A series of 37 1-ethyl- and 1-n-propyl-1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole-1-acetic acids bearing one, or two, substituents on the benzene ring has been synthesized via the acid-catalyzed condensation of a substituted tryptophol with ethyl propionylacetate or ethyl butyrylacetate. Antiinflammatory and ulcerogenic effects were examined and the results show that 1, 8-diethyl-1, 3, 4, 9-tetrahydropyrano[3, 4-b]indole-1-acetic acid (etodolic acid, USAN) is a potent agent, particularly active against a chronic rat model of inflammation (ED50 0.7 + 1-0.1 mg/kg po in the adjuvant arthritis model) and which has a relatively low acute ulcerogenic potential in the same species.

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...

A general synthesis of various substituted benzonorbornene derivatives is described. Benzenesulfonyl aziridines of these compounds were prepared and their acetolysis was studied. The influence of various substitution patterns on the direction of the aziridine rearrangement is discussed and it is shown that the rearrangements may be used as a convenient approach to the synthesis of ring B bridged diterpene alkaloids. Considerable general synthetic utility of these techniques is anticipated.

generated it will have a longer lifetime under relatively acidic conditions, due to less frequent interception by hydroxide ion. Whether alone or in concert, these circumstances with regard to 5 and 7 provide for greater probability of encountering and alkylating DNA and, in effect, represent a form of selective cross-linking.There are significant unanswered questions which must be addressed in connection with the biologically pertinent chemistry of 5, and our continued work in this area will employ, among other methods, multinuclear NMR techniques.

(i)‐Isobutaclamol (I) wird in die (+)‐ und (‐)‐Isobutaclamolhydrobromide getrennt.