JP2012229269A - 多形体 - Google Patents

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JP2012229269A
JP2012229269A JP2012180151A JP2012180151A JP2012229269A JP 2012229269 A JP2012229269 A JP 2012229269A JP 2012180151 A JP2012180151 A JP 2012180151A JP 2012180151 A JP2012180151 A JP 2012180151A JP 2012229269 A JP2012229269 A JP 2012229269A
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methyl
polymorph
butyn
quinazolin
xanthine
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JP5800773B2 (ja
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Peter Sieger
ペーター シーゲル
Dirk Kemmer
ディルク ケマー
Peter Kohlbauer
ペーター コールバウアー
Nicola Thomas
トーマス ニコラ
Martin Renz
マルティン レンツ
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Boehringer Ingelheim International GmbH
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Abstract

【課題】I型及びII型糖尿病、前糖尿病又は減少した糖耐性、さらに関節リウマチ、肥満、又はカルシトニン誘導骨粗鬆症を有する患者、並びに同種移植が行われた患者を治療するのに好適な医薬組成物を提供すること。
【解決手段】1-[(4-メチル-キナゾリン-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)-キサンチンの多形体結晶修飾、それらの製造及び薬剤の調製のためのそれらの使用方法を提供する。
【選択図】なし

Description

本発明は、DPP-IV阻害剤の多形体結晶修飾、その調製及び薬剤を調製するためのその使用に関する。
名称CD26としても公知な酵素DPP-IVは、N末端にプロリン又はアラニン基を有する蛋白質におけるジペプチドの開裂を促進するセリンプロテアーゼである。それによって、DPP-IV阻害剤は、ペプチドGLP-1を含む生理活性ペプチドの血栓濃度に影響を与える。このタイプの化合物は、増加したDPP-IV活性に関連するか、又は該DPP-IV活性を減少させることによって予防又は軽減することのできる病状又は疾患、特にI型又はII型の糖尿病、前糖尿病、又は減少した糖耐性の予防又は治療に有用である。WO 2004/018468は、有用な薬理学的特性を有するDPP-IV阻害剤を記載している。そこで開示されている阻害剤の一例は、1-[(4-メチル-キナゾリン-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)-キサンチンである。
国際公開第2004/018468号パンフレット
本発明の範囲内では、1-[(4-メチル-キナゾリン-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)-キサンチンが種々の多形体結晶修飾となり、且つWO 2004/018468で調製された化合物が周囲温度下で2種のエナンチオトロピー多形体の混合物として存在することが見出された。該2種の多形体がもう1種に変形する温度は25±15℃である(図1及び2参照)。
該混合物を>40℃の温度まで加熱することによって得ることのできる純粋な高温形体(多形体A)は、206±3℃で融解する。粉末X線図(図3参照)では、この形体は以下のd値:11.49Å、7.60Å、7.15Å、3.86Å、3.54Å及び3.47Å(表1及び2も参照)で特徴的な反射を示す。
無水形体A/Bの熱分析。 エナンチオトロピー相転移の周期的DSC図。 無水形体Aの粉末X線図。 無水形体Bの粉末X線図。 多形体Cの粉末X線図。 形体Cの熱分析。
無水多形体Aは、(a)1-[(4-メチル-キナゾリン-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)-キサンチンを無水エタノール中でリフラックスし、任意に該混合物を濾過する工程、(b)この熱い溶液又は熱い濾過物を結晶化が開始するまで冷却する工程、(c)tert.-ブチルメチルエーテルなどの溶媒で希釈する工程、(d)該溶媒混合物を吸引濾過する工程、及び(e)多形体Aを45℃の真空下で乾燥する工程、によって調製され得る。
低温形体(多形体B)は、<10℃の温度まで冷却することによって得られる。粉末X線図(図4参照)では、この形体は以下のd値:11.25Å、9.32Å、7.46Å、6.98Å及び3.77Å(表3及び4も参照)で特徴的な反射を示す。
無水多形体Bは、(a)1-[(4-メチル-キナゾリン-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)-キサンチンを無水エタノール中に溶解させてリフラックスし、任意に該混合物を濾過する工程、(b)この熱い溶液又は濾過物を結晶化のために10℃以下の温度まで冷却する工程、(c)tert.-ブチルメチルエーテルなどの溶媒で希釈する工程、(d)溶媒混合物を吸引濾過する工程、及び(e)多形体を10℃以下の温度の真空下で乾燥する工程、によって調製され得る。
別の多形体(多形体C)は、粉末X線図(図5参照)において以下のd値:12.90Å、11.10Å、6.44Å、3.93Å及び3.74Å(図5も参照)で特徴的な反射を示す。
多形体Cは、(a)1-[(4-メチル-キナゾリン-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)-キサンチンをメタノール中に溶解させて還流し、活性炭の存在下で任意に濾過する工程、(b)該メタノール性溶液を40-60℃の温度まで冷却する工程、(c)tert.-ブチルメチルエーテル又はジイソプロピルエーテルなどの溶媒を加える工程、(d)得られた懸濁液をまずは15-25℃まで、続いて0-5℃まで穏やかに冷却する工程、(e)形成した結晶を吸引濾過し、tert.-ブチルメチルエーテル又はジイソプロピルエーテルで再び洗浄する工程、及び(f)得られた結晶を70℃の温度の真空乾燥機で乾燥する工程、で得られる。
別の多形体(多形体D)は150±3℃で融解する。この多形体は、多形体Cを30-100℃の温度まで加熱し、この温度で乾燥させると得られる。
最後に、175±3℃の温度で融解する多形体Eも存在する。無水多形体Eは、多形体Dが融解すると形成される。さらに加熱すると、多形体Eは該融解物から晶出する。
得られた多形体は、I型及びII型糖尿病、前糖尿病又は減少した糖耐性、さらに関節リウマチ、肥満、又はカルシトニン誘導骨粗鬆症を有する患者、並びに同種移植が行われた患者を治療するのに好適な医薬組成物を調製するためのWO 2004/018468に記載された2種の多形体A及びBの混合物と同一の方法で用いられ得る。これらの薬剤は、1種以上の不活性キャリアに加え、少なくとも0.1%〜0.5%、好ましくは少なくとも0.5%〜1.5%、及び特に好ましくは少なくとも1%〜3%の多形体A、B、又はCの1種を含有する。
以下の実施例は、本発明をより詳細に説明することを目的とする。
実施例1 多形体Aの結晶化
粗い1-[(4-メチル-キナゾリン-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)-キサンチンを5倍量の無水エタノールでリフラックスし、この熱い溶液を活性炭に通して濾過した。濾過物を20℃まで冷却して結晶化を開始した後、該溶液をtert.-ブチルメチルエーテルで2倍の容積まで希釈した。続いて、この懸濁液を2℃まで冷却し、2時間攪拌し、吸引濾過し、及び真空乾燥機において45℃で乾燥させた。
多形体Aは206±3℃で融解する。該DSC図では、別のわずかな吸熱信号が約25℃で見ることができる。これは、該2種のエナンチオトロピー結晶修飾A及びBの間の完全に可逆な固体-固体の相転移である。該形体Aはこの変形温度よりも高温で熱力学的に安定な修飾であり、形態Bはこの変形温度よりも低温で熱力学的に安定な修飾である。
図2は周期的なDSC図を示しており、-40℃〜120℃の相転移及びその逆が計3回起こっている。加熱中、相転移は吸熱信号として観察され、従って冷却中は発熱信号として観察される。第一の加熱サイクル中に、相転移は吸熱の二重信号か又は非常にブロードな信号としても観察され、全ての他のサイクルにおいて該信号は非常に鋭い吸熱又は発熱信号として起こり、加熱又は冷却が起こるか否かに依存する
表1: 無水形体Aの30°以下の標識化されたX線反射2θと強度(標準化)
Figure 2012229269

Figure 2012229269
表2:無水形体のAの格子定数
Figure 2012229269
実施例2 多形体Bの結晶化
多形体Bは、実施例1からの形体Aを<10℃の温度まで冷却することによって得られる。
表3:無水形体Bの30°以下の標識化されたX線反射2θと強度(標準化)
Figure 2012229269

Figure 2012229269
表4:無水形体Bの格子定数
Figure 2012229269
実施例3 多形体Cの結晶化
粗い1-[(4-メチル-キナゾリン-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(26kg)を、157Lのメタノールでリフラックスし、1.3kgの活性炭と混合し、30分攪拌した後に該混合物を濾過して26Lのメタノールで漱いだ。122Lのメタノールを濾過物から蒸留し、続いて残渣を45-55℃まで冷却した。52Lのtert.-ブチルメチルエーテルを30分かけて残渣に加えた。続いて、該混合物を45-55℃でさらに60分間攪拌した。結晶化がこの時間内に起こった。さらに78Lのtert. ブチルメチルエーテルを30分かけて該懸濁液に加え、続いて45-55℃でさらに60分間再び攪拌した。それを4倍の体積に希釈した。該懸濁液を15-25℃まで穏やかに冷却し、この温度で終夜攪拌した。該懸濁液を0-5℃まで冷却した後、結晶を吸引濾過し、2バッチのtert.-ブチルメチルエーテルで洗浄し、及び70℃の真空乾燥機で乾燥させた。
表5:無水形体Cの30°以下のX線反射2θと強度(標準化)
Figure 2012229269
実施例4 多形体Dの結晶化
多形体Cは、実施例3からの多形体Cを30-100℃の温度まで加熱し、この温度で乾燥して得られる。
実施例5 多形体Eの結晶化
無水多形体Eは、多形体Dが融解すると得られる。さらなる加熱により、多形体Eが該融解物から晶出する。
形体CのDSC図では、全範囲の信号を観察することができる。最も強い信号は約206℃における無水形体Aの融点であり、これはDSC実験で製造される。融点前では、複数の吸熱及び発熱信号を観察することができる。従って、例えば、非常にブロードで弱い吸熱信号が30〜100℃で見ることができ、これは熱重量分析(TR)における主な質量損失と相互に関連する。TG/IRの同時実験は、水のみがこの温度範囲で該サンプルから抜け出るという情報を提供する。
100℃の温度で保持されたサンプルに関する粉末X線図は、出発物質からの異なるX線反射を示しており、形体Cがおよそ半水化物又は一水和物の領域にある化学量論比を有する水和物相であることを示唆している。温度制御されたサンプルは別の無水修飾Dであり、無水条件下でのみ安定である。該D形体は約150℃で融解する。別の無水結晶修飾Eは該融解物から結晶化し、さらに加熱されると約175℃で融解する。最後に、形体Aは形体Eの融解物から結晶化する。形体Eは高温でのみ起こる準安定な結晶修飾でもある。

Claims (12)

  1. 206±3℃で融解することを特徴とする、化合物1-[(4-メチル-キナゾリン-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)-キサンチンの無水多形体A。
  2. 粉末X線図において、以下のd値:11.49Å、7.60Å、7.15Å、3.86Å、3.54Å及び3.47Åで特徴的な反射を有する、請求項１記載の多形体A。
  3. 10-40℃の温度で請求項１記載の多形体Aに可逆的に変形することを特徴とする、化合物1-[(4-メチル-キナゾリン-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)-キサンチンの無水多形体B。
  4. 粉末X線図において、以下のd値:11.25Å、9.32Å、7.46Å、6.98Å及び3.77Åで特徴的な反射を有する、請求項３記載の多形体B。
  5. 30-100℃の温度で水を失い、且つDSC図において約150〜175℃でさらなる熱効果を示すことを特徴とする、化合物1-[(4-メチル-キナゾリン-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)-キサンチンの多形体C。
  6. 粉末X線図において、以下のd値:12.90Å、11.10Å、6.44Å、3.93Å及び3.74Åで特徴的な反射を有する、請求項５記載の多形体C。
  7. 150±3℃で融解することを特徴とする、化合物1-[(4-メチル-キナゾリン-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)-キサンチンの無水多形体D。
  8. 175±3℃で融解することを特徴とする、化合物1-[(4-メチル-キナゾリン-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)-キサンチンの無水多形体E。
  9. 請求項５記載の多形体Cを調製する方法であって、(a)1-[(4-メチル-キナゾリン-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)-キサンチンをメタノール中で還流する工程、(b)該メタノール性溶液を40-60℃の温度まで冷却する工程、(c)tert.-ブチルメチルエーテルなどの溶媒を加える工程、(d)得られた懸濁液をまずは15-25℃まで、続いて0-5℃まで冷却する工程、(e)結晶を吸引濾過する工程、及び(f)70℃の温度の真空下で乾燥する工程、を特徴とする方法。
  10. 工程(a)の後に前記熱い溶液を濾過する、請求項９記載の方法。
  11. I型及びII型糖尿病、前糖尿病又は減少した糖耐性、さらに関節リウマチ、肥満、又はカルシトニン誘導骨粗鬆症を有する患者、並びに同種移植が行われた患者の治療のための医薬組成物を調製するための、化合物1-[(4-メチル-キナゾリン-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)-キサンチンの多形体A、B、又はCの1種の使用。
  12. 化合物1-[(4-メチル-キナゾリン-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)-キサンチンに加えて1種以上の不活性キャリア及び/又は希釈剤を含有する薬剤であって、少なくとも0.1%〜0.5%の多形体A、B、又はCの1種を含有することを特徴とする、薬剤。
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