Synthesis and pharmacological evaluation of novel 9- and 10-substituted cytisine derivatives. Nicotinic ligands of enhanced subtype selectivity

Abstract

We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.

Figure 1

Figure 2

Figure 3

Scheme 1

^aReagents and conditions: (a) BH₃-THF, THF, 0 °C, 5 h, 85%; (b) CH₂(OMe)₂, BF₃·OEt₂, CH₂Cl₂, 0 °C, 3 h, 85%.

Scheme 2

^aReagents and conditions: (a) Pd(PPh₃)₄, DMF, 130 °C, 15 h, 79%; (b) LiAlH₄, THF, -20 °C, 3.5 h, 59%; (c) BnBr, CH₃CN, reflux, 2 h; (d) H₂ (1 atm), PtO₂, Et₃N, MeOH, rt, 15 h, cis : trans = 5:1; cis, 67%; (e) MsCl, Et₃N, DCM, 0 °C, 30 min, 84%; (f) Toluene, reflux, 3 h, 83%; (g) TFA, rt, 3 h, 91%; (h) H₂ (1 atm), 10% Pd-C (1eq w/w), MeOH, rt, 15 h; (i) H₂ (1 atm), 20% Pd(OH)₂-C (0.1 eq), (Boc)₂O, MeOH, reflux, 30 min, 92%; (j) TFA, CH₂Cl₂, rt, 1 h, 87-93%.

Scheme 3

^aReagents and conditions: (a) PdCl₂(PPh₃)₂, Dioxane, 120 °C, 1 h, 73%; (b) TFA, CH₂Cl₂, 30 min, 81%. (c) Pd (PPh₃)₄, K₂CO₃, DME/H₂O, 85 °C, 15 h, 87%; (d) TFA, CH₂Cl₂, 30 min, 85%.