A variety of substituent groups has been attached to the exocyclic imine function of 2-imino-3-methylthiazolidine (1) in a search for metabolic precursors of this potent inhibitor of the enzyme indoleethylamine N-methyltransferase (INMT) which would exhibit superior pharmacodynamic properties in animals. It has been determined that chemically stable derivatives of 1 based on succinic, nicotinic, and N-acylated amino acids, although they lack in vitro efficacy, are potent inhibitors of INMT when administered orally or intravenously to rabbits. Metabolic studies carried out with 14C-labeled N,N'-bix(3-methyl-2-thiazolidinylidene)succinamide (3) have established that conversion of this compound to 1 occurs both in the whole rabbit and in the isolated rabbit liver. 1 itself has been shown to be metabolically inert in rabbits, being excreted primarily in the urine.

Syntheses of a large number of mono- and bicyclic, as well as a few tricyclic, amidine derivatives related to 2,3,4,6,7,8,-hexahydropyrrolo[1,2-a]pyrimidine (DBN) are reported. In vitro potencies for inhibition of the enzyme indolamine N-methyltransferase (INMT) from rabbit and human lung are presented. Four bicyclic amidine derivatives and 11 monocyclic derivatives were found to be equal or superior to DBN in in vitro potencies. With the bicyclic amidines, increasing ring size or introduction of substituents reduced activity. Among the monocyclic analogues, the most potent representatives were five- or six-membered systems with an exocyclic imino group, combined with methyl of ethyl substituents on the endocyclic nitrogen. Introduction of additonal substituents decreased inhibitory potency. 2,3,5,6-Tetrahydro-8H-imidazo[2,1-c][1,4]thiazine and 3-methyl-2-iminothiazolidine have been shown to cause inhibition of lung INMT when administered orally to rabbits.

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GEORGE JUST, GRANT READER, and BERNADETTE CHALARD-FAURE. Can. J. Chern. 54, 849 (1976).The Diels-Alder adduct of cyclopentadiene and 8-brorno acrylic acid 1 was converted to ~,~-exo-6,7-(dihydroxy-di-O-isopropylidene)-2-hydroxy-3-oxabicyclo[3.2.1]octane (9) in an eight-step sequence and a 24% yield based on 1. Alternatively, the hemiacetal9 was obtained in five steps and 22% yield from norbornadiene through the intermediate lactone 11. The thiosernicarbazone and sernicarbazone of 9 were prepared. The synthesis of the free aldehyde 13 as well as that of the Wittig reaction products 12 and 19 are described. GEORGE JUST, GRANT READER et BERNADETTE CHALARD-FAURE. Can. J. Chern. 54, 849 (1976).La rkction de l'acide 8-bromo acrylique 1 sur le cyclopentadkne conduit au produit d'addition de Diels-Alder correspondant; ce dernier peut Ctre transformi en huit Ctapes avec un rendernent global de 24y0 bask sur 1 en D,L-exo-(dihydroxy-di-0-isopropylidene-6,7 hydroxy-2-oxa-3 bicyclo[3.2.l]octane 9. L'hCmiacCtal 9 a Cgalernent Ct C obtenu en cinq Ctapes avec un rendement de 22'g ? i partir du norbornadikne et en passant par la lactone 11. On d k r i t la preparation de la thiosernicarbazone et de la semicarbazone de 9 ainsi que la synthtse de 1'aldChyde 13 et des produits 12 et 19 provenant de rkctions de Wittig.In a preliminary communication (I), we reported the synthesis of lactol9 and lactone 11. In this paper, we are giving a full account of this work and the description of a second pathway leading to 9 and 11. The syntheses of related derivatives and of the free aldehyde 13 are also described. These compounds are potential intermediates for the preparation of carbocyclic analogues of C-nucleosides.Condensation of 0-bromoacrylic acid 1 with cyclopentadiene in benzene (2) gave the DielsAlder adduct 2 in 75% yield. This compound was almost exclusively the endo carboxylate isomer (3). Treatment of the acid 2 with diazomethane gave, in essentially quantitative yield, the ester 2a which was oxidized to the diol 3 with hydrogen peroxide and a catalytic (4) amount of osmium tetroxide. The diol3, mp 145 "C, was obtained in 50% yield. The stereochemistry of the hydroxy groups in 3 was assigned on the basis of previous work (4, 5) which had shown the preferential exo-hydroxylation of bicyclic[2.2.1] systems of type 2.Attempts to hydroxylate the acid 2 directly were unsuccessful. Crude diol3 was converted to its isopropylidene derivative 3a in 60% yield based on adduct 2. Elimination of hydrogen bromide by treatment of 3a with 1,Sdiazabicyclo[5.4.0]undec-Sene afforded the olefinic ester 4. Upon treatment of diol 3 with acetic anhydride -pyridine, the olefinic diacetate 4a was obtained. Similarly, the olefinic carbonate derivative 4b was the major product from the reaction of diol 3 with phosgene in pyridine. It was not possible to obtain a pure sample of 3a for elemental analysis, although the compound was otherwise well characterized. Attempts at purification by column chromatography, on either silica gel or alumina (activity 1 or...

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