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Pyridone derivatives and their preparation and use

A derivative, pyridone technology, applied in the field of medicine, can solve difficult problems such as tumor metastasis and recurrence

Active Publication Date: 2016-08-17
SICHUAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are more and more treatments and drugs available, these treatments are still difficult to solve the metastasis and recurrence of tumors

Method used

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  • Pyridone derivatives and their preparation and use
  • Pyridone derivatives and their preparation and use
  • Pyridone derivatives and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] Example 1 5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-N-((1-methyl-3-oxo-3,5,6,7- Preparation of tetrahydro-2H-cyclopenta[c]pyridin-4-yl)methyl)-4'-(morpholinemethyl)biphenyl-3-carboxamide (compound A-1)

[0198]

[0199] Step 1 2-Methyl-3-nitro-5-bromobenzoic acid

[0200]

[0201] N-bromosuccinimide (15g, 84.3mmol) was added to 2-methyl-3-nitro-benzoic acid (15g, 82.8mmol) in concentrated sulfuric acid solution (60ml), then the reaction solution was stirred at room temperature overnight. When the reaction was completed, the reaction solution was slowly poured into ice water (400ml). The precipitate was suction-filtered and vacuum-dried to obtain 21 g of the expected product 2-methyl-3-nitro-5-bromobenzoic acid with a yield of 98%.

[0202] Step 2 Methyl 5-bromo-2-methyl-3-nitrobenzoate

[0203]

[0204] 2-Methyl-3-nitro-5-bromobenzoic acid (16g, 61.5mmol) was dissolved in DMF (160ml) solution, then iodomethane (35.7g, 248mmol) and sodium carbonate (...

Embodiment 2

[0228] Example 2 5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-N-((1-methyl-3-oxo-2,3,5,6, Preparation of 7,8-hexahydroquinolin-4-yl)methyl)-4'-(morpholinemethyl)biphenyl-3-carboxamide (compound A-2)

[0229]

[0230] step 1

[0231]

[0232]Add 2-acetylcyclohexanone (1.4g, 10mmol), cyanoacetamide (8.4g, 10mmol) and triethylenediamine hexahydrate (2.2g, 10mmol) into absolute ethanol, stir at 90°C for 8h, Stop the reaction, after cooling down to room temperature, filter the precipitate with suction, and recrystallize with ethanol or methanol or ethyl acetate.

[0233] step 2

[0234]

[0235] The product from the previous step (1.88g, 10mmol) was placed in a tetrahydrofuran solution, in an ice bath at 0°C, sodium borohydride (0.87g, 23mmol) and iodine (2.53g, 10mmol) were added, stirring was continued for 15 minutes, and the ice bath was removed. Slowly warm up to 72°C and stir overnight. The reaction was stopped, and 3N hydrochloric acid (1 ml) was added dropw...

Embodiment 3

[0242] Example 3 5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-N-((1-methyl-3-oxo-3,5,6,7, Preparation of 8,9-hexahydro-2H-cyclohepta[c]pyridin-4-yl)methyl)-4'-(morpholinemethyl)biphenyl-3-carboxamide (Compound A-3)

[0243]

[0244] step 1

[0245]

[0246] At -78°C, the THF solution of cycloheptanone (2.25g, 20mmol) was slowly added dropwise to the THF solution of lithium diisopropylamide (2N in THF) (20ml, 40mmol), and the temperature was maintained at -78°C. Stir for 1 h, then slowly add a THF solution of pre-cooled acetyl chloride (1.7 ml, 24 mmol) dropwise, after the addition is complete, continue stirring for 1 h. When the reaction is complete, add an appropriate amount of saturated ammonium chloride solution at -78°C to quench the reaction solution. The reaction solution was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to obtain a liquid crude product. It was used direc...

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PUM

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Abstract

The invention belongs to the field of chemical medicines, and particularly relates to a pyridone derivative, a preparation method and an application thereof. The pyridone derivative is represented as the formula (I). The invention also provides the preparation method of the pyridone derivative and the application thereof in preparation of a drug for treating tumor. The preparation method is short in synthetic route, is simple in reaction conditions, is high in yield and is easy for derivatization. The compounds in the invention have high anti-tumor activity and low toxicity. The invention provides a new selection for preparing an anti-tumor drug.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to pyridone derivatives and their preparation methods and applications. Background technique [0002] Epigenetic modifications play an important role in the regulation of many cellular processes including cell proliferation, differentiation and cell survival. Include global alterations in DNA and / or histone methylation, noncoding RNA, and dysregulation of nucleosome remodeling, which lead to aberrant activation or inactivation of oncogenes, tumor suppressor genes, and signaling pathways. Tumor is still one of the most harmful diseases to human health and life in today's society. Although there are more and more treatments and drugs available, these treatments are still difficult to solve the metastasis and recurrence of tumors. Accumulating evidence suggests that long-term efficacy of anticancer therapy requires co-repression of two or more oncogene pathways, and that modulatio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/18C07D405/14C07D471/04C07D491/113C07D405/12C07D401/12C07D217/24A61K31/5377A61K31/4725A61K31/496A61P35/00A61P37/02A61P35/02A61P17/06
CPCC07D217/24C07D401/12C07D405/12C07D405/14C07D471/04C07D471/18C07D491/113
Inventor 余洛汀魏于全
Owner SICHUAN UNIV
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