The stereochemistry of a nine-membered ring analogue of nefopam, a nonnarcotic analgesic drug

Glaser, Rainer; Shiftan, Dror; Drouin, Marc

doi:10.1007/bf02263525

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…Other analogues of this ring system afford different conformations; e.g. the (1 RS ,6 RS )-1-phenyl-6-methyl-1,3,4,5,6,7-hexahydro-2,6-benzoxazonine ( 24 ) moiety in both the hydrogen fumarate salt (crystalline solid state) and in the hydrochloride salt (CD 2 Cl 2 solution) exists in what is now called the “TCBtype-3” conformation . Two related crystalline state structures with 2,5-benzoxazonine ring skeletons and a substituted benzothieno analogue are known.…”

Section: Resultsmentioning

confidence: 99%

“…A search of the Cambridge Crystallographic DataBase (CCDB) was undertaken as part of our studies on benzannelated medium-size rings related to the octagonal ring nonnarcotic analgesic drug nefopam hydrochloride and its nine-membered ring analogue homonefopam hydrogenfumarate . The CCDB provides crystallographic examples of 10 of the 13 cis- cyclononene conformations.…”

Section: Introductionmentioning

confidence: 99%

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cis-Cyclononene Conformational Families and a Crystallographic Example of a Skew-Chair−Boat Type-2 Conformation

et al. 2002

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Cyclononanes from the 7 low-energy conformational archetypal families (twist-boat[bond]chair, twist-chair[bond]boat, twist-chair[bond]chair, twist-chair[bond]twist-chair, skew-chair[bond]boat, skew-chair[bond]chair, and skew-boat[bond]boat) were transformed into 12 of 13 MM3 stochastically generated cis-cyclononenes. This was done by systematically converting single bond synclinal endocyclic torsion angles, one-at-a-time, into double-bond synperiplanar analogues, followed by geometry optimization [e.g. density functional theory B3LYP/6-31G(d)]. Torsion angles adjacent to the new double bond maintained their signs, while their magnitudes usually changed considerably to accommodate the new neighboring synperiplanar torsion angles. The six remaining torsion angles all maintained their signs and approximate magnitudes compared to corresponding values in the seven saturated parent structures. As a result, the same "twist"/"skew" conformational descriptors previously used for the saturated conformers can now also be applied to the corresponding unsaturated analogues. Three conformational families have multiple members (subtypes) in which the double bond is located at different positions on the same ring conformation. The solid-state structures of (+/-)-1-phenyl-1,3,4,5,6,7-hexahydro-2,6-benzoxazonine-6-carbonitrile (22) and (1RS,3SR)-1-phenyl-3-methyl-1,3,4,5,6,7-hexahydro-2,6-benzoxazonine-6-carbonitrile (23) were determined by single-crystal X-ray diffraction analysis. The asymmetric unit of the Ponemacr; unit cell for 22 contains two symmetry-unrelated molecules, both of which exhibit a skew-chair-boat (SCBtype-2) conformation identical to that found for crystalline 23. This subtype has yet to be found in the Cambridge Crystallographic DataBase. Crystal lattice packing considerations alone cannot explain the observation of the SCBtype-2 conformation since (1)H NMR spectroscopy shows the same conformational bias when the crystals are dissolved in CDCl(3).

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

cis-Cyclononene Conformational Families and a Crystallographic Example of a Skew-Chair−Boat Type-2 Conformation

et al. 2002

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“…This is still a relatively unexplored area chemically and pharmacologically, although some medium ring heterocycles have been incorporated in useful therapeutics (eg. Nefopam [61]). …”

Section: Combined Approachmentioning

confidence: 96%

Ligand Design for Alpha1 Adrenoceptors

Bremner

Griffith²,

Çoban³

2001

CMC

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An area of continuing interest in medicinal chemistry is the design, synthesis and pharmacological evaluation of ligands which bind at adrenoceptor subtypes, which include alpha(1A), alpha(1B), alpha(1D); alpha(2A), alpha(2B), alpha(2C); beta(1), beta(2), beta(3) and possibly beta(4) subtypes. The selective blockade or stimulation of these receptor subtypes is of on-going pharmacological and medicinal interest. However, the design principles for ligand differentiation at these subtypes still need further development. This review focuses on alpha(1) adrenoceptors with a concentration on literature over the past five years. Structural, physiological and therapeutic aspects of the alpha(1A), alpha(1B) and alpha(1D) subtypes are discussed together with ligands binding to these receptor subtypes. Approaches to alpha(1) adrenoceptor ligand design based on known ligands and on receptor docking are evaluated. A new combined approach using pharmacophores and receptor docking affords possibilities for deeper insights into achieving small molecule binding selectivity.

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2015

Symmetry, Spectroscopy, and Crystallography

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The stereochemistry of a nine-membered ring analogue of nefopam, a nonnarcotic analgesic drug

Abstract: The solid-state structure of a (+)-homonefopam hydmgenfumarate salt having an --O(CH2)3N--fragment was determined by single-crystal X-ray diffraction analysis. Homonefo-

Cited by 5 publications

References 24 publications

cis-Cyclononene Conformational Families and a Crystallographic Example of a Skew-Chair−Boat Type-2 Conformation

cis-Cyclononene Conformational Families and a Crystallographic Example of a Skew-Chair−Boat Type-2 Conformation

Ligand Design for Alpha1 Adrenoceptors

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