METHOD FOR TREATMENT OF PANCREATITIS

Abstract

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

Claims

1. A method for treating and/or preventing pancreatitis in a subject in need thereof or for treating one or more symptoms for treating pancreatitis in a subject suffering from pancreatitis, said method comprising administering, to the subject, an effective amount of a compound of the following chemical formula 1: ##STR00056## wherein L is (C6-C20)arylene, (C3-C20)heteroarylene, or (C3-C20)fused heterocycle; R.sup.1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, —O—(CH.sub.2).sub.m—R.sup.11, (CH.sub.2).sub.m—R.sup.12, —NH—(CH.sub.2).sub.m—R.sup.13, —NHCO—(CH.sub.2).sub.n—R.sup.14, or —SiR.sup.16R.sup.17—(CH.sub.2).sub.m—R.sup.15; R.sup.11 to R.sup.15 are independently of one another (C3-C20)heterocycloalkyl; R.sup.16 and R.sup.17 are independently of each other (C1-C20)alkyl; m is an integer of 1 to 3; and n is an integer of 0 or 1; Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano, —NR.sup.21R.sup.22, (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, —SO.sub.2—R.sup.23, and —OSO.sub.2—R.sup.24; R.sup.21 and R.sup.22 are independently of each other hydrogen, (C1-C20)alkylsulfonyl, or (C3-C20)cycloalkylsulfonyl; R.sup.23 and R.sup.24 are independently of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl; R.sup.2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy, or (C1-C20)alkylsulfonyloxy; the heterocycloalkyl or heteroaryl of R.sup.1 and the heterocycloalkyl of RH to R.sup.15 may be further substituted by one or more selected from the group consisting of (C1-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino, (C 1-C20)alkoxycarbonyl, hydroxy, hydroxy(C 1-C20)alkyl, and di(C1-C20)alkylamino(C1-C20)alkyl; and the heterocycloalkyl and heteroaryl contains one or more heteroatoms selected from the group consisting of N, O and S, and the heterocycloalkyl is a saturated or unsaturated mono-, bi-, or spirocycle having a carbon atom or nitrogen atom in a ring as a binding site, or an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.

2. The method of claim 1, wherein the compound of the chemical formula 1, an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound of the following chemical formula 6: ##STR00057## wherein R.sup.1 is (C3-C10)heterocycloalkyl or or —O—(CH2).sub.m—R.sup.11; R.sup.11 is (C3-C10)heterocycloalkyl; m is an integer of 1 to 3; Ar is s (C6-C12)aryl or (C3-C12)heteroaryl, wherein the heterocyclalkyl, the aryl, or heteroaryl may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (Cl-C10)alkoxy, nitro, cyano, amino, (Cl-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkyl sulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylc arb onylamino, guanidino, (C1-C10)alkyl sulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonylo xy, and (C3-C10)cyclo alkylsulfonyloxy; and R.sup.2 is hydroxyl, halogen, (C1-C10) alkylcarbonyloxy, or (C 1-C10)alkylsulfonyloxy, or an isomer, a pharmaceutically acceptable salt thereof or a solvate thereof.

3. The method of claim 1, wherein the compound of the chemical formula 1, an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound of the following chemical formula 2, 3, 4, or 5: ##STR00058## wherein denotes a single bond or a double bond; and R.sup.1, Ar and R.sup.2 are as defined in claim 1, or an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.

4. The method of claim 1, wherein the compound of the chemical formula 1, an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof is a compound selected from the following compounds: ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## or an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.

5. The method of claim 1, wherein the pancreatitis is acute pancreatitis.

6. The method of claim 1, wherein the pancreatitis is chronic pancreatitis.

7. The method of claim 1, wherein the pancreatitis is hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

8. The method of claim 1, wherein the subject is a mammal.

9. The method of claim 8, wherein the mammal is human.

10. The method of claim 6, wherein the compound of Chemical Formula 1, an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof is selected from the following compounds: ##STR00073## ##STR00074## or an isomer, a pharmaceutically acceptable salt thereof, or a solvate thereof.

11. The method of claim 6, wherein the compound is (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol of the following chemical formula: ##STR00075## or an isomer, a pharmaceutically acceptable salt, or a solvate thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0063] The patent or application file contains at least one drawing executed 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.

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

[0065] FIGS. 1A and 1B show differential regulation of ERRa and ERRg in mouse pancreas by Caerulein. FIG. 1A shows ERRa or ERRg mRNA expression levels from indicated mouse pancreas (n=4 per group) 16 hr after Caerulein challenge (50 ug/kg i.p., hourly injection, 6×), determined by real-time quantitative PCR (RT-qPCR) upon and expressed as fold change compared to the levels of expression in mice treated with saline (n=3). FIG. 1B shows the results of immunoblotting of pancreas tissue extracts, wherein the pancreas tissue extracts were subjected to SDS-PAGE and immunoblotted by anti-ERRa or anti-ERRg antibodies.

[0066] FIGS. 2A and 2B shows enhancement of serum amylase and lipase secretion in mice by Caerulein. Amylase level (FIG. 2A) or Lipase level (FIG. 2B) were measured in mice serum challenged with Caerulein or saline.

[0067] FIG. 3 shows a differential effect of ERRg inverse agonists on Caerulein-induced ERRg protein level in pancreatic acinar cells. Pancreatic acinar cells were isolated from mouse and stimulated with Caerulein (10 nM) for 16 hr in the absence or presence of indicated molecules. Protein extracts from these cells were subjected to SDS-PAGE and immunoblotted by anti-ERRg antibody.

[0068] FIGS. 4A, 4B, 4C, and 4D show the activity of DMRC200434 molecule that rescues mice from Caerulein-induced acute pancreatitis. Mice were intraperitoneally injected with Caerulein in the absence or presence of compound DMRC200434 (20 mg/kg). Serum amylase (FIG. 4A), lipase levels (FIG. 4B) of these treated mice were indicated. Trypsin activity (FIG. 4C) in the pancreatic tissues of these treated mice were indicated. Hematoxylin-Eosin staining (FIG. 4D) was performed in the tissue sections of these treated mice as indicated.

[0069] FIGS. 5A, 5B, and 5C show the activity of compound DMRC200434 molecule that rescues mice from Sodium Taurocholate-induced acute pancreatitis. Mice were intraperitoneally injected with Sodium taurocholate in the absence or presence of compound DMRC200434 (20 mg/kg). Serum amylase (FIG. 5A) and lipase levels (FIG. 5B) of these treated mice were indicated. Hematoxylin-Eosin staining (FIG. 5C) was performed in the tissue sections of these treated mice as indicated.

DETAILED DESCRIPTION OF EMBODIMENTS

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

##STR00011##

[0071] wherein

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

[0073] R.sup.1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, —O—(CH.sub.2).sub.m—R.sup.11, —(CH.sub.2).sub.m—R.sup.12, —NH—(CH.sub.2).sub.m—R.sup.13, —NHCO—(CH.sub.2).sub.n—R.sup.14, or —SiR.sup.16R.sup.17(CH.sub.2).sub.m—R.sup.15;

[0074] R.sup.11 to R.sup.15 are independently of one another (C3-C20)heterocycloalkyl;

[0075] R.sup.16 and R.sup.17 are independently of each other (C1-C20)alkyl;

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

[0077] n is an integer of 0 or 1;

[0078] Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C20)alkyl, halo(C1-C20)alkyl, (C 1-C20)alkoxy, nitro, cyano, —NR.sup.21R.sup.22, (C 1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, —SOO.sub.2—R.sup.23, and —OSO.sub.2—R.sup.24;

[0079] R.sup.21 and R.sup.22 are independently of each other hydrogen, (C1-C20)alkylsulfonyl, or (C3-C20)cycloalkylsulfonyl;

[0080] R.sup.23 and R.sup.24 are independently of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl;

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

[0082] the heterocycloalkyl or heteroaryl of R.sup.1 and the heterocycloalkyl of R.sup.11 to R.sup.15 may be further substituted by one or more selected from the group consisting of (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

[0083] the heterocycloalkyl and heteroaryl contains one or more heteroatoms selected from the group consisting of N, O and S, and the heterocycloalkyl is a saturated or unsaturated mono-, bi-, or spirocycle having a carbon atom or nitrogen atom in a ring as a binding site,

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

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

##STR00012##

[0086] wherein, R.sup.1, R.sup.2, and Ar each have the same meaning as described above with regard to Chemical Formula 1.

[0087] According to some embodiments, in Chemical Formula 2,

[0088] R.sup.1 is (C3-C10)heterocycloalkyl or —O—(CH.sub.2).sub.m—R.sup.11;

[0089] R.sup.11 is (C3-C10)heterocycloalkyl;

[0090] m is an integer of 1 to 3;

[0091] the heterocycloalkyl of R.sup.1 and R.sup.11 may be further substituted by one or more selected from the group consisting of (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;

[0092] Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more 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

[0093] R.sup.2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy,

[0094] or a solvate, an isomer, or a pharmaceutically acceptable salt thereof.

[0095] In exemplary embodiments, the arylethene derivative that can be employed in the methods described herein may be represented by the following Chemical Formulae 3 to 5:

##STR00013##

[0096] wherein denotes a single bond or a double bond; and R.sup.1, Ar and R.sup.2 are as defined in the above Chemical Formula 1.

[0097] According to an embodiment, the compound can be a compound of the following Chemical Formula 6:

##STR00014##

wherein

[0098] R.sup.1 is (C3-C10)heterocycloalkyl or or —O—(CH2).sub.m-R.sup.11;

[0099] R.sup.11 is (C3-C10)heterocycloalkyl;

[0100] m is an integer of 1 to 3;

[0101] Ar is s (C6-C12)aryl or (C3-C12)heteroaryl,

[0102] wherein the heterocyclalkyl, the aryl, or heteroaryl may be further substituted by one or more 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)alkyl sulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkyl sulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and

[0103] R.sup.2 is hydroxyl, halogen, (C1-C10) alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy, a pharmaceutically acceptable salt thereof or a solvate thereof.

[0104] The arylethene derivative that can be employed in the methods according to embodiments of the present invention include the compound of Chemical Formulas 1-6, in which R.sup.1 is (C3-C10)heterocycloalkyl, (C3-C10)heteroaryl, —O—(CH).sub.m—R.sup.11, —(CH.sub.2).sub.m—R.sup.12, —NH—(CH.sub.2).sub.m—R.sup.13, —NHCO—(CH.sub.2).sub.n—R.sup.14, or —SiR.sup.16R.sup.17—(CH.sub.2).sub.m—R.sup.15; R.sup.11 to R.sup.15 are independently of one another (C3-C10)heterocycloalkyl; R.sup.16 and R.sup.17 are independently of each other (C1-C10)alkyl; m is an integer of 1 to 3; n is an integer of 0 or 1; Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C3-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)alkysulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonloxy, and (C3-C10)cycloalkylsulfonyloxy; R.sup.2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy; and the heterocycloalkyl or heteroaryl of R.sup.1 and the heterocycloalkyl of R.sup.11 to R.sup.15 may be further substituted by one or more selected from the group consisting of (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl , hydroxy(C1-C10)alkyl, and di(C1-C10)alkylamino(C1-C10)alkyl.

[0105] The arylethene derivative that can be employed in the methods according to embodiments of the present invention include the compound of Chemical Formulas 1-6, in which R.sup.1 is (C3-C10)heterocycloalkyl or —O—(CH.sub.2).sub.m—R.sup.11; R.sup.11 is (C3-C10)heterocycloalkyl; m is an integer of 1 to 3; and the heterocycloalkyl of R.sup.1 and R.sup.11 may be further substituted by one or more selected from the group consisting of (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and di(C1-C10)alkylamino(C1-C10)alkyl.

[0106] According to another embodiment, the compound of Chemical Formulas 1-6 can be one selected from the following compounds (“Listed Compounds”):

##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##

[0107] In still another embodiment, the compound of Chemical Formula 1 can be any of the following compounds:

Compound 18a (=DMRC200434)

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

[0108] ##STR00029##

Compound 18k (=DMRC2001000)

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

[0109] ##STR00030##

Compound22i (DMRC200699)

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

[0110] ##STR00031##

Compound 22r (DMRC200996)

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

[0111] ##STR00032##

[0112] The pharmaceutical composition according to an embodiment comprises a compound as described above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an isomer thereof, as an active ingredient. The pharmaceutical composition may include a pharmaceutically acceptable carrier, excipient, or additive, known in the art.

Methods of Use

[0113] In general, the disclosure relates to methods or uses for treating pancreatitis, in particular acute pancreatitis, which comprises administering arylethene compounds of Chemical Formula 1 or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0114] The methods of treatment according to an embodiment comprise administering a therapeutically effective amount of a compound of Chemical Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a patient in need thereof. Individual embodiments include methods of treating pancreatitis by administering a therapeutically effective amount of a compound of Chemical Formula 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a patient in need thereof. As used herein, “pancreatitis” may include a chronic pancreatitis or acute pancreatitis.

[0115] The term “acute pancreatitis” as used herein may include severe acute pancreatitis that may be associated with organ failure and/or local complications such as necrosis, abscess, or pseudocyst as well as mild acute pancreatitis that may be associated with minimal organ dysfunction and an uneventful recovery and lacks the features of severe acute pancreatitis. . As used herein, “treat” or “treatment” in reference to a disorder means: (1) to ameliorate the disorder or one or more of the biological manifestations of the disorder, (2) to interfere with (a): one or more points in the biological cascade that leads to or is responsible for the disorder, or (b): one or more of the biological manifestations of the disorder, (3) to alleviate one or more of the symptoms or effects associated with the disorder, or (4) to slow the progression of the disorder or one or more of the biological manifestations of the disorder.

[0116] The term “treatment” of a disorder may include prevention or prophylaxis of the disorder. The term “prevention” refers to a prophylactic administration of a drug to substantially diminish the likelihood or severity of a disorder or biological manifestation thereof, or to delay the onset of such disorder or biological manifestation thereof.

[0117] The term “effective amount” as used herein in reference to a compound of Chemical Formula 1, or a pharmaceutically acceptable salt thereof, or other pharmaceutically active agent means an amount of the compound sufficient to treat the patient's condition within the scope of sound medical judgment. An effective amount of a compound will vary with the particular compound chosen (for example, the potency, efficacy, and half-life of the compound will be considered); the route of administration chosen; the disorder being treated; the severity of the disorder being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.

[0118] The term “patient” or “subject” as used herein refers to a human or other mammal In one embodiment, “patient” refers to a human.

[0119] An embodiment of the disclosure further provides a method for the treatment of pancreatitis, which method comprises administering to a patient in need thereof an effective amount of a compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. In an embodiment, the pancreatitis is acute pancreatitis. In an embodiment, the pancreatitis is chronic pancreatitis. In other embodiments, the pancreatitis may be hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0120] In one embodiment there is provided a method for the treatment of pancreatitis, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0121] In one embodiment there is provided a method for the treatment of pancreatitis, which method comprises administering to a patient in need thereof a therapeutically effective amount of (E)-5-(4-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (Compound DMRC200344 or 18a) or a pharmaceutically acceptable salt thereof or a solvate thereof. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0122] In another embodiment there is provided a method for the treatment of pancreatitis, which method comprises administering to a patient in need thereof a therapeutically effective amount of (E)-5-(5-hydroxyphenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (Compound DMRC2001000 or 18k), a pharmaceutically acceptable salt thereof, or a solvate thereof. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0123] In another embodiment there is provided a method for the treatment of pancreatitis, which method comprises 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), a pharmaceutically acceptable salt thereof, or a solvate thereof. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0124] In another embodiment there is provided a method for the treatment of pancreatitis, which method comprises 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), a pharmaceutically acceptable salt thereof, or a solvate. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0125] In a further aspect, there is provided a compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof for use in therapy.

[0126] In one embodiment there is provided a compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof for use in the treatment of acute pancreatitis.

[0127] In one embodiment there is provided the use of a compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for use in the treatment of acute pancreatitis.

[0128] 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), a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for use in the treatment of pancreatitis. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0129] 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), a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for use in the treatment of pancreatitis. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0130] In one embodiment there is provided the use of (E)-5-(4-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-ol (DMRC200699 or 22i), a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for use in the treatment of pancreatitis. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0131] In one embodiment there is provided the use of (E)-5-(5-hydroxyphenyl)-5-(4-(N-cyclopropylpiperidin-4-yl)phenyl)-4-phenylpent-4-en-1-01 (DMRC200699 or 22r), a pharmaceutically acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for use in the treatment of pancreatitis. The pancreatitis may be acute pancreatitis, chronic pancreatitis, hemorrhagic pancreatitis, necrotizing pancreatitis, or hemorrhagic-necrotizing pancreatitis.

[0132] In one aspect, the disclosure relates to a method or use for treating pancreatitis, which comprises administering a compound of Chemical Formula 6:

##STR00033##

wherein

[0133] R.sup.1 is (C3-C10)heterocycloalkyl or or —O—(CH2).sub.m-R.sup.11;

[0134] R.sup.11 is (C3-C10)heterocycloalkyl;

[0135] m is an integer of 1 to 3;

[0136] Ar is s (C6-C12)aryl or (C3-C12)heteroaryl,

[0137] wherein the heterocyclalkyl, the aryl, or heteroaryl may be further substituted by one or more 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)alkyl sulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkyl sulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and

[0138] R.sup.2 is hydroxyl, halogen, (C1-C10) alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy, a pharmaceutically acceptable salt thereof or a solvate thereof to a patient in need thereof. In an 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.

[0139] In another aspect, the present disclosure relates to a method or use for treating pancreatitis, which comprises administering a compound of Chemical Formula 6, wherein R.sup.2 is hydroxyl, and R.sup.1 is a heterocycloalkyl group selected from the following structures:

##STR00034##

[0140] wherein R.sup.31 and R.sup.32 are independently hydrogen, (C1-C10)alkyl, (C3-10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and

[0141] L is O or S,

a pharmaceutically acceptable salt thereof or a solvate thereof to a patient in need thereof. In an 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.

[0142] In still another aspect, the present disclosure relates to a method or use for treating pancreatitis, which comprises administering a compound selected from the above-described “Listed Compounds,” a pharmaceutically acceptable salt thereof, or a solvate thereof, a patient in need thereof. In an 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.

[0143] In still another aspect, the present disclosure relates to a method or use for treating pancreatitis, which comprises 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 (Compound22i, 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, a patient in need thereof. In an 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.

[0144] In some embodiments, the present disclosure relates to a method for treating one or more symptoms of pancreatitis in patients by administering a therapeutically effective amount of a compound of chemical formula 1 to treat one or more symptoms of pancreatitis. The symptoms of pancreatitis may be abdominal pain, back pain, swollen abdomen, nausea, vomiting, fever, rapid pulse, or a combination of two or more thereof.

[0145] In an aspect, the compound of chemical formula 1 can be administered at a dose ranging from 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 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.

Compositions

[0146] The compounds of the disclosure may, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in one aspect, there is provided a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable excipient or carrier. The pharmaceutical composition, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories.

[0147] Suitable pharmaceutically acceptable excipient or carrier will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipient or carrier may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipient or carrier may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipient or carrier may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipient or carrier may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of formula 1 or pharmaceutically acceptable salts thereof once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipient or carrier may be chosen for their ability to enhance patient compliance.

[0148] Suitable pharmaceutically acceptable excipient or carrier includes the following types of excipients or carriers: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavouring agents, flavour-masking agents, colouring agents, anti-caking agents, humectants, chelating agents, plasticisers, viscosity increasing agents, antioxidants, preservatives, stabilisers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other excipients are present in the formulation.

[0149] Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipient or carrier in appropriate amounts.

[0150] The pharmaceutical composition according to an embodiment is prepared using techniques and methods known to those skilled in the art.

[0151] The pharmaceutical composition according to an embodiment, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories.

[0152] The pharmaceutical composition may contain from 0.1% to 99% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned conditions or disorders will vary in the usual way with the seriousness of the conditions or disorders, the weight of the subject, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 5000 mg, 1.0 to 500 mg or 1.0 to 200 mg and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks, months or years.

[0153] In one embodiment, the pharmaceutical composition is formulated into injectable or infusible solutions, or reconstitutable powders.

[0154] In one embodiment, the pharmaceutical composition is adapted for oral formulation.

[0155] Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize 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 glycollate); and acceptable wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated according to methods well known in normal pharmaceutical practice.

[0156] Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may 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 may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid), and, if desired, conventional flavorings or colorants, buffer salts and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

[0157] For parenteral administration, fluid unit dosage forms are prepared utilizing a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilizing a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

[0158] Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilizing agents, solubilizingagents or suspending agents. They may also contain a preservative.

[0159] The pharmaceutical composition may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

[0160] The pharmaceutical composition may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may 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.

[0161] For intranasal administration, the compounds of formula (I) may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. Thus compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).

[0162] The pharmaceutical composition may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.

[0163] An aspect of the disclosure provides for a pharmaceutical composition for use in the treatment of pancreatitis which comprises a compound of formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable excipient or carrier. In an 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.

Reference Preparation Example

[0164] The compound of chemical formula 1 can be prepared by following the procedure described in U.S. application Ser. No. 16/313,360, of which entire contents are incorporated herein by reference.

Reference Preparation Example 1: Preparation of (E)-5-(4-(2-(aziridin-1-ypethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-en-1-ol hydrochloride salt (Compound 18t)

[0165] By employing the following reaction scheme, compound 18t was prepared:

##STR00035##

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

[0166] 4-Iodophenyl pivalate (2 g, 6.6 mmol), copper (I) chloride (0.13 g, 0.66 mmol), bis(triphenylphosphine)palladium (II) dichloride (PdCl.sub.2(PPh.sub.3).sub.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 the reaction was carried out at 50° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and 1.1 g of the desired compound C-1 (58%) was obtained using column chromatography.

Step 2: Preparation of (E)-tert-butyl 3-(4-(5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl)phenyl)azetidin-1-carboxylate (C-2)

[0167] tert-Butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)azetidin-1-carboxylate (0.27 g, 0.75 mmol), compound C-1 (0.14 g, 0.5 mmol), and iodobenzene (84 μL, 0.75 mmol) were dissolved in DMF (8 mL) and water (4 mL), 0.025 M PdCl.sub.2(PhCN).sub.2 (0.2 mL, 5 μmol) was added thereto, and heating was performed at 45° C. for 10 minutes. Cesium carbonate (0.24 g, 0.75 mmol) was added thereto, and heating was performed at 45° C. for 12 hours. When the reaction was completed, brine and ethyl acetate was further added to the reaction solution, and an organic layer was extracted. The organic layer was dried with anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was distilled under reduced pressure to obtain a residue, which was purified using column chromatography, thereby obtaining 81 mg of the desired compound C-2 (27%).

Step 3: Preparation of tert-butyl (E)-3-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)azetidine-1-carboxylate (18t)

[0168] Compound C-2 (0.021 mmol) was added to tetrahydrofuran (2 mL), the 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 thereto. The temperature was raised to room temperature, and stirring was performed for 1 hour. Water and ethyl acetate were further added to the reaction solution and an organic layer was extracted. The organic layer was dried with anhydrous Na2SO4 and filtered. The solvent was distilled under reduced pressure to obtain a residue, which was purified using column chromatography and then dissolved in methanol:dichloromethane (1:1), the temperature was lowered to 0° C., a 1M aqueous HCl solution was slowly added thereto, and distillation under reduced pressure was performed, thereby obtaining 24 mg of the desired compound 18t (78%).

Reference Preparation Examples 2-3

[0169] Compounds 18a and 18t were prepared using the process of Reference Preparation Example 1. Identification data of the thus-prepared compounds 18a and 18t is shown in the following Table 1.

TABLE-US-00001 TABLE 1 [00036]           Example         Cmpd No. [00037]           R           Identification data 1 18t [00038] [00039] .sup.1H-NMR (CD.sub.3OD, 400 MHz) δ 7.18-7.10 (m, 5H), 7.05 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.25 (t, J = 8.4 Hz, 2H), 3.81 (t, J = 6.6 Hz, 2H), 3.66 (m, 1H), 3.43 (t, J = 6.8 Hz, 2H), 2.55 (m, 2H), 1.57 (m, 2H), 1.45 (s, 9H). MS (ESI) m/z: 386 [M + H].sup.+. 2 18a [00040] [00041] .sup.1H-NMR (CD.sub.3OD, 400 MHz) δ 7.14-7.07 (m, 5H), 7.02 (d, J = 8.0 Hz, 2H), 6.78 (m, 4H), 6.69 (d, J = 8.3 Hz, 2H), 3.76 (m, 2H), 3.52 (m, 3H), 3.41 (t, J = 6.4 Hz, 2H), 3.23 (m, 2H), 2.96 (m, 2H), 2.51 (m, 2H), 1.53 (m, 2H), 1.39 (d, J = 6.5 Hz, 6H). MS (ESI) m/z: 457 [M + H].sup.+. 3 18k [00042] [00043] .sup.1H-NMR (CD.sub.3OD, 400 MHz) δ 7.19-7.09 (m, 6H), 6.81 (d, J = 8.7 Hz, 2H), 6.69 (m, 4H), 6.63 (m, 1H), 3.76 (m, 2H), 3.53 (m, 3H), 3.40 (t, J = 5.6 Hz, 2H), 3.21 (m, 2H), 2.91 (m, 2H), 2.50 (m, 2H), 1.53 (m, 2H), 1.38 (d, J = 6.6 Hz, 6H). MS (ESI) m/z: 457 [M + H].sup.+.

Reference Preparation Example 4

Preparation of (E)-4-(5-hydroxy-1-(4-(1-isopropylazetidin-3-yl)phenyl)-2-phenylpent-1-en-1-yl)phenol (Compound 22a)

[0170] By employing the following reaction scheme, compound 22a was prepared:

##STR00044##

Step 1: Preparation of methyl (E)-5-(4-(1-isopropylazetidin-3-yl)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (E-2)

[0171] Compound E-1 (0.03 g, 0.06 mmol), acetone (0.14 mL, 1.9 mmol), and sodium triacetoxyborohydride (NaBH(OAc).sub.3, 41 mg, 0.19 mmol) were added to dichloroethane (3 mL), and stirred at room temperature for 1 hour. Water and ethyl acetate were further added to the reaction solution and an organic layer was extracted. The organic layer was dried with anhydrous Na.sub.2SO.sub.4 and filtered. The solvent was distilled under reduced pressure to obtain a residue, which was purified using column chromatography, thereby obtaining 18 mg of the desired compound E-2 (54%).

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

[0172] 4 mg of the desired compound 22a (27%) was obtained by the same process as step 3 of Example 4, using compound E-2.

Reference Preparation Examples 5-6

[0173] Compounds 22i and 22r e were prepared, using the process of Reference Preparation Example 4. Identification data of the thus-prepared compounds 22i and 22r is shown in the following Table 2.

TABLE-US-00002 TABLE 3 [00045]           Example         Cmpd No. [00046]           R           Identification data 4 22a [00047] [00048] .sup.1H-NMR (CD.sub.3OD, 400 MHz) δ 7.17-7.08 (m, 5H), 7.08-7.02 (m, 4H), 6.94 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 4.38 (t, J = 8.3 Hz, 2H), 4.21 (m, 1H), 4.10 (t, J = 9.8 Hz, 2H), 3.98 (m, 1H), 3.43 (t, J = 7.5 Hz, 2H), 2.55 (m, 2H), 1.56 (m, 2H), 1.24 (d, J = 6.4 Hz, 6H). MS (ESI) m/z: 428 [M + H].sup.+. 5 22i [00049] [00050] 1H-NMR (CD3OD, 400 MHz) δ 7.15-7.06 (m, 5H), 7.01 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 3.68 (m, 2H), 3.41 (t, J = 6.6 Hz, 2H), 3.24 (m, 2H), 2.79 (m, 2H), 2.52 (m, 2H), 2.02 (m, 2H), 1.78 (m, 2H), 1.54 (m, 2H), 0.97 (m, 4H). MS (ESI) m/z: 454 [M + H]+. 6 22r [00051] [00052] .sup.1H-NMR (CD.sub.3OD, 400 MHz) δ 7.21-7.10 (m, 7H), 6.90 (m, 4H), 6.72 (d, J = 7.9 Hz, 2H), 3.71 (m, 2H), 3.43 (t, J = 6.8 Hz, 2H), 3.27 (m, 2H), 2.80 (m, 2H), 2.52 (m, 2H), 2.01 (m, 2H), 1.79 (m, 2H), 1.52 (m, 2H), 0.98 (m, 4H). MS (ESI) m/z: 454 [M + H].sup.+.

[0174] Compounds 18a (DMRC200434), Compound 18k (DMRC2001000), Compound22i (DMRC200699), and Compound 22r (DMRC200996), which were used in the Biological Examples, have the following structure.

##STR00053## ##STR00054##

A reference compound GSK5182 has the following structure:

##STR00055##

Biological Example 1

(A) Materials and Methods

[0175] Materials: Caerulein (C9026) and Taurolithocholic acid 3-sulfate disodium salt (TLCS; T0512) was purchased from Sigma. [0176] Animal models: Eight to ten-week male C57BL/6 mice (Jackson Lab) were used according to an animal protocol approved by the Institutional Animal Care and Use Committee of Kyungpook National University.

[0177] 1. Caerulein-Induced Model of Pancreatitis

[0178] Acute pancreatitis (AP) was induced by intraperitoneal injections of caerulein at 50 μg/kg/h given 6 times. As an ERRg antagonist, Compound DMRC 200434 (20 mg/kg) was dissolved in a solution of 5%—DMSO: 95% -20% PEG400(Saline) and was injected at two points—at 24 hours prior to, and at the start of the Caerulein treatment—and animals were sacrificed 16 hours after the last injection of Caerulein.

[0179] 2. Intraductal Bile Acid Infusion Model of Pancreatitis

[0180] Pancreatitis was induced by retrograde infusion of the bile acid TLCS (1%) dissolved in saline into the distal common bile duct and pancreatic duct. Mice were anesthetized with a ketamine (120 mg/kg)/xylazine (12 mg/kg) mixture (Butler Schein, Chicago, Ill.). A ventral incision was made to reveal the abdominal cavity. The duodenum was flipped to reveal its distal side and held in place by ligatures. The bile duct was identified, and a 30-gauge needle was inserted through the antimesenteric aspect of the duodenum to cannulate the biliopancreatic duct. TLCS was infused at 10 μl/min for 5 min using a P33 perfusion pump (Harvard Apparatus, Holliston, Mass.). The exterior wound was closed using 7-mm wound clips, and a single injection of buprenorphine (0.075 mg/kg) was given immediately after the surgery. Normal saline-infused animals served as shams Animals were allowed to recover on a heating pad for 90 min after the procedure. Mice were euthanized 24 h after induction.

[0181] Upon completion of experiments with above-mentioned animal models (1) and (2), pancreas tissue were snap frozen in liquid nitrogen and stored at −80° C. for analysis of trypsin activity, for protein analysis by Western blots and for gene expression analysis by RT-qPCR. Pancreas were dissected and fixed in 10% neutral-buffered formalin and embedded in paraffin. Five-μm sections were prepared and stained with hematoxylin and eosin (H&E). Pancreas injury was determined by measuring serum amylase (K711-100, Biovision), serum lipase (MAK046, Sigma) and pancreatic tissue trypsin activity (Biovision) was determined using commercially available kit.

(B) Mouse Primary Acinar Cell Culture and Treatment.

[0182] Primary acinar cells were isolated from mice as described previously (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).

(C) Western Blotting.

[0183] Cells were lysed in cell lysis buffer (Cell Signaling Technology, 9803) supplemented with protease inhibitor (Thermo Fisher Scientific, A32953) and phosphatase inhibitor (PhosSTOP™, Sigma Aldrich, 04906837001). Proteins were separated on 4-20% MINI-PROTEAN® TGX Precast Protein Gels by SDS PAGE electrophoresis and transferred to onto PVDF membranes (IPVH00010, EMD Millipore). Membranes were blocked in 5% BSA (Blotting-Grade Blocker, BioRad, 1706404) dissolved in TBS-T for 1 h and incubated overnight at 4° C. with primary antibody for ERRA (PP-H5844-00, R&D Systems) and ERRG (PP-H6812-00, R&D Systems). Membranes were washed three times with TB S-T and incubated with secondary antibodies for 1 h at room temperature: anti-mouse IgG, HRP-linked (Cell Signaling Technology, 7076). Images were obtained by Chemiluminescence buffer ECL (GE Healthcare) using a CHEMIDOC™ (GE Healthcare).

(D) Quantitative Reverse-Transcription PCR (RT-qPCR)

[0184] Total RNA was extracted using TRIZOL® (Thermo Fisher Scientific) and, and then reversed transcribed using REVERTAID™ First Strand cDNA Synthesis Kit (K1622Thermo Fisher Scientific) with oligo-dT primers. Quantitative PCR was performed with SYBR® Green Supermix (Bio-rad) on the ABI Prism 7300 sequence detection system (Applied Biosystems). The reaction conditions were as follows: pre-denaturation at 95° C. for 10 minutes and 40 cycles of denaturation at 95° C. for 15 s, annealing at 60° C. for 60 s, and extending at 72° C. for 1 minutes. The quantity of mRNA was calculated using the ACt method and normalized by the 36b4 (also known as Rplp0) house-keeping gene. Sequences for qPCR primers are as follows:

TABLE-US-00003 Esrra-forward: (SEQ ID NO: 1) 5′-TACGGTGTGGCATCCTGTGA Esrra-reverse: (SEQ ID NO: 2) 5′-CTCCCCTGGATGGTCCTCTT Esrrg-forward: (SEQ ID NO: 3) 5′-GCCCAGCCACGAATGAAT Esrrg-reverse: (SEQ ID NO: 4) 5′-GCAGGCCTGGCAGGATTT 36b4-forward: (SEQ ID NO: 5) 5′-ACCTCCTTCTTCCAGGCTTT 36b4-reverse: (SEQ ID NO: 6) 5′-CTCCAGTCTTTATCAGCTGC

(E) Results:

Upregulation of Esrrg in Caerulein-Treated Mouse Pancreas.

[0185] In contrast to Esrra mRNA expression pattern, Esrrg mRNA expression was highly increased in the pancreas of caerulein-challenged mouse when compared to control treatment (FIG. 1A). Immunoblotting confirmed that ERRG protein was highly increased upon caerulein-challenge in mouse pancreas (FIG. 1B). To analyze and confirm the extent of pancreatic injury upon caerulein-challenge, the inventors analyzed serum amylase and lipase levels in these animals. The inventors found that Caerulein treatment led to a dramatic upregulation in the amylase (FIG. 2A) and lipase (FIG. 2B) levels in the serum samples of these mice. These results indicated that pancreatic injury induced by caerulein can preferentially upregulated ERRG when compared to ERRA.

Reduction of Caerulein-Induced ERRG Protein Level in Mouse Pancreatic Acinar Cells.

[0186] Next, the inventors analyzed the toxicity of these compounds in vivo (Table 3). Table 3 shows biochemical properties of Compounds 18a (DMRC200434), 18k (DMRC2001000), 22i (DMRC200699), and 22r (DMRC200996), and reference compound GSK5182.

TABLE-US-00004 TABLE 3 Biochemistry of several ERRγ inverse agonist molecules. GSK5182 DMRC200434 DMRC200699 Binding ERRγ IC.sub.50 (μM) 0.110 0.040 0.056 Selectivity ERRα IC.sub.50 (μM) >10 >10 >10 ERRβ IC.sub.50 (μM) >10 1.33 1.7 ERα IC.sub.50 (μM) 2 1.24 2.1 ERRγ functional assay IC.sub.50 (μM) 0.077 0.006 0.044 Molecular Weight 417.6 456.6 453.6 Water Solubility (mg/mL) >1 >1 >1 In vitro CYP (% remaining at 10 μM) OK All >73% OK All >64% 1A2(57), 2C9(64), safety 2C19(32), 2D6(48), 3A4(54) hERG binding IC.sub.50 (μM) >30 >10 >30 hERG current IC.sub.50 (μM) — 21.3 5.9 Ames (at 2 mM Max) — OK OK MS (% of control) H (43), d (10), h (27), d (50), h (36), d (92), r (26), m (7) r (33), m (20) r (92), m (84) Plasma Stability — h (92.1), r (97.1) — (% of remaining after 2 h) Permeability (PAMPA) (10.sup.−6 cm/s) 0.11~0.82 0.46 0.35 PK po AUC (μMh) 0.68 0.82 2.24 iv AUC (μMh) 0.89 0.42 0.50 BA % 8.4 22 46 Cmax (nM) 130 208 380 CL (ml/min/kg) 44 75 68 T½ (h) 2.3 3.7 3.0 Vss (L/kg) 9.1 16 12 In vitro Single dose Tax (mg/kg) — LD50 >2000 — safety Repeated dose Tax — Done — DMRC200966 DMRC2001000 Binding ERRγ IC.sub.50 (μM) 0.533 0.035 Selectivity ERRα IC.sub.50 (μM) >10 >10 ERRβ IC.sub.50 (μM) 3.1 >10 ERα IC.sub.50 (μM) >10 1.94 ERRγ functional assay IC.sub.50 (μM) 0.134 0.020 Molecular Weight 453.6 456.6 Water Solubility (mg/mL) >1 >1 In vitro CYP (% remaining at 10 μM) OK All >83% 1A2(100), 2C9(76), safety 2C19(100), 2D6(66), 3A4(48) hERG binding IC.sub.50 (μM) 17 25 hERG current IC.sub.50 (μM) >30 >30 Ames (at 2 mM Max) OK OK MS (% of control) h (62), d (57), h (65), d (61), r (50), m (25) r (55), m (27) Plasma Stability — — (% of remaining after 2 h) Permeability (PAMPA) (10.sup.−6 cm/s) 0.014 1.29 PK po AUC (μMh) 4.93 4.18 iv AUC (μMh) 0.85 0.99 BA (%) 58.2 42.4 Cmax (nM) 1,510 970 CL (ml/min/kg) 45 37 T½ (h) 1.8 1.2 Vss (L/kg) 4.6 3.0 In vitro Single dose Tax (mg/kg) — LD50 >2000 safety Repeated dose Tax — Done

[0187] To test the effectiveness of the compound of Chemical Formula 1 (DMRC200434, DMRC2001000, DMRC200699, and DMRC200996), and reference compound GSK5182 in vitro, the inventors isolated, harvested and cultured primary acinar cells from mouse and treated them with Caerulein for 16 hours in the absence or presence of these compounds (FIG. 3). Caerulein treatment led to marked increase in ERRG protein level in mouse primary acinar cells as demonstrated by immunoblotting. It was found the compound of Chemical Formula 1 which has ERRG antagonistic activity, showed activity. In particular compound of Chemical Formula 1 showed strongest inhibitory effect on caerulein-induced ERRG protein level at a very low dose. This result indicated that compound of Chemical Formula 1 can be a potential candidate to inhibit ERRG during pancreatic injury.

Biological Example 2. Preventive Effects on Pancreatic Injury-Induced Pancreatitis.

[0188] Next, the inventors analyzed the efficacy of the compound of Chemical Formula 1 in vivo using two different animal models of acute pancreatitis. As a compound of Chemical Formula 1, DMRC200434 was employed. They pretreated mice with a single dose of compound of Chemical Formula 1, 24 hours prior to Caerulein challenge. An additional dose of compound of Chemical Formula 1 was administered to the animals at the beginning of Caerulein challenge. Upon completion of the experimental timeline, these animals were sacrificed and serum and pancreas tissue samples were collected and analyzed. The inventors found that when compared to Caerulein-challenge alone, mice treated with Caerulein in the presence of compound of Chemical Formula 1 showed a dramatic reduction in serum amylase (FIG. 4A), serum lipase (FIG. 4B) and tissue trypsin activity (FIG. 4C). The inventors further found that the pancreatic histopathology was dramatically improved in compound of Chemical Formula 1-treated mice, when compared to Caerulein-challenged mice alone (FIG. 4D). These results indicated that compound of Chemical Formula 1 can protect against and ameliorate Caerulein-induced acute pancreatitis in vivo.

[0189] Additionally, the inventors assessed the efficacy of compound of Chemical Formula 1 using a different animal model of acute pancreatitis, viz., biliary pancreatitis which is a leading 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 mimicked experimentally by challenging mice with TLCS. To that end, the inventors pretreated mice with a single dose of compound of Chemical Formula 1, 24 hours prior to TLCS challenge. An additional dose of compound of Chemical Formula 1 was administered to the animals at the beginning of TLCS challenge. Upon completion of the experimental timeline, these animals were sacrificed and serum and pancreas tissue samples were collected and analyzed. The inventors found that when compared to TLCS-challenge alone, mice treated with TLCS in the presence of compound of Chemical Formula lshowed a dramatic reduction in serum amylase (FIG. 5A), serum lipase (FIG. 5B). The inventors further observed that the pancreatic histopathology was dramatically improved in compound of Chemical Formula 1-treated mice, when compared to TLCS-challenged mice alone (FIG. 5C).

[0190] These results indicated that compound of Chemical Formula 1, which shows an ERRg antagonistic activity can protect against TLCS-induced acute pancreatitis in vivo and ameliorate pancreatic pathology in this condition. In particular compound of Chemical Formula 1 showed strongest activity for preventing and/or treating pancreatitis.

[0191] Hereinabove, although various aspects have been described in detail with reference to the exemplary embodiments, it will be apparent to those skilled in the art that various modifications and alterations may be made without departing from the scope and spirit of the present disclosure. It should be understood that these modifications and alterations fall within the scope defined by the following claims.