Pyrazine-2-carboxamide

Employing the classical Taylor pyrazine sequence, aminocyano-acetamide [170] was condensed with bromopyruvaldoxime [171] to yield the pyrazine carboxamide (336). Alkylation of (35) with (336) gave (337) which was deoxygenated with phosphorus trichloride and then saponified to furnish (338). 

The Ugi-4CR provides straightforward access to precursors of the pyrazine ring that are suitable for a Davidson cyclization [72], The reaction between arylglyoxals, amines, isocyanides, and benzoylformic acid in ether afforded adducts 114, which cyclized on treatment with an excess of ammonium acetate in acetic acid to give pyrazine carboxamides 115 (Scheme 2.41). 

Amino-IV-ethyl-6-phenyl-2-pyrazine-carboxamide 4-oxide... 

Carboxamides containing alkylamine arms like (34), synthesized from dialkylmalonate and ethylene-diamine, act as chelating dianionic N4-donors,44,45 whereas the geometric isomer (35) was prepared from 1,3-diaminopropane and chloroacetyl chloride.46 The hexadentate bis(pyrazine)-carboxamides (36) and (37) can be obtained by the addition of 1,3-propanediamine to the appropriate carboxylic acid.47 Compound (36), in the dianionic form, can be used to obtain homo- and hetero-metal bridged complexes, whereas (37) has been shown to yield tetranuclear copper(II) complexes involving opened-up dianionic ligand molecules.47... 

There are, in fact, very few occurrences of binary hydrogen-bond-based cocrystals that do not contain a primary intermolecular interaction between the two different molecules. Two such examples include 4-nitrobenzamide pyrazine-carboxamide (1 1) [70] and 3,5-dintrobenzoic acid 4-(N,N-dimethylamino)benzoic acid (1 1) [132]. The latter is a rare example of a carboxylic acid- carboxylic acid cocrystal that contains two homomeric dimers instead of one heteromeric dimer [133]. 

Pyrazine carboxamide crystallizes in four modifications, a,P,y,S [57], of which the structures of the a,p, and S forms have been reported. The a-form [58] contains two types of cyclic hydrogen-bonded pairs with N - H. .. O distances of 2.90 A and N-H. .. N(aromatic) distances of 3.14 A. The and S form exhibit a different... 

Fig. 8. Polymorphs A-D of pyrazine carboxamide (PYRAZIN). A possible fifth polymorph E is very similar to A...

From the point of view taken in this review, only those epithelia having sodium channels which can be blocked by defined chemical compounds, particularly the pyrazine carboxamides, will be discussed. 

As a general rule, channels blocked by the pyrazine compounds are found only in tight but not leaky epithelia. Thus pyrazine carboxamides block sodium entry into the cells of the kidney distal tubule [149], salivary duct [150], colon [ISl] and epididymis [152], but not into the cells of the small intestine of kidney proximal tubule. Sodium channels sensitive to pyrazine carboxamides are not confined either to epithelia or to mammalian cells. For example, sodium entry into the cells of frog skin epithelium [153], toad urinary bladder [154], chicken coprodeum, fish gills of some species [ISS], body wall of the leech [155] and crustacean gills [155] are also sensitive. In addition, there are reports that sodium entry sites in ova [3] and erythrocytes [156] are also susceptible to the effects of the pyrazine derivatives. 

N-Amidinopyrazine carboxamides. The synthesis and biological activity of a great number of compounds of this type were described in a series of papers between 1965 and 1 68 [159—162]. The first of these described the diuretic activity in adrenalectomised DOC A-treated rats of a series of A -amidino-3-amino-6-halopyrazine carboxamides. In the second paper, it was discovered that the introduction of a 5-amino group into the pyrazine ring increased the diuretic potency. One of the compounds, amiloride (A -amidino-3,5-diamino-6-chloro-pyrazine carboxamide (Figure 1.13)) later became widely used in clinical practice, particularly in combination with other diuretics. Its use in combination with diuretics acting more proximally in the nephron is related to the prevention of potassium loss which results when an excess sodium load is delivered to the distal tubule. Thus, amiloride is a potassium-sparing diuretic [163]. 

Table 1.2. STRUCTURE-ACTIVITY RELATIONSHIPS OF PYRAZINE CARBOXAMIDES...

Inner-sphere mechanism, f Pz = pyrazine-carboxamide the complex is actually the radical ion species Calculated from K k, using Ki... 

The IR spectrum of Cu2( ii,i-NCO)2(NCO)2(phen)2 includes bands due to both terminal and bridging NCO ligands (VasNCO 2186, 2235 cm" respectively)d The IR and Raman spectra of [Cu(pyza)2(NCS)2]n, where pyza = pyrazine-carboxamide, are consistent with the presence of end-to-end bridging NCS ligands. ... 

With pyrazine carboxamides Co(2-C4H3N2 CONH2)2Cl2 room 5.18 Gouy octahedral coordination suggested 74T14... 

A series of novel bicyclic triazolopyridazine cannabinoid receptor-1 (CB1) antagonists is described. We previously reported a series of di-aryl pyrazine carboxamide CB1 antagonists, and the progression of this series to include fused bicyclic triazolopyridazine CB1 antagonists is reported herein. The bicyclic series leads to compounds with greater in vitro potency and selectivity (CB1/CB2) as compared to the monocyclic series. In vitro and in vivo profiling of the triazolopyridazine CB1 antagonists is described. 

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