Benzoxazoles, benzthiazoles and related analogs as sirtuin modulators

A compound and alkyl technology, applied in the direction of drug combination, antiviral agent, active ingredient of heterocyclic compound, etc., can solve the problem of reducing and prolonging the life span of wild-type cells

Inactive Publication Date: 2011-09-07
SIRTRIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Benzoxazoles, benzthiazoles and related analogs as sirtuin modulators
  • Benzoxazoles, benzthiazoles and related analogs as sirtuin modulators
  • Benzoxazoles, benzthiazoles and related analogs as sirtuin modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0292] Example 1. N-(2-(3-(trifluoromethoxy)phenyl)benzo[d] Synthesis of oxazol-4-yl)thiazole-4-carboxamide (compound 104):

[0293] Step 1) 4-nitro-2-(3-(trifluoromethoxy)phenyl)benzo[d] Preparation of azole (2):

[0294]

[0295] 2-Amino-3-nitrophenol (1; 2.00 g, 0.0130 mol) was dissolved together with 3-trifluoromethoxybenzoic acid (50; 2.67 g. 0.0130 mol) in 10 mL of polyphosphoric acid (PPA). The reaction mixture was stirred at 165°C for 3 hours. It was then cooled to about 100°C and carefully poured into 300 mL of water. Sufficient solid NaOH was added to bring pH=6. The resulting solid was collected by filtration, washed with water, and dried to give 800 mg of 4-nitro-2-(3-(trifluoromethoxy)phenyl)benzo[d] Azole 2, as light brown solid. MS(ESI) calculated value C 14 h 7 f 3 N 2 o 4 : 324.04; measured value: 325 [M+H]. Other compounds shown in Table 1 were prepared by using the appropriate carboxylic acids.

[0296] Step 2) 2-(3-(trifluoromethoxy)pheny...

Embodiment 2

[0303] Example 2. N-(thiazol-2-yl)-2-(2-(trifluoromethyl)phenyl)benzo[d] Synthesis of azole-4-carboxamide (compound 137):

[0304] Step 1) 2-(2-(Trifluoromethyl)phenyl)benzo[d] Preparation of azole-4-carboxylic acid methyl ester (6):

[0305]

[0306] Methyl 2-amino-3-hydroxybenzoate (4; 0.5 g, 3 mmol) and 2-(trifluoromethyl)benzoic acid (5; 0.57 g, 3 mmol) were dissolved in 20 mL of PPA. The reaction mixture was stirred at 140°C for 3 hours. The reaction mixture was cooled to approximately 100°C and carefully diluted with 50 mL of water. The resulting solid was collected by filtration and dried. Purification by chromatography afforded 2-(2-(trifluoromethyl)phenyl)benzo[d] Methyl azole-4-carboxylate 6 (0.3 g, 31%). Calculated MS(ESI): C 16 h 10 f 3 NO 3 : 321.04; measured value: 322 [M+H].

[0307] The other compounds shown in Table 1 were prepared according to the general procedure shown in this procedure using the appropriate carboxylic acid.

[0308] Step ...

Embodiment 3

[0315] Example 3: N-(thiazol-2-yl)-2-(3-(trifluoromethyl)phenyl)benzo[d] Synthesis of azole-7-carboxamide (compound 107):

[0316] Step 1) Preparation of 2-hydroxyl-3-(3-(trifluoromethyl)benzamido)methyl benzoate (11):

[0317]

[0318] Methyl 2-hydroxy-3-nitrobenzoate (9; 1.00 g) was dissolved in 100 mL of a 2:1 THF / MeOH solution. After adding 10% Pd / C (100 mg), the reaction mixture was stirred at room temperature under 1 atm of hydrogen for 18 hours. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated under reduced pressure to afford crude methyl 3-amino-2-hydroxybenzoate in essentially quantitative yield.

[0319] For the subsequent step, methyl 3-amino-2-hydroxybenzoate 10 (850 mg, 5.1 mmol) was dissolved with 3-trifluoromethylbenzoyl chloride (52; 0.75 mL, 5.1 mmol) at 10 °C In 15mL of pyridine. The resulting reaction mixture was stirred at room temperature for 18 hours, then diluted with 250 mL of EtOAc. The organic layer...

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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] related application [0002] This application claims the benefit of US Provisional Application No. 61 / 188,688, filed August 12, 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 typhimurium, function...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D417/12C07D263/57A61P3/00A61K31/42A61P3/10A61K31/423C07D277/66
CPCA61K31/42C07D277/68A61K31/423C07D513/04C07D417/12C07D413/12A61K45/06A61P1/18A61P17/00A61P17/14A61P19/02A61P25/00A61P25/02A61P25/28A61P27/00A61P27/06A61P27/12A61P3/00A61P31/18A61P37/06A61P43/00A61P7/00A61P9/02A61P9/10A61P3/10A61K2300/00C07D417/14A61K31/427
Inventor 奇·B·武
Owner SIRTRIS PHARMA INC
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