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 1hew compounds reverse the electrolyte excretion effects of deox!co~ti~oEteroiiein the adreiialec,toniizetl rat and cause iiatriiuesis in the intact rat, arid dog while leaving unaffected or eveii repressing K + excretion.
Oiie objective of this laboratory i q the deve1ol)liieiit of iiiiI)rovcd diurel ic agents. The ixicrea5ed uriliary t~cretioriof sodiuni hicarbonate produced b y : L Wazol~ :itiiidc aiid of S a C l by the thiazide diuretic. is ; i ( ~ ~ ) i i i p:iiiied b y illcreased excretion of l800 was evaporated a t reduced pressure, and the syrupy residue stirred with ethanol to obtain a crystalline solid which was reThe scores of the 3-amidino-3-aniinopyrazinecarbox- crystallized from aqueous ethanol to yield 12.5 g. (41%) of product, m.p. 127-135" (hygroscopic). amides should be compared with those determined Anal. Calcd. for C & O N ~ @ ~ Sc, : 23.68; H , 6.63; N, 27.62. for the aldosterone antagonistg spironolactone1° (+1) Found: C,23.91; H,6.48; N,27.39. and for 2.4.7-triamino-6-phenylpteridinell ($2). 1,l-Dibutylguanidine Hydrochloride.-Dibutylamine (71.5 N-Amidino-3-amino-6-chloropyrazinecarboxamide g., 0.55 mole) was added to a mixture of 41 ml. of concentrated HCl and 125 ml. of water to give a solution of pH 9.2. While (1) is the most potent DOCA inhibitor of this series, the solution was held a t looo, a 507, aqueous solution of cyanproducing a 50% reversal of the DOCA effect at 36 amide (65.1 g., 0.775 mole) was added during 3 hr. After 1 ylrat. Substitution on the guanidine moiety generally additional hr. a t loo", the solution was evaporated a t reduced lowered activity, the lowering being, very roughly, pressure. The residual salt was dissolved in 100 ml. of water, proportional to the bulk of the substituents. Only 50 ml. of 407, KaOH solution was added, and CO? was bubbled in to precipitate the bicarbonate salt of 1,l-dibutylguanidine. 3 with two methyl substituents, 11 with a benzyl, This salt was dissolved in 100 ml. of warm water, 1 eqniv. of arid 13 with a hydroxyethyl substituent were apconcentrated HC1 was added, and the solution was chilled to Replacement of the proximately equipotent with 1. precipitate 88.8 g. (777,) of the product, m.p. 101-106". -4 chlorine atom by bromine or iodine reduced activity. sample recrystallized from water melted at 104.5-106'. Anal. Calcd. for CgHZlNa.HC1: C, 52.03; H , 10.6i; N, The acylation products of 1, 29, and 30 were weakly 20.23. Foimd: C, 52.11; H , 10.20; N, 20.17. active (score *). 1sopropylideneaminoguanidine.-The reaction of acetone with The conipounds of this series function as nonspecific aminoguanidine hydrochloride was carried out by the method of inhibitors of the mineralocorticoids since, at a higher Finnegan, et aLZ3 The reaction solution was made strongly dose, the more highly active members not only combasic by addition of 407, S a O H solution to precipitate isopropylideneaminoguanidine which was recrystallized from a cyclopletely reverse the electrolyte effects of DOCA but hexane-isopropyl alcohol mixture. The product, m.p. 104-109", produce an added natriuresis and antikaliuresis thus was obtained in 86% yield.24 giving urinary Ka/K ratios greater than those found Anal. Calcd. for CIH~ON,:K, 49.09. Found: N, 49.50. for adrenalectomized rats. Methyl 3-Amino-6-chloropyrazinecarboxylate (IIa).-A mixture of methyl 3-aminopyrazinecarboxylate3 (90 g., 0.588 mole), The diuretic and natriuretic activities in intact rats 750 ml. of acetic acid, and 3180 ml. of water was heated to 41" to and dogs1*closely parallel the DOCA inhibitory activiobtain a solution. The solution then was placed in a n ice bath
*
ties; compound 1 is most highly active in both species. ,it comparable doses, the compounds are generally inore effective in the rat than in the dog. This activity
(13) hIelting points were taken in open capillaries and are corrected. (14) R. Kitawaki, S i p p o n Kagaku Zasshi, 73, 1435 (1957). Bannard, -1. .
