JP2022191415A - 短鎖デヒドロゲナーゼ活性を調節する組成物および方法 - Google Patents
短鎖デヒドロゲナーゼ活性を調節する組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2013年10月15日に出願された米国仮出願第61/891,260号、2014年3月17日に出願された同61/954,202号、2014年7月1日に出願された同62/019,597号、および2014年8月29日に出願された同62/043,694号の優先権を主張する。これらの出願の内容は参照によりその全体が本明細書に組み込まれる。
本発明は、米国国立衛生研究所により授与された認可番号第R01CA127306号、同R01CA127306-03S1号、同1P01CA95471-10号、および同5P50CA150964号による政府支援に基づいて行われた。米国政府は、本発明に対し一定の権利を有する。
R1およびR3は、同じであるかまたは異なり、それぞれ:
R2はNまたはCR7であり;
R4は、H、Cl、F、NH2、およびN(R6)2からなる群から選択され;
R5は、-(CH2)n1CH3(n1=0~7)、
それぞれR6およびR7は、同じであるかまたは異なり、かつ水素、置換または非置換C1-C24アルキル、C2-C24アルケニル、C2-C24アルキニル、C3-C20アリール、5~6個の環原子(この内、1~3個の環原子は、N、NH、N(C1-C6アルキル)、NC(O)(C1-C6アルキル)、O、およびSから独立に選択される)を含むヘテロシクロアルケニル、5~14個の環原子(この内、1~6個の環原子は、N、NH、N(C1-C3アルキル)、O、およびSから独立に選択される)を含むヘテロアリールまたはヘテロシクリル、C6-C24アルカリル、C6-C24アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、C1-C24アルコキシ、C2-C24アルケニルオキシ、C2-C24アルキニルオキシ、C5-C20アリールオキシ、アシル(C2-C24アルキルカルボニル(-CO-アルキル)およびC6-C20アリールカルボニル(-CO-アリール)を含む)、アシルオキシ(-O-アシル)、C2-C24アルコキシカルボニル(-(CO)-O-アルキル)、C6-C20アリールオキシカルボニル(-(CO)-O-アリール)、C2-C24アルキルカルボナト(-O-(CO)-O-アルキル)、C6-C20アリールカルボナト(-O-(CO)-O-アリール)、カルボキシ(-COOH)、カルボキシラト(-COO-)、カルバモイル(-(CO)-NH2)、C1-C24アルキルカルバモイル(-(CO)-NH(C1-C24アルキル))、アリールカルバモイル(-(CO)-NH-アリール)、チオカルバモイル、(-(CS)-NH2)、カルバミド(-NH-(CO)-NH2)、シアノ(-CN)、イソシアノ(-N+C-)、シアナト(-O-CN)、イソシアナト(-O-N+=C-)、イソチオシアナト(-S-CN)、アジド(-N=N+=N-)、ホルミル(-(CO)-H)、チオホルミル(-(CS)-H)、アミノ(-NH2)、C1-C24アルキルアミノ、C5-C20アリールアミノ、C2-C24アルキルアミド(-NH-(CO)-アルキル)、C6-C20アリールアミド(-NH-(CO)-アリール)、スルホンアミド(sulfanamido)(Rは独立にH、アルキル、アリールまたはヘテロアリールである-SO2NR2)、イミノ(Rは水素、C1-C24アルキル、C5-C20アリール、C6-C24アルカリル、C6-C24アラルキルなどである-CR=NH)、アルキルイミノ(R=水素、アルキル、アリール、アルカリル、アラルキルなどである、-CR=N(アルキル))、アリールイミノ(R=水素、アルキル、アリール、アルカリルなどである、-CR=N(アリール))、ニトロ(-NO2)、ニトロソ(-NO)、スルフォ(-SO2-OH)、スルホナト(-SO2-O-)、C1-C24アルキルスルファニル(-S-アルキル;「アルキルチオ」とも呼ばれる)、アリールスルファニル(-S-アリール;「アリールチオ」とも呼ばれる)、C1-C24アルキルスルフィニル(-(SO)-アルキル)、C5-C20アリールスルフィニル(-(SO)-アリール)、C1-C24アルキルスルホニル(-SO2-アルキル)、C5-C20アリールスルホニル(-SO2-アリール)、スルホンアミド(-SO2-NH2、-SO2NY2(Yは独立にH、アリール(arlyl)またはアルキルである)、ホスホノ(-P(O)(OH)2)、ホスホナト(-P(O)(O-)2)、ホスフィナト(-P(O)(O-))、ホスフォ(-PO2)、ホスフィノ(-PH2)、ポリアルキルエーテル(-[(CH2)nO]m)、ホスフェート、ホスフェートエステル[R=H、メチルまたはその他のアルキル基である-OP(O)(OR)2]、生理的なpHで正電荷または負電荷を持つと予測されるアミノ酸またはその他の成分を組み込んだ基、およびこれらの組み合わせからなる群から選択される1つまたは複数の置換基であり;
R1がH、非置換チオフェン、もしくは非置換チアゾールであり、かつR5がブチルである場合は、R3は水素ではないか;またはR1がH、もしくは非置換フェニル、チオフェン、もしくはチアゾールであり、かつR5がベンジルもしくは(CH2)n5(CH3)(n5=0~5)である場合は、R3は非置換フェニルではない]を有する化合物;および薬学的に許容可能なそれらの塩を含んでよい。
R3は、
R2はNまたはCR7であり;
R4は、H、Cl、F、NH2、およびN(R6)2からなる群から選択され;
R5は、-(CH2)n1CH3(n1=0~7)、
それぞれR6およびR7は、同じであるまたは異なり、かつ水素、置換または非置換C1-C24アルキル、C2-C24アルケニル、C2-C24アルキニル、C3-C20アリール、5~6個の環原子(この内、1~3個の環原子は、N、NH、N(C1-C6アルキル)、NC(O)(C1-C6アルキル)、O、およびSから独立に選択される)を含むヘテロシクロアルケニル、5~14個の環原子(この内、1~6個の環原子は、N、NH、N(C1-C3アルキル)、O、およびSから独立に選択される)を含むヘテロアリール、C6-C24アルカリル、C6-C24アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、C1-C24アルコキシ、C2-C24アルケニルオキシ、C2-C24アルキニルオキシ、C5-C20アリールオキシ、アシル(C2-C24アルキルカルボニル(-CO-アルキル)およびC6-C20アリールカルボニル(-CO-アリール)を含む)、アシルオキシ(-O-アシル)、C2-C24アルコキシカルボニル(-(CO)-O-アルキル)、C6-C20アリールオキシカルボニル(-(CO)-O-アリール)、C2-C24アルキルカルボナト(-O-(CO)-O-アルキル)、C6-C20アリールカルボナト(-O-(CO)-O-アリール)、カルボキシ(-COOH)、カルボキシラト(-COO-)、カルバモイル(-(CO)-NH2)、C1-C24アルキルカルバモイル(-(CO)-NH(C1-C24アルキル))、アリールカルバモイル(-(CO)-NH-アリール)、チオカルバモイル、(-(CS)-NH2)、カルバミド(-NH-(CO)-NH2)、シアノ(-CN)、イソシアノ(-N+C-)、シアナト(-O-CN)、イソシアナト(-O-N+=C-)、イソチオシアナト(-S-CN)、アジド(-N=N+=N-)、ホルミル(-(CO)-H)、チオホルミル(-(CS)-H)、アミノ(-NH2)、C1-C24アルキルアミノ、C5-C20アリールアミノ、C2-C24アルキルアミド(-NH-(CO)-アルキル)、C6-C20アリールアミド(-NH-(CO)-アリール)、スルホンアミド(Rは独立にH、アルキル、アリールまたはヘテロアリールである-SO2NR2)、イミノ(Rは水素、C1-C24アルキル、C5-C20アリール、C6-C24アルカリル、C6-C24アラルキルなどである-CR=NH)、アルキルイミノ(R=水素、アルキル、アリール、アルカリル、アラルキルなどである、-CR=N(アルキル))、アリールイミノ(R=水素、アルキル、アリール、アルカリルなどである、-CR=N(アリール))、ニトロ(-NO2)、ニトロソ(-NO)、スルフォ(-SO2-OH)、スルホナト(-SO2-O-)、C1-C24アルキルスルファニル(-S-アルキル;「アルキルチオ」とも呼ばれる)、アリールスルファニル(-S-アリール;「アリールチオ」とも呼ばれる)、C1-C24アルキルスルフィニル(-(SO)-アルキル)、C5-C20アリールスルフィニル(-(SO)-アリール)、C1-C24アルキルスルホニル(-SO2-アルキル)、C5-C20アリールスルホニル(-SO2-アリール)、スルホンアミド(-SO2-NH2、-SO2NY2(Yは独立にH、アリールまたはアルキルである)、ホスホノ(-P(O)(OH)2)、ホスホナト(-P(O)(O-)2)、ホスフィナト(-P(O)(O-))、ホスフォ(-PO2)、ホスフィノ(-PH2)、ポリアルキルエーテル(-[(CH2)nO]m)、ホスフェート、ホスフェートエステル[R=H、メチルまたはその他のアルキル基である-OP(O)(OR)2]、生理的なpHで正電荷または負電荷を持つと予測されるアミノ酸またはその他の成分を組み込んだ基、およびこれらの組み合わせからなる群から選択される1つまたは複数の置換基であり;
R5がブチルである場合は、R3は水素ではないか;またはR5がベンジルもしくは(CH2)n5(CH3)(n5=0~5)である場合は、R3は非置換フェニルではない]を有する化合物;および薬学的に許容可能なそれらの塩を含んでよい。
R1およびR3は、同じであるかまたは異なり、それぞれ、
R2はNまたはCR7であり;
R4は、H、Cl、F、NH2、およびN(R6)2からなる群から選択され;
R5は、-(CH2)n1CH3(n1=0~7)、
それぞれR6およびR7は、同じであるかまたは異なり、水素、置換または非置換C1-C24アルキル、C2-C24アルケニル、C2-C24アルキニル、C3-C20アリール、5~6個の環原子(この内、1~3個の環原子は、N、NH、N(C1-C6アルキル)、NC(O)(C1-C6アルキル)、O、およびSから独立に選択される)を含むヘテロシクロアルケニル、5~14個の環原子(この内、1~6個の環原子は、N、NH、N(C1-C3アルキル)、O、およびSから独立に選択される)を含むヘテロアリールまたはヘテロシクリル、C6-C24アルカリル、C6-C24アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、C1-C24アルコキシ、C2-C24アルケニルオキシ、C2-C24アルキニルオキシ、C5-C20アリールオキシ、アシル(C2-C24アルキルカルボニル(-CO-アルキル)およびC6-C20アリールカルボニル(-CO-アリール)を含む)、アシルオキシ(-O-アシル)、C2-C24アルコキシカルボニル(-(CO)-O-アルキル)、C6-C20アリールオキシカルボニル(-(CO)-O-アリール)、C2-C24アルキルカルボナト(-O-(CO)-O-アルキル)、C6-C20アリールカルボナト(-O-(CO)-O-アリール)、カルボキシ(-COOH)、カルボキシラト(-COO-)、カルバモイル(-(CO)-NH2)、C1-C24アルキルカルバモイル(-(CO)-NH(C1-C24アルキル))、アリールカルバモイル(-(CO)-NH-アリール)、チオカルバモイル、(-(CS)-NH2)、カルバミド(-NH-(CO)-NH2)、シアノ(-CN)、イソシアノ(-N+C-)、シアナト(-O-CN)、イソシアナト(-O-N+=C-)、イソチオシアナト(-S-CN)、アジド(-N=N+=N-)、ホルミル(-(CO)-H)、チオホルミル(-(CS)-H)、アミノ(-NH2)、C1-C24アルキルアミノ、C5-C20アリールアミノ、C2-C24アルキルアミド(-NH-(CO)-アルキル)、C6-C20アリールアミド(-NH-(CO)-アリール)、スルホンアミド(Rは独立にH、アルキル、アリールまたはヘテロアリールである-SO2NR2)、イミノ(Rは水素、C1-C24アルキル、C5-C20アリール、C6-C24アルカリル、C6-C24アラルキルなどである-CR=NH)、アルキルイミノ(R=水素、アルキル、アリール、アルカリル、アラルキルなどである、-CR=N(アルキル))、アリールイミノ(R=水素、アルキル、アリール、アルカリルなどである、-CR=N(アリール))、ニトロ(-NO2)、ニトロソ(-NO)、スルフォ(-SO2-OH)、スルホナト(-SO2-O-)、C1-C24アルキルスルファニル(-S-アルキル;「アルキルチオ」とも呼ばれる)、アリールスルファニル(-S-アリール;「アリールチオ」とも呼ばれる)、C1-C24アルキルスルフィニル(-(SO)-アルキル)、C5-C20アリールスルフィニル(-(SO)-アリール)、C1-C24アルキルスルホニル(-SO2-アルキル)、C5-C20アリールスルホニル(-SO2-アリール)、スルホンアミド(-SO2-NH2、-SO2NY2(Yは独立にH、アリールまたはアルキルである)、ホスホノ(-P(O)(OH)2)、ホスホナト(-P(O)(O-)2)、ホスフィナト(-P(O)(O-))、ホスフォ(-PO2)、ホスフィノ(-PH2)、ポリアルキルエーテル(-[(CH2)nO]m)、ホスフェート、ホスフェートエステル[R=H、メチルまたはその他のアルキル基である-OP(O)(OR)2]、生理的なpHで正電荷または負電荷を持つと予測されるアミノ酸またはその他の成分を組み込んだ基、およびこれらの組み合わせからなる群から選択される1つまたは複数の置換基であり;
R1がH、非置換チオフェン、もしくは非置換チアゾールでありかつR5がブチルである場合R3は水素ではない;またはR1がH、もしくは非置換フェニル、チオフェン、もしくはチアゾールでありかつR5がベンジルもしくは(CH2)n5(CH3)(n5=0~5)である場合はR3は非置換フェニルではない]を有する化合物;および薬学的に許容可能なそれらの塩を含む15-PGDH阻害剤であってよい。
R3は、
R2はNまたはCR7であり;
R4は、H、Cl、F、NH2、およびN(R6)2からなる群から選択され;
R5は、-(CH2)n1CH3(n1=0~7)、
それぞれR6およびR7は、同じであるかまたは異なり、水素、置換または非置換C1-C24アルキル、C2-C24アルケニル、C2-C24アルキニル、C3-C20アリール、5~6個の環原子(この内、1~3個の環原子は、N、NH、N(C1-C6アルキル)、NC(O)(C1-C6アルキル)、O、およびSから独立に選択される)を含むヘテロシクロアルケニル、5~14個の環原子(この内、1~6個の環原子は、N、NH、N(C1-C3アルキル)、O、およびSから独立に選択される)を含むヘテロアリール、C6-C24アルカリル、C6-C24アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、C1-C24アルコキシ、C2-C24アルケニルオキシ、C2-C24アルキニルオキシ、C5-C20アリールオキシ、アシル(C2-C24アルキルカルボニル(-CO-アルキル)およびC6-C20アリールカルボニル(-CO-アリール)を含む)、アシルオキシ(-O-アシル)、C2-C24アルコキシカルボニル(-(CO)-O-アルキル)、C6-C20アリールオキシカルボニル(-(CO)-O-アリール)、C2-C24アルキルカルボナト(-O-(CO)-O-アルキル)、C6-C20アリールカルボナト(-O-(CO)-O-アリール)、カルボキシ(-COOH)、カルボキシラト(-COO-)、カルバモイル(-(CO)-NH2)、C1-C24アルキルカルバモイル(-(CO)-NH(C1-C24アルキル))、アリールカルバモイル(-(CO)-NH-アリール)、チオカルバモイル、(-(CS)-NH2)、カルバミド(-NH-(CO)-NH2)、シアノ(-CN)、イソシアノ(-N+C-)、シアナト(-O-CN)、イソシアナト(-O-N+=C-)、イソチオシアナト(-S-CN)、アジド(-N=N+=N-)、ホルミル(-(CO)-H)、チオホルミル(-(CS)-H)、アミノ(-NH2)、C1-C24アルキルアミノ、C5-C20アリールアミノ、C2-C24アルキルアミド(-NH-(CO)-アルキル)、C6-C20アリールアミド(-NH-(CO)-アリール)、スルホンアミド(Rは独立にH、アルキル、アリールまたはヘテロアリールである-SO2NR2)、イミノ(Rは水素、C1-C24アルキル、C5-C20アリール、C6-C24アルカリル、C6-C24アラルキルなどである-CR=NH)、アルキルイミノ(R=水素、アルキル、アリール、アルカリル、アラルキルなどである、-CR=N(アルキル))、アリールイミノ(-CR=N(アリール)、R=水素、アルキル、アリール、アルカリル、など)、ニトロ(-NO2)、ニトロソ(-NO)、スルフォ(-SO2-OH)、スルホナト(-SO2-O-)、C1-C24アルキルスルファニル(-S-アルキル;「アルキルチオ」とも呼ばれる)、アリールスルファニル(-S-アリール;「アリールチオ」とも呼ばれる)、C1-C24アルキルスルフィニル(-(SO)-アルキル)、C5-C20アリールスルフィニル(-(SO)-アリール)、C1-C24アルキルスルホニル(-SO2-アルキル)、C5-C20アリールスルホニル(-SO2-アリール)、スルホンアミド(-SO2-NH2、-SO2NY2(Yは独立にH、アリールまたはアルキルである)、ホスホノ(-P(O)(OH)2)、ホスホナト(-P(O)(O-)2)、ホスフィナト(-P(O)(O-))、ホスフォ(-PO2)、ホスフィノ(-PH2)、ポリアルキルエーテル(-[(CH2)nO]m)、ホスフェート、ホスフェートエステル[R=H、メチルまたはその他のアルキル基である-OP(O)(OR)2]、生理的なpHで正電荷または負電荷を持つと予測されるアミノ酸またはその他の成分を組み込んだ基、およびこれらの組み合わせからなる群から選択される1つまたは複数の置換基であり;
R5がブチルである場合はR3は水素ではないか;またはR5がベンジルもしくは(CH2)n5(CH3)(n5=0~5)である場合はR3は非置換フェニルではない]を有する化合物;および薬学的に許容可能なそれらの塩を含んでよい。
R1およびR11は、同じであるかまたは異なり、水素、置換または非置換C1-C24アルキル、C2-C24アルケニル、C2-C24アルキニル、C3-C20アリール、5~6個の環原子(この内、1~3個の環原子は、N、NH、N(C1-C6アルキル)、NC(O)(C1-C6アルキル)、O、およびSから独立に選択される)を含むヘテロシクロアルケニル、5~14個の環原子(この内、1~6個の環原子は、N、NH、N(C1-C3アルキル)、O、およびSから独立に選択される)を含むヘテロアリール、C6-C24アルカリル、C6-C24アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、C1-C24アルコキシ、C2-C24アルケニルオキシ、C2-C24アルキニルオキシ、C5-C20アリールオキシ、アシル(C2-C24アルキルカルボニル(-CO-アルキル)およびC6-C20アリールカルボニル(-CO-アリール)を含む)、アシルオキシ(-O-アシル)、C2-C24アルコキシカルボニル(-(CO)-O-アルキル)、C6-C20アリールオキシカルボニル(-(CO)-O-アリール)、C2-C24アルキルカルボナト(-O-(CO)-O-アルキル)、C6-C20アリールカルボナト(-O-(CO)-O-アリール)、カルボキシ(-COOH)、カルボキシラト(-COO-)、カルバモイル(-(CO)-NH2)、C1-C24アルキルカルバモイル(-(CO)-NH(C1-C24アルキル))、アリールカルバモイル(-(CO)-NH-アリール)、チオカルバモイル、(-(CS)-NH2)、カルバミド(-NH-(CO)-NH2)、シアノ(-CN)、イソシアノ(-N+C-)、シアナト(-O-CN)、イソシアナト(-O-N+=C-)、イソチオシアナト(-S-CN)、アジド(-N=N+=N-)、ホルミル(-(CO)-H)、チオホルミル(-(CS)-H)、アミノ(-NH2)、C1-C24アルキルアミノ、C5-C20アリールアミノ、C2-C24アルキルアミド(-NH-(CO)-アルキル)、C6-C20アリールアミド(-NH-(CO)-アリール)、スルホンアミド(Rは独立にH、アルキル、アリールまたはヘテロアリールである-SO2NR2)、イミノ(Rは水素、C1-C24アルキル、C5-C20アリール、C6-C24アルカリル、C6-C24アラルキルなどである-CR=NH)、アルキルイミノ(R=水素、アルキル、アリール、アルカリル、アラルキルなどである、-CR=N(アルキル))、アリールイミノ(R=水素、アルキル、アリール、アルカリルなどである、-CR=N(アリール))、ニトロ(-NO2)、ニトロソ(-NO)、スルフォ(-SO2-OH)、スルホナト(-SO2-O-)、C1-C24アルキルスルファニル(-S-アルキル;「アルキルチオ」とも呼ばれる)、アリールスルファニル(-S-アリール;「アリールチオ」とも呼ばれる)、C1-C24アルキルスルフィニル(-(SO)-アルキル)、C5-C20アリールスルフィニル(-(SO)-アリール)、C1-C24アルキルスルホニル(-SO2-アルキル)、C5-C20アリールスルホニル(-SO2-アリール)、スルホンアミド(-SO2-NH2、-SO2NY2(Yは独立にH、アリールまたはアルキルである)、ホスホノ(-P(O)(OH)2)、ホスホナト(-P(O)(O-)2)、ホスフィナト(-P(O)(O-))、ホスフォ(-PO2)、ホスフィノ(-PH2)、ポリアルキルエーテル(-[(CH2)nO]m)、ホスフェート、ホスフェートエステル[R=H、メチルまたはその他のアルキル基である-OP(O)(OR)2]、生理的なpHで正電荷または負電荷を持つと予測されるアミノ酸またはその他の成分を組み込んだ基、およびこれらの組み合わせからなる群から選択される1つまたは複数の置換基であり;
X10、X11、X12、X13、およびX14は独立に、NまたはCRcであり、ここでRcがHまたは直鎖、分枝、もしくは環式であり非置換または置換のC1-8アルキルであり、X11、X12、X13、およびX14の内の少なくとも1つがCRcであり;
Z2はO、S、CRaRbまたはNRaであり、ここでRaおよびRbが独立に、Hまたは直鎖、分枝、または環状であり非置換、または置換のC1-8アルキルである]
を有する化合物;および薬学的に許容可能なそれらの塩を含んでよい。
この実施例は、酵素15-プロスタグランジンデヒドロゲナーゼ(15-PGDH)(遺伝子HPGDによりコードされる)に関する4つの化合物の活性を説明する。化合物はSW033291、SW054384、SW124531、SW145753であり、次式:
15-PGDH阻害剤であるリード化合物SW033291の類似体の分析
この実施例はSW033291の一群の構造類似体に関するデータを提供する。インビトロアッセイにおける組換え型15-PGDHの酵素活性を阻害するための各化合物のIC50がデータとして提供される。特に指示がない限り、組換え型15-PGDHはヒト型である。
反応混合物を、100℃で30分間撹拌した。その後、反応物をEtOAcで希釈し、飽和NaHCO3溶液で洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧下で濃縮して、81%の単離収率で意図した生成物を得た。1H NMR(400MHz、CDCl3)δ8.23(d、J=8.5Hz、1H)、8.09(dd、J=8.2、1.6Hz、2H)、7.89(d、J=2.1Hz、1H)、7.59-7.39(m、4H)、3.39-3.10(m、2H)、1.92-1.68(m、2H)、1.54-1.27(m、2H)、0.91(t、J=7.3Hz、3H)。ESI-MS(m/z):332.1[M+H]+。
室温に冷却後、反応混合物をEtOAcで希釈し、水、次にブラインで洗浄した。有機層を硫酸マグネシウム上で乾燥させ、減圧下で溶媒を除去した。粗生成物をフラッシュクロマトグラフィー(ヘキサン/EtOAc:8/2)により精製し、意図した生成物を32%収率で得た。1H NMR(400MHz、CDCl3)δ8.09-8.00(m、2H)、7.93(d、J=8.3Hz、1H)、7.69(d、J=8.3Hz、1H)、7.52-7.34(m、4H)、2.99(t、J=7.9Hz、2H)、1.77-1.63(m、2H)、1.53-1.38(m、2H)、0.92(t、J=7.3Hz、3H)。ESI-MS(m/z):300.1[M+H]+。
反応混合物を-78℃でさらに1時間撹拌し、その後反応を停止させた。粗生成物をフラッシュクロマトグラフィーにより精製して、意図した生成物を得た。1H NMR(400MHz、CDCl3)δ8.62-8.56(m、2H)、8.06-7.98(m、2H)、7.61-7.41(m、7H)、3.01(t、J=7.3、2H)、1.76-1.62(m、2H)、1.55-1.38(m、2H)、0.92(t、J=7.4Hz、3H)。ESI-MS(m/z):377.1[M+H]+。
ESI-MS(m/z):415.0[M+H]+。
ESI-MS(m/z):416.6[M+H]+。
LC/MSにより反応が不十分であることが示された。反応物をセライトを通して濾過し、DCMで洗浄後、減圧下で濾液を濃縮した。粗製混合物をDCM(2.3mL)に再溶解し、MnO2(5当量)を加えた。この溶液を室温で24時間撹拌し、セライトを通して濾過し、DCMで洗浄した。濾液を減圧下濃縮し、得られた粗生成物を自動フラッシュクロマトグラフィー(55%EtOAc、45%ヘキサン)で精製し、24%の単離収率を得た。1H NMR(400MHz、CDCl3)δ10.13(s、1H)、8.11-7.99(m、3H)、7.92(d、J=3.1Hz、1H)、7.75-7.62(m、2H)、7.51(d、J=3.2Hz、1H)、4.56(s、2H)、3.29(ddd、J=12.8、8.8、6.3Hz、1H)、3.11(ddd、J=12.8、8.9,6.9Hz、1H)、1.82-1.66(m、2H)、1.54-1.41(m、2H)、0.94(t、J=7.3Hz、3H)。ESI-MS(m/z):442.1[M+H]+。
1H NMR(400MHz、CDCl3)δ7.97(d、J=3.1Hz、1H)、7.91(s、1H)、7.56(d、J=3.1Hz、1H)、4.57(d、J=13.3Hz、1H)、4.46(d、J=13.3Hz、1H)、3.05(hept、J=6.9Hz、1H)、2.57(s、3H)、1.38(d、J=7.1Hz、3H)、1.36(d、J=6.7Hz、3H)。ESI-MS(m/z):338.0[M+H]+。
ESI-MS(m/z):417.0[M+H]+。
SW033291および関連化合物による15-PGDH阻害のメカニズムの分析
下記実施例は、SW033291が15-PGDHを阻害する作用機序に関するデータを提供する。
SW033291の毒性の分析
表4は、SW033291の毒性を評価した対照またはSW033291処理群における、8~12週齢雄FVBマウス群の特性をまとめたものである。試験各群当たりのマウスは6匹である。
骨髄機能に対するSW033291の効果の分析
この実施例は、SW033291の骨髄機能に対する効果を示す。
放射線生存に対するSW033291の効果の分析
この実施例は、全身照射を受けているマウスにおけるSW033291の効果の試験を示す。
部分肝切除後の肝臓再生に対するSW033291の効果の分析
この実施例は、部分肝切除後のマウスにおける肝臓再生に対するSW033291の効果を評価する試験を示す。
アセトアミノフェン(タイレノール)過剰投与後の生存に対するSW033291の効果の分析
この実施例は、致死用量の肝臓毒素アセトアミノフェン(タイレノール)に対する抵抗性の調節におけるSW033291の効果を示すデータを提供する。
デキストラン(dextan)硫酸ナトリウム(DSS)誘導大腸炎に対するSW033291の効果の分析
この実施例は、デキストラン硫酸ナトリウム(DSS)処理マウスにおける大腸炎の誘導の防止に対するSW033291の効果の試験からのデータを提供する。この試験では、8~12週齢FVB雄マウスに2%DSSを含む飲料水を1~7日目の間与え、その後、8日目から通常の飲料水に切り換え、22日目まで継続した。マウスを1日2回、125μg/200μlの、10%エタノール、5%クレモフォールEL、85%D5Wのビークル中のSW033291で5mg/kgにてIPにより処理し、また、これと対比してマウスをビークルのみで処理する。臨床スコア(体重、直腸出血、便の硬さ)を毎日記録し、内視鏡スコア(潰瘍数、粘膜肥厚、および血管パターン)を、8、11、15日目に評価する。結腸長、結腸重量、潰瘍数、潰瘍面積、および陰窩損傷の評価のために、マウスを、1、8、15および22日目に屠殺する。
骨髄移植後の生存に対するSW033291の効果の分析
図81は、骨髄移植を受け、さらに15-PGDH阻害剤SW033291を投与されたマウスにおける、向上した生存を示す。図81Aは、この試験の計画を示す。0日目に、マウスを11Gyの骨髄破壊的照射量で照射し、続けて、SW033291を5mg/kgにて、10%エタノール、5%クレモフォールEL、85%D5Wのビークル中、125μg/200μlの濃度で、1日2回、腹腔内の注射により投与した。対応する対照コホートはビークルのみの注射を受けた。1日目に、マウスは、100,000個の細胞、200,000個の細胞、または500,000個の細胞数のドナー骨髄の注入を受けた。図81Bは、100,000個のドナー細胞を移植されたマウスの生存曲線の図を示す。図81Cは、200,000個のドナー細胞を移植されたマウスの生存曲線の図を示す。図81Dは、500,000個のドナー細胞を移植されたマウスの生存曲線の図を示す。さらに図81Eは、試験30日目での試験における全マウスの生存データの表を示す。100,000個のドナー細胞を受けるマウスでは、全マウスが死亡しているが、SW033291処理マウスは約2倍の生存期間中央値を示している。200,000個のドナー細胞を受けるマウスでは、すべての対照マウスが12日目までに死亡した。対照的に、200,000個のドナー細胞とSW033291を受ける全てのマウスは、観察の30日で生存し、生着に成功した。500,000個のドナー細胞を受けるマウスでは、対照マウスは37.5%の死亡率を示し、一方、SW033291を受けるマウスは、この場合も、全て生存した。
15-PGDH阻害剤であるSW033291の異性体の活性の分析
図95は、SW033291の異性体を示す。上段に示すのは、スルホキシド(S=O基)はステレオジェニックであり、そのため、SW033291は2つの非相互変換異性体のラセミ混合物として存在するということである。これらの鏡像異性体は分取HPLCにより分離されて、異性体A(最初に溶出)および異性体B(2番目に溶出)として表される異性体が得られる。1cmのCheralcel-ODHカラムにより、ヘキサン中のイソプロパノールを使って鏡像異性体が分離される。代表的分析用HPLC結果を下段に示す。異性体Aは、主に左旋性の鏡像異性体[a]D=-97(c=0.22、アセトン)からなることが明らかになった。異性体Bは、主に右旋性の鏡像異性体[a]D=+95(c=0.22、アセトン)からなることが明らかになった。X線結晶解析法により、(-)異性体AはS異性体として、異性体Bは(R)異性体として帰属された(表1に示すとおり)。
SW033291の15-PGDHへのインシリコドッキングの分析
図99は、SW209415の15-PGDH結晶構造上への結合配置像を示す。このモデルは、SW209415上のスルホキシド部分が15-PGDHのTyr-151に配位することを示し、このTyr-151は15-PGDHの触媒活性に必要であり、かつ短鎖デヒドロゲナーゼファミリー全体で厳密に保存されている。さらに、SW209415のスルホキシドはSer-138にも配位し、このSer-138もまた15-PGDHの触媒活性に必要であり、かつ短鎖デヒドロゲナーゼファミリー全体で高度に保存されている。したがって、阻害剤のコア構造は、その触媒機能が15-PGDHのTyr-151に類似のチロシンおよび/またはSer-138に類似のセリンに依存する、任意の短鎖デヒドロゲナーゼと広範囲に相互作用し、これを阻害する可能性があることが推測される。
15-PGDH阻害剤であるリード化合物SW033291の類似体の分析
この実施例は、一群のSW033291の構造類似体に関するデータを提供する。提供されるデータは、レポーターを含むように操作され、化合物で処理された、3つの結腸癌細胞株、V9m、V503、およびLS174Tにおける、基礎レベルに対するルシフェラーゼ活性の増加%として報告される、15-PGDH-ルシフェラーゼ融合遺伝子レポーターの誘導のレベルを含む(すなわち、値は、100がベースラインレベルに対するルシフェラーゼ活性の2倍を示すスケールで記録される)。
図107は、SW209271~SW209283の範囲の個別化合物名称を有するセット20と命名された、SW033291に構造的に関連する一連の13種の化合物の化学構造を示す。それぞれの化合物に対し、分子量、tPSA、およびCLogPも示されている。
Claims (12)
- 式(V):
R1は、
R3は、H、アルキル、-CO2H、-CO2アルキル、-CONH2、-CONH(アルキル)、-CON(アルキル)2、
R2はNまたはCHであり;
R4は、HまたはNH2であり;
R5は、分岐アルキル、-(CH2)n1CH3(n1=0~7)または、
それぞれのR6は、水素、置換または非置換C1-C24アルキル、C2-C24アルケニル、C2-C24アルキニル、置換または非置換C3-C20アリール、5~6個の環原子を含むヘテロシクロアルケニル、5~14個の環原子を含む置換または非置換ヘテロアリールまたはヘテロシクリル、C6-C24アルカリル、C6-C24アラルキル、ハロ、シリル、ヒドロキシル、スルフヒドリル、C1-C24アルコキシ、C2-C24アルケニルオキシ、C2-C24アルキニルオキシ、C5-C20アリールオキシ、アシル、アシルオキシ、C2-C24アルコキシカルボニル、C6-C20アリールオキシカルボニル、C2-C24アルキルカルボナト、C6-C20アリールカルボナト、カルボキシ、カルボキシラト、カルバモイル、C1-C24アルキルカルバモイル、アリールカルバモイル、チオカルバモイル、カルバミド、シアノ、イソシアノ、シアナト、イソシアナト、イソチオシアナト、アジド、ホルミル、チオホルミル、アミノ、C1-C24アルキルアミノ、C5-C20アリールアミノ、C2-C24アルキルアミド、C6-C20アリールアミド、スルホンアミド、イミノ、アルキルイミノ、アリールイミノ、ニトロ、ニトロソ、スルフォ、スルホナト、C1-C24アルキルスルファニル、アリールスルファニル、C1-C24アルキルスルフィニル、C5-C20アリールスルフィニル、C1-C24アルキルスルホニル、C5-C20アリールスルホニル、スルホンアミド、ホスホノ、ホスホナト、ホスフィナト、ホスフォ、ホスフィノ、ポリアルキルエーテル、ホスフェート、またはホスフェートエステルから独立して選択され、;かつ、
R1が非置換チオフェン、もしくは非置換チアゾールであり、かつR5がブチルである場合R3は水素ではなく;
R1が非置換フェニル、非置換チオフェン、もしくは非置換チアゾールであり、かつR5が(CH2)n5(CH3)(n5=0~5)である場合R3は非置換フェニルではなく;
R1が非置換チアゾールであり、かつR5がベンジルである場合R3は非置換フェニルではない]
を有する化合物、または薬学的に許容可能なその塩。 - R2がNまたはCHである、請求項1に記載の化合物または薬学的に許容可能なその塩。
- nが1である、請求項1に記載の化合物または薬学的に許容可能なその塩。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、G-CSF、GM-CSF、EPO、IL-3、IL-6、TPO、TPO-RA(トロンボポエチン受容体アゴニスト)およびSCFのうち1つまたは複数をさらに含む、医薬組成物。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、創傷治癒、組織修復、および組織再生のうち1つまたは複数を促進するための医薬組成物。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、対象中の幹細胞を増やすための医薬組成物。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、ドナーグラフトとしての骨髄の適応度を高めるため、ドナーグラフトとしての幹細胞調製物の適応度を高めるため、組織グラフト拒絶を緩和させるため、組織および/もしくは骨髄グラフト生着を高めるため、または前駆幹細胞グラフト、造血幹細胞グラフト、もしくは臍帯幹細胞グラフトの生着を高めるための医薬組成物。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、前記組成物は対象の骨髄の治療後に前記対象に投与されるか、または前記組成物は対象の放射線療法、化学療法、もしくは免疫抑制療法の後に前記対象に投与される、医薬組成物。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、骨髄、造血幹細胞、または臍帯血を用いる造血細胞移植後に好中球数を増加させるための医薬組成物。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、好中球減少症、再生不良性貧血、脊髄形成異常症、骨髄線維症、他の骨髄疾患に起因する好中球減少症、薬物誘発好中球減少症、自己免疫性好中球減少症、特発性好中球減少症、またはウイルス感染後の好中球減少症の対象中の好中球数を増加させるための医薬組成物。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、骨密度を増加させるため、骨粗鬆症を治療するため、骨折の治癒を促進するため、または骨手術もしくは関節置換後の治癒を促進するための医薬組成物。
- 請求項1~3のいずれか1項に記載の化合物または薬学的に許容可能なその塩を含む医薬組成物であって、骨対骨移植、骨対人工物移植、歯科インプラント、および骨移植の治癒を促進するための医薬組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
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US11718589B2 (en) | 2017-02-06 | 2023-08-08 | Case Western Reserve University | Compositions and methods of modulating short-chain dehydrogenase |
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AU2023200740A1 (en) | 2023-03-09 |
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JP6517197B2 (ja) | 2019-05-22 |
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JP6789542B2 (ja) | 2020-11-25 |
EP3057973A1 (en) | 2016-08-24 |
AU2021201332B2 (en) | 2022-11-10 |
EP3057973B1 (en) | 2019-09-04 |
US20230285402A1 (en) | 2023-09-14 |
AU2019202208A1 (en) | 2019-04-18 |
AU2014342811A1 (en) | 2016-05-12 |
US20170173028A1 (en) | 2017-06-22 |
CA2927730A1 (en) | 2015-05-07 |
EP3057973A4 (en) | 2017-04-05 |
AU2014342811B2 (en) | 2019-01-03 |
US20210106587A1 (en) | 2021-04-15 |
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