Xanthines, 8-aryl

Chemiluminescence and bioluminescence are also used in immunoassays to detect conventional enzyme labels (eg, alkaline phosphatase, P-galactosidase, glucose oxidase, glucose 6-phosphate dehydrogenase, horseradish peroxidase, microperoxidase, xanthine oxidase). The enhanced chemiluminescence assay for horseradish peroxidase (luminol-peroxide-4-iodophenol detection reagent) and various chemiluminescence adamantyl 1,2-dioxetane aryl phosphate substrates, eg, (11) and (15) for alkaline phosphatase labels are in routine use in immunoassay analyzers and in Western blotting kits (261—266). 

For a wide variety of 6-aryl-3(2//)-pyridazinones (including those discussed in the chapter on cardiotonic agents and antithrombotics [1]), bronchodila-tor activity has been claimed in patents [104,114-116,129,423,424]. Thus, for instance, the bronchospasmolytic effects (guinea-pig tracheal-chain preparations) of compounds of type (99) have been found to exceed those of xanthines [425]. The therapeutic index of these compounds (which inhibit phosphodiesterase at lower concentrations than xanthines and do not interact with adenosine receptors) is larger than that of xanthines. 

Aryl-8-azaadenines 300, 8-azahypoxanthine 301, and 6-thiolo-8-azapurines 302 were tested for their inhibitory effect on adenosine deaminase, guanine deaminase, and xanthine oxidase from mammalian sources. Compounds 300 were the most efficient inhibitors of adenosine deaminase and... 

A number of 8-aryl substituted pyrido[3,4-t/]-l,2,3-triazin-4(3//)-ones have been found to be most efficacious as inhibitors of xanthine oxidase, potential compounds for the treatment of ischemia and gout <88EUP274654>. A number of 3//,4//-pyrido[3,2-e]-l,2,4-triazine and 3/f,4//-pyrido[3,4-e]-1,2,4-triazine 3-acetamides have shown antiinflammatory, diuretic, antihypertensive, and psychotropic effects <89FES279>. During a search for potential antidepressant compounds, the pyrido-1,2,3-triazinone (399) was found to be more active than its isomer (400) <87EJM337>. 

Sulphophenvl)-theophylline] (aryl xanthine) Synthetic - cf. Theophylline A AD-R selective antagonist (polar excluded from brain by blood brain barrier (BBB))... 

Selective C-arylation of free (AW)-purines via catalytic C-H bond functionalization has been developed <03JA5274>. Substitution at the 2 or 8 positions of 9-ethyladenine with a variety of side-chains was accomplished in order to obtain non-xanthine adenosine receptor antagonists... 

The more reactive alkyl or aryl chloroformates can be used to produce 2-oxopurines under milder conditions than those obtained in urea fusions. Xanthine for example resulted from the aminoimidazolecarboxamide and ethyl chloroformate at 0 °C followed by cycliza-tion of the intermediate urethane (343), either by fusion or by heating with aqueous ammonia (Scheme 137) (sojbQ 185)439). 

Methoxy-, 6-ethoxy-, and 6-methylthio-9-ribofuranosyl-8-azapurines turned out to be substrates for adenosine kinase, and the first two examples were bound by adenosine deaminase. Their cytotoxic action was attributed to affinity for the kinase. 6-Imino-9-phenyl-l,6-dihydro-8-azapurine was found to be an efficient inhibitor of adenosine deaminase and guanine deaminase. Xanthine oxidase was inhibited by both this compound and 9-aryl-8-azapurin-6-ones. ° ... 

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]. 

A number of isocytosines are of pharmacological interest. Some 5-alkyl-6-aryl derivatives, such as (LXV), were found to be potent diuretics in rats [387,388]. Compound (LXV) is orally active at 5 mg/kg. The sodium clearance increased even while the urine volume decreased. In the dog, however, the activity was low or inconsistent by the oral route, probably due to variable absorption. The mode of action seems to be like that of the xanthines. The... 

Febuxostat 88 is an inhibitor of xanthine oxidase that has been developed by Teijin Pharma as a new drug for the treatment of gout and hyperuricemia [62]. The 2-aryl-thiazole structure is prepared by Teijin via a condensation between 2-chloroacetate 83 and arylthioamide 82 (Scheme 20a) [63]. However, Cipla, a... 

Miura and Hirano reported a copper-mediated cross-couphng reaction between 2-arylazines 102 and 1,3-azoles 100 including (benz)oxazoles and xanthines giving the products 103 (Scheme 45) (2011JA2160). The corresponding arylated heteroarenes were obtained in moderate yields under rather harsh conditions (high temperature in the presence of superstoichiometric... 

Lam, Richardson and co-workers had also N-arylated various nucleoside bases such as purine, inosine, hypoxanthine and xanthine [39]. The results are listed in the Appendix. 

Keywords 5,6-Diamino-l,3-dimethyluracils, aryl/cycloaryl/heteroaryl aldehydes, N-bromosuccinimide (NBS), 2,2 -azoisobutyronitrile (AIBN), aqueous acetonitrile, room temperature, condensation, ring closure, 8-substituted xanthines... 

Malakar CC, Schmidt D, Conrad J, Beifuss U (2011) Double C-H activation the palladium-catalyzed direct C-arylation of xanthines with arenes. Org Lett 13 1378-1381... 

In addition, other electrophiles, such as arylsulfonyl hydrazides, aryl sulfamates, aryl sulfinates, or alkenyl phosphates, have been reported to arylate heterocycles, such as benzoxazoles or xanthines. 

C8-arylated xanthines could be prepared via a ligand-free Pd-catalyzed methodology (eq 12). ... 

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