JP2010516639A - Hsp90阻害剤としてのトリアゾール誘導体 - Google Patents
Hsp90阻害剤としてのトリアゾール誘導体 Download PDFInfo
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Abstract
Description
本発明は、価値ある特性を有する新規化合物、特に医薬の製造に用いることができる化合物を見出すとの目的に基づく。
本発明は、HSP90の阻害、調節および/または調整が関与する化合物に関し、さらにこの化合物を含む医薬組成物に関し、およびHSP90が関与する疾患の処置のための前記化合物の使用に関する。
組織の細胞は、例えば熱、低酸素、酸化ストレスなどの外的ストレス、または例えば重金属もしくはアルコールなどの毒性物質に対して、「熱ショックタンパク質(HSP)」の名称で知られている多数のシャペロンを活性化させて反応する。HSPの活性化は、かかるストレス因子による損傷から細胞を保護し、生理学的状態の回復を促進し、細胞のストレス耐性状態をもたらす。HSPにより促進される、外的ストレスに対するこの最初に発見された防御機構に加えて、時とともに、個別のHSPに対し、さらなる重要なシャペロン機能がストレスのない通常状態において記載されている。したがって種々のHSPは、例えば、細胞の生物学的に重要な多数のタンパク質の、正しい折りたたみ、細胞内局在や機能、または調節された分解などを調節している。HSPは、異なる細胞においてその細胞発現や機能、局在化が異なる個別の遺伝子産物を有する、遺伝子ファミリーを形成する。ファミリー内での名称および分類は、その分子量に基づき、例えばHSP27、HSP70、およびHSP90などである。
HSP90が細胞の多数の中心的発癌性シグナル伝達経路に関与し、癌阻害活性を有するある天然の産物がHSP90を標的とするとの事実は、HSP90の機能の阻害が、腫瘍疾患の処置に感受性があるであろうと考えさせる。HSP90阻害剤である、ゲルダナマイシンの誘導体17−アリルアミノ−17−デメトキシゲルダナマイシン(17AAG)は、現在臨床試験されている。
HSP90は、全細胞タンパク質質量の約1〜2%を占める。これは通常、細胞内で二量体の形態であり、タンパク質の多様性に関与し、いわゆるコシャペロンである(例えばPratt, 1997参照)。HSP90は細胞の活力に不可欠であり(Young et al., 2001)、細胞ストレスに対する応答において、その天然の折りたたみが熱ショックなどの外的ストレスにより変更させられた多くのタンパク質と相互作用することにより、重要な役割を果たして、元の折りたたみを回復させるか、またはタンパク質の凝集を妨げる(Smith et al., 1998)。
発見された第1のクラスのHSP90阻害剤は、化合物ハービマイシンAおよびゲルダナマイシンを伴うベンゾキノンアンサマイシンであった。最初に、v−Srcオンコジーンによる形質転換により誘発された、線維芽細胞における悪性表現型の復帰突然変異(reversion)が、それらと共に発見された(Uehara et al., 1985)。
次に強力な抗腫瘍活性が、in vitro(Schulte et al., 1998)で、およびin vivoの動物モデルにおいて(Supko et al., 1995)実証された。
大環状抗生物質であるラディシコールも同様に、線維芽細胞のv−Srcおよびv−Ha−Ras誘発性の悪性表現型の復帰突然変異を示す(Kwon et al., 1992;Zhao et al., 1995)。ラディシコールは、HSP90の阻害の結果、多数のシグナルタンパク質を分解する(Schulte et al., 1009)。X線結晶解析により、ラディシコールも同様にHSP90のN末端ドメインに結合し、内因性ATPアーゼ活性を抑制することが示された(Roe et al., 1998)。
ノボビオシンによるHSP90の阻害は、多数のHSP90依存性シグナルタンパク質の分解を引き起こす(Marcu et al., 2000a)。
例えばERBB2などのシグナルタンパク質の分解は、プリン由来のHSP90阻害剤であるPU3を用いて実証された。PU3は、乳癌細胞系において細胞周期の停止および分化を引き起こす(Chiosis et al., 2001)。
腫瘍の表現型において非常に重要である多数のシグナル伝達経路の調節にHSP90が関わっていること、またある天然産物が、HSP90の活性の阻害を通してそれらの生物学的効果を発揮するとの発見により、現在HSP90は、腫瘍治療剤の開発の新規な標的として試験されている(Neckers et al., 1999)。
したがって、HSP90を特異的に阻害、調節および/または調整する小化合物の同定は望ましく、本発明の目的である。
したがって本発明は、前記疾患の処置および/または予防における医薬および/または医薬活性成分としての5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミドに、ならびに、5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミドの、前記疾患の処置および/または予防のための薬剤の製造のための使用に、ならびにまた、前記疾患の処置のための方法であって、5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミドを、かかる投与が必要な患者に投与することを含む前記方法に関する。
WO 2006/087077には、HSP90阻害剤としてのトリアゾール誘導体が記載されている。本発明は、これに対する選択発明とみなされるべきである。これから言及すべき最も近い従来技術は、化合物5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−プロピルベンズアミド(“A47”)である。
WO 03/041643 A2には、HSP90を阻害するゼアララノール誘導体が開示されている。
3−または5位において芳香族基により置換された、HSP90を阻害するピラゾール誘導体は、WO 2004/050087 A1およびWO 2004/056782 A1に開示されている。
WO 03/055860 A1には、HSP90阻害剤としての3,4−ジアリールピラゾールが記載されている。
HSP90阻害特性を有するプリン誘導体は、WO 02/36075 A2に開示されている。
プロドラッグ誘導体とは、例えば、アルキルまたはアシル基、糖またはオリゴペプチドにより修飾されており、本発明の活性な化合物を生じさせるために生物内で急速に開裂する、本発明の化合物を意味すると解釈される。
これらはまた、例えば、Int. J. Pharm. 115, 61-67 (1995)に記載されているように、本発明の化合物の生分解性ポリマー誘導体も含む。
これらは、特に好ましくは立体異性体化合物の混合物である。
特に好ましい溶媒は、例えばテトラヒドロフランである。
保護基は、当業者に公知の方法により除去する。例えばメチルエーテルなどのエーテルの開裂は、上記のような好適な溶媒中で、好ましくは三臭化ホウ素の付加により行う。
本発明の化合物はさらに、これらをその官能性誘導体から、加溶媒分解により、特に加水分解、または水素化分解により遊離することにより得ることができる。
複数の、−同一または異なる−保護アミノおよび/またはヒドロキシル基が、出発物質の分子中に存在することも可能である。存在する保護基が互いに異なる場合、これらは多くの場合、選択的に開裂して除去することができる。
本発明の前述の化合物を、その最終的な非塩形態で用いることができる。一方、本発明はまた、この化合物を、当該分野において知られている手順により、種々の有機および無機酸類および塩基類から由来し得るその薬学的に許容し得る塩の形態で用いることを包含する。本発明の化合物の薬学的に許容し得る塩形態は、大部分、慣用の方法により調製される。好適な塩は、当該化合物を好適な塩基と反応させて対応する塩基付加塩を得ることにより、生成することができる。このような塩基は、例えば、水酸化カリウム、水酸化ナトリウムおよび水酸化リチウムを含むアルカリ金属水酸化物;アルカリ土類金属水酸化物、例えば水酸化バリウムおよび水酸化カルシウム;アルカリ金属アルコキシド類、例えばカリウムエトキシドおよびナトリウムプロポキシド;ならびに種々の有機塩基、例えばピペリジン、ジエタノールアミンおよびN−メチルグルタミンである。
塩基付加塩を、遊離酸形態を十分な量の所望の塩基と接触させ、慣用の方法で塩の生成を生じることにより、調製する。遊離酸を、塩形態を酸と接触させ、慣用の方法で遊離酸を単離することにより、再生することができる。遊離酸形態は、ある観点において、一定の物理的特性、例えば極性溶媒への溶解性の点で、これらの対応する塩形態と異なる;しかし、本発明の目的のために、当該塩は、他の点では、これらのそれぞれの遊離酸形態に相当する。
医薬製剤を、投与単位あたり所定量の活性成分を含む投与単位の形態で、投与することができる。このような単位は、処置される疾患の状態、投与の方法ならびに患者の年齢、体重および状態に依存して、例えば0.1mg〜3g、好ましくは1mg〜700mg、特に好ましくは5mg〜100mgの本発明の化合物を含むことができるか、または医薬製剤を、投与単位あたり所定量の活性成分を含む投薬単位の形態で投与することができる。好ましい投与単位製剤は、前に示したように、毎日の用量もしくは部分的用量を含むもの、または活性成分のこの対応する部分である。さらに、このタイプの医薬製剤を、薬学分野において周知の方法を用いて製造することができる。
局所的投与用に適合する医薬化合物を、軟膏、クリーム、懸濁液、ローション、粉末、溶液、ペースト、ゲル、スプレー、エアゾールまたは油として製剤化することができる。
眼への局所的適用に適合する医薬製剤には点眼剤が含まれ、ここで、活性成分を、好適な担体、特に水性溶媒中に溶解するかまたは懸濁させる。
直腸内投与に適合する医薬製剤を、坐剤または浣腸剤の形態で投与することができる。
担体物質が固体である鼻腔内投与に適合する医薬製剤は、例えば20〜500ミクロンの範囲内の粒子の大きさを有する粗粉末を含み、これを、嗅ぎタバコを服用する方法で、即ち鼻に近接して保持した粉末を含む容器からの鼻孔を介しての迅速な吸入により、投与する。担体物質としての液体を有する、鼻腔内スプレーまたは鼻腔内ドロップとしての投与に適する製剤は、水または油に溶解した活性成分溶液を包含する。
膣内投与に適合する医薬製剤を、膣坐薬、タンポン、クリーム、ゲル、ペースト、発泡体またはスプレー製剤として投与することができる。
上で特定的に述べた構成成分に加えて、製剤はまた、製剤の特定のタイプに関して当該分野において通例の他の剤を含むことができることは、言うまでもない;したがって、例えば、経口投与に適する製剤は、風味剤を含んでいてもよい。
本発明の化合物と組み合わせて用いることのできる抗悪性腫瘍薬の例は、一般に、アルキル化剤、代謝拮抗物質;エピドフィロトキシン;抗悪性腫瘍酵素;トポイソメラーゼ阻害剤;プロカルバジン;ミトキサントロンまたはプラチナ配位錯体を含む。
前記のクラスにおいて特に好ましいのは、例えば、カルミノマイシン、ダウノルビシン、アミノプテリン、メトトレキサート、メトプテリン、ジクロロメトトレキサート、マイトマイシンC,ポルフィロマイシン、5−フルオロウラシル、5−フルオロデオキシウリジン一リン酸、シタラビン、5−アザシチジン、チオグアニン、アザチオプリン、アデノシン、ペントスタチン、エリスロヒドロキシノニルアデニン、クラドリビン、6−メルカプトプリン、ゲムシタビン、シトシンアラビノシド、ポドフィロトキシンまたはポドフィロトキシン誘導体、例えばエトポシド、リン酸エトポシドまたはテニポシド、メルファラン、ビンブラスチン、ビノレルビン、ビンクリスチン、ロイロシジン、ビンデシン、ロイロシン、ドセタキセルおよびパクリタキセルである。他の好ましい抗悪性腫瘍薬は、ジスコデルモリド、エポチロンD、エストラムスチン、カルボプラチン、シスプラチン、オキサリプラチン、シクロホスファミド、ブレオマイシン、ゲムシタビン、イフォスファミド、メルファラン、ヘキサメチルメラミン、チオテパ、イダトレキセート、トリメトレキセート、ダカルバジン、L−アルパラギナーゼ、カンプトテシン、CPT−11、トプテカン、アラビノシルシトシン、ビカルタミド、フルタミド、ロイプロリド、ピリドベンゾインドール誘導体、インターフェロンおよびインターロイキンの群から選択される。
さらなる医薬活性成分は、好ましく酵素阻害剤である。好ましい酵素阻害剤は、ヒストン脱アセチル化阻害剤(例えばスベロイルアニリドヒドロキサム酸[SAHA]およびチロシンキナーゼ阻害剤(例えばZD1839[イレッサ])の群から選択される。
さらなる医薬活性成分は、好ましくは免疫抑制剤である。好ましい免疫抑制剤は、ラパマイシン、CCI−779(Wyeth)、RAD001(Novartis)、AP23573(Ariad Pharmaceuticals)の群から選択される。
(a)本発明の化合物および/または、この薬学的に使用可能な誘導体、溶媒和物および立体異性体、ならびにそれらの全ての比率での混合物の有効量、
および
(b)さらなる医薬活性成分の有効量、
の個別のパックからなるセット(キット)に関する。
本発明の化合物は、HSP90が関与する疾患の処置における、哺乳類のための、特にヒトのための医薬活性成分として好適である。
したがって、本発明は、5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド、およびその薬学的に使用し得る誘導体、溶媒和物および立体異性体、ならびにそれらの全ての比率での混合物の、HSP90の阻害、調節および/または調整が関与する疾患の処置のための医薬の製造のための使用に関する。
移植における免疫抑制のため;炎症誘発性疾患、例えば関節リューマチ、喘息、多発性硬化症、1型糖尿病、紅斑性狼瘡(エリテマトーデス)、乾癬、炎症性腸疾患;嚢胞性繊維症;脈管形成が関与する疾患、例えば糖尿病性網膜症、血管腫、子宮内膜症、腫瘍脈管形成;感染症;自己免疫疾患;虚血;神経再生の促進;線維形成疾患、例えば硬腫、多発性筋炎、全身性狼瘡、肝硬変、ケロイド形成、間質性腎炎、および肺線維症。
ゲルダナマイシンまたは17−アリルアミノ−17−デメトキシゲルダナマイシン(17AAG)のHSP90への結合、およびその競合的阻害は、本発明の化合物の阻害活性を決定するために利用可能である(Carreras et al. 2003, Chiosis et al. 2002)。特定の場合においては、放射性リガンドフィルタ結合試験を用いる。ここで用いる放射性リガンドは、トリチウム標識17−アリルアミノゲルダナマイシン、[3H]17AAGである。このフィルタ結合試験により、ATP結合部位を妨害する阻害剤を標的とした探索が可能となる。
組換えヒトHSP90α(大腸菌発現、95%純度);
[3H]17AAG(17−アリルアミノゲルダナマイシン、[アリルアミノ−2,3−3H.特異的活性:1.11×1012Bq/mmol(Moravek, MT-1717);
HEPESフィルタ緩衝液(50mMのHEPES、pH7.0、5mMのMgCl2、BSA0.01%)
マルチスクリーンFB(1μm)フィルタプレート(Millipore, MAFBNOB 50)。
96ウェルマイクロタイターフィルタプレートを最初に洗浄し、0.1%のポリエチレンイミンで被覆する。試験は次の条件下で行う:
反応温度22℃
反応時間:30分、800rpmにて振とう
試験容積:50μl
最終濃度:
50mMのHEPES HCl、pH7.0、5mMのMgCl2、0.01%(w/v)BSA
HSP90:1.5μg/アッセイ
[3H]17AAG:0.08μM。
「対照の%」は、「1分あたりの計測数」の値から決定し、化合物のIC50値はこれから計算する。
以下の表は、本発明の化合物の、従来技術における最も近い化合物“A47”との比較測定を示す。本発明の化合物“C1”は、約10倍高いHSP90阻害活性を有する。
Hewlett Packard SystemのHP1100シリーズは以下の特徴を有する:イオン源:エレクトロスプレー(陽モード);スキャン:100〜1000m/e;断片化電圧:60V;気体温度:300℃、DAD:220nm。
流速:2.4ml/分。用いたスプリッターは、MS用の流速をDAD後に0.75ml/分に低下させた。
カラム:Chromolith SpeedROD RP-18e 50-4.6
溶媒:Merck KGaAのLiChrosolvグレード
溶媒A:H2O(TFAの0.01%)
溶媒B:ACN(TFAの0.008%)
勾配:
20%のB→100%のB:0分〜2.8分
100%のB:2.8分〜3.3分
100%のB→20%のB:3.3分〜4分
以下の例に示す保持時間RfまたはRt[分]およびM+H+データMWは、LC−MS測定の測定結果である。
5−(2,4−ジヒドロキシ−5−フェネチルフェニル)−4−(2−フルオロフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール(“A1”)の製造
1.1
100mlのN,N−ジメチルホルムアミド(DMF)中の15gの5−ブロモ−2,4−ジヒドロキシ安息香酸、14.4mlのヨードメタンおよび62.9gの炭酸セシウムを、還流下で16時間加熱する。混合物を慣用のワークアップに供して、16.7gの5−ブロモ−2,4−ジメトキシ安息香酸(“1”)を得る。
40mlの塩化チオニル中の4gの“1”とDMF2滴の混合物を、室温で16時間撹拌する。溶媒を除去して、4.3gの5−ブロモ−2,4−ジメトキシベンゾイルクロリド(“2”)、Rf1.610;MW280.5を得る。生成物は、さらなる精製なしで反応させる。
1.3
25mlのジクロロメタン中3.8gの“2”の溶液を1滴ずつ、25mlのジクロロメタン中の1.314mlの2−フルオロアニリンおよび1.13mlのピリジンの氷冷溶液に加え、混合物を室温で5時間撹拌する。慣用のワークアップおよびイソプロパノールからの結晶化により、4.5gの5−ブロモ−N−(2−フルオロフェニル)−2,4−ジメトキシベンズアミド(“3”)、Rf2.217;MW355.2を得る。
2.9gのPCl5を、窒素雰囲気下で、60mlのトルエン中の4.5gの“3”の溶液に加え、混合物を還流下で3時間加熱する。溶媒を除去し、残留物を100mlのTHFに溶解し、溶液を1滴ずつ、0℃にてTHF中の138mlの1Mヒドラジン溶液に加える。混合物をさらに16時間撹拌し、慣用のワークアップおよびイソプロパノールからの結晶化により、3.6gのN−(2−フルオロフェニル)−3−ブロモ−4,6−ジメトキシベンズアミドヒドラゾン(“4”)、Rf0.952;MW369.2を得る。
1.86gの1,1’−カルボニルジイミダゾール(“5”)を、300mlのTHF中の3.6gの“4”の溶液に加え、混合物をさらに16時間撹拌する。混合物を慣用のワークアップに供し、残留物をMTBエーテルと共に煮沸して冷却し、結晶を分離して、700mgの5−(2,4−ジメトキシ−5−ブロモフェニル)−4−(2−フルオロフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール(“6”)、Rf1.413;MW395.2を得る。
600mgの“6”、178.4μlのスチレン(安定化)、430.2μlのトリエチルアミン、14.1mgの酢酸パラジウム(II)(Pd47%)、19.17mgのトリ−o−トリルホスフィンおよび4mlのアセトニトリルを、10mlのバイアルに導入する。混合物を電子レンジで30分間170℃で照射する。少量の触媒を加え、混合物をさらに2回照射する。トルエンを混合物に加え、これを次に、水で多数回抽出する。有機相を乾燥し、濃縮する。残留物をRPクロマトグラフィで精製し、140mgの“7”、Rf1.765;MW418.4、および4mgの“8”を得る。
140mgの“7”を、標準の条件下で、0.14gのPt/C(5%)の存在下、10mlのTHF中において水素化する。次に触媒を分離し、慣用のワークアップに供して、140mgの“9”、Rf1.920;MW420.5を得る。
158.5μlの三臭化ホウ素を、−10℃で、2mlのジクロロメタン中の140mgの“9”の溶液に加え、混合物を室温でさらに16時間撹拌する。メタノールを0℃で加え、溶媒を分離し、残留物をRPクロマトグラフィで精製して、74mgの“A1”、Rf1.537;MW392.4、および27mgの“A2”、Rf1.884;MW398.4を得る。
5−[4−(2−フルオロフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−プロピルベンズアミド(“A46”)の製造
2.1
20mlのメタノール中の、100mgの5−(2,4−ジメトキシ−5−ブロモフェニル)−4−(2−フルオロフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール(“6”)、7mgの[(R)−(+)−2,2’−ビス−(ジフェニルホスフィノ)−1,1’−ビナフチル]パラジウム(II)クロリド、5.7mlの一酸化炭素および35μlのトリエチルアミンの溶液を、オートクレーブ中100℃、7.5barで20時間処理する。得られた溶液を次に濃縮し、エタノールから結晶化させて、91mgの5−[4−(2−フルオロフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジメトキシ安息香酸メチルを得る。
例1.8と同様にして、90mgの5−[4−(2−フルオロフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジメトキシ安息香酸メチルの反応により、57.2mgの化合物5−[4−(2−フルオロフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ安息香酸、Rt0.598分、m/e332を得る。
2mlのTHF中、55mgの5−[4−(2−フルオロフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ安息香酸、2モル当量のt−ブチルジメチルクロロシランおよび3モル当量のイミダゾールを室温で3時間撹拌し、次の化合物を得る。
2.3で得た生成物を1.5mlのTHFに溶解し、2当量の1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩を加える。室温で1時間後に、1.2当量のプロピルメチルアミンを加え、混合物をさらに18時間撹拌する。3当量のフッ化テトラメチルアンモニウムを次に加え、混合物を室温で2時間撹拌する。濃縮後、生成物を分離し、42mgの“A46”、Rt1.139分、m/e387;MW386を得る。
5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−プロピルベンズアミド(“A47”)、MW383.4。
本発明の化合物5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド(“C1”)を、“A47”の製造と同様にして得る。
3.55kgの2,4−ジヒドロキシ安息香酸を、30Lの氷酢酸に溶解する。10Lの氷酢酸中の1060mlのブロミンの溶液を、次に、1滴ずつ15℃で8時間かけて加える。次に20℃で16時間撹拌を続け、混合物を真空で蒸発させ、結晶残留物を20Lのジクロロメタン中にスラリー化し、1時間撹拌する。ろ過および空中乾燥により、4.9kgの白色粗生成物を得る。30Lのトルエン/アセトニトリル(1:1)からの再結晶化および乾燥により、3.549kg(収率66%)の5−ブロモ−2,4−ジヒドロキシ安息香酸(m.p.210〜211.5℃;MW233.0)を得る。
8.9kgの5−ブロモ−2,4−ジヒドロキシ安息香酸を、70Lのメタノールに溶解し、55℃に加熱する。次に800mlの硫酸(w=95〜98%)を計測して入れ、混合物をゆっくり還流しつつ4日間撹拌し、この間、さらに500mlの硫酸(w=95〜98%)を毎日加える(3回)。反応混合物を、100Lの水中の9kgの炭酸水素ナトリウムの冷却溶液(5℃)に撹拌して入れる。ろ過および50℃真空中での乾燥により、7.87kg(83%)の5−ブロモ−2,4−ジヒドロキシ安息香酸メチル(白色結晶)、MW247.1を得る。
7.86kg(83%)の5−ブロモ−2,4−ジヒドロキシ安息香酸メチルおよび9.65kgの炭酸カリウムを、100Lのアセトニトリル中に0℃で懸濁させる。混合物を次に80℃に加熱し、7575mlの臭化ベンジルを、40分かけて滴下ジョウゴ(dropping funnel)を介して加える。80℃で16時間の撹拌後、混合物をろ過し、集めたろ液を真空で濃縮する:12.95kg(95%)の2,4−ビスベンジルオキシ−5−ブロモ安息香酸メチル(わずかに黄色の結晶);MW427.3。
18LのTHF中の6.4kgの2,4−ビスベンジルオキシ−5−ブロモ安息香酸メチルを、30Lの水中の3kgの水酸化ナトリウム溶液に加える。68℃で一晩撹拌した後、混合物を10℃に冷却し、7.5LのHCl(w:37%)を滴下ジョウゴを介して加える(pH1)。混合物をさらに1時間撹拌し、続いてろ過する。残留物を、60℃の真空で定重量まで乾燥する;5.687kg(91%)の2,4−ビスベンジルオキシ−5−ブロモ安息香酸(m.p.150〜152℃;MW413.3)。
80mlのDMFを、42Lの塩化チオニルに加える。混合物を2〜9℃に冷却し、11.55kgの2,4−ビスベンジルオキシ−5−ブロモ安息香酸を1時間かけて加える。この温度で撹拌をさらに1時間続け、次に25℃で16時間続ける。塩化チオニルを次に真空で蒸留して除去する(300mbar、46℃)。得られた残留物に3Lのトルエンを加え、混合物を再度蒸発乾固し、この操作をさらに2回繰り返す。得られた生成物を、さらなる精製なしで次の反応に用いる。13.6kg(トルエンを加えて)。
1.75kgの五塩化リンを、3℃で、60Lのトルエン中の3.5kgの2,4−ビスベンジルオキシ−5−ブロモ−N−o−トリルベンズアミドに加える。混合物を次に135℃で4時間加熱し、次に撹拌を25℃で16時間続ける。真空での蒸発により、3.6kgの結晶物質を得る。後者を18LのTHFにとり、30LのTHF中の1.38kgのBoc−ヒドラジン溶液に、3℃で1.5時間かけて加える。25℃に温めて16時間撹拌した後、生成物を吸引してろ別し(4.3kgの白色生成物、THF湿潤)、これを続く反応に直接用いる。
25LのTHF中の、2kgの5−(2,4−ビスベンジルオキシ−5−ブロモフェニル)−4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール、90gの(1,1’−ビス(ジフェニルホスフィノ)−フェロセン)パラジウム(II)塩化物、83Lの一酸化炭素、479gのトリエチルアミンおよび400gのN−メチルブチルアミンの溶液を、120℃および5〜10barで20時間、オートクレーブ内で処理する。得られた溶液を続いて蒸発させ、エタノールから結晶化させて、1.4kg(70%)の5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ビスベンジルオキシ−N−メチル−N−ブチルベンズアミド、MW476.7を得る。
10LのTHF中の、1.1kgの5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ビスベンジルオキシ−N−メチル−N−ブチルベンズアミド、5%Pd/C(水50.5%)および85Lの水素の溶液を、23℃で7時間オートクレーブ内で処理する。得られた溶液を続いて蒸発させ、エタノールから結晶化させて、738g(95%)の5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド(“C1”);MW396.5を得る。
融点:
A1形態:m.p.238.5±0.1℃(n=6)
A2形態:m.p.209.6±0.2℃(n=6)
A1形態は熱力学的により安定な形態である。
2つの多形形態の粉末X線回折スペクトルを図1に示す。
多形A1およびA2の粉末XRDスペクトルデータ:
各ケースにおいて、10個の特性ピークを評価に用いた。
X線粉末回折法(XRD)
全試料をXRDにより測定した。
RT162−07:
・D5000回折計[Bruker AXS]
・透過モード
・ジェネレータ電力30kV/40mA
・CuKα1−放射、1.5406Å(一次モノクロメータ)
・位置敏感型検出器
範囲:3〜65°2θ
解像度:0.05°2θ
ステップ時間:1.4s
RT2214−07:
・Stoe粉末X線回折システムSTADIP 611 KL
・透過モード
・ジェネレータ電力40kV/40mA
・CuKα1−放射、1.5406Å(一次モノクロメータ)
・位置敏感型検出器
範囲:3〜65°2θ
解像度:0.5°2θ
ステップ時間:15s
プロドラッグ化合物の製造
例3
モノ−[2−(ブチルメチルカルバモイル)−5−ヒドロキシ−4−(5−オキソ−4−o−トリル−4,5−ジヒドロ−1H−1,2,4−トリアゾール−3−イル)フェニル]ホスフェートの製造
モノ−[4−(ブチルメチルカルバモイル)−2−(5−オキソ−4−o−トリル−4,5−ジヒドロ−1H−1,2,4−トリアゾール−3−イル)−5−ホスホノオキシフェニル]ホスフェート(E)の製造
モノ−[4−(ブチルメチルカルバモイル)−5−ヒドロキシ−2−(5−オキソ−4−o−トリル−4,5−ジヒドロ−1H−1,2,4−トリアゾール−3−イル)フェニル]ホスフェート(F)の製造
“C1”のグルクロン酸誘導体の製造
LC−MS条件
以下の特性のHewlett Packard HP 1100シリーズのシステム:
イオン源:エレクトロスプレー(陽モード);スキャン:100〜1000m/e;
断片化電圧:60V;
気体温度:300℃;
DAD:220nm。
カラム:Chromolith SpeedROD RP-18e 50-4.6
溶媒: Merck KGaAのLiChrosolvグレード
溶媒A:H2O(TFAの0.01%)
溶媒B:アセトニトリル(TFAの0.008%)
分極勾配:
5%のB→100%のB:0分〜3.0分
100%のB→3.0分〜3.3分
100%のB→20%のB:3.3分〜4分。
1.307、1.406および1.465分。
異性体Hは、NMR分光法により曖昧さなしで同定された。
1次元1H−NMRスペクトルならびに2次元HSQC、HMBCおよびROESYスペクトルを、次の条件下で得た:
Bruker DRX 500分光計;TMSを標準として、DMSO−d6、303K。
100gの本発明の活性成分および5gのリン酸水素二ナトリウムを3Lの2回蒸留水に溶解した溶液を、2N塩酸を用いてpH6.5に調整し、滅菌濾過し、注射バイアル中に移送し、滅菌条件下で凍結乾燥し、滅菌条件下で密封する。各々の注射バイアルは、5mgの活性成分を含む。
例B:座剤
20gの本発明の活性成分と100gの大豆レシチンおよび1400gのココアバターとの混合物を、溶融し、型中に注入し、放冷する。各々の座剤は、20mgの活性成分を含む。
1gの本発明の活性成分、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gの塩化ベンザルコニウムから、940mlの2回蒸留水中に溶液を調製する。pHを6.8に調整し、溶液を1Lにし、放射線により滅菌する。この溶液を、点眼剤の形態で用いることができる。
例D:軟膏
500mgの本発明の活性成分を、99.5gのワセリンと、無菌条件下で混合する。
1kgの本発明の活性成分、4kgのラクトース、1.2kgのジャガイモデンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を、慣用の方法で圧縮して錠剤を得、各々の錠剤が10mgの活性成分を含むようにする。
例F:糖衣錠
例Eと同様にして、錠剤を圧縮し、次に、慣用の方法で、スクロース、ジャガイモデンプン、タルク、トラガカントおよび染料の被膜で被覆する。
2kgの本発明の活性成分を、硬質ゼラチンカプセル中に、慣用の方法で導入して、各々のカプセルが20mgの活性成分を含むようにする。
例H:アンプル
1kgの本発明の活性成分を60Lの2回蒸留水に溶解した溶液を、滅菌濾過し、アンプル中に移送し、滅菌条件下で凍結乾燥し、滅菌条件下で密封する。各々のアンプルは、10mgの活性成分を含む。
Claims (13)
- 化合物:5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド、
またはその薬学的に使用し得る誘導体、塩、溶媒和物、互変異性体もしくは立体異性体、あるいはそれらの全ての比率での混合物。 - 薬学的に使用し得る誘導体が、一および二リン酸誘導体、チオキソ誘導体、モノおよびジグルクロン酸誘導体の群から選択される、請求項1に記載の化合物。
- 5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド、および/またはその薬学的に使用し得る誘導体、塩、溶媒和物、互変異性体もしくは立体異性体、あるいはそれらの全ての比率での混合物、ならびに任意に賦形剤および/またはアジュバントを含む、医薬。
- 5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド、またはその薬学的に使用し得る誘導体、塩、溶媒和物、互変異性体もしくは立体異性体、あるいはそれらの全ての比率での混合物の、HSP90の阻害、調節および/または調整が関与する疾患の、処置および/または予防のための医薬の製造のための使用。
- 5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド、またはその薬学的に使用し得る誘導体、塩、溶媒和物、互変異性体もしくは立体異性体、あるいはそれらの全ての比率での混合物の、
腫瘍疾患、ウイルス疾患、移植における免疫抑制、炎症誘発性疾患、嚢胞性線維症、脈管形成が関与する疾患、感染症、自己免疫疾患、虚血、線維形成疾患の処置および/または予防のための、
神経再生の促進のための、
癌の増殖、腫瘍細胞および腫瘍転移の抑制のための、
化学療法による毒性から正常細胞を保護するための、
不正確なタンパク質の折りたたみまたは凝集が主要な原因因子である疾患の処置のための、
医薬の製造のための、請求項4に記載の使用。 - 腫瘍疾患が、線維肉腫、粘液肉腫、脂肪肉腫、軟骨肉腫、骨肉腫、脊索腫、血管肉腫、内皮肉腫、リンパ管肉腫、リンパ管内皮肉腫、骨膜腫、中皮腫、ユーイング腫瘍、平滑筋肉腫、横紋筋肉腫、大腸癌、膵臓癌、乳癌、卵巣癌、前立腺癌、扁平上皮癌、基底細胞癌、腺癌、汗腺癌、皮脂腺癌、乳頭状癌、乳頭状腺癌、嚢胞腺癌、骨髄癌、気管支原生癌、腎細胞癌、肝細胞癌、胆管癌、絨毛癌、精上皮腫、胎生期癌、ウィルムス腫瘍、頸部癌、精巣腫瘍、肺癌、小細胞肺癌、膀胱癌、上皮癌、神経膠腫、星状細胞腫、髄芽細胞腫、頭蓋咽頭腫、脳室上衣細胞腫、松果体腫、血管芽細胞腫、聴神経腫、乏突起神経膠腫、髄膜腫、黒色腫、神経芽細胞腫、網膜芽細胞腫、白血病、リンパ腫、多発性骨髄腫、ワルデンストレームマクログロブリン血症、およびH鎖病である、請求項5に記載の使用。
- ウイルス疾患のウイルス病原体が、A型肝炎、B型肝炎、C型肝炎、インフルエンザ、水痘、アデノウイルス、I型単純ヘルペス(HSV−I)、II型単純ヘルペス(HSV−II)、牛疫、ライノウイルス、エコーウイルス、ロタウイルス、呼吸器合胞体ウイルス(RSV)、パピローマウイルス、パポバウイルス、サイトメガロウイルス、エキノウイルス、アルボウイルス、ハンタウイルス、コクサッキーウイルス、耳下腺炎ウイルス、麻疹ウイルス、風疹ウイルス、ポリオウイルス、ヒトI型免疫不全ウイルス(HIV−I)およびヒトII型免疫不全ウイルス(HIV−II)からなる群から選択される、請求項5に記載の使用。
- 炎症誘発性疾患が、関節リューマチ、喘息、多発性硬化症、1型糖尿病、紅斑性狼瘡(エリテマトーデス)、乾癬、および炎症性腸疾患である、請求項5に記載の使用。
- 脈管形成が関与する疾患が、糖尿病性網膜症、血管腫、子宮内膜症、および腫瘍脈管形成である、請求項5に記載の使用。
- 線維形成疾患が、硬腫、多発性筋炎、全身性狼瘡、肝硬変、ケロイド形成、間質性腎炎、および肺線維症である、請求項5に記載の使用。
- 不正確なタンパク質の折りたたみまたは凝集が主要な原因因子である疾患が、スクレイピー、クロイツフェルト−ヤコブ病、ハンチントン病またはアルツハイマー病である、請求項5に記載の使用。
- 5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド、および/またはその薬学的に使用し得る誘導体、塩、溶媒和物、互変異性体および立体異性体、またはそれらの全ての比率での混合物、および少なくとも1種のさらなる医薬活性成分を含む、医薬。
- (a)有効量の5−[4−(2−メチルフェニル)−3−ヒドロキシ−4H−1,2,4−トリアゾール−5−イル]−2,4−ジヒドロキシ−N−メチル−N−ブチルベンズアミド、および/またはその薬学的に使用し得る誘導体、塩、溶媒和物、互変異性体および立体異性体、またはそれらの全ての比率での混合物の、
および
(b)有効量のさらなる医薬活性成分
の個別のパックからなるセット(キット)。
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DE102007002715A DE102007002715A1 (de) | 2007-01-18 | 2007-01-18 | Triazolderivat |
PCT/EP2007/010775 WO2008086857A1 (de) | 2007-01-18 | 2007-12-11 | Triazolderivat als hsp 90 inhibitor |
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FR2949467B1 (fr) | 2009-09-03 | 2011-11-25 | Sanofi Aventis | Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation |
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DE102010024338A1 (de) | 2010-06-18 | 2011-12-22 | Merck Patent Gmbh | Verfahren zur Herstellung von 5-[4-(2-Methyl-phenyl)-3-hydroxy-4H-[1,2,4]triazol-5-yl]-2,4-dihydroxy-methyl-butyl-benzamid |
WO2012043791A1 (ja) * | 2010-10-01 | 2012-04-05 | 大正製薬株式会社 | 1,2,4-トリアゾロン誘導体 |
JP2014505705A (ja) * | 2011-02-02 | 2014-03-06 | ザ トラスティーズ オブ プリンストン ユニヴァシティ | ウイルス生成モジュレーターとしてのサーチュインモジュレーター |
CA2853806C (en) | 2011-11-02 | 2020-07-14 | Synta Pharmaceuticals Corp. | Combination therapy of hsp90 inhibitors with platinum-containing agents |
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US8816070B2 (en) | 2014-08-26 |
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AU2007344512B2 (en) | 2012-11-01 |
EP2102175A1 (de) | 2009-09-23 |
ZA200905700B (en) | 2010-05-26 |
WO2008086857A1 (de) | 2008-07-24 |
KR20090101381A (ko) | 2009-09-25 |
PE20090051A1 (es) | 2009-01-26 |
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CA2675737A1 (en) | 2008-07-24 |
CA2675737C (en) | 2015-03-24 |
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US20100113542A1 (en) | 2010-05-06 |
ES2455504T3 (es) | 2014-04-15 |
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MX2009007479A (es) | 2009-08-13 |
MY151452A (en) | 2014-05-30 |
UA98320C2 (en) | 2012-05-10 |
CL2008000134A1 (es) | 2008-05-16 |
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