Efficient asymmetric syntheses, determination of absolute configurations and biological activities of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine as a novel potent dopamine uptake inhibitor in the central nervous system.
An efficient asymmetric synthesis of the chiral N-(3-chloro-2-hydroxypropyl)anilines (2a and 2b) was achieved through the regioselective ring-opening reaction of chiral epichlorohydrin with aniline. This was applied to an asymmetric synthesis of the enantiomers of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1 as a novel potent dopamine uptake inhibitor. Both enantiomers as trihydrochlorides, 4a.3HCl and 4b.3HCl, could be synthesized in good total yields and optical purities of 100% ee in three steps synthesis, respectively. The absolute configurations of 4a.3HCl and 4b.3HCl were determined using the modified Mosher's method with the related compounds, the intermediates (2a and 2b) and the free bases (4a and 4b). The analytical results indicated that 4a.3HCl and 4b.3HCl have the (S)- and (R)-configuration, respectively, and a series of reactions to provide them proceeded without the apparent influence on the stereochemistry at the chiral centers. In in vitro pharmacological evaluations, 4a.3HCl and 4b.3HCl showed potent dopamine transporter binding affinities, high dopamine, moderate serotonin, and weak norepinephrine uptake inhibitory activities, and 4a.3HCl exhibited a more potent and selective dopamine uptake inhibition over the serotonin or norepinephrine uptake inhibition as compared with 4b.3HCl. An ex vivo evaluation revealed that the oral administrations of both enantiomers at a dose of 30 mg/kg in rats displayed apparent dopamine uptake inhibitory activities and 4a.3HCl had a stronger tendency to inhibit dopamine uptake compared with 4b.3HCl.
Kimura
Makoto
M
POLA Chemical Industries, Inc., Pharmaceutical R&D Laboratories, 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa 244-0812, Japan. m-kimura@pola.co.jp
Masuda
Tomoko
T
Yamada
Koji
K
Mitani
Masaki
M
Kubota
Nobuo
N
Kawakatsu
Nobuyuki
N
Kishii
Kenichi
K
Inazu
Masato
M
Kiuchi
Yuji
Y
Oguchi
Katsuji
K
Namiki
Takayuki
T
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D027981:Symporters / Q000037:antagonists & inhibitors
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C495011:1-(4,4-bis(4-fluorophenyl)butyl)-4-(2-hydroxy-3-(phenylamino)propyl)piperazine; C493226:Slc6a2 protein, rat