CN112028773B - 一类ppar蛋白激活剂的双酯类化合物 - Google Patents
一类ppar蛋白激活剂的双酯类化合物 Download PDFInfo
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- CN112028773B CN112028773B CN201910480301.1A CN201910480301A CN112028773B CN 112028773 B CN112028773 B CN 112028773B CN 201910480301 A CN201910480301 A CN 201910480301A CN 112028773 B CN112028773 B CN 112028773B
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Classifications
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- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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Abstract
本发明涉及一类PPAR蛋白激活剂的双酯类化合物。该化合物为式(I)化合物及其药学上可接受的盐、前药和溶剂合物,及包含所述化合物的药物组合物,并涉及其合成方法。此外,本发明涉及包含所述化合物的药物组合物,可用于预防或治疗与PPPAR蛋白相关疾病的PPAR蛋白激活剂。
Description
技术领域
本发明涉及一类PPAR蛋白激活剂的双酯类化合物。该化合物为式I化合物及其药学上可接受的盐、前药和溶剂合物,及包含所述化合物的药物组合物,并涉及其合成方法。此外,本发明涉及包含所述化合物的药物组合物,可用于预防或治疗与PPAR蛋白相关疾病的PPAR蛋白激活剂。
背景技术
PPAR是一种甾体激素受体,是能被脂肪酸样化合物过氧化物酶体增殖剂和脂肪酸激活的核转录因子,属于配体激活的核受体超家族成员之一。根据其结构及功能可分为四种亚型:PPARα、PPARβ、PPARγ及PPARδ。
PPARα是核受体超家族成员之一,主要分布在代谢活性较高的组织,如肝、肾、心脏、肌肉组织,在血管内皮细胞、平滑肌细胞、单核巨噬细胞及淋巴细胞内也有表达,参与调节脂质分解酶的表达,此外,PPARα也发挥多效的抗炎和抗增殖效应,防止巨噬细胞中胆固醇堆积引起的促动脉粥样硬化等作用。PPARα激活时,会引起了全身性的脂质正常化反应,促进它们脂解作用,促进HDL代谢和RCT,促进胆固醇从周围组织向肝脏转运。PPARγ是一种细胞核受体,主要分布在肝脏、结肠、小肠、视网膜、胸腺、脾脏、胰腺、睾丸、骨骼肌、血管内皮细胞、单核细胞/巨噬细胞、T细胞和骨髓前体细胞和脑组织中的小胶质细胞、星形胶质细胞、神经元等中,但在脂肪组织中的分布最多。它有γl,和γ2两种不同的亚型,γ2的N末端比γ1多30个氨基酸。该基因有基因由4个功能区组成,分别为A/B、C、D和E/F,其中N末端A/B区域为非配体依赖性转录活化区,又称激活功能-1(AF-1),C区又称DNA结合区(BDB),E/F区是配体结合区(LBD),是功能上最重要的区域。PPARγ的生物效应广泛,主要包括脂肪细胞分化、糖、脂代谢、炎性反应、动脉粥样硬化、癌细胞的分化形成等。目前认为PPARγ对动脉粥样硬化的抑制作用主要表现为抑制炎症反应和调节细胞增生和迁移。PPARγ配体或激动剂可减少炎症因子IL-1β、IL-6、肿瘤坏死因子-α(TNF-α)、诱导型一氧化氮合酶(iNOS)、基质金属蛋白酶-9(MMP-9)的表达,抑制单核细胞/巨噬细胞转录因子AP-1、NF-κB和转录活化因子(Stat)的活性,从而抑制动脉粥样硬化。除此之外,PPARγ还可通过正向调节脂肪细胞的分化,调控脂代谢相关基因的表达和糖代谢过程中某些关键酶基因的表达以达到调控脂肪和糖代谢、能量平衡、抗动脉粥样硬化、降血脂和降血压等作用。
因此,PPAR受体激活后具有促进脂肪细胞分化、调节体内糖和脂类平衡、抑制炎症因子生成及炎症形成、抑制肿瘤细胞生长、参与心血管保护等作用。
不饱和的氧化脂肪酸及其衍生物和硝基脂肪酸是PPAR的天然激动剂,他们在结构上有一个共同点,即含有羧基极性头和一个疏水性的尾巴,此外,双键、三键和环等刚性结构也是必要的。在天然激动剂结构的指导下,设计合成出PPARγ合成配体噻唑烷二酮类,如罗格列酮、吡格列酮都可以有效减少动脉粥样硬化。除此之外,还有贝特类药物及其类似物,因为这类化合物均有一个苯氧芳酸基团,所以又称为取代苯氧芳酸类衍生物。现已证实这类药物可以同时激活PPARα和PPARγ来实现降低血脂的治疗作用。
目前PPAR激活剂还处于研究阶段,急需要开发更好药效和安全性的新化合物。本专利在已合成和发现的激活剂的基础上,发明了一类具有良好的生物活性和安全性的PPAR激活剂。
发明内容
本发明的目的在于:合成一类PPAR蛋白激活剂的双酯类化合物。
本发明的另一目的是提供一种本发明所述一类PPAR蛋白激活剂新化合物的合成方法。
本发明的另一目的是一类PPAR蛋白激活剂新化合物在治疗降血脂作用中的应用。
本发明的一类PPAR蛋白激活剂双酯类新化合物结构为:一种式(Ⅰ)的新化合物:
包括其药学上可接受的盐、前药和溶剂合物,其中:
A选自A1,A2
E选自H,Cl、Br和甲氧基。
B选自H,Cl、Br、氨基、吡咯基、哌啶基、吡嗪基、咪唑基、羟基乙基、磷酰基、苯基烯丙基。
M选自(CH2)n(n=1,2,3,4,5,6)烷基以及有支链的仲、叔类烷烃基;M选自(CH=CH)n(n=1,2,3,4,5,6)烯基及有支链的烯烃基;
M选自(C≡C)n(n=1,2,3,4,5,6)有支链的炔基;
M选自C6H6等不饱和芳香环及有饱和烃基支链的芳香环,C4-C6的环烷烃基及有饱和烷烃基支链的环烷烃。
N,Z选自H,OR1,COR2,SR3,C1-C3饱和烷烃基,C4-C6的环烷烃基。
R1选在H,COR2,C1-C6的饱和烷基及烯烃基、炔烃基,C4-C6环烷烃基及含氧官能团的多原子环烷烃基。
R2选自N,Cl,OCOR4,C1-C6的饱和烷基及烯烃基、炔烃基,C4-C6环烷烃基及含氧官能团的多原子环烷烃基,含N的链烃基或含氮杂环。
R3选自H,R1。
R4选自C1-C6的烷烃基及有支链的饱和烷烃基。
式(Ι)的化合物选自:
(1)3-{4-[2-(4-氯苯氧基)-2-甲基丙氧基]-3-甲氧基苯基-丙烯酸2-(联苯氧基)-乙基酯
(2)3-{3-甲氧基-4-[2-(4-甲氧基-苯氧基)-2-甲基-丙酰氧基]-苯基}-丙烯酸4-(联苯-4-基氧基)-苯基酯
(3)3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸4-(联苯-4-基氧基)-环己基酯
(4)3-{4-[2-(4-溴-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸1-(联苯-4-基氧基)-1-甲基-乙酯
(5)3-{3-甲氧基-4-[2-(4-甲氧基-苯氧基)-2-甲基-丙酰氧基]-苯基}-丙烯酸4-(联苯-4-基氧基)-丁-2-烯基酯
(6)3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸4-(联苯-4-基氧基)-丁-2-炔基酯
(7)3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基-丙烯酸2-(4'-甲基-联苯-4-羟基)-乙基酯
(8)3--[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸2-(4'-环己基-联苯-4-基氧基)-乙酯
(9)5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[4-(联苯-4-基氧基)-丁-2-烯氧基羰基]-乙烯基}-2-甲氧基-苯酯
(10)3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸4-(联苯-4-基氧基)-苯基酯
(11)4'-[2-(3-{4-[4-(4-氯苯氧基)-2-甲基丙酰氧基]-3-甲氧基-苯基-丙烯酰氧基)-乙氧基]-联苯-4-羧酸甲酯
(12)3-{4-[2-(4-溴-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸4-(4'-乙酰氧基-联苯-4-基氧基)-环己基酯
(13)4'-(2-{3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酰氧基}-乙氧基)-联苯-4-四氢吡喃-4-羧酸酯
(14)4'-[4-(3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酰氧基)-环己氧基]-联苯-4-羧酸甲酯
(15)4'-[2-(3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酰氧基)-乙氧基]-联苯-4-羧酸烯丙基酯
(16)3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸4-[4'-(四氢-呋喃-3-羰基硫基)-联苯-4-基氧基]-环己基酯
(17)5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[3-(联苯-4-基氧基)-2,2-二甲基-丙氧基羰基]-乙烯基}-2-甲氧基-苯基酯
(18)3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸2-(4'-环己氧基-联苯-4-基氧基)-乙酯
(19)3-{4-[2-(4-溴-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸4-(4'-乙酰氧基-3'-丙基-联苯-4-基氧基))-苯酯
(20)4'-[2-(3-{4-[4-(4-氯苯氧基)-2-甲基丙酰氧基]-3-甲氧基-苯基-丙烯酰氧基)-乙氧基]-联苯-3-羧酸甲酯
(21)3-羟基-4'-[2-(3-{3-甲氧基-4-[2-(4-甲氧基-苯氧基)-2-甲基-丙酰氧基]-苯基}丙烯酰氧基)-乙氧基]-联苯-4--羧酸甲酯
(22)3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸2-(3'-甲氧基-4'-丙基-联苯-4-基氧基)-乙酯
(23)4'-[2-(3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酰氧基)-乙氧基]-联苯-4-羧酸烯丙基酯
(24)5-[4-(二甲氧基-磷酰基)-2,5-二甲基-苯氧基]-2,2-二甲基-戊酸2-甲氧基-4-{2-[2-(4'-甲氧基-联苯-4-)(氧代)-乙氧基羰基]-乙烯基}-苯基酯
(25)4'-[2-(3-{4-[5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酰]-3-甲氧基-苯基}丙烯酰氧基)-乙氧基]-联苯-4-羧酸甲酯
(26)5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[2-(4'-羟基-联苯-4-基氧基)-乙氧基羰基]-乙烯基}-2-甲氧基-苯酯
(27)5-(4-氯-2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[4-(联苯-4-基氧基)-环己氧基羰基]-乙烯基}-2-甲氧基-苯酯
(28)5-(4-溴-2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[4-(4'-乙氧基-联苯-4-基氧基)-苯氧基羰基]-乙烯基}2-甲氧基-苯基酯
(29)5-(4-氨基-2,5-二甲基-苯氧基)-2,2-二甲基-戊酸2-甲氧基-4-{2-[4-(4'-丙基-联苯-4-基氧基)-苯氧基羰基]-乙烯基}-苯基酯
(30)5-(2,5-二甲基-4-吡咯-1-基-苯氧基)-2,2-二甲基-戊酸4-{2-[4-(4'-乙酰基硫基-联苯-4-基氧基)-环己氧基羰基]-乙烯基}-2-甲氧基-苯基酯
具体实施方式
实施案例1.
化合物名称:3-{4-[2-(4-氯苯氧基)-2-甲基丙氧基]-3-甲氧基苯基-丙烯酸2-(联苯氧基)-乙基酯
化合物结构:
合成路线:
合成方法:
在三口圆底烧瓶中投入适量的对氯苯酚、丙酮,搅拌,再分次投入适量的固体NaOH,充分搅拌,形成混悬液,水浴加热回流至42℃,再缓慢滴加适量的氯仿,滴加氯仿时反应温度始终控制在42~48℃之间,加毕,升温至50~59℃,保持搅拌回流1.5h,保温完毕,停搅拌,蒸馏出剩余的丙酮,反应物呈稠糊状时,加入适量热水,加热至70℃使反应物全部溶解,第二次蒸馏丙酮,蒸馏丙酮完毕后,用15%HCl中和至PH=2,冷却至结晶产生,抽滤,析晶先用水洗涤,后用石油醚洗涤,再用水洗,再用甲苯洗涤,最后再用水洗涤,得对氯苯氧异丁酸的粗品。
取上述干燥的粗品置于杯中,加入蒸馏水,水浴加热至60~65℃,用10%NaOH液调pH为8,加入适量活性炭,趁热抽滤,滤液冷却后,用18%C.P盐酸调节pH=2,析出沉淀,抽滤,水洗沉淀,干燥,得到精制的对氯苯氧异丁酸香草醛酯。
取一干净的三口圆底烧瓶,加入定量的氯化亚砜和定量的DMF,搅拌,然后再缓慢滴加一定量的对氯苯氧异丁酸香草醛酯,保证在一定时间段内滴加完毕,加热到45℃,搅拌加热回流反应2h,用TLC检测反应,待反应彻底结束后,减压蒸馏出反应剩余的氯化亚砜和DMF,收集馏分,得到一定量的化合物a。
取一干净的三口圆底烧瓶,在烧瓶中加入一定量乙二醇,在冰浴条件下滴加一定量的化合物a与吡啶混合液,保证在一定时间段内滴加完毕,待加毕后,撤去冰浴,室温下搅拌反应,用TLC检测反应,待反应结束后,将反应体系倒入冰水中,抽滤分离出有机相,并用碳酸氢钠水溶液洗涤,后用水溶液洗涤,然后用无水磷酸钙干燥,过滤,浓缩,得到化合物b。
在三口圆底烧瓶中加入一定量的除水的苯,加入一定量的化合物b及定量的碳酸钾,边搅拌边缓慢加入定量的氯化亚砜,待加毕,将反应体系的温度升高,加热回流到无酸气逸出,用TLC检测反应,反应结束后,减压蒸馏出未反应的苯和氯化亚砜,收集馏分,得到化合物c。
在三口圆底烧瓶中加入对苯基苯酚,乙腈以及定量的碳酸钾,搅拌混匀,往反应体系中滴加化合物c与乙腈的混合溶液,搅拌加热回流,用TLC检测反应,结束后,蒸馏出未反应的溶剂,剩余的馏分用水洗至中性,得到粗品,用乙醇重结晶得到化合物3-{4-[2-(4-氯苯氧基)-2-甲基丙氧基]-3-甲氧基苯基-丙烯酸2-(联苯氧基)-乙基酯,产率50%-70%。
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.32(1H),δ7.22(1H),δ7.32(1H),δ7.48(1H),δ7.48(1H),δ7.37(1H),δ6.83(1H),δ6.83(1H),δ7.37(1H),δ4.22(2H),δ4.57(2H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ1.61(3H),δ1.61(3H),δ6.71(1H),δ7.16(1H),δ7.16(1H),δ6.71(1H),δ3.73(3H),δ6.39(1-0H),δ7.64(1-0H).
实施案例2.
化合物名称:3-{3-甲氧基-4-[2-(4-甲氧基-苯氧基)-2-甲基-丙酰氧基]-苯基}-丙烯酸4-(联苯-4-基氧基)-苯基酯
化合物结构:
合成方法参照实施案例1
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ6.66(1H),δ6.66(1H),δ6.66(1H),δ6.66(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ7.03(1H),δ6.89(1H),δ6.89(1H),δ7.03(1H),δ6.98(1H),δ7.44(1H),δ7.44(1H),δ6.98(1H),δ7.48(1H),δ7.32(1H)δ7.22(1H),δ7.32(1H),δ7.48(1H),δ3.73(3H),δ7.64(1-0H),δ6.39(1-0H)
实施案例3.
化合物名称:3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸4-(联苯-4-基氧基)-环己基酯
化合物结构:
合成路线参照实施案例1
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.15(1H),δ6.82(1H),δ7.15(1H),δ6.77(1H),δ6.77(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ3.91(1H),δ1.68(2H),δ1.82(2H),δ3.64(1H),δ1.82(2H),δ1.68(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.48(1H),δ7.32(1H),δ7.22(1H),δ7.32(1H),δ7.48(1H),δ7.64(1-0H),δ6.39(1-0H)
实施案例4.
化合物名称:3-{4-[2-(4-溴-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸1-(联苯-4-基氧基)-1-甲基-乙酯
化合物结构:
合成路线参照实施案例1
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.32(1H),δ7.32(1H),δ6.66(1H),δ6.66(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ1.82(3H),δ1.82(3H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.48(1H),δ7.32(1H),δ7.22(1H),δ7.32(1H),δ7.48(1H),δ7.64(1-0H),δ6.39(1-0H)
实施案例5.
化合物名称:3-{3-甲氧基-4-[2-(4-甲氧基-苯氧基)-2-甲基-丙酰氧基]-苯基}-丙烯酸4-(联苯-4-基氧基)-丁-2-烯基酯
化合物结构:
合成路线参考实施案例1.
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ6.66(1H),δ6.66(1H),δ6.66(1H),δ6.66(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.82(2H),δ4.61(2H),δ6.87(1H),δ7.35(1H),δ7.35(1H),δ6.87(1H),δ7.48(1H),δ7.32(1H),δ7.22(1H),δ7.32(1H),δ7.48(1H),δ3.73(3H),δ7.64(1-0H),δ6.39(1-0H),δ5.87(1-0H),δ5.87(1-0H)
实施案例6.
化合物名称:3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸4-(联苯-4-基氧基)-丁-2-炔基酯
化合物结构:
合成路线参考实施案例1
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.16(1H),δ7.16(1H),δ6.71(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.84(2H),δ4.63(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.48(1H),δ7.32(1H),δ7.22(1H),δ7.32(1H),δ7.48(1H),δ7.09(1-0H),δ5.96(1-0H)
实施案例7.
化合物名称:3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基-丙烯酸2-(4'-甲基-联苯-4-羟基)-乙基酯
化合物结构:
用4-(4-甲基苯基)苯酚和化合物c做为反应物,参考实施案例1的合成方法得到3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基-丙烯酸2-(4'-甲基-联苯-4-羟基)-乙基酯。
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.16(1H),δ7.16(1H),δ6.71(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.36(1H),δ7.12(1H),δ7.12(1H),δ7.36(1H),δ2.35(3H),δ7.64(1-0H),δ6.39(1-0H).
实施案例8.
化合物名称:3--[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸2-(4'-环己基-联苯-4-基氧基)-乙酯
化合物结构:
合成路线参照实施案例1
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.15(1H),δ6.82(1H),δ7.15(1H),δ6.77(1H),δ6.77(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.40(1H),δ7.19(1H),δ7.19(1H),δ7.40(1H),δ4.22(2H),δ2.72(1H),δ1.73(2H),δ1.44(2H),δ1.44(2H),δ1.44(2H),δ1.73(2H),δ7.64(1-0H),δ6.39(1-0H).
实施案例9.
化合物名称:5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[4-(联苯-4-基氧基)-丁-2-烯氧基羰基]-乙烯基}-2-甲氧基-苯酯
化合物结构:
合成路线参考实施案例1
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.16(1H),δ7.16(1H),δ6.71(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.40(1H),δ7.19(1H),δ7.19(1H),δ7.40(1H),δ3.12(1H),δ4.22(2H),δ1.29(3H),δ1.29(3H),δ7.64(1-0H),δ6.39(1-0H).
实施案例10.
化合物名称:3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸4-(联苯-4-基氧基)-苯基酯
化合物结构:
合成路线参照实施案例1
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.16(1H),δ7.16(1H),δ6.71(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ6.78(1H),δ6.62(1H),δ6.87(1H),δ5.0(OH),δ3.91(1H),δ1.68(2H),δ1.82(2H),δ3.64(1H),δ1.82(2H),δ1.68(2H),δ5.0(OH),δ7.64(1-0H),δ6.39(1-0H)
实施案例11.
化合物名称:4'-[2-(3-{4-[4-(4-氯苯氧基)-2-甲基丙酰氧基]-3-甲氧基-苯基-丙烯酰氧基)-乙氧基]-联苯-4-羧酸甲酯
化合物结构:
合成路线:
取一三口圆底烧瓶,加入适量的甲醇,再加入4'-羟基-联苯-4-羧酸,搅拌混悬液,再加入浓硫酸(98%wt)和甲苯,加热回流,用TLC检测反应,待反应结束后,将温度冷却到室温,用水洗涤之后,再用乙酸乙酯洗涤,去除乙酸乙酯相,加入硫酸镁干燥,过滤,浓缩,获得粗品,再通过柱层析分离得到纯净的化合物e。
用化合物e和化合物c做为反应物,合成方法参考合成案例1,加入适量的碳酸钠和DMF,逐渐升高温度到80℃,搅拌回流,待反应过夜后,用TLC检测反应,既得到化合物4'-[2-(3-{4-[4-(4-氯苯氧基)-2-甲基丙酰氧基]-3-甲氧基-苯基-丙烯酰氧基)-乙氧基]-联苯-4-羧酸甲酯。
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.16(1H),δ7.16(1H),δ6.71(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.59(1H),δ8.03(1H),,δ8.03(1H),δ7.59(1H),δ3.88(3H),δ7.64(1-0H),δ6.39(1-0H).
实施案例12.
化合物名称:3-{4-[2-(4-溴-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸4-(4'-乙酰氧基-联苯-4-基氧基)-环己基酯
化合物结构:
合成路线参考实施案例11
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ6.66(1H),δ6.66(1H),δ6.66(1H),δ6.66(1H),δ1.61(3H),δ1.61(3H),δ6.91(1H),δ6.83(1H),δ6.78(1H),δ3.73(3H),δ7.03(1H),δ6.89(1H),δ6.89(1H),δ7.03(1H),δ6.98(1H),δ7.44(1H),δ7.44(1H),δ6.98(1H),δ7.45(1H),δ7.13(1H),δ7.13(1H),δ7.45(1H),δ2.27(1H),δ1.44(2H),δ1.44(2H),δ1.44(2H),δ1.67(2H),δ3.73(3H),δ7.09(1-0H),δ5.96(1-0H)
实施案例13.
化合物名称:4'-(2-{3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酰氧基}-乙氧基)-联苯-4-四氢吡喃-4-羧酸酯
化合物结构:
合成路线参照实施案例11
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.15(1H),δ6.82(1H),δ7.15(1H),δ6.77(1H),δ6.77(1H),δ1.61(3H),δ1.61(3H),δ6.91(1H),δ6.83(1H),δ6.78(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.45(1H),δ7.13(1H),δ7.13(1H),δ7.45(1H),δ2.43(1H),δ1.83(2H),δ3.60(2H),δ3.60(2H),δ1.83(2H),δ7.09(1-0H),δ5.96(1-0H)
实施案例14.
化合物名称:4'-[4-(3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酰氧基)-环己氧基]-联苯-4-羧酸甲酯
化合物结构:
合成路线参照实施案例11
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.16(1H),δ7.16(1H),δ6.71(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.91(1H),δ6.83(1H),δ6.78(1H),δ3.73(3H),δ3.91(1H),δ1.68(2H),δ1.82(2H),δ3.64(1H),δ1.82(2H),δ1.68(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.59(1H),δ8.03(1H),δ8.03(1H),δ7.59(1H),δ3.88(3H),δ7.09(1-0H),δ5.96(1-0H)
实施案例15.
化合物名称:4'-[2-(3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酰氧基)-乙氧基]-联苯-4-羧酸烯丙基酯
化合物结构:
合成路线参照实施案例11
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.16(1H),δ7.16(1H),δ6.71(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.91(1H),δ6.83(1H),δ6.78(1H),,δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.59(1H),δ8.03(1H),δ8.03(1H),δ7.59(1H),δ4.92(2H),δ7.09(1-0H),δ5.96(1-0H)δ5.89(1-0H),δ5.24(1-0H),δ5.23(1-0H)
实施案例16.
化合物名称:3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸4-[4'-(四氢-呋喃-3-羰基硫基)-联苯-4-基氧基]-环己基酯
化合物结构:
合成路线参照实施案例11
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.15(1H),δ6.82(1H),δ7.15(1H),δ6.77(1H),δ6.77(1H)δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ3.91(1H),δ3.94(3H),δ1.68(2H),δ1.82(2H),δ3.64(1H),δ1.82(2H),δ1.68(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.32(1H),δ7.24(1H),δ7.24(1H),δ7.32(1H),δ2.71(1H),δ2.14(2H),δ3.75(2H),δ4.04(2H),δ7.64(1-0H),δ6.39(1-0H)
实施案例17.
化合物名称:3-{4-[2-(4-溴-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸2-(4'-氯羰基-联苯-4-基氧基)-乙酯
化合物结构:
合成路线参照实施案例11
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.32(1H),δ7.32(1H),δ6.66(1H),δ6.66(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.69(1H),δ8.13(1H),δ8.13(1H),δ7.69(1H),δ7.09(1-0H),δ5.96(1-0H).
实施案例18.
化合物名称:3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸2-(4'-环己氧基-联苯-4-基氧基)-乙酯
化合物结构:
合成路线参照实施案例11
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.15(1H),δ6.82(1H),δ7.15(1H),δ6.77(1H),δ6.77(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.37(1H),δ6.83(1H),δ6.83(1H),δ7.37(1H),δ4.22(2H),δ3.64(1H),δ1.82(2H),δ1.44(2H),δ1.44(2H),δ1.82(2H),δ7.64(1-0H),δ6.39(1-0H).
实施案例19.
化合物名称:3-{4-[2-(4-溴-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酸4-(4'-乙酰氧基-3'-丙基-联苯-4-基氧基))-苯酯
化合物结构:
合成路线参照实施案例11
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.32(1H),δ7.32(1H),δ6.66(1H),δ6.66(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ6.98(1H),δ7.44(1H),δ7.44(1H),δ6.98(1H),δ7.31(1H),δ7.08(1H),δ7.27(1H),δ7.03(1H),δ6.89(1H),,δ6.89(1H),δ7.03(1H),δ2.55(2H),δ2.08(3H),δ1.66(2H),δ0.96(3H),δ7.64(1-0H),δ6.39(1-0H)
实施案例20.
化合物名称:4'-[2-(3-{4-[4-(4-氯苯氧基)-2-甲基丙酰氧基]-3-甲氧基-苯基-丙烯酰氧基)-乙氧基]-联苯-3-羧酸甲酯
化合物结构:
合成路线:
在三口圆底烧瓶中,加入适量的4'-羟基-联苯-3-甲腈的氢氧化钠溶液和乙醇,搅拌加热回流24h,用TLC检测反应,在反应结束后再搅拌反应数小时,待反应结束后,蒸馏出溶剂乙醇,冷却至室温,加入盐酸,调PH为1,待析出晶体后,抽滤,冷水洗涤,得到粗品,用联苯重结晶,得到较为纯净的化合物f
参照实施案例6,用化合物f和甲醇做为反应物,合成化合物g。
参照实施案例1,用化合物g和化合物c做为反应物,合成4'-[2-(3-{4-[4-(4-氯苯氧基)-2-甲基丙酰氧基]-3-甲氧基-苯基-丙烯酰氧基)-乙氧基]-联苯-3-羧酸甲酯。
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.16(1H),δ7.16(1H),δ6.71(1H),δ6.71(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.69(1H),δ7.43(1H),δ7.93(1H),δ8.19(1H),δ3.88(3H),δ7.09(1-0H),δ5.96(1-0H).
实施案例21.
化合物名称:3-羟基-4'-[2-(3-{3-甲氧基-4-[2-(4-甲氧基-苯氧基)-2-甲基-丙酰氧基]-苯基}丙烯酰氧基)-乙氧基]-联苯-4-羧酸甲酯
化合物结构:
合成路线参照实施案例20
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ6.66(1H),δ6.66(1H),δ6.66(1H),δ6.66(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.06(1H),δ7.86(1H),δ7.15(1H),δ5.0(OH),δ3.73(3H),δ3.88(3H),δ7.64(1-0H),δ6.39(1-0H)
实施案例22.
化合物名称:3-[3-甲氧基-4-(2-甲基-2-苯氧基-丙酰氧基)-苯基]-丙烯酸2-(3'-甲氧基-4'-丙基-联苯-4-基氧基)-乙酯
化合物结构:
合成路线参照实施案例20
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ7.15(1H),δ6.82(1H),δ7.15(1H),δ6.77(1H),δ6.77(1H),δ1.61(3H),δ1.61(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ6.94(1H),δ7.07(1H),δ6.99(1H),δ2.55(2H),δ1.66(2H),δ0.96(3H),δ3.73(3H),δ7.64(1-0H),δ6.39(1-0H)
实施案例23.
化合物名称:4'-[2-(3-{4-[2-(4-氯-苯氧基)-2-甲基-丙酰氧基]-3-甲氧基-苯基}-丙烯酰氧基)-乙氧基]-联苯-4-羧酸烯丙基酯
化合物结构:
合成路线:
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取三口圆底烧瓶,加入适量的5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酸,再加入适量的DCC,搅拌混匀成溶液,在冰浴条件下,边搅拌边缓慢滴加二氯甲烷,保证在10min中内滴加完毕,滴加完毕后,常温搅拌数小时后,在冰浴条件下,缓慢滴加香草醛的N,N’-二环己基碳酸亚胺溶液,保证在一段时间内滴加完毕,滴毕常温反应12h,用TLC检测反应,反应完毕后,将反应溶液倒入碎冰中,静置有沉淀析出,静置数小时后,抽滤,用4%的氢氧化钠溶液洗涤5次,再用水洗5次,得到化合物g的粗品。用乙醇重结晶得到精制的较为纯净的化合物g的粉末。
取适量的化合物g、丙二酸、苯胺及DCC溶液,置于三口圆底烧瓶中,在90℃的条件下,搅拌冷凝反应5h,用TLC检测反应,待反应结束后,将反应溶液倒入含有浓盐酸的碎冰中,搅拌后静置,有沉淀析出,抽滤,滤渣用0.14mmol/L的盐酸洗涤,再用蒸馏水洗涤至中性,干燥,得到化合物h的粗品,用乙醇重结晶,得到较为纯净的固体化合物h。
用化合物h和对苯基苯酚做为反应物,合成方法参考实施案例1,得到化合物5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[2-(联苯-4-基氧基)-乙氧基羰基]-乙烯基}-3-甲氧基-苯基酯。
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ1.48(2H),δ1.24(3H),δ1.24(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.48(1H),δ7.32(1H),δ7.22(1H),δ7.32(1H),δ7.48(1H),δ1.71(2H),δ3.94(2H),δ6.83(1H),δ6.50(1H),δ6.45(1H),δ2.35(3H),δ2.35(3H),δ7.64(1-0H),δ6.39(1-0H).
实施案例24.
化合物名称:5-[4-(二甲氧基-磷酰基)-2,5-二甲基-苯氧基]-2,2-二甲基-戊酸2-甲氧基-4-{2-[2-(4'-甲氧基-联苯-4-)(氧代)-乙氧基羰基]-乙烯基}-苯基酯
化合物结构:
合成路线参照实施案例23
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ1.48(2H),δ1.24(3H),δ1.24(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.37(1H),δ6.83(1H),δ6.83(1H),δ7.37(1H),δ1.71(2H),δ3.94(2H),δ7.29(1H),δ6.59(1H),δ2.35(3H),δ2.35(3H),δ3.73(3H),δ3.39(3H),δ3.39(3H),δ7.64(1-0H),δ6.39(1-0H).
实施案例25.
化合物名称:4'-[2-(3-{4-[5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酰]-3-甲氧基-苯基}丙烯酰氧基)-乙氧基]-联苯-4-羧酸甲酯
化合物结构:
合成路线参照实施案例23
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ1.48(2H),δ1.24(3H),δ1.24(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.59(1H),δ8.03(1H),δ8.03(1H),δ7.59(1H),δ1.71(2H),δ3.94(2H),δ6.83(1H),δ6.50(1H),δ6.45(1H),δ2.35(3H),δ2.35(3H),δ3.88(3H),δ7.64(1-0H),δ6.39(1-0H).
实施案例26.
化合物名称:5-(2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[2-(4'-羟基-联苯-4-基氧基)-乙氧基羰基]-乙烯基}-2-甲氧基-苯酯
化合物结构:
合成路线参照实施案例23
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ1.48(2H),δ1.24(3H),δ1.24(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ4.57(2H),δ4.22(2H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.31(1H),δ6.79(1H),δ6.79(1H),δ7.31(1H),δ5.0(OH),δ1.71(2H),δ3.94(2H),δ6.83(1H),δ6.50(1H),δ6.45(1H),δ2.35(3H),δ2.35(3H),δ7.64(1-0H),δ6.39(1-0H)
实施案例27.
化合物名称:5-(4-氯-2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[4-(联苯-4-基氧基)-环己氧基羰基]-乙烯基}-2-甲氧基-苯酯
化合物结构:
合成路线参照实施案例23
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ1.48(2H),δ1.24(3H),δ1.24(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ3.91(1H),δ3.64(1H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ3.73(3H),δ6.83(1H),,δ7.48(1H),,δ7.32(1H),,δ7.22(1H),δ7.32(1H),δ7.48(1H),δ1.71(2H),δ3.94(2H),δ6.84(1H),δ6.39(1H),δ2.35(3H),δ2.35(3H),δ1.68(2H),δ1.82(2H),δ1.82(2H),δ1.68(2H),δ7.64(1-0H),δ6.39(1-0H)
实施案例28.
化合物名称:5-(4-溴-2,5-二甲基-苯氧基)-2,2-二甲基-戊酸4-{2-[4-(4'-乙氧基-联苯-4-基氧基)-苯氧基羰基]-乙烯基}2-甲氧基-苯基酯
化合物结构:
合成路线参照实施案例23
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ1.48(2H),δ1.24(3H),δ1.24(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ6.98(1H),δ7.44(1H),δ7.44(1H),δ6.98(1H),δ7.37(1H),,δ6.83(1H),,δ6.83(1H),δ7.37(1H),δ1.71(2H),δ3.94(2H),δ7.00(1H),,δ6.34(1H),δ2.35(3H),δ2.35(3H),δ7.03(1H),δ6.89(1H),δ6.89(1H),δ7.03(1H),δ3.98(2H),δ1.33(3H),δ7.64(1-0H),δ6.39(1-0H)
实施案例29.
化合物名称:5-(4-氨基-2,5-二甲基-苯氧基)-2,2-二甲基-戊酸2-甲氧基-4-{2-[4-(4'-丙基-联苯-4-基氧基)-苯氧基羰基]-乙烯基}-苯基酯
化合物结构:
合成路线参照实施案例23
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ1.48(2H),δ1.24(3H),δ1.24(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H)δ3.73(3H),δ6.98(1H),δ7.44(1H),δ7.44(1H),δ6.98(1H),δ7.43(1H),δ7.18(1H),δ7.18(1H),δ7.43(1H),δ1.71(2H),δ3.94(2H),δ6.03(1H),δ6.20(1H),δ2.35(3H),δ2.35(3H),δ4.0(NH),δ7.03(1H),δ6.89(1H),δ6.89(1H),δ7.03(1H),δ2.55(2H),δ1.66(2H),δ0.96(3H),δ7.64(1-0H),δ6.39(1-0H)
实施案例30.
化合物名称:5-(2,5-二甲基-4-吡咯-1-基-苯氧基)-2,2-二甲基-戊酸4-{2-[4-(4'-乙酰基硫基-联苯-4-基氧基)-环己氧基羰基]-乙烯基}-2-甲氧基-苯基酯
化合物结构:
合成路线参照实施案例23
1H-NMR(400MHZ,CDCl3,TMS,ppm):
δ1.48(2H),δ1.24(3H),,δ1.24(3H),δ6.78(1H),δ6.83(1H),δ6.91(1H),δ3.73(3H),δ3.91(1H),,δ3.64(1H),δ6.83(1H),δ7.37(1H),δ7.37(1H),δ6.83(1H),δ7.32(1H),δ7.24(1H),δ7.24(1H),δ7.32(1H),δ1.71(2H),δ3.94(2H),δ6.8(1H),δ6.4(1H),δ2.35(3H),δ2.35(3H),δ1.68(2H),δ1.82(2H),δ1.82(2H),δ1.68(2H),δ6.95(1H),δ6.19(1H),δ6.19(1H),δ6.95(1H),δ2.40(3H),δ7.64(1-0H),δ6.39(1-0H)
实施例31:对PPAR蛋白的激活作用
研究化合物对纯化的重组PPAR活性的影响,是从酶学水平研究化合物对PPAR的激活活性。其实验原理为采用一种发光法酶检测方法,用于检测PPAR与底物Poly(4:1Glu,Tyr)肽反应产生的ADP含量:ADP转化为ATP后,ATP即可作为Ultra-Glo萤光素酶催化反应的底物,产生光信号。发光信号与ADP的量和酶活性正相关。因此,通过观察化合物对PPAR与底物反应产生的发光信号来确定其对重组的PPAR的激活效果。
实验方法:
基本过程如下:选用取最低浓度0.0001递增为8um的10个浓度单位的化合物与PPAR在37度孵育1小时,然后加入底物及ATP混合,37度反应1小时后加入一定量的ADP-Glo混合2分钟,室温反应1小时。再加入检测试剂,室温孵育1小时,用化学发光仪检测。观察化合物对PPAR的激活作用,用IC50表示。结果见表1。
表1 PPAR的激活作用实验结果
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实施例32:小鼠急性毒性试验
取化合物,观察小鼠单次口服灌胃给药急性毒性,计算LD50。结果见表2。
表2小鼠单次口服灌胃给药急性毒性实验结果
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Claims (1)
1.以下化合物:(1)
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101304983A (zh) * | 2005-11-07 | 2008-11-12 | Irm责任有限公司 | 作为ppar调节剂的化合物和组合物 |
CN101304984A (zh) * | 2005-11-07 | 2008-11-12 | Irm责任有限公司 | 唑和噻唑ppar调节剂 |
CN101830863A (zh) * | 2005-05-07 | 2010-09-15 | 财团法人首尔大学校产学协力财团 | 制备PPARδ的配体的方法和用于制备该配体的中间化合物 |
CN102887968A (zh) * | 2012-10-19 | 2013-01-23 | 河北工业大学 | 合成宽/双峰聚乙烯的非茂双金属催化体系及其应用 |
CN106977477A (zh) * | 2016-01-15 | 2017-07-25 | 许军 | 一类stat3蛋白抑制剂的新化合物 |
CN107108458A (zh) * | 2014-12-25 | 2017-08-29 | Dic株式会社 | 聚合性化合物和光学各向异性体 |
CN107151232A (zh) * | 2016-03-04 | 2017-09-12 | 许军 | 一类stat3蛋白抑制剂的三元环类化合物 |
CN109369583A (zh) * | 2018-12-07 | 2019-02-22 | 广东药科大学 | 一类PPARγ/δ双重激动剂、其制备方法及其作为药物的用途 |
-
2019
- 2019-06-04 CN CN201910480301.1A patent/CN112028773B/zh active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101830863A (zh) * | 2005-05-07 | 2010-09-15 | 财团法人首尔大学校产学协力财团 | 制备PPARδ的配体的方法和用于制备该配体的中间化合物 |
CN101304983A (zh) * | 2005-11-07 | 2008-11-12 | Irm责任有限公司 | 作为ppar调节剂的化合物和组合物 |
CN101304984A (zh) * | 2005-11-07 | 2008-11-12 | Irm责任有限公司 | 唑和噻唑ppar调节剂 |
CN102887968A (zh) * | 2012-10-19 | 2013-01-23 | 河北工业大学 | 合成宽/双峰聚乙烯的非茂双金属催化体系及其应用 |
CN107108458A (zh) * | 2014-12-25 | 2017-08-29 | Dic株式会社 | 聚合性化合物和光学各向异性体 |
CN106977477A (zh) * | 2016-01-15 | 2017-07-25 | 许军 | 一类stat3蛋白抑制剂的新化合物 |
CN107151232A (zh) * | 2016-03-04 | 2017-09-12 | 许军 | 一类stat3蛋白抑制剂的三元环类化合物 |
CN109369583A (zh) * | 2018-12-07 | 2019-02-22 | 广东药科大学 | 一类PPARγ/δ双重激动剂、其制备方法及其作为药物的用途 |
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