Xanthines are a widely known group of alkaloids, commonly used as bronchodilators and psycho and cardiac stimulants. Most of their actions are principally connected with either antagonism of adenosine receptors or phosphodiesterase inhibition; nevertheless, other profiles of their biological activity – antiviral, antitumor or anticancer – are also known. Here, we present a review of the main synthetic methods to obtain xanthine-derived heterocyclic fused systems. The five-, six- or seven-membered heterocyclic ring is attached to the purine-2,6-dione core with one or two bridgehead (ring junction) nitrogen atoms. The biological activity profile of the individual heterocyclic systems is mentioned.
The pyrimidine and purine ring systems undoubtedly belong to the most ubiquitous heterocycles in nature, as they represent the main structure of many biologically significant compounds, including nucleosides and nucleotides. Among numerous important compounds based on the structure of the purine, there is a group of natural xanthines, including caffeine, theobromine and theophylline. Xanthine derivatives exhibit a variety of physiological effects, such as positive inotropic and chronotropic effects on the heart, decreased airway resistance in the lung and respiratory stimulation, as well as significant behavioral effects on measures of locomotor activity, schedule-controlled behavior, drug self-administration, and learning and memory [1–4]. The respiratory-stimulant effects of xanthines seem to be mainly linked to the inhibition of phosphodiesterases, enzymes responsible for the hydrolytic inactivation of cyclic AMP and cyclic GMP [1, 5]. By contrast, it is suggested that the psychostimulant and cardiac effects of xanthines are principally connected with the antagonism of adenosine receptors, located both in the heart and brain [1, 4].
In recent years, many studies have been conducted in the direction of the potential use of synthetic xanthine derivatives, including polycyclic fused ring systems, as potent antagonists at various adenosine receptor subtypes [1–3, 6–9]. Compounds with this profile have been suggested to be useful as neuroprotective agents in diseases such as stroke, traumatic brain injury, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and multiple sclerosis [8–11], cardioprotective agents in myocardial ischemia , as well as potential treatment of schizophrenia, epilepsy  or asthma . Xanthines have also been suggested to be useful in diseases with etiology independent of adenosine receptors and phosphodiesterases, showing confirmed antiviral , antitumor and antimicrobial activity [7, 14]. Some of pyrimido[2,1-f]theophylline derivatives show potent affinity towards the 5-HT1A receptor .
Here, we review the main methods of the synthesis of xanthine-derived heterocyclic fused systems. The five-, six- or seven-membered heterocyclic unit is attached to the xanthine core with one or two bridgehead (ring junction) nitrogen atoms (with retention of the three-coordinate neutral character of N). For the purpose of this article, all described compounds were divided into six groups depending on the peripheral side of the parent xanthine component, identified by a letter locant according to IUPAC rules  (Figure 1).
Group A includes tricyclic structures with a five- or six-membered heterocyclic ring fused to the a-bond of the 6-purinone system (Figure 1). Compounds of this series are classified to one of the following subgroups according to the structure and depending on the number and type of heteroatoms in the third ring:
imidazo[1,2-a]purinones and pyrimido[1,2-a]purinones,
triazolo[1,5-a]purinones and triazolo[4,3-a]purinones,
Imidazo[1,2-a]purinones and pyrimido[1,2-a]purinones
One of the synthetic pathways leading to pyrimido or imidazo fused purinones is presented in Scheme 1. The starting material, 2-(methylthio)-1H-purin-6(7H)-one (1) is treated with aminoalcohol, (un)substituted 2-aminoethanol or 3-amino-1-propanol, affording the corresponding intermediates 2a or 2b. Cyclization of 2-aminoethanol derivatives 2a is achieved by treatment with polyphosphoric acid (PPA) or phosphoryl chloride followed by oxidation of the resultant product 3 by manganese dioxide in the next step to give the desired 2-, 4-, 6- or 7-substituted 1H-imidazo[1,2-a]purin-9(4H)-ones 4 . In the alternative method, thionyl chloride is used for cyclization of 2, forming the final 6,7-dihydro-1H-imidazo[1,2-a]purin-9(4H)-ones 5 and 4,6,7,8-tetrahydro-pyrimido[1,2-a]purin-10(1H)-ones 6 .
Xanthine derivatives with a structure based on the imidazo[1,2-a]purinone scaffold have been tested as inhibitors of phosphodiesterases, showing selective but moderate affinity towards phosphodiesterase 4 (PDE4) in the micromolar range .
Triazolo[1,5-a]purinones and triazolo[4,3-a]purinones
The first group of synthetic methods leading to triazolo[1,5-a]purin-9-ones 9 is based on the addition of the third heterocyclic ring to the existing purinone structure (Scheme 2). The nucleophilic substitution of 2-methylthio fragment of the starting purinone 1 with an amine group results in the guanine derivative 7, which is then allowed to react with hydroxylamine-O-sulfonic acid (HAOS) in sodium hydroxide. Cyclization of the obtained compound 8 is achieved by treatment with either ortho ester or with aldehyde and diethyl azodicarboxylate (DEAD) in DMF to yield the corresponding 1H-[1,2,4]triazolo[1,5-a]purin-9(4H)-ones 9 .
Another method of synthesis of 9 is based on the cyclocondensation of the obtained triazolo[1,5-a]pyrimidin-7-one system (Scheme 3) . The reaction between aminoguanidine 10 and carboxylic acid gives 5-amino-1,2,4-triazole 11, which is then treated with alkyl cyanoacetate to afford a bicyclic structure of 5-amino-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one 12. Electrophilic substitution of 12 with sodium nitrite, followed by reduction of the 6-nitroso group using Na2S2O4 (or a similar reducing agent) and then acylation with appropriate carboxylic acid results in the formation of the key 5-amino bicyclic intermediate 13. Cyclization of this compound with sodium hydroxide gives the target triazolopurinone 9.
Screening tests in the group of triazolopurinone derivatives 9, conducted to find selectivity for adenosine receptors, have pointed to a few strong antagonists with nanomolar affinity to human A1 receptors with over 300-fold greater selectivity for A1 than A2A receptors .
The synthesis of another series of triazolo fused derivatives, triazolo[4,3-a]purin-5-ones 16, starts from 2-thioxanthines (Scheme 4) [20, 21]. Treatment of 14 with 50% aqueous hydrazine affords the 2-hydrazinylpurine-6-ones 15, which are then allowed to react with appropriate ortho esters giving the substituted 6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-ones 16.
The convenient starting material for the synthesis of tetrazolo[1,5-a]purinones is hydrazino-substituted derivative 15 (Scheme 5). Treatment of 2-hydrazinopurin-6-ones with nitrous acid affords 4,7-dihydro-1H-tetrazolo[1,5-a]purin-8(2H)-ones 17 [20, 21].
In the first step of synthesis of oxazolo[3,2-a]purin-9-one derivatives, 6-aminouracil (18) is silylated with hexamethyldisilazane (HMDS) (Scheme 6). Subsequent reaction with propargyl bromide, catalyzed by iodine, yields 3-propargyl-6-aminouracil (20), which is nitrosated at the 5-position by treatment with nitrous acid followed by reduction of the intermediate nitroso compound to the 5,6-diaminouracil derivative 21 . The reaction with carboxylic acid in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) gives compound 22, which in the next step is treated with polyphosphoric acid trimethylsilyl ester (PPSE) to obtain the final oxazolo[3,2-a]purin-9(1H)-ones 23 .
In the A1 and A2A adenosine receptor binding studies at rat brain membranes, oxazolo[3,2-a]purinones showed antagonism against adenosine receptors with selectivity over 26-fold greater for A1 than A2A; however, their affinity was demonstrated only in the micromolar range .
This group contains tricyclic and tetracyclic fused systems created by the attachment of an additional ring(s) to the 6-purinone core, using carbon C2 and nitrogen N3 atoms as ring junctions (group B, Figure 1). Compounds in this group belong to one of the following three classes according to their structure:
imidazo[2,1-b]purinones and pyrimido[2,1-b]purinones,
Imidazo[2,1-b]purinones and pyrimido[2,1-b]purinones
A general approach to the synthesis of the imidazo and pyrimido[2,1-b]purinones is presented in Scheme 7. The starting material, 1-substituted xanthine 24, is treated with phosphoryl chloride to form the chloropurinone 25, which is then allowed to react with an appropriate (un)substituted aminoalcohol to give the corresponding intermediates 2-(hydroxyalkylamino)purinones 26a, 26b. The final 7,8-dihydro-3H-imidazo[2,1-b]purin-4(5H)-one 27a and 5,7,8,9-tetrahydropyrimido[2,1-b]purin-4(3H)-one 27b are obtained by cyclocondensation of 26a and 26b by means of thionyl chloride [18, 24].
An interesting example of application of the method discussed above is the preparation of tetracyclic purinone derivatives including spiro compounds (Scheme 8) [25–27]. To add the third and the fourth ring, 2-chloropurinone 25 is treated with 2-aminocyclopentanol or 1-amino-1-cyclopentanemethanol in N,N-diisopropylethylamine (DIPEA) and N-methyl-2-pyrrolidinone (NMP) to yield structures 28 and 30. Cyclization in both pathways is conducted by the use of thionyl chloride leading to final hexahydrocyclopenta[d]imidazo[2,1-b]- and 5′,8′-dihydrospirocyclopentane-1,7′-imidazo[2,1-b]purinones 29 and 31, respectively.
Xanthine derivatives with a structure based on the imidazo[2,1-b]- or pyrimido[2,1-b]purinone scaffold have been tested as inhibitors of phosphodiesterases  and showed selective micromolar affinity towards PDE4. Some of them exhibit single digit nanomolar potency and isozyme selectivity to PDE5, which is greater than those for the approved drugs sildenafil, vardenafil and tadalafil . Tetracyclic purinones show selective, high-binding affinity towards PDE1 in the nanomolar range .
To obtain triazolo[5,1-b]purinone derivatives, 3-amino-1,2,4-triazole (32) is first reacted with ethyl cyanoacetate (Scheme 9). The resultant 7-amino[1,2,4]triazolo[1,5-a]pyrimidinone (33) is in the next step nitrosated by treatment with isoamyl nitrite and the intermediate nitroso compound is then reduced to the diamino pyrimidinone intermediate 34. Acylation of 34 with carboxylic acid chloride followed by cyclization of the resultant compound 35 with sodium and calcium hydroxide gives target 3a,4-dihydro-1H-[1,2,4]triazolo[5,1-b]purin-5(6H)-ones 36 .
Purinone derivatives with a structure of 36 have been tested as antagonists of adenosine receptors, showing selective high affinity towards human A1 receptors and A3 receptors in the nanomolar range .
Pyrimido[1,2,3-cd]purinediones and diazepino[1,2,3-cd]purinediones
This group collects together compounds with an additional six- or seven-membered heterocyclic ring created partially by bonds c and d of the 2,6-purinedione core, with N3 and N9 atoms at ring junctions (Figure 1). One of the synthetic methods leading to this type of structures is presented in Scheme 10. The starting material, 5,6-diamino-3-substituted uracil 37, is treated with an appropriate aldehyde, and the resultant intermediate 38 is then converted to the pyrimido[1,6-a]pyrimidine-6,8-dione derivative 39 by reaction with 1,3-dibromopropane. The final ring closure is achieved oxidatively with thionyl chloride as reagent and solvent, to give 5,6-dihydropyrimido[1,2,3-cd]purine-8,10(4H,9H)-dione 40a .
An alternative procedure for preparation of tricyclic compounds 40a has been explored (Scheme 11). The 5,6-diaminouracil derivative 37 is reacted with carboxylic acid and the product 41 is then converted to the bicyclic compound 42a by reaction with 1,3-dibromopropane, in analogy to the preparation of the amide derivatives 39. The final ring formation is achieved by the reaction with hexamethyldisilazane to form the target 5,6-dihydropyrimido[1,2,3-cd]purine-8,10(4H,9H)-dione 40a .
For formation of the final ring a microwave oven can be used as well (Scheme 12); this modification has been described for preparation of both pyrimido[1,2,3-cd]- and diazepino[1,2,3-cd]purinediones . 6-Aminouracil derivative 41 is treated with α,ω-dibromoalkane (1,3-dibromopropane or 1,4-dibromobutane) affording intermediates 42a or 42b, respectively. Compounds 42a and 42b are cyclized by treatment with HMDS in the microwave oven, which yields the respective 5,6-dihydropyrimido[1,2,3-cd]purine-8,10(4H,9H)-dione 40a and 6,7-dihydro-4H-[1,3]diazepino[1,2,3-cd]purine-9,11(5H,10H)-dione 40b.
Another short, two-step method leading to pyrimido or diazepino fused purinediones is presented in Scheme 13. The starting nitropyrimidines 43a or 43b are hydrogenated over palladium on carbon and the obtained diamines 44a, 44b are then treated with ethyl orthoformate to form the corresponding condensed compounds 40a or 40b, respectively .
Preliminary radioligand binding studies have indicated that the substituted pyrimido[1,2,3-cd]purine-8,10(9H)-diones exhibit high, nanomolar concentration affinity and selectivity for the A1 adenosine receptor . These compounds have also been tested as inhibitors of phosphodiesterases, but showed no activity against PDE1, PDE3 and PDE4 .
Group D contains tricyclic structures with a five- or six-membered heterocyclic ring fused through the adjacent C8 and N9 atoms of the 2,6-purinedione core (Figure 1). Depending on the attached ring, such compounds are divided into two groups:
The general methods of the synthesis of triazolo[3,4-e]purinediones are presented in Scheme 14. A convenient starting material in both pathways is substituted 8-hydrazinoxanthine 45. Condensation of 45 with appropriate aldehydes in boiling ethanol yields the 8-(arylidenehydrazino)purinediones 46, that are cyclized using bromine in the presence of anhydrous sodium carbonate, giving the final 5H-[1,2,4]triazolo[3,4-e]purine-6,8(7H,9H)-diones 47. By contrast, refluxing 45 with carbon disulfide in the presence of sodium hydroxide leads to a tricyclic xanthine derivative with a thioxo substituent at the third ring. Alkylation of 48 with different alkyl halides gives the corresponding 3-alkylthio- or 3-arylthio-5H-[1,2,4]triazolo[3,4-e]purine-6,8(7H,9H)-diones 49 .
The target tricyclic triazino[3,4-e]purine-4,7,9-triones are prepared following the synthetic pathways depicted in Scheme 15. In first step, the 8-aminoxanthine derivative 50 is converted into diazonium salt, which is then treated with an alkyl cyanide in dry pyridine to give 8-substituted 2,6-purinediones 52. Heating 52 in ethanol under reflux results in intramolecular cyclocondensation and leads to 4-imino-6,8-dihydro-[1,2,4]triazino[3,4-e]purine-7,9(1H,4H)-dione (53), which is subsequently hydrolyzed by treatment with hydrochloric acid to afford [1,2,4]triazino[3,4-e]purine-4,7,9(1H,6H,8H)-triones 54 .
Compounds fused with a triazine or triazole ring to the e-bond of the 2,6-purinedione system (47–49, 53, 54) have been tested to determine their potential antitumor activity. Among this series, only 4-imino-6,8-dihydro-[1,2,4]triazino[3,4-e]purine-7,9(1H,4H)-diones 53 show promising activity against the breast MCF-7 cell line, reducing the growth of breast cell line to <32% .
This group comprises tricyclic compounds with an additional five-, six- or seven- membered ring fused to the f-bond of the 2,6-purinedione system (Figure 1). Compounds of this series are classified to one of the following subgroups according to the number and type of heteroatoms in the third ring:
oxazolo[3,2-f]purinediones, oxazino[4,3-f]purinediones and oxazepino[4,3-f]purinediones,
pyrrolo[1,2-f]purinediones and pyrido[1,2-f]purinediones,
imidazo[1,2-f]purinediones, pyrimido[1,2-f]purinediones and diazepino[1,2-f]purinediones,
imidazo[1,2-f]purinetriones and pyrimido[1,2-f]purinetriones,
The general synthetic pathway leading to thiazolo[3,2-f]purinedione derivatives is presented in Scheme 16. In this short, one-step method the starting material, the 1,3-substituted 8-bromoxanthine 55, is treated with 2-(un)substituted thiirane under basic conditions, giving the final 6,7-dihydrothiazolo[3,2-f]purine-2,4(1H,3H)-dione 56 .
Oxazolo[3,2-f]purinediones, oxazino[4,3-f]purinediones and oxazepino[4,3-f]purinediones
Convenient methods for synthesis of 1,3-dialkylxanthine derivatives with fused oxazole, oxazine and oxazepine rings are presented in Scheme 17. Target 6,7-dihydrooxazolo[3,2-f]purine-2,4(1H,3H)-diones 57 are prepared by the reaction of 8-bromopurinedione 55 with oxiranes in pyridine (Scheme 17A) [34, 35]. The starting material for the syntheses of oxazino[4,3-f]purinediones 60 and oxazepino[4,3-f]purinediones 62 is 8-hydroxyalkyl-substituted xanthine 59, obtained by melting of 5,6-diaminouracil 37 with a hydroxy acid followed by dehydration of the resulting 6-amino-5-(hydroxyacetamido)uracil (58) in an alkaline medium (Scheme 17B) . The intermediate product 59 is cyclized in a catalytic two-phase reaction with 1,2-dibromoethane in the presence of K2CO3 and benzyltriethylammonium chloride (TEBA) as a phase-transfer catalyst to form the final 6,7-dihydro-1H-[1,4]oxazino[4,3-f]purine-2,4(3H,9H)-dione 60. By contrast, cyclization of 59 to the final, oxazepine ring-containing derivative 62 requires a two-step reaction. First, 7-(3-chloropropyl)-8-hydroxyalkyl-substituted purinedione 61 is obtained by reaction of 59 with 1-bromo-3-chloropropane under the catalytic two-phase conditions mentioned above. The ring closure condensation is then carried out in an alcoholic solution of KOH, yielding 6,7,8,10-tetrahydro-[1,4]oxazepino[4,3-f]purine-2,4(1H,3H)-dione 62.
Tricyclic oxazolo[2,3-f]purinediones with a structure of 57 are adenosine receptor ligands with moderate affinity mostly exhibiting selectivity for A2A versus A1 receptors. The most potent A2A ligands demonstrate a Ki value of 0.998 μm towards rat A2A receptors .
Pyrrolo[1,2-f]- and pyrido[1,2-f]purinediones
The synthesis of 1H-pyrrolo[1,2-f]purine-2,4(3H,6H)-diones 65 requires the conversion of compounds 59 (Scheme 18) into 8-bromomethyl-7-oxoalkylxanthines 64 through intermediary of 63. To obtain the pyrrole fused xanthines 65, the reaction of 64 with triphenylphosphine and subsequent intramolecular Wittig cyclization of the obtained phosphonium salt in the presence of sodium methoxide are used .
The pyrido[1,2-f]purine-2,4(1H,3H)-dione derivatives 66 are synthesized in a short, two-step one-pot reaction, presented in Scheme 19 . The synthetic procedure includes the treatment of the 6-aminouracil derivative 18 with N-bromosuccinimide (NBS) in acetonitrile to generate the intermediate 5,5-dibromo-6-imino derivative, not isolated but treated in situ with various 4-substituted pyridines to afford the target compounds 66.
Compounds including the pyrrole or pyridine ring fused to the f-bond of the 2,6-purinedione system have been evaluated in radioligand binding assays to determine their affinities for human A1, A2A and A3 adenosine receptors. Both types of xanthine derivatives are active towards the adenosine A3 receptor subtype with Ki values in the low nanomolar concentration range of 3.5–200 nm [36, 37].
Imidazo[1,2-f]purinediones, pyrimido[1,2-f]purinediones and diazepino[1,2-f]purinediones
The synthesis of tricyclic systems containing perhydroimidazole, pyrimidine or diazepine ring fused to 2,6-purinedione core with C8 and N7 atoms as ring junctions can be accomplished as shown in Scheme 20. The starting 1,3-substituted-8-bromoxanthine 55 is treated with α,ω-dibromoalkane giving intermediate 7-(ω-bromoalkyl)purinediones 67a–c. The final cyclization is achieved by refluxing 67a–c with appropriate amines, which leads to 7,8-dihydro-1H-imidazo[1,2-f]purine-2,4(3H,6H)-diones 68a, 6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4 (1H,3H)-diones 68b and 7,8,9,10-tetrahydro-1H-[1,3]diazepino[1,2-f]purine-2,4(3H,6H)-diones 68c [38–41].
The obtained compounds have been evaluated for their affinity to rat adenosine A1 and A2A receptors. Selected compounds were additionally investigated for affinity to the human A1, A2A, A2B and A3 receptor subtypes. The results of the radioligand binding assays at adenosine A1 and A2A receptors show that the compounds bind to the adenosine A2A receptor at micromolar or submicromolar concentrations; a fused pyrimidine ring was beneficial for A2A affinity. The most potent A2A ligands demonstrated Ki values of 0.31 mm towards human A2A and 0.33 mm towards rat A2A receptors [38–41].
Another group of synthetic methods leading to tricyclic imidazo fused xanthines is presented in Scheme 21. The first step of synthesis leading to 1H-imidazo[1,2-f]purine-2,4(3H,8H)-dione derivatives 72 starts from 1,3-dialkyl-8-nitroxanthine 69, which is reduced by treatment with hydrazine and 10% Pd/C in methanol to furnish intermediates 70. Compounds 70 are then alkylated at N7-position by treatment with α-bromoketone to obtain 8-amino-7-oxoalkylxanthines 71. The imidazole ring closure is performed by refluxing 71 in acetic acid to yield the final tricycles 72 . An alternative group of methods begins with alkylation of 1,3-dialkyl-8-bromoxanthine 55 at N7-position in a manner indicated above, followed by cyclization into 1H-imidazo[1,2-f]purine-2,4(3H,8H)-diones 72 by reaction with liquid ammonia .
1H-Imidazo[1,2-f]purine-2,4(3H,8H)-dione derivatives have been examined as antagonists of adenosine receptors and showed selective high nanomolar affinity towards human A3 receptors . Compounds with this structure have also been tested as ligands of 5-HT1A, 5-HT2A and D2 receptors showing selective, potent affinity to 5-HT1A receptor with a Ki value of the nanomolar range .
Imidazo[1,2-f]purinetriones and pyrimido[1,2-f]purinetriones
The first step in the synthesis of 1H-imidazo[1,2-f]purine-2,4,7(3H,6H,8H)-triones 76 is N7-alkylation of 8-(un)substituted amino xanthine 74 with 2-bromoacetic acid in anhydrous DMF (Scheme 22). Intramolecular condensation of 2-(8-amino-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetic acid 75 is carried out by refluxing in acetic anhydride . The second series, pyrimido[1,2-f]purine-2,4,8(1H,3H,9H)-triones 77, can be obtained directly in the reaction of 74 with ethyl 2,3-dibromopropanoate, as a result of one-step substitution and cyclocondensation .
In the synthesis of target pyrazino[1,2-f]purinedione derivatives, 1,3-dialkyl-8-hydroxymethylxanthine 59 is first N-alkylated by 2-chloroethanol (Scheme 23). The product, dihydroxy compound 78, is subsequently chlorinated by treatment with thionyl chloride, which leads to 7-(2-chloroethyl)-8-(chloromethyl)purinedione 79. The final cyclocondensation of 79 is achieved by refluxing with an appropriate amine, resulting in final 6,7,8,9-tetrahydropyrazino[1,2-f]purine-2,4(1H,3H)-dione 80 .
Xanthine derivatives with a structure based on the tetrahydropyrazino[1,2-f]purinedione core have been tested as antagonists of adenosine receptors, showing micromolar affinity and selectivity for the A1 adenosine receptor .
3-Methyl-1H-[1,2,4]triazolo[4,3-f]purine-5,7(6H,8H)-dione derivatives 81 can be prepared by a cycloaddition reaction between a 1,3-dialkyl-8-nitroxanthine derivative and the N-(2-bromo-4-substituted)acetohydrazonoyl bromide (Scheme 24) .
All compounds 81 are completely inactive at all four adenosine receptor subtypes independently of their substitution pattern .
The last group contains compounds with an additional five-, six-, seven- or eight-membered heterocyclic unit fused to the i-bond of the 2-purinone system (Figure 1). Compounds of this series are collected into one of the following subgroups:
imidazo[1,2-i]purinones, pyrimido[1,2-i]purinones, diazepino[1,2-i]purinones and diazocino[1,2-i]purinones,
Imidazo[1,2-i]purinones, pyrimido[1,2-i]purinones, diazepino[1,2-i]purinones and diazocino[1,2i]purinones
The first group of synthetic methods leading to purinone derivatives with an additional five-, six-, seven-, or eight-membered ring containing two atoms of nitrogen is presented in Scheme 25. In the first step, 3,7-substituted purinones 82 are treated with phosphorus pentasulfide to give the required 6-thioxanthine 83. The subsequent reaction with methyl iodide in the presence of sodium hydroxide gives S-methyl derivatives, which are allowed to react with an appropriate aminoalcohol leading to intermediate products 85a–d. Final cyclization is performed by treatment with thionyl chloride, which gives the final 7,8-dihydro-1H-imidazo[1,2-i]purin-5(4H)-ones 86a, 4,7,8,9-tetrahydropyrimido[1,2-i]purin-5(1H)-ones 86b, 7,8,9,10-tetrahydro-1H-[1,3]diazepino[1,2-i]purin-5(4H)-ones 86c or 4,7,8,9,10,11-hexahydro-[1,3]diazocino[1,2-i]purin-5(1H)-ones 86d .
An alternative method of synthesis of imidazo[1,2-i]- and pyrimido[1,2-i]purin-5-ones 86a,b is based on the reaction between either 6-chloro-3,7-disubstituted purinone 87 or 6-triazolo-3,7-disubstituted purinone 88 and an appropriate aminoalcohol (Scheme 26). The products 85 are then treated with methanesulfonyl chloride (MSCl), which results in intramolecular cyclocondensation and gives final compounds 86a or 86b, differing in the size of the fused ring .
Screening tests of diazolo[1,2-i]purinone derivatives have been conducted to find selective agents for phosphodiesterases and adenosine receptors. Imidazo[1,2-i]purinones show antagonism against A1 adenosine receptors (Ki= 7.4 nm) with selectivity >100-fold for A1 than that for A2A and 100-fold greater than that for A3 adenosine receptors [47–49]. Some of these antagonists exhibit a Ki value of 2.3 nm at human A3 adenosine receptors and are several hundred-fold selective versus A1, A2A and A2B adenosine receptors [6, 49, 50]. Compounds from this group have also demonstrated inhibition towards PDE4 enzymes in the nanomolar concentration range and lacked certain adverse reactions of xanthine derivatives and known PDE4 inhibitors [51, 52]. Pyrimido[1,2-i]purinones exhibit micromolar affinity towards A1 and A2A adenosine receptors  and to PDE4 enzyme in the micromolar concentration range . Diazepino[1,2-i]- and diazocino[1,2-i]purinones have demonstrated similar, micromolar affinity and selectivity towards A1 and A2A adenosine receptors .
Another short, one-step method leading to condensed imidazo[1,2-i]purinones is based on the methylation of 86a. Taking into account the tautomeric balance and possible structures of 86a, substitution with an alkyl group (CH3-) can occur at the N1, N3 and N9 positions, depending on the reaction conditions and the presence of other groups in the structure. Methylation of 2-unsubstituted imidazo[1,2-i]purinones has been reported to yield N1-methylated products , whereas a phenyl group present at position 2 affects the N1/N9 substitution ratio . After reaction optimization, the substitution exclusively at N9-position has been achieved, using methyl iodide and sodium hydride in dry dimethylformamide to yield the final 9-methyl-8,9-dihydro-4H-imidazo[1,2-i]purin-5(7H)-ones 89 (Scheme 27) .
Compounds from this group have been tested as ligands of adenosine receptors and demonstrated selectivity and moderate affinity for the A1 adenosine receptor. Several compounds show antagonism towards the A1 adenosine receptor with a Ki value of approximately 395 nm .
The synthesis of the other series of imidazo[1,2-i]purinones derivatives starts from 6-chloroxanthine 87 (Scheme 28). Treatment of 87 with aqueous ammonia affords the 6-aminoxanthine 90, which is then reacted with 2-chloroacetaldehyde giving the substituted 1H-imidazo[1,2-i]purin-5(4H)-one 91 .
Imidazopurin-2-ones with the structure 91 were tested as inhibitors of phosphodiesterases and demonstrated selective inhibitory activity for the PDE4 in the micromolar concentration range .
The synthesis of tetrazolpurinones 92 can start from either 6-chloro- or 6-triazolo-3,7-disubstituted purinones (Scheme 29), the convenient starting compounds also used in the synthesis of diazolo[1,2-i]purinones described above (Scheme 28). Treatment of 87 or 88 with sodium azide leads to the closure to the tetrazole ring, yielding the target 6,9-dihydro-5H-tetrazolo[1,5-i]purin-5-one (92) .
Xanthine derivatives with a structure based on the tetrazolo[1,5-i]purin-5-one scaffold that have been tested as inhibitors of phosphodiesterases exhibit selectivity and micromolar affinity towards PDE4 .
By synthetic modification of the 2,6-purinedione core various tri- or tetracyclic fused systems can be obtained. An additional ring, usually a nitrogen-based heterocycle such as five-membered (imidazole, triazole, tetrazole) or six-membered moiety (pyrimidine, pyrazine, triazine) is built into the structure, using nitrogen atoms as ring junctions. Derivatives of oxygen- and sulfur-based heterocycles as well as seven-membered rings can also be obtained. Compounds with such structures often show activity either as adenosine receptor antagonists or phosphodiesterase inhibitors.
The support of the Polish National Science Centre is kindly acknowledged – grant DEC-2012/04/M/N24/00219.
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