Tachykinin antagonists

Benzhydryl-perhydropyrazino[2,l-f][l,4]oxazines and -thiazines are tachykinin antagonists <2002W0055518>. 

Diaryl-octahydro-pyra/ino[2,1 -c 1,4]thiazines are useful as melanine concentrating hormone receptor ligands <2002W02002/094799>. Pyrazino[2,l-f][l,4]oxazines 245 (Y = 0) and pyrazino[2,1 -c][ 1,4]thiazines 245 (Y = S) exert a tachykinin antagonistic effect <2002W0055518>. 

Non-peptidic tachykinine antagonists were converted to photoprobe ligands by Ward. First, a piperidine derivative, CP-99,994 (Glaxo) was appended with a diazirine photophore (6, Fig. 7) to study SP (NK1) receptors [74]. A similar modification on a neurokinin A antagonist, SR 48968 (Sanofi) produced a photoligand (5, Fig. 7) in order to investigate NK2 receptor proteins [75]. 

Folkers, K., Feng, D. M., Asano, N., Hakanson, R., Wiesenfeld-Hallin, Z., Leander, S. Spantide II, an effective tachykinin antagonist having high potency and negligible neurotoxicity, Proc. Natl. Acad. Sci. U S.A. 1990, 87, 4833-4835. 

Hakanson, R. and Sundler, F. Tachykinin Antagonists, Fernstrom Foundation Series. (Elsevier, Amsterdam, NL 1985). 

Ko, S.Y. and Walpole, C. (Sandoz Ltd., Switz.) Preparation ofcarbamoylprolylnaphthylalanineamides and related compounds as tachykinin antagonists, W09618643. 

Kulagowski, J. J. (Merck, Sharp Dohme) Spirocyclic ketones and their use as tachykinin antagonists, WO 0047562. 

Lembeck, F., Donnerer, J., Tsuchiya, M., Nagahisa, A. The non-peptide tachykinin antagonist, CP-... 

Sakurada, T., Katsumata, K., Tan-No, K., Sakurada, S., and Kisara, K. (1992). The capsaicin test in mice for evaluating tachykinin antagonists in the spinal cord. Neuropharmacology 31, 1279-1285. 

Crystallization-induced asymmetric transformation has already been described by Leuchs in 1913 during the resolution of 2-(2-carboxybenzyl)-l-indanone with brucine.34 In this case spontaneous racemization occurred. More recently researchers at Sanofi observed spontaneous racemization during the resolution of 3-cyano-3-(3,4-dichlorophenyl)propionic acid (7), most likely as a result of the basic resolving agent [>-(-)-N-1 n etli y I g I near nine [d-(-)-MGA] (8) (Scheme 7.6).35 The enantiopure cyano acid, obtained in 91% overall yield, is subsequently reduced to (+)-4-amino-3-(3,4-dichlorophenyl)-l-butanol (9), a key intermediate in the phase 2 synthesis of tachykinin antagonists. 

Two other examples of iV-arylation under basic conditions were reported. One is the azidation of a 7-[l,3]dioxan-2-yl-benzofuran-5-yllead triacetate 56 in the synthesis of tachykinin antagonists (Equation (52)).76 The second one is the efficient. V-/ -tolylation of (3-oxoisoindolin-l-ylidine)propandinitrile 57 by reaction with/i-tolyllead triacetate 58 under mild neutral non-catalyzed conditions (Equation (53)).77,77a... 

Horwell, D.C., Howson, W., Higginbottom, M., Naylor, D., Ratcliffe, G.S. and Williams, S. (1995). Quantitative Structure-Activity Relationships (QSARs) of N-Terminus Fragments of NKl Tachykinin Antagonists A Comparison of Classical QSARs and Three-Dimensional QSARs from Similarity Matrices. J.Med.Chem.,38, 4454-4462. 

Advenier C, Emonds-Alts X (1996) Tachykinin antagonists and cough. Pulm Pharmacol 9 329-324... 

Swern oxidation has been used as a key synthetic step in the construction of 3-aryloxy-4-arylfuran-2-ones, which are useful as inhibitors of COX-2 [1323], and in the synthesis of spirocydic ketones as intermediates in the preparation of a tachykinin antagonist [1324, 1325]. 

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