JP6894449B2 - 癌を治療するためのマクロ環状mcl1阻害剤 - Google Patents
癌を治療するためのマクロ環状mcl1阻害剤 Download PDFInfo
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- JP6894449B2 JP6894449B2 JP2018553226A JP2018553226A JP6894449B2 JP 6894449 B2 JP6894449 B2 JP 6894449B2 JP 2018553226 A JP2018553226 A JP 2018553226A JP 2018553226 A JP2018553226 A JP 2018553226A JP 6894449 B2 JP6894449 B2 JP 6894449B2
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- BBEUDPAEKGPXDG-UHFFFAOYSA-N protopanaxatriol Natural products CC(CCC=C(C)C)C1CCC2(C)C1C(O)CC3C4(C)CCC(O)C(C)(C)C4C(O)CC23C BBEUDPAEKGPXDG-UHFFFAOYSA-N 0.000 description 1
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- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
一実施形態において、17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸(式I)
いくつかの実施形態において、式(I)、(II)、及び(III)の化合物又はその薬学的に許容できる塩の固体形態が開示される。「固体形態」という用語は、式(I)、(II)、又は(III)の化合物の多形体、結晶性の塩、溶媒和物、水和物、及び非晶質形態を含む。「多形体」という用語は、同じ化学組成を有するが異なる分子充填を有する結晶性の物質を含む。表現「結晶性の塩」は、同じ化学物質を有するが、結晶構造の分子充填内に酸又は塩基付加塩を組み込んでいる結晶構造を含む。「溶媒和物」という用語は、同じ化学物質であるが、結晶構造の分子充填内に溶媒の分子を組み込んでいる結晶構造を含む。「水和物」という用語は、同じ化学物質であるが、結晶構造の分子充填内に水の分子を組み込んでいる結晶構造を含む。「非晶質形態」という言葉は、同じ分子材料の化合物であるが、同じ分子材料の結晶構造(例えば、多形体、結晶性の塩、溶媒和物、又は水和物)の分子秩序のない化合物を含む。
いくつかの実施形態において、形態A(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸一水和物が開示される。
いくつかの実施形態において、形態B(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸、メタノール溶媒和物が開示される。
いくつかの実施形態において、形態C(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸が開示される。
いくつかの実施形態において、形態D(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸が開示される。
いくつかの実施形態において、形態E(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸が開示される。
いくつかの実施形態において、形態F(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸五水和物が開示される。
いくつかの実施形態において、(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸、ナトリウム塩が開示される。
いくつかの実施形態において、(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸、メグルミン塩が開示される。
いくつかの実施形態において、式(I)、(II)、及び(III)の化合物並びに薬学的に許容できる賦形剤、担体、又は希釈剤を含む医薬組成物が開示される。
一態様において、それを必要とする対象における癌を治療する方法であって、対象に、有効量の式(I)、(II)、若しくは(III)の化合物又はその薬学的に許容できる塩を投与することを含む方法が開示される。
(i)全合成は、特記されない限り、周囲温度、すなわち17〜25℃で、窒素などの不活性ガスの雰囲気下で実施した;
(ii)蒸発は、ロータリーエバポレーションにより、又はジェネバック装置若しくはバイオタージv10エバポレーターを利用して、減圧下で実施した;
(iii)シリカゲルクロマトグラフィー精製は、事前充填されたRediSep Rf Gold(商標)シリカカラム(20〜40μm、球状粒子)、GraceResolv(商標)カートリッジ(Davisil(登録商標)シリカ)又はSilicycleカートリッジ(40〜63μm)を使用して、自動Teledyne Isco CombiFlash(登録商標)Rf又はTeledyne Isco CombiFlash(登録商標)Companion(登録商標)で実施した。
(iv)キラル分取クロマトグラフィーは、MS−及びUV−トリガー回収を備えたWaters Prep 100 SFC−MS装置又はUV回収を備えたThar MultiGram III SFC装置で実施した。
(v)キラル分析クロマトグラフィーは、UV検出を備えたWaters X5 SFC−MS又はUV及びELSD検出を備えたWaters UPC2 SFC−MSで実施した。
(vi)収率は、存在する場合、必ずしも達成可能な最大値ではない;
(vii)一般に、式Iの最終生成物の構造はNMR分光法により確認した;NMRケミカルシフト値は、溶媒残留ピークを内部標準として使用してデルタスケールで測定した[プロトン磁気共鳴スペクトルは、Bruker Avance 500(500MHz)、Bruker Avance 400(400MHz)、Bruker Avance 300(300MHz)、又はBruker DRX(300MHz)装置で測定した];測定は、特記されない限り周囲温度で行った;以下の略語を使用した:s、シングレット;d、ダブレット;t、トリプレット;q、カルテット;m、マルチプレット;dd、ダブレットのダブレット;ddd、ダブレットのダブレットのダブレット;dt、トリプレットのダブレット;bs、ブロードなシグナル;ABq、ABカルテット。
(viii)一般に、式Iの最終生成物は、液体クロマトグラフィー(UPLC)の後に質量分析法でも特性化した;Waters SQ質量分析計(カラム温度40℃、UV=220〜300nm又は190〜400nm、質量分析=ポジティブ/ネガティブスイッチングのあるESI)を備えたWaters UPLCを、1mL/分の流量で、1.50分かけて97%A+3%Bから3%A+97%Bへの溶媒系を使用する(平衡を出発状態に戻すなどを含む全ランタイムは1.70分)、ここで、A=水中0.1%ギ酸若しくは0.05%トリフルオロ酢酸(酸性処理用(for acidic work))又は水中0.1%水酸化アンモニウム(塩基性処理用(for basic work))及びB=アセトニトリルである。酸性の分析では、使用したカラムはWaters Acquity HSS T3(1.8μm、2.1×50mm)であり、塩基性分析では、使用したカラムはWaters Acquity BEH C18(1.7μm、2.1×50mm)であった。或いは、UPLCは、Waters SQ質量分析計(カラム温度30℃、UV=210〜400nm、質量分析=ポジティブ/ネガティブスイッチングのあるESI)を備えたWaters UPLCを、1mL/分の流量で、1.5分かけて2〜98%Bの溶媒勾配を利用して実施したが(平衡を出発状態に戻す全ランタイムは2分)、ここで、A=水中0.1%ギ酸及びB=アセトニトリル中0.1%ギ酸(酸性処理用)であるか、又はA=水中0.1%水酸化アンモニウム及びB=アセトニトリル(塩基性処理用)であった。酸性分析では、使用したカラムはWaters Acquity HSS T3(1.8μm、2.1×30mm)であり、塩基性分析では、使用したカラムはWaters Acquity BEH C18(1.7μm、2.1×30mm)であった;報告される分子イオンは、特記されない限り[M+H]+に相当する;複数の同位体のパターン(Br、Clなど)を有する分子では、報告される値は、特記されない限り、最高強度で得られたものである。
(x)中間体純度は、薄層クロマトグラフィー、質量分析法、LCMS、UPLC/MS、HPLC及び/又はNMR分析により評価した;
(xi)以下の略語を使用した:
ACN アセトニトリル
aq.水性
conc.濃
DCM ジクロロメタン
di−t−BPF 1,1’−ビス(ジ−tert−ブチルホスフィノ)フェロセン
DMAP 4−ジメチルアミノピリジン
DMF N,N−ジメチルホルムアミド
DSC 示差走査熱量測定
DTBAD ジ−tert−ブチルジアゼン−1,2−ジカルボキシラート
e.e.鏡像体過剰率
equiv.当量
ES エレクトロスプレーモード
HPLC 高速液体クロマトグラフィー
Inj.注入
IPA イソプロピルアルコール
LAH 水素化アルミニウムリチウム
LCMS 液体クロマトグラフィー質量分析法
MS 質量分析法
NaHMDS ヘキサメチルジシラザンナトリウム
NBS N−ブロモスクシンイミド
NMR 核磁気共鳴
PE 石油エーテル
PMB 4−メトキシベンジル
RBF 丸底フラスコ
RT 室温/周囲温度
sat.飽和
SFC 超臨界流体クロマトグラフィー
TBAF テトラブチルアンモニウムフルオリド
TBDPS tert−ブチルジフェニルシリル
TBDPSCl tert−ブチルクロロジフェニルシラン
TFA トリフルオロ酢酸
TGA 熱重量分析
THF テトラヒドロフラン
Tol.トルエン
UPLC 超高速液体クロマトグラフィー
wt% 重量パーセント
XRPD 粉末X線回折
キラル分析方法:SFC:Chiralpak IA(登録商標)カラム、4.6×100mm、5μm、温度=40℃、35:65 i−PrOH:CO2、220nmでのUV検出、流量=5.0mL/分、出口圧力=125バール。1.63分の保持時間、>98%ee、[α]D +64°(c=0.1、MeOH)
中間体24と同じキラル分析方法。3.77分の保持時間、>98%ee、[α]D −64°(c=0.1、MeOH)
キラル分析方法:SFC:Chiralpak ID(登録商標)カラム、4.6×250mm、5μm、温度=40℃、40:60 MeOH:CO2、220nmでのUV検出、流量=2.8mL/分、出口圧力=100バール、7.33分の保持時間、>98%e.e.、[α]D +87°(c=0.042、MeOH)
実施例2と同じキラル分析方法:9.36分の保持時間、>98%e.e.、[α]D −92°(c=0.048
カスパーゼ活性アッセイ
これは、6時間の処理後のMOLP−8(多発性骨髄腫)、KMS−12−BM(多発性骨髄腫)、MV−4−11(急性骨髄性白血病)、及びNCI−H23(非小細胞肺癌)細胞におけるアポトーシスの誘導を測定する細胞アッセイである。第1日に、3000(MOLP−8、KMS−12−BM、MV−4−11)又は1250(NCI−H23)細胞/ウェルを、384ウェル白色マイクロプレート中の50μLの増殖培地(MV−4−11には、IMDM+10%FBS+2mM、並びにL−Glu及び他の全細胞株には、RPMI−1640+10%FBS+2mM L−Glu)に播種し、一晩インキュベートした(37℃、5%CO2、80%RH)。第2日に、ECHOアコースティックリキッドハンドラーを使用して細胞をMcl−1阻害剤で処理した(10点のハーフログ段階希釈、31.5μM最高濃度、0.3%最終DMSO濃度)。6時間のインキュベーション後(37℃、5%C02、80%RH)、25μLのCaspase−Glo 3/7試薬(Promega)を各ウェルに加え、プレートを、遮光して室温で30分間インキュベートした。Infinite M200マイクロプレートリーダー(Tecan)を使用して、100msの積分時間で、ルミネセンスを記録した。EC50値を、GeneData分析ソフトウェアを使用して計算した。
XRPD分析は、Bruker AXS Inc(商標)(Madison、Wisconsin)から市販されているBruker D4回折計を使用して実施した。XRPDスペクトルは、分析用の材料の試料(およそ20mg)を、シリコン単結晶ウエハーマウント(例えば、Brukerケイ素ゼロバックグラウンドX線回折試料ホルダー)に載せ、顕微鏡スライドを利用して試料を広げて薄膜にすることにより得た。試料を毎分30回転で回転し(計数統計を改善するため)、40kV及び40mAで運転している銅ロング・ファイン・フォーカス管により発生させた1.5406Å(すなわち約1.54Å)の波長のX線を照射した。試料を、シータ−シータモードで、2度から40度の2−シータの範囲にわたり0.02度の2−シータ増分あたり1秒間曝露させた(連続スキャンモード)。ランニングタイムは31分、41秒であった。
DSC分析は、標準的な方法に従って調製した試料に対して、TA INSTRUMENTS(登録商標)(New Castle、Delaware)から入手可能なQ SERIES(商標)Q1000 DSC熱量計を使用して実施した。試料(およそ2mg)をアルミニウム試料パンに量り入れ、DSCに移した。装置を50mL/分で窒素置換し、データを、約10℃/分の動的加熱速度(dynamic heating rate)で、約22℃〜300℃で収集した。熱データを、標準的なソフトウェア、例えば、TA INSTRUMENTS(登録商標)のUniversal v.4.5Aを使用して分析した。
TGAは、標準的な方法に従って調製した試料に対して、TA Instruments INSTRUMENTS(登録商標)(New Castle、Delaware)から入手可能なQ SERIES(商標)Q5000熱重量分析器を使用して実施した。試料(およそ5mg)をアルミニウム試料パン中に配置し、TGAファーネスに移した。装置を50mL/分で窒素置換し、データを、約10℃/分の動的加熱速度で、25℃〜300℃で収集した。熱データを、標準的なソフトウェア、例えば、TA INSTRUMENTS(登録商標)のUniversal v.4.5Aを使用して分析した。
方法1:10mgの(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸を、1.0mLのMeOH及び5滴の水に溶解させた。生じた溶液を周囲条件で蒸発乾固させた。生じた白色粉末を形態Aと特定した。
(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸形態Bの単結晶を、(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸と、1:1モル比のメグルミンとのMeOH溶液の緩徐な蒸発から得た。結晶が溶液から現れると、1つを手作業で回収した。単結晶構造分析は、形態Bが遊離酸の一メタノール溶媒和物であることを確認した。結晶学的データ:空間群斜方晶系P2(1)2(1)2(1)、単位格子寸法:a=7.530(7)Å、b=13.956(12)Å、c=34.44(3)Å、V=3619(5)Å3。
方法1:300mgの非晶質(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸をEtOH(3mL)に吸収させ、加熱して溶解させた。室温に冷却した後、溶液を一晩撹拌すると、固体が沈殿していた。これを濾過により回収し、乾燥させると、形態Cが生じた(266mg、81%)。
方法1:10mgの非晶質(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸を0.2mLのEtOAcに懸濁させた。生じたスラリーを1日撹拌すると、部分的に結晶性の物質が得られた。バイアルの外部温度を100℃に加熱し、生じたスラリーを15分間撹拌した。周囲温度に冷却した後スラリーを3日間撹拌し、形態Dを特定した。
5mgの(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸を、0.5mLの熱IPA/H2O(3:1)に溶解させ、溶液を冷却した後に、結晶を得た。溶液をゆっくりと蒸発乾固させた。形態Eを特定した。
5mgの(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸を、1.0mLのEtOH/H2O(3:1)に溶解させ、生じた溶液をフード中でゆっくりと蒸発させた。生じた結晶性物質を形態Fと特定した。
135mgの(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸形態C(0.2mmol)を5mLのMeOHに懸濁させ、懸濁液に200μLの1.0N NaOH水溶液を加える。固体が溶解するまでスラリーを撹拌した。透明な溶液を蒸発させ、生じた固体をEtOAcにより3日間スラリー化した。スラリーを蒸発乾固させた後、結晶性の物質を得た。
135mgの(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸(0.2mmol)を2mLのMeOHに懸濁させ、0.05MメグルミンのMeOH溶液4mLを加えた。スラリーを一晩撹拌し、次いで蒸発乾固させた。約2mLのEtOAcを加えると、スラリーが生じ、スラリーを3日間撹拌した。スラリーを蒸発乾固させた後に、結晶性物質を得た。
方法:実施例2を、30%2−ヒドロキシプロピル−β−シクロデキストリン(HPBCD)、pH9中に製剤し、静脈内に(iv)5ml/kgの体積で投薬した。5×106MOLP−8腫瘍細胞又は107NCI−H929腫瘍細胞を、C.B−17 SCID雌性マウスの右脇腹に、0.1mLの体積で皮下注射した。腫瘍体積(カリパスにより測定)を、式:長さ(mm)×幅(mm)2/0.52を利用して計算した。効能の試験には、マウスを腫瘍体積に基づいて無作為化し、成長阻害を、対照群と処置群の間の腫瘍体積の差の比較により評価した。投薬は、平均腫瘍サイズが、MOLP−8ではおよそ160mm3に、NCI−H929ではおよそ230mm3に達したときに開始した。
方法:実施例2を、30%2−ヒドロキシプロピル−β−シクロデキストリン(HPBCD)、pH9中に製剤し、単回静脈内(iv)投与として5ml/kgの体積で投薬した。106MV−4−11腫瘍細胞を、C.B−17SCID雌性マウスの右脇腹に、0.1mLの体積で皮下注射した。腫瘍体積(カリパスにより測定)、動物の体重、及び腫瘍状態を、試験の期間の間、週に2回記録した。腫瘍体積(カリパスにより測定)は、式:長さ(mm)×幅(mm)2/0.52を利用して計算した。効能の試験には、マウスを腫瘍体積に基づいて無作為化し、成長阻害を、対照群と処置群の間の腫瘍体積の差の比較により評価した。投薬は、平均腫瘍サイズがおよそ230mm3に達したときに開始した。
タンパク質複合体の分裂を測定する生化学的結合TR−FRETアッセイ
TR−FRETアッセイを利用して、化合物が組換え型ヒトMcl−1と標識されたBIMペプチドプローブとの間の相互作用を乱す能力を評価した。
比率の計算=665nmの発光/612の発光*10000
阻害%=100−[(試験比率−最低(化合物対照))/(最大(DMSO対照−最低(化合物対照))]
Claims (24)
- 請求項1に記載の化合物。
- 請求項1に記載の化合物の薬学的に許容できる塩。
- 請求項4に記載の化合物。
- 請求項4に記載の化合物の薬学的に許容できる塩。
- 請求項7に記載の化合物。
- 請求項7に記載の化合物の薬学的に許容できる塩。
- 請求項1〜9のいずれか一項に記載の化合物又はその薬学的に許容できる塩の結晶。
- 固体形態が、約7.0°、8.4°、及び12.5°から選択される2θ(±0.2°)として表される少なくとも1つのピークを含むXRPDパターンを有する形態A(Ra)−17−クロロ−5,13,14,22−テトラメチル−28−オキサ−2,9−ジチア−5,6,12,13,22−ペンタアザヘプタシクロ[27.7.1.14,7.011,15.016,21.020,24.030,35]オクタトリアコンタ−1(37),4(38),6,11,14,16,18,20,23,29,31,33,35−トリデカエン−23−カルボン酸一水和物である、請求項11に記載の固体形態。
- 固体形態が、約5.4°、7.0°、8.4°、10.7°、12.5°、13.1°、14.4°、15.1°、15.6°、17.1°、及び18.2°から選択される2θ(±0.2°)として表される少なくとも1つのピークを含むXRPDパターンを有する、請求項11に記載の固体形態。
- 固体形態が、約121℃での脱溶媒和開始及び約152℃でのピークを有する吸熱を含むDSCサーモグラムを有する、請求項12に記載の固体形態。
- 固体形態が、約181℃での融解/分解開始及び約194℃でのピークを有する吸熱を含むDSCサーモグラムを有する、請求項12に記載の固体形態。
- 固体形態が、約25℃から約160℃への加熱時に約4.0%の質量減少を示すTGAサーモグラムを有する、請求項12に記載の固体形態。
- 請求項1〜19のいずれか一項に記載の化合物又はその薬学的に許容できる塩及び医薬賦形剤、担体、若しくは希釈剤を含む医薬組成物。
- 癌の治療のための、請求項1〜19のいずれか一項に記載の化合物又はその薬学的に許容できる塩及び医薬賦形剤、担体、若しくは希釈剤を含む医薬組成物。
- 癌が、血液系癌または固形腫瘍である、請求項21に記載の医薬組成物。
- 血液系癌が、急性骨髄性白血病、多発性骨髄腫、マントル細胞リンパ腫、慢性リンパ球性白血病、びまん性大細胞型B細胞リンパ腫、バーキットリンパ腫、および濾胞性リンパ腫から選択される、請求項22に記載の医薬組成物。
- 固形腫瘍が、非小細胞肺癌、小細胞肺癌、乳癌、神経芽細胞腫、前立腺癌、メラノーマ、膵臓癌、子宮癌、子宮内膜癌、及び結腸癌から選択される、請求項22に記載の医薬組成物。
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