JP2009502870A - 1−[(3−シアノピリジン−2−イル)メチル]−3−メチル−7−(2−ブチン−1−イル)−8−(3−アミノピペリジン−1−イル)キサンチンの塩酸塩及び水和物、その合成及びその薬剤としての使用 - Google Patents
1−[(3−シアノピリジン−2−イル)メチル]−3−メチル−7−(2−ブチン−1−イル)−8−(3−アミノピペリジン−1−イル)キサンチンの塩酸塩及び水和物、その合成及びその薬剤としての使用 Download PDFInfo
- Publication number
- JP2009502870A JP2009502870A JP2008523353A JP2008523353A JP2009502870A JP 2009502870 A JP2009502870 A JP 2009502870A JP 2008523353 A JP2008523353 A JP 2008523353A JP 2008523353 A JP2008523353 A JP 2008523353A JP 2009502870 A JP2009502870 A JP 2009502870A
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- Prior art keywords
- methyl
- butyn
- xanthine
- cyano
- pyridin
- Prior art date
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- Granted
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Abstract
Description
所望の適応症に対するその実際の効果に加えて、活性物質は、またその他の要求を満足し、医薬組成物として使用できなければならない。これらのパラメータは、活性物質の物理化学的性質に大きく関係している。
これに制限されるものではないが、これらのパラメータの例は、異なる周囲条件の下での活性物質の効果の安定性、医薬組成物の調製中の安定性及び医薬製剤の最終組成の安定性である。医薬組成物を調製するために使用される医薬活性物質は、したがって高い安定性を有していなければならず、それは異なる環境条件の下でさえ保証されなければならない。これは、活性物質自身に加えて、例えばその分解生成物を含む医薬組成物の使用を防止するために絶対に必要なものである。そのような場合に、医薬組成物に含まれている活性物質の含有量は、指定のものよりも少ないかもしれない。
水分の吸収は、水の取り込みによって生じる重量の増加の結果として医薬活性物質の含有量を減少させる。水分を吸収する傾向がある医薬組成物は、保存の際に、例えば適切な乾燥剤の添加によって、又はそれが水分から保護される環境に薬剤を保管することによって水分から保護されなければならない。さらに、水分の取り込みは、医薬物質が水分からまったく保護されない環境にさらされる場合、製造の際に医薬活性物質の含量を減少させるかもしれない。したがって、好ましくは医薬活性物質の吸湿性はほんのわずかでなければならない。
組成物の選択又は組成物の製造方法の選択に依存するある特定の環境の下で、非常に重要であるかもしれない別の特徴は、活性物質の溶解性である。例えば、医薬溶液が調製される場合(例えば、点滴のために)、活性物質は、生理学的に許容される溶媒に十分に溶解することが必須である。活性物質が十分に溶解することは、経口摂取される薬物にとっても非常に重要である。
本発明の課題は、薬理学的効能が高いという特徴だけでなく、上述の物理化学的要求をできる限り満足する医薬活性物質を提供することである。
以下の用語は同意語として使用される:
塩酸との塩-塩酸塩。
したがって、本発明は、1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-(3-アミノ-ピペリジン-1-イル)-キサンチンの塩酸との塩、並びにその鏡像異性体、混合物及び水和物に関する。このようなものとしては、例えば1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-[(R)-3-アミノ-ピペリジン-1-イル]-キサンチン及び1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-[(S)-3-アミノ-ピペリジン-1-イル]-キサンチンの一及び二塩酸塩及びこれらの混合物が挙げられ、ラセミ体を含む。本発明は、さらに上述の塩又はその水和物の少なくとも1つを含む医薬組成物及び医薬組成物の調製方法に関する。
前記効果を適切に得るために必要な服用量は、静脈内経路によって、1〜100mg、好ましくは1〜30mgであり、経口経路によって、1〜1000mg、好ましくは1〜100mgであり、それぞれ1日に1〜4回である。この目的のために、本発明に従って合成される式(I)の化合物は、必要によりその他の活性物質と組合せて、1又は複数の不活性な従来のキャリア及び/又は希釈剤、例えばコーンスターチ、ラクトース、グルコース、微結晶性セルロース、ステアリン酸マグネシウム、ポリビニルピロリドン、クエン酸、酒石酸、水、水/エタノール、水/グリセロール、水/ソルビトール、水/ポリエチレングリコール、プロピレングリコール、セチルステアリルアルコール、カルボキシメチルセルロース又は固い脂肪のような脂肪質の物質又はこれらの適した混合物と一緒に素錠又は被覆錠剤、カプセル剤、散剤、懸濁剤又は坐剤のような従来のガレヌス製剤に組み込んでもよい。
以下の実施例は、本発明を説明することを目的としている。
また、反応はそれほど極端でない圧力下でも進む。
湿った粗生成物を、50リットルのアセトンと90リットルの水の混合物中で、溶液が形成されるまで還流した。次いで、この混合物を5℃に冷却して生成物を晶出した。懸濁液を30分間5℃で攪拌し、生成物を遠心分離し、最後に20リットルのアセトンと10リットルの水の混合物で洗浄した。45℃で不活性状態としながら乾燥カップボードで乾燥させた。
収量:11.7〜12.5kg
1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-[(R)-3-アミノ-ピペリジン-1-イル]-キサンチン塩基の調製
a.3-シアノ-2-(クロロメチル)-ピリジン
165.5g(0.98モル)の2-ヒドロキシメチル-3-ピリジンカルボキサミドを270mlのオキシ塩化リンとともに1時間90〜100℃で加熱した。反応混合物を周囲温度に冷却し、次いで約800mlの水に50〜60℃の温度で滴下した。オキシ塩化リンの加水分解後、この混合物を水酸化ナトリウム溶液で冷却しながら中和して、生成物を沈殿させた。濾過し、300mlの水で洗浄し、次いで35〜40℃で乾燥させた。
収量:122.6g(理論の82%)
収量:257.5g(理論の91%)
収量:275g(理論の88%)
収量:273.25g(理論の86.2%)
融点:188±3℃(無水形)
無水形の1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-(3-(R)-アミノ-ピペリジン-1-イル)-キサンチンは、約50%まで(50%r.h.超)の相対湿度で安定である。図4の吸収ダイヤグラムからも明らかなように、この形態は約4%の水を吸収し、一水和物に変化する。相対湿度が実質的に50%以下に戻されると、無水形が再び形成される。すなわち、一水和物への変換は完全に可逆である。
1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-[(R)-3-アミノ-ピペリジン-1-イル]-キサンチン一塩酸塩
5.00gの1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-[(R)-3-アミノ-ピペリジン-1-イル]-キサンチン塩基を50mlのメタノールに溶解した。次いで、イソプロパノール中3.9モルの塩化水素溶液3.0mlを加えた。溶媒を蒸留し、残渣を40mlの酢酸エチルに懸濁し、還流して沈殿を形成した。周囲温度に冷却し、沈殿を濾過し、1リットルの酢酸エチルで洗浄し、乾燥させた。
次いで、生成物を無水エタノールから再結晶させた。
収量:2.7g(理論の50%)
融点:265±5℃(分解)
1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-[(R)-3-アミノ-ピペリジン-1-イル]-キサンチン-二塩酸塩
1-[(3-シアノ-ピリジン-2-イル)メチル]-3-メチル-7-(2-ブチン-1-イル)-8-[(R)-3-アミノ-ピペリジン-1-イル]-キサンチン塩基(1.00g;2.31ミリモル)を9.5mlの無水エタノール及び0.5mlのメチル-tert.-ブチルエテルに沸点温度で溶解した。次いで、イソプロパノール中3.9モルの塩化水素溶液1.2mlを加えた。沈殿を形成した。周囲温度に冷却した後、混合物を濾過し、1リットルのMTBEで洗浄し、乾燥させた。
収量:1.04g(理論の89.0%)
融点:205±5℃(分解);約150℃を超えるとガス状HClが放出される。
1つだけを例外とし、STOE Stadi P X線粉末回折計を用いてX線粉末ダイヤグラムを記録した。この回折計は、CuKα1線(λ=1.5406Å)及び位置敏感検出器とともに動作する。X線発生器を40mA及び40kVで動作させた。
遊離塩基の一水和物のX線粉末ダイヤグラムを、MRIによって作られた特殊空気湿度セルを配置したBruker D8 Advance X線粉末回折計で記録した。ダイヤグラムを約72%r.h.で記録した。Bruker D8 Advanceは、CuKα線(λ=1.5418Å)及び位置敏感検出器とともに動作する。X線発生器を30mA及び40kVで動作させた。
75mgの活性物質を含む被覆錠剤
1錠剤コア当たり:
活性物質 75.0mg
リン酸カルシウム 93.0mg
コーンスターチ 35.5mg
ポリビニルピロリドン 10.0mg
ヒドロキシプロピルメチルセルロース 15.0mg
ステアリン酸マグネシウム 1.5mg
230.0mg
活性物質をリン酸カルシウム、コーンスターチ、ポリビニルピロリドン、ヒドロキシプロピルメチルセルロース及び示した量の半分のステアリン酸マグネシウムと混合した。直径約13mmのブランク(Blanks)を錠剤生成機で生成し、次いでこれらを適切な機械で1.5mmのメッシュサイズのスクリーンに通し、ステアリン酸マグネシウムの残りと混合した。この粒状物を錠剤生成機で圧縮して所望の形状の錠剤を形成した。
コアの重量:230mg
ダイ:9mm、凸状
こうして生成した錠剤コアをヒドロキシプロピルメチルセルロースから本質的になるフィルムで被覆した。出来上がったフィルム被覆錠剤を蜜蝋で磨いた。
被覆錠剤の重量:245mg
100mgの活性物質を含む錠剤
組成:
1錠剤当たり:
活性物質 100.0mg
ラクトース 80.0mg
コーンスターチ 34.0mg
ポリビニルピロリドン 4.0mg
ステアリン酸マグネシウム 2.0mg
220.0mg
活性物質、ラクトース及びスターチを一緒に混合し、ポリビニルピロリドンの水溶液で均一に湿らせた。湿った組成物を篩(2.0mmメッシュサイズ)にかけ、50℃でラック型乾燥機で乾燥させた後、再度篩(1.5mmメッシュサイズ)にかけ、滑剤を加えた。出来上がった混合物を圧縮して錠剤を形成した。
錠剤の重量:220mg
直径:10mm、バイプラナー(biplanar)、両側に切子面を刻み、片側にノッチを付けた。
150mgの活性物質を含む錠剤
組成:
1錠剤当たり:
活性物質 150.0mg
粉末ラクトース 89.0mg
コーンスターチ 40.0mg
コロイダルシリカ 10.0mg
ポリビニルピロリドン 10.0mg
ステアリン酸マグネシウム 1.0mg
300.0mg
ラクトース、スターチ及びシリカと混合した活性物質を、20%ポリビニルピロリドン水溶液で湿らせ、1.5mmのメッシュサイズの篩に通した。
45℃で乾燥させた粒状物を再度同じ篩に通し、示した量のステアリン酸マグネシウムと混合した。混合物から錠剤を圧縮した。
錠剤の重量:300mg
ダイ:10mm、フラット
150mgの活性物質を含む硬質ゼラチンカプセル
1カプセル当たり:
活性物質 150.0mg
コーンスターチ(乾燥) 約180.0mg
ラクトース(粉末) 約 87.0mg
ステアリン酸マグネシウム 3.0mg
約420.0mg
活性物質を賦形剤と混合し、0.75mmのメッシュサイズの篩に通し、適切な装置を用いて均一に混合した。出来上がった混合物をサイズ1硬質ゼラチンカプセルに詰めた。
カプセル充填:約320mg
カプセルシェル:サイズ1硬質ゼラチンカプセル
150mgの活性物質を含む坐剤
1坐剤当たり:
活性物質 150.0mg
ポリエチレングリコール1500 550.0mg
ポリエチレングリコール6000 460.0mg
ポリオキシエチレンソルビタンモノステアラート 840.0mg
2,000.0mg
坐剤練薬を溶解した後、それに活性物質を一様に分布させ、溶解物を急冷モールドに流し込んだ。
50mgの活性物質を含む懸濁剤
100mlの懸濁剤当たり:
活性物質 1.00g
カルボキシメチルセルロースナトリウム塩 0.10g
メチルp-ヒドロキシベンゾアート 0.05g
プロピルp-ヒドロキシベンゾアート 0.01g
グルコース 10.00g
グリセロール 5.00g
70%ソルビトール溶液 20.00g
フレーバー 0.30g
蒸留水 ad 100ml
蒸留水を70℃に加熱した。この中でメチル及びプロピルp-ヒドロキシベンゾアートをグリセロール及びカルボキシメチルセルロースナトリウム塩と一緒に攪拌して溶解した。この溶液を周囲温度に冷却し、活性物質を加え、攪拌して均一に分散させた。糖、ソルビトール溶液及びフレーバーを加えて溶解した後、懸濁剤から攪拌により空気を除去した。
5mlの懸濁剤は50mgの活性物質を含む。
10mgの活性物質を含むアンプル剤
組成:
活性物質 10.0mg
0.01Nの塩酸 q.s.
再蒸留水 ad 2.0ml
活性物質を必要な量の0.01Nの塩酸に溶解し、塩化ナトリウムで等張にし、無菌濾過し、2mlのアンプルに移した。
50mgの活性物質を含むアンプル剤
組成:
活性物質 50.0mg
0.01Nの塩酸 q.s.
再蒸留水 ad 10.0ml
活性物質を必要な量の0.01Nの塩酸に溶解し、塩化ナトリウムで等張にし、無菌濾過し、10mlのアンプルに移した。
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DE102005035891A DE102005035891A1 (de) | 2005-07-30 | 2005-07-30 | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
DE102005035891.8 | 2005-07-30 | ||
PCT/EP2006/064657 WO2007014886A1 (de) | 2005-07-30 | 2006-07-26 | Hydrochloride und hydrate von 1-[(3-cyano-pyridin-2-yl) methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-amino-piperidin-1-yl)-xanthin, deren herstellung und deren verwendung als arzneimittel |
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JP2012112773A Division JP2012153723A (ja) | 2005-07-30 | 2012-05-16 | 1−[(3−シアノピリジン−2−イル)メチル]−3−メチル−7−(2−ブチン−1−イル)−8−(3−アミノピペリジン−1−イル)キサンチンの塩酸塩及び水和物、その合成及びその薬剤としての使用 |
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JP2009502870A true JP2009502870A (ja) | 2009-01-29 |
JP5145224B2 JP5145224B2 (ja) | 2013-02-13 |
Family
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JP2008523353A Active JP5145224B2 (ja) | 2005-07-30 | 2006-07-26 | 1−[(3−シアノピリジン−2−イル)メチル]−3−メチル−7−(2−ブチン−1−イル)−8−(3−アミノピペリジン−1−イル)キサンチンの塩酸塩及び水和物、その合成及びその薬剤としての使用 |
JP2012112773A Pending JP2012153723A (ja) | 2005-07-30 | 2012-05-16 | 1−[(3−シアノピリジン−2−イル)メチル]−3−メチル−7−(2−ブチン−1−イル)−8−(3−アミノピペリジン−1−イル)キサンチンの塩酸塩及び水和物、その合成及びその薬剤としての使用 |
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JP2012112773A Pending JP2012153723A (ja) | 2005-07-30 | 2012-05-16 | 1−[(3−シアノピリジン−2−イル)メチル]−3−メチル−7−(2−ブチン−1−イル)−8−(3−アミノピペリジン−1−イル)キサンチンの塩酸塩及び水和物、その合成及びその薬剤としての使用 |
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US (2) | US8106060B2 (ja) |
EP (2) | EP2540724B1 (ja) |
JP (2) | JP5145224B2 (ja) |
KR (1) | KR101446692B1 (ja) |
CN (2) | CN102276609A (ja) |
AR (1) | AR055101A1 (ja) |
BR (1) | BRPI0614700B8 (ja) |
CA (1) | CA2617090C (ja) |
CY (1) | CY1114563T1 (ja) |
DE (1) | DE102005035891A1 (ja) |
DK (1) | DK1912990T3 (ja) |
EA (1) | EA013411B1 (ja) |
EC (1) | ECSP088148A (ja) |
ES (1) | ES2428368T3 (ja) |
HK (1) | HK1122809A1 (ja) |
HR (1) | HRP20130868T1 (ja) |
IL (1) | IL189099A0 (ja) |
ME (1) | ME01593B (ja) |
MX (1) | MX2008000932A (ja) |
MY (1) | MY147274A (ja) |
NO (1) | NO20076510L (ja) |
NZ (1) | NZ566187A (ja) |
PE (1) | PE20070219A1 (ja) |
PL (1) | PL1912990T3 (ja) |
PT (1) | PT1912990E (ja) |
RS (1) | RS52836B (ja) |
SG (1) | SG164390A1 (ja) |
SI (1) | SI1912990T1 (ja) |
TW (1) | TWI393720B (ja) |
UA (1) | UA96577C2 (ja) |
UY (1) | UY29700A1 (ja) |
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JP2018520120A (ja) * | 2015-05-29 | 2018-07-26 | 江蘇天士力帝益薬業有限会社Jiangsu Tasly Diyi Pharmaceutical Co., Ltd. | キサンチン誘導体 |
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