[go: up one dir, main page]

WO2018103766A1 - 一种化合物、其制备方法及用途 - Google Patents

一种化合物、其制备方法及用途 Download PDF

Info

Publication number
WO2018103766A1
WO2018103766A1 PCT/CN2018/074689 CN2018074689W WO2018103766A1 WO 2018103766 A1 WO2018103766 A1 WO 2018103766A1 CN 2018074689 W CN2018074689 W CN 2018074689W WO 2018103766 A1 WO2018103766 A1 WO 2018103766A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
oah2
compound according
cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/074689
Other languages
English (en)
French (fr)
Inventor
王一飞
袁晓
赵振岭
范建军
李金菊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong Carecode Biological Technology Co Ltd
Original Assignee
Guangdong Carecode Biological Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong Carecode Biological Technology Co Ltd filed Critical Guangdong Carecode Biological Technology Co Ltd
Publication of WO2018103766A1 publication Critical patent/WO2018103766A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • the present invention relates to an olean type derivative, and more particularly to an olean type amide compound, a preparation method thereof and use thereof.
  • Oleanolic acid is an important pentacyclic triterpenoid compound, which is widely found in nature. It is rich in oleanolic acid in plants such as Ligustrum lucidum and C. chinensis. Oleanolic acid has many important biological activities, such as liver protection, anti-inflammatory, anti-tumor, hypolipidemic, anti-ulcer, etc., but most of the activity is weak and has no practical value; in addition, the water solubility of oleanolic acid is very Poor, low bioavailability, which also greatly limits its clinical application; in addition, oleanolic acid is widely distributed in various plants in the form of saponins, and many of its saponins also have important pharmacological effects, such as Anti-tumor, blood sugar lowering, etc.
  • Oleanolic acid compounds have a unique three-dimensional structure and a chiral rigid skeleton. They tend to exhibit better biological activity after derivatization, and have strong potential development value in terms of fat solubility, recognition, and transmembrane ability. Modification of such compounds into novel drug molecules will increase the targeting ability and bioavailability of the drug.
  • the most important problem to be solved at present is to design and synthesize a series of new oleanolic acid derivatives, and to pass the cell activity test, in order to achieve high efficiency, low toxicity, bioavailability and better biological activity. effect.
  • R 1 is any one of hydrogen and a C 1 -C 12 alkyl group
  • R 1 is any one of hydrogen and a C 1 -C 8 alkyl group
  • R 1 is hydrogen
  • R 3 is selected from the group consisting of amino groups, C 1 -C 12 linear, cyclic and branched aliphatic amine groups, C Any one of 1 - C 12 substituted or unsubstituted aromatic amine group, C 5 -C 8 substituted or unsubstituted azaaryl group.
  • R 3 is selected from the group consisting of an amino group, a C 1 -C 12 linear, cyclic and branched aliphatic amine group.
  • R 3 is selected from the group consisting of an amino group, a C 1 -C 4 linear, cyclic and branched aliphatic amine group.
  • R 3 is selected from the group consisting of cyclopropylamino, isopropylamino, isobutylamino, N,N-dimethylamino, n-propylamino, n-butyl Any one of an amino group, an amino group, and a methylamino group.
  • the compound of formula I is the following compound:
  • the compound of formula I is the following compound:
  • the compound of formula I is any one of the following compounds:
  • the method comprises the steps of:
  • the molar ratio of the amine compound to CDDO is 3 to 5:1; the molar ratio of oxalyl chloride to CDDO is 5 to 6:1; and the molar ratio of the triethylamine to CDDO is 2 to 3:1.
  • the molar ratio of the amine compound to CDDO is 3:1; the molar ratio of oxalyl chloride to CDDO is 5:1; and the molar ratio of the triethylamine to CDDO is 2:1.
  • the method comprises the steps of:
  • the molar ratio of the amine compound to the compound of the formula III is from 3 to 5:1; and the molar ratio of the N,N'-carbonyldiimidazole to the compound of the formula III is from 1 to 2:1; The molar ratio of the triethylamine to the compound of the formula III is from 2 to 3:1.
  • the molar ratio of the amine compound to the compound of formula III is 3:1; the molar ratio of N,N'-carbonyldiimidazole to the compound of formula III is 1:1; The molar ratio of triethylamine to the compound of formula III is 2:1.
  • the present invention provides the use of a compound of the formula I in the preparation of an anticancer drug, an anti-inflammatory drug; preferably, the cancer is liver cancer, lung cancer, laryngeal cancer and esophageal cancer; preferably, the inflammation is inducible Inflammation caused by high expression of nitric oxide synthase.
  • the invention provides the use of a compound of formula I for the manufacture of a medicament for the treatment of hepatitis C.
  • olean amides of the present invention are tested for cytotoxicity against cancer cells (eg, liver cancer, lung cancer, laryngeal cancer, esophageal cancer, etc.). Among them, the effect is better than the common chemical drug cisplatin for cancer treatment.
  • the inhibitory effect of most of the olean amide compounds of the present invention on the induction of nitric oxide synthase (iNOS) is similar to that of the existing anti-inflammatory drug dexamethasone, but is better than CDDO-Me.
  • the inventors have also found that most of the olean type amide compounds of the present invention have similar toxicity to normal hepatocytes and kidney cells as ledipasvir, but are smaller than CDDO-Me.
  • the olean type amide compound of the present invention is expected to be a new generation of anticancer, anti-inflammatory and anti-hepatitis C drugs.
  • composition comprising a compound of the formula I or a pharmaceutically acceptable salt thereof.
  • the olean type amide compound of the present invention is a series of novel olean type derivatives, and the above compound skeleton has not been reported in the literature.
  • the olean type amide compound of the present invention has good activity in anticancer, anti-inflammatory and treatment of hepatitis C and is less toxic to normal hepatocytes and kidney cells, and is expected to be a candidate for a new generation of related diseases. .
  • Figure 1 is a mass spectrum of the olean type amide compound OAH1-1 according to the present invention.
  • Figure 3 is a nuclear magnetic resonance carbon spectrum of the olean type amide compound OAH1-1 according to the present invention.
  • Figure 4 is a mass spectrum of the olean type amide compound OAH1-2 according to the present invention.
  • Figure 5 is a nuclear magnetic resonance spectrum of the olean type amide compound OAH1-2 according to the present invention.
  • Figure 6 is a nuclear magnetic resonance carbon spectrum of the olean type amide compound OAH1-2 according to the present invention.
  • Figure 7 is a mass spectrum of the compound OAH2-2 of the present invention.
  • Figure 8 is a nuclear magnetic resonance spectrum of the compound OAH2-2 of the present invention.
  • Figure 9 is a nuclear magnetic resonance carbon spectrum of the compound OAH2-2 of the present invention.
  • Figure 10 is a mass spectrum of the olean type amide compound OAH2-5 according to the present invention.
  • Figure 11 is a nuclear magnetic resonance spectrum of the olean type amide compound OAH2-5 according to the present invention.
  • Figure 12 is a nuclear magnetic resonance carbon spectrum of the olean type amide compound OAH2-5 according to the present invention.
  • Figure 13 is a mass spectrum of the olean type amide compound OAH2-6 according to the present invention.
  • Figure 14 is a nuclear magnetic resonance spectrum of the olean type amide compound OAH2-6 according to the present invention.
  • Figure 15 is a nuclear magnetic resonance carbon spectrum of the olean type amide compound OAH2-6 according to the present invention.
  • Figure 16 is a mass spectrum of the olean type amide compound OAH2-7 according to the present invention.
  • Figure 17 is a nuclear magnetic resonance spectrum of the olean type amide compound OAH2-7 according to the present invention.
  • Figure 18 is a nuclear magnetic resonance carbon spectrum of the olean type amide compound OAH2-7 according to the present invention.
  • Figure 19 is a mass spectrum of the olean type amide compound OAH2-8 according to the present invention.
  • Figure 20 is a nuclear magnetic resonance spectrum of the olean type amide compound OAH2-8;
  • Figure 21 is a nuclear magnetic resonance carbon spectrum of the olean type amide compound OAH2-8 according to the present invention.
  • Figure 22 is a mass spectrum of the olean type amide compound OAH2-9 according to the present invention.
  • Figure 23 is a nuclear magnetic resonance spectrum of the olean type amide compound OAH2-9 according to the present invention.
  • Figure 24 is a nuclear magnetic resonance carbon spectrum of the olean type amide compound OAH2-9 according to the present invention.
  • Figure 25 is a mass spectrum of the olean type amide compound OAH2-10 according to the present invention.
  • Figure 26 is a nuclear magnetic resonance spectrum of the olean type amide compound OAH2-10 according to the present invention.
  • Figure 27 is a nuclear magnetic resonance carbon spectrum of the olean type amide compound OAH2-10 according to the present invention.
  • Figure 28 is a mass spectrum of the olean type amide compound OAH2-11 of the present invention.
  • Figure 29 is a mass spectrum of the olean type amide compound OAH2-12 according to the present invention.
  • Figure 30 is a schematic diagram showing the principle of testing according to Embodiment 15 of the present invention.
  • alkyl is understood to be a straight-chain, cyclic, branched alkyl group.
  • C 1 -C 12 alkyl is understood to mean a straight, cyclic, branched chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. alkyl.
  • C 1 -C 8 alkyl is understood to mean a straight-chain, cyclic, branched alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • C 1 -C 4 alkyl is understood to mean a straight-chain, cyclic, branched alkyl group having 1, 2, 3 or 4 carbon atoms.
  • substituted aromatic amine group means that one of the nitrogen atoms is a group linking moiety and the aryl group thereof is a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a nitro group, a nitrile group or a hydroxyl group.
  • a mono- or poly-substituted aromatic amine group such as a halogen. For example, an anilino group, a naphthylamino group, and the like.
  • azaaryl refers to a five-, six-, or poly-azaheteroaryl group in which one of the nitrogen atoms is a linking moiety of the group.
  • imidazolyl pyrazolyl, benzimidazolyl and the like.
  • CDDO oxalyl chloride in dichloromethane
  • a solution of oxalyl chloride in dichloromethane was added dropwise, and the reaction was carried out at low temperature for 2 h; the solvent was removed under reduced pressure, and excess oxalyl chloride was removed and dissolved in 5 mL of dichloromethane to give CDDO.
  • the acid chloride solution was used; the N,N-dimethylethylenediamine was dissolved in 10 mL of anhydrous dichloromethane, triethylamine was added thereto, and the temperature was lowered to 0 ° C.
  • the CDDO acid chloride solution was slowly dropped at a low temperature and allowed to react overnight at room temperature. . After the reaction mixture was subjected to TLC, it was washed with water, extracted with ethyl acetate, and purified by silica gel column column chromatography to obtain pure OAH1-2.
  • 2-n-propylamine was dissolved in 15 mL of anhydrous dichloromethane, and the temperature was lowered to 0 ° C. Triethylamine was added thereto, and the solution of 1 was slowly added dropwise at -1 to -5 ° C, and the reaction was allowed to stand overnight at room temperature.
  • 2-n-butylamine was dissolved in 15 mL of anhydrous dichloromethane, and the temperature was lowered to 0 ° C. Triethylamine was added thereto, and the solution of 1 was slowly added dropwise at -1 to -5 ° C, and the reaction was allowed to proceed overnight at room temperature.
  • nitric oxide synthase (iNOS) The level of nitric oxide synthase (iNOS) in the specimens was determined by double antibody sandwich assay.
  • the microporous plate was coated with purified nitric oxide synthase (NOS) antibody to prepare a solid phase antibody, and nitric oxide synthase (NOS) was sequentially added to the microcapsules of the coated monoclonal antibody, followed by oxidation with HRP.
  • the nitrogen synthase (NOS) antibody binds to form an antibody-antigen-enzyme-labeled antibody complex, which is thoroughly washed and then added to the substrate TMB for color development. TMB is converted to blue under the catalysis of HRP enzyme and converted to the final yellow color by the action of an acid.
  • the color depth is positively correlated with nitric oxide synthase (NOS) in the sample.
  • the absorbance (OD value) was measured with a microplate reader at a wavelength of 450 nm, and the concentration of human nitric oxide synthase (NOS) in the sample was calculated from a standard curve.
  • Mouse Raw-264.7 cell line cell digestive juice (pancreatin 0.25%; EDTA 0.02%); LPS (10 ug/mL); 10% fetal bovine serum; 1% double antibody (penicillin, streptomycin) DMEM (Gbico) medium; test compound; dexamethasone; 96-well plate; multi-function microplate reader; cell culture incubator; Bai Olebo mouse iNOS enzyme-linked immunosorbent assay (ELISA) detection kit.
  • LPS 10 ug/mL
  • 10% fetal bovine serum 1% double antibody (penicillin, streptomycin) DMEM (Gbico) medium
  • test compound dexamethasone
  • 96-well plate multi-function microplate reader
  • cell culture incubator Bai Olebo mouse iNOS enzyme-linked immunosorbent assay (ELISA) detection kit.
  • ELISA enzyme-linked immunosorbent assay
  • test compound dissolved in a small amount of DMSO, CDDO-Me, dexamethasone sample (stock concentration 10 mM / L) sample plus serum-free medium sequence dilution 9 concentration gradients of 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 ⁇ M / L, 100 ⁇ L per well was added to the above culture solution and continued to culture for 4-6 h;
  • sample loading set blank control holes (the blank control hole does not add sample and enzyme standard reagent, the other steps are the same operation), the sample hole to be tested. Add 40 ⁇ L of the sample dilution to the sample well to be tested on the enzyme-labeled plate, and then add 10 ⁇ L of the sample solution to be tested (the final dilution of the sample is 5 times);
  • dosing solution 30 (48T 20 times) times concentrated washing solution diluted with distilled water 30 times to prepare a washing solution;
  • washing carefully remove the sealing film, discard the liquid, dries, fill each hole with washing liquid, let stand for 30 seconds, then discard, so repeat 5 times, pat dry;
  • color development first add color developer A50 ⁇ L, then add color developer B 50 ⁇ L, gently shake and mix, 37 ° C light-proof color for 15 minutes;
  • termination add 50 ⁇ L of stop solution to each well to terminate the reaction (at this time, the blue turns yellow);
  • RNA multimerization (RNA) n + NTP ⁇ (RNA) n+1 + PPi.
  • PPi is converted to Pi.
  • the product after the enzymatic reaction of Pi and MESG has a maximum absorption peak at 360 nm.
  • HCV-RNA polymerase NS5B Prospec Cat# HCV-269
  • pyrophosphate activity detection kit AnaSpec Cat#E-6645
  • sofosbuvir Gilead Cat#HY-15005
  • test compound CDDO-Me
  • RNA polymerization buffer (20 mM Hepes, pH 7.1, 7.5 mM DTT, 60 mM NaCl, 100 ⁇ g/mL BSA, 20 U/mL RNAsin, 50 ⁇ g/mL Poly C, 5 ⁇ g/mL Oligo G 12 , 10 ⁇ M GTP) and HCV.
  • RNA polymerase NS5B 500 ⁇ g/mL
  • reaction solution of the step 4 50 ⁇ L was added to the 96-well plate of the step 5, and the mixture was uniformly mixed, and then incubated at 22 ° C for 30 to 60 minutes.
  • the HCV NS3-4A protease cleaves viral non-structural polypeptide products at multiple sites such as NS3-4A, NS4A-4B, NS4B-5A and NS5A-5B, and these cleavage are essential for the maturation of hepatitis C virus proteins.
  • the Fluorescence Energy Resonance Transfer (FRET) peptide sequence contains the NS4A-4B cleavage site. Under the action of HCV NS3-4A protease, the FRET peptide was cleaved into two segments, EDANS/DABCYL, resulting in recovery of EDANS fluorescence quenched by DABCYL (see Figure 30).
  • HCV NS3-4A protease (AnaSpec Cat#61017); HCV protease activity assay kit (AnaSpec Cat#AS-72087); ledipasvir (Gilead Cat#HY-15602); test compound; CDDO-Me
  • test compound dissolved in DMSO, CDDO-Me, ledipasvir (stock concentration 10 mM / L) plus serum-free medium sequence dilution 9 concentration gradients of 100, 50, 25, 12.5, 6.25, 3.13, 1.56, 0.78 0.39uM/L, 40 ⁇ L per well was added to the 96-well plate, then add 10 ⁇ L of HCV NS3-4A protease to the above dilution to make the final concentration of 20ng/well, incubate for 10-15min at 37°C; and set HCVNS3-4A at the same time.
  • Protease positive control HCV NS3-4A protease substrate control.
  • Liver cancer (HepG-2/Huh7), lung cancer (A549), laryngeal cancer (Hep2), esophageal cancer (Eca-109/K450/510/TE-1)
  • MTT is widely used for the detection of cell proliferation and cytotoxicity.
  • MTT is a yellow compound, a fuel that accepts hydrogen ions, which can be reduced by some dehydrogenases in the mitochondria into a crystalline dark purple product formazan, which can be completely dissolved in the presence of a specific solvent. This product has a maximum absorption peak at 570 nm. The more the cells proliferate, the higher the absorbance; the greater the cytotoxicity, the lower the absorbance.
  • Hepatocarcinoma (HepG-2/Huh7), lung cancer (A549), laryngeal cancer (Hep2), esophageal cancer (Eca-109/K450/510/TE-1) and other cancer cell lines mainly composed of respiratory and digestive system cancer; % fetal calf serum; 1% double antibody (penicillin, streptomycin) in DMEM (Gbico) medium; cell digestive juice (pancreatin 0.25%; EDTA 0.02%); 1% double antibody (penicillin, streptomycin) DMEM (Gbico) medium; test compound (A1/A4/OAH2-1/OAH2-1-C/OAH2-2/OAH2-2-C); CDDO-Me; ledipasvir (Gilead Cat#HY-15602) ; 96-well plate; multi-function microplate reader; cell culture incubator.
  • % fetal calf serum 1% double antibody (penicillin, streptomycin) in DMEM (Gbico) medium
  • cell digestive juice
  • the cancer cell line mainly composed of respiratory cancer and digestive system cancer, such as liver cancer, lung cancer, stomach cancer, esophageal cancer, etc., which are grown in a bottle, is digested with cell digestive juice, and the cells are 6000/well. 100 ⁇ L/well was placed in a 96-well plate and placed in a 37 ° C, 5% CO 2 incubator overnight until adherent.
  • test compound/B compound dissolved in a small amount of DMSO, CDDO-Me, dexamethasone sample (stock concentration 10 mM / L) sample was diluted with serum-free medium sequence to 9 concentration gradients, the dosing concentration was 100, 50, respectively. 25, 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 uM/L, set a group of DMSO, cells and blank control group, each group of 5 duplicate wells. The 96-well plate culture medium was discarded, and test compounds of different concentration gradients, DMSO and blank medium were added. Place in an incubator and incubate overnight.
  • the blank group contained only the medium, and the control group was the normal cultured cell group.
  • Inhibition rate (experimental group A570nm - blank group A570nm) / (control A570nm - blank group A570nm).
  • Oleanolic type test compound and amides Ledipasvir (positive control) on liver cell line (LO-2 / HL-7702 ) , and kidney cell lines (293T / HK-2) IC 50.
  • MTT is widely used for the detection of cell proliferation and cytotoxicity.
  • MTT is a yellow compound, a fuel that accepts hydrogen ions, which can be reduced by some dehydrogenases in the mitochondria into a crystalline dark purple product formazan, which can be completely dissolved in the presence of a specific solvent. This product has a maximum absorption peak at 570 nm. The more the cells proliferate, the higher the absorbance; the greater the cytotoxicity, the lower the absorbance.
  • Hepatocytes LO-2/HL-7702 and kidney cell lines (293T/HK-2); 10% South American/fetal bovine serum; cell digestive juice (pancreatin 0.25%; EDTA 0.02%); 1% double Anti-(penicillin, streptomycin) 1640/DMEM (Gbico) medium; test compound; CDDO-Me; ledipasvir (Gilead Cat #HY-15602); 96-well plate; multi-function microplate reader; cell culture incubator.
  • (1) Plating When the liver or kidney cells with good growth in the culture bottle grow to about 80%, they are digested with cell digestive juice. The cells are plated at 4,000 cells/well, 200 ⁇ L/well in 96-well plates, and placed at 37 ° C, 5%. The CO 2 incubator was cultured overnight to adherence.
  • test compound CDDO-Me, dexamethasone sample (stock concentration 10 mM / L) sample dissolved in a small amount of DMSO was diluted with a serum-free medium sequence to 10 concentration gradients, and the dosing concentrations were 200, 100, 50, 25, respectively. 12.5, 6.25, 3.13, 1.56, 0.78, 0.39 ⁇ M/L, a set of ethyl acetate groups (concentration of 20 ⁇ L/mL) and a blank control group, four replicate wells per group. The 96-well plate stock medium was discarded, and test compounds of different concentration gradients, ethyl acetate and blank medium were added. Place in an incubator and incubate overnight.
  • the blank group contained only the medium, and the control group was the normal cultured cell group.
  • Inhibition rate (experimental group A570nm - blank group A570nm) / (control A570nm - blank group A570nm)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种如通式I所示的化合物。此外，本发明还公开了所述化合物的合成方法。另外，本发明还公开了所述化合物在制备抗癌、抗炎和治疗丙肝的药物中的用途。

Description

一种化合物、其制备方法及用途 技术领域
本发明涉及一种齐墩果型衍生物，尤其涉及一种齐墩果型酰胺类化合物、其制备方法及其用途。
背景技术
齐墩果酸(Oleanolic acid，简称OA)是一种重要的五环三萜化合物，广泛存在于自然界中，女贞子、青叶胆等植物中均富含齐墩果酸。齐墩果酸具有多种重要的生物活性，如保肝、抗炎、抗肿瘤、降血脂、抗溃疡等，但大多数活性较弱而没有实用价值；另外，齐墩果酸的水溶性很差，生物利用度低，这也大大限制了它在临床上的应用；此外，齐墩果酸还以皂苷的形式广泛分布在多种植物中，它的许多皂苷也具有重要的药理作用，如抗肿瘤、降血糖等。
多数中药成分作为抗肿瘤药物的前体化合物，需经过适当的结构修饰才能表现出较强的抗肿瘤活性。目前，发现和引入活性关键基团是中药抗肿瘤有效成分结构修饰的主要途径，也是高效抗肿瘤药物的研发重点。齐墩果酸类化合物具有独特的立体结构和手性刚性骨架，衍生化后往往表现出更为优良的生物活性，并且在脂溶性、识别、跨膜能力等方面具有较强的潜在开发价值，将此类化合物修饰后应用于新型药物分子中必能提高药物的靶向能力和生物利用度。
近几年，以齐墩果酸为基础物质进行结构修饰后形成的一系列衍生物(CDDO-Im、CDDO-Me、AMR、AMR-Me等)受到科研工作者的重视，大量的体内和体外实验表明，它们具有很强的生物学活性，可以通过多种途径抑制肿瘤的生长。但是，却较少有关它们对正常细胞影响的研究。如果此类衍生物能抑制肿瘤的同时对正常细胞产生较小危害，将会大大促进肿瘤治疗学的发展。为了实现这一目的，当前最重要的待解决的问题是设计合成一系列新型的齐墩果酸衍生物，并通过细胞活性测试，以期达到高效、低毒、生物利用度及生物活性更好的效果。
发明内容
本发明的目的在于提供一种具有抗癌、抗炎和治疗丙肝活性的齐墩果型酰胺类化合物。
为实现上述目的，本发明所采取的技术方案为：
一种化合物，其化学结构式如式I所示：
Figure PCTCN2018074689-appb-000001
其中，所述R 1为氢、C 1-C 12的烷基中任意一种；所述R 2为2-甲基-2-羟基丙基、N,N-二甲基胺乙基、R 3-(C＝O)-CH 2-中任意一种；所述R 3选自氨基、C 1-C 12的直链、环状和支链的脂肪胺基、C 1-C 12的取代或者未取代的芳香胺基、C 5-C 8的取代或者未取代的氮杂芳基中任意一种。
作为本发明所述化合物的优选实施方式，其中，所述R 1为氢、C 1-C 8的烷基中任意一种；所述R 2为2-甲基-2-羟基丙基、N,N-二甲基胺乙基、R 3-(C＝O)-CH 2-中任意一种。
作为本发明所述化合物的更优选的实施方式，其中，所述R 1为氢、C 1-C 4的烷基中任意一种；所述R 2为2-甲基-2-羟基丙基、N,N-二甲基胺乙基、R 3-(C＝O)-CH 2-中任意一种。
作为本发明所述化合物的更优选的实施方式，其中，所述R 1为氢；所述R 3选自氨基，C 1-C 12的直链、环状和支链的脂肪胺基、C 1-C 12的取代或者未取代的芳香胺基、C 5-C 8的取代或者未取代的氮杂芳基中任意一种。
作为本发明所述化合物的优选实施方式，其中，所述R 3选自氨基、C 1-C 12的直链、环状和支链的脂肪胺基中任意一种。
作为本发明所述化合物的更优选的实施方式，其中，所述R 3选自氨基、C 1-C 4的直链、环状和支链的脂肪胺基中任意一种。
作为本发明所述化合物的更优选的实施方式，其中，所述R 3选自环丙胺基、异丙胺基、异丁胺基、N,N-二甲基胺基、正丙胺基、正丁胺基、氨基、甲基氨基中任意一种。
在本发明所述化合物的某些实施例中，所述结构式I所示的化合物为下列化合物：
Figure PCTCN2018074689-appb-000002
在本发明所述化合物的某些实施例中，所述结构式I所示的化合物为下列化合物：
Figure PCTCN2018074689-appb-000003
在本发明所述化合物的某些实施例中，所述结构式I所示的化合物为下列化合物中任意一种：
Figure PCTCN2018074689-appb-000004
此外，本发明的目的还在于提供如上所述化合物的合成方法，
为实现上述目的，本发明所采取的技术方案为：
当所述R 2为2-甲基-2-羟基丙基或N,N-二甲基胺乙基时，所述方法包括以下步骤：
Figure PCTCN2018074689-appb-000005
(1)0℃下，将CDDO用二氯甲烷溶解，向其中加入草酰氯的二氯甲烷溶液；
(2)减压除去溶剂并除去多余的草酰氯后，加入二氯甲烷溶解，得到CDDO的酰氯溶液；
(3)用二氯甲烷溶解胺类化合物，向其中加入三乙胺，降温至0℃，低温下向其中加入步骤(2)所得到的CDDO的酰氯溶液，常温下反应，即可；
其中，所述胺类化合物与CDDO的摩尔比为3～5:1；草酰氯与CDDO的摩尔比为5～6:1；所述三乙胺与CDDO的摩尔比为2～3:1。
更为优选地，所述胺类化合物与CDDO的摩尔比为3:1；草酰氯与CDDO的摩尔比为5:1；所述三乙胺与CDDO的摩尔比为2:1。
当所述R 2为R 3-(C＝O)-CH 2-时，所述方法包括以下步骤：
Figure PCTCN2018074689-appb-000006
(1)0℃下，将如结构式III所示的化合物用二氯甲烷或氯仿溶解；
(2)向步骤(1)所得溶液中加入N,N'-羰基二咪唑(CDI)后反应1～3小时；
(3)将胺类化合物用二氯甲烷溶解后，加入三乙胺，-1至-5℃下加入步骤(2)所得的反应液中，常温下反应12～18小时，即可制备出入结构式II所示的化合物；
其中，所述胺类化合物与结构式III所示的化合物的摩尔比为3～5:1；N,N'-羰基二咪唑与结构式III所示的化合物的摩尔比为1～2:1；所述三乙胺与结构式III所示的化合物的摩尔比为2～3:1。
更为优选地，所述胺类化合物与结构式III所示的化合物的摩尔比为3:1；N,N'-羰基二咪唑与结构式III所示的化合物的摩尔比为1:1；所述三乙胺与结构式III所示的化合物的摩尔比为2:1。
此外，本发明的目的还在于提供如结构式I所述的化合物的用途。
本发明提供了如结构式I所述化合物在在制备抗癌药物、抗炎症药物中的用途；优选地，所述癌症为肝癌、肺癌、喉癌和食道癌；优选地，所述炎症为诱导型一氧化氮合成酶高表达所引发的炎症。
本发明提供了如结构式I所述化合物在制备治疗丙肝的药物中的用途。
在下文中，为了表述方便，发明人将上述化学结构式I所示的化合物称为“齐墩果型酰胺类化合物”。
值得注意的是，发明人经过一系列研究后证实，本发明所述的大多数齐墩果型酰胺类化合物在对癌细胞(例如，肝癌、肺癌、喉癌和食道癌等)的细胞毒性测试中，效果比癌症治疗的常用化学药物顺铂效果好。本发明所述的大多数齐墩果型酰胺类化合物对诱导一氧化氮合成酶(iNOS)的抑制效果与现有的抗炎药物地塞米松效果相近，但比CDDO-Me效果更好。本发明所述的大多数齐墩果型酰胺类化合物对HCV-RNA聚合酶、HCV蛋白酶的抑制效果与现有的丙肝治疗药物索非布韦(sofosbuvir)和雷迪帕韦(ledipasvir)相近，但比CDDO-Me效果更好。
此外，发明人还发现本发明所述的大多数齐墩果型酰胺类化合物对于正常肝细胞和肾细胞的毒性与雷迪帕韦(ledipasvir)相近，但比CDDO-Me小。
因此，本发明所述的齐墩果型酰胺类化合物有望成为新一代的抗癌、抗炎和治疗丙肝的药物。
另外，本发明的目的还在于提供一种含有如结构式I所述化合物或其药学上可接受的盐的药物组合物。
与现有技术相比，本发明的技术方案具有以下有益效果：
1、本发明所述的齐墩果型酰胺类化合物是一系列新型的齐墩果型衍生物，以上化合物骨架未见文献报道。
2、本发明所述的齐墩果型酰胺类化合物在抗癌、抗炎和治疗丙肝方面具有良好的活性且对正常肝细胞和肾细胞毒性较小，有望成为新一代相关疾病的备选药物。
附图说明：
图1为本发明所述的齐墩果型酰胺类化合物OAH1-1的质谱；
图2为本发明所述的齐墩果型酰胺类化合物OAH1-1的核磁共振氢谱；
图3为本发明所述的齐墩果型酰胺类化合物OAH1-1的核磁共振碳谱；
图4为本发明所述的齐墩果型酰胺类化合物OAH1-2的质谱；
图5为本发明所述的齐墩果型酰胺类化合物OAH1-2的核磁共振氢谱；
图6为本发明所述的齐墩果型酰胺类化合物OAH1-2的核磁共振碳谱；
图7为本发明的化合物OAH2-2的质谱；
图8为本发明的化合物OAH2-2的核磁共振氢谱；
图9为本发明的化合物OAH2-2的核磁共振碳谱；
图10为本发明所述的齐墩果型酰胺类化合物OAH2-5的质谱；
图11为本发明所述的齐墩果型酰胺类化合物OAH2-5的核磁共振氢谱；
图12为本发明所述的齐墩果型酰胺类化合物OAH2-5的核磁共振碳谱；
图13为本发明所述的齐墩果型酰胺类化合物OAH2-6的质谱；
图14为本发明所述的齐墩果型酰胺类化合物OAH2-6的核磁共振氢谱；
图15为本发明所述的齐墩果型酰胺类化合物OAH2-6的核磁共振碳谱；
图16为本发明所述的齐墩果型酰胺类化合物OAH2-7的质谱；
图17为本发明所述的齐墩果型酰胺类化合物OAH2-7的核磁共振氢谱；
图18为本发明所述的齐墩果型酰胺类化合物OAH2-7的核磁共振碳谱；
图19为本发明所述的齐墩果型酰胺类化合物OAH2-8的质谱；
图20为本发明所述的齐墩果型酰胺类化合物OAH2-8的核磁共振氢谱；
图21为本发明所述的齐墩果型酰胺类化合物OAH2-8的核磁共振碳谱；
图22为本发明所述的齐墩果型酰胺类化合物OAH2-9的质谱；
图23为本发明所述的齐墩果型酰胺类化合物OAH2-9的核磁共振氢谱；
图24为本发明所述的齐墩果型酰胺类化合物OAH2-9的核磁共振碳谱；
图25为本发明所述的齐墩果型酰胺类化合物OAH2-10的质谱；
图26为本发明所述的齐墩果型酰胺类化合物OAH2-10的核磁共振氢谱；
图27为本发明所述的齐墩果型酰胺类化合物OAH2-10的核磁共振碳谱；
图28为本发明所述的齐墩果型酰胺类化合物OAH2-11的质谱；
图29为本发明所述的齐墩果型酰胺类化合物OAH2-12的质谱；
图30为本发明实施例15的测试原理示意图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点，下面结合具体实施例对本发明作进一步说明。
在本文中，术语“烷基”应理解为直链、环状、支链的烷基。“C 1-C 12烷基”应理解为表示具有1、2、3、4、5、6、7、8、9、10、11或12个碳原子的直链、环状、支链的烷基。例如，甲基、乙基、丙基、异丙基、环丙基、丁基、环丁基、异丁基、环丁基、戊基、环戊基、己基、环己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基或其同分异构体。“C 1-C 8 烷基”应理解为表示具有1、2、3、4、5、6、7或8个碳原子的直链、环状、支链的烷基。“C 1-C 4烷基”应理解为表示具有1、2、3或4个碳原子的直链、环状、支链的烷基。
术语“取代的芳香胺基”指指其中的一个氮原子为基团连接部位且其芳基上被C 1-C 6烷基、C 1-C 6烷氧基、硝基、腈基、羟基、卤素等单取代或者多取代的芳香胺基。例如，苯胺基、萘胺基等。
术语“氮杂芳基”是指其中的一个氮原子为基团连接部位的五元、六元或多元氮杂芳基。例如，咪唑基、吡唑基、苯并咪唑基等。
一、化合物的合成及表征
实施例1：
OAH1-1的合成
目的：CDDO和2-甲基-2-羟基丙胺(HA)的酰胺化反应
Figure PCTCN2018074689-appb-000007
投料：
Figure PCTCN2018074689-appb-000008
注：2-甲基-2-羟基丙胺(HA)自己制备
制备过程：0℃下，0.3gCDDO加10mL二氯甲烷溶解，滴加草酰氯的二氯甲烷溶液，低温下反应2h；减压除去溶剂，并除去多余的草酰氯，并用5mL二氯甲烷溶解，得到CDDO的酰氯溶液，备用；2-甲基-2-羟基丙胺(HA)用10mL无水二氯甲烷溶解，向其中加入三乙胺，降温至0℃，低温下将CDDO的酰氯溶液缓慢滴入，常温反应过夜。反应液经TLC检测后，水洗，乙酸乙酯萃取，硅胶柱快速柱层析，得到OAH1-1纯品。
化合物OAH1-1表征数据：
1H NMR(500MHz,DMSO-d 6)δ8.65(s,1H),7.42(q,J＝5.7Hz,4H),6.21(s,1H),5.69(s,2H),4.63–4.42(m,4H),3.21–3.01(m,12H),2.87(d,J＝13.9Hz,5H),2.43–2.35(m,3H),2.18(s,2H),1.92(s,4H),1.69(d,J＝14.1Hz,7H),1.64–1.56(m,14H),1.42(d,J＝15.1Hz,8H),1.24(s,8H),1.19–1.12(m,32H),1.10(d,J＝9.2Hz,6H),1.08–1.03(m,35H),0.95(s,10H),0.88(d,J＝13.8Hz,24H). 13C NMR(126MHz,DMSO-d 6)δ199.73,177.60,175.98,168.82,124.04,123.92,70.34,50.57,49.21,49.05,48.51,46.72,46.15,46.10,46.07,45.81,45.50,44.84,43.02,42.02,41.73,38.56,36.06,35.91,34.71,33.68,31.69,31.29,30.70,30.67,28.07,28.05,28.00,27.95,27.81,27.56,26.81,26.61,26.38,25.00,24.14,23.62,23.59,22.55,22.46,21.77,21.54,21.49,19.68,18.76,17.92.
实施例2
OAH1-2的合成
Figure PCTCN2018074689-appb-000009
投料：
Figure PCTCN2018074689-appb-000010
Figure PCTCN2018074689-appb-000011
制备过程：
0℃下，0.3gCDDO加10mL二氯甲烷溶解，滴加草酰氯的二氯甲烷溶液，低温下反应2h；减压除去溶剂，并除去多余的草酰氯，并用5mL二氯甲烷溶解，得到CDDO的酰氯溶液，备用；N,N-二甲基乙二胺用10mL无水二氯甲烷溶解，向其中加入三乙胺，降温至0℃，低温下将CDDO的酰氯溶液缓慢滴入，常温反应过夜。反应液经TLC检测后，水洗，乙酸乙酯萃取，硅胶柱快速柱层析，得到OAH1-2纯品。
化合物OAH1-2表征数据：
1H NMR(500MHz,DMSO-d 6)δ7.63(d,J＝5.7Hz,1H),5.68(s,1H),3.39–3.27(m,2H),3.10(dd,J＝13.0,6.4Hz,2H),2.85(d,J＝13.5Hz,2H),2.44–2.31(m,4H),2.21(d,J＝5.1Hz,8H),1.90(d,J＝10.4Hz,2H),1.76–1.54(m,9H),1.42(d,J＝18.3Hz,3H),1.33–1.24(m,5H),1.23–1.17(m,5H),1.14(d,J＝10.2Hz,7H),1.09–1.01(m,6H),0.96(s,2H),0.94(s,3H),0.87(d,J＝15.2Hz,9H). 13C NMR(126MHz,DMSO-d 6)δ176.97,175.94,123.97,78.14,58.74,49.00,48.49,45.91,45.49,45.46,45.43,41.72,38.56,37.15,35.99,34.67,33.73,33.61,31.22,30.73,27.88,27.55,24.12,23.61,23.33,22.40,21.56,19.68,18.79.
实施例3
CDDO-甘氨酸酰胺类的化合物OAH2-5～OAH2-12的合成
通用合成路线：
Figure PCTCN2018074689-appb-000012
实施例4
OAH2-2的合成：CDDO和甘氨酸甲酯的酰胺化
Figure PCTCN2018074689-appb-000013
投料：
Figure PCTCN2018074689-appb-000014
制备过程：0℃下，100mL单口瓶中加入3g CDDO,用30mL二氯甲烷溶解，加入0.9gCDI反应2h；甘氨酸甲酯盐酸盐用20mL无水二氯甲烷溶解，加入三乙胺，-1至-5℃下滴入到CDDO的反应溶液中，滴加完毕后常温反应12～18h。反应液经TLC检测后，水洗，乙酸乙酯萃取，硅胶柱快速柱层析，得到OAH2-2纯品。
化合物OAH2-2表征数据：
1H NMR(500MHz,DMSO-d 6)δ8.65(s,1H),8.16(t,J＝5.8Hz,1H),6.20(s,1H),3.90(dd,J＝17.0,5.9Hz,1H),3.74(dd,J＝17.0,5.6Hz,1H),3.62(s,3H),3.33(s,2H),3.07(d,J＝4.7Hz,1H),2.86(dt,J＝13.9,4.2Hz,1H),2.51(t,J＝1.9Hz,2H),2.30–2.11(m,2H),1.98–1.79(m,5H),1.65(p,J＝13.7,13.2Hz,6H),1.42(d,J＝17.5Hz,9H),1.35(d,J＝10.2Hz,2H),1.27(d,J＝ 14.2Hz,7H),1.18(s,7H),1.08(s,6H),0.95(s,4H),0.88(d,J＝16.6Hz,9H). 13C NMR(126MHz,DMSO-d 6)δ199.68,197.77,177.74,171.07,169.80,168.85,123.79,115.56,113.27,52.06,49.14,46.73,45.88,45.83,44.85,43.03,42.08,41.36,35.82,34.62,33.68,33.58,31.72,31.28,30.68,27.57,26.82,26.61,26.37,25.01,23.59,22.49,21.78,21.61,17.94.
实施例5
OAH2-4的合成：CDDO-甘氨酸甲酯的酰胺化
Figure PCTCN2018074689-appb-000015
投料：
Figure PCTCN2018074689-appb-000016
制备过程：100mL单口瓶中加入3g OAH2-2，用25mL甲醇溶解，将0.43gNaOH,用3mL水溶解，加入到OAH2-2的甲醇溶液中，室温下反应2h。经TLC检测反应完毕后，水洗，乙酸乙酯萃取，硅胶柱快速柱层析，得到OAH2-4纯品。
实施例6
OAH2-5～OAH2-12系列化合物的合成：OAH2-4和胺类化合物的酰胺化
Figure PCTCN2018074689-appb-000017
投料：
Figure PCTCN2018074689-appb-000018
OAH2-5～OAH2-10系列化合物的通用制备过程：
0℃下，50mL单口瓶中加入0.3g OAH2-4,用10mL二氯甲烷溶解，加入0.09gCDI反应2h；amine用5mL无水二氯甲烷溶解，加入三乙胺，-1至-5℃下滴入到OAH2-4的反应溶液中，滴加完毕后常温反应12～18h。反应液经TLC检测后，水洗，乙酸乙酯萃取，硅胶柱快速柱层析，得到OAH2系列化合物纯品。
实施例7
OAH2-5的合成：OAH2-4和环丙胺的酰胺化
Figure PCTCN2018074689-appb-000019
投料：
Figure PCTCN2018074689-appb-000020
制备过程：
②20℃，OAH2-4加10mL二氯甲烷溶解，加CDI反应2h；
②环丙胺用15mL无水二氯甲烷溶解，降温至0℃，加入三乙胺，-1至-5℃下将①中溶液缓慢滴入，常温反应过夜。
化合物OAH2-5表征数据：
1H NMR(500MHz,Chloroform-d)δ8.01(s,1H),6.87(t,J＝5.3Hz,1H),6.78(d,J＝3.2Hz,1H),5.91(s,1H),3.82(dd,J＝8.7,5.1Hz,3H),3.41(s,2H),3.07(s,1H),2.99(d,J＝4.7Hz,1H),2.93(s,2H),2.65–2.57(m,1H),1.97(s,2H),1.70(d,J＝2.0Hz,6H),1.51(dd,J＝22.7,10.2Hz,6H),1.41(s,5H),1.27(d,J＝13.6Hz,8H),1.18(s,9H),1.15(d,J＝7.4Hz,3H),1.09(s,4H),1.05(d,J＝1.5Hz,1H),1.01(s,1H),0.94(d,J＝8.2Hz,4H),0.91(s,4H),0.83(s,6H),0.70–0.65(m,3H),0.44(s,3H). 13C NMR(126MHz,Chloroform-d)δ199.04,196.63,178.20,170.63,168.65,165.93,143.84,124.00,114.50,114.42,106.58,49.43,47.70,46.52,45.87,45.01,43.32,42.56,42.12,39.58,35.92,34.61,34.08,33.24,31.63,31.55,30.60,29.68,27.75,26.97,26.60,24.73,23.08,22.54,21.66,21.55,18.22,7.22,6.42,6.39.
实施例8
OAH2-6的合成：OAH2-4和一异丙胺的酰胺化
Figure PCTCN2018074689-appb-000021
投料：
Figure PCTCN2018074689-appb-000022
制备过程：
②0℃，OAH2-4加10mL二氯甲烷溶解，加CDI反应2h；
②一异丙胺用15mL无水二氯甲烷溶解，降温至0℃，加入三乙胺，-1至-5℃下将①中溶液缓慢滴入，常温反应过夜。
化合物OAH2-6表征数据：
1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),5.92(s,1H),4.04(d,J＝47.2Hz,3H),2.96(d,J＝12.3Hz,2H),1.99(d,J＝19.0Hz,1H),1.67(d,J＝40.8Hz,7H),1.52(d,J＝13.5Hz,3H),1.41(s,3H),1.36(s,1H),1.28(s,1H),1.27–1.21(m,4H),1.17(d,J＝15.1Hz,13H),1.10(s,4H),1.04–0.97(m,1H),0.95(s,3H),0.91(s,3H),0.84(s,4H). 13C NMR(126MHz,Chloroform-d)δ198.91,196.55,168.63,165.74,124.08,114.58,114.39,49.46,47.72,46.71,45.85,45.02,42.56,42.09,35.79,34.60,33.98,33.19,31.66,31.36,30.55,27.88,26.99,23.05,22.93,22.11,21.61,21.56,18.23.
实施例9
OAH2-7的合成：OAH2-4和一异丁胺酰胺化
Figure PCTCN2018074689-appb-000023
投料：
Figure PCTCN2018074689-appb-000024
制备过程：
②0℃，OAH2-4加10mL二氯甲烷溶解，加CDI反应2h；
②一异丁胺用15mL无水二氯甲烷溶解，降温至0℃，加入三乙胺，-1至-5℃下将①中溶液缓慢滴入，常温反应过夜。
化合物OAH2-7表征数据：
1H NMR(500MHz,Chloroform-d)δ8.03(s,1H),3.07(d,J＝84.9Hz,4H),2.05(s,2H),1.74(s,8H),1.59–1.39(m,5H),1.38–1.25(m,4H),1.20(d,J＝13.2Hz,7H),1.14–1.05(m,4H),1.05–0.88(m,10H),0.83(d,J＝15.3Hz,8H). 13C NMR(126MHz,Chloroform-d)δ196.58,166.17,114.66,114.42,48.04,46.69,45.91,45.03,42.75,42.73,42.72,42.28,35.96,34.65,34.43,33.26,32.11,31.65,30.63,29.69,29.65,28.79,28.31,28.24,27.09,23.45,23.18,22.01,21.70,21.08,18.37.
实施例10
OAH2-8的合成：OAH2-4和二甲胺的酰胺化
Figure PCTCN2018074689-appb-000025
投料：
Figure PCTCN2018074689-appb-000026
制备过程：
②0℃，OAH2-4加10mL二氯甲烷溶解，加CDI反应2h；
②二甲胺用15mL无水二氯甲烷溶解，降温至0℃，加入三乙胺，-1至-5℃下将①中溶液缓慢滴入，常温反应过夜。
化合物OAH2-8表征数据：
1H NMR(500MHz,Chloroform-d)δ8.07(s,1H),5.97(s,1H),4.12(q,J＝21.3,19.6Hz,2H),3.22–2.91(m,8H),2.06(dd,J＝27.3,14.1Hz,1H),1.84(td,J＝13.6,4.5Hz,2H),1.77(s,3H),1.70(dd,J＝14.5,6.4Hz,1H),1.61(t,J＝11.1Hz,3H),1.53(d,J＝12.4Hz,2H),1.48(s,3H),1.31(s,5H),1.28(s,1H),1.25(d,J＝2.8Hz,5H),1.23(s,2H),1.18(s,1H),1.16(d,J＝1.8Hz,3H),1.08(dd,J＝20.3,11.9Hz,1H),1.01(d,J＝8.6Hz,6H),0.90(s,4H). 13C NMR(126MHz,Chloroform-d)δ198.96,196.64,168.25,165.95,124.03,114.41,49.34,47.70,46.46,45.82,44.99,42.52,42.14,40.91,35.89,34.65,34.04,33.25,31.62,31.46,30.59,29.67,27.81,26.97,26.59,24.72,23.24,23.09,21.61,21.55,18.23.
实施例11
OAH2-9的合成：OAH2-4和一正丙胺的酰胺化
Figure PCTCN2018074689-appb-000027
投料：
Figure PCTCN2018074689-appb-000028
制备过程：
②0℃，OAH2-4加10mL二氯甲烷溶解，加CDI反应2h；
②一正丙胺用15mL无水二氯甲烷溶解，降温至0℃，加入三乙胺，-1至-5℃下将①中溶液缓慢滴入，常温反应过夜。
化合物OAH2-9表征数据：
1H NMR(500MHz,Chloroform-d)δ8.07(s,1H),6.05(s,1H),3.33(s,3H),3.05(s,2H),2.08(d,J＝21.2Hz,2H),1.80(s,8H),1.73(d,J＝7.5Hz,3H),1.66(s,5H),1.60(d,J＝12.4Hz,10H),1.44(s,4H),1.38(s,3H),1.35(s,2H),1.28(d,J＝6.3Hz,16H),1.20(d,J＝8.9Hz,8H),1.13(s,3H),1.05(s,4H),0.97(d,J＝21.1Hz,10H),0.94–0.81(m,10H). 13C NMR(126MHz, Chloroform-d)δ199.00,196.55,168.88,165.84,114.61,114.40,47.78,46.77,45.95,45.02,42.61,42.10,35.79,34.59,34.04,33.19,31.76,31.41,30.55,29.69,28.00,27.03,26.91,23.07,22.95,22.38,21.70,21.61,18.27,11.63.
实施例12
OAH2-10的合成：OAH2-4和一正丁胺的酰胺化
Figure PCTCN2018074689-appb-000029
投料：
Figure PCTCN2018074689-appb-000030
制备过程：
②0℃，OAH2-4加10mL二氯甲烷溶解，加CDI反应2h；
②一正丁胺用15mL无水二氯甲烷溶解，降温至0℃，加入三乙胺，-1至-5℃下将①中溶液缓慢滴入，常温反应过夜。
化合物OAH2-10表征数据：
1H NMR(500 MHz,Chloroform-d)δ8.00(s,1H),5.92(s,1H),4.21–3.95(m,2H),3.22(d,J＝14.5 Hz,2H),2.96(d,J＝10.3Hz,2H),1.99(d,J＝16.4 Hz,1H),1.71(s,5H),1.67–1.57(m,3H),1.56–1.44(m,6H),1.42(s,3H),1.36(s,1H),1.29(s,3H),1.26(s,1H),1.22(d,J＝6.9 Hz,3H),1.19(s,9H),1.12(s,1H),1.10(s,3H),1.08–0.99(m,2H),0.95(s,3H),0.91(s,3H),0.84(d,J＝8.8 Hz,8H),0.79–0.74(m,1H). 13C NMR(126 MHz,Chloroform-d)δ196.55,168.59,165.75,124.06,114.57,114.40,49.46,47.70,46.69,45.83,45.01,43.32,42.55,42.07,40.40,35.78,34.60,33.97,33.18,31.65,31.39,31.00,30.54,29.69,27.86,26.99,24.72,23.03,22.92,21.60,21.56,20.03,18.22,13.69.
实施例13
OAH2-11的合成：OAH2-4和一正丁胺的酰胺化
Figure PCTCN2018074689-appb-000031
投料：
Figure PCTCN2018074689-appb-000032
制备过程：
②0℃，OAH2-4加10mL二氯甲烷溶解，加CDI反应2h；
②足量NH 3通入到15mL无水二氯甲烷溶解，降温至0℃，加入三乙胺，-1至-5℃下将①中溶液缓慢滴入，常温反应过夜。
实施例14
OAH2-12的合成：OAH2-4和一正丁胺的酰胺化
Figure PCTCN2018074689-appb-000033
投料：
Figure PCTCN2018074689-appb-000034
制备过程：
②0℃，OAH2-4加10mL二氯甲烷溶解，加CDI反应2h；
②足量CH 3NH 2通入到15mL无水二氯甲烷溶解，降温至0℃，加入三乙胺，-1至-5℃下将①中溶液缓慢滴入，常温反应过夜。
二、化合物的生物活性测试
实施例15
抑制诱导一氧化氮合成酶(iNOS)活性检测，抗炎活性测试：
表1：对诱导一氧化碳合成酶(iNOS)半数抑制率IC 50的结果
Figure PCTCN2018074689-appb-000035
实验原理：
应用双抗体夹心法测定标本中一氧化氮合成酶(iNOS)水平。用纯化的一氧化氮合成酶(NOS)抗体包被微孔板，制成固相抗体，往包被单抗的微孔中依次加入一氧化氮合成酶(NOS)，再与HRP标记的一氧化氮合成酶(NOS)抗体结合，形成抗体-抗原-酶标抗体复合物，经过彻底洗涤后加底物TMB显色。TMB在HRP酶的催化下转化成蓝色，并在酸的作用下转化成最终的黄色。颜色的深浅和样品中的一氧化氮合成酶(NOS)呈正相关。用酶标仪在450nm波长下测定吸光度(OD值)，通过标准曲线计算样品中人一氧化氮合成酶(NOS)浓度。
试剂及材料:
小鼠Raw-264.7细胞株；细胞消化液(胰酶0.25％；EDTA0.02％)；LPS(10ug/mL)；10％的胎牛血清；1％双抗(青霉素、链霉素)的DMEM(Gbico)培养基；测试化合物；地塞米松；96孔板；多功能酶标仪；细胞培养箱；柏奥莱博小鼠iNOS酶联免疫分析(ELISA)检测试剂盒。
实验步骤：
(1)、取处于对数生长期的Raw-264.7细胞用细胞消化液进行消化、离心，重悬后按照每孔100μL,细胞数6×104接种于96孔板中，37℃、5％CO2的细胞培养箱中培养。留3孔作为没有细胞的空白对照；
(2)、培养12～48h至细胞为80～90％满后吸除原培养液，加入不含血清的DMEM培养基90μL，再加入LPS(10ug/mL)10μL，即最终浓度为1μg/mL，然后放入培养箱中37℃继续培养24h；
(3)、用少量DMSO溶解的测试化合物、CDDO-Me、地塞米松样品(储存液浓度10mM/L)样品加无血清培养基序列稀释9个浓度梯度100、50、25、12.5、6.25、3.13、1.56、0.78、0.39μM/L，每孔100μL加入到前述培养液中继续培养4～6h；
(4)、标准品的稀释与加样：在酶标包被板上设标准品孔10孔，每孔加样量都为50μL，浓度分别为60U/L，40U/L，20U/L，10U/L，5U/L，2个复孔；
(5)、加样：分别设空白对照孔(空白对照孔不加样品及酶标试剂，其余各步操作相同)、待测样品孔。在酶标包被板上待测样品孔中先加样品稀释液40μL，然后再加待测样品液10μL(样品最终稀释度为5倍)；
(6)、温育：用封板膜封板后置37℃温育30分钟；
(7)、配液：将30(48T的20倍)倍浓缩洗涤液用蒸馏水30倍稀释后制成洗涤液备用；
(8)、洗涤：小心揭掉封板膜，弃去液体，甩干，每孔加满洗涤液，静置30秒后弃去，如此重复5次，拍干；
(9)、加酶：每孔加入酶标试剂50μL，空白孔除外；
(10)、温育：操作同(3)；洗涤：操作同(5)；
(11)、显色：每孔先加入显色剂A50μL，再加入显色剂B 50μL，轻轻震荡混匀，37℃避光显色15分钟；
(12)、终止：每孔加终止液50μL，终止反应(此时蓝色立转黄色)；
(13)、测定：以空白空调零，450nm波长依序测量各孔的吸光度(OD值)。测定应在加终止液后15min以内进行。
实施例16
测试齐墩果型酰胺类化合物和sofosbuvir(阳性对照物)的HCV-RNA聚合酶IC 50，结果如下表2：
表2
Figure PCTCN2018074689-appb-000036
测试原理：
RNA多聚化合成过程中，焦磷酸(PPi)被释放出来：(RNA) n+NTP→(RNA) n+1+PPi。在焦磷酸酶的催化作用下，PPi被转化成Pi。Pi和MESG酶促反应后产物在360nm处具有最大吸收峰。
试剂及材料:
HCV-RNA聚合酶NS5B(Prospec Cat#HCV-269)；焦磷酸盐活性检测试剂盒(AnaSpec Cat#E-6645)；sofosbuvir(Gilead Cat#HY-15005)；测试化合物；CDDO-Me
实验步骤：
(1)、加入20mL去离子水至MESG酶底物(ComponentA)中，制成1mM的储存液，分装后储存于-20℃冰箱中；用前将分装好冻存的MESG酶底物储存液放入37℃快速溶解(不超过5min)，涡旋震荡，放于冰上。
(2)、加入0.2mL去离子水至无机焦磷酸酶(Component E)中，制成30U/mL的储存液,4℃保存。
(3)、加入0.5mL去离子水至嘌呤核酸磷酸化酶(Component B)中，制成100U/mL的储存液,4℃保存。
(4)、添加100μLRNA聚合反应缓冲液(20mM Hepes,pH 7.1,7.5mM DTT,60mMNacl,100μg/mL BSA,20U/mL RNAsin,50μg/mLPoly C,5μg/mL Oligo G 12,10μM GTP)和HCV-RNA聚合酶NS5B(500μg/mL)，30℃孵育1h。
(5)、添加23μL去离子水至新的96孔板中，然后依次加入5μL 20×反应缓冲液(Component C)，20μL MESG酶底物储存液,1μL嘌呤核酸磷酸化酶储存液，1μL无机焦磷酸酶储存液，22℃孵育10min。
(6)、吸取步骤4反应液50μL添加至步骤5的96孔板中，混合均匀后22℃孵育30～60min。
(7)、在酶标仪上读取360nm吸光值。
实施例17
测试齐墩果型酰胺类化合物和ledipasvir(阳性对照)的HCV蛋白酶体的IC 50，结果如下表3：
表3
Figure PCTCN2018074689-appb-000037
测试原理：
HCVNS3-4A蛋白酶可以在多个位点如NS3-4A，NS4A-4B,NS4B-5A和NS5A-5B处切割病毒的非结构多肽产物，而这些切割对于丙肝病毒蛋白的成熟是必不可少的。荧光能量共振转移(FRET)肽序列含有NS4A-4B切割位点。在HCVNS3-4A蛋白酶作用下，FRET肽被切为EDANS/DABCYL两段,致使被DABCYL淬火的EDANS荧光得以恢复(参见图30)。通过检测ex/em＝340nm/490nm荧光强度的变化，可以检测HCVNS3-4A蛋白酶活性。
试剂及材料:
HCV NS3-4A蛋白酶(AnaSpec Cat#61017)；HCV蛋白酶活性检测试剂盒(AnaSpec Cat#AS-72087)；ledipasvir(Gilead  Cat#HY-15602)；测试化合物；CDDO-Me
实验步骤：
(1)、制备分析缓冲液：添加5mL2×分析缓冲液(Component C)和300μL DTT(Component E)至4.7mL去离子水，制成10mL 1×分析缓冲液。
(2)、添加100μLHCV NS3-4A蛋白酶底物(50×,ComponentA)至4.9mL 1×分析缓冲液中，制成5mL HCV NS3-4A蛋白酶底物溶解液。
(3)、用DMSO溶解的测试化合物、CDDO-Me、ledipasvir(储存液浓度10mM/L)加无血清培养基序列稀释9个浓度梯度100、50、25、12.5、6.25、3.13、1.56、0.78、0.39uM/L，每孔40μL加入到96孔板，再加入10μL HCV NS3-4A蛋白酶至上述稀释液中，使其终浓度为20ng/孔，37℃孵育10～15min；同时设置HCVNS3-4A蛋白酶阳性对照、HCVNS3-4A蛋白酶底物对照。
(4)、加入50μLHCVNS3-4A蛋白酶底物溶解液至前述稀释液中，室温下轻轻震荡30～60min混匀。
(5)、避光加入50μL终止液(Component D)后，用荧光酶标仪检测ex/em＝340nm/490nm荧光强度的变化。
实施例18
测试齐墩果型酰胺类化合物和顺铂(阳性对照)对癌细胞IC50
肝癌(HepG-2/Huh7)，肺癌(A549)，喉癌(Hep2)，食道癌(Eca-109/K450/510/TE-1)
表4
Figure PCTCN2018074689-appb-000038
实验原理：
MTT广泛应用于细胞增殖和细胞毒性的检测。MTT为黄色化合物，是一种接受氢离子的燃料，可以被线粒体内的一些脱氢酶还原成结晶状的深紫色产物formazan，在特定溶剂存在的情况下，可以被完全溶解。该产物在570nm处具有最大吸收峰。细胞增殖越多越快，则吸光度越高；细胞毒性越大，则吸光度越低。
测试材料：
肝癌(HepG-2/Huh7)，肺癌(A549)，喉癌(Hep2)，食道癌(Eca-109/K450/510/TE-1)等呼吸和消化系统癌为主的癌细胞细胞株；10％的胎牛血清；1％双抗(青霉素、链霉素)的DMEM(Gbico)培养基；细胞消化液(胰酶0.25％；EDTA0.02％)；1％双抗(青霉素、链霉素)的DMEM(Gbico)培养基；测试化合物(A1/A4/OAH2-1/OAH2-1-C/OAH2-2/OAH2-2-C)；CDDO-Me；ledipasvir(Gilead Cat#HY-15602)；96孔板；多功能酶标仪；细胞培养箱。
实验步骤：
(1)铺板：培养瓶内生长良好的肝癌，肺癌，胃癌，食道癌等呼吸和消化系统癌为主的癌细胞细胞株长至80％左右时用细胞消化液消化，细胞以6000个/孔、100μL/孔铺于96孔板，放置于37℃、5％CO 2培养箱培养过夜至贴壁。
(2)加药。用少量DMSO溶解的测试化合物/B类化合物、CDDO-Me、地塞米松样品(储存液浓度10mM/L)样品加无血清培养基序列稀释9个浓度梯度，加药浓度分别为100、50、25、12.5、6.25、3.13、1.56、0.78、0.39uM/L，设置一组DMSO、细胞以及空白对照组，每组5个复孔。将96孔板原培养基弃去，加入不同浓度梯度的测试化合物，DMSO以及空白培养基。放置于培养箱培养过夜。
(3)加MTT。加药24小时后，96孔板每孔加10μLMTT(5mg/mL)。后用锡箔纸包好放培养箱培养4小时。
(4)加DMSO。加MTT4小时后，将96孔板中培养基小心吸出弃去，后每孔加入100μL DMSO。加完DMSO后，将96孔板包好放于摇床摇10分钟左右后于酶标仪570-630nm波长进行测板。
(5)空白组只含有培养基，对照组是正常培养的细胞组。抑制率＝(实验组A570nm-空白组A570nm)/(对照A570nm-空白组A570nm)。
实施例19
测试齐墩果型酰胺类化合物和Ledipasvir(阳性对照)对肝细胞株(LO-2/HL-7702)和肾细胞株(293T/HK-2)IC 50。
表5
Figure PCTCN2018074689-appb-000039
Figure PCTCN2018074689-appb-000040
实验原理：
MTT广泛应用于细胞增殖和细胞毒性的检测。MTT为黄色化合物，是一种接受氢离子的燃料，可以被线粒体内的一些脱氢酶还原成结晶状的深紫色产物formazan，在特定溶剂存在的情况下，可以被完全溶解。该产物在570nm处具有最大吸收峰。细胞增殖越多越快，则吸光度越高；细胞毒性越大，则吸光度越低。
试剂及材料:
肝细胞(LO-2/HL-7702)和肾细胞株(293T/HK-2)；10％的南美/胎牛血清；细胞消化液(胰酶0.25％；EDTA0.02％)；1％双抗(青霉素、链霉素)的1640/DMEM(Gbico)培养基；测试化合物；CDDO-Me；ledipasvir(Gilead Cat#HY-15602)；96孔板；多功能酶标仪；细胞培养箱。
实验步骤：
(1)铺板：培养瓶内生长良好的肝或肾细胞长至80％左右时用细胞消化液消化，细胞以4000个/孔、200μL/孔铺于96孔板，放置于37℃、5％CO 2培养箱培养过夜至贴壁。
(2)加药。用少量DMSO溶解的测试化合物、CDDO-Me、地塞米松样品(储存液浓度10mM/L)样品加无血清培养基序列稀释10个浓度梯度，加药浓度分别为200、100、50、25、12.5、6.25、3.13、1.56、0.78、0.39μM/L，设置一组乙酸乙酯组(浓度为20μL/mL)以及空白对照组，每组四个复孔。将96孔板原培养基弃去，加入不同浓度梯度的测试化合物，乙酸乙酯以及空白培养基。放置于培养箱培养过夜。
(3)加MTT。加药24小时后，96孔板每孔加10μLMTT。后用锡箔纸包好放培养箱培养4小时。
(4)加DMSO。加MTT 4小时后，将96孔板中培养基小心吸出弃去，后每孔加入100μL DMSO。加完DMSO后，将96孔板包好放于摇床摇10分钟左右后于酶标仪570nm波长进行测板。
(5)空白组只含有培养基，对照组是正常培养的细胞组。抑制率＝(实验组A570nm-空白组A570nm)/(对照A570nm-空白组A570nm)
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

Claims (11)

  1. 一种化合物，其特征在于，其化学结构式如式I所示：
    Figure PCTCN2018074689-appb-100001
    其中，所述R 1为氢；
    所述R 2为2-甲基-2-羟基丙基、N,N-二甲基胺乙基、R 3-(C＝O)-CH 2-中任意一种；所述R 3选自氨基、C 1-C 12的直链、环状和支链的脂肪胺基、C 1-C 12的取代或者未取代的芳香胺基、C 5-C 8的取代或者未取代的氮杂芳基中任意一种。
  2. 根据权利要求1所述的化合物，其特征在于，所述R 3选自氨基、C 1-C 12的直链、环状和支链的脂肪胺基中任意一种。
  3. 根据权利要求2所述的化合物，其特征在于，所述R 3选自氨基、C 1-C 4的直链、环状和支链的脂肪胺基中任意一种。
  4. 根据权利要求3所述的化合物，其特征在于，所述R 3选自环丙胺基、异丙胺基、异丁胺基、N,N-二甲基胺基、正丙胺基、正丁胺基、氨基、甲基氨基中任意一种。
  5. 根据权利要求1所述的化合物，其特征在于，所述化合物为下列化合物中任意一种：
    Figure PCTCN2018074689-appb-100002
    Figure PCTCN2018074689-appb-100003
  6. 一种合成权利要求1～4任意一项所述的化合物的方法，其特征在于，包括以下步骤：
    Figure PCTCN2018074689-appb-100004
    (1)0℃下，将如结构式III所示的化合物用二氯甲烷或氯仿溶解；
    (2)向步骤(1)所得溶液中加入N,N'-羰基二咪唑后反应1-3小时；
    (3)将胺类化合物用二氯甲烷溶解后，加入三乙胺，-1至-5℃下加入步骤(2)所得的反应液中，常温下反应12～18小时，即可制备出入结构式II所示的化合物；
    其中，所述胺类化合物与结构式III所示的化合物的摩尔比为3～5:1；N,N'-羰基二咪唑与结构式III所示的化合物的摩尔比为1～2:1；所述三乙胺与结构式III所示的化合物的摩尔比为2～3:1。
  7. 一种权利要求1～5任意一项所述的化合物在制备抗癌药物、抗炎症药物中的用途。
  8. 根据权利要求7所述的化合物在制备抗癌药物、抗炎症药物中的用途，其特征在于，所述癌症为肝癌、肺癌、喉癌和食道癌。
  9. 根据权利要求7所述的化合物在制备抗癌药物、抗炎症药物中的用途，其特征在于，所述炎症为诱导型一氧化氮合成酶高表达所引发的炎症。
  10. 一种权利要求1～5任意一项所述的化合物在制备治疗丙肝的药物中的用途。
  11. 一种含有权利要求1～5任意一项所述的化合物或其药学上可接受的盐的药物组合物。
PCT/CN2018/074689 2016-12-07 2018-01-31 一种化合物、其制备方法及用途 Ceased WO2018103766A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201611115899.7 2016-12-07
CN201611115899.7A CN106632574B (zh) 2016-12-07 2016-12-07 一种化合物、其制备方法及用途

Publications (1)

Publication Number Publication Date
WO2018103766A1 true WO2018103766A1 (zh) 2018-06-14

Family

ID=58819007

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/074689 Ceased WO2018103766A1 (zh) 2016-12-07 2018-01-31 一种化合物、其制备方法及用途

Country Status (2)

Country Link
CN (1) CN106632574B (zh)
WO (1) WO2018103766A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116410257A (zh) * 2023-03-09 2023-07-11 汕头大学医学院 一种具有聚集诱导发光中心的化合物及其制备方法与应用

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632574B (zh) * 2016-12-07 2018-05-29 广东天键生物科技有限公司 一种化合物、其制备方法及用途
CN107540722A (zh) * 2017-09-29 2018-01-05 广东天键生物科技有限公司 一种c13‑c18位双键齐墩果酸型化合物、其制备方法及其用途
CN107674109A (zh) * 2017-09-29 2018-02-09 广东天键生物科技有限公司 一种c13位羟基或甲氧基齐墩果型类化合物、制备方法及其用途
CN113135976A (zh) * 2021-04-22 2021-07-20 中国药科大学 Cddo衍生物及其制备方法与医药用途
CN113234053B (zh) * 2021-05-30 2022-12-20 吉林农业大学 裂环羽扇豆烷衍生物及在制备ask1抑制剂中的应用
CN120349366A (zh) * 2025-03-07 2025-07-22 国科大杭州高等研究院 五环三萜类衍生物、制备方法及其医药用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014040056A1 (en) * 2012-09-10 2014-03-13 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
WO2015027206A1 (en) * 2013-08-23 2015-02-26 Reata Pharmaceuticals, Inc. Methods of treating and preventing endothelial dysfunction using bardoxololone methyl or analogs thereof
US20150225352A1 (en) * 2014-02-11 2015-08-13 Trustees Of Dartmouth College Cddo-me amino acid conjugates and methods of use
CN106632574A (zh) * 2016-12-07 2017-05-10 广东天键生物科技有限公司 一种化合物、其制备方法及用途

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071632B2 (en) * 2008-04-18 2011-12-06 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: novel derivatives of oleanolic acid
CN102872025A (zh) * 2012-10-26 2013-01-16 江西农业大学 齐墩果酸在制备抗丙型肝炎病毒药物和试剂中的应用
CN103788166A (zh) * 2012-10-30 2014-05-14 中国药科大学 △13（18）-cddo衍生物、其制备方法与在制药中的用途
CN104861027A (zh) * 2014-02-24 2015-08-26 上海兰蒂斯生物医药科技有限公司 新型齐墩果酸衍生物、其制备方法及其应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014040056A1 (en) * 2012-09-10 2014-03-13 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
WO2015027206A1 (en) * 2013-08-23 2015-02-26 Reata Pharmaceuticals, Inc. Methods of treating and preventing endothelial dysfunction using bardoxololone methyl or analogs thereof
US20150225352A1 (en) * 2014-02-11 2015-08-13 Trustees Of Dartmouth College Cddo-me amino acid conjugates and methods of use
CN106632574A (zh) * 2016-12-07 2017-05-10 广东天键生物科技有限公司 一种化合物、其制备方法及用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AI, YONG: "Synthesis of CDDO-Amino Acid-Nitric Oxide Donor Trihybrids as Potential Antitumor Agents against Both Drug-Sensitive and Drug-Resistant Colon Cancer", J. MED. CHEM., vol. 58, no. 5, 12 February 2015 (2015-02-12), pages 2452 - 2464, XP055613043 *
EVANS ONYANGO: "Synthesis and biological evaluation of amino acid me- thyl ester conjugates of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid against the production of nitric oxide (NO", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 24, no. 2, 15 December 2013 (2013-12-15), pages 532 - 534, XP055613048 *
MARK M. YORE: "The synthetic triterpenoid 1-[2-cyano-3, 12-dioxoolea- na-1, 9(11)-dien-28-oyl]imidazole blocks nuclear factor-KB activation throu- gh direct inhibition of IKB kinase B", MOLECULAR CANCER THERAPEUTICS, 5 December 2006 (2006-12-05) *
TADASHI HONDA: "Design, Synthesis, and Biological Evaluation of Biotin Conjugates of 2-Cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic Acid for the Isolation of the Protein Targets", J. MED. CHEM., vol. 47, no. 20, 18 August 2004 (2004-08-18), pages 4924, XP002537851 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116410257A (zh) * 2023-03-09 2023-07-11 汕头大学医学院 一种具有聚集诱导发光中心的化合物及其制备方法与应用

Also Published As

Publication number Publication date
CN106632574A (zh) 2017-05-10
CN106632574B (zh) 2018-05-29

Similar Documents

Publication Publication Date Title
WO2018103766A1 (zh) 一种化合物、其制备方法及用途
CZ285104B6 (cs) Deriváty kyseliny žlučové, způsob jejich přípravy a použití těchto sloučenin jako léčiv
WO2018010202A1 (zh) 一种抗肿瘤药物三元偶联物及合成和应用
CN117679529A (zh) 核酸适配体-多价药物偶联物及其制备方法与应用
CN111646941A (zh) 一种磺酰胺类衍生物及其制备方法和应用
CN107721975A (zh) 具有抗肿瘤活性的brd4小分子抑制剂、合成方法及其应用
CN104045680B (zh) 桦木醇的乙酰氨基酸酰类衍生物及其制备方法
CN104817568B (zh) 5,6‑双脱氢去甲斑蝥醇衍生物及其抗肿瘤应用
CN106046105A (zh) 一种甘草次酸、阿魏酸和硒代蛋氨酸三元化合物的制备方法及应用
CN115010658A (zh) 一种化合物及其制备方法与应用
CN114874281A (zh) 一种齐墩果酸衍生物及其制备方法与应用
WO2025223438A1 (zh) 新型青蒿琥酯-氨基酸-靶向基团衍生物及纳米制剂和应用
CN111393318B (zh) 一种粉背蕨酸酰胺衍生物的合成及其在抗肿瘤药物中的应用
CN113651683A (zh) 一种萘嵌苯酮类化合物及其应用
CN117143091B (zh) 基于疏水标签技术的hbv核心蛋白降解剂及其制备方法与应用
CN103232509B (zh) 氟尿嘧啶类化合物、其制备方法及其应用
CN117338777A (zh) 靶向IKKε激酶抑制剂及其在抗肿瘤药物中的应用
CN109761915B (zh) 靶向mct1转运体的5-氟尿嘧啶成酯前药
CN110041239B (zh) N-(苯甲酰基)-l-半胱氨酸甲酯类衍生物及其制备方法和用途
CN115215771A (zh) 和厚朴酚衍生物及制备方法和在制备抗肿瘤药物中的应用
CN109400597B (zh) 一种基于vegfr-2抑制剂abt-869的蛋白降解靶向嵌合体及制备方法和应用
Li et al. Small molecule PZL318: forming fluorescent nanoparticles capable of tracing their interactions with cancer cells and activated platelets, slowing tumor growth and inhibiting thrombosis
CN105218377B (zh) 一种羟基酪醇no供体衍生物及其制备方法和应用
CN106243063B (zh) 一种西红花酸衍生物gx-d及其制备方法、以及在预防或治疗心脑血管疾病中的应用
CN118290341B (zh) 一种具有抗肿瘤活性的脲类化合物、制备方法及应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18729009

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 13/08/2019)

122 Ep: pct application non-entry in european phase

Ref document number: 18729009

Country of ref document: EP

Kind code of ref document: A1