Design and Synthesis of New N1 and C3-Substituted 4-Fluoroindolic Melatoninergics

Abstract

A series of new C-3 and N1-substituted 4-fluorotryptamides have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT(1) and MT(2) melatonin receptor subtypes expressed in NIH 3T3 cells. Planar sp(2) geometry at C-3-betaC seems to decrease the population of the preferred conformation as it renders 4-fluoroindoles 4b-d weaker antagonists than their C-3-betaC-unsubstituted congeners 3a-e. This effect is not preclusively linked with the C-3 region, as the same geometry around N1 (compounds 5a-c) similarly leads to weak antagonistic action. Last, the new C-3 substituted 4-fluorotryptamides presented herein are substantially more potent than their respective N-OMe functionalized congeners, previously reported.

Stereoselective Synthesis of Pyrroloquinolines by a Brønsted Acid Catalyzed [4+2]‐Heterocyclization of Indole‐7‐Carbaldehydes, Anilines and Electron‐Rich Alkenes

“…For example, compound I and some other similar molecules have been tested for their ability to bind the recombinant human MT1 and MT2 melatonin receptor subtypes expressed in NIH 3T⋅cells 1. The interest of compound II as anticonvulsant2 and III as a potential drug for the treatment of type II diabetes has also been demonstrated 3.…”

“…[1] Thei nteresto fc ompound II as anticonvulsant [2] and III as ap otential drug for the treatment of type II diabetes has also been demonstrated. [3] Other pyrrolo[3,2,1-ij]-quinoline derivatives with potentiala pplicationi n medicine are IV, [4] for the managemento fe pilepsy and obesity,a nd V (KC11404) for the treatment of asthma.…”

“…was added at the temperature shown and the reactionw as stirred for the time shown. [b] Determined by 1 HNMR analysis of the crude reaction mixture. [c] Theyield of isolated product 4 based on starting material 1a is shown in parenthesis.…”

A New, Stereoselective, Ring-Forming Reaction of 1,2-Ethanedithiol with N-Acylated Indoles

“…3 We prepared the 4-fluoroindole analogue 3 (Scheme 1) in 40% yield by standard treatment of the ketone 2 with 1,2-ethanedithiol and boron trifluoride etherate. Compound 3 was a modest melatonin antagonist (pIC 50 ) 4.96 nM) 4 with some selectivity (11-fold) for the MT 2 receptor. 5 In an attempt to improve potency and receptor site selectivity we decided to relocate the side chain from C3 to N1 (compound 8a, Scheme 2).…”

A general intramolecular Friedel–Crafts approach to functionalized pyrrolo[3,2,1-ij]quinolin-4-ones

“…[14][15][16][17][18][19][20] For instance, processes that involve the formation of the PQ framework via Fischer indolization are limited by the preparation of the requisite 1-amino-THQs. 5,6,8…”