Design, synthesis and structure-affinity relationships of 4-methylidenepiperidine and 4-aryl-1,2,3,6-tetrahydropyridine derivatives as corticotropin-releasing factor1 receptor antagonists.

Abstract Recently, various non-peptide corticotropin-releasing factor 1 (CRF 1 ) receptor antagonists have been reported. Structure–affinity relationships (SARs) of non-peptide CRF 1 antagonists suggest that such antagonists can be constructed of three units: a hydrophobic unit (Up-Area), a proton accepting unit (Central-Area), and an aromatic unit (Down-Area). Our interest focused on the Up-Area in deriving the novel methylidenepiperidine derivatives Figure 2 , Scheme 1 Download high-res image (65KB) Download full-size image Figure 2 . Download high-res image (189KB) Download full-size image Scheme 1 . Reagents and reaction conditions: (a) 4-(R 4 ,R 5 C=)piperidine, isoPr 2 NEt, EtOH; (b) X 3 ,X 2 ,X 1 -Ar-NH 2 , iso Pr 2 NEt, (CH 2 OH) 2 , reflux; (c) R 3 -l or -Br, NaH, DMF; (d) 4-(1,3-dioxolan2-yl)piperadine, iso Pr 2 NEt, EtOH; (e) 2-Br-4 iso Pr-Ar-NH 2 , iso Pr 2 NEt, (CH 2 OH) 2 , reflux; (f) Et-l, NaH, DMF; (g) 1 N Cl, THF; (h) R 4 ,R 5 =PPh 3 , THF; (i) cyclopentadiene, Et 3 N. Method A: a, b, c; Method B: d, e, f, g; Method C: h; Method D: i. and 4-aryl-1,2,3,6-tetrahydropyridine derivatives Figure 2 , Scheme 2 Download high-res image (123KB) Download full-size image Scheme 2 . Reagents and reaction conditions: (j) 4-Ar-1,2,3,6-tetrahydropyridine, iso Pr 2 NEt, EtOH; (k) X 3 , X 2 , X 1 -Ar-NH 2 , iso Pr 2 NEt, (CH 2 OH) 2 , reflux; (l) R 3 -I or -Br, NaH, DMF; (m) X 3 , X 2 , X 1 -Ar-NHR 3 , iso Pr 2 NEt, (CH 2 OH) 2 , reflux; (n) ArMg-Br or -I, THF, and then TFA-CH 2 Cl 2 ; (o) furanel, LDA, THF and then MsCl, Et 3 N, DMAP, CH 2 Cl 2 ; (p) thiophene, LDA, THF and then HCO 2 H. Method E: j; Method F: k, l; Method G: m; Method H: n; Method I: o; Method J: p. as non-peptide CRF 1 receptor antagonists. Compounds 8a and Figure 2 , Scheme 2 had moderate affinity for CRF 1 receptor, but compounds Figure 2 , Scheme 1 , Scheme 2 did not exhibit CRF 1 receptor affinity. Modification of derivatives Figure 2 , Scheme 2 afforded compounds 11i (CRA1001) and 11x (CRA1000), which had high affinity and selectivity for CRF 1 receptors with potent anxiolytic-like and antidepressant-like properties in some experimental animal models. These findings suggest that the hydrophonic unit (Up-Area) may be useful for design of CRF 1 antagonists. We report here the design, synthesis and SARs of the derivatives Figure 2 , Scheme 2 and isosteres Figure 2 , Scheme 1 , Scheme 2 .