Pteridine compounds

An interesting new development has been the discovery that certain pteridine compounds promote sodium excretion and, at the same time, potassium retention. Clinical studies in hypertensive patients carried out with triamterene indicated that the drug was not in itself sufficiently potent as a natriuretic agent in hypertensive patients to be clinically useful (10). When combined with half-strength doses of hydrochlorothiazide, however, its natriuretic effect was comparable to that obtained with full doses of hydrochlorothiazide but without significant urinary loss of potassium or reduction in serum potassium concentration. Thus, triamterene may represent a beginning in the development of new compounds with more specific natriuretic properties. 

It is important to realise that sodium channels in epithelia are different from those in excitable membranes. One clear piece of pharmacological evidence for this point of view is that epithelial sodium channels are relatively unaffected by TTX in high concentrations [147,148]. Furthermore, it is likely that there is more than one type of sodium channel in epithelia. For example, there are a number of pyrazine and pteridine compounds which block sodium transport by blocking sodium entry into the cells of the distal kidney tubule but do not block sodium entry into cells of the proximal tubules. 

However, 4,6-diamino-2-methylpyrimidine in alcoholic solution reacts with xylose to give 6-amino-4-D-xylosylamino-2-methylpyrimidine 48) The reaction of glucose and fructose with 2,4,5-triamino-6-hydroxypyrimidine yields pteridine compounds 50) which, when subjected to a folic acid -forming reaction, do not give biologically active compounds 50) ... 

A choice between these two variations depends, then, on the nature of the pteridine compound which is reduced by TPNH. Evidence has already been presented in favor of the view that the compound which is reduced by TPNH has the structure of a 5,6-dihydropteridine, and on this basis the hydroxylation scheme represented by reactions a, b, and d can apparently be ruled out. The evidence for the dihydropteridine nature of the intermediate rests primarily on the fact that an active compound can be prepared from the tetrahydropteridine by a stoichiometric oxidation with 2,6-dichlorophenolindophenol. From these facts alone, the possibility cannot be ruled out that the dihydropteridine is inactive and only forms the active compound by hydration to yield a hydroxytetrahydropteridine (e.g., by a reversal of reaction c). If this possibility exists, hydroxylation via reactions a, b, and d is still a possibility. 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

Amino groups a to nitrogen are hydrolyzed to the corresponding oxo compounds (as in the purines and pteridines) in bo h acid and alkaline conditions. Schiff bases are reduced to benzylamino derivatives with borohydride. 

The molecular features of covalent hydration are also present in the dihydroxy series, i.e., in pteridine-2,6-dione (30) and in pteridine-4,6-dione. The latter compound is hydrated only at the C(7)—N(8) double bond, whereas (30) forms two hydrated species, 7-hydroxy-7,8-dihydro- (29) and 4-hydroxy-3,4-dihydro-pteridin-2,6-dione (31) (equation 8). Structure (29) is thermodynamically the more stable substance (31) is formed more rapidly in solution but disappears slowly with time (63JCS5151). Insertion of a 4-methyl group greatly reduces the extent of 3,4- in favour of 7,8-hydration by a blocking effect . 

There is no easy understanding of the spectral properties of these compounds in general, which may or may not have a built-in chromophoric system responsible for a long-wavelength absorption like 7,8-dihydropteridin-4-one or a blue-shifted excitation like its 5,6-dihydro isomer. More important than the simple dihydropteridine model substances are the dihydropterins and dihydrolumazines, which are naturally occurring pteridine derivatives and reactive intermediates in redox reactions. 

A great variety of differently substituted pteridine derivatives have been synthesized starting from (109) or the 2,4,6,7-tetrabromo compound (60USP2940972), which shows a corresponding reactivity pattern. Amines at low temperature substitute only the 6- and... 

Aminopteridine is the most sensitive to acid hydrolysis, and 6-amino- and 6-dimethyl-amino-pteridine are also hydrolyzed, even by cold 0.0IN hydrochloric acid, too rapidly for accurate determination of the cation form (52JCS1620). 2-Amino- and 4-amino-pteridine are not readily attacked by IN HCl at 20 °C but at 100 °C the former compound is destroyed and the latter converted into pteridin-4-one (5UCS474). 2,4-Diaminopteridine can be hydrolyzed by refluxing in 6N HCl for 30 minutes to 2-aminopteridin-4-one (pterin 2) and after... 

When hydroxypteridines are considered, it must be borne in mind that these compounds exist principally in the pteridinone forms, containing thermodynamically stable amide functions, and consequently have low reactivity. Their stability towards acid and alkali correlates well with the number of electron-donating groups which apparently redress the deficit of ir-electrons located at the ring nitrogen atoms. Quantitative correlations can be seen in the decomposition studies of various pteridinones (Table 7). These results are consistent with the number of the oxy functions and their site at the pteridine nucleus. The... 

As a result of the 7r-deficiency of the pteridine nucleus, alkyl pteridines are activated in the a-positions. The common reactions based on C—H acidity are found with a wide variety of compounds. Bromination of 6- and 7-methyl groups leads to mono- and di-substitution selective formation of the monobromomethyl derivatives has not yet been achieved satisfactorily. 6-Methylisoxanthopterin is claimed to give the 6-bromomethyl derivative with bromine in acetic and sulfuric acids at 100 °C for 2 min (50ZN(B)132) and with 1,7-dimethyl-lumazine a 90% yield of the 7-bromomethyl derivative (60CB2668) is obtained after 4h... 

Since the structures of the Gabriel-Isay condensation products of 5,6-diaminopyrimidines with unsymmetrical 1,2-dicarbonyl or a-substituted monocarbonyl compounds are always ambiguous, the synthesis of 6- and 7-substituted pteridines by an unambiguous approach was and still is a necessity and an important challenge. 

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