CN108084204A - Ginkgolide derivatives and its application - Google Patents
Ginkgolide derivatives and its application Download PDFInfo
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- CN108084204A CN108084204A CN201711189761.6A CN201711189761A CN108084204A CN 108084204 A CN108084204 A CN 108084204A CN 201711189761 A CN201711189761 A CN 201711189761A CN 108084204 A CN108084204 A CN 108084204A
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- HPJUNRWKACXNEJ-BJQYBCMWSA-O CCCCO[C@H]([C@@H](C1=C2C)OC2=O)[C@@](CC[C@@H](CC(C)(C)CC(COCC)NC)C23[C@H]4CCC)(C2[OH+]C2=O)[C@@]12OC3(CN)OC4=O Chemical compound CCCCO[C@H]([C@@H](C1=C2C)OC2=O)[C@@](CC[C@@H](CC(C)(C)CC(COCC)NC)C23[C@H]4CCC)(C2[OH+]C2=O)[C@@]12OC3(CN)OC4=O HPJUNRWKACXNEJ-BJQYBCMWSA-O 0.000 description 1
- XCYRBMXZHUBRNJ-ZNIRPZTQSA-N CC[C@H]([C@]([C@@H]([C@@](C)(C1=C2C)OC2=O)OCCCCN2CCNCC2)(C2(CC(C)(C)C)[C@H]3O)[C@@]11O[C@@H]2OC3=O)OC1=O Chemical compound CC[C@H]([C@]([C@@H]([C@@](C)(C1=C2C)OC2=O)OCCCCN2CCNCC2)(C2(CC(C)(C)C)[C@H]3O)[C@@]11O[C@@H]2OC3=O)OC1=O XCYRBMXZHUBRNJ-ZNIRPZTQSA-N 0.000 description 1
- VJYIQCHCZVCSEA-OQQRBGRBSA-N C[C@@H]([C@@]([C@H]([C@H]([C@@]1([C@@H](C[C@H]2C(C)(C)C)OC3=O)C22[C@H]4O)OCCCCCN5CCNCC5)O5)([C@]13O[C@@H]2OC4=O)O)C5=O Chemical compound C[C@@H]([C@@]([C@H]([C@H]([C@@]1([C@@H](C[C@H]2C(C)(C)C)OC3=O)C22[C@H]4O)OCCCCCN5CCNCC5)O5)([C@]13O[C@@H]2OC4=O)O)C5=O VJYIQCHCZVCSEA-OQQRBGRBSA-N 0.000 description 1
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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
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Abstract
The present invention modifies ginkgolides, a series of ginkolide B or the derivative of K are obtained, the ginkgolide derivatives structural formula such as formula I, shown in II, III or IV, it is shown experimentally that, after GB or GK structure of modification, to compound activity have promotion, especially with alkyl connect morpholine or it is piperazine modified after, activity improve it is particularly evident.The derivative has a wide range of applications in preventing or treating cardiovascular and cerebrovascular disease.
Description
Technical field
The present invention relates to technical field of traditional Chinese medicines more particularly to ginkgolide derivatives, pharmaceutically acceptable salt and its answer
With.
Background technology
Cerebral ischemia/reperfusion injury has serious harm property to human life and health, and brain blood is accounted for according to related research report
The 70%-85% of pipe disease, pathophysiological process is also sufficiently complex, its early stage can not only cause meronecrosis, also can be in evening
Phase causes Apoptosis.The exception of blood platelet (blood platelet, PLT) function accounts for important in cerebral ischemia re-pouring injured
Status, in ischemic tissue of brain, because of a variety of inducement stimulations, PTL adhesivenesses enhance and assemble so that tissue blood flow subtracts
It is few, the recovery of block cell function；During Reperfu- sion, the oxygen radical of abnormal increase makes the adhesiveness of PTL further
Increase, cause angiemphraxis and No-reflow phenoment occurs, and the cell assembled discharges oxygen radical, forms vicious circle.
Platelet activating factor (PAF) is the most strong platelet aggregation of presently found function, participate in it is hematoblastic activation and
The pathological processes such as inflammatory reaction.PAF is widely distributed in brain tissue, it mainly by with cell surface specific receptor knot
It closes and plays a role, such as Calcium overload, activation inflammatory mediator approach occurs, and then make nerve cell that irreversibility damage occur
Wound.
Ginkgo related preparations are widely used in clinic, treat the ischemic diseases such as the heart, brain, blood vessel and central nervous system,
Its therapeutic effect is notable.Have it is relevant the experimental results showed that, ginkgolides plays an important role of significant antagonism PAF, can be effectively pre-
The formation of anti-platelet aggregation and thrombus, while ginkgolides can also effectively mitigate ischemic Inflammatory Lesions, and guarantor is played to body
Shield acts on.But the drug effect of existing ginkgolide compound, Oral Availability etc. have deficiency, it is necessary to its structure into
Row modification, to find a kind of better compound.
The content of the invention
It is contemplated that modifying existing ginkgolide monomer, the higher derivative of activity is desirably to obtain.
The present invention proposes ginkgolide derivatives and its pharmaceutically acceptable salt, the ginkgolide derivatives structural formula
As shown in formula I, II, III or IV,
Wherein, R1 representatives-X-het, X represent the alkylidene with 3 to 5 carbon atoms, and het represents morpholinyl or piperazine
Base.
Specifically, which is selected from following compound,
Further, above-mentioned ginkgolide derivatives pharmaceutically acceptable salt is selected from trifluoroacetate, p-methyl benzenesulfonic acid
Salt, mesylate, hydrochloride, hydrobromate, sulfate or citrate any one.
The invention also provides above-mentioned ginkgolide derivatives and its pharmaceutically acceptable salt are preparing prevention or treatment
Application in cardiovascular and cerebrovascular diseases medicament.
Specifically, the cardiovascular and cerebrovascular disease includes acute myocardial infarction AMI, cerebral arterial thrombosis.
The present invention modifies ginkgolides, has obtained a series of ginkolide B or the derivative of K, and has passed through
After experiment shows GB or GK structure of modification, improve its platelet aggregation inhibitory activity, add its reduce infarction volume in rats,
Serum enzyme caused by oxidativestress damage, reduction rat heart infarct size, inhibition acute myocardial infarction caused by inhibiting cerebral ischemia
The increase of index reduces effect in terms of optic nerve in rat number, protection nerve cell, connects morpholine with alkyl or piperazine is repaiied
After decorations, activity change is particularly evident.
Specific embodiment
As previously mentioned, the present invention is intended to provide a kind of ginkgolide derivatives, pharmaceutically acceptable salt and its application.With
The lower content by Binding experiment example is specifically described.
In particular, it should be pointed out that for the similar replacement made of the present invention and change to those skilled in the art come
Say it is it will be apparent that they are considered as being included in the present invention.Related personnel can substantially not depart from present invention, spirit
Method described herein and application are modified or suitably changed with combining in scope, to realize and using skill of the present invention
Art.Obviously, described embodiment is only part of the embodiment of the present invention, instead of all the embodiments.
The present invention is such as not specified actual conditions person, the condition progress suggested according to normal condition or manufacturer, original used
Expect medicine or auxiliary material and reagents or instruments used without specified manufacturer, being can be with conventional products that are commercially available.
The preparation of ginkgolide derivatives and its salt
First, ginkgolide derivatives structural formula I synthetic routes are as follows：
Reaction condition:a)K2CO3,CH3CN, rm (room temperature), for 24 hours；b)CH3CN,rm,24h。
1st, the synthesis of target product I-1：
Ginkolide B (424mg, 1mmol) is taken to be dissolved in 10mL acetonitriles, 2,3- of addition dichloropropanes (124mg,
1.1mmol), it is stirred overnight at room temperature, the reaction was complete, and stopping reaction adding in water, ethyl acetate extracts, saturated common salt water washing 2 times,
Anhydrous sodium sulfate is dried, and is concentrated to dryness, rapid column chromatography, obtains intermediate compound I-A, 370mg, yield 74%.(remarks：Ginkgolides
B, Jiangsu Zhongkang Medicine Science ＆ Technology Co., Ltd provides, the same below)
Intermediate compound I-A (251mg, 0.5mmol) is taken to be dissolved in 10mL acetonitriles, adds in morpholine (87mg, 1mmol), room temperature is stirred
It mixes overnight, the reaction was complete, and stopping reaction adding in water, ethyl acetate extracts, saturated common salt water washing 2 times, anhydrous sodium sulfate drying,
It is concentrated to dryness, rapid column chromatography, obtains final product I-1,179mg, yield 65%.
1H NMR(DMSO-d6,400MHz),δ(ppm):5.63 (1H, d, J=6.5Hz), 4.44 (1H, d, J=
6.8Hz), 4.27 (1H, m), 3.80 (1H, d, J=6.8Hz), 3.67 (4H, m), 3.63 (1H, s), 3.37 (2H, m), 2.54
(1H,m),2.34-2.28(6H,m),1.84(1H,m),1.56-1.59(3H,m),1.46(1H,m),1.24(3H,m),1.10
(9H,s)；HR-MS(ESI)m/z:calcd for C27H37NO11[M+H]+552.2445,found552.2458.
2nd, the synthesis of target product I-2：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 58%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.66 (1H, d, J=6.4Hz), 4.46 (1H, d, J=6.6Hz), 4.29 (1H, m), 3.80 (1H, d, J=6.6Hz), 3.69
(4H,m),3.63(1H,s),3.37(2H,m),2.58(1H,m),2.34-2.28(6H,m),1.87(1H,m),1.56-1.59
(5H,m),1.46(1H,m),1.24(3H,m),1.10(9H,s)；HR-MS(ESI)m/z:calcd for C28H39NO11[M+H
]+566.2601,found566.2611。
3rd, the synthesis of target product I-3：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 70%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.69 (1H, d, J=6.4Hz), 4.45 (1H, d, J=6.6Hz), 4.24 (1H, m), 3.83 (1H, d, J=6.6Hz), 3.67
(4H,m),3.63(1H,s),3.35(2H,m),2.54(1H,m),2.34-2.28(6H,m),1.88(1H,m),1.56-1.58
(7H,m),1.48(1H,m),1.24(3H,m),1.10(9H,s)；HR-MS(ESI)m/z:calcd for C29H41NO11[M+H
]+580.6439,found580.6445。
4th, the synthesis of target product I-4：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 70%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.53 (1H, d, J=6.3Hz), 4.54 (1H, d, J=6.8Hz), 4.37 (1H, m), 3.80 (1H, d, J=6.8Hz), 3.77
(4H,m),3.74(1H,s),3.46(2H,m),2.62(1H,m),2.38-2.28(6H,m),1.88(1H,m),1.63-1.55
(3H,m),1.56(1H,m),1.14(3H,m),1.12(9H,s)；HR-MS(ESI)m/z:calcd for C27H38N2O10[M+
H]+551.2605,found551.2624.
5th, the synthesis of target product I-5：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 59%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.56 (1H, d, J=6.4Hz), 4.56 (1H, d, J=6.7Hz), 4.39 (1H, m), 3.87 (1H, d, J=6.7Hz), 3.77
(4H,m),3.74(1H,s),3.49(2H,m),2.67(1H,m),2.38-2.25(6H,m),1.86(1H,m),1.63-1.52
(5H,m),1.58(1H,m),1.14(3H,m),1.12(9H,s)；HR-MS(ESI)m/z:calcd for C28H40N2O10[M+
H]+565.2761,found565.2767.
6th, the synthesis of target product I-6：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 70%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.66 (1H, d, J=6.4Hz), 4.66 (1H, d, J=6.7Hz), 4.44 (1H, m), 3.83 (1H, d, J=6.7Hz), 3.76
(4H,m),3.74(1H,s),3.56(2H,m),2.76(1H,m),2.48-2.35(6H,m),1.88(1H,m),1.66-1.52
(7H,m),1.59(1H,m),1.15(3H,m),1.12(9H,s)；HR-MS(ESI)m/z:calcd for C29H42N2O10[M+
H]+579.2918,found579.2928.
2nd, ginkgolides and derivant structure Formula II synthetic route are as follows：
Reaction condition:a)K2CO3,CH3CN, rm (room temperature), for 24 hours；b)H2,Pd/C,CH3CN, rm, for 24 hours；
1st, the synthesis of target product II-1：
Ginkolide B (424mg, 1mmol) is taken to be dissolved in 10mL acetonitriles, adds in benzyl chloride (139mg, 1.1mmol), potassium carbonate
(152mg, 1.1mmol) is stirred overnight at room temperature, and the reaction was complete, stops reaction and adds in water, ethyl acetate extraction, saturated common salt washing
It washs 2 times, anhydrous sodium sulfate drying is concentrated to dryness, rapid column chromatography, obtains intermediate II-A, 324mg, yield 63%.
Intermediate II-A (257mg, 0.5mmol) is taken to be dissolved in 10mL acetonitriles, 2,3- of addition dichloropropanes (68mg,
0.6mmol), potassium carbonate (89mg, 0.6mmol) is stirred overnight at room temperature, and the reaction was complete, stops reaction and adds in water, ethyl acetate extraction
It takes, saturated common salt water washing 2 times, anhydrous sodium sulfate drying is concentrated to dryness, rapid column chromatography, obtains final product II-B, 236mg, produces
Rate 80%.
Intermediate II-B (148mg, 0.25mmol) is taken to be dissolved in 10mL acetonitriles, adds in morpholine (26mg, 0.3mmol), carbon
Sour potassium (81mg, 0.3mmol) is stirred overnight at room temperature, and the reaction was complete, stops reaction and adds in water, ethyl acetate extraction, saturated common salt
Water washing 2 times, anhydrous sodium sulfate drying, is concentrated to dryness, rapid column chromatography, obtains final product II-C, 119mg, yield 74%.
Intermediate II-C (109mg, 0.17mmol) is taken to be dissolved in 10mL acetonitriles, palladium carbon (10mg) is passed through hydrogen, and room temperature is stirred
It mixes overnight, the reaction was complete, and stopping reaction adding in water, ethyl acetate extracts, saturated common salt water washing 2 times, anhydrous sodium sulfate drying,
It is concentrated to dryness, rapid column chromatography, obtains final product II-1,84mg, yield 90%.
1H NMR(DMSO-d6,400MHz),δ(ppm):5.83 (1H, d, J=6.5Hz), 4.62 (1H, d, J=
6.8Hz), 4.34 (1H, m), 3.78 (1H, d, J=6.8Hz), 3.70 (4H, m), 3.61 (1H, s), 3.47 (2H, m), 2.65
(1H,m),2.34-2.28(6H,m),1.94(1H,m),1.61-1.55(3H,m),1.50(1H,m),1.24(3H,m),1.10
(9H,s)；HR-MS(ESI)m/z:calcd for C27H37NO11[M+H]+552.2445,found552.2455.
2nd, the synthesis of target product II-2：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 83%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.84 (1H, d, J=6.6Hz), 4.60 (1H, d, J=6.3Hz), 4.30 (1H, m), 3.75 (1H, d, J=6.3Hz), 3.73
(4H,m),3.61(1H,s),3.47(2H,m),2.67(1H,m),2.34-2.26(6H,m),1.98(1H,m),1.61-1.55
(5H,m),1.55(1H,m),1.24(3H,m),1.10(9H,s)；HR-MS(ESI)m/z:calcd for C28H39NO11[M+H
]+565.2523,found565.2525.
3rd, the synthesis of target product II-3：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 80%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.80 (1H, d, J=6.6Hz), 4.60 (1H, d, J=6.3Hz), 4.35 (1H, m), 3.75 (1H, d, J=6.3Hz), 3.70
(4H,m),3.61(1H,s),3.49(2H,m),2.66(1H,m),2.34-2.24(6H,m),1.90(1H,m),1.61-1.55
(7H,m),1.58(1H,m),1.24(3H,m),1.14(9H,s)；HR-MS(ESI)m/z:calcd for C29H41NO11[M+H
]+580.2758,found580.2768.
4th, the synthesis of target product II-4：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 78%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.71 (1H, d, J=6.6Hz), 4.71 (1H, d, J=6.3Hz), 4.45 (1H, m), 3.85 (1H, d, J=6.3Hz), 3.74
(4H,m),3.61(1H,s),3.53(2H,m),2.76(1H,m),2.44-2.37(6H,m),1.97(1H,m),1.61-1.57
(3H,m),1.51(1H,m),1.25(3H,m),1.18(9H,s)；HR-MS(ESI)m/z:calcd for C27H38N2O10[M+
H]+551.2605,found551.2635.
5th, the synthesis of target product II-5：
Experimental implementation is the same as the synthesis of II-1.White solid, 76%. white solid of yield, yield 78%.1H NMR(DMSO-
d6,400MHz),δ(ppm):5.74 (1H, d, J=6.6Hz), 4.61 (1H, d, J=6.3Hz), 4.49 (1H, m), 3.86 (1H,
D, J=6.3Hz), 3.74 (4H, m), 3.65 (1H, s), 3.55 (2H, m), 2.78 (1H, m), 2.44-2.37 (6H, m), 1.90
(1H,m),1.61-1.57(5H,m),1.53(1H,m),1.23(3H,m),1.18(9H,s)；HR-MS(ESI)m/z:calcd
for C28H40N2O10[M+H]+565.2761,found 565.2766.
6th, the synthesis of target product II-6：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 80%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.94 (1H, d, J=6.7Hz), 4.81 (1H, d, J=6.5Hz), 4.65 (1H, m), 3.98 (1H, d, J=6.5Hz), 3.79
(4H,m),3.70(1H,s),3.57(2H,m),2.79(1H,m),2.49-2.38(6H,m),1.98(1H,m),1.61-1.57
(7H,m),1.50(1H,m),1.23(3H,m),1.18(9H,s)；HR-MS(ESI)m/z:calcd for C29H42N2O10[M+
H]+579.2918,found579.2936.
3rd, the synthesis of ginkgolide derivatives formula II I
1st, the synthesis of target product III-1：(remarks：Bilobalide K, Jiangsu Zhongkang Medicine Science ＆ Technology Co., Ltd provide, with
Similarly hereinafter)
Experimental implementation is the same as the synthesis of I-1.White solid, yield 65%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.65 (1H, d, J=6.5Hz), 4.46 (1H, d, J=6.9Hz), 4.23 (1H, m), 3.89 (1H, d, J=6.8Hz), 3.67
(4H,m),3.63(1H,s),3.35(2H,m),2.34-2.28(6H,m),1.85(1H,m),1.56-1.59(3H,m),1.46
(1H,m),1.26(3H,m),1.10(9H,s)；HR-MS(ESI)m/z:calcd for C27H35NO10[M+H]+534.2339,
found 534.2347.
2nd, the synthesis of target product III-2：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 45%.H NMR (DMSO-d6,400MHz), δ (ppm):
5.66 (1H, d, J=6.4Hz), 4.56 (1H, d, J=6.6Hz), 4.39 (1H, m), 3.85 (1H, d, J=6.6Hz), 3.69
(4H,m),3.63(1H,s),3.35(2H,m),2.34-2.28(6H,m),1.87(1H,m),1.56-1.59(5H,m),1.48
(1H,m),1.24(3H,m),1.11(9H,s)；HR-MS(ESI)m/z:calcd for C28H37NO10[M+H]+548.6020,
found 548.6031.
3rd, the synthesis of target product III-3：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 59%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.79 (1H, d, J=6.6Hz), 4.47 (1H, d, J=6.6Hz), 4.29 (1H, m), 3.84 (1H, d, J=6.6Hz), 3.61
(4H,m),3.60(1H,s),3.38(2H,m),2.34-2.28(6H,m),1.89(1H,m),1.56-1.58(7H,m),1.44
(1H,m),1.26(3H,m),1.10(9H,s)；HR-MS(ESI)m/z:calcd for C28H37NO10[M+H]+562.6286,
found 562.6280.
4th, the synthesis of target product III-4：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 78%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.55 (1H, d, J=6.3Hz), 4.58 (1H, d, J=6.8Hz), 4.39 (1H, m), 3.80 (1H, d, J=6.8Hz), 3.77
(4H,m),3.74(1H,s),3.41(2H,m),2.36-2.28(6H,m),1.88(1H,m),1.63-1.55(3H,m),1.56
(1H,m),1.16(3H,m),1.11(9H,s)；HR-MS(ESI)m/z:calcd for C27H36N2O9[M+H]+533.2499,
found533.2490.
5th, the synthesis of target product III-5：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 60%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.56 (1H, d, J=6.4Hz), 4.58 (1H, d, J=6.7Hz), 4.35 (1H, m), 3.85 (1H, d, J=6.7Hz), 3.75
(4H,m),3.71(1H,s),3.49(2H,m),2.39-2.25(6H,m),1.89(1H,m),1.63-1.52(5H,m),1.58
(1H,m),1.14(3H,m),1.10(9H,s)；HR-MS(ESI)m/z:calcd for C28H38N2O9[M+H]+547.2656,
found547.2649.
6th, the synthesis of target product III-6：
Experimental implementation is the same as the synthesis of I-1.White solid, yield 73%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.76 (1H, d, J=6.4Hz), 4.69 (1H, d, J=6.7Hz), 4.48 (1H, m), 3.87 (1H, d, J=6.7Hz), 3.79
(4H,m),3.74(1H,s),3.56(2H,m),2.77(1H,m),2.48-2.35(6H,m),1.88(1H,m),1.66-1.52
(7H,m),1.54(1H,m),1.15(3H,m),1.10(9H,s)；HR-MS(ESI)m/z:calcd for C29H40N2O9[M+H
]+561.2812,found561.2808.
4th, the synthesis of ginkgolide derivatives structural formula IV
1st, the synthesis of target product IV-1：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 73%.5.86 (1H, d, J=6.5Hz), 4.65 (1H, d,
), J=6.8Hz 4.44 (1H, m), 3.75 (1H, d, J=6.8Hz), 3.71 (4H, m), 3.65 (1H, s), 3.47 (2H, m),
2.34-2.25(6H,m),1.93(1H,m),1.61-1.52(3H,m),1.50(1H,m),1.26(3H,m),1.10(9H,s)；
HR-MS(ESI)m/z:calcd for C27H35NO10[M+H]+534.2339,found 534.2330.
2nd, the synthesis of target product IV-2：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 80%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.83 (1H, d, J=6.6Hz), 4.62 (1H, d, J=6.3Hz), 4.30 (1H, m), 3.75 (1H, d, J=6.3Hz), 3.73
(4H,m),3.61(1H,s),3.49(2H,m),2.34-2.23(6H,m),1.98(1H,m),1.65-1.55(5H,m),1.57
(1H,m),1.24(3H,m),1.10(9H,s)；HR-MS(ESI)m/z:calcd for C28H37NO10[M+H]+548.2496,
found 548.2488.
The synthesis of 3 target product IV-3：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 74%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.80 (1H, d, J=6.6Hz), 4.64 (1H, d, J=6.3Hz), 4.35 (1H, m), 3.75 (1H, d, J=6.3Hz), 3.70
(4H,m),3.61(1H,s),3.49(2H,m),2.38-2.24(6H,m),1.94(1H,m),1.61-1.55(7H,m),1.59
(1H,m),1.24(3H,m),1.11(9H,s)；HR-MS(ESI)m/z:calcd for C29H39NO10[M+H]+562.2652,
found 562.2640.
4th, the synthesis of target product IV-4：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 78%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.73 (1H, d, J=6.6Hz), 4.75 (1H, d, J=6.3Hz), 4.45 (1H, m), 3.88 (1H, d, J=6.3Hz), 3.78
(4H,m),3.61(1H,s),3.55(2H,m),2.44-2.37(6H,m),1.99(1H,m),1.61-1.57(3H,m),1.50
(1H,m),1.21(3H,m),1.18(9H,s)；HR-MS(ESI)m/z:calcd for C27H36N2O9[M+H]+533.2499,
found 533.2490.
5th, the synthesis of target product IV-5：
Experimental implementation is the same as the synthesis of II-1.White solid, yield 70%.1H NMR(DMSO-d6,400MHz),δ(ppm):
5.71 (1H, d, J=6.6Hz), 4.60 (1H, d, J=6.3Hz), 4.48 (1H, m), 3.84 (1H, d, J=6.3Hz), 3.70
(4H,m),3.65(1H,s),3.50(2H,m),2.44-2.37(6H,m),1.90(1H,m),1.61-1.57(5H,m),1.50
(1H,m),1.20(3H,m),1.13(9H,s)；HR-MS(ESI)m/z:calcd for C28H38N2O9[M+H]+547.2656,
found 547.2646.
6th, the synthesis of target product IV-6：
Experimental implementation is the same as the synthesis of same II-1.White solid, yield 83%.1H NMR(DMSO-d6,400MHz),δ
(ppm):5.91 (1H, d, J=6.7Hz), 4.82 (1H, d, J=6.5Hz), 4.66 (1H, m), 3.91 (1H, d, J=6.5Hz),
3.70(4H,m),3.70(1H,s),3.51(2H,m),2.49-2.38(6H,m),1.98(1H,m),1.61-1.57(7H,m),
1.50(1H,m),1.20(3H,m),1.18(9H,s)；HR-MS(ESI)m/z:calcd for C29H40N2O9[M+H]+
561.2812,found 561.2810.
5th, the preparation of ginkgolide derivatives salt
1st, compound I-1 trifluoroacetates
Compound I-1 (110mg, 0.2mmol) is taken to be dissolved in 10ml ethyl alcohol, adds in 1ml trifluoroacetic acids and 1ml water, flow back 3h,
50 DEG C are cooled to, adds in 12mg activated carbons, flow back 1h, and heat filtering is cooled to 5-10 DEG C, there is solid precipitation, filters to obtain product,
107mg, yield 80%.
2nd, compound II-3 tosilate
Compound II-3 (116mg, 0.2mmol) is taken to be dissolved in 10ml ethyl alcohol, adds in 100mg p-methyl benzenesulfonic acid and 1ml water, is returned
3h is flowed, is cooled to 50 DEG C, adds in 12mg activated carbons, flow back 1h, and heat filtering is cooled to 5-10 DEG C, there is solid precipitation, and filtering must produce
Object, 127mg, yield 85%.
3rd, compound III-2 hydrochlorides
Compound III-2 (114mg, 0.2mmol) is taken to be dissolved in 10ml ethyl alcohol, adds in 100mg p-methyl benzenesulfonic acid and 1ml water,
Flow back 3h, is cooled to 50 DEG C, adds in 12mg activated carbons, and flow back 1h, and heat filtering is cooled to 5-10 DEG C, has solid precipitation, filter
Product, 104mg, yield 86%.
Inhibit the platelet aggregation activity that platelet activating factor (PAF) induces to measure
Sodium citrate and whole blood are pressed 1 by new zealand male rabbit, lidocaine local anaesthesia, arteria carotis intubation bloodletting：9
Ratio is uniformly mixed, and is centrifuged 10min with 1000r/min, is taken platelet rich plasma (PRP), remainder with 3000r/min from
The heart takes platelet poor plasma (PPP).Aggregation inducing agent is added in every 250 μ L PRP of pipe with PAF (final concentration 7.46ng/mL)
The drug (GB, GK, GB-1, GK-1, I-1 to I-6, II-1 to II-6, III-1 to III-6, IV-1 to IV-6) 10 of various concentration
5% dimethyl sulfoxide solution is added in μ L, control group PRP, PPP zeroings incubate 3min, then add in 10 μ L derivants, small with blood
Plate assembles clotting factor analysis-e/or determining platelet aggregation rate, and inhibiting rate according to the following formula.With drug quality concentration certainly
Right logarithm is abscissa, and inhibiting rate is ordinate, establishes dependent equation, medicinal substances when by equation calculation inhibiting rate being 50%
Measure concentration (IC50)。
Assemble inhibiting rate=(control group aggregation rate-administration group aggregation rate)/control group aggregation rate × 100%.
Remarks：Compound GB-1, Jiangsu Zhongkang Medicine Science ＆ Technology Co., Ltd provide, and structural formula is as follows；Compound GK-1, river
Su Zhongkang drugs Science and Technology Ltd. provides, and structural formula is as follows：
1 target compound of table inhibits the platelet aggregation activity of PAF inductions
Table 1 the result shows that, after carrying out structure of modification to GB or GK, derivative platelet aggregation inhibitory activity higher than parent nucleus GB or
GK, the derivative platelet aggregation inhibitory activity as modification group of morpholine or piperazine is connected using alkyl substantially to be increased, partization
It is especially pronounced to close object improvement result.
Protective effect to cerebral ischemia-reperfusion injury in rats cerebral infarction
SD rats are randomly divided into sham-operation group, ischemia model group, GB administration groups, GK administration groups, GB-1 administration groups, GK-1
Administration group, GB derivatives group, GK derivative groups.Using the focal rat ischemia model of line brush, every group 20, each group animal in
It is administered immediately by sublingual vein after ischemic, gives a medicine after 8h again.Sham-operation group and model group give the physiology salt of equivalent
Water.By every group of 10 rats be used as measure cerebral infarction volume, remaining 10 be only used as detection SOD (superoxide dismutase) activity,
The content of GSH (glutathione) and MDA (malonaldehyde).
Brain stem injury measures：Break end after when rat is when ischemic 1 is small, Reperfu- sion 24 is small, be immediately placed on ice pan and take
Brain removes cerebellum, olfactory bulb and low brain stem, after by brain homogenate be cut into 6 be placed on fill 2% red tetrazolium dyestuff
(TTC) in bottle, and put it into temperature and be incubated 30min for 37 DEG C of incubators, 10% formalin is placed it in after being incubated
Solution is fixed.Rose has been dyed in the part of non-ischemic, and ischemic section is then white.Each area is calculated with planimeter
Area determines Brain stem injury as follows：Brain stem injury=(the sum of the sum of infarcted region area/whole br ain slices product) ×
100%.
Biochemical Indexes are homogenized in brain tissue：Rat perform the operation 24 it is small when after broken end take brain, remove cerebellum, olfactory bulb and low
Ipsilateral rat brain hemisphere, is then placed in ice-cold normal saline, 10% brain tissue homogenate is then made by position brain stem.With life
10% brain homogenate is diluted to kit (SOD (article No. A001-3), GSH (article No. A006-2), MDA (article No. A003- by reason brine
1) kit is purchased from Nanjing and builds up Bioengineering Research Institute) needed for concentration homogenate, 4000r/min centrifuge 10 minutes, take
Clearly, by the activity and the content of GSH, MDA for illustrating to measure SOD one by one in assay kit.Calculate the activity per SOD in mg albumen
With the content of GSH, MDA.
2 ginkgolides of table influences Ischemia and Reperfusion in vivo in Rats cerebral infarction volume
Compared with model group, * P<0.05, * * P<0.01.
The influence of index of correlation after rats after cerebral ischemic reperfusion is administered in 3 ginkgolides of table
Compared with model group, * P<0.05, * * P<0.01.
Table 2 and table 3 show that compared with ischemia model group the compound after modification can effectively reduce infarction volume in rats,
Oxidativestress damage caused by inhibiting cerebral ischemia to a certain extent, part of compounds improvement result are fairly obvious.
Protective effect to acute myocardial infarction of rat
By SD rats be randomly divided into sham-operation group, acute myocardial infarction AMI (AMI) model group, GB administration groups, GK administration groups,
GB-1 administration groups, GK-1 administration groups, GB derivatives group, GK derivative groups.Rat is established using coronary artery anterior descending branch desmurgia
AMI models, skin of neck tracheostomize connect lung ventilator, and every group 20, each group animal passes through sublingual vein immediately after ischemic
It is administered, gives a medicine after 8h again.Sham-operation group and model group give the physiological saline of equivalent.Every group of 10 rats are removed into the heart
It is dirty, as measure myocardial infarction area, remaining 10 be only used as detection CK (creatine kinase) and LDH (lactic dehydrogenase) content.
Myocardial infarction area measures：Rat is put to death after the completion of modeling, is put to death animal and is removed heart and weighs.Along coronary sulcus
Cut off big vascular root and atrium, claim left ventricle weight, and by its it is equably cross-section be cut into 5, be placed in N-BT dye liquors, at 37 DEG C
15min is dyed in constant water bath box.Measuring every myocardium bilateral infarcted region (NBT the area of no dyeing), (NBT is dyed with non-infarct
Area), it is taken out immediately when infarcted myocardium boundary line understands, cuts infarcted myocardium and weigh.With infarcted myocardium and ventricle weight in wet base or the heart
The percentage of dirty weight is as myocardial infarction area (MIS).
Rat blood serum Biochemical Indexes measure：After the completion of modeling, from rat aorta blood sampling 3ml, natural separation serum
After (centrifugation 10 minutes, rotating speed 3000rpm), in strict accordance with kit (CK (article No. A032), LDH (article No. A020-2) kit
It is purchased from Nanjing and builds up Bioengineering Research Institute) illustrate the content that CK, LDH in serum are detected in microplate reader.
Influence of 4 ginkgolide derivatives of table to acute myocardial infarction of rat volume
Compared with model group, * P<0.05, * * P<0.01.
The influence for the index of correlation that acute myocardial infarction rat is administered in 5 ginkgolide derivatives of table
Compared with model group, * P<0.05, * * P<0.01.
Table 4 and table 5 show that compared with ami model group, derivative can effectively reduce rat heart infarct
Area, the increase of serum enzyme index caused by inhibiting acute myocardial infarction to a certain extent, part of compounds improvement result ten are clearly demarcated
It is aobvious.
Protective effect to optic nerve in rat
Wistar rats 270, weight 200-220g, male and female are unlimited (being provided by Qinglongshan animal breeding field).It is divided into pair
According to group, model group, GB, GK, GB-1, GK-1 group and 24 compound administration groups, every group of 10 rats, wherein left eye are damage
Eye, is experimental group, and right eye is control group (n=270), only optic nerve is separated by performing the operation, without crushing god not damage eye
Through.For administration group daily by 6mg/kg eye drop administrations, control group and model group give normal saline.
Conventional 0.5% yellow Jackets of intraperitoneal injection, injection standard 1ml/kg.Surgical operation microscope (OMS-110,
Topcon it is operated, is done in upper eyelid edge center after vertical incision upwardly extends 1cm under), then do row notch, is about
1cm, entire notch are " T " shape.Fornical conjunctiva is cut off, is separated along superior rectus direction, finds optic nerve.Cut off vagina nervi optici
Film presss from both sides (OX60, Germany) with 40g optic nerve injuries and causes optic nerve injury perpendicular to optic nerve trunnion axis at 2mm after ball, presss from both sides
The time is held as 9s, is grouped by the time-to-live.Layering suture conjunctiva, subcutaneous tissue and skin.
Microsyringe is fixed on big stereotaxic apparatus, with reference to Paxinos collection of illustrative plates using bregma as standard, locator tune
To zero point, then after move 6.5mm, symmetric points at center line 1.5mm are opened by both sides, diameter is made on parietal bone about with No. 11 sharp knives
The bone hole of 1mm, microforceps tear the endocranium at bone hole, using Bregma points as zero point after move 4.3mm and 6.3mm at bone hole
It is interior, it is other respectively to open 4.4mm and 1.4mm, 3% fluorogold (Biotium, Hayward, the U.S.) is slowly injected on the outside of a side back
In knee core and superior colliculus, 0.5 μ L are injected separately into, the syringe needle for finishing microsyringe indwelling 10min in rat brain is noted in 5min,
Injection depth is respectively 4.6mm and 3.5mm, then slowly exits microsyringe.Another side back lateral geniculate nucleus and superior colliculus are same
Sample operates, and 7d is carried out before damage.
Under disecting microscope (Olympus SZ-PT, Japan), with micro- Smooth forceps careful separation retina.By view
Film is laid on glass slide, amplifies 400 on away from the temporo at optic papilla edge 1mm, under temporo, on nose and in a visual field under nose
It observes and takes pictures under fluorescence microscope (Olympus IX70, Japan) again, using image analysis system (Image-Pro Plus)
Count the rat RGC that labeled retinal ganglial cells (RGC) measures be counted as more than 4 quadrant RGC number summations.RGC
Mark rate=every Damage of Rats eye RGC/ does not damage RGC × 100%).
Protective effect of 6 ginkgolides of table to optic nerve in rat
Compared with model group, * P<0.05, * * P<0.01.
Table 6 shows that compared with optic nerve in rat model group, derivative can effectively reduce optic nerve in rat
Number, protects nerve cell, and part of compounds improvement result is fairly obvious.
By after testing show GB or GK structure of modification above, having promotion to the activity of compound, especially being connected with alkyl
Connect morpholine or it is piperazine modified after, activity greatly improves.
It the above is only the preferred embodiment of the present invention, it is noted that come for those skilled in the art
It says, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should be regarded as
Protection scope of the present invention.
Claims (5)
1. ginkgolide derivatives and its pharmaceutically acceptable salt, the ginkgolide derivatives structural formula such as formula I, II, III or
Shown in IV,
Wherein, R1 representatives-X-het, X represent the alkylidene with 3 to 5 carbon atoms, and het represents morpholinyl or piperazinyl.
2. ginkgolide derivatives as described in claim 1 and its pharmaceutically acceptable salt, which is characterized in that in the ginkgo
Ester derivant is selected from following compound,
3. ginkgolide derivatives as claimed in claim 1 or 2 and its pharmaceutically acceptable salt, salt is selected from trifluoroacetic acid
Salt, tosilate, mesylate, hydrochloride, hydrobromate, sulfate or citrate.
4. ginkgolide derivatives as claimed in claim 1 or 2 and its pharmaceutically acceptable salt are preparing prevention or treatment
Application in cardiovascular and cerebrovascular diseases medicament.
5. application as claimed in claim 4, the cardiovascular and cerebrovascular disease include acute myocardial infarction AMI, cerebral arterial thrombosis.
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Citations (5)
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| CN1139435A (en) * | 1993-12-31 | 1997-01-01 | 鲜京工业股份有限公司 | New ginkgolide derivatives and process for preparing them |
| CN1749257A (en) * | 2005-04-29 | 2006-03-22 | 秦引林 | Platelet activation factor resisting compound |
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| CN101302221A (en) * | 2007-05-09 | 2008-11-12 | 秦引林 | Anti-platelet activating factor compound |
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| CN1139435A (en) * | 1993-12-31 | 1997-01-01 | 鲜京工业股份有限公司 | New ginkgolide derivatives and process for preparing them |
| CN1749257A (en) * | 2005-04-29 | 2006-03-22 | 秦引林 | Platelet activation factor resisting compound |
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