Xanthine /methylxanthines

The compounds known as xanthines, methylxanthines, or xanthine derivatives constitute a particularly interesting class of drugs. Since they possess diverse phar-... 

Methylxanthine (xanthine) Methylxanthine is a bronchodilator that stimulates the central nervous system to increase respirations, dilate coronary and pulmonary vessels, and increase urination (diuresis). 

Examples of the xanthine derivatives (drag that stimulate the central nervous system [CNS] resulting in bronchodilation, also called methylxanthines) are theophylline and aminophylline. Additional information concerning the xanthine derivatives is found in the Summary Drag Table Bronchodilators. 

In the clinical area, the largest share of analytical methods development and publication has centered on the determination of theophylline in various body fluids, since theophylline is used as a bronchodilator in asthma. Monitoring serum theophylline levels is much more helpful than monitoring dosage levels.44 Interest in the assay of other methylxanthines and their metabolites has been on the increase, as evidenced by the citations in the literature with a focus on the analysis of various xanthines and methylxanthines. 

As in the case in the analysis of food samples, the introduction of relatively inexpensive MS detectors for GC has had a substantial impact on the determination of methylxanthines by GC. For example, in 1990, Benchekroun published a paper in which a GC-MS method for the quantitation of tri-, di-, and monmethylxanthines and uric acid from hepatocyte incubation media was described.55 The method described allows for the measurement of the concentration of 14 methylxanthines and methyluric acid metabolites of methylxanthines. In other studies, GC-MS has also been used. Two examples from the recent literature are studies by Simek and Lartigue-Mattei, respectively.58 57 In the first case, GC-MS using an ion trap detector was used to provide confirmatory data to support a microbore HPLC technique. TMS derivatives of the compounds of interest were formed and separated on a 25 m DB-% column directly coupled to the ion trap detector. In the second example, allopurinol, oxypurinol, hypoxanthine, and xanthine were assayed simultaneously using GC-MS. 

Foods derived from cocoa beans have been consumed by humans since at least 460 to 480 AD. The source of cocoa beans, the species Theobroma, contains a variety of biologically active components. These include the purine alkaloids theobromine, caffeine, and theophylline. Structurally, they are methylated xanthines and, thus, are often referred to as methylxanthines. Theobromine (3, 7-dimethylxanthine) is the predominant purine alkaloid in cocoa and chocolate. Caffeine (1, 3, 7-trimethylxanthine), the major purine alkaloid found in coffee and tea, is found in cocoa and chocolate at about one eighth the concentration of theobromine. Only trace amounts of theophylline (1, 3-dimethylxanthine) are detected in cocoa and chocolate products. 

This chapter has compiled and evaluated information on the methylxanthine composition of cocoa and various chocolate foods and beverages, as well as the consumption pattern for these commodities. Cacao is the major natural source of the xanthine base theobromine. Small amounts of caffeine are present in the bean along with trace amounts of theophylline. Numerous factors, including varietal type and fermentation process, influence the methylxanthine content of beans. 

Xanthine, caffeine 36 and other N-methylxanthines are selectively reduced in 75% sulphuric acid at a lead cathode to the 4-desoxy compounds in good yields [153,167,168],... 

MefaboZ/sm/Excref/on-Xanthines are biotransformed in the liver (85% to 90%) to 1, 3-dimethyluric acid, 3-methylxanthine and 1-methyluric acid 3-methylxanthine accumulates in concentrations approximately 25% of those of theophylline. 

The principal xanthines of medical interest include caffeine, theophylline and aminophylline. Caffeine is synthesized by several plants and was originally isolated from tea in 1838. It is a methylxanthine (Figure 1.12) which stimulates the central nervous system, increasing mental alertness. It also acts as a diuretic and stimulates gastric acid secretion. It is absorbed upon oral administration and is frequently included in drugs containing an analgesic, such as aspirin or paracetamol. 

All the xanthines, but especially theophylline, are capable of producing some degree of diuresis in humans. This specific action of the methylxanthines is discussed in greater detail in Chapter 21. 

Xanthines (usually caffeine) are frequently combined with aspirin in the treatment of headaches. In combination with an ergot derivative, methylxanthines have been used to treat migraine. These effects are likely due to their ability to produce vasoconstriction of cerebral blood vessels. Aminophylline is useful in the rehef of pain due to acute biliary colic. 

The methylxanthine molecule is built on a foundation common to many biologic compounds, the xanthine double ring of carbons. The three methylxanthines, caffeine, theophylline, and theobromine, all block the action of the body s adenosine molecule, sending a signal that helps slow the chemical buildup inside cells. Because the methylxanthines closely resemble adenosine at the molecular level, they can occupy the molecular sites on cells that normally recognize, and react to, adenosine. Caffeine prevents the normal slowing action of adenosine at the cellular level, in both nerves and muscle. 

As shown below, theophylline is 1,3-dimethylxanthine theobromine is 3,7-dimethylxanthine and caffeine is 1,3,7-trimethylxanthine. A theophylline preparation commonly used for therapeutic purposes is aminophylline, a theophylline-ethylenediamine complex. A synthetic analog of theophylline (dyphylline) is both less potent and shorter-acting than theophylline. The pharmacokinetics of theophylline are discussed below (see Clinical Use of Methylxanthines). The metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine. 

Heteroxanthine, 7-Methylxanthine, yields desoxyhetero-xanthine, or 7-methyl-2-oxy-1.6-dihydropurin ... 

Methyl derivatives of xanthine (2,3-dioxypurine) namely caffeine (1,3,7-trimethyl-xanthine), theobromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine) (Section 1, Appendix) are variously found in plants used for stimulatory drinks such as Ilex paraguayensis (mate) (Aquifoliaceae), Coffea species (coffee) (Rubiaceae), Paullinia cupana (guarana) (Sapindaceae), Cola acuminata (cola) and Theabroma cacao (cocoa) (Sterculiaceae) and Camellia sinensis (tea) (Theaceae). These methylxanthines are variously active as inhibitors of... 

The prototypical structural class of nonselective PDE inhibitors is represented by the methylxanthines (Figure 9.4), a family of plant-derived alkaloids that includes theophylline (1), caffeine (2), and theobromine (3) [9], Although limited in potency, these simple naturally occurring xanthines were the parents in the later discoveries of more potent synthetic derivatives such as pentoxyfylline (4) and isobutylmethyl-xanthine (IBMX, 5). In particular, the latter compound has been widely used and has been regarded for decades as the gold standard nonselective inhibitor of all PDEs. Only recently has it become clear that some of the newer PDEs (8 and 9) are not inhibited by IBMX. Derivatives of IBMX carrying substituents at the 8 position confer increased potency [10], An example is compound 6, which retains most of... 

Almost identical bell-shaped rate-pH curves are produced by [8- H]theophylline (1,3-dimethylxanthine 8), xanthine (77T803) and 1-methylxanthine (79T663) whereas the characteristic curve shown by 9-isopropylpurine is also reproduced by [8- H]caffeine (1,3,7-trimethylxanthine) (77T803), [8- H]-theobromine (3,7-dimethylxanthine), 7-methylxanthine and xanthosine (79T663) in which substituents also occur in the imidazole ring. 3-Methylxanthine (71) on the other hand shows a rate-pH profile which is exceptional. 

In alkaline solutions, xanthine alkylates on nitrogen in the order N-3, N-7, N-1, i.e. in decreasing order of acidity, and substitution is easier when the first position has been alkylated so to this extent dialkyl derivatives tend to be most easily produced. Thus 3,7-dimethylxanthine (theobromine) is produced by methylation of xanthine or 3-methylxanthine with methyl iodide and barium carbonate (33JCS662) or dimethyl sulfate in potassium hydroxide at 60 °C (50CB201). However when the oxygen functions are blocked by trimethylsilylation, alkylation occurs at N-7 (64CB934). 

Further methylation of theobromine readily produces caffeine (31MI40900). Similarly, 1-methylxanthine is methylated by dimethyl sulfate in alkaline solution to furnish 1,3-dimethylxanthine (theophylline) which is further converted into caffeine (31MI40900). Scheme 18 outlines the major stages of xanthine alkylation. 

Under acidic or neutral conditions methylation of xanthine proceeds at N-7 or N-9. Thus with methyl iodide the 7,9-dimethylxanthine betaine (107) results after heating in a sealed tube at 150 °C for 5 h. In solvents such ag DMSO or dimethylacetamide using dimethyl sulfate or methyl p-toluenesulfonate, better yields may be obtained (62CB1812). The same betaine is also produced by similar methylation of 9-methylxanthine (62JA1914,61LA(647)l6l). 

Electron-releasing groups are required in the purine ring system before nitration can occur. In this way 8-nitro-caffeine (149), -theophylline (150), and -theobromine (151) have been prepared by nitration of the appropriate purine with nitric acid, neat or in acetic acid (71HC(24-2)i, p. 402). Similarly, 9-methylxanthine, but not xanthine, undergoes nitration to 9-methyl-8-nitroxanthine (60JA3773). 

Aminoimidazole esters have also been used as a source of 2-oxopurines, the additional nitrogen being derived from urea, cyanates and similar compounds. In this manner the amino ester (340) and potassium cyanate furnished a ureidoimidazole which smoothly cyclized to xanthine with dilute alkali (Scheme 142) (42JCS232). Methyl isocyanate similarly gave 1-methylxanthine and related derivatives have also been prepared (49JCS1071,50JCS1884). 

Methylxanthine is the major purine constituent of human urine (3.1 g in 10001) (1898ZPC(24)364). 3- and 7-Methylpurines are also minor constituents of urine, especially following large doses of caffeine or other methylated xanthines. 1,3-Dimethylxanthine (theophylline) occurs with caffeine in tea leaves and is a powerful diuretic and has been used clinically for this purpose (generally as an adduct with salts of organic acids) and also in the treatment of asthma. 1,7-Dimethylxanthine (paraxanthine) is also an efficient diuretic and, in addition, possesses antithyroid properties (45JCS751). The main purine constituent... 

In order to achieve nitration of the more sensitive jV-substituted xanthine derivatives, nitronium tetrafluoroborate is applied in various solvents at elevated temperatures e.g. nitration of 3-benzyl-7-methylxanthine to give the 8-nitro product 3 (R = H R = Bn R = Me). ... 

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