138925-60-7Relevant academic research and scientific papers
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.
Spirocyclic compounds incorporating five-membered rings with two heteroatoms for treating psychotic disorders, etc.
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, (2008/06/13)
The present invention provides a compound of formula I or a salt or prodrug thereof: STR1 wherein the dotted line represents an optional chemical bond in one of the two possible positions; A represents a group of formula II: STR2 in which R1 represents hydrogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, benzyloxy, hydroxy (C1-6)alkyl, halogen, amino, cyano, nitro, --CONR6 R7 or --SO2 NR6 R7, in which R6 and R7 independently represent hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; R2 represents hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or C1-6 alkylcarbonyl; V represents nitrogen, --CH or --C--; and W represents oxygen, sulphur or --NR8, in which R8 represents hydrogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; two of X, Y and Z are the same or different and each represents oxygen, sulphur or nitrogen; and the remaining group X, Y or Z is carbon, or Y is carbonyl (C=O); and Q is the residue of an azacyclic or azabicyclic ring system; which compounds are useful in the treatment of psychotic disorders (e.g. schizophrenia and mania); anxiety; alcohol or drug withdrawal or dependence; pain; gastric stasis; gastric dysfunction (such as occurs with dyspepsia, peptic ulcer, reflux oesophagitis and flatulence); migraine, nausea and vomiting; movement disorders; and presenile and senile dementia.
