- A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D-Shaped Triquinazine Ring System from Chemical Space
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The generated databases (GDBs) enumerate billions of possible molecules following simple rules of chemical stability and synthetic feasibility. Exploring the GDBs shows that many chiral, 3D-shaped ring systems, often containing quaternary centers, have never been exploited for drug design. Shown herein is that such ring systems can be useful for medicinal chemistry by using the example of the enantioselective synthesis of triquinazine, a novel chiral piperazine analogue derived from angular triquinane. It is used to design a nanomolar and selective inhibitor of Janus Kinase 1 and is related to the marketed drug Tofacitinib, which is useful for treating autoimmune diseases.
- Meier, Kris,Arús-Pous, Josep,Reymond, Jean-Louis
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- Cationic NHC-Phosphine Iridium Complexes: Highly Active Catalysts for Base-Free Hydrogenation of Ketones
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Novel bidentate N-heterocyclic carbene-phosphine iridium complexes have been synthesized and evaluated in the hydrogenation of ketones. Reported catalytic systems require base additives and, if excluded, need elevated temperature or high pressure of hydrogen gas to achieve satisfactory reactivity. The developed catalysts showed extremely high reactivity and good enantioselectivity under base-free and mild conditions. In the presence of 1 mol % catalyst under 1 bar hydrogen pressure at room temperature, hydrogenation was complete in 30 minutes giving up to 96 % ee. Again, this high reactivity was achieved in additive-free conditions. Mechanistic experiments demonstrated that balloon pressure of hydrogen was sufficient to form the activate species by reducing and eliminating the 1,5-cyclooctadiene ligand. The pre-activated catalyst was able to hydrogenate acetophenone with 89 % conversion in 5 min.
- Quan, Xu,Kerdphon, Sutthichat,Peters, Bram B. C.,Rujirawanich, Janjira,Krajangsri, Suppachai,Jongcharoenkamol, Jira,Andersson, Pher G.
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supporting information
p. 13311 - 13316
(2020/09/22)
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- Synthesis of Cyclic N-Hydroxylated Ureas and Oxazolidinone Oximes Enabled by Chemoselective Iodine(III)-Mediated Radical or Cationic Cyclizations of Unsaturated N-Alkoxyureas
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In this study we describe the reactivity of unsaturated N-alkoxyureas in the presence of different combinations of a hypervalent iodine(III) reagent and a bromide source or TEMPO. Three complementary cyclizations can be achieved depending on the reaction conditions. On the one hand, PIFA with pyridinium bromide leads to an oxybromination reaction. On the other hand, bis(tert-butylcarbonyloxy)iodobenzene with tetrabutylammonium bromide or TEMPO triggers aminobromination or aminooxyamination reactions, respectively. Control experiments showed that the three reactions proceed through distinct mechanisms: the first process is ionic while the other two follow a radical manifold. (Figure presented.).
- Peilleron, Laure,Retailleau, Pascal,Cariou, Kevin
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p. 5160 - 5169
(2019/11/11)
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- TRIAZOLOPYRIDINE INHIBITORS OF MYELOPEROXIDASE
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The present invention provides compounds of Formula (I). wherein A and Z are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are myeloperoxidase (MPO) inhibitors and may be useful for for the treatment and/or prophylaxis of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.
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Page/Page column 89; 90
(2017/10/18)
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- The discovery of new human coagulation factor XIa (FXIa) inhibitors by synthesis, biological evaluation, and structure-based modeling
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Factor XIa (FXIa) is an enzyme that is activated during the earliest stage of initiation of the intrinsic pathway of the blood coagulation mechanism. In this study, we attempted to discover a new FXIa inhibitor based on structure-based molecular modeling. We found that compound 16 exhibits satisfactory predicted properties while maintaining important binding interactions with FX1a.
- Lee, Myeong Hwi,Song, Ho Young,Kim, Hyoungrae,Park, Kyung Eun,Kim, Jinyeong,Park, Tae Kyo,Kim, Yong Ju,Kang, Nam Sook
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p. 1105 - 1113
(2016/07/15)
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- Enantioselective Synthesis of 3,3-Difluoropyrrolidin-4-ol, a Valuable Building Block in Medicinal Chemistry
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In this paper, we report for the first time two enantioselective routes to 4,4-difluoropyrrolidin-3-ol, a valuable building block in medicinal chemistry. In the first route, we took advantage of the C2 symmetry of (3R,4R)-3,4-dihydroxypyrrolidine in which the desired chirality was derived from the chiral pool (l-(+)-tartaric acid). In the second route, we efficiently assembled the pyrrolidine ring in the presence of a gem-difluoro moiety to avoid using potentially hazardous deoxofluorinating reagents and subsequently introduced the chirality by a stereoselective iridium-diamine-catalyzed asymmetric transfer hydrogenation reaction.
- Si, Chong,Fales, Kevin R.,Torrado, Alicia,Frimpong, Kwame,Kaoudi, Talbi,Vandeveer, Harold George,Njoroge, F. George
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p. 4359 - 4363
(2016/06/09)
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- Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: A pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues
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A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Bronsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Bronsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.
- Khan, Imran A.,Saxena, Anil K.
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p. 11656 - 11669
(2014/01/06)
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- NOVEL OXABISPIDINE COMPOUNDS AND THEIR USE IN THE TREATMENT OF CARDIAC ARRHYTHMIAS
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There is provided compounds of formula I, wherein R1, R2, R4, R41 to R46, A, B and G have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.
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Page/Page column 83-84
(2008/06/13)
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- Scope and limitations of the alkylidene carbene 1,5-CH insertion reactions of α-amino acid-derived substrates
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A range of α-amino acid-derived cyclisation precursors were synthesised from suitably protected α-amino esters, via a Dibal-H/Wittig/catalytic hydrogenation strategy and each of these was subjected to alkylidene carbene-forming conditions (lithio(trimethy
- Mapitse, Renameditswe,Hayes, Christopher J
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p. 3541 - 3542
(2007/10/03)
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- Enantioselective synthesis of 1,2-, 1,3- and 1,4- aminoalcohols by the addition of dialkylzincs to 1,2-, 1,3- and 1,4- aminoaldehydes
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Chiral 1,3- and 1,4- aminoalcohols were prepared by the addition of functionalized dialkylzincs to 1,3-aliphatic and 1,4-unsaturated aminoaldehydes with good to excellent enantioselectivity. Syn- or anti-1,2- aminoalcohols are stereoselectively obtained by asymmetric addition of dialkylzincs to α-aminoaldehydes depending on the choice of the chiral catalyst. A chelate controlled addition is observed if less than stoichiometric amounts of Ti(Oi-Pr)4 are used.
- Lutz, Christian,Lutz, Volker,Knochel, Paul
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p. 6385 - 6402
(2007/10/03)
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- Renin inhibitors having all retro-inverted peptide bonds
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Renin-inhibiting peptides of the formula STR1 in which X represents a group of the formula STR2 represents hydroxyl, alkoxy having up to 8 carbon atoms, benzyloxy or a group of the formula --NR4 R5, A, B, D and E are identical or different and in each case represent a direct bond, represent a radical of the formula STR3 in which Q1 denotes oxygen, sulphur or the methylene group represent a grouping of the formula STR4 m represents a number 0, 1 or 2, and L represents a group of the formula --CH2 NR2 R3 and physiologically acceptable salts thereof.
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