CN106518791B - A kind of ligustrazine derivant, preparation method and applications - Google Patents
A kind of ligustrazine derivant, preparation method and applications Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The present invention relates to field of medicinal chemistry, more particularly to a kind of ligustrazine derivant (I) and (II) and preparation method thereof, pharmacodynamics test proves, ligustrazine derivant of the invention has certain anti-tumor activity and significant inhibition tumor cell migration and invasion effect, can be used for the treatment of tumour.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of ligustrazine derivant, preparation method and oncotherapy
Medical usage.
Background technique
Cancer is to seriously threaten the major disease of human life and social development, the morbidity and mortality one of global lung cancer
The straight trend increased that presents is [referring to Rebecca Siegel, Jiemin Ma, Zhaohui Zou, et al.Cancer
Statistics[J].CA Cancer J Clin,2014,64(1):9-29].The invasion transfer of tumour cell is malignant tumour
One of Main Biological, be malignant tumour occurrence and development during distress phase, prognosis mala is tumour
The main reason for death.According to statistics, there are about invasion and transfer that 80%~90% dies of tumour cell for clinical tumor patient
[referring to Bi Lei, Yan Xiaojing, Yang Ye, influence of the flat ligustrazine of Chen Wei to hepatoma Hep G 2 cells migration, invasion and cytoskeleton
[J] Chinese Pharmacological Bulletin, 2016,32 (2): 194-198].
Ligustrazine is a kind of Chinese medicine for treating cardiovascular and cerebrovascular disease, has expansion blood vessel, inhibits platelet aggregation, anti-hemostasis
Bolt such as forms at a variety of effects, is clinically widely used in the treatment of ischemic cerebrovascular disease and obtains good therapeutic effect.It grinds in recent years
Studying carefully proves that ligustrazine can be with inducing apoptosis of tumour cell [referring to Yu K, Chen Z, Pan X, et
al.Tetramethylpyrazine-mediated suppression of C6 gliomas involves inhibition
of chemokine receptor CXCR4expression[J].Oncol.Rep.2012,28:955-960.].Also it has been reported that
Ligustrazine inhibits lung cancer A549 cell proliferation and migration [referring to Chunyan Zheng, Wei by blocking COX-2 to generate
Xiao,Maoxiang Zhu,et al.Inhibition of cyclooxygenase-2 by tetramethylpyrazine
and its effects on A549cell invasion and metastasis[J].International Journal
of Oncology,2012,40:2029-2037.]。
Main active in turmeric prime system Turmeric, pharmacological research show that curcumin has and inhibit kinds of tumor cells
Proliferation, invasion, transfer and angiogenesis function [referring to Ajaikumar B, Kunnumakkara, Preetha Anand,
Bharat B.Aggarwal Curcumin inhibits proliferation,invasion,angiogenesis and
metastasis of different cancers through interaction with multiple cell
signaling proteins[J].Cancer Letters,2008,269:199-225].The structural formula of ligustrazine and curcumin
It is as follows:
Summary of the invention
The present invention is based on pharmacophore hydridization Theoretical Design and a kind of ligustrazine derivant has been synthesized, pharmacological research is shown, this
The ligustrazine derivant of invention has certain anti-tumor activity and significant inhibition tumor cell migration and invasion effect, can use
In the treatment of tumour.
The compound of the present invention structural formula such as (I) or (II):
Wherein R1、R3It is independently represented each other H or OCH3,
R2Represent H, CH3、OCH3, Cl, Br or N (CH3)2；
N=0 or 1.
Preferred structural formula of compound are as follows:
For compound Z1, the compound of the present invention the preparation method is as follows:
Compound of the present invention can add pharmaceutically acceptable carrier and common pharmaceutical formulation, such as piece is made
Fragrance, sweetener, liquid or solid filler or diluent can be added in agent, capsule, pulvis, syrup, liquor, suspending agent, injection
Etc. common medicinal supplementary materials.
The administration mode of compound of the present invention clinically can be using modes such as oral, injections.
Dosage used in the compound of the present invention clinic is 0.01mg~1000mg/ days, can also be according to the weight or agent of the state of an illness
The difference of type deviates this range.
Here is the part pharmacodynamics test and result of the compounds of this invention:
One mtt assay measures influence of the untested compound to cancer cell and normal cell proliferation
A549, A549/DDP and HBE cell of logarithmic growth phase are with 5 × 103A/hole is inoculated in 96 orifice plates, and every group 6
A multiple holes, it is spare after culture for 24 hours.Experimental group is separately added into the test compounds of various concentration in diluted method again from low to high
Object, final concentration are respectively that 0.079,0.158,0.315,0.625,1.25,2.5,5,10,20,40 μ g/mL negative control group only adds
Drug is not added in culture medium, and using cis-platinum (3 μ g/mL) as positive control drug.After drug effect 48h, MTT solution (5mg/ is added
ML) 20 μ L continues to cultivate 4h, discards liquid in each hole, and every hole is added 200 μ L dimethyl sulfoxides (DMSO) and sets shakes on oscillator
5min measures A570 and finds out the IC of group of cells50, experimental data be shown in Table 1 (inhibiting rate is calculated according to the following formula: inhibiting rate=
(control group OD value-medicine group OD value)/control group OD value × 100%).By calculating IC50(HBE)/IC50(A549)Ratio, to examine
Untested compound is examined to the selective inhibitory of normal cell and cancer cell.
Inhibiting effect of the ligustrazine derivant of the present invention of table 1. to A549, A549/DDP and HBE cell Proliferation
(note: not further accurate measurement when inhibitory activity > 0.2mM)
MTT experiment is the results show that the compound of the present invention Z1, Z8, Z9, Z10 all have centainly the proliferation of each cell strain
Inhibiting effect, wherein Z1, Z8, Z10 are significantly stronger than cis-platinum (DDP), chemical combination to the inhibiting effect of the A549 tumor strain of cisplatin resistance
The IC of object Z1, Z8, Z9, Z1050(HBE)/IC50(A549)Ratio is all larger than the ratio of DDP, and is much larger than 1, illustrates to normal cell
And the inhibiting effect of tumour cell has certain selectivity.Compound Z10 all has stronger inhibition to A549 and A549/DDP
Activity, and cis-platinum is lower than to the toxicity of normal cell, show certain development prospect.
Two scratch experiments
(1) cell culture: the A549 of logarithmic growth phase is inoculated in 24 orifice plates with the concentration of 50,000/cell, raw to cell
It is spare when length to 90% area.(2) untested compound is prepared: IC of a cis-platinum to A549 cell50About 3.2 μ g/mL, when its dosage
Inhibitory rate of cell growth is 16.5% after 48 hours when for 0.8 μ g/mL, belongs to relatively less toxic dosage, therefore selects 0.8 μ of the cis-platinum
G/mL is as the positive control for inhibiting cell migration；B uses the 5 μ g/mL (10% < cell inhibitory rate < 20%) of less toxic dosage of Z10
In detection untested compound to the inhibiting effect of cell migration；Cis-platinum or untested compound is not added in c blank control group.(3) scratch:
The Tip head of 200 μ L specifications is selected to carry out scratch, it is desirable that scratch is straight and equivalent width；(4) take pictures: after scratch and add medicine to be measured
After object for 24 hours, 48h is photographed to record respectively.The compounds of this invention inhibits the activity of A549 cell migration to see Fig. 1.
Synthesized compound Z1, Z2, Z8, Z10 all has one to tumour cell A549 migration to scratch experiment as the result is shown
Fixed inhibiting effect, the activity that wherein Z8 and Z10 inhibits the activity of tumor cell migration to be better than positive control drug DDP illustrate this
Invention compound is diffused with apparent inhibiting effect for the transfer of tumour cell.Comprehensive MTT experiment and scratch experiment are as a result, change
It closes object Z10 and stronger inhibitory activity is all had to A549 and A549/DDP, inhibit tumour cell A549 migratory activity strong, and to just
The toxicity of normal cell is lower than cis-platinum, shows certain development prospect.
Three cell transwell methods detect cell A549 invasive ability
Matrigel is diluted to normal concentration with cold filtering distilled water, is added in the cell transwell.It is standby to prepare cell suspension
With.Gel is rinsed with serum free medium, is rinsed 3 times with PBS.In small indoor 105 cells of addition, with containing various concentration
Untested compound Z8 and Z10 are incubated for altogether (is typically chosen middle less toxic concentration, the concentration of this experimental selection is in IC20Near).Under cell
The culture solution that 500 μ L contain 10% fetal calf serum (FBS) and 100ng/mL EGF (epidermal growth factor) is added in layer, under the conditions of 37 DEG C
It is incubated for 24 hours.At the end of incubation, Matrigel gel is gently carefully wiped with wet cotton swab in the upper surface layer cell of film and is gathered
The cell of carbon ester film upper surface, and mark, the fixed 30min of ice-cold formaldehyde.Invade the cell of basilar memebrane lower surface
It is fixed and 0.5% violet staining 30min with methanol.Cell is face-down, is placed on glass slide, camera shooting, micro- in 200 times of inversions
Counted under mirror move to microporous barrier lower layer wear theca cell number.Each sample takes the 5-10 visual field to take pictures counting at random, finds out each
Theca cell number is averagely worn in the visual field, as shown in Figure 2.
Experimental result is shown in Fig. 3, Fig. 3 to be shown in IC20Change synthesized by [5 μM (Z10), 10 μM (Z8), 3 μM (DDP)] nearby
Closing object Z10, Z8 and DDP has conspicuousness inhibiting effect to cell invasion, and the inhibiting effect of Z10 is better than Z8.In summary three
A experiment, compound Z10 have significant inhibiting effect to the migration of A549 and invasive ability, and low to the toxicity of normal cell
In cis-platinum, certain development prospect is showed.
Detailed description of the invention
Fig. 1 is the compounds of this invention to the active scratch experiment result of tumour cell A549 inhibition of metastasis
Fig. 2 is inhibiting effect of the compounds of this invention to tumour cell A549 invasive ability
Fig. 3 is the statistical analysis (* * *: P < 0.001) that the compounds of this invention inhibits tumour cell A549 invasive ability
Specific embodiment
Embodiment 1
(2E, 5E) -2- (4- methoxybenzylidene) -5- ((3,5,6-3- methylpyrazine -2- base) methylene) cyclopentanone
(Z1) synthesis
The synthesis of 1.1 2- methylol -3,5,6- trimethylpyrazines
Reaction equation
Reaction step
Ligustrazine (15.0g, 0.1mol), 30%H are sequentially added in 250mL three-neck flask2O2Solution (24mL,
0.2mol), glacial acetic acid 15mL, it is cooling after 94 DEG C of reaction 12h, TLC (petroleum ether-ethyl acetate 1:1) detection reactions substantially completely
Under, pH=10 is adjusted with 50%NaOH solution, methylene chloride extracts (3 × 30mL), merges organic phase, through anhydrous Na2SO4It is dry,
Ligustrazine list nitrogen oxides white crystal 13.2g, yield 78.8%, mp 82.4-84.1 DEG C are obtained after solvent is recovered under reduced pressure.
Ligustrazine list nitrogen oxides (13.2g, 86.8mmol), acetic anhydride are sequentially added in 250mL three-neck flask
(31.2mL, 330.4mmol) is evaporated off after 130 DEG C of reaction 5h, TLC (petroleum ether-ethyl acetate 1:1) detection reactions substantially completely
Excessive acetic acid acid anhydride obtains (3,5,6- trimethylpyrazine -2- base) methyl acetate crude intermediate.
Up step reaction obtains that 20%NaOH solution 80mL is added in (3,5,6- trimethylpyrazine -2- base) methyl acetate,
12h is reacted at room temperature, substantially completely, filtering, filtrate is extracted with dichloromethane (3 for TLC (petroleum ether-ethyl acetate 1:1) detection reaction
× 50mL), merge organic phase, anhydrous Na2SO4Dry, concentration, petroleum ether recrystallization obtains faint yellow acicular crystal, as 2- hydroxyl
Methyl -3,5,6- trimethylpyrazine sterling 9.7g, yield 57.8%, mp 75.3-77.2 DEG C.
The synthesis of 1.2 3,5,6- trimethylpyrazine -2- formaldehyde
Reaction equation
Reaction step
Sequentially add 2- methylol -3,5 in 250mL three-neck flask, 6- trimethylpyrazine (9.5g, 62.5mmol),
MnO2(16.2g, 187.5mmol), dehydrated alcohol 100mL, flow back 12h, and TLC (petroleum ether-ethyl acetate 2:1) detects reactive group
This is completely cooling, and filtering is recovered under reduced pressure ethyl alcohol, obtains yellow solid, pure through silica gel column chromatography (petroleum ether-ethyl acetate 4:1)
Change, obtains faint yellow solid 8.8g, yield 93.9%, mp 84.7-86.5 DEG C.
1.3 (2E, 5E) -2- (4- methoxybenzylidene) -5- ((3,5,6- trimethylpyrazine -2- base) methylene) ring
The synthesis of pentanone (Z1)
Reaction equation
Experimental procedure: sequentially adding cyclopentanone (10mL, 0.115mol) in 250mL three-neck flask, morpholine (10mL,
0.114mol), benzene 100mL, in back flow reaction to oil water separator after anhydrous generation, reaction solution is cooled to room temperature, and is added to first
Oxygroup benzaldehyde (13mL, 0.115mol), flow back 8h, and TLC (petroleum ether-ethyl acetate=1:1) detection reaction substantially completely, is delayed
Slowly the HCl 50mL of 6mol/L is added dropwise, stirs 1h under room temperature, adds 10%NaHCO3Solution 115mL is stirred under room temperature
30min pours into solution in separatory funnel, stratification, and organic layer is dry with anhydrous sodium sulfate, concentration.It is anhydrous with 40mL
Ethyl alcohol dissolution, is added 1.5g Rhizoma Chuanxiong aldehyde (0.01mol), and 10% NaOH ethanol solution 5mL, reaction are slowly added dropwise under condition of ice bath
About 1h, TLC (petroleum ether-ethyl acetate=2:1) detection reaction substantially completely, filter out precipitating, and precipitating is washed with dehydrated alcohol, warp
Silica gel column chromatography (methylene chloride: ethyl acetate=2:1) purifies to obtain Z1 yellow crystals 2.0g, yield 61.2%,
m.p.160.2-161.7℃。1H NMR(300MHz,CDCl3) δ: 7.62 (t, J=3.0Hz, 1H, Py-CH=), 7.58-7.55
(m, 3H, Ar-CH=and ArH), 6.96 (d, J=8.7Hz, 2H, ArH), 3.85 (s, 3H, OCH3),3.37-3.31(m,2H,
CH2),3.04-2.98(m,2H,CH2),2.65(s,3H,CH3),2.53(s,3H,CH3),2.51(s,3H,CH3)；13C NMR
(75MHz,CDCl3)δ:195.66,159.69,150.04,148.92,148.15,144.67,142.47,134.44,
133.22,131.69,127.62,124.55,113.29,54.35,26.25,25.53,20.82,20.78,20.23；ESI-
Mass for C21H22N2O2:m/z 335.25[M++H].
Embodiment 2
(2E, 5E) -2- (3- methyl benzylidene) -5- ((3,5,6- trimethylpyrazine -2- base) methylene) cyclopentanone
(Z2) synthesis
Reaction equation
Reaction step: operating to obtain Z2 yellow crystals 2.03g by 1.3 methods in embodiment 1, yield 63.8%,
m.p.168.2-169.7℃。1H NMR(300MHz,CDCl3) δ: 7.57 (t, J=3.0Hz, 1H, Py-CH=), 7.50 (t, J=
3.0Hz, 1H, Ar-CH=), 7.35 (d, J=7.8Hz, 2H, ArH), 7.26 (t, J=7.5Hz, 1H, ArH), 7.12 (d, J=
7.5Hz,1H,ArH),3.31–3.25(m,2H,CH2),3.02–2.96(m,2H,CH2),2.58(s,3H,CH3),2.46(s,
3H,CH3),2.44(s,3H,CH3),2.32(s,3H,CH3)；13C NMR(75MHz,CDCl3)δ:196.77,151.17,
150.10,149.17,145.53,143.11,138.32,137.57,135.77,134.39,131.64,130.31,128.62,
127.90,125.95,27.31,26.64,21.86,21.79,21.46,21.24；ESI-Mass for C21H22N2O:m/z
319.26[M++H].
Embodiment 3
The synthesis of (2E, 5E) -2- benzylidene -5- ((3,5,6- trimethylpyrazine -2- base) methylene) cyclopentanone (Z3)
Reaction equation
Reaction step: operating to obtain Z3 light yellow crystal 1.85g by 1.3 methods in embodiment 1, yield 60.9%,
m.p.197.5-198.1℃。1H NMR(300MHz,CDCl3) δ: 7.66 (t, J=3.0Hz, 1H, Py-CH=), 7.63-7.60
(m, 3H, Ar-CH=and ArH), 7.47-7.38 (m, 3H, ArH), 3.40-3.34 (m, 2H, CH2),3.11-3.05(m,2H,
CH2),2.67(s,3H,CH3),2.54(s,3H,CH3),2.52(s,3H,CH3)；13C NMR(75MHz,CDCl3)δ:196.87,
151.23,150.20,149.22,145.53,143.06,137.79,135.83,134.23,130.85,129.46,128.77,
126.16,27.30,26.63,21.91,21.83,21.29；ESI-Mass for C20H20N2O:m/z 305.30[M++H].
Embodiment 4
(2E, 5E) -2- (4- bromobenzene methylene) -5- ((3,5,6- trimethylpyrazine -2- base) methylene) cyclopentanone (Z4)
Synthesis
Reaction equation
Reaction step: operating to obtain Z4 yellow crystals 1.90g by 1.3 methods in embodiment 1, yield 49.8%,
m.p.205.4-206.5℃。1H NMR(300MHz,CDCl3) δ: 7.66 (t, J=3.0Hz, 1H, Py-CH=), 7.57 (d, J=
7.8Hz, 2H, ArH), 7.52 (t, J=3.0Hz, 1H, Ar-CH=), 7.46 (d, J=8.4Hz, ArH) 3.41-3.35 (m,
2H,CH2),3.05-2.99(m,2H,CH2),2.67(s,3H,CH3),2.55(s,3H,CH3),2.53(s,3H,CH3)；13C
NMR(75MHz,CDCl3)δ:196.55,151.21,150.21,149.30,145.45,142.75,138.38,134.69,
132.75,132.09,131.99,126.34,123.80,27.24,26.56,21.84,21.81,21.19；ESI-Mass for
C20H19BrN2O:m/z383.18[M++H].
Embodiment 5
(2E, 5E) -2- (4- chlorobenzene methylene) -5- ((3,5,6- trimethylpyrazine -2- base) methylene) cyclopentanone (Z5)
Synthesis
Reaction equation
Reaction step: by 1.3 methods in embodiment 1 operate Z5 light yellow crystal 1.60g, yield are 47.3%,
m.p.205.5-206.5℃。1H NMR(300MHz,CDCl3) δ: 7.56 (t, J=3.0Hz, 1H, Py-CH=), 7.45-7.42
(m, 3H, Ar-CH=and ArH), 7.31 (d, J=8.7Hz, 2H, ArH), 3.31-3.25 (m, 2H, CH2),2.97-2.91
(m,2H,CH2),2.57(s,3H,CH3),2.45(s,3H,CH3),2.43(s,3H,CH3)；13C NMR(75MHz,CDCl3)δ:
196.57,151.28,150.27,149.24,145.41,142.72,138.23,135.38,134.29,132.68,131.89,
129.02,126.36,27.24,26.54,21.90,21.81,21.25；ESI-Mass for C20H19ClN2O:m/z 339.28
[M++H].
Embodiment 6
(2E, 5E) -2- (4- dimethylamino) benzylidene) -5- ((3,5,6- trimethylpyrazine -2- base) methylene) ring penta
The synthesis of ketone (Z6)
Reaction equation
Reaction step: operating to obtain Z6 dark red crystal 1.85g by 1.3 methods in embodiment 1, yield 53.4%,
m.p.209.7-210.8℃。1H NMR(300MHz,CDCl3) δ: 7.60-7.57 (m, 2H, Py-CH=and Ar-CH=),
7.53 (d, J=8.7Hz, 2H, ArH), 6.71 (d, J=8.8Hz, 2H, ArH), 3.40-3.24 (m, 2H, CH2),3.03(s,
6H,NCH3×2),3.01-2.97(m,2H,CH2),2.65(s,3H,CH3),2.53(s,3H,CH3),2.50(s,3H,CH3)；13C NMR(75MHz,CDCl3)δ:196.36,151.04,150.88,149.63,149.03 145.97,144.39,135.60,
133.00,132.94,124.63,123.79,111.82,40.07,27.33,26.72,21.86,21.82,21.34；ESI-
Mass for C22H25N3O:m/z348.25[M++H].
Embodiment 7
(2E, 5E) -2- (3,5- dimethoxybenzyliden) -5- ((3,5,6- trimethylpyrazine -2- base) methylene) ring
The synthesis of pentanone (Z7)
Reaction equation
Reaction step: operating to obtain Z7 light yellow crystal 2.27g by 1.3 methods in embodiment 1, yield 62.4%,
m.p.197.9-199.2℃。1H NMR(300MHz,CDCl3) δ: 7.65 (t, J=3.0Hz, 1H, Py-CH=), 7.51 (t, J=
3.0Hz, 1H, Ar-CH=), 6.76 (d, J=2.3Hz, 2H, ArH), 6.50 (t, J=2.2Hz, 1H, ArH), 3.83 (s, 6H,
OCH3×2),3.39-3.33(m,2H,CH2),3.10–3.04(m,2H,CH2),2.66(s,3H,CH3),2.54(s,3H,CH3),
2.52(s,3H,CH3)；13C NMR(75MHz,CDCl3)δ:196.80,160.79,151.26,150.23,149.22,
145.48,142.98,138.21,137.57,134.23,126.22,108.74,101.79,55.41,27.29,26.65,
21.92,21.81,21.29；ESI-Mass for C22H24N2O3:m/z 365.21[M++H].
Embodiment 8
(2E, 5E) -2- (3,4,5- trimethoxy benzylidene) -5- ((3,5,6- trimethylpyrazine -2- base) methylene)
The synthesis of cyclopentanone (Z8)
Reaction equation
Reaction step: operating to obtain Z8 yellow crystals 2.31g by 1.3 methods in embodiment 1, yield 58.7%,
m.p.192.6-193.8℃。1H NMR(300MHz,CDCl3) δ 7.66 (t, J=3.0Hz, 1H, Py-CH=), 7.53 (t, J=
3.0Hz, 1H, Ar-CH=), 6.87 (s, 2H, ArH), 3.92 (s, 6H, OCH3×2),3.91(s,3H,OCH3),3.43-3.37
(m,2H,CH2),3.13-3.07(m,2H,CH2),2.67(s,3H,CH3),2.54(s,3H,CH3),2.53(s,3H,CH3)；13C
NMR(75MHz,CDCl3)δ:196.61,153.23,151.25,150.21,149.19,145.51,143.03,139.56,
136.88,134.47,131.38,126.07,108.17,61.00,56.22,56.13,27.31,26.56,21.92,21.80,
21.29；ESI-Mass for C23H26N2O4:m/z 395.20[M++H].
Embodiment 9
The synthesis of (2E, 5E) -2,5- two ((3,5,6- trimethylpyrazine -2- base) methylene) cyclopentanone (Z9)
Reaction equation
Reaction step: operating to obtain Z9 light yellow crystal 1.57g by 1.3 methods in embodiment 1, yield 45.3%,
m.p.210.4-211.4℃。1H NMR(300MHz,CDCl3) δ 7.67 (s, 2H ,=CH × 2), 3.33 (s, 4H, CH2×2),
2.67(s,6H,CH3×2),2.54(s,6H,CH3×2),2.52(s,6H,CH3×2)；13C NMR(75MHz,CDCl3)δ:
197.37,151.29,150.23,149.22,145.52,143.52,126.46,27.39,21.90,21.78,21.28；ESI-
Mass for C21H24N4O:m/z 349.23[M++H].
Embodiment 10
The synthesis of (2E, 5E) -2,5- two ((3,5,6- trimethylpyrazine -2- base) methylene) cyclohexanone (Z10)
Reaction equation
Reaction step: operating to obtain Z10 yellow crystals 1.83g by 1.3 methods in embodiment 1, yield 50.6%,
m.p.198.4-199.2℃。1H NMR(300MHz,CDCl3) δ 7.76 (s, 2H ,=CH × 2), 3.16-3.11 (m, 4H, CH2×
2),2.57(s,6H,CH3×2),2.51(s,6H,CH3×2),2.50(s,6H,CH3×2),1.81-1.72(m,2H,CH2)；13C NMR(75MHz,CDCl3)δ:190.75,150.63,150.02,148.66,145.84,141.12,130.06,28.37,
22.25,21.83,21.69,21.38；ESI-Mass for C22H26N4O:m/z 363.23[M++H]。
Claims (5)
1. the ligustrazine derivant or its pharmaceutically acceptable salt of logical formula (I) or (II):
Wherein R1、R3It is independently represented each other H or OCH3,
R2Represent H, CH3、OCH3, Cl, Br or N (CH3)2；
N=0 or 1.
2. the ligustrazine derivant of claim 1 or its pharmaceutically acceptable salt, be following any structure compound or its
Pharmaceutically acceptable salt:
3. the compound of claim 1 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt be compound (I) or
(II) hydrochloride, sulfate, phosphate, maleate, fumarate, citrate, mesylate, tosilate,
Tartaric acid or acetate.
4. a kind of pharmaceutical composition, wherein the compound containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically may be used
The carrier of receiving.
5. the purposes that the compound of claim 1 or its pharmaceutically acceptable salt are used to prepare anti-tumor drug.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212008A (en) * | 2010-04-09 | 2011-10-12 | 暨南大学 | Tanshinol ligustrazine derivative and preparation method and application thereof |
| CN102234283A (en) * | 2010-04-23 | 2011-11-09 | 湖北工业大学 | 4'-demethyl epipodophyllotoxin derivatives, and synthesis method and application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102212008A (en) * | 2010-04-09 | 2011-10-12 | 暨南大学 | Tanshinol ligustrazine derivative and preparation method and application thereof |
| CN102234283A (en) * | 2010-04-23 | 2011-11-09 | 湖北工业大学 | 4'-demethyl epipodophyllotoxin derivatives, and synthesis method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Investigation of fatty acid conjugates of 3,5-bisarylmethylene-4-piperidone derivatives as antitumor agents and human topoisomerase-IIα inhibitors;Elizabeth Potter，et al.;《Bioorganic & Medicinal Chemistry》;20151231;第23卷;第411-421页 |
| 新型姜黄素衍生物的合成及其抗癌活性研究;林锦璇等;《中国实验方剂学杂志》;20141231;第20卷(第7期);第113-117页 |
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