CN104910250A - 1-carbonyl tanshinone IIA sodium sulfonate analogue, preparation and application thereof - Google Patents
1-carbonyl tanshinone IIA sodium sulfonate analogue, preparation and application thereof Download PDFInfo
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- CN104910250A CN104910250A CN201410227077.2A CN201410227077A CN104910250A CN 104910250 A CN104910250 A CN 104910250A CN 201410227077 A CN201410227077 A CN 201410227077A CN 104910250 A CN104910250 A CN 104910250A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/006—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by sulfur as hetero atom
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Abstract
The invention relates to a 1-carbonyl tanshinone IIA sodium sulfonate analogue, preparation and application thereof. The 1-carbonyl tanshinone IIA sodium sulfonate analogue provided by the invention is shown as formula (I), has good treatment effect on cardiovascular diseases, cerebrovascular diseases, liver and kidney diseases, respiratory system diseases and tumors, and has high stability to light, acid, alkali and high temperature. (formula (I) as shown in the specification).
Description
Technical field
The present invention relates to 1-carbonyl sodium tanshinone IIA sulfate analogue and preparation thereof and purposes.
Background technology
Summary of the invention
For solving the defect that prior art exists, the invention provides a kind of 1-carbonyl sodium tanshinone IIA sulfate analogue and Synthesis and applications thereof.
The present invention relates to a kind of 1-carbonyl sodium tanshinone IIA sulfate analogue, structure is such as formula shown in I:
Further, X is O.
The invention still further relates to the preparation method of 1-carbonyl sodium tanshinone IIA sulfate, described method comprises the steps:
Compounds Ⅳ oxidation preparation compound III reaction conditions is: 1-hydroxyl TANSHINONES-IIA in the organic solvents such as methylene dichloride, toluene, acetic acid, acetone, sulfuric acid or its arbitrary proportion mixed solvent, through MnO
2(Manganse Dioxide), CrO
3(chromium trioxide), Jones reagent (Jones reagent), TEMPO(2,2,6,6-tetramethyl piperidine oxide compound), PCC(pyridinium chlorochromate drone salt) oxidizingly obtain 1-carbonyl TANSHINONES-IIA.1-hydroxyl TANSHINONES-IIA is 1:0.5-1:5 with the mol ratio of oxygenant; Temperature of reaction is: 0-110 DEG C; Reaction times is: 1-16h.The wherein preferred 1:1-1:2 of mol ratio of 1-hydroxyl TANSHINONES-IIA and oxygenant.Organic solvent is preferred: methylene dichloride, toluene, acetone, acetic acid or its arbitrary proportion mixed solvent.Oxygenant is preferred: MnO
2, Jones reagent, CrO
3.
Compound III prepares Compound II per reaction conditions :-IIA is at Glacial acetic acid for 1-carbonyl TANSHINONES, generate 1-carbonyl TANSHINONES-IIA sulfonic acid with strong sulfuric acid response under aceticanhydride condition, 1-carbonyl TANSHINONES-IIA and vitriol oil mol ratio are 1:1-1:5, temperature of reaction is: 10-50 DEG C, and the reaction times is: 0.25-2.5h.1-carbonyl TANSHINONES-IIA and the preferred 1:5 of vitriol oil mol ratio, temperature of reaction is preferred: 15-30 DEG C, and the reaction times is preferred: 0.5-1h.
Compound II per prepares Compound I reaction conditions: 1-carbonyl TANSHINONES-IIA sulfonic acid and sodium chloride solution react and generate 1-carbonyl TANSHINONES-IIA sodium sulfonate, and temperature of reaction is: 10-50 DEG C.Temperature of reaction is preferred: 20-30 DEG C.
The invention still further relates to above-mentioned 1-carbonyl TANSHINONES-IIA sodium sulfonate analogue and preparing Cardiovarscular medicine, cerebrovascular disease medicament, treatment liver, kidney diaseases medicine, treatment medicament for treating respiratory system thing, the application of tumor.
Specific embodiment
Citing below by way of embodiment illustrates in greater detail the present invention.Above embodiment is to technical purpose of the present invention and beneficial effect are described and provide, and is never intended to limit the present invention by any way.Those skilled in the art are by the record of claims of the present invention and specification sheets summary of the invention; to easily recognize; can by changing or improveing various non-key parameter; to obtain the result of substantially the same technical scheme, these results also will fall into the protection domain of claims of the present invention.
The preparation of 1-carbonyl TANSHINONES-IIA
Embodiment 1:
By 1-hydroxyl TANSHINONES-IIA(31.2mg, 0.1mmol) be dissolved in methylene dichloride 50mL, add MnO
2(17.4mg, 0.2mmol), stirring at room temperature reaction 16h.Solid 3.1mg is obtained through column chromatography for separation, yield: 10%, [M+H] after reaction terminates
+: 309.2.
Embodiment 2:
By 1-hydroxyl TANSHINONES-IIA(31.2mg, 0.1mmol) be dissolved in toluene 35mL, add MnO
2(8.6mg, 0.1mmol), stirs, and is warming up to 110 DEG C of reaction 8h.Solid 4.5mg is obtained through column chromatography for separation, yield: 15% after reaction terminates.
Embodiment 3:
By 1-hydroxyl TANSHINONES-IIA(31.2mg, 0.1mmol) be dissolved in acetic acid 5mL, add CrO
3(10mg, 0.1mmol), stirring at room temperature reaction 8h.Solid 17.3mg is obtained through column chromatography for separation, yield: 56% after reaction terminates.
Embodiment 4:
By 1-hydroxyl TANSHINONES-IIA(31.2mg, 0.1mmol) be dissolved in acetone 5mL, add the vitriol oil 1, CrO
3(20mg, 0.2mmol), 0 DEG C of stirring reaction 3h.Solid 7.8mg is obtained through column chromatography for separation, yield: 25% after reaction terminates.
Embodiment 5:
By 1-hydroxyl TANSHINONES-IIA(31.2mg, 0.1mmol) be dissolved in acetone 5mL, add Jones reagent 10,0 DEG C of stirring reaction 1h.Solid 15.7mg is obtained through column chromatography for separation, yield: 51% after reaction terminates.
The preparation of 1-carbonyl Tanshinone II A sulfonic acid
Embodiment 6:
By 1-carbonyl TANSHINONES-IIA(154mg, 0.5mmol) be added in the mixed solution of Glacial acetic acid (1mL) and acetic anhydride (1mL).Stir, be cooled to 10 DEG C.Drip the vitriol oil (49mg, 0.5mmol).50 DEG C of reaction 0.25h are warming up to after dropping terminates.Reaction solution obtains 1-carbonyl Tanshinone II A sulfonic acid 97.1mg through column chromatography for separation, yield 50%.
Embodiment 7:
By 1-carbonyl TANSHINONES-IIA(154mg, 0.5mmol) be added in the mixed solution of Glacial acetic acid (1mL) and acetic anhydride (1mL).Stir, be cooled to 10 DEG C.Drip the vitriol oil (245mg, 2.5mmol).50 DEG C of reaction 0.25h are warming up to after dropping terminates.Reaction solution obtains 1-carbonyl Tanshinone II A sulfonic acid 116.5mg through column chromatography for separation, yield 60%.
The preparation of 1-carbonyl sodium tanshinone IIA sulfate
Embodiment 8:
1-carbonyl Tanshinone II A sulfonic acid (116.5mg, 0.3mmol) is dissolved in 5mL water, 20-30 DEG C of agitation condition, drips saturated nacl aqueous solution and separate out to a large amount of solid, the target compound 82mg of filtration, yield: 66.7%.MS ES-：387.1，1H-NMR(400MHz，DMSO)；δ（ppm）：7.83(d，1H)，7.56(d，1H)，2.33 (s，3H)，1.95 (m，2H)，1.61(m，2H)，1.29(s，6H)。
Biological detection example:
The effect of embodiment 9:1-carbonyl sodium tanshinone IIA sulfate In Vitro Anti myocardial cell injury
Cultivate H9C2 rat myocardial cell, the myocardial cell of separation is inoculated in (cell concn 1 × 104/mL) in 96 well culture plates, every hole 100 μ L, cultivates replaced medium after 48 h, add Racemic isoproterenol (final concentration 10 μm of ol/L), establish parallel hole 3 simultaneously.Set up control group, administration group adds the trial-product (1 μM, 2.5 μMs, 5 μMs, 10 μMs, 20 μMs) of Racemic isoproterenol (final concentration 10 μm of ol/L) and different concns, positive controls adds the esmolol of respective concentration, in 37 DEG C, continue cultivation 48 h under 5% CO2 condition, measure optical density (A) value by CCK-8 method.Calculate medicine anti-myocardial damage effect, formula is: [normal-OD administration of 1-(OD)/(normal-OD model of OD)] × 100%.Concentration EC is recovered with SPSS software analysis half antibody Monoclonal
50.Result is as follows
1-carbonyl sodium tanshinone IIA sulfate is to the effect of Myocytes Anoxia sugar deficiency injury
。
Embodiment 10:1-carbonyl sodium tanshinone IIA sulfate is to the effect of MCAO models in rats
Adopt internal carotid artery line brush to prepare intraluminal middle cerebral artery occlusion in rats and block (Middle cerebral artery, MCAO) cerebral ischemia re-pouring model.Establish six groups, that is: model control group altogether, sham operated rats, Edaravone group, high, medium and low three the dosage groups of 1-carbonyl sodium tanshinone IIA sulfate.Intravenous administration 1 time immediately after cerebral ischemia re-pouring, measures brain infarction area in after Reperfu-sion 24 hours after TTC dyeing.The per-cent of brain infarction area adopts following formulae discovery:
Test-results:
1-carbonyl sodium tanshinone IIA sulfate is on the impact of MCAO rat cerebral infarction area
Mean value ± standard error.* P < 0.05, compares with model group.
Effect in the pulmonary hypertension model in rats that embodiment 11:1-carbonyl sodium tanshinone IIA sulfate is induced at Monocrotaline
Male SD rat, body weight 220g ± 20g, adopts the method for subcutaneous injection Monocrotaline (60mg/kg) to prepare pulmonary hypertension model in rats.Right cardiac catheter detection assay pulmonary artery blood pressure and hemodynamic index.Within after injection two weeks, detect pulmonary artery blood pressure, determine that whether modeling is successful, successful for modeling animal is divided into following group (n=10): sham operated rats: iv physiological saline 2ml/kg; Model group: iv physiological saline 2ml/kg; High dose group: iv 10mg/kg; Middle dosage group: iv 3mg/kg; Low dose group: iv 1mg/kg.Start administration after determining modeling success, injection 2 weeks, detects each treated animal pulmonary artery root footpath, pulmonary artery flow velocity, pulmonary artery and carotid artery mean pressure after last administration continuously,
Test-results: see the following form lattice
1-carbonyl sodium tanshinone IIA sulfate Monocrotaline is induced pulmonary hypertension model in rats rat pulmonary artery flow velocity, the effect of pulmonary artery root internal diameter
* P < 0.05 is compared with model group; * compares P < 0.05 with model group
1-carbonyl sodium tanshinone IIA sulfate is to the effect of pulmonary hypertension model in rats rat mPAP and mCAP that Monocrotaline is induced
* P < 0.05 is compared with model group; * compares P < 0.05 with model group
The pulmonary hypertension symptom that Monocrotaline causes can be reduced after can finding out GB drug administration by injection by above-mentioned test-results significantly, there is the effect for the treatment of pulmonary hypertension.
Embodiment 12 1-carbonyl sodium tanshinone IIA sulfate is to the restraining effect of nude mice by subcutaneous Transplanted Human cancer of the stomach SGC-7901
BALB/ C nude mice, 18-22g, male.The people cancer of the stomach SGC-7901 cell of taking the logarithm vegetative period, it is 1 × 107 single cell suspension that collecting cell is prepared into concentration, in the cell suspension of nude mice right fore dorsal sc injection 0. 2 ml in Bechtop.BALB/C nude mice is divided into 4 groups (often organizing 12) at random, each group gives physiological saline (negative control group), the high, medium and low dosage group of 1-carbonyl sodium tanshinone IIA sulfate (40 μ g/kg, 20 μ g/kg, 10 μ g/kg) respectively at the injection of inoculation 24h pneumoretroperitoneum, every d is administered once, altogether administration 2 weeks.Nude mice spirit, diet and defecation situation is observed during nursing.24h after last administration puts to death nude mice and peels off tumor nodule and weigh, and calculates tumour inhibiting rate:
Tumour inhibiting rate=[(control group average knurl weight-experimental group average knurl weight) the average knurl weight of/control group)] × 100%
Test-results:
As shown in following table data, the growing multiplication of 1-carbonyl sodium tanshinone IIA sulfate middle and high dosage group to people cancer of the stomach SGC-7901 has good restraining effect, high dose group 40 μ g/kg tumour inhibiting rate more than 50%,
1-carbonyl sodium tanshinone IIA sulfate is to the restraining effect (X ± SD) of nude mice by subcutaneous Transplanted Human cancer of the stomach SGC-7901
Note: compared with control group, * P<0.05; * P<0.01.
Claims (10)
1. a 1-carbonyl sodium tanshinone IIA sulfate analogue, its molecular structural formula is:
Wherein, X is O, NH, S.
2. as claimed in claim 1, X is O.
3. prepare the method for compound 1-carbonyl sodium tanshinone IIA sulfate according to claim 2, it is characterized in that, described method comprises the steps:
According to claim 3, preparation method, compounds Ⅳ oxidation preparation compound III, is characterized in that: 1-hydroxyl TANSHINONES-IIA(compounds Ⅳ) be 1:0.5-1:5 with the mol ratio of oxygenant; Temperature of reaction is: 0-110 DEG C; Reaction times is: 1-16h; Oxygenant comprises: MnO
2(Manganse Dioxide); CrO
3(chromium trioxide); Jones reagent (Jones reagent); TEMPO(2,2,6,6-tetramethyl piperidine oxide compound); PCC(pyridinium chlorochromate drone salt) etc.
4. organic solvent comprises: methylene dichloride, toluene, acetic acid, acetone, sulfuric acid or its arbitrary proportion mixed solvent etc.
5. preparation method according to claim 3, compound III prepares compound ii, it is characterized in that: 1-carbonyl TANSHINONES-IIA(compound III) at Glacial acetic acid, generate 1-carbonyl TANSHINONES-IIA sulfonic acid with strong sulfuric acid response under aceticanhydride condition, 1-carbonyl TANSHINONES-IIA and vitriol oil mol ratio are 1:1-1:5, temperature of reaction is: 10-50 DEG C, and the reaction times is: 0.25-2.5h.
6. preparation method according to claim 3, compound ii prepares chemical compounds I, it is characterized in that: 1-carbonyl TANSHINONES-IIA sulfonic acid (compound ii) and sodium chloride solution react and generate 1-carbonyl TANSHINONES-IIA sodium sulfonate, and temperature of reaction is: 10-50 DEG C.
7. preparation method according to claim 4, is characterized in that: 1-hydroxyl TANSHINONES-IIA is 1:1-1:2 with the mol ratio of oxygenant; Temperature of reaction is: 0-110 DEG C; Reaction times is: 1-16h; Organic solvent comprises: methylene dichloride, toluene, acetone, acetic acid or its arbitrary proportion mixed solvent, oxygenant comprises: MnO
2, Jones reagent, CrO
3.
8. preparation method according to claim 5, is characterized in that: 1-carbonyl TANSHINONES-IIA and vitriol oil mol ratio are 1:5.
9. preparation method according to claim 6, is characterized in that: temperature of reaction is: 20-30 DEG C.
10. compound is preparing Cardiovarscular medicine, cerebrovascular disease medicament according to claim 1, treatment liver, kidney diaseases medicine, treatment medicament for treating respiratory system thing, the application of tumor.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905408A (en) * | 2015-12-22 | 2017-06-30 | 江苏柯菲平医药股份有限公司 | 1- carbonyl tanshinone IIA derivatives and its preparation |
| CN109824753A (en) * | 2018-11-20 | 2019-05-31 | 中国科学院昆明植物研究所 | Tanshinone IIA derivative with IDO/TDO double selectivity inhibitory activity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002092A (en) * | 2010-09-30 | 2011-04-06 | 上海第一生化药业有限公司 | 3-hydroxytanshinone IIA sodium sulfonate as well as preparation method and application thereof |
| CN103497230A (en) * | 2013-10-21 | 2014-01-08 | 中国科学院昆明植物研究所 | Method of preparing high-purity tanshinone IIA sodium sulfonate |
-
2014
- 2014-05-27 CN CN201410227077.2A patent/CN104910250A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002092A (en) * | 2010-09-30 | 2011-04-06 | 上海第一生化药业有限公司 | 3-hydroxytanshinone IIA sodium sulfonate as well as preparation method and application thereof |
| CN103497230A (en) * | 2013-10-21 | 2014-01-08 | 中国科学院昆明植物研究所 | Method of preparing high-purity tanshinone IIA sodium sulfonate |
Non-Patent Citations (1)
| Title |
|---|
| PENG LI ET AL.: "《Characterization of metabolites of tanshinone IIA in rats by liquid chromatography/tandem mass spectrometry》", 《JOURNAL OF MASS SPECTROMETRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905408A (en) * | 2015-12-22 | 2017-06-30 | 江苏柯菲平医药股份有限公司 | 1- carbonyl tanshinone IIA derivatives and its preparation |
| CN106905408B (en) * | 2015-12-22 | 2020-10-27 | 江苏柯菲平医药股份有限公司 | 1-carbonyl tanshinone IIA derivative and preparation thereof |
| CN109824753A (en) * | 2018-11-20 | 2019-05-31 | 中国科学院昆明植物研究所 | Tanshinone IIA derivative with IDO/TDO double selectivity inhibitory activity |
| CN109824753B (en) * | 2018-11-20 | 2021-11-26 | 中国科学院昆明植物研究所 | Tanshinone IIA derivative with IDO/TDO double-selective inhibitory activity |
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Application publication date: 20150916 |