JP4201135B2 - 新規結晶性化合物 - Google Patents
新規結晶性化合物 Download PDFInfo
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Description
を有する。
本発明は、ヒトを含む哺乳類において、(a)臓器移植の拒絶反応、異種移植、狼瘡、多発性硬化症、リウマチ様関節炎、乾癬、1型糖尿病及び糖尿病由来の合併症、ガン、喘息、アトピー性皮膚炎、自己免疫甲状腺障害、潰瘍性大腸炎、クローン病、アルツハイマー病、白血病、及びその他の自己免疫障害から選択された障害若しくは状態の治療若しくは予防、又は(b)プロテインキナーゼ若しくはジャヌスキナーゼ3(JAK3)の阻害に有効である、3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の新規結晶形に関する。前記新規結晶形は、温度約203℃〜約210℃で融解し、図1に示すように、2シータ(2θ)度が5.7,16.1,20.2,及び20.5において特徴的なピークを有するX線回折パターンを示す。X線パワー回折パターン理論の議論は、Stout及びJensen,X−Ray Structure Determination; A Practical Guide, MacMillan Co., New York,N.Y.(1986)に見出すことができ、これは、それ全体が参照として本明細書に含まれる。
図1は、3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の特徴的なX線粉末回折パターンである〔垂直軸:強度(計数);水平軸:2θ(度)〕。
図2は、3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の特徴的な示差走査熱量温度記録図である〔走査速度:1分間あたり5℃;垂直軸:熱流量(w/g);水平軸:温度(℃)〕。
《発明の詳細な説明》
〈JAK3(JH1:GST)酵素アッセイ〉
JAK3キナーゼアッセイは、グルタチオンセパハロース上のアフィニティクロマトグラフィーによって精製された、バキュロウイルス感染SF9細胞中に発現されたタンパク質(GSTとヒトJAK3の触媒性ドメインとの融合タンパク質)を利用する。反応用の基質は、ポリグルタミン酸−チロシン〔PGT(4:1)、シグマカタログ#P0275〕であり、ヌンク・マキシィー・ソープ(Nunc Maxi Sorp)プレートに、100μg/mLで37℃で一晩かけてコートした。コーティングした次の日の朝、前記プレートを3回洗い、そしてキナーゼ緩衝液100μL(50mM HEPES,pH7.3,125mM NaCl,24mM MgCl2)+0.2uM ATP+1mMオルトバナジン酸ナトリウム)を含むウエルにJAK3を加える。反応を30分間、室温で進行させ、そして前記プレートを更に3回洗う。与えられた或るウエル中のリン酸化されたチロシンのレベルは、抗ホスホチロシン抗体(ICN PY20,cat.#69−151−1)を利用する標準的なELISAアッセイによって定量することができる。
このスクリーンでは、インビトロで、IL−2依存性T−細胞芽細胞(blast)増殖に対する化合物の阻害効果を測定する。IL−2レセプターを通過するシグナルがJAK−3を必要とするので、JAK−3の細胞活性阻害剤がIL−2依存性T−細胞芽細胞増殖を阻害するはずである。
エタノール(13L)、(3R,4R)−メチル−(4−メチル−ピペリジン−3−イル)−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)アミン(1.3kg)、シアノ酢酸2,5−ジオキソ−ピロリジン−1−イルエーテル(1.5kg)、及びトリエチルアミン(1.5L)を一緒にし、そして周囲温度で攪拌した。反応の完了〔高圧液体クロマトグラフィー(HPLC)分析で決定;約30分間〕に際し、その溶液を濾過し、濃縮し、メチレンクロライド15Lと共に共沸した。前記反応混合物を、0.5N水酸化ナトリウム溶液12L、塩水12L、及び水12Lによって順に洗った。その有機層を濃縮し、アセトン3Lと共に共沸した(最終容器温度は42℃であった)。得られた溶液を20℃〜25℃に冷却し、その後にアセトン10Lを添加した。この溶液を濾過し、それから水性クエン酸(水4L中0.8kg)をイン・ライン・フィルターを経て加えた。前記反応混合物を放置して粒状体とした。そのスラリーを、冷却してから濾過によって固体を集めた。前記固体を乾燥し、(3R,4R)−3−{4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノサイトレート1.9kg(71%)を得た。次に、その材料をエタノール/水(比率1:1)15Lと一緒にし、そしてそのスラリーを一晩攪拌した。その固体を濾過し、乾燥して、標記の化合物1.7kg〔(3R,4R)−メチル−(4−メチル−ピペリジン−3−イル)−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)アミンから63%〕を白色結晶固体として得た。
1H NMR(400MHZ)(D2O)δHOD:0.92(2H,d、J=7.2Hz),0.96(1H,d、J=7.6Hz),1.66(1H,m),1.80(1H,m),2.37(1H,m),2.58(2H,1/2ABq,J=15.4Hz),2.70(2H,1/2ABq,J=154Hz),3.23(2H,s),3.25(1H,s),3.33(1H,m),3.46(1H,m),3.81(4H,m),4.55(1H,m),6.65(1H,d,J=3.2Hz),7.20(1H,t,J=3.2Hz),8.09(1H,m)。
エタノール2L中に((3R,4R)−1−ベンジル−4−メチル−ピペリジン−3−イル)−メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミン79gを溶解した溶液に、カーボン上の20%水酸化パラジウム79g(水50重量%)を添加し、そしてその混合物を水素50psiの圧力雰囲気下で3日間攪拌した(高められた温度〔50℃〜70℃〕における水添分解の実施は、反応時間を有意に減少する)。セライト(商標)を通す濾過によって触媒を除去した後、シアノ酢酸2,5−ジオキソ−ピロリジン−1−イルエステル51gをエタノール溶液に加え、そして得られた混合物を室温で1時間攪拌し、その時点で減圧下で前記エタノールを除去した。その残渣を、ジクロロメタン1.0Lに再び溶解し、そして飽和水性炭酸水素ナトリウム0.6L及び飽和炭酸水素ナトリウム0.4Lで順に洗った。その一緒にした水性層をジクロロメタン0.4Lでバック・ウォッシングし、ジクロロメタン層を一緒にし、硫酸マグネシウムで乾燥して、濾過して、そして真空で濃縮して、琥珀色のオイル61gを得た。次に、この材料をアセトン2.1L中に再び溶解し、そしてその溶液を40℃に加熱した。細かく粉砕されたクエン酸37gを溶液に(固体として)ゆっくり加えた。その混合物を40℃で2時間、継続して攪拌した(顆粒化が完了した)。室温に冷却した後、固体を濾過によって集め、アセトンで洗い、そして真空で乾燥して、標記の化合物78.5g〔((3R,4R)−1−ベンジル−4−メチル−ピペリジン−3−イル)−メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミンから66%〕を僅かに灰白色の結晶固体として得た。
アセトン23mL中に溶解した(3R,4R)−3−{4−メチル−3−〔メチル−(7H−ピロロ〔2,3d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリル(230mg/0.74mmol)の攪拌溶液を40℃に加熱した。前記溶液に、細かく粉砕したクエン酸155mg(0.81mmol)を加えた。得られた混合物を40℃で2時間、そして、30℃で4時間攪拌し、続いて室温で更に18時間攪拌した。この時点で、濾過によって固体を集めて、アセトンで洗い、そして真空で乾燥して、標記の化合物280mg(75%)を白色結晶固体として得た。
銅輻射、固定したスリット(1.0,1.0,0.6mm)、及びケベックス(Kevex)固体状態検出器を備えたブルカー(Bruker)D5000回折計(マジソン,ウィスコンシン)を用いて、3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の粉末X線回折パターンを収集した。データを以下の通り収集した:銅アノード;波長1:1.54056;波長2:1.54439(相対強度:0.500);ステップサイズ0.04°及びステップタイム1.0秒用い、2θで3.0°〜40.0°。その結果を表1に要約する。
Claims (7)
- 3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の結晶。
- 角度2θで表される特徴ピークを5.7±0.2、16.1±0.2、20.2±0.2、及び20.5±0.2に有するX線粉末回折パターンを含む、請求項1に記載の3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の結晶。
- 角度2θで表される特徴ピークを、
- 199℃から206℃の間に開始融解温度を有する、請求項1に記載の3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の結晶。
- 3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の非晶形。
- 3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルとクエン酸とを反応させることを含む、3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩の製造方法。
- 3−{(3R,4R)−4−メチル−3−〔メチル−(7H−ピロロ〔2,3−d〕ピリミジン−4−イル)−アミノ〕−ピペリジン−1−イル}−3−オキソ−プロピオニトリルモノクエン酸塩。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US33898401P | 2001-12-06 | 2001-12-06 | |
PCT/IB2002/004948 WO2003048162A1 (en) | 2001-12-06 | 2002-11-25 | Novel crystalline compound |
Publications (2)
Publication Number | Publication Date |
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JP2005511696A JP2005511696A (ja) | 2005-04-28 |
JP4201135B2 true JP4201135B2 (ja) | 2008-12-24 |
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Application Number | Title | Priority Date | Filing Date |
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JP2003549352A Expired - Lifetime JP4201135B2 (ja) | 2001-12-06 | 2002-11-25 | 新規結晶性化合物 |
Country Status (30)
Country | Link |
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US (2) | US6965027B2 (ja) |
EP (1) | EP1451192B1 (ja) |
JP (1) | JP4201135B2 (ja) |
KR (1) | KR100691590B1 (ja) |
CN (1) | CN1325498C (ja) |
AR (1) | AR037635A1 (ja) |
AT (1) | ATE497962T1 (ja) |
AU (1) | AU2002348857B2 (ja) |
BR (1) | BR0214761A (ja) |
CA (1) | CA2469350C (ja) |
CO (1) | CO5580780A2 (ja) |
CY (1) | CY1111311T1 (ja) |
DE (1) | DE60239146D1 (ja) |
DK (1) | DK1451192T3 (ja) |
ES (1) | ES2357942T3 (ja) |
GT (1) | GT200200234A (ja) |
HK (1) | HK1070653A1 (ja) |
HN (1) | HN2002000349A (ja) |
IL (1) | IL161914A0 (ja) |
MX (1) | MXPA04005401A (ja) |
NO (1) | NO20042721L (ja) |
NZ (1) | NZ532366A (ja) |
PA (1) | PA8560201A1 (ja) |
PE (1) | PE20030807A1 (ja) |
PL (1) | PL221493B1 (ja) |
RU (1) | RU2315052C2 (ja) |
TW (1) | TW200300690A (ja) |
UY (1) | UY27567A1 (ja) |
WO (1) | WO2003048162A1 (ja) |
ZA (1) | ZA200404270B (ja) |
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