US20190167820A1 - Novel aryl ethene derivative and pharmaceutical composition containing same as active ingredient - Google Patents

Novel aryl ethene derivative and pharmaceutical composition containing same as active ingredient Download PDF

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US20190167820A1
US20190167820A1 US16/313,360 US201616313360A US2019167820A1 US 20190167820 A1 US20190167820 A1 US 20190167820A1 US 201616313360 A US201616313360 A US 201616313360A US 2019167820 A1 US2019167820 A1 US 2019167820A1
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alkyl
heterocycloalkyl
hydroxy
heteroaryl
independently
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Sung Yeoun HWANG
Sung Jin Cho
Jina Kim
Jungwook Chin
Hayoung HWANG
In-Kyu Lee
Yong-Hyun Jeon
Jaetae LEE
Jae-Han Jeon
Sang Wook Kim
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Kemimedi CoLtd
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Kemimedi CoLtd
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Priority claimed from KR1020160080124A external-priority patent/KR101819639B1/ko
Priority claimed from KR1020160117200A external-priority patent/KR101835133B1/ko
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    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/025—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus inorganic Tc complexes or compounds
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
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    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines

Definitions

  • the present invention relates to an arylethene derivative inhibiting an activity of an estrogen-related receptor gamma (hereinafter, referred to as ERR ⁇ ), or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound as an active ingredient.
  • ERR ⁇ estrogen-related receptor gamma
  • a hormone receptor which responds to the hormone is required for regulating development, growth or differentiation of cells through change in intracellular gene expression, and is largely classified into a cell membrane receptor and a nuclear receptor. Among them, there is an increasing interest in an orphan nuclear receptor which is the nuclear receptor and of which the binding ligand has not been revealed.
  • Estrogen-related receptor which is one of the orphan nuclear receptors has three types which are ERR ⁇ , ERR ⁇ , and ERR ⁇ , and each position to be activated is different.
  • ERR ⁇ shows an activity in spinal cords and a central nervous system, and is a nuclear hormone receptor which is a transcriptional regulatory protein involved in glucose biosynthesis in a liver, and has an increased transcriptional activity for itself when bound to a ligand, thereby helping gene expression related to glucose synthesis. That is, ERR ⁇ is directly involved in glucose metabolism.
  • ERR ⁇ is a human nuclear receptor protein called NR3B3, and is encoded by a ESRRG gene. ERR ⁇ functions as a constitutive activator in transcription. ERR ⁇ is a member of a nuclear hormone receptor family of a steroid hormone receptor.
  • An ERR ⁇ protein is known as a main modulator of various genes related to fatty acid oxidation and mitochondria biogenesis in a myocardium, and also known to be involved in glucose production in a liver.
  • diabetic retinopathy is a disease developed by occurrence of circulatory failure in a retina which is specific to diabetic patients, and belongs to one of the three major microvascular complications of diabetes together with diabetic neuropathy and diabetic nephropathy.
  • Occurrence of diabetic retinopathy is related to a disease period during which a patient suffers from diabetes, and in the case of the diabetes diagnosed before the age of 30 corresponding to type 1, the diabetic retinopathy occurs in 17% when the disease period is 5 years or less, and in 98% when the disease period is 15 years or more, and among them, worsening proliferative diabetic retinopathy occurs in about 1% when the disease period is 10 years or less, and in 67% when the disease period is 35 years or more.
  • the diabetic retinopathy occurs in 29% when the disease period is 5 years or less, and in 78% when the disease period is 15 years or more, and the proliferative diabetic retinopathy occurs in 2% when the disease period is 5 years or less, and in 16% when the disease period is 15 years or more.
  • vascular change in a capillary such as hypertrophy of a retinal capillary basement membrane, loss of perivascular cells, and occurrence of microaneurysm occurs, and as time passes, retinal neovascularization subsequent to a wide range of capillary nonperfusion may also occur.
  • This diabetic retinopathy is a kind of diabetes complications, but once develops, the progression thereof is difficult to be prevented by glycemic control, and a treatment method specific to retinopathy is demanded.
  • GSK5182 which is (Z)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol functions as a ligand in ERR ⁇ to inhibit the ERR ⁇ activity, thereby showing an anti-diabetes effect such as relieving hyperglycemia and insulin resistance, and a treatment effect of retinopathy.
  • anaplastic thyroid cancer is one of the most aggressive and deadly cancers known to develop in humans.
  • ATC rapidly metastasizes from a thyroid gland to lungs, bones, focal lymph nodes, and the brain. This is in contrast with the nature of well-differentiated benign thyroid cancer which explains most of the thyroid cancer, and thus, treatment of ATC which is surgery, a radiation therapy, and a chemotherapy alone or in combination thereof has not exhibited an effect on patient survival. As a result, development of a novel treatment method is urgently demanded.
  • a sodium iodide symporter is a plasma membrane glycoprotein which mediates intracellular active inflow of iodine.
  • endogenous NIS accepts a wide range of application of a radioiodine therapy in a clinical situation, which is known as an effective treatment method to remove malignant cells with minimal side effects over the years.
  • Low-differentiated cancer cells including ATC cells tend to represent gradual dedifferentiation leading to a decrease in a NIS level. This prevents ATC cells from accumulating iodine in the cells with a high concentration, and accordingly, causes cell resistance to the radioiodine therapy, leading to a poor prognosis. Therefore, there has been many attempts to recover an NIS function from ATC cells, using several methods such as epigenetic regulation using gene transfer, an epigenome-altering drug, and the like, however, no satisfactory result has been obtained so far.
  • ERR ⁇ The biological effect of ERR ⁇ has been extensively studied in various disease models (type 2 diabetes mellitus, alcohol-derived oxidative stress, microbial infection by liver damage and gluconeogenesis of the damaged liver, some metabolic diseases such as liver insulin signaling and iron metabolism), however, the role of ERR ⁇ for the NIS function in ATC has not been clearly studied so far.
  • GSK5182 which is (Z)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol functions as a ligand in ERR ⁇ to inhibit the ERR ⁇ activity, thereby improving the function of NIS to increase an ATC intracellular radioiodine uptake and finally exhibit an effect of increasing radioiodine treatment.
  • GSK5182 when GSK5182 was administered to an ATC mouse tumor model, a radioiodine uptake in the tumor was not increased. Accordingly, development of a new material which may specifically and significantly inhibit ERR ⁇ transcriptional activity as compared with GSK5182, and as a result, cause a radioactive isotope uptake increase from a cellular level to an animal level is demanded.
  • an activity to inhibit ERR ⁇ is better as compared with the conventionally reported activity of GSK5182, and at the same time, drug stability, a pharmacological activity, and toxicity were improved, thereby completing the present invention.
  • An object of the present invention is to provide a novel arylethene derivative which may effectively inhibit an ERR ⁇ activity, or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating ERR ⁇ -mediated diseases, comprising the arylethene derivative, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating retinopathy, comprising the arylethene derivative, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for treating thyroid cancer, comprising the arylethene derivative, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and being used in combination of radioactive iodine.
  • Another object of the present invention is to provide a kit for treating thyroid cancer, comprising the arylethene derivative, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and radioiodine.
  • an arylethene derivative represented by the following Chemical Formula 1 as a novel compound which may effectively inhibit an activity of ERR ⁇ , or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof:
  • L is (C6-C20)arylene, (C3-C20)heteroarylene, or (C3-C20)fused heterocycle;
  • R 1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, —O—(CH 2 ) m R 11 , —(CH 2 ) m —R 12 , NH—(CH 2 ) m —R 13 , —NHCO—(CH 2 ) n —R 14 , or —SiR 16 R 17 —(CH 2 ) m —R 15 ;
  • R 11 to R 15 are independently of one another (C3-C20)heterocycloalkyl
  • R 16 and R 17 are independently of each other (C1-C20)alkyl
  • n is an integer of 1 to 3;
  • 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 21 R 22 , (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, —SO 2 —R 23 , and —OSO 2 —R 24 ;
  • R 21 and R 22 are independently of each other hydrogen, (C1-C10)alkylsulfonyl, or (C6-C20)cycloalkylsulfonyl;
  • R 23 and R 24 are independently of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl;
  • R 2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy, or (C1-C20)alkylsulfonyloxy;
  • heterocycloalkyl or heteroaryl of R 1 and the heterocycloalkyl of R 11 to R 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
  • 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.
  • a pharmaceutical composition for preventing or treating ERR ⁇ -mediated diseases includes: the arylethene derivative, or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof as an active ingredient, by confirming an excellent ERR ⁇ inhibitory activity of the arylethene derivative represented by Chemical Formula 1.
  • a pharmaceutical composition for preventing or treating retinopathy includes: the arylethene derivative of Chemical Formula 1 which may effectively inhibit an ERR ⁇ activity, or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for treating thyroid cancer includes: the arylethene derivative of Chemical Formula 1 which may specifically and significantly inhibit an ERR ⁇ transcriptional activity, or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and is used in combination of radioactive iodine.
  • a kit for treating thyroid cancer includes: the arylethene derivative of Chemical Formula 1 which may specifically and significantly inhibit an ERR ⁇ transcriptional activity, or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and radioactive iodine.
  • the arylethene derivative of the present invention is a novel compound, and exhibits very high inhibitory activity to ERR ⁇ as compared with a conventional GSK5182 compound, and at the same time, shows an effect of improved drug stability, pharmacological activity and toxicity.
  • the arylethene derivative may be useful as efficient prophylactic agent and therapeutic agent for diseases mediated by ERR ⁇ , in particular, metabolic diseases such as obesity, diabetes, hyperlipidemia, fatty liver, or atherosclerosis, as well as retinopathy, without side effects.
  • the arylethene derivative of the present invention may specifically and significantly inhibit ERR ⁇ transcriptional activity as compared with GSK5182, and as a result, cause a radioactive isotope uptake increase from a cellular level to an animal level. Accordingly, the arylethene derivative of the present invention may significantly increase a treatment effect of radioactive iodine therapy for treating cancer, and when administered to cancer cells, may effectively produce cancer cells having an improved sodium iodide symporter (NIS) function, thereby having an excellent effect of being more easily applied to related research and clinical practice for treating anaplastic thyroid cancer.
  • NIS sodium iodide symporter
  • FIGS. 1 to 3 illustrate an effect of compound 18a for a radioactive iodine uptake in anaplastic thyroid cancer cells.
  • FIGS. 4 and 5 illustrate an effect of compound 18a for regulating endogenous ERR ⁇ and NIS mRNA expression in anaplastic thyroid cancer cells.
  • FIGS. 6 and 7 illustrate an effect of compound 18a for regulating endogenous ERR ⁇ protein expression in anaplastic thyroid cancer cells.
  • FIGS. 8 and 9 illustrate a compound 18a-derived MAP kinase activity in anaplastic thyroid cancer cells.
  • FIGS. 10 and 11 illustrate a degree of iodine uptake inhibition in compound 18a-treated anaplastic thyroid cancer cells, by PD98059 or U0126.
  • FIGS. 12 and 13 illustrate a degree of inversion of activated MAK kinase signaling, by PD98059 or U0126.
  • FIGS. 14 and 15 illustrate an increase aspect of an amount of membrane-localized NIS protein in anaplastic thyroid cancer cells by compound 18a.
  • FIGS. 16 and 17 illustrate results showing increased cytotoxicity of increased 131 I after treating anaplastic thyroid cancer cells with compound 18a.
  • FIGS. 18 to 22 illustrate an effect of compound 18a for a radioactive iodine uptake by administrating compound 18a in an ATC tumor model.
  • the present invention provides an arylethene derivative represented by the following Chemical Formula 1, or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof:
  • L is (C6-C20)arylene, (C3-C20)heteroarylene, or (C3-C20)fused heterocycle;
  • R 1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, —O—(CH 2 ) m —R 11 , —(CH 2 ) m —R 12 , NH—(CH 2 ) m —R 13 , —NHCO—(CH 2 ) n —R 14 , or —SiR 16 R 17 —(CH 2 ) m —R 15 ;
  • R 11 to R 15 are independently of one another (C3-C20)heterocycloalkyl
  • R 16 and R 17 are independently of each other (C1-C20)alkyl
  • n is an integer of 1 to 3;
  • 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 21 R 22 , (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, —SO 2 —R 23 , and —OSO 2 —R 24 ;
  • R 21 and R 22 are independently of each other hydrogen, (C1-C10)alkylsulfonyl, or (C6-C20)cycloalkylsulfonyl;
  • R 23 and R 24 are independently of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl;
  • R 2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy, or (C1-C20)alkylsulfonyloxy;
  • heterocycloalkyl or heteroaryl of R 1 and the heterocycloalkyl of R 11 to R 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
  • 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.
  • the arylethene derivative of Chemical Formula 1 according to the present invention which is a novel compound, has a very high inhibitory activity to ERR ⁇ , and thus, is useful as a therapeutic agent and a prophylactic agent of ERR ⁇ -mediated diseases, in particular, metabolic diseases such as obesity, diabetes, hyperlipidemia, fatty liver or arteriosclerosis, and also may be used as an active ingredient for preventing or treating retinopathy.
  • the arylethene derivative of Chemical Formula 1 regulates expression of endogenous ERR ⁇ protein to regulate mitogen-activated protein (MAP) kinase, and improves a sodium iodide symporter (NIS) function to increase membrane-localized NIS, thereby increasing a radioactive iodine uptake when treating thyroid cancer.
  • MAP mitogen-activated protein
  • NIS sodium iodide symporter
  • alkyl refers to a monovalent straight-chain or branched-chain saturated hydrocarbon radical consisting of only carbon and hydrogen atoms
  • an example of the alkyl radical includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, nonyl, or the like, but not limited thereto.
  • aryl refers to a monovalent organic radical of an aromatic ring derived from aromatic hydrocarbon by removal of one hydrogen, including a single- or fused ring system containing appropriately 4 to 7, preferably 5 or 6 ring atoms in each ring, and even a form in which a plurality of aryls are linked by a single bond.
  • a specific example thereof includes phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, or the like, but not limited thereto.
  • heteroaryl refers to a monovalent radical of a heteroaromatic ring which is an aryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S as an aromatic ring backbone atom, and carbons as remaining aromatic ring backbone atoms, and is a 5- or 6-membered monocyclic heteroaryl and a polycyclic heteroaryl fused with one or more benzene rings, which may be partially saturated.
  • the heteroaryl in the present invention also includes a form in which one or more heteroaryls are linked by a single bond.
  • heteroaryl group includes pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, imidazolyl, benzimidazolyl, isoxazolyl, benzisoxazolyl, thiophenyl, benzothiophenyl, furyl, benzofuryl, or the like, but not limited thereto.
  • arylene and “heteroarylene” refer to divalent radicals of aromatic ring and heteroaromatic ring.
  • fused heterocycle refers to a divalent radical of a fused ring in which a non-aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and an aromatic ring are fused, and has a carbon atom or a nitrogen atom in the fused heterocycle as a bonding site.
  • An example of the fused heterocycle includes indoline, dihydrobenzofuran, dihydrobenzothiophene, or the like, but not limited thereto.
  • heterocycloalkyl is a monovalent radical of a non-aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O, and S, and the non-aromatic heterocycle includes a saturated or unsaturated monocycle, polycycle or spirocycle form, and may be bonded via a heteroatom or a carbon atom.
  • heterocycloalkyl radical may include monovalent radicals of non-aromatic heterocycles such as aziridine, pyrrolidine, azetidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, 3-azabicyclo[3.1.0]hexane, octahydropyrrolo[3,4-c]pyrrole, 2,7-diazispiro[4.4]nonane, 2-azaspiro[4.4]nonane, or the like.
  • non-aromatic heterocycles such as aziridine, pyrrolidine, azetidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, 3-azabicyclo[3.1.0]hexane, octahydropyrrolo[3,4-c]pyrrole, 2,7-diazispiro[4.4]nonane, 2-azaspiro[4.4]n
  • halo or halogen refers to fluorine, chlorine, bromine or iodine atom.
  • haloalkyl refers to alkyl substituted by one or more halogens, and an example thereof may include trifluoromethyl, or the like.
  • alkenyl is a monovalent radical of a straight chain or branched chain unsaturated hydrocarbon including one or more double bonds between two or more carbon atoms, and specifically includes ethenyl, propenyl, prop-1-en-2-yl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, or the like, but not limited thereto.
  • alkoxy refers to an —O-alkyl radical, wherein the alkyl is as described above.
  • An example of the alkoxy radical includes methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, or the like, but not limited thereto.
  • alkylcarbonyloxy refers to an —OC( ⁇ O)alkyl radical, wherein the alkyl is as described above.
  • An example of the alkylcarbonyloxy radical includes methylcarbonyloxy, ethylcarbonyloxy, isopropylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, t-butylcarbonyloxy, or the like, but not limited thereto.
  • alkylcarbonylamino refers to a —NHC( ⁇ O)alkyl radical, wherein the alkyl is as described above.
  • An example of the alkylcarbonylamino radical includes methylcarbonylamino, ethylcarbonylamino, isopropylcarbonylamino, propylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, t-butylcarbonylamino, or the like, but not limited thereto.
  • alkoxycarbonyl refers to a —C( ⁇ O)alkoxy radical, wherein the alkoxy is as described above.
  • An example of the alkoxycarbonyl radical includes methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, or the like, but not limited thereto.
  • cycloalkyl refers to a monovalent saturated carbocyclic radical composed of one or more rings.
  • An example of the cycloalkyl radical includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like, but not limited thereto.
  • alkylsulfonyl refers to a —SO 2 -alkyl radical, wherein the alkyl is as described above.
  • An example of the alkylsulfonyl radical includes methylsulfonyl, ethylsulfonyl, or the like, but not limited thereto.
  • cycloalkylsulfonyl refers to a —SO 2 -cycloalkyl radical, wherein the cycloalkyl is as described above.
  • An example of the cycloalkylsulfonyl radical includes cyclopropylsulfonyl, cyclohexylsulfonyl, or the like, but not limited thereto.
  • alkylsulfonyloxy refers to a —OSO 2 -alkyl radical, wherein the alkyl is as described above.
  • An example of the alkylsulfonyloxyl radical includes methylsulfonyloxy, ethylsulfonyloxy, or the like, but not limited thereto.
  • hydroxyalkyl refers to alkyl substituted by one or more hydroxys, and an example thereof may include hydroxymethyl or the like.
  • the arylethene derivative may be represented by the following Chemical Formulae 2 to 5:
  • R 1 is (C3-C10)heterocycloalkyl, (C3-C10)heteroaryl, —O—(CH) m —R 11 , —(CH 2 ) m —R 2 , NH—(CH 2 ) m —R 13 , —NHCO—(CH 2 ) n —R 14 , or —SiR 16 R 17 —(CH 2 ) m —R 15 ; R 11 to R 15 are independently of one another (C3-C10)heterocycloalkyl; R 16 and R 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
  • R 1 is (C3-C10)heterocycloalkyl or —O—(CH 2 ) m —R 11 ;
  • R 11 is (C3-C10)heterocycloalkyl;
  • m is an integer of 1 to 3; and the heterocycloalkyl of R 1 and R 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.
  • heterocycloalkyl of the R 1 and R 11 to R 15 may be independently of each other selected from the following structures:
  • R 31 and R 32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
  • the arylethene derivative may be more preferably represented by the following Chemical Formula 6:
  • R 1 is (C3-C10)heterocycloalkyl or —O—(CH 2 ) m —R 11 ;
  • R 11 is (C3-C10)heterocycloalkyl
  • n is an integer of 1 to 3;
  • heterocycloalkyl of R 1 and R 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;
  • 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
  • R 2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy.
  • R 1 and R 11 may be independently of each other heterocycloalkyl selected from the following structures:
  • R 31 and R 32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
  • Ar is (C6-C20)aryl, in which the aryl 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 (C
  • R 2 may be hydroxy
  • R 2 may be hydroxy, and R 1 may be heterocycloalkyl selected from the following structures:
  • R 31 and R 32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
  • R 2 is hydroxy and R 1 is —O—(CH 2 ) m —R 11 ; m is an integer of 1 or 2; and R 11 is heterocycloalkyl selected from the following structures:
  • R 31 and R 32 are independently of each other hydrogen, (C1-C10)alkyl, (C1-C10)alkoxycarbonyl, or hydroxy(C1-C10)alkyl; and L is O or S.
  • Ar is (C6-C12)aryl, in which the aryl 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)alkylsulfonyl
  • R 31 and R 32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
  • Ar is (C6-C12)aryl, in which the aryl 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)alkylsulfony
  • R 31 and R 32 are independently of each other hydrogen, (C1-C20)alkyl, (C1-C10)alkoxycarbonyl, or hydroxy(C1-C10)alkyl; and L is O or S.
  • the arylethene derivative may be specifically selected from the following structure, but not limited thereto:
  • the arylethene derivative may be preferably selected from the following structures:
  • the arylethene derivative may be more preferably selected from the following structures:
  • the arylethene derivative may be still more preferably selected from the following structures:
  • the arylethene derivative according to the present invention may be used in the form of a prodrug, solvate, and pharmaceutically acceptable salt thereof for increasing in vivo absorption or increasing solubility, the prodrug, the solvate, and the pharmaceutically acceptable salt also fall within the scope of the present invention.
  • the arylethene derivative has a chiral carbon, the stereoisomer thereof exists, and the stereoisomer also falls within the scope of the present invention.
  • the arylethene derivative according to the present invention may be prepared by various methods known in the art depending on the kinds of substituents, and as an example thereof, the following Reaction Formulae 1 to 21 are illustrated, and the following preparation methods do not limit a method of preparing the arylethene derivative of the present invention.
  • the specific details will be described in the following Examples 1 to 121.
  • the preparation methods presented in the following Reaction Formulae 1 to 21 are only illustrative, and it is apparent to a person skilled in the art that the preparation methods may be easily modified by a person skilled in the art depending on certain substituents.
  • the present invention provides an ERR ⁇ inhibitor composition
  • an ERR ⁇ inhibitor composition comprising the arylethene derivative of Chemical Formula 1, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating an ERR ⁇ -mediated disease, comprising the arylethene derivative of Chemical Formula 1, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof as an active ingredient, and further a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable composition comprising them as an active ingredient may be useful for treating or preventing ERR ⁇ -mediated diseases, for example, metabolic diseases such as obesity, diabetes, hyperlipidemia, fatty liver, or atherosclerosis.
  • a pharmaceutical composition for preventing or treating retinopathy includes: the arylethene derivative of Chemical Formula 1 which may effectively inhibit an ERR ⁇ activity, or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof as an active ingredient.
  • the “retinopathy” is a disease caused by chronic or acute damage to a retina of an eye.
  • the retinopathy may involve ongoing inflammation and vascular remodeling.
  • retinopathy also appears as visual manifestation of a systemic disease such as diabetes or hypertension.
  • the kind of retinopathy includes diabetic retinopathy, retinopathy of prematurity (ROP), or the like.
  • the diabetic retinopathy refers to an eye complication in which decreased visual acuity occurs due to a disorder following a peripheral circulatory disorder caused by diabetes which is a systemic disease.
  • Diabetic retinopathy has no symptoms at the beginning, but as macular invasion occurs, decreased visual acuity appears.
  • Diabetic retinopathy involves various pathological features such as microaneurysm, phlebectasia, retinal hemorrhage, retinal infarction, macular edema, neovascularization, vitreous hemorrhage, traction membrane, or the like, and when these phenomena are observed as ocular fundus symptoms, diabetic retinopathy is diagnosed.
  • the diabetic retinopathy is a disease caused by a complex combination of various symptoms as described above, and it is unclear whether the disease is treated when one of these symptoms is alleviated.
  • retinopathy of prematurity is proliferative retinopathy which may occur in premature babies, in particular low birth weight infants.
  • retinopathy of prematurity is proliferative retinopathy which may occur in premature babies, in particular low birth weight infants.
  • abnormal fibrovascular proliferation occurs at a border of an angiogenic site and a non-angiogenic site of a retina, whereby the retina is detached, eventually leading to blindness.
  • the arylethene derivative according to the present invention may be used in the form of a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt may be prepared by a conventional method in the art, and may include for example, a salt with an inorganic acid such as a hydrochloric acid, a bromic acid, a sulfuric acid, sodium hydrogen sulfate, a phosphoric acid, a nitric acid, or a carbonic acid, a salt with an organic acid such as a formic acid, an acetic acid, a trifluoroacetic acid, a propionic acid, an oxalic acid, a succinic acid, a benzoic acid, a citric acid, a maleic acid, a malonic acid, a mandelic acid, a cinnamic acid, a stearic acid, a palmitic acid, a glycolic acid, a glutamic acid, a tartaric acid, a gluconic acid, a lactic acid
  • the arylethene derivative of the present invention may exist in a solvated form, for example, a hydrated form and a non-solvated form, and the solvate of the arylethene derivative according to the present invention includes all solvated forms having a pharmaceutical activity. That is, the arylethene derivative of the present invention is dissolved in water-compatible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, and then a free acid or a free base is added thereto to perform crystallization or recrystallization, thereby forming a solvate including a hydrate. Accordingly, as a novel compound of the present invention, stoichiometric solvates including hydrates may be included, in addition to a compound containing various amounts of water which may be prepared by a method such as lyophilization.
  • water-compatible solvent such as methanol, ethanol, acetone, and 1,4-dioxane
  • the arylethene derivative of the present invention may have a chiral center, and exist as a racemate, a racemic mixture, and individual enantiomer or diastereomer. These isomers may be separated or resolved by a common method, and an optional predetermined isomer may be obtained by a common synthesis method or stereospecific or asymmetric synthesis. These isomer forms and mixtures thereof are all included in the scope of the present invention.
  • the arylethene derivative of the present invention may be administered in the form of a prodrug which is decomposed in a human or animal body to provide the compound of the present invention.
  • the prodrug may be used for modifying or improving a physical and (or) pharmacokinetic profile of a parent compound, and may be formed when the parent compound contains an appropriate group or substituent which may be derived to form the prodrug.
  • the pharmaceutical composition of the present invention may be formulated into a conventional preparation in the pharmaceutical field, for example, a preparation for oral administration such as a tablet, a pill, a hard/soft capsule, a liquid, a suspension, an emulsion, syrup, granules, and elixirs, or a preparation for parenteral administration of a sterile aqueous or oily solvent for intravenous, subcutaneous, sublingual, intramuscular, or intradermal administration, by adding conventional non-toxic pharmaceutically acceptable carrier, excipient, and the like to the arylethene derivative represented by Chemical Formula 1, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof.
  • a preparation for oral administration such as a tablet, a pill, a hard/soft capsule, a liquid, a suspension, an emulsion, syrup, granules, and elixirs
  • the pharmaceutically acceptable carrier which may be used in the pharmaceutical composition of the present invention is commonly used in formulation, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and/or mineral oil, and the like, but not limited thereto.
  • the excipient which may be used in the pharmaceutical composition of the present invention may be a sweetener, a binder, a solubilizer, a solubilizing aid, a wetting agent, an emulsifier, an isotonic agent, an adsorbent, a disintegrant, an antioxidant, a preservative, a lubricant, a filler, a fragrance, or the like, and a ratio and properties of the excipient may be determined by solubility and chemical properties of a selected tablet, a selected administration route, and standard pharmaceutical practice.
  • excipient may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethyleneglycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, or the like.
  • composition of the present invention may be formulated into a parenteral administration form, and in this case, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, topical administration, or the like may be used, and ocular administration or the like may be used, in that the composition is a therapeutic agent for retinopathy, but not limited thereto.
  • the pharmaceutical composition may be produced into a solution or suspension by mixing the active ingredient, that is, the arylethene derivative of Chemical Formula 1, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof with water together with a stabilizer or a buffer, and the solution or suspension may be produced into a unit dosage form of an ampoule or vial.
  • the pharmaceutical composition of the present invention may be sterilized, or further include an adjuvant such as a preservative, a stabilizer, a hydrating agent or an emulsifying accelerator, a salt for regulating osmotic pressure, and/or a buffer, and other therapeutically useful materials, and may be formulated according to a conventional method of mixing, granulating or coating.
  • an adjuvant such as a preservative, a stabilizer, a hydrating agent or an emulsifying accelerator, a salt for regulating osmotic pressure, and/or a buffer, and other therapeutically useful materials
  • a dosage of the arylethene derivative represented by Chemical Formula 1, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof as the active ingredient in the pharmaceutical composition according to the present invention for mammals including a human may be varied depending on the age, weight, gender, dosage form, health status, and disease severity of a patient.
  • an effective amount of 0.001 to 100 mg/kg (body weight), preferably 0.01 to 100 mg/kg (body weight) per day may be included in the pharmaceutical composition, and the pharmaceutical composition may be divided into once or twice per day, and administered via an oral or parenteral route.
  • the amount may be increased or decreased depending on the administration route, severity of the disease, gender, weight, age, and the like, and thus, the administration amount in no way limits the scope of the present invention.
  • the present invention provides a pharmaceutical composition for treating thyroid cancer comprising the arylethene derivative of Chemical Formula 1 which may specifically and significantly inhibit an ERR ⁇ transcriptional activity, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and used in combination of radioactive iodine.
  • the present invention provides a kit for treating thyroid cancer comprising the arylethene derivative of Chemical Formula 1 which may specifically and significantly inhibit an ERR ⁇ transcriptional activity, or the prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and radioactive iodine.
  • the arylethene derivative according to the present invention regulates expression of endogenous ERR ⁇ protein to regulate mitogen-activated protein (MAP) kinase, and improves a sodium iodide symporter (NIS) function to increase membrane-localized NIS, thereby increasing a radioactive iodine uptake when treating thyroid cancer.
  • MAP mitogen-activated protein
  • NIS sodium iodide symporter
  • Step 1 Preparation of [4-[4-(2,2-dimethylpropanoyloxy)benzoyl]phenyl] 2,2-dimethylpropanoate (A-1)
  • Step 3 Preparation of (E)-5-[4-(2,2-dimethylpropanoyloxy)phenyl]-5-(4-hydroxyphenyl)-4-phenyl-pent-4-enoate (A-3)
  • Zinc (8.8 g, 134 mmol) was added to tetrahydrofuran (130 mL), the temperature was lowered to 0° C., and titanium chloride (7.35 mL, 67 mmol) was slowly added thereto.
  • the reaction solution was heated at 60° C. for 2 hours, and then compound A-2 (5 g, 16.8 mmol) and methyl-3-benzoylpropionate (4.8 g, 25.1 mmol) were added thereto.
  • the reaction solution was heated at 50° C. for 1 hour.
  • the reaction mixture was poured into a 10% aqueous potassium carbonate solution, stirring was performed for 30 minutes, and filtration was performed using celite.
  • Step 4 Preparation of (E)-tert-butyl 4-(2-(4-(5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl)phenoxy)ethyl)piperazine-1-carboxylate (A-4)
  • Step 5 Preparation of (Z)-4-(5-hydroxy-1-(4-(2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)ethoxy)phenyl)-2-phenylpent-1-en-1-yl)phenol (6a)
  • 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 4 mg of the desired compound 7a (17%).
  • Step 1 Preparation of (4-bromophenyl)(4-methoxyphenyl)methanone (B-1)
  • Step 3 Preparation of (E)-methyl 5-(4-bromophenyl)-5-(4-hydroxyphenyl)-4-phenylpent-4-enoate (B-3)
  • Step 4 Preparation of (E)-methyl 5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-enoate (B-4)
  • Step 5 Preparation of (E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-en-1-ol hydrochloride salt (13a)
  • Step 1 Preparation of methyl 5-(4-(pivaloyloxy)phenyl)pent-4-ynoate (C-1)
  • 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)
  • 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)
  • Step 1 Preparation of methyl (E)-5-(4-bromophenyl)-4-phenyl-5-(4-(piperazin-1-yl)phenyl)pent-4-enoate (D-2)
  • Step 2 Preparation of (E)-5-(4-bromophenyl)-4-phenyl-5-(4-(piperazin-1-yl)phenyl)pent-4-en-1-ol (20a)
  • Step 1 Preparation of methyl (E)-5-(4-(1-isopropylazetidin-3-yl)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (E-2)
  • Step 2 Preparation of (E)-4-(5-hydroxy-1-(4-(1-isopropylazetidin-3-yl)phenyl)-2-phenylpent-1-en-1-yl)phenol (22a)
  • 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 1 mg of the desired compound 27a (17%).
  • Step 1 Preparation of methyl (E)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (H-2)
  • Step 2 Preparation of (E)-4-(5-hydroxy-1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-phenylpent-1-en-1-yl)phenol (30a)
  • Step 1 Preparation of methyl (Z)-5-(indolin-5-yl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (I-2)
  • Step 2 Preparation of methyl (Z)-4-phenyl-5-(4-(pivaloyloxy)phenyl)-5-(1-(2-(pyrrolidin-1-yl)ethyl)indolin-5-yl)pent-4-enoate (I-3)
  • Step 3 Preparation of (Z)-4-(5-hydroxy-2-phenyl-1-(1-(2-(pyrrolidin-1-yl)ethyl)indolin-5-yl)pent-1-en-1-yl)phenol (33)
  • Step 1 Preparation of methyl (Z)-5-(1H-indol-5-yl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (J-2)
  • Step 2 Preparation of methyl (Z)-4-phenyl-5-(1-(2-(piperidin-1-yl)ethyl)-1H-indol-5-yl)-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (J-3)
  • Step 3 Preparation of (Z)-4-(5-hydroxy-2-phenyl-1-(1-(2-(piperidin-1-yl)ethyl)-1H-indol-5-yl)pent-1-en-1-yl)phenol (36)
  • Step 1 Preparation of methyl (E)-5-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (K-2)
  • Step 2 Preparation of (Z)-4-(1-(4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)ethoxy)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol (38a)
  • Step 1 Preparation of methyl (Z)-5-(4-(dimethyl((4-methylpiperazin-1-yl)methyl)silyl)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (L-2)
  • Step 2 Preparation of (Z)-4-(1-(4-(dimethyl((4-methylpiperazin-1-yl)methyl)silyl)phenyl)-5-hydroxy-2-phenylpent-1-en-1-yl)phenol (42a)
  • Step 1 Preparation of methyl (E)-4-phenyl-5-(4-(2-(piperidin-1-yl)acetamido)phenyl)-5-(4-(pivaloyloxy)phenyl)pent-4-enoate (M-2)
  • Step 2 Preparation of (E)-N-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)-2-(piperidin-1-yl)acetamide (44)
  • 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 0.5 mg of the desired compound 45 (6%).
  • Step 1 Preparation of tert-butyl (3aR,6aS)-5-(2-((4-((E)-5-methoxy-5-oxo-2-phenyl-1-(4-(pivaloyloxy)phenyl)pent-1-en-1-yl)phenyl)amino)-2-oxoethyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (N-1)
  • Step 2 Preparation of tert-butyl (3aR,6aS)-5-(2-((4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)amino)-2-oxoethyl)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (N-2)
  • Step 3 Preparation of 2-((3aR,6aS)-3a,6a-dimethylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)acetamide (46)
  • Step 1 Preparation of (Z)-5-(4-aminophenyl)-5-(4-(4-isopropylpiperazin-1-yl)phenyl)-4-phenylpent-4-en-1-ol (O-1)
  • Step 2 Preparation of (Z)-1-(4-(5-hydroxy-1-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-phenylpent-1-en-1-yl)phenyl)guanidine (50)
  • Step 1 Preparation of tert-butyl ((E)-((tert-butoxycarbonyl)imino)(4-(4-((E)-5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-1-en-1-yl)phenyl)piperazin-1-yl)methyl)carbamate (P-1)
  • Step 2 Preparation of (E)-4-(4-(5-hydroxy-1-(4-hydroxyphenyl)-2-phenylpent-i-en-1-yl)phenyl)piperazine-1-carboximidamide (52)
  • the arylethene derivative of the present invention was sequentially added to a 384 well plate from a concentration of 10 ⁇ M to a final concentration of two-fold dilution. Then, a GST-bound ERR gamma ligand-binding domain (LBD) was added to a final concentration of 5 nM, and a fluorescein-conjugated coactivator PGC1a and a Tb-a-GST antibody were added to 500 nM and 5 nM, respectively. After all reagents were added, a reaction was carried out with gentle shaking at 20° C. for 1 hour, and after the reaction, a binding activity was measured by a TR-FRET method.
  • LBD ERR gamma ligand-binding domain
  • ER alpha binding assay In an ER alpha binding assay, a GST-bound ER alpha ligand-binding domain (LBD) was added to a 384 well plate to which the arylethene derivative of the present invention was added to a final concentration of 7.3 nM. Then, a fluorescein-conjugated coactivator PGC1a and a Tb-a-GST antibody were added to 250 nM and 5 nM, respectively, and beta-estradiol as an agonist was added to a final concentration of 4 nM. All subsequent experiments was the same as the ERR gamma binding assay.
  • AD293 was cultured in a 24-well plate for 24 hours, using a DMEM High glucose culture medium (Hyclone, USA) to which 0.5% FBS was added at a concentration of 9 ⁇ 10 4 /well.
  • the culture medium was replaced with a DMEM High glucose culture medium to which 10% FBS was added, treatment was performed with a mixture of a TransIT-LT1 transfection reagent (Mirus, USA) and pCMX-Gal4-ERR ⁇ , pFR-luciferase reporter plasmid, pCMV- ⁇ -gal, and culturing was performed for 24 hours.
  • Cpds refers to an inverse agonist functional activity when the compound was treated
  • Ref 5182 refers to an activity of a reference compound GSK5182 for data verification for every essay
  • Cpds/Ref 5182 refers to an activity degree of the arylethene derivative of the present invention, relative to the reference compound.
  • Human liver microsomes (0.25 mg/ml) with 0.1 M phosphate buffer solution (pH 7.4), a substrate drug cocktail of five drug metabolizing enzymes (Phenacetin 50 ⁇ M, Diclofenac 10 ⁇ M, S-mephenytoin 100 ⁇ M, Dextromethorphan 5 ⁇ M, Midazolam 2.5 ⁇ M), and the arylethene derivative of the present invention were added at concentrations of 0 ⁇ M and 10 ⁇ M, respectively, culturing was performed at 37° C. for 5 minutes in advance, a NADPH generation system solution was added, and culturing was performed at 37° C. for 15 minutes.
  • a substrate drug cocktail of five drug metabolizing enzymes Phenacetin 50 ⁇ M, Diclofenac 10 ⁇ M, S-mephenytoin 100 ⁇ M, Dextromethorphan 5 ⁇ M, Midazolam 2.5 ⁇ M
  • the arylethene derivative of the present invention were added at concentrations of
  • liver microsomes Human, Dog, Rat, Mouse 0.5 mg/ml
  • a 0.1 M phosphate buffer solution pH 7.4
  • the arylethene derivative of the present invention were added to a concentration of 1 ⁇ M, culturing was performed at 37° C. for 5 minutes in advance, a NADPH regeneration system solution was added thereto, and culturing was performed at 37° C. for 30 minutes.
  • PAMPA is a method which has been developed for testing cell membrane permeability of a material in a test tube, and has been performed using a lipid tri-layer PVDF membrane available from Corning Gentest (NY, US), the used reagents were all purchased from Sigma (MO, US).
  • a test material is diluted in PBS (pH 7.4) to a final concentration of 10 mM, 300 mL of the solution is added to the bottom well of a 96-transwell equipped with a PVDF membrane, and 200 mL of PBS is added to the upper well. Then, a plate is reacted at 25° C.
  • E-4031 (effective IC50: 10-90 nM) compound as a positive control was diluted stepwise with 3-fold, a pre-prepared membrane containing a hERG channel and a fluorescent tracer were mixed and reacted for 4 hours, and then a polarization values for each concentration were measured to obtain IC 50 .
  • fluorescence intensity (excitation at 530 nm, emission at 590 nm) at a concentration of stepwise diluted 16 points was measured and compared with a DMSO solvent control.
  • An oral administration group fasts the day before.
  • a drug is orally administered at a dose of 10 mg/kg (oral zondec)
  • blood of the intravenous administration group was collected through a jugular vein 8 times at 0.08, 0.25, 0.5, 1, 2, 4, 6, and 8 hours.
  • One collected blood amount is 400 to 500 ul.
  • blood of the oral administration group was collected through a jugular vein 6 times at 0.25, 0.5, 1, 4, 6 and 8 hours.
  • One collected blood amount is 400 to 500 ul.
  • Each blood is mixed with a 3.8% sodium citrate solution and stored on ice.
  • the supernatant plasma was injected into a LC-MS/MS system and the drug is analyzed.
  • CAL-62 which is an anaplastic thyroid cancer cell line was purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen. The cell lines were all maintained in a DMEM medium highly supplemented with 10% FBS, 1% antibiotic-antifungal agent (Hyclone), at 37° C. under the atmosphere of 5% CO 2 .
  • a retrovirus from which an enhanced firefly luciferase gene (effluc) is expressed was treated with CAL-62 cells to establish cell lines in which the effluc genes are stably expressed. The thus-established cell lines were referred to as CAL-62/effluc cells.
  • the cells were plated in a 24-well plate for 24 hours, treated with compound 18a, produced into a 100 mM stock solution in DMSO, and stored at ⁇ 80° C. for 24 hours. After adsorbing a drug-containing medium, the cells were washed with 1 mL of HBSS, and incubated with 500 t of a Hank' balanced salt solution (HBSS) containing 0.5% bovine serum albumin (bHBSS), 3.7 kBq carrier-free 125 I (Perkin-Elmer), and 10 ⁇ mol/L of sodium iodide (inactive 740 MBq/mmol) at 37° C. for 30 minutes.
  • HBSS Hank' balanced salt solution
  • bHBSS bovine serum albumin
  • Perkin-Elmer 3.7 kBq carrier-free 125 I
  • 10 ⁇ mol/L of sodium iodide active 740 MBq/mmol
  • the cells were washed twice with ice-cold bHBSS, and lysed with 500 ⁇ l of 2% sodium dodecyl sulfate (SDS). Radioactivity was measured using a gamma counter (Cobra II; Canberra Packard, Packard Bioscience). The radioactivity of the cells was normalized using a total protein concentration determined by a BCA kit (Pierce Protein Biology).
  • the cells were treated with compound 18a at various concentrations (vehicle, 6, 12 uM), and then a 125 I uptake test was performed as described above.
  • the cells were pre-incubated with 300 ⁇ M KClO 4 (as a specific inhibitor to NIS) for 30 minutes to inhibit iodine uptake, and then a 125 I uptake test was performed as described above.
  • 300 ⁇ M KClO 4 as a specific inhibitor to NIS
  • 125 I uptake inhibition assay by MAK kinase inhibitor The cells were pre-incubated with PD98059 or U0126 (as a specific inhibitor to MAP kinase) for 30 minutes to inhibit iodine uptake, and then a 125I uptake test was performed as described above.
  • each target gene is as follows: ERR ⁇ (forward, 5′-CAG ACG CCA GTG GGA GCT A-3′; reverse, 5′-TGG CGA GTC AAG TCC GTT CT-3′), NIS (forward, 5′-TCT AAC CGA TGC TCA CCT CTT CTG-3′; reverse, 5′-AGA TGA TGG CAC CTC CTT GAA CC-3′), and acidic ribosomal protein 36B4 (forward, 5′-CCA CGC TGC TGA ACA TGC T-3′; reverse, 5′-TCG AAC ACC TGC TGG ATG AC-3′). Each target gene was normalized using a 36B4 gene.
  • the cells were plated in a 6-well plate, and allowed to stand for 24 hours.
  • the cells were treated with 12 ⁇ M compound 18a for 24 hours, the drug-containing medium was discarded, and the cells were washed twice with PBS. Thereafter, the medium was replaced with DMEM for 6 hours in the presence or absence of 50 ⁇ Ci 131 I (KIRAMS, Korea).
  • the cells were washed with cold bHBSS, and allowed to stand in a normalized culture medium for a time corresponding to six doublings. Finally, the cells were fixed in a 4% paraformaldehyde (PFA) solution and stained with 0.05% crystal violet. Control colonies having more than 50 cells and 131 I-treated colonies were counted.
  • PFA paraformaldehyde
  • the cells were treated with or without compound 18a for 24 hours, washed twice with cold PBS, and lysed with a RIPA (Roche) buffer containing a complete protease inhibitor cocktail.
  • RIPA Roche
  • samples were prepared using a protein biotinylation kit (EZ-LinkTM Sulfo-NHS-Biotin, Thermo Scientific) according to the manufacturer's instruction.
  • any one of non-treated cells or treated cells were washed twice with ice-cold PBS/CM (PBS containing 0.1 mM calcium chloride and 1 mM magnesium chloride, pH 7.3), and incubated with EZ link NHS-sulfo-SS-biotin in PBS/CM (1 mg/mL) at 4° C. for 30 minutes.
  • the reaction was quenched by washing twice using cold 100 mM glycine in PBS/CM, and further incubated with 100 mM glycine in PBS/CM at 4° C. for 20 minutes. Thereafter, the cells were constantly shaken at 4° C.
  • the beads were washed three times using a RIPA buffer, the bound protein was eluted using 50 ⁇ L of Laemmli buffer (62.5M Tris, pH 6.8; 20% glycerol; 2% SDS; 5% b-mercaptoethanol; and 0.01% bromophenol blue) at room temperature for 30 minutes. Equivalent amounts of the total cell membrane protein and biotinylated cell membrane protein were loaded on each lane, and resolved by a Bis-Tris gel (Invitrogen) with a 4-12% slope. The protein was moved to a 0.2 ⁇ m PVDF membrane (Invitrogen).
  • Laemmli buffer 62.5M Tris, pH 6.8; 20% glycerol; 2% SDS; 5% b-mercaptoethanol; and 0.01% bromophenol blue
  • the membrane was incubated with a primary rat monoclonal human NIS-specific antibody (dilution 1:1000, Thermo Scientific, Catalog#: MS-1653-P1, clone: FP5A), and then incubated with a HRP-conjugated secondary antibody at room temperature.
  • ECL-Plus (Amersham Pharmacia) was used for detecting a peroxidase activity, depending on the manufacturer's method.
  • an equivalent amount of protein was loaded to each lane, and resolved by a Bis-Tris gel (Invitrogen) with a 4-12% slope.
  • the protein was moved to a 0.2 ⁇ m PVDF membrane (Invitrogen).
  • the membrane was incubated with a primary antibody (ERR ⁇ , pERK1/2, ⁇ -actin) at 4° C. for one night, and then incubated with an appropriate HRP-conjugated secondary antibody at room temperature. According to the manufacturer's protocol, the peroxidase activity was detected using ECL-Plus. A band density was determined using an ImageJ software.
  • Nude mice (Balb/c nu/nu, female, 6 weeks old) were used, and all animals were normally raised in DMRC center animal laboratory of Kyungbuk National University Hospital in Chilgok. 5 ⁇ 10 6 CAL-62/effluc cells were subcutaneously injected into the left femoral region of the nude mouse to form a tumor. The tumor was extracted, divided into small pieces (20 mg or more), and then intradermally injected into the nude mouse to form a tumor.
  • the CAL-62/effluc mouse tumor model was divided into the following groups: Group 1: vehicle, Group 2: 100 mpk compound 18a, Group 3: 100 mpk compound 18a.
  • the vehicle (100% PEG) and compound 18a 100 mpk, 200 mpk were orally administered daily for 6 days.
  • optical imaging bioluminescent imaging
  • an organ distribution study (Bio-distribution study) was performed as follows. After finally administrating the drug, 125 I (5 uCi/mouse) was administered to the mouse by intravenous injection on the next day. After 4 hours of administration, all organs including a parent tumor were extracted, and each organ was weighed. Thereafter, each organ was transferred to a 5 mL test tube, and radioactivity in the organ was measured using a gamma counter. A 125 I uptake degree in the organ was expressed by percentage injected dose per gram (% ID/g).
  • D-luciferin 3 mg/mouse was intraperitoneally injected to the mouse. After about 10 minutes of injection, the mouse was anesthetized by inhalation (1-2% isoflurane gas), and then positioned on a IVIS Lumina III (PerkinElmer) imaging bed. The time for obtaining the image was automatically set, and then an optical image was obtained.
  • a Living imaging software version 2.12, PerkinElmer was used to quantify an optical image signal from the tumor.
  • a significant increase in a phosphorylated MPP kinase level such as p44 and p42 ERK was found in ATC cells treated with compound 18a ( FIG. 8 ).
  • the relative increase of the phosphorylated forms oERK1 and ERK2f was 2.2 times and 2.8 times, respectively ( FIG. 9 ).
  • radioactive iodine uptake increase ( FIGS. 10 and 11 ) and the relative increase of the phosphorylated form of ERK1 and ERK2 by compound 18a were completely inhibited by selective MEK inhibitors, PD98059 and U0126 ( FIGS. 12 and 13 ).
  • Compound 18a derived a sharp increase in cell membrane-localized NIS protein having mature and immature forms in ATC cells, as compared with control cells ( FIG. 14 ).
  • Qualitative analysis of band intensity showed increases in membrane fully glycosylated and partially glycosylated NIS protein in CAL62 cells by 8.1 times and 6.4 times, respectively ( FIG. 15 ).
  • a clone formation assay using I-131 showed a minimal cytotoxic effect in CAL62 cells treated with any one of compounds 18a and I-131 alone ( FIG. 16 ).
  • Relative colony formability of I-131 or GSK5182 group was 92.9 ⁇ 5.8% and 94.5 ⁇ 10.8%, respectively in CAL62 cells ( FIG. 17 ).
  • colony-formability was significantly decreased to about 58.5 ⁇ 7.4% in CAL-62 ( FIG. 17 ).
  • the CAL62-effluc mouse tumor model was divided into the following groups ( FIG. 18 , Group 1: vehicle, Group 2: 100 mpk compound 18a, Group 3: 200 mpk compound 18a). To the mice of each group, the vehicle (100% PEG) and compound 18a (100 mpk, 200 mpk) were orally administered daily for 6 days. In order to observe a difference in tumor growth between before administration and after administration, optical imaging (bioluminescent imaging) was performed. After finally administering the drug, a radioactive isotope (1-125) was administered to the mice on the next day, and after 2 hours, the mice were sacrificed, all organs thereof were extracted, and a radiation level was measured with a gamma counter.
  • radioactive iodine uptake in CAL62 tumor was concentration-dependently increased by treatment with compound 18a ( FIG. 19 ).
  • the radioactive uptake was increased by 4.4 times and 16.2 times in the 100 mpk and 200 mpk compound 18a groups, respectively.
  • significant tumor growth inhibitory efficiency was shown in the compound 18a group ( FIG. 20 ).
  • Drug concentration-dependent tumor growth inhibitory efficiency was shown ( FIG. 21 ).
  • An abrupt weight change in the mice was not shown in all groups ( FIG. 22 ).
  • the arylethene derivative of the present invention is a novel compound, and exhibits very high inhibitory activity to ERR ⁇ as compared with a conventional GSK5182 compound, and at the same time, shows an effect of improved drug stability, pharmacological activity and toxicity.
  • the arylethene derivative may be useful as efficient prophylactic agent and therapeutic agent for diseases mediated by ERR ⁇ , in particular, metabolic diseases such as obesity, diabetes, hyperlipidemia, fatty liver, or atherosclerosis, as well as retinopathy, without side effects.
  • the arylethene derivative of the present invention may specifically and significantly inhibit ERR ⁇ transcriptional activity as compared with GSK5182, and as a result, cause a radioactive isotope uptake increase from a cellular level to an animal level. Accordingly, the arylethene derivative of the present invention may significantly increase a treatment effect of radioactive iodine therapy for treating cancer, and when administered to cancer cells, may effectively produce cancer cells having an improved sodium iodide symporter (NIS) function, thereby having an excellent effect of being more easily applied to related research and clinical practice for treating anaplastic thyroid cancer.
  • NIS sodium iodide symporter
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US11413270B2 (en) 2020-06-22 2022-08-16 Novmetapharma Co., Ltd. Method for the treatment of pancreatitis

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US4696949A (en) * 1982-06-25 1987-09-29 Farmos Group Ltd. Novel tri-phenyl alkane and alkene derivatives and their preparation and use
WO1992006068A1 (en) * 1990-10-01 1992-04-16 Board Of Regents, The University Of Texas System High affinity tamoxifen derivatives and uses thereof
US20080255089A1 (en) * 2005-11-22 2008-10-16 Smithkline Beecham Corporation Triphenylethylene Compounds Useful as Selective Estrogen Receptor Modulators

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TW593256B (en) * 1999-11-16 2004-06-21 Hormos Medical Oy Ltd Triphenylalkene derivatives and their use as selective estrogen receptor modulators
KR101579008B1 (ko) * 2013-09-25 2015-12-22 경북대학교 산학협력단 ERR-γ 저해제를 포함하는, 망막병증의 예방 또는 치료용 약학적 조성물 및 이의 용도

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US4696949A (en) * 1982-06-25 1987-09-29 Farmos Group Ltd. Novel tri-phenyl alkane and alkene derivatives and their preparation and use
WO1992006068A1 (en) * 1990-10-01 1992-04-16 Board Of Regents, The University Of Texas System High affinity tamoxifen derivatives and uses thereof
US20080255089A1 (en) * 2005-11-22 2008-10-16 Smithkline Beecham Corporation Triphenylethylene Compounds Useful as Selective Estrogen Receptor Modulators

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Publication number Priority date Publication date Assignee Title
US11413270B2 (en) 2020-06-22 2022-08-16 Novmetapharma Co., Ltd. Method for the treatment of pancreatitis

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