Dimethylxanthines

For many years oral xanthines, shown in Table 2, were the preferred first-line treatment for asthma in the United States, and if the aerosol and oral formulations of P2" go sts are considered separately, as they are in Table 1, this was still the case in 1989. Within this class of compounds theophylline (8), or one of its various salt forms, such as aminophylline [317-34-0] (theophylline ethylenediamine 2 l), have been the predominant agents. Theophylline, 1,3-dimethylxanthine [58-55-9], is but one member of a class of naturally occurring alkaloids. Two more common alkaloids are theobromine (9), isomeric with theophylline and the principal alkaloid in cacao beans, and caffeine, (10), 1,3,7-Trimethylxanthine [58-08-2], found in coffee and tea. 

Pentoxifylline is stmcturaHy related to other methylxanthine derivatives such as caffeine [58-02-2] (1,3,7-trimethylxanthine), theobromine [83-67-0] (3,7-dimethylxanthine), and theophylline [58-55-9] (3,7-dihydro-1,3-dimethyl-1 H-piirine-2,6-dione or 1,3-dimethylxanthine), which also show radioprotective activity in some instances, suggesting that methylxanthines as a dmg class may radioprotect through a common mechanism (see Alkaloids). In a retrospective analysis of cervical and endometrial cancer patients receiving primary or adjuvant XRT, no association between caffeine consumption and incidence of acute radiation effects has been found. However, there was a decreased incidence of severe late radiation injury in cervical cancer patients who consumed higher levels of caffeine at the time of thek XRT (121). The observed lack of correlation between caffeine consumption and acute radiation effects is consistent with laboratory investigations using pentoxifylline. 

Tea leaf contains 2.5-4.0% caffeine (1,3,7-trimethylxanthine) on a dry weight basis and smaller quantities of the related methylxanthines, theobromine (3,7-dimethylxanthine 0.2-0.4%) and theophylline (1,3-dimethylxanthine ca. 0.02%). Although it is said that var. sinensis is slightly lower in caffeine than var. assamica, black, green and oolong tea beverages all contain about the same levels of caffeine (Cheng and Chen, 1994). 

The methylxanthines of interest are caffeine (1,3,7-trimethylxanthine), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethylxanthine) and they occur in coffee, tea, mate, cocoa products, and cola beverages. This chapter is an introduction to their chemistry, isolation, and biosynthesis. While the class of methylxanthines is large and comprised of more members than these three, this chapter will essentially be limited to caffeine, theobromine, and theophylline. 

Midha, K.K., Sved, S., Hossie, R.D., and McGilveray, I.J., High performance liquid chromatographic and mass spectrometric identification of dimethylxanthine metabolites of caffeine in human plasma, Biomed. Mass. Spectrom., 4,172,1977. 

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. 

Theobromine and theophylline also occur in mate, although several investigators have failed to find these dimethylxanthines.8 Likely levels of these substances in the dried product are theobromine, 0.3% theophylline, 0.004%.5... 

The key metabolites of caffeine (a trimethylxanthine) found in plasma, are the dimethylxanthines paraxanthine, theophylline, and theobromine the monomethylxanthine 1-methylxanthine the C-8 oxidized monomethylxanthine 1-methyluric acid and the ring oxidized uracil 5-acetyl-amino-6-amino-3-methyluracil. 

Fig. 11. Mechanism for formation of parabanic acids from the methylated uric acid-4,5-diol derived from theobromine (3,7-dimethylxanthine) and caffeine (1,3,7-trimethylxan-thine). Molar amounts of products are those formed in 1 M HOAc...

Thermolysis of 5-amino-6-azido-1,3-dimethylxanthine 289 in chlorobenzene gave 3-aminoisofervenulin 290 possibly through a C-nitrene intermediate (92MI1). 

Thermolysis of 7-amino-6-azido-l,3-dimethylxanthine (386) in chlorobenzene gave 3-aminofervenulin (387) through a nitrene intermediate (92MI1). 7-Aminotheophylline 388 and 389 were oxidized by various oxidizing agents to give 309 and 311, respectively (89KGS95). 

Heating 7,8-diamino-1,3-dimethylxanthine 802 with hydrochloric acid gave azapteridine 803, which on treatment with alkylamines gave [1,2,4]-triazino[2,3-/]purines 804 (87CPB4031). 

Fig. 2. Caffeine and some metabolites TMX, trimethylxanthine DMX, dimethylxanthine MMX, monomethylxanthine...

A cnp of coffee can contain 50-150 mg of caffeine, and cola drinks can have 35-55 mg. Theophiline,l,3-dimethylxanthine, a principal, characteristic alkaloid of tea, and theobromine, 3,7-dimethylxanthine (23.3.19), a principal alkaloid of cocoa, are among a number of methylxanthines. In small doses, caffeine is a relatively weak psychostimulant and is used for increasing awareness as well as for relieving headaches associated with blood flow disorders of the brain. Caffeine has a stimulatory effect on the respiratory and vasomotor centers, and it stimnlates centers of the vagus nerve. It has a direct stimulatory effect on the myocardium, and in large doses can cause tachycardia and arrhythmia. 

Related xanthines - theobromine (3,7-dimethylxanthin) and theophylline (1,3-dimethylxanthine)... 

Closely related methylxanthines include theophylline (1,3-dimethylxanthine), theobromine (3,7 dimethylxanthine) and paraxanthine (1,7-dimethylxanthine). Theobromine is found primarily in chocolate. These derivatives of caffeine are important because they are pharmacologically active and also are the common metabolites of caffeine. 

Caffeine and the related dimethylxanthines have similar pharmacological or therapeutic effects and similar toxic effects. The primary actions include stimulation of the central nervous system, relaxation of bronchial muscles, mild cardiac muscle stimulation, and diuretic effects on the kidney. 

Theophylline, a dimethylxanthine, causes broncho-dilation, possibly by inhibiting the enzyme phosphodiesterase in smooth muscle of the bronchioli. An other proposed mechanism of action is that of adenosine receptor antagonism. It has positive chronotropic and inotropic, CNS stimulant and weak diuretic properties. In obstructive lung disease sustained release tablets are to be preferred. Theophy-line has a narrow therapeutic index. Therapeutic plasma concentrations are between 7-15 mg/1. Theophylline undergoes N-demethylation via CYPl A2 in the liver and is eliminated in the urine as metabolites... 

Brand Name(s) Pentopak, Pentoxil, Trental Cfiemical Class Dimethylxanthine derivative... 

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. The clinical use of theophylline is discussed below. The metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine. 

Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent. However, no evidence suggests that this therapy is superior to exercise conditioning. 

Figure 17.4—Measurement of caffeine by HPLC/MS with isotopic dilution. The stable isotope used in this determination is deuterium D. Caffeine-d3 is obtained by methylation of 1,3-dimethylxanthine.

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