CN85109409A - 治疗哺乳动物肿瘤的改进 - Google Patents
治疗哺乳动物肿瘤的改进 Download PDFInfo
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- CN85109409A CN85109409A CN85109409.0A CN85109409A CN85109409A CN 85109409 A CN85109409 A CN 85109409A CN 85109409 A CN85109409 A CN 85109409A CN 85109409 A CN85109409 A CN 85109409A
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- deoxidation
- compound
- purine
- amino
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
Abstract
二氟核苷用于治疗哺乳动物的瘤。
Description
虽然曾经认为治疗癌症是完全不可能的,但是在过去十年期间在控制这种通常是致命的病症的危害方面取得了很大进展。几种有助于增加生存率的药物现在照例在临床使用。最常用的抗肿癌剂包括氨甲喋呤、阿霉素和生物碱蔓长春花例如长春新碱。然而,研究工作仍在继续进行,以寻求对接受治疗的病人更为安全、更为有效的化合物。本发明在***方面提供了有价值的改进。
本发明提供了一种治疗哺乳动物易感瘤的方法,此方法包括给上述哺乳动物服用有效药量的(Ⅰ)式的化合物或者一种它的可供药用的盐:
式中:
R1是氢,C1-C4的烷基或
;
R2是下式之一定义的一种碱
X是N或C-R4;
R4是氢、C1-C4的烷基、氨基、溴、氟、氯或碘;
每一个R5分别是氢或C1-C4的烷基。
本发明提供(Ⅰ)式的化合物用于制备治疗易感瘤的药物。
本发明也提供了一种新的(Ⅱ)式的化合物或一种它的可供药用的盐:
式中:
R6是氢或C1-C4的烷基;
R7是下式之一的嘧啶或嘌呤碱
Q是N、C-(C2-C4的烷基)或C-氨基;
X是N或C-R4;
R8是氢或C1-C4的烷基;
R4是氢、C1-C4的烷基、氨基、溴、氟、氯和碘;但仅当X是N时R6和R8两者才可以都是氢。
本发明进一步提供了一种(Ⅲ)式的化合物或者一种它的可供药用的盐:
式中:
R6是氢或C1-C4的烷基;
此外,还提供了一种制备如上述定义的式(Ⅱ)或式(Ⅲ)化合物的方法,该方法包括:
(a)将式R7H的一种嘧啶碱或者它的一种保护了的衍生物与式Ⅳ的一种糖或它的一种保护了的衍生物进行偶合:
其中R7H嘧啶碱和R6如上定义,而Leav是一个离去基团,如果需要,除去存在的任一保护基以产生嘧啶碱产物;和
(b)如果需要式中的碱是嘌呤的式(Ⅲ)或式(Ⅱ)化合物,使相应的嘌呤核苷化合物(其中化合物的嘌呤部分的C-2和/或C-6取代基是卤素)与氨反应,并且,如果需要,将产物烷基化。
本发明也提供了用于治疗哺乳动物易感瘤的药物配方,它包含一种与一合适的可供药用的载体、稀释剂或赋形剂相结合的式(Ⅱ)或式(Ⅲ)化合物。
另外,提供了一种用于哺乳动物化学疗法的式(Ⅱ)或式(Ⅲ)化合物。
用于本发明的化合物用下述方法制备较好:将D-甘油醛酮化合物与溴二氟醋酸C1-C4的烷基酯反应以制取3-二氧代戌环-2,2-二氟-3羟基丙酸烷基酯。水介羟基丙酸酯成内酯,将其保护和还原以制取2-脱氧-2,2-二氟核糖或木糖衍生物。这种化合物的羟基上有一离去基团将得到的糖与合适的碱偶合。最后将得到的保护的核苷除去保护基以提供所需的化合物。全部反应路线图示如下:
式中R10和R11分别是C1-C3的烷基,“Prot”是一个羟基保护基,而“Leav”是一个离去基团。
在将2-脱氧-2,2-二氟糖与碱偶合时,通常最好是将自由羟基转化为被保护了的羟基。保护基是那些通常用于合成有机化学的基团。化学家们习惯于选择能够有效地结合到羟基上,并且当反应完成时易于除去的基团。合适的基可以是那些在一般的教科书中所描述的基,如“有机化学保护基”第三章(Mcomie,Ed,PlenumPress,New York)(1973)和“有机合成保护基”第二章(Greene,John Wiley & Sons,New York)(1981)。
通常使用的羟基保护基包括甲酰基、
(C1-C4的烷基)、2-氯乙酰基、苄基、二苯基甲基、三苯基甲基、4-硝基苄基、苯氧基羰基、C1-C4的烷基(如叔丁基)、甲氧基甲基、四氢吡喃基、烯丙基、四氢噻吩、2-甲氧基乙氧基甲基、甲氧基乙酰基、苯氧基乙酰基、异丁酰、乙氧基羰基和苄氧基羰基。甲硅烷基羟基保护基尤其适宜,因为通过与水或醇接触它们大多数易于断开。这样的基团尤其可以包括三甲基甲硅烷基,以及异丙基二甲基甲硅烷基。甲基二异丙基甲硅烷基或三异丙基甲硅烷基。叔丁基二甲基甲硅烷基是一种特殊情况,并且在此合成中作为保护基是较好的,断开它较为困难,需要一种反应剂如氢卤酸,将它从羟基上除去。
核糖或木糖在它的环的1-位上有一个羟基。为了使糖与碱反应,生成使用于本发明的化合物,在1-位上必需接上一个那些一般用于有机合成的离去基。较好的离去基是磺酸盐,其中最好的是甲磺酸盐。也可以使用其它的典型的离去基,例如甲苯磺酸盐、乙磺酸盐、异丙基磺酸盐、4-甲氧基苯磺酸盐、4-硝基苯磺酸盐、2-氯苯磺酸盐、氯和溴。
用来合成用于本发明的化合物的糖由下式D-甘油醛酮化合物与溴二氟醋酸C1-C4的烷基酯(乙酯较优)反应而制得,
式中R10和R11如上述定义。
较好的甘油醛酮化合物是丙酮化合物,式中R10和R11二者都是甲基(见Fischer and Baer,Helv.Chim.Acta.17,622(1934))。More(与Dawans首次制备了溴二氟醋酸乙酯(Tet 33,1445(1977)。酮化合物和卤代醋酸酯的反应在活化金属如镁或优选锌存在下进行。用超声波能量作用于反应混合物最易达到活化。用这种方法活化弥补了反应混合物中存在少量水的问题,无需保持无水状态,并且也无需制备和小心贮存活化金属。然而,如果需要,可以用现有技术已知的一般方法使金属活化。大约一个等摩尔的金属量是最有利的量。
在中等温度下,于醚(如四氢呋喃和***)中完成反应。然而,可以使用对反应条件惰性的其它有机溶剂,它们包括卤代链烷例如氯仿、二氯甲烷或三氯乙烷和芳族溶剂,包括苯、甲苯和二甲苯。可以使用的温度范围为大约环境温度至大约150℃,然而从大约环境温度至大约80℃为佳。从几分钟到数小时的反应时间范围内得到了经济上满意的产率。应当注意此反应是放热反应,根据反应的规模和加入反应物的速率需将混合物进行冷却。
第一步反应的产物是3-二氧戊环基-2,2-二氟-3-羟基丙酸烷基酯,其结构式如下:
式中R10和R11如上所述。
3-R-羟基中间产物与它的3-S-羟基对映体之比通常大约为3∶1.3-R-羟基对映体具有制取天然构型的木糖衍生物的特有的立体化学结构,并且因此它是所希望的第一步对映体产物。通常能将3-R-羟基对映体从3-S对映体中分离干净,其方法是用色层法在硅胶柱中分离,用含0.5%甲醇的氯仿洗脱。
用非常温和的条件水解两种形式的羟基丙酸酯,生成下式的内酯:
适当控制水解这一步就会断开酮化合物官能团和酯基,一步提供内酯。水解剂是弱酸离子交换树脂较好,其中Dowex 50W12(Dow Chemical Company)最好。也可以使用其它的作用和缓的水解剂,虽然可能得到大量付产品。例如,醋酸水溶液或其它比较强的酸如丙酸、甲酸、氯代乙酸或乙二酸可以用于水解。
在内酯的酮氧还原之前应将内酯的羟基保护起来。根据所选择的保护基使用一般的反应条件。例如,将叔丁基二甲基甲硅烷基以三氟甲磺酸酯形式提供是最合适的,并且在碱(例如二甲基吡啶、吡啶等)的存在下进行保护反应。用内酯与酰化剂(例如酰基氯、溴化物、氰化物或叠氮化合物)反应的方法将酰基保护基(例如乙酰基、苯甲酰基等)加进去。反应便于在碱性溶剂(例如吡啶、喹啉或异喹啉)或者在叔胺溶剂(例如三乙基胺、三丁基胺或甲基哌啶)中进行。反应也可以在惰性溶剂中进行,其中加入了酸清除剂如叔胺。如果需要,可以在反应中使用酰化催化剂(例如4-二甲基氨基吡啶或4-吡咯烷吡啶)。于-25℃至100℃中等温度范围内进行在羟基提供保护基的酰化反应。这样的酰化也可以用合适的羧酸酸催化反应方法在惰性有机溶剂中完成或者无溶剂(neat)完成,可用的酸催化剂如硫酸、多磷酸或甲磺酸。
也可以用生成一种合适的酸的活性酯的方法提供酰基保护基,例如用与反应剂如二环己基碳化二亚胺、酰基咪唑、硝基酚类、五氯代酚、N-羟基琥珀酰亚胺和1-羟基苯并***反应的方法生成的酯。
醚类型保护基由内酯与例如一种合适的重氮化合物(如重氮甲烷、苯基重氮甲烷或甲硅烷基重氮甲烷)反应而制得。这样的反应通常在溶剂中进行,这些溶剂包括酯(如醋酸乙酯)、卤代溶剂(包括二氯甲烷和氯仿)和醚(包括***和四氢呋喃)。一般在从大约-50℃至大约0℃的低温下进行操作。这样的成醚反应也可以在反应剂如氢氧化三甲氧基锍、氢氧化三甲基锍和氢氧化三甲基硒的存在下于溶剂如二甲基亚砜、二甲基甲酰胺、六甲基磷酰胺、丙酮或乙腈中进行。
用通常的方法将上面讨论的甲硅烷基保护基连接在羟基上,例如用与合适的甲硅烷基甲酰胺或二(取代甲硅烷基)甲酰胺或合适的取代硅氮烷反应的方法。合适的甲磺酸取代甲硅烷基酯、甲苯基磺酸酯等也是可用的。反应中如果没有用碱性溶剂,则在反应混合物中通常需要等当量的碱。
当羟基已被保护时,将内酯的酮氧还原成醇,生成保护了的2-脱氧-2,2-二氟核糖或木糖。最佳的还原剂是在大约-100℃至-20℃低温下使用的氢化二异丁基铝。必需十分小心地进行反应以避免反应条件剧烈到在氧原子处将环打开。其它的金属氢化物如广泛使用的氢化锂铝也可用于还原,但是必须保持十分低的温度,并且保证在温度升至高于大约-20℃之前氢化物就被破坏。在还原阶段必须用有很低冰点的溶剂例如甲苯。当然,其它的溶剂包括较低链烷醇(尤其乙醇)或醚(如***)也可以使用。
为达到与碱进行有效的反应,在糖类的1-位上必需结合一合适的离去基。较佳的离去基是甲磺酰基,并且由在一当量的合适的酸净化剂如三乙基胺等存在下与甲磺酰氯反应的方法容易制得带有这一离去基的化合物。其它磺酰基离去基用同样方法由与合适的磺酰卤化物反应而生成。
当准备使用氯或溴离去基时,用与乙酸酐或其它乙酰基源在一当量或多于一当量的酸净化剂存在下反应的方法首先制出1-醋酸酯衍生物常常是有益的。然后在例如大约-50℃至大约0℃低温下,用气体溴化氢或氯化氢将醋酸酯基除去。由于气体卤化氢可以有助于移去保护基(特别是甲硅烷基保护基),在低温下操作和缓慢地少量地加入卤化氢是必需的。
较佳的合成用于本发明的具有由嘌呤基构成碱部分的化合物的方法是:将在3-位和5-位上有保护基的1-羟基糖类似物与碱在偶氮二羧酸二乙酯和三苯基膦存在下进行反应。如果需要,然后对嘌呤基作一般性处理。
通常用来生成用于本发明的化合物的碱是为本技术领域的熟练技术人员所熟知的,不必讨论如何合成它们。然而,在碱与糖偶联之前,应将某些碱上存在的伯氨基保护起来。一般使用的氨基保护基包括例如已讨论过的甲硅烷基以及这样的典型基团如叔丁氧基羰基、苄氧基羰基、4-甲氧基苄氧基羰基、4-硝基苄氧基羰基、甲酰基或乙酰基。
为了使碱成为更高的芳香碱并让碱与糖更迅速地反应,将碱上的酮氧原子转变成烯醇形式是合理的。通过生成甲硅烷基保护基达到稀醇化是最方便的。如上述的一般的甲硅烷基保护基可以使用于此目的。
在大约50℃至大约200℃温度范围内无溶剂进行保护了的糖和碱之间的反应较好。然而,将较高沸点的溶剂(例如二甲基甲酰胺、二甲基乙酰胺或者六甲基磷酰胺)用于反应是可能的。如果偶合反应于高压力下进行以避免低沸点溶剂馏出,任一合适的惰性反应溶剂都可使用。
如果使用如三氟甲磺酰氧基硅烷反应引发剂,偶合反应可于低温下进行。如上所述,于大约环境温度至大约100℃温度范围内可以使用一般的惰性反应溶剂。
反应顺序的最后一步是除去保护基。通过与水或一种醇接触大多数甲硅烷基保护基容易离去。为使叔丁基二甲基甲硅烷基保护基离去需要酸条件,例如与气态卤化氢接触。
用强或中等强度的碱(例如碱金属氢氧化物),于大约环境温度至大约100℃温度下,通过简单的水解方法除去酰基保护基。对每一保护基至少需要一当量的碱。这样的水解在羟基溶剂中,尤其含水链烷醇中进行较合适。然而,反应可在任何合适的溶剂中进行,例如多醇(包括1,2-乙二醇)、醚(例如四氢呋喃)、酮(例如丙酮和甲基乙基酮)和其它极性溶剂(例如二甲基亚砜)。除去酰基保护基也可用其它碱来进行,包括例如甲醇钠、叔丁醇钾、肼、羟基胺、氨、碱金属酰胺和仲胺如二乙基胺。酰基保护基也可用酸催化剂(例如甲磺酸、氢氯酸、氢溴酸、硫酸)除去,或者也可用酸性离子交换树酯除去。在相对高的温度下(例如混合物迥流温度)进行这样的水解较佳。但当使用特别强的酸时,也可使用低到环境温度的温度。
用已知方法(例如用乙硫醇和氯化铝)进行除去醚保护基。
当然,有羟基或氨基酰基或烷基的本发明化合物或者被有选择地除去保护基,或者可以将这些基除去并通过标准条件有选择地置换它们。
没有哪个反应阶段要求异常过量的反应物。如同在有机合成中一样,使用中等的过量(在1.05X至2X范围内)是合理的。
用于本发明的化合物可以生成可作药用的加成盐。这样的盐被认为包括在本发明范围内,并且它们可以包括氢溴化物、氢氯化物、单、双或三磷酸酯和这些磷酸的钠盐、硫酸盐、钠、钾、锂或铵盐,以及本技术领域熟练技术人员熟知的其它盐。可作药用的盐是那些在热血动物化学疗法中有用的盐。
定义用于本发明的化合物的结构式没有指明它们的立体化学结构。相信所有构型的化合物都是有用的,并且化合物的立体化学结构不被看作是一局限。较佳的化合物具有自然存在的木糖结构,例如
在木糖和碱之间的连接处的较好构型如下:
一个本技术领域的熟练技术人员都知道用于本发明的核苷的合成中所用的碱,但还是给出了下列具体的核苷以进一步补充完善在本发明中可以使用的试剂的类型。
1-(2,4-二氧代-1H,3H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
1-(4-氨基-5-氯-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
1-(4-氨基-5-溴-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
1-(4-氨基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
1-(4-氨基-5-碘-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
1-(4-氨基-5-甲基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
1-(2-氨基-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖。
1-(6-氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖。
1-(4-氨基-5-氟-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
1-(4-氨基-5-氯-2-氧代-1H-吡啶-1-基)-2-脱氧-2,2-二氟木糖。
1-(4-氨基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟木糖。
1-(4-氨基-5-氟-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2二氟木糖。
1-(4-氨基-5-甲基-2-氟代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟木糖。
1-(2-氨基-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟木糖。
1-(6-氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟木糖。
或其可药用的盐。
下面提供不受限制的实施例进一步说明本发明。
实施例1
1-(4-氨基-2-氧代-1H-嘧啶-1-
基)-2-脱氧-2,2-二氟核糖
将48.0g(0.16mol)双三甲基甲硅烷基N-乙酰基胞嘧啶加入含有47.3g(0.1mol)3,5-双(叔丁基二甲基甲硅烷氧基)-1-甲基磺酰氧基-2-脱氧-2,2-二氟核糖的940ml无水1,2-二氯乙烷中,再加入39.23g(0.177mol)三氟甲基磺酰氧基三甲基硅烷。反应混合物在氮气氛下回流大约15小时,冷却到室温,加入16ml甲醇稀释。得到的混合物搅拌30分钟,在真空下浓缩至原来体积的一半,用冰冷却。沉淀的固体用过滤收集,滤液与大约300ml 10%碳酸氢钠摇混一次,与盐与水摇混一次。分离有机层,在45℃真空浓缩至干燥。残余物溶解在1.3L氨饱和的甲醇中,得到的溶液搅拌一夜。在45℃用真空除去挥发性组分,得到32g残余物。残余物溶解在275ml甲醇中,将100g Biorad阳离子交换树脂(AG50W×8)加入得到的溶液中。该悬浮液在室温下搅拌一夜。用过滤除去树脂,用100ml甲醇漂洗一次。除去滤液,将树脂悬浮在100ml甲醇和50ml浓氢氧化铵中。该混合物剧烈搅拌15分钟,过滤出树脂。用另外的新鲜的甲醇和浓氢氧化氨(methanolic ammonia)重复该步骤两次。将碱性的甲醇滤液合并,在45℃真空蒸发,得到棕色泡沫体,重13.8g。该物质用Waters Prep 500C18反相柱用100%的水作为洗脱液进行色谱分离,得到1.26g 1-(4-氨基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
核磁共振谱(CD3OD,90mH2,δ)3.7-4.65(m,4H),4.83(S,4H),5.97(d,J=8H2,1H),6.24(t,J=7Hz,1H),7.88(d,J=8Hz,1H)。
质谱m/e=263=p
实施例2
1-(4-氨基-5-碘代-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖
将2.08g(0.0046mol)三-三甲基甲硅烷基-5-碘代胞嘧啶加入含有1.99g(0.0042mol)3,5-双(叔丁基二甲基甲硅烷氧基)-1-甲基磺酰氧基-2-脱氧-2,2-二氟核糖的35ml无水1,2-二氯乙烷中,再加入1.11g(0.005mol)三氟甲基磺酰氧基三甲基硅烷。反应混合物在氮气氛下回流大约16小时,冷却至室温。将5ml甲醇加入反应混合物中,该混合物再搅拌30分钟。过滤混合物并收集沉淀的固体。滤液在减压下蒸发至干燥,得到的残余物溶解在20ml无水溴化氢饱和的二氯甲烷中。该混合物搅拌大约3小时。在45℃用真空除去挥发性组分。残余物溶解在15ml水中,用10%碳酸氢钠中和至pH7-8,得到的溶液用10ml乙酸乙酯洗涤一次。水层在Whatman Prep ODS-3反相柱中用水/甲醇(9∶1,V∶V)作洗脱液进行色谱分离,每次2.0ml,得到30mg 1-(4-氨基-5-碘代-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
核磁共振谱(CD3OD,90mH2,δ)3.47-4.66(m,4H),4.78(S,4H),6.14(t,J=7Hz,1H),8.32(S,1H)。
质谱 m/e=389=P
实施例3
1-(2,4-二氧代-1H,3H-嘧啶-1-
基)-2-脱氧-2,2-二氟核糖
将含有190mg(0.0007mol)1-(4-氨基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖的16ml冰醋酸和4ml水的溶液回流大约24小时。反应混合物冷却到室温,在大约60℃-70℃真空蒸发挥发性组成。残余物与5.0ml甲苯一起搅拌,得到的溶液蒸发几次。残余物溶解在12ml甲醇中,得到的混合物冷却到-15℃,用无水氨饱和。溶液在室温下搅拌一夜。在45℃用真空除去挥发性组分。残余物悬浮在大约5ml热水中,不溶的物质用过滤除去。滤液在Whatman 50cm微粒形硅胶ODS-3反相柱中用水/甲醇(9∶1,V∶V)作洗脱液进行色谱分离,得到0.05g含微量未反应原料的产物。未反应的原料用使含有0.05g该混合物的大约5.0ml二氯甲烷/甲醇(9∶1,V∶V)溶剂的溶液通过Waters Silica Sep-Pak除去。在45℃用真空蒸发洗脱液,得到0.036g 1-(2,4-二氧代-1H,3H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
核磁共振谱(CD3OD,90mHz,δ)3.54-4.48(m,4H),4.83(S,3H),5.69(d,J=8Hz,1H),6.10(dd,J=7Hz,9Hz,1H),7.8(d,J=8Hz,1H)。
质谱 m/e=264=P
实施例4
1-(4-氨基-5-甲基-2-氧代-1H-嘧
啶-1-基)-2-脱氧-2,2-二氟核糖
将含有1.86g(0.0039mol)3,5-双(叔丁基二甲基甲硅烷氧基)-1-甲基磺酰氧基-2-脱氧-2,2-二氟核糖,1.87g(0.0055mol)双三甲基甲硅烷基-5-甲基胞嘧啶和1.34g(0.006mol)三氟甲基磺酰氧基三甲基硅烷的37ml无水二氯甲烷的溶液回流一夜。反应混合物冷却到室温,将1.0ml甲醇加入其中。沉淀的固体用过滤收集,滤液在45℃用真空蒸发。残余物溶解在20ml水中,得到的溶液在50℃(在该温度产生沉淀)用真空浓缩到大约10ml。沉淀的固体用过滤收集,滤液在50℃用真空浓缩,得到22g残余物。残余物用热丙酮研制几次,每次用丙酮10ml。合并倾析的有机层,在45℃用真空蒸发,得到1.67g黄色油状物。将该物质溶解在15ml甲醇/水(V∶V,1∶1)中,得到的溶液与5.0g Biorad AG50W×8一起搅拌一夜。悬浮液用无水氨饱和,再搅拌10分钟。用过滤收集树脂,并将其悬浮在30ml甲醇/氨(V∶V,2∶1)中。悬浮液搅拌10分钟。用真空过滤收集树脂,将碱性滤液合并,在50℃用真空浓缩,得到1.5g橙色油状物。将该油状物溶于10ml水中,并在Whatman微粒形硅胶ODS-350cm反相柱中用水作为洗脱液进行色谱分离,每次2ml,得到0.07g1-(4-氨基-5-甲基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖。
核磁共振谱(CD3OD,90mHz,δ)1.94(S,3H),3.53-4.62(m,4H),4.75(S,4H),6.17(t,J=8Hz,1H),7.67(S,1H)。
质谱 m/e=277=P
实施例5
1-(4-氨基-2-氧代-1H-嘧啶-1-
基)-2-脱氧-2,2-二氟木糖
在氮气氛下,将23.0g(0.063mol)三-三甲基胞嘧啶加入含有17.89g(0.0375mol)3,5-双(叔丁基二甲基甲硅烷氧基)-1-甲基磺酰氧基-2-脱氧-2,2-二氟木糖的300ml无水二氯甲烷中,再加入10.84g(0.0488mol)三氟甲基磺酰氧基三甲基硅烷。该溶液回流一夜,并冷却到室温。将20ml甲醇加入反应混合物中,得到的溶液剧烈搅拌大约1小时。沉淀的固体用过滤收集。向滤液中加入100ml水,该悬浮液剧烈搅拌30分钟。分离有机层,在45℃用真空浓缩,得到11.2g棕色油状物。将该油状物溶解在已经加入33g Biorad AG50W×8阳离子交换树脂的95ml甲醇中,该悬浮液在室温下搅拌一夜。用过滤收集树脂,并用50ml甲醇洗涤。树脂和100ml甲醇/氨(V∶V,1∶1)的溶液一起剧烈搅拌。用过滤收集树脂,并在该溶液中再搅拌。收集树脂,合并碱性滤液,在50℃用真空浓缩,得到209g黄色残余物。将该物质悬浮在25ml水中,剧烈搅拌15分钟。过滤出不溶的沉淀物,得到0.250g标定的化合物A。滤液在50℃用真空浓缩,得到0.86g标定的化合物B。化合物A溶解在20ml甲醇中,在室温下和Bioraa AG50W×8一起搅拌3天。用过滤收集树脂,并在30ml甲醇/浓氢氧化铵(V∶V,1∶1)溶液中浆化。用过滤收集树脂,滤液在50℃用真空浓缩,得到0.14g1-(2-脱氧-2,2-二氟-β-D-木呋喃糖基)胞嘧啶。
核磁共振谱(CD3OD,90mHz,δ)3.72-4.34(m,4H),4.78(S,4H),5.86(d,J=8Hz,1H),6.17(d,J=15Hz,1H),7.78(d,J=8Hz,1H)。
质谱 m/e=263=P
标定的化合物B在Whatman 50cm ODS-3反相制备柱中用水/甲醇(V∶V,1∶1)作为洗脱液进行色谱分离,得到0.06g 1-(2-脱氧-2,2-二氟-α-D-木呋喃糖基)胞嘧啶。
核磁共振谱(CD3OD,90mHz,δ)3.53-3.9(m,2H),4.1-4.57(m,2H),4.83(S,4H),5.9(d,J=8Hz,1H),6.3(dd,J=7H2,12H2,1H),7.55(d,J=8H2,1H)。
质谱 m/e=263=P
实施例6
1-(6-氨基-9H-嘌呤-9-基)-2-脱氧-
2,2-二氟核糖
A、1-(6-氯-9H嘌呤-9-基)-3,5-双(叔丁基二甲基甲硅烷氧基)-2-脱氧-2,2-二氟核糖
将1.31g(5.0mmol)三苯基膦和0.87g(5.0mmol)偶氮二羧酸二乙酯加入含有0.77g(5.0mmol)6-氯嘌呤的50ml四氢呋喃溶液中。将含有1.99g(5.0mmol)3,5-双(叔丁基二甲基甲硅烷氧基)-1-羟基-2-脱氧-2,2-二氟核糖的四氢呋喃溶液加入该溶液中。反应混合物在室温下搅拌大约60小时,再将另外的0.66g(1.7mmol)3,5-双(叔丁基二甲基甲硅烷氧基)-1-羟基-2-脱氧-2,2-二氟核糖加入反应混合物中。该混合物在室温下再搅拌6小时。在真空下蒸发出溶剂,残余物在少量***中搅拌一夜。沉淀的固体用真空过滤除去,滤液在真空下浓缩至干燥。残余物在70g硅胶柱上进行色谱分离,用氯仿洗脱。将含有主要组分的馏分合并,从其中蒸发出溶剂,得到1.0g 1-(6-氯-9H-嘌呤-9-基)-3,5-双(叔丁基二甲基甲硅烷氧基)-2-脱氧-2,2-二氟核糖。产物的结构用核磁共振谱鉴定。质谱=477〔534-(叔丁基)〕
B、1-(6-氨基-9H-嘌呤-9-基)-
3,5-双(叔丁基二甲基甲硅烷氧基)-2-脱氧-2,2-二氟核糖
将含有0.5g(0.936mmol)1-(6-氯-9H-嘌呤-9-基)-3,5-双(叔丁基二甲基甲硅烷氧基)-2-脱氧-2,-2-二氟核糖的75ml无水乙醇溶液,在大约0℃,用无水氨饱和。密封反应烧瓶,使混合物升至室温。混合物在室温搅拌大约72小时,在减压下蒸发出挥发性组分,得到420mg 1-(6-氨基-9H-嘌呤-9-基)-3,5-双(叔丁基二甲基甲硅烷氧基)-2-脱氧-2,2-二氟核糖。
质谱=458〔515-(叔丁基)〕
C、将含有100mg(0.194mmol)1-(6-氨基-9H-嘌呤-9-基)-3,5-双(叔丁基二甲基甲硅烷氧基-2-脱氧-2,2-二氟核糖的25ml二氯乙烷溶液用外冰浴冷却到大约0℃,用无水溴化氢气体饱和。混合物在大约0℃搅拌大约4小时,使氮气鼓泡通过反应混合物。过滤混合物,收集的固体用甲醇洗涤,得到110mg固体。该固体用高效液体色谱(HPLC)提纯,得到121mgβ-1-(6-氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖。
核磁共振谱(CD3OD,30mHz,δ)3.8-4.65(m,4H),4.83(bs,4H),6.33(dd,1H),8.22(S,1H),8.4(S,1H)。
质谱 m/e=287
实施例7
A、1-(2,6-二氯-9H-嘌呤-9-基)-
3,5-双(叔丁基二甲基甲硅烷氧基)-2-
脱氧-2,2-二氟核糖
将2.62g(10.0mmol)三苯基膦和1.74g(10.0mmol)偶氮二羧酸二乙酯加入含有1.89g(10.0mmol)2,6-二氯嘌呤的100ml四氢呋喃溶液中。再将含有3.98g(10.0mmol)3,5-双(叔丁基二甲基甲硅烷氧基)-1-羟基-2-脱氧-2,2-二氟核糖的25ml四氢呋喃溶液加入该混合物中,混合物在室温下搅拌一夜。沉淀的固体用真空过滤除去,滤液在真空下浓缩。残余物溶解在100ml***中,该溶液在室温下搅拌一夜。过滤混合物,滤液在真空下浓缩至干燥。残余物溶解在25ml乙酸乙酯中,混合物放在冷藏箱中。过滤混合物,滤液用高效液体色谱(HPLC)进行色谱分离,用己烷/乙酸乙酯(4/1,V/V)洗脱。合并含有几种馏分的第一发色团(Chromaphore),从其中蒸发出溶剂,得到2.5g1-(2,6-二氯-9H-嘌呤-9-基)-3,5-双(叔丁基二甲基甲硅烷氧基)-2-脱氧-2,2-二氟核糖。m/e=〔568-(叔丁基)〕=511。
B、1-(2-氯-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖和1-(2-氯-6-溴-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖
将含有0.5g(0.88mmol)1-(2,6-二氯-9H-嘌呤-9-基)-3,5-双(叔丁基二甲基甲硅烷氧基)-2-脱氧-2,2-二氟核糖溶解在100ml二氯甲烷中,得到的溶液冷却到大约0℃,用无水溴化氢气体饱和。混合物在0℃搅拌大约7小时,然后在室温下搅拌大约16小时。混合物进行过滤,沉淀的固体溶解在甲醇中。甲醇溶液在真空下浓缩,得到160mg 1-(2-氯-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖和1-(2-氯-6-溴-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖的混合物,浅黄色固体。m/e分别为322和386。
C、1-(2-氯-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖
将1.18g(3mmol)1-(2-氯-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖和1-(2-氯-6-溴-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖溶解在11ml 1.0N氢氧化钠中,得到的溶液在室温下搅拌3小时。用2N盐酸使混合物的PH值降到大约7。混合物在大约45℃真空浓缩。使残余物在热甲醇中浆化,过滤,重复该步骤。合并滤液,该溶液在15℃真空浓缩,得到1.36g1-(2-氯-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖。m/e=322。
D、这个实施例是1-(2-氨基-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖的优选合成方法。用下面反应制备的化合物用作后面合成生物学上评价的化合物的参照标准。
在温度大约0℃将无水氨加入含有1.3g1-(2-氯-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖的30ml无水乙醇溶液中。混合物放在密闭的反应器中,在大约150℃加热一夜。冷却混合物,收集固体。滤液悬浮在15ml热甲醇中,混合物再过滤。滤液在真空下浓缩,残余物用高效液体色谱进行色谱分离,用水/甲醇(9/1,V/V)作洗脱液,流速4ml/分,得到10mg α-1-(2-氨基-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖和5mg β-1-(2-氨基-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖。m/e=303
生物学上试验的化合物制备如下:
在大约0℃在20分钟内将无水氨加入含有0.26g 1-(2-氯-6-氧代-1H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖和1-(2-氯-6-溴-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖在10ml无水乙醇中的混合物中。密封烧瓶,并将其放在大约150℃的油浴中大约16小时。在减压下蒸发出挥发性组分,残余物用标准方法提纯,得到9.6mg α-1-(2-氯-6-氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖,m/e=322;8.2mg β-1-(2-氯-6-氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖,m/e=322,核磁共振谱(CD3OD,300mHz,δ)3.8-4.65(m,4H);4.93(bs,4H);6.25(dd,1H);8.35(S,1H);6.5mg α-1-(2,6-二氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖和β-1-(2,6-二氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖的混合物,(m+1)/e=304,m/e,计算值303.1017,观测值303.1009;9.0mg1-(2-氨基-6-氧代-1H,9H嘌呤-9-基)-2-脱氧-2,2-二氟核糖,(m+H)/e,计算值304.0857,观测值304.0857,核磁共振谱(CD3OD,300mHz,δ)3.85-4.65(m,4H);4.9(bs,5H);6.15(dd,1H);7.98(S,1H);9.0mg α-1-(2,6-二氧代-1H,3H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖和β-1-(2,6-二氧代-1H,3H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖,m/e=304。
本发明提供了治疗哺乳动物易感瘤的方法,包括将药物上有效量的式Ⅰ的化合物供给需要这样治疗的哺乳动物。该方法包括用各种途径把化合物供给哺乳动物,有口服的,直肠的,经皮肤的,皮下的,静脉内的,肌肉内的或鼻内的途径。
术语“药物上有效量”指的是能够提供给哺乳动物化学治疗的式Ⅰ化合物的适当的量。活性化合物在宽的剂量范围内是有效的。例如每天的剂量通常在约0.1到约1200mg/kg体重范围内。对于治疗成年人,优选剂量范围为约0.1到约50mg/kg,以单次剂量或均分剂量。可是,当然实际供给化合物的量由医师根据有关情况决定,包括治疗条件,供给的具体化合物,选择的给药途径,年龄,体重,个体病人的反应和病人症状的严重程度。因此,无论如何上述剂量范围不限制本发明的范围。
正如在本说明书中定义的术语“易感瘤”表示能够用式Ⅰ化合物治疗的哺乳动物组织的异常生长。在式Ⅰ化合物有效抗瘤的同时,由于该化合物的细胞毒素性质,该化合物,固体和非固体类型,对控制单个细胞的快速生长是有效的。这些化合物的特征是它们有广谱活性,因此它们对抗各种瘤是有效的。
本方法得到的化合物优选以药物配方供给。因此,现在还提供本发明的另一方案,即用于治疗哺乳动物易感瘤的药物配方,该配方包含式Ⅱ或式Ⅲ的化合物和药物载体、稀释剂或赋形剂。
配方中存在的活性组分在大约1%到大约90%(重量)范围内。活性组分通常与载体混合,或者用载体稀释,或者包装在载体内,载体可做成胶囊、小药囊、纸或其它容器。当载体用作稀释剂时,其可以是固体、半固体或液体物质,对活性组分起载体、赋形剂或介质的作用。因此,组合物可制成片剂、丸剂、粉剂、锭剂、小药囊、扁囊剂、酏剂、悬浮液、乳剂、溶液、糖浆、气雾剂(固体或在液体介质中)、软膏,组合物中含有直到10%(重量)活性化合物,软和硬的胶囊、栓剂、无菌注射液和无菌包装粉剂。
一些合适的载体、赋形剂和稀释剂包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、***树胶、磷酸钙、藻酸盐、西黄蓍酸、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、甲基羟基苯甲酸酯、丙基羟基苯甲酸酯、滑石、硬脂酸镁和矿物油。另外,配方可包含润滑剂、湿润剂、乳化剂、悬浮剂、防腐剂、香化剂或调味剂。可用本技术领域熟知的方法配制本发明的组合物的条件是快速供给,在用供给病人以后持续释放活性组分。
组合物优选以单位剂量形式配制,每剂含有活性组分大约5mg到大约500mg,较通常是25mg到300mg。术语“单位剂量形式”指的是对于人受治疗者和其它哺乳动物实际上适用作单元剂量的独立单位,每个单位含有产生希望治疗效果的预先测定量的活性物质和适合的药物载体。
下面的配制实施例表示应用本方法包括的化合物的特殊药物配方。配方可应用式Ⅰ化合物中的任何一个作为活性化合物。这些实施例只是说明性的,无论如何不想限制本发明的范围。
配制1
硬胶囊用下列组份制备:
数量(mg/胶囊)
1-(4-氨基-5-甲基-2-氧代
-1H-嘧啶-1-基-2-脱氧-2,
2-二氟核糖 250
干淀粉 200
硬脂酸镁 10
将上面组份混合,装入硬胶囊中,其量460mg。
配制2
片剂用下面组份制备:
数量(mg/片)
1-(2-氧代-4-氨基-1H-
嘧啶-1-基)-2-脱氧-2,2
-二氟核糖 250
微晶纤维素 400
气相法二氧化硅 10
硬脂酸 5
将上面组份混合,压成片,每片重665mg。
制备3
含有下列组份的气雾剂溶液制备如下:
重量%
1-(2,4-二氧代-1H,3H-
嘧啶-1-基)-2-脱氧-2,2-
二氟核糖 0.25
乙醇 29.75
气雾剂基质22 70.00
(氯二氟甲烷)
将活性化合物与乙醇混合,混合物加入部份气雾剂基质22中,冷却到-30℃,装入填充设备中。然后,把需要量放入不锈钢容器中,用剩余的气雾剂基质稀释。将阀门设备装在该容器上。
配制4
每片含有60mg活性组份的片剂制备如下:
1-(4-氨基-2-氧代-1H-嘧啶-1-
基)-2-脱氧-2,2-二氟核糖 60mg
淀粉 45mg
微晶纤维素 35mg
聚乙烯吡咯烷酮 4mg
(10%水溶液)
羧甲基淀粉钠 4.5mg
硬脂酸镁 0.5mg
滑石 1mg
将二氟核苷淀粉和纤维素通过45目美国筛,充分混合。将聚乙烯吡咯烷酮溶液与通过14目美国筛得到的粉末混合。这样得到的颗粒在50°-60℃干燥,通过18目美国筛。羧甲基淀粉钠、硬脂酸镁和滑石预先通过60目美国筛,然后加入颗粒中,混合后在压片机上压片,得到片剂,每片重150mg。
配制5
每个含有80mg药物的胶囊制备如下:
1-(4-氨基-2-氧代-1H-嘧啶-1-
基)-2-脱氧-2,2二氟木糖 80mg
淀粉 59mg
微晶纤维素 59mg
硬脂酸镁 2mg
将活性组份、纤维素、淀粉和硬脂酸镁混合,通过45目美国筛,装入硬胶囊中,其量200mg。
配制6
每个含有225mg核苷的栓剂制备如下:
1-(2,4-二氧代-1H,3H-嘧啶
-1-基)-2-脱氧-2,2-二氟核糖 225mg
饱和脂肪酸甘油酯 2g
将核苷通过60目美国筛,再悬浮在饱和脂肪酸甘油酯中,后者预先用必须的最少的热熔化。然后将混合物倒入标准容量2g的栓剂模型中,使其冷却。
配制7
每5ml剂量含有50mg药物悬浮剂制备如下:
1-(4-氨基-5-甲基-2-氧代-1H-
嘧啶-1-基)-2-脱氧-2,2-二氟核糖 50mg
羧甲基纤维素钠 50mg
糖浆 1.25ml
苯甲酸溶液 0.10ml
调味剂 适量
色料 适量
净化水 5ml
将药物通过45目美国筛,与羧甲基纤维素钠和糖浆混合,形成均匀的糊。苯甲酸、调味剂和色料用一些水稀释,在搅拌下加入糊中。然后,加入足够的水,达到需要的体积。
配制8
静脉内配方制备如下:
1-(4-氨基-2-氧代-1H-嘧啶
-1-基)-2-脱氧-2,2-二氟核糖 100mg
等渗盐水 1000ml
上面组份的溶液以1ml/分的速度通过静脉引入需要治疗易感瘤的哺乳动物体内。
本发明应用的有代表性的化合物的活性用本技术领域内的专业人员为试验具有抗肿瘤活性化合物通常应用的标准筛选法所证明。例如这些筛选法已经用于证明市场上买得到的癌药物如生物碱蔓长春花(Vinca alkaloids)的抗肿瘤活性。例如,参见Mille et al.,j,Med.Chem.Vol.20,No.3 409(1977)和Swelney et al.,Cancer Research38 2886(1978)。
式Ⅰ所示的化合物是细胞抑制性的,它们抑制人白血病细胞(CCRF-CEM细胞系列)的生长。下面表1中给出式Ⅰ化合物中有代表性的一些化合物的试验结果。在表中,第一栏是化合物的名称,第二栏是IC50(抑制50%生长的浓度)(mcg/ml)。
表1
细胞毒性筛选
化合物名称 LC50mcg/ml
1-(4-氨基-2-氧代-1H- 0.0039
嘧啶-1-基)-2-脱氧-2,2 0.0057
-二氟核糖 0.0068
0.0260
1-(4-氨基-2-氧代-1H- 0.3
嘧啶-1-基)-2-脱氧-2,2-
二氟木糖
1-(2,4-二脱氧-1H,3H- 5.4
嘧啶-1-基)-2-脱氧-2,2-
二氟核糖
1-(4-氨基-5-甲基-2-氧代 0.3
-1H,-嘧啶-1-基)-2-脱氧
-2,2-二氟核糖
β-1-(6-氨基-9H-嘌呤- 0.5
9-基)-2-脱氧-2,2-二氟
核糖
α-1-(6-氨基-9H-嘌呤-
9-基)-2-脱氧-2,2-二氟 6.9
核糖
α-1-(2-氯-6-氨基-9H- >20.0
嘌呤-9-基)-2-脱氧-2,2-
二氟核糖
β-1-(2-氯-6-氨基-9H- 0.4
嘌呤-9-基)-2-脱氧-2,2-
二氟核糖
1-(2,6-二氨基-9H-嘌呤 0.075
-9-基)-2-脱氧-2,2-二氟
核糖
1-(2-氨基-6-氧代-1H, 0.10
9H-嘌呤-9-基)-2-脱氧
-2,2-二氟核糖
1-(2,6-二氧代-1H,3H, 0.30
9H-嘌呤-9-基)-2-脱氧
-2,2-二氟核糖
为了进一步证明式Ⅰ化合物治疗哺乳动物易感瘤的能力,实施例1的化合物,1-(4-氨基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖,实施例5的化合物,1-(4-氨基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟木糖,和实施例6的化合物,1-(6-氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖在具有代表性的L1210V淋巴细胞白血病的肿瘤***的动物体内进行试验。
试验这些化合物抗L1210V白血病效力的研究通过腹膜内(IP)接种1×106细胞开始。接种24小时后开始治疗。对治疗的反应通过比较十个受治疗动物的平均寿命与十个对照动物的平均寿命测定;试验动物寿命超过对照动物寿命的延长部份用百分数表示。表2给出在有这种瘤的鼠体中的一些试验结果。在表中,第1栏是试验化合物的实施例序号;第2栏是试验序号;第3栏是化合物的剂量值(mg/kg);第4栏是给药途径;第5栏是剂量计划,即在那些天将化合物供给鼠;第6栏是受治疗的鼠寿命与对照鼠比增加的平均值;第7栏是每组鼠的中毒死亡数;第8栏是长时期生存鼠,即每组生存45天鼠的数量。
实施例1的化合物,1-(4-氨基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟核糖和实施例5的化合物,1-(4-氨基-2-氧代-1H-嘧啶-1-基)-2-脱氧-2,2-二氟木糖也可用其它瘤试验***证明其活性。这些***包括6C3HED淋巴肉瘤,通称Gardner淋巴肉瘤(6C3HED);CA-755腺瘤(CA755);P1534J淋巴白血病(P1534J);和X5563浆细胞骨髓瘤(X5563)。这些***中每一个在下
面详细描述。
6C3HED-6C3HED淋巴肉瘤是在1979年从国立癌症研究所(N.C.I)癌治疗部在E.G.和G.Mason Researeh(Worchester,MA)保存的瘤库中得到的。第一个继代移种瘤用标准的工艺方法贮藏在液氮中。移植的瘤每六个月或根据需要从瘤库重建。该瘤用每周两次连续继代移种保留在C3H鼠体内(Charles River;Wilmington,MA)。
CA755-腺瘤755是未分化的***癌,是在1980年从国内癌症研究所癌治疗部在E.G.和G.Mason Research(Worchester,MA)保存的瘤库中得到的。第一个继代移种瘤用标准的工艺方法贮藏在液氮中。移植的瘤每六个月和根据需要从瘤库重建。该瘤用每周一次的连续继代移种保留在C57BL/6雌性鼠体中(Jackson实验室;BarHarbor,ME)。
P1534J-P1534J淋巴细胞白血病(固体形式)在1973年从Jackson实验室(Bar Harbor,ME)得到。第一个继代移种瘤用标准的工艺方法贮藏在液氮中。有这种瘤的瘤库其后的补充从第一继代移种瘤完成。移植的瘤每六个月或根据需要从瘤库重建。该瘤用每周一次的连续继代移种保留在DBA/2鼠体中(Charles River;Wilmington,MA)。
X5563骨髓瘤一该瘤保留在C3H鼠体中。
下面的方法用于证明这些化合物抵抗瘤***的活性。瘤从继代移种动物中用消毒设备取出并切成1到3mm2的碎片。瘤片用抗菌素介质1(Antibiotic Mediuml)和脑心注入法(Brain Heart Infusion)(Difco;Detroit,MI)进行无菌检验。刮受试鼠,瘤片用套针植入腋部位的皮下。合适的计划中的药物治疗在瘤植入后的那天开始。对于所有的试验,化合物都溶于盐水中。所有动物在药物治疗开始和终了都称重。食物和水随意供给。在第10天到第12天用游标卡尺测量所有瘤的二维尺寸(宽和长)。瘤重量由这些尺寸用下面公式计算:
瘤重量(mg)=瘤长度(mm)×瘤宽度(mm)2/2
为了分析,瘤重的所有数据都四舍五入到最接近十分之一克。在治疗活性的分析中没有一个组可由于药物毒性引起的死亡超过治疗组的30%。
在下面的表3中,第1栏是试验化合物的实施例序号;第2栏是瘤***;第3栏是剂量值;第4栏是给药途径;第5栏是剂量计划;第6栏是瘤抑制的百分数;第7栏是试验结束前观察到的中毒死亡。
用于本方法的化合物对于治疗病毒感染,特别是治疗由疱疹属病毒引起的感染也是有效的。这些化合物可有效地以口服、局部或肠道外途径供给。通常,剂量值在大约5mg/kg到大约500mg/kg范围内是有效的。以剂量值在大约10mg/kg到大约100mg/kg范围内供给是较优选的。
Claims (5)
2、一种制备式(Ⅱ)化合物或其可作药用的盐的方法,
式中:
R6是氢或C1-C4的烷基;
R7是下式之一的嘧啶或嘌呤碱
Q是N、C-(C2-C4的烷基)或C-氨基;
X是N或C-R4;
R8是氢或C1-C4的烷基;
R4是氢、C1-C4的烷基、氨基、溴、氟、氯和碘;
但仅当X是N时R6和R8两者才可以都是氢,本方法包括:
(a)将式R7H的一种嘧啶碱或者它的一种保护了的衍生物与式Ⅳ的一种糖或它的一种保护了的衍生物进行偶合:
其中R7H嘧啶碱和R6如上述定义,而Leav是一个离去基团,如果需要,除去存在的任一保护基以制备嘧啶碱产物;和
(b)如果需要式中的碱是嘌呤的式(Ⅲ)或式(Ⅱ)化合物,使相应的嘌呤核苷化合物(其中化合物的嘌呤部份的C-2和/或C-6取代基是氢)与氨反应,并且,如果需要,将产物烷基化。
4、一种根据权利要求1至3中任何一个的制备下列化合物或其可作药用的盐的方法:
1-(2-氯-6-氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖;
1-(2,6-二氨基-9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖;
1-(2,6-二氧代-1H,3H,9H-嘌呤-9-基)-2-脱氧-2,2-二氟核糖。
5、无论何时,按照权利要求1至4中任何一个所要求保护的方法制备的式(Ⅱ)或式(Ⅲ)化合物或其可作药用的盐。
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US67778384A | 1984-12-04 | 1984-12-04 | |
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US78641985A | 1985-10-10 | 1985-10-10 |
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- 1985-12-03 KR KR1019850009042A patent/KR890003439B1/ko not_active IP Right Cessation
- 1985-12-03 EG EG771/85A patent/EG17765A/xx active
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- 1985-12-03 HU HU854620A patent/HU194273B/hu unknown
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN106317147A (zh) * | 2015-07-06 | 2017-01-11 | 扬州硒瑞恩生物医药科技有限公司 | 新的核苷类化合物及其制备方法 |
CN106317147B (zh) * | 2015-07-06 | 2018-11-27 | 扬州硒瑞恩生物医药科技有限公司 | 核苷类化合物及其制备方法 |
CN110684062A (zh) * | 2019-10-18 | 2020-01-14 | 大连大学 | 一种治疗非小细胞肺癌的药物及其制备方法 |
Also Published As
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HU194273B (en) | 1988-01-28 |
IL77133A (en) | 1991-01-31 |
DE3587500D1 (de) | 1993-09-09 |
IE60328B1 (en) | 1994-06-29 |
EP0184365A2 (en) | 1986-06-11 |
HUT39188A (en) | 1986-08-28 |
IE853038L (en) | 1986-06-04 |
KR890003439B1 (ko) | 1989-09-21 |
JPS61148193A (ja) | 1986-07-05 |
AU5055585A (en) | 1986-06-12 |
CN1020194C (zh) | 1993-03-31 |
KR890003426B1 (ko) | 1989-09-20 |
CY1806A (en) | 1995-09-08 |
CA1264738A (en) | 1990-01-23 |
PT81559B (pt) | 1988-03-03 |
DK549685A (da) | 1986-06-05 |
PH23172A (en) | 1989-05-19 |
DK162965C (da) | 1992-06-01 |
EP0184365A3 (en) | 1988-01-27 |
EG17765A (en) | 1990-08-30 |
ATE92499T1 (de) | 1993-08-15 |
DE3587500T2 (de) | 1993-12-16 |
US5464826A (en) | 1995-11-07 |
DK162965B (da) | 1992-01-06 |
EP0184365B1 (en) | 1993-08-04 |
ES549547A0 (es) | 1987-08-01 |
AU581269B2 (en) | 1989-02-16 |
HK113693A (en) | 1993-10-29 |
DK549685D0 (da) | 1985-11-28 |
GR852858B (zh) | 1986-03-28 |
NZ214364A (en) | 1988-11-29 |
PT81559A (en) | 1985-12-01 |
ES8801546A1 (es) | 1987-08-01 |
JPH0637394B2 (ja) | 1994-05-18 |
KR860004920A (ko) | 1986-07-16 |
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