Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents.
Synthesis of 1'-methyl-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (7a, HP 365) and the demethyl analogue 9a (HP 505) was prompted by recognition of an aminoalkyl(aryl)isobenzofuran moiety common to the antidepressants talopram (Lu 3-010) and trans-10,11-dihydro-5,10-epoxy-5-[3-(methylamino)propyl]-5H-dibenzo[a,d]cyclohepten-11-ol (MK-940). Convenient laboratory synthesis of 7a was provided by lithiation of 2-bromobenzhydryl methyl ether, followed by addition of 1-methyl-4-piperidone and acid-catalyzed cyclization. N-Dealkylation by standard methods afforded 9a. Synthesis of analogues was stimulated by discovery of marked inhibition of tetrabenazine-induced ptosis for lead compounds 7a and 9a. Optimal antitetrabenazine activity is associated with the 3-phenylspiro-[isobenzofuran-1(3H),4'-piperidine] moiety where nitrogen is basic. Modification of this moiety by introduction of large nitrogen substituents or a C-3 substituent greater than H significantly reduced antitetrabenazine activity. A series of analogues with aromatic substituents was investigated; however, few of these compounds were significantly more active than 7a and 9a. Compound 9a was selected for additional studies.
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013329:Structure-Activity Relationship; D013747:Tetrabenazine / Q000037:antagonists & inhibitors
D000928:Antidepressive Agents; D001572:Benzofurans; D013747:Tetrabenazine