Pteridine

X-ray structural analysis shows that the two fused six-membered rings in pteridine (pyrazino[2,3 /]pyrimidine) are virtually coplanar. Its C-C and C-N bond lengths and C-N-C bond angles (with values less than 120°) are comparable to those of pyrimidine and pyrazine (see Fig. 6.23)  

The spectroscopic data, especially the strong downfield shifts of the H- and C-atoms in the NMR spectra, are characteristic of pteridine as a strong r-deficient heteroaromatic system. Pteridines are coloured (yellow to red), the parent compound being yellow. 

Pteridine is inert [161] towards electrophiles, but reacts with nucleophiles. Because of the reversible addition of water across the N-3/C-4 bond, pteridine can act as an acid or a base in an aqueous system. The amidine configuration in the pyrimidine ring (diazaallyl system) stabilizes the positive charge after protonation and the negative charge after deprotonation  

The synthesis of pteridines usually starts from 4,5-diamino-substituted pyrimidine derivatives (see p 411). 

Unsymmetrical 1,2-dicarbonyl compounds lead to isomeric mixtures a-keto aldehydes react regioselectively and the corresponding a,a-dichloro ketones behave in a complementary manner, e.g.  

Salts of piperazine (citrate, phosphate, adipate) or its hexahydrate are used as antithelmintics. The piperazine ring is frequently used as a building block for pharmaceuticals. Benzhydrylpiperazines, such as cinnarizine (8) and its difluoro analog flunarizin (9), are used as peripheral and cerebral vasodilators hydroxyzine (10) is used as a tranquilizer. 

I g I Pteridine is inert toward electrophiles, but undergoes reactions with nucleophiles [295]. 

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Subsequent knowledge of the stmcture, function, and biosynthesis of the foHc acid coenzyme gradually allowed a picture to be formed regarding the step in this pathway that is inhibited by sulfonamides. The biosynthetic scheme for foHc acid is shown in Figure 1. Sulfonamides compete in the step where condensation of PABA with pteridine pyrophosphate takes place to form dihydropteroate (32). The amino acids, purines, and pyrimidines that are able to replace or spare PABA are those with a formation that requkes one-carbon transfer catalyzed by foHc acid coenzymes (5). 

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. 

The spectra of protonated polyaza heterocycles are frequently complicated by the occurrence of covalent hydration. This is more common with polycyclic systems, e.g. pteridine. 

Pyrimidines from pteridines and related fused systems... 

Most pteridines are degraded to pyrazines and when they do yield pyrimidines, these may well be the ones from which they were made. However, some useful preparations of pyrimidines from pteridines are known. Thus, reduction of pteridin-7(8//)-one (732) and subsequent hydrolysis yields N-(4-aminopyrimidin-5-yl)glycine (733) (52JCS1620) and hydrolysis of 5,8-dimethylpteridine-6,7(5Ff,8Ff)-dione (734) gives dimethyl-... 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

The mass spectra of pyridopyrimidines in general show many features in common with those of other related N-heterocycles, in particular quinazolines and pteridines. The pyridopyrimidines show strong molecular ions, and when breakdown of the hetero ring occurs, fragments arising from loss of CO, CN, HCN and HCNO are observed. 

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. 

Apart from the nuclear bromination observed (Section 2.15.13.1) in the attempted radical bromination of a side-chain methyl group leading to (396), which may or may not have involved radical intermediates, the only other reaction of interest in this section is a light-induced reduction of certain hydroxypyrido[3,4-f)]pyrazines or their 0x0 tautomers analogous to that well-known in the pteridine field (63JCS5156). Related one-electron reduction products of laser photolysis experiments with 1 -deazaflavins have been described (79MI21502). 

The only reaction of this type noted involved the reaction of pteridines, e.g. (415), with malonodinitrile (or cyanoacetamide), via ring opening to (416), with final [6 + 0 ( )] cyclization to give the 6-amino-7-nitrile (amide) (417) (73JCS(P1)1615, 73JCS(P1)1974). 

By far the most important reaction for the synthesis of pyridopyrazines is the reaction of diaminopyridines with two-carbon fragments, the pyridopyrazine equivalent of the well-known Isay reaction in the pteridine field. 

The pyridopyrazine group does not contain any actual natural products, but the considerable scope for synthesis of 1- and 3-deaza analogues of various natural pteridines or pteridine drugs has been widely exploited. 

Synthetic Pteridines with Chemotherapeutic Effects Folic Acid and Related Derivatives... 

The basic pteridine nucleus (1) consists, according to X-ray crystallographic studies (75JCS(P2)40), of a more or less planar molecule with no unexpected features in so far as... 

Studies on covalent hydration of N-heterocycles (67AG(E)919,76AHC(20)117) have revealed the diagnostic value of alkyl substituents in structural assignments due to their steric hindrance effects in addition reactions. C-Methyl substituents are therefore also considered as molecular probes to solve fine-structural problems in the pteridine field. The derivatives... 

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