Introduction of a putative dopaminergic prodrug moiety into a 6,7-substitution pattern characteristic of certain 2-aminotetralin dopaminergic agonists

Abstract

On the basis of the premise that the dopaminergic agonist profile of 2-(di-n-propylamino)-5-hydroxy-6-methyltetralin (1a) is due to in vivo oxidation of the 6-methyl moiety and that 1a may represent a novel prodrug strategy, the vicinal methyl-hydroxyl substitution pattern was incorporated into the 6- and 7-positions of 2-(di-n-propylamino)tetralin to give the 6-methyl-7-hydroxy and 6-hydroxy-7-methyl isomers 8 and 9, respectively. A multistep synthetic approach was devised which permitted preparation of target molecules 8 and 9. Pharmacological data revealed that both target compounds exhibit modest dopamine-like effects in the cardioaccelerator nerve assay in the cat, but neither appeared to be metabolically activated as was the case with 1a. The effects of 9 (but not of 8) were antagonized by pretreatment with haloperidol. Thus, the 5-hydroxy-6-methyl substitution pattern in the 2-aminotetralins remains unique as a dopaminergic agonist prodrug structure.

Synthesis and pharmacological evaluation of 1-(aminomethyl)-3,4-dihydro-5-hydroxy-1H-2-benzopyrans as dopamine D1 selective ligands

“…Finally, this centrally mediated response is unique to the 5,6-like substitution in the 2-aminotetralin partial structure as the analogous 2-(di-n-propylamino)-7-hydroxy-6-methyltetralin, as well as other ring systems incorporating this hydroxymethyl substitution pattern, failed to show any dopaminergic effects of any kind. 22 The reasons for these behavioral effects remain unclear. Furthermore, the in vivo agonist activity of 23 remains very puzzling, as there is no data to suggest that metabolic activation of a bromophenol in a dopaminergic series of compounds can impart agonist activity.…”

Regiodefined synthesis of brominated hydroxyanthraquinones related to proisocrinins

“…It was derivatized to its MOM derivative 31 using MOMCl and DIEPA in DCM. Darzens glycidic ester condensation of 31 with methyl 2-chloroacetate and sodium methoxide in methanol ( Scheme 4 ) afforded the desired epoxide 32 [ 44 ]. The epoxide 32 was characterized by the signals corresponding to two protons of the epoxide at δ 4.18 and 3.54 [ 44 ].…”

“…Darzens glycidic ester condensation of 31 with methyl 2-chloroacetate and sodium methoxide in methanol ( Scheme 4 ) afforded the desired epoxide 32 [ 44 ]. The epoxide 32 was characterized by the signals corresponding to two protons of the epoxide at δ 4.18 and 3.54 [ 44 ]. Since the yield of 32 was low, we considered a Horner–Wadsworth–Emmons reaction of aldehyde 31 with triethyl phosphonoacetate as an alternative.…”

Ligand-Free Suzuki Coupling of Arylboronic Acids with Methyl (E)-4-Bromobut-2-enoate: Synthesis of Unconventional Cores of HIV-1 Protease Inhibitors

“…Some strategies to prepare ( E )-4-arylbut-2-enoates in moderate to good yield imply a new CC bond formation by Wittig-like reaction, modified Julia olefination, or alkene cross-metathesis . However, some limitations remain: (1) required starting materials are not readily accessible and (2) some functional groups are not tolerated.…”