WO2020253814A1 - 一类雷公藤红素衍生物、其制备方法及用途 - Google Patents

一类雷公藤红素衍生物、其制备方法及用途 Download PDF

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WO2020253814A1
WO2020253814A1 PCT/CN2020/097028 CN2020097028W WO2020253814A1 WO 2020253814 A1 WO2020253814 A1 WO 2020253814A1 CN 2020097028 W CN2020097028 W CN 2020097028W WO 2020253814 A1 WO2020253814 A1 WO 2020253814A1
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alkyl
coora
nhc
alkynyl
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张翱
罗成
丁春勇
张豪
徐珩
李阳
蒋华良
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中国科学院上海药物研究所
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

Definitions

  • the invention relates to a class of tripterygium wilfordii derivatives, a preparation method thereof and their use in the preparation of peroxidase inhibitors and drugs for the preparation of anti-tumor diseases.
  • Peroxidoreductase family is a type of antioxidant enzymes in cells, which maintain the balance of intracellular hydrogen peroxide levels, remove reactive oxygen species (ROS) and other functions, and are important for intracellular signal transduction and cell metabolism. Regulation. Peroxidase-1 (Prdx1) is a type of protease in the Prdx family. It is composed of homodimers containing conserved cysteine residues at the C-terminus and N-terminus. Its crystal structure is five dimers. Composition of ring complex. Prdx1 has a variety of biological functions, including antioxidant function, molecular chaperone function, and inflammation and tumor cell regulation functions. Prdx1 is widely distributed in the cytoplasm and nucleus.
  • Prdx1 In the cytoplasm, Prdx1 participates in the removal of reactive oxygen species and interacts with a variety of kinases to prevent cell apoptosis due to oxidative stress. In the nucleus, Prdx1 mainly acts as a molecular chaperone to regulate gene expression and affect tumor cell growth.
  • Prdx1 mainly produces different physiological functions by regulating the level of active oxygen in the body. When Prdx1 is inhibited, ROS levels increase, which inhibits the formation of proximal tubules and hinders the development of the pre-kidney during embryonic stage. Studies have reported that Prdx1 maintains the level of corpus luteum in mice by regulating the UPR signaling pathway; female mice knocked out of Prdx1 have increased ROS levels in the body, leading to a significant decrease in the level of corpus luteum. In addition, Prdx1 indirectly affects tumor signaling pathways related to ROS by regulating ROS signaling.
  • Prdx1 inhibits cell apoptosis by inhibiting the activation of ASK1/JNK and ASK1/p38MAPK signaling pathways. During oxidative stress, Prdx1 binds to the thioredoxin domain of ASK1 to form a complex, which inhibits the activity of ASK1 and downstream signal transduction, and inhibits cell apoptosis. In summary, Prdx1 can be used as a drug target for the treatment of peroxidase-1 related diseases.
  • Tripterygium wilfordii (celastrol) is a triterpenoid compound extracted from the root of the natural plant Tripterygium wilfordii. It has a variety of pharmacological activities, including anti-inflammatory, antioxidant, and anti-tumor effects. However, the mechanism of action of this natural product is complicated and the target is not clear. Although there are reports in the literature that heat shock protein 90 is its target, its activity is weaker, and the more active target needs to be further clarified.
  • Tripterygium wilfordii has Prdx1 inhibitory effect.
  • the inventors synthesized a series of derivatives of tripterygium wilfordii and tested the Prdx1 inhibitory activity of these derivatives. The results showed that these compounds all have significant Prdx1 inhibitory activity. This completes the present invention.
  • the present invention provides a tripterygium wilfordii derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the same, and its use in the preparation of a Prdx1 inhibitor and in preparation for treatment or prevention Prdx1 related diseases, especially the use of drugs for tumor growth and metastasis.
  • the triptorubin derivative of the present invention has a structure as shown in formula I:
  • R 1 and R 2 are each independently hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, three to six membered heterocycloalkyl, halogenated C1-C3 alkyl (such as three (Fluoromethyl, difluoromethyl), C2-C3 alkenyl, C2-C3 alkynyl, cyano, amide, -COORa, etc.; more preferably, R 1 and R 2 are each independently hydrogen, C1-C3 Alkyl, halogenated C1-C3 alkyl (for example, trifluoromethyl, difluoromethyl), C2-C3 alkenyl,
  • Y is oxygen
  • Z is selected from oxygen or sulfur
  • hydroxymethyl hydroxymethyl
  • amino, halo C1-C3 alkyl e.g. Trifluoromethyl, difluoromethyl
  • hydroxy-substituted C1-C3 alkoxy C2-C3 alkenyl, C2-C3 alkynyl, cyano, -COORa, amide, carbamate, ether , Thioether group, carboxylic acid group, C6-C10 aryl group, halogen, etc.
  • C1-C3 alkyl substituted with one, two or more substituents such as halogenated C1-C3 alkyl, such as trifluoromethyl Group, difluoromethyl, etc.
  • C3-C6 cycloalkyl, three- to six-membered heterocycloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, ether group, thioether group, -COORa, amide group , -NHC( NH)NH 2 , -NHC(S)NH 2 etc.;
  • R 4 and R 5 together with the carbon to which they are connected form a C3-C6 cycloalkyl group, a three- to six-membered heterocyclic group, etc.;
  • R 3 is connected with one of R 4 and R 5 to form a substituted or unsubstituted three- to six-membered N-containing heterocyclic group, and the substituted substituent is one or two selected from the group consisting of hydroxyl and C1-C3 alkyl.
  • One or more substituents; the other of R 4 and R 5 is as defined above, preferably hydrogen;
  • R 6 is -COORa, amido, amino, halogen, C1-C6 alkyl, etc., or C1-C3 alkyl substituted by halogen, hydroxyl, hydroxy (for example, hydroxymethyl), amino, halogenated C1-C3 Alkyl (e.g.
  • C1-C6 alkyl substituted with one, two or more substituents, C3-C6 cycloalkyl, three To six-membered heterocycloalkyl, C-C6 alkenyl, C2-C6 alkynyl, ether, thioether, -COORa, amide, -NHC( NH)NH 2 , -NHC(S)NH 2 Etc.; preferably hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, three- to six-membered heterocycloalkyl, halogenated C1-C3 alkyl (such as trifluoromethyl, difluoromethyl, etc.), C2-C3 alkenyl, C2-3 alkynyl, cyano, amide, -COORa, etc.;
  • Ra is a C1-C6 alkyl group.
  • Z is oxygen
  • R 7 , R 8 and R 9 are hydrogen.
  • C1-C6 alkyl refers to a linear or branched saturated aliphatic hydrocarbon group containing 1-6 carbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert Butyl, sec-butyl, etc.;
  • C3-C6 cycloalkyl refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents containing 3-6 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, etc., polycyclic cycloalkanes Groups include spirocyclic, fused ring and bridged cycloalkyl;
  • a three- to six-membered heterocycloalkyl group refers to a saturated or unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which includes 3 to 6 ring atoms, one or more of which is selected from nitrogen, oxygen, Sulfur heteroatoms, such as oxirane, propylene oxide, pyrrolidinyl, tetrahydrofuranyl, dihydroimidazolyl, etc.;
  • C2-C6 alkenyl refers to a hydrocarbon group with one less hydrogen atom in an olefin molecule containing 2-6 carbons, such as vinyl, propenyl, allyl, etc.;
  • C2-C6 alkynyl refers to a hydrocarbyl substituent containing 2-6 carbons and a carbon-carbon triple bond, such as ethynyl, propynyl, propargyl, etc.;
  • Amido group refers to a compound containing a -C(O)NR 1 R 2 group, such as -CONH 2 , -CONHCH 3 etc.;
  • the ether group refers to a compound containing -(CH 2 ) m O(CH 2 ) n CH 3 , where m and n are each independently an integer of 1-6, for example, -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 2 CH 3 etc.;
  • the thioether group refers to a compound containing -(CH 2 ) m S(CH 2 ) n CH 3 , where m and n are each independently an integer of 1-6, for example, -CH 2 SCH 2 CH 3 , -CH 2 CH 2 SCH 2 CH 3 etc.;
  • the carbamate group refers to a compound containing -NHC(O)R 1 , such as -NHCOOCH 3 , -NHCOOC(CH 3 ) 3 ;
  • Carboxy refers to -C(O)OH
  • C6-C10 aryl refers to a 6 to 10-membered all-carbon monocyclic or fused polycyclic ring (rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, such as phenyl and naphthyl;
  • a three- to six-membered N-containing heterocyclic group refers to a saturated or unsaturated monocyclic cyclic substituent containing 1 to 3 N atoms, such as tetrahydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, piper Ridinyl, piperazinyl, etc.
  • Halogen refers to F, Cl, Br, I.
  • Typical compounds of the present invention include but are not limited to the following compounds:
  • Another aspect of the present invention provides a method for preparing the above-mentioned triptorubin derivative according to the present invention
  • R3, R4, R5, R6, R7, R8, R9, X, Y, Z are defined as described above,
  • the method includes the following steps:
  • Step 1 The compound represented by formula 1 undergoes a curtius rearrangement reaction to produce the compound represented by formula 2.
  • the reaction can be carried out in the presence of, for example, diphenyl azide phosphate, the reaction time is, for example, 3 hours, and the reaction temperature is, for example, 100°C ;
  • Step 2 The compound represented by formula 2 is coupled with the compound represented by formula 3 to produce the compound represented by formula I; the reaction can be carried out in the presence of, for example, Pd2(dba) 3 , tBu-Xphos, and potassium carbonate. Reaction time For example, it is 3 hours, and the reaction temperature is 80 degreeC, for example.
  • the compounds according to the present invention and their pharmaceutically acceptable salts may also include stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, and racemates. It exists in the form of variants such as polymorphs, solvates or isotopically-labeled compounds, and these variants are also included in the scope of the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more selected from the group consisting of triptorubin derivatives represented by formula I and their pharmaceutically acceptable salts.
  • the above composition further contains pharmaceutically acceptable excipients.
  • the present invention also provides the use of the above-mentioned triptorubin derivative or a pharmaceutically acceptable salt thereof according to the present invention in the preparation of a peroxidase 1 inhibitor or in preparation for prevention or treatment with peroxidase 1 Related diseases, especially the use of drugs for tumor growth and metastasis.
  • the present invention also provides a method for inhibiting the activity of Prdx1 or preventing or treating diseases related to peroxidase 1, especially tumor growth and metastasis, the method comprising administering to a subject a therapeutically effective amount of the compound represented by formula I The compound, or a pharmaceutically acceptable salt thereof.
  • the diseases related to peroxidase 1 refer to diseases whose occurrence or progression is related to the peroxidase 1 signaling pathway, including inflammation, cancer, obesity, and diabetes.
  • the tumor includes leukemia, rectal cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, and melanoma.
  • Figure 1 shows the survival curve corresponding to each compound
  • Figure 2 shows the effect of each compound on the weight change of mice, where M stands for mouse, and the serial number after M is the mouse number.
  • each compound including tripterygium wilfordii (CEL) and compound S1-S13 was incubated with peroxidoreductase PRDX1 for 25 minutes at 37°C, and then 20mM HEPES, pH 7.0, 5mM EDTA, 5 ⁇ M cofactor protein A, 2 ⁇ M cofactor protein B, 300 ⁇ M NADPH mixed with pre-reaction buffer and transferred to a 96-well assay plate (volume of 120 ⁇ L per well), and then add the target protein incubated with the compound to the assay plate (the final protein concentration is 200nM, each The pore volume is 40 ⁇ l), and finally 40 ⁇ L 200 ⁇ M hydrogen peroxide is added to the system to start the enzymatic reaction cycle.
  • CEL tripterygium wilfordii
  • PRDX1 peroxidoreductase
  • the absorbance at 340nm was used to detect the oxidation of NADPH.
  • the reading of the test board is cycled every 90 seconds, and the reading is performed at least 20 cycles.
  • the initial linear part of the reading is used to characterize the NADPH consumption rate in the system, which can indirectly reflect the hydrogen peroxide consumption rate.
  • Table 1 shows the PRDX1 enzyme inhibitory activities of natural product CEL and compounds S1-S13. Compared to CEL, most of the compounds showed enhanced activity.
  • Experimental method Use 50 ⁇ L 1640+10% FBS medium to seed 5000 NB4 cells in each well in a 96-well flat bottom plate.
  • the compound was first dissolved in DMSO into a 20mM stock solution, and then diluted 3 times with 1640+10% FBS medium from a final concentration of 10 ⁇ M down to a total of 9 concentration points, each concentration point was set to three replicates. After the compound and the cells were incubated for 72 hours, the cell-titer glo of Promega was used to detect the number of cells in each well and graphpad prism 5.0 was used to fit the NB4 cell proliferation inhibition curve of each compound.
  • Table 1 shows the inhibitory activities of natural products CEL and compounds S1-S13 on the proliferation of NB4 cells. Most of the compounds have strong cell proliferation inhibitory activity with nanomolar IC50 values.
  • each compound including triptolide (CEL) and compound S1-S13 were incubated with peroxidoreductase PRDX family member protein PRDX2-PRDX6 for 25 minutes at 37°C, and then 20mM HEPES, pH7.0, 5mM EDTA, 5 ⁇ M cofactor protein A, 2 ⁇ M cofactor protein B, 300 ⁇ M NADPH were mixed with pre-reaction buffer and transferred to a 96-well assay plate (each well volume 120 ⁇ L), and then the target protein ( The final protein concentration is PRDX2: 2 ⁇ M, PRDX3: 0.3 ⁇ M, PRDX4: 0.9 ⁇ M, PRDX5: 0.1 ⁇ M, PRDX6: 10 ⁇ M, the volume of each well is 40 ⁇ L), finally add 40 ⁇ L 200 ⁇ M hydrogen peroxide to the system to start the enzymatic reaction cycle .
  • PRDX2 2 ⁇ M
  • PRDX3 0.3 ⁇ M
  • PRDX4 0.9 ⁇ M
  • PRDX5
  • the absorbance at 340nm was used to detect the oxidation of NADPH.
  • the reading of the test board is cycled every 90 seconds, and the reading is performed at least 20 cycles.
  • the initial linear part of the reading is used to characterize the NADPH consumption rate in the system, which can indirectly reflect the hydrogen peroxide consumption rate.
  • Three concentration points were set for small molecule incubation of PRDX family member protein PRDX2-PRDX6, respectively 30 ⁇ M, 10 ⁇ M, 3 ⁇ M.
  • Table 2 The data shown in Table 2 is the half concentration value of each compound inhibiting enzyme activity. Compared with triptorubin, compounds S1-S13 have better selectivity for PRDX1 in the PRDX1-6 family.
  • mice 6-week-old FVB mice were used, and each compound was administered to two males and two females. Use a high-energy linear acceleration irradiator to irradiate 4.5Gy radiation before administration. Each compound was administered by intraperitoneal injection at two concentrations, the low concentration was 5 mg/kg and the high concentration was 10 mg/kg. Observe the weight and survival of the mice for 15 days after one administration.
  • the survival curve suggests (Figure 1) that the acute toxicity of compounds S1, S5 and S6 is significantly less than that of triptorubin. Among them, when 5 mg/kg was administered, the compounds S1 and S5 did not die in 15 days; while on the sixth day, the mice had all died of triptorubin.

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Abstract

本申请涉及一类式I所示的雷公藤红素衍生物、其制备方法及用途，所述雷公藤红素衍生物具有显著的Prdx1抑制活性，可以用于预防或治疗生物体内与过氧化物酶1相关的疾病，尤其是用于预防或治疗肿瘤生长与转移。(I)

Description

一类雷公藤红素衍生物、其制备方法及用途 技术领域
本发明涉及一类雷公藤红素衍生物、其制备方法及其在制备过氧化物酶抑制剂和在制备抗肿瘤等疾病的药物中的用途。
背景技术:
过氧化还原蛋白酶家族(Prdx)是细胞中的一类抗氧化酶，具有维持细胞内过氧化氢水平的平衡，清除活性氧簇(ROS)等功能，对细胞内信号转导以及细胞代谢具有重要调控作用。过氧化物酶-1(Prdx1)是Prdx家族中的一类蛋白酶，由C端和N端含有保守的半胱氨酸残基的同源二聚体组成，其晶体结构为五个二聚体组成的环形复合物。Prdx1具有多种生物学功能，包括抗氧化功能，分子伴侣功能，以及炎症和肿瘤细胞调控等功能。Prdx1广泛分布在细胞质及细胞核内。在细胞质内，Prdx1参与清除活性氧簇，与多种激酶相互作用，防止细胞因氧化应激而凋亡；细胞核内，Prdx1主要起分子伴侣作用，调控基因表达，影响肿瘤细胞生长。
Prdx1主要通过调节体内活性氧的水平产生不同生理功能。Prdx1受到抑制时，ROS水平升高，抑制了近端小管的形成，阻碍胚胎期前肾的发育。有研究报道Prdx1通过调节UPR信号通路维持小鼠体内黄体水平；Prdx1敲除的雌鼠，体内ROS水平上升，导致黄体水平显著下降。此外，Prdx1通过调节ROS信号间接影响与ROS有关的肿瘤信号通路。Prdx1抑制细胞凋亡是通过抑制ASK1/JNK和ASK1/p38MAPK信号通路的活化实现的。氧化应激时，Prdx1与ASK1的硫氧蛋白结构域结合形成复合物，抑制了ASK1的活性及下游信号的传导，抑制细胞凋亡。综上所述，Prdx1可作为药物靶点用于与过氧化物酶1相关疾病的治疗。
Figure PCTCN2020097028-appb-000001
雷公藤红素(celastrol)是从天然植物雷公藤的根部提取的三萜类化合物，具有多种药理学活性，包括抗炎，抗氧化，抗肿瘤等功效。然而，该天然天然产物作用机制复杂，靶点不明确，尽管有文献报道热休克蛋白90是其靶点，但活性较弱，更强活性的靶点有待进一步阐明。
发明内容
目前，尚未有报道显示雷公藤红素具有Prdx1抑制作用。本发明人合成了一系列雷公藤红素衍生物，并对这些衍生物的Prdx1抑制活性做了测试，结果显示，这类化合物均具有显著的Prdx1抑制活性。由此完成了本发明。
本发明提供了一种雷公藤红素衍生物或其药学上可接受的盐、其制备方法，包含其的药物组合物，及其用于制备Prdx1抑制剂的用途和在制备用于治疗或预防与Prdx1相关的疾病，尤其是肿瘤生长与转移的药物中的用途。
本发明所述的雷公藤红素衍生物具有如式I所示的结构：
Figure PCTCN2020097028-appb-000002
其中
X为-O-R 1或-NR 1R 2，其中R 1和R 2各自独立地为氢、C1-C6烷基、C3-C6环烷基、三至六元杂环烷基、C2-C6烯基、C2-C6炔基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2等，或被选自羟基、羟基取代的C1-C3烷基(例如羟甲基)、氨基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素等中的一个、两个或更多个取代基取代的C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、醚基、硫醚基、-COORa、酰胺基、-NHC(＝NH)NH 2或-NHC(S)NH 2等；优选地，R 1和R 2各自独立地为氢、C1-C3烷基、C3-C6环烷基、三至六元杂环烷基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、C2-C3烯基、C2-C3炔基、氰基、酰胺基、-COORa等；更优选地，R 1和R 2各自独立地为氢、C1-C3烷基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、C2-C3烯基、C2-C3炔基、氰基等；
Y为氧；
Z选自氧或硫；
R 3为氢、C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2等，或被选自羟基、羟基取代的C1-C3烷基(例如羟甲基)、氨基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、C2-C6烯 基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素等中的一个、两个或更多个取代基取代的C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、醚基、硫醚基、-COORa、酰胺、-NHC(＝NH)NH 2或-NHC(S)NH 2等；优选为氢、C1-C3烷基、C3-C6环烷基、三元至六元杂环烷基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、C2-C3烯基、C2-C3炔基、氰基、酰胺基、-COORa等；
R 4和R 5各自独立地为氢、C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2等，或被选自羟基、羟基取代的C1-C3烷基(例如羟甲基)、氨基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、羟基取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素等中的一个、两个或更多个取代基取代的C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、醚基、硫醚基、-COORa、酰胺基、-NHC(＝NH)NH 2、-NHC(S)NH 2等；优选为氢、C1-C3烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C3烯基、C2-C3炔基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2等，或被选自羟基、羟基取代的C1-C3烷基(例如羟甲基)、氨基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、羟基取代的C1-C3烷氧基、C2-C3烯基、C2-C3炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素等中的一个、两个或更多个取代基取代的C1-C3烷基(例如卤代C1-C3烷基，例如三氟甲基、二氟甲基等)、C3-C6环烷基、三元至六元杂环烷基、C2-C3烯基、C2-C3炔基、醚基、硫醚基、-COORa、酰胺基、-NHC(＝NH)NH 2、-NHC(S)NH 2等；
或者R 4与R 5和与其相连的碳一起形成C3-C6环烷基、三元至六元杂环基等；
或者，R 3与R 4和R 5之一相连形成取代或未取代的三至六元含N杂环基，所述取代的取代基为选自羟基和C1-C3烷基中的一个、两个或更多个取代基；R 4和R 5中的另一个定义如上，优选为氢；
R 6为-COORa、酰胺基、氨基、卤素、C1-C6烷基等，或被选自卤素、羟基、羟基取代的C1-C3烷基(例如羟甲基)、氨基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素等中的一个、两个或更多个取代基取代的C1-C6烷基；优选为-COORa、酰胺基、氨基、卤素等；
R 7、R 8和R 9各自独立地为氢、C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-6炔基、醚基、硫醚基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2等，或被选自羟基、羟基取代的C1-C3烷基(例如羟甲基)、氨基、卤代C1-C3烷基(例如三氟甲基、二氟甲基)、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、 醚基、硫醚基、羧酸基、C6-C10芳基、卤素等中的一个、两个或更多个取代基取代的C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C-C6烯基、C2-C6炔基、醚基、硫醚基、-COORa、酰胺基、-NHC(＝NH)NH 2、-NHC(S)NH 2等；优选为氢、C1-C3烷基、C3-C6环烷基、三元至六元杂环烷基、卤代C1-C3烷基(例如三氟甲基、二氟甲基等)、C2-C3烯基、C2-3炔基、氰基、酰胺基、-COORa等；
Ra为C1-C6烷基。
在一个实施方式中，Z为氧。
在一个实施方式中，R 7、R 8和R 9为氢。
本公开中，
C1-C6烷基指的是含1-6个碳的直链或支链饱和脂肪族烃基团，例如甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，仲丁基等；
C3-C6环烷基指的是含3-6个碳的饱和或部分不饱和单环或多环环状烃基取代基，例如环丙基，环丁基，环戊基等，多环环烷基包括螺环、稠环和桥环的环烷基；
三至六元杂环烷基指的是饱和或不饱和的单环或多环环状烃取代基，其中包括3至6个环原子，其中一个或多个环原子为选自氮、氧、硫的杂原子，例如环氧乙烷基，环氧丙烷基，吡咯烷基，四氢呋喃基，二氢咪唑基等；
C2-C6烯基指的是含2-6个碳的烯烃分子中少一个氢原子而成的烃基，例如乙烯基，丙烯基，烯丙基等；
C2-C6炔基指的是含2-6个碳且包含一个碳碳三键的烃基取代基，例如乙炔基，丙炔基，炔丙基等；
酰胺基指的是含有-C(O)NR 1R 2基团的化合物，例如-CONH 2，-CONHCH 3等；
醚基指的是含有-(CH 2) mO(CH 2) nCH 3的化合物，其中，m和n各自独立地为1-6的整数，例如-CH 2OCH 2CH 3，-CH 2CH 2OCH 2CH 3等；
硫醚基指的是含有-(CH 2) mS(CH 2) nCH 3的化合物，其中，m和n各自独立地为1-6的整数，例如-CH 2SCH 2CH 3，-CH 2CH 2SCH 2CH 3等；
氨基甲酸酯基指的是含有-NHC(O)R 1的化合物，例如-NHCOOCH 3，-NHCOOC(CH 3) 3；
羧基指的是-C(O)OH；
C6-C10芳基指的是具有共轭π电子体系的6至10元全碳单环或稠合多环(共享毗邻碳原子对的环)，例如苯基，萘基；
三至六元含N杂环基指的是饱和或不饱和的单环环状取代基，包含1至3个N原子，例如四氢吡咯基，二氢咪唑基，二氢吡唑基，哌啶基，哌嗪基等；
卤素指的是F、Cl、Br、I。
本发明的典型化合物包括但不限于下列化合物：
Figure PCTCN2020097028-appb-000003
本发明另一方面提供了一种制备上述根据本发明的雷公藤红素衍生物的方法，
Figure PCTCN2020097028-appb-000004
其中，R3、R4、R5、R6、R7、R8、R9、X、Y、Z的定义如上所述，
所述方法包括如下步骤：
步骤1：使式1所示化合物发生curtius重排反应生成式2所示化合物，所述反应可以在例如叠氮磷酸二苯酯存在下进行，反应时间例如为3小时，反应温度例如为100℃；
步骤2：使式2所示化合物与式3所示化合物发生偶联反应生成式I所示化合物；所述反应可以在例如Pd2(dba) 3，tBu-Xphos，碳酸钾存在下进行，反应时间例如为3小时，反应温度例如为80℃。
根据本发明的化合物及其药学上可接受的盐还可能以包括立体异构体、对映异构体、非对映异构体、阻转异构体、光学异构体、外消旋体、多晶型物、溶剂合物或经同位素标记之化合物等变体的形式存在，这些变体同样包含在本发明范围内。
本发明还提供了一种药物组合物，其包含选自上述式I表示的雷公藤红素衍生物及其药学上可接受的盐中的一种或多种。上述组合物中进一步包含药学上可接受的辅料。
本发明还提供了上述根据本发明的雷公藤红素衍生物或其药学上可接受的盐在制备过氧化物酶1抑制剂中的用途或者在制备用于预防或治疗与过氧化物酶1相关的疾病，尤其是肿瘤生长与转移的药物中的用途。
本发明还提供了一种抑制Prdx1活性或预防或治疗与过氧化物酶1相关的疾病，尤其是肿瘤生长与转移的方法，该方法包括向受试者使用治疗有效量的由式I表示的化合物，或其药学上可接受的盐。
所述与过氧化物酶1相关的疾病指的是其发生或进展与过氧化物酶1信号通路相关的疾病，包括炎症，癌症，肥胖症，糖尿病。优选地，所述肿瘤包括白血病、直肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、卵巢癌、黑色素瘤。
附图说明
图1示出了各化合物对应的生存曲线；
图2示出了各化合物对小鼠体重变化的影响，其中M代表小鼠，M后的序号为小鼠的编号。
具体实施方式：
下面结合具体实施例对本发明作进一步阐述。这些实施例仅是出于解释说明的目的，而不限制本发明的范围和实质。
1H-NMR用Varian MercuryAMX300型仪测定；叠氮磷酸二苯酯[DPPA]、N,N-二异丙基乙胺[DIPEA]购于上海沃凯化学试剂有限公司，其余试剂由上海毕得医药科技有限公司生产。所有溶剂在使用前均经过重新蒸馏，所使用的无水溶剂均是按标准方法干燥处理获得；除说明外，所有反应均是在氮气保护下进行并TLC跟踪，后处理时均经饱和氯化钠水溶液洗涤和无水硫酸钠干燥过程；产品的纯化除说明外均使用硅胶(200-300目)柱色谱法；其中硅胶(200-300目)由青岛海洋化工厂生产，GF-254薄层硅胶板由烟台江友硅胶开发有限公司生产。
制备例1：化合物1-1的制备
Figure PCTCN2020097028-appb-000005
将雷公藤红素(1g，2.2mmol)溶于甲苯(10ml)中，向溶液中加入DIPEA(1.16ml，6.7mmol)，叠氮磷酸二苯酯(0.62ml，2.9mmol)，100℃下搅拌3小时。反应液用乙酸乙酯稀释，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(PE:EA＝6:1)，得610mg红色固体(产率62％)。 1H NMR(400MHz,CDCl 3)δ7.03(d,J＝6.0Hz,2H),6.54–6.50(m,1H),6.36(d,J＝7.1Hz,1H),2.21(s,3H),2.16–2.05(m,2H),1.96–1.86(m,3H),1.82–1.64(m,6H),1.60–1.51(m,3H),1.43(s,3H),1.40(s,3H),1.25(s,3H),1.05(s,3H),1.03–0.97(m,1H),0.92(s,3H)。
实施例1：化合物S1的制备
Figure PCTCN2020097028-appb-000006
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入1-氨基环丙烷羧酸乙酯盐酸盐(37mg，0.22mmol)，三乙胺(31μl，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝30:1)，得42mg红色固体(产率65％)。 1H NMR(400MHz,CDCl 3)δ7.01(d,J＝8.5Hz,2H),6.51(s,1H),6.35(d,J＝6.9Hz,1H),4.93(s,1H),4.38(s,1H),4.07(q,J＝7.2Hz,2H),2.89(d,J＝14.0Hz,1H),2.20(s,3H),2.11(dd,J＝12.8,4.4Hz,1H),2.02–1.60(m,10H),1.53(m,J＝9.1Hz,5H),1.37(s,3H),1.26(s,3H),1.17(t,J＝7.1Hz,3H),1.10(s,3H),0.98(m,2H),0.75(s,3H)。MS(ESI)：[M+Na] +m/z 599.4
实施例2：化合物S2的制备
Figure PCTCN2020097028-appb-000007
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入1-氨基环丁甲酸甲酯盐酸盐(36mg，0.22mmol)，三乙胺(31μl，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝30:1)，得45mg红色固体(产率71％)。 1H NMR(400MHz,CDCl 3)δ7.02(d,J＝8.6Hz,2H),6.49(s,1H),6.36(d,J＝6.3Hz,1H),5.05(s,1H),4.35(s,1H),3.69(s,3H),2.89(d,J＝15.4Hz,1H),2.49(d,J＝38.2Hz,2H),2.20(s,3H),1.93(d,J＝15.4Hz,7H),1.70(dd,J＝12.8,5.9Hz,2H),1.62–1.47(m,6H),1.41(s,3H),1.34(s,3H),1.24(s,3H),1.09(s,3H),0.94(d,J＝12.4Hz,1H),0.80(s,3H)。MS(ESI)：[M+Na] +m/z 599.4
实施例3：化合物S3的制备
Figure PCTCN2020097028-appb-000008
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入3-氨基氧杂环丁烷-3-甲酸甲酯(29mg，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝20:1)，得42mg红色固体(产率69.7％)。 1H NMR(400MHz,CDCl 3)δ7.04(s,2H),6.49(s,1H),6.42–6.31(m,1H),4.74(d,J＝136.6Hz,5H),3.76(s,3H),2.74(d,J＝14.3Hz,1H),2.20(s,3H),2.10(d,J＝11.7Hz,1H),1.99–1.60(m,10H),1.52(s,2H),1.41(s,3H),1.35(s,3H),1.25(s,3H),1.09(s,3H),0.95(s,1H),0.80(s,3H)。MS(ESI)：[M+Na] +m/z 601.4
实施例4：化合物S4的制备
Figure PCTCN2020097028-appb-000009
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入L-脯氨酸甲酯盐酸盐(37mg，0.22mmol)，三乙胺(31μl，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝40:1)，得46mg红色固体(产率72％)。 1H NMR(400MHz,CDCl 3)δ7.00(d,J＝7.5Hz,2H),6.53(d,J＝1.2Hz,1H),6.35(d,J＝7.1Hz,1H),4.35–4.28(m,1H),4.00(s,1H),3.64(s,3H),3.21(s,2H),2.94(d,J＝15.2Hz,1H),2.19(s,3H),2.07–1.67(m,12H),1.57(s,3H),1.54–1.45(m,2H),1.40(d,J＝12.0Hz,7H),1.25(s,3H),1.10(s,3H),0.97(d,J＝13.7Hz,1H),0.82(s,3H)。MS(ESI)：[M+Na] +m/z 599.4
实施例5：化合物S5的制备
Figure PCTCN2020097028-appb-000010
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入L-丙氨酸甲酯盐酸盐(31mg，0.22mmol)，三乙胺(31μl，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝30:1)，得42mg红色固体(产率69％)。 1H NMR(400MHz,CDCl 3)δ7.05–6.95(m,2H),6.51(s,1H),6.35(d,J＝7.1Hz,1H),4.68(d,J＝7.2Hz,1H),4.35(p,J＝7.3Hz,1H),3.62(s,3H),2.82(d,J＝13.8Hz,1H),2.21(s,3H),2.10(d,J＝13.3Hz,1H),2.01–1.61(m,9H),1.54(m,3H),1.38(s,3H),1.29(d,J＝7.2Hz,3H),1.25(s,3H),1.10(s,3H),0.95(d,J＝13.8Hz,1H),0.77(s,3H)。MS(ESI)：[M+Na] +m/z 573.4
实施例6：化合物S6的制备
Figure PCTCN2020097028-appb-000011
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入L-丝氨酸盐酸盐(35mg，0.22mmol)，三乙胺(31μl，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝30:1)，得53mg红色固体(产率87％)。 1H NMR(400MHz,CDCl 3)δ7.09–6.99(m,2H),6.47(d,J＝1.3Hz,1H),6.33(d,J＝7.2Hz,1H),5.68(s,1H),5.00(s,1H),4.43–4.33(m,1H),3.97–3.69(m,3H),3.57(s,3H),2.79(d,J＝13.7Hz,1H),2.18(s,3H),2.09–1.55(m,10H),1.50(d,J＝10.7Hz,3H),1.36(s,3H),1.34(s,3H),1.22(s,3H),1.09(s,3H),0.91(d,J＝13.2Hz,1H),0.71(s,3H)。MS(ESI)：[M+Na] +m/z 589.4
实施例7：化合物S7的制备
Figure PCTCN2020097028-appb-000012
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入丝氨醇(20mg，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝15:1)，得39mg红色固体(产率65％)。 1H NMR(400MHz,CDCl 3)δ7.04(d,J＝6.8Hz,1H),6.49(s,1H),6.26(d,J＝7.1Hz,1H),5.73(s,1H),5.11(s,1H),3.73–3.41(m,6H),2.80(d,J＝14.9Hz,1H),2.21(s,3H),2.08–1.99(m,1H),1.64(s,2H),1.48(s,7H),1.29(d,J＝2.9Hz,6H),1.16(s,3H),1.05(s,3H),0.91(d,J＝13.4Hz,1H),0.48(s,3H)。MS(ESI)：[M+Na] +m/z 561.4
实施例8：化合物S8的制备
Figure PCTCN2020097028-appb-000013
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入三羟甲基氨基甲烷(27mg，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝15:1)，得42mg红色固体(产率66％)。 1H NMR(400MHz,DMSO-d 6)δ8.76(s,1H),7.10(d,J＝7.0Hz,1H),6.43–6.35(m,2H),6.25(s,1H),5.63(s,1H),3.30(q,J＝10.7Hz,6H),2.84(d,J＝15.7Hz,1H),2.19(d,J＝9.8Hz,1H),2.10(s,3H),1.99(t,J＝13.9Hz,1H),1.87(d,J＝12.0Hz,1H),1.73–1.42(m,10H),1.39(s,3H),1.25(s,3H),1.22(s,3H),1.07(s,3H),0.87(d,J＝13.7Hz,1H),0.73(s,3H)。MS(ESI)：[M+Na] +m/z 591.5
实施例9：化合物S9的制备
Figure PCTCN2020097028-appb-000014
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入(1R,2R,4S)4-氨基-2-(羟甲基)环戊醇(29mg，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝10:1)，得33mg红色固体(产率52％)。 1H NMR(400MHz,CDCl 3)δ7.30(s,1H),7.06(d,1H),6.42(s,1H),6.34(s,1H),5.35(s,1H),5.03–3.93(m,5H),3.57(s,2H),2.81(d,J＝14.7Hz,1H),2.18(s,3H),2.11-1.40(m,17H),1.34(s,3H),1.31(s,3H),1.20(s,3H),1.07(s,3H),0.90(d,J＝12.8Hz,1H),0.60(s,3H)。MS(ESI)：[M+Na] +m/z 601.4
实施例10：化合物S10的制备
Figure PCTCN2020097028-appb-000015
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入二甘醇胺(23mg，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝20:1)，得22mg红色固体(产率36％)。 1H NMR(400MHz,CDCl 3)δ7.08–6.96(m,2H),6.54–6.50(s,1H),6.32(d,J＝7.0Hz,1H),5.18(s,1H),4.48(s,1H),3.60(s,2H),3.46(d,J＝5.5Hz,4H),3.23(s,3H),2.85(d,J＝14.4Hz,1H),2.21(s,3H),2.10(dd,J＝13.6,3.8Hz,1H),1.95–1.79(m,3H),1.74(dd,J＝17.9,13.2Hz,2H),1.63–1.44(m,7H),1.38(s,3H),1.36(s,3H),1.22(s,3H),1.08(s,3H),0.93(d,J＝13.4Hz,1H),0.60(s,3H)。MS(ESI)：[M+Na] +m/z 575.4
实施例11：化合物S11的制备
Figure PCTCN2020097028-appb-000016
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入D-氨基丙醇(26μL，0.33mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝15:1)，得18mg红色固体(产率32％)。1H NMR(400MHz,CDCl 3)δ7.03(d,J＝6.8Hz,1H),6.97(s,1H),6.50(s,1H),6.35(d,J＝6.9Hz,1H),4.44(s,2H),3.80–3.29(m,4H),2.85(d,J＝14.7Hz,1H),2.21(s,3H),1.99–1.68(m,7H),1.64(d,J＝14.7Hz,3H),1.52(m,2H),1.41(s,3H),1.37(s,3H),1.25(s,3H),1.10(s,3H),1.01(m,4H),0.71(s,3H)。MS(ESI)：[M+Na] +m/z 545.4
实施例12：化合物S12的制备
Figure PCTCN2020097028-appb-000017
将化合物1-1(50mg，0.11mmol)溶于四氢呋喃(2ml)中，向溶液中加入反式-4-羟基-L-脯氨酸甲酯(27mg，0.22mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝15:1)，得42mg红色固体(产率66％)。 1H NMR(400MHz,CDCl 3)δ7.01(dd,J＝7.1,1.4Hz,1H),6.97(s,1H),6.54(d,J＝1.4Hz,1H),6.36(d,J＝7.1Hz,1H),4.48(s,1H),4.41(t,J＝7.3Hz,1H),4.02(s,1H),3.69(s,3H),3.44(dd,J＝9.5,4.9Hz,1H),2.20(s,3H),2.18–1.87(m,7H),1.84–1.77(m,2H),1.72(td,J＝13.1,12.4,5.0Hz,2H),1.64–1.60(m,2H),1.47(s,2H),1.43(s,3H),1.40(s,3H),1.26(s,3H),1.11(s,3H),0.99(d,J＝14.1Hz,1H),0.82(s,3H)。MS(ESI)：[M+Na] +m/z 615.4
实施例13：化合物S13的制备
Figure PCTCN2020097028-appb-000018
将化合物1-1(425mg，0.95mmol)溶于二氯甲烷(5ml)中，-15℃下加入三乙胺(198μL，1.42mmol)搅拌五分钟，缓慢滴加三氟甲磺酸酐(208μL，1.23mmol)，搅拌15分钟，加水淬灭，用水萃取，有机相旋干过柱，得化合物1-2，为黄色固体268mg(产率49％)。
将化合物1-2(234mg，0.4mmol)溶于四氢呋喃(4ml)中，向溶液中加入L-丙氨酸甲酯盐酸盐(169mg，1.21mmol)，三乙胺(168μL，1.21mmol)，50℃搅拌4小时，旋干溶剂，用乙酸乙酯溶解，加水萃取，有机层用饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(DCM:MeOH＝100:1)，得250mg化合物1-3，为黄色固体(产率91％)。
将化合物1-3(250mg，0.37mmol)溶于甲苯(3ml)中，加入碳酸钾(152mg，1.10mmol)，三氟乙酰胺(124mg，1.10mmol)，Pd 2(dba) 3(41mg，0.04mmol)，t-Bu-Xphos(94mg，0.22mmol)，80℃，100W反应3小时，硅胶薄层板分离(DCM:MeOH＝50:1)，得1mg红色固体(产率0.5％)。 1H NMR(400MHz,CDCl 3)δ6.85(d,J＝6.9Hz,1H),6.45(d,J＝1.3Hz,1H),6.29(d,J＝7.2Hz,1H),4.64(d,J＝7.7Hz,1H),4.36(p,J＝7.3Hz,1H),4.11(s,1H),3.63(s,3H),2.78(d,J＝13.5Hz,1H),2.08(s,3H),2.01–1.94(m,1H),1.88(dd,J＝14.0,6.1Hz,2H),1.83–1.72(m,3H),1.64(d,J＝4.5Hz,4H),1.53(d,J＝7.4Hz,3H),1.41(s,3H),1.38(s,3H),1.29(d,J＝7.1Hz,3H),1.25(s,3H),1.10(s,3H),0.95(d,J＝13.6Hz,1H),0.78(s,3H)。MS(ESI)：[M+Na] +m/z 572.4
实验例1：雷公藤红素(CEL)及其衍生物在分子水平对PRDX1酶抑制活性检测
实验方法：首先将各化合物包括雷公藤红素(CEL)及化合物S1-S13分别与过氧化还原酶PRDX1在37℃共孵育25分钟，然后将20mM HEPES，pH 7.0,5mM EDTA,5μM辅因子蛋白A,2μM辅因子蛋白B,300μM NADPH配成预反应缓冲液转移至96孔检测板中(每孔体积120μL)，后续在检测板中加入孵育了化合物的靶蛋白(蛋白终浓度为200nM，每孔体积为40μl)，最后在体系中加入40μL 200μM过氧化氢，开始酶活反应循环。检测中利用340nm处吸光值检测NADPH的氧化。检测板读值每90秒一个循环，读值至少进行20个循环。读值初始的线性部分用于表征体系中NADPH的消耗速率，该消耗速率可以间接反映过氧化氢的消耗速率。
天然产物CEL及化合物S1-S13的PRDX1酶抑制活性如表1所示。相比于CEL，大部分化合物都显示出增强的活性。
实验例2：细胞水平雷公藤红素及其衍生物对NB4细胞增殖抑制的检测
实验方法：96孔平底板中每孔用50μL 1640+10％FBS培养基种5000个NB4细胞。化合物先用DMSO溶解成20mM母液，后用1640+10％FBS培养基从终浓度10μM向下3倍等比稀释共9个浓度点，每个浓度点设置三个重复。化合物和细胞孵育72小时后用promega 公司的cell-titer glo检测每孔细胞个数并用graphpad prism 5.0拟合每个化合物的NB4细胞增殖抑制曲线。
天然产物CEL及化合物S1-S13对NB4细胞增殖抑制活性如表1所示。大部分化合物都具有较强的细胞增殖抑制活性，具有纳摩尔级IC50值。
表1.化合物的Prdx1抑制活性及NB4细胞抑制活性(IC50)
化合物 Prdx1(nM) NB4(nM) 化合物 Prdx1(nM) NB4(nM)
S1 157 82.41 S8 138 484
S2 188 141.1 S9 126 1230
S3 126 74.25 S10 119 154.1
S4 655 59.76 S11 159 140
S5 232 146.5 S12 153 133.2
S6 130 141.8 S13 310 157.2
S7 192 1140 CEL 171 138.6
实验例3：雷公藤红素及其衍生物分子水平对PRDX家族成员酶抑制活性评价(选择性研究)
实验方法：首先将各化合物包括雷公藤红素(CEL)及化合物S1-S13分别与过氧化还原酶PRDX家族成员蛋白PRDX2-PRDX6在37℃共孵育25分钟，然后将20mM HEPES，pH7.0,5mM EDTA,5μM辅因子蛋白A,2μM辅因子蛋白B,300μM NADPH配成预反应缓冲液转移至96孔检测板中(每孔体积120μL)，后续在检测板中加入孵育了化合物的靶蛋白(蛋白终浓度为PRDX2:2μM，PRDX3:0.3μM，PRDX4:0.9μM，PRDX5:0.1μM，PRDX6:10μM，每孔体积为40μL)，最后在体系中加入40μL 200μM过氧化氢，开始酶活反应循环。检测中利用340nm处吸光值检测NADPH的氧化。检测板读值每90秒一个循环，读值至少进行20个循环。读值初始的线性部分用于表征体系中NADPH的消耗速率，该消耗速率可以间接反映过氧化氢的消耗速率。小分子孵育PRDX家族成员蛋白PRDX2-PRDX6设置三个浓度点，分别为30μM,10μM,3μM。
表2中所示数据为各化合物对酶活性抑制的半数浓度值。相对于雷公藤红素，化合物S1-S13对PRDX1-6家族中PRDX1具有较好的选择性。
表2.天然产物CEL及化合物S1-S13对PRDX1-6家族成员酶抑制活性
Figure PCTCN2020097028-appb-000019
实验例4：雷公藤红素及其衍生物S1、S5和S6等在模型小鼠上的急性毒性研究
实验方法：采用6周龄FVB小鼠，每个化合物给药雌雄各2只。给药前使用高能线性加速辐照仪进行4.5Gy辐射射线照射。每个化合物腹腔注射给药两个浓度，低浓度为5mg/kg，高浓度为10mg/kg。给药一次后观察小鼠体重、存活等情况15天。
生存曲线提示(图1)，化合物S1、S5和S6的急性毒性明显小于雷公藤红素。其中，5mg/kg给药时，化合物S1和S5在15天中，无任何死亡；而雷公藤红素在第六天时，小鼠已经全部死亡。
此外存活至第15天的小鼠体重没有显著的变化(图2)，暗示毒性较小。

Claims (10)

  1. 一种雷公藤红素衍生物或其药学上可接受的盐，所述雷公藤红素衍生物具有如式I所示的结构：
    Figure PCTCN2020097028-appb-100001
    其中
    X为-O-R 1或-NR 1R 2，其中R 1和R 2各自独立地为氢、C1-C6烷基、C3-C6环烷基、三至六元杂环烷基、C2-C6烯基、C2-C6炔基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2，或被选自羟基、羟基取代的C1-C3烷基、氨基、卤代C1-C3烷基、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素中的一个、两个或更多个取代基取代的C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、醚基、硫醚基、-COORa、酰胺基、-NHC(＝NH)NH 2或-NHC(S)NH 2；
    Y为氧；
    Z选自氧或硫；
    R 3为氢、C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2，或被选自羟基、羟基取代的C1-C3烷基、氨基、卤代C1-C3烷基、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素中的一个、两个或更多个取代基取代的C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、醚基、硫醚基、-COORa、酰胺、-NHC(＝NH)NH 2或-NHC(S)NH 2；
    R 4和R 5各自独立地为氢、C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2，或被选自羟基、羟基取代的C1-C3烷基、氨基、卤代C1-C3烷基、羟基取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素中的一个、两个或更多个取代基取代的C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-C6炔基、醚基、硫醚基、-COORa、酰胺基、-NHC(＝NH)NH 2、 -NHC(S)NH 2；
    或者R 4与R 5和与其相连的碳一起形成C3-C6环烷基、三元至六元杂环基；
    或者，R 3与R 4和R 5之一相连形成取代或未取代的三至六元含N杂环基，所述取代的取代基为选自羟基和C1-C3烷基中的一个、两个或更多个取代基；R 4和R 5中的另一个定义如上，优选为氢；
    R 6为-COORa、酰胺基、氨基、卤素、C1-C6烷基，或被选自卤素、羟基、羟基取代的C1-C3烷基、氨基、卤代C1-C3烷基、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素中的一个、两个或更多个取代基取代的C1-C6烷基；
    R 7、R 8和R 9各自独立地为氢、C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C6烯基、C2-6炔基、醚基、硫醚基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2，或被选自羟基、羟基取代的C1-C3烷基、氨基、卤代C1-C3烷基、C2-C6烯基、C2-C6炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素中的一个、两个或更多个取代基取代的C1-C6烷基、C3-C6环烷基、三元至六元杂环烷基、C-C6烯基、C2-C6炔基、醚基、硫醚基、-COORa、酰胺基、-NHC(＝NH)NH 2、-NHC(S)NH 2；
    Ra为C1-C6烷基。
  2. 根据权利要求1所述的雷公藤红素衍生物或其药学上可接受的盐，其中，
    X为-O-R 1或-NR 1R 2，R 1和R 2各自独立地为氢、C1-C3烷基、C3-C6环烷基、三至六元杂环烷基、卤代C1-C3烷基、C2-C3烯基、C2-C3炔基、氰基、酰胺基、-COORa；
    R 3为氢、C1-C3烷基、C3-C6环烷基、三元至六元杂环烷基、卤代C1-C3烷基、C2-C3烯基、C2-C3炔基、氰基、酰胺基、-COORa；
    R 4和R 5各自独立地为氢、C1-C3烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C3烯基、C2-C3炔基、氰基、酰胺基、-COORa、-NHC(＝NH)NH 2、-NHC(S)NH 2，或被选自羟基、羟基取代的C1-C3烷基、氨基、卤代C1-C3烷基、羟基取代的C1-C3烷氧基、C2-C3烯基、C2-C3炔基、氰基、-COORa、酰胺基、氨基甲酸酯基、醚基、硫醚基、羧酸基、C6-C10芳基、卤素中的一个、两个或更多个取代基取代的C1-C3烷基、C3-C6环烷基、三元至六元杂环烷基、C2-C3烯基、C2-C3炔基、醚基、硫醚基、-COORa、酰胺基、-NHC(＝NH)NH 2、-NHC(S)NH 2；
    或者R 4与R 5和与其相连的碳一起形成C3-C6环烷基、三元至六元杂环基；
    或者，R 3与R 4和R 5之一相连形成取代或未取代的三至六元含N杂环基，所述取代的取代基为选自羟基和C1-C3烷基中的一个、两个或更多个取代基；R 4和R 5中的另一个定义 如上；
    R 6为-COORa、酰胺基、氨基、卤素；
    R 7、R 8和R 9各自独立地为氢、C1-C3烷基、C3-C6环烷基、三元至六元杂环烷基、卤代C1-C3烷基、C2-C3烯基、C2-3炔基、氰基、酰胺基、-COORa；
    Ra为C1-C6烷基。
  3. 根据权利要求2所述的雷公藤红素衍生物或其药学上可接受的盐，其中，
    X为-O-R 1或-NR 1R 2，其中R 1和R 2各自独立地为氢、C1-C3烷基、卤代C1-C3烷基、C2-C3烯基、C2-C3炔基、氰基；和/或
    Z为氧；和/或
    R7、R8和R9为氢。
  4. 根据权利要求1所述的雷公藤红素衍生物或其药学上可接受的盐，其选自如下化合物：
    Figure PCTCN2020097028-appb-100002
    Figure PCTCN2020097028-appb-100003
  5. 一种制备权利要求1-4中任一项所述的雷公藤红素衍生物或其药学上可接受的盐的方法，该方法包括如下步骤：
    Figure PCTCN2020097028-appb-100004
    其中，R3、R4、R5、R6、R7、R8、R9、X、Y、Z的定义如相应权利要求中所述，
    步骤1：使式1所示化合物发生curtius重排反应生成式2所示化合物；以及
    步骤2：使式2所示化合物与式3所示化合物发生偶联反应生成式I所示化合物。
  6. 一种药物组合物，其包含选自根据权利要求1至4中任一项所述的雷公藤红素衍生物和其药学上可接受的盐中的一种或多种。
  7. 根据权利要求1至4中任一项所述的雷公藤红素衍生物和其药学上可接受的盐在制备过氧化物酶1抑制剂或者用于预防或治疗与过氧化物酶1相关的疾病的药物中的用途。
  8. 根据权利要求7所述的用途，其中，所述与过氧化物酶1相关的疾病指的是与肿瘤生长与转移相关的疾病。
  9. 根据权利要求8所述的用途，其中，所述与过氧化物酶1相关的疾病包括炎症、癌症、肥胖症、糖尿病。
  10. 根据权利要求9所述的用途，其中，所述肿瘤包括白血病、直肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、卵巢癌、黑色素瘤。
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