64168-09-8Relevant articles and documents
Orthogonal Catalysis for an Enantioselective Domino Inverse-Electron Demand Diels?Alder/Substitution Reaction
Beeck, Sebastian,Ahles, Sebastian,Wegner, Hermann A.
supporting information, (2021/12/09)
An enantioselective domino process for the synthesis of substituted 1,2-dihydronaphthalenes has been developed by the combination of chiral amines and a bidentate Lewis acid in an orthogonal catalysis. This new method is based on an inverse electron-demand Diels?Alder and a subsequent group exchange reaction. An enamine is generated in situ from an aldehyde and a chiral secondary amine catalyst that reacts with phthalazine, activated by the coordination to a bidentate Lewis acid catalyst. The absolute configuration of the product is controlled by chiral information provided by the amine. The formed ortho-quinodimethane intermediate is then transformed via a group exchange reaction with thiols. The new method shows a broad scope and tolerates a wide range of functional groups with enantiomeric ratios up to 91 : 9. All-in-all, this enantioselective synthesis tool provides an easy access to complex 1,2-dihydronaphthalenes starting from readily available phthalazine, aldehydes and thiols in a combinatorial way.
(2S)-1-(arylacetyl)-2-(aminomethyl)piperidine derivatives: Novel, highly selective κ opioid analgesics
Vecchietti,Giordani,Giardina,Colle,Clarke
, p. 397 - 403 (2007/10/02)
This paper describes the synthesis and structure-activity relationships as κ opioid analgesics of a novel class of 1-(arylacetyl)-2-(aminomethyl)piperidine derivatives (8). The active conformation of the pharmacophore, with a torsional angle (N1C2C7N8) of 60°, was defined with computational studies and 1H NMR. A quantitative structure-activity relationship study of the arylacetic moiety substitution indicated that the presence of an electron-withdrawing and lipophilic substituent in para and/or meta positions is required for good analgesic activity and κ affinity. The lead compounds (2S)-1-[(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-ylmethyl) piperidine hydrochloride (14) and (2S)-1-[[4-(trifluoromethyl)phenyl]acetyl]-2-(pyrrolidin-1- ylmethyl)piperidine hydrochloride (21) are the most κ/μ selective (respectively 6500:1 and 4100:1) and among the most potent (K(i) κ 0.24 and 0.57 nM, respectively) κ ligands identified so far. In the mouse tail flick model of antinociception, compound 14 (ED50 = 0.05 mg/kg sc) was 25 times more potent than morphine and 16 times more potent than the standard κ ligand U-50488.
CONDENSED DIAZEPINONES, THEIR COMPOSITIONS AND METHODS OF USE AS PHARMACEUTICALS
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, (2008/06/13)
Disclosed are novel condensed diazepinones of formula I STR1 wherein B is a fused ring selected from STR2 X is--CH--or, when B is ortho-phenylene, X can also be nitrogen; A 1 is C 1-C. sub.2 alkylene; A 2 is C 1-C 2 when it is in the 2-position relative to the saturated heterocyclic ring nitrogen or a single bond or methylene when it is in the 3-or 4-position; R 1 is C 1-C 3 alkyl; R 2 is C. sub.1-C 7 alkyl, optionally hydroxy-substituted on at least one of its second to seventh carbon, or C 3-C 7 cycloalkyl, optionally hydroxy substituted, or C 3-C 7 cycloalkylmethyl; or R 1 and R 2 can, together with the nitrogen therebetween, be a 4-to 7-membered saturated monocyclic, heterocyclic ring which can optionally include an oxygen or N--CH 3 ; R 3 is hydrogen, chlorine, or methyl; R 4 is hydrogen or C 1-C 4 alkyl, R 5 is hydrogen, chlorine or C 1-C 4 alkyl; and Z is a single bond, oxygen, methylene or 1,2-ethylene; and NR 1 R 2--N oxides and nontoxic, pharmaceutically acceptable addition salts thereof. Also disclosed are pyrrolobenzodiazepinone intermediates, pharmaceutical compositions containing the condensed diazepinones and methods of using them to treat cardiovascular disorders, particularly bradycardia and bradyarrhythmia.
