Syntheses of R and S isomers of AF-DX 384, a selective antagonist of muscarinic M2 receptors.
Enantiomers of 5,11-dihydro-11-[2-[2-[(N,N-dipropylaminomethyl)piperidin-1- yl]ethylamino]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (AF-DX 384) 1, have been synthesized from (S)-(+) and (R)-(-)-2-[N,N-dipropylaminomethyl]piperidine 4. The enantiomeric excess of 1 has been determined by capillary electrophoresis by using the alpha-highly sulphated cyclodextrin (alpha-HSCD) as chiral selector within the running electrolyte. (S)-(+)-(4) was prepared from (S)-(-)-pipecolic acid in a 4-step procedure (overall yield: 30%, ee: 99%) and (R)-(-)-AF-DX 384 from (R)-(+)-pipecolic acid. The (R)-(-) isomer exhibited in vitro a 23-fold higher affinity than its enantiomer (S)-(+) towards muscarinic receptors of subtype 2.
Martin
J
J
Laboratoire de Chimie Moléculaire et Thio-organique, (CNRS UMR 6507), Institut des Sciences de la Matière et du Rayonnement, Caen, France.
Deagostino
A
A
Perrio
C
C
Dauphin
F
F
Ducandas
C
C
Morin
C
C
Desbène
P L
PL
Lasne
M C
MC
D000818:Animals; D001667:Binding, Competitive; D003505:Cyclodextrins; D019075:Electrophoresis, Capillary; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry; D019832:N-Methylscopolamine / Q000378:metabolism; D010276:Parasympatholytics / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000378:metabolism; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D012997:Solvents; D013237:Stereoisomerism; D014316:Tritium
D003505:Cyclodextrins; D008024:Ligands; D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D012997:Solvents; D014316:Tritium; C065959:AFDX 384; D010890:Pirenzepine; D019832:N-Methylscopolamine