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Chromone analogs as sirtuin modulators

A compound and alkyl technology, applied in the field of chromenone analogues as sirtuin regulators, can solve the problems of reducing and prolonging the lifespan of wild-type cells

Inactive Publication Date: 2015-09-16
SIRTRIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, mutations that reduce the activity of the yeast glucose-responsive cAMP (adenosine 3′,5′-monophosphate)-dependent (PKA) pathway extend lifespan in wild-type cells but not in mutant sir2 strains extension, which demonstrates that SIR2 may be a key downstream component of the caloric restriction pathway

Method used

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  • Chromone analogs as sirtuin modulators
  • Chromone analogs as sirtuin modulators
  • Chromone analogs as sirtuin modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0380] Example 1. Synthesis of N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8-yl)thiazole-4-carboxamide (compound 204) .

[0381] Step 1. Preparation of 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one (2):

[0382]

[0383] 1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (1.2 g, 6.61 mmol) was mixed with 3-trifluoromethylbenzoyl chloride 48 (1.2 mL, 7.9 mmol) and DBU (2.9 mL, 14.5 mmol) were dissolved together in 20 mL of pyridine. The reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with EtOAc and washed with dilute 1N HCl. The organic layer was dried (Na 2 SO 4 ), and concentrated under reduced pressure. Purification by chromatography (1:1 pentane / EtOAc) afforded 300 mg of 2. MS(ESI) calculated value C 16 h 8 f 3 NO 4 : 335.04; measured value: 336 [M+H].

[0384] Step 2. Preparation of 8-amino-2-(3-(trifluoromethyl)phenyl)-4H-chro...

Embodiment 2

[0390] Example 2. Synthesis of N-(4-oxo-2-(pyridin-3-yl)-4H-chromen-8-yl)thiazole-4-carboxamide (compound 215) :

[0391] Step 1. Preparation of niacin 2-acetyl-6-nitrophenyl ester (5):

[0392]

[0393]1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (1.0g, 5.5mmol), nicotinic acid 4 (0.8g, 5.8mmol), DCC (2.4g, 11.6mmol) and DMAP (0.7g , 5.8mmol) in CH 2 Cl 2 (30 mL) was stirred at room temperature for 12 hours. After cooling to 0°C, the precipitated dicyclohexylurea was removed by filtration, and the filtrate was concentrated. The crude residue was purified by flash chromatography eluting with pentane / EtOAc (10:1) to afford 5 (1.3 g, 81% yield).

[0394] Step 2. Preparation of 8-nitro-2-(pyridin-3-yl)-4H-chromen-4-one (6):

[0395]

[0396] Nicotinic acid 2-acetyl-6-nitrophenyl ester 5 (1.3 g, 4.4 mmol) was dissolved in pyridine (10 mL) and heated to 50 °C. Finely powdered KOH (3.4 g, 6.1 mmol) was added in small portions. After cooling to room temperature, the reaction ...

Embodiment 3

[0403] Example 3. Synthesis of N-(4-oxo-2-(2-(trifluoromethyl)phenyl)-4H-chromen-8-yl)thiazole-4-carboxamide (compound 227):

[0404] Step 1. Preparation of (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (9) :

[0405]

[0406] 1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (788 mg, 4.4 mmol), 2-(trifluoromethyl)benzaldehyde 8 (1.1 g, 6.5 mmol) and 25% aqueous KOH (90 mL ) in EtOH (90 mL) was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water and the pH was adjusted to 2 using concentrated HCl. The resulting precipitate was collected by filtration and washed with H 2 O washed and dried under vacuum to afford 9 (1.4 g, 95% yield) as a yellow solid.

[0407] Step 2. Preparation of 8-nitro-2-(2-(trifluoromethyl)phenyl)-4H-chromen-4-one (10):

[0408]

[0409] (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one 9 (1.4g, 4.2mmol ) and SeO 2 (1.4g, 12.5mmol) DMSO / di The solution in a...

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Abstract

The present invention relates to novel sirtuin-modulating compounds, corresponding pharmaceutical compositions comprising a sirtuin-modulating compound, alone and / or in combination with another therapeutic agent, and methods of use thereof. Sirtuin-modulating compounds of the present invention may be used for increasing the lifespan of a cell, and treating and / or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and / or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity.

Description

[0001] References to related applications [0002] This application claims the benefit of US Provisional Application No. 61 / 194,576, filed September 29, 2008, the contents of which are incorporated herein by reference. Background technique [0003] The Silent Information Regulator (SIR) family of genes represents a highly conserved group of genes present in the genomes of organisms ranging from archaebacteria to eukaryotes. The encoded SIR proteins are involved in various programs ranging from the regulation of gene silencing to DNA repair. Proteins encoded by members of the SIR gene family show a high degree of sequence conservation in the 250 amino acid core domain. A well-characterized gene in this family is S. cerevisiae SIR2, which involves a silent HM locus containing information specifying yeast mating type, telomere position effects, and cellular aging. The yeast Sir2 protein belongs to the family of histone deacetylases. The Sir2 homologue (CobB), in Salmonella typ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/22A61K31/353A61P3/10
CPCA61K31/4025C07D311/30C07D417/14C07D405/14A61K45/06A61K31/506A61K31/4155A61K31/5377C07D417/12A61K31/4433C07D405/12A61K31/353A61K31/422A61K31/4439A61K31/497A61K31/427A61P1/04A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P5/50A61P9/00A61P9/04A61P9/10A61P9/12A61P11/00A61P13/08A61P13/12A61P15/00A61P15/08A61P19/02A61P19/06A61P19/10A61P25/00A61P25/28A61P27/02A61P35/00A61P43/00A61K2300/00C07D311/22
Inventor 克里斯托弗·奥尔曼罗伯特·B·珀尼奇·B·武
Owner SIRTRIS PHARMA INC
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