JP2022536092A - 増殖性疾患の治療のための、ヒトctps1阻害剤としてのn-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-4-(2-(メチルスルホンアミド)ピリミジン-4-イル)テトラヒドロ-2h-ピラン-4-カルボキサミド誘導体及び関連化合物 - Google Patents
増殖性疾患の治療のための、ヒトctps1阻害剤としてのn-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-4-(2-(メチルスルホンアミド)ピリミジン-4-イル)テトラヒドロ-2h-ピラン-4-カルボキサミド誘導体及び関連化合物 Download PDFInfo
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004449 vismodegib Drugs 0.000 description 1
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-OUBTZVSYSA-N water-17o Chemical compound [17OH2] XLYOFNOQVPJJNP-OUBTZVSYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000003357 wound healing promoting agent Substances 0.000 description 1
- 229910001928 zirconium oxide Inorganic materials 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
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Abstract
Description
式中、
(a)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(b)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(c)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(d)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(e)A、X、Y、Z、R1、R4、及びR5が以下:
(f)A、V、W、R1、R4、R5、R10、及びR12が以下:
(g)A、V、W、R1、R4、R5、R10、及びR12が以下:
(h)A、V、W、R1、R4、R5、R10、及びR12が以下:
上記化合物を提供する。
式(I):
式中、
(a)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(b)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(c)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(d)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(e)A、X、Y、Z、R1、R4、及びR5が以下:
(f)A、V、W、R1、R4、R5、R10、及びR12が以下:
(g)A、V、W、R1、R4、R5、R10、及びR12が以下:
上記化合物も提供する。
式中、
(a)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(b)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(c)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(d)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(e)A、X、Y、Z、R1、R4、及びR5が以下:
(f)A、V、W、R1、R4、R5、R10、及びR12が以下:
(g)A、V、W、R1、R4、R5、R10、及びR12が以下:
上記化合物、あるいは薬学的に許容されるその塩ならびに/または溶媒和物も提供する。
N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-4-(2-(メチルスルホンアミド)ピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
1-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)シクロヘキサン-1-カルボキサミド、
N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-1-(2-(メチルスルホンアミド)ピリミジン-4-イル)シクロヘキサン-1-カルボキサミド、
1-(6-(シクロプロパンスルホンアミド)ピラジン-2-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)シクロヘキサン-1-カルボキサミド、
4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N-(4-(6-エトキシピラジン-2-イル)-2-メチルフェニル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
1-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)シクロブタン-1-カルボキサミド、
4-(4-(シクロプロパンスルホンアミド)ピリミジン-2-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
4-(2-(シクロペンタンスルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-4-(2-((1-メチルシクロプロパン)-1-スルホンアミド)ピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-1-メチルピペリジン-4-カルボキサミド、
4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-1-イソプロピルピペリジン-4-カルボキサミド、
4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N4-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-N1-イソプロピルピペリジン-1,4-ジカルボキサミド、
4-(2-((1,1-ジメチルエチル)スルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
N-(4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-イル)-5-(6-エトキシピラジン-2-イル)ピコリンアミド、
1-アセチル-4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)ピペリジン-4-カルボキサミド、
N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-4-(2-((2-メチルプロピル)スルホンアミド)ピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N-(5-(6-シクロプロピルピラジン-2-イル)ピリジン-2-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
N-(5’-クロロ-[3,3’-ビピリジン]-6-イル)-4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、
N-(1-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)シクロプロピル)-5-(6-エトキシピラジン-2-イル)ピコリンアミド、
4-(2-(シクロプロパンスルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)テトラヒドロ-2H-チオピラン-4-カルボキサミド1,1-ジオキシド、
N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-4-(2-(エチルスルホンアミド)ピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド、及び
4-(2-(シクロプロピルメチルスルホンアミド)ピリミジン-4-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)テトラヒドロ-2H-ピラン-4-カルボキサミド。
4-(4-(シクロプロパンスルホンアミド)ピリミジン-2-イル)-N-(5-(6-エトキシピラジン-2-イル)ピリジン-2-イル)-1-メチルピペリジン-4-カルボキサミドも提供する。
本発明はまた、式(II)~(LVIX)の化合物などの、式(I)の化合物の合成における新規な中間体にも関する。特に興味深い中間体は、可変の基及び関連する選択が式(I)の化合物に関して上記で定義された通りである、以下の一般式の化合物、すなわち、
・式(II):
・式(XXXIII):
式中、Rは、H、C1~4アルキル(例えばメチル及びエチル)、またはベンジルである上記化合物、
・式(XXXIV):
式中、Rは、H、C1~4アルキル(例えばメチル及びエチル)、またはベンジルである上記化合物、
・式(XXXIVa):
式中、Rは、H、C1~4アルキル(例えばメチル及びエチル)、またはベンジルである上記化合物、
・式(LXI):
(LXI)中の全ての変数は、本明細書の他所で定義された通りである上記化合物、
・式(LXII):
(LXII)中の全ての変数は、本明細書の他所で定義された通りである上記化合物、
・式(XXXI):
(XXXI)中の全ての変数は、本明細書の他所で定義された通りである上記化合物、
・式(XXXXII):
(XXXXII)中の全ての変数は、本明細書の他所で定義された通りである上記化合物
の中間体である。
式中、Rは、H、C1~4アルキル(例えばメチル及びエチル)、またはベンジルであり、X、Y、Z、及びR1は本明細書で定義された通りである上記化合物、
・式(XXXIII-a):
式中、Rは、H、C1~4アルキル(例えばメチル及びエチル)、またはベンジルであり、X、Y、及びZは定義された通りである上記化合物、
・式(XXXIVa-a):
式中、Rは、H、C1~4アルキル(例えばメチル及びエチル)、またはベンジルであり、X、Y、及びZは本明細書で定義された通りである上記化合物
からなる群より選択される化合物、または薬学的に許容されるその塩などの塩もまた提供される。
・中間体INTC185、
・中間体INTC189、
・中間体INTC193~INTC196、
・中間体INTC200、
・中間体INTC202、
・中間体INTC204、
・中間体INTC206、
・中間体INTC209、
・中間体INTC211、
・中間体INTC213、
・中間体INTC217、
・中間体INTC219~INCT222、
・中間体INTC241~INTC243、ならびに
・中間体INTC246及びINTC247
を含む、実施例に記載の全ての中間体が本発明の態様として包含される。
本発明の式(I)の化合物はCTPS1の阻害剤としての有用性を有する。
*円形脱毛症、アトピー性皮膚炎、湿疹、乾癬、扁平苔癬、乾癬性関節炎、白斑、
*ブドウ膜炎、
*強直性脊椎炎、ライター症候群/反応性関節炎、
*再生不良性貧血、自己免疫性リンパ増殖症候群/障害、血球貪食性リンパ組織球症、
*1型糖尿病、及び
*難治性セリアック病
・移植組織及び移植器官の急性拒絶;骨髄細胞または造血前駆体細胞及び/または幹細胞を含む同種異形細胞の任意の他の供給源の移植後の急性移植片対宿主病(GVHD)
を含む、主としてT細胞の活性化及び増殖によって駆動される疾患または障害が特に興味深い。
*アレルギー、
*瘢痕性類天疱瘡、水疱性類天疱瘡、後天性表皮水疱症、落葉状天疱瘡、尋常性天疱瘡、疱疹状皮膚炎、
*ANCA関連脈管炎及び顕微鏡的多発血管炎、脈管炎、ウェゲナー肉芽腫症;チャーグ・ストラウス症候群(CSS)、結節性多発動脈炎、クリオグロブリン症候群及び本態性混合型クリオグロブリン血症、
*全身性エリテマトーデス(SLE)、抗リン脂質症候群(ヒューズ症候群)、皮膚ループス、ループス腎炎、混合性結合組織疾患、
*甲状腺炎、橋本甲状腺炎、グレーブス病、眼球突出症、
*自己免疫性溶血性貧血、自己免疫性好中球減少症、ITP、悪性貧血、真正赤血球性貧血、微小血管症性溶血性貧血、
*原発性糸球体腎炎、ベルガー病、グッドパスチャー症候群、IgA腎症、及び
*慢性特発性多発性神経炎、慢性炎症性脱髄性多発神経障害(CIPD)、慢性再発性多発神経障害(ギラン・バレー症候群)、ミラー・フィッシャー症候群、全身硬直症候群、ランバート・イートン筋無力症症候群、重症筋無力症、
・B細胞の関与があまり明確にキャラクタライズされておらず(時として抗CD20モノクローナル抗体または免疫グロブリンの静脈内注入の効力によって説明されてはいるが)、該関与が病原性抗体の産生に対応していないか、またはそれに限定されない可能性が高い(それにもかかわらず、非病原性抗体が時として報告され、またはさらに多くの場合に診断用バイオマーカーとして存在し且つ使用される)、以下を含む疾患及び障害:
*アジソン病、自己免疫性卵巣炎及び無精子症、多腺性症候群(ホイッティカー症候群)、シュミット症候群、
*自己免疫性心筋炎、心筋症、川崎病、
*関節リウマチ、シェーグレン症候群、混合性結合組織疾患、多発性筋炎及び皮膚筋炎、多発性軟骨炎、
*原発性糸球体腎炎、
*多発性硬化症、
*自己免疫性肝炎、原発性胆汁性肝硬変症/自己免疫性胆管症、
*移植器官の超急性拒絶、
*移植片または移植の慢性拒絶、
*慢性移植片対宿主反応/骨髄細胞または造血前駆体細胞の移植後の疾患
を含む、T細胞及びB細胞の活性化及び増殖によって駆動され、B細胞の重要な関与を伴う疾患または障害も興味深い。
・COPD、特発性肺線維症、間質性肺疾患、サルコイドーシス、
・B細胞及び病原性抗体も関与する可能性がある成人発症型スティル病、若年性特発性関節炎、全身性硬化症、クレスト症候群;スウィート症候群;高安動脈炎、側頭動脈炎/巨細胞動脈炎、
・潰瘍性胆管炎(ulcerative cholangitis)、クローン病及び潰瘍性大腸炎を含む炎症性腸疾患(IBD)、原発性硬化性胆管炎
を含む、機序がT細胞の活性化/増殖と、先天的免疫細胞及び他の炎症性細胞の分集団(マクロファージまたは顆粒球などの骨髄細胞を含む)及び常在性細胞(線維芽細胞及び内皮細胞などの)の活性化/増殖の間で共有される疾患または障害も興味深い。
・以下を含む自己免疫性リンパ増殖障害:
*自己免疫性リンパ増殖症候群及びX連鎖リンパ球増殖性疾患
を含む、機序が十分にキャラクタライズされないままであるが、該機序がT細胞の活性化及び増殖を含む疾患または障害も興味深い。
治療に使用する場合、本発明の化合物は通常医薬組成物として投与される。本発明は、式(I)の化合物、または薬学的に許容されるその塩及び/もしくは溶媒和物(例えば塩)及び/もしくは誘導体と、薬学的に許容される担体または賦形剤とを含む医薬組成物も提供する。
一実施形態において、本発明の化合物または上記化合物を含む医薬組成物は、医療機器中に組み入れることが可能になるように製剤化されてもよく、そのようにして、本明細書に開示の疾病を予防または治療するための、本化合物または組成物の当該部位への直接の適用を提供する。
すべての出発物質及び溶媒は、商業的供給源から入手するか、または文献に従って調製した。別段の明示がない限り、全ての反応は撹拌下で実施した。有機溶液は定法により無水硫酸マグネシウム上で脱水した。水素化はThales H-cube流通式反応器において、記載した条件下で実施した。
・分取HPLC
・酸性での分取
Waters X-Select CSHカラム C18、5um(19×50mm)、流速28mL/分、6.5分にわたる0.1% v/vギ酸を含むH2O-MeCN勾配、254nmのUV検出を使用して溶離。
Waters X-Bridge分取カラム C18、5um(19×50mm)、流速28mL/分、6.5分にわたる10mM NH4HCO3-MeCN勾配、254nmのUV検出を使用して溶離。
LCMS分析方法に対する逆相HPLC条件
分析LCMSを、0.1%ギ酸のMeCN溶液/0.1%ギ酸の水溶液の勾配で溶離するWaters X-Select CSH C18、2.5um、4.6×30mmカラムを使用して実施した。0.00~3.00分を2.5mL/分での5~95%の0.1%ギ酸のMeCN溶液の勾配とし、3.01~3.5分を4.5mL/分でのフラッシュとする。3.60~4.00分を2.5mL/分での5% MeCNへのカラム再平衡化とする。254nmでAgilent 1260 Infinity VWDを使用して、溶離ピークのUVスペクトルを測定した。ポジティブ/ネガティブ切り替えで運転するAgilent 6120 MSDを使用して、質量スペクトルを測定した。
分析LCMSを、MeCN/10mM炭酸水素アンモニウム水溶液の勾配で溶離するWaters X-Select BEH C18、2.5um、4.6×30mmカラムを使用して実施した。0.00~3.00分を2.5mL/分での5~95%のMeCNの勾配とし、3.01~3.5分を4.5mL/分でのフラッシュとする。3.60~4.00分を2.5mL/分での5% MeCNへのカラム再平衡化とする。254nmでAgilent 1260 Infinity VWDを使用して、溶離ピークのUVスペクトルを測定した。ポジティブ/ネガティブ切り替えで運転するAgilent 6120 MSDを使用して、質量スペクトルを測定した。
UPLC酸性:酸性UPLC 3分
分析UPLC/MSを、0.1%ギ酸のMeCN溶液/0.1%ギ酸の水溶液の勾配で溶離するWaters Acquity CSH C18、1.7um、2.1×30mmカラムを使用して実施した。開始点を5% MeCNとし、0.0~0.11分にこれを保持することで勾配を構築する。0.11~2.15分を5~95%の勾配とし、2.15~2.56分をフラッシュとする。2.56~2.83分を5% MeCNへのカラム再平衡化とする。Acquity PDA4を使用して溶離ピークのUVスペクトルを測定し、ESIポジティブ/ネガティブ切り替えのAcquity QDa検出器を使用して質量スペクトルを記録した。
分析UPLC/MSを、0.1%ギ酸のMeCN溶液/0.1%ギ酸の水溶液の勾配で溶離するWaters Acquity CSH C18、1.7um、2.1×30mmカラムを使用して実施した。開始点を5% MeCNとし、0.0~0.08分にこれを保持することで勾配を構築する。0.08~0.70分を5~95%の勾配とし、0.7~0.8分をフラッシュとする。0.8~0.9分を5% MeCNへのカラム再平衡化とする。Acquity PDAを使用して溶離ピークのUVスペクトルを測定し、ESIポジティブ/ネガティブ切り替えのAcquity QDa検出器を使用して質量スペクトルを記録した。
分析UPLC/MSを、MeCN/10mM炭酸水素アンモニウム水溶液の勾配で溶離するWaters Acquity BEH C18、1.7um、2.1×30mmカラムを使用して実施した。開始点を5% MeCNとし、0.0~0.11分にこれを保持することで勾配を構築する。0.11~2.15分を5~95%の勾配とし、2.15~2.56分をフラッシュとする。2.56~2.83分を5% MeCNへのカラム再平衡化とする。Acquity PDAを使用して溶離ピークのUVスペクトルを測定し、ESIポジティブ/ネガティブ切り替えのAcquity QDa検出器を使用して質量スペクトルを記録した。
分析UPLC/MSを、MeCN/10mM炭酸水素アンモニウム水溶液の勾配で溶離するWaters Acquity BEH C18、1.7um、2.1×30mmカラムを使用して実施した。開始点を5% MeCNとし、0.0~0.08分にこれを保持することで勾配を構築する。0.08~0.70分を5~95%の勾配とし、0.7~0.8分をフラッシュとする。0.8~0.9分を5% MeCNへのカラム再平衡化とする。Acquity PDAを使用して溶離ピークのUVスペクトルを測定し、ESIポジティブ/ネガティブ切り替えのAcquity QDa検出器を使用して質量スペクトルを記録した。
400MHzのBruker Avance III分光器または500MHzのBruker Avance III HD分光器において、残留する未重水素化溶媒を基準として使用して1H NMRスペクトルを得て、別段の明示がない限りDMSO-d6中で測定した。
公知の合成中間体は商業的供給源より入手するか、または刊行された文献の手順を用いて入手した。さらなる中間体は、本明細書に記載の代表的な合成プロセスによって調製した。
2-(2-クロロピリミジン-4-イル)マロン酸1-(tert-ブチル)3-メチル INTC1
・2-(2-クロロピリミジン-4-イル)酢酸メチル INTC4
・4-(2-クロロピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-カルボン酸メチル INTC52
4-(2-クロロピリミジン-4-イル)ピペリジン-1,4-ジカルボン酸1-tert-ブチル4-メチル INTC66
・1-(2-クロロピリミジン-4-イル)シクロプロパンカルボン酸メチル INTC146[INTC13と同等]
1-(2-クロロピリミジン-4-イル)シクロプロパンカルボン酸 INTC147
(1-(2-クロロピリミジン-4-イル)シクロプロピル)カルバミン酸tert-ブチル INTC148
・N-(4-(1-アミノシクロプロピル)ピリミジン-2-イル)シクロプロパンスルホンアミド塩酸塩 INTC156
・方法E:ハロアニリンのヘテロ芳香族ボロナートとのSuzukiカップリング
・1-(2-クロロピリミジン-4-イル)シクロヘキサンカルボン酸メチル INTC180
・(4-(2-(メチルチオ)ピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-イル)カルバミン酸tert-ブチル INTC194
・5-(6-エトキシピラジン-2-イル)-N-(4-(2-(メチルチオ)ピリミジン-4-イル)テトラヒドロ-2H-ピラン-4-イル)ピコリンアミド INTC196
・アミドの形成
・方法1:HATUを使用したアミドカップリング
・生物学的実施例1 - ヒトCTPS1酵素の阻害
着目する標的に対して発明された化合物の酵素阻害活性をADP-Glo(商標)Maxアッセイ(Promega, UK)を使用して測定した。ヒトCTPS1に関するアッセイは、50mM Tris、10mM MgCl2、0.01% Tween-20を含み、それに応じてpH8.0の1×アッセイバッファー中で実施した。最後に、使用直前に、上記1×アッセイバッファーに、最終濃度2mMとなるようにL-システインを添加した。別段の明示がない限り、全ての試薬はSigma-Aldrich製である。ヒト全長活性C末端FLAG―His8-tag CTPS1(UniProtKB - P17812, CTPS1[1-591]-GGDYKDDDDKGGHHHHHHHH(CTPS1[1-591]-配列番号1))をProteros biostructures GmbHから入手した。
3×ヒトCTPS1タンパク質を、1×アッセイバッファー中で、当該の反応に必要な最終的な作業タンパク質濃度に調製した。ウェル当り2uLの3×ヒトCTPS1タンパク質をウェル当り2uLの3×被検化合物(1×アッセイバッファー中で、被検化合物向けに設計した濃度反応曲線に応じた適宜の最終的な3×化合物濃度になるように化合物溶液を調製した)と25℃で10分間混合した。ウェル当り2uLの容量の予備混合した基質混合物(ADP-Glo(商標)Maxキット由来のUltraPure ATP(0.31mM)、GTP(0.034mM)、UTP(0.48mM)、及びL-グルタミン(0.186mM))を添加することによって酵素反応を開始させ、この混合物を、密封プレート条件下、500回転/分(rpm)で一定の撹拌をしながら、25℃で、測定された当該反応の線形期内の適宜の長さの時間インキュベートした。ADP-Glo(商標)Max試薬を60分間添加し(6μL/ウェル)、続いてADP-Glo(商標)Max現像試薬を60分間添加し(12μL/ウェル)、その後マイクロプレートリーダー(EnVision(登録商標)Multilabel Reader、Perkin Elmer)でシグナルを検出した。上記アッセイの過程において、それぞれの試薬の添加に続いて、アッセイプレートを500rpmで30秒間、パルス遠心分離した。
RapidFire/MS分析によるヒトCTPS1対CTPS2選択性評価
本発明の化合物の、着目するそれぞれのイソ型に対する酵素阻害活性を、最適化されたRapidFire高処理質量分析(RF/MS)アッセイ方式を使用して測定することができる。ヒトCTPS1及びCTPS2の両方に関するRF/MSアッセイは、50mM HEPES(Merck)、20mM MgCl2、5mM KCl、1mM DTT、0.01% Tween-20からなり、それに応じてpH8.0のアッセイバッファー中で実施することができる。ヒト全長活性C末端FLAG-His-tag CTPS1(UniProtKB - P17812, CTPS1[1-591]-GGDYKDDDDKGGHHHHHHHH(CTPS1[1-591]-配列番号1))をProteros biostructures GmbHから入手することができる。ヒト全長活性C末端FLAG-His-Aviをタグ付けしたCTPS2(UniProtKB - Q9NRF8, CTPS2 [1-586]-DYKDDDDKHHHHHHGLNDIFEAQKIEWHE(ヒトCTPS2 [1-586]-配列番号2))をHarker Bioから入手することができる。
ヒトCTPS(1または2)タンパク質を、1×アッセイバッファー中で、当該の反応に必要な最終的な作業タンパク質濃度に調製することができる。アコースティック(ECHO)デリバリーを使用して、ウェル当り2ul容積の2×CTPS(1または2)タンパク質を40nLの化合物と混合し、25℃で10分間インキュベートしてもよい。続いて、ウェル当り2uLの、アッセイバッファー中の2×基質混合物を添加することによって、それぞれのイソ型の酵素反応を開始させることができる。hCTPS1の場合:ATP(0.3mM)、UTP(0.2mM)、GTP(0.07mM)、及びL-グルタミン(0.1mM)。hCTPS2の場合:ATP(0.1mM)、UTP(0.04mM)、GTP(0.03mM)、及びL-グルタミン(0.1mM)。それぞれの混合物を、25℃で、イソ型毎に測定された当該反応の線形期内の適宜の長さの時間インキュベートすることができる。60uLの停止溶液(0.5uM 13C9-15N3-CTPを含む1%ギ酸H2O溶液)を添加し、直後にプレートを熱シールし、4,000rpmで10分間遠心分離することができる。遠心分離後に、プレートを、API4000トリプル四重極質量分析計(RF/MS)と結合したAgilent RapidFire微小流体固相抽出システム上にロードし、分析を行うことができる。
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Claims (42)
- 式(I):
式中、
(a)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(b)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(c)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(d)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(e)A、X、Y、Z、R1、R4、及びR5が以下:
(f)A、V、W、R1、R4、R5、R10、及びR12が以下:
(g)A、V、W、R1、R4、R5、R10、及びR12が以下:
(h)A、V、W、R1、R4、R5、R10、及びR12が以下:
前記化合物、あるいは薬学的に許容されるその塩ならびに/または溶媒和物。 - 式(I):
式中、
(a)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(b)A、V、W、X、Y、Z、R1、R10、及びR12が以下:
(c)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(d)A、V、W、X、Y、Z、R4、R5、R10、及びR12が以下:
(e)A、X、Y、Z、R1、R4、及びR5が以下:
(f)A、V、W、R1、R4、R5、R10、及びR12が以下:
(g)A、V、W、R1、R4、R5、R10、及びR12が以下:
前記化合物である請求項1に記載の化合物、あるいは薬学的に許容されるその塩ならびに/または溶媒和物。 - 薬学的に許容される塩の形態である、請求項1~25のいずれか1項に記載の化合物。
- 塩の形態ではない、請求項1~25のいずれか1項に記載の化合物。
- 医薬としての使用のための、請求項1~27のいずれか1項に記載の化合物。
- 対象におけるT細胞及び/またはB細胞の低減における使用のための、請求項28に記載の化合物。
- 乾癬または扁平苔癬などの炎症性皮膚疾患;ステロイド耐性急性GVHDなどの急性及び/または慢性GVHD;急性リンパ増殖性症候群(ALPS);全身性エリテマトーデス、ループス腎炎、もしくは皮膚ループス;移植;重症筋無力症、多発性硬化症もしくは強皮症/全身性硬化症;血液癌などのがんの治療または予防における使用のための;あるいは、対象における血管損傷または血管の手術からの回復の向上、及び新生内膜及び再狭窄に関連する疾病率ならびに死亡率の低減における使用のための、請求項28に記載の化合物。
- 前記血液癌が、急性骨髄性白血病、血管免疫芽球性T細胞性リンパ腫、B細胞性急性リンパ芽球性白血病、スイート症候群、T細胞性非ホジキンリンパ腫(ナチュラルキラー細胞/T細胞性リンパ腫、成人T細胞性白血病/リンパ腫、腸管症型T細胞性リンパ腫、肝脾T細胞性リンパ腫、及び皮膚T細胞性リンパ腫を含む)、T細胞性急性リンパ芽球性白血病、B細胞性非ホジキンリンパ腫(バーキットリンパ腫、びまん性大細胞型B細胞性リンパ腫、濾胞性リンパ腫、マントル細胞リンパ腫、辺縁帯リンパ腫を含む)、有毛細胞性白血病、ホジキンリンパ腫、リンパ芽球性リンパ腫、リンパ形質細胞性リンパ腫、粘膜関連リンパ組織リンパ腫、多発性骨髄腫、骨髄異形成症候群、形質細胞性骨髄腫、縦隔原発B細胞性大細胞型リンパ腫、慢性骨髄増殖性疾患(慢性骨髄性白血病、原発性骨髄線維症、本態性血小板血症、真性多血症など)、及び慢性リンパ球性白血病からなる群より選択される、請求項30に記載の化合物。
- 請求項1~27のいずれか1項に記載の化合物を含む医薬組成物。
- INTC180~INTC183、INTC185、INTC189、INTC193~INTC196、INTC200、INTC202、INTC204、INTC206、INTC209、INTC211、INTC213、INTC217、INTC219~INCT222、INTC241~INTC243、INTC246、及びINTC247からなる群より選択される化合物、または薬学的に許容されるその塩などの塩。
- 前記式(I)の化合物が天然の同位体形態である、請求項1~27のいずれか1項に記載の化合物、使用のための化合物、または組成物。
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EP4232425A4 (en) * | 2020-10-23 | 2024-07-24 | Nimbus Clotho Inc | CTPS1 INHIBITORS AND USES THEREOF |
US20240109859A1 (en) * | 2021-02-01 | 2024-04-04 | University Of Southern California | Enzyme inhibitors and viral infection therapy |
WO2023166076A1 (en) | 2022-03-01 | 2023-09-07 | Step Pharma S.A.S. | Combinations of ctps1 and bcl2 inhibitors for cancer |
WO2023166078A1 (en) | 2022-03-01 | 2023-09-07 | Step Pharma S.A.S. | Combination treatments comprising a ctps1 inhibitor and a chek1 inhibitor |
WO2023166080A1 (en) | 2022-03-01 | 2023-09-07 | Step Pharma S.A.S. | Combination treatments comprising a ctps1 inhibitor and a wee1 inhibitor |
WO2023166077A1 (en) | 2022-03-01 | 2023-09-07 | Step Pharma S.A.S. | Combination of a ctps1 inhibitor and a atr inhibitor in cancer therapy |
WO2024133721A1 (en) | 2022-12-21 | 2024-06-27 | Step Pharma S.A.S. | Combinations of ctps1 inhibitor with iap inhibitor for use in the treatment of cancer |
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