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

a technology of aryl ethene and derivative, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, organic chemistry, etc., can solve the problems of poor prognosis, poor drug stability, and no satisfactory result so far, and achieves improved drug stability, pharmacological activity and toxicity, and inhibit the activity of err transcriptional activity

Inactive Publication Date: 2019-06-06
HWANG SUNG YEOUN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is a new compound that has high inhibitory activity against ERRγ, a receptor involved in metabolic diseases such as obesity, diabetes, and hyperlipidemia, as well as retinopathy and atherosclerosis. Compared to a conventional compound, the arylethene derivative has improved drug stability, pharmacological activity, and toxicity. It can also increase the treatment effect of radioactive iodine therapy for cancer and improve sodium iodide symporter function in cancer cells. Overall, the arylethene derivative is a promising therapeutic agent for diseases influenced by ERRγ with no side effects.

Problems solved by technology

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.
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.
However, when GSK5182 was administered to an ATC mouse tumor model, a radioiodine uptake in the tumor was not increased.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

examples 2 to 13

[0142]Compounds 6b to 6m were prepared according to the process of Example 1. Compounds 6b to 6m were prepared by the same process, except that in step 4 of Example 1, 2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)ethanol was replaced with different ethanol. Identification data of the thus-prepared compounds 6a to 6m is shown in the following Table 1.

TABLE 1CmpdExampleNo.RIdentification data16a1H-NMR (CD3OD, 400 MHz) δ 7.22-7.11 (m, 7H), 7.05 (d, J = 4.1 Hz, 2H), 6.80 (d, J = 6.5 Hz, 2H), 3.77 (s, 4H), 3.43 (m, 6H), 2.56 (m, 2H), 1.59 (m, 2H), 1.49 (s, 9H). MS (ESI) m / z: 515 [M + H]+.26b1H-NMR (CD3OD, 400 MHz) δ 7.19-7.08 (m, 5H), 7.05-7.02 (m, 2H), 6.85-6.78 (m, 4H), 6.66-6.63 (m, 2H), 4.19 (t, J = 4.6 Hz, 2H), 3.50-3.37 (m, 12H), 2.94 (s, 3H), 2.53 (t, J = 2.8 Hz, 2H), 1.53 (m, 2H). MS (ESI) m / z: 473 [M + H]+.36c1H-NMR (DMSO-d6, 400 MHz) δ 7.17 (m, 2H), 7.10 (m, 3H), 6.97 (d, J = 8.5 Hz, 2H), 6.75 (m, 4H), 6.66 (d, J = 8.8 Hz, 2H), 4.24 (t, J = 4.3 Hz, 2H), 3.93 (m, 2H), 3.74 (m, 2H)...

example 14

[Example 14] Preparation of (Z)-4-(5-hydroxy-2-phenyl-1-(4-(2-(piperazin-1-yl)ethoxy)phenyl)pent-1-en-1-yl)phenol 2hydrochloride salt (7a)

[0143]

[0144]Compound 6a (28 mg, 0.05 mmol) was added to dichloromethane (5 mL), the temperature was lowered to 0° C., and trifluoroacetic acid (0.08 mL, 1.00 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 4 mg of the desired compound 7a (17%).

[0145]1H-NMR (CD3OD, 400 MHz) δ 7.16-7.07 (m, 5H)...

example 15

[Example 15] Preparation of (E)-5-(4-(2-(aziridin-1-yl)ethoxy)phenyl)-5-(4-bromophenyl)-4-phenylpent-4-en-1-ol hydrochloride salt (13a)

[0146]

Step 1: Preparation of (4-bromophenyl)(4-methoxyphenyl)methanone (B-1)

[0147]4-Bromobenzoyl chloride (8.2 g, 50.9 mmol) and aluminum chloride (6.1 g, 50.9 mmol) were dissolved in dichloromethane (90 mL), and anisole (5 g, 46.2 mmol) was slowly added thereto. Stirring was performed for 3 hours, the temperature was lowered to 0° C., and 1N HCl (50 mL) was added thereto. Ethyl acetate was added to extract an aqueous layer, which was dried with anhydrous Na2SO4 and filtered. The solvent was distilled under reduced pressure to obtain a residue, which was purified using column chromatography, thereby obtaining 11 g of the desired compound B-1 (99%).

Step 2: Preparation of (4-bromophenyl)(4-hydroxyphenyl)methanone (B-2)

[0148]Compound B-1 (10 g, 34.3 mmol) was added to toluene (80 mL), the temperature was lowered to 0° C., and aluminum chloride (11.5 g, ...

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Abstract

The present invention relates to an aryl ethene derivative, for inhibiting an estrogen-related receptor gamma (ERRγ) activity, a prodrug of same, a solvate of same, a stereoisomer of same or pharmaceutically acceptable salts of same, and a pharmaceutical composition containing same as an active ingredient.

Description

TECHNICAL FIELD[0001]The present invention relates to an arylethene derivative inhibiting an activity of an estrogen-related receptor gamma (hereinafter, referred to as ERRγ), or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound as an active ingredient.BACKGROUND ART[0002]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.[0003]Estrogen-related receptor (ERR) which is one of the orphan nuclear receptors has three types which are ERRα, ERRβ, and ERRγ, and each position to be activated is different.[0004]In particular, ERRγ shows an activity in sp...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K51/02A61K31/495A61K31/445A61K31/5375A61K31/40A61K31/396A61K31/397A61K31/454A61K31/404A61K31/695A61K31/407A61K31/403A61K31/496A61K31/4192A61P35/00
CPCA61K51/025A61P35/00A61K31/445A61K31/5375A61K31/40A61K31/396A61K31/397A61K31/454A61K31/404A61K31/695A61K31/407A61K31/403A61K31/496A61K31/4192A61K31/495A61K31/535C07D241/04C07D203/08C07D265/28
Inventor HWANG, SUNG YEOUNCHO, SUNG JINKIM, JINACHIN, JUNGWOOKHWANG, HAYOUNGLEEJEON, YONG-HYUNLEE, JAETAEJEON, JAE-HANKIM, SANG WOOK
Owner HWANG SUNG YEOUN
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