CN104892420A - Preparation method and application of esterification derivatives of resveratrol and carboxylic acid non-steroidal anti-inflammatory drugs - Google Patents

Preparation method and application of esterification derivatives of resveratrol and carboxylic acid non-steroidal anti-inflammatory drugs Download PDF

Info

Publication number
CN104892420A
CN104892420A CN201510152874.3A CN201510152874A CN104892420A CN 104892420 A CN104892420 A CN 104892420A CN 201510152874 A CN201510152874 A CN 201510152874A CN 104892420 A CN104892420 A CN 104892420A
Authority
CN
China
Prior art keywords
resveratrol
compound
trans
carboxylic acid
steroidal anti
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201510152874.3A
Other languages
Chinese (zh)
Inventor
杜志云
胡明卿
赵登高
马燕燕
张焜
彭伟
周爱玉
张玉
月圆
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong University of Technology
Original Assignee
Guangdong University of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong University of Technology filed Critical Guangdong University of Technology
Priority to CN201510152874.3A priority Critical patent/CN104892420A/en
Publication of CN104892420A publication Critical patent/CN104892420A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
    • C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
    • C07C229/58—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • 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
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • 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
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/86—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified hydroxyl groups
    • 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
    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses a series of derivatives prepared by esterification of resveratrol and carboxylic acid non-steroidal anti-inflammatory drugs and a preparation method thereof. The derivatives have a chemical formula as shown in a formula (I) which is described in the specification. The invention relates to application of the derivatives as shown in the formula (I) to anti-inflammatory drugs, drugs for the skin, functional cosmetics, etc.

Description

The preparation method of a kind of trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent esterified derivative and application
Technical field
The present invention relates to new drug compound technical, be specifically related to the preparation and application of trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent esterification products.
Technical background
NSAID (non-steroidal anti-inflammatory drug) (nonsteraidal anti-inflammatory drugs, NSAIDs) be a class have antipyretic, analgesia, anti-inflammatory curative effect medicine, belong to Class B nonprescription drugs, be widely used in the treatment of heating, pain, inflammatory diseases, rheumatism and soft tissue and sport injury at present.But the oral NSAIDs of long-term, high-dose can bring series of side effects to patient, as gastrointestinal hemorrhage, lesions of liver and kidney, Cardiovascular Damage etc.
Trans-resveratrol is extensively present in spermatophyte, as the Vitis of Vitaceae, Ampelopsis, the Arachis of pulse family, Cassia, Sophora, liliaceous Veratrum, the eucalyptus of ma Yao Jin section belongs to, the Polygonum etc. of polygonaceae, wherein multiple is Common Medicinal Herbs, as black false hellebore, Rhizome of Glabrous Greenbrier, giant knotweed, Cassia tora, Psoralea corylifolia etc.People's daily bread; as also contained trans-resveratrol in grape, peanut; further investigate along with to it; find that trans-resveratrol has multiple pharmacologically active; as suppressed COX, LOX in arachidonic acid metabolism process active; suppress monoamine oxidase, protein-tyrosine enzyme, protein kinase C activity and there is the effects such as anticoagulation, anti-oxidant, antibacterial, anti inflammatory immunity, anticancer, cardiovascular protection and neuroprotective.Owing to there are 3 phenolic hydroxyl groups in the structure of trans-resveratrol, its less stable, be easily subject to the impact of light and heat etc. and be destroyed, activity is in vivo on the low side, and absorb not exclusively, bioavailability is low, significantly limit its application.
Summary of the invention
The object of the present invention is to provide the compound of trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent esterification.
Another object of the present invention is to provide a kind of above-mentioned trans-resveratrol and and the preparation method of Verakanol derivative and carboxylic acid non-steroidal anti-inflammatory agent esterification.
Another object of the present invention is to provide the derivative of a kind of above-mentioned trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent esterification oral or inject the application of anti-inflammatory drug, dermatologic thing, functionalization cosmetic etc.
Above-mentioned purpose of the present invention is achieved by following scheme:
The present invention relates to the series compound of trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent esterification, its chemical structure is such as formula shown in (I):
R 1, R 2and R 3can be structure (illustrate with this, be not limited thereto) wherein R shown in formula (1)-(13) formula at the same time or separately 1, R 2and R 3but any one or two are H, can be divided into monosubstituted, two replace, and three replace.
The preparation method of the trans-resveratrol that the present invention relates to and carboxylic acid non-steroidal anti-inflammatory agent esterification.The method comprises the steps:
Trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent are placed in round-bottomed flask, the mol ratio of trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent is 1: 1 or 1: 3, add the DMAP (N of 30mL methylene dichloride and catalytic amount, N-4-dimethyl aminopyridine, slowly drip the dichloromethane solution stirring reaction 1 ~ 4h under room temperature (25 ~ 30 DEG C) containing EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, the mol ratio of trans-resveratrol and DMAP and EDCI is 1: 0.1: 1.5, and product is passed through column chromatographic isolation and purification.The eluent that column chromatography analyzes purifying is ethyl acetate: normal hexane=1: 10 ~ 1: 2, be spin-dried for solvent and obtain thick product, use acetone or alcohol recrystallization, vacuum-drying obtains target product.
The trans-resveratrol that the present invention relates to and carboxylic acid non-steroidal anti-inflammatory agent esterification gained derivative and anti-inflammatory action thereof confirm through overtesting.
Trans-resveratrol of the present invention and carboxylic acid non-steroidal anti-inflammatory agent esterification gained derivative, under the auxiliary combination that can receive with pharmacy and makeup specification, be prepared as emulsion, cream frost, aqua etc.
Compared with prior art, the present invention has following beneficial effect:
1. the derivative of of the present invention provided trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent esterification gained has good anti-inflammatory action, can form the lead compound of the anti-inflammatory drug of a new generation.
2. the derivative of trans-resveratrol provided by the present invention and carboxylic acid non-steroidal anti-inflammatory agent esterification gained, can solve part side effect and absorption problem that carboxylic acid non-steroidal anti-inflammatory agent brings.
Embodiment
Below by way of specific embodiment, the present invention will be further described, but specific embodiment does not do any restriction to the present invention.
Embodiment 1: the synthesis of compound 1
The trans-resveratrol of 1mmol and the Ketoprofen BP 93 of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and catalytic amount, N-4-dimethyl aminopyridine) 0.1mmol, slowly drip the dichloromethane solution stirring reaction 2h under room temperature (25 ~ 30 DEG C) containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, product is passed through column chromatographic isolation and purification.The eluent of column chromatography separation and purification is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and it is 80% that vacuum-drying obtains compound 1 productive rate.
Compound 1: white solid. 1H NMR(400MHz，CDCl 3)δ7.80(s，6H)，7.77-7.78(m，3H)，7.71-7.70(m，6H)，7.63(d，J＝7.6Hz，2H)，7.56-7.55(m，3H)，7.49-7.47(m，6H)，7.43-7.42(m，3H)，7.32(d，J＝1.6Hz，1H)，7.15-7.07(m，5H)，6.74(d，J＝15.6Hz，1H)，4.01-3.99(m，1H)，3.86-3.83(m，2H)，1.68-1.64(m，9H).
Embodiment 2: the synthesis of compound 2
The trans-resveratrol of 1mmol and the diflunisal of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and catalytic amount, N-4-dimethyl aminopyridine) 0.1mmol, slowly drip the dichloromethane solution stirring reaction 2h under room temperature (25 ~ 30 DEG C) containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, product is passed through column chromatographic isolation and purification.The eluent of column chromatography separation and purification is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and it is 70% that vacuum-drying obtains compound 1 productive rate.
Compound 2: 1h NMR (400MHz, CDCl 3) δ 6.64-6.65 (m, 2H), 6.89-6.91 (m, 2H), 7.13-7.19 (m, 5H), 7.26-7.29 (m, 5H), 7.32-7.37 (m, 4H), 7.40 (dd, J=8.4,1.6Hz, 1H), 7.48 (d, J=1.6Hz, 2H), 7.65 (d, J=1.6Hz, 2H), 8.06 (m, 2H), 8.15 (m, 1H), 12.05 (s, 3H).
Embodiment 3: the synthesis of compound 3
The trans-resveratrol of 1mmol and the Naproxen Base of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 75%.
Compound 3: 1h NMR (400MHz, CDCl 3) δ 1.61 (m, 3H), 1.68 (m, 3H), 3.91 (S, 9H), 4.24 (m, 1H), 4.36 (m, 2H), 6.74 (m, 1H), 7.07 (m, 2H), 7.13-7.18 (m, 9H), 7.32 (s, 1H), 7.44 (m, 3H), 7.63 (m, 2H), 7.70 (m, 6H), 7.75 (m, 3H).
Embodiment 4: the synthesis of compound 4
The trans-resveratrol of 1mmol and the Whitfield's ointment of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 55%.
Compound 4: 1h NMR (400MHz, CDCl 3) δ 6.91 (m, 4H), 6.98 (m, 4H), 7.13-7.19 (m, 5H), 7.32 (m, 1H), 7.48 (m, 3H), 7.65 (m, 2H), (8.14 d, J=8.4Hz, 3H), (10.30 s, 3H).
Embodiment 5: the synthesis of compound 5
The trans-resveratrol of 1mmol and the vialidon of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 67%.
Compound 5: 1h NMR (400MHz, CDCl 3) δ 2.16 (s, 9H), 2.32 (s, 9H), 6.53-6.58 (m, 6H), 6.81 (dd, J=1.6Hz 1H), 6.97 (m, 3H), 7.12-7.17 (m, 11H), 7.31-7.33 (m, 4H), (7.65 d, J=8.4Hz, 2H), 7.90 (d, J=8.4Hz, 3H).
Embodiment 6: the synthesis of compound 6
The trans-resveratrol of 1mmol and the tolfenamic acid of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 59%.
Compound 6: 1h NMR (400MHz, CDCl 3) δ 2.26 (s, 9H), 6.53-6.59 (m, 6H), (6.71 dd, J=1.6Hz, 1H), 6.96 (m, 3H), 7.14-7.17 (m, 11H), 7.30-7.35 (m, 4H), (7.69 d, J=8.4Hz, 2H), 7.93 (d, J=8.4Hz, 3H).
Embodiment 7: the synthesis of compound 7
The trans-resveratrol of 1mmol and the Tecramine of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 62%.
Compound 7: 1h NMR (400MHz, CDCl 3) δ 6.81 (dd, J=1.6Hz, 1H), 6.88 (m, 3H), 7.12-7.17 (m, 6H), 7.21-7.27 (m, 6H), 7.29-7.32 (m, 7H), 7.36 (m, 3H), 7.65 (dd, J=8.0,1.6Hz, 2H), 7.90 (dd, J=8.4,1.6Hz, 2H).
Embodiment 8: the synthesis of compound 8
The trans-resveratrol of 1mmol and the diclofenac of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 77%.
Compound 8: 1h NMR (400MHz, CDCl 3) δ 6.83 (dd, J=1.6Hz, 1H), 6.98 (m, 3H), 7.14-7.17 (m, 4H), 7.24-7.27 (m, 6H), 7.29-7.31 (m, 7H), 7.47 (m, 3H), 7.55 (dd, J=8.0,1.6Hz, 2H), 7.97 (dd, J=8.4,1.6Hz, 2H).
Embodiment 9: the synthesis of compound 9
The trans-resveratrol of 1mmol and the indomethacin of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 77%.
Compound 9: 1h NMR (400MHz, CDCl 3) δ 2.34 (s, 9H), 3.85 (s, 9H), 4.06-4.08 (m, 6H), 6.79-6.81 (m, 4H), 6.88 (dd, J=1.6Hz, 3H), 7.07-7.09 (m, 3H), 7.15 (dd, J=8.0,1.6Hz, 2H), 7.32 (m, 1H), 7.56-7.57 (m, 6H), 7.67-7.69 (m, 2H), 7.87-7.88 (m, 3H).
Embodiment 10: the synthesis of compound 10
The trans-resveratrol of 1mmol and the acetylsalicylic acid of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 85%.
Compound 4: 1h NMR (400MHz, CDCl 3) δ 2.31 (s, 9H), 6.87 (m, 4H), 6.91 (m, 4H), 7.15-7.19 (m, 5H), 7.36 (m, 1H), 7.48 (m, 3H), 7.65 (m, 2H), 8.13 (d, J=8.4Hz, 3H).
Embodiment 11: the synthesis of compound 11
The trans-resveratrol of 1mmol and the Ibuprofen BP/EP of 3.5mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and catalytic amount, N-4-dimethyl aminopyridine) 0.1mmol, slowly drip the dichloromethane solution stirring reaction 2h under room temperature (25 ~ 30 DEG C) containing 4mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, product is passed through column chromatographic isolation and purification.The eluent of column chromatography separation and purification is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and it is 91% that vacuum-drying obtains compound 1 productive rate.
Compound 1: white solid. 1H NMR(400MHz，CDCl 3)δ0.88(m，18H)，1.66(m，9H)，1.86(m，3H)，2.46-2.47(m，6H)，3.98-4.02(m，3H)，6.74-6.77(m，1H)，7.03-7.07(m，2H)，7.10-7.13(m，6H)，7.13(dd，J＝8.4，1.6Hz，2H)，7.01-7.03(m，8H)，7.63-7.65(m，2H).
Embodiment 12: the synthesis of compound 12
The trans-resveratrol of 1.2mmol and the Ketoprofen BP 93 of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and catalytic amount, N-4-dimethyl aminopyridine) 0.1mmol, slowly drip the dichloromethane solution stirring reaction 2h under room temperature (25 ~ 30 DEG C) containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, product is passed through column chromatographic isolation and purification.The eluent of column chromatography separation and purification is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and it is 65% that vacuum-drying obtains compound 1 productive rate.
Compound 12: white solid. 1H NMR(400MHz，CDCl 3)δ8.76(s，2H)，7.80(s，2H)，7.78(m，1H)，7.72-7.70(m，2H)，7.63(d，J＝7.6Hz，2H)，7.55(m，1H)，7.48(m，2H)，7.44(m，1H)，7.13(d，J＝1.6Hz，1H)，7.07(m，2H)，6.91(m，1H)，6.52(d，J＝15.6Hz，1H)，6.23(m，1H)，4.00(m，1H)，1.68-1.64(m，3H).
Embodiment 13: the synthesis of compound 13
The trans-resveratrol of 1.2mmol and the diflunisal of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and catalytic amount, N-4-dimethyl aminopyridine) 0.1mmol, slowly drip the dichloromethane solution stirring reaction 2h under room temperature (25 ~ 30 DEG C) containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, product is passed through column chromatographic isolation and purification.The eluent of column chromatography separation and purification is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and it is 61% that vacuum-drying obtains compound 1 productive rate.
Compound 13: 1h NMR (400MHz, CDCl 3) δ 9.86 (s, 3H), 7.65 (m, 2H), 7.48 (m, 1H), 7.34 (m, 1H), 7.26 (m, 2H), 7.19 (m, 2H), 7.13 (m, 1H), 6.91 (m, 1H), 6.64 (m, 1H), 6.52 (m, 2H), 6.23 (m, 1H)
Embodiment 14: the synthesis of compound 14
The trans-resveratrol of 1.2mmol and the Naproxen Base of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 66%.
Compound 14: 1h NMR (400MHz, CDCl 3) δ 1.61 (m, 3H), 3.91 (S, 3H), 4.24 (m, 1H), 6.23 (m, 1H), 6.52 (m, 2H), 6.91 (m, 1H), 7.07 (m, 2H), 7.13-7.18 (m, 3H), 7.44 (m, 1H), 7.63 (m, 2H), 7.70 (m, 2H), 7.75 (m, 1H), 8.76 (s, 2H)
Embodiment 15: the synthesis of compound 15
The trans-resveratrol of 1.2mmol and the Whitfield's ointment of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 51%.
Compound 15: 1h NMR (400MHz, CDCl 3) δ 6.23 (m, 1H), 6.52 (m, 2H), 6.91 (m, 2H), 6.98 (m, 1H), 7.13-7.19 (m, 2H), 7.48 (m, 1H), 7.65 (m, 2H), 8.14 (d, J=8.4Hz, 1H), 9.27 (s, 3H)
Embodiment 16: the synthesis of compound 16
The trans-resveratrol of 1.2mmol and the vialidon of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 57%.
Compound 16: 1h NMR (400MHz, CDCl 3) δ 2.16 (s, 3H), 2.32 (s, 3H), 6.23 (m, 1H), 6.52-6.58 (m, 3H), 6.91 (dd, J=1.6Hz 1H), 6.97 (m, 1H), 7.13-7.17 (m, 5H), 7.31 (m, 1H), 7.65 (d, J=8.4Hz, 2H), 7.90 (m, 1H), 8.94 (s, J=8.4Hz, 3H).
Embodiment 17: the synthesis of compound 17
The trans-resveratrol of 1.2mmol and the tolfenamic acid of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 55%.
Compound 17: 1h NMR (400MHz, CDCl 3) δ 2.26 (s, 3H), 6.23 (m, 1H), 6.52 (m, 2H), 6.70 (m, 1H), 6.88 (dd, J=1.6Hz, 1H), 6.91 (m, 1H), 7.09 (m, 1H), 7.13-7.17 (m, 5H), 7.31 (m, 1H), 7.65 (d, J=8.4Hz, 2H), 7.90 (d, J=8.4Hz, 1H), 9.03 (s, 3H)
Embodiment 18: the synthesis of compound 18
The trans-resveratrol of 1.2mmol and the Tecramine of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 57%.
Compound 18: 1h NMR (400MHz, CDCl 3) δ 6.23 (m, 1H), 6.52 (dd, J=1.6Hz, 2H), 6.88 (m, 1H), 6.91 (m, 1H), 7.13-7.27 (m, 4H), 7.21-7.27 (m, 2H), 7.29-7.32 (m, 2H), 7.36 (m, 1H), 7.65 (dd, J=8.0,1.6Hz, 2H), 7.90 (dd, J=8.4,1.6Hz, 1H), 9.02 (s, 3H)
Embodiment 19: the synthesis of compound 19
The trans-resveratrol of 1.2mmol and the diclofenac of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 65%.
Compound 8: 1h NMR (400MHz, CDCl 3) δ 6.23 (m, 1H), 6.52 (m, 2H), 6.74 (dd, J=1.6Hz, 1H), 6.91 (m, 1H), 6.98 (m, 3H), 7.13-7.17 (m, 4H), 7.34 (m, 1H), 7.54 (dd, J=8.0,1.6Hz, 1H), 7.65 (m, 2H), 7.90 (dd, J=8.4,1.6Hz, 1H), 8.96 (m, 3H)
Embodiment 20: the synthesis of compound 20
The trans-resveratrol of 1.2mmol and the indomethacin of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 57%.
Compound 20: 1h NMR (400MHz, CDCl 3) δ 2.34 (s, 3H), 3.85 (s, 3H), 4.06 (m, 2H), 6.23 (m, 1H), 6.52 (m, 2H), 6.81 (m, 1H), (6.88 dd, J=1.6Hz, 1H), 6.91 (m, 1H), 7.09 (m, 2H), 7.13 (dd, J=8.0,1.6Hz, 1H), 7.45 (m, 2H), 7.56 (m, 2H), 7.67 (m, 2H), 7.87 (m, 1H), 8.76 (s, 2H)
Embodiment 21: the synthesis of compound 21
The trans-resveratrol of 1.2mmol and the acetylsalicylic acid of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and 0.1mmol, N-4-dimethyl aminopyridine), slowly drip the dichloromethane solution containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, stirring reaction 4h under room temperature (25 ~ 30 DEG C), passes through column chromatographic isolation and purification by product.Eluent is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and vacuum-drying obtains compound, and productive rate is 77%.
Compound 4: 1h NMR (400MHz, CDCl 3) δ 2.30 (s, 3H), 6.23 (m, 1H), 6.52 (m, 2H), 6.91 (m, 1H), 7.13-7.18 (m, 3H), 7.29 (m, 1H), 7.48 (m, 1H), 7.65-7.67 (m, 3H), 8.22 (d, J=8.4Hz, 1H), 8.76 (s, 2H)
Embodiment 22: the synthesis of compound 22
The trans-resveratrol of 1.2mmol and the Ibuprofen BP/EP of 1mmol are placed in round-bottomed flask, add the DMAP (N of 50mL methylene dichloride and catalytic amount, N-4-dimethyl aminopyridine) 0.1mmol, slowly drip the dichloromethane solution stirring reaction 2h under room temperature (25 ~ 30 DEG C) containing 1.5mmol EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, product is passed through column chromatographic isolation and purification.The eluent of column chromatography separation and purification is ethyl acetate: sherwood oil=1: 10 ~ 1: 2, is spin-dried for solvent, and it is 83% that vacuum-drying obtains compound 1 productive rate.
Compound 1: white solid. 1H NMR(400MHz，CDCl 3)δ0.88(m，6H)，1.66(m，3H)，1.86(m，1H)，2.46(m，2H)，3.98(m，1H)，6.23(m，1H)，6.52(m，2H)，6.91(m，1H)，7.07(m，2H)，7.01-7.03(m，3H)，7.20(m，2H)，7.63(m，2H)，8.76(s，2H)
Embodiment 23: Verakanol derivative is to the effect of mouse inflammatory model
Experiment material
SPF level kunming mice, female, body weight is 18 ~ 22g about, is provided (conformity certification number: SCXK/20130002) by Zhongshan University's Experimental Animal Center.Punch tool (diameter 6mm), buys voluntarily.
Experimental technique
Get female KM mouse, be divided into blank group at random, phorbol exters (TPA) causes scorching group, medicine group, often organize 3.Ear smears administration, the TPA 2.5 μ g that after 10min, equivalent is all smeared on each positive and negative two sides organizing left and right two ears of mouse causes inflammation, after 6 hours, de-cervical vertebra puts to death mouse, the disk at the same position of left and right ear is swept away with diameter 6mm punch tool, weigh on analytical balance, it is inflammation swelling that every mouse two ear organizes two auricle weight difference with blank.
Inhibiting rate calculates as follows: (TPA group ear swell counterpoise-each experimental group ear swell counterpoise)/TPA group ear swells counterpoise × 100%.
Experimental result
TPA is caused to the impact of mice auricle swelling
In order to investigate trans-resveratrol analog derivative concentration to the impact of mice auricle swelling inhibition, smear different medicines to mouse ear respectively according to above-mentioned animal model.By the effect that the different trans-resveratrol analog derivative of weight recording Mice Auricle suppresses mice auricle swelling.
Table 1 Verakanol derivative causes the impact of mice auricle swelling to TPA
As shown in table 1, the inhibiting rate of independent parent drug 0.6 μM of trans-resveratrol is 14.5%, and the inhibiting rate of all Verakanol derivatives is all better than parent drug trans-resveratrol.And in these compounds, compound 1 pair of TPA induction causes scorching mice auricle swelling and has obvious restraining effect, and its inhibiting rate reaches 83.6%.Compound 1 is obtained by reacting by the trans-resveratrol of 1 equivalent and the Ketoprofen BP 93 of 3 equivalents, 0.6 μM of trans-resveratrol is 17.8% with the inhibiting rate of 1.8 μMs of Ketoprofen BP 93 mixing administration groups, and this shows that the anti-inflammatory activity of compound 1 is significantly better than parent drug trans-resveratrol and Ketoprofen BP 93.
Proved by above-described embodiment, the magnolol ester derivative according to NSAID (non-steroidal anti-inflammatory drug) provided by the present invention can play significant antiinflammation.Above-described, be only preferred embodiment of the present invention, and be not used to limit scope of the present invention, the above embodiment of the present invention can also make a variety of changes.Namely every claims according to the present patent application and description are done simple, equivalence change and modify, and all fall into the claims of patent of the present invention.The not detailed description of the present invention be routine techniques content.

Claims (3)

1. the present invention relates to the series compound of trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent esterification, its chemical structure is such as formula shown in (I):
R 1, R 2and R 3can be structure (illustrate with this, be not limited thereto) wherein R shown in formula (1)-(13) formula at the same time or separately 1, R 2and R 3but any one or two are H, can be divided into monosubstituted, two replace, and three replace.
2. the preparation side of a compound according to claim 1 (I), the method comprises the steps: trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent to be placed in round-bottomed flask, the mol ratio of trans-resveratrol and carboxylic acid non-steroidal anti-inflammatory agent is 1: 1 or 1: 3, add the DMAP (N of 30mL methylene dichloride and catalytic amount, N-4-dimethyl aminopyridine, slowly drip the dichloromethane solution stirring reaction 1 ~ 4h under room temperature (25 ~ 30 DEG C) containing EDCI (1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate) again, the mol ratio of trans-resveratrol and DMAP and EDCI is 1: 0.1: 1.5, product is passed through column chromatographic isolation and purification, the eluent that column chromatography analyzes purifying is ethyl acetate: normal hexane=1: 10 ~ 1: 2, be spin-dried for solvent and obtain thick product, use acetone or alcohol recrystallization, vacuum-drying obtains target product.
Reaction formula is as follows:
3. compound described in claim 1 (I) is as nonsteroidal anti-inflammatory drug lead compound of new generation and its application in anti-inflammatory drug and functionalization cosmetic etc.
CN201510152874.3A 2015-03-27 2015-03-27 Preparation method and application of esterification derivatives of resveratrol and carboxylic acid non-steroidal anti-inflammatory drugs Pending CN104892420A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510152874.3A CN104892420A (en) 2015-03-27 2015-03-27 Preparation method and application of esterification derivatives of resveratrol and carboxylic acid non-steroidal anti-inflammatory drugs

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510152874.3A CN104892420A (en) 2015-03-27 2015-03-27 Preparation method and application of esterification derivatives of resveratrol and carboxylic acid non-steroidal anti-inflammatory drugs

Publications (1)

Publication Number Publication Date
CN104892420A true CN104892420A (en) 2015-09-09

Family

ID=54025445

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510152874.3A Pending CN104892420A (en) 2015-03-27 2015-03-27 Preparation method and application of esterification derivatives of resveratrol and carboxylic acid non-steroidal anti-inflammatory drugs

Country Status (1)

Country Link
CN (1) CN104892420A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109847067A (en) * 2018-12-20 2019-06-07 药大制药有限公司 A kind of Diclofenac-glycine-resveratrol conjugate, preparation method and application
CN111747921A (en) * 2020-07-16 2020-10-09 中国药科大学 Preparation method and medical application of daphnetin derivative

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109847067A (en) * 2018-12-20 2019-06-07 药大制药有限公司 A kind of Diclofenac-glycine-resveratrol conjugate, preparation method and application
CN109847067B (en) * 2018-12-20 2022-06-07 药大制药有限公司 Diclofenac-glycine-resveratrol conjugate, preparation method and application
CN111747921A (en) * 2020-07-16 2020-10-09 中国药科大学 Preparation method and medical application of daphnetin derivative

Similar Documents

Publication Publication Date Title
Intagliata et al. Strategies to improve resveratrol systemic and topical bioavailability: An update
Teixeira et al. Dietary polyphenols and mitochondrial function: role in health and disease
Ding et al. Discovery and development of natural product oridonin-inspired anticancer agents
Oh et al. Preparation of quercetin esters and their antioxidant activity
Kannaiyan et al. Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer
Masuda et al. Chemical studies on antioxidant mechanism of curcumin: analysis of oxidative coupling products from curcumin and linoleate
Sang et al. Increased growth inhibitory effects on human cancer cells and anti-inflammatory potency of shogaols from Zingiber officinale relative to gingerols
Ouimet et al. Biodegradable ferulic acid-containing poly (anhydride-ester): degradation products with controlled release and sustained antioxidant activity
KR101802415B1 (en) Compositions of bakuchiol and methods of making the same
Gaspar et al. Dietary phenolic acids and derivatives. Evaluation of the antioxidant activity of sinapic acid and its alkyl esters
Muangnoi et al. A curcumin-diglutaric acid conjugated prodrug with improved water solubility and antinociceptive properties compared to curcumin
Trivedi et al. Solid and liquid state characterization of tetrahydrocurcumin using XRPD, FT-IR, DSC, TGA, LC-MS, GC-MS, and NMR and its biological activities
Wu et al. Novel compounds from Piper methysticum Forst (Kava Kava) roots and their effect on cyclooxygenase enzyme
Wong et al. Cocrystallization of curcumin with benzenediols and benzenetriols via rapid solvent removal
Patel et al. Design and evaluation of transdermal drug delivery system for curcumin as an anti-inflammatory drug
Islam et al. Catalytic asymmetric synthesis of indole derivatives as novel α-glucosidase inhibitors in vitro
Popławski et al. Synthesis and hypolipidemic and antiplatelet activities of α-asarone isomers in humans (in vitro), mice (in vivo), and rats (in vivo)
Procopio et al. Lipophilic hydroxytyrosol esters: fatty acid conjugates for potential topical administration
Maloney et al. A stereocontrolled synthesis of δ-trans-tocotrienoloic acid
de Souza Ferreira et al. Improving the bioavailability of curcumin: is micro/nanoencapsulation the key?
US20060234990A1 (en) Compositions of boswellic acids derived from Boswellia serrata gum resin, for treating lymphoproliferative and autoimmune conditions
Kuczyńska et al. Future prospects of ketoprofen in improving the safety of the gastric mucosa
Cai et al. Bone-targeting glycol and NSAIDS ester prodrugs of rhein: synthesis, hydroxyapatite affinity, stability, anti-inflammatory, ulcerogenicity index and pharmacokinetics studies
CN105884614A (en) Preparation method and application of derivative containing magnolol and obtained by esterifying honokiol analogs and nonsteraidal anti-inflammatory drugs
Park et al. Total synthesis of chiricanine A, arahypin-1, trans-arachidin-2, trans-arachidin-3, and arahypin-5 from peanut seeds

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
DD01 Delivery of document by public notice
DD01 Delivery of document by public notice

Addressee: Hu Mingqing

Document name: Notification of before Expiration of Request of Examination as to Substance

WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20150909