Treatment of pancreatitis

Abstract

Disclosed are a composition for preventing and / or treating pancreatitis and a method of preventing and / or treating pancreatitis. The composition includes an arylethylene compound, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Also disclosed is the use of the arylethylene compound, the pharmaceutically acceptable salt thereof, or the solvate thereof in the manufacture of a medicament for preventing and / or treating pancreatitis in a patient or for treating one or more symptoms of pancreatitis in a patient. The method includes administering to a subject in need thereof an effective amount of the arylethylene compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Application No. 16 / 908,195, filed June 22, 2020, which is incorporated herein by reference in its entirety.

[0003] Government Interest Statement

[0004] The research described in this application was supported by a grant from the Daegu-Gyeongbuk / Osong Medical Group R&D Project funded by the Ministry of Science and ICT, Ministry of Trade, Industry and Energy, and Ministry of Health and Welfare of the Republic of Korea (Grant No. HI19C0760). Technical Field

[0005] The present disclosure includes methods and compositions for treating acute pancreatitis. In one aspect, the present disclosure relates to the use of molecules that reduce or prevent the secretion of pancreatic digestive enzymes within the pancreas. The molecules are used to prevent mitochondrial dysfunction and autophagy dysfunction in pancreatic acinar cells, which leads to the prevention of premature activation of pancreatic digestive enzymes and autodigestion of the pancreas. The present disclosure also relates to methods of treating a mammal suffering from pancreatitis by administering the molecules. Background Art

[0006] In mammals, the pancreas, a large gland structurally similar to the salivary glands, contains acinar cells responsible for producing digestive enzymes and ductal cells that secrete large quantities of a sodium bicarbonate solution. The physiological function of pancreatic acinar cells is to synthesize, transport, store, and secrete digestive enzymes. This is achieved through the coordinated and sequential action of the endoplasmic reticulum (ER), the Golgi apparatus, the endolysosomal system, storage and secretory organelles, and the mitochondria. The combined secretory product is called "pancreatic juice"; this fluid flows through the pancreatic duct into the duodenum. The precise composition of pancreatic juice appears to be influenced by the types of compounds (carbohydrates, lipids, proteins, and / or nucleic acids) present in the chyme.

[0007] Pancreatic juice is composed of various proteases (trypsin, chymotrypsin, carboxypeptidases), nucleases (RNase and DNase), pancreatic amylase, and lipases (pancreatic lipase, cholesterolesterase, and phospholipase). Many of these enzymes are initially synthesized as zymogens by the acinar cells in an inactive form, e.g., trypsin is synthesized as trypsinogen. These enzymes are activated in a cascade, where initially trypsin is activated by proteolytic cleavage by enteropeptidase. Trypsinogen can also be activated autocatalytically by trypsin. In turn, trypsin activates both chymotrypsinogen and carboxypeptidase pro to form their active protease counterparts. Normally, the enzymes are activated only when they enter the intestinal mucosa, in order to prevent autodigestion of the pancreas. As an intrinsic countermechanism to prevent premature activation, the acinar cells additionally secrete trypsin inhibitors. This inhibitor prevents premature activation of proteolytic enzymes within the secretory cells and in the pancreatic duct. Subsequently, inhibition of trypsin activity also prevents activation of other proteases.

[0008] Pancreatitis is a serious medical condition involving inflammation of the pancreas, and can occur when an excess of trypsin saturates the supply of trypsin inhibitors. Accumulation of trypsin in the acinar cells of the pancreas can be due to insufficient production of trypsin inhibitors or an excess of trypsin production. In acute or chronic pancreatitis, this precipitation forms inflammation, which manifests as release and activation of pancreatic enzymes within the organ, leading to the onset of autodigestion of the pancreas. In many cases of acute pancreatitis, the condition can lead to death. Genetic factors, gallstones, and alcohol abuse are among the main factors associated with the development of pancreatitis. The current paradigm is that pancreatitis is triggered by acinar cell injury, leading to parenchymal necrosis and inflammation, which are the main pathological features of the disease. It is well documented in science and in the clinic that chronic pancreatitis (CP) is caused by repeated episodes of acute pancreatitis (AP), or can occur without prior AP.

[0009] AP is a major cause of gastroenterological-related complications in humans, and the main etiological factor is the formation of gallstones. Although the most common severity of AP is mild to moderate, the mortality rate of patients is significantly increased (about 1 in 3) due to persistent multi-organ dysfunction. In addition, some studies have shown that patients with hereditary pancreatitis carry mutations in genes encoding digestive enzymes. However, it has been reported that these patients repeatedly attack a high-risk group that will develop CP rather than severe AP.

[0010] As mentioned earlier, AP is believed to be induced by injured pancreatic acinar cells. Digestive enzymes are synthesized, stored and exported from pancreatic acinar cells upon appropriate stimuli. The synthesis of these enzymes begins in the endoplasmic reticulum and ends with the secretion of proteins temporarily stored in zymogen granules. ATP produced by mitochondria is utilized by different pancreatic organelles to transport and modify these unprocessed proteins in a sequential manner through several vesicular compartments. Like several other cellular processes, the autophagy-lysosome-endosome pathway acts as a checkpoint to maintain acinar cell homeostasis by removing damaged / dysfunctional organelles and recycling cellular components as source substrates and energy.

[0011] In attempts to study and delineate the stepwise initiation, development and treatment of this disease, several non-invasive models of experimental acute pancreatitis have been developed. Among these, caerulein, a cholecystokinin-pancreozymin analogue, has been widely used to successfully induce acute pancreatitis in mammals. The caerulein-induced acute pancreatitis model can be produced by intravenous, subcutaneous or intraperitoneal injection routes in experimental animals. In addition, caerulein has been successfully used to understand the molecular pathogenesis of pancreatitis in various in vitro models. The structural changes in acinar cells observed in human acute pancreatitis show remarkable similarities with caerulein-induced acute pancreatitis in mice. In particular, the specific changes in intracellular organelles in acinar cells are similar in humans and caerulein-induced acute pancreatitis.

[0012] In addition to the caerulein-induced AP model, various compounds have been infused into the pancreatic duct to induce acute pancreatitis. Retrograde injection of bile salts into the pancreatic duct at the ampulla after duodenotomy has been shown to induce severe acute pancreatitis. The pressure or concentration of the bile salts used in this model is a key determinant of the severity of the disease. Bile salt-induced acute severe pancreatitis occurs within 2-24 hours, which is characterized by the development of edema, pancreatic necrosis and hemorrhage. One of the best standardized compounds used to develop acute pancreatitis is sodium taurocholate. Infusion of 1-5% solutions induces acute hemorrhagic pancreatitis within 72 hours with significant mortality. This model is suitable for studying the underlying systemic problems of pancreatitis.

[0013] Despite extensive research (experimental and clinical) and significant progress in elucidating the pathophysiology of the disease associated with pancreatitis, and some potentially promising therapeutic approaches, no drugs have been approved by the Food and Drug Administration for the treatment of AP or CP, and the morbidity remains high, thus underscoring the unmet need for identifying potential therapeutic targets for drug targeting.

[0014] The nuclear receptor (NR) superfamily represents a large class of ligand-dependent transcription factors. The nuclear receptor family is uniquely distinguished from other classes of receptors in their ability to directly interact with and control the expression of genomic DNA. As such, nuclear receptors play a key role in both embryonic development and adult metabolic homeostasis. The estrogen-related receptors (ERRs) are the first orphan members of the nuclear receptor superfamily to be identified, and the subfamily is now known to contain three related isoforms, ERRa (also known as NR3B1, Esrra, ERRa), b (also known as NR3B2, Esrr, ERRb), and g (also known as NR3B3, Esrrg, ERRg). Despite being named for their structural homology with the estrogen receptor, ERRs are not activated by estrogen (the ligand for the estrogen receptor) or any known natural compound. ERRs play an important role in the transcriptional control of metabolic genes involved in the production and utilization of cellular energy, and thus play a key role in critical aspects of organ development as well as cellular homeostasis. ERRs are primarily expressed in the heart, skeletal muscle, brain, kidney, pancreas, placenta, and liver, and are predicted to have significant differences in their synthetic ligand binding preferences.

[0015] Recent findings in various mammalian experimental models suggest that ERRg, as a downstream mediator of multiple extracellular signals, plays a key role in coordinating endocrine and metabolic signals, leading to changes in glucose, alcohol, lipid, and iron metabolism. As such, dysregulation of ERRg contributes to the pathogenesis of metabolic diseases such as hyperglycemia, insulin resistance, and alcoholic liver injury. Interestingly, ERRg has been shown to be involved in the pathogenesis of bacterial infection. These findings suggest the importance of ERRg in endocrine and metabolic control of metabolism and suggest that ERRg can be a promising therapeutic target for several diseases.

[0016] U.S. Application 16 / 313,360 (U.S. Application Publication No. 2019 / 0167820 Al) and 16 / 677,596 (Application Publication No. 20200078476 Al) disclose new aryl ethane derivatives as estrogen-related receptor gamma (ERRg) inhibitors, the entire contents of which are hereby incorporated by reference.

[0017] The present disclosure is based on the new finding that certain compounds having ERRg inhibitory activity can be used to treat pancreatitis and acute inflammatory conditions. SUMMARY

[0018] In general, the present disclosure relates to methods and / or uses for treating pancreatitis comprising administering an aryl ethene compound of Formula (I), an isomer, prodrug, pharmaceutically acceptable salt, or solvate thereof.

[0019] The present disclosure relates to a method for preventing and / or treating pancreatitis in a subject in need thereof, comprising administering to the subject an aryl ethylene compound of Chemical Formula 1 or a solvate, isomer, or pharmaceutically acceptable salt thereof:

[0020]

[0021] wherein L is (C6-C20)arylene, (C3-C20)heteroarylene, or (C3-C20) fused heterocycle;

[0022] R 1 (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, -O-(CH2) m R 11 -(CH2) m R 12 -(CH2) m R 13 -(CH2) n R 14 or -SiR 16 R 17 -(CH2) m R 15 ;

[0023] R 11 to R 15 each independently is (C3-C20)heterocycloalkyl;

[0024] R 16 and R 17 each independently is (C1-C20)alkyl;

[0025] m is an integer of 1-3; and

[0026] n is an integer of 0 or 1;

[0027] Ar is (C6-C20)aryl or (C3-C20)heteroaryl, wherein the aryl or heteroaryl of Ar can be further substituted with one or more groups selected from hydroxyl, halogen, (C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano, -NR 21 R 22 , (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, -SO2-R 23 , and -OSO2-R 24 ;

[0028] R 21 and R 22are each independently hydrogen, (C1-C20)alkylsulfonyl or (C3-C20)cycloalkylsulfonyl;

[0029] R 23 and R 24 Each is independently (C1-C20)alkyl, halogenated (C1-C20)alkyl or (C3-C20)cycloalkyl;

[0030] R 2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy or (C1-C20)alkylsulfonyloxy;

[0031] R 1 Heterocycloalkyl or heteroaryl and R 11 -R 15 The heterocycloalkyl group may be further substituted by one or more groups selected from (C1-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino, (C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl and di(C1-C20)alkylamino(C1-C20)alkyl; and

[0032] Heterocycloalkyl and heteroaryl contain one or more heteroatoms selected from N, O and S, and heterocycloalkyl is a saturated or unsaturated mono-, bi- or spirocyclic ring having a carbon atom or a nitrogen atom in the ring as a binding site.

[0033] Another aspect of the present disclosure is a method for treating and / or preventing pancreatitis in a subject in need thereof, comprising administering a compound of Chemical Formula 2 or a pharmaceutically acceptable salt or solvate thereof,

[0034]

[0035] Among them, R 1 is (C3-C10) heterocycloalkyl or -O-(CH2) m -R 11 ;

[0036] R 11 is (C3-C10)heterocycloalkyl;

[0037] m is an integer from 1 to 3;

[0038] R 1 and R 11 The heterocycloalkyl group may be further substituted by one or more groups selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl and di(C1-C20)alkylamino(C1-C20)alkyl;

[0039] Ar is (C6-C12)aryl or (C3-C12)heteroaryl, wherein the aryl or heteroaryl of Ar can be further substituted with one or more groups selected from hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and R 2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy.

[0040] Another aspect of the present disclosure is a method of treating and / or preventing pancreatitis in a subject in need thereof, comprising administering a compound of Formula 6,

[0041]

[0042] wherein R 1 is (C3-C10)heterocycloalkyl or -O-(CH2) m -R 11 ;

[0043] R 11 is (C3-C10)heterocycloalkyl;

[0044] m is an integer from 1-3;

[0045] Ar is (C6-C12)aryl or (C3-C12)heteroaryl,

[0046] wherein the heterocycloalkyl, aryl, or heteroaryl can be further substituted with one or more groups selected from hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and

[0047] R 2hydroxy, halogen, (C1-C10)alkylcarbonyloxy or (C1-C10)alkylsulfonyloxy.

[0048] According to one embodiment, the compound of Chemical Formula 1 is selected from the following compounds:

[0049]

[0050] In one aspect, the pancreatitis is acute pancreatitis. In other aspects, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis can be hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0051] In another aspect, the subject is a mammal, particularly a human.

[0052] One aspect of the present disclosure further relates to a pharmaceutical composition for preventing and / or treating pancreatitis, comprising a therapeutically effective amount of a compound of Chemical Formula 1, a solvate, an isomer, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable excipient.

[0053] One aspect of the present disclosure further relates to a pharmaceutical composition for preventing and / or treating pancreatitis, comprising a therapeutically effective amount of a compound of Chemical Formula 2, a solvate, an isomer, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable excipient.

[0054] One aspect of the present disclosure further relates to a pharmaceutical composition for preventing and / or treating pancreatitis, comprising a therapeutically effective amount of a compound of Chemical Formula 6, a solvate, an isomer, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable excipient.

[0055] In one embodiment, the composition comprises a compound selected from the following compounds:

[0056]

[0057] a solvate, an isomer, or a pharmaceutically acceptable salt thereof.

[0058] Another aspect of the present disclosure relates to use of a compound of Chemical Formula 1, a solvate, an isomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing and / or treating pancreatitis. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis can be hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0059] Another aspect of the present disclosure is the use of a compound of Formula 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating pancreatitis. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis may be hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0060] Another aspect of the present disclosure is the use of a compound of Formula 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating pancreatitis. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis may be hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0061] Another aspect of this embodiment is the following compound:

[0062]

[0063] or its pharmaceutically acceptable salt, or its solvate, or its isomer in the preparation of a medicament for preventing and / or treating pancreatitis. In one embodiment, pancreatitis is acute pancreatitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] The following drawings form part of this specification and are included to further demonstrate certain aspects of the present disclosure. The present disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0065] The patent or application file contains at least one drawing drawn in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Figure 1A and 1B Caerulein differentially regulates ERRa and ERRg in mouse pancreas. Figure 1A Shown are ERRa or ERRg mRNA expression levels from pancreas of the indicated mice (n=4 per group) 16 hours after cilostane stimulation (50 μg / kg ip injection every hour, 6×), as determined by real-time quantitative PCR (RT-qPCR), and expressed as fold change compared to the expression level in mice treated with saline (n=3). Figure 1B Shown are the results of immunoblotting of pancreatic tissue extracts subjected to SDS-PAGE and immunoblotting with anti-ERRa or anti-ERRg antibodies.

[0066] Figure 2A and 2BThe results showed that cilostane enhanced the secretion of serum amylase and lipase in mice. The amylase level in the serum of mice stimulated with cilostane or saline was measured ( Figure 2A ) or lipase levels ( Figure 2B ).

[0067] Figure 3 The differential effects of ERRg inverse agonists on the ERRg protein levels induced by cilostane in pancreatic acinar cells were shown. Pancreatic acinar cells were isolated from mice and stimulated with cilostane (10 nM) for 16 hours in the presence or absence of the indicated molecules. Protein extracts from these cells were subjected to SDS-PAGE and immunoblotted with anti-ERRg antibodies.

[0068] Figure 4A 、 4B 4C and 4D show the activity of DMRC200434 in rescuing mice from acute pancreatitis induced by cilostane. Mice were injected intraperitoneally with cilostane in the presence or absence of compound DMRC200434 (20 mg / kg). The serum amylase ( Figure 4A ), lipase levels ( Figure 4B ). Trypsin activity in pancreatic tissue of these treated mice was shown ( Figure 4C Hematoxylin-eosin staining was performed on tissue sections from these treated mice as indicated ( Figure 4D ).

[0069] Figure 5A 、 5B Figures 5 and 5C show the activity of the compound DMRC200434 molecule, which rescues sodium taurocholate-induced acute pancreatitis in mice. Mice were intraperitoneally injected with sodium taurocholate in the presence or absence of compound DMRC200434 (20 mg / kg). Serum amylase ( Figure 5A ) and lipase levels ( Figure 5B Hematoxylin-eosin staining was performed on tissue sections from these treated mice as indicated ( Figure 5C ). DETAILED DESCRIPTION

[0070] The present disclosure relates to a method for preventing and / or treating pancreatitis, comprising administering an arylene compound of Chemical Formula 1:

[0071]

[0072] wherein L is (C6-C20)arylene, (C3-C20)heteroarylene, or (C3-C20)fused heterocyclic ring;

[0073] R 1(C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, -O-(CH2) m -R 11 , -(CH2) m -R 12 , -NH-(CH2) m -R 13 , -NHCO-(CH2) n -R 14 or -SiR 16 R 17 -(CH2) m -R 15 ;

[0074] R 11 to R 15 each independently is (C3-C20)heterocycloalkyl;

[0075] R 16 and R 17 each independently is (C1-C20)alkyl;

[0076] m is an integer from 1 to 3; and

[0077] n is an integer from 0 to 1 ;

[0078] Ar is (C6-C20)aryl or (C3-C20)heteroaryl, wherein the aryl or heteroaryl of Ar can be further substituted by one or more groups selected from the group consisting of hydroxy, halogen, (C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano, -NR 21 R 22 , (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, -SO2-R 23 and -OSO2-R 24 ;

[0079] R 21 and R 22 each independently is hydrogen, (C1-C20)alkylsulfonyl or (C3-C20)cycloalkylsulfonyl;

[0080] R 23 and R 24 each independently is (C1-C20)alkyl, halo(C1-C20)alkyl or (C3-C20)cycloalkyl;

[0081] R 2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy or (C1-C20)alkylsulfonyloxy;

[0082] R 1heterocycloalkyl or heteroaryl of R 11 -R 15 The heterocycloalkyl group of R

[0083] The heterocycloalkyl group of R

[0084] or a solvate, isomer, or pharmaceutically acceptable salt thereof.

[0085] According to one embodiment, the compound can be a compound of the following Chemical Formula 2:

[0086]

[0087] wherein R 1 is (C3-C10)heterocycloalkyl or -O-(CH2) m -R 11 ;

[0088] R 11 is (C3-C10)heterocycloalkyl;

[0089] m is an integer of 1 to 3;

[0090] R 1 and R 11 The heterocycloalkyl group of R

[0091] Ar is (C6-C12)aryl or (C3-C12)heteroaryl, wherein the aryl or heteroaryl of Ar can be further substituted with one or more groups selected from the group consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and R 2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy,

[0092] or a solvate, isomer, or pharmaceutically acceptable salt thereof.

[0093] According to one embodiment, the compound can be a compound of Formula 6:

[0094]

[0095] wherein R 1 is (C3-C10)heterocycloalkyl or -O-(CH2) m -R 11 ;

[0096] R 11 is (C3-C10)heterocycloalkyl;

[0097] m is an integer from 1 to 3;

[0098] Ar is (C6-C12)aryl or (C3-C12)heteroaryl,

[0099] wherein the heterocycloalkyl, aryl, or heteroaryl can be further substituted with one or more groups selected from the group consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and

[0100] R 2hydroxy, halogen, (Ci-Cio)alkylcarbonyloxy or (Ci-Cio)alkylsulfonyloxy,

[0101] a pharmaceutically acceptable salt thereof or a solvate thereof.

[0102] According to another embodiment, the compound of Chemical Formula 1 can be one selected from the following compounds ("listed compounds"):

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111] In another embodiment, the compound of Chemical Formula 1 can be any one of the following compounds:

[0112] Compound 18a (= DMRC200434)

[0113] (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4- en-1-ol

[0114]

[0115] Compound 18k (= DMRC2001000)

[0116] (E)-5-(5-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4- en-1-ol

[0117]

[0118] Compound 22i (DMRC200699)

[0119] (E)-5-(4-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4- en-1-ol

[0120]

[0121] Compound 22r (DMRC200996)

[0122] (E)-5-(5-Hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol

[0123]

[0124] The pharmaceutical composition according to one embodiment comprises the compound as described above as an active ingredient, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an isomer thereof. The pharmaceutical composition may include pharmaceutically acceptable carriers, excipients, or additives known in the art.

[0125] How to use

[0126] In general, the present disclosure relates to a method or use for treating pancreatitis, particularly acute pancreatitis, comprising administering an arylene compound of Chemical Formula 1 or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0127] According to one embodiment, a method of treatment comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Further embodiments include methods of treating pancreatitis by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0128] As used herein, "pancreatitis" can include chronic pancreatitis or acute pancreatitis. The term "acute pancreatitis" as used herein can include severe acute pancreatitis that can be associated with organ failure and / or local complications such as necrosis, abscesses, or pseudocysts, as well as mild acute pancreatitis that can be associated with minimal organ dysfunction and unexpected recovery and lack features of severe acute pancreatitis.

[0129] As used herein, "treat" or "treatment" with respect to a disorder means: (1) ameliorating one or more biological manifestations of the disorder, (2) interfering with (a): one or more points in the biological cascade leading to or responsible for the disorder, or (b): one or more biological manifestations of the disorder, (3) alleviating one or more symptoms or effects associated with the disorder, or (4) slowing the progression of one or more biological manifestations of the disorder.

[0130] The term "treatment" of a condition may include preventing or prophylaxis of the condition. The term "prevention" refers to the prophylactic administration of a drug to significantly reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations.

[0131] The term "effective amount" as used herein with respect to a compound of Formula 1 or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent refers to an amount of the compound that is sufficient, within the scope of sound medical judgment, to treat a patient's condition. The effective amount of the compound will vary with the particular compound chosen (e.g., the potency, efficacy, and half-life of the compound will be considered); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, body weight, and health of the patient being treated; the medical history of the patient being treated; the duration of treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by one skilled in the art.

[0132] The term "patient" or "subject" as used herein refers to a human or other mammal. In one embodiment, "patient" refers to a human.

[0133] One embodiment of the present disclosure also provides a method of treating pancreatitis, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis can be hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0134] In one embodiment, there is provided a method of treating pancreatitis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. The pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0135] In one embodiment, there is provided a method of treating pancreatitis, the method comprising administering to a patient in need thereof a therapeutically effective amount of (E)-5-(4- hydroxyphenyl)-5-(4-(4-isopropylpiperazin-l-yl)phenyl)-4-phenylpent-4-en-l-ol (Compound DMRC200344 or 18a), or a pharmaceutically acceptable salt thereof, or a solvate thereof. The pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0136] In another embodiment, there is provided a method of treating pancreatitis, the method comprising administering to a patient in need thereof a therapeutically effective amount of (E)-5-(5- hydroxyphenyl)-5-(4-(4-isopropylpiperazin-l-yl)phenyl)-4-phenylpent-4-en-l-ol (Compound DMRC2001000 or 18k), a pharmaceutically acceptable salt thereof, or a solvate thereof. The pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0137] In another embodiment, there is provided a method of treating pancreatitis comprising administering to a patient in need thereof a therapeutically effective amount of (E)-5-(4- hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (Compound DMRC200699 or 22i), its pharmaceutically acceptable salt or solvate thereof. The pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis or hemorrhagic necrotizing pancreatitis.

[0138] In another embodiment, there is provided a method of treating pancreatitis comprising administering to a patient in need thereof a therapeutically effective amount of (E)-5-(5- hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (Compound DMRC200699 or 22r), its pharmaceutically acceptable salt or solvate thereof. The pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis or hemorrhagic necrotizing pancreatitis.

[0139] In another aspect, there is provided a compound of Formula 1, its pharmaceutically acceptable salt or solvate thereof for use in therapy.

[0140] In one embodiment, there is provided a compound of Formula 1, its pharmaceutically acceptable salt or solvate thereof for use in the treatment of acute pancreatitis.

[0141] In one embodiment, there is provided the use of a compound of Formula 1, its pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of acute pancreatitis.

[0142] In one embodiment, there is provided the use of (E)-5-(4-hydroxyphenyl)-5-(4-(4- isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC200344 or 18a), its pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of pancreatitis. The pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis or hemorrhagic necrotizing pancreatitis.

[0143] In one embodiment, there is provided the use of (E)-5-(5-hydroxyphenyl)-5-(4-(4- isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC2001000 or 18k), its pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of pancreatitis. The pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis or hemorrhagic necrotizing pancreatitis.

[0144] In one embodiment, provided is (E)-5-(4-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC200699 or 22i), and the use of a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating pancreatitis. Pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0145] In one embodiment, provided is (E)-5-(5-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC200699 or 22r), and the use of a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating pancreatitis. Pancreatitis can be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0146] In one aspect, the present disclosure relates to a method or use for treating pancreatitis, comprising administering a compound of Chemical Formula 6:

[0147]

[0148] Among them, R 1 is (C3-C10) heterocycloalkyl or -O-(CH2) m -R 11 ;

[0149] R 11 is (C3-C10)heterocycloalkyl;

[0150] m is an integer from 1 to 3;

[0151] Ar is (C6-C12)aryl or (C3-C12)heteroaryl,

[0152] wherein the heterocycloalkyl, aryl or heteroaryl group may be further substituted by one or more groups selected from hydroxy, halogen, (Cl-C10)alkyl, halo-substituted (Cl-C10)alkyl, (Cl-C10)alkoxy, nitro, cyano, amino, (Cl-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((Cl-C10)alkylsulfonyl)amino, (Cl-C10)alkylcarbonyloxy, (Cl-C10)alkylcarbonylamino, guanidino, (Cl-C10)alkylsulfonyl, (Cl-C10)alkylsulfonyloxy, halo-substituted (Cl-C10)alkylsulfonyloxy and (C3-C10)cycloalkylsulfonyloxy; and

[0153] R 2hydroxy, halogen, (C1-C10)alkylcarbonyloxy or (C1-C10)alkylsulfonyloxy,

[0154] a pharmaceutically acceptable salt thereof or a solvate thereof. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis can be hemorrhagic pancreatitis, necrotizing pancreatitis or hemorrhagic necrotizing pancreatitis.

[0155] In another aspect, the present application relates to a method of treatment or use for the treatment of pancreatitis comprising administering to a patient in need thereof a compound of Formula 6, wherein R 2 is hydroxy, R 1 is a heterocycloalkyl selected from the following structures:

[0156]

[0157] wherein R 31 and R 32 each independently is hydrogen, (C1-C10)alkyl, (C3-10)cycloalkyl, (C2-C10)alkenyl, amidino, (Cl-C10)alkoxycarbonyl, hydroxy(Cl-C10)alkyl or di(Cl-C10)alkylamino(Cl-C10)alkyl; and L is O or S, a pharmaceutically acceptable salt thereof or a solvate thereof. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis can be hemorrhagic pancreatitis, necrotizing pancreatitis or hemorrhagic necrotizing pancreatitis.

[0158] In another aspect, the present application relates to a method of treatment or use for the treatment of pancreatitis comprising administering to a patient in need thereof a compound selected from the "List of Compounds" described above, a pharmaceutically acceptable salt thereof or a solvate thereof. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis can be hemorrhagic pancreatitis, necrotizing pancreatitis or hemorrhagic necrotizing pancreatitis.

[0159] In yet another aspect, the present disclosure relates to a method or use for treating pancreatitis comprising administering (E)-5-(4-hydroxyphenyl)-5-(4-(4- isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (Compound 18a, DMRC200434), (E)-5-(5-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4- phenylpent-4-en-1-ol (Compound 18k, DMRC2001000), (E)-5-(4-hydroxyphenyl)-5- (4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (Compound 22i, DMRC200699), or (E)-5-(5-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4- yl)phenyl)-4-phenylpent-4-en-1-ol (Compound 22r, DMRC200996), a pharmaceutically acceptable salt thereof, or a solvate thereof. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis can be hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0160] In some embodiments, the present disclosure relates to a method of treating one or more symptoms of pancreatitis in a patient by administering a therapeutically effective amount of a compound of Formula 1 to treat one or more symptoms of pancreatitis in a patient. The symptoms of pancreatitis can be abdominal pain, back pain, abdominal swelling, nausea, vomiting, fever, rapid pulse, or a combination of two or more thereof.

[0161] In one aspect, the compound of Formula 1 can be administered at a dose of about 0.01 mg / kg to about 1,000 mg / kg, about 0.01 mg / kg to about 500 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to 500 mg / kg, about 0.05 mg / kg to 100 mg / kg, about 0.01 mg / kg to about 200 mg / kg, about 0.01 mg / kg to 100 mg / kg, about 0.1 mg / kg to 500 mg / kg, about 0.1 mg / kg to 200 mg / kg, about 0.1 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 50 mg / kg, or about 0.1 mg / kg to about 10 mg / kg.

[0162] Compositions

[0163] The compounds of the present disclosure may, but not necessarily, be formulated into pharmaceutical compositions before being administered to a patient. Therefore, in one aspect, the pharmaceutical compositions provided include a compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable excipients or carriers. Pharmaceutical compositions, which can be prepared by mixing at ambient temperature and atmospheric pressure, are generally suitable for oral, parenteral or rectal administration, and therefore can be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, rehydratable powders, injectable or infusible solutions or suspensions or suppositories.

[0164] Suitable pharmaceutically acceptable excipients or carriers will vary according to the specific dosage form selected. In addition, suitable pharmaceutically acceptable excipients or carriers can be selected to enable them to perform specific functions in the composition. For example, certain pharmaceutically acceptable excipients or carriers can be selected because they can promote the production of uniform dosage forms. Certain pharmaceutically acceptable excipients or carriers can be selected because they can promote the production of stable dosage forms. Certain pharmaceutically acceptable excipients or carriers can be selected because they can promote the carry or transport of the compound of Formula 1 or a pharmaceutically acceptable salt thereof from one organ or part of the body to another organ or another part of the body once they are administered to the patient. Certain pharmaceutically acceptable excipients or carriers can be selected because they can enhance the patient's compliance.

[0165] Suitable pharmaceutically acceptable excipients or carriers include the following types of excipients or carriers: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavorings, taste masking agents, coloring agents, anti-caking agents, wetting agents, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. It will be appreciated by those skilled in the art that certain pharmaceutically acceptable excipients can serve more than one function and can serve alternative functions, depending on how much excipient is present in the formulation and what other excipients are present in the formulation.

[0166] Those skilled in the art have the knowledge and skills in the art to enable them to select appropriate pharmaceutically acceptable excipients or carriers in appropriate amounts.

[0167] The pharmaceutical composition according to one embodiment is prepared using techniques and methods known to those skilled in the art.

[0168] The pharmaceutical composition according to one embodiment can be prepared by mixing at a suitable ambient temperature and atmospheric pressure, is generally suitable for oral, parenteral or rectal administration, and can therefore be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstituted powders, injectable or infusible solutions or suspensions or suppositories.

[0169] Pharmaceutical compositions can contain from 0.1% to 99% by weight of the active agent, depending on the method of administration. Dosage of the compound for treatment of the above-mentioned conditions or diseases will vary according to the severity of the condition or disease, the subject's body weight, and other similar factors as is customary. However, as a general guide, a suitable unit dose can be 0.05 to 5000 mg, 1.0 to 500 mg, or 1.0 to 200 mg, and such unit doses can be administered more than once a day, for example, twice or three times a day. Such treatment can continue for weeks, months, or years.

[0170] In one embodiment, the pharmaceutical composition is formulated as an injectable or insoluble solution, or a reconstitutable powder.

[0171] In one embodiment, the pharmaceutical composition is suitable for oral formulation.

[0172] Tablets and capsules for oral administration can be in unit dosage forms and can contain conventional excipients such as binding agents (e.g. pregelatine corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate) and acceptable wetting agents (e.g. sodium lauryl sulfate). The tablets can be coated according to methods well known in the art.

[0173] Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which can include edible oils, e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl p-hydroxybenzoate or sorbic acid), and, if desired, conventional flavouring or colouring agents, buffers and sweetening agents. Formulations for oral administration can suitably be formulated to give controlled release of the active compound.

[0174] For parenteral administration, fluid unit dosage forms are prepared utilizing a compound of the application or a pharmaceutically acceptable salt thereof and a sterile vehicle. Formulations to be injected can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with the compound of the application or a pharmaceutically acceptable salt thereof and a sterile vehicle, optionally including a preservative. Compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Depending on the vehicle and concentration used, the drug can be either suspended or dissolved in the vehicle. In preparing solutions, the compound is dissolved in the vehicle, filtered as necessary, and filled into a suitable vial or ampule and sealed. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents are dissolved in the vehicle. To enhance

[0175] Lotions can be formulated in an aqueous or oily base, and typically contain one or more emulsifying, stabilizing, dispersing, suspending, thickening, or coloring agents. Drops can be formulated in aqueous or non-aqueous vehicle, and can contain one or more dispersing agents, solubilizers, or suspending agents. They can also contain preservatives.

[0176] Pharmaceutical compositions can also be formulated as rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0177] Pharmaceutical compositions can also be formulated as depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the application can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0178] For intranasal administration, the compounds of formula (I) can be formulated as solutions for administration via a suitable metering or single dose device, or as a powder mix with a suitable carrier for administration using a suitable delivery device. Thus, the compounds of formula (I) can be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), long acting or rectal administration, or in a form suitable for administration by inhalation or insufflation, (either through the mouth or nose).

[0179] Pharmaceutical compositions can be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols, or drops (e.g., eye drops, ear drops, or nose drops). Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Ointments for application to the eye can be prepared using sterilized components in a sterile manner.

[0180] One aspect of the present disclosure provides a pharmaceutical composition for treating pancreatitis comprising a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pancreatitis is acute pancreatitis. In one embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis can be hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

[0181] Reference Preparation Example

[0182] The compound of Formula 1 can be prepared according to the methods described in U.S. Application No. 16 / 313,360, the entire contents of which are hereby incorporated by reference.

[0183] Reference Preparation Example 1: Preparation of (E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-en-1-ol hydrochloride (Compound 18t)

[0184] Compound 18t is prepared by employing the following reaction scheme:

[0185]

[0186] Step 1: Preparation of methyl 5-(4-(pivaloyloxy)phenyl)pent-4-ynoate (C-1)

[0187] Pivalic acid 4-iodophenyl ester (2 g, 6.6 mmol), copper (I) chloride (0.13 g, 0.66 mmol), bis(triphenylphosphine)palladium (II) dichloride (PdCl2(PPh3)2, 0.23 g, 0.33 mmol), and methyl pent-4-ynoate (0.74 g, 0.66 mmol) were dissolved in trimethylamine (15 mL) and reacted at 50 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and column chromatography was performed to obtain 1.1 g of the desired compound C-1 (58%).

[0188] Step 2: Preparation of (E)-3-(4-(5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl)phenyl)azetidine-1-carboxylic acid tert-butyl ester (C-2)

[0189] tert-Butyl 3-(4-(5-hydroxy-l-(4-hydroxyphenyl)-2-phenylpent-l-en-l- yl)phenyl)azetidine-l-carboxylate (18t) was prepared according to the procedure described in Reference Preparation Example 2-3.

[0190] Step 3: Preparation of (E)-3-(4-(5-hydroxy-l-(4-hydroxyphenyl)-2-phenylpent-l-en-l- yl)phenyl)azetidine-l-carboxylate (18t)

[0191] Compound C-2 (0.021 mmol) was taken in tetrahydrofuran (2 mL), temperature was lowered to 0 °C and 1 M lithium aluminum hydride, diisobutylaluminum hydride or lithium borohydride (0.024 mL, 0.024 mmol) was added to it. Temperature was raised to room temperature and stirred for 1 h. To the reaction solution was further added water and ethyl acetate and organic layer was extracted. Organic layer was dried over anhydrous Na2SO4and filtered. Solvent was distilled off under reduced pressure to obtain a residue which was purified using column chromatography and then dissolved in methanol: dichloromethane (1 : 1), temperature was lowered to 0 °C and 1 M aqueous HC1 was slowly added to it and distilled off under reduced pressure to obtain 24 mg of the desired compound 18t (78%).

[0192] Reference Preparation Example 2-3

[0193] Compounds 18a and 18t were prepared using the procedure described in Reference Preparation Example 1 and the characterization data of the compounds 18a and 18t thus prepared is shown in Table 1 below.

[0194] Table 1

[0195]

[0196] Reference Preparation Example 4:

[0197] Preparation of (E)-4-(5-hydroxy-l-(4-(l-isopropylazetidin-3-yl)phenyl)-2- phenylpent-l-en-l-yl)phenol (Compound 22a)

[0198] Compound 22a was prepared by following the reaction scheme below:

[0199]

[0200] Step 1: Preparation of (E)-5-(4-(1-isopropylazetidin-3-yl)phenyl)-4-phenyl-5-(4- (neopentanoyloxy)phenyl)pent-4-enoic acid methyl ester (E-2)

[0201] Compound E-1 (0.03 g, 0.06 mmol), acetone (0.14 mL, 1.9 mmol) and sodium triacetoxyborohydride (NaBH(OAc)3, 41 mg, 0.19 mmol) were added into dichloroethane (3 mL) and stirred at room temperature for 1 h. To the reaction solution was further added water and ethyl acetate and the organic layer was extracted. The organic layer was dried over anhydrous Na2SO4and filtered. The solvent was distilled off under reduced pressure to obtain a residue which was purified by column chromatography to obtain 18 mg of the desired compound E-2 (54%).

[0202] Step 2: Preparation of (E)-4-(5-hydroxy-1-(4-(1-isopropylazetidin-3-yl)phenyl)-2- phenylpent-1-en-1-yl)phenol (22a)

[0203] By following the same procedure as for Step 3 of Example 4, 4 mg of the desired compound 22a (27%) was obtained.

[0204] Reference Preparation Examples 5-6

[0205] Compounds 22i and 22r were prepared according to the procedure of Reference Preparation Example 4 and the identifying data for compounds 22i and 22r thus prepared are set out in Table 2 below.

[0206] Table 3

[0207]

[0208] Compounds 18a (DMRC 200434), 18k (DMRC 2001000), 22i (DMRC 200699) and 22r (DMRC 200996) used in the biological examples have the following structures.

[0209]

[0210] Reference compound GSK5182 has the following structure:

[0211] GSK5182

[0212]

[0213] Biological Example 1

[0214] (A) Materials and Methods

[0215] Materials: Siroimus (C9026) and Tauroursodeoxycholic acid 3-sulfate disodium salt (TLCS; T0512) were purchased from Sigma.

[0216] Animal model: Eight to ten-week-old male C57BL / 6 mice (Jackson Lab) were used according to an approved animal protocol by the Animal Care and Use Committee of Kyungpook National University.

[0217] 1. Siroimus-induced pancreatitis model

[0218] Acute pancreatitis (AP) was induced by intraperitoneal injection of siroimus 6 times at 50 pg / kg / h. As ERRg antagonist, the compound DMRC 200434 (20 mg / kg) was dissolved in a solution of 5%-DMSO: 95%-20% PEG400 (saline) and injected at two points - 24 hours before siroimus treatment and at the beginning of siroimus treatment - and animals were sacrificed 16 hours after the last injection of siroimus.

[0219] 2. Pancreatitis intra-ductal bile acid infusion model

[0220] Pancreatitis was induced by retro-injection of bile acid TLCS (1%) dissolved in saline into the distal common bile duct and pancreatic duct. Mice were anesthetized with a mixture of ketamine (120 mg / kg) / xylazine (12 mg / kg) (Butler Schein, Chicago, IL). An abdominal incision was made to expose the abdominal cavity. The duodenum was flipped to expose its distal side and secured in place by ligation. The bile duct was identified and a 30-gauge needle was inserted into the antimesenteric portion of the duodenum to cannulate the biliopancreatic duct. A P33 perfusion pump (Harvard Apparatus, Holliston, MA) was used to infuse TLCS at 10 mΐ / min for 5 min. The external wound was closed using 7 mm wound clips and a single injection of buprenorphine (0.075 mg / kg) was performed immediately after surgery. Animals injected with physiological saline served as sham-operated. After this procedure, animals were allowed to recover on a heating pad for 90 minutes. Mice were euthanized 24 hours after induction.

[0221] After completing the experiments in the above animal models (1) and (2), pancreatic tissue was snap-frozen in liquid nitrogen and stored at -80°C for analysis of trypsin activity, for Western blot analysis, and for RT-qPCR gene expression analysis. The pancreas was dissected and fixed in 10% neutral buffered formalin and embedded in paraffin. 5-μm sections were prepared and stained with hematoxylin and eosin (H&E). Pancreatic damage was determined by measuring serum amylase (K711-100, Biovision), serum lipase (MAK046, Sigma), and pancreatic tissue trypsin activity was determined using a commercially available kit (Biovision).

[0222] Mouse primary acinar cell culture and treatment.

[0223] Primary acinar cells were isolated from mice according to a previous method (Isolation and Culture of Mouse Primary Pancreatic Acinar Cells..Johann Gout, Roxane M Pommier, David F Vincent, Bastien Kaniewski, Sylvie Martel, Ulrich Valcourt, Laurent Bartholin. J Vis Exp. 2013(78):50514).

[0224] Western blotting.

[0225] The cells were cultured in the presence of protease inhibitors (Thermo Fisher Scientific, A32953) and phosphatase inhibitors (PhosSTOP TM , Sigma Aldrich, 04906837001) in a cell lysis buffer (Cell Signaling Technology, 9803). Proteins were separated on TGX precast protein gels and transferred to PVDF membranes (IPVH00010, EMD Millipore). The membranes were blocked for 1 hour in 5% BSA (blotting grade Blocker, BioRad, 1706404) dissolved in TBS-T and incubated overnight at 4°C with primary antibodies for ERRA (PP-H5844-00, R&D Systems) and ERRG (PP-H6812-00, R&D Systems). The membranes were washed three times with TBS-T and incubated for 1 hour at room temperature with secondary antibodies: anti-mouse IgG, HRP-linked (Cell Signaling Technology, 7076). The membranes were stained using CHEMIDOC. TM (GE Healthcare) Images were acquired using chemiluminescent buffer ECL (GE Healthcare).

[0226] Quantitative reverse transcription PCR (RT-qPCR)

[0227] use Total RNA was extracted using RevertAid (Thermo Fisher Scientific). TM Reverse transcription was performed using the First Strand cDNA Synthesis Kit (K1622, Thermo Fisher Scientific) and oligo-dT primers. Quantitative PCR was performed using Bio-rad Green Supermix. Reaction conditions were as follows: 40 cycles of pre-denaturation at 95°C for 10 minutes, denaturation at 95°C for 15 seconds, annealing at 60°C for 60 seconds, and extension at 72°C for 1 minute. mRNA levels were calculated using the ΔCt method and normalized to the 36b4 (also known as Rplp0) housekeeping gene. The sequences of the qPCR primers are as follows:

[0228] Esrra-Forward: 5'-TACGGTGTGGCATCCTGTGA (SEQ ID NO: 1)

[0229] Esrra-reverse: 5'-CTCCCCTGGATGGTCCTCTT (SEQ ID NO: 2)

[0230] Esrrg-Forward: 5′-GCCCAGCCACGAATGAAT (SEQ ID NO: 3)

[0231] Esrrg-reverse: 5'-GCAGGCCTGGCAGGATTT (SEQ ID NO: 4)

[0232] 36B4-forward: 5'-ACCTCCTTCTTCCAGGCTTT (SEQ ID NO: 5)

[0233] 36B4-reverse: 5'-CTCCAGTCTTTATCAGCTGC (SEQ ID NO: 6)

[0234] (B) Results:

[0235] Upregulation of Esrrg in the pancreas of cerulean-treated mice.

[0236] In contrast to the Esrra mRNA expression pattern, Esrrg mRNA expression was highly increased in the pancreas of cerulean-stimulated mice when compared to control treatment ( Figure 1A ). Immunoblotting confirmed a high increase of ERRG protein in the pancreas of mice after cerulean stimulation ( Figure 1B ). To analyze and confirm the extent of pancreatic damage after cerulean stimulation, the inventors analyzed serum amylase and lipase levels in these animals. The inventors found that cerulean treatment led to a significant upregulation of amylase ( Figure 2A ) and lipase ( Figure 2B ) levels in serum samples of these mice. These results indicate that pancreatic damage induced by cerulean preferentially upregulates ERRG compared to ERR A.

[0237] Reduction of ERRG protein levels in mouse pancreatic acinar cells by cerulean.

[0238] Next, the inventors analyzed the toxicity of these compounds in vivo (Table 3). Table 3 shows the biochemical properties of compounds 18a (DMRC200434), 18k (DMRC2001000), 22i (DMRC200699) and 22r (DMRC200996) and the reference compound GSK5182.

[0239] Table 3. Biochemistry of several ERRy inverse agonist molecules.

[0240]

[0241] Table 3 (continued). Biochemistry of several ERRy inverse agonist molecules.

[0242]

[0243] To test the effectiveness of compounds of Formula 1 (DMRC200434, DMRC2001000, DMRC200699, and DMRC200996) and the reference compound GSK5182 in vitro, the inventors isolated, harvested, and cultured primary acinar cells from mice and treated them with cellostatin in the absence or presence of these compounds for 16 hours Figure 3 ). Cellostatin treatment resulted in a significant increase in ERRG protein levels in mouse primary acinar cells, as demonstrated by immunoblotting. Compounds of Formula 1 with ERRG antagonistic activity were found to show activity. In particular, compound DMRC200434 had the strongest inhibitory effect on cellostatin-induced ERRG protein levels at very low doses. This result indicates that DMRC200434 can be a potential candidate to inhibit ERRG during pancreatic injury.

[0244] Preventive effect on pancreatitis induced by pancreatic injury.

[0245] Next, the inventors analyzed the efficacy of compounds of Formula 1 in vivo using two different animal models of acute pancreatitis. Compound DMRC200434 was used as a compound of Formula 1, and they pre-treated mice with a single dose of DMRC200434 24 hours prior to cellostatin stimulation. At the start of cellostatin stimulation, the animals were administered an additional dose of DMRC200434. Upon completion of the experimental schedule, the animals were sacrificed, and serum and pancreatic tissue samples were collected and analyzed. The inventors found that mice treated with cellostatin in the presence of DMRC200434 showed a significant reduction in serum amylase Figure 4A ), serum lipase Figure 4B ), and tissue trypsin activity Figure 4C ) when compared to cellostatin stimulation alone. The inventors further found that pancreatic histopathology in DMRC200434-treated mice was significantly improved Figure 4D ) when compared to cellostatin-stimulated mice alone. These results indicate that compounds of Formula 1, particularly DMRC200434, can protect and ameliorate cellostatin-induced acute pancreatitis in vivo.

[0246] In addition, the inventors evaluated the efficacy of the compounds of Formula 1 using different animal models of acute pancreatitis, i.e. biliary pancreatitis is the main cause of acute pancreatitis in humans. The reflux of bile into the pancreatic duct is considered to be the cause of pancreatitis and this phenomenon was experimentally mimicked by stimulating mice with TLCS. To this end, the inventors pre-treated mice with a single dose of DMRC200434 24 hours prior to TLCS stimulation. At the beginning of the TLCS challenge, the animals were administered an additional dose of DMRC200434. Upon completion of the experimental schedule, these animals were sacrificed, serum and pancreatic tissue samples were collected and analyzed. The inventors found that mice treated with TLCS in the presence of DMRC200434 showed a significant reduction in serum amylase ( Figure 5A ), serum lipase ( Figure 5B ) when compared to TLCS stimulation alone. The inventors further observed that the pancreatic tissue histopathology of DMRC200434 treated mice was significantly improved ( Figure 5C ) compared to TLCS stimulated mice alone.

[0247] These results indicate that the compounds of Formula 1 having ERRg antagonistic activity can have a protective effect on TLCS-induced acute pancreatitis in vivo and improve the pancreatic pathology in this case. In particular, DMRC200434 showed the strongest activity in preventing and / or treating pancreatitis.

[0248] In the foregoing, although various aspects have been described in detail with reference to exemplary embodiments, various modifications and alterations are possible without departing from the scope and spirit of the present disclosure. It should be understood that the modifications and alterations fall within the scope of the claims, and the scope of the present disclosure is not limited to the specific embodiments described herein. SEQUENCE LISTING <110> Nomata Pharmaceuticals, LLC <120> Methods of treating pancreatitis <130> P81172SUM <150> US 16 / 908,195 <151> 2020-06-22 <160> 6 <170> PatentIn version 3.5 <210> 1 <211> 20 <212> DNA <213> artificial sequence <220> <223> Esrra forward primer <400> 1 tacggtgtgg catcctgtga 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Essr reverse primer <400> 2 ctcccctgga tggtcctctt 20 <210> 3 <211> 18 <212> DNA <213> Artificial sequence <220> <223> Esrrg forward primer <400> 3 gcccagccac gaatgaat 18 <210> 4 <211> 18 <212> DNA <213> Artificial sequence <220> <223> Esrrg reverse primer <400> 4 gcaggcctgg caggattt 18 <210> 5 <211> 20 <212> DNA <213> Artificial sequence <220> <223> 36b4 forward primer <400> 5 acctccttct tccaggcttt 20 <210> 6 <211> 20 <212> DNA <213> Artificial sequence <220> <223> 3664 reverse primer <400> 6 ctccagtctt tatcagctgc 20

Claims

1. Use of a compound or an isomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating pancreatitis in a subject in need thereof: 。 2. Use according to claim 1, wherein, the pancreatitis is acute pancreatitis.

3. Use according to claim 1, wherein, the pancreatitis is chronic pancreatitis.

4. The use according to claim 1, wherein, the pancreatitis is hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic necrotizing pancreatitis.

5. The use according to claim 1, wherein, the subject is a mammal.

6. Use according to claim 5, wherein, the mammal is a human.

7. The use according to claim 1, wherein, the compound is (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4- phenylpent-4-en-1-ol of the following formula: , or an isomer or a pharmaceutically acceptable salt thereof.

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