Axially Chiral N-Benzyl-N,7-dimethyl-5-phenyl-1,7-naphthyridine-6-carboxamide Derivatives as Tachykinin NK₁ Receptor Antagonists:  Determination of the Absolute Stereochemical Requirements

Abstract

A potent and orally active NK1 antagonist, trans-N-[3, 5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N, 7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1t), was shown to exist as a mixture of separable and stable (R)- and (S)-atropisomers (1t-A and 1t-B) originating from the restricted rotation around the -C(6)-C(=O)- bond; the antagonistic activities of 1t-A were ca. 6-13-fold higher than those of 1t-B. Analogues of 1t (3), which have (S)- and (R)-methyl groups at the benzylic methylene portion of 1t, were prepared and separated into the diastereomeric atropisomers, 3a-A, 3a-B and 3b-A, 3b-B, in enantiomerically pure forms. Among the four isomers of 3, the (aR, S)-enantiomer (3a-A) exhibited the most potent antagonistic activities with an IC50 value of 0.80 nM (in vitro inhibition of [125I]BH-SP binding in human IM-9 cells) and ED50 values of 9.3 micrograms/kg (iv) and 67.7 micrograms/kg (po) (in vivo inhibition of capsaicin-induced plasma extravasation in guinea pig trachea), while the activity of the (aS,R)-enantiomer (3b-B) was the weakest with an IC50 value of 620 nM. The structure-activity relationships in this series of antagonists indicate that the (R)-configuration at the axial bond and the stacking (or stacking-like) conformation between the two phenyl rings as shown in 1t-A and 3a-A are essential for high-affinity binding and suggest that the amide moiety functions as a hydrogen bond acceptor in the interaction with the receptor.

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

“…These data indicate that the conformers (atropisomers) of 4 are rapidly interconverted 9 even on the NMR timescale at room temperature, whereas those of 5 are slowly interconverted, with the methylene protons being diastereotopic. 2,4 Thus, although the separation of the atropisomers of 5 has not been attempted, we presume that compounds 5 exist as racemates.…”

“…In our previous papers, [1][2][3][4] we described the synthesis of the axially chiral 1,7-naphthyridine-6-carboxamide derivatives, represented by 1 (Scheme 1) 1,2 and TAK-637 (Scheme 2), 3,4 as orally active tachykinin NK 1 -receptor antagonists. Because the carboxamide moiety of these compounds exists at the sterically hindered position, rotation around the -C (6)[or (5a)] -C(vO)-bond is restricted, yielding separable and stable atropisomers.…”

“…The enantiomeric atropisomers differed in activity at the tachykinin NK 1 -receptor, with aR isomer being more active (i.e., eutomer) [IC 50 , nM: aR, 0.24; aS, 1.4] (Scheme 1). 2 TAK-637 [(aR,9R)-3], which is an 8-membered cyclic analogue of 1 with aR stereochemistry, was formed atropodiastereoselectively by cyclization of the chiral (R) methyl intermediate R-2 in preference to the aS-isomer [(aS,9R)-3] in a ratio of ca. 98:2.…”

The Application of Molecular Tethers in Controlling Axial Chirality

“…There are many other examples of axially chiral biologically active compounds, such as pyrimidol [1,2-a] [1,4]benzodiazepine and colchicine, where the configuration around the biaryl linkage has a significant effect on bioactivity. [11][12][13][14] Axial chirality may be controlled via a variety of different methods such as the use of chiral auxiliaries, chiral catalysts, the "lactone method" and molecular tethers. Significant advances have been made in recent years in the use of chiral ligands and transition metal catalysts in the stereoselective synthesis of biaryl systems.…”

Non‐Biaryl Atropisomers in Organocatalysis

“…Nonetheless, this is only a sub-class of atropisomers and in recent years several groups have focussed on another sub-class of atropisomers, the non-biaryl atropisomeric anilides 1 and aromatic amides 2. [4][5][6][7][8] What started out as a textbook curiosity [9] has been developed to be a prosperous field of organic chemistry with applications in enantioselective synthesis, [10] asymmetric catalysis, [11] medicinal chemistry [12] and a model system for allosteric interactions. [13] While a variety of synthetic approaches are now available for the biaryl atropisomers, [14] ways to access enantiopure non-biaryl atropisomers are still limited.…”