Quinazolinone, quinolone and related analogs as sirtuin modulators

A compound, alkyl technology, applied in the field of quinazolinones, quinolones and related analogs as sirtuin regulators, which can solve the problems of reducing and extending the lifespan of wild-type cells

Inactive Publication Date: 2011-10-26
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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  • Quinazolinone, quinolone and related analogs as sirtuin modulators
  • Quinazolinone, quinolone and related analogs as sirtuin modulators
  • Quinazolinone, quinolone and related analogs as sirtuin modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0334] Example 1. N-(3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-yl) Synthesis of pyridine-2-carboxamide (compound 239):

[0335] Step 1. 8-Nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3] Preparation of oxazin-4-one (3):

[0336]

[0337] 3-(Trifluoromethyl)benzoyl chloride 2 (4.5 mL, 30.2 mmol) was added to a suspension of 2-amino-3-nitrobenzoic acid 1 (5.0 g, 27.5 mmol) in pyridine (65 mL). The reaction mixture was stirred at room temperature for 12 h, then poured into ice-cooled H 2 O (300mL). The resulting precipitate was collected by filtration and washed with H 2 O washed and dried in vacuo to afford 3 (5 g, 51% yield) as a yellow solid which was used without further purification.

[0338] Step 2. Preparation of 3-methyl-8-nitro-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (4):

[0339]

[0340]Methylamine (6.3 mL, 12.5 mmol) in THF was added to 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3] In a suspension of a...

Embodiment 2

[0347] Example 2. N-(3-methyl-4-oxo-2-phenyl-3,4-dihydroquinazolin-8-yl)pyridine-3-sulfonamide Synthesis of (Compound 361):

[0348]

[0349] Pyridine-3-sulfonyl chloride hydrochloride 7 (280 mg, 1.3 mmol) was added to 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl)quinazoline-4(3H)- Ketone 5 (100 mg, 0.313 mmol) in pyridine (5 mL). The reaction mixture was heated at 80°C for 12 hours. Pyridine was removed in vacuo. The residue was dissolved in CH 2 Cl 2 , with saturated NaHCO 3 Washed with aqueous solution, dried (MgSO 4 ) and concentrate. The crude residue was purified by MPLC with CH 2 Cl 2 / MeOH (0-10%) elution followed by CH 3 CN was recrystallized to give compound 361 (77 mg, 53% yield). MS(ESI) calculated value C 21 h 15 f 3 N 4 o 3 S: 460.08; found value: 461 [M+H].

Embodiment 3

[0350] Example 3. N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-8-yl)pyridine-2- Synthesis of formamide (compound 231):

[0351] Step 1. Preparation of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (8):

[0352]

[0353] 8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3] Azin-4-one 3 (150 mg, 0.45 mmol) was added to a solution of ammonia (5.0 mL, 10 mmol) in IPA. The reaction mixture was heated at gentle reflux for 12 hours and then cooled to room temperature. Pour the reaction mixture into H 2 O, the resulting precipitate was collected by filtration and washed with H 2 O washed and dried in vacuo. The crude residue was recrystallized from EtOAc to afford 8 (91 mg, 62% yield) as a yellow solid.

[0354] Step 2. Preparation of 8-amino-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (9):

[0355]

[0356] Compound 9 was prepared in 99% yield by a method analogous to the preparation of 8-amino-3-methyl-2-(3-(trifluoromethyl)phenyl...

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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 / 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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IPC IPC(8): C07D401/12A61K31/5377C07D405/12A61K31/4375A61P3/10C07D413/12A61K31/439A61P5/50C07D417/12A61K31/4709C07D239/91C07D417/14A61K31/497C07D401/14C07D453/02A61K31/506C07D403/12A61K31/517C07D403/14
CPCC07D311/30C07D405/12C07D405/14C07D417/12C07D417/14A61K31/353A61K31/4025A61K31/4155A61K31/422A61K31/427A61K31/4433A61K31/4439A61K31/497A61K31/506A61K31/5377A61K45/06A61P1/04A61P1/16A61P3/00A61P3/04A61P3/06A61P3/10A61P5/50A61P9/00A61P9/04A61P9/10A61P9/12A61P11/00A61P13/08A61P13/12A61P15/00A61P15/08A61P19/02A61P19/06A61P19/10A61P25/00A61P25/28A61P27/02A61P35/00A61P43/00A61K2300/00C07D311/22
Inventor 奇·B·武克里斯托弗·奥尔曼罗伯特·B·珀尼布赖恩·怀特
Owner SIRTRIS PHARMA INC
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