2.6- Diamino-5 -chloropyrazine

Chemical Name 3,5-Diamino-N-(aminoiminomethyl)-6-chloropyrazine carboxamide hydrochloride... 

Attempted preparations of the acid chloride from 2,6-diamino-3-carboxy-5-chloropyrazine under a variety of conditions were unsuccessful (1331) and in that respect it resembled anthranilic acid. 

Diamino-3-carboxy-5-chloropyrazine A, 7V-diphenylcarbamic anhydride (19), an active ester, has been prepared by addition of diphenylcarbamoyl chloride to 2,6-diamino-3-carboxy-5-chloropyrazine and triethylamine in dimethylformamide, (and other similar compounds were also prepared) (1330, 1344, 1345). This compound was better prepared from 2,6-diamino-3-carboxy-5-chloropyrazine and... 

Diamino-3-carboxy-5-chloropyrazine in dimethyl sulfoxide (a) with N,N dicyclohexylcarbodiimide gave 2,6-diamino-3-chloro-5-(2, 5 -dioxopyrrolidin-l ylcarbonyOpyrazine ( ) (962), (6) with dicyclohexylcarbodiimide (and 2-hydrazino pyrimidine) gave 2,6-diamino-3-chloro-5-(A -cyclohexyl-V-cyclohexylcarbamoyl) carbamoylpyrazine (1331), and (c) as its triethylamine salt with V-ethyl-5-phenyl... 

A comparison has been made of the reactivity of active esters (12,19,29,30) of 2,6-diamino-3-carboxy-5-chloropyrazine in reactions with various amines to give amides (1345). Compound (19) was the most reactive followed by (12) and both more reactive than the others (1345). Compound (12) with sulfurylamide in acetonitrile with triethylamine gave 2,6-diamino-3-aminosulfonylcarbamoyl-5-chloropyrazine (463). 

Dimethoxycarbonylpyrazine heated with hydrazine hydrate in ethanol gave some 5,8-dihydroxypyrazino[2,3-with hydrazines (and amines) has been described in Section 2C(2)(a) (961,1330, 1331). An analogous active ester was prepared from 2-amino-3-carboxy-5-chloro-6-methoxypyrazine and with hydrazine in tetrahydrofuran gave 2-amino-5-chloro-... 

Carbamoyl-3-hydroxypyrazine refluxed with aniline gave 2-hydroxy-3-7V-phenylcarbamoylpyrazine (1055) and 2-amino-3-carbamoyl-5,6-diphenylpyrazine refluxed with benzylamine gave 2-amino-3-A -benzylcarbamoyl-5,6-diphenylpyrazine but a similar reaction with piperidine was unsuccessful (451). 3-Methylamino-2-yV-methylcarbamoyl-5-phenylpyrazine was unchanged when heated with liquid ammonia in dry ethanol at 210° for 2 hours (453). 2,6-Diamino-3-carbamoyl-5-chloropyrazine in isopropanol with 1 mol of potassium hydroxide and 1 -amidino-... 

Diamino-3-chloro-5-hydrazinocarbonylpyrazine with nitrous acid at 50-55° formed 2,6-diamino-3-azidocarbonyl-5-chloropyrazine, which, refluxed with a solution of guanidine hydrochloride and sodium isopropoxide in propan-2-ol, gave 2,6-diamino-3-chloro-5-guanidinocarbonylpyrazine and many similar preparations were reported (1371). 2-Amino-5-chloro-3-hydrazinocarbonylpyrazine treated with nitrous acid gave 2-amino-3-azidocarbonyl-5-chloropyrazine, which was pyrolyzed to 5-chloro-2-hydroxyimidazo(4,5-Z)]pyrazine (1226). 

Figure 1.13. Stmcrural formulae of amiloride fti-amidino-3,5-diamino-6-chloropyrazine-2-carboxamide) (I), 2,4-diamino-6,7-dialkylpteridine (2), 2-aryl-4,7-diaminopteridine-6-carb-oxamide (3) and 2.4.7-triamino-6-arylpteridine (4). Triamterene is 2,4,7-triamino-6-phenyl-...

In amphibian epithelia (skins and bladders), amiloride blocks sodium transport when applied to the mucosal fate [153,154,183-185]. The essential part of the molecule is the guanidine moiety, as the methyl ester of 3,5-diamino-6-chloropyrazine carboxylic acid is without activity [154]. Furthermore, it is necessary for the guanidine group to be protonated for blocking activity [148, 186-188]. The p/fg of amiloride is 8.7 and is therefore largely protonated in the conditions existing in the distal tubule. In the absence of calcium ions (and in the presence of a calcium chelator), amiloride fails to block sodium entry [189] although it apparently still binds to the receptor [190]. 

Modern diuretics contain no mercury. Many of them, like amiloride (N-amidino-3,5 diamino-6-chloropyrazine-2-carboxamide) and the pteri-dine diuretic, triamterene ( Dytac ) (r. i), act on the membrane lining the distal tubule, preventing resorption of sodium ions (and hence of water) (Crabbe, 1968 Wiebelhaus et al. 1965). The simpler molecule 2,4-diamino-6,7-dimethylpteridine is almost as active. Others, like frus-emide and ethacrynic acid, seem to act somewhat similarly. It is less certain that the thiazides, such as (14.2), act in this way. For more information on the action of diuretics, see Suki, Eknoyan, and Martinez-Maldonado... 

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