WO2021204193A1 - Sirt1受体激动剂及包含其的药物 - Google Patents

Sirt1受体激动剂及包含其的药物 Download PDF

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WO2021204193A1
WO2021204193A1 PCT/CN2021/085919 CN2021085919W WO2021204193A1 WO 2021204193 A1 WO2021204193 A1 WO 2021204193A1 CN 2021085919 W CN2021085919 W CN 2021085919W WO 2021204193 A1 WO2021204193 A1 WO 2021204193A1
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compound
solvates
salts
nmr
salt
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温尧林
孙俊哲
申凯
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苏州凯祥生物科技有限公司
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Definitions

  • the invention belongs to the field of medicines or health products, and specifically relates to a SIRT1 receptor agonist and a medicine containing the same.
  • uric acid is the final metabolite of human purine compounds.
  • Disorders of purine metabolism lead to hyperuricemia.
  • the fasting blood uric acid level of men is higher than 420 ⁇ mol/L twice on different days and that of women is higher than 360 ⁇ mol/L, which is called hyperuricemia.
  • hyperuricemia Normally, there are no symptoms in a purely hyperuricemia state, but if you stay in this state for a long time, urate in the blood will crystallize and deposit in joints, subcutaneous tissues, kidneys, etc., and then gout and gout will be complicated. A series of clinical manifestations such as disease.
  • drugs that promote uric acid excretion are suitable, such as: Benzbromarone, Resinard, etc.
  • drugs that inhibit uric acid production mainly xanthine oxidase inhibitors
  • allopurinol, febuxostat are suitable.
  • Allopurinol is the first drug to inhibit the production of uric acid on the market. Since its clinical application in 1963, it has been the main drug for the treatment of chronic gout because of its low price and good uric acid lowering effect. However, with the promotion of allopurinol, reports of adverse reactions have gradually increased. Since the 1970s, reports have shown that allopurinol can cause liver and kidney damage, leukopenia, skin rash and other adverse reactions. About 1.5% of allergies Risks, serious, fatal allergies may occur, causing worldwide concern. Therefore, in order to reduce adverse reactions, allopurinol should be used from a small dose.
  • Febuxostat (Febuxostat, trade name: Uloric, Takeda North America Pharmaceuticals) is a non-purine selective xanthine oxidase inhibitor, listed in the European Union in May 2008, and approved by the US FDA in March 2009. Entered the Chinese market in 2013 for long-term treatment of hyperuricemia accompanied by gout. Compared with other drugs for the treatment of hyperuricemia, febuxostat has higher selectivity and stronger activity. However, related studies and clinical practice have shown that febuxostat also has certain adverse reactions: common adverse reactions include abnormal liver function (3.5%), diarrhea (2.7%), headache (1.8%), and nausea (1.7%) And skin rash (1.5%).
  • Silent information regulator 1 is a member of the sirtuin protein family and exists in eukaryotic and prokaryotic organisms. It plays an important physiological role in the process of cell survival and proliferation. Its dysfunction involves the occurrence and development of physiological activities such as aging, as well as various diseases such as tumors, diabetes, cardiovascular diseases, chronic inflammation and some metabolic diseases. Specifically, related to cell metabolism: SIRT1 regulates cell differentiation, proliferation and senescence with the transcription factors FOXO and p53. By up-regulating SIRT1, it can restore the function of FOXO3 in aging mouse embryonic fibroblasts and repair damage through its deacetylation effect. DNA, activate cell cycle regulator protein D, cell cycle regulator p27Kip1, etc. to enhance the detoxification effect of reactive oxygen free radicals.
  • SIRT1 agonists can also inhibit the release of inflammatory factors such as tumor necrosis factor TNF-a, interleukin IL-1 ⁇ , IL-6, etc., and slow the progression of chronic inflammatory diseases such as chronic obstructive pulmonary disease and colitis.
  • TNF-a tumor necrosis factor
  • IL-6 interleukin-6
  • the high level of expression of SIRT1 in CD4+ and CD8+ T cells suggests that it is involved in the regulation of immune function. It can act on the transcription factor FOXP3 to increase the number and function of regulatory T cells through deacetylation, and it also inhibits cell excess Autophagy, reduce cell death, regulate the biological process of fat metabolism, reduce fat deposition, regulate endothelial cell function, and protect the heart.
  • SIRT1 agonists can improve glucose tolerance and enhance insulin secretion, and mouse model tests have also found that SIRT agonists can significantly reduce hyperuricemia induced by potassium oxinate and yeast extract. It also improves the infiltration of inflammatory cells in the kidney tissue, thereby improving chronic renal failure and reducing blood creatinine levels.
  • SIRT1 is structurally expressed in articular cartilage, but SIRT1 is almost undetectable in the cartilage of patients with severe arthritis. Increasing the expression of SIRT1 can delay the progression of osteoarthritis, and it can also regulate the activity of osteoclasts and osteoblasts to improve bone metabolism, thereby reducing osteoporosis. Studies have also shown that SIRT1 inhibitors can reduce the activity of rheumatoid arthritis synovial cells and inhibit synovial cell hypertrophy, thereby reducing rheumatoid arthritis. The preventive administration of SIRT1 agonists can significantly inhibit the joint inflammation induced by urate crystals. [Zhu Xiaoxia, Liu Qiong, Chen Haiyan, et al. Research progress on silent information regulator 1 and its association with gout and hyperuricemia[J]. Shanghai Medicine, 2015(11):19-22.]
  • SIRT1 can promote the expression of ABCG2 in the ileum, thereby promoting the excretion of uric acid from the intestine. At the same time, it can inhibit the mRNA level of URAT1 in the kidney, indicating that SIRT1 agonists may achieve the effect of lowering uric acid by promoting the excretion of uric acid in the intestines and kidneys.
  • the applicant has discovered through long-term research that a series of compounds with SIRT1 agonistic activity can be used to lower uric acid.
  • the purpose of the present invention is to provide a novel compound with SIRT1 agonistic activity.
  • R 1 and R 2 are independently selected from hydrogen, hydroxyl, carboxyl, Rm substituted or unsubstituted C 1 -C 7 alkyl, Rm substituted or unsubstituted C 1 -C 7 alkenyl, Rm substituted Or unsubstituted C 1 -C 7 keto group, Rm substituted or unsubstituted C 1 -C 7 ester group;
  • R 3 is selected from Rm substituted or unsubstituted C 1 -C 7 alkyl, Rm substituted or unsubstituted C 1 -C 7 alkenyl, Rm substituted or unsubstituted C 1 -C 7 keto group;
  • Rm is selected from OH, CHO, OCOCH 3 , and by At least one of the formed glycosyl residues.
  • R 1 is selected from CH 3 , COOH, COCH 3 ,
  • R 2 is selected from H, OH, CH 3 ,
  • R 3 is selected from
  • Rm is selected from OH, CHO, OCOCH 3 , and by At least one of the glycosyl residues formed in;
  • the present invention also provides a compound represented by the following general formula (II), or its enantiomers, diastereomers, salts, esters, prodrugs, solvates or salt solvates,
  • R is H or COCH 3 .
  • the present invention also provides any of the above-mentioned compounds, or their enantiomers, diastereomers, salts, esters, prodrugs, solvates or salt solvates as Sirt1 receptor agonists Applications.
  • the application includes the preparation of drugs for preventing and/or treating diseases related to Sirt1 receptor dysfunction; wherein the diseases related to Sirt1 receptor dysfunction are aging, tumors, diabetes, cardiovascular diseases, chronic inflammation, At least one of osteoporosis, obesity, hyperuricemia, and gout; the chronic inflammation is at least one of chronic obstructive pulmonary disease, colitis, rheumatoid arthritis, chronic renal failure, and gouty arthritis.
  • the present invention also provides a medicine, which contains an effective amount of one or more of the above-mentioned compounds, or its enantiomers, diastereomers, salts, esters, prodrugs, and solvents. And one or more pharmaceutically acceptable excipients.
  • it contains an effective amount of one or more of the above-mentioned compounds, or enantiomers, diastereomers, salts, esters, prodrugs, solvates, or solvents of the salts. Combination and one or more other active ingredients.
  • the compounds prepared by the present invention all have Sirt1 activating effect and can be used as potential Sirt1 agonists. It is found through hyperuricemia animal models that the compound of the present invention has a significant uric acid-lowering effect in the body. As a potential medicine for lowering uric acid or treating gout.
  • the compounds can be prepared according to the methods of the examples of the present invention, or can be prepared according to the methods in the prior art documents.
  • the volume ratio of gasoline and ether was 9:1, 7:1, 5:1, respectively. 3:1, 1:1, 1:3, and finally eluted with ether. All the above mobile phases eluted 3BV. According to the TLC test results, the eluates were combined to obtain compounds 1-1, 1-2, 1-3, 1-4 and mixture Fr1-1. Separate the mixture Fr1-1 with a silica gel column again, using the mixture of gasoline and ether as the eluent, and perform gradient elution according to the following procedure.
  • the volume ratio of gasoline/ether is 3:1, 2:1, 1:1 1:2, 1:3, 1:5, all the above mobile phases eluted 3BV, and the eluates were combined according to the TLC detection results to obtain compounds 1-5 and 1-6.
  • the structures of the compounds prepared above were confirmed by 1 H NMR, 13 C NMR and HPLC-MS, respectively.
  • the structure confirmation data refer to the following documents:
  • GLC C1’(101.7), C2’(74.3), C3’(73.5), C4’(71.5), C5’(77.8), C6’(62.3)
  • the crude extract was mixed with silica gel and used silica gel column chromatography, respectively N-hexane: ethyl acetate (volume ratio 25:1, 20:1, 15:1, 10:1, 7:1, 4:1, 2:1, 1:1), and ethyl acetate as the mobile Phase gradient elution, each of the above mobile phases eluted 3BV, combined according to the detection results of thin layer chromatography (TLC), to obtain 5 components Fra-Fre.
  • Frc was separated by Sephadex LH-20 column chromatography, using methanol aqueous solution gradient elution (15%, 30%, 40%, 50%, 60%, 70%, 85%, 100% methanol aqueous solution).
  • the structures of the compounds 3-1 to 3-6 prepared above were confirmed by 1 H-NMR, 13 C-NMR and HPLC-MS, ultraviolet full-wavelength scanning and infrared spectroscopy, respectively.
  • the structure confirmation data refer to the following literature: Hartmut Laatsch und Alke Pudleiner, Synthese von ⁇ -Acetyl- ⁇ -methylenpolyencarbonsaureester[J].J.prakt.Chem.336(1994)663-677
  • Step b): Add 2mmol ICH 2 CH 2 Cl, (PPh 3 ) 4 Pd (5mol-%), KOH (4.2mmol, 1M, H 2 O) to the product of step a), add 60mLTHF, reflux, and then add 2mmolCH ⁇ C-TMS, CuI (10mol-%), PdCl 2 (PhCN) 2 (5mol-%), piperidine 45mL, react at room temperature for 10 minutes.
  • step g) After replacing compound 16 in step e) with compound 18 in the aforementioned reaction, after performing steps d), e), and f), directly react with compound 19 (instead of compound 17) in step g) to obtain compound 4-2.
  • the compounds prepared above were analyzed by 1 H-NMR, 13 C-NMR and HPLC-MS, ultraviolet full-wavelength scanning and infrared spectroscopy respectively.
  • Step e Add 5 mmol K 2 CO 3 and 10 mL MeOH to the product of step d), and react at room temperature for 14 hours to obtain compound 13;
  • the raw material 7 is replaced with the raw material 21 or the raw material 22 or the raw material 23, respectively, and the reaction of step a) is performed, and the other steps are unchanged to obtain compounds 5-3, 5-4, and 5-5.
  • the residue is eluted with a gradient of silica gel column chromatography and a gradient of CH 2 Cl 2 methanol solution (7: 1, 12:1, 20:1, 30:1), each of the above mobile phases eluted 3BV to obtain compounds 5-10, 5-11, 5-12, and 5-13, respectively.
  • the boron ether complex was heated to 0° C. and stirred for 5 hours. 50 mL of saturated sodium bicarbonate was added to quench the reaction, the pH was adjusted to 7.5, and the organic solvent was removed by concentration under reduced pressure to obtain compound 6.
  • each of the above mobile phases eluted 3BV, and collected 60% ethanol for elution. Liquid, concentrated under reduced pressure to obtain extract.
  • the extract was separated using silica gel column chromatography, and chloroform methanol gradient elution (the volume ratio of chloroform to methanol was 100:1, 50:1, 35:1, 20:1, 10:1, 5:1, 3: 1, 2:1, 1:1 mixed solution, each of the above mobile phases are eluted 3BV) to obtain an eluent containing compound 7, and the eluent is separated by Sephadex LH-20 column chromatography, using methanol aqueous solution Gradient elution (10%, 15%, 30%, 45%, 55%, 70%, 100% methanol aqueous solution), each of the above mobile phases eluted 3BV to obtain Fr6.5-1 to Fr6.5-7, Among them, Fr6.5-3 was separated by reversed-phase silica gel preparative column chromatography, and methanol aqueous solution gradient elution (30%
  • the compounds prepared in the foregoing examples can be made into injections after adding a solvent for injection according to a conventional method, precision filtration, and potting and sterilization.
  • the compounds prepared in the foregoing examples are dissolved in sterile water for injection, filtered with a sterile funnel, subpackaged, freeze-dried at a low temperature, and then aseptically melt-sealed to obtain a powder injection.
  • each tablet or capsule contains 0.5- of pharmaceutical ingredients. 300mg tablets or capsules.
  • Sirt1 Fluorometric Drug Discovery Kit (Sirt1 activity fluorescent quantitative detection kit) was used to detect the influence of compounds on Sirt1 in vitro activity according to the method of the kit instructions.
  • First formulated containing 0.5U Sirt1 (at 37 °C 1U 1 pmol ⁇ min -1) (except control group), 1000 ⁇ mol ⁇ L -1 NAD +, 100 ⁇ mol ⁇ L -1 deacetylase enzyme substrate, SIRT1 buffer (50mmol ⁇ L - 1 Tris-HCl, pH 8.0, 137mmol ⁇ L -1 NaCl, 2.7mmol ⁇ L -1 KCl, 1mmol ⁇ L - 1 MgCl 2 , 1mg ⁇ ml -1 BSA) test system.
  • SIRT1 buffer 50mmol ⁇ L - 1 Tris-HCl, pH 8.0, 137mmol ⁇ L -1 NaCl, 2.7mmol ⁇ L -1 KCl, 1mmol ⁇ L - 1 MgCl 2 , 1mg ⁇ m
  • the experimental group was added with each compound to be tested prepared in the previous example, the blank group and the agonist (resveratrol) or inhibitor (nicotinamide) control group were added with the same amount of solvent to dissolve the compound; then added to the prepared test system , So that the total volume of the compound to be tested and the test system is 25 ⁇ L (the final concentration of the compound to be tested, agonist, and inhibitor are all 200 ⁇ M). After incubating at 37°C for 30 minutes, add 25 ⁇ L of 1 ⁇ Fluor de Lys developer solution (containing 2mmol ⁇ L -1 nicotinamide) to each test well to stop the reaction (final concentration of nicotinamide is 200 ⁇ M), and the reaction is carried out in a 96-well plate . Measure the fluorescence value of each well under the condition of 360nm excitation light and 460nm emission light with the multifunctional microplate reader.
  • the compounds prepared in the present invention have Sirt1 activating effect and can be used as potential Sirt1 agonists, and among them, compounds 1-8, 1-9, 1-10, 1-11, 1-12, 1-13 , 1-14, 1-15, 1-17, 1-18, 1-19, 1-20, 2, 4-1, 4-2, 4-3, 4-4, 5-2, 5-5
  • the relative activities of 5-9, 5-12, 6 and 7 have a better activation effect on Sirt1.
  • Healthy male KM mice weighing 15-18g, were provided by Shanghai Lingchang Biotechnology Co., Ltd.; 5 mice per cage were divided into cages and then reared adaptively in the barrier system for 4 days.
  • mice with a concentrated weight are randomly divided into groups according to their body weight. Each group contains 10 mice, which are blank control group, model control group, positive control group, and compound group (see the result summary table for specific compounds).
  • mice were given intragastric administration immediately, once a day in the morning, for 7 consecutive days.
  • the compound group was given 30 mg/kg of the compound prepared in the example, in which the compound was suspended with 0.5% sodium carboxymethyl cellulose (CMC-Na) solution; the positive control group was given febuxostat 1.0 mg/kg, with the same The volume of 0.5% carboxymethyl cellulose sodium (CMC-Na) solution was suspended; the blank control group and the model control group were all given 0.5% carboxymethyl cellulose sodium (CMC-Na) solution by gavage; each group was continuous Gavage for 7 days. After 0.5 hours of intragastric administration on the morning of the 7th day, mice in each group were injected intraperitoneally to make hyperuricemia models.
  • CMC-Na sodium carboxymethyl cellulose
  • the blank control group was intraperitoneally injected with 0.5% carboxymethyl cellulose sodium (CMC-Na) solution; the model control group, the positive control group, and the compound group were all injected with 300 mg/kg of the animal’s body weight of potassium oxazine (OA), with CMC -Na solution to dissolve.
  • CMC-Na carboxymethyl cellulose sodium
  • mice in each group had their eyeballs removed for blood collection, with a blood volume of not less than 0.5 mL, and the blood sample was collected at room temperature for about 1 hour. After the blood was completely coagulated, it was centrifuged at 3500 rpm/4°C. After 10 minutes, take the serum for 5 minutes under the same conditions, and then take 0.2mL of serum to detect the UA value with a biochemical analyzer.
  • the compound of the present invention has a significant effect of lowering uric acid in the body, and can be used as a potential lowering uric acid drug.
  • SIRT1 prevents hyperuricemia via the PGC-1 ⁇ /PPAR ⁇ -ABCG2 pathway[J].
  • Endocrine, 2016, 53(2): 443-452. Reported that SIRT1 can promote the expression of ABCG2 in the ileum, thereby promoting the excretion of uric acid in the intestine, and can also inhibit the mRNA level of URAT1 in the kidney, indicating that the compound of the present invention may be achieved by promoting the excretion of uric acid in the intestine and kidney Reduce the effect of uric acid.

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Abstract

本发明属于药品或保健品领域，具体涉及下述通式(I)所示的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，其中，R1、R2、R3如本发明说明书的定义所示，本发明制备的化合物具有Sirt1激活作用，可作为潜在的Sirt1激动剂，通过高尿酸血症动物模型发现，本发明的化合物在体内具有显著的降尿酸作用，可以作为潜在的降尿酸或治疗痛风的药物。

Description

SIRT1受体激动剂及包含其的药物 技术领域
本发明属于药品或保健品领域，具体涉及一种SIRT1受体激动剂及包含其的药物。
背景技术
在化学医药领域中，尿酸是人类嘌呤化合物的最终代谢产物。嘌呤代谢紊乱导致高尿酸血症。在正常嘌呤饮食状态下，非同日两次空腹血尿酸水平男性高于420μmol/L，女性高于360μmol/L，即称为高尿酸血症(hyperuricemia)。通常，单纯的处于高尿酸血症状态并没有自觉症状，但如果长时间处于该状态，血液中的尿酸盐将发生结晶，沉积在关节、皮下组织、肾脏等部位，进而出现痛风及痛风并发症等一系列临床表现。在最近公布的《2017年中国痛风现状报告白皮书》中显示，我国高尿酸血症患者人数已达1.7亿，其中痛风患者超过8000万人，而且正以每年9.7％的年增长率迅速增加。预计2020年，痛风人数将达到1亿。现今痛风已经成为我国仅次于糖尿病的第二大代谢类疾病，并严重危害着人们的生命和健康。
目前，治疗高尿酸血症、高尿酸血症引起的痛风及痛风并发症时，需要对血液中的尿酸进行控制：对于尿酸排泄不良型患者(占90％)适用促进尿酸排泄的药物，如：苯溴马隆、雷西纳德等；对于尿酸生成过多型患者适用抑制尿酸生产的药物(主要为黄嘌呤氧化酶抑制剂)，如：别嘌醇、非布司他。但随着这些药物临床应用的增加，其不良反应也逐渐暴露。
别嘌呤醇(allopurinol)是最早上市的抑制尿酸生成的药物，自1963年应用于临床以来，因其价格低廉、降尿酸效果好，一直是治疗慢性痛风的主要药物。但随着别嘌呤醇的推广，不良反应的报道也逐渐增多，从20世纪70年代开始就有报道表明别嘌呤醇可引起肝肾损伤、白细胞减低、皮疹等不良反应，有约1.5％的过敏风险，严重的可能发生致死性过敏，引 起了全世界范围的关注。因此，为减少不良反应，对于别嘌呤醇需从小剂量起用。
非布司他(Febuxostat，商品名：Uloric，武田北美制药公司)是一种非嘌呤类选择性黄嘌呤氧化酶抑制剂，于2008年5月在欧盟上市，2009年3月经美国FDA批准上市，2013年进入中国市场，用于长期治疗伴随痛风的高尿酸血症。相较于其他治疗高尿酸血症的药物，非布司他具有更高的选择性和更强的活性。但是，相关研究及临床实践表明，非布司他也具有一定的不良反应：常见的不良反应有肝功能异常(3.5％)、腹泻(2.7％)、头痛(1.8％)、恶心(1.7％)和皮疹(1.5％)等。2017年11月15日，FDA发布了非布司他心脏相关性死亡风险警告；2018年2月7日，CFDA发布药物警戒快讯“一项由6000例痛风患者参与的安全性临床试验的初步结果表明，与别嘌醇相比，非布司他可能增加心脏相关性死亡的风险”。
上述药物常规剂量下毒副作用较大，加之上述药物耐受性普遍较低，在一定程度上限制了这些药物的临床应用。
沉默信息调节因子1(silent information regulator 1,SIRT1)为sirtuin蛋白家族成员之一，存在于真核和原核生物中。其在细胞存活、增殖过程中发挥着重要的生理作用，其功能失调涉及生理活性如衰老，以及多种疾病，如肿瘤、糖尿病、心血管疾病、慢性炎症及部分代谢性疾病的发生与发展。具体来说，在细胞代谢相关：SIRT1对转录因子FOXO和p53来调节细胞分化、增殖和衰老，通过上调SIRT1可以通过其脱乙酰化作用恢复衰老小鼠胚胎成纤维细胞的FOXO3的功能，修复损伤的DNA，激活细胞周期调节蛋白D、细胞周期调控因子p27Kip1等提高对活性氧自由基解毒作用。
SIRT1激动剂还可以抑制炎症因子如肿瘤坏死因子TNF-a，白介素IL-1β、IL-6等的释放，减缓慢性阻塞性肺部疾病、结肠炎等多种慢性炎症疾病的进展。SIRT1在CD4+和CD8+T细胞的高水平表达提示其参与免疫功能调节过程，其可作用于转录因子FOXP3，通过脱乙酰化作用提高调节性T细胞的数量和功能，并且还有抑制细胞的过度自体吞噬、减少细胞死 亡、调节脂肪代谢的生物过程、减少脂肪沉积以及调节内皮细胞功能、保护心脏的作用。
同时，在代谢性疾病相关，SIRT1激动剂可以提高对葡萄糖的耐受性、增强胰岛素的分泌，并且小鼠模型试验还发现SIRT激动剂可明显减轻氧秦酸钾和酵母膏诱导的高尿酸血症，并改善肾脏组织炎性细胞浸润，从而改善慢性肾衰，降低血肌酐水平。
SIRT1结构性表达于关节软骨，但在严重关节炎患者的软骨中却几乎检测不到SIRT1。提高SIRT1表达可以延缓骨关节炎的进展，同时还可以调节破骨细胞和成骨细胞的活性改善骨代谢，从而减轻骨质疏松症。还有研究表明SIRT1抑制剂可以通过降低类风湿关节炎滑膜细胞的活性二抑制滑膜细胞肥大，由此来减轻类风湿关节炎。而预防型的给与SIRT1激动剂治疗，能够显著抑制尿酸盐结晶诱导的关节炎症反应。[朱小霞,刘琼,陈海燕,等.沉默信息调节因子1及其与痛风和高尿酸血症关联的研究进展[J].上海医药,2015(11):19-22.]
另有文献报道，SIRT1可促进回肠中ABCG2的表达，从而促进肠道对于尿酸的排泄。而同时可以抑制肾脏中URAT1的mRNA水平，说明SIRT1激动剂可能通过促进肠道和肾脏对尿酸的排泄来达到降尿酸的效果。[Wang J,Zhu X X,Liu L,et al.SIRT1 prevents hyperuricemia via the PGC-1α/PPARγ-ABCG2 pathway[J].Endocrine,2016,53(2):443-452。]
本申请人经过长期研究发现一系列具有SIRT1激动活性的化合物可用于降尿酸的作用。
发明内容
本发明的目的在于提供具有SIRT1激动活性的新型化合物。
为此，本发明提供了如下技术方案来：
下述通式(I)所示的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，
Figure PCTCN2021085919-appb-000001
其中，R 1、R 2彼此独立地选自氢、羟基、羧基、Rm取代或未取代的C 1-C 7的烷基、Rm取代或未取代的C 1-C 7的烯基、Rm取代或未取代的C 1-C 7的酮基、Rm取代或未取代的C 1-C 7的酯基；
R 3选自Rm取代或未取代的C 1-C 7的烷基、Rm取代或未取代的C 1-C 7的烯基、Rm取代或未取代的C 1-C 7的酮基；
Rm选自OH、CHO、OCOCH 3，以及由
Figure PCTCN2021085919-appb-000002
中的至少一种所形成的糖基残基。
进一步地，R 1选自CH 3、COOH、COCH 3、
Figure PCTCN2021085919-appb-000003
Figure PCTCN2021085919-appb-000004
R 2选自H、OH、CH 3、
Figure PCTCN2021085919-appb-000005
R 3选自
Figure PCTCN2021085919-appb-000006
Figure PCTCN2021085919-appb-000007
Rm选自OH、CHO、OCOCH 3，以及由
Figure PCTCN2021085919-appb-000008
中的至少一种所形成的糖基残基；
其中，
Figure PCTCN2021085919-appb-000009
表示选自-或＝。
进一步地，当R 3选自
Figure PCTCN2021085919-appb-000010
Figure PCTCN2021085919-appb-000011
Figure PCTCN2021085919-appb-000012
时，R 3的＊端连接在通式(I)所示的化合物炔基端。
进一步地，式(I)所示的化合物选自：
Figure PCTCN2021085919-appb-000013
Figure PCTCN2021085919-appb-000014
Figure PCTCN2021085919-appb-000015
Figure PCTCN2021085919-appb-000016
本发明还提供了下述通式(II)所示的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，
Figure PCTCN2021085919-appb-000017
其中，
Figure PCTCN2021085919-appb-000018
表示选自-或＝，R为H或COCH 3。
进一步地，式(II)所示的化合物选自：
Figure PCTCN2021085919-appb-000019
本发明还提供了上述任一所述的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物作为Sirt1受体激动剂的应用。
进一步地，所述应用包括制备预防和/或治疗与Sirt1受体功能失调相关的疾病的药物；其中，与Sirt1受体功能失调相关的疾病为衰老、肿瘤、糖尿病、心血管疾病、慢性炎症、骨质疏松症、肥胖、高尿酸血症和痛风 中的至少一种；所述慢性炎症为慢阻肺、结肠炎、类风湿关节炎、慢性肾衰和痛风性关节炎中的至少一种。
本发明还提供了一种药物，其含有有效量的上述任一所述的一种或多种化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物以及一种或多种药学上可接受的赋形剂。
进一步地，其含有有效量的上述任一所述的一种或多种化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物以及一种或多种其他活性成分的组合。
本发明的技术方案具有如下优点：
本发明通过Sirt1活性测试发现，本发明制备的化合物均具有Sirt1激活作用，可作为潜在的sirt1激动剂，通过高尿酸血症动物模型发现，本发明的化合物在体内具有显著的降尿酸作用，可以作为潜在的降尿酸或治疗痛风的药物。
具体实施方式
本发明以下实施例和实验例中，化合物可以按照本发明实施例的方法进行制备获得，也可以按照现有技术文献中的方法制备获得。
实施例1
Figure PCTCN2021085919-appb-000020
取菊科植物大丽花(Dahlia pinnata Cav)的干燥根茎5kg，粉碎后用3倍重量的体积浓度为70％的乙醇水溶液，室温下浸泡提取一周，提取两次，合并两次提取液，减压浓缩除去有机溶剂，得浸膏。将浸膏用1倍体积的乙醚萃取两次，将乙醚萃取液减压浓缩，得到胶状物，将该胶状物溶解于其10倍重量的汽油乙醚(体积比为9：1)溶液中，作为上样液，用硅胶柱分离，以汽油和乙醚的混合液为流动相，按照以下程序进行梯度洗脱，汽油与乙醚的体积比分别为9:1、7:1、5:1、3:1、1:1、1:3，最后用乙醚洗脱，上述各流动相均洗脱3BV，根据TLC检测结果合并洗脱液，得到化合物1-1、1-2、1-3、1-4及混合物Fr1-1。将混合物Fr1-1再次用硅胶柱分离，以汽油和乙醚的混合液为洗脱液，按照如下程序进行梯度洗脱，汽油/乙醚的体积比为3:1、2:1、1:1、1:2、1:3、1:5，上述各流动相均洗脱3BV，根据TLC检测结果合并洗脱液，得到化合物1-5和1-6。
取100mg化合物1-5，500mg的MnO 2，溶于50mL二氯甲烷，20℃震荡2小时，将混合液用硅胶柱层析，洗脱液为汽油和乙醚的混合液(体积比1：1)，根据TLC检测结果合并洗脱液得到Fr2-1，Fr2-2，Fr2-3，将Fr2-2用二氯甲烷和汽油的混合液(体积比1：1)重结晶，得到化合物1-7。
取1mmol化合物1-5，加入1.1mmolDess-Martin试剂，30mlCH 2Cl 2，室温下反应5分钟，将所得产物经过反相硅胶制备柱色谱进行分离，以甲醇和水的混合液为洗脱液按照如下程序进行梯度洗脱，甲醇的体积百分数为20％、25％、30％、35％，上述各流动相均洗脱3BV，根据TLC检测结果合并洗脱液，分别浓缩干燥得到化合物1-8～1-11及化合物1-20(本合成反应可同比例放大，以制备足量的化合物，下同)。
取化合物1-8～1-10(各1mmol)，分别加入1.2mmolPd/SiO 2，与三辛胺和正丁醇的混合液(体积比1：1)50ml混合，在45℃，pH为7.5，搅拌条件下反应4小时，分别得到化合物1-12～1-14。
取2mmol化合物1-5，加入4mmolCCl 4，8mmolPPh 3，75mlCH 2Cl 2室温5小时，N 2保护下，加入4mmoln-BuLi，50mlTHF，在-78℃下搅拌5分钟，将所得产物反相硅胶制备柱色谱进行分离，以甲醇和水的混合液为洗脱液按照如下程序进行梯度洗脱，甲醇的体积百分数为30％、35％，上述各流动相均洗脱3BV，根据TLC检测结果合并洗脱液，分别浓缩干燥得到化合物1-15和1-16。
取1.2mmol化合物1-10溶于45ml无水CH 2Cl 2中，加入全乙酰化溴代葡萄糖1.35mmol，于室温下搅拌30min，加入1.35mmolAg 2CO 3，N 2保护下，避光反应约24小时，过滤，滤液依次用饱和50mlNaHCO 3，50ml饱和NaCl，和50ml蒸馏水洗涤，无水MgSO 4干燥，减压浓缩，残余物溶于30ml无水甲醇中，加入甲醇钠0.6mmol，于室温反应约30min，稀盐酸调节pH为6，减压浓缩，残余物经硅胶柱层析法纯化，用CH 2Cl 2和甲醇的混合溶液按照如下程序进行梯度洗脱，CH 2Cl 2和甲醇的体积比为7:1、18:1、30:1，上述各流动相均洗脱3BV，得到化合物1-17。
取1mmol化合物1-7溶于35ml无水CH 2Cl 2中，加入全乙酰化溴代葡萄糖1.1mmol，于室温下搅拌30min，加入1.1mmolAg 2CO 3，N 2保护下，避光反应约24小时，过滤，滤液依次用30ml饱和NaHCO 3，30ml饱和NaCl，和30ml蒸馏水洗涤，无水MgSO 4干燥，减压浓缩，残余物溶于18ml无水甲醇中，加入0.5mmol甲醇钠，于室温反应约30min，稀盐酸调节pH为6，减压浓缩，残余物经硅胶柱层析法纯化，用CH 2Cl 2和甲醇的混合溶液按照如下程序进行梯度洗脱，CH 2Cl 2和甲醇的体积比为7:1、15:1、30:1，上述各流动相均洗脱3BV，得到化合物1-19。
取2mmol乙酰氯，0℃下缓慢滴加到化合物1-13中，30min之后，再加入1mmol的乙酸，回流10小时，减压浓缩，浓缩液用CH 2Cl 2萃取，所得产物经过反相硅胶制备柱色谱进行分离，用甲醇等度洗脱(体积百分数为25％甲醇水溶液)，根据TLC检测结果合并洗脱液，浓缩干燥得到化合物1-18。
将上述制备得到的化合物分别通过 1H NMR、 13C NMR和HPLC-MS进行结构确认，结构确认数据参考如下文献：
化合物1-1～1-3和1-5～1-7参考如下文献：Fairbrother J R F,et al.natural acetylenes.part xlix.polyacetylenes from dahlia scapigera(a.dietr.)link and otto var.scapigera f.scapigera and some dahlia hybrids.J Chemischer Informationsdienst,1976,7(25):735-741。
化合物1-4参考如下文献：He J,Shen Y,Jiang J S,et al.New polyacetylene glucosides from the florets of Carthamus tinctorius and their weak anti-inflammatory activities[J].Carbohydrate Research,2011,346(13):1903-1908。
化合物1-8
ESI-MS:213[M] +, 1H-NMR(CDCl 3):7.265(1H,dd,J＝15.6Hz,10.8Hz,C5-H),6.87(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.37(1H,dd,J＝15.6Hz,6.8Hz,C13-H), 6.33(1H,d,J＝15.6Hz,C4-H),5.86(1H,d,J＝15.6Hz,C7-H),5.62(1H,d,J＝15.6Hz,C12-H),4.13(2H,s,C2-H),1.847(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(197.4),C-2(54.8),C-3(198.5),C-4(133.2),C-5(143.0),C-6(141.3),C-7(110.61),C-8(79.9),C-9(75.24),C-10(73.41),C-11(80.5),C-12(109.41),C-13(141.76),C-14(18.46)
化合物1-9
ESI-MS:215[M] +, 1H-NMR(CDCl 3):6.683(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.40(1H,dd,J＝15.6Hz,10.8Hz,C5-H),6.32(1H,dd,J＝15.6Hz,6.8Hz,C13-H),6.01(1H,dd,J＝15.6Hz,5.6Hz,C4-H),5.89(1H,d,J＝15.6Hz,C7-H),5.76(1H,d,J＝15.6Hz,C12-H),4.36(1H,m,C3-H),2.71(1H,dd,J＝11.6Hz,4Hz,C2-H),2.41(1H,dd,J＝11.6Hz,4Hz,C2-H),1.80(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(202.01),C-2(51.87),C-3(66.63),C-4(143.76),C-5(129.71),C-6(144.7),C-7(109.71),C-8(80.3),C-9(75.98),C-10(72.89),C-11(81.87),C-12(108.61),C-13(145.76),C-14(18.57)
化合物1-10
ESI-MS:213[M] +, 1H-NMR(CDCl 3):6.87(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.56(1H,d,J＝15.6Hz,10.8Hz,C5-H),6.51(1H,d,J＝15.6Hz,C4-H),6.29(1H,d,J＝6.4Hz,C2-H),6.18(1H,dd,J＝15.6Hz,6.8Hz,C13-H),5.78(1H,d,J＝15.6Hz,C7-H),5.56(1H,d,J＝15.6Hz,C12-H),1.77(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(196.4),C-2(109.1),C-3(189.0),C-4(122.5),C-5(130.8),C-6(140.3),C-7(110.9),C-8(80.2),C-9(76.4),C-10(72.41),C-11(81.3),C-12(110.41),C-13(141.6),C-14(18.67)
化合物1-11
ESI-MS:213[M] +, 1H-NMR(CDCl 3):7.15(1H,dd,J＝15.6Hz,10.8Hz,C5-H),6.87(1H,d,J＝15.6Hz,10.8Hz,C6-H),6.71(1H,d,J＝11.2Hz,C2-H),6.65(1H,d,J＝15.6Hz,C4-H),6.15(1H,dd,J＝15.6Hz,6.8Hz,C13-H),5.83(1H,d,J＝11.2Hz, C1-H),5.74(1H,d,J＝15.6Hz,C7-H),5.66(1H,d,J＝15.6Hz,C12-H),1.82(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(186.4),C-2(105.1),C-3(188.2),C-4(124.5),C-5(151.8),C-6(140.9),C-7(110.9),C-8(80.1),C-9(75.4),C-10(74.41),C-11(80.9),C-12(109.1),C-13(141.3),C-14(18.07)
化合物1-12
ESI-MS:227[M] -, 1H-NMR(CDCl 3):7.18(1H,dd,J＝15.6Hz,10.8Hz,C5-H),6.78(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.33(1H,d,J＝15.6Hz,C4-H),6.17(1H,dd,J＝15.6Hz,6.8Hz,C13-H),5.82(1H,d,J＝15.6Hz,C7-H),5.66(1H,d,J＝15.6Hz,C12-H),3.88(2H,s,C2-H),1.83(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(172.4),C-2(47.8),C-3(198.9),C-4(131.2),C-5(142.7),C-6(142.3),C-7(110.11),C-8(78.9),C-9(74.1),C-10(72.7),C-11(80.1),C-12(111.2),C-13(141.6),C-14(18.35)
化合物1-13
ESI-MS:229[M] -, 1H-NMR(CDCl 3):6.87(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.48(1H,dd,J＝15.6Hz,10.8Hz,C5-H),6.12(1H,dd,J＝15.6Hz,6.8Hz,C13-H),5.91(1H,dd,J＝15.6Hz,5.6Hz,C4-H),5.79(1H,d,J＝15.6Hz,C7-H),5.71(1H,d,J＝15.6Hz,C12-H),4.36(1H,m,C3-H),2.55(1H,dd,J＝11.6Hz,4Hz,C2-H),2.30(1H,dd,J＝11.6Hz,4Hz,C2-H),1.81(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(177.3),C-2(45.2),C-3(69.8),C-4(133.7),C-5(129.5),C-6(143.2),C-7(111.1),C-8(80.1),C-9(74.9),C-10(71.8),C-11(81.8),C-12(109.1),C-13(143.7),C-14(18.7)
化合物1-14
ESI-MS:227[M] -, 1H-NMR(CDCl 3):6.85(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.51(1H,d,J＝15.6Hz,10.8Hz,C5-H),6.48(1H,d,J＝15.6Hz,C4-H),6.17(1H,dd,J＝15.6Hz,6.8Hz,C13-H),6.09(1H,s,C2-H),5.98(1H,d,J＝15.6Hz,C7-H),5.61(1H,d,J＝15.6Hz,C12-H),1.81(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(170.4),C-2(101.1),C-3(183.3),C-4(119.9),C-5(135.6),C-6(145.2),C-7(112.1),C-8(84.2),C-9(79.4),C-10(77.41),C-11(81.3),C-12(109.41),C-13(142.6),C-14(18.96)
化合物1-15
ESI-MS:197[M] +, 1H-NMR(CDCl 3):7.35(1H,dd,J＝15.6Hz,10.8Hz,C5-H),6.77(1H,d,J＝15.6Hz,10.8Hz,C6-H),6.65(1H,d,J＝15.6Hz,C4-H),6.61(1H,dd,J＝11.2Hz,15.6Hz,C2-H),6.18(1H,dd,J＝15.6Hz,6.8Hz,C13-H),5.82(1H,d,J＝11.2Hz,C1-H),5.82(1H,d,J＝15.6Hz,C1-H),5.75(1H,d,J＝15.6Hz,C7-H),5.61(1H,d,J＝15.6Hz,C12-H),1.83(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(137.7),C-2(137.8),C-3(188.6),C-4(126.9),C-5(150.9),C-6(143.2),C-7(109.9),C-8(79.9),C-9(77.4),C-10(75.1),C-11(80.1),C-12(110.2),C-13(142.3),C-14(17.9)
化合物1-16
ESI-MS:199[M] +, 1H-NMR(CDCl 3):6.89(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.58(1H,d,J＝15.6Hz,10.8Hz,C5-H),6.11(1H,dd,J＝15.6Hz,6.8Hz,C13-H),5.91(1H,dd,J＝15.6Hz,6.4Hz,C4-H),5.89(1H,m,C2-H),5.78(1H,d,J＝15.6Hz,C7-H),5.65(1H,d,J＝15.6Hz,C12-H),5.23(1H,d,J＝10.8Hz,C1-H),5.34(1H,d,J＝15.6Hz,C1-H),4.59(1H,dd,J＝6.4Hz,5.6Hz,C3-H)1.83(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(117.7),C-2(139.8),C-3(76.3),C-4(128.9),C-5(129.9),C-6(140.2),C-7(110.9),C-8(79.8),C-9(75.4),C-10(73.1),C-11(81.2),C-12(110.8),C-13(141.3),C-14(18.0)
化合物1-17
ESI-MS:375[M] +, 1H-NMR(MeOD-d4):6.81(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.52(1H,d,J＝15.6Hz,10.8Hz,C5-H),6.49(1H,d,J＝15.6Hz,C4-H),5.15(1H,d,J＝6.4Hz,C2-H),6.09(1H,dd,J＝15.6Hz,6.8Hz,C13-H),5.76(1H,d,J＝15.6Hz,C7-H),5.56(1H,d,J＝15.6Hz,C12-H),1.87(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
GLC:5.32(1H,d,J＝7.8Hz,C1’-H),3.26(1H,m,C2’-H),3.39(1H,m,C3’-H),3.31(1H,m,C4’-H),3.29(1H,m,C5’-H),3.86,3.66(2H,m,C6’-H)；
13C-NMR(CDCl 3):C-1(191.4),C-2(102.9),C-3(169.0),C-4(122.4),C-5(130.3),C-6(141.5),C-7(110.1),C-8(79.8),C-9(72.4),C-10(72.1),C-11(79.6),C-12(109.9),C-13(142.1),C-14(18.07)
GLC:C1’(101.7),C2’(74.3),C3’(73.5),C4’(71.5),C5’(77.8),C6’(62.3)
化合物1-18
ESI-MS:229[M] -, 1H-NMR(CDCl 3):6.70(1H,dd,J＝15.6Hz,10.8Hz,C6-H),6.37(1H,dd,J＝15.6Hz,10.8Hz,C5-H),6.32(1H,dd,J＝15.6Hz,6.8Hz,C13-H),5.86(1H,dd,J＝15.6Hz,6.8Hz,C4-H),5.82(1H,d,J＝15.6Hz,C7-H),5.64(1H,d,J＝15.6Hz,C12-H),5.18(1H,m,C3-H),2.63(1H,dd,J＝11.6Hz,4Hz,C2-H),2.38(1H,dd,J＝11.6Hz,4Hz,C2-H),2.05(3-C＝O-CH 3,S),1.81(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(175.3),C-2(45.2),C-3(72.3),C-4(135.7),C-5(132.5),C-6(145.2),C-7(112.1),C-8(80.1),C-9(74.9),C-10(71.8),C-11(81.8),C-12(110.7.1),C-13(144.7),C-14(18.88),-C＝O-CH 3(21.1),-C＝O-CH 3(170.3)
化合物1-19
ESI-MS:377[M] +
1H-NMR(CDCl 3):1.71(3H,dd,J＝1.6HZ,6.8HZ),6.08(1H,m),5.50(1H,d,J＝15.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),7.40(1H,dd,J＝11.2HZ,11.6HZ),6.33(1H,d,J＝15.6HZ),3.48(2H,t,J＝5.2HZ,5.6HZ),3.11(2H,t,J＝5.2HZ,5.6HZ),5.03(1H,d,J＝6.8HZ),3.73(1H,s),3.49(1H,s),3.40(1H,s),3.75(1H,s),3.54(2H,d,J＝5.6HZ)；
13C-NMR(CDCl 3)
130.2，142.1，140.9，110.9，79.9，77.5，77.5，79.9，110.9，141.6，200.4，18，43.1，59.8，104.2，77.7，71.5，73.4，73.8，62.3
化合物1-20
ESI-MS:215[M] +,
1H-NMR(CDCl 3):7.165(1H,dd,J＝15.6Hz,11.2Hz,C5-H),6.756(1H,dd,J＝15.6Hz,11.2Hz,C6-H),6.377(1H,m,J＝15.6Hz,6.8Hz,C13-H),6.249(1H,d,J＝15.6Hz,C4-H),6.099(1H,d,J＝15.6Hz,C7-H),5.611(1H,d,J＝15.6Hz,C12-H),3.907(2H,t,J＝10.8Hz,1.6Hz,C1-H),2.834(2H,t,J＝10.8Hz,1.6Hz,C2-H),1.847(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl 3):C-1(57.98),C-2(42.52),C-3(200.00),C-4(131.30),C-5(141.0),C-6(141.3),C-7(119.61),C-8(81.40),C-9(79.24),C-10(79.10),C-11(84.43),C-12(109.71),C-13(144.76),C-14(18.96)
实施例2 化合物2的制备
取干燥长毛风毛菊全草20kg，用5倍重量的体积浓度为70％的乙醇水溶液室温浸泡提取，每次浸泡提取三天，提取两次，合并两次提取液，减压浓缩去除乙醇，得到浸膏。所得浸膏用两倍体积乙酸乙酯萃取两次，合并两次乙酸乙酯层萃取液，减压浓缩得到粗提取物，将该粗提取物经过硅胶拌样，使用硅胶柱层析，分别以正己烷：乙酸乙酯(体积比分别为25:1、20:1、15:1、10:1、7:1、4:1、2:1、1：1)，以及乙酸乙酯作为流动相梯度洗脱，上述各流动相均洗脱3BV，根据薄层色谱(TLC)检测结果进行合并，得到5个组分Fra～Fre。Frc使用Sephadex LH-20柱层析分离，使用甲醇水溶液梯度洗脱(15％，30％，40％，50％，60％，70％，85％，100％甲醇水溶液)，上述各流动相均洗脱3BV，根据薄层色谱(TLC)检测结果进行合并，得到含有化合物2的洗脱液，该洗脱液使用Agilent SD-1反相制备液相色谱进行分离，以甲醇水溶液作为流动相梯度洗脱(30％，35％，40％，95％甲醇水溶液)，上述各流动相均洗脱3BV，得到化合物2，其结构式如下所示：
Figure PCTCN2021085919-appb-000021
将上述制备得到的化合物分别通过 1H NMR、 13C NMR和HPLC-MS，紫外全波长扫描及红外图谱进行结构确认，结构确认数据参考如下文献：Ferdinand Bohlmann und Winfried Karl Polyacetylenverbindungen,202Notiz uber die Biogenese des Athusins[J].Chem.Ber.1972,105,355-357.
实施例3 化合物3-1～3-6的制备
Figure PCTCN2021085919-appb-000022
将30mmol底物A和30mmol底物B和2mmol醋酸铜混合，然后充入CO 2(1个大气压)，在CO 2气氛下加入二氯甲烷400mL，在室温下搅拌30min后，在60℃搅拌反应10h，最后冷却至室温，用乙酸乙酯80mL淬灭反应液，在室温下搅拌30min。用硅藻土或少量硅胶过滤后浓缩旋干，纯化，得到产物1、2、3；
取15mmol产物1溶于200mL二氯甲烷中，室温下加入0.5mmol钡锰酸盐催化剂(Barium manganate)反应10h，反应结束，反应液加200mL二氯甲烷稀释并过滤，滤饼经润洗、纯化，得到产物4、5、6；
取6mmol产物5溶于90mL二氯甲烷中，加10mmoL的Ph 3P＝CHCOCH 3室温条件下催化反应6h，反应结束，产物经浓缩旋干、纯化，得到目标化合物3-1，3-3，3-5。
取1mmol目标化合物3-1，3-3，3-5分别溶于30mL二氯甲烷中，加入15mLDMSO和1mmolIBX后于0℃反应2h，产物经分离，纯化，得到目标化合物3-2，3-4，3-6。
将上述制备得到的化合物3-1～3-6分别通过 1H-NMR、 13C-NMR和HPLC-MS，紫外全波长扫描及红外图谱进行结构确认，结构确认数据参考如下文献：Hartmut Laatsch und Alke Pudleiner，Synthese von ω-Acetyl-α-methylenpolyencarbonsaureester[J].J.prakt.Chem.336(1994)663-677
实施例4 化合物4-1～4-4的制备
Figure PCTCN2021085919-appb-000023
Figure PCTCN2021085919-appb-000024
步骤a)：取2mmolHBBr 2-DMS 5加入60mlCH 2Cl 2溶剂，室温，加入NaOH(4.4mmol，2M，水溶液)，加入2.2mmol1,3丙二醇，50ml正戊烷溶剂混合，室温反应5分钟。
步骤b)：向步骤a)的产物中加入2mmolICH 2＝CH 2Cl，(PPh 3) 4Pd(5mol-％)，KOH(4.2mmol，1M，H 2O)，加入60mLTHF，回流，随后加入2mmolCH≡C-TMS，CuI(10mol-％)，PdCl 2(PhCN) 2(5mol-％)，哌啶45mL，室温反应10分钟。
步骤c)：向步骤b)的产物中加入2.2mmol K 2CO 3加入5mLMeOH，室温，加入2.1mmolEtMgBr，3mLTHF，室温，随后加入I 2溶液(2.2mmolI 2溶于60mL的THF溶剂中)，室温反应10分钟，得到化合物17。
步骤d)：取2.2mmolMe 3Si-C≡C-H，2mmolBuLi，20mLTHF，-78℃，5分钟，0℃，反应10分钟，置于-78℃，加入2mmolI 2，室温反应10分钟，得到2.2mmolMe 3Si-C≡C-I；无需后续处理，立即使用。
步骤e)：取2.2mmolMe 3Si-C≡C-I，Pd(dba) 2(2mol-％)，AsPh 3(8mol-％)，2mmol化合物16，40mLTHF混合，室温反应3小时。
步骤f)：向步骤e)的产物中加入2mmolK 2CO 3，4mLMeOH，室温反应14小时。
步骤g)：将步骤f)的产物加入2mmol化合物17，PdCl 2(PPh 3) 2(3mol-％)，CuI(3mol-％)，50mLTHF/iPr 2NH(5：8，体积比)，室温反应15分钟，可得到化合物4-1。
将前述反应中步骤e)的化合物16更换为化合物18，进行d)，e)，f)步骤反应后，直接与化合物19(代替化合物17)进行g)步骤反应可得化合物4-2。
取4mmol乙酰氯，0℃下缓慢滴加到1mmol化合物4-1中，30min之后，再加入的20mL乙酸，回流10小时，减压浓缩，浓缩液用40mLCH 2Cl 2萃取，所得产物经过反相硅胶制备柱色谱进行分离，用体积百分数25％甲醇水溶液等度洗脱，根据TLC检测结果合并洗脱液，分别浓缩干燥得到化合物4-3。
取4mmol乙酰氯，0℃下缓慢滴加到1mmol化合物4-2中，30min之后，再加入的20mL乙酸，回流10小时，减压浓缩，浓缩液用40mLCH 2Cl 2萃取，所得产物经过反相硅胶制备柱色谱进行分离，用体积百分数25％甲醇水溶液等度洗脱，根据TLC检测结果合并洗脱液，分别浓缩干燥得到化合物4-4。
将上述制备得到的化合物分别通过 1H-NMR、 13C-NMR和HPLC-MS，紫外全波长扫描及红外图谱进行结构解析。
化合物4-1
ESI-MS 301[M] -
1H-NMR(CDCl 3):
3.53(4H,m),1.67(4H,m),3.90(2H,m),5.91(2H,dd,J＝15.6HZ,5.6HZ),6.48(2H,dd,J＝11.2HZ,11.6HZ),6.87(2H,dd,J＝11.2HZ,11.6HZ),5.74(2H,d,J＝15.6HZ)；
13C-NMR(CDCl 3):132.8，128.9，140.9，110.9，79.9，77.5，77.5，79.9，110.9，140.9，69.3，128.9，39.8，56.8，132.8，69.3，39.8，56.8，
化合物4-2
ESI-MS 305[M] -
1H-NMR(CDCl 3):
3.54(4H,m),1.63(4H,m),3.21(2H,m),1.48(4H,m),1.96(4H,m),6.08(2H,m),5.50(2H,d,J＝15.6HZ)；
13C-NMR(CDCl 3):38.4，26.3，146.3，109.4，79.9，77.5，77.5，79.9，109.4，146.3，68，40.1，56.7，26.3，38.4，68，40.1，56.7
化合物4-3
ESI-MS 469[M] -
1H-NMR(CDCl 3):
2.01(6H,dd,J＝1.6HZ,6.8HZ),4.08(4H,dd,J＝6.8HZ,8HZ),1.85(4H,m),4.64(2H,m),2.04(6H,dd,J＝1.6HZ,6.8HZ),5.91(2H,dd,J＝15.6HZ,5.6HZ),6.48(2H,dd,J＝11.2HZ,11.6HZ),6.87(2H,dd,J＝11.2HZ,11.6HZ),5.74(2H,d,J＝15.6HZ)；
13C-NMR(CDCl 3):132.8，128.9，140.9，110.9，79.9，77.5，77.5，79.9，110.9，140.9，72.4，170.3，21.1，33.2，59.1，170.3，20.7，128.9，132.8，72.4，33.2，170.3，21.1，59.1，170.3，20.7
化合物4-4
ESI-MS 473[M] -
1H-NMR(CDCl 3):
2.01(6H,dd,J＝1.6HZ,6.8HZ),4.08(4H,dd,J＝6.8HZ,8HZ),1.81(4H,m),3.95(2H,m),1.57(4H,m),1.96(4H,m),6.08(2H,m),5.51(2H,d,J＝15.6HZ),2.04(6H,dd,J＝1.6HZ,6.8HZ)；
13C-NMR(CDCl 3):34.8，26.5，146.3，109.4，79.9，77.5，77.5，79.9，109.4，146.3，73.2，170.3，21，33.5，59，170.3，20.7，26.5，34.8，73.2，33.5，59，170.3，20.7，170.3，21
实施例5 化合物5-1～5-13的合成
Figure PCTCN2021085919-appb-000025
步骤a)：取5mmo原料7，10mmolCBr 4和20mmolPPh 3，150mlCH 2Cl 2混合，室温反应4小时，得到化合物8；
步骤b)：取5mmo原料9，5mmolBuLi和50mLTHF混合，置于-78℃，5分钟，0℃，10分钟，-78℃，加入5mmol I 2室温反应10分钟，得到Me 3Si-C≡C-I(化合物10)；无需后续处理，立即使用；
步骤c)：向步骤a)的产物中加入11mmolMeLi，50mLTHF，-78℃，20分钟，室温10分钟，加入5mmol I 2，从-78℃升温至室温，在室温下反应1小时，得到化合物11；
步骤d)：取5.5mmolMe 3Si-C≡C-I，Pd(dba) 2(2mol-％)，AsPh 3(8mol-％)，5mmo原料15和50mLTHF混合，室温反应3小时，得到化合物12；
步骤e)：向步骤d)的产物中加入5mmol K 2CO 3和10mLMeOH，室温反应14小时，得到化合物13；
步骤f)：取步骤c)的产物与步骤e)的产物混合，加入Pd(dba) 2(5mol-％)，CuI(15mol-％)和80mLTHF/iPr 2NH(5：8，体积比)，室温反应15分钟，得到化合物5-1(重复制备步骤a-f以得到足量的化合物5-1用于后续的实验)；
步骤g)：向5mmol化合物5-1中加入5.5mmol Dess-Martin试剂和150mLCH 2Cl 2，室温反应5分钟，得到化合物5-2。
将原料7分别更换为原料21或原料22或原料23进行步骤a)的反应，其他步骤不变，得到化合物5-3，5-4，5-5。
将原料15更换为原料31进行步骤d)的反应，并且将原料7更换为原料21或原料22或原料23或原料24，其他步骤不变，得到化合物5-6，5-7，5-8，5-9。
取1mmol化合物5-1，5-3，5-4，5-5分别溶于30mL无水CH 2Cl 2中，加入全乙酰化溴代葡萄糖1.1mmol，于室温下搅拌30min，加入1.1mmol Ag 2CO 3，N 2保护下，避光反应约24小时，过滤，滤液依次用30mL饱和 NaHCO 3，30mL饱和NaCl，和30mL蒸馏水洗涤，无水MgSO 4干燥，减压浓缩，残余物溶于25mL无水甲醇中，加入甲醇钠0.5mmol，于室温反应30min，稀盐酸调节pH为6，减压浓缩，残余物经硅胶柱层析梯度洗脱，CH 2Cl 2甲醇溶液梯度洗脱(7:1、12:1、20:1、30:1)，上述各流动相均洗脱3BV，分别得到化合物5-10，5-11，5-12，5-13。
将上述制备得到的化合物分别通过 1H-NMR、 13C-NMR和HPLC-MS进行结构确认，化合物5-1和5-2结构确认数据参考如下文献：Ferdinand Bohlmann und Christa Zdero Polyacetylene compounds.CLXIV.Components of Coreopsis gigantean[J].Chem.Ber.102,1691-1697(1969)；Siegel K,Brückner,Reinhard.First Synthesis of Xerulin,an Inhibitor of the Biosynthesis of Cholesterol[J].Synlett,1999,1999(8):1227-1230.
化合物5-3
ESI-MS 187[M] -
1H-NMR(CDCl 3):
4.21(2H,d,J＝5.2HZ,5.6HZ),5.91(1H,m),6.48(1H,dd,J＝11.2HZ,11.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),5.71(1H,d,J＝15.6HZ),6.27(1H,m),4.20(2H,d,J＝5.2HZ,5.6HZ)；
13C-NMR(CDCl 3):110.1，79.9，77.5，77.5，79.9，110.9，140.2，64.3，140.9，129.5，127.3，65.6。
化合物5-4
ESI-MS 201[M] -
1H-NMR(CDCl 3):
4.21(2H,d,J＝5.2HZ,5.6HZ),5.91(1H,m),6.48(1H,dd,J＝11.2HZ,11.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.70(1H,d,J＝15.6HZ),6.43(1H,d,J＝11.6HZ)；
13C-NMR(CDCl 3):127.7，79.9，77.5，77.5，79.9，110.9，120.3，170.6，140.9，129.5，127.3，65.6
化合物5-5
ESI-MS 199[M] -
1H-NMR(CDCl 3):
4.20(2H,d,J＝5.2HZ,5.6HZ),5.91(1H,m),6.48(1H,dd,J＝11.2HZ,11.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.63(1H,d,J＝15.6HZ),6.69(1H,d,J＝11.2HZ),2.30(3H,s)；
13C-NMR(CDCl 3):122.6，79.9，77.5，77.5，79.9，110.9，137.6，197.7，140.9，129.5，127.3，65.6，28.3
化合物5-6
ESI-MS 201[M] -
1H-NMR(CDCl 3):
6.07(1H,d,J＝15.6HZ),7.47(1H,dd,J＝11.2HZ,11.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),5.71(1H,d,J＝15.6HZ),6.27(1H,m),4.20(2H,d,J＝5.2HZ,5.6HZ)；
13C-NMR(CDCl 3):110.1，79.9，77.5，77.5，79.9，110.9，140.2，64.3，140.9，147.2，117.5，170.6
化合物5-7
ESI-MS 215[M] -
1H-NMR(CDCl 3):
6.07(1H,d,J＝15.6HZ),7.47(1H,dd,J＝11.2HZ,11.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.70(1H,d,J＝15.6HZ),6.43(1H,d,J＝15.6HZ)；
13C-NMR(CDCl 3):127.7，79.9，77.5，77.5，79.9，110.9，120.3，170.6，140.9，147.2，117.5，170.6
化合物5-8
ESI-MS 213[M] -
1H-NMR(CDCl 3):
6.07(1H,d,J＝15.6HZ),7.47(1H,dd,J＝11.2HZ,11.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.63(1H,d,J＝15.6HZ),6.69(1H,d,J＝15.6HZ),2.30(3H,s)；
13C-NMR(CDCl 3):122.6，79.9，77.5，77.5，79.9，110.9，137.6，197.7，140.9，147.2，117.5，170.6，28.3
化合物5-9
ESI-MS 243[M] -
1H-NMR(CDCl 3):
6.07(1H,d,J＝15.6HZ),7.47(1H,dd,J＝11.2HZ,11.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),5.71(1H,d,J＝15.6HZ),6.27(1H,m),4.75(2H,d,J＝5.2HZ),2.01(3H,s)；
13C-NMR(CDCl 3):110.1，79.9，77.5，77.5，79.9，110.9，140.2，140.9，147.2，117.5，170.6，65.8，170.3，20.8
化合物5-10
ESI-MS 333[M] -
1H-NMR(CDCl 3):
1.71(3H,dd,J＝1.6HZ,6.8HZ),6.08(1H,m),5.50(1H,d,J＝15.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.48(1H,dd,J＝11.2HZ,11.6HZ),5.91(1H,m),4.04(2H,d,J＝5.2HZ),5.03(1H,d,J＝6.8HZ),3.73(1H,s),3.49(1H,s),3.40(1H,s),3.75(1H,s),3.54(2H,d,J＝5.6HZ)；
13C-NMR(CDCl 3):125.4，128.9，140.9，110.9，79.9，77.5，77.5，79.9，110.9，141.6，68.8，18，77.7，71.5，73.4，73.9，104.6，62.3
化合物5-11
ESI-MS 349[M] -
1H-NMR(CDCl 3):
4.20(2H,d,J＝5.2HZ),6.27(1H,m),5.71(1H,d,J＝15.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.48(1H,dd,J＝11.2HZ,11.6HZ),5.91(1H,m),4 .04(2H,d,J＝5.2HZ),5.03(1H,d,J＝6.8HZ),3.73(1H,s),3.49(1H,s),3.40(1H,s),3.75(1H,s),3.54(2H,d,J＝5.6HZ)；
13C-NMR(CDCl 3):125.4，128.9，140.9，110.9，79.9，77.5，77.5，79.9，110.1，140.2，68.8，64.3，77.7，71.5，73.4，73.9，104.6，62.3
化合物5-12
ESI-MS 363[M] -
1H-NMR(CDCl 3):
6.43(1H,d,J＝15.6HZ),6.70(1H,d,J＝15.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.48(1H,dd,J＝11.2HZ,11.6HZ),5.91(1H,m),4.04(2H,d,J＝5.2HZ),5.03(1H,d,J＝6.8HZ),3.73(1H,s),3.49(1H,s),3.40(1H,s),3.75(1H,s),3.54(2H,d,J＝5.6HZ)；
13C-NMR(CDCl 3):125.4，128.9，140.9，110.9，79.9，77.5，77.5，79.9，127.7，120.3，68.8，170.6，77.7，71.5，73.4，73.9，104.6，62.3
化合物5-13
ESI-MS 361[M] -
1H-NMR(CDCl 3):
2.30(3H,s),6.69(1H,d,J＝15.6HZ),6.63(1H,d,J＝15.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.48(1H,dd,J＝11.2HZ,11.6HZ),5.91(1H,m),4.04(2H,d,J＝5.2HZ),5.03(1H,d,J＝6.8HZ),3.73(1H,s),3.49(1H,s),3.40(1H,s),3.75(1H,s),3.54(2H,d,J＝5.6HZ)；
13C-NMR(CDCl 3):125.4，128.9，140.9，110.9，79.9，77.5，77.5，79.9，122.6，137.6，68.8，197.7，77.7，71.5，73.4，73.9，104.6，62.3，28.3
实施例6 化合物6的制备
Figure PCTCN2021085919-appb-000026
步骤a)：氮气保护下，取5mmol化合物1-10，6mmol三甲基氯化硅和60mLN-甲基吗啉体系混合，室温反应8小时；
步骤b)：向步骤a)的混合液中加入5.5mmolK 2CO 3，10mLMeOH，室温反应10小时，5.2mmolEtMgBr，THF10mL，室温，随后加入5.5mmol的I 2(溶于THF溶剂150mL)，反应10分钟；
步骤c)：在-15℃下向步骤b)的产物中滴加6mmol的异丙基氯化镁-氯化锂的THF溶液(1.3M)，搅拌2小时，将5mmol三甲基硅脂保护的葡萄糖酸内酯的正庚烷溶液缓慢滴加至体系中，升温至-10℃，反应3小时。滴加6mmol甲磺酸的甲醇溶液(0.62mol/L)，自然升至室温，搅拌，反应8小时。滴加饱和碳酸氢钠溶液50mL淬灭反应，调整至pH7.5，石油醚萃取，旋蒸除去溶剂后得产物。
步骤d)：将步骤c)的产物溶于乙腈和二氯甲烷的混合溶液60ml(体积比1：1)，冷却至-8℃，加入三乙基硅烷10mmol，然后滴加7.5mmol三氟化硼乙醚络合物，升温至0℃搅拌5小时，加入饱和碳酸氢钠50mL淬灭反应，调整pH7.5，减压浓缩除去有机溶剂，得到化合物6。
将上述制备得到的化合物分别通过 1H-NMR、 13C-NMR和HPLC-MS进行结构确认：
化合物6：
ESI-MS：359[M] +
1H-NMR(CDCl 3):
1.71(3H,dd,J＝1.6HZ,6.8HZ),6.08(1H,m),5.50(1H,d,J＝15.6HZ),6.87(1H,dd,J＝11.2HZ,11.6HZ),5.74(1H,d,J＝15.6HZ),6.51(1H,dd,J＝11.2HZ,11.6HZ),6.50(1H,d,J＝15.6HZ),6.21(1H,d,J＝4.2HZ),9.68(1H,d,J＝4.2HZ),4.36(1H,d,J＝5.2HZ),3.44(1H,m),3.49(1H,m),3.40(1H,m),3.76(1H,m),3.79(1H,m),3.54(1H,m)；
13C-NMR(CDCl 3):135.2，130.4，140.9 110.9，79.9，77.5，79.9，110.9，141.6，168.7，127.2 191.1，18，81.9，71.6，77.6，75.5，89.7，62.4
实施例7 化合物7的制备
取干燥的菊科鬼针草60kg，加入5倍重量的体积百分数为70％乙醇水溶液，室温浸泡提取三天，提取两次，合并提取液，减压浓缩去除乙醇，得浸膏。将所得浸膏用HPD-100大孔树脂进行柱层析，用纯水和体积百分数为70％的乙醇水溶液进行洗脱，将所得的70％乙醇洗脱液减压浓缩得到2.1kg固体。将该固体用D101大孔树脂进行柱层析，依次用纯水，20％，35％，60％，95％乙醇水溶液进行洗脱，上述各流动相均洗脱3BV，收集60％乙醇洗脱液，减压浓缩得到浸膏。将该浸膏使用硅胶柱层析进行分离，氯仿甲醇梯度洗脱(氯仿与甲醇的体积比100:1、50:1、35:1、20:1、10:1、5:1、3:1、2:1、1:1的混合溶液，上述各流动相均洗脱3BV)，得到 含有化合物7的洗脱液，将该洗脱液使用Sephadex LH-20柱层析分离，使用甲醇水溶液梯度洗脱(10％，15％，30％，45％，55％，70％，100％甲醇水溶液)，上述各流动相均洗脱3BV，得到Fr6.5-1至Fr6.5-7，其中Fr6.5-3使用反相硅胶制备柱色谱进行分离，使用甲醇水溶液梯度洗脱(30％，40％，50％，60％，95％甲醇水溶液)，上述各流动相均洗脱3BV，其中40％甲醇水溶液洗脱组分减压浓缩得到化合物7，其结构式如下所示：
Figure PCTCN2021085919-appb-000027
将上述制备得到的化合物分别通过 1H-NMR、 13C-NMR和HPLC-MS进行结构确认，结构确认数据参考如下文献：
化合物7：Wang X Y,Chen G R,Pan C X,et al.Polyacetylenes from Bidens bipinnata L.and their biological activities[J].Phytochemistry Letters,2014,7:198-201.
实施例8：
前述实施例中制备的各化合物，按常规法加注射用溶媒，精滤，灌封灭菌后可制成注射液。
实施例9：
前述实施例中制备的各化合物，将其溶于无菌注射用水中，用无菌漏斗过滤，分装，低温冷冻干燥后无菌熔封即得粉针剂。
实施例10：
前述实施例中制备的各化合物，作为药物活性成分，使用几种常规赋形剂作为制备组合药物片剂或胶囊剂的辅料成分，按照常规方法制成每片或每粒胶囊含有药物成分0.5-300mg的片剂或胶囊剂。
实验例1 Sirt1活性测试
本实验利用Sirt1 Fluorometric Drug Discovery Kit(Sirt1活性荧光定量检测试剂盒)并按照该试剂盒说明书的方法检测化合物对Sirt1体外活性的影响。首先配制含0.5U Sirt1(在37℃1U＝1pmol·min -1)(除空白组外)，1000μmol·L -1NAD +，100μmol·L -1去乙酰酶底物，SIRT1缓冲液(50mmol·L - 1Tris-HCl，pH 8.0，137mmol·L -1NaCl，2.7mmol·L -1KCl，1mmol·L - 1MgCl 2，1mg·ml -1BSA)的试验体系。实验组分别加入前述实施例制备的各个待检测化合物，空白组与激动剂(白藜芦醇)或抑制剂(烟酰胺)对照组加入等量溶解化合物的溶剂；再加入已配好的试验体系，使加入待检测化合物与试验体系的总体积为25μL(待测化合物、激动剂和抑制剂的终浓度均为200μM)。37℃条件下孵育30min后于每个试验孔中加入1×Fluor de Lys developer solution(含有2mmol·L -1烟酰胺)25μL终止反应(烟酰胺终浓度为200μM)，反应在96孔板中进行。多功能酶标仪360nm激发光，460nm发射光条件下测取各孔荧光值。
化合物激活Sirt1活性试验结果(n＝3)，应用单因素方差分析的统计学方法，计量数据以均数±标准差表示，与空白组比较， *表示和空白对照组相比p＜0.05， **表示和空白对照组相比p＜0.01， ***表示和空白对照组相比p＜0.001。
表1 化合物1-7～化合物2的Sirt1相对活性(％，和空白组相比)
组别 相对活性％
空白组 100.0±3.3
烟酰胺对照组 59.8±5.3 ***
白藜芦醇对照组 127.1±4.9 **
化合物1-7 116.4±6.3 *
化合物1-8 139.6±7.7 ***
化合物1-9 142.9±7.2 ***
化合物1-10 151.3±6.4 ***
化合物1-11 146.2±5.9 ***
化合物1-12 138.9±7.5 ***
化合物1-13 144.5±8.2 ***
化合物1-14 136.5±4.6 ***
化合物1-15 138.3±5.6 ***
化合物1-17 140.8±4.8 ***
化合物1-18 139.7±6.6 ***
化合物1-19 142.7±6.9 ***
化合物1-20 144.6±7.1 ***
化合物2 147.4±6.6 ***
表2 化合物3-1-化合物6的Sirt1相对活性(％，和空白组相比)
组别 相对活性 组别 相对活性
空白组 100.0±3.3 化合物4-4 138.9±5.1 ***
烟酰胺对照组 59.8±5.3 *** 化合物5-2 151.2±5.6 ***
白藜芦醇对照组 127.1±4.9 ** 化合物5-4 123.3±4.6 **
化合物3-1 124.6±6.6 ** 化合物5-5 136.3±5.2 ***
化合物3-2 121.1±4.8 ** 化合物5-6 127.5±5.5 **
化合物3-3 123.5±5.2 ** 化合物5-7 126.4±5.8 **
化合物3-4 122.4±5.9 ** 化合物5-8 127.2±7.6 **
化合物3-5 119.8±6.7 ** 化合物5-9 141.4±6.8 ***
化合物3-6 117.3±5.4 * 化合物5-12 142.6±6.2 ***
化合物4-1 145.5±7.2 *** 化合物5-13 122.5±7.1 **
化合物4-2 148.3±6.6 *** 化合物6 147.8±6.9 ***
化合物4-3 136.9±7.3 *** 化合物7 135.4±7.5 ***
由上述结果可知，本发明制备的化合物均具有Sirt1激活作用，可作为潜在的Sirt1激动剂，且其中化合物1-8，1-9，1-10，1-11，1-12，1-13，1-14，1-15，1-17，1-18，1-19，1-20，2，4-1，4-2，4-3，4-4，5-2，5-5，5-9，5-12，6和7相对活性和空白对照组相比p＜0.001，对Sirt1的激活作用更佳。
实验例2 本发明化合物降尿酸活性测试
1、实验材料
健康雄性KM小鼠，体重为15-18g，由上海灵畅生物科技有限公司提供；按每笼5只进行分笼处理后，在屏障系统内适应性饲养4天。
2、实验方法
2.1实验分组
选取体重集中的小鼠按体重随机平均分组，每组10只，分别为空白对照组、模型对照组、阳性对照组、化合物组(具体化合物见结果汇总表格)。
2.2给药方法
适应期过后随即对小鼠进行灌胃给药，每天上午灌胃1次，连续灌胃给药7天。
化合物组分别给予实施例制备的化合物30mg/kg，其中化合物分别用0.5％羧甲基纤维素钠(CMC-Na)溶液进行混悬；阳性对照组给予非布司他1.0mg/kg，用相同体积的0.5％羧甲基纤维素钠(CMC-Na)溶液进行混悬；空白对照组和模型对照组均用0.5％羧甲基纤维素钠(CMC-Na)溶液灌胃；各组均连续灌胃给药7天。在第7天上午灌胃给药0.5小时后，对各组小鼠进行腹腔注射进行高尿酸血症造模。其中，空白对照组腹腔注射0.5％羧甲基纤维素钠(CMC-Na)溶液；模型对照组、阳性对照组、化合物组均注射300mg/kg动物体重的氧嗪酸钾(OA)，用CMC-Na溶液进行溶解。
3、实验数据检测与处理
3.1检测指标
高尿酸血症造模1.5小时后，各组小鼠摘除眼球进行采血，采血容量不低于0.5mL，血样采集后于室温放置约1小时，待血液完全凝固后于3500rpm/4℃条件下离心10分钟，取血清在同等条件下复离5分钟，然后取0.2mL血清通过生化分析仪检测UA值。
3.2统计学分析
用Excel和SPSS对数据进行统计分析，计算平均数和SD，经单因素方差分析后比较各实验组的组间差异。
4、实验结果
给药7天后，各组对高尿酸血症小鼠的血清尿酸水平的影响如下表所示。
表3 对高尿酸血症小鼠血清中尿酸水平的影响(均值μmol/L)
样品 尿酸(μmol/L) 样品 尿酸(μmol/L)
空白对照组 61.18 化合物1-18 44.72 **
模型对照组 140.61 ## 化合物1-19 58.67 **
阳性对照组 42.23 ** 化合物1-20 55.71 **
化合物1-8 58.79 ** 化合物4-1 59.23 **
化合物1-9 90.33 * 化合物4-2 67.73 **
化合物1-10 102.58 * 化合物4-3 80.26 *
化合物1-11 57.64 ** 化合物4-4 59.27 **
化合物1-12 74.36 * 化合物5-2 64.48 **
化合物1-13 92.25 * 化合物5-5 58.43 **
化合物1-14 48.74 ** 化合物5-9 77.25 *
化合物1-15 66.15 ** 化合物5-12 65.32 **
化合物1-17 100.77 * 化合物6 58.87 **
化合物2 84.46 * 化合物7 62.71 **
注： ##表示和空白对照组相比，P<0.01； **表示和模型对照组相比，P<0.01； *表示和模型对照组相比，P<0.05(t-test检验)
由表3可知：
(1)与空白对照组相比，模型对照组小鼠的血清中尿酸显著升高(P<0.01)，这表明高尿酸血症模型造模成功；
(2)与模型对照组相比，化合物组小鼠的血清中尿酸水平的降低具有显著性差异(P<0.01或P<0.05)。
5、实验结论
本发明化合物在体内具有显著的降尿酸作用，可以作为潜在的降尿酸的药物。
根据文献[Wang J,Zhu X X,Liu L,et al.SIRT1 prevents hyperuricemia via the PGC-1α/PPARγ-ABCG2 pathway[J].Endocrine,2016,53(2):443-452。]的报道，SIRT1可促进回肠中ABCG2的表达，从而促进肠道对于尿酸的 排泄，并且还可以抑制肾脏中URAT1的mRNA水平，说明本发明化合物可能通过促进肠道和肾脏对尿酸的排泄来达到降低尿酸的效果。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (10)

  1. 下述通式(I)所示的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，
    Figure PCTCN2021085919-appb-100001
    其中，R 1、R 2彼此独立地选自氢、羟基、羧基、Rm取代或未取代的C 1-C 7的烷基、Rm取代或未取代的C 1-C 7的烯基、Rm取代或未取代的C 1-C 7的酮基、Rm取代或未取代的C 1-C 7的酯基；
    R 3选自Rm取代或未取代的C 1-C 7的烷基、Rm取代或未取代的C 1-C 7的烯基、Rm取代或未取代的C 1-C 7的酮基；
    Rm选自OH、CHO、OCOCH 3，以及由
    Figure PCTCN2021085919-appb-100002
    中的至少一种所形成的糖基残基。
  2. 根据权利要求1所述的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，其特征在于：
    R 1选自CH 3、COOH、COCH 3、
    Figure PCTCN2021085919-appb-100003
    Figure PCTCN2021085919-appb-100004
    R 2选自H、OH、CH 3、
    Figure PCTCN2021085919-appb-100005
    R 3选自
    Figure PCTCN2021085919-appb-100006
    Figure PCTCN2021085919-appb-100007
    Rm选自OH、CHO、OCOCH 3，以及由
    Figure PCTCN2021085919-appb-100008
    中的至少一种所形成的糖基残基；
    其中，
    Figure PCTCN2021085919-appb-100009
    表示选自
    Figure PCTCN2021085919-appb-100010
  3. 根据权利要求1或2所述的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，其特征在于：
    R 3选自
    Figure PCTCN2021085919-appb-100011
    Figure PCTCN2021085919-appb-100012
    且R 3的＊端连接在通式(I)所示的化合物炔基端。
  4. 根据权利要求1-3中任一所述的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，其特征在于，式(I)所示的化合物选自：
    Figure PCTCN2021085919-appb-100013
    Figure PCTCN2021085919-appb-100014
  5. 下述通式(II)所示的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，
    Figure PCTCN2021085919-appb-100015
    其中，
    Figure PCTCN2021085919-appb-100016
    表示选自
    Figure PCTCN2021085919-appb-100017
    R为H或COCH 3。
  6. 根据权利要求5所述的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物，其特征在于，式(II)所示的化合物选自：
    Figure PCTCN2021085919-appb-100018
  7. 权利要求1-6中任一所述的化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物作为Sirt1受体激动剂的应用。
  8. 根据权利要求7所述的应用，其特征在于，所述应用包括制备预防和/或治疗与Sirt1受体功能失调相关的疾病的药物；其中，与Sirt1受体功能失调相关的疾病为衰老、肿瘤、糖尿病、心血管疾病、慢性炎症、骨质疏松症、肥胖、高尿酸血症和痛风中的至少一种；所述慢性炎症为慢阻肺、结肠炎、类风湿关节炎、慢性肾衰和痛风性关节炎中的至少一种。
  9. 一种药物，其特征在于，其含有有效量的权利要求1-6中任一所述的一种或多种化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物以及一种或多种药学上可接受的赋形剂。
  10. 根据权利要求9所述的药物，其特征在于，其含有有效量的权利要求1-6中任一所述的一种或多种化合物、或其对映异构体、非对映异构体、盐、酯、前药、溶剂合物或盐的溶剂合物以及一种或多种其他活性成分的组合。
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