Use of Obatoclax Derivatives and Pharmaceutical Compositions Thereof in the Prevention and Treatment of Renal Fibrosis

Abstract

The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of renal fibrosis and / or a renal disease associated therewith. The compound of formula (I) has the following structure. [Chemical Formula 1] JPEG2025523271000009.jpg52169

Description

Technical Field

[0001] This application claims the priority of a prior application filed with the State Intellectual Property Office of China on July 20, 2022, with an application number of 202210861718.4 and an invention title of "Use of Ovatodiolide Derivatives and Pharmaceutical Compositions Thereof in the Prevention and Treatment of Renal Fibrosis". The entire content of the above application is incorporated herein by reference.

[0002] The present invention belongs to the field of medicinal chemistry, and specifically relates to the use of Ovatodiolide derivatives and pharmaceutical compositions thereof in the prevention and treatment of renal fibrosis (RF) and / or renal diseases associated therewith.

Background Art

[0003] Chronic kidney disease (CKD) is a globally significant public health problem that seriously threatens human health, affecting 10 - 15% of the total population. Currently, there are approximately 130 million adult CKD patients in China. Moreover, with the increase in diabetes, hypertension, obesity, and the aging population, the global incidence of CKD is increasing year by year. Between 1990 and 2017, the prevalence of CKD in all age groups worldwide increased by 29.3%, and CKD has become an increasingly growing health and social burden.

[0004] Regardless of the primary disease of the kidney, once CKD occurs, it continues to progress and ultimately leads to end-stage renal disease (ESRD). Pathologically, ESRD appears as RF. RF is a common pathological pathway for all CKDs (including primary and secondary glomerular diseases, tubulointerstitial and vascular diseases, chronic rejection lesions of transplanted kidneys, etc.) to progress to end-stage renal disease (ESRD), mainly manifested as massive deposition of extracellular matrix (ECM), glomerulosclerosis, and tubular atrophy, indicating that the renal injury response has advanced to the final pathway characterized by tissue structure reconstruction and organ function loss.

[0005] To date, except for etiology and diet therapy, there are few approved treatments specific for RF.

[0006] (1) Clinically, existing anti-RF treatment strategies are mainly based on hemodynamic mechanisms and aim to reduce glomerular filtration pressure, including renin-angiotensin-aldosterone system (RAAS) blockers and sodium-glucose cotransporter (SGLT)-2 inhibitors. However, although RAAS blockade can delay the progression of CKD, it cannot completely block it, and it is prone to inducing hyperkalemia, acute kidney injury, etc., and cannot achieve satisfactory effects. SGLT-2 inhibitors have a certain renal protective effect, but their use is restricted in the middle to late stages (stages 3b - 5) of CKD.

[0007] (2) Over the past decade or more, there have been numerous anti-RF treatment methods based on molecular mechanisms for vascular endothelial cell proliferation and dysfunction (such as endothelin receptor antagonists), inflammatory cell infiltration and inflammatory microenvironment (such as CCL2 selective inhibitors), epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells (RTECs) and related secretory phenotypes (such as NF-κB inhibitors), and fibroblast activation (such as transforming growth factor-β1 antagonists), etc. However, most of these clinical trials have ended in failure.

[0008] Therefore, once CKD patients develop RF, they will inevitably progress to ESRD and ultimately have to rely on dialysis treatment or kidney transplantation, which will bring an extremely heavy economic burden to families and society. Therefore, how to effectively prevent and treat RF has become a common concern of the medical community worldwide. Actively researching and developing new drugs for RF treatment with significant therapeutic effects, few toxicities and side effects, controllable quality, and easy use has very important significance.

[0009] Currently, there is no report on the use of the obatoclide derivative of formula (I) provided by the present invention or its pharmaceutical composition for the prevention and treatment of RF and / or related kidney diseases.

Summary of the Invention

[0010] In order to improve the technical problems existing in the prior art, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of renal fibrosis and / or renal diseases associated therewith. The structure of the compound of formula (I) is as follows:

[0011]

Chemical formula

[0012] In the above formula (I), the above R1, R2, and R3 are each independently selected from H, halogen, C 1-6 alkyl group, C 1-6 alkoxy group.

[0013] Each R4 is independently selected from halogen, C 1-6 alkyl group, C 1-6 alkoxy group, and n is selected from 0, 1, 2, 3, or 4.

[0014] According to an embodiment of the present invention, preferably, the above R1, R2, and R3 are selected from a methyl group, an ethyl group, and a propyl group.

[0015] According to an embodiment of the present invention, the pharmaceutically acceptable salt is an acid addition salt formed by the compound of the above formula (I) and an inorganic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfate, or an organic acid such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl group)benzoic acid, camphanic acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfate or thiocyanic acid.

[0016] Preferably, the compound of the above formula (I) has the following structure

[0017]

Chemical formula

[0018] and is as follows.

[0019] More preferably, the pharmaceutically acceptable salt of the compound of the above formula (I) has the following structure

[0020]

Chemical formula

[0021] and is as follows.

[0022] According to an embodiment of the present invention, the kidney disease is selected from diabetic nephropathy, primary and secondary glomerulonephritis, hereditary kidney disease, acute kidney injury, chronic renal failure, lupus nephritis, renal vasculitis, glomerulosclerosis, hypertensive nephropathy (nephrosclerosis), interstitial nephritis, autosomal dominant polycystic kidney, Alport syndrome, analgesic nephropathy, and kidney allograft injury related to ischemia-reperfusion or rejection.

[0023] In some embodiments, the kidney disease is selected from various primary and secondary glomerular diseases, tubulointerstitial diseases, hereditary kidney diseases, renal vascular diseases, acute kidney injury, chronic renal failure, and kidney allograft injury related to ischemia-reperfusion or rejection.

[0024] In some embodiments, the drug contains 0.1 wt% to 99 wt%, preferably 0.5 wt% to 90 wt% of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the drug further contains a pharmaceutically acceptable carrier and / or excipient.

[0026] In some embodiments, the pharmaceutical composition contains one or more other drugs for prevention / treatment.

[0027] In some embodiments, the drug can be administered by two forms: injection including intravenous injection and intramuscular injection, and oral administration. The drug can be manufactured as oral preparations, injection preparations, topical preparations, etc., such as injection solutions, tablets, pills, capsules.

[0028] According to an embodiment of the present invention, the drug can be manufactured in a single-dose form or a divided-dose form.

[0029] The term "renal fibrosis" of the present invention is synonymous with "kidney fibrosis".

Advantages of the Invention

[0030] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the prevention / treatment of kidney fibrosis and / or kidney diseases associated therewith. It has been experimentally confirmed that the compound ACT004 of the present invention inhibits the activation of the transforming growth factor (TGF)-β1 / Smad signaling pathway, the STAT3 signaling pathway, and the NF-κB signaling pathway by controlling the expression of RALB, inhibits the EMT process of tubular epithelial cells, delays kidney fibrosis, and further plays a role in preventing and treating related kidney diseases.

Brief Description of the Drawings

[0031]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0032] The technical solution of the present invention will be further described in detail in accordance with specific embodiments below. It should be understood that the following examples are merely illustrative explanations of the present invention and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0033] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or may also be manufactured by known methods.

[0034] Example 1: Preparation of the Compound The compound of formula (I) of the present invention or its pharmaceutically acceptable salt can be prepared with reference to CN111303178. Among them, referring to the preparation of Compound 10, the compound with the following structure (code name: ACT004) can be obtained.

[0035]

Chemical formula

[0036] Its chemical name is (1aS,4Z,7S,9E,10aS,13S,13aS,15aS)-9,15a-dimethyl-13-((4-methylpiperazin-1-yl)methyl)-1a,2,3,8,10a,13,13a,14,15,15a-10H-4,7-(methylene)furo[2,3-f]oxononanoic acid [2,3-j][1]oxocyclopentene-5,12(7H)-dione fumarate.

[0037] Example 2: Anti-RF Activity Test of ACT004 In the initial stage of kidney injury, the generation of the fibrotic matrix is a tissue repair mechanism. After mild injury, this part of the fibrotic matrix is gradually absorbed without affecting the structure and function of the kidney. However, when CKD occurs, the fibrotic matrix continuously deposits, escapes surveillance and suppression, leading to the disintegration of tissue organ structure, reduction of blood flow supply, decline of organ function, and ultimately reducing the repair function of kidney tissue and causing renal insufficiency. Therefore, the main feature of RF is that excessive deposition of ECM causes scar formation, and the pathological symptoms are that due to the proliferation of ECM-producing cells such as fibroblasts and myofibroblasts, collagen fibers and cohesin are excessively produced and accumulated, progressively leading to glomerulosclerosis and interstitial renal fibrosis, and ultimately causing loss of kidney function.

[0038] The generation mechanism of RF controlled by complex multiple factors has not been fully elucidated. Tubuloepithelial-mesenchymal transition (TEMT) involving chronic inflammatory responses and the injury repair process are two important mechanisms. Many cells, mediators, growth factors, and signaling pathways, such as monocytes macrophages, Notch, Wnt, and Hedgehog signaling pathways, TGF-β1, basic fibroblast growth factor, and angiotensin II, are directly or indirectly involved in this process. RTECs injury is an initial event that triggers a fibrotic response and is controlled by many factors, including various transcription factors, growth factors, cytokines, hormones, and extracellular signals. Among many fibrosis-promoting factors, TGF-β1 is the most important growth factor that causes the occurrence and progression of EMT and controls the EMT process through the classical Smad-dependent pathway. RTECs that have undergone EMT lose their normal substance transport function, cells undergo G2 / M arrest, resulting in a decrease in proliferation and repair ability, and a significant secretory phenotypic transformation occurs, including a significant upregulation of the expression levels of various fibrosis-promoting factors, including TGF-β1. Through the secreted fibrosis-promoting factors, RTECs that have undergone EMT interact with fibroblasts in the renal interstitium, induce the proliferation and activation of interstitial fibroblasts, and further promote the progression of RF. Selective blockade of TEMT can not only protect RTECs function and inhibit myofibroblast formation, but also significantly reduce the expression levels of various inflammatory factors in the kidney and the infiltration of inflammatory cells in the interstitial region, and can effectively delay the formation of RF in various CKD models.

[0039] 2.1 Experimental materials 2.1.1 Test drugs ACT004.

[0040] 2.1.2 Experimental animals Sixty 8-week-old C57 mice, of SPF grade, were provided by the Experimental Animal Center of Zhujiang Hospital, Southern Medical University, Guangzhou. Before the experiment, the animals were acclimated to the indoor environment at room temperature of 18°C - 22°C and relative humidity of 65% for 7 days. All mice were allowed to freely ingest water and were fed with normal feed (protein content 3.14 mg / g).

[0041] 2.1.3 Experimental cell line The immortalized cell line of mouse-derived renal tubular epithelial cells is derived from the donation of Professor Nie Xiaoli's research group from the School of Traditional Chinese Medicine, Southern Medical University.

[0042] 2.2 Experimental methods 2.2.1 Therapeutic effects of ACT004 on unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI) rat models 2.2.1.1 Establishment and grouping of animal models Construction method of UUO model Under anesthesia by intraperitoneal injection of tribromoethanol, the hair in the midline abdominal incision area was shaved and disinfected. After midline abdominal incision, the left ureter was found, the upper ureter was freed, and complete ureteral occlusion double ligation was performed using 4-0 suture (UUO group). For the mice in the sham operation group (sham group), the ureter was exposed and freed in the same way, but ligation was not performed. The abdominal incision was sutured in sequence and disinfected with iodophor. The mice that underwent UUO surgery were randomly divided into UUO group, UUO + low-dose ACT004 (12.5 mg / kg·d) group, UUO + medium-dose ACT004 (25 mg / kg·d) group, UUO + high-dose ACT004 (50 mg / kg·d) group. Adding the sham operation group (sham group), there were a total of 5 groups, with 6 mice in each group. From the 4th day after surgery, an equal volume of physiological saline was administered by gavage to the sham group and UUO group for control treatment, and the left kidney tissue was collected on the 11th day after surgery.

[0043] Construction method of IRI model Mice were intraperitoneally anesthetized with tribromoethanol, and a midline abdominal incision or a dorsal incision was made. The left renal vein was dissected, clamped with an arterial clip, left on a thermostatic pad at 37.5 °C for 30 min, covered with a PBS-moistened gauze, the arterial clip was loosened after 30 min, and the abdomen was closed after observing renal congestion recovery. The mice that underwent IRI surgery were randomly divided into an IRI group, an IRI + low-dose ACT004 (12.5 mg / kg·d) group, an IRI + medium-dose ACT004 (25 mg / kg·d) group, and an IRI + high-dose ACT004 (50 mg / kg·d) group. A sham operation group (sham group) was added, for a total of 5 groups, with 6 mice in each group. From the 4th day after surgery, an equal volume of physiological saline was administered intragastrically to the sham group and the IRI group for control treatment. Right nephrectomy was performed on the 10th day after surgery, and left kidney tissue was collected on the 11th day after surgery.

[0044] 2.2.1.2 Setting of drug dosage and administration According to the results of the preliminary experiment, the medium dose of ACT004 in mice was 25 mg / kg·d. Therefore, low-dose (12.5 mg / kg·d), medium-dose (25 mg / kg·d), and high-dose groups (50 mg / kg·d) were set. ACT004 was prepared as a solution with physiological saline and orally administered once a day for one week starting from the 4th day after surgery. The mice in the sham group, UUO group, and IRI group were all orally administered an equal amount of physiological saline per day for one week.

[0045] 2.2.1.3 Collection and processing of specimens After one week of intragastric administration, kidney tissue was collected. The mice were anesthetized by intraperitoneal injection of tribromoethanol at a concentration of 200 mg / kg once, the eyeballs were removed for blood collection, the serum was separated and stored at -20 °C or -70 °C. An abdominal incision was made, the abdominal organs were separated with sterile gauze, and the heart was perfused with cold PBS until the organs turned white. The kidney tissue was taken, the whole left kidney was weighed, then incised along the median sagittal plane, washed clean with PBS, the capsule was removed, and it was placed in 10% neutral buffered formaldehyde solution for fixation in preparation for pathological examination.

[0046] 2.2.1.4 Observation indicators and measurement methods 2.2.1.4.1 Renal pathology The pathological structure of the kidney and the deposition of collagen fibers were observed by Masson staining.

[0047] 2.2.1.4.2 Detection at the protein level Ras GTPase superfamily member RALB, EMT-related index α-SMA, fibrosis phenotype-related indices Fibronectin, Collagen I.

[0048] 2.2.2 Effect of ACT004 on TGF-β1-induced EMT of renal tubular epithelial cells 2.2.2.1 Construction of cell models and grouping Construction method of RF cell models Human recombinant TGF-β1 cytokine (10 ng / μL) was taken and intervened in renal tubular epithelial cells (NRK) for 48 hours, causing NRK to show fibrotic changes and an increase in the expression of the fibrosis phenotype (Fibronectin, Collagen I, α-SMA). At the same time as adding TGF-β1, different concentrations of ACT004 intervention (2.5 μM, 5 μM, 10 μM) were administered, and it was divided into a total of 6 groups: blank control group, blank control + ACT004 (5 μM) group, TGF-β1 model group, TGF-β1 + different concentrations of ACT004 intervention groups (2.5 μM, 5 μM, 10 μM).

[0049] 2.2.2.2 Observation indicators and measurement methods Detection at the protein level Ras GTPase superfamily member RALB, EMT-related index α-SMA, fibrosis phenotype-related indices Fibronectin, Collagen I.

[0050] 2.2.3 Exploration of the relationship between the effect of ACT004 against RF and the RALB protein 2.2.3.1 Construction of a cell line with stable overexpression of RALB Suzhou Genepharma Co., Ltd. constructed a plasmid pc-RALB targeting the RALB sequence (pcDNA3.1 with an empty vector as a negative control) and transfected it into NRK.

[0051] 2.2.3.2 Observation Indicators and Measurement Methods Detection at the Protein Level RALB, EMT-related indicator α-SMA, fibrosis phenotype-related indicators Fibronectin, Collagen I.

[0052] 2.3 Experimental Results 2.3.1 Pathological Changes in Mouse Kidney Tissue From A in Figure 1, Masson staining shows that the expansion of the renal interstitium, deposition of extracellular matrix, increase in collagen fibers, and the situation of inflammatory cell infiltration in the UUO model and IRI model mice are significantly reduced in the ACT004 treatment group. However, the immunohistochemical staining results of fibrosis indicators Fibronectin, Collagen I, and α-SMA objectively show that ACT004 treatment inhibits the expression of Fibronectin, Collagen I, and α-SMA. The Wb bands in Figures C and D reflect that ACT004 can exert the effect of inhibiting the progression of RF at both in vivo and in vitro levels, and the difference is statistically significant.

[0053] 2.3.2 ACT004 Improves Renal Fibrosis by Effectively Regulating the TGF-β1 / Smad, STAT3, and NF-κB Signaling Pathways From A and B in Figure 2, the expression levels of p-Smad2, p-Smad3, p-Stat3, and p-NFκB in the kidney tissues of the UUO model and IRI model are clearly upregulated, and in the ACT004 treatment group, the expression levels are clearly decreased. The band in Figure C reflects the increase in the expression levels of p-Smad2, p-Smad3, p-Stat3, and p-NFκB in renal tubular epithelial cells induced by TGF-β1, and the expression after ACT004 intervention decreases, and the difference is statistically significant. From the above results, it was fully confirmed that ACT004 can inhibit the activation of the TGF-β1 / Smad signaling pathway, STAT3 signaling pathway, and NF-κB signaling pathway in the renal fibrosis model in both in vivo and in vitro environments.

[0054] 2.3.3 ACT004 achieves the effect of anti-renal fibrosis by controlling RALB expression. From Figure 3A, the expression levels of RALB in the kidney tissues of the UUO model and the IRI model were clearly up-regulated, and the expression levels were significantly decreased in the ACT004 treatment group. The bands in Figure B reflect the obvious up-regulation of RALB levels in the cells of the pcRALB group, indicating the successful construction of the cell line with stable overexpression. Under this condition, the fibrosis index (C) and p-Smad2, p-Smad3, p-Stat3, p-NFκB indexes (D) were detected, and the protein levels of the fibrosis indexes Fibronectin, Collagen I, α-SMA, and p-Smad2, p-Smad3, p-Stat3, p-NFκB were all significantly up-regulated, and the difference was statistically significant. The above results positively confirm the possibility that in the in vitro environment, RALB can promote the EMT process of renal tubular epithelial cells and promote renal fibrosis by activating the TGF-β1 / Smad signaling pathway, the STAT3 signaling pathway, and the NF-κB signaling pathway.

[0055] 2.4 Discussion 2.4.1 Animal Model At the end of the unilateral ureteral obstruction (UUO) experiment, the renal cortex of the animal model was thin and showed obvious hydronephrosis, belonging to a typical obstructive renal fibrosis model. During the experimental process of ischemia-reperfusion injury (IRI), after the microartery clip blocked the renal pedicle, it was observed that the kidney changed from bright red to white and then to purple-black, indicating the success of the clamp. After removing the arterial clip and restoring blood flow perfusion, the rapid change of the kidney from purple-black to bright red is seen as a typical phenomenon of renal ischemia-reperfusion.

[0056] 2.4.2 Therapeutic Effect ACT004 can significantly improve the changes in kidney fibrosis in UUO mice and IRI mice, inhibit the synthesis of renal interstitial matrix proteins Fibronectin, Collagen I, and α-SMA, and inhibit the occurrence of EMT in tubular epithelial cells. The kidney protection function of ACT004 is mainly achieved by inhibiting the activation of the TGF-β1 / Smad signaling pathway, STAT3 signaling pathway, and NF-κB signaling pathway. ACT004 downregulates the expression of RALB in the kidney tissue of the UUO model and IRI model at the in vivo level, and overexpression of RALB exacerbates kidney fibrosis and induces the activation of the TGF-β1 / Smad signaling pathway, STAT3 signaling pathway, and NF-κB signaling pathway. In short, by controlling the expression of RALB, ACT004 inhibits the activation of the TGF-β1 / Smad signaling pathway, STAT3 signaling pathway, and NF-κB signaling pathway, inhibits the EMT process of renal interstitial tubular epithelial cells, delays kidney fibrosis, and further plays a role in treating related kidney diseases.

[0057] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included within the scope of the claims of the present invention.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of renal fibrosis and / or renal diseases associated therewith, wherein the structure of the compound of formula (I) is as follows: 【Chemical 1】 In the formula (I), Said R 1 , R 2 , R 3 are each independently H, halogen, C 1-6 alkyl group, C 1-6 alkoxy group, and are selected from Each R 4 is independently selected from halogen, C 1-6 alkyl group, C 1-6 alkoxy group, and n is selected from 0, 1, 2, 3 or 4. Use.

2. Said R 1 , R 2 , R 3 is characterized by being selected from a methyl group, an ethyl group, and a propyl group. Use according to claim 1.

3. The pharmaceutically acceptable salt is an acid addition salt formed by the compound of formula I and an inorganic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfate, or an organic acid such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphanic acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfate or thiocyanic acid, characterized in that it is selected from acid addition salts formed with organic acids Use according to claim 1.

4. The compound of formula (I) has the following structure 【Chemical Formula 2】 characterized in that Use according to claim 1.

5. The pharmaceutically acceptable salt of the compound of formula (I) has the following structure [Chemical Formula 3] characterized in that Use according to claim 1.

6. The renal disease is selected from various primary and secondary glomerular diseases, tubulointerstitial diseases, hereditary renal diseases, renal vascular diseases, acute kidney injury, chronic renal failure, and renal allograft injury associated with ischemia-reperfusion or rejection reaction, etc., characterized in that Use according to any one of claims 1 to 5.

7. The drug is characterized by containing 0.1 wt% to 99 wt%, preferably 0.5 wt% to 90 wt% of the compound of formula I or a pharmaceutically acceptable salt thereof. Use according to any one of claims 1 to 5.

8. The drug is further characterized by further containing a pharmaceutically acceptable carrier and / or excipient. Use according to any one of claims 1 to 5.

9. The drug is characterized by being administrable by two forms, injection including intravenous injection and intramuscular injection and oral administration. Use according to any one of claims 1 to 5.

10. The drug is characterized by being manufacturable as an oral preparation, an injection preparation, an external preparation, etc., for example, an injection solution, a tablet, a pill, a capsule. Use according to any one of claims 1 to 5.

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