JP2020533399A - 新規低分子化合物 - Google Patents
新規低分子化合物 Download PDFInfo
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Abstract
Description
本出願は、2017年9月13日に出願された米国仮特許出願第62/558,323号に対する優先権を主張し、この出願は参照によりその全体が本明細書に組み入れられる。
ミトコンドリアは、細胞エネルギー生産、酸化還元バランス、細胞Ca2+濃度の緩衝化、および重要な生合成経路の実施といった、多数の基本的な生理学的プロセスを保証するために必須である真核細胞中における象徴的な細胞小器官である(Wallace 2005)。それらはまた、がんおよび神経変性疾患などの主要な疾患状態において決定的な経路であるアポトーシス経路に参加することによって細胞の運命を左右する(Hedskog et al. 2012)。細胞内のミトコンドリアの形状、体積、数および分布は厳密に制御される(Cahill et al. 2006)。これらのパラメータは、特に神経筋系において、ミトコンドリア機能に決定的に影響を与え、そこでは、ミトコンドリアは、高い局所エネルギー需要を恐らく満たすために、戦略的細胞内分布を採用する。従って、健康なミトコンドリア集団の維持は、細胞および生物の健康にとって不可欠である。これを達成するために、細胞は、損傷したミトコンドリアを除去するために、またはそれらを再生するために、品質管理の複雑なシステムを伴うメカニズムを発達させた。これらのプロセスに欠陥があると、損傷したミトコンドリアが蓄積され、最終的に疾患状態をもたらし得る(Pickrell and Youle 2015)、(Rugarli and Langer 2012)。
1.式Iに従う化合物:
またはその薬学的に許容される塩。
2.ミトコンドリア機能不全に関連する疾患または状態を処置するための薬学的組成物であって、式Iに従う態様1記載の化合物、その薬学的に許容される塩、またはその誘導体と、薬学的に許容される担体とを含む、薬学的組成物。
3.ミトコンドリア機能不全に関連する疾患または状態を処置するための方法であって、その必要がある対象への有効量の態様1記載の化合物または有効量の態様2記載の組成物を含む、方法。
4.有効量が治療有効量である、態様3記載の方法。
5.有効量が予防有効量である、態様3記載の方法。
6.疾患ががんである、態様3記載の方法。
7.がんが、T急性リンパ芽球性白血病(T-ALL)、小細胞肺がん(SCLC)、非小細胞肺がん(NSCL)、神経膠芽腫、結腸直腸がん、乳がん、または卵巣がんである、態様6記載の方法。
8.疾患が神経変性疾患である、態様3記載の方法。
9.神経変性疾患が、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症、またはハンチントン病である、態様8記載の方法。
10.状態が脳状態である、態様3記載の方法。
11.脳状態が、脳卒中、発作、神経因性疼痛、外傷性脳損傷、脊髄損傷、動脈瘤、またはクモ膜下出血である、態様10記載の方法。
12.疾患または状態が非神経障害である、態様3記載の方法。
13.非神経障害が、敗血症、急性腎傷害、心腎症候群、心虚血再灌流障害、肺動脈高血圧症、慢性閉塞性肺疾患、または血管収縮である、態様14記載の方法。
14.状態が、ミトコンドリア機能不全によって引き起こされるヒトの加齢である、態様3記載の方法。
I.発明の分野
本発明は、概して、ミトコンドリア機能不全に関連する疾患を処置する組成物および方法に関する。特に、本発明は、ミトコンドリア活性酸素種(ROS)生成、電子伝達系活性、ミトコンドリア形態、またはミトコンドリア活性を変化させるために、CPT-2008またはその誘導体を使用して、がん、神経変性疾患(パーキンソン病、アルツハイマー病、ALS、ハンチントン病を含む)、脳損傷(脳卒中、発作、神経因性疼痛、外傷性脳損傷、脊髄損傷、動脈瘤、クモ膜下出血を含む)、および特定の非神経障害(敗血症、急性腎傷害、心腎症候群、心虚血再灌流障害、肺動脈高血圧症、慢性閉塞性肺疾患、血管収縮を含む)を処置する方法に関する。
本明細書において使用される場合、「CPT-2008」は、6-クロロ-3-(2,4-ジクロロ-5-メトキシフェニル)-2-メルカプト-7-メトキシキナゾリン-4(3H)-オン、即ち、C16H11Cl3N2O3Sの式および式I:
に従う構造を有する化合物を指す。
CPT-2008と、1つまたは複数の薬学的に許容される担体または他の賦形剤とを含有する薬学的組成物を本明細書に提供する。薬学的組成物は、薬学および薬物送達の技術分野において周知の方法のいずれかによって調製することができる。一般に、組成物を調製する方法は、活性成分と1つまたは複数の副成分を含有する担体とを合わせるステップを含む。薬学的組成物は、活性成分を液体担体または微粉化固体担体または両方と一様にかつ密接に合わせ、次いで、必要に応じて、生成物を所望の製剤へ成形することによって、典型的に調製される。組成物は、好都合には、単位投薬形態に調製および/または包装され得る。
CPT-2008およびその組成物は、ミトコンドリア機能不全に関連する疾患および状態を処置するために有用である。そのような疾患としては、がん、神経変性疾患、脳状態、および非神経障害が挙げられるが、これらに限定されない。
下記の実施例は、ここに特許請求される化合物、組成物、物品、装置および/または方法を作製および評価する方法の完全な開示および説明を当業者に提供するために示され、純粋に本発明を例示するように意図され、本発明者らが本発明者らの発明とみなす範囲を限定するようには意図されない。しかし、当業者は、本開示を考慮して、本発明の精神および範囲を逸脱することなく、開示される具体的な態様において多くの変更が行われ、依然として同様または類似の結果を得ることができることを認識するべきである。
CPT-2008を作製するためにコンバージェント合成アプローチを取り、ここで、下記に記載されるように、2つの断片(化合物3および化合物5)を別々に作製し、そして組み合わせて最終生成物(図1)を作製した。最終生成物は、C16H11Cl3N2O3Sの式、417.69 g/モルの分子量、ならびにHPLCおよびLCMS/1H NMRによって決定される場合に95%を超える純度を有した。
(a)試薬および材料
CellTiter-Glo Luminescent Cell Viability Assay KitをPromegaから得た。RPMI 1640をInvitrogenから得た。ウシ胎仔血清(FBS)をCorningから得た。L-グルタミンをInvitrogenから得た。100Xペニシリン-ストレプトマイシンをHyCloneから得た。0.05%トリプシン-EDTA (T-E)をInvitrogenから得た。DPBSをCorningから得た。DMSOをSigmaから得た。黒色384ウェルプレートをGreinerから得た。96ウェルV底プレートをAxygenから得た。
細胞播種(第「-1」日):8種の接着細胞株の細胞密度を、供給業者の推奨情報に従って調節した。50μLの細胞を4個の384ウェルプレートに播種し、端のウェルに50μLのDPBSを添加した。
計算式:阻害% = (最大値-サンプル値)/最大値*100
CPT-2008は複数のがん細胞モデルにおいて強力な抗腫瘍活性を示す
CPT-2008の抗腫瘍活性を評価するために、72時間のインキュベーション後、様々なヒトがん細胞株において化合物の増殖阻害効果を測定した。アッセイにおいて、全ての細胞株が、最初の細胞平板培養中、接着/混合細胞の生存可能性は90%よりも大きく、浮遊細胞の生存可能性は85%よりも大きいという基準を満たした。このアッセイ中の細胞プレートの全てが変動係数(CV)<10%という基準を満たした。パクリタキセル参照化合物について記録されたデータは、過去の公表データと一致した。
広範囲のがんモデルに対するCPT-2008の効能は、がん細胞増殖に必要とされる一般的な細胞機序を標的とする、その作用機序が独特であることを示唆している。がん細胞、特にがん幹細胞の維持におけるミトコンドリアの重要な役割を考慮して、ヒト神経膠芽腫(GBM)細胞中の多くのミトコンドリアのパラメータに対するCPT-2008の効果を次に示した。先ず、ミトコンドリアROSレベルに対するCPT-2008の効果を研究した。この目的のために、mito-SOX色素を使用した。Mito-SOXはミトコンドリアROSレベルを特異的にモニターすることができる。図15に示されるように、CPT-2008はGBM細胞中のミトコンドリアROSの有意な増加を引き起こした。ミトコンドリアの健康および活性を決定する主要因である、ミトコンドリア膜電位に対するCPT-2008の効果をまた、TRM色素を使用して測定した。図17に示されるように、CPT-2008は、GBM細胞中のミトコンドリア膜電位の劇的な減少を引き起こした。ミトコンドリアカルシウム恒常性に対するCPT-2008の効果をまた、ミトコンドリアカルシウムレベルを特異的にモニターする、Rhod-2AM色素を使用して測定した。図14に示されるように、CPT-2008はミトコンドリアカルシウムの増加を引き起こした。ミトコンドリア形態に対するCPT-2008の効果をまた、ミトコンドリア外膜マーカーTom20の免疫染色を使用して測定した。図16に示されるように、CPT-2008は、ミトコンドリアの劇的な断片化を引き起こし、対照細胞中の長い管状のミトコンドリアとは対照的に小さい円形のミトコンドリアを生じさせた。まとめると、これらの結果は、CPT-2008がミトコンドリア機能に影響を与えることを示している。最後に、GBM細胞の自己再生に対するCPT-2008の効果を試験した。図18に示されるように、CPT-2008は、培養下でニューロスフェアを形成する能力によって測定されるような、GBM細胞の自己再生を有意に阻害した。
エダラボン(3-メチル-1-フェニル-2-ピラゾリン-5-オン)は、日本においては脳卒中およびALSの処置について、米国においてはALSの処置について認可された活性酸素種(ROS)スカベンジャーである。ラット中大脳動脈閉塞(MCOA)モデル中における脳損傷の予防についてのCPT-2008の効能を、エダラボンの効能と比較した。Sprague-Dawleyラットに、ビヒクル、エダラボン(6 mg/kg)、またはCPT-2008 (25-100 mg/kg)を投薬し、梗塞脳組織のレベルを評価した。この研究において、ラットは、1.5時間の中大脳動脈閉塞(MCAO)、続いて24時間の再灌流を受けた。再灌流から0時間および8時間後にCPT-2008を腹腔内に与え、行動欠陥および脳損傷を、それぞれ、LongaスコアスケールおよびTTC染色によって評価した。図19Aおよび図19Bに示されるように、CPT-2008での処置での壊死脳組織のレベル低下は、CPT-2008がエダラボンより優れていることを示している。CPT-2008の改善された利益は、部分的に、脳組織ミトコンドリア中におけるROS形成の防止に起因すると考えられる。
化学療法を受けているがん患者の推定30〜40%が、末梢性神経因性疼痛を経験し、これは、患者に処置を早期に停止させるかまたはより低用量を服用させる神経炎症誘発衰弱副作用である。神経因性疼痛の減少におけるCPT-2008の効果を、パクリタキセル処置ラットにおいて研究した。8日間のパクリタキセル処置後、Sprague-Dawleyラットをさらに数日間収容した。第22日に、16匹のラットを無作為に2つの群に分けた。一方の群にビヒクルを投与し、他方の群に腹腔内注射によってCPT-2008を100 mg/kgで投与した。疼痛(機械的アロディニア)試験対象を、Xieによって記載されたような足逃避試験(PWT)を使用して評価した(“Activation of notch signaling mediates the induction and maintenance of mechanical allodynia in a rat model of neuropathic pain.” Molecular Medicine Reports 12: 639-644, 2015)。ラットを、1.5時間、3時間、および4.5時間で試験化合物の投薬後の足逃避閾値について測定した。パクリタキセル処置動物へのCPT-2008の投与は、図20に示される閾値の増加によって示されるように、痛覚感受性を減少させた。
Sprague-DawleyラットにIVまたはPOによってCPT-2008を投与した。血液サンプル(約1 mL)を、投薬後5分、15分、30分、1時間、2時間、4時間、8時間、24時間で、二酸化炭素吸入による安楽死後に心臓穿刺を介して採取した。血液サンプルを、ヘパリンナトリウムを含有するチューブへ置き、4℃にて10分間3500 rpmで遠心分離し、サンプルから血漿を分離した。遠心分離後、結果として得られた血漿を、標識されたチューブへ移し、生物分析を待つ間、-80℃で凍結保存した。動物を二酸化炭素吸入によって安楽死させた後、各時点での各研究動物の脳を収集した。全組織を採取し、切除し、次いで1匹の動物当たり1つの組織当たり1本のチューブ中に置いた。組織サンプルをドライアイス上に置き、生物分析まで-80℃で保存した。
Claims (14)
- ミトコンドリア機能不全に関連する疾患または状態を処置するための薬学的組成物であって、式Iに従う請求項1記載の化合物、その薬学的に許容される塩、またはその誘導体と、薬学的に許容される担体とを含む、薬学的組成物。
- ミトコンドリア機能不全に関連する疾患または状態を処置するための方法であって、その必要がある対象への有効量の請求項1記載の化合物または有効量の請求項2記載の組成物を含む、方法。
- 有効量が治療有効量である、請求項3記載の方法。
- 有効量が予防有効量である、請求項3記載の方法。
- 疾患ががんである、請求項3記載の方法。
- がんが、T急性リンパ芽球性白血病(T-ALL)、小細胞肺がん(SCLC)、非小細胞肺がん(NSCL)、神経膠芽腫、結腸直腸がん、乳がん、または卵巣がんである、請求項6記載の方法。
- 疾患が神経変性疾患である、請求項3記載の方法。
- 神経変性疾患が、パーキンソン病、アルツハイマー病、筋萎縮性側索硬化症、またはハンチントン病である、請求項8記載の方法。
- 状態が脳状態である、請求項3記載の方法。
- 脳状態が、脳卒中、発作、神経因性疼痛、外傷性脳損傷、脊髄損傷、動脈瘤、またはクモ膜下出血である、請求項10記載の方法。
- 疾患または状態が非神経障害である、請求項3記載の方法。
- 非神経障害が、敗血症、急性腎傷害、心腎症候群、心虚血再灌流障害、肺動脈高血圧症、慢性閉塞性肺疾患、または血管収縮である、請求項14記載の方法。
- 状態が、ミトコンドリア機能不全によって引き起こされるヒトの加齢である、請求項3記載の方法。
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AU2018331371A1 (en) | 2020-04-02 |
JP7170341B2 (ja) | 2022-11-14 |
EP3681874B1 (en) | 2022-04-06 |
US11186550B2 (en) | 2021-11-30 |
CA3075649A1 (en) | 2019-03-21 |
IL273242B1 (en) | 2023-04-01 |
AU2018331371C1 (en) | 2024-05-09 |
IL273242B2 (en) | 2023-08-01 |
US11912669B2 (en) | 2024-02-27 |
EP3681874A1 (en) | 2020-07-22 |
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