JP2011522016A - 4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩、この結晶形態、調製、および治療的使用 - Google Patents
4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩、この結晶形態、調製、および治療的使用 Download PDFInfo
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- JP2011522016A JP2011522016A JP2011512184A JP2011512184A JP2011522016A JP 2011522016 A JP2011522016 A JP 2011522016A JP 2011512184 A JP2011512184 A JP 2011512184A JP 2011512184 A JP2011512184 A JP 2011512184A JP 2011522016 A JP2011522016 A JP 2011522016A
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- Prior art keywords
- diazabicyclo
- nonane
- bromophenyl
- carboxylate
- fumarate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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Abstract
Description
赤外スペクトル
4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートの2種の結晶形態の赤外(IR)スペクトルを、分解能4cm−1で4000cm−1から400cm−1まで、フーリエ変換分光光度計(Nicolet、Magna−IR550)で記録した。KBrと混合したこれらの化合物(生成物の約1%w/w)をペレットにし、透過モードで検査した。
I型およびII型の粉末試料から開始して、粉末X線回折図を記録した。
温度の関数としての示差熱量測定は、窒素を通しながら、TA InstrumentsのQ1000熱分析計で行う。
4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラート(WO00/58311)232.45gを、6lジャケット付反応器のエタノール2331mlに入れる。反応媒質を60℃にする。フマル酸87.17gのエタノール1000mlおよび水97ml溶液を、予め60℃に加熱し、その後添加する。続いて、溶媒1900mlを留去し、次いで反応媒質を2.5時間かけて20℃に冷却する。20℃で2.5時間の接触時間の後、4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩のI型を濾別し、エタノール400mlで2回洗浄し、その後真空下50℃で乾燥する。
1H NMR(400MHz,d6−DMSO)δ(ppm):1.80(bs(a),2H),2.10(bs,2H),3.10(bs,6H),3.71(bs,1H),3.84(bs,1H),4.25(bs,0.5H),4.40(bs,0.5H),6.58(s,2H),7.14(m,2H),7.57(m,2H),11(bs,2H)
(a)bs=ブロードシングレット。
4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラート24.26kgおよびフマル酸8.52kg(1.1当量)を、630lジャケット付ホウロウ反応器のメタノール197lに入れる。完全に溶解するまで、反応媒質を65℃で攪拌する。これを2時間かけて45℃に冷却し、その後、4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩のI型0.5%で開始する。この温度を1時間保持する。続いて、反応媒質を4.5時間かけて0℃に冷却し、その後、この温度で2時間保持する。4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩のI型を濾別し、冷メタノール24lで2回洗浄し、その後真空下60℃で乾燥する。
1H NMR(400MHz,d6−DMSO)δ(ppm):1.80(bs(a),2H),2.10(bs,2H),3.10(bs,6H),3.71(bs,1H),3.84(bs,1H),4.25(bs,0.5H),4.40(bs,0.5H),6.58(s,2H),7.14(m,2H),7.57(m,2H),11(bs,2H)
(a)bs=ブロードシングレット。
A)添加剤の添加によるII型の結晶化
4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩のI型のメタノール溶液Aを、濃度約30mg/mlで調製する。必要であれば、生成物をすべて溶解するために、約40℃に加熱を行い、その後濾過を行う。
4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩I型のメタノール溶液Eを、濃度約100mg/mlで調製する。この溶液を約15分間加熱還流し、その後濾過する。溶液Eの温度を約10℃に下げる。
カラム:Inertsil ODS3 150×4.6mm、5μm、25℃で保持
移動相:
緩衝液pH4.5:0.01M KH2PO4、0.5g/lヘプタスルホン酸ナトリウム
1M KOHでpH4.5に調節
相A:90V 緩衝液pH4.5
10V アセトニトリル
相B:20V 緩衝液pH4.5
80V アセトニトリル
勾配:40分で相A100%から相B80%
流速:1.0ml/分
検出:UV、λ=220nm(光路:1cm)
注入溶液:水50容量およびアセトニトリル50容量の混合物中の(塩基または塩)0.2mg/ml溶液
注釈:定量のため、得られた結果は非分解塩基の%(w/w)で表わす(周囲温度で保管した非分解塩基または塩コントロールで検定することによる。)。
式(I)の化合物の塩基およびフマル酸塩を、
80℃
80℃および相対湿度(RH)80%
で1、7、および14日保管した後、分析する。
結果を下記の表2に記載する。
クロマトグラフィの条件
カラム:Inertsil ODS3 150×4.6mm、5μm、25℃で保持
移動相:
緩衝液pH4.5:0.01M KH2PO4、0.5g/lヘプタスルホン酸ナトリウム
1M KOHでpH4.5に調節
相A:90V 緩衝液pH4.5
10V アセトニトリル
相B:20V 緩衝液pH4.5
80V アセトニトリル
勾配:40分で相A100%から相B80%
流速:1.0ml/分
検出:UV、λ=220nm(光路:1cm)
注入溶液:水50容量およびアセトニトリル50容量の混合物中の(塩基または塩)0.2mg/ml溶液
注釈:定量のため、得られた結果は非分解塩基の%(w/w)で表わす(周囲温度で保管した非分解塩基または塩コントロールで検定することによる。)。
式(I)の化合物の塩基およびフマル酸塩の即時溶解性を以下の媒質で求めた。
緩衝液pH1.2:0.01M KH2PO4、オルトリン酸でpH調節
緩衝液pH7.2:0.2M KH2PO4、KOHでpH調節
緩衝液pH9.0:0.04M Na2B4O7・10H2O、ホウ酸でpH調節
ジメチルスルホキシド(DMSO)
瞬時溶解性の測定:化合物が溶解するまで、連続容量の媒質を試験試料に添加する。ボルテックスミキサを用い、周囲温度で攪拌を行う。
Claims (16)
- 4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩。
- 結晶多形I型であることを特徴とする、請求項1に記載の4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩。
- 融点が176℃±2℃であり、平均エンタルピーが107J/g±2J/gであることを特徴とする、請求項2に記載の4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩。
- 結晶多形II型であることを特徴とする、請求項1に記載の4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩。
- 融点が175℃±2℃であり、平均エンタルピーが109J/g±2J/gであることを特徴とする、請求項6に記載の4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩。
- 遊離塩基形態の4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートを溶媒中、フマル酸と反応させることを特徴とする、4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩I型を調製する方法。
- 4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩I型を溶媒中、2,4−ジブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩と合わせることを特徴とする、4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩II型を調製する方法。
- 4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩を含むことを特徴とする薬剤。
- 活性成分として4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩、および少なくとも1種の医薬的に許容される賦形剤を含むことを特徴とする医薬組成物。
- ニコチン受容体の機能不全に関連する障害を治療または予防するための薬剤の調製における、4−ブロモフェニル1,4−ジアザビシクロ[3.2.2]ノナン−4−カルボキシラートのフマル酸塩の使用。
- アルツハイマー病に関連する実行機能の障害を治療または予防するための薬剤の調製における、請求項14に記載の使用。
- 統合失調症に伴う認知機能障害を治療または予防するための薬剤の調製における、請求項14に記載の使用。
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FR08/02995 | 2008-06-02 | ||
FR0802995A FR2931823B1 (fr) | 2008-06-02 | 2008-06-02 | Sel de fumarate du 1,4-diazabicyclo°3.2.2!nonane-carboxylate de 4-bromophenyle, ses formes cristallines, leur preparation et leur utilisation en therapeutique |
PCT/FR2009/051039 WO2009156678A2 (fr) | 2008-06-02 | 2009-06-02 | Sel de fumarate du 1,4-diazabicyclo[3.2.2]nonane-4-carboxylate de 4-bromophenyle, ses formes cristallines, leur préparation et leur utilisation en therapeutique |
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US8569289B2 (en) | 2013-10-29 |
WO2009156678A2 (fr) | 2009-12-30 |
CY1113134T1 (el) | 2016-04-13 |
ES2389589T3 (es) | 2012-10-29 |
DK2300473T3 (da) | 2012-10-01 |
WO2009156678A3 (fr) | 2010-05-14 |
PL2300473T3 (pl) | 2012-11-30 |
SI2300473T1 (sl) | 2012-10-30 |
PT2300473E (pt) | 2012-09-11 |
HRP20120733T1 (hr) | 2012-10-31 |
FR2931823B1 (fr) | 2012-08-17 |
FR2931823A1 (fr) | 2009-12-04 |
US20110130389A1 (en) | 2011-06-02 |
EP2300473A2 (fr) | 2011-03-30 |
EP2300473B1 (fr) | 2012-06-20 |
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