Compound was prepared from chloroindole by acylation to
Compound was prepared from 6-chloroindole () () by acylation, to give , and subsequent reduction to give . The thiazole was then installed using conditions developed by Buchwald and co-workers to give . Hydrolysis of the ester yielded the thiazole Cucurbitacin B derivative (). Derivatives and were prepared directly from and , respectively, as outlined (). Derivatives – and – () were prepared from intermediate using similar conditions. The requisite bromides were commercially available, except for ethyl 2-bromo-1,3-oxazole-4-carboxylate which was prepared from ethyl 2-amino-1,3-oxazole-4-carboxylate (isoamyl nitrite, CuBr, MeCN, 60°C).
Analogues and – were prepared in analogous manner to (), reacting 6-chloroindole () with the appropriate acylating agent.
The 3-trifluoroethyl analogue () was prepared by acylation of 6-chloroindole (), followed by protection to give the -butyloxycarbonyl derivative (). The ketone moiety was reduced to the corresponding alcohol which then underwent a modified Barton radical deoxygenation and deprotection to give 6-chloro-3-trifluorethylindole () (). Buchwald chemistry was again employed, as in , to convert to .
Buchwald conditions were also used to prepare derivative from 6-chloro-3-isopropylindole (). The synthesis of commenced from 4-chloro-2-nitroaniline () which was converted to the corresponding iodide by Sandmeyer reaction. Reduction of the nitro moiety delivered 5-chloro-2-iodoaniline () which was alkylated to give . Palladium-mediated cyclization of delivered the aforementioned intermediate ().
Derivatives – were prepared as outlined in . Reaction of 6-chloroindole () with dimethylcarbamoyl chloride gave which was converted to using Buchwald conditions. (). Derivative was prepared from using Mannich–Eschenmoser conditions and was converted to via Buchwald coupling. (). Homologated analogue was prepared in three steps from by acylation with oxalyl chloride, reaction with dimethylamine and reduction. Again, Buchwald chemistry was employed to convert to ().
Compounds in (–) were prepared from commercially available 6-substituted indoles, as described in .
Derivative was prepared from (). Firstly, the carboxylic acid was converted to the corresponding methyl ketone () via the Weinreb amide. Willgerodt–Kindler reaction and subsequent hydrolysis furnished ().
Compounds and were prepared by alkylation of 6-chloro-3-isobutylindole () as outlined below ().
Derivative was prepared as described in from 6-chloro-2-methylindole () which was prepared as described below ().
Compounds generally showed good selectivity (100- to 10,000-fold) over the EP receptor subtype and similar or lower selectivity over the thromboxane (TP receptor), for example (EP FLIPR p 9.3, EP FLIPR p 6.5, TP FLIPR p 7.5), (EP FLIPR p 8.4, EP FLIPR p 6.4, TP FLIPR p 7.1), (EP FLIPR p 9.7, EP FLIPR p 6.4, TP FLIPR p 7.3), (EP FLIPR p 10.2, EP FLIPR p 6.3), (EP FLIPR p 8.9, EP FLIPR p 6.3, TP FLIPR p 6.4), (EP FLIPR p 7.7, EP FLIPR p 6.1).
In conclusion, we have identified a novel series of indole EP receptor antagonists by scaffold hopping and explored the SAR in the 1-, 2-, 3-, 5-, and 6-positions. Although there are similarities between the SAR in this series and previous series there is some divergence, in particular the 3-position which forms a lipophilic interaction. Several compounds with high in vitro affinity were identified. From this, compound was found to combine the best balance of in vitro DMPK properties and in vitro EP activity and was thus assessed in an in vivo model of inflammatory pain where it showed excellent efficacy, with an ED of 2.17mg/kg, and equivalent efficacy to celecoxib.
We thank Emma Ward for generating data in the FLIPR assay and Anabel Molero Milan for the first synthesis of compound 10a.
Introduction Suicide is a major public health problem and is considered as one of the leading causes of death in young age groups and particularly in psychiatric patients (World Health Organization, 2005). Both genetic and environmental factors are involved in the pathogenesis of suicidal behaviors (Brent and Mann, 2005, World Health Organization, 2005). The genetic component of suicidal behaviors has been demonstrated by family, twin and adoption studies (Brent and Mann, 2005, Roy et al., 1997). Even though most suicide victims and suicide attempters have a diagnosable psychiatric illness (Beautrais et al., 1996, Robins et al., 1959, Shaffer et al., 1996, Van Heeringen, 2003), most psychiatric patients never attempt suicide, indicating that the predisposition to suicidal behaviors is independent of psychiatric disorders (Ernst et al., 2009, Mann, 1998, Mann, 2003, Rujescu et al., 2007).