WO2021260560A1 - Composition for treating pulmonary fibrosis - Google Patents

Composition for treating pulmonary fibrosis Download PDF

Info

Publication number
WO2021260560A1
WO2021260560A1 PCT/IB2021/055521 IB2021055521W WO2021260560A1 WO 2021260560 A1 WO2021260560 A1 WO 2021260560A1 IB 2021055521 W IB2021055521 W IB 2021055521W WO 2021260560 A1 WO2021260560 A1 WO 2021260560A1
Authority
WO
WIPO (PCT)
Prior art keywords
pulmonary fibrosis
formula
group
compound
composition
Prior art date
Application number
PCT/IB2021/055521
Other languages
French (fr)
Korean (ko)
Inventor
윤치호
김민경
Original Assignee
제이더블유중외제약 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 제이더블유중외제약 주식회사 filed Critical 제이더블유중외제약 주식회사
Priority to KR1020237002576A priority Critical patent/KR20230031304A/en
Publication of WO2021260560A1 publication Critical patent/WO2021260560A1/en

Links

Classifications

    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to pulmonary fibrosis (Pulmonary Fibrosis), particularly for pulmonary fibrosis caused by Idiopathic Pulmonary Fibrosis (IPF) and/or coronavirus infection-19. It relates to a therapeutic composition comprising a compound having a high therapeutic effect. Background air pulmonary fibrosis proceeds from interstitial lung inflammation caused by various causes, and idiopathic pulmonary fibrosis (IPF) of unknown cause is the most frequent form, and the average survival period after diagnosis is within 2-3 years. It is an intractable lung disease with no effective treatment to such an extent that the 5-year survival rate is only 20%.
  • lung inflammatory response and unregulated immune mechanism abnormal signal transduction system in alveolar epithelial cells, suppression of fibrinolytic activity due to epithelial cell damage, activation of fibroblasts in lung interstitium, mesenchymal transformation of epithelial cells, endothelium Cell-derived fibroblast differentiation, influx of inactive blood fibroblasts into the lungs, and cell transformation such as differentiation into fibroblasts are important factors in lung fibrosis as a mechanism of myofibroblast differentiation and proliferation.
  • TGF-P As a factor related to lung fibrosis, TGF-P is best known, and it is known to induce fibrosis by activating AKT/mTOR, SMAD, ffnt/p-catenin, and YAP/TAZ signaling systems.
  • oxidative stress which increases simultaneously with the activation of the signal transduction system, plays an important role, and microRNAs that increase or inhibit post-transcriptional expression of fibrosis regulators or intermediate mediators, DNA methyl at ion, PDGF growth factor and IL -4 is known as a major factor involved in fibrosis.
  • SARS-Cov-2 severe acute respiratory syndrome coronavirus
  • An object of the present invention is to provide a composition for treating pulmonary fibrosis or a pharmaceutical formulation comprising the same.
  • Another object of the present invention is to provide a method for treating pulmonary fibrosis comprising administering the composition for treating pulmonary fibrosis or a pharmaceutical formulation comprising the same to an individual in need of pulmonary fibrosis treatment.
  • the present invention provides a pharmaceutical composition for treating pulmonary fibrosis comprising a compound having the structure of Formula I, a prodrug thereof, a salt thereof, or an isomer thereof.
  • 3 ⁇ 4 is an alkyl group of 6 or an alkenyl group of 0 2 6
  • prodrug of the compound of formula (I) according to the present invention has the structure of formula (III).
  • the prodrug of the compound of formula (I) according to the present invention, formula (III), may have the structure of formula (IV) to formula (VI), but is not limited thereto 2021/260560 ? €1/162021/055521 is not.
  • the compound having the structures of Formulas I to VI according to the present invention may be prepared by the method described in Korean Patent No. 1,692,921, but is not limited thereto.
  • the present invention also relates to pharmaceutically acceptable salts of compounds of formulas (I) to (VI).
  • Non-limiting examples of the pharmaceutically acceptable salts of the compounds of Formulas I to VI include hydrochloric acid, ]3-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, horse rate, 2021/260560 €1/162021/055521 di-!-toluyl salts of tartaric acid, ortinic acid, edicylic acid, hemi-edicylic acid and mandelic acid may be exemplified, but not limited thereto.
  • the therapeutic composition comprising the compounds of formulas (I) to (VI) according to the present invention may include one or more pharmaceutically acceptable carriers.
  • the therapeutic composition according to the present invention may be administered orally or parenterally, and parenteral administration is intranasal, intranasal, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous , It may be prepared in a formulation suitable for intraperitoneal, intestinal, topical, sublingual or rectal dosage forms and administered by the above route, but is not limited thereto. Accordingly, the present invention provides a pharmaceutical formulation for oral or parenteral administration comprising the therapeutic composition according to the present invention.
  • the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same may be administered orally, or may be administered intranasally or intranasally, especially in the form of a spray (large) or aerosol (large) when administered intranasally or intranasally administration of It is more preferable to be formulated and administered in a dosage form for administration, but is not limited thereto.
  • the pharmaceutical formulation for intranasal or intranasal administration may be prepared according to techniques well known in the art to which the present invention pertains, and benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons and/or others It can be prepared as a solution in saline using solubilizing or dispersing agents known in the art.
  • the therapeutic composition according to the present invention may be formulated in a sterile injectable formulation as a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents.
  • Sterile injectable formulations are also non-toxic It may be a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent (eg, a solution in 1,3-butanediol).
  • a parenterally acceptable diluent or solvent eg, a solution in 1,3-butanediol.
  • pharmaceutically acceptable vehicles and solvents include mannitol, water, Ringel's solution, and isotonic sodium chloride solution.
  • sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil with less irritation may be used, including synthetic mono or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are pharmaceutically acceptable natural oils (eg, olive oil or castor oil), especially polyoxyethylated ones thereof, and are useful in injection preparations.
  • the therapeutic composition according to the present invention is not limited thereto, but may be formulated in any orally acceptable pharmaceutical dosage form, including capsules, pellets, tablets, aqueous suspensions and solutions, and administered orally.
  • excipients When formulated for oral administration, it may be formulated to include one or more pharmaceutically acceptable excipients in the therapeutic composition according to the present invention, and such excipients include a filler (diluent), disintegrant, binder, lubricant (Lubricant), preservatives, antioxidants, buffers, chelating agents, solubilizers and at least one selected from the group consisting of a sweetener may be used.
  • the filler (diluent) is mannitol, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, Microcrystalline cellulose (microcrystal 1 ine cel lulose), microcrystalline silicified cellulose (microcrystal 1 ine si l ici fied cel lulose), powdered cellulose, dextrates, dextrose, fructose ( fructose), lactitol (lact itol), lactose anhydrous (lactose anhydrous) , lactose monohydrate ( lactose monohydrate) , lactose dihydrate ( lactose dihydrate) , lactose trihydrate , mannitol sorbitol , starch , pregelat inized starch , sucrose , talc , xylitol , maltose maltose Lin (maltose maltodextr in
  • the pharmaceutical formulation for oral administration according to the present invention is preferably a capsule, pellet or tablet, but is not limited thereto, and the tablet is more preferably a film-coated tablet including a film coating layer.
  • the film coating layer is selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methacrylic acid copolymer, polyethylene oxide and xanthan gum.
  • the film coating layer is polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, meta It may include one or more film coating bases selected from the group consisting of acrylic acid copolymer, polyethylene oxide and xanthan gum, but is not limited thereto.
  • the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same can be used for the treatment of pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19.
  • the present invention uses the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same for the treatment of pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19, and It relates to a method of treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19, characterized in that the pharmaceutical formulation according to the present invention is administered to a patient in need of the treatment.
  • FIG. 1 is a view showing the overall experimental conditions according to the present invention.
  • FIG. 2 is a view showing changes in inflammatory cells in a mouse model of Bleomycin-induced pulmonary fibrosis following administration of a compound of Formula II according to the present invention and pirfenidone, a control drug.
  • FIG. 3 is a view showing changes in inflammation-related cytokines in a mouse model of Bleomycin-induced pulmonary fibrosis following administration of the compound of Formula II according to the present invention.
  • TGF Tissue Growth Factor
  • FIG. 4 is an ashcroe in a mouse model of Bleomycin-induced pulmonary fibrosis according to the administration of the compound of Formula II according to the present invention. It is a drawing showing the score (Ashcroft Score). 5 is a view showing changes in total collagen in the lungs of a mouse model of Bleomycin-induced pulmonary fibrosis according to administration of a compound of Formula II according to the present invention. 6 is a view showing changes in alveolar surface area, alveolar bronchus and perivascular wall thickness in a mouse model of bleomycin vs. 1601 ⁇ (: ⁇ )-induced pulmonary fibrosis according to the administration of the compound of Formula II according to the present invention. (A) Alveolar surface area
  • Lung fibrosis was induced in mice by intratracheal injection of 3 mg/kg bleomycin under isof lurane saw lip anesthesia (Matrix, Orchard Park, NY, USA).
  • pirfenidone 200 mg/kg/bid, po, 2% DMSO, 0.5% CMC
  • B291 in all the drawings means a compound of Formula II, and the numbers 0.1, 1.0 and 5.0 after B291 mean that the dosage of the compound of Formula II is 0.1 mg/kg, 1.0 mg/kg and 5.0 mg/kg, respectively. do.
  • BPFD is pirfenidone (pirfenidone)
  • pirfenidone is a normal control group (sa ine-inst i 1 led mice administered with drug vehicle, SAL + VEH) administered drug vehicle to the saline (saline) treated experimental animals
  • BV refers to the pulmonary fibrosis group administered with drug vehicle to bleomycin-treated animals (bleomycin-inst il led mice administered with drug vehicle, BLM+VEH).
  • the test group for the effect of the compound of formula II is a 6-species group, a normal control group (saline-inst i 1 led mice administered with drug vehicle, SAL+VEH), a lung fibrosis group (bleomycin) -inst il led mice administered with drug vehicle, BLM+VEH), 3 groups (0.1 mg/kg, 1.0 mg/kg and 5.0 mg/kg) administered with a compound of Formula II at 0.1 mg/kg in a mouse model of bleomycin-induced pulmonary fibrosis ), and a group administered with 200.0 mg/kg of pirfenidone as a drug control group in a mouse model of bleomycin-induced lung fibrosis (see Table 1).
  • Example 2 Inflammatory cell change After sacrificing the mouse according to Example 1, the chest cavity was opened so that the lungs could be sufficiently expanded, the trachea was incised, and 1 mi PBS was slowly injected into the lungs through a tube inserted into the airway, and this was recovered. to 4 (the bronchial lavage fluid..., and stored in the bronchoalveolar lavage fluid were used to using the (Chemometec, Gydevang, Denmark NucleoCounter) measuring the total number of inflammatory cells, in PBS the cells precipitated after centrifugation It was resuspended and spread on slides with cytospin (Thermo Electron, Waltham, MA, USA) and used for differentiation of inflammatory cells.
  • cytospin Thermo Electron, Waltham, MA, USA
  • the total number of inflammatory cells was significantly reduced, and the number of macrophages, lymphocytes and neutrophils also decreased.
  • the pirfenidone drug control group there was no change in the increase in the total number of inflammatory cells along with the increase in macrophages, and the number of lymphocytes and neutrophils showed a tendency to decrease.
  • a significant decrease in the total number of inflammatory cells was confirmed with a decrease in macrophages in a dose-related manner in the groups administered with the compound of Formula II at 0.1 mg/kg and 1.0 mg/kg.
  • Example 3 Inflammatory cytokine change After extracting and electrophoresis-separated proteins from mouse lung tissue, the expression of TGF-p, TNF-a, IL-lp and IL-17 was confirmed by Western blotting and quantitatively analyzed. The significantly increased expression of TGF-IL-17, TNF-a and IL-1 ⁇ proteins in the bleomycin-induced pulmonary fibrosis reaction was decreased in the group administered with the compound of Formula II.
  • IL-ip was significantly decreased in the group administered with the compound of formula II at 1.0 mg/kg and 5.0 mg/kg, and the expression of TGF- and IL-17 was maximally reduced in the group administered with the compound of formula II at 1.0 mg/kg.
  • TNF-a showed a significant decrease in the 5.0 mg/kg administration group, there is a difference in pro-inflammatory protein expression according to the administration dose.
  • the increase in IL-17 in the lungs tended to decrease in all drug administration groups, but there was no statistical significance.
  • the pirfenidone drug control group had no effect on increasing the expression of TGF-y ⁇ and IL-17, and showed a tendency to decrease the protein expression of TNF-a and IL-1 y ⁇ .
  • both TGF-/37 ⁇ were significantly reduced in the group administered with the compound of Formula II, and the reduction of IL-17 in the previous administration group, TNF-a reduction and 1.0 mg at the same level in the 5.0 mg/kg administration group
  • TNF-a reduction and 1.0 mg at the same level in the 5.0 mg/kg administration group There was a decrease in IL-1 in the /kg and 5.0 mg/kg administration groups.
  • Example 4 Example 4.
  • a mouse lung tissue slide was prepared and the degree of tissue change was observed by staining with Hemetoxylin & eosin (H&E), and the degree of inflammation was measured and quantified in the stained tissue.
  • H&E Hemetoxylin & eosin
  • the concentration of collagen extracted from mouse lung tissue was quantified by Sircol assay to analyze the deposited amount.
  • the Ashcroft Score a quantitative indicator for the severity of pulmonary fibrosis, was decreased by administration of the compound of Formula II (see FIG. 4 , the plot is the mean ⁇ standard error of 6 mouse groups, # is ⁇ C0.05, ## means ⁇ C0.01, and ⁇ means ⁇ C0.001) .
  • Collagen deposition amount was reduced to a level equivalent to that of the drug control group, or the statistical significance level of the decrease was high in the 5.0 mg/kg administration group (see FIG. 5 , the plot is the mean ⁇ standard error of 6 mouse groups, # is ⁇ C0.05, ## means three 01, and ⁇ means ⁇ C0.0()1) .
  • the decrease in the alveolar surface area, the thickening of the alveolar wall, the bronchial wall, and the blood vessel wall were alleviated (see FIGS. 6(A) to 6(D), the plot shows that of the six mouse groups 2021/260560 ? €1/162021/055521 mean ⁇ standard error, # means ⁇ 0.05, ## means ⁇ 0.01, and ⁇ means ⁇ 0.001).
  • the compounds of Formulas I to VI according to the present invention can achieve excellent effects in treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, or pulmonary fibrosis caused by coronavirus infection-19.
  • pulmonary fibrosis particularly idiopathic pulmonary fibrosis, or pulmonary fibrosis caused by coronavirus infection-19.

Abstract

The present invention relates to a therapeutic composition, comprising a compound having excellent therapeutic efficacy for pulmonary fibrosis, in particular, idiopathic pulmonary fibrosis (IPF) or pulmonary fibrosis caused by coronavirus disease-19 infection.

Description

폐섬유화증 치료용 조성물 발명의 분야 본 발명은 폐섬유화증 (Pulmonary Fibrosis) , 특히 원인불명의 특발성 폐섬유화증 (Idiopathic Pulmonary Fibrosis, IPF) 및/또는 코로나바이러스감염증- 19로 인한 폐섬유화증에 대한 높은 치료효과를 가지는 화합물을 포함하는 치료용 조성물에 대한 것이다. 배경기숨 폐섬유화는 다양한 원인에 의해 발생한 간질성 폐 염증으로부터 진행되며， 원인 불명의 특발성 폐섬유화증 (Idiopathic Pulmonary Fibrosis, IPF)이 가장 빈번한 형태로， 진단 후 평균 생존기간이 2-3년 이내이고 5년 생존율이 20%에 불과할 정도로 효율적인 치료법이 없는 난치성 폐질환이다. 현재에도 정확한 병인과 발병기전을 밝히기 위한 연구와 치료제 개발이 지속적으로 이루어지고 있는데， endothel in 수용체 길항제， IFN- y -lb 생성성 약물， 닌테다닙 (nintedanib) 또는 피르페니돈 (pirfenidone) 성분의 항섬유화 제제를 이용한 치료가 시도되고있지만， 단지 증상의 진행을 늦추는 정도에 불과할 뿐 아니라， 부작용의 발현 빈도가 높고， 중증 폐 섬유화 환자에서 그 효과가 기대에 미치지 못하고 있다. 폐섬유화증의 발병기전과 관련해서， 폐포 상피세포 (alveolar epithel ial cel Is)의 지속적인 손상에 대한 비정상적인 치유과정에 의해 섬유화가 진행되는 것으로 알려져 있는데， 손상되어 쉽게 재생되지 못하는 폐 상피세포에 대해 섬유모세포가 활성화되고 과도한 세포외 매트릭스 (extracel lular matrix) 생성으로 이어져， 폐 간질의 섬유화를 초래하게 된다. 이는 폐포의 유순도를 감소시키고 폐 능력을 비가역적으로 감소시켜， 산소를 모세관으로 수송시키는 능력을 감소시킨다고 알려져 있다. 또한， 폐 염증 반응과 조절되지 않는 면역 기전， 폐포 상피세포 내 신호전달체계의 이상， 상피세포 손상에 의한 섬유소 용해 활성의 억제와 더불어 폐 간질내 섬유모세포의 활성화， 상피세포의 중간엽성 변환， 내피세포 유래 섬유모세포 분화， 혈중 불활성 섬유아세포의 폐내 유입과 섬유모세포로의 분화와 같은 세포 변환이 근육섬유모세포 분화 증식의 기전으로 폐 섬유화증의 중요 요인이 된다. 폐섬유화와 관련된 인자로는 TGF-P가 가장 잘 알려져 있으며， AKT/mTOR, SMAD, ffnt/p -catenin, YAP/TAZ 신호전달 체계들을 활성화시켜 섬유화를 유발하는 것으로 알려져 있다. 또한， 신호전달체계 활성화와 동시에 증가하는 산화 스트레스가 중요한 역할을 하는 것으로 관찰되고， 섬유화 조절인자 또는 중간 매개인자의 전사 후 발현을 증가시키거나 억제하는 microRNAs , DNA methyl at ion, PDGF 성장인자와 IL-4 등이 섬유화에 관여하는 주요인자로 알려져 있다. 최근어］는 SARS-Cov-2 ( Severe acute respiratory syndrome coronavirusField of the Invention of Compositions for Treatment of Pulmonary Fibrosis The present invention relates to pulmonary fibrosis (Pulmonary Fibrosis), particularly for pulmonary fibrosis caused by Idiopathic Pulmonary Fibrosis (IPF) and/or coronavirus infection-19. It relates to a therapeutic composition comprising a compound having a high therapeutic effect. Background air pulmonary fibrosis proceeds from interstitial lung inflammation caused by various causes, and idiopathic pulmonary fibrosis (IPF) of unknown cause is the most frequent form, and the average survival period after diagnosis is within 2-3 years. It is an intractable lung disease with no effective treatment to such an extent that the 5-year survival rate is only 20%. Even now, research and development of therapeutic agents to elucidate the exact etiology and pathogenesis are continuously being carried out. Treatment using fibrotic agents has been attempted, but only to the extent of slowing the progression of symptoms, the frequency of side effects is high, and the effect is not as expected in patients with severe pulmonary fibrosis. With respect to the pathogenesis of pulmonary fibrosis, it is known that fibrosis proceeds due to an abnormal healing process for continuous damage to alveolar epithelial cells (alveolar epithel ial cel Is). Hair cells are activated and lead to excessive extracellular matrix production, leading to fibrosis of the lung interstitium. This reduces the compliance of the alveoli and irreversibly reduces the ability of the lungs to transport oxygen into the capillaries. It is known to reduce ability. In addition, lung inflammatory response and unregulated immune mechanism, abnormal signal transduction system in alveolar epithelial cells, suppression of fibrinolytic activity due to epithelial cell damage, activation of fibroblasts in lung interstitium, mesenchymal transformation of epithelial cells, endothelium Cell-derived fibroblast differentiation, influx of inactive blood fibroblasts into the lungs, and cell transformation such as differentiation into fibroblasts are important factors in lung fibrosis as a mechanism of myofibroblast differentiation and proliferation. As a factor related to lung fibrosis, TGF-P is best known, and it is known to induce fibrosis by activating AKT/mTOR, SMAD, ffnt/p-catenin, and YAP/TAZ signaling systems. In addition, it is observed that oxidative stress, which increases simultaneously with the activation of the signal transduction system, plays an important role, and microRNAs that increase or inhibit post-transcriptional expression of fibrosis regulators or intermediate mediators, DNA methyl at ion, PDGF growth factor and IL -4 is known as a major factor involved in fibrosis. The latest word] is SARS-Cov-2 (Severe acute respiratory syndrome coronavirus)
2)에 감염된 코로나바이러스감염증- 19 환자 다수에서 폐섬유화증이 발생된다는 보고가 이어지고 있다. 현재에도 전세계 다수의 제약회사에서 폐섬유화증， 특히 원인불명의 특발성 폐섬유화증 및/또는 코로나바이러스감염증- 19로 인한 폐섬유화증 치료제 개발을 위한 노력을 기울이고 있으나， 아직 만족할만한 치료 효과를 나타내는 치료제는 보고되고 있지 않으며， 여전히 폐섬유화증에 대한 치료 효과가 우수한 치료제에 대한 수요는 절실한 상황이다. 이러한 배경 하에서， 본 발명자들은 기존에 항암 효과를 갖던 화합물이 2021/260560 1^(:1^2021/055521 폐섬유화증， 특히 원인불명의 특발성 폐섬유화증 및/또는 코로나바이러스감염증-2) Infected with coronavirus infection- A number of 19 patients have been reported to develop pulmonary fibrosis. Even now, a number of pharmaceutical companies around the world are making efforts to develop a treatment for pulmonary fibrosis caused by pulmonary fibrosis, particularly idiopathic pulmonary fibrosis of unknown cause and/or coronavirus infection-19, but a therapeutic agent that still shows satisfactory therapeutic effect has not been reported, and there is still an urgent need for a therapeutic agent with excellent therapeutic effects for pulmonary fibrosis. Under this background, the present inventors found that a compound having an anticancer effect 2021/260560 1^(:1^2021/055521 Pulmonary fibrosis, especially idiopathic pulmonary fibrosis of unknown etiology and/or coronavirus infection-
19로 인한 폐섬유화증에 대한 우수한 치료 효과를 나타내어， 이러한 질환의 치료용도로 사용될 수 있음을 확인하고 본 발명을 완성하였다. ［선행기술문헌］ 19 showed an excellent therapeutic effect on pulmonary fibrosis, confirmed that it can be used for the treatment of these diseases, and completed the present invention. [Prior art literature]
（특허문헌 1） 대한민국 등록특허 제 1 ,692,921호 발명의 요약 본 발명의 목적은 폐섬유화증 치료용 조성물 또는 이를 포함하는 약제학적 제형을 제공하는데 있다. 본 발명의 또 다른 목적은 상기 폐섬유화증 치료용 조성물 또는 이를 포함하는 약제학적 제형을 폐섬유화증 치료를 필요로 하는 개체에 투여하는 단계를 포함하는 폐섬유화증 치료방법을 제공하는데 있다. 상기 목적을 달성하기 위하여， 본 발명은 화학식 I의 구조를 가지는 화합물， 이의 프로드럭， 이의 염， 또는 이의 이성체를 포함하는 폐섬유화증 치료용 약학 조성물을 제공한다. (Patent Document 1) Republic of Korea Patent No. 1,692,921 Summary of the Invention An object of the present invention is to provide a composition for treating pulmonary fibrosis or a pharmaceutical formulation comprising the same. Another object of the present invention is to provide a method for treating pulmonary fibrosis comprising administering the composition for treating pulmonary fibrosis or a pharmaceutical formulation comprising the same to an individual in need of pulmonary fibrosis treatment. In order to achieve the above object, the present invention provides a pharmaceutical composition for treating pulmonary fibrosis comprising a compound having the structure of Formula I, a prodrug thereof, a salt thereof, or an isomer thereof.
［화학식 I］
Figure imgf000005_0001
2021/260560 ?€1/162021/055521 상기 화학식 I에서， ¾는 -¾의 알킬기，
Figure imgf000006_0001
알키닐기이고， ¾는 아릴기， 치환된 아릴기， 또는 _ =0）¾이고， ¾는 - 의 알킬기， 알케닐기， 또는 02 6의 알키닐기이다. 본 발명에 따른 코로나바이러스감염증- 19 치료용 약학 조성물에 포함되는 상기 화학식 I의 화합물에 있어， ¾는 6의 알킬기 또는 02 6의 알케닐기이고， ¾ 는 （=0）¾이고， ¾는 - 의 알킬기인 것이 바람직하며， ¾는 메틸（1 내기）이고， ¾는 _ =0）抑 3인 것이 보다 바람직하지만 이에 한정되는 것은 아니다. 화학식 I의 화합물에 있어 ¾는 메틸（1 내기）이고， ¾는 - ［：（=（））抑 3인 경우， 화학식 II의 구조를 가진다. [Formula I]
Figure imgf000005_0001
2021/260560 ? €1/162021/055521 In Formula I, ¾ is an alkyl group of -¾,
Figure imgf000006_0001
an alkynyl group, ¾ is an aryl group, a substituted aryl group, or _ = 0) ¾, and ¾ is an alkyl group of -, an alkenyl group, or an alkynyl group of 0 2 6 . In the compound of Formula I included in the pharmaceutical composition for treatment of coronavirus infection-19 according to the present invention, ¾ is an alkyl group of 6 or an alkenyl group of 0 2 6 , ¾ is (=0) ¾, and ¾ is - It is preferably an alkyl group of, ¾ is methyl (1 group), and ¾ is _ = 0) more preferably 抑3 , but is not limited thereto. In the compound of formula (I), ¾ is methyl (1 group), and ¾ is - [: (=()) When 抑3 is 3, it has the structure of formula (II).
［화학식 II］
Figure imgf000006_0002
또한 본 발명에 따른 상기 화학식 I의 화합물의 프로드럭은 화학식 III의 구조를 가진다. [Formula II]
Figure imgf000006_0002
In addition, the prodrug of the compound of formula (I) according to the present invention has the structure of formula (III).
［화학식 III］ 2021/260560 ?€1/162021/055521
Figure imgf000007_0001
상기 화학식 III에서， ¾는 - 의 알킬기， 。厂 의 알케닐기， 또는 02 - ¾ 의 알키닐기이고， ¾는 아릴기， 치환된 아릴기， 또는 _ =0)¾이고， ¾는 01- ¾ 의
Figure imgf000007_0002
알키닐기이고， ¾는 구03¾， _卵03一[Formula III] 2021/260560 ?€1/162021/055521
Figure imgf000007_0001
In Formula III, ¾ is-an alkenyl group, or 0 2 in the alkyl group,厂of - and alkynyl groups ¾, ¾ it is an aryl group, a substituted aryl group, or _ = 0) ¾, ¾ is 0 1 - ¾ of
Figure imgf000007_0002
It is an alkynyl group, and ¾ is 0 3 ¾, _卵0 3一
¾+ ， -쌔32- 2 +， _灰)32¾+， ~?03 2~^2+, _灰)32 2+， 구조식 1， 구조식 2， 또는 구조식 3이다.
Figure imgf000007_0004
특히 본 발명에 따른 화학식 1111의 화합물에 있어， ¾는 - 의 알킬기
Figure imgf000007_0003
알케닐기이고， ¾는 - =0)¾이고， ¾는 -¾의 알킬기， ¾는 구03¾， -卵03 - + 또는 -쌔32 32인 것이 바람직하며， ¾는 메틸 (1 내기)이고， ¾는 - 0(=0)¾, ¾는 -쌔3¾， -卵03 - + 또는 -쌔32_此2인 것이 보다 바람직하지만 이에 한정되는 것은 아니다. 가장 바람직하게는 본 발명에 따른 화학식 I의 화합물의 프로드럭인 화학식 III는 화학식 IV내지 화학식 VI의 구조를 가질 수 있지만 이에 한정되는 2021/260560 ?€1/162021/055521 것은 아니다. 본 발명에 따른 화학식 I 내지 화학식 VI의 구조를 갖는 화합물은 대한민국 등록특허공보 제 1 ,692,921호에 기재된 방법 등에 의해 제조될 수 있지만 이에 한정되는 것은 아니다.
Figure imgf000008_0001
또한 본 발명은 화학식 I 내지 화학식 VI의 화합물의 약학적으로 허용가능한 염에 관한 것이다. 화학식 I 내지 화학식 VI의 화합물의 약학적으로 허용가능한 염의 비제한적인 예로는 염산， ］3-톨루엔설폰산， 푸마르산， 시트르산， 숙신산， 살리실산， 옥살산， 브롬산， 인산， 메탄설폰산， 타르타르산， 말레이트， 2021/260560 ?€1/162021/055521 디-！）-톨루오일 타르타르산， 오르틴산， 에디실산， 헤미 에디실산 및 만델산의 염이 예시될 수 있지만 이에 한정되는 것은 아니다. 본 발명에 따른 화학식 I 내지 화학식 VI의 화합물을 포함하는 치료용 조성물에는 약제학적으로 허용 가능한 담체가 하나 이상 포함될 수 있다 . 본 발명에 따른 치료용 조성물은 경구 투여 또는 비경구 투여될 수 있으며， 비경구 투여는 비내， 비강내， 구강， 정맥내， 근육내， 동맥내， 골수내， 경막내， 심장내， 경피， 피하， 복강내， 장관， 국소， 설하 또는 직장 투여 형태에 적합한 제형으로 제조되어 상기 경로로 투여될 수 있지만， 이에 한정되는 것은 아니다. 이에 따라 본 발명은 본 발명에 따른 치료용 조성물을 포함하는 경구 또는 비경구 투여용 약제학적 제형을 제공한다. 바람직하게는 본 발명에 따른 치료용 조성물 또는 이를 포함하는 약제학적 제형은 경구 투여되거나， 비내 또는 비강내 투여될 수 있으며， 특히 비내 또는 비강내 투여시에는 스프레이（ 크 ） 또는 에어로솔（크 ） 형태로의 투여，
Figure imgf000009_0001
투여용 제형으로 제형화되어 투여되는 것이 더욱 바람직하지만 이에 한정되는 것은 아니다 . 상기 비내 또는 비강내 투여용 약제학적 제형은 본 발명이 속하는 기술분야에 잘 알려진 기술에 따라 제조될 수 있으며 벤질 알코올 또는 다른 적합한 보존제， 생체 이용율을 증강시키기 위한 흡수 촉진제， 플루오로카본 및/또는 기타 본 분야에 알려진 가용화제 또는 분산제를 사용하여 염수중의 용액으로서 제조될 수 있다. 또 다른 형태로서， 본 발명에 따른 치료용 조성물은 멸균 주사용 수성 또는 유성 현탁액으로서 멸균 주사용 제형으로 제형화될 수 있다. 이 현탁액은 적합한 분산제 또는 습윤제（예， 트윈 80） 및 현탁화제를 사용하여 본 분야에 공지된 기술에 따라 제형화될 수 있다. 멸균 주사용 제제는 또한 무독성의 비경구적으로 허용되는 희석제 또는 용매중의 멸균 주사용액 또는 현탁액 (예， 1,3 -부탄디올중의 용액 )일 수 있다. 약학적으로 허용될 수 있는 비히클 및 용매의 비제한적인 예시로는 만니톨， 물， 링겔 용액 및 등장성 염화나트륨 용액이 있다. 또한， 멸균 불휘발성 오일이 통상적으로 용매 또는 현탁화 매질로서 사용된다. 이러한 목적을 위해， 합성 모노 또는 디글리세라이드를 포함하여 자극성이 적은 어떠한 불휘발성 오일도 사용할 수 있다. 올레산 및 이의 글리세라이드 유도체와 같은 지방산이 약제학적으로 허용되는 천연 오일 (예， 올리브유 또는 피마자유)， 특히 이들의 폴리옥시에틸화된 것과 마찬가지로 주사 제제에 유용하다 . 또한 본 발명에 따른 치료용 조성물은 이들로 한정되는 것은 아니지만 캡슐， 펠렛， 정제， 수성 현탁액 및 용액을 포함하여 경구적으로 허용되는 어떠한 약제학적 제형의 형태로 제형화되어 경구 투여될 수 있다. 경구 투여용으로 제형화되는 경우， 본 발명에 따른 치료용 조성물에 약학적으로 허용되는 하나 이상의 부형제를 포함하여 제형화될 수 있으며， 그러한 부형제로는 충전제 (희석제 )， 붕해제， 결합제， 활택제 (윤활제)， 방부제， 산화방지제， 완충제， 킬레이트제， 가용화제 및 감미제로 구성된 군에서 선택된 하나 이상이 사용될 수 있다. 비제한적인 예시로， 충전제 (희석제 )는 만니톨 (mannitol )， 탄산 칼슘 (calcium carbonate) , 제 2인산 칼슘 (calcium phosphate dibasic) , 제 3인산 칼슘 (calcium phosphate tribasic) , 황산 칼슘 (calcium sulfate) , 미세결정성 셀룰로오스 (microcrystal 1 ine cel lulose) , 미세결정성 규화 셀룰로오스 (microcrystal 1 ine si l ici f ied cel lulose) , 분말 셀룰로오스， 덱스트레이트 (dextrates)， 덱스트로오스 (dextrose)， 프럭토오스 (fructose)， 락티톨 (lact itol)， 무수 락토오스 ( lactose anhydrous) , 락토오스 모노하이드레이트 ( lactose monohydrate) , 락토오스 디하이드레이트 ( lactose dihydrate) , 락토오스 트리하이드레이트 ( lactose trihydrate) , 소르비톨 (mannitol sorbitol ) , 전분 (starch) , 전호화 전분 (pregelat inized starch) , 수크로오스 (sucrose) , 탈크 (talc) , 자일리톨 (xyl itol ) , 말토오스 말토텍스트린 (maltose maltodextr in) 및 말티톨 (malt itol )로 구성된 군에서 선택된 하나 이상; 붕해제는 크로스포비돈， 알긴산， 이산화탄소， 카르복시메틸셀룰로오스 칼슘， 카르복시메틸 셀룰로오스 소둠， 미세결정성 셀룰로오스， 분말 셀룰로오스， 크로스카멜로오스 소둠， 크로스포비돈， 소윰 도큐세이트， 구아 검， 하이드록시프로필 셀룰로오스， 메틸셀룰로오스， 폴라크릴린 포타슘 (polacri l in potassium) , 폴록사머， 포비돈， 소듐 알지네이트， 소듐 글리신 카보네이트， 소듐 라우릴 설페이트， 소듐 스타치 글리콜레이트， 전분 및 전호화 전분으로 구성된 군에서 선택된 하나 이상; 결합제는 하이드록시에틸 셀룰로오스， 하이드록시프로필 셀룰로오스， 하이드록시프로필 메틸 셀룰로오스， 아카시아 뮤실라지 (acacia muci lage) , 알긴산 (alginic acid) , 카보머 (carbomer ) , 카르복시메틸셀룰로오스 칼슘， 카르복시메틸셀룰로오스 소둠， 미세결정성 셀룰로오스， 분말 셀룰로오스， 에틸 셀룰로오스， 젤라틴， 액상 글루코오스， 구아 검， 말토텍스트린， 메틸셀룰로오스， 폴리텍스트로오스， 폴레에틸렌 옥사이드， 포비돈， 소듐 알지네이트， 전분 패이스트， 전호화 전분 및 수크로오스로 구성된 군에서 선택된 하나 이상; 활택제 (윤활제 )는 탈크， 소듐 스테아릴 푸마레이트， 마그네슘 스테아레이트， 콜로이드성 이산화규소， 폴리에틸렌 글리콜 4000， 폴리에틸렌 글리콜 6000， 소듐 라우릴 설페이트， 전분， 글리세릴 베헤네이트 (glyceryl behenate) , 수소화된 피마자 기름， 스테아린산， 글리세릴 팔미토스테아레이트， 글리세릴 모노스테아레이트， 칼슘 실리케이트， 분말화 셀룰로오스 및 전분으로 구성된 군에서 선택된 하나 이상이 사용될 수 있지만， 이에 한정되는 것은 2021/260560 ?€1/162021/055521 아니다. 본 발명에 따른 경구 투여용 약제학적 제형은 캡슐， 펠렛 또는 정제인 것이 바람직하지만 이에 한정되는 것은 아니며， 상기 정제는 필름 코팅층을 포함하는 필름 코팅 정제인 것이 보다 바람직하다. 상기 필름 코팅층은 폴리비닐 알코올， 폴리비닐 알코올과 폴리에틸렌과의 공중합체， 히드록시프로필메틸셀룰로오스 ， 히드록시프로필셀룰로오스， 폴리비닐피롤리돈， 메타아크릴산 공중합체， 폴리에틸렌 옥사이드 및 잔탄 검으로 이루어진 군에서 선택된 하나 이상의 코팅 기제를 이용하여 형성될 수 있으며， 이에 따라 상기 필름 코팅층은 폴리비닐 알코올， 폴리비닐 알코올과 폴리에틸렌과의 공중합체， 히드록시프로필메틸셀룰로오스， 히드록시프로필셀룰로오스， 폴리비닐피롤리돈， 메타아크릴산 공중합체， 폴리에틸렌 옥사이드 및 잔탄 검으로 이루어진 군에서 선택된 하나 이상의 필름 코팅 기제를 포함할 수 있지만 이에 한정되는 것은 아니다. 본 발명에 따른 치료용 조성물 또는 이를 포함하는 약제학적 제형은 폐섬유화증， 특히 특발성 폐섬유화증 및/또는 코로나바이러스감염증- 19로 인한 폐섬유화증의 치료에 이용될 수 있다. 이에 따라 본 발명은 본 발명에 따른 치료용 조성물 또는 이를 포함하는 약제학적 제형을 폐섬유화증， 특히 특발성 폐섬유화증 및/또는 코로나바이러스감염증- 19로 인한 폐섬유화증의 치료에 사용하는 용도， 및 상기 치료가 필요한 환자에게 본 발명에 따른 약제학적 제형을 투여하는 것을 특징으로 하는 폐섬유화증， 특히 특발성 폐섬유화증 및/또는 코로나바이러스감염증- 19로 인한 폐섬유화증의 치료 방법에 대한 것이다. 도면의 간단한 설명 도 1은 본 발명에 따른 전체적 인 실험 조건을 나타내는 도면이다 . 도 2는 본 발명에 따른 화학식 II의 화합물과 대조약인 피르페니돈 (Pirfenidone)의 투여에 따른 블레오마이신 (Bleomycin) 유도 폐섬유화증 마우스 모델에서의 염증세포 변화를 나타내는 도면이다 . ¾ + , -sae3 2 - 2 + , _灰)3 2 ¾ + , ~ ?0 3 2~ ^ 2+ , _灰)3 2 2+ , Structural Formula 1, Structural Formula 2, or Structural Formula 3.
Figure imgf000007_0004
In particular, in the compound of Formula 1111 according to the present invention, ¾ is an alkyl group of -
Figure imgf000007_0003
It is an alkenyl group, and ¾ is - = 0) ¾, ¾ is an alkyl group of -¾, ¾ is gu 0 3 ¾, -卵03 - + or -Sa 3 2 3 2 is preferable, ¾ is methyl (1 bet ), and ¾ is - 0 (= 0) ¾, ¾ is -sae3¾, -卵03 - + or -sae3 2_此2 is more preferable, but is not limited thereto. Most preferably, the prodrug of the compound of formula (I) according to the present invention, formula (III), may have the structure of formula (IV) to formula (VI), but is not limited thereto 2021/260560 ?€1/162021/055521 is not. The compound having the structures of Formulas I to VI according to the present invention may be prepared by the method described in Korean Patent No. 1,692,921, but is not limited thereto.
Figure imgf000008_0001
The present invention also relates to pharmaceutically acceptable salts of compounds of formulas (I) to (VI). Non-limiting examples of the pharmaceutically acceptable salts of the compounds of Formulas I to VI include hydrochloric acid, ]3-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, horse rate, 2021/260560 €1/162021/055521 di-!)-toluyl salts of tartaric acid, ortinic acid, edicylic acid, hemi-edicylic acid and mandelic acid may be exemplified, but not limited thereto. The therapeutic composition comprising the compounds of formulas (I) to (VI) according to the present invention may include one or more pharmaceutically acceptable carriers. The therapeutic composition according to the present invention may be administered orally or parenterally, and parenteral administration is intranasal, intranasal, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous , It may be prepared in a formulation suitable for intraperitoneal, intestinal, topical, sublingual or rectal dosage forms and administered by the above route, but is not limited thereto. Accordingly, the present invention provides a pharmaceutical formulation for oral or parenteral administration comprising the therapeutic composition according to the present invention. Preferably, the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same may be administered orally, or may be administered intranasally or intranasally, especially in the form of a spray (large) or aerosol (large) when administered intranasally or intranasally administration of
Figure imgf000009_0001
It is more preferable to be formulated and administered in a dosage form for administration, but is not limited thereto. The pharmaceutical formulation for intranasal or intranasal administration may be prepared according to techniques well known in the art to which the present invention pertains, and benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons and/or others It can be prepared as a solution in saline using solubilizing or dispersing agents known in the art. In another form, the therapeutic composition according to the present invention may be formulated in a sterile injectable formulation as a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents. Sterile injectable formulations are also non-toxic It may be a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent (eg, a solution in 1,3-butanediol). Non-limiting examples of pharmaceutically acceptable vehicles and solvents include mannitol, water, Ringel's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil with less irritation may be used, including synthetic mono or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are pharmaceutically acceptable natural oils (eg, olive oil or castor oil), especially polyoxyethylated ones thereof, and are useful in injection preparations. In addition, the therapeutic composition according to the present invention is not limited thereto, but may be formulated in any orally acceptable pharmaceutical dosage form, including capsules, pellets, tablets, aqueous suspensions and solutions, and administered orally. When formulated for oral administration, it may be formulated to include one or more pharmaceutically acceptable excipients in the therapeutic composition according to the present invention, and such excipients include a filler (diluent), disintegrant, binder, lubricant (Lubricant), preservatives, antioxidants, buffers, chelating agents, solubilizers and at least one selected from the group consisting of a sweetener may be used. As a non-limiting example, the filler (diluent) is mannitol, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, Microcrystalline cellulose (microcrystal 1 ine cel lulose), microcrystalline silicified cellulose (microcrystal 1 ine si l ici fied cel lulose), powdered cellulose, dextrates, dextrose, fructose ( fructose), lactitol (lact itol), lactose anhydrous (lactose anhydrous) , lactose monohydrate ( lactose monohydrate) , lactose dihydrate ( lactose dihydrate) , lactose trihydrate , mannitol sorbitol , starch , pregelat inized starch , sucrose , talc , xylitol , maltose maltose Lin (maltose maltodextr in) and maltitol (malt itol) at least one selected from the group consisting of; Disintegrants include crospovidone, alginic acid, carbon dioxide, carboxymethyl cellulose calcium, carboxymethyl cellulose small, microcrystalline cellulose, powdered cellulose, croscarmellose small, crospovidone, soium docusate, guar gum, hydroxypropyl cellulose, methyl cellulose , at least one selected from the group consisting of polacri l in potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch and pregelatinized starch; The binder is hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose small, fine The group consisting of crystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, maltotextrin, methylcellulose, polytextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch and sucrose at least one selected from; Lubricant (lubricant) is talc, sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, glyceryl behenate, hydrogenated castor At least one selected from the group consisting of oil, stearic acid, glyceryl palmitostearate, glyceryl monostearate, calcium silicate, powdered cellulose and starch may be used, but is limited thereto 2021/260560 ?€1/162021/055521 No. The pharmaceutical formulation for oral administration according to the present invention is preferably a capsule, pellet or tablet, but is not limited thereto, and the tablet is more preferably a film-coated tablet including a film coating layer. The film coating layer is selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methacrylic acid copolymer, polyethylene oxide and xanthan gum. It may be formed using one or more coating bases, and thus the film coating layer is polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, meta It may include one or more film coating bases selected from the group consisting of acrylic acid copolymer, polyethylene oxide and xanthan gum, but is not limited thereto. The therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same can be used for the treatment of pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19. Accordingly, the present invention uses the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same for the treatment of pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19, and It relates to a method of treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19, characterized in that the pharmaceutical formulation according to the present invention is administered to a patient in need of the treatment. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view showing the overall experimental conditions according to the present invention. FIG. 2 is a view showing changes in inflammatory cells in a mouse model of Bleomycin-induced pulmonary fibrosis following administration of a compound of Formula II according to the present invention and pirfenidone, a control drug.
(A) 총 염증세포 (A) Total inflammatory cells
(B) 대식세포 (macrophages) (B) macrophages
(C) 림프구 ( lymphocytes) (C) Lymphocytes
(D) 중성구 (neutrophi Is) 도 3은 본 발명에 따른 화학식 II의 화합물 투여에 따른 블레오마이신 (Bleomycin) 유도 폐섬유화증 마우스 모델에서의 염증 관련 사이토카인 (cytokines) 들의 변화를 나타내는 도면이다 . (D) Neutrophils (Neutrophi Is) FIG. 3 is a view showing changes in inflammation-related cytokines in a mouse model of Bleomycin-induced pulmonary fibrosis following administration of the compound of Formula II according to the present invention.
(A) TGF(Tissue Growth Factor )-|3 (A) TGF (Tissue Growth Factor)-|3
(B) IL( Inter leukin)-17 (B) IL (Inter leukin)-17
(C) TNF(Tumor Necrosis Factor)- a (C) TNF (Tumor Necrosis Factor)- a
(D) IL-ip 도 4는 본 발명에 따른 화학식 II의 화합물 투여에 따른 블레오마이신 (Bleomycin) 유도 폐섬유화증 마우스 모델에서의 애쉬크로
Figure imgf000013_0001
스코어 (Ashcroft Score)를 나타내는 도면이다 . 도 5는 본 발명에 따른 화학식 II의 화합물 투여에 따른 블레오마이신 (Bleomycin) 유도 폐섬유화증 마우스 모델의 폐에서의 총 콜라겐 (col lagen) 변화를 나타내는 도면이다 . 도 6은 본 발명에 따른 화학식 II의 화합물 투여에 따른 블레오마이신대1601^(：比) 유도 폐섬유화증 마우스 모델에서의 폐포 표면적 폐포 기관지 및 혈관 주위 월두께의 변화를 나타내는 도면이다 . (A) 폐포 표면적 (alveolar surface area) (D) IL-ip Figure 4 is an ashcroe in a mouse model of Bleomycin-induced pulmonary fibrosis according to the administration of the compound of Formula II according to the present invention.
Figure imgf000013_0001
It is a drawing showing the score (Ashcroft Score). 5 is a view showing changes in total collagen in the lungs of a mouse model of Bleomycin-induced pulmonary fibrosis according to administration of a compound of Formula II according to the present invention. 6 is a view showing changes in alveolar surface area, alveolar bronchus and perivascular wall thickness in a mouse model of bleomycin vs. 1601^(:比)-induced pulmonary fibrosis according to the administration of the compound of Formula II according to the present invention. (A) Alveolar surface area
(B) 폐포 월두께 (alveolar wal l thickness) (B) alveolar wall thickness
(C) 기관지 주위 월두께 (per ibronchial wal l thickness) (C) per ibronchial wall thickness
(D) 혈관 주위 월두께 (per ivascular wal l thickness) 발명의 상세한 설명 및 구체적인 구현예 이하， 실시예를 통하여 본 발명을 보다 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로， 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당해 기술분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. 실시예 1. 폐섬유화증 동물 모델 제작 및 약물 투여 방법 1.1 폐섬유화증 동물 모델 제작 C57BL/6종 암컷 8주령 마우스를 Orientbio Inc. (성남， 한국)로부터 구입하여 AAALAC international 국제 인증 동물실험실에서 유지하였고， 동물실험윤리위원회가 cuh-IA ⑶ C-2019-1-1 동물실험을 승인하였다 . 마우스는 isof lurane 톱입마취 (Matrix, Orchard Park, NY, USA) 꾸 3 mg/kg bleomycin을 기도 내 주입하여 폐 섬유화를 유도하였다. (D) Per ivascular wall thickness (per ivascular wall thickness) Detailed Description and Specific Examples of the Invention Hereinafter, the present invention will be described in more detail through Examples. These examples are only for illustrating the present invention in more detail, and it is obvious to those of ordinary skill in the art that the scope of the present invention is not limited by these examples. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents. Example 1. Production of an animal model of pulmonary fibrosis and drug administration method 1.1 Production of an animal model of pulmonary fibrosis C57BL/6 female 8-week-old mice were treated with Orientbio Inc. It was purchased from (Seongnam, Korea) and maintained in an AAALAC international accredited animal laboratory, and the Animal Experimental Ethics Committee approved cuh-IA ⑶ C-2019-1-1 animal testing. Lung fibrosis was induced in mice by intratracheal injection of 3 mg/kg bleomycin under isof lurane saw lip anesthesia (Matrix, Orchard Park, NY, USA).
1.2 약물 투여 상기 실시예 1.1에서 제작된 폐섬유화증 유도 마우스에 0.1 mg/kg , 1.0 mg/kg와 5.0 mg/kg 화학식 II의 화합물을 폐섬유화증 유도 24시간 후와 그 후 2일 간격으로 흡입 투여하였다 (0.05 % DMSO, sal ine) . 블레오마이신 주입 후 14일에 마우스를 희생시킨 후 기관지 폐포세척을 시행하였고， 폐조직을 적출하였다. 화학식 II의 화합물의 효능 평가를 위해 항 섬유화제인 피르페니돈 (200 mg/kg/bid, po, 2 % DMSO, 0.5 % CMC)을 대조 물질로 투여하여 비교하였다. 이하， 모든 도면에서의 B291은 화학식 II의 화합물을 의미하며， B291 다음에 0.1， 1.0 및 5.0이라는 숫자는 화학식 II의 화합물 투여량이 각각 0.1 mg/kg， 1.0 mg/kg 및 5.0 mg/kg임을 의미한다. 또한， BPFD는 피르페니돈 (pirfenidone)을， 는 살린 (sal ine) 처리된 실험동물에 drug vehicle을 투여한 정상대조군 (sal ine-inst i 1 led mice administered with drug vehicle, SAL+VEH)을， BV는 블레오마이신 처리된 동물에 drug vehicle을 투여한 폐 섬유화군 (bleomycin-inst i l led mice administered with drug vehicle, BLM+VEH)을 의미한다. 블레오마이신 유도 폐섬유화증의 마우스 모델에서 화학식 II의 화합물의 효과 시험군은 종 6군으로， 정상대조군 (sal ine-inst i 1 led mice administered with drug vehicle, SAL+VEH) , 폐섬유화군 (bleomycin-inst i l led mice administered with drug vehicle, BLM+VEH) , 블레오마이신 유도 폐섬유화의 마우스 모델에 0.1 mg/kg 화학식 II의 화합물 투여군 3개 (0.1 mg/kg, 1.0 mg/kg 및 5.0 mg/kg) , 그리고 블레오마이신 유도 폐 섬유화의 마우스 모델에 약물대조군으로 200.0 mg/kg의 피르페니돈 투여군의 실험을 진행하였다 (표 1 참조) . 표 1. 실험군 개요
Figure imgf000016_0001
실시예 2. 염증세포 변화 실시 예 1에 따른 마우스를 희생시킨 후 폐가 충분히 확장될 수 있도록 흉강을 개방하고 기관을 절개하여 기도 내로 삽입한 관을 통해 1 mi PBS를 서서히 폐 내로 주입하였고， 이를 회수하여 기관지폐포세척 액으로 4 。(:에 보관하였다. 기관지폐포세척 액은 NucleoCounter (Chemometec.， Gydevang , Denmark)를 이용하여 전체 염증 세포수를 측정하는데 사용하였고， 원심분리 후 침전된 세포들을 PBS에 재부유하여 cytospin (Thermo Electron, Waltham, MA, USA)으로 슬라이드에 도말하여 염증세포감별에 사용하였다. 세포감별은 준비된 세포도말을 Di ff-Quik solut ion (Dade Diagnost ics of Puerto Rico Inc. , Aguada , Puerto Rico, USA)으로 염색한 후 슬라이드의 서로 다른 곳에서 400개 이상의 세포를 세어 시행하였다. 본 명세서에서의 모든 도면에 도시된 실험 결과는 평균과 평균의 표준 오차로 표시하였다. GraphPad Prism 5를 이용하였고， One-way AN0VA , Two-way ANONA 또는 t-test 분석을 하였다. Bonferroni's multiple comparison test , paired t-test 또는 Mann Whitney test에서 P value < 0.05인 경우를 통계적으로 유의한 것으로 해석하였다. 블레오마이신 유도 폐섬유화증의 마우스 모델은 기관지 폐포내 대식세포， 림프구， 중성구의 세포수 증가와 함께 총 염증세포의 수가 유의하게 증가하였다. 화학식 II의 화합물을 투여한 시험군에서 총 염증세포의 수가 유의하게 감소하였고， 대식세포， 림프구와 중성구의 세포수도 감소하였다. 피르페니돈 약물대조군은 대식세포의 증가와 함께 총 염증세포 수의 증가에서 변화가 없었고， 림프구와 중성구의 수는 감소하는 경향을 보였다. 피르페니돈 약물 대조군과 비교하여 0.1 mg/kg와 1.0 mg/kg 화학식 II의 화합물 투여군에서 용량 상관성 있게 대식세포의 감소와 함께 총 염증세포 수의 유의한 감소를 확인하였다. 림프구와 중성구의 세포수는 약물대조군과 시험 약물 투여군에 유의한 차이가 없었다 (도 2(A) 내지 도 2(D) 참조， 각 플롯은 6개 마우스 그룹의 평균 ±표준오차를， #는 戶 C0.05, ##는 세 01， 그리고 ■는 戶 C0.001인 경우를 의미한다) . 실시예 3. 염증성 사이토카인 변화 마우스 폐 조직의 단백질을 추출하여 전기 영동으로 분리한 후 TGF-p, TNF-a, IL-lp와 IL-17의 발현을 Western blotting으로 확인하여 정량 분석하였다. 블레오마이신 유도 폐섬유화 반응에서 유의하게 증가된 TGF- IL-17, TNF-a와 IL-l^ 단백질의 발현이 화학식 II의 화합물 투여군에서 감소되었다1.2 Drug Administration 0.1 mg/kg, 1.0 mg/kg, and 5.0 mg/kg of the compound of Formula II to the pulmonary fibrosis-induced mice prepared in Example 1.1 were inhaled 24 hours after pulmonary fibrosis induction and 2 days thereafter. was administered (0.05 % DMSO, saline). On day 14 after bleomycin injection, mice were sacrificed, bronchial alveolar lavage was performed, and lung tissue was was extracted. In order to evaluate the efficacy of the compound of Formula II, pirfenidone (200 mg/kg/bid, po, 2% DMSO, 0.5% CMC), an anti-fibrotic agent, was administered as a control and compared. Hereinafter, B291 in all the drawings means a compound of Formula II, and the numbers 0.1, 1.0 and 5.0 after B291 mean that the dosage of the compound of Formula II is 0.1 mg/kg, 1.0 mg/kg and 5.0 mg/kg, respectively. do. In addition, BPFD is pirfenidone (pirfenidone), is a normal control group (sa ine-inst i 1 led mice administered with drug vehicle, SAL + VEH) administered drug vehicle to the saline (saline) treated experimental animals, BV refers to the pulmonary fibrosis group administered with drug vehicle to bleomycin-treated animals (bleomycin-inst il led mice administered with drug vehicle, BLM+VEH). In a mouse model of bleomycin-induced pulmonary fibrosis, the test group for the effect of the compound of formula II is a 6-species group, a normal control group (saline-inst i 1 led mice administered with drug vehicle, SAL+VEH), a lung fibrosis group (bleomycin) -inst il led mice administered with drug vehicle, BLM+VEH), 3 groups (0.1 mg/kg, 1.0 mg/kg and 5.0 mg/kg) administered with a compound of Formula II at 0.1 mg/kg in a mouse model of bleomycin-induced pulmonary fibrosis ), and a group administered with 200.0 mg/kg of pirfenidone as a drug control group in a mouse model of bleomycin-induced lung fibrosis (see Table 1). Table 1. Overview of experimental groups
Figure imgf000016_0001
Example 2. Inflammatory cell change After sacrificing the mouse according to Example 1, the chest cavity was opened so that the lungs could be sufficiently expanded, the trachea was incised, and 1 mi PBS was slowly injected into the lungs through a tube inserted into the airway, and this was recovered. to 4 (the bronchial lavage fluid..., and stored in the bronchoalveolar lavage fluid were used to using the (Chemometec, Gydevang, Denmark NucleoCounter) measuring the total number of inflammatory cells, in PBS the cells precipitated after centrifugation It was resuspended and spread on slides with cytospin (Thermo Electron, Waltham, MA, USA) and used for differentiation of inflammatory cells. Aguada , Puerto Rico, USA) and then counted more than 400 cells in different places on the slide.The experimental results shown in all figures in this specification are expressed as the mean and the standard error of the mean. GraphPad Prism 5 was used, One-way AN0VA , Two-way ANONA or t-test analysis was performed. In Bonferroni's multiple comparison test, paired t-test, or Mann Whitney test, a case of P value < 0.05 was interpreted as statistically significant. The mouse model of bleomycin-induced pulmonary fibrosis significantly increased the number of total inflammatory cells along with the increase in the number of macrophages, lymphocytes, and neutrophils in the bronchoalveolar alveoli. In the test group administered with the compound of Formula II, the total number of inflammatory cells was significantly reduced, and the number of macrophages, lymphocytes and neutrophils also decreased. In the pirfenidone drug control group, there was no change in the increase in the total number of inflammatory cells along with the increase in macrophages, and the number of lymphocytes and neutrophils showed a tendency to decrease. Compared with the pirfenidone drug control group, a significant decrease in the total number of inflammatory cells was confirmed with a decrease in macrophages in a dose-related manner in the groups administered with the compound of Formula II at 0.1 mg/kg and 1.0 mg/kg. The cell numbers of lymphocytes and neutrophils did not differ significantly between the drug control group and the test drug administration group (see FIGS. 2(A) to 2(D), each plot represents the mean ± standard error of 6 mouse groups, # is 戶C0.05, ## means three 01, and ■ means 戶 C0.001) . Example 3. Inflammatory cytokine change After extracting and electrophoresis-separated proteins from mouse lung tissue, the expression of TGF-p, TNF-a, IL-lp and IL-17 was confirmed by Western blotting and quantitatively analyzed. The significantly increased expression of TGF-IL-17, TNF-a and IL-1^ proteins in the bleomycin-induced pulmonary fibrosis reaction was decreased in the group administered with the compound of Formula II.
(Figure 3(A) 내지 3(D) 참조， ¾Kbar)는 6개 마우스 그룹의 평균 ±표준오차를， #는戶 C0.05, ##는戶 C0.01, 그리고 ■는戶 C0.001인 경우를 의미한다) . 구체적으로 IL-ip는 1.0 mg/kg와 5.0 mg/kg 화학식 II의 화합물 투여군에서 유의하게 감소하였고， TGF- 와 IL-17의 발현은 1.0 mg/kg화학식 II의 화합물 투여군에서 최대로 감소하였다. TNF-a는 5.0 mg/kg투여군에서 유의미한 감소를 보여， 투여 용량에 따라 전염증성 단백질 발현 에 차이가 있다. IL-17의 폐 내 증가는 약물 투여군에서 모두 감소하는 경향이었으나 통계적 유의성은 없다. 피르페니돈 약물 대조군은 TGF-y^와 IL-17의 발현 증가에 효과가 없고， TNF-a와 IL-ly好의 단백질 발현을 감소시키는 경향을 보였다. 피르페니돈 약물 대조군과 비교하여 화학식 II의 화합물 투여군에서 TGF-/37} 모두 유의하게 감소하였고， 전 투여군에서 IL-17의 감소， 5.0 mg/kg투여군에서 동등한 수준의 TNF-a감소 및 1.0 mg/kg와 5.0 mg/kg투여군에서 IL-1 의 감소가 있었다. 실시예 4. 병리조직학적 변화 분석 마우스 폐 조직 슬라이드를 제작하여 Hemetoxylin & eosin (H&E) 염색으로 조직의 변화정도를 관찰하였고， 염색된 조직에서 염증정도를 측정하여 정량화 하였다. 또한 마우스 폐 조직에서 추출한 콜라겐의 농도를 Sircol assay로 정량하여 침적된 양을 분석하였다. 그 결과， 폐섬유화증 심각도에 대한 정량지표인 애쉬그로프트 스코어(Ashcroft Score)가 화학식 II의 화합물 투여에 의해 감소하였다 (도 4 참조， 플롯은 6개 마우스 그룹의 평균 ±표준오차를， #는 戶C0.05, ##는 戶C0.01 , 그리고 ■는戶C0.001인 경우를 의미한다) . 콜라겐 침적량은 약물대조군과 동등한 수준으로 감소하였거나， 5.0 mg/kg 투여군에서 감소의 통계적 유의수준이 높다 (도 5 참조， 플롯은 6개 마우스 그룹의 평균 ±표준오차를 , #는 戶C0.05, ##는 세 01， 그리고 ■는 戶C0.0()1인 경우를 의미한다) . 또한 폐포 표면적의 감소， 폐포벽 및 기관지 벽과 혈관벽의 비후는 완화되었다 (도 6(A) 내지 도 6(D) 참조， 플롯은 6개 마우스 그룹의 2021/260560 ?€1/162021/055521 평균 ±표준오차를， #는 片0.05， ##는 片0.01， 그리고 ■는 片0.001인 경우를 의미한다）. 산업상 이용가능성 본 발명에 따른 화학식 I 내지 화학식 VI의 화합물은 폐섬유화증， 특히 특발성 폐섬유화증이나， 코로나바이러스감염증- 19로 인한 폐섬유화증 치료에 탁월한 효과를 거둘 수 있다. 이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는
Figure imgf000019_0001
당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며， 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서， 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. (See Figure 3(A) to 3(D), ¾Kbar) is the mean ± standard error of 6 mouse groups, # is 戶 C0.05, ## is 戶 C0.01, and ■ is 戶 C0.001 case). Specifically, IL-ip was significantly decreased in the group administered with the compound of formula II at 1.0 mg/kg and 5.0 mg/kg, and the expression of TGF- and IL-17 was maximally reduced in the group administered with the compound of formula II at 1.0 mg/kg. TNF-a showed a significant decrease in the 5.0 mg/kg administration group, there is a difference in pro-inflammatory protein expression according to the administration dose. The increase in IL-17 in the lungs tended to decrease in all drug administration groups, but there was no statistical significance. The pirfenidone drug control group had no effect on increasing the expression of TGF-y ^ and IL-17, and showed a tendency to decrease the protein expression of TNF-a and IL-1 y好. Compared with the pirfenidone drug control group, both TGF-/37} were significantly reduced in the group administered with the compound of Formula II, and the reduction of IL-17 in the previous administration group, TNF-a reduction and 1.0 mg at the same level in the 5.0 mg/kg administration group There was a decrease in IL-1 in the /kg and 5.0 mg/kg administration groups. Example 4. Analysis of histopathological changes A mouse lung tissue slide was prepared and the degree of tissue change was observed by staining with Hemetoxylin & eosin (H&E), and the degree of inflammation was measured and quantified in the stained tissue. In addition, the concentration of collagen extracted from mouse lung tissue was quantified by Sircol assay to analyze the deposited amount. As a result, the Ashcroft Score, a quantitative indicator for the severity of pulmonary fibrosis, was decreased by administration of the compound of Formula II (see FIG. 4 , the plot is the mean ± standard error of 6 mouse groups, # is戶C0.05, ## means 戶C0.01, and ■ means 戶C0.001) . Collagen deposition amount was reduced to a level equivalent to that of the drug control group, or the statistical significance level of the decrease was high in the 5.0 mg/kg administration group (see FIG. 5 , the plot is the mean ± standard error of 6 mouse groups, # is 戶C0.05, ## means three 01, and ■ means 戶C0.0()1) . In addition, the decrease in the alveolar surface area, the thickening of the alveolar wall, the bronchial wall, and the blood vessel wall were alleviated (see FIGS. 6(A) to 6(D), the plot shows that of the six mouse groups 2021/260560 ?€1/162021/055521 mean ±standard error, # means 片0.05, ## means 片0.01, and ■ means 片0.001). Industrial Applicability The compounds of Formulas I to VI according to the present invention can achieve excellent effects in treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, or pulmonary fibrosis caused by coronavirus infection-19. In the above, a specific part of the content of the present invention has been described in detail.
Figure imgf000019_0001
For those of ordinary skill in the art, these specific descriptions are only preferred embodiments, and it will be apparent that the scope of the present invention is not limited thereby. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims

2021/260560 1^(:1^ 2021/055521 청구의 범위 2021/260560 1^(:1^ 2021/055521 claims
1. 화학식 I의 구조를 가지는 화합물， 이의 프로드럭， 이의 염， 또는 이의 이성체를 포함하는 폐섬유화증(Pulmonary Fibrosis) 치료용 조성물 [화학식 I]
Figure imgf000020_0001
상기 화학식 I에서， Ra는 - 의 알킬기， - 의 알케닐기， 또는 - 의 알키닐기이고， Rb는 아릴기， 치환된 아릴기， 또는 -C(=0)Re이고， Re는 CrC6의 알킬기， C2-C6의 알케닐기， 또는 C2-C6의 알키닐기이다. 1. A composition for treating pulmonary fibrosis (Pulmonary Fibrosis) comprising a compound having the structure of Formula I, a prodrug thereof, a salt thereof, or an isomer thereof [Formula I]
Figure imgf000020_0001
In Formula I, R a is an alkyl group of -, an alkenyl group of -, or an alkynyl group of -, R b is an aryl group, a substituted aryl group, or -C(=0)R e , R e is CrC 6 alkyl group, C 2 -C 6 alkenyl group, or C 2 -C 6 alkynyl group.
2. 제 1항에 있어서， 상기 화학식 I에서 Ra는 -¾의 알킬기 또는 C2-C6의 알케닐기이고， Rb는 -C(=0)Re이고， Re는 -¾의 알킬기인 것을 특징으로 하는 폐섬유화증(Pulmonary Fibrosis) 치료용 조성물. 2. The method of claim 1, wherein in Formula I, R a is an alkyl group of -¾ or a C 2 -C 6 alkenyl group, R b is -C(=0)R e , and R e is an alkyl group of -¾ Pulmonary fibrosis (Pulmonary Fibrosis) treatment composition, characterized in that.
3. 제 1항에 있어서， 상기 화학식 I의 화합물은 화학식 II의 구조를 가지는 것을 특징으로 하는 폐섬유화증(Pulmonary Fibrosis) 치료용 조성물. [화학식 II]
Figure imgf000021_0001
3. The composition for treating pulmonary fibrosis according to claim 1, wherein the compound of Formula I has a structure of Formula II. [Formula II]
Figure imgf000021_0001
4. 제 1항에 있어서， 상기 화학식 I의 구조를 가지는 화합물의 프로드럭은 화학식 III의 구조를 가지는 것을 특징으로 하는 폐섬유화증 (Pulmonary Fibrosis) 치료용 조성물. 4. The composition for treating pulmonary fibrosis according to claim 1, wherein the prodrug of the compound having the structure of Formula I has the structure of Formula III.
[화학식 III]
Figure imgf000021_0002
상기 화학식 III에서， ¾는 - 의 알킬기， 。厂 의 알케닐기， 또는 02- ¾ 의 알키닐기이고， ¾는 아릴기， 치환된 아릴기， 또는 - =0)¾이고， 이때， ¾는
Figure imgf000021_0003
卵03- +， -쌔32- 2 +， -쌔32-¾+， -쌔3 21梅2+， -쌔3 2-^+， 구조식 1， 구조식 2， 또는 구조식 3이다.
Figure imgf000022_0001
[Formula III]
Figure imgf000021_0002
In Formula III, ¾ is - alkynyl group of ¾, ¾ is an aryl group, a substituted aryl group, or - an alkenyl group, or an alkyl group of 02,厂in. A = 0) ¾, At this time, the ¾
Figure imgf000021_0003
卵0 3- + , -sae3 2 - 2 + , -sae3 2 -¾ + , -sae 3 2 1梅2+ , -sae 3 2 -^ + , Structural Formula 1, Structural Formula 2, or Structural Formula 3.
Figure imgf000022_0001
5. 제 4항에 있어서， 상기 화학식 III의 화합물에 있어， Ra는 Ci-C6£l 알킬기 또는 C2-C6의 알케닐기이고， Rb는 -C(=0)Re이고， Re는 CfC6의 알킬기， Rp는 -P03¾， -HP03 Na+ 또는 -P03 2_Na2인 것을 특징으로 하는 폐섬유화증 (Pulmonary Fibrosis) 치료용 조성물. 5. The method according to claim 4, wherein in the compound of Formula III, R a is a Ci-C 6 £1 alkyl group or a C 2 -C 6 alkenyl group, R b is -C(=0)R e , R e is C f C 6 An alkyl group, R p is -P0 3 ¾, -HP0 3 Na + or -P0 3 2 _Na 2 Pulmonary fibrosis (Pulmonary Fibrosis) treatment composition, characterized in that.
6. 제 4항에 있어서， 상기 화학식 III의 화합물에 있어， Ra는 메틸 (methyl)이고， Rb는 _C(=0)CH3, Rp는 구03¾, -HP03 Na+ 또는 -P03 2_Na2인 것을 특징으로 하는 폐섬유화증 (Pulmonary Fibrosis) 치료용 조성물. 6. The method of claim 4 wherein in the compound of Formula III, R is a methyl (methyl) a, R b is _C (= 0) CH 3, R p is nine 0 3 ¾, -HP0 3 Na +, or -P0 3 2 _Na 2 Pulmonary fibrosis (Pulmonary Fibrosis) treatment composition, characterized in that.
7. 제 5항에 있어서， 상기 화학식 III의 화합물은 화학식 IV 내지 화학식7. The method of claim 5, wherein the compound of Formula III is a compound of Formulas IV to
VI에서 선택된 구조를 가지는 것을 특징으로 하는 폐섬유화증 (PulmonaryPulmonary fibrosis, characterized in that it has a structure selected from VI
Fibrosis) 치료용 조성물. Fibrosis) therapeutic composition.
Figure imgf000023_0001
Figure imgf000023_0001
8. 제 1항에 있어서， 상기 폐섬유화증은 원인불명의 특발성 폐섬유화증 (Idiopathic Pulmonary Fibrosis , IPF) 또는 코로나바이러스감염증- 19로 인한 폐섬유화증인 것을 특징으로 하는 폐섬유화증 (Pulmonary Fibrosis) 치료용 조성물 . 8. The treatment of Pulmonary Fibrosis according to claim 1, wherein the pulmonary fibrosis is pulmonary fibrosis caused by Idiopathic Pulmonary Fibrosis (IPF) or coronavirus infection-19 of unknown cause. composition for .
9. 제 1항 내지 제 8항 중 어느 한 항에 있어서， 약제학적으로 허용 가능한 담체를 하나 이상 포함하는 것을 특징으로 하는 폐섬유화증 (Pulmonary Fibrosis) 치료용 조성물 . 9. The composition for treating pulmonary fibrosis (Pulmonary Fibrosis) according to any one of claims 1 to 8, which comprises at least one pharmaceutically acceptable carrier.
10. 제 9항에 따른 치료용 조성물을 포함하는 경구 또는 비경구 투여용 약제학적 제형 . 10. A pharmaceutical formulation for oral or parenteral administration comprising the composition for treatment according to item 9.
11. 제 10항에 있어서 상기 비경구 투여는 비내， 비강내， 구강， 정맥내， 근육내， 동맥내， 골수내， 경막내， 심장내， 경피， 피하， 복강내， 장관， 국소， 설하 또는 직장 투여인 것을 특징으로 하는 약제학적 제형 . 11. The method of claim 10, wherein the parenteral administration is intranasal, intranasal, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, enteral, topical, sublingual or A pharmaceutical formulation, characterized in that it is rectal administration.
12. 제 11항에 있어서， 상기 비내 또는 비강내 투여는 스프레이， 에어로솔 또는 흡입 (inhalat ion) 형태로 투여되는 것을 특징으로 하는 약제학적 제형 . 12. The pharmaceutical formulation according to claim 11, wherein the intranasal or intranasal administration is administered in the form of a spray, aerosol or inhalation.
13. 제 10항에 있어서， 상기 경구 투여는 캡슐， 펠렛， 정제， 수성 현탁액 또는 용액의 형태로 투여되는 것을 특징으로 하는 약제학적 제형 . 13. The pharmaceutical formulation according to claim 10, wherein the oral administration is administered in the form of a capsule, pellet, tablet, aqueous suspension or solution.
PCT/IB2021/055521 2020-06-26 2021-06-23 Composition for treating pulmonary fibrosis WO2021260560A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020237002576A KR20230031304A (en) 2020-06-26 2021-06-23 Composition for the treatment of pulmonary fibrosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2020-0078130 2020-06-26
KR1020200078130A KR20220000460A (en) 2020-06-26 2020-06-26 Composition for Treating Pulmonary Fibrosis

Publications (1)

Publication Number Publication Date
WO2021260560A1 true WO2021260560A1 (en) 2021-12-30

Family

ID=79282077

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/055521 WO2021260560A1 (en) 2020-06-26 2021-06-23 Composition for treating pulmonary fibrosis

Country Status (2)

Country Link
KR (2) KR20220000460A (en)
WO (1) WO2021260560A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010044485A1 (en) * 2008-10-14 2010-04-22 Prism Biolab Corporation Alpha helix mimetics in the treatment of cancer
WO2012050393A2 (en) * 2010-10-14 2012-04-19 제이더블유중외제약 주식회사 Novel compound of a reverse-turn mimetic and a production method and use therefor
US20160166577A1 (en) * 2012-10-19 2016-06-16 Prism Pharma Co., Ltd. Treatment of pulmonary fibrosis using an inhibitor of cbp/catenin
US20160303137A1 (en) * 2015-04-20 2016-10-20 Indiana University Research And Technology Corporation Dual pi3k and wnt pathway inhibition as a treatment for cancer
WO2017184808A1 (en) * 2016-04-20 2017-10-26 University Of Southern California Compounds and methods for increasing hematopoiesis

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100267672A1 (en) 2009-04-15 2010-10-21 Choongwae Pharma Corporation Novel compounds of reverse-turn mimetics, method for manufacturing the same and use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010044485A1 (en) * 2008-10-14 2010-04-22 Prism Biolab Corporation Alpha helix mimetics in the treatment of cancer
WO2012050393A2 (en) * 2010-10-14 2012-04-19 제이더블유중외제약 주식회사 Novel compound of a reverse-turn mimetic and a production method and use therefor
US20160166577A1 (en) * 2012-10-19 2016-06-16 Prism Pharma Co., Ltd. Treatment of pulmonary fibrosis using an inhibitor of cbp/catenin
US20160303137A1 (en) * 2015-04-20 2016-10-20 Indiana University Research And Technology Corporation Dual pi3k and wnt pathway inhibition as a treatment for cancer
WO2017184808A1 (en) * 2016-04-20 2017-10-26 University Of Southern California Compounds and methods for increasing hematopoiesis

Also Published As

Publication number Publication date
KR20230031304A (en) 2023-03-07
KR20220000460A (en) 2022-01-04

Similar Documents

Publication Publication Date Title
EP1163910B1 (en) Rho kinase inhibitors for the prevention or treatment of interstitial pneumonia and pulmonary fibrosis
KR20180021682A (en) Therapeutic agent for fibrosis
EP1908473B1 (en) Clarithromycin or salt thereof for use in the treatment pulmonary emphysema
JP2023506496A (en) Compounds and their use for the treatment of α1-antitrypsin deficiency
US20100317671A1 (en) Xanthine-based cyclic gmp-enhancing rho-kinase inhibitor inhibits physiological activities of lung epithelial cell line
WO2021260560A1 (en) Composition for treating pulmonary fibrosis
JP6594899B2 (en) Treatment of idiopathic pulmonary fibrosis
WO2017217071A1 (en) Pulmonary hypertension preventative or therapeutic agent containing component exhibiting selenoprotein p activity-inhibiting effect
CN116437929A (en) Inhalation formulations of antimicrobial compounds
TWI537246B (en) Compounds for use in the treatment of inflammatory bowel disease
KR20180065224A (en) A pharmaceutical composition for treating or alleviating pulmonary fibrosis
JP6469727B2 (en) Method for inhibiting or treating fibrosis
AU2021255160B2 (en) Pulmonary fibrosis medicine containing pyrazole derivative
WO2014122638A2 (en) Thalidomide and thalidomide analogues for the stimulation in human/animals of stem cell factor to increase regenerative potential in aging conditions
JP2020040892A (en) Pulmonary hypertension therapeutic agent
RU2817989C1 (en) Agent for pulmonary fibrosis containing pyrazole derivative
CN116509850A (en) Use of N-aryl pyridones in pneumoconiosis treatment
KR20230121888A (en) Pharmaceutical composition containing fexofenadine, famotidine and melatonin
TW202310839A (en) Pharmaceutical composition for preventing or treating fibrosis
JPWO2005063250A1 (en) Neutropenia inhibitor
CN117412751A (en) Pharmaceutical preparation for preventing or treating pulmonary fibrosis
CA3171882A1 (en) Use of cyclosporine analogues for treating fibrosis
KR20210127085A (en) composition of pyrazole derivatives for treatment of pulmonary fibrosis
CN117562915A (en) Application of adenosine derivative in preparing medicament for preventing, relieving or treating fibrosis diseases
JPWO2020091052A1 (en) Arthritis remedy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21828300

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 20237002576

Country of ref document: KR

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21828300

Country of ref document: EP

Kind code of ref document: A1