# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
Found C, 60.21; H, 5.35; N, 24.91. **3-[(5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyropyridazine-3-carbonyl]-amino]-benzoic acid, 9p. ** To a suspension of 9n (0.1 mmol) in 2 mL of ethanol, 0.5 mL of 2N NaOH was added, and the mixture was stirred at room temperature for 15 min. Then, the mixture was concentrated in vacuo, diluted with cold water (5-10 mL), and acidified with 2N HCl. Finally, the suspension was extracted with CH\({}_{2}\)Cl\({}_{2}\) (3 \(\times\) 10 mL), and the evaporation of the solvent afforded the desired compound 9p. Yield = 66%; oil; \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) 8.13 (m, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.15 (q, 2H, CH\({}_{3}\)CH\({}_{2}\),N, \(J\) = 7.2 Hz), 6.32 (m, 1H, pyrazole), 7.48-7.88 (m, 6H: 3H, Ar; 1H, pyrazole; exch br, 2H, NH\({}_{2}\)), 8.32 (m, 1H, Ar), 10.90 (exch br s, 1H, NH), 13.22 (exch br s, 1H, NH). Anal. Calcd for C\({}_{17}\)H\({}_{16}\)N\({}_{6}\)O\({}_{4}\): C, 55.43; H, 4.38; N, 22.82. Found C, 55.56; H, 4.39; N, 22.88. **General procedure for 10a, 10c-d, 10f-i and 10p-q. ** A mixture of 4-amino-5-pyrazoyl derivatives 9a-g and 9o-p (0.23 mmol), acetic anhydride (10-21 mmol), and a catalytic amount of concentrated sulfuric acid was stirred at room temperature for 15-20 min. The mixture was diluted with cold water (10 mL) and neutralized with 10% KHCO\({}_{3}\). Compound 10p was filtered off and recrystallized from ethanol, while for compounds 10a, 10c-d, 10f-i and 10q the mixture was extracted with CH\({}_{2}\)Cl\({}_{2}\) (3 \(\times\) 15 mL), and the solvent was evaporated under vacuum. Final compounds were purified by flash column chromatography using CH\({}_{2}\)Cl\({}_{2}\)/CH\({}_{3}\)OH as eluent in different ratios. **3-Ethyl-6-methyl-4-oxo-3,4-dihydropyrazolo [1/5,5':1.6]pyrimidine [4,5-d]pyridazine-1-(N,N-diethylcarboxamide), 10a. ** Yield = 59%; mp = 221-222 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8.120 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 6.8 Hz), 1.45 (m, 6H, 3H (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N), 3.10 (s, 3H, C6-CH\({}_{3}\)), 3.25 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 3.70 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 4.40 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 6.8 Hz), 6.99 (m, 1H, Ar), 8.20 (m, 1H, Ar). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) 8 12.21, 12.84, 18.67, 36.48, 43.53, 96.92, 119.91, 133.81, 141.75, 146.39, 152.94, 157.24, 158.79, 167.75. ESI-HRMS (\(m/Z\)) [M+H]\({}^{+}\): calculated for C\({}_{16}\)H\({}_{21}\)N\({}_{6}\)O\({}_{2}\) 329.1721; found 339.1723. Anal. Calcd for C\({}_{16}\)H\({}_{20}\)N\({}_{6}\)O\({}_{2}\): C, 58.52; H, 6.14; N, 25.59. Found C, 58.68; H, 6.13; N, 25.53. **3-Ethyl-9-furyl-6-methyl-4-oxo-3,4-dihydropyrazolo [1/5,5':1,6]pyrimidine [4,5-d] pyridazine-1-(N,N-diethylcarboxamide), 10c. ** Yield = 24%; mp = 238-241 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.20 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 1.44-1.50 (m, 6H, 3H (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N), 3.16 (s, 3H, C6-CH\({}_{3}\)), 3.31 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 3.75 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 6.8 Hz), 4.39 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 6.91 (s, 1H, furane), 7.05 (m, 1H, furane), 7.57 (m, 1H, furane), 8.02 (s, 1H, Ar). \({}^{13}\)C-NMR (100 MHz, CDCl\({}_{3}\)) 8.12.22, 12.79, 18.60, 36.53, 43.52, 101.68, 108.82, 119.90, 129.32, 131.04, 138.50, 141.27, 144.12, 146.42, 153.01, 157.28, 158.82, 167.78. ESI-HRMS (\(m/z\)) [M+H]\({}^{+}\): calculated for C\({}_{20}\)H\({}_{23}\)N\({}_{6}\)O\({}_{3}\) 395.1826; found 395.1832. Anal. Calcd for C\({}_{20}\)H\({}_{22}\)N\({}_{6}\)O\({}_{3}\): 60.90; H, 5.62; N, 21.31. Found C, 61.07; H, 5.61; N, 21.38. **3-Ethyl-6-methyl-4-oxo-3,4-dihydropyrazolo [1/5,5':1,6]pyrimidine [4,5-d]pyridazine-1-(N-benzyl-N-methyl-carboxylate), 10d.