CN113582951A - 10- (S) -17-hydrogen-7-dehydro-andrographolide and industrial chromatographic preparation method and application thereof - Google Patents
10- (S) -17-hydrogen-7-dehydro-andrographolide and industrial chromatographic preparation method and application thereof Download PDFInfo
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- dehydroandrographolide
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical class C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 claims description 29
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
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- A61K31/365—Lactones
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- B01D15/08—Selective adsorption, e.g. chromatography
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Abstract
The invention provides a novel compound 10- (S) -17-hydro-7-dehydroandrographolide; in vitro experiments show that the compound has significant inhibitory effect on the generation of Nitric Oxide (NO) in RAW264.7 macrophages induced by Lipopolysaccharide (LPS), so that the compound can be used as a nitric oxide inhibitor to prepare an anti-inflammatory drug and can be used for treating novel coronavirus pneumonia (COVID-19); the preparation method of 10- (S) -17-hydro-7-dehydroandrographolide provided by the invention is convenient to operate, high in yield, capable of preparing a large amount of high-purity compound by adopting an industrial chromatographic technology, and suitable for large-scale production.
Description
Technical Field
The invention relates to an andrographolide derivative 10- (S) -17-hydro-7-dehydroandrographolide, a preparation method thereof and application thereof in preparing a medicament for treating inflammation.
Background
Andrographolide is a labdane diterpenoid compound extracted from the whole herb of Andrographis paniculata (Burm.F.) Nees of Acanthaceae, has the effects of resisting bacteria, diminishing inflammation, detoxifying and the like, and is an important active natural product. Andrographolide and its derivatives have been made into various dosage forms (tablet, dripping pill, capsule, etc.) for clinical application, such as Xiyanping injection, Lianbizhi injection, Yanhuning injection, andrographolide tablet, etc., all showing good effects of clearing heat and removing toxicity, resisting bacteria and diminishing inflammation. Luvone et al believe that Nitric Oxide (NO) is associated with both the development of acute and chronic inflammation [ Luvone T, Carnuccio R, Di RM.modulation of grandioloma formation endogenous nitrile oxide [ J ]. Eur J Pharmacol,1994,265(1/2):89-92 ]. The andrographolide can obviously reduce the expression of inflammatory factors NO, tumor necrosis factor-alpha (TNF-alpha) and Interleukin (IL) -6 in mouse macrophage RAW264.7 induced by lipopolysaccharide, thereby inhibiting inflammatory reaction.
The Xiyanping injection which is widely used clinically at present has the functions of clearing away heat and toxic materials, resisting bacteria and diminishing inflammation and the like, but the active component of the Xiyanping injection is a sulfonated product of andrographolide, and the Xiyanping injection is not of a single structure. The micromolecule compound with a single structure is adopted to further define the mechanism, and has important significance on the research of the drug effect and the toxicology thereof; although andrographolide compounds have achieved some research results, there are no new andrographolide derivatives or analogues that are particularly effective in the clinical setting for a variety of diseases, particularly in the anti-inflammatory field. Therefore, the development of new andrographolide derivative monomer drugs with anti-inflammatory activity has important social significance.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a novel andrographolide derivative 10- (S) -17-hydro-7-dehydroandrographolide and a preparation method and application thereof.
In a first aspect of the present invention, there is provided a novel andrographolide derivative, 10- (S) -17-hydro-7-dehydroandrographolide formula (I),
in a second aspect of the present invention, there is provided a method for preparing a novel andrographolide derivative, 10- (S) -17-hydro-7-dehydroandrographolide, comprising the steps of:
(1) purifying by using a macroporous adsorption resin column: dissolving andrographolide sulfonate with water, loading onto macroporous adsorbent resin column, eluting with mixed solvent of organic solvent and water, mixing eluates containing 10- (S) -17-hydro-7-dehydroandrographolide, and concentrating to obtain crude product 1;
(2) silica gel column purification: dissolving the crude product 1 by using a mixed organic solvent (A/B), loading the solution to a silica gel column for purification, eluting by using the mixed organic solvent (A/B), detecting the separation condition by using an ultraviolet online detector, determining the start and stop time of eluent collection according to the peak emergence time and the chromatographic peak height, collecting the eluent for HPLC detection, merging the eluent containing 10- (S) -17-hydro-7-dehydroandrographolide according to the detection result, and concentrating to obtain a crude product 2;
(3) and (3) recrystallization: dissolving the crude product 2 with organic solvent, volatilizing part of the organic solvent, separating out solid, filtering and drying.
Preferably, in the step (1), the macroporous adsorption resin is styrene type macroporous adsorption resin, and more preferably, the styrene type macroporous adsorption resin is HPD-100S, D101S or LX-1180.
Preferably, in the step (1), the organic solvent is an alcohol solvent, such as methanol or ethanol.
Preferably, in the step (1), the mixed solvent of the organic solvent and the water is 0-60% methanol aqueous solution (preferably 35-55% methanol aqueous solution) or 0-60% ethanol aqueous solution (preferably 30-50% ethanol aqueous solution).
Preferably, in the step (1), the elution is a gradient elution, such as: sequentially eluting with 35%, 45%, and 55% methanol-water solution, or sequentially eluting with 30%, 40%, and 50% ethanol-water solution.
Preferably, in the step (1), the concentration temperature is 40-50 ℃.
Preferably, in the step (2), in the mixed organic solvent (a/B), a is one of petroleum ether and cyclohexane, and B is one of ethyl acetate, dichloromethane, chloroform and acetone;
more preferably, the mixed organic solvent (A/B) is a petroleum ether/acetone solution;
further preferably, a petroleum ether/acetone solution with the volume ratio of 5: 1-4: 1 is adopted during dissolving; and/or the solvent is petroleum ether/acetone solution with the volume ratio of 5: 1-1: 1 during elution.
Preferably, in the step (2), the elution is a gradient elution, such as: eluting with petroleum ether-acetone solution at volume ratio of 5:1, 3:1, 2:1, and 1: 1.
Preferably, in the step (2), the concentration temperature is 40-50 ℃.
Preferably, in step (2), the packing material of the HPLC column is reversed-phase C18 packing material, more preferably XAquA, ODS-A or ODS-AQ.
Preferably, in the step (2), the detection wavelength of the ultraviolet online detector is 150-300 nm, and more preferably 225 nm.
Preferably, in the step (3), the organic solvent is ethyl acetate.
Preferably, in the step (3), the number of recrystallization is 2 or more.
Preferably, in the step (3), the drying method is drying under reduced pressure.
Preferably, in the step (3), the drying temperature is 40-50 ℃.
In a third aspect of the present invention, there is provided a pharmaceutical preparation containing the novel andrographolide derivative 10- (S) -17-hydro-7-dehydroandrographolide as the active ingredient, including but not limited to injection, tablet, capsule, dispersible tablet.
In a fourth aspect of the present invention, there is provided a use of the above-mentioned novel andrographolide derivative 10- (S) -17-hydro-7-dehydroandrographolide or the above-mentioned pharmaceutical preparation in the preparation of a medicament for treating an inflammatory disease, preferably pneumonia, preferably novel coronavirus pneumonia (COVID-19).
The invention has the beneficial technical effects
1. The invention provides a novel andrographolide derivative 10- (S) -17-hydro-7-dehydroandrographolide compound shown in formula (I), and in-vitro experiments show that the compound has a remarkable inhibiting effect on generation of Nitric Oxide (NO) in RAW264.7 macrophages induced by Lipopolysaccharide (LPS), so that the compound can be used as a nitric oxide inhibitor to prepare an anti-inflammatory drug for treating inflammatory diseases, and further can be used for treating pneumonia, such as novel coronavirus pneumonia (COVID-19).
2. The preparation method of 10- (S) -17-hydro-7-dehydroandrographolide provided by the invention is convenient to operate, high in yield, capable of preparing a large amount of high-purity compound by adopting an industrial chromatographic technology, and suitable for large-scale production.
Drawings
FIG. 1: the NMR spectrum of 10- (S) -17-hydro-7-dehydroandrographolide of example 2;
FIG. 2: the NMR carbon spectrum of 10- (S) -17-hydro-7-dehydroandrographolide of example 2;
FIG. 3: HPLC assay of 10- (S) -17-hydro-7-dehydroandrographolide of example 2;
FIG. 4: the anti-inflammatory activity of 10- (S) -17-hydro-7-dehydroandrographolide of example 2 was tested.
Detailed Description
The chemical structural formula of 10- (S) -17-hydro-7-dehydroandrographolide indicated in the following examples (the Arabic numerals in the structure are the positions of carbon atoms in the chemical structure):
example 1: preparation of andrographolide general sulfonate
Taking 50L of absolute ethyl alcohol, placing the absolute ethyl alcohol in a reaction kettle, slowly adding 20L of concentrated sulfuric acid, stirring uniformly, adding 50.00kg of andrographolide, stirring, and standing at normal temperature for 72 hours. Controlling temperature, adding 50L 95% ethanol, stirring, adding 50% sodium hydroxide solution, adjusting pH to 7.0, adding ethanol until the alcohol content is 85%, standing for 24 hr, filtering, recovering ethanol from filtrate, concentrating into soft extract, and vacuum drying to obtain andrographolide total sulfonate.
Examples 2 to 5: preparation of 10- (S) -17-hydro-7-dehydroandrographolide
Example 2
(1) Purifying by using a macroporous adsorption resin column: taking 200.00g of andrographolide total sulfonate, adding a proper amount of purified water to dissolve, loading the andrographolide total sulfonate into a D101S macroporous adsorption resin column, sequentially eluting by using 30 percent, 40 percent and 50 percent ethanol-water solution in volume ratio, combining elution fractions containing 10- (S) -17-hydrogen-7-dehydro-andrographolide, and concentrating and drying at 40 ℃ under reduced pressure to obtain a crude product 1;
(2) silica gel column purification: dissolving the crude product 1 with petroleum ether-acetone at a proper volume ratio of 5:1, loading the solution into a silica gel column, eluting with petroleum ether-acetone solution at a volume ratio of 5:1, 3:1, 2:1 and 1:1 in sequence, detecting the separation condition with an ultraviolet online detector, determining the start and stop time of eluent collection according to the peak emergence time and the chromatographic peak height, collecting the eluent for HPLC detection, wherein the HPLC chromatographic column filler is XAqua (reverse C18 filler), and the ultraviolet detection wavelength is 225 nm. Mixing the eluate containing 10- (S) -17-hydro-7-dehydroandrographolide according to the detection result, and concentrating under reduced pressure at 40 deg.C to obtain crude product 2;
(3) and (3) recrystallization: dissolving the crude product 2 in a proper amount of ethyl acetate, placing the mixture in a fume hood to volatilize part of the solvent until a large amount of solid is separated out, filtering, continuously adding a proper amount of ethyl acetate into the solid to dissolve, placing the mixture in a fume hood to volatilize part of the solvent until a large amount of solid is separated out, filtering, and drying the solid at 40 ℃ under reduced pressure to obtain 4.53g of 10- (S) -17-hydrogen-7-dehydroandrographolide with the purity of 96.33%.
The chemical structure of the compound 10- (S) -17-hydrogen-7-dehydroandrographolide is identified by modern spectral techniques such as NMR and ESI-MS, the absolute configuration of the compound is determined by X-ray single crystal diffraction, and the physicochemical properties are as follows:
white powder with molecular formula of C20H30O5；
High resolution mass spectrum HRESIMS M/z 349.2021[ M-H ]]–(cald.for.C20H29O5,349.2015). Hydrogen spectrum of nuclear magnetic resonance1H-NMR(400MHZ) And nuclear magnetic resonance carbon spectrum13C-NMR(100MHZ) See fig. 1 and 2, and the data is shown in table 1.
TABLE 110 hydrogen and carbon spectra data (400/100MHz, DMSO) of (S) -17-hydro-7-dehydroandrographolide
Example 3
(1) Purifying by using a macroporous adsorption resin column: dissolving 200.08g andrographolide sulfonate in purified water, loading onto HPD-100S macroporous resin column, sequentially eluting with 35%, 45%, and 55% methanol-water solution, mixing eluates containing 10- (S) -17-hydro-7-dehydroandrographolide, and concentrating at 50 deg.C under reduced pressure to obtain crude product 1;
(2) silica gel column purification: dissolving the crude product 1 by using A proper amount of petroleum ether/acetone mixed solvent with A volume ratio of 5:1, loading the dissolved crude product into A silicA gel column for purification, sequentially eluting by using petroleum ether-acetone solutions with volume ratios of 5:1, 3:1, 2:1 and 1:1, detecting the separation condition by using an ultraviolet online detector, determining the start and stop time of eluent collection according to the peak emergence time and the chromatographic peak height, collecting the eluent for HPLC detection, wherein the HPLC chromatographic column filler is ODS-A (reverse C18 filler), and the ultraviolet detection wavelength is 225 nm. Mixing the eluate containing 10- (S) -17-hydro-7-dehydroandrographolide according to the detection result, and concentrating under reduced pressure at 50 deg.C to obtain crude product 2;
(3) and (3) recrystallization: dissolving the crude product 2 in a proper amount of ethyl acetate, placing the mixture in a fume hood to volatilize part of the solvent until a large amount of solids are separated out, filtering, continuously adding a proper amount of ethyl acetate into the solids to dissolve, placing the mixture in a fume hood to volatilize part of the solvent until a large amount of solids are separated out, filtering, and drying the solids at 50 ℃ under reduced pressure to obtain 4.39g of 10- (S) -17-hydrogen-7-dehydroandrographolide with the purity of 96.54%.
Example 4
(1) Purifying by using a macroporous adsorption resin column: dissolving 200.15g of andrographolide total sulfonate in a proper amount of purified water, loading to LX-1180 macroporous resin adsorption column, sequentially eluting with 30%, 40% and 50% ethanol-water solution by volume ratio, mixing elution fractions containing 10- (S) -17-hydro-7-dehydroandrographolide, and concentrating under reduced pressure at 40 deg.C to obtain crude product 1;
(2) silica gel column purification: dissolving the crude product 1 with a proper amount of petroleum ether/acetone solution in a volume ratio of 4:1, loading the solution to a silica gel column for purification, sequentially eluting with petroleum ether-acetone solution in a volume ratio of 5:1, 3:1, 2:1 and 1:1, detecting the separation condition with an ultraviolet online detector, determining the start and stop time of eluent collection according to the peak emergence time and the chromatographic peak height, collecting the eluent for HPLC detection, wherein the HPLC column filler is ODS-AQ (reverse C18 filler), and the ultraviolet detection wavelength is 225 nm. Mixing the eluate containing 10- (S) -17-hydro-7-dehydroandrographolide according to the detection result, and concentrating under reduced pressure at 40 deg.C to obtain crude product 2;
(3) and (3) recrystallization: dissolving the crude product 2 in a proper amount of ethyl acetate, placing the mixture in a fume hood to volatilize part of the solvent until a large amount of solids are separated out, filtering, continuously adding a proper amount of ethyl acetate into the solids to dissolve, placing the mixture in a fume hood to volatilize part of the solvent until a large amount of solids are separated out, filtering, and drying the solids at 50 ℃ under reduced pressure to obtain 4.72g of 10- (S) -17-hydrogen-7-dehydroandrographolide with the purity of 96.19%.
Example 5
(1) Purifying by using a macroporous adsorption resin column: taking 20.15kg of andrographolide total sulfonate, adding a proper amount of purified water to dissolve, loading the andrographolide total sulfonate into an HPD-100S macroporous resin column, sequentially eluting with 35 vol%, 45 vol% and 55 vol% methanol-water solution, combining elution fractions containing 10- (S) -17-hydrogen-7-dehydro-andrographolide, and concentrating and drying at 50 ℃ under reduced pressure to obtain a crude product 1;
(2) purifying by using an industrial chromatographic grade silica gel column: dissolving the crude product 1 with A proper amount of petroleum ether/acetone mixed solvent in A volume ratio of 5:1, then loading the solution to an industrial chromatographic system for purification (DAC-HB300 dynamic axial compression column and silicA gel packing), eluting with petroleum ether-acetone solutions in volume ratios of 5:1, 3:1, 2:1 and 1:1 in sequence, detecting the separation condition with an ultraviolet on-line detector, determining the start-stop time of eluent collection according to the peak-out time and the chromatographic peak height, collecting the eluent for HPLC detection, wherein the HPLC column packing is ODS-A (reverse C18 packing), and the ultraviolet detection wavelength is 225 nm. Mixing the eluate containing 10- (S) -17-hydro-7-dehydroandrographolide according to the detection result, and concentrating under reduced pressure at 40 deg.C to obtain crude product 2;
(3) and (3) recrystallization: dissolving the crude product 2 in a proper amount of ethyl acetate, placing the mixture in a fume hood to volatilize part of the solvent until a large amount of solids are separated out, filtering, continuously adding a proper amount of ethyl acetate into the solids to dissolve, placing the mixture in a fume hood to volatilize part of the solvent until a large amount of solids are separated out, filtering, and drying the solids under reduced pressure at 40 ℃ to obtain 415.28g of 10- (S) -17-hydrogen-7-dehydroandrographolide with the purity of 96.08%.
Example 6: anti-inflammatory activity test of 10- (S) -17-hydro-7-dehydroandrographolide
The compound obtained in example 2 was allowed to act on Lipopolysaccharide (LPS) -induced RAW264.7 mouse macrophages, the NO level in the culture supernatant was measured by Griess reagent color development, and the anti-inflammatory activity of the compound was evaluated using the ability of the test drug to inhibit NO release as a screening index.
1. Preparation of pharmaceutical solutions
The monomer compounds were dissolved in DMSO to prepare solutions of 1.564, 3.125, 6.250, 12.50, 25.00. mu.g/ml.
2. Test method
(1) Preparing single mouse macrophage suspension with 10% fetal calf serum culture solution, and collecting logarithmic phase mouse macrophage RAW264.7 inoculation into 96-well plates, 10 per well5Cell number, 3 multiple wells were set.
(2) After 24 hours incubation, different concentrations of test drug were added to each well along with 1ug/mL LPS.
(3) After culturing at 37 ℃ for 24 hours, 100ul of Griess solution was added to each well and the culture was continued for 5 minutes, and the culture was stopped.
(4) The Optical Density (OD) value at a wavelength of 570nm was measured by an enzyme-linked immunosorbent assay (ELISA) apparatus, and the NO inhibition rate was calculated.
3. Results of the experiment
The NO inhibitory effect IC50 of 10- (S) -17-hydro-7-dehydroandrographolide compounds on RAW264.7 cells was 9.184 μ g/ml, see FIG. 4 for details.
The result shows that the 10- (S) -17-hydro-7-dehydroandrographolide compound has obvious inhibition effect on the generation of mouse macrophage RAW264.7 NO induced by Lipopolysaccharide (LPS), can be used as a nitric oxide inhibitor, and shows that the compound has obvious anti-inflammatory activity; therefore, can be used for preparing novel anti-inflammatory active medicaments; further, it can be used for treating pneumonia, such as novel coronavirus pneumonia (COVID-19).
Claims (10)
1. A novel andrographolide derivative 10- (S) -17-hydro-7-dehydroandrographolide has formula (I),
2. a method for preparing a novel andrographolide derivative 10- (S) -17-hydro-7-dehydroandrographolide is characterized by comprising the following steps:
(1) purifying by using a macroporous adsorption resin column: dissolving andrographolide sulfonate with water, loading onto macroporous adsorbent resin column, eluting with mixed solvent of organic solvent and water, mixing eluates containing 10- (S) -17-hydro-7-dehydroandrographolide, and concentrating to obtain crude product 1;
(2) silica gel column purification: dissolving the crude product 1 by using a mixed organic solvent (A/B), loading the solution to a silica gel column for purification, eluting by using the mixed organic solvent (A/B), detecting the separation condition by using an ultraviolet online detector, determining the start and stop time of eluent collection according to the peak emergence time and the chromatographic peak height, collecting the eluent for HPLC detection, merging the eluent containing 10- (S) -17-hydro-7-dehydroandrographolide according to the detection result, and concentrating to obtain a crude product 2;
(3) and (3) recrystallization: dissolving the crude product 2 with organic solvent, volatilizing part of the organic solvent, separating out solid, filtering and drying.
3. The method of claim 2, wherein: in the step (1), the macroporous adsorption resin is styrene type macroporous adsorption resin, preferably resin model HPD-100S, D101S or LX-1180.
4. The method of claim 2, wherein: in the step (1), the organic solvent is an alcohol solvent; and/or the mixed solvent of the organic solvent and the water is methanol-water solution with the volume ratio of 0-60% or ethanol-water solution with the volume ratio of 0-60%; and/or the concentration temperature is 40-50 ℃.
5. The method of claim 2, wherein: in the step (2), the step (c),
in the mixed organic solvent (A/B), A is one of petroleum ether or cyclohexane, and B is one of ethyl acetate, dichloromethane, chloroform or acetone;
preferably, the mixed organic solvent (A/B) is a petroleum ether/acetone solution;
more preferably, a petroleum ether/acetone solution with the volume ratio of 5: 1-4: 1 is adopted during dissolving; and/or the solvent is petroleum ether/acetone solution with the volume ratio of 5: 1-1: 1 during elution.
6. The method of claim 2, wherein: in the step (2), the packing of the HPLC column is reversed phase C18 packing, preferably XAquA, ODS-A or ODS-AQ.
7. The method of claim 2, wherein: in the step (2), the detection wavelength of the ultraviolet online detector is 150-300 nm; and/or the concentration temperature is 40-50 ℃.
8. The method of claim 2, wherein: in the step (3), the organic solvent is ethyl acetate; and/or the number of recrystallizations is greater than or equal to 2; and/or the drying method is reduced pressure drying.
9. A medicinal preparation containing 10- (S) -17-hydro-7-dehydroandrographolide derivative as active component comprises injection, tablet, capsule, and dispersible tablet.
10. Use of the novel andrographolide derivative 10- (S) -17-hydro-7-dehydroandrographolide prepared according to claim 1 or by the method of any one of claims 2 to 8 or the pharmaceutical formulation according to claim 9 in the manufacture of a medicament for the treatment of an inflammatory disease, preferably pneumonia, preferably novel coronavirus pneumonia (COVID-19).
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| CN103145657A (en) * | 2012-04-12 | 2013-06-12 | 江西青峰药业有限公司 | 17-hydro-9-dehydroandrographolide compound and its preparation method and use in drug preparation |
| WO2016065264A1 (en) * | 2014-10-24 | 2016-04-28 | Biogen Ma Inc. | Diterpenoid derivatives and methods of use thereof |
| CN107973764A (en) * | 2016-10-24 | 2018-05-01 | 江西青峰药业有限公司 | Andrographolide class compound, its preparation method, pharmaceutical composition and application |
| CN108148022A (en) * | 2016-12-02 | 2018-06-12 | 上海迪诺医药科技有限公司 | Andrographolide class compound, its pharmaceutical composition and application |
| CN108392478A (en) * | 2017-02-07 | 2018-08-14 | 江西青峰药业有限公司 | Application of the andrographolide class compound in terms of preparing for radioactive damage drug |
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| CN103145657A (en) * | 2012-04-12 | 2013-06-12 | 江西青峰药业有限公司 | 17-hydro-9-dehydroandrographolide compound and its preparation method and use in drug preparation |
| WO2016065264A1 (en) * | 2014-10-24 | 2016-04-28 | Biogen Ma Inc. | Diterpenoid derivatives and methods of use thereof |
| US20170354639A1 (en) * | 2014-10-24 | 2017-12-14 | Biogen Ma Inc. | Diterpenoid derivatives and methods of use thereof |
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