No abstract

Series of iV-alkyl and N-dialkylaminoalkyl-S-azabicyclo[3.2.0]heptane-2,4-dione have been prepared from the reaction of the appropriate primary amines and cis-1,2-cyclobutane dicarboxylic anhydride and cyclization of the resulting amic acids. The A-alkyl and iV-dialkylammoalkyl imides thus obtained were reduced to the corresponding iV-alkyl and iV-dialkylaminoalkyl-3-azabicyck> [3.2.0 jheptanes with lithium aluminum hydride. These bases were characterized as hydrochlorides, mono-and bis-methiodides and picrates. The bis-quaternary salts derived from the 3-azabicyclo[3.2.0]heptane nucleus with a dialkylaminoalkyl side chain possessed hypotensive activity in cannulated dogs. The most favorable structure was one in which the number of methylene carbon atoms between the onium centers was 2 or 3 and the introduced quaternary group was a short chain alkyl group such as methyl or ethyl.

During the past several years we have prepared a relatively large number of cyclic bases which have been screened for hypotensive activity as hydrochlorides and quaternary salts. We have found with the majority of compounds prepared in the several series studied so far that the bases could be prepared conveniently and in good yields by the reduction of the corresponding imides with lithium aluminum hydride. As a result of this continued study we have prepared a large number of N-alkyl-and N-dialkyl-aminoalkyl imides as intermediates in the synthesis of the desired bases.A survey of the literature concerning the particular series of imides that we wish to report here revealed that one t o several members had been reported in each series but that in many cases the physical data were scanty. Also, the previously reported imides, prepared by a variety of methods, are scattered in many sources in the literature. We have prepared the present four series of N-alkyl imides, in amounts varying from 4 to 90 grams, by a single general method and have assembled complete data on boiling points, melting points, densities, and refractive indices.In the present article we wish to report the N-alkyl succinimides from butyl through dodecyl (I) ; the N-alkyl-cis-A4-tetrahydrophthalimides, methyl through dodecyl (11) ; the N-alkyl-cis-3, 6-endomethylene-A4-tetrahydrophthalimides, butyl through dodecyl (111) ; and the N-alkyl hexahydrophthalimides, methyl through dodecyl (IV). 0 0 0 0

Series of nonane-2,4-diones have been prepared from cts-hexahydroisophthalic anhydride and the corresponding alkyl and dialkylaminoalkylamines. These imides have been reduced to the corresponding 3-alkyl and 3-dialkylaminoalkyl-3-azabicyclo[3.3.1]nonanes and hydrochloride and mono-and bis-quaternary salts prepared for screening as hypotensive agents. These compounds exhibited only a low degree of hypotensive activity or were inactive. When compared to the very active compounds encountered in the closely related isoindole, 2-azabicyclo-[4.3.0] nonane series, this was quite an unexpected result and illustrates again the difficulties and pitfalls frequently encountered in structural-physiological activity predictions and correlation. In this case just changing the bridging in the bicyclic ring from the [4.3.0] to the [3.3.1] structure resulted in marked reduction or almost complete loss of hypotensive activity.

The investigation of various nitrogen heterocycles for use in the formation of symmetrical and unsymmetrical bis-ammonium salts for screening as hvpotensive agents demonstrated dramatic changes in activity with variation in ring bridging.In the bicyclic rings derived from cyclohexane a change in the points of attachment of the second ring from the 1,2 positions (isoindole or 2-azabicyclo [4.3.0]nonane) to the 1,3 positions (3-azabicyclo [3.3.1 Inonane) resulted in almost complete loss of hypotensive activity. Accordingly, we have investigated the effect of changing the points of attachment to the cyclopentane ring. N-Alkyl and N-dialkylaminoalliyl imides have been synthesized from cis-1,Z-cyclopentane dicarboxylic anhydride and reduced to 3-azabicyclo [3.3.0]octanes. On comparison of the bis-quaternary salts with previously reported derivatives of the 1,3-anhydrideI 3-azabicyclo [3.2.1 ]octane, Rhich were verj-potent as hypotensive agents, significant loss of activity was not observed in the present series.For many yearh we have boen concerned with the synthesis of fused ring bi-and tricyclic nitrogen heterocycles for use a h one or both of the terminal groups in the preparation of alpha, omega symmetrical and unsymmetrical bis-ammonium salt. for screening in our hypertenLion chemotherapy program. Among the theories and methods advocated for the chemotherapeutic treatment of hypertensive disease the two most iiqortunt have involved, a t the extremes, emphasis on ganglioplegic agents and centrally acting agents. The pendulum of emphnsi3 on the most desirable of either type of these agents for such use has vacillated frequently in the past decade. This shifting emphasis has probably been largely influenced by the therapeutic limitations of the chemical agents available from time to time.I n surveys of large groupb of ~yninietrica15-~ and unsymmetrical4 bis-ammonium salts hyputensive activity ha3 been encountered widely in both type? In the symmetrical types maximal therapeutic effectivelies has been generally attained when the terminal groups are small aliphatic radicals (hexanlet honiuni hexane-1,B-bistrimethylammonium ration) or m a l l heterocycles (pentoliniuni, pentane-l,5-bis-S-methyl pyrrolidiniuni cation) in which the oniuni centers are separated by a 5 or 6 membered polymethylene chain.On the contrary. extensive studies by Cavallito