A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.

The title reagent engaged in the modified Julia olefination with aldehydes under mild reaction conditions (DBU, CH(2)Cl(2), rt or -78 degrees C) to yield alpha,beta-unsaturated esters; aryl aldehydes and aliphatic aldehydes possessing significant chain branching elements gave trans alkene products with high stereoselectivity (E : Z up to >98 : 2), while straight chain aliphatic aldehydes gave cis products preferentially (Z : E up to 92 : 8).

No abstract

No abstract

Carboxylic acid esters Q 0530Ethyl(benzothiazol-2-ylsulfonyl)acetate: A New Reagent for the Stereoselective Synthesis of α,β-Unsaturated Esters from Aldehydes. -Sulfone (III) is used for the synthesis of α,β-unsaturated esters from aldehydes. Under mild conditions in the presence of DBU, (E)-isomers are obtained as the major products. For the aliphatic aldehydes n-hexanal (IIIg) and citronellal (VII), (Z)-isomers are preferentially isolated. When NaHMDS in refluxing THF is used, the (E)-isomer (Vg) can be isolated as the main component. A complex mixture of intractable products is identified in the case of cinnamaldehyde (IIIj). The reaction of phenylacetaldehyde (X) is non-regiospecific and affords predominantly the β,γ-unsaturated ester (XII). -(BLAKEMORE*, P. R.; HO, D. K. H.; NAP, W. M.; Org. Biomol. Chem. 3 (2005) 8, 1365-1368; Sch. Chem., Univ. Leeds, Leeds LS2 9JT, UK; Eng.) -S. Adam 37-080