WO2015111947A1 - Composition for preventing or treating acute lung injury and acute respiratory distress syndrome - Google Patents
Composition for preventing or treating acute lung injury and acute respiratory distress syndrome Download PDFInfo
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- WO2015111947A1 WO2015111947A1 PCT/KR2015/000708 KR2015000708W WO2015111947A1 WO 2015111947 A1 WO2015111947 A1 WO 2015111947A1 KR 2015000708 W KR2015000708 W KR 2015000708W WO 2015111947 A1 WO2015111947 A1 WO 2015111947A1
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- thiomorpholine
- tetrahydropyran
- dioxo
- indole
- methyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Definitions
- the present invention relates to the composition comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine as an active ingredient for preventing or treating acute lung injury and acute respiratory distress syndrome.
- ALI and ARDS are defined as follows: According to the AECC (American-European Consensus Conference) criteria, given that the pressure of the left atrium is not high (equal to or less than 18 mmHg) and an assessment of pulmonary edema according to chest X-ray examination indicates the increase of shade in both lungs, in ALI the ratio of the partial pressure of oxygen in the arterial blood to the fraction of oxygen in the inhaled air (PaO 2 /FiO 2 ) is equal to or less than 300 mmHg, whereas in ARDS the PaO 2 /FiO 2 ratio is equal to or less than 200 mmHg.
- AECC American-European Consensus Conference
- ALI and ARDS show various pathophysiological phenomena with severe inflammatory reaction in the lungs for cases of development in both alveoli and pulmonary blood vessels. From the view of pathology for ALI, mainly inflammatory cells and proteins are filled in alveoli instead of air, hyaline membrane is generated, and inflammatory cells permeate into even the pulmonary interstitium. In this stage, various cytokines play a role in particular for dysfunctional vascular coagulation.
- ALI is the pathology which can occur from various causes as described above, accompanying permeation of the inflammatory cells around bronchial cells, hypersensitive airways, increase in vascular permeability and exudation of plasma.
- the present inventors have carried out the present invention by verifying reduction for the total number of inflammatory cells, macrophages, lymphocytes and neutrophils, and the degrees of lung damage and inflammation; and the resolution of vascular permeability and protein exudation after treating with (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in a lipopolysaccharide (LPS)-induced ALI model.
- LPS lipopolysaccharide
- the object of the present invention is to provide a pharmaceutical composition for preventing or treating ALI and ARDS by using (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine.
- the present invention provides a pharmaceutical composition comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine as an active ingredient for preventing or treating ALI and ARDS.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine as an active ingredient for prevention, treatment or relief of ALI and ARDS by using the effect thereof for reducing the number of inflammatory cells, macrophages, lymphocytes and neutrophils, in a bronchoalveolar lavage of mice having LPS-induced ALI, relief of a degree of lung damage and inflammation, and reduction of vascular permeability and protein exudation.
- the method for preparing the compound of the present invention can refer to the process disclosed in Korean Patent Application Publication No. 10-2009-0018593. The above document will be wholly contained in this specification as a reference.
- the compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention can also form a pharmaceutically acceptable salt.
- Such a “pharmaceutically acceptable salt” includes non-toxic acid addition salt containing a pharmaceutically acceptable anion ⁇ for example, a salt with inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc.; a salt with 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, etc.; or a salt with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.
- a salt with inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid,
- a pharmaceutically acceptable base addition salt thereof would include, for example, a salt with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, etc.; a salt with amino acids such as lysine, arginine, guanidine, etc.; or an organic salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc.
- the compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention may be converted to salts thereof according to any of the conventional methods, and the salt formation could be easily carried out by a skilled artisan without additional explanations thereon.
- the term “isomer” in the present invention means those compounds having the same chemical or molecular formula as, but optically or sterically different from, the compounds or salts thereof.
- the compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention may have an asymmetric carbon center(s) in the structure, and so may exist in the form of an optical isomer (R or S isomer), racemate, mixture of diastereomers, an individual diastereomer, or a geometric isomer (trans or cis isomer) etc. All the isomers and their mixtures are also covered by the present invention.
- the compounds of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention may include pharmaceutically acceptable salts and isomers thereof, unless otherwise indicated.
- the compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine can reduce the number of inflammatory cells, macrophages, lymphocytes and neutrophils in a bronchoalveolar lavage of mice having LPS-induced ALI, relieve a degree of lung damage and inflammation, and reduce vascular permeability and protein exudation.
- the compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention can be used as a medicament in the treatment of ALI and ARDS.
- composition of the present invention can be prepared by further comprising at least one pharmaceutically acceptable carrier other than the ingredient as stated above.
- pharmaceutically acceptable carriers include saline, sterilized water, Ringer’s solution, buffered saline, dextrose solution, maltodextrin solution, glycerol or ethanol, or can be used by mixing at least two selected from specified components. If needed, other conventional additives such as antioxidant, buffer solution, bacteriostatic agent etc. can be added.
- the formulation for injection as an aqueous solution, a suspension, an emulsion, a pill, a capsule, a granule or a tablet can also be prepared by adding a diluent, a dispersant, a surfactant, a binder and/or a lubricant. Furthermore, the formulation can be prepared by using the proper method in the art or the method disclosed in Remington’s Pharmaceutical Science (newest edition), Mack Publishing Company: Easton, PA.
- composition of the present invention can be administered orally or parenterally (for example, by intravenous, subcutaneous, intraperitoneal or local administration).
- the dose can include various ranges depending on body weight, age, sex, physical condition, diet, dosing time, dosing method, clearance of the patient and severance of disease.
- the daily dose of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine is, by oral administration, approximately 3 ⁇ 100 mg/kg, preferably approximately 10 ⁇ 80 mg/kg, or by intravenous one, approximately 0.3 ⁇ 50mg/kg, preferably approximately 10 ⁇ 50mg/kg. Dosing once a day or several times per a day is acceptable.
- Fig. 1 shows the result regarding the effect of dosing time for (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention on the number of inflammatory cells in a bronchoalveolar lavage in a mouse model of ALI and ARDS.
- Fig. 2 shows the result of analyzing vascular permeability with dosing time for (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Fig. 3 shows the result of analyzing inflammatory cells in a bronchoalveolar lavage with various doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Fig. 4 shows the result of analyzing vascular permeability with various doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Fig. 5 shows the result of analyzing inflammatory cells in a bronchoalveolar lavage with two doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Fig. 6 shows the result of analyzing vascular permeability with two doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Fig. 7 shows the result of analyzing pathological alteration with two doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Fig. 8 shows the result of analyzing reactive oxygen species (ROS) with two doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- ROS reactive oxygen species
- Fig. 9 shows the result of analyzing pro-inflammatory mediators in lung tissue with (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Fig. 10 shows the result of analyzing the signaling pathways of lung tissue with (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Example 1 Effect of the dosing time of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine
- Test groups of dosing time of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in a mouse model of ALI and ARDS consisting of a total of 5 groups are as follows: i) saline-treated mice to which a drug vehicle was administered (SAL+VEH), ii) LPS-treated mice to which a drug vehicle was administered (LPS+VEH), iii) LPS-treated mice to which 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered at 1 hr after the LPS treatment (LPS+Compound30-1h), iv) LPS-treated mice to which 30 mg/kg of (tetrahydropyr
- mice were used in each test group.
- (Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine and a drug vehicle were administered once by intravenous route after 1 hr, 8 hrs or 24 hrs following injection of LPS.
- Example 1-1 Result regarding the effect of dosing time for (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine on the number of inflammatory cells in a bronchoalveolar lavage
- Example 1-2 Result of analyzing vascular permeability with dosing time for (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in a disease model of ALI
- Test groups regarding the minimal effective dose of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine consisting of a total of 6 groups are as follows: i) saline-treated mice to which a drug vehicle was administered (SAL+VEH), ii) LPS-treated mice to which a drug vehicle was administered (LPS+VEH), iii) LPS-treated mice to which 1 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered (LPS+ Compound 1), iv) LPS-treated mice to which 3 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-
- mice were used in each test group.
- (Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine and a drug vehicle were administered once intravenously after 1 hr and 24 hrs thereafter following injection of LPS.
- Example 2-1 Result of analyzing inflammatory cells in a bronchoalveolar lavage with various doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine
- Example 2-2 Result of analyzing vascular permeability with various doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
- Example 3 The effect of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in an LPS-induced mouse model of ALI and ARDS
- Test groups regarding the effect of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in an LPS-induced mouse model of ALI and ARDS consisting of a total of 4 groups are as follows: i) saline-treated mice to which a drug vehicle was administered (SAL+VEH), ii) LPS-treated mice to which a drug vehicle was administered (LPS+VEH), iii) LPS-treated mice to which 10 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine (LPS+ Compound 10) was administered and iv) LPS-treated mice to which 30 mg/kg of (tetrahydropyran-4-yl)-[2-phen
- mice were used in every test group.
- (Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine, and a drug vehicle were administered once intravenously after 1 hr and 24 hrs thereafter following injection of LPS.
- Example 3-1 Analysis of inflammatory cells in a bronchoalveolar lavage with various doses
- Example 3-2 Analysis of vascular permeability with various doses
- Example 3-5 Analysis of pro-inflammatory mediator with various doses
- Powder was prepared by mixing the above components and filling them to seal.
- Tablet was prepared according to the conventional method of preparing a tablet by compression after mixing the above components.
- Capsule was prepared according to the conventional method of preparing a capsule by filling into a gelatin capsule after mixing the above components.
- Injectable formulation per 1 ampule (2 ml) was prepared according to the conventional method of preparing injections by mixing the above components.
Abstract
The present invention relates to the composition comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine as an active ingredient for preventing or treating acute lung injury and acute respiratory distress syndrome. (Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention can be used for prevention, or treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) by reducing the number of inflammatory cells, macrophages, lymphocytes and neutrophils in a bronchoalveolar lavage of mice having LPS-induced ALI, relief of a degree of lung damage and inflammation, and reduction of vascular permeability and protein exudation.
Description
The present invention relates to the composition comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine as an active ingredient for preventing or treating acute lung injury and acute respiratory distress syndrome.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) corresponding to the most serious form of ALI are clinically important diseases due to their high morbidity and mortality in infants as well as adults. ALI and ARDS are defined as follows: According to the AECC (American-European Consensus Conference) criteria, given that the pressure of the left atrium is not high (equal to or less than 18 mmHg) and an assessment of pulmonary edema according to chest X-ray examination indicates the increase of shade in both lungs, in ALI the ratio of the partial pressure of oxygen in the arterial blood to the fraction of oxygen in the inhaled air (PaO2/FiO2) is equal to or less than 300 mmHg, whereas in ARDS the PaO2/FiO2 ratio is equal to or less than 200 mmHg.
ALI and ARDS show various pathophysiological phenomena with severe inflammatory reaction in the lungs for cases of development in both alveoli and pulmonary blood vessels. From the view of pathology for ALI, mainly inflammatory cells and proteins are filled in alveoli instead of air, hyaline membrane is generated, and inflammatory cells permeate into even the pulmonary interstitium. In this stage, various cytokines play a role in particular for dysfunctional vascular coagulation.
ALI is the pathology which can occur from various causes as described above, accompanying permeation of the inflammatory cells around bronchial cells, hypersensitive airways, increase in vascular permeability and exudation of plasma.
Many researchers have studied treatment of ALI for a long period. However, they did not achieve eventual success but applied conservative treatment, and thus the fatality of ALI has remained high.
In the meantime, (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine has been known as a compound which can indicate an inhibitory effect of cell death from toxin or stress, increasing the effect of cell viability and antioxidant and anti-inflammatory effect as well as being an inhibitor of cell necrosis specifically for mitochondria.
Hence, it is known that (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine is effective for various diseases relating to cell necrosis. However, its effect has never been known nor has research been conducted on the prevention or treatment of ALI and ARDS.
The present inventors have carried out the present invention by verifying reduction for the total number of inflammatory cells, macrophages, lymphocytes and neutrophils, and the degrees of lung damage and inflammation; and the resolution of vascular permeability and protein exudation after treating with (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in a lipopolysaccharide (LPS)-induced ALI model.
The object of the present invention is to provide a pharmaceutical composition for preventing or treating ALI and ARDS by using (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine.
To obtain the above object, the present invention provides a pharmaceutical composition comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine as an active ingredient for preventing or treating ALI and ARDS.
The present invention provides a pharmaceutical composition comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine as an active ingredient for prevention, treatment or relief of ALI and ARDS by using the effect thereof for reducing the number of inflammatory cells, macrophages, lymphocytes and neutrophils, in a bronchoalveolar lavage of mice having LPS-induced ALI, relief of a degree of lung damage and inflammation, and reduction of vascular permeability and protein exudation.
The present invention is described in detail below.
The method for preparing the compound of the present invention can refer to the process disclosed in Korean Patent Application Publication No. 10-2009-0018593. The above document will be wholly contained in this specification as a reference.
The compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention can also form a pharmaceutically acceptable salt. Such a “pharmaceutically acceptable salt” includes non-toxic acid addition salt containing a pharmaceutically acceptable anion―for example, a salt with inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc.; a salt with 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, etc.; or a salt with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc. A pharmaceutically acceptable base addition salt thereof would include, for example, a salt with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, etc.; a salt with amino acids such as lysine, arginine, guanidine, etc.; or an organic salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. The compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention may be converted to salts thereof according to any of the conventional methods, and the salt formation could be easily carried out by a skilled artisan without additional explanations thereon.
The term “isomer” in the present invention means those compounds having the same chemical or molecular formula as, but optically or sterically different from, the compounds or salts thereof. The compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention may have an asymmetric carbon center(s) in the structure, and so may exist in the form of an optical isomer (R or S isomer), racemate, mixture of diastereomers, an individual diastereomer, or a geometric isomer (trans or cis isomer) etc. All the isomers and their mixtures are also covered by the present invention.
Hereinafter, the compounds of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention may include pharmaceutically acceptable salts and isomers thereof, unless otherwise indicated.
The compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention can reduce the number of inflammatory cells, macrophages, lymphocytes and neutrophils in a bronchoalveolar lavage of mice having LPS-induced ALI, relieve a degree of lung damage and inflammation, and reduce vascular permeability and protein exudation. Hence, the compound of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention can be used as a medicament in the treatment of ALI and ARDS.
For administration, the composition of the present invention can be prepared by further comprising at least one pharmaceutically acceptable carrier other than the ingredient as stated above. Pharmaceutically acceptable carriers include saline, sterilized water, Ringer’s solution, buffered saline, dextrose solution, maltodextrin solution, glycerol or ethanol, or can be used by mixing at least two selected from specified components. If needed, other conventional additives such as antioxidant, buffer solution, bacteriostatic agent etc. can be added. The formulation for injection as an aqueous solution, a suspension, an emulsion, a pill, a capsule, a granule or a tablet can also be prepared by adding a diluent, a dispersant, a surfactant, a binder and/or a lubricant. Furthermore, the formulation can be prepared by using the proper method in the art or the method disclosed in Remington’s Pharmaceutical Science (newest edition), Mack Publishing Company: Easton, PA.
The composition of the present invention can be administered orally or parenterally (for example, by intravenous, subcutaneous, intraperitoneal or local administration). The dose can include various ranges depending on body weight, age, sex, physical condition, diet, dosing time, dosing method, clearance of the patient and severance of disease. The daily dose of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine is, by oral administration, approximately 3~100 mg/kg, preferably approximately 10~80 mg/kg, or by intravenous one, approximately 0.3~50mg/kg, preferably approximately 10~50mg/kg. Dosing once a day or several times per a day is acceptable.
(Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention can be used for prevention, treatment or relief of ALI and ARDS by using the effect thereof for reducing the number of inflammatory cells, macrophages, lymphocytes and neutrophils in a bronchoalveolar lavage of mice having LPS-induced ALI, relief of a degree of lung damage and inflammation, and reduction of vascular permeability and protein exudation.
Fig. 1 shows the result regarding the effect of dosing time for (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention on the number of inflammatory cells in a bronchoalveolar lavage in a mouse model of ALI and ARDS.
Fig. 2 shows the result of analyzing vascular permeability with dosing time for (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
Fig. 3 shows the result of analyzing inflammatory cells in a bronchoalveolar lavage with various doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
Fig. 4 shows the result of analyzing vascular permeability with various doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
Fig. 5 shows the result of analyzing inflammatory cells in a bronchoalveolar lavage with two doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
Fig. 6 shows the result of analyzing vascular permeability with two doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
Fig. 7 shows the result of analyzing pathological alteration with two doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
Fig. 8 shows the result of analyzing reactive oxygen species (ROS) with two doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
Fig. 9 shows the result of analyzing pro-inflammatory mediators in lung tissue with (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
Fig. 10 shows the result of analyzing the signaling pathways of lung tissue with (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
To facilitate understanding of the present invention, the desirable Examples are described as below. However, they are provided only for easy understanding of the present invention, and thus the scope cannot be limited by these Examples.
Example 1: Effect of the dosing time of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine
Test groups of dosing time of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in a mouse model of ALI and ARDS consisting of a total of 5 groups are as follows: i) saline-treated mice to which a drug vehicle was administered (SAL+VEH), ii) LPS-treated mice to which a drug vehicle was administered (LPS+VEH), iii) LPS-treated mice to which 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered at 1 hr after the LPS treatment (LPS+Compound30-1h), iv) LPS-treated mice to which 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered at 8 hrs after the LPS treatment (LPS+ Compound 30-8h), and v) LPS-treated mice to which 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered at 24 hrs after the LPS treatment (LPS+ Compound 30-24h). 5 mice were used in each test group. (Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine and a drug vehicle were administered once by intravenous route after 1 hr, 8 hrs or 24 hrs following injection of LPS.
Example 1-1: Result regarding the effect of dosing time for (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine on the number of inflammatory cells in a bronchoalveolar lavage
In an LPS-induced mouse model of ALI and ARDS, the total number of inflammatory cells was significantly increased along with that of cells such as macrophages, lymphocytes and neutrophils. In a test group to which (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered at 24 hrs after treating with LPS, the number of total inflammatory cells was significantly reduced along with that of macrophages and neutrophils. In a test group to which the compound was administered at 1 hr after treating with LPS, the significantly reduced total number of inflammatory cells was verified (Fig. 1). However, in a test group to which (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered at 8 hrs after treating with LPS, a significantly reduced number of total inflammatory cells was not verified.
Example 1-2: Result of analyzing vascular permeability with dosing time for (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in a disease model of ALI
In an LPS-induced mouse model of ALI and ARDS, the total amount of protein in a bronchoalveolar lavage and pulmonary vascular permeability from EBD analysis were significantly increased. In a test group to which (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered at 1 hr, 8 hrs and 24 hrs after treating with LPS, the amount of protein exuded from pulmonary blood vessels into lacunae of bronchial alveoli was significantly decreased, and thus vascular permeability was reduced. In all test groups to which (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered, EBD exuded by binding with plasma albumin at 48 hrs after treating with LPS was reduced but there was no statistical difference. Therefore, in this case the administration of the drug did not significantly affect vascular permeability (Fig. 2).
Example 2: Minimal effective dose of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine
Test groups regarding the minimal effective dose of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine consisting of a total of 6 groups are as follows: i) saline-treated mice to which a drug vehicle was administered (SAL+VEH), ii) LPS-treated mice to which a drug vehicle was administered (LPS+VEH), iii) LPS-treated mice to which 1 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered (LPS+ Compound 1), iv) LPS-treated mice to which 3 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered (LPS+Compound 3), v) LPS-treated mice to which 10 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered (LPS+ Compound 10), and vi) LPS-treated mice to which 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered (LPS+ Compound 30). 5 mice were used in each test group. (Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine and a drug vehicle were administered once intravenously after 1 hr and 24 hrs thereafter following injection of LPS.
Example 2-1: Result of analyzing inflammatory cells in a bronchoalveolar lavage with various doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine
In an LPS-induced mouse model of ALI and ARDS, the total number of inflammatory cells was significantly increased along with that of cells such as macrophages, lymphocytes and neutrophils. In test groups to which 3 mg/kg, 10 mg/kg and 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine were administered at 1 hr and 24 hrs after treating with LPS, the total number of inflammatory cells was significantly reduced along with that of macrophages and neutrophils. In a test group to which 1 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered, the total number of neutrophils and inflammatory cells was significantly reduced (Fig. 3).
Example 2-2: Result of analyzing vascular permeability with various doses of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention in a disease model of ALI.
In an LPS-induced mouse model of ALI and ARDS, the total amount of protein in a bronchoalveolar lavage and pulmonary vascular permeability from EBD analysis were significantly increased. In test groups to which 3 mg/kg, 10 mg/kg and 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine were administered, the amount of protein exuded from pulmonary blood vessels into lacunae of bronchial alveoli and EBD exuded by binding with plasma albumin at 48 hrs after treating with LPS were significantly reduced, and thus vascular permeability was reduced. In a test group to which 1 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered, there was no statistical difference for the total amount of protein and EBD analysis (Fig. 4).
Example 3: The effect of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in an LPS-induced mouse model of ALI and ARDS
Test groups regarding the effect of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine in an LPS-induced mouse model of ALI and ARDS consisting of a total of 4 groups are as follows: i) saline-treated mice to which a drug vehicle was administered (SAL+VEH), ii) LPS-treated mice to which a drug vehicle was administered (LPS+VEH), iii) LPS-treated mice to which 10 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine (LPS+ Compound 10) was administered and iv) LPS-treated mice to which 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine (LPS+ Compound 30) was administered. 6 mice were used in every test group. (Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine, and a drug vehicle were administered once intravenously after 1 hr and 24 hrs thereafter following injection of LPS.
Example 3-1: Analysis of inflammatory cells in a bronchoalveolar lavage with various doses
In an LPS-induced mouse model of ALI and ARDS, the number of inflammatory cells was significantly increased along with those of macrophages, lymphocytes and neutrophils. However, in a test group to which 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered, the total number of inflammatory cells was significantly reduced along with that of lymphocytes and neutrophils. In a test group to which 10 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine was administered, the number of lymphocytes was significantly reduced whereas that of neutrophils and total inflammatory cells was apparently reduced (Fig. 5).
Example 3-2: Analysis of vascular permeability with various doses
In an LPS-induced mouse model of ALI and ARDS, the total amount of protein in a bronchoalveolar lavage and pulmonary vascular permeability were significantly increased. In both test groups to which 10 mg/kg and 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine were administered, the amount of protein exuded from pulmonary blood vessels into lacunae of bronchial alveoli and EBD exuded by binding with plasma albumin at 48 hrs after treating with LPS were significantly reduced, and thus vascular permeability was reduced (Fig. 6).
Example 3-3: Analysis of pathological alteration with various doses
As a result of a pathological biopsy and Micro-CT, in a test group administered with (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine, pathological factors and alteration such as permeation of inflammatory cells in airways which can be increased from the LPS-induced pulmonary inflammatory reaction, and precipitation of hyaline and formation of microthrombi etc. were reduced (Fig. 7).
Example 3-4: ROS analysis with various doses
In an LPS-induced mouse model of ALI and ARDS, the level of ROS in cells was increased largely along with expression of mitochondrial ROS. In both test groups to which 10 mg/kg and 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine were administered, both the expression of mitochondrial ROS and the level of ROS in cells were significantly reduced (Fig. 8).
Example 3-5: Analysis of pro-inflammatory mediator with various doses
In the test groups administered with 10 mg/kg and 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine, the expressions of IL-1b, NLRP-3, VEGF, KC, IL-17 and TNF-α protein, which were significantly increased in the LPS-induced inflammatory reaction, were reduced. In the test group of 30 mg/kg, the rising of pro-inflammatory mediator in the lungs was significantly reduced.
Example 3-6: Analysis of signaling pathways with various doses
In an LPS-induced mouse model of ALI and ARDS, the nucleus transposition of NF-kB p65 and expression of TLR4 were significantly increased. In both test groups to which 10 mg/kg and 30 mg/kg of (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine were administered, the expression of TLR4 was significantly reduced and nucleus transposition of NF-kB p65 was decreased.
As indicated above, it is verified that (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine according to the present invention can treat bacterial infection, ALI and ARDS caused by various factors by significantly inhibiting expression of inflammatory cells which have an important role for ALI regarding bacterial infection, and increases of inflammatory cells in a bronchoalveolar lavage and vascular permeability.
Formulation Example 1: Preparation of pharmaceutical formulation
(1) Preparation of powder
(Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine 100 mg
lactose 100 mg
Powder was prepared by mixing the above components and filling them to seal.
(2) Preparation of tablet
(Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine 100 mg
lactose 100 mg
Tablet was prepared according to the conventional method of preparing a tablet by compression after mixing the above components.
(3) Preparation of capsule
(Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine 100 mg
lactose 100 mg
Capsule was prepared according to the conventional method of preparing a capsule by filling into a gelatin capsule after mixing the above components.
(4) Preparation of injectable formulation
(Tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine 100 mg
Na2HPO4·12H2O 2 mg
Distilled water for injection residual
Injectable formulation per 1 ampule (2 ㎖) was prepared according to the conventional method of preparing injections by mixing the above components.
Claims (5)
- A pharmaceutical composition comprising (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine as an active ingredient for prevention or treatment of acute lung injury and acute respiratory distress syndrome.
- The pharmaceutical composition according to Claim 1 wherein (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine reduces the total number of inflammatory cells and the number of macrophages, lymphocytes and neutrophils in a bronchoalveolar lavage of an acute lung injury model.
- The pharmaceutical composition according to Claim 1 wherein (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine reduces vascular permeability and protein exudation in a bronchoalveolar lavage of an acute lung injury model.
- The pharmaceutical composition according to Claim 1 wherein (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine reduces mitochondrial reactive oxygen species (ROS) in cells in a bronchoalveolar lavage of an acute lung injury model.
- The pharmaceutical composition according to Claim 1 for prevention or treatment of acute lung injury and acute respiratory distress syndrome, characterized in that (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholine-4-yl)methyl-1H-indole-7-yl]amine reduces various inflammatory cytokines in a bronchoalveolar lavage of an acute lung injury model and lung tissue.
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BR112023021066A2 (en) | 2021-04-12 | 2023-12-12 | Mitoimmune Therapeutics Inc | CRYSTALLINE FORM A, METHOD FOR PREPARING CRYSTALLINE FORM A, PHARMACEUTICAL COMPOSITION, AND, COMPOSITION |
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US11166953B2 (en) | 2017-04-17 | 2021-11-09 | Yale University | Compounds, compositions and methods of treating or preventing acute lung injury |
CN110753546B (en) * | 2017-04-17 | 2023-11-10 | 耶鲁大学 | Compounds, compositions and methods for treating or preventing acute lung injury |
US11890283B2 (en) | 2017-04-17 | 2024-02-06 | Yale University | Compounds, compositions and methods of treating or preventing acute lung injury |
CN109010357A (en) * | 2018-02-12 | 2018-12-18 | 温州医科大学 | The construction method of acute lung injury inflammatory resolution animal model |
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KR20150088753A (en) | 2015-08-03 |
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