Pyrrolo[4,3,2-de]isoquinolines with central nervous system and antihypertensive activities

Abstract

Two synthetic pathways are described leading to a novel series of pyrrolo[4,3,2-de]isoquinolines. Some of these derivatives show high activity in preventing reserpine-induced ptosis and in lowering the blood pressure of spontaneously hypertensive rats, In a continuation of investigations of novel peri-fused tricyclic heterocyclic systems,l two synthetic routes to the pyrrolo[4,3,2-de]isoquinoline system (e.g., 3-1 1, see Scheme I) have been developed and various reactions of this system have been studied. This report describes the use of these routes for the preparation of a variety of pyrrolo[4,3,2-de]isoquinolines bearing substituents at one or more of positions 1, 3, 4, and 5, as well as a derivative containing a ring fused at the 4 and 5 positions. Some of these derivatives have been evaluated pharmacologically and the results are discussed. Scheme I R2 1. R = H 8 2, R = Me 3-11Chemistry. The first synthetic route to the pyrrolo[4,3,2-delisoquinoline system (Scheme I) involved a n internal Mannich reaction of 4-aminomethylindole ( 1 ) 2 or 4-methylaminomethylindole (2)s with aliphatic or aromatic aldehydes to afford a series of 3-substituted and 3,4-disubstituted 1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolines 3-11. Their structures and physical data are collected in Table I.?The second synthetic pathway (Scheme 11) consisted of' the conversion of methyl indole-4-carboxylate5 (12) uia a Vilsmeier reaction to the 3-formyl derivative 13, oximation to the aldoxime 14, and reduction of 14 and reduction of 14 catalytically with palladium in the presence of hydrochloric acid to afford the key intermediate, methyl 3-aminomethylindole-4-carboxylate hydrochloridewhich could be isolated and characterized by nmr spectroscopy but for which an analysis was not obtained because of the ease with which it converts to 16. Thus, treatment of 15 with sodium methoxide in ethanol at room temperature gave the 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5( 1H) -one (16) in 84% yield. Alternatively, when the aldoxime 14 was reduced in acetic acid using platinum as the catalyst and the reaction mixture made alkaline during the work-up procedure, 16 was obtained directly but in only 22% yield.$ :After this work had been completed, the preparation, by a similar route. of 3 and I 1 was reported in the patent literature.* SchemeI1 MeOOC R M a O C CH,NH,. HCI I I I 1 12, R = H 13, R = CHO 14, R=CHNOH 15 H H 16 17Reduction of lactam 16 with diborane afforded the unsubstituted form of the ring system, 17, which made accessible for pharmacological screening a series of monoand disubstituted derivatives bearing alkyl and dialkylaminoalkyl groups on the nitrogen atoms. These transformations of 17 are shown in Scheme I11 and involved the use of conventional series of reactions. Thus, the 1-alkyl compounds 21 and 22 were obtained from 17 uia the benzyloxycarbonyl derivatives 18-20. The 1,4-dialkyl derivative 24 was prepared from 21 uia acylation and reduction. Alternatively, the 1,4-dimethyl analog 27 could be obtained from 17 by 1-alkylation of th...

Novel Tricyclic Poly(ADP-ribose) Polymerase-1 Inhibitors with Potent Anticancer Chemopotentiating Activity: Design, Synthesis, and X-ray Cocrystal Structure

“…The [5,6,7]tricyclic indole intermediate, 3, was also iodinated at the 2-position with bis[(trifluoroacetoxy)iodo]benzene and iodine to give the 2-iodo- [5,6,6]-tricyclic indole, 6 (Scheme 2). Each tricyclic bromide underwent Suzikitype couplings (Scheme 3) with a variety of arylboronic acids to give the 2-aryl- [5,6,7]-or [5,6,6]-tricyclic indole lactams (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), which were evaluated for PARP-1 activity. Formyl substituted 2-aryl tricyclic indole lactams (20)(21)(22)(23) were further functionalized through reductive amination with sodium cyanoborohydride and a variety of primary and secondary amines (24-28, Scheme 4).…”

Synthesis and Characterization of Novel Functionally Substituted Planar Pyrimidothienoisoquinolines and Nonplanar (3aR, 4S, 9aS)-pyrazolo[3,4-g]isoquinolines

“…Isoquinoline and its derivatives are an essential class of heterocyclic compounds that may be found in several naturally occurring alkaloids. , Isoquinoline derivatives show a wide range of biological activities. Some of them show antihypertensive, anti-inflammatory, anti-oxidant, antipyretic, analgesic, antibacterial, antifungal, and antimalarial activities. − Others may act as antidepressants and antipsychotic agents . Several isoquinolines were found to exhibit antitumor or antiproliferative activity. − In particular, the isoquinoline ring constitutes an important molecular part of the topical anesthetic drug quinisocaine (A), whereas the tetrahydroisoquinoline moiety is found in the structure of the antihypertensive drugs quinapril (B) and debrisoquine (C) (Figure ).…”

Study of the Biological Activity of Alkyl Derivatives of Tetrahydroisoquinolines

“…In particular derivatives of tetrahydroisoquinolines are of interest in this point of view because they contain several reaction centers, which makes them very promising as new pharmacological drugs. So, isoquinolines have a wide spectrum of biological properties [1][2][3][4], including both antitumor and antimicrobial effects [5][6][7].…”