Structure−Activity Studies for a Novel Series of Tricyclic Substituted Hexahydrobenz[e]isoindole α_1A Adrenoceptor Antagonists as Potential Agents for the Symptomatic Treatment of Benign Prostatic Hyperplasia (BPH)

Abstract

In search of a uroselective agent that exhibits a high level of selectivity for the alpha(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6-OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the alpha(1) adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.

Synthesis of Some Thienopyrimidine Derivatives

“…The structures of compounds 1-10 were confirmed from their IR, 1 H-NMR, 13 C-NMR and MS spectral data. Substitution of the mercapto group in 4a,d by hydrazine hydrate afforded the 2-hydrazino derivative 11 which was then cyclized by glacial acetic acid to give the triazolo derivative 12 [17,18]; the latter compound is sparingly soluble in CDCl 3 and DMSO-d 6 , precluding the use of 13 C-NMR spectroscopy as a characterization tool. Oxidation of 4a,d by iodine (Scheme 3) gave the disulfides 13a,b [19].…”

“…Many thienopyrimidines are found to exhibit a variety of biological activities, including antiinflammatory [1,2], antimicrobial [3] and analgesic [4] properties, inhibition of cancer cell proliferation [5], antagonism of α 1 adrenoceptors [6] and prevention of cartilage destruction in articular diseases [7]. In continuation with our previous work on the title compounds [8,9], we report herein the synthesis of a series of novel thienopyrimidine derivatives.…”

“…The solid formed was filtered, washed with water, dried and recrystallized from ethanol. [4,5]thieno [2,3- 3, 5,6,7,8,5]thieno [2,3-d] -5,6,7,8-tetrahydrobenzo[4,5]thieno [2,3-…”

Synthesis of benzothienopyridopyrimidinones and benzothienopyrimidoisoquinolinone by microwave-assisted dehydrogenation of the corresponding tetrahydro derivatives

“…Thienopyrimidines and thienopyrimidinones are found to exhibit a variety of biological activities, including anti-inflammatory, 1 antimicrobial 2 and analgesic 3 properties, inhibition of cancer cell proliferation, 4 anti-angiogenic activities, 5 antagonism of α1-adrenoceptors, 6 and antagonism of mGluR1. 7 Consequently, thienopyrimidines have become a well-sought privileged class of compounds in drug discovery programs.…”

High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

“…The choice of the 8-position for the insertion of side chains was made taking into account the structure-activity relationships previously seen in a series of α 1 -AR ligands designed using RN17 as template and developed at Abbott Laboratories [21]. These compounds, based on a pyrazino [2',3':4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione tricyclic scaffold, bear different substituents (hydrogen, methyl, methoxy, chloro, phenyl) at the 7-and/or Figure 1) is one of them: the presence in it of a bulky substituent such as a phenyl ring at the 8-position is well tolerated whereas the shifting of the same substituent to the 7-position causes a marked drop in affinity for all three α 1 -AR subtypes [21].…”