194151-99-0Relevant articles and documents
Switchable Regioselective 6-endo or 5-exo Radical Cyclization via Photoredox Catalysis
Blakey, Simon B.,Hendy, Cecilia M.,Jui, Nathan T.,Maust, Mark C.
supporting information, p. 3776 - 3781 (2022/03/08)
Controlling the regioselectivity of radical cyclizations to favor the 6-endo mode over its kinetically preferred 5-exo counterpart is difficult without introducing substrate prefunctionalization. To address this challenge, we have developed a simple method for reagent controlled regioselective radical cyclization of halogenated N-heterocycles onto pendant olefins. Radical generation occurs under mild photoredox conditions with control of the regioselectivity governed by the rate of hydrogen atom transfer (HAT). Utilizing a polarity-matched thiol-based HAT agent promotes the highly selective formation of the 5-exo cyclization product. Conversely, limiting the solubility of the HAT reagent Hantzsch ester (HEH) leads to selective formation of the thermodynamically favored 6-endo product. This occurs through an initial 5-exo cyclization, with the resulting alkyl radical intermediate undergoing neophyl rearrangement to form the 6-endo product. Development of this switchable catalysis strategy allows for two modes of divergent reactivity to form either the 6-endo or 5-exo product, generating fused N-heteroaromatic/saturated ring systems.
Cyclic gyrase and topoisomerase IV inhibitor
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Paragraph 0285; 0286; 0287, (2017/01/02)
The invention belongs to the technical field of medicament, and particularly relates to a compound shown in formula (I) (please see the formula (I) in the description), and acceptable salt, ester or stereoisomer of the compound in pharmacy. R1, R2, a ring
Development of orally active oxytocin antagonists: Studies on 1-(1-{4- [1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy].2methoxybenzoyl}- 4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines
Bell, Ian M.,Erb, Jill M.,Freidinger, Roger M.,Gallicchio, Steven N.,Guare, James P.,Guidotti, Maribeth T.,Halpin, Rita A.,Hobbs, Doug W.,Homnick, Carl F.,Kuo, Michelle S.,Lis, Edward V.,Mathre, David J.,Michelson, Stuart R.,Pawluczy, Joseph M.,Pettibone, Douglas J.,Reiss, Duane R.,Vickers, Stanley,Williams, Peter D.,Woyden, Carla J.
, p. 2146 - 2163 (2007/10/03)
The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N- oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.
