Medicine containing small molecule compound with 2-aryl formyl benzo-aza structure and application of medicine

Abstract

The invention discloses a medicine containing a small molecule compound with a 2-aryl formyl benzo-aza structure and application of the medicine. The small molecule compound with the 2-arylformyl benzo-aza structure and pharmaceutically acceptable salt or eutectic, deuterated compound, solvate and enantiomer thereof can be used for preparing medicines for preventing and / or treating inflammatory lung diseases, or preparing medicines for inhibiting alveolar macrophages from generating inflammatory factors; the medicine is a medicine which contains a small molecule compound with a 2-aryl formyl benzo-aza structure and is used for preventing and / or treating inflammatory lung diseases. The compound provided by the invention can provide a new treatment strategy for preventing or treating inflammatory lung diseases, and has a wide application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, and discloses a drug containing a small-molecule compound with a 2-aroylbenzazepine structure and application thereof. BACKGROUND

[0002] Pulmonary macrophages (MC) are resident cells in alveoli, which have physiological characteristics such as adhesion, deformation, migration, chemotaxis, phagocytosis and secretion, and are the first line of defense of the lung. When the alveoli are damaged by exogenous substances (including bacteria, toxic chemical gas particles), MC will quickly migrate to the damaged site, identify damaged cells or exogenous substances and release inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-6. The inflammatory mediators released by MC cause vasodilation and increased permeability, and promote the aggregation of other inflammatory cells, thereby removing pathogens and damaged cells. However, excessive inflammation will exacerbate the inflammatory response in the lung, damage the alveolar epithelial cells and the microvascular wall, cause lung tissue damage and rupture of the alveolar capillary barrier, and form pulmonary edema. Long-term persistent and high-intensity inflammatory response will cause acute respiratory distress syndrome and even death. Therefore, during the excessive inflammatory response period of inflammatory lung disease, inhibiting the secretion of inflammatory factors by MC can reduce the infiltration of inflammatory cells and lung tissue damage, thereby maintaining the normal structure and function of lung tissue.

[0003] At present, the treatment methods for the excessive inflammatory response period of inflammatory lung disease in clinical practice mainly rely on supportive treatments such as mechanical ventilation and fluid management, as well as large-dose glucocorticoid anti-inflammatory treatment, plasma inflammatory factor replacement and other treatment methods. However, during the excessive inflammatory response period of severe pneumonia, large-dose hormone shock treatment has serious complications such as thrombosis and gastrointestinal bleeding, and plasma inflammatory factor replacement is expensive and requires high clinical equipment, so it is difficult for ordinary hospitals to carry out treatment. Therefore, the development of new anti-inflammatory drugs can better meet the clinical treatment needs. By inhibiting the secretion of inflammatory factors by MC, the progress of the inflammatory response in the lung can be controlled from the source, thereby providing strong support for the development of new treatment strategies for inflammatory lung disease. SUMMARY

[0004] In view of the above problems in the prior art, the present application provides a drug containing a small-molecule compound with a 2-aroylbenzazepine structure and application thereof.

[0005] To achieve the above object, the technical scheme adopted by the present application to solve its technical problems is: I. Application of a small-molecule compound with a 2-aroylbenzazepine structure The small-molecule compound with a 2-aroylbenzoazepine structure and a pharmaceutically acceptable salt or co-crystal, deuterated product, solvate, enantiomer thereof are used for preparing a drug for preventing and / or treating an inflammatory lung disease, or for preparing a drug for inhibiting alveolar macrophages from producing inflammatory factors. The small-molecule compound with a 2-aroylbenzoazepine structure has the following structural formula:

[0006] wherein R represents a substituent.

[0007] Preferably, the small-molecule compound has any one of the following structural formulas: .

[0008] Most preferably, the small-molecule compound has the following structural formula: .

[0009] Specifically, the inflammatory lung disease can be acute lung injury.

[0010] More specifically, the inflammatory lung disease can be LPS-induced acute lung injury.

[0011] More specifically, the inflammatory lung disease can be LPS-induced acute lung injury in mice.

[0012] The small-molecule compound prevents and / or treats the inflammatory lung disease by inhibiting alveolar macrophages from producing inflammatory factors.

[0013] II. A drug for preventing and / or treating an inflammatory lung disease The active ingredient of the drug is a small-molecule compound with a 2-aroylbenzoazepine structure; the small-molecule compound with a 2-aroylbenzoazepine structure has the following structural formula:

[0014] wherein R represents a substituent.

[0015] Preferably, the small-molecule compound has any one of the following structural formulas: .

[0016] Most preferably, the small-molecule compound has the following structural formula: .

[0017] The present application has the following beneficial effects: The active small molecule compounds in this invention can effectively inhibit the secretion of inflammatory factors by macrophages (MCs). Cellular experiments have confirmed that they have a significant inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory responses in MCs, with almost no physiological toxicity. Further evidence from cell-selected compound L2 in a mouse model of LPS-induced acute lung injury induced by intrapulmonary nebulization confirms its good anti-inflammatory and therapeutic effects on acute lung injury; its anti-inflammatory effect is comparable to that of glucocorticoids. These compounds or compositions hold promise for the prevention or treatment of inflammatory lung diseases, such as acute lung injury and acute exacerbations of chronic obstructive pulmonary disease (COPD). Attached Figure Description

[0018] Figure 1 It is the 2-(4-methoxybenzoyl)-1,5-dihydro-4-dihydrobenzoyl given in example compound L1. H -benzo[ b [1H NMR spectrum of azido-4-one]

[0019] Figure 2 It is the 2-(4-fluorobenzoyl)-1,5-dihydro-4- substituted compound L2 from the examples. H -benzo[ b [1H NMR spectrum of azido-4-one]

[0020] Figure 3 It is the 2-(4-cyanobenzoyl)-1,5-dihydro-4-cyanobenzoyl) given in example compound L3. H -benzo[ b [1H NMR spectrum of azido-4-one]

[0021] Figure 4 It is the 2-(3-chlorobenzoyl)-1,5-dihydro-4-dichlorobenzoyl given in example compound L4. H -benzo[ b [1H NMR spectrum of azido-4-one]

[0022] Figure 5 It is the 2-(3-fluorobenzoyl)-1,5-dihydro-4- substituted compound L5 from the examples. H -benzo[ b [1H NMR spectrum of azido-4-one]

[0023] Figure 6 It is the 2-(4-methoxybenzoyl)-1,5-dihydro-4-dihydrobenzoyl given in example compound L1. H -benzo[ b [CNC NMR spectrum of aziro-4-one]

[0024] Figure 7 It is the 2-(4-fluorobenzoyl)-1,5-dihydro-4- substituted compound L2 from the examples. H-benzo[ b [CNC NMR spectrum of aziro-4-one]

[0025] Figure 8 It is the 2-(4-cyanobenzoyl)-1,5-dihydro-4-cyanobenzoyl) given in example compound L3. H -benzo[ b [CNC NMR spectrum of aziro-4-one]

[0026] Figure 9 It is the 2-(3-chlorobenzoyl)-1,5-dihydro-4-dichlorobenzoyl given in example compound L4. H -benzo[ b [CNC NMR spectrum of aziro-4-one]

[0027] Figure 10 It is the 2-(3-fluorobenzoyl)-1,5-dihydro-4- substituted compound L5 from the examples. H -benzo[ b [CNC NMR spectrum of aziro-4-one]

[0028] Figure 11 This is an ELISA test of the effects of compounds L1-L5 on LPS-induced secretion of inflammatory factors in MH-S cells (* indicates P<0.05 vs NC group; # indicates P<0.05 vs LPS group). Among them, (A) is a comparison of the results of different concentrations of compounds L1-L5 inhibiting the secretion of inflammatory factor TNF-α, (B) is a comparison of the results of different concentrations of compounds L1-L5 inhibiting the secretion of inflammatory factor IL-1β, (C) is a comparison of the results of different concentrations of compounds L1-L5 inhibiting the secretion of inflammatory factor IL-6, and (D) is a comparison of the results of compounds L1-L5 and glucocorticoids inhibiting the secretion of inflammatory factors TNF-α, IL-1β and IL-6 at the same concentration.

[0029] Figure 12 The effect of the preferred L2 compound on LPS-induced acute lung injury in mice is shown in Figure 1 (* indicates P<0.01 vsctrl group; # indicates P<0.05 vs LPS group, N=6). Among them, (A) is the HE staining result figure and (B) is the Smith score result figure. Detailed Implementation

[0030] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0031] The first aspect of this invention provides an application of a small molecule compound having a 2-arcarboxylbenzozaza heterostructure.

[0032] Includes at least one of the following applications: a) Small molecule compounds having a 2-arcarboxylbenzozaza structure and their pharmaceutically acceptable salts or eutectics, deuterated derivatives, solvates, and enantiomers for the preparation of medicaments for the prevention and / or treatment of inflammatory lung diseases.

[0033] Specifically, inflammatory lung disease can be acute lung injury.

[0034] More specifically, inflammatory lung disease can be LPS-induced acute lung injury.

[0035] More specifically, inflammatory lung disease can be LPS-induced acute lung injury in mice.

[0036] Among them, the mechanism of action of small molecule compounds in preventing and / or treating inflammatory lung diseases is to inhibit the production of inflammatory factors by alveolar macrophages.

[0037] b) Small molecule compounds having a 2-arcarboxylbenzozaza structure and their pharmaceutically acceptable salts or cocrystals, deuterated derivatives, solvates, and enantiomers for the preparation of drugs that inhibit the production of inflammatory factors by alveolar macrophages.

[0038] Specifically, the inflammatory factor is at least one of TNF-α, IL-6, and IL-1β.

[0039] The general structural formula of small molecule compounds having a 2-arcarboxylbenzo[a]azine heterostructure is as follows:

[0040] Wherein, R represents different substituents, preferably 4-OMe (L1), 4-F (L2), 4-CN (L3), 3-Cl (L4) or 3-F (L5).

[0041] Preferably, the structural formula of the small molecule compound is shown in any of the following: .

[0042] Most preferably, the structural formula of the small molecule compound is as follows: .

[0043] A second aspect of the present invention provides a medicament for the prevention and / or treatment of inflammatory lung diseases. The active ingredient of the medicament is a small molecule compound having a 2-arcarboxylbenzozaza heterostructure, or a pharmaceutically acceptable salt or eutectic, deuterated, solvated, or enantiomer thereof.

[0044] Preferably, the structural formula of the small molecule compound is shown in any of the following: .

[0045] Most preferably, the structural formula of the small molecule compound is as follows: .

[0046] Preferably, the inflammatory lung disease is acute lung injury.

[0047] More preferably, inflammatory lung disease is LPS-induced acute lung injury.

[0048] More preferably, the inflammatory lung disease is LPS-induced acute lung injury in mice.

[0049] Preferably, the inflammatory factor is at least one of TNF-α, IL-6 and IL-1β.

[0050] Preferably, the above-mentioned drugs can be administered orally, by injection, rectal instillation, sublingual administration, inhalation, external local application, or systemic transdermal administration.

[0051] Preferably, the dosage form of the above-mentioned drug can be an injection, capsule, tablet, sustained-release preparation, suppository, or spray.

[0052] Specific embodiments of the present invention are as follows: Example 1

[0053] In this embodiment, the small molecule compound L1: 2-(4-methoxybenzoyl)-1,5-dihydro- ... H -benzo[ b Azazo-4-one. The structural formula of the small molecule compound L1 is shown in the figure below: .

[0054] The 1H NMR spectrum and 1C NMR spectrum of the small molecule compound L1 obtained in this embodiment are shown below. Figure 1 , Figure 6 As shown. The proton, carbon, and mass spectrometry information is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.90 (d, J = 7.2 Hz, 2H), 7.28(d, J = 41.2 Hz, 5H), 7.04 (d, J = 7.2 Hz, 2H), 6.12 (s, 1H), 3.97 (s, 3H), 3.81 (s, 2H).

[0055] 13C NMR (100 MHz, CDCl3) δ 192.7, 189.8, 164.2, 145.4, 139.2, 132.7,130.6, 127.9, 127.6, 126.7, 123.4, 119.9, 114.0, 113.7, 55.8, 50.1.

[0056] HRMS (ESI): m / z calcd for C 18 H 15 NO3[M+H] + :294.1125, found:294.1128.

[0057] Example 2

[0058] In this embodiment, the small molecule compound L2: 2-(4-fluorobenzoyl)-1,5-dihydro- ... H -benzo[ b Azazo-4-one. The structural formula of the small molecule compound L2 is shown in the figure below: .

[0059] The 1H NMR spectrum and 1C NMR spectrum of the small molecule compound L2 obtained in this embodiment are shown below. Figure 2 , Figure 7 As shown. The proton, carbon, and mass spectrometry information is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.96 – 7.79 (m, 2H), 7.34 (dd, J = 17.2, 4.4 Hz, 4H), 7.22 (d, J = 6.0 Hz, 3H), 6.06 (s, 1H), 3.78 (s, 2H).

[0060] 13 C NMR (100 MHz, CDCl3) δ 193.2, 189.9, 144.9, 139.3, 132.9, 132.8,131.6, 130.9, 128.2, 127.1, 123.5, 120.2, 116.3, 116.1, 114.5, 50.3.

[0061] HRMS (ESI): m / z calcd for C 17 H 12 FNO2[M+H]+ :282.0925, found:282.0921.

[0062] Example 3

[0063] In this embodiment, the small molecule compound L3: 2-(4-cyanobenzoyl)-1,5-dihydro- ... H -benzo[ b Azazo-4-one. The structural formula of the small molecule compound L3 is shown in the figure below: .

[0064] The 1H NMR spectrum and 1C NMR spectrum of the small molecule compound L3 obtained in this embodiment are shown below. Figure 3 , Figure 8 As shown. The proton, carbon, and mass spectrometry information is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.81 (q, J = 8.4 Hz, 4H), 7.32(dd, J = 7.2, 4.8 Hz, 1H), 7.29 – 7.26 (m, 2H), 7.18 (d, J = 7.6 Hz, 1H), 5.93 (s, 1H), 3.74 (s, 2H).

[0065] 13 C NMR (100 MHz, CDCl3) δ 193.4, 189.6, 143.8, 139.0, 138.8, 132.4,130.7, 130.0, 128.2, 127.1, 123.2, 120.1, 117.7, 116.6, 115.1, 50.1.

[0066] HRMS (ESI): m / z calcd for C 18 H 12 N2O3[M+H]+:289.0972, found:289.0971.

[0067] Example 4

[0068] In this embodiment, the small molecule compound L4: 2-(3-chlorobenzoyl)-1,5-dihydro-4 ... H -benzo[ b Azazo-4-one. The structural formula of the small molecule compound L4 is shown in the figure below: .

[0069] The 1H NMR spectrum and 1C NMR spectrum of the small molecule compound L4 obtained in this embodiment are shown below. Figure 4 , Figure 9 As shown. The proton, carbon, and mass spectrometry information is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.68 (s, 1H), 7.60 – 7.53 (m,2H), 7.39 (t, J = 8.0 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.23 (d, J = 4.4 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1H), 5.98 (s, 1H), 3.70 (s, 2H).

[0070] 13 C NMR (100 MHz, CDCl3) δ 193.3, 189.7, 144.2, 139.0, 136.9, 135.0,133.3, 130.7, 129.9, 129.6, 128.1, 127.8, 126.9, 123.3, 120.0, 114.8, 50.1.

[0071] HRMS (ESI): m / z calcd for C 17 H 12 ClNO2[M+H] + : 298.0629, found: 298.0633.

[0072] Example 5

[0073] In this embodiment, the small molecule compound L5: 2-(3-fluorobenzoyl)-1,5-dihydro-4 ...dihydro-1,5-dihydro-4 H -benzo[ b Azazo-4-one. The structural formula of the small molecule compound L5 is shown in the figure below: .

[0074] The 1H NMR spectrum and 1C NMR spectrum of the small molecule compound L5 obtained in this embodiment are shown below. Figure 5 , Figure 10 As shown. The proton, carbon, and mass spectrometry information is as follows: 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.44 –7.38 (m, 2H), 7.29 – 7.24 (m, 2H), 7.21 (d, J = 4.4 Hz, 2H), 7.12 (d, J = 7.6 Hz,1H), 5.98 (s, 1H), 3.68 (s, 2H).

[0075] 13 C NMR (100 MHz, CDCl3) δ 193.3, 189.7, 163.7, 161.2, 144.2, 139.0,137.2 130.81 – 130.2, 128.06, 126.9, 125.6, 123.3, 120.5, 120.3, 120.0,116.8, 116.6, 114.7, 50.1.

[0076] HRMS (ESI): m / z calcd for C 17 H 12 FNO2[M+H] + :282.0925, found:282.0831.

[0077] Example 6

[0078] In this embodiment, the cytotoxicity of compounds L1-L5 and their inhibitory effect on LPS-induced MH-S cell inflammatory response were detected through the following process.

[0079] The specific process is as follows: 1. Detection of the cytotoxicity of compounds L1-L5 to MH-S cells using the CCK-8 assay. Detection procedure: MH-S cells (mouse alveolar macrophage cell line) were prepared at a ratio of 5 × 10⁻⁶. 3Cells were seeded into 96-well plates at the specified density, with 9 groups per plate: one control group (containing only the drug solvent dimethyl sulfoxide) and eight drug-treated groups (containing compounds L1-L5 at concentrations of 1, 5, 10, 50, 100, 500, 1000, and 5000 nM, respectively). Each group had 5 replicates. The culture medium was complete (DMEM + 10% (v / v) FBS + 1% (v / v) antibiotics), and the cells were incubated for 24, 48, and 72 hours. At the corresponding time points, 10 μL of CCK-8 reagent was added to each well, and the cells were incubated in the dark for 1 hour. After incubation, the cells were shaken thoroughly on a microplate reader, and the absorbance at 450 nm was measured (the higher the number of viable cells, the higher the absorbance).

[0080] Detection results: The IC50 values ​​of each compound for MH-S cell cytotoxicity are as follows (Table 1).

[0081] Table 1. IC50 of compounds L1-L5 on MH-S cytotoxicity 50 Example Cytotoxicity (nM) L1 2678.75±50.87 L2 1547.59±74.82 L3 1897.11±61.75 L4 2456.94±98.39 L5 3145.88±45.16 2. The effects of compounds L1-L5 on LPS-induced inflammatory responses in MH-S cells were detected using ELISA. Detection process: MH-S cells were prepared at a ratio of 5 × 10⁻⁶ 6 Cells were seeded in 6-well plates and starved for 8 hours in serum-free medium after cell attachment. A gradient concentration of candidate compounds was added, with the final dose determined according to Test 1, using six non-cytotoxic drug doses: 5, 10, 50, 100, 500, and 1000 nM. When cells reached 70% confluence, the medium was replaced with serum-free DMEM for another 8 hours of starvation. After 30 minutes of stimulation, 1 μg / mL of LPS (Sigma-L3129) was added for 6 hours of stimulation. Cell supernatant was collected, and the secretion levels of IL-1β, IL-6, and TNF were detected using an ELISA kit (from Linke Biotechnology).

[0082] Test results: such as Figure 11 As shown in (A) to (C), the levels of TNF-α, IL-6, and IL-1β in the supernatant of LPS-induced MH-S cells were significantly higher than those in the control group. This indicates that compounds L1 to L5 can reduce the LPS-induced increase in TNF-α, IL-6, and IL-1β levels, with compound L2 showing the most significant inhibitory effect at the same dose.

[0083] Subsequently, based on the results of the cytotoxicity test of each compound on MH-S cells, a 100 nM dose of the compound that had no cytotoxic effect on the MH-S cell line was selected, and the inhibitory effect of the compound on LPS-induced inflammatory factor expression at this dose was tested. At the same time, the classic anti-inflammatory drug dexamethasone (Dex) (MCE-HY-14648) was selected as an anti-inflammatory positive control.

[0084] Detection Procedure: MH-S cells were seeded in 6-well plates with the following solutions: PBS + solvent, LPS + solvent, LPS + L1 100nM, LPS + L2 100nM, LPS + L3 100nM, LPS + L4 100nM, LPS + L5 100nM, and LPS + Dex 100nM. When the cells reached 70% confluence, they were starved for 8 hours in serum-free DMEM medium. Then, the solvent, compounds L1-L5 (100nM), and Dex (100nM) were added for 30 minutes each. Following this, PBS or 100 ng / mL LPS was added for 6 hours. The cell supernatant was then collected, and the secretion levels of IL-1β, IL-6, and TNF were detected using an ELISA kit.

[0085] Test results: such as Figure 11 As shown in (D), the levels of TNF-α, IL-6 and IL-1β in the supernatant of LPS-induced MH-S cells were significantly higher than those in the control group. Among them, the inhibitory effect of compound L2 was the most significant at the same dose, and its inhibitory effect on inflammatory factors was not different from that of Dex.

[0086] Specifically: at a dose of 100 nM, the positive control dexamethasone showed inhibition rates (%) of 62.81±2.32, 58.53±1.55, and 63.54±2.38 against TNF-α, IL-6, and IL-1β, respectively; while the test compound L2 at a dose of 100 nM showed inhibition rates (%) of 59.39±3.94, 54.57±1.64, and 61.64±6.56 against TNF-α, IL-6, and IL-1β, respectively, with no statistically significant difference compared to the positive control (Table 2).

[0087] Table 2. Inhibition rate of compound L1-L5 on LPS-induced secretion of inflammatory factors in MH-S cells Group TNF inhibition rate (%) IL-6 inhibition rate (%) IL-1 β inhibition rate (%) NC 99.08±0.09 99.14±0.04 99.16±0.02 LPS-vehicle 0.00±5.89 0.00±2.55 0.00±3.03 LPS-L1 45.24±1.82 41.87±1.34 43.69±8.66 LPS-L2 59.39±3.94 54.57±1.64 61.64±6.56 LPS-L3 50.61±2.55 47.35±1.59 53.02±8.03 LPS-L4 50.19±2.49 42.41±5.40 46.02±4.05 LPS-L5 38.45±1.97 42.19±3.33 38.83±8.41 LPS-DEX 62.81±2.32 58.53±1.55 63.54±2.38 3. The inhibitory effect of the preferred compound L2 on LPS-induced acute lung injury in mice. Establishment of an acute lung injury model: After anesthetizing mice with isoflurane inhalation, the mice were fixed in a supine position on a mouse restraint board. The pharynx of the mice was irradiated with a fiber optic cable, and the tongue of the mice was gently lifted outward with forceps. Tracheal pulsation could be observed through the mouth. At a dose of 10 μL / 10g of mouse body weight, the appropriate volume of LPS solution (final LPS concentration of 4 mg / mL, the control group received an equal volume of physiological saline) was drawn up using a quantitative nebulizer. The quantitative nebulizer was slowly inserted into the trachea to nebulize the corresponding volume of LPS solution. After instilling the LPS solution (or physiological saline), the mice were held upright for about 5 minutes, and then laid supine in the cage to await awakening.

[0088] Intratracheal nebulization administration: The preferred candidate compound L2 was administered via intratracheal nebulization at 2 and 6 hours after LPS instillation at a dose of 0.3 mg / mL, 10 μL / 10g mouse body weight; the Dex positive control group was administered at a dose of 0.3 mg / mL, 10 μL / 10g mouse body weight, and the control and model groups were given only the same volume of solvent.

[0089] Mouse tissue collection: Mice were sacrificed 24 hours after being given LPS. 1 mL of 4% paraformaldehyde (Biosharp-BL539A) was injected into the trachea, and the whole lungs were then immersed in 4% paraformaldehyde solution for 1 week. After paraffin embedding and sectioning, HE staining was performed to observe the infiltration of inflammatory cells in the lungs. The standard Smith scoring method was used to semi-quantitatively score pulmonary edema, alveolar and interstitial inflammation, alveolar and interstitial hemorrhage, atelectasis, and hyaline membrane formation.

[0090] Test results: such as Figure 12 As shown in (A) and (B), compared with the control group (ctrl), HE staining of lung tissue in the model group (LPS) mice showed thickened alveolar walls, inflammatory cell infiltration, and septal edema. After administration of Dex (LPS + Dex 0.3 mg / mL), inflammatory cell infiltration and septal edema in the lung tissue of mice were significantly improved. At the same time, after administration of L2 compound (LPS + L2 0.3 mg / mL), inflammatory cell infiltration and septal edema in the lung tissue of mice were significantly reduced. There was no statistically significant difference in Smith scores between the two groups.

[0091] In summary, these small molecule compounds or combinations thereof with a 2-arcarboxylbenzozaza structure can be used for the prevention or treatment of inflammatory lung diseases, especially acute lung injuries such as severe pneumonia and acute exacerbations of chronic obstructive pulmonary disease.

[0092] The above descriptions are merely some preferred embodiments of the present invention, used to help illustrate the invention. The scope of protection of the present invention is not limited to the above embodiments; all technical solutions falling within the scope of the present invention's concept are within its protection.

Claims

1. The application of a small molecule compound having a 2-arcarboxylbenzozazahexastructure, characterized in that: The small molecule compounds having the 2-arcarboxylbenzozaza structure and their pharmaceutically acceptable salts or cocrystals, deuterated derivatives, solvates, and enantiomers are used to prepare drugs for the prevention and / or treatment of inflammatory lung diseases, or to prepare drugs for the inhibition of inflammatory factors produced by alveolar macrophages. The structural formula of the small molecule compound having a 2-arcarboxylbenzozaza-hexanedioic structure is as follows: ； Where R represents a substituent.

2. The application according to claim 1, characterized in that: The structural formula of the small molecule compound is shown in any of the following: 。 3. The application according to claim 1, characterized in that: The structural formula of the small molecule compound is shown below: 。 4. The application according to any one of claims 1 to 3, characterized in that: The inflammatory lung disease mentioned is acute lung injury.

5. The application according to claim 4, characterized in that: The inflammatory lung disease is lipopolysaccharide-induced acute lung injury.

6. A drug for the prevention and / or treatment of inflammatory lung disease, characterized in that: The active ingredient of the drug is a small molecule compound having a 2-arcarboxylbenzo[a]azine structure; the structural formula of the small molecule compound having the 2-arcarboxylbenzo[a]azine structure is as follows: ； Where R represents a substituent.

7. The drug according to claim 6, characterized in that: The structural formula of the small molecule compound is shown in any of the following: 。 8. The drug according to claim 6, characterized in that: The structural formula of the small molecule compound is shown below: 。

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