# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
Found C, 62.28; H, 5.75; N, 19.11. **6-Ethyl-3-(2-furan-3-yl-vinyl)-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid diethylamide, 8b. ** To a suspension of 7a (0.36 mmol) and 3-furylaldehyde (0.54 mmol) in anhydrous methanol (1 mL), CH\({}_{3}\)ONa (0.9 mmol) was added. The mixture was refluxed for 10 min. After cooling, the suspension was concentrated under vacuum, and the solid was recovered by _vacuum_ filtration and purified by crystallization from ethanol. Yield = 46%; mp = 195-197 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) & 1.28-1.46 (m, 9H, 3H, CH\({}_{3}\)CH\({}_{2}\)N, 6H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N), 3.44 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 3.64 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 4.28 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 6.65 (s, 1H, furane), 7.02 (d, 1H, CH=CH, \(J\) = 16 Hz), 7.50 (m, 1H, furane), 7.61 (d, 1H, CH=CH, \(J\) = 16 Hz), 7.70 (m, 1H, furane). Anal. Calcd for C\({}_{18}\)H\({}_{20}\)N\({}_{4}\)O\({}_{4}\): C, 60.66; H, 5.66; N, 15.72. Found C, 60.52; H, 5.65; N, 15.76. **General Procedure for 9a-o. ** A mixture of 8a-o (0.47 mmol) and hydrazine hydrate (7.5-16 mmol) in 2-3 mL of ethanol was stirred at room temperature for 1-3 h (compounds **9b-f**). For compounds **9a** and **9g-o** the reaction was carried out at 60 \({}^{\circ}\)C for 1-8 h. After cooling, the mixture was concentrated in vacuo, and compounds **9a, 9c, 9f-h** and **9l** were isolated by filtration. For compounds **9b** and **9d-e**, after concentration, cold water was added, and the suspension was extracted with CH\({}_{2}\)Cl\({}_{2}\). Evaporation of the solvent afforded the desired final compounds, which were purified by crystallization from ethanol (for **9b** and **9e-f**) or by flash column chromatography usingpressure and the residue was directly purified by flash column chromatography using as eluent CH\({}_{2}\)Cl\({}_{2}\)/CH\({}_{3}\)OH 9.5:0.5 (for **9i-j** and **9m**), cyclohexane/ethyl acetate 1:3 (for **9k**) or CH\({}_{2}\)Cl\({}_{2}\)/CH\({}_{3}\)OH 9:1 (for **9n-o**) as eluents. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid diethylamide, 9a. ** Yield = 71%; mp = 200-201 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.00 (t, 3H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 1.20 (t, 3H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 1.42 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 3.15 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 3.55 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 4.25 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 6.60 (d, 1H, pyrazole, \(J\) = 6.8 Hz), 7.60 (d, 1H, pyrazole, \(J\) = 6.8 Hz). Anal. Calcd for C\({}_{14}\)H\({}_{20}\)N\({}_{6}\)O\({}_{2}\): C, 55.25; H, 6.62; N, 27.61. Found C, 55.37; H, 6.61; N, 27.70. **5-Amino-1-ethyl-4-(5-furan-3-yl-2H-pyrazol-3-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid diethylamide, 9b. ** Yield = 56%; mp = 185 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.09 (t, 3H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 1.23 (t, 3H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 1.41 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 3.19 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 3.56 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 4.25 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 6.63 (s, 1H, pyrazole), 6.67 (s, 1H, furane), 7.49 (s, 1H, furane), 7.81 (s, 1H, furane). Anal. Calcd for C\({}_{18}\)H\({}_{22}\)N\({}_{6}\)O\({}_{3}\): C, 58.37; H, 5.99; N, 22.69. Found C, 58.53; H, 5.98; N, 22.62. **5-Amino-1-ethyl-6-oxo-4-(2H-pyrazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid benzyl-methylamide, 9c.