CN1050359C - Diterpene salicylate alkaloid, preparation and use thereof - Google Patents
Diterpene salicylate alkaloid, preparation and use thereof Download PDFInfo
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- CN1050359C CN1050359C CN97112872A CN97112872A CN1050359C CN 1050359 C CN1050359 C CN 1050359C CN 97112872 A CN97112872 A CN 97112872A CN 97112872 A CN97112872 A CN 97112872A CN 1050359 C CN1050359 C CN 1050359C
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Abstract
The present invention provides four compounds of ATISINE type diterpene salicylate alkaloid Q, T, U and P, a preparation method of the four compounds, applications of four compounds of ATISINE type diterpene salicylate alkaloid Q, T, U and P used as PAF antagonists and arachidonic acid antagonists, and applications of the four compounds of ATISINE type diterpene salicylate alkaloid Q, T, U and P in the preparation of medicines for treating cerebral ischemia, inflammation, allergy and asthma.
Description
The present invention relates to the ATISINE type diterpene salicylate alkaloid shown in the general formula (I), its preparation method, and as the application of PAF antagonist, arachidonic acid antagonist, and the application in preparation treatment cardiac-cerebral ischemia, inflammation, allergy, asthma disease medicine.
Do not see the alkaloidal report that from pink blossom Ramulus et Folium Spiraeae Salicifolia (Spiraea japonica) plant separated structures feature such as general formula (I) are arranged in the prior art.
The object of the present invention is to provide the ATISINE type diterpene alkaloid shown in the general formula (I), the method for preparing general formula (I) compound, and the alkaloid shown in the general formula (I) is as the application and the application in preparation treatment cardiac-cerebral ischemia, inflammation, allergy, asthma disease medicine of PAF antagonist, arachidonic acid antagonist.
The invention provides the ATISINE type diterpene alkaloid shown in the following general formula (I):
R in the formula
1Represent methylidene or hydroxyl, R
2Represent methylidene or hydroxyl, R
3Represent hydrogen or ethanoyl, 19 carbon are R configuration or S configuration.
The present invention provides the method for preparing compound shown in the general formula (I) simultaneously: the dried root powder of getting pink blossom Ramulus et Folium Spiraeae Salicifolia (Speraeajaponica) was with 75-95% ethanol cold soaking 5-7 days, remove ethanol through concentrating under reduced pressure and get medicinal extract, use the 2-4% dissolving with hydrochloric acid, acid solution uses sherwood oil-benzene (1: 1) to extract 3 times with degreasing respectively, alkalize to the PH=11 with the NaOH aqueous solution again, with chloroform extraction 3 times, extraction liquid is through being washed to neutrality, anhydrous sodium sulfate drying, concentrating under reduced pressure gets the total alkaloids part, through silica gel H decompression short column chromatography, sherwood oil-acetone-diethylamine gradient elution in varing proportions promptly obtains each alkaloid shown in the general formula (I) respectively then.
The present invention also provides the application of general formula (I) alkaloid in the preparation anti-inflammatory drug; Application in the preparation Claritin; Application in the preparation anti-asthmatic medicament; Application in preparation treatment cardiac-cerebral ischemia medicine, and with general formula (I) alkaloid as PAF antagonist and arachidonic acid antagonist.
The pharmacological results with the ATISINE type diterpene alkaloid shown in the general formula of the present invention (I) illustrates beneficial effect of the present invention below:
Laboratory animal: healthy rabbits, the 2-3 kilogram, male and female are all used.
Medicine and reagent: general formula of the present invention (I) alkaloid is with dissolved in distilled water and transfer PH to 6.5.
Platelet activation factor (Platelet activating factor) and arachidonic acid (Arachidonicacid) all are Sigma company product, and the former is dissolved in the tris-NaCl damping fluid that contains 0.25%BSA, PH7.6; The latter is dissolved in the dehydrated alcohol, uses preceding with 1%Na
2CO
3Be diluted to 0.5% working fluid, Adenosine diphosphate is sweet to be dissolved in the phosphate buffered saline buffer.
Method: prepare platelet rich plasma (PRP) and platelet poor plasma (PPP) according to a conventional method, in the experimentation, the platelet count among the PRP is controlled at 5X10
8Cell/L.Carry out platelet aggregation mensuration then.
1, experiment in vitro: adopt BS-631 type platelet aggregation instrument to carry out by BornShi turbidimetry principle, medicine and thrombocyte effect are after 5 minutes, add inductor test and the maximum cohesion of record percentage, calculate the platelet aggregation inhibiting rate with [(control tube cohesion %-sample hose cohesion %)/control tube cohesion %] X100%.
Experiment in vitro shows that spiradine Q obviously suppresses the platelet aggregation of AA inductive, and is amount-result relation, IC
50Be 18.7 μ mol/L, and PAF and the platelet aggregation of ADP inductive are not had obvious restraining effect, spiradine T, U, V significantly suppress the platelet aggregation of PAF inductive, and the concentration dependence is arranged, IC
50Be respectively 57.8 μ mol/L, 55.4 μ mol/L and 52.2 μ mol/L, but do not suppress AA or the platelet aggregation of ADP inductive.
2, experiment in the body: rabbit is divided two groups, one group through ear edge injection alkaloid (all 2.0mg/kg), another group is injected isopyknic distilled water, get blood before the administration once, get blood respectively at different time points from carotid artery after the administration and prepare PRP and PPP, observe vivo medicine-feeding, medicine is to the influence of PAF, AA and the platelet aggregation of ADP inductive, and method is the same.
Experiment shows in the body, behind the spiradine Q intravenously administrable (2mg/kg), the platelet aggregation of main inhibition AA inductive, its effect characteristics are: promptly showed very strong restraining effect (inhibiting rate: 100%) after the administration in 10 minutes, 90 minutes inhibiting rate of administration is still up to 81.3%, drug effect disappear substantially (table 1) during to 180 minutes.
Spiradine T or U or P (2mg/kg) not only suppress the platelet aggregation of PAF inductive in vivo, also significantly suppress the cohesion of AA inductive, its effect shows as: the PAF inductive is condensed, (inhibiting rate is more than 65.0% in 2 hours stronger restraining effect of demonstration after the administration, P＜0.05vs 0min), still had obvious restraining effect to 4 hours; To AA inductive cohesion, in promptly having very strong restraining effect (inhibiting rate is more than 99%) in 1 hour after the administration, 4 hours inhibiting rate is still up to more than 75.0%.As an illustration, only list the restraining effect of spiradine T to AAPAF and the platelet aggregation of ADP inductive with table 2.Table 1. alkaloid Q is to AA, the restraining effect of PAF and the platelet aggregation of ADP inductive
Table1.Effects?of?Spiramine?Q(2mg/kg，i.v.)on?the?Platelet?aggregationinduced?by?AA，PAF?or?ADP.n＝2rabbits，x±s，P
*＜0.05
Time(min)/Inducer AA PAF ADP
Aggregant?rate/％
0 75.0±1.4 67.5±0.7 69.0±6.4
10 0.0±0.0
* 60.5±9.2 62.5±3.1
30 0.0±0.0
* 67.0±1.4 64.5±4.7
60 0.0±0.0
* 65.0±1.4 66.4±2.7
90 14.0±9.8
* 65.0±0.0 61.0±3.5
120 62.0±11.3 62.5±4.9 64.0±2.3
180 71.5 ± 2.1 66.3 ± 2.3 66.6 ± 1.4 table 2. spiradine T are to AA, the restraining effect Table2.Effects of Spiramine T (2mg/kg of PAF and the platelet aggregation of ADP inductive, i.v.) on the Platelet Aggregation inducedby AA, PAF or ADP.n=5rabbits, x ± s, P
*＜0.05
Time/Inducer AA PAF ADP
Aggregant?rate/％
0min 61.6±2.1 57.2±4.1 57.2±4.1
15min 61.4±1.1 52.8±1.9 51.0±5.5
1h 0.6±0.8
* 47.8±1.9 50.6±6.3
2h 0.0±0.0
* 19.2±2.8
* 47.0±8.1
3h 2.4±2.6
* 13.4±7.9
* 47.8±9.4
4h 13.8±8.6
* 10.4±6.1
* 50.8±8.3
Containing the alkaloidal medicine of general formula of the present invention (I) can make with following method: described alkaloid is converted into suitable form of administration, uses inert auxiliary and excipient promptly to can be made into medicine where necessary.The pharmaceutical composition that the application aforesaid method is made can be ointment, gel, paste, creme, sprays, suspension agent, activeconstituents solution or emulsion, syrup, particle or the pulvis in water or non-diluent water.
Use general formula of the present invention (I) alkaloid as medicine, the formulation that can adopt is the lid human relations form of administration of habitually practising, for example: plaster, tablet, pill, capsule, suppository, emulsion, input liquid and injection liquid, these preparations can be by well-known method, use traditional additive and excipient to make, the medicine that makes thus as required can be by part, non-enteron aisle, administration such as oral.
Any currently known methods that above-mentioned medicinal compositions or medicine production can be used in this technology carries out, and for example one or more activeconstituentss and one or more mixing diluents is formed medicinal compositions, again composition is made medicine.General formula of the present invention (I) alkaloid is as the dosage of clinical medicine, preferably within 1 to 5 milligram/kilogram scope.
Further specify flesh and blood of the present invention with embodiment below, but content of the present invention is not limited thereto:
Embodiment one:
Adopt pink blossom Ramulus et Folium Spiraeae Salicifolia (Spiraea japonica) sample, with 5 kilograms in its dried root powder, with one week of 95% ethanol cold soaking, remove ethanol through concentrating under reduced pressure and get medicinal extract 850 grams, it is used 3% dissolving with hydrochloric acid, acid solution uses sherwood oil-benzene (1: 1) to extract 3 times with degreasing respectively, after alkalizing to the PH=11 with the NaOH aqueous solution again, with chloroform extraction 3 times, chloroform extraction liquid is through being washed to neutrality, and anhydrous sodium sulfate drying, concentrating under reduced pressure get total alkaloids part 35 grams, total alkali is through silica gel H decompression short column chromatography, sherwood oil-acetone-diethylamine gradient elution in varing proportions obtains spiradine P (V) 230mg respectively, Q (I) 250mg respectively, T (III) 1200mg, and U (II) 1000mg.
Embodiment two:
Adopt pink blossom Ramulus et Folium Spiraeae Salicifolia (Spiraea japonica) sample, with 5 kilograms in its dried root powder, with one week of 75% ethanol cold soaking, remove ethanol through concentrating under reduced pressure and get medicinal extract 800 grams, it is used 2% dissolving with hydrochloric acid, acid solution uses sherwood oil-benzene (1: 1) to extract 3 times with degreasing respectively, after alkalizing to the PH=11 with the NaOH aqueous solution again, with chloroform extraction 3 times, chloroform extraction liquid is through being washed to neutrality, and anhydrous sodium sulfate drying, concentrating under reduced pressure get total alkaloids part 32 grams, total alkali is through silica gel H decompression short column chromatography, sherwood oil-acetone-diethylamine gradient elution in varing proportions obtains spiradine P (V) 210mg respectively, Q (I) 220mg respectively, T (III) 1000mg, and U (II) 900mg.
Embodiment three:
Adopt pink blossom Ramulus et Folium Spiraeae Salicifolia (Spiraea japonica) sample, with 5 kilograms in its dried root powder, with one week of 80% ethanol cold soaking, remove ethanol through concentrating under reduced pressure and get medicinal extract 820 grams, it is used 4% dissolving with hydrochloric acid, acid solution uses sherwood oil-benzene (1: 1) to extract 3 times with degreasing respectively, after alkalizing to the PH=11 with the NaOH aqueous solution again, with chloroform extraction 3 times, chloroform extraction liquid is through being washed to neutrality, and anhydrous sodium sulfate drying, concentrating under reduced pressure get total alkaloids part 35 grams, total alkali is through silica gel H decompression short column chromatography, sherwood oil-acetone-diethylamine gradient elution in varing proportions obtains spiradine P (V) 220mg respectively, Q (I) 210mg respectively, T (III) 1100mg, and U (II) 800mg.
Embodiment four:
Adopt pink blossom Ramulus et Folium Spiraeae Salicifolia (Spiraea japonica) sample, with 5 kilograms in its dried root powder, with one week of 90% ethanol cold soaking, remove ethanol through concentrating under reduced pressure and get medicinal extract 840 grams, it is used 3% dissolving with hydrochloric acid, acid solution uses sherwood oil-benzene (1: 1) to extract 3 times with degreasing respectively, after alkalizing to the PH=11 with the NaOH aqueous solution again, with chloroform extraction 3 times, chloroform extraction liquid is through being washed to neutrality, and anhydrous sodium sulfate drying, concentrating under reduced pressure get total alkaloids part 35 grams, total alkali is through silica gel H decompression short column chromatography, sherwood oil-acetone-diethylamine gradient elution in varing proportions obtains spiradine P (V) 220mg respectively, Q (I) 220mg respectively, T (III) 1000mg, and U (II) 1000mg.
The physico-chemical property of four compounds that obtain with aforesaid method is as follows:
1. spiradine Q (spiramine Q) is (II):
C
22H
33O
4N, colourless needle (sherwood oil-acetone-diethylamine), mp195-197 ℃, [α]
D-70 ° of (c0.84, CHCl
3); Ultimate analysis: C, 69.78; H, 8.90. calculated value: C, 70.40; H, 8.80; EIMS m/z:375 (M), 319 (20), 288 (10), 180 (30); IR (KBr) v:3420,1520,1200,1120cm
-1 1H NMR δ (ppm, CDCl
3): 4.56 (1H, br.m, H-15 β), 4.52 (1H, br.s, H-20), 3.84 (1H, br.S, H-19), 3.60,3.18 (each 1H, m, H2-22), 3.30 (1H, d, J=5Hz, H-7 β), 3.46,3.28 (each 1H, m, H2--21), 1.28 (3H, s, H3-17), 1.15 (3H, s, H3-18);
13C NMR δ (ppm, CDCl
3): 40.9 (C-1), 22.7 (C-2), 47.3 (C-3), 35.2 (C-4), 42.2 (C-5), 27.3 (C-6), 69.4 (C-7), 36.3 (C-8), 40.8 (C-9), 35.6 (C-10), 29.1 (C-11), 55.9 (C-12), 23.5 (C-13), 20.3 (C-14), 73.9 (C-15), 73.9 (C-16), 33.1 (C-17), 22.7 (C-18), 95.1 (C-19), 85.5 (C-20), 51.0 (C-21), 63.1 (C-22).
2. spiradine T (spiramine T) is (III):
C
24H
35O
5N, colourless needle (sherwood oil-acetone-diethylamine), mp183-185 ℃, [α]
D-151.6 ° of (c0.67, CHCl
3), high resolution mass spectrum: 417.2538 (M); EIMS m/z:417 (M, 100), 400 (10), 389 (17), 374 (75), 105 (70); IR (KBr) v:3520,2960,1720,1250,1090,920cm
-1 1H NMR δ (ppm, C
5D
5N): 5.26 (1H, m, H-15 β), 4.77 (1H, br.s, H-20), 4.05 (1H, br.s, H-19), 3.82,3.79 (each 1H, m, H2-22), 3.55 (1H, d, J=4.6Hz, H-7 β), 2.99,2.96 (each 1H, m, H2--21), 2.02 (3H, s, H3-24), 1.27 (3H, s, H3-17), 0.88 (3H, s, H3-18).
13C NMR δ (ppm, CDCl
3): 33.8 (C-1), 22.7 (C-2), 45.4 (C-3), 36.2 (C-4), 41.2 (C-5), 26.5 (C-6), 70.0 (C-7), 34.7 (C-8), 38.3 (C-9), 36.1 (C-10), 29.0 (C-11), 56.3 (C-12), 23.5 (C-13), 20.3 (C-14), 70.8 (C-15), 73.7 (C-16), 30.1 (C-17), 22.5 (C-18), 91.4 (C-19), 83.1 (C-20), 47.3 (C-21), 64.9 (C-22), 169.6 (C=O), 21.3 (CH
3).
3. Spiramine U (spiramine U) is (IV):
C
24H
35O
5N, colourless needle (sherwood oil-acetone-diethylamine), mp 216-218 ℃, [α]
D-129.9 ° of (c0.86, CHCl
3); High resolution mass spectrum: 417.2515 (M); EIMS m/z:417 (M, 100), 400 (10), 389 (40), 374 (56), 72 (42); IR (KBr) v:3520,3400,2920,1720,1030,750cm
-1 1HNMR δ (ppm, C
5D
5N): 5.53 (1H, m, H-15 β), 4.60 (1H, br.s, H-20), 3.84 (1H, br.S, H-19), 3.71,3.35 (each 1H, m, H2-22), 3.79 (1H, d, J=4.6Hz, H-7 β), 3.30,3.12 (each 1H, m, H2--21), 1.96 (3H, s, H3-24), 1.70 (3H, s, H3-17), 1.24 (3H, s, H3-18).
13C NMR δ (ppm, CDCl
3): 40.7 (C-1), 21.9 (C-2), 48.3 (C-3), 36.9 (C-4), 43.7 (C-5), 27.2 (C-6), 71.1 (C-7), 35.4 (C-8), 39.6 (C-9), 35.7 (C-10), 29.3 (C-11), 52.8 (C-12), 23.0 (C-13), 20.6 (C-14), 71.5 (C-15), 71.3 (C-16), 31.9 (C-17), 23.0 (C-18), 94.8 (C-19), 85.6 (C-20), 51.3 (C-21), 63.5 (C-22), 169.6 (C=O), 21.1 (CH
3).
4. spiradine P (spiramine P) is (V):
C
22H
33O
4N, colourless needle (sherwood oil-acetone-diethylamine), mp 235-236 ℃, [α]
D-49 ° of (c0.81, CHCl
3); Ultimate analysis: C, 70.25; H, 8.86. calculated value: C, 70.40; H, 8.80; EIMS m/z:375 (M), 345 (18), 319 (18), 278 (10), 180 (30); IR (KBr) v:3420,1520,1200,1120cm
-1 1HNMR δ (ppm, CDCl
3): 4.63 (1H, br.m, H-15 β), 4.52 (1H, br.s, H-20), 3.84 (1H, br.S, H-19), 3.59,3.27 (each 1H, m, H2-22), 3.30 (1H, d, J=5Hz, H-7 β), 3.40,3.55 (each 1H, m, H2--21), 1.35 (3H, s, H3-17), 1.16 (3H, s, H3-18);
13C NMR δ (ppm, CDCl
3): 40.7 (C-1), 22.8 (C-2), 47.9 (C-3), 35.3 (C-4), 43.1 (C-5), 26.6 (C-6), 69.5 (C-7), 36.7 (C-8), 39.2 (C-9), 35.6 (C-10), 29.2 (C-11), 56.1 (C-12), 21.3 (C-13), 20.3 (C-14), 74.0 (C-15), 72.6 (C-16), 31.3 (C-17), 22.5 (C-18), 95.1 (C-19), 85.2 (C-20), 51.0 (C-21), 63.2 (C-22).
Claims (8)
1, the ATISINE type diterpene alkaloid shown in the general formula (I):
R in the formula
1Represent methylidene or hydroxyl, R
2Represent methylidene or hydroxyl, R
3Represent hydrogen or ethanoyl, 19 carbon are R configuration or S configuration.
2, the method for preparing the described general formula of claim 1 (I) compound, the dried root powder that it is characterized in that getting pink blossom Ramulus et Folium Spiraeae Salicifolia (Speraea japonica) was with 75-95% ethanol cold soaking 5-7 days, remove ethanol through concentrating under reduced pressure and get medicinal extract, use the 2-4% dissolving with hydrochloric acid, acid solution uses sherwood oil-benzene (1: 1) to extract 3 times with degreasing respectively, alkalize to the PH=11 with the NaOH aqueous solution again, with chloroform extraction 3 times, extraction liquid is through being washed to neutrality, anhydrous sodium sulfate drying, concentrating under reduced pressure get the total alkaloids part, then through silica gel H decompression short column chromatography, sherwood oil-acetone-diethylamine gradient elution in varing proportions promptly obtains each alkaloid shown in the general formula (I) respectively.
3, the application of the described general formula of claim 1 (I) alkaloid in the preparation anti-inflammatory drug.
4, the application of the described general formula of claim 1 (I) alkaloid in the preparation Claritin.
5, the application of the described general formula of claim 1 (I) alkaloid in the preparation anti-asthmatic medicament.
6, the application of the described general formula of claim 1 (I) alkaloid in preparation treatment cardiac-cerebral ischemia medicine.
7, the described general formula of claim 1 (I) alkaloid is as the application of PAF antagonistic activity composition.
8, the described general formula of claim 1 (I) alkaloid is as the application of arachidonic acid antagonistic activity composition.
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|---|---|---|---|
| CN97112872A CN1050359C (en) | 1997-07-23 | 1997-07-23 | Diterpene salicylate alkaloid, preparation and use thereof |
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| CN1050359C true CN1050359C (en) | 2000-03-15 |
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| CN101239964B (en) * | 2008-03-07 | 2012-01-04 | 中国科学院昆明植物研究所 | 15-oxospiramilactone and its medicament composition, preparation method and application |
| CN103749456A (en) * | 2013-12-25 | 2014-04-30 | 贵州大学 | Application of diterpene alkaloid compound and preparation to prevention of crop virus diseases |
| CN105541631B (en) * | 2015-10-26 | 2017-09-05 | 云南西力生物技术股份有限公司 | Raw element A (spiratisanin A) of meadow sweet Ah Ti and preparation method thereof and the application on medicine |
| CN113717105B (en) * | 2021-08-09 | 2023-06-30 | 沈阳药科大学 | Diterpene alkaloid compound and extraction method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1147766A (en) * | 1994-03-18 | 1997-04-16 | 株式会社津村 | Remedy for infectious diseases |
| JP3086824B2 (en) * | 1990-06-19 | 2000-09-11 | 紀久男 酒井 | Adhesive tape cutting equipment |
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| JP3086824B2 (en) * | 1990-06-19 | 2000-09-11 | 紀久男 酒井 | Adhesive tape cutting equipment |
| CN1147766A (en) * | 1994-03-18 | 1997-04-16 | 株式会社津村 | Remedy for infectious diseases |
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