- PREPARATION AND ALKYLATION OF CYCLIC β-TRIMETHYLSTANNYL α,β-UNSATURATED ESTERS. A NEW, GENERAL ANNULATION SEQUENCE
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The key steps of a newly developed annulation method involve (a) reaction of cyclic β-trifluoromethanesulfonyloxy α,β-unsaturated esters (e.g. 14-16) with lithium(phenylthio)(trimethylstannyl)cuprate, (b) alkylation of the resultant products (e.g.17-19) with 1,ω-dihaloalkanes, and (c) transmetalation-cyclization of suitable substrates (e.g.25, 26, 28, 30) derived from the alkylation products (e.g. 20-24).
- Piers, Edward,Tse, Hoi Lun Allan
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- The Discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1 H -inden-4-yl)pyridin-2-yl)-5-methyl-1 H -pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma
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Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.
- Ehara, Takeru,Adams, Christopher M.,Bevan, Doug,Ji, Nan,Meredith, Erik L.,Belanger, David B.,Powers, James,Kato, Mitsunori,Solovay, Catherine,Liu, Donglei,Capparelli, Michael,Bolduc, Philippe,Grob, Jonathan E.,Daniels, Matthew H.,Ferrara, Luciana,Yang, Louis,Li, Byron,Towler, Christopher S.,Stacy, Rebecca C.,Prasanna, Ganesh,Mogi, Muneto
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p. 2552 - 2570
(2018/03/26)
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- CYCLOHEXEN-1-YL-PYRIDIN-2-YL-1H-PYRAZOLE-4-CARBOXYLIC ACID DERIVATIVES AND THE USE THEREOF AS SOLUBLE GUANYLATE CYCLASE ACTIVATORS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacolo
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- Rh2(II)-catalyzed ester migration to afford 3 H-indoles from trisubstituted styryl azides
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Rh2(II)-Complexes trigger the formation of 3H-indoles from ortho-alkenyl substituted aryl azides. This reaction occurs through a 4π-electron-5-atom electrocyclization of the rhodium N-aryl nitrene followed by a [1,2]-migration to afford only 3H-indoles. The selectivity of the migration is dependent on the identity of the β-styryl substituent.
- Kong, Chen,Driver, Tom G.
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p. 802 - 805
(2015/04/27)
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- Promoting reductive tandem reactions of nitrostyrenes with Mo(CO)6 and a palladium catalyst to produce 3 h -indoles
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The combination of Mo(CO)6 and 10 mol % of palladium acetate catalyzes the transformation of 2-nitroarenes to 3H-indoles through a tandem cyclization-[1,2] shift reaction of in situ generated nitrosoarenes. Mo(CO)6 appears to have dual roles in this transformation: generate CO and promote C-N bond formation to increase the yield of the N-heterocycle product.
- Jana, Navendu,Zhou, Fei,Driver, Tom G.
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supporting information
p. 6738 - 6741
(2015/06/16)
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- A new annulation method. Total syntheses of the sesquiterpenoids (+/-)-chiloscyphone and (+/-)-6-epi-chiloscyphone
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The efficacy of a new annulation method, developed for the construction of functionalized bicyclic compounds, is illustrated by conversion of the β-keto esters 18 and 19 into the bicyclonon-1-enes 33 and 34, respectively, and by transformation of 2-methoxycarbonylcyclopentanone (20) into the bicyclonon-6-ene 38 and the bicyclodec-7-enes 48 and 51.Application of the method to total syntheses of the structurally unusual sesquiterpenoids (+/-)-chiloscyphone (16) and (+/-)-6-epi-chiloscyphone (17) is described.
- Piers, Edward,Tse, Hoi Lun Allan
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p. 983 - 994
(2007/10/02)
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