CN108069980B - Novel derivative of ginkgolide K and preparation method and application thereof - Google Patents
Novel derivative of ginkgolide K and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a novel derivative of ginkgolide K shown as a formula (I) and a preparation method and application thereof. The invention obtains the novel derivative of the ginkgolide K with better water solubility and good activity by carrying out structural modification on the ginkgolide K, and can be used for inhibiting platelet aggregation and preventing and treating cardiovascular and cerebrovascular diseases, nervous system diseases and immune system diseases. Meanwhile, the preparation process of the ginkgolide K derivative is simple and convenient, and is suitable for industrial production.
Description
Technical Field
The invention relates to a series of novel ginkgolide K derivatives, in particular to ginkgolide K derivatives and a preparation method and application thereof.
Background
The ginkgolide compounds are main active ingredients in the ginkgo leaves, and proved to have wide pharmacological action and pharmaceutical value. Ginkgolides compounds that have been discovered to date include ginkgolide a, ginkgolide B, ginkgolide C, bilobalide, ginkgolide J, ginkgolide M, ginkgolide L, ginkgolide K, and the like. The ginkgolide K is widely noticed after obtaining a trace sample by the methods of preparing liquid and the like and performing structural characterization by the methods of nuclear magnetism and infrared ray.
Firstly, patent CN1424315A discloses a ginkgolide K compound, an extraction method and a pharmaceutical composition containing ginkgolide K; subsequently, patents CN1919848A, CN102002052A, CN101824041A and CN105001231A successively reported methods for preparing ginkgolide K from ginkgolide B; in recent years, documents such as' Chinese journal of pharmacy 2011,46(13): 993-. Therefore, the ginkgolide K has an obvious protective function on cerebral ischemia and has good medicinal prospect. Ginkgolide K (GK) has the following structure:
because the ginkgolide K is a diterpene compound with a six-ring cage-shaped structure, has strong structural rigidity, is difficult to dissolve in water and has poor bioavailability, the full play of the drug effect is limited to a certain extent, and the clinical medicinal effect is influenced.
Therefore, there is a need for further structural modification of ginkgolide K to obtain novel derivatives of ginkgolide K with improved water solubility and improved bioavailability and bioactivity for the prevention and treatment of cardiovascular and cerebrovascular diseases, nervous system diseases and immune system diseases.
Disclosure of Invention
In order to solve the above problems, the present invention provides a compound represented by formula (I), or an optical isomer thereof, or a cis-trans isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof:
wherein R represents-Ar or-A-Ar;
ar represents phenyl, pyridyl or pyrazinyl, which may be unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxy, cyano, carboxy, C1～C6Alkyl of (C)2～C6Alkenyl of, C2～C6Alkynyl of (A), C1～C6Halogenoalkyl of, C1～C6Alkoxy group of (C)1～C6Acyloxy group or C of1～C6An ester group of (a);
a represents C2～C8The alkenylene group of (a) may be unsubstituted or substituted by C1～C6Is substituted with an alkyl group.
Further, a represents a vinylidene group.
Further, said C1～C6The alkyl group of (a) is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl; said C is1～C6The alkoxy group of (a) is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or sec-butoxy; said C is1～C6The acyloxy group is selected from formyloxy, acetyloxy, n-propionyloxy, iso-propionyloxy, n-butyryloxy, iso-butyryloxy, tert-butyryloxy or sec-butyryloxy.
Further, the compound is one of the following compounds:
further, the pharmaceutically acceptable salt is selected from an organic acid salt or an inorganic acid salt.
Further, the organic acid salt is selected from the group consisting of methanesulfonate, p-toluenesulfonate, lactate, citrate, succinate, salicylate or acetate; the inorganic acid salt is selected from hydrochloride, sulfate or phosphate.
The present invention also provides a process for preparing the aforementioned compound, or an optical isomer thereof, or a cis-trans isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
dissolving ginkgolide K and a compound shown as a formula (II) in an organic solvent, and adding a catalyst and a condensing agent to prepare a compound shown as a formula (I);
wherein the organic solvent is selected from acetonitrile or N, N-dimethylformamide; the catalyst is selected from 4-dimethylamino pyridine or 1-hydroxybenzotriazole; the condensing agent is selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide or diisopropylcarbodiimide.
Further, the molar ratio of the ginkgolide K to the compound shown in the formula (II) is 1: 1-1: 5; the molar ratio of the ginkgolide K to the catalyst is 1: 0.1-1: 0.3; the molar ratio of the ginkgolide K to the condensing agent is 1: 1.1-1: 1.6.
The invention also provides application of the compound or the optical isomer, the cis-trans isomer, the solvate or the pharmaceutically acceptable salt thereof in preparing platelet aggregation inhibitor medicines.
The invention also provides the application of the compound, or the optical isomer, the cis-trans isomer, the solvate or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing, treating and/or relieving cardiovascular and cerebrovascular diseases, nervous system diseases and immune system diseases; preferably, the cardiovascular and cerebrovascular diseases are hypertension, congenital heart disease, coronary heart disease, myocardial infarction, acute coronary syndrome, coronary artery disease, coronary revascularization, atherosclerosis, left trunk lesion, bifurcation lesion, angina pectoris, thrombus, myocarditis, rheumatic heart disease, essential hypertension, pulmonary heart disease, infectious heart disease, endocrinological heart disease, anemic heart disease, cardiac neurosis, nutritional metabolic heart disease, aortic aneurysm, lower limb arteriosclerosis disease, peripheral arterial disease, intracranial aneurysm, arteriosclerotic aneurysm, ischemic stroke, hemorrhagic stroke, hyperlipidemia, arteriosclerosis, sudden exercise death, sudden cardiac death, stroke, hypotension, vascular embolism, pulmonary embolism, arrhythmia, ventricular arrhythmia, complex arrhythmia, complicated arrhythmia, cerebral hemorrhage, hereditary arrhythmia, malignant arrhythmia, atrial fibrillation, heart failure, myocardial disease, pericardial disease, valvular disease, hypertensive encephalopathy, hypertension complicated with apoplexy, cerebral hemorrhage, cerebral thrombosis, cerebral embolism, cerebral infarction, cerebral arteritis, cerebral arteriosclerosis, lacunar infarction, vascular dementia, kidney disease, kidney damage, chronic renal disease, metabolic syndrome, chronic cardiac insufficiency, gouty nephropathy, diabetic nephropathy or renal dysfunction.
Experimental results prove that the ginkgolide K derivative with better water solubility and good activity is obtained by carrying out structural modification on the ginkgolide K, and can be used for inhibiting platelet aggregation and preventing and treating cardiovascular and cerebrovascular diseases, nervous system diseases and immune system diseases. Meanwhile, the preparation process of the ginkgolide K derivative is simple and convenient, and is suitable for industrial production.
In the present invention, said C1～C6Alkyl of (A) means C1、C2、C3、C4、C5、C6The alkyl group of (1) is a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, and the like. Similarly, C1～C6Alkyl of (C)1～C6Alkenyl of, C1～C6Alkynyl of (A), C1～C6Halogenoalkyl of, C1～C6Alkoxy group of (C)1～C6Acyloxy group or C of1～C6The ester group of (A) also refers to a group having 1 to 6 carbon atoms or 2 to 6 carbon atoms, respectively.
In the present invention, "treatment" also includes recurrent (relapse) or phase (phase) prevention, as well as treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment may be symptomatic treatment, e.g. suppression of symptoms. It can be achieved in the short term, adjusted in the medium term, or it can be said that it is a long term treatment, for example in maintenance therapy.
As used herein, "pharmaceutically acceptable" means that the carrier, cargo, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and is physiologically compatible with the recipient.
In the present invention, the "salt" is an acid and/or base salt of a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitterionic salt (inner salt), and also includes a quaternary ammonium salt such as an alkylammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. The compound, or a stereoisomer thereof, may be obtained by appropriately (e.g., equivalentlymixing) a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a liquid chromatography mass spectrometry (LC-MS) spectrum of 10-O-nicotinic acid bilobalide K (GKY-2);
FIG. 2 shows the nuclear magnetic hydrogen spectrum of 10-O-nicotinic acid bilobalide K (GKY-2) ((R))1H-NMR)。
Detailed Description
The sources of the raw materials and reagents used in the invention are as follows:
bilobalide k (gk): self-made, batch number: 20160701.
acetylsalicylic acid: chengdu Kelong chemical reagent factory, lot number 2013101601
Cinnamic acid: beijing Bailingwei science and technology Co., Ltd, batch number: 159270.
ferulic acid: avastin reagent, lot number: l 1517121.
Nicotinic acid: metropolis chemical reagent factory, batch number: 2015040101
Isonicotinic acid: metropolis chemical reagent factory, batch number: 2015101601.
5-methylpyrazine-2-carboxylic acid: chengdu Huaxia chemical reagent Co., Ltd, batch number: l050904
Benzoic acid: metropolis chemical reagent factory, batch number: 2015080101
3,5, 6-trimethylpyrazine-2-carboxylic acid: self-made, batch number: 20160715
4-Dimethylaminopyridine (DMAP): metropolis chemical reagent factory, batch number: 2016020101
EXAMPLE 1 preparation of ginkgolide K-10-O-nicotinate (GKY-2)
3.0g (7.38mmol) GK and 1.09g (8.86mmol,1.2eq) nicotinic acid were weighed out and dissolved in 50mL acetonitrile and mixed with stirring in an ice bath. Then 0.09g (0.74mmol, 0.1eq) of 4-Dimethylaminopyridine (DMAP) and 1.56g (8.12mmol,1.1eq) of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (EDC. HCl), after stirring for 1h in an ice bath, the mixture was reacted at 20 ℃ for 6h, the solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate and 5% NaHCO was used3Washing was performed twice, and washing was performed once with saturated saline. The organic phase was collected, dried, filtered and concentrated to give a white solid after column chromatography (petroleum ether: ethyl acetate: 2:1) 1.68g, 44.56% yield and 99.50% HPLC purity.
LC-MS：512.20[M+H+]As shown in fig. 1.
1H-NMR(CDCl3，400MHz)：1.06(s,9H,t-Bu),2.41-2.45(dd,1H,8-H),2.04-2.13(m,5H,-CH3(ii) a 7-H),4.27-4.29(dd,1H,1-H),5.08-5.10(d,1H,2-H),5.87-5.88(d,1H,1-OH),6.21(s,1H,10-H),6.31(dd,1H,6-H),7.26(s,1H,12-H),7.39-7.43(dd,1H,21-H),8.31-8.33(d,1H,22-H),8.63-8.64(d,1H,20-H),9.38(s,1H,19-H), as shown in FIG. 2.
EXAMPLE 2 preparation of ginkgolide K-10-O-Isonicotinate (GKYY)
3.0g (7.38mmol) GK and 0.91g (7.38mmol,1.0eq) isonicotinic acid were weighed out and dissolved in 50mL acetonitrile and mixed with stirring in an ice bath. Then 0.09g (0.74mmol, 0.1eq) of 4-Dimethylaminopyridine (DMAP) and 1.56g (8.12mmol,1.1eq) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) were added, the mixture was stirred for 1 hour in an ice bath, the mixture was reacted at 20 ℃ for 6 hours, the solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate and 5% NaHCO was used3Washing was performed twice, and washing was performed once with saturated saline. The organic phase is dried, filtered and concentrated. Column chromatography purification (V)Petroleum ether：VEthyl acetate2:1) to obtain white solid 1.32g GKYY, yield 35.01% and HPLC purity 99.15%.
LC-MS：512.18[M+H+]。
1H-NMR(CDCl3，400MHz)：1.04(s,9H,t-Bu),2.16-2.22(dd,1H,8-H),2.06-2.13(m,5H,-CH3；7-H),3.91-3.95(dd,1H,1-H),5.02-5.03(d,1H,2-H),5.43-5.45(d,1H,1-OH),5.64(s,1H,10-H),6.02(dd,1H,6-H),7.12(s,1H,12-H),8.05-8.06(d,2H,pyridine),8.84-8.86(d,2H,pyridine)
EXAMPLE 3 preparation of ginkgolide K-10-O-Phenylacetate (GKB)
3.0g (7.38mmol) GK and 1.35g (11.07mmol,1.5eq) benzoic acid were weighed into 50mL acetonitrile and mixed with stirring in an ice bath. Then 0.09g (0.74mmol, 0.1eq) of 4-Dimethylaminopyridine (DMAP) and 2.12g (11.07mmol,1.5eq) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) were added, the mixture was stirred for 1 hour in an ice bath, the mixture was reacted at 20 ℃ for 6 hours, the solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate and 5% NaHCO was used3Washing was performed twice, and washing was performed once with saturated saline. The organic phase is dried, filtered and concentrated. Column chromatography purification (V)Petroleum ether：VEthyl acetate1.62g GKB as white solid obtained after 3:1), yield 43.20%, HPLC purity 99.04%.
LC-MS：511.16[M+H+]。
1H-NMR(CDCl3，400MHz)：1.03(s,9H,t-Bu),2.40-2.43(dd,1H,8-H),2.05-2.13(m,5H,-CH3；7-H),4.12-4.18(dd,1H,1-H),4.80-4.82(d,1H,2-H),5.62-5.64(d,1H,1-OH),6.15(s,1H,10-H),6.27(dd,1H,6-H),7.20(s,1H,12-H),7.39-7.40(d,2H,Ph),7.98-8.02(d,1H,Ph),8.63-8.67(d,2H,Ph)
EXAMPLE 4 preparation of ginkgolide K-10-O-acetylsalicylate (GKS)
3.0g (7.38mmol) GK and 1.60g (8.86mmol,1.2eq) acetylsalicylic acid are weighed out and dissolved in 50mL acetonitrile and mixed with stirring in an ice bath. Then 0.18g (1.48mmol, 0.2eq) of 4-Dimethylaminopyridine (DMAP) and 2.12g (11.07mmol,1.5eq) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added(EDC. HCl), after stirring for 1h in an ice bath, the mixture was reacted at 20 ℃ for 6h, the solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate and 5% NaHCO was used3Washing was performed twice, and washing was performed once with saturated saline. The organic phase is dried, filtered and concentrated. Column chromatography purification (V)Petroleum ether：VEthyl acetate2:1) to yield 1.70g GKS as a white solid in 40.47% yield and 98.86% HPLC purity.
LC-MS：569.17[M+H+]。
1H-NMR(CDCl3，400MHz)：1.01(s,9H,t-Bu),2.34-2.36(dd,1H,8-H),2.10-2.19(m,5H,-CH3；7-H),2.25(s,3H,-COCH3)4.01-4.03(dd,1H,1-H),4.86-4.88(d,1H,2-H),5.12-5.15(d,1H,1-OH),6.04(s,1H,10-H),6.12(dd,1H,6-H),7.08(s,1H,12-H),7.39-7.45(d,1H,Ph),8.31-8.36(d,1H,Ph),8.60-8.64(d,1H,Ph),9.08-9.10(d,1H,Ph)
EXAMPLE 5 preparation of ginkgolide K-10-O-5-methylpyrazine-2-carboxylate (GKC)
3.0g (7.38mmol) of GK and 1.22g (8.86mmol,1.2eq) of 5-methylpyrazine-2-carboxylic acid are weighed out and dissolved in 50mL of acetonitrile and mixed with stirring in an ice bath. Then 0.09g (1.48mmol, 0.1eq) of 4-Dimethylaminopyridine (DMAP) and 1.84g (9.59mmol,1.3eq) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) were added, the mixture was stirred for 1 hour in an ice bath, the mixture was reacted at 20 ℃ for 4 hours, the solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate and 5% NaHCO was used3The washing was performed twice, and the washing was performed once with saturated brine. The organic phase is dried, filtered and concentrated. Column chromatography purification (V)Petroleum ether：VEthyl acetate2:1) to yield 1.82g GKC as a white solid in 46.91% yield and 98.96% HPLC purity.
LC-MS：527.18[M+H+]。
1H-NMR(CDCl3，400MHz)：1.02(s,9H,t-Bu),2.41-2.45(dd,1H,8-H),2.04-2.13(m,5H,-CH3；7-H),2.84-2.86(d,3H,CH3-pyrazine),4.27-4.29(dd,1H,1-H),5.08-5.10(d,1H,2-H),5.87-5.88(d,1H,1-OH),6.21(s,1H,10-H),6.31(dd,1H,6-H),7.03(s,1H,12-H),8.81-8.83(m,1H,pyrazine),9.05-9.09(m,1H,pyrazine)
EXAMPLE 6 preparation of ginkgolide K-10-O-3,5, 6-trimethylpyrazine-2-carboxylate (GKZ)
3.0g (7.38mmol) of GK and 1.47g (8.86mmol,1.2eq) of 3,5, 6-trimethylpyrazine-2-carboxylic acid are weighed out and dissolved in 50mL of acetonitrile and mixed with stirring in an ice bath. Then 0.09g (1.48mmol, 0.1eq) of 4-Dimethylaminopyridine (DMAP) and 1.84g (9.59mmol,1.3eq) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) were added, the mixture was stirred for 1 hour in an ice bath, the mixture was reacted at 20 ℃ for 5 hours, the solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate and 5% NaHCO was used3The washing was performed twice, and the washing was performed once with saturated brine. The organic phase is dried, filtered and concentrated. Column chromatography purification (V)Petroleum ether：VEthyl acetate2:1) to yield 1.80g GKZ as a white solid in 44.01% yield and 99.04% HPLC purity.
LC-MS：555.20[M+H+]。
1H-NMR(CDCl3，400MHz)：1.05(s,9H,t-Bu),2.23-2.26(dd,1H,8-H),2.05-2.16(m,5H,-CH3；7-H),2.54-2.63(m,6H,CH3-pyrazine),2.84-2.93(s,3H,CH3-pyrazine),4.01-4.05(dd,1H,1-H),4.86-4.88(d,1H,2-H),5.51-5.53(d,1H,1-OH),6.10(s,1H,10-H),6.26(dd,1H,6-H),7.03(s,1H,12-H)
Example 7 preparation of ginkgolide K-10-O-cinnamate (GKR)
3.0g (7.38mmol) of GK and 1.31g (8.86mmol,1.2eq) of cinnamic acid are weighed out and dissolved in 50mL of acetonitrile and mixed with stirring in an ice bath. Then 0.24g (1.48mmol, 0.2eq) of 1-hydroxybenzene was addedTriazole and 1.84g (9.59mmol,1.3eq)1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) were stirred under ice-bath conditions for 1 hour, the mixture was reacted at 20 ℃ for 5h, the solvent was removed by rotary evaporation, the crude product was dissolved with ethyl acetate, and 5% NaHCO was used3The washing was performed twice, and the washing was performed once with saturated brine. The organic phase is dried, filtered and concentrated. Column chromatography purification (V)Petroleum ether：VEthyl acetate1:1) to yield 1.61g of GKR as a white solid in 40.66% yield and 98.51% HPLC purity.
LC-MS：537.16[M+H+]。
1H-NMR(CDCl3，400MHz)：1.06(s,9H,t-Bu),2.28-2.30(dd,1H,8-H),2.06-2.19(m,5H,-CH3；7-H),3.86-3.91(dd,1H,1-H),4.26-4.28(d,1H,2-H),5.43-5.45(d,1H,1-OH),6.03(s,1H,10-H),6.22(dd,1H,6-H),6.81-6.83(d,1H,-CH＝CH-),7.10(s,1H,12-H),7.39-7.43(t,1H,Ph),7.61-7.63(t,2H,Ph),7.93-7.94(d,2H,Ph),8.38(s,1H,-CH＝CH-)
Example 8 preparation of ginkgolide K-10-O-Ferulic acid ester (GKA)
3.0g (7.38mmol) GK and 1.72g (8.86mmol,1.2eq) ferulic acid were dissolved in 50mL acetonitrile and mixed with stirring in an ice bath. Then 0.24g (1.48mmol, 0.2eq) of 1-hydroxybenzotriazole and 1.84g (9.59mmol,1.3eq) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) were added, the mixture was stirred for 1 hour in ice bath, after which it was reacted at 20 ℃ for 6 hours, the solvent was removed by rotary evaporation, the crude product was dissolved in ethyl acetate and 5% NaHCO was used3The washing was performed twice, and the washing was performed once with saturated brine. The organic phase is dried, filtered and concentrated. Column chromatography purification (V)Petroleum ether：VEthyl acetate1:1) to yield 1.38g GKA as white solid in 32.09% yield and 98.64% HPLC purity.
LC-MS：583.19[M+H+]。
1H-NMR(CDCl3，400MHz)：1.06(s,9H,t-Bu),2.46-2.47(dd,1H,8-H),2.01-2.15(m,5H,-CH3；7-H),2.84-2.85(s,3H,-OCH3),4.05-4.08(dd,1H,1-H),4.85-4.87(d,1H,2-H),5.36-5.39(d,1H,1-OH),5.97-5.98(d,1H,Ph-OH),6.06(s,1H,10-H),6.14(dd,1H,6-H),6.81-6.85(d,1H,-CH＝CH-),7.13(s,1H,12-H),7.39-7.43(d,1H,Ph),7.51-7.53(d,1H,Ph),7.63-7.64(d,1H,Ph),8.38(d,1H,-CH＝CH-)
EXAMPLE 9 preparation of ginkgolide K-10-O-5-methylpyrazine-2-carboxylate (GKC) hydrochloride
Heating 1.0g of ginkgolide K-10-O-5-methylpyrazine-2-carboxylate to 40-50 ℃, stirring and dissolving in 20mL of absolute ethanol, slowly dropwise adding 10mL of hydrogen chloride ethanol solution (with the content of 30-40%), refrigerating and crystallizing after dropwise adding, filtering and drying to obtain 0.82g of ginkgolide K-10-O-5-methylpyrazine-2-carboxylate (GKC) hydrochloride with the yield of 80.25%. EXAMPLE 10 preparation of ginkgolide K-10-O-3,5, 6-trimethylpyrazine-2-carboxylate (GKZ) hydrochloride
Heating 1.0g of ginkgolide K-10-O-3,5, 6-trimethyl pyrazine-2-carboxylate (GKZ) to 40-50 ℃, stirring and dissolving in 20mL of absolute ethanol, slowly dropwise adding 10mL of hydrogen chloride ethanol solution (with the content of 30-40%), refrigerating and crystallizing after dropwise adding, filtering and drying to obtain 0.73g of ginkgolide K-10-O-3,5, 6-trimethyl pyrazine-2-carboxylate hydrochloride, wherein the yield is 70.08%.
The advantageous effects of the present invention will be described below by way of test examples.
Test example 1 Water solubility test
The determination method comprises the following steps: the sample is ground into fine powder, the target compound is quantitatively weighed and added into purified water, and the solubility of the target compound is examined by ultrasonic. The results are shown in Table 1.
TABLE 1 Water solubility test
The results show that the water solubility of the ginkgolide K derivatives and the salts thereof is obviously improved compared with that of the ginkgolide K.
Test example 2 biological Activity test
The samples for this activity test were selected from the group consisting of ginkgolide K, ginkgolide K-10-O-nicotinate (GKY-2), ginkgolide K-10-O-isonicotinate (GKYY), ginkgolide K-10-O-phenylacetate (GKB), ginkgolide K-10-O-acetylsalicylate (GKS), ginkgolide K-10-O-5-methylpyrazine-2-carboxylate (GKC), ginkgolide K-10-O-3,5, 6-trimethylpyrazine-2-carboxylate (GKZ), ginkgolide K-10-O-cinnamate (GKR) and ginkgolide K-10-O-ferulate (GKA).
Test reagents: PAF and dimethyl sulfoxide (DMSO) were obtained from sigma, sodium citrate and sodium pentobarbital from Chemicals, Inc., of the national drug group.
The platelet aggregation reaction is closely related to the formation of thrombus, atherosclerosis and other cardiovascular and cerebrovascular disease processes. The inventor adopts a turbidimetric method, takes PAF as an inducer, preliminarily inspects the influence of each in vitro sample on PAF-induced platelet aggregation, and takes the platelet aggregation inhibition rate as an index. The specific experimental method is as follows:
A. taking a healthy New Zealand white rabbit, anesthetizing with 3% sodium pentobarbital in ear vein, taking blood from abdominal aorta via a cannula, anticoagulating with 3.8% sodium citrate (the volume ratio of blood to anticoagulant is 9:1), centrifuging at room temperature of 200 Xg for 10min, sucking upper layer Platelet Rich Plasma (PRP), and residual blood of 3000 r.min-1Centrifugation was carried out for 10min, and Platelet Poor Plasma (PPP) was aspirated as supernatant. The prepared PRP should be used up within 3 h.
B. Precisely sucking 1 mul of different concentrations (2 mul mol. L)-1、4μmol·L-1、8μmol·L-1、16μmol·L-1) Adding the sample solution into 200 μ L PRP, adding equal volume of solvent DMSO into blank control group, incubating at 37 deg.C for 3min, zeroing with PPP, and adding 5 mg.L-1The maximum aggregation rate of PRP within 5min before and after administration of PAF solution (5. mu.l) was observed under stirring at 37 ℃ and the platelet aggregation inhibition rate was calculated according to the following formula. The results are shown in Table 2.
Platelet aggregation inhibition/% (maximum aggregation rate of blank control group-maximum aggregation rate of administration group)/maximum aggregation rate of blank control group × 100%.
TABLE 2 inhibition of PAF-induced platelet aggregation in vitro
Note: p < 0.05, P < 0.01 for each drug group compared to the control blank.
Experimental results prove that the ginkgolide K series derivatives and the ginkgolide K have obvious biological activity.
In conclusion, the novel derivative of ginkgolide K with better water solubility and good activity is obtained by modifying the structure of ginkgolide K, and can be used for inhibiting platelet aggregation and preventing and treating cardiovascular and cerebrovascular diseases, nervous system diseases and immune system diseases. Meanwhile, the preparation process of the ginkgolide K derivative is simple and convenient, and is suitable for industrial production.
Claims (13)
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is one of the following:
2. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is selected from organic acid salt or inorganic acid salt.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: the organic acid salt is selected from mesylate, p-toluenesulfonate, lactate, citrate, succinate, salicylate or acetate; the inorganic acid salt is selected from hydrochloride, sulfate or phosphate.
4. A process for preparing a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: the method comprises the following steps:
dissolving ginkgolide K and a compound shown as a formula (II) in an organic solvent, and adding a catalyst and a condensing agent to prepare a compound shown as a formula (I);
wherein the organic solvent is selected from acetonitrile or N, N-dimethylformamide; the catalyst is selected from 4-dimethylamino pyridine or 1-hydroxybenzotriazole; the condensing agent is selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide or diisopropylcarbodiimide.
5. The method of claim 4, wherein: the molar ratio of the ginkgolide K to the compound shown in the formula (II) is 1: 1-1: 5; the molar ratio of the ginkgolide K to the catalyst is 1: 0.1-1: 0.3; the molar ratio of the ginkgolide K to the condensing agent is 1: 1.1-1: 1.6.
6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament from the class of platelet aggregation inhibitors.
7. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention, treatment and/or alleviation of cardiovascular and cerebrovascular diseases.
8. The use according to claim 7, wherein the cardiovascular and cerebrovascular diseases are hypertension, congenital heart disease, coronary heart disease, myocardial infarction, acute coronary syndrome, atherosclerosis, left trunk lesion, bifurcation lesion, angina pectoris, and stroke.
9. The use according to claim 7, wherein the cardiovascular and cerebrovascular diseases are acute myocardial infarction, coronary artery disease, essential hypertension, peripheral artery disease, arrhythmia.
10. The use according to claim 7, wherein the cardiovascular and cerebrovascular diseases are myocarditis, rheumatic heart disease, cor pulmonale, infectious heart disease, endocrinological heart disease, anemic heart disease, cardiac neurosis, nutritional metabolic heart disease, aortic aneurysm, arteriosclerosis of lower limbs, and cerebral embolism.
11. The use according to claim 7, wherein the cardiovascular and cerebrovascular diseases are intracranial aneurysm, arteriosclerotic aneurysm, ischemic stroke, hemorrhagic stroke, hyperlipidemia, myocardial diseases, and pericardial diseases.
12. The use according to claim 7, wherein the cardiovascular and cerebrovascular diseases are arteriosclerosis, sudden exercise death, sudden cardiac death, cerebral stroke, hypotension, vascular embolism, pulmonary embolism, ventricular arrhythmia, complex arrhythmia, hereditary arrhythmia, malignant arrhythmia, atrial fibrillation, heart failure, valvular disease, hypertensive encephalopathy.
13. The use according to claim 7, wherein the cardiovascular and cerebrovascular diseases are hypertension complicated with cerebral apoplexy, cerebral hemorrhage, cerebral infarction, cerebral arteritis, cerebral arteriosclerosis, lacunar infarction and vascular dementia.
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Denomination of invention: Novel derivative of ginkgolide K and its preparation method and Application Effective date of registration: 20220316 Granted publication date: 20210416 Pledgee: Bank of Guiyang Limited by Share Ltd. Chengdu branch Pledgor: CHENGDU BAIYU PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980002594 |