CN108250123B - 2-arylmethylene-1-indanone analogue and application thereof - Google Patents
2-arylmethylene-1-indanone analogue and application thereof Download PDFInfo
- Publication number
- CN108250123B CN108250123B CN201810066661.2A CN201810066661A CN108250123B CN 108250123 B CN108250123 B CN 108250123B CN 201810066661 A CN201810066661 A CN 201810066661A CN 108250123 B CN108250123 B CN 108250123B
- Authority
- CN
- China
- Prior art keywords
- indanone
- arylmethylene
- inflammation
- arh
- inflammatory
- 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
Links
Images
Classifications
-
- 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
- C07D209/12—Radicals substituted by oxygen atoms
-
- 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
- C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
-
- 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
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 2-arylmethylene-1-indanone analogue, which has a structure shown in a formula (I), wherein in the formula (I), R is selected from substituted or unsubstituted aryl or heteroaryl, and substituent groups on the aryl or heteroaryl are selected from C1～C5Alkyl radical, C1～C5Alkoxy, halogen or trifluoromethyl. Research results show that most of the 2-arylmethylene-1-indanone analogues have good anti-inflammatory activity and can avoid the drug property of a contrast drug xanthohumolAnd (5) a defect.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a 2-arylmethylene-1-indanone analogue and application thereof.
Background
Inflammation is a reaction of the body to pathogenic factors and their damaging effects, and can be generally classified into two categories according to the course of disease: acute inflammation (acute inflammation) and chronic inflammation (chronic inflammation). A great deal of research shows that inflammation is closely related to the occurrence and development of various diseases such as tumors, coronary heart disease, atherosclerosis and diabetes, so that inflammation becomes a marker feature of various diseases of human beings. In the development process of inflammation, the closely related inflammatory factors mainly include Tumor Necrosis Factor-alpha (TNF-alpha), interleukin-6 (interleukin-6, IL-6), interleukin-1 beta and the like (interleukin-1 beta, IL-1 beta). These inflammatory factors not only activate and amplify the inflammatory response, but also induce apoptosis of cells, playing a vital role in the inflammatory response process. At present, with the continuous and deep research on inflammatory signaling pathways, TNF-alpha and IL-6 have become effective therapeutic targets for acute and chronic inflammation, and play an important role in the treatment of inflammatory diseases.
Xanthohumol (XAN)) is an isopentene flavonoid compound unique in hops, and has wide biological activities, such as antitumor activity, antioxidation activity, prevention and treatment of diabetes and complications thereof, and the like. In addition, the research shows that the xanthohumol can also effectively inhibit inflammatory factors TNF-alpha and IL-6 induced by Lipopolysaccharide (LPS), thereby having better anti-inflammatory activity. However, the defects of poor water solubility, low bioavailability and the like of the xanthohumol itself become one of the most important reasons for limiting the clinical application of the xanthohumol. The indenone structure is widely existed in active natural products, and the discovered natural products with the skeleton have more than 100 kinds, and some have higher pharmaceutical activity. For example, Donepezil inhibits the activity of acetylcholinesterase and has been approved by the FDA for the treatment of dementia in parkinson's disease. The azafluorone (azafluoroenone) is a plant separation component, and activity tests show that the azafluorone (azafluoroenone) can inhibit the activity of topoisomerase and can effectively inhibit the proliferation of colon cancer cells.
Disclosure of Invention
The invention provides a 2-arylmethylene-1-indanone analogue and application thereof, wherein the 2-arylmethylene-1-indanone analogue has better anti-inflammatory activity and can avoid the defect of drug formation of a contrast drug xanthohumol.
A2-arylmethylene-1-indanone analogue has a structure shown in formula (I):
in formula (I), R is selected from substituted or unsubstituted aryl or heteroaryl;
the substituent on the aryl or the heteroaryl is selected from C1～C5Alkyl radical, C1～C5Alkoxy, halogen or trifluoromethyl.
The invention designs a novel 2-arylmethylene-1-indanone compound by a conformation restriction drug design method on the basis of a xanthohumol and 1-indanone structural framework. In vitro anti-inflammatory activity test results show that most of the 2-arylmethylene-1-indanone analogues have higher anti-inflammatory activity.
Preferably, the aryl group is phenyl;
the heteroaryl is thienyl, thiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl or indolyl.
Preferably, the substituents on the aryl or heteroaryl groups are selected from methyl, methoxy or trifluoromethyl.
Preferably, R is selected from the following groups:
the invention also provides an application of the 2-arylmethylene-1-indanone analogue, and the 2-arylmethylene-1-indanone analogue is used for preparing anti-inflammatory drugs.
Preferably, the 2-arylmethylene-1-indanone analogs treat inflammation and inflammation-related disorders by inhibiting the secretion of TNF- α and IL-6.
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.
Preferably, the structural formula of the 2-arylmethylene-1-indanone analogue is as follows:
the invention also provides a pharmaceutical preparation which comprises an effective component and pharmaceutic adjuvant, wherein the effective component comprises the 2-arylmethylene-1-indanone 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:
the research is based on a xanthohumol and 1-indanone structural framework, and a novel 2-arylmethylene-1-indanone compound is designed by a conformation restriction drug design method. In vitro anti-inflammatory activity test results show that most of the compounds have good inhibition capacity on proinflammatory factors TNF-alpha and IL-6, particularly the compounds have the highest inhibition capacity on the proinflammatory factors TNF-alpha and IL-6 for 3h, the inhibition rates under the concentration of 10 mu M are respectively 64.5% and 73.9%, and reference can be provided for further designing novel anti-inflammatory drugs with higher synthetic activity and stronger selectivity.
Drawings
FIG. 1 is data showing the inhibition of LPS-induced secretion of TNF-. alpha.and IL-6 by each compound obtained in test example 1.
Detailed Description
The invention is further described with reference to specific examples.
Instruments and reagents: the melting point was measured using an X-4 micro melting point apparatus (temperature not corrected); NMR spectra were determined using a Brukeravence III 500 NMR spectrometer (CDCl)3As solvent, TMS as internal standard); the mass spectrum is measured by an Agilent 1100 quadrupole liquid chromatography-mass spectrometer. Silica gel GF for thin layer chromatography254Purchased from aladin reagent, inc (aladdin, Shanghai crystal purificationization science and technology, Inc.); silica gel FCP (200-300 mesh) for column chromatography is purchased from chemical reagents of national drug group, Inc.; other used reagents and solvents are all domestic analytical purifiers and are used after being dried without water according to requirements.
EXAMPLE 16 Synthesis of tetrahydro-2H-pyran-2-yloxy) -1-indanone
1.0g (6.75mmol) of 6-hydroxy-1-indanone (1) and 2.83g (33.75mmol) of 3, 4-dihydro-2H-pyran are dissolved in 10mL of dry methylene Chloride (CH)2Cl2) While stirring, 0.169g (0.675mmol) of 4-methylbenzenesulfonic acid pyridine (PPTS) was slowly added thereto, and the mixture was refluxed at 40 ℃ for 4 hours. After the reaction, ultrapure water was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate (30 mL. times.3), and the organic phases were combined, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate, separating by silica gel column chromatography to obtain 1.38g of colorless liquid 6- (tetrahydro-2H-pyran-2-yloxy) -1-indanone (2), with the yield of 92.1 percent.
Example 2 general Synthesis of 112-Arylmethylene-1-indanone analogs 3a-3 j (example 3 a)
0.05g (0.22mmol) of 6- (tetrahydro-2H-pyran-2-yloxy) -1-indanone (2) and 0.025g (0.22mmol) of thiophene-2-carbaldehyde are dissolved in 10mL of ethanol, 3mL of 20% sodium hydroxide (NaOH) is slowly dropped under stirring, and the reaction system is stirred at room temperature overnight. After the reaction was completed, an excess amount of ice water was added to the system until a yellow precipitate was precipitated. Suction filtration is carried out, and a filter cake is washed by a small amount of ice water and then is drained. The filter cake was dissolved in 5mL methanol (MeOH)/Tetrahydrofuran (THF) ═ 1: 1, 0.5mL of 1.0mol/L hydrochloric acid was slowly dropped into the mixed solvent at room temperature, the reaction was continued for 1 hour, and after the completion of the reaction, ice water was added to the reaction solution until a yellow precipitate was precipitated. And (4) pumping filtration, washing a filter cake with ice water, and pumping to dry. The residue was further recrystallized from ethanol to obtain 0.044g of the yellow aimed product 3a in 81.7% yield. The yield, physicochemical properties and spectral data of the synthesized 10 target compounds are shown in table 1, and the reaction route is as follows:
TABLE 1 yield and characterization data for target compounds 3a to 3j
The characterization data of the resulting compounds are as follows:
compound 3 a:
1H-NMR(DMSO-d6,500MHz)δ：9.85(1H,s,Ar-OH),7.92(1H,d,J＝4.91Hz,Thiophene-H),7.76(1H,s,Ar-CH＝),7.67(1H,d,J＝3.26Hz,Thiophene-H),7.50(1H,d,J＝8.20Hz,ArH),7.26(1H,t,J＝4.41Hz,Thiophene-H),7.14(1H,d,J＝8.16Hz,ArH),7.07(1H,s,ArH),3.82(2H,s,Ar-CH2-).
13C-NMR(DMSO-d6,125MHz)δ：192.62,157.19,139.86,139.13,139.05,133.84,133.57,131.79,128.46,127.47,125.44,123.24,108.12,31.03.
compound 3 b:
1H-NMR(DMSO-d6,500MHz)δ：9.82(1H,s,Ar-OH),7.66(1H,s,Ar-CH＝),7.48(1H,d,J＝8.03Hz,Thiophene-H),7.47(1H,s,ArH),7.12(1H,d,J＝8.08Hz,ArH),7.05(1H,s,Thiophene-H),6.96(1H,s,ArH),3.76(2H,s,Ar-CH2-),2.54(3H,s,Thiophene-CH3).
13C-NMR(DMSO-d6,125MHz)δ：192.53,157.15,146.23,139.74,139.19,137.15,134.41,132.33,127.39,127.14,125.82,123.04,108.08,30.94,15.35.
compound 3 c:
1H-NMR(DMSO-d6,500MHz)δ：9.87(1H,s,Ar-OH),9.26(1H,s,Thiazole-H),7.68(1H,s,Ar-CH＝),7.49(1H,d,J＝8.17Hz,ArH),7.13(1H,d,J＝8.12Hz,ArH),7.06(1H,s,ArH),3.77(2H,s,Ar-CH2-),2.59(3H,s,Thiazole-CH3).
13C-NMR(DMSO-d6,125MHz)δ：192.17,157.24,156.94,156.06,139.80,138.92,135.50,127.52,127.29,123.45,121.85,108.17,30.78,15.51.
compound 3 d:
1H-NMR(DMSO-d6,500MHz)δ：11.52(1H,s,Pyrrole-NH),9.79(1H,s,Ar-OH),7.45(1H,s,Ar-CH＝),7.44(1H,d,J＝8.04Hz,ArH),7.14(1H,s,ArH),7.09(1H,d,J＝8.24Hz,ArH),7.04(1H,s,ArH),6.69(1H,s,ArH),6.32(1H,s,ArH),3.74(2H,s,Ar-CH2-).
13C-NMR(DMSO-d6,125MHz)δ：192.59,157.04,139.69,139.62,129.35,128.67,127.13,123.39,122.99,122.43,114.05,111.28,107.99,31.14.
compound 3 e:
1H-NMR(DMSO-d6,500MHz)δ：13.36(1H,s,Pyrazole-NH),9.84(1H,s,Ar-OH),7.84(1H,s,Ar-CH＝),7.47(1H,d,J＝7.69Hz,ArH),7.44(1H,s,Pyrazole-H),7.14(1H,d,J＝7.34Hz,ArH),7.06(1H,s,ArH),6.72(1H,s,Pyrazole-H),3.87(2H,s,Ar-CH2-).
13C-NMR(DMSO-d6,125MHz)δ：193.12,157.12,140.51,138.96,135.35,127.43×2,124.49,123.33,108.10×2,107.02,31.18.
1H-NMR(DMSO-d6,500MHz)δ：9.84(1H,s,Ar-OH),7.48(1H,d,J＝6.73Hz,ArH),7.42(1H,s,Ar-CH＝),7.14(1H,d,J＝6.01Hz,ArH),7.07(1H,s,ArH),6.91(2H,s,ArH2),6.59(1H,s,ArH),3.99(2H,s,Ar-CH2-),3.81(6H,s,Ar-OCH3).
13C-NMR(DMSO-d6,125MHz)δ：193.26,160.63×2,157.14,140.84,138.38,136.72,136.47,132.45,127.44,123.48,108.52×2,108.13,101.86,55.33×2,31.01.
compound 3 g:
1H-NMR(DMSO-d6,500MHz)δ：9.86(1H,s,Ar-OH),7.66(1H,s,Ar-CH＝),7.47(2H,s,Pyrimidine-H),7.12(1H,d,J＝7.73Hz,ArH),7.05(1H,s,ArH),6.96(1H,s,ArH),3.76(2H,s,Ar-CH2-),2.54(3H,s,Pyrimidine-CH3).
13C-NMR(DMSO-d6,125MHz)δ：192.54,157.21,146.23,139.70,139.19,137.16,134.42,132.34,127.40,127.15,125.82,123.06,108.08,30.94,15.36.
compound 3 h:
1H-NMR(DMSO-d6,500MHz)δ：8.01(1H,s,-N-CH＝),7.90(1H,d,J＝7.00Hz,ArH),7.83(1H,s,Ar-CH＝),7.54(1H,d,J＝7.43Hz,ArH),7.44(1H,d,J＝7.43Hz,ArH),7.29(1H,t,J＝6.90Hz,ArH),7.22(1H,s,ArH),7.10(1H,d,J＝7.41Hz,ArH),7.06(1H,s,ArH),3.92(3H,s,-N-CH3),3.82(2H,s,Ar-CH2-).
13C-NMR(DMSO-d6,125MHz)δ：192.41,157.58,139.87,139.07,136.65,132.59,130.42,127.91,126.94,123.93,122.59×2,120.84,118.31,110.74,110.50,108.17,33.08,31.94.
compound 3 i:
1H-NMR(DMSO-d6,500MHz)δ：9.85(1H,s,Ar-OH),7.66(1H,s,Ar-CH＝),7.54(1H,s,ArH),7.48(1H,d,J＝8.17Hz,ArH),7.18(1H,d,J＝7.64Hz,ArH),7.13(2H,d,J＝6.75Hz,ArH2),7.09(1H,s,ArH),3.92(2H,s,Ar-CH2-),2.36(3H,s,Ar-CH3),2.34(3H,s,Ar-CH3)
13C-NMR(DMSO-d6,125MHz)δ：193.16,157.11,141.05,138.56,136.41,135.49,135.20,133.38,130.53,130.12,129.78,129.04,127.40,123.39,108.15,30.72,20.64,19.08.
1H-NMR(DMSO-d6,500MHz)δ：8.07(1H,d,J＝6.11Hz,ArH),8.06(1H,s,ArH),7.78(1H,d,J＝7.70Hz,ArH),7.72(1H,t,J＝7.95Hz,ArH),7.57(1H,s,Ar-CH＝),7.50(1H,d,J＝8.22Hz,ArH),7.15(1H,d,J＝8.18Hz,ArH),7.08(1H,s,ArH),4.02(2H,s,Ar-CH2-).
13C-NMR(DMSO-d6,125MHz)δ：193.13,157.22,140.87,138.21,137.93,136.04,133.96,130.58,129.99,127.49,126.93,126.91,125.84,123.73,108.20,30.87.
test example 1 Compounds inhibit LPS-induced secretion of TNF-. alpha.and IL-6
The inhibitory activity of the target compounds 3a to 3j on the secretion of TNF-alpha and IL-6 induced by LPS was tested by enzyme-linked immunosorbent assay (ELISA). Mouse macrophage RAW264.7 was cultured in DMEM high-glucose medium containing 10% FBS, 1% streptomycin and 5% CO at 37 deg.C2The constant temperature incubator is used for culture. LPS (0.5ug/ml) was added 2h after the cells were dosed, and the medium was collected after further incubation for 22 h. Expression of proinflammatory cytokines TNF-alpha and IL-6 was detected by double antibody sandwich ELISA using an ELISA kit, the experimental procedure is briefly as follows: coating an elisa plate with coating buffer, standing at 4 ℃ overnight, adding Phosphate Buffer Solution (PBST) of Tween-20, washing for 3 times, spin-drying, adding assay solution, blocking, adding collected culture medium, washing out a sample which is not combined with the coated antibody by the PBST, adding detection antibody, incubating, adding avidin-labeled HRP, adding enzyme substrate TMB, developing, adding 2M H after 15min2SO4The reaction was stopped and the OD measured at 450 nm.
To evaluate the ability of the synthesized compounds to inhibit the release of the pro-inflammatory factors TNF- α and IL-6 from the LPS-stimulated mouse macrophage RAW 264.7. We stimulated macrophages with LPS in the presence or absence of compound. 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 enzyme-linked immunosorbent assay (ELISA) and the total protein concentration of the same dish was used as a standard. The results are shown in FIG. 1, where FIG. 1 gives the relative anti-inflammatory values for 10 synthesized compounds. As can be seen from FIG. 1, these compounds all inhibited the release of inflammatory factors to different extents, and when the aromatic ring was substituted with a five-membered mono-heterocyclic ring (compounds 3a-3e), the anti-inflammatory activity was generally higher than that of a six-membered mono-heterocyclic ring (compound 3g), and when the aromatic ring was a benzo-heterocyclic ring (compound 3h), the inhibitory activity against the pro-inflammatory factors TNF-. alpha.and IL-6 was the highest, and the anti-inflammatory activity was significantly better than that of the other compounds, and the inhibition rates at 10. mu.M concentration were 64.5% and 73.9%, respectively.
Claims (6)
1. A2-arylmethylene-1-indanone analogue is characterized by having a structure shown in formula (I):
in the formula (I), R is
Wherein "-" represents a substitution position.
2. Use of a 2-arylmethylene-1-indanone analog according to claim 1 in the preparation of an anti-inflammatory agent.
3. The use of a 2-arylmethylene-1-indanone analog according to claim 2, wherein the 2-arylmethylene-1-indanone analog is used to treat inflammation and inflammation-related disorders by inhibiting the secretion of TNF- α and IL-6.
4. The use of 2-arylmethylene-1-indanone analogues according to claim 3, wherein said inflammation-related disorders include sepsis, rheumatoid arthritis, systemic lupus erythematosus and related syndromes, osteoarthritis, digestive tract inflammation, polymyositis, dermatomyositis, vascular inflammatory 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.
5. A pharmaceutical formulation comprising an active ingredient and a pharmaceutical excipient, wherein said active ingredient comprises the 2-arylmethylene-1-indanone analog of claim 1.
6. The pharmaceutical preparation according to claim 5, 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810066661.2A CN108250123B (en) | 2018-01-24 | 2018-01-24 | 2-arylmethylene-1-indanone analogue and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810066661.2A CN108250123B (en) | 2018-01-24 | 2018-01-24 | 2-arylmethylene-1-indanone analogue and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108250123A CN108250123A (en) | 2018-07-06 |
| CN108250123B true CN108250123B (en) | 2021-07-02 |
Family
ID=62741848
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810066661.2A Active CN108250123B (en) | 2018-01-24 | 2018-01-24 | 2-arylmethylene-1-indanone analogue and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108250123B (en) |
-
2018
- 2018-01-24 CN CN201810066661.2A patent/CN108250123B/en active Active
Non-Patent Citations (5)
| Title |
|---|
| Aarajana Shrestha et al..Design, synthesis, and structure-activity relationship study of halogen containing 2-benzylidene -1-indanone derivatives for inhibition of LPS-stimulated ROS production in RAW 264.7 macrophages.《European Journal of Medicinal Chemistry》.2017,第133卷第121-138页. * |
| Design, synthesis, and structure-activity relationship study of halogen containing 2-benzylidene -1-indanone derivatives for inhibition of LPS-stimulated ROS production in RAW 264.7 macrophages;Aarajana Shrestha et al.;《European Journal of Medicinal Chemistry》;20170327;第133卷;第121-138页 * |
| Discovery and structure-activity relationship studies of 2-benzylidene-2,3-dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives as a novel class of potential therapeutics for inflammatory bowel disease;Tara Man Kadayat et al.;《European Journal of Medicinal Chemistry》;20170610;第137卷;第575-597页 * |
| Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis;Hongming Lv et al.;《Redox Biology》;20170302;第12卷;第311-324页 * |
| 含茚酮骨架化合物的合成与抑菌活性研究;李世学;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20090815(第8期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108250123A (en) | 2018-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109053731B (en) | P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| JP7123417B2 (en) | Anxiolytic deuterium compound and its medicinal use | |
| CN105712932B (en) | A kind of preparation and application of the pyrazoles oxime ether compound of -3- of methyl containing 1- aryl -4- chlorine pyrrazole structure | |
| CN111704646A (en) | Steroid compound and preparation method and application thereof | |
| CN111072682A (en) | Chelidonine furazan nitric oxide donor derivative and preparation method and application thereof | |
| CN108250123B (en) | 2-arylmethylene-1-indanone analogue and application thereof | |
| CN110128444B (en) | P-nitrophenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| JP7101781B2 (en) | Salt morphology as an Akt inhibitor and its crystalline morphology | |
| CN109942499B (en) | Quinazoline derivative and preparation method and application thereof | |
| CN110981882A (en) | Chelidonium nitric oxide donor derivatives, and preparation method and application thereof | |
| CN110511214A (en) | Diamine substituted aromatic heterocyclic compound and preparation method and application thereof | |
| CN108586226B (en) | 3-methyl-3-butene-2-alcohol chalcone compound and synthesis and application thereof | |
| CN110183467B (en) | P-methoxyphenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN108586432B (en) | 3- (indole-5-yl) -indazole derivative and application thereof | |
| CN108358841B (en) | 4- ((2-substituted quinoline-4-yl) amino) benzoyl hydrazine derivatives, and preparation method and application thereof | |
| CN109232570B (en) | Pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN105175352A (en) | Preparation method of nitazoxanide | |
| CN106432153B (en) | A kind of sulfur-bearing andrographolidume derivative, its pharmaceutical composition, synthetic method, the application in preparation treatment prostate cancer drug | |
| CN110143971B (en) | Methylthiophenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN110156672A (en) | A kind of application of semicarbazide compound preparation method and obtained compound | |
| CN115925530B (en) | 3, 4-dihydronaphthalene-1 (2H) -one compound, preparation method and application | |
| CN110128447B (en) | P-methylphenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN109608388B (en) | Dicarbonylcurcumin derivative and application thereof | |
| CN110128446B (en) | 3,4, 5-trimethoxy phenyl substituted spiro [ indazole-isoxazole ] derivative containing chromone structure, and preparation method and application thereof | |
| CN109053732B (en) | Para-fluorine substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application 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 |