8-Substituted xanthines

The Schiff base derivative 65, prepared from the respective 5,6-diaminouracil 63 and aldehydes 64, can be converted into the C-8 substituted xanthines 66 through an oxidative cyclization with m-chloroperbenzoic acid <99H29>. 

Since the Suzuki coupling of purine derivatives was covered by recent reviews,1 we only present a selection lfom these reactions. Xanthine (3,6-dihydropurine-2,6-dione) derivatives were coupled with different boronic acids, including styrylboronic acid, in the presence of the conventional tetrakis(triphenylphosphino)palladium catalyst and tripotassium phosphate as a mild base (8.1.), to obtain the appropriate 8-substituted xanthines in acceptable yield.4 The advantage of the use of anhydrous tripotassium phosphate as base over the classical aqueous carbonate or hydroxide reagents might be attributed to the sensitivity of the 8-halopurine core towards nucleophilic attack. 

Sebastiao AM, Stone TW, Ribeiro JA (1990) The inhibitory adenosine receptor at the neuromuscular junction and hippocampus of the rat antagonism by 1,3,8-substituted xanthines. Br J Pharmacol 101 453-9... 

Condensation of 6-amino-5-nitrosouracils with ethanethiol and phenyl-methanethiol leads to formation of 8-substituted xanthines and 1,2,5-thiadiazolo[3,4-t/]pyrimidines [75JCS(P1) 1857]. Oxidation with lead tetraacetate forms furazano[3,4-with sodium nitrite or potassium nitrate and subsequent heating in DMF [73JHC415, 73JHC993 76JCS(P 1) 1327] (Scheme 65). 

Xanthine 3-oxide on the other hand is readily converted into 3-acetoxyxanthine (190) which reacts under very mild conditions with a wide variety of Inorganic or organic nucleophiles to produce 8-substituted xanthines (Scheme 39) in high yields (B-72MI40901, p. 550). The mechanism has been extensively investigated by the same workers and it is proposed that intermediate nitrenium (191) and carbo cations (192) are involved (Scheme 40). 

As adenosine antagonists, a great number of 8-substituted xanthines with varying substitution patterns in the 1- and 3-position have been prepared. As starting materials, l,3-dialkyl-5,6-di-aminouracils are used, which are transformed to the 1,3,8-trisubstituted xanthines by one of three methods. The first consists of condensing diaminouracil with an aldehyde to form the imine which is oxidatively cyclized by treatment with diethyl azodicarboxylate (DEAD) in a modification of a reported general procedureto give the appropriate xanthine derivative, e.g. formation of 10. 

Doichinova, I.A., Natcheva, R.N. and Mihailova, D.N. (1994). OSAR Studies of 8-Substituted Xanthines as Adenosine Receptor Antagonists. Eur.J.Med.Chem., 29,133-138. 

Carrupt PA, Testa B, Bechalany A, El Tayar N, Descas P and Perrissoud D, Morphine-6-glucuronide and morphine-3-glucuronide as molecular chameleons with unexpected lipophilicity, /. Med. Chem., 34, 1272-1275 (1991). NB See Walther B, Carrupt PA, El Tayar N and Testa B, 8-Substituted xanthines as phosphodiesterase inhibitors Conformation-dependent lipophilicity and structure-activity relationships, Helv. Chim. Acta, 72,507-517 (1989). 

Walther B, Carrupt P-A, El Tayar N and Testa B, 8-Substituted xanthines as phosphodiesterase inhibitors Conformation-dependent lipophilicity and structure-activity relationships, Helv. Chim. Acta, 72, 507-517 (1989). 

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... 

Bandyopadhyay, P., Agrawal, S. K., Sathe, M., Sharma, P., and Kaushik, M. P. (2012). A facile and rapid one-step synthesis of 8-substituted xanthine derivatives via tandem ling closure at room temperature. 

Thus, a comparison between HPLC-derived lipophilicity indices and calculated log P values for a series of 8-substituted xanthines showed a clear influence of conformational effects. 8 In this case, Rekker s method was unable to take 3D effects into account, but the difference between experimental and predicted values was structure dependent rather than constant. Conformational analyses confirmed that a smaller than predicted lipophilicity was associated with folded conformers stabilized by hydrophobic and van der Waals forces and having part of their nonpolar surface masked from the aqueous phase. A 4D theoretical approach (log P calculations by MLP for conformers generated by high temperature molecular dynamics) suggests that these effects should be lower in an w-octanol/water system than in RP-HPLC. Indeed, the n-octanol/water system is not the most suitable model to study intramolecular interactions in nonpolar media because a surprisingly high proportion of water is dissolved in the w-octanol. Recall, however, that w-octanol, despite some limitations, was selected by many workers in the field as a model for biological membranes. 

B. Walther, P.-A. Carrupt, N. El Tayar, and B. Testa, Hebr. Chim. Acta, 72, 507 (1989). 8-Substituted Xanthines as Phosphodiesterase Inhibitors Conformation-Dependent Lipophilicity and Structure-Activity Relationships. 

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