CN108530314B - Gallic acid methyl ester analogue and application thereof - Google Patents

Gallic acid methyl ester analogue and application thereof Download PDF

Info

Publication number
CN108530314B
CN108530314B CN201810500851.0A CN201810500851A CN108530314B CN 108530314 B CN108530314 B CN 108530314B CN 201810500851 A CN201810500851 A CN 201810500851A CN 108530314 B CN108530314 B CN 108530314B
Authority
CN
China
Prior art keywords
inflammatory
inflammation
gallic acid
methyl ester
acid methyl
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.)
Active
Application number
CN201810500851.0A
Other languages
Chinese (zh)
Other versions
CN108530314A (en
Inventor
刘志国
赵云洁
钱建畅
梁广
李校堃
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.)
Wenzhou Medical University
Original Assignee
Wenzhou Medical University
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 Wenzhou Medical University filed Critical Wenzhou Medical University
Priority to CN201810500851.0A priority Critical patent/CN108530314B/en
Publication of CN108530314A publication Critical patent/CN108530314A/en
Application granted granted Critical
Publication of CN108530314B publication Critical patent/CN108530314B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Communicable Diseases (AREA)
  • Neurology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses a gallic acid methyl ester analogue and application thereof, wherein the gallic acid methyl ester analogue has a structure shown in a formula (I), wherein R is selected from C1～C6Alkyl, N-methylpiperazine substituted C1～C6Alkyl, N-alkyl carbazolyl. The gallic acid methyl ester analogue can better inhibit the release of inflammatory factors TNF-alpha and IL-6, particularly the anti-inflammatory activity of the compound 4e is obviously superior to that of the lead gallic acid methyl ester, which shows that the compound has certain anti-inflammatory capability and can be used as a potential anti-inflammatory drug.
Figure DDA0001670271260000011

Description

Gallic acid methyl ester analogue and application thereof
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to a gallic acid methyl ester analogue, and a synthesis method and application thereof.
Background
Inflammation is a physiological response of the body to various stimuli, such as infection and tissue damage, and includes both acute and chronic. Acute inflammatory responses are often beneficial as part of innate and adaptive immunity. While excessive or uncontrolled inflammatory responses lead to tissue damage.
The existing anti-inflammatory drugs are mainly divided into two types, namely steroid and non-steroid anti-inflammatory drugs, wherein the steroid hormone anti-inflammatory drugs have obvious side effects although good anti-inflammatory effect and are not suitable for long-term use. At present, the non-steroidal anti-inflammatory drugs clinically applied are mainly organic acids, such as aspirin, indomethacin, phenylbutazone and the like, and the drugs are also greatly limited in practical application due to unclear anti-inflammatory targets, long medication period, poor anti-inflammatory effect, poor tolerance of patients and few toxic and side effects.
Therefore, the development of novel non-steroidal anti-inflammatory drugs has become an important task for the prevention and treatment of diabetic complications at present. Methyl gallate (MG, structure shown in the following formula) is a main active ingredient separated and extracted from gallic acid, and has pharmacological activity of resisting inflammation, allergy, virus and asthma.
Figure BDA0001670271240000011
Disclosure of Invention
The invention provides a gallic acid methyl ester analogue and application thereof, and research results show that the gallic acid methyl ester analogue has good anti-inflammatory activity and can be used as a potential anti-inflammatory drug.
A gallic acid methyl ester analogue has a structure shown in formula (I):
Figure BDA0001670271240000021
in the formula (I), R is selected from C1～C6Alkyl, N-methylpiperazine substituted C1～C6Alkyl, N-alkyl carbazolyl.
Preferably, the compound is one of the compounds 4a to 4f, and the structure of the compound 4a to 4f is as follows:
Figure BDA0001670271240000022
the invention provides an application of a gallic acid methyl ester analogue, and the gallic acid methyl ester analogue is used for preparing anti-inflammatory drugs.
Preferably, the anti-inflammatory agent is used for treating acute lung injury caused by inflammation or inflammation-related diseases caused by the expression and release of inflammatory cytokines in excess of normal amounts.
Preferably, the inflammation-related disorder includes sepsis, rheumatoid arthritis, systemic lupus erythematosus and related syndromes, osteoarthritis, digestive tract inflammation, polymyositis, dermatomyositis, vasculitic syndrome, gouty arthritis, neuroinflammation, rheumatoid arthritis, chemical pain, inflammatory pain, granuloma, granulomatous vasculitis, arteritis, skin inflammation, autoimmune diseases, panniculitis, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, systemic inflammatory response syndrome, sepsis, septic shock.
The invention provides a pharmaceutical preparation, which comprises an effective component and a pharmaceutic adjuvant, wherein the effective component comprises the gallic acid methyl ester analogue.
Preferably, the pharmaceutical preparation is any one of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, ointment, controlled release agent, sustained release agent or nano preparation.
Compared with the prior art, the invention has the beneficial effects that:
in vitro anti-inflammatory activity test results show that the compound can better inhibit the release of inflammatory factors TNF-alpha and IL-6, particularly the anti-inflammatory activity of the compound 4e is obviously superior to that of the lead gallic acid methyl ester, which shows that the compound has certain anti-inflammatory capability and can be used as a potential anti-inflammatory drug.
Drawings
FIG. 1 is a graph showing the effect of each compound of test example 1 on the release of TNF-. alpha.and IL-6.
Detailed Description
The invention is further described with reference to specific examples.
Instruments and reagents:
the melting point was measured using a Merther-toledo MP70 type melting point apparatus; measuring the hydrogen nuclear magnetic resonance spectrum by using a BurkerAV-300/500 type nuclear magnetic resonance instrument, and taking TMS as an internal standard; mass spectrum is measured by a WatersESI-MS type mass spectrometer; detecting the thin-layer plate under a ZF-1 type three-purpose ultraviolet analyzer (Shanghai Gucun photoelectric instrument factory); the samples were weighed with a ZA220R4 electronic balance (shanghai temporarily zavier ltd). The reagents and solvents used are both chemically pure and analytically pure. Mouse TNF-alpha and IL-6ELISA kits were purchased from eBioscience, USA; protein concentration extraction and assay kits were purchased from Bio-rad, USA.
Synthesis procedures for Compounds 4a-4 f: reacting compound 3,4, 5-trihydroxybenzoic acid (1) with benzyl bromide under alkaline condition to obtain 3,4, 5-tribenzyloxybenzoic acid (2), (2) condensing with various substituted amines under the action of HATU and DIPEA to obtain various benzamide compounds, and finally condensing under the action of Pd/C, H, D2And removing the benzyl protecting group under the condition to obtain the target compound 4a-4 f. The synthetic route is as follows:
Figure BDA0001670271240000041
EXAMPLE 1 Synthesis of intermediate 2
A50 mL round-bottom flask was charged with 3,4, 5-trihydroxybenzoic acid (0.5g, 2.94mmol), 20mL tetrahydrofuran, 3.66g potassium carbonate, and 4.19mL benzyl bromide was slowly added dropwise under nitrogen protection at 40 ℃ to complete the reaction at 40 ℃ for 12 hours, and 20mL water was added to the reaction mixture to terminate the reaction. Extracting with chloroform for three times, each time 20mL, separating out an organic phase, washing with water for 2 times, drying with anhydrous MgSO4, evaporating the solvent under reduced pressure on a rotary evaporator, dissolving the residue in 40mL of 50% ethanol solution containing 5mol/L of sodium hydroxide, refluxing at normal temperature for 12 hours, adjusting the pH value to 2 with dilute hydrochloric acid after cooling, precipitating, filtering to obtain a white solid 2, and directly carrying out the next reaction without further purification.
EXAMPLE 2 Synthesis of intermediates 3a-3f
Taking the synthesis example of 3a, the specific operation is as follows: a50 mL round-bottom flask was charged with 3,4, 5-tribenzyloxybenzoic acid (0.3g, 0.7mol), 2- (7-benzotriazole oxide) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (0.26g, 0.7mol), 0.2mLN, N ' -diisopropylethylamine and 10mL of dichloromethane, and after stirring and refluxing at room temperature for 20 minutes, slowly dropped from a dropping funnelEthylpropylamine (0.06g, 0.7mol) was added thereto, and after completion of the dropwise addition, the mixture was stirred at room temperature for 5 hours, and 20mL of water was added to the reaction mixture to terminate the reaction. Extracting with ethyl acetate for 2 times (30 mL each time), separating organic phase, washing with water for 2 times, and removing anhydrous MgSO4Drying, evaporating solvent under reduced pressure on rotary evaporator, and recrystallizing the residue with methanol-water (1: 1) solvent system to obtain off-white solid 0.15g with yield of compound 3a-3f of 80.2-88.5%.
EXAMPLE 3 Synthesis of target Compounds 4a-4f
Taking the synthesis example of 4a, the specific operation is as follows: a50 mL round-bottom flask was charged with the product of the previous step 3a (0.29g, 0.6mmol), 12mL methanol-water (1:1v/v) and a catalytic amount of 10% palladium on carbon (0.1mmol), and then the mixture was reacted with hydrogen gas under stirring at room temperature for 1 hour, and the reaction mixture was filtered under reduced pressure. And (3) decompressing and evaporating methanol on a rotary evaporator, slowly dropwise adding dichloromethane into residual liquid until all precipitates are separated out, and filtering to obtain gray solid, namely the target compound, 0.04g, wherein the yield of the compounds 4a-4f is 33.3-46.6%.
Product characterization data were as follows:
3,4,5-Trihydroxy-N-propylbenzamide(4a)
Gyay powder,33.3％yield.m.p:143.8-146.2℃.1H NMR(500MHz,DMSO-d6)δ:9.02(2H,s,Ar-OH),8.65(1H,s,Ar-OH),8.06(1H,s,Ar-NH2),6.81(2H,s,ArH2),3.12(2H,d,-CH2-),1.49-1.45(2H,m,-CH2-),0.86(3H,t,J＝7.13Hz,-CH3).13C NMR(125MHz,DMSO-d6)δ(ppm):166.26,145.32×2,135.96,125.16,106.63×2,40.82,22.44,11.41.ESI-MS m/z:212.26(M+H)+,calcd for C10H13NO4:211.22.
N-Butyl-3,4,5-trihydroxybenzamide(4b)
Gyay powder,35.1％yield.m.p:146.1-148.6℃.1H NMR(500MHz,DMSO-d6)δ:8.88(3H,s,Ar-OH),8.02(1H,s,Ar-NH),6.80(2H,s,ArH2),3.18-3.14(2H,m,-CH2-),1.47-1.41(2H,m,-CH2-),1.32-1.25(2H,m,-CH2-),0.88(3H,t,J＝7.31Hz,-CH3).13C NMR(125MHz,DMSO-d6)δ(ppm):166.20,145.31×2,135.95,125.11,106.59×2,38.66,31.31,19.62,13.71.ESI-MS m/z:225.97(M+H)+,calcd for C11H15NO4:225.24.
3,4,5-Trihydroxy-N-pentylbenzamide(4c)
Gyay powder,40.2％yield.m.p:114.6-117.1℃.1H NMR(500MHz,DMSO-d6)δ:9.00(2H,s,Ar-OH),8.63(1H,s,Ar-OH),8.03(1H,s,Ar-NH),6.79(2H,s,ArH),3.34(2H,s,-CH2),1.45(2H,t,J＝7.31Hz,-CH2-),1.26(4H,m,-CH2-CH2-),0.85(3H,t,J＝7.31Hz,CH3).13C NMR(125MHz,DMSO-d6)δ(ppm):166.16,145.29×2,135.93,125.11,106.58×2,28.86,28.68,21.86×2,13.93.ESI-MS m/z:240.03(M+H)+,calcd for C12H17NO4:239.27.
N-Cyclohexyl-3,4,5-trihydroxybenzamide(4d)
White powder,46.5％yield.m.p:233.9-235.7℃.1HNMR(500MHz,DMSO-d6)δ:8.97(2H,s,Ar-OH),8.61(1H,s,Ar-OH),7.80(1H,d,J＝7.99Hz,Ar-NH),6.81(2H,s,ArH),3.67(1H,t,J＝3.18Hz,NH-),1.75-1.70(4H,m,-CH2-CH2-),1.58(1H,d,J＝12.1Hz,-CH2-),1.31-1.24(4H,m,-CH2-),1.09(1H,d,J＝8.66Hz,-CH2-).13C NMR(125MHz,DMSO-d6)δ(ppm):170.72,150.53×2,141.15,130.58,112.04×2,53.32,37.68×2,30.52,30.23×2.ESI-MS m/z:252.01(M+H)+,calcd for C13H17NO4:251.28.
3,4,5-Trihydroxy-N-[3-(4-methylpiperazin-1-yl)propyl]benzamide(4e)
Yellow powder,46.2％yield.m.p:96.3-100.2℃.1H NMR(500MHz,DMSO-d6)δ:8.11(1H,t,J＝8.04Hz,Ar-NH),6.80(2H,s,ArH),3.21-3.17(2H,m,-CH2),2.51(2H,s,-CH2-),2.30(8H,t,J＝6.59Hz,N-CH2),2.15(3H,s,N-CH3),1.64-1.59(2H,m,-CH2-).13C NMR(125MHz,DMSO-d6)δ(ppm):166.24,145.39×2,136.05,125.07,106.62×2,55.84,54.64×2,52.62×2,45.62,37.86,26.22.ESI-MS m/z:310.16(M+H)+,calcd for C15H23N3O4:309.37.
N-(9-Ethyl-9H-carbazol-3-yl)-3,4,5-trihydroxybenzamide(4f)
White powder,46.6％yield.m.p:220.9-224.1℃.1H NMR(500MHz,DMSO-d6)δ:9.97(1H,s,Ar-NH),9.06(3H,s,Ar-OH),8.54(1H,s,ArH),8.08(1H,d,J＝7.66Hz,ArH),7.74(1H,d,J＝7.88Hz,ArH),7.58(2H,t,J＝8.45Hz,ArH),7.45(1H,t,J＝7.46Hz,ArH),7.19(1H,t,J＝7.40Hz,ArH),7.04(2H,s,ArH),4.45-4.40(2H,m,N-CH2),1.31(3H,t,J＝6.97Hz,-CH3).13C NMR(125MHz,DMSO-d6)δ(ppm):165.29,145.48,139.94,136.55,136.22,131.43,125.62,125.34,122.15,121.74,120.21,120.10,118.48,112.49,109.10,108.69,107.14,36.94,13.66.ESI-MS m/z:363.10(M+H)+,calcd for C21H18N2O4:362.39.
test example 1 anti-inflammatory Activity study of Compounds
To examine the anti-inflammatory activity of the synthesized compounds, we used an enzyme-linked immunosorbent assay (ELISA) method to examine the ability of the compounds to inhibit the release of the pro-inflammatory factors TNF- α and IL-6 from Lipopolysaccharide (LPS) -stimulated mouse macrophage RAW 264.7. Cells were preincubated with compound (10. mu.M) and DMSO (as a control) for 2h, stimulated with LPS (0.5. mu.g/mL) for 22h, and cell culture medium and total protein were collected. The total amount of TNF-. alpha.and IL-6 in the medium was measured by ELISA and the total protein concentration of the same dish was used as a standard. The result is shown in figure 1 (in figure 1, MG represents gallic acid methyl ester), part of compounds can better inhibit the release of inflammatory factors TNF-alpha and IL-6, especially the anti-inflammatory activity of compound 4e is obviously better than that of the lead gallic acid methyl ester, which indicates that the compound synthesized by us has certain anti-inflammatory capability.

Claims (7)

1. The gallic acid methyl ester analogue is a compound 4e, and the structure of the compound 4e is as follows:
Figure FDA0002730228690000011
2. the use of a methyl gallate analog of claim 1, wherein the methyl gallate analog is used in the preparation of an anti-inflammatory agent.
3. The use of a methyl gallate analogue according to claim 2, wherein the anti-inflammatory medicament is used for the treatment of acute lung injury caused by inflammation or inflammation-related diseases caused by the over-normal expression and release of inflammatory cytokines.
4. The use of a methyl gallate analogue as claimed in claim 2 wherein the anti-inflammatory agent inhibits both TNF- α and IL-6 release.
5. The use of a methyl gallate analogue as claimed in claim 3 wherein the disease associated with inflammation comprises sepsis, rheumatoid arthritis, systemic lupus erythematosus and related syndromes, osteoarthritis, inflammation of the digestive tract, polymyositis, dermatomyositis, vasculitic syndromes, gouty arthritis, neuroinflammation, rheumatoid arthritis, chemical pain, inflammatory pain, granuloma, granulomatous vasculitis, arteritis, skin inflammation, autoimmune diseases, panniculitis, retroperitoneal fibrosis, hepatitis, pneumonia, pancreatitis, allergic inflammation, systemic inflammatory response syndrome, sepsis, septic shock.
6. A pharmaceutical formulation comprising an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the gallic acid methyl ester analog of claim 1.
7. The pharmaceutical preparation of claim 6, wherein the pharmaceutical preparation is any one of an injection, a tablet, a capsule, an aerosol, a suppository, a membrane, a dropping pill, an ointment, a controlled release agent, a sustained release agent or a nano-preparation.
CN201810500851.0A 2018-05-23 2018-05-23 Gallic acid methyl ester analogue and application thereof Active CN108530314B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810500851.0A CN108530314B (en) 2018-05-23 2018-05-23 Gallic acid methyl ester analogue and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810500851.0A CN108530314B (en) 2018-05-23 2018-05-23 Gallic acid methyl ester analogue and application thereof

Publications (2)

Publication Number Publication Date
CN108530314A CN108530314A (en) 2018-09-14
CN108530314B true CN108530314B (en) 2021-03-16

Family

ID=63472552

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810500851.0A Active CN108530314B (en) 2018-05-23 2018-05-23 Gallic acid methyl ester analogue and application thereof

Country Status (1)

Country Link
CN (1) CN108530314B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114028376A (en) * 2021-09-17 2022-02-11 武汉翼博济生生物科技有限公司 Application of MG in preparation of NLRP3 pathway inhibitor for hyperuricemia nephropathy and/or gouty arthritis
CN114931571A (en) * 2022-03-30 2022-08-23 上海中医药大学附属曙光医院 Application of gallic acid methyl ester in preparation of osteoarthritis treatment medicine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60199850A (en) * 1984-03-26 1985-10-09 Eisai Co Ltd Novel gallic acid derivative
JP2004217600A (en) * 2003-01-17 2004-08-05 Shionogi & Co Ltd Nitrogen monoxide synthetase inhibitor
WO2014022287A1 (en) * 2012-07-29 2014-02-06 The Regents Of The University Of Colorado, A Body Corporate Antagonists of the toll-like receptor 1/2 complex
KR20150130939A (en) * 2014-05-13 2015-11-24 가천대학교 산학협력단 Gallamide derivatives and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60199850A (en) * 1984-03-26 1985-10-09 Eisai Co Ltd Novel gallic acid derivative
JP2004217600A (en) * 2003-01-17 2004-08-05 Shionogi & Co Ltd Nitrogen monoxide synthetase inhibitor
WO2014022287A1 (en) * 2012-07-29 2014-02-06 The Regents Of The University Of Colorado, A Body Corporate Antagonists of the toll-like receptor 1/2 complex
KR20150130939A (en) * 2014-05-13 2015-11-24 가천대학교 산학협력단 Gallamide derivatives and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Protective mechanism of gallic acid and its novel derivative against ethanol-induced gastric ulcerogenesis: Involvement of immunomodulation markers, Hsp70 and Bcl-2-associated X protein;Siddig Ibrahim Abdelwahab;《International Immunopharmacology》;20130417;第296-305页 *

Also Published As

Publication number Publication date
CN108530314A (en) 2018-09-14

Similar Documents

Publication Publication Date Title
EP1935892B1 (en) Glycyrrhetinic acid-30-amide derivatives and the uses thereof
CA2464068C (en) .alpha.-form or .beta.-form crystal of (r)-2-(2-aminothiazol-4yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl)acetanilide
KR100716389B1 (en) N-Hydroxy??????????5?isopropyl???methyl??,??thiazol?4?yl?phenoxy?pentoxy?benzamidine ? methansulfonic acid salt
AU2005238199A1 (en) CRTh2 receptor antagonists
CN108530314B (en) Gallic acid methyl ester analogue and application thereof
CA3013433A1 (en) Sulfonamide derivative and pharmaceutical composition containing same
US20220153685A1 (en) Small molecule ampk activators
KR20150022816A (en) N-Ethyl-4-Hydroxyl-1-Methyl-5-(Methyl(2,3,4,5,6-Pentahydroxyhexyl)Amino)-2-Oxo-N-Phenyl-1,2-Dihydroquinoline-3-Carboxamide
CA3008485C (en) Alkynyl dihydroquinoline sulfonamide compounds
JP6034960B2 (en) Fluorine-substituted (3R, 4R, 5S) -5-guanidino-4-acetamido-3- (pentan-3-yloxy) cyclohexene-1-carboxylic acid, ester thereof and use thereof
US8399501B2 (en) Crystalline alkoxyimidazol-1-ylmethyl biphenyl carboxylic acid and methods for preparing thereof
JP3922431B2 (en) Hydroxamic acid derivatives as soluble human CD23 formation inhibitors
KR101496094B1 (en) A compound and a pharmaceutical compound for treatment of inflammatory diseases
CN105753938A (en) Pidotimod crystal form as well as preparation method and application thereof
CN103919770A (en) Application of curcumin analog S5 containing thiapyrone structure in preparation of anti-inflammation drugs
JP2024506140A (en) Crystalline forms of anti-influenza virus compounds and their production methods and uses
CN109608388B (en) Dicarbonylcurcumin derivative and application thereof
CN112851643B (en) Hydrochloride of pyrimidine benzamide compound and application thereof
ES2391319T3 (en) New crystals of 4- {3- [4- (3- {4- [amino (butoxycarbonylimino) methyl] phenoxy} propyl) -1-piperidinyl] propoxy] -N '- (butoxycarbonyl) benzamidine
CN108912005B (en) Diphenyloxyalkylamine derivatives and pharmaceutical compositions containing the same
BR112019006830B1 (en) COMPOUNDS THAT INTERRUPT THE INTERACTION BETWEEN Fbxo48 AND PHOSPHORYLATED AMPK AND PHARMACEUTICAL COMPOSITION COMPRISING THEM
RU2594154C2 (en) CRYSTALLINE FORM OF METHYL ESTER 3-(N-P-TOLYLACETAMIDO) METHYL)-2,3,4,5-TETRAHYDROBENZO[f][1,4]OXAZEPINE-4-CARBOXAMIDE)THIOPHENE-2-CARBOXYLIC ACID, ACTIVE COMPONENT, PHARMACEUTICAL COMPOSITION AND DRUG
RU2544853C1 (en) N-HETARYL-SUBSTITUTED 4-HYDROXY-1-METHYL-2,2-DIOXO-1H-2λ6,1-BENZOTHIAZINE-3-CARBOXAMIDES, EXHIBITING ANALGESIC ACTIVITY
WO2012174926A1 (en) N-substituted isopropyldimethyl azulene sulfonamide derivatives, and preparation method and use thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant