CN102786484B - Ligustrazine methanoyl cinnamic acid derivative and preparation method thereof and application - Google Patents
Ligustrazine methanoyl cinnamic acid derivative and preparation method thereof and application Download PDFInfo
- Publication number
- CN102786484B CN102786484B CN201210297075.1A CN201210297075A CN102786484B CN 102786484 B CN102786484 B CN 102786484B CN 201210297075 A CN201210297075 A CN 201210297075A CN 102786484 B CN102786484 B CN 102786484B
- Authority
- CN
- China
- Prior art keywords
- ligustrazine
- methanoyl
- cinnamic acid
- acid derivative
- trimethylpyrazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to Ligustrazine methanoyl cinnamic acid derivative and preparation method thereof and application, there is following general structure: wherein R is one or more combinations in hydrogen, hydroxyl, halogen atom substituent or methoxyl group, and R ' is-H ,-CH
3or-C
2h
5.Ligustrazine methanoyl cinnamic acid derivative of the present invention can be used as medicament for resisting platelet aggregation or vascular endothelial cell protection medicinal application.Cinnamate group in Ligustrazine methanoyl cinnamic acid derivative has definite platelet aggregation inhibitory activity and anti-oxidant activity, and can produce phenolic hydroxyl group, to play antioxygenation with comparatively faster speed hydrolysis in vivo.Ligustrazine methanoyl cinnamic acid derivative does not have the side effect of calcium channel blocker in addition, and can not produce amine substance.
Description
Technical field
The present invention relates to ligustrazine derivant, particularly Ligustrazine methanoyl cinnamic acid derivative and its preparation method and application, belongs to medicament against cardiovascular disease technical field.
Background technology
Cardiovascular and cerebrovascular diseases is a kind of disease of serious harm human health, has " high incidence, high disability rate, high mortality, high relapse rate, many complication " the i.e. feature of " four is high by more than ".According to statistics, the death toll that the whole world is caused by various cardiovascular and cerebrovascular diseases is in the first place of various Death causes.In China, cardiovascular and cerebrovascular diseases sickness rate constantly raises, the death toll caused by cardiovascular and cerebrovascular diseases every year nearly 3,000,000, while serious threat human health, also brings heavy economical load to society.Therefore, one of cardiovascular medicament important content being still drug research is researched and developed.
Chuanxiong is the dry rhizome of samphire Ligusticum wallichii, has out the effects such as strongly fragrant eliminating dampness, wind-expelling pain-stopping.Ligustrazine is isolated alkaloid from Ligusticum wallichii, and be its principle active component, chemical structure is 2，3，5，6-tetramethylpyrazine (Tetramethylpyrazine, TMP), and structural formula is as follows:
Ligustrazine has the diversified pharmacological actions such as vasodilation, platelet aggregation-against, scavenging free radicals, is therefore widely used in the treatment of the disease such as ischemic cerebrovascular and coronary atherosclerosis clinically.But Ligustrazine pharmacokinetic display in vivo, the features such as its bioavailability is low, metabolism is fast, the transformation period is short make it apply to be restricted (first superfine see journey, the structure of modification of Ligustrazine and modification, pharmacy is in progress, 2005,6 (29), 241-246).Therefore take Ligustrazine as lead compound, structural modification and transformation are carried out to it, research and development Ligustrazine class cardiovascular medicament of new generation is had great importance.
According to the principle of hybridization in medicinal design; Ligustrazine was once combined with the cinnamic acid substituting group with phenolic hydroxyl group by this seminar; obtain a series of Ligustrazine styracin phenolic ether analog derivative; and the inhibit activities experiment of the platelet aggregation of ADP induction and the activity experiment of protection vascular endothelial cell peroxide injury have been carried out to it, find that part has compared with high antiplatelet aggregation activity and compound vascular endothelial cell to better protecting activity.(see HongfeiChen, GuoningLi, PengZhan, XinyongLiu, Ligustrazinederivatives.Part5:Design, synthesisandbiologicalevaluationofnovelligustrazinyloxy-cinnamicacidderivativesaspotentcardiovascularagents, EuropeanJournalofMedicinalChemistry, 2011, 46, 5609-5615) on this basis, further structural modification is carried out to Ligustrazine, design and synthesis Ligustrazine methanoyl cinnamic acid derivative, to finding Ligustrazine class cardiovascular medicament of new generation.
Summary of the invention
The present invention is to provide a kind of Ligustrazine methanoyl cinnamic acid derivative and its preparation method and application, and this analog derivative has the function of better platelet aggregation-against, protection vascular endothelial cell.
The technical scheme that the present invention takes is:
Ligustrazine methanoyl cinnamic acid derivative, has following general structure:
Wherein R is one or more combinations in hydrogen, hydroxyl, halogen atom substituent or methoxyl group, and R ' is-H ,-CH
3or-C
2h
5.
Described Ligustrazine methanoyl cinnamic acid derivative, preferably:
(E)-3-(4-((3, 5, 6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) ethyl propenoate, (E)-3-(3-((3, 5, 6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid, (E)-3-(2-((3, 5, 6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid, (E)-3-(4-methoxyl group-3-((3, 5, 6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid, (E)-3-(3-hydroxyl-4-((3, 5, 6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid, (E)-3-(3-hydroxyl-4-((3, 5, 6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) ethyl propenoate.
The preparation method of above-mentioned Ligustrazine methanoyl cinnamic acid derivative, comprises step as follows:
(1) get Ligustrazine soluble in water, stir under 30-40 ° of C condition and slowly add KMnO
4the aqueous solution, reaction 10-30h, TLC monitoring react completely after, in reaction solution, add the paramount potassium manganate red-purple of bisulfite saturated aqueous solution of sodium take off completely, filter mixed liquor, filter residue hot water (30-40 ° of C) cleaning, merging filtrate, concentrated hydrochloric acid reconciles pH=2-3, extraction into ethyl acetate, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent obtains 3,5,6-trimethylpyrazine-2-formic acid;
(2) get 3,5,6-trimethylpyrazine-2-formic acid and be dissolved in anhydrous methylene chloride, add oxalyl chloride under condition of ice bath, stirring reaction 0.5-1h, TLC monitoring, to after reacting completely, removes residual solvent and oxalyl chloride under reduced pressure, obtains 3,5,6-trimethylpyrazine-2-formyl chloride;
(3) substituted benzaldehyde is dissolved in pyridine, adds propanedioic acid and piperidines, under 120 ° of C, react 1-2h, TLC monitoring after completion of the reaction, steam except pyridine, resistates is dissolved in water, and adjusts pH for 2-3, extraction into ethyl acetate with HCl, organic layer is dry, and filter, steaming desolventizes, and obtains substituted cinnamic acid;
(4) 3,5, the 6-trimethylpyrazine-2-formyl chlorides getting step (2) are dissolved in anhydrous methylene chloride, substituted cinnamic acid, triethylamine is added under stirring at room temperature, after 20-30 ° of C reaction 0.5-1h, TLC monitoring reacts completely, steam except residual solvent, residue is dissolved in ethyl acetate, use water, saturated NaCl solution washing respectively, organic over anhydrous dried over sodium sulfate, filter, concentrate to obtain crude product, be separated through quick post, ethyl alcohol recrystallization obtains sterling Ligustrazine methanoyl styracin;
(5) getting Ligustrazine methanoyl styracin is dissolved in ethanolic soln, dropwise add sulfur oxychloride under condition of ice bath, reaction solution reflux 24h, TLC monitoring is to reacting completely, steam except residual solvent, resistates is dissolved in ethyl acetate, and respectively with water, saturated sodium-chloride water solution washing, organic layer is by anhydrous sodium sulfate drying, filter, concentrate to obtain crude product, quick post is separated, and normal hexane recrystallization obtains product.
In above-mentioned preparation method:
Ligustrazine described in step (1) and KMnO
4mol ratio be 1:1 ~ 4, preferred 1:4, the mass/volume of Ligustrazine and water is than being 1:25, g/mL.
In step (2), the mol ratio of 3,5,6-trimethylpyrazine-2-formic acid and oxalyl chloride is 1:1 ~ 2, and preferred 1:1,3,5,6-trimethylpyrazine-2-formic acid is 1:25, g/mL with the mass/volume ratio of anhydrous methylene chloride.
In step (3), the mol ratio of substituted benzaldehyde, propanedioic acid and piperidines is 1:1:0.1, and substituted benzaldehyde is 1:25, g/mL with the mass/volume ratio of pyridine.Substituted benzaldehyde is: 4-hydroxy benzaldehyde, 3-hydroxy benzaldehyde, Benzaldehyde,2-hydroxy, Vanillin, 3-hydroxyl-4-methoxybenzaldehyde, 2-hydroxy 3-methoxybenzene formaldehyde, 2-hydroxyl-4-methoxybenzaldehyde, 2-hydroxy-5-methyl oxygen benzaldehyde, 4-hydroxyl-3,5-dimethoxy benzaldehyde, 3,4-Dihydroxy benzaldehyde, 2-hydroxyl-5-chlorobenzaldehyde or 3,4,5-tri hydroxybenzaldehyde.
In step (4), the mol ratio of 3,5,6-trimethylpyrazine-2-formyl chlorides, substituted cinnamic acid, triethylamine is 1:1:3,3,5,6-trimethylpyrazine-2-formyl chloride is 1:25-30, g/mL with the mass/volume ratio of anhydrous methylene chloride.
In step (5), the mol ratio of Ligustrazine methanoyl styracin and sulfur oxychloride is 1:1.2, and Ligustrazine methanoyl styracin is 1:30, g/mL with the mass/volume ratio of ethanol.
The synthetic route of Ligustrazine methanoyl cinnamic acid derivative is as follows:
In above-mentioned reaction formula, wherein R is H, OH, halogen atom or methoxyl group or these substituent independent assortments, and R ' is H or C
2h
5.Reagent: (i) propanedioic acid, pyridine, piperidines, 120 ° of C, (ii) KMnO
4, H
2o, 35 ° of C, (iii) oxalyl chloride, methylene dichloride, ice bath, (iv) Et
3n, methylene dichloride, rt, (v) EtOH, SOCl
2, backflow.
The Ligustrazine methanoyl cinnamic acid derivative that table 1. synthesizes
Ligustrazine methanoyl cinnamic acid derivative of the present invention can be used as medicament for resisting platelet aggregation or vascular endothelial cell protection medicinal application.Specifically, protect medicine for the preparation of medicament against cardiovascular disease as medicament for resisting platelet aggregation or vascular endothelial cell.In activity test, show good activity, prove that this compounds has the value of research and development further, the lead compound that can be used as resisting cardiovascular disease is used.
A kind of medicament against cardiovascular disease composition, is made up of Ligustrazine methanoyl cinnamic acid derivative of the present invention and pharmaceutically acceptable auxiliary material.
The invention has the beneficial effects as follows compared with the prior art:
Compared with prior art, Ligustrazine acid of the present invention is by KMnO from Ligustrazine
4carry out direct oxidation to obtain.Prior art route is then be oxidized through single nitrogen by Ligustrazine, and Boekelheide resets, hydrolysis, the process of oxidation and obtained Ligustrazine acid.Wherein single nitrogen oxidation, hydrolysis reaction two-step reaction is consuming time longer, and Boekelheide rearrangement needs high-temperature anhydrous, severe reaction conditions, and total reaction yield is low.The present invention by Ligustrazine directly with KMnO
4oxidation, by controlling temperature of reaction and reaction times, a step obtains Ligustrazine acid, and yield is higher, can reach more than 60%.
Compare with Ligustrazine acid amides with Liyustrazine acyl piperazine, Ligustrazine methanoyl cinnamic acid derivative is the compound being combined with various styracin by Ligustrazine formyl radical and obtaining.Liyustrazine acyl piperazine is that nicotinoyl etc. are put together with piperazine ring by Ligustrazine and acetyl salicylic acyl group, and Ligustrazine acid amides is then by Ligusticum wallichii amine and salicyloyl, and 2-pyridine acyl etc. is put together.Compared with the group in this two compounds, cinnamate group in Ligustrazine methanoyl cinnamic acid derivative has definite platelet aggregation inhibitory activity and anti-oxidant activity, and phenolic hydroxyl group can be produced, to play antioxygenation with comparatively faster speed hydrolysis in vivo.Ligustrazine methanoyl cinnamic acid derivative does not have the side effect of calcium channel blocker in addition, and can not produce amine substance.
Embodiment
Further illustrate below in conjunction with embodiment.
The preparation of embodiment 1.3,5,6-trimethylpyrazine-2-formyl chloride
Get Ligustrazine (13.6g, 0.1mol) water-soluble, slowly add KMnO
4the aqueous solution of (63.2g, 0.4mol), in 35 ° of C stirring reaction 24h.TLC monitoring is to reacting completely, in reaction solution, add the paramount potassium manganate red-purple of bisulfite saturated aqueous solution of sodium take off completely, filter mixed liquor, filter residue hot water (30-40 ° of C) cleans, merging filtrate, concentrated hydrochloric acid reconciles pH=2-3, extraction into ethyl acetate, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent.Solid, with re-crystallizing in ethyl acetate, obtains 3,5,6-trimethylpyrazine-2-formic acid, productive rate 67%.Get 0.1mol3,5,6-trimethylpyrazine-2-formic acid is dissolved in anhydrous methylene chloride, adds 0.1mol oxalyl chloride under condition of ice bath, stirring reaction 0.5h, TLC monitoring, to after reacting completely, removes residual solvent and oxalyl chloride under reduced pressure, obtain 3,5,6-trimethylpyrazine-2-formyl chloride.
The preparation of embodiment 2. (E)-3-(4-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (F1)
Negate formula 4-hydroxycinnamic acid (0.33g, 2mmol), is dissolved in 10mL methylene dichloride, adds triethylamine (0.51g, 6mmol), stir 5min, add 3,5,6-trimethylpyrazine-2-formyl chloride (0.37g, 2mmol), stirred at ambient temperature reaction 2h.TLC monitoring after completion of the reaction, remove solvent under reduced pressure, resistates adds 50mL ethyl acetate, washing, and organic layer is with anhydrous sodium sulfate drying, filter, steaming desolventizes, and the quick post of crude product obtained is separated (ethyl acetate: hexanaphthene=1:5), and ethyl alcohol recrystallization obtains product, productive rate 63%, mp:212-214 ° of C.
1H-NMR(600MHz,CDCl
3,δppm):12.46(s,1H,COOH)，7.82(d，2H，Ar-H，J=8.4Hz)，7.65(d，1H，Ar-
CH=C，J=15.6Hz)，7.35(d，2H，Ar-H，J=7.8Hz),6.57(d,1H,C=
CH-C=O,J=15.6Hz),2.72(s,3H,CH
3),2.57(s,3H,CH
3),2.55(s,3H,CH
3).IR(KBr，cm
-1):3400(OH),2925(CH
3),1743,1693(C=O),1628(C=C),1599,1583,1506(C=N,C=C),1164(C-O).ESI-MS:313.3(M+H)
+,calcd.forC
17H
16N
2O
4312.32.
The preparation of embodiment 3. (E)-3-(3-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (F2)
Get 3-hydroxycinnamic acid (0.33g, 2mmol), be dissolved in 10mL methylene dichloride, add triethylamine (0.51g, 6mmol), stir 5min, add 3,5,6-trimethylpyrazine-2-formyl chloride (0.37g, 2mmol), stirred at ambient temperature reaction 2h.TLC monitoring after completion of the reaction, remove solvent under reduced pressure, resistates adds 50mL ethyl acetate, washing, and organic layer is with anhydrous sodium sulfate drying, filter, steaming desolventizes, and the quick post of crude product obtained is separated (ethyl acetate: hexanaphthene=1:5), and ethyl alcohol recrystallization obtains product, productive rate 54%, mp:208-210 ° of C.
1h-NMR (600MHz, CDCl
3, δ ppm): 12.50 (s, 1H, COOH), 7.68-7.61 (m, 3H, Ar-H, Ar-
cH=C), 7.54 (t, 1H, Ar-H), 7.36 (dd, 1H, Ar-H, J
1=1.2Hz, J
2=7.8Hz), 6.63 (d, 1H, C=
cH-C=O, J=16.2Hz), 2.73 (s, 3H, CH
3), 2.57 (s, 3H, CH
3), 2.55 (s, 3H, CH
3) .IR (KBr, cm
-1): 3450 (OH), 2966,2852 (CH
3), 1736,1692 (C=O), 1631 (C=C), 1580,1539 (C=N, C=C), 1172 (C-O) .ESI-MS:313.4 (M+H)
+, calcd.forC
17h
16n
2o
4312.32.
The preparation of embodiment 4. (E)-3-(2-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (F3)
Get 2 hydroxy cinnamic acid 98 (0.33g, 2mmol), be dissolved in 10mL methylene dichloride, add triethylamine (0.51g, 6mmol), stir 5min, add 3,5,6-trimethylpyrazine-2-formyl chloride (0.37g, 2mmol), stirred at ambient temperature reaction 2h.TLC monitoring after completion of the reaction, remove solvent under reduced pressure, resistates adds 50mL ethyl acetate, washing, and organic layer is with anhydrous sodium sulfate drying, filter, steaming desolventizes, and the quick post of crude product obtained is separated (ethyl acetate: hexanaphthene=1:5), and ethyl alcohol recrystallization obtains product, productive rate 57%, mp:204-206 ° of C.
1h-NMR (600MHz, CDCl
3, δ ppm): 12.48 (s, 1H, COOH), 7.94 (d, 1H, Ar-H, J=7.8Hz), 7.67 (d, 1H, Ar-
cH=C, J=15.6Hz), 7.56-7.53 (t, 1H, Ar-H), 7.42-7.38 (m, 2H, Ar-H), 6.75 (d, 1H, C=
cH-C=O, J=15.6Hz), 2.71 (s, 3H, CH
3), 2.58 (s, 3H, CH
3), 2.50 (s, 3H, CH
3) .IR (KBr, cm
-1): 3450 (OH), 2980,2929 (CH
3), 1733,1692 (C=O), 1627 (C=C), 1577,1543 (C=N, C=C), 1166 (C-O) .ESI-MS:313.4 (M+H)
+, calcd.forC
17h
16n
2o
4312.32.
The preparation of embodiment 5. (E)-3-(3-methoxyl group-4-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (F4)
Get ferulic acid (0.38g, 2mmol), be dissolved in 11.4mL methylene dichloride, add triethylamine (0.51g, 6mmol), stir 5min, add 3,5,6-trimethylpyrazine-2-formyl chloride (0.37g, 2mmol), stirred at ambient temperature reaction 2h.TLC monitoring after completion of the reaction, remove solvent under reduced pressure, resistates adds 50mL ethyl acetate, washing, and organic layer is with anhydrous sodium sulfate drying, filter, steaming desolventizes, and the quick post of crude product obtained is separated (ethyl acetate: hexanaphthene=1:5), and ethyl alcohol recrystallization obtains product, productive rate 61%, mp:214-218 ° of C.
1h-NMR (600MHz, CDCl
3, δ ppm): 12.44 (s, 1H, COOH), 7.63 (d, 1H, Ar-
cH=C, J=15.6Hz), 7.56 (s, 1H, Ar-H), 7.34 (d, 1H, Ar-H, J=7.8Hz), 7.30 (d, 1H, Ar-H, J=7.8Hz), 6.65 (d, 1H, C=
cH-C=O, J=16.2Hz), 3.85 (s, 3H, OCH
3), 2.70 (s, 3H, CH
3), 2.56 (s, 3H, CH
3), 2.51 (s, 3H, CH
3) .IR (KBr, cm
-1): 3422 (OH), 2924,2852 (CH
3), 1745,1696 (C=O), 1630 (C=C), 1591 (C=N, C=C), 1152 (C-O) .ESI-MS:343.4 (M+H)
+, calcd.forC
18h
18n
2o
5342.35.
The preparation of embodiment 6. (E)-3-(4-methoxyl group-3-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (F5)
Get 3-hydroxyl-4-methoxy cinnamic acid (0.38g, 2mmol), be dissolved in 11.4mL methylene dichloride, add triethylamine (0.51g, 6mmol), stir 5min, add 3,5,6-trimethylpyrazine-2-formyl chloride (0.37g, 2mmol), stirred at ambient temperature reaction 2h.TLC monitoring after completion of the reaction, remove solvent under reduced pressure, resistates adds 50mL ethyl acetate, washing, and organic layer is with anhydrous sodium sulfate drying, filter, steaming desolventizes, and the quick post of crude product obtained is separated (ethyl acetate: hexanaphthene=1:5), and ethyl alcohol recrystallization obtains product, productive rate 64%, mp:202-204 ° of C.
1h-NMR (600MHz, CDCl
3, δ ppm): 12.36 (s, 1H, COOH), 7.68-7.61 (m, 3H, Ar-H, Ar-
cH=C), 7.24 (d, 1H, Ar-H, J=8.4Hz), 6.48 (d, 1H, C=
cH-C=O, J=16.2Hz), 3.84 (s, 3H, OCH
3), 2.71 (s, 3H, CH
3), 2.57-2.49 (m, 6H, CH
3× 2) .IR (KBr, cm
-1): 3488 (OH), 2957,2927,2848 (CH
3), 1753,1720 (C=O), 1636 (C=C), 1610 (C=N, C=C), 1161 (C-O) .ESI-MS:343.5 (M+H)
+, calcd.forC
18h
18n
2o
5342.35.
The preparation of embodiment 7. (E)-3-(4-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) ethyl propenoate (F ' 1)
Get (E)-3-(4-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (0.62g, 2mmol) is dissolved in ethanol, slowly drip 2.4mmol sulfur oxychloride under condition of ice bath, drip complete reflux 24h.TLC monitoring is to reacting completely, and steaming is except residual solvent, and resistates is dissolved in ethyl acetate, and respectively with water, saturated sodium-chloride water solution washing, organic layer, by anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product.Quick post is separated, normal hexane recrystallization, productive rate 81%, mp:77-80 ° of C.
1h-NMR (600MHz, CDCl
3, δ ppm): 7.82 (d, 2H, Ar-H, J=8.4Hz), 7.65 (d, 1H, Ar-
cH=C, J=15.6Hz), 7.35 (d, 2H, Ar-H, J=7.8Hz), 6.57 (d, 1H, C=
cH-C=O, J=15.6Hz), 4.23 (q, 2H, OCH
2), 2.72 (s, 3H, CH
3), 2.57 (s, 3H, CH
3), 2.55 (s, 3H, CH
3), 1.30 (t, 3H, CH
3) .IR (KBr, cm
-1): 3063 (C=
c-H), 2988,2929 (CH
3), 1747,1712 (C=O), 1642 (C=C), 1601,1541,1509 (C=N, C=C), 1169 (C-O) .ESI-MS:341.4 (M+H)
+, calcd.forC
19h
20n
2o
4340.37.
The preparation of embodiment 8. (E)-3-(3-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) ethyl propenoate (F ' 2)
Get (E)-3-(3-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (0.62g, 2mmol) is dissolved in ethanol, slowly drip 2.4mmol sulfur oxychloride under condition of ice bath, drip complete reflux 24h.TLC monitoring is to reacting completely, and steaming is except residual solvent, and resistates is dissolved in ethyl acetate, and respectively with water, saturated sodium-chloride water solution washing, organic layer, by anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product.Quick post is separated, normal hexane recrystallization, productive rate 81%, mp:87-91 ° of C.
1h-NMR (600MHz, CDCl
3, δ ppm): 7.68-7.61 (m, 3H, Ar-H, Ar-
cH=C), 7.54 (t, 1H, Ar-H), 7.36 (dd, 1H, Ar-H, J
1=1.2Hz, J
2=7.8Hz), 6.63 (d, 1H, C=
cH-C=O, J=16.2Hz), 2.73 (s, 3H, CH
3), 4.23 (q, 2H, OCH
2), 2.57 (s, 3H, CH
3), 2.55 (s, 3H, CH
3), 1.30 (t, 3H, CH
3) .IR (KBr, cm
-1): 3061 (C=
c-H), 2977,2927 (CH
3), 1731,1716 (C=O), 1637 (C=C), 1604,1583,1541 (C=N, C=C), 1169 (C-O) .ESI-MS:341.4 (M+H)
+, calcd.forC
19h
20n
2o
4340.37.
The preparation of embodiment 9. (E)-3-(2-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) ethyl propenoate (F ' 3)
Get (E)-3-(2-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (0.62g, 2mmol) is dissolved in ethanol, slowly drip 2.4mmol sulfur oxychloride under condition of ice bath, drip complete reflux 24h.TLC monitoring is to reacting completely, and steaming is except residual solvent, and resistates is dissolved in ethyl acetate, and respectively with water, saturated sodium-chloride water solution washing, organic layer, by anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product.Quick post is separated, normal hexane recrystallization, productive rate 81%, mp:77-79 ° of C.
1h-NMR (600MHz, CDCl
3, δ ppm): 12.48 (s, 1H, COOH), 7.94 (d, 1H, Ar-H, J=7.8Hz), 7.67 (d, 1H, Ar-
cH=C, J=15.6Hz), 7.56-7.53 (t, 1H, Ar-H), 7.42-7.38 (m, 2H, Ar-H), 6.75 (d, 1H, C=
cH-C=O, J=15.6Hz), 4.23 (q, 2H, OCH
2), 2.71 (s, 3H, CH
3), 2.58 (s, 3H, CH
3), 2.50 (s, 3H, CH
3), 1.30 (t, 3H, CH
3) .IR (KBr, cm
-1): 3080 (C=
c-H), 2988,2957 (CH
3), 1745,1705 (C=O), 1629 (C=C), 1601,1577,1541 (C=N, C=C), 1151 (C-O) .ESI-MS:341.4 (M+H)
+, calcd.forC
19h
20n
2o
4340.37.
The preparation of embodiment 10. (E)-3-(3-methoxyl group-4-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) ethyl propenoate (F ' 4)
Get (E)-3-(3-methoxyl group-4-((3,5,6-trimethylpyrazine-2-carbonyl) oxygen) phenyl) vinylformic acid (0.68g, 2mmol) be dissolved in ethanol, slowly drip 2.4mmol sulfur oxychloride under condition of ice bath, drip complete reflux 24h.TLC monitoring is to reacting completely, and steaming is except residual solvent, and resistates is dissolved in ethyl acetate, and respectively with water, saturated sodium-chloride water solution washing, organic layer, by anhydrous sodium sulfate drying, filters, and concentrates to obtain crude product.Quick post is separated, normal hexane recrystallization, productive rate 81%, mp:107-110 ° of C.
1h-NMR (600MHz, CDCl
3, δ ppm): 7.70 (d, 1H, Ar-
cH=C, J=16.2Hz), 7.61 (s, 1H, Ar-H), 7.38 (d, 1H, Ar-H, J=7.8Hz), 7.31 (d, 1H, Ar-H, J=8.4Hz), 6.77 (d, 1H, C=
cH-C=O, J=15.6Hz), 4.23 (q, 2H, OCH
2), 3.86 (s, 3H, OCH
3), 2.70 (s, 3H, CH
3), 2.56 (s, 3H, CH
3), 2.51 (s, 3H, CH
3), 1.30 (t, 3H, CH
3) .IR (KBr, cm
-1): 3064 (C=
c-H), 2983,2928 (CH
3), 1737,1703 (C=O), 1676 (C=C), 1601,1510 (C=N, C=C), 1158 (C-O) .ESI-MS:371.4 (M+H)
+, calcd.forC
20h
22n
2o
5370.40.
The Activity Screening Test of Ligustrazine methanoyl cinnamic acid derivative:
Carried out platelet aggregation-against test to Ligustrazine methanoyl cinnamic acid derivative, experimental procedure is as follows:
Rabbit Heart gets blood, Trisodium Citrate BP anti-freezing (v/v blood: antithrombotics=9:1) with 3.8%, after leaving standstill 30min, namely obtain Platelet-rich plasm (PRP) by getting supernatant liquor after centrifugal for its 1000rpmin 5min, namely remainder is obtained platelet poor plasma (PPP) to get supernatant liquor after the centrifugal 15min of 3000rpmin.Number is adjusted to be 3 × 10 PRP with PPP
11/ L (counting with tally under microscope) for subsequent use.The PRP prepared should be finished in 2h.
Get 90 μ LPRP, add in 96 orifice plates, add 5 μ L candidate drug (final concentration 400,200,100,50 μMs), 37 DEG C of incubation jolting 5min.Be placed in microplate reader by 96 orifice plates, jolt 10S fast, measure absorbancy under 570nm, every 30S measures once, surveys 3 times continuously, remembers that each Kong Sanci absorbancy average is A
0.Add 5 μ LADP (working concentration 5 μMs) afterwards, continue every 30S and measure an absorbancy until absorbancy no longer changes, the absorbancy average of note parallel hole is A.
Result OD
570nmwith
represent, whether significant difference is had between t check analysis test group and control group, calculate platelet aggregation rate (aggregationrate, AR) as follows: AR=(AbsPRP-Abssample)/(AbsPRP-AbsPPP).Calculate medicine to the inhibiting rate (aggregationinhibitionrate, AIR) of platelet aggregation: AIR=[1-(delivery tube is assembled percentage/control tube and assembled percentage)] × 100% simultaneously.The half-inhibition concentration IC of medicine is obtained with return law of the straight line
50.
With ozagrel (ozagrel), clopidogrel (clopidogrel) is positive control, and its activity is listed in table 2.As can be seen from Table 2, compound F 17-hydroxy-corticosterone ' 1, F2, F3 show obvious platelet aggregation inhibitory activity, IC
50reach 24.4,26.4 and 9.59 μMs respectively, activity is better than contrast medicine ozagrel (IC
50=144 μMs), wherein compound F 17-hydroxy-corticosterone 3 activity is the strongest, close to contrast medicine clopidogrel (IC
50=7.57 μMs).
The L-Arginine of table 2. Ligustrazine methanoyl cinnamic acid derivative
IC
50: the half-inhibition concentration that compounds on platelet is assembled
Also carried out vascular endothelial cell damage protection test to Ligustrazine methanoyl cinnamic acid derivative, experimental procedure is as follows:
After Ea.hy926 cell cultivates 24h in the RPMI-1640 nutrient solution containing 10% calf serum, add in normal group containing H
2o
2with the normal nutrient solution of medicine, in model group, add concentration is 0.15mmol.L
-1h
2o
2nutrient solution, add in protection group containing different concns medicine and containing final concentration be 0.15mmol.L
-1h
2o
2nutrient solution, continue to cultivate 12h, then every hole adds 0.01mLMTT solution (5mg.mL
-1), cultivate 4h for 37 DEG C, incline supernatant liquor, and every hole adds dimethyl sulfoxide (DMSO) 0.lmL, places 10min.The inherent full-automatic microplate reader of 30min measures absorbance (A in 570nm place
570nm), calculate Ea.hy926 cell proliferation percentage.
Result OD
570nmwith
represent, whether have significant difference between t check analysis test group and control group, be calculated as follows cell proliferation rate P (%).
(OD-protection group OD value, ODa-model group OD value, OD
b-normal group OD value)
With Thioctic Acid (lipoicacid) and butylated hydroxy anisole (BHA) for contrast, its activity is listed in table 3, and.As can be seen from Table 3, compound F 17-hydroxy-corticosterone 5, F10 and F ' 10 show obvious vascular endothelial cell damage prolection, EC
50reach 8.84,2.23 and 1.71 μMs respectively, activity is better than contrast medicine Thioctic Acid and BHA(EC
50be respectively 68.0 μMs and 111 μMs), wherein compound F 17-hydroxy-corticosterone ' 10 activity is the strongest, reaches 40 times of Thioctic Acid.
Table 3. Ligustrazine methanoyl cinnamic acid compound is to EA.hy926 cell proliferation rate and EC thereof
50
Claims (8)
1. Ligustrazine methanoyl cinnamic acid derivative, has following general structure:
Wherein
R is selected from-H ,-OH ,-Cl ,-Br ,-OCH
3; R ' is selected from-H or-C
2h
5.
2. the preparation method of Ligustrazine methanoyl cinnamic acid derivative according to claim 1, is characterized in that, comprise step as follows:
(1) get Ligustrazine soluble in water, stir under 30-40 DEG C of condition and slowly add KMnO
4the aqueous solution, reaction 10-30h, TLC monitoring react completely after, in reaction solution, add the paramount potassium manganate red-purple of bisulfite saturated aqueous solution of sodium take off completely, filter mixed liquor, filter residue hot water cleans, merging filtrate, concentrated hydrochloric acid regulates pH=2-3, extraction into ethyl acetate, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent obtains 3,5,6-trimethylpyrazine-2-formic acid;
(2) get 3,5,6-trimethylpyrazine-2-formic acid and be dissolved in anhydrous methylene chloride, under condition of ice bath, add oxalyl chloride, stirring reaction 0.5-1h, TLC monitoring, to after reacting completely, removes residual solvent and oxalyl chloride under reduced pressure, obtain 3,5,6-trimethylpyrazine-2-formyl chloride;
(3) substituted benzaldehyde is dissolved in pyridine, adds propanedioic acid and piperidines, at 120 DEG C, react 1-2h, TLC monitoring after completion of the reaction, steam except pyridine, resistates is dissolved in water, and adjusts pH for 2-3, extraction into ethyl acetate with HCl, organic layer is dry, and filter, steaming desolventizes, and obtains substituted cinnamic acid;
(4) 3,5, the 6-trimethylpyrazine-2-formyl chlorides getting step (2) are dissolved in anhydrous methylene chloride, substituted cinnamic acid, triethylamine is added under stirring at room temperature, after 20-30 DEG C of reaction 0.5-1h, TLC monitoring reacts completely, steam except residual solvent, residue is dissolved in ethyl acetate, use water, saturated NaCl solution washing respectively, organic over anhydrous dried over sodium sulfate, filter, concentrate to obtain crude product, be separated through quick post, ethyl alcohol recrystallization obtains sterling Ligustrazine methanoyl styracin;
(5) getting Ligustrazine methanoyl styracin is dissolved in ethanolic soln, dropwise add sulfur oxychloride under condition of ice bath, reaction solution reflux 24h, TLC monitoring is to reacting completely, steam except residual solvent, resistates is dissolved in ethyl acetate, and respectively with water, saturated sodium-chloride water solution washing, organic layer is by anhydrous sodium sulfate drying, filter, concentrate to obtain crude product, quick post is separated, and normal hexane recrystallization obtains product.
3. the preparation method of Ligustrazine methanoyl cinnamic acid derivative according to claim 2, is characterized in that, the Ligustrazine described in step (1) and KMnO
4mol ratio be 1:1 ~ 4, the mass/volume of Ligustrazine and water is than being 1:25, g/mL.
4. the preparation method of Ligustrazine methanoyl cinnamic acid derivative according to claim 2, it is characterized in that, in step (2) 3,5, the mol ratio of 6-trimethylpyrazine-2-formic acid and oxalyl chloride is 1:1 ~ 2,3,5,6-trimethylpyrazine-2-formic acid is 1:25, g/mL with the mass/volume ratio of anhydrous methylene chloride.
5. the preparation method of Ligustrazine methanoyl cinnamic acid derivative according to claim 2, it is characterized in that, in step (3), the mol ratio of substituted benzaldehyde, propanedioic acid and piperidines is 1:1:0.1, and substituted benzaldehyde is 1:25, g/mL with the mass/volume ratio of pyridine.
6. the preparation method of Ligustrazine methanoyl cinnamic acid derivative according to claim 2, it is characterized in that, in step (4) 3,5, the mol ratio of 6-trimethylpyrazine-2-formyl chloride, substituted cinnamic acid, triethylamine is 1:1:3,3,5,6-trimethylpyrazine-2-formyl chloride is 1:25-30, g/mL with the mass/volume ratio of anhydrous methylene chloride.
7. the preparation method of Ligustrazine methanoyl cinnamic acid derivative according to claim 2, it is characterized in that, in step (5), the mol ratio of Ligustrazine methanoyl styracin and sulfur oxychloride is 1:1.2, Ligustrazine methanoyl styracin is 1:30, g/mL with the mass/volume ratio of ethanol.
8. Ligustrazine methanoyl cinnamic acid derivative according to claim 1 is preparing the application in medicament for resisting platelet aggregation or vascular endothelial cell protection medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210297075.1A CN102786484B (en) | 2012-08-20 | 2012-08-20 | Ligustrazine methanoyl cinnamic acid derivative and preparation method thereof and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210297075.1A CN102786484B (en) | 2012-08-20 | 2012-08-20 | Ligustrazine methanoyl cinnamic acid derivative and preparation method thereof and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102786484A CN102786484A (en) | 2012-11-21 |
| CN102786484B true CN102786484B (en) | 2015-11-18 |
Family
ID=47152089
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210297075.1A Active CN102786484B (en) | 2012-08-20 | 2012-08-20 | Ligustrazine methanoyl cinnamic acid derivative and preparation method thereof and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102786484B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017165B (en) * | 2015-07-07 | 2018-04-03 | 广州喜鹊医药有限公司 | A kind of new pyrazines derivatives and preparation method thereof and medical applications |
| CN106977464B (en) * | 2016-01-15 | 2019-12-10 | 雷海民 | Ligustrazine substituted cinnamic acid derivative (LQC-W) with neuroprotective activity and application thereof |
| CN113620889B (en) * | 2021-08-23 | 2023-12-12 | 天津大学 | Ligustrazine memantine and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424313A (en) * | 2002-12-20 | 2003-06-18 | 山东大学 | Chuanxiong alkoxide derivative and its preparation and medicinal composition containing it and use thereof |
| CN102028690A (en) * | 2010-11-09 | 2011-04-27 | 山东大学 | Application of ligustrazine cinnamic acid phenolic ether derivatives in preparing medicines |
-
2012
- 2012-08-20 CN CN201210297075.1A patent/CN102786484B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424313A (en) * | 2002-12-20 | 2003-06-18 | 山东大学 | Chuanxiong alkoxide derivative and its preparation and medicinal composition containing it and use thereof |
| CN102028690A (en) * | 2010-11-09 | 2011-04-27 | 山东大学 | Application of ligustrazine cinnamic acid phenolic ether derivatives in preparing medicines |
Non-Patent Citations (2)
| Title |
|---|
| 川芎嗪体内代谢产物的合成;刘新泳等;《山东医科大学学报》;19970331;第35卷(第1期);83 * |
| 川芎嗪新型衍生物的设计、合成及其生物活性研究;陈洪飞;《中国优秀硕士学位论文全文数据库（医药卫生科技辑）》;20100915(第09期);E057-27 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102786484A (en) | 2012-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Singh et al. | 4-Aminoquinoline-ferrocenyl-chalcone conjugates: Synthesis and anti-plasmodial evaluation | |
| Rosini et al. | Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer’s disease | |
| Kim et al. | Synthesis and cytotoxicity of 1-substituted 2-methyl-1H-imidazo [4, 5-g] phthalazine-4, 9-dione derivatives | |
| Kim et al. | Synthesis and cytotoxicity of 3, 4-diaryl-2 (5H)-furanones | |
| EP1773775A1 (en) | Six-membered heterocycles useful as serine protease inhibitors | |
| CN101580477A (en) | Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments | |
| CN107501250B (en) | Benzofuranone analog derivative and its preparation method and application | |
| Öztürk et al. | Synthesis of 4 (1H)-pyridinone derivatives and investigation of analgesic and antiinflammatory activities | |
| Wang et al. | 4, 5-Diaryl-3H-1, 2-dithiole-3-thiones and related compounds as combretastatin A-4/oltipraz hybrids: Synthesis, molecular modelling and evaluation as antiproliferative agents and inhibitors of tubulin | |
| CN102786484B (en) | Ligustrazine methanoyl cinnamic acid derivative and preparation method thereof and application | |
| CN100586937C (en) | Ligustrazine stilbenoids derivatives, preparation method thereof, medicament composition and use | |
| CN105669657A (en) | Benzopyran-4-one substituted naphthalimide-polyamine conjugate and preparing method and usage thereof | |
| Tiwari et al. | Synthesis and pharmacological study of novel pyrido-quinazolone analogues as anti-fungal, antibacterial, and anticancer agents | |
| CN105153136A (en) | Brefeldin A ester derivatives, and preparation and application thereof | |
| CN103833756B (en) | One-class pyridazinone compounds and its production and use | |
| CN103554122A (en) | Chromone structure-containing pyrazole norcantharidin derivative as well as preparation method and application thereof | |
| CN106810560A (en) | A kind of synthetic method of 8 azepine cumarin and its application in antineoplastic | |
| CN111747921A (en) | Preparation method and medical application of daphnetin derivative | |
| Zhang et al. | Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer’s disease | |
| CN103382195A (en) | Benzopyran chalcone compound, and preparation method and application thereof | |
| CN103524559B (en) | Ester derivant of polysubstituted 4-methylamino benzenecarboximidamide and its production and use | |
| CN104387399A (en) | Synthetic method of oxidized nantenine and application of oxidized nantenine | |
| CN104326957B (en) | Aminoacetophenone thiosemicarbazone derivative and application thereof | |
| CN102250099B (en) | Non-peptide thrombin inhibitors as well as preparation method and medical application thereof | |
| CN108715589A (en) | A kind of coumarin derivatives and its application as caspase-3 activator |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |