Theophylline, 7- -, acetylation with

The course of acid-catalyzed acetylations with acetic anhydride may depend markedly on the concentration of the acid and the type of acid. Reaction of 7-(3-deoxy-3-nitro-/3-D-galactopyrano-syl)theophylline with acetic anhydride in the presence of one molar equivalent of perchloric acid gave the 2, 4, 6 -triacetate in 89% yield, but, in the presence of only a trace of the acid, 82% of the 4, 6 -diacetate was obtained.93 Treatment of the manno isomer of the nucleoside with acetic anhydride-boron trifluoride gave the 4, 6 -diacetate as a crystalline product (24%), whereas phosphoric acid as the catalyst yielded the 2, 4, 6 -triester (45%). 

Caffeine pharmacokinetics are nonlinear. For example, when comparing a 500 mg dose to a 250 mg dose, the clearance is reduced and elimination half-life is prolonged with the higher dose (Kaplan et al. 1997). Thus, larger doses prolong the action of the drug. Active metabolites of caffeine are paraxanthine, and to a lesser degree, theobromine, and theophylline. Urinary metabolites are I-methylxanthine, l-methyluric acid, and an acetylated uracil derivative. 

Unsaturated ketonucleosides have been shown to be remarkably stable under acidic conditions. 7-(3-0-Acetyl-4,6-dideoxy-/ -L-g/t/cm>-hex-3-enopyranosyl-2-ulose)theophylline (61a) proved to be stable in 0.1 M hydrochloric acid, as no glycosylic cleavage had occurred51 after 20 h. Similarly, no decomposition was observed when 7-(3,6-di-0-ace-tyl-2-deoxy-/ -D-gh/cero-hex-2-enopyranosyl-4-ulose)theophylline (66) was treated with 0.1 M sulfuric acid during 48 h at room temperature, and attempted, ionic hydrogenation with triethylsilane - trifluoroacetic acid failed.31... 

Some examples of the behavior of unsaturated ketonucleosides under alkaline conditions have also been reported. The enol acetate 61a is more stable than the parent ketonucleoside 36a. In 0.1 M methanolic sodium hydroxide, free theophylline was detected only after 4 h, by which time, loss of the acetyl group was complete a reaction time of more than 18 h was needed for complete cleavage of the glycosylic bond.51 In alcoholic solution, the unsaturated 4 -ketonucleoside 66 was very sensitive to nucleophilic attack, and decomposed rapidly, with elimination of the nitrogenous base.31 Thus, treatment with sodium borohydride at — 70° led to complete decomposition within 10 min but, when sodium borohydride was added to a solution of 66 in 1,2-dichloroethane containing acetic acid, fast reduction occurred, and no degradation was observed.31... 

Fast reduction was observed when the unsaturated 4 -ketonucleoside 66 was treated with sodium borohydride in solution in 1,2-dichloroeth-ane containing acetic acid.31 An unexpected attack from the most-hindered side gave 7-(4,6-di-0-acetyl-2-deoxy-/ -D-arahino-hexopyrano-syl)theophylline (92) almost exclusively. The mechanism proposed... 

Hydroxylamine reacted with 71 to give the oxime of 7-(2,3,4,6-tetra-deoxy-/ -L-gh/cero-hex-2-enopyranosyl-4-ulose)theophylline (102), a new type of unsaturated nucleoside. Treatment of 71 with sodium boro-hydride reduced the carbonyl group, and afforded 7-(2,3,6-trideoxy-/ -L-en/thro-hex-2-enopyranosyl)theophylline (103). The n.m.r. spectrum of acetylated 103 showed H-4, 5 to be trans-diaxial and that axial addition of hydride to the carbonyl group of 71 had occurred.42... 

Addition of ammonia to 71 was less stereospecific than the addition50 of amine to bromoketonucleoside 72b. Thus, treatment of 71 with ammonia in acetonitrile, and acetylation of the product, gave a mixture of erythro and threo acetamido-nucleosides from which only the 7-(2-acet-amido - 2,3,6 - trideoxy -/ - l - threo - hexopyranosyl - 4 - ulose)theophylline (104) could be isolated.42... 

Because of the great interest in the naturally occurring nucleosides, studies of the synthesis of D-ribosides of purines and pyrimidines have been numerous. The first attempt in this direction was made by Levene and Sobotka146 who condensed the silver salt of theophylline with tri-acetyl- 8-D-ribopyranosyl bromide to obtain what was probably triacetyl-7- 8-D-ribopyranosyl theophylline (LXXVI). Subsequently Hilbert and Rist94 condensed 2,4-diethoxypyrimidine (LXXVII) with triacetyl-0-D-ribopyranosyl bromide (LXXVIII) to form ethyl bromide and 1-triacetyl-D-ribopyranosyl-4-ethoxyuracil (LXXX), which, on deacetylation with hydrogen chloride, gave 1-D-ribopyranosyluracil (LXXIX), an isomer of... 

Disposition in the Body. Rapidly absorbed after oral administration bioavailability almost 100%. Metabolic reactions include V-demethylation and oxidation to uric acid derivatives. About 85% of a dose is excreted in the urine in 48 hours with up to 40% of the dose as 1-methyluric acid, 10 to 15% as 1-methylxanthine and up to 35% as 5-acetylamino-6-formylamino-3-methyluracil and 5-acetylamino-6-amino-3-methyluracil other metabolites excreted in the urine include theophylline, 1,7-dimethylxanthine (paraxanthine), 7-methylxanthine, and 1,3-dimethyluric acid. Less than 10% is excreted in the urine as unchanged drug. The extent of V-acetylation is genetically determined. Caffeine, theophylline, theobromine, and paraxanthine are found in plasma from dietary sources especially coffee, tea and cocoa. An average cup of coffee or tea contains approximately 100 mg of caffeine. 

S3mthesis of Xanthine.— The synthesis of xanthine which is the immediate mother substance of theobromine, theophylline and caffeine has been accomplished as follows Starting with urea or carbamide, this is treated with cyano acetic acid in the presence of phosphorus oxychloride whereby the cyan acetyl radical is introduced into urea. The cyan acetyl urea by treatment with sodium hydroxide yields an isomeric imino compound. 

Lactosides of several alkaloids, including theophylline, theobromine, and morphine, were prepared for the same purpose by their interaction with hepta-0-acetyl- -lactosyl bromide. 

In a study by Bodmeier et al., it was demonstrated that plasticizer selection strongly influenced the rate of theophylline release in 0.1N HCl from beads coated with Aquacoai ECD (68). The results of this. study are shown in Figure 11. From this figure it can be seen that incomplete film formation resulted from plasticization with triacetin as a result of incompatibility between the hydrophilic plasticizer and the hydrophobic ethylcellulose latex particles. Complete film formation was achieved with all other investigated plasticizers TEC, Myvacet, tributyl citrate, DBS, and acetyl tributyl citrate however, faster drug release was seen with TEC due to the water solubility of TEC versus the water-insolubility of the other investigated plasticizers. 

Treatment of 1,2,3,4-tetra-O-acetyl-L-rhamnose with theophylline in the presence of an acid catalyst gave the first known nucleoside of this class, namely 7-(2,4-di-0-acetyl-3,6-dideoxy-L-erythro-hex-2-enopyranosyl)theophylline (53a), which was assigned the a-L configuration on account of its negative optical rotation.1053... 

A mixture of 4.80 mmol theophylline and 1.4 mL iV,0-bis(trimethylsilyl)acetamide (BSTMA, 5.80 mmol) in 15 mL dry CHCI3 was stirred under nitrogen for 40 min at 20°C. A solution of 4.0 mmol tetraacetyl ribose and 0.1 mL trimethylsilyl trifluoromethanesulfonate (5.80 mmol) in 5 mL CHCI3 was then added, and the reaction mixture was heated at reflux under nitrogen for 4 h. Saturated aqueous NaHC03 (120 mL) and dichloromethane were then added. After the system had been stirred for 15 min, the two layers were separated, and the aqueous one was extracted with dichloromethane (3 x 120 mL). The combined organic layers and extracts were combined and washed with brine, dried over anhydrous MgS04, and filtered. The solvents were evaporated to dryness. The residue was crystallized from MeOH to provide 43% 7-(2, 3, 4 -tri-0-acetyl-jS-D-ribofuranosyl)theophylline as a white solid, m.p. 106°C. 

Purified acetyl-CoA carboxylase (ACC) which had been dialyzed in Trie buffer without citrate was incubated with 0.24 fj.M palmityl-CoA in buffer containing 50 laM Tris-HCl, pH 7.5,1 mAf DTT, 1 mM theophylline for 15 minutes at 37°C. Following this incubation, additional ligands were added as indicated, and the reaction mixtures were further incubated for 30 minutes at 37°C. The carboxylase was assayed for 3 minutes in the absence of citrate and BSA. 

A comparison between three standard methods of synthesis of purine nucleosides, namely fusion, condensation of acetylated glycosyl chlorides, and from 1-acetates in the presence of titanium(iv) chloride has been made. Thus when the glucosaminyl acetate (1) was fused with theophylline in the presence of p-toluenesulphonic acid and p-nitrophenol, a 45 % yield of the nucleoside (2) was obtained. In contrast to the findings of Ishido et al. Carbohydrate Res., 1975, 44, 215), lower yields were obtained when the activating agents were omitted. The nucleoside (3) synthesized in 32 % yield from the glucosyl acetate... 

Silver fluoride in pyridine is frequently used in the dehydrohalogenation of 5 -deoxy-5 -iodo-nucleosides for example, the theophylline and uracil nucleosides (383) and (384) respectively, were prepared in this way (see Scheme 89), whereas 3, 5 -dideoxy-3, 5 -di-iodothymidine gave the diene (236) when treated with silver fluoride in pyridine. However, 9-(2,5-dideoxy-j8-D- /ycero-pent-4-enofuranosyl)adenine (385) was best prepared by the action of DBU on 3 -0-acetyl-5 -bromo-2, 5 -dideoxyadenosine. In a synthesis of the 2, 3 -unsaturated... 

Cytidine has been converted into l-(5-amino-5-deoxy-j8-D-arabinofuranosyl) cytosine by a sequence of reactions involving A-benzoylation, sulphonation, acetylation, displacement with azide ion, e/c., and l-(3-amino-3-deoxy-jS-D-arabinofuranosyl)-6-azauracil was derived from 2, 3 -di-0-methanesulphonyl-5 -O-trityl-6-azauridine via 2,2 - and 2, 3 -anhydro-nucleosides. Other syntheses have been accomplished by the condensation of an appropriately derivatized amino-sugar with either a pyrimidine or purine derivative for example, the Hilbert route was used to prepare l-(2-amino-2-deoxy-a-D-arabino- and -jS-o-xylo-furanosyl)cytosine. > The reactivity of l,3,4,6-tetra-0-acetyl-2-acyl-amido-2-deoxy-j3-D-glucopyranoses in condensation reactions with 2,6-dichloro-purine, theophylline, and 6-benzylaminopurine was shown to be in the order benzamido > acetamido > phthalimido. 9-(3-Acetamido-2,5-di-0-acetyl-3-deoxy-j8-D-ribofuranosyl)-2,6-dichloropurine has been synthesized and converted into the corresponding 2,6-diamino- and 6-amino-2-chloro(fluoro)-nucleosides. ... 

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