- Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles: The Fundamental Role of the Azole as a Ligand for Palladium
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An in-depth mechanistic study on the palladium-catalyzed direct arylation of imidazoles at the C-5 position is presented. The interactions of triphenylphosphine (PPh3)-ligated aryl-Pd species with 1,2-dimethyl-1H-imidazole (dmim) have been studied in detail. In contrast with previous suggestions, phosphine-ligated organo-Pd species are not active and the reaction proceeds through imidazole-ligated organo-Pd intermediates. The kinetics of the oxidative addition of aryl halides with dmim-ligated Pd(0) species have been characterized in a Pd(dba)2/dmim model system. A thorough study of the equilibria involving novel [ArPd(dmim)2X] complexes (X=I, OAc) and the unexpected cationic [ArPd(dmim)3]+ is also reported. The ability of these species to effect the C-H arylation of dmim at room temperature in the presence of acetate is also demonstrated.
- Perego, Luca Alessandro,Grimaud, Laurence,Bellina, Fabio
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supporting information
p. 597 - 609
(2016/02/27)
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- NOVEL THIOPHENE INHIBITORS OF S-NITROSOGLUTATHIONE REDUCTASE
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The present invention is directed to novel thiophene inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
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Page/Page column 53
(2011/07/07)
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- PYRROLOTHIAZOLES AS PI3-KINASE INHIBITORS
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A series of 4,5-dihydro-6H-pyrrolo[3,4-d][1,3]thiazol-6-one derivatives, and analogues thereof, which are substituted in the 2-position by an optionally substituted morpholin-4-yl moiety, being selective inhibitors of PI3 kinase enzymes, are accordingly o
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Page/Page column 83
(2009/07/17)
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- NITROGEN CONTAINING HETEROAROMATICS AS FACTOR Xa INHIBITORS
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The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula (I) or pharmaceutically acceptable salt or prodrug forms thereof, wherein J is N or NH and D may be C(=NH)NH2, which are useful as inhibitors of factor Xa.
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Page/Page column 65
(2009/10/01)
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- Discovery of 1-(3′-aminobenzisoxazol-5′-yl)-3-trifluoromethyl- N-[2-fluoro-4-[(2′-dimethylaminomethyl)imidazol-1-yl]phenyl] -1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor
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Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P1 ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P4 moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3′-aminobenzisoxazol-5′-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2′-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).
- Quan, Mimi L.,Lam, Patrick Y. S.,Han, Qi,Pinto, Donald J. P.,He, Ming Y.,Li, Renhua,Ellis, Christopher D.,Clark, Charles G.,Teleha, Christopher A.,Sun, Jung-Hui,Alexander, Richard S.,Bai, Steve,Luettgen, Joseph M.,Knabb, Robert M.,Wong, Pancras C.,Wexler, Ruth R.
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p. 1729 - 1744
(2007/10/03)
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- NOVEL GUANIDINE MIMICS AS FACTOR Xa INHIBITORS
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The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula (I) or pharmaceutically acceptable salt forms thereof, wherein rings D-E represent guanidine mimics, which are useful as inhibitors of factor Xa.
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Page/Page column 52-53
(2010/02/13)
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- 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as potent factor Xa inhibitors. Part 2: A survey of P4 motifs
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A variety of P4 motifs have been examined to increase the binding affinity and in vitro anticoagulant potency of our biphenyl 1-(2-naphthyl)-1H-pyrazole-5- carboxylamide-based fXa inhibitors. Highly potent 2-naphthyl-P1 fXa inhibitors (Ki≤2 nM) with improved in vitro anticoagulant activity (2×TG≤1 μM) and respectable pharmacokinetic properties have been discovered.
- Jia, Zhaozhong J.,Wu, Yanhong,Huang, Wenrong,Zhang, Penglie,Clizbe, Lane A.,Goldman, Erick A.,Sinha, Uma,Arfsten, Ann E.,Edwards, Susan T.,Alphonso, Merlyn,Hutchaleelaha, Athiwat,Scarborough, Robert M.,Zhu, Bing-Yan
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p. 1221 - 1227
(2007/10/03)
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- Guanidine mimics as factor Xa inhibitors
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The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula I: or pharmaceutically acceptable salt forms thereof, wherein rings D—E represent guanidine mimics, which are useful as inhibitors of factor Xa.
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Page column 118, 119
(2010/02/04)
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- Nitrogen containing heteroaromatics as factor Xa inhibitors
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The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula I: or pharmaceutically acceptable salt or prodrug forms thereof, wherein J is N or NH and D may be C(=NH)NH2, which are useful as inhibitors of factor Xa.
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- Bis-aryl amide and urea antagonists of platelet activating factor
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Bis-aryl amide and urea compounds of the general formula: STR1 wherein X is a divalent amide or urea substituent and Y is a nitrogen containing heterocycle, which compounds are inhibitors of platelet activating factor. Pharmaceutical compositions containing the compounds and methods of treating platelet activating factor associated conditions are also included.
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- Method of preparing bis-aryl amide and urea antagonists of platelet activating factor
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Methods of preparing bis-aryl amide and urea compounds of the general formula: STR1 wherein x is a divalent amide or urea substituent and Y is a nitrogen containing heterocycle, which compounds are inhibitors of platelet activating factor.
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- Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles
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Novel heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles, useful as antifungal and antibacterial agents.
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- Novel imidazole compound and anti-depressing agent containing the same
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An imidazole compound of the formula: STR1 wherein R1 is lower alkyl, R2 is hydrogen or lower alkyl, and R3, R4 and R5 are hydrogen, lower alkyl, trifluoromethyl, amino, mono- or di-lower alkylamino,
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