Human Neurokinin-1 Receptor Antagonists

Hale, J.J., Mills, S.G., MacCoss, M., et al. (2000) Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. 7. Med. Chem. 43 1234-1241. 

Figure 13.20 Preparation of (lR,2R)-2-(4-fluorophenyl)-3-oxocydopentanecarboxylate, core element of human neurokinin-1 receptor antagonists.

SCHEME 34.41. Asymmetric secondary alcohol oxidation kinetic resolution step in the synthesis of human neurokinin receptor antagonist h-NKl 156. 

A third example of drug synthesis consists in the preparation of the human neurokinin receptor antagonist h-NKl 156. An chiral intermediate toward its synthesis is prepared by kinetic resolution of a 2-aryl-cyclopentenol derivative 157 in chloroform with the usual Pd(II) with (—)-sparteine 132 obtaining very high selectivity up to 82.7, which is a really impressive result, with conversion of 50.8% and ee of 94.7% of the product 158 (Scheme 34.41). 

Mechanism of Action Aselective human substance P and neurokinin-1 (NK,) receptor antagonist that inhibits chemotherapy-induced nausea and vomiting centrally in the... 

Fong, T. M., Huang, R.-R. C., Strader, C. D. Localization of agonist and antagonist binding domains of the human neurokinin-1 receptor, J. Biol. Chem. 1992, 267, 25664-25667. 

Ketoester 79, containing a tetrasubstituted C=C bond, has been successfully reduced with a panel of commercial ene reductases affording (lJi,2R)-80 (Scheme 3.21), useful precursor of nonpeptide antagonists of human neurokinin-1 (hNK-1) receptor. With ERED114 the product is obtained quantitatively with 93% ee and 88% de (see Chapter 13 for further details) [94]. This is a particularly relevant example, given the difficulty in obtaining a good diastereoselectivity in the bioreduction of tetrasubstituted olefins (Scheme 3.21). 

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