CN105732748A - 一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用 - Google Patents
一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用 Download PDFInfo
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- CN105732748A CN105732748A CN201410767141.6A CN201410767141A CN105732748A CN 105732748 A CN105732748 A CN 105732748A CN 201410767141 A CN201410767141 A CN 201410767141A CN 105732748 A CN105732748 A CN 105732748A
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- Prior art keywords
- amide
- pyrazine
- base
- oxygen
- pharmaceutical composition
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Abstract
目前急需开发新型特效治疗药物，降低致病性A型流感病毒的危害。本发明公开了一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用，本发明核苷酸类似物的结构式如式(I)所示：其中，X为O、S或NH，R1为H、OH、RO或卤素，R2为OH、RO或卤素，所述的R为烷基或芳香基。本发明的核苷类化合物具有优良的抗流感病毒活性，并具有较低的毒性和很高的安全性。
Description
技术领域
本发明属于药物领域，具体地说是一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用。
背景技术
由病毒引起的传染病在世界范围内时有发生，特别是近些年出现的H1N1、H3N1、H5N1、H7N9等致病性A型流感病毒在全球范围引起的致命性疾病，由于没有特效药物引起了整个社会的恐慌，目前急需开发新型特效治疗药物，降低该种病毒的危害。
US20030130213公布了一种化合物，其结构式如下：
其具有抗流感病毒性能，到目前为止，该类化合物还没有上市。
发明内容
本发明的目的在于提供一种具有优良抗流感病毒活性，并具有较低毒性和很高安全性的核苷酸类似物。
为此，本发明采用如下的技术方案：一种核苷酸类似物，其结构式如式(I)所示：
其中，X为O、S或NH，R1为H、OH、RO或卤素，R2为OH、RO或卤素，所述的R为烷基或芳香基。
进一步，所述的烷基为C1～C6脂肪烷基、三元环的环烷基、四元环的环烷基、五元环的环烷基或六元环的环烷基；所述的芳香基为苯基、烷基苯或卤代苯基。
进一步，式(I)所示的化合物优选为下列化合物中的一种：
(1)(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；
(2)(1S,3R,4R,7R)-1-羟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；
(3)(1S,3R,4R,7S)-1-氟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；
(4)(1S,3R,4R,7R)-1-氟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷。
本发明的另一个目的在于提供上述核苷酸类似物的制备方法，其步骤如下：
3-氧基吡嗪-2-酰胺与1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰基甲基-5-O-甲磺酰基-D-核糖或1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰基甲基-5-O-甲磺酰基-L-核糖缩合，再经过Vorbruggen偶合反应在1’-C处引入3-羟基-2-吡嗪酰胺，经过闭环、脱除甲磺酰基和脱除苄基得到目标化合物。
本发明的又一个目的在于提供一种抗A型流感病毒的药物组合物，其含有治疗有效量的核苷酸类似物或其药学上可接受的盐，以及一种或多种药学上可接受的载体。
进一步，所述的药物组合物包含5-75重量％的式(I)所示结构的化合物或其药学上可接受的盐的任一种或其组合，余量为药学上可接受的载体。
进一步，所述药学上可接受的盐为无机酸盐、有机酸盐、无机碱盐或有机碱盐；所述的无机酸盐选用盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐、高氯酸盐中的任一种或其组合；所述的有机酸盐选用对甲苯磺酸盐、甲磺酸盐、乙酸盐、三氟乙酸盐、丙酸盐、枸橼酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐、苯甲酸盐中的任一种或其组合；所述的无机碱盐为碱土金属盐；所述的有机碱盐为有机胺盐。本发明的更优选方案中，所述的碱土金属盐为镁盐或钙盐；所述的有机胺盐为吗啉盐、哌啶盐、三烷基胺盐、吡啶盐、二甲胺盐或二乙胺盐。
本发明的再一个目的在于提供一种上述含有核苷酸类似物的药物组合物在制备抗由A型流感病毒导致的疾病药物中的应用。
本发明的优选方案中，所述药物组合物适用于肠内(例如口服或直肠给药)、局部或肠胃外给药，例如，口服、注射、植入、外用、喷雾、吸入等。
进一步，所述的药物组合物为片剂、胶囊剂、丸剂、颗粒剂、口服液体制剂、注射剂或外用制剂。
本发明的优选方案中，所述口服药物组合物选自片剂(普通片、含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、阴道片或阴道泡腾片、缓释片、控释片、肠溶片、口腔速释片等)、胶囊剂(硬胶囊、软胶囊、缓释胶囊、控释胶囊、肠溶胶囊等)、丸剂(滴丸、糖丸、小丸)、口服液体制剂(糖浆剂、混悬剂、口服溶液剂、口服混悬剂、口服乳剂、糖浆剂、合剂、露剂或茶剂)、颗粒剂(混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒、控释颗粒等)、散剂的任一种。
本发明的优选方案中，所述注射剂包括注射液、注射用无菌粉末或无菌块状物(包括采用溶剂结晶法、喷雾干燥法或冷冻干燥法等工艺制备)、输液、注射用浓溶液的任一种。
本发明的优选方案中，所述外用制剂选自栓剂、气雾剂、粉雾剂、喷雾剂、膜剂、凝胶剂、贴剂、胶剂、贴膏剂、膏药、软膏剂、搽剂、洗剂、涂抹剂、凝膏剂的任一种。
本发明的优选方案中，可采用本领域熟知的制剂技术手段来制备本发明组合物。
本发明的优选方案中，所述药物组合物选自包合制剂或分散制剂。
本发明的优选方案中，所述的药学上可接受的载体为本领域熟知用于制备上述制剂的常用赋形剂或辅料，其中，口服制剂或外用制剂常用的赋形剂或辅料包括但不仅限于填充剂或稀释剂、润滑剂或助流剂或抗粘着剂、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂等。粘合剂，例如糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮，优选的纤维素衍生物为微晶纤维素、羧甲基纤维素钠、乙基纤维素、羟丙甲基纤维素；填充剂，例如乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐、山梨醇或甘氨酸，优选无机钙盐为硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙；润滑剂，例如微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇；崩解剂，例如淀粉及其衍生物、聚乙烯吡咯烷酮或微晶纤维素，优选的淀粉衍生物为羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉；湿润剂，例如十二烷基硫酸钠、水或醇等，优选药学上可接受的载体为环糊精(α-环糊精、β-环糊精或γ-环糊精)、Celldone102CG、PolyplasdoneXL-10、滑石粉、硬脂酸镁或乙醇等。
本发明的优选方案中，所述注射剂常用的赋形剂或辅料包括但不仅限于：抗氧剂，例如硫代硫酸钠、亚硫酸钠、亚硫酸氢钠、二丁基苯酸或焦亚硫酸钠等；抑菌剂，例如0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇；pH调节剂，例如盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠、缓冲剂(如磷酸二氧钠和磷酸氢二钠组成的缓冲剂)；乳化剂，例如聚山梨酯-80、没酸山梨坦、普流罗尼克F-68，卵磷酯、豆磷脂；增溶剂，例如吐温-80、甘油等。
本发明的优选方案中，还可将活性成分与药学上可接受的缓控释载体按其制备要求加以混合，再按照本领域熟知的缓控释制剂的制备方法，如加入阻滞剂包衣或将活性成分微囊化后再制成微丸，如缓释微丸或控释微丸；所述的缓控释载体包括但不仅限于油脂性掺入剂、亲水胶体或包衣阻滞剂等，所述的油脂性掺入剂为单硬脂酸甘油酯、氢化蓖麻油、矿油、聚硅氧烷、二甲基硅氧烷；所述的亲水胶体为羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素等纤维素衍生物，或PVP、阿拉伯胶、西黄耆胶或卡波普等；所述的包衣阻滞剂为乙基纤维素(EC)、羟丙甲基纤维素(HMPC)、聚乙烯吡咯烷酮(PVP)、邻苯二甲酸醋酸纤维素(CAP)、丙烯酸类树脂等。
本发明的核苷类化合物具有优良的抗流感病毒活性，并具有较低的毒性和很高的安全性。
附图说明
图1为化合物I2的1HNMR图。
图2为化合物2的1HNMR图。
具体实施方式
下面，通过以下实例来对本发明作进一步具体说明，但并不仅限于以下实施例和实施例中的工艺参数范围。
本发明的化合物可以通过以下路线制备目标化合物：
参考已经发表的文献方法(J.Org.Chem.1979,44,1301‐1309；TheJournaloforganicchemistry,2001,66(25):8504‐8512)制备中间体I。
然后以上述中间体I为原料按照下列路线制备目标化合物。
实施例1化合物4-(2-O-乙酰基-3-O-苄基-4-C-甲磺酰基氧甲基-5-O-甲磺酰基-β-D-核糖)-3-氧-吡嗪-2-酰胺(I1)的制备
称取1.08g(7.8mmol)3-氧基吡嗪-2-酰胺溶于50mL乙腈中，滴加3.835mLN,O-双三甲硅基乙酰胺，升温至80℃，加热回流反应2个小时，体系为浅红色溶液，降至室温，加入3.32g中间体I，滴加1.9mL四氯化锡，加热回流，搅拌反应2个小时，降至室温，加入75mL冰饱和碳酸氢钠溶液，用乙酸乙酯萃取后，柱层析分离得到2.89g白色絮状固体，收率62.8％。
产品结构鉴定1HNMR(DMSO,400MHz)：δppm,1.95,2.36,2.38(9H.s),4.05(1H,d,J＝6.8Hz),4.15(1H,d,J＝10.8),4.20(1H，d,J＝3.6Hz),4.33(3H，m),4.44(1H,d,J＝6.4Hz),5.46(1H,d,J＝5.6Hz),5.67(1H,s),7.30(7H,m),7.60(1H,d,J＝4.4Hz),8.14(1H，brs)。
实施例2(1S,3R,4R,7S)-1-甲磺酰基氧甲基-3-[4-(3-氧代吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I2)的制备
取上述实施例1制得的化合物(I1)(2.7g，4.58mmol)溶于30mLCH3OH和H2O，加入3.8g无水碳酸钾(27.48mmol)，室温下搅拌反应8个小时。反应完毕后加入醋酸中和，二氯甲烷萃取，蒸除溶剂，柱色谱纯化得到白色粉末1.4g，产率68％。结构鉴定1HNMR(DMSO,400MHz)：δ2.38(1H,s),3.82(2H,m),3.91(1H,s),4.43(2H,m),4.48(1H,d,J＝12Hz),4.59(1H,s),4.66(1H,d,J＝12Hz),5.7(1H,s),7.27(5H,m),7.57(1H,d,J＝4.4Hz),7.62(1H,d,J＝4.4Hz),7.75,8.32(2H,s)。
实施例3(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I3)的制备
将实施例2制得的化合物(I2)1.3g(2.88mmol)溶于30mL1,4-二氧六环中，加入醋酸钾(1.23g，14.4mmol)和18-冠醚-6(1.52g，5.76mmol)，加热回流15个小时，反应完毕后直接蒸除溶剂，用二氯甲烷溶解过滤，干燥后得到(1S,3R,4R,7S)-1-乙酰基氧甲基-3-[4-(3-氧代吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷945mg，然后溶于10mL甲醇氨的饱和溶液，室温搅拌3小时，减压蒸除溶剂，柱层析分离得到浅黄色固体粉末530mg，产率62.5％。
产品结构鉴定1HNMR(CDCl3,400)：δ3.93-3.95(1H,d),4.00-4.0(1H,d),4.17-4.19(1H，d),4.65-4.68(1H，d),4.74-4.77(1H，d),4.85(1H，s),6.00(1H，brs),6.09(1H，s),7.36(5H，m),7.85(2H,s)9.04(1H，brs)。
实施例4(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(1)的制备
取500mg上述实施例3制得的化合物(I3)制备的化合物溶于无水甲醇中，加入20％的Pd/C(100mg)，向反应体系中通入氢气，加热回流2个小时，冷却至室温，过滤，减压蒸出溶剂得到浅黄色固体粉末139mg，产率36.9％。
产品结构鉴定1HNMR(CDCl3,400MHz)：δppm3.96(1H,d),4.10(1H,s),4.30(1H,m),4.21(1H,m),4.47(1H,d),4.67(1H,m),5.34(1H,m),5.68(1H,s)6.97(1H,m),7.12(1H,d),7.22(1H,s),7.61(1H,m),7.79(1H,d,J＝4Hz).IRvmax:3340,2929,1680,1452,1105,963,826,741cm-1。
实施例54-(2-O-乙酰基-3-O-苄基-4-C-甲磺酰基氧甲基-5-O-甲磺酰基-β-L-核糖基)-3-氧代吡嗪-2-酰胺(I4)的制备
参照实施例1化合物4-(2-O-乙酰基-3-O-苄基-4-C-甲磺酰基氧甲基-5-O-甲磺酰基-β-D-核糖)-3-氧-吡嗪-2-酰胺(I1)的合成方法，可以制备化合物4-(2-O-乙酰基-3-O-苄基-4-C-甲磺酰基氧甲基-5-O-甲磺酰基-β-L-核糖基)-3-氧代吡嗪-2-酰胺(I4)。
产品的结构鉴定1HNMR(DMSO,400MHz)δ2.05,3.22,3.26(9H,s),4.38(1H,d,J＝4Hz),4.42(2H,d,J＝2.4Hz),4.47(1H,d,J＝10.8Hz),4.64(3H,m),5.52(1H,t),6.29(1H,d,J＝4.4Hz),7.27(5H,m),7.49(1H,d,J＝4.4Hz),7.84(1H,d,J＝4Hz),7.74,8.17(2H,brs)。
实施例6(1S,3R,4R,7R)-1-甲磺酰基氧甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I5)的制备
参照实施例2化合物(1S,3R,4R,7S)-1-甲磺酰基氧甲基-3-[4-(3-氧代吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I2)的合成方法，可以制备化合物(1S,3R,4R,7R)-1-甲磺酰基氧甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I5)。
产品的结构鉴定1HNMR(DMSO,400MHz)：δppm2.40(3H,s),3.77(1H,d,J＝8.4Hz),3.88(2H,d,J＝8.4Hz),4.08(1H,d,J＝12Hz),4.18(1H,d,J＝2Hz),4.32(2H,m),4.56(1H,d,J＝11.2Hz),4.69(1H,d,J＝11.6Hz),5.64(1H,s),6.89(2H,m),7.22(2H,m),7.34(1H,d,J＝4Hz),7.66(1H,d,J＝4.4Hz),7.75,8.32(2H,brs)。
实施例7(1S,3R,4R,7R)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I6)的制备
参照实施例3化合物(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I3)的合成方法，可以制备化合物(1S,3R,4R,7R)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I6)。
产品的结构鉴定1HNMR(DMSO,400)：δ3.80-3.82(1H,d,J＝8.4Hz),3.92(2H,d,J＝5.2Hz)3.97(1H,d,J＝5.6Hz),4.03(1H,d,J＝8.4Hz),4.11(1H,dJ＝2.4Hz),4.16(1H,d,J＝12Hz),4.35(1H,d,J＝2Hz),4.44(1H,dJ＝11.6Hz),5.20(3H,t),5.68(1H,s),6.97(2H,m),7.24(3H,m),7.45(2H,d，J＝4.4Hz),7.77(1H，brs),7.80(2H,d，J＝4.4Hz),8.40(1H，brs)。
实施例8(1S,3R,4R,7R)-1-羟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(2)的制备
参照实施例4化合物(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(1)的合成方法可以得到化合物(1S,3R,4R,7R)-1-羟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(2)。
产品的结构鉴定1HNMR(CDCl3,400MHz)：δppm3.66(3H,s),4.3(4H,t),5.34(1H,t),7.51(2H,m),7.70(2H,m)。IRVmax:3360,2931,1664,1420,1080,878,752cm-1。
实施例9(1S,3R,4R,7S)-1-氟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(3)和(1S,3R,4R,7R)-1-氟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(4)的制备
分别将0.1mol化合物I3和I6溶解在二氯甲烷中，加入0.12mol二乙氨基三氟化硫，搅拌反应10小时后，蒸出溶剂后，用纯洁水洗涤烘干。将柱色谱分离得到的固体参照实施例4的方法制备目标化合物3和4。
产品3的结构鉴定1HNMR(CDCl3,400MHz)：δppm3.97(1H，d)，4.08(1H，s)，4.32(1H，m)，4.21(1H，m)，4.47(1H，d)，4.67(1H，m),5.34(1H，m),5.68(1H，s)6.97(1H，m)，7.12(1H，d)，7.22(1H，s)，7.79(1H，d，J＝4Hz)。
产品4的结构鉴定1HNMR(CDCl3,400MHz)：δppm3.76(3H,s),4.35(4H,t),5.44(1H,t),7.70(2H,m)。
本发明的化合物抗流感病毒实验
本实验采用的病毒株：流感病毒A/天津津南/15/2009,以MDCK(狗肾)细胞为病毒宿主，测定样品抑制病毒引起细胞病变程度，结果如表1所示。
从实验结果可以看出本发明的系列化合物在对达菲没有活性的病毒株而具有明显的抗流感病毒性能，相对于已经上市的产品(达菲)具有更加优异的性能。
Claims (10)
1.一种核苷酸类似物，其结构式如式(I)所示：
其中，X为O、S或NH，R1为H、OH、RO或卤素，R2为OH、RO或卤素，所述的R为烷基或芳香基。
2.根据权利要求1所述的核苷酸类似物，其特征在于，所述的烷基为C1～C6脂肪烷基、三元环的环烷基、四元环的环烷基、五元环的环烷基或六元环的环烷基；所述的芳香基为苯基、烷基苯或卤代苯基。
3.根据权利要求1所述的核苷酸类似物，其特征在于，式(I)所示的化合物为下列化合物中的一种：(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；(1S,3R,4R,7R)-1-羟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；(1S,3R,4R,7S)-1-氟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；(1S,3R,4R,7R)-1-氟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷。
4.权利要求1-3任一项所述核苷酸类似物的制备方法，其步骤如下：
3-氧基吡嗪-2-酰胺与1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰基甲基-5-O-甲磺酰基-D-核糖或1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰基甲基-5-O-甲磺酰基-L-核糖缩合，再经过Vorbruggen偶合反应在1’-C处引入3-羟基-2-吡嗪酰胺，经过闭环、脱除甲磺酰基和脱除苄基得到目标化合物。
5.含有权利要求1-3任一项所述核苷酸类似物的药物组合物，其特征在于，其含有治疗有效量的核苷酸类似物或其药学上可接受的盐，以及一种或多种药学上可接受的载体。
6.根据权利要求5所述的药物组合物，其特征在于，其包含5-75重量％的式(I)所示结构的化合物或其药学上可接受的盐的任一种或其组合，余量为药学上可接受的载体。
7.根据权利要求5所述的药物组合物，其特征在于，所述药学上可接受的盐为无机酸盐、有机酸盐、无机碱盐或有机碱盐；所述的无机酸盐选用盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐、高氯酸盐中的任一种或其组合；所述的有机酸盐选用对甲苯磺酸盐、甲磺酸盐、乙酸盐、三氟乙酸盐、丙酸盐、枸橼酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐、苯甲酸盐中的任一种或其组合；所述的无机碱盐为碱土金属盐；所述的有机碱盐为有机胺盐。
8.权利要求5所述药物组合物在制备抗由A型流感病毒导致的疾病药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述的药物组合物适用于肠内、局部或肠胃外给药。
10.根据权利要求9所述的应用，其特征在于，所述的药物组合物为片剂、胶囊剂、丸剂、颗粒剂、口服液体制剂、注射剂或外用制剂。
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| CN1418220A (zh) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | 新的吡嗪衍生物或其盐、含有该衍生物或盐的药物组合物和制备二者的中间体 |
| CN1551777A (zh) * | 2001-08-14 | 2004-12-01 | 富山化学工业株式会社 | 新的病毒增殖抑制剂/杀病毒方法,以及新的吡嗪核苷酸/吡嗪核苷类似物 |
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