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Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases

A compound, alkyl technology, applied in the direction of anti-inflammatory agents, drug combinations, antiviral agents, etc., can solve problems such as reducing and extending the lifespan of wild-type cells

Inactive Publication Date: 2012-01-11
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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  • Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
  • Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases
  • Triazolopyridines as phosphodiesterase inhibitors for treatment of dermal diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0441] Example 1 N-(1-oxo-2-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)pyrazine-2-methan Preparation of Amide (Compound 101):

[0442] Step 1) Synthesis of 2-methyl-6-nitrobenzoic acid methyl ester (2):

[0443]

[0444] Dissolve 2-methyl-6-nitrobenzoic acid (1; 10 g, 55.2 mol) together with methyl iodide (17.2 mL, 276.0 mmol) and anhydrous potassium carbonate (38.1 g, 276.0 mmol) in 200 mL of methyl in ethyl ketone. 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 (2x50 mL), brine, dried (Na 2 SO 4 ), and concentrated under reduced pressure to obtain 10.80 g of 2-methyl-6-nitrobenzoic acid methyl ester 2. MS (ESI): C 9 h 9 NO 4 Calculated: 195.05; Measured 196 [M+H].

[0445] Step 2) Synthesis of 2-(bromomethyl)-6-nitrobenzoic acid methyl ester (3):

[0446]

[0447] Methyl 2-methyl-6-nitrobenzoate (2; 10.8g, 55.2mmo...

Embodiment 2

[0469] Example 2 Preparation of 8-amino-2-(3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one (compound 103):

[0470] Step 1) Synthesis of 8-nitro-2-(3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one (10):

[0471]

[0472] Dissolve methyl 2-formyl-6-nitrobenzoate (4; 500 mg, 2.40 mmol) in 3 mL of 1,4-bis Alkanes, 1 mL of glacial acetic acid and 3-trifluoromethylphenylhydrazine (20; 420 mg, 2.40 mmol). The reaction mixture was stirred at 200°C for 20 minutes in a microwave reactor. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with dilute NaHCO 3 Wash with aqueous solution. The organic layer was dried (Na 2 SO 4 ), and concentrated under reduced pressure to obtain 720 mg of 8-nitro-2-(3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one 10. MS(ESI)C 16 h 8 f 3 N 3 o 3 Calculated: 335.05; Measured: 336 [M+H].

[0473] Step 2) Synthesis of 8-amino-2-(3-(trifluoromethyl)phenyl)phthalazin-1(2H)-one (11):

[0474]

[0475] 8-Nitro...

Embodiment 3

[0481] Example 36-(2,3-dihydroxypropoxy)-N-(4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydrophthalazine-5- base) the preparation of pyridine-2-carboxamide (compound 105):

[0482] Step 1) Synthesis of 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridine-2-carboxylic acid (14):

[0483]

[0484] To a mixture of NaH (7.12 g, 178 mmol, 60% in oil) in anhydrous THF (400 mL) was added solketal (13; 23.5 g, 178 mmol) at 0°C. The mixture was stirred for 1 hour. 6-bromopyridine-2-carboxylic acid (12; 12.0 g, 59.4 mmol) was added, and stirred under reflux for 1.5 hours. Water (50 mL) was added and the pH was adjusted to 2-3. The mixture was extracted with EtOAc (4x50 mL). The combined organic layers were washed with water (3x25mL), washed with Na 2 SO 4 Drying and concentration in vacuo gave 6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyridine-2-carboxylic acid 14 as a white solid (10.0 g , 66% yield). MS(ESI)C 12 h 15 NO 5 Calculated: 253; Measured: 254 [M+H].

[0485] Ste...

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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 / 201,966, filed December 16, 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 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 Salmonel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D405/12A61K31/5377A61P5/50C07D417/12A61K31/4725C07D401/12A61K31/497A61K31/502
CPCC07D403/12C07D405/12C07D417/12C07D401/12A61P1/16A61P3/00A61P3/04A61P3/10A61P5/50A61P7/02A61P7/06A61P9/10A61P17/00A61P17/14A61P19/00A61P21/00A61P25/00A61P25/14A61P25/16A61P25/28A61P27/02A61P29/00A61P31/12A61P31/16A61P31/18A61P31/20A61P31/22A61P35/00A61P35/02A61P43/00A61K31/497
Inventor 奇·B·武
Owner SIRTRIS PHARMA INC
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