Synthesis and preliminary pharmacological evaluation of some cytisine derivatives

CC4, a dimer of cytisine, is a selective partial agonist at α4β2/α6β2 nAChR with improved selectivity for tobacco smoking cessation

“…In our search for new Cyt‐derived subtype‐selective drugs, with improved brain penetration and a longer half‐life, we concentrated on 1,2‐bis N ‐cytisinylethane (CC4) (see Figure ), which was synthesized and has been partially characterized by our group (Canu Boido and Sparatore, ; Carbonnelle et al ., ). It is part of a set of compounds containing two Cyt molecules joined by linkers of different length and nature (Canu Boido et al ., ).…”

Synthesis and Antiplasmodial Activity of Novel Chloroquine Analogues with Bulky Basic Side Chains

“…[43][44][45][46] the closed tube was heated at 100 8Cf or 24 h. After cooling, the solvent was evaporated, and the residue was taken up with H 2 O( 10 mL), alkalized, (2 n NaOH until strongly alkaline), and extracted with CH 2 Cl 2 (3 40mL). As olution of an equimolar amount of N-(2chloroethyl)cytisine [49] (65)o rN-(4-chloropropyl)cytisine [49] (66)i n CH 3 CN (5 mL) was dropwise slowly added, and the solution was stirred at room temperature for 72 h. The solvent was removed, and the residue was taken up in 1 n HCl (5 mL). General method for the preparation of 4-[(1R,9aR)-(octahydro-2H-quinolizin-1-yl)methyl)thio]-7-substituted quinolines 22 and 23:Asuspension of 4,7-dichloroquinoline (0.51 g, 2.6 mmol) or 4chloro-7-trifluoromethylquinoline (0.6 g) in Dowtherm A( 4mL) was heated at 100 8Cu ntil ac lear solution was obtained, and then asolution of thiolupinine [35] (0.48 g, 2.6 mmol) in Dowtherm A( 1mL) was added.…”

“…Required4 -[N-(w-bromoalkyl)amino]-7-chloroquinolines 54-58 were obtained by treating 4,7-dichloroquinoline with the suitable w-hydroxyalkylamines and subsequent bromination by means of 48 %h ydrobromic acid in the presence of concentrated sulfuric acid, as previously described for some of them. [43][44][45][46] Compounds 22 and 23 were obtained by treating thiolupinine (28) [35] with the proper 4-chloro-7-substituted quinolines, whereas compounds 24-27 wereo btained from 7-chloro-4-thioquinoline (62), [47] which was treated with S-(haloalkyl)thiolupi-nines 63 and 64 [32,48] and N-(w-haloalkyl)cytisines 65 and 66 [49] (Scheme 4).…”

“…General method for the preparation of 7-chloro-4-{S-[w-(citisin-3-yl)alkyl]thio}quinolines 26 and 27:Am ixture of 7-chloro-4-thioquinoline [47] (0.28 g, 1.43 mmol) and KOH (ground pellets, 80 mg, 1.43 mmol) in CH 3 CN (5 mL) was stirred for 30 min under an atmosphere of nitrogen. As olution of an equimolar amount of N-(2chloroethyl)cytisine [49] (65)o rN-(4-chloropropyl)cytisine [49] (66)i n CH 3 CN (5 mL) was dropwise slowly added, and the solution was stirred at room temperature for 72 h. The solvent was removed, and the residue was taken up in 1 n HCl (5 mL). The acid solution was filtered, alkalized (2 n NaOH until strongly alkaline) and extracted with CH 2 Cl 2 (3 20mL).…”

Chemical Medicine: Novel 10‐Substituted Cytisine Derivatives with Increased Selectivity for α4β2 Nicotinic Acetylcholine Receptors

“…[37,38] In spite of these clinical shortcomings, the interesting pharmacological profile of cytisine has led to a number of medicinal chemistry efforts in recent years to create analogues with an improved subtype selectivity or PK parameters. [8,10,[39][40][41][42] Most of these reported structural modifications involve the introduction of substituents at the alicyclic nitrogen (position 3), or at the 9-or 11-positions of the pyridone ring ( Figure 1). …”