JP2017057200A - 抗dnaウィルス活性などの生理活性を有するヌクレオシド誘導体 - Google Patents
抗dnaウィルス活性などの生理活性を有するヌクレオシド誘導体 Download PDFInfo
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- JP2017057200A JP2017057200A JP2016181449A JP2016181449A JP2017057200A JP 2017057200 A JP2017057200 A JP 2017057200A JP 2016181449 A JP2016181449 A JP 2016181449A JP 2016181449 A JP2016181449 A JP 2016181449A JP 2017057200 A JP2017057200 A JP 2017057200A
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- 239000003795 chemical substances by application Substances 0.000 claims description 20
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Abstract
Description
<1> 下記一般式(1)で表されるヌクレオシド誘導体。
<2> 前記式中、R1が、炭素数1以上のアルキル基によって置換されているアミノ基、置換基を有していてもよい炭素数2以上のアルコキシ基、又は炭素数1以上のアルキル基によって置換されているメルカプト基である、<1>に記載のヌクレオシド誘導体。
<3> R1が、メチルアミノ基、ジメチルアミノ基、エチルアミノ基、シクロプロピルアミノ基、エトキシ基、アリルオキシ基、ベンジルオキシ基及びメチルメルカプト基からなる群から選択される一の官能基であり、かつR2が、水素原子又はアミノ基である、<2>に記載のヌクレオシド誘導体。
<4> <1>〜<3>のうちのいずれか一に記載のヌクレオシド誘導体を有効成分とする、抗DNAウィルス剤。
<5> 抗B型肝炎ウィルス剤である、<4>に記載の抗ウィルス剤。
後述の実施例において示す通り、下記式で表されるヌクレオシド誘導体は、B型肝炎ウィルスに対して抗ウィルス活性を有することが明らかになった。したがって、本発明は、抗DNAウィルス活性を示すヌクレオシド誘導体に関し、より詳しくは、少なくともB型肝炎ウィルスに対して抗ウィルス活性を有する、下記一般式(1)で表されるヌクレオシド誘導体を提供するものである。
後述の実施例において示す通り、本発明のヌクレオシド誘導体は、少なくともB型肝炎ウィルスに対して抗ウィルス活性を有する。したがって、本発明のヌクレオシド誘導体を有効成分とする抗DNAウィルス剤を提供することができる。
2−アミノ−2’−デオキシ−4’−フルオロメチルアデノシン(化合物5)を合成すべく、先ず、下記化合物2(2’−O−Acetyl−2−amino−3’,5’−di−O−benzyl−4’−fluoromethyladenosine)を、以下の通りにして合成した。
1H−NMR(CD3CN):δ7.65(1H,s,H−8),7.24−7.08(10H,m,aromatic),6.02(1H,d,H−1’),5.98(1H,t,H−2’),5.70(2H,br.s,NH2),4.95(2H,br.s,NH2),4.82(1H,d,H−3’),4.71(1H,dd,4’−CHaF),4.61(1H,dd,4’−CHbF),4.62(1H,d,Ph−CHa),4.59(2H,d,Ph−CHb),4.56(1H,d,Ph−CHc),4.53(1H,d,Ph−CHd),3.70(2H,m,H−5’),2.01(3H,s,Ac)。
1H−NMR(DMSO−d6):δ7.84(1H,s,H−8),7.38−7.28(10H,m,aromatic),6.72(2H,br.s,NH2),5.86(1H,d,H−1’),5.81(2H,br.s,NH2),5.74(1H,d,2’−OH),5.01(1H,dd,H−2’),4.89(1H,d,Ph−CHa),4.68−4.53(5H,m,Ph−CH,4’−CH2F),4.28(1H,d,H−3’),3.68(1H,dd,H−5’a),3.64(1H,dd,H−5’b)。
1H−NMR(DMSO−d6):δ7.87(1H,s,H−8),7.37−7.26(10H,m,aromatic),6.71(2H,br.s,NH2),6.23(1H,d,H−1’),5.80(2H,br.s,NH2),4.70−4.50(7H,m,4’−CH2F,Ph−CH2&H−3’),3.64(2H,dd,H−5’a),3.60(2H,dd,H−5’b),2.91(1H,m,H−2’a),2.59(1H,m,H−2’b)。
1H−NMR(DMSO−d6):δ7.91(1H,s,H−8),6.70(2H,br.s,NH2),6.24(1H,dd,H−1’),5.72(2H,br.s,NH2),5.36−5.35(2H,m,3’−OH&5’−OH),4.60(1H,dd,4’−CHaF),4.50(1H,dd,4’−CHbF),4.51(1H,m,H−3’),3.54(1H,br.s,H−5’a),3.53(1H,br.s,H−5’b),2.81(1H,m,H−2’a),2.22(1H,m,H−2’b)。
合成例1にて得られた化合物5を用い、下記の通り6、4’−フルオロメチル−2’−デオキシグアノシン(化合物6)を合成した。
1H−NMR(DMSO−d6):δ10.58(1H,br.s,NH),7.91(1H,s,H−8),6.42(2H,br.s,NH2),6.19(1H,dd,H−1’),5.37(1H,3’−OH),5.09(1H,t,5’−OH),4.59(1H,dd,4’−CHaF),4.49(1H,dd,4’−CHbF),4.49(1H,m,H−3’),3.50(2H,m,H−5’),2.71(1H,m,H−2’a),2.25(1H,m,H−2’b)。
2−アミノ−2’−デオキシ−4’−フルオロメチル−N6−メチルアデノシン(化合物8)を合成すべく、先ず、下記化合物7(3’,5’−Di−O−Acetyl−4’−fluoromethyl−2’−deoxyguanosine)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):δ10.60(1H,s,NH),7.89(1H,s,H−8),6.42(2H,br.s,NH2),6.19(1H,t,H−1’),5.59(1H,dd,H−3’),4.59(1H,dd,4’−CHaF),4.50(1H,dd,4’−CHbF),4.26(1H,dd,H−5’a),4.16(1H,dd,H−5’b),3.02(1H,m,H−2’a),2.48(1H,m,H−2’b),2.07(3H,s,Ac),2.00(3H,s,Ac)。
1H−NMR(DMSO−d6):δ7.87(1H,s,H−8),7.20(1H,s,NH),6.25(1H,dd,H−1’),5.76(2H,br.s,NH2),5.37(1H,t,5’−OH),5.34(1H,d,3’−OH),4.60(1H,dd,4’−CHaF),4.50(1H,dd,4’−CHbF),4.50(1H,m,H−3’),3.53(1H,br.s,H−5’a),3.52(1H,br.s,H−5’b),2.88(3H,br.s,Me),2.80(1H,m,H−2’a),2.22(1H,m,H−2’b)。
2−アミノ−N6−シクロプロピル−2’−デオキシ−4’−フルオロメチルアデノシン(化合物9)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):7.89(1H,s,H−8),7.33(1H,s,NH),6.25(1H,dd,H−1’),5.77(2H,br.s,NH2),5.36−5.35(2H,m,5’−OH&3’−OH),4.59(1H,dd,4’−CHaF),4.50(1H,dd,4’−CHbF),4.50(1H,m,H−3’),3.53(1H,br.s,H−5’a),3.52(1H,br.s,H−5’b),3.02(1H,br.s,cyclopropyl),2.79(1H,m,H−2’a),2.22(1H,m,H−2’b),0.62(4H,m,cyclopropyl)。
4’−フルオロメチル−2’−デオキシ−O6−メチルグアノシン(化合物10)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):8.05(1H,s,H−8),6.37(1H,s,NH),6.29(1H, dd, H−1’),5.36(1H,d,3’−OH),5.12(1H,t,5’−OH),4.59(1H,dd,4’−CHaF),4.51(1H,m,H−3’),4.49(1H,dd,4’−CHbF),3.96(3H,s,OMe),3.52(1H,br.s,H−5’a),3.51(1H,br.s,H−5’b),2.78(1H,m,H−2’a),2.26(1H,m,H−2’b)。
2’−デオキシ−2−フルオロ−4’−フルオロメチルアデノシン(化合物12)を合成すべく、先ず、下記化合物11(3’,5’−Di−O−acetyl−2−amino−2’−deoxy−4’−fluoromethyladenosine)を、以下の通りにして合成した。
1H−NMR(CDCl3):7.61(1H,s,H−8),6.27(1H,t,H−1’),5.81(1H,dd,H−3’),5.35(2H,br.s,NH2),4.82(2H,br.s,NH2),4.68(1H,dd,H−5’a),4.64(1H,dd,4’−CHaF),4.55(1H,dd,4’−CHbF),4.32(1H,dd,H−5’b),3.27(1H,m,H−2’a),2.55(1H,m,H−2’b),2.15(3H,s,Ac),2.07(3H,s,Ac)。
1H−NMR(DMSO−d6):8.31(1H,s,H−8),7.81(2H,br.s,NH2),6.30(1H,dd,H−1’),5.43(1H,d,3’−OH),5.10(1H,t,5’−OH),4.62(1H,dd,CHaF),4.56(1H,m,H−3’),4.56(1H,dd,CHbF),3.54(2H,m,H−5’),2.87(1H,m,H−2’a),2.32(1H,m,H−2’b)。
2−クロロ−2’−デオキシ−4’−フルオロメチルアデノシン(化合物13)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):8.34(1H,s,H−8),7.78(2H,br.s,NH2),6.33(1H,dd,H−1’),5.42(1H,d,3’−OH),5.10(1H,t,5’−OH),4.62(1H,dd,CHaF),4.57−4.49(2H,m,H−3’&CHbF),3.55(1H,s,H−5’a),3.54(1H,s,H−5’b),2.85(1H,m,H−2’a),2.34(1H,m,H−2’b)。
2−アミノ−2’−デオキシ−4’−メチルアデノシン(化合物18)を合成すべく、先ず、下記化合物15(2’−O−Acetyl−2−amino−3’,5’−di−O−benzyl−4’−methyladenosine)を、以下の通りにして合成した。
1H−NMR(CDCl3):δ7.76(1H、s、H−8),7.35−7.29(10H,m,aromatic),6.10(1H,d,H−1’),5.83(1H,dd,H−2’),5.41(2H,br.s,NH2),4.62(2H,br.s,NH2),4.60(1H,d,PhCHa),4.53(1H,d,H−3’),4.52(1H,d,PhCHb),4.50(1H,d,PhCHc),4.47(1H,d,PhCHd),3.55(1H,d,H−5’a),3.37(1H,d,H−5’b),2.08(3H,s,Ac),1.34(3H,s,4’−Me)。
1H−NMR(CDCl3):δ7.68(1H、s、H−8),7.35−7.24(10H,m,aromatic),5.91(1H,d,H−1’),5.83(2H,br.s,NH2),4.96(2H,br.s,NH2),4.79(1H,d,PhCHa),4.74(1H,t,H−2’),4.66(1H,d,PhCHb),4.52(1H,d,PhCHc),4.47(1H,d,PhCHd),4.23(1H,d,H−3’),3.50(1H,d,H−5’a),3.37(1H,d,H−5’b),2.51(1H,br.s,2’−OH),1.36(3H,s,4’−Me)。
1H−NMR(CDCl3):δ7.84(1H、s、H−8),7.35−7.28(10H,m,aromatic),6.26(1H,t,H−1’),5.25(2H,br.s,NH2),4.61(1H,d,PhCHa),4.59(2H,br.s,NH2),4.56(1H,d,PhCHb),4.51(2H,d,PhCHc&PhCHd),4.39(1H,t,H−3’),3.57(1H,d,H−5’a),3.45(1H,d,H−5’b),2.71(1H,m,H−2’a),2.57(1H,m,H−2’b),1.32(3H,s,4’−Me)。
1H−NMR(DMSO−d6):δ7.90(1H,s,H−8),6.70(2H,br.s,NH2),6.13(1H,t,H−1’),5.69(2H,br.s,NH2),5.36(1H,dd,5’−OH),5.12(1H,d,3’−OH),4.31(1H,q,H−3’),3.48(1H,m,H−5’a),3.34(1H,dd,H−5’b),2.71(1H,m,H−2’a),2.21(1H,m,H−2’b),1.09(3H,s,4’−Me)。
2’−デオキシ−4’−メチルグアノシン(化合物19)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):δ10.59(1H,br.s,NH),7.93(1H,s,H−8),6.43(2H,br.s,NH2),6.08(1H,t,H−1’),5.16(1H,d,3’−OH),5.00(1H,t,5’−OH),4.31(1H,q,H−3’),3.44(1H,dd,H−5’a),3.33(1H,dd,H−5’b),2.61(1H,m,H−2’a),2.25(1H,m,H−2’b),1.09(3H,s,4’−Me)。
2−アミノ−2’−デオキシ−4’−メチル−N6−メチルアデノシン(化合物21)を合成すべく、先ず、下記化合物20(3’,5’−Di−O−Acetyl−2’−deoxy−4’−methylguanosine)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):δ10.65(1H,br.s,NH),7.91(1H,s,H−8),6.48(2H,br.s,NH2),6.13(1H,t,H−1’),5.42(1H,dd,H−3’),4.18(1H,dd,H−5’a),4.05(1H,dd,H−5’b),3.03(1H,m,H−2’a),2.50(1H,m,H−2’b),2.11(3H,s,Ac),2.02(3H,s,Ac),1.18(3H,s,4’−Me)。
1H−NMR (DMSO−d6):δ7.90(1H,s,H−8),7.24(1H,br.s,NH),6.14(1H,dd,H−1’),5.79(2H,br.s,NH2),5.34(1H,t,5’−OH),5.14(1H,d,3’−OH),4.31(1H,q,H−3’),3.47(1H,dd,H−5’a),3.33(1H,dd,H−5’b),2.87(3H,br.s,N6−Me),2.70(1H,m,H−2’a),2.21(1H,m,H−2’b),1.09(3H,s,4’−Me)。
2−アミノ−2’−デオキシ−4’−ビニルアデノシン(化合物24)を合成すべく、先ず、下記化合物23(2−Benzamido−N6−benzoyl−3’,5’−di−O−tert−butyldimethylsilyl−2’−deoxy−4’−vinyladenosine)を以下の通りにして合成した。
1H−NMR(CDCl3):δ9.29(1H,br.s,NH),9.24(1H,br.s,NH),8.44(1H,s,H−8),8.04−7.49(10H,m,aromatic),6.49(1H,t,H−1’),5.98(1H,dd,vinyl),5.57(1H,dd,vinyl),5.34(1H,dd,vinyl),4.90(1H,t,H−3’),3.72(1H,d,H−5’a),3.68(1H,dd,H−5’b),2.87(3H,br.s,N6−Me),2.49(2H,m,H−2’),0.94(9H,s,tert−Bu−Si),0.91(9H,s,tert−Bu−Si),0.04,0.03(12H,s,Me−Si)。
粗ジオールをメタノール(10mL)、40%メチルアミン水溶液(10mL)に溶解し、室温で48時間撹拌した。反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=10:1〜5:1)により精製した。残渣を脱イオン水から再結晶化し、化合物24を得た(83mg、0.28mmol、70%)。
1H−NMR(DMSO−d6):δ7.94(1H,s,H−8),6.71(1H,br.s,NH2),6.16(1H,t,H−1’),5.95(1H,dd,vinyl),5.69(2H,br.s,NH2),5.49(1H,t,5’−OH),5.35(1H,dd,vinyl),5.19−5.16(2H,m,3’−OH&vinyl),5.18(1H,dd,vinyl),4.58(1H,q,H−3’),3.50(1H,dd,H−5’a),3.41(1H,dd,H−5’b),2.54(1H,m,H−2’a),2.17(1H,m,H−2’b)。
2’−デオキシ−4’−ビニルグアノシン(化合物25)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):δ10.60(1H,br.s,NH),7.98(1H,s,H−8),6.44(1H,br.s,NH2),6.10(1H,dd,H−1’),5.95(1H,dd,vinyl),5.34(1H,dd,vinyl),5.24(1H,br.s,OH),5.19(1H,dd,vinyl),5.11(1H,br.s,OH&),4.57(1H,t,H−3’),3.50(1H,d,H−5’a),3.40(1H,d,H−5’b),2.44(1H,m,H−2’a),2.19(1H,m,H−2’b)。
2−アミノ−2’−デオキシ−N6−メチル−4’−ビニルアデノシン(化合物27)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):δ7.94(1H,s,H−8),7.26(1H,br.s,NH),6.18(1H,t,H−1’),5.96(1H,dd,vinyl),5.82(2H,br.s,NH2),5.48(1H,t,5’−OH),5.35(1H,dd,vinyl),5.22(1H,d,3’−OH),5.18(1H,dd,vinyl),4.58(1H,q,H−3’),3.50(1H,dd,H−5’a),3.42(1H,dd,H−5’b),2.87(3H,br.s,N6−Me),2.53(1H,m,H−2’a),2.18(1H,m,H−2’b),1.09(3H,s,4’−Me)。
2’−デオキシ−2−フルオロ−4’−ビニルアデノシン(化合物29)を合成すべく、先ず、下記化合物28(3’,5’−Di−O−acetyl−2−amino−2’−deoxy−4’−vinyladenosine)を、以下の通りにして合成した。
1H−NMR(CDCl3):δ7.73(1H,s,H−8),6.28(1H,t,H−1’),5.85(1H,dd,vinyl),5.72(1H,t,H−3’),5.61(1H,dd,vinyl),5.37(1H,dd,vinyl),5.32(2H,br.s,NH2),4.77(2H,br.s,NH2),4.47(1H,d,H−5’a),4.25(1H,d,H−5’b),3.07(1H,m,H−2’a),2.48(1H,m,H−2’b),2.11(3H,s,Ac),2.08(3H,s,Ac)。
1H−NMR(DMSO−d6):δ8.36(1H,s,H−8),7.83(2H,br.s,NH2),6.22(1H,dd,H−1’),5.96(1H,dd,vinyl),5.38(1H,dd,vinyl),5.29(1H,d,3’−OH),5.21(1H,dd,vinyl),5.11(1H,t,5’−OH),4.64(1H,q,H−3’),3.50(1H,dd,H−5’a),3.45(1H,dd,H−5’b),2.58(1H,m,H−2’a),2.25(1H,m,H−2’b)。
2−アミノ−2’−デオキシ−4’−エチルアデノシン(化合物30)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):δ7.93(1H,s,H−8),6.81(2H,br.s,NH2),6.13(1H,dd,H−1’),5.79(2H,br.s,NH2),5.27(1H,br.s,5’−OH),5.10(1H,d,3’−OH),4.36(1H,q,H−3’),3.48(1H,d,H−5’a),3.41(1H,d,H−5’b),2.75(1H,m,H−2’a),2.18(1H,m,H−2’b),1.63(1H,m,CH3−CHa),1.55(1H,m,CH3−CHb),0.87(3H,t,CH3)。
2−アミノ−2’−デオキシ−4’−エチルグアノシン(化合物31)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):δ10.59(1H,br.s,NH),7.93(1H,s,H−8),6.44(2H,br.s,NH2),6.08(1H,dd,H−1’),5.12(1H,d,3’−OH),4.91(1H,t,5’−OH),4.35(1H,q,H−3’),3.42(2H,m,H−5’),2.65(1H,m,H−2’a),2.21(1H,m,H−2’b),1.60(1H,m,CH3−CHa),1.55(1H,m,CH3−CHb),0.86(3H,t,CH3)。
2−アミノ−4’−シアノ−2’−デオキシ−N6−メチルアデノシン(化合物35)を合成すべく、先ず、下記化合物33(3’,5’−Di−O−tert−butyldimethylsilyl−4’−cyano−2’−deoxyguanosine)を、以下の通りにして合成した。
1H−NMR(DMSO−d6):δ10.69(1H,br.s,NH),7.99(1H,s,H−8),6.55(2H,br.s,NH2),6.30(1H,dd,H−1’),4.68(1H,dd,H−3’),3.86(1H,d,H−5’a),3.79(1H,d,H−5’b),2.99(1H,m,H−2’a),2.41(1H,m,H−2’b),0.92(9H,s,tert−Bu),0.87(9H,s,tert−Bu),0.17(3H,s,Me),0.16(3H,s,Me),0.06(3H,s,Me),0.05(3H,s,Me)。
1H−NMR(CDCl3):δ7.55(1H,s,H−8),6.32(1H,t,H−1’),5.59(1Hbr.s,6−NH),4.92(1H,t,H−3’),4.66(2H,br.s,2−NH2),4.01(1H,d,H−5’a),3.86(1H,d,H−5’b),3.11−3.07(4H,m,N6−Me&H−2’a),2.48(1H,m,H−2’b),0.96(9H,s,tert−Bu),0.89(9H,s,tert−Bu),0.19(3H,s,Me),0.17(3H,s,Me),0.08(3H,s,Me),0.04(3H,s,Me)。
1H−NMR(DMSO−d6):δ7.91(1H,s,H−8),7.29(1H,br.s,6−NH),6.34(1H,t,H−1’),6.26(1H,d,3’−OH),5.93(2H,br.s,2−NH2),5.85(1H,t,5’−OH),4.63(1H,q,H−3’),3.77(1H,dd,H−5’a),3.65(1H,dd,H−5’b),2.87(4H,m,N6−Me&H−2’a),2.37(1H,m,H−2’b)。
4’−アジド−2’−デオキシ−O6−メチルグアノシン(化合物39)を合成すべく、先ず、下記化合物36(4’−Azido−N2,O3’−dibenzoyl−5’−(3−chlorobenzoyl)−2’−deoxyguanosine)を、以下の通りにして合成した。
1H NMR(CDCl3,500MHz)δ12.08(brs,1H),9.62(s,1H),8.17−8.16(m,2H),8.04−8.02(m,2H),7.76(s,1H),7.73−7.70(m,2H),7.64−7.57(m,4H),7.48−7.43(m,3H),7.17(t,J=8.0Hz,1H),7.01(dd,J=9.2,7.5Hz,1H),6.37(dd,J=8.0,2.3Hz,1H),5.12(d,J=12.0Hz,1H),4.66(d,J=12.0Hz,1H),3.26(ddd,J=13.2,7.5,2.3Hz,1H),2.90−2.84(m,1H)。
1H NMR(CDCl3,500MHz)δ8.59(bs,1H),8.12−8.10(m,2H),8.03(s,1H),7.89(t,J=1.7Hz,1H),7.79−7.74(m,3H),7.63−7.41(m,7H),7.23(s,2H),7.19(t,J=8.0Hz,1H),6.85(t,J=8.0Hz,1H),6.52(dd,J=8.0,3.4Hz,1H),5.05(d,J=12.0,1H),4.88(d,J=12.0,1H),4.28(sep,J=6.9Hz,2H),3.54−3.48(m,1H),2.96−2.87(m,2H),1.29(d,J=6.9,6H),1.28(d,J=6.9,6H),1.26(d,J=6.9,6H)。
1H NMR(DMSO−d6,500MHz)δ8.08(s,1H),6.54(brs,2H),6.38(dd,J=7.5,5.2Hz,1H),5.78(d,J=4.6,1H),5.48(dd,J=6.3,5.8Hz,1H),4.66(dt,J=6.3,5.2Hz,1H),3.96(s,3H),3.67(dd,J=12.0,6.3Hz,1H),3.57(dd,J=12.0,5.8Hz,1H)2.75−2.70(m,1H),2.47−2.41(m,1H)。
4’−アジド−2’−デオキシ−O6−エチルグアノシン(化合物40)を、以下の通りにして合成した。
1H NMR(DMSO−d6,500MHz)δ8.06(s,1H),6.48(brs,2H),6.38(dd,J=7.5,5.2Hz,1H),5.77(d,J=5.7Hz,1H),5.48(t,J=5.7Hz,1H),4.66(dd,J=10.9,5.7Hz,1H),4.45(q,J=6.9Hz,2H),3.67(dd,J=12.0,5.7Hz,1H),3.57(dd,J=12.0,5.7Hz,1H),2.74−2.68(m,1H),2.47−2.40(m,1H),1.35(t,J=6.9Hz,3H)。
O6−アリル−4’−アジド−2’−デオキシグアノシン(化合物41)を、以下の通りに合成した。
1H NMR(Methanol−d4,500MHz)δ8.05(s,1H),6.48(dd,J=7.5,5.2Hz,1H),6.18−6.08(m,1H),5.48−5.42(m,1H),5.29−5.24(m,1H),5.01−4.98(m,2H),4.81(t,J=6.9Hz,1H),3.83(d,J=12.0Hz,1H),3.71(d,J=12.0Hz,1H),2.91−2.84(m,1H),2.56−2.51(m,1H)。
4’−アジド−O6−ベンジル−2’−デオキシグアノシン(化合物42)を、以下の通りにして合成した。
1H NMR(Methanol−d4,500MHz)δ;8.03(s,1H),7.50−7.49(m,2H),7.37−7.28(m,3H),6.47(dd,J=6.9,5.2Hz,1H),5.53(s,2H),4.81(t,J=6.9Hz,1H),3.82(d,J=12.0Hz,1H),3.70(d,J=12.0Hz,1H),2.87(ddd,J=12.0,6.9,5.2Hz,1H),2.56−2.50(m,1H)。
2−アミノ−4’−アジド−2’−デオキシ−N6−メチルアデノシン(化合物43)を、以下の通りにして合成した。
1H NMR(Methanol−d4,500MHz)δ7.89(s,1H),6.44(t,J=6.3Hz,1H),4.75(dd,J=6.3,5.7Hz,1H),3.82(d,J=12.0Hz,1H),3.66(d,J=12.0Hz,1H),3.03(brs,3H),2.92−2.87(m,1H),2.53−2.48(m,1H)。
2−アミノ−4’−アジド−2’−デオキシ−N6−エチルアデノシン(化合物44)を、以下の通りにして合成した。
1H NMR(Methanol−d4,500MHz)δ7.89(s,1H),6.44(t,J=6.3Hz,1H),4.78(dd,J=6.3,5.7Hz,1H),3.82(d,J=12.0Hz,1H),3.66(d,J=12.0Hz,1H),3.53(m,2H),2.89(ddd,J=13.2,6.3,6.3Hz,1H),2.54−2.48(m,1H),1.25(t,J=7.2Hz,3H)。
2−アミノ−4’−アジド−2’−デオキシ−N6−シクロプロピルアデノシン(化合物45)を、以下の通りにして合成した。
1H NMR(Methanol−d4,500MHz)δ7.90(s,1H),6.44(t,J=6.3Hz,1H),4.75(t,J=6.3Hz,1H),3.81(d,J=12.0Hz,1H),3.66(d,J=12.0Hz,1H),2.91−2.84(m,1H),2.90(brs,1H),2.54−2.47(m,1H),0.85−0.80(m,2H),0.62−0.57(m,2H)。
4’−アジド−2’−デオキシ−2−フルオロ−O6−メチルイノシン(化合物46)を、以下の通りにして合成した。
1H NMR(DMSO−d6,500MHz)δ8.55(d,J=0.6Hz,1H),6.49(ddd,J=7.6,4.0,0.6Hz,1H),5.80(dd,J=5.7,0.6Hz,1H),5.38(ddd,J=6.3,5.7,0.6Hz,1H),4.74(ddd,J=13.2,7.5,0.6Hz,1H),4.12(s,3H),3.69(ddd,J=12.0,5.7,0.6Hz,1H),3.60(ddd,J=12.0,5.7,0.6Hz,1H),2.84−2.78(m,1H),2.56−2.51(m,1H)。
4’−アジド−2’−デオキシイノシン(化合物47)を、以下の通りにして合成した。
1H NMR(DMSO−d6,500MHz)δ12.45(s,1H),8.31(s,1H),8.09(s,1H),6.48(dd,J=7.5,4.7Hz,1H),5.83(brs,1H),5.48(brs,1H),4.69(t,J=7.2Hz,1H),3.68(d,J=12.0Hz,1H),3.58(d,J=12.0Hz,1H),2.77(ddd,J=13.4,7.2,4.7Hz,1H),2.51−2.49(m,1H)。
2−アミノ−4’−アジド−2’−デオキシアデノシン(化合物53)を合成すべく、先ず、下記化合物48(2−Amino−2’,5’−dideoxy−5’−iodoadenosine)を、以下の通りにして合成した。
1H NMR(DMSO−d6,500MHz)δ7.94(s,1H),6.72(brs,2H),6.20(dd,J=8.0,6.3Hz,1H),5.82(brs,2H),5.50(d,J=4.0Hz,1H),4.37−4.33(m,1H),3.95−3.90(m,1H),3.53(dd,J=10.3,6.9Hz,1H),3.41(dd,J=10.3,6.6Hz,1H),2.88−2.80(m,1H),2.24−2.18(m,1H)。
1H NMR(DMSO−d6,500MHz)δ7.90(s,1H),6.74(brs,2H),6.40(t,J=6.3Hz,1H),5.85(brs,2H),5.57(d,J=5.2Hz,1H),4.93−4.89(m,1H),4.22(s,1H),4.12(s,1H),2.92−2.85(m,1H),2.35−2.28(m,1H)。
1H NMR(DMSO−d6,500MHz)δ7.97(s,1H),6.75(brs,2H),6.38(t,J=6.9Hz,1H),6.20(d,J=5.2Hz,1H),5.87(brs,2H),4.79−4.74(m,1H),3.76(d,J=10.9Hz,1H),3.61(d,J=10.9Hz,1H),3.04−2.97(m,1H),2.48−2.41(m,1H)。
1H NMR(DMSO−d6,500MHz)δ8.10−8.07(m,2H),8.02(s,1H),7.76−7.72(m,1H),7.63−7.59(m,2H),6.81(brs,2H),6.58(t,J=6.9Hz,1H),6.04(dd,J=6.3,4.0Hz,1H),5.91(brs,2H),3.99(d,J=11.5Hz,1H),3.78(d,J=11.5Hz,1H),3.48−3.41(m,1H),2.86−2.79(m,1H)。
1H NMR(DMSO−d6,500MHz)δ10.66(brs,1H),10.52(brs,1H),8.52(s,1H),8.12−8.08(m,2H),7.77−7.72(m,1H),7.64−7.59(m,2H),6.76(t,J=6.9Hz,1H),6.21(dd,J=6.3,4.6Hz,1H),4.17(d,J=11.5Hz,1H),3.85(d,J=11.5Hz,1H),3.67−3.60(m,1H),2.89−2.82(m,1H),2.31(s,3H),2.22(s,3H)。
1H NMR(DMSO−d6,500MHz)δ7.92(s,1H),6.77(brs,2H),6.34(dd,J=7.5,5.7Hz,1H),5.83(brs,2H),5.78(brs,1H),5.66(brs,1H),4.64(t,J=6.3Hz,1H),3.67(dd,J=12.0,4.0Hz,1H),3.54(dd,J=12.0,4.6Hz,1H),2.76−2.69(m,1H),2.44−2.37(m,1H)。
後述の化合物80、82、84及び97を合成するに際し、これら化合物に共通する中間体(化合物78)を、以下に示す反応工程にて合成した。
1H−NMR(CDCl3,500MHz);δ12.08(1H,brs),8.36(1H,brs),7.73(1H,s),6.19(1H,dd,J=9.0,5.5Hz),5.21(1H,d,J=10.5Hz),4.61(1H,d,J=5.5Hz),4.12(1H,d,J=1.0Hz),3.94(1H,m),3.74(1H,m),2.79(1H,m),2.65(1H,m),2.23(1H,m),1.28(3H,d,J=3.0Hz),1.27(3H,d,J=3.0Hz),0.93(9H,s),0.118(3H,s),0.115(3H,s)。
1H−NMR(CDCl3,500MHz);δ12.08(1H,brs),9.78(1H,brs),7.92(1H,s),6.27(1H,t,J=7.0Hz),4.83(1H,dd,J=7.0,4.0Hz),4.76(1H,brs),3.95(1H,d,J=12.0Hz),3.89(1H,d,J=11.0Hz),3.68−3.61(3H,m),2.85−2.77(2H,m),2.41(1H,m),1.25(3H,d,J=7.0Hz),1.22(3H,d,J=7.0Hz),0.90(9H,s),0.13(3H,s),0.12(3H,s)。
1H−NMR(CDCl3,500MHz);δ12.03(1H,brs),8.68(1H,brs),7.94(1H,s),6.24(1H,t,J=6.0Hz),4.79(1H,dd,J=6.5,5.0Hz),3.83(1H,dd,J=12.0,4.5Hz),3.75(1H,d,J=10.5Hz),3.69−3.65(2H,m),2.68−2.58(3H,m),2.50−2.45(1H,m),1.27(3H,d,J=7.0Hz),1.24(3H,d,J=7.0Hz),0.92(9H,s),0.91(9H,s),0.14(3H,s),0.13(3H,s),0.08(3H,s),0.07(3H,s)。
1H−NMR(CDCl3,500MHz);δ12.00(1H,brs),7.97(1H,brs),7.81(1H,s),6.36(1H,t,J=6.5Hz),4.82(1H,t,J=6.0Hz),3.91(2H,s),2.66−2.55(3H,m),1.31(6H,d,J=7.0Hz),0.97(9H,s),0.90(9H,s),0.19(3H,s),0.17(3H,s),0.11(3H,s),0.07(3H,s)。
1H−NMR(CDCl3,500MHz);δ7.99(1H,s),7.95(1H,brs),7.23(2H,s),6.38(1H,t,J=6.5Hz),5.18(1H,t,J=5.5Hz),4.25(2H,m),4.12(1H,d,J=11.5Hz),3.95(1H,d,J=11.0Hz),3.20(1H,m),2.94(1H,m),2.69(1H,brs),2.51(1H,m),1.30−1.26(18H,m),1.23(3H,d,J=2.0Hz),1.21(3H,d,J=1.5Hz),0.96(9H,s),0.88(9H,s),0.22(3H,s),0.14(3H,s),0.070(3H,s),0.065(3H,s)。
2−アミノ−9−(4−C−シアノ−2−O−デオキシ−β−D−リボフラノシル)−6−ジメチルアミノプリン(化合物80)の合成に際し、先ず、合成例30にて得られた化合物78を用い、化合物79(2−アミノ−9−(3,5−ジ−O−tert−ブチルジメチルシリル−4−C−シアノ−2−O−デオキシ−β−D−リボフラノシル)−6−ジメチルアミノプリン)を、以下の通りにして合成した。
1H−NMR(CDCl3,500MHz);δ7.69(1H,s),7.63(1H,brs),6.36(1H,t,J=6.5Hz),5.03(1H,t,J=5.5Hz),4.04(1H,d,J=11.0Hz),3.93(1H,d,J=11.0Hz),3.47(6H,brs),3.11(2H,m),2.48(1H,m),1.26(6H,d,J=7.0Hz),0.97(9H,s),0.89(9H,s),0.21(3H,s),0.16(3H,s),0.083(3H,s),0.066(3H,s)。
1H−NMR(CD3OD,500MHz);δ7.82(1H,s),6.43(1H,t,J=7.0Hz),4.78(1H,dd,J=6.0,4.0Hz),3.96(1H,d,J=12.0Hz),3.88(1H,d,J=12.5Hz),3.40(6H,brs),2.95(1H,m),2.48(1H,m)。
2−アミノ−9−(4−C−シアノ−2−O−デオキシ−β−D−リボフラノシル)−6−シクロプロピルアミノプリン(化合物82)の合成に際し、先ず、合成例30にて得られた化合物78を用い、化合物81(2−アミノ−9−(3,5−ジ−O−tert−ブチルジメチルシリル−4−C−シアノ−2−O−デオキシ−β−D−リボフラノシル)−6−シクロプロピルアミノプリン)を、以下の通りにして合成した。
1H−NMR(CDCl3,500MHz);δ7.56(1H,s),6.32(1H,t,J=6.5Hz),5.73(1H,brs),4.92(1H,t,J=6.0Hz),4.71(2H,brs),4.01(1H,d,J=11.0Hz),3.86(1H,d,J=11.0Hz),3.08(1H,m),2.97(1H,brs),2.48(1H,m),0.96(9H,s),0.89(9H,s),0.86(2H,m),0.61(2H,m),0.19(3H,s),0.17(3H,s),0.085(3H,s),0.043(3H,s)。
1H−NMR(CD3OD,500MHz);δ7.86(1H,s),6.42(1H,t,J=6.5Hz),4.80(1H,m),3.96(1H,d,J=12.0Hz),3.88(1H,d,J=12.5Hz),2.95(1H,m),2.90(1H,brs),2.49(1H,m),0.83(1H,d,J=5.0Hz),0.60(1H,s)。
2−アミノ−9−(4−C−シアノ−2−O−デオキシ−β−D−リボフラノシル)−6−エチルアミノプリン(化合物84)の合成に際し、先ず、合成例30にて得られた化合物78を用い、化合物83(2−アミノ−9−(3,5−ジ−O−tert−ブチルジメチルシリル−4−C−シアノ−2−O−デオキシ−β−D−リボフラノシル)−6−エチルアミノプリン)を、以下の通りにして合成した。
1H−NMR(CDCl3,500MHz);δ7.56(1H,s),6.33(1H,t,J=6.5Hz),5.57(1H,brs),4.92(1H,t,J=6.0Hz),4.67(2H,brs),4.01(1H,d,J=11.0Hz),3.86(1H,d,J=11.0Hz),3.59(2H,brs),3.08(1H,m),2.47(1H,m),1.26(3H,t,J=7.5Hz),0.96(9H,s),0.89(9H,s),0.19(3H,s),0.17(3H,s),0.078(3H,s),0.047(3H,s)。
1H−NMR(CD3OD,500MHz);δ7.85(1H,s),6.42(1H,t,J=7.0Hz),4.80(1H,dd,J=6.5,4.5Hz),3.97(1H,d,J=12.0Hz),3.89(1H,d,J=12.0Hz),3.54(2H,brs),2.96(1H,m),2.49(1H,m),1.25(3H,t,J=7.0Hz)。
2−アミノ−9−(4−C−シアノ−2−O−デオキシ−β−D−リボフラノシル)−6−チオメトキシアミノプリン(化合物97)を、以下の通りにして合成した。
1H−NMR(CDCl3,500MHz);δ7.74(1H,s),6.37(1H,t,J=6.5Hz),4.91(3H,m),3.98(1H,d,J=11.0Hz),3.87(1H,d,J=11.0Hz),3.03(1H,m),2.62(3H,s),2.51(1H,m),0.97(9H,s),0.88(9H,s),0.20(3H,s),0.17(3H,s),0.09(3H,s),0.04(3H,s)。
1H−NMR(CD3OD,500MHz);δ7.99(1H,s),6.42(1H,t,J=6.5Hz),4.83(1H,t,J=6.0Hz),3.92(1H,d,J=12.5Hz),3.84(1H,d,J=12.0Hz),2.95(1H,m),2.55(3H,s),2.51(1H,m)。
供試細胞として、ヒト肝ガン由来細胞株(HepG2細胞)にHBV遺伝子を導入することにより、持続的にHBVを産生するように調製された、HepG2 2.2.15細胞を用いた。なお、HepG2 2.2.15細胞は、10%胎児ウシ血清含有DMEMにおける継続培養にて維持した。また、当該細胞は、エピソームとして産生するHBV遺伝子を有するため、このエピソームHBVのDNAを定量し、上記ヌクレオシド誘導体の存在下における当該量の減少度によって抗HBV活性を評価とした。得られた結果を表2〜4に示す。
5’−GCGAGGACTGGGGACCCTGTGACGAAC−3’(配列番号:1)、及び 5’−GTCCACCACGAGTCTAGACTCTGC−3’(配列番号:2)。
また、PCRの反応は、95℃で10分間、その後、95℃で15秒と60℃で1分間とを40サイクル行った。
上記ヌクレオシド誘導体に関し、HepG2細胞及びHepG2 2.2.15細胞に対する細胞毒性試験も行った。様々な濃度の各ヌクレオシド誘導体を添加した培地と共に、HepG2細胞に関しては2×103cells/100μLの濃度になるよう、またHepG2 2.2.15細胞に関しては1.5×104/100μLの濃度になるよう、各々播種した。このようにして様々な濃度の各ヌクレオシド誘導体の存在下で5日間、これら細胞を培養した後、各ウェルの生存細胞数をCell Counting Kit−8を使用して計測した。そして、得られた生存細胞数に基づき、各ヌクレオシド誘導体に関し、CC50を算出した。得られた結果を表2〜4に示す。
供試細胞として、前記HepG2 2.2.15細胞を親株とする、HepG2 2.2.15.7細胞を用いた。なお、HepG2 2.2.15細胞は、10%胎児ウシ血清、G418(500μg/ml)及び抗生剤(ペニシリンとカナマイシン)含有DMEMにおける継続培養にて維持した。また、HepG2 2.2.15.7細胞は、HepG2 2.2.15細胞同様、ゲノムに統合されたDNAだけでなくエピソームとして産生されるHBV遺伝子を保持するHBV持続産生細胞である。そこで、各ヌクレオシド誘導体と共培養し、培養上清に放出されるウイルスのDNAコピー数を定量し、その減少度を抗HBV活性の評価の指標とした。
上記ヌクレオシド誘導体に関し、HepG2細胞に対する細胞毒性試験も行った。段階希釈後の各濃度の各ヌクレオシド誘導体を添加した培地と共に、HepG2細胞を1×104cells/mlの濃度になるよう播種した。このようにして様々な濃度の各ヌクレオシド誘導体の存在下、37℃、5%CO2の標準培養条件で7日間、これら細胞を培養した後、各ウェルの生存細胞数をMTTアッセイで定量化した。そして、得られた生存細胞数に基づき、各ヌクレオシド誘導体に関し、CC50を算出した。得られた結果を表5〜7に示す。
化合物24、8、35及び21に関し、ETV耐性株(遺伝子型:HBV/Ce、後述の表においては「HBV ETVr」と表記する)をトランスフェクトしたHuh−7細胞に各々添加した。そして、その72時間後に各細胞から常法に沿ってDNAを抽出し、HBV遺伝子に対するプローブを用いたサザンブロットにて分析し、ウイルスのDNAコピー数を定量し、上記同様にEC50値を算出した。得られた結果を表2及び4に示す。
<223> 人工的に合成されたプライマーの配列
Claims (5)
- 下記一般式(1)で表されるヌクレオシド誘導体。
- 前記式中、R1が、炭素数1以上のアルキル基によって置換されているアミノ基、置換基を有していてもよい炭素数2以上のアルコキシ基、又は炭素数1以上のアルキル基によって置換されているメルカプト基である、請求項1に記載のヌクレオシド誘導体。
- R1が、メチルアミノ基、ジメチルアミノ基、エチルアミノ基、シクロプロピルアミノ基、エトキシ基、アリルオキシ基、ベンジルオキシ基及びメチルメルカプト基からなる群から選択される一の官能基であり、R2が、水素原子又はアミノ基であり、かつR3が、メチル基、モノフルオロメチル基、エテニル基、シアノ基及びアジド基からなる群から選択される一の官能基である、請求項2に記載のヌクレオシド誘導体。
- 請求項1〜3のうちのいずれか一項に記載のヌクレオシド誘導体を有効成分とする、抗DNAウィルス剤。
- 抗B型肝炎ウィルス剤である、請求項4に記載の抗DNAウィルス剤。
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