Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 6. Synthesis, 13C NMR, and biological evaluation of cis- and trans-4-amino-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofuran] derivatives
Autor: | Hansjoerg Kruse, Harry M. Geyer, J. C. Wilker, Manfred Worm, Lawrence L. Martin, Marc N. Agnew |
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Rok vydání: | 1981 |
Předmět: |
Male
Magnetic Resonance Spectroscopy Tertiary amine Isobenzofuran Chemical Phenomena Metalation Stereochemistry Tetrabenazine Cyclohexanone chemistry.chemical_compound Seizures Drug Discovery Animals Spiro Compounds Benzofurans Aryl Benzanilide Drug Synergism Stereoisomerism Antidepressive Agents Rats Chemistry chemistry Molecular Medicine Amine gas treating Cis–trans isomerism |
Zdroj: | Journal of medicinal chemistry. 24(5) |
ISSN: | 0022-2623 |
Popis: | 4-(Dimethylamino)- and 4-(methylamino)-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofuran] derivatives were prepared as analogues of previously reported 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Metalation of benzanilide with n-butyllithium, addition of 4-(dimethylamino)cyclohexanone, and acidification afforded a mixture of cis- and trans-4-(dimethylamino)spiro[cyclohexane-1,1'(3'H)-isobenzofuran]-3'-ones (1a,b), which were separated by fractional crystallization. Addition of aryllithium or aryl Grignard reagents to 1a,b and formic acid reduction afforded cis- and trans-4-(dimethylamino)-3'-arylspiro[cyclohexane-1,1'(3'H)-isobenzofurans] 3a-f, which were converted to secondary amine analogues 5a-e. Tentative stereochemical assignments are based on chemical arguments and are supported by 13C NMR chemical shift data. Marked inhibition of tetrabenazine-induced ptosis is a property of most antidepressants, and significant antitetrabenazine activity is observed for several of these compounds. Optimal antitetrabenazine activity is associated with the cis-3'-phenyl series, and the cis secondary amine 5a is approximately twice as potent as the cis tertiary amine 3a. The various compounds are relatively weak with respect to potentiation of L-5-hydroxytryptophan-induced seizures. |
Databáze: | OpenAIRE |
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