Amide-based atropisomers in tachykinin NK1-receptor antagonists: synthesis and antagonistic activity of axially chiral N-benzylcarboxamide derivatives of 2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocin-6-one

Ishichi, Yuji; Ikeura, Yoshinori; Natsugari, Hideaki

doi:10.1016/j.tet.2004.01.097

Cited by 37 publications

(10 citation statements)

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“…Tachykinin NK 1 ‐receptor antagonists have clinical potential in the intervention of a number of pathological states including pain, inflammation, arthritis, asthma, and migraines . The atropisomers of the orally active tachykinin NK1‐receptor antagonist 42 were separated and evaluated for binding potency . The M (aR) enantiomer was found to be more active than the P (aS) enantiomer ( M or aR, IC 50 = 0.24 nM; P or aS, IC 50 = 1.4 nM).…”

Section: Resultsmentioning

confidence: 94%

“…37 The atropisomers of the orally active tachykinin NK1-receptor antagonist 42 were separated and evaluated for binding potency. 38 The M (aR) enantiomer was found to be more active than the P (aS) enantiomer (M or aR, IC 50 = 0.24 nM; P or aS, IC 50 = 1.4 nM). While stable at 37 C for 16 hours, the atropisomers racemized after 6 days at 50 C. Cyclization of the mesylate 43 containing an R-methyl group, gave predominantly the (P)-isomer of the corresponding eight-membered ring analog (98:2 M:P).…”

Section: Axially Chiral Tachykinin Nk 1 -Receptor Antagonistsmentioning

confidence: 94%

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Biological Stereoselectivity of Atropisomeric Natural Products and Drugs

2013

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Selected examples of natural product and drug atropisomers that exhibit stereoselectivity towards receptor and enzyme targets are reviewed. The atropisomeric preference of the receptors and enzyme binding domains makes these agents attractive molecules for drug development in the treatment of various diseases. Included are commonly recognized atropisomers containing a chiral biaryl axis along with some less common examples of atropisomers without a biaryl axis. The biological targets include: antiapoptotic proteins; bacteria; microtubules; kinases; vasopressin receptors; a G-protein coupled receptor related to obesity; monocarboxylate transporters; tachykinin NK1 -receptors; cyclooxygenase-1 and squalene synthase.

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Section: Resultsmentioning

confidence: 94%

Section: Axially Chiral Tachykinin Nk 1 -Receptor Antagonistsmentioning

confidence: 94%

Biological Stereoselectivity of Atropisomeric Natural Products and Drugs

2013

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“…Among a series of aromatic amides, nicotinamide is important because it is an essential element of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are known for their part in biomimetic asymmetric reduction and oxidation in NAD/NADH model systems. The importance of nicotinamides has been demonstrated in both biology and chemistry [22][23][24][25][26]; however, only a few examples of axially chiral nicotinamides have been reported and used for asymmetric synthesis [26][27][28][29][30][31][32][33]. We are interested in the development of convenient methods for preparing axially chiral nicotinamides through dynamic resolution by crystallization.…”

Section: Introductionmentioning

confidence: 99%

Deracemization of Axially Chiral Nicotinamides by Dynamic Salt Formation with Enantiopure Dibenzoyltartaric Acid (DBTA)

et al. 2013

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Dynamic atroposelective resolution of chiral salts derived from oily racemic nicotinamides and enantiopure dibenzoyltartaric acid (DBTA) was achieved by crystallization. The absolute structures of the axial chiral nicotinamides were determined by X-ray structural analysis. The chirality could be controlled by the selection of enantiopure DBTA as a chiral auxiliary. The axial chirality generated by dynamic salt formation was retained for a long period after dissolving the chiral salt in solution even after removal of the chiral acid. The rate of racemization of nicotinamides could be controlled based on the temperature and solvent properties, and that of the salts was prolonged compared to free nicotinamides, as the molecular structure of the pyridinium ion in the salts was different from that of acid-free nicotinamides.

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“…In the course of our research aimed at developing new γ-secretase inhibitors, we have been interested in LY-411575 ( 1 ) and prepared several new derivatives (e.g., 1a ) . Our recent interest in relationships between axial chirality and biological activity also prompted us to elucidate the stereochemistry of the dibenzo[ b , d ]azepin-6-one moiety that constitutes the scaffold of LY-411575. The stereochemistry is of interest in that, in addition to the one asymmetric center at C7, the moiety has chirality based on the sp 2 −sp 2 axis arising from a biphenyl (Figure ).…”

mentioning

confidence: 99%