CN1378450A - 新型细胞分化剂和组蛋白脱乙酰基酶抑制剂及其使用方法 - Google Patents
新型细胞分化剂和组蛋白脱乙酰基酶抑制剂及其使用方法 Download PDFInfo
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- CN1378450A CN1378450A CN00814006A CN00814006A CN1378450A CN 1378450 A CN1378450 A CN 1378450A CN 00814006 A CN00814006 A CN 00814006A CN 00814006 A CN00814006 A CN 00814006A CN 1378450 A CN1378450 A CN 1378450A
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Images
Classifications
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07C311/42—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明提供了具有分子式(I)的化合物,其中每个R1和R2是,取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油(naphtha),吡啶基氨基,哌啶子基,叔丁基,芳氧基,芳基烷氧基,或者吡啶基;其中A是酰氨基,-O-,-S-,-NH-,或-CH2-;并且其中n是从3到8的整数。本发明还提供选择性地诱导生长停滞,成体终末分化和/或肿瘤细胞凋亡并由此抑制这种细胞增生的方法。此外,本发明提供了治疗带有以肿瘤细胞增生为特征的肿瘤的患者的方法。最后,本发明提供包括制药上可接受的载体和治疗上可接受量的上述化合物的药物组合物。
Description
本申请要求得到于2000年6月1日提交的第60/208,688号美国临时申请,和于1999年9月8日提交的第60/152,755号美国临时申请的权利。
在本篇申请中通过在括号内的阿拉伯数字引用了多种出版物。关于这些出版物的详尽的引用可以在详述的结尾处在权利要求书的前面直接找到。为了更全面地描述与本发明有关领域的状况,这些出版物全部的批露都由此通过引证收入到本申请中。
本发明的背景
癌症是一种病症,其中细胞群变得不同程度地对正常情况下控制增生和分化的控制机制反应迟钝。目前对癌症治疗的研究是试图诱导肿瘤细胞(1)的成体终末分化。在细胞培养模型中,已有通过将细胞暴露在多种刺激物下报道分化,这些刺激物包括:周期性的AMP和维生素A酸(2,3),阿克拉霉素A和其他蒽基类(4)。
充足的证据表明肿瘤的转化并没有必然地破坏肿瘤细胞分化的可能性(1,5,6)。许多不对一般分化调节剂起反应和似乎是它们的分化程序的表达被阻塞的肿瘤细胞的实例,仍然可以被导致分化和中止复制。各种各样的助剂,包括有些相关单一极性的化合物(5,7-9),维生素D和维生素A酸的衍生物(10-12),甾类激素(13),增长因子(6,14),蛋白酶(15,16),肿瘤促进剂(17,18),和DNA或RNA合成抑制剂(4,19-24),可以促使许多转化了的细胞系和初期的人类肿瘤分离块表达更多分化型特性。
通过一些本发明发明者较早的研究确定了一系列极性化合物是一些转化了的细胞系(8,9)分化的有效诱导剂。一个这样的有效诱导剂是混合极性/非极性化合物N,N1-环己烷双乙酰胺(HMBA)(9),另一个是N-辛二酰基酰基苯胺异羟肟酸(SAHA)(39,50)。这些化合物用于诱导鼠类的红白血病(MEL)细胞经受致瘤性遏制的红血球的分化证明了对于研究转化了的细胞(5,7-9)诱导剂居间分化的有用的模型。
HMBA诱导的MEL细胞终末的红血球的分化是个多步骤的过程。通过向培养出来的MEL细胞(745A-DS19)中加入HMBA,在参与成体终末分化被探测到以前有10到12小时的潜伏期。参与被定义为细胞表达成体终末分化的能力即使诱导剂(25)被移去。在连续的暴露于HMBA的时候,细胞逐渐的补充分化。本发明的发明者已经公布了抗相对低量的长春新碱的MEL细胞系,对HMBA诱导作用的明显变得更加敏感,并且会在短时间或没有潜伏期(26)就被诱导分化。
HMBA有在广泛种类细胞系(5)中诱导和分化一致的表型变化的能力。该药物诱导效果的特征已经在鼠类的红白血病细胞系统(5,25,27,28)中被极其集中的研究。MEL细胞的分化诱导作用不但由时间而且由浓度决定。用于证明在实验室条件下在大多数品系中的效果所需要的最小的浓度为2到3mM,在没有连续药物暴露的情况下为了在对象总体的物质部分(>20%)诱导分化通常要求的持续暴露最短持续时间大约为36小时。
在此有蛋白酶C涉及诱导剂居间分化(29)的路径的证据。在实验室条件下的研究提供了用于评估HMBA在治疗人类的肿瘤(30)中作为细胞分化剂的可能性的根据。一些I阶段关于HMBA的临床试验已经完成(31-36)。临床试验显示此化合物可以引起肿瘤(35,36)患者的治疗反应。然而,这些I阶段的临床试验也证明HMBA潜在的疗效是有限的,在某种程度上,通过剂量关联的毒性阻止达到最佳血液水平并且通过大量剂量该药剂静脉给药的需求,越过持续期。因此,一些本发明的发明者已经致力于合成更加有效的和可能比HMBA(37)毒性更小的化合物。
最近,一类诱导分化的化合物已经被证实有抑制组蛋白脱乙酰基酶的作用。一些试验性的抗癌化合物,例如,曲古柳菌素A(trichostatin A)(TSA),trapoxin,辛二酰基酰基苯胺异羟肟酸(SAHA),和丁酸苯酯通过抑制组蛋白脱乙酰基酶(38,39,42)被证明,至少部分地,起作用。另外,二烯丙基硫醚和有关的分子(43),oxamflatin(44),MS-27-275,合成的苯甲酰胺衍生物(45),丁酸衍生物(46),FR901228(47),depudecin(48),和m-羧基苯乙烯酸双羟基酰胺(39)已经被证实有抑制组蛋白脱乙酰基酶的作用。在实验室条件下,这些化合物可以通过在G1和G2阶段(49-52)造成细胞周期停滞来抑制成纤维细胞的生长,并且可以导致成体终末分化和多种转化了的细胞系(49-51)的转变潜能的损失。在活的有机体内,丁酸苯酯和维生素A酸(53)一起在治疗急性促骨髓性(promyelocytic)的白血病时是有效的。SAHA在预防老鼠乳腺肿瘤和老鼠(54,55)肺肿瘤的形成中是有效的。
授予一些本发明的发明者的美国专利第5,369,108号(41)透露的对选择性的诱导肿瘤细胞的成体终末分化有效的化合物,这些化合物有两个被亚甲基的柔性链分开的极性末端基,其中一个或两个极性末端基都是巨大的疏水基。这样的化合物都表明比HMBA和与HMBA相关的化合物更有效。
可是,美国专利第5,369,108号没有揭示在分子同一端附加的大疏水基作为第一疏水剂将进一步在酶分析中增加分化活性约100倍,在细胞分化分析中增加约50倍。
本发明的新型化合物也可用来选择性地诱导肿瘤细胞成体终末分化并帮助治疗患者的肿瘤。
本发明的摘要
其中R1和R2都各自是一个相同或不同的疏水组成;其中R3是异羟肟酸,羟氨基,羟基,氨基,烷基氨基,或烷氧基;n是从3到10的整数,或者该化合物制药上可接受的盐。
其中各个R1和R2是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,支链的或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基;其中R3是异羟肟酸,羟氨基,羟基,氨基,烷氨基,或烷氧基;其中R4是氢,卤素,苯基,或环烷基;其中A可以是相同或不同的,代表酰胺,-O-,-S-,-NR5-,或-CH2-,其中R5是取代的或未被取代的C1-C5的烷基;其中n是从3到10的整数,或者是它们的制药上可接受的盐。
本发明还提供选择性的诱导肿瘤细胞成体终末分化并由此抑制这样的细胞增生的方法,它包括在适当的条件下用有效量的前述化合物接触这些细胞。
有关插图的描述
图1.依照本发明的化合物1对MEL细胞分化的影响。
图2.依照本发明的化合物1对组蛋白脱乙酰基酶1活性的影响。
图3.依照本发明的化合物2对MEL细胞分化的影响。
图4.依照本发明的化合物3对MEL细胞分化的影响。
图5.依照本发明的化合物3对组蛋白脱乙酰基酶1活性的影响。
图6.依照本发明的化合物4对MEL细胞分化的影响。
图7.依照本发明的化合物4对组蛋白脱乙酰基酶1活性的影响。
图8.光亲和标记(3H-498)直接与HDAC1结合。
图9.SAHA导致乙酰化组蛋白H3和H4在老鼠上的CWR22肿瘤异种移植物中的积聚。
图10.SAHA导致乙酰化组蛋白H3和H4在患者体内的外围血液单核细胞中的积聚。SAHA以每日三次的静脉内输注服用。实例为隔离前(pro),输注之后(post)和输注2小时以后。
图11a-11f.显示所选的化合物对亲和提纯的人类抗原表位标记的HDAC1的影响。
本发明的详细描述
其中R1和R2都各自是一个相同或不同的疏水组成;其中R3是异羟肟酸,羟氨基,羟基,氨基,烷基氨基,或烷氧基;n是从3到10的整数,或者该化合物制药上可接受的盐。
在前述的化合物中,每个R1和R2都直接或通过衔接物连接,并且是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
所使用的衔接物可以是酰胺,-O-,-S-,-NH-,或-CH2-。
依照本发明,n可以是3-10,优选的是3-8,更优选的是3-7,进一步优选的是4,5或6,最优选的是5。
在本发明的另一个实施方案中,该化合物的分子式如下:
其中每个R4是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。R2可以是-酰胺-R5,其中R5是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
在本发明进一步的实施方案中,该化合物的分子式如下图:
其中每个R1和R2是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基;其中R3是异羟肟酸,羟氨基,羟基,氨基,烷基氨基,或烷氧基;其中R4是氢,卤素,苯基,或环烷基;其中R5是被取代或未被取代的C1-C5的烷基;其中n是从3到10的整数,或者它们制药上可接受的盐。
其中每个R1和R2是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,t-丁基,芳氧基,芳基烷氧基,或吡啶基;其中n是从3到8的整数。
芳基或环烷基可以被取代为甲基,氰基,硝基,三氟甲基,氨基,甲酰胺基,甲基氰基,氯代,氟代,溴代,碘代,2,3-二氟,2,4-二氟,2,5-二氟,3,4-二氟,3,5-二氟,2,6-二氟,1,2,3-三氟,2,3,6-三氟,2,4,6-三氟,3,4,5-三氟,2,3,5,6-四氟,2,3,4,5,6-五氟,叠氮基,己基,t-丁基,苯基,羧基,羟基,甲氧基,苯基羟基,苄氧基,苯基氨氧基,苯基氨基羰基,甲酯基,甲基氨基羰基,二甲基氨基,二甲基氨基羰基,或羟基氨基羰基。
在进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。在又进一步的实施方案中,该化合物的分子式是:或者是它的对映异构物。在进一步的实施方案中,该化合物的分子式是:或者是它的对映异构物。在更进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。在进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。在还进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。在仍进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。在进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。在进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。在进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。在进一步的实施方案中,该化合物的分子式为:或者是它的对映异构物。本发明也打算包括上述化合物的对映异构物和盐。在进一步的实施方案中,该化合物的分子式为:
其中R1和R2都各自是一个相同或不同的疏水组成;其中R5是-C(O)-NHOH(异羟肟酸),-C(O)-CF3(三氟代乙酰基),-NH-P(O)OH-CH3,-SO2NH2(氨磺酰),-SH(硫醇),-C(O)-R6,其中R6是羟基,氨基,烷基氨基,或烷氧基;n是从3到10的整数,或者它的制药上可接受的盐。
在前述的化合物中,每个R1和R2可以直接被连接或通过衔接物连接,并且是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
衔接物可以是酰胺,-O-,-S-,-NH-,或-CH2-。
其中每个R7是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
在前述的化合物中,R2可以是-磺胺药物-R8,或-酰胺-R8,其中R8是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
其中R1和R2都各自是一个相同或不同的疏水组成;其中R5是-C(O)-NHOH(异羟肟酸),-C(O)-CF3(三氟代乙酰基),-NH-P(O)OH-CH3,-SO2NH2(氨磺酰基),-SH(硫醇),-C(O)-R6,其中R6是羟基,氨基,烷基氨基,或烷氧基;其中衔接物L包括-(CH2)-,-C(O)-,-S-,-O-,-(CH=CH)-,苯基,或环烷基,或它们的任何化合物,或它的制药上可接受的盐。
衔接物L也可包括-(CH2)n-,-C(O)-,-S-,-O-,-(CH=CH)m-,苯基,或环烷基,或它们的任何化合物,其中n是从3到10的整数,m是从0到10的整数.
在前述的化合物中,n可以从4到7,m从0到7。优选的n为5或6,更优选的n为6。优选的m从1到6,更优选的m是3或4。
在这些化合物中,每个R1和R2都可以连接直接或通过衔接物连接,并且是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
衔接物可以是酰胺,-O-,-S-,-NH-,或-CH2-。
本发明也打算包括上述化合物的对映异构物,盐和在此公开的化合物的药物前体。
在另一个实施方案中,该化合物有如下分子式:
其中L为衔接物,选自-(CH2)-,-(CH=CH)-,苯基,或环烷基,或它们的任何化合物;其中每个R7和R8都独立地是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
任何被批露的化合物可以和制药上可接受的载体一起组成药物组合物。
任何此化合物也可以运用众所周知的制药技术组成该化合物制药上可接受的盐。
任何此化合物的药物前体也可运用众所周知的制药技术制造。
任何此化合物可用于在肿瘤内诱导肿瘤细胞分化的方法中,包括用有效量的该化合物接触这些细胞以便由此分化肿瘤细胞。
任何此化合物也可用于抑制组蛋白脱乙酰基酶的活性的方法中,包含用有效量的该化合物接触此组蛋白脱乙酰基酶以便由此抑制组蛋白脱乙酰基酶的活性。
本发明,除了上面所列出的化合物以外,进一步打算包括利用这样化合物的同系物和类似物。在这里,同系物是相对上面描述的化合物有大体上的结构相似性的分子,类似物是大体上的生物相似性而不管结构相似性的分子。
在进一步的实施方案中,本发明提供包括在制药上有效量的任何一种前述的化合物和制药上可接受的载体的药物组合物。
在还进一步的实施方案中,本发明提供选择性诱导生长停滞,成体终末分化和/或肿瘤细胞凋亡并由此抑制这样的细胞的增生的方法,包括在适合的状况下用有效量的任何一种前述化合物接触该细胞。
此接触应该在一个持续期内连续的完成,例如至少48小时,优选的大约4到5天或更长。
该方法可以在活体内或在生物体外实践。如果该方法在活体内实践,接触可以通过用此化合物培育这些细胞来实现。和细胞接触的化合物的浓度可以从约1nM到约25mM,优选的从约20nM到约25mM,更优选的从约4nM到约100uM,再优选的从约40nM到约200nM。该浓度取决于独特的化合物和肿瘤细胞的状况。
该方法还可以包括最初用抗癌药剂处理这些细胞,以便使得他们对抗癌药剂产生抵抗,随后在合适的状况下用有效量的任一上述化合物接触由此得到的具有抵抗力的细胞,有效的选择性诱导这样细胞的成体终末分化。
本发明也提供治疗有以肿瘤细胞增生为特征的肿瘤的患者的方法,包括向患者供给有效量的任一上述化合物,有效的选择性诱导生长停滞,成体终末分化和/或肿瘤细胞的凋亡并由此抑制它们的增生。
本发明提供的方法准备用作治疗人类患者的肿瘤。然而,本方法将在治疗其他哺乳动物的肿瘤上有效也是很可能的。这里所说的肿瘤规定为任何由肿瘤细胞增生引起的肿瘤,例如前列腺瘤,肺部肿瘤,急性白血病,多发性骨髓瘤,膀胱瘤,成神经细胞瘤或恶性皮肤瘤。
本发明的化合物的给药方法包括任何常规的和生理学上可接受的方法,例如,口服的,由肺部进行的,肠胃外的(肌肉的,腹膜内的,静脉内的(IV),皮下的注射),吸入的(通过细小的粉末配方或细小的雾剂),通过皮肤的,鼻的,阴道的,直肠的,或者舌下的给药方法,并可配制成适合于每种给药方式的剂型。
本发明还提供包括制药上可接受的载体的药物组合物,例如无菌的无热原的水,和治疗上可接受数量的上述任一化合物。优选的,有效量是指对于选择性诱导适当的肿瘤细胞成体终末分化有效并少于在患者体内产生毒性的量。
本发明提供上面的药物组合物与抗癌药剂,激素,类固醇,或者类维生素A结合。
抗癌药剂可以是众多的化学治疗药剂之一,例如烷化剂,抗代谢物,激素制剂,抗生素,秋水仙碱,长春花属生物碱,L-天门冬酰胺酶,甲基苄肼,羟基脲,邻氯苯对氯苯二氯乙烷,亚硝基脲,或咪唑羧基酰胺。适合的药剂都是那些促进微管蛋白去极化的药剂。优选的抗癌药剂是秋水仙碱或长春花属生物碱,更优选的是长春花碱和长春新碱。在以长春新碱为抗癌药剂的实施方案中,致使细胞对长春新碱有抵抗力的用药量浓度约为5mg/ml。药剂的给药基本上按照上面描述的任何化合物的用法实行。优选的,药剂的给药是至少3到5天的周期。任何上述化合物的给药按照如先前的描述执行。
药物组合物给药可以按每天2-6小时输注3-21天的周期,例如,每天4小时输注周期为5天。
本发明由于随后试验的详述将被更好的理解。然而,此领域的熟练技术人员将迅速地意识到这里所论述的特殊的方法和结果仅仅对本发明起说明性的作用,更加充分的描述在其后的权利要求书中。试验的详述
实例1-5说明依照本发明的被取代的L-α-氨基辛二异羟肟酸的合成法,实例6和7说明化合物1-5对MEL细胞分化和组蛋白乙酰基酶活性的影响。
实例1-化合物1的合成
N-Boc-ω-甲基-(L)-α-氨基辛二酸盐,Boc-Asu(OMe)依照公开发表的程序(40)制取。(“Boc”=叔丁氧羰基;“Asu”=α-氨基辛二酸盐(或α-氨基辛二酸))
N-Cbz-ω-叔丁基-(L)-α-氨基辛二酸盐,双环己基胺盐从Research Plus,Bayonne,NJ获得。
N-Boc-ω-甲基-(L)-α-氨基辛二酸盐(493mg,1.63mmoles)在Ar(氩气)下溶解于7ml的无水CH2Cl2中。加入EDC(470mg,2.45mmoles),接着加入苯胺(230μL,2.52mmoles)。溶液在室温下搅拌2小时30分钟,然后用稀盐酸(ph2.4,2×5M1),饱和NaHCO3(10mL),和水(2×10mL)洗涤。产物通过柱层析法(硅胶,己烷∶AcOEt 3.5∶1)提纯。离析出来的产物有366mg(60%)。
1H-核磁共振和质谱分析与产物符合。
90mg的N-Bloc-ω-甲基-(L)-α-氨基辛二酸盐酰基苯胺(0.238mmoles)用3.2mL的25%的三氟乙酸(TFA)处理30分钟。溶剂被脱除而剩余物留置在高真空下12小时。将剩余物在Ar(氩气)下溶解于3mL的无水CH2Cl2和苯并三唑-1-yloxy-三-吡咯烷基六氟磷酸酯(PyBOP)(149mg,0.286mmoles),安息香酸(44mg,0.357mmoles)和二异丙基乙胺(114μL,0.655mmoles)中。溶液在室温下搅拌约1小时。产物通过柱层析法(硅胶,己烷∶AcOEt 3∶1-2∶1)提纯为白色固体:75mg,82%。
1H-核磁共振和质谱分析与产物符合。
在反应物为1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺氢氯化物(EDC)时前述联结反应也成功地实现。
75mg(0.196mmoles)的N-苯甲酰基--氨基辛二酸盐酰基苯胺在0℃下1M的NaOH∶THF∶MeOH 1∶1∶1中搅拌6小时。在起始物料完全消失以后,溶液被中和(1M HCl)并用AcOEt提取。有机相被收集并干燥。溶剂脱除的产物是白色固体:67mg,93%。
1H-核磁共振和质谱分析与产物符合。
向含26mg的N-苯甲酰基-ω-甲基-(L)-α-氨基辛二酸盐酰基苯胺(I2)的1mL无水CH2Cl2的悬浮液中加入58mL的H2NOTBDPS(H2NO-叔丁基二苯基甲硅烷基)随后加入22mg的EDC。反应在室温下搅拌4小时。中间体保护的异羟肟酸通过柱层析法(硅胶,CH2Cl2∶MeOH 100∶0-98-2)提纯。它通过含5%的TFA的CH2Cl2溶液处理1小时30分钟而被去保护。产品从丙酮-戊烷中沉析出来。
1H-核磁共振(d6-DMSO,500MHz)δ=10.29(s,1H),8.53(d,1H),7.90(d,2H),7.60(d,2H),7.53(m,1H),7.46(t,2H),7.28(t,2H),7.03(t,2H),4.53(q,1H),1.92(t,2H),1.78(m,2H),1.50-1.25(m,6H)。
ESI-MS:384(M+1),406(M+Na),422(M+K)
实例2-化合物2的合成
它由N-Boc-ω-甲基-(L)-α-氨基辛二酸盐按照同样的步骤之后用苯甲酰基的类似物配制。产品和层析特性都是类似的。
1H-核磁共振(d6-DMSO,500MHz)δ=10.30(s,1H),10.10(s,1H),9.05(m,1H),8.80(m,1H),8.71(m,1H),8.24(m,1H),7.60(m,2H),7.30(m,2H),7.04(m,1H),4.65(m,1H),1.93(t,2H),1.79(m,2H),1.55-1.30(m,6H)。ESI-MS:385(M+1),407(M+Na)。
实例3-化合物3的合成
N-Cbz-(L)-Asu(OtBu)-OH,二环己胺盐(100mg,0.178mmole)在1M HCl(5mL)和EtOAc(10mL)之间分开。有机层被移去,含水的部分用EtOAc(3×3mL)洗涤。有机部分混合,用盐水(1×2mL)洗涤,并干燥(MgSO4)。混合物被过滤和浓缩为无色的薄膜(67mg,0.176mmol,99%)。这个化合物立刻在下一个步骤被使用。
N-苄氧基羰基-ω-叔丁基-(L)-α-氨基辛二酸盐酰基苯胺,N-Cbz-(L)-Asu(OtBu)-NHPh.
N-Cbz-(L)-Asu(OtBu)-OH(67mg,0.176mmole)溶解于无水CH2Cl2(2.5ml)中。加入苯胺(17μL,0.187mmol),PyBOP(97mg,0.187mmol),及iPr2Net(46μL,0.266mmol)然后混合物搅拌2小时。反应如TLC指示完成。混合物用EtOAc(5mL)和水(5mL)稀释,且各层分开。含水的部分用EtOAc(3×3mL)洗涤,有机部分合并。溶液用1M HCl(1×2mL)和盐水(1×2mL),干燥(MgSO4),过滤,并浓缩成粗制的油状物。通过硅胶(30%EtOAc/己烷)塞子除去原始的杂质,得到该化合物(76mg,0.167mmol,94%)。
1H-核磁共振(CDCl3,400MHz,无TMS)δ8.20(br s,1H),7.47(d,2H),7.32(m,5H),7.28(t,2H),7.08(t,1H),5.39(d,1H),5.10(m,2H),4.26(m,1H),2.18(t,2H),1.93(m,1H),1.67(m,1H),1.55(m,3H),1.42(s,9H),1.36(m,3H)。
N-苄氧基羰基-(L)-α-氨基辛二酸盐酰基苯胺,
N-Cbz-(L)-Asu(OtBu)-酰基苯胺(76mg,0.167mmol)溶解于无水CH2Cl2(5ml)中,并逐滴加入TFA(0.5mL)。反应如TLC指示3小时后完成。混合物在真空中浓缩得到标题化合物(80mg,粗制的)。该化合物不经提纯被下一步骤采用。
1H-核磁共振(DMSO-d6,400MHz)δ11.93(br s,1H),9.99(br s,1H),7.57(m,3H),7.34(m,5H),7.29(t,2H),7.03(t,1H),5.02(m,2H),4.11(m,1H),2.17(t,2H),1.61(m,2H),1.46(m,2H),1.27(m,4H)。
N-Cbz-(L)-Asu(OH)-酰基苯胺(80mg,粗制的)和O-叔丁基二苯基甲硅烷基-羟基胺基(60mg,0.221mmol)溶于CH2Cl2(4ml)中。向其中加入ByBOP(125mg,0.241mmol)和iPr2NEt(52μL,0.302mmol)并搅拌过夜。TLC指示反应完成。混合物在真空中浓缩然后通过硅胶(50%EtOAc/己烷)塞以除去的基准杂质。蒸发掉挥发物得到的107mg的物质随后溶于无水CH2Cl2(5mL)中并加入TFA(0.25mL)。通过TLC监控显示1.5小时以后反应完成。在真空中浓缩来除去挥发性物质。留存的部分溶解于EtOAc(3mL),然后慢慢加入己烷以引起白色凝胶体的沉淀。上层清液被去掉,沉淀物用己烷洗涤(3×2mL)。该物质然后在减压状态下干燥,得到标题化合物(40mg,0.097mmol,59%)。
1H-核磁共振(DMSO-d6,400MHz)δ10.32(s,1H),10.00(s,1H),8.64(br s,1H),7.57(m,3H),7.37(m,5H),7.30(t,2H),7.04(t,1H),5.02(m,2H),4.12(m,1H),1.93(t,2H),1.62(m,2H),1.45(m,2H),1.29(m,4H);ESI-MS4.14(M+1)。
实例4-化合物4的合成
以与化合物3相似的方式配制。
1H-核磁共振(DMSO-d6,400MHz)δ10.45(s,1H),10.31(s,1H),8.85(dd,1H),8.63(dd,1H),8.42(dd,1H),8.13(dd,1H),8.68(m,2H),7.60(t,1H),7.37(m,2H),7.28(m,2H),5.10(m,2H),4.24(m,1H),1.93(t,2H),1.85(m,1H),1.70(m,1H),1.50(m,2H),1.42(m,2H),1.30(m,2H);ESI-MS 465(M+1)。
实例5-化合物5的合成
N-Cbz-ω-叔丁基L-α-氨基辛二酰基-8-喹啉酰胺基(90mg,0.178mmoles)的样本由先前的合成法获得。Cbz基通过MeOH中C上的5%的Pd的氢化作用被移去。由此得到的自由胺在无水CH2Cl2(69%多于两个步骤)中通过EDC与苯甲酸结合。经叔丁基酯的TFA去保护以后,按惯例与H2NOTBDPS结合继之以去保护得到所要的异羟肟酸。
1H-核磁共振(d6-DMSO,500MHz)δ=10.55(s,1H),10.30(s,1H),9.03(m,1H),8.78(m,1H),8.62(m,1H),8.40(m,1H),7.97(m,2H),7.67-7.46(m,6H),4.66(m,1H),1.94(t,2H),1.87(m,1H),1.80-1.20(m,7H).ESI-MS 435(M+1)。
实例6-带转化了的胺基的化合物的合成
化合物分子式如下:
其中R′被脱去而转换为异羟肟酸(NHOH),正如前面的实例。
在前述方案中,R可为叔丁基,用三氟乙酸脱去;R′可为甲基,用碱或LiI脱去;每个R″可以是相同或不同的,取决于所使用的反应物。
实例7-化合物1(N-苯甲酰基-(L)-α-氨基辛二酸盐酰
基苯胺-ω-异羟肟酸,PhCOHN-Asu(NHOH)-NHPh)对
MEL细胞分化和组蛋白脱乙酰基酶活性的影响。
鼠类红白血病细胞(MEL)分化。
MEL细胞分化分析用于评估化合物1诱导成体终末分化的能力。MEL细胞(对数分裂)用标明浓度的化合物1培养。在5天培养期之后,细胞生长用Coulter计数器测定而分化显微地用对苯二铵基联苯分析确定血红蛋白蛋白质在每个细胞基础上的积聚来测定。
如图1所示,可以注意到化合物1(200nM)可以诱导MEL细胞分化。
组蛋白脱乙酰基酶(HDAC)的酶活性。
化合物1对亲和提纯的人类抗原决定基示踪(标记)的HDAC1的影响通过在缺少培养基储备的情况下用标明量的化合物1培养酶制剂20分钟来化验。培养基([3H]乙酰基标记的鼠类红白血病细胞衍生组蛋白)加入后,总量为30μl样品在37℃下培养20分钟。然后停止反应,释放的醋酸盐被提取,所释放的放射能的量用闪烁计数法测定。
如图2所示,可以注意到化合物1是HDAC1酶活性(ID50=1nM)的有效的抑制剂。
实例8-化合物2(N-烟酰基-(L)-α-氨基辛二酸盐
酰基苯胺-ω-异羟肟酸,C5H4NCO-Asu(NHOH)-NHPh
)对MEL细胞分化的影响。
鼠类红白血病(MEL)细胞分化:
MEL细胞分化分析用于评估化合物2诱导成体终末分化的能力。MEL细胞(对数分裂)用标明浓度的化合物1培养。在5天培养期之后,分化显微地用对苯二铵基联苯分析确定血红蛋白蛋白质在每个细胞基础上的积聚来测定。
如图3所示,可以注意到化合物2(800nM)可以诱导MEL细胞分化。
实例9-化合物3(N-苄氧基羰基-(L)-α-氨基辛二酸盐酰
基苯胺-ω-异羟肟酸,N-Cbz-(L)-Asu(NH-OH)-NHPh)对
MEL细胞分化和组蛋白脱乙酰基酶活性的影响。
鼠类红白血病(MEL)细胞分化:
MEL细胞分化分析用于评估化合物3诱导成体终末分化的能力。MEL细胞(对数分裂)用标明浓度的化合物3培养。在5天培养期之后,分化显微地用对苯二铵基联苯分析确定血红蛋白蛋白质在每个细胞基础上的积聚来测定。
如图4所示,可以观察到化合物3(400nM)可以诱导MEL细胞分化。
组蛋白脱乙酰基酶(HDAC)的酶活性。
化合物3对亲和提纯的人类抗原决定基示踪(标记)的HDAC1的影响通过在缺少培养基储备的情况下用标明量的HPC培养酶制剂20分钟来鉴定。培养基([3H]乙酰基标注的鼠类红白血病细胞衍生组蛋白)加入后,总量为30μl样品在37℃下培养20分钟。然后停止反应,释放的醋酸盐被提取,所释放的放射能的量用闪烁计数法测定。
如图5所示,可以注意到化合物3是HDAC1酶活性(ID50~100nM)的有效的抑制剂。
实例10-化合物4(N-苄氧基羰基-(L)-α-氨基辛二酰基-
喹啉酰胺基-ω-异羟肟酸)对MEL细胞分化和组蛋白
脱乙酰基酶活性的影响。
鼠类红白血病(MEL)细胞分化:
MEL细胞分化分析用于评估化合物4诱导成体终末分化的能力。MEL细胞(对数分裂)用标明浓度的化合物4培养。在5天培养期之后,分化显微地用对苯二铵基联苯分析确定血红蛋白蛋白质在每个细胞基础上的积聚来测定。
如图6所示,可以注意到化合物4(40nM)可以诱导MEL细胞分化。
组蛋白脱乙酰基酶(HDAC)的酶活性:
化合物4对亲和提纯的人类抗原决定基示踪(标记)的HDAC1的影响通过在缺少培养基储备的情况下用标明量的HPC培养酶制剂20分钟来鉴定。培养基([3H]乙酰基标注的鼠类红白血病细胞衍生组蛋白)加入后,总量为30μl样品在37℃下培养20分钟。然后停止反应,释放的醋酸盐被提取,所释放的放射能的量用闪烁计数法测定。
如图7所示,可以注意到化合物4是HDAC1酶活性(ID50<10nM)的有效的抑制剂。
SAHA抑制了亲和提纯的HDAC1和HDAC3(39)的活性。对SAHA和HDAC相关的蛋白质的结晶研究显示SAHA通过对催化部位(66)的直接相互作用抑制HDAC。另外的研究证明氚示踪的包含叠氮化合物部分(67)的光亲和SAHA类似物(3H-498)直接约束HDAC1(图8)。这些结果显示这一类异羟肟酸基的化合物通过与HDAC蛋白质的直接相互作用抑制HDAC的活性。
SAHA导致乙酰化组蛋白H3和H4在活的有机体内的积聚。SAHA在活体内的影响已经通过在老鼠体内的CWR22人类前列腺的异种移植物(68)进行了研究。SAHA(50mg/kg/day)与用没有明显毒性的控制相比较导致最后肿瘤体积平均97%的缩减量。SAHA的这个给药剂量导致在肿瘤异种移植物中乙酰化组蛋白H3和H4的增加(图9)。
SAHA目前用在有肿瘤体的患者的第I阶段临床试验中。SAHA导致乙酰化组蛋白H3和H4在从进行治疗的患者中分离的外围血液单核细胞中的积聚(图10)。
表1归纳了实例7-10的结果,检验化合物1-4,也与从使用SAHA获得的结果进行了比较。
表1.检验化合物1-4的结果和与SAHA的结果比较
MEL分化 HDAC抑制
化合物 | 范围 | Opt. | %B+ | 范围 | ID50 |
1 | 0.1-50μM | 200nM | 44% | 0.0001-100μM | 1nM |
2 | 0.2-12.5μM | 800nM | 27% | TBT | |
3 | 0.1-50μM | 400nM | 16% | 0.01-100μM | 100nM |
4 | 0.01-50μM | 40nM | 8% | 0.01-100μM | <10nM |
SAHA | 2500nM | 68% | 0.01-100μM | 200nM |
实例12-改良的HDAC抑制剂
在另外的研究中,我们发现如下面所示的化合物6和7是酶HDAC非常有效的抑制剂。化合物6的ID50为2.5nM,化合物7的ID50为50nM。这与ID50为1μM的SAHA对比,要高多了。注意到作为HDAC抑制剂的SAHA的1μM ID50和它作为MEL细胞的细胞分化的2.5μM最佳剂量有着同样的数量级,但是这一接近的相似性并非对于所检验的所有化合物都是正确的。在有些情形非常有效的HDAC抑制剂在作为细胞分化剂时有较差的效果,或许是因为该药物在细胞化验中产生了代谢变化。同样,不是所有细胞类型都是相同的,有些化合物在抵御人类肿瘤细胞例如HT-29时比它们在抵御MEL细胞时要好得多。因此,HDAC细胞抑制是初步的指示剂。
实例13-不含异羟肟酸部分的化合物的形成
从上面带异羟肟酸的化合物,我们发现它们经受酶水解比起羧酸要稍微迅速些,因此它们的生物学寿命都短。我们对于发展在活体内可能更加稳定的化合物比较感兴趣。这样,我们已经发展不含异羟肟酸的HDAC抑制剂,并且它可以作为有较长生物学寿命的细胞分化剂使用。此外,我们发现新近发展的化合物对HDAC相对于如SAHA有更好的选择性。
我们已经发展的化合物有双键,类似于Trichostain A(TSA)以了解合成出来的化合物是否有更大的功效。而且,TSA中的化学链仅有五个碳,不像SAHA有六个。在Oxamflatin中有含四个碳包括双键的化学链和连接在异羟肟酸和第一苯环之间乙炔基,Oxamflatin已经声称是HDAC有效的抑制剂。我们将某些这些特征合并到我们的化合物中,包括那些不是异羟肟酸的化合物。
同样公开的都是用于筛选多种这样的关于HDAC抑制的功效和选择性的化合物的基本组合方法。
既然对于HDAC的目标是组蛋白的乙酰基赖氨酸的侧链,我们制备的化合物其中基质的过渡态类似物都是现有的。例如,我们合成类似SAHA的化合物其中异羟肟酸基-CO-NHOH-被三氟乙酰基-CO-CF3-取代。合成出来的8将轻易地构成水合物,并由此与HDAC在过渡态10的摸拟物9中的Zn(II)结合进行脱乙酰作用。这与Lipscomb[56]发表的通过结合到包含CF3-CO-CH2基的基质类似物11的羧肽酶A上代替常态的酰胺基的研究有关。与zn(II)配位的酮的水合物作为过渡态的摸拟物用来催化酰胺基基质的水解。我们在氟代酮系列方面的合成法的详细的实例12如下面的方案所示:
在丙二酸酯烷基化作用以后,醛就被准备好然后用Rupperts试剂转变成三氟甲基甲醇[57][58]。丙二双酰基苯胺被准备好,并且甲醇用Dess-Martin试剂氧化成酮12[59]。尝试的其它途径的都不成功。尤其是,直接将羧酸衍生物转化为三氟甲基酮的尝试是行不通的。
化合物12已经用HDAC进行了测试并发现是该酶的抑制剂。这样,我们也使这一合成法适应于制备12的在该化学链中带不饱和现象及其它的类似物,而其它基在分子的左端。
实例14-异羟肟酸基被NH-P(O)OH-CH3
所取代的化合物的形成
其中CH2-CO-NHOH基被NH-P(O)OH-CH3取代的SAHA的类似物可以依照下面所示的概括图表合成。合成的化合物13,通过以相关的基与如Bartlett制备的羧肽酶类似物中的Zn(II)结合的方式与HDAC中的Zn(II)结合[60]。
Zn(II)酶碳酸酐酶的典型的抑制剂是磺酰胺,其阴离子与Zn(II)结合[61]。因而化合物14,带磺酰胺基的SAHA类似物,如下面所示被合成。在最后的步骤,我们将羧基磺酰二氯和苯胺及氨水反应。由于羧酸氯化物反应更快,我们按顺序先是苯胺,然后氨水,但是如果两者有相似的反应速率,那么顺序可以颠倒或混合物可被分离。
在合成14的过程中,我们使用容易地从相应的卤代酸制备的硫醇15。硫醇类也是Zn(II)酶如羧肽酶A和相关的肽酶如血管紧张肽转化酶(ACE)的抑制剂,于是我们将15和16转化为HDAC的抑制剂。类似的合成法可用于把NH-P(O)OH-CH3基结合到其它化合物上,尤其是化合物6和7。
实例15-改变Zn(II)结合基和疏水性结合基之间的衔接物
根据Oxamflatin的结果,苯环似乎可以是Zn(II)结合基团和如图所示的分子左手部分之间的链的一部分,特别是在苯环被间位取代的时候。从而,我们提供结合这样的间位取代链到我们其他的化合物中的合成法。我们构造化合物17和18。这一简单的合成法,没有详细的说明,仅要求取代与苯环结合的异羟肟酸而获得芳基酰胺17和18。
另外的化合物也可以合成,例如19和20与我们所知的在HDAC中作为有效的Zn(II)的结合基的12的三氟甲基酮基结合。该合成法包括准备化合物21和22然后加入CF3以形成甲醇,继之以如12的合成法的氧化作用。简单的合成法包括化合物23和24与丙烯酸乙酯的Heck连接,然后通过还原为甲醇将酯转化为醛21和22,然后再次氧化。
到目前为止说明的所有的链仅包括碳原子,但是硫醚链也许是可以接受甚至是有用的,它们增加合成的便利。从而,磺酰胺如25和26,与19和20有关的,通过相应的苯硫酚和溴代甲基磺酰胺得到。如果这一类别证明是有用的HDAC抑制剂和细胞分化剂,有关的合成法可以用于制备相应的磷酰酰胺化物27和28。在这样的情况下,(氮保护的)间氨基苯酸被用于酰化芳基胺,然后磷酸化苯胺基。
实例16-改变分子的左边,携带疏水基
在该合成法中,氧保护的羟胺与溴代己酸发生酰化作用,其化合物然后烷基化由丙二酸制成的双五氟代酯。由此合成的29然后与不同的胺反应,保护基用酸移去。
用这一化合物作为起始物料,我们合成相关的库携载其他Zn(II)结合基。例如,用化合物32烷基化丙二酸让我们获得膦酰酰胺化物库,化合物33将使我们获得CF3-CO库。以同样的方式,也可以获得磺酰胺库,如果较早描述的研究表明这是HDAC期望的Zn(II)结合基。当然,在丙二酸烷基化和氨基分解以后,用32制备的化合物将被脱去甲基,而用33制备的化合物将被氧化。
这也允许用于详细地说明化合物6,氨基辛二酸的衍生物的结构。正如所描述的,这是我们研究过的最有效的HDAC抑制剂之一。我们利用酶催化水解制备这一化合物以实现在34的两个甲酯基之间的光学离析和选择性,以便我们能把其中一个转化成6的氨基喹啉酰胺,而保护氮作为苄酯基。在合成结束时,我们转化少许的甲酯基为异羟肟盐。可是,6是中间体可以用来制备其他衍生物。由6来的苄酯基可以被移去,胺35可以用多种羧酸乙酰化来制备36的库,或者是磺酰氯来制备相应的磺酰胺。
同样,我们合成与6有关的酰胺类37的不同的库,然后通过在去保护作用以后酰化氨基用其他的酰胺类38的库扩展它。我们还合成一组化合物39,其中在37的苄酯基被除去后,我们用多种磺酰氯获得氨磺酰的库。在所有这些中,异羟肟酸基也许是受保护的。
前面的合成方案可用于生成有大量变化的化合物。某些取代基很可能导致化合物对HDAC有潜在有效的亲和力或者获得分化活性,它们如下:
某些胺可以被结合取代SAHA中的苯胺,或作为化合物37和38中的X基:
实例17-利用前面的方案的合成
试剂和起始物料都从商业供应者获得,使用时不需进一步提纯,除非另外指明。对于湿度敏感性的反应,溶剂在使用前都刚蒸馏过:四氢呋喃在氩气保护下从金属钠中利用二苯甲酮作为指示剂蒸馏出来;二氯甲烷和乙腈都从粉末状的氢化钙蒸馏出来。无水的苯,无水DIEA,和无水吡啶都用注射器从购自Aldrich的密封的瓶子中吸取。叔丁醇在使用前通过4_的分子筛干燥。氢化钠以60%分散在矿物油中的状态购买。苯胺,二异丙胺,N-甲基苯胺,和苯甲醇在使用前刚蒸馏过。氘化了的溶剂从Cambrige同位素实验室获得。空气或湿度敏感的反应都在干氩气的环境下在烘干或烤干的并装备有紧密配合的橡胶隔膜的玻璃器皿中完成。注射器和针在使用前都被烘干。0℃的反应都在冰/水浴中完成。-78℃的反应在干冰/丙酮浴中完成。
色谱法
薄层分析色谱分析法(TCL)在由德国EM Science制造的用0.25mm厚的硅胶60 F-254预涂的玻璃片上进行。洗提出的化合物通过一种或多种下面的方法显像:短波紫外线光,I2蒸汽,KMnO4着色,或FeCl3着色。初步的TCL在500μm或1000μm厚硅胶的Whatman预涂片上进行。闪蒸柱色谱法在230-400目的Merck硅藻胶60上进行。
测试设备
在Bruker DPX300和DRX400分光仪上测量核磁共振光谱;在300和400MHz下观察1H,在376MHz下观察19F。化学位移作为δ值相对于溶剂的剩余最大值以ppm值被记录。质谱在Nermag R-10-1仪器上获得化学电离(CI)或电子碰撞电离(EI)光谱,并且在Jeol JMS Lcmate获得电子喷射电离(ESI+)光谱。CI光谱采用氨(NH3)或甲烷(CH4)作为电离气体。
向搅动着的NaH(60%分散体,234mg,5.85mmol)的THF(35mL)的0℃溶液中逐滴加入二叔丁基丙二酸盐(1.20mL,5.37mmol)。观测到气体发生,溶液允许加热到周围环境的温度并搅拌6小时。分液瓶中的甲基6-溴基-2,4-己二烯酯(62)(1.00g,4.88mmol)的THF(20mL)溶液在水浴中搅拌。装插管于其中逐滴加入丙二酸盐的混合物,让反应进行过夜。反应由于饱和而被抑制。加入NH4Cl(5mL),然后是H2O(10mL),混合物用Et2O(3×15mL)提取。有机部分与H2O(1×10mL)混合并洗涤,然后用盐水洗,经MgSO4干燥,然后过滤。在减压状态下蒸发接着用闪蒸色谱法(0-20%EtOAc/己烷)得到的40是清澈无色的油(850mg,2.49mmol,51%)。TLC Rf 0.66(20% EtOAc/己烷);1H-核磁共振(CDCl3,400MHz)δ7.26(dd,1H),6.26(dd,1H),6.10(m,1H),5.82(d,1H),3.78(s,3H),3.12(t,1H),2.64(t,2H),1.41(s,18H)。
(E,E)-7-羧基-辛-2,4-二烯二酸1-甲酯(41)
向搅动中的40(200mg,0.59mmol)的CH2Cl2(10mL)溶液中加入TFA(1mL)。反应进行过夜。挥发物在减压状态下被移去剩下41的白色固体(112mg,0.49mmol,83%)。1H-核磁共振(CD3OD,400MHz)δ7.11(dd,1H),6.33(dd,1H),6.16(m,1H),5.81(d,1H),3.76(s,3H),3.15(t,1H),2.70(t,2H)。4-戊烯酸苯酰胺(42)
向搅拌着的乙二酰氯(2.0M的CH2Cl2溶液,11.5mL,23.1mmol)的CH2Cl2(100mL)和DMF(一滴)0℃的溶液中加入4-戊烯酸(2.25mL,22.0mmol)。反应允许加热到周围环境温度。气体蒸发刚一中止,就将混合物降到0℃然后逐滴加入苯胺(2.00mL,22.0mmol)和TEA(6.72mL,26.3mmol)的CH2Cl2(5mL)溶液。在加热到周围环境温度以后,反应持续进行3小时。混合物在减压环境下浓缩,然后在HCl(1N,10mL)和EtOAc(30mL)间分离并且将各层分开。含水的部分用EtOAc(3×15mL)提取,而有机层与盐水混合并冲洗,用MgSO4干燥,然后过滤。在减压状况下浓缩得到微黄色的固体,通过甲苯再结晶获得42的白色晶体(1.97g,11.24mmol,51%)。TLC Rf 0.68(50% EtOAc/己烷);1H-核磁共振(300MHz,CDCl3)δ7.49(d,2H),7.29(t,2H),7.08(t,1H),5.88(m,1H),5.10(dd,2H),4.42(br s,4H)。
(E,E)-辛-2,4-二烯二酸8-叔丁基酯1-甲酯(43)
向搅动着的二异丙胺(2.06mL,14.7mmol)的-78℃的THF(25mL)溶液中加入n-BuLi(2.0M己烷溶液中,6.2mL,12.4mmol)然后在该温度下搅拌20分钟。随后逐滴加入膦酸酯43a(63)(2.66g,11.3mmol)的THF(4mL)溶液,刚一加入就出现深黄色。在-78℃下保持20分钟以后,混合物被加热到0℃然后逐滴加入乙醛43b(64)(1.78g,11.3mmol)的THF(4mL)溶液。在添加完以后,溶液允许加热到周围环境温度并搅拌过夜。用Et2O(30mL)稀释并用水(3×10mL)冲洗。含水洗涤物与Et2O(2×10mL)混合并被提取,而有机部分与盐水混合并冲洗,经MgSO4干燥,并被过滤。在减压状态下蒸发接着用闪蒸色谱法(10-20%EtOAc/己烷)得到的43是清澈的油状物(1.54g,57%)。TLC Rf 0.56(20%EtOAc/己烷);1H-核磁共振(400MHz,CDCl3)δ7.22(dd,1H),6.19(dd,1H),6.08(m,1H),5.77(d,1H),2.42(m,2H),2.32(t,2H),1.42(s,9H)。
向搅动着的二元酸酯43(1.00g,4.61mmol)的CH2Cl2(40mL)溶液中加入TFA(4.0mL)然后让反应进行6小时。混合物在减压状态下浓缩以去掉挥发物。剩余的白色固体由粗制酸(710mg,3.85mmol)构成。该酸(400mg,2.17mmol)溶于CH2Cl2(20mL)中然后向搅拌着的该溶液加入DMAP(13mg),苯胺(218μL,2.39mmol),和EDC(500mg,2.61mmol)。1.5小时以后,混合物用EtOAc稀释然后用水冲洗。各层分开,含水部分被EtOAc(3×15mL)提取。有机部分与HCl(1N,1×5mL)然后用盐水混合并冲洗,经MgSO4干燥,然后过滤。在减压状态下的浓缩物是棕色固体。棕色固体溶于最少量的CH2Cl2中,然后通过硅胶(20-30% EtOAc/己烷,200mL)制的塞子以除去原始的杂质。洗脱液被浓缩成淡棕色的油状物溶于少量的CH2Cl2中,并且在加入己烷/二乙酯后从中析出晶体。母液被排干,晶体用乙醚漂洗,液体部分浓缩并且这一过程重复若干次,最后得到的44是灰白色的晶体(324mg,1.25mmol,58%)。TLC Rf 0.44(50% EtOAc/己烷);1H-核磁共振(400MHz,CDCl3)δ7.47(d,1H),7.30(t,2H),7.24(m,1H),7.09(t,1H),6.24(dd,1H),6.14(m,1H),5.81(d,1H),3.72(s,3H),2.60(m,2H),2.47(t,2H)。
从制备44的第一步骤得到的粗制酸中间体(200mg,1.09mmol)和N-甲基苯胺(130μL,1.19mmol)溶于CH2Cl2(10mL)中并搅拌。然后加入EDC(271mg,1.41mmol)和DMAP(5mg)并且反应过夜。混合物在水和EtOAc间被分开然后各层分离。含水层用EtOAc(3×10mL)提取,有机部分与HCl(1N,1×5mL)混合并冲洗,然后用盐水,经MgSO4干燥,并被过滤。在减压状态下蒸发留下的纯净的45的棕色的油状物(286mg,1.05mmol,96%)。TLC Rf 0.81(5% MeOH/CH2Cl2);1H-核磁共振(300MHz,CDCl3)δ7.40(t,2H),7.35(t,1H),7.20(d,2H),7.15(dd,1H),6.20(m,2H),5.76(d,1H),3.70(s,3H),3.24(s,3H),2.42(m,2H),2.18(t,2H)。(E,E)-7-苯基氨基甲酰基-七-2,4-二烯二酸(46)
将酯45(260mg,0.95mmol)溶于MeOH(7.5mL)中。然后加入LiOH·H2O(200mg,4.76mmol)的水(2.5mL)溶液,混合物搅拌6小时。反应用HCl(1N)酸化直到PH2然后用EtOAc(3×10mL)提取。有机部分与H2O然后用盐水混合并冲洗,经MgSO4干燥,并被过滤。在减压状态下蒸发留下的产物是纯净的46的棕色油状物(200mg,0.77mmol,81%)。TLC Rf 0.13(40% EtOAc/己烷);1H-核磁共振(300MHz,CD3OD)δ7.47(t,2H),7.41(d,1H),7.28(d,2H),7.19(dd,1H),6.18(dd,2H),6.05(m,1H),3.27(s,3H),3.40(m,2H),2.22(t,2H)。
酸46(200mg,0.77mmol)和TBDPSO-NH2(220mg,0.81mmol)溶于CH2Cl2(8mL)中。向搅拌的该溶液中加入EDC(178mg,0.93mmol)和DMAP(5mg)然后将反应进行过夜。混合物浓缩后通过硅胶(EtOAc)制的塞子。在减压状态下蒸发留下淡棕色油状物(383mg,0.75mmol,97%)。保护的异羟肟盐(270mg,0.53mmol)溶于CH2Cl2(10mL)中并加入TFA(0.5mL)。该溶液搅拌2小时,然后通过TCL观测到被FeCl3染色的新的色谱斑。溶液在减压状态下浓缩然后加入二乙醚,得到粘附于烧瓶上的剩余物。液相被排干,剩余物和EtOAc被磨成粉末,去掉液体,从剩余物中蒸发掉所有挥发物得到的47是棕色胶质(23mg,0.084mmol,16%)。TLC Rf 0.22(5% MeOH/CH2Cl2);1H-核磁共振(400MHz,CD3OD)δ7.50(t,2H),7.40(t,1H),2.27(d,2H),7.08(m,1H),6.11(m,1H),5.97(m,1H),5.80(m,1H),3.23(s,3H),3.39(m,2H),2.21(t,2H)。
标题化合物48的棕色胶质(9mg)通过一系列的类似于制备47的步骤获得。TLC Rf 0.20(5% MeOH/CH2Cl2);1H-核磁共振(400MHz,CD3OD)δ7.51(t,2H),7.41(t,1H),7.30(d,2H),3.29(s,3H),2.11(m,4H),1.58(m,4H),1.22(m,4H)。
辛二酸 苯甲酰胺(49)
向搅拌着的辛二酰氯化物(1.00mL,5.55mmol)的0℃的THF(40mL)溶液中逐滴加入苯甲酰胺(0.61mL,5.55mmol)和DIEA(1.45mL,8.33mmol)的THF(10mL)溶液。混合物允许加热到周围环境温度并搅拌1小时。然后,加入HCl(10mL,1N)并将混合物搅拌0.5小时。内含物用EtOAc(30mL)稀释并将各层分离。含水部分用EtOAc(3×10mL)提取,有机部分用盐水(5mL)混合洗涤,然后用MgSO4干燥。在减压状态下过滤并浓缩得到的49是灰白色固体。1H-核磁共振(300MHz,DMSO-d6)δ11.98(br s,1H),9.80(t,1H),7.32(m,2H),7.23(m,3H),4.25(d,2H),2.19(t,2H),2.12(t,2H),1.50(m,4H),1.25(m,4H)。
辛二酸 苯甲酰胺 羟基酰胺(50)
本化合物由49通过它的如前面描述的用于较早化合物的受保护的异羟肟盐制备。所获得的50是白色固体。1H-核磁共振(400MHz,DMSO-d6)δ10.30(s,1H),8.27(t,1H),7.28(m,2H),7.23(m,3H),5.65(d,2H),2.11(t,2H),1.91(t,2H),1.46(m,4H),1.23(m,4H)。(7S)-苄氧基羰基氨基-7-苯基氨基甲酰基-庚酸叔丁基酯(51)
N-Cbz-L-2-氨基辛二酸 8-叔丁基酯,二环己基胺盐(100mg,0.18mmol)溶于HCl(5mL,1N)并用EtOAc(3×10mL)提取。提取物与盐水混合并洗涤,然后通过MgSO4干燥。蒸发作用后留下的游离酸是白色固体(68mg,0.179mmol)。将它溶于CH2Cl2(2.5mL),并加入苯胺(17μL,0.19mmol),DIEA(46μL,0.27mmol),最后加入Py·BOP(97mg,0.19mmol)。溶液搅拌1小时,然后浓缩,剩余物在H2O(5mL)和EtOAc(10mL)之间分离。各层被分开,含水部分用EtOAc(3×10mL)提取。提取物集中用HCl(1N)冲洗,然后用盐水冲洗,经MgSO4干燥,并被过滤。在减压状态下浓缩得到的固体剩余物通过硅胶(30%EtOAc/己烷)制的塞子。蒸发收集的洗脱液得到的51是白色固体(76mg,0.167mmol,94%)。TLC Rf 0.38(30% EtOAc/己烷);1H-核磁共振(400MHz,CDCl3)δ8.21(s,1H),7.48(d,2H),7.32(m,5H),7.28(t,2H),7.08(t,1H),5.39(br d,1H),5.10(m,2H),4.26(br dd,1H),2.07(t,2H),1.92(m,1H),1.66(m,1H),1.55(m,2H),1.42(s,9H),1.38(m,4H)。(7S)-7-苄氧基羰基氨基-7-苯基氨基甲酰基-庚酸(52)
向酯51(76mg,0.167mmol)的CH2Cl2(5mL)溶液中加入TFA(0.5mL)并将反应溶液搅拌5小时。溶液在减压状态下浓缩得到的粗制的52是白色固体(80mg),它将不经提纯在下面的步骤中使用。TLC Rf 0.32(5% MeOH/CH2Cl2);1H-核磁共振(400MHz,DMSO-d6)δ11.93(br s,1H),9.99(s,1H),7.58(d,2H),7.55(d,1H),7.35(m,4H),7.29(t,2H),7.03(t,1H),5.02(m,2H),4.11(br dd,1H),2.17(t,2H),1.59(m,2H),1.48(m,2H),1.22(m,4H)。
向粗制酸52(80mg)和TBDPSO-NH2(60mg,0.221mmol)的CH2Cl2溶液中加入DIEA(52μL,0.302mmol),随后加入Py·BOP(125mg,0.241mmol)。溶液搅拌3小时,然后在减压状态下浓缩。剩余物通过硅胶(50%EtOAc/己烷)制的塞子并将所收集到的洗脱液蒸干。获得白色泡沫材料(107mg,0.164mmol,82%),将它溶于CH2Cl2(5mL)中并加入TFA(0.25mL),将溶液搅拌2小时。通过TCL分析观测到被FeCl3染色的新的色谱斑。混合物在减压状态下浓缩,剩余物溶于最少量的EtOAc中成为溶剂化物然后产品用己烷沉淀。最后所得到的白色凝胶体用己烷漂洗并在真空状态下干燥,得到的53是白色的固体(40mg,0.097mmol,58%超过三个步骤)。1H-核磁共振(400MHz,DMSO-d6)δ10.31(s,1H),9.99(s,1H),7.59(d,2H),7.56(d,1H),7.37(m,4H),7.29(t,2H),7.02(t,1H),5.02(m,2H),4.11(dt,1H),1.90(t,2H),1.61(m,2H),1.47(m,2H),1.30(m,4H)。MS(ESI+)计算C22H27N3O5413,得到414[M+H]+。
(7S)-7-苄氧基羰基氨基-7-(喹啉-8-基氨基甲酰基)-庚酸 叔丁基酯(54)
标题化合物用N-Cbz-L-2-氨基辛二酸8-叔丁基酯,二环己基胺盐,以类似于制备51的方式制取。闪蒸色谱法(0-1% MeOH/CH2Cl2)得到的54是浅棕色固体(70mg,0.138mmol,82%)。TLCRf 0.42(2%MeOH/CH2Cl2);1H-核磁共振(400MHz,CDCl3)δ10.19(s,1H),8.77(dd,1H),8.71(dd,1H),8.15(dd,1H),7.52(m,2H),7.45(m,1H),7.33(m,4H),5.50(br d,1H),5.15(m,2H),4.51(br dd,1H),2.17(t,2H),2.00(m,1H),1.79(m,1H),1.56(m,2H),1.45(m,2H),1.40(s,9H),1.38(m,2H)。(7S)-7-苄氧基羰基氨基-7-(喹啉-8-基氨基甲酰基)-庚酸(55)
以与52相类似的方式由54制备。得到的55是棕色固体(72mg,0.129mmol)。TLC Rf 0.16(50% EtOAc/己烷);1H-核磁共振(400MHz,DMSO-d6)δ11.92(br s,1H),10.46(s,1H),8.49(dd,1H),8.63(dd,1H),8.42(dd,1H),8.10(d,1H),7.68(dd,1H),7.58(t,1H),7.36(m,2H),7.28(m,2H),5.09(m,2H),4.22(m,1H),2.19(t,2H),1.83(m,1H),1.67(m,1H),1.48(m,2H),1.39(m,2H),1.28(m,2H)。
以与53相类似的方式由55制备。得到的56是白色固体(15mg,0.032mmol,44%)。1H-核磁共振(400MHz,DMSO-d6)δ10.46(s,1H),10.31(s,1H),8.85(dd,1H),8.63(dd,1H),8.42(dd,1H),8.12(d,1H),8.66(m,2H),7.58(t,1H),7.37(m,2H),7.28(m,2H),7.20-6.90(1H),5.10(m,2H),4.10(m,1H),1.92(t,2H),1.82(m,1H),1.68(m,1H),1.49(m,2H),1.40(m,2H),1.26(m,2H)。MS(ESI+)计算C25H28N4O5464,得到465[M+H]+。(7S)-(环己烷羰基-氨基)-7-苯氨羰基-庚酸甲酯(57)
向5(81mg,0.214mmol)的CH2Cl2(10mL)溶液中加入TFA(0.5mL)并将溶液搅拌2小时。混合物在减压状态下浓缩。向该胺(62mg,0.233mmol)和环己烷羧酸(31μL,0.245mmol)的CH2Cl2(4mL)溶液中加入Py·BOP(140mg,0.268mmol)和DIEA(58μL,0.335mmol)。溶液搅拌2小时,在减压状态下浓缩,产品经闪蒸色谱法(40%EtOAc/己烷)提纯。蒸发剩下粗制的57是白色固体(95mg)包含有少量未反应的环己烷酸杂质。该产物不经过进一步的提纯就用于接下来的步骤。TLC Rf0.58(50%EtOAc/己烷);1H-核磁共振(400MHz,CDCl3)δ8.58(s,1H),7.50(d,2H),7.28(t,2H),7.07(t,1H),6.14(d,1H),4.56(dt,1H),3.64(s,3H),2.28(t,2H),2.13(tt,1H),1.94(m,1H),1.85(m,2H),1.76(m,2H),1.64(m,4H),1.41(m,5H),1.22(m,4H)。(7S)-(环己烷羰基-氨基)-7-苯氨羰基-庚酸(58)
向酯57(95mg)的MeOH(2.5mL)0℃溶液中加入NaOH(1M,2.5mL)溶液。刚一加入添加物就形成白色的沉淀物,在加入THF(2.5mL)以后沉淀物重新溶解。在3小时以后再补充加入NaOH(1M,1.0mL)溶液并将温度保持在0℃。在通过TLC分析到起始物料刚一完全消失时,反应物用HCl(1N)酸化以获得白色沉淀物。上层清液被排走,固体在抽吸状态下过滤。混合溶液用EtOAc(3×5mL)提取,提取液用混合盐水洗涤,经MgSO4干燥,然后过滤。在减压状态下浓缩留下与滤饼结合在一起的白色固体在真空状态下干燥得到羧酸58(75mg,0.200mmol,90%)。1H-核磁共振(400MHz,DMSO-d6)δ11.95(s,1H),9.98(s,1H),7.90(d,1H),7.58(d,1H),7.28(t,2H),7.02(t,1H),4.33(dt,1H),2.22(tt,1H),2.17(t,2H),1.67(m,6H),1.60(m,2H),1.46(m,2H),1.22(m,9H)。(2S)-2-(环己烷羰基-氨基)-辛二酸8-羟基酰胺1-苯基酰胺(59)
酸58(70mg,0.187mmol),TBDPSO-NH2(61mg,0.224mmol),和DMAP(5mg)溶于CH2Cl2(4ml)中,并加入EDC(47mg,0.243mmol)。溶液搅拌过夜。在减压状态下浓缩后的物质通过闪蒸色谱法(50%EtOAc/己烷)提纯。化合产品分馏物蒸发得到白色泡沫材料(80mg,0.131mmol,70%)。向该受保护的异羟肟盐的CH2Cl2(2ml)和THF(3mL)溶液中加入TFA(0.25mL)并搅拌1.5小时。通过TCL观测到被FeCl3立刻染色的新的色谱斑。溶液浓缩并在真空状态下除去所有挥发物。残余物和EtOAc一起研磨获得的白色凝胶体沉淀物用EtOAc(5mL)转化为塑性管状物。该管状物在离心作用下形成小球,上层清液排掉,并加入EtOAc(10mL)。小球用声裂法使之再悬浮,然后再次离心脱水,排掉上层清液,剩余物在真空状态下干燥。得到白色固体59(18mg,0.046mmol,35%)。1H-核磁共振(400MHz,DMSO-d6)δ10.31(s,1H),9.97(s,1H),7.89(d,1H),7.57(d,2H),7.28(t,2H),7.02(t,1H),4.33(dt,1H),2.22(t,2H),1.91(t,2H),1.61(m,6H),1.68(m,2H),1.45(m,2H),1.21(9H)。辛二酸羟基酰胺喹啉-8-基酰胺基(60)
本化合物由辛二酸一甲基酯以与48类似的方式,通过使用8-氨基喹啉来制备。在将受保护的异羟肟盐TFA去保护以后获得的粗制剩余物溶解于少量的EtOAc中经己烷沉淀得到白色固体60(18mg,0.057mmol,21%由羧酸)。1H-核磁共振(400MHz,DMSO-d6)δ10.31(s,1H),10.02(s,1H),8.92(dd,1H),8.61(dd,1H),8.40(dd,1H),7.65(dd,1H),7.63(dd,1H),7.56(t,1H),2.56(t,1H),1.93(t,1H),1.63(m,2H),1.49(m,2H),1.28(m,4H)。MS(ESI+)计算C17H21N3O3315,得到316[M+H]+。
向搅拌着的NaH(60%分散体,197mg,4.913mmol)在0℃的THF(25mL)的悬浮体中加入丙二酸二叔丁基酯(1.00mL,4.466mmol)并且混合物允许加热到周围环境温度。1小时以后,停止释放出气体,接着逐滴加入6-溴己酸乙酯(0.88mL,4.913mmol)。将反应回流过夜。将反应小心地用水(10mL)冷却然后用EtOAc稀释。在将各层分开以后,含水部分用EtOAc(3×10mL)提取。提取物汇集后用水冲洗,然后用盐水,经MgSO4干燥,然后过滤。在减压状态下的浓缩后得到的黄色油状物通过硅胶(10%EtOAc/己烷)制的塞子。蒸发后得到淡黄色的浓缩溶剂61(1.52g,4.24mmol,95%)。TLC Rf 0.44(10% EtOAc/己烷);1H-核磁共振(400MHz,CDCl3)δ4.10(q,2H),3.08(t,1H),2.26(t,2H),1.76(m,2H),1.60(m,2H),1.43(s,18H),1.32(m,4H),1.23(m,3H)。
向三酯物61(500mg,1.395mmol)的CH2Cl2(20ml)溶液加入TFA(2.0mL),然后让反应混合物搅拌反应过夜。在真空状态下蒸发掉挥发性的成分,剩余物重复溶于CH2Cl2中并蒸发以除去所有微量的TFA。得到的固体62(327mg,1.33mmol)不经进一步的提纯直接用于下面的步骤。1H-核磁共振(400MHz,DMSO-d6)δ12.62(br s,2H),4.03(q,2H),3.16(t,1H),2.25(t,2H),1.67(m,2H),1.49(m,2H),1.25(m,4H),1.16(t,3H)。7,7-二-(喹啉8-基氨基甲酰基)-庚酸乙酯(65)
二酸62(150mg,0.609mmol),8-氨基喹啉(211mg,1.462mmol),和DMAP(5mg)溶于THF(6mL)中。向这一溶液中加入EDC(350mg,1.827mmol)反应允许进行过夜。混合物在减压状态下浓缩,产品通过闪蒸色谱法(40%EtOAc/己烷)提纯。混合的产品部分蒸发得到的63是浅棕色固体(100mg,0.201mmol,14%)。1H-核磁共振(400MHz,DMSO-d6)δ10.85(s,2H),8.92(dd,2H),8.64(dd,2H),8.40(dd,2H),7.68(dd,2H),7.62(dd,2H),7.57(t,2H),4.35(t,1H),3.98(q,2H),2.24(t,2H),2.00(m,2H),1.51(m,2H),1.37(m,4H),1.12(t,3H)。
向酯63(94mg,0.212mmol)的MeOH(3mL)和THF(1mL)的溶液中加入LiOH H2O(44mg,1.062mmol)的水(1mL)溶液,并且混合物搅拌5小时。在用HCl(1N)酸化中和至pH值为7后,加入EtOAc(10mL)然后各层分开。含水部分用EtOAc(3×5mL)提取,提取物与饱和NH4Cl(3mL)混合洗涤,然后用水(3mL),然后用盐水,经MgSO4干燥,然后过滤。在减压状态下浓缩得到的64是白色固体(94mg,0.200mmol,94%)。TLC Rf 0.21(50%EtOAc/己烷);1H-核磁共振(400MHz,DMSO-d6)δ11.88(s,1H),10.85(s,2H),8.93(dd,2H),8.65(dd,2H),8.40(dd,2H),7.69(dd,2H),7.63(dd,2H),7.58(t,2H),4.35(t,1H),2.16(t,2H),2.00(m,2H),1.49(m,2H),1.38(m,4H)。
酸64(94mg,0.200mmol),TBDPSO-NH2(74mg,0.272mmol),和DMAP(5mg)溶于CH2Cl2(4ml)中并加入EDC(57mg,0.295mmol)。溶液搅拌过夜,然后在减压状态下浓缩。通过闪蒸色谱法(30-50%EtOAc/己烷)提纯然后蒸发混合产品部分得到白色泡沫材料。向该受保护的异羟肟盐的CH2Cl2(4ml)溶液中加入TFA(0.2mL)然后将溶液搅拌4小时。TLC指示起始物料完全消耗并且观测到被FeCl3染色的新的色谱斑。溶液在减压状态下浓缩,剩余物溶解于最小量的EtOAc中。添加己烷得到白色沉淀物,从中排除母液。在用己烷漂洗之后,剩余物在真空状态下干燥留下的65是白色固体(30mg,0.061mmol,22%由羧酸)。1H-核磁共振(400MHz,CDCl3)δ10.85(s,2H),10.30(s,1H),8.93(dd,2H),8.65(dd,2H),8.40(dd,2H),7.69(dd,2H),7.63(dd,2H),7.58(t,2H),4.35(t,1H),1.99(m,2H),1.92(t,2H),1.48(m,2H),1.35(m,4H)。MS(ESI+)计算C27H27N5O4485,得到486[M+H]+。
标题化合物由二酸62以类似于制备65的方法制取。1H-核磁共振(400MHz,DMSO-d6)δ10.60(s,1H),10.34(s,1H),8.95(dd,2H),8.74(s,2H),7.93(dd,2H),7.64(dd,2H),7.56(dd,2H),3.71(t,1H),1.96(m,4H),1.51(m,2H),1.34(m,4H)。6-溴己酸苯酰胺(76)
向6-溴己酰氯(1.00mL,6.53mmol)的0℃的THF(35mL)溶液中逐滴加入苯胺(0.60mL,6.53mmol)和TEA(1.09mL,7.84mmol)的THF(5mL)溶液。反应混合物允许加热到周围环境温度并且搅拌2小时。然后将混合物过滤,固体物用EtOAc漂洗,再在真空状态下过滤。剩余物在水(15mL)和EtOAc(20mL)之间沉淀然后各层分开。含水部分用EtOAc(3×10mL)提取而有机层与HCl(1N)混合洗涤,然后用盐水,经MgSO4干燥,接着过滤。在减压状态下浓缩留下的棕色油状物借助抽吸作用通过硅胶(30%EtOAc/己烷)制的塞子。在减压状况下蒸发得到固态的67(1.55g,5.74mmol,88%)。TLC Rf 0.36(25%EtOAc/己烷);1H-核磁共振(400MHz,DMSO-d6)δ9.85(s,1H),7.57(d,2H),7.27(t,2H),7.01(t,1H),3.53(t,2H),2.30(t,2H),1.81(t,2H),1.63(m,2H),1.42(m,2H);MS(ESI+)计算C12H16BrNO 268+270,得到269+271[M+H]+。
硫代乙酸S-(5-苯氨羰基-戊基)酯(68)
溴化物67(200mg,0.74mmol),硫代乙酸钾(110mg,0.96mmol),和碘化钠(10mg)在THF(6mL)中混合,然后将混合物剧烈搅拌促使回流过夜。反应混合物浓缩,借助抽吸作用下通过硅胶(20%EtOAc/己烷,200mL)制的塞子。在减压状态下蒸发留下68是橙黄色晶状固体(190g,0.72mmol,97%)。TLC Rf 0.22(25%EtOAc/己烷);1H-核磁共振(400MHz,DMSO-d6)δ9.83(s,1H),7.56(d,2H),7.27(t,2H),7.00(t,1H),2.82(t,2H),2.30(s,3H),2.28(t,2H),1.57(m,2H),1.52(m,2H),1.35(m,2H)。
6-氨基己酸(904mg,6.89mmol)和NaOH(415mg,10.34mmol)溶于水(30mL)中并冷却至0-5℃。逐滴加入甲磺酰氯(0.586mL,7.58mmol)反应混合物搅拌2小时,然后加热到周围环境温度再搅拌2小时。混合物用HCl(1N)酸化并用EtOAc(3×15mL)提取。提取物与水混合洗涤,然后用盐水,经MgSO4干燥,接着过滤。在减压状况下蒸发得到的69是白色晶状物(207mg,0.99mmol,14%)。1H-核磁共振(400MHz,DMSO-d6)δ11.95(s,1H),6.91(t,1H),2.90(dt,2H),2.87(s,3H),2.20(t,2H),2.48(m,2H),2.43(m,2H),1.27(m,2H)。6-甲磺酰氨基-己酸苯酰胺(70)
向酸69(100mg,0.48mmol),苯胺(60μL,0.66mmol),和DMAP(5mg)的THF(5mL)溶液中加入EDC(119mg,0.57mm0l)。反应混合物搅拌过夜,然后在水(10mL)和EtOAc(15mL)之间分开。各层分离,含水部分用EtOAc(3×10mL)提取。有机部分与饱和NH4Cl(5mL)混合洗涤,然后用盐水,经MgSO4干燥,接着过滤。在减压状态下浓缩得到的70是白色晶状固体(130mg,0.46mmol,95%)。1H-核磁共振(400MHz,DMSO-d6)δ9.84(s,1H),7.57(d,2H),7.26(t,2H),7.00(t,1H),6.92(t,1H),2.91(dt,2H),2.85(s,3H),1.58(m,2H),1.47(m,2H),1.31(m,2H)。
向辛二酸一甲基酯(1.00g,5.31mmol)的THF(15mL)溶液中加入乙二酰氯(2mL)接着加入DMP(一滴)。溶液搅拌2小时,然后在减压状态下浓缩。在高真空状态下过夜除去挥发物,留下黄色油状物(1.08g,5.22mmol,98%)。该粗制酸氯化物于是依照如下所述文献资料的方法被转化为三氟甲酮。(65)向该酸氯化物(1.08g,5.22mmol)的0℃的CH2Cl2(45mL)溶液中加入三氟乙酸酐(4.64mL,32.81mmol)和吡啶(3.54mL,43.74mmol)。混合物允许升温到周围环境温度并搅拌2小时。再重新回到0℃以后,小心地加入冰冷的水(20mL)。补充加入水(100mL)以后,各层分离。水相用CH2Cl2(2×30ml)提取,而有机层与盐水混合冲洗,经MgSO4干燥,接着过滤。在减压状态下蒸发得到棕色油状物,再通过闪蒸色谱法(2-4%MeOH/CH2Cl2)提纯得到的71是清澈的油状物(641mg,2.67mmol,49%)。TLC Rf0.24(2%MeOH/CH2Cl2);1H-核磁共振(400MHz,CDCl3)δ3.67(s,3H),2.71(t,2H),2.31(t,2H),1.65(m,4H),1.35(m,4H)。
向酯71(300mg,1.25mmol)的THF(18mL)溶液中加入LiOH·H2O(262mg,6.24mmol)的水(6mL)溶液并将悬浮液搅拌过夜。混合物然后用HCl(1N)酸化至pH值为2再然后用EtOAc(3×15mL)提取。提取物与盐水混合洗涤,经MgSO4干燥,接着过滤。在减压状态下浓缩得到白色固体(211mg,0.93mmol,75%)。向该酸(109mg,0.48mmol),EDC(111mg,0.58mmol),DMAP(5mg)的CH2Cl2(5ml)溶液中加入苯胺(49μL,0.53mmol),反应允许持续过夜。溶液在水(5mL)和EtOAc(10mL)之间分离。各层分开,水相用EtOAc(3×5mL)提取。有机部分与盐水混合洗涤,经MgSO4干燥,接着过滤。在减压状态下蒸发留下的固体用预制的TLC(30%EtOAc/己烷)通过由EtOAc提取而离析最小极性带来提纯。提取物经过浓缩得到的72是微黄色固体(92mg,0.31mmol,65%)。TLC Rf 0.48(50%EtOAc/己烷);1H-核磁共振(400MHz,CDCl3)δ7.51(d,2H),7.32(t,2H),7.10(t,1H),2.72(t,2H),2.36(t,2H),1.72(m,4H),1.40(m,4H);19F核磁共振(?MHz,CDCl3)-78.40(s,3F);MS(APCI+)计算C15H19F3NO2301,得到325[M+Na]+。
向N-Boc-6-氨基己酸(2.50g,10.81mmo1),EDC(2.69g,14.05mmol),和DMAP(20mg)的CH2Cl2(100mL)溶液中加入苯胺(1.04mL,11.35mmol)然后混合液搅拌过夜。溶液在减压状态下蒸发至较小的量,然后在水(20mL)和EtOAc(30mL)之间分离。各层分开,水相用EtOAc(3×15mL)提取。有机部分与饱和NH4Cl(5mL)混合洗涤,然后用盐水,经MgSO4干燥,接着过滤。在减压状态下浓缩得到的纯净的73是白色固体(3.14g,10.25mmol,95%)。TLC Rf 0.40(50%EtOAc/己烷);1H-核磁共振(400MHz,DMSO-d6)δ9.81(s,1H),7.56(d,2H),7.26(t,2H),7.00(t,1H),6.74(t,1H),2.89(dt,2H),2.27(t,2H),1.56(m,2H),1.38(m,2H),1.35(s,9H),1.25(m,2H)。6-氨基己酸苯酰胺,TFA(三氟乙酰丙酮)盐(74)
向氨基甲酸酯73(300mg,0.98mmol)的CH2Cl2(15mL)溶液中加入TFA(0.75mL)然后溶液搅拌过夜。通过TLC确认完全消耗掉起始物料。混合物在减压状态下蒸发以除去所有挥发性物质,剩下灰白色固体(295mg,0.92mmol,94%)。粗制的74将不经进一步的提纯继续使用。
向搅拌着的铵盐74(197mg,0.62mmol)和DIEA(148μL,0.85mmol)溶在0℃的CH2Cl2(7ml)的悬浮液中逐滴加入氯代磷酸二甲基酯(77μL,0.72mmol)。混合物允许升温到周围环境温度并搅拌过夜。然后溶液用水(10mL)稀释并将各层分开。水相用CH2Cl2(3×10mL)提取,有机部分用饱和NH4Cl(5mL)混合洗涤,然后用盐水,经MgSO4干燥,接着过滤。在浓缩以后,剩余物通过闪蒸色谱法(2-5%MeOH/CH2Cl2)提纯,包含TLC的两个紫外线活跃波段的更多的极性的部分被合并然后浓缩,得到的75是清澈的油状物(40mg,0.13mmol,20%)。TLC Rf 0.23(5%MeOH/CH2Cl2);1H-核磁共振(400MHz,DMSO-d6)δ9.84(s,1H),7.57(d,2H),7.26(t,2H),7.00(t,1H),4.90(dt,1H),3.51(d,6H),2.71(m,2H),2.28(t,2H),1.56(m,2H),1.40(m,2H),1.29(m,2H)。
向铵盐74(155mg,0.48mmol)的CH3CN(8mL)的悬浮液中加入DIEA(0.21mL)和甲基甲基二氧膦酰基氯化物(77mg,0.600mmol)。反应混合物搅拌过夜,期间被澄清。溶液在水(10mL)和EtOAc(15mL)之间分离然后各层分开。含水部分用EtOAc(3×10mL)提取,有机部分用饱和NH4Cl(1×5mL)混合洗涤,然后用盐水,经MgSO4干燥,接着过滤。产品通过闪蒸色谱法(2-5%MeOH/CH2Cl2)提纯,包含更多的极性色谱斑的部分被合并浓缩,得到的76是清澈油状物(102mg,0.34mmol,71%)。TLCRf 0.16(5%MeOH/CH2Cl2);1H-核磁共振(400MHz,DMSO-d6)δ9.85(s,1H),7.57(d,2H),7.26(t,2H),7.00(t,1H),4.52(dt,1H),3.43(d,3H),2.73(m,2H),2.28(t,2H),1.57(m,2H),1.38(m,2H),1.28(m,2H),1.26(d,3H)。实例18-化合物77的合成二乙基 3-溴苯基丙二酸
二乙基3-溴苯基丙二酸依照Cehnevert,R和Desjardins,M.Can.J.Chem.1994.72,3212-2317中的程序制备。1H-核磁共振(CDCl3,300MHz)δ7.6(s,1H),7.50(d,1H,J=7.9Hz),7.37(d,1H,J=7.9Hz),7.26(t,1H,J=7.9Hz),4.58(s,1H),4.22(m,4H),1.29(t,J=10Hz)。
二乙基3-溴苯基丙二酸盐(1g,3.2mmol)被加入到苯胺(5mL)中。反应混合物用Ar(g)提纯然后被回流2小时。经冷却后,反应混合物用10%的HCl(20mL)和乙酸乙酯(50mL)稀释。有机层被分离然后浓缩以提供白色粉末状态的3-溴苯基丙二酰基二(苯基酰胺)。(540mg,1.3mmol,42%)。1H-核磁共振(d6-DMSO,300MHz)δ10.3(bs,2H),7.65(s,1H),7.60(d,4H,J=7.9Hz),7.54(d,1H,J=7.9Hz),7.46(d,1H,J=7.8Hz),7.35(t,1H,J=7.8Hz),7.31(t,4H,J=7.8Hz),7.06(t,2H,J=7.6Hz),4.91(s,1H)。
3-溴苯基丙二酰基二(苯基酰胺)(500mg,1.22mmol),丙烯酸(115mg,1.6mmol,1.3个当量),Pd(OAc)2(2mg),三-邻-甲苯基膦酰(20mg),三丁胺(0.6mL)和二甲苯(5mL)在一个密封容器中被加热到120℃持续6小时。经冷却后,反应用5%HCl(10mL)和乙酸乙酯(50mL)稀释。有机层被分离,过滤得到3-丙二酰基二(苯基酰胺)肉桂酸的沉淀是白色粉末(450mg,1.12mmol,92%)。1H-核磁共振(d6-DMSO,300MHz)δ12.4(bs,1H),10.3(bs,2H),7.73(s,1H),7.7-7.5(m,6H),7.52(d,1H,J=7.7Hz),7.43(t,1H,J=7.6Hz),7.31(t,4H,J=7.5Hz),7.06(t,2H,J=7.4Hz),6.52(d,1H,J=16Hz),4.95(s,1H)。APCI-MS 401(M+1)。
3-(丙二酰基二(苯基酰胺))肉桂基异羟肟酸(77)
3-(丙二酰基二(苯基酰胺))肉桂酸(200mg,0.5mmol)溶于无水CH2Cl2(10mL)中。一边搅拌一边加入0℃的异丁基氯甲酸酯(0.10mL,0.77mmol)和三乙胺(0.20mL)。2小时后至25℃,加入邻-(叔丁基联苯甲硅烷基)羟胺混合物再搅拌4小时。粗制的反应混合物直接提供给硅胶(15g)衬垫,然后用20%的乙酸乙酯/己烷洗提得到相应的甲硅烷基保护的异羟肟酸(Rf=0.58,50%乙酸乙酯/己烷)的泡沫材料。将它用10%的三氟乙酸的二氯甲烷(10mL)溶液直接处理4小时。溶剂在50℃下通过rotavap浓缩,剩余物悬浮在乙醚(10mL)中。过滤合成的沉淀物得到白色粉末状的化合物77(150mg,0.365mmol,73%)。1H-核磁共振(d6-DMSO,300MHz)δ10.8(bs,0.5H),10.2(bs,2H),9.06(bs,0.5H),7.7-7.55(m,5H),7.53-7.38(m,4H),7.31(t,4H,J=7.7Hz),7.06(t,2H,J=7.3Hz),6.50(d,1H,J=16Hz),4.92(s,1H)。APCI-MS 416(M+1)。
化合物77对MEL细胞分化和组蛋白脱乙酰基酶活性的影响如表2所示。与化合物77相一致的结构683见表2。从表2可以明显看出,化合物77预期将是非常有效的细胞分化剂。
结论
制备的所有化合物都经过了试验。下面的表2显示的仅仅是化合物子群的测试结果。表2是由类似于在前面的实例7-10所描述试验的试验汇编而成的。所测试的化合物都指定了如表2所示的结构代码。这些结构代码都是随意指定的,并不和在这次公开中其他地方使用的化合物代码相关联。
表2显示的结果证实用于构造具有前面的公开中所论述的细胞分化和HDAC活性抑制能力的化合物的预言性的规则的一般准确性。基于该规则和公开的合成图解,许多额外的化合物可以轻易地被构造,制备和测试用于细胞分化和HDAC活性抑制。
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Claims (54)
2.根据权利要求1的化合物,其中每个R1和R2都直接或通过
衔接物连接,并且是,被取代的或未被取代的,芳基,环
烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤
基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯
基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
3.根据权利要求2的化合物,其中衔接物是酰胺,-O-,-S-,
-NH-,或-CH2-。
4.根据权利要求1的化合物,分子式为:
其中每个R4是,被取代的或未被取代的,芳基,环烷
基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基
-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,
烷氧基,芳氧基,芳基烷氧基,或吡啶基。
5.根据权利要求4的化合物,其中R2可以是-酰胺-R5,
其中R5是,被取代的或未被取代的,芳基,环烷基,
环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-
胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,
烷氧基,芳氧基,芳基烷氧基,或吡啶基。
7.根据权利要求6的化合物,分子式为:
10.根据权利要求9的化合物,其中芳基或环烷基可以被取代为甲基,氰基,硝基,三氟甲基,氨基,甲酰胺基,甲基氰基,氯,氟代,溴代,碘代,2,3-二氟,2,4-二氟,2,5-二氟,3,4-二氟,3,5-二氟,2,6-二氟,1,2,3-三氟,2,3,6-三氟,2,4,6-三氟,3,4,5-三氟,2,3,5,6-四氟,2,3,4,5,6-五氟,叠氮基,己基,t-丁基,苯基,羧基,羟基,甲氧基,苯基羟基,苄氧基,苯基氨氧基,苯基氨基羰基,甲酯基,甲基氨基羰基,二甲基氨基,二甲基氨基羰基,或羟基氨基羰基。
11.根据权利要求6的化合物,分子式为:
或它的对映异构体。
12.根据权利要求11的化合物,其中n=5。
14.根据权利要求13的化合物,其中n=5。
15.根据权利要求6的化合物,分子式为:
或它的对映异构体。
16.根据权利要求15的化合物,其中n=5。
17.根据权利要求6的化合物,分子式为:
或它的对映异构体。
18.根据权利要求17的化合物,其中n=5。
19.根据权利要求6的化合物,分子式为:
或它的对映异构体。
20.根据权利要求19的化合物,其中n=5。
21.根据权利要求6的化合物,分子式为:
或它的对映异构体。
22.根据权利要求21的化合物,其中n=5。
23.根据权利要求6的化合物,分子式为:
或它的对映异构体。
24.根据权利要求23的化合物,其中n=5。
25.根据权利要求6的化合物,分子式为:
或它的对映异构体。
26.根据权利要求25的化合物,其中n=5。
27.根据权利要求6的化合物,分子式为:
或它的对映异构体。
28.根据权利要求27的化合物,其中n=5。
30.根据权利要求29的化合物,其中n=5。
32.根据权利要求31的化合物,其中n=5。
33.一种药物组合物,包括制药上有效量的权利要求1-9中任何一个的化合物和制药上可接受的载体。
34.一种选择性诱导肿瘤细胞成体终末分化并由此抑制该细胞增生的方法,包括在合适的状况下用有效量的权利要求1-9中任何一个的化合物接触这些细胞。
35.一种治疗患有以肿瘤细胞增生为特征的肿瘤的患者的方法,包括向患者供给有效量的权利要求1-9中任何一个的化合物。
37.依照权利要求36的化合物,其中每个R1和R2都直接或通过衔接物连接,并且是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
38.依照权利要求37的化合物,其中衔接物可以是酰胺,-O-,-S-,-NH-,或-CH2-。
40.依照权利要求39的化合物,其中R2是-磺胺药物-R8,或-酰胺-R8,其中R8是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
44.依照权利要求43的化合物,其中n为从4到7,m为从1到3。
45.依照权利要求43的化合物,其中每个R1和R2都直接或通过衔接物连接,并且是,被取代的或未被取代的,芳基,环烷基,环烷基氨基,石脑油,吡啶基氨基,哌啶基,9-嘌呤基-6-胺基,噻唑基氨基,羟基,带支链或直链的烷基,烯基,烷氧基,芳氧基,芳基烷氧基,或吡啶基。
46.依照权利要求43的化合物,其中衔接物是酰胺,-O-,-S-,-NH-,或-CH2-。
50.一种药物组合物,包括权利要求1,36或43的化合物和制药上可接受的载体。
51.一种权利要求1,36或43的化合物的制药上可接受的盐。
52.一种权利要求1,36或43的化合物的药物前体。
53.一种在肿瘤内诱导肿瘤细胞分化的方法,包括用有效量的权利要求1,36或43的化合物接触该细胞以便由此分化肿瘤细胞。
54.一种抑制组蛋白脱乙酰基酶活性的方法,包括用有效量的权利要求1,36或43的化合物接触组蛋白脱乙酰基酶以便由此抑制组蛋白脱乙酰基酶活性。
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- 2000-08-24 CN CN00814006A patent/CN1378450A/zh active Pending
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101001851B (zh) * | 2004-08-09 | 2011-04-20 | 安斯泰来制药有限公司 | 具有作为组蛋白脱乙酰酶(hdac)抑制剂的活性的羟基酰胺化合物 |
CN102020588A (zh) * | 2009-09-16 | 2011-04-20 | 深圳微芯生物科技有限责任公司 | 具有组蛋白去乙酰化酶抑制活性的三环化合物、其制备方法及应用 |
CN102020588B (zh) * | 2009-09-16 | 2014-01-29 | 深圳微芯生物科技有限责任公司 | 具有组蛋白去乙酰化酶抑制活性的三环化合物、其制备方法及应用 |
CN102775368A (zh) * | 2011-05-10 | 2012-11-14 | 中国科学院上海药物研究所 | 一类噻唑类化合物及其制备方法和用途 |
CN102775368B (zh) * | 2011-05-10 | 2016-08-17 | 上海驺虞医药科技有限公司 | 一类噻唑类化合物及其制备方法和用途 |
CN103732577A (zh) * | 2011-09-19 | 2014-04-16 | 希格马托制药工业公司 | 作为有效hdac抑制剂的携带内酰胺的新硫代衍生物和它们作为药物的用途 |
CN103732577B (zh) * | 2011-09-19 | 2017-04-05 | 希格马托制药工业公司 | 作为有效hdac抑制剂的携带内酰胺的硫代衍生物和它们作为药物的用途 |
CN107698464A (zh) * | 2017-10-12 | 2018-02-16 | 江苏师范大学 | 具有组蛋白去乙酰化酶抑制作用的贝利司他结构类似物及其应用 |
CN107822916A (zh) * | 2017-11-14 | 2018-03-23 | 江苏师范大学 | 一种美白活性成分 |
Also Published As
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HUP0202707A2 (hu) | 2002-12-28 |
EA007649B1 (ru) | 2006-12-29 |
US20060241129A1 (en) | 2006-10-26 |
US7345174B2 (en) | 2008-03-18 |
EP1231919B1 (en) | 2015-09-30 |
US7126001B2 (en) | 2006-10-24 |
KR20020059393A (ko) | 2002-07-12 |
SK3302002A3 (en) | 2002-07-02 |
IL148497A0 (en) | 2002-09-12 |
US6511990B1 (en) | 2003-01-28 |
PL200861B1 (pl) | 2009-02-27 |
EP1231919A2 (en) | 2002-08-21 |
US20070010669A1 (en) | 2007-01-11 |
BR0014254A (pt) | 2002-08-27 |
UA74345C2 (uk) | 2005-12-15 |
EA200200333A1 (ru) | 2002-10-31 |
WO2001018171A2 (en) | 2001-03-15 |
EP1231919A4 (en) | 2005-02-23 |
US20070010536A1 (en) | 2007-01-11 |
YU22402A (sh) | 2006-01-16 |
TR200201052T2 (tr) | 2003-01-21 |
MXPA02002505A (es) | 2004-09-10 |
NZ517613A (en) | 2004-01-30 |
PL364175A1 (en) | 2004-12-13 |
US20040002506A1 (en) | 2004-01-01 |
CA2383999A1 (en) | 2001-03-15 |
EA200601252A1 (ru) | 2006-10-27 |
HUP0202707A3 (en) | 2003-11-28 |
JP2003509343A (ja) | 2003-03-11 |
WO2001018171A3 (en) | 2002-06-27 |
AU6932700A (en) | 2001-04-10 |
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