Pharmaceutical composition for preventing or treating systemic sclerosis

Abstract

The pharmaceutical composition according to the present invention can be usefully used for the prevention or treatment of systemic sclerosis.

Description

Technology Field

[0001] The present invention is intended to provide a pharmaceutical composition for the prevention or treatment of systemic sclerosis. Background Technology

[0002] Systemic sclerosis (SSc) is a degenerative disease that causes hypertrophy or hardening of the skin, blood vessels, and internal organs, and it belongs to the category of autoimmune rheumatic diseases. This disease is chronic and can progress over a long period. Although the cause of systemic sclerosis has not yet been identified, there are reports linking specific chemicals (such as toluene, benzene, vinyl chloride, and silica) to its onset. Diagnosis is made by integrating medical history, physical examination, tissue biopsy, and blood tests. The extent of internal organ damage can be assessed through upper and lower gastrointestinal examinations, X-rays, pulmonary function tests, electrocardiograms, and echocardiograms.

[0004] Systemic sclerosis generally has a good prognosis, but it can be life-threatening if it metastasizes to the lungs, kidneys, or heart. Progression of interstitial lung disease and pulmonary hypertension can lead to shortness of breath, and a renal crisis accompanied by severe hypertension may occur.

[0006] Systemic sclerosis is a type of autoimmune disease caused by errors in the internal immune system. It is diagnosed in the rheumatology department, where treatment is administered to alleviate various symptoms resulting from autoimmune suppression. Systemic sclerosis is broadly classified into limited or diffuse cutaneous systemic sclerosis depending on the extent of skin involvement; some patients with systemic sclerosis exhibit symptoms of systemic sclerosis-associated lung disease (SSc-ILD) along with immunomodulatory disorders. SSc-ILD is more commonly observed in diffuse systemic sclerosis. Furthermore, 25 to 30% of these patients progress to progressive SSc-ILD, which is known to be a leading cause of death in patients with systemic sclerosis (Lancet, 2017; 390:1685-1699).

[0008] Systemic sclerosis-associated lung disease (SCA-associated lung disease) is a respiratory condition occurring in patients with systemic sclerosis; it is diagnosed and treated by pulmonologists to improve lung function. SCA-associated lung disease is highly associated with early mortality in SCA patients. Research in the United States indicates that the mortality rate due to pulmonary fibrosis in SCA patients increased more than fivefold from 6% to 33% over approximately 20 years, making interstitial lung disease the most frequent cause of SCA-related deaths. Furthermore, EULAR studies have revealed that it influences the mortality rate of over 35% of SCA patients. (Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007;66:940-4)

[0010] Risk factors for the onset or progression of interstitial lung disease in patients with systemic sclerosis include the presence of diffuse cutaneous systemic sclerosis (dcsSc), African American heritage, age at onset (advanced age), a shorter disease duration, and the absence of anti-Scl-70 / anti-topoisomerase I antibodies and anti-centromere antibodies; the disease develops when conditions for its development are met due to various reasons that are yet to be identified. However, none of these risk factors are absolute, and the induction of systemic sclerosis does not necessarily lead to the development of systemic sclerosis-associated lung disease. Furthermore, since not all patients exhibit respiratory symptoms, physicians and researchers are actively working on early diagnosis and the development of treatments through various methods (Respiratory Research volume 20, Article number: 13 (2019)).

[0012] In particular, recent studies using clinical samples show that while systemic sclerosis-associated lung disease originates from patients with systemic sclerosis, it exhibits significant differences in various blood cytokines and biomarkers such as IGFBP-1, MMP-9, and H3.1, suggesting that the disease characteristics of these patients differ. These studies are currently being conducted to utilize these as biomarkers for diagnosing systemic sclerosis-associated lung disease within the current systemic sclerosis cohort, and this data can serve as a basis for viewing the two diseases as independent classifications despite their high association. Furthermore, the fact that MMP-7 and MMP-9 are specifically elevated in the blood of patients with systemic sclerosis-associated lung disease compared to patients with systemic sclerosis is interpreted not only as evidence supporting the reasons for pulmonary fibrotic onset and the rapid and high mortality rate of up to one-third of patients with systemic sclerosis-associated lung disease, but also as a basis for distinguishing systemic sclerosis-associated lung disease from systemic sclerosis not only clinically but also pathologically ((i) Clin Epigenetics. 2020 Aug 17;12(1):124, (ii) Sarcoidosis Vasc Diffuse Lung Dis. 2015 Sep 14; 32(3):228-36, (iii) European Respiratory Journal 2021 58: 2101560).

[0014] To date, there is no treatment available to halt the progression of systemic sclerosis, although certain medications can alleviate specific symptoms and reduce organ damage. Non-steroidal anti-inflammatory drugs (NSAIDs) help relieve joint pain, and calcium channel blockers can relieve symptoms of Raynaud's phenomenon, although they may cause gastrointestinal problems. Corticosteroids can relieve symptoms of myositis, immunosuppressants can alleviate lung inflammation, and antihypertensive drugs can alleviate acute kidney injury and elevated blood pressure; however, these methods have limitations as they only provide relief for specific symptoms, and there are no medications available for overall symptom relief.

[0016] Ofev® (nintedanib) and Actemra® (tocilizumab) have been approved as treatments for systemic sclerosis-associated lung disease. Nintedanib is known as a treatment for idiopathic pulmonary fibrosis that improves lung function in patients with the condition. However, since nintedanib is effective only in improving pulmonary fibrosis and has failed to demonstrate therapeutic efficacy for skin hardening symptoms, it is currently prescribed only as an adjuvant therapy to improve lung function in patients with end-stage systemic sclerosis-associated lung disease accompanied by advanced interstitial lung disease. Tocilizumab is an immunosuppressant used to treat rheumatoid arthritis and is known to alleviate the symptoms of rheumatic diseases. However, as tocilizumab has not demonstrated alleviation or improvement of fibrosis, it is used as a preventive adjuvant therapy for patients with early-stage systemic sclerosis-associated lung disease who have not yet experienced severe lung function impairment. In other words, neither of the two approved drugs provides a fundamental therapeutic effect for patients with systemic sclerosis or lung disease associated with systemic sclerosis, so they are not prescribed as first-line treatment, and patients still have to rely on immunosuppressants with severe side effects such as cyclophosphamide and mycophenolate.

[0018] Meanwhile, prolyl-tRNA synthetase (PRS) is one of the aminoacyl-tRNA synthetase (ARS) family enzymes that plays a role in activating amino acids for protein synthesis. Specifically, ARS performs a translational function by forming aminoacyl adenylate (AA-AMP) and then transferring the activated amino acid to the third terminus of the corresponding tRNA. Because ARS plays a key role in protein synthesis, inhibition of ARS suppresses the growth and development of all cells. Accordingly, ARS is recognized as a promising target for antibiotics or therapeutic agents for diseases that require the inhibition of cellular overexpression (Nature, 2013, 494: 121-125).

[0020] PRS exists and functions as a multisynthetase complex (MSC) in the form of EPRS (Glutamyl-Prolyl-tRNA Synthetase). In particular, among various MSCs, EPRS functions as a translational silencer that inhibits the production of VEGF A (vascular endothelial growth factor A), a key factor in angiogenesis, and has also been reported to be closely associated with various solid tumors (Nat. Rev. Cancer, 2011, 11, 708-718).

[0022] Accordingly, the inventors of the present invention have completed the present invention by diligently researching methods for the prevention or treatment of systemic sclerosis and confirming that a specific PRS inhibitor described below is useful for the prevention or treatment of systemic sclerosis. The problem to be solved

[0023] The present invention is intended to provide a pharmaceutical composition that can be usefully used for the prevention or treatment of systemic sclerosis. means of solving the problem

[0024] To solve the above problem, the present invention provides a pharmaceutical composition for the prevention or treatment of systemic sclerosis as follows:

[0025] A pharmaceutical composition for the prevention or treatment of systemic sclerosis comprising a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof:

[0026] [Chemical Formula 1]

[0027] .

[0029] The compound represented by the above chemical formula 1 or the pharmaceutically acceptable salt thereof is a compound described in Korean Patent Registration No. 10-2084772, specifically the substance described in Example 40 of the said specification.

[0031] The pharmaceutical composition according to the present invention can be usefully employed for the prevention or treatment of systemic sclerosis, particularly systemic sclerosis-associated interstitial lung disease (SSc-ILD). In particular, the pharmaceutical composition according to the present invention has a dual effect of alleviating skin hardening and improving lung function in systemic sclerosis-associated lung disease. The term "improvement of lung function" used in the present invention refers to the improvement of the ability to supply blood to the body, which is a fundamental function of the lungs; this is not an effect that naturally follows from the improvement of pulmonary fibrosis, and can be confirmed through internal oxygen saturation independently of pulmonary fibrosis indicators.

[0033] As used in the present invention, the term "prevention" refers to any act of suppressing or delaying the occurrence, spread, and recurrence of the said disease through the administration of the composition of the present invention, and the term "treatment" refers to any act of improving or beneficially altering the symptoms of the said disease through the administration of the composition of the present invention.

[0035] Meanwhile, the compound represented by Chemical Formula 1 above may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. Inorganic and organic acids may be used as the free acid. As inorganic acids, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used, and as organic acids, citric acid, acetic acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid, or aspartic acid, etc. Preferably, the pharmaceutically acceptable salt of the compound represented by Chemical Formula 1 above is a hydrochloride salt.

[0037] In addition, the compound represented by Chemical Formula 1 may be prepared in a crystalline or amorphous form, and if prepared in a crystalline form, it may be optionally hydrated or solvated. The present invention may include not only the stoichiometric hydrate of the compound represented by Chemical Formula 1 but also compounds containing varying amounts of water. The solvates of the compound represented by Chemical Formula 1 include both stoichiometric solvates and non-stoichiometric solvates.

[0039] The pharmaceutical composition of the present invention may be formulated into oral or parenteral administration forms in accordance with standard pharmaceutical practices. These formulations may contain, in addition to the active ingredient, pharmaceutically acceptable additives such as carriers, adjuvants, or diluents.

[0041] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate, and diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, but are not limited thereto. In addition, the compounds of the present invention may be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injectable solutions. Furthermore, the compounds of the present invention may be formulated into ointments or creams for topical action.

[0043] The pharmaceutical administration forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts or solvates, and may also be used alone, in combination with other pharmaceutically active compounds, or in suitable combinations. For example, the pharmaceutical composition according to the present invention may additionally include other active ingredients used for the prevention or treatment of systemic sclerosis. Examples of such other active ingredients include Ofev® (Nintedanib) or Actemra® (tocilizumab). Additionally, when the pharmaceutical composition according to the present invention additionally includes other active ingredients, the weight ratio of the compound represented by Formula 1, or its pharmaceutically acceptable salt, to the other active ingredients is preferably 1:0.1 to 1:10.

[0045] The compounds of the present invention may be formulated into injectables by dissolving, suspending, or emulsifying the compounds in a water-soluble solvent such as ordinary saline solution or 5% dextrose, or in a water-insoluble solvent such as synthetic fatty acid glycerides, higher fatty acid esters, or propylene glycol. The formulations of the present invention may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0047] The pharmaceutical composition according to the present invention may be administered via an oral or parenteral route. Depending on the method of administration, the composition according to the present invention may contain 0.001 to 99 weight%, preferably 0.01 to 60 weight%, of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

[0049] The pharmaceutical composition of the present invention may be administered to mammals, including rats, mice, livestock, and humans, by various routes. All modes of administration are expected, for example, orally, rectally or intravenously, intramuscularly, subcutaneously, or intradurally or intracerebroventricularly. Effects of the invention

[0050] As described above, the pharmaceutical composition according to the present invention can be usefully used for the prevention or treatment of systemic sclerosis. Brief explanation of the drawing

[0051] Figure 1 shows the results of confirming the thickness of a 3D skin organoid through H&E immunohistochemical staining in Experimental Example 1 of the present invention. Figure 2 shows the results of confirming the skin thickness of a systemic scleroderma skin organoid transplant mouse model through immunohistochemical staining in Experimental Example 2 of the present invention. Figure 3 shows the results of confirming the fibrosis factors Collagen I, Collagen III, and αSMA in the skin tissue of a systemic scleroderma skin organoid transplant mouse model through immunohistochemical staining in Experimental Example 2 of the present invention. Figure 4 shows the experimental schedule for a mouse in Experimental Example 3 of the present invention. Figure 5 shows the results of the change in body weight of a mouse in Experimental Example 3-1 of the present invention. Figure 6 shows the results of the change in lung weight of a mouse in Experimental Example 3-2 of the present invention. Figure 7 shows the results of the lung function evaluation of a mouse in Experimental Example 3-3 of the present invention. Figure 8 shows the results of the skin thickness evaluation of a mouse in Experimental Examples 3-4 of the present invention. Figure 9 shows the results of measuring the body collagen content of a mouse in Experimental Examples 3-5 of the present invention. Specific details for implementing the invention

[0052] The present invention will be explained in more detail below through the following examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

[0054] Examples

[0055] The following compound was prepared in the same manner as Example 40 of Korean Patent Registration No. 10-2084772 and was hereinafter referred to as the 'active ingredient' or 'Example'.

[0056]

[0057] 1 H NMR (500 MHz, MeOD): δ 9.67 (s, 1H). 8.02 (d, 1H), 7.82 (d, 1H), 4.62 (m, 2H), 3.60 (m, 1H), 3.28 (m, 1H), 2.99 (m, 2H), 2.25 (m, 2H), 2.08 (m, 2H), 1.99 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H)

[0059] Experimental Example 1: Confirmation of skin hardening alleviation effect in a 3D skin organoid model

[0060] 3D skin organoids were constructed using iPSC-derived fibroblasts from patients with systemic scleroderma according to the method described in the literature (Lancet. 2009 Nov 21;374(9703):1745-53), and H&E immunohistochemical staining confirmed that the thickness of the 3D skin organoids decreased when treated with 1 uM of the active ingredient in DMSO solution (Fig. 1). The control group was treated only with DMSO.

[0062] Experimental Example 2: Confirmation of Skin Hardening Alleviation Effect in a 3D Skin Organoid Implant Mouse Model

[0063] A mouse model of Systemic Scleroderma (SSCID) was constructed by transplanting a previously established 3D skin organoid derived from iPSCs of SSCID patients into SCID mice. Mouse skin tissue was cut into 1 x 2 cm sections, and the 3D skin organoid tissue was sutured to the mouse skin. The skin graft was performed on the back of the mice using the clinical tie-over dressing method. After placing gauze on the suture site, it was tied with sutures and dressed with a bandage.

[0065] The active ingredient was administered subcutaneously at doses of 3 mg / kg and 10 mg / kg daily for 2 weeks to a mouse model of systemic scleroderma skin organoid transplantation. Physiological saline was administered to normal skin tissue in the negative control group (NC), and physiological saline was administered to skin tissue of the systemic scleroderma skin organoid transplantation in the positive control group (SSc). Skin thickness, the primary endpoint of systemic scleroderma, was measured by immunohistochemical staining, and the results are shown in Figure 2. As shown in Figure 2, it was confirmed that the thickness of the skin tissue was significantly reduced by the active ingredient (***p<0.001).

[0067] Immunohistochemical staining was performed to determine whether fibrosis factors in systemic scleroderma skin tissue were reduced by the active ingredient, and the results are shown in Figure 3. As shown in Figure 3, it was confirmed that the fibrosis factors Collagen I, Collagen III, and αSMA were significantly reduced by the active ingredient (*p<0.05, ***p<0.001).

[0069] Experimental Example 3: Confirmation of therapeutic effect in a mouse model of systemic sclerosis-associated lung disease (SSc-ILD).

[0070] C57BL / 6 mice were 7 weeks old and acclimatized indoors for more than 5 days. A model of systemic sclerosis-associated lung disease was designed using an osmotic pump. This is because, if the modeling did not use an osmotic pump, it would require injecting BLM subcutaneously into the backs of the test animals daily for 4 weeks, and such a test could cause severe pain at the injection site.

[0072] As shown in Figure 4, the drug administration rate using the osmotic pump was 0.5 ul / hr (7 days), and the size of the osmotic pump was 1.5 cm. After suturing the incision site and inserting the osmotic pump, bleomycin was administered for one week, and the osmotic pump was removed on the 10th day. It was confirmed that systemic sclerosis-associated lung disease was induced in the mouse model administered BLM for one week, and the specific experimental groups are as shown in Table 1 below.

[0073] Number of animals (parts) Route of administration (Osmotic pump) Route of administration (oral) Test group Administered substance Dosage (U / kg) Administered solution volume (µl) Administered substance Dosage (mg / kg) Administered solution volume (µl) G1 9 Saline - 100 Saline - 100 G2 9 BLM 100U / kg 100 Saline - 100 G3 9 BLM 100U / kg 100 Nintedanib 60 100 G4 9 BLM 100U / kg 100 Active ingredient 3 100 G5 9 BLM 100U / kg 100 Active ingredient 10 100 G6 9 BLM 100U / kg 100 Active ingredient 30 100

[0075] Experimental Example 3-1: Body weight (%)

[0076] Based on the results of 28 days of administration of the active ingredient (Table 2 and Figure 5), the change in body weight showed significant results starting from 3 mg / kg of the active ingredient, and at 30 mg / kg, it was confirmed that body weight increased significantly compared to the vehicle with p<0.01.

[0077] Saline BLM Active ingredient (3 mg / kg) Active ingredient (10 mg / kg) Active ingredient (30 mg / kg) NIN 1 16.94 -0.73 8.65 0.48 9.52 2.46 2 16.1 -1.15 3.02 0.14 5.35 4.14 3 17.47 -1.19 -0.36 4.88 -2.86 1.78 4 11.99 -5.16 1.07 4.78 7.57 4.49 5 10.58 -4.1 -2.45 4.62 12.09 -0.45 6 7.85 -5.9 -2.14 2.54 7.78 0.58 7 8.63 -0.75 1.34 1.96 2.13 8.79 8 13.47 -4 -0.33 -4.1 2.34 0.44 9 12.59 -2.17 -1.93 -2.48 1.45 -2.94

[0079] Experimental Example 3-2: Lung weight

[0080] Changes in lung weight showed a significant trend only at 30 mg / kg, but when adjusted for body weight, significance appeared starting from 10 mg / kg, and it was confirmed that the significance increased to p<0.01 at 30 mg / kg (Table 3 and Figure 6).

[0081] Saline BLM Active ingredient (3 mg / kg) Active ingredient (10 mg / kg) Active ingredient (30 mg / kg) NIN 1 0.8 1.03 1.14 1.16 0.94 0.99 2 0.8 1.05 0.98 0.99 0.98 0.98 3 0.8 1.14 1.15 0.93 1.09 1.16 4 0.8 1.19 0.92 1.08 0.97 0.89 5 0.8 1.19 1.01 0.98 1.10 0.96 6 0.8 1.14 1.14 1.22 0.99 0.99 7 0.8 1.26 1.08 1.14 0.90 1.04 8 0.9 1.20 0.98 1.12 0.98 0.95 9 0.9 1.14 1.08 0.95 1.03 1.01

[0083] Experimental Example 3-3: Evaluation of Lung Function (SpO2 2 (%))

[0084] This lung function evaluation is an experiment designed to demonstrate the therapeutic effect of the active substance in patients with systemic sclerosis-associated lung disease. Unlike general pulmonary fibrosis improvement effects, it is the most direct and important evaluation indicator that has the greatest influence on the symptoms and quality of life of patients with systemic sclerosis-associated lung disease. By measuring oxygen concentration in the body, this experiment can most directly demonstrate the effect of improving lung function in animal models of systemic sclerosis-associated lung disease.

[0086] On the 28th day, SpO2 was measured through the abdomen of the mouse using a Berry Veterinary Pulse Oximeter. The results are shown in Figure 7.

[0088] As shown in Figure 7, significant results were observed starting from 10 mg / kg of the active ingredient, and at 30 mg / kg of the active ingredient, oxygen saturation was found to be higher compared to the vehicle with a p<0.001. In addition, it was confirmed that the group administered 30 mg / kg of the active ingredient showed an oxygen saturation recovery rate equivalent to that of the control group administered 60 mg / kg of nintedanib.

[0090] Experimental Example 3-4: Evaluation of Skin Thickness

[0091] Skin tissues were extracted from mice on day 28 and stained with H&E and Mansson's Trichrome (MT stain). Skin thickness was measured at 10 random locations on the stained images using ImageJ (with a minimum interval of 200–300 μm). The entire area of ​​the image was measured as evenly as possible, and areas where the stained tissue was damaged were excluded. The results are shown in Figure 8 and Table 4.

[0093] As shown in Figure 8, it was confirmed that in the BLM group, collagen was well induced, filling not only the dermis of the skin but also the areas where adipose tissue should be present. Significant results were observed starting from 10 mg / kg of the active ingredient, and at 30 mg / kg, highly significant results were observed with a P value of < 0.0001. Furthermore, it was confirmed that the collagen density in the skin decreased overall upon administration of the active ingredient, as evidenced by the low MT staining level. In particular, at 3 mg / kg of the active ingredient, while skin thickness did not decrease significantly, a tendency for skin collagen density to decrease was observed. Notably, a superior skin thickness improvement effect was confirmed at 10 mg / kg of the active ingredient compared to 60 mg / kg of nintedanib.

[0094] μm Saline BLM Active ingredient (3 mg / kg) Active ingredient (10 mg / kg) Active ingredient (30 mg / kg) NIN 1 436.567 663.945 677.319 593.826 443.336 620.302 2 412.602 723.118 744.986 601.558 601.558 651.572 3 445.578 844.957 904.141 809.106 558.530 856.355 4 437.536 819.822 641.841 708.308 479.961 664.973 5 378.447 835.348 809.254 526.170 475.515 675.558 6 494.174 926.507 771.562 521.027 412.271 623.019 7 458.348 706.216 778.660 425.415 525.311 651.831 8 420.379 681.761 688.725 456.862 593.963 660.809 9 443.032 768.854 759.037 672.616 526.388 649.479

[0096] Experimental Example 3-5: Measurement of collagen content in the body

[0097] We intended to indirectly measure collagen content by measuring the amount of hydroxyproline in the mouse body. The analysis was performed using the INSOLUBLE Collagen Assay (Biocolor, S2000), and specifically as follows.

[0099] First, 10 mg of frozen skin tissue was pulverized with 100 µl of Fragmentation Reagent. 100 µl of 37% HCl was added, and the mixture was incubated at 65°C for 3 hours. The contents of the tube were shaken at 30-minute intervals to aid in tissue disintegration. The mixture was centrifuged at 12,000 rpm for 10 minutes. After centrifugation, the contents were transferred to a 1.5 ml tube. 50 µl was taken from a sample between 10 and 100 µl, and distilled water was added to bring the total volume to 100 µl to prepare the sample.

[0101] 1 ml of dye was added to 100 µl of the prepared sample and mixed for 30 minutes. After centrifuging at 12,000 rpm for 10 minutes, the sample was transferred to a new tube. The dye was removed using 750 µl of ice-cold Acid-Salt Wash Reagent. After centrifuging at 12,000 rpm for 10 minutes, the sample was transferred to a new tube. Using a vortex mixer, the collagen binding dye was mixed with the solution, and the collagen binding dye was dissolved within 10 minutes to complete the preparation for measurement (measurements must be completed within 2 to 3 hours). The tube lid was kept closed until the absorbance was ready for measurement.

[0103] 200 µl of each sample was transferred to individual wells of a 96-micro-well plate, and absorbance was measured at 560 nm. The results were expressed as ratio values ​​relative to the normal group, and the results are shown in Table 5 and Figure 9.

[0105] Upon examining the BLM group, it was confirmed that the hydroxyproline in the skin increased by more than twofold compared to the Saline group, confirming that the modeling was well done. In addition, significant results were observed starting from 10 mg / kg of the active ingredient, and at 30 mg / kg of the active ingredient, highly significant results were observed with P<0.001.

[0106] Saline BLM Active ingredient (3 mg / kg) Active ingredient (10 mg / kg) Active ingredient (30 mg / kg) NIN 1 1.00 2.19 1.74 1.57 1.75 1.37 2 1.24 2.08 1.51 2.16 1.77 1.43 3 1.28 2.20 1.57 1.82 2.09 1.65 4 1.13 1.98 2.01 2.10 1.28 1.45 5 1.16 1.76 1.51 2.27 1.70 1.34 6 1.13 2.05 1.96 2.26 1.48 1.83 7 1.00 1.89 1.66 1.70 1.81 1.63 8 1.06 2.04 1.94 2.26 2.04 1.53 9 1.08 2.40 1.85 1.93 2.09 1.08

[0108] As can be confirmed from the experimental results above, the active ingredient of the present invention exhibited two completely different effects: a therapeutic effect on systemic sclerosis and an improvement in the impairment of lung function associated with systemic sclerosis-associated lung disease. This dual effect cannot be predicted from the therapeutic effect of either one alone and is understood as a characteristic of the active substance of the present invention.

Claims

Claim 1 A pharmaceutical composition for the prevention or treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD), comprising a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] . Claim 2 delete Claim 3 In claim 1, the pharmaceutical composition has a dual effect of alleviating skin hardening and improving lung function in systemic sclerosis-associated lung disease. Claim 4 A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt. Claim 5 A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises other active ingredients used for the prevention or treatment of systemic sclerosis. Claim 6 A pharmaceutical composition according to claim 5, wherein the other active ingredient used for the prevention or treatment of systemic sclerosis is nintedanib or tocilizumab.

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