# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
Yield = 94%; mp = 133-135 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.24 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 1.37 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 3.06 (s, 12H, N(CH\({}_{3}\))\({}_{2}\), 3.08 (s, 6H, NCH\({}_{3}\)), 4.08 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.23 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.63 (s5.30 (d, 1H, CH=CHN, \(J\) = 13.2 Hz), 7.58 (d, 1H, CH=CHN, \(J\) = 12.8 Hz). Anal. Calcd for C\({}_{16}\)H\({}_{21}\)N\({}_{5}\)O\({}_{4}\): C, 55.32; H, 6.09; N, 20.16. Found C, 55.51; H, 6.08; N, 20.19. **3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroiosoxazole [3,4-\(d\)]pyridazine-4-carboxylic acid methylpropylamide, 8e. ** Yield = 92%; oil; 1H-NMR (400 MHz, CDCl\({}_{3}\)) & 0.80 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{2}\)N, \(J\) = 6.8 Hz), 1.00 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{2}\)N, \(J\) = 6.8 Hz), 1.35 (t, 6H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 1.60-1.75 (m, 4H, CH\({}_{3}\)CH\({}_{2}\)CH\({}_{2}\)N), 3.05 (s, 6H, NCH\({}_{3}\)), 3.10 (s, 12H, N(CH\({}_{3}\))\({}_{2}\)), 3.28 (t, 2H, NCH\({}_{2}\)CH\({}_{2}\)CH\({}_{3}\), \(J\) = 7.2 Hz), 3.51 (t, 2H, NCH\({}_{2}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.15 (m, 4H, CH\({}_{3}\)CH\({}_{2}\)N), 5.21 (d, 1H, CH=CHN, \(J\) = 12.8 Hz), 5.27 (d, 1H, CH=CHN, \(J\) = 12.8 Hz), 7.55 (d, 2H, CH=CHN). Anal. Calcd for C\({}_{16}\)H\({}_{23}\)N\({}_{5}\)O\({}_{3}\): C, 57.64; H, 6.95; N, 21.01. Found C, 57.50; H, 6.96; N, N, 21.06. **3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroiosoxazole [3,4-\(d\)]pyridazine-4-carboxylic acid butylmethylamide, 8f. ** Yield = 91%; oil; 1H-NMR (400 MHz, CDCl\({}_{3}\)) & 0.85 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{3}\)N, \(J\) = 7.2 Hz), 0.98 (t, 3H, CH\({}_{3}\)(CH\({}_{2}\))\({}_{3}\)N, \(J\) = 7.2 Hz), 1.18-132 (m, 2H, CH\({}_{3}\)CH\({}_{2}\)(CH\({}_{2}\))\({}_{2}\)N), 1.35 (t, 6H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 1.36-1.45 (m, 2H, CH\({}_{3}\)CH\({}_{2}\)(CH\({}_{2}\))\({}_{2}\)N), 1.59-1.71 (m, 4H, CH\({}_{3}\)CH\({}_{2}\)CH\({}_{2}\)CH\({}_{2}\)N), 3.00 (s, 6H, NCH\({}_{3}\)), 3.15 (s, 12H, N(CH\({}_{3}\))\({}_{2}\)), 3.31 (t, 2H, NCH\({}_{2}\)(CH\({}_{2}\))\({}_{2}\)CH\({}_{3}\)), 3.57 (t, 2H, NCH\({}_{2}\)(CH\({}_{2}\))\({}_{2}\)CH\({}_{3}\)), 4.20 (m, 4H, CH\({}_{3}\)CH\({}_{2}\)N), 5.22 (d, 1H, CH=CHN, \(J\) = 13.2 Hz), 5.28 (d, 1H, CH=CHN, \(J\) = 13.2 Hz), 7.55 (d, 2H, CH=CHN, \(J\) = 12.4 Hz). Anal. Calcd for C\({}_{17}\)H\({}_{25}\)N\({}_{5}\)O\({}_{3}\): C, 58.77; H, 7.25; N, 20.16. Found C, 58.90; H, 7.23; N, 20.23. **3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroiosoxazole [3,4-\(d\)]pyridazine-4-carboxylic acid ethylmethylamide, 8h. ** Yield = 67%; mp = 115-118 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, CDCl\({}_{3}\)) & 1.23-1.30 (m, 6H, CH\({}_{3}\)CH\({}_{2}\)NCO), 1.38 (t, 6H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 3.05 (s, 12H, N(CH\({}_{3}\))\({}_{2}\)), 3.15 (s, 6H, NCH\({}_{3}\)), 3.41 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)NCO), \(J\) = 6.8 Hz), 3.63 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)NCO, \(J\) = 6.8 Hz), 4.22 (m, 4H, CH\({}_{3}\)CH\({}_{2}\)N), 5.30 (m, 2H, CH=CHN), 7.57 (m, 2H, CH=CHN). Anal. Calcd for C\({}_{15}\)H\({}_{21}\)N\({}_{5}\)O\({}_{3}\): C, 56.41; H, 6.63; N, 21.93. Found C, 56.56; H, 6.62; N, 21.97. **3-(2-Dimethylaminovinyl)-6-ethyl-4-(4-phenylpiperazine-1-carbonyl)-6-fi-isoxazole [3,4-\(d\)]pyridazin-7-one, 8i. ** Yield = 77%; mp = 189-191 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, CDCl\({}_{3}\)) & 1.37 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 2.90 (s, 3H, (CH\({}_{3}\))\({}_{2}\)N), 2.97 (s, 3H, (CH\({}_{3}\))\({}_{2}\)N), 3.08-3.33 (m, 4H, piperazine), 3.78 (m, 2H, piperazine), 4.05 (m, 2H, piperazine), 4.20 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 5.31 (d, 1H, CH=CHN, \(J\) = 13.2), 7.00 (m, 3H, Ar), 7.43 (m, 2H, Ar), 7.60 (d, 1H, CH=CHN, \(J\) = 13.2 Hz). Anal. Calcd for C\({}_{22}\)H\({}_{26}\)N\({}_{6}\)O\({}_{3}\): C, 62.54; H, 6.20; N, 19.89. Found C, 62.70; H, 6.21; N, 19.83.