# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
** Yield = 82%; oil; 1\({}^{\rm H}\)-NMR (400 MHz, CDCl3) \(\delta\) 0.87 (t, 3H, CH3(CH2)4N, \(J\) = 6.8 Hz), 0.96 (t, 3H, CH3(CH2)4N, \(J\) = 6.8 Hz), 1.18-1.36 (m, 8H, CH3(CH2)2 CH2), 1.38 (t, 6H, CH3 CH2N, \(J\) = 7.2 Hz), 1.70 (m, 4H, CH3(CH2)2 CH2 CH2N), 2.77 (s, 3H, C3-CH3), 2.79 (s, 3H, C3-CH3), 3.15 (s, 3H, NCH3), 3.16 (s, 3H, NCH3), 3.45 (t, 2H, NCH2(CH2)2 CH2), \(J\) = 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 ethylpentylamide, 7. ** Yield = 82%; oil; 1\({}^{\rm H}\)-NMR (400 MHz, CDCl3) \(\delta\) 0.87 (t, 3H, CH3(CH2)4N, \(J\) = 6.8 Hz), 0.96 (t, 3H, CH3(CH2)4N, \(J\) = 6.8 Hz), 1.08-1.36 (m, 8H, CH3(CH2)2 CH2), 1.38 (t, 6H, CH3 CH2N, \(J\) = 7.2 Hz), 1.07 (m, 4H, CH3(CH2)2 CH2 CH2N), 2.77 (s, 3H, C3-CH3), 2.79 (s, 3H, C3-CH3), 3.15 (s, 3H, NCH3), 3.36 (s, 3H, NCH3), 3.45 (t, 2H, NCH2(CH2)3 CH3, \(J\) = 7.6 Hz), 3.58 (t, 2H, NCH2(CH2)3, \(J\) = 7.6 Hz), 4.24 (m, 4H, CH3 CH2N). Anal. Calcd for C15H22N4O3: C, 58.81; H, 7.24; N, 18.24. **6-Ethyl-3-methyl-7-oxo-6,7-dihydroiosoxazole [3,4-d]pyridazine-4-carboxylic acid ethylmethylamide, 7. ** Yield = 66%; mp = 82-85 \({}^{\circ}\)C (EtOH); 1\({}^{\rm H}\)-NMR (400 MHz, CDCl3) \(\delta\) 1.30 (t, 6H, CH3 CH2N,CO, \(J\) = 6.8 Hz), 1.40 (t, 6H, CH3 CH2N, \(J\) = 7.2 Hz), 2.79 (s, 3H, C3-CH3), 2.80 (s, 3H, C3-CH3), 3.15 (s, 6H, NCH3), 3.50 (q, 2H, CH3 CH2 NCO, \(J\) = 6.8 Hz), 3.65 (q, 2H, CH3 CH2 NCO, \(J\) = 7.2 Hz), 4.24 (q, 4H, CH3 CH2N, \(J\) = 6.8 Hz). Anal. Calcd for C12H16N4O3: C, 54.54; H, 6.10; N, 21.20. Found C, 54.43; H, 6.11; N, 21.15. **6-Ethyl-3-methyl-4-(4-phenylpiperazine-1-carbonyl)lyisoxazole [3,4-d]pyridazine-7(6H)-one, 7. ** Yield = 86%; mp = 166-168 \({}^{\circ}\)C (EtOH); 1\({}^{\rm H}\)-NMR (400 MHz, CDCl3) \(\delta\) 1.39 (t, 3H, CH3 CH2, \(J\) = 7.2 Hz), 2.83 (s, 3H, C3-CH3), 3.31-3.37 (m, 4H, piperazine), 3.98 (m, 2H, piperazine), 4.06 (m, 2H, piperazine), 4.24 (q, 2H, CH3 CH2, \(J\) = 7.2 Hz), 6.95-7.06 (m, 3H, Ar), 7.37 (m, 2H, Ar). Anal. Calcd for C19H21N5O3: C, 62.11; H, 5.76; N, 19.06. Found C, 62.29; H, 5.77; N, 19.02. **4-(4-Benzylpiperazine-1-carbonyl)-6-ethyl-3-methylisoxazole [3,4-d]pyridazine-7(6H)-one, 7. ** Yield = 77%; mp = 118-120 \({}^{\circ}\)C (EtOH); 1\({}^{\rm H}\)-NMR (400 MHz, DMSO-d\({}_{\delta}\)) \(\delta\) 1.25 (t, 3H, CH3 CH2, \(J\) = 7.2 Hz), 2.36 (m, 2H, piperazine), 2.54 (m, 2H, piperazine), 2.70 (s, 3H, C3-CH3), 3.52 (s, 2H, NCH2 Ph), 3.57 (m, 2H, piperazine), 3.70 (m, 2H, piperazine), 4.06 (q, 2H, CH3 CH2, \(J\) = 6.8 Hz), 7.26-7.34 (m, 5H, Ar). Anal. Calcd for C20H23N5O3: C, 62.98; H, 6.08; N, 18.36. Found C, 63.20; H, 6.09; N, 18.41. **6-Ethyl-3-methyl-7-oxo-6,7-dihydroiosoxazole [3,4-d]pyridazine-4-carboxylic acid (3-methoxy)amide, 7. ** Yield = 88%; mp = 178-180 \({}^{\circ}\)C (EtOH); 1\({}^{\rm H}\)-NMR (400 MHz, CDCl3) \(\delta\) 1.48 (t, 3H, CH3 CH2, \(J\) = 7.2 Hz), 3.19 (s, 3H, C3-CH3), 3.88 (s, 3H, OCH3), 4.34 (q, 2H, CH3 CH2, \(J\) = 7.2 Hz), 6.77 (m, 1H, Ar), 7.18 (m, 1H, Ar), 7.33 (t, 1H, Ar, = 8.0 Hz), 7.39 (s, 1H, Ar), 8.88 (exch br s, 1H, NH). Anal. Calcd for C16H16N4O4: C, 58.53; H, 4.91; N, 17.06. Found C, 58.69; H, 4.90; N, 17.01. **6-Ethyl-3-methyl-7-oxo-6,7-dihydroisoxazole [3,4-d]pyridazine-4-carboxylic acid [2-G,4-dimethoxyyphenyl)ethyl]amide, 7k. Yield = 78%; mp = 142-144 \({}^{\circ}\)C (EtOH); \({}^{1}\)H-NMR (400 MHz, DMSO-d\({}_{6}\)) \(\delta\) 1.32 (t, 3H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 2.79 (t, 2H, NHCH\({}_{2}\)CH\({}_{2}\), \(J\) = 6.8 Hz ), 2.95 (s, 3H, C3-CH\({}_{3}\)), 3.48 (m, 2H, NHCH\({}_{2}\)CH\({}_{2}\)), 3.71 (s, 3H, OCH\({}_{3}\)), 3.37 (s, 3H, OCH\({}_{3}\)), 4.12 (q, 2H, CH\({}_{3}\)CH\({}_{2}\), \(J\) = 7.2 Hz), 6.75-6.88 (m, 3H, Ar), 8.62 (exch br s, 1H, NH). Anal. Calcd for C\({}_{19}\)H\({}_{22}\)N\({}_{4}\)O\({}_{5}\): C, 59.06; H, 5.74; N, 14.50. Found C, 59.22; H, 5.73; N, 14.54.