Sunepitron Explained

Sunepitron (developmental code name CP-93,393) is a combined 5-HT1A receptor agonist and α2-adrenergic receptor antagonist.[1] [2] It was previously under development by Pfizer for the treatment of depression and anxiety.[3] It made it to phase III clinical trials before being discontinued.[2] [3]

Chemistry

Synthesis

The synthesis starts by conversion of the pyridine dicarboxylic acid (1) to its acid chloride; rxn with MeOH then affords the ester (2). Catalytic hydrogenation serves to reduce the pyridine ring to a piperidine of undefined stereochemistry (3). Alkylation of this intermediate with chloroacetonitrile affords (4). Treatment of that intermediate with Raney nickel reduces the cyano group to the corresponding primary amine; this product then undergoes an internal ester-amine interchange to yield the cyclized lactam (5). LAH serves to reduce the lactam to an amine; the ester on the other ring is reduced to a carbinol in the process, affording the aminoalcohol (7). The basic function is next alkylated with 2-chloropyrimidine (7). Rxn of the alcoholin (8) with MsCl leads to the mesylate; that group is next displaced by sodium azide (9); the azide group is next reduced to the primary amine. Resolution of this product as its mandelate salt then yields (10) as a single enantiomer. Rxn of that product with succinic anhydride converts the pendant amine to a succinimide, affording the anxiolytic agent sunepitron (1).

See also

Notes and References

  1. Goodnick PJ . Psychopharmacology of depression in the next millennium . CNS Spectrums . 4 . 7 . 21–35 . July 1999 . 18438295 . 10.1017/s1092852900011998 . 28460185 .
  2. Book: Stahl SM . Essential psychopharmacology: neuroscientific basis and practical application . Cambridge University Press . Cambridge, UK . 2000 . 0-521-64615-4 . registration . 265 .
  3. Book: Kaplan EP, Turkington C . Making the antidepressant decision: how to choose the right treatment option for you and your loved ones . Contemporary Books . Chicago, Ill . 2001 . 0-7373-0417-0 .