JP2017531624A - mTORC1阻害剤 - Google Patents
mTORC1阻害剤 Download PDFInfo
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- JP2017531624A JP2017531624A JP2017513748A JP2017513748A JP2017531624A JP 2017531624 A JP2017531624 A JP 2017531624A JP 2017513748 A JP2017513748 A JP 2017513748A JP 2017513748 A JP2017513748 A JP 2017513748A JP 2017531624 A JP2017531624 A JP 2017531624A
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Abstract
Description
本出願は、2014年9月11日に出願された米国特許仮出願第62,049,186号の利益を主張し、その内容は、すべての目的のためにその全体が本明細書に組み込まれる。
2015年9月7日に作成された、40,375バイト、IBM−PC、MS−Windowsオペレーティングシステムマシンフォーマットの、ファイル48536−551001WO_ST25.TXTに書かれた配列表は、参照により本明細書に組み込まれる。
本明細書で使用される略語は、化学及び生物学分野におけるその従来の意味を有する。本明細書に記載される化学構造及び式は、化学分野で知られている化学原子価の標準的な規則に従って構成される。
(A)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、無置換のアルキル、無置換のヘテロアルキル、無置換のシクロアルキル、無置換のヘテロシクロアルキル、無置換のアリール、無置換のヘテロアリール、ならびに
(B)以下から選択される少なくとも1つの置換基で置換される、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール:
(i)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、無置換のアルキル、無置換のヘテロアルキル、無置換のシクロアルキル、無置換のヘテロシクロアルキル、無置換のアリール、無置換のヘテロアリール、ならびに
(ii)以下から選択される少なくとも1つの置換基で置換される、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール:
(a)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、無置換のアルキル、無置換のヘテロアルキル、無置換のシクロアルキル、無置換のヘテロシクロアルキル、無置換のアリール、無置換のヘテロアリール、及び
(b)以下から選択される少なくとも1つの置換基で置換される、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール:オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、無置換のアルキル、無置換のヘテロアルキル、無置換のシクロアルキル、無置換のヘテロシクロアルキル、無置換のアリール、無置換のヘテロアリール。
一態様では、一価のラパマイシンまたは一価のラパマイシン類似体に共有結合している一価の活性部位mTOR阻害剤を含む化合物が提供される。
(l)金属酸化ケイ素結合、ならびに
(m)例えば、リン酸ジエステル結合を形成するための反応性リン基(例えば、ホスフィン)への金属結合。
(n)銅触媒環状付加クリック化学を使用してアルキンに結合したアジド。
R49、R52、R55及び/またはR58は独立に、無置換の3〜6員ヘテロシクロアルキルである。実施形態では、R22、R25、R28、R31、R34、R37、R40、R43、R46、R49、R52、R55及び/またはR58は独立に、無置換のフェニルである。実施形態では、R22、R25、R28、R31、R34、R37、R40、R43、R46、R49、R52、R55及び/またはR58は独立に、無置換の5〜6員ヘテロアリールである。
別の態様では、(例えば、一態様、実施形態、実施例、図、表または特許請求の範囲における)実施形態を含めた本明細書に記載の医薬的に許容可能な賦形剤及び化合物または医薬的に許容可能なその塩を含む医薬組成物が提供される。
一態様では、異常なレベルのmTORC1活性と関連する疾患を治療することを、そうした治療を必要としている対象において行うが提供される。疾患は、異常に高いmTORC1活性(例えば、mTORC1の過剰活性またはmTORC1活性レベルの増大またはmTORC1量の増大またはmTOR変異)に起因し得る。この方法は、本明細書に記載の化合物を対象に投与することを含む。この方法は、治療有効量の本明細書に記載の化合物(例えば、上記のmTORC1モジュレーター(例えば、阻害剤))を対象に投与することを含むことができる。
別の態様では、mTORC1活性を調節することを、それを必要とする対象において行う方法が提供され、これは、有効量の本明細書に記載の化合物または医薬的に許容可能なその塩を対象に投与することを含む。実施形態では、この方法は、mTORC1活性の阻害を含む。実施形態では、この方法は、mTORC1活性の阻害を含み、mTORC2活性の阻害を含まない。実施形態では、この方法は、mTORC2活性の阻害を上回るmTORC1活性の阻害を含む。実施形態では、この方法は、mTORC2活性の阻害の少なくとも1.1倍(例えば、少なくとも1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90、100、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000、6000、7000、8000、9000、10000、10000、20000、30000、40000、50000、60000、70000、80000、90000、100000、100000、200000、300000、400000、500000、600000、700000、800000、900000または1000000倍)のmTORC1活性の阻害を含む。
1.一価のラパマイシンまたは一価のラパマイシン類似体に共有結合している一価の活性部位mTOR阻害剤を含む化合物。
L1は前記二価のリンカーであり、R3は水素、オキソ、ハロゲン、−CX3、−CN、−SOnR10、−SOvNR7R8、−NHNR7R8、−ONR7R8、−NHC=(O)NHNR7R8、−NHC=(O)NR7R8、−NHC=(O)NR7R8、−N(O)m、−NR7R8、−C(O)R9、−C(O)−OR9、−C(O)NR7R8、−OR10、−NR7SO2R10、−NR7C=(O)R9、−NR7C(O)OR9、−NR7OR9、−OCX3、−OCHX2、置換もしくは無置換のアルキル、置換もしくは無置換のヘテロアルキル、置換もしくは無置換のシクロアルキル、置換もしくは無置換のヘテロシクロアルキル、置換もしくは無置換のアリールまたは置換もしくは無置換のヘテロアリールであり、R7、R8、R9及びR10は独立に、水素、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)OH、−NHOH、−OCF3、−OCHF2、置換もしくは無置換のアルキル、置換もしくは無置換のヘテロアルキル、置換もしくは無置換のシクロアルキル、置換もしくは無置換のヘテロシクロアルキル、置換もしくは無置換のアリールまたは置換もしくは無置換のヘテロアリールであり、同じ窒素原子に結合したR7及びR8置換基は、任意で結合して、置換もしくは無置換のヘテロシクロアルキルまたは置換もしくは無置換のヘテロアリールを形成することができ、W1はNまたはCHであり、m及びvは独立に、1または2であり、nは独立に、0〜4の整数であり、Xは独立に−Cl、−Br、−Iまたは−Fである)。
F.実施例
TORC2に対するMLN0128の作用は、その抗癌活性に必要であると考えられていない。これは、Akt駆動性リンパ腫形成の遺伝子改変マウスモデルにおいて解析された10。eIF4Eを構成的に阻害することができる4E−BP1の非リン酸化性突然変異体は、Akt駆動性リンパ腫形成をブロックし、これによって、mTORのこの単一の基質が、癌細胞の増殖及び生存を支援するのに十分であることが示唆される。構成的活性型Akt及び構成的活性型4E−BP1を持ついくつかの動物では、いくつかの腫瘍は、まだ4E−BP1突然変異体(4EBP1M)を発現する。おそらく、4EBP1Mによって課せられたブロックを迂回する別の経路が活性化された。これらの細胞は、asTORiクラスの阻害剤の作用機構の遺伝子的試験を提供する。細胞に対するasTORiの作用が4E−BP1のリン酸化によって媒介されるならば、4EBP1Mを迂回する細胞に添加したときに、該薬物の効果はないはずである。asTORi、すなわちPP242は、そのような細胞において有意な効果がなく(図1)、これによって、asTORiの細胞死滅効果は、完全にではないにせよ、大部分が、eIF4Eの活性化につながる4E−BP1のリン酸化によって媒介されることが確証される10。
第3のクラスのmTOR阻害剤−「Rapa−Link」の設計及び生成。昨年、Pavletich及び共同研究者によってmTORの一部の結晶構造が解明された17。この構造は、さらに早期の、単離されたFRB及びFKBPタンパク質に結合したラパマイシン構造18とともに、完全に新しいクラスのmTOR阻害剤を開発する機会を与える。ラパマイシンのTORC1選択的性質を利用すること、及び(FKBP12またはmTORのFRBドメインへのラパマイシンの結合を乱さない方法で)ラパマイシンをasTORi(例えば、MLN0128)に結合させることによって、本発明者らは、mTORを標的とするための新しいタイプの薬理学的薬剤を開発することができ得ると予測した(図2A及び2B)。mTOR阻害剤を設計するためのこのアプローチは、以前に提案されておらず、且つmTORシグナリングをブロックする新規な薬理学的手段を提供する。本設計の重要な態様は、asTORi(例えば、MLN0128)をmTORC1の活性部位に「送達」して、pS6及び4E−BP1の両方を効果的にブロックするために、ラパマイシンを使用することである。本設計の第二の態様は、ラパマイシンをasTORi(例えば、MLN0128)に結合させることが、細胞中でFKBP12への結合をもたらすことになると思われ、asTORi(例えば、MLN0128)−Rapa/FKBP12というこの大きな複合体において、asTORi(例えば、MLN0128)は、mTORC2に結合するその能力が低下し、それによりAkt S473に対する影響を低減させるであろうということである。
ラパマイシンをasTORi(例えば、MLN0128)に結合させるための最適な位置化学及びクロスリンカー長を決定するために、mTOR(PDB:4JT5)17及びFRB:FKBP12:ラパマイシン(1FAP)18の2つの独立の結晶構造を、両方の構造に含まれる共通のFRBドメインを使用してオーバーレイした(図4A)。
化学合成。分子の2つの部分をカップリングするための急速な手段(アジド/アルキン環化)を提供すると思われる薬物様クロスリンカー(ポリエチレングリコールベース)を持つRapa−Link阻害剤(M−1071、M−1111、M−3059、M−1115など)を設計した。本発明者らは、ラパマイシンの構造的複雑性及びそのコストを考慮し、収束的合成経路(スキーム1−A)を適用することに決めた。したがって、前駆体としてプロパルギルエチレングリコール導入ラパマイシン(III−A)を合成した(スキーム3)。asTORi(スキーム2)については、アタッチメント「A」を有する2つのタイプの化合物(II−C)を調製し、1)タイプAはアミノ基を末端の位置に有し、2)タイプBは末端の位置にカルボキシレートを有する。こうした末端官能基は、アミド形成反応によって活性部位阻害剤をクロスリンカーに結合するのに使用される。様々な種類のクロスリンカーの中で、ポリエチレングリコール(PEG)リンカーを選択し、これは、このリンカーが多数の医薬品で見られるからである20。アジドPEGリンカーを使用してasTORi(IIc−A)を結合させ、続いて、ラパマイシンのプロパルギル誘導体(III−A)とトリアゾール形成反応を行った(スキーム1−A)。主要な中間体を使用することによって、mTORへの最適な二重結合を可能にするには短すぎると予想されるリンカーを有するように設計されている陰性対照化合物(M−1115)も合成した(図4B)。
合成の説明で使用される略語。AcOH:酢酸、DME:1,2−ジメトキシエタン、DMF:N,N−ジメチルホルムアミド、DMSO:ジメチルスルホキシド、dPEG:ディスクリートポリ−(エチレングリコール)、EDCI:1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド、ESI:エレクトロスプレーイオン化、EtOAc:酢酸エチル、HOBt:1−ヒドロキシベンゾトリアゾール、HPLC:高速液体クロマトグラフィー、HR−MS:高分解能質量分析、LC−MS:液体クロマトグラフィー−質量分析、LTQ−FT:リニアトラップ四重極型−フーリエ変換(linear trap quadrupole−Fourier transform)、MeOH:メタノール、NHS:N−ヒドロキシスクシンイミド、NMR:核磁気共鳴、RP−HPLC:逆相−高速液体クロマトグラフィー、THF:テトラヒドロフラン、TLC:薄層クロマトグラフィー、TMS:テトラメチルシラン。
3クラスのmTOR阻害剤(ラパマイシン−クラスI、MLN0128−クラスII及びRapa−Link−クラスIII)の比較。ヒト結腸直腸癌細胞株HCT−15、ヒト肝細胞癌細胞株SNU−449、ヒト腎臓癌細胞株786−O、L6筋芽細胞及び3T3−L細胞をアメリカ培養細胞系統保存機関(ATCC)(Manassas、VA USA)から購入した。これらの細胞を、5%CO2及び95%空気の雰囲気下において37℃で維持される加湿インキュベーター中に設置した組織培養ディッシュにおいて、10%の熱失活ウシ胎仔血清(FBS)を補充した(供給業者推奨の)適切な培地中で生育させた。
クラスI−II−III mTOR阻害剤の細胞シグナリング効果。細胞を60mmの細胞培養ディッシュに播種し、70〜90%の培養密度まで、1〜2日インキュベートした。細胞をDMSO中の化合物溶液(1000×)で処理し、5%CO2の加湿インキュベーター中で所与の時間37℃でインキュベートした。全細胞可溶化物を、ホスファターゼ阻害剤カクテル錠剤PhosStopとプロテアーゼ阻害剤カクテル錠剤cOmplete Mini(Roche Diagnostics GmbH、Mannheim、Germany)とを含むRIPA緩衝液(R3792)(TEKnova、Hollister、CA USA)を使用して調製した。細胞可溶化物(Pierce BCAプロテインアッセイキット(PI−23225)(Thermo Fisher Scientific Inc.、Waltham、MA USA)によって決定した一定量のタンパク質に基づく)をCriterion Tris−HClゲル4〜20%(Bio−Rad Laboratories、Hercules、CA USA)を使用して電気泳動し、ニトロセルロース膜(162−0115)(Bio−Rad Laboratories、Hercules、CA USA)にトランスファーした。ブロッキングバッファーとともに室温で1時間超インキュベーションした後、4℃で一晩インキュベーションすることによって一次抗体で膜を標識し、続いて、これを、西洋ワサビペルオキシダーゼ−コンジュゲート化(HRP−コンジュゲート化)二次抗体とともに室温で1時間インキュベーションした。以下の抗体を免疫ブロットに使用した:ホスホ−Akt(S473)(#9271)、ホスホ−Akt(T308)(#2965)、総−Akt(#9272)、ホスホ−S6(Ser240/Ser244)(#2215L)、S6リボソームタンパク質(#2217)、ホスホ−4E−BP1(T37/T46)(#2855)、総4E−BP1(#9644)(Cell Signaling Technology、Inc.、Danvers、MA USA)、FKBP12(sc−28814)マウスβ−アクチン(sc−8432)(Santa Cruz Biotechnology、Inc.、Dallas、Texas USA)、西洋ワサビペルオキシダーゼ(HRP)とコンジュゲートした抗ウサギIgG(#7074)及びHRPとコンジュゲートした抗マウスIgG(#7076)(Cell Signaling Technology、Inc.、Danvers、MA USA)。ニトロセルロース膜をSuperSignal(登録商標)West Pico Chemiluminescent SubstrateまたはFemto Maximum Sensitivity Substrate(Thermo Fisher Scientific Inc.、Waltham、MA USA)にさらし、シグナルをCL−Xposureフィルム(Thermo Fisher Scientific Inc.、Waltham、MA USA)で記録した。
マウスのヒト腎臓癌786−O異種移植腫瘍におけるM1071の薬力学的研究。M−1071を、クレモフォールEL−エタノール[2/1w/w]を使用すること、及びこれをビヒクルとしての5%w/vグルコース水溶液で1:5希釈することによって、腫瘍移植マウスに腹腔内投与した。薬物を投与してから3時間後に腫瘍試料を収集した。MWF群については、M−1071を1日1回隔日で投与した。最後に投与してから4時間後に、腫瘍試料を収集した。腫瘍試料を凍らせた後、それをホモジナイズし、ホスファターゼ阻害剤及びプロテアーゼ阻害剤を含むRIPA緩衝液で処理した。次のウェスタンブロット解析を前述の方法と同様の方法で行った。
血中グルコースレベルへの影響。M−1071、ラパマイシン及びMLN0128を、クレモフォールEL−エタノール[2/1w/w]を使用すること、及びこれをビヒクルとしての5%w/vグルコース水溶液で1:5希釈することによって、マウス(n=3)に腹腔内投与した。血中グルコースレベル(mg/dL)をモニターした。
薬物ウォッシュアウト実験。SNU−449細胞を30nMの化合物で3時間処理した。培地を吸引除去し、新鮮な10%FBSのRPMI1640培地で細胞を洗浄した。次いで、細胞を新鮮な10%FBSのRPMI1640培地とともに37℃で記載の時間にわたってインキュベートした。
さらなるRapa−Link化合物。mTORのATP部位へのより弱い結合剤の効果を探索するために、さらなる2つのRapa−Link化合物、E1010及びE1035を合成した。
OHプロトンは10−OHまたは28−OHについて4.81 (1H, s)で観察された。別のOHプロトンは同定されなかった。
NHxプロトンはPP−NH2について6.08 (br)で観察された。
一定分量のジオキサン:H2O(3:1)(1mL)に1−Boc−5−TBDMS−O−インドール−2−ボロン酸(5)(以前に合成した)(50mg、0.12mmol)、(1−(tert−ブトキシカルボニル)−5−((tert−ブチルジメチルシリル)オキシ)−1H−インドール−2−イル)ボロン酸(135mg、0.35mmol)、K3PO4(34mg、0.35mmol)、SPhos(10.2mg、24.8μmol)及びトリス(ジベンジリデンアセトン)ジパラジウム(0)(12.2mg、13.3μmol)をアルゴン雰囲気下において室温で加えた。この混合物をマイクロ波によって150℃で20分間加熱した。次いで、これを冷却し、H2O(5mL)とDCM(5mL)の間に分配した。水性層を分離し、DCM(5mL×2)で抽出した。有機層を混合し、無水MgSO4で乾燥した。不溶性物を濾過して取り除き、濾液を真空濃縮した。粗製物質をシリカゲルカラムクロマトグラフィー(シリカゲル:125g、溶媒:100%DCM、続いて0〜10%MeOHのDCM溶液)によって精製した。1H NMR (400MHz, DMSO−d6) δ 11.43 (1H, br s), 8.42 (1H, s), 8.27 (1H, s), 7.25 (1H, d, J =8.8 Hz), 7.12 (2H, br s), 6.92 (1H, d, J =2.3Hz), 6.69 (1H, dd, J =8.3, 2.3Hz), 6.68 (1H, br s), 4.38 (2H, t, J =6.4Hz), 3.58 (2H, br s), 2.76 (2H, t, J =7.1 Hz), 1.92 (2H, m), 1.50 (2H, m)。LC−MS (ESI) m/z = 550.81 (M−H)−。
Claims (56)
- 一価のラパマイシンまたは一価のラパマイシン類似体に共有結合している一価の活性部位mTOR阻害剤を含む化合物。
- 二価のリンカーが前記一価の活性部位mTOR阻害剤を前記一価のラパマイシンまたは前記一価のラパマイシン類似体に結合させる、請求項1に記載の化合物。
- 前記二価のリンカーが少なくとも17Åの長さである、請求項2に記載の化合物。
- 前記二価のリンカーが少なくとも32Åの長さである、請求項2に記載の化合物。
- 以下の式を有する、請求項2に記載の化合物:
L1は前記二価のリンカーであり、
R3は水素、−OH、ハロゲン、−CX3、−CN、−SOnR10、−SOvNR7R8、−NHNR7R8、−ONR7R8、−NHC=(O)NHNR7R8、−NHC=(O)NR7R8、−N(O)m、−NR7R8、−C=(O)R9、−C=(O)OR9、−C=(O)NR7R8、−OR10、−NR7SO2R10、−NR7C=(O)R9、−NR7C=(O)OR9、−NR7OR9、−OCX3、−OCHX2、置換もしくは無置換のアルキル、置換もしくは無置換のヘテロアルキル、置換もしくは無置換のシクロアルキル、置換もしくは無置換のヘテロシクロアルキル、置換もしくは無置換のアリールまたは置換もしくは無置換のヘテロアリールであり、
R7、R8、R9及びR10は独立に、水素、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC=(O)OH、−NHOH、−OCF3、−OCHF2、置換もしくは無置換のアルキル、置換もしくは無置換のヘテロアルキル、置換もしくは無置換のシクロアルキル、置換もしくは無置換のヘテロシクロアルキル、置換もしくは無置換のアリールまたは置換もしくは無置換のヘテロアリールであり、同じ窒素原子に結合したR7及びR8置換基は、任意で結合して、置換もしくは無置換のヘテロシクロアルキルまたは置換もしくは無置換のヘテロアリール形成することができ、
W1はNまたはCHであり、
m及びvは独立に、1または2であり、
nは独立に、0〜4の整数であり、及び
Xは独立に、−Cl、−Br、−Iまたは−Fである)。 - R3が置換もしくは無置換のアルキル、置換もしくは無置換のヘテロアルキル、置換もしくは無置換のシクロアルキル、置換もしくは無置換のヘテロシクロアルキル、置換もしくは無置換のアリールまたは置換もしくは無置換のヘテロアリールである、請求項5に記載の化合物。
- R3が置換もしくは無置換のアリールまたは置換もしくは無置換のヘテロアリールである、請求項5に記載の化合物。
- R3が置換または無置換の縮合環ヘテロアリールである、請求項5に記載の化合物。
- R3が置換ベンゾオキサゾリル、置換ピリミジニル、置換チオフェニル、置換フラニル、置換インドリル、置換ベンゾオキサジアゾリル、置換ベンゾジオキソリル、置換ベンゾジオキサニル、置換チアナフサニル、置換ピロロピリジニル、置換インダゾリル、置換キノリニル、置換キノキサリニル、置換ピリドピラジニル、置換キナゾリノニル、置換ベンゾイソオキサゾリル、置換イミダゾピリジニル、置換ベンゾフラニル、置換ベンゾチオフェニル、置換フェニル、置換ナフチル、置換ビフェニル、置換ピロリル、置換ピラゾリル、置換イミダゾリル、置換ピラジニル、置換オキサゾリル、置換イソオキサゾリル、置換チアゾリル、置換フリルチエニル、置換ピリジル、置換ピリミジル、置換ベンゾチアゾリル、置換プリニル、置換ベンズイミダゾリル、置換イソキノリル、置換チアジアゾリル、置換オキサジアゾリル、置換ピロリル、置換ジアゾリル、置換トリアゾリル、置換テトラゾリル、置換ベンゾチアジアゾリル、置換イソチアゾリル、置換ピラゾロピリミジニル、置換ピロロピリミジニル、置換ベンゾトリアゾリルまたは置換キノリルである、請求項5に記載の化合物。
- L1がL2−L3−L4−L5であり、
L2が前記一価のラパマイシンまたは前記一価のラパマイシン類似体に直接的に結合し、
L2が置換もしくは無置換のアルキレン、置換もしくは無置換のヘテロアルキレン、置換もしくは無置換のシクロアルキレン、置換もしくは無置換のヘテロシクロアルキレン、置換もしくは無置換のアリーレンまたは置換もしくは無置換のヘテロアリーレンであり;
L3が結合、置換もしくは無置換のアルキレン、置換もしくは無置換のヘテロアルキレン、置換もしくは無置換のシクロアルキレン、置換もしくは無置換のヘテロシクロアルキレン、置換もしくは無置換のアリーレンまたは置換もしくは無置換のヘテロアリーレンであり;
L4が結合、置換もしくは無置換のアルキレン、置換もしくは無置換のヘテロアルキレン、置換もしくは無置換のシクロアルキレン、置換もしくは無置換のヘテロシクロアルキレン、置換もしくは無置換のアリーレンまたは置換もしくは無置換のヘテロアリーレンであり、及び
L5が結合、置換もしくは無置換のアルキレン、置換もしくは無置換のヘテロアルキレン、置換もしくは無置換のシクロアルキレン、置換もしくは無置換のヘテロシクロアルキレン、置換もしくは無置換のアリーレンまたは置換もしくは無置換のヘテロアリーレンである、請求項5に記載の化合物。 - L2が置換または無置換の3〜8員ヘテロアルキレンであり、
L3が置換または無置換の5〜10員ヘテロアリーレンであり、
L4が置換または無置換の2〜12員ヘテロアルキレンであり、及び
L5が置換または無置換の2〜12員ヘテロアルキレンである、請求項11に記載の化合物。 - 前記化合物がmTORC1特異的阻害剤である、請求項1に記載の化合物。
- 医薬的に許容可能な賦形剤及び請求項1〜13のいずれか一項に記載の化合物を含む、医薬組成物。
- 患者においてmTORC1の活性を阻害するのに使用するための請求項14に記載の医薬組成物であって、前記使用が有効量の前記医薬組成物を前記患者に投与することを含む、前記医薬組成物。
- 前記化合物が、TORC2の活性レベルの阻害の少なくとも1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90、100、1000、10000または100000倍、mTORC1の活性レベルを阻害する、請求項15に記載の医薬組成物。
- 異常なmTORC1活性と関連する疾患を治療することを、そうした治療を必要としている患者において行うのに使用するための請求項14に記載の医薬組成物であって、前記使用が治療有効量の前記医薬組成物を前記患者に投与することを含む、前記医薬組成物。
- 前記疾患が癌である、請求項17に記載の医薬組成物。
- 対象において疾患を治療するのに使用するための請求項14に記載の医薬組成物であって、前記使用が前記医薬組成物を前記対象に投与することを含み、前記疾患が、癌、自己免疫疾患、炎症性疾患、代謝疾患、神経変性疾患、真菌感染症、移植拒絶反応、加齢、狭窄症、新生内膜増殖、心血管疾患または多発生嚢胞疾患である、前記医薬組成物。
- 前記疾患が癌である、請求項19に記載の医薬組成物。
- 前記疾患が自己免疫疾患である、請求項19に記載の医薬組成物。
- 前記疾患が炎症性疾患である、請求項19に記載の医薬組成物。
- 前記疾患が代謝疾患である、請求項19に記載の医薬組成物。
- 前記疾患が神経変性疾患である、請求項19に記載の医薬組成物。
- 前記疾患が真菌感染症である、請求項19に記載の医薬組成物。
- 前記疾患が移植拒絶反応である、請求項19に記載の医薬組成物。
- 前記疾患が加齢である、請求項19に記載の医薬組成物。
- 前記疾患が狭窄症である、請求項19に記載の医薬組成物。
- 前記狭窄症が再狭窄症である、請求項28に記載の医薬組成物。
- 前記疾患が新生内膜増殖である、請求項19に記載の医薬組成物。
- 前記疾患が多発生嚢胞疾患である、請求項19に記載の医薬組成物。
- 前記多発生嚢胞疾患が多発性嚢胞腎疾患である、請求項31に記載の医薬組成物。
- 前記投与が薬物溶出ステントを介する、請求項19に記載の医薬組成物。
- L1がL2−L3−L4−L5であり、
L2が少なくとも1つのNHまたはOを含む2〜8員ヘテロアルキレンであり、
L3が5〜10員ヘテロアリーレンであり、
L4が−[(CH2)b11O]b12−であり、
L5がCH2CH2C=(O)NH(CH2)b10であり、
b10が1〜6の整数であり、
b11が1〜3の整数であり、及び
b12が1〜8の整数である、請求項5に記載の化合物。 - L1がL2−L3−L4−L5であり、
L2が−CH2CH2OCH2−であり、
L3がトリアゾリレンであり、
L4が−(CH2CH2O)b−であり、
L5が−CH2CH2C=(O)NH(CH2)4であり、及び
bが4〜8の整数である、請求項5に記載の化合物。 - 以下の式を有する請求項2に記載の化合物:
L1は前記二価のリンカーであり、
R3は水素、−OH、ハロゲン、−CX3、−CN、−SOnR10、−SOvNR7R8、−NHNR7R8、−ONR7R8、−NHC=(O)NHNR7R8、−NHC=(O)NR7R8、−N(O)m、−NR7R8、−C=(O)R9、−C=(O)−OR9、−C=(O)NR7R8、−OR10、−NR7SO2R10、−NR7C=(O)R9、−NR7C=(O)OR9、−NR7OR9、−OCX3、−OCHX2、置換もしくは無置換のアルキル、置換もしくは無置換のヘテロアルキル、置換もしくは無置換のシクロアルキル、置換もしくは無置換のヘテロシクロアルキル、置換もしくは無置換のアリールまたは置換もしくは無置換のヘテロアリールであり、
R7、R8、R9、R10及びR11は独立に、水素、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC=(O)OH、−NHOH、−OCF3、−OCHF2、置換もしくは無置換のアルキル、置換もしくは無置換のヘテロアルキル、置換もしくは無置換のシクロアルキル、置換もしくは無置換のヘテロシクロアルキル、置換もしくは無置換のアリールまたは置換もしくは無置換のヘテロアリールであり、同じ窒素原子に結合したR7及びR8置換基は、任意で結合して、置換もしくは無置換のヘテロシクロアルキルまたは置換もしくは無置換のヘテロアリール形成することができ、
W1はNまたはCR11であり、
m及びvは独立に、1または2であり、
nは独立に、0〜4の整数であり、及び
Xは独立に、−Cl、−Br、−Iまたは−Fである)。 - 医薬的に許容可能な賦形剤及び請求項34〜36のいずれか一項に記載の化合物を含む、医薬組成物。
- 患者においてmTORC1の活性を阻害するのに使用するための請求項37に記載の医薬組成物であって、前記使用が有効量の前記医薬組成物を前記患者に投与することを含む、前記医薬組成物。
- 前記化合物が、TORC2の活性レベルの阻害の少なくとも1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90、100、1000、10000または100000倍、mTORC1の活性レベルを阻害する、請求項38に記載の医薬組成物。
- 異常なmTORC1活性と関連する疾患を治療することを、そうした治療を必要としている患者において行うのに使用するための請求項37に記載の医薬組成物であって、前記使用が治療有効量の前記医薬組成物を前記患者に投与することを含む、前記医薬組成物。
- 前記疾患が癌である、請求項40に記載の医薬組成物。
- 対象において疾患を治療するのに使用するための請求項37に記載の医薬組成物であって、前記使用が前記医薬組成物を前記対象に投与することを含み、前記疾患が、癌、自己免疫疾患、炎症性疾患、代謝疾患、神経変性疾患、真菌感染症、移植拒絶反応、加齢、狭窄症、新生内膜増殖、心血管疾患または多発生嚢胞疾患である、前記医薬組成物。
- 前記疾患が癌である、請求項42に記載の医薬組成物。
- 前記疾患が自己免疫疾患である、請求項42に記載の医薬組成物。
- 前記疾患が炎症性疾患である、請求項42に記載の医薬組成物。
- 前記疾患が代謝疾患である、請求項42に記載の医薬組成物。
- 前記疾患が神経変性疾患である、請求項42に記載の医薬組成物。
- 前記疾患が真菌感染症である、請求項42に記載の医薬組成物。
- 前記疾患が移植拒絶反応である、請求項42に記載の医薬組成物。
- 前記疾患が加齢である、請求項42に記載の医薬組成物。
- 前記疾患が狭窄症である、請求項42に記載の医薬組成物。
- 前記狭窄症が再狭窄症である、請求項51に記載の医薬組成物。
- 前記疾患が新生内膜増殖である、請求項42に記載の医薬組成物。
- 前記疾患が多発生嚢胞疾患である、請求項42に記載の医薬組成物。
- 前記多発生嚢胞疾患が多発性嚢胞腎疾患である、請求項54に記載の医薬組成物。
- 前記投与が薬物溶出ステントを介する、請求項42に記載の医薬組成物。
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US11452780B2 (en) | 2022-09-27 |
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US10117945B2 (en) | 2018-11-06 |
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