CN1675232A - 用于药物发现的单糖衍生物 - Google Patents
用于药物发现的单糖衍生物 Download PDFInfo
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- CN1675232A CN1675232A CNA038191717A CN03819171A CN1675232A CN 1675232 A CN1675232 A CN 1675232A CN A038191717 A CNA038191717 A CN A038191717A CN 03819171 A CN03819171 A CN 03819171A CN 1675232 A CN1675232 A CN 1675232A
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- 229920005989 resin Polymers 0.000 claims description 41
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- 239000002243 precursor Substances 0.000 claims description 17
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- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 2
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- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
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- 239000010452 phosphate Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
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- 125000004001 thioalkyl group Chemical group 0.000 claims description 2
- 125000005000 thioaryl group Chemical group 0.000 claims description 2
- FZTIWOBQQYPTCJ-UHFFFAOYSA-N 4-[4-(4-carboxyphenyl)phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(O)=O)C=C1 FZTIWOBQQYPTCJ-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 15
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 53
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 40
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 235000000346 sugar Nutrition 0.000 description 25
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 15
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
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- 239000000243 solution Substances 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
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- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
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- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dithiothreitol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 4
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Abstract
用于制备潜在生物活性化合物的组合库的新化合物和方法基于式(I)的单糖,其为呋喃糖或吡喃糖形式的单糖衍生物。
Description
技术领域
本发明涉及基于天然与非天然单糖的用于制备潜在生物活性化合物的组合库的新化合物和方法。将这些化合物官能化,目的在于改变油溶性、大小、功能和其它性质,具体目标是发现新药物或类似药物的化合物,或者具有有用性质的化合物。本发明提供用于单糖的溶解或固相合成的中间体、方法和合成策略,所述单糖的糖环被不同地官能化,包括加入芳香性和电荷、加入药效基团和放置氨基酸和肽侧链单元或其电子等排体。
背景技术
在药物发现领域,一直需要能够合理设计潜在生物活性分子的新骨架。糖类近来已被研究来提供允许高度取代和获得功能和结构多样性的骨架来源。单糖分子的特性是存在多种不同的立体异构体,它们可以提供比目前用于药物发现的骨架更高程度的分子空间。
糖类单体主要含有羟基,但也可能含有其它官能团,如氨基和/或羧酸酯官能团。本质上,基于分子和结构多样性的通过糖类进行的药物发现中涉及的概念有两方面:(1)第一概念涉及利用在糖环周围发现的高官能团密度来显示几个不同的生物相关基团。这种取代存在如下双重意义:(i)环周围的取代基相对位置可以相对于彼此改变,和(ii)各单独的基团可以被一类这种基团取代,因而它们本身可以改变(例如:精氨酸模拟物可以在与其它肽模拟物有关的环周围的1、2、3、4或5位被取代,同理,精氨酸模拟物可以代表一类不同的精氨酸生物电子等排体,它们都可被类似地取代)。(2)第二个概念涉及利用糖异构体中固有的结构多样性。糖环周围的各取代基理论上可以轴向或平伏构型存在,其允许获得非常多样的分子空间。许多单糖是天然存在的,除了其本身可用外,它们还可以作为廉价的原料以获得更多奇异构型。
存在促进糖类作为药物发现的有用结构单元的其它因素,例如糖环上官能团的相对位置被方便地分隔,使得它们能够有效地模拟(例如)肽基序如肽转角和螺旋以及环肽。
在将单糖用作骨架的尝试中遇到的主要困难与单糖化学反应有关。在过去,认为糖化学反应是费力、耗时的,且不是低成本并有效的。特别地,认为允许自由接近任何一个单糖官能团(通常5个)所需的正交保护基团化学反应的程度太高以至于从不能以商业上可行的方式实现。作为必然的结果,更易实现的肽合成仅需要最多三个正交保护基,此外肽合成所需的条件一般是温和的,因此目前肽合成能够比糖类合成更容易地实现。幸运地,合成糖类化学反应的近来的发展已开始允许常规地获得作为分子骨架的糖类。在最近的专利申请(PCTAU00/00025)中,我们公开了一些适于寡糖合成的正交保护的结构单元。本申请提供的结构单元也适于用作合成本发明的化合物的中间体,并代表定义现有技术的化合物和方法。
现已在科学文献中公开了许多基于糖类的模板和骨架。一篇关于Gruner等人的主要贡献的综述(Chem.Rev.,2002,102,p491-514)突出这种活性。在该一般文献中,存在二种不同类型的糖模板(i)糖氨基酸和(ii)糖骨架。
糖氨基酸为含有胺官能团和羧酸官能团的糖类,并在肽型合成中代替氨基酸使用。用于此目的的单糖的合成的实例为Fleet(Tetrahedron,1996,52,p10711;Tetrahedron Assym.,1996,7,p387;Tetrahedron Assym.,1996,7,p157)和Le Merrer(Tet.Lett.,1995,36,p6887)关于呋喃型糖类的工作,以及Dondoni(J.Org.Chem.,1994,59,p6404)、Vogel(J.Carbohyd.Chem.,1994,13,p37)和Kessler(参见以上化学综述)关于吡喃型糖类的工作。
糖氨基酸已用于肽合成,并用于形成为不同生物目的的直链寡聚体(参见以上化学综述)。重要的是,所有这些化合物都含有与糖环直接连接的氨基官能团和羧酸酯官能团,且这些官能团在酰胺键形成中涉及,酰胺键形成是它们的应用的重要概念。这种类型的化合物明显不同于本发明的化合物。
糖类骨架也已在科学文献中受到相当的关注,至少是一种迫切的需要。在概念上,这些化合物提供手性骨架,在该骨架上呈现药学活性基团。这是本发明的领域,它加入并区别于现有技术。
糖类作为骨架的使用由Hirschmann和同事公布(Hirschmann等人,J.Am.Chem.Soc.,114,9217-9218,1992),他们采用这种概念开发有效的NK-1受体拮抗剂(Hirschmann等人,J.Am.Chem.Soc.,115,12550-12568,1993)、(Hirschmann等人,J.Med.Chem.,39,2441-2448,1996)。这项工作的基本原理也已由Hirschmann等人申请专利(PCT/US1994/012233)。
以类似的方式,Papageorgiou等人已将该概念应用于呋喃型结构,在该过程中研制出弱的促生长素抑制素抑制剂(Papageorgiou等人,Bioorg.Med.Chem.Lett.,2,135-140,1992)。
整联蛋白受体和内皮缩血管肽受体的弱抑制剂也已通过应用这种概念而开发出(Nicolaou,K.C.等人,Tetrahedron,1997,53,p8751;Moitessier,N.等人,Lett.Pep.Sci.,1998,5,p75;Moitessier,N.等人,Bioorg.Med.Chem.,2001,9,p511)。
许多其它研究组已开发了基于这种骨架元素的化合物库,这些研究组在Gruner的综述(见上)中提到。尽管迄今已进行过多的工作,但以上公开的化合物具有区别于目前工作的三个共同特征:(i)所有取代基均通过氧键连接到骨架上,(ii)端基异构位置总是O糖苷,和(iii)所有存在的羟基位置均被取代。
这些特征,当组合在一起时,明显限制化合物的应用。例如,醚键提供相当大的旋转自由度,而一般认为旋转自由度通常导致生物活性降低(Murphy等人,J.Org.Chem.,68,5692-5704,2003)。为此,本发明涉及具有一个或两个直接连接到糖环上的胺的糖模板,例如它允许引入酰胺连接的基团、磺酰胺连接的基团、脲连接的基团和氨基甲酰基连接的基团,它们具有明显降低的旋转自由度和一般而言更好的物理性质。
以类似的方式,所有要取代的位置的要求可以导致更高亲脂性、更高分子量和更低溶解度且不带来更高生物活性的化合物。在本发明中,我们公开具有一个或两个未被取代的羟基位置的化合物,它们通常允许改善溶解特征和降低分子量,这对相应的完全取代的分子而言将会预期到。
这两个特征代表对文献中所述化合物的显著改善,并且是本发明的发明人作出的显著的新方法发展的结果。
在迄今的科学和专利文献中所报道的所有糖类骨架工作中,我们几乎没有发现含糖氨基酸种类之外的含胺骨架的实例。Kunz等人(WO 99/07718)要求保护作为用于药物发现的骨架的2-脱氧2-氨基糖。此引文没有教导或例证在两个位置或任何其它位置具有与环直接连接的胺基的化合物。
Kunz的公开具体涉及葡萄糖、半乳糖和甘露糖作为骨架的使用,且所述的方法一般不适用于其它单糖骨架。相比而言,本发明的化合物都为O糖苷,它们进一步受到由在所公开的合成条件下糖羟基的低反应性支配的少数几种未取代的取代基的限制。显然这种技术相对于本发明表现出明显的缺点;本发明的转化效率、可能取代基的范围、引入候选的氧和氨基立体化学取向的各种反转化学反应和通用的烷基化化学反应代表相对于Kunz申请的方法而言的显著改进。特别地,本发明提供在单糖或四氢呋喃/吡喃环系统的3、4、5和6位具有连接到环上的氮或碳原子的单糖立体异构体。对于药物化学家来说特别感兴趣的是包括这样的连接官能团,其可能对生理条件稳定,从而使药物完整地或以活性形式到达理想的靶。
尽管文献中提到通常极少量的含有胺的糖骨架,但仍有许多用于寡糖合成的单糖结构单元和被保护的氨基糖的实例。例如,US4818816公开了用于合成的类肝素寡聚体的合成的单糖结构单元,化合物1-甲基-2-苄氧羰基,3-苄基葡糖胺。本发明的化合物在可获得的多样性和复杂性方面均明显不同于简单的结构单元型氨基糖。为了进一步将本发明的化合物与现有技术区别开,在糖类合成中特别排除标准胺保护基的使用。
Sabesan(美国专利5220008)公开了一系列作为流感抑制剂的高级寡糖。在这篇专利的权利要求书中还公开了被部分保护的单糖(结构IV)。这种结构的化合物是用于寡糖合成的被保护的单糖,其在现有技术中是已知的,不代表用于药物发现的化合物。
类似地,Alchemia Pty Ltd在PCT/AU01/01307中公开了涉及使用单糖化合物作为类似药物的分子的结构单元、合成方法和最终产物。PCT/AU01/01307的化合物具体涉及酶的胞壁酰级联抑制剂,因此通过引用这篇文献而未将其包括在说明书中。许多其它涉及胞壁酰型化合物的出版物出现在该文献中。Liu等人(Biorg.Med Chem Lett.,10,2000,1361-1363)提供了一系列含有端基异构位置的苄基糖苷、葡糖胺骨架C-2位的乙酸酯和C-3位的肽同一的乳酸酯(peptidehomologated lactate)的化合物。这些化合物和Xiao(Peptides:Biol andChem.,Proc.5th Int.Chinese Peptide Symp.,1998 CA:134:178795)公开的化合物代表有助于定义糖类化学的领域但与本发明小直接相关的化合物和方法。
可以清楚地理解,如果本文提及现有技术出版物,则这种引用并不是承认该出版物构成在澳大利亚或任何其它国家的该领域的公知常识的一部分。
发明内容
在第一方面,本发明包括式I的化合物,其为呋喃糖或吡喃糖形式的单糖衍生物,
式I
其中,
n为0或1;
R1为XR,其中,
X选自O、S、S=O和SO2,
R选自C1-C9烷基、C1-C15链烯基、C1-C15炔基、C1-C15杂烷基、C6-C15芳基、C6-C15杂芳基、C6-C15芳基烷基或C6-C15杂芳基烷基,它们任选被取代、为环状或非环状、支链和/或直链,
基团R2-R5选自OH、OR和N(Y)Z,从而:
基团R2-R5中至少一个和基团R2-R5中不多于两个为OH,基团R2-R5中至少一个和基团R2-R5中不多于两个为OR,其中R如以上定义,条件是当基团R2-R5中两个为OR时,R基团不可以都为甲基或未取代的苄基,
基团R2-R5中至少一个和基团R2-R5中不多于两个为N(Y)Z,其中Z选自氢或R,而Y选自以下,其中G指与N(Y)Z中的氮原子连接的点,N(Y)Z基团不可以相同;
基团Q和W独立地选自氢或如以上定义的R,且Q和W可以结合形成环,
基团Z和Y可以结合形成环,
基团R1-R5不可以结合在一起形成环。
在更特定的形式中,本发明涉及上述的化合物,条件是当式I的化合物中的两个基团为N(Y)Z时,这些基团不同,进一步条件是当R2或R5为N(Y)Z时,N(Y)Z不可以为叠氮基、乙酰基、苄氧羰基或叔丁氧羰基,进一步条件是当R2为N(Y)Z时,N(Y)Z不可以为苯二甲酰亚氨基、4-[N-[1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基丁基]-氨基}苄酯(ODmab)、N-1-(4,4-二甲基-2,6-二氧代亚环己基)乙基(Dde)、2,2,2-三氯乙氧羰基(Troc)、9-芴基甲氧羰基(Fmoc)或5-酰基-1,3-二甲基巴比妥酸酯型保护基(DTPM),进一步条件是当骨架为2-脱氧-2-氨基葡萄糖构型且R5和R4均为羟基时,R3不可以为甘醇酸酯[-CH2-CO2H]或乳酸酯醚[-CH(CH3)-CO2H]或者它们的酯或酰胺衍生物。
适宜地,该化合物为呋喃糖形式的单糖衍生物,且其中n为0。
适宜地,该化合物为呋喃糖形式的单糖衍生物,且其中n为0。
适宜地,该化合物n=1,基团R2-R5中至少一个和基团R2-R5中不多于两个为N(Y)Z,其中Z选自氢或R,而Y选自以下,其中G指与N(Y)Z中的氮原子连接的点,N(Y)Z部分不可以相同;
基团Q和W独立地选自氢或如以上定义的R,条件是Y和Z不可以都为氢,且当式I的化合物中的两个基团为N(Y)Z时,这些基团不同,基团Z和Y可以结合形成环,基团R1-R5不可以结合在一起形成环,条件是当式I的化合物中的两个基团为N(Y)Z时,这些基团不同,进一步条件是当R2或R5为N(Y)Z时,N(Y)Z不可以为叠氮基、乙酰基、苄氧羰基或叔丁氧羰基,进一步条件是当R2为N(Y)Z时,N(Y)Z不可以为苯二甲酰亚氨基、4-[N-[1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基丁基]-氨基}苄酯(ODmab)、N-1-(4,4-二甲基-2,6-二氧代亚环己基)乙基(Dde)、2,2,2-三氯乙氧羰基(Troc)、9-芴基甲氧羰基(Fmoc)或5-酰基-1,3-二甲基巴比妥酸酯型保护基(DTPM),进一步条件是当骨架为2-脱氧-2-氨基葡萄糖构型且R5和R4均为羟基时,R3不可以为甘醇酸酯[-CH2-CO2H]或乳酸酯醚[-CH(CH3)-CO2H]或者它们的酯或酰胺衍生物。
适且地,该杂芳基烷基被选自以下的基团取代:OH、NO、NO2、NH2、N3、卤素、CF3、CHF2、CH2F、腈、烷氧基、芳氧基、脒、胍盐、羧酸、羧酸酯、羧酸酰胺、芳基、环烷基、杂烷基、杂芳基、氨基烷基、氨基二烷基、氨基三烷基、氨基酰基、羰基、取代或未取代的亚胺、硫酸酯、磺酰胺、磷酸酯、磷酰胺、酰肼、异羟肟酸酯、异羟肟酸、杂芳氧基、氨基烷基、氨基芳基、氨基杂芳基、硫代烷基、硫代芳基或硫代杂芳基,它们可以进一步被取代,条件是基团R不可以为或含有另一糖基团、肽、蛋白或氨基酸。
该化合物可以固定在载体上。该载体可以是可溶性或不溶性的。不溶性载体的非限制性实例包括衍生聚苯乙烯、tentagel、wang树脂、MBHA树脂、氨基甲基聚苯乙烯、rink酰胺树脂等。可溶性载体的非限制性实例包括DOX-mpeg、聚乙二醇等。
具体实施方式
参照以下实施例描述本发明的实施方案。如果合适的话,使用以下缩写。
Ac 乙酰基
DTPM 5-酰基-1,3-二甲基巴比妥酸酯
Ph 苯基
TBDMS 叔丁基二甲基甲硅烷基
TBDPS 叔丁基二苯基甲硅烷基
Bn 苄基
Bz 苯甲酰基
Me 甲基
DCE 1,2-二氯乙烷
DCM 氯甲烷
Tf 三氟甲磺酰基
Ts 4-甲基苯基磺酰基,对甲苯磺酰基
DMF N,N-二甲基甲酰胺
DMAP N,N-二甲基氨基吡啶
.-DMT .-二甲氧基甲苯,苯甲醛二甲基缩醛
DMSO 二甲亚砜
DTT 二硫苏糖醇
DMTST 二甲基(甲硫基)锍三氟-甲磺酸盐
TBAF 四正丁基氟化铵
部分A:制备结构单元:
为了能够完全实施本发明,我们以下详细描述在本发明的化合物的制备中所用的某些结构单元的制备方法。所述的结构单元适于溶液和固相合成本发明的化合物。
实施例A:合成含2,4-二氮的吡喃半乳糖苷结构单元
条件:(i).-二甲氧基甲苯(.-DMT),对甲苯磺酸(TsOH),乙腈(MeCN),76℃,85%;(ii)苯甲酰氯(BzCl),三乙胺;DCM,99%;(iii)甲醇(MeOH)/MeCN/水,TsOH,75℃,98%;(iv)叔丁基二苯基甲硅烷基氯(TBDPS-Cl),咪唑,吡啶,120℃,99%;(v)Tf2O,吡啶,DCM,0℃,100%;(b)NaN3,DMF,16hr,RT,99%。
实施例B:合成含3-氮吡喃葡糖苷结构单元
条件:(i)(a)三氟甲磺酸酐(Tf2O),吡啶,-20℃,二氯甲烷(DCM),1小时,100%,(b)叠氮化钠(NaN3),N,N-二甲基甲酰胺(DMF),50℃,5小时,定量;(ii)TsOH,MeCN/MeOH/水(12∶3∶1),90℃,6小时,88%(iii)TBDPSCl,DMAP,吡啶,120℃,12小时,93%。
实施例C:合成2,6-二氮取代的吡喃葡糖苷结构单元
条件:(i)(a)甲苯磺酰氯,吡啶,RT,24小时,33%(b)NaN3,DMF,RT,168小时。
实施例D:合成含2-氮的Tallopyranoside结构单元
条件:(i)TBDPSCl,咪唑,1,2-DCE,回流;(ii)NaOMe/MeOH;(iii)(a)Tf2O,吡啶,-20℃,DCM,1小时,(b)NaN3,DMF,50℃,5小时;(iv)TsOH,MeCN/MeOH/水;(v)苯甲酰氯,DMAP,1,2-DCE,-20℃。
实施例E:合成含两个3-氮的吡喃阿卓糖苷结构单元
条件:(i)环己酮二甲基缩醛,TsOH,MeCN;(ii)对甲氧基苯甲醛二甲基缩醛,TsOH,MeCN;(iii)DIBAL,-78℃,乙醚;(iv)(a)Tf2O,吡啶,-20℃,DCM,1小时,(b)NaN3,DMF,50℃,5小时;(v)TsOH,MeCN/MeOH/水;(vi)TBDPSCl,DMAP,1,2-DCE;(vii)(a)CAN,(b)BzCl,DMAP,1,2-DCE,(c)TsOH,MeCN/MeOH/水;(viii)TBDPSCl,DMAP,1,2-DCE。
实施例F:合成含2-氮的吡喃葡糖苷结构单元
条件:(i).-DMT,TsOH,MeCN;(ii)1,2-DCE,BzCl,DMAP;(iii)TsOH,MeOH/MeCN;(iv)TBDPS-Cl,DMAP,1,2-DCE。
条件:(i)TBDPSCl,DMAP,吡啶,1200℃,0.5小时,81%;(ii)a.(Bu)2SnO,MeOH;b.苯甲酰氯,RT,24小时;
实施例G:合成含2-氮的吡喃阿洛糖苷结构单元
条件:(i)DCM/吡啶,MsCl,DMAP,0℃;(ii)苯甲酸钠,二甲亚砜(DMSO),140℃;(iii)TsOH,MeOH/MeCN/水;(iv)TBDPS-Cl,咪唑,DCM,1小时,回流。
实施例H:合成含3-氮的吡喃阿洛糖苷结构单元
条件:(i)Tf2O,吡啶,DCM;(b)NaN3,DMF;(ii)丙酮,H+;(iii)Ac2O,吡啶;(iv)六甲基二硅氮烷,I2,CH3-S-S-CH3;(v)NaOMe/MeOH;(vi)TsOH,.-二甲氧基甲苯,MeCN;(vii)苯甲酰氯,1,2-DCE,吡啶,DMAP;(viii)TsOH,MeOH,H2O,MeCN;(ix)TBDPS-Cl,咪唑,1,2-DCE。
实施例I:合成含两个2-氮并在3或4位具有羟基的Tallopyranoside
结构单元
条件:(i)(a)Tf2O/Py,(b)NaN3,DMF;(ii)TsOH,MeOH/MeCN/水;(iii)BzCl,DMAP,1,2-DCE;(iv)(a)苯氧乙酰基-Cl(PACl)/吡啶;(b)Bz2O/吡啶;(v)MeNH2/THF。
实施例J:合成含氮呋喃糖苷结构单元
条件:(i)(a).2,2-二甲氧基丙烷,TsOH,DMF;(b).TBDPSi-Cl,咪唑,DMF;(ii)(a)Tf2O/Py,(b)NaN3,DMF;(iii)(a)TsOH,MeOH/MeCN/水;(b)苯甲酰氯,吡啶,DCM;(iv)4-甲氧苄基氯,NaH,DMF;(v)(a)TBAF,THF;(b)Tf2O/Py,(c)NaN3,DMF;(d)TsOH,MeOH/MeCN/水;(e)苯甲酰氯,吡啶,DCM;(vi)(a)TsOH,MeOH/MeCN/水;(b)苯甲酰氯,吡啶,DCM;(c)R-OH或R-SH,三氟化硼乙醚化物,DCM,分子筛;(d)Tf2O/Py,(e)NaN3,DMF;
实施例K:合成含3-氮的吡喃葡糖苷结构单元
条件:(i)(a)三氟甲磺酸酐(Tf2O),吡啶,-20℃,二氯甲烷(DCM),1小时,100%,(b)叠氮化钠(NaN3),N,N-二甲基甲酰胺(DMF),50℃,5小时,定量;(ii)NaOH/H2O/THF/MeOH,99%;(iii)乙酰丙酸,N,N’-二环己基二酰亚胺,DMAP,DCM,定量;(iv)TsOH,MeCN/MeOH/水(15∶15∶1),50℃,16小时,56%;(v)TBDPSCl,DMAP,吡啶,120℃,2小时,85%;(vi)苯甲酰氯,吡啶,RT,2小时,95%;(vii)乙酸肼,DCM。
部分B:固定到固体载体上和糖基化:
本发明的化合物可以方便地在溶液相或固体载体上制备。由于本发明的化合物中总是存在游离羟基,因而方便通过羟基官能团将结构单元固定在固体载体上,该羟基官能团在最终化合物中变成游离羟基。许多上述的结构单元具有适于固定的4位羟基。当需要游离羟基在不同位置时,首先进行保护/脱保护程序。
实施例L:候选固定位置
条件:(i)4-甲氧基苄基氯,NaH,DMF,用柠檬酸收集(workup);(ii)NaOMe/MeOH/THF;(iii)TBAF/THF;HOAc至中性pH。
实施例M:端基异构位置的糖基化
在大部分情况下,含有一个游离羟基的硫代甲基糖苷结构单元可以用于糖基化反应而不采用游离羟基保护。通常使用过量的醇受体。当要将硫醇糖基化时,受体醇供应不足,否则结果不令人满意,硫代甲基糖苷供体可能首先被转化成溴代糖或亚氨酸酯(imidate),这些供体用于糖基化。或者,如果用游离羟基供体如K-3、K-4、G-4观察到明显的副反应的话,则糖基化可以用被完全保护的前体,如K-2实现。
在典型方法中,将1mmol供体(例如G-4、K-2、K-3、K-4、A-6、B-4、C-1等)溶于无水二氯甲烷8mL中,并加入等重的干燥4A分子筛。将混合物在室温下搅拌30分钟,然后加入4mmol受体醇,接着加入DMTST溶液(6当量,在12ml DCM中)。通过t.l.c监测反应。当反应完成时,加入三乙胺(1.2mmol)。用100mL二氯甲烷稀释混合物,并用碳酸氢钠(10%水溶液)、柠檬酸(10%水溶液)和氯化钠(饱和溶液)萃取,用硫酸镁干燥,并在真空下除去溶剂。用硅胶色谱处理粗产物,然后进行固定,或者在K-2的情况下除去一个醇保护基。
在一个候选方法中,首先用溴处理在二氯甲烷8mL中的1mmol供体,得到粗糖卤化物。用5%硫代硫酸钠简短地洗涤此溶液,用硫酸镁干燥,并在真空下除去溶剂。将粗糖卤化物直接如上述与作为代替DMTST的活化剂的三氟甲磺酸银(silver triflate)一起使用。通过这种方法可将醇和硫醇都糖基化。
实施例N:固定在固相上
在真空烘箱中在500ml圆底烧瓶内将Wang树脂(13.3g;0.85mmol/g,对苄氧基苄醇聚苯乙烯-二乙烯基苯树脂)干燥过夜。将烧瓶放置在氮气氛下,然后加入无水DCM(133ml)和三氯乙腈(20ml)。用冰浴冷却混合物,同时轻轻搅拌。冷却15分钟后在15分钟内滴加DBU(1.3ml),将所得混合物在冰浴冷却下搅拌1小时。过滤收集树脂,用DMF、THF和DCM(各三次)洗涤。在真空烘箱中用P2O5将树脂干燥24小时,得到15克三氯亚氨逐乙酸酯(TriChloroAcetimidate)Wang(TCA-Wang)树脂。在氮气氛下包装树脂并在4℃下贮存。收率100%;装载约0.754mmol/g。
(可以使用候选的树脂)。
将含有一个游离羟基的糖基化结构单元固定在TCA-Wang树脂上。在典型方法中,在真空烘箱中将TCA Wang树脂(3.6克)干燥过夜,然后在氮气氛下用无水THF(3×36ml)洗涤。加入结构单元(3当量),然后加入无水DCM(18ml)。将反应混合物振荡5分钟(直至所有醇溶解),并加入BF3.Et2O(0.35ml,1当量)。将反应混合物剧烈振荡10分钟并排干;用DCM(3×30ml)、DMF(3×30ml)、THF(3×30ml)洗涤树脂并干燥。
部分C:库制备:
通过顺续脱保护和在固体载体或溶液相中的接合化学反应来制备本发明的化合物。可以根据需要使用以下典型化学反应。
除去叔丁基二苯基甲硅烷基:
将树脂结合的结构单元悬浮在含有10当量四正丁基氟化铵的无水THF/甲醇(20/1 v/v)中。将混合物在65℃下搅拌24小时,排干;将树脂过滤,用二甲基甲酰胺洗涤,然后用THF洗涤,最后用二氯甲烷洗涤。在候选的方法中,可以方便地用HF.吡啶代替TBAF,并在塑料器皿中实现反应。还可以用HF.“质子海绵”复合物代替TBAF,结果良好。
除去苯甲酸酯、对氯苯甲酸酯或其它酯保护基:
将树脂结合的结构单元悬浮在无水THF和甲醇(3/1 v/v)混合物中,并加入甲醇钠(0.5当量)。将混合物振荡24小时,排干,进一步用新鲜的试剂再处理24小时。将树脂过滤,用二甲基甲酰胺洗涤,然后用THF洗涤,最后用二氯甲烷洗涤。
除去对甲氧基苄基:
将树脂结合的结构单元悬浮在DCM中,并加入少量水(大约1%),然后加入2,3-二氯-5,6-二氰基苯醌(10当量)。将混合物振荡3小时,排干,进一步用新鲜的试剂再处理3小时。将树脂过滤,用THF洗涤,然后用甲醇洗涤,最后用二氯甲烷洗涤。
酯化羟基位置:
将先前羟基己脱保护的树脂结合的结构单元洗涤三次,然后悬浮在无水DMF中,加入3当量叔丁醇钾(可以使用候选的碱),振荡,在5分钟后排干,然后加入在DMF中的烷基化试剂(3当量)。将混合物振荡10分钟,排干,并如上述用新鲜试剂再处理两次。将树脂过滤,用二甲基甲酰胺洗涤,然后用THF洗涤,最后用二氯甲烷洗涤。
还原叠氮化物:
将树脂结合的结构单元悬浮在无水DMF中;加入5当量DTT(1,4-二硫代-DL-苏糖醇)和3当量叔丁醇钾(可以使用候选的碱)。将混合物于氮气氛下搅拌24小时,排干,用二甲基甲酰胺洗涤树脂,然后用THF洗涤,最后用二氯甲烷洗涤。
除去DTPM基团:
将树脂结合的结构单元悬浮在DMF和水合肼(50/1 v/v)混合物中,搅拌2小时,排干,用二甲基甲酰胺洗涤树脂,然后用THF洗涤,最后用二氯甲烷洗涤。
酰胺形成:
用HBTU(10当量)和二异丙基乙胺(10当量)处理在无水DMF中的适宜的羧酸(10当量)的溶液,并振荡5分钟。然后将此溶液加入在DMF中的先前胺基团己脱保护的树脂结合的结构单元的悬浮液中,并将混合物振荡30分钟。然后将树脂排干,再用新鲜的试剂处理30分钟。将树脂过滤,用DMF洗涤,然后用甲醇洗涤,最后用二氯甲烷洗涤。如果需要的话,可以进行定量茚三酮测定以确定反应完成。可以使用包括HOAT、EDC/NHS或酸酐的候选的偶联系统达到类似的效果。
脲和硫脲形成:
异氰酸酯和异硫氰酸酯可以购买或适宜地通过相应的胺与三光气、双光气、光气或硫光气根据“Organic Functional Group Preparation”Vol I,2nd Ed.,Sandler和Karo,Academic Press,ISBN:0-12-618601-4pp 359-375所概括的标准方法进行反应来制备。
将先前胺基团己脱保护的树脂结合的结构单元悬浮在无水THF中,并加入2当量异氰酸酯或异硫氰酸酯,然后立即加入三乙胺(1当量)。将混合物振荡2小时,并可以放热,这取决于所用的异氰酸酯或异硫氰酸酯的规模和反应性,排干,进一步用新鲜的试剂再处理2小时。将树脂过滤,用THF洗涤,然后用甲醇洗涤,最后用二氯甲烷洗涤。
氨基甲酸酯形成:
氯甲酸酯和亚氨甲酸酯(imidoylformate)可以购买或适宜地通过相应的醇与光气或羰基二咪唑根据“Organic Functional GroupPreparation”Vol I,2nd Ed.,Sandler和Karo,Academic Press,ISBN:0-12-618601-4pp 359-375所概括的标准方法进行反应来制备。
将先前胺基团已脱保护的树脂结合的结构单元悬浮在无水THF中,并加入2当量氯甲酸酯或亚氨甲酸酯,然后立即加入三乙胺(1当量)。将混合物振荡2小时,并可以放热,这取决于所用的异氰酸酯或异硫氰酸酯的规模和反应性,排干,进一步用新鲜的试剂再处理2小时。将树脂过滤,用THF洗涤,然后用甲醇洗涤,最后用二氯甲烷洗涤。
磺酰胺形成:
将先前胺基团已脱保护的树脂结合的结构单元悬浮在无水THF或DMF中,并加入2当量磺酰氯,然后立即加入三乙胺(2当量)。将混合物振荡2小时,排干,进一步用新鲜的试剂再处理2小时。将树脂过滤,用THF或DMF洗涤,然后用甲醇洗涤,最后用二氯甲烷洗涤。
除去Fmoc:
将树脂结合的结构单元悬浮在哌啶/DMF(1/4,v/v)混合物中,搅拌1小时,排干,再重复一次;将树脂过滤,用二甲基甲酰胺洗涤,然后用THF洗涤,最后用二氯甲烷洗涤。
胍形成:
将树脂结合的结构单元悬浮在含有3当量3,5-二甲基吡唑基甲脒鎓硝酸盐和15当量DIPEA的无水DMF中。将混合物于65℃下搅拌24小时,排干;将树脂过滤,用二甲基甲酰胺洗涤,然后用THF洗涤,最后用二氯甲烷洗涤。
裂解树脂结合的产物:
将树脂结合的化合物悬浮在含有20%TFA和20%Et3SiH的无水DCM中。将混合物于RT下搅拌3小时,并收集等分试样;用无水DCM洗涤树脂,合并所有的DCM溶液,在减压真空下蒸发至干,得到目标产物。
本发明的化合物库已基于以下骨架得到制备:
衍生自A-6的骨架W1 衍生自B-4或K-8的骨架W2
衍生自C-1的骨架W3 衍生自D-5或I-6的骨架W4
衍生自E-9和E-7的骨架W5 衍生自F-5或F-7的骨架W6
衍生自G-4的骨架W7 衍生自H-9的骨架W8
衍生自J-4的骨架W9 衍生自J-6的骨架W10
衍生自J-7的骨架W11
以下基团为在位置R1的基团的实例,其中波浪线表示与糖环连接的点:
以下基团是醚连接基团的实例,其中波浪线表示与糖环上的氧连接的点:
Y1 Y2
Y21 Y22 Y23
以下基团是胺连接基团的实例,其中波浪线表示与糖环上的氮连接的点:
库化合物实例:
化合物号 | 骨架 | R1 | R2 | R3 | R4 | R5 |
1 | W6 | X1 | Z43 | Y3 | OH | Y21 |
2 | W6 | X1 | Z44 | Y3 | OH | Y22 |
3 | W6 | X1 | Z45 | Y3 | OH | Y23 |
4 | W6 | X1 | Z46 | Y3 | OH | Y24 |
5 | W6 | X1 | Z47 | Y3 | OH | Y25 |
6 | W6 | X1 | Z48 | Y3 | OH | Y26 |
7 | W6 | X1 | Z49 | Y3 | OH | Y27 |
8 | W6 | X1 | Z50 | Y3 | OH | Y28 |
9 | W6 | X1 | Z51 | Y3 | OH | Y29 |
10 | W6 | X1 | Z52 | Y3 | OH | Y30 |
11 | W6 | X1 | Z53 | Y3 | OH | Y21 |
12 | W6 | X1 | Z54 | Y3 | OH | Y22 |
13 | W6 | X1 | Z55 | Y3 | OH | Y23 |
14 | W6 | X1 | Z56 | Y3 | OH | Y24 |
15 | W6 | X1 | Z57 | Y3 | OH | Y25 |
16 | W6 | X1 | Z58 | Y3 | OH | Y26 |
17 | W6 | X1 | Z59 | Y3 | OH | Y27 |
18 | W6 | X1 | Z60 | Y3 | OH | Y28 |
19 | W6 | X3 | Z12 | Y9 | OH | Y29 |
20 | W6 | X3 | Z29 | Y9 | OH | Y30 |
21 | W6 | X3 | Z12 | Y9 | OH | Y12 |
22 | W6 | X3 | Z29 | Y9 | OH | Y12 |
23 | W6 | X3 | Z13 | Y9 | OH | Y8 |
24 | W6 | X3 | Z26 | Y9 | OH | Y8 |
25 | W6 | X3 | Z13 | Y3 | OH | Y10 |
26 | W6 | X3 | Z26 | Y3 | OH | Y10 |
27 | W6 | X4 | Z3 | Y3 | OH | Y8 |
28 | W6 | X4 | Z17 | Y3 | OH | Y8 |
29 | W6 | X4 | Z3 | Y3 | OH | Y10 |
30 | W6 | X4 | Z17 | Y3 | OH | Y10 |
31 | W6 | X4 | Z12 | Y3 | OH | Y9 |
32 | W6 | X4 | Z29 | Y3 | OH | Y9 |
33 | W6 | X4 | Z3 | Y12 | OH | Y8 |
34 | W6 | X4 | Z17 | Y12 | OH | Y8 |
35 | W6 | X4 | Z3 | Y12 | OH | Y10 |
36 | W6 | X4 | Z17 | Y12 | OH | Y10 |
37 | W6 | X4 | Z12 | Y12 | OH | Y9 |
38 | W6 | X4 | Z29 | Y12 | OH | Y9 |
39 | W6 | X4 | Z3 | Y8 | OH | Y3 |
40 | W6 | X4 | Z17 | Y8 | OH | Y3 |
41 | W6 | X4 | Z3 | Y8 | OH | Y12 |
42 | W6 | X4 | Z17 | Y8 | OH | Y12 |
43 | W6 | X4 | Z13 | Y8 | OH | Y9 |
44 | W6 | X4 | Z26 | Y8 | OH | Y9 |
45 | W6 | X4 | Z3 | Y10 | OH | Y3 |
46 | W6 | X4 | Z17 | Y10 | OH | Y3 |
47 | W6 | X4 | Z3 | Y10 | OH | Y12 |
48 | W6 | X4 | Z17 | Y10 | OH | Y12 |
49 | W6 | X4 | Z13 | Y10 | OH | Y9 |
50 | W6 | X4 | Z26 | Y10 | OH | Y9 |
51 | W6 | X4 | Z12 | Y9 | OH | Y3 |
52 | W6 | X4 | Z29 | Y9 | OH | Y3 |
53 | W6 | X4 | Z12 | Y9 | OH | Y12 |
54 | W6 | X4 | Z29 | Y9 | OH | Y12 |
55 | W6 | X4 | Z13 | Y9 | OH | Y9 |
56 | W6 | X4 | Z26 | Y9 | OH | Y9 |
57 | W6 | X4 | Z13 | Y9 | OH | Y10 |
58 | W6 | X4 | Z26 | Y9 | OH | Y10 |
59 | W6 | X4 | Z3 | Y2 | OH | Y8 |
60 | W6 | X4 | Z17 | Y2 | OH | Y8 |
61 | W6 | X4 | Z3 | Y2 | OH | Y10 |
62 | W6 | X4 | Z17 | Y2 | OH | Y10 |
63 | W6 | X4 | Z12 | Y2 | OH | Y9 |
64 | W6 | X4 | Z29 | Y2 | OH | Y9 |
65 | W6 | X4 | Z3 | Y8 | OH | Y1 |
66 | W6 | X10 | Z17 | Y8 | OH | Y1 |
67 | W6 | X10 | Z3 | Y8 | OH | Y2 |
68 | W6 | X10 | Z17 | Y8 | OH | Y2 |
69 | W6 | X10 | Z1 | Y8 | OH | Y9 |
70 | W6 | X10 | Z4 | Y8 | OH | Y9 |
71 | W6 | X10 | Z3 | Y10 | OH | Y1 |
72 | W6 | X10 | Z17 | Y10 | OH | Y1 |
73 | W6 | X10 | Z3 | Y10 | OH | Y2 |
74 | W6 | X10 | Z17 | Y10 | OH | Y2 |
75 | W6 | X10 | 71 | Y10 | OH | Y9 |
76 | W6 | X10 | Z4 | Y10 | OH | Y9 |
77 | W6 | X10 | Z12 | Y9 | OH | Y1 |
78 | W6 | X10 | Z29 | Y9 | OH | Y1 |
79 | W6 | X10 | Z12 | Y9 | OH | Y2 |
80 | W6 | X10 | Z29 | Y9 | OH | Y2 |
81 | W6 | X10 | Z1 | Y9 | OH | Y9 |
82 | W6 | X10 | Z4 | Y9 | OH | Y9 |
83 | W6 | X15 | Z11 | Y1 | OH | Y17 |
84 | W6 | X15 | Z4 | Y9 | OH | Y10 |
85 | W8 | X6 | Y8 | Z33 | OH | Y9 |
86 | W8 | X6 | Y10 | Z24 | OH | Y19 |
87 | W8 | X6 | Y7 | Z18 | OH | Y12 |
88 | W8 | X9 | Y9 | Z25 | OH | Y3 |
89 | W8 | X9 | Y19 | Z1 | OH | Y4 |
90 | W8 | X9 | Y12 | Z20 | OH | Y13 |
91 | W8 | X12 | Y3 | Z25 | OH | Y17 |
92 | W8 | X12 | Y4 | Z20 | OH | Y11 |
93 | W8 | X12 | Y13 | Z20 | OH | Y18 |
94 | W8 | X10 | Y17 | Z36 | OH | Y8 |
95 | W8 | X10 | Y11 | Z42 | OH | Y10 |
96 | W8 | X10 | Y18 | Z18 | OH | Y13 |
97 | W1 | X6 | Z33 | Y4 | Z37 | OH |
98 | W1 | X6 | Z37 | OH | Z33 | Y3 |
99 | W1 | X6 | Z42 | OH | Z18 | Y3 |
100 | W1 | X9 | Z33 | Y4 | Z37 | OH |
101 | W1 | X9 | Z37 | OH | Z33 | Y3 |
102 | W1 | X9 | Z42 | OH | Z18 | Y3 |
103 | W1 | X12 | Z33 | Y4 | Z37 | OH |
104 | W1 | X12 | Z37 | OH | Z33 | Y3 |
105 | W1 | X12 | Z42 | OH | Z18 | Y3 |
106 | W6 | X12 | Z11 | Y5 | OH | Y1 |
107 | W6 | X12 | Z16 | Y5 | OH | Y1 |
108 | W6 | X12 | Z5 | Y5 | OH | Y1 |
109 | W6 | X12 | Z11 | Y17 | OH | Y1 |
110 | W6 | X12 | Z16 | Y17 | OH | Y1 |
111 | W6 | X12 | Z5 | Y17 | OH | Y1 |
112 | W6 | X12 | Z11 | Y3 | OH | Y1 |
113 | W6 | X12 | Z16 | Y3 | OH | Y1 |
114 | W6 | X12 | Z5 | Y3 | OH | Y1 |
115 | W6 | X12 | Z11 | Y4 | OH | Y1 |
116 | W6 | X12 | Z16 | Y4 | OH | Y1 |
117 | W6 | X12 | Z5 | Y4 | OH | Y1 |
118 | W6 | X9 | Z11 | Y5 | OH | Y1 |
119 | W6 | X9 | Z16 | Y5 | OH | Y1 |
120 | W6 | X9 | Z5 | Y5 | OH | Y1 |
121 | W6 | X9 | Z11 | Y17 | OH | Y1 |
122 | W6 | X9 | Z16 | Y17 | OH | Y1 |
123 | W6 | X9 | Z5 | Y17 | OH | Y1 |
124 | W6 | X9 | Z11 | Y3 | OH | Y1 |
125 | W6 | X9 | Z16 | Y3 | OH | Y1 |
126 | W6 | X9 | Z5 | Y3 | OH | Y1 |
127 | W6 | X9 | Z11 | Y4 | OH | Y1 |
128 | W6 | X9 | Z16 | Y4 | OH | Y1 |
129 | W6 | X9 | Z5 | Y4 | OH | Y1 |
130 | W6 | X12 | Z11 | Y1 | OH | Y5 |
131 | W6 | X12 | Z16 | Y1 | OH | Y5 |
132 | W6 | X12 | Z5 | Y1 | OH | Y5 |
133 | W6 | X19 | Z28 | Y1 | OH | Y3 |
134 | W6 | X19 | Z13 | Y1 | OH | Y17 |
135 | W6 | X19 | Z13 | Y17 | OH | Y1 |
136 | W6 | X3 | Z29 | Y12 | OH | Y9 |
137 | W6 | X3 | Z17 | Y8 | OH | Y3 |
138 | W6 | X3 | Z17 | Y8 | OH | Y12 |
139 | W7 | X12 | Z11 | Y11 | OH | Y1 |
140 | W7 | X12 | Z16 | Y15 | OH | Y1 |
141 | W7 | X12 | Z3 | Y16 | OH | Y1 |
142 | W7 | X8 | Z11 | Y11 | OH | Y1 |
143 | W7 | X8 | Z16 | Y15 | OH | Y1 |
145 | W7 | X8 | Z3 | Y16 | OH | Y1 |
146 | W7 | X15 | Z11 | Y11 | OH | Y1 |
147 | W7 | X15 | Z16 | Y15 | OH | Y1 |
148 | W7 | X15 | Z3 | Y16 | OH | Y1 |
149 | W7 | X17 | Z11 | Y4 | OH | Y1 |
150 | W7 | X15 | Z7 | OH | Y4 | Y17 |
151 | W7 | X15 | Z31 | OH | Y4 | Y17 |
152 | W7 | X15 | Z9 | OH | Y4 | Y17 |
153 | W7 | X15 | Z32 | OH | Y4 | Y17 |
154 | W6 | X15 | Z42 | Y6 | Y1 | OH |
155 | W6 | X15 | Z37 | Y20 | Y1 | OH |
156 | W6 | X15 | Z39 | Y2 | Y1 | OH |
157 | W6 | X14 | Z42 | Y6 | Y8 | OH |
158 | W6 | X14 | Z37 | Y20 | Y8 | OH |
159 | W6 | X6 | Z17 | Y8 | Y3 | OH |
160 | W2 | X8 | OH | Z13 | Y4 | Y1 |
161 | W2 | X8 | OH | Z16 | Y4 | Y1 |
162 | W3 | X15 | Z36 | Y4 | OH | Z37 |
163 | W3 | X5 | Z11 | Y4 | OH | Z33 |
164 | W3 | X5 | Z8 | Y4 | OH | Z24 |
165 | W3 | X5 | Z36 | Y4 | OH | Z37 |
166 | W3 | X1 | Z11 | OH | OH | Z33 |
167 | W3 | X1 | Z8 | OH | OH | Z24 |
168 | W3 | X1 | Z36 | OH | OH | Z37 |
169 | W3 | X15 | Z11 | Y4 | OH | Z33 |
170 | W3 | X15 | Z8 | Y4 | OH | Z24 |
171 | W4 | X12 | Z10 | Y4 | Y8 | OH |
172 | W4 | X12 | Z41 | Y8 | Y3 | OH |
173 | W5 | X8 | Y17 | Z13 | Y4 | OH |
174 | W5 | X8 | Y17 | Z16 | Y4 | OH |
175 | W9 | X22 | Y4 | Z3 | 不存在 | OH |
176 | W9 | X23 | Y5 | Z11 | 不存在 | OH |
177 | W9 | X26 | Y8 | Z3 | 不存在 | OH |
178 | W9 | X21 | Y17 | Z11 | 不存在 | OH |
179 | W10 | X3 | Y6 | OH | 不存在 | Z25 |
180 | W10 | X5 | Y12 | OH | 不存在 | Z30 |
181 | W10 | X10 | Y19 | OH | 不存在 | Z40 |
182 | W11 | X6 | Z25 | OH | 不存在 | Y6 |
183 | W11 | X8 | Z30 | OH | 不存在 | Y12 |
184 | W11 | X10 | Z40 | OH | 不存在 | Y19 |
存固相上合成化合物85(W6-X15-Z11-Y1-OH-Y17)的实施例
条件:(i)a.Br2,DCM;b.4-氯苄醇,AgOTf,DCM;(ii)TCA-Wang树脂,BF3.Et2O,DCM,THF;(iii)NaOMe,THF,MeOH;(iv)a.KOBut,DMF;b.碘甲烷,DMF;(v)HF.‘质子海绵’,AcOH,DMF,65℃;(vi)a.KOBut,DMF;b.2-溴甲基-萘,DMF;(vii)1,4-二硫代-DL-苏糖醇,KOBut,DMF;(viii)HBTU,Fmoc-Gly-OH,DIPEA,DMF;(ix)哌啶/DMF(1/4);(x)3,5-二甲基吡唑基甲脒鎓硝酸盐,DIPEA,DMF;(xi)TFA,Et3SiH,DCM。
LCMS方法:
时间 水% 乙腈% 流速(ml/分钟)
0.00 95.0 5.0 2.000
1.00 95.0 5.0 2.000
7.00 0.0 100.0 2.000
12.00 0.0 100.0 2.000
M+H=557.3;Rt=3.98分钟
在溶液相中合成化合物159(W6-Z17-Y8-Y3-OH)的实施例:
条件:(i)4-甲氧基苯甲醛二甲基缩醛,TsOH,CH3CN;(ii)NaH(95%),溴乙酸叔丁酯,DMF;(iii)NaBH3CN,TFA,DMF;(iv)KOBut,BnBr,DMF;(v)a.Zn,NH4Cl,MeOH,H2O;b.HBTU,3-Boc-NH-苯甲酸,DIPEA,DMF;(vi)CH3CN,H2O,TsOH。
应该认识到,可以在不背离本发明的精神和范围的前提下对这些实施方案作出各种改变和修饰。
Claims (27)
1.式I的化合物,其为呋喃糖或吡喃糖形式的单糖衍生物,
式I
其中,
n为0或1;
R1为XR,其中,
X选自O、S、S=O和SO2,
R选自C1-C9烷基、C1-C15链烯基、C1-C15炔基、C1-C15杂烷基、C6-C15芳基、C6-C15杂芳基、C6-C15芳基烷基或C6-C15杂芳基烷基,它们任选被取代、为环状或非环状、支链和/或直链,
基团R2-R5选自OH、OR和N(Y)Z,从而:
基团R2-R5中至少一个和基团R2-R5中不多于两个为OH,
基团R2-R5中至少一个和基团R2-R5中不多于两个为OR,其中R如以上定义,条件是当基团R2-R5中两个为OR时,R基团不可以都为甲基或未取代的苄基,
基团R2-R5中至少一个和基团R2-R5中不多于两个为N(Y)Z,其中Z选自氢或R,而Y选自以下,其中G指与N(Y)Z中的氮原子连接的点,N(Y)Z基团不可以相同;
基团Q和W独立地选自氢或如以上定义的R,且Q和W可以结合形成环,
基团Z和Y可以结合形成环,
基团R1-R5不可以结合在一起形成环,
条件是当式I的化合物中的两个基团为N(Y)Z时,这些基团不同,
进一步条件是当R2或R5为N(Y)Z时,N(Y)Z不可以为叠氮基、乙酰基、苄氧羰基或叔丁氧羰基,
进一步条件是当R2为N(Y)Z时,N(Y)Z不可以为苯二甲酰亚氨基、4-[N-[1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基丁基]-氨基}苄酯(ODmab)、N-1-(4,4-二甲基-2,6-二氧代亚环己基)乙基(Dde)、2,2,2-三氯乙氧羰基(Troc)、9-芴基甲氧羰基(Fmoc)或5-酰基-1,3-二甲基巴比妥酸酯型保护基(DTPM),
进一步条件是当骨架为2-脱氧-2-氨基葡萄糖构型且R5和R4均为羟基时,R3不可以为甘醇酸酯[-CH2-CO2H]或乳酸酯醚[-CH(CH3)-CO2H]或者它们的酯或酰胺衍生物。
2.权利要求1的化合物,其为吡喃糖形式的单糖衍生物,且其中n为1。
3.权利要求1的化合物,其为呋喃糖形式的单糖衍生物,且其中n为0。
4.权利要求2的化合物,其中
n为1,
基团R2-R5中至少一个和基团R2-R5中不多于两个为N(Y)Z,其中Z选自氢或R,而Y选自以下,其中G指与N(Y)Z中的氮原子连接的点,N(Y)Z基团不可以相同;
基团Q和W独立地选自氢或如以上定义的R,条件是Y和Z不可以都为氢,且当式I的化合物中的两个基团为N(Y)Z时,这些基团不同,基团Z和Y可以结合形成环,
基团R1-R5不可以结合在一起形成环,
条件是当式I的化合物中的两个基团为N(Y)Z时,这些基团不同,
进一步条件是当R2或R5为N(Y)Z时,N(Y)Z不可以为叠氮基、乙酰基、苄氧羰基或叔丁氧羰基,
进一步条件是当R2为N(Y)Z时,N(Y)Z不可以为苯二甲酰亚氨基、4-[N-[1-(4,4-二甲基-2,6-二氧代亚环己基)-3-甲基丁基]-氨基}苄酯(ODmab)、N-1-(4,4-二甲基-2,6-二氧代亚环己基)乙基(Dde)、2,2,2-三氯乙氧羰基(Troc)、9-芴基甲氧羰基(Fmoc)或5-酰基-1,3-二甲基巴比妥酸酯型保护基(DTPM),
进一步条件是当骨架为2-脱氧-2-氨基葡萄糖构型且R5和R4均为羟基时,R3不可以为甘醇酸酯[-CH2-CO2H]或乳酸酯醚[-CH(CH3)-CO2H]或者它们的酯或酰胺衍生物。
5.权利要求1-4之任一项的化合物,其中杂芳基烷基被选自以下组中的基团取代:OH、NO、NO2、NH2、N3、卤素、CF3、CHF2、CH2F、腈、烷氧基、芳氧基、脒、胍盐、羧酸、羧酸酯、羧酸酰胺、芳基、环烷基、杂烷基、杂芳基、氨基烷基、氨基二烷基、氨基三烷基、氨基酰基、羰基、取代或未取代的亚胺、硫酸酯、磺酰胺、磷酸酯、磷酰胺、酰肼、异羟肟酸酯、异羟肟酸、杂芳氧基、氨基烷基、氨基芳基、氨基杂芳基、硫代烷基、硫代芳基或硫代杂芳基,它们可以进一步被取代,条件是基团R不可以为或含有另一糖基团、肽、蛋白或氨基酸。
7.权利要求1的化合物,其包括作为前体的
8.权利要求1的化合物,其包括作为前体的
9.权利要求1的化合物,其包括作为前体的
12.权利要求1的化合物,其包括作为前体的
15.权利要求1的化合物,其包括作为前体的
16.权利要求1的化合物,其包括作为前体的
17.权利要求1的化合物,其包括作为前体的
21.权利要求1的化合物,其包括作为前体的
22.权利要求1的化合物,其固定在载体上。
23.权利要求22的化合物,其中该化合物通过羟基固定在该载体上。
24.权利要求23的化合物,其中该载体选自衍生聚苯乙烯、tentagel、wang树脂、MBHA树脂、氨基甲基聚苯乙烯、rink酰胺树脂、DOX-mpeg和聚乙二醇。
25.权利要求1的化合物,其中R1选自
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US7138531B2 (en) | 2001-10-15 | 2006-11-21 | Kemin Pharma B.V.B.A. | Preparation and use of carbohydrate-based bicyclic ring structures with antimicrobial and cytostatic activity |
AU2002950657A0 (en) | 2002-08-08 | 2002-09-12 | Alchemia Limited | Derivatives of monosaccharides for drug discovery |
AU2002951995A0 (en) | 2002-10-11 | 2002-10-31 | Alchemia Limited | Classes of compounds that interact with gpcrs |
US7125853B2 (en) | 2003-01-07 | 2006-10-24 | Kemin Pharma B.V.B.A. | Bicyclic carbohydrate compounds useful in the treatment of infections caused by Flaviviridae sp., such as hepatitis C and bovine viral diarrhea viruses |
US7368475B2 (en) | 2003-03-12 | 2008-05-06 | Kemin Pharma Bvba | Furanose-type bicyclic carbohydrates with biological activity |
US7098243B2 (en) | 2003-09-16 | 2006-08-29 | Kemin Pharma Europe B.V.B.A. | Bicyclic carbohydrates as antiviral bioactives for the treatment of infections caused by the alphaherpesvirinae HSV-1 and HSV-2 |
JP2007532489A (ja) * | 2004-04-08 | 2007-11-15 | アルケミア リミティッド | 抗血管新生特性を有する生物学的に活性な化合物 |
EP1843760A4 (en) * | 2005-02-04 | 2009-03-25 | Alchemia Ltd | CLASSES OF COMPOUNDS THAT INTERACT WITH THE INTEGRINS |
AU2006209794B2 (en) * | 2005-02-04 | 2010-07-08 | Alchemia Limited | Classes of compounds that interact with integrins |
EP2545923A1 (en) * | 2005-12-22 | 2013-01-16 | Alchemia Limited | Antibacterial agents |
EP2260864A1 (en) | 2009-06-10 | 2010-12-15 | University of Melbourne | Therapeutic applications |
US8288515B2 (en) * | 2009-07-31 | 2012-10-16 | Reliable Biopharmaceutical Corporation | Process for preparing Fondaparinux sodium and intermediates useful in the synthesis thereof |
US8420790B2 (en) | 2009-10-30 | 2013-04-16 | Reliable Biopharmaceutical Corporation | Efficient and scalable process for the manufacture of Fondaparinux sodium |
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