2012
DOI: 10.1016/j.ejmech.2012.10.005
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Synthesis and structure–activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors: Application of weakly basic sulfoximine group as novel S4 binding element

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Cited by 34 publications
(23 citation statements)
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“…11 Syntheses and structureactivity relationships of orally active anthranilamide-based factor Xa inhibitors have been studied as well. 12 Apart from their biological significance, anthranilamides II are versatile starting materials for further chemical transformations. Recent reports deal with palladium-catalyzed one-pot ring-closure reactions of anthranilamides with tert-butyl isocyanide to quinazolinones 13 (which are also of great biological interest), ruthenium-catalyzed amide-directed C Ar −N activation/C−C coupling reactions with organoboronates under cleavage of the C Ar −N bond, 14 and intramolecular oxidative aryl-aryl couplings by hypervalentiodine-mediated rearrangements.…”
Section: Introductionmentioning
confidence: 99%
“…11 Syntheses and structureactivity relationships of orally active anthranilamide-based factor Xa inhibitors have been studied as well. 12 Apart from their biological significance, anthranilamides II are versatile starting materials for further chemical transformations. Recent reports deal with palladium-catalyzed one-pot ring-closure reactions of anthranilamides with tert-butyl isocyanide to quinazolinones 13 (which are also of great biological interest), ruthenium-catalyzed amide-directed C Ar −N activation/C−C coupling reactions with organoboronates under cleavage of the C Ar −N bond, 14 and intramolecular oxidative aryl-aryl couplings by hypervalentiodine-mediated rearrangements.…”
Section: Introductionmentioning
confidence: 99%
“…Both routes utilize sulfide intermediate 3 , which was prepared by treating 2‐chloro‐5‐(chloromethyl)pyridine ( 2 ) with sodium thiomethoxide to give the desired thioether 3 . As shown in route 1 of Scheme , sulfide 3 was oxidized with m CPBA to provide sulfoxide 4 , which was iminated with sodim azide in the presence of concentrated sulfuric acid to give the sulfoximine intermediate 5 . The nitrogen of sulfoximine 5 was cyanated with cyanogen bromide to give the desired intermediate 6 .…”
Section: Resultsmentioning
confidence: 99%
“…As shown in route 1 of Scheme 3, sulfide 3 was oxidized with mCPBA to provide sulfoxide 4, which was iminated with sodim azide in the presence of concentrated sulfuric acid to give the sulfoximine intermediate 5. 19,20 The nitrogen of sulfoximine 5 was cyanated with cyanogen bromide to give the desired intermediate 6. Concern over the safety of heating sodium azide on a larger scale prompted the development of an alternative route to 6.…”
Section: Synthesis and Characterizationmentioning
confidence: 99%
“…S4 pocket is aromatic box which lined by aromatic side chains of Tyr99, Phe174 and Trp215. Present research has proved that when a p4 motif embodies a cation atom, commonly nitrogen atom under protonation state, can form an arene-cation interaction to improve binding affinity, [26,27] thus the p4 motif interacted with any aromatic side chain of Tyr99, Phe174 and Trp215 can improve binding affinity resulted in the increase of Ki value. Therefore, it made the p4 motif to be various, which explained the reason why there is no pharmacophore generated in the p4 motif.…”
Section: Discussionmentioning
confidence: 99%