74862-25-2Relevant articles and documents
Synthesis and structural, conformational, biochemical, and pharmacological study of new compounds derived from tropane-3-spiro-4'(5')-imidazoline as potential 5-HT3 receptor antagonists
Whelan,Iriepa,Galvez,Orjales,Berisa,Labeaga,Garcia,Uceda,Sanz-Aparicio,Fonseca
, p. 101 - 106 (2007/10/02)
A series of tropane-3-spiro-4'(5')-imidazolines was synthesized and studied by 1H and 13C NMR spectroscopy, and the crystal structure of 2'- (1H-indol-3-yl)tropane-3-spiro-4'(5')-imidazoline hydrochloride 5(6)f was determined by X-ray diffraction. In CD3OD solution, compounds 5(6)a-f display the same preferred conformation. The pyrrolidine and piperidine rings adopt an envelope conformation flattened at N8 and a distorted chair conformation puckered at N8 and flattened at C3, respectively, with the N- substituent in the equatorial position with respect to the piperidine ring. This conformation is similar to that observed for compound 5(6)f in the solid state. From binding studies on the compounds synthesized, compound 5(6)d demonstrated the ability to efficiently displace the binding of [3H]GR65630 to bovine brain area postrema membranes to an extent comparable to MDL 72222. In the von Bezold-Jarisch reflex, compound 5(6)d was equipotent with metoclopramide. It is, therefore, likely that the imidazoline ring may provide a useful bioisosteric replacement for the carbonyl group in 5-HT3 antagonists.
Novel 5-HT3 antagonists: Indol-3-ylspiro(azabicycloalkane-3,5'(4'H)- oxazoles)
Swain,Baker,Kneen,Herbert,Moseley,Saunders,Seward,Stevenson,Beer,Stanton,Watling,Ball
, p. 1019 - 1031 (2007/10/02)
The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.
SYNTHESIS AND PROPERTIES OF AZOLES AND THEIR DERIVATIVES. 32. SYNTHESIS AND SOME TRANSFORMATIONS OF HYDROCHLORIDES OF IMIDO ESTERS OF INDOLECARBOXYLIC ACIDS
Kelarev, V. I.,Shvekhgeimer, G. A.
, p. 501 - 506 (2007/10/02)
The Pinner reaction with the nitriles of indole-3-carboxylic and 3-indolylacetic acids was studied.The hydrochlorides of the imide esters of these acids, which were converted to the free bases, amides, and esters, were synthesized.Imidazolines, benzimidazoles, and benzoxazoles that contain indole substituents were obtained by condensation of the hydrochlorides of the imido esters of the indolecarboxylic acids with ethylenediamine, o-phenylenediamine, and o-aminophenol.
