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Substituted bridged urea analogs useful as sirtuin modulators

Technology of a compound, alkyl, in the field of substituted bridged urea analogs useful as sirtuin modulators

Inactive Publication Date: 2018-10-23
GLAXO SMITHKLINE LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Moreover, 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 useful as sirtuin modulators
  • Substituted bridged urea analogs useful as sirtuin modulators
  • Substituted bridged urea analogs useful as sirtuin modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0325] Example 1. (4S)-N-(pyridin-2-yl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methylene (methano) Preparation of pyrido[2,3-b][1,4]diazepine-5-(2H)-carboxamide:

[0326] Step 1. Synthesis of (S)-dimethyl 2-((6-chloro-3-nitropyridin-2-yl)amino)succinate:

[0327]

[0328] Add (100 g, 0.52 mol) of 2,6-dichloro-3-nitropyridine, (205 g, 1.04 mol) of (S)-asparagus to a 2 L flask equipped with a thermometer, reflux condenser, and mechanical stirrer Amino acid dimethyl ester hydrochloride, (174g, 2.07mol) in NaHCO 3 and 1 L of tetrahydrofuran. The reaction was stirred at 40 °C for 16 h and monitored by HPLC for the disappearance of 2,6-dichloropyridine. After the reaction was complete, the solid was filtered off and washed with ethyl acetate (3 x 300 mL). The combined filtrate and washings were concentrated to dryness, and the residue was dissolved in 1 L of ethyl acetate. The solution was stirred with 200 g of charcoal at room temperature for 2 h, and the charcoal wa...

Embodiment 2

[0350] Example 2. (4S)-N-phenethyl-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methylenepyrido[2,3- b] Preparation of [1,4]diazepine-5(2H)-carboxamide:

[0351]

[0352] At 0°C, to (4S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1,4-methylenepyrido[2,3-b ][1,4]diazepine (0.100g, 0.326mmol) in CH 2 Cl 2 To a solution in (10 mL) was added pyridine (0.0775 g, 0.980 mmol) and phenyl chloroformate (0.06117 g, 0.392 mmol). After 2 h, the mixture was washed with saturated Na 2 CO 3 The aqueous solution was quenched with CH 2 Cl 2 (3 x 75mL) extracted, washed with brine, washed with Na 2 SO 3 Dried and concentrated. The residue was purified by flash silica gel chromatography to afford (4S)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methylenepyrido[2,3 -b][1,4]Phenyldiazepine-5(2H)-carboxylate (0.120 g, 84% yield).

[0353] (4S)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methylenepyrido[2,3-b][1,4]diazepine A solution of phenylheptatriene-5(2H)-carboxylate,...

Embodiment 3

[0354] Example 3. (4S)-N-(3-(3-aminoprop-1-yn-1-yl)-5-(oxazol-5-yl)phenyl)-7-(3-(trifluoro Methyl)phenyl)-3,4-dihydro-1,4-methylenepyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide Preparation of:

[0355]

[0356](4S)-N-(3-(3-aminoprop-1-yn-1-yl)-5-(oxazol-5-yl)phenyl)-7-(3-(trifluoromethyl) Phenyl)-3,4-dihydro-1,4-methylenepyrido[2,3-b][1,4]diazepine-5(2H)-carboxamide (A, 0.050 g, 0.08 mmol) in 4N HCl in dioxane (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and washed with CH 3 CN grinding. Dissolve the residue in CH 3 CN:H 2 O and lyophilized to give (4S)-N-(3-(3-aminoprop-1-yn-1-yl)-5-(oxazol-5-yl)phenyl)-7-(3-( Trifluoromethyl)phenyl)-3,4-dihydro-1,4-methylenepyrido[2,3-b][1,4]diazepine-5(2H)- Formamide (0.030 g, 70% yield). MS(ESI) calculated value C 29 h 23 f 3 N 6 o 2 :544.18; measured value: 545[M+H].

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Abstract

The present invention provides novel substituted bridged ureas and related analogs and methods of their use. The sirtuin-modulating compounds are useful for increasing cell lifespan, and for treating and / or preventing a variety of diseases and disorders, including, for example, diseases or disorders associated with aging or stress, diabetes, obesity, neurodegenerative diseases, Cardiovascular disease, blood clotting disorders, inflammation, cancer and / or flushing, and diseases or disorders that benefit from increased mitochondrial activity. Compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent are also provided.

Description

Background technique [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 a variety of processes ranging from the regulation of gene silencing to DNA repair. The yeast Sir2 protein belongs to the family of histone deacetylases. 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCA61K31/4995A61K31/506A61K31/551A61P17/10C07D471/18C07D487/04C07D513/18C07D519/00A61K45/06
Inventor C.A.布卢姆C.奥尔曼B.G.什切潘基维茨R.D.考德威尔R.卡索邦B.H.怀特R.B.珀尼K.科佩奇J.S.迪施P.Y.恩格R.M.福克斯
Owner GLAXO SMITHKLINE LLC
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