CN113493374B - SIRT1 receptor agonist and medicine containing same - Google Patents

SIRT1 receptor agonist and medicine containing same Download PDF

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CN113493374B
CN113493374B CN202010276581.7A CN202010276581A CN113493374B CN 113493374 B CN113493374 B CN 113493374B CN 202010276581 A CN202010276581 A CN 202010276581A CN 113493374 B CN113493374 B CN 113493374B
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compound
compounds
nmr
cdcl
sirt1
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CN113493374A (en
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孙俊哲
申凯
温尧林
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SUZHOU KAIXIANG BIOTECHNOLOGY CO Ltd
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Abstract

The invention belongs to the field of medicines or health care products, and particularly relates to a compound shown in the following general formula (I), or an enantiomer, a diastereoisomer, a salt, an ester, a prodrug, a solvate or a solvate of the salt,
Figure DDA0002444997130000011
wherein R is 1 、R 2 、R 3 As shown by the definitions in the specification, the compound prepared by the invention has Sirt1 activation effect, can be used as a potential Sirt1 agonist,the hyperuricemia animal model shows that the compound has a remarkable uric acid reducing effect in vivo and can be used as a potential medicament for reducing uric acid or treating gout.

Description

SIRT1 receptor agonist and medicine containing same
Technical Field
The invention belongs to the field of medicines or health care products, and particularly relates to a SIRT1 receptor agonist and a medicine containing the same.
Background
In the field of chemical medicine, uric acid is the final metabolite of human purine compounds. Disorders of purine metabolism lead to hyperuricemia. Under normal purine diet, the level of uric acid in fasting blood twice a day is higher than 420 mu mol/L in male and higher than 360 mu mol/L in female, namely hyperuricemia (hyperuricemia). Generally, there is no subjective symptom when the patient is in a hyperuricemia symptom state, but if the patient is in the hyperuricemia symptom state for a long time, urate in blood is crystallized and deposited on joints, subcutaneous tissues, kidneys and other parts, and a series of clinical manifestations such as gout and gout complications occur. Recently published white paper of the status report of gout in China in 2017 shows that the number of hyperuricemia patients in China reaches 1.7 hundred million, wherein the number of gout patients exceeds 8000 ten thousand, and the annual growth rate is rapidly increased by 9.7 percent each year. In 2020, the number of gout people is estimated to reach 1 hundred million. Nowadays, gout becomes the second major metabolic disease of China, which is second only to diabetes, and seriously harms the life and health of people.
At present, when treating hyperuricemia, gout caused by hyperuricemia and gout complications, uric acid in blood needs to be controlled: for patients with uric acid excretion (90% of patients), drugs for promoting uric acid excretion are available, such as: benzbromarone, lei Xina de, etc.; for patients with hyperuricemia, the medicine for inhibiting uric acid production (mainly xanthine oxidase inhibitor) is suitable, such as: allopurinol and febuxostat. However, as the clinical application of these drugs increases, adverse reactions are gradually exposed.
Allopurinol (allopurinol) is the earliest marketed drug for inhibiting the generation of uric acid, and has been the main drug for treating chronic gout because of low price and good uric acid reducing effect since the application in clinic in 1963. However, with the popularization of allopurinol, the reports of adverse reactions are increased gradually, and the reports from the 70 th of the 20 th century show that allopurinol can cause adverse reactions such as liver and kidney injury, leucopenia, rash and the like, has about 1.5% of allergy risks, can cause fatal allergy seriously, and arouses worldwide attention. Therefore, in order to reduce adverse reactions, a small dose of allopurinol is required.
Febuxostat (Febuxostat, trade name: uloric, wutian north american pharmaceutical company) is a non-purine selective xanthine oxidase inhibitor, which is marketed in the european union in 5 months in 2008, approved by the U.S. FDA in 3 months in 2009, and introduced into the chinese market in 2013, for long-term treatment of hyperuricemia associated with gout. Compared with other medicaments for treating hyperuricemia, the febuxostat has higher selectivity and stronger activity. However, related research and clinical practice show that febuxostat also has certain adverse reactions: common adverse reactions include liver dysfunction (3.5%), diarrhea (2.7%), headache (1.8%), nausea (1.7%), rash (1.5%), and the like. 11/15/2017, the FDA issued febuxostat cardiac-related death risk warnings; day 7/2/2018, CFDA issued a pharmacological alert "a preliminary result of a safety clinical trial involving 6000 gout patients indicated that febuxostat may increase the risk of heart-related death compared to allopurinol.
The drugs have large toxic and side effects under the conventional dosage, and the tolerance of the drugs is generally low, so that the clinical application of the drugs is limited to a certain extent.
Sitelematic regulator 1 (SIRT1) is one of the sirtuin protein family members and is present in eukaryotes and prokaryotes. It plays an important physiological role in the process of cell survival and proliferation, and the dysfunction of the cell plays an important role in the physiological activities such as aging and the occurrence and development of various diseases such as tumors, diabetes, cardiovascular diseases, chronic inflammation and partial metabolic diseases. Specifically, in cellular metabolism there is a correlation: SIRT1 regulates cell differentiation, proliferation and aging by transcription factors FOXO and p53, and can restore the function of FOXO3 of aged mouse embryonic fibroblasts by up-regulating SIRT1 through deacetylation, repair damaged DNA, activate cell cycle regulatory protein D, cell cycle regulatory factor p27Kip1 and the like to improve detoxification of active oxygen radicals.
The SIRT1 agonist can also inhibit the release of inflammatory factors such as tumor necrosis factor TNF-a, interleukin IL-1 beta, IL-6 and the like, and slow down the progress of various chronic inflammatory diseases such as chronic obstructive pulmonary disease, colitis and the like. The high level expression of SIRT1 in CD4+ and CD8+ T cells indicates that the SIRT1 is involved in the immune function regulation process, can act on a transcription factor FOXP3, improves the number and the function of regulatory T cells through deacetylation, and also has the effects of inhibiting excessive autophagy of cells, reducing cell death, regulating biological processes of fat metabolism, reducing fat deposition, regulating the functions of endothelial cells and protecting the heart.
Meanwhile, in relation to metabolic diseases, the SIRT1 agonist can improve the tolerance to glucose and enhance the secretion of insulin, and a mouse model test also finds that the SIRT agonist can obviously relieve hyperuricemia induced by oxygen Qin Suanjia and yeast extract and improve inflammatory cell infiltration of kidney tissues, so that chronic renal failure is improved, and the blood creatinine level is reduced.
SIRT1 is structurally expressed in articular cartilage, but little SIRT1 is detected in cartilage of patients with severe arthritis. The SIRT1 expression can be improved to delay the progress of osteoarthritis, and simultaneously, the activity of osteoclast and osteoblast can be regulated to improve bone metabolism, so that osteoporosis is relieved. Further studies have shown that SIRT1 inhibitors can alleviate rheumatoid arthritis by reducing the activity of rheumatoid arthritis synovial cells, inhibiting synovial cell hypertrophy. And the prevention type treatment of the SIRT1 agonist can obviously inhibit the joint inflammatory response induced by urate crystallization. [ Zhu Xiaoxia, liu Qiong, chen Haiyan, etc.. Silent information regulator 1 and its research progress associated with gout and hyperuricemia [ J ]. Shanghai medicine 2015 (11): 19-22 ]
There are also reports in the literature that SIRT1 promotes the expression of ABCG2 in the ileum, thereby promoting excretion of uric acid in the intestine. Meanwhile, the SIRT1 agonist can inhibit the mRNA level of URAT1 in the kidney, so that the SIRT1 agonist can achieve the effect of reducing uric acid by promoting the excretion of uric acid in the intestinal tract and the kidney. [ Wang J, zhu X X, liu L, et al, SIRT1 precursors hyperuricemia via the PGC-1 α/PPAR γ -ABCG2 pathway [ J ]. Endocrine,2016,53 (2): 443-452.]
The applicant finds that a series of compounds with SIRT1 agonistic activity can be used for reducing uric acid through long-term research.
Disclosure of Invention
The object of the present invention is to provide a novel compound having SIRT1 agonistic activity.
Therefore, the invention provides the following technical scheme:
a compound represented by the following general formula (I), or an enantiomer, a diastereomer, a salt, an ester, a prodrug, a solvate or a solvate of a salt thereof,
Figure BDA0002444997120000041
wherein R is 1 、R 2 Independently of one another, from hydrogen, hydroxyl, carboxyl, rm substituted or unsubstituted C 1 -C 7 Alkyl, rm substituted or unsubstituted C 1 -C 7 Alkenyl of (A), rm substituted or unsubstituted C 1 -C 7 Keto group of (A), rm substituted or unsubstituted C 1 -C 7 An ester group of (a);
R 3 selected from Rm substituted or unsubstituted C 1 -C 7 Alkyl, rm substituted or unsubstituted C 1 -C 7 Alkenyl of (A), rm substituted or unsubstituted C 1 -C 7 A ketone group of (a);
rm is selected from OH, CHO, OCOCH 3 And is prepared by
Figure BDA0002444997120000042
At least one glycosyl residue formed.
Further, R 1 Is selected from CH 3 、COOH、COCH 3 、
Figure BDA0002444997120000043
Figure BDA0002444997120000044
R 2 Selected from H, OH, CH 3 、
Figure BDA0002444997120000045
R 3 Is selected from
Figure BDA0002444997120000046
Figure BDA0002444997120000047
Rm is selected from OH, CHO, OCOCH 3 And is prepared by
Figure BDA0002444997120000051
(ii) at least one formed glycosyl residue;
wherein the content of the first and second substances,
Figure BDA0002444997120000052
represents selected from-or = = =.
Further, when R is 3 Is selected from
Figure BDA0002444997120000053
Figure BDA0002444997120000054
Figure BDA0002444997120000055
When R is 3 Is linked to the alkyne end of a compound of the formula (I).
Further, the compound represented by formula (I) is selected from:
Figure BDA0002444997120000056
Figure BDA0002444997120000061
Figure BDA0002444997120000071
the invention also provides a compound shown in the general formula (II), or an enantiomer, a diastereoisomer, a salt, an ester, a prodrug, a solvate or a solvate of the salt,
Figure BDA0002444997120000072
wherein the content of the first and second substances,
Figure BDA0002444997120000073
represents selected from-or = =, R is H or COCH 3 。
Further, the compound represented by the formula (II) is selected from:
Figure BDA0002444997120000074
the invention also provides the use of any of the compounds described above, or an enantiomer, diastereomer, salt, ester, prodrug, solvate or solvate of a salt thereof, as an agonist of the Sirt1 receptor.
Further, the use comprises preparing a medicament for the prevention and/or treatment of a disease associated with Sirt1 receptor dysfunction; wherein the disease associated with Sirt1 receptor dysfunction is at least one of aging, tumor, diabetes, cardiovascular disease, chronic inflammation, 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 invention also provides a medicament containing an effective amount of one or more compounds as described in any of the above, or an enantiomer, diastereomer, salt, ester, prodrug, solvate or solvate of a salt thereof, and one or more pharmaceutically acceptable excipients.
Further, it contains an effective amount of one or more compounds described above, or a combination of an enantiomer, diastereomer, salt, ester, prodrug, solvate, or solvate of a salt thereof, and one or more other active ingredients.
The technical scheme of the invention has the following advantages:
sirt1 activity tests show that the compounds prepared by the method have Sirt1 activation effect, can be used as potential Sirt1 agonists, and hyperuricemia animal models show that the compounds have obvious uric acid reducing effect in vivo and can be used as potential uric acid reducing drugs or gout treatment drugs.
Detailed Description
In the following examples and experimental examples of the present invention, the compounds can be prepared according to the methods of the examples of the present invention, and can also be prepared according to the methods of the prior art documents.
Example 1
Figure BDA0002444997120000091
Pulverizing 5kg of dried rhizome of Dahlia (Dahlia pinnata Cav) of Compositae, soaking in 3 times of 70% ethanol water solution at room temperature for one week, extracting twice, mixing the two extractive solutions, and concentrating under reduced pressure to remove organic solvent to obtain extract. Extracting the extract twice with 1 volume of diethyl ether, concentrating the diethyl ether extract under reduced pressure to obtain a jelly, dissolving the jelly in 10 weight times of gasoline diethyl ether (volume ratio of 9:1) solution, separating with silica gel column as sample liquid, performing gradient elution with mixed solution of gasoline and diethyl ether as mobile phase according to the following procedures, wherein the volume ratios of gasoline and diethyl ether are 9:1, 7:1, 5:1, 3:1, 1:1 and 1:3 respectively, eluting with diethyl ether, and eluting for 3BV, and combining eluents according to TLC detection results to obtain compounds 1-1, 1-2, 1-3, 1-4 and a mixture Fr1-1. Separating the mixture Fr1-1 again by using a silica gel column, performing gradient elution by using a mixed solution of gasoline and diethyl ether as an eluent according to the following procedure, wherein the volume ratio of gasoline to diethyl ether is 3:1, 2:1, 1:1, 1:2, 1:3 and 1:5, all the mobile phases elute 3BV, and combining the eluents according to a TLC detection result to obtain the compounds 1-5 and 1-6.
Providing 100mg of compound 1-5, 500mg of MnO 2 Dissolving in 50mL dichloromethane, shaking at 20 deg.C for 2 hr, subjecting to silica gel column chromatography, eluting with mixed solution of gasoline and diethyl ether (volume ratio 1:1), mixing eluates according to TLC detection result to obtain Fr2-1, fr2-2, and Fr2-3, and recrystallizing Fr2-2 with mixed solution of dichloromethane and gasoline (volume ratio 1:1) to obtain compound 1-7.
1mmol of compound 1-5 is taken and added with 1.1mmol of dess-Martin reagent and 30ml of CH 2 Cl 2 Reacting for 5 minutes at room temperature, separating the obtained product by reverse phase silica gel preparative column chromatography, performing gradient elution by using a mixed solution of methanol and water as an eluent according to the following procedure, wherein the volume percentage of the methanol is 20%, 25%, 30% and 35%, eluting 3BV from each mobile phase, combining the eluents according to TLC detection results, concentrating and drying respectively to obtain compounds 1-8-1-11 and compounds 1-20 (the synthetic reaction can be amplified in the same proportion to prepare enough compounds, and the same is given below).
Taking compounds 1-8-1-10 (each 1 mmol), and adding 1.2mmol Pd/SiO 2 Mixing with 50ml of mixed solution of trioctylamine and n-butanol (the volume ratio is 1:1), reacting for 4 hours under the conditions of 45 ℃ and pH value of 7.5 and stirring, and respectively obtaining the compounds 1-12-1-14.
2mmol of compound 1-5 is added with 4mmol CCl 4 ，8mmolPPh 3 ，75mlCH 2 Cl 2 5 hours at room temperature, N 2 Under protection, 4 mmol-BuLi and 50ml THF are added, the mixture is stirred for 5 minutes at minus 78 ℃, the obtained product is separated by reversed phase silica gel preparative column chromatography, gradient elution is carried out by taking a mixed solution of methanol and water as an eluent according to the following procedures, the volume percentage of methanol is 30 percent and the volume percentage of methanol is 35 percent, all mobile phases elute 3BV, the eluent is combined according to TLC detection results, and compounds 1 to 15 and 1 to 16 are obtained by concentration and drying respectively.
1.2mmol of the compound 1-10 are dissolved in 45ml of anhydrous CH 2 Cl 2 Adding acetylated bromoglucose 1.35mmol, stirring at room temperature for 30min, addingInto 1.35 mmoleAg 2 CO 3 ，N 2 Reacting for about 24 hours in the dark under protection, filtering, and sequentially using saturated 50ml NaHCO for filtrate 3 50ml of saturated NaCl, and 50ml of distilled water, anhydrous MgSO 4 Drying, concentrating under reduced pressure, dissolving the residue in 30ml anhydrous methanol, adding sodium methoxide 0.6mmol, reacting at room temperature for about 30min, adjusting pH to 6 with dilute hydrochloric acid, concentrating under reduced pressure, purifying the residue by silica gel column chromatography, and purifying with CH 2 Cl 2 Gradient elution with methanol mixed solution was performed according to the following procedure, CH 2 Cl 2 And methanol at a volume ratio of 7:1, 18,1, 30, eluting 3BV for each mobile phase above, to give compounds 1-17.
Dissolving 1mmol of compound 1-7 in 35ml of anhydrous CH 2 Cl 2 Adding acetylated bromoglucose 1.1mmol, stirring at room temperature for 30min, adding 1.1mmol Ag 2 CO 3 ，N 2 The mixture is reacted for about 24 hours under protection and protection from light, filtered, and the filtrate is sequentially added with 30ml of saturated NaHCO 3 30ml of saturated NaCl, and 30ml of distilled water, anhydrous MgSO 4 Drying, concentrating under reduced pressure, dissolving the residue in 18ml anhydrous methanol, adding 0.5mmol sodium methoxide, reacting at room temperature for about 30min, adjusting pH to 6 with dilute hydrochloric acid, concentrating under reduced pressure, purifying the residue by silica gel column chromatography, and purifying with CH 2 Cl 2 Gradient elution with methanol mixed solution was performed according to the following procedure, CH 2 Cl 2 And methanol at a volume ratio of 7:1, 15,1, 30, eluting 3BV for each mobile phase described above, to give compounds 1-19.
Slowly dripping 2mmol acetyl chloride into compound 1-13 at 0 deg.C, adding 1mmol acetic acid after 30min, refluxing for 10 hr, concentrating under reduced pressure, and concentrating with CH 2 Cl 2 Extracting, separating the product by reversed phase silica gel column chromatography, eluting with methanol isocratic (volume percentage of 25% methanol water solution), mixing eluates according to TLC detection result, concentrating, and drying to obtain compounds 1-18.
Respectively passing the compounds prepared above through 1 H NMR、 13 Structure confirmation was performed by C NMR and HPLC-MS, and the structure confirmation data were referenced in the following documents:
compounds 1-1 to 1-3 and 1-5 to 1-7 are referred to the following documents: fairbrother J R F, et al, natural acrylics, part xlix, polyurethanes from dahlia scapigera (a.dietr.) link and otto var. Scapigera f.scapigera and sodium dahlia hybrids, J Chemischer information, dense, 1976,7 (25): 735-741.
Compounds 1-4 are referred to the following references: he J, shen Y, jiang J S, et al, new polyethylene glycols from the streams of Carboamus tinctorius and the hair anti-inflammatory [ J ]. Carbohydrate Research,2011,346 (13): 1903-1908.
Compounds 1 to 8
ESI-MS:213[M] + , 1 H-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)；
13 C-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)
Compounds 1 to 9
ESI-MS:215[M] + , 1 H-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)；
13 C-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)
Compounds 1 to 10
ESI-MS:213[M] + , 1 H-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)；
13 C-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)
Compounds 1 to 11
ESI-MS:213[M] + , 1 H-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)；
13 C-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)
Compounds 1 to 12
ESI-MS:227[M] - , 1 H-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)；
13 C-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)
Compounds 1 to 13
ESI-MS:229[M] - , 1 H-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)；
13 C-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)
Compounds 1 to 14
ESI-MS:227[M] - , 1 H-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)；
13 C-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)
Compounds 1 to 15
ESI-MS:197[M] + , 1 H-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)；
13 C-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)
Compounds 1 to 16
ESI-MS:199[M] + , 1 H-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)；
13 C-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)
Compounds 1 to 17
ESI-MS:375[M] + , 1 H-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)；
13 C-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)
Compounds 1 to 18
ESI-MS:229[M] - , 1 H-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)；
13 C-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)
Compounds 1 to 19
ESI-MS:377[M] +
1 H-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)；
13 C-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
Compounds 1 to 20
ESI-MS:215[M] + ,
1 H-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)；
13 C-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)
EXAMPLE 2 preparation of Compound 2
Taking 20kg of dry saussurea involucrata whole plant, soaking and extracting with 5 times of ethanol aqueous solution with volume concentration of 70% for three days at room temperature, extracting twice, combining the two extracting solutions, and removing ethanol by decompression concentration to obtain extract. Extracting the obtained extract twice by using ethyl acetate with twice volume, combining the two ethyl acetate layer extraction liquids, concentrating under reduced pressure to obtain a crude extract, mixing the crude extract with silica gel, and performing silica gel column chromatography by using normal hexane: ethyl acetate (volume ratios of 25, 1, 20, 1, 15, 10. Frc was separated by Sephadex LH-20 column chromatography using a gradient elution with aqueous methanol (15%, 30%,40%,50%,60%,70%,85%,100% aqueous methanol), eluting 3BV of each of the above mobile phases, pooled according to Thin Layer Chromatography (TLC) assay results to give an eluate containing Compound 2, which was separated by Agilent SD-1 reverse phase preparative liquid chromatography using aqueous methanol as the mobile phase, eluting 3BV of each of the above mobile phases with aqueous methanol as the mobile phase (30%, 35%,40%,95% aqueous methanol), to give Compound 2, having the formula shown below:
Figure BDA0002444997120000161
respectively passing the compounds prepared above through 1 H NMR、 13 C NMR and HPLC-MS, ultraviolet full-wavelength scanning and infrared spectrum are adopted for structure confirmation, and the structure confirmation data refer to the following documents: ferdinand Bohlmann und Winfried Karl Polyacetylanenverbindungen, 202 Notiz uber die Biogenese des Athusins [ 2 ], [ J ]].Chem.Ber.1972,105,355-357.
EXAMPLE 3 preparation of Compounds 3-1 to 3-6
Figure BDA0002444997120000171
30mmol of substrate A and 30mmol of substrate B are mixed with 2mmol of copper acetate and then charged with CO 2 (1 atmosphere) in CO 2 Adding 400mL of dichloromethane under the atmosphere, stirring at room temperature for 30min, then stirring at 60 ℃ for reaction for 10h, finally cooling to room temperature, quenching the reaction solution with 80mL of ethyl acetate, and stirring at room temperature for 30min. Filtering with diatomite or a little silica gel, concentrating, spin-drying and purifying to obtain products 1, 2 and 3;
dissolving 15mmol of product 1 in 200mL of dichloromethane, adding 0.5mmol of Barium manganate catalyst (Barium mangonate) at room temperature for reaction for 10h, after the reaction is finished, adding 200mL of dichloromethane into the reaction solution for dilution and filtration, and rinsing and purifying a filter cake to obtain products 4,5 and 6;
6mmoL of product 5 are dissolved in 90mL of dichloromethane and 10mmoL of Ph are added 3 P＝CHCOCH 3 And (3) carrying out catalytic reaction for 6h at room temperature, after the reaction is finished, concentrating, spin-drying and purifying the product to obtain the target compound 3-1,3-3,3-5.
Dissolving 1mmol of target compound 3-1,3-3,3-5 in 30mL of dichloromethane respectively, adding 15mLDMSO and 1mmol of IBX, reacting at 0 ℃ for 2h, separating and purifying the product to obtain the target compound 3-2,3-4,3-6.
Respectively passing the compounds 3-1 to 3-6 prepared above through 1 H-NMR、 13 C-NMR and HPLC-MS, ultraviolet full-wavelength scanning and infrared spectrum are carried out for structure confirmation, and the structure confirmation data refer to the following documents: hartmut Laatsch und Alke Pudleiner, synthetic von omega-Acetyl-alpha-methyl phenyl carbonsaurester [ J ]].J.prakt.Chem.336(1994)663-677
EXAMPLE 4 preparation of Compounds 4-1 to 4-4
Figure BDA0002444997120000191
Figure BDA0002444997120000201
Step a): taking 2mmol HBBr 2 -DMS 5 Adding 60ml of CH 2 Cl 2 The solvent was added with NaOH (4.4 mmol,2M, aqueous solution) at room temperature, 2.2mmol of 1, 3-propanediol and 50ml of n-pentane solvent, and the mixture was reacted at room temperature for 5 minutes.
Step b): adding 2mmolICH to the product of step a) 2 ＝CH 2 Cl，(PPh 3 ) 4 Pd(5mol-％)，KOH(4.2mmol，1M，H 2 O), 60ml of THF are added, reflux is carried out and then 2mmol of CH.ident.C-TMS, cuI (10 mol-%), pdCl are added 2 (PhCN) 2 (5 mol-%), 45mL of piperidine, room temperatureThe reaction was carried out for 10 minutes.
Step c): adding 2.2mmol K to the product of step b) 2 CO 3 5mM MyOH, room temperature, 2.1mmol EtMgBr,3 mM THF, room temperature, followed by I 2 Solution (2.2 mmole I) 2 Dissolved in 60mL of THF solvent) at room temperature for 10 minutes to give compound 17.
Step d): taking 2.2mmol Me 3 Si-C.ident.C-H, 2mmolBuLi,20mlTHF, reaction at-78 deg.C for 5 min at 0 deg.C for 10 min, placing at-78 deg.C, adding 2mmolI 2 Reaction at room temperature for 10 minutes to give 2.2mmol Me 3 Si-C ≡ C-I; the product can be used immediately without subsequent treatment.
Step e): taking 2.2mmol of Me 3 Si-C≡C-I，Pd(dba) 2 (2mol-％)，AsPh 3 (8 mol-%), 2mmol of compound 16, 40ml of THF are mixed and reacted at room temperature for 3 hours.
Step f): adding 2 mmoleK to the product of step e) 2 CO 3 4mM LEOH, room temperature for 14 hours.
Step g): the product of step f) is added to 2mmol of compound 17, pdCl 2 (PPh 3 ) 2 (3mol-％)，CuI(3mol-％)，50mLTHF/iPr 2 NH (5:8, volume ratio), and reacting at room temperature for 15 minutes to obtain compound 4-1.
Compound 4-2 can be obtained by replacing compound 16 of step e) in the above reaction with compound 18, and carrying out d), e), f) reaction, and then directly carrying out g) reaction with compound 19 (instead of compound 17).
Slowly dripping 4mmol acetyl chloride into 1mmol compound 4-1 at 0 deg.C, adding 20mL acetic acid after 30min, refluxing for 10 hr, concentrating under reduced pressure, and concentrating with 40mL CH 2 Cl 2 Extracting, separating the obtained product by reversed phase silica gel column chromatography, isocratically eluting with 25% methanol water solution by volume percentage, combining the eluates according to TLC detection result, concentrating and drying respectively to obtain compound 4-3.
Slowly dripping 4mmol acetyl chloride into 1mmol compound 4-2 at 0 deg.C, adding 20mL acetic acid after 30min, refluxing for 10 hr, concentrating under reduced pressure, and concentrating with 40mL CH 2 Cl 2 Extracting, separating the obtained product by reversed phase silica gel column chromatography, isocratically eluting with 25% methanol water solution by volume percentage, combining the eluates according to TLC detection result, concentrating and drying respectively to obtain compound 4-4.
Respectively passing the compounds prepared above through 1 H-NMR、 13 C-NMR and HPLC-MS, ultraviolet full-wavelength scanning and infrared spectrum for structural analysis.
Compound 4-1
ESI-MS 301[M] -
1 H-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)；
13 C-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，
Compound 4-2
ESI-MS 305[M] -
1 H-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)；
13 C-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
Compound 4-3
ESI-MS 469[M] -
1 H-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)；
13 C-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
Compound 4-4
ESI-MS 473[M] -
1 H-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)；
13 C-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
EXAMPLE 5 Synthesis of Compounds 5-1 to 5-13
Figure BDA0002444997120000231
Step a): taking 5mmo of 7, 10 mmols of CBr as raw material 4 And 20 mmolePPh 3 ，150mlCH 2 Cl 2 Mixing and reacting for 4 hours at room temperature to obtain a compound 8;
step b): mixing 5mmo of 9,5mmol BuLi with 50mL THF, standing at-78 deg.C for 5 min, 0 deg.C for 10 min, and adding 5mmol I 2 Reaction at room temperature for 10 minutes to give Me 3 Si-C.ident.C-I (Compound 10); the product can be used immediately without subsequent treatment;
step c): adding 11mmolMeLi,50mlTHF to the product of step a), adding 5mmol of I to the mixture at-78 deg.C, 20 min, 10 min at room temperature 2 Heating from-78 ℃ to room temperature, and reacting at room temperature for 1 hour to obtain a compound 11;
step d): taking 5.5mmol of Me 3 Si-C≡C-I，Pd(dba) 2 (2mol-％)，AsPh 3 (8 mol-%), 5mm of raw material 15 and 50ml of THF are mixed and reacted for 3 hours at room temperature to obtain a compound 12;
step e): adding 5mmol K to the product of step d) 2 CO 3 Reacting with 10mM LEOH at room temperature for 14 hours to obtain a compound 13;
step f): mixing the product of step c) with the product of step e), adding Pd (dba) 2 (5 mol-%), cuI (15 mol-%) and 80mL THF/iPr 2 NH (5:8, vol.) at room temperature for 15 min to give compound 5-1 (preparation steps a-f were repeated to give sufficient compound 5-1 for subsequent experiments);
step g): 5mmol of the compound 5-1 was added with 5.5mmol of Dess-Martin reagent and 150mL CH 2 Cl 2 The reaction was carried out at room temperature for 5 minutes to obtain compound 5-2.
The reaction of step a) was carried out by replacing the raw material 7 with the raw material 21, the raw material 22 or the raw material 23, respectively, and the other steps were not changed to obtain the compounds 5-3,5-4,5-5.
The reaction of step d) was carried out by replacing the raw material 15 with the raw material 31 and the raw material 7 with the raw material 21 or 22 or the raw material 23 or 24, and the other steps were not changed to obtain the compound 5-6,5-7,5-8,5-9.
1mmol of compound 5-1,5-3,5-4,5-5 are respectively dissolved in 30mL of anhydrous CH 2 Cl 2 Adding acetylated bromoglucose 1.1mmol, stirring at room temperature for 30min, adding Ag 1.1mmol 2 CO 3 ，N 2 The reaction is carried out for about 24 hours under protection and protection from light, the reaction solution is filtered, and the filtrate is sequentially added with 30mL of saturated NaHCO 3 30mL of saturated NaCl, and 30mL of distilled water, anhydrous MgSO 4 Drying, concentrating under reduced pressure, dissolving the residue in 25mL anhydrous methanol, adding sodium methoxide 0.5mmol, reacting at room temperature for 30min, adjusting pH to 6 with dilute hydrochloric acid, concentrating under reduced pressure, gradient eluting the residue with silica gel column chromatography, and eluting with CH 2 Cl 2 Methanol solution gradient elution (7:1, 12,1, 20, 1, 30.
Respectively passing the compounds prepared above through 1 H-NMR、 13 The structure of the compounds 5-1 and 5-2 is confirmed by C-NMR and HPLC-MS, and the following references are made to the data for the structure confirmation: ferdinand Bohlmann und Christa Zadeo Polyacetoene Compoundds.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.
Compound 5-3
ESI-MS 187[M] -
1 H-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)；
13 C-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。
Compound 5-4
ESI-MS 201[M] -
1 H-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)；
13 C-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
Compound 5-5
ESI-MS 199[M] -
1 H-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)；
13 C-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
Compounds 5 to 6
ESI-MS 201[M] -
1 H-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)；
13 C-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
Compounds 5 to 7
ESI-MS 215[M] -
1 H-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)；
13 C-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
Compounds 5 to 8
ESI-MS 213[M] -
1 H-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)；
13 C-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
Compounds 5 to 9
ESI-MS 243[M] -
1 H-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)；
13 C-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
Compounds 5 to 10
ESI-MS 333[M] -
1 H-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)；
13 C-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
Compounds 5 to 11
ESI-MS 349[M] -
1 H-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)；
13 C-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
Compounds 5 to 12
ESI-MS 363[M] -
1 H-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)；
13 C-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
Compounds 5 to 13
ESI-MS 361[M] -
1 H-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)；
13 C-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
EXAMPLE 6 preparation of Compound 6
Figure BDA0002444997120000291
Step a): under the protection of nitrogen, 5mmol of compound 1-10,6mmol of trimethyl silicon chloride and 60 mLN-methylmorpholine are mixed and reacted for 8 hours at room temperature;
step b): adding 5.5 mmoleK to the mixture of step a) 2 CO 3 10mM LEOH, room temperature for 10 hours, 5.2mmol EtMgBr, THF10mL, room temperature, followed by addition of 5.5mmol of I 2 (dissolved in THF solvent 150 mL) for 10 min;
step c): 6mmol of isopropylmagnesium chloride-lithium chloride THF solution (1.3M) is dropped into the product of the step b) at-15 ℃, stirred for 2 hours, 5mmol of trimethylsilyl protected glucolactone n-heptane solution is slowly dropped into the system, and the temperature is raised to-10 ℃ for reaction for 3 hours. 6mmol of methanesulfonic acid in methanol (0.62 mol/L) was added dropwise, and the mixture was allowed to warm to room temperature, stirred, and reacted for 8 hours. And (3) dropwise adding 50mL of saturated sodium bicarbonate solution to quench the reaction, adjusting the pH to 7.5, extracting with petroleum ether, and removing the solvent by rotary evaporation to obtain a product.
Step d): the product of step c) was dissolved in 60ml of a mixed solution of acetonitrile and dichloromethane (volume ratio 1: 1) Cooling to-8 ℃, adding 10mmol of triethylsilane, then dropwise adding 7.5mmol of boron trifluoride diethyl etherate, heating to 0 ℃, stirring for 5 hours, adding 50mL of saturated sodium bicarbonate to quench the reaction, adjusting the pH value to 7.5, and concentrating under reduced pressure to remove the organic solvent to obtain a compound 6.
Respectively passing the compounds prepared above through 1 H-NMR、 13 C-NMR and HPLC-MS for structure confirmation:
compound 6:
ESI-MS：359[M] +
1 H-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)；
13 C-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
EXAMPLE 7 preparation of Compound 7
Taking 60kg of dried spanishneedles herb of Compositae, adding 70% ethanol water solution with volume percentage of 5 times of the weight of the spanishneedles herb, soaking and extracting for three days at room temperature, extracting twice, combining extracting solutions, and removing ethanol by decompression and concentration to obtain extract. Performing column chromatography on the obtained extract by using HPD-100 macroporous resin, eluting by using pure water and 70% ethanol water solution by volume percentage, and concentrating the obtained 70% ethanol eluent under reduced pressure to obtain 2.1kg of solid. Performing column chromatography on the solid with D101 macroporous resin, sequentially eluting with pure water, 20%,35%,60%, and 95% ethanol water solution, eluting 3BV of each mobile phase, collecting 60% ethanol eluate, and concentrating under reduced pressure to obtain extract. The extract was separated by silica gel column chromatography, and eluted by chloroform methanol gradient (mixed solution of chloroform and methanol in a volume ratio of 100:1, 50:1, 20:1, 10:1, 5:1, 3:1, 2:1, 1:1, each of the above mobile phases eluting 3 BV) to obtain an eluate containing compound 7, which was separated by Sephadex LH-20 column chromatography, and eluted by methanol aqueous solution gradient (10%, 15%,30%,45%,55%,70%,100% methanol aqueous solution), each of the above mobile phases eluting 3BV, to obtain fr6.5-1 to fr6.5-7, wherein fr6.5-3 was separated by reverse phase silica gel preparative column chromatography, and eluted by methanol aqueous solution gradient (30%, 40%,50%,60%,95% methanol aqueous solution), each of the above mobile phases eluting 3BV, wherein 40% methanol aqueous solution eluted fraction was concentrated under reduced pressure to obtain compound 7, represented by the following structural formula:
Figure BDA0002444997120000311
respectively passing the compounds prepared above through 1 H-NMR、 13 C-NMR and HPLC-MS for structure confirmation, the following references are referred to the structure confirmation data:
compound 7: wang X Y, chen G R, pan C X, et al.Polyacetylenes from Bidens bipinnata L.and the ir biological activities [ J ]. Phytochemistry Letters,2014, 7.
Example 8:
the compounds prepared in the previous examples can be prepared into injections by adding injection solvents according to a conventional method, fine filtering, encapsulating and sterilizing.
Example 9:
dissolving the compounds prepared in the previous examples in sterile water for injection, filtering with a sterile funnel, subpackaging, freeze-drying at low temperature, and aseptically sealing by melting to obtain the powder for injection.
Example 10:
the compounds prepared in the previous examples are used as pharmaceutical active ingredients, several conventional excipients are used as auxiliary ingredients for preparing combined pharmaceutical tablets or capsules, and tablets or capsules containing 0.5-300mg of pharmaceutical ingredients are prepared according to a conventional method.
Experimental example 1 Sirt1 Activity test
In this experiment, the influence of a compound on the in vitro activity of Sirt1 was detected using the Sirt1 Fluorometric Drug Discovery Kit (Sirt 1 Activity fluorescent quantitative detection Kit) and following the methods described in the Kit instructions. First, a solution containing 0.5U of Sirt1 (1U= 1pmol. Min. At 37 ℃ C.) was prepared -1 ) (except for blank group), 1000. Mu. Mol. L -1 NAD + ，100μmol·L -1 Deacetylase substrate, SIRT1 buffer (50 mmol. Multidot.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). The experimental group is added with each compound to be detected prepared in the previous embodiment, and the blank group and the agonist (resveratrol) or inhibitor (nicotinamide) control group are added with solvent which is equivalent to the compound; then adding the prepared test system, and ensuring that the total volume of the compound to be detected and the test system is 25 mu L (the final concentration of the compound to be detected, the agonist and the inhibitor is 200 mu M). After incubation at 37 ℃ for 30min, 1 XFluor de Lys developer solution (containing 2 mmol. L.) was added to each well -1 Nicotinamide) 25. Mu.L of the termination reaction (final concentration of nicotinamide 200. Mu.M) was performed in a 96-well plate. And measuring the fluorescence value of each hole by using a multifunctional microplate reader under the conditions of 360nm exciting light and 460nm emitting light.
Compound-activated Sirt1 activity assay results (n = 3), statistical methods using one-way anova, with the metric data expressed as mean ± standard deviation, compared to the blank, * indicates that p <0.05 compared to the blank control, ** indicates that p <0.01 compared to the blank control, *** represents p < 0.001 compared to the blank control.
TABLE 1 relative Sirt1 activity (%, as compared to blank) for compounds 1-7 through 2
Figure BDA0002444997120000321
Figure BDA0002444997120000331
TABLE 2 relative Sirt1 Activity of Compounds 3-1-6 (%, vs. blank)
Group of Relative activity Group of Relative activity
Blank group 100.0±3.3 Compound 4-4 138.9±5.1 ***
Nicotinamide control group 59.8±5.3 *** Compound 5-2 151.2±5.6 ***
Resveratrol control group 127.1±4.9 ** Compound 5-4 123.3±4.6 **
Compound 3-1 124.6±6.6 ** Compound 5-5 136.3±5.2 ***
Compound 3-2 121.1±4.8 ** Compounds 5 to 6 127.5±5.5 **
Compound 3-3 123.5±5.2 ** Compounds 5 to 7 126.4±5.8 **
Compound 3-4 122.4±5.9 ** Compounds 5 to 8 127.2±7.6 **
Compounds 3 to 5 119.8±6.7 ** Compounds 5 to 9 141.4±6.8 ***
Compounds 3 to 6 117.3±5.4 * Compounds 5 to 12 142.6±6.2 ***
Compound 4-1 145.5±7.2 *** Compounds 5 to 13 122.5±7.1 **
Compound 4-2 148.3±6.6 *** Compound 6 147.8±6.9 ***
Compound 4-3 136.9±7.3 *** Compound 7 135.4±7.5 ***
From the above results, the compounds prepared by the present invention all have Sirt1 activation effect and can be used as potential Sirt1 agonists, and among them, the compounds 1-8,1-9,1-10,1-11,1-12,1-13,1-14,1-15,1-17,1-18,1-19,1-20,2,4-1,4-2,4-3,4-4,5-34 zxft 3734-57 zxft 3757-9,5-3575 zxft 3775 and 7 have relative activity and compared with the blank group p < 0.001, the activation effect of Sirt 371 is better.
Experimental example 2 uric acid-lowering Activity test of the Compound of the present invention
1. Experimental materials
Healthy male KM mice, weighing 15-18g, were provided by Shanghai Ling Chang Biotech limited; after 5 cages of the strain were treated in separate cages, the strain was kept in a barrier system for 4 days.
2. Experimental method
2.1 Experimental groups
The mice with concentrated body weight are selected to be randomly and averagely grouped according to the body weight, and each group comprises 10 mice, namely a blank control group, a model control group, a positive control group and a compound group (specific compounds are shown in a result summary table).
2.2 methods of administration
After the adaptation period, the mice were administered by gavage for 7 days, with gavage being performed 1 time in the morning every day.
Compound groups 30mg/kg of the compound prepared in examples, in which the compound was suspended with 0.5% sodium carboxymethylcellulose (CMC-Na) solution, respectively; the positive control group is given with febuxostat 1.0mg/kg and suspended by 0.5 percent sodium carboxymethyl cellulose (CMC-Na) solution with the same volume; both the blank control group and the model control group are subjected to intragastric perfusion by using 0.5% sodium carboxymethylcellulose (CMC-Na) solution; each group was administered by continuous gavage for 7 days. After the gavage administration was performed for 0.5 hour on the 7 th morning, the mice of each group were subjected to abdominal injection for hyperuricemia modeling. Wherein the blank control group is administered by intraperitoneal injection of 0.5% sodium carboxymethylcellulose (CMC-Na) solution; potassium Oxonate (OA) was injected at a concentration of 300mg/kg of animal body weight into each of the model control group, the positive control group and the compound group, and dissolved in CMC-Na solution.
3. Experimental data detection and processing
3.1 detection criteria
After 1.5 hours of hyperuricemia modeling, removing eyeballs from all groups of mice to collect blood, wherein the blood collecting capacity is not lower than 0.5mL, placing the mice at room temperature for about 1 hour after the blood is collected, centrifuging the mice for 10 minutes at 3500rpm/4 ℃ after the blood is completely coagulated, taking serum to re-separate for 5 minutes under the same condition, and then taking 0.2mL serum to detect UA value through a biochemical analyzer.
3.2 statistical analysis
Statistical analysis of the data was performed using Excel and SPSS, mean and SD calculated, and differences between groups were compared after one-way anova.
4. Results of the experiment
The effect of each group on serum uric acid levels in hyperuricemic mice 7 days after administration is shown in the following table.
TABLE 3 Effect on uric acid levels in serum of hyperuricemic mice (mean. Mu. Mol/L)
Sample(s) Uric acid (mu mol/L) Sample(s) Uric acid (mu mol/L)
Blank control group 61.18 Compounds 1 to 18 44.72 **
Model control group 140.61 ## Compounds 1 to 19 58.67 **
Positive control group 42.23 ** Compounds 1 to 20 55.71 **
Compounds 1 to 8 58.79 ** Compound 4-1 59.23 **
Compounds 1 to 9 90.33 * Compound 4-2 67.73 **
Compounds 1 to 10 102.58 * Compound 4-3 80.26 *
Compounds 1 to 11 57.64 ** Compound 4-4 59.27 **
Compounds 1 to 12 74.36 * Compound 5-2 64.48 **
Compounds 1 to 13 92.25 * Compound 5-5 58.43 **
Compounds 1 to 14 48.74 ** Compounds 5 to 9 77.25 *
Compounds 1 to 15 66.15 ** Compounds 5 to 12 65.32 **
Compounds 1 to 17 100.77 * Compound 6 58.87 **
Compound 2 84.46 * Compound 7 62.71 **
Note: ## indicates P in comparison with the blank control group<0.01； ** Representation and model control group, P<0.01； * Representation and comparison with model control group, P<0.05 (t-test)
As can be seen from Table 3:
(1) Compared with a blank control group, the serum of the mouse of the model control group has obviously increased uric acid (P < 0.01), which indicates that the model building of the hyperuricemia model is successful;
(2) The reduction in serum uric acid levels in compound mice was significantly different (P <0.01 or P < 0.05) compared to the model control group.
5. Conclusion of the experiment
The compound has a remarkable uric acid reducing effect in vivo, and can be used as a potential uric acid reducing medicine.
According to the literature [ Wang J, zhu X, liu L, et al, SIRT1 previous hyperuricemia via the PGC-1. Alpha./PPAR. Gamma. -ABCG2 path [ J ]. Endocrine,2016,53 (2): 443-452. SIRT1 was reported to promote ABCG2 expression in the ileum, thereby promoting excretion of uric acid in the intestine, and also to inhibit the mRNA level of URAT1 in the kidney, suggesting that the compounds of the present invention may achieve uric acid lowering effects by promoting excretion of uric acid in the intestine and kidney.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (3)

1. A compound having the structure:
Figure FDA0003852483900000011
Figure FDA0003852483900000012
2. use of the compound or salt thereof according to claim 1 for the preparation of a medicament having uric acid lowering effect.
3. A medicament comprising an effective amount of one or more compounds of claim 1 or salts thereof and one or more pharmaceutically acceptable excipients.
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