CN107474085B - Hsp90 C端抑制剂及其医药组合物和用途 - Google Patents
Hsp90 C端抑制剂及其医药组合物和用途 Download PDFInfo
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- CN107474085B CN107474085B CN201710729038.6A CN201710729038A CN107474085B CN 107474085 B CN107474085 B CN 107474085B CN 201710729038 A CN201710729038 A CN 201710729038A CN 107474085 B CN107474085 B CN 107474085B
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- QCIWZIYBBNEPKB-UHFFFAOYSA-N tert-butyl(dimethyl)silane Chemical compound C[SiH](C)C(C)(C)C QCIWZIYBBNEPKB-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 150000004905 tetrazines Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- YGNGABUJMXJPIJ-UHFFFAOYSA-N thiatriazole Chemical class C1=NN=NS1 YGNGABUJMXJPIJ-UHFFFAOYSA-N 0.000 description 1
- 150000004897 thiazines Chemical class 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 150000004886 thiomorpholines Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 150000004882 thiopyrans Chemical class 0.000 description 1
- 238000002723 toxicity assay Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Abstract
本申请提供Hsp90 C端抑制剂和含有所述化合物的医药组合物。本公开书的化合物可用于治疗和/或预防神经退化病症,例如糖尿病性周围神经病变。
Description
本申请是申请日为2013年2月8日、申请人为堪萨斯大学、发明名称为“Hsp90C端抑制剂”的中国专利申请201380019057.X的分案申请。
相关申请
本申请作为PCT国际申请于2013年2月8日提交,并且要求2012年2月9日提交的美国临时申请第61/597,004号的优先权,所述美国临时申请以引用的方式并入本文中。
关于联邦赞助的研究或研发的声明
本发明是在美国国家卫生研究院所资助的基金号CA120458、CA109265、NS054847和DK073594的政府支持下完成的。政府对本发明享有特定权利。
技术领域
本发明涉及针对感觉神经元葡萄糖毒性具有细胞保护活性的新颖热休克蛋白90(Hsp 90)C端抑制剂。
背景技术
大约有2千6百万美国人罹患1型或2型糖尿病。虽然使用了胰岛素和口服抗糖尿病药物帮助维持血糖正常,但是这些个体中的约60-70%仍然发生糖尿病性周围神经病变(DPN)(Veves,A.;Backonja,M.;Malik,R.A.,Painful diabetic neuropathy:Epidemiology,natural history,early diagnosis,and treatment options.PainMed.2008,9,660-674)。
至今为止,用于治疗DPN的方法都把目标放在直接受限于高血糖的路径/标靶(即多元醇和己糖胺路径、晚期糖基化终产物(AGE)、增强的氧化应激、PKC活化)上(Tomlinson,D.R.;Gardiner,N.J.,Glucose neurotoxicity.Nat Rev Neurosci 2008,9(1),36-45)。
不幸的是,这些标靶/路径对于DPN发展的贡献在个体之间是不同的并且不存在生化均一性,因此这些方法在管理DPN方面只获得了很少的成功。作为一种替代方法,我们探索了对分子伴侣蛋白进行药理学调节以促进广泛的细胞保护反应,所述反应可以增强患者耐受高血糖损害的能力并且改善DPN的症状。
例如热休克蛋白90和70(Hsp90、Hsp70)等分子伴侣蛋白对于新生多肽折叠成其生物活性结构和在细胞应激时出现的经过聚集和变性的蛋白进行再折叠是必不可少的(Mayer,M.P.;Bukau,B.,Hsp70 chaperones:cellular functions and molecularmechanism.Cell Mol Life Sci 2005,62(6),670-84;Peterson,L.B.;Blagg,B.S.,Tofold or not to fold:modulation and consequences of Hsp90inhibition.Future MedChem 2009,1(2),267-283)。
引起细胞应激的许多条件也会诱导“热休克反应”(HSR),也就是抗氧化基因和伴侣蛋白例如Hsp70的转录上调。重要的是,Hsp90的小分子抑制足以诱导HSR。KU-32(图1)是基于新生霉素(novobiocin)的小分子Hsp90 C端抑制剂,新生霉素是一种天然存在的抑制DNA促旋酶的抗微生物剂。在Blagg等人的美国专利第7,622,451号和Blagg的美国专利第7,960,353号中公开了KU-32。虽然DPN的病原学与一种特定的错误折叠或聚集的蛋白质的积累无关,但是高血糖可以增加氧化应激和氨基酸的氧化修饰(Obrosova,I.G.,Diabetesand the peripheral nerve.Biochim Biophys Acta 2009,10,931-940;Akude,E.;Zherebitskaya,E.;Roy Chowdhury,S.K.;Girling,K.;Fernyhough,P.,4-Hydroxy-2-Nonenal Induces Mitochondrial Dysfunction and Aberrant Axonal Outgrowth inAdult Sensory Neurons that Mimics Features of Diabetic Neuropathy.NeurotoxRes 2009,1,28-38),从而妨碍蛋白折叠(Muchowski,P.J.;Wacker,J.L.,Modulation ofneurodegeneration by molecular chaperones.Nat Rev Neurosci 2005,6(1),11-22),减少线粒体蛋白输入(Baseler,W.A.;Dabkowski,E.R.;Williamson,C.L.;Croston,T.L.;Thapa,D.;Powell,M.J.;Razunguzwa,T.T.;Hollander,J.M.,Proteomic alterations ofdistinct mitochondrial subpopulations in the type 1 diabetic heart:contribution of protein import dysfunction.Am J Physiol Regul Integr CompPhysiol 2011,300(2),R186-200)并且促进线粒体功能失调(Tomlinson等人,2008版;Obrosova等人,2009版)。
即使在不存在单一的疾病特异性蛋白聚集体的情况下,也已经显示细胞保护性分子伴侣蛋白的药理学诱导可以改善葡萄糖毒性应激的细胞模型和DPN的动物模型中的有髓鞘和无髓鞘纤维的功能(Urban,M.J.;Li,C.;Yu,C.;Lu,Y.;Krise,J.M.;McIntosh,M.P.;Rajewski,R.A.;Blagg,B.S.J.;Dobrowsky,R.T.,Inhibiting Heat Shock Protein90Reverses Sensory Hypoalgesia in Diabetic Mice.ASN Neuro 2010,2,e00040DOI:189-199)。
在机械学上,KU-32无法防止神经调节蛋白(neuregulin)诱导从Hsp70.1和70.3双重基因敲除小鼠制备的感觉神经元的有髓鞘培养物发生脱髓鞘反应,表明Hsp70对于KU-32所表现出的神经保护活性是必需的。类似地,用KU-32每周治疗使糖尿病野生型小鼠的感觉和运动神经功能恢复正常,但是在糖尿病Hsp70基因敲除小鼠中不能逆转DPN的多项临床指标(Urban等人,2010,见上)。总地来说,这些研究提供生物学和临床基础来支持调节分子伴侣蛋白可以作为一种治疗DPN的可行方法。
KU-32的一个有利方面在于其在远低于抑制Hsp90的蛋白折叠能力所需的浓度诱导Hsp70(Urban等人,2010,见上)。因此,KU-32具有非常宽的治疗窗,其将细胞保护性质与可能由Hsp90依赖性客户蛋白的降解所引起的细胞毒性作用分开(Peterson等人,2009,见上)。这个实验室先前证明了含有苯甲酰胺(如在新生霉素中所发现的)的分子展现出抗增殖活性,而含有乙酰胺的分子(例如KU-32)表现出神经保护特性。然而,这些先前研究致力于评估新生霉素类似物作为抗癌剂的结构-活性关系(Burlison,J.A.;Avila,C.;Vielhauer,G.;Lubbers,D.J.;Holzbeierlein,J.;Blagg,B.S.,Development ofnovobiocin analogues that manifest anti-proliferative activity againstseveral cancer cell lines.J Org Chem 2008,73(6),2130-7;Donnelly,A.C.;Mays,J.R.;Burlison,J.A.;Nelson,J.T.;Vielhauer,G.;Holzbeierlein,J.;Blagg,B.S.J.,TheDesign,Synthesis,and Evaluation of Coumarin Ring Derivatives of theNovobiocin Scaffold that Exhibit Antiproliferative Activity.J.Org.Chem.2008,73(22),8901-8920),而不是探索可以增强以新生霉素为基础的类似物的神经保护特性的化学属性。因此,探索了KU-32骨架的多样化以鉴别出新颖化合物,所述新颖化合物缺乏香豆素环系统,但是仍然意外地增强Hsp90 C端抑制剂所表现出的神经保护特性。
发明内容
本发明涉及可用作Hsp90抑制剂并且尤其可用作神经保护剂的新颖化合物。具体来说,本发明涉及所述化合物用于在有需要的受试对象中治疗和/或预防糖尿病性周围神经病变或其它神经退化病症的治疗用途。
在一个实施方案中,本公开书提供一种根据式(I)的化合物或药学上可接受的盐:
其中
R1是氢、羟基、卤基、三氟烷基、烷基、烯基、炔基、碳环基、杂环基、芳基、芳烷基、羧基、酰胺基、氨基、烷氧基、卤基、三氟甲基、硫烷基、亚磺酰基(sulfenyl)、磺酰基或醚;
R2是氢、卤基、羟基、三氟甲基、烷氧基、烷基、烯基、炔基、碳环基、烷基碳环基、烷基杂环基、杂环基或-R9-OR10,其中R9是共价键或烷基,并且R10是氢、烷基、C-酰胺基或酰基;或者R2和R3连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R3是氢、羟基、卤基、三氟烷基、烷基、烷氧基、硫烷基或-R11-O-R12,其中R11是共价键或烷基,并且R12是烷基、C-酰胺基或酰基;或者R3和R2连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R4是氢、羟基、烷基、芳基烷氧基、羧基、-R13-O-R14或-R13-R15;并且其中R13是共价键或烷基,并且R14是氢、C-酰胺基或酰基,并且R15是N-酰胺基、-POR16R17-SO2R18或磺酰胺基,并且其中R16、R17、R18独立地是烷氧基;
R5是氢、羟基、烷基、芳基烷氧基、烯基、炔基、芳基或芳烷基;
R6是氢、羟基、硫烷基、烷基、烯基、炔基、芳基、芳基烷基、烷氧基、芳氧基、芳基烷氧基或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R7是氢、羟基、芳基烷氧基、烷基、酰基、羧基或不存在;
R8是氢、羟基或芳基烷氧基;
R22是氢、羟基、氨基、酰胺基、氰基、烷氧基、卤素、三氟烷基、烷基、烯基、炔基、酯、硝基、羧基、芳烷基、芳基、碳环基、杂环基、三氟甲基、磺酰基、硫烷基、亚磺酰基、醚、R25-OR26或R25-NR26;其中R25是共价键或烷基,并且R26是氢、烷基、C-酰胺基或酰基;
R23是氢、羟基、氨基、酰胺基、氰基、烷氧基、卤素、三氟烷基、烷基、烯基、炔基、酯、硝基、羧基、芳烷基、芳基、碳环基、杂环基、三氟甲基、磺酰基、硫烷基、亚磺酰基、醚、R27-OR28或R27-NR28;其中R27是共价键或烷基,并且R28是氢、烷基、C-酰胺基或酰基;或者R23和R24连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R24是氢、羟基、氨基、酰胺基、氰基、烷氧基、卤素、三氟烷基、烷基、烯基、炔基、酯、硝基、羧基、芳烷基、芳基、碳环基、杂环基、三氟甲基、磺酰基、硫烷基、亚磺酰基、醚、R29-OR30或R29-NR30;其中R29是共价键或烷基,并且R30是氢、烷基、C-酰胺基或酰基;或者R24和R23连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
X1是-CHR19-或-CR19=,并且其中R19选自氢、卤基、烷基、烯基或炔基;或者X1连同X2一起形成具有3到7个环成员的碳环;或者其中X1-X2是-C≡C-;
X2是-CHR20-或=CR20-,并且其中R20选自氢、卤基、烷基、烯基或炔基;或者X2连同X1一起形成具有3到7个环成员的碳环;或者其中X1-X2是-C≡C-;
X3是O或CH2;
X是=CR21-或=N-,其中R21是氢、卤基、三氟甲基、烷基、烯基、炔基、烷氧基或羟基;
R’是H或烷基;
R”是烷基、烷氧基、卤代烷基、烷基环烷基或烷基酰胺基烷基;
Y是=CR3-或=N-;
Z是CH,或者Z-Z1是-C=C-;
Z1是CH、O、S、N,或者Z-Z1是-C=C-;以及
n是0、1、2或3。
在一些实施方案中,本公开书提供一种根据式(I)的化合物或盐,其中X1是-CHR19-,并且R19是氢或烷基;或者X1连同X2一起形成具有3到7个环成员的碳环;并且X2是-CHR20-,并且其中R20是氢或烷基;或者X2连同X1一起形成具有3到7个环成员的碳环。
在一些实施方案中,本公开书提供一种根据式(I)的化合物或盐,其中X1是CH2并且X2是CH2。
在一些实施方案中,本公开书提供一种根据式(I)的化合物或盐,其中R’是H并且R”是CH3。
在另一方面中,本公开书提供一种根据式(I)的化合物或盐,其中R4和R5独立地是甲基或氢。
在另一方面中,本公开书提供一种根据式(I)的化合物或盐,其中R6选自氢、羟基、甲氧基、硫烷基或烷基。
在另一方面中,本公开书提供一种根据式(I)的化合物或盐,其中R7和R8是羟基。
在另一方面中,本公开书提供式(II)的化合物:
其中
R1是氢、卤基、羟基、三氟烷基、烷氧基或硫烷基;
R2是氢、卤基、羟基、三氟烷基、烷氧基、硫烷基或烷基,或者R2和R3连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R3是氢、卤基、羟基、三氟烷基、烷氧基、硫烷基、烷基;或者R3和R2连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
X是=CR21-或=N-,其中R21是氢、卤基或三氟甲基;以及
Y是=CR3-或=N-。
在另一方面中,本公开书提供一种根据式(II)的化合物或盐,其中R1是氢、卤基、烷氧基或硫烷基;R2是氢、羟基、卤基、三氟烷基、烷氧基或硫烷基;R3是氢、羟基、卤基、三氟烷基、烷氧基或硫烷基;X是=CR21-,其中R21是氢、卤基或三氟甲基;并且Y是=CR3-。
在具体方面中,本公开书提供可用于治疗或预防神经退化病症的化合物,其选自N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11a);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11b);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11c);N-(2-(2'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯-2-基)乙基)乙酰胺(11d);N-(2-(3'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11e);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11f);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11g);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2'-(甲硫基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11h);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(11i);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(11j);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-甲基-[1,1'-联苯]-2-基)乙基)乙酰胺(11k);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-(吗啉基甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11l);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(11m);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(11m);N-(2-(苯并[d][1,3]间二氧杂环基戊烯-5-基)-4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)苯乙基)乙酰胺(11n);N-(4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2-(吡啶-3-基)苯乙基)乙酰胺(11o);N-(4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2-(吡啶-4-基)苯乙基)乙酰胺(11p);N-(4'-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3”-氟-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(20a);N-(4'-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3”-(三氟甲基)-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(20b);N-(2-(5-((4-(苄氧基)环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(24);N-(2-(5-((4-(苄氧基)环己-2-烯-1-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(36);N-(2-(5-((4-(苄氧基)-2,3-二羟基环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(37);N-(2-(5-((4-(叔丁基)环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(39);N-(2-(3'-氟-5-((4-(哌啶-4-基)环己基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(40);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-6-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(41);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-3-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(42);和N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-4-甲基-[1,1'-联苯]-2-基)乙基)乙酰胺(43)。
在一个具体方面中,所述化合物选自:N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11b);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11c);N-(2-(2'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11d);N-(2-(3'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11e);N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11f);或N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11g)。
在另一个具体方面中,所述化合物选自N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11b);N-(2-(3'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11e);或N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11f)。
在一些实施方案中,本公开书提供一种医药组合物,其包含治疗有效量的式(I)化合物或式(I)化合物的药学上可接受的盐以及药学上可接受的载体,在所述式(I)化合物中取代基是如以上对R1、R2、R3、R4、R5、R6、R7、R8、R22、R23、R24、Z、Z1、X1、X2、X3、R’、R”、X、Y和n所定义。
在一些实施方案中,本公开书提供一种其中X3是O的式(I)化合物。在一些实施方案中,本公开书提供一种其中X3是CH2的式(I)化合物。在一些实施方案中,本公开书提供一种其中R1、R2和R3中的一个不是H的式(I)化合物。在一些实施方案中,本公开书提供一种其中R1、R2和R3中的一个是卤基的式(I)化合物。在一些实施方案中,本公开书提供一种其中R22、R23和R24中的一个不是H的式(I)化合物。在一些实施方案中,本公开书提供一种其中R22、R23和R24中的一个是羟基、烷氧基或烷基的式(I)化合物。在一些实施方案中,本公开书提供一种其中X1是-CH=并且X2是=CH-的式(I)化合物。在一些实施方案中,本公开书提供一种其中X1和X2都是CH2的式(I)化合物。在一些实施方案中,本公开书提供一种其中Z-Z1是-C=C-的式(I)化合物。在一些实施方案中,本公开书提供一种其中R4和R5独立地是烷基的式(I)化合物。在一些实施方案中,本公开书提供一种其中R6是烷氧基、芳烷氧基或烷基的式(I)化合物。在一些实施方案中,n=1。
在一些实施方案中,Z1是O并且R7不存在。在一些实施方案中,Z1是S并且R7不存在。在一些实施方案中,Z1是N并且R7是烷基、氢或羧基。
在一些实施方案中,式(I)化合物选自式(Ia)化合物,其中取代基如以上对R1、R2、R3、R4、R5、R6、R7、R8、X1、X2、R’、R”、X、Y和n所定义。
在一些实施方案中,式(I)化合物选自式(Ia)化合物,其中取代基如以上对R1、R2、R3、R4、R5、R6、R7、R8、X1、X2、R’、R”、X、Y和n所定义。
在其它实施方案中,本公开书提供一种用于治疗或预防有需要的受试对象的神经退化病症的方法,其包括对受试对象施用治疗有效量的式(I)化合物或式(I)化合物的药学上可接受的盐,其中取代基如以上所定义。
在其它实施方案中,本公开书提供一种式(I)化合物或其药学上可接受的盐用于制造用以治疗有需要的受试对象的神经退化病症的组合物的用途;其中所述组合物将会以可有效缓解或预防神经元葡萄糖毒性的症状的量施用。在一具体实施方案中,神经元葡萄糖毒性是感觉神经元葡萄糖毒性。
在另一具体实施方案中,神经退化病症是糖尿病性周围神经病变。
在又一实施方案中,本发明的化合物通过上调Hsp70展现神经保护作用。
附图说明
图1显示新生霉素和KU-32的化学结构。
图2的A显示对接到Hsp90 C端结合位点的KU-32的分子模型。
图2的B显示对接到Hsp90 C端结合位点的新生霉素类似物(novologue)(结构显示在图2的D中)的分子模型。
图2的C显示对接到Hsp90 C端结合位点的KU-32和新生霉素类似物(结构显示在图2的D中)的重叠。
图2的D显示新生霉素类似物的化学结构和其属性。
图3显示所选新生霉素类似物KU-32、11f、11l、11b、11n、11h和11o的EC50的测定。将DRG感觉神经元在不存在或存在0.1-1000nM指定新生霉素类似物的情况下培育过夜,然后经历4小时的高血糖条件。如实施例2中所述测量细胞活力,并且将数据表示为正常血糖对照组的百分比。在高血糖条件下和不存在任何新生霉素类似物的情况下,细胞活力是20%±7。
图4显示来自图3的所选新生霉素类似物KU-32、11f、11l、11b、11n、11h和11o的EC50的测定。使用GraphPad Prism 5.0的ECanything函数测定EC50,并且示出了平均值±SEM(n=3-8)。#,对比KU-32,p<0.05。
图5显示对于所选新生霉素类似物KU-32、11n和11b诱导Hsp70的免疫印迹分析。将DRG感觉神经元在存在DMSO(对照组)或10-1000nM指定新生霉素类似物的情况下培育过夜,然后经历4小时的高血糖条件。收集神经元,并且通过免疫印迹分析测定Hsp70和β-肌动蛋白的水平。使用Image J定量条带强度,将Hsp70表达标准化为β-肌动蛋白的水平。
具体实施方式
除非另外指明,否则分子术语在本申请中使用时具有其常用含义。应注意本发明的化学式中使用的字母表字母应解释为如本文所定义的官能团、部分或取代基。除非另外定义,否则符号将具有其对于所属领域技术人员来说普通且习惯的意义。
术语“酰基”是指-COR,其中所述定义中使用的R是氢、烷基、烯基、炔基、碳环基、杂环基、芳基或芳烷基。最优选地,R是氢、烷基、芳基或芳烷基。
术语“酰胺基”指示C-酰胺基例如-CONR'R"或N-酰胺基例如-NR'COR",其中在所述定义中使用的R'和R"独立地是氢、烷基、烯基、炔基、烷氧基、碳环基、杂环基、芳基或芳烷基。“磺酰胺基”包括-NR'-SO2-R"。最优选地,R'和R"是氢、烷基、芳基或芳烷基。
术语“氨基”表示式-NR'R"的伯氨基、仲氨基或叔氨基,其中所述定义中使用的R'和R"独立地是氢、烷基、烯基、炔基、芳烷基、碳环基、杂环基、芳烷基或其它氨基(在酰肼的情况下),或者R'和R”连同它们所连接的氮原子一起形成具有4到8个原子的环。因此,本文中使用的术语“氨基”包括未取代、单取代(例如单烷基氨基或单芳基氨基)和二取代(例如二烷基氨基或芳烷基氨基)的氨基。氨基包括-NH2、甲氨基、乙氨基、二甲氨基、二乙氨基、甲基-乙氨基、吡咯烷-1-基、或哌啶基、吗啉基等。其它示例性的形成环的“氨基”包括吡咯基、咪唑基、吡唑基、异噻唑基、异唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、吲哚基、吲唑基、嘌呤基、喹嗪基。含有氨基的环可以任选地被另一氨基、烷基、烯基、炔基、卤基或羟基取代。
术语“烷基”是指具有1到24个碳原子的分支或未分支的饱和烃基,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、辛基、癸基、十四烷基、十六烷基、二十烷基、二十四烷基等。本文中的优选“烷基”含有1到12个碳原子。最优选的是“低碳烷基”,其是指具有1到6个、更优选1到4个碳原子的烷基。烷基可以任选地被氨基、烷基、环烷基、卤基或羟基取代。
术语“烷氧基”表示被烷基或环烷基取代的含氧基团。实例包括(不限于)甲氧基、乙氧基、叔丁氧基和环己氧基。最优选的是具有1到6个碳原子的“低碳烷氧基”。所述基团的实例包括甲氧基、乙氧基、丙氧基、丁氧基、异丙氧基和叔丁氧基。
术语“烯基”和“炔基”是指长度和可能的取代与以上描述的烷基类似,但分别含有至少一个双键或三键的不饱和脂肪族基团。
术语“芳基”意思是含有1、2或3个环的碳环芳香族系统,其中所述环可以侧接方式连接在一起或者可以稠合。术语“稠合”意味着通过具有与第一个环共有(即共用)的两个相邻原子而存在(即连接或形成)第二个环。术语“稠合”和术语“缩合”相等。术语“芳基”涵盖芳香族基团,例如苯基、萘基、四氢萘基、茚满和联苯基。芳基可以任选地被氨基、烷基、卤基、羟基、碳环基、杂环基或另一芳基取代。
术语“芳烷基”涵盖被芳基取代的烷基部分。优选的芳烷基是“低碳芳烷基”,其中芳基连接到具有1到6个碳原子的烷基上。所述基团的实例包括苄基、二苯甲基、三苯甲基、苯乙基和二苯乙基。术语苄基和苯甲基可以互换。
术语“芳氧基”涵盖连接到氧原子上的如上文所定义的芳基。芳氧基可以任选地被卤基、羟基或烷基取代。所述基团的实例包括苯氧基、4-氯-3-乙基苯氧基、4-氯-3-甲基苯氧基、3-氯-4-乙基苯氧基、3,4-二氯苯氧基、4-甲基苯氧基、3-三氟甲氧基苯氧基、3-三氟甲基苯氧基、4-氟苯氧基、3,4-二甲基苯氧基、5-溴-2-氟苯氧基、4-溴-3-氟苯氧基、4-氟-3-甲基苯氧基、5,6,7,8-四氢萘氧基、3-异丙基苯氧基、3-环丙基苯氧基、3-乙基苯氧基、4-叔丁基苯氧基、3-五氟乙基苯氧基和3-(1,1,2,2-四氟乙氧基)苯氧基。
术语“芳基烷氧基”涵盖通过氧原子连接到其它基团上的含氧芳烷基。“低碳芳基烷氧基”是连接到如上所述的低碳烷氧基上的那些苯基。所述基团的实例包括苄氧基、1-苯基乙氧基、3-三氟甲氧基苄氧基、3-三氟甲基苄氧基、3,5-二氟苄氧基、3-溴苄氧基、4-丙基苄氧基、2-氟-3-三氟甲基苄氧基和2-苯基乙氧基。
术语“羧基”是指-R'C(=O)OR",其中所述定义中使用的R'和R"独立地是氢、烷基、烯基、炔基、碳环基、杂环基、芳基或芳烷基,或者R'可以另外是共价键。“羧基”包括羧酸和羧酸酯。术语“羧酸”是指其中R"是氢的羧基。所述酸包括甲酸、乙酸、丙酸、丁酸、戊酸、2-甲基丙酸、环氧乙烷羧酸和环丙烷羧酸。术语“羧酸酯”或“酯”是指其中R"是烷基、烯基、炔基、碳环基、杂环基、芳基或芳烷基的羧基。
术语“碳环基”是指含有一个或多个共价闭合的环结构并且其中形成所述环的骨架的原子都是碳原子的基团。所述环结构可以是饱和或不饱和的。所述术语因此区分碳环基与其中环骨架含有至少一个非碳原子的杂环。术语碳环基涵盖环烷基环系统。
术语“环烷烃”或“环状烷烃”或“环烷基”是指碳环基团,其中所述环是环状脂肪烃,例如优选具有3到12个环碳的环状烷基。“环烷基”包括例如环丙基、环丁基、环戊基、环己基、环庚基或环辛基等。环烷基可以任选地被氨基、烷基、卤基或羟基取代。
术语“醚”是指-R'-O-R"基团,其中所述定义中使用的R'和R"独立地是氢、烷基、烯基、炔基、碳环基、杂环基、芳基或芳烷基,并且R'可以另外是连接到碳上的共价键。
术语“卤基”或“卤素”是指氟、氯、溴或碘,通常涉及对有机化合物中的氢原子的卤基取代。
术语“杂环基”、“het”或“杂环”意思是任选地经取代的饱和或不饱和芳香族或非芳香族环烃基团,其具有4个到约12个碳原子、优选约5个到约6个,其中1个到约4个碳原子被氮、氧或硫取代。芳香族的示例性杂环基包括哌啶基、吡啶基、呋喃基、苯并呋喃基、异苯并呋喃基、吡咯基、噻吩基、1,2,3-三唑基、1,2,4-三唑基、吲哚基、咪唑基、噻唑基、噻二唑基、嘧啶基、唑基、三嗪基和四唑基。示例性杂环包括苯并咪唑、二氢噻吩、二氧芑、二烷、二氧戊环、二噻烷(dithiane)、二噻嗪、二噻唑、二硫戊环、呋喃、吲哚、3-H-吲唑、3-H-吲哚、咪唑、吲哚嗪、异吲哚、异噻唑、异唑、吗啉、唑、二唑、噻唑、噻唑烷、嗪、二嗪、哌嗪、哌啶、嘌呤、吡喃、吡嗪、吡唑、吡啶、嘧啶、嘧啶、哒嗪、吡咯、吡咯烷、四氢呋喃、四嗪、噻二嗪、噻二唑、噻三唑、噻嗪、噻唑、硫代吗啉、噻吩、噻喃、三嗪和三唑。杂环可以任选地被氨基、烷基、烯基、炔基、卤基、羟基、碳环基、硫基、其它杂环基或芳基取代。示例性杂环基包括1-哌啶基、2-哌啶基、3-哌啶基、4-哌啶基、1-吡咯基、2-吡咯基、3-吡咯基、1-吲哚基、2-吲哚基、3-吲哚基、1-吡啶基、2-吡啶基、3-吡啶基、4-吡啶基、1-咪唑基、2-咪唑基、3-咪唑基、4-咪唑基、1-吡唑基、2吡唑基、3-吡唑基、4-吡唑基、5-吡唑基、1-吡嗪基、2-吡嗪基、1-嘧啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、1-哒嗪基、2-哒嗪基、3-哒嗪基、4-哒嗪基、1-吲嗪基、2-吲嗪基、3-吲嗪基、4-吲嗪基、5-吲嗪基、6-吲嗪基、7-吲嗪基、8-吲嗪基、1-异吲哚基、2-异吲哚基、3-异吲哚基、4-异吲哚基、5-异吲哚基。
术语“羟基(hydroxy)”或“羟基(hydroxyl)”是指-OH取代基。
术语“氧代”应指=O取代基。
术语“硝基”意思是-NO2。
术语“硫烷基”是指-SR',其中所述定义中使用的R'是氢、烷基、烯基、炔基、碳环基、杂环基、芳基或芳烷基。
术语“亚磺酰基”是指-SOR',其中所述定义中使用的R'是氢、烷基、烯基、炔基、碳环基、杂环基、芳基或芳烷基。
术语“磺酰基”是指-SOR',其中所述定义中使用的R'是氢、烷基、烯基、炔基、碳环基、杂环基、芳基或芳烷基。
“任选的”或“任选地”意思是随后描述的事件或情况可能发生或可能不发生,并且该描述包括其中所述事件或情况发生的情形和其中所述事件或情况未发生的情形。“任选地”包括其中存在所描述的条件的实施方案和其中不存在所描述的条件的实施方案。举例来说,“任选地取代的苯基”意思是该苯基可以被取代或可以未被取代,并且该描述包括未取代的苯基和其中存在取代的苯基。“任选地”包括其中存在所描述的条件的实施方案和其中不存在所描述的条件的实施方案。
本发明的化合物可以互变异构体、几何异构体或立体异构体形式存在。本发明涵盖所有此类化合物,包括顺式和反式几何异构体、E-和Z-几何异构体、R-和S-对映异构体、非对映异构体、d-异构体、l-异构体、其外消旋混合物和其其它混合物,它们都属于本发明的范围内。
本发明的化合物的家族中还包括其药学上可接受的盐、酯和前药。术语“药学上可接受的盐”涵盖通常用于形成碱金属盐和形成游离酸或游离碱的加成盐的盐。所述盐的性质并不关键,条件是其是药学上可接受的。本发明化合物的合适的药学上可接受的酸加成盐可以从无机酸或从有机酸制备。所述无机酸的实例有盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。适当的有机酸可以选自脂肪族、环脂族、芳香族、芳脂族、杂环、羧酸和磺酸类的有机酸,其实例有甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡萄糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡萄糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、甲磺酸、水杨酸、对羟基苯甲酸、苯乙酸、扁桃酸、帕莫酸(embonic)(亚甲基双羟萘酸(pamoic))、甲烷磺酸、乙基磺酸、苯磺酸、对氨基苯磺酸、硬脂酸、环己基氨基磺酸、海藻酸、半乳糖醛酸。本发明化合物的合适的药学上可接受的碱加成盐包括从铝、钙、锂、镁、钾、钠和锌制备的金属盐,或从N,N'-二苄基乙二胺、胆碱、氯普鲁卡因、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因制备的有机盐。所有这些盐都可以通过常规方法从对应化合物制备,例如通过使适当的酸或碱与本发明的化合物反应。
如本文所使用,术语“药学上可接受的酯”是指在体内水解的酯,其包括(但不限于)在人体内轻易地分解以留下母体化合物或其盐的那些。合适的酯基包括(例如)衍生自药学上可接受的脂肪族羧酸、尤其烷酸、烯酸、环烷酸和烷二酸的那些,其中每个烷基或烯基部分有利地具有不超过6个碳原子。具体酯的实例包括甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯和琥珀酸乙酯。
本文所使用的术语“药学上可接受的前药”是指下述的本发明化合物的那些前药,其处在合理医学判断范围内,适合与人和比人低等的动物的组织接触使用而不会有过度的毒性、刺激性、过敏反应等,与合理的风险/收益比相称,并且就其关于本发明化合物的预期使用(当可能时)来说是有效的。术语“前药”是指在体内快速转化以产生具有以上化学式的母体化合物的化合物,例如通过在血液中水解。在T.Higuchi和V.Stella,Prodrugs asNovel delivery Systems,A.C.S.Symposium Series第14卷和Edward B.Roche编,Bioreversible Carriers in Drug Design,American Pharmaceutical Association andPergamon Press,(1987)中提供了详细讨论,两者皆以引用的方式并入本文中。
术语“神经保护”涵盖对导致细胞死亡的神经元进行性退化的抑制。
术语“神经退化病症”涵盖一种其中在周围神经系统中或在中枢神经系统中发生神经元进行性丧失的病症。在一个实施方案中,由本公开书的化合物、组合物和方法治疗和/或预防的病状是神经退化病症。不受理论束缚,认为本公开书的化合物和组合物在通过抑制导致细胞死亡的神经元进行性衰退来治疗神经退化病症的过程中提供(一种或多种)Hsp90抑制剂的神经保护作用。
在一个方面中,神经退化病症是感觉神经元葡萄糖毒性,其例如从与糖尿病病状相关的高血糖引起并且例如导致糖尿病性周围神经病变。
神经退化病症的实例包括(但不限于)慢性神经退化疾病,例如糖尿病性周围神经病变(包括第三脑神经麻痹、单神经病、多发性单神经病、糖尿病性肌萎缩症、自主神经病和胸腹神经病)、阿尔茨海默病(Alzheimer's disease)、年龄相关的记忆丧失、衰老、年龄相关的痴呆、皮克病(Pick's disease)、弥漫性路易体病、进行性核上性麻痹(斯提尔-理查德森综合征(Steel-Richardson syndrome))、多系统变性(夏伊-德雷格综合征(Shy-Dragersyndrome))、运动神经元疾病(包括肌萎缩侧索硬化(“ALS”)、退化性共济失调、皮质基底节变性、关岛ALS-帕金森病-痴呆综合征(ALS-Parkinson's-Dementia complex of Guam)、亚急性硬化性全脑炎、亨丁顿舞蹈症(Huntington's disease)、帕金森病、多发性硬化(“MS”)、突触核蛋白病(synucleinopathy)、原发性进行性失语、纹状体黑质变性、马查多-约瑟夫病(Machado-Joseph disease)/3型脊髓小脑共济失调和橄榄体脑桥小脑变性)、图雷特氏病(Gilles De La Tourette's disease)、延髓和假性延髓麻痹、脊柱和脊髓延髓肌萎缩症(肯尼迪病(Kennedy's disease))、原发性侧索硬化、家族性痉挛性截瘫、与沃尼克-科萨科夫综合征(Wernicke-Korsakoff)相关的痴呆(酒精诱导的痴呆)、韦德尼希-霍夫曼病(Werdnig-Hoffmann disease)、库格柏-伟兰德症(Kugelberg-Welander disease)、泰-萨氏病(Tay-Sach's disease)、山德霍夫病(Sandhoff disease)、家族性痉挛性疾病、沃法特-库格柏-伟兰德症(Wohifart-Kugelberg-Welander disease)、痉挛性轻截瘫、进行性多灶性白质脑病和朊蛋白病(包括库贾氏病(Creutzfeldt-Jakob)、戈斯曼-斯托斯乐-辛科病(Gerstmann-Straussler-Scheinker disease)、库鲁症(Kuru)和致死性家族性失眠症)。本发明的方法内另外包括的其它病状包括年龄相关的痴呆和其它痴呆,以及存在记忆丧失的病状,包括血管性痴呆、弥漫性脑白质病(宾斯万格病(Binswanger's disease))、内分泌或代谢起源的痴呆、头部外伤和弥漫性脑损伤的痴呆、拳击手痴呆和额叶痴呆。从脑缺血或梗死引起的其它神经退化病症包括栓塞性阻塞(embolic occlusion)和血栓性阻塞(thrombotic occlusion)以及任何类型的颅内出血(包括(但不限于)硬膜外、硬膜下、蛛网膜下和脑内),和颅内和脊柱内病变(包括(但不限于)挫伤、穿刺、剪切、压迫和裂伤)。因此,所述术语还涵盖急性神经退化病症,例如涉及中风、外伤性脑损伤、精神分裂症、周围神经损伤、低血糖症、脊髓损伤、癫痫和缺氧症和低氧症的那些。
在一些实施方案中,所述神经退化病症是淀粉样变性。淀粉样变性在以下疾病中观察到:阿尔茨海默病、遗传性脑血管病、非神经性遗传性淀粉样变性、唐氏综合征(Down'ssyndrome)、巨球蛋白血症、继发性家族性地中海热、穆-韦二氏综合征(Muckle-Wellssyndrome)、多发性骨髓瘤、胰腺相关性和心脏相关性淀粉样变性、慢性血液透析关节病以及芬兰和爱荷华淀粉样变性(Finnish and Iowa amyloidosis)。在优选实施方案中,使用本公开书的方法和组合物治疗和/或预防的神经退化病症是糖尿病性周围神经病变。
短语“药学上可接受的”在本文明中用于指代下述的那些化合物、物质、组合物和/或剂型,其处在合理医学判断范围内,适合与人和动物的组织接触使用而不会有过度的毒性、刺激性、过敏反应或其它问题或并发症,与合理的收益/风险比相称。
本文所使用的短语“药学上可接受的载体”意思是药学上可接受的物质、组合物或运载体(例如液体或固体填充剂、稀释剂、赋形剂、溶剂或封装材料),其参与将类似物或衍生物从身体的一个器官或部分携带或输送到身体的另一个器官或部分。在和制剂的其它成分相容并且对患者无害的意义上,每种载剂都必须是“可接受的”。可用作药学上可接受的载体的物质的一些实例包括:(1)糖,例如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉;(3)纤维素和其衍生物,例如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;(4)粉末状黄芪胶;(5)麦芽;(6)明胶;(7)滑石粉;(8)赋形剂,例如可可脂和栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯,例如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)磷酸盐缓冲溶液;和(21)医药制剂中使用的其它无毒的相容物质。
欲用本发明的化合物治疗的“患者”或“受试对象”可以是任何动物,例如狗、猫、小鼠、猴、大鼠、兔、马、牛、豚鼠、羊,并且优选是哺乳动物,例如驯养动物或家畜动物。在另一方面中,患者是人。
术语“抑制(inhibit)”或“抑制(inhibiting)”是指神经毒性在统计学上显著的且可测量的降低,优选地通过一种或多种本文所论述的分析所测量,优选地相比对照组降低至少约10%,更优选地降低约50%或更高,更优选地降低约60%、70%、80%、90%或更高。
本文所使用的术语“预防”意思是,当对在施药时未被诊断出可能患有所述病症或疾病但通常预期将发展所述病症或疾病或处于所述病症或疾病的高风险下的患者施药时,本发明的化合物是有用的。本发明的化合物将减缓所述病症或疾病的症状的发展,延迟所述病症或疾病的发作,或者从根本上预防个体发展所述病症或疾病。预防还包括对因为年龄、家族史、基因或染色体异常和/或因为存在所述病症或疾病的一种或多种生物标记而被认为有发生所述病症或疾病的倾向的那些个体施用本发明的化合物。
本文所使用的术语“治疗”一般来说意思是本发明的化合物可以用于至少初步诊断有所述病症或疾病的人或动物。本发明的化合物将延迟或减缓所述病症或疾病的发展,从而赋予个体更有用的寿命。术语“治疗”涵盖在患者体内至少获得与所述病症或疾病相关的症状的改善,其中改善是在广义上使用,是指与所治疗的病状相关的参数(例如症状)的量值至少获得减小。因此,“治疗”还包括下述的情形,其中所述病状或病症或至少与其相关的症状被完全抑制(例如避免发生)或被停止(例如终止),使得患者不再受所述病状或病症折磨,或者至少不再受表征所述病状或病症的症状折磨。
“治疗有效量”是完全地或部分地抑制所述病状的发展或至少部分地缓解所述病状的一种或多种症状的本发明的化合物或两种或更多种所述化合物的组合的量。治疗有效量还可以是预防上有效的量。治疗上有效的量将取决于患者的体型和性别、欲治疗的病状、病状的严重性和想要的结果。对于指定患者和病状来说,治疗有效量可以通过所属领域技术人员已知的方法确定。
KU-32是第一代新生霉素类似物(基于新生霉素的热休克蛋白90(Hsp90)C端抑制剂),其在小鼠中减少葡萄糖诱导的初级感觉神经元死亡并且逆转糖尿病性周围神经病变的许多临床指数。图1显示KU-32和新生霉素的结构。本公开书提供一系列新的Hsp90 C端抑制剂,其被设计成用于优化氢键结合和疏水相互作用,旨在增强神经保护活性。在合成途径中使用一系列经取代的苯基硼酸以用芳基部分(例如联苯部分)取代KU-32的香豆素内酯。鉴别了位于B环间位的带负电原子,所述带负电原子展现提高的细胞保护活性,不希望受理论束缚,认为所述细胞保护活性是由与Hsp90 C端结合口袋中的Lys539的有利相互作用引起。与这些结果一致,间位经3-氟苯基取代的新生霉素类似物(11b)在针对葡萄糖诱导的初级感觉神经元毒性的保护方面意外地展现比KU-32低14倍的ED50。
最近,这个实验室进行了分子建模研究,并且使用含有叠氮化物的新生霉素衍生物作为光亲和性探针首次阐明了Hsp90 C端结合位点(Matts,R.L.;Dixit,A.;Peterson,L.B.;Sun,L.;Voruganti,S.;Kalyanaraman,P.;Hartson,S.D.;Verkhivker,G.M.;Blagg,B.S.,Elucidation of the Hsp90 C-Terminal Inhibitor Binding Site.ACS Chem Biol2011)。如图2的A-C所示,KU-32对接到这个区域上并且似乎展现与蛋白质骨架和氨基酸侧链两者的结合相互作用,这和新生霉素所表现出来的类似。有趣的是,KU-32的香豆素内酯显得距离Lys539太远,无法提供与这个残基的互补相互作用。此外,3-酰胺基侧链似乎伸入可以容纳更多柔性连接基的较大疏水口袋中。由于这些观察,新生霉素类似物骨架(图2的D)被设计成将B环伸入Lys539所在的口袋中并用作先导化合物以用于进一步多样化。不受理论束缚,从A环伸出的柔性乙基酰胺可以适应多种取向,导致可以更好地占据在存在KU-32的情况下保持空缺的较大疏水口袋。
基于所述新生霉素类似物设计,设计了平行库的构建以验证这个骨架用作神经保护剂。基于显示诺维糖上的3’-氨基甲酸酯基对Hsp90抑制活性有害的先前研究,所述库被设计成省略所述基团(Burlison,J.A.;Neckers,L.;Smith,A.B.;Maxwell,A.;Blagg,B.S.J.,Novobiocin:Redesigning a DNA Gyrase Inhibitor for Selective Inhibitionof Hsp90.Journal of the American Chemical Society 2006,128(48),15529-15536)。
相比之下,通过在3-芳基取代基(B环)上掺入官能团来提供额外的疏水和氢键结合相互作用,所述3-芳基取代基被设计成用于提供与Lys539的互补相互作用。包括了4-乙基乙酰胺以用于占据香豆素环系统周围的结合口袋。在一个方面中,与从先前研究获得的数据一致,7-诺维糖基(noviosyl)键和必需的2’,3’-二醇得以保持。本公开书提供作为Hsp90 C端抑制剂的经过合理设计的新生霉素类似物的平行合成和其神经保护活性的评定。
以反向合成方法,经由四种组分设计了新生霉素类似物的库以用于构建用途(流程1):间苯二酚苯甲醛(1)、各种市面有售的硼酸(2a-p)、诺维糖(3)和乙酰胺侧链(流程1)。来自这个实验室的先前工作证实了诺维糖碳酸酯的三氯乙酰亚胺酯经历与酚类的快速偶联,从而得到高产率的期望α-端基异构体。
流程1.用于构建新生霉素类似物的逆向合成分析.
所选择的用于这一研究的硼酸含有可有助于阐明结构-活性关系并且提供与Lys539和周围口袋的关键相互作用的电子部分和空间部分。为实现这一目标,研究了在间位和对位含有带负电原子的苯基硼酸(流程2)。此外,在这些位置包括了氢键受体以提供与Lys539的质子化形式的潜在氢键结合相互作用。为了用作对照组,在这个系列中包括了疏水基团(2j,2k)和叔胺(2l)。
流程2.所选择的用于掺入到新生霉素类似物X骨架中的硼酸.
含有乙基乙酰胺侧链的新生霉素类似物11a-p的合成始于市面有售的2,4-二羟基苯甲醛1。将间苯二酚苯甲醛1的4-苯酚保护成对应的苄基醚4的形式(Lee,M.;Gubernator,N.G.;Sulzer,D.;Sames,D.,Development of pH-Responsive Fluorescent FalseNeurotransmitters.Journal of the American Chemical Society 2010,132(26),8828-8830),并且使用三氟甲烷磺酸酐和三乙胺将所述2-苯酚转化成三氟甲烷磺酸酯5(流程3)。化合物5随后在标准铃木条件下与市面有售的芳基硼酸(2a-p)偶联以得到高产率的联芳基环系统6a-p(Grasa,G.A.;Viciu,M.S.;Huang,J.;Zhang,C.;Trudell,M.L.;Nolan,S.P.,Suzuki-Miyaura Cross-Coupling Reactions Mediated by Palladium/ImidazoliumSalt Systems.Organometallics 2002,21(14),2866-2873;Olson,J.P.;Gichinga,M.G.;Butala,E.;Navarro,H.A.;Gilmour,B.P.;Carroll,F.I.,Synthesis and evaluationof1,2,4-methyltriazines as mGluR5antagonists.Organic&Biomolecular Chemistry2011,9(11),4276-4286)。
通过与硝基甲烷和乙酸铵进行亨利反应,将苯甲醛6a-p转化成对应的硝基苯乙烯(7a-p)(Fuganti,C.;Sacchetti,A.,Biocatalytic enantioselective approach to 3-aryl-2-nitropropanols:Synthesis of enantioenriched(R)-5-methoxy-3-aminochroman,a key precursor to the antidepressant drug Robalzotan.Journal ofMolecular Catalysis B:Enzymatic 2010,66(3-4),276-284;Wood,K.;Black,D.S.;Kumar,N.,Ring closing metathesis strategies towards functionalised 1,7-annulated 4,6-dimethoxyindoles.Tetrahedron 2011,67(22),4093-4102)。
用氢化铝锂还原硝基和烯烃官能团,随后酰化得到的胺以提供高产率的乙酰胺8a-p。在氢解条件下裂解化合物8a-p的苄基醚以提供酚类9a-p,其与诺维糖碳酸酯1014的三氯乙酰亚胺酸酯在存在催化量的三氟化硼乙醚络合物的情况下偶联(Burlison,J.A.;Neckers,L.;Smith,A.B.;Maxwell,A.;Blagg,B.S.J.,Novobiocin:Redesigning a DNAGyrase Inhibitor for Selective Inhibition of Hsp90.Journal of the AmericanChemical Society 2006,128(48),15529-15536;Kusuma,B.R.;Peterson,L.B.;Zhao,H.;Vielhauer,G.;Holzbeierlein,J.;Blagg,B.S.J.,Targeting the Heat Shock Protein90 Dimer with Dimeric Inhibitors.Journal of Medicinal Chemistry 2011,54(18),6234-6253)。
使得到的诺维糖基化(noviosylated)联芳基系统暴露于甲醇氨溶液以便溶剂分解环状碳酸酯并且得到高产率至中等产率的期望的新生霉素类似物(11a-p)。
11a,R1,R2,R3=H,X,Y=C;11b,R1,R3=H,R2=F,X,Y=C
11c,R1,R2=H,R3=F,X,Y=C;11d,R2,R3=H,R1=Cl,X,Y=C
11e,R1,R3=H,R2=Cl,X,Y=C;11f,R1,R3=H,R2=CF3,X,Y=C
11g R1,R2=H,R3=CF3,X,Y=C;11h,R2,R3=H,R1=SMe,X,Y=C
11i,R2,R3=H,R1=OMe,X,Y=C;11j,R1,R3=H,R2=OMe,X,Y=C;
11k,R1,R3=H,R2=Me,X,Y=C;11l,R1,R3=H,R2=CH2-吗啉,X,Y=C
11m,R1,R2=H,R3=OHX,Y=C;11n,R1=H,,R2,R3=OCH2O-,X,Y=C
11o,R1,R2,R3=H,X=N,Y=C;11p,R1,R2,R3=H,X=C,Y=N
流程3.含有乙基乙酰胺侧链的新生霉素类似物的合成.
以类似方式,通过流程3中所示的方案制备化合物41-43。
在一些实施方案中,本公开书提供一种式(I)化合物,其中X2连同X1一起形成具有3到7个环成员的碳环。举例来说,制备两种环己烯类似物20a-b以测试关于围绕柔性侧链的区域的假设(流程4)。虽然这些分子含有相同的连接基长度,但是这些类似物在联芳基环系统与乙酰胺之间含有庞大的环己烷束缚基团。
环己烯类似物20a-b的合成始于先前描述的苯酚4,所述苯酚4被保护成甲氧基甲基(MOM)醚13的形式(Toda,N.T.,K.;Marumoto,S.;Takami,K.;Ori,M.;Yamada,N.;Koyama,K.;Naruto,S.;Abe,K.i;Yamazaki,R.;Hara,T.;Aoyagi,A.;Abe,Y.;Kaneko,T.;Kogen,H,Monoenomycin:a simplified trienomycin A analog that manifests anticanceractivity.Bioorganic&Medicinal Chemistry Letters,ACS ASAP),随后其醛在亨利条件下转化成硝基苯乙烯14(Olson等人,2011,见上)。缺电子硝基苯乙烯(14)经历与过量丁二烯的狄尔斯-阿尔德环加成反应(Diels-Alder cycloaddition)以得到极高产率的环己烯衍生物15的对映异构体混合物(Bryce,M.R.;Gardiner,J.M.,Functionalised(+/-)-cephalotaxine analogues.Journal of the Chemical Society,ChemicalCommunications 1989,(16),1162-1164)。
经由锌粉和酸性异丙醇将15的硝基选择性地还原成胺(Brandt,G.E.L.;Blagg,B.S.J.,Monoenomycin:a simplified trienomycin A analog that manifestsanticancer activity.ACS Medicinal Chemistry Letters,ACS ASAP;Pei,Z.;Li,X.;vonGeldern,T.W.;Madar,D.J.;Longenecker,K.;Yong,H.;Lubben,T.H.;Stewart,K.D.;Zinker,B.A.;Backes,B.J.;Judd,A.S.;Mulhern,M.;Ballaron,S.J.;Stashko,M.A.;Mika,A.K.;Beno,D.W.A.;Reinhart,G.A.;Fryer,R.M.;Preusser,L.C.;Kempf-Grote,A.J.;Sham,H.L.;Trevillyan,J.M.,Discovery of((4R,5S)-5-Amino-4-(2,4,5-trifluorophenyl)cyclohex-1-enyl)-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone(ABT-341),a Highly Potent,Selective,Orally Efficacious,and Safe Dipeptidyl Peptidase IV Inhibitor for theTreatment of Type 2 Diabetes.Journal of Medicinal Chemistry 2006,49(22),6439-6442),随后进行乙酰化以经过两个步骤提供71%产率的乙酰胺16。为了构建联芳基环系统,裂解MOM醚以得到苯酚,然后将苯酚转化成对应的三氟甲烷磺酸酯17。17与3-氟苯基硼酸或3-(三氟甲基)苯基硼酸进行铃木反应,分别得到联芳基化合物18a或18b。最后,三氟化硼乙醚络合物促进去除化合物18a–b上的苄基醚(Andrieux,C.P.;Farriol,M.;Gallardo,I.;Marquet,J.,Thermodynamics and kinetics of homolytic cleavage of carbon-oxygen bonds in radical anions obtained by electrochemical reduction of alkylaryl ethers.Journal of the Chemical Society,Perkin Transactions 2 2002,(5),985-990)并且得到酚类19a-b。用活性诺维糖碳酸酯(10)对19a-b进行由路易斯酸催化的诺维糖基化反应,随后进行甲醇分解,得到非对映异构体产物20a-b的不可分离的混合物。
流程4.含环己烯的新生霉素类似物的合成.
在一些实施方案中,本公开书提供其中X3是CH2的式(I)化合物;换句话说,其中诺维糖取代基被碳环糖类似物取代基所取代。
其中R’、R”、R1、R2、R3、R4、R5、R6、R7、R8、X、X1、X2、X3、Y、Z和Z1如以上对式(I)化合物所定义。在一些实施方案中,本公开书提供一种其中X3是CH2的式(IV)化合物。
举例来说,通过流程5所示的合成途径制备特定化合物。
流程5.碳环糖类似物化合物24的合成.
流程5中的苯酚核心中间物23可以通过流程6所示的合成途径制备。
流程6.苯酚核心中间物23的合成.
在一些实施方案中,本公开书提供其中X3是CH2,Z是CH并且Z1是CH的式(I)或式(IV)化合物。在一些实施方案中,本公开书提供其中X3是CH2并且Z-Z1是-C=C-的式(I)或式(IV)化合物。举例来说,流程7显示其中X3是CH2并且或者Z-Z1是-C=C-的式(I)或式(IV)化合物(例如化合物36)的代表性合成。举例来说,流程7显示其中X3是CH2并且Z是CH的式(I)或式(IV)化合物(例如化合物37)的代表性合成。
流程7.碳环糖类似物36和37的合成.
在一些实施方案中,本公开书提供一种其中X3是CH2并且R6是烷基的式(I)或式(IV)化合物。流程8显示代表性合成途径。
流程8.碳环化合物39的合成.
神经保护效力的评估
在合成于B环上含有各种取代(氢键受体、氢键供体、疏水基团和叔胺)的乙基乙酰胺侧链新生霉素类似物11a-p时,评估其针对胚胎背根神经节(DRG)感觉神经元培养物的由葡萄糖诱导的毒性的神经保护效力。如表1所示,经间位取代的乙酰胺新生霉素类似物(11b、11e和11f)显示针对葡萄糖毒性的显著保护并且与在KU-32情况下观察到的相当。虽然对应的经邻位和对位取代(11c、11d和11g)的衍生物也显示针对由葡萄糖诱导的细胞死亡的显著保护,但是其不如新生霉素类似物11b、11e和11f有效。然而,在类似物11i(邻位-OMe)和11j(间位-OMe)的情况下,观察到相反的趋势。在间位的带负电原子(F、Cl、CF3)展现更大的细胞保护活性,这被认为是由与Hsp90 C端结合口袋中的Lys539的有利相互作用引起的。与这个假设一致,增加在间位的带负电原子的尺寸(F到Cl到CF3)导致了神经保护活性的降低。类似地,空间位阻也不受欢迎。类似物11b(间位-F)是评估出的细胞保护性最强(95%±14)的化合物。
在B环上的邻位或对位的带负电原子(11c、11d和11g)表现出与未经取代的类似物(11a)相当的活性并且活性低于对应的经间位取代的类似物(11b、11e和11f)。虽然新生霉素类似物11d和11g表现出针对神经元葡萄糖毒性的保护,但是其不如KU-32和11b有效。在B环的对位具有氢键供体特征的化合物(11m)(对位-OH)也有略微的保护性,但是所述保护性并不显著弱于未经取代的类似物(11a)。
表1.乙基乙酰胺侧链新生霉素类似物的细胞活力数据.
a在存在1μM每种新生霉素类似物+20mM过量葡萄糖的情况下。在存在20mM过量葡萄糖+DMSO的情况下的活力是54%±2,并且在存在葡萄糖+1μM KU-32的情况下的活力是86%±2。#,相比葡萄糖+DMSO,p<0.05;*,对于每种新生霉素类似物,相比葡萄糖+KU-32(n=6-24),p<0.05。
另一方面,在对位的氢键受体(11c和11g)针对由葡萄糖诱导的神经元死亡提供保护,但是相比含有对位氢键供体的新生霉素类似物(11m),并不展现显著增加的保护作用。
还合成了含吡啶的类似物(11o-p)并且评估其神经保护活性。3-吡啶类似物(11o)不能针对葡萄糖诱导的毒性提供保护,并且保护性也显著弱于对应的4-吡啶类似物11p、KU-32和未经取代的苯基类似物11a。虽然与简单苯基类似物11a相比时,含4-吡啶的类似物(11p)展现适度提高的神经保护活性,但是效力上的这种差异并不显著。
对于在B环的间位含有氟或三氟甲烷取代基的含环己烯的新生霉素类似物(20a-b)也测定到神经保护活性。一般来说,含环己烯的类似物20a-b的效力要低于对应的含有柔性侧链的衍生物(11b对比20a,和11f对比20b)。虽然在统计学上没有不同,但是新生霉素类似物20a(间位-F)展现略微好于类似物20b(间位-CF3)的细胞保护活性,这遵循对于含柔性乙酰胺的化合物所观察到的相同趋势(11b对比11f)。虽然这些数据与疏水口袋的容纳将提高效力这一假设不符,但是环己烯环可能超过这个结合槽中所允许的空间。
表2.环己烯类似物的细胞活力数据.
编号 | R<sub>2</sub> | 细胞活力%<sup>a</sup> |
20a | F | 78%±18%<sup>#</sup> |
20b | CF<sub>3</sub> | 69%±15%<sup>#,*</sup> |
a在存在1μM新生霉素类似物+20mM过量葡萄糖的情况下。在存在20mM过量葡萄糖+DMSO的情况下的活力是54%±2,并且在存在葡萄糖+1μM KU-32的情况下的活力是86%±2。#,相比葡萄糖+DMSO,p<0.05;*,对于每种新生霉素类似物,相比葡萄糖+KU-32(n=8),p<0.05。
表1中的数据明确支持所合成的大部分新生霉素类似物都降低由高血糖应激诱导的神经元毒性。虽然这些化合物中的一些在1μM下显得比KU-32更有效,但是差别相对较小。因此,为了仔细检查其效力,进一步评估了展现高神经保护活性的化合物以测定EC50值。因为在11b和11f上具有间位-F和间位-CF3取代的新生霉素类似物的效力在1μM下与KU-32或彼此之间没有显著不同,所以沿着11h、11l、11n和11o测定这些化合物的EC50值。如图4所示,在更仔细检查时EC50值显著增加并且获得明显区别。新生霉素类似物11b展现比KU-32(240.2±42.5nM)或11f(187.7±43.5nM)低大约14倍的EC50值(13.0±3.6nM)。对于新生霉素类似物11n也观察到类似结果,所述新生霉素类似物11n展现18.4±3.2nM的EC50值。相比之下,在1μM下表现出与KU-32类似的效力的新生霉素类似物11h展现384±108nM的EC50,大约是KU-32的1.6倍。
图4中的数据证明新生霉素类似物11b和11n的细胞保护性比初始的先导化合物KU-32令人惊讶地高。因为先前证实了KU-32所表现出的细胞保护活性需要Hsp70,所以测定相比KU-32的11b和11n诱导Hsp70的能力。将渐增浓度的KU-32、11n和11b与DRG感觉神经元一起培育24小时,然后使所述细胞经历4小时的葡萄糖毒性应激。通过用细胞溶解产物执行免疫印迹分析来检查Hsp70水平(图5)。11n和11b在类似浓度(10nM)下诱导Hsp70水平,所述浓度是神经保护所必需的。尽管具有相关性,但是这些数据提供了神经保护与11b和11n诱导热休克反应的能力之间的明显关联,如Hsp70水平所例示。
通过新生霉素类似物B环上的取代基的系统取代(参看表2),鉴别出作为神经保护剂的化合物11b,其针对葡萄糖诱导的毒性意外地展现比先导化合物KU-32高大约14倍的效力。表现神经保护活性所需的11b浓度与其诱导Hsp70水平的能力有很好的相关性,并且因此将细胞保护与Hsp70诱导关联起来。当合并时,这些数据证明经过合理设计的新生霉素类似物骨架提供一个有前景的平台,在所述平台上通过B环的多样化可以产生展现更好神经保护活性的化合物。
在一个实施方案中,本公开书提供一种根据式(I)的化合物或药学上可接受的盐:
其中
R1是氢、羟基、卤基、三氟烷基、烷基、烯基、炔基、碳环基、杂环基、芳基、芳烷基、羧基、酰胺基、氨基、烷氧基、卤基、三氟甲基、硫烷基、亚磺酰基、磺酰基或醚;
R2是氢、卤基、羟基、三氟甲基、烷氧基、烷基、烯基、炔基、碳环基、烷基碳环基、烷基杂环基、杂环基或-R9-OR10,其中R9是共价键或烷基,并且R10是氢、烷基、C-酰胺基或酰基;或者R2和R3连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R3是氢、羟基、卤基、三氟烷基、烷基、烷氧基、硫烷基或-R11-O-R12,其中R11是共价键或烷基,并且R12是烷基、C-酰胺基或酰基;或者R3和R2连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R4是氢、羟基、烷基、芳基烷氧基、羧基、-R13-O-R14或-R13-R15;并且其中R13是共价键或烷基,并且R14是氢、C-酰胺基或酰基,并且R15是N-酰胺基、-POR16R17-SO2R18或磺酰胺基,并且其中R16、R17、R18独立地是烷氧基;
R5是氢、羟基、烷基、芳基烷氧基、烯基、炔基、芳基或芳烷基;
R6是氢、羟基、硫烷基、烷基、烯基、炔基、芳基、芳基烷基、烷氧基、芳氧基、芳基烷氧基或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R7是氢、羟基、芳基烷氧基、烷基、酰基、羧基或不存在;
R8是氢、羟基或芳基烷氧基;
R22是氢、羟基、氨基、酰胺基、氰基、烷氧基、卤素、三氟烷基、烷基、
烯基、炔基、酯、硝基、羧基、芳烷基、芳基、碳环基、杂环基、三氟甲基、磺酰基、硫烷基、亚磺酰基、醚、R25-OR26或R25-NR26;其中R25是共价键或烷基,并且R26是氢、烷基、C-酰胺基或酰基;
R23是氢、羟基、氨基、酰胺基、氰基、烷氧基、卤素、三氟烷基、烷基、
烯基、炔基、酯、硝基、羧基、芳烷基、芳基、碳环基、杂环基、三氟甲基、磺酰基、硫烷基、亚磺酰基、醚、R27-OR28或R27-NR28;其中R27是共价键或烷基,并且R28是氢、烷基、C-酰胺基或酰基;或者R23和R24连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R24是氢、羟基、氨基、酰胺基、氰基、烷氧基、卤素、三氟烷基、烷基、烯基、炔基、酯、硝基、羧基、芳烷基、芳基、碳环基、杂环基、三氟甲基、磺酰基、硫烷基、亚磺酰基、醚、R29-OR30或R29-NR30;其中R29是共价键或烷基,并且R30是氢、烷基、C-酰胺基或酰基;或者R24和R23连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
X1是-CHR19-或-CR19=,并且其中R19选自氢、卤基、烷基、烯基或炔基;或者X2连同X1一起形成具有3到7个环成员的碳环;或者其中X1-X2是-C≡C-;
X2是-CHR20-或=CR20-,并且其中R20选自氢、卤基、烷基、烯基或炔基;或者X2连同X1一起形成具有3到7个环成员的碳环;或者其中X1-X2是-C≡C-;
X3是O或CH2;
X是=CR21-或=N-,其中R21是氢、卤基、三氟甲基、烷基、烯基、炔基、烷氧基或羟基;
R’是H或烷基;
R”是烷基、烷氧基、卤代烷基、烷基环烷基或烷基酰胺基烷基;
Y是=CR3-或=N-;
Z是CH,或者Z-Z1是-C=C-;
Z1是CH、O、S、N,或者Z-Z1是-C=C-;以及
n是0、1、2或3。
在一些实施方案中,本公开书提供式(II)化合物:
其中R1、R2、R3、X和Y如以上所定义。
在另一个实施方案中,本公开书提供一种式(II)的化合物或盐,其中R1是氢、卤基、羟基、三氟烷基、烷氧基或硫烷基;
R2是氢、卤基、羟基、三氟烷基、烷氧基、硫烷基或烷基,或者R2和R3连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
R3是氢、卤基、羟基、三氟烷基、烷氧基、硫烷基、烷基;或者R3和R2连同它们所连接的原子一起形成具有5到7个环成员的碳环或具有4到8个环成员的杂环,所述杂环具有至少一个选自氧或氮的杂原子;
X是=CR21-或=N-,其中R21是氢、卤基或三氟甲基;以及
Y是=CR3-或=N-。
在一些实施方案中,本公开书提供式(III)化合物,其中R1、R2、R3、R22、R23、R24、X和Y如以上所定义。
在一些实施方案中,本公开书提供一种式(III)化合物,其中R22、R23和R24中的一个不是H。
在一具体实施方案中,神经保护化合物选自:
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11a);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11b);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11c);
N-(2-(2'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11d);
N-(2-(3'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11e);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11f);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11g);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2'-(甲硫基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11h);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(11i);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(11j);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-甲基-[1,1'-联苯]-2-基)乙基)乙酰胺(11k);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-(吗啉基甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11l);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(11m);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(11m);
N-(2-(苯并[d][1,3]间二氧杂环戊烯-5-基)-4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)苯乙基)乙酰胺(11n);
N-(4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2-(吡啶-3-基)苯乙基)乙酰胺(11o);
N-(4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2-(吡啶-4-基)苯乙基)乙酰胺(11p);
N-(4'-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3”-氟-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(20a);
N-(4'-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3”-(三氟甲基)-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(20b);
N-(2-(5-((4-(苄氧基)环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(24);
N-(2-(5-((4-(苄氧基)环己-2-烯-1-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(36);
N-(2-(5-((4-(苄氧基)-2,3-二羟基环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(37);
N-(2-(5-((4-(叔丁基)环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(39);
N-(2-(3'-氟-5-((4-(哌啶-4-基)环己基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(40);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-6-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(41);
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-3-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(42);以及
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-4-甲基-[1,1'-联苯]-2-基)乙基)乙酰胺(43)。
本发明的一些化合物已经显示可体外抑制Hsp90。因此,预期治疗有效量的本发明化合物将可用作神经保护剂,在特定条件下(例如体外由葡萄糖诱导的毒性)或在体内糖尿病条件下,所述神经保护剂导致细胞活力相比对照组在给定时期增强至少10%。
在神经保护的情况下,预期本发明的一些化合物可以与其它Hsp90抑制剂和/或神经保护剂一起使用。
以下实施例用于说明本发明并且不打算限制其范围。所属领域技术人员将容易理解,以下制备程序的条件和方法的已知变体可用于制备这些化合物。
本发明涉及使用治疗有效量的一种或多种本文所公开的化合物治疗和/或预防神经退化病症例如糖尿病性周围神经病变和/或提供神经保护。
本发明的组合物
根据另一方面,本发明提供一种医药组合物,其包含治疗有效量的一种或多种本发明的化合物或其药学上可接受的盐、酯或前药,以及药学上可接受的稀释剂或载体。所述医药组合物提供神经保护并且用于治疗和/或预防神经退化病症。
所述组合物可经配制以用于任何给药途径,尤其用于口服、直肠、经皮、皮下、静脉内、肌肉内或鼻内给药。所述组合物可以配制成任何常规形式,例如片剂、胶囊、囊片、溶液、悬浮液、分散液、糖浆、喷雾、凝胶、栓剂、贴片和乳液。
因此,本发明的化合物可用于治疗或缓解神经退化病症,例如阿尔茨海默病、帕金森病、葛雷克氏症(Lou Gehrig's disease)或多发性硬化,这只是几个例子,更不用说中枢或周围神经系统损害、机能失调或涉及起源于水肿、损伤或外伤的中枢或周围神经系统损害、机能失调的并发症。所述损害、机能失调或并发症的特征可以是明显的神经、神经退化、生理、心理或行为异常,其症状可以通过施用治疗有效量的本发明的化合物来减轻。
以下实施例用于进一步说明本发明并且不限制本发明。
实施例
实施例1.胚胎背根神经节(DRG)神经元培养物的制备.
将来自15-18天的胚胎期Sprague Dawley大鼠幼仔的DRG收集到Leibovitz L15培养基(L15)中并用0.25%胰蛋白酶在37℃下解离30分钟。将神经节在1,000×g下沉降5分钟,再悬浮于生长培养基[无酚红的Neurobasal培养基(Gibco,Grand Island,NY),含有25mM葡萄糖、1×B-27添加剂、50ng/ml NGF(Harlan Bioscience,Indianapolis,IN)、4mM谷氨酰胺、100U/mL青霉素和100μg/mL链霉素]中,并用火焰磨光的玻璃吸管捣碎。在包被有胶原蛋白(0.1mg/mL胶原蛋白,随后在层流净化罩中空气干燥过夜)的黑壁96孔板(CorningIncorporated Corning,NY)上以每孔2-3×104个细胞的接种密度培养细胞。在第二天对DRG神经元再供给含有40μM氟脱氧尿苷和10μMβ-D-阿糖胞苷(两者都来自Sigma Aldrich,St.Louis,MO)的新鲜生长培养基维持2天,以去除增殖细胞。在培养第三天将细胞置于新鲜生长培养基中后,对DRG神经元执行实验。
实施例2.葡萄糖毒性分析.
不成熟的DRG容易发生高血糖诱导的死亡(Vincent,A.M.;Kato,K.;McLean,L.L.;Soules,M.E.;Feldman,E.L.,Sensory Neurons and Schwann Cells Respond toOxidative Stress by Increasing Antioxidant Defense Mechanisms.Antioxid RedoxSignal 2009,11,425-438)。因此,将额外的20mM葡萄糖加入到实施例1的生长培养基中(得到总共45mM葡萄糖)维持4小时。初步实验发现,维持4小时的20mM过量葡萄糖足以诱导神经元活力的40-50%的可再现性丧失。因此,由葡萄糖浓度的急性变化所诱导的毒性令其成为用于药物筛选的有用模型(Urban,M.J.;Li,C.;Yu,C.;Lu,Y.;Krise,J.M.;McIntosh,M.P.;Rajewski,R.A.;Blagg,B.S.J.;Dobrowsky,R.T.,Inhibiting Heat Shock Protein 90Reverses Sensory Hypoalgesia in Diabetic Mice.ASN Neuro 2010,2,e00040 DOI:189-199;Vincent,A.M.;Stevens,M.J.;Backus,C.;McLean,L.L.;Feldman,E.L.,Cellculture modeling to test therapies against hyperglycemia-mediated oxidativestress and injury.Antioxid Redox Signal 2005,7(11-12),1494-506)。
由于神经元在体外生长的时间范围很短,所以它们不是纯的神经元培养物,但实际上浓度很高。重要的是,留在培养物内的污染性SC对葡萄糖诱导的死亡具有抗性,如我们和其他人先前所报道(Vincent,A.M.;Kato,K.;McLean,L.L.;Soules,M.E.;Feldman,E.L.,Sensory Neurons and Schwann Cells Respond to Oxidative Stress by IncreasingAntioxidant Defense Mechanisms.Antioxid Redox Signal 2009,11,425-438;Zhang,L.;Yu,C.;Vasquez,F.E.;Galeva,N.;Onyango,I.;Swerdlow,R.H.;Dobrowsky,R.T.,Hyperglycemia alters the schwann cell mitochondrial proteome and decreasescoupled respiration in the absence of superoxide production.J Proteome Res2010,9(1),458-71)。
不幸的是,使用高度纯化的培养物存在问题,因为细胞延伸出神经突并且彼此之间建立联系,因此变得对高血糖诱导的死亡具有抗性(Yu,C.;Rouen,S.;Dobrowsky,R.T.,Hyperglycemia and downregulation of caveolin-1 enhance neuregulin-induceddemyelination.Glia 2008,56,877-887)。
在仅存在Neurobasal培养基、50ng/ml NGF和抗生素的情况下将DRG神经元和测试化合物一起培育过夜。为了监测所述化合物在保护DRG神经元对抗葡萄糖毒性方面的效率,利用钙黄绿素(Calcein)AM(Invitrogen,Carlsbad,CA)测量细胞活力。钙黄绿素AM水解成荧光产物只能在活细胞内发生。将过量葡萄糖加入到培养物中维持4小时,并通过在暗处在37℃下将细胞和2μM钙黄绿素AM一起培育30分钟来测量细胞活力。然后使用酶标仪测量荧光,其中激发波长和发射波长分别设定为485nm和520nm。用来自每个对应孔的神经元培养物的蛋白质的总量标准化任意荧光读数。使用DC Protein Assay(Bio-Rad)测定每个孔中的蛋白质浓度。使用Kruskal-Wallis非参数方差分析(non-parametric ANOVA)和邓氏后检验(Dunn’s post-test)测定到新生霉素类似物在增加细胞活力的功效方面的显著差异。
实施例3.基础化学-NMR.
在400或500MHz(Bruker DRX-400Bruker,使用H/C/P/F QNP梯度探针)光谱仪上记录1H NMR,并且在125MHz(具有宽频反向三重谐振的Bruker DRX500,和高分辨率魔角旋转HR-MA探针光谱仪)下记录13C NMR光谱;相对于内部参考氯仿-d(CDCl3,7.27ppm)以δ(ppm)为单位报道化学位移。
实施例4.基础化学-质谱分析和HPLC.
用LCT Premier(Waters Corp.,Milford,MA)记录FAB(HRMS)光谱。
除非另外说明,否则在通过1H NMR和13C NMR光谱测定时,测得所有化合物的纯度为>95%。活性最高的5种化合物通过HPLC分析验证到纯度为>95%。在玻璃底硅胶板(Uniplate)上进行TLC,其中的斑点通过UV光观察。所有溶剂都是试剂级,并且在必要时,通过标准方法进行纯化和干燥。反应和萃取之后溶液的浓缩涉及使用在减压下操作的旋转蒸发器。
实施例5.三氟甲烷磺酸5-(苄氧基)-2-甲酰苯酯(3)的合成:在0℃下搅拌苯酚2(11.2g,mmol)于无水DCM(245mL)中的溶液并历经5分钟先后加入三乙胺(10.2mL,73.5mmol)和三氟甲烷磺酸酐(13.8mL,63.5mmol)。完成后,通过加入水(50mL)终止反应,用饱和NaCl水溶液洗涤,干燥(Na2SO4),过滤并浓缩。通过柱色谱(SiO2,4:1,Hex:EtOAc)纯化残余物以得到黄色油状的三氟甲烷磺酸酯3(8.4g,23.6mmol,48%)。立即用于铃木偶联反应中。
实施例6.用于三氟甲烷磺酸酯3和硼酸2a-p的铃木偶联反应的通用程序:
5-(苄氧基)-[1,1'-联苯基]-2-甲醛(6a):在密封管中在氩气氛下将三氟甲烷磺酸酯5(0.246g,0.68mmol)、苯基硼酸2a(92mg,0.75mmol)、四(三苯膦)钯(0)(70.4mg,0.068mmol)和K2CO3(0.169g,1.2mmol)溶解于DMF(6.8mL)中。密封得到的反应混合物并将其加热到回流维持16小时。将反应物冷却到室温,用饱和碳酸氢钠终止,用EtOAc(3×5mL)萃取,用饱和氯化钠水溶液洗涤,经无水Na2SO4干燥,过滤并浓缩。通过柱色谱(SiO2,3:1,Hex:EtOAc)纯化粗产物以得到非晶固体状的6a(0.16g,0.56mmol,82%)。1H NMR(400MHz,CDCl3)δ9.90(s,1H),8.08(d,J=8.7Hz,1H),7.55-7.34(m,10H),7.11(d,J=8.7Hz,1H),7.03(d,J=2.4Hz,1H),5.19(s,2H);13C NMR(100MHz,CDCl3)δ191.2,162.8,148.6,137.8,136.0,130.0,128.8,128.4,127.6,116.3,114.7,70.4;HRMS(FAB)m/z:针对C20H16O2Na的[M+Na+],计算值,311.1042;实验值,311.1046。
5-(苄氧基)-3'-氟-[1,1'-联苯基]-2-甲醛(6b):使用3-氟苯基硼酸。1H NMR(500MHz,CDCl3)δ9.85(d,J=0.7Hz,1H),8.03(d,J=8.7Hz,1H),7.49-7.33(m,6H),7.20-7.13(m,2H),7.13-7.08(m,2H),7.03(d,J=2.5Hz,1H),5.15(s,2H);13C NMR(125MHz,CDCl3)δ190.7,162.9,161.7,147.2,140.1,136.0,130.5,129.0,128.6,127.8,126.0,117.1,116.9,116.4,115.5,115.1,70.6;HRMS m/z:针对C20H15FO2Na的[M+Na+],计算值,329.0948;实验值,329.0952。
5-(苄氧基)-4'-氟-[1,1'-联苯基]-2-甲醛(6c):使用4-氟苯基硼酸。1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.06(dd,J=8.7,1.0Hz,1H),7.49-7.40(m,4H),7.40-7.32(m,3H),7.21-7.13(m,2H),7.12-7.06(dd,J=8.0,2.5Hz,1H),7.03(d,J=2.2Hz,1H),5.17(s,2H);13C NMR(100MHz,CDCl3)δ190.9,162.8,147.4,136.0,131.7,131.6,130.5,128.8,128.5,127.7,127.6,116.5,115.6,115.4,114.7,70.4;HRMS m/z:针对C20H15FO2Na的[M+Na+],计算值,329.0948;实验值,329.0944。
5-(苄氧基)-2'-氯-[1,1'-联苯基]-2-甲醛(6d):使用2-氯苯基硼酸。1H NMR(500MHz,CDCl3)δ9.70(s,1H),8.08(d,J=8.7Hz,1H),7.55-7.49(m,1H),7.49-7.32(m,8H),7.17-7.12(dd,J=8.6,2.5Hz,1H),6.99(d,J=2.6Hz,1H),5.16(s,2H);13C NMR(125MHz,CDCl3)δ190.3,162.9,145.1,136.8,135.9,133.5,131.6,130.0,129.8,129.6,128.8,128.4,127.6,127.6,126.9,116.7,115.1,70.4;HRMS m/z:针对C20H15ClO2Na的[M+Na+],计算值,345.0658;实验值,345.0653。
5-(苄氧基)-3'-氯-[1,1'-联苯基]-2-甲醛(6e):使用3-氯苯基硼酸。1H NMR(400MHz,CDCl3)δ9.85(s,1H),8.04(d,J=8.7Hz,1H),7.49-7.33(m,8H),7.26(m,1H),7.13-7.07(dd,J=8.3,2.8Hz,1H),6.96(d,J=2.5Hz,1H),5.17(s,2H);13C NMR(100MHz,CDCl3)δ190.4,162.8,146.8,139.7,135.9,134.5,130.5,129.8,129.7,128.8,128.5,128.4,128.3,127.6,127.5,116.3,115.0,70.4;HRMS m/z:针对C20H15Cl2O2的[M+Cl-],计算值,341.0505;实验值,341.0508。
5-(苄氧基)-3'-(三氟甲基)-[1,1'-联苯基]-2-甲醛(6f):使用3-(三氟甲基)苯基硼酸。1H NMR(400MHz,CDCl3)δ9.82(s,1H),8.05(m,1H),7.72(m,1H),7.67-7.64(td,J=1.6,0.8Hz,1H),7.64-7.53(m,2H),7.50-7.35(m,5H),7.15-7.11(dd,J=8.7,2.2Hz,1H),6.96(d,J=2.5Hz,1H),5.19(s,2H);13C NMR(100MHz,CDCl3)δ190.4,163.0,146.8,138.8,135.9,133.4,131.0,130.9,129.0,129.0,128.6,127.8,127.6,126.6,126.5,125.2,116.7,115.2,70.6;HRMS m/z:针对C21H15F3O2Na的[M+Na+],计算值,379.0922;实验值,379.0926。
5-(苄氧基)-4'-(三氟甲基)-[1,1'-联苯基]-2-甲醛(6g):使用4-(三氟甲基)苯基硼酸。1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.06(d,J=8.7Hz,1H),7.75(d,J=8.0Hz,2H),7.55-7.49(m,2H),7.49-7.34(m,6H),7.17-7.12(dd,J=9.1,2.2Hz,1H),6.98(d,J=2.5Hz,1H),5.19(s,2H);13C NMR(100MHz,CDCl3)δ190.2,162.9,146.7,141.7,135.9,130.8,130.3,128.9,128.6,127.7,127.5,125.5,125.4,122.8,116.6,115.1,70.5;HRMSm/z:针对C21H16F3O2的[M+H+],计算值,357.1097;实验值,357.1096。
5-(苄氧基)-2'-(甲硫基)-[1,1'-联苯基]-2-甲醛(6h):使用2-(甲硫基)苯基硼酸。1H NMR(400MHz,CDCl3)δ9.62(s,1H),8.05(d,J=8.7Hz,1H),7.47-7.32(m,6H),7.30-7.23(m,2H),7.24-7.20(m,1H),7.13-7.09(m,1H),6.93-6.90(m,1H),5.17(s,2H),2.36(d,J=1.1Hz,3H);13C NMR(100MHz,CDCl3)δ190.8,163.,146.3,138.4,136.2,136.1,130.4,129.5,129.1,128.8,128.4,127.8,127.7,124.7,124.6,116.4,115.3,70.4,15.6;HRMS m/z:针对C21H18O2SNa的[M+H+],计算值,357.0920;实验值,357.0923。
5-(苄氧基)-2'-甲氧基-[1,1'-联苯基]-2-甲醛(6i):使用2-甲氧基苯基硼酸。1HNMR(500MHz,CDCl3)δ9.73(s,1H),8.07(d,J=8.7Hz,1H),7.48-7.39(m,5H),7.37(d,J=6.5Hz,1H),7.32-7.27(m,1H),7.13-7.07(m,2H),7.02(d,J=8.3Hz,1H),6.98-6.95(dd,J=2.4,1.1Hz,1H),5.15(s,2H),3.75(s,3H);13C NMR(125MHz,CDCl3)δ191.5,163.1,156.6,144.5,136.2,131.4,130.1,129.2,128.8,128.4,127.9,127.7,126.8,121.0,116.9,114.5,110.8,70.3,55.5;HRMS m/z:针对C21H19O3的[M+H+],计算值,319.1329;实验值,319.1333。
5-(苄氧基)-3'-甲氧基-[1,1'-联苯基]-2-甲醛(6j):使用3-甲氧基苯基硼酸。1HNMR(400MHz,CDCl3)δ9.93(s,1H),8.06(d,J=9.0Hz,1H),7.52-7.35(m,6H),7.10(d,J=8.6Hz,1H),7.05-6.93(m,4H),5.20(s,2H),3.89(s,3H);HRMS m/z:针对C21H18O3Na的[M+Na+],计算值,341.1154;实验值,341.1150。
5-(苄氧基)-3'-甲基-[1,1'-联苯基]-2-甲醛(6k):使用3-甲基苯基硼酸。1H NMR(500MHz,CDCl3)δ9.85(d,J=0.9Hz,1H),8.03(d,J=8.6Hz,1H),7.49-7.39(m,3H),7.39-7.32(m,2H),7.27(d,J=8.1Hz,1H),7.22-7.16(m,2H),7.09-7.05(ddd,J=8.8,2.6,0.9Hz,1H),6.98(d,J=2.5Hz,1H),5.15(s,2H),2.43(s,3H);13C NMR(125MHz,CDCl3)δ191.4,162.8,148.9,138.3,137.9,136.2,130.9,130.1,129.2,128.9,128.5,128.5,127.8,127.3,116.3,114.8,70.5,21.7;HRMS m/z:针对C21H18O2Na的[M+H+],计算值,325.1205;实验值,325.1217。
5-(苄氧基)-3'-(吗啉基甲基)-[1,1'-联苯基]-2-甲醛(6l):使用3-(4-吗啉基甲基)苯基硼酸频哪醇酯。1H NMR(400MHz,CDCl3)δ9.87(s,1H),8.83(d,J=8.7Hz,1H),7.47-7.31(m,7H),7.32-7.24(m,1H),7.12-7.04(dd,J=8.7,2.5Hz,1H),7.05(d,J=2.5Hz,1H),5.17(s,2H),3.79-3.68(t,J=4.6Hz,4H),3.56(s,3H),2.49(d,J=6.5Hz,4H);13C NMR(100MHz,CDCl3)δ191.0,162.7,148.5,138.3,137.8,136.0,130.7,130.2,129.1,128.8,128.4,127.6,127.6,116.4,114.5,70.4,67.1,63.2,53.7;HRMS m/z:C25H25NO3Na的[M+Na+],计算值,410.1726;实验值,410.1730。
5-(苄氧基)-4'-羟基-[1,1'-联苯基]-2-甲醛(6m):使用4-羟基苯基硼酸。
用DCM中的TBSCl(1.2eq.)和咪唑(3eq.)处理部分纯化的联芳基苯酚并将其在室温下搅拌2小时。通过TLC检测到反应完成后,浓缩得到的反应混合物。通过柱色谱(SiO2,4:1,Hex:EtOAc)纯化粗产物以得到非晶固体状的6m(94%)。1H NMR(500MHz,CDCl3)δ9.89(s,1H),8.03(d,J=8.7Hz,1H),7.52-7.33(m,5H),7.26(dd,J=6.6,1.8Hz,2H),7.05(dd,J=8.7,2.3Hz,1H),7.02-6.93(m,3H),5.17(s,2H),1.05(s,9H),0.29(s,6H);13C NMR(125MHz,CDCl3)δ191.2,162.7,156.0,148.4,136.1,131.2,130.6,130.0,128.7,128.3,127.6,127.5,120.0,116.1,114.3,70.3,25.7,18.3,4.3;ESI-HRMS m/z:针对C26H30NaO3Si的[M+Na]+,计算值,441.5899,实验值441.5896。
2-(苯并[d][1,3]间二氧杂环戊烯-5-基)-4-(苄氧基)苯甲醛(6n):使用3,4-(亚甲二氧基)苯基硼酸。1H NMR(500MHz,CDCl3)δ9.90(s,1H),8.08(d,J=8.7Hz,1H),7.48-7.39(m,4H),7.39-7.35(m,1H),7.06(d,J=8.6Hz,1H),6.97(d,J=2.5Hz,1H),6.91-6.86(m,2H),6.83-6.79(m,1H),6.03(s,2H),5.15(s,2H);13C NMR(125MHz,CDCl3)δ191.2,162.8,148.2,147.9,147.9,136.1,131.6,130.2,128.8,128.4,127.7,127.6,124.0,116.2,114.5,110.3,108.3,101.5,70.4;HRMS(FAB)m/z:针对C21H16O4Na的[M+Na+],计算值,355.0941;实验值,355.0935。
4-(苄氧基)-2-(吡啶-3-基)苯甲醛(6o):1H NMR(400MHz,CDCl3)δ9.79(s,1H),8.65(dd,2H,J=5.1,8.3Hz),8.01(d,1H,J=8.8Hz),7.67(m,1H),7.48-7.26(m,6H),7.09(dd,1H,J=2.4,8.7Hz),6.93(d,1H,J=2.4Hz),5.14(s,2H);13C NMR(125MHz,CDCl3)δ187.8,165.3,160.5,135.8,131.2,129.0,128.7,127.8,120.0,109.5,102.1,91.0,70.8;HRMS(FAB)m/z:针对C19H16NO2的[M+H+],计算值,290.1181;实验值,290.1177。
4-(苄氧基)-2-(吡啶-4-基)苯甲醛(6p):1H NMR(500MHz,CDCl3)δ9.82(s,1H),8.67(d,J=5.9Hz,2H),8.02(d,J=8.7Hz,1H),7.49-7.33(m,6H),7.30(d,J=6.0Hz,1H),7.15-7.10(dd,J=8.6,2.6Hz,1H),6.95(d,J=2.6Hz,1H),5.15(s,2H);13C NMR(125MHz,CDCl3)δ189.7,162.9,149.8,145.8,145.2,135.7,131.0,128.8,128.5,127.6,127.1,124.6,116.3,115.4,70.5;HRMS(FAB)m/z:针对C19H16NO2的[M+H+],计算值,290.1181;实验值,290.1183。
实施例7.用于化合物6a-p的亨利反应的通用程序:
(E)-5-(苄氧基)-2-(2-硝基乙烯基)-1,1'-联苯(7a):将硝基甲烷(1.4mL)加入到醛6a(0.16g,0.56mmol)与乙酸铵(77mg,1.0mmol)的混合物中并加热到50℃。完成(约15-30分钟)后,将反应混合物冷却到室温并且不经后处理即通过柱色谱(SiO2,3:1,Hex:EtOAc)纯化以得到黄色油状的硝基苯乙烯7a(182mg,0.55mmol,98%)。1H NMR(400MHz,CDCl3)δ8.02(d,J=13.6Hz,1H),7.64(d,J=9.5Hz,1H),7.50-7.35(m,10H),7.31(d,J=2.1Hz,2H),7.04(d,J=2.5Hz,1H),5.15(s,2H);13C NMR(100MHz,CDCl3)δ161.8,146.1,138.1,136.4,136.3,135.5,131.8 131.7,129.9,129.2,128.8,128.0,121.3,117.3,116.3,116.0,115.6,70.7;HRMS(FAB)m/z:针对C21H18NO3的[M+Na+],计算值,332.1281;实验值,332.1290。
(E)-5-(苄氧基)-3'-氟-2-(2-硝基乙烯基)-1,1'-联苯(7b):1H NMR(400MHz,CDCl3)δ8.07(d,J=13.5Hz,1H),7.65(d,J=8.7Hz,1H),7.49-7.35(m,7H),7.20-7.13(ddd,J=9.3,7.9,2.6Hz,1H),7.09-7.03(m,2H),7.02(d,J=2.8Hz,2H),5.16(s,2H);13CNMR(100MHz,CDCl3)δ164.0,161.5,145.4,141.4,137.6,136.1,136.0,130.5,130.4,129.6,128.6,127.7,125.7,121.0,116.9,116.6,115.6,115.4,70.5;HRMS m/z:针对C21H17FNO3的[M+H+],计算值,350.1187;实验值,350.1185。
(E)-5-(苄氧基)-4'-氟-2-(2-硝基乙烯基)-1,1'-联苯(7c):1H NMR(400MHz,CDCl3)δ8.08(d,J=13.6Hz,1H),7.64(d,J=8.7Hz,1H),7.50-7.34(m,6H),7.32-7.24(m,2H),7.23-7.14(t,J=8.3Hz,2H),7.10-7.00(m,2H),5.17(s,2H);13C NMR(100MHz,CDCl3)δ161.5,145.7,137.8,136.1,136.0,131.5,131.4,129.6,128.9,128.5,127.7,121.0,117.0,115.9,115.7,115.3,70.4;HRMS m/z:针对C21H16FNO3Na的[M+Na+],计算值,372.1006;实验值,372.1011。
(E)-5-(苄氧基)-2'-氯-2-(2-硝基乙烯基)-1,1'-联苯(7d):1H NMR(500MHz,CDCl3)δ7.85-7.75(m,1H),7.74-7.66(m,1H),7.55(m,1H),7.53-7.34(m,8H),7.31(d,J=5.3Hz,1H),7.17(d,J=8.3Hz,1H),7.01(t,J=2.0Hz,1H),5.20-5.11(m,2H);13C NMR(125MHz,CDCl3)δ161.4,143.8,137.7,137.0,135.9,133.2,131.4,130.0,130.0,129.3,128.7,128.3,127.6,127.1,123.4,121.5,117.1,115.6,70.3;HRMS m/z:针对C21H17ClNO3的[M+H+],计算值,366.0892;实验值,366.0895。
5-(苄氧基)-3'-氯-2-(2-硝基乙烯基)-1,1'-联苯(7e):1H NMR(400MHz,CDCl3)δ7.95(d,J=13.5Hz,1H),7.64(d,J=8.8Hz,1H),7.50-7.36(m,8H),7.33(s,1H),7.18(d,J=7.0Hz,1H),7.09-7.04(m,1H),7.00(d,J=2.6Hz,1H),5.17(s,2H);13C NMR(125MHz,CDCl3)δ145.1,141.1,140.9,137.4,136.1,134.7,129.9,129.6,129.6,129.5,129.0,128.8,128.5,128.4,128,0,127.6,120.9,116.9,115.5,109.9,70.4;HRMS m/z:针对C21H16Cl2NO3的[M+Cl-],计算值,400.0513;实验值,400.0505。
(E)-5-(苄氧基)-2-(2-硝基乙烯基)-3'-(三氟甲基)-1,1'-联苯(7f):1H NMR(400MHz,CDCl3)δ7.90(d,J=13.5Hz,1H),7.78-7.70(m,1H),7.69-7.55(m,3H),7.51-7.34(m,7H),7.13-7.05(dd,J=8.8,2.6Hz,1H),7.02(d,J=2.6Hz,1H),5.17(s,2H);13C NMR(100MHz,CDCl3)δ161.6,155.7,152.1,145.1,140.6,140.0,137.2,136.4,136.0,133.2,129.7,129.3,129.0,128.6,127.7,121.0,117.1,115.8,70.6;HRMS m/z:针对C22H17F3NO3的[M+H+],计算值,400.1161;实验值,400.1157。
(E)-5-(苄氧基)-2-(2-硝基乙烯基)-4'-(三氟甲基)-1,1'-联苯(7g):通过SiO2柱塞。TS1-189:1H NMR(400MHz,CDCl3)δ7.98-7.90(m,1H),7.80(d,J=8.0Hz,2H),7.68(d,J=8.8Hz,1H),7.52-7.37(m,8H),7.11(d,J=8.8Hz,1H),7.04(s,1H),5.19(s,2H);13C NMR(100MHz,CDCl3)δ161.4,147.8,144.9,144.3,139.8,138.6,137.1,136.4,135.8,133.5,131.2,129.5,129.1,128.8,128.5,127.6,124.2,120.8,120.4,117.0,115.6,70.4;HRMSm/z:针对C22H17F3NO3的[M+H+],计算值,400.1155;实验值,400.1151。
(E)-(5'-(苄氧基)-2'-(2-硝基乙烯基)-[1,1'-联苯]-2-基)(甲基)硫烷(7h):1HNMR(400MHz,CDCl3)δ7.71(d,J=13.6Hz,1H),7.62(d,J=8.6Hz,1H),7.45-7.31(m,7H),7.31-7.29(m,1H),7.25-7.19(t,J=7.2Hz,1H),7.13-6.99(m,2H),6.95(d,J=2.8Hz,1H),5.09(s,2H),2.35(s,3H);13C NMR(100MHz,CDCl3)δ161.5,144.9,138.0,137.5,137.2,136.1,135.7,130.0,129.4,129.3,128.8,128.4,127.7,125.0,124.9,121.6,117.0,115.8,70.3,15.6;HRMS m/z:针对C22H19NO3SK的[M+K+],计算值,416.0718;实验值,416.0756。
(E)-5-(苄氧基)-2'-甲氧基-2-(2-硝基乙烯基)-1,1'-联苯(7i):1H NMR(500MHz,CDCl3)δ7.86(d,J=13.8Hz,1H),7.65(d,J=8.7Hz,1H),7.57-7.34(m,7H),7.24-7.17(m,1H),7.16-6.99(m,4H),5.15(s,2H),3.74(s,3H);13C NMR(125MHz,CDCl3)δ161.6,156.4,143.7,138.8,136.3,135.3,131.4,130.4,128.9,128.4,127.7,122.0,121.1,117.5,115.1,111.4,70.4,55.6;HRMS m/z:针对C22H19NO4的[M+H+],计算值,362.1387;实验值,362.1389。
(E)-5-(苄氧基)-3'-甲氧基-2-(2-硝基乙烯基)-1,1'-联苯(7j):1H NMR(500MHz,CDCl3)δ8.04(d,J=13.6Hz,1H),7.62(d,J=9.5Hz,1H),7.46-7.37(m,6H),7.07-7.02(m,3H),7.02-6.97(ddd,J=8.2,2.6,0.9Hz,1H),6.88-6.84(m,1H),6.84-6.80(dd,J=2.6,1.6Hz,1H),5.15(s,2H),3.85(s,3H);13C NMR(125MHz,CDCl3)δ161.5,159.8,146.8,140.6,138.2,136.2,135.9,129.9,129.5,129.0,128.6,127.7,122.3,121.1,116.8,115.4,115.4,114.1,70.5,55.6;HRMS m/z:针对C22H19NO4Na的[M+Na+],384.1212;实验值,384.1218。
(E)-5-(苄氧基)-3'-甲基-2-(2-硝基乙烯基)-1,1'-联苯(7k):1H NMR(500MHz,CDCl3)δ8.01(d,J=13.6Hz,1H),7.62(m,1H),7.48-7.39(m,7H),7.39-7.33(t,J=7.7Hz,1H),7.14-7.07(m,2H),7.05-6.99(m,2H),5.15(s,2H),2.43(s,3H);13C NMR(125MHz,CDCl3)δ138.4,135.8,130.4,129.5,129.3,128.9,128.7,128.5,127.8,127.8,126.9,121.1,116.8,115.3,77.5,77.4,77.2,77.0,70.5 21.7;HRMS m/z:针对C22H19NO3N的[M+Na+],计算值,368.1263;实验值,368.1257。
(E)-4-((5'-(苄氧基)-2'-(2-硝基乙烯基)-[1,1'-联苯]-3-基)甲基)吗啉(7l):1H NMR(400MHz,CDCl3)δ7.98(d,J=13.6Hz,1H),7.63(d,J=9.5Hz,1H),7.48-7.33(m,8H),7.33(d,J=1.7Hz,1H),7.23-7.20(dd,J=6.7,1.8Hz,1H),7.08-6.99(m,2H),5.15(d,J=1.6Hz,2H),3.79-3.67(t,J=4.1Hz,4H),3.56(s,2H),2.55-2.40(dd,J=5.7,3.4Hz,4H);13C NMR(100MHz,CDCl3)δ161.5,146.9,139.2,138.5,138.1,136.1,135.8,130.6,129.5,129.3,128.9,128.8,128.5,128.4,127.7,121.0,116.9,115.1,70.4,67.1,63.3,53.8;HRMS m/z:针对C26H27N2O4的[M+H+],计算值,431.1971;实验值,431.1974。
(E)-((5'-(苄氧基)-2'-(2-硝基乙烯基)-[1,1'-联苯]-4-基)氧基)(叔丁基)二甲基硅烷(7m):1H NMR(400MHz,CDCl3)δ8.03(d,J=13.7Hz,1H),7.61(d,J=8.3Hz,1H),7.49-7.33(m,6H),7.17(d,J=8.4Hz,2H),7.02(s,2H),6.95(d,J=8.5Hz,2H),5.15(s,2H),1.04(s,9H),0.30(s,6H);13C NMR(100MHz,CDCl3)δ161.5,156.2,146.8,138.5,136.2,135.8,132.2,131.0,129.6,128.9,128.5,127.7,121.1,120.4,116.8,115.0,70.4,25.9,18.4,-4.1;HRMS(FAB)m/z:针对C27H31NO4SiNa的[M+Na+],计算值,484.1914;实验值,484.1936。
(E)-5-(5-(苄氧基)-2-(2-硝基乙烯基)苯基)苯并[d][1,3]间二氧杂环戊烯(7n):1H NMR(400MHz,CDCl3)δ8.03(d,J=13.6Hz,1H),7.59(d,J=8.0Hz,1H),7.50-7.33(m,6H),7.05-6.98(m,2H),6.92-6.85(m,1H),6.79(s,1H),6.71(d,J=7.9Hz,1H),6.03(s,2H),5.17(s,2H);13C NMR(100MHz,CDCl3)δ161.4,148.0,147.9,146.5,138.1,136.1,135.7,132.9,129.5,128.8,128.4,127.6,123.6,121.0,116.7,115.0,109.9,108.5,101.5,70.3;HRMS(FAB)m/z:针对C22H18NO5的[M+H+],计算值,376.1185;实验值,376.1160。
(E)-3-(5-(苄氧基)-2-(2-硝基乙烯基)苯基)吡啶(7o):1H NMR(400MHz,CDCl3)δ8.70(dd,J=4.8,1.6Hz,1H),8.59(d,J=1.6Hz,1H),7.89(d,J=13.5Hz,1H),7.68-7.60(m,2H),7.47-7.32(m,8H),7.12-7.06(dd,J=8.7,2.5Hz,1H),7.00(d,J=2.6Hz,1H),5.15(s,2H);13C NMR(100MHz,CDCl3)δ161.5,149.9,149.6,142.8,136.9,136.8,136.3,135.8,134.8,129.7,128.8,128.5,127.6,123.4,121.1,117.1,115.8,70.4;HRMS(FAB)m/z:针对C20H17N2O3的[M+Na+],333.1239;实验值,333.1234。
(E)-4-(5-(苄氧基)-2-(2-硝基乙烯基)苯基)吡啶(7p):1H NMR(500MHz,CDCl3)δ8.74(dd,2H,J=1.6,4.4Hz),7.91(d,1H,J=13.6Hz),7.67(d,1H,J=8.8Hz),7.48(d,1H,J=13.4Hz),7.41(m,5H),7.25(dd,2H,J=1.6,4.4Hz),7.11(dd,1H,J=2.6,8.7Hz),7.01(d,1H,J=2.5Hz),5.17(s,2H);13C NMR(125MHz,CDCl3)δ161.2,150.2,147.0,143.7,136.7,136.6,135.8,128.9,127.6,124.5,120.7,116.8,116.1,70.6;ESI-HRMS m/z:C20H17N2O3[M+H]+的计算值333.1239,实验值333.1249。
实施例8.用于从7a-p制备8a-p的通用程序:
N-(2-(5-(苄氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(8a):在氩气氛下和室温下将THF(0.7mL)中的硝基苯乙烯7a(182mg,0.55mmol)逐滴加入到氢化铝锂(42mg,1.12mmol)于THF(2mL)中的溶液中。完成后(几乎立即),通过加入水(42μL)、3M NaOH(42μL)和水(84μL)终止反应。将得到的混合物通过硅藻土柱塞过滤,用DCM洗涤并经K2CO3干燥。过滤后混合物被浓缩成油状物并且不经进一步纯化即使用。在氩气氛下和室温下将乙酸酐(58μL,0.62mmol)和三乙胺(93μL,0.67mmol)加入到所述粗胺于DCM(5.6mL)中的溶液中。3小时后,用饱和氯化铵水溶液终止反应并用DCM(3×10mL)萃取;用饱和氯化钠水溶液洗涤合并后的有机级分,经Na2SO4干燥,过滤并浓缩。通过柱色谱(SiO2;3:1,Hex:EtOAc)纯化残余物以得到乙酰胺8a(0.12g,0.35mmol,64%)。1H NMR(400MHz,CDCl3)δ7.50-7.38(m,8H),7.38-7.30(m,2H),7.23(d,J=8.4Hz,1H),7.01-6.95(dd,J=8.4,2.7Hz,1H),6.93(d,J=2.7Hz,1H),5.71(br s,NH),5.08(s,2H),3.42-3.16(q,J=7.0Hz,2H),2.89-2.64(t,J=7.2Hz,2H),1.85(s,3H);13C NMR(100MHz,CDCl3)δ170.2,157.2,143.4,141.4,137.0,130.8,129.1,128.7,128.6,128.4,128.0,127.6,127.2,116.6,114.2,70.1,40.7,31.9,23.2;HRMS m/z:针对C23H23NO2K的[M+K+],计算值,384.1361;实验值,384.1359。
N-(2-(5-(苄氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(8b):1H NMR(400MHz,CDCl3)δ7.48-7.30(m,6H),7.24-7.18(d,J=8.4Hz,1H),7.12-7.04(m,2H),7.04-6.92(ddd,J=18.6,8.2,2.5Hz,2H),6.85(d,J=2.7Hz,1H),5.34(br s,NH),5.05(s,2H),3.32-3.21(q,J=6.4,5.9Hz,2H),2.79-2.68(t,J=7.1Hz,2H),1.86(s,3H);13C NMR(100MHz,CDCl3)δ170.3,157.3,143.7,142.2,136.9,131.0,130.1,123.0,128.8,128.6,128.2,127.7,125.0,116.5,116.4,114.6,114.4,70.2,40.8,32.0,23.3;HRMS m/z:针对C23H23FNO2的[M+H+],计算值,364.1713;实验值,364.1705。
N-(2-(5-(苄氧基)-4'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(8c):1H NMR(400MHz,CDCl3)δ7.44-7.31(m,6H),7.27-7.22(dd,J=8.4,5.5Hz,1H),7.21-7.17(d,J=8.4Hz,1H),7.12-7.05(m,3H),6.96-6.91(dd,J=8.3,3.0Hz,1H),5.83(br s,NH),5.05(s,2H),3.33-3.15(q,J=6.7Hz,2H),2.78-2.66(t,J=7.2Hz,2H),1.87(s,3H);13C NMR(100MHz,CDCl3)δ170.5,157.3,142.4,137.0,130.9,130.8,130.7,128.7,128.7,128.2,127.7,116.8,115.5,115.3,114.3,70.2,40.8,32.0,23.1;HRMS m/z:针对C23H22FNO2Na的[M+Na+],计算值,386.1527;实验值,386.1529。
N-(2-(5-(苄氧基)-2'-氯-[1,1'-联苯]-2-基)乙基)乙酰胺(8d):1H NMR(500MHz,CDCl3)δ7.52-7.45(m,1H),7.45-7.40(m,2H),7.40-7.35(m,3H),7.35-7.29(m,3H),7.25-7.21(m,1H),7.05-6.95(dd,J=8.5,2.8Hz,1H),6.82(d,J=2.7Hz,1H),5.93(d,J=5.4Hz,1H),5.05(s,2H),3.36-3.19(ddq,J=19.3,13.0,6.1Hz,2H),2.67-2.49(m,2H),1.93(s,3H);13C NMR(125MHz,CDCl3)δ175.7,171.0,157.1,140.4,139.8,136.9,133.1,131.3,130.4,129.6,129.0,128.6,128.0,127.6,126.8,116.4,114.9,70.1,40.3,31.8,22.9;HRMS m/z:针对C23H23ClNO2的[M+H+],计算值,380.1417;实验值,380.1415。
N-(2-(5-(苄氧基)-3'-氯-[1,1'-联苯]-2-基)乙基)乙酰胺(8e):1H NMR(500MHz,CDCl3)δ7.47-7.28(m,8H),7.25-7.17(m,2H),6.99-6.92(dd,J=8.5,2.7Hz,1H),6.84(d,J=2.8Hz,1H),5.46(br s,NH),5.06(s,2H),3.34-3.25(m,2H),2.83-2.68(t,J=7.3Hz,2H),2.03(s,3H);13C NMR(125MHz,CDCl3)δ171.6,157.5,143.2,142.1,136.9,134.3,131.1,129.9 129.3,128.8,128.3,127.7,127.6,127.5,116.7,114.8,70.3,46.1,41.3,31.7,22.5,8.8;HRMS m/z:针对C23H23ClNO2的[M+H+],计算值,380.1412;实验值,380.1414。
N-(2-(5-(苄氧基)-3'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(8f):1HNMR(400MHz,CDCl3)δ7.64(d,J=7.7Hz,1H),7.59-7.54(m,2H),7.55-7.49(t,J=7.3Hz,1H),7.47-7.32(m,5H),7.24(d,J=8.5Hz,1H),7.01-6.96(dd,J=8.5,2.7Hz,1H),6.87(d,J=2.7Hz,1H),5.90(br s,NH),5.06(s,2H),3.34-3.23(q,J=6.9Hz,2H),2.79-2.68(t,J=7.3Hz,2H),1.99(s,3H);13C NMR(100MHz,CDCl3)δ170.7,157.4,142.2,141.9,136.9,132.6,131.1,129.0,128.8,128.5,128.2,127.7,124.2,116.7,114.8,70.3,40.8 31.9,23.0;HRMS m/z:针对C24H23F3NO2的[M+H+],计算值,414.1676;实验值,414.1681。
N-(2-(5-(苄氧基)-4'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(8g):1HNMR(400MHz,CDCl3)δ7.66(d,J=8.1Hz,2H),7.46-7.23(m,8H),6.99-6.94(dd,J=8.5,2.7Hz,1H),6.84(d,J=2.7Hz,1H),6.03(t,J=5.5Hz,1H),5.06(s,2H),3.33-3.19(dd,J=14.3,6.4Hz,2H),2.76-2.68(dd,J=8.3,6.6Hz,2H),1.85(s,3H);13C NMR(100MHz,CDCl3)δ170.3,157.1,145.1,141.8,136.8,130.9,129.5,129.1,128.6,128.6,127.5,125.6,125.2,125.2,122.9,116.4,114.6,70.1,40.6,31.9;HRMS m/z:针对C24H22F3NO2Na的[M+Na+],计算值,436.1495;实验值,436.1489。
N-(2-(5-(苄氧基)-2'-(甲硫基)-[1,1'-联苯]-2-基)乙基)乙酰胺(8h):1H NMR(400MHz,CDCl3)δ7.48-7.30(m,7H),7.28-7.18(m,2H),7.14(s,1H),7.03-6.98(ddd,J=8.5,2.8,1.0Hz,1H),6.87-6.83(m,1H),5.63(br s,NH),5.05(s,2H),3.43-3.16(ddt,J=42.5,13.3,6.6Hz,2H),2.66-2.52(t,J=6.7Hz,2H),2.39(d,J=1.0Hz,3H),1.84(d,J=1.0Hz,3H);13C NMR(100MHz,CDCl3)δ170.3,157.3,141.1,139.1,137.6,137.0,130.6,129.8,129.4,128.7,128.4,128.1,127.7,124.5,124.0,116.5,115.2,70.2,40.1,31.7,23.3,15.2;HRMS m/z:针对C24H25NO2SNa的[M+Na+],计算值,414.1504;实验值,414.1509。
N-(2-(5-(苄氧基)-2'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(8i):1H NMR(400MHz,CDCl3)δ7.47-7.30(m,5H),7.22(d,J=8.5Hz,1H),7.17-7.13(dd,J=7.4,1.9Hz,1H),7.07-6.95(m,4H),6.85(d,J=2.7Hz,1H),5.51(br s,NH),5.07(s,2H),3.77(s,3H),3.44-3.18(m,2H),2.68-2.56(td,J=6.8,3.7Hz,2H),1.86(s,3H);13C NMR(125MHz,CDCl3)δ170.0,157.2,156.4,139.9,137.1,131.2,130.1,129.2,128.7,128.1,127.8,120.9,116.8,114.4,111.2,70.1,55.8,40.4,31.9,23.5;HRMS m/z:针对C24H26NO3的[M+H+],计算值,376.1913;实验值,376.1902。
N-(2-(5-(苄氧基)-3'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(8j):1H NMR(400MHz,CDCl3)δ7.48-7.36(m,4H),7.36-7.30(m,3H),7.21(d,J=8.4Hz,1H),6.98-6.92(m,1H),6.92-6.82(m,3H),5.49(br s,NH),5.06(s,2H),3.85(s,3H),3.34-3.22(q,J=6.6,6.2Hz,2H),2.85-2.68(t,J=7.2Hz,2H),1.85(s,3H);13C NMR(100MHz,CDCl3)δ170.1,159.5,157.2,143.3,142.9,137.0,130.8,129.5,128.7,128.1,128.1,127.7,121.6,116.5,114.9,114.3,112.7,70.17,55.4,40.8,32.0,23.3;HRMS m/z:针对C24H25NO3Na的[M+H+],计算值,398.1732;实验值,398.1725。
N-(2-(5-(苄氧基)-3'-甲基-[1,1'-联苯]-2-基)乙基)乙酰胺(8k):1H NMR(400MHz,CDCl3)δ7.45(m,3H),7.40(m,3H),7.37-7.30(q,J=7.7,7.1Hz,1H),7.21(d,J=1.4Hz,1H),7.15-7.10(m,2H),6.96(d,J=8.1Hz,1H),6.90(s,1H),5.51(br s,NH),5.08(s,2H),3.34-3.24(q,J=6.5Hz,2H),2.83-2.71(t,J=7.0Hz,2H),2.41(s,3H),1.84(s,3H);13C NMR(100MHz,CDCl3)δ170.0,157.2,143.5,141.4,138.0,137.0,130.7,129.9,128.7,128.7,128.3,128.1,128.0,127.6,126.2,116.5,114.2,70.1,40.8,31.9,23.3,21.6;ESI-HRMS m/z:针对C24H25NO2Na的[M+Na]+,计算值,382.1777,实验值382.1770。
N-(2-(5-(苄氧基)-3'-(吗啉基甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(8l):1HNMR(400MHz,CDCl3)δ7.47-7.30(m,7H),7.28(s,1H),7.24-7.18(m,2H),6.98-6.93(dd,J=8.4,2.8Hz,1H),6.89(d,J=2.7Hz,1H),5.40(s,1H),5.05(s,2H),3.75-3.69(t,J=4.7Hz,4H),3.55(s,2H),3.36-3.22(q,J=6.9Hz,2H),2.80-2.68(t,J=7.1Hz,2H),2.47(m,4H),1.85(s,3H);13C NMR(100MHz,CDCl3)δ170.0,157.3,143.4,141.5,138.0,137.1,130.9,123.0,128.7,128.7,128.4,128.2,128.2,128.0,127.7,116.8,114.1,70.2,67.1,63.5,53.8,40.6,32.1,23.4;HRMS m/z:针对C28H33N2O3的[M+H+],计算值,445.2491;实验值,445.2494。
N-(2-(5-(苄氧基)-4'-((叔丁基二甲基硅烷基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(8m):1H NMR(500MHz,CDCl3)δ7.44(d,J=7.5Hz,3H),7.42-7.36(dt,J=10.5,5.7Hz,3H),7.36-7.31(m,1H),7.21-7.14(m,3H),6.94-6.86(m,2H),5.08(s,2H),3.34-3.23(q,J=6.7Hz,2H),2.75(t,J=7.1Hz,2H),1.74(s,3H),1.97(s,9H),0.25(s,6H);13CNMR(125MHz,CDCl3)δ169.9,157.3,155.0,143.3,137.2,134.5,130.8,130.2,128.7,128.1,127.7,120.0,116.8,114.0,70.2,53.6,40.7,32.1,25.8,23.4,18.4,-4.2;HRMS(FAB)m/z:针对C29H37NO3SiNa的[M+Na+],计算值,498.2440;实验值,498.2447。
N-(2-(苯并[d][1,3]间二氧杂环戊烯-5-基)-4-(苄氧基)苯乙基)乙酰胺(8n):1HNMR(400MHz,CDCl3)δ7.49-7.36(m,5H),7.34(d,J=4.4Hz,1H),7.20(d,J=8.3Hz,1H),6.96-6.89(dd,J=8.4,2.8Hz,1H),6.90-6.84(m,2H),6.81-6.73(m,1H),6.00(s,2H),5.69-5.60(t,J=5.8Hz,1H),5.06(s,2H),3.42-3.16(m,2H),2.93-2.68(t,J=7.3Hz,2H),1.87(s,3H);13C NMR(100MHz,CDCl3)δ170.4,157.2,147.5,146.8,143.0,137.0,135.2,130.8,129.3,128.8,128.1,127.6,123.2,122.4,116.7,114.1,109.7,108.3,101.2,70.1,40.7,31.9,23.2;HRMS(FAB)m/z:针对C24H23NO4Na的[M+Na+],412.1519;实验值,412.1524。
N-(4-(苄氧基)-2-(吡啶-3-基)苯乙基)乙酰胺(8o):1H NMR(400MHz,CDCl3)δ8.69-8.52(dd,J=18.2,4.0Hz,2H),7.71-7.63(dt,J=7.8,2.0Hz,1H),7.49-7.31(m,7H),7.06-6.97(dd,J=8.5,2.8Hz,1H),6.84(d,J=2.8Hz,1H),5.06(s,2H),3.36-3.20(q,J=6.5Hz,2H),2.78-2.67(dd,J=8.1,6.6Hz,2H),1.90(s,3H);13C NMR(125MHz,CDCl3)δ170.1,157.5,149.6,148.5,139.5,136.9,131.2,129.0,128.8,128.3,127.7,123.5,116.9,115.0,70.3,40.7,32.2,23.5;HRMS(FAB)m/z:针对C22H23N2O2的[M+H+],计算值,347.1759;实验值,347.1754。
N-(4-(苄氧基)-2-(吡啶-4-基)苯乙基)乙酰胺(8p):1H NMR(400MHz,CDCl3)δ8.66(d,J=5.1Hz,2H),7.46-7.39(m,5H),7.36(s,1H),7.30(s,2H),7.06-7.01(m,1H),6.84(d,J=2.7Hz,1H),5.94(d,J=4.8Hz,1H),5.09(s,2H),3.35-3.23(dd,J=14.5,6.4Hz,2H),2.74(t,J=7.5Hz,2H),1.90(s,3H);13C NMR(100MHz,CDCl3)δ171.4,158.1,156.3,137.2,132.3,132.2,130.8,128.7,128.5,129.7,127.5,117.9,106.2,103.0,69.9,41.1,29.7,29.6,23.1;HRMS(FAB)m/z:针对C22H22N2O2Na的[M+Na+],计算值,369.1579;实验值,369.1573。
实施例9.用于化合物8a-p的通用氢解程序.
N-(2-(5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(9a):将碳载钯(10%,5mg)加入到脱气MeOH(3.5mL)中的8a(120mg,0.35mmol)中并将溶液置于H2气氛下。12小时后,用DCM稀释溶液并通过硅藻土过滤。浓缩洗脱液以得到黄色固体,其通过柱色谱(SiO2,100:5,DCM:MeOH)纯化以得到浅黄色非晶固体状的苯酚9a(64mg,0.25mmol,79%)。1H NMR(400MHz,CDCl3)δ7.25-7.14(m,5H),7.11-7.05(m,1H),6.90(d,J=8.3Hz,1H),6.64(d,J=8.3Hz,1H),6.59(d,J=2.5Hz,1H),5.61(t,J=5.5Hz,1H),3.12-3.02(m,2H),2.55(t,J=7.1Hz,2H),1.66(s,3H);13C NMR(100MHz,CDCl3)δ171.2,155.2,143.4,141.6,130.8,129.1,128.4,127.2,127.2,117.4,115.0,41.1,31.8,23.2;HRMS m/z:针对C16H17NO2Na的[M+Na+],计算值,278.1151;实验值,278.1155。
N-(2-(3'-氟-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(9b):1H NMR(500MHz,MeOD)δ7.88(s,1H),7.39(d,J=7.5Hz,1H),7.16-6.99(m,4H),6.77(d,J=8.1Hz,1H),6.62(d,J=2.6Hz,1H),3.15(t,J=6.6Hz,2H),2.66(t,J=7.4Hz,2H),1.80(s,3H);13C NMR(125MHz,MeOD)δ173.1,164.8,162.9,156.7,145.5,143.3,132.0,131.0,128.3,126.1,117.6,115.9,114.7,41.8,32.8,22.5;HRMS m/z:针对C16H16FNO2Na的[M+Na+],计算值,296.1063;实验值,296.1059。
N-(2-(4'-氟-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(9c):1H NMR(400MHz,MeOD)δ7.26-7.20(m,2H),7.11-7.03(m,3H),6.71(dd,J=8.3,2.5Hz,1H),6.56(d,J=2.5Hz,1H),3.07(t,J=7.6Hz,2H),2.60(t,J=7.6Hz,2H),1.78(s,3H);13C NMR(100MHz,MeOD)δ173.0,156.7,143.5,139.2,131.9,131.9,131.8,128.5,117.8,116.0,115.8,115.7,41.8,32.9,22.5;HRMS m/z:针对C16H16FNO2Na的[M+Na+],计算值,296.1063;实验值,296.1065。
N-(2-(2'-氯-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(9d):1H NMR(400MHz,CDCl3)δ8.37(br s,OH),7.45-7.39(m,1H),7.32-7.24(m,2H),7.21-7.15(m,1H),7.09(d,J=8.3Hz,1H),6.85(dd,J=8.3,2.5Hz,1H),6.68(d,J=2.6Hz,1H),5.62(s,1H),3.40-3.14(m,2H),2.63-2.44(dd,J=7.1,5.1Hz,2H),1.86(s,3H);13C NMR(125MHz,CDCl3)δ171.1,155.1,140.5,140.0,133.2,131.4,130.5,129.7,129.0,127.7,126.9,117.3,115.7,40.5,31.8,23.3;HRMS m/z:针对C16H17ClNO2的[M+H+],290.0948;实验值,290.0941。
N-(2-(3'-氯-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(9e):1H NMR(500MHz,CDCl3)δ7.40-7.09(m,5H),6.83-6.76(dq,J=8.1,4.9,3.8Hz,1H),6.76-6.67(dd,J=18.3,2.7Hz,1H),3.34-3.23(p,J=6.6Hz,2H),2.77-2.64(dt,J=14.3,7.2Hz,2H),1.76(s,3H);13C NMR(125MHz,CDCl3)δ170.8,154.9,143.6,141.6,131.0,130.9,129.7,129.2,128.5,127.5,117.4,115.5,115.0,41.0,32.0,23.4;HRMS m/z:针对C16H16ClNO2Na的[M+Na+],计算值,312.0762;实验值,312.0788。
N-(2-(5-羟基-3'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(9f):1H NMR(400MHz,CDCl3)δ7.64-7.39(m,4H),7.07(s,1H),6.82(s,1H),6.73(s,1H),6.00(s,1H),3.34-3.18(q,J=6.8Hz,2H),2.66(t,J=7.0Hz,2H),1.87(s,3H);13C NMR(100MHz,CDCl3)δ171.3,155.4,142.4,141.8,132.6,131.0,130.8,128.9,126.9,125.8,125.8,124.0,117.3,115.6,60.7,41.0,21.2;HRMS m/z:针对C17H16F3NO2Na的[M+Na+],计算值,346.1031;实验值,346.1040.
N-(2-(5-羟基-4'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(9g):1H NMR(400MHz,CDCl3)δ7.54(d,2H,J=8.0Hz),7.31(d,2H,J=8.0Hz),7.03(d,1H,J=8.3Hz),6.72(dd,1H,J=2.5,8.3Hz),6.59(d,1H,J=2.5Hz),4.09(br s,2H),3.10(t,J=7.5Hz,2H),2.56(t,2H,J=7.5Hz),1.76(s,3H);13C NMR(100MHz,CDCl3)δ170.5,155.1,146.3,141.7,130.8,129.5,127.1,125.1(q,J=4.2Hz),116.9,116.5,115.3,45.6,40.6,23.0;HRMS m/z:针对C17H16F3NO2Na的[M+H+],计算值,346.1031;实验值,346.1025。
N-(2-(5-羟基-2'-(甲硫基)-[1,1'-联苯]-2-基)乙基)乙酰胺(9h):1H NMR(500MHz,CDCl3)δ7.40-7.34(m,1H),7.25-7.14(m,3H),7.12-7.07(m,1H),6.86-6.82(dd,J=8.4,2.7Hz,1H),6.68(d,J=2.7Hz,1H),5.51(br s,NH),3.42-3.16(m,2H),2.55(t,J=6.8Hz,2H),2.37(s,3H),1.85(s,3H);13C NMR(125MHz,CDCl3)δ170.5,154.5,141.2,139.1,137.6,130.7,123.0,128.8,128.5,124.6,124.0,117.3,115.6,40.2,31.6,23.4,15.2;HRMS m/z:针对C17H19NO2SNa的[M+Na+],计算值,324.1034;实验值,324.1035。
N-(2-(5-羟基-2'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(9i):1H NMR(400MHz,CDCl3)δ7.52(br s,OH),7.41-7.31(m,1H),7.14-7.07(dd,J=8.4,6.4Hz,1H),7.05-6.94(m,3H),6.83-6.76(dd,J=8.3,2.7Hz,1H),6.70(d,J=2.7Hz,1H),5.55(s,1H),3.76(s,3H),3.41-3.17(ddt,J=34.4,13.1,6.5Hz,2H),2.57(t,J=6.9Hz,2H),1.85(s,3H);13C NMR(125MHz,CDCl3)δ171.0,156.4,155.1,139.9,131.3,130.5,130.1,129.1,128.5,121.0,117.7,115.2,111.4,55.9,40.7,31.7,23.3;HRMS m/z:针对C17H19NO3Na的[M+Na+],计算值,308.1263;实验值,308.1264。
N-(2-(5-羟基-3'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(9j):1H NMR(400MHz,CDCl3)δ7.83(br s,OH),7.30-7.24(m,1H),7.06(d,J=8.2Hz,1H),6.90-6.70(m,5H),5.59(t,J=5.7Hz,1H),3.79(s,3H),3.33-3.19(q,J=6.9Hz,2H),2.69(t,J=7.1Hz,2H),1.85(s,3H);13C NMR(100MHz,CDCl3)δ171.1,159.4,155.1,143.3,143.0,130.9,129.5,127.3,121.7,117.2,115.1,115.0,112.6,55.4,41.1,31.8,23.3;HRMS m/z:针对C17H20NO3的[M+H+],计算值,286.1443;实验值,286.1436。
N-(2-(5-羟基-3'-甲基-[1,1'-联苯]-2-基)乙基)乙酰胺(9k):1H NMR(400MHz,CDCl3)δ7.50(br s,OH),7.30-7.24(m,1H),7.15(d,J=7.6Hz,1H),7.09-7.03(m,3H),6.80(d,J=7.6Hz,1H),6.73(s,1H),5.53(br s,NH),3.31-3.21(q,J=6.7Hz,2H),2.71(t,J=7.0Hz,2H),2.37(s,3H),1.85(s,3H);13C NMR(1001MHz,CDCl3)δ170.9,155.0,143.6,141.6,138.1,130.8,1230.0,128.3,128.0,127.4,126.3,117.4,114.9,41.1,31.8,23.3,21.7;HRMS m/z:针对C17H19NO2Na的[M+Na+],计算值,292.1308;实验值,292.1314。
N-(2-(5-羟基-3'-(吗啉基甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(9l):1H NMR(500MHz,CDCl3)δ7.36-7.23(m,4H),7.16(d,J=7.2Hz,1H),7.07(d,J=8.2Hz,1H),6.74-6.69(dd,J=8.2,2.7Hz,1H),6.62(d,J=2.6Hz,1H),5.50(br s,NH),3.74(m,4H),3.53(s,3H),3.29-3.20(q,J=6.7Hz,2H),2.69(t,J=7.0Hz,2H),2.49(t,J=4.8Hz,4H),1.87(s,3H);13C NMR(125MHz,CDCl3)δ170.5,155.0,143.4,141.7,130.9,130.2,128.4,128.2,117.5,115.0,66.9,63.4,53.8,40.8,32.0,23.4;HRMS m/z:针对C21H27N2O3的[M+H+],计算值,355.2022;实验值,355.2024。
N-(2-(4'-((叔丁基二甲基硅烷基)氧基)-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(9m):1H NMR(500MHz,CDCl3)δ7.16-7.10(d,J=6.7Hz,2H),7.10-7.06(d,J=8.2Hz,1H),7.00(br s,OH),6.91-6.84(d,J=8.4Hz,2H),6.79-6.72(m,2H),5.38(s,1H),3.34-3.21(q,J=6.6Hz,2H),2.78-2.64(t,J=6.9Hz,2H),1.93-1.81(s,3H),1.00(s,9H),0.24(s,6H);13C NMR(125MHz,CDCl3)δ170.7,155.0,154.9,143.3,134.6,130.9,130.3,127.8,120.0,117.5,114.7,41.0,32.0,26.0,23.4,18.4,-4.1;HRMS(FAB)m/z:针对C22H31NO3SiNa的[M+Na+],计算值,408.1965;实验值,408.1960。
N-(2-(苯并[d][1,3]间二氧杂环戊烯-5-基)-4-羟基苯乙基)乙酰胺(9n):1H NMR(500MHz,CDCl3)δ8.00(br s,OH),7.08-6.98(d,J=8.3Hz,1H),6.81-6.73(m,2H),6.73-6.68(m,2H),6.68-6.64(dd,J=7.9,1.7Hz,1H),5.97-5.92(s,2H),5.70-5.63(t,J=5.7Hz,1H),3.29-3.21(td,J=7.1,5.6Hz,2H),2.75-2.63(t,J=7.2Hz,2H),1.89-1.81(s,3H);13C NMR(125MHz,CDCl3)δ171.1,155.1,147.5,146.8,143.0,135.4,130.8,127.4,122.4,117.5,114.9,109.8,108.3,101.2,41.1,31.9,23.3;HRMS(FAB)m/z:针对C17H17NO4Na的[M+Na+],计算值,322.1050;实验值,322.1022。
N-(4-羟基-2-(吡啶-3-基)苯乙基)乙酰胺(9o):1H NMR(400MHz,CDCl3)δ8.54(s,2H),7.72(d,J=7.9Hz,1H),7.42-7.34(dd,J=8.0,4.8Hz,1H),7.14(d,J=8.4Hz,1H),6.90-6.84(dd,J=8.3,2.7Hz,1H),6.73(d,J=2.7Hz,1H),5.82(t,J=5.9Hz,2H),3.33-3.19(q,J=6.8Hz,2H),2.69(t,J=7.2Hz,2H),1.85(s,3H);13C NMR(100MHz,CDCl3)δ170.7,156.1,149.1,147.7,138.8,138.0,131.4,127.3,123.7,117.5,116.4,100.2,40.9,32.0,23.4;HRMS(FAB)m/z:针对C15H17N2O2的[M+H+],计算值,257.1290;实验值,257.1297。
N-(4-羟基-2-(吡啶-4-基)苯乙基)乙酰胺(9p):1H NMR(400MHz,CDCl3)δ8.69-8.60(m,2H),7.25(d,J=1.5Hz,2H),7.17(d,J=8.4Hz,1H),6.90-6.83(dd,J=8.4,2.7Hz,1H),6.70(d,J=2.7Hz,1H),6.02(br s,OH),5.47(s,1H),3.33-3.24(q,J=7.0Hz,2H),2.71(t,J=7.4Hz,2H),1.90(s,3H);13C NMR(125MHz,CDCl3)δ173.0,157.1,152.8,149.7,149.6,141.3,132.4,128.0,126.2,117.2,117.1,116.9,41.8,32.8,22.5;HRMS(FAB)m/z:针对C15H16N2O2Na的[M+Na+],计算值,279.1104;实验值,279.1109。
实施例10.用于化合物9a-p的活性诺维糖氨基甲酸酯偶联和随后的甲醇分解的通用程序:
将三氟化硼乙醚络合物(6.2μL,0.05mmol)加入到2.5mL无水DCM中的9a-p(0.25mmol)和活性诺维糖(0.2mmol)中。在室温下搅拌2小时后,加入三乙胺(150μL)并浓缩溶剂。经由柱色谱(SiO2,100:8DCM:丙酮)部分纯化残余物以得到无色泡沫状的与诺维糖偶联的产物,其直接用于下一步骤。将三乙胺(0.22mL,10%)加入到MeOH(2.2mL)中的环状碳酸酯(100mg,0.22mmol)中。12小时后,浓缩溶剂并经由柱色谱(SiO2,10:1,DCM:丙酮)纯化残余物以得到无色非晶固体状的不可分离的非对映异构体11a-p(参看以下针对非对映选择性的实验章节)。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11a):无色非晶固体(63%产率,经过2个步骤);1HNMR(500MHz,CDCl3)δ7.41-7.28(m,3H),7.28-7.18(dt,J=5.9,3.2Hz,2H),7.13(m,1H),6.97(m,1H),6.92-6.78(dd,J=7.6,2.7Hz,1H),5.55-5.47(dd,J=7.7,2.7Hz,1H),5.39(m,1H),4.14(m,2H),3.58-3.46(m,3H),3.34-3.15(m,4H),3.03(d,J=5.5Hz,1H),2.77-2.65(m,2H),1.84-1.76(m,3H),1.31(d,J=4.9Hz,3H),1.21-1.10(m,3H);13C NMR(125MHz,CDCl3)δ170.3,155.4,143.5,141.4,130.8,129.5,129.2,128.5,127.4,118.2,115.2,98.1,84.5,78.4,71.5,68.8,62.0,40.8,32.1,29.2,23.4,23.1;HRMS m/z:针对C24H32NO6的[M+H+],计算值,430.2224;实验值,430.2227。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11b):无色非晶固体(51%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ7.39(dd,1H,J=7.9,13.9Hz),7.22(d,1H,J=8.5Hz),7.07(dd,2H,J=7.5,10.5Hz),7.02(dd,1H,J=2.8,8.4Hz),6.99(m,1H),6.91(d,1H,J=2.7Hz),5.34(d,1H,J=1.3Hz),5.28(s,1H),4.20(d,1H,J=2.2Hz),3.80(m,1H),3.63(s,3H),3.30(d,1H),3.28(m,2H),2.75(t,2H,J=7.2Hz),2.63(m,2H,J=15.9Hz),1.87(s,3H),1.41(s,3H),1.28(s,3H);13C NMR(125MHz,CDCl3)δ169.9,163.5-161.6(d,J=251Hz)155.0,143.2(d,J=7.8Hz),142.1(d,J=1.8Hz),130.9,130.1,130.0(d,J=8.8Hz),124.8(d,J=2.8Hz),118.0,116.0(d,J=8.8Hz),115.4,114.3(d,J=21.6Hz),93.8,84.2,76.0,71.3,71.1,62.0,40.4,32.0,28.6,23.3,18.5;HRMS m/z:针对C24H31FNO6的[M+H+],计算值,448.2180;实验值,448.2174。通过HPLC(Phenomenex Luna C-18,5μm,10×250mm柱,用30%CH3CN和70%H2O洗脱,流速5.0mL/min)测定这种物质具有95.6%纯度(保留时间=6.401)。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(11c):无色非晶固体(57%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ7.25(dd,2H,J=5.4,8.6Hz),7.18(d,1H,J=8.5Hz),7.10(t,2H,J=8.7Hz),7.01(dd,1H,J=2.7,8.5Hz),6.87(d,1H,J=2.7Hz),5.54(d,1H,J=2.2Hz),5.37(t,1H,J=5.2Hz),4.20(dd,1H,J=3.3,9.1Hz),4.15(m,1H),3.59(s,3H),3.33(d,1H,J=9.1Hz),3.26(q,2H,J=6.9Hz),2.97(s,1H),2.81(s,1H),2.72(t,2H,J=7.3),1.87(s,3H),1.36(s,3H),1.22(s,3H);13C NMR(125MHz,CDCl3)δ170.2,163.2-161.3(d,J=250Hz),155.3,142.3,137.2(d,J=3.2Hz),130.8,130.8,130.7,129.5,118.1,115.4,115.3,115.3,97.9,84.4,78.3,71.4,68.7,62.0,40.6,32.1,29.1,23.4,23.1;HRMSm/z:针对C24H30FNO6的[M+Na+],计算值,470.1955;实验值,470.1958。
N-(2-(2'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11d):无色非晶固体(62%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ7.46(m,1H),7.31(m,2H),7.21(m,2H),7.03(m,1H),6.86(dd,1H,J=2.7,13.2Hz),5.55(m,1H),5.42(s,1H),4.20(dt,1H,J=3.0,9.1Hz),4.14(m,1H),3.59(s,3H),3.33(dd,1H,J=2.5,9.1Hz),3.26(ddt,2H,J=4.8,6.8,9.3Hz),3.11(s,1H),2.93(s,1H),2.58(tq,2H,J=7.1,14.2Hz),1.86(s,3H),1.35(d,3H,J=2.4Hz),1.20(t,3H,J=5.8Hz);13C NMR(125MHz,CDCl3)δ170.2,155.2,140.6,140.5,139.8,133.4,131.4,130.5,129.8,126.9,118.1,117.9,116.05,97.9,84.5,78.4,71.5,71.4,68.7,62.1,62.0,40.2,40.2,32.1,32.1,29.3,29.2,23.5,23.1,23.0;HRMS m/z:针对C24H30ClNO6Na的[M+Na+],486.1659;实验值,486.1652。
N-(2-(3'-氯-5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11e):无色非晶固体(55%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ7.35(m,2H),7.28(m,1H),7.18(m,2H),7.03(dd,1H,J=2.7,8.5Hz),6.87(d,1H,J=2.7Hz),5.55(t,1H,J=2.5Hz),5.34(m,1H),4.21(dd,1H,J=3.1,9.1Hz),4.16(m,1H),3.60(s,3H),3.34(dd,1H,J=1.9,9.1Hz),3.28(m,2H),2.75(dt,4H,J=7.3,14.5Hz),1.88(s,3H),1.37(s,3H),1.22(s,3H);13C NMR(125MHz,CDCl3)δ170.1,155.4,143.5,142.0,134.3,131.0,130.9,129.8,129.4,128.5,127.6,127.4,118.2,115.7,97.9,84.6,78.4,71.5,68.7,62.1,40.8,32.1,29.2,23.6,23.1;HRMS m/z:针对C24H30ClNO6Na的[M+Na+],计算值,486.1659;实验值,486.1642。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11f):无色非晶固体(52%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ7.64(d,1H,J=7.7Hz),7.55(t,2H,J=7.6Hz),7.49(m,1H),7.23(d,1H,J=8.5Hz),7.06(dd,1H,J=2.7,8.4Hz),6.89(d,1H,J=2.7Hz),5.56(d,1H,J=2.2Hz),5.31(s,1H),4.19(m,2H),3.60(s,3H),3.34(d,1H,J=9.1Hz),3.29(dd,2H,J=7.0,13.3Hz),2.72(t,2H,J=7.3Hz),2.69(s,1H),2.64(s,1H),1.87(s,3H),1.37(s,3H),1.22(s,3H);13C NMR(125MHz,CDCl3)δ170.1,155.4,142.1,141.9,132.6,131.0,130.7(q,J=31.5Hz),129.4,129.0,125.9(q,J=3.6,7.2Hz),125.3,124.2(q,J=3.6,7.2Hz),123.1,118.0,115.8,97.9,84.4,77.4,71.4,68.7,62.0,40.6,32.1,29.8,29.2,23.4,23.0;HRMS m/z:针对C25H30F3NO6Na的[M+Na+],520.1923;实验值,520.1932。通过HPLC(Phenomenex Luna C-18,5μm,10×250mm柱,用30%CH3CN和70%H2O洗脱,流速5.0mL/min)测定这种物质具有97.2%纯度(保留时间=7.631)。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11g):无色非晶固体(49%产率,经过2个步骤);1H NMR(400MHz,CDCl3)δ7.70(d,J=7.6Hz,2H),7.43(d,J=7.9Hz,2H),7.24(d,J=8.4Hz,1H),7.09-7.03(dd,J=8.6,2.7Hz,1H),6.90(d,J=2.7Hz,1H),5.55(d,J=2.3Hz,1H),5.33(m,1H),4.26-4.11(m,2H),3.60(s,3H),3.36-3.25(m,3H),2.74(t,J=7.4Hz,2H),2.56(br s,2OH),1.88(s,3H),1.37(s,3H),1.22(s,3H);13C NMR(125MHz,MeOD)δ173.1,156.8,146.9,143.2,132.1,130.9,130.7,130.5,130.2,126.3,126.2,124.7,118.5,116.8,100.1,85.3,79.5,72.8,69.5,62.1,41.7,32.9,29.2,23.6,22.5;HRMS m/z:针对C25H30F3NO6Na的[M+Na+],520.1923;实验值,520.1934。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2'-(甲硫基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11h):无色非晶固体(63%产率,经过2个步骤);1H NMR(400MHz,CDCl3)δ7.36(t,1H,J=7.0Hz),7.27(m,3H),7.09(m,1H),7.01(m,1H),6.87(s,1H),5.64(s,1H),5.54(m,1H),4.16(m,2H),3.32(d,2H,J=8.8Hz),3.27(m,2H),3.06(s,1H),2.56(t,2H,J=6.2Hz),2.36(d,3H,J=7.6Hz),1.83(s,3H),1.33(s,3H),1.20(s,3H);13C NMR(100MHz,CDCl3)δ170.3,155.1,155.0,141.0,138.9,130.5,130.1,129.8,128.4,124.6,124.2,118.3,116.2,115.9,97.9,84.5,78.3,71.5,68.7,62.0,53.6,40.1,31.7,29.3,23.3,15.3,15.2;HRMS m/z:针对C25H33NO6SNa的[M+Na+],计算值,498.1926;实验值,498.1925。通过HPLC(Phenomenex Luna C-18,5μm,10×250mm柱,用30%CH3CN和70%H2O洗脱,流速5.0mL/min)测定这种物质具有95%纯度(保留时间=7.465)。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(11i):无色非晶固体(41%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ7.36(ddd,1H,J=1.8,7.6,8.2Hz),7.18(d,1H,J=8.3Hz),7.12(t,1H,J=5.8Hz),7.02(m,3H),6.87(dd,1H,J=2.3,11.3Hz),5.54(s,1H),5.39(s,1H),4.21(dt,1H,J=3.3,9.0Hz),4.15(m,1H),3.77(d,3H,J=6.9Hz),3.60(s,3H),3.33(d,1H,J=8.7Hz),3.29(m,2H),2.73(s,1H),2.66(s,1H),2.60(dd,2H,J=6.5,12.8Hz),1.84(s,3H),1.37(s,3H),1.24(s,3H);13C NMR(125MHz,CDCl3)δ170.0,156.4,155.2,139.9,131.2,130.8,130.2,130.0,129.2,120.9,118.6,118.3,115.7,115.2,111.4,111.2,98.0,97.9,84.5,78.2,71.4,68.7,62.0,55.9,55.9,40.3,31.9,30.2,29.3,29.2,23.4,23.1;HRMS m/z:针对C25H34NO7的[M+H+],计算值,460.2335;实验值,460.2336。通过HPLC(Phenomenex Luna C-18,5μm,10×250mm柱,用30%CH3CN和70%H2O洗脱,流速5.0mL/min)测定这种物质具有96.1%纯度(保留时间=5.057)。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺(11j):无色非晶固体(53%产率,经过2个步骤);1H NMR(400MHz,CDCl3)δ7.31(t,J=7.9Hz,1H),7.17(d,J=8.5Hz,1H),7.02-6.96(dd,J=8.5,2.7Hz,1H),6.92-6.83(m,4H),6.81(d,J=1.5Hz,2H),5.54(d,J=2.2Hz,1H),5.45(s,1H),4.25-4.16(dd,J=9.1,3.2Hz,1H),4.17-4.10(dd,J=3.3,2.2Hz,1H),3.82(s,3H),3.58(s,3H),3.39-3.20(m,3H),3.24(br s,OH),2.97(br s,OH),2.75(t,J=7.1Hz,2H),1.85(s,3H),1.35(s,3H),1.20(s,3H);13C NMR(125MHz,CDCl3)δ170.4,159.5,155.3,143.3,142.8,130.8,129.5,129.5,121.7,118.0,115.3,115.1,112.7,98.1,84.5,78.4,71.5,68.7,62.0,55.4,40.9,32.0,29.1,23.4,23.1;HRMS m/z:针对C25H34NO7的[M+H+],计算值,460.2335;实验值,460.2322。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-甲基-[1,1'-联苯]-2-基)乙基)乙酰胺(11k):无色非晶固体(44%产率,经过2个步骤);1H NMR(400MHz,CDCl3)δ7.32-7.27(m,1H),7.16(d,J=6.6Hz,2H),7.10-7.04(m,2H),6.99(d,J=8.5Hz,1H),6.88(s,1H),5.55(s,1H),5.41(s,1H),4.25-4.08(m,2H),3.57(s,3H),3.37-3.20(m,5H),2.75(t,J=7.0Hz,2H),2.39(s,3H),1.83(s,3H),1.35(s,3H),1.20(s,3H);13C NMR(100MHz,CDCl3)δ170.4,155.3,143.6,141.3,138.1,130.8,130.0,129.5,128.3,128.1,126.3,118.1,115.1,98.1,84.5,78.4,71.5,68.7,62.0,40.9,32.0,29.2,23.4,23.1,21.7;HRMS m/z:针对C25H33NO6Na的[M+H+],计算值,466.2206;实验值,466.2203。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3'-(吗啉基甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺(11l):无色非晶固体(47%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ7.41-7.29(m,2H),7.27(m,1H),7.19(d,J=8.1Hz,2H),7.04-6.99(dd,J=8.5,2.7Hz,1H),6.91(d,J=2.7Hz,1H),5.55(d,J=2.4Hz,1H),5.35(s,1H),4.26-4.18(dd,J=9.0,3.3Hz,1H),4.15(t,J=2.8Hz,1H),3.72(t,J=4.7Hz,4H),3.59(s,3H),3.56(s,2H),3.34(d,J=9.0Hz,1H),3.30-3.21(q,J=6.7Hz,2H),2.75(t,J=7.1Hz,2H),2.58-2.41(m,6H),1.85(s,3H),1.36(s,3H),1.23(s,3H);13C NMR(125MHz,CDCl3)δ155.4,143.4,141.5,137.8,130.9,130.1,129.6,128.5,128.3,128.2,118.2,115.3,98.1,84.6,78.4,71.5,68.8,67.1,63.5,62.0,53.8,40.7,32.2,29.2,23.5,23.2;HRMS(FAB)m/z:针对C29H40N2O7Na的[M+Na+],计算值,551.2728;实验值,551.2734。
N-(2-(5-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-4'-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(11m):
在遵循与化合物11a-p相同的程序进行环状碳酸酯水解后,将经过TBS保护的粗化合物溶解于THF(2mL)中并在0℃和氩气氛下逐滴加入四丁基氟化铵(1.5eq.)。1小时后,用水终止反应并用EtOAc(3×10mL)萃取;用饱和氯化钠水溶液洗涤合并后的有机级分,经无水Na2SO4干燥,过滤并浓缩。通过柱色谱(SiO2;10:1,DCM:丙酮)纯化残余物以得到非晶固体状的乙酰胺11m(40%产率,经过3个步骤)。1H NMR(500MHz,MeOD)δ7.20(d,J=8.4Hz,1H),7.15-7.08(d,J=8.4Hz,2H),6.96(dd,J=8.4,2.6Hz,1H),6.85-6.79(m,3H),5.45(d,J=2.4Hz,1H),4.12(dd,J=9.3,3.3Hz,1H),3.96(t,J=2.8Hz,1H),3.59(s,3H),3.21(d,J=9.3,Hz,1H),3.16(dd,J=8.5,6.5Hz,2H),2.70(dd,J=8.5,6.5Hz,2H),1.84(s,3H),1.32(s,3H),1.18(s,3H);13C NMR(125MHz,MeOD)δ173.1,157.7,156.6,144.7,134.0,131.7,131.2,131.1,118.9,116.0,115.7,100.1,85.4,79.4,72.8,69.5,62.1,41.8,33.0,29.2,23.6,22.5;HRMS(FAB)m/z:针对C24H31NO7Na的[M+Na+],计算值,468.1998;实验值,468.1999。
N-(2-(苯并[d][1,3]间二氧杂环戊烯-5-基)-4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)苯乙基)乙酰胺(11n):无色非晶固体(51%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ7.15(d,J=8.5Hz,1H),7.00-6.96(dd,J=8.5,2.7Hz,1H),6.88(d,J=2.6Hz,1H),6.84(d,J=7.9Hz,1H),6.76(d,J=1.6Hz,1H),6.74-6.69(m,1H),6.01(s,2H),5.54(d,J=2.4Hz,1H),5.40(s,1H),4.21(dd,J=9.1,3.3Hz,1H),4.14(t,J=2.7Hz,2H),3.58(s,3H),3.33(d,J=9.1Hz,1H),3.30-3.23(q,J=6.9Hz,2H),3.11(br s,OH),2.92(br s,OH),2.74(t,J=7.2Hz,2H),1.86(s,3H),1.34(s,3H),1.20(s,3H);13C NMR(125MHz,CDCl3)δ170.2,155.4,147.7,147.0,143.1,135.3,130.8,129.7,122.6,118.3,115.2,109.9,108.4,101.3,98.1,84.6,78.4,71.5,68.8,62.0,40.8,32.1,29.2,23.4,23.2;HRMS(FAB)m/z:针对C25H31NO8Na的[M+Na+],计算值,496.1947;实验值,496.1940。通过HPLC(Phenomenex Luna C-18,5μm,10×250mm柱,用40%CH3CN和60%H2O洗脱,流速5.0mL/min)测定这种物质具有98.4%纯度(保留时间=4.384)。
N-(4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2-(吡啶-3-基)苯乙基)乙酰胺(11o):无色非晶固体(37%产率,经过2个步骤);1H NMR(500MHz,CDCl3)δ8.55(d,J=3.9Hz,1H),8.49(s,1H),7.60(m,1H),7.35(dd,J=7.8,4.5Hz,1H),7.20(d,J=8.5Hz,1H),7.05-6.99(dd,J=8.4,2.7Hz,1H),6.85(d,J=2.6Hz,1H),5.52(d,J=2.4Hz,1H),5.36(s,1H),4.14(dd,J=3.4,9.1Hz,1H),4.10(t,J=2.7Hz,1H),3.59(s,3H),3.31(d,J=9.0Hz,1H),3.27-3.20(m,2H),2.68(t,J=7.3Hz,2H),1.86(s,3H),1.33(s,3H),1.17(s,3H);13C NMR(125MHz,CDCl3)δ170.2,155.5,149.8,148.7,139.5,136.8,131.1,131.0,130.6,129.8,123.4,118.3,118.2,116.1,98.0,84.5,78.5,71.4,68.7,62.1,40.7,32.2,29.2,23.5,23.1;HRMS(FAB)m/z:针对C23H31N2O6的[M+Na+],计算值,431.2182;实验值,431.2194。
N-(4-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-2-(吡啶-4-基)苯乙基)乙酰胺(11p):无色非晶固体(42%产率,经过2个步骤);1H NMR(400MHz,CDCl3)δ8.73-8.63(dd,J=5.7,3.9Hz,2H),7.27-7.23(m,3H),7.11-7.03(m,1H),6.86(t,J=2.8Hz,1H),5.55(d,J=2.3Hz,1H),5.41-5.31(m,2H),4.26-4.13(m,2H),4.05(d,J=6.9Hz,1H),3.61(s,3H),3.36-3.25(m,2H),2.78-2.71(dd,J=8.3,6.8Hz,2H),1.90(s,3H),1.39(s,3H),1.24(s,3H);13C NMR(125MHz,CDCl3)δ170.1,155.5,149.8,140.5,131.4,129.1,124.4,117.9,116.3,98.0,94.1,84.5,71.5,71.4,68.7,62.1,40.7,32.2,29.2,28.8,23.5,23.1,18.7;HRMS(FAB)m/z:针对C23H30N2O6Na的[M+Na+],计算值,453.2001;实验值,453.1972。
实施例11.(Z)-4-(苄氧基)-2-(甲氧基甲氧基)-1-(2-硝基乙烯基)苯(14):将硝基甲烷(11.5mL)加入到醛13(1.24g,4.6mmol)与乙酸铵(0.63g,8.2mmol)的混合物中并加热到50℃。完成(20分钟)后,将反应混合物冷却到室温并且不经处理即通过柱色谱(SiO2,4:1,Hex:EtOAc)纯化以得到透明的无色油状的硝基苯乙烯14(1.22g,3.87mmol,84%)。1HNMR(400MHz,CDCl3)δ8.17(d,J=13.4Hz,1H),7.80(d,J=13.6Hz,1H),7.50-7.32(m,6H),6.88(d,J=2.5Hz,1H),6.67(m,1H),5.30(s,2H),5.12(s,2H),3.52(s,3H);13C NMR(100MHz,CDCl3)δ163.4,159.0,136.1,136.0,135.6,133.5,128.8,128.5,127.7,127.7,113.0,108.6,102.2,94.7,70.5,56.6;HRMS(FAB)m/z:针对C17H17NO5Na的[M+Na+],计算值,338.1004;实验值,338.1007。
实施例12.4'-(苄氧基)-2'-(甲氧基甲氧基)-2-硝基-1,2,3,6-四氢-1,1'-联苯(15):在2mL密封管中将硝基苯乙烯14(0.65g,2.06mmol)溶解于甲苯(0.6mL)中并冷却到-78℃。将丁二烯鼓入溶液中使体积翻倍,然后密封所述管并加热到回流维持48小时。为了防止丁二烯气体爆沸,所述管再次冷却到-78℃并且直接通过柱色谱(SiO2;3:1,Hex:EtOAc)纯化以得到环己烯15(0.72g,1.96mmol,95%)。1H NMR(500MHz,CDCl3)δ7.40(m,4H),7.36-7.28(m,1H),7.06(d,J=8.4Hz,1H),6.80(d,J=2.4Hz,1H),6.56(dd,J=8.4,2.5Hz,1H),5.86-5.77(m,1H),5.71(ddd,J=9.8,5.1,2.3Hz,1H),5.27-5.20(m,1H),5.20(s,2H),5.00(s,2H),3.70(dt,J=17.0,8.7Hz,1H),3.49(s,J=12.7Hz,3H),2.84-2.74(m,1H),2.71(ddd,J=13.2,8.4,1.5Hz,1H),2.45(m,2H);13C NMR(125MHz,CDCl3)δ159.2,156.1,136.9,129.3,128.6,127.0,122.5,120.9,107.8,120.6,94.6,85.6,70.1,31.5,31.3,29.7。
实施例13.N-(4'-(苄氧基)-2'-(甲氧基甲氧基)-1,2,3,6-四氢-[1,1'-联苯]-2-基)乙酰胺(16):将硝基化合物13(0.23g,0.62mmol)溶解于异丙醇(12.4mL)和1M HCl水溶液(6.2mL)中。加入锌粉(811mg,12.4mmol)并在50℃下剧烈搅拌混合物1.5小时。冷却到室温后,加入饱和NaHCO3(8mL)并另外搅拌得到的混合物20分钟。通过过滤去除固体并用DCM(3×20mL)萃取剩余溶液。合并有机层并用饱和氯化钠水溶液洗涤,干燥(Na2SO4)并浓缩以得到透明的无色油状的胺(0.20g,0.59mmol,95%)。
在大气气氛和室温下将乙酸酐(62μL,0.65mmol)和三乙胺(95μL,0.68mmol)加入到胺(0.62mmol)于DCM(6.2mL)中的溶液中。3小时后,用饱和氯化铵水溶液终止反应并用DCM(3×10mL)萃取;用盐水洗涤合并后的有机级分,干燥(Na2SO4),过滤并浓缩。通过柱色谱(SiO2;3:1,Hex:EtOAc)纯化残余物以得到乙酰胺16(0.17g,0.46mmol,74%)。1H NMR(500MHz,CDCl3)δ7.42(d,J=7.8Hz,2H),7.39-7.33(t,J=7.2Hz,2H),7.33-7.28(m,1H),7.12(d,J=8.5Hz,1H),6.77(s,1H),6.63(d,J=8.5Hz,1H),5.90(d,J=8.4Hz,1H),5.71(d,J=36.2Hz,2H),5.17(s,2H),5.02(s,2H),4.36-4.23(dtd,J=13.8,10.4,9.9,7.2Hz,1H),3.50(s,3H),3.31-3.22(dd,J=18.6,7.9Hz,1H),2.59(d,J=17.3Hz,1H),2.33(s,2H),2.02-1.93(m,1H),1.74(s,3H);13C NMR(125MHz,CDCl3)δ169.8,158.3,156.1,136.9,128.5,128.3,127.9,127.6,126.7,125.0,124.4,108.0,102.9,95.6,70.0,56.2,48.8,37.4,33.0,32.6,23.1;HRMS(FAB)m/z:针对C23H27NO4Na的[M+Na+],计算值,404.1832;实验值,404.1827。
实施例14.N-(4'-(苄氧基)-2'-羟基-1,2,3,6-四氢-[1,1'-联苯]-2-基)乙酰胺:将催化量的浓HCl(几滴)加入到甲醇(7.1mL)中的经MOM保护的苯酚16(0.27g,0.71mmol)中并在50℃下剧烈搅拌过夜。完成后,浓缩反应混合物并通过柱色谱(SiO2;5:100,MeOH:DCM)纯化以得到苯酚(0.19g,0.58mmol,81%)。1H NMR(400MHz,CDCl3)δ8.86(s,1H),7.41-7.25(m,5H),7.01(d,J=8.5Hz,1H),6.73(d,J=2.4Hz,1H),6.48(d,J=6.0Hz,1H),5.73(m,1H),5.65(m,1H),4.96(s,2H),4.26(m,1H),3.42(m,1H),2.55-2.12(m,4H),1.98(s,3H);13CNMR(100MHz,CDCl3)δ173.2,158.3,155.4,136.9,128.5,128.0,127.9,127.6,127.0,123.9,121.1,107.2,103.4,69.9,51.9,50.0,36.6,31.6,21.0;HRMS(FAB)m/z:针对C21H23NO3Na的[M+Na+],计算值,360.1576;实验值,360.1571。
实施例15.三氟甲烷磺酸2'-乙酰胺基-4-(苄氧基)-1',2',3',6'-四氢-[1,1'-联苯]-2-酯(17):在0℃下搅拌苯酚(0.19g,0.58mmol)于无水DCM(5.8mL)中的溶液并加入三乙胺(0.12mL,0.87mmol),随后加入N-苯基-双(三氟甲烷磺酰亚胺)(0.31g,0.87mmol)。完成后,通过加入水(50mL)终止反应,用饱和NaCl水溶液洗涤,干燥(Na2SO4),过滤并浓缩。通过柱色谱(SiO2,3:1,Hex:EtOAc)纯化残余物以得到透明的黄色油状的三氟甲烷磺酸酯17(0.23g,0.49mmol,85%)。1H NMR(400MHz,CDCl3)δ7.45-7.31(m,6H),7.00(d,J=11.2Hz,1H),6.84(d,J=2.4Hz,1H),5.70(m,2H),5.60(d,J=9.3Hz,1H),5.04(s,2H),4.53-4.38(dt,J=15.2,10.2Hz,1H),3.18-3.03(td,J=11.2,5.2Hz,1H),2.63-2.50(dd,J=16.2,4.2Hz,1H),2.42-2.32(m,1H),2.28-2.15(m,1H),2.11-1.97(t,J=14.5Hz,1H),1.71(s,3H);13C NMR(100MHz,CDCl3)δ169.7,158.2,147.6,136.0,129.9,128.8,128.5,128.1,127.7,126.1,125.4,115.8,108.2,70.7,48.3,38.5,34.8,33.7,23.2;HRMS(FAB)m/z:针对C22H22F3NO5SNa的[M+Na+],计算值,492.106318;实验值,492.1067。
实施例16.N-(4'-(苄氧基)-3”-氟-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(18a):遵循以上对于6a-p所述的相同的铃木偶联程序。1H NMR(400MHz,CDCl3)δ7.47-7.30(m,7H),7.13-7.05(t,J=8.9Hz,1H),7.05-7.00(t,J=7.2Hz,2H),6.97(d,J=10.9Hz,1H),6.80(d,J=2.7Hz,1H),5.72-5.53(m,2H),5.06(s,2H),4.91(d,J=8.7Hz,1H),4.36-4.24(m,1H),2.90-2.75(dd,J=19.2,8.2Hz,1H),2.59-2.45(dt,J=16.3,4.4Hz,1H),2.36(m,2H),1.75(s,3H);13C NMR(100MHz,CDCl3)δ169.3,156.8,143.9,142.3,137.0,132.6,130.2,130.2,128.8,128.5,128.2,127.8,126.7,125.2,125.0,116.4,116.2,116.0,115.2,114.5,114.3,70.2,49.4,40.5,35.3,33.4,23.5;HRMS(FAB)m/z:针对C27H26FNO2Na的[M+Na+],计算值,438.1840;实验值,438.1818。
N-(4'-(苄氧基)-3”-(三氟甲基)-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(18b):遵循以上对于6a-p所述的相同的铃木偶联程序。1H NMR(400MHz,CDCl3)δ7.73-7.30(m,10H),7.05(d,J=8.7Hz,1H),6.85(s,1H),5.66(m,2H),5.16(d,J=8.5Hz,1H),5.08(s,2H),4.43-4.29(m,1H),2.90-2.74(q,J=10.0,9.0Hz,1H),2.50(d,J=17.7Hz,1H),2.40-2.28(dd,J=6.9,3.9Hz,2H),1.75(s,3H);13C NMR(101MHz,CDCl3)δ169.7,156.9,142.4,141.9,136.9,132.6,131.1,130.8,129.1,128.7,128.6,128.2,127.7,126.6,126.0,125.9,125.0,124.3,124.2,116.3,115.3,70.2,49.4,40.6,35.2,33.1,23.4;HRMS(FAB)m/z:针对C28H26F3NO2Na的[M+Na+],计算值,488.1813;实验值,488.1812。
实施例17.N-(3”-氟-4'-羟基-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(19a):将1,2-乙二醇(0.22mL,2.66mmol)和BF3OEt2(0.176mL,1.4mmol)加入到DCM(1.8mL)中的苄基醚18a(64mg,0.14mmol)中。8小时后,浓缩反应混合物并通过柱色谱(SiO2,10:100,MeOH:DCM)纯化以得到非晶固体状的苯酚19a(45mg,0.12mmol,86%)。1H NMR(500MHz,CDCl3)δ8.98(s,1H),7.40-7.34(q,J=7.1,6.2Hz,1H),7.27(d,J=7.6Hz,1H),7.10-7.01(m,2H),6.96(d,J=9.4Hz,1H),6.84-6.79(dd,J=8.5,2.6Hz,1H),6.68(d,J=2.6Hz,1H),5.73-5.52(m,2H),4.51-4.38(dt,J=9.9,5.0Hz,1H),2.88-2.77(q,J=9.5,7.9Hz,1H),2.43(d,J=17.3Hz,1H),2.34(m,2H),2.18(s,1H),1.77(s,3H);13C NMR(125MHz,CDCl3)δ170.5,163.6-161.7(d,J=244.0Hz),155.2,144.2(d,J=7.6Hz),142.3,130.8,130.1(d,J=8.4Hz),128.2,127.0,125.0(d,J=2.2Hz),124.7,116.5,116.3(d,J=20.3Hz),115.9,114.2(d,J=20.3Hz,49.6,40.8,35.5,33.5,23.2;HRMS(FAB)m/z:针对C21H25FNO2Na的[M+Na+],348.1376;实验值,348.1379。
N-(4'-羟基-3”-(三氟甲基)-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(19b):遵循与19a相同的程序。1H NMR(400MHz,CDCl3)δ9.20(s,1H),7.66-7.56(m,4H),7.29(d,J=8.5Hz,1H),6.82-6.72(d,J=10.5Hz,1H),6.65(s,1H),5.65(m,1H),5.54(m,1H),5.21(d,J=9.7Hz,2H),4.56-4.33(m,1H),2.76-2.61(m,1H),2.46-2.24(m,3H),1.75(s,3H);13C NMR(100MHz,CDCl3)δ170.5,155.3,142.7,142.0,132.6,130.8,130(q,J=32.5Hz),128.8,128.4,126.9,126.0(m),124.7,124.0(m),116.7,116.0,49.6,40.9,35.6,33.5,23.2;HRMS(FAB)m/z:针对C21H20F3NO2Na的[M+Na+],计算值,398.1344;实验值,398.1346。
实施例18.N-(4'-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3”-氟-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(20a):遵循以上对于11a-p所述的相同的诺维糖偶联程序以得到作为非对映异构体的不可分离的混合物的20a。1H NMR(500MHz,CDCl3)δ7.32(ddd,1H,J=6.0,7.9,13.9Hz),7.22(dd,1H,J=2.8,8.7Hz),7.00(m,2H),6.94(d,1H,J=7.6Hz),6.87(m,1H),6.77(dd,1H,J=2.7,8.7Hz),5.59(m,1H),5.52(m,1H),5.49(d,1/2H,J=2.4Hz),5.45(d,1/2H,J=2.4Hz),4.81(dd,1H,J=2.5,8.8Hz),4.21(m,1H),4.12(m,1H),4.07(m,1H),3.52(s,3H),3.25(dd,1H,J=0.9,9.0Hz),2.89(br s,1H),2.76(m,1H),2.67(s,1H),2.26(m,2H),1.69(m,1H),1.65(s,3/2H),1.64(s,3/2H),1.29(s,3/2H),1.28(s,3/2H),1.13(s,3/2H),1.12(s,3/2H);13C NMR(125MHz,CDCl3)δ169.4,169.4,163.7-161.7(d,J=249.0Hz),154.9,154.7,143.0(dd,J=1.7,8.5Hz),142.2(d,J=1.7Hz),133.4,133.3,130.2(dd,J=1.7,8.5Hz),128.4(d,J=5.0Hz),126.6(d,J=3.2Hz),125.1(d,J=3.6Hz),125.0(m),117.2,116.9,116.6,116.3(dd,J=13.4,20.9Hz),116.2,114.3(dd,J=1.5,20.9Hz),98.0,97.7,84.5,84.4,78.3,78.3,77.4,71.5,71.4,68.8,62.0,61.9,49.6,49.6,40.5,40.5,35.2,35.1,33.4,29.2,23.6,23.5,23.2,23.1;HRMS(FAB)m/z:针对C28H34FNO6Na的[M+Na+],522.2262;实验值,522.2267。
N-(4'-(((3R,4S,5R)-3,4-二羟基-5-甲氧基-6,6-二甲基四氢-2H-吡喃-2-基)氧基)-3”-(三氟甲基)-1,2,3,6-四氢-[1,1':2',1”-三联苯]-2-基)乙酰胺(20b):遵循以上对于11a-p所述的相同的诺维糖偶联程序以得到作为非对映异构体的不可分离的混合物的20b。1H NMR(500MHz,CDCl3)δ7.65(d,1H,J=8.2Hz),7.56(t,1H,J=7.7Hz),7.49(s,1H),7.45(d,1H,J=7.6Hz),7.32(dd,1H,J=3.0,8.7Hz),7.08(td,1H,J=2.7,8.6Hz),6.85(dd,1H,J=2.7,8.5Hz),5.65(m,1H),5.59(m,1H),5.57(d,1/2H,J=2.4Hz),5.53(d,1/2H,J=2.3Hz),4.90(t,1H,J=8.2Hz),4.30(m,1H),4.19(dd,1H,J=4.3,8.2Hz),4.14(m,1H),3.59(s,3/2H),3.59(s,3/2H),3.33(d,1H,J=9.0Hz),3.17(s,1H),2.95(s,1H),2.76(m,1H),2.49(m,1H),2.33(m,1H),1.74(m,1H),1.73(s,3/2H),1.72(s,3/2H),1.36(s,3/2H),1.35(s,3/2H),1.21(s,3/2H),1.20(s,3/2H);13C NMR(100MHz,CDCl3)δ169.4,169.4,155.0,154.8,142.3,141.8,133.4,133.3,132.8,132.6,131.8(dq,J=2.2,32.5Hz),129.1,128.6,126.5,125.9(q,J=3.2,7.0Hz),125.0,124.2,117.6,117.0,116.8,98.1,97.8,84.5,84.4,78.4,78.3,71.3,71.3,68.7,68.7,61.9,61.9,49.4,49.3,40.5,40.5,35.1,35.0,33.1,29.0,29.0,23.4,23.4,23.1,23.0;HRMS(FAB)m/z:针对C29H34F3NO6Na的[M+Na+],计算值,572.2230;实验值,572.2227。
实施例19.羧酸类似物N-(2-(5-((4-(苄氧基)环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(24)的合成:
4-甲基苯磺酸4-羟基环己酯(21):
在室温下向吡啶(4g,0.025mol)于CHCl3(25mL)中的溶液中加入环己二醇(2.5g,0.021mol)。然后将混合物冷却到0℃,并向混合物中加入甲苯磺酰氯(4.1g,0.021)。反应物在氩气下和室温下搅拌16小时。通过TLC测定反应完成后,将反应混合物倒入稀HCl中,并通过过滤收集固体沉淀,用水洗涤并干燥(Na2SO4)。
4-甲基苯磺酸4-(苄氧基)环己酯(22):
在0℃下向21(0.5mg,1.8mmol)于乙腈(3mL)中的溶液中加入氢化钠(0.11g,2.7mmol)。然后在氩气氛下将苄基溴(0.48mL,2mmol)于乙腈(2mL)中的溶液逐滴加入到混合物中。反应物在室温下搅拌16小时。完成后,将蒸馏水(10mL)加入到混合物中并将有机层萃取入乙酸乙酯中。合并有机层,干燥并浓缩以得到粗混合物,所述粗混合物通过柱色谱(硅胶,己烷中的10%-20%EtOAc)纯化以得到白色固体状的22(300mg)。
N-(2-(5-((4-(苄氧基)环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(24):
向苯酚23(45mg,0.16mmol)于DMF(1mL)中的溶液中加入碳酸钾(30mg,0.19mmol)并在室温下搅拌30分钟,随后将22(75mg,0.19mmol)和TBAI(7mg,0.016mmol)加入到溶液中,并加热到回流维持过夜。完成后,将蒸馏水(5mL)加入到混合物中并将有机层萃取入乙酸乙酯中。在旋转蒸发器上去除溶剂后,通过柱色谱(硅胶,己烷中的40%EtOAc)纯化粗混合物以得到白色固体状的24(8mg)。
苯酚核心中间物23的合成.
4-(苄氧基)-2-羟基苯甲醛(25):
将2,4-二羟基苯甲醛(10g,0.072mol)溶解于乙腈(83mL)中。向该溶液中加入NaHCO3(9.1g,0.10mol)并搅拌5分钟。在氩气氛下加入苄基溴(12.9mL,0.10mol)。将反应物加热到回流维持16小时。冷却到室温后,通过加入蒸馏水终止反应,并将有机层萃取入二氯甲烷(3×50mL)中,并合并有机层,用水和盐水洗涤,干燥(Na2SO4)并浓缩。通过柱色谱(硅胶,己烷中的10%-20%EtOAc)纯化粗混合物以得到65%产率的25。
三氟甲烷磺酸5-(苄氧基)-2-甲酰苯酯(26):
在0℃下搅拌25(1.1g,4.9mmol)于新鲜蒸馏的二氯甲烷(10mL)中的溶液。历经5分钟先后将三乙胺(1.02mL,7.35mmol)和三氟甲磺酸酐(1.38mL,6.35mmol)加入到该溶液中。通过TLC测定反应完成后,通过加入蒸馏水终止反应,并将反应物萃取入二氯甲烷(3×10mL)中。合并有机层并干燥(Na2SO4)。在旋转蒸发器上去除溶剂后,通过柱色谱(硅胶,己烷中的10%EtOAc)纯化棕色粗混合物以得到55%产率的26。
5-(苄氧基)-3'-氟-[1,1'-联苯基]-2-甲醛(27):
将密封管中的26(246mg,0.68mmol)、硼酸(92mg,0.75mmol)、Pd(PPh3)4(70.4mg,0.068mmol)和K2CO3(0.169g,1.2mmol)于无水DMF(7mL)中的溶液在室温下用氩气脱气10分钟。此后,将反应混合物加热到回流维持16小时。通过TLC测定反应完成后,将反应物冷却到室温并通过加入饱和NaHCO3终止并萃取入乙酸乙酯(3×5mL)中。合并有机层并用盐水洗涤,干燥(Na2SO4)并浓缩。通过柱色谱(硅胶,己烷中的20%EtOAc)纯化棕色粗混合物以得到期望产物。
(E)-5-(苄氧基)-3'-氟-2-(2-硝基乙烯基)-1,1'-联苯(28):
将0.37g(1.2mmol)的7加入到含有3.3mL硝基甲烷的烧瓶中。将乙酸铵(1.8g,2.2mmol)加入到该溶液中并在50℃下搅拌得到的混合物直到反应完成,这通过在TLC上起始物质的消失来表明。反应混合物然后冷却到室温,并通过使用3:1己烷:EtOAc混合物作为洗脱剂的硅胶柱色谱纯化,得到93%产率的期望产物。
2-(5-(苄氧基)-3'-氟-[1,1'-联苯]-2-基)乙胺(29):
在0℃下和氩气氛下将新鲜蒸馏的THF(2mL)中的硝基苯乙烯28(400mg,1.1mmol)逐滴加入到LiAlH4(87mg,2.2mmol)溶液中。反应完成后(根据TLC),通过加入水(45μL)、3MNaOH(45μL)和另外的80μL水和20mL EtOAc终止反应。将得到的混合物在室温下搅拌1小时,通过硅藻土柱塞过滤,用EtOAc洗涤,干燥(Na2SO4)并浓缩成棕色粗混合物,所述粗混合物通过柱色谱(硅胶,DCM中的10%MeOH)纯化以得到期望产物。
N-(2-(5-(苄氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(30):
在氩气氛下将80mg(0.25mmol)的29加入到含有5mL新鲜蒸馏的DCM的25mL烘干烧瓶中。然后将乙酸酐(21μL,0.22mmol)和三乙胺(35μL)加入到该溶液中并在室温下搅拌得到的混合物3小时。然后通过加入饱和氯化铵终止反应混合物,并将所述混合物萃取入DCM中。将合并后的有机层干燥(Na2SO4)并浓缩成粗混合物,所述粗混合物通过柱色谱(硅胶,3:1己烷:EtOAc)纯化以得到期望产物。
N-(2-(3'-氟-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺(23):
将400mg的10加入到含有甲醇的10mL圆底烧瓶中,并向烧瓶中加入10mol%Pd(OH)2。使用连接的氢气球将混合物脱气10分钟,然后在室温下和氢气氛下搅拌8小时。将反应物过滤并浓缩以得到纯产物23,其不经进一步纯化即使用。
实施例20.碳环类似物N-(2-(5-((4-(苄氧基)环己-2-烯-1-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(36)和N-(2-(5-((4-(苄氧基)-2,3-二羟基环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(37)的合成:
1,2-二(环氧乙烷-2-基)乙烷(32):
向在0℃的1,5-己二烯(5g,0.12mol)于新鲜蒸馏的DCM(100mL)中的溶液中加入mCPBA(12.5g,0.146mol,70重量%)。将悬浮液在室温下搅拌2小时。用饱和NaHCO3溶液(4×80mL)洗涤反应物,随后用盐水(100mL)洗涤。然后干燥(Na2SO4)有机层并浓缩。通过使用5-20%EtOAc/hex作为洗脱剂的快速柱色谱纯化残余物以得到65%产率的期望产物。
1,6-庚二烯-3,5-二醇(33):
向经搅拌的在-10℃下的三甲基碘化锍(6.12g,30mmol)于无水THF(50mL)中的溶液中逐滴加入丁基锂(14mL,2.5M己烷溶液)。将反应混合物在-10℃下搅拌30分钟,并加入二环氧化物32(570mg,5mmol)于无水THF(5mL)中的溶液。将反应混合物升温到室温,并搅拌白色悬浮液过夜。用饱和NH4Cl水溶液(15mL)处理混合物,用CH2Cl2(3×10mL)萃取,经Na2SO4干燥并浓缩。在硅胶(戊烷/乙醚50/50)上纯化粗产物以得到化合物33(360mg,45%产率)。
环己-2-烯-1,4-二醇(34):
向经搅拌的33(190mg,1.3mmol)于DCM(0.1M)中的溶液中加入第2代格拉布催化剂(Grubbs Catalyst)(22mg,0.026mmol)。将反应混合物加热到回流维持2小时,然后在真空下浓缩。通过使用50-100%EtOAc/hex的硅胶柱色谱纯化粗产物以得到期望化合物。
4-(苄氧基)环己-2-烯-1-醇(35):
在0℃下向34(79mg,0.69mmol)于DMF(1mL)中的溶液中加入氢化钠(14mg,0.62mmol)。在氩气氛下将苄基溴(73μL,0.62mmol)逐滴加入到混合物中。反应物在室温下搅拌16小时。完成后,将蒸馏水(3mL)加入到混合物中并将有机层萃取入乙酸乙酯中。合并有机层,干燥并浓缩以得到粗混合物,所述粗混合物通过柱色谱(硅胶,己烷中的10%-20%EtOAc)纯化以得到油状的35。
N-(2-(5-((4-(苄氧基)环己-2-烯-1-基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(36):
向在0℃下的35(70mg,0.34mmol)于新鲜蒸馏的THF(3mL)中的溶液中加入三苯膦(180mg,0.68mmol)和23(90mg,0.34mmol)。将DIAD(0.135mL,0.68mmol)逐滴加入到混合物中。将反应物升温到室温并搅拌4小时。反应混合物用饱和NaHCO3水溶液(2mL)处理,用水洗涤,随后用盐水洗涤,经Na2SO4干燥并浓缩以得到粗混合物,所述粗混合物通过柱色谱(己烷中的30%-50%EtOAc)纯化以得到油状的36。
N-(2-(5-((4-(苄氧基)-2,3-二羟基环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(37):
向36(15mg,0.032mmol)于THF/H2O(1:1,1mL)混合物中的溶液中加入催化量的OsO4(0.0032mmol)和NMO.(5.7mg,0.048mmol)。得到的溶液在室温下搅拌过夜。蒸发THF并用EtOAc萃取残余物。有机层用饱和NaHCO3洗涤,随后用饱和NH4Cl洗涤,干燥(Na2SO4),浓缩并纯化(己烷中的50%-100%EtOAc)以得到37。
实施例21.碳环类似物N-(2-(5-((4-(叔丁基)环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(39)的合成:
4-甲基苯磺酸4-(叔丁基)环己酯(38):
将4-(叔丁基)环己-1-醇(500mg,3mmol)溶解于吡啶(50mL)中并在室温下搅拌30分钟。将甲苯磺酰氯(915mg,4.79mmol)加入到反应混合物中并搅拌过夜。反应通过加入水(50mL)终止并用醚(3×20mL)萃取,用饱和CuSO4、水、饱和NaHCO3水溶液、水洗涤,干燥(Na2SO4),浓缩并纯化(己烷中的10%EtOAc)以得到白色固体状的38。
N-(2-(5-((4-(叔丁基)环己基)氧基)-3'-氟-[1,1'-联苯]-2-基)乙基)乙酰胺(39):
向38(50mg,0.16mmol)于无水DMF(2mL)中的溶液中加入K2CO3(24mg)、38(44mg,0.16mmol)和TBAI(6mg)。将溶液混合物加热到80℃维持4天。完成后,将蒸馏水(4mL)加入到混合物中并将有机层萃取入乙酸乙酯中。在旋转蒸发器上去除溶剂后,通过柱色谱(己烷中的50%EtOAc)纯化粗混合物以得到39。
根据前文将看出,本发明非常适合于实现上文阐述的所有目的和目标,以及显而易见的并且为本发明所固有的其它优点。因为可由本发明产生许多可能的实施方案而不会脱离其范围,所以应了解本文阐述或附图所示的所有主题都应解释为说明性的,而不是限制性的。虽然已经展示和讨论了具体实施方案,但是当然可以进行各种修改,并且本发明不限于本文中描述的部分和步骤的具体形式或安排,除了所述限制被包括在以下权利要求书中。此外,应理解某些特征和子组合是有用的并且可以在不参考其它特征和子组合的情况下使用。这被权利要求书的范围所涵盖并且属于其中。
Claims (2)
1.化合物,其选自:
N-(2-(5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(3'-氟-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(4'-氟-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(2'-氯-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(3'-氯-5-羟基-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(5-羟基-3'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(5-羟基-4'-(三氟甲基)-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(5-羟基-2'-(甲硫基)-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(5-羟基-2'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(5-羟基-3'-甲氧基-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(5-羟基-3'-甲基-[1,1'-联苯]-2-基)乙基)乙酰胺;
N-(2-(苯并[d][1,3]间二氧杂环戊烯-5-基)-4-羟基苯乙基)乙酰胺;
N-(4-羟基-2-(吡啶-3-基)苯乙基)乙酰胺;
N-(4-羟基-2-(吡啶-4-基)苯乙基)乙酰胺;
或其药学上可接受的盐。
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