5-(2-Pyrrolidinyl)oxazolidinones and 2-(2-pyrrolidinyl)benzodioxanes: Synthesis of all the stereoisomers and α4β2 nicotinic affinity

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 3, 2009, Pages 854-859

  Pallavicini, Marco ^a   Bolchi, Cristiano ^a   Binda, Matteo ^a   Cilia, Antonio ^c   Clementi, Francesco ^b   Ferrara, Rossana ^a   Fumagalli, Laura ^a   Gotti, Cecilia ^b   Moretti, Milena ^b   Pedretti, Alessandro ^a   Vistoli, Giulio ^a   Valoti, Ermanno ^a  

^a UNIVERSITY OF MILAN   (Italy)

^b CNR   (Italy)

^c Recordati spa   (Italy)

Author keywords

Affinity; Benzodioxane; Ligand; nAChR; Nicotine; Oxazolidinone

Indexed keywords

2 (1 METHYL 2 PYRROLIDINYL) 1,4 BENZODIOXANE; 2 (2 PYRROLIDINYL)BENZODIOXANE DERIVATIVE; 5 (2 PYRROLIDINYL)OXAZOLIDINONE DERIVATIVE; CARBON; METHYL GROUP; NICOTINE; NICOTINIC RECEPTOR ALPHA4BETA2; NITROGEN; OXAZOLIDINONE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; BINDING SITE; CHIRALITY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; METHYLATION; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ACETYLCHOLINE; ANIMALS; BINDING SITES; BRAIN; CARBON; DIOXANES; HYDROGEN BONDING; KINETICS; LIGANDS; MODELS, CHEMICAL; OXAZOLIDINONES; PYRROLIDINES; RATS; RECEPTORS, NICOTINIC; STEREOISOMERISM;

EID: 58849083627     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.12.002     Document Type: Article

References (58)

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13. 3) δ 1.42, 1.43 and 1.46 (3s, 9H), 1.85-2.19 (m, 4 H), 3.42-3.50 (m, 2H), 4.19 and 4.28 (2br s, 1H), 5.38 and 5.47 (2br s, 1H).
14. 3) δ 1.41 and 1.44 (2s, 9H), 1.87-2.03 (m, 3H), 2.12-2.29 (m, 1H), 3.41-3.56 (m, 2H), 4.02-4.17 (m, 2H), 4.45-4.55 (m, 1H).
15. 6, 100 °C) δ 1.24 (s, 9H), 1.51-1.77 (m, 3H), 1.98-2.07 (m, 1H), 3.23-3.33 (m, 2H), 3.37 (s, 2H), 3.61-3.74 (2d, 4H), 4.27-4.32 (dd, 1H), 7.20-7.36 (m, 10H).
16. 6, 100 °C) δ 1.37 (s, 9H), 1.57-1.77 (m, 4H), 2.39-2.53 (m, 2H), 3.00-3.05 (m, 1H), 3.29-3.36 (m, 1H), 3.57-3.70 (m, 4H), 3.76-3.79 (m, 1H), 3.95-3.98 (m, 1H), 4.17 (br s, 1H), 7.17-7.34 (m, 10H).
17. 6, 100 °C) δ 1.35 (s, 6H), 1.41 (s, 3H), 1.42-1.96 (m, 4H), 2.38-2.47 (m, 2H), 3.07-3.15 (m, 1H), 3.28-3.36 (m, 1H), 3.43-3.48 (m, 2H), 3.69-3.74 (m, 2H), 3.77-3.79 (m, 1H), 4.12-4.15 (m, 1H), 4.16 (br s, 1H), 7.18-7.35 (m, 10H).
18. 1H NMR spectrum as described in Ref. 11.
19. 3) δ 1.34-1.39 (m, 1H), 1.62-1.77 (m, 3H), 2.17-2.33 (m, 2H), 2.35 (s, 3H), 2.48 (d, J = 6 Hz, 2H), 2.97-3.03 (m, 1H), 3.56-3.63 (m, 1H), 3.50 and 3.76 (2 d, J = 13.5 Hz, 4H), 7.21-7.32 (m, 10H).
20. 3) δ 1.53-1.56 (m, 1H), 1.70-1.77 (m, 2H), 1.85-1.94 (m, 1H), 2.31-2.42 (m, 2H), 2.43 (s, 3H), 2.58 (dd, J = 12.7, 8.3 Hz, 1H), 2.77 (dd, J = 12.7, 3.3 Hz, 1H), 3.01-3.07 (m, 1H), 3.20-3.26 (m, 1H).
21. 1H NMR spectrum as described in Ref. 11.
22. 3) δ 1.49-1.60 (m, 1H), 1.72-1.98 (m, 3H), 2.30 (pseudo q, J = 8.7 Hz, 1H), 2.45 (s, 3H), 2.63 (pseudo q, J = 8.7 Hz, 1H), 3.05-3.11 (m, 1H), 3.33 (pseudo t, J = 8.5 Hz, 1H), 3.57 (pseudo t, J = 8.5 Hz, 1H), 4.65 (pseudo q, J = 7.7 Hz, 1H), 5.40 (br s, 1H).
23. 1H NMR spectrum as described in Ref. 11.
24. 1H NMR identical to the enantiomer.
25. 1H NMR identical to the enantiomer.
26. 1H NMR identical to the enantiomer.
27. 1H NMR identical to the enantiomer.
28. 1H NMR identical to the enantiomer.
29. 1H NMR identical to the enantiomer.
30. 1H NMR identical to the enantiomer.
31. 1H NMR identical to the enantiomer.
32. 1H NMR identical to the enantiomer.
33. 1H NMR identical to the enantiomer.
34. 1H NMR identical to the enantiomer.
35. 3) δ 1.48 and 1.51 (2s, 9H), 1.61-2.21 (m, 4H), 3.34-3.59 (m, 2H), 3.94 (d, J = 11.0 Hz, 1H), 4.09-4.14 (m, 1.5H), 4.27-4.30 (m, 0.5H), 6.83-6.94 (m, 4H).
36. 3) δ 1.48 (s, 9H), 1.50-2.10 (m, 4H), 3.26-3.34 (m, 1H), 3.48-3.58 (m, 1H), 3.81 (br s, 1H), 3.98 (dd, J = 10.5, 5.2 Hz, 1H), 4.05-4.12 (m, 2H), 6.74-6.80 (m, 1H), 6.90-6.96 (m, 3H).
37. 3) δ 1.46 (s, 9H), 1.79-2.05 (m, 4H), 3.23-3.31 (m, 1H), 3.46-3.54 (m, 1H), 3.86-3.92 (m, 1H), 4.04-4.10 (m, 3H), 6.77-6.82 (m, 1H), 6.89-6.96 (m, 3H).
38. 3) δ 1.45 (s, 9H), 1.89-2.06 (m, 4H), 3.32-3.55 (m, 2H), 3.92-3.95 (m, 1H), 4.22-4.37 (m, 3H), 6.80-6.88 (m, 4H).
39. 3) δ 1.47 (s, 9H), 1.91-2.06 (m, 3H), 2.16-2.22 (br s, 1H), 3.39-3.49 (m, 2H), 3.93-4.10 (m, 3H), 4.29-4.33 (dd, J = 11.3, 1.9 Hz, 1H), 6.81-6.89 (m, 4H).
40. 25 +33.3 (c2, EtOH).
41. 6) δ 1.87-2.10 (m, 4H), 3.11-3.14 (m, 1H), 2.89 and 2.90 (2s, 3H), 3.50-3.60 (m, 1H), 3.70-3.80 (m, 1H), 3.94 (dd J = 11.6, 8.5 Hz, 1H), 4.42 (dd, J = 11.6, 2.2 Hz, 1H), 4.70-4.73 (m, 1H), 6.85-6.95 (m, 4H), 9.95 (br s, 1H).
42. 6) δ 1.75-2.12 (m, 4H), 3.11-3.23 (m, 2H), 3.59-3.68 (m, 1H), 4.07 (dd, J = 11.8, 6.6 Hz, 1H), 4.32 (dd, J = 11.8, 2.5 Hz, 1H), 4.45-4.50 (m, 1H), 6.83-6.93 (m, 4H), 9.46 (br s, 2H).
43. 6) δ 1.80-2.07 (m, 4H), 3.18 (br s, 2H), 3.70-3.82 (m, 1H), 4.02 (dd, J = 11.6, 7.4 Hz, 1H), 4.46 (dd, J = 11.6, 2.2 Hz, 1H), 4.52 (dt, J = 7.4, 2.2 Hz, 1H), 6.82-6.91 (m, 4H), 9.46 (br s, 1H), 10.10 (br s, 1H).
44. 1H NMR identical to the enantiomer.
45. 1H NMR identical to the enantiomer.
46. 1H NMR identical to the enantiomer.
47. 1H NMR identical to the enantiomer.
48. 1H NMR identical to the enantiomer.
49. 25 -35.5 (c2, EtOH).
50. 1H NMR identical to the enantiomer.
51. 1H NMR identical to the enantiomer.
52. 1H NMR identical to the enantiomer.
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57. All the ligands were built by VEGA in their protonated form and the conformational space was explored by systematically rotating the unique rotatable bond connecting the two rings. The docking and scoring procedures involved extensive rigid-body sampling with the OpenEye Scientific Software package FRED, using the rat α4β2 nicotinic model (PDB Id 1OLE). The FRED-based sampling was performed in box defined by known residues implicated in ligand recognition (namely, Trp55, Lys77, Trp147, and Tyr188). The docking results were scored using the ChemGauss3 function (as compiled in Table 2) which accounts for interactions, steric fitting and desolvation.
58. Kanne D.B., and Abood L.G. J. Med. Chem. 31 (1988) 2227