CN113493374A - SIRT1 receptor agonist and medicine containing same - Google Patents

SIRT1 receptor agonist and medicine containing same Download PDF

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CN113493374A
CN113493374A CN202010276581.7A CN202010276581A CN113493374A CN 113493374 A CN113493374 A CN 113493374A CN 202010276581 A CN202010276581 A CN 202010276581A CN 113493374 A CN113493374 A CN 113493374A
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compound
solvate
salt
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ester
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CN113493374B (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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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 is1、R2、R3As shown in the definition of the specification of the invention, the compound prepared by the invention has Sirt1 activation effect, can be used as a potential Sirt1 agonist, is discovered by a hyperuricemia animal model, has a remarkable uric acid reducing effect in vivo, and can be used as a potential uric acid reducing or gout treating drug.

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 '2017 Chinese gout status report white paper', 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% per 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 dysexcretion (90% of the patients) are applicable to drugs for promoting uric acid excretion, such as: benzbromarone, rasidone, etc.; for patients with hyperuricemia, drugs (mainly xanthine oxidase inhibitors) for inhibiting uric acid production are 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, to reduce adverse reactions, a small dose of allopurinol is required.
Febuxostat (trade name: Uloric, pharmaceutical company in north america of the wutian) is a non-purine selective xanthine oxidase inhibitor, which is marketed in the european union in 5 months in 2008, approved by the FDA in the united states in 3 months in 2009, and introduced into the chinese market in 2013, and is used for the long-term treatment of hyperuricemia associated with gout. Compared with other drugs 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 a febuxostat heart-related death risk warning; 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.
Sirtuin 1 (silence information 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 for transcription factors FOXO and p53, restores the function of FOXO3 of aged mouse embryonic fibroblasts through deacetylation by up-regulating SIRT1, repairs damaged DNA, activates cell cycle regulatory protein D, and increases detoxification of active oxygen radicals by cell cycle regulatory factor p27Kip 1.
The SIRT1 excitant 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 suggests that it is involved in immune function regulation process, it can act on the transcription factor FOXP3, increase the number and function of regulatory T cells through deacetylation, and also inhibit excessive autophagy of cells, reduce cell death, regulate biological processes of fat metabolism, reduce fat deposition and regulate endothelial cell function, protect 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 potassium Oxyzine and yeast extract, and improve the inflammatory cell infiltration of kidney tissues, thereby improving chronic renal failure and reducing the level of blood creatinine.
SIRT1 is structurally expressed in articular cartilage, but little SIRT1 is detectable in cartilage of patients with severe arthritis. Increasing SIRT1 expression can delay the progress of osteoarthritis, and simultaneously can regulate the activity of osteoclast and osteoblast to improve bone metabolism, thereby relieving osteoporosis. Further studies have shown that SIRT1 inhibitors can reduce rheumatoid arthritis by reducing the activity of synovial cells in rheumatoid arthritis and inhibiting synovial cell hypertrophy. And the prevention type treatment of the compound with the SIRT1 agonist can obviously inhibit the joint inflammatory response induced by urate crystallization. [ Succinum cinnabarinum, Liu Qiong, Chenhai Yan, etc.. Silent information regulatory factor 1 and its research progress relating to gout and hyperuricemia [ J ] Shanghai medicine 2015(11):19-22 ]
In other documents, SIRT1 is reported to promote the expression of ABCG2 in ileum, thereby promoting the excretion of uric acid in intestinal tract. 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-. ]
The applicant finds that a series of compounds with SIRT1 agonist activity can be used for reducing uric acid through long-term research.
Disclosure of Invention
The invention aims to provide a novel compound with SIRT1 agonist 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 is1、R2Independently of one another, from hydrogen, hydroxyl, carboxyl, Rm substituted or unsubstituted C1-C7Alkyl, Rm substituted or unsubstituted C1-C7Alkenyl of (A), Rm substituted or unsubstituted C1-C7Keto group of (A), Rm substituted or unsubstituted C1-C7An ester group of (a);
R3selected from Rm substituted or unsubstituted C1-C7Alkyl, Rm substituted or unsubstituted C1-C7Alkenyl of (A), Rm substituted or unsubstituted C1-C7A ketone group of (a);
rm is selected from OH, CHO, OCOCH3And is prepared by
Figure BDA0002444997120000042
At least one glycosyl residue formed.
Further, R1Is selected from CH3、COOH、COCH3、
Figure BDA0002444997120000043
Figure BDA0002444997120000044
R2Selected from H, OH, CH3、
Figure BDA0002444997120000045
R3Is selected from
Figure BDA0002444997120000046
Figure BDA0002444997120000047
Rm is selected from OH, CHO, OCOCH3And is prepared by
Figure BDA0002444997120000051
At least one glycosyl residue formed in (a);
wherein the content of the first and second substances,
Figure BDA0002444997120000052
represents selected from-or ═ or.
Further, when R is3Is selected from
Figure BDA0002444997120000053
Figure BDA0002444997120000054
Figure BDA0002444997120000055
When R is3The terminal of (a) is linked to the terminal of a compound of formula (I) on the alkyne side.
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 COCH3。
Further, the compound represented by the formula (II) is selected from:
Figure BDA0002444997120000074
the invention also provides the use of any one 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 application comprises the preparation of a medicament for preventing and/or treating diseases related to 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:
according to the invention, Sirt1 activity tests show that the compounds prepared by the invention have Sirt1 activation effect, can be used as potential Sirt1 agonist, 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 or gout treating 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 extractive solution under reduced pressure to obtain a gel, dissolving the gel in 10 weight times of gasoline diethyl ether (volume ratio of 9: 1) solution, separating with silica gel column, performing gradient elution with mixed solution of gasoline and diethyl ether as mobile phase according to the following procedures, wherein the volume ratio of gasoline to diethyl ether is 9:1, 7:1, 5:1, 3:1, 1:1, and 1:3, eluting with diethyl ether, and eluting with 3BV for each mobile phase, and mixing eluates according to TLC detection result to obtain compounds 1-1, 1-2, 1-3, 1-4, and mixture Fr 1-1. 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, 1:2, 1:3 and 1:5, eluting 3BV of each mobile phase, and combining the eluents according to the TLC detection result to obtain the compounds 1-5 and 1-6.
Providing 100mg of compound 1-5, 500mg of MnO2Dissolving in 50mL of dichloromethane, shaking at 20 ℃ for 2 hours, carrying out silica gel column chromatography on the mixed solution, wherein the eluent is a mixed solution of gasoline and diethyl ether (volume ratio is 1: 1), combining the eluents according to the TLC detection result to obtain Fr2-1, Fr2-2 and Fr2-3, and recrystallizing Fr2-2 with a mixed solution of dichloromethane and gasoline (volume ratio is 1: 1) to obtain the compound 1-7.
1mmol of compound 1-5 is taken and added with 1.1mmol of dess-Martin reagent and 30ml of CH2Cl2Reacting 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 of each mobile phase, combining the eluates according to a TLC detection result, 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 1-8-1-10 (1 mmol each) of the compounds, and respectively adding 1.2mmol of Pd/SiO2And mixing the mixture with 50ml of a mixed solution (volume ratio is 1: 1) of trioctylamine and n-butanol, and reacting for 4 hours at 45 ℃ under the condition of stirring at the pH value of 7.5 to respectively obtain compounds 1-12-1-14.
Taking 2mmol of compound 1-5, adding 4mmol CCl4，8mmolPPh3，75mlCH2Cl25 hours at room temperature, N2Adding 4 mmol-BuLi and 50ml THF under protection, stirring at-78 deg.C for 5 min, and subjecting the obtained product to reverse phase silica gel column chromatographySeparating by spectrum, performing gradient elution with mixed solution of methanol and water as eluent according to the following procedures, wherein the volume percentage of methanol is 30% and 35%, eluting 3BV of each mobile phase, combining eluates according to TLC detection results, concentrating and drying respectively to obtain compounds 1-15 and 1-16.
1.2mmol of the compound 1-10 are dissolved in 45ml of anhydrous CH2Cl2Adding acetylated bromoglucose 1.35mmol, stirring at room temperature for 30min, adding 1.35mmol Ag2CO3，N2Reacting for about 24 hours in the dark under protection, filtering, and sequentially using saturated 50ml NaHCO for filtrate350ml of saturated NaCl, and 50ml of distilled water, anhydrous MgSO4Drying, 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 CH2Cl2Gradient elution with methanol mixed solution was performed according to the following procedure, CH2Cl2And methanol at a volume ratio of 7:1, 18:1, 30:1, eluting 3BV of each mobile phase to obtain compounds 1-17.
Dissolving 1mmol of compound 1-7 in 35ml of anhydrous CH2Cl2Adding acetylated bromoglucose 1.1mmol, stirring at room temperature for 30min, adding 1.1mmol Ag2CO3，N2The mixture is reacted for about 24 hours under protection and protection from light, filtered, and the filtrate is sequentially added with 30ml of saturated NaHCO330ml of saturated NaCl, and 30ml of distilled water, anhydrous MgSO4Drying, 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 CH2Cl2Gradient elution with methanol mixed solution was performed according to the following procedure, CH2Cl2And methanol at a volume ratio of 7:1, 15:1, 30:1, eluting 3BV of each mobile phase to obtain 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 CH2Cl2Extracting, 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 through1H NMR、13Structure 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, polyacetylenes from dahlia scapigera (a. di.) link and otto var. scapigera f.scapigera and some dahlia hybrids J Chemischer information, 1976,7(25): 735-.
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 Carbohydrus tinctorius and the hair anti-inflammatory [ J ]. Carbohydrate Research,2011,346(13): 1903) and 1908.
Compounds 1 to 8
ESI-MS:213[M]+,1H-NMR(CDCl3):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(CDCl3):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]+,1H-NMR(CDCl3):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(CDCl3):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]+,1H-NMR(CDCl3):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(CDCl3):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]+,1H-NMR(CDCl3):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(CDCl3):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]-,1H-NMR(CDCl3):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(CDCl3):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]-,1H-NMR(CDCl3):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(CDCl3):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]-,1H-NMR(CDCl3):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(CDCl3):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]+,1H-NMR(CDCl3):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(CDCl3):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]+,1H-NMR(CDCl3):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(CDCl3):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]+,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(CDCl3):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]-,1H-NMR(CDCl3):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-CH3,S),1.81(3H,dd,J＝6.8Hz,1.6Hz,C14-H)；
13C-NMR(CDCl3):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-CH3(21.1),-C＝O-CH3(170.3)
Compounds 1 to 19
ESI-MS:377[M]+
1H-NMR(CDCl3):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(CDCl3)
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]+,
1H-NMR(CDCl3):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(CDCl3):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 ratio 25:1, 20:1, 15:1, 10:1, 7:1, 4:1, 2:1, 1:1, respectively) and ethyl acetate were used as mobile phases for gradient elution, 3BV was eluted from each of the mobile phases, and the elution was combined according to the results of Thin Layer Chromatography (TLC) to obtain 5 fractions Fra to Fre. 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 a gradient elution with aqueous methanol as the mobile phase (30%, 35%, 40%, 95% aqueous methanol), eluting 3BV of each of the above mobile phases to give Compound 2, having the formula shown below:
Figure BDA0002444997120000161
respectively passing the compounds prepared above through1H NMR、13C 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 biogeneses des Athusins [ 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 and2mmol of copper acetate, then charging CO2(1 atmosphere) in CO2Adding 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 30 min. Filtering with diatomite or a small amount of 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 added3P＝CHCOCH3And (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 compounds 3-1, 3-3 and 3-5 in 30mL of dichloromethane respectively, adding 15mLDMSO and 1mmol of IBX, reacting at 0 ℃ for 2h, and separating and purifying the product to obtain the target compounds 3-2, 3-4 and 3-6.
Respectively passing the prepared compounds 3-1-3-6 through1H-NMR、13C-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 HBBr2-DMS560ml of CH are added2Cl2Solvent, room temperature, adding NaOH(4.4mmol, 2M in water), 2.2mmol of 1, 3-propanediol and 50ml of n-pentane solvent were added and mixed to react at room temperature for 5 minutes.
Step b): adding 2mmolICH to the product of step a)2＝CH2Cl，(PPh3)4Pd(5mol-％)，KOH(4.2mmol，1M，H2O), 60ml of THF are added, reflux is carried out and then 2mmol of CH.ident.C-TMS, CuI (10 mol-%), PdCl are added2(PhCN)2(5 mol-%), 45mL of piperidine, and 10 minutes at room temperature.
Step c): adding 2.2mmol K to the product of step b)2CO35mM MyOH at room temperature, 2.1mmol EtMgBr, 3 mM THF at room temperature, then I2Solution (2.2 mmole I)2Dissolved in 60mL of THF solvent) at room temperature for 10 minutes to give compound 17.
Step d): taking 2.2mmol Me3Si-C.ident.C-H, 2mmol BuLi, 20mL THF, -78 deg.C, 5 min, 0 deg.C, reacting for 10 min, placing at-78 deg.C, adding 2mmol I2Reaction at room temperature for 10 minutes to obtain 2.2mmol Me3Si-C ≡ C-I; the product can be used immediately without subsequent treatment.
Step e): taking 2.2mmol Me3Si-C≡C-I，Pd(dba)2(2mol-％)，AsPh3(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)2CO34mM LEOH, room temperature for 14 hours.
Step g): adding the product of step f) to 2mmol of compound 17, PdCl2(PPh3)2(3mol-％)，CuI(3mol-％)，50mLTHF/iPr2NH (5: 8, volume ratio), and reacting at room temperature for 15 minutes to obtain the 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 acetyl chloride 4mmol at 0 deg.C into compound 4-1 mmol, adding acetic acid 20mL after 30min, refluxing for 10 hr, concentrating under reduced pressure, and concentratingLiquid 40mLCH2Cl2Extracting, 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 40mLCH2Cl2Extracting, 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 through1H-NMR、13C-NMR and HPLC-MS, ultraviolet full-wavelength scanning and infrared spectrum for structure analysis.
Compound 4-1
ESI-MS 301[M]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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 material4And 20 mmolePPh3，150mlCH2Cl2Mixing and reacting for 4 hours at room temperature to obtain a compound 8;
step b): mixing 5mmo of 9, 5mmol BuLi and 50mlTHF, standing at-78 deg.C for 5 min, 0 deg.C for 10 min, and adding 5mmol of I2Reaction at room temperature for 10 minutes to give Me3Si-C.ident.C-I (Compound 10); the product can be used immediately without subsequent treatment;
step c): go to stepAdding 11mmol MeLi, 50mL THF, 20 min at-78 deg.C, 10 min at room temperature, adding 5mmol I2Heating from-78 ℃ to room temperature, and reacting at room temperature for 1 hour to obtain a compound 11;
step d): taking 5.5mmol Me3Si-C≡C-I，Pd(dba)2(2mol-％)，AsPh3(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)2CO3Reacting 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/iPr2NH (5: 8, vol.) at room temperature for 15 minutes to give compound 5-1 (preparation steps a-f were repeated to give compound 5-1 in sufficient quantity for subsequent experiments);
step g): 5mmol of the compound 5-1 was added with 5.5mmol of Dess-Martin reagent and 150mLCH2Cl2The 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 starting material 7 with the starting material 21, 22 or 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 with starting material 15 replaced by starting material 31 and starting material 7 replaced by starting material 21 or starting material 22 or starting material 23 or starting material 24, the other steps being unchanged to give compounds 5-6, 5-7, 5-8, 5-9.
Dissolving 1mmol of compound 5-1, 5-3, 5-4, 5-5 in 30mL of anhydrous CH respectively2Cl2Adding acetylated bromoglucose 1.1mmol, stirring at room temperature for 30min, adding Ag 1.1mmol2CO3，N2The mixture is reacted for about 24 hours in the dark under protection, filtered, and the filtrate is sequentially added with 30mL of saturated NaHCO330mL of saturated NaCl, and 30mL of distilled water, anhydrous MgSO4Drying, 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, and purifying the residue with silica gel column chromatographyMild elution, CH2Cl2Gradient elution with methanol (7:1, 12:1, 20:1, 30:1) and elution with 3BV of each mobile phase to obtain compounds 5-10, 5-11, 5-12, 5-13, respectively.
Respectively passing the compounds prepared above through1H-NMR、13The 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 Zadero Polyacrylonitrile Compounds CLXIV Compounds 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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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]-
1H-NMR(CDCl3):
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(CDCl3):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)2CO310mM LEOH, 10 hours at room temperature, 5.2mmol EtMgBr, THF10mL, at room temperature, followed by addition of 5.5mmol of I2(dissolved in THF solvent 150mL) 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 (0.62mol/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 through1H-NMR、13C-NMR and HPLC-MS for structure confirmation:
compound 6:
ESI-MS：359[M]+
1H-NMR(CDCl3):
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(CDCl3):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 with HPD-100 macroporous resin, eluting with pure water and 70% ethanol water solution by volume percent, and concentrating the obtained 70% ethanol eluate 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. Separating the extract by silica gel column chromatography, performing chloroform-methanol gradient elution (mixed solution of chloroform and methanol at volume ratio of 100:1, 50:1, 35:1, 20:1, 10:1, 5:1, 3:1, 2:1 and 1:1, eluting 3BV of each mobile phase) to obtain eluent containing the compound 7, separating the eluent by Sephadex LH-20 column chromatography, performing gradient elution by methanol water solution (10%, 15%, 30%, 45%, 55%, 70%, 100% methanol water solution), eluting 3BV of each mobile phase to obtain Fr6.5-1 to Fr6.5-7, wherein Fr6.5-3 is separated by reversed phase silica gel column chromatography, performing gradient elution by methanol water solution (30%, 40%, 50%, 60%, 95% methanol water solution), eluting 3 of each mobile phase, concentrating BV of 40% methanol water solution under reduced pressure to obtain the compound 7, the structural formula is as follows:
Figure BDA0002444997120000311
respectively passing the compounds prepared above through1H-NMR、13C-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, Polyacrylonitrile from Bidens bipinnata L.and the biological activities [ J ]. Phytochemistry Letters,2014,7: 198-.
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
The effect of a compound on the in vitro activity of Sirt1 was tested using the Sirt1 Fluorometric Drug Discovery Kit (Sirt1 activity fluorescent quantitative test Kit) and following the protocol described in the Kit. First, a formulation containing 0.5U of Sirt1 (1U. 1 pmol. min. at 37 ℃ C.) was prepared-1) (except for blank group), 1000. mu. mol. L-1NAD+，100μmol·L-1Deacetylase substrate, SIRT1 buffer (50 mmol. multidot.L)-1Tris-HCl，pH 8.0，137mmol·L-1NaCl，2.7mmol·L- 1KCl，1mmol·L-1MgCl2，1mg·ml-1BSA). 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-1Nicotinamide) 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.
Results of the compound-activated Sirt1 activity assay (n-3) using a statistical method of one-way anova, the metric data are 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 (%, vs. blank) for compounds 1-7 through 2
Figure BDA0002444997120000321
Figure BDA0002444997120000331
TABLE 2 relative Sirt1 activity (%, vs. blank) for compounds 3-1-6
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, it can be seen that the compounds prepared by the present invention all 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, 5-9, 5-12, 6 and 7 are relatively active compared with the blank group, p is less than 0.001, and have better Sirt1 activating effect.
Experimental example 2 uric acid-lowering Activity test of the Compound of the present invention
1. Experimental Material
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 methods
2.1 Experimental groups
Selecting mice with concentrated body weight, and randomly and averagely grouping the mice according to the body weight, wherein each group comprises 10 mice, namely a blank control group, a model control group, a positive control group and a compound group (the 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 administration by gavage 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 with 0.5% sodium carboxymethylcellulose (CMC-Na) solution via intraperitoneal injection; 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 index
After 1.5 hours of hyperuricemia modeling, removing eyeballs from each group 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 blood collection, centrifuging the mice for 10 minutes at 3500rpm/4 ℃ after the blood is completely coagulated, taking serum to re-separate the mice for 5 minutes under the same condition, and then taking 0.2mL of 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 (I) Uric acid (mu mol/L) Sample (I) 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 comparison with 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 precursors 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 (10)

1. 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 FDA0002444997110000011
wherein R is1、R2Independently of one another, from hydrogen, hydroxyl, carboxyl, Rm substituted or unsubstituted C1-C7Alkyl, Rm substituted or unsubstituted C1-C7Alkenyl of (A), Rm substituted or unsubstituted C1-C7Keto group of (A), Rm substituted or unsubstituted C1-C7An ester group of (a);
R3selected from Rm substituted or unsubstituted C1-C7Alkyl, Rm substituted or unsubstituted C1-C7Alkenyl of (A), Rm substituted or unsubstituted C1-C7A ketone group of (a);
rm is selected from OH, CHO, OCOCH3And is prepared by
Figure FDA0002444997110000012
At least one glycosyl residue formed.
2. The compound of claim 1, or an enantiomer, diastereomer, salt, ester, prodrug, solvate, or solvate of a salt thereof, wherein:
R1is selected from CH3、COOH、COCH3、
Figure FDA0002444997110000013
Figure FDA0002444997110000014
R2Selected from H, OH, CH3、
Figure FDA0002444997110000015
R3Is selected from
Figure FDA0002444997110000016
Figure FDA0002444997110000021
Rm is selected from OH, CHO, OCOCH3And is prepared by
Figure FDA0002444997110000022
At least one glycosyl residue formed in (a);
wherein the content of the first and second substances,
Figure FDA0002444997110000023
is selected from-or
Figure FDA0002444997110000024
3. The compound according to claim 1 or 2, or an enantiomer, diastereomer, salt, ester, prodrug, solvate or solvate of a salt thereof, characterized in that:
R3is selected from
Figure FDA0002444997110000025
Figure FDA0002444997110000026
And R is3The terminal of (a) is linked to the terminal of a compound of formula (I) on the alkyne side.
4. A compound according to any one of claims 1 to 3, or an enantiomer, diastereomer, salt, ester, prodrug, solvate or solvate of a salt thereof, wherein the compound of formula (I) is selected from:
Figure FDA0002444997110000031
Figure FDA0002444997110000032
Figure FDA0002444997110000041
5. a compound represented by the following general formula (II), or an enantiomer, a diastereomer, a salt, an ester, a prodrug, a solvate or a solvate of a salt thereof,
Figure FDA0002444997110000042
wherein the content of the first and second substances,
Figure FDA0002444997110000043
is selected from-or
Figure FDA0002444997110000044
R is H or COCH3。
6. The compound of claim 5, or an enantiomer, diastereomer, salt, ester, prodrug, solvate or solvate of a salt thereof, wherein the compound of formula (II) is selected from:
Figure FDA0002444997110000051
7. use of a compound of any one of claims 1-6, or an enantiomer, diastereomer, salt, ester, prodrug, solvate, or solvate of a salt thereof, as an agonist of the Sirt1 receptor.
8. The use according to claim 7, wherein said use comprises the manufacture of a medicament for the prevention and/or treatment of a disease associated with dysfunction of the Sirt1 receptor; 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.
9. A medicament containing an effective amount of one or more compounds of any one of claims 1-6, or an enantiomer, diastereomer, salt, ester, prodrug, solvate, or solvate of a salt thereof, and one or more pharmaceutically acceptable excipients.
10. Pharmaceutical according to claim 9, characterized in that it contains an effective amount of one or more compounds according to any one of claims 1 to 6, or a combination of one or more of their enantiomers, diastereomers, salts, esters, prodrugs, solvates or solvates of salts, and one or more other active ingredients.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114349723A (en) * 2021-12-23 2022-04-15 中山大学 Polyene acetylene compound and preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109893521A (en) * 2017-12-07 2019-06-18 苏州凯祥生物科技有限公司 A kind of new application of poly- acetylene compound anti-trioxypurine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012091115A1 (en) * 2010-12-29 2012-07-05 キッセイ薬品工業株式会社 Acetylene derivative and pharmaceutical application therefor
CN109893533B (en) * 2017-12-07 2021-08-24 苏州凯祥生物科技有限公司 New application of polyacetylene compounds in reducing uric acid
CN109893517B (en) * 2017-12-07 2022-01-11 苏州凯祥生物科技有限公司 Application of polyacetylene compound in treating gout
CN109893538B (en) * 2017-12-07 2021-05-07 苏州凯祥生物科技有限公司 Novel application of polyacetylenes in reducing uric acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109893521A (en) * 2017-12-07 2019-06-18 苏州凯祥生物科技有限公司 A kind of new application of poly- acetylene compound anti-trioxypurine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FERDINAND BOHLMANN 等: "Polyacetylene Compounds . X . Synthesis of the Polyynes from Oenanthe Crocata", 《CHEMISCHE BERICHTE》 *
L . CROMBIE 等: "Lipids.Ⅷ.Syntheses of cis-and trans-Octadec 13- Ene -9 , 11-Di - ynoic Acids , and Octadeca-cis -13 , trans - 15 –and-trans-13 , trans-15-Diene -9 , 11-Diynoic Acids : Their Status in Nature", 《JOURNAL OF THE CHEMICAL SOCIETY》 *
SVEN SOMMERWERK等: "Chemoenzymatic synthesis and cytotoxicity of oenanthotoxin and analogues", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114349723A (en) * 2021-12-23 2022-04-15 中山大学 Polyene acetylene compound and preparation method and application thereof
CN114349723B (en) * 2021-12-23 2024-02-02 中山大学 Polyene alkyne compound as well as preparation method and application thereof

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