# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
Calcd for C\({}_{21}\)H\({}_{22}\)N\({}_{4}\)O\({}_{4}\): C, 63.95; H, 5.62; N, 14.20. Found C, 63.69; H, 5.60; N, 14.14. **General procedure for 7a-n.** A mixture of compound 6 [19] (0.92 mmol), SOC\({}_{2}\) (2-3 mL), and a catalytic amount of Et\({}_{3}\)N was refluxed for 2 h. After cooling, the excess of SOCI\({}_{2}\) was removed in vacuo, the residue was dissolved in anhydrous THF (2-3 mL), and appropriate alkyl(aryl)amine was added (1.40-2.30 mmol). The mixture was stirred for 30-40 min at room temperature. After evaporation of the solvent, ice-cold water (20-30 mL) was added, and compounds 7a, 7h, 7j, 7k, and 7m were recovered by vacuum filtration, while compounds 7b-g, 7i, 7l, and 7n were recovered by extraction with CH\({}_{2}\)Cl\({}_{2}\) (3 \(\times\) 15 mL). The crude products were purified by crystallization with a suitable solvent or by flash column chromatography to obtain the desired compounds. **6-Ethyl-3-methyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid diethylamide, 7a. ** Yield = 61%; mp = 98-101 \({}^{\circ}\)C (Cyclohexane); 1\({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.40 (m, 6H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N), 1.45 (t, 3H, CH\({}_{3}\)CH\({}_{2}\)N, \(J\) = 6.8 Hz), 2.75 (s, 3H, C\({}_{3}\)-CH\({}_{3}\)), 3.40 (q, 2H, (CH\({}_{3}\)CH\({}_{2}\))\({}_{2}\)N, \(J\) = 7.2 Hz), 3.60 (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). Anal. Calcd for C\({}_{13}\)H\({}_{18}\)N\({}_{4}\)O\({}_{3}\): C, 56.10; H, 6.52; N, 20.13. Found C, 56.23; H, 6.53; N, 20.19. **6-Ethyl-3-methyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid benzylmethylamide, 7b. ** Yield = 83%; oil; \({}^{1}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.22 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz) 1.38 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 6.8 Hz), 2.79 (s, 3H, C\({}_{3}\)-CH\({}_{3}\)), 2.80 (s, 3H, C\({}_{3}\)-CH\({}_{3}\)), 3.12 (s, 3H, NCH\({}_{3}\)), 3.15 (s, 3H, NCH\({}_{3}\)), 4.08 (q, 2H, CH\({}_{2}\)CH\({}_{3}\), \(J\) = 7.2 Hz), 4.24 (q, 2H, CH\({}_{2}\)CH\({}_{3}\), \(J\) = 7.2 Hz), 4.74 (s, 2H, NCH\({}_{2}\)Ph), 4.80 (s, 2H, NCH\({}_{2}\)Ph), 7.23-7.40 (m, 10H, Ar). Anal. Calcd for C\({}_{17}\)H\({}_{18}\)N\({}_{4}\)O\({}_{3}\): C, 62.57; H, 5.56; N, 17.17. Found C, 62.43; H, 5.57; N, 17.22. **6-Ethyl-3-methyl-4-(morpholine-4-carbonyl)isoxazole [3,4-d]pyridazine-7(6H)-one,7c. ** Yield = 95%; mp =line), 4.20 (q, 2H, NCH2 CH3, \(J\) = 7.0 Hz). Anal. Calcd for C13H16N4O4: C, 53.42; H, 5.52; N, 19.17. Found C, 53.54; H, 5.52; N, 19.12. **6-Ethyl-3-methyl-7-oxo-6,7-dihydroiosoxazole [3,4-d]pyridazine-4-carboxylic acid methylpropylamide, 7. ** Yield = 66%; oil; 1\({}^{\rm H}\)-NMR (400 MHz, CDCl3) \(\delta\) 0.85 (t, 3H, CH3 CH2 CH2N, \(J\) = 7.2 Hz), 0.99 (t, 3H, CH3 CH2 CH2N, \(J\) = 7.2 Hz), 1.35 (t, 6H, CH3 CH2N, \(J\) = 7.2 Hz), 1.67-1.74 (m, 4H, CH3 CH2 CH2N), 2.75 (s, 3H, C3-CH3), 2.76 (s, 3H, C3-CH3), 3.13 (s, 3H, NCH3), 3.14 (s, 3H, NCH3), 3.41 (t, 2H, NCH2 CH3, \(J\) = 7.2 Hz), 3.54 (t, 2H, NCH2 CH2 CH3, \(J\) = 7.2 Hz), 4.20 (m, 4H, NCH2 CH3). Anal. Calcd for C13H18N4O3: C, 56.10; H, 6.52; N, 20.13. Found C, 56.23; H, 6.53; N, 20.19. **6-Ethyl-3-methyl-7-oxo-6,7-dihydroiosoxazole [3,4-d]pyridazine-4-carboxylic acid butylmethyl amide, 7. ** Yield = 41%; oil; 1\({}^{\rm H}\)-NMR (400 MHz, CDCl3) \(\delta\) 0.88 (t, 3H, CH3(CH2)3N, \(J\) = 6.8 Hz), 1.03 (t, 3H, CH3(CH2)3N, \(J\) = 6.8 Hz), 1.25 (q, 2H, CH3 CH2(CH2)2, \(J\) = 7.6 Hz), 1.38 (t, 6H, CH3 CH2N, \(J\) = 7.2 Hz), 1.43 (q, 2H, CH3 CH2(CH2)2, \(J\) = 7.6 Hz), 1.68 (m, 4H, CH3 CH2 CH2 CH2N), 2.76 (s, 3H, C3-CH3), 3.278 (s, 3H, C3-CH3), 3.14 (s, 3H, NCH3), 3.15 (s, 3H, NCH3), 3.45 (t, 2H, NCH2(CH2)2 CH3, \(J\) = 7.6 Hz), 3.58 (t, 2H, NCH2(CH2)2 CH3, \(J\) = 7.6 Hz), 4.20 (m, 4H, NCH2 CH3). Anal. Calcd for C14H20N4O3: C, 57.52; H, 6.90; N, 19.17. Found C, 57.68; H, 6.91; N, 19.12. **6-Ethyl-3-methyl-7-oxo-6,7-dihydroiosoxazole [3,4-d]pyridazine-4-carboxylic acid methylpentylamide, 7.