JP2011500676A - プロテアソーム阻害剤 - Google Patents
プロテアソーム阻害剤 Download PDFInfo
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- JP2011500676A JP2011500676A JP2010529907A JP2010529907A JP2011500676A JP 2011500676 A JP2011500676 A JP 2011500676A JP 2010529907 A JP2010529907 A JP 2010529907A JP 2010529907 A JP2010529907 A JP 2010529907A JP 2011500676 A JP2011500676 A JP 2011500676A
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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Abstract
Description
本発明は、プロテアソームの1つ以上のペプチターゼ活性に対する有効な阻害剤である化合物を提供する。これらの化合物は、インビトロおよびインビボでのプロテアソーム活性の阻害に有用であり、特に、様々な細胞増殖性の病気の処置に有用である。
Pは水素またはアミノ基ブロッキング部分(amino−group−blocking moiety)であり;
Raは0〜1個のRAで置換されたC1〜4脂肪族基またはC1〜4フルオロ脂肪族基であるか;または、RaおよびRbは、これらが結合される炭素原子と一体となって、置換または非置換の3〜6員の脂環式基を形成し;RAは置換または非置換の芳香族環または脂環式環であり;
RbはC1〜4脂肪族基またはC1〜4フルオロ脂肪族基であるか;または、RaおよびRbは、これらが結合される炭素原子と一体となって、置換または非置換の3〜6員の脂環式基を形成し;
Rcは0〜1個のRCで置換されたC1〜4脂肪族基またはC1〜4フルオロ脂肪族基であり;RCは置換または非置換の芳香族環または脂環式環であり;そして、
Z1およびZ2は、それぞれ独立に、ヒドロキシ、アルコキシ、アリールオキシまたはアラルコキシであるか;またはZ1およびZ2は、ボロン酸錯化剤から誘導された部分を、一緒になって形成する。)
各R4は、独立して、水素または任意に置換された脂肪族基、アリール基、ヘテロアリール基もしくはヘテロシクリル基であるか;または同一の窒素原子上の2つのR4は、当該窒素原子と一体となって、任意に置換された4〜8員のヘテロシクリル環を形成し、当該環は、窒素原子に加えて、N、OおよびSより独立して選択される0〜2個の環ヘテロ原子を有し;
各R5は、独立して、水素または任意に置換された脂肪族基、アリール基、ヘテロアリール基もしくはヘテロシクリル基であり;そして、
各R6は、独立して、任意に置換された脂肪族基、アリール基またはヘテロアリール基である)
である。
式(I)の化合物は、当業者に周知の方法により調製され得る。例えば、Adamsら(米国特許第5,780,454号)およびPickersgillら(国際公開第2005/097809号)を参照のこと。代表的な合成経路が、以下のスキーム1に示されている。
本発明は、プロテアソームの1つ以上のペプチターゼ活性に対する強力な阻害剤である化合物を提供する。当該化合物は、インビトロまたはインビボで、プロテアソームが介在するペプチド加水分解またはタンパク質分解を阻害する能力について、アッセイされ得る。
ACN アセトニトリル
AIB アミノイソ酪酸
BOC tert−ブトキシカルボニル
DCM 塩化メチレン
DIEA ジイソプロピルエチルアミン
DMF ジメチルホルムアミド
EDCI N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩
EtOAc 酢酸エチル
h 時間
HPLC 高速液体クロマトグラフィ
HATU O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスファート
HOBt 1−ヒドロキシベンゾトリアゾール水和物
LC/MS 液体クロマトグラフィ 質量スペクトル
MeOH メタノール
min 分
NMM 4−メチルモルホリン
Rt ダイオードアレイスペクトルからの保持時間
TBTU o−ベンゾトリアゾール−1−イル−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボラート
(分析的LC−MS法)
ボロン酸のLC−MS分析を、Hewlett−Packard社製HP1100およびWaters社製Symmetry C18 3.5μm 4.6×100mm IDカラムで、以下の勾配を用いて行った(ギ酸純度法(Formic acid Purity method))。
酢酸アンモニウム法:H2O中に10mM酢酸アンモニウムを0〜100パーセント含むACNの、2.5ml/min、3分間の勾配。
(実施例1:[(1R)−2−(2−フルオロフェニル)−1−({2−メチル−2−[(キノキサリン−2−イルカルボニル)アミノ]プロパノイル}アミノ)エチル]ボロン酸(37))
ステップ1A:tert−ブチル(2−{[(1R)−2−(2−フルオロフェニル)−1−(3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル)エチル]アミノ}−1,1−ジメチル−2−オキソエチル)カルバマート。
工程2A:tert−ブチル(1,1−ジメチル−2−{[3−メチル−1−(3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル)ブチル]アミノ}−2−オキソエチル)カルバマート。
工程3F:メチル2−メチル−2−[(ピラジン−2−イルカルボニル)アミノ]プロパノアート。
水(19.6mL)中にメチル2−メチル−2−[(ピラジン−2−イルカルボニル)アミノ]プロパノアート(9.8mmol)および1M NaOHを含む溶液を、メタノール中で6時間撹拌した。この反応をブラインおよびEtOAcで希釈し、層を分離させた。水層を、水(28mL)中の1M HClで酸性化し、およそpH2以下にした。この水溶液をEtOAcで抽出した(3回)。これら3つの抽出物を合わせたものを乾燥し(Na2SO4)、濾過し、濃縮して、1.96g(2回の工程にわたって96%)の表題化合物を得た。1H NMR (300 MHz,CD3OD)δ 9.16(d,J = 1.3 Hz,1H); 8.75(d,J = 2.4 Hz,1H); 8.65(dd,J = 1.5,2.4 Hz,1H); 1.63(s,6H).LC/MS:Rt=1.27min、ES+210(ギ酸法)。
工程4A:tert−ブチル{1−[({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)カルボニル]シクロプロピル}カルバマート。
工程5A:tert−ブチル[1,1−ジメチル−2−({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)−2−オキソエチル]カルバマート。
表題化合物を、実施例1の工程Dに記載された方法に従って、適切な試薬を用いて調製し、生成物を白色の固形物(0.05g、56%)として得た。LC/MS:Rt=5.28min、ES+317(M−H2O)(ギ酸純度法)。
工程6A:tert−ブチル[1,1−ジメチル−2−({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)−2−オキソエチル]カルバマート。
工程7A:tert−ブチル{1−[({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)カルボニル]シクロプロピル}カルバマート。
工程8A:tert−ブチル[(1S)−1−ベンジル−1−メチル−2−({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)−2−オキソエチル]カルバマート。
表題化合物を、実施例1の工程Dに記載された方法に従って、適切な試薬を用いて調製し、生成物を白色の固形物(0.088g、96%)として得た。LC/MS:Rt=5.93min、ES+381(M−H2O)(ギ酸純度法)。
工程9A:tert−ブチル[(1R)−1−ベンジル−1−メチル−2−({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)−2−オキソエチル]カルバマート。
工程10A:tert−ブチル{(1S,2S)−1−[({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)カルボニル]−2−フェニルシクロプロピル}カルバマート。
工程11A:tert−ブチル{1−[({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)カルボニル]シクロプロピル}カルバマート。
工程12A:tert−ブチル{1−[({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)カルボニル]シクロプロピル}カルバマート。
工程13A:ベンジル[1,1−ジメチル−2−({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)−2−オキソエチル]カルバマート。
工程15A:tert−ブチル{1−[({(1R)−2−フェニル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)カルボニル]シクロブチル}カルバマート。
表題化合物を、実施例1の工程Dに記載された方法に従って、適切な試薬を用いて調製し、生成物を白色の固形物(0.387g、93%)として得た。LC/MS:Rt=6.03min、ES+345(M−H2O)(ギ酸純度法)。
工程16A:tert−ブチル{1−[({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)カルボニル]シクロブチル}カルバマート。
工程17A:tert−ブチル{1−[({(1R)−2−フェニル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)カルボニル]シクロプロピル}カルバマート。
工程18A:ベンジル{1−[({(1R)−3−メチル−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]ブチル}アミノ)カルボニル]シクロブチル}カルバマート。
表題化合物を、実施例1の工程Dに記載された方法に従って、適切な試薬を用いて調製し、生成物を白色の固形物(0.181g、45%)として得た。LC/MS:Rt=6.04min、ES+345(M−H2O)(ギ酸純度法)。
工程19A:tert−ブチル[1,1−ジメチル−2−({(1R)−2−(3−メチルフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−2−オキソエチル]カルバマート。
工程20A:tert−ブチル[1,1−ジメチル−2−({(1R)−2−(3−メチルフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−2−オキソエチル]カルバマート。
工程21A:tert−ブチル[1,1−ジメチル−2−({(1R)−2−(3−メチルフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−2−オキソエチル]カルバマート。
工程22A:tert−ブチル[2−({(1R)−2−(4−クロロフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−1,1−ジメチル−2−オキソエチル]カルバマート。
工程23A:tert−ブチル[2−({(1R)−2−(4−クロロフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−1,1−ジメチル−2−オキソエチル]カルバマート。
工程24A:tert−ブチル[2−({(1R)−2−(4−クロロフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−1,1−ジメチル−2−オキソエチル]カルバマート。
工程25A:tert−ブチル[1,1−ジメチル−2−({(1R)−2−(4−メチルフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−2−オキソエチル]カルバマート。
工程26A:tert−ブチル[1,1−ジメチル−2−({(1R)−2−(4−メチルフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−2−オキソエチル]カルバマート。
工程27A:tert−ブチル[1,1−ジメチル−2−({(1R)−2−(4−メチルフェニル)−1−[(3aS,4S,6S,7aR)−3a,5,5−トリメチルヘキサヒドロ−4,6−メタノ−1,3,2−ベンゾジオキサボロール−2−イル]エチル}アミノ)−2−オキソエチル]カルバマート。
工程28F:メチル2−メチル−2−[(ピラジン−2−イルカルボニル)アミノ]プロパノアート。
MeOH/H2O(2:1)(6mL)中にメチル2−メチル−2−[(ピラジン−2−イルカルボニル)アミノ]プロパノアート(0.36、1.6mmol)の溶液を、LiOH(0.08g、3.2mmol)で処理し、22℃で撹拌した。12時間後、この反応をH2OおよびEtOAcで希釈して、層を分離させた。水層を、水(28mL)中の1M HClで酸性化し、およそpH2以下にした。この水溶液をEtOAcで抽出した(3回)。これら3つの抽出物を合わせたものを乾燥し(Na2SO4)、濾過し、濃縮して、表題化合物(0.286g、88%)を得た。
工程29F:メチル2−[(4−クロロベンゾイル)アミノ]−2−メチルプロパノアート。
工程30F:エチル1−[(4−クロロベンゾイル)アミノ]シクロプロパンカルボキシラート。
工程31F:エチル1−[(4−クロロベンゾイル)アミノ]シクロプロパンカルボキシラート。
工程32F:エチル1−[(4−クロロベンゾイル)アミノ]シクロプロパンカルボキシラート。
工程33F:エチル1−[(4−クロロベンゾイル)アミノ]シクロプロパンカルボキシラート。
工程34F:エチル1−[(ピラジン−2−イルカルボニル)アミノ]シクロプロパンカルボキシラート。
工程35F:エチル1−[(ピラジン−2−イルカルボニル)アミノ]シクロプロパンカルボキシラート。
工程36F:エチル1−[(ピラジン−2−イルカルボニル)アミノ]シクロプロパンカルボキシラート。
工程37F:エチル1−{[2−(トリフルオロメチル)ベンゾイル]アミノ}シクロプロパンカルボキシラート。
工程38F:エチル1−{[2−(トリフルオロメチル)ベンゾイル]アミノ}シクロプロパンカルボキシラート。
ラット20S(PA28活性化)β1iプロテアソームアッセイ。
10%ウシ胎仔血清(Invitrogen社製)が追加されている適切な細胞培地(HCT−116に対してはMcCoy’s 5A、Invitrogen社製)100μL中のHCT−116(1000)または他の腫瘍細胞が、96ウェルの細胞培養プレートのウェルに播種され、そして、37℃にて一晩インキューべートされる。試験化合物がウェルに添加され、そして、プレートが96時間37℃にてインキュベートされる。MTT試薬またはWST試薬(10μL、Roche社製)が各ウェルに添加され、そして、上記製造業者によって記載されたように、4時間、37℃にてインキュベートされる。MTTでは、代謝された染料が製造業者の説明書(Roche)に従って一晩可溶化される。各ウェルの光学密度が、MTTでは595nm(主)および690nm(基準)にて、WSTでは450nmにて、分光光度計(Molecular Devices社製)を用いて読み取られる。MTTでは、基準光学密度値が、主波長の値から差し引かれる。阻害率が、100%に設定されたDMSOコントロールの値を用いて計算される。
PRMI−1640培地(Sigma−Aldrich社製)100μL中に解離直後のHCT−116(2〜5×106)または他の腫瘍細胞が、雌CD−1ヌードマウス(5〜8週齢、Charles River社製)の右背側腹部の皮下腔内に、1ml 26 3/8−ゲージ針(Becton Dickinson社製Ref#309625)を用いて無菌注射される。代替的に、いくつかの異種移植モデルは、腫瘍断片の連続継代を必要とする。これらの場合、腫瘍細胞(およそ1mm3)の小断片が、麻酔下(3〜5%イソフルラン/酸素混合物)のC.B−17/SCIDマウス(5〜8週齢、Charles River社製)の右背側腹部に、13−ゲージトロカール(Popper & Sons社製7927)を介して皮下移植される。移植後、第7日目から、腫瘍が、週2回、副尺付きカリパスを用いて測定される。腫瘍体積が、標準的な手順を用いて計算される(0.5×(長さ×幅2))。腫瘍が、およそ200mm3の体積に達したら、マウスが無作為に処置グループに分けられ、そして、薬剤による処置を受け始める。投薬およびスケジュールが、各実験に対して、薬物動態学/薬力学的な研究および最大耐量の研究から得られた以前の結果に基づいて、決定される。コントロール群は、いかなる薬剤をも含まないビヒクルが投与される。代表的に、試験化合物(100〜200μL)が、静脈内経路(27−ゲージ針)、経口経路(20−ゲージガバージュ針(gavage needle))または皮下経路(27−ゲージ針)を介して、様々な用量およびスケジュールで投与される。腫瘍サイズおよび体重が週2回測定され、そして、コントロールの腫瘍がおよそ2000mm3に達したとき本研究が終了される。
Claims (12)
- 式(I):
Pは、水素またはアミノ基ブロッキング部分であり;
Raは、0〜1個のRAで置換された、C1〜4脂肪族基またはC1〜4フルオロ脂肪族基であるか;または、RaおよびRbは、これらが結合される炭素原子と一体となって、置換または非置換の3〜6員の脂環式基を形成し;
RAは、置換または非置換の芳香族環または脂環式環であり;
Rbは、C1〜4脂肪族基またはC1〜4フルオロ脂肪族基であるか;またはRaおよびRbは、これらが結合される炭素原子と一体となって、置換または非置換の3〜6員の脂環式基を形成し;
Rcは、0〜1個のRCで置換された、C1〜4脂肪族基またはC1〜4フルオロ脂肪族基であり;
RCは、置換または非置換の芳香族環または脂環式環であり;そして、
Z1およびZ2は、それぞれ独立してヒドロキシ、アルコキシ、アリールオキシまたはアラルコキシであるか;または、Z1およびZ2は、ボロン酸錯化剤から誘導された部分を、一緒になって形成する、
化合物またはその薬学的に受容可能な塩もしくはそのボロン酸無水物。 - Pは、Rd−C(O)−、Rd−O−C(O)−、Rd−N(R4X)−C(O)−、Rd−S(O)2−またはRd−N(R4X)−S(O)2−であり;
Rdは、C1〜6脂肪族、C1〜6フルオロ脂肪族、−RD、−T1−RDおよび−T1−R2dからなる群より選択され;
T1は、独立して選択される0〜2個のR3aまたはR3bで置換されたC1〜6アルキレン鎖であり、該アルキレン鎖は−C(R5)=C(R5)−、−C≡C−または−O−で任意に分断されており;
RDは、置換または非置換の芳香族環、ヘテロシクリル環または脂環式環であり、いずれの環も、置換または非置換の芳香族環、ヘテロシクリル環または脂環式環に任意に縮合されており;
R2dは、ハロ、−OR5、−SR6、−S(O)R6、−SO2R6、−SO2N(R4)2、−N(R4)2、−NR4C(O)R5、−NR4C(O)−N(R4)2、−NR4CO2R6、−N(R4)SO2R6、−N(R4)SO2N(R4)2、−O−C(O)R5、−OC(O)N(R4)2、−C(O)R5、−CO2R5または−C(O)N(R4)2であり;
各R3aは、独立して、−F、−OH、−O(C1〜4アルキル)、−CN、−N(R4)2、−C(O)(C1〜4アルキル)、−CO2H、−CO2(C1〜4アルキル)、−C(O)NH2および−C(O)NH(C1〜4アルキル)からなる群より選択され;
各R3bは、独立して、R3aまたはR7で任意に置換されたC1〜3脂肪族であり;
各R4は、独立して、水素または任意に置換された脂肪族基、アリール基、ヘテロアリール基もしくはヘテロシクリル基であるか;または同一の窒素原子上の2つのR4は、該窒素原子と一体となって、該窒素原子に加えてN、OおよびSから独立して選択される0〜2個の環ヘテロ原子を有する任意に置換された4〜8員のヘテロシクリル環を形成し;
各R5は、独立して、水素または任意に置換された、脂肪族基、アリール基、ヘテロアリール基もしくはヘテロシクリル基であり;
各R6は、独立して、任意に置換された、脂肪族基、アリール基またはヘテロアリール基であり;
各R7は、置換または非置換の芳香族基であり;そして、
R4Xは、水素、C1〜4アルキル、C1〜4フロオロアルキルまたはC6〜10アラ(C1〜4)アルキルであり、そのアリール部分は置換または非置換である、請求項1に記載の化合物。 - PはRd−C(O)−である、請求項2に記載の化合物。
- RAは置換または非置換のフェニルである、請求項1に記載の化合物。
- RaおよびRbは、これらが結合される炭素原子と一体となって、シクロプロピル環またはシクロブチル環を形成し、これらの環のうち、どちらでも0〜2個の置換基−RBで置換されており;
各RBは、独立して、C1〜4脂肪族、C1〜4フルオロ脂肪族、−R1b、−T2−R1bであり;
T2は、C1〜4アルキレンであり;そして、
R1bは、置換または非置換の芳香族基または脂環式基である、請求項1に記載の化合物。 - R1bは置換または非置換のフェニルである、請求項4に記載の化合物。
- RaおよびRbはそれぞれ−CH3である、請求項1に記載の化合物。
- Rcは式−(CH2)m−RCを有し、mは1または2であり、そして、RCは置換または非置換のフェニルである、請求項1に記載の化合物。
- RcはC1〜4脂肪族である、請求項1に記載の化合物。
- Rcはイソブチルである、請求項9に記載の化合物。
- 薬学的組成物であって、該薬学的組成物は、
請求項1に記載の化合物;および
薬学的に受容可能なキャリア
を含む、薬学的組成物。 - がんを処置するための方法であって、該方法は、
そのような処置を必要とする患者に、請求項11に記載の薬学的組成物を投与する工程、
を含む、方法。
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JP2015502387A (ja) * | 2011-12-22 | 2015-01-22 | アレス トレーディング ソシエテ アノニム | α−アミノボロン酸誘導体、選択性免疫プロテアソーム阻害剤 |
KR101953671B1 (ko) * | 2017-08-21 | 2019-03-04 | 충남대학교산학협력단 | 프로테아좀 억제제를 유효성분으로 함유하는 아토피성 피부질환의 예방, 개선 또는 치료용 조성물 |
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