CN104910174A - Piplartine analogue, preparation method therefor and applications - Google Patents

Piplartine analogue, preparation method therefor and applications Download PDF

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Publication number
CN104910174A
CN104910174A CN201510243672.XA CN201510243672A CN104910174A CN 104910174 A CN104910174 A CN 104910174A CN 201510243672 A CN201510243672 A CN 201510243672A CN 104910174 A CN104910174 A CN 104910174A
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analogue
lhc
piperlongumine
pyridine
acceptable salt
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CN104910174B (en
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李家明
何广卫
王杰
储昭兴
左键
谢迪
刘会财
黄伟军
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HEFEI ENRUITE PHARMACEUTICAL CO., LTD.
Hefei Medical and Pharmaceutical Co., Ltd.
Anhui University of Traditional Chinese Medicine AHUTCM
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Hefei Enruite Pharmaceutical Co Ltd
HEFEI YIGONG MEDICINE CO Ltd
Anhui University of Traditional Chinese Medicine AHUTCM
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The invention relates to the pharmaceutical chemistry field, and concretely relates to a piplartine analogue (I) or (II), a preparation method therefor and pharmaceutical compositions containing the piplartine analogue (I) and (II). The pharmacodynamic experiments prove that piplartine analogue can be used for treating or preventing thromboembolism diseases. The structural formulas of the piplartine analogue (I) and (II) are shown in the specification.

Description

Piperlongumine analogue, preparation method and application thereof
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a class Piperlongumine analogue, preparation method and the pharmaceutical composition containing them, Piperlongumine analogue of the present invention can be used for treatment or prevention of thromboembolic disorders.
Background technology
Piperlongumine (piplartine) is the main active ingredient in the piperaceae Piper perennial herbaceous stem rattan wood plant Bi roots of grass.Research finds, Piperlongumine and derivative thereof be not when affecting normal cell physiology function, can propagation (the Raj L of inhibition tumor cell significantly, Takao I, Aditi UG, et al.Selective killing of cancer cells by a small molecule targeting the stress response to ROS [J] .Nature, 475 (2011): 231 ~ 234; Li Shaolu. the purposes of Piperlongumine derivative in the medicine preparing Therapeutic cancer and pharmaceutical composition CN102125552A (2011-07-20) thereof); Piperlongumine and derivative thereof to the platelet aggregation that collagen protein, arachidonic acid and platelet activation factor are induced have significant inhibit activities (Gao Yuan, Yu Minghui. the purposes CN101810612A (2010-08-25) of Piperlongumine compounds platelet aggregation-against; Fontenelea JB, Leal KAM, Edilberto RS, et al.Antiplatelet effects of piplartine, an alkamide isolated from Piper tuberculatum:possible involvement of cyclooxygenase blockade and antioxidant activity [J] .J.Pharm.Pharmacol, 61 (2009): 511 ~ 515).Thienopyridines medicine as ticlopidine, clopidogrel and prasugrel, for acting on P2Y 12the medicament for resisting platelet aggregation of target spot, is mainly used in the embolic cardiovascular and cerebrovascular diseases of prevention and therapy caused by blood platelet disorders are assembled clinically.But the renal toxicity of Piperlongumine is larger, can cause closing on uriniferous tubules and glomerular epithelium edema and uriniferous tubules hemorrhage, limit its clinical application (see Zhang Peng, Huang Qi comes, Hua Zichun. the Advance on Pharmacological Activities [J] of Piperlongumine. herbal medicine, 2012,43 (1): 201-204.); Also there is deficiency that Hemorrhage and " clopidogrel " resist (see Yang Hongyan in Thienopyridines medicament for resisting platelet aggregation, Wang Xiao. antiplatelet drug progress [J]. Chinese Pharmaceutical Journal, 2012,47 (4): 250-254.), therefore find safer effective medicament for resisting platelet aggregation is the target that people constantly study always.
Summary of the invention
The present invention is lead compound with Piperlongumine, has synthesized class Piperlongumine analogue (I) or (II), and pharmacodynamics test display the compounds of this invention has significant inhibit activities to the platelet aggregation that ADP, AA induce.
The compounds of this invention comprises general formula (I) and general formula (II):
Wherein R 1represent hydrogen or methoxyl group; R 2represent methyl, methoxyl group, chlorine, nitro, hydroxyl or-OR 4; R 3represent hydrogen, methoxyl group or-OR 4; N=1 or 2, wherein R 4representative:
R 2preferably represent nitro, hydroxyl or methoxyl group.
R 2preferably represent OR 4, R 4preferably represent ethanoyl.
R 3preferably represent hydrogen or methoxyl group.
Compound of the present invention, the compound of preferential following arbitrary structural formula:
The present invention is following arbitrary compound more preferably:
Wherein said pharmacy acceptable salt is the hydrochloride of the Piperlongumine analogue of general formula I of the present invention or II, vitriol, phosphoric acid salt, toxilic acid, fumaric acid, Citric Acid, methylsulfonic acid, tosic acid, tartrate or acetate.
LHC-13 is that the preparation method of example the compounds of this invention comprises the steps:
Other compounds of the present invention can get corresponding raw material with reference to aforesaid method preparation.
Here is pharmacodynamics test and the result of part of compounds:
Method one: new zealand rabbit, male, body weight 1.8-2.2kg, 3.8% Sodium Citrate becomes the liquor sodii citratis of 3.8% with 10mL normal saline, with 1% vovocan toponarcosis, the bloodletting of carotid artery intubate, mix with 9:1 with liquor sodii citratis, with the centrifugal 10min of 1000r/min, get platelet rich plasma (PRP), remainder is centrifugal with 3000r/min, gets platelet poor plasma (PPP), the adenosine diphosphate (ADP) (ADP) of aggregation inducing agent 10ug/mL.(Piperlongumine and LHC-1 ~ LHC-21 all dissolve with DMSO often to add the medicine of different concns in pipe 280uL PRP, add pure water to be diluted to desired concn and to be respectively 0.8 μ g/ml, 4 μ g/ml, 20 μ g/ml, 100 μ g/ml, 500 μ g/ml, acetylsalicylic acid DMSO dissolves, add pure water to be diluted to concentration and to be respectively 2.88 μ g/ml, 14.4 μ g/ml, 72 μ g/ml, 360 μ g/ml, 1.8mg/ml) 10uL, physiological saline 10uL is added in control group PRP, incubation 3min, then above-mentioned inductor is added, platelet aggregation rate is detected with LG-PABER-1 type platelet aggregation instrument, and calculate IC 50value.
Method two: liver microsome incubation method: microsome vitro reactions system has 1mL altogether, gets NADP, G-PD, G-PDH, MgCl respectively 2and hepatomicrosome is appropriate, adds KCl-phosphate buffered saline buffer, makes reaction system final volume be 1mL, respectively containing 0.5mmol/L NADP, 5.0mmol/L G-6-PD, 1.0U/mL G-6-PDH, 5.0mmol/L MgCl in reaction system 2, 1.0mg/ml hepatomicrosome.Get and need the screening of medicaments of carrying out hatching to join in microsome reaction system, in 37 DEG C of water-baths, temperature incubates vibration 60min, puts into-20 DEG C of refrigerator termination reactions.Get platelet poor plasma (PPP), the adenosine diphosphate (ADP) (ADP) of aggregation inducing agent 10ug/mL.Often add the medicine 10uL of different concns through the process of microsome reaction system in pipe 280uL PRP, add physiological saline 10uL in control group PRP, incubation 3min, then add above-mentioned inductor, detect platelet aggregation rate with LG-PABER-1 type platelet aggregation instrument, and calculate IC 50value.
The compounds of this invention LHC-1 ~ LHC-12 employing method one carries out platelet aggregation inhibitory activity mensuration; Compound L HC-13 ~ LHC-21 adopts method two to measure its platelet aggregation inhibitory activity.In the present invention advantage compound to the inhibit activities of the platelet aggregation that ADP induces in table 1.
Table 1 Piperlongumine analogue is to the inhibit activities of the platelet aggregation that ADP induces
Compound IC 50(mM) Compound IC 50(mM)
LHC-1 6.929 LHC-13 4.656
LHC-4 8.013 LHC-15 0.185
LHC-5 0.315 LHC-16 0.400
LHC-7 0.286 LHC-17 2.197
LHC-8 6.715 LHC-18 2.730
LHC-9 2.027 LHC-19 1.259
LHC-11 4.887 LHC-20 1.419
LHC-12 1.968 LHC-21 0.065
Piperlongumine 10.296
The pharmacological results shows, and Piperlongumine analogue of the present invention all has good inhibit activities to the platelet aggregation that ADP induces, and is better than positive reference substance Piperlongumine.Particularly compound L HC-5, LHC-7 and LHC-21 demonstrates good prospect in medicine.
Present invention also offers the pharmaceutical composition of a kind for the treatment of or prevention cardiovascular and cerebrovascular diseases, wherein containing the treatment general formula I of significant quantity or II compound and pharmaceutically acceptable carrier.Described pharmaceutical composition can be dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet capsule, controlled release tablet or capsule, oral liquid, injection.
Usually, when compound of the present invention is used for the treatment of, people's dosage range is 1mg ~ 1000mg/ days.Also can according to the difference of formulation and disease severity, using dosage exceeds this scope.
Embodiment
Embodiment 1
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(3,4,5-trimethoxyphenyl) third-2-alkene-1-ketone (LHC-1)
1.1 (E)-3-(3,4,5-trimethoxyphenyl) acrylic acid synthesis
At 500mL three-necked flask, add 3 successively, 4,5-TMB (10.0g, 51.0mmol), propanedioic acid (6.41g, 61.5mmol), pyridine (35mL), piperidines (2mL) and benzene (150mL), load onto water-and-oil separator, in 110 DEG C backflow 6h.The reaction of TLC [V (chloroform): V (methyl alcohol)=10:1 is developping agent] detection display is substantially complete, be cooled to room temperature, add 75 (mL) saturated aqueous sodium carbonate, continue to stir 30min, be separated, water intaking phase, the hydrochloric acid of aqueous phase 3mol/L adjusts pH to 4, separates out a large amount of white solid; Suction filtration, filter cake dehydrated alcohol recrystallization, dry white solid 7.92g, yield 65.2%, m.p.124.3 ~ 125.7 DEG C.
The synthesis of 1.2 (E)-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(3,4,5-trimethoxyphenyl) third-2-alkene-1-ketone (LHC-1)
In 250ml round-bottomed flask, add (E)-3-(3,4,5-trimethoxyphenyl) vinylformic acid (3.00g successively, 12.6mmol), thionyl chloride (15mL) and toluene (45mL), in 80 DEG C of reaction 5h.Concentrating under reduced pressure, and with the thionyl chloride that toluene (20mL) remains with steaming three removings, obtain 3,4,5-elemicin acyl chlorides, add anhydrous methylene chloride (15mL) and dissolve for subsequent use.
Separately get a 250mL three-necked flask, add 4 successively, 5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride (1.86g, 13.4mmol), methylene dichloride (50mL) and triethylamine (6mL), 30min is stirred under normal temperature condition, under condition of ice bath, slowly drip 3,4,5-elemicin acyl chlorides dichloromethane solution, dropwises rear continuation reaction 2.5h.The reaction of TLC [V (ethyl acetate): V (sherwood oil)=1:1 is developping agent] detection display is substantially complete, reaction solution uses water (100mL × 2), 1% dilute hydrochloric acid (100mL × 3) and 1mol/L sodium carbonate solution (50mL × 3) to wash respectively, anhydrous sodium sulfate drying, concentrating under reduced pressure, be separated through silicagel column, obtain LHC-1 white solid 2.43g, yield 53.3%, m.p.151.4 ~ 152.7 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.63 (d, J=15.6Hz, 1H, ArCH=), 7.16 (d, J=5.1Hz, 1H, ThH), 6.85-6.80 (m, 2H ,-CH=and ThH), 6.76 (s, 2H, ArH), 4.78 (s, 2H, Py-CH 2), 3.98 (t, 2H, J=4.5Hz, Py-CH 2), 3.91 (s, 6H, OCH 3× 2), 3.88 (s, 3H, OCH 3), 2.96 (br s, 2H, Py-CH 2); 13c-NMR (CDCl 3, 75MHz) and δ: 166.0,153.4,143.0,139.6,132.4,130.8,125.2,124.5,123.6,116.6,105.1,61.0,56.2,46.0,43.3,26.1; IR (KBr, cm -1) υ: 2998.3,2935.6,2833.9,1642.7,1587.0,1505.6,1437.4,1252.2,1266.5,1124.4,1058.1,1008.1,977.9,826.2,717.9,613.2; ESI-Mass for C 19h 21nO 4s:m/z (M ++ H) 360.06.
Embodiment 2
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(4-p-methoxy-phenyl) third-2-alkene-1-ketone (LHC-2)
(E)-3-(4-p-methoxy-phenyl) vinylformic acid is by 1.1 method operation synthesis in embodiment 1, by obtained (E)-1-(6 of 1.2 method operation in embodiment 1,7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(4-p-methoxy-phenyl) third-2-alkene-1-ketone (LHC-2) faint yellow solid, m.p.131.4 ~ 132.7 DEG C; 1h-NMR (CDCl 3, 400MHz) and δ: 7.67 (d, J=15.2Hz, 1H, ArCH=), 7.50 (d, J=8.0Hz, 2H, ArH), 7.15 (d, J=5.2Hz, 1H, ThH), 6.90 (d, J=8.4Hz, 2H, ArH), 6.83-6.79 (m, 2H, ThH and-CH=), 4.76 (s, 2H, Py-CH 2), 3.97 (br s, 2H, Py-CH 2), 3.84 (s, 3H, OCH 3), 2.94 (br s, 2H, Py-CH 2); 13c-NMR (CDCl 3, 100MHz) and δ: 166.3,160.9,142.6,132.3,129.4,127.9,125.2,124.5,123.5,114.9,114.2,55.3,45.9,43.3,26.0; IR (KBr, cm -1) υ: 3004.3,2962.5,2905.6,1649.8,1593.0,1506.3,1437.5,1249.2,1165.5,1060.8,1027.9,980.1,896.4,824.6,716.9; ESI-Mass for C 17h 17nO 2s:m/z (M ++ H) 300.13.
Embodiment 3
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(4-aminomethyl phenyl) third-2-alkene-1-ketone (LHC-3)
(E)-3-(4-aminomethyl phenyl) vinylformic acid is by 1.1 method operation synthesis in embodiment 1, by obtained (E)-1-(6 of 1.2 method operation in embodiment 1,7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(4-aminomethyl phenyl) third-2-alkene-1-ketone (LHC-3) white solid, m.p.145.8 ~ 147.2 DEG C; 1h-NMR (CDCl 3, 400MHz) and δ: 7.69 (d, J=15.6Hz, 1H, ArCH=), 7.45 (d, J=7.6Hz, 2H, ArH), 7.19 (d, J=8.0Hz, 2H, ArH), 7.15 (d, J=5.2Hz, 1H, ThH), 6.89 (d, J=15.6Hz, 1H,-CH=), 6.83 (d, J=4.8Hz, 1H, ThH), 4.77 (s, 2H, Py-CH 2), 3.97 (br s, 2H, Py-CH 2), 2.95 (br s, 2H, Py-CH 2), 2.37 (s, 3H, CH 3); 13c-NMR (CDCl 3, 100MHz) and δ: 166.2,142.9.139.9,132.4,129.5,127.6,125.2,124.5,123.5,116.5,116.2,45.9,43.2,25.9,21.4; IR (KBr, cm -1) υ: 3076.1,2923.6,2833.9,1643.9,1596.0,1518.3,1455.5,1452.5,1323.9,1219.3,1054.8,1013.0,968.1,812.6,737.9,660.1; ESI-Mass for C 17h 17nOS:m/z (M ++ H) 284.08.
Embodiment 4
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(4-chloro-phenyl-) third-2-alkene-1-ketone (LHC-4)
(E)-3-(4-chloro-phenyl-) vinylformic acid is by 1.1 method operation synthesis in embodiment 1, by obtained (E)-1-(6 of 1.2 method operation in embodiment 1,7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(4-chloro-phenyl-) third-2-alkene-1-ketone (LHC-4) white solid, 169.5 ~ 170.9 DEG C; 1h-NMR (CDCl 3, 400MHz) and δ: 7.65 (d, J=15.2Hz, 1H, ArCH=), 7.47 (d, J=8.0Hz, 2H, ArH), 7.35 (d, J=8.0Hz, 2H, ArH), 7.16 (d, J=5.2Hz, 1H, ThH), 6.92 (d, J=15.6Hz, 1H,-CH=), 6.83 (d, J=4.8Hz, 1H, ThH), 4.76 (s, 2H, Py-CH 2), 3.97 (br s, 2H, Py-CH 2), 2.95 (br s, 2H, Py-CH 2); 13c-NMR (CDCl 3, 100MHz) and δ: 165.7,141.5,135.4,133.7,132.2,129.0,128.9,125.1,124.5,123.6,118.0,45.9,43.3,25.9; IR (KBr, cm -1) υ: 2926.1,2869.3,2833.4,1607.3,1646.2,1487.7,1439.9,1401.0,1326.2,1215.6,1182.7,1081.0,1048.1,970.4,805.9,704.2; ESI-Mass for C 16h 14clNOS:m/z (M ++ H) 314.17.
Embodiment 5
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(4-nitrophenyl) third-2-alkene-1-ketone (LHC-5)
(E)-3-(4-nitrophenyl) vinylformic acid is by 1.1 method operation synthesis in embodiment 1, by obtained (E)-1-(6 of 1.2 method operation in embodiment 1,7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(4-nitrophenyl) third-2-alkene-1-ketone (LHC-5) white solid, 191.3 ~ 192.4 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 8.24 (d, J=8.7Hz, 2H, ArH), 7.75-7.67 (m, 3H, ArCH=and ArH), 7.18 (d, J=5.1Hz, 1H, ThH), 7.09 (d, J=15.6Hz, 1H ,-CH=), 6.84 (d, J=3.6Hz, 1H, ThH), 4.79 (s, 2H, Py-CH 2), 3.94 (d, J=30.3Hz, 2H, Py-CH 2), 2.99 (br s, 2H, Py-CH 2); 13c-NMR (CDCl 3, 100MHz) and δ: 165.0,148.1,141.5,140.1,128.4,125.2,124.4,124.1,123.8,122.0,121.8,46.1,44.0,26.0; IR (KBr, cm -1) υ: 3106.0,2929.6,2851.8,1649.8,1605.0,1512.3,1449.5,1344.9,1216.3,1183.4,1108.6,1051.8,962.1,839.5,746.8,708.0,669.1; ESI-Mass for C 16h 14n 2o 3s:m/z (M ++ H) 315.06.
Embodiment 6
(E)-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also) synthesis (E)-3-(4-hydroxy phenyl) vinylformic acid of-3-(4-hydroxy phenyl) third-2-alkene-1-ketone (LHC-6) is by 1.1 methods operation synthesis in embodiment 1.
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(4-hydroxy phenyl) third-2-alkene-1-ketone (LHC-6)
In a 250mL round-bottomed flask, add 4 successively, 5,6,7-tetramethylene sulfide [3,2-C] pyridine hydrochloride (5.00g, 28.6mmol), sodium hydroxide (1.70g, 42.5mmol) and methylene dichloride (60mL), stirring at normal temperature 3.5h.The reaction of TLC [V (chloroform): V (methyl alcohol)=10:1 is developping agent] detection display is substantially complete, and with water (80mL × 2) washing, anhydrous sodium sulfate drying, concentrates to obtain pale yellow oil 3.12g.
Separately get a 250mL three-necked flask, add (E)-3-(4-hydroxy phenyl) vinylformic acid (3.50g, 21.3mmol), 4,5,6,7-tetramethylene sulfide [3,2-C] pyridine (3.00g, 21.6mmol), DCC (5.30g, 25.7mmol) and methylene dichloride (60mL), stir 6h under condition of ice bath.The reaction of TLC [V (chloroform): V (methyl alcohol)=10:1 is developping agent] detection display is substantially complete, freezing, suction filtration, concentrating under reduced pressure, is separated through silicagel column, obtains LHC-6 white solid 3.40g, yield 54.1%, m.p.209.6 ~ 212.1 DEG C; 1h-NMR (DMSO-d 6, 300MHz) and δ: 9.86 (s, 1H, OH), 7.57 (d, J=8.4Hz, 2H, ArH), 7.44 (d, J=15.0Hz, 1H, ArCH=), 7.34 (d, J=4.8Hz, 1H, ThH), 7.13 (d, J=15.6Hz, 1H ,-CH=), 6.90 (d, J=3.0Hz, 1H, ThH), 6.78 (d, J=8.4Hz, 2H, ArH), 4.79 (s, 1H, Py-CH 2), 4.62 (s, 1H, Py-CH 2), 3.90 (d, J=30.3Hz, 2H, Py-CH 2), 2.83 (d, J=23.1Hz, 2H, Py-CH 2); 13c-NMR (DMSO-d 6, 75MHz) and δ: 165.5,159.5,142.2,132.7,129.8,125.9,125.4,125.1,123.6,115.7,114.2,45.1,43.1,25.6; IR (KBr, cm -1) υ: 3120.9,3016.3,2935.6,2842.9,1640.9,1578.0,1518.3,1449.5,1273.1,1219.3,1192.4,1162.5,1063.8,983.1,821.6,764.8; ESI-Mass for C 16h 15nO 2s:m/z (M ++ H) 286.15.
Embodiment 7
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(4-hydroxy 3-methoxybenzene base) third-2-alkene-1-ketone (LHC-7)
By obtained (the E)-1-(6 of embodiment 6 method operation, 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(4-hydroxy 3-methoxybenzene base) third-2-alkene-1-ketone (LHC-7) white solid, m.p.196.2 ~ 197.5 DEG C; 1h-NMR (CDCl 3, 400MHz) and δ: 7.64 (d, J=15.2Hz, 1H, ArCH=), 7.16 (d, J=5.2Hz, 1H, ThH), 7.13 (d, J=8.4Hz, 1H, ArH), 7.01 (s, 1H, ArH), 6.93 (d, J=8.4Hz, 1H, ArH), 6.83 (d, J=4.8Hz, 1H, ThH), 6.78 (d, J=14.8Hz, 1H ,-CH=), 4.77 (s, 2H, Py-CH 2), 4.03-3.99 (m, 1H, Py-CH 2), 3.94 (s, 4H, Py-CH 2and OCH 3), 2.97 (br s, 2H, Py-CH 2); 13c-NMR (CDCl 3, 100MHz) and δ: 165.4,148.5,147.8,142.5,132.7,126.6,125.4,125.1,123.6,122.5,115.4,114.6,111.3,55.8,45.2,42.9,25.7; IR (KBr, cm -1) υ: 3100.0,2929.6,2842.9,1766.5,1640.9,1581.1,1524.2,1452.5,1362.8,1297.0,1243.2,1162.5,1120.6,1057.8,1030.9,977.1,896.4,833.6,797.7; ESI-Mass for C 17h 17nO 3s:m/z (M +-H) 314.17.
Embodiment 8
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(3-hydroxyl-4-p-methoxy-phenyl) the third-2-alkene-1-ketone (LHC-8)
(E)-3-(3-hydroxyl-4-p-methoxy-phenyl) vinylformic acid is by 1.1 method operation synthesis in embodiment 1, by obtained (the E)-1-(6 of embodiment 6 method operation, 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(3-hydroxyl-4-p-methoxy-phenyl) third-2-alkene-1-ketone (LHC-8) white solid, m.p.176.3 ~ 177.8 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.62 (d, J=15.3Hz, 1H, ArCH=), 7.20 (d, J=2.1Hz, 1H, ArH), 7.15 (d, J=5.4Hz, 1H, ThH), 7.04 (dd, J 1=2.1Hz, J 2=8.4Hz, 1H, ArH), 6.85-6.77 (m, 3H ， – CH=, ThH and ArH), 4.76 (s, 2H, Py-CH 2), 4.01-3.99 (m, 1H, Py-CH 2), 3.92 (s, 4H, Py-CH 2and OCH 3), 2.94 (br s, 2H, Py-CH 2); 13c-NMR (CDCl 3, 75MHz) and δ: 166.4,157.0,148.3,145.9,143.0,128.7,125.2,124.5,123.5,121.6,115.2,112.7,110.6,56.0,45.9,43.3,24.9; IR (KBr, cm -1) υ: 3091.0,2929.6,2845.9,1634.9,1578.1,1524.3,1425.6,1312.0,1261.1,1219.3,1126.6,1051.8,1027.9,977.1,803.7,737.87; ESI-Mass for C 17h 17nO 3s:m/z (M +-H) 314.17.
Embodiment 9
(E) synthesis of-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also)-3-(4-hydroxyl-3,5-Dimethoxyphenyl) third-2-alkene-1-ketone (LHC-9)
(E)-3-(4-hydroxyl-3,5-Dimethoxyphenyl) vinylformic acid is by 1.1 methods operation synthesis in embodiment 1, by obtained (the E)-1-(6 of embodiment 6 method operation, 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(4-hydroxyl-3,5-Dimethoxyphenyl) the third-2-alkene-1-ketone (LHC-9) faint yellow solid, m.p.155.7 ~ 156.4 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.64 (d, J=15.0Hz, 1H, ArCH=), 7.16 (d, J=5.1Hz, 1H, ThH), 6.83 (d, J=5.1Hz, 1H, ThH), 6.81 ~ 6.76 (m, 3H ,-CH=and ArH), 4.77 (s, 2H, Py-CH 2), 3.98 (t, J=5.4Hz, 2H, Py-CH 2), 3.94 (s, 6H, OCH 3× 2), 2.96 (t, J=5.1Hz, 2H, Py-CH 2); 13c-NMR (CDCl 3, 75MHz) and δ: 166.3,157.0,147.2,143.5,136.7,126.7,125.2,124.6,123.6,115.1,104.9,56.4,46.1,43.3,25.0; IR (KBr, cm -1) υ: 3100.0,2929.6,2839.8,1643.9,1605.0,1512.3,1455.5,1428.6,1335.9,1264.1,1210.3,1150.5,1108.6,1057.8,974.1,905.3,824.6,705.0; ESI-Mass for C 18h 19nO 4s:m/z (M +-H) 344.59.
Embodiment 10
(E)-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also) synthesis of-3-(4-(3-(dimethylamino) propoxy-) phenyl) the third-2-alkene-1-ketone (LHC-10)
In a 100mL round-bottomed flask, add N, N-dimethyl chloropropane hydrochloride (1.7g, 10.8mmol), salt of wormwood (3.50g), KI (0.20g) and Virahol (50ml), stirring at room temperature 2h is for subsequent use; Separately get a 250mL three-necked flask, add LHC-6 compound (2.50g, 8.77mmol), salt of wormwood (3.00g) and Virahol (50ml), and add N, N-dimethyl chloride propane aqueous isopropanol, in 80 DEG C of reaction 9h.The reaction of TLC [V (chloroform): V (methyl alcohol)=6:1 is developping agent] detection display is substantially complete, suction filtration while hot, concentrating under reduced pressure, dissolves with 60mL methylene dichloride, and water (60mL × 2) washs, anhydrous sodium sulfate drying, suction filtration, concentrating under reduced pressure, is separated to obtain LHC-10 white solid 1.23g through silicagel column, yield 37.5%, m.p.110.3 ~ 110.8 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.66 (d, J=15.3Hz, 1H, ArCH=), 7.44 (d, J=8.7Hz, 2H, ArH), 7.15 (d, J=5.1Hz, 1H, ThH), 6.89 (d, J=8.7Hz, 2H, ArH), 6.83-6.76 (m, 2H, ThH and-CH=), 4.76 (s, 2H, Py-CH 2), 4.06 (t, J=6.3Hz, 2H, OCH 2cH 2cH 2n), 3.93 (br s, 2H, Py-CH 2), 2.95 (br s, 2H, Py-CH 2), 2.61 (t, J=7.2Hz, 2H, OCH 2cH 2cH 2n), 2.38 (s, 6H, CH 3× 2), 2.10-2.01 (m, 2H, OCH 2cH 2cH 2n); 13c-NMR (CDCl 3, 75MHz) and δ: 166.4,147.4,146.7,143.2,127.8,125.2,124.5,123.6,121.9,114.8,110.0,56.0,46.0,43.9,43.3,40.4,26.0,24.8; IR (KBr, cm -1) υ: 3067.1,2947.5,2917.6,2851.8,2815.9,1643.9,1593.0,1572.1,1515.3,1452.5,1285.1,1252.2,1177.4,1054.8,1021.9,980.1,893.4,893.5,705.0; ESI-Mass for C 21h 26n 2o 2s:m/z (M ++ H) 371.23.
Embodiment 11
(E)-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also) synthesis of-3-(4-(3-(dimethylamino) propoxy-)-3-p-methoxy-phenyl) the third-2-alkene-1-ketone (LHC-11)
By obtained (the E)-1-(6 of embodiment 10 method operation, 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(4-(3-(dimethylamino) propoxy-)-3-p-methoxy-phenyl) the third-2-alkene-1-ketone (LHC-11) white solid, m.p.123.4 ~ 125.1 DEG C; 1h-NMR (CDCl 3, 400MHz) and δ: 7.64 (d, J=15.2Hz, 1H, ArCH=), 7.15 (d, J=5.2Hz, 1H, ThH), 7.12 (d, J=7.6Hz, 1H, ArH), 7.05 (s, 1H, ArH), 6.89 (d, J=8.0Hz, 1H, ArH), 6.84-6.77 (m, 2H, ThH and-CH=), 4.77 (s, 2H, Py-CH 2), 4.12 (t, J=6.4Hz, 2H, OCH 2cH 2cH 2n), 4.01 (br s, 2H, Py-CH 2), 3.91 (s, 3H, OCH 3), 2.96 (br s, 2H, Py-CH 2), 2.64 (t, J=7.2Hz, 2H, OCH 2cH 2cH 2n), 2.38 (s, 6H, CH 3× 2), 2.15-2.08 (m, 2H, OCH 2cH 2cH 2n); 13c-NMR (CDCl 3, 100MHz) and δ: 165.3,149.1,142.1,132.6,128.4,125.4,125.1,123.7,122.2,116.3,116.0,113.0,110.9,65.9,55.9,53.9,45.3,43.0,42.0,25.7,23.8; IR (KBr, cm -1) υ: 3129.9,2962.5,2929.6,2848.8,1634.9,1596.0,1512.3,1458.5,1422.6,1264.1,1228.2,1138.5,1051.8,1024.9,974.7,714.0; ESI-Mass for C 22h 28n 2o 3s:m/z (M ++ H) 401.12.
Embodiment 12
(E)-1-(6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-Ji also) synthesis of-3-(3-(3-(dimethylamino) propoxy-)-4-p-methoxy-phenyl) the third-2-alkene-1-ketone (LHC-12)
By obtained (the E)-1-(6 of embodiment 10 method operation, 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-Ji)-3-(3-(3-(dimethylamino) propoxy-)-4-p-methoxy-phenyl) the third-2-alkene-1-ketone (LHC-12) white solid, m.p.108.9 ~ 110.2 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.53 (d, J=15.6Hz, 1H, ArCH=), 7.04-6.99 (m, 3H, ArHand ThH), 6.76 (s, 1H, ArH), 6.74-6.70 (m, 2H, ThHand-CH=), 4.66 (s, 2H, Py-CH 2), 4.02 (t, J=6.6Hz, 2H, OCH 2cH 2cH 2n), 3.84 (br s, 2H, Py-CH 2), 3.77 (s, 3H, OCH 3), 2.85 (br s, 2H, Py-CH 2), 2.45 (t, J=7.2Hz, 2H, OCH 2cH 2cH 2n), 2.21 (s, 6H, CH 3× 2), 2.01-1.91 (m, 2H, OCH 2cH 2cH 2n); 13c-NMR (CDCl 3, 75MHz) and δ: 166.3,151.0,148.5,143.0,132.4,128.1,125.2,124.6,123.5,122.4,115.0,111.6,111.4,67.3,56.1,55.9,45.2,43.8,34.0,27.1,25.0; IR (KBr, cm -1) υ: 3055.2,2923.6,2851.8,2816.0,1640.9,1599.0,1512.3,1458.5,1315.0,1249.2,1219.3,1177.4,1090.7,1057.8,977.1,896.4,839.5,708.0; ESI-Mass for C 22h 28n 2o 3s:m/z (M ++ H) 401.28.
Embodiment 13
(E) synthesis of-5-(3-(3,4,5-trimethoxyphenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-13)
13.1, the synthesis of (E)-5-(3-(3,4,5-trimethoxyphenyl) acryl)-4,5,6,7a-tetramethylene sulfides also [3,2-c] pyridine-2 (4H)-one
By obtained (E)-5-(3-(3,4,5-trimethoxyphenyl) acryl)-4 of 1.2 method operation in embodiment 1,5,6,7a-tetramethylene sulfide also [3,2-c] pyridine-2 (4H)-one yellow solid, m.p.87.4 ~ 89.6 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.52 (d, J=15.3Hz, 1H, ArCH=), 6.69-6.64 (m, 3H, ArH and – CH=), 6.12 (s, 1H, ThH), 4.35-4.29 (m, 1H, Py-CH 2), 4.20 (s, 1H, Py-CH 2), 3.82 (s, 9H, OCH 3× 3), 3.80 (s, 2H, Py-CH 2), 3.37 (br s, 1H, Py-CH 2), 2.46 (br s, 2H, Py-CH 2); 13c-NMR (CDCl 3, 75MHz) and δ: 197.8,165.9,153.4,144.4,144.2,139.9,130.3,127.3,115.4,105.2,61.0,56.3,51.0,44.5,42.9,22.6; ESI-Mass for C 19h 21nO 5s:m/z (M ++ H) 376.10.
13.2, the synthesis of (E)-5-(3-(3,4,5-trimethoxyphenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-13)
(E)-5-(3-(3, 4, 5-trimethoxyphenyl) acryl)-4, 5, 6, 7a-tetramethylene sulfide also [3, 2-c] pyridine-2 (4H)-one (2.00g, 5.33mmol), aceticanhydride (1.5mL), acetonitrile (40mL) and triethylamine (1.5mL), stirring at normal temperature 5h, the reaction of TLC [V (ethyl acetate): V (sherwood oil)=2:1 is developping agent] detection display is substantially complete, concentrating under reduced pressure, dissolve with methylene dichloride (50mL), water (60mL × 2) washs, anhydrous sodium sulfate drying, concentrating under reduced pressure, LHC-13 faint yellow solid 1.36g is separated to obtain through silicagel column, yield 61.3%, m.p.121.8 ~ 123.7 DEG C, 1h-NMR (CDCl 3, 400MHz) and δ: 7.61 (d, J=15.2Hz, 1H, ArCH=), 6.81-6.72 (m, 3H, ArH and-CH=), 6.20 (s, 1H, ThH), 4.66 (s, 2H, Py-CH 2), 4.00 (br s, 2H, Py-CH 2), 3.91 (s, 6H, OCH 3× 2), 3.88 (s, 3H, OCH 3), 2.85 (br s, 2H, Py-CH 2), 2.30 (s, 3H, CH 3), 13c-NMR (CDCl 3, 100MHz) and δ: 167.8,166.0,153.4,150.1,143.2,139.6,130.8,116.8,116.4,111.7,111.4,105.1,61.0,56.2,45.7,43.1,25.4,20.7, IR (KBr, cm -1) υ: 2938.5,2836.9,1763.5,1643.9,1587.0,1500.3,1422.6,1335.9,1273.1,1186.4,1126.6,1057.8,1004.0,884.4,827.6,722.9, ESI-Mass for C 21h 23nO 6s:m/z (M ++ H) 418.01.
Embodiment 14
(E) synthesis of-5-(3-(4-p-methoxy-phenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-14)
By obtained (the E)-5-(3-(4-p-methoxy-phenyl) acryl)-4 of embodiment 13 method operation, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-acetic ester (LHC-14) faint yellow solid, m.p.126.3 ~ 127.4 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.68 (d, J=15.3Hz, 1H, ArCH=), 7.50 (d, J=8.7Hz, 2H, ArH), 6.90 (d, J=8.7Hz, 2H, ArH), 6.79 (d, J=15.3Hz, 1H,-CH=), 6.41 (s, 1H, ThH), 4.65 (s, 2H, Py-CH 2), 3.96 (t, J=5.4Hz, 2H, Py-CH 2), 3.83 (s, 3H, OCH 3), 2.84 (t, J=5.4Hz, 2H, Py-CH 2), 2.29 (s, 3H, CH 3); 13c-NMR (CDCl 3, 75MHz) and δ: 167.7,166.3,160.9,150.0,142.8,129.4,127.9,115.0,114.6,114.2,111.8,111.3,55.4,45.6,43.0,25.4,20.7; IR (KBr, cm -1) υ: 2938.5,2839.9,1757.5,1643.9,1599.0,1503.3,1440.5,1371.8,1303.0,1252.2,1207.3,1144.5,1030.9,977.1,926.3,890.4,818.6,728.9; ESI-Mass for C 19h 19nO 4s:m/z (M ++ H) 357.98.
Embodiment 15
(E) synthesis of-5-(3-(4-aminomethyl phenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-15)
By obtained (the E)-5-(3-(4-aminomethyl phenyl) acryl)-4 of embodiment 13 method operation, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-acetic ester (LHC-15) faint yellow solid, m.p.117.2 ~ 118.6 DEG C; 1h-NMR (CDCl 3, 400MHz) and δ: 7.68 (d, J=15.2Hz, 1H, ArCH=), 7.44 (d, J=8.0Hz, 2H, ArH), 7.19 (d, J=8.0Hz, 2H, ArH), 6.87 (d, J=15.6Hz, 1H,-CH=), 6.41 (s, 1H, ThH), 4.66 (s, 2H, Py-CH 2), 3.96 (br s, 2H, Py-CH 2), 2.84 (br s, 2H, Py-CH 2), 2.37 (s, 3H, CH 3), 2.29 (s, 3H, CH 3); 13c-NMR (CDCl 3, 100MHz) and δ: 167.7,166.2,150.1,143.1,140.0,132.4,129.5,127.8,116.4,116.1,111.7,111.3,45.6,43.0,25.4,21.4,20.7; IR (KBr, cm -1) υ: 2935.6,2896.7,2848.8,1757.5,1646.8,1596.0,1494.4,1434.6,1365.8,1219.3,1144.5,1042.9,983.1,893.4,812.6; ESI-Mass for C 19h 19nO 3s:m/z (M ++ H) 342.07.
Embodiment 16
(E) synthesis of-5-(3-(4-chloro-phenyl-) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-16)
By obtained (the E)-5-(3-(4-chloro-phenyl-) acryl)-4 of embodiment 13 method operation, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-acetic ester (LHC-16) faint yellow solid, m.p.115.4 ~ 116.2 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.65 (d, J=15.6Hz, 1H, ArCH=), 7.47 (d, J=8.7Hz, 2H, ArH), 7.35 (d, J=8.7Hz, 2H, ArH), 6.89 (d, J=15.3Hz, 1H,-CH=), 6.41 (s, 1H, ThH), 4.65 (s, 2H, Py-CH 2), 3.96 (br s, 2H, Py-CH 2), 2.84 (br s, 2H, Py-CH 2), 2.29 (s, 3H, CH 3); 13c-NMR (CDCl 3, 75MHz) and δ: 167.7,165.7,150.1,141.7,135.5,133.7,129.1,124.8,118.1,117.8,111.7,111.3,45.7,43.0,25.4,20.7; IR (KBr, cm -1) υ: 2920.6,2866.8,1748.5,1643.9,1604.9,1584.1,1503.3,1428.6,1362.8,1332.9,1225.3,1204.3,1150.5,1087.7,1042.8,971.1,893.4,812.6; ESI-Mass for C 18h 16clNO 3s:m/z (M ++ H) 361.96.
Embodiment 17
(E) synthesis of-5-(3-(4-nitrophenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-17)
By obtained (the E)-5-(3-(4-nitrophenyl) acryl)-4 of embodiment 13 method operation, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-acetic ester (LHC-17) faint yellow solid, m.p.127.6 ~ 128.3 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 8.24 (d, J=8.7Hz, 2H, ArH), 7.74-7.67 (m, 3H, ArCH=and ArH), 7.10-7.05 (m, 1H ,-CH=), 6.42 (s, 1H, ThH), 4.67 (s, 2H, Py-CH 2), 4.00 (t, J=12.0Hz, 2H, Py-CH 2), 2.87 (br s, 2H, Py-CH 2), 2.30 (s, 3H, CH 3); 13c-NMR (CDCl 3, 75MHz) and δ: 167.7,165.0,150.2,148.1,141.4,140.2,128.4,126,8,124.1,122.0,121.6,111.7,45.8,43.1,25.4,20.7; IR (KBr, cm -1) υ: 2930.3,2895.2,2840.6,1754.8,1645.9,1607.5,1508.2,1440.9,1203.9,1104.6,1059.8,960.5,838.8,755.5; ESI-Mass for C 18h 16n 2o 5s:m/z (M ++ H) 373.00.
Embodiment 18
(E)-5-(3-(4-acetoxyl group phenyl) acryl)-4; 5; 6; the also synthesis 18.1 of [3,2-c] pyridine-2-acetic ester (LHC-18) of 7-tetramethylene sulfide, (E)-3-(4-acetoxyl group phenyl) acrylic acid synthesis
In a round-bottomed flask, add aceticanhydride (12mL), pyridine (2mL) and p-Coumaric Acid (6.00g, 36.6mmol), stirring at normal temperature 3.5h, FeCl 3solution detects p-Coumaric Acid and reacts completely, and add water stirring, suction filtration, filter cake use water 300mL washs, and filter cake is put in beaker, adds saturated sodium carbonate solution and adjusts pH=9 ~ 10, suction filtration, filtrate adjusts pH=2 ~ 3 with concentrated hydrochloric acid, separates out white solid, suction filtration, filter cake water 150mL washs 3 times, dry (E)-3-(4-acetoxyl group phenyl) vinylformic acid 6.17g, yield 81.9%, m.p.216.4 ~ 218.7 DEG C.
18.2, the synthesis of (E)-5-(3-(4-acetoxyl group phenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-18)
By obtained (the E)-5-(3-(4-acetoxyl group phenyl) acryl)-4 of embodiment 13 method, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-acetic ester (LHC-18) faint yellow solid, m.p.103.6 ~ 106.2 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.68 (d, J=15.6Hz, 1H, ArCH=), 7.55 (d, J=8.7Hz, 2H, ArH), 7.11 (d, J=8.7Hz, 2H, ArH), 6.87 (d, J=15.3Hz, 1H,-CH=), 6.41 (s, 1H, ThH), 4.65 (s, 2H, Py-CH 2), 3.95 (br s, 2H, Py-CH 2), 2.84 (br s, 2H, Py-CH 2), 2.31 (s, 3H, CH 3), 2.29 (s, 3H, CH 3); 13c-NMR (CDCl 3, 75MHz) and δ: 169.2,167.7,165.9,151.6,150.1,142.0,133.0,128.9,122.0,117.8,117.4,111.8,111.3,45.7,43.0,25.4,21.2,20.7; IR (KBr, cm -1) υ: 3068.0,2927.1,2839.9,1751.6,1645.9,1613.9,1585.1,1424.9,1370.5,1047.0,909.2,896.4,848.4; ESI-Mass for C 20h 19nO 5s:m/z (M ++ H) 386.00.
Embodiment 19
(E) synthesis of-5-(3-(4-acetoxy-3-p-methoxy-phenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-19)
By obtained (the E)-5-(3-(4-acetoxy-3-p-methoxy-phenyl) acryl)-4 of embodiment 18 method operation, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-acetic ester (LHC-19) faint yellow solid, m.p.130.1 ~ 130.9 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.65 (d, J=15.6Hz, 1H, ArCH=), 7.17 (dd, J 1=1.5Hz, J 2=8.1Hz, 1H, ArH), 7.09-7.03 (m, 2H, ArH), 6.84 (d, J=15.3Hz, 1H ,-CH=), 6.42 (s, 1H, ThH), 4.65 (s, 2H, Py-CH 2), 3.96 (br s, 2H, Py-CH 2), 3.88 (s, 3H, OCH 3), 2.85 (br s, 2H, Py-CH 2), 2.33 (s, 3H, CH 3), 2.29 (s, 3H, CH 3); 13c-NMR (CDCl 3, 75MHz) and δ: 168.8,167.7,165.8,151.3,150.1,142.3,140.9,134.2,128.4,124.8,123.1,120.4,117.9,117.6,111.6,55.9,45.7,43.0,25.4,20.7,20.6; IR (KBr, cm -1) υ: 3068.0,3010.3,2930.3,2869.4,1767.6,1649.1,1613.9,1591.5,1511.4,1456.9,1399.3,1300.0,1255.2,1123.8,1047.0,973.3,890.0,822.8,745.9; ESI-Mass for C 21h 21nO 6s:m/z (M ++ H) 416.00.
Embodiment 20
(E) synthesis of-5-(3-(3-acetoxyl group-4-p-methoxy-phenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-20)
By obtained (the E)-5-(3-(3-acetoxyl group-4-p-methoxy-phenyl) acryl)-4 of embodiment 18 method operation, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-acetic ester (LHC-20) faint yellow solid, m.p.140.6 ~ 142.2 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.62 (d, J=15.3Hz, 1H, ArCH=), 7.38 (dd, J 1=2.1Hz, J 2=8.4Hz, 1H, ArH), 7.28 (s, 1H, ArH), 7.96 (d, J=8.4Hz, 1H, ArH), 6.77 (d, J=15.6Hz, 1H ,-CH=), 6.41 (s, 1H, ThH), 4.65 (s, 2H, Py-CH 2), 3.99 (br s, 2H, Py-CH 2), 3.86 (s, 3H, OCH 3), 2.84 (br s, 2H, Py-CH 2), 2.34 (s, 3H, CH 3), 2.29 (s, 3H, CH 3); 13c-NMR (CDCl 3, 75MHz) and δ: 168.9,167.7,165.9,151.3,150.1,142.4,140.9,134.2,128.4,127.1,123.2,120.4,117.9,117.5,111.6,56.0,45.7,43.0,25.4,20.9,20.7; IR (KBr, cm -1) υ: 3093.6,3055.2,2923.8,2843.8,1767.6,1649.1,1604.3,1511.4,1434.5,1364.1,1300.0,1268.0,1127.1,1053.4,1027.8,886.9,822.8; ESI-Mass for C 21h 21nO 6s:m/z (M ++ H) 416.00.
Embodiment 21
(E) synthesis of-5-(3-(4-acetoxy-3,5-Dimethoxyphenyl) acryl)-4,5,6,7-tetramethylene sulfides also [3,2-c] pyridine-2-acetic ester (LHC-21)
By obtained (E)-5-(3-(the 4-acetoxy-3 of embodiment 18 method operation, 5-Dimethoxyphenyl) acryl)-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine-2-acetic ester (LHC-21) white solid, m.p.136.8 ~ 137.7 DEG C; 1h-NMR (CDCl 3, 300MHz) and δ: 7.61 (d, J=15.3Hz, 1H, ArCH=), 6.82 (d, J=15.3Hz, 1H ,-CH=), 6.76 (s, 2H, ArH), 6.43 (s, 1H, ThH), 4.66 (s, 2H, Py-CH 2), 3.97 (br s, 2H, Py-CH 2), 3.86 (s, 6H, OCH 3× 2), 2.85 (br s, 2H, Py-CH 2), 2.35 (s, 3H, CH 3), 2.30 (s, 3H, CH 3); 13c-NMR (CDCl 3, 75MHz) and δ: 168.6,167.7,165.8,152.3,150.1,142.9,133.6,129.9,118.0,117.5,111.7,111.3,104.5,56.2,45.7,43.0,24.2,20.7,20.5; IR (KBr, cm -1) υ: 3074.4,3007.1,2978.3,2943.1,2847.0,1761.2,1642.7,1604.3,1505.0,1460.1,1421.7,1370.5,1338.4,1194.3,1130.3,1063.0,1011.7,883.6,832.4,794.7; ESI-Mass for C 22h 23nO 7s:m/z (M ++ H) 446.00.

Claims (9)

1. the Piperlongumine analogue of general formula I or II or its pharmacy acceptable salt:
Wherein R 1represent hydrogen or methoxyl group; R 2represent methyl, methoxyl group, chlorine, nitro, hydroxyl or-OR 4, R 3represent hydrogen, methoxyl group or-OR 4; N=1 or 2, wherein R 4representative:
2. the Piperlongumine analogue of claim 1 or its pharmacy acceptable salt, wherein R 2represent nitro, hydroxyl or methoxyl group.
3. the Piperlongumine analogue of claim 1 or its pharmacy acceptable salt, wherein R 2represent OR 4, R 4represent ethanoyl.
4. the Piperlongumine analogue of claim 1 or its pharmacy acceptable salt, wherein R 3represent hydrogen or methoxyl group.
5. the Piperlongumine analogue of claim 1 or its pharmacy acceptable salt, the compound for following arbitrary structure:
6. the Piperlongumine analogue of claim 1 or its pharmacy acceptable salt, wherein said pharmacy acceptable salt is the hydrochloride of the general formula I of claim 1 or the Piperlongumine analogue of II, vitriol, phosphoric acid salt, toxilic acid, fumaric acid, Citric Acid, methylsulfonic acid, tosic acid, tartrate or acetate.
7. a pharmaceutical composition, wherein containing the general formula I of claim 1 or the Piperlongumine analogue of II or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
8. the general formula I of claim 1 or the Piperlongumine analogue of II or its pharmacy acceptable salt are for the preparation of the purposes of the medicine for the treatment of cardiovascular and cerebrovascular diseases.
9. the purposes of claim 8, cardiovascular and cerebrovascular diseases is wherein platelet aggregation or thrombotic disease.
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