Nonpeptidic neurokinin antagonists

Neurokinins comprise a group of peptides involved in nerve transmission. Specific members of this class of mediators control such diverse functions as visceral regulation and CNS function. The nonpeptide neurokinin antagonist talnetant (32-6), for example, has been evaluated for its effect on irritable bowel syndrome and urinary incontinence as well as depression and schizophrenia [36]. The quinoline portion of this compound is prepared by base-catalyzed Pfitzinger condensation of isatin (32-1) with the methoxy acetophenone (32-2). The methoxy ether in the product (32-3) is next cleaved by means of hydrogen bromide (32-4). Amide formation with the chiral a-phenylpropylamine (32-5) affords the neurokinin antagonist talnetant (32-6) [37]. 

Neurokinins comprise a group of peptides involved in nerve transmission. Specific members of this class of mediators control such diverse functions as visceral regulation, and CNS function. The nonpeptide neurokinin antagonist talnetant (51), for example, is currently being evaluated for its effect on irritable bowel syndrome, urinary... 

Sarau HM, Griswold DE, Potts W, et al. Nonpeptide tachykinin receptor antagonists I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist. / Pharmacol Exp Ther. 1997, 281(3) 1303-1311. 

An oxazole-olefin Diels-Alder reaction was also used in an approach to nonpeptide neurokinin-3 receptor antagonists. Thus when 4-phenyloxazole 55 is melted together with maleic acid at 110°C for 15 min, 2-phenyl-4-pyridinecar-boxylic acid 56 is obtained in 18% yield after decarboxylation (Fig. 3.16). This compound is then coupled with methyl phenylglycinate to give the desired final product 57. 

A recent publication described a short enantioselective synthesis of (+)-L-733,060, a selective and potent nonpeptide neurokinin substance P receptor antagonist. The key chirality-inducing step involved a Shi epoxidation of homoallylic carboxylate 89. Subsequent intramolecular reductive cyclization of azidolactone constructed the piperidine ring. 

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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