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Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators

A compound and heterocycle technology, applied in organic chemistry, metabolic diseases, drug combination, etc., can solve problems such as reduction

Inactive Publication Date: 2014-08-20
GLAXO SMITHKLINE LLC
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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, This demonstrates that SIR2 may be a key downstream component of the caloric restriction pathway

Method used

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  • Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators
  • Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators
  • Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0273] The preparation of embodiment 1.N-(thiazol-2-yl)-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamide:

[0274] Step 1. Synthesis of 4-bromo-6-chloropyridazin-3-amine:

[0275]

[0276] To a mixture of 3-amino-6-chloropyridazine (45.0 g, 347.0 mmol) and sodium bicarbonate (58.4 g, 695.0 mmol) in MeOH (1000.0 mL) was added bromine (55.5 g, 347.0 mmol) dropwise. The resulting mixture was stirred at room temperature for 16 hours, then filtered. Water (500.0 mL) was added to the filtrate and the solution was extracted with EtOAc. The organic layers were combined and concentrated in vacuo, and the resulting residue was purified by flash chromatography to give 4-bromo-6-chloropyridazin-3-amine (35.0 g, 48.3%). MS(ESI) calculated value C 4 h 3 BrClN 3 :206.92.

[0277] Step 2. Synthesis of 2-bromo-1-(2-(trifluoromethyl)phenyl)ethanone:

[0278]

[0279] To a solution of 1-(2-(trifluoromethyl)phenyl)ethanone (71.0 g, 377.0 mmol) and HBr (2.0 mL, 45% ...

Embodiment 2

[0297] The preparation of embodiment 2.2-(3-fluorophenyl)-6-morpholino-N-(thiazol-2-yl)imidazo[1,2-b]pyridazine-8-carboxamide:

[0298] Step 1. Synthesis of 6-chloro-2-(3-fluorophenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid:

[0299]

[0300] To 6-chloro-2-(3-fluorophenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid methyl ester (2.0g, 6.54mmol) in THF (250.0mL) and water (250.0mL) Sodium hydroxide (0.52 g, 13.09 mmol) was added to the solution in . After the addition, the mixture was stirred overnight. The pH of the mixture was adjusted to 5, filtered and the solid was washed with water then ether and dried to give 6-chloro-2-(3-fluorophenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid (1.3 g, 4.46 mmol, 68.1%). MS(ESI) calculated value C 13 h 7 ClFN 3 o 2 :291.02.

[0301] Step 2. Synthesis of 2-(3-fluorophenyl)-6-morpholinoimidazo[1,2-b]pyridazine-8-carboxylic acid:

[0302]

[0303] 6-Chloro-2-(3-fluorophenyl)imidazo[1,2-b]pyridazine-8-carboxylic acid (1.3g, ...

Embodiment 3

[0308] The preparation of embodiment 3.N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine-7-carboxamide:

[0309] Step 1. Synthesis of 1-ethoxy-1,3-dioxopropan-2-sodium (sodium1-ethoxy-1,3-dioxopropan-2-ide):

[0310]

[0311] To a particle suspension of sodium (16.0 g, 696.0 mmol) in 2-isopropoxypropane (1000.0 mL) was added ethanol (3 drops) followed by ethyl acetate (73.6 g, 835.0 mmol) under nitrogen atmosphere and ethyl formate (67.0 g, 905.0 mmol). After the addition, the suspension was stirred at room temperature for 60 hours. The solid was filtered and washed with diethyl ether to give sodium 1-ethoxy-1,3-dioxopropane-2-ide (50.0 g, 62.4%). MS(ESI) calculated value C 5 h 7 NaO 3 :138.03.

[0312] Step 2. Synthesis of 2-(2-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-ol:

[0313]

[0314] (1-Ethoxy-1,3-dioxopropan-2-yl)sodium (48.6g, 352.0mmol) and 5-(2-(trifluoromethyl)phenyl)-1H-pyrazole- A solution of 3-amine (20.0 g, 88.0 mmo...

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Abstract

Provided herein are novel substituted bicyclic aza-heterocycle 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

Background of the invention [0001] The Silent Information Regulator (SIR) gene family 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. A well-characterized gene in this family is S. cerevisiae SIR2, which is involved in a silent HM locus containing information specifying yeast mating type, telomere position effects, and cellular aging. Proteins encoded by members of the SIR gene family show a high degree of sequence conservation in the 250 amino acid core domain. The Sir2 homologue CobB in Salmonella typhimurium functions as an NAD (nicotinamide adenine dinucleotide)-dependent ADP-ribosyltransferase. [0002] Sir2 proteins are class III deacetylases that use NAD as a cooperative substrate. Unlike other deacetylases, many of which are involved in gene silencing, Sir2 is insensitive to...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04A61P3/00A61P3/10A61P5/50A61P43/00
Inventor C.A.布卢姆J.S.迪希S.K.斯普林格
Owner GLAXO SMITHKLINE LLC
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