CN112961143B - Ligustrazine derivative and preparation method thereof - Google Patents

Ligustrazine derivative and preparation method thereof Download PDF

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CN112961143B
CN112961143B CN202110157843.2A CN202110157843A CN112961143B CN 112961143 B CN112961143 B CN 112961143B CN 202110157843 A CN202110157843 A CN 202110157843A CN 112961143 B CN112961143 B CN 112961143B
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acid
pharmaceutically acceptable
ligustrazine
ligustrazine derivative
derivative
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CN112961143A (en
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杜恩明
宋宗明
王艳歌
陶冶
王刚
王月波
李苗
魏圆梦
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Henan Provincial Peoples Hospital
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • 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
    • C07D241/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention discloses a ligustrazine derivative and a preparation method thereof, comprising a compound shown in a general formula (I) or pharmaceutically acceptable salt thereof and application thereof in pharmacy, wherein Ar is selected from aryl, monosubstituted or polysubstituted aryl; x represents a linker separated by 4 atoms (C, N, O or S). The ligustrazine derivative can obviously activate ATP binding cassette transporter A1 (ABCA 1), and is used for regulating blood fat and treating or preventing atherosclerosis, hyperlipidemia, cardiovascular and cerebrovascular diseases, diabetes, inflammation, hypertension and other diseases. The invention also applies to the use of said compounds for up-regulating ABCA1 activity, and to pharmaceutical compositions for the treatment or prevention of said use, containing a therapeutically effective amount of an active ingredient selected from the group consisting of, optionally, a pharmaceutically acceptable carrier.

Description

Ligustrazine derivative and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a ligustrazine derivative and a preparation method thereof, a pharmaceutical composition containing the compound and medical application thereof, and particularly relates to the application of the compound in preparing medicines for treating or preventing atherosclerosis.
Background
Atherosclerosis (AS) is one of ischemic cardiovascular and cerebrovascular diseases, and is the pathological basis of various cardiovascular and cerebrovascular diseases. The cause of AS formation is complex, and most students consider that vascular endothelial cell injury caused by factors such AS hyperlipidemia is the initiating factor of AS formation at present. Studies have shown that rutaecarpine (Rutacarpine, 1) is capable of upregulating the activity of ATP-binding cassette transporter A1 (ABCA 1) (EC 50 =0.27 μmol/L), facilitating the efflux of excess cholesterol from peripheral tissue macrophages into lipid-depleted or lipid-free apolipoprotein a-I (ApoA-I) to form High Density Lipoprotein (HDL). HDL, in turn, can reduce the deposition of lipids on the vessel wall through the Reverse Cholesterol Transport (RCT) process, and can also protect the vessel against atherosclerosis by means of anti-inflammatory, antioxidant, antithrombotic and fibrinolytic effects. Based on the structure of rutaecarpine, researchers perform a great amount of structure optimization work and screen a series of rutaecarpine derivatives CD1 (2), CD6 (3), BCD1 (4) and BCD2 (5) with simplified structures, which show good up-regulation activity on ABCA1, and EC 50 The values were 0.81, 0.21, 0.035 and 0.121. Mu. Mol/L, respectively.
Ligustrazine (Ligustrazine) is an active alkaloid monomer extracted from rhizoma Ligustici Chuanxiong, and is a main active ingredient thereof, and has various cardiovascular and cerebrovascular pharmacological activities such as anticoagulation, platelet aggregation resistance, blood vessel dilation, myocardial ischemia reperfusion injury resistance, etc., and can be widely applied to the treatment of coronary atherosclerosis, ischemic cerebrovascular diseases, etc. clinically. The literature reports that ligustrazine has the effects of reducing free radical generation and scavenging free radicals, and simultaneously, ligustrazine can also play an anti-atherosclerosis role by resisting oxygen free radicals, blocking calcium inflow, relieving endothelial cell injury and repairing endothelial cell functions.
In order to find safer and more effective anti-atherosclerosis therapeutic drugs, the invention designs and synthesizes a series of ligustrazine derivatives, and discovers that the derivatives have the characteristics of high efficiency and low toxicity.
Disclosure of Invention
The invention aims to provide a ligustrazine derivative and a preparation method thereof, which solve the problems in the prior art.
In order to achieve the above purpose, the present invention provides the following technical solutions: a ligustrazine derivative and a preparation method thereof comprise a compound shown in a general formula (I) or pharmaceutically acceptable salt thereof:
wherein Ar is selected from aryl, monosubstituted or polysubstituted aryl;
x represents a linker separated by 4 atoms (C, N, O or S).
As a preferred embodiment of the present invention, the Ar represents: benzene, pyrrole, furan, thiophene, benzopyrrole, benzofuran, benzothiophene, quinoline, isoquinoline, and the like, and the substituent is selected from hydroxyl, amino, carboxyl, hydrogen, halogen, nitro, alkyl, alkoxy, and the like.
As a preferred embodiment of the present invention, said X represents: a linker containing amide, ester, ether, thioether, amine, C1-C4 alkyl.
As a preferred embodiment of the present invention, the process for preparing the compound or a pharmaceutically acceptable salt thereof comprises:
as a preferred embodiment of the present invention, the pharmaceutically acceptable salt is a salt of a compound of formula (I) with hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, citric acid, lactic acid, acetic acid, maleic acid, sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
As a preferred embodiment of the present invention, the preparation reaction conditions of the compound or a pharmaceutically acceptable salt thereof are:
a1, the activator is thionyl chloride (SOCl) 2 ) Oxalyl chloride ((COCl) 2 ) benzotriazole-N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), 1-hydroxybenzotriazole (HOBt), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), N, N ' -Carbonyldiimidazole (CDI);
a2 the catalyst is 4-Dimethylaminopyridine (DMAP), N-Diisopropylethylamine (DIEA), triethylamine (Et) 3 N), 1, 8-diazabicyclo undec-7-ene (DBU), sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like;
a3, the solvent is dichloromethane, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide and dimethylformamide;
a4, the reaction temperature is room temperature to reflux.
Particularly preferred compounds of the present invention include, but are not limited to, the compounds detailed in table 1, or pharmaceutically acceptable salts thereof:
TABLE 1 Structure and numbering of ligustrazine derivatives
As a preferred embodiment of the invention, the compound or the pharmaceutically acceptable salt thereof is used for preparing medicaments for treating or preventing cardiovascular and cerebrovascular diseases, in particular atherosclerosis, platelet aggregation and thromboembolic diseases.
Compared with the prior art, the invention has the following beneficial effects:
the compound tested by the invention can obviously activate ABCA1 at the cellular level, can mediate transfer of intracellular phospholipid and free cholesterol to lipid-deficient or lipid-free apolipoprotein A-I (apoA-I), thereby promoting the generation of High Density Lipoprotein (HDL), starting the reverse cholesterol transfer process, playing an important role in the process of removing excessive lipid by organisms, and has better application prospect in the treatment or prevention of atherosclerosis, hyperlipidemia, cardiovascular and cerebrovascular diseases, diabetes, inflammation and hypertension.
Drawings
FIG. 1 is the L1 of the present invention 1 H_NMR；
FIG. 2 is a diagram of the invention L2 1 H NMR；
FIG. 3 is the L3 form of the present invention 1 H NMR；
FIG. 4 is a diagram of the invention L4 1 H NMR；
FIG. 5 is a graph showing the results of up-regulating ABCA1 activity by the compounds of the present invention.
Detailed Description
Example 1
Synthesis of L1: compound 3-indoleacetic acid (100 mg,0.57 mmoL) and HBTU (220 mg,0.58 mmoL) were dissolved in 10mL of methylene chloride, DIEA (104. Mu.L, 0.60 mmoL) was added thereto and stirred at room temperature for 10min, followed by 3,5, 6-trimethylpyrazine-2-methylamine (88 mg,0.58 mmoL) was added thereto and reacted at room temperature for 2h. The reaction solution was extracted with methylene chloride, dried, concentrated, and subjected to column chromatography to obtain compound L1 (150 mg, 85.4%). HRMS calcd.for C 18 H 21 N 4 O[M+H] + 309.1715,found 309.1710； 1 H NMR(600MHz,CDCl 3 )δ8.32(brs,1H),7.61(d,J＝7.8Hz,1H),7.42(d,J＝8.4Hz,1H),7.32(brs,1H),7.25-7.20(m,2H),7.14-7.10(m,1H),4.42(d,J＝4.2Hz,2H),3.85(s,2H),2.40(s,6H),2.13(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ171.7,149.5,147.9,147.6,145.0,136.6,127.4,123.7,122.7,120.1,119.1,111.4,109.5,41.2,33.5,21.4,21.1,20.1。
Example two
Synthesis of L2: the compound 3,5, 6-trimethylpyrazine-2-carboxylic acid (105 mg,0.63 mmoL) and HBTU (250 mg,0.66 mmoL) were dissolved in 10mL of dichloromethane, DIEA (120. Mu.L, 0.69 mmoL) was added and stirred at room temperature for 10min, then 3-indoloethylamine (100 mg,0.63 mmoL) was added and reacted at room temperature for 2h. The reaction solution was extracted with dichloromethane, dried, concentrated, and subjected to column chromatography to obtain compound L2 (159 mg, 81.9%). HRMS calcd.for C 18 H 21 N 4 O[M+H] + 309.1715,found 309.1719； 1 H NMR(400MHz,CD 3 OD)δ7.61(dt,J＝8.0,1.2Hz,1H),7.33(dt,J＝8.0,1.2Hz,1H),7.13(s,1H),7.08(dt,J＝8.0,1.2Hz,1H),6.98(dt,J＝8.0,1.2Hz,1H),3.68(t,J＝7.2Hz,1H),3.07(dt,J＝7.2,0.8Hz,1H),2.72(s,3H),2.54(s,3H),2.49(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ167.6,155.2,151.1,150.1,141.7,138.2,128.8,123.6,122.4,119.6,119.4,113.2,112.2,41.5,26.2,22.2,21.6,21.3。
Example III
Synthesis of L3: compound 3,5, 6-trimethylpyrazine-2-carboxylic acid (100 mg,0.60 mmole) and HBTU (250 mg,0.66 mmole) were dissolved in 10mL of dichloromethane, DIEA (120. Mu.L, 0.69 mmole) was added and stirred at room temperature for 10min, then 2- (2-aminoethyl) phenol (86 mg,0.63 mmole) was added and reacted at room temperature for 2h. The reaction solution was extracted with methylene chloride, dried, concentrated, and subjected to column chromatography to obtain compound L3 (135 mg, 78.9%). HRMS calcd.for C 16 H 20 N 3 O 2 [M+H] + 286.1555,found 286.1559； 1 H NMR(400MHz,CD 3 OD)δ7.11(dd,J＝6.4,1.6Hz,1H),7.07-7.00(m,1H),6.79-6.72(m,2H),3.60(t,J＝7.2Hz,2H),2.92(t,J＝7.2Hz,2H),2.73(s,3H),2.54(s,3H),2.53(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ167.6,156.7,155.2,151.0,150.1,141.7,131.7,128.7,126.7,120.6,116.0,41.0,31.0,22.2,21.6,21.3。
Example IV
Synthesis of L4: compound 2- (2- ((tert-butoxycarbonyl) amino) phenyl) acetic acid (166 mg,0.66 mmole) and HBTU (250 mg,0.66 mmole) were dissolved in 10mL of methylene chloride, DIEA (120. Mu.L, 0.69 mmole) was added and stirred at room temperature for 10min, then 3,5, 6-trimethylpyrazine-2-methylamine (100 mg,0.66 mmole) was added and reacted at room temperature for 2h. The reaction solution was extracted with dichloromethane, dried, concentrated, and then saturated ethyl acetate hydrochloride solution was added thereto, followed by stirring at room temperature for 5 hours. After the reaction, the reaction mixture was concentrated and subjected to column chromatography to give Compound L4 (115 mg, 61.4%). HRMS calcd.for C 16 H 21 N 4 O[M+H] + 285.1715,found 285.1720； 1 H NMR(400MHz,CDCl 3 )δ7.29(brs,1H),7.16-7.08(m,2H),6.80-6.70(m,2H),4.41(d,J＝4.4Hz,2H),4.18(brs,2H),3.59(s,2H),2.46(s,3H),2.41(s,3H),2.39(s,3H)； 13 C NMR(150MHz,CDCl 3 )δ171.3,149.7,147.6,145.9,144.7,131.1,128.7,120.3,118.9,116.5,41.2,40.9,21.4(2C),20.0。
Example five
Abca1 upregulation Activity assay
The measurement principle is as follows:
the recombinant plasmid pGL3-ABCA1 cloned with the upstream regulatory sequence of the ABCA1 gene at the upstream of the luciferase reporter gene and pcDNA3 are co-transfected into human hepatoma cell HepG2, a stable transfected cell strain is obtained through screening, a high-flux drug screening model which takes a promoter as a drug action target and luciferase as the reporter gene is established, and the up-regulation activity of the drug on receptor gene expression is indirectly reflected by measuring the change of fluorescence intensity of the high-flux drug screening model.
The experimental method comprises the following steps:
the recombinant reporter plasmid (pGL 3-ABCA 1) and pcDNA3 are co-transfected into human hepatoma cell HepG2, so that the upstream regulatory sequence of ABCA1 and the reporter gene are randomly integrated on the chromosome of the cell, and the stably transfected cell strain ABCA1-LUC HepG2 is obtained by screening, so that Luciferase (LUC) can be stably expressed along with the growth of the cell, and the recombinant reporter plasmid can be used for constructing an expression up-regulation screening model suitable for high-throughput screening.
The experimental steps are as follows:
taking ABCA1-LUC HepG2 cells in logarithmic growth phase, and the concentration of cell suspension is 5×10 5 100 mu L of single cell suspension in each well is inoculated in a 96-well plate, after the cells are attached, the culture medium is removed, PBS is used for washing, 200 mu L of serum-free RPMI-1640 culture medium containing different concentration compounds is added in each well, 0.1% DMSO serum-free culture medium is used as a control, and the culture medium is washed once at 37 ℃ and 5% CO 2 Continuously culturing for 18-24h, removing culture medium, washing twice with PBS, adding cell lysate (20 μL/hole), and incubating for 15-30min; after observing the complete cell lysis by a microscope, adding luciferase (60 mu L/hole), and measuring the luciferase activity by using an enzyme-labeled instrument; ABCA1 upregulating activity was calculated using the following formula:
abca1 up regulatory activity =a/B (a: luciferase activity measured by adding the sample group to be measured; B: luciferase activity measured by DMSO control group).
See fig. 5 for results: the compounds L2 and L3 can obviously up-regulate the activity of ABCA1 to 1.8 times and 2.4 times respectively, and EC 50 The values were 0.85 and 1.33. Mu. Mol/L, respectively. The results show that the L2 and the L3 have better application prospects in the treatment or prevention of diseases such as atherosclerosis, hyperlipidemia, cardiovascular and cerebrovascular diseases, diabetes, inflammation, hypertension and the like which are related to the activity of ABCA 1.
While the fundamental and principal features of the invention and advantages of the invention have been shown and described, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (6)

1. A ligustrazine derivative or a pharmaceutically acceptable salt thereof, characterized in that the ligustrazine derivative is the following compound:
。
2. the ligustrazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a salt of the ligustrazine derivative of claim 1 with hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, citric acid, lactic acid, acetic acid, maleic acid, sulfonic acid, methanesulfonic acid or p-toluenesulfonic acid.
3. The method for preparing the ligustrazine derivative of claim 1, characterized in that: the preparation method of the ligustrazine derivative comprises the following steps:
the method comprises the steps of carrying out a first treatment on the surface of the Wherein Ar is->。
4. A method of preparation according to claim 3, characterized in that: the reaction conditions are as follows:
a1, the activator is thionyl chloride, oxalyl chloride, benzotriazole-N, N',N'-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole, bis (2-oxo-3-oxazolidinyl) hypophosphorous acid chloride, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide or N, N' -carbonyldiimidazole;
a2, the catalyst is 4-dimethylaminopyridine, N-diisopropylethylamine, triethylamine, 1, 8-diazabicyclo undec-7-ene, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate;
a3, the solvent is dichloromethane, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide;
a4, the reaction temperature is room temperature to reflux.
5. Use of a ligustrazine derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of cardiovascular and cerebrovascular diseases.
6. The use according to claim 5, wherein the cardiovascular and cerebrovascular diseases are atherosclerosis, platelet aggregation or thromboembolic diseases.
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CN108456178A (en) * 2017-02-20 2018-08-28 雷鹏程 Ligustrazine with neuroprotective activity replaces p-Hydroxybenzylalcohol analog derivative（LQC-F）And its application

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CN101362724A (en) * 2008-09-27 2009-02-11 山东大学 Tetramethylpyrazine acidamides derivates, preparation method and medicament composition and application
CN108456178A (en) * 2017-02-20 2018-08-28 雷鹏程 Ligustrazine with neuroprotective activity replaces p-Hydroxybenzylalcohol analog derivative（LQC-F）And its application

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