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Isoindolinone and related analogs as sirtuin modulators

A compound, alkyl technology, applied in the field of isoindolinone and related analogues as sirtuin regulators, which can solve the problem of reducing and extending the lifespan of wild-type cells

Inactive Publication Date: 2012-01-04
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 prolong lifespan in wild-type cells but not in mutant sir2 strains , which demonstrates that SIR2 may be a key downstream component of the caloric restriction pathway

Method used

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  • Isoindolinone and related analogs as sirtuin modulators
  • Isoindolinone and related analogs as sirtuin modulators
  • Isoindolinone and related analogs as sirtuin modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0491] Example 1 Preparation of N-(3-oxo-2-(3-(trifluoromethyl)phenyl)isoindoline-4-yl)pyrazine-2-carboxamide (compound 100):

[0492] Step 1) Synthesis of 2-methyl-6-nitrobenzoic acid methyl ester (2):

[0493]

[0494] 2-Methyl-6-nitrobenzoic acid (1; 10 g, 0.0552 mol) was dissolved in 200 mL of methyl ethyl ketone together with methyl iodide (17.2 mL, 0.276 mol) and anhydrous potassium carbonate (38.1 g, 0.276 mol) . The reaction mixture was stirred at reflux for 18 hours. It was then cooled to room temperature and filtered. The filtrate was diluted with EtOAc (300 mL), washed with water (2 x 50 mL), brine, dried (Na 2 SO 4 ), and concentrated under reduced pressure to obtain methyl 2-methyl-6-nitrobenzoate 2 (10.80g).

[0495] Step 2) Synthesis of 2-(bromomethyl)-6-nitrobenzoic acid methyl ester (3):

[0496]

[0497]Methyl 2-methyl-6-nitrobenzoate (2; 10.8g, 0.0552mol) was mixed with N-bromosuccinimide (9.82g, 0.0552mol) and 100mg of azo-bis(isobutyronitrile ...

Embodiment 2

[0507] Example 2: Preparation of additional N-(3-oxo-2-(optionally substituted phenyl)isoindolin-4-yl)carboxamides according to the invention:

[0508] Synthesis of 7-nitro-2-(3-(trifluoromethoxy)phenyl)isoindolin-1-one (6):

[0509]

[0510] Methyl 2-(bromomethyl)-6-nitrobenzoate (from Example 1, step 2) (3; 0.86 g, 3.14 mmol), 3-(trifluoromethoxy ) aniline (21; 0.56g, 3.14mmol) and HOAc (0.3mL) in di The mixture in alkanes (3 mL) was stirred for 20 minutes. The mixture was adjusted to pH = 7 and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with Na 2 SO 4 Drying, concentration in vacuo, and purification by silica gel chromatography afforded 7-nitro-2-(3-(trifluoromethoxy)phenyl)isoindolin-1-one 6 (0.67 g, 1.98 mmol, 63 %). MS(ESI)C 15 h 9 f 3 N 2 o 4 Calculated: 338; Measured: 339 [M+H]. 7-nitro-2-(3-(trifluoromethoxy)phenyl)isoindolin-1-one 6 was converted into the corresponding amine, and then according to the steps 3-4 m...

Embodiment 3

[0512] Example 3: N-(3-oxo-2-(3-(piperidin-4-yloxy)phenyl)isoindoline-4-yl)-2-(pyridin-3-yl)ethyl Preparation of Amide (Compound 102):

[0513] Step 1) Synthesis of 4-(3-nitrophenoxy)piperidine-1-carboxylic acid tert-butyl ester (9):

[0514]

[0515] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (8; 6.27 g, 47.44 mmol), 3-nitrophenol (7; 6.0 g, 43.13 mmol) and triphenylphosphine ( To a solution of 12.44 g, 47.44 mmol) in anhydrous THF (40 mL) was added diethyl azodicarboxylate (8.26 g, 47.44 mmol) dropwise. The mixture was then warmed to room temperature and stirred overnight. The reaction mixture was concentrated and then purified by column chromatography (EtOAc:petroleum ether=1:6) to give tert-butyl 4-(3-nitrophenoxy)piperidine-1-carboxylate 9 as an oil (8.2 g) . MS(ESI)C 16 h 22 N 2 o 5 Calculated: 322; Measured: 323 [M+H].

[0516] Step 2) Synthesis of 4-(3-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (10):

[0517]

[0518] tert-Bu...

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Abstract

Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds 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. Also provided are compositions comprising a sirtuin- modulating compound in combination with another therapeutic agent.

Description

[0001] References to related applications [0002] This application claims the benefit of US Provisional Application No. 61 / 201,263, filed December 8, 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 higher 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 for determining 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 Salm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61P7/02A61P31/16A61K31/4035A61P7/06A61P31/22A61K31/427A61P9/00A61P35/00A61K31/437A61P9/10A61P35/02A61K31/443A61P11/00A61P37/00A61K31/4439A61P11/06A61P37/06A61K31/4523A61P19/02A61P43/00A61K31/498A61P21/00C07C201/12A61K31/4985A61P25/06C07C205/57A61K31/519A61P25/08C07C205/58A61K31/5377A61P25/14C07D209/46A61P1/00A61P25/16C07D213/61A61P3/04A61P25/28C07D401/12A61P3/06A61P27/02C07D401/14A61P3/10A61P27/04C07D405/12A61P5/14A61P27/06C07D417/12A61P5/38A61P27/12
CPCC07D417/12C07D471/04C07D295/12C07D213/61C07D487/04C07D209/46C07D405/12C07D403/12C07D401/14C07D401/12A61P1/00A61P3/00A61P3/04A61P3/06A61P3/10A61P5/14A61P5/38A61P5/50A61P7/02A61P7/06A61P9/00A61P9/10A61P11/00A61P11/06A61P19/02A61P21/00A61P25/06A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P27/04A61P27/06A61P27/12A61P31/12A61P31/16A61P31/22A61P35/00A61P35/02A61P37/00A61P37/06A61P43/00A61K31/497
Inventor C·B·武L·麦克弗森吴佩仪C·布卢姆
Owner SIRTRIS PHARMA INC
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