CN1229084A - 嘌呤和嘧啶的不饱和膦酸酯衍生物 - Google Patents
嘌呤和嘧啶的不饱和膦酸酯衍生物 Download PDFInfo
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- CN1229084A CN1229084A CN99101008A CN99101008A CN1229084A CN 1229084 A CN1229084 A CN 1229084A CN 99101008 A CN99101008 A CN 99101008A CN 99101008 A CN99101008 A CN 99101008A CN 1229084 A CN1229084 A CN 1229084A
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Abstract
公开了可用作抗病毒药的某些嘌呤或嘧啶的新不饱和膦酸酯衍生物,用于制备它们的方法和这些化合物作为对抗DNA病毒、逆转录病毒和肿瘤形成中相关病毒的抗病毒药的用途。
Description
本发明涉及可用作抗病毒药的某些嘌呤或嘧啶的不饱和膦酸酯衍生物,它们的制备方法和有用中间体,及其作为有效对抗DNA病毒(疱疹病毒1和2,巨细胞病毒、水痘-带状疱疹病毒、E-B病毒)、逆转录病毒(人免疫缺陷病毒1和2和维斯那病毒)和与肿瘤形成有关的病毒的抗病毒药的用途。
嘌呤或嘧啶碱基的某些衍生物已显示出抗病毒和抗肿瘤活性。例如见EP0,173,624;FP0,253,412;EP0,353,955;WO92/01698;EP0,481,214;和J.Org.Chem.57:2320-2327(1992)。本发明的化合物是衍生自嘌呤和嘧啶碱基的新化合物。
更具体地讲,本发明涉及式I和式II的新化合物:其立体异构形式、互变异构形式和药学上可接受的盐,其中X1为H或NH2;X2为OH或NH2;X3为H或CH3;及X4为NH2或OH;Z不存在或为CH2、CH2CH2、CH2O或CH2OCH2;W为W为其中R1和R2各自独立地为H、F或CH2OH;T不存在或为T’或T″,其中T′为CH2CH2,CH=CH,CH2CH(OH),CH2CH(CH2OH),或CH2CH(CH2F),及T″为CH=CH-CH(OH),CH=CH-CH(CH2OH),CH2OCH2,
CH2OCH(CH2OH),CH2CH(CH2OH)CH2,CH2CH2CH(OH),
CH2CH2CH(CH2OH),或CH2CH2CH(CH2F);及
R3和R4各自独立地为OH、OR5、OR5’或-O-CH(R6)-O-C(O)R5,条件是当R3或R4之一为OH时,另一个不为-O-CH(R6)-O-C(O)R5,其中R5和R5’各自独立地为C1-15烷基或苯基,R6为H或C1-10烷基,条件是当T为CH=CH或CH2CH2,W为Wc,及Z为CH2时,X1为NH2和X2为OH不同时发生;条件是当W为We时,Z不存在或为CH2,条件是当T不存在时,W不为Wc,条件是当Z为CH2且W为Wa时,T不能为CH=CH,及条件是当Z不存在及W=Wc时,T不为CH=CH。
本发明还包括使用式I和式II化合物制备治疗病毒感染的药物组合物。
本发明化合物为带有膦酸酯残基的嘌呤衍生物(式I)或嘧啶衍生物(式II),本文称为核酸碱基(点线表示与分子的其余部分相连):膦酸酯残基与嘌呤或嘧啶衍生物的连结是T、W和Z基团片段。这些残基与分子其余部分相连的一个实例是这样:其中T为T″为CH=CH-CH(CH2OH),W为Wa,其中R1和R2均为H,Z为CH2O:优选下列组合的本发明的较小分子:
当W=Wa或Wb且T=T″时,则Z不为CH2OCH2;
当W=Wc或Wa且T=T’时,则Z为CH2OCH2;
当W=Wc或Wa且T=T″时,则Z为CH2;
其它优选化合物为当T为T’,更优选T’为CH=CH;当T为T″,更优选T″为CH2OCH2;当W为Wa、Wc或Wd;当R1和R2均为H;和/或Z为CH2、CH2CH2或CHO时的化合物。式I比式II更优选。优选的嘧啶型碱基为胞嘧啶、尿嘧啶、和胸腺嘧啶。优选的嘌呤碱基为2,6-二氨基嘌呤(DAP)、鸟嘌呤和腺嘌呤。
本文所用的前提条件“当T为CH=CH或CH2CH2,W为Wc且Z为CH2时,则X1为NH2和X2为OH不同时发生”意在从权利要求中排除碱基为鸟嘌呤的情况(X1=NH2同时X2=OH)。这一前提排除了其中碱基为鸟嘌呤的两个化合物:当(1)T为CH=CH,W为Wc,Z为CH2,和(2)T为CH2CH2,W为Wc,Z为CH2。
术语C1-10烷基或C1-15烷基分别指具有1-10个碳原子或1-15个碳原子的烷基。烷基可为直链或支链,如叔丁基。对于C1-15烷基,优选C1-10烷基,更优选C1-6烷基,最优选C1-3烷基。对于C1-10烷基,优选C1-6烷基,最优选C1-3烷基。
术语“药学上可接受的盐”指在已知制备适于最终应用的药物制剂中无毒并为有用衍生物的酸加成盐和金属及胺盐。
药学上可接受的酸加成盐包括式I和式II碱基化合物的已知无毒的有机或无机酸加成盐。形成适宜盐的有机酸例如包括一元、二元和三元羧酸。这种酸例如为乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苯甲酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、和2-苯氧苯甲酸。形成适宜盐的其它有机酸为磺酸如甲磺酸和2-羟乙磺酸。既可形成一元酸盐也可形成二元酸盐,这种盐可以水合物形式或以基本无水形式存在。用标准技术制备酸盐,如将游离碱溶于含有适当酸的水溶液或水-醇溶液或其它适宜溶剂中,然后蒸发溶剂分离,或在有机溶剂中与游离碱反应,此时可直接分离盐或经溶液浓缩得到盐。本发明的酸加成盐一般为结晶物,其可溶于水和各种亲水物中,显示高熔点,稳定性提高。
药学上可接受的金属和胺盐为那些在室温下稳定且其中阳离子对盐的生物活性无明显贡献的盐。适宜的金属盐包括钠盐、钾盐、钙盐、钡盐、锌盐和铝盐。优选钠盐和钾盐。适宜的胺盐从具有足以形成稳定盐的碱性之胺制备,优选包含那些因毒性低适于医用而常用于药物化学中的胺。这包括三烷胺如三乙胺,其它还有普鲁卡因、二苄胺、N苄基-β-苯乙胺、1,2-二苯基-2-羟基N-甲胺、和N,N’-二苄基乙二胺、脱氢枞胺、N-乙基哌啶、苄胺、和二环己基胺。
式I和式II化合物的“立体异构形式”是这些化合物的仅在其原子空间取向上有区别的所有异构体的总称,包括镜像异构件(对映异构件)、几何异构体(顺/反)、和具有一个以上手性中心药物的不互为镜像的异构体(非对映异构体)。可用本领域中熟知的常规和标准步骤拆分或分离此混合物,例如,色谱分离、分级结晶、利用光学活性酸、酶拆分等。在嘌呤核的6-位可存在烯醇-酮互变异构形式,嘧啶存在胺-亚胺互变异构形式。虽然本文将“Wc”画成顺式,但应理解为指顺式和反式。
本发明化合物或使用本领域中已知的类似化学反应制备,反应物为已知的或可用本领域中已知的标准方法和技术制备。简言之,制备式I和式II化合物的总方法可用下述反应式I表示。
除非另有说明,下述反应式中所含变量具有前述定义的意义。“Pg”指适当的保护基团。适当的保护基可以在“Protective groups inOrganic Synthesis”,2nd ed.Theodora W.Greene,John Wiky and Sons,Inc.,New-York(1991)中找到,后者并入本文作为参考。一些实例为THP(四氢吡喃基)、TBDMS(叔丁基二甲基甲硅烷基)、TBDPS(叔丁基二苯基甲硅烷基)。Pg的下标用于区分保护基,使某些保护基被选择性裂解,而其它的保持完整。“B”或“BASE”指本文中定义的核酸碱基。“DEAD”指偶氮二羧酸二乙酯。“TMS Br”指溴化三甲基甲硅烷。“Ph”指苯基。“K2CO3”指碳酸钾。“DMF”指二甲基甲酰胺。M指药学上可接受的碱金属阳离子。“n”为1或2。
反应式I-III表示如何制备反应式A的中间体(3)、(6)和(9)。反应式IV-VI表示从中间体(3)、(6)和(9)开始的合成。反应式A表示这些反应式的大部分是如何连在一起的。反应式B为反应式A一部分的替代合成,而反应式C是反应式A的补加。反应式D、E和F是关于R3和R4位的变量。
反应式I:
中间体(3)的制备(当T为饱和残基时)
CH(CH2OPg2,或CH2CH(CH2OPg2)。n=1或2。X=卤素(Cl,Br,I)。R=C1-15烷基或苄基。
反应式I中产生的式(3)化合物的制备典型地是利用Arbuzov反应,将三烷基膦或三苄基膦和适当保护的式(1)醇卤化物一起加热,Engel R.等,Chem.Rev.77:349(1977)和Holy A.等,Collect.Czech.Chem.Commun.52:2801(1987)。选择羟基保护基Pg1和Pg2使其在反应条件下稳定,且反应完成后在步骤6中选择性裂解生成式(3)化合物。
反应式II:
中间体(6)的制备
(当T为不饱和残基时)
反应式II中,用式(4)的醛通过Wittig反应获得式(6)化合物,Jonts G和Moffot,J.Org.Chem.(1968),Waszkuc W等,Synthe-sis1025(1984)。例如,适当的式(4)醛在非质子溶剂如四氢呋喃中与稍过量于一摩尔当量的四亚乙基二膦酸酯的锂盐反应。反应一般在约-78℃搅拌进行10~24小时。相应的链烯基膦酸酯(5)用本领域熟知的萃取方法从反应混合物中回收。反应b中,选择性地裂解羟基保护基Pg1生成式(6)的醇。
反应式III:
中间体(9)的制备
(当T残基含氧时)
X-Y3-W-(CH2)n-OPg1 (7)Y3=CH2或CH(CH2OPg2)。W=同反应式AX=离去基闭如甲磺酸根、对甲苯磺酸根、三氟甲磺酸根或卤原子(Cl,Br,I)。R=C1-15烷基或苄基。
或者X=对甲苯磺酸根或甲磺酸根。W,Pg和Y3=如前所定义R=C1-15烷基或苄基。反应式III中,步骤a:式(7)烯丙型、炔丙型或丙二烯型卤化物用羟甲基膦酸二酯的烷氧阴离子于-10℃到50℃亲核取代6-24小时,获得式(8)化合物。在步骤b,选择性裂解羟基保护基Pg1得到(9)的醇。
或者,在如上所述相同反应条件下对甲苯磺酰氧基甲基膦酸二酯用式(10)醇的烷氧阴离子亲核取代获得式(8)化合物。
反应式IV:
从反应式I、II和III的中间体
表IV(续)
在反应式IV、V、VI中,分别向化合物(3)、(6)或(9)中加入适当的本文所定义的嘌呤或嘧啶碱基,分别得到化合物(13)、(16)和(19)。
反应式IV中,化合物(3)、(6)或(9)中羟基被核酸碱基取代是通过将醇转化成离去基团(步骤a),得到化合物(11),然后与一摩尔当量保护形式(BPg3)的适当核酸碱基(B)反应,需要时在碱如碳酸钾存在下在有机溶剂如无水二甲基甲酰胺中进行(步骤b)。反应物在约0℃到室温下搅拌10-48小时,生成化合物(12)。然后可以多种方法将碱基脱保护并用溴化三甲基甲硅烷水解膦酸二酯,得到化合物(13)。Bronson J.等,J.Med.Chem.32:1457(1989)和Kim C.等,J.Mec.Chem.33:1207(1990)。脱酯化或脱保护步骤可以反过来进行。
或者,(3)、(6)和(9)中的羟基用核酸碱基取代可用Mitsunson反应进行-Jenny T.Tet.Lett.32:2029(1991),得到中间体(12)后如上所述处理得到式(13)化合物。
反应式V:
从(3)、(6)或(9)开始,
当Z=CH2OCH2
B,Pg,W和T=如前文所定义
R=C1-15烷基或苄基
反应式V中,化合物(17)中连结于核酸碱基的甲氧甲基酯官能团(Z=CH2OCH2)是这样形成的:(3)、(6)或(9)(当n=1时)的位一化合物和多聚甲醛的混合物用氯化氢气体在1,2-二氯乙烷中处理,形成中间体氯甲基醚(14)(步骤a),后者在消除过量氢氯酸后用核酸碱基的甲硅烷基化形式(BTMS)处理,后者是用过量双三甲基甲硅烷基乙酰胺处理相应的核酸碱基而获得的(步骤b)。接下来的碱基脱保护和膦酸二酯的水解按反应式I(步骤c和d)所述进行,得到化合物(17),Ogilvie K等,Can.J.Chem.60:3005(1982)和Ogilvie K等,Nucleosides and Nudeotides 2:147(1983)。
反应式VI:
从中间体(3)、(6)或(9)开始,当Z
反应式VI中,适当功能化的醇(3),(6)或(9)与1-羟基嘧啶或9-羟基嘌呤用三苯膦、偶氮二羧酸二乙酯在二甲基甲酰胺中通过Mitsunobu反应偶联(步骤a),Parkin A.,J.Chem.Soc、Perkin Trans、2983(1991)。按反应式IV所述进行碱基和膦酸二酯脱保护。
反应式A
Lg=离去基团如对甲苯磺酸根、甲磺酸根、三氟甲磺酸根、
Cl,Br或I。
B,W,和T=如前文所定义。
X=卤素
R=C1-15烷基或苄基对于具有连在磷原子上的亚甲氧基甲基的特便(T=CH2OCH2),可用如下的对称二卤化物(氯化物)烷基化:
反应式B:
反应式A的替代合成
在反应式B引入式(21)的对称单元这一特例中,连续进行反应式III的步骤a和反应式IV步骤b所述的取代,反应条件与分别在此两例中所述条件相同,批应式III的步骤a引入甲氧基膦酸二酯得到化合物(22),反应式IV的步骤b引入保护的核酸碱基得到化合物(23)。接下来碱基脱保护和膦酸二酯水解,得到化合物(24)。
反应式C:
对反应式A的补充
当Z=0时,W总为丙二烯残基,式(26)化合物从乙炔衍生物(24)(根据不同的T,由上述方法之一制得)用碱处理将乙炔官能团异构化为丙二烯官能团而获得,如Phadtar S.等在J.Am.Chem.Soc.111:5925(1989)中所述。
在反应式D,步骤(a)中,二羟基膦酸酯(27)与亚硫酰氯反应得到二氧膦酸酯,后者再与醇R5OH反应得到二取代的膦酸酯(28)。步骤(b)中,二取代的膦酸酯(28)水解产生(29)。步骤(c)中,单酰氧基烷基单烷基膦酸酯(29)与亚硫酰氯如前所述进行反应,再与R5’OH反应生成不对称二取代的膦酸酯,其中R5和R5’不同。
如反应式D中所定义。
反应式E表示二羟基膦酸酯(27)与取代的氯甲基醚(31)在有机碱如取代的吗啉存在下反应,生成二取代的膦酸酯(32)。
如反应式D中所定义。
反应式F表示单酰氧烷基单烷基膦酸酯(29)与氯甲基醚(31)如前所述进行反应,生成单酰氧烷基膦酸酯(32)。
E-9-(5-二羟基磷酰基-3-亚甲基-4-戊烯基)鸟嘌呤(其中X1为NH2,X2为OH,Z为CH2CH2,W为Wa,其中R1和R2都为H,T为T’为CH=CH)。A步:4-叔丁基二甲基氧基-2-亚甲基丁醛
4-叔丁基二甲基氧基-2-乙酰氧基-1-丁醇(14g,50mmol)、粉状分子筛、N-甲基-吗啉N-氧化物(9.9g,75mmol)和四丙基铵过钌酸盐(TPAP)10.34g,2.5mmol)在无水二氧甲烷(250ml)中的混合物于20℃搅拌过夜。将反应混合物滤过硅藻土,真空浓缩,在硅酸上快速层析纯化标题产物(8.25g,77%)。B步:
E-5-叔丁基二甲基甲硅烷氧基-3-亚甲基-1-戊烯基膦酸二乙酯
将1.6M正丁基锂的己烷溶液(4.7ml,7.45mmol)于-78℃氩气下加至亚甲二膦酸四乙酯(2.14g,7.45mmol)与无水四氢呋喃(70ml)的混合物中。1小时后,滴加4-叔丁基二甲基氧基-2-亚甲基丁醛(1.14g,5.3mmol)的无水四氢呋喃(10ml)溶液。反应混合物于-78℃搅拌3小时,20℃搅拌过夜,然后用氯化铵饱和溶液水解,用乙醚萃取。在硅酸上快速层析分离标题产物(1.7g,91%)。C步:
E-5-羟基-3-亚甲基-1-戊烯基-膦酸二乙酯
E-5-叔丁基二甲基甲硅烷氧基-3-亚甲基-1-戊烯基-膦酸二乙酯(1.7g,4.86mmol)和1M氯化四丁基氟化铵在四氢呋喃(8ml,8mmol)中的混合物于20℃搅拌2小时。然后真空浓缩反应混合物,在硅胶上快速层析纯化标题产物(1.1g,94%)。D步:E-5-对甲苯磺酰氧基-3-亚甲基-1-戊烯基-膦酸二乙酯E-5-羟基-3-亚甲基-1-戊烯基-膦酸二乙酯(1.07g,4.6mmol)、三乙胺(0.7ml,5mmol)、对甲苯磺酰氯(0.96g,5mmol)和二甲氨基吡啶(0.005g,0.04mmol)在无水二氯甲烷中的混合物于20℃搅拌4小时,真空浓缩,在硅酸上快速层析得到标题产物(1.55g,87%)。E步:E-9-(5-二乙氧基膦酰基-3-亚甲基-4-戊烯基)-6-氯-2-氨基嘌呤
6-氯-2-氨基嘌呤(0.74g,4.3mmol)、氢化钠(0.175g,4.3mmol,油中,60%)在无水二甲基甲酰胺(10mmol)中的混合物于20℃搅拌30分钟。然后加入E-5-对甲苯磺酰氧基-3-亚甲基-1-戊烯基-膦酸二乙酯(1.5g,3.9mmol)的无水二甲基甲酰胺(5ml)溶液,形成的混合物于20℃搅拌过夜。然后真空浓缩反应混合物,残余物在硅酸上快速层析纯化。得到标题产物(1.1g,73%)。F步:E-9-(5-二羟基膦酰基-3-亚甲基-4-戊烯基)-6-氯-2-氨基嘌呤E-9-(5-二乙氧基膦酰基-3-亚甲基-4-戊烯基-6-氧-2-氨基嘌呤(0.96g,2.5mmol)和溴化三甲基甲硅烷(1.3ml,10mmol)在无水乙腈(5ml)中的混合物于20℃搅拌过夜。然后用甲酸(5ml)处理反应混合物,真空浓缩。粗产品(0.8g)不经进一步纯化用于下步。G步:E-9-(5-二羟基膦酰基-3-亚甲基-4-戊烯基)鸟嘌呤
E-9-(5-二羟基膦酰基-3-亚甲基-4-戊烯基)-6-氯-2-氨基嘌呤(0.8g,~0.245mmol)粗品和1N盐酸(5ml)的混合物于20℃搅拌过夜。真空浓缩反应混合物,用无水乙醇稀释,冷却生成标题产物(0.46g,60%)。
实施例2E-9-[(4-二羟基磷酰基-2-亚甲基-3-丁烯氧基)甲基]鸟嘌呤(其中X1为NH2,X2为OH,Z为CH2CH2,W为Wa,其中R1和R2均为H,T为T’为CH=CH)A步:2-叔丁基二苯基甲硅烷氧基甲基-2-丙烯-1-醇
将氯化叔丁基二苯基甲硅烷(45g,165mmol)的无水二氯甲烷(60ml)的溶液于0℃搅拌下滴加到2-羟甲基-2-丙烯-1-醇(12g,165mmol)、三乙胺(27.5ml)和4-二甲氨基吡啶(2g)的无水二氯甲烷(300ml)溶液中。然后于20℃搅拌此混合物过夜,用饱和氯化铵和盐水洗涤。在硅胶上快速层析得到标题产物(19.4g,40%)。B步:2-叔丁基二苯基甲硅烷氧甲基-2-丙烯醛
2-叔丁基二苯基甲硅烷氧甲基-2-丙烯-1-醇(25.5g,86.7mmol)、粉状分子筛(26g)、N-甲基吗啉-N氧化物(15.3g,130mmol)和四丙基铵过钌酸盐(1.5g,4mmol)在无水二氯甲烷(400ml)中的混合物于20℃搅拌过夜。然后真空浓缩反应混合物,在硅胶上快速层析纯化,得到标题产物(21g,83%)。C步:E-4-叔丁基二苯基甲硅烷氧基-1.3-丁二烯基膦酸二乙酯
将1.6M的正丁基锂己烷溶液(70ml,120mmol)于-78℃加至亚甲二膦酸四乙酯(34.5g,120mmol)无水四氢呋喃(150ml)溶液中。30分钟后,滴加2-叔丁基二苯基甲硅烷氧基甲基-2-丙烯醛(21g,71.5mmol)的无水四氢呋喃溶液。反应混合物于-78℃搅拌4小时,20℃搅拌过夜,然后用氯化铵饱和溶液水解,用乙醚萃取。在硅胶上快速层析得到标题产物(20g,55%)。D步:E-4-羟基-1.3-丁二烯基膦酸二乙酯
将E-4-叔丁基二苯基甲硅烷氧基-1.3-丁二烯基膦酸二乙酯(11g,26.4mmol),和氟化四丁基铵三水合物(10g,31mmol)在四氢呋喃(100ml)中的混合物于20℃搅拌2小时。真空浓缩反应混合物,用乙酸乙酯稀释,用盐水洗涤。在硅胶上快速层析得到标题产物(4.6g,80%)。E步:E-9-[(4-二乙氧基磷酰基-2-亚甲基-3-丁烯氧基)甲基]-6-(2-三甲基甲硅烷基乙氧基)-2-氨基嘌呤
向多聚甲醛(0.17g,5.0mmol),E-4-羟基-1.3-丁二烯基膦酸二乙酯(0.9g,4.5mmol)在无水1.2-二氯乙烷(5ml)中的0℃混合物中通入无水氯化氢15分钟。于20℃搅拌反应混合物2小时,真空浓缩,用1.2-二氯甲烷(10ml)稀释,并加至双三甲基甲硅烷基-6-(2-三甲基甲硅烷基乙氧基)-2-氨基嘌呤(6-(2-三甲基甲硅烷基乙氧基)-2-氨基嘌呤(1.3g,5mmol)和双三甲基甲硅烷基乙酰胺(2.5g)在1.2-二氯乙烷(5ml)中于60℃加热1小时得到)和碘化四丁铵(0.19g,0.5mmol)的溶液中。于20℃搅拌反应混合物3小时,回流4小时,用饱和氯化铵溶液水解,用氯仿萃取。在硅胶上快速层析获得标题产物(0.37g,96%)。F步:E-9-[(4-二羟基膦酰基-2-亚甲基-3-丁烯氧基)甲基]鸟嘌呤
E-9-[(4-二乙氧基膦酰基-2-亚甲基-3-丁烯氧基)甲基]-6-(2-三甲基甲硅烷基乙氧基)-2-氨基嘌呤(10.24g,0.5mmol)和溴化三甲基甲硅烷(0.26ml,2mmol)在无水乙腈(3ml)中的混合物于20℃搅拌过夜。用甲醇(2ml)处理反应混合物,真空浓缩,在乙醇:水中结晶得到标题产物(0.12g,65%]。
9-(3-二羟基膦酰基甲氧基-2-亚甲基丙基)鸟嘌呤(其中X1为NH2,X2为OH,Z为CH2,W为Wa,其中R1和R2均为H,T为T″为CH2OCH2)A步:(2-氯甲基-2-丙烯氧基甲基)膦酸二乙酯
向羟甲基膦酸二乙酯(0.84g,5mmol)、1-氯-2-氯甲基-2-丙烯(0.95g,7.6mmol)和碘化四丁基铵(0.18g,0.5mmol)在无水四氢呋喃(10ml)中的混合物0℃下加入氢化钠(0.24g,6mmol,油中60%)。于20℃搅拌此混合物过夜。用饱和氯化铵溶液水解反应混合物,用乙酸乙酯萃取,在硅胶上快速层析得到标题产物(0.35g,27%)。B步:9-(3-二乙氧磷酰基甲氧基-2-亚甲基-丙基)-6-氯-2-氨基嘌呤
(2-氯甲基-2-丙烯氧基甲基)膦酸二乙酯(0.285g,1.1mmol)、6-氯-2-氨基嘌呤(0.25g,1.5mmol)和碳酸钾(0.24g,1.5mmol)在无水二甲基甲酰胺中的混合物于20℃搅拌2天。真空浓缩反应混合物,在硅胶上快速层析得到标题产物(0.22g,51%)。C步:9-(3-二羟基膦酰基甲氧基-2-亚甲基-丙基)鸟嘌呤
9-(3-二乙氧基磷酰基甲氧基-2-亚甲基-丙基)-6-氯-2-氨基鸟嘌呤(0.22g,0.56mmol)、溴化三甲基甲硅烷(0.43g,2.8mmol)和2.6-二甲基吡啶(0.59g,5.5mmol)在无水乙腈(2ml)中的混合物于20℃氩气下搅拌24小时。然后,真空浓缩反应混合物,用1M NaOH(10ml)于20℃处理2天。用乙酸沉淀得到标题产物(0.11g,61%)。
实施例4Z-9-(4-二羟基磷酰基甲氧基-2-丁烯基)鸟嘌呤(其中X1为NH2,X2为OH,Z为CH2,W为Wc,其中R1和R2均为H,T为T″为CH2OCH2)A步:Z-(4氯-2-丁烯氧基)甲基膦酸二乙酯
向羟甲基膦酸二乙酯(1.68g,10mmol)、Z-1.4-二氯-2-丁烯(1.9g,15mmol)、和碘化四正丁基铵(0.36g,1mmol)在无水四氢呋喃(15ml)中的混合物中0℃下加入氢化钠(0.48g,12mmol,油中60%)。形成的混合物于20℃搅拌过夜,用饱和氯化铵水解,用乙醚萃取。在硅胶上快速层析得到标题产物(1.2g,45)。B步:Z-9-(4-二乙氧基磷酰基甲氧基-2-丁烯基)-6-氯-2-氨基嘌呤
Z-(4-氯-2-丁烯-氧基)甲基膦酸二乙酯(1.05g,4mmol)、6-氯-2-氨基嘌呤(1g,6mmol)和碳酸钾(0.92g,6mmol)在无水二甲基甲酰胺(10ml)中的混合物于20℃搅拌2天。真空浓缩反应混合物,残余物在硅胶上快速层析纯化,得到标题产物(0.858,55%)。C步:Z-9-(4-二羟基磷酰基甲氧基-2-丁烯基)鸟嘌呤
Z-9-(4-二羟基膦酰基甲氧基-2-丁烯基)-6-氯-2-氨基嘌呤(0.788,2mmol),溴化三甲基甲硅烷(1.5g,10mmol)和2.6-二甲基吡啶(2.15g,20mmol)在无水乙腈(10ml)中的混合物于20℃氩气下搅拌24小时。真空浓缩反应混合物,残余物用1MNaOH(15ml)于20℃处理2天。用乙醇∶水连续沉淀,得到标题化合物的钠盐(0.55g,75%)。
9-(4-二羟基磷酰基甲氧基-2-丁炔基)鸟嘌呤(其中X1为NH2,X2为OH,Z为CH2,W为Wa,T为T″为CH2OCH2)。A步:(4-氯-2-丁炔氧基)甲基膦酸二乙酯
向羟甲基膦酸二乙酯(3.35g,20mmol),1,4-二氯-2-丁炔(3.8g,30mmol)和碘化四正丁基铵(0.75g,2mmol)在无水四氢呋喃(100ml)中的混合物中,于0℃下分批加入氢化钠(0.95g,24mmol,油中60%)。形成的混合物于0℃搅拌过夜。反应混合物于20℃搅拌过夜,用氯化铵饱和水溶液水解,用乙醚萃取。在硅胶上快速层析获得标题产物(2.3g,30%)。B步:9-(4-二乙氧基磷酰基甲氧基-2-丁炔基)-6-氯-2-氨基嘌呤
(4-氯-2-丁炔氧基)甲基膦酸二乙酯(2.03g,8mmol)、6-氯-2-氨基嘌呤(2g,12mmol)和碳酸钾(1.85g,12mmol)在无水二甲基甲酰胺(15ml)中的混合物于20℃氩气下搅拌2天。真空浓缩反应混合物,在硅胶上快速层析纯化残余物,得到标题化合物(1.7g,65%)。C步:9-(4-二羟基磷酰基甲氧基-2-丁炔基)鸟嘌呤
9-(4-二乙氧基磷酰基甲氧基-2-丁炔基)-6-氯-2-氨基嘌呤(1.5ml,4mmol)、溴化三甲基甲硅烷(3g,20mmol)和2.6-二甲基吡啶(4.3g,40mmol)在无水乙腈(20ml)中的混合物于在氩气下20℃搅拌1天。真空浓缩反应混合物,残余物用1M氢氧化钠(20ml)于20℃处理2天。在乙醇∶水中连续沉淀,得到标题化合物的钠盐(1.05g,70%)。
实施例69-(3-二新戊酰甲氧基膦酰基甲氧基-2-亚甲基丙基)鸟嘌呤(其中X1=NH2,X2=OH,Z=CH2,W=Wa其中R1和R2均为H,T=T″=CH2OCH2,R3和R4均为-O-CH(R6)-O-C(O)R5,其中R6为H)
将N1N’-二环己基碳化二亚胺(1.13g,0.4mmol)和新戊酸氯甲酯(1.8g,12mmol)加至9-(3-二羟基磷酰基甲氧基-2-亚甲基丙基)乌嘌呤(630mg,2mmol)在无水DMF(10ml)中的混合物中,于20℃搅拌混合物过夜;然后滤除不溶物,真空浓缩滤液。残余物用甲苯稀释,用水洗涤。在硅胶上快速层析纯化,用5%MaOH/CH2洗脱得到标题化合物。
实施例7核酸碱基修饰腺嘌呤衍生物
在使用6-氯-2-氯基嘌呤的所有实验中,也或以使用腺嘌呤,在用溴化三甲基甲硅烷处理膦酸二酯脱保护后得到相应的9-取代的腺嘌呤。胞嘧啶衍生物
在所有实验中,可用4-N-乙酰胞嘧啶代替6-氯-2-氨基嘌呤。脱保护可分两步进行:
a)用氨的乙醇溶液处理去除N-乙酰基团,和
b)用溴化三甲基甲硅烷处理水解膦酸二酯胸腺嘧啶衍生物
在所有实验中,可用胸腺嘧啶代替6-氯-2-氨基嘌呤。可用溴化三甲基甲硅烷处理进行膦酸二酯的水解。2.6-二氨基嘌呤
通过溴化三甲基甲硅烷处理或在相应实验中用2,6-二氨基嘌呤代替2-氯-2-氨基嘌呤可得到二氨基嘌呤类似物。
本发明化合物在医疗中有用,特别是在治疗或预防病毒感染中,例如作为抗病毒药有效地对抗DNA病毒(疱疹病毒1和2,巨细胞病毒、水痘一带状疱疹病毒,E-B病毒),逆转录病毒(人免疫缺陷病毒1和2及维斯那病毒)和相关的临床状况如AIDS相关综合组(ARC),以及抗与肿瘤形成有关的病毒。本发明的抗病毒药可作为单一治疗药使用,也可以与其它抗病毒药联合治疗特别是人逆转录病毒感染;特别是人免疫缺陷病毒感染。特别优选与2’3’-二脱氧嘌呤核苷联合治疗,它们是2’,3’-二脱氧腺苷、2’,3’-二脱氧乌苷、2’,3’-二脱氧硫代肌苷和2’,3’-二脱氧肌苷。其它可能的联合治疗药包括治疗或预防病毒感染或相关状况有效的药物,如3’-叠氮-3’-脱氧胸腺嘧啶(Zidovudine),2’,3’-二脱氧核苷,如2’,3’-二脱氧胞苷、2’,3’-二脱氧腺苷和2’,3’-二脱氧肌苷,非环核苷(如acyclovir),干扰素如α-干扰素,肾分泌抑制剂如羧苯磺胺,核苷转运抑制剂如潘生丁,以及免疫调节剂如白细胞介素II和粒巨细胞集落刺激因子。这种联合治疗的各化合物成分可或分剂或合剂同时使用,或在不同时间使用,如相继使用,以取得联合效果。
可用任何适当的方法测定本发明化合物的抗病毒效力。以下是检测这些化合物效力的几种代表性方法。对人免疫缺陷病毒(HIV)的MTT细胞存活力实验。
MTT细胞存活力实验最早是由Pauwe等描述的(J.Virol.Mth-ods,1988:20,309-321)。它是一种基于能存活又没有死亡的细胞将黄色3-(4,5-二甲基-2-基)-2,5-二苯基-四唑翁溴化物(MTT)(Sigma Chemical Co.Ltd.)还原为蓝色甲产物能力的比色实验。这一还原反应是通过代谢活性细胞的线粒体脱氢酶进行的。该实验能够快速准确地评估潜在抗病毒药物HIV活性,同时得到它们的细胞毒性,使得可以确定选择性指数(S.I)。
使用对HIV感染高敏性的MT-4细胞,用HIV-1RF毒株感染。在一96孔平底塑料微滴定板(Sterilin Ltd.)的中央60孔中加入100ul含试验化合物的系列稀释的生长培养基,浓度为所需终浓度的2倍。外周的孔中加入无菌蒸馏水以防止在温育时蒸发。对化合物的每个浓度,有两套三孔,以便能同时评价化合物对感染和未感染细胞的作用。一些孔中不含药物作为拟感染和病毒感染细胞的未处理对照。对指数生长期MT-4细胞计数,调节细胞数边每孔5×104细胞。然后沉降细胞并分成两组。一半细胞用病毒(100TCID50/5×104细胞)感染,另一半摸拟感染。室温吸收病毒1小时。然后沉降细胞,用RPMI洗涤一次,然后再悬浮于一定体积培养其中使得能向微滴定板的每个孔中加入100μl。培养板在含5%CO2的孵箱中37℃温育。
温育6天后,向每孔中加入10μlMTT的PBS溶液(7.5mg/ml),再于37℃温育1小时。加入100μl10%(v/v)Triton X-100的酸性异丙醇溶液(2ml浓HCl/500ml溶剂)并混合使甲结晶溶解。最后用Multiskan MCC分光光度计(Flow Ladoratories)读取540nm处的吸光度。对每一化合物,拟感染和病毒感染细胞的光密度(O.D.)读数均对药物浓度做图。可用下式计算代表50%终点的O.D.值,从而可以确定试验化合物的50%细胞毒剂量(CD50)和(IC50):
(模拟感染组平均O.D.-病毒感染组平均O.D.)/2用C-8166检测化合物的抗HIV活性的方法
向一96孔平底塑料微滴定板中央60孔中加入100μl含系列稀释的试验化合物的生长培养基,浓度为所需终浓度的2倍。外周孔中加入无菌蒸馏水以防止在温育时蒸发。化合物每个浓度使用三个孔。一些孔中不含药物作为对照。将指数生长期C-8166细胞计数,调节细胞数至1×105细胞/孔。浓降细胞并用HIV感染,感染量为0.001-0.0001感染单位/细胞。
室温下吸收病毒1小时。然后沉降细胞,用RPMI洗涤三次,再悬于一定体积培养基中使得可以向微滴定板的每孔中加入100μl。培养板在含5%CO2的孵箱中温育。三天后观察感染细胞,并根据含细胞体的存在打分:+++=50%-100%cpe;++=10%-50%cpe;+=<10%cpe和○=无合胞体。从每孔中收集100μl上清液,用ELISA测定P24病毒核抗原的水平。P24 ELISA
一96孔‘U’形底微滴定板(Falcon,Becton Dickinson)的中央60孔用100μl亲和纯化的羊抗=HIV-1-P24(Aalto Bioreagents,Rath-farnham,Dublin,Ireland,code D7320)在包被缓冲液(100mMNaH-CO3,PH8.5)中浓度为10μg/ml的溶液包被。此产品是用三种相当于HIV-1 BH-10毒株P24 gag蛋白的氨基酸283-297(LDIRQGPKEPFRDYV);173-188(SALSEGATPODLNTML)和226-237(GQM-REPRGSDIA)的合成肽免疫羊而产生的。+4℃静置培养板过夜让抗体附着,然后用Tris缓冲盐水(TBS)(0.144M Nacl,25mM TrispH7.5)用微滴定板洗涤器(Laminar Technologies)洗涤2次,然后用溶于TBS中的2%脱脂牛奶(Cadburys Marvel)于室温封闭1小时(200μl/孔)。用TBS洗两次后,向孔中加入100μl无细胞培养液,以及10μl 1%(v/v)两性表面活性剂Empigtnl(Cal biochem)的溶液。根据所期望的P24水平,将培养溶筛至纯细胞或1∶10或1∶100的稀释度。样品于室温温育过夜,再洗孔三次,与100μl第二抗-P24抗体——与碱性磷酸酯酶直接偶联的EH12E1-AP(APP452)一起温育,此抗体在含20%羊血清(Seralab)、2%脱脂牛奶(Cadburys Mavtl)和0.5%Tween20(Sigma chemical CO.)的TBS中,浓度为1∶3000。此抗体是由Bridget Ftrns、Richard Tedder和他们的同事在MiddlessexHospotal Medical School对HIV-1 CB1-1分离物产生的,并经分析它是针对一种含两种不同肽序列的复合表位。它们是GHQAAMQMLKETINEEAAEWDRVHPVHAGIPLAPGQ(aa 193-227)和NPPIPVGEIYKRWII(aa 253-267),并在不同HIV-1株间保守。EH12E1的碱性磷酸酯酶偶连物(EH12E-AP)是由Novo Biolabs,Cambridge,U.K.制备的。通过APP试剂库得到此偶联抗体。培养板用孵箱/摇床(Luminar Technologies)于37℃温育1小时,然后用TBS洗孔三次。这些孔用市场上供应的碱性磷酸酯酶检测和扩增试剂盒AMPAK(IQ(Bio)Ltd.)中提供的缓冲液最后洗涤,按制造商的指示加入50μl AMPAK底物。室温30分钟后,加入50μlAMPAK扩增剂,用酸停止反应后的紫色强度,在约10分钟后用Multiskan Mcc/340分光光计(Flow Laboratorits)在492nm处读取。
采用经ADP获得的重组HIV-IP24(American BiotechnologiesInc.),用从100ng/ml开始的一系列两倍稀释进行免疫检测的标定。该检测一般得到300-10,000pg/ml范围内的线性反应,尽管每天之间存在差异。检测化合物的抗疱疹(HSV-1和HSV-2)活性
为了检测,将适当生长培养基中的LeLa(人宫颈癌)细胞(0.8×105/0.1ml)或Vero(非洲绿猴肾)细胞(1.0×105/0.1ml)转至一平底96孔(0.1ml细胞/孔)微滴定板(Falcon)上。在一加湿CO2(5%CO2,95%空气)孵箱中37℃培养24小时后,培养物待用。
每次检测从微滴定板培养物中吸出生长培养基并换入100μl维持培养基(细胞和病毒对照)或用维持培养基稀释至2倍检测浓度的化合物(毒性对照,实验孔)。在加湿CO2孵箱中37℃培养3小时后,每个培养物中加入100μl维持培养基(细胞和毒性对照)或用维持培养基稀释的病毒[1型单纯性疱疹病毒(HSV-1;HF株,ATCC VR-260)或2型单纯性疱疹病毒(HSV-2;G株,ATCC VR-734)](病毒对照,化合物实验孔)。然后所有培养物于37℃培养,于48和72小时(疱疹病毒)或7、10和14天(CMV)用显微镜检查病毒和化合物诱导的细胞病变效果(CPE)。CPE分级为0(无)、1+(25%)、3+(75%)或4+(100%)细胞单层破坏。然后这些数据用于计算化合物的50%抑制浓度(IC50)。检测化合物的抗巨细胞病毒活性
为进行检测,将在适当生长培养基中的MRC-5细胞(1.2×105/0.1ml)转至平底96孔(0.1ml细胞/孔)微滴定板上(Falcon)。在一加湿CO2(5%CO2,95%空气)孵箱中于37℃培养24小时,培养物待用。
每次检测从微滴定板培养物中吸出生长培养基并换入100μl维持培养基(细胞和病毒对照)或用维持培养基稀释至2倍检测浓度的的化合物(毒性对照,实验孔)。在加湿CO2孵箱中37℃培养3小时后,每个培养物中加入100μl维持培养基(细胞和毒性对照)或用维持培养基稀释的病毒[人巨细胞病毒(CMV-1;AD169株,ATCCVR-538)](病毒对照,化合物实验孔)。然后所有培养物于37℃培养,于48和72小时(疱疹病毒)或7、10和14天(CMV)用显微镜检查病毒和化合物诱导的细胞病变效果(CPE)。CPE分级为0(无)、1+(25%)、3+(75%)或4+(100%)细胞单层破坏。然后这些数据用于计算化合物的50%抑制浓度(IC50)。
鸟嘌呤的非环核苷酸衍生物通过鸟苷酸激酶磷酰化的效力(定义为Vmax/Km比)与用作参照底物的GMP的磷酰化效力比较。用于确定Vmax和Vm参数的实验如Nave等在Arch.Biochem.Biophys.(1992),295,253-257中所述。
活性成分的给药量根据所用的具体剂量单位、治疗时间、治疗的患者年龄和性别和所治疗疾病的性质和程度,在一宽范围内变化。所用活性成分有效抗病毒量的总量一般为约1ng/kg到100mg/kg,优选3-25mg/kg。单位剂量可含有25-500mg活性成分,每天可用一次或多次。式I或II活性化合物可与药物载体一起用常规剂量单位形式通过口服、肠外、表皮或透皮途径给药。
本文所用术语“患者”包括哺乳动物如小鼠、大鼠、猫、狗、牛、羊、猪和包括人的灵长类。
对口服给药,可将化合物配制成固态或液态制剂,如胶囊、丸剂、片剂、锭剂、糖锭、熔化物、粉剂、溶液、悬液、或乳液。固体单位剂量形式可为胶囊,它可为普通的硬壳或软壳明胶型,含有例如表面活性剂、润滑剂、和惰性填充剂如乳糖、蔗糖、磷酸钙、和玉米淀粉。在另一方案中,本发明化合物可与常规片基如乳糖、蔗糖、和玉米淀粉一起压制成片,并结合粘合剂如阿拉伯胶、玉米淀粉、或明胶;给药后帮助片剂破裂并溶解的崩解剂如马铃薯淀粉、藻酸、玉米淀粉、瓜尔胶;用于提高片剂颗粒的流动性防止片剂材料粘附在片剂冲模和冲床上的润滑剂,如滑石粉、硬脂酸、或硬脂酸镁、钙或锌;和用于提高片剂的美学性质使它们对病人更易接受的颜料、着色剂和调味剂。用于口服液态剂型的适当赋形剂包括稀释剂如水和醇如乙醇、苯甲醇、和聚乙烯醇,添加或不添加药用表面活性剂、悬浮剂、或乳化剂。
本发明式I化合物还可以肠外给药,即皮下、静脉内、肌内、或腹膜内,以生理可接受的稀释剂中的化合物的可注射剂型给药,其中还含有药用载体,可为无菌液体或液体混合物如水、盐水、葡萄糖水溶液和有关的糖溶液,醇如乙醇、异丙醇、或十六烷醇,二醇如丙二醇或聚乙二醇,甘油缩酮,如2,2-二甲基-1,3-二氧戊环-4-甲醇,醚如聚乙二醇400,油,脂肪酸,脂肪酸酯或甘油脂,或乙酰化脂肪酸甘油酯,加或不加药学上可接受的表面活性剂如皂或洗涤剂,悬浮剂如果胶、carbomers、甲基纤维素、羟丙基甲基纤维素、或羧甲基纤维素,或乳化剂和其它药学上可接受的添加剂。可用于本发明的肠外制剂的油的实例为那些来自石油、动物、植物、或合成的油,例如花生油、豆油、芝麻油、棉籽油、玉米油、橄榄油、石油、和矿物油。适当的脂肪酸包括油酸、硬脂酸、和异硬脂酸。适合的脂肪酸酯例如为油酸乙酯和肉豆莞酸异丙酯。适宜的皂包括脂肪酸碱金碱盐、铵盐、和二乙醇胺盐,适宜的洗涤剂包括阳离子洗涤剂如二甲基二烷基卤化铵、烷基吡啶翁卤化物、烷基胺醋酸盐;阴离子洗涤剂如烷基、芳基和烯属磺酸盐,烷基、烯属、醚、和单甘油酯硫酸盐,和磺基琥珀酸盐;非离子洗涤剂如脂肪胺氧化物,脂肪酸烷醇酰胺,和聚氧亚乙基聚亚丙基共聚物;和两性洗涤剂如β-氨基丙酸烷基酯、和2-烷基咪唑啉季铵盐,及其混合物。本发明的肠外用组合物一般在溶液中含有约0.5到约25%(重量)的活性成分。最好还使用防腐剂和缓冲剂。为了将注射位点的刺激减至最小或将其消除,这种组合物可含有亲水-亲脂平衡值(HLB)为约12到约17的非离子表面活性剂。在这种制剂中此表面活性剂的量为约5%到约15%(重量)。这种表面活性剂可以是具有以上HLB值的单一成分或两种或多种成分的具有所需HLB的混合物。用于肠外用制剂的表面活性剂的实例是聚乙烯脱水山梨醇脂肪酸酯类,例如脱水山梨醇单油酸酯和环氧乙烷与一疏水基的高分子量加合物,通过环氧丙烷与丙二醇缩合而成。
本发明化合物还可以表皮给药。这可通过简单地制备所需化合物的溶液来进行,优先用已知促进透皮吸收的溶剂如乙醇或二甲基亚砜(DMSO),加或不加其它赋形剂来制备溶液。优选的表皮给药使用贮器和多孔膜型的药包或具有固体基质变化的药包来进行。表皮给药还包括将本发明化合物掺入适于眼或耳给药的溶液或悬液中。
一些适宜的透皮装置描述在美国专利3,742,951、3,797,494、3,996,934和4,031,894中。这些装置一般含有限定其一个外表面的背衬、一个可透过活性药物的限定另一外表面的粘性层和置于外表面间的含有活性药物的至少一个贮器。或者,活性药物包含在分布于整个可透性粘性层中的许多微胶囊中。无论那种情形,活性药物从贮器或微胶囊通过一膜连续地运送至可透过活性药物的粘性层,后者与患者的皮肤或粘膜接触。如果活性药物透过皮肤被吸收,则可将有控制的和预定流速的活性药物施用于患者。当用微胶囊时,包被剂还起到膜的作用。
将本发明化合物透皮给品的另一装置中,药物活性化合物包含在基质中,它从基质中以预期的逐步、恒定和可控制的速度释放。基质是通透性的,化合物通过扩散或微孔流释放。释放速度可以控制。这种系统不需要任何膜,见美国专利3,921,636中。在这些系统中至少有两类释放是可能的。当基质为非多孔性时发生扩散释放。药物活性化合物溶解在基质中并扩散透过基质本身。当药物活性化合物在基质的小孔中通过液相运输时,发生微孔流释放。
下表代表本发明的一些优选化合物,其中R1和R2存在时均为氢,R3和R4均代表OH。
X1和X2 | X3和X4 | Z | W | T |
NH2,OH | CH2 | Wa | CH=CH | |
NH2,OH | CH2OCH2 | Wa | CH=CH | |
NH2,OH | CH2 | Wa | CH2OCH2 | |
NH2,OH | CH2 | Wc | CH2OCH2 | |
NH2,OH | CH2 | Wd | CH2OCH2 | |
NH2,NH2 | CH2 | Wa | CH2OCH2 | |
NH2,NH2 | CH2 | Wc | CH2OCH2 | |
H,NH2 | CH2 | Wa | CH2OCH2 | |
H,NH2 | CH2 | Wc | CH2OCH2 | |
H,NH2 | CH2 | Wd | CH2OCH2 | |
NH2,NH2 | CH2 | Wd | CH2OCH2 | |
H,NH2 | CH2 | Wd | CH2OCH2 | |
H,NH2 | CH2 | Wa | CH2OCH2 | |
H,NH2 | CH2 | Wb | CH2OCH2 | |
H,NH2 | CH2 | Wc | CH2OCH2 |
下表为本发明的优选化合物,其中X1和X2分别为MH2和OH,Z为CH2,W为Wa,T为CH2OCH2。R5和R5’各自为CH3,CH2CH3,CH(CH3)2,CH2C(CH3)2或苄基,但R5和R5’不同。
R3 | R4 |
OH | OR5 |
OR5 | OR5 |
OR5 | OR5 |
OR5 | OCH2OC(O)R5 * |
OCH2OC(O)R5 * | OCH2OC(O)R5′* |
还包括叔丁基作为R5或R5’。
Claims (9)
其立体异构形式和其混合物、互变异构形式或药学上可接受的盐,其中
X3为H或CH3;
X4为NH2或OH;
其中R1和R2各自独立地为H、F或CH2OH;
T不存在或为T′或T″,其中
T′为CH2CH2,CH=CH,CH2CH(OH),CH2CH(CH2OH),或CH2CH(CH2F),及
T″为CH=CH-CH(OH),CH=CH-CH(CH2OH),CH2OCH2,CH2OCH(CH2OH),CH2CH(CH2OH)CH2,CH2CH2CH(OH),CH2CH2CH(CH2OH),或CH2CH2CH(CH2F);
R3和R4各自独立地为OH,OR5,OR5′或-O-CH(R6)-O-C(O)R5,条件是当R3或R4之一为OH时,另一个不为-O-CH(R6)-O-C(O)R5,其中R5和R5′各自独立地为C1- 15烷基或苄基,R6为H或C1-10烷基,
条件是当T为CH=CH或CH2CH2,W为Wc,及Z为CH2时,X1为NH2和X2为OH不同时发生;
条件是当W为We时,Z不存在或为CH2,
条件是当T不存在时,W不为Wc,
条件是当Z为CH2且W为Wa时,T不能为CH=CH,及
条件是当Z不存在及W=Wc时,T不为CH=CH。
2.权利要求1的化合物,其中
当W=Wa或Wb且T=T″时,Z不为CH2OCH2;
当W=Wc或Wd且T=T′时,Z不为CH2OCH2;
当W=Wc或Wd且T=T″时,Z为CH2。
3.权利要求1的化合物,其中W为Wa或Wc。
4.权利要求1的化合物,其中T为T′,T′为CH=CH。
5.权利要求1的化合物,其中T为T″,T″为CH2OCH2。
6.权利要求1的化合物,其中Z为CH2或CH2O。
7.含有权利要求1的化合物和药学上可接受的载体的药物组合物。
8.权利要求1的化合物的用途,其任选与药学上可接受的载体结合用于制备治疗DNA病毒、逆转录病毒或肿瘤形成中相关病毒的病毒感染的药物组合物。
其中:
X3为H或CH3;
X4为NH2或OH;
Z不存在或为CH2,CH2CH2,CH2O或CH2OCH2;
其中R1和R2各自独立地为H、F或CH2OH;
T不存在或为T′或T″,其中
T′为CH2CH2,CH=CH,CH2CH(OH),CH2CH(CH2OH),或CH2CH(CH2F),及
T″为CH=CH-CH(OH),CH=CH-CH(CH2OH),CH2OCH2,CH2OCH(CH2OH),CH2CH(CH2OH)CH2,CH2CH2CH(OH),CH2CH2CH(CH2OH),或CH2CH2CH(CH2F);
R3和R4各自独立地为OH,OR5,OR5′,或-O-CH(R6)-O-C(O)R5,条件是当R3或R4之一为OH时,另一个不为-O-CH(R6)-O-C(O)R5,其中R5和R5各自独立地为C1-15烷基或苄基,R6为H或C1-10烷基,
条件是当T为CH=CH或CH2CH2,W为Wc,及Z为CH2时,X1为NH2和X2为OH不同时发生;
条件是当W为We时,Z不存在或为CH2,
条件是当T不存在时,W不为Wc,
条件是当Z为CH2且W为Wa时,T不能为CH=CH,及
条件是当Z不存在及W=Wc时,T不为CH=CH,
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EP93400842.6 | 1993-04-01 | ||
EP93400842A EP0618214A1 (en) | 1993-04-01 | 1993-04-01 | Unsaturated phosphonate derivatives of purines and pyrimidines |
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CN99101008A Pending CN1229084A (zh) | 1993-04-01 | 1999-01-07 | 嘌呤和嘧啶的不饱和膦酸酯衍生物 |
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AT (1) | ATE154605T1 (zh) |
AU (1) | AU681395B2 (zh) |
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HU (1) | HUT72459A (zh) |
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NO (1) | NO953878L (zh) |
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CN101189249A (zh) * | 2005-04-01 | 2008-05-28 | 加利福尼亚大学董事会 | 膦酰基-戊-2-烯-1-基核苷和类似物 |
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US5977061A (en) * | 1995-04-21 | 1999-11-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | N6 - substituted nucleotide analagues and their use |
TW369536B (en) * | 1996-01-18 | 1999-09-11 | Mitsubishi Chem Corp | Phosphonate nucleotide compounds |
FR2781229B1 (fr) * | 1998-07-17 | 2001-11-30 | Univ Nice Sophia Antipolis | Nouveaux composes analogues des nucleotides, leurs procedes de preparation et leurs applications |
GB9821058D0 (en) | 1998-09-28 | 1998-11-18 | Univ Cardiff | Chemical compound |
BRPI0210746B8 (pt) * | 2001-06-29 | 2021-05-25 | Inst Of Organic Chemistry And Biochemistry Ascr | derivados de 6-'2-(fosfonometóxi)alcóxi-pirimidina e seu método de preparação |
JP2005508924A (ja) * | 2001-08-30 | 2005-04-07 | 三菱ウェルファーマ株式会社 | 抗ウイルス剤 |
WO2004111064A1 (en) | 2003-06-16 | 2004-12-23 | Institute Of Organic Chemistry And Biochemistry, Academy Of Sciences Of The Czech Republic | Pyrimidine compounds having phosphonate groups as antiviral nucleotide analogs |
US7579332B2 (en) | 2003-07-30 | 2009-08-25 | Gilead Sciences, Inc. | Nucleobase phosphonate analogs for antiviral treatment |
JP2008538771A (ja) * | 2005-04-25 | 2008-11-06 | インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー, アカデミー オブ サイエンシズ オブ ザ チェコ リパブリック | テロメラーゼのプロセッシビティーを向上させるための化合物の使用 |
CN100352823C (zh) * | 2005-08-19 | 2007-12-05 | 浙江车头制药有限公司 | 一种腺嘌呤衍生物的制备方法 |
US8324179B2 (en) | 2007-02-09 | 2012-12-04 | Gilead Sciences, Inc. | Nucleoside analogs for antiviral treatment |
TWI444384B (zh) | 2008-02-20 | 2014-07-11 | Gilead Sciences Inc | 核苷酸類似物及其在治療惡性腫瘤上的用途 |
ES2734495T3 (es) | 2011-12-22 | 2019-12-10 | Geron Corp | Análogos de guanina como sustratos de telomerasa y afectores de la longitud de los telómeros |
US11110112B2 (en) | 2016-02-18 | 2021-09-07 | Invirsa, Inc. | Methods for the use of 5'-adenosine diphosphate ribose (ADPR) |
WO2019191026A2 (en) | 2018-03-27 | 2019-10-03 | Invirsa, Inc. | Methods for the use of 5'-adenosine diphosphate ribose (adpr) |
CN108383872B (zh) * | 2018-04-18 | 2019-07-12 | 南京师范大学 | 一种-1,1-二氟-3-磺酰基-2,4-戊二烯膦酸酯类化合物及其合成方法和应用 |
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CA2017054C (en) * | 1990-05-16 | 1999-08-10 | Jack S. Wilson | Automatic storage and retrieval system |
US5356886A (en) * | 1990-07-19 | 1994-10-18 | Beecham Group P.L.C. | Antiviral phosphono-alken derivatives of purines |
EP0531597A1 (en) * | 1991-09-12 | 1993-03-17 | Merrell Dow Pharmaceuticals Inc. | Novel unsaturated acyclic phosphonate derivatives of purine and pyrimidine |
EP0630381B1 (en) * | 1991-10-11 | 1997-04-09 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiviral acyclic phosphonomethoxyalkyl substituted, alkenyl and alkynyl purine and pyrimidine derivatives |
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1993
- 1993-04-01 EP EP93400842A patent/EP0618214A1/en not_active Withdrawn
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1994
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CN101189249A (zh) * | 2005-04-01 | 2008-05-28 | 加利福尼亚大学董事会 | 膦酰基-戊-2-烯-1-基核苷和类似物 |
CN101189249B (zh) * | 2005-04-01 | 2013-04-17 | 加利福尼亚大学董事会 | 膦酰基-戊-2-烯-1-基核苷和类似物 |
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DK0701562T3 (da) | 1997-07-07 |
FI954615A0 (fi) | 1995-09-28 |
NO953878L (no) | 1995-12-01 |
HUT72459A (en) | 1996-04-29 |
NZ263904A (en) | 1996-11-26 |
HU9502854D0 (en) | 1995-11-28 |
NO953878D0 (no) | 1995-09-29 |
CN1046288C (zh) | 1999-11-10 |
ZA942092B (en) | 1994-10-24 |
EP0701562A1 (en) | 1996-03-20 |
DE69403910D1 (de) | 1997-07-24 |
ATE154605T1 (de) | 1997-07-15 |
AU681395B2 (en) | 1997-08-28 |
GR3024788T3 (en) | 1998-01-30 |
WO1994022882A1 (en) | 1994-10-13 |
CA2159451A1 (en) | 1994-10-13 |
FI113539B (fi) | 2004-05-14 |
CN1120338A (zh) | 1996-04-10 |
EP0701562B1 (en) | 1997-06-18 |
JPH08508481A (ja) | 1996-09-10 |
EP0618214A1 (en) | 1994-10-05 |
CA2159451C (en) | 1999-04-13 |
AU6516294A (en) | 1994-10-24 |
ES2105684T3 (es) | 1997-10-16 |
DE69403910T2 (de) | 1998-01-29 |
IL109152A0 (en) | 1994-06-24 |
FI954615A (fi) | 1995-09-28 |
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