JP2010116403A - 4−ピリジルアルキルチオ基を置換基として有する新規化合物 - Google Patents
4−ピリジルアルキルチオ基を置換基として有する新規化合物 Download PDFInfo
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- OUTHNFIRHCFEAH-UHFFFAOYSA-N C=[Br]c1ccc(C(Nc(cc2)ccc2Cl)=O)[o]1 Chemical compound C=[Br]c1ccc(C(Nc(cc2)ccc2Cl)=O)[o]1 OUTHNFIRHCFEAH-UHFFFAOYSA-N 0.000 description 1
- SSCCXXRVBZENCO-UHFFFAOYSA-N CBc1ccncc1 Chemical compound CBc1ccncc1 SSCCXXRVBZENCO-UHFFFAOYSA-N 0.000 description 1
- HVEBHSFYRWPASA-UHFFFAOYSA-N CC(C)(C)c(cc1)ccc1NC(c([s]cc1)c1SCc1ccncc1)=O Chemical compound CC(C)(C)c(cc1)ccc1NC(c([s]cc1)c1SCc1ccncc1)=O HVEBHSFYRWPASA-UHFFFAOYSA-N 0.000 description 1
- HYBALJMVPJTQQE-UHFFFAOYSA-N CC(C)Oc1cc(CO)ccn1 Chemical compound CC(C)Oc1cc(CO)ccn1 HYBALJMVPJTQQE-UHFFFAOYSA-N 0.000 description 1
- CRJXFRCZMRIXAM-UHFFFAOYSA-N CC(C)c1cccc(NC(c([o]2)ccc2SCc2ccncc2)=O)c1 Chemical compound CC(C)c1cccc(NC(c([o]2)ccc2SCc2ccncc2)=O)c1 CRJXFRCZMRIXAM-UHFFFAOYSA-N 0.000 description 1
- 0 CCCC(C)(*)CCC(C)(*)COCN Chemical compound CCCC(C)(*)CCC(C)(*)COCN 0.000 description 1
- HYDPHYXAOUSTSR-UHFFFAOYSA-N CCCc(cc1)ccc1NC(c([s]cc1)c1SCc1ccncc1)=O Chemical compound CCCc(cc1)ccc1NC(c([s]cc1)c1SCc1ccncc1)=O HYDPHYXAOUSTSR-UHFFFAOYSA-N 0.000 description 1
- IGTMQHLEJKSRLJ-UHFFFAOYSA-N CCOC(c(cn[n]1C)c1I)=O Chemical compound CCOC(c(cn[n]1C)c1I)=O IGTMQHLEJKSRLJ-UHFFFAOYSA-N 0.000 description 1
- SRTHCEDWYUGFOX-UHFFFAOYSA-N CCOC(c(cn[n]1C)c1SCc1ccncc1)=O Chemical compound CCOC(c(cn[n]1C)c1SCc1ccncc1)=O SRTHCEDWYUGFOX-UHFFFAOYSA-N 0.000 description 1
- PDDYQZBHYUVWCJ-UHFFFAOYSA-N CN1C(Cl)=CC(CSc2ncccc2C(O)=O)=CC1 Chemical compound CN1C(Cl)=CC(CSc2ncccc2C(O)=O)=CC1 PDDYQZBHYUVWCJ-UHFFFAOYSA-N 0.000 description 1
- BEMKIZYLGKEXBW-UHFFFAOYSA-N COC(c([s]cc1)c1SCc1ccncc1)=O Chemical compound COC(c([s]cc1)c1SCc1ccncc1)=O BEMKIZYLGKEXBW-UHFFFAOYSA-N 0.000 description 1
- XGAOTPCEGDKYCS-UHFFFAOYSA-N COC(c1c(SCc2ccncc2)[s]cc1)=O Chemical compound COC(c1c(SCc2ccncc2)[s]cc1)=O XGAOTPCEGDKYCS-UHFFFAOYSA-N 0.000 description 1
- JQWZKQXZKYIABK-UHFFFAOYSA-N C[Si+](C)(C)OCc1cc(C#N)ncc1 Chemical compound C[Si+](C)(C)OCc1cc(C#N)ncc1 JQWZKQXZKYIABK-UHFFFAOYSA-N 0.000 description 1
- DTZFVGZAUZDNDJ-UHFFFAOYSA-N Cc1cc(NC(c2c(SCc3ccncc3)[s]c3c2CCCC3)=O)cc(C)c1 Chemical compound Cc1cc(NC(c2c(SCc3ccncc3)[s]c3c2CCCC3)=O)cc(C)c1 DTZFVGZAUZDNDJ-UHFFFAOYSA-N 0.000 description 1
- LRFLCZLPBVWTKT-UHFFFAOYSA-N O=C(c([s]cc1)c1SCc1ccncc1)Nc1cc(C(F)(F)F)ccc1 Chemical compound O=C(c([s]cc1)c1SCc1ccncc1)Nc1cc(C(F)(F)F)ccc1 LRFLCZLPBVWTKT-UHFFFAOYSA-N 0.000 description 1
- JPPBHAZCFBKTIG-UHFFFAOYSA-N O=C(c([s]cc1)c1SCc1ccncc1)Nc1cccc(Cl)c1 Chemical compound O=C(c([s]cc1)c1SCc1ccncc1)Nc1cccc(Cl)c1 JPPBHAZCFBKTIG-UHFFFAOYSA-N 0.000 description 1
- FVMQNMNRLYVTQZ-UHFFFAOYSA-N O=C(c1c(SCc2ccncc2)[s]cc1)Nc1ccc(C(F)(F)F)cc1 Chemical compound O=C(c1c(SCc2ccncc2)[s]cc1)Nc1ccc(C(F)(F)F)cc1 FVMQNMNRLYVTQZ-UHFFFAOYSA-N 0.000 description 1
- PZWCAKMBBHYTJA-UHFFFAOYSA-N O=C(c1c(SCc2ccncc2)[s]cc1)Nc1ccc(CCC2)c2c1 Chemical compound O=C(c1c(SCc2ccncc2)[s]cc1)Nc1ccc(CCC2)c2c1 PZWCAKMBBHYTJA-UHFFFAOYSA-N 0.000 description 1
- KKINYMHWPPQMHX-UHFFFAOYSA-N O=C(c1ccc(SCc2ccncc2)[s]1)Nc1ccc(CCC2)c2c1 Chemical compound O=C(c1ccc(SCc2ccncc2)[s]1)Nc1ccc(CCC2)c2c1 KKINYMHWPPQMHX-UHFFFAOYSA-N 0.000 description 1
- WQBWIIZVSAFRJE-UHFFFAOYSA-N OC(c1cccnc1SCc1ccncc1)=O Chemical compound OC(c1cccnc1SCc1ccncc1)=O WQBWIIZVSAFRJE-UHFFFAOYSA-N 0.000 description 1
- YMDSQKHPXSUJSG-UHFFFAOYSA-N OCc1cc(OCc2ccccc2)ncc1 Chemical compound OCc1cc(OCc2ccccc2)ncc1 YMDSQKHPXSUJSG-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
血管内皮細胞増殖因子(以下、VEGFとする)は、血管内皮細胞表面に存在する受容体(Flt−1、KDR/Flk−1等)に特異的に作用して、血管内皮細胞の増殖、遊走、管腔形成による毛細血管ネットワークの構築等を促進し、また、血管透過性を亢進する因子であり、血管新生の発生において非常に重要な役割を担っている。そのため、このVEGFを阻害して、血管新生の発生や血管透過性の亢進を制御することで、血管新生や血管透過性の亢進が関与する疾患を治療する試みが数多く報告されている。このような治療に用いられる薬物として、例えば、インドリン−2−オン誘導体(特許文献1参照)、フタラジン誘導体(特許文献2参照)、キナゾリン誘導体(特許文献3参照)、アントラニル酸アミド誘導体(特許文献4参照)、2−アミノニコチン酸誘導体(特許文献5参照)等を挙げることができる。しかし、これらの特許文献には、4−ピリジルアルキルチオ基を置換基として有する化合物に関する記載は一切なされていない。
Bはアルキレン基を示し;
R1およびR2は同一または異なって、水素原子、ヒドロキシ基、置換若しくは無置換アルコキシ基、置換若しくは無置換アリールオキシ基、置換若しくは無置換アルキル基、置換若しくは無置換シクロアルキル基、置換若しくは無置換アリール基、置換若しくは無置換複素環基、アミノ基、置換若しくは無置換アルキルアミノ基、置換若しくは無置換アリールアミノ基、または置換若しくは無置換アシル基を示し;
R1とR2は一緒になって、置換または無置換複素環を形成してもよく;
XおよびYは同一または異なって、水素原子、ハロゲン原子、ヒドロキシ基、置換若しくは無置換アルコキシ基、置換若しくは無置換アリールオキシ基、置換若しくは無置換アルキル基、置換若しくは無置換シクロアルキル基、置換若しくは無置換アリール基、メルカプト基、置換若しくは無置換アルキルチオ基、置換若しくは無置換アリールチオ基、カルボキシ基またはそのエステル若しくはそのアミド、シアノ基、およびニトロ基から選択される1または複数の基を示し;
pは0、1または2を示し;
qは0または1を示す。以下、同じ。]
前記で規定した各基について、以下に詳しく説明する。
イ)R1およびR2が同一または異なって、水素原子、置換若しくは無置換アルコキシ基、置換若しくは無置換アルキル基、置換若しくは無置換シクロアルキル基、置換若しくは無置換アリール基、置換若しくは無置換複素環基、置換若しくは無置換アルキルアミノ基、または置換若しくは無置換アリールアミノ基を示すもの、
ロ)あるいは、R1とR2が一緒になって、形成された置換または無置換複素環基であるもの、
ハ)XおよびYが水素原子、ハロゲン原子、置換若しくは無置換アルコキシ基、置換若しくは無置換アルキル基、置換若しくは無置換アルキルチオ基、カルボキシ基またはそのエステル若しくはそのアミド、およびシアノ基から選択される1または複数の基を示すもの、
ニ)pが0または1であるものである。
イ)R1が水素原子、置換アルコキシ基、置換若しくは無置換アルキル基、無置換シクロアルキル基、置換若しくは無置換アリール基、置換若しくは無置換複素環基、無置換アルキルアミノ基、または置換アリールアミノ基であるもの、
ロ)R2が水素原子、または置換若しくは無置換アルキル基であるもの、
ハ)あるいは、R1とR2が一緒になって、形成された置換または無置換複素環基であるもの、
ニ)Xが水素原子、ハロゲン原子および置換アルキル基から選択される1または複数の基であるもの、
ホ)Yが水素原子、ハロゲン原子、置換若しくは無置換アルコキシ基、無置換アルキル基、無置換アルキルチオ基、カルボキシ基またはそのエステル若しくはそのアミド、およびシアノ基から選択される1または複数の基であるものである。
薬物のin vitroにおける血管新生阻害効果を評価する汎用される方法の一つであるVEGF誘発HUVEC増殖反応評価系(尚、HUVECは、正常ヒトさい帯静脈由来血管内皮細胞を意味する)を用いて、本発明化合物の細胞増殖阻害作用試験を実施した。
δ 4.38(s,2H),7.27(dd,J = 8.1,4.8 Hz,1H),7.42(dd,J = 4.4,1.5 Hz,2H),8.22(dd,J = 8.1,1.8 Hz,1H),8.46(dd,J = 4.4,1.5 Hz,2H),8.63(dd,J = 4.8,1.8 Hz,1H),13.70(br s,1H)
以下、参考例1と同様に参考化合物1−9を得た。
δ 4.35(s,2H),7.19(d,J = 5.2 Hz,1H),7.45(d,J = 5.8 Hz,2H),7.84(d,J = 5.2 Hz,1H),8.51(d,J = 5.8 Hz,2H),13.06(s,1H)
δ 7.36(d,J = 8.9 Hz,2H),7.42(dd,J = 7.7,4.8 Hz,1H),7.61(d,J = 8.9 Hz,2H),8.22(s,1H),8.23(dd,J = 7.7,1.9 Hz,1H),8.53(dd,J = 4.8,1.9 Hz,1H)
以下、参考例2と同様に参考化合物2−4〜7を得た。
δ 6.84(d,J = 3.7 Hz,1H),7.38(d,J = 3.7 Hz,1H),7.41(d,J = 7.0 Hz,2H),7.76(d,J = 7.0 Hz,2H),10,33(s,1H)
δ 7.38(d,J = 4.0 Hz,1H),7.42(d,J = 8.9 Hz,2H),7.73(d,J = 8.9 Hz,2H),7.85(d,J = 4.0 Hz,1H),10.38(s,1H)
δ 2.26(s,6H),6.75(d,J = 0.7 Hz,1H),6.82(d,J = 3.7 Hz,1H),7.35(d,J = 0.7 Hz,2H),7.35(d,J = 3.7 Hz,1H),10.02(s,1H)
δ 2.26(s,6H),6.76(s,1H),7.33(s,2H),7.36(d,J = 4.0 Hz,1H),7.85(d,J = 4.0 Hz,1H),10.12(s,1H)
δ 4.77(s,2H),7.47(d,J = 7.1 Hz,2H),8.22(d,J = 7.1 Hz,2H)
δ 4.56(d,J = 5.8 Hz,2H),5.54(t,J = 5.8 Hz,1H),7.34(d,J = 4.9 Hz,1H),7.41(s,1H),8.34(d,J = 4.9 Hz,1H)
以下、参考例7と同様に参考化合物7−2〜3を得た。
δ 2.16(br s,1H),2.56(s,3H),4.68(s,2H),6.95(dt,J = 5.1,0.7 Hz,1H),7.19(dd,J = 1.4,0.7 Hz,1H),8.38(d,J = 5.1 Hz,1H)
δ 2.44(s,3H),4.49(d,J = 5.5 Hz,2H),5.36(t,J = 5.5 Hz,1H),7.10(d,J = 5.1 Hz,1H),7.17(s,1H),8.35(d,J = 5.1 Hz,1H)
δ 1.89(s,1H),3.94(s,3H),4.69(d,J = 4.3 Hz,2H),6.75(s,1H),6.85(d,J = 5.2 Hz,1H),8.12(d,J = 5.2 Hz,1H)
以下、参考例9と同様に参考化合物9−2〜4を得た。
δ 1.39(t,J = 7.1 Hz,3H),2,32(br s,1H)4.34(q,J = 7.1 Hz,2H),4.67(s,2H),6.73(dd,J = 1.5,1.0 Hz,1H),6.82(dd,J = 5.4,1.0 Hz,1H),8.08(d,J = 5.4 Hz,1H)
δ 1.34(d,J = 6.5 Hz,6H),1.78(br s,1H),4.71(s,2H),5.30(m,1H),6.69(s,1H),6.81(d,J = 5.2 Hz,1H),8.10(d,J = 5.2 Hz,1H)
δ 4.52(s,2H),5.36(s,2H),6.89(m,1H),6.98(m,1H),7.32(d,J = 7.0 Hz,1H),7.37(t,J = 7.0 Hz,2H),7.43(d,J = 7.0 Hz,2H),8.10(d,J= 5.5 Hz,1H),7.00−8.20(br s,1H)
δ 0.16(s,9H),4.79(s,2H),7.66(m,1H),7.92(dd,J = 1.6,0.7 Hz,1H),8.71(dd,J = 5.1,0.7 Hz,1H)
δ 4.61(d,J = 5.8 Hz, 2H),5.64(t,J = 5.8 Hz,1H),7.67(ddd,J = 4.0,1.5,0.6 Hz,1H),7.92(dd,J = 1.5,0.9 Hz,1H),8.69(dd,J = 5.0,0.6 Hz,1H)
δ 1.33(t,J = 7.0 Hz,3H),4.35(q,J = 7.0 Hz,2H),4.62(d,J = 5.8 Hz,2H),5.56(t,J = 5.8 Hz,1H),7.55(m,1H),8.01(dd,J = 1.6,0.6 Hz,1H),8.63(dd,J = 4.6,0.6 Hz,1H)
以下、参考例12と同様に参考化合物12−2を得た。
δ 3.88(s,3H),4.62(d,J = 5.8 Hz,2H),5.57(t,J = 5.8 Hz,1H),7.56(dt,J = 4.9,0.9 Hz,1H),8.02(dd,J = 1.5,0.6 Hz,1H),8.64(dd,J = 4.9,0.6 Hz,1H)
δ 4.61(d,J = 6.1 Hz,2H),5.52(t,J = 6.1 Hz,1H),7.50(dt,J = 4.9,0.9 Hz,1H),7.60(s,1H),8.01(d,J = 0.9 Hz,1H),8.08(s,1H),8.55(d,J = 4.9 Hz,1H)
δ 4.40(s,2H),7.27(dd,J = 7.7,4.7 Hz,1H),7.45(dd,J = 5.2,1.5 Hz,1H),7,55(d,J = 0.6 Hz,1H),8.24(dd,J = 7,7,1.9 Hz,1H),8.30(dd,J = 5.2,0.6 Hz,1H),8.64(dd,J = 4,7,1.9 Hz,1H),13.52(s,1H)
以下、参考例14と同様に参考化合物14−8を得た。
δ 4.38(s,2H),7.19(d,J = 5.2 Hz,1H),7.49(dd,J = 5.2,1.5 Hz,1H),7.59(d,J = 0.9 Hz,1H),7.86(d,J = 5.2 Hz,1H),8.36(dd,J = 5.2,0.9 Hz,1H),13.11(s,1H)
δ 4.04(s,3H),8.47(d,J = 2.1 Hz,1H),8.56(d,J = 2.1 Hz, 1H)
以下、参考例15と同様に参考化合物15−2〜4を得た。
δ 1.28(t,J = 7.1 Hz,3H),3.92(s,3H),4.23(q,J = 7.1 Hz,2H),7.92(s,1H)
δ 3.89(s,3H),7.32(d,J = 5.7 Hz,1H),7.41(d,J = 5.7 Hz,1H)
δ 3.89(s,3H),7.51(d,J = 3.5 Hz,1H),8.07(d,J = 3.5 Hz,1H)
δ 4.03(s,3H),4.37(s,2H),7.35(dd,J = 4.3,1.5 Hz,2H),8.39(d,J = 2.1 Hz,1H),8.52(dd,J = 4.3,1.5 Hz,2H),8.53(d,J = 2.1 Hz,1H)
以下、参考例16と同様に参考化合物16−2〜5を得た。
δ 1.40(t,J = 7.1 Hz,3H),3.56(s,3H),4.11(s,2H),4.36(q,J = 7.1 Hz,2H),6.99(dd,J = 4.6,1.5 Hz,2H),7.95(s,1H),8.48(dd,J = 4.6,1.5 Hz,2H)
δ 3.87(s,3H),4.20(s,2H),7.09(d,J = 5.5 Hz,1H),7.30(dd,J = 4.4,1.5 Hz,2H),7.41(d,J = 5.5 Hz,1H),8.55(dd,J = 4.4,1.5 Hz,2H)
δ 3.88(s,3H),4.10(s,2H),6.77(d,J = 3.3 Hz,1H),7.33−7.35(m,2H),8.16(d,J = 3.3 Hz,1H),8.67(br s,2H)
δ 3.86(s,3H),4.75(s,2H),7.17(d,J = 5.3 Hz,1H),7.45(dd,J = 4.3,1.5 Hz,2H),7.88(d,J= 5.3 Hz,1H),8.50(dd,J = 4.3,1.5 Hz,2H)
δ 4.38(s,2H),7.43(dd,J = 4.6,1.5 Hz,2H),8.47(d,J = 2.4 Hz,1H),8.48(dd,J = 4.6,1.5 Hz,2H),8.70(d,J = 2.4 Hz,1H),13.74(br s,1H)
以下、参考例17と同様に参考化合物17−2〜4を得た。
δ 3.48(s,3H),4.27(s,2H),7.07(d,J = 4.6,1.5 Hz,2H),7.73(s,1H),8.40(dd,J = 4.6,1.5 Hz,2H)
δ 4.32(s,2H),7.31(d,J = 5.4 Hz,1H),7.41(d,J = 5.4 Hz,1H),7.43(dd,J = 4.4,1.7 Hz,2H),8.52(dd,J = 4.4,1.7 Hz,2H),12.83(s,1H)
δ 4.20(s,2H),7.20(m,1H),7.44−7.45(m,2H),8.36(m,1H),8.50−8.51(m,2H),12.86(s,1H)
δ 4.42(s,2H),7.30(dd,J = 7.6,4.7 Hz,1H),7.37−7.43(m,4H),7.72(d,J = 7.6 Hz,2H),7.98(dd,J = 7.6,1.7 Hz,1H),8.45(dd,J = 4.5,1.8 Hz,2H),8.59(dd,J = 4.7,1.7,1H),10.60(s,1H)
δc 32.0,119.3,121.3,124.0,127.5,128.5,129.8,135.8,137.6,147.7,149.3,150.2,155.9,164.6
実施例1と同様に以下の化合物1−244〜293を得た。
δ 3.74(s,3H),4.28(s,2H),6.91(dd,J = 6.8,2.2 Hz,2H),7.23(d,J = 6.4 Hz,1H),7.34(dd,J = 4.4,1.5 Hz,2H),7.53(dd,J = 6.8,2.2Hz,2H),7.81(d,J = 6.4 Hz,1H),8.46(dd,J = 4.4,1.5 Hz,2H),9.87(s,1H)
δ 4.28(s,2H),7.18(d,J = 9.0 Hz,2H),7.24(d,J = 5.4 Hz,1H),7.34(d,J = 4.7 Hz,2H),7.65(d,J = 9.0 Hz,2H),7.84(d,J = 5.4 Hz,1H),8.45(dd,J = 4.7,1.5 Hz,2H),10.04(s,1H)
δ 1.25(d,J = 6.1 Hz,6H),4.27(s,2H),4.56(m,1H),6.88(dd,J = 7.0,2.1 Hz,2H),7.22(d,J = 5.4 Hz,1H),7.33(dd,J = 4.5,1.7 Hz,2H),7.50(dd,J = 7.0,2.1 Hz,2H),7.80(d,J = 5.4 Hz,1H),8.46(dd,J = 4.5,1.7 Hz.2H),9.85(s,1H)
δ 2.95(s,6H),3.99(s,2H),6.73(dd,J = 6.8,2.2 Hz,2H),6.93(d,J = 5.2 Hz,1H),7.02(dd,J = 4.3,1.7 Hz,2H),7.42(dd,J = 6.8,2.2Hz,2H),7.44(d,J= 5.2 Hz,1H),8.47(dd,J= 4.3,1.7 Hz,2H),9.69(s,1H)
δ 2.19(d,J = 1.6 Hz,3H),4.28(s,2H),7.22(m,1H),7.25(d,J = 5.2 Hz,1H),7.32(m,1H),7.34(dd,J = 4.3,1.5 Hz,2H),7.54(dd,J = 12.2,2.1 Hz,1H),7.84(d,J = 5.2 Hz,1H),8.46(dd,J = 4.3,1.5 Hz,2H),10.08(s,1H)
δ 4.00(s,2H),6.98(d,J = 5.2 Hz,1H),7.01(dd,J = 4.5,1.6 Hz,2H),7.12(ddd,J = 8.1,2.0,0.9 Hz,1H),7.28(m,1H),7.42(ddd,J = 8.1,2.0,0.9 Hz,1H),7.52(d,J = 5.2 Hz.1H),7.64(t,J = 2.0 Hz,1H),8.47(d,J = 4.5 Hz,2H),9.90(S,1H)
δ 3.99(s,2H),6.98−7.00(m,3H),7.31(dd,J = 6.9,2.0 Hz,2H),7.48−7.50(m,3H),8.46(dd,J = 4.4,1.8 Hz,2H),9.87(s,1H)
δ 2.25(s,6H),4.28(s,2H),6.75(d,J = 0.6 Hz,1H),7.23−7.25(m,3H),7.32(d,J = 5.2 Hz,1H),7.45(d,J = 0.9 Hz,1H),7.84(d,J = 5.2 Hz,1H),8.28(m,1H),9.86(s,1H)
δ 2.23(s,3H),4.28(s,2H),7.10(t,J = 9.2 Hz,1H),7.23(d,J = 5.2 Hz,1H),7.34(dd,J = 4.3,1.5 Hz,2H),7.45(m,1H),7.55(dd,J = 7.0,2.1 Hz,1H),7.83(d,J = 5.2 Hz,1H),8.46(dd,J = 4.3,1.5 Hz,2H),9.96(s,1H)
δ 2.18(s,3H),2.21(s,3H),4.27(s,2H),7.08(d,J = 8.3 Hz,1H),7.23(d,J = 5.2 Hz,1H),7.33(dd,J = 4.3,1.5 Hz,2H),7.35(dd,J = 8.3,2.1 Hz,1H),7.40(d,J = 2.1 Hz,1H),7.81(d,J = 5.2 Hz,1H),8.45(dd,J = 4.3,1.5 Hz,2H),9.84(s,1H)
δ 4.30(s,2H),7.08(dt,J = 8.2,1.2 Hz,1H),7.26(d,J = 5.2 Hz,1H),7.35(dd,J = 4.6,1.5 Hz,2H),7.46(t,J = 8.2 Hz,1H),7.63(dt,J = 8.2,1.2 Hz,1H),7.79(br s,1H),7.87(d,J = 5.2 Hz,1H),8.46(dd,J = 4.6,1.5 Hz,2H),10.25(s,1H)
δ 4.01(s,2H),7.00(dd,J = 4.3,1.5 Hz,2H),7.01(d,J = 5.2 Hz,1H),7.54(d,J = 5.2 Hz,1H),7.61(d,J = 8.6 Hz,2H),7.67(d,J = 8.6 Hz,2H),8.45(dd,J = 4.3,1.5 Hz,2H),10.03(s,1H)
δ 1.27(s,9H),4.28(s,2H),7.23(d,J = 5.2 Hz,1H),7.34(dd,J = 4.3,1.5 Hz,2H),7.35(d,J = 8.6 Hz,2H),7.54(d,J = 8.6 Hz,2H),7.82(d,J = 5.2 Hz,1H),8.46(dd,J = 4.3,1.5 Hz,2H),9.93(s,1H)
δ 4.30(s,2H),7.26(d,J = 5.2 Hz,1H),7.35(dd,J = 4.6,1.5 Hz,2H),7.59(d,J = 8.9 Hz,1H),7.62(dd,J = 8.9,2.1 Hz,1H),7.87(d,J = 5.2 Hz,1H),8.01(d,J = 2.1 Hz,1H),8.46(dd,J = 4.6,1.5 Hz,2H),10.24(s,1H)
δ 2.27(s,3H),4.28(s,2H),7.14(d,J = 8.3 Hz,2H),7.23(d,J = 5.2 Hz,1H),7.33(dd,J = 4.3,1.5 Hz,2H),7.51(d,J = 8.3 Hz,2H),7.82(d,J = 5.2 Hz,1H),8.45(dd,J = 4.3,1.5 Hz,2H),9.91(s,1H)
δ 3.75(s,3H),4.28(s,2H),6.68(ddd,J = 7.6,2.4,1.5 Hz,1H),7.19−7.23(m,2H),7.25(d,J = 5.2 Hz,1H),7.32(dd,J = 2.4,1.5 Hz,1H),7.34(dd,J = 4.6,1.5 Hz,2H),7.83(d,J = 5.2 Hz,1H),8.46(dd,J = 4.6,1.5 Hz,2H),9.97(s,1H)
δ 2.79(t,J = 7.0 Hz,2H),3.41(td,J = 7.0,5.5 Hz,2H),4.21(s,2H),7.14(d,J = 5.2 Hz,1H),7.26(dd,J = 6.4,2.1 Hz,2H),7.28(dd,J = 4.3,1.5 Hz,2H),7.34(dd,J = 6.4,2.4 Hz,2H),7.71(d,J = 5.2 Hz,1H),8.07(t,J = 5.5 Hz,1H),8.47(dd,J = 4.3,1.5 Hz,2H)
δ 3.07(t,J = 4.9 Hz,4H),3.74(t,J = 4.9 Hz,4H),4.27(s,2H),6.92(d,J = 9.3 Hz,2H),7.22(d,J = 5.1 Hz,1H),7.33(dd,J = 4.4,1.5 Hz,2H),7.48(d,J = 9.3 Hz,2H),7.80(d,J = 5.1 Hz,1H),8.45(dd,J = 4.4,1.5 Hz,2H),9.81(s,1H)
δ 3.42(s,3H),4.03(s,2H),6.67(d,J = 5.1 Hz,1H),7.05(dd,J = 8.5 Hz,2H),7.16(d,J = 5.1 Hz,1H),7.23−7.30(m,4H),8.52(d,J = 5.9 Hz,2H)
δ 2.30(s,3H),4.28(s,2H),6.92(d,J = 7.2 Hz,1H),7.19−7.25(m,2H),7.33(dd,J = 4.4,1.7 Hz,2H),7.41(d,J = 8.0 Hz,1H),7.47(s,1H),7.83(d,J = 5.1 Hz,1H),8.46(dd,J = 4.4,1.7 Hz,2H),9.92(s,1H)
δ 1.28(s,9H),4.28(s,2H),7.13(ddd,J = 8.0,1.9,1.0 Hz,1H),7.24−7.27(m,2H),7.34(dd,J = 4.3,1.5 Hz,2H),7.49(ddd,J = 8.0,1.9,1.0 Hz,1H),7.63(m,1H),7.83(d,J = 5.2 Hz,1H),8.46(dd,J = 4.3,1.5 Hz,2H),9.93(s,1H)
δ 4.28(s,2H),7.11(m,1H),7.24(d,J = 5.5 Hz,1H),7.32−7.36(m,4H),7.61−7.64(m,2H),7.83(m,1H),8.46(dd,J = 4.4,1.6 Hz,2H),10.00(s,1H)
δ 2.72(t,J = 7.3 Hz,2H),3.35−3.40(m,2H),3.71(s,3H),4.20(s,2H),6.86(dd,J = 6.6,1.9 Hz,2H),7.14−7.16(m,3H),7.27(dd,J = 4.4,1.7 Hz,2H),7.71(d,J = 5.1 Hz,1H),8.06(t,J = 5.6 Hz,1H),8.46(dd,J = 4.4,1.7 Hz,2H)
δ 4.29(s,2H),7.25(d,J = 2.0 Hz,1H),7.36(dd,J = 4.4,1.7 Hz,2H),7.40(m,1H),7.60(m,1H),7.86(d,J = 5.2 Hz,1H),7.94(dd,J = 7.0,2.6 Hz,1H),8.47(dd,J = 4.4,1.7 Hz,2H),10.17(s,1H)
δ 2.32(s,3H),4.28(s,2H),7.24(d,J = 5.4 Hz,1H),7.33−7.37(m,3H),7.50(dd,J = 8.5,2.4 Hz,1H),7.64(d,J = 2.4 Hz,1H),7.84(d,J = 5.4 Hz,1H),8.46(dd,J = 4.4,1.7 Hz,2H),10.04(s,1H)
δ 4.29(s,2H),7.25(d,J = 5.2 Hz,1H),7.35(dd,J = 4.3,1.5 Hz,2H),7.40−7.43(m,2H),7.78(m,1H),7.86(d,J = 5.2 Hz,1H),8.46(dd,J = 4.3,1.5 Hz,2H),10.18(s,1H)
δ 0.89(t,J = 7.3 Hz,3H),1.55−1.60(m,2H),2.49−2.51(m,2H),4.28(s,2H),7.14(d,J = 8.5 Hz,2H),7.23(d,J = 5.4 Hz,1H),7.33(dd,J = 4.4,1.7 Hz,2H),7.51−7.53(m,2H),7.82(d,J = 5.4 Hz,1H),8.45(dd,J = 4.4,1.7 Hz,2H),9.93(s,1H)
δ 4.29(s,2H),7.25(d,J = 5.2 Hz,1H),7.34(dd,J = 4.4,1.7 Hz,2H),7.52(dd,J = 6.8,2.0 Hz,2H),7.62(dd,J = 6.8,2.0 Hz,2H),7.85(d,J = 5.2 Hz,1H),8.46(dd,J = 4.4,1.7 Hz,2H),10,12(s,1H)
δ 4.29(s,2H),7.25(d,J = 5.2 Hz,1H),7.34−7.36(m,4H),7.73−7.77(m,2H),7,85(d,J = 5.2 Hz,1H),8.46(dd,J = 4.4,1.5 Hz,2H),10.18(s,1H)
δ 4.34(s,2H),7.28−7.31(m,3H),7.58(m,1H),7.75(m,1H),7.92−7.96(m,2H),8.10(d,J = 7.9 Hz,1H),8.39(dd,J = 4.2,1.5 Hz,2H),8.47(s,1H),9.20(s,1H),10.58(s,1H)
δ 2.25(s,6H),4.28(s,2H),6.74(d,J = 0.7 Hz,1H),7.23(d,J = 5.1 Hz,1H),7.25(d.J = 0.7 Hz,2H),7.33(dd,J = 4.4,1.5 Hz,2H),7.82(d,J = 5.1 Hz,1H),8.45(dd,J = 4.4,1.5 Hz,2H),9.85(s,1H)
δ 4.02(s,2H),7.00(d,J = 5.1 Hz,1H),7.01(d,J = 5.1 Hz,2H),7.40(d,J = 7.8 Hz,1H),7.48(m,1H),7.54(d,J = 5.1 Hz,1H),7.76(s,1H),7.79(d,J = 5.1 Hz,1H),8.47(d,J = 5.1 Hz,2H),10.00(br s,1H)
δ 4.01(s,2H),6.99−7.01(m,3H),7.25−7.26(m,2H),7.48(m,1H),7.54(d,J = 5.1 Hz,1H),8.48−8.49(m,2H),9.93(br s,1H)
δ 2.29(s,3H),4.29(s,2H),7.25(d,J = 5.1 Hz,1H),7.30(d,J = 8.3 Hz,1H),7.35(dd.J = 4.4,1.5 Hz,2H),7.47(dd,J = 8.3,2.0 Hz,1H),7.80(d,J = 2.0 Hz,1H),7.85(d,J = 5.1 Hz,1H),8.46(dd,J = 4.4,1.5 Hz,2H),10.07(s,1H)
δ 0.95(s,9H),3.18(d,J = 6.1 Hz,2H),3.97(s,2H),6.89(d,J = 5.2 Hz,1H),7.02(dd,J = 4.3,1.5 Hz,2H),7.41(d,J = 5.2 Hz,1H),7.91(br s,1H),8.51(dd,J = 4.3,1.5 Hz,2H)
δ 1.66−1.69(m,6H),3.47−3.50(m,4H),3.98(s,2H),6.71(d,J = 5.0 Hz,1H),7.17(dd,J = 4.6,1.5 Hz,2H),7.23(d,J = 5.0 Hz,1H),8.49(dd,J = 4.6,1.5 Hz,2H)
δ 1.19−1.29(m,4H),1.37−1.46(m,2H),1.59−1.63(m,2H),1.67−1.72(m,2H),3.93(m,1H),3.96(s,2H),6.89(d,J = 5.2 Hz,1H),7.02(dd,J = 4.3,1.5 Hz,2H),7.39(d,J = 5.2 Hz,1H),7.80(d,J = 6.7 Hz,1H),8.51(dd,J = 4.3,1.5 Hz,2H)
δ 2.40(s,3H),4.00(s,2H),6.98(d,J = 5.1 Hz,1H),7.01(dd,J = 4.4,1.7 Hz,2H),7.25(dd,J = 8.6,2.4 Hz,1H),7.47−7.51(m,3H),8.47(dd,J = 4.4,1.7 Hz,2H),9.82(br s,1H)
δ 1.98−2.05(m,2H),2.82−2.85(m,4H),4.27(s,2H),7.16(d,J = 8.1 Hz,1H),7.23(d,J = 5.1 Hz,1H),7.32−7.34(m,3H),7.52(s,1H),7.81(d,J = 5.1 Hz,1H),8.45−8.46(m,2H),9.89(s,1H).
δ 4.25(s,2H),7.34(dd,J = 4.4,1.6 Hz,2H),7.40(dd,J = 6.9,2.2 Hz,2H),7.56(s,2H),7.74(dd,J = 6.9,2.2 Hz,2H),8.48(dd,J = 4.4,1.6 Hz,2H),10.10(s,1H)
δ 2.30(s,3H),4.25(s,2H),6.91(d,J = 7.8 Hz,1H),7.21(t,J = 7.8 Hz,1H),7.35(dd,J = 4.4,1.7 Hz,2H),7.48(d,J = 7.8 Hz,1H),7.54−7.56(m,3H),8.48(dd,J = 4.4,1.7 Hz,2H),9.91(s,1H)
δ 3.65(s,3H),3.95(s,2H),6.92(dd,J = 4.4,1.5 Hz,2H),7.32(dd, J= 7.1,1.7 Hz,2H),7.52(dd,J = 7.1,1.7 Hz,2H),8.12(s,1H),8.47(dd,J= 4.4,1.5 Hz,2H),8.86(s,1H)
δ 1.99−2.05(m,2H),2.81−2.87(m,4H),4.24(s,2H),7.17(d,J = 7.9 Hz,1H),7.33−7.34(m,2H),7.40(d,J = 7.9 Hz,1H),7.54(s,2H),7.61(s,1H),8.47−8.48(m,2H),9.87(br s,1H)
δ 4.25(s,2H),7.34−7.36(m,4H),7.56(s,2H),7.81(dt,J = 9.8,2.7 Hz,2H),8.48(dd,J = 4.6,1.8 Hz,2H),10.16(s,1H)
δ 2.34(s,3H),4.25(s,2H),7.34(dd,J = 4.4,1.7 Hz,2H),7.49(dd,J = 8.8,2.4 Hz,1H),7.53(d,J = 8.8 Hz,1H),7.55(d,J = 5.5 Hz,1H),7.56(d,J = 5.5 Hz,1H),7.72(d,J = 2.4 Hz,1H),8.48(dd,J = 4.4,1.7 Hz,2H),10.02(s,1H)
δ 4.01(s,2H),6.98(dd,J = 4.6,1.5 Hz,2H),7.38(d,J = 5.5 Hz,1H),7.61(d,J = 8.6 Hz,2H),7.65(d,J = 5.5 Hz,1H),7.68(d,J = 8.6Hz,2H),8.44(dd,J = 4.6,1.5 Hz,2H),9.43(s,1H)
δ 2.26(s,6H),4.24(s,2H),6.74(s,1H),7.32−7.35(m,4H),7.53(d,J = 5.4 Hz,1H),7.56(d,J = 5.4 Hz,1H),8.48−8.49(m,2H),9.82(s,1H)
δ 2.30(s,3H),4.19(s,2H),6.91(d,J = 7.3 Hz,1H),7.21(t,J = 7.8 Hz,1H),7.29(d,J = 3.2 Hz,1H),7,39(dd,J = 4.5,1.5 Hz,2H),7.47(d,J = 8.5 Hz,1H),7.56(s,1H),8.29(d,J =3.2 Hz,1H),8.48(dd,J = 4.5,1.5 Hz,2H),10.10(s,1H)
δ 4.25(s,2H),6.91(d,J = 7.6 Hz,1H),7.21(t,J = 7.8 Hz,1H),7.34(dd,J = 4.7,1.7 Hz,2H),7.48(m,1H),7.54−7.56(m,3H),8.48(dd,J = 4.4,1.7 Hz,2H),9.90(s,1H)
δ 2.33(s,6H),3.59(s,3H),3.97(s,2H),6.80(s,1H),6.94(dd,J = 4.4,1.6 Hz,2H),7.22(s,2H),8.11(s,1H),8.48(dd,J = 4.4,1.6 Hz,2H),8.81(s,1H)
δ 2.08−2.11(m,2H),2.88−2.95(m,4H),3.60(s,3H),3.97(s,2H),6.94(d,J = 5.7 Hz,2H),7.19(d,J = 7.9 Hz,1H),7.26(m,1H),7.54(s,1H),8.11(s,1H),8.48(d,J = 5.7 Hz,2H),8.83(s,1H)
δ 2.39(s,3H),3.63(s,3H),3.96(s,2H),6.93(dd,J = 4.6,1.5 Hz,2H),7.30(d,J = 8.6 Hz,1H),7.34(dd,J = 8.6,2.5 Hz,1H),7.48(d,J = 2.5 Hz,1H),8.11(s,1H),8.47(dd,J = 4.6,1.5 Hz,2H),8.82(s,1H)
δ 3.67(s,3H),3.96(s,2H),6.92(dd,J = 4.4,1.6 Hz,2H),7.61(d,J = 8.2 Hz,2H),7.70(d,J = 8.2 Hz,2H),8.15(s,1H),8.46(dd,J = 4.4,1.6 Hz,2H),9.04(s,1H)
δ 3.64(s,3H),3.96(s,2H),6.91−6.92(m,2H),7.21(d,J = 8.9 Hz,2H),7.60(d,J = 8.9 Hz,2H),8.13(s,1H),8.45−8.47(m,2H),8.96(s,1H)
δ 1.34(d,J = 6.1 Hz,6H),3.61(s,3H),3.96(s,2H),4.54(m,1H),6.89(dt,J = 9.8,2.8 Hz,2H),6.93(dd,J = 4.4,1.5 Hz,2H),7.46(dt,J = 9.8,2.8 Hz,2H),8.11(s,1H),8.47(dd,J = 4.4,1.5 Hz,2H),8.74(s,1H)
δ 1.74−1.84(m,4H),2.06−2.12(m,2H),2.68(t,J = 6.1 Hz,2H),2.78(t,J = 6.0 Hz,2H),2.88−2.94(m,4H),3.92(s,2H),7.07(dd,J = 4.3,1.5 Hz,2H),7.20(s,2H),7.55(s,1H),8.17(s,1H),8.46(dd,J = 4.3,1.5 Hz,2H)
δ 1.77−1.82(m,4H),2.33(s,6H),2.68(t,J = 6.1 Hz,2H),2.79(t,J = 6.1 Hz,2H),3.92(s,2H),6.80(s,1H),7.07(dd,J = 4.5,1.6 Hz,2H),7.19(s,2H),8.16(s,1H),8.47(dd,J = 4.5,1.6 Hz,2H)
δ 1.76−1.84(m,4H),2.39(s,3H),2.70(t,J = 6.1 Hz,2H),2.78(t,J = 6.1 Hz,2H),3.92(s,2H),7.05(dd,J = 4.3,1.5 Hz,2H),7.27−7.29(m,2H),7.48(s,1H),8.22(s,1H),8.47(dd,J = 4.3,1.5 Hz,2H)
δ 1.77−1.86(m,4H),2.71(t,J = 6.2 Hz,2H),2.79(t,J = 6.2 Hz,2H),3.92(s,2H),7.03(dd,J = 4.3,1.5 Hz,2H),7.61(d,J = 8.8 Hz,2H),7.66(d,J = 8.8 Hz,2H),8.46(dd,J = 4.3,1.5 Hz,2H),8.49(s,1H)
δ 1.75−1.84(m,4H),2.70(t,J = 6.3 Hz,2H),2.78(t,J = 6.1 Hz,2H),3.92(s,2H),7.04(dd,J = 4.6,1.5 Hz,2H),7.21(d,J = 8.6 Hz,2H),7.57(d,J = 8.6 Hz,2H),8.30(br s,1H),8.46(dd,J = 4.6,1.5 Hz,2H)
δ 1.34(d,J = 6.1 Hz,6H),1.78−1.82(m,4H),2.69(t,J = 6.0 Hz,2H),2.78(t,J = 6.0 Hz,2H),3.92(s,2H),4.53(m,1H),6.89(d,J = 8.9 Hz,2H),7.07(dd,J = 4.4,1.7 Hz,2H),7.44(d,J = 8.9 Hz,2H),8.05(s,1H),8.47(dd,J = 4.4,1.7 Hz,2H)
δ 2.38(s,3H),3.98(s,2H),6.98(m,1H),7.12−7.13(m,3H),7.25−7.26(m,2H),7.41(dd,J = 8.2,2.4 Hz,1H),7.48(s,1H),7.79(s,1H),8.57(dd,J = 4.3,1.5 Hz, 2H)
δ 2.06−2.13(m,2H),2.88−2.95(m,4H),3.98(s,2H),6.48(d,J = 3.4 Hz,1H),7.12−7.14(m,3H),7.21(d,J = 8.1 Hz,1H),7.29(dd,J = 8.1,2.0 Hz,1H),7.58(s,1H),7.78(s,1H),8.57(dd,J = 4.6,1.8 Hz,2H)
δ 2.26(d,J = 1.8 Hz,3H),3.98(s,2H),6.49(d,J = 3.7 Hz,1H),7.13−7.16(m,5H),7.54(dd,J = 12.2,1.8 Hz,1H),7.77(s,1H),8.57(dd,J = 4.3,1.5 Hz,2H)
δ 1.28(d,J = 6.7 Hz,6H),2.94(m,1H),3.99(s,2H),6.48(d,J = 3.4 Hz,1H),7.04(d,J = 7.6 Hz,1H),7.13−7.14(m,3H),7.30(t,J = 7.8 Hz,1H),7.46(m,1H),7.50(m,1H),7.79(s,1H),8.57(dd,J = 4.6,1.5 Hz,2H)
δ 2.30(d,J = 1.8 Hz,3H),3.98(s,2H),6.49(d,J = 3.4 Hz,1H),7.00(t,J = 8.9 Hz,1H),7.13−7.14(m,3H),7.37(m,1H),7.49(dd,J = 6.7,2.4 Hz,1H),7.71(s,1H),8.57(dd,J = 4.6,1.8 Hz,2H)
δ 4.04(s,2H),6.46(d,J = 3.4 Hz,1H),7.14(dd,J = 4.4,1.6 Hz,2H),7.20(d,J = 3.4 Hz,1H),7.52(m,1H),7.69(m,1H),7.87(dd,J = 8.2,0.9 Hz,1H),7.93(dd,J = 8.2,0.9 Hz,1H),8.56(dd,J = 4.4,1.6 Hz,2H),8.67(s,1H),8.79(s,1H),9.06(s,1H)
δ 3.99(s,2H),6.50(d,J = 3.4 Hz,1H),7.13−7.16(m,4H),7.30(t,J = 8.1 Hz,1H),7.45(ddd,J = 8.2,2.1,0.9 Hz,1H),7.78(br s,1H),7.78(t,J = 2.1 Hz,1H),8.58(dd,J = 4.3,1.5 Hz,2H)
δ 3.99(s,2H),6.52(d,J = 3.6 Hz,1H),7.15(dd,J = 4.3,1.5 Hz,2H),7.17(d,J = 3.6 Hz,1H),7.32(m,1H),7.50(dd,J = 8.9,2.4 Hz,1H),7.75(br s,1H),7.92(d,J = 2.7 Hz,1H),8.58(dd,J = 4.3,1.5 Hz,2H)
δ 2.36(s,3H),3.98(s,2H),6.49(d,J = 3.4 Hz,1H),7.13−7.14(m,3H),7.21(d,J = 8.1 Hz,1H),7.38(dd,J = 8.1,2.1 Hz,1H),7.73(br s,1H),7.74(d,J = 2.1 Hz,1H),8.57(dd,J = 4.3,1.5 Hz,2H)
δ 1.33(s,9H),3.98(s,2H),6.49(d,J = 3.4 Hz,1H),7.13−7.14(m,3H),7.39(d,J = 8.9 Hz,2H),7.54(d,J = 8.9 Hz,2H),7.74(br s,1H),8.57(dd,J = 4.3,1.5 Hz,2H)
δ 4.01(s,2H),6.53(d,J = 3.4 Hz,1H),7.16(dd,J = 4.4,1.7 Hz,2H),7.20(d,J = 3.4 Hz,1H),7.42(dd,J = 8.8,4.3 Hz,1H),7.71(dd,J = 8.8,2.4 Hz,1H),8.00(br s,1H),8.12(d,J = 9.2 Hz,1H),8.17(m,1H),8.44(d,J = 2.4 Hz,1H),8.59(dd,J = 4.4,1.7 Hz,2H),8.87(dd,J = 4.0,1.5 Hz,1H)
δ 2.42(s,3H),3.98(s,2H),6.49(d,J = 3.4 Hz,1H),7.13−7.14(m,3H),7.33(dd,J = 8.6,2.4 Hz,1H),7.51(d,J = 8.6 Hz,1H),7.56(d,J = 2.4 Hz,1H),7.73(br s,1H),8.57(dd,J = 4.6,1.8 Hz,2H)
δ 3.98(s,2H),6.51(d,J = 3.5 Hz,1H),7.15(dd,J = 4.4,1.5 Hz,2H),7.16(d,J = 3.5 Hz,1H),7.23(d,J = 8.2 Hz,2H),7.66(d,J = 8.9 Hz,2H),7.78(br s,1H),8.58(dd,J = 4.4,1.5 Hz,2H)
δ 2.95(s,6H),3.97(s,2H),6.47(d,J = 3.5 Hz,1H),6.74(d,J = 9.0 Hz,2H),7.09(d,J = 3.5 Hz,1H),7.13(dd,J = 4.6,1.7 Hz,2H),7.47(d,J = 9.0 Hz,2H),7.67(br s,1H),8.56(dd,J = 4.6,1.7 Hz,2H)
δ 2.23(s,3H),3.23(t,J = 8.5 Hz,2H),3.98(s,2H),4.09(t,J = 8.5 Hz,2H),6.47(d,J = 3.4 Hz,1H),7.12−7.17(m,4H),7.78(d,J = 2.0 Hz,1H),7.83(br s,1H),8.19(d,J = 8.5 Hz,1H),8.56(dd,J = 4.4,1.5 Hz,2H)
δ 1.34(d,J = 6.1 Hz,6H),3.97(s,2H),4.52(m,1H),6.48(d,J = 3.4 Hz,1H),6.89(dd,J = 6.6,2.2 Hz,2H),7.10(m,3H),7.51(dd,J = 6.6,2.2 Hz,2H),7.73(s,1H),8.56(dd,J = 4.4,1.7 Hz,2H)
δ 3.99(s,2H),6.52(d,J = 3.4 Hz,1H),7.15(dd,J = 4.4,1.7 Hz,2H),7.18(d,J = 3.4 Hz,1H),7.66(d,J = 8.8 Hz,2H),7.71(d,J = 8.8 Hz,2H),7.84(s,1H),8.58(dd,J = 4.4,1.7 Hz,2H)
δ 3.98(s,2H),6.50(d,J = 3.4 Hz,1H),7.14(dd,J = 4.4,1.7 Hz,2H),7.15(d,J = 3.4 Hz,1H),7.49(d,J = 9.2 Hz,2H),7.54(d,J = 9.2 Hz,2H),7.77(br s,1H),8.57(dd,J = 4.4,1.5 Hz,2H)
δ 2.35(s,3H),3.98(s,2H),6.87(d,J = 3.9 Hz,1H),6.97(d,J = 7.6 Hz,1H),7.13(dd,J = 4.3,1.5 Hz,2H),7.23(t,J = 7.9 Hz,1H),7.35(m,1H),7.39(d,J = 3.9 Hz,1H),7.43(m,1H),7.60(s,1H),8.53(dd,J = 4.3,1.5 Hz,2H)
δ 2.07−2.10(m,2H),2.86−2.92(m,4H),3.98(s,2H),6.87(d,J = 3.9 Hz,1H),7.13(dd,J = 4.4,1.5 Hz,2H),7.18(d,J = 8.2 Hz,1H),7.23(dd,J = 7.9,2.1 Hz,1H),7.38(d,J = 3.9 Hz,1H),7.51(s,1H),7.57(br s,1H),8.53(dd,J = 4.4,1.5 Hz,2H)
δ 2.24(d,J = 1.8 Hz,3H),3.99(s,2H),6.86(d,J = 3.9 Hz,1H),7.13(m,4H),7.40(d,J = 3.9 Hz,1H),7.47(m,1H),7.71(s,1H),8.52(dd,J = 4.6,1.5 Hz,2H)
δ 1.25(d,J = 7.0 Hz,6H),2.91(m,1H),3,99(s,2H),6.87(d,J = 4.0 Hz,1H),7.03(d,J = 7.8 Hz,1H),7.13(dd,J = 4,6,1.5 Hz,2H),7.27(t,J = 7.8 Hz,1H),7.38(dd,J = 2.1,0.9 Hz,1H),7.40(d,J = 4.0 Hz,1H),7.46(t,J = 2.1 Hz,1H),7.62(s,1H),8.53(dd,J = 4.6,1.5 Hz,2H)
δ 2.27(d,J = 1.8 Hz,3H),3.99(s,2H),6.87(d,J = 3.9 Hz,1H),6.98(t,J = 8.9 Hz,1H),7.13(dd,J = 4.5,1.7 Hz,2H),7.31(m.1H),7.39(d,J = 3.9 Hz,1H),7.44(dd,J = 6.6,2.6 Hz,1H),7.56(s,1H),8.53(dd,J = 4.5,1.7 Hz,2H)
δ 4.02(s,2H),6.92(d,J = 4.0 Hz,1H),7.16(dd,J = 4.5,1.5 Hz,2H),7.49−7.53(m,2H),7.68(m,1H),7.85(d,J = 8.2 Hz,1H),7.92(d,J = 7.6 Hz,1H),8.45(s,1H),8.54(dd,J = 4.5,1.5 Hz,2H),8.64(s,1H),9.00(s,1H)
δ 4.00(s,2H),6.89(d,J = 3.9 Hz,1H),7.13(m,1H),7.14(dd,J = 4.6,1.5 Hz,2H),7.28(t,J = 8.1 Hz,1H),7.40(d,J = 3.9 Hz,1H),7.43(ddd,J = 8.1,2.1,0.9 Hz,1H),7.57(s,1H),7.70(t,J = 2.1 Hz,1H),8.53(dd,J = 4.6,1.5 Hz,2H)
δ 4.01(s,2H),6.89(d,J = 3.9 Hz,1H),7.15(dd,J = 4.3,1.5 Hz,2H),7.30(m,1H),7.43(d,J = 3.9 Hz,1H),7.49(dd,J = 8.9,2.4 Hz,1H),7.68(s,1H),7.85(d,J = 2.7 Hz,1H),8.53(dd,J = 4.3,1.5 Hz,2H)
δ 2.34(s,3H),3.99(s,2H),6.87(d,J = 3.9 Hz,1H),7.13(dd,J = 4.6,1.5 Hz,2H),7.18(d,J = 8.2 Hz,1H),7.35(dd,J = 8.2,2.1 Hz,1H),7.40(d,J = 3.9 Hz,1H),7.66(d,J = 2.1 Hz,1H),7.70(br s,1H),8.52(dd,J = 4.6,1.5 Hz,2H)
δ 1.31(s,9H),3.98(s,2H),6.86(d,J = 3.7 Hz,1H),7.13(dd,J = 4.4,1.6 Hz,2H),7.37(d,J = 8.8 Hz,2H),7.39(d,J = 3.7 Hz,1H),7.49(d,J = 8.8 Hz,2H),7.64(s,1H),8.52(dd,J = 4.4,1.6 Hz,2H)
δ 4.01(s,2H),6.91(d,J = 3.9 Hz,1H),7.15(dd,J = 4.6,1.5 Hz,2H),7.41(dd,J = 8.2,4.3 Hz,1H),7.49(d,J = 4.0 Hz,1H),7.65(dd,J = 8.9,2.4 Hz,1H),7.97(s,1H),8.08(d,J = 9.2 Hz,1H),8.14(dd,J = 8.2,1.5 Hz,1H),8.42(d,J = 2.4 Hz,1H),8.54(dd,J = 4.6,1.5 Hz,2H),8.86(dd,J = 4.3,1.5 Hz,1H)
δ 2.39(s,3H),3.99(s,2H),6.88(d,J = 4.0 Hz,1H),7.13(dd,J = 4.6,1.5 Hz,2H),7.28(dd,J = 8.6,2.5 Hz,1H),7.39(d,J = 4.0 Hz,1H),7.48(d,J = 8.6 Hz,1H),7.52(d,J = 2.5 Hz,1H),7.58(br s,1H),8.53(dd,J = 4.6,1.5 Hz,2H)
δ 4.00(s,2H),6.88(d,J = 4.0 Hz,1H),7.14(dd,J = 4.5,1.5 Hz,2H),7.21(d,J = 8.6 Hz,2H),7.42(d,J = 4.0 Hz,1H),7.62(d,J = 8.6 Hz,2H),7.75(s,1H),8.53(dd,J = 4.5,1.5 Hz,2H)
δ 2.23(s,3H),3.22(t,J = 8.6 Hz,2H),3.99(s,2H),4.08(t,J = 8.6 Hz,2H),6.88(d,J = 4.0 Hz,1H),7.06(dd,J = 8.6,2.1 Hz,1H),7.13(dd,J = 4.6,1.5 Hz,2H),7.39(d,J = 4.0 Hz,1H),7.56(s,1H),7.76(s,1H),8.16(d,J = 8.6 Hz,1H),8.53(dd,J = 4.6,1.5 Hz,2H)
δ 1.33(d,J = 5.8 Hz,6H),3.98(s,2H),4.52(m,1H),6.87(d,J = 4.0 Hz,1H),6.87(d,J = 8.9 Hz,2H),7.13(dd,J = 4.3,1.5 Hz,2H),7.38(d,J = 4.0 Hz,1H),7.45(d,J = 8.9 Hz,2H),7.54(br s,1H),8.52(dd,J = 4.3,1.5 Hz,2H)
δ 4.01(s,2H),6.90(d,J = 4.0 Hz,1H),7.14(dd,J = 4.5,1.5 Hz,2H),7.43(d,J = 4.0 Hz,1H),7.63−7.68(m,4H),7.70(s,1H),8.53(dd,J = 4.5,1.5 Hz,2H)
δ 3.99(s,2H),6.87(d,J = 3.9 Hz,1H),7.13(dd,J = 4.6,1.5 Hz,2H),7.41(d,J = 3.9 Hz,1H),7.45−7.50(m,4H),7.77(s,1H),8.52(dd,J = 4.6,1.5 Hz,2H)
δ 4.27(s,2H),7.32(m,1H),7.35(d,J = 6.1 Hz,2H),7.41(d,J = 8.2 Hz,1H),7.46(m,1H),7.50(d,J = 8.2 Hz,1H),7.58(d,J = 7.3 Hz,1H),7.88(d,J = 11.0 Hz,1H),7.98(s,1H),8.45(d,J = 6.1 Hz,2H),10.87(s,1H)
実施例11と同様に以下の化合物11−2〜5を得た。
δ 4.25(s,2H),6.63(d,J = 3.7 Hz,1H),7.24(dd,J = 4.4,1.7 Hz,2H),7.28(d,J = 3.7 Hz,1H),7.41(d,J = 9.0 Hz,2H),7.77(d,J = 9.0 Hz,2H),8.48(dd,J = 4.4,1.7 Hz,2H),10.26(s,1H)
δ 4.23(s,2H),7.13(d,J = 3.9 Hz,1H),7.28(dd,J = 4.4,1.7 Hz,2H),7.40(d,J = 9.0 Hz,2H),7.72(d,J = 9.0 Hz,2H),7.85(d,J = 3.9 Hz,1H),8.49(dd,J = 4.4,1.7 Hz,2H),10.31(s,1H)
δ 2.26(s,6H),4.25(s,2H),6.61(d,J = 3.4 Hz,1H),6.76(s,1H),7.23(dd,J = 4.3,1.5 Hz,2H),7.24(d,J = 3.4 Hz,1H),7.36(s,2H),8.48(dd,J = 4.3,1.5 Hz,2H),9.94(s,1H)
δ 2.31(s,6H),3.98(s,2H),6.79(s,1H),6.86(d,J = 4.0 Hz,1H),7.13(dd,J = 4.6,1.8 Hz,2H),7.21(s,2H),7.38(d,J = 4.0 Hz,1H),7.55(br s,1H),8.52(dd,J = 4.6,1.8 Hz,2H)
本発明化合物の代表的な製剤例を以下に示す。
本発明化合物 1mg
乳糖 66.4mg
トウモロコシデンプン 20mg
カルボキシメチルセルロースカルシウム 6mg
ヒドロキシプロピルセルロース 4mg
ステアリン酸マグネシウム 0.6mg
上記処方の錠剤に、コーティング剤(例えば、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコーン樹脂等の通常のコーティング剤)2mgを用いてコーティングを施し、目的とするコーティング錠を得る。また、本発明化合物ならびに添加物の種類および量を適宜変更することにより、所望の錠剤を得ることができる。
処方2 150mg中
本発明化合物 5mg
乳糖 145mg
本発明化合物と乳糖の混合比を適宜変更することにより、所望のカプセル剤を得ることができる。
処方3 100ml中
本発明化合物 100mg
塩化ナトリウム 900mg
ポリソルベート80 200mg
水酸化ナトリウム 適量
塩酸 適量
滅菌精製水 適量
本発明化合物ならびに添加物の種類および量を適宜変更することにより、所望の点眼剤を得ることができる。
1.血管新生阻害効果の評価試験
薬物の血管新生阻害効果を評価する汎用される方法の一つとして、VEGF誘発HUVEC増殖反応評価系を用いた細胞増殖阻害作用試験がCancer Res.,59,99−106(1999)に報告されている。そこで、前記文献記載の方法に準じて、本発明化合物の細胞増殖阻害作用試験を行い、その細胞増殖阻害率を算出して、それを指標に本発明化合物の血管新生阻害効果を評価した。
被験化合物をジメチルスルホキシド(以下、DMSO)に溶解し、得られた溶液を市販のリン酸緩衝溶液(以下、PBS)で希釈し、20μg/mLの被験化合物溶液を調製した。
HUVECを0.5%ウシ胎児血清(以下、FBS)含有F12K培地に懸濁し、2×104cells/mLのHUVEC懸濁液を調製した。
VEGFを0.1%ウシ血清アルブミン含有PBSに溶解し、得られた溶液を0.5%FBS含有F12K培地で希釈し、400ng/mLのVEGF溶液を調製した。
1)I型コラーゲンでコートした96穴プレートの各穴にHUVEC懸濁液を100μLずつ播種した(1穴あたり2×103cells)。
以下に示す計算式から、血管新生阻害効果の指標となる細胞増殖阻害率(%)を算出した。
細胞増殖阻害率(%)
=100−{(被験化合物懸濁液の吸光度−A)/(コントロールの吸光度−A)}×100
A:細胞懸濁液(細胞+培地)のみの吸光度
試験結果の一例として、被験化合物(化合物1−246、化合物1−248、化合物1−249、化合物1−250、化合物1−251、化合物1−252、化合物1−253、化合物1−255、化合物1−256、化合物1−263、化合物1−269、化合物1−270、化合物1−273、化合物1−274、化合物1−275、化合物1−276、化合物1−283、化合物1−284、化合物1−285、化合物1−287、化合物1−289、化合物1−290、化合物1−291、化合物1−292)の細胞増殖阻害率(%)を表1に示す。
Claims (9)
- 下記一般式[I]で表される化合物またはその塩。
Bはアルキレン基を示し;
R1およびR2は同一または異なって、水素原子、ヒドロキシ基、置換若しくは無置換アルコキシ基、置換若しくは無置換アリールオキシ基、置換若しくは無置換アルキル基、置換若しくは無置換シクロアルキル基、置換若しくは無置換アリール基、置換若しくは無置換複素環基、アミノ基、置換若しくは無置換アルキルアミノ基、置換若しくは無置換アリールアミノ基、または置換若しくは無置換アシル基を示し;
R1とR2は一緒になって、置換または無置換複素環を形成してもよく;
XおよびYは同一または異なって、水素原子、ハロゲン原子、ヒドロキシ基、置換若しくは無置換アルコキシ基、置換若しくは無置換アリールオキシ基、置換若しくは無置換アルキル基、置換若しくは無置換シクロアルキル基、置換若しくは無置換アリール基、メルカプト基、置換若しくは無置換アルキルチオ基、置換若しくは無置換アリールチオ基、カルボキシ基またはそのエステル若しくはそのアミド、シアノ基、およびニトロ基から選択される1または複数の基を示し;
pは0、1または2を示し;
qは0または1を示す。] - 一般式[I]において、部分構造[C]と部分構造[D]が環A上の隣接する炭素原子に結合しており、かつ、それらの炭素原子の位置が環A上のヘテロ原子に対してα位およびβ位である請求項1に記載の化合物またはその塩。
- 一般式[I]において、
R1およびR2が同一または異なって、水素原子、置換若しくは無置換アルコキシ基、置換若しくは無置換アルキル基、置換若しくは無置換シクロアルキル基、置換若しくは無置換アリール基、置換若しくは無置換複素環基、置換若しくは無置換アルキルアミノ基、または置換若しくは無置換アリールアミノ基を示し;
R1およびR2が一緒になって、置換または無置換複素環基を形成してもよく;
XおよびYが水素原子、ハロゲン原子、置換若しくは無置換アルコキシ基、置換若しくは無置換アルキル基、置換若しくは無置換アルキルチオ基、カルボキシ基またはそのエステル若しくはそのアミド、およびシアノ基から選択される1または複数の基を示し;
pが0または1を示す請求項1〜3のいずれかに記載の化合物またはその塩。 - 一般式[I]において、
R1が水素原子、置換アルコキシ基、置換若しくは無置換アルキル基、無置換シクロアルキル基、置換若しくは無置換アリール基、置換若しくは無置換複素環基、無置換アルキルアミノ基、置換アリールアミノ基を示し;
R2が水素原子、または置換若しくは無置換アルキル基を示し;
R1およびR2が一緒になって、置換または無置換複素環基を形成してもよく;
Xが水素原子、ハロゲン原子および無置換アルキル基から選択される1または複数の基を示し;
Yが水素原子、ハロゲン原子、置換若しくは無置換アルコキシ基、無置換アルキル基、無置換アルキルチオ基、カルボキシ基またはそのエステル若しくはそのアミド、およびシアノ基から選択される1または複数の基を示す請求項4記載の化合物またはその塩。 - ・N−(4−イソプロポキシフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(3−フルオロ−4−メチルフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(3−クロロフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(4−クロロフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・3−(2−クロロピリジン−4−イルメチルチオ)−N−(3,5−ジメチルフェニル)チオフェン−2−カルボキサミド、
・N−(4−フルオロ−3−メチルフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(3,4−ジメチルフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・3−(4−ピリジルメチルチオ)−N−(4−トリフルオロメチルフェニル)チオフェン−2−カルボキサミド、
・N−(4−tert−ブチルフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(3−メチルフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(3,4−ジフルオロフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(4−n−プロピルフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・3−(4−ピリジルメチルチオ)−N−(4−トリフルオロメトキシフェニル)チオフェン−2−カルボキサミド、
・N−(3−イソキノリル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(3,5−ジメチルフェニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・3−(4−ピリジルメチルチオ)−N−(3−トリフルオロメチルフェニル)チオフェン−2−カルボキサミド、
・N−(5−インダニル)−3−(4−ピリジルメチルチオ)チオフェン−2−カルボキサミド、
・N−(4−クロロフェニル)−2−(4−ピリジルメチルチオ)チオフェン−3−カルボキサミド、
・N−(3−メチルフェニル)−2−(4−ピリジルメチルチオ)チオフェン−3−カルボキサミド、
・N−(5−インダニル)−2−(4−ピリジルメチルチオ)チオフェン−3−カルボキサミド、
・N−(4−プロモ−3−メチルフェニル)−2−(4−ピリジルメチルチオ)チオフェン−3−カルボキサミド、
・2−(4−ピリジルメチルチオ)−N−(4−トリフルオロメチルフェニル)チオフェン−3−カルボキサミド、
・N−(3,5−ジメチルフェニル)−2−(4−ピリジルメチルチオ)チオフェン−3−カルボキサミド、および、
・N−(3−メチルフェニル)−4−(4−ピリジルメチルチオ)チオフェン−3−カルボキサミドから選択される化合物またはその塩。 - 請求項1〜6のいずれかに記載の化合物またはその塩を含有する医薬組成物。
- 請求項1〜6のいずれかに記載の化合物またはその塩を有効成分として含有する血管新生または血管透過性の亢進が関与する疾患の治療剤。
- 血管新生または血管透過性の亢進が関与する疾患が、癌、関節リウマチ、加齢性黄斑変性、糖尿病網膜症、未熟児網膜症、網膜静脈閉塞症、ポリープ状脈絡膜血管症、糖尿病黄斑浮腫、尋常性乾癬または粥状動脈硬化である請求項8記載の治療剤。
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TWI422583B (zh) | 2014-01-11 |
US20120202817A1 (en) | 2012-08-09 |
PL1602647T3 (pl) | 2014-05-30 |
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US20090286786A1 (en) | 2009-11-19 |
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TW200510377A (en) | 2005-03-16 |
ES2441176T3 (es) | 2014-02-03 |
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