Carbazole derivative and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses a pyran carbazole derivative, a preparation method thereof, a pharmaceutical composition thereof and an application of the pyran carbazole derivative. Specifically, the invention discloses pyranocarbazole derivatives as shown in general formulas I and II. The derivatives are prepared in an artificial synthesis mode, pharmaceutical compositions containing the derivatives and application of the derivatives in the anti-inflammatory aspect.

Description

Technical Field

[0001] This invention relates to the fields of natural medicines and medicinal chemistry, specifically to a class of pyranocarbazole oximes and pyranocarbazole nitroketone derivatives. The invention also discloses methods for preparing these derivatives, pharmaceutical compositions, and their uses in treating inflammation-related diseases. Background Technology

[0002] Inflammation is the body's self-protective response to harmful internal and external stimuli, and it is generally classified into acute and chronic inflammation based on its course. Acute inflammation has a rapid onset and short duration, while chronic inflammation lasts longer, sometimes for months or years. Although inflammation can be beneficial to the body to some extent, excessive or prolonged inflammatory responses often exacerbate the development of many diseases, such as autoimmune diseases. Currently, anti-inflammatory drugs used clinically are mainly divided into two categories: steroidal anti-inflammatory drugs (SIADs) and non-steroidal anti-inflammatory drugs (NSAIDs). However, these drugs have problems such as uncertain efficacy, significant side effects, and high cost. Therefore, actively searching for safe, effective, and long-term usable anti-inflammatory drugs has always been a hot topic of concern for medical professionals.

[0003] Pyranocarbazole alkaloids possess a wide range of biological activities. This invention introduces oxime and nitroketones into the pyranocarbazole alkaloid core to obtain a series of derivatives. Pharmacological experiments have confirmed that these derivatives can significantly inhibit NO production by LPS-stimulated Raw264.7 macrophages, suggesting that this type of compound has significant anti-inflammatory activity, thus completing this invention. Summary of the Invention

[0004] The technical problem solved by this invention is to provide a class of carbazole derivatives and their uses.

[0005] This invention discloses compounds of general formulas I and II. Pharmacological experiments have shown that these compounds significantly improve the inflammatory response induced by lipopolysaccharide (LPS) stimulation of Raw264.7 macrophages. Therefore, these compounds can be used to prevent and / or treat various inflammatory diseases, including but not limited to dermatitis, encephalitis, keratitis, conjunctivitis, rhinitis, otitis media, gingivitis, pharyngitis, tonsillitis, pneumonia, hepatitis, enteritis, dysentery, prostatitis, endometritis, cervicitis, pelvic inflammatory disease, paronychia, rheumatoid arthritis, asthma, and psoriasis.

[0006] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0007] The first aspect of the present invention is to provide a class of pyranocarbazole oxime derivatives or pharmaceutically acceptable salts thereof represented by general formula I:

[0008]

[0009] R1 and R2 are independent and can be selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, Bu, etc. t , OCH3, OCH2CH3, OCH2CH2CH3, CF3, OCF3;

[0010] R3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3.

[0011] This invention relates to a class of pyranocarbazole nitroketone derivatives of general formula II or pharmaceutically acceptable salts thereof:

[0012]

[0013] R1 and R2 are independent and can be selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, Bu, etc. t , OCH3, OCH2CH3, OCH2CH2CH3, CF3, OCF3;

[0014] R3 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3;

[0015] R4 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, t-Bu, Ph, Bn.

[0016] The structures and numbers of some compounds in this invention are as follows:

[0017]

[0018]

[0019] The second aspect of the present invention is that the compound represented by general formula I of the present invention can be prepared by the following methods:

[0020]

[0021] The reaction conditions (a) were hydroxylamine hydrochloride, 1 mol / L sodium hydroxide solution, ethanol as solvent, and room temperature.

[0022] The compounds represented by general formula II of this invention can be prepared by the following methods:

[0023]

[0024] The reaction conditions (b) were: R4NHOH, triethylamine, sodium sulfate, ethanol solvent, and heating at 90°C.

[0025] For the preparation methods of intermediates 1 and 2, please refer to "European Journal of Medicinal Chemistry. 2020, 190, 112079".

[0026] A third aspect of the present invention is to provide a pharmaceutical composition in which the compound described in the first aspect of the present invention is used as an active ingredient. This pharmaceutical composition is prepared according to methods known in the art. It can be formulated into any dosage form suitable for human or animal use by combining the compound of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is typically 0.1-95% by weight.

[0027] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0028] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0029] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0030] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannose, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0031] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0032] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. Various diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0033] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure adjusters can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc. pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0034] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0035] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0036] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.001-150 mg / kg body weight, preferably 0.1-100 mg / kg body weight, more preferably 1-60 mg / kg body weight, and most preferably 2-30 mg / kg body weight. The above doses can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0037] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation.

[0038] The compounds represented by general formulas I and II in this invention underwent anti-inflammatory pharmacological experiments. Inflammation is a complex biological process that plays a crucial role in various human diseases. The latest theories of inflammatory response suggest that pathogens or non-infectious factors can activate endothelial cells in the body, releasing large amounts of inflammatory mediators and pain-inducing substances, including histamine, prostaglandin PGE2, leukotrienes, and nitric oxide (NO); and by activating specific receptors on the surface of immune cells, releasing inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukins, and interferons. The release of various inflammatory mediators and inflammatory factors is a significant cause of inflammatory responses.

[0039] Lipopolysaccharide (LPS)-induced inflammatory macrophage models are among the most commonly used in vitro models for inflammation research, characterized by low requirements for model establishment, ease of technique mastery, high reliability, and good reproducibility. LPS activates the immune system, particularly macrophages, by releasing various pro-inflammatory mediators. Macrophages recognize LPS, activating downstream intracellular signaling cascades, leading to the production of several inflammatory mediators and cytokines (including NO), thereby mediating inflammation. Therefore, in this study, an LPS-stimulated Raw 264.7 macrophage model was used to detect the anti-inflammatory activity of compounds.

[0040] The inventors have discovered that the compounds of general formulas I and II provided by this invention exhibit excellent anti-inflammatory activity in the inflammatory response induced by lipopolysaccharide (LPS) stimulation of macrophages.

[0041] Pharmacological experiments have shown that the compounds represented by general formulas I and II have a good protective effect against inflammatory responses induced by bacterial lipopolysaccharides and can be used to prepare drugs for the prevention and / or treatment of inflammatory responses.

[0042] The preferred inflammatory diseases are selected from a variety of common inflammatory reactions, such as respiratory system inflammation, musculoskeletal system inflammation, skin inflammation, and autoimmune diseases.

[0043] The fourth aspect of the present invention provides the use of the compound described in the first aspect or a pharmaceutically acceptable salt thereof in the preparation of an anti-inflammatory drug.

[0044] The inflammation mentioned is selected from respiratory system inflammation, musculoskeletal system inflammation, skin inflammation, and autoimmune diseases. Attached Figure Description

[0045] Figure 1 Effect of the compound on NO production in LPS-stimulated Raw264.7 macrophages (means±SEM, n=3). Detailed Implementation

[0046] Example 1: Preparation of CXT-1

[0047]

[0048] Compound 1 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then tert-butylhydroxylamine (53.5 mg, 2 eq), triethylamine (60.7 mg, 2 eq), and anhydrous sodium sulfate (128 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 82 mg of a yellow powder, with a yield of 67.8%. 1 H NMR (800MHz, Acetone) δ10.58(s,1H),10.15(s,1H),8.17(s,1H),8.04(d,J=1.9Hz,1H),7.41(dd,J=8.4,1.9Hz, 1H),7.36(d,J=7.8Hz,1H),6.96(d,J=9.8Hz,1H),5.83(d,J=9.8Hz,1H),1.62(s,9H),1.51(s,6H),1.41(s,9H). 13 C NMR(200MHz,Acetone)δ150.22,143.42,139.51,138.86,129.94,124.76,123.97,123.46,120.30,118.34,1 17.79,116.61,114.10,111.21,105.07,77.58,70.74,35.25,32.37,28.54,27.76.ESI-MS(m / z):404.2[M+H] + .

[0049] Example 2: Preparation of CXT-2

[0050]

[0051] Compound 2 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then methylhydroxylamine (28.2 mg, 2 eq), triethylamine (60.7 mg, 2 eq), and anhydrous sodium sulfate (128 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 73 mg of a yellow powder, with a yield of 67%. 1 H NMR (800MHz, Acetone) δ10.05(s,1H),8.02(d,J=1.4Hz,3H),7.42(dd,J=8.4,1.1Hz,1H),7.37(d,J=8 .4Hz,1H),6.95(dd,J=9.8,2.0Hz,1H),5.82(d,J=9.7Hz,1H),3.88(s,3H),1.49(s,6H),1.41(s,9H). 13 C NMR(200MHz,Acetone)δ149.82,143.46,139.40,138.94,130.11,129.37,124.65,123.57,120.05,118.2 4,117.82,116.52,113.88,111.19,105.07,77.64,54.75,35.24,32.34,27.68.ESI-MS(m / z):362.2[M+H] + .

[0052] Example 3: Preparation of CXT-3

[0053]

[0054] Compound 3 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then benzylhydroxylamine (74 mg, 2 eq), triethylamine (60.7 mg, 2 eq), and anhydrous sodium sulfate (128 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 92 mg of a yellow powder, with a yield of 70%. 1H NMR (800MHz, Acetone) δ10.58(s,1H),10.04(s,1H),8.23(s,1H),8.00(s,1H),7.59(d,J=7.1Hz,1H),7.40(t,J=7 .4Hz,1H),7.38-7.32(m,3H),6.94(d,J=9.8Hz,1H),5.80(d,J=9.8Hz,1H),5.17(s,3H),1.47(s,6H),1.39(s,9H). 13 C NMR(200MHz,Acetone)δ150.07,143.46,139.50,139.04,136.27,130.08,129.95,129.26,129.09,129.03,124.61,123.5 4,120.18,118.20,117.87,116.59,113.67,111.21,105.13,77.61,71.45,35.21,32.32,27.66.ESI-MS(m / z):438.2[M+H] + .

[0055] Example 4: Preparation of CXT-4

[0056]

[0057] Compound 4 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then hydroxylamine hydrochloride (50.4 mg, 2 eq) and 1 M NaOH solution (0.6 mL, 2 eq) were added. The mixture was stirred at room temperature for 5 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was evaporated to dryness under ethyl acetate. The crude product was purified by silica gel column chromatography to give 90 mg of yellow powder, with a yield of 86%. 1 H NMR (800MHz, Acetone) δ10.35(s,1H),10.01(s,1H),8.55(s,1H),8.36(s,1H),8.10(d,J=1.9Hz,1H),7.42(dd,J =8.4,1.9Hz,1H),7.35(d,J=8.4Hz,1H),6.92(d,J=9.8Hz,1H),5.83(d,J=9.7Hz,1H),1.50(s,6H),1.42(s,9H). 13CNMR(200MHz,Acetone)δ150.22,145.66,143.26,139.66,138.97,130.35,124.27,123.74,118.98,11 8.17,117.24,116.77,114.26,111.10,105.50,77.29,35.20,32.31,27.75.ESI-MS(m / z):348.1[M+H] + .

[0058] Example 5: Preparation of CXT-5

[0059]

[0060] Compound 5 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, then phenylhydroxylamine (64.5 mg, 2 eq), triethylamine (60.7 mg, 2 eq), and anhydrous sodium sulfate (128 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 86 mg of a yellow powder, with a yield of 67.7%. ESI-MS (m / z): 424.2 [M+H] + .

[0061] Example 6: Preparation of CXT-6

[0062]

[0063] Compound 6 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then tert-butylhydroxylamine (64.3 mg, 2 eq), triethylamine (73 mg, 2 eq), and anhydrous sodium sulfate (154 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 76 mg of a yellow powder, with a yield of 60.3%. 1 H NMR (800MHz, Acetone) δ10.66(s,1H),10.15(s,1H),8.17(s,1H),7.98(d,J=7.7Hz,1H),7.43(d,J=8.0Hz,1H),7. 30(t,J=7.0Hz,1H),7.16(t,J=7.4Hz,1H),6.97(d,J=9.8Hz,1H),5.84(d,J=9.8Hz,1H),1.61(s,9H),1.51(s,6H).13 C NMR(200MHz,Acetone)δ150.36,141.39,138.41,130.09,125.61,124.96,123.78,120.31,11 8.25,117.46,114.40,111.71,105.10,77.64,70.79,28.53,27.74.ESI-MS(m / z):348.1[M+H] + .

[0064] Example 7 Preparation of CXT-7

[0065]

[0066] Compound 7 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then methylhydroxylamine (34 mg, 2 eq), triethylamine (73 mg, 2 eq), and anhydrous sodium sulfate (154 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 68 mg of a yellow powder, with a yield of 61.9%. 1 H NMR(800MHz,MeOD)δ9.70(s,1H),8.10(s,1H),7.91(d,J=7.7Hz,1H),7.41(d,J=8.0Hz,1H),7.32(t,J=7.5H z,1H),7.16(t,J=7.4Hz,1H),6.82(d,J=9.7Hz,1H),5.79(dd,J=9.8,3.8Hz,1H),3.89(s,4H),1.50(s,6H). 13 C NMR(200MHz,MeOD)δ151.65,142.16,140.27,135.72,130.59,126.34,124.96,121.74,120.99,1 20.43,118.36,118.12,112.09,111.94,105.53,78.58,53.82,27.76.ESI-MS(m / z):306.1[M+H] + .

[0067] Example 8: Preparation of CXT-8

[0068]

[0069] Compound 8 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then benzylhydroxylamine (88.9 mg, 2 eq), triethylamine (73 mg, 2 eq), and anhydrous sodium sulfate (154 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 93 mg of a yellow powder, with a yield of 67.9%. 1 H NMR (800MHz, Acetone) δ10.63(s,1H),10.03(s,1H),8.20(s,1H),7.97(d,J=7.8Hz,1H),7.59(d,J=6.9Hz,1H),7.44-7.39(m,2H),7.37(t,J= 7.4Hz,1H),7.31(td,J=7.6,1.2Hz,1H),7.17(td,J=7.6,1.0Hz,1H),6.94(d,J=9.7Hz,1H),5.83(d,J=9.8Hz,1H),5.15(s,2H),1.48(s,6H). 13 CNMR(200MHz,Acetone)δ150.19,141.42,138.56,136.30,130.26,130.00,129.28,128.72,125.72,124.86 ,120.61,120.33,118.11,117.53,114.07,111.74,105.16,77.69,71.52,27.66.ESI-MS(m / z):382.2[M+H] + .

[0070] Example 9: Preparation of CXT-9

[0071]

[0072] Compound 9 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, then hydroxylamine hydrochloride (60.6 mg, 2 eq) and 1 M NaOH solution (0.72 mL, 2 eq) were added. The mixture was stirred at room temperature for 5 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 76 mg of a yellow powder, with a yield of 72%. ESI-MS (m / z): 292.1 [M+H] + .

[0073] Example 10: Preparation of CXT-10

[0074]

[0075] Compound 10 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, then phenylhydroxylamine (78.7 mg, 2 eq), triethylamine (73 mg, 2 eq), and anhydrous sodium sulfate (154 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 90 mg of a yellow powder, with a yield of 68%. ESI-MS (m / z): 368.1 [M+H] + .

[0076] Example 11 Preparation of CXT-11

[0077]

[0078] Compound 11 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then tert-butylhydroxylamine (51.6 mg, 2 eq), triethylamine (58.6 mg, 2 eq), and anhydrous sodium sulfate (123 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 89 mg of a yellow powder, with a yield of 73%. ESI-MS (m / z): 416.2 [M+H] + .

[0079] Example 12 Preparation of CXT-12

[0080]

[0081] Compound 12 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then methylhydroxylamine (27.2 mg, 2 eq), triethylamine (58.6 mg, 2 eq), and anhydrous sodium sulfate (123 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 64 mg of a yellow powder, with a yield of 59%. 1H NMR (800MHz, Acetone) δ11.11(s,1H),10.12(s,1H),8.35(s,1H),8.05(s,1H),7. 62(s,2H),6.96(d,J=9.8Hz,1H),5.87(d,J=9.8Hz,1H),3.90(s,3H),1.51(s,6H). 13 C NMR(200MHz,Acetone)δ150.66,143.21,139.13,130.71,129.06,127.15,125.80,124.64,122.37 ,120.37,117.78,116.84,115.10,112.18,105.53,78.05,54.86,27.70.ESI-MS(m / z):374.1[M+H] + .

[0082] Example 13 Preparation of CXT-13

[0083]

[0084] Compound 13 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, then benzylhydroxylamine (71.3 mg, 2 eq), triethylamine (58.6 mg, 2 eq), and anhydrous sodium sulfate (123 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 72 mg of a yellow powder, with a yield of 55%. ESI-MS (m / z): 450.2 [M+H] + .

[0085] Example 14 Preparation of CXT-14

[0086]

[0087] Compound 14 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then hydroxylamine hydrochloride (49 mg, 2 eq) and 1 M NaOH solution (0.58 mL, 2 eq) were added. The mixture was stirred at room temperature for 5 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was evaporated to dryness under ethyl acetate. The crude product was purified by silica gel column chromatography to give 62 mg of a yellow powder, with a yield of 59.6%. 1H NMR (800MHz, Acetone) δ10.14(s,1H),8.54(s,1H),8.46(d,J=8.3Hz,1H),7.65-7.59(m,2H),6.94(d,J=9.8Hz,1H),5.89(d,J=9.8Hz,1H),1.53(s,6H). 13 C NMR(200MHz,Acetone)δ151.18,145.36,143.43,139.23,131.08,127.26,125.92,124.44,122.68, 122.20,118.19,118.06,117.83,115.79,112.12,106.06,77.82,27.89.ESI-MS(m / z):360.1[M+H] + .

[0088] Example 15 Preparation of CXT-15

[0089]

[0090] Compound 15 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then phenylhydroxylamine (63.2 mg, 2 eq), triethylamine (58.6 mg, 2 eq), and anhydrous sodium sulfate (123 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the ethyl acetate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a yellow powder (mg, yield %). ESI-MS (m / z): 436.1 [M+H] + .

[0091] Example 16 Preparation of CXT-16

[0092]

[0093] Compound 16 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then tert-butylhydroxylamine (49.3 mg, 2 eq), triethylamine (56 mg, 2 eq), and anhydrous sodium sulfate (118 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 76 mg of a yellow powder, with a yield of 63.9%. 1H NMR (800MHz, Acetone) δ10.17(s,1H),8.17(s,1H),8.08(d,J=1.9Hz,1H),7.50(dd,J=8.5,1.9Hz,1H),7.43(d,J=8.5Hz,1H),7. 12(d,J=9.9Hz,1H),5.88(d,J=9.9Hz,1H),4.53(q,J=7.2Hz,2H),1.61(s,9H),1.51(s,6H),1.46(t,J=7.2Hz,3H),1.45(s,9H). 13 C NMR(200MHz,Acetone)δ150.87,143.54,140.18,137.69,129.82,124.12,123.43,123.41,120.10,118.93,118.19, 116.25,114.30,109.07,105.88,76.30,70.60,40.29,35.07,32.16,28.35,26.93,15.04.ESI-MS(m / z):432.3[M+H] + .

[0094] Example 17 Preparation of CXT-17

[0095]

[0096] Compound 17 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then methylhydroxylamine (26 mg, 2 eq), triethylamine (56 mg, 2 eq), and anhydrous sodium sulfate (118 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 78 mg of a yellow powder, with a yield of 72%. 1 H NMR (800MHz, Acetone) δ10.02(s,1H),8.07(s,1H),8.04(d,J=1.9Hz,1H),7.49(dd,J=8.5,2.0Hz,1H),7.41(d,J=8.5Hz,1H),7.09(d, J=9.9Hz,1H),5.86(d,J=9.9Hz,1H),4.50(q,J=7.2Hz,2H),3.88(s,2H),3.31(s,3H),1.49(s,6H),1.44(t,J=7.2Hz,3H),1.41(s,9H). 13C NMR (200MHz, Acetone) δ150.90,143.80,140.37,138.13,130.24,124.08,123.77,120.39,118.89,118.44,116. 35,113.72,109.31,106.09,76.62,54.54,49.71,40.43,35.18,32.27,26.97,15.19.ESI-MS(m / z):390.2[M+H] + .

[0097] Example 18 Preparation of CXT-18

[0098]

[0099] Compound 18 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then benzylhydroxylamine (68 mg, 2 eq), triethylamine (56 mg, 2 eq), and anhydrous sodium sulfate (118 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 86 mg of a yellow powder, with a yield of 66.7%. 1 H NMR (800MHz, Acetone) δ9.80(s,1H),8.02(s,1H),7.83(d,J=1.9Hz,1H),7.40-7.36(m,2H),7.28(dd,J=8.5,2.0Hz,1H),7.23-7.18(m,3H),7.18 -7.14(m,1H),6.89(d,J=9.9Hz,1H),5.66(d,J=9.9Hz,1H),4.95(s,2H) ,4.30(q,J=7.2Hz,2H),1.26(s,6H),1.23(t,J=7.2Hz,3H),1.21(s,9H). 13 C NMR (200MHz, Acetone) δ151.00,143.82,140.36,138.11,136.16,130.24,130.02,129.31,129.28,129.07,124.11,123.73,120. 32,118.91,118.47,116.44,113.81,109.29,106.11,76.57,71.37,40.45,35.20,32.28,26.99,15.18.ESI-MS(m / z):466.3[M+H] + .

[0100] Example 19 Preparation of CXT-19

[0101]

[0102] Compound 19 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then hydroxylamine hydrochloride (46.6 mg, 2 eq) and 1 M NaOH solution (0.55 mL, 2 eq) were added. The mixture was stirred at room temperature for 5 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 86 mg of a yellow powder, with a yield of 83%. 1 H NMR (800MHz, Acetone) δ10.17(s,1H),8.17(s,1H),8.08(d,J=1.8Hz,1H),7.49(dd,J=8.5,1.9Hz,1H),7.37(d,J=8.5Hz,1H ),7.26(d,J=9.9Hz,1H),5.81(d,J=9.9Hz,1H),4.02(s,3H),3.33(d,J=4.7Hz,2H),1.62(s,9H),1.51(s,6H),1.44(s,9H). 13 C NMR (200MHz, Acetone) δ151.11,143.59,141.25,139.04,129.30,124.02,123.53,120.22,119.29,118.11,116. 31,114.33,109.29,106.43,76.58,70.77,49.80,35.23,33.23,32.35,28.52,27.19.ESI-MS(m / z):376.2[M+H] + .

[0103] Example 20: Preparation of CXT-20

[0104]

[0105] Compound 20 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, then benzylhydroxylamine (68 mg, 2 eq), triethylamine (56 mg, 2 eq), and anhydrous sodium sulfate (118 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 86 mg of a yellow powder, with a yield of 69%. ESI-MS (m / z): 452.3 [M+H]+ .

[0106] Example 21 Preparation of CXT-21

[0107]

[0108] Compound 21 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, then tert-butylhydroxylamine (51.3 mg, 2 eq), triethylamine (58 mg, 2 eq), and anhydrous sodium sulfate (123 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 85 mg of a yellow powder, with a yield of 71%. ESI-MS (m / z): 418.3 [M+H] + .

[0109] Example 22 Preparation of CXT-22

[0110]

[0111] Compound 22 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then methylhydroxylamine (27 mg, 2 eq), triethylamine (58 mg, 2 eq), and anhydrous sodium sulfate (123 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 76 mg of a yellow powder, with a yield of 70%. 1 H NMR (800MHz, Acetone) δ9.22(s,1H),7.21-7.18(m,1H),6.66(dd,J=8.5,2.0Hz,1H),6.55(d,J=8.5Hz,1H),6.42( d,J=9.9Hz,1H),4.97(d,J=9.9Hz,1H),3.19(s,3H),3.03(s,1H),2.49(d,J=3.9Hz,3H),0.66(s,6H),0.59(s,9H). 13C NMR(200MHz,Acetone)δ150.73,143.63,141.31,139.15,129.46,123.92,123.64,119.98,119.22,118.15,1 16.21,114.08,109.36,106.48,76.65,54.77,49.79,35.22,33.25,32.32,27.10.ESI-MS(m / z):376.2[M+H] + .

[0112] Example 23 Preparation of CXT-23

[0113]

[0114] Compound 23 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then benzylhydroxylamine (70.9 mg, 2 eq), triethylamine (58 mg, 2 eq), and anhydrous sodium sulfate (123 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 86 mg of a yellow powder, with a yield of 66%. 1 H NMR (800MHz, Acetone) δ8.21(s,1H),8.03(d,J=1.9Hz,1H),7.59(d,J=6.9Hz,1H),7.49(dd,J=8.5,1.9Hz,1H),7.43-7.35(m, 4H),7.27(d,J=9.9Hz,1H),5.82(d,J=10.0Hz,1H),5.15(s,2H),4.04(s,2H),3.31(d,J=4.3Hz,3H),1.48(s,6H),1.42(s,9H). 13 C NMR(200MHz,Acetone)δ150.97,143.70,141.33,139.24,136.30,130.03,129.52,129.28,128.79,123.94,123.64,120.10,1 19.21,118.22,116.34,114.00,109.35,106.53,76.66,71.53,49.80,35.23,33.27,32.32,27.11.ESI-MS(m / z):452.3[M+H] + .

[0115] Example 24 Preparation of CXT-24

[0116]

[0117] Compound 19 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then hydroxylamine hydrochloride (48 mg, 2 eq) and 1 M NaOH solution (0.58 mL, 2 eq) were added. The mixture was stirred at room temperature for 5 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was evaporated to dryness under ethyl acetate. The crude product was purified by silica gel column chromatography to give 86 mg of a yellow powder, with a yield of 83%. 1 H NMR (800MHz, Acetone) δ10.01(s,1H),8.55(s,1H),8.37(s,1H),8.10(d,J=1.9Hz,1H),7.49(dd,J=8.5,1.9Hz, 1H),7.37(d,J=8.6Hz,1H),7.28(d,J=9.9Hz,1H),5.82(d,J=9.9Hz,1H),4.03(s,3H),1.51(s,6H),1.42(s,9H). 13 CNMR(200MHz,Acetone)δ151.16,145.73,143.43,141.50,139.34,129.75,123.83,123.58,119.34,119.2 0,117.34,116.52,114.53,109.22,106.92,76.37,35.20,33.27,32.29,27.23.ESI-MS(m / z):362.2[M+H] + .

[0118] Example 25 Preparation of CXT-25

[0119]

[0120] Compound 23 (100 mg, 1 eq) was dissolved in 2 mL of ethanol, and then benzylhydroxylamine (71 mg, 2 eq), triethylamine (58 mg, 2 eq), and anhydrous sodium sulfate (123 mg, 3 eq) were added. The mixture was heated and stirred at 90°C for 2 h, and the reaction was stopped. The reaction was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (5 mL × 3). The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, filtered, and the crude product was obtained by rotary evaporation of ethyl acetate. The crude product was purified by silica gel column chromatography to give 78 mg of a yellow powder, with a yield of 62%. ESI-MS (m / z): 438.2 [M+H] + .

[0121] Pharmacological experiments:

[0122] Experimental Example 1: Protective effect of compound CST 1-25 on the inflammatory response of LPS-stimulated macrophages Raw264.7

[0123] Methods: Frozen cells were quickly removed from liquid nitrogen and placed in a 37°C water bath, gently shaken to thaw, and 3 mL of preheated to room temperature complete culture medium (DMEM + 10% fetal bovine serum + 1% penicillin-streptomycin mixture) was added. After centrifugation at 800g for 3 min, the supernatant was discarded, and the cells were resuspended and transferred to a culture dish containing fresh complete culture medium. The cells were incubated at 37°C in a CO2 incubator. In this experiment, revived cells were considered stable after two passages before being used in experiments. Raw264.7 cells are semi-adherent cells, appearing round at rest, with several cells clustered in a "grape-like" shape. Cells were passaged when they reached approximately 90% confluence. The culture medium was discarded, fresh complete culture medium was added, and the cells were detached by pipetting. The cell suspension was collected in a centrifuge tube and centrifuged at 800g for 3 min. Discard the supernatant and collect the cell pellet. Add 1 mL of culture medium to resuspend the cell pellet. Gently pipette to disperse the cell pellet into single cells. Inoculate the cells into culture dishes at a ratio of 1:3 and incubate in a CO2 incubator at 37°C.

[0124] Cells were divided at ρ = 5 × 10 5 Cells / mL were evenly seeded into 96-well plates and incubated at 37°C in a CO2 incubator for 17-24 hours before proceeding with the next operation. The cell culture medium was then replaced with starvation medium containing 1% fetal bovine serum (FBS) for 4 hours. After 4 hours, the cell culture medium was replaced with maintenance medium containing 8% FBS, and 10 μL / well of the drug was added for 2 hours of treatment. Then, 1 μg / mL of lipopolysaccharide (LPS) was added for 12 hours of stimulation. The cell culture medium was collected for subsequent experiments.

[0125] NO content was determined using the Griess reagent method: 1% sulfanilamide solution and 0.1% NED solution were prepared and brought to room temperature. 0.1M sodium nitrite was diluted to 100 μM with complete culture medium, and then serially diluted 1:2 to obtain eight standard concentrations. 50 μL / well of sample and standard solutions were added to each well of a 96-well plate. 50 μL / well of 1% sulfanilamide solution was added to each well, and the plate was incubated at room temperature in the dark for 5 min. 50 μL / well of 0.1% NED solution was added to each well; the color reaction should appear immediately, and the plate was incubated at room temperature in the dark for 5 min. The absorbance at 525 nm was recorded from each well. A linear fit was performed on the absorbance of the standard solutions to obtain the linear equation C = a*A525 + b between the concentration C and the absorbance A525. The NO concentration in each sample was then calculated by substituting the sample absorbance into the equation.

[0126] The results of screening for the anti-inflammatory effects of compound CXT 1-25 on LPS-stimulated Raw264.7 macrophages are detailed in Table 1. LPS stimulation significantly increased NO secretion by cells, while 10 μmol / L CXT 1-25 significantly reduced NO secretion, demonstrating significant anti-inflammatory effects.

[0127] Table 1. Effect of compound CXT 1-25 on NO release from Raw264.7 macrophages after LPS stimulation (means±SEM, n=3)

[0128] Serial Number Code Name Concentration NO Content (μM) 1 Control - 1.12±0.02 2 Model - 25.10 ± 0.77 ### ]] 3 CXT-1 10μM 17.68 ± 0.56 *** ]] 4 CXT-2 10μM 12.88 ± 0.63 *** ]] 5 CXT-3 10μM 13.94 ± 0.64 *** <!-- 12 -->]] 6 CXT-4 10μM 7.35 ± 0.30 *** ]] 7 CXT-5 10μM 10.74 ± 0.43 *** ]] 8 CXT-6 10μM <![CDATA[13.71±0.84 *** ]]> 9 CXT-7 10μM <![CDATA[17.27±1.54 *** ]]> 10 CXT-8 10μM <![CDATA[9.96±0.58 *** ]]> 11 CXT-9 10μM <![CDATA[9.49±0.34 *** ]]> 12 CXT-10 10μM <![CDATA[11.92±0.48 *** ]]> 13 CXT-11 10μM <![CDATA[8.48±0.46 *** ]]> 14 CXT-12 10μM <![CDATA[9.91±0.32 *** ]]> 15 CXT-13 10μM <![CDATA[12.46±0.43 *** ]]> 16 CXT-14 10μM <![CDATA[7.93±3.19 *** ]]> 17 CXT-15 10μM <![CDATA[17.03±0.91 *** ]]> 18 CXT-16 10μM <![CDATA[9.43±0.62 *** ]]> 19 CXT-17 10μM <![CDATA[13.52±0.21 *** ]]> 20 CXT-18 10μM <![CDATA[16.50±0.89 *** ]]> 21 CXT-19 10μM <![CDATA[13.82±0.42 *** ]]> 22 CXT-20 10μM <![CDATA[12.93±0.42 *** ]]> 23 CXT-21 10μM <![CDATA[12.34±0.28 *** ]]> 24 CXT-22 10μM <![CDATA[12.68±0.44 *** ]]> 25 CXT-23 10μM <![CDATA[9.32±0.87 *** ]]> 26 CXT-24 10μM <![CDATA[13.88±0.42 *** ]]> 27 CXT-25 10μM <![CDATA[13.35±0.30 *** ]]>

Claims

1. A class of pyrano-carbazole oxime derivatives represented by the general formula I: ###0001### or a pharmaceutically acceptable salt thereof: R1 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3; R2 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3; R3 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3; R4 is selected from the group consisting of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, t-Bu, Ph, Bn. R1, R2, independently of each other, can be selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, Bu t OCH3, OCH2CH3, OCH2CH2CH3, CF3, OCF3; 2. A class of pyrano-carbazole nitrone derivatives represented by the general formula II: ###0002### or a pharmaceutically acceptable salt thereof: R1 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3; R2 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3; R3 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3; R4 is selected from the group consisting of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, t-Bu, Ph, Bn.

3. The compound of claim 1 or 2, wherein R1 is H; R2 is H; R3 is H; and R4 is selected from the group consisting of CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, t-Bu, Ph, Bn. R1, R2, independently of each other, can be selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, Bu t OCH3, OCH2CH3, OCH2CH2CH3, CF3, OCF3; 4. A pharmaceutical composition comprising, as an effective ingredient, the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

5. Use of the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of an anti-inflammatory drug.

3. The compound according to any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, characterized in that, 6. The use of claim 5, wherein the inflammation is selected from the group consisting of respiratory system inflammation, bone and joint system inflammation, skin inflammation, and autoimmune diseases. ​ ​ 6. Use according to claim 5, characterised in that, ​

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