CN104910174B - Piplartine analogue, preparation method therefor and applications - Google Patents

Piplartine analogue, preparation method therefor and applications Download PDF

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CN104910174B
CN104910174B CN201510243672.XA CN201510243672A CN104910174B CN 104910174 B CN104910174 B CN 104910174B CN 201510243672 A CN201510243672 A CN 201510243672A CN 104910174 B CN104910174 B CN 104910174B
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piperlongumine
analog
pyridine
pharmaceutically acceptable
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CN104910174A (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
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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 analog, preparation method and applications
Technical field
The present invention relates to medicinal chemistry art, and in particular to a class piperlongumine analog, preparation method and contain it Pharmaceutical composition, the present invention piperlongumine analog can be used for treatment or prevention of thromboembolic disorders.
Background technology
Piperlongumine (piplartine) is the chief active in the perennial herbaceous stem rattan wood plant Bi roots of grass of Piperaceae Piper Composition.Research finds that piperlongumine and its derivative significantly can press down in the case where normal cell physiology function is not affected Propagation (Raj L, Takao I, Aditi UG, the et al.Selective killing of cancer of tumour cell processed cells by a small molecule targeting the stress response to ROS[J].Nature,475 (2011):231～234；Li Shaolu. purposes and its drug regimen of the piperlongumine derivative in the medicine for preparing treating cancer Thing CN102125552A (2011-07-20))；Piperlongumine and its derivative are lived to collagen, arachidonic acid and blood platelet Change the factor induction platelet aggregation have significant inhibitory activity (high source, Yu Minghui. piperlongumine class compounds for resisting platelet gather Purposes CN101810612A (2010-08-25) of collection；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 such as ticlopidine, Clopidogrel and prasugrel, for acting on P2Y12The medicament for resisting platelet aggregation of target spot, is clinically mainly used in preventing and controlling Treat the embolic cardiovascular and cerebrovascular disease caused by blood platelet disorders are assembled.But the renal toxicity of piperlongumine is larger, can cause to face Nearly renal tubule and glomerular epithelium cell oedema and renal tubule bleeding, (referring to Zhang Peng, Huang is opened and, China to limit its clinical practice The sub- spring. the Advance on Pharmacological Activities [J] of piperlongumine. Chinese herbal medicine, 2012,43 (1):201-204.)；Thienopyridines resist Platelet aggregation drugs there is also Hemorrhage and " clopidogrel " is resisted deficiency (referring to Yang Hongyan, Wang Xiao. antiplatelet Research progress of drugs [J]. Chinese Pharmaceutical Journal, 2012,47 (4):250-254.), therefore find safer effectively anti-blood Platelet aggregation medicine is always the target that people constantly study.
The content of the invention
The present invention has synthesized class piperlongumine analog (I) or (II), pharmacodynamics with piperlongumine as lead compound Test shows that the compounds of this invention has significant inhibitory activity to the platelet aggregation that ADP, AA are induced.
The compounds of this invention includes logical formula (I) and logical formula (II)：
Wherein R1Represent hydrogen or methoxyl group；R2Represent methyl, methoxyl group, chlorine, nitro, hydroxyl or-OR4；R3Represent hydrogen, first Epoxide or-OR4；N=1 or 2, wherein R4Represent：
R2It is preferred that representing nitro, hydroxyl or methoxyl group.
R2It is preferred that representing OR4, R4It is preferred that representing acetyl group.
R3It is preferred that representing hydrogen or methoxyl group.
The compound of the present invention, the compound of preferential following any structure formula：
The more preferably following arbitrary compound of the present invention：
Wherein described pharmaceutically acceptable salt is the hydrochloric acid of the piperlongumine analog of the formula I or II of the present invention Salt, sulfate, phosphate, maleic acid, fumaric acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, tartaric acid or acetate.
As a example by LHC-13, the preparation method of the compounds of this invention comprises the steps：
Other compounds of the present invention can take corresponding raw material and use with reference to said method preparation.
Pharmacodynamics test and the result of part of compounds is presented herein below：
Method one：New zealand rabbit, male, body weight 1.8-2.2kg, 3.8% sodium citrate and 10mL normal salines Into 3.8% liquor sodii citratis, with 1% procaine hydrochloride local anaesthesia, arteria carotis intubation bloodletting, and liquor sodii citratis With 9:1 mixing, is centrifuged 10min with 1000r/min, takes platelet rich plasma (PRP), and remainder is centrifuged with 3000r/min, is taken Platelet poor plasma (PPP), adenosine diphosphate (ADP) (ADP) of the aggregation inducing agent with 10ug/mL.Often add not in pipe 280uL PRP With concentration medicine (piperlongumine and LHC-1～LHC-21 with DMSO dissolve, plus pure water be diluted to desired concn difference For 0.8 μ g/ml, 4 μ g/ml, 20 μ g/ml, 100 μ g/ml, 500 μ g/ml, aspirin DMSO dissolves, plus pure water is diluted to Concentration is respectively 2.88 μ g/ml, 14.4 μ g/ml, 72 μ g/ml, 360 μ g/ml, 1.8mg/ml) 10uL, add in control group PRP Physiological saline 10uL, incubates 3min, is subsequently adding above-mentioned derivant, detects blood platelet with LG-PABER-1 types platelet aggregation instrument PAR, and calculate IC50Value.
Method two：Liver microsome incubation method：Microsome vitro reactions system has 1mL altogether, takes NADP, G- respectively PD、G-PDH、MgCl2And appropriate hepatomicrosome, KCl- phosphate buffers are added, makes reaction system final volume be 1mL, instead Answer in system NADP containing 0.5mmol/L, 5.0mmol/L G-6-PD, 1.0U/mL G-6-PDH, 5.0mmol/L respectively MgCl2, 1.0mg/ml hepatomicrosomes.Taking needs the screening medicine being incubated to be added in microsome reaction system, in 37 DEG C The middle temperature of water-bath incubates vibration 60min, is put into terminating reaction in -20 DEG C of refrigerators.Platelet poor plasma (PPP) is taken, aggregation inducing agent is used The adenosine diphosphate (ADP) (ADP) of 10ug/mL.The medicine for often adding variable concentrations Jing microsomes reaction system to process in pipe 280uL PRP Thing 10uL, adds physiological saline 10uL, incubates 3min, be subsequently adding above-mentioned derivant, use LG-PABER-1 types in control group PRP Platelet aggregation instrument detects platelet aggregation rate, and calculates IC50Value.
The compounds of this invention LHC-1～LHC-12 carries out platelet aggregation inhibitory activity measure using method one；Compound LHC-13～LHC-21 determines its platelet aggregation inhibitory activity using method two.In the present invention, advantage compound is induced to ADP The inhibitory activity of platelet aggregation is shown in Table 1.
The inhibitory activity of the platelet aggregation that 1 piperlongumine analog of table is induced to ADP
Compound IC50(mM) Compound IC50(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 show, the piperlongumine analog of the present invention platelet aggregation that ADP is induced is respectively provided with compared with Good inhibitory activity, is better than positive reference substance piperlongumine.Particularly compound L HC-5, LHC-7 and LHC-21 shows preferably Prospect in medicine.
Present invention also offers the pharmaceutical composition of a kind for the treatment of or prevention cardiovascular and cerebrovascular disease, wherein effective containing treatment The formula I or II compound of amount and pharmaceutically acceptable carrier.Described pharmaceutical composition can be conventional tablet or capsule, delay Conventional dosage form on the galenic pharmacy such as release tablet formulations capsule, Dospan or capsule, oral liquid, injection.
Usually, when compound of the invention is used for treating, people's dosage range is 1mg～1000mg/ days.Also dependent on The different and disease severity of formulation, dosage exceed the scope.
Specific embodiment
Embodiment 1
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (3,4,5- trimethoxyphenyls) propyl- The synthesis of 2- alkene -1- ketone (LHC-1)
1.1 (E) -3- (3,4,5- trimethoxyphenyls) acrylic acid synthesis
In 500mL three-neck flasks, 3,4,5-Trimethoxybenzaldehyde (10.0g, 51.0mmol), malonic acid is sequentially added (6.41g, 61.5mmol), pyridine (35mL), piperidines (2mL) and benzene (150mL), load onto oil water separator, flow back in 110 DEG C 6h.TLC [V (chloroform):V (methyl alcohol)=10:1 is solvent] detect display reaction substantially completely, room temperature is cooled to, 75 are added (mL) saturated aqueous sodium carbonate, continues stirring 30min, separates, and phase of fetching water, water mutually adjust pH to 4 with the hydrochloric acid of 3mol/L, separate out A large amount of white solids；Suction filtration, filter cake are recrystallized with absolute ethyl alcohol, dry white solid 7.92g, yield 65.2%, M.p.124.3～125.7 DEG C.
1.2 (E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (3,4,5- trimethoxyphenyls) The synthesis of propyl- 2- alkene -1- ketone (LHC-1)
In 250ml round-bottomed flasks, sequentially add (E) -3- (3,4,5- trimethoxyphenyl) acrylic acid (3.00g, 12.6mmol), thionyl chloride (15mL) and toluene (45mL), react 5h in 80 DEG C.Reduced pressure concentration, and steamed with toluene (20mL) band The thionyl chloride for removing residual three times, obtains 3,4,5- elemicin acyl chlorides, adds anhydrous methylene chloride (15mL) dissolving It is standby.
Separately take 250mL three-neck flasks, sequentially add 4,5,6,7- thiophane [3,2-c] pyridine hydrochlorides (1.86g, 13.4mmol), dichloromethane (50mL) and triethylamine (6mL), stir 30min under normal temperature condition, under condition of ice bath, slow to drip Plus 3,4,5- elemicin acyl chlorides dichloromethane solutions continue reaction 2.5h after completion of dropping.TLC [V (acetic acid second Ester):V (petroleum ether)=1:1 is solvent] detection show reaction substantially completely, reactant liquor respectively with water (100mL × 2), 1% Watery hydrochloric acid (100mL × 3) and 1mol/L sodium carbonate liquors (50mL × 3) washing, anhydrous sodium sulfate drying, reduced pressure concentration, Jing silicon Glue post separation, obtains LHC-1 white solid 2.43g, yield 53.3%, m.p.151.4～152.7 DEG C；1H-NMR(CDCl3, 300MHz)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-CH2), 3.98 (t, 2H, J=4.5Hz, Py-CH2),3.91 (s,6H,OCH3×2),3.88(s,3H,OCH3),2.96(br s,2H,Py-CH2)；13C-NMR(CDCl3,75MHz)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 C19H21NO4S:m/z(M++H)360.06.
Embodiment 2
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- methoxyphenyls) propyl- 2- alkene -1- The synthesis of ketone (LHC-2)
(E) -3- (4- methoxyphenyls) acrylic acid is synthesized by 1.1 methods operation in embodiment 1, by 1.2 sides in embodiment 1 Method operation be obtained (E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- methoxyphenyls) propyl- 2- alkene - 1- ketone (LHC-2) faint yellow solid, m.p.131.4～132.7 DEG C；1H-NMR(CDCl3,400MHz)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-CH2),3.97(br s,2H,Py- CH2),3.84(s,3H,OCH3),2.94(br s,2H,Py-CH2)；13C-NMR(CDCl3,100MHz)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 C17H17NO2S:m/z(M++H)300.13.
Embodiment 3
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- aminomethyl phenyls) propyl- 2- alkene -1- ketone (LHC-3) synthesis
(E) -3- (4- aminomethyl phenyls) acrylic acid is synthesized by 1.1 methods operation in embodiment 1, by 1.2 methods in embodiment 1 Operation is obtained (E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- aminomethyl phenyls) propyl- 2- alkene -1- ketone (LHC-3) white solid, m.p.145.8～147.2 DEG C；1H-NMR(CDCl3,400MHz)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-CH2), 3.97(br s,2H,Py-CH2),2.95(br s,2H,Py-CH2),2.37(s,3H,CH3)；13C-NMR(CDCl3,100MHz) 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 C17H17NOS:m/z(M++H)284.08.
Embodiment 4
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- chlorphenyls) propyl- 2- alkene -1- ketone (LHC-4) synthesis
(E) -3- (4- chlorphenyls) acrylic acid is grasped by 1.2 methods in embodiment 1 by 1.1 methods operation synthesis in embodiment 1 Make (E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- chlorphenyls) propyl- 2- alkene -1- ketone is obtained (LHC-4) white solid, 169.5～170.9 DEG C；1H-NMR(CDCl3,400MHz)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-CH2),3.97(br s,2H,Py-CH2),2.95(br s,2H,Py-CH2)；13C-NMR(CDCl3,100MHz)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 C16H14ClNOS:m/z(M++H)314.17.
Embodiment 5
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- nitrobenzophenones) propyl- 2- alkene -1- ketone (LHC-5) synthesis
(E) -3- (4- nitrobenzophenones) acrylic acid is synthesized by 1.1 methods operation in embodiment 1, by 1.2 methods in embodiment 1 Operation is obtained (E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- nitrobenzophenones) propyl- 2- alkene -1- ketone (LHC-5) white solid, 191.3～192.4 DEG C；1H-NMR(CDCl3,300MHz)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-CH2), 3.94 (d, J=30.3Hz, 2H, Py-CH2), 2.99(br s,2H,Py-CH2)；13C-NMR(CDCl3,100MHz)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 C16H14N2O3S:m/z(M++H)315.06.
Embodiment 6
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- hydroxy phenyls) propyl- 2- alkene -1- ketone (LHC-6) synthesis (E) -3- (4- hydroxy phenyls) acrylic acid is by 1.1 methods operation synthesis in embodiment 1.
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- hydroxy phenyls) propyl- 2- alkene -1- ketone (LHC-6) synthesis
In 250mL round-bottomed flasks, sequentially add 4,5,6,7- thiophane [3,2-C] pyridine hydrochlorides (5.00g, 28.6mmol), NaOH (1.70g, 42.5mmol) and dichloromethane (60mL), stirring at normal temperature 3.5h.TLC [V (chloroform):V (methyl alcohol)=10:1 is solvent] detect display reaction substantially completely, to be washed with water (80mL × 2), anhydrous sodium sulfate drying is dense Contract to obtain pale yellow oil 3.12g.
Separately take 250mL three-neck flasks, add (E) -3- (4- hydroxy phenyls) acrylic acid (3.50g, 21.3mmol), 4,5, 6,7- thiophanes [3,2-C] pyridine (3.00g, 21.6mmol), DCC (5.30g, 25.7mmol) and dichloromethane (60mL), 6h is stirred under condition of ice bath.TLC [V (chloroform):V (methyl alcohol)=10:1 is solvent] detect display reaction substantially completely, freezing, Suction filtration, reduced pressure concentration, Jing silica gel post separations obtain LHC-6 white solid 3.40g, yield 54.1%, m.p.209.6～212.1 ℃；1H-NMR(DMSO-d6,300MHz)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-CH2),4.62(s,1H,Py-CH2), 3.90 (d, J=30.3Hz, 2H, Py-CH2), 2.83 (d, J=23.1Hz, 2H, Py-CH2)；13C-NMR(DMSO-d6,75MHz) 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 C16H15NO2S:m/z(M++H)286.15.
Embodiment 7
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- hydroxy 3-methoxybenzene bases) propyl- The synthesis of 2- alkene -1- ketone (LHC-7)
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- are obtained by the operation of 6 method of embodiment Hydroxy 3-methoxybenzene base) propyl- 2- alkene -1- ketone (LHC-7) white solid, m.p.196.2～197.5 DEG C；1H-NMR(CDCl3, 400MHz)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-CH2),4.03-3.99(m,1H,Py-CH2),3.94(s,4H,Py- CH2and OCH3),2.97(br s,2H,Py-CH2)；13C-NMR(CDCl3,100MHz)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 C17H17NO3S:m/z(M+-H)314.17.
Embodiment 8
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (3- hydroxyl -4- methoxyphenyls) propyl- The synthesis of 2- alkene -1- ketone (LHC-8)
(E) -3- (3- hydroxyl -4- methoxyphenyls) acrylic acid is synthesized by 1.1 methods operation in embodiment 1, by embodiment 6 Method operation is obtained (E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (3- hydroxyl -4- methoxybenzenes Base) propyl- 2- alkene -1- ketone (LHC-8) white solid, m.p.176.3～177.8 DEG C；1H-NMR(CDCl3,300MHz)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,J1=2.1Hz, J2=8.4Hz, 1H, ArH), 6.85-6.77 (m, 3H, CH=, ThH and ArH), 4.76 (s, 2H, Py-CH2),4.01-3.99(m,1H,Py-CH2),3.92(s,4H,Py-CH2and OCH3),2.94(br s,2H,Py-CH2) ；13C-NMR(CDCl3,75MHz)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 C17H17NO3S:m/z(M+-H)314.17.
Embodiment 9
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- hydroxyl -3,5- dimethoxy benzenes Base) propyl- 2- alkene -1- ketone (LHC-9) synthesis
(E) -3- (4- hydroxyl -3,5- Dimethoxyphenyls) acrylic acid is synthesized by 1.1 methods operation in embodiment 1, by reality Apply the operation of 6 method of example and (E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- hydroxyls -3,5- two are obtained Methoxyphenyl) propyl- 2- alkene -1- ketone (LHC-9) faint yellow solid, m.p.155.7～156.4 DEG C；1H-NMR(CDCl3, 300MHz)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-CH2), 3.98 (t, J=5.4Hz, 2H, Py-CH2),3.94(s,6H,OCH3× 2), 2.96 (t, J=5.1Hz, 2H, Py-CH2)；13C-NMR(CDCl3,75MHz)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 C18H19NO4S:m/z(M+-H)344.59.
Embodiment 10
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- (the third oxygen of 3- (dimethylamino) Base) phenyl) propyl- 2- alkene -1- ketone (LHC-10) synthesis
In 100mL round-bottomed flasks, N, N- dimethyl chloropropane hydrochlorides (1.7g, 10.8mmol), potassium carbonate is added (3.50g), KI (0.20g) and isopropanol (50ml), are stirred at room temperature 2h standby；250mL three-neck flasks are separately taken, LHC-6 is added Compound (2.50g, 8.77mmol), potassium carbonate (3.00g) and isopropanol (50ml), and add N, N- dimethyl chloride propane isopropanols Solution, reacts 9h in 80 DEG C.TLC [V (chloroform):V (methyl alcohol)=6:1 is solvent] detect display reaction substantially completely, while hot Suction filtration, reduced pressure concentration are dissolved with 60mL dichloromethane, and water (60mL × 2) washing, anhydrous sodium sulfate drying, suction filtration are reduced pressure dense Contracting, Jing silica gel post separations obtain LHC-10 white solid 1.23g, yield 37.5%, m.p.110.3～110.8 DEG C；1H-NMR (CDCl3,300MHz)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-CH2), 4.06 (t, J=6.3Hz, 2H, OCH2CH2CH2N),3.93(br s,2H,Py-CH2),2.95(br s,2H, Py-CH2), 2.61 (t, J=7.2Hz, 2H, OCH2CH2CH2N),2.38(s,6H,CH3×2),2.10-2.01(m,2H, OCH2CH2CH2N)；13C-NMR(CDCl3,75MHz)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 C21H26N2O2S:m/ z(M++H)371.23.
Embodiment 11
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (4- (the third oxygen of 3- (dimethylamino) Base) -3- methoxyphenyls) propyl- 2- alkene -1- ketone (LHC-11) synthesis
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- is obtained by the operation of 10 method of embodiment (4- (3- (dimethylamino) propoxyl group) -3- methoxyphenyls) propyl- 2- alkene -1- ketone (LHC-11) white solid, m.p.123.4 ～125.1 DEG C；1H-NMR(CDCl3,400MHz)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-CH2), 4.12 (t, J=6.4Hz, 2H, OCH2CH2CH2N),4.01 (br s,2H,Py-CH2),3.91(s,3H,OCH3),2.96(br s,2H,Py-CH2), 2.64 (t, J=7.2Hz, 2H, OCH2CH2CH2N),2.38(s,6H,CH3×2),2.15-2.08(m,2H,OCH2CH2CH2N)；13C-NMR(CDCl3,100MHz) 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 C22H28N2O3S:m/z(M++H)401.12.
Embodiment 12
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- (3- (the third oxygen of 3- (dimethylamino) Base) -4- methoxyphenyls) propyl- 2- alkene -1- ketone (LHC-12) synthesis
(E) -1- (6,7- dihydro-thiophenes simultaneously -5 (4H)-yl of [3,2-c] pyridine) -3- is obtained by the operation of 10 method of embodiment (3- (3- (dimethylamino) propoxyl group) -4- methoxyphenyls) propyl- 2- alkene -1- ketone (LHC-12) white solid, m.p.108.9 ～110.2 DEG C；1H-NMR(CDCl3,300MHz)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-CH2),4.02 (t, J=6.6Hz, 2H, OCH2CH2CH2N),3.84(br s,2H,Py-CH2),3.77(s,3H,OCH3),2.85(br s,2H, Py-CH2), 2.45 (t, J=7.2Hz, 2H, OCH2CH2CH2N),2.21(s,6H,CH3×2),2.01-1.91(m,2H, OCH2CH2CH2N)；13C-NMR(CDCl3,75MHz)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 C22H28N2O3S:m/z(M++H)401.28.
Embodiment 13
(E) -5- (3- (3,4,5- trimethoxyphenyls) acryloyl group) -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine - The synthesis of 2- acetic acid esters (LHC-13)
13.1st, (E) -5- (3- (3,4,5- trimethoxyphenyls) acryloyl group) -4,5,6,7a- thiophanes simultaneously [3,2- C] pyridine -2 (4H) -one synthesis
(E) -5- (3- (3,4,5- trimethoxyphenyls) acryloyl group) -4,5 is obtained by 1.2 methods operation in embodiment 1, 6,7a- thiophanes simultaneously [3,2-c] pyridine -2 (4H) -one yellow solid, m.p.87.4～89.6 DEG C；1H-NMR(CDCl3, 300MHz)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-CH2),4.20(s,1H,Py-CH2),3.82(s,9H,OCH3×3),3.80(s,2H,Py- CH2),3.37(br s,1H,Py-CH2),2.46(br s,2H,Py-CH2)；13C-NMR(CDCl3,75MHz)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 C19H21NO5S:m/z(M++H)376.10.
13.2nd, -4,5,6,7- thiophanes are simultaneously [3,2-c] for (E) -5- (3- (3,4,5- trimethoxyphenyls) acryloyl group) The synthesis of pyridine -2- acetic acid esters (LHC-13)
(E) -5- (3- (3,4,5- trimethoxyphenyls) acryloyl group) -4,5,6,7a- thiophanes simultaneously [3,2-c] pyrrole Pyridine -2 (4H) -one (2.00g, 5.33mmol), aceticanhydride (1.5mL), acetonitrile (40mL) and triethylamine (1.5mL), stirring at normal temperature 5h, TLC [V (ethyl acetate):V (petroleum ether)=2:1 is solvent] detect display reaction substantially completely, reduced pressure concentration uses dichloro Methane (50mL) dissolves, water (60mL × 2) washing, anhydrous sodium sulfate drying, reduced pressure concentration, and it is light that Jing silica gel post separations obtain LHC-13 Yellow solid 1.36g, yield 61.3%, m.p.121.8～123.7 DEG C；1H-NMR(CDCl3,400MHz)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- CH2),4.00(br s,2H,Py-CH2),3.91(s,6H,OCH3×2),3.88(s,3H,OCH3),2.85(br s,2H,Py- CH2),2.30(s,3H,CH3)；13C-NMR(CDCl3,100MHz)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 C21H23NO6S:m/z(M++H)418.01.
Embodiment 14
(E) -5- (3- (4- methoxyphenyls) acryloyl group) -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- acetic acid The synthesis of ester (LHC-14)
(E) -5- (3- (4- methoxyphenyls) acryloyl group) -4,5,6,7- tetrahydrochysene thiophenes are obtained by the operation of 13 method of embodiment Fen simultaneously [3,2-c] pyridine -2- acetic acid esters (LHC-14) faint yellow solid, m.p.126.3～127.4 DEG C；1H-NMR(CDCl3, 300MHz)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-CH2),3.96(t,J =5.4Hz, 2H, Py-CH2),3.83(s,3H,OCH3), 2.84 (t, J=5.4Hz, 2H, Py-CH2),2.29(s,3H,CH3)；13C-NMR(CDCl3,75MHz)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 C19H19NO4S:m/z(M++H)357.98.
Embodiment 15
(E) -5- (3- (4- aminomethyl phenyls) acryloyl group) -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- acetic acid esters (LHC-15) synthesis
(E) -5- (3- (4- aminomethyl phenyls) acryloyl group) -4,5,6,7- thiophanes are obtained by the operation of 13 method of embodiment And [3,2-c] pyridine -2- acetic acid esters (LHC-15) faint yellow solid, m.p.117.2～118.6 DEG C；1H-NMR(CDCl3, 400MHz)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-CH2), 3.96(br s,2H,Py-CH2),2.84(br s,2H,Py-CH2),2.37(s,3H,CH3),2.29(s,3H,CH3)；13C-NMR (CDCl3,100MHz)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 C19H19NO3S:m/z(M++H)342.07.
Embodiment 16
(E) -5- (3- (4- chlorphenyls) acryloyl group) -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- acetic acid esters (LHC-16) synthesis
(E) -5- (3- (4- chlorphenyls) acryloyl group) is obtained by the operation of 13 method of embodiment, and -4,5,6,7- thiophanes are simultaneously [3,2-c] pyridine -2- acetic acid esters (LHC-16) faint yellow solid, m.p.115.4～116.2 DEG C；1H-NMR(CDCl3,300MHz) 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-CH2),3.96(br s, 2H,Py-CH2),2.84(br s,2H,Py-CH2),2.29(s,3H,CH3)；13C-NMR(CDCl3,75MHz)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 C18H16ClNO3S:m/z(M++H)361.96.
Embodiment 17
(E) -5- (3- (4- nitrobenzophenones) acryloyl group) -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- acetic acid esters (LHC-17) synthesis
(E) -5- (3- (4- nitrobenzophenones) acryloyl group) -4,5,6,7- thiophanes are obtained by the operation of 13 method of embodiment And [3,2-c] pyridine -2- acetic acid esters (LHC-17) faint yellow solid, m.p.127.6～128.3 DEG C；1H-NMR(CDCl3, 300MHz)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-CH2), 4.00 (t, J=12.0Hz, 2H, Py-CH2),2.87(br s,2H,Py-CH2),2.30(s,3H,CH3)；13C-NMR(CDCl3,75MHz)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 C18H16N2O5S:m/z(M++H)373.00.
Embodiment 18
(E) -5- (3- (4- acetoxyl group phenyl) acryloyl group) -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- second The synthesis 18.1 of acid esters (LHC-18), (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, FeCl3Solution detection p-Coumaric Acid reaction is complete, and add water stirring, suction filtration, and filter cake is used Water 300mL is washed, and filter cake is put in beaker, plus saturated sodium carbonate solution adjusts pH=9～10, suction filtration, filtrate to adjust pH=2 with concentrated hydrochloric acid ～3, white solid is separated out, suction filtration, filter cake water 150mL wash 3 times, dry (E) -3- (4- acetoxyl group phenyl) acrylic acid 6.17g, yield 81.9%, m.p.216.4～218.7 DEG C.
18.2nd, (E) -5- (3- (4- acetoxyl group phenyl) acryloyl group) -4,5,6,7- thiophanes simultaneously [3,2-c] pyrrole The synthesis of pyridine -2- acetic acid esters (LHC-18)
(E) -5- (3- (4- acetoxyl group phenyl) acryloyl group) -4,5,6,7- thiophanes are obtained by 13 method of embodiment And [3,2-c] pyridine -2- acetic acid esters (LHC-18) faint yellow solid, m.p.103.6～106.2 DEG C；1H-NMR(CDCl3, 300MHz)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-CH2),3.95(br s,2H,Py-CH2),2.84(br s,2H,Py-CH2),2.31(s,3H,CH3),2.29(s,3H,CH3)；13C-NMR(CDCl3, 75MHz)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 C20H19NO5S:m/z(M++H)386.00.
Embodiment 19
(E) -4,5,6,7- thiophanes are simultaneously [3,2-c] for -5- (3- (4- acetoxy-3s-methoxyphenyl) acryloyl group) The synthesis of pyridine -2- acetic acid esters (LHC-19)
(E) -5- (3- (4- acetoxy-3s-methoxyphenyl) acryloyl group) -4 is obtained by the operation of 18 method of embodiment, 5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- acetic acid esters (LHC-19) faint yellow solid, m.p.130.1～130.9 DEG C；1H- NMR(CDCl3,300MHz)δ:7.65 (d, J=15.6Hz, 1H, ArCH=), 7.17 (dd, J1=1.5Hz, J2=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-CH2),3.96(br s,2H,Py-CH2),3.88(s,3H,OCH3),2.85(br s,2H,Py-CH2),2.33(s,3H, CH3),2.29(s,3H,CH3)；13C-NMR(CDCl3,75MHz)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 C21H21NO6S:m/z(M++H)416.00.
Embodiment 20
(E) -4,5,6,7- thiophanes are simultaneously [3,2-c] for -5- (3- (3- acetoxyl group -4- methoxyphenyls) acryloyl group) The synthesis of pyridine -2- acetic acid esters (LHC-20)
(E) -5- (3- (3- acetoxyl group -4- methoxyphenyls) acryloyl group) -4 is obtained by the operation of 18 method of embodiment, 5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- acetic acid esters (LHC-20) faint yellow solid, m.p.140.6～142.2 DEG C；1H- NMR(CDCl3,300MHz)δ:7.62 (d, J=15.3Hz, 1H, ArCH=), 7.38 (dd, J1=2.1Hz, J2=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-CH2),3.99(br s,2H,Py-CH2),3.86(s,3H,OCH3),2.84(br s, 2H,Py-CH2),2.34(s,3H,CH3),2.29(s,3H,CH3)；13C-NMR(CDCl3,75MHz)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 C21H21NO6S:m/z(M++H)416.00.
Embodiment 21
(E) -5- (3- (4- acetoxy-3s, 5- Dimethoxyphenyls) acryloyl group) -4,5,6,7- thiophanes simultaneously [3, 2-c] pyridine -2- acetic acid esters (LHC-21) synthesis
(E) -5- (3- (4- acetoxy-3s, 5- Dimethoxyphenyls) acryloyls are obtained by the operation of 18 method of embodiment Base) -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- acetic acid esters (LHC-21) white solid, m.p.136.8～137.7 ℃；1H-NMR(CDCl3,300MHz)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-CH2),3.97(br s,2H,Py-CH2),3.86 (s,6H,OCH3×2),2.85(br s,2H,Py-CH2),2.35(s,3H,CH3),2.30(s,3H,CH3)；13C-NMR (CDCl3,75MHz)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 C22H23NO7S:m/z(M++H) 446.00。

Claims (9)

1. the piperlongumine analog or its pharmaceutically acceptable salt of formula I or II：
Wherein R1Represent hydrogen or methoxyl group；R2Represent methyl, methoxyl group, chlorine, nitro, hydroxyl or-OR4, R3Represent hydrogen, methoxyl group Or-OR4；N=1 or 2, wherein R4Represent：
2. the piperlongumine analog or its pharmaceutically acceptable salt of claim 1, wherein R2Represent nitro, hydroxyl or methoxy Base.
3. the piperlongumine analog or its pharmaceutically acceptable salt of claim 1, wherein R2Represent OR4, R4Represent acetyl Base.
4. the piperlongumine analog or its pharmaceutically acceptable salt of claim 1, wherein R3Represent hydrogen or methoxyl group.
5. the piperlongumine analog or its pharmaceutically acceptable salt of claim 1, is the compound of following any structure：
6. the piperlongumine analog or its pharmaceutically acceptable salt of claim 1, wherein described is pharmaceutically acceptable Salt is the hydrochloride of piperlongumine analog of the formula I or II of claim 1, sulfate, phosphate, maleic acid, fumaric acid, Citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, tartaric acid or acetate.
7. a kind of pharmaceutical composition, the piperlongumine analog of formula I or II wherein containing claim 1 or its pharmaceutically may be used The salt of acceptance and pharmaceutically acceptable carrier.
8. the piperlongumine analog or its pharmaceutically acceptable salt of the formula I or II of claim 1 is used for preparing the treatment heart The purposes of the medicine of cranial vascular disease.
9. the purposes of claim 8, cardiovascular and cerebrovascular disease therein is platelet aggregation or thrombotic disease.
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