Synthesis, chemical reactivity and fungicidal activity of pyrido[1,2-b][1,2,4]triazine derivatives

Abstracts

The synthesis of some new pyrido[1,2-b][1,2,4]triazines (2-12) was achieved by cyclocondensation of 4-aryl-1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles (1a, b) with α,β-bifunctional compounds. Pyrido[1,2:2´,3´]triazino[5´,6´-f]triazines (13-14) were also prepared. The behavior of 1a, b toward interactions with indole-2,3-dione and its N-acetyl analogue have been studied under different reaction conditions. The structures of the new products have been deduced from elemental analysis and spectral data (UV, IR, ¹H NMR, 13C NMR and mass spectra). The new synthesized compounds were screened for their antifungal activities.

synthesis; o-diamines; pyridotriazines; fungicidal activity

A síntese de alguns novos derivados de pirido[1,2-b][1,2,4]triazinas (2-12) foi obtida através da ciclocondensação de 4-aril-1,6-diamino-2-oxo-1,2-diidropiridina-3,5-dicarbonitrilas (1a, b) com compostos α,β-bifuncionais. Foram também preparadas pirido[1,2:2´,3´]triazino[5´,6´-f]triazinas (13-14). O comportamento de 1a, b frente às interações com indol-2,3-diona e seu análogo N-acetil foi estudado em diferentes condições de reação. As estruturas dos novos produtos foram deduzidas a partir de análise elementar e de dados espectroscópicos (UV, IR, ¹H RMN, 13C RMN e espectrometria de massas). Os novos compostos sintetizados foram testados quanto à atividade antifungos.

ARTICLE

Synthesis, chemical reactivity and fungicidal activity of pyrido[1,2-b][1,2,4]triazine derivatives

Magdy A. Ibrahim^*; Reda M. Abdel-Rahman; Ali M. Abdel-Halim; Salah S. Ibrahim; Hassan A. Allimony

Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, 11711, Cairo-Egypt

ABSTRACT

The synthesis of some new pyrido[1,2-b][1,2,4]triazines (2-12) was achieved by cyclocondensation of 4-aryl-1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles (1a, b) with α,β-bifunctional compounds. Pyrido[1,2:2´,3´]triazino[5´,6´-f]triazines (13-14) were also prepared. The behavior of 1a, b toward interactions with indole-2,3-dione and its N-acetyl analogue have been studied under different reaction conditions. The structures of the new products have been deduced from elemental analysis and spectral data (UV, IR, ¹H NMR, ¹³C NMR and mass spectra). The new synthesized compounds were screened for their antifungal activities.

Keywords: synthesis, o-diamines, pyridotriazines, fungicidal activity

RESUMO

A síntese de alguns novos derivados de pirido[1,2-b][1,2,4]triazinas (2-12) foi obtida através da ciclocondensação de 4-aril-1,6-diamino-2-oxo-1,2-diidropiridina-3,5-dicarbonitrilas (1a, b) com compostos α,β-bifuncionais. Foram também preparadas pirido[1,2:2´,3´]triazino[5´,6´-f]triazinas (13-14). O comportamento de 1a, b frente às interações com indol-2,3-diona e seu análogo N-acetil foi estudado em diferentes condições de reação. As estruturas dos novos produtos foram deduzidas a partir de análise elementar e de dados espectroscópicos (UV, IR, ¹H RMN, ¹³C RMN e espectrometria de massas). Os novos compostos sintetizados foram testados quanto à atividade antifungos.

Introduction

Polyfunctional pyridines are highly reactive intermediates that have been extensively used in heterocyclic synthesis.¹ o-Diamines are very active substrates for building of various heterocyclic systems² and are largely used in formation of complexes.³ In symmetrical diamines, the product will be the same irrespective of which amine participates first in the reaction. In the case of unsymmetrical diamines, the substituents influence the initial participation of a particular amino group in the reaction, resulting in chemoselective products. The electron withdrawing/donating nature of substituents in diamine influences the nucleophilicity of the amino group. On the other hand, 1,2,4-triazine derivatives exhibit marked biological and pharmacological effects and are use for the building fused, condensed and isolated heterobicyclic systems.⁴ On the basis of these observations, the objective of this work is the study of the chemical reactivity of 4-aryl-1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles (1a, b) and their use for preparation of nitrogen bridgehead pyrido[1,2-b] [1,2,4]triazines in view of their antifungal activity.

Results and Discussion

1,6-Diamino-4-(4-chlorophenyl or 3,4,5-trimethoxyphenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles (1a, b) have been obtained from refluxing alcoholic solution of 2-cyanoacetohydrazide and arylmethylidinemalononitriles in the presence of few drops of piperidine as a catalyst.⁵¹H NMR spectra for compounds 1a, b showed two signals for each compound at 5.6 and 8.4 ppm characteristic for the (N-NH₂) and (C-NH₂) protons, respectively. These results indicate the difference in nucleophilicity between the two amino groups. Thus, It is expected the hydrazide β-nitrogen (N-NH₂) more nucleophilic and would react more rapidly with the electron deficient carbon than the amino group at carbon atom (C-NH₂). Mass spectra for compounds 1a and 1b showed the molecular ion peaks at m/z 341 and 285, respectively (the base peaks), indicating the high stability the pyridine moiety. Heterocyclic systems containing 1,2-diamine centers⁶ are used for building fused heterocyclic systems via a nitrogen bridge. Thus, the regio-isomeric 8-aryl-2,6-dioxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (2) and 3,6-dioxo-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (3) have been obtained from alkylation and acylation of compound 1b with monochloroacetic acid and chloroacetyl chloride, respectively (Scheme 1). ¹H NMR spectra of compounds 2 and 3 showed signals for each CH₂ protons at 2.91 and 3.23 ppm, respectively, while their ¹³C NMR spectra exhibited signals for each CH₂ carbons at 36.66 and 40.05 ppm, respectively.

Heterocyclization of diaminopyridones 1a, b with phenacyl bromide⁷ in refluxing aqueous NaOH yielded 8-aryl-1,2,5,6-tetrahydro-6-oxo-3-phenyl-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (4a, b), while the perhydropyridotriazine 5 was obtained from treatment of compound 1b with 1,2-dibromoethane in alcoholic KOH (Scheme 1). The IR spectra of 4a and 4b showed absorption bands at 3445 and 3320 cm^-1 assigned to NH groups, respectively, while the IR spectrum of 5 showed two absorption bands at 3327 and 3243 cm^-1 for two NH groups.

Some new 8-aryl-2,6-dioxo-1,2-dihydropyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (6a-g) have been synthesized by cyclocondensation of compounds 1a, b with α–oxocarboxylic acids, namely pyruvic, α-oxobutyric, 4-chlorostyrylglyoxalic and phenoxypyruvic acids in refluxing glacial acetic acid (Scheme 2). It should be noted that this reaction occurred preferentially between the N¹-amino group (N-NH₂) and the α-keto function of the electrophile to form a hydrazone intermediate, which underwent a cyclodehydration reaction between the other amino group at C⁶ (C-NH₂) and the hydroxyl group of the acid function affording the target pyridotriazine derivatives 6a-g. ¹³C NMR spectra gave good evidence for the formation of compounds 6a-g. For examples, the ¹³C NMR spectrum of compound 6a showed a new signal at 18.60 ppm characteristic for a methyl group in position 3. In the case of compound 6f the vinyl carbons were observed in the spectrum in their expected positions at 122.75 and 135.70 ppm for C_α and C_β, respectively.

Cyclic 1,2-bioxygen compounds were also used for building various fused heterocyclic systems.⁸ Thus, compounds 7a, b were prepared from refluxing compound 1a, b with diethyl oxalate in dry dioxane and/or with oxalyl chloride in warm DMF (Scheme 2).

Some new pyridotriazines were obtained from cyclocondensation of 1,6-diaminopyridones 1a, b with α-dicarbonyl compounds. Thus, treatment of 1a with butane-2,3-dione in glacial acetic acid afforded 2,3-dimethylpyrido[1,2-b][1,2,4]triazine (8), while the corresponding 2,3-diphenylpyridotriazine derivatives 9a, b were obtained from refluxing 1a, b with benzil in glacial acetic acid. Dihydro analogues 10a, b were obtained by refluxing compounds 1a, b with benzoin under the same reaction conditions. Oxidation of compounds 10a, b in methanolic ferric chloride⁹ produced compounds 9a, b (the same mp and mixed mp) (Scheme 2). ¹H NMR of compound 10b showed a signal at 5.62 ppm assigned to CH proton in position 2, while its ¹³C NMR spectrum showed a signal at 77.83 ppm characteristic for the corresponding carbon atom.

Chlorination of compound 7a using phosphorus oxychloride afforded 2,3-dichloro-6-oxo-8- (3,4,5-trimethoxy)-6H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (11) (Scheme 3).

Compounds 7a, b were used as starting materials for the synthesis of fused heteropolycyclic systems. Thus, hydroxymethylation of 7a, b by refluxing with methanol-formaldehyde solution produced 8-aryl-2,3,6-trioxo-1,4-dihydroxymethyl-1,2,3,4,5,6-hexa- hydropyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (12a, b), which upon heterocyclization by refluxing with thiosemicarbazide in acetic acid led to 7-oxo-2-thioxo-2,3,5,6,7,11-hexahydropyrido[1,2:2´,3´][1,2,4]triazino[5´,6´-f]triazine-8,10-dicarbonitriles(13a, b). Hydrazinolysis of 13b in boiling ethanol furnished the hydrazinotriazine 14 (Scheme 3).

The course of the reactions of cyclic 1,2-bi-oxygen heterocyclic compounds with aromatic heterocyclic o-diamines was shown to depend on the reaction conditions, type of solvent and also the substituents in the diamino compounds.¹⁰ Thus, reaction of compounds 1a, b with indole-2,3-dione (isatine) in different media can yield different products. Treating 1a with indole-2,3-dione in absolute ethanol and few drops of piperidine produced the Schiff base condensate, 6-amino-4-(3,4,5-trimethoxyphenyl)-2-oxo-1-[2-oxo-1,2-dihydro-3-indolo-3-ylidine)amino]-1,2-dihydropyridine-3,5-dicarbonitrile (15). Alternatively, warming indole-2,3-dione with alcoholic NaOH solution yielded a 2-aminophenylglyoxalic acid that adds to 1,6-diaminopyridinone 1b to give the condensation product 16. Indolotriazinopyridines 17a, b were produced from ring closure reaction of compounds 15 and/or 16 in boiling glacial acetic acid in the presence of freshly fused sodium acetate. Acetylation of compound 17a by refluxing with acetic anhydride afforded the N-acetyl derivative 18 (Scheme 4). IR spectrum of 18 indicated that NH group disappeared and a new characteristic band at 1734 cm^-1 appeared for the C=O of the acetyl group. The mass spectrum revealed the parent peak at m/z 494 which is coincident with the formula weight in agreement with the postulated structure.

N-acetylisatine showed a different behavior.¹¹ Reaction of 1a with N-acetylisatine in absolute ethanol in the presence of few drops of piperidine led to 8-(3,4,5-trimethoxyphenyl)-2-(2-acetanilido)-3,6-dioxo-3,6-dihydro-4H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (20) and not to the isomeric product 21 (Scheme 4). This reaction can be explained by an increase in the positive charge on the α-carbon atom in comparison to isatine itself due to the electron withdrawing acetyl group which facilitates the nucleophilic attack of more nucleophilic amino group (N-NH₂) at this position with concomitant opening of five membered ring. Apparently, the reaction can be claimed to proceed via intermediate 19, as also observed by previous workers in reaction with other diamines.¹² However, this type of intermediate was reported to be unstable and not isolated.

Fungicidal activity

Several new synthesized compounds were screened for their antifungal activities against two species of fungi, namely Alternaria alternata and Aspergillus niger using the disc diffusion method.¹³ The tested compounds were dissolved in DMF (which has no inhibitory activity) to get concentrations of 1 mg mL^-1 solution. The antibiotic fluconazole was used as standard antifungal reference. The inhibition zones of microbial growth surrounding the filter paper disc (2.5 mm) were measured in millimeters at the end of an incubation period at 30 C for 3 days. Inhibition of the organisms was evidenced by a clear zone surrounding each disk (Table 1).

All the tested compounds showed variable activities toward the two species of fungi, some of them comparable to standard fluconazole. The most active triazines were 2d, 3, 9b and 10.

From the results obtained, it is clear that increasing the percentage of nitrogen in the tested compounds led to higher effects toward the tested fungi. The antifungal effects decrease in the order of: 10 > 9b > 3 > 2d for higher activity and 14 > 6b > 4 > 8b > 5b >1a for moderate activity. The lower activity was observed by compound 17a (Table 1).

Conclusion

Cyclocondensation of 4-aryl-1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles with α,β-bifunctional compounds takes place regioselectively through condensation of (N-NH₂) group with the more electrophilic carbon center followed by cyclization to produce several new pyrido[1,2-b][1,2,4]triazine derivatives.

Experimental

Melting points are uncorrected and were recorded in open capillary tubes on a Stuart SMP3 melting point apparatus. Infrared spectra were recorded on FT-IR Bruker Vector 22 spectrophotometer using KBr wafer technique. UV absorption spectra (DMF) were recorded on a Jasco model (V-550) UV spectrophotometer. ¹H NMR and ¹³C NMR spectra were measured on Gemini (200 MHz) spectrometer and Bruker (250 MHz) AC spectrometer using DMSO-d₆ as solvent and TMS (chemical shift in ppm) as an internal standard. Mass spectra were obtained using a Shimadzu GCMS qp 1000 ex instrument mass spectrometer (70 eV).

4-Aryl-1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles (1a,b)

Compounds 1a and 1b have been prepared according to the reported method.⁵

Compound 1a

Crystallized from DMF as white crystals, yield 80%, mp 255-256 ºC. UV λ_max/nm (log ε): 344 (3.39), 276 (3.58). IR (KBr) ν_max/cm^-1: 3334, 3194 (2 NH₂), 2998, 2941, 2839 (CH₃ groups), 2215 (2 C≡N), 1669 (C=O), 1633 (def. NH₂), 1591 (C=N), 1513 (C=C), 1466, 1416 (def. CH₃). ¹H NMR (δ, DMSO): 3.78 (s, 3H, CH₃O), 3.81 (s, 6H, 2CH₃O), 5.60 (s, 2H, N-NH₂), 6.82 (s, 2H, Ar-H), 8.40 ppm (s, 2H, C-NH₂). ¹³C NMR (δ, DMSO): 56.47 (2 CH₃O), 60.47 (CH₃O), 74.63 (C₅-CN), 86.67 (C₃-CN), 116.01 (C≡N), 116.88 (C≡N), 106.32 (C2' and C6'), 129.94 (C1'), 139.03 (C4'), 153.00 (C3' and C5'), 156.98 (C₄), 159.62 (C₆), 162.65 ppm (C₂ as C=O). M/z (Int.%) 342 (20.1), 341 (100), 326 (49.18), 298 (20.77), 283 (8.89), 268 (10.06), 236 (2.82), 168 (2.88). Anal. Calc. for C₁₆H₁₅N₅O₄ (341.3): C, 59.96; H, 2.39; N, 15.21. Found: C, 59.34; H, 2.62; N, 15.34.

Compound 1b

Crystallized from dioxane as white crystals, yield 90%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3455, 3400, 3350, 3310 (2 NH₂), 2222 (2 C≡N), 1665 (C=O), 1624 (def. NH₂), 1590 (C=N), 1562 (C=C). ¹H NMR (δ, DMSO): 5.60 (s, 2H, N-NH₂), 7.63 (d, 2H, Ar-H), 7.84 (d, 2H, Ar-H), 8.40 ppm (s, 2H, C-NH₂). Anal. Calc. for C₁₃H₈ClN₅O (285.69): C, 54.60; H, 2.80; N, 24.51. Found: C, 54.59; H, 2.86; N, 24.53.

8-(4-Chlorophenyl)-2,6-dioxo-1,3,4,6-tetraahydro-2H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (2)

A mixture of 1b (10 mmol) and monochloroacetic acid (10 mmol) in DMF (50 mL) was refluxed for 4 h, after cooling the reaction mixture was poured onto ice. The solid obtained was filtered and crystallized from methanol to give 2 as yellow crystals, yield 66%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3397 (OH), 3265 (NH), 2218 (2 C≡N), 1640 (C=O), 1522 (C=C), 1491, 1465 (def. CH₂). ¹H NMR (δ, DMSO): 2.91 (s, 2H, CH₂), 5.75 (s, 1H, NH), 7.52 (d, 2H, Ar-H), 7.73 (d, 2H, Ar-H), 8.51 ppm (s, 1H, OH of 1,2,4-triazin-5-ol).¹³C NMR (δ, DMSO): 36.66 (CH₂), 75.19 (C₉-CN), 87.29 (C₇-CN), 116.22 (C≡N), 117.09 (C≡N), 129.65, 130.89, 134.31 and 135.95 (6C of aryl carbons), 157.48 (C₈), 159.27 (C_9a), 159.99 (C₂ as C=O), 161 ppm (C₆ as C=O). Anal. Calc. for C₁₅H₈ClN₅O₂ (325.72): C, 55.13; H, 2.48; N, 21.50. Found: C, 55.00; H, 2.72; N, 21.81.

8-(4-Chlorophenyl)-3,6-dioxo-1,3,4,6-hexahydro-2H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (3)

Compound 1b (10 mmol) was dissolved in DMF (50 mL), chloroacetyl chloride (10 mmol) was added dropwise within 15 min, then refluxed for 4 h. After cooling the reaction mixture was poured onto ice. The solid obtained was filtered and crystallized from ethanol to give 3 as yellow crystals, yield 52%, mp 235-236 ºC. IR (KBr) ν_max/cm^-1: 3450 (br, OH NH), 2967 (CH₂), 2214 (2 C≡N), 1650 (C=O), 1560 (C=C), 1492, 1423 (def. CH₂). ¹H NMR (δ, DMSO): 3.23 (s, 2H, CH₂), 5.30, 5.40 (each s, 2H, 2NH), 8.23 (d, 2H, Ar-H), 8.42 ppm (d, 2H, Ar-H). ¹³C NMR (δ, DMSO): 40.05 (CH₂), 83.01 (C₉-CN), 89.19 (C₇-CN), 122.13 (C≡N), 123.46 (C≡N), 134.20, 135.63, 136.11 and 140.05 (6C of aryl carbons), 140.20 (C₈), 159.87 (C_9a), 161.50 (C₃ as C=O), 162.39 ppm (C₆ as C=O). Anal. Calc. for C₁₅H₈ClN₅O₂ (325.72): C, 55.13; H, 2.48; N, 21.50. Found: C, 54.99; H, 2.72; N, 21.81.

8-Aryl-1,2,5,6-tetrahydro-6-oxo-3-phenyl-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (4a,b)

A mixture of 1a or 1b (5 mmol) and phenacyl bromide (5 mmol) was refluxed in aqueous NaOH (5%, 50 mL) for 4 h, after cooling the reaction mixture was neutralized with conc. HCl. The solid obtained was filtered, washed several times with water and crystallized to give 4a, b.

Compound 4a

Crystallized from ethanol as white crystals, yield 74%, mp 195-196 ºC. IR (KBr) ν_max/cm^-1: 3445 (NH), 2940, 2838 (CH₃ and CH₂), 2211 (2 C≡N), 1653 (C=O), 1588 (C=N), 1508 (C=C), 1459, 1417 (def. CH₂). ¹H NMR (δ, DMSO): 3.31 (s, 2H, CH₂), 4.43 (s, 3H, CH₃O), 4.52 (s, 3H, CH₃O), 4.64 (s, 3H, CH₃O), 6.22 (s, 1H, NH exchangeable with D₂O), 7.59 (s, 2H, Ar-H), 8.36 ppm (s, 5H, Ar-H). Anal. Calc. for C₂₄H₁₉N₅O₄ (441.45): C, 65.30; H, 4.34; N, 15.86. Found: C, 65.13; H, 4.25; N, 15.69.

Compound 4b

Crystallized from ethanol as white crystals, yield 71%, mp 143-144 ºC. IR (KBr) ν_max/cm^-1: 3320 (NH), 2980 (CH₂), 2208 (C≡N), 1636 (C=O), 1591 (C=N), 1516 (C=C), 1495, 1443 (def. CH₂). Anal. Calc. for C₂₁H₁₂ClN₅O (385.81): C, 65.32; H, 3.11; N, 18.14. Found: C, 64.89; H, 3.07; N, 18.12.

8-(4-Chlorophenyl)-6-oxo-1,3,4,6-tetrahydro-2H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (5)

A mixture of 1b (5 mmol) and 1,2-dibromoethane (5 mmol) in alcoholic KOH (5%, 50 mL) was refluxed for 4 h, cooled and neutralized with conc. HCl. The solid so formed was filtered, washed with water and crystallized from methanol to give 5 as white crystals, yield 67%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3327 and 3243 (2NH), 2900 (CH₂), 2210 (2 C≡N), 1649 (C=O), 1581 (C=N). ¹H NMR (δ, DMSO): 3.31 (m, 4H, 2 CH₂), 4.98-5.06 (bs, 2H, 2NH exchangeable with D₂O), 8.22 (d, 2H, Ar-H), 8.40 ppm (d, 2H, Ar-H). Anal. Calc. for C₁₅H₁₀ClN₅O (311.73): C, 57.80; H, 3.23; N, 22.47. Found: C, 57.68; H, 3.17; N, 22.32.

8-Aryl-2,6-dioxo-3-substituted-1,2,5,6-tetrahydropyrido [1,2-b][1,2,4]triazine-7,9-dicarbonitriles (6a-g)

A mixture of 1a or 1b (10 mmol) and acyclic 1,2-bioxo compounds such as pyruvic acid, α-oxo-butyric acid, p-chlorostyryl glyoxalic acid and phenoxy pyruvic acids (10 mmol) in glacial acetic acid (30 mL) was refluxed for 4 h. The solid obtained after cooling was filtered, washed with water and crystallized from a proper solvents to give 6a-g. IR (KBr) ν_max/cm^-1 of 6a-g: 3463 (OH NH), 2211-2219 (2 C≡N), 1695-1633 (2 C=O).

Compound 6a

Crystallized from ethanol as white crystals, yield 90%, mp > 300 ºC. ¹H NMR (d, DMSO): 1.60 (s, 3H, CH₃), 2.31 (s, 1H, NH of triazinone), 3.76 (s, 3H, CH₃O), 3.82 (s, 6H, 2 CH₃O), 6.81 ppm (s, 2H, Ar-H). ¹³C NMR (δ, DMSO): 18.60 (CH₃), 56.99 (2 CH₃O), 60.99 (CH₃O), 82.00 (C₉-CN), 86.10 (C₇-CN), 107.04 (C2' and C6'), 118.12 (2 C≡N), 132.24 (C1'), 137.00 (C4'), 153.41 (C3'and C5'), 154.09 (C3), 155.02 (C₈), 157.16 (C_9a), 159.00 (C₂ as C=O), 161.05 ppm (C₆ as C=O). Anal. Calc. for C₁₉H₁₅N₅O₅ (393.36): C, 58.02; H, 3.84; N, 17.80. Found: C, 57.98; H, 3.77; N, 17.74.

Compound 6b

Crystallized from ethanol as white crystals, yield 88%, mp > 300 ºC. ¹H NMR (δ, DMSO): 1.91 (s, 3H, CH₃), 3.43 (bs, 1H, NH of triazinone), 7.53 (d, 2H, Ar-H), 7.68 ppm (d, 2H, Ar-H).

Compound 6c

Crystallized from methanol as white crystals, yield 91%, mp 130-131 ºC. Anal. Calc. for C₂₀H₁₇N₅O₃ (407.39): C, 58.97; H, 4.21; N, 17.19. Found: C, 59.72; H, 4.13; N, 17.04.

Compound 6d

Crystallized from methanol as white crystals, yield 84%, mp 120-122 ºC. M/z (Int.%): 351 (0.5), 257 (36.36), 201 (45.0), 180 (100), 152 (87.88), 139 (33.33), 124 (39.39), 96 (54.55).

Compound 6e

Crystallized from methanol as white crystals, yield 87%, mp 248-249 ºC. ¹H NMR (δ, DMSO): 3.77 (s, 3H, CH₃O), 3.84 (s, 6H, 2 CH₃O), 6.85 (s, 2H, Ar-H of trimethoxy ring), 7.34 and 8.16 (each d, 2H of CH=CH), 7.49-7.78 ppm (m, 4H, Ar-H), 8.42 (bs, 1H, NH of triazinone). Anal. Calc. for C₂₆H₁₈ClN₅O₅ (515.92): C, 60.53; H, 3.52; N, 13.57. Found: C, 60.42; H, 3.41; N, 13.44.

Compound 6f

Crystallized from ethanol as white crystals, yield 85%, mp > 300 ºC. ¹H NMR (δ, DMSO): 7.25 and 8.25 (each d, 2H of CH=CH), 7.35-7.82 ppm (m, 8H, Ar-H), 8.50 (bs, 1H, NH of triazinone). ¹³C NMR (δ, DMSO) 75.19 (C₉-CN), 87.28 (C₇-CN), 116.21 (C≡N), 117.09 (C≡N), 122.75 (C _α of C=C), 129.50-138.56 (12C of aryl groups and C _β of C=C), 148.46 (C₈), 157.48 (C_9a), 157.77 (C₃), 159.26 (C₂ as C=O) and 159.99 ppm (C₆ as C=O). Anal. Calc. for C₂₃H₁₁Cl₂N₅O₂ (460.28): C, 60.02; H, 2.41; N, 15.22. Found: C, 60.00; H, 2.34; N, 15.10.

Compound 6g

Crystallized from methanol as white crystals, yield 65%, mp > 300 ºC. M/z (Int.%): 429 (0.19), 285 (100), 256 (25.84), 173 (10.76), 146 (1.17) and 111 (26.39).

8-Aryl-2,3,6-trioxo-1,2,3,4,5,6-hexahydropyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (7a,b)

Method 1

A mixture of 1a or 1b (0.01 mol) and diethyl oxalate (0.01 mol) in dry dioxane (50 mL) was refluxed for 4 h, after cooling the reaction mixture was concentrated. The solid obtained was filtered and crystallized to give 7a, b.

Method 2

Compound 1a or 1b (10 mmol) was dissolved in DMF (50 mL), oxalyl chloride (10 mmol) was added dropwise within 15 min. The reaction mixture was refluxed for 4 h, after cooling the reaction mixture was poured into ice. The solid obtained was filtered and crystallized to give 7a, b.

Compound 7a

Crystallized from benzene as white crystals, yield 82%, mp 146-147 ºC. UV λ_max/nm (log ε): 349 (0.131), 273 (2.857). IR (KBr) ν_max/cm^-1: 3269, 3195 (2 NH), 2989, 2969, 2935, 2904, 2841 (CH₃ groups), 2255 (2 C≡N), 1741 (weak band for C=O), 1462, 1424 (def. CH₃). ¹H NMR (δ, DMSO) 3.65 (s, 3H, CH₃O), and 3.80 (s, 6H, 2 CH₃O), 5.10 (s, 2H, 2OH of 1,2,4-triazinediol), 6.72 (s, 2H, Ar-H). ¹³C NMR (δ, DMSO): 56.73 (2 CH₃O), 60.84 (CH₃O), 107.57 (C₇–CN and C₉–CN), 115.01 (2 C≡N), 131.12 (aromatic carbons), 137.93 (C₈), 153.70 ppm (3 C=O and C_9a). Anal. Calc. for C₁₈H₁₃N₅O₆ (395.33): C, 54.69; H, 3.31; N, 17.71. Found: C, 54.67; H, 3.30; N, 17.73.

Compound 7b

Crystallized from DMF as yellow crystals, yield 80%, mp > 300 ºC. ¹H NMR (δ, DMSO): 7.54 (d, 2H, Ar-H), 7.63 (d, 2H, Ar-H), 8.39 ppm (s, 2H, 2OH of 1,2,4-triazinediol). ¹³C NMR (δ, DMSO): 74.31 (C₉-CN), 86.54 (C₇-CN), 115.18 (C≡N), 115.98 (C≡N), 128.69, 129.90, 133.39 and 135.07 (6C of aryl carbons), 156.49 (C₈), 158.27 (C_9a), 158.90 (C₂ and C₃ as 2 C=O), 171.77 ppm (C₆ as C=O). M/z (Int.%): 339 (33.33), 187 (100), 175 (23.81), 142 (54.76), 124 (60.61) and 86 (42.42). Anal. Calc. for C₁₅H₆ClN₅O₃ (339.69): C, 53.04; H, 1.78; N, 20.62. Found: C, 52.91; H, 1.75; N, 20.58.

2,3-Dimethyl-6-oxo-8-(3,4,5-trimethoxy)-6H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (8)

A mixture of 1a (5 mmol) and butane-2,3-dione (5 mmol) in glacial acetic acid (20 mL) was refluxed for 2 h, after cooling the reaction mixture was concentrated. The solid obtained was filtered, washed with cold ethanol and crystallized from acetic acid to give 8 as yellow crystals, yield 70%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 2926, 2849 (CH₃ groups), 2213 (2 C≡N), 1696 (C=O), 1635 (C=N), 1585 (C=C), 1466, 1412 (def. CH₃). ¹H NMR (δ, DMSO): 3.20 (s, 3H, CH₃), 3.62 (s, 3H, CH₃), 3.75 (s, 3H, CH₃O), 4.01 (s, 6H, 2 CH₃O), 6.65 ppm (s, 2H, Ar-H). M/z (Int.%): 391 (2.99), 365 (4.25), 337 (6.77), 224 (5.20), 197 (8.50), 171 (21.42), 167 (15.91), 137 (21.57), 109 (38.92), 82 (37.46), 55 (100). Anal. Calc. for C₂₀H₁₇N₅O₄ (391.39): C, 61.23; H, 2.55; N, 17.88. Found: C, 60.94; H, 2.10; N, 17.50.

8-Aryl-2,3-diphenyl-6-oxo-5,6-dihydropyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (9a,b)

A mixture of 1a or 1b (5 mmol) and benzil (5 mmol) in glacial acetic acid (50 mL) and anhydrous sodium acetate (1 g) was refluxed for 8 h, after cooling the reaction mixture was poured onto ice. The solid obtained was filtered and crystallized to give 9a, b. For compound 9a; Crystallized from DMF/H₂O as yellow crystals, yield 60%, mp 265 ºC. UV λ_max/nm (log ε): 347 (4.33), 282 (4.084). IR (KBr) ν_max/cm^-1: 2935, 2861 (CH₃ groups), 2215 (2 C≡N), 1674 (C=O), 1611 (C=N), 1593 (C=C), 1466, 1418 (def. CH₃). ¹H NMR (d, DMSO): 3.78 (s, 3H, CH₃O), 3.80 (s, 2H, 2 CH₃O), 6.97 (s, 2H, Ar-H of trimethoxy ring), 7.14-7.52 ppm (m, 10H, Ar-H). M/z (Int.%): 515 (45.83), 426 (41.67), 328 (100), 232 (41.67), 221 (45.83) and 147 (45.83). Anal. Calc. for C₃₀H₂₁N₅O₄ (515.53): C, 69.83; H, 4.07; N, 13.58. Found: C, 70.06; H, 3.97; N 13.54.

Compound 9b

Crystallized from DMF/H₂O as yellow crystals, yield 54%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 2219 (2 C≡N), 1669 (C=O), 1608 (C=N), 1585 (C=C). ¹H NMR (δ, DMSO): 7.19-7.55 ppm (m, 10H, Ar-H), 7.72 (d, 2H, Ar-H), 7.83 (d, 2H, Ar-H). Anal. Calc. for C₂₇H₁₄ClN₅O (459.89): C, 70.52; H, 3.07; N, 15.23. Found: C, 70.36; H, 3.02; N, 15.20.

8-Aryl-2,3-diphenyl-6-oxo-1,2,5,6-tetrahydropyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (10a,b )

Method 1

A mixture of 1a or 1b (5 mmol) and benzoin (5 mmol) in glacial acetic acid (50 mL) and anhydrous sodium acetate (1 g) was refluxed for 8 h, after cooling the reaction mixture was poured onto ice. The solid obtained was filtered, washed several times with water and crystallized to give 10a, b.

Method 2

Compounds 10a or 10b (5 mmol) was dissolved in methanol (50 mL), ferric chloride (10%, 20 mL) in methanol (30 mL) was added and refluxed for 3 h, after cooling the reaction mixture was concentrated. The solid obtained was filtered and crystallized to give 9a, b. Melting point and mixed melting point showed no depression with 9a, b obtained from the above experiment.

Compound 10a

Crystallized from DMF/H₂O as yellow crystals, yield 49%, mp 278-279 ºC. IR (KBr) ν_max/cm^-1: 3449 (NH), 2977, 2944, 2846 (CH₃), 2212 (2 C≡N), 1650 (C=O), 1591 (C=N), 1562 (C=C), 1458, 1416 (def. CH₃). Anal. Calc. for C₃₀H₂₃N₅O₄ (517.55): C, 69.62; H, 4.48; N, 13.53. Found: C, 69.50; H, 4.35; N 13.38.

Compound 10b

Crystallized from DMF/H₂O as white crystals, yield 44%, mp 290-291 ºC. ¹H NMR (δ, DMSO): 5.62 (s, 1H, CH of 1,2,4-triazin-5-yl), 7.21-8.05 (m, 14H, Ar-H), 8.53 ppm (s, 1H, NH). ¹³C NMR (δ, DMSO): 75.19 (C₉-CN), 77.83 (C₂), 87 (C₇-CN), 117.09 (2 C≡N), 129.51-135.95 (18C of aryl carbons), 157.49 (C₈), 159.27 (C_9a), 170.78 (C₃), 194.49 ppm (C₆ as C=O). Anal. Calc. for C₂₇H₁₆ClN₅O (461.91): C, 70.21; H, 3.49; N, 15.16. Found: C, 70.09; H, 3.42; N, 15.08.

2,3-Dichloro-6-oxo-8-(3,4,5-trimethoxy)-6H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (11)

A mixture of 7a (5 mmol) and phosphorus oxychloride (10 mL) was refluxed for 2 h, after cooling the reaction mixture was poured onto ice with stirring. The solid obtained was filtered, washed several times with water and crystallized from benzene to give 11 as white crystals, yield 55%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 2964, 2936, 2842 (CH₃ groups), 2240 (2 C≡N), 1680 (C=O), 1605 (C=N), 1582 (C=C), 1473, 1414 (def. CH₃). ¹H NMR (δ, DMSO): 3.79 (s, 3H, CH₃O), 3.83 (s, 6H, 2CH₃O) and 6.81 (s, 2H, Ar-H). Anal. Calc. for C₁₈H₁₁Cl₂N₅O₄ (432.22): C, 50.20; H, 2.57; N, 16.20. Found: C, 50.31; H, 2.46; N, 16.24.

8-Aryl-2,3,6-trioxo-1,4-dihydroxymethyl-1,2,3,4,5,6-hexahydropyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (12a,b)

A mixture of 7a or 7b (5 mmol) and formaldehyde solution (10 mmol) in methanol (50 mL) was refluxed for 6 h. The solid obtained after cooling was filtered, washed several times with water and crystallized to give 12a, b.

Compound 12a

Crystallized from methanol as yellow crystals, yield 73%, mp 214-215 ºC. UV λ_max/nm (log ε): 348 (1.89), 337 (1.54), 269 (2.55). IR (KBr) ν_max/cm^-1: 3399, 3280 (2 OH), 2940, 2940, 2839 (CH₃), 2215 (2 C≡N), 1660 (C=O), 1595 (C=C), 1467, 1414 (def. CH₃). ¹H NMR (δ, DMSO): 3.25 (s, 4H, 2-CH₂-), 3.75 (s, 3H, CH₃O), 3.81 (s, 6H, 2 CH₃O), 5.68 (s, 1H, OH), 6.84 (s, 1H, Ar-H), 6.86 (s, 1H, Ar-H), 8.41 ppm (s, 1H, OH). Anal. Calc. for C₂₀H₁₇N₅O₈ (455.39): C, 52.70; H, 3.37; N, 15.37. Found: C, 52.52; H, 3.15; N, 15.25.

Compound 12b

Crystallized from methanol as yellow crystals, yield 69%, mp 219-220 ºC. IR (KBr) ν_max/cm^-1: 3293, 3212 (2 OH), 2990, 2932 (CH₂), 2217 (2 C≡N), 1667 (C=O), 1618 (def. OH), 1497, 1450 (def. CH₂). M/z (Int.%) 399 (26.19), 239 (35.17), 187 (100), 142 (26.19), 124 (28.57), 112 (30.95) and 88 (26.19).

9-Aryl-5,11-dihydroxymethyl-7-oxo-2-thioxo-2,3,5,6,7,11-hexahydropyrido[1,2:2´,3´] triazino[5´,6´-f]triazine-8,10-dicarbonitriles (13a,b)

A mixture of 12a or 12b (2 mmol) and thiosemicarbazide (2 mmol dissolved in hot water) in acetic acid (40 mL) was refluxed for 4 h. The solid obtained after cooling was filtered and crystallized to give 13a, b.

Compound 13a

Crystallized from acetic acid as yellow crystals, yield 77%, mp > 300 ºC. UV λ_max/nm (log ε): 379 (3.9), 345 (4.4). IR (KBr) ν_max/cm^-1: 3412, 3281 (2-OH), 3214 (NH), 2973, 2941, 2840 (CH₃), 2213 (2 C≡N), 1670 (C=O), 1609 (C=N), 1513 (C=C), 1468, 1413 (def. CH₃), 1184 (C=S). ¹H NMR (δ, DMSO): 3.04 (s, 4H, 2 CH₂O-), 3.77 (s, 3H, CH₃O), 3.80 (s, 6H, 2 CH₃O), 5.95 (s, 1H, OH), 6.84 (s, 1H, Ar-H), 6.89 (s, 1H, Ar-H), 8.63 (s, 1H, OH), 10.25 ppm (s, 1H, NH). Anal. Calc. for C₂₁H₁₈N₈O₆S (510.49): C, 49.41; H, 3.55; N, 21.94. Found: C, 49.94; H, 4.10; N, 22.10.

Compound 13b

Crystallized from acetic acid as yellow crystals, yield 65%, mp > 300 ºC. λ_max /nm(ε): 346 (3.4), 273 (2.98). IR (KBr) ν_max/cm^-1: 3416 (OH), 3344 (OH), 3307 (NH), 2217 (C≡N), 1668 (C=O), 1613 (C=N), 1549 (C=C).¹H NMR (δ, DMSO): 2.87 (s, 4H, 2 CH₂), 5.43 (s, 2H, 2 OH), 7.54 (d, 2H, Ar-H), 7.65 (d, 2H, Ar-H), 9.89 ppm (s, 1H, 1NH).

9-(4-Chlorophenyl)-5,11-dihydroxymethyl-7-oxo-2-hydrazino-2,3,5,6,7,11-hexahydropyrido[1,2:2´,3´]triazino[5´,6´-f]triazine-8,10-dicarbonitrile (14)

A mixture of 13b (10 mmol) and hydrazine hydrate (100 mmol) in absolute ethanol (100 mL) was refluxed for 12 h. The solid obtained after cooling was filtered and crystallized from DMF to give 14 as yellow crystals, yield 54%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3470 (OH), 3304, 3187 (NH, NH₂), 2926 (CH₂), 2214 (2 C≡N), 1636 (C=O), 1579 (C=N), 1489 (def. CH₂). ¹H NMR (δ, DMSO): 2.73 (s, 2H, CH₂), 2.89 (s, 2H, CH₂), 5.09 (bs, 2H, NH₂), 5.75 (s, 2H, 2OH), 7.54 (d, 2H, Ar-H), 7.65 (d, 2H, Ar-H), 7.94 ppm (s, 1H, 1NH). Anal. Calc. for C₁₈H₁₃ClN₁₀O₃ (452.82): C, 47.70; H, 2.87; N, 30.92. Found: C, 47.84; H, 2.53; N, 30.89.

6-Amino-4-(3,4,5-trimethoxyphenyl)-2-oxo-1-[2-oxo-1,2-dihydro-3-indolo-3-ylidine)amino]-1,2-dihydropyridine-3,5-dicarbonitrile (15)

A mixture of 1a (5 mmol) and isatine (5 mmol) in ethanol (75 mL) and piperidine (2 drops) was refluxed for 4 h. The solid obtained was filtered and crystallized from ethanol to give 15 as yellow crystals, yield 51%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3310, 3172 (NH₂, NH), 2921, 2851 (CH₃), 2207 (2 C≡N), 1646 (C=O), 1518 (C=N), 1496, 1442 (def. CH₃). ¹H NMR (δ, DMSO): 3.03 (s, 1H, NH), 3.79 (s, 3H, CH₃O), 3.83 (s, 3H, CH₃O), 3.85 (s, 3H, CH₃O), 6.97 (s, 2H, Ar-H of trimethoxy phenyl), 7.39-7.99 (m, 4H, Ar-H of indole), 8.28 ppm (s, 2H, NH₂). Anal. Calc. for C₂₄H₁₈N₆O₅ (470.45): C, 61.28; H, 3.86; N, 17.86. Found: C, 61.19; H, 3.84; N, 17.81.

3-(2-Aminophenyl)-8-(4-chlorophenyl)-2,6-dioxo-1,6-dihydro-2H-pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (16)

A mixture of 1a (5 mmol) and isatine (5 mmol) in alcoholic NaOH (5%, 50 mL) was refluxed for 4 h, cooled and neutralized with conc. HCl. The solid so formed was filtered, washed several times with water and crystallized from DMF/H₂O to give 16 as yellow crystals, yield 46%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3500-3336 (b, OH, NH₂), 2200 (2 C≡N), 1621 (C=O), 1548 (C=N). ¹H NMR (δ, DMSO): 4.87 (bs, 2H, NH₂), 7.23-8.10 (m, 8H, Ar-H), 11.62 ppm (bs, 1H, NH). Anal. Calc. for C₂₁H₁₁ClN₆O₂ (414.81): C, 60.81; H, 2.67; N, 20.26. Found: C, 61.04; H, 2.61; N, 20.14.

8-Aryl-10-oxo-11-hydroindolo[2,3-e]pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitriles (17a,b)

Compound 15 or 16 (2 mmol), glacial acetic acid (50 mL) and anhydrous sodium acetate (1 g) was refluxed for 12 h, after cooling the reaction mixture was concentrated. The solid so formed was filtered and crystallized to give 17a, b (Table 2).

Compound 17a

Crystallized from acetic acid as orange crystals, yield 73%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3491 (NH), 2996, 2943, 2834 (CH₃), 2218 (2 C≡N), 1667 (C=O), 1640 (C=N), 1587 (C=C), 1474, 1428 (def. CH₃). M/z (Int.%): 452 (3.27), 377 (4.24), 337 (6.63), 339 (12.68), 309 (6.34), 172 (23.44), 145 (40.44), 117 (65.03), 108 (36.31), 90 (19.88). Anal. Calc. for C₂₄H₁₆N₆O₄ (452.43): C, 63.71; H, 3.56; N, 18.58. Found: C, 63.59; H, 3.49; N, 18.45.

Compound 17b

Crystallized from DMF as orange-yellow crystals, yield 84%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3381 (NH), 2202 (2 C≡N), 1622 (C=O). ¹H NMR (δ, DMSO): 6.80-7.82 (m, 8H, Ar-H), 12.30 ppm (s, 1H, NH). ¹³C NMR (δ, DMSO): 75.19 (C₇-CN), 87.29 (C₉-CN), 116.22 (C≡N), 117.09 (C≡N), 129.65-135.95 (18C of aryl carbons), 157.48 (C₈ and C_12a), 159.26 (C_5a), 160 (C_6a), 163.17 ppm (C₁₀ as C=O). M/z (Int.%): 396 (3.39), 368 (9.05), 319 (15.49), 285 (12.14), 254 (41.10), 209 (6.03), 117 (13.50), 111 (64.20), 57 (100). Anal. Calc. for C₂₁H₉ClN₆O (396.80): C, 63.57; H, 2.29; N, 21.18. Found: C, 63.42; H, 2.25; N, 20.98.

8-(3,4,5-Trimethoxy)-5-acetyl-10-oxo-11-hydroindolo[2,3-e]pyrido[1,2-b][1,2,4]triazine-7,9-dicarbonitrile (18)

A mixture of 17a (5 mmol) and acetic anhydride (10 mL) was refluxed for 2 h. The solid obtained after cooling was filtered, washed with cold ethanol and crystallized from acetic acid to give 18 as yellow crystals, yield 80%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 2999, 2947, 2840 (CH₃), 2216 (2 C≡N), 1695 (C=O), 1604 (C=N), 1583 (C=C), 1477, 1416 (def. CH₃). M/z (Int.%): 494 (5.57), 452 (3.27), 337 (4.62), 327 (5.89), 311 (7.01), 299 (6.69), 211 (8.76), 185 (5.57), 133 (8.28), 116 (10.35), 93 (10.67) and 55 (100). Anal. Calc. for C₂₆H₂₀N₆O₅ (494.47): C, 63.16; H, 3.67; N, 17.00. Found: C, 63.10; H, 3.54; N, 16.84.

8-(3,4,5-Trimethoxyphenyl)-2-(2-acetylaminophenyl)-3,6-dioxo-3,6-dihydro-4H-pyrido[1,2-b] triazine-7,9-dicarbonitrile (20)

A mixture of 1a (5 mmol) and N-acetylisatine (5 mmol) in absolute ethanol (100 mL) and few drops of piperidine was refluxed for 4 h, after cooling the reaction mixture was concentrated. The solid obtained was filtered, washed with cold ethanol and crystallized from DMF to give 20 as orange crystals, yield 65%, mp > 300 ºC. IR (KBr) ν_max/cm^-1: 3452, 3283 (2NH), 2939, 2838 (CH₃), 2213 (2 C≡N), 1673, 1680 (3C=O), 1618 (C=N), 1589 (C=C), 1490, 1415 (def. CH₃). ¹H NMR (δ, DMSO): 2.02 (s, 3H, COCH₃), 3.79 (s, 3H, CH₃O), 3.83 (s, 6H, 2CH₃O), 5.69 (s, 1H, NH), 6.85 (s, 1H, Ar-H of trimethoxy phenyl), 6.96 (s, 1H, Ar-H trimethoxy phenyl), 7.27 (s, 1H, Ar-H), 7.57 (s, 1H, Ar-H), 7.94 ppm (s, 2H, Ar-H), 10.8 (s, 1H, NH). Anal. Calc. for C₂₆H₂₀N₆O₆ (512.48): C, 60.94; H, 3.93; N, 16.40. Found: C, 60.91; H, 3.88; N, 16.35.

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Received: September 16, 2008

Web Release Date: June 4, 2009

Publication Dates

• Publication in this collection
  27 Aug 2009
• Date of issue
  2009

History

• Accepted
  04 June 2009
• Received
  16 Sept 2008