# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
**4-(4-Benzylpiperazine-1-carbonyl)-3-(2-dimethylaminovinyl)ethyl-6-fi-isoxazole [3,4-\(d\)]pyridazin-7-(6H)-one, 8j. ** Yield = 49%; oil; 1H-NMR (400 MHz, CDCl\({}_{3}\)) & 1.34 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.47-2.57 (m, 4H, piperazine), 2.90-3.10 (m, 6H, (CH\({}_{3}\))\({}_{2}\)N), 3.60 (m, 4H, piperazine), 3.85 (s, 2H, CH\({}_{2}\)Ph), 4.18 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 5.28 (d, 1H, CH=CHN, \(J\) = 12.8 Hz), 7.45 (m, 5H, Ar), 7.60 (d, 1H, CH=CHN, \(J\) = 13.2 Hz). Anal. Calcd for C\({}_{23}\)H\({}_{28}\)O\({}_{3}\): C, 63.29; H, 6.47; N, 19.25. Found C, 63.08; H, 6.46; N, 19.30. **3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroiosoxazole [3,4-\(d\)]pyridazine-4-carboxylic acid (3-methoxyphenyl)amide, 8k. ** Yield = 66%; mp = 161-163 \({}^{\circ}\)C dec. (EtOH); 1H-NMR (400 MHz, CDCl\({}_{3}\))(s, 3H, OCH\({}_{3}\)), 4.28 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.75 (d, 1H, CH=CHN), \(J\) = 16 Hz), 7.19 (m, 1H, Ar), 7.33 (m, 2H, Ar), 7.42 (s, 1H, Ar), 7.60 (m, 1H, CH=CHN), 9.05 (exch br s, 1H, NH). Anal. Calcd for C\({}_{19}\)H\({}_{21}\)N\({}_{5}\)O\({}_{4}\): C, 59.52; H, 5.52; N, 18.27. Found C, 59.68; H, 5.50; N, 18.31. **3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid [2-(3,4-dimethoxyyphenyl)ethyllamide, 8l. Yield = 69%; mp = 165-167 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) & 1.33 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.89 (t, 2H, NHCH\({}_{2}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 3.10 (s, 6H, (CH\({}_{3}\))\({}_{2}\)N), 3.67 (m, 2H, NHCH\({}_{2}\)CH\({}_{2}\)), 3.87 (s, 6H, 2 OCH\({}_{3}\)), 4.18 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.78-6.85 (m, 3H: 1H, CH=CHN; 2H, Ar), 7.28 (s, 1H, Ar), 7.63 (m, 1H, CH=CHN), 9.10 (exch br s, 1H, NH). Anal. Calcd for C\({}_{22}\)H\({}_{27}\)N\({}_{5}\)O\({}_{5}\): C, 59.85; H, 6.16; N, 15.86. Found C, 59.97; H, 6.15; N, 15.80. **3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid (3-methoxybenzyl)methylamide, 8m. Yield = 72%; oil; \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) & 1.26 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 1.39 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.90 (s, 3H, NCH\({}_{3}\)), 2.98 (s, 3H, NCH\({}_{3}\)), 3.06 (s, 6H, N(CH\({}_{3}\))\({}_{2}\)), 3.08 (s, 6H, N(CH\({}_{3}\))\({}_{2}\)), 3.88 (s, 3H, OCH\({}_{3}\)), 4.10 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.21(q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.60 (s, 2H, NCH\({}_{2}\)), 4.76 (s, 2H, NCH\({}_{2}\)), 5.40 (m, 2H, CH=CHN), 6.81-6.91 (m, 6H, Ar), 7.24 (m, 2H, Ar), 7.58 (m, 2H, CH=CHN). Anal. Calcd for C\({}_{21}\)H\({}_{25}\)N\({}_{5}\)O\({}_{4}\): C, 61.30; H, 6.12; N, 17.02. **3-[3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carbonyl]amino]benzoic acid ethyl ester, 8n. Yield = 80%; mp = 192-193 \({}^{\circ}\)C dec. (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) & 1.40-1.50 (m, 6H: 3H, CH\({}_{3}\)CH\({}_{2}\)N; 3H, CH\({}_{3}\)CH\({}_{2}\)O), 3.13 (s, 6H, N(CH\({}_{3}\))\({}_{2}\)), 4.28 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 4.45 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)O, \(J\) = 7.2 Hz), 6.22 (m, 1H, CH=CHN), 7.50 (t, 1H, Ar, \(J\) = 8.0 Hz), 7.67 (m, 1H, CH=CHN), 7.88 (d, 1H, Ar, \(J\) = 7.6 Hz), 8.10 (m, 1H, Ar), 8.20 (s, 1H, Ar), 9.15 (exch br s, 1H, NH). Anal. Calcd for C\({}_{21}\)H\({}_{23}\)N\({}_{5}\)O\({}_{5}\): C, 59.29; H, 5.45; N, 16.46. Found C, 59.40; H, 5.44; N, 16.51. **3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid benzylamide, 8o. ** Yield = 63%; mp = 158-160 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) & 1.43 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 3.10 (s, 6H, N(CH\({}_{3}\))\({}_{2}\)), 4.31 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 4.65 (m, 2H, NHCH\({}_{2}\)Ph), 7.28-7.40 (m, 5H, Ar), 8.28 (exch br s, 1H, NH). Anal. Calcd for C\({}_{19}\)H\({}_{21}\)N\({}_{5}\)O\({}_{3}\): C, 62.11; H, 5.76; N, 19.06.