JP4732693B2 - 最終分化を誘導する方法 - Google Patents
最終分化を誘導する方法 Download PDFInfo
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- JP4732693B2 JP4732693B2 JP2003574115A JP2003574115A JP4732693B2 JP 4732693 B2 JP4732693 B2 JP 4732693B2 JP 2003574115 A JP2003574115 A JP 2003574115A JP 2003574115 A JP2003574115 A JP 2003574115A JP 4732693 B2 JP4732693 B2 JP 4732693B2
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- 0 C*(C(*)=O)C(N(C)*)=O Chemical compound C*(C(*)=O)C(N(C)*)=O 0.000 description 5
- APBBTKKLSNPFDP-UHFFFAOYSA-N CC1c2ccccc2CCC1 Chemical compound CC1c2ccccc2CCC1 APBBTKKLSNPFDP-UHFFFAOYSA-N 0.000 description 1
- WESDBLALURHRDL-UHFFFAOYSA-N Cc1c2nccnc2ncn1 Chemical compound Cc1c2nccnc2ncn1 WESDBLALURHRDL-UHFFFAOYSA-N 0.000 description 1
- KDYVCOSVYOSHOL-UHFFFAOYSA-N Cc1cc2ncccc2cc1 Chemical compound Cc1cc2ncccc2cc1 KDYVCOSVYOSHOL-UHFFFAOYSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N Cc1cccc2cccnc12 Chemical compound Cc1cccc2cccnc12 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
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Description
本発明は、2002年3月4日に出願された合衆国仮出願第60/361,759号の利益を主張する。この仮出願の全体の教示は、本明細書に参考として援用される。
本発明は、国立癌研究所によって授与される認可番号1R21 CA 096228−01の下、全部または一部が政府の支持でなされた。政府は、本発明において特定の権利を有し得る。
本発明は、新生物細胞の最終分化、細胞増殖停止および/またはアポトーシスを選択的に誘導すること、および/またはヒストンデアセチラーゼ(HDAC)インヒビターを含む薬学的組成物のHDAC阻害投与の方法を提供する。この薬学的組成物の経口処方物は、高いバイオアベイラビリティーのような好ましい薬物動態学プロフィールを有し、そして驚くべきことに、延長された時間の期間に亘り、活性化合物の高い血中レベルを生じる。
本出願を通じて、種々の刊行物が括弧内のアラビア数字によって参照される。これら刊行物の完全な引用が、特許請求の範囲のすぐ前にある明細書の末端に見出され得る。これら刊行物のそれら全部の開示は、本発明が関係する当該技術分野の状態をより詳細に記載するために、本出願中に参考として本明細書によって援用される。
本発明は、投与の後少なくとも2時間の期間に亘り、被験体においてインビボでヒストンデアセチラーゼを阻害し得る平均血漿濃度のヒストンデアセチラーゼ(HDAC)インヒビターを生成する方法を提供し、これは、上記被験体に、HDACインヒビターまたは薬学的に受容可能なその塩またはその水和物、および薬学的に受容可能なキャリアまたは希釈剤を含む薬学的組成物の有効量を投与する工程を包含する。
本発明は、投与後の少なくとも2時間の期間にわたって、被験体においてインビボでヒストンデアセチラーゼを阻害し得る平均血漿濃度のヒストンデアセチラーゼ(HDAC)を生成する方法を提供し、この方法は、この被験体に、HDACインヒビターまたはその薬学的に受容可能な塩もしくは水和物、および薬学的に受容可能なキャリアまたは希釈剤を含む有効量の薬学的組成物を投与する工程を包含する。
ヒストンデアセチラーゼ(HDAC)は、この用語が本明細書中で使用される場合、ヌクレオソームコアヒストンのアミノ末端テイル中のリジン残基からのアセチル基の除去を触媒する酵素である。それ自体、HDACは、ヒストンアセチルトランスフェラーゼ(HAT)と共に、ヒストンのアセチル化状態を調節する。ヒストンアセチル化は、HDACの遺伝子発現およびインヒビターに影響を与える(例えば、ヒドロキサム酸ベースのハイブリッド極性化合物であるスベロイルアニリドヒドロキサム酸(suberoylanilide hydroxamic acid)(SAHA)は、形質転換した細胞の増殖停止、分化および/またはアポトーシスをインビトロで誘導し、そして腫瘍増殖をインビボで阻害する)。HDACは、構造的相同性に基づいて3つのクラスに分割され得る。クラスI HDAC(HDAC1、2、3および8)は、酵母RPD3タンパク質に対する類似性を保有し、核に位置し、そして転写共リプレッサーと関連して複合体中に見出される。クラスII HDAC(HDAC4、5、6、7および9)は、酵母HDA1タンパク質と類似であり、核および細胞質の両方の細胞内局在を有する。クラスIおよびクラスIIの両方のHDACは、ヒドロキサム酸ベースのHDACインヒビター(例えば、SAHA)によって阻害される。クラスIII HDACは、酵母SIR2タンパク質に関連するNAD依存性酵素の構造的に遠いクラスを形成し、そしてヒドロキサム酸ベースのHDACインヒビターによって阻害されない。
(A.ヒドロキサム誘導体)
例えば、スベロイルアニリドヒドロキサム酸(SAHA)(Richonら、Proc.Natl.Acad.Sci.USA 95,3003−3007(1998));m−カルボキシ桂皮酸ビスヒドロキサミド(CBHA)(Richonら、前出);ピロキサミド;トリコスタチン(trichostatin)アナログ(例えば、トリコスタチンA(TSA)およびトリコスタチンC(Kogheら、1998.Biochem.Pharmacol.56:1359−1364));サリチルヒドロキサム酸(SBHA)(Andrewsら、International J.Parasitology 30,761−768(2000));スベロイルビスヒドロキサム酸(SBHA)(米国特許第5,608,108号);アゼライック(azelaic)ビスヒドロキサム酸(ABHA)(Andrewsら、前出);アゼライック−1−ヒドロキサメート−9−アニリド(AAHA)(Qiuら、Mol.Biol.Cell 11,2069−2083(2000));6−(3−クロロフェニルウレイド)カプロニックヒドロキサム酸(3C1−UCHA);オキサムフラチン[(2E)−5−[3−[(フェニルスルホニル)アミノールフェニル]−ペンタ−2−エン−4−イノヒドロキサム酸](oxamflatin[(2E)−5−[3−[(phenylsufonyl)aminol phenyl]−pent−2−en−4−ynohydroxamic acid])(Kimら、Oncogene,18:2461−2470(1999));A−161906,Scriptaid(Suら、2000 Cancer Research,60:3137−3142);PXD−101(Prolifix);LAQ−824;CHAP;MW2796(Andrewsら、前出);MW2996(Andrewsら、前出);または米国特許第5,369,108号、同第5,932,616号、同第5,700,811号、同第6,087,367号および同第6,511,990号に開示されるようなヒドロキサム酸のいずれか。
例えば、トラポキシン(trapoxin)A(TPX)−環状テトラペプチド(シクロ−(L−フェニルアラニル−L−フェニルアラニル−D−ピペコリニル−L−2−アミノ−8−オキソ−9,10−エポキシデカノイル))(Kijimaら、J Biol.Chem.268,22429−22435(1993));FR901228(FK 228,デプシペプチド)(Nakajimaら、Ex.Cell Res.241,126−133(1998));FR225497環状テトラペプチド(H.Moriら、PCT出願WO00/08048(2000年2月17日));アピシジン(apicidin)環状テトラペプチド[シクロ(N−O−メチル−L−トリプトファニル−L−イソロイシニル−D−ピペコリニル−L−2−アミノ−8−オキソデカノイル)](Darkin−Rattrayら、Proc.Natl.Acad.Sci.USA 93,13143−13147(1996));アピシジンIa、アピシジンIb、アピシジンIc、アピシジンIIaおよびアピシジンIIb(P.Dulskiら、PCT出願WO97/11366);CHAP、HC−毒素環状テトラペプチド(Boschら、Plant Cell 7,1941−1950(1995));WF27082環状テトラペプチド(PCT出願WO98/48825);およびクラミドシン(chlamydocin)(Boschら、前出)。
例えば、酪酸ナトリウム(Cousensら、J.Biol.Chem.254,1716−1723(1979));イソバレレート(McBainら、Biochem.Pharm.53:1357−1368(1997));バレレート(McBainら、前出);4−フェニルブチレート(4−PBA)(LeaおよびTulsyan,Anticancer Research,15,879−873(1995));フェニルブチレート(PB)(Wangら、Cancer Research,59,2766−2799(1999));プロピオネート(McBainら、前出);ブチルアミド(LeaおよびTulsyan、前出);イソブチルアミド(LeaおよびTulsyan、前出);フェニルアセテート(LeaおよびTulsyan、前出);3−ブロモプロピオネート(LeaおよびTulsyan、前出);トリブチリン(Guanら、Cancer Research,60,749−755(2000));バルプロ酸およびバルプロエート。
例えば、CI−994;MS−27−275[N−(2−アミノフェニル)−4−[N−(ピリジン−3−イルメトキシカルボニル)アミノメチル]ベンズアミド](Saitoら、Proc.Natl.Acad.Sci.USA 96,4592−4597(1999));およびMS−27−275の3’−アミノ誘導体(Saitoら、前出)。
例えば、トリフルオロメチルケトン(Freyら、Bioorganic&Med.Chem.Lett.(2002),12,3443−3447;米国特許第6,511,990号)およびα−ケトアミド(例えば、N−メチル−α−ケトアミド)。
例えば、デプデシン(depudecin)(Kwonら、1998.PNAS 95:3356−3361)。
従って、1実施形態において、本発明は、式1の構造:
式31の構造によって表される化合物:
本発明の化合物、その誘導体、フラグメント、アナログ、ホモログ、薬学的に受容可能な塩または水和物は、経口投与するのに適切な薬学的組成物に薬学的に受容可能なキャリアまたは賦形剤と共に組み込まれ得る。このような組成物は、代表的に、治療有効量の上記の化合物のいずれか、および薬学的に受容可能なキャリアを含む。好ましくは、有効量とは、適切な新生物細胞の末端分化を選択的に誘導するのに有効であり、かつ患者に毒性を引き起こす量よりも小さい量である。
I.他の顕著な神経学的徴候(例えば、アルツハイマー病;アルツハイマー型の老人性痴呆症;およびピック病(脳葉萎縮))の非存在下での進行性痴呆によって特徴付けられる障害。
(実施例1)
(SAHAの合成)
SAHAは、以下に概説される方法、または米国特許第5,369,108号(この内容は、その全体が参考として援用される)に記載される方法もしくは任意の他の方法に従って、合成され得る。
(工程1−スベルアニリン酸(suberanilic acid)の合成)
粗SAHAを、メタノール/水から再結晶化した。メカニカルスターラー、熱電対、凝縮器および不活性雰囲気のための入口を備えた50Lフラスコに、結晶化させる粗SAHA(2,525.7g)、続いて、2,625mlの脱イオン水および15,755mlのメタノールを入れた。この物質を加熱還流させて、溶液を得た。次いで、5,250mlの脱イオン水をこの反応混合物に添加した。熱を遮断し、そしてこの混合物を、冷却させた。フラスコを安全に操作し得るようにこの混合物を十分に冷却した(28℃)とき、フラスコを熱マントルから除き、そして冷却浴として使用するためにタブに配置した。氷/水をタブに添加して、この混合物を−5℃に冷却した。この混合物を2時間その温度未満に維持した。この生成物を濾過によって単離し、そしてフィルターケーキを、1.5Lの冷メタノール/水(2:1)で洗浄した。漏斗をカバーし、そして生成物を1.75時間、減圧下で部分的に乾燥させた。生成物を漏斗から取り出し、そして6個のガラストレーに配置した。トレーを減圧オーブンに配置し、そして生成物を、減圧供給源としてNashポンプを使用し、そしてアルゴンブリードを使用して、60℃で64.75時間乾燥させた。トレーを秤量のために取り出し、次いで、オーブンに戻し、そしてさらに4時間60℃で乾燥して、一定の重量を得た。第2の乾燥期間の間、減圧供給源は、オイルポンプであり、アルゴンブリードを使用しなかった。この物質を、二重4−ミルポリエチレンバッグに包装し、そしてプラスチック外側容器内に配置した。サンプリング後の最終重量は、2,540.9g(92.5%)であった。
(スベロイルアニリドヒドロキサム酸(SAHA)の経口投薬)
(背景):ハイブリッド極性細胞性分化剤での処置は、ヒト固形腫瘍由来細胞株および移植片の増殖を阻害した。この効果は、一部、ヒストンデアセチラーゼの阻害によって媒介される。SAHAは、実験室および前臨床研究における腫瘍細胞増殖停止、分化およびアポトーシスを誘導する能力を有することが示された強力なヒストンデアセチラーゼインヒビターである。
(スベロイルアニリドヒドロキサム酸(SAHA)の経口投薬−用量増加)
別の実験において、表4に示されるように、固形腫瘍を有する25人の患者は、アームAに登録され、ホジキンリンパ腫または非ホジキンリンパ腫を有する13人の患者は、アームBに登録され、そして急性白血病を有する1人の患者および骨髄形成異常を有する1人の患者は、アームCに登録された。
コホートIIで処置された11人の患者のうち、1人の患者が、最初の処置サイクルの間、グレード3の下痢およびグレード3の脱水のDLTを経験した。9人の患者が、コホートIIIに入力された。2人の患者は、迅速な疾患の進行に起因して、初期に研究を停止したので、28日毒性評価について評価不可能であった。7人の残りの患者のうち、5人が、最初の処置サイクルの間、DLTを経験した:下痢/脱水(n=1)、疲労/脱水(n=1)、食欲不振(n=1)、脱水(n=1)および食欲不振/脱水(n=1)。これらの5人の患者は、研究薬物を持続した後約1週間で回復した。これらの患者は、後に、400mgQDに減少した用量であり、これは十分に耐えられるようであった。コホートIIIにおける全ての患者について400mgのBIDで中央日は、21日であった。これらの知見に基づいて、400mg q12時間投薬スケジュールは、最大寛容用量を超えていると判断した。プロトコル訂正後、1日1回の600mgの投薬でコホートIVで自然増加(accrual)を続けた。コホートIVに登録された7人の患者のうち、2人が、迅速な疾患の進行に起因して、初期に研究を停止したので、28日毒性評価について評価不可能であった。3人の患者は、最初の処置サイクルの間、DLTを経験した:食欲不振/脱水/疲労(n=1)、および下痢/脱水(n=2)。従って、600mgの用量は、最大の許容用量を超えていると判断し、1日当たり1回400mgの用量は、毎日1回の経口投与について最大の許容用量として規定された。連続的に投与される200mgのBIDおよび300mgのBIDで、1日2回の投薬スケジュールのさらなる用量レベルを評価するために、プロトコルを訂正した。
(SAHAの静脈内投薬)
表5は、静脈内でSAHAを受容する患者についての投薬スケジュールを示す。患者は、コホートIで開始し、300mg/m2のSAHAを、1週間週に5日の連続した日で、合計1500mg/m2の用量を受容する。次いで、患者は、処置が、疾患の進行、腫瘍後退、受容不可能な副作用または他の処置を受けた患者に起因して終了しない限り、2週間の間、観察され、そしてコホートIIに続けられ、次いで、コホートを通じて進めた。
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