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Substituted bridged urea analogs as sirtuin modulators

A compound, heterocyclic group technology, applied in the field of substituted bridged urea analogs as sirtuin regulators, can solve problems such as reducing

Inactive Publication Date: 2017-09-26
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 extended 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

[1225] Synthesis of (8S)-N9-(4-((R)-2,3-dihydroxypropoxy)pyridin-2-yl)-4-methyl-N2-((R)-1,1,1- Trifluoroprop-2-yl)-7,8-dihydro-5,8-methylenepyrimidino[4,5-b][1,4]diazepine -2,9(6H)-Diformamide

[1226]

[1227] To (8S)-N9-(4-(((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridine-2- Yl)-4-methyl-N2-((R)-1,1,1-trifluoroprop-2-yl)-7,8-dihydro-5,8-methylenepyrimidino[4,5 -b][1,4]diazepine To a stirred solution of -2,9(6H)-dimethylamide (350 mg, 0.619 mmol) in methanol (5 mL) was added aqueous HCl solution (1.5 mL, 18.00 mmol) and the reaction mixture was stirred at 28°C for 2 h. (TLC eluent: 5% MeOH in DCM, R f : 0.3), then the solvent is evaporated and the resulting residue is NaHCO 3 The solution was neutralized, the resulting solid was filtered and triturated with pentane (20 mL), and dried under reduced pressure to obtain the desired product (8S)-N9-(4-((R)-2,3-dihydroxypropoxy) Pyridin-2-yl)-4-methyl-N2-((R)-1,1,1-trifluoroprop-2-yl)-7,8-dihydro-5,8-methylenepyrimidino [4,5...

Embodiment 2

[1230] Synthesis of (8S)-N9-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N2-(2,2,2-trifluoroethyl)-7,8- Dihydro-5,8-methylenepyrimido[4,5-b][1,4]diazepine -2,9(6H)-Diformamide

[1231]

[1232] To (8S)-9-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-6,7,8,9-tetrahydro-5 , 8-methylenepyrimido[4,5-b][1,4]diazepine Add DIPEA (0.490mL, 2.81mmol), HATU (46.8mg, 0.123mmol) and 2,2,2-trifluoroethane to a stirred solution of -2-formic acid (200mg, 0.561mmol) in DMF (2mL) at once Amine (55.6 mg, 0.561 mmol). The reaction mixture was stirred at room temperature for 16 h. (TLC eluent: 5% MeOH in DCM: R f -0.5; UV activity). The reaction mixture was diluted with cold water and extracted with ethyl acetate (2x 50ml). The combined organic layer was washed with brine solution (20 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain crude product. The crude product was purified by combi flash chromatography (using silica gel column 12g, el...

Embodiment 3

[1235] Synthesis of (8S)-N-(pyridin-2-yl)-2-(3-(trifluoromethyl)phenyl)-7,8-dihydro-5,8-methylenepyrimido[4,5 -b][1,4]diazepine -9(6H)-formamide

[1236]

[1237] To (8S)-2-(3-(trifluoromethyl)phenyl)-6,7,8,9-tetrahydro-5,8-methylenepyrimido[4,5-b] at 0℃ [1,4] Diaza (550mg, 1.796mmol), 3-(pyridin-2-yl)-2H-pyrido[1,2-a][1,3,5]triazine-2,4(3H)-dione (863mg, 3.59 mmol) Sodium hydride (359 mg, 8.98 mmol) was added to a solution in THF (15 mL). The reaction mixture was heated to 60°C for 16 h. It was returned to room temperature and the reaction mixture was poured into cold water (100 mL), and extracted with ethyl acetate (2x200 mL). Use anhydrous Na for the combined organic layer 2 SO 4 Dry and concentrate under reduced pressure to obtain a crude product. The crude product mixture was purified by flash column chromatography (silica gel: 100-200 mesh, using a gradient mixture of 70 to 100% ethyl acetate in petroleum ether) to obtain 400 mg of a semi-pure compound with 91% purity...

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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.

Description

Technical field [0001] In general, the present invention relates to substituted cyclic urea analog compounds of formula (I) to (VI), their corresponding analogs or derivatives, or their pharmaceutically acceptable salts, corresponding pharmaceutical compositions, and the compounds The preparation method and its use alone or in combination with other therapeutic agents as sirtuin modulators for increasing cell lifespan, and for the treatment and / or prevention of various diseases and disorders, the diseases and disorders Including, but not limited to, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular diseases, coagulopathy, inflammation, cancer, and / or flushing, and will benefit from increased mitochondria Active diseases or disorders. Background technique [0002] The Silent Information Regulator (SIR) gene family represents a group of highly conserved genes that exist in the genomes of organisms ranging f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/18A61K31/551A61P35/00A61P29/00A61P17/06A61P17/10A61P19/10A61P19/02A61P37/02A61P27/02A61P3/00A61P3/10A61P9/00A61P25/28
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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