Use of 4-amino-1-benzylpiperidine for the preparation of a medicament for the prevention and / or treatment of acute lung injury

Abstract

The application belongs to the technical field of medicine, and discloses application of 4-amino-1-benzylpiperidine in a drug for preventing and / or treating acute lung injury. The application carries out experimental research on the effect of 4-amino-1-benzylpiperidine in preventing and / or treating acute lung injury through in-vivo and in-vitro models, and the result shows that 4-amino-1-benzylpiperidine can significantly inhibit neutrophil chemotaxis, reduce the number of inflammatory cells and the release of inflammatory factors in bronchoalveolar lavage fluid of an animal with LPS-induced acute lung injury, and improve pathological damage of lung tissue, and can be used for preparing a protective drug for acute lung injury. The application provides a new use of 4-amino-1-benzylpiperidine in preparing a protective drug for acute lung injury, and provides a safe, effective and economical solution for treatment and prevention of acute lung injury.

Description

TECHNICAL FIELD

[0001] The present application relates to a new application of 4-amino-1-benzylpiperidine in the preparation of drugs, to a pharmaceutical composition containing 4-amino-1-benzylpiperidine; to the use of 4-amino-1-benzylpiperidine and its pharmaceutical composition in the preparation of drugs for preventing and / or treating acute lung injury, belonging to the technical field of medicine. BACKGROUND

[0002] Respiratory diseases have high incidence and heavy disease burden. Common respiratory diseases, whether acute (such as acute lung injury, bacterial pneumonia, viral pneumonia, etc.) or chronic (chronic obstructive pulmonary disease, asthma, bronchiectasis, pulmonary fibrosis, etc.), all have airway inflammation and varying degrees of damage to airway structure and function, so improving airway inflammation and protecting airway function are the main treatment strategies for treating respiratory diseases. Glucocorticoids are used for the treatment of respiratory diseases by inhibiting airway inflammation, including acute lung injury / acute respiratory distress syndrome, chronic obstructive pulmonary disease, asthma, etc. caused by various reasons, but they increase the risk of lung infection and have various side effects such as endocrine disorders, gastrointestinal ulceration and hemorrhage, femoral head necrosis, etc. There is an urgent need for new safe and effective drugs for the treatment of respiratory diseases in clinical practice.

[0003] Acute lung injury is caused by non-cardiogenic various internal and external pathogenic factors to damage lung capillary endothelial cells and alveolar epithelial cells, and then cause alveolar capillary barrier damage, lung inflammatory cell infiltration, diffuse alveolar and interstitial edema, leading to acute hypoxic respiratory insufficiency, which is clinically manifested as dyspnea, hypoxemia, etc. In severe cases, it can develop into acute respiratory distress syndrome, respiratory failure, etc., and even endanger life, with a mortality rate of 30% to 50% after the onset of the disease. Even if they survive, their lung function is severely damaged, affecting the quality of life of patients, and bringing huge medical and economic burden to patients, families and society.

[0004] Neutrophils play a key role in the occurrence and development of acute lung injury. Once they are recruited from the blood circulation to the lung tissue, they release cytotoxic molecules, leading to lung tissue damage. The main pathological changes of acute lung injury are the aggregation of a large number of neutrophils and the destruction of alveolar-capillary barrier, and the uncontrolled inflammatory response caused by the aggregation, activation and apoptosis of a large number of neutrophils is the fundamental cause of acute lung injury caused by various causes. In lung injury caused by infectious and non-infectious factors, neutrophils accumulate and activate in the lung microcirculation system, release a variety of toxic mediators (including proteases, pro-inflammatory cytokines and pro-coagulation molecules) and degranulation, causing increased vascular permeability and loss of endothelial barrier function, ultimately leading to a clinical syndrome characterized by respiratory distress and progressive hypoxemia, which can develop into acute respiratory distress syndrome, respiratory failure, etc. in severe cases.

[0005] At present, the treatment measures of acute lung injury and acute respiratory distress syndrome are still mainly supportive, aiming to improve the gas exchange of the lung and prevent the oxygen supply deficiency of other tissues and organs, and prevent the occurrence of complications. Although various drugs are used for the treatment of acute lung injury, there is no effective drug that can reduce mortality. Therefore, finding effective drugs for the treatment of acute lung injury has become a research hotspot.

[0006] At present, there is no report on the activity of 4-amino-1-benzylpiperidine, and there is no report on its prevention and treatment effect on acute lung injury. SUMMARY

[0007] Therefore, the purpose of the present application is to provide the application of 4-amino-1-benzylpiperidine in the preparation of drugs for preventing and / or treating acute lung injury, in order to solve the problems in the prior art. The present application finds that 4-amino-1-benzylpiperidine has great clinical application value by inhibiting neutrophil chemotaxis, reducing the number of inflammatory cells, reducing the release of inflammatory factors, and improving the pathological damage of lung tissue.

[0008] To achieve the above-mentioned purpose, the present application provides the following scheme:

[0009] The present application provides the application of 4-amino-1-benzylpiperidine as shown in formula I in the preparation of drugs for preventing and / or treating acute lung injury.

[0010]

[0011] The 4-amino-1-benzylpiperidine is an organic compound, and the molecular formula is C12H18N2, and the molecular weight is 190.29.

[0012] Further, the present application provides the application of 4-amino-1-benzylpiperidine, or a pharmaceutically acceptable salt, a solvate thereof, or a solvate of the salt thereof in the preparation of drugs for preventing and / or treating acute lung injury.

[0013] Further, the acute lung injury is a disease with lung inflammation as the main pathological feature caused by excessive accumulation and activation of neutrophils in lung tissue.

[0014] Further, 4-amino-1-benzylpiperidine treats acute lung injury by reducing lung inflammation.

[0015] Further, the reduction of lung inflammation includes inhibiting neutrophil chemotaxis, reducing the number of inflammatory cells, reducing the release of inflammatory factors, and improving the pathological damage of lung tissue.

[0016] The present application also provides a use of a pharmaceutical composition in the preparation of a medicament for preventing and / or treating acute lung injury, characterized in that the pharmaceutical composition is 4-amino-1-benzylpiperidine or a pharmaceutically acceptable salt thereof as shown in formula I and a pharmaceutically acceptable carrier or excipient.

[0017]

[0018] The pharmaceutical preparation can be prepared according to the methods known in the art. The 4-amino-1-benzylpiperidine of the present application can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to form any dosage form for human or animal use. The content of the compound of the present application in the pharmaceutical composition thereof is usually 0.1-99%.

[0019] Further, the pharmaceutical preparation includes oral preparations or non-oral administration dosage forms.

[0020] Further, the oral preparation is tablets, capsules, dripping pills, liquid preparations; the non-oral administration dosage form is intramuscular injection, intravenous injection, intravenous drip, skin administration, mucosal administration.

[0021] The administration dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid dosage form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), eye drops, nose drops, lotion and liniment, etc.; the solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, oral disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosol (powder) sprays, spray, etc.; the semi-solid dosage form can be ointments, gels, pastes, etc.

[0022] The compound of the present application can be prepared into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle administration systems.

[0023] For the preparation of tablets of the present compound, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agents can be water, ethanol, isopropyl alcohol, etc.; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, acacia paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, carboxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the 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 dodecylsulfate, etc.; the lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0024] The tablets can also be further prepared into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0025] For the preparation of capsules of the administration unit, the effective ingredient, the present compound, can be mixed with diluents and glidants, and the mixture can be directly placed in hard or soft capsules. The effective ingredient, the present compound, can also be mixed with diluents, binders and disintegrants to prepare granules or pellets, and then placed in hard or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used for the preparation of tablets of the present compound can also be used for the preparation of capsules of the present compound.

[0026] For the preparation of injections of the present compound, water, ethanol, isopropyl alcohol, propylene glycol or their mixtures can be used as solvents, and appropriate amounts of solubilizers, co-solvents, pH adjustors and osmotic pressure adjustors commonly used in the art can be added. The solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjustors can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjustors can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If lyophilized powder injections are prepared, mannitol, glucose, etc. can also be added as supporting agents.

[0027] In addition, if desired, coloring agents, preservatives, flavoring agents, corrigents, or other additives can also be added to the pharmaceutical preparation. The pharmaceutical or pharmaceutical composition of the present application can be administered by any known method of administration in order to achieve the intended purpose, to enhance the therapeutic effect. The dosage of the pharmaceutical composition of the compound of the present application 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, etc. Generally, the suitable dosage of the compound of the present application per day is in the range of 0.001-100 mg / kg of body weight. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the administration schedule including the use of other therapeutic means.

[0028] The compound of the present application can be administered alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present application has a synergistic effect with other therapeutic drugs, the dosage thereof should be adjusted according to the actual situation. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 4-Amino-1-benzylpiperidine inhibits chemotaxis of neutrophils in vitro.

[0030] Figure 2 4-Amino-1-benzylpiperidine reduces lung tissue wet / dry weight ratio in acute lung injury.

[0031] Figure 3 4-Amino-1-benzylpiperidine reduces the number of inflammatory cells in bronchoalveolar lavage fluid in acute lung injury.

[0032] Figure 4 4-Amino-1-benzylpiperidine reduces the release of inflammatory factors in bronchoalveolar lavage fluid in acute lung injury.

[0033] Figure 5 4-Amino-1-benzylpiperidine improves pathological changes in lung tissue after acute lung injury. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical scheme, advantages of the present application more clear, the present application will be further described in detail below with reference to the accompanying drawings.

[0035] Example 1: Effect of 4-amino-1-benzylpiperidine on chemotaxis of neutrophils in vitro

[0036] The male SD rats with the weight of 140-160 g were used in the experiment. The blood was taken from the abdominal aorta after the rats were anesthetized with chloral hydrate. The peripheral blood was extracted from the rats and then separated. The 3.8% sodium citrate solution 1:9 was added for anti-coagulation and to separate the neutrophils. The separated neutrophils were identified by the trypan blue rejection experiment and Giemsa staining experiment. The cell viability and purity were both greater than 90%. The extracted cells were cultured in the 96-well chemotaxis plate using the RPMI-1640 medium. The cells were divided into the normal control group, the model group, the model+positive drug group (10 μg / mL), and the model+4-amino-1-benzylpiperidine group (1, 3, 10 μg / mL). 50 μL of the neutrophils (density: 5×10 4 The liquid in the upper chamber was aspirated after the cells were cultured in the incubator at 37 degrees and in the 5% CO2 condition for 3 hours. The Giemsa staining solution was added to the lower chamber for staining. Then, the pictures were collected by the inverted microscope and the cell number was counted.

[0037] The results are shown in Table 1. Figure 1 Compared with the normal control group, the neutrophil chemotaxis in the model group was obviously increased. Compared with the model group, 4-amino-1-benzylpiperidine could inhibit the neutrophil chemotaxis in a dose-dependent manner, and the effect of the high-dose group was the most obvious. The experimental results showed that 4-amino-1-benzylpiperidine could inhibit the neutrophil chemotaxis.

[0038] Table 1 The effect of 4-amino-1-benzylpiperidine on the neutrophil chemotaxis in vitro.

[0039]

[0040] Example 2: The effect of 4-amino-1-benzylpiperidine on the lung tissue wet / dry weight ratio of acute lung injury

[0041] BALB / c mice were purchased from Vantianlihua (Beijing Vantianlihua Experimental Animal Technology Co., Ltd.), with a body weight range of 18-22 g, and were anesthetized with isoflurane. 20-30 minutes after anesthesia, 50 μl (concentration of 8 mg / ml), a total of 400 μg of LPS was dripped into the nose; the normal control group of mice was dripped with the same volume of normal saline. After modeling, the mice were placed in a 37°C constant temperature system. The mice in each group were fasted the night before modeling, and half an hour and 12 hours after the mice inhaled LPS, the mice were injected intraperitoneally with 4-amino-1-benzylpiperidine prepared with normal saline according to the dose, and the normal control group and the model group were given the corresponding volume of normal saline. The experiment was divided into a sham operation group, a model group, a positive drug group (cethexonium sodium, 50 mg / kg), and 4-amino-1-benzylpiperidine (25, 50, 100 mg / kg). 24 hours after the end of modeling, the left lung was weighed, and then baked in a 60-degree constant temperature oven for 48 hours until the dry weight was constant, and the dry weight was weighed to calculate the wet / dry weight ratio (W / D) of the lung.

[0042] The results are shown in Table 2. Figure 2 Compared with the normal control group, the lung W / D of the model group increased significantly. Compared with the model group, 4-amino-1-benzylpiperidine can dose-dependently reduce lung edema caused by acute lung injury, and the high-dose group has the most obvious effect. The experimental results show that 4-amino-1-benzylpiperidine can significantly improve lung edema caused by acute lung injury.

[0043] Table 2 Effect of 4-amino-1-benzylpiperidine on the lung tissue wet / dry weight ratio of acute lung injury.

[0044]

[0045] Example 3: Effect of 4-amino-1-benzylpiperidine on the number of inflammatory cells in bronchoalveolar lavage fluid of acute lung injury.

[0046] The animal modeling and drug administration method are the same as in Example 3. After 24 hours of acute lung injury, bronchoalveolar lavage was performed, and the lavage fluid was collected for cell classification and statistics, and then Giemsa staining was used to count the number of inflammatory cells.

[0047] The results are shown in Table 2. Figure 3 As shown in Table 2, 24 hours after acute lung injury, the number of total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid of the model group mice increased significantly compared with the normal control group. Compared with the model group, each dose of 4-amino-1-benzylpiperidine can reduce the number of total cells, neutrophils, and macrophages, and the high-dose group has the most obvious effect. The experimental results show that 4-amino-1-benzylpiperidine can significantly reduce the increase in the number of inflammatory cells caused by acute lung injury.

[0048] Table 4 Effect of 4-amino-1-benzylpiperidine on the release of inflammatory factors in the bronchoalveolar lavage fluid of acute lung injury.

[0049]

[0050] Example 4: Effect of 4-amino-1-benzylpiperidine on the concentration of inflammatory factors in the bronchoalveolar lavage fluid of acute lung injury.

[0051] The animal modeling and administration method were the same as in Example 3. After 24 hours of acute lung injury, bronchoalveolar lavage was performed, and the expression levels of IL-6, TNF-α and IL-1β in the bronchoalveolar lavage fluid were detected by a kit.

[0052] The results are shown in Table 3. After 24 hours of acute lung injury, the concentrations of IL-6, TNF-α and IL-1β in the bronchoalveolar lavage fluid of the model group mice were significantly higher than those of the normal control group. Compared with the model group, 4-amino-1-benzylpiperidine dose-dependently reduced the concentrations of inflammatory factors, and the effect of the high-dose group was the most obvious. The experimental results showed that 4-amino-1-benzylpiperidine could significantly improve the release of inflammatory factors caused by acute lung injury. Figure 4

[0053] Table 4 Effect of 4-amino-1-benzylpiperidine on the release of inflammatory factors in the bronchoalveolar lavage fluid of acute lung injury.

[0054]

[0055] Example 5: Effect of 4-amino-1-benzylpiperidine on the pathological changes of lung tissue after acute lung injury.

[0056] The animal modeling and administration method were the same as in Example 3. After 24 hours of acute lung injury, the left lung was removed, and part of the left lung tissue was fixed in a 4% paraformaldehyde solution for 48 hours for pathological section analysis.

[0057] The results are shown in Table 3. After 24 hours of acute lung injury, the concentrations of IL-6, TNF-α and IL-1β in the bronchoalveolar lavage fluid of the model group mice were significantly higher than those of the normal control group. Compared with the model group, 4-amino-1-benzylpiperidine dose-dependently reduced the concentrations of inflammatory factors, and the effect of the high-dose group was the most obvious. The experimental results showed that 4-amino-1-benzylpiperidine could significantly improve the release of inflammatory factors caused by acute lung injury. Figure 5

[0058] ​​In summary, the therapeutic effect of 4-amino-1-benzylpiperidine on acute lung injury was investigated by in vitro neutrophil and acute lung injury animal model. The results showed that 4-amino-1-benzylpiperidine significantly inhibited neutrophil chemotaxis in in vitro experiment. In in vivo experiment, intraperitoneal injection of 4-amino-1-benzylpiperidine significantly reduced the number of inflammatory cells in bronchoalveolar lavage fluid and the release of inflammatory factors caused by LPS, and improved the pathological damage of lung tissue. Therefore, 4-amino-1-benzylpiperidine has the effect of preventing and / or treating acute lung injury. Using 4-amino-1-benzylpiperidine as an active substance, alone or / and with other compounds and / or extracts with pharmacological activity to form a compound, according to the conventional preparation method in the field of pharmacy, various dosage forms of anti-acute lung injury drugs are prepared, or other anti-acute lung injury drugs are prepared into compound preparations, which can be used to reduce adverse reactions in drug action while maintaining efficacy, and can provide a safe, effective and economical solution for the prevention and treatment of acute lung injury.

[0059] Finally, it should be pointed out that the above examples are only used to illustrate the technical solutions of the present application and are not limiting. Although the present application has been described by referring to the preferred embodiments of the present application, it should be understood by those skilled in the art that various changes in form and details can be made without departing from the spirit and scope of the present application defined in the appended claims.

Claims

1. Use of 4-amino-1-benzylpiperidine or its pharmaceutically acceptable salt as shown in formula I in the preparation of a medicament for preventing and / or treating acute lung injury.

2. Use according to claim 1, characterized in that, The acute lung injury is an acute and persistent inflammatory reaction syndrome of lung, which causes diffuse pulmonary interstitial and edema by damaging alveolar epithelial cells and capillary endothelial cells, leading to progressive hypoxemia, non-cardiogenic pulmonary edema and acute respiratory distress syndrome.

3. Use according to claim 2, characterized in that, The acute lung injury is a disease with lung inflammation as the main pathological feature, which is caused by excessive accumulation and activation of neutrophils in lung tissue.

4. Use according to claim 1, characterized in that, 4-amino-1-benzylpiperidine treats acute lung injury by reducing lung inflammatory response.

5. Use according to claim 4, characterized in that, The reduction of lung inflammation includes inhibiting neutrophil chemotaxis, reducing the number of inflammatory cells, reducing the release of inflammatory factors, and improving lung tissue pathological damage.

6. Use according to claim 5, characterized in that, The inflammatory cells include neutrophils, eosinophils, monocytes, macrophages and lymphocytes; the inflammatory factors include TNF-α, IL-6, IL-1β and chemotactic factors.

7. Use of a pharmaceutical composition for the manufacture of a medicament for the prevention and / or treatment of acute lung injury, characterized in that, The pharmaceutical composition is 4-amino-1-benzylpiperidine or its pharmaceutically acceptable salt as shown in formula I and a pharmaceutically acceptable carrier or excipient.

8. Use according to claim 7, characterised in that, The pharmaceutical composition can be prepared into oral preparations or non-oral preparations.

9. Use according to claim 8, characterised in that, The oral preparations include tablets, capsules, dripping pills, liquid preparations; the non-oral preparations include intramuscular injection, intravenous injection, intravenous infusion, skin administration and mucosal administration.

10. Use according to claim 8, characterised in that, The oral preparations can be prepared into sustained-release preparations or controlled-release preparations.

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