A number of substituted piperazines, hexahydro-l,4-diazepines and octahydro-1,5-diazocines possessing the ethyl guanidine side chain were prepared and found to have cardiovascular properties.The disclosure that certain amidoximes and guanidines, particularly when associated with large membered heterocyclic systems, possess antihypertensive properties,2-3 has resulted in a study of other ring systems in the hope that they might give biologically active compounds.4Early in the study it was found that [2-(4-methyl-1-piperazinyl)ethyl ]-guanidine sulfate also manifests interesting cardiovascular properties. This compound suppresses sympathetic nerve impulses, presumably at the efferent nerve terminals; it interferes with powerful vasoconstrictor reflexes to the limb while apparently reducing or eliminating their neurogenic tone. Since it has only mild hypotensive activity in normotensive animals and produces a minimum of early sympathetic-like actions following intravenous administration, it seemed a potential drug against those peripheral vascular diseases where sympathetic hyperactivity is suspected to play a part. As a result of these findings a representative array of related piperazines and higher homologs of piperazine was prepared for pharmacological testing.In addition to the 4-methyl derivative, several other 4-alkyl and 4-phenyl piperazines proved to have cardiovascular properties. With (1) For the preceding paper in this series, see R.
2201product with alloxan monohydrate and boric acid was found to give a better yield when stirred a t room temperature for three days. After recrystallization from 18% hydrochloric acid, a 75% yi$d of orange product was obtained, which melted a t 238-240 . The reported value3 is 237-243'.Metal Chelates of Riboflavin.-To a mixture of 2 g. (0.005 mole) of riboflavin (U.S.P.) and 50 ml. of water was added sufficient 5% sodium hydroxide solution to dissolve the riboflavin. An aqueous solution (10 ml.) of metal salt (0.005 mole), either ferrous sulfate, cobaltous chloride, nickel nitrate, zinc chloride, cupric chloride or manganese chloride of analytical grades, was added slowly (ten minutes) to the stirred solution along with sufficient 5% sodium hydroxide solution to maintain a pH of 9. After 30 minutes further of stirring and adjusting the pH, the mixture was filtered. The filtrate was acidified with 5% hydrochloric acid, and the unreacted riboflavin was collected and dried for further use. The residue was washed with several portions of water, extracted with acetone in a Soxhlet extractor for four hours, and dried in vacuo. Quantitative yields of brown product were obtained, which had characteristic softening points, as shown in Table I, but did not melt below 300'.The formation of a mercury salt with mercuric chloride was carried out in the same manner, except that no additional alkali was needed to maintain a pH of 9. Metal Chelates of 6,7-Dichloro-9-( 1 '-D-sorbityl)-isodloxazinc.-Metal chelates of this compound were prepared in an identical manner to that for the riboflavin chelates, using cobaltous chloride and nickel nitrate. A 94% yield of green-brown cobaltous chelate was obtained, which softened a t 160-165".Anal. Calcd. for C I~H~~O~N~C~~C O~.~H~O : Co, 18.11.Found: Co, 18.48. The orange nickeLchelate was obtained in 93% yield, and softened at 135-140 .The preparation of pyridazine from hydrazine salts and maleic anhydride, previously described (ref.3), has been extended 4-Methylpyridazine has been obtained from citraconic anhydride and t o the synthesis of various substituted pyridazines. hydrazine dihydrochloride in high over-all yield; some properties of this potentially interesting substance are discussed.The preparation of pyridazine and 3,G-dichloropyridazine from maleic anhydride was described in a recent paper.3 In a test of the generality of this method, a number of substituted maleic anhydrides were condensed with hydrazine dihydrochloride in aqueous medium. followed by chlorination with phosphorus oxychloride and catalytic hydrogenolysis under mild conditions. This process found ready application in the case of citraconic anhydride; 4-methylpyridazine, previously unknown, was obtained in high yield. The transformation of chloromaleic anhydride into 4-chloro-3,G-pyridazinediol and 3,4,6-trichloropyridazine proceeded easily and in good yield. &-Aconitic anhydride in turn was converted to 4-(3,6-dihydroxypyridazy1)-acetic acid.These results lend further testimony to the marked effect of reaction ...
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