Potential antidepressants and selective inhibitors of 5-hydroxytryptamine re-uptake in the brain: Synthesis of several potential metabolites of moxifetin and of two A-ring fluorinated analogues

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Title:Potential antidepressants and selective inhibitors of 5-hydroxytryptamine re-uptake in the brain: Synthesis of several potential metabolites of moxifetin and of two A-ring fluorinated analogues
Creators:
Šindelář, Karel
Pomykáček, Josef
Holubek, Jiří
Svátek, Emil
Valchář, Martin
Dobrovský, Karel
Metyšová, Jiřina
Polívka, Zdeněk
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 56, 2, pp. 459-477

Abstract

A series of potential metabolites of the potent inhibitor of 5-hydroxytryptamine re-uptake in the brain structures – moxifetin (<i>I</i>) – i.e. the O-methylated and hydroxylated, further methoxylated, and N-monodemethylated analogues (<i>III – VII, IX</i>, and <i>X</i>) was synthesized from the acids <i>XV, XIX, XXIIIa, XXIIIb, XXVIIa</i>, and <i>XXVIIb</i>. The synthesis of <i>III</i> and <i>V</i> proceeded with protection of one hydroxyl group by benzyl and by the final debenzylation by short heating with hydrobromic acid. Compound <i>IV</i> was obtained by partial demethylation of N,N-dimethyl-(3-,4-dimethoxyphenylthio)benzylamine with sodium 4-toluenethiolate. Synthesis of <i>VI, VII, IX</i>, and <i>X</i> proceeded without protection of the hydroxyl group via the mixed anhydrides of the mentioned acids and methanesulfonic acid which were coupled with dimethylamine and the dimethylamides obtained were directly reduced to the final products. Two A-ring fluorinated analogues of <i>I</i>, i.e. <i>VIII</i> and <i>XI</i> were prepared from the acids <i>XXIIIc</i> and <i>XXVIIc</i> via acid chlorides, dimethylamides, and amines <i>XXVIc</i> and <i>XXXc</i>. The final step was demethylation by heating with hydrobromic acid. The N-oxide <i>XII</i> was obtained by oxidation of <i>I</i> with hydrogen peroxide in ethanol. Compounds <i>III</i> (VUFB-18285) and especially <i>XI</i> (VUFB-17724) were found to be selective inhibitors of the 5-hydroxytryptamine re-uptake in the brain. Some compounds (<i>IV, VI, VII, X</i>) indicate a similar type of activity. In addition to <i>II</i> (described previously), compounds <i>IV</i> and <i>V</i> were found to be moxifetin metabolites in the animals.

Title:Potential antidepressants and selective inhibitors of 5-hydroxytryptamine re-uptake in the brain: Synthesis of several potential metabolites of moxifetin and of two A-ring fluorinated analogues
Creators:
Šindelář, Karel
Pomykáček, Josef
Holubek, Jiří
Svátek, Emil
Valchář, Martin
Dobrovský, Karel
Metyšová, Jiřina
Polívka, Zdeněk
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:56
Number:2
Page Range:pp. 459-477
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc19910459UNSPECIFIED
ID Code:4966
Item Type:Article
Deposited On:22 Feb 2010 11:27
Last Modified:22 Feb 2010 10:27

Citation

Šindelář, Karel; Pomykáček, Josef; Holubek, Jiří; Svátek, Emil; Valchář, Martin; Dobrovský, Karel; Metyšová, Jiřina; Polívka, Zdeněk (1991) Potential antidepressants and selective inhibitors of 5-hydroxytryptamine re-uptake in the brain: Synthesis of several potential metabolites of moxifetin and of two A-ring fluorinated analogues. Collection of Czechoslovak Chemical Communications, 56 (2). pp. 459-477. ISSN 0010-0765

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