CN115806501A - N-草酰-d-苯丙氨酸类化合物及其酯类前药、制法、药物组合物和应用 - Google Patents
N-草酰-d-苯丙氨酸类化合物及其酯类前药、制法、药物组合物和应用 Download PDFInfo
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- CN115806501A CN115806501A CN202211593436.7A CN202211593436A CN115806501A CN 115806501 A CN115806501 A CN 115806501A CN 202211593436 A CN202211593436 A CN 202211593436A CN 115806501 A CN115806501 A CN 115806501A
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Images
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种N‑草酰‑D‑苯丙氨酸类化合物及其酯类前药、制法、药物组合物和应用,N‑草酰‑D‑苯丙氨酸类化合物如通式(I)所示。本发明提供了一系列具有高选择性且高活性FIH小分子抑制剂及其前药,其能够选择性地抑制FIH活性,且能够在细胞及动物层面有效降低甘油三酯含量,可用于改善肥胖、高血脂、高胆固醇血症、非酒精性脂肪肝炎等脂肪代谢性疾病。此外,此类FIH小分子抑制剂还有望为FIH分子机制及药理功能研究提供分子基础,助力缺氧应答通路调控研究。
Description
技术领域
本发明涉及小分子化合物,尤其涉及N-草酰-D-苯丙氨酸类化合物及其酯类前药、制法、药物组合物和应用。
背景技术
充足而持续的氧气供应是生命体生存的基础,缺氧诱导因子HIF-α(Hypoxiainducible factor-α)是细胞氧稳态的主要调控者,它对于氧气浓度的变化高度敏感。当机体处于缺氧状态时,HIF-α才能够稳定存在并行使其转录因子的功能;而当处于常氧状态时,HIF-α将受到两个主要的细胞氧感受器脯氨酰羟化酶(Prolyl Hydroxylase Domain,PHD)及天冬酰胺酰羟化酶——HIF抑制因子(Factor Inhibiting HIF,FIH)调控。FIH作为JmjC家族的Fe(II)依赖加氧酶,能够催化HIF-α亚基C端转录激活域特定天冬酰胺残基(Asn803)的羟基化,这一修饰阻碍HIF-α与转录辅激活因子p300/CBP的结合,从而抑制HIF的转录活性。相比PHD抑制剂的火热研究,对于FIH抑制剂的研究却被大家所忽视。然而,FIH抑制剂因为其独特的调控功能,如改变机体代谢、缺氧应答等,值得进一步深入研究(J.Med.Chem.2021,64(11),7189-7209.)。
研究表明,FIH基因敲除或抑制能够造成细胞内代谢的明显变化,FIH的降低伴随着氧化代谢的增加,这意味着FIH的抑制能够为代谢性疾病的治疗提供新手段。FIH的缺失能明显降低机体体重,改善肥胖(Cell Metab.201011(5):364-378.)。这是由于FIH的缺失导致氧消耗及卡路里的消耗提升约20%,代谢率也明显提升。与此同时,FIH的缺乏也使得脂肪细胞显著减少。对于高脂饮食诱导的脂肪肝小鼠,FIH的缺失有明显改善及保护作用。FIH缺失的小鼠能够表现出明显的较低甘油三酯及胆固醇水平,同时对于肝肥大也有明显改善(Cell Metab.2018 27(4):898-913.)。因此,FIH抑制剂能够通过加速体内脂肪代谢,从而达到治疗肥胖、高血脂、高胆固醇血症、非酒精性脂肪肝炎等脂肪代谢性疾病的效果。
目前,鲜有FIH抑制剂的报道,尤其是FIH选择性抑制剂,仅有的FIH选择性抑制剂N-草酰-D-苯丙氨酸对于FIH抑制活性较差且不具有细胞活性(J.Am.Chem.Soc.2005,127(21),7680-7681.),这极大限制了对于FIH调控功能的研究。(J.Med.Chem.2021,64(11),7189-7209.)。
发明内容
发明目的:本发明的目的是提供一种具有高选择性、高活性的N-草酰-D-苯丙氨酸类化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐;本发明的另一目的是提供一种N-草酰-D-苯丙氨酸类化合物的制法;本发明的另一目的是提供一种药物组合物;本发明的另一目的是提供一种N-草酰-D-苯丙氨酸类化合物在制备FIH抑制剂中的应用。
技术方案:本发明的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐,
其中R1为氢;
R2选自羧基、羟基、氨基甲酰基、氰基、五元芳杂基;
L1为位于Ar和苯环间位之间长度为0-3个原子长度的连接链;
Ar为5-10个环成员的单环或双环芳基或芳杂基;
R3为位于Ar上的一个或相同或不同的多个取代基,其中取代基任选自氢、C1-C4烷基、C1-C4烷氧基、C1-C4环烷氧基、C1-C4烷氨基、C1-C4酰基、C1-C4酰氨基、氨基甲酰基、C1-C4烷氨甲酰基、C1-C4磺酰基、C1-C4磺酰氨基、氨基磺酰基、C1-C4烷氨磺酰基、卤素、氰基、羟基、氨基。
进一步地,所述化合物选自:
进一步地,根据通式(I)的化合物可含足以形成盐的酸性官能团。代表性的盐包括可药用金属盐如钠、钾、锂、钙、镁、铝和锌盐;可药用金属阳离子如钠、钾、锂、钙、镁、铝和锌的碳酸盐和碳酸氢盐;可药用有机伯胺、仲胺和叔胺,包括脂肪胺、芳香胺、脂肪二胺和羟基烷基胺,如甲胺、乙胺、2-羟基乙基胺、二乙胺、三乙胺、乙二胺、乙醇胺、二乙醇胺。
优选的,所述前药为R1与R2任意一侧或两侧形成的酯类前药。
更进一步地,所述酯类前药选自:
另一方面,本发明提供一种制备上述所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐的方法,所述方法为以下任一方法之一:
方法一:
由原料II在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体III;中间体III在催化剂的条件下发生偶联反应得到目标化合物或中间体IV;最后,中间体IV经氢氧化锂水解得到目标化合物;
方法二:
由原料II在三乙胺的碱性条件下与草酰氯苄酯发生缩合反应得到中间体V;中间体V在催化剂催化下发生偶联反应得到中间体VI;最后,中间体VI经氢气和钯碳还原得到目标化合物;
方法三:
由原料II经氢化铝锂还原得到中间体VII;中间体VII在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体VIII;中间体VIII在催化剂条件下发生偶联反应得到中间体IX;最后中间体IX经氢氧化锂水解得到目标化合物;
方法四:
由原料X与氨气缩合得到中间体XI;中间体XI在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体XII;中间体XIII在催化剂的条件下发生偶联反应得到中间体XIII;最后,中间体XIII经氢氧化锂水解得到目标化合物;
方法五:
中间体XI在三氟乙酸酐催化下脱水得到中间体XIX;中间体XIX在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体XX;中间体XX在催化剂的条件下发生偶联反应得到中间体XXI;最后,中间体XXI经氢氧化锂水解得到目标化合物I或中间体XXII;中间体XXII与四丁基氟化铵环加成反应得到目标化合物I。
另一方面,本发明提供一种药物组合物其含有上述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐,以及药学上可接受的载体。
另一方面,本发明提供一种上述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐或者上述药物组合物在制备FIH抑制剂中的应用。具体的,在制备用于抑制FIH来起到缺氧应答的用途,同时加快脂肪代谢,改善脂肪代谢性疾病,所述疾病如高脂血症、高胆固醇血症、非酒精性脂肪肝、肥胖等,其可通过抑制FIH达到治疗效果。
本发明的化合物临床所用剂量为0.01mg~500mg/天,也可根据病情轻重或剂型不同偏离此范围。
另一方面,本发明提供一种上述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐或者根据上述药物组合物在制备治疗与FIH活性相关的疾病的药物中的应用。
优选的,其中所述疾病选自脂肪代谢性疾病,如肥胖、高血脂、高胆固醇血症、非酒精性脂肪肝炎等。
有益效果:与现有技术相比,本发明具有如下显著优点:本发明的化合物是一类具有体内外FIH抑制活性的候选化合物,其能够选择性且高效地FIH抑制活性,从而增强HIF转录活性,起到调控缺氧应答的作用,同时加快脂肪代谢,用于改善肥胖、高血脂、高胆固醇血症、非酒精性脂肪肝炎等脂肪代谢性疾病。
附图说明
图1为本发明化合物改善肥胖、高血脂及脂肪肝等脂肪代谢性疾病的作用;(A)为各组小鼠的体重变化图;(B)为各组小鼠的血清甘油三酯含量图;(C)为各组小鼠的肝脏甘油三酯含量图。
具体实施方式
下面对本发明的技术方案作进一步说明。
本发明实施例涉及的典型的化合物包括:
本发明实施例涉及的典型化合物的酯类前药包括:
本发明实施例提供了上述典型化合物的制备方法:
方法一:
由原料II在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体III;中间体III在催化剂的条件下发生偶联反应得到目标化合物(实施例33-36、45-47、52-53)或中间体IV;最后,中间体IV经氢氧化锂水解得到目标化合物(实施例1-32、37-40)。
方法二:
由原料II在三乙胺的碱性条件下与草酰氯苄酯发生缩合反应得到中间体V;中间体V在催化剂催化下发生偶联反应得到中间体VI;最后,中间体VI经氢气和钯碳还原得到目标化合物(实施例50-51)。
方法三:
由原料II经氢化铝锂还原得到中间体VII;中间体VII在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体VIII;中间体VIII在催化剂条件下发生偶联反应得到中间体IX;最后中间体IX经氢氧化锂水解得到目标化合物(实施例41)。
方法四:
由原料X与氨气缩合得到中间体XI;中间体XI在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体XII;中间体XIII在催化剂的条件下发生偶联反应得到中间体XIII;最后,中间体XIII经氢氧化锂水解得到目标化合物(实施例42)。
方法五:
中间体XI在三氟乙酸酐催化下脱水得到中间体XIX;中间体XIX在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体XX;中间体XX在催化剂的条件下发生偶联反应得到中间体XXI;最后,中间体XXI经氢氧化锂水解得到目标化合物I(实施例43)或中间体XXII;中间体XXII与四丁基氟化铵环加成反应得到目标化合物I(实施例44)。
其中R代表氢、C1-C4脂肪烃如甲基、乙基、叔丁基,或苄基;A代表脂肪或芳香含N杂环;R1,R2,R3,L1,L2以及Ar的定义如前。
实施例
以下各实施例(实施例1-40)采用方法一制备所得。
实施例1:I-1的制备
(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol)溶于10mL甲醇中,冰浴下加入0.37mL氯化亚砜,常温下搅拌30min后,升温至80℃下搅拌6h,反应完全。反应结束后,减压蒸馏除去有机溶剂得淡黄色固体溶于10mL二氯甲烷中,加入0.43mL三乙胺,常温下搅拌5min后,加入0.22mL草酰氯甲酯,常温下搅拌30min,反应完全。反应结束后,加入适量的水淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1),得白色固体溶于10mL四氢呋喃,加入67.15mg四三苯基膦钯,0.87mL的2M磷酸钾水溶液以及苯硼酸(78mg,0.64mmol),常规加热至65℃4h,反应完全。反应结束后,抽滤除去四三苯基膦钯,减压蒸馏后,粗品用硅胶柱层析(石油醚:乙酸乙酯=2:1),得淡黄色油状物溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,加入3mmol稀盐酸至pH为1-2,乙酸乙酯萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸馏得淡黄色油状物103mg,总收率54.1%。δ8.39(s,1H),7.62(d,J=7.6Hz,2H),7.48–7.42(m,3H),7.34(q,J=8.0Hz,2H),7.17(d,J=7.7Hz,1H),4.37(s,1H),3.19–3.15(m,2H).;EI-MSm/z:313[M]+。
实施例2:I-2的制备
制备方法同实施例1,用3-呋喃硼酸(78.03mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物98mg,总收率55.61%。δ8.91(d,J=8.4Hz,1H),8.12(t,J=1.2Hz,1H),7.74(t,J=1.7Hz,1H),7.49(d,J=1.8Hz,1H),7.45(dt,J=7.8,1.5Hz,1H),7.28–7.24(m,1H),7.12(dt,J=7.6,1.4Hz,1H),6.93–6.90(m,1H),4.53–4.48(m,1H),3.15(d,J=2.7Hz,1H),3.08(d,J=4.0Hz,1H).;EI-MS m/z:303[M]+。
实施例3:I-3的制备
制备方法同实施例1,用苯并呋喃-2-硼酸(112.94mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物101mg,总收率49.44%。δ7.79(d,J=7.7Hz,2H),7.58(s,1H),7.49(s,2H),7.34(d,J=7.8Hz,3H),7.10(d,J=7.4Hz,1H),4.05(q,J=7.2Hz,1H),3.27–3.23(m,1H),3.06(d,J=5.2Hz,1H).;EI-MS m/z:353[M]+。
实施例4:I-4的制备
制备方法同实施例1,用4-吡啶硼酸(85.55mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物96mg,总收率52.22%。δ9.00(s,1H),8.89–8.71(m,1H),8.64(s,1H),7.88(d,J=5.8Hz,1H),7.71(s,2H),7.63–7.56(m,2H),7.49–7.33(m,2H),4.56(s,1H),3.15(s,1H).;EI-MS m/z:314[M]+。
实施例5:I-5的制备
制备方法同实施例1,用2-甲基苯硼酸(94.63mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物95mg,总收率50.04%。δ13.02(s,1H),8.95(d,J=8.4Hz,1H),7.35(t,J=7.6Hz,1H),7.28(d,J=2.0Hz,1H),7.26(dd,J=3.4,1.4Hz,1H),7.24(dt,J=5.1,2.6Hz,2H),7.19(d,J=1.8Hz,1H),7.18–7.15(m,2H),4.55–4.49(m,1H),3.21(d,J=9.3Hz,1H),3.13–3.07(m,1H),2.18(s,3H).;EI-MS m/z:327[M]+。
实施例6:I-6的制备
制备方法同实施例1,用3-甲基苯硼酸(94.63mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物87mg,总收率45.83%。δ13.01(s,1H),8.99(d,J=8.3Hz,1H),7.53(d,J=1.9Hz,1H),7.50–7.44(m,2H),7.42(d,J=8.0Hz,1H),7.35(q,J=7.5Hz,2H),7.22(d,J=7.6Hz,1H),7.18(d,J=7.4Hz,1H),4.52(dt,J=9.0,4.9Hz,1H),3.25–3.20(m,1H),3.17–3.11(m,1H),2.38(s,3H).;EI-MS m/z:327[M]+。
实施例7:I-7的制备
制备方法同实施例1,用4-甲基苯硼酸(94.63mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物90mg,总收率47.41%。δ8.60(s,1H),7.48(d,J=8.1Hz,2H),7.43–7.39(m,2H),7.24–7.21(m,3H),7.06(d,J=7.8Hz,1H),4.40(s,1H),3.17–3.15(m,1H),3.15–3.13(m,1H),2.32(s,3H).;EI-MS m/z:327[M]+。
实施例8:I-8的制备
制备方法同实施例1,用3-吡啶硼酸(85.55mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物91mg,总收率49.92%。δ8.94(d,J=8.4Hz,1H),8.87(d,J=2.5Hz,1H),8.57(d,J=4.7Hz,1H),8.05(d,J=7.9Hz,1H),7.62(s,1H),7.57(d,J=3.7Hz,1H),7.49(dd,J=8.0,4.7Hz,1H),7.42(t,J=7.6Hz,1H),7.29(d,J=7.6Hz,1H),4.60–4.47(m,1H),3.24(d,J=9.0Hz,1H),3.16–3.08(m,1H).;EI-MS m/z:314[M]+。
实施例9:I-9的制备
制备方法同实施例1,用2-吡啶硼酸(85.55mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物94mg,总收率51.57%。δ7.68–7.52(m,2H),7.43–7.36(m,2H),7.28–7.19(m,3H),6.90(dd,J=21.2,8.3Hz,1H),4.02(td,J=8.9,8.2,4.5Hz,1H),3.05(d,J=9.3Hz,1H),2.82(dd,J=13.7,9.7Hz,1H).;EI-MS m/z:314[M]+。
实施例10:I-10的制备
制备方法同实施例1,用3-氟苯基硼酸(97.38mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物103mg,总收率53.60%。δ8.89(d,J=8.2Hz,1H),8.05–6.71(m,8H),4.54(s,1H),3.23(d,J=13.6Hz,1H),3.16–3.08(m,1H).;EI-MS m/z:331[M]+。
实施例11:I-11的制备
制备方法同实施例1,用3-氯苯基硼酸(108.83mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物105mg,总收率52.06%。δ8.93(d,J=8.4Hz,1H),7.71(t,J=1.9Hz,1H),7.64–7.59(m,2H),7.55–7.47(m,2H),7.44–7.36(m,2H),7.27(dt,J=7.6,1.4Hz,1H),4.58–4.52(m,1H),3.24(d,J=9.2Hz,1H),3.13(d,J=3.9Hz,1H).;EI-MS m/z:348[M]+。
实施例12:I-12的制备
制备方法同实施例1,用3-甲氧基苯硼酸(105.76mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物99mg,总收率49.71%。δ8.94(d,J=8.7Hz,1H),7.56–7.48(m,2H),7.36(td,J=7.8,2.4Hz,2H),7.24–7.15(m,3H),6.93(dd,J=8.2,2.6Hz,1H),4.54(td,J=9.0,4.2Hz,1H),3.83(s,3H),3.22(t,J=6.8Hz,1H),3.13(dd,J=13.9,9.9Hz,1H).;EI-MS m/z:343[M]+。
实施例13:I-13的制备
制备方法同实施例1,用3-羟基苯硼酸(96mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物94mg,总收率49.21%。δ9.55(s,1H),7.65(d,J=1.3Hz,1H),7.63(s,1H),7.54(dd,J=3.0,1.3Hz,1H),7.47–7.41(m,2H),7.34(dd,J=7.5,3.5Hz,1H),7.24–7.19(m,2H),4.63(s,1H),3.06(d,J=11.3Hz,1H),2.82(dd,J=14.1,10.4Hz,1H).;EI-MS m/z:329[M]+。
实施例14:I-14的制备
制备方法同实施例1,用3-(三氟甲基)苯硼酸(132.19mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物102mg,总收率46.12%。δ8.97(d,J=8.4Hz,1H),7.97(dd,J=6.9,2.0Hz,2H),7.74–7.65(m,3H),7.59(dt,J=7.7,1.4Hz,1H),7.41(t,J=7.6Hz,1H),7.30(d,J=7.6Hz,1H),4.56(ddd,J=10.0,8.3,4.5Hz,1H),3.26(d,J=9.3Hz,1H),3.17–3.11(m,1H).;EI-MS m/z:381[M]+。
实施例15:I-15的制备
制备方法同实施例1,用3-硝基苯硼酸(116.18mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物98mg,总收率47.16%。δ8.97(d,J=8.3Hz,1H),8.45(d,J=2.3Hz,1H),8.26–8.12(m,2H),7.78–7.61(m,3H),7.43(t,J=7.5Hz,1H),7.33(d,J=7.8Hz,1H),4.62–4.52(m,1H),3.27(dd,J=13.9,4.6Hz,1H),3.15(dd,J=13.8,9.9Hz,1H).;EI-MS m/z:358[M]+。
实施例16:I-16的制备
制备方法同实施例1,用3-乙酰基苯硼酸(114.12mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物101mg,总收率49.00%。δ8.99(d,J=8.4Hz,1H),8.18(q,J=1.7Hz,1H),7.93(ddt,J=13.2,6.5,1.5Hz,2H),7.65–7.57(m,3H),7.41(td,J=7.4,1.8Hz,1H),7.31–7.26(m,1H),4.56(td,J=9.3,4.4Hz,1H),3.26(d,J=9.3Hz,1H),3.18–3.12(m,1H),2.67(s,3H).;EI-MS m/z:355[M]+。
实施例17:I-17的制备
制备方法同实施例1,用3-联苯硼酸(137.83mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物107mg,总收率47.37%。δ8.97(d,J=8.4Hz,1H),7.90(s,1H),7.77(d,J=7.6Hz,2H),7.68–7.48(m,7H),7.44–7.36(m,2H),7.26(d,J=7.6Hz,1H),4.57(ddd,J=9.9,8.3,4.5Hz,1H),3.26(dd,J=13.9,4.6Hz,1H),3.16(dd,J=13.9,9.9Hz,1H).;EI-MS m/z:389[M]+。
实施例18:I-18的制备
制备方法同实施例1,用3-氰基苯硼酸(102.27mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物96mg,总收率48.92%。δ8.98(d,J=8.4Hz,1H),8.14(t,J=1.7Hz,1H),8.03–7.98(m,1H),7.82(dt,J=7.7,1.3Hz,1H),7.69–7.58(m,3H),7.41(t,J=7.6Hz,1H),7.30(dt,J=7.6,1.4Hz,1H),4.58(ddd,J=10.0,8.3,4.5Hz,1H),3.26(dd,J=13.8,4.6Hz,1H),3.14(dd,J=13.8,10.1Hz,1H).;EI-MS m/z:338[M]+。
实施例19:I-19的制备
制备方法同实施例1,用3-叔丁基苯硼酸(123.92mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物102mg,总收率47.64%。δ8.91(d,J=8.3Hz,1H),7.60(d,J=2.0Hz,1H),7.54–7.47(m,2H),7.42–7.35(m,4H),7.22(d,J=7.7Hz,1H),4.54(dt,J=8.8,4.4Hz,1H),3.25–3.21(m,1H),3.18–3.12(m,1H),1.34(s,9H).;EI-MS m/z:369[M]+。
实施例20:I-20的制备
制备方法同实施例1,用1-萘硼酸(119.71mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物99mg,总收率46.98%。δ8.94(d,J=8.4Hz,1H),8.02–7.93(m,2H),7.79(d,J=8.3Hz,1H),7.59–7.40(m,5H),7.37–7.30(m,3H),4.56(td,J=9.0,4.3Hz,1H),3.27–3.23(m,1H),3.15(dd,J=13.9,9.8Hz,1H).;EI-MS m/z:363[M]+。
实施例21:I-21的制备
制备方法同实施例1,用3-(三氟甲氧基)苯硼酸(143.33mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物105mg,总收率46.36%。δ9.01(d,J=8.4Hz,1H),7.71(dt,J=7.9,1.3Hz,1H),7.64–7.54(m,4H),7.42–7.35(m,2H),7.29(d,J=7.7Hz,1H),4.55(td,J=9.0,8.4,4.5Hz,1H),3.25(dd,J=13.8,4.5Hz,1H),3.18–3.13(m,1H).;EI-MS m/z:397[M]+。
实施例22:I-22的制备
制备方法同实施例1,用3-乙基苯硼酸(104.39mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物97mg,总收率48.99%。δ8.99(d,J=8.1Hz,1H),7.54(s,1H),7.50–7.34(m,5H),7.23(q,J=7.7,7.0Hz,2H),4.54(td,J=9.0,4.3Hz,1H),3.24(dd,J=13.8,4.5Hz,1H),3.15(dd,J=8.9,5.4Hz,1H),2.67(q,J=7.5Hz,2H),1.23(t,J=7.6Hz,3H).;EI-MS m/z:341[M]+。
实施例23:I-23的制备
制备方法同实施例1,用3-异丙基苯硼酸(114.15mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物95mg,总收率46.09%。δ9.00(d,J=8.4Hz,1H),7.55(t,J=1.8Hz,1H),7.48(p,J=2.2Hz,2H),7.43–7.34(m,3H),7.25–7.22(m,2H),4.55(ddd,J=9.7,8.3,4.5Hz,1H),3.25(dd,J=13.9,4.5Hz,1H),3.19–3.14(m,1H),1.26(d,J=6.9Hz,6H).;EI-MS m/z:355[M]+。
实施例24:I-24的制备
制备方法同实施例1,用3-甲磺酰基苯硼酸(139.21mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物107mg,总收率48.41%。δ9.05(d,J=8.4Hz,1H),8.17(s,1H),8.02(d,J=8.4Hz,1H),7.92(d,J=8.0Hz,1H),7.75(t,J=7.8Hz,1H),7.68(s,1H),7.61(d,J=7.9Hz,1H),7.43(t,J=7.7Hz,1H),7.32(d,J=7.6Hz,1H),4.57(ddd,J=10.2,8.3,4.5Hz,1H),3.31(s,3H),3.29–3.24(m,1H),3.17(dd,J=9.5,4.4Hz,1H).;EI-MSm/z:391[M]+。
实施例25:I-25的制备
制备方法同实施例1,用3,5-二氯苯硼酸(132.81mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物103mg,总收率46.38%。δ8.99(d,J=8.3Hz,1H),7.73(d,J=1.9Hz,2H),7.66(s,1H),7.62–7.56(m,2H),7.39(t,J=7.7Hz,1H),7.30(d,J=7.6Hz,1H),4.56(ddd,J=10.2,8.4,4.4Hz,1H),3.24(dd,J=13.8,4.5Hz,1H),3.13(dd,J=10.5,3.7Hz,1H).;EI-MS m/z:382[M]+。
实施例26:I-26的制备
制备方法同实施例1,用3,5-二氟苯硼酸(109.91mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物99mg,总收率48.87%。δ8.99(d,J=8.4Hz,1H),7.65(s,1H),7.59(d,J=7.7Hz,1H),7.41(dd,J=9.7,7.2Hz,3H),7.30(d,J=7.6Hz,1H),7.23(dd,J=9.1,6.5Hz,1H),4.55(td,J=9.3,4.4Hz,1H),3.24(dd,J=13.8,4.5Hz,1H),3.13(dd,J=9.2,4.6Hz,1H).;EI-MS m/z:349[M]+。
实施例27:I-27的制备
制备方法同实施例1,用3-氯-5-甲基苯基硼酸(118.60mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物98mg,总收率46.70%。δ8.96(d,J=8.4Hz,1H),7.58(s,1H),7.55–7.47(m,2H),7.44(s,1H),7.37(t,J=7.6Hz,1H),7.26(s,2H),4.54(td,J=9.2,4.4Hz,1H),3.23(dd,J=13.8,4.5Hz,1H),3.12(dd,J=13.8,10.0Hz,1H),2.38(s,3H).;EI-MS m/z:362[M]+。
实施例28:I-28的制备
制备方法同实施例1,用3-氟-5-甲基苯基硼酸(107.15mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物95mg,总收率47.48%。δ8.97(d,J=8.4Hz,1H),7.62–7.49(m,2H),7.40–7.23(m,4H),7.02(d,J=9.8Hz,1H),4.54(td,J=9.3,4.4Hz,1H),3.24(dd,J=13.8,4.5Hz,1H),3.13(dd,J=13.8,10.0Hz,1H),2.39(s,3H).;EI-MS m/z:345[M]+。
实施例29:I-29的制备
制备方法同实施例1,用3-氯-5-异丙基苯基硼酸(138.12mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物106mg,总收率46.87%。δ8.97(d,J=8.8Hz,1H),7.71(s,1H),7.60(s,1H),7.48(d,J=9.0Hz,2H),7.41–7.35(m,2H),7.28(s,1H),4.57–4.53(m,1H),3.23(s,1H),3.15(d,J=10.8Hz,1H),3.02–2.95(m,1H),1.25(d,J=6.5Hz,6H).;EI-MS m/z:390[M]+。
实施例30:I-30的制备
制备方法同实施例1,用3-氟-5-异丙基苯基硼酸(126.67mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物103mg,总收率47.56%。δ9.02(d,J=10.6Hz,1H),7.60–7.47(m,3H),7.35(s,1H),7.26(d,J=9.8Hz,2H),7.08(d,J=9.6Hz,1H),4.51(d,J=11.4Hz,1H),3.22(s,1H),3.14(d,J=4.1Hz,1H),3.01–2.95(m,1H),1.25(d,J=6.9Hz,6H).;EI-MS m/z:373[M]+。
实施例31:I-31的制备
制备方法同实施例1,用2-氟-5-甲基苯硼酸(107.15mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物103mg,总收率51.45%。δ8.94(d,J=8.4Hz,1H),7.36(s,1H),7.30(d,J=7.3Hz,1H),7.24(d,J=10.6Hz,3H),7.10(t,J=7.4Hz,1H),6.99(d,J=9.7Hz,1H),4.55–4.49(m,1H),3.22(dd,J=13.9,4.5Hz,1H),3.15–3.10(m,1H),2.15(s,3H).;EI-MS m/z:345[M]+。
实施例32:I-32的制备
制备方法同实施例1,用2-氯-5-甲基苯硼酸(107.15mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物103mg,总收率51.45%。δ8.95(d,J=8.4Hz,1H),7.36(t,J=7.6Hz,1H),7.32(d,J=1.4Hz,2H),7.26(d,J=7.8Hz,1H),7.20(t,J=8.4Hz,3H),4.54(ddd,J=10.0,8.4,4.5Hz,1H),3.22(dd,J=13.8,4.5Hz,1H),3.11(dd,J=13.8,10.0Hz,1H),2.16(s,3H).;EI-MS m/z:362[M]+。
实施例33:I-33的制备
制备方法同实施例1,用(R)-2-(3-溴苯基)-1-呋喃-3-基)乙胺(500mg,1.88mmol)替换(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol),(3-乙酰基-5-氨基甲酰基苯基)硼酸(411.91mg,1.99mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物127mg,总收率47.63%。1H NMR(500MHz,Chloroform-d)δ8.26(t,J=2.1Hz,1H),8.17(dt,J=11.9,2.2Hz,2H),7.77(d,J=8.6Hz,1H),7.55–7.47(m,2H),7.44(dd,J=1.8,0.9Hz,2H),7.40(t,J=1.6Hz,1H),7.39(s,2H),7.26(dtt,J=6.4,2.0,1.1Hz,1H),6.32(t,J=1.1Hz,1H),5.11(dt,J=8.8,6.4Hz,1H),3.04(qdt,J=14.1,6.4,0.9Hz,2H).;EI-MS m/z:420[M]+。
实施例34:I-34的制备
制备方法同实施例1,用(R)-2-(3-溴苯基)-1-(1H-咪唑-4-基)乙烷-1-胺(500mg,1.88mmol)替换(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol),(3-(异丙基氨基)-5-氨基磺酰基苯基)硼酸(513.62mg,1.99mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物125mg,总收率44.78%。1H NMR(500MHz,Chloroform-d)δ8.27(d,J=8.8Hz,1H),7.96(t,J=2.1Hz,1H),7.74(dd,J=5.9,1.7Hz,1H),7.58(ddd,J=7.7,1.9,1.2Hz,1H),7.54–7.47(m,2H),7.33(d,J=9.3Hz,1H),7.30(dd,J=4.9,1.6Hz,1H),7.28–7.21(m,2H),7.12(t,J=2.1Hz,1H),6.94(t,J=2.2Hz,1H),6.77(dd,J=6.0,4.9Hz,1H),5.45(dt,J=8.6,6.4Hz,1H),5.01(d,J=7.5Hz,1H),3.63(dhept,J=7.5,6.2Hz,1H),3.25(qdt,J=15.6,6.6,1.1Hz,2H),1.20(d,J=6.2Hz,3H),1.15(d,J=6.2Hz,3H).;EI-MS m/z:472[M]+。
实施例35:I-35的制备
制备方法同实施例1,用(R)-2-(3-溴苯基)-1-异恶唑-4-基)乙烷-1-胺(500mg,1.87mmol)替换(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol),3-(甲基氨基甲酰基)-5-(N-甲基氨基磺酰基)苯基)硼酸(527.39mg,1.94mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物130mg,总收率46.21%。1H NMR(500MHz,Chloroform-d)δ8.60(d,J=1.6Hz,1H),8.38(d,J=1.8Hz,1H),8.20(p,J=2.2Hz,2H),8.17(t,J=2.2Hz,1H),8.05(q,J=5.1Hz,1H),7.85(d,J=9.2Hz,1H),7.59(dt,J=7.8,1.5Hz,1H),7.54–7.47(m,2H),7.26(ddq,J=7.9,2.0,1.0Hz,1H),6.80(q,J=6.8Hz,1H),5.28(dt,J=9.2,6.8Hz,1H),3.12–
2.99(m,2H),2.93(d,J=5.1Hz,3H),2.58(d,J=6.6Hz,3H).;EI-MS m/z:486[M]+。
实施例36:I-36的制备
制备方法同实施例1,用(R)-2-(3-溴苯基)-1-恶唑-4-基)乙胺(500mg,1.87mmol)替换(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol),(3-乙酰氨基-5-(甲基磺酰胺基)苯基)硼酸(532.28mg,1.95mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物133mg,总收率47.32%。1H NMR(500MHz,Chloroform-d)δ9.25(s,1H),8.31(s,1H),7.95(d,J=1.6Hz,1H),7.83(d,J=8.6Hz,1H),7.59–7.54(m,2H),7.54–7.47(m,2H),7.43(dt,J=8.1,2.2Hz,2H),7.39(t,J=2.2Hz,1H),7.27(ddt,J=6.9,2.2,1.1Hz,1H),5.27(dt,J=8.6,6.3Hz,1H),3.17(dq,J=6.4,1.0Hz,2H),2.94(s,2H).;EI-MS m/z:486[M]+。
实施例37:I-37的制备
(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol)溶于10mL甲醇中,冰浴下加入0.37mL氯化亚砜,常温下搅拌30min后,升温至80℃下搅拌6h,反应完全。反应结束后,减压蒸馏除去有机溶剂得淡黄色固体溶于10mL二氯甲烷中,加入0.43mL三乙胺,常温下搅拌5min后,加入0.22mL草酰氯甲酯,常温下搅拌30min,反应完全。反应结束后,加入适量的水淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1),得白色固体溶于10mL甲苯,加入13.05mg醋酸钯,72.37mg BINAP,378.68mg碳酸铯以及苄胺(124.54mg,1.16mmol),常规加热至110℃,反应过夜,反应完全。反应结束后,抽滤除去醋酸钯,减压蒸馏后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得淡黄色油状物溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,加入3mmol稀盐酸至pH为1-2,乙酸乙酯萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸馏得淡黄色油状物72mg,总收率36.2%。δ7.36–7.21(m,5H),7.12(q,J=8.1Hz,1H),6.72(ddd,J=33.5,19.0,8.7Hz,3H),4.55(s,1H),4.30(d,J=12.8Hz,2H),3.07(dd,J=14.0,4.6Hz,1H),2.87(dd,J=13.8,7.8Hz,1H).;EI-MS m/z:342[M]+。
实施例38:I-38的制备
制备方法同实施例37,用苯甲酰胺(140.52mg,1.16mmol)替换苄胺(124.54mg,1.16mmol),得淡黄色油状物88mg,总收率42.58%。δ10.25(s,1H),8.96(d,J=8.2Hz,1H),7.97(d,J=7.4Hz,2H),7.72(s,1H),7.65(t,J=7.9Hz,2H),7.57(d,J=7.3Hz,2H),7.28(t,J=7.8Hz,1H),7.01(d,J=7.5Hz,1H),4.51(td,J=8.9,4.9Hz,1H),3.14(dd,J=11.9,7.1Hz,2H).;EI-MS m/z:356[M]+。
实施例39:I-39的制备
制备方法同实施例37,用甲基苄胺(140.57mg,1.16mmol)替换苄胺(124.54mg,1.16mmol),得淡黄色油状物89mg,总收率44.59%。δ8.76(d,J=8.2Hz,1H),7.36(dd,J=7.5,2.1Hz,2H),7.28(t,J=7.4Hz,2H),7.19–7.15(m,1H),6.85(t,J=7.8Hz,1H),6.42(dt,J=9.1,1.9Hz,1H),6.34–6.27(m,2H),4.35(dd,J=10.2,5.8Hz,1H),2.90(q,J=9.8,8.9Hz,2H),1.39(d,J=6.7Hz,3H).;EI-MS m/z:356[M]+。
实施例40:I-40的制备
制备方法同实施例37,用苯乙胺(140.57mg,1.16mmol)替换苄胺(124.54mg,1.16mmol),得淡黄色油状物85mg,总收率41.12%。δ9.03(d,J=8.1Hz,1H),7.71(ddt,J=7.5,4.3,1.4Hz,1H),7.63–7.62(m,1H),7.39(dd,J=5.2,2.5Hz,1H),7.29(d,J=2.3Hz,2H),6.97(t,J=7.7Hz,1H),6.47–6.41(m,2H),4.42(dd,J=8.6,5.0Hz,1H),3.22–3.19(m,2H),3.06–3.03(m,1H),3.01–2.98(m,1H),2.82(dd,J=8.5,6.5Hz,2H).;EI-MS m/z:356[M]+。
以下实施例41采用方法三制备所得。
实施例41:I-41制备
(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol)溶于10mL甲醇中,冰浴下加入0.37mL氯化亚砜,常温下搅拌30min后,升温至80℃下搅拌6h,反应完全。反应结束后,减压蒸馏除去有机溶剂得淡黄色固体溶于10mL无水四氢呋喃中,冰浴下加入233.21mg氢化铝锂,常温下搅拌反应过夜,反应完全。反应结束后,加入适量的水和10%氢氧化钠淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1),得白色固体溶于10mL二氯甲烷,加入0.54ml三乙胺,常温下搅拌5min后,加入0.16mL草酰氯甲酯,常温下搅拌30min,反应完全。反应结束后,加入适量的水淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得淡黄色油状物溶于10mL四氢呋喃,加入71.64mg四三苯基膦钯,0.31mL的2M磷酸钾水溶液以及3-氟-5-甲基苯硼酸(114.54mg,0.74mmol),常规加热至65℃4h,反应完全。反应结束后,抽滤除去四三苯基膦钯,减压蒸馏后,粗品用硅胶柱层析(石油醚:乙酸乙酯=2:1),得淡黄色油状物溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,加入3mmol稀盐酸至pH为1-2,乙酸乙酯萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸馏得淡黄色油状物117mg,总收率48.82%。1H NMR(400MHz,Chloroform-d)δ7.51–7.35(m,4H),7.25(d,J=7.5Hz,1H),7.18(s,1H),7.09(d,J=9.9Hz,1H),6.89(d,J=9.5Hz,1H),4.30(qd,J=7.2,2.9Hz,1H),3.91(s,3H),3.81–3.66(m,2H),3.02(dd,J=7.3,2.2Hz,2H),2.43(s,3H).;EI-MS m/z:331[M]+。
以下实施例42采用方法四制备所得。
实施例42:I-42制备
(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol)溶于10mL甲醇中,冰浴下加入0.37mL氯化亚砜,常温下搅拌30min后,升温至80℃下搅拌6h,反应完全。反应结束后,减压蒸馏除去有机溶剂得淡黄色固体溶于10mL无水四氢呋喃中,冰浴下加入233.21mg氢化铝锂,常温下搅拌反应过夜,反应完全。反应结束后,加入适量的水和10%氢氧化钠淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1),得白色固体溶于10mL二氯甲烷,加入0.54ml三乙胺,常温下搅拌5min后,加入0.16mL草酰氯甲酯,常温下搅拌30min,反应完全。反应结束后,加入适量的水淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得淡黄色油状物溶于10mL四氢呋喃,加入71.64mg四三苯基膦钯,0.31mL的2M磷酸钾水溶液以及3-氟-5-甲基苯硼酸(114.54mg,0.74mmol),常规加热至65℃4h,反应完全。反应结束后,抽滤除去四三苯基膦钯,减压蒸馏后,粗品用硅胶柱层析(石油醚:乙酸乙酯=2:1),得淡黄色油状物溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,加入3mmol稀盐酸至pH为1-2,乙酸乙酯萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸馏得淡黄色油状物117mg,总收率48.82%。δ8.94(d,J=8.4Hz,1H),7.36(s,1H),7.30(d,J=7.3Hz,1H),7.24(d,J=10.6Hz,3H),7.10(t,J=7.4Hz,1H),6.99(d,J=9.7Hz,1H),4.55–4.49(m,1H),3.22(dd,J=13.9,4.5Hz,1H),3.15–3.10(m,1H),2.15(s,3H).;EI-MS m/z:344[M]+。
以下各实施例(实施例43-444)采用方法五制备所得。
实施例43:I-44制备
(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol)溶于10mL二氯甲烷中,冰浴下缓慢滴入氨气,常温下搅拌6h,反应完全。反应结束后,减压蒸馏除去有机溶剂,乙酸乙酯萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(二氯甲烷:甲醇=100:1),得淡黄色油状物溶于10mL四氢呋喃中,冰浴下加入0.37ml三乙胺,187.48ml三氟乙酸酐,0℃搅拌反应2h,反应完全。反应结束后,旋蒸除去有机溶剂,乙酸乙酯萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=4:1),得白色固体溶于10mL二氯甲烷,加入0.42ml三乙胺,常温下搅拌5min后,加入0.12mL草酰氯甲酯,常温下搅拌30min,反应完全。反应结束后,加入适量的水淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得淡黄色油状物溶于10mL四氢呋喃,加入84.36mg四三苯基膦钯,1.10mL的2M磷酸钾水溶液以及3-氟-5-甲基苯硼酸(134.86mg,0.88mmol),常规加热至65℃4h,反应完全。反应结束后,抽滤除去四三苯基膦钯,减压蒸馏后,粗品用硅胶柱层析(石油醚:乙酸乙酯=2:1),得淡黄色油状物溶于10mL四氢呋喃,加入3mL 1M氢氧化锂溶液,加热至30℃反应2h,反应完全。反应结束后,减压蒸馏除去反应液中的四氢呋喃,加入3mmol稀盐酸至pH为1-2,乙酸乙酯萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥。减压蒸馏得淡黄色油状物127mg,总收率53.78%。1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.28(s,1H),7.43(d,J=7.6Hz,1H),7.29(d,J=13.5Hz,2H),7.24(s,1H),7.16(d,J=10.3Hz,1H),7.09(d,J=7.4Hz,1H),6.99(d,J=9.8Hz,1H),5.29(s,1H),3.28(d,J=10.7Hz,2H),2.37(s,3H).;EI-MS m/z:326[M]+。
实施例44:I-44制备
制备方法同实施例43,将黄色油状物溶于10mL四氢呋喃,加入0.24ml叠氮基三甲基硅烷,2ml 1M四丁基氟化铵,常规加热至85℃反应过夜,反应完全。反应结束后,减压旋蒸,粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=1:1),得淡黄色油状物113mg,总收率48.91%。1H NMR(400MHz,DMSO-d6)δ9.63–9.45(m,1H),7.66(s,1H),7.58(d,J=7.4Hz,1H),7.41(t,J=7.7Hz,1H),7.35(s,1H),7.32–7.24(m,2H),7.04(d,J=9.5Hz,1H),5.05(q,J=8.0Hz,1H),3.24(d,J=7.9Hz,2H),2.39(s,3H).;EI-MS m/z:369[M]+。
以下各实施例(实施例45-49)采用方法一制备所得。
实施例45:I-45的制备
制备方法同实施例1,用3-氯-5-异丙基苯基硼酸(138.12mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物114mg,总收率47.03%。δ7.54(s,1H),7.48(d,J=7.9Hz,1H),7.40(d,J=7.6Hz,1H),7.35(s,1H),7.30(s,1H),7.22(s,1H),7.13(d,J=7.4Hz,1H),4.97(d,J=8.5Hz,1H),3.92(s,3H),3.79(s,3H),3.27(dd,J=8.1,5.8Hz,2H),3.00–2.94(m,1H),1.32(s,3H),1.30(s,3H).;EI-MS m/z:418[M]+。
实施例46:I-46的制备
制备方法同实施例1,用3-氟-5-甲基苯基硼酸(107.15mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物108mg,总收率49.87%。δ7.56(d,J=8.3Hz,1H),7.48(d,J=7.8Hz,1H),7.39(t,J=7.6Hz,1H),7.31(s,1H),7.15(d,J=8.1Hz,1H),7.05(d,J=9.9Hz,1H),6.89(d,J=9.4Hz,1H),4.99–4.94(m,1H),3.92(s,3H),3.78(s,3H),3.26(dd,J=8.6,5.9Hz,2H),2.43(s,3H).;EI-MS m/z:373[M]+。
实施例47:I-47的制备
制备方法同实施例1,用3-氯-5-甲基苯基硼酸(118.60mg,0.70mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物111mg,总收率49.09%。δ7.55(d,J=8.2Hz,1H),7.47(d,J=7.9Hz,1H),7.39(t,J=7.6Hz,1H),7.34(s,1H),7.29(d,J=6.0Hz,1H),7.18(s,1H),7.13(d,J=7.5Hz,1H),4.96(dt,J=8.4,5.8Hz,1H),3.92(s,3H),3.78(s,3H),3.31–3.22(m,2H),2.42(s,3H).;EI-MS m/z:390[M]+。
实施例48:I-48的制备
(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol)溶于10mL甲醇中,冰浴下加入0.37mL氯化亚砜,常温下搅拌30min后,升温至80℃下搅拌6h,反应完全。反应结束后,减压蒸馏除去有机溶剂得淡黄色固体溶于10mL二氯甲烷中,加入0.43mL三乙胺,常温下搅拌5min后,加入871.78mg草酰氯苄酯,常温下搅拌30min,反应完全。反应结束后,加入适量的水淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入68.74mg四三苯基膦钯,0.89mL的2M磷酸钾水溶液以及3-氟-5-甲基苯基硼酸(109.90mg,0.71mmol),常规加热至65℃4h,反应完全。反应结束后,抽滤除去四三苯基膦钯,减压蒸馏后,粗品用硅胶柱层析(石油醚:乙酸乙酯=1:1),得淡黄色油状物溶于10mL甲醇中,加入100mg氢氧化钯,置换氢气,室温下搅拌反应过夜,反应完全。反应结束后,抽滤除去氢氧化钯,减压蒸馏后得淡黄色油状物83mg,总收率39.59%。δ9.16(d,J=8.2Hz,1H),7.72(s,1H),7.68(s,1H),7.59(s,1H),7.53(d,J=7.8Hz,1H),7.33(s,1H),7.26(s,1H),7.03(d,J=9.7Hz,1H),4.61(q,J=6.9,4.6Hz,1H),3.67(s,3H),3.22(d,J=9.1Hz,1H),3.16–3.09(m,1H),2.39(s,3H).;EI-MS m/z:359[M]+。
实施例49:I-49的制备
制备方法同实施例45,用3-氯-5-甲基苯基硼酸(121.64mg,0.71mmol)替换3-氟-5-甲基苯基硼酸(109.90mg,0.71mmol),得淡黄色油状物87mg,总收率39.24%。δ9.23(s,1H),7.60(s,1H),7.52(d,J=14.2Hz,2H),7.44(s,1H),7.38(d,J=7.6Hz,1H),7.26(s,2H),4.62(s,1H),3.66(s,3H),3.23(dd,J=14.0,4.5Hz,1H),3.16–3.10(m,1H),2.38(s,3H).;EI-MS m/z:376[M]+。
以下各实施例(实施例50-51)采用方法二制备所得。
实施例50:I-50的制备
(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol)溶于10mL乙腈中,加入710mg碳酸钾以及0.49mL溴化苄,常温下搅拌4h,反应完全。反应结束后,减压蒸馏除去有机溶剂得淡黄色固体溶于10mL二氯甲烷中,加入0.43mL三乙胺,常温下搅拌5min后,加入871.78mg草酰氯甲酯,常温下搅拌30min,反应完全。反应结束后,加入适量的水淬灭反应,二氯甲烷萃取,取有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸后,粗品用硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1),得白色固体溶于10mL四氢呋喃,加入68.74mg四三苯基膦钯,0.89mL的2M磷酸钾水溶液以及3-氟-5-甲基苯基硼酸(109.90mg,0.71mmol),常规加热至65℃4h,反应完全。反应结束后,抽滤除去四三苯基膦钯,减压蒸馏后,粗品用硅胶柱层析(石油醚:乙酸乙酯=1:1),得淡黄色油状物溶于10mL甲醇中,加入100mg氢氧化钯,置换氢气,室温下搅拌反应过夜,反应完全。反应结束后,抽滤除去氢氧化钯,减压蒸馏后得淡黄色油状物87mg,总收率40.70%。δ9.14(d,J=8.2Hz,1H),7.53(s,1H),7.49–7.44(m,2H),7.42(d,J=7.8Hz,1H),7.35(d,J=2.6Hz,1H),7.22(d,J=7.9Hz,1H),7.18(d,J=7.5Hz,1H),4.52(ddd,J=9.8,8.1,4.4Hz,1H),3.75(s,3H),3.23(d,J=9.4Hz,1H),3.14–3.08(m,1H),2.38(s,3H).;EI-MS m/z:359[M]+。
实施例51:I-51的制备
制备方法同实施例50,用3-氯-5-甲基苯基硼酸(121.64mg,0.71mmol)替换3-氟-5-甲基苯基硼酸(109.90mg,0.71mmol),得淡黄色油状物86mg,总收率38.02%。δ9.13–8.99(m,1H),7.54(d,J=20.8Hz,2H),7.29(d,J=24.2Hz,4H),7.03(s,1H),4.52(s,1H),3.75(s,3H),3.28–3.19(m,1H),3.11(t,J=12.1Hz,1H),2.38(s,3H).;EI-MS m/z:376[M]+。
实施例52:I-52的制备
制备方法同实施例1,用(R)-2-氨基-3-(3-溴苯基)丙酸乙酯(500mg,1.84mmol)替换(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol),2-氯-2-氧代乙酸环丙酯(300.20mg,2.02mmol)替换草酰氯甲酯(0.22ml),3-氯-5-甲基苯基硼酸(322.06mg,1.89mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物113mg,总收率47.52%。1H NMR(500MHz,Chloroform-d)δ8.49(d,J=9.5Hz,1H),7.58(t,J=2.1Hz,1H),7.52–7.36(m,4H),7.19–7.12(m,2H),4.75(p,J=4.9Hz,1H),4.64(dt,J=9.3,7.3Hz,1H),4.15(q,J=6.3Hz,2H),3.10–2.98(m,2H),1.69–1.57(m,2H),1.54–1.42(m,2H),1.25(t,J=6.4Hz,3H).;EI-MS m/z:430[M]+。
实施例53:I-53的制备
制备方法同实施例1,用(R)-2-氨基-3-(3-溴苯基)丙酸苯酯(500mg,1.56mmol)替换(R)-2-氨基-3-(3-溴苯基)丙酸(500mg,2.05mmol),3-氯-5-甲基苯基硼酸(275.56mg,162mmol)替换苯硼酸(78mg,0.64mmol),得淡黄色油状物118mg,总收率46.37%。1H NMR(500MHz,Chloroform-d)δ8.40(d,J=9.1Hz,1H),7.58(t,J=2.1Hz,1H),7.49(dt,J=7.9,1.6Hz,1H),7.45(t,J=7.8Hz,1H),7.42–7.35(m,4H),7.19–7.10(m,5H),4.66(dt,J=9.2,7.1Hz,1H),3.82(s,2H),3.06(dq,J=7.1,1.0Hz,2H).;EI-MS m/z:452[M]+。
下面是本发明所述化合物的部分药理学实验及结果:
对FIH抑制活性采用荧光偏振的方法测试(FP实验):
测试化合物与荧光基团标记的HIF-1α肽段(FITC-HIF-1α788-822)竞争性结合FIH蛋白的能力,测试中使用384孔黑板(型号为Corining#3575),测试终体积选择60μL,所测试的化合物和FITC-HIF-1α788-822分别溶解于DMSO和纯水中备用。将化合物用assay buffer三倍比稀释12个浓度梯度后每孔加入20μL稀释好的300nM/LFIH蛋白。每个化合物浓度设定两个附孔,每次试验设置空白对照(20μL FITC-HIF-1α788-822+40μL assay buffer)和阴性对照(20μL FITC-HIF-1α788-822+20μL FIH+20μL assay buffer)。室温孵育1小时,用Synergy读板器扫板,激发波长设置为485nm,发射波长设置为535nm。计算公式:%抑制率=100*(1-(实测值-空白)/(阴性值-空白)),得出具体浓度所对应的抑制率。将所得数据导入Graphpad prism 8.0分析拟合得IC50值。代表性化合物FP测试结果见表1及表2。
表1本发明中部分化合物的FIH抑制活性
由表1可见,本发明的化合物具有较强的FIH抑制活性,26个化合物的IC50小于100nM,7个化合物IC50小于10nM。,其中:A表示IC50值在1nM至10nM的范围;B表示IC50值在10nM至100nM的范围;C表示IC50值在100nM至1000nM的范围;D表示IC50值大于1μM。
对部分化合物的酯类前药进行细胞水平降脂活性评价:前脂肪细胞3T3-L1是一类同时具有增殖和分化为成熟脂肪细胞能力的前体细胞,此种前体细胞在不同的生长因子、激素等物质的作用下,经历有丝分裂克隆期、生长停滞期、进一步的克隆期、终末分化四个阶段,细胞本身的成纤维状态发生改变,通过胞质内甘油三脂聚集形成成熟脂肪细胞。对于诱导分化成熟的脂肪细胞给予FIH抑制剂酯类前药,作用两天后,测定细胞内甘油三酯水平,结果见表2。
表2本发明中部分化合物的酯类前药FIH抑制活性及细胞水平降脂活性
由表2可见,本发明部分化合物的酯类前药能够保持较好的FIH抑制活性,同时具有明显的细胞水平降脂活性。
对表2部分酯类前药进行了动物水平的脂肪肝改善试验(剂量:10mg/kg、模型:小鼠C57BL/6J雄性7-8周),方法参照(J.Med.Chem.2021,64(2),1037-1053)。由图1可见,本发明的化合物在动物水平均可以明显降低脂肪肝小鼠体重,改善肥胖,同时降低血清及肝脏甘油三酯,改善高血脂及脂肪肝,其中以I-47和I-48效果最优。
Claims (10)
1.一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐,其特征在于,
其中R1为氢;
R2选自羧基、羟基、氨基甲酰基、氰基、五元芳杂基;
L1为位于Ar和苯环间位之间长度为0-3个原子长度的连接链;
Ar为5-10个环成员的单环或双环芳基或芳杂基;
R3为位于Ar上的一个或相同或不同的多个取代基,其中取代基任选自氢、C1-C4烷基、C1-C4烷氧基、C1-C4环烷氧基、C1-C4烷氨基、C1-C4酰基、C1-C4酰氨基、氨基甲酰基、C1-C4烷氨甲酰基、C1-C4磺酰基、C1-C4磺酰氨基、氨基磺酰基、C1-C4烷氨磺酰基、卤素、氰基、羟基、氨基。
4.根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐,其特征在于,所述前药为R1与R2任意一侧或两侧形成的酯类前药。
6.一种制备根据权利要求1-3任一所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐的方法,其特征在于,所述方法为以下任一方法之一:
方法一:
由原料II在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体III;中间体III在催化剂的条件下发生偶联反应得到目标化合物或中间体IV;最后,中间体IV经氢氧化锂水解得到目标化合物;
方法二:
由原料II在三乙胺的碱性条件下与草酰氯苄酯发生缩合反应得到中间体V;中间体V在催化剂催化下发生偶联反应得到中间体VI;最后,中间体VI经氢气和钯碳还原得到目标化合物;
方法三:
由原料II经氢化铝锂还原得到中间体VII;中间体VII在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体VIII;中间体VIII在催化剂条件下发生偶联反应得到中间体IX;最后中间体IX经氢氧化锂水解得到目标化合物;
方法四:
由原料X与氨气缩合得到中间体XI;中间体XI在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体XII;中间体XIII在催化剂的条件下发生偶联反应得到中间体XIII;最后,中间体XIII经氢氧化锂水解得到目标化合物;
方法五:
中间体XI在三氟乙酸酐催化下脱水得到中间体XIX;中间体XIX在三乙胺的碱性条件下与草酰氯甲酯发生缩合反应得到中间体XX;中间体XX在催化剂的条件下发生偶联反应得到中间体XXI;最后,中间体XXI经氢氧化锂水解得到目标化合物I或中间体XXII;中间体XXII与四丁基氟化铵环加成反应得到目标化合物I。
7.一种药物组合物,其特征在于,其含有根据权利要求1-3任一所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐,以及药学上可接受的载体。
8.一种根据权利要求1-3任一所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐或者根据权利要求7所述的药物组合物在制备FIH抑制剂中的应用。
9.一种根据权利要求1-3任一所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐或者根据权利要求7所述的药物组合物在制备治疗与FIH活性相关的疾病的药物中的应用。
10.根据权利要求9所述的用途,其特征在于,所述药物用于治疗脂肪代谢性疾病。
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