CN108069980A - Bilobalide K new derivatives and its preparation method and application - Google Patents
Bilobalide K new derivatives and its preparation method and application Download PDFInfo
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- CN108069980A CN108069980A CN201611008733.5A CN201611008733A CN108069980A CN 108069980 A CN108069980 A CN 108069980A CN 201611008733 A CN201611008733 A CN 201611008733A CN 108069980 A CN108069980 A CN 108069980A
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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 discloses bilobalide K new derivatives shown in formula (I) and its preparation method and application.The present invention has obtained water-soluble more preferable, activity bilobalide K new derivatives well, available for the prevention for inhibiting platelet aggregation and cardiovascular and cerebrovascular disease, the nervous system disease and disease of immune system by carrying out structural modification to bilobalide K.Meanwhile bilobalide K derivative preparation process of the invention is easy, is suitable for industrialized production.
Description
Technical field
The present invention relates to the bilobalide K derivatives of a series of new, and in particular to bilobalide K derivative and its preparation
Method and purposes.
Background technology
Ginkgolide compound is main active ingredient in ginkgo leaf, it turned out that they have extensive pharmacological action
And pharmacy value.The ginkgolide compound having now been found that includes ginkalide A, ginkolide B, ginkalide C, white
Fruit lactone, bilobalide J, ginkgolides M, ginkgolides L, bilobalide K etc..Wherein, bilobalide K is logical through Lou Fengchang et al.
It has crossed since the equal means of preparation solution obtain micro-example and carry out structural characterization through nuclear-magnetism and IR interface, is closed extensively
Note.
First, patent CN1424315A discloses bilobalide K compound, extracting method and the medicine containing bilobalide K
Compositions；Subsequent patent CN1919848A, CN102002052A, CN101824041A and CN105001231A are sequentially reported
The method that bilobalide K is prepared by ginkolide B；In recent years, document " Chinese Pharmaceutical Journal .2011,46 (13):993-997”、
" Chinese Journal of Modern Applied Pharmacy .2011,28 (10):877-880 " etc. also reports bilobalide K and is not only a kind of strong blood platelet work
Change the factor (PAF) receptor antagonist, moreover it is possible to which the damage of mouse Nerve cell caused by improving cerebral ischemia re-pouring reduces tissue
Necrosis and Neuron Apoptosis.It can be seen that bilobalide K has apparent defencive function to cerebral ischemia, have good medicinal
Prospect.Bilobalide K (GK) structure is as follows：
Since bilobalide K is a kind of diterpene compound of six rings cage structure, structural rigidity is stronger, is insoluble in water, raw
Object availability is poor, and giving full play to for drug effect is caused to be subject to certain restrictions, and influences clinical medicinal effects.
Therefore, it is necessary to carry out further structural modification to bilobalide K, improved to obtain water solubility, people
The bilobalide K new derivatives that body bioavilability and bioactivity are improved, for cardiovascular and cerebrovascular disease, nerveous system
The prevention of disease of uniting and disease of immune system.
The content of the invention
To solve the above problems, the present invention provides formula (I) compound represented or its optical isomer or its along anti-
Isomers or its solvate or its pharmaceutically acceptable salt：
Wherein, R expression-Ar or-A-Ar；
Ar represents phenyl, pyridyl group or pyrazinyl, they can not be substituted or be substituted by 1~5 substituent group, substituent group
Selected from halogen, hydroxyl, cyano, carboxyl, C1~C6Alkyl, C2~C6Alkenyl, C2~C6Alkynyl, C1~C6Halogenated alkyl,
C1~C6Alkoxy, C1~C6Acyloxy or C1~C6Ester group；
A represents C2~C8Alkenylene, the alkenylene can not be substituted or by C1~C6Alkyl substituted.
Further, A represents ethenylidene.
Further, the C1~C6Alkyl be selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle
Butyl or sec-butyl；The C1~C6Alkoxy be selected from methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, different
Butoxy, tert-butoxy or sec-butoxy；The C1~C6Acyloxy be selected from formyloxy, acetoxyl group, positive propionyloxy,
Isopropenoxy, positive butyryl acyloxy, isobutyl acyloxy, tertiary butyryl acyloxy or secondary butyryl acyloxy.
Further, the compound is one of following compound：
Further, the pharmaceutically acceptable salt is selected from acylate or inorganic acid salt.
Further, the acylate is selected from mesylate, tosilate, lactate, citrate, succinic acid
Salt, salicylate or acetate；The inorganic acid salt is selected from hydrochloride, sulfate or phosphate.
The present invention also provides it is a kind of prepare foregoing compound or its optical isomer or its cis-trans-isomer or its
The method of solvate or its pharmaceutically acceptable salt, comprises the following steps：
Compound shown in bilobalide K and formula (II) is dissolved in organic solvent, catalyst and condensing agent is added in, is prepared into
To compound shown in formula (I)；
Wherein, organic solvent is selected from acetonitrile or n,N-Dimethylformamide；Catalyst is selected from 4-dimethylaminopyridine or 1-
Hydroxybenzotriazole；It is sub- that condensing agent is selected from 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, dicyclohexyl carbon two
Amine or diisopropylcarbodiimide.
Further, the molar ratio of compound shown in the bilobalide K and formula (II) is 1:1~1:5；Bilobalide K
Molar ratio with catalyst is 1:0.1~1:0.3；The molar ratio of bilobalide K and condensing agent is 1:1.1~1:1.6.
The present invention also provides foregoing compounds or its optical isomer or its cis-trans-isomer or its solvent to close
The purposes of object or its pharmaceutically acceptable salt in platelet aggregation inhibitor class drug is prepared.
The present invention also provides foregoing compounds or its optical isomer or its cis-trans-isomer or its solvent to close
Object or its pharmaceutically acceptable salt are preparing for preventing, handle, treat and/or mitigate cardiovascular and cerebrovascular disease, nervous system
The purposes of disease and disease of immune system drug；Preferably, the cardiovascular and cerebrovascular disease for hypertension, congenital heart disease, coronary heart disease,
Myocardial infarction, acute myocardial infarction AMI, acute coronary syndrome, coronary artery disease, coronary artery lead to art, artery again
Atherosis, Left main stem disease, bifurcated lesions, angina pectoris, thrombus, myocarditis, rheumatic heart disease, essential hypertension, lung
Source property heart disease, infectious heart disease, endocrine characteristic of disease heart disease, anemic cardiopathy, cardioneurosis, the Nutrition and Metabolism heart
Popular name for, aortic aneurysm, lower extremities disease, peripheral arterial disease, intracranial aneurysm, arteriosclerotic aneurysm, ischemic
Property cerebral apoplexy, hemorrhagic apoplexy, hyperlipidemia, artery sclerosis, exercise related sudden death, sudden cardiac death, apoplexy, headstroke, low blood pressure,
Blood vessel embolism, pulmonary embolism, arrhythmia cordis, ventricular arrhythmia, complex arrhythmias, heredity arrhythmia cordis, malignant cardiac rhythm
Not normal, atrial fibrillation, heart failure, cardiomyopathies, pericardial disease, valvular heart disease, hypertensive encephalophathy, hypertensive patients cerebral apoplexy, brain
Bleeding, cerebral thrombus, cerebral embolism, cerebral infarction, cerebral arteritis, cerebral arteriovenous malformation, lacunar infarction, vascular dementia, kidney trouble,
Kidney damage, chronic kidney disease, metabolic syndrome, chronic cardiac insufficiency, gouty nephropathy, diabetic nephropathy or renal function are different
Often.
The results show, the present invention have obtained water-soluble more preferable, activity by carrying out structural modification to bilobalide K
Good bilobalide K derivative, available for inhibiting platelet aggregation and cardiovascular and cerebrovascular disease, the nervous system disease and exempt from
The prevention of epidemic disease systemic disease.Meanwhile bilobalide K derivative preparation process of the invention is easy, is suitable for industrialized production.
In the present invention, the C1~C6Alkyl refer to C1、C2、C3、C4、C5、C6Alkyl, i.e., with 1~6 carbon atom
Linear chain or branch chain alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, sec-butyl, amyl,
Hexyl etc..Similar, C1~C6Alkyl, C1~C6Alkenyl, C1~C6Alkynyl, C1~C6Halogenated alkyl, C1~C6's
Alkoxy, C1~C6Acyloxy or C1~C6Ester group also refer to corresponding 1~6 carbon atom or 2~6 carbon atoms
Group.
In the present invention, " treatment " also includes recurrent (relapse) prevention or interim (phase) prevention and acute
Or the treatment of chronic sign, symptom and/or malfunction.Treatment can be symptomatic treatment, such as inhibit symptom.It can be short
It is realized in phase, adjusts or can be described as long-term treatment in mid-term, such as inside maintenance therapy.
In the present invention, " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material and/or is formed
Salt is usually in chemistry or physically with forming the other compatible into split-phase of certain pharmaceutical dosage form, and physiologically mutually simultaneous with receptor
Hold.
In the present invention, " salt " is the acid with the formation of inorganic and/or organic bronsted lowry acids and bases bronsted lowry by compound or its stereoisomer
And/or basic salt, also including amphoteric ion salt (inner salt), further include quaternary ammonium salt, such as alkylammonium salt.These salt can changed
Close being finally separating and being directly obtained in purifying for object.Can also be by by compound or its stereoisomer, with certain amount
Acid or alkali appropriate (such as equivalent) be obtained by mixing.These salt may be formed in the solution precipitation and with filter method
It collects or recycles after the solvent evaporates and obtain or be freeze-dried after reacting in aqueous medium to be made.Heretofore described salt can
Be the hydrochloride of compound, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphate, acetate,
Propionate, succinate, oxalates, malate, succinate, fumarate, maleate, tartrate or trifluoroacetic acid
Salt.
Obviously, the above according to the present invention according to the ordinary technical knowledge and customary means of this field, is not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically the above of the present invention
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
Description of the drawings
Fig. 1 is the LC-MS collection of illustrative plates (LC-MS) of 10-O- niacin bilobalide K (GKY-2)；
Fig. 2 be 10-O- niacin bilobalide K (GKY-2) nucleus magnetic hydrogen spectrum (1H-NMR)。
Specific embodiment
Raw materials used in the present invention, reagent source is as follows：
Bilobalide K (GK)：Self-control, lot number：20160701.
Acetylsalicylic acid：Chengdu Ke Long chemical reagents factory, lot number 2013101601
Cinnamic acid：Beijing lark prestige Science and Technology Ltd., lot number：159270.
Forulic acid：Aladdin reagent, lot number：l1517121.
Niacin：Chengdu Ke Long chemical reagents factory, lot number：2015040101
Isonicotinic acid：Chengdu Ke Long chemical reagents factory, lot number：2015101601.
5-Methylpyrazine-2-carboxylic acid：Chemical reagent Co., Ltd of Chengdu China, lot number：L050904
Benzoic acid：Chengdu Ke Long chemical reagents factory, lot number：2015080101
3,5,6- trimethylpyrazine -2- formic acid：Self-control, lot number：20160715
4-dimethylaminopyridine (DMAP)：Chengdu Ke Long chemical reagents factory, lot number：2016020101
The preparation of 1 bilobalide K -10-O- nicotinates (GKY-2) of embodiment
It weighs 3.0g (7.38mmol) GK and 1.09g (8.86mmol, 1.2eq) niacin to be dissolved in 50mL acetonitriles, in ice bath
In be stirred.Then add in 0.09g (0.74mmol, 0.1eq) 4-dimethylaminopyridine (DMAP) and 1.56g (8.12mmol,
1.1eq) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCHCl), when stirring 1 is small under condition of ice bath
Afterwards, mixture reacts 6h in 20 DEG C, and revolving removes solvent, dissolves crude product with ethyl acetate, and uses 5%NaHCO3Cleaning two
Secondary, saturated brine cleans once.Organic phase is collected, is dried, filtered and concentrated, column chromatographic isolation and purification (petroleum ether：Ethyl acetate
=2:1) white solid 1.68g, yield 44.56% are obtained after, HPLC purity is 99.50%.
LC-MS：512.20[M+H+], as shown in Figure 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；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 Figure 2.
The preparation of 2 bilobalide K -10-O- iso-nicotinates (GKYY) of embodiment
It weighs 3.0g (7.38mmol) GK and 0.91g (7.38mmol, 1.0eq) isonicotinic acid to be dissolved in 50mL acetonitriles, Yu Bing
It is stirred in bath.Then 0.09g (0.74mmol, 0.1eq) 4-dimethylaminopyridine (DMAP) and 1.56g are added in
(8.12mmol, 1.1eq) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCHCl), under condition of ice bath
Stir 1 it is small when after, mixture reacts 6h in 20 DEG C, and revolving removes solvent, dissolves crude product with ethyl acetate, and with 5%
NaHCO3Twice, saturated brine washed once for cleaning.Organic phase is filtered, concentrated after drying.Column chromatography purifies (VPetroleum ether：VEthyl acetate
=2:1) white solid 1.32g GKYY, yield 35.01%, HPLC purity 99.15% are obtained after.
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)
The preparation of 3 bilobalide K -10-O- phenylacetates (GKB) of embodiment
It weighs 3.0g (7.38mmol) GK and 1.35g (11.07mmol, 1.5eq) benzoic acid to be dissolved in 50mL acetonitriles, Yu Bing
It is stirred in bath.Then 0.09g (0.74mmol, 0.1eq) 4-dimethylaminopyridine (DMAP) and 2.12g are added in
(11.07mmol, 1.5eq) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCHCl), under condition of ice bath
Stir 1 it is small when after, mixture reacts 6h in 20 DEG C, and revolving removes solvent, dissolves crude product with ethyl acetate, and with 5%
NaHCO3Twice, saturated brine washed once for cleaning.Organic phase is filtered, concentrated after drying.Column chromatography purifies (VPetroleum ether：VEthyl acetate
=3:1) white solid 1.62g GKB, yield 43.20%, HPLC purity 99.04% are obtained after.
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)
The preparation of 4 bilobalide K -10-O- acetylsalicylates (GKS) of embodiment
3.0g (7.38mmol) GK and 1.60g (8.86mmol, 1.2eq) acetylsalicylic acid is weighed to be dissolved in 50mL acetonitriles,
It is stirred in ice bath.Then 0.18g (1.48mmol, 0.2eq) 4-dimethylaminopyridine (DMAP) and 2.12g are added in
(11.07mmol, 1.5eq) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCHCl), under condition of ice bath
Stir 1 it is small when after, mixture reacts 6h in 20 DEG C, and revolving removes solvent, dissolves crude product with ethyl acetate, and with 5%
NaHCO3Twice, saturated brine washed once for cleaning.Organic phase is filtered, concentrated after drying.Column chromatography purifies (VPetroleum ether：VEthyl acetate
=2:1) white solid 1.70g GKS, yield 40.47%, HPLC purity 98.86% are obtained after.
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)
The preparation of 5 bilobalide K -10-O-5- methylpyrazine-2-carboxylic acids ester (GKC) of embodiment
It weighs 3.0g (7.38mmol) GK and 1.22g (8.86mmol, 1.2eq) 5-Methylpyrazine-2-carboxylic acid and is dissolved in 50mL
In acetonitrile, it is stirred in ice bath.Then add in 0.09g (1.48mmol, 0.1eq) 4-dimethylaminopyridine (DMAP) and
1.84g (9.59mmol, 1.3eq) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCHCl), ice bath item
After when stirring 1 is small under part, mixture reacts 4h in 20 DEG C, and revolving removes solvent, dissolves crude product with ethyl acetate, and with 5%
NaHCO3It washes twice, saturated brine washed once.Organic phase is filtered, concentrated after drying.Column chromatography purifies (VPetroleum ether：VEthyl acetate
=2:1) white solid 1.82g GKC, yield 46.91%, HPLC purity 98.96% are obtained after.
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)
The preparation of 6 bilobalide K -10-O-3,5,6- trimethylpyrazine -2- carboxylates (GKZ) of embodiment
It is molten to weigh 3.0g (7.38mmol) GK and 1.47g (8.86mmol, 1.2eq) 3,5,6- trimethylpyrazine -2- carboxylic acids
In 50mL acetonitriles, it is stirred in ice bath.Then 0.09g (1.48mmol, 0.1eq) 4-dimethylaminopyridine is added in
(DMAP) and 1.84g (9.59mmol, 1.3eq) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC
HCl), after when stirring 1 is small under condition of ice bath, mixture reacts 5h in 20 DEG C, and revolving removes solvent, dissolves thick production with ethyl acetate
Object, and use 5%NaHCO3It washes twice, saturated brine washed once.Organic phase is filtered, concentrated after drying.Column chromatography purifies
(VPetroleum ether：VEthyl acetate=2:1) white solid 1.80g GKZ, yield 44.01%, HPLC purity 99.04% are obtained after.
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)
The preparation of 7 bilobalide K -10-O- cinnamates (GKR) of embodiment
It weighs 3.0g (7.38mmol) GK and 1.31g (8.86mmol, 1.2eq) cinnamic acid to be dissolved in 50mL acetonitriles, Yu Bing
It is stirred in bath.Then add in 0.24g (1.48mmol, 0.2eq) I-hydroxybenzotriazoles and 1.84g (9.59mmol,
1.3eq) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCHCl), when stirring 1 is small under condition of ice bath
Afterwards, mixture reacts 5h in 20 DEG C, and revolving removes solvent, dissolves crude product with ethyl acetate, and uses 5%NaHCO3Washing two
Secondary, saturated brine washed once.Organic phase is filtered, concentrated after drying.Column chromatography purifies (VPetroleum ether：VEthyl acetate=1:1) obtained in vain after
Color solid 1.61g GKR, yield 40.66%, HPLC purity 98.51%.
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-)
The preparation of 8 bilobalide K -10-O- ferulic acid esters (GKA) of embodiment
It weighs 3.0g (7.38mmol) GK and 1.72g (8.86mmol, 1.2eq) forulic acid to be dissolved in 50mL acetonitriles, Yu Bing
It is stirred in bath.Then add in 0.24g (1.48mmol, 0.2eq) I-hydroxybenzotriazoles and 1.84g (9.59mmol,
1.3eq) 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCHCl), when stirring 1 is small under condition of ice bath
Afterwards, mixture reacts 6h in 20 DEG C, and revolving removes solvent, dissolves crude product with ethyl acetate, and uses 5%NaHCO3Washing two
Secondary, saturated brine washed once.Organic phase is filtered, concentrated after drying.Column chromatography purifies (VPetroleum ether：VEthyl acetate=1:1) obtained in vain after
Color solid 1.38g GKA, yield 32.09%, HPLC purity 98.64%.
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-)
The preparation of embodiment 9 bilobalide K -10-O-5- methylpyrazine-2-carboxylic acids ester (GKC) hydrochloride
By 1.0g bilobalide K -10-O-5- methylpyrazine-2-carboxylic acid esters be heated to 40-50 DEG C of stirring and dissolving in 20mL without
In water-ethanol, 10mL ethanol solution of hydrogen chloride (content 30-40%) is slowly added dropwise thereto, drop refrigerates crystallization after finishing, and filters, and does
It is dry to get bilobalide K -10-O-5- methylpyrazine-2-carboxylic acids ester (GKC) hydrochloride 0.82g, yield 80.25%.Embodiment
The preparation of 10 bilobalide K -10-O-3,5,6- trimethylpyrazine -2- carboxylates (GKZ) hydrochlorides
1.0g bilobalide K -10-O-3,5,6- trimethylpyrazine -2- carboxylates (GKZ) are heated to 40-50 DEG C of stirring
It is dissolved in 20mL absolute ethyl alcohols, 10mL ethanol solution of hydrogen chloride (content 30-40%) is slowly added dropwise thereto, after being added dropwise
Crystallization is refrigerated, filtering is dry to get bilobalide K -10-O-3,5,6- trimethylpyrazine -2- carboxylate hydrochloride 0.73g, receives
Rate 70.08%.
Illustrate beneficial effects of the present invention with the mode of test example below.
1 soluble test of test example
Assay method：Sample is taken to be ground into fine powder, target compound is quantitatively weighed and adds in purified water, ultrasound investigates its dissolving
Property.The results are shown in Table 1.
1 soluble test of table
The result shows that the water solubility of bilobalide K derivative and its salt improves significantly compared with bilobalide K.
2 biological activity test of test example
The sample of this activity test be selected from bilobalide K, bilobalide K -10-O- nicotinates (GKY-2), bilobalide K -
10-O- iso-nicotinates (GKYY), bilobalide K -10-O- phenylacetates (GKB), bilobalide K -10-O- acetylsalicylates
(GKS), bilobalide K -10-O-5- methylpyrazine-2-carboxylic acids ester (GKC), bilobalide K -10-O-3,5,6- trimethyl pyrroles
Piperazine -2- carboxylates (GKZ), bilobalide K -10-O- cinnamates (GKR) and bilobalide K -10-O- ferulic acid esters (GKA).
Test reagent：Purchased from sigma companies, sodium citrate, yellow Jackets are purchased from state for PAF, dimethyl sulfoxide (DMSO) (DMSO)
Chemical reagent Co., Ltd of medicine group.
Platelet aggregation reacts the close phase of pathogenic process with many cardiovascular and cerebrovasculars such as formation, the atherosclerosis of thrombus
It closes.Inventor uses turbidimetry, and using PAF as derivant, the external each sample of preliminary examinations is to the shadow of the PAF platelet aggregations induced
It rings, and using L-Arginine as index.Specific experiment method is as follows：
A. the New Zealand White Rabbit of health is taken, is anaesthetized with 3% yellow Jackets auricular vein, abdominal aortic cannulation takes blood, with
(blood is 9 with anti-coagulants volume ratio for 3.8% sodium citrate anti-freezing:1), 200 × g centrifuges 10min at room temperature, draws upper strata Fu Xue little
Plate blood plasma (platelet rich plasma, PRP), residual blood 3000rmin-1Centrifuge 10min, Aspirate supernatant anaemia
Platelet-poor plasma (platelet poor plasma, PPP).The PRP prepared should be finished in 3h.
B. it is accurate to draw 1 μ l various concentrations (2 μm of olL-1、4μmol·L-1、8μmol·L-1、16μmol·L-1) sample
Product solution is added in 200 μ lPRP, and blank control group adds in isometric solvent DMSO, after 37 DEG C are incubated 3min, with PPP tune
Zero, add 5mgL-15 μ l of PAF solution observe maximum aggregations of the PRP in 5min before and after medication under 37 DEG C of stirring conditions
Rate, and L-Arginine is calculated as follows.The results are shown in Table 2.
L-Arginine/%=(blank control group maximum aggregation rate-administration group maximum aggregation rate)/blank pair
According to group maximum aggregation rate × 100%.
Table 2 inhibits the platelet aggregation of PAF inductions in vitro
Note：Each medicine group is compared with blank control group, * P ＜ 0.05, * * P ＜ 0.01.
The results show, bilobalide K series derivates are respectively provided with significant bioactivity with bilobalide K.
In conclusion the present invention has obtained water-soluble more preferable, activity very well by carrying out structural modification to bilobalide K
Bilobalide K new derivatives, available for inhibiting platelet aggregation and cardiovascular and cerebrovascular disease, the nervous system disease and exempt from
The prevention of epidemic disease systemic disease.Meanwhile bilobalide K derivative preparation process of the invention is easy, is suitable for industrialized production.
Claims (10)
1. formula (I) compound represented or its optical isomer or its cis-trans-isomer or its solvate or its pharmaceutically
Acceptable salt：
Wherein, R expression-Ar or-A-Ar；
Ar represents phenyl, pyridyl group or pyrazinyl, they can not be substituted or be substituted by 1~5 substituent group, and substituent group is selected from
Halogen, hydroxyl, cyano, carboxyl, C1~C6Alkyl, C2~C6Alkenyl, C2~C6Alkynyl, C1~C6Halogenated alkyl, C1~
C6Alkoxy, C1~C6Acyloxy or C1~C6Ester group；
A represents C2~C8Alkenylene, the alkenylene can not be substituted or by C1~C6Alkyl substituted.
2. compound according to claim 1, it is characterised in that：A represents ethenylidene.
3. compound according to claim 1 or 2, it is characterised in that：The C1~C6Alkyl be selected from methyl, ethyl, just
Propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl or sec-butyl；The C1~C6Alkoxy be selected from methoxyl group, ethyoxyl,
Positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or sec-butoxy；The C1~C6Acyloxy be selected from
Formyloxy, acetoxyl group, positive propionyloxy, isopropenoxy, positive butyryl acyloxy, isobutyl acyloxy, tertiary butyryl acyloxy or secondary
Butyryl acyloxy.
4. compound according to claim 1, it is characterised in that：The compound is one of following compound：
5. according to claim 1-4 any one of them compound or its optical isomer or its cis-trans-isomer or its is molten
Object or its pharmaceutically acceptable salt are closed in agent, it is characterised in that：The pharmaceutically acceptable salt is selected from acylate or inorganic
Hydrochlorate.
6. the compound according to claim 5 or its optical isomer or its cis-trans-isomer or its solvent
Close object or its pharmaceutically acceptable salt, it is characterised in that：The acylate is selected from mesylate, tosilate, breast
Hydrochlorate, citrate, succinate, salicylate or acetate；The inorganic acid salt is selected from hydrochloride, sulfate or phosphoric acid
Salt.
7. it is a kind of prepare claim 1-6 any one of them compound or its optical isomer or its cis-trans-isomer or
The method of its solvate or its pharmaceutically acceptable salt, it is characterised in that：Comprise the following steps：
Compound shown in bilobalide K and formula (II) is dissolved in organic solvent, catalyst and condensing agent is added in, formula is prepared
(I) compound shown in；
Wherein, organic solvent is selected from acetonitrile or n,N-Dimethylformamide；Catalyst is selected from 4-dimethylaminopyridine or 1- hydroxyls
Benzotriazole；Condensing agent be selected from 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, dicyclohexylcarbodiimide or
Diisopropylcarbodiimide.
8. preparation method according to claim 7, it is characterised in that：Compound shown in the bilobalide K and formula (II)
Molar ratio be 1:1~1:5；The molar ratio of bilobalide K and catalyst is 1:0.1~1:0.3；Bilobalide K and condensing agent
Molar ratio be 1:1.1~1:1.6.
9. claim 1-6 any one of them compound or its optical isomer or its cis-trans-isomer or its solvent close
The purposes of object or its pharmaceutically acceptable salt in platelet aggregation inhibitor class drug is prepared.
10. claim 1-6 any one of them compound or its optical isomer or its cis-trans-isomer or its solvent close
Object or its pharmaceutically acceptable salt are preparing for preventing, handle, treat and/or mitigate cardiovascular and cerebrovascular disease, nervous system
The purposes of disease and disease of immune system drug；Preferably, the cardiovascular and cerebrovascular disease for hypertension, congenital heart disease, coronary heart disease,
Myocardial infarction, acute myocardial infarction AMI, acute coronary syndrome, coronary artery disease, coronary artery lead to art, artery again
Atherosis, Left main stem disease, bifurcated lesions, angina pectoris, thrombus, myocarditis, rheumatic heart disease, essential hypertension, lung
Source property heart disease, infectious heart disease, endocrine characteristic of disease heart disease, anemic cardiopathy, cardioneurosis, the Nutrition and Metabolism heart
Popular name for, aortic aneurysm, lower extremities disease, peripheral arterial disease, intracranial aneurysm, arteriosclerotic aneurysm, ischemic
Property cerebral apoplexy, hemorrhagic apoplexy, hyperlipidemia, artery sclerosis, exercise related sudden death, sudden cardiac death, apoplexy, headstroke, low blood pressure,
Blood vessel embolism, pulmonary embolism, arrhythmia cordis, ventricular arrhythmia, complex arrhythmias, heredity arrhythmia cordis, malignant cardiac rhythm
Not normal, atrial fibrillation, heart failure, cardiomyopathies, pericardial disease, valvular heart disease, hypertensive encephalophathy, hypertensive patients cerebral apoplexy, brain
Bleeding, cerebral thrombus, cerebral embolism, cerebral infarction, cerebral arteritis, cerebral arteriovenous malformation, lacunar infarction, vascular dementia, kidney trouble,
Kidney damage, chronic kidney disease, metabolic syndrome, chronic cardiac insufficiency, gouty nephropathy, diabetic nephropathy or renal function are different
Often.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112194568A (en) * | 2019-07-08 | 2021-01-08 | 福建中医药大学 | Long-chain triterpenoid compound and preparation method and application thereof |
| CN115109068A (en) * | 2021-03-19 | 2022-09-27 | 澳门科技大学 | Compound for preventing or treating cardiovascular and cerebrovascular diseases and preparation method and application thereof |
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| CN102382121A (en) * | 2010-09-02 | 2012-03-21 | 秦引林 | Ginkgolide derivative and application thereof to pharmacy |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112194568A (en) * | 2019-07-08 | 2021-01-08 | 福建中医药大学 | Long-chain triterpenoid compound and preparation method and application thereof |
| CN112194568B (en) * | 2019-07-08 | 2023-04-14 | 福建中医药大学 | Long-chain triterpenoid compound and preparation method and application thereof |
| CN115109068A (en) * | 2021-03-19 | 2022-09-27 | 澳门科技大学 | Compound for preventing or treating cardiovascular and cerebrovascular diseases and preparation method and application thereof |
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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 |