Spirocyclic Oxetanes: Synthesis and Properties

Wuitschik, Georg; Rogers‐Evans, Mark; Buckl, Andreas; Bernasconi, Maurizio; Märki, Moritz; Godel, Thierry; Fischer, Holger; Wagner, Björn; Parrilla, Isabelle; Schuler, Franz; Schneider, Jennifer; Alker, André; Schweizer, W. Bernd; Müller, Klaus; Carreira, Erick M.

doi:10.1002/ange.200800450

Cited by 73 publications

(55 citation statements)

References 15 publications

(11 reference statements)

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“…Considering the specific properties of the strained spiro oxetanylazetidinyl moiety in AZD1979 and the increasing interest in incorporating spirocycles as scaffolds in drug design (Wuitschik et al, 2008;Stepan et al, 2011;Carreira and Fessard, 2014;Zheng et al, 2014), it was of particular interest to characterize the metabolic pathways of this compound and the enzymology contributing to its clearance. In this study, we describe the non-P450-mediated formation of a metabolite M1 of AZD1979 and its structural characterization.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Hayes

Grönberg

et al. 2016

Drug Metabolism and Disposition

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Oxetane moieties are increasingly being used by the pharmaceutical industry as building blocks in drug candidates because of their pronounced ability to improve physicochemical parameters and metabolic stability of drug candidates. The enzymes that catalyze the biotransformation of the oxetane moiety are, however, not well studied. The in vitro metabolism of a spiro oxetane-containing compound AZD1979 [(3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone] was studied and one of its metabolites, M1, attracted our interest because its formation was NAD(P)H independent. The focus of this work was to elucidate the structure of M1 and to understand the mechanism(s) of its formation. We established that M1 was formed via hydration and ring opening of the oxetanyl moiety of AZD1979. Incubations of AZD1979 using various human liver subcellular fractions revealed that the hydration reaction leading to M1 occurred mainly in the microsomal fraction. The underlying mechanism as a hydration, rather than an oxidation reaction, was supported by the incorporation of 18 O from H 2 18O into M1. Enzyme kinetics were performed probing the formation of M1 in human liver microsomes. The formation of M1 was substantially inhibited by progabide, a microsomal epoxide hydrolase inhibitor, but not by trans-4-[4-(1-adamantylcarbamoylamino)cyclohexyloxy]-benzoic acid, a soluble epoxide hydrolase inhibitor. On the basis of these results, we propose that microsomal epoxide hydrolase catalyzes the formation of M1. The substrate specificity of microsomal epoxide hydrolase should therefore be expanded to include not only epoxides but also the oxetanyl ring system present in AZD1979.

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Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Hayes

Grönberg

et al. 2016

Drug Metabolism and Disposition

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“…The synthesis of the oxalate salt of 2-oxa-6-azaspiro [3.3]heptane 1a starting from the condensation of 3-bromo-2,2-bis(bromomethyl)propan-1-ol with p-tosylamide has been described [4]. The expanded analogue 1b is commercially available but expensive, and a new synthetic pathway is now reported (Scheme 1).…”

Section: Synthesis Of Spirocyclic Oxetanesmentioning

confidence: 99%

“…Bis (2-oxa-6-azaspiro [3.3]heptan-6-ium) ethanedioate (oxalate salt of 1a) was prepared according to the literature [4].…”

Section: Synthesis Of Spirocyclic Oxetanesmentioning

confidence: 99%

“…Spirocyclic oxetanes such as 2-oxa-6-azaspiro [3.3]heptane (1a) and 2-oxa-7-azaspiro [3.5]nonane (1b) were proposed as valuable structural alternatives to ubiquitous morpholine in medicinal chemistry [4]. A drug discovery project within our group demanded a substituent that enabled higher binding affinities to the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site [5].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of a Spirocyclic Oxetane-Fused Benzimidazole

2015

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Abstract:A new synthesis of 2-oxa-7-azaspiro[3.5]nonane is described. Spirocyclic oxetanes, including 2-oxa-6-azaspiro[3.3]heptane were converted into o-cycloalkylaminoacetanilides for oxidative cyclizations using Oxone ® in formic acid. The expanded spirocyclic oxetane successfully gave the [1,2-a] ring-fused benzimidazole. X-ray crystal structure of the resultant new tetracyclic system, 1ʹ,2ʹ-dihydro-4ʹH-spiro[oxetane-3,3ʹ-pyrido[1,2-a]benzimidazole] and the azetidine ring-opened adduct, N- (2-acetamido-4-bromophenyl)-N-{[3-(chloromethyl) oxetan-3-yl]methyl}acetamide are disclosed.

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“…1 2,octane and 2-oxa-6-azaspiro[3.4] octane 目前, 关于 2,6-二氮杂螺[3,4]环辛烷的合成报道仅有 Engel 等采用 1,1,2-乙烷三羧酸乙酯和 1,3,5-三苄基六氢-1,3,5-三嗪为原料的方法 [7] . 而对于 2-氧-6-氮杂螺 [3,4]环辛烷的合成, Carreira [8] 和 Xu 等 [9] 的方法涉及了一多聚甲醛通过 Baylis-Hillman 反应生成化合物 9. 但在该条件下, 产率仅有 47% (Scheme 2) [16] .…”

Section: 螺[34]环辛烷(图 1a)和 2-氧-6-氮杂螺[34]环辛烷(图 1b)unclassified