JP2021522301A - ジペプチジルケトアミドメタ−メトキシフェニル誘導体およびその使用 - Google Patents
ジペプチジルケトアミドメタ−メトキシフェニル誘導体およびその使用 Download PDFInfo
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Abstract
Description
R1は、C1〜C6アルキルおよびC3〜C6シクロアルキルからなる群より選択され、
R2は、HおよびC1〜C6アルキルからなる群より選択され、
R3は、C1〜C6アルコキシおよびC3〜C6シクロアルキルからなる群より選択される]、またはその薬学的に許容される塩もしくは立体異性体に関する。
R1aは、C1〜C6アルキルおよびC3〜C6シクロアルキルからなる群より選択され、
R2aは、HおよびC1〜C6アルキルからなる群より選択され、
R3aは、C3〜C6シクロアルキルである]、またはその薬学的に許容される塩もしくは立体異性体に関する。
いくつかの定義が、本発明の理解を容易にする目的において含まれる。
好ましくは乳癌、結腸直腸癌、および白血病である。
第一の態様において、本発明は、再潅流を伴うまたは伴わない梗塞、虚血によって引き起こされる心臓損傷;神経変性障害;マラリア;糖尿病性腎症;HIV型ウイルスによって引き起こされる神経毒性;癌;および線維性疾患からなる群より選択される疾患または状態の治療および/または予防における使用のための、下記式(I)の化合物:
R1は、C1〜C6アルキルおよびC3〜C6シクロアルキルからなる群より選択され、
R2は、HおよびC1〜C6アルキルからなる群より選択され、
R3は、C1〜C6アルコキシおよびC3〜C6シクロアルキルからなる群より選択される]、またはその薬学的に許容される塩もしくは立体異性体を提供する。
第三の態様において、本発明は、下記式(II)の化合物:
R1aは、C1〜C6アルキルおよびC3〜C6シクロアルキルからなる群より選択され、
R2aは、HおよびC1〜C6アルキルからなる群より選択され、
R3aは、C3〜C6シクロアルキルである]、またはその薬学的に許容される塩もしくは立体異性体を提供する。
別の態様において、本発明は、上記において定義される式(II)の化合物またはその立体異性体もしくはその薬学的に許容される塩と、一種または複数種の薬学的に許容される賦形剤とを含む医薬組成物を提供する。
上記において説明されるように、式(II)の化合物は、式(I)の化合物のサブグループである。したがって、式(II)の化合物も、カルパイン−1の阻止剤である。
当該神経変性障害は、アルツハイマー病、パーキンソン病、多発性硬化症、急性自己免疫性脳炎、およびクロイツフェルト−ヤコブ病からなる群より選択される。
好ましくはR3がシクロアルキル基である、式(I)および(II)の当該化合物は、下記に示される合成スキームに従って、式(VIII)のN置換された3−アミノ−2−ヒドロキシ−アミドヒドロクロリドから出発して調製され得る。
実施例において、以下の略語が使用される。
Boc:tert−ブトキシカルボニル
conc:濃縮
Boc2O:ジ−tert−ブチルジカーボネート
DCM:ジクロロメタン
DIPEA:N,N−ジイソプロピルエチルアミン
DMSO:ジメチルスルホキシド
EDC・HCl:1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミドヒドロクロリド
EtOAc:酢酸エチル
HBTU:N,N,N′,N′−テトラメチル−O−(1H−ベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロホスフェート
HCl:塩酸
HEPES:4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸
HOBt:ヒドロキシベンゾトリアゾール
LC−MS:液体クロマトグラフィ−質量分析法
Leu−OH:ロイシン
MeOH:メタノール
Min:分
Phe OH:フェニルアラニン
Sat:飽和
T3P=プロピルホスホン酸無水物
TBME:tert−ブチルメチルエーテル
THF:テトラヒドロフラン
tR:保持時間
Val−OH:バリン
LC−MS:実施例の生成物を、質量分析に連結された液体クロマトグラフィを使用してキャラクタリゼーションを行った。HPLC−MS分析は、以下の手順を使用して実施した:
2996フォトダイオードアレイ検出器を備え、質量3100検出器LC/MSに連結されたAlliance HT 2795(Waters)クロマトグラフにおいて。分離は、XBridge C18カラム(50×4.6mm、S−3.5μm)を使用し、溶離液として、pH=9の10mMのNH4CO3水溶液(A)とアセトニトリル(B)との混合物を50℃で1.6mL/分の流量において使用し、以下の溶離条件:3.5分において5%から100%のBを使用して実施した。当該検出器は、100〜700の質量範囲において電子スプレー正電荷モード(ESI+)に設定した。コーン電圧10V。ソースT:120℃。脱溶媒T:350℃。
中間体1:(S)−tert−ブチル(1−(メトキシ(メチル)アミノ)−1−オキソ−3−フェニルプロパン−2−イル)カルバメート
LC−MS:tR=2.58分;m/z=309
LC−MS:tR=2.48分;m/z=250
LC−MS:tR=2.32分;m/z=335
LC−MS:tR=1.50分;m/z=235
LC−MS(方法A):tR=2.60分;m/z=448
LC−MS:tR=1.92〜2.03分;m/z=348
LC−MS:tR=2.47分;m/z=482
LC−MS:tR=2.47分;m/z=434
LC−MS:tR=1.77〜1.88分;m/z=334
LC−MS:tR=2.32分;m/z=468
LC−MS:tR=2.5分;m/z=446
LC−MS(方法A):tR=1.82〜1.92分;m/z=346
LC−MS:tR=2.37分;m/z=480
LC−MS:tR=2.83分;m/z=277
完全な転化が達成された後、当該混合物をKHSO4でpH2まで酸性化し、EtOAcで抽出した。有機層を蒸発除去して、当該生成物をさらなる精製を行わすに次の工程に使用した。5.1gを得た(17.2mmol、73%の収率、2工程)。
LC−MS:tR=1.62分;m/z=296
LC−MS:tR=1.58〜1.65分;m/z=210
LC−MS:tR=2.64分;m/z=421
LC−MS:tR=1.78分;m/z=321
当該粗混合物をEtOAcで抽出し、NaHCO3の飽和溶液で洗浄した。当該粗材料を、溶離液としてDCM/DCM:メタノール(8:2)を使用して、DCM:メタノール(8:2)中0%から50%において、フラッシュクロマトグラフィ(Biotage)により精製し、生成物は25%において溶離した。1gの生成物を得た(2.2mmol、42%)。
LC−MS:tR=2.47m分;m/z=455
LC−MS:tR=1.85分;m/z=441
LC−MS:tR=2.18分;m/z=470
LC−MS:tR=2.35分;m/z=482
LC−MS:tR=2.47分;m/z=482。
実施例1:N−((S)−1−(((S)−4−(シクロプロピルアミノ)−3,4−ジオキソ−1−フェニルブタン−2−イル)アミノ)−4−メチル−1−オキソペンタン−2−イル)−3−メトキシベンズアミド
LC−MS:tR=2.63分;m/z=480。
1H−NMR(400MHz、DMSO−d6)δ8.75(dd、J=26.3、5.1Hz、1H)、8.38(dd、J=18.9、8.1Hz、1H)、8.33(d、J=7.7Hz、1H)、7.49〜7.31(m、3H)、7.27〜7.15(m、5H)、7.09(m、1H)、5.22〜5.13(m、1H)、4.54(m、1H)、3.80(s、3H)、3.13(m、1H)、2.88〜2.77(m、1H)、2.76〜2.70(m、1H)、1.67〜1.55(m、1H)、1.53〜1.43(m、1H)、1.29(m、1H)、0.91〜0.78(m、6H)、0.65(m、2H)、0.61〜0.53(m、2H)。
LC−MS:tR=2.52分;m/z=466。
1H−NMR(400MHz、DMSO−d6)δ0.61(s、2H)、0.61〜0.68(m、2H)、0.73(dd、J=23.0、6.7Hz、3H)、0.87(dd、J=6.7、1.8Hz、3H)、1.92〜2.10(m、1H)、2.68〜2.85(m、2H)、3.07〜3.18(m、1H)、3.81(d、J=1.1Hz、3H)、4.32(td、J=8.3、5.6Hz、1H)、5.18〜5.28(m、1H)、7.10(dddd、J=8.0、2.8、1.9、1.1Hz、1H)、7.15〜7.25(m、5H)、7.34〜7.46(m、3H)、8.15(dd、J=11.8、9.0Hz、1H)、8.45(dd、J=14.4、7.2Hz、1H)、8.76(dd、J=21.8、5.1Hz、1H)。
LC−MS:tR=2.57min;m/z=478。
1H−NMR(400MHz、DMSO−d6)δ−0.01〜0.20(m、2H)、0.25〜0.43(m、1H)、0.54〜0.70(m、4H)、0.70〜0.79(m、1H)、1.18〜1.35(m、1H)、1.47〜1.68(m、2H)、2.69〜2.88(m、2H)、3.12(td、J=13.5、4.2Hz、1H)、3.80(d、J=1.2Hz、3H)、4.55(td、J=8.7、5.1Hz、1H)、5.20(dtd、J=9.0、7.8、4.1Hz、1H)、7.08〜7.12(m、1H)、7.16〜7.25(m、5H)、7.34〜7.46(m、3H)、8.29〜8.45(m、2H)、8.75(dd、J=27.7、5.1Hz、1H)。
LC−MS:tR=2.03分;m/z=468。
1H−NMR(400MHz、DMSO−d6)δ−0.04〜0.23(m、1H)、0.34(ddd、J=17.7、9.1、5.5Hz、1H)、1.43〜1.68(m、1H)、2.52(d、J=1.9Hz、1H)、2.67〜2.83(m、1H)、3.10〜3.22(m、2H)、3.65(d、J=13.1Hz、2H)、3.79(d、J=2.2Hz、3H)、4.53(tt、J=9.0、4.6Hz、1H)、5.32(s、1H)、6.95〜7.33(m、6H)、7.33〜7.46(m、3H)、8.09(d、J=72.5Hz、1H)、8.34(dd、J=26.3、8.3Hz、1H)。
LC−MS:tR=2.60分;m/z=480。
1H−NMR(400MHz、DMSO−d6)δ8.74(dd、J=25.5、5.1Hz、1H)、8.33(dd、J=34.8、7.4Hz、1H)、8.19(dd、J=14.2、8.4Hz、1H)、7.88−7.82(m、2H)、7.24〜7.14(m、5H)、7.03〜6.95(m、2H)、5.17(m、1H)、4.52(m、1H)、3.81(s、3H)、3.12(m、1H)、2.91〜2.74(m、1H)、2.74〜2.65(m、1H)、1.60(m、1H)、1.48(m、1H)、1.30(m、1H)、0.92〜0.78(m、6H)、0.68〜0.61(m、2H)、0.58(m、2H)。
LC−MS:tR=2.68分;m/z=480。
1H−NMR(400MHz、DMSO−d6)δ8.78(dd、J=19.7、5.1Hz、1H)、8.51(dd、J=32.3、7.5Hz、1H)、8.26(dd、J=8.2、6.1Hz、1H)、7.79(m、1H)、7.49(m、1H)、7.25〜7.21(m、4H)、7.20〜7.13(m、2H)、7.05(m、1H)、5.24〜5.17(m、1H)、4.63〜4.55(m、1H)、3.86(s、3H)、3.15(m、1H)、2.85〜2.75(m、1H)、2.75〜2.70(m、1H)、1.66〜1.46(m、2H)、1.36(m、1H)、0.91〜0.77(m、6H)、0.67〜0.62(m、2H)、0.61〜0.55(m、2H)。
カルパイン1を阻害する能力の特定のためのアッセイ
Promega製のCalpain−Glo Proteaseキットを使用して、カルパイン1の活性を測定した。透明底の384ウェルブラックプレートにおいてアッセイを実施した。10mのMHEPESおよび1mのMEDTAによる水溶液中における化合物5μlを、16ng/mLのカルパイン1(Sigma Aldrich)の溶液15μLと共に2分間インキュベートし、次いで、当該キットにおいて提供されるCalpain−Glo(商標)試薬20μLを、各ウェルに加えた。カルパイン1誘発基質溶解によって誘発された発光を、Hamamatsu FDSS 7000読み取り機において測定し、データを、最大発光ピークから計算した。カルパイン阻害を以下の式から計算した:
阻害%=(LT−LB)*100/(LC−LB)
式中、LTは、試験した化合物において観察された発光であり、LBは、カルパイン1を含まないウェルから得られたブランク発光であり、ならびにLCは、阻害剤の不在下でカルパイン1を含むコントロールウェルにおいて観察された発光である。
Claims (32)
- 再潅流を伴うまたは伴わない梗塞、虚血によって引き起こされる心臓損傷;神経変性障害;マラリア;糖尿病性腎症;HIV型ウイルスによって引き起こされる神経毒性;癌;および線維性疾患からなる群より選択される疾患または状態の治療および/または予防における使用のための、下記式(I)の化合物:
R1は、C1〜C6アルキルおよびC3〜C6シクロアルキルからなる群より選択され、
R2は、HおよびC1〜C6アルキルからなる群より選択され、
R3は、C1〜C6アルコキシおよびC3〜C6シクロアルキルからなる群より選択される。]、
またはその薬学的に許容される塩もしくは立体異性体、
あるいは前記化合物と薬学的に許容される賦形剤とを含む医薬組成物。 - R1が、C1〜C3アルキルおよびC3〜C5シクロアルキルからなる群より選択され、
R2が、HおよびC1〜C3アルキルからなる群より選択され、
R3が、C1〜C3アルコキシおよびC3〜C5シクロアルキルからなる群より選択される、
請求項1に記載の使用のための式(I)の化合物または医薬組成物。 - R1が、メチル、イソプロピル、およびシクロプロピルからなる群より選択される、請求項1または2のいずれか一項に記載の使用のための式(I)の化合物または医薬組成物。
- R2が、Hおよびメチルからなる群より選択される、請求項1〜3のいずれか一項に記載の使用のための式(I)の化合物または医薬組成物。
- R3が、シクロプロピルおよびメトキシからなる群より選択される、請求項1〜4のいずれか一項に記載の使用のための式(I)の化合物または医薬組成物。
- 前記疾患または状態が、再潅流を伴うまたは伴わない梗塞、虚血によって引き起こされる心臓損傷である、請求項1〜8のいずれか一項に記載の使用のための式(I)の化合物または医薬組成物。
- 前記心臓損傷が、心筋梗塞の後のリモデリングである、請求項9に記載の使用のための式(I)の化合物または医薬組成物。
- 前記神経変性障害が、アルツハイマー病、パーキンソン病、多発性硬化症、急性自己免疫性脳炎、およびクロイツフェルト−ヤコブ病からなる群より選択され;および/または、前記癌が、乳癌、結腸直腸癌、および白血病からなる群より選択される、請求項1〜8のいずれか一項に記載の使用のための式(I)の化合物または医薬組成物。
- 前記線維性疾患が、心筋繊維症、肺線維症、肝線維症、腎線維症、および後腹膜線維症からなる群より選択される、請求項1〜8のいずれか一項に記載の使用のための式(I)の化合物または医薬組成物。
- 再潅流を伴うまたは伴わない梗塞、虚血によって引き起こされる心臓損傷;神経変性障害;マラリア;糖尿病性腎症;HIV型ウイルスによって引き起こされる神経毒性;癌;および線維性疾患からなる群より選択される疾患または状態の治療および/または予防のための医薬品の製造のための、請求項1〜8のいずれか一項において定義される式(I)の化合物または当該化合物と薬学的に許容される賦形剤とを含む医薬組成物の使用。
- 前記疾患または状態が、再潅流を伴うまたは伴わない梗塞、虚血によって引き起こされる心臓損傷である、請求項13記載の使用。
- 前記心臓損傷が、心筋梗塞後のリモデリングである、請求項14に記載の使用。
- 前記神経変性障害が、アルツハイマー病、パーキンソン病、多発性硬化症、急性自己免疫性脳炎、およびクロイツフェルト−ヤコブ病からなる群より選択され;および/または、前記癌が、乳癌、結腸直腸癌、および白血病からなる群より選択される、請求項13に記載の使用。
- 前記線維性疾患が、心筋繊維化、肺線維症、肝線維症、腎線維症、および後腹膜線維症からなる群より選択される、請求項13に記載の使用。
- 再潅流を伴うまたは伴わない梗塞、虚血によって引き起こされる心臓損傷;神経変性障害;マラリア;糖尿病性腎症;HIV型ウイルスによって引き起こされる神経毒性;癌;および線維性疾患からなる群より選択される疾患または状態の治療および/または予防の方法であって、治療有効量の、請求項1〜8のいずれか一項において定義される式(I)の化合物あるいは当該化合物と薬学的に許容される賦形剤とを含む医薬組成物を、それを必要とする対象に投与する工程を含む、方法。
- 前記疾患または状態が、再潅流を伴うまたは伴わない梗塞、虚血によって引き起こされる心臓損傷である、請求項18に記載の方法。
- 前記心臓損傷が、心筋梗塞後のリモデリングである、請求項19に記載の方法。
- 前記神経変性障害が、アルツハイマー病、パーキンソン病、多発性硬化症、急性自己免疫性脳炎、およびクロイツフェルト−ヤコブ病からなる群より選択され;および/または、前記癌が、乳癌、結腸直腸癌、および白血病からなる群より選択される、請求項18に記載の方法。
- 前記線維性疾患が、心筋繊維化、肺線維症、肝線維症、腎線維症、および後腹膜線維症からなる群より選択される、請求項18に記載の方法。
- R1が、C1〜C3アルキルおよびC3〜C5シクロアルキルからなる群より選択され、
R2が、HおよびC1〜C3アルキルからなる群より選択され、
R3が、C3〜C5シクロアルキルである、
請求項23に記載の式(I)の化合物。 - R1が、メチル、イソプロピル、およびシクロプロピルからなる群より選択される、請求項23または24のいずれか一項に記載の式(II)の化合物。
- R2が、Hおよびメチルからなる群より選択される、請求項23〜25のいずれか一項に記載の式(II)の化合物。
- R3が、シクロプロピルである、請求項23〜26のいずれか一項に記載の式(II)の化合物。
- 請求項23〜30のいずれか一項において定義される式(II)化合物と、薬学的に許容される賦形剤とを含む医薬組成物。
- 医薬品における使用のための、請求項23〜30のいずれか一項において定義される式(II)の化合物または請求項31において定義される医薬組成物。
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EP18382306.1A EP3564211A1 (en) | 2018-05-03 | 2018-05-03 | Dipeptidyl ketoamide meta-methoxyphenyl derivatives and uses thereof |
PCT/EP2019/061369 WO2019211434A1 (en) | 2018-05-03 | 2019-05-03 | Dipeptidyl ketoamide meta-methoxyphenyl derivatives and uses thereof |
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JP2017532371A (ja) * | 2014-09-08 | 2017-11-02 | ランドステイナー ジェンメド、エセ.エレ.Landsteiner Genmed, S.L. | ジペプチジルケトアミド化合物ならびに脂肪蓄積の治療および/または予防のためのそれらの使用 |
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GB2467562A (en) * | 2009-02-06 | 2010-08-11 | Summit Corp Plc | Dual calpain-ROS inhibitors |
AU2017229591B2 (en) | 2016-03-09 | 2021-08-19 | Blade Therapeutics Pty Ltd | Calpain modulators and methods of production and use thereof |
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2018
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2019
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JP2003534233A (ja) * | 1998-09-22 | 2003-11-18 | セフアロン・インコーポレーテツド | ヒドロキサメート含有システインおよびセリンプロテアーゼ阻害剤 |
WO2004078908A2 (en) * | 2003-03-06 | 2004-09-16 | Santhera Pharmaceuticals (Schweiz) Gmbh | Alpha-keto carbonyl calpain inhibitors |
WO2005056519A1 (en) * | 2003-12-12 | 2005-06-23 | Senju Pharmaceutical Co., Ltd. | Alpha-ketoamide derivative, and production method and use thereof |
WO2012021788A2 (en) * | 2010-08-13 | 2012-02-16 | Banyan Biomarkers | Dipeptide calpain inhibitors |
JP2017532371A (ja) * | 2014-09-08 | 2017-11-02 | ランドステイナー ジェンメド、エセ.エレ.Landsteiner Genmed, S.L. | ジペプチジルケトアミド化合物ならびに脂肪蓄積の治療および/または予防のためのそれらの使用 |
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ES2964159T3 (es) | 2024-04-04 |
AU2019263953A1 (en) | 2020-11-26 |
AU2019263953B2 (en) | 2023-11-23 |
US11242312B2 (en) | 2022-02-08 |
KR20210005705A (ko) | 2021-01-14 |
EP3788031A1 (en) | 2021-03-10 |
BR112020022364A2 (pt) | 2021-02-02 |
CN112368263A (zh) | 2021-02-12 |
WO2019211434A1 (en) | 2019-11-07 |
US20210317075A1 (en) | 2021-10-14 |
PL3788031T3 (pl) | 2024-02-26 |
HUE064420T2 (hu) | 2024-03-28 |
EP3788031B1 (en) | 2023-09-27 |
MX2020011700A (es) | 2023-01-26 |
BR112020022364B1 (pt) | 2023-11-21 |
CA3100188A1 (en) | 2019-11-07 |
EP3564211A1 (en) | 2019-11-06 |
JP7307498B2 (ja) | 2023-07-12 |
EP3788031C0 (en) | 2023-09-27 |
CN112368263B (zh) | 2023-09-26 |
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