CN114874138B - 8-quinoline sulfonamide compound and application thereof - Google Patents

8-quinoline sulfonamide compound and application thereof Download PDF

Info

Publication number
CN114874138B
CN114874138B CN202210398431.2A CN202210398431A CN114874138B CN 114874138 B CN114874138 B CN 114874138B CN 202210398431 A CN202210398431 A CN 202210398431A CN 114874138 B CN114874138 B CN 114874138B
Authority
CN
China
Prior art keywords
compound
dmso
nmr
bromo
medicament
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
CN202210398431.2A
Other languages
Chinese (zh)
Other versions
CN114874138A (en
Inventor
汪国兴
邢思齐
刘培培
樊丽
徐文亮
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.)
Anhui Rubiox Vision Biotechnology Co ltd
Original Assignee
Anhui Rubiox Vision Biotechnology Co ltd
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 Anhui Rubiox Vision Biotechnology Co ltd filed Critical Anhui Rubiox Vision Biotechnology Co ltd
Priority to CN202210398431.2A priority Critical patent/CN114874138B/en
Publication of CN114874138A publication Critical patent/CN114874138A/en
Application granted granted Critical
Publication of CN114874138B publication Critical patent/CN114874138B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an 8-quinoline sulfonamide compound and application thereof. The structural formula of the 8-quinoline sulfonamide compound is shown as a general formula A:
Figure DDA0003598470440000011
wherein R is any one of hydrogen, 4-methyl, 4-isopropyl, 2,4, 6-triisopropyl, 4-tert-butyl, 2, 4-dimethoxy, 3, 4-dimethoxy, 2-fluoro, 3-fluoro, 4-fluoro, 2, 6-difluoro, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3, 5-bistrifluoromethyl, 2-trifluoromethoxy, 4-trifluoromethoxy, 2-chloro, 4-chloro, 2, 6-dichloro, 3, 5-dichloro, 2-bromo, 3-bromo, 4-bromo, 3-bromo-5-trifluoromethyl and the like. The compound has an inhibiting effect on the generation of macrophage NO after LPS stimulation, can reduce the release of inflammatory related cytokines and the expression of proteins, and has potential to be developed into a medicament for treating inflammatory diseases.

Description

8-quinoline sulfonamide compound and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an 8-quinoline sulfonamide compound and application thereof.
Background
Rheumatoid Arthritis (RA) is a chronic autoimmune disease whose pathological features are mainly represented by synovial inflammatory cell infiltration in the joint cavity and bone erosion due to pannus formation. In recent years, the prevalence of RA has increased year by year with the aging of the global population. When RA is severe, joint distortion, limited movement and even loss of function of patients can be caused, and the traditional Chinese medicine composition has stronger disability.
The pathogenesis of RA is extremely complex, and no exact etiology has been known to date. The pathogenesis of RA currently includes immune factors, environmental factors, genetic susceptibility factors, and the like. Many studies have reported that immune factors of the body play an important role in the pathogenesis of RA. Interleukin (IL-1. Beta.) and tumor necrosis factor (TNF-. Alpha.) are extremely important cytokines in the occurrence of RA, and elevated levels are found in both the blood and joints of patients with severe RA. Interleukin (IL-1. Beta.) induces fibroblast proliferation, activates osteoclasts, and promotes articular cartilage and bone invasion. Tumor necrosis factor (TNF-alpha) enhances the erosive power of inflammatory cells, promoting RA joint destruction. Therefore, reducing the production of TNF- α and IL-1β at the site of inflammation is important for the treatment of RA. In addition, in inflammatory response, membrane recognition receptors on the surface of macrophages activate inflammatory pathways after being stimulated by Lipopolysaccharide (LPS), and macrophage activation also leads to overexpression of cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS).
Current FDA approved drugs for the treatment of RA often provide temporary or incomplete relief from symptoms with serious side effects. Thus, there is an urgent need to develop more effective medicaments for treating RA with lower side effects.
Disclosure of Invention
In order to solve the above technical problems, an object of the present invention is to provide an 8-quinoline sulfonamide compound.
The technical scheme adopted by the invention is as follows:
an 8-quinoline sulfonamide compound has a structural formula shown in a formula (A):
Figure GDA0004213188240000021
wherein R is any one of hydrogen, 4-methyl, 4-isopropyl, 2,4, 6-triisopropyl, 4-tert-butyl, 2, 4-dimethoxy, 3, 4-dimethoxy, 2-fluoro, 3-fluoro, 4-fluoro, 2, 6-difluoro, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3, 5-bistrifluoromethyl, 2-trifluoromethoxy, 4-trifluoromethoxy, 2-chloro, 4-chloro, 2, 6-dichloro, 3, 5-dichloro, 2-bromo, 3-bromo, 4-bromo, 3-bromo-5-trifluoromethyl, 5-bromo-2-methoxy, 4-iodo, 4-cyano, 3-nitro, 4-acetamido. .
The preparation route of the 8-quinoline sulfonamide compound is as follows:
Figure GDA0004213188240000022
i. according to the method reported in the literature, 8-quinoline sulfonyl chloride is used for carrying out substitution reaction with m-nitroaniline to obtain a compound c, specifically: dissolving 8-quinoline sulfonyl chloride and m-nitroaniline in dichloromethane, dropwise adding triethylamine to dissolve the 8-quinoline sulfonyl chloride, adding a proper amount of tetrahydrofuran to provide an alkaline environment, reacting at room temperature overnight, and performing suction filtration to obtain an intermediate c;
reduction of compound c to give intermediate d, specifically: adding the intermediate C into methanol, adding hydrazine hydrate and Pb/C when the temperature is increased to 40 ℃, and then reducing the intermediate C to obtain an intermediate d;
dissolving the intermediate d in pyridine, reacting with benzene sulfonyl chloride with various substituents, and purifying by column chromatography to obtain 8-quinoline sulfonamide compounds f1-f31.
Wherein the substituents are any of hydrogen, 4-methyl, 4-isopropyl, 2,4, 6-triisopropyl, 4-tert-butyl, 2, 4-dimethoxy, 3, 4-dimethoxy, 2-fluoro, 3-fluoro, 4-fluoro, 2, 6-difluoro, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3, 5-bistrifluoromethyl, 2-trifluoromethoxy, 4-trifluoromethoxy, 2-chloro, 4-chloro, 2, 6-dichloro, 3, 5-dichloro, 2-bromo, 3-bromo, 4-bromo, 3-bromo-5-trifluoromethyl, 5-bromo-2-methoxy, 4-iodo, 4-cyano, 3-nitro, 4-acetamido.
The second purpose of the invention is to provide the application of the 8-quinoline sulfonamide compound in anti-inflammatory drugs.
Preferably, the anti-inflammatory agent is an agent for treating arthritis.
Preferably, in the 8-quinoline sulfonamide compound, R is 2,4, 6-triisopropyl, and the structural formula is shown as formula (B):
Figure GDA0004213188240000031
preferably, the medicament is any one of injection, tablet, pill, capsule, suspending agent or emulsion.
The invention also provides a medicine for treating arthritis, which contains the 8-quinoline sulfonamide compound with pharmaceutically effective dose.
Preferably, R in the 8-quinoline sulfonamide compound is 2,4, 6-triisopropyl.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier.
Preferably, the pharmaceutically acceptable carrier comprises one or more functional auxiliary materials such as excipient, stabilizer, antioxidant, colorant, diluent, slow release agent, etc., such as starch, lipid, wax, dextrin, sucrose, lactose, microcrystalline cellulose, gelatin, citric acid, inorganic salts, hydroxypropyl methylcellulose, hydroxyethyl cellulose, etc.
Preferably, the medicine is any one of injection, tablet, pill, capsule, suspending agent or emulsion
The beneficial effects of the invention are as follows:
1. cell experiments prove that the 8-quinoline sulfonamide compound provided by the invention can well inhibit the release of NO, and the compound can be used as an anti-inflammatory drug.
2. The 8-quinoline sulfonamide compound provided by the invention can reduce the expression of inflammation-related protein cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) in a concentration-dependent manner, and reduce the generation of inflammatory factors TNF-alpha and IL-1 beta in rat serum in a dose-dependent manner, so that the 8-quinoline sulfonamide compound has potential to develop into a medicament for treating arthritis.
Drawings
Fig. 1 shows the effect of compounds f1-f33 on NO in cell RAW264.7 supernatant, p <0.001, p <0.0001 compared to LPS-stimulated cells.
FIG. 2 is an IC of compound (f 4, f15, f25, f 30) on NO in cell RAW264.7 supernatant 50 Value analysis, p<0.001，**p<0.001，***p<0.0001 compared to LPS-stimulated cells.
Fig. 3 shows the effect of compound f4 on IL-1 β and TNF- α in cell RAW264.7 supernatant in example 33, p <0.001, p <0.0001 compared to LPS-stimulated cells.
FIG. 4 shows the effect of compound f4 of example 34 on the expression of inflammation-associated protein.
Fig. 5 is a graph showing the effect of compound f4 on expression of inflammation-associated protein in example 34, # # p <0.0001 compared to control group, # p <0.01, # p <0.001, # p <0.0001 compared to LPS-stimulated cells.
FIG. 6 shows the results of the foot characteristics of each treatment group of rats in example 35.
Fig. 7 is the effect of compound f4 in example 35 on adjuvant-induced arthritis model rats, wherein fig. 7A, fig. 7B, and fig. 7C correspond to body weight, swelling degree, and arthritis index, respectively.
Fig. 8 shows the inhibition of inflammatory factors in rats in an adjuvant-induced arthritis model by compound f4 of example 35, # # p <0.0001 compared to control group, # p <0.001 compared to LPS-stimulated cells.
Detailed Description
Unless otherwise indicated, terms used herein have meanings conventionally understood by those skilled in the art. The following describes the technical scheme of the present invention in more detail with reference to examples:
example 1
Synthesis of compound f 1:
Figure GDA0004213188240000051
compound d (299 mg,1 mM) was dissolved in 2mL of pyridine, followed by addition of benzenesulfonyl chloride (substituent R is hydrogen) (176 mg,1 mM) and reaction at room temperature for 8-12h. TLC detects the progress of the reaction. After the reaction, the reaction solvent was removed. Ethyl acetate: purifying by petroleum ether (1:4) column chromatography to obtain the compound f1, wherein f1 is white solid, and the yield is 68%.
1 H NMR(500MHz,DMSO-d 6 )δ10.09(d,J＝28.9Hz,2H),9.11(dd,J＝4.3,1.8Hz,1H),8.50(d,J＝8.4Hz,1H),8.28(dd,J＝15.5,7.1Hz,2H),7.79(d,J＝7.0Hz,1H),7.60(t,J＝7.7Hz,1H),7.54(t,J＝7.4Hz,2H),7.50(d,J＝7.1Hz,2H),7.40(t,J＝7.8Hz,2H),7.06(s,1H),6.89(t,J＝8.1Hz,1H),6.69(d,J＝8.1Hz,1H),6.54(d,J＝8.0Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.38,142.61,139.27,138.10,136.84,134.97,134.14,132.69,132.10,129.23,128.93,127.67,126.37,125.51,122.54,115.39,110.96。
Example 2
Synthesis of compound f 2:
Figure GDA0004213188240000052
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 4-methyl, to give compound f2 as a white solid in 70% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.31(s,2H),9.33(dd,J＝4.2,1.9Hz,1H),8.72(d,J＝8.2Hz,1H),8.51(dd,J＝23.6,7.9Hz,2H),7.98–7.86(m,2H),7.61(d,J＝8.3Hz,2H),7.40(d,J＝7.9Hz,2H),7.28(s,1H),7.10(t,J＝8.1Hz,1H),6.89(d,J＝8.1Hz,1H),6.74(d,J＝8.0Hz,1H),2.50(s,3H)； 13 C NMR(126MHz,DMSO)δ151.46,143.07,142.67,138.50,138.31,136.90,136.44,135.00,134.21,132.23,129.44,128.38,126.53,125.57,122.61,115.17,110.63,20.91。
Example 3
Synthesis of compound f 3:
Figure GDA0004213188240000061
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 4-isopropyl, to give compound f3 as a white solid in 76% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.15(s,2H),9.12(dd,J＝4.2,1.8Hz,1H),8.52(dd,J＝8.4,1.8Hz,1H),8.33(dd,J＝7.3,1.5Hz,1H),8.28(dd,J＝8.3,1.4Hz,1H),7.75–7.66(m,2H),7.46(d,J＝8.5Hz,2H),7.27(d,J＝8.5Hz,2H),7.10(t,J＝2.1Hz,1H),6.88(t,J＝8.1Hz,1H),6.67(dd,J＝8.1,1.2Hz,1H),6.53(dd,J＝8.1,1.2Hz,1H),2.89(p,J＝6.9Hz,1H),1.14(d,J＝6.9Hz,7H)； 13 C NMR(126MHz,DMSO)δ153.51,151.48,142.71,138.56,138.37,136.95,135.06,134.24,132.25,129.35,128.41,126.98,126.66,125.60,122.63,114.99,110.23,33.27,23.37。
Example 4
Synthesis of compound f 4:
Figure GDA0004213188240000062
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 2,4, 6-triisopropyl to give compound f4 as a white solid in 79% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.12(s,1H),10.03(s,1H),9.08(dd,J＝4.2,1.8Hz,1H),8.48(dd,J＝8.4,1.8Hz,1H),8.27–8.16(m,2H),7.68(dd,J＝8.3,4.2Hz,1H),7.64(t,J＝7.8Hz,1H),7.14(s,2H),6.93(t,J＝2.1Hz,1H),6.89(t,J＝8.1Hz,1H),6.64(dd,J＝7.8,1.9Hz,1H),6.53(dd,J＝8.2,2.0Hz,1H),4.00(p,J＝6.6Hz,2H),2.88(p,J＝6.9Hz,1H),1.17(d,J＝6.9Hz,6H),0.99(d,J＝6.7Hz,12H)； 13 C NMR(126MHz,DMSO)δ151.94,150.37,143.26,139.17,138.62,137.48,135.63,134.72,133.47,132.66,129.70,128.96,126.06,124.19,123.12,115.70,112.46,33.78,29.30,23.90。
Example 5
Synthesis of compound f 5:
Figure GDA0004213188240000071
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 4-t-butyl, to give compound f5 as a white solid in 70% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.10(d,J＝15.6Hz,2H),9.12(dd,J＝4.2,1.8Hz,1H),8.52(dd,J＝8.4,1.8Hz,1H),8.34(dd,J＝7.3,1.4Hz,1H),8.28(dd,J＝8.3,1.4Hz,1H),7.73–7.70(m,2H),7.52–7.44(m,2H),7.44–7.39(m,2H),7.11(t,J＝2.1Hz,1H),6.89(t,J＝8.1Hz,1H),6.67(ddd,J＝8.1,2.1,0.9Hz,1H),6.55(ddd,J＝8.1,2.2,1.0Hz,1H),1.24(s,9H)； 13 C NMR(126MHz,DMSO)δ155.66,151.39,142.66,138.50,136.84,135.12,134.13,132.10,129.25,128.35,127.33,126.30,125.78,125.52,122.55,114.96,110.21,34.73,30.66。
Example 6
Synthesis of compound f 6:
Figure GDA0004213188240000072
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 2, 4-dimethoxy, to give compound f6 as a white solid in 61% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.04(s,1H),9.75(s,1H),9.10(dd,J＝4.2,1.8Hz,1H),8.51(dd,J＝8.4,1.8Hz,1H),8.31–8.23(m,2H),7.76–7.63(m,2H),7.40(d,J＝8.7Hz,1H),6.99(t,J＝2.1Hz,1H),6.86(t,J＝8.1Hz,1H),6.65–6.55(m,2H),6.54(d,J＝2.4Hz,1H),6.44(dd,J＝8.8,2.3Hz,1H),3.76(d,J＝10.2Hz,6H)； 13 C NMR(126MHz,DMSO)δ164.37,157.84,151.43,142.70,138.57,138.30,136.92,135.11,134.16,132.14,129.03,128.38,125.55,122.59,118.35,115.01,110.74,104.71,99.02,55.71。
Example 7
Synthesis of compound f 7:
Figure GDA0004213188240000081
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 3, 4-dimethoxy, to give compound f7 as a white solid in 63% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.14(s,1H),10.00(s,1H),9.10(dd,J＝4.3,1.8Hz,1H),8.49(dd,J＝8.4,1.8Hz,1H),8.29(dd,J＝7.3,1.5Hz,1H),8.25(dd,J＝8.3,1.5Hz,1H),7.79–7.58(m,2H),7.15(d,J＝2.2Hz,1H),7.09–7.05(m,2H),6.89(dt,J＝8.1,3.8Hz,2H),6.68–6.63(m,1H),6.57(dd,J＝8.1,1.1Hz,1H),3.79(s,3H),3.68(s,3H)； 13 C NMR(126MHz,DMSO)δ152.07,151.44,148.43,142.69,138.50,138.48,136.92,135.03,134.23,132.20,130.79,129.29,128.38,125.50,122.60,120.41,115.10,110.78,109.24,55.63。
Example 8
Synthesis of compound f 8:
Figure GDA0004213188240000082
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 2-fluoro, to give compound f8 as a white solid in 55% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.54(s,1H),10.14(s,1H),9.09(dd,J＝4.2,1.8Hz,1H),8.48(dd,J＝8.4,1.7Hz,1H),8.25(ddd,J＝15.7,7.8,1.5Hz,2H),7.71–7.64(m,2H),7.66–7.54(m,2H),7.35–7.28(m,1H),7.24(td,J＝7.7,1.1Hz,1H),7.03(t,J＝2.1Hz,1H),6.91(t,J＝8.1Hz,1H),6.68(dd,J＝8.1,1.2Hz,1H),6.60(dd,J＝8.0,1.3Hz,1H)； 13 C NMR(126MHz,DMSO)δ157.00,151.46,142.66,138.58,137.65,136.92,135.85,134.95,134.24,132.22,130.36,129.41,128.36,125.56,124.76,122.61,117.22,115.40,110.54。
Example 9
Synthesis of compound f 9:
Figure GDA0004213188240000091
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 3-fluoro, to give compound f9 as a white solid in 58% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.26(s,1H),10.16(s,1H),9.10(dd,J＝4.2,1.8Hz,1H),8.50(dd,J＝8.4,1.8Hz,1H),8.28(ddd,J＝18.9,7.8,1.5Hz,2H),7.74–7.65(m,2H),7.52–7.40(m,2H),7.31(dd,J＝17.5,7.9Hz,2H),7.04(t,J＝2.1Hz,1H),6.92(t,J＝8.1Hz,1H),6.74–6.68(m,1H),6.60–6.49(m,1H)； 13 C NMR(126MHz,DMSO)δ160.46,151.46,142.64,141.26,138.58,137.73,136.94,134.90,134.28,132.22,131.51,129.46,128.36,125.52,122.61,120.18,115.62,113.63,111.09。
Example 10
Synthesis of compound f 10:
Figure GDA0004213188240000092
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 4-fluoro, to give compound f10 as a white solid in 54% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.11(d,J＝34.8Hz,2H),9.11(dd,J＝4.2,1.8Hz,1H),8.50(dd,J＝8.4,1.8Hz,1H),8.30(dd,J＝7.3,1.4Hz,1H),8.27(dd,J＝8.3,1.5Hz,1H),7.73–7.67(m,2H),7.56(dd,J＝8.9,5.1Hz,2H),7.25(t,J＝8.8Hz,2H),7.02(t,J＝2.1Hz,1H),6.91(t,J＝8.1Hz,1H),6.71(ddd,J＝8.3,2.2,1.0Hz,1H),6.55(ddd,J＝8.0,2.2,1.0Hz,1H)； 13 C NMR(126MHz,DMSO)δ165.13,151.39,142.61,138.49,137.90,136.85,134.98,134.15,132.08,129.48,129.31,128.32,125.47,122.54,116.24,115.59,111.15。
Example 11
Synthesis of compound f 11:
Figure GDA0004213188240000101
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 2, 6-difluoro, to give compound f11 as a white solid in 49% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.77(s,1H),10.13(s,1H),9.08(dd,J＝4.3,1.8Hz,1H),8.48(dd,J＝8.3,1.8Hz,1H),8.23(t,J＝8.2Hz,2H),7.71–7.64(m,3H),7.19(t,J＝9.0Hz,2H),7.00(s,1H),6.94(t,J＝8.1Hz,1H),6.70–6.63(m,2H)； 13 C NMR(126MHz,DMSO)δ159.79,151.39,142.61,138.63,137.38,136.90,134.91,134.21,132.08,129.43,128.32,125.48,122.57,115.67,114.42,113.45,110.58。
Example 12
Synthesis of compound f 12:
Figure GDA0004213188240000102
the procedure was as in example one, except that substituent R in benzenesulfonyl chloride was 2-trifluoromethyl, to give compound f12 as a white solid in 57% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.06(s,1H),9.71(s,1H),8.63(dd,J＝4.3,1.8Hz,1H),8.03(dd,J＝8.4,1.8Hz,1H),7.79(dd,J＝7.8,2.7Hz,2H),7.50(d,J＝6.7Hz,1H),7.35(q,J＝7.6Hz,2H),7.27–7.18(m,3H),6.55(t,J＝2.1Hz,1H),6.48(t,J＝8.1Hz,1H),6.26(dd,J＝7.3,1.6Hz,1H),6.17–6.11(m,1H)； 13 C NMR(126MHz,DMSO)δ151.41,142.63,138.62,138.09,137.67,136.90,134.94,134.23,133.36,133.05,132.14,130.56,129.46,128.33,125.49,123.78,122.58,121.60,115.33,110.66。
Example 13
Synthesis of compound f 13:
Figure GDA0004213188240000111
the procedure was as in example 1 except that the substituent R in the benzenesulfonyl chloride was 3-trifluoromethyl, to give compound f13 as a white solid in 60% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.33(s,1H),10.19(s,1H),9.09(dd,J＝4.2,1.8Hz,1H),8.48(dd,J＝8.4,1.8Hz,1H),8.26(ddd,J＝20.1,7.8,1.4Hz,2H),7.96(d,J＝7.8Hz,1H),7.87(s,1H),7.73(d,J＝8.0Hz,1H),7.68(td,J＝8.2,3.2Hz,3H),7.04(t,J＝2.1Hz,1H),6.93(t,J＝8.1Hz,1H),6.73(dd,J＝8.2,1.2Hz,1H),6.55(dd,J＝8.1,1.3Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.43,142.65,140.36,138.68,137.52,136.91,134.92,134.26,132.19,130.66,130.42,129.51,128.36,125.48,124.31,122.58,122.14,115.80,111.37。
Example 14
Synthesis of compound f 14:
Figure GDA0004213188240000112
the procedure was as in example 1 except that the substituent R in the benzenesulfonyl chloride was 4-trifluoromethyl, to give compound f14 as a white solid in 63% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.44(s,1H),10.18(s,1H),9.11(dd,J＝4.2,1.8Hz,1H),8.50(dd,J＝8.4,1.8Hz,1H),8.31(dd,J＝7.3,1.4Hz,1H),8.26(dd,J＝8.2,1.5Hz,1H),7.84(d,J＝8.3Hz,2H),7.75(d,J＝8.2Hz,2H),7.73–7.65(m,2H),7.05(t,J＝2.1Hz,1H),6.92(t,J＝8.1Hz,1H),6.71(dd,J＝7.8,1.8Hz,1H),6.60–6.51(m,1H)； 13 C NMR(126MHz,DMSO)δ151.49,143.16,142.67,138.65,137.62,136.92,134.97,134.26,132.23,129.54,128.38,127.51,126.38,126.35,125.52,122.63,115.66,110.96。
Example 15
Synthesis of compound f 15:
Figure GDA0004213188240000121
the procedure was as in example 1 except that the substituent R in the benzenesulfonyl chloride was 3, 5-bistrifluoromethyl, to give compound f15 as a white solid in 53% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.44(s,1H),10.18(s,1H),9.11(dd,J＝4.2,1.8Hz,1H),8.50(dd,J＝8.4,1.8Hz,1H),8.31(dd,J＝7.3,1.4Hz,1H),8.26(dd,J＝8.2,1.5Hz,1H),7.84(d,J＝8.3Hz,2H),7.75(d,J＝8.2Hz,2H),7.73–7.65(m,2H),7.05(t,J＝2.1Hz,1H),6.92(t,J＝8.1Hz,1H),6.71(dd,J＝7.8,1.8Hz,1H),6.60–6.51(m,1H)； 13 C NMR(126MHz,DMSO)δ151.38,142.65,141.69,138.86,136.93,134.91,134.29,132.13,131.43,131.16,129.66,128.38,127.07,125.34,123.47,122.55,116.07,111.79。
Example 16
Synthesis of compound f 16:
Figure GDA0004213188240000122
the procedure was as in example 1 except that the substituent R in the benzenesulfonyl chloride was 2-trifluoromethoxy, to give compound f16 as a white solid in 57% yield.
1 H NMR(500MHz,DMSO-d 6 )δ9.59(s,1H),9.26(s,1H),8.22(dd,J＝4.2,1.8Hz,1H),7.62(dd,J＝8.4,1.8Hz,1H),7.38(dd,J＝7.8,1.6Hz,2H),6.96–6.75(m,4H),6.60(d,J＝8.9Hz,1H),6.54(t,J＝7.7Hz,1H),6.10(t,J＝2.1Hz,1H),6.04(t,J＝8.1Hz,1H),5.81(ddd,J＝8.1,2.1,0.9Hz,1H),5.71(ddd,J＝8.1,2.2,0.9Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.43,142.66,138.54,137.63,136.91,135.34,134.97,134.23,132.15,131.30,130.91,129.35,128.36,127.24,125.51,122.59,120.86,115.27,114.67,110.49。
Example 17
Synthesis of compound f 17:
Figure GDA0004213188240000131
the procedure was as in example 1 except that the substituent R in the benzenesulfonyl chloride was 4-trifluoromethoxy, to give compound f17 as a white solid in 61% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.30(s,1H),10.15(s,1H),9.11(dd,J＝4.2,1.8Hz,1H),8.51(dd,J＝8.4,1.8Hz,1H),8.29(ddd,J＝16.1,7.8,1.5Hz,2H),7.70( 1 H NMR(500MHz,DMSO-d 6 )δ10.30(s,1H),10.15(s,1H),9.11(dd,J＝4.2,1.8Hz,1H),8.51(dd,J＝8.4,1.8Hz,1H),8.29(ddd,J＝16.1,7.8,1.5Hz,2H),7.75–7.66(m,2H),7.64(d,J＝8.9Hz,2H),7.43(d,J＝7.8Hz,2H),7.04(t,J＝2.1Hz,1H),6.91(t,J＝8.1Hz,1H),6.69(ddd,J＝8.1,2.1,0.9Hz,1H),6.53(ddd,J＝8.1,2.2,0.9Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.49,150.96,142.66,138.60,138.17,137.79,136.93,134.97,134.25,132.22,129.48,129.11,128.38,125.54,122.63,121.20,115.56,110.92。
Example 18
Synthesis of compound f 18:
Figure GDA0004213188240000132
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 2-chloro, to give compound f18 as a white solid in 60% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.50(s,1H),10.13(s,1H),9.09(dd,J＝4.3,1.8Hz,1H),8.49(dd,J＝8.4,1.8Hz,1H),8.25(dd,J＝7.8,3.7Hz,2H),7.79(dd,J＝7.9,1.6Hz,1H),7.74–7.63(m,2H),7.55(dt,J＝13.3,6.4Hz,2H),7.45–7.35(m,1H),7.01(s,1H),6.90(t,J＝8.1Hz,1H),6.63(ddd,J＝32.5,8.0,2.1Hz,2H)； 13 C NMR(126MHz,DMSO)δ151.43,142.64,138.54,137.49,136.91,136.26,134.49,131.68,130.60,129.37,128.35,127.50,125.55,122.59,115.22,114.43,110.23。
Example 19
Synthesis of compound f 19:
Figure GDA0004213188240000141
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 4-chloro, to give compound f19 as a white solid in 52% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.26(s,1H),10.15(s,1H),9.11(dd,J＝4.3,1.8Hz,1H),8.50(dd,J＝8.4,1.8Hz,1H),8.28(ddd,J＝18.7,7.8,1.5Hz,2H),7.75–7.63(m,2H),7.50(s,4H),7.03(t,J＝2.1Hz,1H),6.92(t,J＝8.1Hz,1H),6.78–6.66(m,1H),6.55(dd,J＝8.2,1.5Hz,1H).； 13 C NMR(126MHz,DMSO)δ151.47,142.65,138.57,138.06,137.83,137.71,136.90,134.95,134.23,132.21,129.45,129.22,128.41,125.53,122.61,115.60,111.03。
Example 20
Synthesis of compound f 20:
Figure GDA0004213188240000142
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 2, 6-dichloro, to give compound f20 as a white solid in 61% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.68(s,1H),10.10(s,1H),9.08(dd,J＝4.2,1.8Hz,1H),8.49(dd,J＝8.4,1.8Hz,1H),8.23(ddd,J＝10.4,7.8,1.5Hz,2H),7.80–7.60(m,2H),7.60–7.39(m,3H),7.13–6.78(m,2H),6.64(ddd,J＝12.8,8.1,1.6Hz,2H)； 13 C NMR(126MHz,DMSO)δ151.41,142.64,138.60,137.32,136.93,134.94,134.26,133.98,133.85,132.09,131.72,129.37,128.36,125.54,122.59,113.97,110.55。
Example 21
Synthesis of compound f 21:
Figure GDA0004213188240000151
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 3, 5-dichloro, to give compound f21 as a white solid in 56% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.37(s,1H),10.24(s,1H),9.09(dd,J＝4.2,1.8Hz,1H),8.46(dd,J＝8.4,1.8Hz,1H),8.31(dd,J＝7.3,1.5Hz,1H),8.23(dd,J＝8.3,1.5Hz,1H),7.86(t,J＝1.9Hz,1H),7.72–7.60(m,2H),7.48(d,J＝1.9Hz,2H),7.04(t,J＝2.1Hz,1H),6.97(t,J＝8.1Hz,1H),6.77(ddd,J＝8.2,2.1,0.9Hz,1H),6.57(ddd,J＝8.1,2.1,0.9Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.40,142.65,142.24,138.75,137.23,136.94,134.96,134.35,132.64,132.22,129.63,128.35,125.42,125.00,122.55,115.89,111.37。
Example 22
Synthesis of compound f 22:
Figure GDA0004213188240000152
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 2-bromo, to give compound f22 as a white solid in 49% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.49(s,1H),10.12(s,1H),9.09(dd,J＝4.3,1.8Hz,1H),8.49(dd,J＝8.4,1.8Hz,1H),8.30–8.19(m,2H),7.89–7.78(m,1H),7.75–7.62(m,3H),7.57–7.39(m,2H),7.00(s,1H),6.90(t,J＝8.1Hz,1H),6.63(dd,J＝31.5,8.0Hz,2H)； 13 C NMR(126MHz,DMSO)δ151.41,142.63,138.53,138.02,137.50,136.90,135.26,134.94,134.41,134.21,132.18,131.63,129.33,128.34,128.03,125.53,122.58,119.04,110.12。
Example 23
Synthesis of compound f 23:
Figure GDA0004213188240000161
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 3-bromo, to give compound f23 as a white solid in 51% yield.
1 H NMR(500MHz,DMSO-d6)δ10.26(s,1H),10.17(s,1H),9.09(dd,J＝4.2,1.8Hz,1H),8.50(dd,J＝8.4,1.8Hz,1H),8.28(ddd,J＝17.7,7.8,1.5Hz,2H),7.78(ddd,J＝8.0,2.0,1.0Hz,1H),7.75–7.64(m,3H),7.45(dt,J＝7.9,1.3Hz,1H),7.37(t,J＝7.9Hz,1H),7.04(t,J＝2.1Hz,1H),6.92(t,J＝8.1Hz,1H),6.71(ddd,J＝8.1,2.1,0.9Hz,1H),6.53(ddd,J＝8.0,2.1,0.9Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.44,142.64,141.21,138.63,137.66,136.95,135.76,134.89,134.32,132.24,131.28,129.48,128.84,125.48,122.60,122.02,115.62,111.09。
Example 24
Synthesis of compound f 24:
Figure GDA0004213188240000162
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 4-bromo, to give compound f24 as a white solid in 48% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.21(s,1H),10.08(s,1H),9.10(dd,J＝4.2,1.8Hz,1H),8.50(dd,J＝8.4,1.8Hz,1H),8.34–8.20(m,2H),7.75–7.67(m,2H),7.64(d,J＝8.6Hz,2H),7.43(d,J＝8.6Hz,2H),7.01(t,J＝2.0Hz,1H),6.91(t,J＝8.1Hz,1H),6.74–6.66(m,1H),6.54(dd,J＝8.0,1.2Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.39,142.60,138.51,137.77,136.84,134.96,134.14,132.08,129.35,128.42,128.31,126.62,125.46,122.54,115.60,115.16,111.07。
Example 25
Synthesis of compound f 25:
Figure GDA0004213188240000171
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 2-bromo-3-trifluoromethyl, to give compound f25 as a white solid in 51% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.40(s,1H),10.24(s,1H),9.07(dd,J＝4.2,1.8Hz,1H),8.48(dd,J＝8.4,1.8Hz,1H),8.29(d,J＝7.4Hz,2H),8.24(dd,J＝8.3,1.5Hz,1H),7.92(s,1H),7.81(s,1H),7.72–7.63(m,2H),7.03(t,J＝2.1Hz,1H),6.96(t,J＝8.1Hz,1H),6.76(dd,J＝7.8,1.4Hz,1H),6.55(dd,J＝8.1,1.3Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.39,142.65,142.07,138.80,137.08,136.95,134.88,134.34,132.91,132.66,132.17,131.47,129.63,128.36,125.38,123.30,122.55,122.12,115.99,111.59。
Example 26
Synthesis of compound f 26:
Figure GDA0004213188240000172
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 5-bromo-2-methoxy, to give compound f26 as a white solid in 46% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.13(s,1H),10.04(s,1H),9.09(dd,J＝4.2,1.8Hz,1H),8.47(dd,J＝8.5,1.8Hz,1H),8.24(ddd,J＝12.1,7.8,1.5Hz,2H),7.74–7.61(m,4H),7.07(d,J＝8.9Hz,1H),7.02(t,J＝2.1Hz,1H),6.91(t,J＝8.1Hz,1H),6.63(ddd,J＝13.9,8.1,1.2Hz,2H),3.77(s,3H)； 13 C NMR(126MHz,DMSO)δ155.58,151.42,142.68,138.45,137.82,136.95,134.97,134.26,132.18,131.90,129.26,128.34,128.06,125.45,122.57,115.51,115.23,111.31,110.96,56.43。
Example 27
Synthesis of compound f 27:
Figure GDA0004213188240000181
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 4-iodo, to give compound f27 as a white solid in 45% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.25(s,1H),10.15(s,1H),9.11(dd,J＝4.2,1.8Hz,1H),8.51(dd,J＝8.5,1.8Hz,1H),8.37–8.24(m,2H),7.82(d,J＝8.5Hz,2H),7.75–7.66(m,2H),7.26(d,J＝8.5Hz,2H),7.02(t,J＝2.1Hz,1H),6.90(t,J＝8.1Hz,1H),6.69(dd,J＝8.2,1.2Hz,1H),6.53(dd,J＝8.1,1.2Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.48,142.65,138.84,138.55,137.96,136.92,134.94,134.23,132.23,129.44,128.35,128.15,125.57,122.63,115.50,110.84,101.13。
Example 28
Synthesis of compound f 28:
Figure GDA0004213188240000182
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 4-cyano, to give compound f28 as a white solid in 48% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.44(s,1H),10.18(s,1H),9.11(dd,J＝4.2,1.8Hz,1H),8.51(dd,J＝8.4,1.8Hz,1H),8.29(t,J＝8.0Hz,2H),7.94(d,J＝8.6Hz,2H),7.75–7.68(m,2H),7.66(d,J＝8.5Hz,2H),7.00(t,J＝2.1Hz,1H),6.93(t,J＝8.1Hz,1H),6.73(dd,J＝7.2,1.7Hz,1H),6.55(dd,J＝8.1,1.3Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.50,143.22,142.64,138.64,137.44,136.96,134.30,133.29,132.25,129.58,128.36,127.24,125.57,122.65,117.56,115.86,115.30,111.19。
Example 29
Synthesis of compound f 29:
Figure GDA0004213188240000191
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 3-nitro, to give compound f29 as a white solid in 58% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.46(s,1H),10.18(s,1H),9.08(dd,J＝4.3,1.8Hz,1H),8.48(dd,J＝8.4,1.8Hz,1H),8.41(ddd,J＝8.2,2.3,1.0Hz,1H),8.38(t,J＝2.0Hz,1H),8.25(ddd,J＝14.0,7.8,1.4Hz,2H),7.85(dt,J＝7.9,1.2Hz,1H),7.76–7.63(m,3H),7.08–6.83(m,2H),6.74(dd,J＝8.2,1.2Hz,1H),6.60(dd,J＝8.1,1.2Hz,1H)； 13 C NMR(126MHz,DMSO)δ150.43,146.77,141.61,139.77,137.66,136.32,135.91,133.89,133.27,131.39,130.10,128.61,127.33,126.56,124.47,121.60,120.33,114.97,110.54。
Example 30
Synthesis of compound f 30:
Figure GDA0004213188240000192
the procedure was as in example 1 except that the substituent R in the benzenesulfonyl chloride was 4-nitro, to give compound f30 as a white solid in 61% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.48(s,1H),10.13(s,1H),9.10(dd,J＝4.2,1.8Hz,1H),8.48(dd,J＝8.4,1.8Hz,1H),8.32(dd,J＝7.4,1.5Hz,1H),8.27–8.22(m,3H),7.80–7.76(m,2H),7.72–7.66(m,2H),7.02(t,J＝2.1Hz,1H),6.94(t,J＝8.1Hz,1H),6.75(ddd,J＝8.2,2.1,1.0Hz,1H),6.60(ddd,J＝8.1,2.1,0.9Hz,1H)； 13 C NMR(126MHz,DMSO)δ151.42,149.69,144.66,142.63,138.64,137.36,136.85,135.01,134.16,132.11,129.54,128.06,125.48,124.36,122.56,115.91,111.34。
Example 31
Synthesis of compound f 31:
Figure GDA0004213188240000201
the procedure was as in example 1 except that substituent R in benzenesulfonyl chloride was 3-nitro, to give compound f31 as a white solid in 66% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.26(s,1H),10.02(d,J＝13.8Hz,2H),9.11(d,J＝2.5Hz,1H),8.47(d,J＝8.3Hz,1H),8.27(dd,J＝30.4,7.8Hz,2H),7.69(d,J＝8.1Hz,2H),7.61(d,J＝8.4Hz,2H),7.44(d,J＝8.5Hz,2H),7.05(s,1H),6.88(t,J＝8.1Hz,1H),6.68(d,J＝7.9Hz,1H),6.53(d,J＝7.8Hz,1H),2.10(s,3H)； 13 C NMR(126MHz,DMSO)δ169.05,151.44,143.00,142.65,138.44,136.88,135.00,134.17,132.87,132.14,129.25,128.33,127.69,125.50,122.57,118.34,115.32,110.94,24.13。
Example 32:
inhibition experiments of NO release: in the LPS-induced RAW264.7 cell model, the anti-inflammatory capacity of the compounds was assessed by their inhibition of NO release.
RAW264.7 cells were cultured in DMEM medium (10% fetal calf serum and penicillin 100U/mL, streptomycin 100U/mL). RAW264.7 cells were plated at 6X 10 cells per well 4 Inoculating into 48-well plate, culturing for 24 hr (37deg.C, 5% CO) 2 ). The old medium was discarded, pretreated with the pre-formulated drug-containing medium (f 1-f 31) for 1 hour, and then incubated with 30. Mu.L LPS (1. Mu.g/ml) per well for 24 hours. 50 mu L of cell culture supernatant is taken in a 96-well plate, 50 mu L Griess assay agent I and Griess assay agent II are sequentially added to each well to be mixed, the mixture is incubated for 10 minutes at room temperature, and the absorbance is measured at 540nm by a multifunctional enzyme-labeled instrument.
The inhibition ability of compounds f1 to f31 against NO at 30. Mu.M was measured, and the results are expressed as the mean.+ -. SD of three experiments, and the results are shown in Table 1 and FIG. 1.
Inhibition ability of the compounds of Table 1 against NO production (30. Mu.M)
Figure GDA0004213188240000202
/>
Figure GDA0004213188240000211
As can be seen from Table 1 and FIG. 1, all the compounds showed a certain inhibitory effect on the production of NO by RAW264.7 cells at 30. Mu.M, among which four compounds f4, f15, f25 and f30 were better in inhibitory ability than the positive drug (indomethacin), and then the four compounds were selected to determine IC 50 。
IC 50 Defined as the concentration of compound at which LPS stimulated RAW264.7 cells to produce 50% NO, the results are expressed as mean ± SD of three experiments, the results are shown in table 2, fig. 2.
Inhibition of NO production by the compounds of Table 2
Figure GDA0004213188240000212
As can be seen from Table 2 and FIG. 2, four compounds showed excellent inhibition of NO production, with compound f4 showing the best inhibitory activity (IC 50 =20.40±0.94 μm), and is significantly superior to positive drugs. Experiments show that the 8-quinoline sulfonamide compound provided by the invention can inhibit the release of inflammatory factor NO to a certain extent, and the 8-quinoline sulfonamide compound has potential to be developed into an anti-inflammatory drug.
Example 33
Release experiments of inflammatory factors IL-1 beta and TNF-alpha
Compound f4 was tested for inhibition of release of inflammatory factors IL-1 beta and TNF-alpha in an LPS-induced RAW264.7 cell model.
Cells were incubated with indomethacin (30. Mu.M), a positive drug, and f4 (7.5. Mu.M, 15. Mu.M, 30. Mu.M, 60. Mu.M, 80. Mu.M) at various concentrations, and the effect of compound f4 on cell supernatants IL-1. Beta. And TNF-a was determined using ELISA kits (GeneMey, wuhan) according to the protocol presented in FIG. 3.
As can be seen from fig. 3, compound f4 was able to reduce the release of inflammatory factors IL-1 beta and TNF-alpha in the cell supernatant in a dose-dependent manner.
Example 34
Western Blot (Western Blot) experiment
RAW264.7 cells were incubated with different concentrations of compound f4 (5. Mu.M, 10. Mu.M and 20. Mu.M) and the positive drug Bay11-7082 (10. Mu.M) for 1 hour, followed by stimulation of the cells with LPS for 24 hours. The anti-inflammatory effect of compound f4 on the expression of cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) was further evaluated by Western blotting, and the results are shown in FIGS. 4 and 5.
FIG. 4 is a graph showing the effect of compound f4 on the expression of inflammation-associated protein, and it can be seen that the expression levels of inflammatory proteins COX-2 and iNOS significantly increased with decreasing concentration of compound f 4. The results in fig. 5 are shown as mean ± SD (n=3) of at least three independent experiments, and it can be seen that compound f4 reduced the expression of COX-2 and iNOS in a concentration-dependent manner compared to the model group (LPS). It was shown that compound f4 can inhibit the expression of inflammatory proteins (COX-2, iNOS).
Example 35
Adjuvant arthritis (Adjuvant arthritis, AA) test
In inflammatory response, membrane recognition receptors on the surface of macrophages are stimulated by Lipopolysaccharide (LPS) to activate inflammatory pathways, and macrophages are therefore often used as in vitro models to study inflammation. Macrophage activation results in overexpression of cyclooxygenase-2 (COX-2), nitric oxide synthase (iNOS). The construction of animal experimental models related to RA is mostly the pathogenesis of laboratory standard conditions, so the experiment attempts to study RA from the combination of the disease and animal models. The RA disease is combined with an animal model to be established on the basis of the RA model, an adjuvant type arthritis (AA) model in the RA model is widely applied, has acute onset and self-healing properties, and can simulate the disease course characteristics of RA acute onset and remission, and on the basis, the experiment selects the adjuvant type arthritis model.
1) Experimental animals:
female SD rats (180-220 g), supplied by the university of Anhui medical science center. The rats are raised under the standard condition of controllable temperature and humidity (23-25 ℃, 40-60 percent and 12 hours).
2) Adjuvant arthritis induction and experimental treatment:
the 50 rats were randomly divided into 5 groups, and the model group was administered to the left hind paw of the rat by injection of 0.1mL of complete Freund's adjuvant (FCA) to cause inflammation, and the normal group was administered to the rat by injection of an equivalent amount of physiological saline at the same site. After FCA injection for 10 days, the normal and model groups were gavaged with 0.5% sodium carboxymethylcellulose (CMC-Na) solution for 14 days, the drug group was gavaged with compound f4 (30 mg/kg, 10 mg/kg) with different concentrations for 14 days, and the positive control group was gavaged with indomethacin (10 mg/kg) for 14 days.
The results of the foot characteristics of the rats in each treatment group are shown in fig. 6 and 7. It can be seen that the use of compound f4 (10 and 30 mg/kg) and a positive drug (10 mg/kg) for the treatment of the rat Adjuvant Arthritis (AA) model reduced the swelling of the feet in a concentration-dependent manner compared to the model group (FIG. 6 and FIG. 7B), and that the weight of the administered group was improved when the administered dose was ≡10mg/kg (FIG. 7A), and that on day 24, 30mg/kg of compound f4 significantly reduced the arthritis index (FIG. 7C).
3) In vivo determination of IL-1 beta and TNF-alpha content
After anesthetizing each treatment group of rats, blood was collected from the heart artery, and serum was collected by centrifugation at 3000r/min at 4℃for 10 minutes after standing for 30 minutes, and then the levels of IL-1. Beta. And TNF-alpha. In the serum were measured by ELISA. The experimental results are shown in FIG. 8.
As can be seen from FIG. 8, the production of inflammatory factors IL-1 beta and TNF-alpha in the serum of rats is significantly increased in both the normal group and the model group, but the compound f4 can reduce the production of inflammatory factors IL-1 beta and TNF-alpha in the serum of rats in a dose-dependent manner.
The above experiments show that the compound f4 has potential to develop into a medicament for treating arthritis.
The above is merely a preferred practical example of the present invention, and is not intended to limit the invention; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. The 8-quinoline sulfonamide compound is characterized by having a structural formula shown in a formula (A):
Figure FDA0004148646640000011
wherein R is any one of hydrogen, 4-methyl, 4-isopropyl, 2,4, 6-triisopropyl, 4-tert-butyl, 2, 4-dimethoxy, 3, 4-dimethoxy, 2-fluoro, 3-fluoro, 4-fluoro, 2, 6-difluoro, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 3, 5-bistrifluoromethyl, 2-trifluoromethoxy, 4-trifluoromethoxy, 2-chloro, 4-chloro, 2, 6-dichloro, 3, 5-dichloro, 2-bromo, 3-bromo, 4-bromo, 3-bromo-5-trifluoromethyl, 5-bromo-2-methoxy, 4-iodo, 4-cyano, 3-nitro, 4-acetamido.
2. Use of the 8-quinoline sulfonamide compound according to claim 1 for the preparation of an anti-inflammatory medicament.
3. The use according to claim 2, wherein said 8-quinolinesulfonamides are used for the preparation of a medicament for the treatment of arthritis.
4. The use according to claim 3, wherein R in the 8-quinolinesulfonamide compound is 2,4, 6-triisopropyl, and the structural formula is shown in formula (B):
Figure FDA0004148646640000012
5. the use according to claim 2 or 3 or 4, wherein the medicament is any one of an injection, a tablet, a pill, a capsule, a suspension or an emulsion.
6. A medicament for the treatment of arthritis containing a pharmaceutically effective dose of the 8-quinolinesulfonamide compound of claim 1.
7. The medicament according to claim 6, wherein R in the 8-quinoline sulfonamide compound is 2,4, 6-triisopropyl.
8. The medicament of claim 6 or 7, further comprising a pharmaceutically acceptable carrier.
9. The medicament of claim 8, wherein the pharmaceutically acceptable carrier comprises one or more of excipients, stabilizers, antioxidants, colorants, diluents, and sustained-release agents.
10. The medicament of claim 8, wherein the medicament is any one of an injection, a tablet, a pill, a capsule, a suspension, or an emulsion.
CN202210398431.2A 2022-04-15 2022-04-15 8-quinoline sulfonamide compound and application thereof Active CN114874138B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210398431.2A CN114874138B (en) 2022-04-15 2022-04-15 8-quinoline sulfonamide compound and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210398431.2A CN114874138B (en) 2022-04-15 2022-04-15 8-quinoline sulfonamide compound and application thereof

Publications (2)

Publication Number Publication Date
CN114874138A CN114874138A (en) 2022-08-09
CN114874138B true CN114874138B (en) 2023-06-09

Family

ID=82668842

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210398431.2A Active CN114874138B (en) 2022-04-15 2022-04-15 8-quinoline sulfonamide compound and application thereof

Country Status (1)

Country Link
CN (1) CN114874138B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117865886B (en) * 2024-03-07 2024-05-10 中国药科大学 N- (quinoline-8-yl) quinoline-8-sulfonamide compound and application thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8143269B2 (en) * 2008-10-03 2012-03-27 Calcimedica, Inc. Inhibitors of store operated calcium release
CN103833671B (en) * 2012-11-27 2016-12-21 中国科学院上海药物研究所 One class thiazoline ketone compounds and pharmaceutical composition thereof and purposes
CN109096156B (en) * 2018-09-28 2021-01-15 吉首大学 Disulfonyl meta-aryl diamine urease inhibitor and preparation method and application thereof

Also Published As

Publication number Publication date
CN114874138A (en) 2022-08-09

Similar Documents

Publication Publication Date Title
ES2762193T3 (en) Protein tyrosine phosphatase 1 agonists containing Src-2 homology domain and treatment methods using the same
RU2210563C9 (en) Derivatives of nitro-esters and compositions based on thereof for using in control of enuresis
CN114874138B (en) 8-quinoline sulfonamide compound and application thereof
KR20030087657A (en) Methods, compounds, and compositions for reducing body fat and modulating fatty acid metabolism
WO2020035040A1 (en) 3-aryloxyl-3-five-membered heteroaryl propylamine compound and use thereof
WO2020177744A1 (en) Salicylic acid berberine-type alkaloid quaternary ammonium compound and use thereof for preparing medicines
CA3112695C (en) Composition for treating fibrotic diseases, comprising benzhydryl thioacetamide compound as active ingredient
CN103906749A (en) Derivatives of protoberberine biological alkaloids and use of same inhibiting ulcerative colitis
US5547970A (en) Use of leflunomide for inhibiting tumor necrosis factor alpha
CN108349911A (en) Releasable nitric oxide production prodrugs
WO2019031472A1 (en) NOVEL ANTHRANILIC ACID-BASED COMPOUND, AND Pin1 INHIBITOR, THERAPEUTIC AGENT FOR INFLAMMATORY DISEASES AND THERAPEUTIC AGENT FOR CANCER THAT USE THE SAME
WO2009051910A1 (en) Compounds having activity in increasing ion transport by mutant-cftr and uses thereof
KR20120041070A (en) Aryloxyphenoxyacryl-based compounds having hif-1 inhibition activity, preparation method thereof and pharmaceutical composition containing the same as an active ingredient
CZ43599A3 (en) Use of hydroxylamine derivatives for preparing a medicament for treating and prevention of diseases connected with dysfunction of vascular endothelial cells and and pharmaceutical composition containing thereof
JP2003533477A (en) Phosphate transport inhibitors
BR112012028919B1 (en) RUPATADINE SALT AS AN ANTI-HISTAMINIC AGENT
Wang et al. Function and inhibition of P38 MAP kinase signaling: Targeting multiple inflammation diseases
CN114874219B (en) 2-aminobenzene sulfonamide substituted tryptanthrin derivative and preparation and application thereof
JP2018538352A (en) CFTR regulator and method of using the same
WO2016081589A2 (en) 13-cis-ramba retinamides that degrade mnks for treating cancer
JP2001513503A (en) Macrophage scavenger receptor antagonists used in the treatment of cardiovascular diseases
SU1598870A3 (en) Method of producing derivatives of 1,4-dihydropyridine
EP4305026A1 (en) Anti-inflammatory carboxamide derivatives
CN105362273B (en) Application of 7-alkoxy fangchinoline compounds in preparation of medicines for treating and improving depression symptoms
CN111205299B (en) STAT3 inhibitor 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