Centrally acting serotonergic and dopaminergic agents. 1. Synthesis and structure-activity relationships of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives

Abstract

The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.

Centrally acting serotonergic and dopaminergic agents. 2. Synthesis and structure-activity relationships of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole derivatives

“…In an earlier report on the structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-l/i-benz[e] indole 2 3 derivatives (1), we demonstrated that the more rigid five/ six fused angular tricyclic 2-aminotetralins indeed show interesting pharmacological properties. 1 In this series, we found that the cis analogs are more potent than the corresponding trans analogs. Analogs with 9-methoxy substitution (Ri) showed mixed 5-HTia receptor agonist that all cis analogs were completely inactive.…”

“…Since our previous SAR study on angular tricyclic analogs (1) showed that a more rigid five/six fused ring structure could indeed improve their pharmacological profile, we thought it would be interesting to examine similar analogs in the linear tricyclic series. Analogs represented by the generic structure 3, 2,3,3a,4,9,9ahexahydro-lH-benz [/] indole derivatives, would be more conformationally restricted than six/six fused ring analogs 2.…”

Palladium-Catalyzed Asymmetric Allylic Alkylation of -Aryl Ketones

“…The absolute configuration of allylated tetralone 11 was established by the synthesis of the known pyrrolidine‐fused tetralin 13 , a family of molecules that has attracted attention due to their serotonin and dopamine agonist activity 11. 12 To this end, the terminal olefin of tetralone 11 was oxidatively cleaved to give unstable keto aldehyde 12 . Aldehyde 12 was reductively aminated with benzhydrylamine and then the tertiary amine was deprotected by hydrogenation with Pearlman's catalyst to give aminotetralin 13 .…”

Synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9-carboxamide: A potent and selective 5-HT1A receptor agonist with good oral availability

“…In an earlier report, we described the SAR on rigid five-/six-fuxed angular tricyclic 2-aminotetralins, 2,3,3a,4,5,-9b-hexahydro-l.£f-benz[e]indole derivatives (2). 8 The analogs, where Rj = OH or OMe and R2 = propyl or allyl, were found to display potent 5-HTia receptor agonist activity. Our study showed that the cis analogs are more potent than the corresponding trans analogs with 5-HTia activity residing in the m-(3aff)-enantiomer.…”

“…Fortunately, the 1:1 maleate salt of (-)-3a, U93385E, produced a crystalline form possessing excellent physicochemical properties suitable for drug formulation (see the Experimental Section). 16 In the second synthesis, as outlined in Scheme II, 8-bromo-2-tetralone (8) was used as the starting material. 16 Regioselective alkylation of the C-l position of tetralone 8 with methyl bromoacetate was carried out by using LDA as the base, yielding the keto ester 9 in 80-85% yield.8 Reductive amination/cyclization of this keto ester 9 with (R)-a-methylbenzylamine afforded the mixture of diastereomeric lactams 10a/10b.17 The mixture of diastereomers was separated by chromatography using the Waters prep-500 HPLC.…”