Pyrazine Diuretics. I. N-Amiclino-3-aniino-6-halopyrazinecarboxa~iiides . I series of S-amidiiio-B-aiuiiio-ti-lialop~rr.aziiiecarboxuiiiides WIJ prepared pi'iitc,ipr.ally try the reaction of iiiethyl 3-ar~iitio-6-halop~ra~iiie~a~bor;3.lates with yiiariidirie or siihstitiited giiatiidiiies. A iiiiriiber of 1 hew compounds reverse the electrolyte excretion effects of deox!co~ti~oEteroiie in the adreiialec,toniizetl rat and cause iiatriiuesis in the intact rat, arid dog while leaving unaffected or eveii repressing K + excretion.
Vol. 69 temperature was maintained below 45°until the exothermic reaction stopped. Excess dimethyl sulfate was decomposed by heating to 90°for two hours. The upper layer of the reaction mixture was washed with water, dried, and fractionally distilled at reduced pressure to give a 60% yield of the ether. Calculated for CnHieO: C, 80.44; H, 9.82. Found: C, 80.37; H, 9.98. Cyclohexyl Methyl Ether.17-Anisóle (750 g., 7 moles) was hydrogenated in the presence of 75 g. of nickel-onkieselguhr catalyst at 180°to give 600 g. of ether, 76%.Cyclopropyl Methyl Ether.-Glycerol was brominated, in approximately 18 mole runs, to glycerol a,7-dibromohydrin, in 60% yields, following the procedure of Braun.18 The dibroinohydrin (10.8 moles, 2347.5 g.) was treated with 1449 g. (11.5 moles) of dimethyl sulfate according to Krantz and co-workers.19 A mixture of 212 g. (2 moles)
The synthesis is described of a series of acylhydroxyalkanoic acids which embody structural modifications of that class of secoprostaglandins which are formally derived from the natural substances by scission of the cyclopentane ring between carbon atoms 11 and 12. These analogues have been tested for their ability to stimulate cAMP formation in the mouse ovary, a characteristic action of the (E)-prostaglandins, and for their ability to bind to the rat lipocyte prostaglandin receptor. Certain members of the series that most closely resemble the prostaglandins in structure (e.g., 8-acetyl-12-hydroxyheptadecanoic acid) markedly stimulate cAMP formation at concentrations in the pharmacological range and show a significant affinity for the prostaglandin receptor. Conversely, these compounds are not substrates for prostaglandin 15-hydroxydehydrogenase which catalyzes a major reaction in the biological deactivation of the prostaglandins.
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