Novel pyrrole or novel imidazole derivative and use thereof for alleviating pulmonary fibrosis

Abstract

Disclosed in the present invention are: a novel pyrrole derivative or a novel imidazole derivative having activities of inhibiting a TGF-y1 signaling pathway and inhibiting EMT without exhibiting significant cytotoxicity against A549 cells, which are lung epithelial cells derived from lung cancer; and a composition for alleviating pulmonary fibrosis using these derivatives.

Description

Novel pyrrole or novel imidazole derivatives and their use in improving pulmonary fibrosis

[0001] The present invention relates to a novel pyrrole or novel imidazole derivative and its use for improving pulmonary fibrosis.

[0002] Pulmonary fibrosis, or idiopathic pulmonary fibrosis (IPF), is a disease characterized by fibrosis of the lung interstitium, which is characterized by excessive deposition of connective tissue, particularly collagen, in the alveolar walls. Pulmonary fibrosis is a life-threatening disease characterized by a slowly progressive decline in lung function, leading to respiratory failure, with a median survival of 2-3 years after diagnosis. The prevalence of pulmonary fibrosis varies, but is estimated to range from 2-29 cases per 100,000 people. In Korea, it is designated as a rare and intractable disease.

[0003] Pulmonary fibrosis is a disease that occurs in the elderly and is expected to increase as the population ages. Recent research results have reported that it occurs in about 7-8% of smokers or the general population, suggesting that the prevalence of pulmonary fibrosis reported to date may be underestimated. Therefore, it is expected that a significant number of elderly people (currently, 1 in 450 men over 70 years of age) will suffer from this disease, but there is still no effective treatment method. In the case of lung transplantation, the number of transplant donors is small compared to the number of people applying for transplantation, requiring a long waiting period (which may lead to deterioration and death during the waiting period). Even if a transplant is obtained with difficulty, there are many cases of death from complications after transplantation (the 5-year survival rate is about 50%). Therefore, there is an urgent need for more effective and safe treatment methods.

[0004] The causes of pulmonary fibrosis are diverse, including lung damage, exposure to toxic substances or toxic environments such as fine dust or ultrafine dust, anticancer drugs, autoimmune diseases, or idiopathic interstitial pneumonia (Proc Am Thorac Soc 2006, 3:285-92; Am J Respir Crit Care Med 2002, 165:277-304). The basic histological changes of pulmonary fibrosis are inflammatory changes such as cellular infiltration, edema, and exudation in the alveolar septa, and destruction of the lung parenchyma due to infiltration and fibrosis of extracellular matrix such as collagen, proteoglycan, fibronectin, and glycoproteins (Am J Respir Crit Care Med 2002, 165:277-304; N Engl J Med 2001, 345:517-25).

[0005] In the past, inflammation was considered the cause of pulmonary fibrosis, and anti-inflammatory treatment was attempted, but the actual effect was minimal (Annals of Internal Medicine 2001, 134:136-51; Chest 1996, 110:1058-67). Therefore, recently, epithelial-mesenchymal transition (EMT) or TGF-β1 signaling that induces EMT, rather than inflammation, has been considered as a new cause and treatment target (Annals of Internal Medicine 2001, 134:136-51; Chest 2007, 132:1311-21; The Journal of Clinical Investigation 2009, 119:213-24).

[0006] EMT is a process in which epithelial cells change into mesenchymal cells and then fibroblasts. Epithelial cells have adhesive proteins between epithelia or stroma, and act as a barrier and perform absorption and secretion functions due to the structure of the cytoskeleton, whereas mesenchymal cells are separated from each other, are mobile, and form connective tissue or extracellular matrix (ECM), which induces diseases such as pulmonary fibrosis.

[0007] The main factor that induces EMT is TGF-β1. TGF-β1 induces the de novo synthesis of α-SMA (α-smooth muscle actin) during the EMT process. The de novo synthesis of α-SMA changes lung fibroblasts into a myofibroblast phenotype. Since the expression of this myofibroblast is upregulated and continuously expressed in areas where lung fibrosis progresses, it is presumed to play a major role in the development and progression of pulmonary fibrosis (Chest 2002, 122: 286S-9S).

[0008] In particular, it is known that the expression of α-SMA, Vimentin, Fibronectin, SMA2 / 3, etc. increases in association with the TGF-β pathway, and that E-cadherin is converted to N-cadherin, promoting EMT and causing pulmonary fibrosis (The Journal of Clinical Investigation 2009,119:213-24; Nat Rev Mol Cell Biol 2006,7:131-42; Cell Biol Int 2002,26:463-76). In addition, it is known that the Smad-dependent pathway and the Smad-independent MAPK (mitogen-activated protein kinases) pathway are involved in cell activation by TGF-β1 (J Am Soc Nephrol 2002,13:1464-72; Proc Natl Acad Sci USA 2001,98:6686-91; Cancer Res 2001;61:4222-8), NOX2, NOX4, and other NOX (NADPH oxidases) are known to be involved in cell activation by TGF-β1 (Thorax. 2010 Aug;65(8):733-8). Oxidative stress is also known to be a factor that progresses pulmonary fibrosis, and bleomycin is known to increase oxidative stress by increasing the synthesis of nitric oxide (NO) in the lungs and increase the expression of NOX through phosphorylation of MAPK signaling pathway factors (Scientific Reports 7(1):2252, 2017).

[0009] Additionally, HIF-1α (Hypoxia-Inducible Factor-1α) and EGFR (epidermal growth factor receptor) signaling are also known to be related to pulmonary fibrosis, and these have been proposed as targets for pulmonary fibrosis treatment (Am J Respir Cell Mol Biol. 2018 Feb; 58(2):216-231; Am J Physiol Lung Cell Mol Physiol. 2019 Jun 1;316(6):L1025-L1034). In particular, in vascular smooth muscle cells, EGFR increases the production of NO and the expression of NOX through increased expression of ERK (extracellular signal-regulated kinase) and AKT, a type of serine / threonine protein kinase, and phosphorylation of their downstream signal transducers (Antioxidants & Redox Signaling 22(1):29-47, 2015), and phosphorylation of EGFR is known to accelerate fibrosis by activating MAPK signaling pathways such as ERK1 / 2, P38, and JNK (c-Jun N-terminal kinases) (Journal of Respiratory Cell and Molecular Biology, 50(4): 723-736, 2014). Treatments such as gefitinib are EGFR tyrosine kinase inhibitors that inhibit fibroblast proliferation and extracellular collagen deposition by inhibiting EGFR phosphorylation (Am J Respir Cell Mol Biol. 2006, 174(5):550-556; Am J Physiol Lung Cell Mol Physiol. 2008., 294(6):L1217-L1225).

[0010] Steroids (glucocorticoids), immunosuppressive agents, and anti-viral cytokines are representative agents used in the treatment of pulmonary fibrosis. However, according to the 2011 ATS / ERS guidelines for idiopathic pulmonary fibrosis, combination therapy with steroids and the immunosuppressant azathioprine actually increased the mortality rate.

[0011] Pulmonary fibrosis is considered to involve alveolar epithelial cells and fibroblasts or myofibroblasts as key pathogenic components, and new drugs are being studied targeting these cells. Furthermore, given the diverse causes of pulmonary fibrosis, new drugs are being developed to inhibit various pathways that contribute to fibrosis, rather than targeting a single pathway, or to inhibit higher-order signaling systems.

[0012] The present invention discloses a novel pyrrole derivative or imidazole derivative having an activity of inhibiting EMT by inhibiting the TGF-β1 signal transduction pathway, and its use for improving pulmonary fibrosis.

[0013] The purpose of the present invention is to provide a novel pyrrole derivative or imidazole derivative.

[0014] Another object of the present invention is to provide a composition for improving pulmonary fibrosis using a novel pyrrole derivative or imidazole derivative.

[0015] Other or specific purposes of the present invention will be presented below.

[0016] The present invention was completed by confirming that the novel pyrrole derivatives or imidazole derivatives of the following chemical formulae 1 to 4 have the activity of inhibiting the TGF-β1 signal transduction pathway and inhibiting EMT without showing any particular cytotoxicity toward A549 cells, which are lung cancer-derived lung epithelial cells, as confirmed in the examples and experimental examples below.

[0017] <Chemical Formula 1>

[0018]

[0019] <Chemical Formula 2>

[0020]

[0021] <Chemical Formula 3>

[0022]

[0023] <Chemical Formula 4>

[0024]

[0025] The present invention is provided based on these experimental results, and in one aspect, the present invention can be understood as a pyrrole or imidazole derivative of the following <Chemical Formula 5> or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and in another aspect, (i) a composition for improving pulmonary fibrosis comprising the pyrrole or imidazole derivative of the following <Chemical Formula 5> or a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

[0026] <Chemical Formula 5>

[0027] R1-X-R2

[0028] In the above,

[0029] X is a pyrrole ring or an imidazole ring,

[0030] R1 and R2 are each independently a -(CO)n-R3 group, n is 0 or 1,

[0031] R3 is R4-COOH group, and R4 is C 0-2 It is an alkyl group,

[0032] The above R1 and R2 modify the carbon atoms of the pyrrole ring or imidazole ring,

[0033] The above R1 and R2 preferably modify the carbon at the 3rd or 5th position of the pyrrole ring, or modify the carbon at the 2nd or 5th position of the imidazole ring.

[0034]

[0035] The novel pyrrole derivative or novel imidazole derivative of the present invention can be used in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt may be a metal salt obtained using a base. Such a metal salt may be obtained, for example, by dissolving the novel pyrrole derivative or novel imidazole derivative compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. In this case, preparing a sodium, potassium, or calcium salt as the metal salt may be pharmaceutically suitable.

[0036] Additionally, the novel pyrrole derivative or novel imidazole derivative of the present invention can be used in the form of a hydrate. A hydrate is a compound bound to water, and includes an inclusion compound in which there is no chemical bonding between the water and the compound.

[0037] Additionally, the novel pyrrole derivative or novel imidazole derivative of the present invention may be used in the form of a solvate. A solvate refers to a compound formed between molecules or ions of a solute and molecules or ions of a solvent.

[0038] Also, in this specification, “active ingredient” means an ingredient that exhibits the desired activity alone or can exhibit the activity together with a carrier that is inactive in itself.

[0039] In the composition of the present invention, the effective ingredient may be included in any amount (effective amount) depending on the purpose, formulation, etc., as long as it can exhibit an effect of improving pulmonary fibrosis, etc., and a typical effective amount will be determined within the range of 0.001 wt % to 99 wt % based on the total weight of the composition. Here, the "effective amount" refers to the amount of the effective ingredient included in the composition of the present invention that can exhibit the intended medical and pharmacological effect, such as an effect of improving pulmonary fibrosis, when the composition of the present invention is administered to a mammal, preferably a human, which is the subject of application, for an administration period recommended by a medical professional, etc. Such an effective amount can be experimentally determined within the normal ability of a person skilled in the art.

[0040] The composition of the present invention can be understood as a food composition in a specific aspect.

[0041] The food composition of the present invention can be manufactured in any form, for example, beverages such as tea, juice, carbonated beverages, and sports beverages; processed dairy products such as milk and yogurt; foods such as gums, rice cakes, Korean traditional sweets, bread, confectionery, and noodles; and health functional food preparations such as tablets, capsules, pills, granules, liquids, powders, flakes, pastes, syrups, gels, jellies, and bars. In addition, the food composition of the present invention can have any product classification as long as it complies with the laws and regulations in effect at the time of manufacturing and distribution in terms of legal and functional classification. For example, it can be a health functional food according to the Korean "Health Functional Food Act", or confectionery, beans, tea, beverages, special-purpose foods, etc. according to each food type according to the Food Code of the Korean "Food Sanitation Act" (the "Standards and Specifications of Foods" announced by the Ministry of Food and Drug Safety).

[0042] The food composition of the present invention may contain food additives in addition to its effective ingredients. Food additives can generally be understood as substances added to, mixed with, or infiltrated into food during the manufacturing, processing, or preservation of food. Since they are consumed daily and over a long period of time with food, their safety must be guaranteed. The Food Additive Codex, which is based on the laws of each country that regulate the manufacturing and distribution of food (in Korea, the "Food Sanitation Act"), provides limited regulations on food additives with guaranteed safety in terms of ingredients or functions. The Korean Food Additive Codex (Ministry of Food and Drug Safety Notice "Food Additive Standards and Specifications") classifies food additives into chemically synthesized products, natural additives, and mixed preparations in terms of ingredients. These food additives are classified into sweeteners, flavoring agents, preservatives, emulsifiers, acidulants, and thickeners in terms of functions.

[0043] Sweeteners are used to impart an appropriate sweetness to foods, and both natural and synthetic sweeteners can be used in the food composition of the present invention. Preferably, a natural sweetener is used. Examples of natural sweeteners include sugar sweeteners such as corn syrup solids, honey, sucrose, fructose, lactose, and maltose.

[0044] Flavoring agents are used to enhance taste or aroma, and both natural and synthetic flavors can be used. Natural flavoring agents are preferred. When using natural flavoring agents, they can also serve the purpose of enhancing nutrition in addition to flavor. Natural flavoring agents can be obtained from apples, lemons, tangerines, grapes, strawberries, peaches, etc., or from green tea leaves, Polygonum multiflorum, bamboo leaves, cinnamon, chrysanthemum leaves, jasmine, etc. Also, flavoring agents obtained from ginseng (red ginseng), bamboo shoots, aloe vera, ginkgo biloba, etc. can be used. Natural flavoring agents can be liquid concentrates or solid extracts. In some cases, synthetic flavoring agents can be used, such as esters, alcohols, aldehydes, and terpenes.

[0045] Preservatives that can be used include calcium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate, EDTA (ethylenediaminetetraacetic acid), etc.; emulsifiers that can be used include acacia gum, carboxymethylcellulose, xanthan gum, pectin, etc.; and acidulants that can be used include citric acid, malic acid, fumaric acid, adipic acid, phosphoric acid, gluconic acid, tartaric acid, ascorbic acid, acetic acid, phosphoric acid, etc. In addition to the purpose of enhancing taste, acidulants can be added to ensure that the food composition has an appropriate acidity for the purpose of inhibiting the growth of microorganisms. Thickeners that can be used include suspending agents, sedimentation agents, gel-forming agents, and puffing agents.

[0046] In addition to the food additives described above, the food composition of the present invention may include physiologically active substances or minerals known in the art and guaranteed to be safe as food additives for the purpose of supplementing and reinforcing functionality and nutrition.

[0047] Examples of such physiologically active substances include catechins contained in green tea, vitamins such as vitamin B1, vitamin C, vitamin E, and vitamin B12, tocopherol, and dibenzoylthiamine, and examples of minerals include calcium preparations such as calcium citrate, magnesium preparations such as magnesium stearate, iron preparations such as ferrous citrate, chromium chloride, potassium iodide, selenium, germanium, vanadium, and zinc.

[0048] The food composition of the present invention may include the aforementioned food additives in an appropriate amount that can achieve the purpose of addition depending on the product type.

[0049] With regard to other food additives that may be included in the food composition of the present invention, reference may be made to the food code or food additive code according to the laws of each country.

[0050] The composition of the present invention may be considered as a pharmaceutical composition in other specific embodiments.

[0051] The pharmaceutical composition of the present invention may be prepared as an oral or parenteral formulation, depending on the route of administration, by a conventional method known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient. "Pharmaceutically acceptable" herein means that the composition does not inhibit the activity of the active ingredient and does not exhibit toxicity exceeding that tolerated by the intended subject.

[0052] When the pharmaceutical composition of the present invention is prepared as an oral dosage form, it can be prepared in the form of powder, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, wafers, etc., using a suitable carrier and a method known in the art. At this time, examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, xylitol, etc.; starches such as corn starch, potato starch, wheat starch, etc.; celluloses such as cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyols, and vegetable oils. In case of formulation, the formulation may include diluents and / or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants, as needed.

[0053] When the pharmaceutical composition of the present invention is prepared as a parenteral dosage form, it can be formulated in the form of eye drops, injections, transdermal administration agents, inhalation agents (agents for delivering drugs directly into the nasal cavity, oral cavity, respiratory tract, bronchial tubes, etc. using a nebulizer, etc.), suppositories, etc., with a suitable carrier according to a method known in the art. When formulated as eye drops, suitable carriers include sterile water, saline, isotonic solutions such as 5% dextrose, etc., and, if necessary, benzalkonium chloride, mephylparaben, ethylparaben, etc. can be added for preservative purposes. When formulated as an injection, suitable carriers include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof, and preferably, Ringer's solution, PBS (phosphate buffered saline) containing triethanolamine, sterile water for injection, isotonic solutions such as 5% dextrose, etc. When formulated as a transdermal agent, it can be formulated in the form of ointments, creams, lotions, gels, external solutions, pastes, liniments, aerosols, etc. In the case of inhalation, it can be formulated in the form of an aerosol spray using a suitable propellant such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, etc. When formulated as a suppository, the base can be witepsol, tween 61, polyethylene glycols, cacao butter, laurin butter, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sorbitan fatty acid esters, etc.

[0054] Specific formulations of pharmaceutical compositions are known in the art and can be found, for example, in Remington's Pharmaceutical Sciences (19th ed., 1995), which is incorporated herein by reference.

[0055] The preferred dosage of the pharmaceutical composition of the present invention may range from 0.001 mg / kg to 10 g / kg per day, preferably from 0.001 mg / kg to 1 g / kg, depending on the patient's condition, weight, sex, age, severity of the condition, and route of administration. Administration may be administered once daily or divided into several doses. Such dosage should not be construed as limiting the scope of the present invention in any way.

[0056] As described above, according to the present invention, a novel pyrrole derivative or novel imidazole derivative having the activity of inhibiting the TGF-β1 signal transduction pathway and EMT inhibition without exhibiting particular cytotoxicity toward A549 cells, which are lung cancer-derived lung epithelial cells, and a composition for improving pulmonary fibrosis using the derivative can be provided. The composition of the present invention can be commercialized as a food such as a health functional food or a drug such as a pharmaceutical.

[0057] Figures 1 to 3 are the 1H-NMR and 13C-NMR results and LC-MS spectra of the novel pyrrole derivative 1, respectively.

[0058] Figures 4 to 6 are the 1H-NMR and 13C-NMR results and LC-MS spectra of the novel imidazole derivative 1, respectively.

[0059] Figures 7 to 9 are the 1H-NMR and 13C-NMR results and LC-MS spectrum of pyrrole derivative 2, respectively.

[0060] Figures 10 to 12 are the 1H-NMR and 13C-NMR results and LC-MS spectra of imidazole derivative 2, respectively.

[0061] Figures 13 to 16 show the results of cytotoxicity evaluation of novel pyrrole derivatives and imidazole derivatives against A549 cells.

[0062] Figures 17 to 21 show the results showing the effects of novel pyrrole derivatives and imidazole derivatives on the expression of factors related to pulmonary fibrosis in A549 cells when treated with TGF-β1.

[0063] Figures 22 to 29 show the results showing the effects of novel pyrrole derivatives and imidazole derivatives on cell migration of A549 cells.

[0064] The present invention is described below with reference to examples and experimental examples. However, the scope of the present invention is not limited to these examples and experimental examples.

[0065]

[0066] <Example> Preparation of novel pyrrole derivatives or novel imidazole derivatives and experiment on their activity in improving pulmonary fibrosis

[0067] <Example 1> Preparation of novel pyrrole derivatives and novel imidazole derivatives

[0068] 1. Preparation of novel pyrrole derivative 1 (compound 3)

[0069] Step 1

[0070]

[0071] Anhydrous AlCl3 (62.24 g, 0.47 mol) was added to a solution of 1-(1H-pyrrol-2-yl)-ethanone (1) (20 g, 0.18 mol) in dichloromethane (200 mL) and stirred vigorously for 30 minutes. Dichloromethane (140 mL) containing trichloroacetyl chloride (31 mL, 0.28 mol) was slowly added, and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was then cooled, poured into an ice-cold solution of HCl (1.5 L, 2 N), and stirred vigorously for 2 hours. The organic layer was separated, washed with a saturated NaHCO3 solution (2 X 1 L) and water (800 mL), dried over sodium sulfate, and filtered. After filtration, the residue was concentrated in vacuo to obtain a pale brown solid 1-(5-acetyl-1H-pyrrol-3-yl)-2,2,2-trichloro-ethanone (2) (22.0 g, 86 mmol. Y = 47%).

[0072] NMR spectroscopy was performed on a Bruker Avance III 400MHz instrument, using tetramethylsilane as a reference. LC-MS was performed on an Agilent LC / MSD 1200 Series instrument, using an ODS2000 (50 x 4.6 mm, 5um) column, using Electrospray Ionization (ESI) as the ionization mode, at 30°C, a flow rate of 1.5 mL / min, and detection at a wavelength of 214 nm.

[0073] 1 H NMR (400 MHz, DMSO-d6) δ: 12.90 (s, 1H), 7.95 - 7.96 (m, 1H), 2.45 (s, 3H).

[0074] Step 2

[0075]

[0076] Potassium carbonate (5.0 g, 39.0 mmol) was added to a solution of 1-(5-acetyl-1H-pyrrol-3-yl)-2,2,2-trichloro-ethanone (2) (22.0 g, 86.0 mmol) in benzyl alcohol (200 mL), and the mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature and concentrated to obtain a crude product, which was purified by flash chromatography (petroleum ether (PE) / ethyl acetate (EA) = 3 / 1, v / v) to obtain benzyl 5-acetyl-1H-pyrrole-3-carboxylate (3) (12.0 g, 49.0 mmol, Y = 57%) as a yellow solid.

[0077] 1 H NMR (400 MHz, DMSO-d6) δ: 12.43 (s, 1H), 7.65 (t, J= 2 Hz, 1H), 7.31 - 7.45 (m, 6H), 5.26 (s, 2H), 3.40 (s, 3H)

[0078] Step 3

[0079]

[0080] SeO2 (2.28 g, 20.54 mmol) was added to a pyridine (50 mL) solution of benzyl 5-acetyl-1H-pyrrole-3-carboxylate (3), and the mixture was refluxed at 110°C for 10 h. The mixture was cooled to room temperature, water was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by Prep-HPLC (Agilent LC / MSD 1200 Series, ODS2000 (50 x 4.6 mm, 5 μm) column, 30 °C, 1.5 mL / min flow rate, 214 nm detection wavelength, 0.1% NH4HCO3 aqueous solution / acetonitrile = 4 / 1 (V / V) mobile phase) to obtain 2-(4-((benzylo-xy)carbonyl)-1H-pyrrol-2-yl)-2-oxoacetic acid (4) (2.4 g, 8.79 mmol, Y = 43%) as a white solid.

[0081] 1 H NMR (400 MHz, DMSO-d6) δ:7.52 (s, 1H), 7.33 - 7.43 (m, 5H), 7.08 (s, 1H), 5.23 (s, 2H), 1.24 (s, 2H).

[0082] Step 4

[0083]

[0084] To a solution of 2-(4-((benzylo-xy)carbonyl)-1H-pyrrol-2-yl)-2-oxoacetic acid (4) (2.2 g, 8.05 mmol) in MeOH (100 mL) was added Pd / C (440 mg, containing 5% Pd, 40-60% H2O), and the mixture was refluxed at 50°C for 3 h in a hydrogen atmosphere. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo to give 5-(carboxy(hydroxy)methyl)-1H-pyrrole-3-carboxylic acid (5) (1.2 g, 6.48 mmol, Y = 80%).

[0085] Step 5

[0086]

[0087] To a solution of 5-(carboxy(hydroxy)methyl)-1H-pyrrole-3-carboxylic acid (1.2 g 6.48 mmol) in a CHCl3 / Tetrahydrofuran (THF) mixture (50 mL CHCl3 / THF = 4: 1) was added MnO2 (5.63 g, 64.71 mmol) and refluxed at 70°C for 2 h in a nitrogen atmosphere (N2atmosphere). The reaction solution was cooled and filtered, and the filtrate was cooled to room temperature and allowed to stand for 3 h. The reaction mass was filtered, and the residue was washed with cold methanol to obtain the target compound, a novel pyrrole derivative 1 (Compound 3) (505 mg 2.76 mmol, Y = 43%) in a solid form.

[0088] 1 H NMR (400 MHz, DMSO-d6) δ: 12.60 (s, 1H), 12.27 (s, 1H), 9.54 (s, 1H), 7.66 (t, J= 2 Hz, 1H), 7.32 (t, J= 2 Hz, 1H); m / z calculated 183.02, found (M-2H) +181.2

[0089] The 1H-NMR, 13C-NMR, and LC-MS spectra of the novel pyrrole derivative 1 (Compound 3) prepared above are shown in Figures 1 to 3.

[0090] 2. Preparation of novel imidazole derivative 1 (compound 4)

[0091] Step 1

[0092]

[0093] To a mixture of methyl 1H-imidazole-5-carboxylate (1) (2.0 g, 15.87 mmol) and PPh3 (5.0 g, 19.06 mmol) in dry THF (60 ml) was added dropwise dry THF (15 ml) containing phenyl methanol (1.72 g, 15.87 mmol), and then to this was added dry THF (15 ml) containing dibenzyl azodicarboxylate (4.38 g, 19.02 mmol) in a nitrogen-filled chamber (N2atmosphere) at -30℃. The mixture was stirred at room temperature for 5 h, concentrated, and then purified by flash chromatography (PE / EA = 4 / 1, v / v) to obtain the crude product methyl 1-benzyl-1H-imidazole-5-carboxylate (2) (1.4 g, Y = 40.8%) as a white solid.

[0094] LC-MS (ESI): m / z 217.2 [M+H] +

[0095] Step 2

[0096]

[0097] To a stirred solution of methyl 1-benzyl-1H-imidazole-5-carboxylate (2) in DCM (30 mL) was added ethyl oxalyl chloride (881.5 mg, 6.48 mmol) dropwise at -40°C in a nitrogen-filled chamber (N2atmosphere), followed by the dropwise addition of DIEA (N,N-Diisopropylethylamine) (1.25 g, 9.69 mmol). The mixture was then heated to room temperature, stirred for 4 h, concentrated, and the concentrate purified by flash chromatography (PE / EA = 6 / 1, v / v) to obtain colorless oily methyl 1-benzyl-2-(2-ethoxy-2-oxoacetyl)-1H-imidazole-5-carboxylate (3) (1.2 g, Y = 58.6%).

[0098] LC-MS (ESI): m / z 317.3 [M+H] +

[0099] 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1 H), 7.36 - 7.27 (m, 3H), 7.06 (s, 1H), 7.05 (s, 1 H), 5.98 (s, 2H), 4.41 - 4.36 (m, 2H), 3.84 (s, 3H), 1.30 (t, J= 6.8 Hz, 3H).

[0100] Step 3

[0101]

[0102] A mixture of methanol (60 ml) containing methyl 1-benzyl-2-(2-ethoxy-2-oxoacetyl)-1H-imidazole-5-carboxylate (3) (5.0 g, 15.82 mmol) and Pd / C (500 mg, 10% w / w) was stirred in a hydrogen-filled chamber (H2atmosphere) at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to obtain methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1H-imidazole-5-carboxylate (4) (3.0 g, Y = 83.2%) as an off-white solid.

[0103] LC-MS (ESI): m / z 229.3 [M+H] +

[0104] 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 5.18 (s, 1H), 4.15 - 4.10 (m, 2H), 3.73 (s, 3 H), 1.16 (t, J= 7.2 Hz, 3H).

[0105] Step 4

[0106]

[0107] A CHCl3 (100 ml) solution containing a mixture of methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1H-imidazole-5-carboxylate (3.0 g, 13.15 mmol) and MnO2 (11.44 g, 13.9 mmol) was stirred in a nitrogen-filled chamber (N2atmosphere) at 60°C for 1 h and cooled to room temperature. The cooled solution was filtered, and the filtrate was concentrated to obtain methyl 2-(2-ethoxy-2-oxoacetyl)-1H-imidazole-5-carboxylate (5) (2.0 g, Y = 67.3%) as an off-white solid, which was used in the next step without further purification.

[0108] LC-MS (ESI): m / z 227.0 [M+H] +

[0109] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 4.44 - 4.39 (m, 2H), 3.81 (s, 3H), 1.33 (t, J= 3.8 Hz, 3H).

[0110] Step 5

[0111]

[0112] LiOH·H2O (1.67 g, 39.8 mmol) was added to a THF / H2O (20 mL / 4 mL) solution of methyl 2-(2-ethoxy-2-oxoacetyl)-1H-imidazole-5-carboxylate (5) (1.8 g, 7.96 mmol) and stirred at room temperature for 16 h. The solution was adjusted to pH 3-4 with HCl (1N), concentrated in vacuo, and the resultant was purified by Prep-HPLC (Agilent LC / MSD 1200 Series, ODS2000 (50 x 4.6 mm, 5um) column, 30 ℃, 1.5 mL / min flow rate, 214 nm detection wavelenth, 0.1% NH4HCO3 aqueous solution / acetonitrile = 4 / 1, V / V mobile phase) to obtain a new imidazole derivative 1 (Compound 4) (650 mg, Y = 44.4%) as an off-white solid.

[0113] 1 H NMR (400 MHz, DMSO-d6) δ: 7.78 (s, 1H); m / z calculated 184.01, found (M+H) + 185.1

[0114] The 1H-NMR, 13C-NMR, and LC-MS spectra of the novel imidazole derivative 1 prepared above are shown in Figures 4 to 6.

[0115] 3. Preparation of novel pyrrole derivative 2 (Compound 5)

[0116] Step 1

[0117]

[0118] To a solution of methyl 1H-pyrrole-2-carboxylate (1) (10.0 g, 79.9 mmol) in DCM (200 mL) was added AlCl3 (46.9 g, 351.5 mmol) and the mixture was stirred vigorously at room temperature for 30 min. Next, nitromethane (14.1 g, 230.1 mmol) was added at 0°C, followed by ethyl 2-chloro-2-oxoacetate (16.4 g, 119.9 mmol), and the mixture was stirred at room temperature for 3 h. The reaction mixture was cooled, poured into ice water, and stirred vigorously for 30 min. The organic layer was separated, washed with saturated NaHCO3 solution (3 Х 300 mL) and water (200 mL), dried over sodium sulfate, and filtered. After filtration, the mixture was concentrated in vacuo to obtain the crude product. The crude material was purified by flash chromatography (dichloromethane / methanol = 20 / 1, v / v) to obtain methyl 4-(2-ethoxy-2-oxoacetyl)-1H-pyrrole-2-carboxylate (2) (13.0 g, 55.4 mmol, yield = 69.3%) as a yellow solid.

[0119] LC-MS (ESI): m / z 226.0 [M+H]+

[0120] 1 H NMR (400 MHz, DMSO-d6) δ: 12.97 (s, 1H), 7.91 - 7.92 (m, 1H), 7.26 (t, J= 2.8 Hz, 1H), 4.36 (q, J= 9.6 Hz, 2H), 1.33 (t, J= 9.6 Hz, 3H).

[0121] Step 2

[0122]

[0123] To a THF (30 mL) solution of methyl 4-(2-ethoxy-2-oxoacetyl)-1H-pyrrole-2-carboxylate(2) (3.0 g, 13.3 mmol) was added H2O (20 mL) containing LiOH·H2O (1.7 g, 39.9 mmol) at 0°C. The mixture was stirred at room temperature for 16 h and extracted with ethyl acetate. The aqueous solution was adjusted to pH 3 using 1 N HCl. When a solid was formed, it was filtered to obtain the target compound, a novel pyrrole derivative 2 (Compound 5) (1.6 g, 8.6 mmol, yield = 64.7%).

[0124] 1 H NMR (400 MHz, DO) δ 7.71 (d, J=1.6 Hz 1H), 7.27 (d, J=1.6 Hz 1H); 13 C NMR (100 MHz, DO) δ190.5, 171.7, 163.8, 131.7, 125.2, 121.5, 115.9; m / z calculated 183.01, found (MH) + 182.0

[0125] The 1H-NMR, 13C-NMR, and LC-MS spectra of the novel pyrrole derivative 2 prepared above are shown in Figures 7 to 9.

[0126] 4. Preparation of novel imidazole derivative 2 (Compound 6)

[0127] Step 1

[0128]

[0129] To a THF solution (30 ml) containing ethyl 1H-imidazole-2-carboxylate (1) (5.0 g, 35.7 mmol) was added NaH (2.2 g, 53.5 mmol) and SEM-Cl (2-(trimethylsilyl)-ethoxymethyl chloride) (8.9 g, 53.5 mmol) at 0°C in a nitrogen atmosphere (N2atmosphere), stirred overnight at room temperature, quenched with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with concentrated brine (100 mL), dried, filtered, and concentrated. The resultant product was purified by chromatography on a silica gel column (PE / EA = 1 / 1, v / v) to obtain ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (2) (7.0 g, 73%) as a yellow solid.

[0130] LC-MS (ESI): m / z 271.2 (M+H + )

[0131] Step 2

[0132]

[0133] To a solution of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 2-carboxylate (2) (6.0 g, 22.2 mmol) in ACN (Acetonitrile) (60 mL) at 0°C was added NBS (N-Bromosuccinimide) (4.7 g, 26.4 mmol), stirred at room temperature for 16 h, cooled with water (50 mL), and extracted with ethyl acetate (2 x 80 mL). The mixed organic layers were

[0134] The residue was washed with brine (100 mL), dried, filtered, and concentrated. The resulting product was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to obtain ethyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (3) (4.4 g, 57%) as a yellow solid.

[0135] LC-MS (ESI): m / z 350.2.0 (M+H + )

[0136] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 5.72 (s, 2H), 4.33-4.38 (m, 2H), 3.59 (t, J= 8 Hz, 2H), 1.36 (t, J= 6.8, 7.2 Hz, 3H), 0.89 (t, J = 8 Hz, 1H), 0.00 (s, 9H);

[0137] Step 3

[0138]

[0139] Ethyl 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (9.0 g, 0.026 mol), tributyl(1-ethoxyethenyl)stannane (10.21 g, 0.028 mol), and tetrakis(triphenylphosphine)palladium (1.48 g, 0.0013 mol) were mixed with dioxane (100 mL), stirred at 100°C for 16 h, added water, and extracted with ethyl acetate. 1 N HCl (40 mL) was added to the organic layer, and stirred at 25°C for 2 h. The organic layer was concentrated and the concentrate was purified by flash chromatography (PE / EA = 3 / 1, v / v) to obtain ethyl 5-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (4) (4.7 g, 0.014 mol, yield = 55.25%) as a yellow oil.

[0140] 1 H NMR (400 MHz, DMSO-d6) δ: 8.37 (s, 1H), 5.78 (s, 2H), 4.41 (q, J= 7.2 Hz, 2H), 3.60 (t, J= 8.0 Hz, 2H), 2.52 (s, 3H), 1.39 (t, J= 7.2 Hz, 3H), 0.90 (t, J= 8.0 Hz, 2H), 0.00 (s, 9H).

[0141] Step 4

[0142]

[0143] Ethyl 5-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxylate (4) (8.0 g, 25.52 mmol) and SeO2 (5.66 g, 51.05 mmol) were mixed with pyridine (80 mL) and stirred at 110℃ for 16 h. Ethyl acetate (200 mL) was added, filtered, and the filtrate was washed with 1 N HCl. The organic layer was concentrated, and the concentrate was purified by flash chromatography (dichloromethane / methanol = 10 / 1, v / v) to obtain 2-(2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 5-yl)-2-oxoacetic acid (5) (2.8 g, 8.15 mmol) as a yellow solid.

[0144] LC-MS (ESI): m / z 343.0 [M+H] +

[0145] 1 H NMR (400 MHz, DMSO-d6) δ: 8.65 (s, 1H), 5.82 (s, 2H), 4.41 (q, J= 7.2 Hz, 2H), 3.62 (t, J= 7.6 Hz, 2H), 1.39 (t, J= 7.2 Hz, 3H), 0.90 (t, J= 7.6 Hz, 2H), 0.00 (s, 9H).

[0146] Step 5

[0147]

[0148] 2-(2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 5-yl)-2-oxoacetic acid (5) (2.8 g, 8.15 mmol) was mixed with TFA (12 mL) and stirred at 25°C for 3 hours. The stirred mixture was concentrated to obtain [2-(ethoxycarbonyl)-1H-imidazol-4-yl](oxo)acetic acid (6) (2.4 g, crude), which was used immediately in the next step.

[0149] LC-MS (ESI): m / z 213.0 [M+H] +

[0150] Step 6

[0151]

[0152] A mixture of [2-(ehoxycarbonyl)-1H-imidazol-4-yl](oxo)acetic acid (6) (2.4 g, 11.31 mmol), LiOH·H2O (2.37 g, 56.56 mmol), and tetrahydrofuran / methanol / water=1 / 1 / 1 (12 mL) was stirred at 25°C for 4 h and adjusted to pH~7 with 1 N HCl. The adjusted mixture was heated to remove tetrahydrofuran and methanol, and the pH was adjusted to pH~3 with 1 N HCl. The resulting yellow solid was filtered, washed with water, and dried under vacuum to obtain a new imidazole derivative 2 (Compound 6) (1.2 g, 6.19 mmol, yield = 54.74%) as a yellow solid.

[0153] 1 H NMR (400 MHz, DMSO-d6+ DO) δ: 8.26 (s, 1H); 13C NMR (100 MHz, DMSO-d6+DO) δ: 181.83, 165.61, 159.56, 140.53, 137.93, 129.88; m / z calculated 184.01, found (M+H) + 185.1

[0154] The 1H-NMR, 13C-NMR, and LC-MS spectra of the novel imidazole derivative 2 (Compound 6) prepared above are shown in Figures 10 to 12.

[0155] <Example 2> Experimental study on the improvement of pulmonary fibrosis activity

[0156] 1. Cytotoxicity evaluation on A549 cells

[0157] To determine whether novel pyrrole derivatives or imidazole derivatives affect cell viability, cell viability was determined using A549 lung cancer cells with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. A549 cells were suspended in medium, seeded into 96-well plates, and cultured for 24 hours. After 24 hours, 200 μL of medium containing TGF-β1 (10 ng / ml) and / or the novel pyrrole derivatives or imidazole derivatives of the examples at different concentrations was added to each well, and cultured for 24 or 48 hours. After the incubation, MTT was diluted (0.5 mg / ml) in PBS (phosphate-buffered saline), seeded into each well (20 μL), and cultured for 4 hours in a CO2 incubator. After 4 hours, the MTT solution was removed, 200 μL of dimethyl sulfoxide (DMSO) was dispensed into each well, the formazan precipitate was dissolved for 5 minutes, and the absorbance was measured at 595 nm.

[0158] The cell viability after 24, 48, and 72 hours is shown as a percentage compared to the control group without treatment in Figures 13 to 16. The four novel pyrrole derivatives or imidazole derivatives of the examples (Compounds 3 to 7) generally did not exhibit cytotoxicity up to 10 μM regardless of the treatment time, whether treated alone or together with TGF-β1 (at least 80% or more cell viability was shown). Therefore, the highest treatment concentration for subsequent experiments was set at 10 μM.

[0159] 2. Effects of TGF-β1 treatment on A549 cells

[0160] (1) Experimental method

[0161] A549 cells, which are lung cancer-derived cells, were cultured in 3.5×10 5After floating the cells on the medium, they were dispensed into 60 mm plates and cultured for 48 hours. After 48 hours of culture, each plate was treated with TGF-β1 (10 ng / ml) alone or together with the novel pyrrole derivatives or imidazole derivatives of the examples at different concentrations and / or NIDB (Nintedanib), a drug for the treatment of idiopathic pulmonary fibrosis and interstitial lung disease, as a positive control. After 48 hours of culture, the cells were lysed with RIPA lysis buffer (RIPA lysis buffer [50 mM Tris]-Cl (pH, 7.4), 1% NP40, 150 mM NaCl, 1 mM EDTA, 1 mM, PMSF (phenylmethylsulfonyl fluoride)) containing MG-132 (10 μM, proteasome inhibitor, protect the HIF-1α subunit from proteasome degradation). Next, the supernatant was collected by centrifugation at 4°C (14,000 rpm and 10 minutes), and only the supernatant was analyzed by SDS-PAGE (SDS-polyacrylamide gel electrophoresis). Proteins were separated by electrophoresis. The separated proteins were transferred to a PVDF membrane (polyvinylidene difluoride membrane), reacted with 5% nonfat dry milk for 3 hours, and then reacted with primary antibodies at 4°C for 12 hours. After 12 hours, additional reaction was performed with secondary antibodies for each primary antibody, and protein bands were confirmed using an ECL kit according to the manufacturer's protocol.

[0162] (2) Experimental results

[0163] The results are shown in Figures 17 to 21.

[0164] Referring to Figure 17, when A549 cells were treated with 10 ng / mL of TGF-β1 and 5 and 10 μM of the novel pyrrole derivative 1 (compound 3) for 6 hours, the levels of HIF-1α, NOX2, NOX4, Col1, Col3, Col4, fibronectin, α-SMA, and E-cadherin proteins, which were increased by TGF-β1 treatment, tended to decrease. E-cadherin, an epithelial cell marker, which was decreased by TGF-β1 treatment, increased.

[0165] Also, referring to Figure 18, when A549 cells were treated with 10 ng / mL of TGF-β1 and 5 and 10 μM of novel imidazole derivative 1 (compound 4) for 6 hours, the proteins HIF-1α, NOX2, NOX4, Col1, Col3, Col4, α-SMA, and E-cadherin, which were increased by TGF-β1 treatment, tended to decrease. E-cadherin, an epithelial cell marker that was decreased by TGF-β1 treatment, increased.

[0166] Also, referring to Figure 19, when A549 cells were treated with 10 ng / mL of TGF-β1 and 10 μM of a novel pyrrole derivative 2 (compound 5) for 6 hours and 24 hours, the results showed a tendency for HIF-1α, NOX2, NOX4, pERK, and COL3A1 proteins, which were increased by TGF-β1 treatment, to decrease. Here, COL3A1 protein is a fibrosis marker protein.

[0167] Also, referring to FIG. 20, when A549 cells were treated with 10 ng / mL of TGF-β1 and 5, 7, and / or 10 μM of the novel imidazole derivative 2 (compound 6) for 6 hours and 24 hours, a tendency was observed for HIF-1α, pERK, N-cad, fibronectin, and COL4A6, which were increased by TGF-β1 treatment, to decrease.

[0168] In Fig. 21, when human bronchial epithelial cells, BBM cells, were treated with 10 ng / mL of TGF-β1 and 10 μM of novel pyrrole derivative 2 (comound 5) and novel imidazole derivative 2 (comound 6) for 24 hours, the results showed that N-cad, HIF-1α, Fibronectin, and COL4A6 increased by TGF-β1 treatment tended to be reduced by the novel derivatives.

[0169] TGF-β1 is a factor used as a typical pro-fibrotic cytokine in both mouse and human type II alveolar epithelial cells. It is known through several studies in the field that in the presence of TGF-β1, epithelial cells are first transformed into mesenchymal cells, then into fibroblasts, and finally into myofibroblasts (TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases, Int J Mol Sci., 2017,18(10):2157-2179).

[0170] 3. Inhibitory effect of epithelial-to-mesenchymal transition (EMT) in A549 cells treated with FG-4592 or CoCl2

[0171] (1) Experimental method

[0172] A549 cells, which are lung cancer-derived cells, were cultured at 4.5×10 4 cells / 200μl (=2.25×10 5After suspending the cells in the medium (10 cells / ml), 200 μl was dispensed per well of a 96-well plate and cultured overnight. The following day, wounds of the same size were created in each well using BioTek's AUTOSCRATCH. All wells with wounds were washed once with 1x PBS, and each well was treated with FG-4592 (50 μM) or CoCl2 (200 μM) alone or together with a novel pyrrole derivative or imidazole derivative. The 96-well plate treated with the samples was placed in BioTek's CYTATION5 imaging reader (37°C, 5% CO2) and cultured for 48 hours. The wounds of each well were photographed at 40x magnification every 2 hours and the wound spacing (μm) was measured.

[0173] (2) Experimental results

[0174] The results are shown in Figures 22 to 29.

[0175] Referring to Figure 22, when A549 cells were treated with FG-4592 (Roxadustat), which promotes EMT, alone or together with the novel pyrrole derivative 1 (Compound 3) or imidazole derivative 1 (Compound 4) of the example, the EMT increased by FG-4592 was significantly reduced by the derivatives. Figure 23 shows microscopic photographs taken at 0, 24, and 48 hours after treatment with one of the samples among the results of three repetitions of the experiment.

[0176] Figure 24 shows the results of treating A549 cells with CoCl2, which promotes EMT, alone or together with the novel pyrrole derivative 1 (Compund 3) or imidazole derivative 1 (Compound 4) of the example. Similar to the results in Figure 22 where FG-4592 was treated, when treated together with the novel pyrrole derivative 1 (Compund 3) or imidazole derivative 1 (Compound 4) of the example, the EMT increased by CoCl2 was significantly reduced by the derivatives. Figure 25 shows microscopic photographs taken at 0, 24, and 48 hours after treatment with one sample among the results of three repetitions of the experiment.

[0177] Next, Fig. 26 shows that when A549 cells were treated with FG-4592 (Roxadustat) alone or together with the novel pyrrole derivative 2 (Compound 5) or imidazole derivative 2 (Compound 6) of the example, the EMT increased by FG-4592 was significantly reduced by the derivatives. Fig. 27 shows microscopic photographs taken at 0, 24, and 48 hours after treatment with one of the samples among the results of three repetitions of the experiment.

[0178] Finally, Fig. 28 shows the results when A549 cells were treated with CoCl2 alone or together with the novel pyrrole derivative 2 (Compound 5) or imidazole derivative 2 (Compound 6) of the example. Similar to the results in Fig. 26 in which FG-4592 was treated, when treated together with the novel pyrrole derivative 2 (Compound 5) or imidazole derivative 2 (Compound 6) of the example, the EMT increased by CoCl2 was significantly reduced by the derivatives. Fig. 29 shows microscopic photographs taken at 0, 24, and 48 hours after treatment with one sample among the results of three repetitions of the experiment.

[0179] The present invention can be used as a functional food or pharmaceutical.

Claims

1. A compound which is a pyrrole or imidazole derivative of the following <Chemical Formula 5>, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof: <Chemical Formula 5> R1-X-R2 In the above, X is a pyrrole ring or an imidazole ring, R1 and R2 are each independently a -(CO)n-R3 group, n is 0 or 1, R3 is R4-COOH group, and R4 is C 0-2 It is an alkyl group, The above R1 and R2 modify the carbon atoms of the pyrrole ring or imidazole ring.

2. In paragraph 1, The above R1 and R2 are compounds that modify the carbon at the 3rd or 5th position of the pyrrole ring or modify the carbon at the 2nd or 5th position of the imidazole ring.

3. In paragraph 1, The above pyrrole derivative is a compound represented by the following <Chemical Formula 1>. <Chemical Formula 1> 4. In paragraph 1, The above imidazole derivative is a compound represented by the following <Chemical Formula 2>. <Chemical Formula 2> 5. In paragraph 1, The above pyrrole derivative is a compound represented by the following <Chemical Formula 3>. <Chemical Formula 3> 6. In paragraph 1, The above imidazole derivative is a compound represented by the following <Chemical Formula 4>. <Chemical Formula 4> 7. A composition for improving pulmonary fibrosis, comprising a compound described in any one of claims 1 to 6 as an active ingredient.

8. In paragraph 7, A composition characterized in that the above pulmonary fibrosis is idiopathic pulmonary fibrosis.

9. In paragraph 7, A composition characterized in that the above composition is a pharmaceutical composition.

10. In paragraph 7, A composition characterized in that the above composition is a food composition.

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