# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
**  
**6-Ethyl-3-methyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid (3-methoxybenzyl)methylamide, 7l** Yield = 88%; oil; \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.23 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 1.35 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 2.76 (s, 3H, C3-CH\({}_{3}\)), 2.78 (s, 3H, C3-CH\({}_{3}\)), 3.11 (s, 3H, NCH\({}_{3}\)), 3.12 (s, 3H, NCH\({}_{3}\)), 3.77 (s, 3H, OCH\({}_{3}\)), 3.80 (s, 3H, OCH\({}_{3}\)), 4.07 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 4.20 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 4.69 (s, 2H, NCH\({}_{2}\)Ph), 4.74 (s, 2H, NCH\({}_{2}\)Ph), 6.77-6.90 (m, 6H, Ar), 7.22-7.28 (m, 2H, Ar). Anal. Calcd for C\({}_{18}\)H\({}_{20}\)N\({}_{4}\)O\({}_{4}\): C, 60.66; H, 5.66; N, 15.72. Found C, 60.82; H, 5.65; N, 15.78. **  
**3-[(6-Ethyl-3-methyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carbonyl] amino]benzoic acid ethyl ester, 7m. Yield = 84%; mp = 156-157 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.47 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 1.50 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)O, \(J\) = 7.2 Hz), 3.20 (s, 3H, C3-CH\({}_{3}\)), 4.36 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 4.44 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)O, \(J\) = 7.2 Hz), 7.52 (t, 1H, Ar), \(J\) = 8 Hz), 7.89 (d, 1H, Ar, \(J\) = 7.6 Hz), 8.13 (d, 2H, Ar, \(J\) = 8 Hz), 8.15 (s, 1H, Ar), 9.02 (exch br s, 1H, NH). Anal. Calcd for C\({}_{18}\)H\({}_{18}\)N\({}_{4}\)O\({}_{5}\): C, 58.37; H, 4.90; N, 15.13. Found C, 58.21; H, 4.90; N, 15.17. **  
**6-Ethyl-3-methyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid benzylamide, 7n. Yield = 75%; mp = 140-142 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.46 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.80 (s, 3H, C3-CH\({}_{3}\)), 4.28 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 4.63 (m, 2H, NHCH\({}_{2}\)Ph), 7.36-7.52 (m, 5H, Ar), 8.87 (exch br s, 1H, NH). Anal. Calcd for C\({}_{16}\)H\({}_{16}\)N\({}_{4}\)O\({}_{3}\): C, 61.53; H, 5.16; N, 17.94. Found C, 61.41; H, 5.15; N, 17.97. **  
**General Procedure for 8a, 8c-o. ** A suspension of 7a-n (0.72 mmol) in N,N-dimethylformammide dimethyl acetal (7.53-15.06 mmol) was stirred at 100 \({}^{\circ}\)C for 30-60 min. The mixture was cooled, and the compounds 8a, 8h-i, 8k-l and 8n-o were recovered by _vacuum_ filtration. For compounds 8c-g, 8j, and 8m, after cooling, the mixture was diluted with cold water (10 mL), and the suspension was extracted with CH\({}_{2}\)Cl\({}_{2}\) (3 \(\times\) 15 mL). Evaporation of the solvent afforded the desired compounds. Compound 8j was purified by flash column chromatography using CH\({}_{2}\)Cl\({}_{2}\)/CH\({}_{3}\)OH 9.5:0.5 as eluent. **3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid diethylamide, 8a. Yield = 75%; mp = 178-180 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) \(\delta\) 1.25 (t, 3H, CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 6.8 Hz), 1.32 (t, 3H, CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 1.37 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 3.00 (s, 6H, N(CH\({}_{3}\))\({}_{2}\)), 3.35 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 6.8 Hz), 2.60 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 6.8 Hz), 4.20 (q, 2H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 7.2 Hz), 5.25 (m, 1H, CH\({}_{3}\)CH\({}_{2}\)), 7.58 (m, 1H, CH=CHN). Anal. Calcd for C\({}_{16}\)H\({}_{23}\)N\({}_{5}\)O\({}_{3}\): C, 57.64; H, 6.95; N, 21.01. Found C, 57.96; H, 4.94; N, 21.07. **  
**3-(2-Dimethylaminovinyl)-6-ethyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid benzylmethylamide, 8c.