトグラフィー精製が、異なる溶出条件を用いて試みられた。乾燥するまで濃縮された(3Z/E,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムの粗製混合物は、2容積のトルエン中で再溶解され、SiO2(5重量)のパッドに装填され、25画分容積の溶出液で溶出された。
画分1〜5:純トルエンでの溶出
画分6〜10:トルエン/MeOH1%vol/volでの溶出
画分10〜15:トルエン/MeOH2%vol/volでの溶出
粗製混合物である(3Z/E,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムから、純粋な(3Z,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムを結晶化することに対する評価の最初のパートは、純粋な(3Z,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムの溶解性と潜在的な結晶化条件を調べることであった。15mg規模で実施された溶解性/結晶化試験の結果は下記の表3で説明される。
(1.4.1 小規模精製)
(3Z,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムの実質的に純粋な形態における単離工程は、オキシムエステルの還元後に単離された粗製の異性体混合物(実施例1のステージ7)の、バイオタージシステム(Biotage AB、SE−751 03 ウプサラ、スウェーデン)を用いたクロマトグラフィーによって実施された。
粗製の(3Z/E,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシム(0.392kg、1.16モル、1.0重量)の様々なバッチが、およそ50%w/wのトルエン溶液としてバイオタージ150L SIMユニットに装填されて、1%メタノールのトルエン溶液(150L)、次に2%メタノールのトルエン溶液(50L)で、分画サイズ5.0Lにて精製された。収集された画分はTLC15とHPLC分析で適切に分析された。不純物を含まない(3Z,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシム(基準:Z異性体が面積96.00%以上、E異性体が面積1.20%以下)を含むと考えられる画分は、混ぜ合わされて、40〜45℃の真空下で濃縮された。無水エタノール(2x2L)が残留物に加えられ、その溶液は、泡状の固体を処理し得るまで、40〜45℃の真空下で濃縮された。所望された生成物、(3Z,5S)−1−[(ビフェニル−4−イル−カルボニル)−5−ヒドロキシ−メチル]ピロリジン−3−オンO−メチルオキシム
(0.089Kg、22.7%w/w、1H NMR(CDCl3)で構造と一致、HPLCにて面積99.3%、98.4:0.9のZ/E比)が、わずかに灰色がかった白色から薄茶色の固体として得られた。
インプット:2.713kg
アウトプット:2.633kg
収量:97.1%w/w
ヒトオキシトシンレセプターへの競合的結合が、シンチレーション近接アッセイによりin vitroで測定された。
妊娠後期(妊娠19−21日目で認証)で体重が350〜400gの、Sprague Dawley CD(SD)BRのメスのラット(Charles River、カルコ、イタリア)が、ウレタン(1.05g/kg、腹腔内投与)で麻酔されて恒温の手術台におかれた。下腹部レベルでの正中切開がなされ、一の妊娠子宮角を露出させて、(卵巣近くの)その卵管端を外科用絹糸での結紮で閉じた。
図1AとBは、麻酔下にある出産間近の妊娠ラット(妊娠日齢19−21)における自発性の子宮収縮の抑制に対する、経口ルートにより投与されたZ異性体とE異性体の投与反応効果を示している。n=6〜8である動物のグループごとの平均±標準誤差としてのデータである。y軸は、投与前を100%として比べたときの%値として子宮収縮を表している。x軸は分単位での投与後の時間を表している。収縮は連続的に記録され、10分間隔ごとに曲線下面積(AUC)が積分された。
Claims (22)
- 式(3Z,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムで表される化合物。
- 前記化合物が実質的に純粋な形態で提供される、請求項1に記載の化合物。
- 前記実質的に純粋な形態の純度が、少なくとも85%から99.9%の範囲にある、請求項2に記載の化合物。
- 前記化合物がオキシトシンレセプターアンタゴニストである、請求項1から請求項3のいずれか1項に記載の化合物。
- 前記化合物がバソプレッシンV1aレセプターアンタゴニストである、請求項1から請求項4のいずれか1項に記載の化合物。
- 前記化合物が子宮収縮を抑制する、請求項1から請求項5のいずれか1項に記載の化合物。
- 前記化合物が50mgから900mgの単回投与量で、前記化合物を必要とする対象に投与される、請求項1から請求項6のいずれか1項に記載の化合物。
- 前記単回投与量が好ましくは100mgから600mgである、請求項7に記載の化合物。
- カルシウムチャネル阻害剤、硫酸マグネシウム、選択的プロスタグランジンモジュレータ、ベータ−2−アドレナリンアゴニスト、ベータ−3−アドレナリンレセプターアゴニスト、および/またはコルチコステロイドを含む群から選択される少なくとも1の化合物と、併用してまたは別々に前記化合物が投与される、請求項1から請求項8のいずれか1項に記載の化合物。
- 前記化合物が血漿中で安定である、請求項1から請求項9のいずれか1項に記載の化合物。
- 前記化合物を必要とする対象が哺乳類、好ましくはヒトである、請求項1から請求項10のいずれか1項に記載の化合物。
- 医薬として使用される、請求項1から請求項11のいずれか1項に記載の化合物。
- 前記化合物を必要とする対象において、オキシトシンレセプター活性およびバソプレッシンV1aレセプター活性のうちの少なくとも1つと関連する疾患の、治療および予防のうちの少なくとも1つに用いられる、請求項1から請求項11のいずれか1項に記載の化合物。
- 前記オキシトシンレセプター活性と関係がある疾患が、早期分娩、未熟児出産、月経困難症、早漏、性的不全、子宮内膜症、子宮収縮による胚着床不全、不妊、良性前立腺過形成、神経精神障害、自閉症、社会的行動障害、心理社会的ストレス、および/または心血管障害を含む群から選択される、請求項13に記載の化合物。
- 請求項1から請求項11のいずれか1項に記載の化合物と、医薬的に許容されるキャリア、希釈剤または賦形剤を含有する医薬組成物。
- 経口、経膣または静注経路で投与がなされる、請求項15に記載の医薬組成物。
- a)式(3Z,5S)−5−(ヒドロキシメチル)−1−[(2′−メチル−1,1′−ビフェニル−4−イル)カルボニル]ピロリジン−3−オンO−メチルオキシムで表される化合物およびその活性代謝物のうちの少なくとも1つを含む粗製の異性体混合物を、シリカゲルクロマトグラフィーカラムに装填する段階と、
b)有機溶媒中において1%アルコールで精製する段階と、
c)有機溶媒中において2%アルコールで精製する段階と、
を備える請求項1から請求項11のいずれか1項に記載の化合物を、実質的に純粋な形態で調製および分離するプロセス。 - 生殖補助医療において用いられる、請求項1から請求項11のいずれか1項に記載の化合物。
- 体外受精−胚移植(IVF−ET)法による不妊の治療に用いられる、請求項1から請求項11のいずれか1項に記載の化合物。
- 子宮収縮による胚着床不全の低減に用いられる、請求項1から請求項11のいずれか1項に記載の化合物。
- 胚移植中に発生する収縮の低減に用いられる、請求項1から請求項11のいずれか1項に記載の化合物。
- オキシトシン誘発性の血管収縮、バソプレッシン誘発性の血管収縮、オキシトシン誘発性の筋収縮、バソプレッシン誘発性の筋収縮に関連する疾病の治療および予防のうちの少なくとも1つに用いられる、請求項1から請求項11のいずれか1項に記載の化合物。
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SG11201804594YA (en) | 2016-01-04 | 2018-06-28 | Merck Serono Sa | L-valinate of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof |
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CN115380122A (zh) | 2020-02-10 | 2022-11-22 | 奥布赛瓦股份公司 | 用于催产素受体拮抗剂疗法的生物标志物 |
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JP2007524702A (ja) * | 2004-02-26 | 2007-08-30 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | ピロリジンオキシムを調製するための方法 |
JP6462030B2 (ja) * | 2013-09-10 | 2019-01-30 | オブセヴァ エス.エー. | オキシトシン/バソプレッシンV1aレセプターのアンタゴニストとしてのピロリジン誘導体を含有する医薬組成物 |
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