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6-oxo-1, 6-dihydropyridine derivative, preparation method thereof and application of 6-oxo-1, 6-dihydropyridine derivative in medicine

A compound, alkoxy technology, applied in hyperlipidemia, diabetes, drugs, can solve the problem of not being able to use

Active Publication Date: 2021-11-26
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, T3 has side effects on the heart, and it cannot be used in the treatment of obesity, hypercholesterolemia, and non-alcoholic fatty liver disease

Method used

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  • 6-oxo-1, 6-dihydropyridine derivative, preparation method thereof and application of 6-oxo-1, 6-dihydropyridine derivative in medicine
  • 6-oxo-1, 6-dihydropyridine derivative, preparation method thereof and application of 6-oxo-1, 6-dihydropyridine derivative in medicine
  • 6-oxo-1, 6-dihydropyridine derivative, preparation method thereof and application of 6-oxo-1, 6-dihydropyridine derivative in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0209] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo Generation-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1

[0210]

[0211] first step

[0212] 3-(prop-1-en-2-yl)pyridin-2(1H)-one 1c

[0213] 3-Bromopyridin-2(1H)-one 1a (1.40g, 8.04mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.), isopropenylboronic acid pinacol ester 1b (1.62g, 9.64mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was dissolved in N,N-dimethylformamide (20mL) and water (5mL), potassium phosphate (3.42g, 16.11mmol), tetrakistriphenylphosphine palladium (465mg, 0.40mmol ), stirred at 95°C for 3 hours. After filtration and concentration under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1c (530 mg, yield: 48.7%).

[0214] MS m / z (ESI): 136.1 [M+1].

[0215] 1 H NMR (400MHz, CDCl 3 ):7.58(dd,1H),7.53(dd,1H),6.49(t,1H),5.66(s,1H)...

Embodiment 2

[0240] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-1,2,4- Triazine-3,5(2H,4H)-dione 2

[0241]

[0242] first step

[0243] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo Dai-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 2a

[0244] Compound 1 (86 mg, 0.20 mmol) was dissolved in acetic acid (6 mL), concentrated hydrochloric acid (1 mL), and stirred at 120° C. for 2 hours. The reaction of the raw materials was not complete, acetic acid (5 mL) and concentrated hydrochloric acid (1 mL) were added and the stirring was continued for 2 hours, and the reaction of the raw materials was complete. After concentration, the obtained residue was purified to obtain the title compound 2a (90 mg, yield: 100%).

[0245] MS m / z (ESI): 451.0 [M-1].

[0246] second step

[0247] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-1,2,4- Triazine-3,5(2H,4H)-dione 2

[0248] Compound 2a (90 mg,...

Embodiment 3

[0252] 2-(3,5-Dibromo-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo Generation-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 3

[0253]

[0254] first step

[0255] 5-(2,6-Dibromo-4-nitrophenoxy)-3-isopropylpyridin-2(1H)-one 3b

[0256] Compound 1e (100mg, 0.65mmol) was dissolved in N,N-dimethylformamide (8mL), and 1,3-dibromo-2-fluoro-5-nitrobenzene 3a (205mg, 0.69mmol) was added successively, Potassium carbonate (722mg, 5.22mmol), stirred at 55°C for 18 hours. After filtering, the filter cake was washed with a mixed solvent (20 mL×2) of dichloromethane and methanol (V / V=5 / 1), and acetic acid was slowly added dropwise until the pH of the filtrate was 5-6. Concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 3b (150 mg, yield: 53.1%).

[0257] MS m / z (ESI): 432.9 [M+1].

[0258] second step

[0259] 5-(4-Amino-2,6-dibromophenoxy)-3-isop...

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Abstract

The invention relates to a 6-oxo-1, 6-dihydropyridine derivative, a preparation method of the 6-oxo-1, 6-dihydropyridine derivative and application of the 6-oxo-1, 6-dihydropyridine derivative in medicine. Specifically, the invention relates to a 6-oxo-1, 6-dihydropyridine derivative as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, especially in preparation of drugs for treating and / or preventing thyroid hormone receptor regulation diseases. Each substituent in the general formula (I) is as defined in the specification.

Description

technical field [0001] The disclosure belongs to the field of medicine, and relates to a 6-oxo-1,6-dihydropyridine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a therapeutic agent thereof , especially for the preparation of medicines for treating and / or preventing diseases such as obesity, diabetes, hyperlipidemia, thyroid disease, nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. Background technique [0002] Thyroid hormones are very important for the normal development of the human body and for maintaining metabolic homeostasis. The three major functions of thyroid hormones: (1) Promote growth and development. The most obvious effect of thyroid hormones on growth and development is in infancy, and it has the greatest impact in the first five months after birth. It mainly promotes the growth and development of bones, brain and reproductive organs. Without thyroid h...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D401/10C07D213/69C07D213/70C07D213/64A61K31/53A61P5/14A61P3/04A61P3/10A61P9/00A61P35/00A61P3/06A61P9/10A61P1/16
CPCC07D401/12C07D401/10C07D213/69C07D213/70C07D213/64A61P5/14A61P3/04A61P3/10A61P9/00A61P35/00A61P3/06A61P9/10A61P1/16
Inventor 杨方龙郑亮亮韩吉慧贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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