CN116554016A - Isopimaric alkane diterpenoid compound and preparation method and application thereof - Google Patents
Isopimaric alkane diterpenoid compound and preparation method and application thereof Download PDFInfo
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- CN116554016A CN116554016A CN202310426766.5A CN202310426766A CN116554016A CN 116554016 A CN116554016 A CN 116554016A CN 202310426766 A CN202310426766 A CN 202310426766A CN 116554016 A CN116554016 A CN 116554016A
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- isopimane
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- compound
- diterpenoid
- alcohol
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
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- 210000000811 metacarpophalangeal joint Anatomy 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
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- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229930184554 neoorthosiphol Natural products 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 239000012808 vapor phase Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/743—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups having unsaturation outside the rings, e.g. humulones, lupulones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/80—Phthalic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes
Abstract
The invention disclosesAn isopimane diterpenoid compound, a preparation method and application thereof are provided, wherein the isopimane diterpenoid compound has a formula (I) or a formula (II);wherein R is 1 Selected from H, C 1～6 Alkyl of (a); r is R 2 And R is 3 Carbonyl groups are formed for H, hydroxyl, or both with the attached carbon atom. The novel isopimane diterpenoid compound provided by the invention has novel structure and no obvious cytotoxicity, can be prepared into medicines for reducing the release of IL-1 beta and IL-6, can reduce proliferation of synovial cells and infiltration of inflammatory cells by inhibiting the release of anti-inflammatory factors IL-1 beta, can be further prepared into medicines for relieving rheumatoid arthritis, and has definite scientific value and practical significance for the development of quality-controllable, low-toxicity and high-efficiency innovative medicines for resisting rheumatoid arthritis.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to an isopimane diterpenoid compound and a preparation method and application thereof.
Background
Rheumatoid arthritis (Rheumatoid arthritis, RA) is a chronic systemic autoimmune disease whose exact cause is not known, frequently occurs in small joints such as proximal interphalangeal joints and metacarpophalangeal joints, the basic pathology is synovitis, pannus formation, and the gradual destruction of articular cartilage and bone tissue, which may eventually lead to joint deformity and loss of function. Many clinically used anti-inflammatory drugs have developed drug resistance, and the continuous discovery of new anti-inflammatory drugs, especially anti-rheumatoid arthritis drugs, remains an important task facing pharmaceutical workers.
It is generally believed that immune disorders are the primary pathogenesis of rheumatoid arthritis, activated CD4 + T cells and Antigen Presenting Cells (APCs) infiltrate the joint synovium where certain specific components or endogenous substances may be presented as antigens by the APCs to activated CD4 + T cells, which initiate a specific immune response, producing corresponding inflammatory symptoms; different T cells proliferate to different degrees due to the stimulation of different antigens in vivo and in vitro, macrophages in synovium are activated by the antigens, more pro-inflammatory factors such as IL-6, IL-1 and the like are generated, the synovium is caused to be in a chronic inflammatory state, and tumor necrosis factor alpha (TNF-alpha) further destroys articular cartilage and bone tissues, and causes joint deformity; in addition, B cells differentiate into plasma cells by activation, secrete a large amount of immunoglobulins, and form immune complexes with antibodies in the body, and can induce inflammation after complement activation.
First-line medicines for treating rheumatoid arthritis are mainly classified into nonsteroidal anti-inflammatory medicines, immunosuppressants, glucocorticoids, biological agents, plant medicines and the like according to the pharmaceutical properties. At present, rheumatoid arthritis cannot be radically treated, and disease activity can be relieved or reduced only through medicines and specific surgical treatment. Therefore, it is an urgent task to find a highly effective and low-toxic drug for treating rheumatoid arthritis in order to improve the quality of life of patients and save lives of patients.
In conclusion, development of the isopimane diterpenoid compound has important significance in solving the problem of drug resistance of the anti-wind-like diseases.
The statements made in the background section do not constitute an admission that they are prior art to the present disclosure.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the first aspect of the present invention proposes an isopimane-type diterpenoid compound which can be effectively used for anti-rheumatoid arthritis.
The second aspect of the invention also provides a preparation method of the isopimane diterpenoid compound.
The third aspect of the present invention also provides a pharmaceutical composition.
The fourth aspect of the invention also provides application of the isopimane diterpenoid compound.
According to the embodiment of the first aspect of the invention, the isopimane diterpenoid compound is provided, and has a compound shown as a formula (I) or a formula (II);
wherein R is 1 Selected from H, C 1～6 Alkyl of (a);
R 2 and R is 3 Carbonyl groups are formed for H, hydroxyl, or both with the attached carbon atom.
The isopimane diterpenoid compound provided by the embodiment of the invention has at least the following beneficial effects:
the novel isopimane diterpenoid compound provided by the invention has novel structure and no obvious cytotoxicity, can be prepared into medicines for reducing the release of IL-1 beta and IL-6, can reduce proliferation of synovial cells and infiltration of inflammatory cells by inhibiting the release of anti-inflammatory factors IL-1 beta, can be further prepared into medicines for relieving rheumatoid arthritis, and has definite scientific value and practical significance for the development of quality-controllable, low-toxicity and high-efficiency innovative medicines for resisting rheumatoid arthritis.
According to some embodiments of the invention, the isopimane-type diterpenoid compound is selected from one of the following structural formulas:
according to a second aspect of the present invention, there is provided a method for preparing isopimane diterpenoid compounds, comprising the steps of:
s1, drying radix ranunculi ternati, soaking and extracting with a solvent I, and concentrating to obtain an extract;
s2, suspending the extract in water, and sequentially extracting with petroleum ether, ethyl acetate and n-butanol to obtain a petroleum ether and ethyl acetate combined layer;
s3, adsorbing the combined layers through a macroporous resin chromatographic column, and performing gradient elution by using a solvent IV to obtain a crude extract;
s4, separating the crude extract by adopting normal phase silica gel column chromatography, eluting with dichloromethane-petroleum ether as an eluent, and alternately separating by normal phase-reverse phase silica gel chromatography to obtain a compound shown in a formula (I);
wherein the solvents I and IV are respectively alcohol-water mixed solutions, and the alcohols in the solvents I and IV are the same or different;
according to some embodiments of the invention, the alcohol is methanol, ethanol or isopropanol;
or reacting orthioiphol K with halogenated alkane to obtain a compound shown in a formula (II); alternatively, orthosip hol K is reacted with Jones reagent to give the compound of formula (II).
According to some embodiments of the invention, the orthoiphol K has the following structural formula:
according to some embodiments of the invention, the soaking extraction in step S1 is performed at normal temperature.
According to some embodiments of the invention, the normal temperature is 0 ℃ to 35 ℃.
According to some embodiments of the invention, the normal temperature is 15 ℃ to 30 ℃.
According to some embodiments of the invention, the number of soaking and extracting operations in the step S1 is three, each seven days.
According to some embodiments of the invention, the macroporous resin chromatography column is a D101 macroporous resin chromatography column or an AB-8 macroporous resin chromatography column.
According to some embodiments of the invention, the volume fraction of alcohol in the solvent I is 95%.
According to some embodiments of the invention, the solvent IV used in the gradient elution process is an alcohol-water mixed solution with an alcohol volume percentage of between 5% and 75%; preferably, the volume percentage of the alcohol is 60-70%.
According to some embodiments of the invention, the volume ratio of petroleum ether in the eluent in the step S4 is 10% -20%.
According to some embodiments of the invention, the compound of formula (II-1) is prepared by:
orthosporol K was dissolved in anhydrous Dimethylformamide (DMF) and Cs was added 2 CO 3 Stirring, placing in ice bath, slowly dropwise adding bromoethane, and refluxing. After the reaction, the reaction system was diffused with ethyl acetate, extracted three times with pure water, sodium chloride solution and saturated sodium chloride solution, the organic phase was retained, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and purified to give the compound of formula (II-1).
According to some embodiments of the invention, the compound of formula (II-2) is prepared by:
orthosporol K was dissolved in anhydrous Dimethylformamide (DMF) and Cs was added 2 CO 3 Stirring, slowly dropwise adding methyl iodide, and refluxing for reaction. After the reaction, the reaction system was diffused with ethyl acetate, extracted three times with pure water, sodium chloride solution and saturated sodium chloride solution, the organic phase was retained, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and purified to give the compound of formula (II-2).
According to some embodiments of the invention, the compound of formula (II-3) is prepared by:
the method comprises the steps of dissolving orthosis hol K in anhydrous acetone, stirring, placing in an ice bath, dropwise adding Jones reagent, reacting at normal temperature, quenching the Jones reagent with a large amount of methanol after the reaction is finished, changing the reaction system from dark brown to dark green, concentrating, diffusing the reaction system with ethyl acetate, extracting three times with pure water, sodium chloride solution and saturated sodium chloride solution respectively, preserving an organic phase, drying the organic phase with anhydrous sodium sulfate, distilling under reduced pressure, concentrating, and purifying to obtain the compound of formula (II-3).
The third aspect of the invention provides a pharmaceutical composition comprising the isopimane diterpenoid compound; pharmaceutically acceptable auxiliary materials.
According to some embodiments of the invention, the pharmaceutically acceptable excipients include at least one of a disintegrant, a diluent, a lubricant, a binder, a flavoring agent, a suspending agent, a surfactant, or a preservative.
According to some embodiments of the invention, the disintegrant is selected from at least one of corn starch, potato starch, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, or alginic acid.
According to some embodiments of the invention, the diluent is selected from at least one of lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate, or crystalline cellulose.
According to some embodiments of the invention, the lubricant is selected from at least one of aerosil, magnesium stearate, calcium stearate, stearic acid, talc or anhydrous silica gel.
According to some embodiments of the invention, the binder is selected from at least one of acacia, gelatin, dextrin, hydroxypropyl cellulose, methylcellulose, or polyvinylpyrrolidone.
According to some embodiments of the invention, the flavoring agent is selected from at least one of aspartame, stevioside, sucrose, maltitol, or citric acid.
According to some embodiments of the invention, the suspending agent is selected from at least one of acacia, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxymethyl cellulose, or aluminum stearate gel.
According to some embodiments of the invention, the surfactant is selected from at least one of lecithin, sorbitan monooleate, or glyceryl monostearate.
According to some embodiments of the invention, the preservative is selected from at least one of methylparaben or propylparaben.
According to some embodiments of the invention, the pharmaceutical composition is in the form of a tablet, capsule, granule, pill, oral liquid, emulsion, dry suspension, dry extract or injection.
The fourth aspect of the invention also provides application of the isopimane diterpenoid compound or the pharmaceutical composition in preparing medicines for treating and/or preventing rheumatoid arthritis.
According to some embodiments of the invention, the rheumatoid arthritis includes a joint swelling phase.
According to some embodiments of the invention, the joint swelling is acute synovitis caused by rheumatoid arthritis.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound represented by the formula (I) obtained in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound represented by the formula (I) obtained in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the compound represented by the formula (II-1) produced in example 1 of the present invention;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of the compound represented by the formula (II-1) produced in example 1 of the present invention;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the compound represented by the formula (II-2) produced in example 2 of the present invention;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of the compound represented by the formula (II-2) produced in example 2 of the present invention;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of the compound represented by the formula (II-3) obtained in example 3 of the present invention;
FIG. 8 is a nuclear magnetic resonance carbon spectrum of the compound represented by the formula (II-3) produced in example 3 of the present invention;
FIG. 9 is a theoretical calculation-determined absolute configuration map of the compound represented by formula (I) obtained in example 1 of the present invention;
FIG. 10 is a graph showing the results of toxicity tests of the compounds of the examples of the present invention at five concentrations (50, 20, 15, 10, 5. Mu.M);
FIG. 11 is a graph showing comparison of cytokine (IL-1. Beta. And IL-6) release rates of the compounds of the examples of the present invention (in the figure, ## representative to control group ratio p<0.01， #### Representative to control group ratio p<0.0001； * Representative to model group ratio p<0.05， ** Representative to model group ratio p<0.01， *** Representative to model group ratio p<0.001， **** Representative to model group ratio p<0.0001)。
Detailed Description
The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described with reference to the embodiments, but the present invention is not limited to these embodiments.
The reagents, methods and apparatus employed in the present invention, unless otherwise specified, are all conventional in the art.
Example 1
The embodiment provides an isopimane diterpenoid compound which is a compound shown in a formula (I) and a compound shown in a formula (II-1), and the steps are as follows:
preparation of a compound of formula (I):
s1, taking 10kg of dried whole plants of the catfish, soaking and extracting for three times by 45L of 95% ethanol at normal temperature (15-30 ℃) for seven days each time, combining the extracting solutions, and recovering the solvent under reduced pressure and vacuum to obtain 823g of crude extract;
s2, suspending the crude extract in 2L of water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol for three times respectively, wherein the solvent consumption is 2L each time, and 223.7g of a petroleum ether layer and ethyl acetate layer combined layer is obtained;
s3, separating the combined layers by D101 macroporous resin, eluting with gradient methanol, wherein the volume percentage of the methanol is 30% -90%, eluting with 30%, 50%, 60%, 70%, 80% and 90% aqueous methanol solution sequentially, discarding 30% of components, and combining 80% -90% of components to obtain 5 effective components (B1-B5);
and (4) subjecting the components S4 and B4 to normal phase silica gel column chromatography, eluting with a dichloromethane-petroleum ether solvent system, wherein the volume percentage of petroleum ether is 10% -20%, and eluting with a dichloromethane-petroleum ether solvent system with the volume percentage of 10%, 15% and 20% sequentially to obtain 28mg of the compound shown in the formula (I) and 839.3mg of the compound Orthosphol K.
Preparation of the Compound of formula (II-1):
weighing 10mg of Orthosporol K at normal temperature (2×10) -2 mmol) in a dry 10mL reaction tube, 1mL anhydrous dimethylformamide was used, and 2.0 equivalents of Cs were added after dissolution 2 CO 3 Stirring for 5min by a magnetic stirrer, slowly dropwise adding 4.0 equivalents of bromoethane compound, refluxing at 80 ℃ for 1.5h, and monitoring the reaction progress by TLC until the reaction is finished. After the reaction, the reaction system was diffused with ethyl acetate, extracted three times with pure water, 5% sodium chloride solution and saturated sodium chloride solution, the organic phase was retained, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and a liquid chromatography flow system was prepared in which methanol, water=80% was purified to give a compound (5.5 mg,53% as a white powder) represented by the formula (ii-1).
The structure of the compound shown in the formula (I) and the structure of the compound shown in the formula (II-1) are characterized by nuclear magnetic resonance, and the results are shown in figures 1-4. Meanwhile, the absolute configuration of the compound is determined by a calculation method based on relative stereochemistry. Theoretical ECD data for the vapor phase B3LYP/6-31G (d) were calculated using the Density Functional Theory (DFT) method and compared to corresponding experimental spectra. In FIG. 9, the experimental ECD curve of the compound of formula (I) and the theoretical ECD curve of (1R, 2S,3S,5S, 7S) -1 in the 310-430nm region show a negative Cotton effect, and the experimental ECD curve in the 230-300nm region show a strong positive Cotton effect, so that the experimental ECD value is more consistent with the theoretical ECD of (1R, 2S,3S,5S, 7S) -1 structure, and the absolute configuration of the compound of formula (I) is more consistent with (1R, 2S,3S,5S, 7S) -1.
Specific detection data are shown in the following tables 1 to 2, wherein Table 1 is a compound represented by the formula (I) and a compound represented by the formula (II-1) 1 HNMR chemical signals belonging to the formula (I) and the formula (II-1) shown in Table 2 13 CNMR chemical signaling assignment FIG. 9 identifies absolute configuration for theoretical calculation of the compound of formula (II-1).
TABLE 1 (delta) H /ppm,J/Hz)
TABLE 2 two compounds at MeOD and CDCl, respectively 3 Detected 13 CNMR (125 MHz) chemical signal attribution (delta) c /ppm)
Note that: the numbers in tables 1 and 2 above correspond to the carbon atom positions as follows:
example 2
Example 2 provides a compound of formula (II-2), the reaction equation and preparation method of which are as follows:
the orthosip hol K (10 mg, 4X 10) was weighed at room temperature -2 mmol) in a dry 10mL reaction tube, 1mL anhydrous DMF was used, and 2.0 equivalents of Cs was added after dissolution 2 CO 3 Placing in ice bath, stirring with magnetic stirrer for 5min, slowly dropwise adding 4.0 equivalents of MeI, heating to 80deg.C, reflux reacting for 24h, and TLC monitoring reaction progress to reaction end. After the reaction, the reaction system was diffused with ethyl acetate, extracted three times with pure water, 5% sodium chloride solution and saturated sodium chloride solution, the organic phase was retained, dried with anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and then silica gel plate was prepared by thin layer chromatography thick and purified under a petroleum ether: ethyl acetate: acetone development system to give a compound represented by formula (II-2) (16.2 mg, yield:89%, white powder).
Structure confirmation as in fig. 5 and 6:
1 H NMR(500MHz,CDCl 3 )δ7.80(d,J＝8.0Hz,2H,1-PhCO),7.62(t,J＝7.3Hz,1H,1-PhCO),7.56(d,J＝7.6Hz,2H,11-PhCO),7.46(t,J＝7.4Hz,1H,11-PhCO),7.38(t,J＝7.6Hz,2H,11-PhCO),7.13(t,J＝7.6Hz,2H,1-PhCO),5.88(t,J＝5.8Hz,1H,H-11),5.72(dd,J＝17.7,10.3Hz,1H,H-15),5.72(s,1H,H-7),5.02(d,J＝3.5Hz,1H,H-1),4.92(d,J＝16.9Hz,1H,H-16cis),4.82(d,J＝10.7Hz,1H,H-16tran),4.41(dd,J＝3.5,2.0Hz,1H,H-2),3.32(d,J＝7.2Hz,1H,H-9),3.17(s,3H,OMe-2),3.12(d,J＝7.0Hz,1H,H-3),2.48(dd,J＝15.4,5.4Hz,1H,H-12α),2.41(dd,J＝13.4,2.3Hz,1H,H-5),2.22(s,3H,7-COCH 3 ),1.98(dt,J＝14.6,3.1Hz,2H,H-6),1.86(dd,J＝15.5,1.4Hz,1H,H-12β),1.49(s,3H,Me-20),1.10(s,3H,Me-17),1.08(s,3H,Me-19),0.85(s,3H,Me-18).
13 C NMR(126MHz,CDCl 3 )δ204.8(C-14),168.9(7-COCH 3 ),167.8(1-COPh),166.3(11-COPh),142.5(C-15),133.6,130.5,129.7,128.3,(1-COPh),132.9,130.1 129.7,128.2(11-COPh),113.3(C-16),79.9(C-2),78.8(C-8),78.4(C-7),69.0(C-11),66.3(C-3),66.1(C-1),51.5(OMe-2),47.9(C-13),44.2(C-10),42.2(C-9),39.9(C-12),37.2(C-4),36.5(C-5),27.9(C-18),25.3(C-17),22.8(C-19),21.5(C-6),21.1(7-COCH 3 ),16.7(C-20).
example 3
Example 3 provides a compound of formula (II-3), which has the following reaction equation and preparation method:
the orthosip hol K was weighed at room temperature (10 mg, 2X 10) -2 mmol) in a dry 10mL reaction tube, it was dissolved in 10mL reaction tube with 0.6mL of anhydrous acetone, placed in an ice bath, and 0.3mL of jones reagent was slowly added dropwise. After 5min of dropwise addition, the ice bath is gradually returned to room temperature, the reaction time is 1.5h, TLC monitors the reaction progress, and the reaction system changes from dark orange to dark brown red after dropwise addition. After the completion of the reaction, the jones reagent was quenched with a large amount of methanol, the reaction system was changed from dark brown to dark green, concentrated, dissolved by adding ethyl acetate, extracted three times with pure water, 5% sodium chloride solution and saturated sodium chloride solution, the organic phase was retained, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and then purified by preparative liquid chromatography at a ratio of acetonitrile: water=70%, to give a compound (11.8 mg, yield:94%, white solid) represented by the formula (ii-3).
Structure confirmation as in fig. 7 and 8:
1 H NMR(500MHz,CDCl 3 )δ7.94(d,J＝7.4Hz,2H,1-PhCO),7.66(t,J＝7.4Hz,1H,1-PhCO),7.58(d,J＝8.0Hz,2H,11-PhCO),7.46(t,J＝7.7Hz,2H,11-PhCO),7.36(t,J＝7.5Hz,1H,11-PhCO),6.98(t,J＝7.7Hz,2H,1-PhCO),5.97(dd,J＝17.6,10.7Hz,1H,H-15),5.84(t,J＝6.8Hz,1H,H-11),5.50(s,1H,H-7),5.15(d,J＝10.7Hz,1H,H-16tran),5.06(d,J＝17.6Hz,1H,H-16cis),4.91(s,1H,H-1),4.41(s,1H,H-2),3.59(d,J＝7.8Hz,1H,H-9),2.69(dd,J＝13.2,2.8Hz,1H,H-5),2.58(dd,J＝15.7,5.9Hz,1H,H-12α),2.20(s,3H,7-COCH3),1.86(d,J＝13.0Hz,1H,H-12β),2.03–1.98(m,2H,H-6),1.32(s,3H,Me-20),1.17(s,3H,Me-17),1.10(s,3H,Me-19),0.89(s,3H,Me-18).
13 C NMR(126MHz,CDCl 3 )δ209.1(C-14),200.1(C-3),168.8(7-COCH 3 ),165.7(1-COPh),164.6(11-COPh),141.5(C-15),133.7,130.0,129.7,128.6,(1-COPh),133.0,129.8 129.6,128.2(11-COPh),114.6(C-16),82.5(C-2),81.2(C-1),75.6(C-8),70.9(C-7),68.3(C-11),48.3(C-13),46.1(C-10),41.5(C-9),41.0(C-12),39.7(C-4),37.6(C-5),26.9(C-18),25.9(C-17),21.9(C-19),21.6(C-6),21.1(7-COCH 3 ),19.9(C-20).
comparative examples 1 to 4
Comparative examples 1 to 4 provide a series of isopimane diterpenoids, see in particular Table 3.
TABLE 3 Table 3
The compounds provided in comparative examples 1 to 4 were prepared with reference to documents 1 and 2 (extracted with reference to the optimum experimental conditions if a plurality of experimental conditions are involved in the documents).
[1]Ohashi K,Bohgaki T,Matsubara T,Shibuya H.Indonesian Medicinal Plants.XXIII.Chemical Structures of Two New Migrated Pimarane-type Diterpenes,Neoorthosiphols A and B,and Suppressive Effects on Rat Thoracic Aorta of Chemical constituents Isolated from the Leaves of Orthosiphon aristatus(Lamiaceae).[J].Chemical and Pharmaceutical Bulletin,2000,48(3):433–435.
[2]Awale S,Tezuka Y,Banskota AH,Adnyana I K,Kadota S.Highly-Oxygenated Isopimarane-Type Diterpenes from Orthosiphon stamineus of Indonesia and Their Nitric Oxide Inhibitory Activity[J].Chemical and Pharmaceutical Bulletin,2003,51(3):268–275.
Effect testing
The four compounds prepared in examples 1 to 3 of the present invention and the four compounds of comparative examples 1 to 4 were subjected to cytotoxicity and anti-inflammatory effect test on arthritic synovial fibroblasts MH7A model.
1. Cytotoxicity test
About 2mg of each isopimane diterpenoid compound is weighed and dissolved in dimethyl sulfoxide (DMSO) for cytotoxicity test. The specific test process is as follows:
1) Cell inoculation:
MH7A cells in log phase (commercially available) were adjusted to cell density 5 x 10 ^3 Each well was inoculated at 100. Mu.L/well into a 96-well plate and cultured overnight in a cell culture incubator at 37 ℃.
2) Drug concentration design:
the concentration gradients were diluted 5-fold with DMEM medium containing 10% total volume of fetal bovine serum prior to dosing.
MH7A cells: the initial concentration was set at 50. Mu.M (concentration gradients 50, 20, 15, 10, 5. Mu.M), after discarding the old supernatant from the well plate, 100. Mu.L of diluted drug per well was added to MH7A cells in 96-well plates in 1), respectively. 5 duplicate wells were set for each drug concentration. The culture medium without the sample is used as a blank control, and dexamethasone is added as a positive control drug.
3) Detecting absorbance:
after 24h incubation in the cell incubator, 10. Mu.L of thiazole blue (MTT) (5 mg/kg) working solution was added to each well and incubation was continued for 4 hours. The absorbance (OD) at 550nm was measured by a microplate reader.
4) Survival rate calculation:
based on the OD values measured, the survival rate of MH7A cells was calculated for each concentration of drug compared to the control group. The results are shown in FIG. 10.
As can be seen from fig. 10, cytotoxicity of 8 compounds of examples 1 to 3 and comparative examples 1 to 4 was evaluated using MH7A cells as a model. The results show that the compounds have no obvious cytotoxicity at the concentration of 15 mu M, the cell survival rate can reach more than 85%, the toxicity is low, and the safety is high.
2. anti-TNF-alpha induced inflammatory activity of human rheumatoid arthritis fibroblasts MH7A cells by isopimane diterpenoid compounds
The isopimane diterpenoid compound has obvious therapeutic effect, can obviously inhibit the release of inflammatory factors such as IL-1 beta, IL-6 and the like, and is specifically tested by the following method:
1) Cell inoculation:
MH7A cells in log phase (commercially available), cell density was adjusted to 2 x 10 ^4 Each well was inoculated at 100. Mu.L/well into a 96-well plate and cultured overnight in a cell culture incubator at 37 ℃.
2) Administration and laying of inducer:
the drug concentration was diluted to 15 μm with DMEM medium containing 10% fetal bovine serum total volume prior to dosing.
MH7A cells: after discarding the old supernatant of the well plate, 100. Mu.L of diluted drug per well was added to MH7A cells in the 96 well plate of 1), respectively, and 3 multiplex wells were set for each drug concentration. The medium without the addition of the inducer was used as Model Control (Model), the medium without the addition of the sample was used as Control (Control), and dexamethasone was added as positive Control drug (Dex). 2h after administration, TNF-alpha inducer with total concentration of 10ng/mL is added to induce the model to produce inflammation and release cytokines.
3) Detecting absorbance:
after culturing in the cell incubator for 24 hours, the absorbance (OD) at 450nm was measured by a microplate reader, according to the instructions of ELISA kit.
4) Cytokine release rate calculation:
based on the OD values measured, the cytokine release rate of the supernatant of the model of MH7A cell inflammation under the action of the drug was calculated as compared to the model group, respectively. The results are shown in FIG. 11. The following information can be seen from the figure:
(1) Compared with the normal group, the factors of IL-1 beta, IL-6 and the like of the model group all show significant changes, and the modeling is proved to be successful.
(2) Compared with a model group, the compounds prepared in the embodiments 1-3 of the invention can obviously reduce the release of IL-1 beta and IL-6 inflammatory factors, thereby showing that the compounds in the embodiments of the invention have the effect of improving rheumatoid arthritis, have good application prospects in the preparation of corresponding medicaments, and especially have comprehensive and obvious effects on the compounds shown in the compound formula (II-1). Specific values are shown in Table 4 (using the pro-inflammatory factor IL-1β as an example).
Table 4 8 IL-1 beta release levels of compounds
Table 5 8 IL-6 Release levels of Compounds
From tables 4 and 5, the isopimane diterpenoid compounds prepared by the present invention have the effect of inhibiting the release of anti-inflammatory factors IL-1 beta and IL-6, and the inhibition effect is better than that of the compounds of comparative examples 1 to 4.
In the test example of the invention, TNF-alpha induced MH7A cells are used as a cell model of Rheumatoid Arthritis (RA), and as for the cell model of RA, the primary synovial cells (HFLS-RA) have limited in-vitro growth potential, and source materials (human rheumatic pannus) are not easily obtained, so that the cell model is difficult to be used as a cell model for large-scale drug screening. MH7A cell lines were immortalized by transfection of RA patients FLSs with SV40 large T antigen. Thus, MH7A has been used in the art as a cell model for drug screening and related studies on the mechanism of action of RA. The TNF-alpha is used for simulating in-vivo inflammatory reaction, so that oxidative damage in cells is stimulated, and therefore, the verification of the drug effect is carried out, the verification process is scientific and reasonable, and the verification result is accurate and reliable. It can be seen from the comprehensive figures 10 and 11 that the isopimane diterpenoid compounds in the embodiments of the invention have good application prospects in preparing medicines for preventing and treating rheumatoid arthritis.
The present invention has been described in detail with reference to the above embodiments, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention.
Claims (10)
1. An isopimane diterpenoid compound, which is characterized by comprising a compound shown in a formula (I) or a formula (II);
wherein R is 1 Selected from H, C 1～6 Alkyl of (a);
R 2 and R is 3 Carbonyl groups are formed for H, hydroxyl, or both with the attached carbon atom.
2. Isopimane-type diterpenoid compound according to claim 1, characterized in that the isopimane-type diterpenoid compound is selected from one of the following structural formulas:
3. the method for preparing isopimane diterpenoid compounds according to claim 1, comprising the steps of:
s1, drying radix ranunculi ternati, soaking and extracting with a solvent I, and concentrating to obtain an extract;
s2, suspending the extract in water, and sequentially extracting with petroleum ether, ethyl acetate and n-butanol to obtain a petroleum ether and ethyl acetate combined layer;
s3, adsorbing the combined layers through a macroporous resin chromatographic column, and performing gradient elution by using a solvent IV to obtain a crude extract;
s4, separating the crude extract by adopting normal phase silica gel column chromatography, eluting with dichloromethane-petroleum ether as an eluent, and alternately separating by normal phase-reverse phase silica gel chromatography to obtain a compound shown in a formula (I);
wherein the solvents I and IV are respectively alcohol-water mixed solutions, and the alcohols in the solvents I and IV are the same or different;
preferably, the alcohol is methanol, ethanol or isopropanol;
or reacting orthioiphol K with halogenated alkane to obtain a compound shown in a formula (II); or reacting orthioiphol K with Jones reagent to obtain the compound shown in the formula (II).
4. The method for preparing isopimane diterpenoid compounds according to claim 1, wherein the soaking extraction in step S1 is performed at normal temperature; preferably, the normal temperature is 0-35 ℃; preferably, the normal temperature is 15-30 ℃; preferably, the number of soaking and extracting operations in the step S1 is three, each seven days; the macroporous resin chromatographic column is a D101 macroporous resin chromatographic column or an AB-8 macroporous resin chromatographic column; the volume ratio of the alcohol in the solvent I is 95%; preferably, the solvent IV used in the gradient elution process is an alcohol-water mixed solution with the volume percentage of alcohol being 5-75%; preferably, the volume percentage of the alcohol is 60-70%; preferably, the volume ratio of petroleum ether in the eluent in the step S4 is 10-20%.
5. A pharmaceutical composition comprising an isopimane diterpenoid compound according to claim 1 or 2; pharmaceutically acceptable auxiliary materials.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable excipients comprise at least one of a disintegrant, a diluent, a lubricant, a binder, a flavoring agent, a suspending agent, a surfactant, or a preservative.
7. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, pill, oral liquid, emulsion, dry suspension, dry extract, or injection.
8. Use of an isopimane diterpenoid compound according to claim 1 or 2 or a pharmaceutical composition according to any one of claims 5 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of rheumatoid arthritis.
9. The use according to claim 8, wherein the rheumatoid arthritis comprises a joint swelling phase.
10. The use according to claim 8, wherein the joint swelling is acute synovitis caused by rheumatoid arthritis.
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