KR20150088753A - Composition for preventing or treating acute lung injury and acute respiratory distress syndrome - Google Patents

Abstract

The present invention relates to a composition for preventing or treating an acute lung injury and an acute respiratory distress syndrome by comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indol-7-yl]amine as an active ingredient. According to the present invention, (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indol-7-yl]amine is capable of reducing the total number of inflammatory cells and the number of macrophages, lymphocytes and neutrophils, respectively, in a bronchoalveolar lavage fluid of mouse having a LPS-induced acute lung injury, is capable of significantly reducing a lung injury and an inflammation degree, and is capable of decreasing vascular permeability and protein effusion. Accordingly, the present invention can be usefully used in preventing or treating an acute lung injury and an acute respiratory distress syndrome.

Description

Technical Field [0001] The present invention relates to a composition for preventing or treating acute lung injury and acute respiratory distress syndrome,

The present invention relates to a process for the production of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- To a composition for preventing or treating acute lung injury and acute respiratory distress syndrome.

Acute lung injury (ALI) and its most serious form, acute respiratory distress syndrome (ARDS), are one of the clinically important diseases due to high morbidity and mortality in adults and children. Acute lung injury and acute respiratory distress syndrome were classified according to the criteria of the American-European consensus conference (AECC), in which the left atrial pressure was not high (left atrial pressure 18 mmHg or less) (PaO ₂ / FiO ₂ ) of less than 300 mmHg is defined as acute lung injury. Arterial oxygen partial pressure and inspiratory oxygen concentration (PaO ₂ / FiO ₂ ) of less than 200 mmHg are defined as acute respiratory It is defined as difficulty syndrome.

Acute lung injury and acute respiratory distress syndrome are progressing in the alveoli or progressing in the pulmonary vessels, ultimately leading to a severe inflammatory reaction of the lungs, resulting in various pathophysiological phenomena. Pathological findings of acute lung injury are mainly inflammatory reaction, which causes inflammation cells and proteins to fill the alveoli, air and vitreous membranes in the alveoli, and infiltration of inflammatory cells into the pulmonary interstitium. Many cytokines play a role in this process, especially in the blood coagulation function.

Thus, acute lung injury is a pathologic condition that can be caused by various causes, and it is known that inflammatory cell infiltration around the bronchus, airway hyperresponsiveness, increase of vascular permeability and plasma exudation are accompanied.

The treatment of acute lung injury has been studied by many researchers for a long period of time, but until now the ultimate treatment has not been reached and only the conservative treatment has been stopped, and its mortality rate is very high.

On the other hand, the (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Is a cell necrosis inhibitor, which is a substance that simultaneously exhibits an inhibitory effect on cell death due to toxin or stress, an increase in cell viability, and an antioxidant and anti-inflammatory effect.

Namely, (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol- Although it is known to be effective for a variety of related diseases, it is not known at all about the prevention or treatment of acute lung injury and acute respiratory distress syndrome.

The present inventors have found that in the LPS-induced acute lung injury model, (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1- dioxo-thiomorpholin- - aminopterin, lymphocyte and neutrophil count, lung injury and inflammation, and vascular permeability and protein excretion were reduced in the bronchoalveolar lavage fluid after the treatment with the aminobutyric acid.

The object of the present invention is to provide a process for the preparation of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- And to provide a pharmaceutical composition for preventing or treating acute lung injury and acute respiratory distress syndrome.

In order to achieve the above object, the present invention provides a process for producing (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- -7-yl] amine as an active ingredient. The present invention also provides a pharmaceutical composition for preventing or treating acute lung injury and acute respiratory distress syndrome.

In the present invention, LPS induction (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Acute lung injury In bronchoalveolar lavage fluid of mice, it is effective to reduce the total number of inflammatory cells, macrophages, lymphocytes and neutrophils, mitigate lung injury and inflammation, and reduce vascular permeability and protein exudation As a composition for preventing, treating or ameliorating acute lung injury and acute respiratory distress syndrome.

Hereinafter, the present invention will be described in detail.

Preparation of the compound (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol-7-yl] A method disclosed in Korean Patent Laid-open Publication No. 10-2009-0018593 can be referred to, and the above patent documents are incorporated herein by reference in their entirety.

The compound (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-lH-indol- Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salt. As used herein, "pharmaceutically acceptable salts" refers to those acids that form non-toxic acid addition salts containing a pharmaceutically acceptable anion, for example, inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like; Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like; Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like. In addition, pharmaceutically acceptable base addition salts include alkali metal or alkaline earth metal salts formed by, for example, lithium, sodium, potassium, calcium, magnesium and the like; Amino acid salts such as lysine, arginine and guanidine; Organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline, triethylamine and the like. The compound (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-lH-indol- Can be converted into its salt by a conventional method known in the art, and the preparation of the salt can be easily carried out by a person skilled in the art without further explanation.

&Quot; Isomer "as used herein means an optically or sterically different compound or salt thereof, having the same chemical or molecular formula. The compound (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-lH-indol- May exist as an optical isomer (R or S isomer), a racemate, a mixture of diastereoisomers, individual diastereoisomers, etc., and geometric isomers (trans, cis isomers) may exist. All of these isomers and mixtures thereof are also included within the scope of the present invention.

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H -Indol-7-yl] < / RTI > amine are all included within the scope of the present invention.

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-lH-indol- Induced acute lung injury Reduces the total number of inflammatory cells and macrophages, lymphocytes and neutrophils in bronchoalveolar lavage fluid of mice, significantly alleviates lung injury and inflammation, and decreases vascular permeability and protein exudation. Thus, the (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol- Can be used as a medicament useful for acute lung injury and acute respiratory distress syndrome.

In addition, the composition of the present invention may further comprise at least one pharmaceutically acceptable carrier in addition to the above-described effective ingredients for administration. The pharmaceutically acceptable carrier may be a mixture of two or more of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol or any combination thereof. If necessary, an antioxidant, Other conventional additives such as a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Further, it can be suitably formulated according to each disease or ingredient, using a suitable method in the art or a method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA.

The composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be appropriately determined depending on the patient's weight, age, , Diet, administration time, administration method, excretion rate, severity of disease, and the like. (Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol- The oral route is about 3 to 100 mg / kg, preferably about 10 to 80 mg / kg, or about 0.3 to 50 mg / kg, preferably about 10 to 50 mg / kg for intravenous injection, It is preferable to administer them in divided doses.

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-lH-indol- In the bronchoalveolar lavage fluid of the induced acute lung injury model, the number of total inflammatory cells and macrophages, lymphocytes and neutrophils are reduced, the lung injury and inflammation degree are remarkably mitigated, the vascular permeability and protein exudation are reduced, May be useful for the prevention or treatment of respiratory distress syndrome.

1 is a schematic diagram of a process for preparing (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Amin on the number of inflammatory cells in bronchoalveolar lavage fluid according to the time of drug administration in the mouse model of acute lung injury and acute respiratory distress syndrome.
2 is a schematic diagram showing the synthesis of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Amin is the result of vascular permeability analysis according to the time of drug administration in ALI disease model.
FIG. 3 is a graph showing the effect of the (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- FIG. 2 is a graph showing the results of analysis of inflammatory cells in a dose-dependent bronchoalveolar lavage fluid in an ALI disease model. FIG.
FIG. 4 is a graph showing the effect of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- FIG. 2 is a graph showing the results of capacity-based vascular permeability analysis in an ALI disease model of amines. FIG.
FIG. 5 is a graph showing the effect of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- A graph showing the results of inflammatory cell analysis in bronchoalveolar lavage fluid at two doses in an ALI disease model of amines.
FIG. 6 is a graph showing the effect of the (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- A graph showing vascular permeability analysis results in two doses in an ALI disease model of amines.
7 is a graph showing the effect of the (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Lt; RTI ID = 0.0 > ALI < / RTI > disease model.
FIG. 8 is a graph showing the effect of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- FIG. 4 is a graph showing the results of analysis of reactive oxygen species (ROS) at two doses in an ALI disease model of amines. FIG.
9 is a graph showing the effect of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Lt; / RTI > is a graph showing the results of analysis of pro-inflammatory mediators of lung tissue in ALI animal models of amines.
FIG. 10 is a graph showing the effect of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- This is the result of analysis of signaling system of lung tissue in ALI animal model of amine.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the scope of the present invention is not limited by these examples.

Example 1: Administration of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol- Effect by time

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H -Indol-7-yl] amine was administered to the mice in a total of 5 groups in physiological saline-treated mice (SAL + VEH), LPS-treated mice (LPS + VEH) , 30 mg / kg of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Treated mice (LPS + Compound 30-1h), 30 mg / kg of (tetrahydropyran-4-yl) - [2-phenyl- LPS-treated mice (LPS + Compound 30-8h) administered at 8 hours after LPS treatment, or 30 mg / kg of LPS-treated mice Yl] methyl- lH-indol-7-yl] amine was treated with LPS to give 24 (tetrahydropyran-4-yl) - [2-phenyl- LPS- A ridoen mouse (LPS + Compound 30-24h), experiments per group were used for each of 5 mice. Yl] methyl-lH-indol-7-yl] amine and drug vehicle were injected intraperitoneally with LPS injection 1 hour, 8 hours, or once every 24 hours.

Example 1-1: Synthesis of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Of inflammatory cells in bronchoalveolar lavage fluid according to the time of administration

The mouse model of LPS induced acute lung injury and acute respiratory distress syndrome showed a significant increase in the number of macrophage, lymphocyte, neutrophil, and total inflammatory cells. (Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4- yl) methyl-lH-indol- , The number of total inflammatory cells was significantly decreased with macrophages and neutrophils, and the number of inflammatory cells was significantly decreased in the group administered 1 hour after LPS injection (Fig. 1). However, after 8 hours Indole-7-yl] amine was administered to a test group administered with (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- There was no significant decrease in the number of inflammatory cells.

Example 1-2: Synthesis of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Analysis of vascular permeability according to time of administration

The mouse model of LPS induced acute lung injury and acute respiratory distress syndrome showed a significant increase in pulmonary vascular permeability in total protein amount and EBD analysis in bronchoalveolar lavage fluid. Yl] methyl-lH-indol-7-yl] amine was added to the solution for 1 hour after the injection of LPS Or 8 hours, or 24 hours, the amount of protein exuding into the lumen of the bronchial alveoli from the pulmonary blood vessels was significantly decreased, thereby reducing the vascular permeability. The EBD excreted in association with plasma albumin at 48 hours after LPS injection was (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- 1H-indol-7-yl] amine treated group, but there was no statistical significance, and the drug administration did not significantly affect the vascular permeability (Fig. 2)

Example 2: A minimum of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol- Effective dose

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol-7-yl] (LPS + VEH) treated with drug vehicle, 1 mg / kg (tetrahydropyran-4-yl) -4-methylphenol LPS-treated mice (LPS + Compound) treated with [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) 1), 3 mg / kg of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- ] Amine (LPS + Compound 3), 10 mg / kg of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholine (LPS + Compound 10) or 30 mg / kg of (tetrahydropyran-4-yl) - [2- Phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol-7-yl] The LPS- treated mice (LPS + Compound 30), the experiment per group were used for each of 5 mice. Yl] methyl-lH-indol-7-yl] amine and drug vehicle were injected intraperitoneally with LPS injection And then intravenously at 1 hour and then 24 hours.

Example 2-1 Synthesis of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Analysis of inflammatory cells in bronchoalveolar lavage fluid by dose

The mouse model of LPS induced acute lung injury and acute respiratory distress syndrome showed a significant increase in the number of macrophage, lymphocyte, neutrophil, and total inflammatory cells. (Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-lH-indole- 7-yl] amine 3 mg / kg, 10 mg / kg and 30 mg / kg, the number of total inflammatory cells was significantly decreased with lymphocytes and neutrophils. (Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol-7-yl] Neutrophils, and total inflammatory cells were significantly decreased (Fig. 3).

Example 2-2 Synthesis of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- Of blood vessel permeability

The mouse model of LPS induced acute lung injury and acute respiratory distress syndrome showed significant increase in pulmonary vascular permeability in the amount of protein and EBD analysis in bronchoalveolar lavage fluid. Indol-7-yl] amine 3 mg / kg, 10 (tetrahydrofuran-4-yl) - [2-phenyl- The amount of protein exuded into the lumen of the bronchoalveolar lumen from the pulmonary vessels and the amount of EBD excreted in conjunction with plasma albumin at 48 hours after injection of LPS were significantly decreased in the test group administered with mg / kg and 30 mg / kg to decrease the vascular permeability . (Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol-7-yl] Total protein content and EBD analysis showed no significant effect (Figure 4).

Example 3: LPS induced acute lung injury and acute respiratory distress syndrome In mice model (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1- dioxo-thiomorpholin- Methyl-lH-indol-7-yl] amine

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H -Indol-7-yl] amine The experimental groups were physiological saline-treated mice (SAL + VEH), LPS-treated mice (LPS + VEH) administered with drug vehicle, (10 mg / kg) of (tetrahydropyran-4-yl) - [2-phenyl- (LPS + Compound 10) or 30 mg / kg of (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholine- -Yl) methyl-1H-indol-7-yl] amine was administered to each of six mice in each experimental group with LPS-treated mice (LPS + Compound 30). Yl] methyl-lH-indol-7-yl] amine and drug vehicle were injected intraperitoneally with LPS injection And then intravenously at 1 hour and then 24 hours.

Example 3-1: Analysis of inflammatory cells in bronchoalveolar lavage fluid according to dose

The mouse models of LPS-induced acute lung injury and acute respiratory distress syndrome showed a significant increase in the number of total inflammatory cells with increasing numbers of macrophages, lymphocytes and neutrophils (tetrahydropyran-4-yl) - [2-phenyl- In the test group in which 30 mg / kg of 5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol-7-yl] amine was administered, the number of total inflammatory cells together with lymphocytes and neutrophils Respectively. (Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol-7-yl] Lymphocytes were significantly decreased and the number of neutrophils and total inflammatory cells decreased (Figure 5)

Example 3-2: Analysis of Vascular Permeability by Capacity

The mouse model of LPS induced acute lung injury and acute respiratory distress syndrome showed a significant increase in pulmonary vascular permeability in total protein amount and EBD analysis in bronchoalveolar lavage fluid. 10 mg / kg, 30 (tetrahydropyran-4-yl) - [2-phenyl- mg / kg, the amount of protein exuded into the lumen of the bronchoalveolar lumen from the pulmonary veins and the EBD excreted in conjunction with plasma albumin decreased significantly after 48 hours of LPS injection, resulting in decreased vascular permeability. 6)

Example 3-3: Analysis of pathological changes by dose

Histopathological examination and Micro-CT showed that (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- The drug-administered group with primary amines reduced pathological factors and changes such as increased airway inflammatory cell infiltration, vitreous deposition, microthrombi formation in the LPS-induced pulmonary inflammatory response (Figure 7)

Example 3-4: Analysis of ROS by Capacity

The mouse model of LPS - induced acute lung injury and acute respiratory distress syndrome showed a significant increase in intracellular ROS in mitochondrial ROS expression and inflammatory cells infiltrating into the bronchial alveoli. 10 mg / kg, 30 (tetrahydropyran-4-yl) - [2-phenyl- mg / kg, the mitochondrial ROS expression was significantly decreased and the intracellular ROS level was also significantly decreased (Fig. 8).

Example 3-5: Analysis of pro-inflammatory mediators by dose

Expression of IL-1b, NLRP-3, VEGF, KC, IL-17 and TNF-α protein significantly increased in LPS- (30 mg / kg) in the drug administration group administered with 10 mg / kg and 30 mg / kg, respectively, (Fig. 9). ≪ RTI ID = 0.0 >

Example 3-6: Capacity-based signal transmission system analysis

In the mouse model of LPS-induced acute lung injury and acute respiratory distress syndrome, nuclear translocation of NF-kB p65 and TLR4 expression were significantly increased. 10 mg / kg, 30 (tetrahydropyran-4-yl) - [2-phenyl- mg / kg, significantly decreased TLR4 protein expression and decreased nuclear potential of NF-kB p65 (Figure 10).

As described above, the (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- -Yl] amine significantly inhibits the expression of inflammatory cells, the increase of inflammatory cells in the bronchoalveolar lavage fluid and the increase of vascular permeability, which plays an important role in the acute lung injury caused by bacterial infection, and the acute lung injury And acute respiratory distress syndrome.

Hereinafter, examples of pharmaceutical formulations of the pharmaceutical composition according to the present invention are exemplified.

Formulation Example 1: Preparation of pharmaceutical preparations

(1) Manufacture of powders

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4- yl) methyl-lH-indol- 100 mg

Lactose 100 mg

The above components were mixed and packed in airtight bags to prepare powders.

(2) Production of tablets

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4- yl) methyl-lH-indol- 100 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

(3) Preparation of capsules

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4- yl) methyl-lH-indol- 100 mg

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

(4) Preparation of injection

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4- yl) methyl-lH-indol- 100 mg

Mannitol 100 mg

_{Na 2 HPO 4 · 2H 2 O} 2 ㎎

Sterile sterilized water for injection Suitable amount

The above components were mixed according to the usual injection preparation method to prepare an injection (2 ml) per ampoule.

Claims (5)

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-1H-indol-7-yl] A pharmaceutical composition for preventing or treating acute lung injury and acute respiratory distress syndrome. 4. The compound of claim 1 which is (tetrahydropyran-4-yl) - [2- phenyl-5- (1,1-dioxo-thiomorpholin- Is a pharmaceutical composition for preventing or treating acute lung injury and acute respiratory syndrome characterized by reducing the total number of inflammatory cells and macrophages, lymphocytes and neutrophils in bronchoalveolar lavage fluid of an acute lung injury model. 4. The compound of claim 1 which is (tetrahydropyran-4-yl) - [2- phenyl-5- (1,1-dioxo-thiomorpholin- Is a pharmaceutical composition for preventing or treating acute lung injury and acute respiratory distress syndrome characterized by decreasing vascular permeability and protein exudation in bronchoalveolar lavage fluid of an acute lung injury model. 4. The compound of claim 1 which is (tetrahydropyran-4-yl) - [2- phenyl-5- (1,1-dioxo-thiomorpholin- Is a pharmaceutical composition for preventing or treating acute lung injury and acute respiratory distress syndrome characterized by reducing intracellular mitochondrial reactive oxygen species in bronchoalveolar lavage fluid of an acute lung injury model. 4. The compound of claim 1 which is (tetrahydropyran-4-yl) - [2- phenyl-5- (1,1-dioxo-thiomorpholin- Is a pharmaceutical composition for preventing or treating acute lung injury and acute respiratory distress syndrome characterized by reducing various inflammatory cytokines in bronchoalveolar lavage fluid and lung tissue of an acute lung injury model.

Images