JP5394423B2 - プロテアソーム酵素阻害のための化合物 - Google Patents
プロテアソーム酵素阻害のための化合物 Download PDFInfo
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Description
relogの法則を以下に述べる。これらの法則は例えばOrganic Chemistry,Fox and Whitesell;Jones and Bartlett Publishers,Boston,MA(1994);Section 5−6,pp177−178に記載されている。これは参考として本明細書に組み込まれる。ペプチド類は反復主鎖構造を有し、その主鎖単位から側鎖が延びている。概して各主鎖単位は主鎖に結合した側鎖を有するが、ある場合には側鎖は水素原子である。その他の実施形態において、あらゆる主鎖単位が結合側鎖を有するわけではない。ペプチドエポキシドまたはペプチドアジリジンに有用なペプチド類は2または3個の主鎖単位を有する。プロテアソームのキモトリプシン様(CT−L)活性を阻害するのに有用な或る実施形態において、2から8までの主鎖単位が存在し、CT−L阻害のある好ましい実施形態においては2から6までの主鎖単位が存在する。
ラルキルから独立的に選択され、より好ましくはR6およびR8は独立的にC1−6アルキルであり、R5およびR7は独立的にC1−6アラルキルである。
明の薬剤を塗布した医学的デバイスを含む処置を受ける疾患および症状の例は、アテローム性硬化症、急性冠動脈症候群、アルツハイマー病、癌、発熱、筋非活動(萎縮)、神経除去、血管閉塞、発作、HIV感染症、神経損傷、アシドーシス性腎不全および肝不全などである。例えばGoldberg,United States Patent No.5,340,736を参照されたい。
たがうものであり、その置換の結果、自発的には再配列、環化、脱離などによる変換を受けない安定化合物が生成するという暗黙の了解を含むことは当然である。ここに使用される用語“置換された”は有機化合物の受容可能な全ての置換基を含むことを考慮している。広い局面において受容可能な置換基は、適切な有機化合物の非環式および環式、分岐および非分岐、炭素環式および複素環式、芳香族および非芳香族置換基を含む。本発明の目的のために、窒素のようなヘテロ原子は水素置換基、および/またはヘテロ原子の原子価を満足させる、本明細書に記載の有機化合物の容認できる任意の置換基を有することができる。置換基は例えばハロゲン、ヒドロキシル、カルボニル(カルボキシル、アルコキシカルボニル、ホルミル、またはアシルなど)、チオカルボニル(チオエステル、チオアセテート、またはチオホルメートなど)、アルコキシル、ホスホリル、ホスフェート、ホスホネート、ホスフィネート、アミノ、アミド、アミジン、イミン、シアノ、ニトロ、アチド、スルフヒドリル、アルキルチオ、スルフェート、スルホネート、スルファモイル、スルホンアミド、スルホニル、ヘテロシクリル、アラルキル、または芳香族またはヘテロ芳香族部分を含むことができる。もし適切ならば、炭化水素鎖上で置換された部分それ自体が置換され得ることは当業者には当然である。
Rel(c−Rel)、およびRelB)を含む。ホモ−およびヘテロダイマーはRelファミリーのメンバーによって形成できる;例えばNF−κBはp50−p65ヘテロダイマーである。IkBおよびp105の燐酸化およびユビキチネーション後、2種類の蛋白はそれぞれ分解し、処理され、細胞質から核へ転位する活性NF−κBを生成する。ユビキチン化p105は精製プロテアソームによっても処理される(Palombella et al.,Cell(1994)78:773−785)。活性NF−κBはその他の転写アクチベータ、例えばHMG1(Y)と共に立体特異的エンハンサ複合体を形成し、特定遺伝子の選択的発現を生成する。
球および白血球において回復せずに酵素活性の停止を誘起することが示された。このような実施形態においては、血球は長い半減期を有するので、寄生虫への反復被曝に対して長期間の治療的防御がもたらされるかも知れない。ある実施形態において、血球のこの長い半減期は、今後の感染に対する化学的予防に関してより長期の防御をもたらすかも知れない。
ングリコール、ラウリル硫酸ナトリウム、およびこれらの混合物;(10)着色料。カプセル、錠剤およびピルの場合には薬学的組成物は緩衝剤も含むことができる。同様なタイプの固体組成物はラクロースまたはミルクシュガー並びに高分子ポリエチレングリコールなどの賦形剤を用いて軟−および硬充填ゼラチンカプセルのフィラーとしても用いられる。
)、抗生物質(ダクチノマイシン(アクチノマイシンD)、ダウノルビシン、ドキソルビシンおよびイダルビシン)、アントラサイクリン類、ミトキサントロン、ブレオマイシン、プリカマイシン(ミトラマイシン)およびマイトマイシンなど、酵素類(全身的にL−アスパラギンを代謝し、それ自体はアスパラギンを合成する能力をもたない細胞を喪失させるL−アスパラギナーゼ);抗血小板剤;ナイトロジェンマスタードのような抗増殖性/抗有糸分裂性アルキル化剤(メクロレタミン、シクロホスファミドおよび類似体、メルファラン、クロランブシル)、エチレンイミン類およびメチルメラミン類(ヘキサメチルメラミンおよびチオテパ)、アルキルスルホネート(ブスルファン)、ニトロソ尿素類(カルムスチン(BCNU)および類似体、ストレプトゾシン)、トラゼンス−デカルバジニン(DTIC);抗増殖性/抗有糸分裂性抗代謝物、例えば葉酸類似物(メトトレキセート)、ピリミジン類似体(フルオロウラシル、フロキシウリジン、およびシタラビン)、プリン類似体および関連インヒビター類(メルカプトプリン、チオグアイン、ペントスタチンおよび2−クロロデオキシアデノシン);アロマターゼインヒビター類(アナストロゾール、エキセメスタン、およびレトロゾール);および白金配位錯体(シスプラチン、カルボプラチン)、プロカルバジン、ヒドロキシウレア、ミトーテン、アミノグルテチミド;ヒストンデアセチラーゼ(HDAC)インヒビター類(トリコスタチン、酪酸ナトリウム、アピシダン、スベロイルアニリドヒドロアミック酸);ホルモン類(すなわちエストロゲン)および、黄体化ホルモン放出ホルモン(LHRH)アゴニストのようなホルモンアゴニスト類(ゴセレリン、ループロリドおよびトリプトレリン)を含む。その他の化学療法剤はメクロレタミン、カンプトテシン、イフォスファミド、タモキシフェン、ラロキシフェン、ゲンシタビン、ナベルビン、または前記のものの任意の類似体または誘導体変形物を含む。
れた(31.0mg)。
に冷やし、BOP(0.13mmol、0.058g、3.8eq.)を数回に分けて与えた。混合物をその後5℃で窒素気流下で一晩撹拌した。反応物をその後飽和NaClで希釈し、EtOAcで抽出した。有機層を水およびブラインで洗い、無水MgSO4上で乾燥し、濾過し、濃縮して油にし、それをフラッシュクロマトグラフィーによって精製すると化合物9が得られた。IC5020SCT−L<50nM、IC50細胞ベースCT−L<50nM。
Claims (18)
- 式:
- 前記組成物が、炎症の治療法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、HIV感染を阻止または軽減する方法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、神経変性疾患の治療法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、筋肉消耗性疾患の治療法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、癌の治療法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、慢性感染症の治療法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、過増殖性状態の治療法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、筋非活動の治療法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、免疫関連症状の治療法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、被験体におけるウイルス遺伝子発現レベルに影響を与える方法における使用のためである、請求項1に記載の組成物。
- 前記組成物が、生体内のプロテアソームによって生成される抗原性ペプチドの種類を変化させる方法における使用のためである、請求項1に記載の組成物。
- 前記骨損失と関連する疾患又は症状の治療法における使用のためである、請求項1に記載の組成物。
- 前記骨損失と関連する疾患又は症状が骨粗鬆症である、請求項13に記載の組成物。
- 前記の組成物が、グラフト対ホスト疾患の治療法における使用のためである、請求項1に記載の組成物。
- 前記過増殖性状態が、糖尿病性網膜症、斑変性、糖尿病性腎症、糸球体硬化症、IgA腎症、肝硬変、胆道閉鎖症、うっ血性心不全、硬皮症、放射線誘起性線維症および肺線維症からなる群から選ばれる、請求項8に記載の組成物。
- 前記免疫関連症状が、狼瘡、リウマチ性関節炎、乾癬、多発性硬化症、および炎症性腸疾患から選ばれる自己免疫病である、請求項10に記載の組成物。
- 前記炎症が、COPD、乾癬、気管支炎、気腫および嚢胞性線維症から選ばれる慢性炎症である、請求項2に記載の組成物。
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US59940104P | 2004-08-06 | 2004-08-06 | |
US60/599,401 | 2004-08-06 | ||
US61000104P | 2004-09-14 | 2004-09-14 | |
US60/610,001 | 2004-09-14 | ||
US11/106,879 US7232818B2 (en) | 2004-04-15 | 2005-04-14 | Compounds for enzyme inhibition |
US11/106,879 | 2005-04-14 |
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US (12) | US7232818B2 (ja) |
EP (4) | EP2266999B1 (ja) |
JP (2) | JP4743720B2 (ja) |
KR (3) | KR101354280B1 (ja) |
CN (1) | CN102286070B (ja) |
AT (1) | ATE496062T1 (ja) |
AU (1) | AU2005271232B2 (ja) |
BR (2) | BR122020008634B8 (ja) |
CA (1) | CA2589765C (ja) |
CY (3) | CY1116771T1 (ja) |
DE (1) | DE602005026019D1 (ja) |
DK (2) | DK3101026T3 (ja) |
ES (2) | ES2525248T3 (ja) |
FR (1) | FR16C0017I2 (ja) |
HK (4) | HK1103525A1 (ja) |
HU (2) | HUE038005T2 (ja) |
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |