CN104926761B - The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace - Google Patents
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue and its synthesis and application that isocyanates, benzoic acid and cinnamic acid replace Download PDFInfo
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- IUQFPKLIXNNTDC-UHONWTQSSA-N C=C([C@]1(CO2)[C@H](COC(/C=C/c(cc3)ccc3Br)=O)C1)C2=O Chemical compound C=C([C@]1(CO2)[C@H](COC(/C=C/c(cc3)ccc3Br)=O)C1)C2=O IUQFPKLIXNNTDC-UHONWTQSSA-N 0.000 description 1
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Abstract
The present invention relates to pharmaceutical technology field, the invention provides the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind isocyanate, benzoic acid and cinnamic acid replace, present invention also offers above-mentioned the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue synthetic method and the application in anti-inflammatory drug is prepared.The compounds of this invention Jing cells anti-inflammatory activity and cytotoxicity experiment, as a result prove, the compounds of this invention has the activity for suppressing macrophage RAW264.7 generation NO well;And cytotoxicity is relatively low.Therefore, the compounds of this invention has preferable anti-inflammatory activity, and there are low toxicity compounds, can be used as new anti-inflammatory drug.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to the southern regions of the Yunnan Province that a kind isocyanate, benzoic acid and cinnamic acid replace
Foreign ear chrysanthemum lactone analogue, and its synthetic method and the application in anti-inflammatory drug is prepared.
Background technology
Compositae (Compositae) Inula (Inula L.) plant there are about 100 kinds, be distributed mainly on Mediterranean Region,
It is also distributed in other areas in Europe, Africa and Asia.This platymiscium has more than 20 kinds and most mutation in China, wherein more than half
Plant have medicinal record(Chinese Plants will editorial board of the Chinese Academy of Sciences, Chinese Plants will [M], Beijing:Scientific publication
Society, 1979,75:248-281).Chinese scholars priority isolated flavone, sesquiterpene lactoness, terpenoid etc. from the platymiscium
The compound of structure type(Zhao YM,Zhang ML,Shi QW,Kiyota H.Chemical constituents of
plants from the genus Inula.Chemistry&Biodiversity2006;3:371-383).Sesquiterpene lactoness
It is the characteristic chemical constituent of this platymiscium, and main active component has antiinflammatory, antitumor, antiviral, anthelmintic parasite killing, immunity
Various effects such as suppression.Document shows that the alpha-methylene in such molecular structure of compounds-gamma lactone fragment is pharmacophoric group,
The fragment can be with some nucleophilic groups, and the sulfydryl fragment of such as cysteine occurs Michael addition reaction, so as to produce medicine
Reason is acted on(S.M.Kupchan,M.A.Eakin,A.M.Thomas.Tumor inhibitors.69.Structure-
cytotoxicity relations among the sesquiterpene lactones,Journal of Medicinal
Chemistry1971;14;1147-1152).Sesquiterpene lactoness are also as its simple structure, and have various mother nucleus structure classes
Type, can be used as the lead compound of research and development medicine.
China's endemic plant Inula wissmanniana (Inula wissmanniana Hand.-Mazz.) is Inulaplants,
Yunnan Province is commonly called as " torch stalk ", is undershrub, produces south of Yunnan (Yuanjiang River, screen side).It is born in low mountain Kai Kuang hillside fields, height above sea level 1200
~1650 meters.
The present inventor is devoted for years to the correlational study of chemical composition and biological activity in Inula wissmanniana.At present from Yunnan
Isolated 28 sesquiterpenoidss compositions, wherein Inula wissmanniana total extract and 6 Germacrane Sesquiterpenoids in southern Herba Inulae cappae
Lactone has good antiinflammatory and anti-anti-tumor activity, has applied for Chinese patent:Chinese patent application
CN201310014911.5, entitled Inula wissmanniana extract and its preparation and the application in anti-inflammatory drug is prepared,
Publication No. CN103058970A;Chinese patent application CN201310014913.4, entitled Inula wissmanniana extract
And its prepare and the application in antitumor drug is prepared, Publication No. CN103102336A.
The present inventor has applied for Chinese patent CN201310560385.2, entitled " the southern regions of the Yunnan Province sheep in 20131112 again
The application of ear chrysanthemum lactone A and its derivant in anti-inflammatory drug is prepared ", described Inula wissmanniana lactone A and its derivant, its
Chemical constitution is as shown in formula A:
It is relevant the new chemical composition with biological activity to be searched out from Inula wissmanniana and in Inula wissmanniana
Ester carries out the research emphasis that structure of modification is this area.
The content of the invention
It is an object of the invention to structure of modification is carried out to Inula wissmanniana lactone, it is more preferable to obtain a class anti-inflammatory activity
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue is the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates, benzoic acid and cinnamic acid replace;This
Bright another object is to provide the synthetic method of such the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue;The third object of the present invention is to provide this
Application of the ear chrysanthemum lactone analogue in anti-inflammatory drug is prepared of class the southern regions of the Yunnan Province ocean.
The present inventor has carried out structure of modification to Inula wissmanniana lactone A, is retaining pharmacophore alpha-methylene-gamma lactone
On the basis of fragment, using the phenyl isocyanate of different substituents, benzoic acid and cinnamic acid and synthesis the southern regions of the Yunnan Province ocean ear chrysanthemum lactone
During the intermediate of hydroxyl there is esterification, synthesized that 32 isocyanates replace, 8 benzoic acid replace, 10 meat
The Inula wissmanniana lactone analog that cinnamic acid replaces, and these compounds have been carried out with extracorporeal anti-inflammatory activity and cytotoxicity reality
Test, as a result show majority of compounds anti-inflammatory activity very well, and have high activity and hypotoxicity concurrently.
At present, isocyanates, benzoic acid, the Inula wissmanniana lactone analog chemosynthesis of cinnamic acid replacement and medicine be there is no
The document report of reason activity, also has no and the Inula wissmanniana lactone isocyanates in the present invention, benzoate, cinnamate derivative
Like the relevant report of thing preparation method, purposes.
A first aspect of the present invention, there is provided the southern regions of the Yunnan Province ocean ear chrysanthemum that a kind of isocyanates, benzoic acid or cinnamic acid replace
Lactone analogue, including its enantiomeric forms, its chemical constitution is as shown in formula 1, formula 2 or formula 3:
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of isocyanates replace, including its enantiomer, selected from following arbitrary:
In formula 1, R1 is respectively:
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of benzoic acid replaces, including its enantiomer, selected from following arbitrary:
In formula 2, R2 is respectively:
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of cinnamic acid replaces, including its enantiomer, selected from following arbitrary:
In formula 3, R3 is respectively:
A second aspect of the present invention, there is provided the southern regions of the Yunnan Province ocean ear that above-mentioned isocyanates, benzoic acid or cinnamic acid replace
The preparation method of chrysanthemum lactone analogue.
Synthetic route is:
Reactions steps are as follows:
Dicyclohexylcarbodiimide (DCC) and ether is dissolved in dimethylamino naphthyridine (DMAP), under the conditions of subzero 30 DEG C by
It is added dropwise to the diethyl ether solution of acetylenecarboxylic acid, cis-butenediol.After completion of dropping, room temperature reaction obtains compound 1 in 12 hours.In catalysis
Agent 1, under the effect of 5- cyclo-octadiene chlorine rhodium dimerization, silver hexafluoroantimonate and chiral ligand dinaphthalene diphenyl phosphine (R-BINAP, S-BINAP),
Compound 1 can change into the compound 2r and 2s of two kinds of configurations of R, S respectively.Compound 2r is with 2s by borane reduction into compound
3r and 3s, compound 3r and 3s substituted isocyanates different from phenyl ring, benzoic acid, Cortex Cinnamomi acid reaction can obtain targeted
Compound 4r, 4s, 5s, 6s.
A third aspect of the present invention, there is provided the southern regions of the Yunnan Province ocean ear that above-mentioned isocyanates, benzoic acid or cinnamic acid replace
Application of the chrysanthemum lactone analogue in anti-inflammatory drug is prepared.
50 compound 4r-1~16,4s-1~16 to present invention synthesis, 5s-1~8,6s-1~10 carry out cell and resist
Scorching activity and cytotoxicity experiment, as a result prove, there is such compound suppression macrophage RAW264.7 well to produce NO
Activity;In cytotoxicity, all toxicity of compound are all relatively low, toxicity IC50It is all higher than 20 μM.
Therefore, such compound has preferable anti-inflammatory activity, and has hypotoxicity concurrently, can to prepare that anti-inflammatory drug provides
Energy.
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates of the present invention, benzoic acid or cinnamic acid replace prepares antiinflammatory
Medicine, is as active component and routine by the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue of isocyanates, benzoic acid or cinnamic acid replacement
Pharmaceutical composition made by pharmaceutical carrier.
Described pharmaceutical composition can be tablet, dispersible tablet, buccal tablet, oral cavity disintegration tablet, slow releasing tablet, capsule, soft capsule,
Drop pill, granule, injection, injectable powder or aerosol etc..
Pharmaceutical composition of the present invention is made up of with pharmaceutic adjuvant as active component compound 4r-1~16
Pharmaceutical composition.
Pharmaceutical composition of the present invention is made up of with pharmaceutic adjuvant as active component compound 4s-1~16
Pharmaceutical composition.
Pharmaceutical composition of the present invention is the medicine being made up of as active component and pharmaceutic adjuvant compound 5s-1~8
Compositions.
Pharmaceutical composition of the present invention is made up of with pharmaceutic adjuvant as active component compound 6s-1~10
Pharmaceutical composition.
Present invention firstly discloses the change of the Inula wissmanniana lactone analog of isocyanates, benzoic acid, cinnamic acid replacement
Synthetic method is learned, and there is provided their cell anti-inflammatory activity and cell toxicity data, new anti-inflammatory drug is provided for clinic
Probability, brings glad tidings to patient, has larger clinical value and higher social benefit.
The present invention provides new medicine for the treatment of inflammation, has larger clinical value.
Description of the drawings
Fig. 1:The single crystal diffraction structure of compound 4r-3;
Fig. 2:The single crystal diffraction structure of compound 4s-8.
Specific embodiment
In conjunction with embodiment and accompanying drawing, the present invention is described in detail, but the enforcement of the present invention is not limited only to this.
Agents useful for same of the present invention and raw material are commercially available or can prepare by literature method.Unreceipted tool in the following example
The experimental technique of concrete conditions in the establishment of a specific crime, generally according to normal condition, or according to the condition proposed by manufacturer.
Embodiment 1:The synthetic method of the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue of 32 isocyanates replacements
Synthetic route is:
Compound 1:Dicyclohexylcarbodiimide (DCC) (2.79g, 13.5mmol) and to dimethylamino naphthyridine (DMAP)
(0.12g, 0.09mmol) is dissolved in ether, and acetylenecarboxylic acid (0.93g, 13.2mmol), maleic are added dropwise under the conditions of subzero 30 DEG C
The diethyl ether solution of glycol (1.05g, 12.0mmol).Room temperature reaction 12 hours after completion of dropping, after reaction terminates, saturated ammonium chloride
Solution is quenched, and organic faciess are extracted three times with ether, merges organic faciess, and anhydrous sodium sulfate drying, concentrated post obtain compound 1
(76%) 1.41g is yellow oil.
Compound 2s:1,5- cyclo-octadiene chlorine rhodium dimerization (50.2mg, 0.102mol), silver hexafluoroantimonate (70.0mg,
0.204mol) add three-necked bottle, argon protection, used syringe that 10ml acetone is added in bottle, 20 minutes is stirred at room temperature, argon
Protection is lower to filter, and filtrate continues to be stirred at room temperature 20 minutes with chiral ligand S- dinaphthalene diphenyl phosphines (127mg, 0.204mol), will
To solution be added in 1, the 2- dichloroethane solutions of compound 1 (1.14g, 8.14mmol), 21 hours are stirred at room temperature, instead
The concentrated post of liquid is answered, (59%) 0.67g is yellow oil to obtain compound 2s.Compound 2r is obtained with same method, chiral
Part changes R- dinaphthalene diphenyl phosphines into.
Compound 3s:At 0 DEG C to compound 2s (39mg, 0.28mmol) tetrahydrofuran solution Deca borine tetrahydrofuran
Solution (0.31mL, 1M in THF, 0.31mmol), response time are 30 minutes, and reaction terminates rear saturated ammonium chloride solution and quenches
Go out, organic faciess are extracted with ethyl acetate three times, merge organic faciess, anhydrous sodium sulfate drying, be concentrated to give compound 3s (0.26g,
65%) it is yellow oil.
Compound 4s-1~16 and 4r-1~16 universal synthesis method:Under room temperature, compound 3s or 3r is different from phenyl ring takes
The isocyanates (1.2eq) in generation are dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product.
Above-claimed cpd1H-NMR、13The data such as C-NMR and high resolution mass spectrum are as follows:
Compound 1:Yellow oil;
1H NMR(500MHz,CDCl3)δ5.82(dt,J=11.6,6.4Hz,1H),5.59(dt,J=11.2,7.0Hz,
1H),4.73(d,J=7.0Hz,2H),4.20(d,J=6.3Hz,2H),2.83(s,1H).
13C NMR(125MHz,CDCl3)δ152.73,134.57,124.26,75.28,74.55,61.85,58.59.
HR-ESI-MS calcd for C7H8O3[M+H]+141.1366,found141.0531.
Compound 2s:Yellow oil;
1H NMR(600MHz,CDCl3)δ9.82(s,1H),6.31(d,J=2.9Hz,1H),5.65(d,J=2.6Hz,1H),
4.65(dd,J=9.3,8.6Hz,1H),3.92(dd,J=9.4,5.9Hz,1H),3.58(ddt,J=11.2,5.7,3.0Hz,
1H),2.99(dd,J=19.0,5.1Hz,1H),2.79(dd,J=19.0,8.7Hz,1H).
13C NMR(150MHz,CDCl3)δ199.15,170.23,137.45,123.00,77.16,71.14,48.33,
33.18.
HR-ESI-MS calcd for C7H9O3[M+H]+141.1366,found141.0537.
Compound 3s:Yellow oil;
1H NMR(500MHz,CDCl3)δ6.27(d,J=2.8Hz,1H),5.63(d,J=2.5Hz,1H),4.55–4.51
(m,1H),4.07(dd,J=9.1,5.9Hz,1H),3.79–3.72(m,2H),3.29–3.23(m,1H),1.94(ddd,J=
14.0,11.4,5.6Hz,1H),1.81–1.73(m,1H).
13C NMR(125MHz,CDCl3)δ171.05,138.35,122.23,71.69,60.03,36.53,36.13.
HR-ESI-MS calcd for C7H11O3[M+H]+143.1525,found143.0702.
Compound 4s-1:Yellow solid;Compound 3s (35.5mg, 0.25mmol) and phenyl isocyanate under room temperature
(1.2eq) it is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane
Extraction, merges organic faciess, and the concentrated post of drying obtains product 46.1mg, yield 70.5%.
1H NMR(500MHz,CDCl3)δ7.38(d,J=7.4Hz,2H),7.31(t,J=8.0Hz,2H),7.08(t,J=
7.4Hz,1H),6.31(d,J=2.7Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.6Hz,1H),4.35–4.22
(m,2H),4.07(dd,J=9.0,5.6Hz,1H),3.23–3.20(m,1H),2.10–2.02(m,1H),1.98–1.90(m,
1H).
13C NMR(125MHz,CDCl3)δ170.62,153.33,137.83,129.24,123.90,122.65,
118.91,71.06,62.27,36.40,33.01.
HR-ESI-MS calcd for C15H16NO4[M+H]+262.2812,found262.2826.
Compound 4r-1:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 52.2mg,
Yield is 80%.
1H NMR(500MHz,CDCl3)δ7.38(d,J=7.5Hz,2H),7.32(t,J=8.0Hz,2H),7.09(t,J=
7.3Hz,1H),6.32(d,J=2.7Hz,1H),5.68(d,J=2.4Hz,1H),4.53(t,J=8.6Hz,1H),4.33–4.24
(m,2H),4.08(dd,J=9.0,5.6Hz,1H),3.22(ddd,J=8.2,5.6,2.7Hz,1H),2.10–2.05(m,1H),
1.96–1.90(m,1H).
13C NMR(125MHz,CDCl3)δ170.61,153.31,137.83,137.65,129.25,123.91,
122.66,118.89,71.05,62.27,36.40,33.03.
HR-ESI-MS calcd for C15H16NO4[M+H]+262.2812,found262.2819.
Compound 4s-2:Yellow solid;Compound 3s (35.5mg, 0.25mmol) and 2,4 difluorobenzene base isocyanide under room temperature
Acid esters (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloro
Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 56.5mg, yield 76.1%.
1H NMR(500MHz,CDCl3)δ7.94(s,1H),6.86(d,J=3.4Hz,1H),6.84(dd,J=7.7,
4.5Hz,1H),6.29(d,J=2.2Hz,1H),5.66(d,J=1.2Hz,1H),4.50(t,J=8.4Hz,1H),4.31–4.21
(m,2H),4.07–4.03(m,1H),3.21(s,1H),2.07–2.03(m,1H),1.93–1.90(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,158.42(d,J=251.1Hz),153.17,153.57–151.37
(m),137.70,122.60,122.38,121.72,111.34(dd,J=21.9,3.3Hz),104.00–103.54(m),
70.93,62.62,36.22,32.87.
HR-ESI-MS calcd for C14H14F2NO4[M+H]+298.2621,found298.2627.
Compound 4r-2:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 55.2mg,
Yield is 74.3%.
1H NMR(500MHz,CDCl3)δ7.97(s,1H),6.87(dd,J=5.2,3.2Hz,1H),6.75(s,1H),
6.32(d,J=3.0Hz,1H),5.67(d,J=2.2Hz,1H),4.52(t,J=8.5Hz,1H),4.40–4.22(m,2H),4.07
(d,J=5.7Hz,1H),3.22(s,1H),2.10–2.05(m,1H),1.97–1.91(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,158.45(d,J=246.2Hz),153.17,153.76–151.37
(m),137.70,122.61,122.39,121.71,111.35(dd,J=21.9,3.3Hz),103.78(t,J=24.9Hz),
70.93,62.63,36.23,32.88.
HR-ESI-MS calcd for C14H14F2NO4[M+H]+298.2621,found298.2628.
Compound 4s-3:Yellow solid;Compound 3s (35.5mg, 0.25mmol) and parachlorobenzyl isocyanic ester under room temperature
(1.2eq) it is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane
Extraction, merges organic faciess, and the concentrated post of drying obtains product 60.6mg, yield 82.2%.
1H NMR(500MHz,CDCl3)δ7.33(d,J=8.2Hz,2H),7.28(d,J=8.9Hz,2H),6.33(d,J=
2.7Hz,1H),5.68(d,J=2.3Hz,1H),4.53(t,J=8.6Hz,1H),4.33–4.23(m,2H),4.08(dd,J=
9.1,5.5Hz,1H),3.25–3.20(m,1H),2.11–2.04(m,1H),1.98–1.90(m,1H).
13C NMR(125MHz,CDCl3)δ170.54,153.12,137.81,136.25,129.29,122.70,
120.15,70.95,62.45,36.39,33.05.
HR-ESI-MS calcd for C14H14ClNO4Na[M+Na]+318.7078,found318.7073.
Compound 4r-3:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 58.7mg,
Yield is 79.6%.
1H NMR(500MHz,CDCl3)δ7.34(d,J=8.1Hz,2H),7.28(s,2H),6.32(d,J=2.6Hz,1H),
5.67(d,J=2.3Hz,1H),4.52(t,J=8.6Hz,1H),4.32–4.23(m,2H),4.08(dd,J=9.0,5.5Hz,
1H),3.26–3.17(m,1H),2.11–2.05(m,1H),1.97–1.92(m,1H).
13C NMR(125MHz,CDCl3)δ170.61,153.16,137.81,136.32,129.24,128.89,
122.68,120.14,71.01,62.44,36.41,32.96.
HR-ESI-MS calcd for C14H14ClNO4Na[M+Na]+318.7078,found318.7069.
The single crystal diffraction structure of compound 4r-3 is as shown in Figure 1.
Compound 4s-4:Yellow solid;Compound 3s (35.5mg, 0.25mmol) and p-bromophenyl isocyanates under room temperature
(1.2eq) it is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane
Extraction, merges organic faciess, and the concentrated post of drying obtains product 72.8mg, yield 85.9%.
1H NMR(500MHz,CDCl3)δ7.41(d,J=8.7Hz,2H),7.29(d,J=8.2Hz,2H),6.31(d,J=
2.7Hz,1H),5.67(d,J=2.3Hz,1H),4.52(t,J=8.6Hz,1H),4.32–4.22(m,2H),4.07(dd,J=
9.1,5.6Hz,1H),3.21(ddd,J=8.1,5.5,2.6Hz,1H),2.14–2.00(m,1H),1.92(ddd,J=14.2,
7.9,5.7Hz,1H).
13C NMR(125MHz,CDCl3)δ170.63,153.12,137.79,136.88,132.1,122.68,120.44,
116.34,71.03,62.45,36.41,32.92.
HR-ESI-MS calcd for C14H15BrNO4[M+H]+340.1693,found340.1726.
Compound 4r-4:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 78.7mg,
Yield is 92.7%.
1H NMR(500MHz,CDCl3)δ7.42(d,J=8.8Hz,2H),7.28(d,J=8.3Hz,2H),6.32(d,J=
2.7Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.6Hz,1H),4.33–4.24(m,2H),4.08(dd,J=
9.1,5.5Hz,1H),3.22(ddd,J=8.2,5.5,2.6Hz,1H),2.07(ddd,J=14.3,12.0,5.6Hz,1H),
1.98–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.57,153.09,137.80,136.82,132.21,122.69,
120.45,70.96,62.45,36.39,33.00.
HR-ESI-MS calcd for C14H15BrNO4[M+H]+340.1693,found340.1725.
Compound 4s-5:Yellow solid;Under room temperature compound 3s (35.5mg, 0.25mmol) with to iodobenzene based isocyanate
(1.2eq) it is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane
Extraction, merges organic faciess, and the concentrated post of drying obtains product 75.1mg, yield 77.6%.
1H NMR(500MHz,CDCl3)δ7.60(d,J=8.2Hz,2H),7.17(d,J=7.5Hz,2H),6.32(s,1H),
5.67(s,1H),4.52(t,J=8.4Hz,1H),4.27(d,J=21.2Hz,2H),4.14–3.98(m,1H),3.22(s,1H),
2.08–2.04(m,1H),1.93(s,1H).
13C NMR(125MHz,CDCl3)δ170.60,153.03,138.14,137.80,137.56,122.70,
120.74,86.81,71.01,62.46,36.40,32.97.
HR-ESI-MS calcd for C14H15INO4[M+H]+387.1698,found387.1692.
Compound 4r-5:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 75.2mg,
Yield is 77.7%.
1H NMR(500MHz,CDCl3)δ7.61(d,J=8.8Hz,2H),7.17(d,J=8.2Hz,2H),6.32(d,J=
2.6Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.6Hz,1H),4.36–4.18(m,2H),4.08(dd,J=
9.1,5.4Hz,1H),3.30–3.14(m,1H),2.31–2.00(m,1H),1.96–1.93(m,1H).
13C NMR(125MHz,CDCl3)δ170.57,153.04,138.15,137.80,137.54,122.70,
120.73,86.83,70.97,62.46,36.39,32.99.
HR-ESI-MS calcd for C14H15INO4[M+H]+387.1698,found387.1689.
Compound 4s-6:Yellow oil;Compound 3s (35.5mg, 0.25mmol) and 2- methyl -6- isopropyls under room temperature
Base phenyl isocyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution
Washing, dichloromethane extraction merge organic faciess, and the concentrated post of drying obtains product 58.6mg, yield 73.9%.
1H NMR(500MHz,CDCl3)δ7.20(d,J=7.6Hz,1H),7.17(d,J=7.3Hz,1H),7.09(d,J=
7.2Hz,1H),6.27(d,J=60.1Hz,1H),5.59(d,J=106.4Hz,1H),4.55(t,J=8.4Hz,1H),4.40–
4.26(m,2H),4.16–4.04(m,1H),3.24(s,1H),3.18–3.08(m,1H),2.26(s,3H),2.04(s,1H),
1.74–1.69(m,1H),1.20(s,6H).
13C NMR(125MHz,CDCl3)δ170.79,154.94,146.58,138.18,136.79,132.14,
128.79,128.47,124.08,122.85,71.33,62.65,36.72,33.55,28.95,23.87,18.87.
HR-ESI-MS calcd for C18H24NO4[M+H]+318.3875,found318.3871.
Compound 4r-6:Yellow oil;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product
60.2mg, yield are 76.0%.
1H NMR(500MHz,CDCl3)δ7.21(d,J=6.4Hz,1H),7.17(d,J=7.1Hz,1H),7.09(d,J=
7.0Hz,1H),6.28(d,J=60.0Hz,1H),5.60(d,J=106.6Hz,1H),4.56(s,1H),4.36–4.26(m,
2H),4.11(s,1H),3.24(s,1H),3.14(d,J=6.1Hz,1H),2.26(s,3H),2.09(s,1H),1.72(s,
1H),1.20(s,6H).
13C NMR(125MHz,CDCl3)δ170.54,154.69,146.33,137.92,136.53,131.89,
128.53,128.22,123.83,122.60,71.08,62.39,36.46,33.30,28.68,23.62,18.62.
HR-ESI-MS calcd for C18H24NO4[M+H]+318.3875,found318.3868.
Compound 4s-7:Yellow solid;Under room temperature compound 3s (35.5mg, 0.25mmol) with to n-butoxycarbonyl benzene
Based isocyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 80.5mg, yield 89.2%.
1H NMR(500MHz,CDCl3)δ7.99(d,J=8.6Hz,1H),7.47(d,J=8.5Hz,1H),6.32(d,J=
2.5Hz,1H),5.67(d,J=2.2Hz,1H),4.52(t,J=8.6Hz,1H),4.42–4.22(m,2H),4.08(dd,J=
9.1,5.5Hz,1H),3.32–3.12(m,1H),2.09–2.05(m,1H),1.96–1.92(m,1H),1.78–1.68(m,
1H),1.52–1.41(m,1H),0.97(t,J=7.4Hz,1H).
13C NMR(125MHz,CDCl3)δ170.67,166.39,152.89,141.98,137.77,131.03,
125.58,122.77,117.82,71.02,64.92,62.54,36.38,32.92,30.91,19.39,13.88.
HR-ESI-MS calcd for C19H23NaNO6[M+Na]+384.3788,found384.3779.
Compound 4r-7:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 77.2mg,
Yield is 85.5%.
1H NMR(500MHz,CDCl3)δ8.00(d,J=7.9Hz,2H),7.46(d,J=7.9Hz,2H),6.33(d,J=
1.7Hz,1H),5.68(d,J=2.3Hz,1H),4.53(t,J=8.6Hz,1H),4.35–4.25(m,2H),4.09(dd,J=
9.1,5.4Hz,1H),3.23(dd,J=6.6,4.2Hz,1H),2.09(dd,J=14.4,5.8Hz,1H),1.95(dd,J=
14.4,7.2Hz,1H),1.77–1.72(m,2H),1.47(dd,J=15.0,7.5Hz,2H),0.97(t,J=7.4Hz,3H).
13C NMR(125MHz,CDCl3)δ170.68,166.39,152.89,141.99,137.76,131.03,
125.58,122.78,117.82,71.04,64.92,62.55,36.38,32.93,30.91,19.40,13.89.
HR-ESI-MS calcd for C19H23NaNO6[M+Na]+384.3788,found384.3776.
Compound 4s-8:Yellow solid;Under room temperature compound 3s (35.5mg, 0.25mmol) with to ethylphenyl Carbimide.
Ester (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane
Alkane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 59.7mg, yield 82.6%.
1H NMR(500MHz,CDCl3)δ7.28(d,J=6.2Hz,1H),7.14(d,J=8.4Hz,2H),6.31(d,J=
2.7Hz,1H),5.67(d,J=2.3Hz,1H),4.52(t,J=8.3Hz,1H),4.33–4.22(m,2H),4.10–4.03(m,
1H),3.21(s,1H),2.61(q,J=7.6Hz,2H),2.09–2.05(m,1H),1.93–1.90(m,1H),1.21(t,J=
7.6Hz,3H).
13C NMR(125MHz,CDCl3)δ170.60,153.46,137.85,135.21,128.56,122.62,
121.48,119.09,71.07,62.21,36.41,33.06,28.32,15.77.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3351.
The single crystal diffraction structure of compound 4s-8 is as shown in Figure 2.
Compound 4r-8:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 56.7mg,
Yield is 79.7%.
1H NMR(500MHz,CDCl3)δ7.27(d,J=1.6Hz,2H),7.15(d,J=8.4Hz,2H),6.32(d,J=
2.7Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.4Hz,1H),4.33–4.21(m,2H),4.09–4.05(m,
1H),3.23–3.20(m,1H),2.61(q,J=7.6Hz,2H),2.10–2.04(m,1H),1.96–1.88(m,1H),1.21
(t,J=7.6Hz,3H).
13C NMR(125MHz,CDCl3)δ170.59,153.50,140.07,137.85,135.20,128.57,
122.62,119.08,71.06,62.21,36.41,33.07,28.33,15.77.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3349.
Compound 4s-9:Yellow solid;Compound 3s (35.5mg, 0.25mmol) and bis- trifluoromethylbenzenes of 3,5- under room temperature
Based isocyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 80.6mg, yield 81.2%.
1HNMR(500MHz,CDCl3)δ7.93(s,1H),7.57(s,1H),6.33(d,J=2.6Hz,1H),5.69(d,J=
2.3Hz,1H),4.55(t,J=8.6Hz,1H),4.37–4.30(m,2H),4.11(dd,J=9.1,5.5Hz,1H),3.29–
3.21(m,1H),2.16–2.08(m,1H),2.00–1.94(m,1H).
13C NMR(125MHz,CDCl3)δ170.77,152.90,139.48,137.76,132.64(q,J=33.5Hz),
122.85,122.13,118.46,117.02,71.02,62.97,36.50,32.80.
HR-ESI-MS calcd for C16H14F6NO4[M+H]+398.2771,found398.2762.
Compound 4r-9:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product 76.7mg,
Yield is 77.3%.
1HNMR(500MHz,CDCl3)δ7.92(s,2H),7.57(s,1H),6.34(d,J=2.7Hz,1H),5.69(d,J=
2.4Hz,1H),4.56–4.52(m,1H),4.38–4.30(m,2H),4.11(dd,J=9.2,5.4Hz,1H),3.26–3.23
(m,1H),2.15–2.05(m,1H),2.00–1.95(m,1H).
13C NMR(125MHz,CDCl3)δ170.76,152.89,139.47,137.76,132.84–132.06(m),
122.84,122.12,118.46,117.03,71.00,62.96,36.49,32.81.
HR-ESI-MS calcd for C16H14F6NO4[M+H]+398.2771,found398.2765.
Compound 4s-10:Yellow solid;Compound 3s (35.5mg, 0.25mmol) and 3,4- 3,5-dimethylphenyls under room temperature
Isocyanates (1.2eq) are dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing,
Dichloromethane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 60.6mg, yield 83.9%.
1H NMR(500MHz,CDCl3)δ7.16(s,1H),7.06(d,J=7.7Hz,2H),6.32(d,J=2.7Hz,1H),
5.67(d,J=2.5Hz,1H),4.52(s,1H),4.40–4.18(m,2H),4.07(s,1H),3.22(s,1H),2.24(s,
3H),2.21(s,3H),2.11–2.02(m,1H),1.97–1.88(m,1H).
13C NMR(125MHz,CDCl3)δ170.55,153.50,137.85,137.53,135.22,130.21,
120.41,118.75,116.56,71.09,62.20,36.42,33.11,20.03,19.20.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3339.
Compound 4r-10:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product
54.5mg, yield are 75.4%.
1H NMR(500MHz,CDCl3)δ7.16(s,1H),7.07(s,2H),6.32(d,J=2.7Hz,1H),5.67(d,J
=2.4Hz,1H),4.53(t,J=8.4Hz,1H),4.31–4.22(m,2H),4.09–4.06(m,1H),3.22(s,1H),2.24
(s,3H),2.22(s,3H),2.10–2.04(m,1H),1.95–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.81,153.76,138.10,137.78,135.47,130.47,
122.88,120.66,119.01,116.81,71.34,62.46,36.68,33.37,20.28,19.46.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3337.
Compound 4s-11:Dark red oil;Compound 3s (35.5mg, 0.25mmol) and cumic aldehyde under room temperature
Based isocyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 60.3mg, yield 79.6%.
1H NMR(500MHz,CDCl3)δ7.29(d,J=6.4Hz,2H),7.17(d,J=8.4Hz,2H),6.31(d,J=
2.6Hz,1H),5.67(d,J=2.1Hz,1H),4.52(t,J=8.2Hz,1H),4.34–4.20(m,2H),4.07(d,J=
5.4Hz,1H),3.21(s,1H),2.89–2.85(m,1H),2.07–2.04(m,1H),1.92–1.87(m,1H),1.22(d,J
=6.9Hz,6H).
13C NMR(125MHz,CDCl3)δ170.59,153.49,144.69,137.85,135.26,127.12,
122.61,119.12,71.07,62.20,36.41,33.62,33.06,24.14.
HR-ESI-MS calcd for C17H22NO4[M+H]+304.3609,found304.3619.
Compound 4r-11:Dark red oil;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product
62.6mg, yield are 82.6%.
1H NMR(500MHz,CDCl3)δ7.29(d,J=5.3Hz,2H),7.17(d,J=8.4Hz,2H),6.32(d,J=
2.5Hz,1H),5.67(d,J=2.1Hz,1H),4.52(t,J=8.3Hz,1H),4.34–4.20(m,2H),4.06(d,J=
7.0Hz,1H),3.21(s,1H),2.90–2.85(m,1H),2.08–2.04(m,1H),1.94–1.90(m,1H),1.23(d,J
=6.9Hz,6H).
13C NMR(125MHz,CDCl3)δ170.57,153.45,144.69,137.85,135.25,127.14,
122.61,119.14,71.06,62.20,36.41,33.63,33.08,24.14.
HR-ESI-MS calcd for C17H22NO4[M+H]+304.3609,found304.3616.
Compound 4s-12:Yellow oil;Compound 3s (35.5mg, 0.25mmol) and 2- fluorophenyl isocyanides under room temperature
Acid esters (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloro
Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 52.3mg, yield 75.0%.
1HNMR(500MHz,CDCl3)δ8.04(s,1H),7.12(dd,J=15.0,7.1Hz,1H),7.07(dd,J=
11.0,1.5Hz,1H),6.85(s,1H),6.33(d,J=2.7Hz,1H),5.69(d,J=2.4Hz,1H),4.53(t,J=
8.6Hz,1H),4.32–4.27(m,2H),4.07(dd,J=9.1,5.5Hz,1H),3.27–3.20(m,1H),2.11–2.04
(m,1H),2.01–1.84(m,1H).
13C NMR(125MHz,CDCl3)δ170.44,153.01,137.74,126.14(d,J=10.0Hz),124.80
(d,J=3.2Hz),123.98,122.73,120.49,115.09(d,J=19.1Hz),70.97,62.56,36.27,33.04.
HR-ESI-MS calcd for C14H15FNO4[M+H]+280.2716,found280.2722.
Compound 4r-12:Yellow oil;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product
53.6mg, yield are 76.8%.
1HNMR(500MHz,CDCl3)δ8.04(s,1H),7.10(dd,J=18.9,4.6Hz,1H),7.06(d,J=
1.3Hz,1H),6.86(s,1H),6.33(d,J=2.6Hz,1H),5.68(d,J=2.3Hz,1H),4.53(t,J=8.6Hz,
1H),4.35–4.23(m,2H),4.10–4.05(m,1H),3.26–3.20(m,1H),2.12–2.06(m,1H),1.99–1.89
(m,1H).
13C NMR(125MHz,CDCl3)δ170.45,153.02,137.73,126.16,124.78(d,J=3.3Hz),
123.98,122.72,120.44,115.08(d,J=19.1Hz),70.97,62.56,36.26,33.02.HR-ESI-MS
calcd for C14H15FNO4[M+H]+280.2716,found280.2725.
Compound 4s-13:Brown solid;Under room temperature, compound 3s (35.5mg, 0.25mmol) is different with p-methoxyphenyl
Cyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, and two
Chloromethanes are extracted, and merge organic faciess, and the concentrated post of drying obtains product 56.4mg, yield 77.5%.
1H NMR(500MHz,CDCl3)δ7.27(d,J=1.8Hz,1H),6.85(d,J=8.9Hz,1H),6.30(d,J=
2.5Hz,1H),5.66(d,J=1.8Hz,1H),4.51(s,1H),4.29–4.22(m,1H),4.06(s,1H),3.79(s,
3H),3.20(s,1H),2.12–2.02(m,1H),1.92–1.86(m,1H).
13C NMR(125MHz,CDCl3)δ170.60,156.31,153.70,137.85,130.68,122.59,
120.92,114.42,71.09,62.20,55.62,36.43,33.03.
HR-ESI-MS calcd for C15H18NO5[M+H]+292.3071,found292.3078.
Compound 4r-13:Brown solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product
54.6mg, yield are 75.1%.
1H NMR(500MHz,CDCl3)δ7.27(d,J=1.9Hz,2H),6.86(d,J=9.0Hz,2H),6.31(d,J=
2.7Hz,1H),5.67(d,J=1.9Hz,1H),4.52(s,1H),4.30–4.19(m,2H),4.07(s,1H),3.79(s,
3H),3.21(s,1H),2.14–1.99(m,1H),1.97–1.86(m,1H).
13C NMR(125MHz,CDCl3)δ170.62,156.27,153.70,137.84,130.71,122.57,
120.90,114.39,71.10,62.19,55.60,36.43,32.98.
HR-ESI-MS calcd for C15H18NO5[M+H]+292.3071,found292.3077.
Compound 4s-14:Yellow solid;Under room temperature, compound 3s (35.5mg, 0.25mmol) is different with to n-butylphenyl
Cyanate (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, and two
Chloromethanes are extracted, and merge organic faciess, and the concentrated post of drying obtains product 60.3mg, yield 76.1%.
1H NMR(500MHz,CDCl3)δ7.26(d,J=1.1Hz,2H),7.12(d,J=8.3Hz,2H),6.31(d,J=
2.6Hz,1H),5.67(d,J=2.1Hz,1H),4.52(t,J=8.1Hz,1H),4.38–4.20(m,2H),4.07(s,1H),
3.21(s,1H),2.63–2.49(m,2H),2.09–2.04(m,1H),1.95–1.91(m,1H),1.60–1.55(m,2H),
1.37–1.32(m,2H),0.91(t,J=7.3Hz,3H).
13C NMR(125MHz,CDCl3)δ170.58,153.44,137.85,135.17,129.12,122.62,
119.05,71.06,62.20,36.41,35.06,33.77,33.07,22.38,14.05.
HR-ESI-MS calcd for C18H24NO4[M+H]+318.3875,found318.3869.
Compound 4r-14:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product
63.6mg, yield are 80.2%.
1H NMR(500MHz,CDCl3)δ7.27(d,J=1.1Hz,2H),7.12(d,J=8.4Hz,2H),6.32(d,J=
2.7Hz,1H),5.67(d,J=2.4Hz,1H),4.52(t,J=8.4Hz,1H),4.38–4.21(m,2H),4.15–4.02(m,
1H),3.22(s,1H),2.58–2.55(m,2H),2.08–2.04(m,1H),1.94–1.91(m,1H),1.57(ddd,J=
15.3,11.1,7.6Hz,2H),1.34(dd,J=14.9,7.4Hz,2H),0.91(t,J=7.4Hz,3H).
13C NMR(125MHz,CDCl3)δ170.59,153.44,137.85,135.17,129.11,122.62,
119.02,71.06,62.21,36.41,35.06,33.77,33.07,22.38,14.04.
HR-ESI-MS calcd for C18H24NO4[M+H]+318.3875,found318.3871.
Compound 4s-15:Yellow solid;Compound 3s (35.5mg, 0.25mmol) and 3,5- 3,5-dimethylphenyls under room temperature
Isocyanates (1.2eq) are dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing,
Dichloromethane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 57.8mg, yield 80%.
1H NMR(500MHz,CDCl3)δ7.01(s,1H),6.72(s,1H),6.31(d,J=2.6Hz,1H),5.66(d,J
=2.3Hz,1H),4.52(t,J=8.6Hz,1H),4.32–4.20(m,1H),4.06(dd,J=9.0,5.7Hz,1H),3.23–
3.20(m,1H),2.28(s,6H),2.08–2.04(m,1H),1.93–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.58,153.33,138.94,137.85,137.46,125.62,
122.56,116.69,71.05,62.18,36.40,33.02,21.46.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3336.
Compound 4r-15:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product
61.9mg, yield are 85.7%.
1H NMR(500MHz,CDCl3)δ7.00(s,1H),6.73(s,1H),6.32(d,J=2.7Hz,1H),5.67(d,J
=2.4Hz,1H),4.52(t,J=8.6Hz,1H),4.31–4.23(m,1H),4.07(dd,J=9.1,5.6Hz,1H),3.24–
3.20(m,1H),2.29(s,6H),2.09–2.06(m,1H),1.95–1.91(m,1H).
13C NMR(125MHz,CDCl3)δ170.54,139.03,137.86,137.42,125.72,122.61,
116.67,71.02,62.20,36.41,33.11,21.50.
HR-ESI-MS calcd for C16H20NO4[M+H]+290.3343,found290.3335.
Compound 4s-16:Yellow solid;Compound 3s (35.5mg, 0.25mmol) and 3- bromophenyl Carbimide .s under room temperature
Ester (1.2eq) is dissolved in dichloromethane, Deca triethylamine (1.2eq), one hour response time, reaction solution washing, dichloromethane
Alkane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 67.8mg, yield 80%.
1H NMR(500MHz,CDCl3)δ7.65(s,1H),7.28(d,J=8.0Hz,1H),7.21(d,J=8.0Hz,1H),
7.17(dd,J=7.9,2.8Hz,1H),6.32(d,J=2.7Hz,1H),5.68(d,J=2.3Hz,1H),4.53(t,J=8.6Hz,
1H),4.34–4.25(m,2H),4.08(dd,J=9.1,5.5Hz,1H),3.23–3.21(m,1H),2.09–2.05(m,1H),
1.96–1.92(m,1H).
13C NMR(125MHz,CDCl3)δ170.64,153.00,153.00,139.01,137.80,130.52,
126.87,122.94,122.71,121.81,117.32,70.96,62.52,36.38,33.00.
HR-ESI-MS calcd for C14H15BrNO4[M+H]+340.1693,found340.1715.
Compound 4r-16:Yellow solid;Reactant becomes 3r, and inventory and synthetic method are constant, obtain product
69.1mg, yield are 81.5%.
1H NMR(500MHz,CDCl3)δ7.65(s,1H),7.28(d,J=7.6Hz,1H),7.23–7.19(m,1H),
7.16(t,J=7.9Hz,1H),6.32(d,J=2.7Hz,1H),5.68(d,J=2.4Hz,1H),4.55–4.51(m,1H),
4.32–4.24(m,2H),4.08(dd,J=9.2,5.5Hz,1H),3.25–3.19(m,1H),2.10–2.04(m,1H),1.97–
1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.59,153.00,139.04,137.80,130.51,126.85,
122.92,122.71,121.81,117.36,70.98,62.52,36.39,32.98.
HR-ESI-MS calcd for C14H15BrNO4[M+H]+340.1693,found340.1713.
Embodiment 2:The synthetic method of the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue of 8 benzoic acid replacements
Compound 5s-1~8 universal synthesis method:Compound 3s substituted benzoic acid different from phenyl ring under room temperature
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product.
Above-claimed cpd1H-NMR、13The data such as C-NMR and high resolution mass spectrum are as follows:
Compound 5s-1:White solid;Under room temperature, compound 3s (35.5mg, 0.5mmol) is dissolved in benzoic acid (1.2eq)
In dichloromethane, EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloromethane are added
Extraction, merges organic faciess, and the concentrated post of drying obtains product 46.6g, and yield is 75.8%.
1H NMR(500MHz,CDCl3)δ8.05(d,J=7.96Hz,2H),7.57(t,J=7.66Hz,1H),7.46(t,J=
7.96,7.66Hz,2H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,
2.70Hz,2H),4.55(dd,J=9.15,7.80Hz,1H),3.81(dd,J=9.15,4.60Hz,1H),3.08–3.12(m,
1H),2.07–2.11(m,1H),1.81–1.86(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,166.35,138.68,133.00,130.14,129.76,
129.76,128.48,128.48,118.83,70.93,62.95,39.27,31.15.
HR-ESI-MS calcd for C14H14O4Na[M+Na]+269.2483,found269.2473.
Compound 5s-2:White solid;Compound 3s (35.5mg, 0.5mmol) and parabromobenzoic acid (1.2eq) under room temperature
It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro
Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 69.5g, and yield is 85.8%.
1H NMR(500MHz,CDCl3)δ7.89(d,J=8.46Hz,2H),7.58(d,J=8.46Hz,2H),6.20(d,J=
2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,2.70Hz,2H),4.55(dd,J=9.15,
7.80Hz,1H),3.82(dd,J=9.15,4.60Hz,1H),3.06–3.15(m,1H),2.05–2.14(m,1H),1.80–
1.87(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,165.54,138.68,133.16,133.16,131.80,
131.80,129.64,127.90,118.86,70.96,62.93,39.32,31.18.
HR-ESI-MS calcd for C14H14O4Br[M+H]+326.1626,found326.1619.
Compound 5s-3:White solid;Compound 3s (35.5mg, 0.5mmol) and 4-Iodobenzoic acid (1.2eq) under room temperature
It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro
Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 80.6g, and yield is 86.7%.
1H NMR(500MHz,CDCl3)δ7.78(d,J=8.29Hz,2H),7.59(d,J=8.29Hz,2H),6.20(d,J=
2.85Hz,1H),5.53(d,J=2.85Hz,1H),4.79(td,J=6.83,2.70Hz,2H),4.54(dd,J=9.15,
7.80Hz,1H),3.81(dd,J=9.15,4.60Hz,1H),3.05–3.12(m,1H),2.04–2.12(m,1H),1.80–
1.86(m,1H)
13C NMR(125MHz,CDCl3)δ170.42,165.79,138.68,136.75,136.75,130.31,
130.31,129.57,118.83,98.61,70.93,62.96,39.29,31.16.
HR-ESI-MS calcd for C14H14O4I[M+H]+373.1630,found373.1626.
Compound 5s-4:White solid;Compound 3s (35.5mg, 0.5mmol) and cumfrey under room temperature
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 61.6g, and yield is 85.6%.
1H NMR(500MHz,CDCl3)δ7.98(d,J=7.95Hz,2H),7.20(d,J=7.95Hz,2H),6.20(d,J=
2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,2.70Hz,2H),4.55(dd,J=9.15,
7.80Hz,1H),3.81(dd,J=9.15,4.60Hz,1H),3.06–3.11(m,1H),2.93–2.98(m,1H),2.03–
2.09(m,1H),1.82–1.88(m,1H),1.24(s,6H).
13C NMR(125MHz,CDCl3)δ170.42,166.32,152.06,138.68,129.06,129.06,
127.13,125.82,125.82,118.83,70.93,62.96,39.29,34.13,31.16,23.29.
HR-ESI-MS calcd for C17H20O4Na[M+Na]+311.3281,found311.3276.
Compound 5s-5:Yellow solid;Compound 3s (35.5mg, 0.5mmol) and p-tert-butyl benzoic acid under room temperature
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 59.7g, and yield is 79.1%.
1H NMR(500MHz,CDCl3)δ7.88(d,J=8.65Hz,2H),7.39(d,J=8.65Hz,2H),7.39(d,J=
8.65Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,2.70Hz,2H),
4.55(dd,J=9.15,7.80Hz,1H),3.81(dd,J=9.15,4.60Hz,1H),3.08–3.13(m,1H),2.03–2.09
(m,1H),1.80–1.88(m,1H),1.35(s,9H).
13C NMR(125MHz,CDCl3)δ170.42,166.06,158.28,138.68,129.42,127.31,
125.62,118.83,70.93,62.96,39.29,35.26,31.16,30.95.
HR-ESI-MS calcd for C18H22O4Na[M+Na]+325.3546,found325.3556.
Compound 5s-6:White solid;Under room temperature compound 3s (35.5mg, 0.5mmol) with to n-amylbenzene formic acid
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 57.2g, and yield is 72.4%.
1H NMR(500MHz,CDCl3)δ8.03(d,J=8.15Hz,2H),7.22(d,J=8.15Hz,2H),6.21(d,J=
2.85Hz,1H),5.55(d,J=2.85Hz,1H),4.81(td,J=6.83,2.70Hz,2H),4.56(dd,J=9.15,
7.80Hz,1H),3.82(dd,J=9.15,4.60Hz,1H),3.08(m,1H),2.62(t,J=7.40Hz,2H),2.07(m,
1H),1.86(m,1H),1.72(m,2H),1.44(m,2H)1.38(m,2H),0.82(t,J=6.80Hz,3H).
13C NMR(125MHz,CDCl3)δ170.41,166.28,149.07,138.68,129.62,129.62,
129.16,129.16,128.24,118.83,70.93,62.96,39.29,35.36,31.54,31.16,30.75,22.51,
13.98.
HR-ESI-MS calcd for C19H24O4Na[M+Na]+339.3812,found339.3819.
Compound 5s-7:Yellow solid;Compound 3s (35.5mg, 0.5mmol) and p-Methoxybenzoic acid under room temperature
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 49.5g, and yield is 71.7%.
1HNMR(500MHz,CDCl3)δ7.96(d,J=8.60Hz,2H),6.93(d,J=8.60Hz,2H),6.20(d,J=
2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.80(td,J=6.83,2.70Hz,2H),4.55(dd,J=9.15,
7.80Hz,1H),3.84(s,3H),3.81(dd,J=9.15,4.60Hz,1H),3.06–3.13(m,1H),2.06–2.12(m,
1H),1.81–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,165.93,165.20,138.68,132.52,123.36,
118.83,115.49,70.93,62.96,56.70,39.29,31.16.
HR-ESI-MS calcd for C15H16O5Na[M+Na]+299.2743,found299.2752.
Compound 5s-8:White solid;Under room temperature compound 3s (35.5mg, 0.5mmol) with to (Trifluoromethyl)benzoic acid.
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 62.8g, and yield is 80%.
1HNMR(500MHz,CDCl3)δ8.10(d,J=8.00Hz,2H),7.86(d,J=8.00Hz,2H),6.19(d,J=
2.85Hz,1H),5.53(d,J=2.85Hz,1H),4.79(td,J=6.83,2.70Hz,2H),4.54(dd,J=9.15,
7.80Hz,1H),3.80(dd,J=9.15,4.60Hz,1H),3.07–3.13(m,1H),2.05–2.11(m,1H),1.80–
1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.41,165.61,138.67,134.51,131.70,129.87,
125.08,123.60,118.82,70.92,62.94,39.28,31.14.
HR-ESI-MS calcd for C15H14O4F3[M+H]+315.2645,found315.2652.
Embodiment 3:The synthetic method of the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue of 10 cinnamic acid replacements
Compound 6s-1~10 universal synthesis method:Compound 3s substituted cinnamic acid different from phenyl ring under room temperature
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product.
Above-claimed cpd1H-NMR、13The data such as C-NMR and high resolution mass spectrum are as follows:
Compound 6s-1:Yellow solid;Under room temperature, compound 3s (35.5mg, 0.5mmol) is dissolved in cinnamic acid (1.2eq)
In dichloromethane, EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloromethane are added
Extraction, merges organic faciess, and the concentrated post of drying obtains product 46.2g, yield 67.9%.
1H NMR(500MHz,CDCl3)δ7.78(d,J=15.88Hz,1H),7.47(d,J=7.51Hz,2H),7.42–
7.45(m,3H),6.50(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H),
3.10–3.17(m,1H),2.05–2.11(m,1H),1.82–1.91(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,144.80,139.18,134.50,130.20,
129.52,129.23,118.83,118.50,71.14,62.75,40.15,31.29.
HR-ESI-MS calcd for C16H17O4[M+H]+273.3038,found273.3052.
Compound 6s-2:White solid;Under room temperature compound 3s (35.5mg, 0.5mmol) with to fluoro cinnamic acid (1.2eq)
It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro
Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 54.2g, yield 75.2%.
1H NMR(500MHz,CDCl3)δ7.60(d,J=15.88Hz,1H),7.51–7.55(m,2H),7.07–7.10(m,
1H),6.39(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49(dd,J=
9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H),3.10–3.18
(m,1H),2.05–2.10(m,1H),1.82–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.41,169.01,164.50,145.26,139.16,130.46,
130.10,118.81,118.40,116.00,71.13,62.73,40.13,31.27.
HR-ESI-MS calcd for C16H15FO4Na[M+Na]+313.2761,found313.2755.
Compound 6s-3:White solid;Under room temperature compound 3s (35.5mg, 0.5mmol) with to chloro-cinnamic acid (1.2eq)
It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro
Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 58.6g, yield 76.6%.
1HNMR(500MHz,CDCl3)δ7.65(d,J=15.88Hz,1H),7.40(d,J=8.51Hz,2H),7.35(d,J=
8.51Hz,2H),6.49(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H),
3.12–3.16(m,1H),2.03–2.09(m,1H),1.80–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.41,169.01,142.63,139.18,136.17,133.44,
129.73,128.46,118.82,117.76,71.14,62.75,40.15,31.28.
HR-ESI-MS calcd for C16H15ClO4Na[M+Na]+329.7304,found329.7335.
Compound 6s-4:White solid;Under room temperature compound 3s (35.5mg, 0.5mmol) with to bromo-cinnamic acid (1.2eq)
It is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution washing, dichloro
Methane is extracted, and merges organic faciess, and the concentrated post of drying obtains product 62.0g, yield 70.9%.
1H NMR(500MHz,CDCl3)δ7.63(d,J=15.88Hz,1H)7.53(d,J=8.59Hz,2H),7.45(d,J=
8.59Hz,2H),6.45(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H),
3.11–3.16(m,1H),2.04–2.10(m,1H),1.82–1.88(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,143.48,139.17,133.74,132.16,
130.06,124.91,118.94,118.83,71.13,62.75,40.14,31.29.
HR-ESI-MS calcd for C16H15BrO4Na[M+Na]+374.1817,found374.1820.
Compound 6s-5:White solid;Compound 3s (35.5mg, 0.5mmol) and p-trifluoromethylcinnamic acid under room temperature
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 61.4g, yield 72.3%.
1H NMR(500MHz,CDCl3)δ7.70(d,J=15.88Hz,1H),7.65(d,J=8.44Hz,2H),7.60(d,J
=8.44Hz,2H),6.42(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H),
3.10–3.16(m,1H),2.02–2.09(m,1H),1.81–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,142.91,139.16,137.76,131.70,
128.10,128.10,125.80,125.80,121.25,123.80,118.82,71.12,62.74,40.13,31.28.
HR-ESI-MS calcd for C17H15F3O4Na[M+Na]+363.2836,found363.2817.
Compound 6s-6:Yellow oil;Under room temperature compound 3s (35.5mg, 0.5mmol) with to methyl mercapto cinnamic acid
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 59.3g, yield 74.6%.
1HNMR(500MHz,CDCl3)δ7.72(d,J=15.88Hz,1H),7.50(d,J=8.50Hz,2H),7.18(d,J=
8.50Hz,2H),6.42(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H),
3.10–3.18(m,1H),2.50(s,3H),2.03–2.09(m,1H),1.83–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,145.92,139.18,137.35,133.36,
129.34,126.92,118.83,118.78,71.14,62.75,40.15,31.29,16.00.
HR-ESI-MS calcd for C17H19O4S[M+H]+319.3964,found319.3957.
Compound 6s-7:White solid;Under room temperature compound 3s (35.5mg, 0.5mmol) with to methyl cinnamic acid
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 58.7g, yield 82.1%.
1H NMR(500MHz,CDCl3)δ7.58(d,J=15.88Hz,1H),7.42(d,J=8.07Hz,2H),7.19(d,J
=8.07Hz,2H),6.43(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.75(dd,J=9.15,4.60Hz,1H),
3.10–3.16(m,1H),2.38(s,3H),2.05–2.10(m,1H),1.85–1.89(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.02,143.33,141.36,139.19,132.39,
130.33,128.77,118.85,118.37,71.15,62.76,40.16,31.30,22.18.
HR-ESI-MS calcd for C17H19O4[M+H]+287.3304,found287.3321.
Compound 6s-8:White solid;Compound 3s (35.5mg, 0.5mmol) and p-methoxycinnamic acid under room temperature
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 59.5g, yield 78.8%.
1HNMR(500MHz,CDCl3)δ7.64(d,J=15.88Hz,1H),7.47(d,J=8.51Hz,2H),6.90(d,J=
8.51Hz,2H),6.34(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.83(s,3H),3.75(dd,J=9.15,
4.60Hz,1H)3.11–3.16(m,1H),2.02–2.08(m,1H),1.82–1.88(m,1H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,162.40,145.36,139.18,131.20,
130.21,118.83,117.17,116.00,71.14,62.75,55.60,40.15,31.29.
HR-ESI-MS calcd for C17H19O5[M+H]+303.3298,found303.3279.
Compound 6s-9:White solid;Under room temperature compound 3s (35.5mg, 0.5mmol) with to ethoxy-cinnamic acid
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 58.6g, yield 74.1%.
1H NMR(500MHz,CDCl3)δ7.64(d,J=15.88Hz,1H),7.49(d,J=8.51Hz,2H),6.98(d,J
=8.51Hz,2H),6.34(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),4.09(q,J=6.96Hz,2H),3.75(dd,J
=9.15,4.60Hz,1H),3.12–3.17(m,1H),2.04–2.09(m,1H),1.83–1.89(m,1H),1.42(t,J=
6.96Hz,3H).
13C NMR(125MHz,CDCl3)δ170.43,169.02,158.86,145.23,139.19,129.89,
127.67,118.84,117.18,115.00,71.15,64.46,62.76,40.16,31.28,14.75.
HR-ESI-MS calcd for C18H21O5[M+H]+317.3563,found317.3577.
Compound 6s-10:White solid;Under room temperature compound 3s (35.5mg, 0.5mmol) with to propoxyl group cinnamic acid
(1.2eq) it is dissolved in dichloromethane, adds EDCI (1.2eq) and DMAP (0.02eq), two hours response time, reaction solution water
Wash, dichloromethane extraction, merge organic faciess, the concentrated post of drying obtains product 62.6g, yield 75.9%.
1H NMR(500MHz,CDCl3)δ7.64(d,J=15.88Hz,1H),7.47(d,J=8.51Hz,2H),6.97(d,J
=8.51Hz,2H),6.34(d,J=15.88Hz,1H),6.20(d,J=2.85Hz,1H),5.54(d,J=2.85Hz,1H),4.49
(dd,J=9.15,7.80Hz,1H),4.25(td,J=6.83,2.70Hz,2H),3.95(t,J=7.11Hz,2H),3.75(dd,J
=9.15,4.60Hz,1H),3.11–3.17(m,1H),2.05–2.10(m,1H),1.85–1.89(m,1H),1.79–1.83(m,
2H),1.04(t,J=7.36Hz,3H).
13C NMR(125MHz,CDCl3)δ170.42,169.01,159.74,145.23,139.18,129.90,
127.45,118.83,117.17,114.89,71.14,69.10,62.75,40.15,31.29,22.20,10.40.
HR-ESI-MS calcd for C19H23O5[M+H]+331.3829,found331.3836.
Embodiment 4:Compound 4r-1~16,4s-1~16,5s-1~8,6s-1~10 suppress LPS induction RAW264.7's
NO generates activity
(1)Sample is configured
4r-1~16,4s-1~16,5s-1~8,6s-1~10, the southern regions of the Yunnan Province ocean ear chrysanthemum lactone A and the positive prepared by embodiment 1
Comparison medicine aminoguanidine(Sigma-Aldrich, purity>98.0%)Use DMSO(Dimethyl sulfoxide)(Merck), after dissolving, add PBS
(-)(Phosphate buffer)The solution of 10mM is made into, the sample of 0,0.1,0.5,5,20 μM of gradient concentration is further diluted to.With
The LPS (Lipopolysaccharides, lipopolysaccharide, sigma, Cat.L-2880) of 10 μ g/mL is derivant.
(2)Experimental technique
Mouse macrophage RAW264.7(It is purchased from Shanghai Sheng Ke institutes cell resource center)At 37 DEG C, 5%CO2In incubator
Cellar culture is in DMEM culture fluid.By 1 μ L/mL LPS during experiment(Lipopolysaccharide)(being dissolved in distilled water) adds 100mL concentration
For 2 × 106In the cell suspension of μ g/mL, between the content after 18h with Griess methods by measure cell supernatant nitrite
It is reversed to reflect NO growing amounts:100mL cell culture fluids are taken, equivalent Griess is added(Ge Lisi)Reagent, determines light absorption value.
(3)Evaluation criterion and statistical method
Trap is surveyed at 570nm wavelength, with NaNO2Standard solution draws standard curve, calculates the concentration of nitrite.
Each group experimental result carries out statistical analysiss in SPSS software one-way ANNOVA methods.
(4)Experimental result
Test result indicate that 4r-1~16,4s-1~16,5s-1~8 and 6s-1~10 pair LPS induction RAW264.7 macrophages
The NO of cell is generated obvious inhibitory activity(The results are shown in Table 1), illustrate which has anti-inflammatory activity.
Table 1:4r-1~16,4s-1~16,5s-1~8,6s-1~10 suppress the NO of LPS induction RAW264.7 to generate activity
Embodiment 5:Compound 4r-1~16,4s-1~16,5s-1~8, the cytotoxicity of 6s-1~10
(1)Sample is configured
4r-1~16 of the preparation of embodiment 1,4s-1~16,5s-1~8,6s-1~10 DMSO(Dimethyl sulfoxide)
(Merck), after dissolving, add PBS (-)(Phosphate buffer)It is made into the solution of 10mM
(2)Experimental technique
Mouse macrophage RAW264.7(It is purchased from Shanghai Sheng Ke institutes cell resource center)At 37 DEG C, 5%CO2In incubator
Cellar culture is in DMEM culture fluid.Take the logarithm during experiment trophophase RAW264.7 cells it is resuspended Jing after trypsinization,
Obtain 1 × 105The cell suspension of/ml.It is plated in 96 orifice plates, continues culture 18 hours.It is further cultured for after dosing 18 hours, per hole
10 Μ l MTT solution (5mg/ml) are added, continues culture 3 hours.
(3)Evaluation criterion and statistical method
Trap is surveyed at 570nm wavelength, each group experimental result is counted in SPSS software one-wayANNOVA methods
Analysis.
(4)Experimental result
Experimental result finds that all toxicity of compound are all relatively low, toxicity IC5020 μM are all higher than, and in the ear chrysanthemum of relative the southern regions of the Yunnan Province ocean
Ester A toxicity is lower.
Below the preferred embodiment to the invention is illustrated, but the invention be not limited to it is described
Embodiment, those of ordinary skill in the art can also make a variety of equivalents on the premise of without prejudice to the invention spirit
Modification or replacement, the modification of these equivalents or replacement are all contained in the application claim limited range.
Claims (5)
1. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of isocyanates, benzoic acid or cinnamic acid replace, its chemical constitution such as formula 1,
Shown in formula 2 or formula 3:
In formula 1, R1 is respectively:
In formula 2, R2 is respectively:
In formula 3, R3 is respectively:
2. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of isocyanates as claimed in claim 1, benzoic acid or cinnamic acid replace
Preparation method, it is characterised in that the synthetic route of the preparation method is:
Reactions steps are as follows:
Dicyclohexylcarbodiimide and ether is dissolved in dimethylamino naphthyridine, under the conditions of subzero 30 DEG C, is added dropwise over acetylenecarboxylic acid, suitable
The diethyl ether solution of butylene glycol;After completion of dropping, room temperature reaction obtains compound 1 in 12 hours;In catalyst 1,5- cyclo-octadiene chlorine
Under the effect of rhodium dimerization, silver hexafluoroantimonate and chiral ligand dinaphthalene diphenyl phosphine, compound 1 can change into two kinds of configurations of R, S respectively
Compound 2r and 2s;, by borane reduction into compound 3r and 3s, compound 3r and 3s is different from phenyl ring for compound 2r and 2s
Substituted isocyanates, benzoic acid, Cortex Cinnamomi acid reaction can obtain target compound 4r, 4s, 5s, 6s.
3. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that a kind of isocyanates as claimed in claim 1, benzoic acid or cinnamic acid replace
Application in anti-inflammatory drug is prepared.
4. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates according to claim 3, benzoic acid or cinnamic acid replace exists
Prepare the application in anti-inflammatory drug, it is characterised in that described anti-inflammatory drug is to be replaced by isocyanates, benzoic acid or cinnamic acid
The southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue as active component and pharmaceutical composition made by conventional pharmaceutical carrier.
5. the southern regions of the Yunnan Province ocean ear chrysanthemum lactone analogue that isocyanates according to claim 4, benzoic acid or cinnamic acid replace exists
Prepare the application in anti-inflammatory drug, it is characterised in that described pharmaceutical composition is tablet, capsule, drop pill, granule, note
Penetrate agent or aerosol.
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