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Substituted bridged urea analogs as sirtuin modulators

A compound, heterocyclic technology, applied in the field of substituted bridged cyclic urea analogs as sirtuin modulators, can solve the problem of reducing

Inactive Publication Date: 2017-08-29
GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
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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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  • Substituted bridged urea analogs as sirtuin modulators
  • Substituted bridged urea analogs as sirtuin modulators
  • Substituted bridged urea analogs as sirtuin modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1075] Synthesis of (9S)-N-(pyridin-2-yl)-2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)-8,9-dihydro-6H-5,9 -Methylenepyrido[2,3-b][1,4]diazacyclotetraene-10(7H)-carboxamide

[1076]

[1077] NaH (0.254 g, 10.57 mmol) was added to (9S)-2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)-7,8,9,10-tetrahydro-6H -5,9-methylenepyrido[2,3-b][1,4]diazaoctacene (0.550 g, 1.761 mmol) in tetrahydrofuran (THF) (30 mL) under nitrogen in a stirred solution at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. Then 3-(pyridin-2-yl)-2H-pyrido[1,2-a][1,3,5]triazine-2,4(3H)-dione (0.635 g, 2.64 mmol ). The reaction mixture was then stirred at 65°C for 24 hours. The reaction mixture was cooled to 28 °C and partitioned between water (10 mL) and EtOAc (25 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 Dry, filter and evaporate the filtrate to give the crude material as a brown solid (TLC eluent: 100% EtOAc:R f -0.3; UV activity). The ...

Embodiment 2

[1080] Synthesis of (9S)-N-(5-fluoropyridin-3-yl)-2-(2-(trifluoromethyl)pyridin-4-yl)-8,9-dihydro-6H-5,9-ylidene Pyrido[2,3-b][1,4]diazacyclotetraene-10(7H)-carboxamide

[1081]

[1082] To (9S)-2-(2-(trifluoromethyl)pyridin-4-yl)-7,8,9,10-tetrahydro-6H-5,9-methylenepyrido[2 ,3-b][1,4]To a stirred solution of diazaoctene (500 mg, 1.561 mmol) in THF (15 mL) was added triethylamine (0.653 mL, 4.68 mmol) and triphosgene (232 mg, 0.780 mmol) and stirred at room temperature for 1 h. 5-Fluoropyridin-3-amine (525 mg, 4.68 mmol) was then added at 30°C and the reaction was heated at 70°C for 16h. THF was evaporated under reduced pressure and the resulting residue was diluted with water and washed with CH 2 Cl 2 (3x50 mL) extraction. The combined organic layers were washed with water, brine and washed with Na 2 SO 4 Drying and solvent evaporation under reduced pressure gave crude compound which was purified by flash column chromatography (silica gel: 100-200 mesh, eluent: 3% M...

Embodiment 3

[1085] Synthesis of (9S)-N-(pyrimidin-5-yl)-2-(5-(trifluoromethyl)pyridin-3-yl)-8,9-dihydro-6H-5,9-methylenepyridine And[2,3-b][1,4]diazacyclooctene-10(7H)-carboxamide

[1086]

[1087] To (9S)-2-(5-(trifluoromethyl)pyridin-3-yl)-7,8,9,10-tetrahydro-6H-5,9-methylenepyrido[2 , 3-b][1,4]diazaoctene (0.6g, 1.873mmol), triethylamine (0.783mL, 5.62mmol) in THF (12mL) was added triphosgene (0.278g , 0.937 mmol) and stirred at room temperature for 30 minutes. Pyrimidin-5-amine was then added and the reaction mixture was stirred at 65 °C for 16 h. The solvent was removed under reduced pressure to give the crude material which was diluted with dichloromethane, washed with water and brine solution and washed with anhydrous Na 2 SO 4 After drying, the organic layer was evaporated under reduced pressure to obtain crude product. The crude product mixture was purified by flash column chromatography (silica gel: 100-200 mesh, with CH 2 Cl 2 2% MeOH in ) to give (9S)-N-(pyrimidin-5-...

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Abstract

The present invention relates to novel substituted bridged urea analog compounds of Formula (I) or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, processes for making and use of such compounds, alone or in combination with other therapeutic agents, as Sirtuin Modulators useful for increasing lifespan of a cell, and in treating and / or preventing a wide variety of diseases and disorders, which include, but are not limited to, 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. (I)

Description

technical field [0001] In general, the present invention relates to substituted bridged urea analog compounds of formulas (I) to (VI), corresponding analogs or derivatives thereof, or pharmaceutically acceptable salts thereof, corresponding pharmaceutical compositions, the compounds and methods or uses thereof alone or in combination with other therapeutic agents as sirtuin modulators for increasing cell lifespan, and for treating and / or preventing various diseases and disorders, said diseases and disorders including, but not limited to, for example, diseases or disorders associated with aging or stress, diabetes, obesity, neurodegenerative disease, cardiovascular disease, coagulation disorders, inflammation, cancer, and / or flushing and would benefit from Diseases or disorders that increase mitochondrial activity. Background technique [0002] The Silent Information Regulator (SIR) gene family represents a highly conserved group of genes present in the genomes of organisms ...

Claims

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Application Information

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IPC IPC(8): C07D471/18A61K31/501A61K31/4995A61K31/506A61P3/10A61P3/00A61P25/28A61P9/00A61P35/00A61P29/00A61P17/06A61P17/00A61P1/00A61P19/10A61P37/00A61P27/02
CPCC07D471/18C07D487/18C07D519/00A61K31/551A61K31/5517A61K31/4995A61P25/28A61P9/00A61P3/10A61K45/06
Inventor J.L.埃利斯K.A.埃文斯R.M.福克斯W.H.米勒M.A.塞费尔德
Owner GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD
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