KR20220000460A - Composition for Treating Pulmonary Fibrosis - Google Patents

Abstract

The present invention relates to a therapeutic composition comprising a compound having excellent therapeutic efficacy for pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF) of unknown cause or pulmonary fibrosis caused by COVID-19.

Description

Composition for Treating Pulmonary Fibrosis

The present invention relates to pulmonary fibrosis (Pulmonary Fibrosis), in particular, idiopathic pulmonary fibrosis (IPF) of unknown etiology and/or pulmonary fibrosis caused by coronavirus infection-19, comprising a compound having a high therapeutic effect to a therapeutic composition.

Pulmonary fibrosis proceeds from interstitial lung inflammation caused by various causes, and Idiopathic Pulmonary Fibrosis (IPF) of unknown etiology is the most frequent form. The average survival time after diagnosis is 2-3 years and 5 years It is an intractable lung disease with no effective treatment to such an extent that the 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 the agent has been attempted, but it only slows the progression of symptoms, the frequency of side effects is high, and the effect does not meet expectations in patients with severe pulmonary fibrosis.

Regarding the pathogenesis of pulmonary fibrosis, it is known that fibrosis proceeds by an abnormal healing process for continuous damage to alveolar epithelial cells. It is activated and leads to excessive extracellular matrix production, leading to fibrosis of the lung interstitium. It is known that this reduces the compliance of the alveoli and irreversibly reduces the lung capacity, thereby reducing the ability to transport oxygen into the capillaries.

In addition, inhibition of fibrinolytic activity due to pulmonary inflammatory response and unregulated immune mechanisms, abnormal signal transduction system in alveolar epithelial cells, and epithelial cell damage, activation of fibroblasts in lung interstitium, mesenchymal transformation of epithelial cells, endothelial Cell transformation, such as cell-derived fibroblast differentiation, influx of inactive blood fibroblasts into the lung, and differentiation into fibroblasts, is a mechanism of myofibroblast differentiation and proliferation and is an important factor in lung fibrosis. TGF-β is the most well-known factor related to lung fibrosis, and it is known to induce fibrosis by activating AKT/mTOR, SMAD, Wnt/β-catenin, and YAP/TAZ signaling systems. In addition, it is observed that oxidative stress, which increases simultaneously with the activation of the signaling system, plays an important role, and microRNAs, DNA methylation, PDGF growth factor and IL-4 that increase or inhibit post-transcriptional expression of fibrosis regulators or intermediate mediators It is known as a major factor involved in fibrosis.

Recently, there have been reports that pulmonary fibrosis occurs in many patients with coronavirus infection-19 infected with SARS-Cov-2 (Severe Acute Respiratory Syndrome Coronavirus 2).

Even now, a number of pharmaceutical companies around the world are making efforts to develop a treatment for pulmonary fibrosis, particularly idiopathic pulmonary fibrosis of unknown cause and/or pulmonary fibrosis caused by COVID-19, but a therapeutic agent that 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 have found that the compound having an anticancer effect in the past shows an excellent therapeutic effect on pulmonary fibrosis, particularly idiopathic pulmonary fibrosis of unknown cause and / or pulmonary fibrosis caused by coronavirus infection-19, such a disease It was confirmed that it can be used for therapeutic purposes, and the present invention was completed.

Republic of Korea Patent No. 1,692,921

It is an object of the present invention 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.

[Formula I]

In Formula I, R _a is a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, or a C ₂ -C ₆ alkynyl group, and R _b is an aryl group, a substituted aryl group, or —C (=O)R _e and R _e is a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, or C ₂ -C ₆ alkynyl group.

In the compound of Formula I included in the pharmaceutical composition for the treatment of coronavirus infection-19 according to the present invention, R _a is a C ₁ -C ₆ alkyl group or C ₂ -C ₆ alkenyl group, and R _b is -C (=O)R _e , R _e is preferably a C ₁ -C ₆ alkyl group, R _a is methyl (methyl), and R _b is more preferably —C(=O)CH ₃ , but limited thereto it is not going to be In the compound of Formula I, when R _a is methyl (methyl) and R _b is -C(=O)CH ₃ , it has the structure of Formula II.

[Formula II]

In addition, the prodrug of the compound of formula (I) according to the present invention has the structure of formula (III).

[Formula III]

In Formula III, R _a is a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, or a C ₂ -C ₆ alkynyl group, and R _b is an aryl group, a substituted aryl group, or —C (=O)R _e , R _e is a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, or a C ₂ -C ₆ alkynyl group, and R _p is -PO ₃ H ₂ , -HPO ₃ ^- Na ⁺ , -PO ₃ ^2- Na ₂ ⁺ , -PO ₃ ^2- K ₂ ⁺ , -PO ₃ ^2- Mg ²⁺ , -PO ₃ ^2- Ca ²⁺ , Structural Formula 1, Structural Formula 2, or Structural Formula 3 to be.

In particular, in the compound of formula IIII according to the present invention, R _a is a C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group, R _b is -C(=O)R _e , and R _e is C ₁ -C ₆ alkyl group, R _p is ^{_{-PO 3 H 2, -HPO 3 -}} Na + or -PO ₃ ^2- Na and ₂ should preferably, R _a is methyl (methyl), R _b is -C ( = O) CH _3, R _p is -PO ₃ H _2, -HPO ₃ ^- but not Na ⁺ or -PO ₃ ^2- Na more preferably ₂ to, but not limited thereto.

Most preferably, the prodrug of the compound of formula (I) according to the present invention, formula (III), may have the structures of formula (IV) to formula (VI), but is not limited thereto.

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 pharmaceutically acceptable salts of compounds of Formulas I-VI include hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, maleate. , di-p-toluoyl tartaric acid, ortinic acid, edicylic acid, hemi-edicylic acid and salts of mandelic acid can be exemplified, but not limited thereto.

One or more pharmaceutically acceptable carriers may be included in the therapeutic composition comprising the compounds of formulas (I) to (VI) according to the present invention.

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, or subcutaneous. , intraperitoneal, enteral, topical, sublingual or rectal dosage forms suitable for administration 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 or aerosol when administered intranasally or intranasally. It is more preferable to be administered in a formulation for administration or inhalation 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, and benzyl alcohol or other suitable preservatives, absorption enhancers to enhance 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. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension (eg, a solution in 1,3-butanediol) in a non-toxic parenterally acceptable diluent or solvent. Non-limiting examples of pharmaceutically acceptable vehicles and solvents include mannitol, water, Ringel's solution, and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as the 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 useful in injectable formulations as are pharmaceutically acceptable natural oils (eg olive oil or castor oil), especially their polyoxyethylated ones.

In addition, the therapeutic composition according to the present invention may be formulated in any orally acceptable pharmaceutical dosage form including, but not limited to, capsules, pellets, tablets, aqueous suspensions and solutions and administered orally.

When formulated for oral administration, the therapeutic composition according to the present invention may be formulated to include one or more pharmaceutically acceptable excipients, 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 sweeteners may be used.

By way of non-limiting example, the filler (diluent) may include mannitol, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, anhydrous Lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose (sucrose), talc (talc), xylitol (xylitol), maltose maltodextrin (maltose maltodextrin) and at least one selected from the group consisting of maltitol (maltitol);

Disintegrants include crospovidone, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, soium docusate, guar gum, hydroxypropyl cellulose, methylcellulose , at least one selected from the group consisting of polacrilin 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 sodium, microcrystals From the group consisting of adult cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch and sucrose one or more selected;

Lubricants (lubricants) include 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 not limited thereto.

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 One or more film coating bases selected from the group consisting of acrylic acid copolymers, polyethylene oxide and xanthan gum, but are 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 relates to the use of the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same for the treatment of pulmonary fibrosis, in particular 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 above treatment.

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.

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) Total inflammatory cells
(B) macrophages
(C) Lymphocytes
(D) neutrophils
3 is a diagram showing changes in inflammation-related cytokines in a mouse model of bleomycin-induced pulmonary fibrosis according to administration of a compound of Formula II according to the present invention.
(A) TGF (Tissue Growth Factor)-β
(B) IL (Interleukin)-17
(C) TNF (Tumor Necrosis Factor)-α
(D) IL-1β
4 is a diagram showing the Ashcroft Score in a mouse model of Bleomycin-induced pulmonary fibrosis according to the administration of the compound of Formula II according to the present invention.
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, bronchial and perivascular wall thicknesses in a mouse model of bleomycin-induced pulmonary fibrosis according to administration of a compound of Formula II according to the present invention.
(A) Alveolar surface area
(B) alveolar wall thickness
(C) peribronchial wall thickness
(D) perivascular wall thickness

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 will be apparent 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. Pulmonary fibrosis animal model production and drug administration method

1.1 Pulmonary Fibrosis Animal Model Fabrication

C57BL/6 female 8-week-old mice were obtained from Orientbio Inc. It was purchased from (Seongnam, Korea) and maintained in an AAALAC international accredited animal laboratory, and the animal experimentation ethics committee approved cuh-IACUC-2019-1-1 animal testing. Lung fibrosis was induced in mice by intratracheal injection of 3 mg/kg bleomycin after isoflurane inhalation anesthesia (Matrix, Orchard Park, NY, USA).

1.2 Drug administration

To the pulmonary fibrosis-induced mice prepared in Example 1.1, 0.1 mg/kg, 1.0 mg/kg, and 5.0 mg/kg of the compound of Formula II were administered by inhalation 24 hours after pulmonary fibrosis induction and at 2-day intervals thereafter ( 0.05% DMSO, saline). On day 14 after bleomycin injection, mice were sacrificed, bronchoalveolar lavage was performed, and lung tissue was excised.

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, in all the drawings, B291 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, SV is a normal control group administered with drug vehicle to experimental animals treated with saline (saline-instilled mice administered with drug vehicle, SAL+VEH), BV is bleomycin It refers to the pulmonary fibrosis group administered with the drug vehicle to the treated animals (bleomycin-instilled mice administered with drug vehicle, BLM+VEH).

In a mouse model of bleomycin-induced pulmonary fibrosis, the effect test group of the compound of formula II was a total of 6 groups, saline-instilled mice administered with drug vehicle, SAL+VEH, and bleomycin-instilled mice administered. with drug vehicle, BLM+VEH), 0.1 mg/kg of the compound of Formula II administered to a mouse model of bleomycin-induced pulmonary fibrosis, 3 groups (0.1 mg/kg, 1.0 mg/kg, and 5.0 mg/kg), and bleomycin-induced In a mouse model of lung fibrosis, an experiment was conducted in a group administered with 200.0 mg/kg of pirfenidone as a drug control group (see Table 1).

Table 1. Overview of experimental groups

Example 2. Inflammatory cell changes

After sacrificing the mouse according to Example 1, the chest cavity was opened so that the lungs could be sufficiently expanded, and 1 ml PBS was slowly injected into the lungs through a tube inserted into the airway by incision of the trachea, and it was collected and collected at 4 °C with bronchoalveolar lavage solution. was stored in

The bronchoalveolar lavage fluid was used to measure the total number of inflammatory cells using NucleoCounter (Chemometec., Gydevang, Denmark). After centrifugation, the precipitated cells were resuspended in PBS and cytospin (Thermo Electron, Waltham, MA, USA) was used. It was spread on a slide and used for differentiation of inflammatory cells. Cell differentiation was performed by staining the prepared cell smear with Diff-Quik solution (Dade Diagnostics of Puerto Rico Inc., Aguada, Puerto Rico, USA) and counting more than 400 cells in different places on the slide.

Experimental results shown in all drawings in this specification are expressed as the mean and the standard error of the mean. GraphPad Prism 5 was used, and one-way ANOVA, two-way ANONA or t-test analysis was performed. In Bonferroni's multiple comparison test, paired t-test, or Mann Whitney test , the case of P value < 0.05 was interpreted as statistically significant.

In the mouse model of bleomycin-induced pulmonary fibrosis, the number of macrophages, lymphocytes, and neutrophils in the bronchoalveolar cells increased and the total number of inflammatory cells significantly increased. 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 P <0.05, ^## means P <0.01, and ^### means P <0.001).

Example 3. Inflammatory cytokine changes

Proteins from mouse lung tissue were extracted and separated by electrophoresis, and the expression of TGF-β, TNF-α, IL-1β and IL-17 was confirmed by Western blotting and quantitatively analyzed.

In the bleomycin-induced pulmonary fibrosis response, the significantly increased expression of TGF-β , IL-17, TNF-α and IL-1 β proteins was decreased in the group administered with the compound of Formula II (Figure 3(A) to 3(D)) For reference, the bar indicates the mean ± standard error of 6 mouse groups, ^# indicates P <0.05, ^## indicates P <0.01, and ^### indicates P <0.001).

Specifically, IL-1 β 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-β and IL-17 was maximally decreased in the group administered with the compound of Formula II at 1.0 mg/kg. did TNF-α showed a significant decrease in the 5.0 mg/kg administration group, and there is a difference in pro-inflammatory protein expression depending on 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. Pireu penny money drug control group showed a tendency to have no effect on the increased expression of TGF- β and IL-17, decreased the protein expression of TNF-α and IL-1 β. Compared with the pirfenidone drug control group, TGF-β was significantly decreased in the group administered with the compound of Formula II, and the reduction of IL-17 in the previous administration group, the reduction of TNF-α at the same level in the group administered at 5.0 mg/kg and 1.0 mg/kg in kg and 5.0 mg / kg group there was a reduction of IL-1 β.

Example 4. Analysis of histopathological changes

A mouse lung tissue slide was prepared and the degree of tissue change was observed with hemetoxylin & eosin (H&E) staining, 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 P <0.05, ^## means P <0.01, and ^### means P <0.001).

Collagen deposition amount was decreased to the same level as that of the drug control group, or the statistical significance 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 P <0.05, ^{# #} means P < 0.01, and ^### means P < 0.001). In addition, the decrease in the alveolar surface area and the thickening of the alveolar and bronchial walls and blood vessel walls were alleviated (see Figs. 6(A) to 6(D), the plot is the mean ± standard error of 6 groups of mice, ^# is P <0.05, ^## means P <0.01, and ^### means P <0.001).

Claims (13)

A composition for treating pulmonary fibrosis comprising a compound having the structure of Formula I, a prodrug thereof, a salt thereof, or an isomer thereof

[Formula I]

In Formula I, R _a is a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, or a C ₂ -C ₆ alkynyl group, and R _b is an aryl group, a substituted aryl group, or —C (=O)R _e and R _e is a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, or C ₂ -C ₆ alkynyl group.
The method according to claim 1, wherein in Formula I, R _a is a C ₁ -C ₆ alkyl group or a C ₂ -C ₆ alkenyl group, R _b is -C(=O)R _e , and R _e is C ₁ - A composition for treating pulmonary fibrosis (Pulmonary Fibrosis), characterized in that it is an alkyl group of C _{6 .}
The composition for treating pulmonary fibrosis according to claim 1, wherein the compound of formula (I) has a structure of formula (II).

[Formula II]

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.

[Formula III]

In Formula III, R _a is a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, or a C ₂ -C ₆ alkynyl group, and R _b is an aryl group, a substituted aryl group, or —C (=O)R _{e ,} wherein R _e is a C ₁ -C ₆ alkyl group, C ₂ -C ₆ alkenyl group, or C ₂ -C ₆ alkynyl group, and R _p is —PO ₃ H ₂ , -HPO ₃ ^- Na ⁺ , -PO ₃ ^2- Na ₂ ⁺ , -PO ₃ ^2- K ₂ ⁺ , -PO ₃ ^2- Mg ²⁺ , -PO ₃ ^2- Ca ²⁺ , Structural Formula 1, Structural Formula 2, or Structural formula 3.

5. The method of claim 4, wherein in the compound of Formula III, R _a is a C ₁ -C ₆ alkyl group or C ₂ -C ₆ alkenyl group, R _b is -C(=O)R _e , R _e an alkyl group of C ₁ -C _6, R _p is ^{_{-PO 3 H 2, -HPO 3 -}} Na + or -PO ₃ ^2- Na ₂ lung fibrosis, characterized in that (pulmonary fibrosis) therapeutic composition.
The method of claim 4 wherein in the compound of Formula III, R is _a methyl (methyl) a, R _b is _{-C (= O) CH 3,} R p is ^{_{-PO 3 H 2, -HPO 3 -}} Na + Or -PO ₃ ^2- Na ₂ Pulmonary fibrosis (Pulmonary Fibrosis) treatment composition, characterized in that.
[Claim 6] The composition for treating pulmonary fibrosis according to claim 5, wherein the compound of Formula III has a structure selected from Formulas IV to VI.

According to claim 1, wherein the pulmonary fibrosis is pulmonary fibrosis (Pulmonary Fibrosis) treatment composition, characterized in that the pulmonary fibrosis caused by Idiopathic Pulmonary Fibrosis (IPF) or coronavirus infection-19 of unknown cause .
The composition for treating pulmonary fibrosis (Pulmonary Fibrosis) according to any one of claims 1 to 8, characterized in that it comprises one or more pharmaceutically acceptable carriers.
10. A pharmaceutical formulation for oral or parenteral administration comprising the composition for treatment according to claim 9.
11. The method of claim 10, wherein the parenteral administration is intranasal, intranasal, buccal, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, enteral, topical, sublingual or rectal administration. A pharmaceutical formulation, characterized in that
The pharmaceutical formulation according to claim 11, wherein the intranasal or intranasal administration is administered in the form of a spray, aerosol or inhalation.
The pharmaceutical formulation according to claim 12, wherein the oral administration is administered in the form of capsules, pellets, tablets, aqueous suspensions or solutions.

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