CN114874219A - 2-aminobenzene sulfonamide substituted tryptanthrin derivative and preparation and application thereof - Google Patents
2-aminobenzene sulfonamide substituted tryptanthrin derivative and preparation and application thereof Download PDFInfo
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- CN114874219A CN114874219A CN202210398436.5A CN202210398436A CN114874219A CN 114874219 A CN114874219 A CN 114874219A CN 202210398436 A CN202210398436 A CN 202210398436A CN 114874219 A CN114874219 A CN 114874219A
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- 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]
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Abstract
The invention relates to a 2-aminobenzene sulfonamide substituted tryptanthrin derivative and a preparation method and application thereof. The structural formula of the compound is shown as a formula (A):
wherein R is hydrogen, 4-tert-butyl, 4-bromo, 4-fluoro, 2-fluoro, 4-acetylamino, 4-trifluoromethoxy, 2, 6-difluoro, 4-trifluoromethyl, 4-methoxy, 3-fluoro, 3, 4-dimethoxy, 2-trifluoromethoxy, 2-trifluoromethyl, 4-Any one of methyl groups. The compound has an inhibiting effect on the generation of macrophage NO after being stimulated by LPS, can reduce the release of inflammation-related cytokines, and has the potential of being developed into a medicament for treating inflammatory diseases.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a 2-aminobenzenesulfonamide-substituted tryptanthrin derivative as well as preparation and application thereof.
Background
Rheumatoid Arthritis (RA) is a chronic autoimmune disease, the pathological features of which are mainly the infiltration of synovial inflammatory cells in the joint cavity and bone erosion due to pannus formation. In recent years, the prevalence of RA has increased year by year as the global population has aged. When RA is severe, the joint of a patient can be distorted, the movement of the patient can be limited, even the function of the patient can be lost, and the joint has stronger disability.
The pathogenesis of RA is extremely complex and to date there is no clear cause. The current pathogenesis of RA comprises immune factors, environmental factors, genetic susceptibility factors and the like. Many studies report that the 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 cytokines that are extremely important in the development of RA, and elevated levels can be found in the blood and joints of critically ill RA-like patients. Interleukin (IL-1 beta) induces fibroblast proliferation, activates osteoclasts, and promotes articular cartilage and bone invasion. Tumor necrosis factor (TNF- α) enhances the erosive power of inflammatory cells, promoting RA joint destruction. Therefore, reducing the production of TNF- α and IL-1 β at sites of inflammation is important for the treatment of RA. In addition, in the inflammatory reaction, the membrane recognition receptor on the surface of macrophage is stimulated by Lipopolysaccharide (LPS) to activate inflammatory pathway, and macrophage activation also causes overexpression of cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS).
Drugs currently approved by the FDA for the treatment of RA often provide temporary or incomplete relief of symptoms, with severe side effects. Therefore, the development of more effective RA therapeutic drugs with lower side effects is urgently required.
Disclosure of Invention
In order to solve the above technical problems, an object of the present invention is to provide 2-aminobenzenesulfonamide-substituted tryptanthrin derivatives.
The technical scheme adopted by the invention is as follows:
a2-aminobenzenesulfonamide substituted tryptanthrin derivative has a structural formula shown as a formula (A):
wherein R is any one of hydrogen, 4-tert-butyl, 4-bromine, 4-fluorine, 2-fluorine, 4-acetamido, 4-trifluoromethoxy, 2, 6-difluoro, 4-trifluoromethyl, 4-methoxy, 3-fluorine, 3, 4-dimethoxy, 2-trifluoromethoxy, 2-trifluoromethyl and 4-methyl.
The second objective of the present invention is to provide a method for preparing the 2-aminobenzenesulfonamide-substituted tryptanthrin derivative, which comprises the following steps:
i.1eq isatoic anhydride a is nitrified in concentrated sulfuric acid concentrated nitric acid ice-water bath to obtain a compound b;
ii.1eq compound b is subjected to dehydration condensation with 1eq compound c (isatin) in toluene to obtain compound d;
adding an ethanol hydrochloric acid solution and stannous chloride tetrahydrate into the compound d to carry out hydrogenation reduction reaction to obtain a compound e;
dissolving the compound e in pyridine, reacting with benzenesulfonyl chloride with a corresponding substituent R, and purifying by column chromatography to obtain tryptanthrin derivatives f1-f 16; wherein R is any one of hydrogen, 4-tert-butyl, 4-bromine, 4-fluorine, 2-fluorine, 4-acetamido, 4-trifluoromethoxy, 2, 6-difluoro, 4-trifluoromethyl, 4-methoxy, 3-fluorine, 3, 4-dimethoxy, 2-trifluoromethoxy, 2-trifluoromethyl and 4-methyl.
The synthetic route described above is represented as follows:
the invention also provides application of the 2-aminobenzene sulfonamide substituted tryptanthrin derivative in preparation of anti-inflammatory drugs.
Preferably, the 2-aminobenzene sulfonamide compound is used for preparing the medicament for treating the arthritis.
Preferably, R in the 2-aminobenzenesulfonamide-substituted tryptanthrin derivative is 4-methoxyl, and the structural formula of the derivative is shown as the formula (B):
preferably, the medicament is any one of injection, tablet, pill, capsule, suspending agent or emulsion.
The present invention also provides a medicament for treating arthritis, which comprises a pharmaceutically effective amount of the 2-aminobenzenesulfonamide-substituted tryptanthrin derivative according to claim 1.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier.
Preferably, the carrier is one or more functional adjuvants such as excipient, stabilizer, antioxidant, colorant, diluent, and sustained release agent, such as starch, lipid, wax, dextrin, sucrose, lactose, microcrystalline cellulose, gelatin, citric acid, inorganic salts, hydroxypropyl methylcellulose, hydroxyethyl cellulose, etc.
Preferably, the medicament is any one of injection, tablet, pill, capsule, suspending agent or emulsion
The invention has the advantages that:
1. through determination in RAW264.7 cells induced by LPS, the 2-aminobenzenesulfonamide substituted tryptanthrin derivative can well inhibit NO release, and the compound can be used as an anti-inflammatory drug.
2. The 2-aminobenzene sulfonamide substituted tryptanthrin derivative provided by the invention can reduce the generation of inflammatory factors TNF-alpha and IL-1 beta in rat serum in a dose-dependent manner, and can relieve the symptom of Adjuvant Arthritis (AA) of rats, thereby indicating that the derivative has potential to be developed into a medicament for treating arthritis.
Drawings
FIG. 1 is a graph showing the effect of compound f10 on inflammatory factors in cells. The results are shown as mean ± SD (n-3) of at least three independent experiments. * p<0.01， ** p<0.001， *** p<0.0001 compared to LPS stimulated cells.
FIG. 2 shows the results of the foot characteristics of rats in each treatment group in example 18.
FIGS. 3-5 are graphs showing the effect of compound f10 of example 18 on adjuvant-induced arthritis model rats, wherein the ordinate of FIGS. 3,4 and 5 are the body weight, swelling degree and arthritis index, respectively.
FIG. 6 shows the inhibition of the inflammatory factor of rats in the adjuvant-induced arthritis model by compound f10 in example 18, wherein FIG. 6A shows TNF-. alpha.and FIG. 6B shows IL-1. beta. The results are shown in the figure as the mean ± SD (n ═ 3), # p <0.0001 compared to control, and # p <0.001, compared to LPS-stimulated cells, of at least three independent experiments.
Detailed Description
Unless otherwise indicated, the terms used herein have the meanings that are conventionally understood by those skilled in the art.
The technical scheme of the invention is more specifically explained by combining the following embodiments:
example 1
Synthesis of compound f 1:
compound e (264mg,1mM) was dissolved in 10mL of pyridine, followed by addition of benzenesulfonyl chloride (R group is hydrogen) (176mg,1mM), and reaction at room temperature for 8-12 hours. The progress of the reaction was checked by TLC. After the reaction, the reaction solvent was removed. The method comprises the following steps of mixing methanol: column chromatography purification of dichloromethane (1:4) afforded compound f1, compound f1 as a yellow solid in 68% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.10(s,1H),8.45–8.41(m,1H),8.01(d,J＝2.6Hz,1H),7.87(d,J＝1.2Hz,1H),7.86(t2J＝2.0Hz,2H)27.85–7.82(m22H),7.67–7.62(m,2H),7.59(dd,J＝8.3,6.5Hz,2H),7.46(td,J＝7.5,0.9Hz,1H).
13 C NMR(126MHz,DMSO)δ182.69,157.66,146.24,144.50,142.80,139.68,139.51,138.14,133.90,131.85,130.05,127.39,127.14,126.36,125.13,124.68,122.78,117.49,115.61.
Example 2
Synthesis of compound f 2:
the procedure is as in example 1, except that the R group is replaced by 4-tert-butyl, giving f2 as a yellow solid in 70% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.09(s,1H),8.43–8.37(m,1H),8.02(d,J＝2.6Hz,1H),7.83(dd,J＝8.8,1.4Hz,1H),7.81(d,J＝6.4Hz,2H),7.80(s22H),7.65(dd,J＝8.8,2.6Hz,1H)27.63–7.57(m,2H),7.41(td,J＝7.6,2.7Hz,1H),1.23(s,9H).
13 C NMR(126MHz,DMSO)δ182.62,157.64,156.90,146.17,144.35,142.59,139.87,138.10,136.92,131.88,127.37,127.03,126.94,125.94,125.09,124.70,122.74,117.44,115.16,35.40,31.14.
Example 3
Synthesis of compound f 3:
the procedure is as in example 1, except that 4-bromobenzenesulfonyl chloride group is replaced by 4-bromo to give f3 as a yellow solid in 76% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.16(s,1H),8.43–8.40(m,1H),7.98(d,J＝2.6Hz,1H),7.86(d,J＝8.5Hz,2H),7.84–7.81(m,2H),7.81(d,J＝2.2Hz,1H),7.78–7.73(m,2H),7.64(dd,J＝8.7,2.6Hz,1H),7.45(td,J＝7.6,0.9Hz,1H).
13 C NMR(126MHz,DMSO)δ182.20,157.17,145.75,144.11,142.54,138.87,138.29,137.69,132.72,131.47,128.68,127.38,126.95,126.08,124.68,124.26,122.29,117.02,115.43.
Example 4
Synthesis of compound f 4:
the procedure is as in example 1, except that the R group is replaced by 4-fluoro, giving f4 as a yellow solid in 79% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.11(s,1H),8.40(d,J＝8.0Hz,1H),7.98(d,J＝2.6Hz,1H),7.95–7.88(m,2H),7.84(d,J＝9.2Hz,2H),7.81(d,J＝7.9Hz,1H),7.64(dd,J＝8.7,2.6Hz,1H),7.45(d,J＝6.1Hz,1H),7.44–7.38(m,2H).
13 C NMR(126MHz,DMSO)δ182.33,157.31,145.89,144.21,142.61,139.19,137.83,131.59,130.04,129.97,127.10,126.19,124.82,124.39,122.44,117.17,117.11,116.93,115.53.
Example 5
Synthesis of compound f 5:
the procedure is as in example 1, except that the R group is replaced by a 2-fluoro group, giving f5 as a yellow solid in 70% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.45(s,1H),8.49–8.30(m,1H),8.00(d,J＝2.6Hz,1H),7.97(td,J＝7.7,1.8Hz,1H),7.88–7.83(m,2H),7.82–7.79(m,1H),7.72(dddd,J＝8.4,7.0,5.1,1.8Hz,1H),7.65(dd,J＝8.8,2.6Hz,1H),7.49–7.44(m,1H),7.42(ddd,J＝7.6,2.9,1.0Hz,2H).
13 C NMR(126MHz,DMSO)δ182.54,159.50,157.48,146.08,144.38,142.69,139.04,138.01,136.85,131.76,130.84,127.27,126.85,125.88,125.61,124.99,124.56,122.62,117.98,117.35,115.09.
Example 6
Synthesis of compound f 6:
the procedure is as in example 1, except that the R group is replaced by a para-acetamido group, giving f6 as a yellow solid in 61% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.97(s,1H),10.32(s,1H),8.41(d,J＝8.1Hz,1H),7.97(d,J＝2.6Hz,1H),7.84(s,1H),7.82(s,2H),7.78(d,J＝8.9Hz,2H),7.73(d,J＝8.6Hz,2H),7.63(dd,J＝8.8,2.6Hz,1H),7.43(t,J＝7.5Hz,1H),2.02(s,3H).
13 C NMR(126MHz,DMSO)δ182.20,169.10,157.20,145.75,143.91,143.53,142.19,139.43,137.66,132.41,131.34,128.06,126.91,125.80,124.64,124.20,122.29,118.75,117.02,115.06,24.11.
Example 7
Synthesis of compound f 7:
the procedure is as in example 1, except that the R group is replaced by 4-trifluoromethoxy, giving f7 as a yellow solid in 63% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.22(s,1H),8.40(dt,J＝7.5,1.1Hz,1H),8.00(d2J＝2.4Hz,2H)27.99(s,1H),7.88–7.83(m,2H),7.82–7.77(m,1H),7.65(dd,J＝8.8,2.6Hz,1H),7.63–7.57(m,2H),7.43(td,J＝7.5,0.9Hz,1H).
13 C NMR(126MHz,DMSO)δ182.67,157.65,151.88,146.23,144.61,143.05,139.35,138.46,138.19,131.99,129.91,127.46,126.56,125.17,124.77,122.78,122.21,121.31,117.51,115.95.
Example 8
Synthesis of compound f 8:
the procedure is as in example 1, except that the R group is replaced by 2, 6-difluoro to give f8 as a yellow solid in 55% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.70(s,1H),8.42(d,J＝8.3Hz,1H),8.06(dd,J＝462.5,2.6Hz,1H),7.90(d,J＝8.8Hz,1H),7.83(t,J＝7.2Hz,2H),7.73(tt,J＝8.4,6.0Hz,1H),7.67(dd,J＝8.8,2.7Hz,1H),7.45(t,J＝7.5Hz,1H),7.32(t,J＝9.3Hz,2H).
13 C NMR(126MHz,DMSO)δ182.55,160.32,158.27,146.10,144.49,142.87,138.81,138.02,136.98,131.88,127.28,125.70,124.99,124.67,122.62,117.38,114.83,114.16,113.98.
Example 9
Synthesis of compound f 9:
the procedure is as in example 1, except that the R group is replaced by 4-trifluoromethyl to give f9 as a yellow solid in 58% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.49(s21H),8.40(d,J＝8.0Hz,1H),8.21(dd,J＝7.9,1.3Hz,1H),8.04(dd,J＝7.8,1.4Hz,1H),7.98(d,J＝2.6Hz,1H),7.92(td,J＝7.8,1.5Hz,1H),7.87(dd,J＝8.5,6.5Hz,2H)27.84–7.77(m,2H),7.65(dd,J＝8.8,2.7Hz,1H),7.43(t,J＝7.5Hz,1H).
13 C NMR(126MHz,DMSO)δ182.70,157.64,146.24,144.57,142.83,139.32,138.34,138.18,134.52,134.23,132.01,131.18,127.45,126.04,125.16,124.77,122.79,117.53,115.30.
Example 10
Synthesis of compound f 10:
the procedure is as in example 1, except that the R group is replaced by 4-methoxy, giving f10 as a yellow solid in 54% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.96(s,1H),8.41(m,1H),7.99(d,J＝2.6Hz,1H),7.83(d,J＝3.7Hz,1H),7.83–7.81(m,2H),7.81(d,J＝2.0Hz,1H),7.79(d,J＝2.1Hz,1H),7.63(dd,J＝8.8,2.6Hz,1H),7.43(td,J＝7.5,0.9Hz,1H),7.11–7.08(m,2H),3.77(s,3H).
13 C NMR(126MHz,DMSO)δ182.52,163.11,157.52,146.06,144.22,142.46,139.83,137.98,131.68,130.92,129.31,127.24,125.99,124.97,124.52,122.63,117.33,115.21,115.02,56.02.
Example 11
Synthesis of compound f 11:
the procedure is as in example 1, except that the R group is replaced by 3-fluoro, giving f11 as a yellow solid in 49% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.18(s,1H),8.41–8.37(m,1H),7.98(d,J＝2.7Hz,1H),7.84(d,J＝8.7Hz,1H),7.81(td,J＝7.5,1.4Hz,2H),7.71–7.67(m,1H),7.66(q,J＝2.7Hz,2H),7.64–7.62(m,1H),7.55–7.50(m,1H),7.42(td,J＝7.5,0.9Hz,1H).
13 C NMR(126MHz,DMSO)δ182.51,161.07,157.48,146.06,142.92,141.40,139.13,138.02,132.48,132.42,131.81,127.28,126.51,125.00,124.57,123.38,122.60,117.35,115.92,114.19,114.00.
Example 12
Synthesis of compound f 12:
the procedure is as in example 1, except that the R group is replaced by 3, 4-bis (trifluoromethyl) to give f12 as a yellow solid in 57% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.91(s,1H),8.44–8.38(m,1H),8.02(d,J＝2.6Hz,1H),7.83(d,J＝4.2Hz,1H),7.83–7.79(m,2H),7.64(dd,J＝8.8,2.6Hz,1H),7.43(dq,J＝8.4,2.6,2.1Hz,2H),7.36(d,J＝2.2Hz,1H),7.09(d,J＝8.7Hz,1H),3.78(d,J＝13.6Hz,6H).
13 C NMR(126MHz,DMSO)δ182.53,157.56,152.84,148.99,146.08,144.24,142.52,139.83,137.99,131.65,130.66,127.24,126.17,124.97,124.48,122.63,121.05,117.35,115.34,111.66,109.68,56.16,56.09.
Example 13
Synthesis of compound f 13:
the procedure is as in example 1, except that the radical R is 2, 4-bis (trifluoromethoxy) to give f13 as a yellow solid in 60% yield.
1 H NMR(500MHz,DMSO-d 6 )δ10.90(s,1H),8.40(dd,J＝8.3,1.7Hz,1H),8.02(d,J＝2.6Hz,1H),7.85–7.82(m,1H),7.81(ddd,J＝6.4,3.9,1.5Hz,2H),7.64(dd,J＝8.7,2.6Hz,1H),7.42(ddd,J＝7.2,5.7,2.0Hz,2H),7.36(d,J＝2.2Hz,1H),7.09(d,J＝8.6Hz,1H),3.78(d,J＝14.0Hz,6H).
13 C NMR(126MHz,DMSO)δ182.52,157.55,152.84,148.99,146.07,144.24,142.51,139.84,137.98,131.65,130.66,127.23,126.17,124.97,124.48,122.62,121.05,117.34,115.34,111.65,109.68,56.15,56.09.
Example 14
Synthesis of compound f 14:
the procedure is as in example 1, except that the radical R is 2-trifluoromethoxy, giving f14 as a yellow solid in 63% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.38(s,1H),8.45–8.41(m,1H),8.09(dd,J＝7.9,1.7Hz,1H),7.98(d,J＝2.6Hz,1H),7.86(d,J＝9.1Hz,2H),7.84–7.82(m,1H),7.80–7.76(m,1H),7.65–7.61(m,1H),7.59(ddd,J＝8.6,5.3,1.5Hz,2H),7.46(td,J＝7.5,0.9Hz,1H).
13 C NMR(126MHz,DMSO)δ182.70,157.66,146.25,145.63,144.55,142.81,139.22,138.15,136.53,131.87,131.59,131.52,128.27,127.42,126.04,125.14,124.69,122.81,121.74,117.52,115.24.
Example 15
Synthesis of compound f 15:
the procedure is as in example 1, except that the radical R is 2-trifluoromethyl, giving f15 as a yellow solid in 53% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.49(s,1H),8.43–8.39(m,1H),8.20(dd,J＝7.9,1.3Hz,1H),8.04(dd,J＝7.8,1.5Hz,1H),7.98(d,J＝2.6Hz,1H),7.92(td,J＝7.8,1.5Hz,1H),7.88(dd,J＝8.3,2.6Hz,2H),7.85–7.79(m,2H),7.65(dd,J＝8.8,2.6Hz,1H),7.45(td,J＝7.5,0.9Hz,1H).
13 C NMR(126MHz,DMSO)δ182.73,157.66,146.27,144.60,142.84,139.32,138.34,138.20,134.53,134.24,132.02,131.17,129.50,129.45,127.46,126.88,126.05,125.18,124.78,122.81,122.17,117.55,115.30.
Example 16
Synthesis of compound f 16:
the procedure is as in example 1, except that the radical R is 4-methyl, giving f16 as a yellow solid in 57% yield.
1 H NMR(500MHz,DMSO-d 6 )δ11.03(s,1H),8.44–8.38(m,1H),7.99(d,J＝2.6Hz,1H),7.83(t,J＝1.7Hz,1H),7.82–7.80(m,2H),7.76–7.71(m,2H),7.63(dd,J＝8.8,2.6Hz,1H),7.43(td,J＝7.5,0.9Hz,1H),7.38(d,J＝8.2Hz,2H),2.31(s,3H).
13 C NMR(126MHz,DMSO)δ182.54,157.53,146.08,144.29,144.24,142.55,139.69,137.99,136.53,131.70,130.34,127.25,127.08,126.07,124.98,124.53,122.64,117.35,115.29,21.32.
Example 17
Inhibition of NO Release
The anti-inflammatory capacity of the compounds was assessed by their ability to inhibit NO release in the LPS-induced RAW264.7 cell model. RAW264.7 cells were cultured in DMEM medium (10% fetal bovine serum and penicillin 100U/mL, streptomycin 100U/mL). RAW264.7 cells were plated at 6X 10 per well 4 One was inoculated in 48-well plates and cultured for 24h (37 ℃, 5% CO) 2 ). The old medium was discarded, pre-treated for 1 hour by adding pre-prepared drug-containing medium of different concentrations (indomethacin as positive control drug), and incubated for 24 hours with 30. mu.L LPS (1. mu.g/ml) per well. 50 mu L of cell culture supernatant is put into a 96-well plate, 50 mu L of Griess assay agent I and Griess assay agent II are sequentially added into each well by adopting an ELISA method, the mixture is incubated for 10 minutes at room temperature, and the absorbance is measured by a multifunctional microplate reader at 540 nm.
The inhibition of NO by compounds f1-f16 at 20. mu.M concentration was expressed as the mean. + -. SD of three experiments and is shown in Table 1.
TABLE 1 inhibition of NO production by the Compounds (20. mu.M)
As can be seen from Table 1, all the compounds can inhibit NO production in RAW264.7 cells induced by LPS at 20 μ M, wherein the compounds f4, f5, f8, f10, f14 and f16 have stronger inhibition effect on NO production and are obviously better than the positive drug Indometacin, and then 6 compounds are selected for further determination of IC 50 The value is obtained.
IC 50 Defined as the concentration of compound at which LPS stimulates RAW264.7 cells to produce 50% NO, results are averaged over three experimentsMean ± SD, results are shown in table 2.
Inhibition of NO production by the Compounds of Table 2
As can be seen from table 2, the above compounds all showed very good inhibitory effect on NO production, of which compound f10 has the most prominent inhibitory activity (IC50 ═ 1.25 ± 0.91 μ M), and is significantly superior to indomethacin, a positive drug. Experiments show that the 2-aminobenzene sulfonamide substituted tryptanthrin derivative provided by the invention can inhibit the release of inflammatory factors NO to a certain extent, and the 2-aminobenzene sulfonamide substituted tryptanthrin derivative has potential to be developed into an anti-inflammatory drug.
Example 18
Release assay for inflammatory factors IL-1 beta and TNF-alpha
In the LPS-induced RAW264.7 cell model, compound f10 was tested for its ability to inhibit the release of the inflammatory factors IL-1 β and TNF- α.
Cells were incubated with the positive drug indomethacin (20. mu.M) and various concentrations of f10 (0.1. mu.M, 1. mu.M, 5. mu.M, 10. mu.M, 20. mu.M) and the effect of compound f10 on cell supernatants IL-1. beta. and TNF-. alpha. was determined using an ELISA kit (Gene America, Wuhan) according to the instructions and the results are shown in FIG. 1.
As can be seen from FIG. 1, compound f10 decreased the release of the inflammatory factors IL-1 β and TNF- α in the cell supernatant in a dose-dependent manner.
Example 19
Adjuvant Arthritis (AA) assay
In inflammatory responses, membrane recognition receptors on the macrophage surface activate inflammatory pathways upon stimulation by Lipopolysaccharide (LPS), 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 establishment of animal experimental models related to RA is mostly the pathogenesis under the standard condition of a laboratory, so the experiment tries to research RA from disease symptoms and animal models. The RA disease is established on the basis of an RA model by combining with an animal model, an Adjuvant Arthritis (AA) model in the RA model is widely applied, has acute onset and self-healing property, and can simulate the characteristics of the course of acute onset and remission of RA, and on the basis, an adjuvant arthritis model is selected in the experiment.
1) Experimental animals:
female SD rats (180-220g) provided by the university of medical, Anhui laboratory center. The rats are raised under the standard condition of controllable temperature and humidity (23-25 ℃, 40-60% and 12 h).
2) Induction and experimental design of adjuvant arthritis:
30 rats were randomly divided into 5 groups, and the left hind paw of the model group was injected with 0.1mL of complete Freund's adjuvant (FCA) to cause inflammation, and the normal group was injected with an equal amount of physiological saline at the same site. After 10 days of FCA injection, the normal and model groups were gavaged with 0.5% sodium carboxymethylcellulose (CMC-Na) solution for 14 days, the drug group with compound f10(30mg/kg, 10mg/kg) at different concentrations for 14 days, and the positive control group with indomethacin (10mg/kg) for 14 days.
The results of the foot characteristics of the rats in each treatment group are shown in FIGS. 2-5. As can be seen, using compound f10(10 and 30mg/kg) and the positive drug (10mg/kg) for the treatment of the rat Adjuvant Arthritis (AA) model, the drug group reduced swelling of the feet in a concentration-dependent manner compared to the model group (FIGS. 2 and 4), and the weight of the group administered was improved when the dose was 10mg/kg or more (FIG. 3), and on day 24, compound f10 at 30mg/kg significantly reduced the arthritis index (FIG. 5).
3) In vivo assay for IL-1 beta and TNF-alpha levels
After anesthetizing the rats in each treatment group, blood was collected from the cardiac artery, left to stand for 30 minutes and then centrifuged at 3000r/min at 4 ℃ for 10 minutes to collect serum, and the levels of IL-1. beta. and TNF-. alpha. in the serum were measured by ELISA. The results of the experiment are shown in FIG. 6.
As can be seen in FIG. 6, the production of inflammatory factors IL-1 beta and TNF-alpha in rat serum was significantly increased in both the normal group and the model group, but the compound f10 could reduce the production of inflammatory factors IL-1 beta and TNF-alpha in rat serum in a dose-dependent manner.
The above experiments indicate that compound f10 has the potential to be developed into a drug for treating arthritis.
The above is only a preferred embodiment of the present invention, and is not intended to limit the invention; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those skilled in the art that: any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A2-aminobenzenesulfonamide substituted tryptanthrin derivative is characterized in that the structural formula is shown as the formula (A):
wherein R is any one of hydrogen, 4-tert-butyl, 4-bromine, 4-fluorine, 2-fluorine, 4-acetamido, 4-trifluoromethoxy, 2, 6-difluoro, 4-trifluoromethyl, 4-methoxy, 3-fluorine, 3, 4-dimethoxy, 2-trifluoromethoxy, 2-trifluoromethyl and 4-methyl.
2. A method for preparing 2-aminobenzenesulfonamide-substituted tryptanthrin derivatives according to claim 1, comprising the steps of:
s1, nitrifying isatoic anhydride a in concentrated sulfuric acid and concentrated nitric acid ice-water bath to obtain a compound product b;
s2, carrying out dehydration condensation on the compound product b and isatin in toluene to obtain a compound product d;
s3, adding an ethanol hydrochloric acid solution and stannous chloride tetrahydrate into the compound product d, and carrying out hydrogenation reduction reaction to obtain a compound product e;
s4, dissolving the compound product e in pyridine, reacting with benzenesulfonyl chloride with a corresponding substituent R, and purifying by column chromatography to obtain a tryptanthrin derivative; wherein R is any one of hydrogen, 4-tert-butyl, 4-bromine, 4-fluorine, 2-fluorine, 4-acetamido, 4-trifluoromethoxy, 2, 6-difluoro, 4-trifluoromethyl, 4-methoxy, 3-fluorine, 3, 4-dimethoxy, 2-trifluoromethoxy, 2-trifluoromethyl and 4-methyl.
3. Use of the 2-aminobenzenesulfonamide-substituted tryptanthrin derivative according to claim 1 in the preparation of an anti-inflammatory medicament.
4. The use according to claim 3, wherein the 2-aminobenzenesulfonamide compounds are used for preparing medicaments for treating arthritis.
5. The use according to claim 4, wherein R in the 2-aminobenzenesulfonamide-substituted tryptanthrin derivative is a 4-methoxy group having a formula shown in formula (B):
6. the use of claim 3 or 4 or 5, wherein the medicament is any one of an injection, a tablet, a pill, a capsule, a suspension or an emulsion.
7. A medicament for treating arthritis comprising a pharmaceutically effective amount of the 2-aminobenzenesulfonamide-substituted tryptanthrin derivative according to claim 1.
8. The medicament of claim 7, further comprising a pharmaceutically acceptable carrier.
9. The medicament of claim 8, wherein the carrier is one or more of an excipient, a stabilizer, an antioxidant, a colorant, a diluent, and a sustained release agent.
10. The medicament of claim 9, wherein the medicament is any one of an injection, a tablet, a pill, a capsule, a suspension or an emulsion.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20040241192A1 (en) * | 2003-01-21 | 2004-12-02 | Chiron Corporation | Use of tryptanthrin compounds for immune potentiation |
| CN102579452A (en) * | 2012-01-20 | 2012-07-18 | 辽宁思百得医药科技有限公司 | Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor |
| CN105330666A (en) * | 2015-11-27 | 2016-02-17 | 西北大学 | Novel tryptanthrin derivative, synthetic method and medicinal application thereof |
| CN108619150A (en) * | 2017-03-24 | 2018-10-09 | 中国海洋大学 | A kind of application of lactams alkaloid compound in drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040241192A1 (en) * | 2003-01-21 | 2004-12-02 | Chiron Corporation | Use of tryptanthrin compounds for immune potentiation |
| CN102579452A (en) * | 2012-01-20 | 2012-07-18 | 辽宁思百得医药科技有限公司 | Preparation method of tryptanthrin compound and new application of tryptanthrin compound in preparing indoleamine-2,3-dioxygenase (IDO) inhibitor |
| CN105330666A (en) * | 2015-11-27 | 2016-02-17 | 西北大学 | Novel tryptanthrin derivative, synthetic method and medicinal application thereof |
| CN108619150A (en) * | 2017-03-24 | 2018-10-09 | 中国海洋大学 | A kind of application of lactams alkaloid compound in drug |
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