CN1080264C - 氧硫杂环戊烷、其制备方法和含此类化合物的药物组合物 - Google Patents
氧硫杂环戊烷、其制备方法和含此类化合物的药物组合物 Download PDFInfo
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- CN1080264C CN1080264C CN95190647A CN95190647A CN1080264C CN 1080264 C CN1080264 C CN 1080264C CN 95190647 A CN95190647 A CN 95190647A CN 95190647 A CN95190647 A CN 95190647A CN 1080264 C CN1080264 C CN 1080264C
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- cytosine
- oxathiolane
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- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001566 pro-viral effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical class OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
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Abstract
本发明涉及有机化学领域,具体地涉及治疗化学。本发明提供通式(I)的顺式5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷,式中R是从单环或双环氮杂环衍生的一个酰基或芳烷基基团,且2位羟甲基基团相对于2位和5位确定的平面处在顺式位置。通式(I)的化合物可作为活性成分用于药物组合物,尤其具有抗病毒活性的药物组合物。
Description
本发明涉及有机化学领域,更确切地说,涉及药物化学领域。
更具体地说,其对象物质是在2位上有一个氧硫杂环戊烷环取代的2′,3′-二脱氧核苷。
具体地说,本发明的对象物质是有顺式构型(2R-5S)或(2S-5R)的5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷,其通式为:可以用以下两种空间表达式中的一种来代表:式中R是一个从单环或双环氮杂环衍生的酰基基团或芳烷基基团,且2位上的羟甲基基团相对于2和5这两个位置所确定的平面而言处于顺式位置。
取代基R所取的各种定义当中,可区分为
a)烟酸衍生物,其中该杂环是一种吡啶结构,且酰基片断处于2、3或4位上,其通式为Ia式中X是一个氢、一个卤原子、一个硝基、一个低级烷氧基或一个三氟甲基基团,而n是1~3的一个整数;
b)二氢吡啶酸衍生物,其中该杂环是一个1,4-二氢吡啶结构,且酰基处于2、3或4位上,其通式为Ib式中R1是一个有1~10个碳原子的烷基基团,X和n的定义同上:
f)季铵化喹啉酸类,通式为If式中R1、X和n′的定义同上,酰基基团在2、3或4位上,而A是一个无机或有机阴离子;
通式I的化合物可以拆解成其光学活性异构体。因此,可以得到异构体(+)和异构体(-)。
逆转录病毒感染是严重感染的原因,尤其是获得性免疫缺陷综合征(AIDS)感染的原因,后者是一种往往致死和在较小程度上导致肝炎的病毒性感染。目前有几种核苷型或杂核苷型化合物在临床上用于治疗这些退行性病毒感染。先有化合物是AZT(3′-叠氮基-2′,3′-二脱氧胸苷)衍生物(Proc.Natl.Acad.Sci.82,7096-7100,1985)、ddC(2′,3′-二脱氧胞苷)衍生物(Proc.Natl.Acad.Sci.86,1911-15,1986)、d4T(2′,3′-二脱氢-3′-脱氧胸苷)衍生物(Biochem.Biophys.Res.Comm.142,128-34,1987)、ddl(2′,3′-二脱氧肌苷)衍生物(Antiviral.Chem.Chemother 2,221,1991)、欧洲专利申请90201335.7中公开的BCH-189或3TC(2′,3′-二脱氧-3′-硫代胞苷)衍生物等。可供医师利用的抗退行性病毒化合物的数目有限和有限疗效,表明需要探索能提高疗效和减少副作用的新化合物。
已经知道2-[(1-羟甲基)-1,3-氧硫杂环戊烷-5-基]胞嘧啶的一些衍生物,即羟甲基官能的酯类(欧洲专利申请0382526)或嘧啶环5位的卤代衍生物(R.F.SCHINAZI et al.Antimicrob.Agents and Chemotherapy36(1992)2423-2431)。
本发明的化合物具有抑制人体逆转录病毒、尤其VIH和B型肝炎(HBV)复制的能力。从BCH-189或TC-3衍生的化合物在其结构中包括一个与胞嘧啶的外环代氨基结合的1,4-二氢-1-甲基-3-喹啉甲酰基。这种特定结构实体使得在实验药理学上能增加和促进血-脑屏障的渗透(Pharmacol.Ther.19,337-396,1983-MethodsEnzymol 112,381-396,1985-Drug Des.Del,1,51-64,(1986)-J.Med.Chem.31,244-249,1988-J.Med.Chem.32,1782-1788,1989-J.Med.Chem.32,1774-1781,1989)。
这些化合物的化学合成已经用经典实验方案进行。这些新型杂核苷的性能要求用化合物2′,3′-二脱氧-3′-硫代胞嘧啶作为起始原料,在化学文献上已报道了它的几种合成方法(J.Org.Chem.56,6503,1991-J.Org.Chem.57,2217,1992-Tet.Letter 33,4625,1992-Nucleosides and Nucleotides 12,225,1993)。本申请中也描述了从这种衍生物出发的、作为本发明对象物质的化合物的合成和与其有关的中间体化合物的合成。
本发明也涉及通式I化合物的生产工艺,该工艺在于让一种顺式5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷与通式ROH羧酸的一种官能衍生物发生作用,式中R是从一个芳族或二氢芳族单环或双环氮杂环衍生的一个酰基片断,或与通式R′Z的一种芳烷基化活性衍生物发生作用,式中R′是从一个芳族或二氢芳族单环或双环氮杂环衍生的一个芳烷基基团,而Z是一个易断裂的不稳定基团。
更准确地说,ROH酸的官能衍生物是一种卤化物,一种酐,一种从碳化二亚胺得到的混酐,或一种活泼酯如苯酚酯。
在芳烷基化衍生物的情况下,Z是一个卤原子或一个烷基-或芳基磺酰基。
本发明也涉及作为对象物质的、有抗病毒作用的药物组合物,其特征在于它们包括至少一种通式I化合物或其与无机酸或有机酸的酸加成盐作为活性组分,并掺合或缔合一种情性、无毒、药物上可接受的载体或赋形制,使之尤其适合于局部或全身性施用。
在这些组合物中,通式I活性组分的含量范围因给药方式而异,为每单元剂量0.1mg~100mg。
实例I
顺式2-(二苯基叔丁基甲硅氧基甲基)-5-[N4-(3″-吡啶基羰基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体1
在室温、氮气流下,向二氯甲烷(7ml)和二甲基甲酰胺(2ml)的混合物中添加1当量烟酸(27mg,0.21mmol)、1.1当量BOP(93mg,0.23mmol)、1.1当量HOBT(31mg,0.23mmol)、1当量5′-叔丁基二苯基甲硅烷基-2′,3′-二脱氧-3′-硫代胞苷(39mg,0.23mmol)和4当量DIEA(146μl,0.84mmol)。混合物在室温搅拌过夜,用5%柠檬酸溶液(10ml)洗涤,然后用5%碳酸氢钠水溶液(10ml)洗涤。得到的混合物用乙酸乙酯(3×10ml)萃取,用Na2SO4干燥,蒸发。残留物在硅胶板上纯化,得到48mg纯化合物。[1H] NMRδ(CDCl3)=1.1(s.9H.tBu).3.1-3. 6(m.2H.CH2-O).3.7-4.2(m.2H.C4H2):5.25(t.1H.C5-H):3.1-3.6(m.2H.CH2-O):5.5(d.1H.C5′-H).6.35(q.1HC2-H):7.4-7.8(m.1H. 芳基):8.0(d.1H.C6′-H);8.3(d.1H.烟酸基):8.8(d.1H,烟酸基):8.8(d.1H.烟酸基):9.1(d.1H.烟酸基).
实例II
顺式2-(羟甲基)-5-[N4-(3″-吡啶基羰基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体2
化合物1(25mg,0.05mmol)溶解在3ml无水四氢呋喃中。向此溶液中添加3当量(135μl,0.15mmol)氟化四丁铵。此溶液在室温混合3小时。蒸发溶剂后,得到的产物在制备硅胶板上色谱法分离(洗脱剂:甲苯/CH3OH15%)。得到13mg所希望的化合物。[1H]NMRδ(CDCl3)=3.1-3.6(m.2H.CH2-O).3.7-4.2(m.2H.C4H2)5.25(t.1H.C5-H).55(d.H.C5′-H):6.35(q.1H.C2-H).7.4-7.8(m.1H.ar芳基ue).8.0(d.1H.C6′-H).8.3(d.1H.烟酸基):8.8(d.1H.烟酸基).9.1(s.1H.烟酸基).
实例III
顺式2-(叔丁基二苯基甲硅氧基甲基)-5-[N4-(3″-(甲苯磺酰基))胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体4
向化合物5(56mg,0.12mmol)的吡啶(3ml)溶液中,在60℃、氮气氛下,添加2当量对甲苯磺酰氯(46mg,0.24mmol)。在室温搅拌20小时后,混合物蒸发、用5%柠檬酸溶液(10ml)洗涤,然后用乙酸乙酯(3×10ml)萃取。合并的有机相用Na2SO4干燥、蒸发,分离出48mg所希望的化合物。[1H]NMR:(CDCl3)=1.1(s,9H,叔丁基);2.45(s,3H,CH3甲苯磺酰基);3.15-3.55(m,2H,C2-CH2-O);3.85-4.2(m,2H,C4H2);5.25(t,1H,C5-H);6.3(t,1H,C2-H);7.3-7.7(m,14H,ArH);8.05(d,1H,C6-H)。
实例IV
顺式2-(二苯基叔丁基甲硅氧基甲基)-5-[N4-(3″-(吡啶基羰基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体3
在90℃、氮气氛下,向衍生物4(47mg,0.075mmol)的卢剔啶(2ml)溶液中添加6当量(46μl,0.45mmol)吡啶基甲胺。在搅拌下使加热保持48小时。冷却后混合物蒸发、用5%柠檬酸溶液(10ml)洗涤,然后用乙酸乙酯(3×10ml)萃取,用Na2SO4干燥。蒸发后残留物用硅胶板色谱法(洗脱剂:EtOAc/MeOH,10/1)纯化。
实例V
顺式2-(叔丁基二苯基甲硅氧基甲基)-5-(胞嘧啶-1′-基)-1,3-氧硫杂环戊烷异构体5
2′,3′-二脱氧-3′-硫代胞苷(105mg,0.45mmol)的吡啶(6ml)溶液在氮气氛下用二苯基叔丁基甲硅烷基氯(140μl,0.5mmol)处理。反应混合物在室温搅拌24小时。真空浓缩后向其中添加30ml水,用乙酸乙酯(3×20ml)萃取。然后,合并的有机相用Na2SO4干燥,浓缩至干,得到白色固体形式的化合物5(210mg,定量产率)。Rf(AcOEt/MeOH2/1)=0,62[1H]NMR(CDCl3)δ:1.1(s,9H,叔丁基);3.1-3.6(m,2H,C2-CH2-O);3.7-4.2(m,2H,C4-H2);5.25(t,1H,C5-H);5.5(d,H,C5-H);6.35(q,1H,C2-H)7.4-7.8(m,10H,2Ph);8.0(d,1H,C6-H)
实例VI
顺式2-(羟甲基)-5-[N4-(1″-甲基-3″-吡啶基羰基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体6,呈碘化物形式
在氮气氛下,向1当量(46mg,0.14mmol)化合物2的4ml无水乙腈溶液中添加9当量(1.25mmol,77μl)甲基碘。得到的溶液在50℃加热48小时。蒸发溶剂后,残留物用闪急色谱法纯化,洗脱剂为BuOH/H2O/乙酸(5∶2.5∶2.5)。得到一种黄色固体(55mg)。[1H]NMR(DMSO d6)δ=3.25(t,2H,CH2-4);3.90(dd,2h,C2-CH2);4.45(s,3H,N+-CH3):5.25(t.1H.CH-5):6.30(t.1H.CH-2);6.92(d.1H.CH-6′):7.30(d.1H.烟酸基):7.85(d.1H,烟酸基):8.05(d.1H,CH-5′);8.20(d.1H.烟酸基):7.85(d.1H.烟酸基):9.01(d.1H.烟酸基).质谱(FAB+)349(M-1)+
实例VII
顺式2-(羟甲基)-5-[N4-(1″-甲基-1″,4″-二氢-3″-吡啶基羰基)胞嘧啶-1′-基]-1.3-氧硫杂环戊烷异构体7
在3ml含10%水的脱气甲醇溶液中溶解30mg(0.06mM)化合物6。向此溶液中添加15mg碳酸氢钠和60mg连二亚硫酸钠。反应混合物在氮气下搅拌3小时。溶液变成橙色。蒸发溶剂,然后把这些盐重新悬浮在少量甲醇中。过滤。滤液用薄层(1mm)制备色谱法(洗涤剂∶甲苯/甲醇,1∶1)纯化,得到6mg黄白色固体。质谱(FAB+)349(M-1)+
实例VIII
顺式2-羟甲基-5-[N4-(3″-喹啉基羰基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体8
向2ml无水二甲基甲酰胺中添加74.4mg(0.43mmol)喹啉基-3-羧酸,然后添加96mg(0.47mmol)1,3-二环己基碳化二亚胺和63.4mg(0.47mmol)羟基苯并***水合物。混合物在室温、氮气下搅拌1小时。出现一种二环己基脲白色沉淀,然后添加100mg(0.43mmol)2,3′-二脱氧-3′-硫代胞苷。混合物搅拌过夜。然后在减压下蒸发二甲基甲酰胺,残留物用NaCl饱和水溶液(10ml)水解。残留物用乙酸乙酯(2×10ml)萃取2次。把有机相合并、用硫酸镁干燥、过滤。蒸发溶剂。产物用闪急色谱法(洗脱剂∶乙酸乙酯/甲醇,98∶2)纯化,得到78mg白色固体(0.2mmol),产率为46.5%。MP=116-118℃ IR=1656cm-1(酰胺官能团的羰基)[1H]NMR(DMSO d6)δ=11.75(s,1H,NH);9.40(d,1H,CH-2″);9.15(d,1H,CH-4″);8.65(d,1H,CH-5′);8.20(m,2H,CH-8″et-CH-5″);8.0(m,1H,CH-6″);7.80(m,1H,CH-7″);7.45(d,1H,CH-6′);6.35(t,1H,CH-2);5.55(t,1H,CH-5);3.98(t,2H,C2-CH2-4)[13C]NMR:(DMSO d6)6=37.14(C-4);61.95(CH2O-C2);87.28(C-2);88.29(C-5);95.85(C-5′):122.21(C-3″);126.28(C-6″);127.71(C-5″);129.63(C-10″);129.87(C-7″);132.08(C-8″);137.65(C-4″):138.89(C-6′);148.91(C-9″);149.29(C-2″);163.16(C-2′):164.51(C-4′)质谱:(Fab+)385(M+1)+,769(2M+1)+
实例IX
顺式2-羟甲基-5-[N4-(1″-甲基-3″-喹啉基羰基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体9,呈碘化物形式
制备化合物8(78mg,0.20mmol)的4ml乙腈溶液。向此溶液中添加112μl(1.8mmol)甲基碘,混合物在氮气下在40℃加热24小时。脱除溶剂,然后把粗残留物溶解在少量乙腈中。添加***使之沉淀。由此得到一种橙色固体(60mg,产率55%)。MP=156-159℃(1H]NMR(CD3OD)δ=3.32(t,2H,CH2-4)3.99(dd,2H,C2-CH2)4.80(s,3H+N-CH3)535(t,1H,CH-5)6.0(d,1H,CH-6)6.33(t,1H,CH-2)513(m,1H,CH7)539(m,1H,CH-6)560(m,2H,CH-8″)8.72(d,1H,CH-5)9.79(d,1H,CH-4)9.95(d,1H,CH-2)质谱(Fab)399[M-1]+,799[2(M-1)]+
实例X
顺式2-羟甲基-5-[N4-(1″-甲基-1″,4″-二氢-3″-喹啉基羰基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体10
向30mg(0.057mmol)化合物9的3ml脱气含水甲醇(3ml含水10%的甲醇)溶液中添加15mg碳酸氢钠和60mg连二亚硫酸钠。整个混合物在氮气下搅拌1小时。蒸发溶剂,粗残留物用制备色谱法(洗脱剂∶乙酸乙酯/甲醇1∶1)纯化。最后得到10mg玻璃态黄色固体,产率46%。[1H]NMR:(D2O)δ=3.24(m,3+2H,NCH3+CH2-4″)3.48(m,2H,CH2-4);3.93(m,2H,C2H2):5.29(t,1H,CH-5);6.96(d,1H,CH-6′):7.13(m,2H,CH-6″+CH-7″):7.27(m,2H,CH-5″+CH-8″):7.45(d,1H,CH-2″):8.23(d,1H,CH-5′)质谱:(Fab+)399(M-1)+
实例XI
顺式2-羟甲基-5-[N4-(2-(α,α,α-三氟间甲苯胺基)烟酸基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷异构体11
向2′,3′-二脱氧-3′-硫代胞苷(50mg,0.2mmol)的5ml无水DMF溶液中添加1.1当量BOP(93mg,0.23mmol)、1当量硝氟灭酸(2-(α,α,α-三氟间甲苯胺基)烟酸)和4当量DIEA(146μl,0.84mmol)。混合物在室温搅拌过夜,用5%柠檬酸溶液(10ml)洗涤,然后用5%碳酸氢钠水溶液(10ml)洗涤。得到的混合物用乙酸乙酯(3×10ml)萃取、用硫酸钠干燥,然后蒸发。
残留物用硅胶柱色谱法(洗脱剂∶乙酸乙酯/甲苯1∶9)纯化。得到一种白色固体(49mg,产率为48%)。
抗病毒性能评估试验
抗HIV试验-实验方案
a)通用条件
仪器:使用一台Beckman TL100型超离心机。放射标记粒子的计数用一台惠普公司仪器Tri Carb Model 1600进行。多核巨细胞(syncithia)是用一台反转显微镜Labovert观察的。
溶菌缓冲剂NTE的组成:
三羟甲基氨基甲烷 10mM
NaCl 100mM
EDTA 1mM
b)细胞培养物中抗病毒性能的评估试验
抗病毒作用评估是以HIV-1病毒对MT4细胞系的致细胞病变效应研究为依据的。MT4细胞系来源于从患者分离的、已被TLHV-I病毒转化的T细胞。HIV-l病毒的致细胞病变效应是通过形成在显微镜下可见的多核巨细胞即所谓《syncithia》而显示出来的。HIV-l的这种效应可在感染之后4~5天观察到。随后有细胞死亡。
这种致细胞病变效应与病毒对细胞的感染、与其细胞内复制并与这些细胞的病毒抗体表达呈正相关。因此,这种效应的抑制对应于对HIV-1病毒增殖的抑制。
MT4细胞在如下RPMI 1640培养基中保持3×105个细胞/ml:10%在56℃去补体30分钟的胎牛血清(激素、血清生长因子……),1%谷氨酰胺,1%青霉素-链霉素,和2μg/ml能促进病毒粘着到细胞上的Polyren。
抗病毒剂处理的作用是连续的。事实上,这种效应存在于该病毒感染之前、期间和之后。用10%胎牛血清进行相继稀释,以便能使MT4细胞培养8天和现察到形成多核巨细胞。
MT4试验
感染之前:把3×106个细胞/100μl分配在一块有96孔的微滴板上,以2000转/分离心3分钟,然后,将沉淀物与100μl不同浓度的待测试抗病毒剂一起在37℃预培养1小时。
感染:感染是在上述微孔中,在添加100TCIU(感染单位)HIV-1病毒时实现的(这一数量的HIV-1病毒被确定为能在4或5天后诱发形成多核巨细胞)。在病毒感染和以100TCIU稀释时,抗病毒剂总是存在的。
感染之后:在37℃培养1小时之后,MT4细胞用RPMI1640培养基洗涤3次,并在24孔的微滴板上,对待测试化合物的每个浓度都以每微升3×105个细胞进行培养。当经过D3这一天时,把MT4细胞稀释到1/3。保持抗病毒剂浓度。在显微镜下观察每天多核巨细胞的出现,以检测相对于HIV-1对照组的任何可能延迟。在D8这一天进行逆转录酶测定。当这些细胞没有被感染时,这就表明受到所试验抗病毒剂的保护。
逆转录酶的测定
逆转录酶是一种依赖于RNA的DNA聚合酶。这种酶使得能发生逆转录病毒复制。多亏有它,转录到DNA上的病毒RNA才能进入细胞染色体组。原病毒DNA被细胞酶转录到病毒RNA上。为了测定逆转录酶活性,要用95000转/分超离心5分钟,使1ml培养物上清液浓缩100倍。超离心后得到的病毒沉淀物重新悬浮于10μl(缓冲剂NTE+TRITON 0.1%(聚氧乙烯醚))中。后者用来溶解病毒并释放出逆转录酶。在离体试验中,逆转录酶活性就是所要寻找的证据。这种酶使用一种具有12~18个残基的引物寡dT的合成板模多聚腺苷酸。这个反应的放射标记基质是[3H]dTTP(1mCi/ml放射活性胸苷三磷酸酯)。新生成的氚际记大分子用三氯乙酸沉淀,用过滤法使之与游离态[3H]TTP分离。逆转录酶的酶活性是通过配合物聚-rA/聚-dT中所结合的放射活性测定的。在添加起放大器作用的闪烁液体之后,用粒子计数器测定这种放射标记。
抗HBV试验-实验方案
在用于评估化合物对B型肝炎病毒(HBV)的活性的几种方法学中,已利用了鸭的B型肝炎病毒(Duck HBV)模式(J.Med.Virology(1990)31,82-89:Viral Hepatitis and LiverDisease(1988)506-509;Hepatology(1989)10,186-191)。离体测试化合物的抗HBV活性所需的培养物材料是用受到鸭B型肝炎病毒(DHBV)感染的鸭肝细胞制作的(Antimicrob.AgentsChemother.(1989)33,336-339:J.Med.Virology 40,59-64;Antivir Res.(1993)21,155-171;Antimicrob.AgentsChemother.(1993)37,1539-1542)。的确,鸭的B型肝炎病毒被公认为非常接近于人体B型肝炎病毒(Viral Hepatitis and LiverDisease(1988)526-529;Antiviral Research(1987)8,189-199)。在标准化条件(Virology(1989)171,564-572)下,鸭肝细胞的培养物使得能进行DHBV的全复制。所测试化合物的抗病毒活性是作为受感染肝细胞培养10天期间产生的病毒DNA数量的函数测定的。
实验步骤
一只受DHBV感染的3周龄雄性幼鸭用来产生肝细胞。这只鸭在麻醉下宰杀,用Guil louzou的方法学(“分离与培养的肝细胞研究”,J.Libbey Eurotex Ltd/INSERN1986)进行肝细胞分离。这些细胞在Leibowitz′s培养基中培养,向其中添加5μg/ml牛胰岛素、7×10-5摩尔可的松半琥珀酸盐和1.5%二甲基亚砜(DMSO)。细胞的密度是8×105个细胞,把它们喷洒在100×20mm的培养盒中。在细胞分散开之后,向培养物中添加被试化合物。在10天期间每天更新培养基。细胞上清液中鸭B型肝炎病毒的病毒DNA产量是借助于Fourel等人的“涂点”(Dot blot)杂化法(Viral Hepatitis andLiver Disease,1988,506-509;Hepatology,1989,10,186-191)测定的。抑制作用用细胞上清液中存在的DNA数量相对于未用核苷衍生物处理的DHBV感染培养物的百分率表示。
病毒学结果
HIV试验
已在本专利申请中描述了其合成并在以前的先有技术中给出了有关结构的化合物,在受感染细胞具有MT4类型的情况下,对BRU HIV-1病毒(BRU是有经验的病毒菌株)复制的抑制有影响。表I中描述了这些试验的结果。第1栏是最有代表性的、所研究的化合物的名称,而在第2栏中报告的是所谓IC50值(该成分对于在受感染MT4细胞中在感染后D7天测定的HIV复制给出50%抑制的浓度)。观察和计数所形成多核巨细胞的数目,并与受感染MT4细胞但未用抗病毒化合物处理的情况下计数的结果比较,确定IC50值。
DBHV试验
按照本文件实验部分介绍的步骤,对最有代表性的所述化合物测试了它们对鸭HBV病毒(DHBV)复制的影响。在表II中描述了这些试验的结果。
缩略语AcOEt:乙酸乙酯DNA:脱氧核糖核酸PTSA:对甲苯磺酸RNA:核糖核酸AZT:3′-叠氮基-2′,3′-二脱氧胸苷或ZidovudineBOP:苯并***甲酰氧三(二甲胺基)鏻六氟磷酸盐TLC:薄层色谱法DCC:N,N′-二环己基碳化二亚胺DCU:N,N′-二环己基脲DIEA:N,N-二异丙基-N-乙基胺DMF:N,N-二甲基甲酰胺DHBV:鸭B型肝炎病毒FAB+:快速正原子轰击3HdTTP:1mCi/ml放射活性标记的胸苷三磷酸酯HOBT:1-羟基苯并***IR:红外光谱MP:熔点NMR:核磁共振AIDS:获得性免疫缺陷综合征MS:质谱TBAF:四丁基二苯基甲硅烷基氟TBDPSCl:四丁基二苯基甲硅烷基氯3-TC:(-)-(2R,3S)-2-羟甲基-5-(胞嘧啶-1′
-基)-1,3-氧杂环戊烷或LamivudineTCIU:感染单位THF:四氢呋喃RPM:转/分TsCl:甲苯磺酰氯UV:紫外HIV:人体免疫缺陷病毒HBV:B型肝炎病毒HLTV:人体亲淋巴T细胞病毒
表I本发明核苷对HIV-I病毒复制的抑制效果,用IC50值表示
化合物号 | 化合物 | IC50 |
9 | >100μM | |
10 | 1-10μM | |
8 | 10μM | |
6 |
化合物号 | 化合物 | IC50 |
7 | ||
2 | 0.1-1μM | |
11 | <100μM | |
BCH-189(参考产物) | 1μM |
表II本发明核苷对DHBV病毒复制的抑制效果
化合物号 | 化合物 | IC50 |
BCH-189(参考化合物) | 1±0.5μM | |
2 | 2±0.5μM | |
8 | 2μM | |
9 | 2μM |
化合物号 | 化合物 | IC50 |
10 | 2μM | |
6 | 在试验中 | |
7 | 在试验中 |
Claims (15)
1.通式I顺式构型(2R-5S)或(2S-5R)的5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷式中R是一个吡啶基羰基,1,4-二氢吡啶基羰基、喹啉基羰基、1,4-二氢喹啉基羰基,所述R可以任选被具有1-10个碳原子的烷基或三氟甲基取代,且2位羟甲基相对于2和5这两个位置所确定的平面处于顺式位置。
4.按照权利要求1~3中任何一项的5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷,其为烟酸化合物,式中R的通式Ia如下:式中X是一个氢、一个卤原子、一个硝基、一个低级烷氧基或一个三氟甲基基团,n是1~3的一个整数,且酰基在2、3或4位上。
7.按照权利要求1~3中任何一项的5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷,其为喹啉酸化合物,式中R的通式Id为:式中羰基在2、3或4位上,
X代表一个氢、一个卤素、一个三氟甲基、一个低级烷氧基或一个硝基基团,和
n′代表1~6的一个整数。
11.权利要求1~10中任何一项的5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷化合物与一种无机酸或有机酸的加成盐。
12.按照权利要求1~11中任何一项的5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷化合物的光学活性异构体。
13.按照权利要求1或权利要求11或权利要求12的5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷,即顺式2-羟甲基-5-[N4-(3″-吡啶基羰基)胞嘧啶-1′-基]-1,3-氧硫杂环戊烷或其与一种无机酸或有机酸的加成盐之一,呈外消旋形式或呈一种光学活性形式。
14.按照权利要求1~13中任何一项的化合物的制备方法,在于让一种顺式5-(胞嘧啶-1-基)-1,3-氧硫杂环戊烷与一种通式ROH羧酸的官能衍生物发生作用,式中R是一个吡啶基羰基,1.4-二氢吡啶基羰基、喹啉基羰基、1,4-二氢喹啉基羰基,所述R可以任选被具有1-10个碳原子的烷基或三氟甲基取代,而Z是一个容易断裂的不稳定基团。
15.有抗病毒作用的药物组合物,其特征在于它们包括通式I的至少一种化合物作为活性成分式中R是一个吡啶基、1,4-二氢吡啶基羰基,喹啉基羰基,1,4-二氢喹啉基羰基,所述R可以任选被具有1-10个碳原子的烷基或三氟甲基取代,和
2位上的羟甲基相对于2和5这两个位置确定的平面处于顺式位置,
或其与一种酸的加成盐,呈外消旋形式或呈光学活性形式,并掺合或缔合一种惰性、无毒、药物上兼容的载体。
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- 1995-05-24 WO PCT/FR1995/000683 patent/WO1995032200A1/fr not_active Application Discontinuation
- 1995-05-24 PL PL95312693A patent/PL181713B1/pl unknown
- 1995-05-24 KR KR1019960700446A patent/KR100242891B1/ko not_active IP Right Cessation
- 1995-05-24 CZ CZ96219A patent/CZ21996A3/cs unknown
- 1995-05-24 US US08/586,892 patent/US5708000A/en not_active Expired - Fee Related
- 1995-05-24 HU HU9600155A patent/HU219299B/hu not_active IP Right Cessation
- 1995-05-24 CN CN95190647A patent/CN1080264C/zh not_active Expired - Fee Related
- 1995-05-24 JP JP7530108A patent/JPH09502453A/ja not_active Ceased
- 1995-05-24 CA CA002167930A patent/CA2167930A1/fr not_active Abandoned
- 1995-05-24 BR BR9506244A patent/BR9506244A/pt active Search and Examination
- 1995-05-24 EP EP95920986A patent/EP0733053A1/fr not_active Withdrawn
- 1995-05-24 RU RU96105063A patent/RU2142462C1/ru active
- 1995-05-25 NZ NZ287478A patent/NZ287478A/en unknown
-
1996
- 1996-01-23 FI FI960316A patent/FI960316A/fi unknown
- 1996-01-23 AP APAP/P/1996/000784A patent/AP612A/en active
- 1996-01-23 NO NO960272A patent/NO306299B1/no not_active IP Right Cessation
- 1996-01-24 OA OA60770A patent/OA10258A/fr unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0515144A1 (en) * | 1991-05-20 | 1992-11-25 | Biochem Pharma Inc. | 1,3-Oxathiolanes useful in the treatment of hepatitis |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS 1993,VOL,119:49821H 1993.1.1 STORES,"RESOTUTION......AGENTS" * |
Also Published As
Publication number | Publication date |
---|---|
NZ287478A (en) | 1997-09-22 |
OA10258A (fr) | 1997-10-07 |
FI960316A (fi) | 1996-03-22 |
AU2620995A (en) | 1995-12-18 |
NO960272D0 (no) | 1996-01-23 |
CA2167930A1 (fr) | 1995-11-30 |
CZ21996A3 (en) | 1996-05-15 |
HU219299B (en) | 2001-03-28 |
AP9600784A0 (en) | 1996-04-30 |
US5708000A (en) | 1998-01-13 |
PL181713B1 (en) | 2001-09-28 |
FI960316A0 (fi) | 1996-01-23 |
BR9506244A (pt) | 1997-08-12 |
EP0733053A1 (fr) | 1996-09-25 |
FR2720397B1 (fr) | 1996-08-23 |
HUT75112A (en) | 1997-04-28 |
AU688052B2 (en) | 1998-03-05 |
NO960272L (no) | 1996-01-23 |
JPH09502453A (ja) | 1997-03-11 |
KR100242891B1 (ko) | 2000-03-02 |
RU2142462C1 (ru) | 1999-12-10 |
CN1130906A (zh) | 1996-09-11 |
PL312693A1 (en) | 1996-05-13 |
NO306299B1 (no) | 1999-10-18 |
WO1995032200A1 (fr) | 1995-11-30 |
KR960703903A (ko) | 1996-08-31 |
FR2720397A1 (fr) | 1995-12-01 |
AP612A (en) | 1997-09-05 |
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