JP2018524353A - 可溶性エポキシド加水分解酵素およびペルオキシソーム増殖活因子活性化受容体の新規な二重調節因子を用いた糖尿病およびメタボリックシンドロームの治療 - Google Patents
可溶性エポキシド加水分解酵素およびペルオキシソーム増殖活因子活性化受容体の新規な二重調節因子を用いた糖尿病およびメタボリックシンドロームの治療 Download PDFInfo
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Abstract
Description
この出願は、2015年7月2日に出願された米国特許出願第62/188,010号の優先権を主張するものであり、前記仮出願の内容は参照により本明細書に組み込まれる。
本発明は、国立衛生研究所により授与された1R01DK103616−0A1に基づく政府の支援によってなされた。政府は本発明に一定の権利を有する。
本発明の材料および方法が記載される前に、本発明は、記載される特定の方法論、プロトコール、材料および試薬に限定されず、これらは変更され得ることが理解される。本明細書で使用する用語は、特定の実施態様のみを説明するためのものであり、後に提出される非仮出願によってのみ限定される本発明の範囲を限定するものではないことも理解されたい。
II.発明
X−YがCH=CまたはCH2−CHであり;R1はCH2CH3、CH3またはHであり;R3はフルオロ置換アリール基であり;またはその塩である。R3のフルオロ置換アリール基は、好ましくはトリフルオロメチルまたはトリフルオロメトキシ置換基を含むフェニル基であり、さらに好ましくはフェニル基のオルト位で置換されているフェニル基である。
であることを必要とする。
であることを必要とする。
III.実施例
[実施例1]N−ベンジルベンズアミド類:経口で利用可能な二重sEH/PPARγモジュレーターのための新規な融合足場
すべての抽出物、試薬および溶媒は、Alfa−Aesar GmbH&Co KG(ドイツ、カールスルーエ)、Sigma−Aldrich Chemie GmbH(ドイツ、ハノーバー)、Apollo Scientific Ltd(英国、マンチェスター)、JRD Fluorochemicals、Ltd.(サリー、英国)から購入し、さらに精製することなく使用した。これらメーカーは97%以上の純度を保証している。TLCは、Merk KGaA(ダルムシュタット、ドイツ)から購入したシリカ被覆アルミニウム箔(粒径60μm)によって行った。合成化合物の精製のために、Varian Medical Systems Deutschland GmbH社(ダルムシュタット、ドイツ)によるIntelli Flash 310クロマトグラフを使用した。SF25−80gとSF25−60gの2種類の充填カラムが使用されているが、どちらもシリカゲル(粒径50μm)が充填され、Varian Medical Systems Deutschland GmbH社(ダルムシュタット、ドイツ)から購入した。Burker(カールスルーエ、ドイツ)のDPX250およびAV400核磁気共鳴分光計で1H(250/400MHz)および13C(64MHz)を測定した。Burker(カールスルーエ、ドイツ)のプログラムTopSpinを用いて、すべてのスペクトルを分析した。内部標準としてテトラメチルシランを使用した。DMSO−d6およびメタノール−d3を溶媒として使用した。HPLCおよび質量分析は、CS Chromatography−Service GmbH(ランガーヴェーエ、ドイツ)のMultoHigh 100RP18,3μ、100×2mmカラムを使用して、Shimadzu(デュースブルク、ドイツ)のLCMS2020によって行った。溶離は、アセトニトリル/水の勾配20〜75%によって維持した。電子スプレーイオン化は陽性(+)および陰性(−)スペクトルを生じ、UVクロマトグラムは2つの波長(λ=254および280nm)を測定した。高分解能質量分析は、Thermo Scientific MALDI LTQ ORBITRAP XLにより実施した。全ての最終化合物は、HPLCで測定し95%以上の純度を有していた。
4−ホルミル安息香酸1g(6.7mmol)、トリエチルアミン0.9ml(6.7mmol)およびイソブチルクロロホルメート1ml(7.3mmol)をアルゴン雰囲気下、0℃でクロロホルム30mlに溶解した。1時間後、0.9ml(6.7mmol)の2−(トリフルオロメチル)ベンジルアミンを添加した。溶液を室温に温め、12時間撹拌した。反応混合物を20mlの2M HCl溶液、20mlの1M NaOH溶液で3回、20mlのブラインで1回洗浄した。有機層をMgSO4で乾燥し、溶媒を減圧下で除去した。粗生成物をEE/Hex混合物から再結晶した。白色固体が残った。
収率:1.43g(70%)。1HNMR(DMSO−d6):δ10.17(s,1H,Ph1−CHOH),9.38(t,J=5.9Hz,1H、Ph1−OCNH),9.08〜8.19(m,4H,CHO−Ph1)7.83−7.52(m,4H,OCNH−CH2−Ph2),4.75(d,J=5.6Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z342[M+Cl-]。
収率:0.99g(68%)。1HNMR(DMSO−d6):δ10.1(s,1H,Ph1−CHO),9.27(t,J=5.9Hz,1H,Ph1−OCNH),8.11−7.99(m,4H,CHO−Ph1)7.37−7.23(m,4H,OCNH−CH2−Ph2),4.52(d,J=5.8Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z240[M+H+]。
収率:1g(65%)。1HNMR(DMSO−d6):δ10.1(s,1H,Ph1−CHO),9.14(t,J=5.4Hz,1H,Ph1−OCNH),8.13−7.99(m,4H,CHO−Ph1),7.31−7.14(m,4H,OCNH−CH2−Ph2),4.49(d,J=5.6Hz,2H,Ph1−OCNH−CH2),2.34(s,3H,Ph2−CH3)ppm。MS−ESI:m/z254[M+H+]。
収率:1.16g(65%)1HNMR(DMSO−d6):δ10.14(s,1H,Ph1−CHO),9.28(t,J=6Hz,1H,Ph1−OCNH),8.13−8.02(m,4H,CHO−Ph1),7.5−7.28(m,4H,OCNH−CH2−Ph2),4.58(d,J=5.8Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z274[M+H+]。
収率:1.33g(69%);1HNMR(DMSO−d6):δ10.11(s,1H,Ph1−CHO),9.29(t,J=5.6Hz,1H,Ph1−OCNH),8.14−8.01(m,4H,CHO−Ph1),7.67−7.02(m,4H,OCNH−CH2−Ph2),4.55(d,J=5.8Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z319[M+H+]。
収率:1.18g(70%);1HNMR(DMSO−d6):δ10.11(s,1H,Ph1−CHO),9.27(t,J=5.7Hz,1H,Ph1−OCNH),8.11−8.02(m,4H,CHO−Ph1),7.51−7.37(m,4H,OCNH−CH2−Ph2),4.59(d,J=5.7Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z324[M+H+]。
収率:0.97g(70%);1HNMR(DMSO−d6):δ10.15(s,1H,Ph1−CHO),9.33(t,J=5.7Hz,1H,Ph1−OCNH),8.16−8.04(m,4H,CHO−Ph1),7.47−7.18(m,4H,OCNH−CH2−Ph2),4.54(d,J=5.9Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z258[M+H+]。
収率:1.3g(70%);1HNMR(DMSO−d6):δ10.1(s,1H,Ph1−CHO),9.37(t,J=5.9Hz,1H,Ph1−OCNH),8.12−8(m,4H,CHO−Ph1),7.74−7.54(m,4H,OCNH−CH2−Ph2),4.6(d,J=5.8Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z308[M+H+]。
収率:1.37g(70%);1HNMR(DMSO−d6):δ10.15(s,1H,Ph1−CHO),9.36(t,J=6Hz,1H,Ph1−OCNH),8.18−8.04(m,4H,CHO−Ph1),7.55−7.36(m,4H,OCNH−CH2−Ph2),4.58(d,J=6Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z324[M+H+]。
収率:1.3g(70%);1HNMR(DMSO−d6):δ10.14(s,1H,Ph1−CHO),9.24(t,J=5.5Hz,1H,Ph1−OCNH),8.15−8.03(m,4H,CHO−Ph1),7.34−6.93(m,4H,OCNH−CH2−Ph2),4.49(d,J=5.9Hz,2H,Ph1−OCNH−CH2)ppm.MS−ESI:m/z270[M+H+]。
収率:1.14g(69%);1HNMR(DMSO−d6):δ10.1(s,1H,Ph1−CHO),9.3(t,J=6.4Hz,1H,Ph1−OCNH),8.1−8.01(m,4H,CHO−Ph1),7.43−7.35(m,4H,OCNH−CH2−Ph2),4.5(d,J=6Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z274[M+H+]。
収率:1.39g(69%);1HNMR(DMSO−d6):δ10.1(s,1H,Ph1−CHO),9.26(t,J=5.9Hz,1H,Ph1−OCNH),8.17−7.99(m,4H,CHO−Ph1),7.42−6.96(m,9H,OCNH−CH2−Ph2+Ph2−O−Ph3),4.5(d,J=6Hz,2H,Ph1−OCNH−CH2)ppm。MS−ESI:m/z332[M+H+]。
収率:1.37g(67%);1HNMR(DMSO−d6):δ10.11(s,1H,Ph1−CHO),9.34(t,J=5.5Hz,1H,Ph1−OCNH),8.17−8.01(m,4H,CHO−Ph1),7.68−7.51(m,3H,OCNH−CH2−Ph2),4.66(d,J=5.5Hz,2H,Ph1−OCNH−CH2)ppm.MS−ESI:m/z326[M+H+]。
収率:1.41g(70%);1HNMR(DMSO−d6):δ10.09(s,1H,Ph1−CHO),9.23(t,J=5.9Hz,1H,Ph1−OCNH),8.1−8(m,4H,CHO−Ph1),7.48(d,J=9.5Hz,1H,OCNH−CH2−Ph2−3H),7.26−7.2(m,2H,OCNH−CH2−Ph2 -2,5H),4.6(d,J=5.7Hz,2H,Ph1−OCNH−CH2),3.81(s,1H,CH2−Ph2−4−OCH3)ppm.MS−ESI:m/z338[M+H+]。
収率:1.38g(70%);1HNMR(DMSO−d6):δ10.11(s,1H,Ph1−CHO),9.36(t,J=5.9Hz,1H,Ph1−OCNH),8.27−8.1(m,4H,CHO−Ph1),7.79−7.46(m,4H,OCNH−CH2−Ph2),4.71(d,J=5.8Hz,2H,Ph1−OCNH−CH2)ppm.MS−ESI:m/z308[M+H+]。
4−ヨード安息香酸1g(6.7mmol)、EDC1.5g(8mmol)およびDMAP0.16g(1.3mmol)を、アルゴン雰囲気下、25mlの乾燥DCM中で混合し、0℃で1時間懸濁液として撹拌した。次に0.9g(7.3mmol)の2−トリフルオロメチルベンジルアミンを一度に加えた。混合物を室温に温め、さらに24時間撹拌した。有機溶液を2M HCl溶液20mlで2回、ブライン20mlで1回洗浄した。有機溶媒をMgSO4で乾燥させ、次いで減圧下で除去した。粗生成物をEE/Hex混合物から再結晶し、白色固体を残した。
収率:0.89g(64%);1HNMR(DMSO−d6):δ9.38(t,J=6.3Hz,1H,Ph1−OCNH),8.11−8(m,4H,CHO−Ph1),7.79−7.48(m,4H,OCNH−CH2−Ph2),4.7(d,J=5.7Hz,2H,Ph1−OCNH−CH2)ppm.MS−ESI:m/z405[M+H+]。
収率:0.92g(65%);1HNMR(DMSO−d6):δ9.38(t,J=6.3Hz,1H,Ph1−OCNH),8.11−8(m,4H,CHO−Ph1),7.79−7.48(m,4H,OCNH−CH2−Ph2),4.7(d,J=5.7Hz,2H,Ph1−OCNH−CH2)ppm.MS−ESI:m/z305[M+H+]。
0℃のアルゴン雰囲気下、5mlの乾燥THF中の156mg(6.5mmol)のNaHの溶液に、1.2ml(4.9mmol)のトリエチル2−ホスホノブチラートをゆっくり加えた。30分後、乾燥混合物10ml中の4−ホルミル−N−(2−(トリフルオロメチル)ベンジル)ベンズアミド(1)1g(3.3mmol)の溶液を反応混合物に加え、2時間撹拌した。反応を停止させるために、水25mlを使用した。得られた混合物を10mlのEEで希釈した。有機層をブラインで3回洗浄し、MgSOで乾燥した。溶媒を減圧下で蒸発させた。EE/Hexからの再結晶後、白色固体が残った。収率:0.92g(70%);1HNMR(DMSO−d6):δ9.25(t,J=5.8Hz,1H,Ph2−OCNH),8.09−7.38(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.67(s,1H,OCNH−Ph1−CH),4.74(d,J=5.4Hz,2H,Ph1−OCNH−CH2),4.3(q,J=7.1Hz,2H,C−COO−CH2),2.4(q,J=6.9Hz,2H,CH−C−CH2),1.36(t,J=7.06Hz,3H,COO−CH2−CH3),1.18(t,J=7.38Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):13C−NMR(DMSO−d6):169.4,167.3,136.9,136.5,136.3,135.8,135.7,131.5,129.4,128.8,128.4,127.3,126.3,125.1,125,124.9,124.1,60.5,40.2,23.7,13.3,10ppm;HRMS:実測値m/z405.1550(理論値:405.1551)。
収率:0.92g(65%);1HNMR(DMSO−d6):δ9.12(t,J=6.1Hz,1H,Ph2−OCNH),7.98−7.21(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.33(s,1H,OCNH−Ph1−CH),4.5(d,J=5.7Hz,2H,Ph1−OCNH−CH2),4.23(q,J=7Hz,2H,C−COO−CH2),2.41(q,J=7Hz,2H,CH−C−CH2),1.3(t,J=7.8Hz,3H,COO−CH2−CH3),1.12(t,J=7.3Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):167.5,165.7,137.9,137.5,137.1,136.1,135.9,131.5,129,128.3,127.5,127.4,126.7,125.6,125.5,124.4,61.7,39.8,24.9,14.2,10.5ppm;HRMS:実測値m/z338.1752(理論値:338.1750)。
収率:0.9g(66%);1HNMR(DMSO−d6):δ9.1(t,J=6Hz,1H,Ph2−OCNH),7.7−7.21(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.2(s,1H,OCNH−Ph1−CH),4.3(d,J=5.7Hz,2H,Ph1−OCNH−CH2),4.18(q,J=6.9Hz,2H,C−COO−CH2),2.39(q,J=6.8Hz,2H,CH−C−CH2),2.41(s,3H,Ph2−CH3),1.25(t,J=7.7Hz,3H,COO−CH2−CH3),1.1(t,J=7.2Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):167.4,165.3,136.8,136.3,136.1,136,135.9,132.5,129,128.4,128.5,127.4,126.5,125.8,125.3,124.1,60.7,40.1,23.9,18.7,13.2,10.1ppm;HRMS:実測値m/z352.1907(理論値:352.1907)。エチル(E)−4−[N−((2−クロロ)ベンジル)ベンズアミド]−アルファ−エチルシンナマート(4a)。収率:0.87g(64%);1HNMR(DMSO−d6):δ9.15(t,J=5.8Hz,1H,Ph2−OCNH),8.02−7.27(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.4(s,1H,OCNH−Ph1−CH),4.57(d,J=5.7Hz,2H,Ph1−OCNH−CH2),4.24(q,J=7.2Hz,2H,C−COO−CH2),2.38(q,J=6.9Hz,2H,CH−C−CH2),1.3(t,J=7.5Hz,3H,COO−CH2−CH3),1.11(t,J=6.7Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):167.3,165.1,138.1,137.4,137.2,135.8,135.7,132.2,129.3,128.1,127.4,127.3,126.5,125.6,125.2,123.9,60.5,39.6,24.7,14.1,10ppm;HRMS:実測値m/z372.1363(理論値:372.1361)。
収率:0.85g(65%);1HNMR(DMSO−d6):δ9.19(t,J=5.8Hz,1H,Ph2−OCNH),8.06−7.23(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.2(s,1H,OCNH−Ph1−CH),4.58(d,J=5.6Hz,2H,Ph1−OCNH−CH2),4.29(q,J=7.3Hz,2H,C−COO−CH2),2.37(q,J=7Hz,2H,CH−C−CH2),1.35(t,J=6.8Hz,3H,COO−CH2−CH3),1.17(t,J=5.4Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):168.3,166.1,137.8,137.4,137.1,135.7,135.5,132.1,129.5,128.2,127.5,127.2,126.3,125.8,125.3,122.9,61.5,40.6,25.7,14.4,10.5ppm;HRMS:実測値m/z416.0855(理論値:416.0856)。
収率:0.86g(66%);1HNMR(DMSO−d6):δ9.1(t,J=5.8Hz,1H,Ph2−OCNH),7.96−7.33(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.4(s,1H,OCNH−Ph1−CH),4.69(d,J=5.5Hz,2H,Ph1−OCNH−CH2),4.3(q,J=7.2Hz,2H,C−COO−CH2),2.57(q,J=7.5Hz,2H,CH−C−CH2),1.37(t,J=7Hz,3H,COO−CH2−CH3),1.18(t,J=7.6Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):173.3,168.5,167.1,138.8,138.4,137.1,136.7,135.4,132.2,129.2,128.4,127.4,127.3,125.3,125.1,124.1,123.1,60.5,42.6,24.7,14.7,10.1ppm;HRMS:実測値m/z421.1501(理論値:421.1503)。
収率:0.93g(67%);1HNMR(DMSO−d6):δ9.18(t,J=6Hz,1H,Ph2−OCNH),8.02−7.18(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.66(s,1H,OCNH−Ph1−CH),4.53(d,J=6.1Hz,2H,Ph1−OCNH−CH2),4.28(q,J=7Hz,2H,C−COO−CH2),2.54(q,J=7.9Hz,2H,CH−C−CH2),1.34(t,J=7.11Hz,3H,COO−CH2−CH3),1.18(t,J=7.6Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):167.5,167.2,161.8,139.7,138.3,138.1,133.4,131.2,128.2,128.1,127.2,127,126.1,125.1,124.5,118.9,61.5,42.6,16.7,14.6,14.1ppm;HRMS:実測値m/z356.1657(理論値:356.1657)。
収率:0.92g(65%);1HNMR(DMSO−d6):δ9.23(t,J=6.5Hz,1H,Ph2−OCNH),7.99−7.53(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.62(s,1H,OCNH−Ph1−CH),4.59(d,J=6.3Hz,2H,Ph1−OCNH−CH2),4.24(q,J=7.4Hz,2H,C−COO−CH2),2.5(q,J=7.9Hz,2H,CH−C−CH2),1.3(t,J=7.4Hz,3H,COO−CH2−CH3),1.12(t,J=7.6Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):167.4,167,164.8,139.3,137.1,136.7,131.3,132.4,130.2,128.6,128.4,127.4,127.1,126.1,124.9,124.3,117.9,61.3,41.6,17.7,14.1,14ppm;HRMS:実測値m/z406.1626(理論値:406.1625)。
収率:0.83g(65%);1HNMR(DMSO−d6):δ9.14(t,J=5.9Hz,1H,Ph2−OCNH),7.99−7.27(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.42(s,1H,OCNH−Ph1−CH),4.5(d,J=5.4Hz,2H,Ph1−OCNH−CH2),4.21(q,J=7.2Hz,2H,C−COO−CH2),2.4(q,J=7.8Hz,2H,CH−C−CH2),1.27(t,J=7.3Hz,3H,COO−CH2−CH3),1.09(t,J=6.6Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):173.1,169,168.3,155.8,140.3,136.7,135.1,131.4,131.2,128.7,128.3,127.6,127.1,125.1,123.9,122.3,116.9,59.3,40.6,16.7,14.5,14.1ppm;HRMS:実測値m/z422.1574(理論値:422.1574)。
収率:0.91g(67%);1HNMR(メタノール−d3):δ7.8−6.6(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.5(s,1H,OCNH−Ph1−CH),4.41(s,2H,Ph1−OCNH−CH2),4.17(q,J=7Hz,2H,C−COO−CH2),3.67(s,Ph2−O−CH3),2.44(q,J=7.5Hz,2H,CH−C−CH2),1.24(t,J=7.6Hz,3H,COO−CH2−CH3),1.05(t,J=5Hz,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):167,166.3,140.4,138.3,135.7,135.1,131.7,130.3,128.7,128.5,127.3,127.1,124.2,123.1,122.1,115.9,58.3,55.1,40.1,16.5,14.6,14.1ppm;HRMS:実測値m/z367.1783(理論値:367.1784)。
収率:0.93g(69%);1HNMR(メタノール−d3):δ7.93−7.34(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.36(s,1H,OCNH−Ph1−CH),4.58(s,2H,Ph1−OCNH−CH2),4.3(q,J=7.5Hz,2H,C−COO−CH2),2.56(q,J=7.4Hz,2H,CH−C−CH2),1.37(t,J=7.5Hz,3H,COO−CH2−CH3),1.18(t,J=7.2Hz,3H,C−CH2−CH3)ppm;13C−NMR(メタノール−d3):166.6,165.3,154.4,137.4,136.1,135.5,131.6,130.2,129.1,128.6,126.9,126.8,125.3,123.1,122.8,115.9,59.3,40.2,16.1,14.6,14.1ppm;HRMS:実測値m/z371.1296(理論値:371.1298)。
収率:0.85g(69%);1HNMR(DMSO−d6):δ9.11(t,J=5.9Hz,1H,Ph1−OCNH),7.97−6.98(m,12H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph2−O−Ph3),7.4(s,1H,OCNH−Ph1−CH),4.49(d,J=6.5,2H,Ph1−OCNH−CH2),4.24(q,J=7.2Hz,2H,C−COO−CH2),2.45(q,J=7.3Hz,2H,CH−C−CH2),1.3(t,J=7.7Hz,3H,COO−CH2−CH3),1.12(t,J=7.8Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):166.1,164.2,156.6,155.4,137.4,136.1,135.5,131.6,130.2,129.1,128.7,128.6,128.3,126.9,126.8,125.3,123.1,122.8,121.5,118.1,118.7,115.9,59.3,40.2,16.2,14.5,14ppm;HRMS:実測値m/z430.2017(理論値:430.2013)。
収率:0.85g(70%);1HNMR(DMSO−d6):δ9.19(t,J=5.3Hz,1H,Ph2−OCNH),8−7.53(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.65(d,J=4.6Hz,2H,Ph1−OCNH−CH2),4.24(q,J=7Hz,2H,C−COO−CH2),2.48(q,J=8.5Hz,2H,CH−C−CH2),1.3(t,J=7.4Hz,3H,COO−CH2−CH3),1.13(t,J=7.1Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):175.4,165.3,141.9,136.3,135.3,135.1,132.6,132.5,129.4,128.8,128.2,126.1,126,125.3,125.1,124.8,124.1,60.4,40.1,24.6,14.1,11ppm;HRMS:実測値m/z424.1530(理論値:424.1530)。
収率:0.9g(70%);1HNMR(DMSO−d6):δ9.1(t,J=4.7Hz,1H,Ph2−OCNH),8.02−7.24(m,7H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.4(s,1H,OCNH−Ph1−CH),4.61(d,J=5.1Hz,2H,Ph1−OCNH−CH2),4.25(q,J=7.1Hz,2H,C−COO−CH2),2.45(q,J=7.7Hz,2H,CH−C−CH2),1.3(t,J=8.5Hz,3H,COO−CH2−CH3),1.12(t,J=7.2Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):168.4,166.3,158.9,136.4,136.3,135.9,135.6,132.5,129.4,128.8,128.2,126.3,126.1,125.3,125,124.8,124.1,60.1,55.3,40.1,23.6,13,11ppm;HRMS:実測値m/z436.1728(理論値:436.1730)。
収率:0.91g(70%);1HNMR(メタノール−d3):δ7.82−7.32(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.48(s,1H,OCNH−Ph1−CH),4.7(s,2H,Ph1−OCNH−CH2),4.18(q,J=7.22Hz,2H,COO−CH2),2.45(q,J=7.6Hz,2H,CH−C−CH2),1.25(t,J=7.1Hz,3H,COO−CH2−CH3),1.07(t,J=7.6Hz,3H,C−CH2−CH3)ppm;13C−NMR(メタノール−d3):169.9,169.4,138.5,137.5,137.4,135.8,133.5,133.2,130,129.8,128.5,128.3,127.1,127,125,124.8,124.1,62.1,41.3,21.7,14.6,14.1ppm;HRMS:実測値m/z405.1552(理論値:405.1553)。
収率:0.78g(67%);1HNMR(DMSO−d6):δ9.19(t,J=6Hz,1H,Ph2−OCNH),8−7.47(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),6.77(d,J=16.2Hz,1H,Ph1−CH−CH),4.69(d,J=5.7Hz,2H,Ph1−OCNH−CH2),4.33(q,J=7.5Hz,2H,CH−COO−CH2),1.28(t,J=7.4Hz,3H,COO−CH2−CH3)ppm;13C−NMR(DMSO−d6):170.9,168.4,137.5,136.5,136.4,135.8,132.5,131.2,130,129.6,128.4,128.1,127.5,127.3,125.1,124.8,124.2,62.3,41.1,14.1ppm;HRMS:実測値m/z378.1312(理論値:378.1312)。
収率:0.83g(65%);1HNMR(DMSO−d6):δ9.23(t,J=6Hz,1H,Ph2−OCNH),8.06−7.51(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.73(d,J=5.6Hz,2H,Ph1−OCNH−CH2),4.28(q,J=7.2Hz,2H,C−COO−CH2),3.37(d,J=2.1,3H,CH−C−CH3),1.34(t,J=7Hz,3H,COO−CH2−CH3)ppm;13C−NMR(DMSO−d6):168,165,139.5,136.4,136.3,135.8,129.5,129.1,128.9,127.4,127.1,126.5,126.3,125.9,125.1,124.4,124.2,59.9,42.1,13.7,11.9ppm;HRMS:実測値m/z392.1469(理論値:392.1468)。
収率:0.81g(65%);1HNMR(DMSO−d6):δ9.18(t,J=6Hz,1H,Ph2−OCNH),8−7.3(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.67(d,J=5.3Hz,2H,Ph1−OCNH−CH2),4.23(q,J=7.4Hz,2H,C−COO−CH2),2.49−2.3(m,2H,CH−C−CH2),1.56−1.47(m,2H,C−CH2−CH2),1.34(t,J=7Hz,3H,COO−CH2−CH3),0.9(t,J=7Hz,3H,CH2−CH2−CH3)ppm;13C−NMR(DMSO−d6):167,165.5,138.5,136.3,136.2,135.7,130.5,129.1,128.7,127.1,127,126.5,126.2,126.1,125.7,125,124.6,60,42.1,29,20.1,14.2,13.7ppm;HRMS:実測値m/z420.1780(理論値:420.1781)。
収率:0.62g(60%);1HNMR(DMSO−d6):δ9.06(t,J=6Hz,1H,Ph2−OCNH),7.98−7.15(m,14H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH+C−Ph4),4.62(d,J=6Hz,2H,Ph1−OCNH−CH2),4.23(q,J=6.6Hz,2H,C−COO−CH2),1.24(t,J=7.4Hz,3H,COO−CH2−CH3)ppm;13C−NMR(DMSO−d6):166.5,165.3,136.5,136.3,136.2,135.7,134.2,130.5,129.1,128.8,128.6,128.5,128.4,127.7,127.1,126.6,126.5,126.6,126.2,126.1,125.7,125,124.6,60,42.1,13.7ppm;HRMS:実測値m/z454.1622(理論値:454.1625)。
250mg(0.617mmol)の1aおよび炭素上パラジウム9.8mg(0.1mmol)を乾燥エタノールに溶解し、水素雰囲気下で12時間撹拌した。反応混合物をセライトで濾過し、溶媒を減圧下で除去した。さらに精製することなく、透明な樹脂状の油状物が生じた。
収率:0.2g(90%);1HNMR(DMSO−d6):δ9.1(t,J=5.8Hz,1H,Ph2−OCNH),7.91−7.34(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.71(d,J=5.5Hz,2H,Ph1−OCNH−CH2),4.11−4.01(m,2H,CH−COO−CH2),2.97−2.83(m,2H,Ph1−CH2),2.73−2.64(m,1H,Ph1−CH2−CH),1.65−1.56(m,2H,Ph1−CH2−CH−CH2),1.14(t,J=6.6Hz,3H,COO−CH2−CH3),0.93(t,J=7.4,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):175.5,168.8,143.8,137,132.6,132.04,131.9,128.2,127.1,127,125.7,125.6,125.5,125.4,124.9,60,49,39.8,37.7,25.2,13.2,10.5ppm;HRMS:実測値m/z408.1781(理論値:408.1781)。
収率:0.21g(84%);1HNMR(メタノール−d3):δ7.69−7.11(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.46(s,2H,Ph1−OCNH−CH2),3.98−3.88(m,2H,CH−COO−CH2),2.86−2.72(m,2H,Ph1−CH2),2.58−2.48(m,1H,Ph1−CH2−CH),1.62−1.47(m,2H,Ph1−CH2−CH−CH2),1.02(t,J=6.3Hz,3H,COO−CH2−CH3),0.83(t,J=8,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):175.5,168.6,143.6,138.8,132.4,128.8,128.1,127.1,127,126.8,125.6,125.5,125.4,125.3,60,49.1,43,37.7,25,13.3,10.7ppm;HRMS:実測値m/z340.191(理論値:340.1907)。
収率:0.19g(75%);1HNMR(DMSO−d6):δ8.85(t,J=5.7Hz,1H,Ph2−OCNH),7.85−7.15(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.46(d,J=6.2,2H,Ph1−OCNH−CH2),4.16−3.96(m,2H,CH−COO−CH2),2.92−2.77(m,2H,Ph1−CH2),2.68−2.59(m,1H,Ph1−CH2−CH),2.34(s,3H,Ph2−CH3),1.61−1.5(m,2H,Ph1−CH2−CH−CH2),1.09(t,J=7.5Hz,3H,COO−CH2−CH3),0.88(t,J=8.1,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):167.8,165.4,137.8,136.2,136,135.8,129,128.2,128.1,127.4,125.9,125.8,125.3,124.2,124,60.3,40.1,38.3,23.9,18.9,13.2,12.1ppm;HRMS:実測値m/z354.2065(理論値:354.2064)。
収率:0.2g(90%);1HNMR(メタノール−d3):δ7.83−7.26(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.61(s,2H,Ph1−OCNH−CH2),4.11−4(m,2H,CH−COO−CH2),3−2.84(m,2H,Ph1−CH2),2.71−2.62(m,1H,Ph1−CH2−CH),1.74−1.59(m,2H,Ph1−CH2−CH−CH2),1.15(t,J=6.8Hz,3H,COO−CH2−CH3),0.96(t,J=8.7,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):167.8,166.2,137.4,136.4,135.9,135.8,129.2,128.5,128.3,127.6,126.9,126.8,125.4,124.5,124,58.3,40,38.6,23.9,18.5,13.1,11.7 ppm;HRMS:実測値m/z375.1423(理論値:375.1422)。
収率:0.18g(70%);1HNMR(メタノール−d3):δ7.81−7.25(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.59(s,2H,Ph1−OCNH−CH2),4.09−4(m,2H,CH−COO−CH2),2.9−2.85(m,2H,Ph1−CH2),2.69−2.61(m,1H,Ph1−CH2−CH),1.72−1.58(m,2H,Ph1−CH2−CH−CH2),1.14(t,J=7.9Hz,3H,COO−CH2−CH3),0.95(t,J=8.1,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):176,167.5,144.9,130.2,129.5,128.5,128.4,128.2,127.2,127,126,125.7,125.6,125.5,61.4,50.4,44.4,39.1,26.6,14.5,11.9ppm;HRMS:実測値m/z418.1013(理論値:418.1012)。
収率:0.2g(90%);1HNMR(メタノール−d3):δ7.69−7.17(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.55(s,2H,Ph1−OCNH−CH2),3.97−3.89(m,2H,CH−COO−CH2),2.86−2.73(m,2H,Ph1−CH2),2.58−2.51(m,1H,Ph1−CH2−CH),1.61−1.47(m,2H,Ph1−CH2−CH−CH2),1.02(t,J=7Hz,3H,COO−CH2−CH3),0.84(t,J=7.6,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.5,175,166.5,145.1,133.5,132.6,130.4,130.3,129.9,128.6,128.4,127,125.8,125.6,61.4,50.5,44.4,39.1,26.5,14.7,12ppm;HRMS:実測値m/z423.1667(理論値:423.1665)。
収率:0.23g(91%);1HNMR(DMSO−d6):δ8.91(t,J=5.8Hz,1H,OCNH),7.75−7.03(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.37(d,J=6,2H,Ph1−OCNH−CH2),3.98−3.86(m,2H,CH−COO−CH2),2.84−2.69(m,2H,Ph1−CH2),2.6−2.48(m,1H,Ph1−CH2−CH),1.53−1.41(m,2H,Ph1−CH2−CH−CH2),1.01(t,J=7.4Hz,3H,COO−CH2−CH3),0.79(t,J=7.4,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):177.6,165.6,143.4,138.6,133.4,133.2,132.1,127.5,127.1,126.7,126.6,126.5,125.4,125.2,56,48.2,45,37.6,24,13.1,11.7ppm;HRMS:実測値m/z358.1814(理論値:358.1813)。
収率:0.23g(87%);1HNMR(メタノール−d3):δ7.7−7.17(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.54(s,2H,Ph1−OCNH−CH2),3.99−3.88(m,2H,CH−COO−CH2),2.87−2.72(m,2H,Ph1−CH2),2.59−2.49(m,1H,Ph1−CH2−CH),1.62−1.46(m,2H,Ph1−CH2−CH−CH2),1.03(t,J=7.5Hz,3H,COO−CH2−CH3),0.83(t,J=7.2,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):175.6,166.3,143.5,132.7,132.3,131.5,130.4,128.8,127.5,127.1,125.1,125.1,125,125,124.9,60,49,42.7,37.7,25.1,13.2,10.7ppm;HRMS:実測値m/z408.178(理論値:408.1781)。
収率:0.24g(94%);1HNMR(メタノール−d3):δ7.69−7.12(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.48(s,2H,Ph1−OCNH−CH2),3.98−3.88(m,2H,CH−COO−CH2),2.87−2.71(m,2H,Ph1−CH2),2.58−2.48(m,1H,Ph1−CH2−CH),1.64−1.42(m,2H,Ph1−CH2−CH−CH2),1.02(t,J=5.7Hz,3H,COO−CH2−CH3),0.84(t,J=7.4,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.8,175.6,168.6,143.8,138.2,132.1,130.2,130.3,128.8,128.7,127,125.3,125.2,125.1,120.7,60.1,49.2,42.5,37.7,25.2,13.1,10.6ppm;HRMS:実測値m/z424.1726(理論値:424.1730)。
収率:0.2g(90%);1HNMR(メタノール−d3):δ7.78−6.88(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.45(s,2H,Ph1−OCNH−CH2),4.1−3.98(m,2H,CH−COO−CH2),3.78(s,3H,Ph2−O−CH3),2.96−2.83(m,2H,Ph1−CH2),2.68−2.61(m,1H,Ph1−CH2−CH),1.73−1.56(m,2H,Ph1−CH2−CH−CH2),1.14(t,J=7.1Hz,3H,COO−CH2−CH3),0.95(t,J=7.5,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.1,160.5,144.9,133.8,132.2,130.1,129.9,128.4,127.2,127,125.3,125.2,125.1,114.9,61.4,55.8,44,39.1,37.7,26.6,14.6,11.9ppm;HRMS:実測値m/z370.2017(理論値:370.2013)。
収率:0.2g(91%);1HNMR(メタノール−d3):δ7.68−7.12(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.46(s,2H,Ph1−OCNH−CH2),3.98−3.87(m,2H,CH−COO−CH2),2.85−2.73(m,2H,Ph1−CH2),2.57−2.5(m,1H,Ph1−CH2−CH),1.62−1.45(m,2H,Ph1−CH2−CH−CH2),1.02(t,J=7.1Hz,3H,COO−CH2−CH3),0.83(t,J=7.4,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177,164.1,145,140.2,130.2,129.5,128.5,128.5,128.4,127,125.5,125.3,125.1,114.4,61.4,50.5,44.5,39,26.6,14.5,12.1ppm;HRMS:実測値m/z374.1518(理論値:374.1518)。
収率:0.2g(90%);1HNMR(メタノール−d3):δ7.68−7.12(m,13H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.46(s,2H,Ph1−OCNH−CH2),3.98−3.87(m,2H,CH−COO−CH2),2.85−2.73(m,2H,Ph1−CH2),2.57−2.5(m,1H,Ph1−CH2−CH),1.62−1.45(m,2H,Ph1−CH2−CH−CH2),1.02(t,J=7.1Hz,3H,COO−CH2−CH3),0.83(t,J=7.4,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):175.7,168.5,157.4,156.5,143.7,136.1,134,132.4,130.2,129.5,128.8,128.7,127,126.9,126.8,125.3,123.1,122,121.5,118.5,118.3,115.9,60.1,42.2,25.2,13.2,10.5ppm;HRMS:実測値m/z370.2017(理論値:370.2013)。
収率:0.2g(90%);1HNMR(メタノール−d3):δ7.83−7.18(m,7H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.63(s,2H,Ph1−OCNH−CH2),4.01−3.86(m,2H,CH−COO−CH2),2.88−2.72(m,2H,Ph1−CH2),2.59−2.49(m,1H,Ph1−CH2−CH),1.65−1.43(m,2H,Ph1−CH2−CH−CH2),1.03(t,J=7.04Hz,3H,COO−CH2−CH3),0.84(t,J=7.7,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):175.6,168.8,163,159.7,143.8,133.1,131.9,131,130.9,128.9,127.1,118.9,118.6,113.3,112.9,60,49.1,39.3,37.4,25.2,13,10.6ppm;HRMS:実測値m/z426.1686(理論値:426.1687)。
収率:0.2g(90%);1HNMR(メタノール−d3):δ7.71−7.02(m,7H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.59(s,2H,Ph1−OCNH−CH2),4.01−3.86(m,2H,CH−COO−CH2),3.74(s,3H,Ph2−O−CH3),2.87−2.72(m,2H,Ph1−CH2),2.59−2.49(m,1H,Ph1−CH2−CH),1.65−1.43(m,2H,Ph1−CH2−CH−CH2),1.03(t,J=7Hz,3H,COO−CH2−CH3),0.84(t,J=7.3,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):175.7,168.8,158.8,151.2,143.9,132.1,130.3,128.8,128.7,128.6,128.3,127.2,116.7,111.8,111.7,67.9,59.9,55.1,39.5,37.9,25.1,13.2,10.8ppm;HRMS:実測値m/z438.1882(理論値:438.1887)。
収率:0.14g(55%);1HNMR(メタノール−d3):δ7.65−7.27(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.69(s,2H,Ph1−OCNH−CH2),3.93(q,J=7.2,2H,CH−COO−CH2),2.87−2.74(m,2H,Ph1−CH2),2.59−2.51(m,1H,Ph1−CH2−CH),1.64−1.46(m,2H,Ph1−CH2−CH−CH2),1.01(t,J=7.1Hz,3H,COO−CH2−CH3),0.84(t,J=7.4Hz,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.1,168.8,141.6,140.5,135.4,133.5,133.5,129.7,129.1,128.5,127.1,126.5,125.5,125.4,124.9,61.5,50.7,39.8,39.2,26.5,14.6,12.1ppm;HRMS:実測値m/z408.1781(理論値:408.1781)。
収率:0.24g(95%);1HNMR(DMSO−d6):δ9.1(t,J=5.8Hz,1H,OCNH),7.94−7.35(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.71(d,J=6.2Hz,2H,Ph1−OCNH−CH2),4.1(q,J=7Hz,2H,CH2−COO−CH2),2.97(t,J=7.6Hz,2H,Ph1−CH2),2.71(t,J=7.1Hz,2H,Ph1−CH2−CH2),1.21(t,J=7Hz,3H,COO−CH2−CH3)ppm;13C−NMR(DMSO−d6):177.1,168.8,141.6,140.5,135.4,133.5,133.5,129.7,129.1,128.5,127.1,126.5,125.5,125.4,124.9,61.5,50.7,39.8,39.2ppm;HRMS:実測値m/z380.1468(理論値:380.1468)。
収率:0.2g(93%);1HNMR(DMSO−d6):δ9.04(t,J=6Hz,1H,OCNH),7.86−7.27(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.65(d,J=5.5Hz,2H,Ph1−OCNH−CH2),4.01(q,J=6.8Hz,2H,CH−COO−CH2),3−2.88(m,1H,Ph1−CH2−CH),2.82−2.7(m,2H,Ph1−CH2),1.14−1.05(m,6H,COO−CH2−CH3+CH2−CH−CH3)ppm;13C−NMR(DMSO−d6):177.4,166.8,143.5,140.5,133.1,132.5,131.5,129.7,129.3,128.6,127.8,126.5,125.5,125.4,124.9,60.2,50.7,39.8,39.2,17.2,14.6ppm;HRMS:実測値m/z394.1625(理論値:394.1525)。
収率:0.17g(66%);1HNMR(DMSO−d6):δ9.06(t,J=5.75Hz,1H,OCNH),7.85−7.28(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.65(d,J=4.25Hz,2H,Ph1−OCNH−CH2),3.99(q,J=7.3Hz,2H,CH−COO−CH2),3.07−2.9(m,2H,Ph1−CH2),2.82−2.76(m,1H,Ph1−CH2−CH),1.61−1.39(m,2H,Ph1−CH2−CH−CH2),1.07(t,J=7.2Hz,3H,COO−CH2−CH3),1.35−1.16(m,2H,Ph1−CH2−CH−CH2−CH2),0.85(t,J=7.13Hz,3H,CH−CH2-CH2−CH3)ppm;13C−NMR(DMSO−d6):175,166.7,143.5,138.1,132.9,132.4,131.5,129.7,129.2,128.6,127.7,126.2,125.5,125.4,124.9,42.7,38.1,34.6,34.4,20.3,14.5,14.2ppm;HRMS:実測値m/z422.1936(理論値:422.1937)。
収率:0.1g(40%);1HNMR(DMSO−d6):δ9.02(t,J=6Hz,1H,OCNH),7.81−7.24(m,13H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+CH2−CH−Ph4),4.63(d,J=5.5Hz,2H,Ph1−OCNH−CH2),4.08−3.92(m,2H,CH−COO−CH2),3.4−3.31(m,2H,Ph1−CH2),3.11−3.03(m,1H,Ph1−CH2−CH),1.07(t,J=7.1Hz,3H,COO−CH2−CH3)ppm;13C−NMR(DMSO−d6):173,166.8,143.1,139,138.2,138.1,133.1,132.5,129.4,129,128.6,128.3,127.7,127.7,127.7,126.6,126.5,126.6,126.2,126.1,125.7,125,124.6,60.9,19,14.5ppm;HRMS:実測値m/z456.1785(理論値:456.1781)。
100mg(0.2mmol)エチル(E)−4−[N−((2−トリフルオロメチル)ベンジル)ベンズアミド]−アルファ−エチルシンナマート(1a)および69mg(1.2mmol)を2mlのTHFの混合物に溶解した。H2O/MeOHを1:2:1の比率で混合し、70℃および35ワットで30分間マイクロ波中で撹拌した。有機層を減圧下で除去した。水層をH2O1mlで希釈し、12MのHCl溶液で酸性化し、4℃で保存した。純粋な生成物が沈殿し、それ以上精製する必要はなかった。収率:0.06g(60%);1HNMR(DMSO−d6):δ12.71(s,1H,COOH),9.24(t,J=5.9Hz,1H,Ph2−OCNH),8.06−7.47(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.74(d,J=5.2Hz,2H,Ph1−OCNH−CH2),2.51(q,J=8Hz,2H,CH−C−CH2),1.17(t,J=7.5Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):169.8,168.4,139.3,137,136.7,133.5,132.1,128.9,128.3,127.9,127.7,127.3,127.1,127,126.9,125.7,125.6,40,20.4,12.8ppm;HRMS:実測値m/z378.1312(理論値:378.1313)。
収率:0.06g(65%);1HNMR(DMSO−d6):δ12.61(s,1H,COOH),9.11(t,J=5.9Hz,1H,Ph2−OCNH),7.99−7.22(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.33(s,1H,Ph1−CH),4.5(d,J=6.1Hz,2H,Ph1−OCNH−CH2),2.47(q,J=7.7Hz,2H,CH−C−CH2),1.11(t,J=7.2Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):168.9,165.7,139.7,138,136.4,136.3,128.9,128.3,127.5,127.2,126.7,125.2,125.1,124,123.5,123,42.7,20.3,13.3ppm;HRMS:実測値m/z310.1438(理論値:310.1438)。
収率:0.02g(19%);1HNMR(DMSO−d6):δ12.62(s,1H,COOH),8.97(t,J=5.8Hz,1H,Ph2−OCNH),7.98−7.13(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),7.17(s,1H,Ph1−CH),4.48(d,J=5.7Hz,2H,Ph1−OCNH−CH2),2.48(q,J=8.5Hz,2H,CH−C−CH2),2.34(s,3H,Ph2−CH3),1.12(t,J=7.1Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):169.8,168.1,139.1,137,136.6,136,135.9,133.9,129.9,128.9,128.6,127.9,127.4,127.2,126.9,126.9,41.4,20.3,18.7,12.8ppm;HRMS:実測値m/z324.1595(理論値:324.1594)。
収率:0.06g(62%);1HNMR(DMSO−d6):δ12.69(s,1H,COOH),9.17(t,J=6Hz,1H,Ph2−OCNH),8.05−7.35(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.62(d,J=5.8Hz,2H,Ph1−OCNH−CH2),2.5(q,J=6.4Hz,2H,CH−C−CH2),1.17(t,J=7.2Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):169.8,168.3,139.2,137,136.6,135.7,133.7,132.9,129.1,128.9,128.6,128.4,127.9,127.3,126.9,126.4,41.2,20.3,12.7ppm;HRMS:実測値m/z344.1052(理論値:344.1048)。
収率:0.06g(61%);1HNMR(DMSO−d6):δ12.68(s,1H,COOH),9.18(t,J=5.7Hz,1H,Ph2−OCNH),8.08−7.26(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.58(d,J=5.4Hz,2H,Ph1−OCNH−CH2),2.5(q,J=8.2Hz,2H,CH−C−CH2),1.18(t,J=7Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):169.8,168.3,139.2,137.2,137,136.6,133.7,132.4,128.9,128.6,127.9,127.4,127.3,126.9,125.6,122.7,43.7,20.4,12.8ppm;HRMS:実測値m/z388.0544(理論値:388.0543)。
収率:0.06g(65%);1HNMR(DMSO−d6):δ12.71(s,1H,COOH),9.15(t,J=6.7Hz,1H,Ph2−OCNH),8.03−7.4(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.62(d,J=5.9Hz,2H,Ph1−OCNH−CH2),2.51(q,J=6.9Hz,2H,CH−C−CH2),1.16(t,J=7.9Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):171.3,169.2,166.5,166.4,149.7,146.6,138.8,136.9,134.1,133.1,132.2,129.7,129.5,129.1,128.2,128,128,37.7,20.8,14.1ppm;HRMS:実測値m/z394.1261(理論値:394.1261)。
収率:0.07g(70%);1HNMR(DMSO−d6):δ12.63(s,1H,COOH),9.12(t,J=6.3Hz,1H,Ph2−OCNH),7.97−7.12(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.48(d,J=5.6Hz,2H,Ph1−OCNH−CH2),2.44(q,J=8.9Hz,2H,CH−C−CH2),1.11(t,J=6.9Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):169.8,168.1,139.1,137,136.6,134.9,133.8,129.1,129,128.9,127.9,127.2,126.8,125.6,114.9,114.6,42.4,20.3,12.7ppm;HRMS:実測値m/z328.1345(理論値:328.1344)。
収率:0.05g(50%);1HNMR(メタノール−d3):δ8.08−7.29(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.7(s,2H,Ph1−OCNH−CH2),2.57(q,J=7.5Hz,2H,CH−C−CH2),1.22(t,J=7.2Hz,3H,C−CH2−CH3)ppm;13C−NMR(メタノール−d3):167.2,166.5,144.2,138.4,138.1,137,136.5,133.8,133.6,132.2,129.6,129.4,128.6,128.5,127.1,127,126.8,29.5,19.4,12.6ppm;HRMS:実測値m/z377.1245(理論値:377.1246)。
収率:0.07g(69%);1HNMR(メタノール−d3):δ7.96−7.24(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.64(s,2H,Ph1−OCNH−CH2),2.56(q,J=7.4Hz,2H,CH−C−CH2),1.19(t,J=9.6Hz,3H,C−CH2−CH3)ppm;13C−NMR(メタノール−d3):169.7,168.2,165.5,145.2,139.2,138.2,137,136.6,134.1,133.7,132.2,129.7,129.5,129.1,128.2,128,120.8,28.5,20.4,12.7ppm;HRMS:実測値m/z394.1258(理論値:394.1261)。
収率:0.06g(64%);1HNMR(DMSO−d6)δ12.51(s,1H,COOH),8.93(t,J=6.2Hz,1H,Ph2−OCNH),7.87−6.78(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.33(d,J=5.7Hz,2H,Ph1−OCNH−CH2),3.64(s,3H,Ph2−O−CH3),2.36(q,J=7.9Hz,2H,CH−C−CH2),1.01(t,J=7.1Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):169.8,168,159,139,137,136.5,133.9,130.8,128.9,128.7,128.5,128.5,127.9,127.2,126.8,113.5,54.3,46.8,20.3,12.7ppm;HRMS:実測値m/z340.1544(理論値:340.1543)。
収率:0.06g(66%);1HNMR(DMSO−d6)δ12.54(s,1H,COOH),9.03(t,J=5.8Hz,1H,Ph2−OCNH),7.87−7.23(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.39(d,J=6.1Hz,2H,Ph1−OCNH−CH2),2.37(q,J=7.4Hz,2H,CH−C−CH2),1.01(t,J=7.6Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):168.7,166.1,137.1,137,135.6,133.9,133.6,129.4,129.2,128.9,128,127.6,126.4,125.4,114.8,114.6,37.4,21.3,12.7ppm;HRMS:実測値m/z344.1045(理論値:344.1048)。
収率:0.02g(16%);1HNMR(メタノール−d3)δ7.96−6.95(m,14H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH+Ph2−O−Ph3),4.6(s,2H,Ph1−OCNH−CH2),2.56(q,J=7.1Hz,2H,CH−C−CH2),1.2(t,J=7.5Hz,3H,C−CH2−CH3)ppm;13C−NMR(メタノール−d3):169.8,168.1,157.4,155.4,139.1,137,136.5,133.9,133.8,133.8,129.5,128.9,128.8,127.9,127.2,126.9,122.9,122.8,121.5,118.5,118.3,115.9,42.8,20.3,12.8ppm;HRMS:実測値m/z402.1696(理論値:402.1699)。
収率:0.06g(60%);1HNMR(メタノール−d3)δ8.11−7.36(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.79(s,2H,Ph1−OCNH−CH2),2.57(q,J=7.43Hz,2H,CH−C−CH2),1.2(t,J=7.4Hz,3H,C−CH2−CH3)ppm;13C−NMR(メタノール−d3):169.7,168.4,141.9,139.4,136.9,136.7,133.5,131.2,131,128.9,128.2,127.3,126,125.3,125.1,124.8,124.1,39.4,20.4,12.8ppm;HRMS:実測値m/z396.1215(理論値:396.1217)。
収率:0.05g(55%);1HNMR(メタノール−d3)δ7.97−6.65(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.75(s,2H,Ph1−OCNH−CH2),3.87(s,3H,Ph2−CH3),2.57(q,J=7.6Hz,2H,CH−C−CH2),1.2(t,J=7.4Hz,3H,C−CH2−CH3)ppm;13C−NMR(メタノール−d3):169.7,168.3,158.9,139.3,137.1,136.6,133.6,130.5,128.9,128.1,127.9,127.3,126.9,126.1,116.7,112,111.8,54.7,20.3,12.6ppm;HRMS:実測値m/z408.1415(理論値:408.1417)。
収率:0.05g(50%);1HNMR(DMSOl−d6):δ12.66(s,1H,COOH),9.22(t,J=5.8,1H,OCNH),8.02−7.47(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+OCNH−Ph1−CH),4.73(d,J=6,2H,Ph1−OCNH−CH2),2.54−2.43(m,2H,CH−C−CH2),1.17(t,J=7.2Hz,3H,C−CH2−CH3)ppm;13C−NMR(DMSO−d6):170,165,137.5,137,136,135.6,133.4,133,130,129.4,128.3,128.3,127.2,127,124.9,124.8,124.1,38.2,20.1,14.2ppm;HRMS:実測値m/z377.3571(理論値:377.3572)。
収率:0.07g(72%);1HNMR(DMSO−d6):δ12.4(s,1H,COOH),9.1(t,J=5.5Hz,1H,Ph2−OCNH),7.91−7.38(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),6.58(d,J=16Hz,1H,H),4.6(d,J=5.7Hz,2H,Ph1−OCNH−CH2)ppm;13C−NMR(DMSO−d6):169.8,168.3,139.3,137,136.7,133.5,132.1,128.9,128.3,127.9,127.3,127.1,127,126.9,126.7,125.7,125.6,40ppm;HRMS:実測値m/z350.1(理論値:350.1)。
収率:0.07g(71%);1HNMR(DMSO−d6):δ12.62(s,1H,COOH),9.23(t,J=5.8Hz,1H,Ph2−OCNH),8.06−7.51(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.74(d,J=5.6Hz,2H,Ph1−OCNH−CH2),2.12(d,J=1.4,3H,CH−C−CH3)ppm;13C−NMR(DMSO−d6):169.1,166,138.6,137.5,136.7,134.9,133.5,132.7,130.2,130,130,129.6,128.2,127.5,127.4,127.3,126.8,41.1,12.3ppm;HRMS:実測値m/z364.1158(理論値:364.1155)。
収率:0.02g(18%);1HNMR(DMSO−d6):δ12.67(s,1H,COOH),9.17(t,J=5.9Hz,1H,Ph2−OCNH),8.05−7.41(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH),4.69(d,J=5.2Hz,2H,Ph1−OCNH−CH2),2.55−2.33(m,2H,CH−C−CH2),1.6−1.42(m,2H,C−CH2−CH2),0.91(t,J=7.7Hz,3H,CH2−CH2−CH3)ppm;13C−NMR(DMSO−d6):168.9,166,138.5,137.5,137.4,136.8,135.1,133.8,133.5,132.7,129.3,129,128.5,128.2,127.6,127.3,125.9,42.1,29,18.4,14ppm;HRMS:実測値m/z392.1471(理論値:392.1468)。
収率:0.02g(17%);1HNMR(DMSO−d6):δ8.94(t,J=5.8Hz,1H,Ph2−OCNH),7.79−6.91(m,14H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH+C−Ph4),4.54(d,J=5.5Hz,2H,Ph1−OCNH−CH2)ppm;13C−NMR(DMSO−d6):166.2,155.5,129.6,129.2,129,128.9,128.3,128.2,128.1,128,128,128,127.5,127.2,126.9,126.2,125.8,125.8,126.1,126,125.3,125,124.6,41ppm;HRMS:実測値m/z426.1309(理論値:426.1312)。
収率:0.06g(60%);1HNMR(DMSO−d6):δ12.2(s,COOH),9.1(t,J=5.9Hz,1H,Ph2−OCNH),7.93−7.36(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.72(d,2H,J=5.6Hz,Ph1−OCNH−CH2),2.98−2.78(m,2H,CH2−CH−CH2),2.59−2.5(m,1H,Ph1−CH2−CH),1.64−1.53(m,Ph1−CH2),0.94(t,J=7.4Hz,CH−CH2−CH3)ppm.13C−NMR(DMSO−d6):177.6,168.9,144.1,137.1,132.1,131.9,128.8,128.1,127,127.4,125.7,125.6,125.5,125.4,122.8,49,39.8,37.6,24.9,10.5ppm;HRMS:m/z380.1469(理論値:380.1468)。
収率:0.05g(55%);1HNMR(メタノール−d3):δ7.83−6.92(m,9H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.46(s,2H,Ph1−OCNH−CH2),2.89−2.67(m,2H,Ph1−CH2),2.51−2.42(m,1H,Ph1−CH2−CH),1.62−1.39(m,2H,Ph1−CH2−CH−CH2),0.85(t,J=7.6,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):178.2,168.7,144.1,138.9,132.1,128.8,128.8,128.1,128.1,127.1,127.1,127,127,126.7,49.5,43.1,37.8,25.2,10.7ppm;HRMS:実測値m/z312.1601(理論値:312.1594)。
収率:0.02g(20%);1HNMR(メタノール−d3):δ8.01−7.03(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.47(s,2H,Ph1−OCNH−CH2),2.91−2.69(m,2H,Ph1−CH2),2.55−2.45(m,1H,Ph1−CH2−CH),2.26(s,3H,Ph2−CH3),1.63−1.42(m,2H,Ph1−CH2−CH−CH2),0.86(t,J=7.4,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):176.1,167.3,166.1,145.1,143.2,137.3,135.6,132.3,129.8,129.3,129,128.7,127.3,126.6,125.6,48.1,37.2,24.7,18.5,11.4ppm;HRMS:実測値m/z326.1752(理論値:326.1751)。
収率:0.05g(50%);1HNMR(メタノール−d3):δ7.68−7.1(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.46(s,2H,Ph1−OCNH−CH2),2.89−2.69(m,2H,Ph1−CH2),2.54−2.44(m,1H,Ph1−CH2−CH),1.63−1.41(m,2H,Ph1−CH2−CH−CH2),0.86(t,J=7.6,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.6,168.7,143.8,138.9,132.2,128.8,128.8,128.1,128.1,127.1,127,126.9,126.8,126.5,49,43.1,37.5,25,10.6ppm;HRMS:実測値m/z346.1206(理論値:346.1205)。
収率:0.05g(51%);1HNMR(DMSO−d6):δ12.12(s,1H,COOH),8.96(t,J=6.1Hz,1H,Ph2−OCNH),7.81−7.19(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.46(d,J=6.1,2H,Ph1−OCNH−CH2),2.9−2.71(m,2H,Ph1−CH2),2.6−2.5(m,1H,Ph1−CH2−CH),1.6−1.41(m,2H,Ph1−CH2−CH−CH2),0.87(t,J=7.6,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):176.4,166.5,143.7,140.2,132.7,129.2,128.7,128.1,128.1,127.7,127.6,126.9,126.8,126.5,48.5,40.5,39.7,25.1,11.9ppm;HRMS:実測値m/z390.07(理論値:390.0699)。
収率:0.07g(66%);1HNMR(DMSO−d6):δ12.18(s,1H,COOH),9.03(t,J=6Hz,1H,Ph2−OCNH),7.88−7.26(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.53(d,J=6,2H,Ph1−OCNH−CH2),2.96−2.76(m,2H,Ph1−CH2),2.63−2.59(m,1H,Ph1−CH2−CH),1.64−1.5(m,2H,Ph1−CH2−CH−CH2),0.9(t,J=7.6,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):177.5,176.4,166.5,143.7,140.2,133.1,132.7,129.2,129,128.7,127.7,127.6,127.1,126.8,126.5,48.5,40.3,39.1,26.5,11.9ppm;HRMS:実測値m/z396.1417(理論値:396.1417)。
収率:0.05g(50%);1HNMR(メタノール−d3):δ7.68−6.91(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.43(s,2H,Ph1−OCNH−CH2),2.89−2.69(m,2H,Ph1−CH2),2.54−2.44(m,1H,Ph1−CH2−CH),1.62−1.41(m,2H,Ph1−CH2−CH−CH2),0.86(t,J=7.4,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.6,168.7,163.7,160.5,143.9,135,135,132.1,129.1,129,129,127,114.9,114.6,49.1,42.4,37.6,25,10.6ppm;HRMS:実測値m/z330.1503(理論値:330.15)。
収率:0.05g(53%);1HNMR(メタノール−d3):δ7.7−7.1(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.61(s,2H,Ph1−OCNH−CH2),3.03−2.82(m,2H,Ph1−CH2),2.66−2.56(m,1H,Ph1−CH2−CH),1.76−1.53(m,2H,Ph1−CH2−CH−CH2),0.99(t,J=8.3,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.5,168.8,144,132.5,132.2,132.1,131.1,129.1,129,127.5,127,125,125,124.9,124.6,49,47.4,37.5,25,10.6ppm;HRMS:実測値m/z380.1467(理論値:380.1468)。
収率:0.06g(60%);1HNMR(メタノール−d3):δ7.82−7.24(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.61(s,2H,Ph1−OCNH−CH2),3.03−2.82(m,2H,Ph1−CH2),2.66−2.56(m,1H,Ph1−CH2−CH),1.76−1.53(m,2H,Ph1−CH2−CH−CH2),0.99(t,J=8.3,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):178,175.6,168.7,148.1,144.1,138.3,132,128.8,128.7,128.5,127,125.3,125.2,125.1,120.7,49.3,47,37.6,25,10.6ppm;HRMS:実測値m/z396.1416(理論値:396.1417)。
収率:0.06g(62%);1HNMR(DMSO−d6):δ12.19(s,1H,COOH),8.95(t,J=6.7Hz,1H,Ph2−OCNH),7.86−6.91(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.45(d,J=5.8,2H,Ph1−OCNH−CH2),3.78(s,3H,Ph2−O−CH3),2.96−2.77(m,2H,Ph1−CH2),2.63−2.6(m,1H,Ph1−CH2−CH),1.64−1.49(m,2H,Ph1−CH2−CH−CH2),0.93(t,J=7.6,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):176.4,166.4,158.6,143.6,132.8,132.2,129.1,129,127.6,127,125.3,125.2,125.1,114.1,55.5,42.4,40.8,37.5,25.1,11.9ppm;HRMS:実測値m/z342.17(理論値:342.17)。
収率:0.05g(50%);1HNMR(DMSO−d6):δ12.13(s,1H,COOH),8.97(t,J=6Hz,1H,Ph2−OCNH),7.83−7.27(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.53(d,J=6.4,2H,Ph1−OCNH−CH2),2.9−2.71(m,2H,Ph1−CH2),2.57−2.52(m,1H,Ph1−CH2−CH),1.58−1.43(m,2H,Ph1−CH2−CH−CH2),0.88(t,J=7.1,3H,CH−CH2−CH3)ppm;13C−NMR(DMSO−d6):176.4,166.7,146.6,143.9,132.4,132.4,129.6,129.2,129.1,128,127.7,125.2,125.1,121.1,48.5,39.4,37.5,25.1,11.9ppm;HRMS:実測値m/z346.1206(理論値:346.1205)。
収率:0.03g(30%);1HNMR(メタノール−d3):δ7.69−6.82(m,13H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.44(s,2H,Ph1−OCNH−CH2),2.89−2.69(m,2H,Ph1−CH2),2.54−2.44(m,1H,Ph1−CH2−CH),1.62−1.41(m,2H,Ph1−CH2−CH−CH2),0.85(t,J=7.6,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.5,168.6,157.4,156.4,133.9,132.4,132.2,129.4,128.8,128.7,127,126.9,126.8,125.3,123.1,122.9,121.5,118.5,118.3,118,47.6,42.2,37.5,25,10.6ppm;HRMS:実測値m/z404.1858(理論値:404.1856)。
収率:0.05g(50%);1HNMR(メタノール−d3):δ7.84−7.18(m,7H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.64(s,2H,Ph1−OCNH−CH2),2.91−2.71(m,2H,Ph1−CH2),2.55−2.45(m,1H,Ph1−CH2−CH),1.64−1.42(m,2H,Ph1−CH2−CH−CH2),0.86(t,J=7.6,3H,CH−CH2−CH3)ppm;13C−NMR(メタノール−d3):177.5,168.9,159.7,144.8,143.1,133.1,131.8,131,131,128.8,127.1,118.8,118.6,112.9,112.9,60,46.7,37.5,25,10.6ppm;HRMS:実測値m/z398.137(理論値:398.1374)。
収率:0.7g(79%);1HNMR(DMSO−d6):δ12.15(s,CH2−CH−COOH),8.97(t,J=5.6Hz,1H,Ph2−OCNH),7.87−7.2(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.58(d,2H,J=5.5,Ph1−OCNH−CH2),3.81(s,3H,Ph2−O−CH3),2.94−2.72(m,2H,CH2−CH−CH2),2.9−2.72(m,1H,Ph1−CH2−CH),1.57−1.46(m,Ph1−CH2),0.9(t,J=7.5Hz,CH−CH2−CH3)ppm.13C−NMR(DMSO−d6):176.8,166.8,158.5,144.3,132.4,130.8,129.6,129.3,128,127.8,127.4,126.5,122.8,118.2,112.1,56.3,50.5,48.4,37.5,25.1,11.8ppm;HRMS:m/z410.1572(理論値:410.1573)。
率:0.06g(60%);1HNMR(DMSO−d6):δ12.15(s,COOH),9.13(t,J=5.5Hz,1H,Ph2−OCNH),7.85−7.43(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.72(d,2H,J=5.1Hz,Ph1−OCNH−CH2),2.99−2.78(m,2H,CH2−CH−CH2),2.66−2.6(m,1H,Ph1−CH2−CH),1.66−1.5(m,Ph1−CH2),0.95(t,J=7.3Hz,CH−CH2−CH3)ppm.13C−NMR(DMSO−d6):176.5,167,140.5,138.2,134.4,133.1,132.4,128.7,128.7,128.2,127.7,126.2,126.1,125.6,122.8,48.7,39.4,37.6,25.1,11.9ppm,HRMS:実測値m/z380.1473(理論値:380.1468)。
収率:0.05g(50%);1HNMR(DMSO−d6):δ12.21(s,1H,COOH),9.04(t,J=6.8Hz,1H,OCNH),7.86−7.34(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.65(d,J=5.6Hz,2H,Ph1−OCNH−CH2),2.88(t,J=8,2H,Ph1−CH2),2.57(t,J=8.6Hz,2H,Ph1−CH2−CH2)ppm;13C−NMR(DMSO−d6):174,166.7,145,138.3,135.4,133.1,132.2,129.7,129.1,128.8,127.8,126.3,125.5,125.4,123.4,50.7,39.8,35.5ppm;HRMS:実測値m/z352.1156(理論値:352.1155)。
収率:0.05g(50%);1HNMR(DMSO−d6):δ12.17(s,1H,COOH),9.04(t,J=6.2Hz,1H,OCNH),7.86−7.3(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.65(d,J=6.6Hz,2H,Ph1−OCNH−CH2),3−2.9(m,1H,Ph1−CH2−CH),2.73−2.64(m,2H,Ph1−CH2),1.05(d,J=6.4,3H,CH2−CH−CH3)ppm;13C−NMR(DMSO−d6):177.1,166.7,143.9,140.5,133.2,132.4,131.5,129.4,129.3,128.6,127.7,126.5,125.4,125.4,124.8,50.7,40.8,39.1,17.2ppm;HRMS:実測値m/z366.1314(理論値:366.1312)。
収率:0.02g(20%);1HNMR(DMSO−d6):δ12.47(s,1H,CCOH),9.04(t,J=4.7Hz,1H,OCNH),7.85−7.29(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.65(d,J=5.5Hz,2H,Ph1−OCNH−CH2),2.91−2.71(m,2H,Ph1−CH2),2.65−2.45(m,1H,Ph1−CH2−CH),1.59−1.2(m,4H,Ph1−CH2−CH−CH2+CH2−CH−CH2−CH2),1.35−0.85(t,J=7.1Hz,3H,CH−CH2-CH2−CH3)ppm;13C−NMR(DMSO−d6):176.6,167.1,144,138.4,133.2,132.4,131.5,129.4,129.2,128.1,127.7,126.2,125.9,125.4,124.9,38,34.6,34.1,20.3,14.5ppm;HRMS:実測値m/z394.1623(理論値:394.1625)。
収率:0.2g(16%);1HNMR(DMSO−d6):δ12.47(s,1H,COOH),9.08(t,J=6.9Hz,1H,OCNH),7.87−7.27(m,13H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+CH2−CH−Ph4),4.7(d,J=5.4Hz,2H,Ph1−OCNH−CH2),3.45−3.05(m,2H,Ph1−CH2),4(t,J=7.8,1H,Ph1−CH2−CH)ppm;13C−NMR(DMSO−d6):174.7,166.9,143.7,139.4,138.2,138.1,133.2,132.2,129.3,128.8,128.6,128.3,127.7,127.7,127.7,126.6,126.5,126.6,126.2,126.1,125.7,125,124.6,52.7ppm;HRMS:実測値m/z428.1465(理論値:428.1468)。
アルゴン雰囲気下、クロロホルム20ml中の4−ホルミル−N−(2−(トリフルオロメチル)ベンジル)ベンズアミド(1)1g(3.3mmol)の溶液に、1.3g(3.6mmol)のN−メトキシ−N−メチル(トリフェニルホスホラニリデン)アセトアミドを添加した。16時間後、溶媒を減圧下で蒸発させた。粗生成物を、1:1の比のEE/Hexの溶媒混合物を用いるフラッシュクロマトグラフィーにより精製した。白色固体は純粋な生成物のままであった。
収率:0.6g(47%);1HNMR(DMSO−d6):δ9.2(t,J=5.8Hz,1H,Ph1−OCNH),8−7.2(m,10H,OCNH−Ph1+OCNH−CH2−Ph2+Ph1−CH+Ph1−CH−CH),4.7(d,J=5.4Hz,2H,Ph1−OCNH−CH2),3.78(s,3H,OCN−O−CH3),3.25(s,3H,OCN−CH3)ppm.MS−ESI:m/z393[M+H+]。
アルゴン雰囲気下、3.15mlの乾燥DMSO中の561mg(2.6mmol)のトリメチルスルホニウムヨージドの溶液に97mg(2.55mmol)のNaHを少量ずつ加えた。反応混合物を1時間撹拌した後、(E)−N−メトキシ−N−メチル3−[4−(N−((2−トリフルオロメチル)ベンジル)ベンズアミド)]500mg(1.3mmol)−2−エナミド(20)を1.05mlの乾燥DMSOに注入した。6時間後、飽和NH4Cl溶液10mlで反応を停止させた。生成物を5mlのDCMで3回抽出した。集めた有機層を塩水4mlで1回洗浄し、MgSO4で乾燥した。溶媒を減圧下で除去した。純粋な生成物をEE/Hex混合物から再結晶し、白色固体を得た。
収率:0.62g(60%);1HNMR(DMSO−d6):δ9.06(t,J=5.4Hz,1H,OCNH),7.88−7.31(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.67(d,J=5.4Hz,2H,Ph1−OCNH−CH2),3.66(s,3H,OCN−O−CH3),3.16(s,3H,OCN−CH3),2.57−2.36(m,2H,Ph1−CH+Ph1−CH−CH),1.54−1.4(m,2H,Ph1−CH−CH2)ppm;13C−NMR(DMSO−d6):167.4,143.8,135.7,130.8,130.6,126.9,126.4,126.2,126.1,125.7,124.6,124.3,123,122.3,122,38.5,37.4,32,27.8,24,20.6ppm;HRMS:実測値m/z407.1578(理論値:407.1577)。
3mlのEtOH中の100mg(0.25mmol)のN−メトキシ−N−メチル3−[4−(N−((2−トリフルオロメチル)ベンジル)ベンズアミド)ベンズアミド)]シクロプロパンカルボキサミド(21)の溶液に3mlのKOH溶液(10%)を添加した。反応混合物を24時間還流した。EtOHを減圧下で反応溶液から除去し、残りの水溶液をDEEで3回洗浄した。水溶液のpHを12MのHCl溶液で1に調整した。純粋な白色生成物が沈殿し、濾過によって集めた。
収率:0.05g(55%);1HNMR(DMSO−d6):δ12.27(s,1H,COOH),8.99(t,J=5.4Hz,1H,OCNH),7.8−7.2(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.59(d,J=5.5Hz,2H,Ph1−OCNH−CH2),2.3−2.4(m,1H,Ph1−CH),1.86−1.8(m,1H,Ph1−CH−CH),1.44−1.31(m,2H,Ph1−CH−CH2)ppm;13C−NMR(DMSO−d6):173.7,166.2,144.2,137.7,137.1,132.6,132.2,131.8,128.1,128,127.4,127.3,125.9,125.9,125.8,39.7,37.4,25.1,24.5ppm;HRMS:実測値m/z364.1158(理論値:364.1155)。
4−ホルミル−N−(2−(トリフルオロメチル)ベンジル)ベンズアミド(1)250mg(0.8mmol)、o−ベンジルヒドロキシルアミン塩酸塩195mg(1.2mmol)およびDIPEA213μl(1.2mmol)を4mlのMeOHに溶解し、12時間撹拌した。溶媒を減圧下で蒸発させ、粗生成物をEE/Hex混合物から再結晶した。白色固体は純粋な生成物のままであった。
収率:0.25g(74%);1HNMR(DMSO−d6):δ9.17(t,J=5.5Hz,1H,OCNH),8.37(s,1H,Ph1−CH),7.98−7.29(m,13H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−CH−N−O−CH2−Ph5),5.2(s,2H,Ph1−CH−N−O−CH2),4.65(d,J=5.7Hz,2H,Ph1−OCNH−CH2)ppm;13C−NMR(DMSO−d6):166,137.4,135,135,132.7,131.5,128.6,128.4,128.3,128.2,127.9,127.6,127.4,127.3,126.8,126.6,126.3,126.1,126,125.9,125.7,125,124.6,50ppm;HRMS:実測値m/z413.1473(理論値:413.1471)。
4−カルボキシベンゼンボロン酸250mg(1.5mmol)、4−ヨード−[N−(2−(トリフルオロメチル)ベンジル)ベンズアミド](24)555mg(1.4mmol)、パラジウム(II)アセタート9.2mg(0.04mmol)および568mg(4.1mmol)のK2CO3をアセトン/H2Oの1:1の混合物に溶解した。反応物を65℃で1時間撹拌した。次いで、混合物をセライトで濾過し、アセトンを減圧下で蒸発させた。水層を12MのHCl溶液で酸性化した後、生成物が沈殿した。白色固体が残っており、さらなる精製は必要なかった。
収率:0.36g(66%);1HNMR(DMSO−d6):δ13.03(s,1H,COOH),9.21(t,J=6.1Hz,1H,OCNH),8.09−7.48(m,12H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−Ph7),4.71(d,J=5.5Hz,2H,Ph1−OCNH−CH2)ppm;13C−NMR(DMSO−d6):167,166,162.4,143.2,142.1,141.8,137.9,134.7,133.5,132.7,130.2,130,128.9,128.2,127.4,127.3,127.1,127.1,127,125.1,125,48.1ppm;HRMS:実測値m/z400.1156(理論値:400.1155)。
収率:0.37g(67%);1HNMR(DMSO−d6):δ13.08(s,1H,COOH),9.14(t,J=5.7Hz,1H,OCNH),8.2−7.39(m,12H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2+Ph1−Ph7),4.63(d,J=5.5Hz,2H,Ph1−OCNH−CH2)ppm;13C−NMR(DMSO−d6):168.1,166,144,143.1,142.1,140.8,136.8,134.8,133.4,132.9,130,130,128.8,128.1,127.7,127.5,127.1,126.1,126,125.1,124,49.1ppm;HRMS:実測値m/z400.1155(理論値:400.1155)。
4−シアノ−[N−(2−(トリフルオロメチル)ベンジル)ベンズアミド](27)100mg(0.3mmol)、NaN343mg(0.7mmol)およびNH4Cl23mg(0.4mmol)をアルゴン雰囲気下乾燥DMFで処理し、150℃で12時間撹拌した。反応混合物が室温に達した後、1mlのH2Oを加えた。水層に12MのHCl溶液を加え、生成物を沈殿させた。ろ過により、さらなる精製を必要としないわずかに黄色の固体を集めた。
収率:0.11g(92%);1HNMR(DMSO−d6):δ9.35(t,J=5.6Hz,1H,OCNH),8.25−7.54(m,8H,OCNH−Ph1+Ph1−OCNH−CH2−Ph2),4.76(d,J=5.6Hz,2H,Ph1−OCNH−CH2)ppm;13C−NMR(DMSO−d6):166.6,160.3,137.9,136.9,135.5,132.7,132.3,129.2,128.6,128.2,127.7,127.2,126.7,125.5,125.1,125,48.2ppm;HRMS:実測値m/z348.1067(理論値:348.1067)。
細胞培養
(1)
Christiansen,E.;Due-Hansen,M.;E.Urban,C.;Grundmann,M.;Schmidt,J.Hansen,S.V.F.Hudson,B.;D.Zaibi,M.;Markussen,S.B.Hagesaether,E.Milligan,G.;Cawthorne,M.;A.Kostenis,E.;Kassack,M.;U. Ulven,T.;Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability.Journal of Medicinal Chemistry 2013,56,982-992.
[実施例2]高血圧肥満自然発症ラット(SHROB)モデルにおけるインビボ研究
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Claims (24)
- 以下の構造を有する化合物またはその塩。
- R3のフルオロ置換アリール基が、トリフルオロメチル置換またはトリフルオロメトキシ置換フェニル基である請求項1に記載の化合物。
- 前記トリフルオロメチル置換またはトリフルオロメトキシ置換が前記フェニル基のオルト位にある請求項2に記載の化合物。
- R3が、以下のいずれかである請求項1に記載の化合物。
- R3が、以下である請求項1に記載の化合物。
- X−YがCH2−CHであり、R1がCH2CH3である請求項1〜5のいずれか1項に記載の化合物。
- X−YがCH=Cであり、R1がCH2CH3である請求項1〜5のいずれか1項に記載の化合物。
- X−YがCH2−CHであり、R1がHである請求項1〜5のいずれか1項に記載の化合物。
- X−YがCH=CHであり、R1がHである請求項1〜5のいずれか1項に記載の化合物。
- 対象に投与した場合の可溶性エポキシド加水分解酵素(sEH)の50%阻害濃度(IC50)およびペルオキシソーム増殖因子活性化受容体ガンマ(PPARγ)の50%効果濃度(EC50)が1.0マイクロモル未満である請求項1に記載の化合物。
- (a)請求項1〜10のいずれか1項に記載の化合物、および(b)薬学的に許容される担体を含む組成物。
- 経口投与剤として処方される請求項11に記載の組成物。
- 対象に治療有効量の請求項1〜10のいずれか1項記載の化合物を対象に投与することを含む、対象におけるメタボリックシンドロームを治療する方法であって、可溶性エポキシド加水分解酵素(sEH)およびペルオキシソーム増殖因子活性化受容体ガンマ(PPARγ)が、前記化合物によって同時に調節されることにより前記対象のメタボリックシンドロームを治療する方法。
- 治療有効量の化合物が、対象において1.0マイクロモル未満のsEHの50%阻害濃度(IC50)およびPPARγの50%効果濃度(EC50)を提供する、請求項13に記載の方法。
- 対象においてメタボリックシンドロームを治療する医薬品の製造のための請求項1〜10のいずれか1項に記載の化合物の使用。
- 対象におけるメタボリックシンドロームの治療に使用するための請求項1〜10のいずれか1項に記載の化合物。
- 治療有効量の請求項1〜10のいずれか1項に記載の化合物を対象に投与することを含む、対象における糖尿病の治療方法であって、可溶性エポキシド加水分解酵素(sEH)およびペルオキシソーム増殖因子活性化受容体ガンマ(PPARγ)が、前記化合物によって同時に調節されることにより前記対象の糖尿病を治療する方法。
- 治療有効量の化合物が、対象において1.0マイクロモル未満のsEHの50%阻害濃度(IC50)およびPPARγの50%効果濃度(EC50)を提供する、請求項17に記載の方法。
- 対象において糖尿病を治療する医薬品の製造のための請求項1〜10のいずれか1項に記載の化合物の使用。
- 対象における糖尿病の治療に使用するための請求項1〜10のいずれか1項に記載の化合物。
- 治療有効量の請求項1〜10のいずれか1項に記載の化合物を対象に投与することを含む、対象における可溶性エポキシド加水分解酵素(sEH)およびペルオキシソーム増殖因子活性化受容体ガンマ(PPARγ)を同時に調節する方法であって、sEHおよびPPARγが、前記化合物によって同時に調節される方法。
- 治療有効量の化合物が、対象において1.0マイクロモル未満のsEHの50%阻害濃度(IC50)およびPPARγの50%効果濃度(EC50)を提供する、請求項21に記載の方法。
- 対象において可溶性エポキシド加水分解酵素(sEH)およびペルオキシソーム増殖因子活性化受容体ガンマ(PPARγ)を同時に調節する医薬品の製造のための請求項1〜10のいずれか1項に記載の化合物の使用。
- 対象における可溶性エポキシド加水分解酵素(sEH)およびペルオキシソーム増殖因子活性化受容体ガンマ(PPARγ)活性を同時に調節するための請求項1〜10のいずれか1項に記載の化合物。
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PCT/US2016/040708 WO2017004525A1 (en) | 2015-07-02 | 2016-07-01 | Diabetes and metabolic syndrome treatment with a novel dual modulator of soluble epoxide hydrolase and peroxisome proliferator-activated receptors |
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WO2021053234A1 (en) * | 2019-09-19 | 2021-03-25 | Johann Wolfgang Goethe-Universität Frankfurt am Main | Compounds and compositions for treating kidney disease |
CN110898047A (zh) * | 2019-12-23 | 2020-03-24 | 河北科技大学 | 一种眼用制剂及其制备方法和应用 |
EP4142795A4 (en) * | 2020-04-27 | 2024-05-22 | The Research Institute at Nationwide Children's Hospital | PPAR AGONISTS FOR THE TREATMENT OF KIDNEY DISEASE |
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WO2024105225A1 (en) | 2022-11-18 | 2024-05-23 | Universitat De Barcelona | Synergistic combinations of a sigma receptor 1 (s1r) antagonist and a soluble epoxide hydrolase inhibitor (sehi) and their use in the treatment of pain |
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