Fused xanthines

Secondary amides remain intact in the presence of LiBH4-MeOH [S03], while at lower temperature or in the absence of MeOH, reduction of tertiary amides seldom takes place. However, an exception has been found with fused xanthines [CK4]. 

Several new /-fused xanthines have been prepared in which the extra ring is pyrazino, pyrido, pyrimido, or pyrrolo, using the purine (109) which is subsequently developed to give appropriately substituted compounds for cyclisation. For examfde, the syntheses of pyrimido-fused (110) and pyrazino-fiised compounds (111) are shown in Scheme 15 [94JHC81]. 

For present purposes, pyrimidines are considered to be important if they occur naturally as such or as part of a natural molecule from which the pyrimidine can be removed easily (fused pyrimidines, e.g. xanthine, are therefore excluded) if they are used as drugs if they are used as agricultural chemicals or if they have been given a generally accepted special name. Although a few pyrimidines are used as industrial chemicals for other purposes, e.g. in photography, these have assumed no great importance. 

Fusion of a barbituric acid motif and a pyrone ring afforded compounds containing a novel pyranopyrimidine core (L) that were discovered as GPR109A agonists [92,93]. This core appears to be distinct from other fused bicyclic cores such as xanthine and anthranilide based on their poor overlap. Furthermore, several compounds, exemplified by 39 and 40, provided remarkable potency in the cAMP assay. The critical acidic functional group is present as the N-PI of barbituric acid motif which has a calculated pKa of 8 [82]. 

Treatment of 2-(chloromethyl)benzimidazole with primary aliphatic amines RNH2 (R = Me, Et) in dichloro-methane under mild conditions provided benzimidazole-fused triazepanes 190 in moderate yields <1990AGE933>. The similar transformation was observed for 8-(chloromethyl)xanthine. The cyclocondensation... 

The 1,3-dipolar cycloaddition of azidoalkylphosphonates to enamines afforded A2-1,2,3-triazoles which are further converted to the 1,2,3-triazoles [95H(40)543] fused triazoles are similarly obtained when a cyclic enamine was employed. Fused 1,2,3-triazole (88), a xanthine oxidase inhibitor, was prepared by the reaction of an alkyl azide with cyanoacetamide with further elaboration of intermediate (87) by treatment with HMDS in xylene [95FES257]. The fused 4H-l,2,3-triazolo[l,5- ][l,4]benzodiazepin-6(5H)-one (90) was obtained from propargylamide (89) via an intermediate azide [95S647]. 

N ], The monohydrate separates in a microcrystalline form on slow acidification with acetic acid of a solution of xanthine in dilute NaOH. It is also precipitated by addition of cone NH3 to its solution in hot 2N HCl (charcoal). After washing with H2O and EtOH, it is dehydrated by heating above 125°. Its solubility in H2O is 1 in 14,000parts at 16° and 1 in l,500parts of boiling H2O, and separates as plates. It has no m, but the perchlorate has m 262-264° [Lister Purines Part II, Fused Pyrimidines Brown Ed, Wiley-Interscience pp252-253 1971, ISBN 0-471-38205-1]. [Beilstein 26 H 447, 26 I 131,26 II 260,26 III/IV 2327.]... 

Two groups of compounds appear to show the most promise as selective xanthine oxidase inhibitors those based on a pyrazolo[l,5-a]pyrimidine nucleus, which show mixed or non-competitive inhibition and substituted triazoles, which are competitive inhibitors [192, 193]. The 3-position of the pyrazolo[l,5-a]pyrimidines (48) is spatially equivalent to the 9-position of purine, and 3-aryl-substituted compounds were found to be 30-160-times better inhibitors than allopurinol (Table 3.8) [ 194]. In contrast, the hetero-rings in the potent substituted triazole inhibitors (49) are no longer fused, but those compounds with substituted aryl groups in the 3-position have the highest levels of intrinsic activity (Table 3.8) [195]. 

Heavily substituted fused-ring derivatives of 1,3-diazocine (37 R = Pr, Bu, -pentyl, allyl) are reportedly formed in low (10-19%) yield, together with several other products, upon the multi-component condensation of xanthines with dimethyl acetylenedicarboxylate in DMF the same reactions in methanol do not afford (37) (Equation (14)) <91CPB270>. 

Methods for the synthesis of xanthine-derived polycyclic fused systems 13HC297. 

Purine bases are a group of compounds found in plants and animals —they include nucleic acids. Their biosynthesis is complex with numerous non-amino-acid precursors (Samuelsson 1992). Xanthine, an oxidised purine that occurs as a breakdown product of nucleic acid metabolism, is itself oxidised in the body to uric acid. Xanthine consists of two fused ring systems each containing two nitrogen atoms. 

A pyranopterin cofactor, consisting of a bicyclic pterin fused to a monocyclic pyran ring, is known to directly coordinate the molybdenum of xanthine oxidase through a dithiolene side chain. The pyranopterin cofactor probably does not directly participate in the catalytic sequence of molybdenum hydroxylases but has been implicated in mediating electron transfer to other redox-active cofactors and/or modulating the reduction potential of the molybdenum. 

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