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Pyridines, bicyclopyridines, and related analogs as sirtuin modulators

A technology of heterocycles and compounds, applied in the field of pyridine, bicyclic pyridine and related analogs as sirtuin regulators, can solve the problems of prolonging the lifespan of wild-type cells and reducing the

Inactive Publication Date: 2011-12-07
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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  • Pyridines, bicyclopyridines, and related analogs as sirtuin modulators
  • Pyridines, bicyclopyridines, and related analogs as sirtuin modulators
  • Pyridines, bicyclopyridines, and related analogs as sirtuin modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0377] Example 1 Preparation of N-(1-(6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)pyrazine-2-carboxamide (compound 204):

[0378] Step 1. Synthesis of 1-(6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethanone (2):

[0379]

[0380] 3-(Trifluoromethyl)phenylboronic acid (43; 500mg, 2.63mmol), 1-(6-bromopyridin-2-yl)ethanone (1; 438mg, 2.19mmol), Pd[Ph 3 P] 4 (100mg) and 2M K 2 CO 3 A mixture of aqueous solution (3 mL) in 25 mL toluene was stirred at 90°C for 1.5 hours. LC showed the reaction was complete. The solution was cooled, extracted with EtOAc (50 mL), washed with 25 mL of 2 mol / L NaOH(aq), 25 mL of brine, washed over anhydrous MgSO 4 Dried and concentrated. The resulting residue was purified by chromatography (EtOAc / petroleum ether = 1:30) to afford 1-(6-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethanone 2 as white Solid (538 mg, yield: 92%). Calculated MS(ESI): C 14 h 10 f 3 NO: 265.07; found value: 266 [M+H].

[0381] Step 2. Synthesis of 1-(6-(3-(trifluo...

Embodiment 2

[0391] Example 2 Preparation of N-2-pyrazinyl-2-{6-[3-(trifluoromethyl)phenyl]-2-pyridyl}propanamide (compound 214):

[0392] Synthesis of step 1.2-(2-pyridyl) ethyl propionate (7):

[0393]

[0394] The method detailed here is similar to that described in WO2005 / 051919. A hexane solution of n-butyllithium (24ml, 60mmol) was added to a solution of diisopropylamine (8.56ml, 60.0mmol) in tetrahydrofuran (20mL). The resulting solution was stirred at -78°C for 15 minutes. Ethyl 2-pyridylacetate (6; 3ml, 19.69mmol) was added, and the mixture was stirred at -78°C for 30 minutes, followed by the addition of iodomethane (6.15ml, 98mmol). The reaction mixture was stirred at -78°C for 15 minutes, then at room temperature for 3 hours. The reaction mixture was cooled in an ice bath, and 20 mL of water was added. It was extracted with EtOAc (3x50ml). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give 7 as a red oil. It was purified by...

Embodiment 3

[0411] Example 3 Preparation of N-({6-[3-(trifluoromethyl)phenyl]-2-pyridyl}methyl)benzamide (compound 208):

[0412] Step 1. Synthesis of 6-[3-(trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (14):

[0413]

[0414] 6-Bromo-2-pyridinecarbaldehyde (13; 1 g, 5.38 mmol) was dissolved in toluene (50 mL), then [3-(trifluoromethyl)phenyl]boronic acid (1.123 g, 5.91 mmol), tetrakis( Triphenylphosphine) palladium (0) (tetrakis) (0.217 g, 0.188 mmol) and 2M potassium carbonate (aq) (6.45 mL, 12.90 mmol). The reaction mixture was stirred overnight at 90 °C. Water was added and the mixture was extracted with EtOAc (100ml). The organics were separated and the solvent was removed.

[0415] Purification by silica gel chromatography (0 to 20% gradient of ethyl acetate in hexanes) afforded the title compound 14 as a yellow oil (880 mg, yield: 32.6%). This product was used directly in the next step. Calculated MS(ESI): C 13 h 8 f 3 NO: 251.20; found value: 252.1 [M+H].

[0416] Syn...

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PUM

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Abstract

The present invention provides novel sirtuin-modulating compounds and methods of using them. The sirtuin-modulating compounds can be used to increase cell lifespan and to treat and / or prevent a variety of diseases and conditions, including, for example, diseases or conditions associated with aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular Diseases, blood clotting disorders, inflammation, cancer and / or flushing and diseases or conditions that would benefit from increased mitochondrial activity. The invention also provides compositions comprising a sirtuin-modulating compound and another therapeutic agent. The compound is a compound of general formula (III), wherein R1, R2, R", X, Y, W, Z1 and Z2 are as defined in the specification.

Description

[0001] References to related applications [0002] This application claims the benefit of US Provisional Application No. 61 / 197,595, filed October 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 typhi...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61P5/50C07D215/16A61K31/14A61P7/00C07D401/14A61K31/4427A61P9/00C07D403/14A61K31/47A61P17/00C07D405/12A61K31/4709A61P25/00C07D405/14A61K31/4995A61P27/00C07D413/12A61K31/506A61P29/00C07D413/14A61K31/5377A61P35/00C07D417/12A61P3/00C07D213/16C07D491/052A61P3/10C07D213/81
CPCC07D413/12C07D213/75C07D491/04C07D213/40C07D213/82C07D213/81C07D405/12C07D401/12C07D417/12C07D401/14C07D405/14A61P3/00A61P3/10A61P5/50A61P7/00A61P9/00A61P17/00A61P25/00A61P27/00A61P29/00A61P35/00A61P43/00A61K31/497
Inventor 拉德哈·纳拉延杰里米·S·迪希罗伯特·B·珀尼奇·B·武
Owner SIRTRIS PHARMA INC
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