WO2018090717A1 - Atg类似物及其制备方法和应用 - Google Patents

Atg类似物及其制备方法和应用 Download PDF

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WO2018090717A1
WO2018090717A1 PCT/CN2017/102936 CN2017102936W WO2018090717A1 WO 2018090717 A1 WO2018090717 A1 WO 2018090717A1 CN 2017102936 W CN2017102936 W CN 2017102936W WO 2018090717 A1 WO2018090717 A1 WO 2018090717A1
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atg
group
analog
compound
mmol
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钟逸斐
何慈江
戴思巴斯卡
刘睿捷
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上海中医药大学附属龙华医院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/74—Unsaturated compounds containing —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present invention relates to an ATG analog, and to a method for preparing an ATG analog, and to the use of the above ATG analog, and to the field of medicine.
  • Angerin ATG has a variety of biological activities. However, for a potential drug, even if it has a significant effect, whether it can be widely applied and how it is actually applied to the human body, further improvement in properties is still needed. Natural ATG has the characteristics of low water solubility and easy to be decomposed in primary metabolism, which limits its further application.
  • the present invention provides the following three compounds of the formula:
  • X/Y/Z can be selected from C, N, S, and O, respectively.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of: H, CH 3 groups, aliphatic or aromatic hydrocarbon groups, nitro groups, phosphoric acid groups, sulfide groups, sulfones. a group, a nitrile group, a heterocyclic group, a boric acid ester or a boronic acid group, an ester group, an amine group.
  • the invention also provides a compound in which the moiety B is ring-opened, and the structural formula is as follows:
  • the present invention provides the use of the above ATG analog as a PP2A agonist, which improves the regulatory effect of PP2A.
  • the three most effective compounds are BT280, BT281 and BT282.
  • the BT282 is more effective.
  • the present invention also provides chemical synthesis methods of BT280, BT281 and BT282, and other compounds listed above can also be synthesized using a similar method.
  • BT280 is synthesized by a boron group reaction
  • BT282 is synthesized from BT280 and water-soluble 3MKHF2.
  • BT282 is then further acidified under conditions of silica and water to give a BT281 boronic acid derivative. details as follows:
  • BT280 Compound C (0.77 mmol, 0.30 g), B2Pin2 (pinacol borate) (1.07 mmol, 0.273 g), ACOK (3.85 mmol, 0.377 g), Pd(PPh3)2Cl2 (0.077 mmol, 0.054 g) was added to a 50 mL round bottom flask along with DMSO (15 mL). The resulting mixture was stirred at room temperature for 10 minutes, and then the resulting mixture was stirred at 80 ° C for 1 day. The mixture was diluted with water (30 mL) andEtOAcEtOAc. The organic layer was dried with sodium sulfate and evaporated The obtained product was subjected to purification column extraction to obtain 0.06 g of pure BT280.
  • BT280 (0.29 mmol, 0.12 g) was added to 15 ml of MeOH, then 3M KHF 2 was added, and after stirring for 2 hr, MeOH was evaporated to leave residue. The residue is in C The ketone was dissolved and filtered, and the filtrate was evaporated to give a white solid.
  • the invention also provides the use of the above ATG analogs, in particular BT280, BT282 and BT282, for increasing PP2A activity.
  • the ATG analog of the present invention has an oxadiazole ring, it has more hydrophilic characteristics and greatly increases water solubility.
  • Both BT280, BT81 and BT282 can increase the biological activity of PP2A.
  • BT282 is better than natural ATG.
  • Figure 1 is the effect of several ATG analogs of the invention on PP2A activity.
  • Figure 2 is a graph showing the effect of several ATG analogs of the invention on the degree of phosphorylation of NF-kB.
  • the invention provides a series of ATG isoforms: including three parts of ABC, and part B has two forms of open loop and closed loop. In both forms, XYZ is respectively selected from C, N, S, O.
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of: H, CH 3 groups, aliphatic or aromatic hydrocarbon groups, nitro groups, phosphoric acid groups, sulfide groups, sulfones. a group, a nitrile group, a heterocyclic group, a boric acid ester or a boronic acid group, an ester group, an amine group.
  • the above analog further includes a compound having a B-opening structure, as follows:
  • the boron-containing pharmacophore is introduced, and the lactone ring is changed to the oxadiazole ring to make it more hydrophilic and to increase the water solubility as much as possible.
  • the best results are three compounds BT280, BT81 and BT282.
  • the boron-containing pharmacophore, the boron-containing group can not only be hydrogen-bonded to the target protein but also covalently bond to produce biological activity, so three compounds are identified for ATG: BT280, BT281, and BT282, the specific structure is shown in the above chemical formula.
  • the synthesized ATG homologue structure is as shown in the above chemical formula.
  • the structure of the compound, the original ATG contains three parts, a part A phenyl ring derivative, a B part lactone ring and a phenyl ring system.
  • Part B the lactone ring is modified to an oxadiazole ring to provide more hydrophilic character and to increase water solubility as much as possible.
  • a boronic acid ester is introduced instead of the phenyl ring, and the boron-containing group can not only be hydrogen-bonded to the target protein but also covalently bonded to produce biological activity.
  • the biological activities of the three compounds were judged by measuring the downstream PP2A activity and the degree of NF-kB phosphorylation. The results are shown in Fig. 1, with DMSO as a reference. 293T cells were stimulated with natural ATG and new compounds BT280, BT281 and BT282, respectively. The concentrations of ATG and three new compounds were selected at 10 ⁇ M. It can be seen that the effect of BT280 on PP2A activity is similar to that of natural ATG. The effect of BT281 on the activity of PP2A was weaker than that of natural ATG, but it was still stronger than that of DMSO. Compound BT282 has a higher activity on PP2A than native ATG. Therefore, all three compounds can be used to increase the biological activity of PP2A.
  • BT282 is the best choice for improving the activity of PP2A.
  • BT280 and BT281 have no significant improvement in the activity of PP2A compared with natural ATG, BT280 and BT281 have better water solubility and better bioreactive groups, suggesting that they are used in animal-level drugs. It can provide better drug delivery effects, for example, because of its better water solubility, it can better reach the affected part through the circulation system of the animal body, and achieve a higher concentration of administration, thereby achieving better administration effect.
  • BT282 is the best target compound.
  • the BT282 is the most obvious improvement compared to the ATG.
  • two other compounds are also available, compared to natural ATG, BT280 and BT281
  • BT280 and BT281 can still be potential drug targets because of their superior water solubility over natural ATG.
  • BT280 is synthesized by a boron group reaction
  • BT282 (trifluoropotassium salt) is synthesized from BT280 and water-soluble 3MKHF2.
  • the trifluoropotassium salt complex is then further acidified under conditions of silica and water to give a BT281 boronic acid derivative.
  • Compound A is trimethoxybenzoic acid in an amount of 0.9 mmol; and Compound B, in an amount of 1.1 mmol, is added to the catalytic cesium CDI (N,N'-dicyclohexylcarbodiimide), dissolved in 1.8 ml of DMF and allowed to stand at room temperature.
  • CDI N,N'-dicyclohexylcarbodiimide
  • XB-A-26 (C) was synthesized by stirring for 30 minutes.
  • XB-A-26 was added in an amount of 1.4 mmol, and the reaction mixture was heated at 75 ° C for 36 hours under reflux and was monitored by TLC.
  • BT280 Compound C (0.75 mmol), B2Pin2 (pinacol borate) (1.05 mmol), ACOK (3.80 mmol), Pd(PPh3)2Cl2 (0.075 mmol) and DMSO (15) ML) was added together in a 50 mL round bottom flask. The resulting mixture was stirred at room temperature for 10 minutes, and then the resulting mixture was stirred at 85 ° C for 1 day. The mixture was diluted with water (30 mL) andEtOAcEtOAc. The organic layer was dried with sodium sulfate and evaporated The obtained product was subjected to purification column extraction to obtain 0.05 g of pure BT280.
  • BT280 is synthesized by a boron group reaction
  • BT282 (trifluoropotassium salt) is synthesized from BT280 and water-soluble 3MKHF2.
  • the trifluoropotassium salt complex is then further acidified under conditions of silica and water to give a BT281 boronic acid derivative.
  • BT280 Compound C (0.77 mmol, 0.30 g), B2Pin2 (pinacol borate) (1.07 mmol, 0.273 g), ACOK (3.85 mmol, 0.377 g), Pd(PPh3)2Cl2 (0.077 mmol, 0.054 g) was added to a 50 mL round bottom flask along with DMSO (15 mL). The resulting mixture was stirred at room temperature for 10 minutes and then The resulting mixture was stirred at 80 ° C for 1 day. The mixture was diluted with water (30 mL) andEtOAcEtOAc. The organic layer was dried with sodium sulfate and evaporated The obtained product was subjected to purification column extraction to obtain 0.06 g of pure BT280.
  • BT280 is synthesized by a boron group reaction
  • BT282 (trifluoropotassium salt) is synthesized from BT280 and water-soluble 3MKHF2.
  • the trifluoropotassium salt complex is then further acidified under conditions of silica and water to give BT281.
  • BT280 Compound C, 0.79 mmol, B2Pin2 (pinacol borate) 1.08 mmol, ACOK, 3.88 mmol, Pd(PPh3)2Cl2, 0.079 mmol, and DMSO, 15 mL. Add together into a 50 mL round bottom flask. The resulting mixture was stirred at room temperature for 10 minutes, and then the resulting mixture was stirred at 80 ° C for 1 day. The mixture was diluted with water (30 mL) andEtOAcEtOAc. The organic layer was dried with sodium sulfate and evaporated The obtained product was subjected to purification column extraction to obtain 0.07 g of pure BT280.

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Abstract

本发明提供ATG类似物及其制备方法和应用，ATG类似物的具体结构如下列三个通式所示: 式(I)，式(II)，式(III) 其中，X/Y/Z可以分别选自C、N、S、O, R1，R2，R3，R4，R5各自分别选自: H，CH3基团，脂肪族或者芳香族碳氢化合物基团，硝基，磷酸基，硫化物基团，砜类基团，腈类基团，杂环基，硼酸酯或硼酸基团，酯类基团，胺类基团。本发明所提供的ATG类似物具有更好的水溶性和防止在一级代谢中被分解的效果。

Description

ATG类似物及其制备方法和应用 技术领域
本发明涉及一种ATG类似物，本发明还涉及ATG类似物的制备方法，本发明还涉及上述ATG类似物的应用，属于医药领域。
背景技术
牛蒡苷元ATG具有多种生物活性。然而，对于一种潜在的药物而言，即使具有显著的疗效，但是能否广泛的开展应用，以及在实际应用于人体上的效果究竟如何，仍然需要进一步的性质的改进。而天然的ATG具有水溶性低和易在一级代谢中被分解的特点，这限制了其进一步的应用。
发明内容
本发明的目的在于提供一种ATG的类似物，以解决上述问题。
本发明采用了如下技术方案：
本发明提供下列三种通式化合物：
Figure PCTCN2017102936-appb-000001
其中，X/Y/Z可以分别选自C、N、S、O。
R1，R2，R3，R4，R5各自分别选自：H，CH3基团，脂肪族或者芳香族碳氢化合物基团，硝基，磷酸基，硫化物基团，砜类基团，腈类基团，杂环基，硼酸酯或硼酸基团，酯类基团，胺类基团。
本发明还提供B部分为开环的化合物，结构式如下：
Figure PCTCN2017102936-appb-000002
Figure PCTCN2017102936-appb-000003
这些化合物均为ATG的类似物，具有与ATG相似的化学性质和生物活性。
本发明提供了上述ATG类似物作为PP2A激动剂的应用，提高了PP2A的调控效果。
优选的，效果最佳的三种化合物是BT280，BT281和BT282。
更优选的，效果更佳的是BT282。
本发明还提供了BT280，BT281和BT282的化学合成方法，以上列举的其它化合物也可以使用类似的方法进行合成。
首先合成化合物
Figure PCTCN2017102936-appb-000004
后面简称之为化合物C，然后用硼基反应合成BT280，再从BT280和水溶的3MKHF2中合成BT282。然后BT282进一步在二氧化硅和水的条件下被酸化，从而得到BT281硼酸衍生物。具体如下：
化合物C的合成.3-(4-bromophenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole
Figure PCTCN2017102936-appb-000005
化合物C的合成步骤：
三甲氧基苯甲酸A，用量1.0毫摩尔(0.212克)；和B，用量1.2毫摩尔(0.195克)加催化剤CDI(N,N'-二环己基碳二亚胺),溶解在1.8毫升DMF中并在室温下搅拌30分钟合成XB-A-26(C)。加入XB-A-26，用量1.2毫摩尔(0.258克)，并将反应混合物在回流下在80℃加热24小时，通过TLC监测。将混合物倾入20毫升水中并用EtOAc(3×10mL)萃取，将合并层用Na2SO4干燥，过滤并真空浓缩。将粗产物通过硅胶纯化(己烷:EtOAc＝3:1)，得到为白色固体的恶二唑产物，这样能得到0.30克的终产物C。
BT280的合成：3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-5-(3,4,5-三甲氧基苯基)-1,2，4-恶二唑。3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole
Figure PCTCN2017102936-appb-000006
BT280的合成步骤：取化合物C(0.77毫摩尔，0.30g)，B2Pin2(频那醇硼酸酯)(1.07毫摩尔，0.273克)，ACOK(3.85毫摩尔，0.377克)，Pd(PPh3)2Cl2(0.077毫摩尔，0.054克)和DMSO(15毫升)一起加入50mL圆底烧瓶中。将所得混合物在室温下搅拌10分钟，然后将所得混合物在80摄氏度下搅拌1天。用水(30毫升)稀释该混合物，用乙酸乙酯(3×30毫升)萃取。将有机层经硫酸钠干燥并真空浓缩。将所得进行纯化柱提取，可以得到0.06克纯品BT280。
BT282的合成：钾三氟(4-(5-(3,4,5-三甲氧基苯基)-1,2,4-恶二唑-3-基)苯基)硼酸盐
Figure PCTCN2017102936-appb-000007
步骤：
将BT280(0.29毫摩尔，0.12克)加入到15毫升MeOH中，然后加入3M的KHF2，搅拌2小时后，蒸发MeOH得到残留。将该残留物在丙 酮中溶解并过滤，该滤液蒸干后得到白色固体，进一步经过EtOAC洗脱得到65毫克最终纯品。
Figure PCTCN2017102936-appb-000008
BT281的合成：(4-(5-(3,4,5-三甲氧基苯基)-1,2,4-恶二唑-3-基)苯基)硼酸
步骤：将BT282(37毫克，0.9毫摩尔)和硅胶(0.18毫摩尔，11毫克)加入到H2O/乙酸乙酯(1.0毫升)中。将反应混合物在室温下搅拌直至反应完全。将反应混合物过滤除去硅胶，将滤饼用丙酮洗涤。水相和有机分离，将有机层干燥得到目的产品BT281。
本发明还提供了上述ATG类似物，尤其是BT280，BT282和BT282在提高PP2A活性中的应用。
发明的有益效果
本发明的ATG类似物由于具有噁二唑环，因此其具备更多亲水性的特点并大幅度增加了水溶性。
在A部分，由于三甲氧基代替苯基环衍生物增加跨细胞膜疏水性特点，并且保护羟基避免终止于一级代谢。
在C部分，引入硼酸酯代替苯基环，提高了与生物分子结合的可能性。
BT280，BT81和BT282均能够提高PP2A的生物活性。其中BT282较天然ATG的效果更好。
附图说明
图1是本发明的几种ATG类似物对PP2A活性的影响。
图2是本发明的几种ATG类似物对NF-kB磷酸化程度的影响。
具体实施方式
以下结合附图来说明本发明的具体实施方式。
Figure PCTCN2017102936-appb-000009
本发明提供一系列ATG同型物：包括ABC三个部分，B部分有开环和闭环两种形式，在两种形式下，XYZ分别选自C、N、S、O。R1，R2，R3，R4，R5各自分别选自：H，CH3基团，脂肪族或者芳香族碳氢化合物基团，硝基，磷酸基，硫化物基团，砜类基团，腈类基团，杂环基，硼酸酯或硼酸基团，酯类基团，胺类基团。
进一步，上述类似物中还包括B部分为开环结构的化合物，如下：
Figure PCTCN2017102936-appb-000010
Figure PCTCN2017102936-appb-000011
上引入含硼的药效基团，内酯环改变为噁二唑环，使其具备更多亲水性的特点并尽可能增加水溶性。经过筛选，效果最佳的是BT280、BT81、BT282三个化合物。
Figure PCTCN2017102936-appb-000012
(1)ATG类似物的结构特点：
含硼的药效基团，含硼的基团不仅可以与靶蛋白通过氢键结合也可以通过共价键结合从而产生生物活性，因此以ATG为目标确定了三种化合物：BT280,BT281,and BT282，具体结构见上面化学式。
合成的ATG同型剂结构如以上化学式所示。化合物的结构，原始的ATG包含三部分，A部分苯基环衍生物，B部分内酯环和苯基环系统。在B部分，将内酯环修正为噁二唑环，使其具备更多亲水性的特点并尽可能增加水溶性。在C部分，引入硼酸酯代替苯基环，含硼的基团不仅可以与靶蛋白通过氢键结合也可以通过共价键结合从而产生生物活性。在A部分，用三甲氧基代替苯基环衍生物增加跨细胞膜疏水性特点，并 且保护羟基避免终止于一级代谢。合成了三种化合物，BT280，BT281和BT 282。
(2)ATG类似物的生物活性：
通过检测下游PP2A活性和NF-kB磷酸化程度来判断该三种化合物的生物活性，结果如图1所示，以DMSO为参照物。分别使用天然ATG和新化合物BT280、BT281和BT282分别刺激293T细胞，ATG和三种新化合物的浓度均选择10μM，可见BT280对PP2A活性的影响程度与天然ATG相似。而BT281对PP2A活性的提高作用较天然ATG弱一些，但仍然强于DMSO组。化合物BT282对PP2A的活性提高作用高于天然ATG。因此三种化合物均能够用于提高PP2A的生物活性。
显然BT282从提高PP2A的活性上来讲是最佳选择。BT280和BT281虽然在提高PP2A活性上与天然ATG相比并没有明显的提升，但是由于BT280和BT281具有更好的水溶性和更佳的生物反应基团，提示其在动物体级别的用药中，能够提供更好的给药效果，例如由于其较佳的水溶性，可以更好的通过动物体的循环系统到达患处，并达到更高的给药浓度，从而达到更佳的给药效果。
对于NF-kB磷酸化程度的结果可见图2。可见NF-kB磷酸化程度与图1中的PP2A结果相对应。提示ATG的类似物在NF-kB通路中的作用也与ATG相似。显示ATG类似物也可以用于对NF-kB的磷酸化程度进行调节。图2的结果中，ATG类似物的刺激浓度为10μM。
综上所述，BT282是最佳的目标化合物。BT282与ATG相比提升的最明显。但是其它两个化合物也可用，相对于天然ATG，BT280和BT281 虽然活化PP2A的效果没有优势，但是在具体的生物体实验中，由于在水溶性上较天然ATG更具优势，因此BT280和BT281仍然可以作为潜在的药物对象。
合成方法：
<实施例一>
首先合成化合物
Figure PCTCN2017102936-appb-000013
后面简称之为化合物C，然后用硼基反应合成BT280，再从BT280和水溶的3MKHF2中合成BT282(三氟钾盐)。然后该三氟钾盐复合物进一步在二氧化硅和水的条件下被酸化，从而得到BT281硼酸衍生物。
化合物C的合成.3-(4-bromophenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole
Figure PCTCN2017102936-appb-000014
化合物C的合成步骤：
化合物A为三甲氧基苯甲酸，用量0.9毫摩尔；和化合物B，用量1.1毫摩尔加催化剤CDI(N,N'-二环己基碳二亚胺),溶解在1.8毫升DMF中并在室温下搅拌30分钟合成XB-A-26(C)。加入XB-A-26，用量1.4毫摩尔，并将反应混合物在回流下在75℃加热36小时，通过TLC监测。将混合物倾入20毫升水中并用EtOAc(3×10mL)萃取，将合并层用Na2SO4干燥，过滤并真空浓缩。将粗产物通过硅胶纯化(己烷:EtOAc＝ 3:1)，得到为白色固体的恶二唑产物，这样能得到0.25克的终产物C。
BT280的合成：3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-5-(3,4,5-三甲氧基苯基)-1,2，4-恶二唑。3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole
Figure PCTCN2017102936-appb-000015
BT280的合成步骤：取化合物C(0.75毫摩尔)，B2Pin2(频那醇硼酸酯)(1.05毫摩尔)，ACOK(3.80毫摩尔)，Pd(PPh3)2Cl2(0.075毫摩尔)和DMSO(15毫升)一起加入50mL圆底烧瓶中。将所得混合物在室温下搅拌10分钟，然后将所得混合物在85摄氏度下搅拌1天。用水(30毫升)稀释该混合物，用乙酸乙酯(3×30毫升)萃取。将有机层经硫酸钠干燥并真空浓缩。将所得进行纯化柱提取，可以得到0.05克纯品BT280。
BT282的合成：钾三氟(4-(5-(3,4,5-三甲氧基苯基)-1,2,4-恶二唑-3-基)苯基)硼酸盐
Figure PCTCN2017102936-appb-000016
步骤：
将BT280(0.28毫摩尔)加入到15毫升MeOH中，然后加入3M的KHF 2，搅拌2小时后，蒸发MeOH得到残留。将该残留物在丙酮中溶解并过滤，该滤液蒸干后得到白色固体，进一步经过EtOAC洗脱得到纯品，62毫克最终纯品。
Figure PCTCN2017102936-appb-000017
BT281的合成：(4-(5-(3,4,5-三甲氧基苯基)-1,2,4-恶二唑-3-基)苯基)硼酸
步骤：将BT282(36毫克)和硅胶(0.18毫摩尔)加入到H2O/乙酸乙酯(1.0毫升)中。将反应混合物在室温下搅拌直至反应完全。将反应混合物过滤除去硅胶，将滤饼用丙酮洗涤。水相和有机分离，将有机层干燥得到目的产品BT281。
<实施例二>
首先合成化合物
Figure PCTCN2017102936-appb-000018
后面简称之为化合物C，然后用硼基反应合成BT280，再从BT280和水溶的3MKHF2中合成BT282(三氟钾盐)。然后该三氟钾盐复合物进一步在二氧化硅和水的条件下被酸化，从而得到BT281硼酸衍生物。
化合物C的合成.3-(4-bromophenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole
Figure PCTCN2017102936-appb-000019
化合物C的合成步骤：
化合物A：三甲氧基苯甲酸，用量1.0毫摩尔；和化合物B，用量1.2毫摩尔加催化剤CDI(N,N'-二环己基碳二亚胺),溶解在1.8毫升DMF中并在室温下搅拌30分钟合成XB-A-26(C)。加入XB-A-26，用量1.3毫摩尔，并将反应混合物在回流下在80℃加热24小时，通过TLC监测。将混合物倾入20毫升水中并用EtOAc(3×10mL)萃取，将合并层用Na2SO4干燥，过滤并真空浓缩。将粗产物通过硅胶纯化(己烷:EtOAc＝3:1)，得到为白色固体的恶二唑产物，这样能得到0.30克的终产物C。
BT280的合成：3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-5-(3,4,5-三甲氧基苯基)-1,2，4-恶二唑。3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole
Figure PCTCN2017102936-appb-000020
BT280的合成步骤：取化合物C(0.77毫摩尔，0.30g)，B2Pin2(频那醇硼酸酯)(1.07毫摩尔，0.273克)，ACOK(3.85毫摩尔，0.377克)，Pd(PPh3)2Cl2(0.077毫摩尔，0.054克)和DMSO(15毫升)一起加入50mL圆底烧瓶中。将所得混合物在室温下搅拌10分钟，然后将 所得混合物在80摄氏度下搅拌1天。用水(30毫升)稀释该混合物，用乙酸乙酯(3×30毫升)萃取。将有机层经硫酸钠干燥并真空浓缩。将所得进行纯化柱提取，可以得到0.06克纯品BT280。
BT282的合成：钾三氟(4-(5-(3,4,5-三甲氧基苯基)-1,2,4-恶二唑-3-基)苯基)硼酸盐
Figure PCTCN2017102936-appb-000021
步骤：
将BT280(0.29毫摩尔，0.12克)加入到15毫升MeOH中，然后加入3M的KHF 2，搅拌2小时后，蒸发MeOH得到残留。将该残留物在丙酮中溶解并过滤，该滤液蒸干后得到白色固体，进一步经过EtOAC洗脱得到纯品，65毫克最终纯品。
Figure PCTCN2017102936-appb-000022
BT281的合成：(4-(5-(3,4,5-三甲氧基苯基)-1,2,4-恶二唑-3-基)苯基)硼酸
步骤：将BT282(37毫克，0.9毫摩尔)和硅胶(0.18毫摩尔，11毫克)加入到H2O/乙酸乙酯(1.0毫升)中。将反应混合物在室温下搅拌直至反应完全。将反应混合物过滤除去硅胶，将滤饼用丙酮洗涤。水相和有机分离，将有机层干燥得到目的产品BT281。
<实施例三>
首先合成化合物
Figure PCTCN2017102936-appb-000023
后面简称之为化合物C，然后用硼基反应合成BT280，再从BT280和水溶的3MKHF2中合成BT282(三氟钾盐)。然后该三氟钾盐复合物进一步在二氧化硅和水的条件下被酸化，从而得到BT281。
化合物C的合成.3-(4-bromophenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole
Figure PCTCN2017102936-appb-000024
化合物C的合成步骤：
化合物A：三甲氧基苯甲酸，用量1.1毫摩尔；和化合物B，用量1.3毫摩尔加催化剤CDI(N,N'-二环己基碳二亚胺)，溶解在1.8毫升DMF中并在室温下搅拌30分钟合成XB-A-26(C)。加入XB-A-26，用量1.3毫摩尔，并将反应混合物在回流下在85℃加热20小时，通过TLC监测。将混合物倾入20毫升水中并用EtOAc(3×10mL)萃取，将合并层用Na2SO4干燥，过滤并真空浓缩。将粗产物通过硅胶纯化(己烷:EtOAc＝3:1)，得到为白色固体的恶二唑产物，这样能得到0.31克的终产物C。
BT280的合成：3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-5-(3,4,5-三甲氧基苯基)-1,2，4-恶二唑。3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazole
Figure PCTCN2017102936-appb-000025
BT280的合成步骤：取化合物C，0.79毫摩尔，B2Pin2(频那醇硼酸酯)1.08毫摩尔，ACOK，3.88毫摩尔，Pd(PPh3)2Cl2，0.079毫摩尔，和DMSO，15毫升。一起加入50mL圆底烧瓶中。将所得混合物在室温下搅拌10分钟，然后将所得混合物在80摄氏度下搅拌1天。用水(30毫升)稀释该混合物，用乙酸乙酯(3×30毫升)萃取。将有机层经硫酸钠干燥并真空浓缩。将所得进行纯化柱提取，可以得到0.07克纯品BT280。
BT282的合成：钾三氟(4-(5-(3,4,5-三甲氧基苯基)-1,2,4-恶二唑-3-基)苯基)硼酸盐
Figure PCTCN2017102936-appb-000026
步骤：
将BT280，0.32毫摩尔，加入到15毫升MeOH中，然后加入3M的KHF 2，搅拌2小时后，蒸发MeOH得到残留。将该残留物在丙酮中溶解并过滤，该滤液蒸干后得到白色固体，进一步经过EtOAC洗脱得到纯品，66毫克最终纯品。
Figure PCTCN2017102936-appb-000027
BT281的合成：(4-(5-(3,4,5-三甲氧基苯基)-1,2,4-恶二唑-3-基)苯基)硼酸
步骤：将BT282，39毫克和硅胶(0.18毫摩尔，11毫克)加入到H2O/乙酸乙酯(1.0毫升)中。将反应混合物在室温下搅拌直至反应完全。将反应混合物过滤除去硅胶，将滤饼用丙酮洗涤。水相和有机分离，将有机层干燥得到目的产品BT281。

Claims (10)

  1. 一种ATG类似物，其特征在于，由A、B、C三部分组成，具体结构如下列三个通式所示：
    Figure PCTCN2017102936-appb-100001
    其中，X/Y/Z各自分别选自：C、N、S、O，
    R1，R2，R3，R4，R5各自分别选自：H，CH3基团，脂肪族或者芳香族碳氢化合物基团，硝基，磷酸基，硫化物基团，砜类基团，腈类基团，杂环基，硼酸酯或硼酸基团，酯类基团，胺类基团。
  2. 如权利要求1所述的ATG类似物，其特征在于：
    其中，X为O。
  3. 如权利要求1所述的ATG类似物，其特征在于：
    其中，Y为N。
  4. 如权利要求1所述的ATG类似物，其特征在于：
    其中，Z为N。
  5. 如权利要求1所述的ATG类似物，其特征在于：
    其中，R2为H3CO-，R3为H3CO-。
  6. 如权利要求1所述的ATG类似物，其特征在于：
    其中，R4为H3CO-。
  7. 如权利要求1所述的ATG类似物，其特征在于：
    其中，B部分为开环结构，结构为下列化合物中的任意一种，
    Figure PCTCN2017102936-appb-100002
  8. 如权利要求1所述的ATG类似物，其特征在于：
    其中，X为O，Y为N，Z为N，R1为H，R2为H3CO-，R3为H3CO-，R4为H3CO-，R5为H。
  9. 如权利要求1-8所述的ATG类似物在调节PP2A活性中的应用。
  10. 一种制备如权利要求8所述的ATG类似物的方法，其特征在于，包括如下步骤：
    步骤一：首先合成化合物
    Figure PCTCN2017102936-appb-100003
    称之为化合物C，合成化合物C的反应式如下：
    Figure PCTCN2017102936-appb-100004
    步骤二：然后用硼基反应合成BT280，反应式如下：
    Figure PCTCN2017102936-appb-100005
    步骤三：再从BT280和水溶的3MKHF2中合成BT282，反应式如下：
    Figure PCTCN2017102936-appb-100006
    步骤四：BT282进一步在二氧化硅和水的条件下被酸化，从而得到BT281，反应式如下：
    Figure PCTCN2017102936-appb-100007
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102046179A (zh) * 2008-04-09 2011-05-04 英菲尼提制药公司 脂肪酸酰胺水解酶抑制剂
WO2012112670A1 (en) * 2011-02-16 2012-08-23 Albert Einstein College Of Medicine Of Yeshiva University Novel lipogenic inhibitors and uses thereof
CN103930126A (zh) * 2011-08-12 2014-07-16 Bsrc亚历山大.弗莱明 Tnf超家族三聚化的抑制剂
CN104447234A (zh) * 2014-12-08 2015-03-25 安徽万邦医药科技有限公司 (3r,4r)-4-(3,4-二甲氧基苄基)-3-(4-羟基-3-甲氧基苄基)-二氢呋喃的制备方法
CN106800569A (zh) * 2016-12-12 2017-06-06 上海中医药大学附属龙华医院 Atg类似物及其制备方法和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102046179A (zh) * 2008-04-09 2011-05-04 英菲尼提制药公司 脂肪酸酰胺水解酶抑制剂
WO2012112670A1 (en) * 2011-02-16 2012-08-23 Albert Einstein College Of Medicine Of Yeshiva University Novel lipogenic inhibitors and uses thereof
CN103930126A (zh) * 2011-08-12 2014-07-16 Bsrc亚历山大.弗莱明 Tnf超家族三聚化的抑制剂
CN104447234A (zh) * 2014-12-08 2015-03-25 安徽万邦医药科技有限公司 (3r,4r)-4-(3,4-二甲氧基苄基)-3-(4-羟基-3-甲氧基苄基)-二氢呋喃的制备方法
CN106800569A (zh) * 2016-12-12 2017-06-06 上海中医药大学附属龙华医院 Atg类似物及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DAS, BHASKAR C.: "Design and synthesis of 3, 5-disubstituted boron-con- taining 1, 2, 4-oxadiazoles as potential combretastatin A-4 ( CA -4) analog s", TETRAHEDRON LETTERS, vol. 53, no. 31, 30 December 2012 (2012-12-30) *
MIURA, TOMOYA: "Facile Synthesis of 2, 5-Disubstituted Thiazoles from Terminal Alkynes, Sulfonyl Azides, and Thionoesters", ORGANIC LETTERS, vol. 17, no. 10, 30 April 2015 (2015-04-30), pages 2454 - 2457, XP055605554, DOI: 10.1021/acs.orglett.5b00960 *

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