CN109988182B - Bilobalide B derivative and application thereof - Google Patents

Bilobalide B derivative and application thereof Download PDF

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CN109988182B
CN109988182B CN201810003060.7A CN201810003060A CN109988182B CN 109988182 B CN109988182 B CN 109988182B CN 201810003060 A CN201810003060 A CN 201810003060A CN 109988182 B CN109988182 B CN 109988182B
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ginkgolide
triazole
oxygen
group
bilobalide
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CN109988182A (en
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张庆文
常玉
胡乐安
崔键
孟凡成
胡元佳
王春明
王瑞兵
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University of Macau
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings

Abstract

The invention relates to a ginkgolide B derivative with a structure shown in a formula (I) and application thereof. The activity of the compound of the invention for inhibiting platelet aggregation is stronger than that of ginkgolide B, and the activity of part of the compound is stronger than that of natural ginkgolide B by more than 3 times.
Figure DDA0001537622060000011

Description

Bilobalide B derivative and application thereof
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a ginkgolide B derivative and application thereof.
Background
Cardiovascular disease is a serious disease threatening human health, the morbidity and mortality of the disease are high, and the disease is the first cause of human death. Therefore, the search for effective drugs for cardiovascular diseases has become an important clinical problem. In the course of the development of cardiovascular diseases such as atherosclerosis, thrombotic complications, stroke and myocardial infarction, abnormal thrombosis caused by platelet aggregation is the final pathophysiological process. Currently, commonly used anti-platelet agents such as aspirin and clopidogrel on the market can cause unnecessary bleeding risks while effectively treating the diseases. Therefore, the search for more safe and effective drugs with less side effects is the current primary task.
The platelet is the smallest blood particle component without nucleus produced by bone marrow megakaryocyte, has special physiological properties of adhesion, release, aggregation and the like, and is mainly involved in physiological hemostasis, blood coagulation function and pathological condition thrombosis of normal organisms. PAF (platelet activating factor) is a biological phospholipid medium synthesized by platelets, leukocytes, endothelial cells and the like, and can act on various receptors to play a wide range of biological actions. PAF acts on G protein-coupled receptors on target cell membranes, catalyzing the hydrolysis of cell membrane phospholipids to produce inositol triphosphate and diacylglycerol. IP3 can induce the release of intracellular Ca2+ and extracellular Ca2+Internal flow of Ca in cells2+The concentration is increased; meanwhile, diacylglycerol can activate protein kinase C, so that target protein is phosphorylated, platelet aggregation and release reaction is triggered, and blood circulation disorder is caused. PAF is the strongest platelet aggregation activator known to date, is closely related to a plurality of cardiovascular and cerebrovascular diseases such as ischemia reperfusion and atherosclerosis, and is generally highly expressed in patients with thrombotic diseases.
The ginkgolide B is one of the main components in the ginkgo extract, has wide pharmacological action, and can inhibit apoptosis, accelerate nerve impulse conduction, protect ischemic injury and the like. It has been reported that ginkgolide B inhibits platelet adhesion and aggregation caused by PAF, preventing thrombosis, but the pharmacological activity of ginkgolide B is still to be further enhanced, making it more suitable for clinical treatment.
Disclosure of Invention
Based on this, the present invention provides a ginkgolide B derivative, which has a stronger inhibitory effect on PAF-induced platelet aggregation than ginkgolide B.
The specific technical scheme is as follows:
a bilobalide B derivative having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof or a solvate thereof:
Figure BDA0001537622040000021
wherein X, Y, Z are each independently selected from: c, N;
r is selected from: h; C1-C4 alkyl; C3-C6 cycloalkyl; phenyl-substituted C1-C3 alkyl;
C1-C6 alkoxy; a phenyl group; substituted phenyl; 5-6 membered heteroaryl; C3-C6 nitrogen-containing cycloalkyl; C3-C6 oxygen-containing naphthenic base.
In some of these embodiments, X, Y, Z are both N.
In some of these embodiments, R is selected from: phenyl-substituted C1-C3 alkyl; a phenyl group; substituted phenyl; 5-6 membered heteroaryl.
In some of these embodiments, R is selected from: phenyl-substituted C1-C3 alkyl; a pyridyl group;
Figure BDA0001537622040000022
wherein R1, R2, R3, R4 and R5 are respectively and independently selected from: h; C1-C6 alkyl; C1-C6 alkoxy; halogen; a hydroxyl group; a carboxyl group; an ester group; a sulfonyl group; a sulfonamide group; halogen-substituted C1-C6 alkyl; a trifluoromethoxy group; a cyano group; a nitro group.
In some of these embodiments, R1, R2, R3, R4, R5 are each independently selected from: h; a tertiary butyl group; a methyl group; a methoxy group; chlorine; bromine; a hydroxyl group; a formate group; a sulfonamide group; a trifluoromethyl group; a cyano group; a nitro group.
In some of these embodiments, R1, R2, R3, R4, R5 are each independently selected from: h; a methyl group; chlorine; bromine; a hydroxyl group; a formate group; a trifluoromethyl group; a cyano group; a nitro group.
In some of these embodiments, R is selected from: a benzyl group; a 3-pyridyl group; a phenyl group; tolyl radicals.
In some of these embodiments, the ginkgolide B derivatives are selected from the following compounds:
10-oxygen- (1-phenyl-1H-1, 2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2, 6-dichlorophenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (4-tert-butylphenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (3-bromophenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (4-hydroxyphenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (4-methoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3-methoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3-benzene sulfonamide) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2-dimethoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2-methyl-4-nitrophenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (2-methylphenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (2-hydroxyphenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (2-cyanophenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3-ethyl benzoate) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (4-nitrophenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (3-pyridyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1-benzyl-1H-1, 2, 3-triazole) ginkgolide B.
The invention also provides application of the ginkgolide B derivative.
The specific technical scheme is as follows:
the application of the ginkgolide B derivative or the pharmaceutically acceptable salt thereof or the stereoisomer thereof or the prodrug molecule thereof or the solvate thereof in preparing PAF receptor antagonists.
The ginkgolide B derivative or the pharmaceutically acceptable salt or the stereoisomer or the prodrug molecule or the solvate thereof can be applied to the preparation of medicines for treating and/or preventing cardiovascular and cerebrovascular diseases and complications thereof related to PAF-induced platelet aggregation; the diseases and complications thereof comprise arrhythmia, ventricular fibrosis, myocardial infarction, coronary heart disease, angina pectoris, heart failure, myocardial ischemia, cardiac ischemia or reperfusion, myocarditis, atherosclerosis, peripheral tissue organ or limb ischemia, and acute and chronic injury, disorder or indirect sequelae of tissue organs caused by shock, ischemia or reperfusion.
The invention also provides a medicament for treating and/or preventing cardiovascular and cerebrovascular diseases and complications thereof related to PAF-induced platelet aggregation.
The specific technical scheme is as follows:
a medicament for treating and/or preventing diseases related to PAF-induced platelet aggregation and complications thereof comprises the bilobalide B derivative or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrug molecules thereof, or solvates thereof as an active ingredient.
The ginkgolide B derivative and the application thereof have the following advantages and beneficial effects:
the inventor of the invention finds out that the pharmacological activity of the ginkgolide B compound can be greatly enhanced, the effect of inhibiting platelet aggregation is obviously enhanced and the curative effect is favorably improved after the structural modification is carried out on the basis of the structure of the ginkgolide B compound and the hydroxyl hydrogen at the C10 position is replaced by the new group. The invention further preliminarily synthesizes more than 10 derivatives and tests the inhibition effect of the derivatives on platelet aggregation induced by PAF, and experimental results show that the activity of the compounds for inhibiting platelet aggregation is stronger than that of ginkgolide B, wherein the activity of some compounds is stronger than that of natural ginkgolide B by more than 3 times.
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FIG. 1 is a graph showing the experimental results of the inhibition effect of the ginkgolide B derivatives of the present invention on PAF-induced platelet aggregation; compared with the solvent control group, the preparation method has the advantages that,#p is less than 0.05; p < 0.05 compared to GB group; GB is ginkgolide B; veh solvent control.
Detailed Description
Various terms used in the present specification have meanings well known to those skilled in the art. For ease of reference, certain terms therein are now defined.
The term "pharmaceutically acceptable" as used herein refers to compounds that have no unacceptable toxicity in the compound, e.g., salt or excipient. Pharmaceutically acceptable salts include inorganic anions such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, phosphate, and the like. Organic anions include acetate, pyruvate, propionate, cinnamate, tosylate, citrate, and the like. "solvate" includes a compound provided by the present invention, or a salt thereof, further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.
The compounds provided by the present methods can be formulated into compositions using methods known in the art for pharmaceutical compounds, and these compositions can include one or more sweetening compounds, coloring compounds, preserving compounds, and flavoring compounds to provide pharmaceutically suitable formulations.
Tablets, pills, hard gelatin capsules, powders or granules may be used as oral solid compositions. In these compositions, suitable excipients or diluents which are acceptable in non-toxic medicaments, such as sucrose, starch or lactose, are admixed. These compositions may contain substances other than diluents, such as lubricants, for example magnesium stearate, talc or hard fatty acids.
Pharmaceutically acceptable solutions, emulsions, syrups, suspensions and elixirs, such as water or liquid paraffin, containing inert diluents may be used as liquid compositions for oral administration. These compositions may also contain flavouring, lubricating or sweetening agents other than diluents.
Compositions for parenteral administration may be in the form of non-toxic physiologically acceptable emulsions or sterile injectable solutions, such as propylene glycol, polyethylene glycol, sterile vegetable oils, or injectable organic esters, such as ethyl oleate, as solvents or carriers. These compositions may also contain adjuvants such as emulsifying agents, wetting agents, isotonicity agents, dispersing agents and stabilizing agents. Sterilization can be performed in several ways, such as heating, irradiation, using bacterial filters, etc.
The active compounds may be administered in the form of suppositories or capsules for rectal administration, mixed with suitable non-irritating excipients such as cocoa butter, polyethylene glycols or semi-synthetic glycerides.
Suitable dosage forms for the compounds of the present invention include, but are not limited to: a tablet; a caplet; capsules such as soft elastic gelatin capsules; a cachet; a lozenge; a lozenge; a dispersant; suppositories; an ointment; pastes (poultices); ointment; powder; a dressing agent; a cream; a plaster; a solution; pasting a piece; aerosols (e.g., nasal sprays or inhalants); gelling; liquid dosage forms suitable for oral or mucosal administration to an individual, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions and elixirs; a liquid dosage form suitable for parenteral administration to an individual; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide a liquid dosage form suitable for parenteral administration to an individual.
Routes of administration of the compounds of the invention include, but are not limited to, parenteral administration, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intratumoral, intrasynovial and rectal administration. In particular embodiments, the compositions are formulated according to conventional procedures as pharmaceutical compositions suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In embodiments, the pharmaceutical composition is formulated for subcutaneous administration to a human according to conventional procedures.
The compound of the invention can be used for treating cardiovascular and cerebrovascular system diseases and complications thereof, including but not limited to arrhythmia, ventricular fibrosis, myocardial infarction, coronary heart disease, angina pectoris caused by coronary heart disease, angina pectoris, heart failure, congestive heart failure, myocardial ischemia, cardiac ischemia or reperfusion, myocarditis, atherosclerosis, peripheral tissue organ or limb ischemia, acute and chronic injury, disorder or indirect sequelae of tissue organs caused by shock, ischemia or reperfusion.
The following are specific examples to aid understanding of the invention, but do not limit the scope of the invention.
Example 1: synthesis of 10-oxygen- (1-phenyl-1H-1, 2, 3-triazole) ginkgolide B (CY02617)
Figure BDA0001537622040000071
Step a, dissolving ginkgolide B (300mg,0.7mmol) in 3mL acetonitrile, adding potassium carbonate (357mg,2.59mmol), 3-bromoprop-1-yne (379mg,2.55mmol) and a small amount of potassium iodide, heating to 100 ℃, refluxing for 2.5h, filtering to remove potassium carbonate, evaporating the solvent under reduced pressure, and performing column chromatography (DCM/EA) to obtain yellow solid 10-oxo-ethynyl ginkgolide B. MS (ESI), M/z 449[ M + H ]]+。
Step b. aminobenzene (0.46mL,5mmol), dilute hydrochloric acid (1.5mL,15mmol) was added and 0.5mL of an aqueous solution of sodium nitrite (621mg,6mmol) was slowly added dropwise to the reaction flask in an ice bath and stirred at 0 ℃ for 10 min. Then sodium azide (325.05mg,5mmol) was added and the reaction was slowly warmed to room temperature for 2h until the reaction was complete. Extracting with ethyl acetate for three times, combining organic phases, evaporating the solvent under reduced pressure, washing with saturated salt water, and drying with sodium sulfate to obtain the compound azidobenzene which is directly used for the next reaction.
Step c.10-O-ethynyl ginkgolide B (38mg,0.08mmol) was dissolved in tetrahydrofuran: water: in a mixed solvent (3mL) of tert-butyl alcohol (1:1:1), azidobenzene is dissolved in 0.5mL of tert-butyl alcohol and is added to the reaction system dropwise, a small amount of copper sulfate is added, and the reaction is carried out overnight at room temperature. Removing solvent by rotation, and extracting with ethyl acetateAnd the organic phases were combined, the solvent was evaporated under reduced pressure, and column chromatography (DCM/EA) was carried out to give 32.4mg (yield: 68%) of a yellow solid.1H NMR(400MHz,DMSO-d6)δ1.02(s,9H),1.13(d,J＝7.2Hz,3H),1.73(,dd,J＝14.4Hz,4.0Hz,1H),1.84(ddd,J＝14.0Hz,13.6Hz,4.0Hz,1H),2.11(dd,J＝13.6Hz,4.0Hz,1H),2.88(q,J＝6.8Hz,1H),4.21(dd,J＝6.8Hz,4.8Hz,1H),4.63(d,J＝6.8Hz,1H),4.93(d,J＝12.0Hz,1H),5.45(d,J＝12.0Hz,1H),5.52(d,J＝4.4Hz,1H),6.20(s,1H),6.47(s,1H),7.50-7.64(m,3H),7.88(d,J＝7.6Hz,2H),8.798(1H,s).13C NMR(125MHz,DMSO-d6)δ7.84,28.64(3C),31.73,36.54,41.56,48.73,63.00,67.34,71.96,73.77,75.16,78.49,82.47,92.62,98.88,109.68,120.23(2C),121.59,128.94,129.96(2C),136.46,143.76,170.12,172.51,176.32.MS(ESI),m/z:582[M+H]+。
Example 2: synthesis of 10-oxygen- (1- (2, 6-dichlorophenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02633)
Figure BDA0001537622040000081
The synthesis was carried out according to example 1 (yield: 48%).
1HNMR(400MHz,DMSO-d6)δ1.03(s,9H),1.12(d,J＝7.2Hz,3H),1.74(dd,J＝14.4Hz,4.0Hz,1H),1.84(ddd,J＝14.2Hz,13.4Hz,4.0Hz,1H),2.13(dd,J＝13.2Hz,4.0Hz,1H),2.87(q,J＝7.2Hz,1H),4.19(dd,J＝7.2Hz,4.6Hz,1H),4.64(d,J＝7.2Hz,1H),4.99(d,J＝12.4Hz,1H),5.24(d,J＝4.4Hz,1H),5.32-5.54(m,2H),5.47(d,J＝12.0Hz,1H),6.20(s,1H),6.48(s,1H),7.68-7.81(m,3H),8.54(s,1H).13C NMR(125MHz,DMSO-d6)δ7.80,28.69(3C),31.74,36.50,41.54,48.68,63.20,67.28,71.91,73.74,75.51,78.45,82.48,92.40,98.82,109.68,125.88,129.26(2C),132.42,132.58(2C),133.04,143.11,170.07,172.38,176.27.MS(ESI),m/z:650[M+H]+。
Example 3: synthesis of 10-oxygen- (1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02631)
Figure BDA0001537622040000091
The synthesis was carried out according to example 1 (yield: 54%).
1HNMR(400MHz,DMSO-d6)δ1.02(s,9H),1.12(d,J＝6.8Hz,3H),1.74(dd,J＝14.4Hz,4.0Hz,1H),1.84(ddd,J＝14.2Hz,13.2Hz,4.0Hz,1H),2.12(dd,J＝12.8Hz,4.0Hz,1H),2.88(q,J＝6.8Hz,1H),4.20(dd,J＝7.2Hz,4.8Hz,1H),4.63(d,J＝7.2Hz,1H),4.96(d,J＝12.4Hz,1H),5.33-5.40(m,2H),5.43-5.48(m,2H),6.20(s,1H),6.47(s,1H),7.68-7.76(m,2H),8.02(d,J＝2.4Hz,1H),8.57(s,1H).13C NMR(125MHz,DMSO-d6)δ7.81,28.64(3C),31.71,36.49,41.53,48.69,59.71,63.03,67.30,71.91,73.71,75.27,78.44,82.45,92.58,98.85,109.65,125.51,128.65,129.49,129.64,130.16,133.34,135.51,143.02,170.07,172.44,176.27.MS(ESI),m/z:650[M+H]+。
Example 4: synthesis of 10-oxygen- (1- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02643)
Figure BDA0001537622040000092
The synthesis was carried out according to example 1 (yield: 53%).
1H NMR(400MHz,DMSO-d6)δ1.03(s,9H),1.13(d,J＝6.8Hz,3H),1.71-1.87(m,2H),2.12(dd,J＝12.8Hz,4.0Hz,1H),2.88(q,J＝6.8Hz,1H),4.21(dd,J＝7.2Hz,4.8Hz,1H),4.64(d,J＝7.2Hz,1H),4.96(d,J＝12.0Hz,1H),5.30-5.33(m,2H),5.35(s,1H),5.47(d,J＝12.0Hz,1H),6.21(s,1H),6.48(s,1H),8.31(s,1H),8.62(s,2H),9.14(s,1H).13C NMR(125MHz,DMSO-d6)δ7.83,28.63(3C),31.71,36.50,41.53,48.71,62.78,71.94,73.77,75.22,78.42,82.49,92.54,98.90,109.68,121.07,121.64,122.64,123.81,131.73(2C),132.00(2C),137.73,144.01,170.07,172.44,176.28.MS(ESI),m/z:718[M+H]+。
Example 5: synthesis of 10-oxygen- (1- (4-tert-butylphenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02647)
Figure BDA0001537622040000101
The synthesis method refers to example 1 (yield: 69%).
1H NMR(400MHz,DMSO-d6)δ1.01(s,9H),1.13(d,J＝7.2Hz,3H),1.33(s,9H),1.73(dd,J＝14.4Hz,3.8Hz,1H),1.83(ddd,J＝14.4Hz,13.2Hz,4.0Hz,1H),2.11(dd,J＝13.2Hz,4.0Hz,1H),2.88(q,J＝7.2Hz,1H),4.21(dd,J＝7.2Hz,4.6Hz,1H),4.63(d,J＝7.2Hz,1H),4.93(d,J＝12.0Hz,1H),5.33(s,2H),5.44(d,J＝12.0Hz,1H),5.58(d,J＝4.4Hz,1H),6.20(s,1H),6.47(s,1H),7.62(d,J＝8.8Hz,2H),7.78(d,J＝8.4Hz,2H),8.75(s,1H).13C NMR(125MHz,DMSO-d6)δ7.80,28.62(3C),30.95(3C),31.70,34.50,36.51,41.54,48.71,62.97,67.32,71.93,73.73,75.09,78.46,82.43,92.60,98.84,109.65,119.98(2C),121.49,126.64(2C),134.13,143.60,151.60,170.08,172.50,176.29.MS(ESI),m/z:638[M+H]+。
Example 6: synthesis of 10-oxygen- (1- (3-bromophenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02648)
Figure BDA0001537622040000111
The synthesis was carried out according to example 1 (yield: 62%).
1H NMR(400MHz,DMSO-d6)δ1.01(s,9H),1.12(d,J＝7.2Hz,3H),1.73(dd,J＝14.4Hz,4.2Hz,1H),1.83(ddd,J＝14.4Hz,13.2Hz,4.0Hz,1H),2.11(dd,J＝13.2Hz,4.0Hz,1H),2.88(q,J＝7.2Hz,1H),4.20(dd,J＝7.2Hz,4.6Hz,1H),4.63(d,J＝7.2Hz,1H),4.93(d,J＝12.0Hz,1H),5.33(s,2H),5.43-5.46(m,2H),6.20(s,1H),6.47(s,1H),7.58(t,J＝8.0Hz,1H),7.73(d,J＝8.4Hz,1H),7.94(dd,J＝8.2Hz,1.4Hz,1H),8.14(t,J＝2.0Hz,1H),8.87(s,1H).13C NMR(125MHz,DMSO-d6)δ7.83,28.62(3C),31.70,36.51,41.53,48.71,62.89,67.29,71.93,73.75,75.13,78.45,82.47,92.60,98.88,109.66,119.23,121.92,122.43,122.77,131.66,131.90,137.55,143.79,170.08,172.46,176.28.MS(ESI),m/z:660[M+H]+。
Example 7: synthesis of 10-oxygen- (1- (4-hydroxyphenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02652)
Figure BDA0001537622040000121
The synthesis was carried out according to example 1 (yield: 58%).
1H NMR(400MHz,DMSO-d6)δ1.01(s,9H),1.11(d,J＝7.2Hz,3H),1.72(dd,J＝14.4Hz,4.2Hz,1H),1.82(ddd,J＝14.4Hz,13.2Hz,4.0Hz,1H),2.13(dd,J＝13.2Hz,4.0Hz,1H),2.86(q,J＝7.2Hz,1H),4.21(dd,J＝7.2Hz,4.6Hz,1H),4.64(d,J＝7.2Hz,1H),4.94(d,J＝12.0Hz,1H),5.32(s,2H),5.43-5.45(m,2H),6.21(s,1H),6.46(s,1H),6.85(d,J＝4.8Hz,2H),7.65(d,J＝4.8Hz,2H),9.12(s,1H),9.90(s,1H).MS(ESI),m/z:598[M+H]+。
Example 8: synthesis of 10-oxygen- (1- (4-methoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02654)
Figure BDA0001537622040000122
The synthesis was carried out according to example 1 (yield: 64%).
1H NMR(400MHz,DMSO-d6)δ1.01(s,9H),1.11(d,J＝7.2Hz,3H),1.72(dd,J＝14.4Hz,4.2Hz,1H),1.82(ddd,J＝14.4Hz,13.2Hz,4.0Hz,1H),2.13(dd,J＝13.2Hz,4.0Hz,1H),2.86(q,J＝7.2Hz,1H),3.85(s,3H),4.21(dd,J＝7.2Hz,4.6Hz,1H),4.64(d,J＝7.2Hz,1H),4.94(d,J＝12.0Hz,1H),5.32(s,2H),5.43-5.45(m,2H),6.21(s,1H),6.46(s,1H),7.15(d,J＝4.8Hz,2H),7.80(d,J＝4.8Hz,2H),9.12(s,1H).MS(ESI),m/z:612[M+H]+。
Example 9: synthesis of 10-oxygen- (1- (3-methoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02657)
Figure BDA0001537622040000131
The synthesis was carried out according to example 1 (yield: 58%).
1H NMR(400MHz,DMSO-d6)δ1.02(s,9H),1.11(d,J＝7.2Hz,3H),1.72(dd,J＝14.4Hz,4.2Hz,1H),1.82(ddd,J＝14.4Hz,13.2Hz,4.0Hz,1H),2.13(dd,J＝13.2Hz,4.0Hz,1H),2.86(q,J＝7.2Hz,1H),3.87(s,3H),4.21(dd,J＝7.2Hz,4.6Hz,1H),4.64(d,J＝7.2Hz,1H),4.94(d,J＝12.0Hz,1H),5.32(s,2H),5.43-5.45(m,2H),6.21(s,1H),6.45(s,1H),7.08(t,J＝3.6Hz,1H),7.45(s,2H),7.52(m,1H),8.80(s,1H).MS(ESI),m/z:612[M+H]+。
Example 10: synthesis of 10-oxygen- (1- (3-benzene sulfonamide) -1H-1,2, 3-triazole) ginkgolide B (CY02672)
Figure BDA0001537622040000141
The synthesis was carried out according to example 1 (yield: 43%).
1H NMR(400MHz,DMSO-d6)δ1.02(s,9H),1.11(d,J＝7.2Hz,3H),1.72(dd,J＝14.4Hz,4.2Hz,1H),1.82(ddd,J＝14.4Hz,13.2Hz,4.0Hz,1H),2.13(dd,J＝13.2Hz,4.0Hz,1H),2.86(q,J＝7.2Hz,1H),4.21(dd,J＝7.0Hz,4.4Hz,1H),4.64(d,J＝7.0Hz,1H),4.94(d,J＝12.0Hz,1H),5.31(s,2H),5.43-5.45(m,2H),6.21(s,1H),6.45(s,1H),7.60(s,2H),7.81(m,1H),7.95(m,1H),8.12(m,1H),8.35(s,1H),8.90(s,1H).MS(ESI),m/z:661[M+H]+。
Example 11: synthesis of 10-oxo- (1- (2-dimethoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02676)
Figure BDA0001537622040000142
The synthesis method was as in example 1 (yield: 41%).
1H NMR(400MHz,DMSO-d6)δ1.01(s,9H),1.10(d,J＝7.0Hz,3H),1.71(dd,J＝14.4Hz,4.2Hz,1H),1.81(ddd,J＝13.8Hz,13.0Hz,4.0Hz,1H),2.13(dd,J＝13.2Hz,4.0Hz,1H),2.86(q,J＝7.2Hz,1H),3.25(s,6H),4.21(dd,J＝7.2Hz,4.6Hz,1H),4.64(d,J＝7.2Hz,1H),4.94(d,J＝12.0Hz,1H),5.32(s,2H),5.43-5.45(m,2H),6.21(s,1H),6.45(s,1H),6.88(m,2H),7.51(m,1H),8.18(s,1H).MS(ESI),m/z:642[M+H]+。
Example 12: synthesis of 10-oxygen- (1- (2-methyl-4-nitrophenyl) -1H-1,2, 3-triazole) ginkgolide B (CY02683)
Figure BDA0001537622040000151
The synthesis was carried out according to example 1 (yield: 47%).
1H NMR(400MHz,DMSO-d6)δ1.01(s,9H),1.11(d,J＝7.2Hz,3H),1.72(dd,J＝14.4Hz,4.2Hz,1H),1.82(ddd,J＝14.4Hz,13.2Hz,4.0Hz,1H),2.13(dd,J＝13.2Hz,4.0Hz,1H),2.31(s,3H),2.86(q,J＝7.2Hz,1H),4.20(dd,J＝7.2Hz,4.6Hz,1H),4.64(d,J＝7.2Hz,1H),4.92(d,J＝12.0Hz,1H),5.32(s,2H),5.43-5.45(m,2H),6.21(s,1H),6.45(s,1H),7.85(m,1H),8.28(m,1H),8.40(s,1H),8.65(s,1H).MS(ESI),m/z:641[M+H]+。
Example 13: synthesis of 10-oxygen- (1- (2-methylphenyl) -1H-1,2, 3-triazole) ginkgolide B (HLA01)
Figure BDA0001537622040000161
The synthesis was carried out according to example 1 (yield: 48%).
1H NMR(600MHz,DMSO-d6)δ8.46(s,1H),7.52–7.47(m,2H),7.46–7.41(m,2H),6.47(s,1H),6.20(s,1H),5.57(d,J＝4.6Hz,1H),5.45(d,J＝12.2Hz,1H),5.35–5.33(m,2H),4.97(d,J＝12.1Hz,1H),4.64(d,J＝7.2Hz,1H),4.21(dd,J＝7.2,4.7Hz,1H),2.89(q,J＝7.0Hz,1H),2.15(s,3H),2.13(dd,J＝13.7,4.5Hz,1H),1.91–1.80(m,1H),1.75(dd,J＝14.4,4.4Hz,1H),1.13(d,J＝7.1Hz,3H),1.03(s,9H).13C NMR(151MHz,DMSO-d6)δ176.83,173.02,170.63,143.35,136.56,133.54,131.90,130.45,127.53,126.45,125.28,110.16,99.33,93.08,82.94,79.01,75.62,74.23,72.43,67.83,63.57,49.20,41.90,37.01,32.22,29.14(3C),17.84,8.32.HRMS(ESI):m/z calcd for C30H34N3O10[M+H]+:596.2244,found 596.2249.
Example 14: synthesis of 10-oxygen- (1- (2-hydroxyphenyl) -1H-1,2, 3-triazole) ginkgolide B (HLA02)
Figure BDA0001537622040000162
The synthesis method was as in example 1 (yield: 41%).
1H NMR(600MHz,DMSO-d6)δ10.59(s,1H),8.51(s,1H),7.60(dd,J＝7.9,1.6Hz,1H),7.36(ddd,J＝8.2,7.5,1.7Hz,1H),7.12(dd,J＝8.2,1.2Hz,1H),7.00(td,J＝7.8,1.3Hz,1H),6.46(s,1H),6.20(s,1H),5.64(d,J＝4.7Hz,1H),5.45(d,J＝12.2Hz,1H),5.34–5.32(m,2H),4.93(d,J＝12.1Hz,1H),4.63(d,J＝7.2Hz,1H),4.22(dd,J＝7.2,4.5Hz,1H),2.92–2.84(m,1H),2.12(dd,J＝13.3,4.4Hz,1H),1.84(td,J＝13.8,4.2Hz,1H),1.74(dd,J＝14.3,4.3Hz,1H),1.13(d,J＝7.1Hz,3H),1.02(s,9H).13C NMR(151MHz,DMSO-d6)δ175.74,171.96,169.55,149.06,141.97,129.74,124.60,124.12,123.73,118.97,116.45,109.07,98.23,91.99,81.83,77.91,74.66,73.13,71.35,66.74,62.61,48.10,40.98,35.93,31.15,28.07(3C),7.23.HRMS(ESI):m/z calcd for C29H32N3O11[M+H]+:598.2037,found 598.2051.
Example 15: synthesis of 10-oxo- (1- (2-cyanophenyl) -1H-1,2, 3-triazole) ginkgolide B (HLA03)
Figure BDA0001537622040000171
The synthesis method was as in example 1 (yield: 42%).
1H NMR(600MHz,DMSO-d6)δ8.74(s,1H),8.16(dd,J＝7.8,1.3Hz,1H),7.98(td,J＝7.9,1.4Hz,1H),7.90–7.86(m,1H),7.79(td,J＝7.7,1.1Hz,1H),6.49(s,1H),6.20(s,1H),5.48(d,J＝12.4Hz,2H),5.37–5.30(m,2H),4.99(d,J＝12.3Hz,1H),4.64(d,J＝7.1Hz,1H),4.22(d,J＝7.1Hz,1H),2.92–2.85(m,1H),2.11(dd,J＝13.5,4.5Hz,1H),1.86(dt,J＝13.7,7.0Hz,1H),1.74(dd,J＝14.4,4.5Hz,1H),1.13(d,J＝7.1Hz,3H),1.02(s,9H).13C NMR(151MHz,DMSO-d6)δ176.81,172.97,170.63,144.21,138.10,135.41,135.30,130.92,126.18,124.91,116.22,110.16,107.43,99.41,93.18,82.97,79.00,75.76,74.22,72.41,67.82,63.48,49.20,42.04,37.01,32.22,29.13(3C),8.35.HRMS(ESI):m/z calcd for C30H31N4O10[M+H]+:607.2040,found 607.2050.
Example 16: synthesis of 10-oxo- (1- (3-ethyl benzoate) -1H-1,2, 3-triazole) ginkgolide B (HLA06)
Figure BDA0001537622040000181
The synthesis was carried out according to example 1 (yield: 52%).
1H NMR(600MHz,DMSO-d6)δ8.94(s,1H),8.40(s,1H),8.18(dd,J＝8.1,0.8Hz,1H),8.08(dd,J＝7.8,0.9Hz,1H),7.79(t,J＝8.0Hz,1H),6.49(s,1H),6.21(s,1H),5.48(d,J＝4.6Hz,1H),5.46(d,J＝12.2Hz,1H),5.36–5.31(m,2H),4.95(d,J＝12.1Hz,1H),4.64(d,J＝7.1Hz,1H),4.38(q,J＝7.1Hz,2H),4.22(dd,J＝7.1,4.6Hz,1H),2.89(q,J＝7.0Hz,1H),2.11(dd,J＝13.4,4.4Hz,1H),1.84(td,J＝13.8,4.2Hz,1H),1.74(dd,J＝14.4,4.4Hz,1H),1.36(t,J＝7.1Hz,3H),1.13(d,J＝7.1Hz,3H),1.02(s,9H).13C NMR(151MHz,DMSO-d6)δ176.81,173.00,170.61,165.21,144.41,137.17,132.08,131.16,129.77,125.17,122.46,120.88,110.16,99.37,93.11,82.96,78.98,75.64,74.23,72.43,67.80,63.39,61.85,49.20,42.04,37.00,32.21,29.12(3C),14.59,8.34.HRMS(ESI):m/z calcd for C32H36N3O12[M+H]+:654.2299,found 654.2309.
Example 17: synthesis of 10-oxygen- (1- (4-nitrophenyl) -1H-1,2, 3-triazole) ginkgolide B (HLA13)
Figure BDA0001537622040000191
The synthesis was carried out according to example 1 (yield: 55%).
1H NMR(600MHz,DMSO-d6)δ9.00(s,1H),8.49–8.47(m,2H),8.23–8.20(m,2H),6.47(s,1H),6.20(d,J＝6.2Hz,1H),5.46(t,J＝12.2Hz,1H),5.40(d,J＝4.6Hz,1H),5.36–5.32(m,2H),4.95(d,J＝12.1Hz,1H),4.64(d,J＝7.1Hz,1H),4.21(dd,J＝7.1,4.6Hz,1H),2.93–2.84(m,1H),2.11(dd,J＝13.4,4.4Hz,1H),1.84(td,J＝13.8,4.2Hz,1H),1.74(dd,J＝14.4,4.4Hz,1H),1.13(d,J＝7.1Hz,3H),1.02(s,9H).13C NMR(151MHz,DMSO-d6)δ176.79,172.97,170.60,147.38,144.82,141.16,126.13(2C),122.76,121.30(2C),110.16,99.39,93.14,82.98,78.96,75.74,74.23,72.41,67.79,63.37,49.19,42.04,37.01,32.22,29.13(3C),8.35.HRMS(ESI):m/z calcd for C29H31N4O12[M+H]+:627.1938,found 627.1948.
Example 18: synthesis of 10-oxy- (1- (3-pyridyl) -1H-1,2, 3-triazole) ginkgolide B (HLA18)
Figure BDA0001537622040000201
The synthesis was carried out according to example 1 (yield: 60%).
1H NMR(600MHz,DMSO-d6)δ9.13(d,J＝2.5Hz,1H),8.88(s,1H),8.71(d,J＝4.8Hz,1H),8.35–8.30(m,1H),7.68(dd,J＝8.4,4.8Hz,1H),6.49(s,1H),6.21(s,1H),5.49(d,J＝4.8Hz,1H),5.47(d,J＝12.0Hz,1H),5.34(d,J＝3.2Hz,2H),4.95(d,J＝12.1Hz,1H),4.64(d,J＝7.1Hz,1H),4.21(dd,J＝7.1,4.5Hz,1H),2.88(q,J＝7.0Hz,1H),2.12(dd,J＝13.5,4.5Hz,1H),1.85(td,J＝13.8,4.2Hz,1H),1.74(dd,J＝14.4,4.4Hz,1H),1.13(d,J＝7.1Hz,3H),1.03(s,9H).13CNMR(151MHz,DMSO-d6)δ176.80,172.99,170.59,150.41,144.45,141.84,133.59,128.59,125.10,122.47,110.07,99.32,92.92,82.84,78.99,75.45,73.96,72.07,67.61,63.29,48.94,42.04,36.71,31.75,29.12(3C),8.16.HRMS(ESI):m/zcalcd for C28H31N4O10[M+H]+:583.2040,found 583.2056.
Example 19: synthesis of 10-oxygen- (1-benzyl-1H-1, 2, 3-triazole) ginkgolide B (HLA19)
Figure BDA0001537622040000202
The synthesis was carried out according to example 1 (yield: 62%).
1HNMR(600MHz,DMSO-d6)δ8.17(s,1H),7.41–7.30(m,5H),6.47(s,1H),6.17(s,1H),5.64(d,J＝4.4Hz,1H),5.61(s,2H),5.35–5.31(m,2H),5.27(s,1H),4.84(d,J＝12.1Hz,1H),4.62(d,J＝7.2Hz,1H),4.17(dd,J＝7.1,4.5Hz,1H),2.86(q,J＝7.0Hz,1H),2.09(dd,J＝12.9,3.9Hz,1H),1.77(td,J＝13.8,4.2Hz,1H),1.70(dd,J＝14.4,4.4Hz,1H),1.12(d,J＝7.1Hz,3H),0.98(s,9H).13C NMR(151MHz,DMSO-d6)δ176.83,172.99,170.62,143.50,136.17,129.26(2C),128.69,128.48(2C),123.01,109.77,98.98,92.78,82.56,78.85,75.51,74.03,72.28,67.54,63.16,53.19,48.92,41.92,36.77,31.99,28.81(3C),8.15.HRMS(ESI):m/z calcdforC30H34N3O10[M+H]+:596.2244,found 596.2266.
Example 20
1. In vitro assay of ginkgolide B derivatives for inhibiting platelet aggregation
Collecting blood from rabbit neck trunk artery, anticoagulating with sodium citrate, centrifuging at 1000r/min for 10min, collecting platelet-rich plasma, centrifuging the rest at 3000r/min for 10min, and collecting platelet-poor plasma. Platelet-rich plasma is used as a platelet donor to detect the platelet aggregation rate of drugs with different concentrations. The experiment was set up with a solvent control group and an experimental group. Zeroing with platelet poor plasma, mixing 215 μ L of platelet rich plasma with solvent (as control group) or 10nM of the drug (i.e. 19 ginkgolide B derivatives (see Table 1) prepared in examples 1-19) or Ginkgolide B (GB), incubating at 37 deg.C for 5min, adding 0.01 μ MPAF after incubation, and detecting platelet aggregation with platelet aggregation analyzer. Each sample was replicated three times.
Platelet aggregation inhibition (%) - (solvent control group platelet aggregation-experimental group platelet aggregation)/control group platelet aggregation × 100%.
TABLE 1 ginkgolide B derivatives number
Figure BDA0001537622040000221
3. The result of the detection
The results are shown in fig. 1, and show that the in vitro activity of the ginkgolide B derivatives of the present invention (especially the compounds numbered 17, 21, 44 and a19) against platelet aggregation is stronger than that of ginkgolide B.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. A bilobalide B derivative having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0002607534430000011
wherein X, Y, Z are both N;
r is selected from: phenyl, benzyl, 3-pyridyl,
Figure FDA0002607534430000012
Wherein R is1、R2、R3、R4、R5Each independently selected from: h; a tertiary butyl group; a methyl group; a methoxy group; chlorine; bromine; a hydroxyl group; a formate group; a sulfonamide group; a trifluoromethyl group; a cyano group; a nitro group.
2. The ginkgolide B derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from the group consisting of: a benzyl group; a 3-pyridyl group; a phenyl group; tolyl radicals.
3. The ginkgolide B derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein R is selected from the group consisting of: a phenyl group; tolyl radicals.
4. The ginkgolide B derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein R is selected from the group consisting of: tolyl radicals.
5. The ginkgolide B derivatives or pharmaceutically acceptable salts thereof according to claim 1, wherein said ginkgolide B derivatives are selected from the group consisting of:
10-oxygen- (1-phenyl-1H-1, 2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2, 6-dichlorophenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (4-tert-butylphenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (3-bromophenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (4-hydroxyphenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (4-methoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3-methoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3-benzene sulfonamide) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2-dimethoxyphenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2-methyl-4-nitrophenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (2-methylphenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (2-hydroxyphenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (2-cyanophenyl) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3-ethyl benzoate) -1H-1,2, 3-triazole) ginkgolide B,
10-oxygen- (1- (4-nitrophenyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1- (3-pyridyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1-benzyl-1H-1, 2, 3-triazole) ginkgolide B.
6. The ginkgolide B derivatives or pharmaceutically acceptable salts thereof according to claim 5, wherein said ginkgolide B derivatives are selected from the group consisting of:
10-oxygen- (1-phenyl-1H-1, 2, 3-triazole) ginkgolide B,
10-oxygen- (1- (3-pyridyl) -1H-1,2, 3-triazole) bilobalide B,
10-oxygen- (1-benzyl-1H-1, 2, 3-triazole) bilobalide B,
10-oxygen- (1- (2-methylphenyl) -1H-1,2, 3-triazole) ginkgolide B.
7. The ginkgolide B derivatives or pharmaceutically acceptable salts thereof according to claim 6, wherein said ginkgolide B derivatives are selected from the group consisting of:
10-oxygen- (1-phenyl-1H-1, 2, 3-triazole) ginkgolide B,
10-oxygen- (1- (2-methylphenyl) -1H-1,2, 3-triazole) ginkgolide B.
8. Use of the ginkgolide B derivative of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the preparation of a PAF receptor antagonist.
9. Use of a ginkgolide B derivative of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of cardiovascular and cerebrovascular diseases and complications thereof associated with PAF-induced platelet aggregation; the cardiovascular and cerebrovascular diseases and the complications thereof comprise arrhythmia, ventricular fibrosis, myocardial infarction, coronary heart disease, angina, heart failure, myocardial ischemia, cardiac ischemia or reperfusion, myocarditis, atherosclerosis, peripheral tissue organ or limb ischemia, shock, acute and chronic tissue organ injury, disorder or indirect sequelae caused by ischemia or reperfusion.
10. A medicament for treating and/or preventing cardiovascular and cerebrovascular diseases and their complications associated with PAF-induced platelet aggregation, characterized in that the active ingredient thereof comprises the ginkgolide B derivative of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.
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WO2005021496A2 (en) * 2003-08-27 2005-03-10 The Trustees Of Columbia University In The City Of New York Synthesis of derivatives of ginkgolide c
CN102382121A (en) * 2010-09-02 2012-03-21 秦引林 Ginkgolide derivative and application thereof to pharmacy
CN106892930A (en) * 2015-12-18 2017-06-27 成都百裕金阁莱药业有限公司 Bilobalide B derivates and preparation method and application

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