JP2008533022A - 炎症性疾患に対するアミノプテリン投与形態及び方法 - Google Patents
炎症性疾患に対するアミノプテリン投与形態及び方法 Download PDFInfo
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- JP2008533022A JP2008533022A JP2008500871A JP2008500871A JP2008533022A JP 2008533022 A JP2008533022 A JP 2008533022A JP 2008500871 A JP2008500871 A JP 2008500871A JP 2008500871 A JP2008500871 A JP 2008500871A JP 2008533022 A JP2008533022 A JP 2008533022A
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- aminopterin
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Abstract
Description
本発明は、国立衛生研究所からの政府支援により開発された。米国政府は、本発明につきある種の権利を有し得る。
図1は、マウス空気嚢(air-pouch)炎症モデルにおけるアミノプテリンおよびメトトレキサートの用量反応プロットである。
図2は、ヒト炎症モデルであるマウス空気嚢モデルでの、それぞれの薬物の最終投与後の日数における、アミノプテリンおよびメトトレキサートの効果を示すプロットである。
図3は、ヒト気管支肺異形成症のモデルである、マウス酸素−毒性モデルでの、アミノプテリンおよびメトトレキサートの相対的な効果を示すプロットである。
詳細に本発明を説明する前に、本明細書で使われる特定の用語の定義を説明することは、その理解に役立ち得る。
本発明の実施態様は、炎症性疾患を有する患者を治療有効量のアミノプテリンまたは医薬的に許容可能なその塩で処置する投薬および方法を提供し、これは、患者の都合に予想外の利益を与え、また、同時に毒性を伴わずに効果を得る。炎症性疾患はヒトに起こり得、例えば、原因のはっきりしない関節炎、リウマチ性関節炎、乾癬性関節炎、若年性リウマチ性関節炎、乾癬、炎症性腸疾患、アトピー性皮膚炎、気管支肺異形成症を含み得る。動物の炎症性疾患は動物に起こり得、例えば、関節炎、イヌのアトピー性皮膚炎およびウシ急性肺パスツレラ症を含み得る。
リウマチ性関節炎の治療のためのアミノプテリンの最適用量を見出すために、そしてメトトレキサートに比較したその効力を定量化するために、メトトレキサートの用量−反応関係が、Cronstein等によって、ヒトにおけるメトトレキサートの用量−反応関係と大変良く相関することが示されている、マウス空気嚢炎症モデルで、アミノプテリンおよびメトトレキサートを試験した[Cronstein, B.N., D. Naime, and E. Ostad, The anti-inflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J. Clin. Invest., 1993. 92(6):2675-82]。
抗炎症作用におけるアミノプテリンとメトトレキサートの43倍のEC50値の相違は、おそらく、アミノプテリンがより効率的に取り込まれるためであると感じていたが、本質的にそれぞれの週投与の前の、1つの薬剤ともう1つの薬剤に渡る「谷」の程度の増加によって、細胞からの薬剤排出速度の相違がこの相違に寄与している可能性を考慮した。したがって、4週間の最高有効用量の投与の中止後、空気嚢モデルにおける抗炎症作用の消失速度を検討した(図2)。
ヒトにおける気管支肺異形成症を処置するためのアミノプテリンの最適用量を見出すため、そしてメトトレキサートと比較したその薬効を定量化するため、ネズミ科の動物の酸素毒性炎症モデルでアミノプテリンおよびメトトレキサートを試験した[Deng, H.; Mason, S. N.; Richard L. Auten, J. Lung inflammation in hyperoxia can be prevented by antichemokine treatment in newborn rats. American Journal of Respiratory Critical Care Medicine 2000, 162, 2316-2323]。
この用量は、粘膜炎が出じるアミノプテリンの忍容される最高用量より数倍低い[Ratliff, A.F., et al., Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies. J. Clin. Oncol., 1998. 16(4):1458-64]。
2,4,5,6-テトラアミノピリミジン.H2SO4.H2O (75.0g、0.293モル)を85-90℃、H2O(1.45 l.)中で、BaCl2.2H2O(71.5 g, 0.293モル)の攪拌溶液に添加した。混合物を90℃で15分間急速に攪拌し、40℃に冷却し、じょうご上で水を用い十分に洗浄したBaSO4からろ過した。澄明な黄色のろ液をさらにH2Oで希釈し、4.35lの体積を得た。そして、テトラアミノピリミジン.2HClの溶液をNaOAc(4N、4.35l.)に加え、ジヒドロキシアセトン(79.3g、0.88モル)およびcysteine.HCl.H2O(51.5g、0.293モル)を溶解させた。空気の遅い流れを連続してそれに26時間通す間、得られた溶液を室温で機械的に攪拌した(黄−橙固体が2時間後分離し始めた)。そして、固体を回収する前16時間、混合物を冷蔵庫に保持し、続いて、25℃でP2O5上の真空で一定重量まで乾燥させる前、氷冷のH2O、EtOHおよびEt2Oで洗浄した。[粗生成物混合物(47g)の重量を量り、臭化水素塩を形成するために必要な48%HBrの体積の見積りを得た。] 乾燥させた固体およびEtOH (6.05l.)の機械的に攪拌した混合物を70℃に加熱し、混合物を70-75℃で維持している間、細い流れで、EtOH(490ml)中の48%HBr(28ml)の溶液を加えた。そして、ほとんど全ての固体が溶解する間、混合物を約5分間、速く攪拌させて還流した。熱い溶液をNoritで処置し、セリットマットを通してろ過した。澄明で黄色のろ液を一晩冷蔵庫に放置し、オレンジ色の固体の第1の収穫を分離した。回収した固体をEtOHで洗浄し、そして、真空で(56℃、P2O5上で)乾燥させ、17.2gの生成物を得た。ろ液をエバポレーション(ロータリーエバポレーター、H2Oアスピレーター、35℃浴)で約2lに濃縮し、そして、冷蔵し、前のように乾燥させて第2の収穫10.2gを得;計27.4gを得た(34%)。CF3CO2D中のこの物質の1H NMRスペクトルは、δ2.83(CH3)およびδ8.85(プテリジン環H)で大変弱いシグナルであることより明らかなように、ほとんど検出できない量のメチル置換2,4-ジアミノプテリジン.HBrが含まれることを示した。望ましい生成物により生じる強いシグナルは、δ5.28(6-CH2O)およびδ9.08(C7-H)にあった。1H NMR積分から、メチル置換混入物質に対する望まれる生成物の割合は、20:1と評価された。1H NMRスペクトルは、また、上記の乾燥させた生成物中に少量のEtOHの保持を明らかにしたが、2への変換を阻害するのには十分でない量であった。
臭素(59.6g、0.373モル)を、約10℃(氷浴)で保たれた486mlの無水ジメチルアセトアミド(DMAC)中で、トリフェニルホスフィン(97.7g、0.373モル)の攪拌溶液に30分以上かけて滴下して加え、周囲の湿気から保護した(じょうごの中に残っている臭素を10mlのDMACでリンスした)。含有する滑らかな懸濁液を丁寧に分割し、結晶トリフェニルホスフィン ジブロマイドを得た。上記の2,4-ジアミノ-6-プテリジンメタノール.HBr(2)(25.4g、0.093 モル)を粉末じょうご(powder funnel)を通して1部に添加した(10mlのDMACを用いて)。氷浴を除き、そして、攪拌された混合物を20-25℃に温めた。約1時間後、完全な溶液が生じた。徐々に暗赤色を呈する溶液を、1時間以上20-25℃で維持し、そして、EtOH(72ml)で処理する前に冷却(氷浴)した。一晩の冷蔵後、溶媒を真空でエバポレーションすることにより取り除いた。暗色で半固体の残渣を、2回の300ml量のベンゼンで攪拌し(トリフェニルホスフィン酸化物を除くため)、デカンテーションによりそれぞれの部分をベンゼン不溶生成物から取り除いた。残った固体を、80℃に予め温められた氷酢酸(glacial AcOH)(660ml)中で攪拌した。混合物を、溶液が完全になるまで80℃浴に維持した。暗色溶液として分離された黄褐色の結晶固体を冷却した。一晩の冷蔵は、AcOHを部分的に凍らした。融解させ、固体を回収し、氷冷AcOHに続きEt2Oを用いて洗浄し、そして、真空中(P2O5およびNaOHペレット上)、25℃、56℃および110℃の連続した温度で乾燥した(高い温度はAcOHの完全な除去に必要であった)。収量は15.3g(49%)であった。(いくつかの実施では60%の収率であった。)このサンプルをEt2O添加MeOH溶液(Norit)から再結晶により、さらに精製した後、真空中(25℃、P2O5)で乾燥し、淡黄色の固体13.0g(42%)を得た。スペクトルデータ:λmax、nm(εx10-3)、0.1 N HCl、249 (17.3)、339 (10.5)、353 (sh); pH 7、258 (21.2)、370 (6.87); 0.1 N NaOH、258 (21.5)、370 (6.94); 1H NMR (CF3CO2D)、δ4.70 (s、2, CH2)およびδ9.08 (s、1, C7-H);メチル置換混入物質に比較した見積もられた割合は、25:1であった。上記2の製造は、典型的には、その1H NMRスペクトルが、メチル置換混入物質に関した2の見積もり割合において僅かに異なる物質の同様の収率を与える、いくつかの試行からなる。割合は通常16:1から25:1の範囲であり、それは、2のパーセントが94から96に一致する。
50mlメタノール中の5mmolの2,4,5,6-テトラアミノピリミジン ジブロマイドの懸濁液を2時間、還流温度で、10mlのメタノール中の7.5mmolβ-ブロモピルバルドキシム(β-bromopyruvaldoxime)の溶液で処理した。2,4-ジアミノ-6-(ブロモメチル)プテリジンを、室温で濃縮NH3を用いて中和した後回収し、メタノール、エーテルで洗浄し、オーブンで100℃で乾燥させた。1H NMR(250MHz、ppm、DMSO-d6)、δ8.84(s、1H、C7-H)、収率は88%であった。
DMAC(2ml)中の2(168mg、0.500mmole)およびN-(4-アミノベンゾイル)-L-グルタミン酸、化合物3(400mg、1.50mmoles)の混合物を光から保護されたストッパー付きのフラスコで、窒素下25℃で攪拌した。溶液が2時間後生じた。18時間後、オレンジ色の溶液を水(15ml)と混合し、攪拌し、細かく分かれた黄色の沈殿物を得た。混合物を遠心し、上清をデカントで除去した。黄色の固体を、4回の15mlのH2Oで攪拌し、それぞれ、水を遠心後デカントにより除去した。そして、固体をEtOH(15-20ml)で懸濁し、ろ過により回収し、Et2Oで洗浄し、真空で乾燥して(25℃、P2O5)、水和した4を68%収率(160mg)得た。分析計算、C19H20N8O5.1.75H2O: C,48.36; H,5.02; N,23.74. 実測値: C,48.72; H,4.91; N,23.36. スペクトルデータ:λmax,nm(εx10-3), 0.1N HCl, 244(18.2), 290(20.5), 335(11.0); pH7,260(26.7), 283(25.5), 370(8.00); 0.1N NaOH, 260(26.9), 283(25.3), 370(8.00); 1H NMR(DMSO-d6),δ2.02(m,2,CHCH2CH2),2.32(m,2,CH2CO2H),4.36(m,1,NHCHCO2H),4.52(s,2,CH2N), 6.85(m,4,2フェニレンプロトン プラス NH2), 7.72(m,2,フェニレン),7.86(ブロード s,2,NH2), 8.13(d,1,NHCO), 8.72(s,1,C7-H)。TLCによる試験で、1つのuv-吸収スポットが明らかにされ、どの点でも蛍光はなかった。生成物を直接活性な医薬成分として使用できるが、場合によっては、アミノプテリンの純度を僅かに改善するために1またはそれ以上の水またはホルムアミドからの再結晶を実施する。活性な医薬成分を乾燥剤の存在下で保存する。
100%アミノプテリン(FW 440.42g/mole)であるとして活性な医薬成分から2.3mg、4.5mgおよび1.8mgを秤量し、それぞれ0.001N NaOH、5.223ml、10.218ml、および4.087mlに溶解して、実施例59により調製された活性な医薬成分の第1バッチの1mMの異なる3溶液を調製した。5mM PicA、10mM NH4H2PO4および20%メタノール、pH6.8からなるアイソクラチックな移動相を用いて、C18カラム(Waters μBondapak 125Å, 10μm, 3.9x150mm)に投入することにより、それぞれの1mM溶液の20μlをHPLC分析にかけた。移動相の流速は1ml/minであり、分析は室温で実施された。Waters 996 PDA UV分光光度計を用いて、210nmから400nmの吸光データを補足した。データを、Waters Millenniumソフトウェアを用い、282nmでのクロマトグラムを抽出し、ピーク面積パーセントを計算することにより分析した。データを、また、個々のピークのスペクトルを抽出することにより分析し、特徴的なスペクトルにより、pABAGlu、葉酸、アミノプテリンおよびプテリンの同定を可能にした。
本実施例は、実質的に不純物のない医薬組成物の調製を説明する。本実施例で使用されているように、「API」は不純物が実質的にない活性な医薬成分を意味し、ここで、API中の抗葉酸剤はアミノプテリン、またはその医薬的に許容され得る塩である。APIのアミノプテリンの純度は、医薬組成物中で、望まれる最終量のアミノプテリンまたはその医薬的に許容され得る塩を得るための、医薬組成物中で必要とされるAPIの量を確立するために用いられる。
3.9gのコロイド状二酸化ケイ素、46.2gのクロスカルメロースナトリウム、および7.7gのステアリン酸マグネシウムに加え、総重量1540gを得る。打錠機を用い圧縮し、約15000錠とし、ここで、それぞれの錠剤は約100mgの重量であり、約1mgのアミノプテリンを含む。
実施例14に従って調製した1mgアミノプテリン錠剤の1バッチ15000に対し、無作為に選択された錠剤10の中からアミノプテリンの平均用量および用量の均一性(つまり、標準偏差)を測定した(表II)。平均用量および用量均一性を走査型分光光度計、およびバインダーとしてジヒドロ葉酸レダクターゼ(DHFR)、標準物質としてメトトレキサートを用いた放射性リガンド結合アッセイにより得た。
多くの参考文献が引用されており、その全開示は、引用によって本明細書に組み込まれている。
Claims (25)
- 中断なしのサイクルで、治療有効量のアミノプテリン、またはその医薬的に許容され得る塩を患者に投与することを含む、該患者における炎症性疾患を処置する方法。
- 中断なしのサイクルの数が少なくとも24である、請求項1に記載の方法。
- 中断なしのサイクルの期間が週単位である、請求項1に記載の方法。
- 各サイクルの投与の数が2である、請求項1に記載の方法。
- 各サイクルの投与の数が1である、請求項1に記載の方法。
- 混合治療において第2の薬剤を使用する付加的な工程を含む、請求項1に記載の方法。
- 第2の薬剤が葉酸である、請求項6に記載の方法。
- 各サイクルで与えられるアミノプテリンの量が患者体重kg当たり0.07mg未満である、請求項1に記載の方法。
- 5錠未満が各サイクルで与えられる、請求項1に記載の方法。
- 各サイクルにおいて1以上の錠剤が0.5mgのアミノプテリンを含む、請求項9に記載の方法。
- 炎症性疾患が、リウマチ性関節炎、若年性リウマチ性関節炎、乾癬、乾癬性関節炎、原因のはっきりしない関節炎、関節炎、アトピー性皮膚炎、炎症性腸疾患、気管支肺異形成症、イヌアトピー性皮膚炎およびウシ急性肺パスツレラ症からなる群から選択される、請求項1に記載の方法。
- 治療有効量の抗葉酸剤、またはその医薬的に許容され得る塩の単回用量を患者に投与することを含む、該患者の炎症性疾患を処置する方法。
- 炎症性疾患が、ヒト気管支肺異形成症、イヌアトピー性皮膚炎およびウシ急性肺パスツレラ症からなる群から選択される、請求項12に記載の方法。
- 抗葉酸剤がアミノプテリンである、請求項12に記載の方法。
- 患者に治療有効量のアミノプテリン、またはその医薬的に許容され得る塩を投与することを含む、該患者における炎症性疾患を処置する方法であって、週当たりに投与されるアミノプテリンの治療有効量が、患者体重kg当たり0.07mg未満のアミノプテリンである、方法。
- 炎症性疾患が、原因のはっきりしない関節炎、リウマチ性関節炎、乾癬性関節炎、若年性リウマチ性関節炎、炎症性腸疾患、アトピー性皮膚炎、気管支肺異形成症、イヌアトピー性皮膚炎および急性肺パスツレラ症からなる群から選択される、請求項15に記載の方法。
- アミノプテリンが1以上の錠剤で投与され、少なくとも1の錠剤が0.5mg未満のアミノプテリンを含む、請求項15に記載の方法。
- 患者に治療有効量のアミノプテリン、またはその医薬的に許容され得る塩を投与することを含む、該患者における炎症性疾患を処置する方法であって、薬効のレベルがメトトレキサートを用いたときよりもより速い速度で達成される、方法。
- 該速度が、ACR20、ACR50、ACR70、ACR-N、JRA30%DOI、JRA50%DOI、JRA70%DOI、PASI、肺機能試験、酸素飽和、損傷スコアおよび掻痒症スコアからなる群から選択される、請求項18に記載の方法。
- 該速度が、作用−時間曲線下の面積により定量化される、請求項18に記載の方法。
- 治療有効量のアミノプテリン、またはその医薬的に許容され得る塩を含む医薬組成物であって、0.5mg未満のアミノプテリンを含む、医薬組成物。
- 医薬組成物が錠剤である、請求項21に記載の医薬組成物。
- 錠剤が、0.2mgアミノプテリンを含む、請求項21に記載の医薬組成物。
- 錠剤が、0.1mgアミノプテリンを含む、請求項21に記載の医薬組成物。
- 活性な医薬成分が実質的に不純物を含まない、請求項21に記載の医薬組成物。
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Publication number | Publication date |
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JP5791864B2 (ja) | 2015-10-07 |
US20080108621A1 (en) | 2008-05-08 |
EP1855682A2 (en) | 2007-11-21 |
US20120128703A1 (en) | 2012-05-24 |
US8129383B2 (en) | 2012-03-06 |
WO2006098979A2 (en) | 2006-09-21 |
US20170128452A1 (en) | 2017-05-11 |
WO2006098979A3 (en) | 2006-11-30 |
US9867828B2 (en) | 2018-01-16 |
ES2658070T3 (es) | 2018-03-08 |
EP1855682A4 (en) | 2008-05-07 |
EP1855682B1 (en) | 2017-11-01 |
US20060205729A1 (en) | 2006-09-14 |
PL1855682T3 (pl) | 2018-04-30 |
JP2013209384A (ja) | 2013-10-10 |
US7312217B2 (en) | 2007-12-25 |
US20080096893A1 (en) | 2008-04-24 |
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