JP2016518381A - 5−クロロ−チオフェン−2−カルボン酸[(s)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドの酒石酸塩 - Google Patents
5−クロロ−チオフェン−2−カルボン酸[(s)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドの酒石酸塩 Download PDFInfo
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- JP2016518381A JP2016518381A JP2016509496A JP2016509496A JP2016518381A JP 2016518381 A JP2016518381 A JP 2016518381A JP 2016509496 A JP2016509496 A JP 2016509496A JP 2016509496 A JP2016509496 A JP 2016509496A JP 2016518381 A JP2016518381 A JP 2016518381A
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- methyl
- oxo
- chloro
- thiophene
- carboxylic acid
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Links
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Classifications
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
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Abstract
Description
X線回折図
式(I)の化合物のL−酒石酸塩の粉末試料から出発して粉末X線回折図を記録した。
式(I)の化合物のL−酒石酸塩の赤外線(IR)スペクトルは、Nexus IRTF分光計において4000〜400cm-1の間、4cm-1の分解能で記録した。このスペクトルは、下の表に示された吸収バンドを特徴とする。
本発明の化合物において実施した示差熱力学的分析は、203.9℃で融解する前になんら熱的事象を示さなかった。
EtOAc 酢酸エチル
Boc tert−ブトキシカルボニル
DAP ジアミノピメリン酸
T3P プロピルホスホン酸無水物
EtOH エタノール
DIEA N,N−ジイソプロピルエチルアミン
HCl 塩化水素
MeTHF 2−メチルテトラヒドロフラン
t−BuOK カリウムtert−ブトキシド
THF テトラヒドロフラン
iPrOH イソプロパノール
℃ 摂氏温度
式(II)の5−クロロ−チオフェン−2−カルボン酸100g(1.1当量)から、80℃でトルエン1.4体積中の塩化チオニル1.5当量との反応によって式(III)の酸塩化物を得た。
式(IV)の化合物を得るために、ステップ(a)で得た酸塩化物(化合物III)を含む反応媒体を、THF 3体積および水1.2体積中の30%NaOH 3.3当量の存在下で、Boc−DAP−OH 1当量を含む5℃の溶液上に移し、それを蒸発させた後、単離した。
ステップ(b)で得た化合物(IV)3当量を、EtOAcの溶液中、カップリング剤としてT3P 1.5当量を用いてメチルピペラジンと18時間カップリングさせることによって化合物(V)を得た。次いで、化合物(V)をEtOAcで抽出し、次いで、EtOAc 1.5〜2体積中の結晶化によって単離した。
化合物(VI)は、化合物(V)のBoc官能基を加水分解することによって得た。EtOH 6.5体積および水0.36体積中の化合物(V)を、1時間の間、加熱された(70℃)12N水性HCl 3当量の上に移した。
化合物(VIII)は、3−ブロモ−メチルアニリン(化合物VII)200gを、THF 5体積中のDIEA 1.2当量の存在下、20℃で4−クロロブチリルクロリド1当量でアシル化することによって製造した。2時間後、生成した混合物を、15℃で水13当量の上に移し、化合物VIIIを沈殿させた。
化合物(IX)は、MeTHF 10体積中のtBuOK 1.2当量の存在下、10℃で化合物(VIII)290gの環化によって得た。
化合物(X)は、トルエン8体積中のベンジルメルカプタン1.2当量、ホスフィン0.06当量、Pd(0)0.03およびDIEA 2当量の存在下、100℃で4時間、化合物(IX)20gから得た。
化合物(XI)は、酢酸5.7当量および水0.3体積中の塩化スルフリル4当量の存在下で化合物(IX)の酸化によって得た。
式(I)の化合物は、化合物(VI)と化合物(XI)とをカップリングすることによって得た。
遊離形態の式(I)の化合物が得られたら、そのL−酒石酸塩を得るためにそれを結晶化反応にかけた。
前に記載したように、塩酸塩の形態の式(I)の化合物はアモルファスであり、それを結晶化させる試みが成功していないことに注目すべきである。
ナトリウム塩、L−乳酸塩およびL−酒石酸塩における式(I)の化合物の物理的性質を下の表にまとめる。
ナトリウム塩、L−乳酸塩およびL−酒石酸塩における式(I)の化合物の結晶化のいくつかの特性を2つの異なる溶媒:非極性溶媒(酢酸エチルまたはEtOAc)および極性プロトン性溶媒(イソプロパノールまたはiPrOH)において分析した。
以下で1週間貯蔵した後、式(I)の化合物のナトリウム塩、L−乳酸塩およびL−酒石酸塩を分析した:
・80℃
・80℃および飽和湿度下
式(I)の化合物のナトリウム塩、L−乳酸塩およびL−酒石酸塩の溶解度を異なる緩衝液中で分析した。
結果を下の表に記載する(試験化合物の溶解度は、mg/mlで表す)。
式(I)の化合物のナトリウム塩、L−乳酸塩およびL−酒石酸塩を、強い酸化性溶液中で1週間の貯蔵後に分析した:3つの化合物を、室温で、0.3%H202の溶液中に維持した。
Claims (8)
- 5−クロロ−チオフェン−2−カルボン酸[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドのL−酒石酸塩。
- 結晶性であることを特徴とする、請求項1に記載の5−クロロ−チオフェン−2−カルボン酸[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドのL−酒石酸塩。
- 図1のX線回折図を有することを特徴とする、請求項1または2に記載の5−クロロ−チオフェン−2−カルボン酸[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドのL−酒石酸塩。
- 5−クロロ−チオフェン−2−カルボン酸[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドのL−酒石酸塩を製造する方法であって、5−クロロ−チオフェン−2−カルボン酸[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドの遊離塩基形態を、溶媒中でL−酒石酸と反応させることを特徴とする方法。
- 5−クロロ−チオフェン−2−カルボン酸[2−アミノ−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロピル]−アミドおよび2−メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルクロリドを加えることによって、5−クロロ−チオフェン−2−カルボン酸[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドの遊離形態を得ることを特徴とする、請求項4に記載の方法。
- 5−クロロ−チオフェン−2−カルボン酸[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドのL−酒石酸塩を含むことを特徴とする薬剤。
- 活性成分として5−クロロ−チオフェン−2−カルボン酸[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドのL−酒石酸塩および、また少なくとも1つの薬学的に許容しうる賦形剤を含むことを特徴とする医薬組成物。
- 心血管障害、血栓塞栓性疾患または再狭窄の治療または予防に使用するための請求項1〜3のいずれか1項に記載の5−クロロ−チオフェン−2−カルボン酸
[(S)−2−[メチル−3−(2−オキソ−ピロリジン−1−イル)−ベンゼンスルホニルアミノ]−3−(4−メチル−ピペラジン−1−イル)−3−オキソ−プロプリル]アミドのL−酒石酸塩。
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EP13305556 | 2013-04-26 | ||
PCT/EP2014/058513 WO2014174102A1 (en) | 2013-04-26 | 2014-04-25 | Tartrate salt of 5-chloro-thiophene-2-carboxylic acid [(s)-2-[methyl-3-(2-oxo-pyrrolidin-1-yl)-benzenesulfonylamino]-3-(4-methyl piperazin-1 -yl)-3-oxo-propryl]amide |
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