# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 2 Materials and Methods
### Chemistry
**4-Chloro-8-methyl-N-(4-methylpiperazine-1-yl)quinoline-3-carboxamide, 2a. ** Yield = 44%; mp = 206-207 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, CD\({}_{3}\)OD-d\({}_{4}\)) 8 2.33 (s, 3H, CH\({}_{3}\) piperazine), 2.60-2.70 (m, 4H, 2 \(\times\) CH\({}_{2}\) piperazine), 2.79 (s, 3H, CH\({}_{3}\)), 2.90-3.10 (m, 4H, 2 \(\times\) CH\({}_{2}\) piperazine), 7.76 (t, 1H, Ar, \(J\) = 8.4 Hz), 7.76 (d, 1H, Ar, \(J\) = 7.2 Hz), 8.20 (d, 1H, Ar, \(J\) = 8.4 Hz), 8.81 (s, 1H, Ar). Anal. Calcd for C\({}_{16}\)H\({}_{19}\)ClN\({}_{4}\)O: C, 60.28; H, 6.01; N, 17.57. Found C, 60.52; H, 6.03; N, 17.64. **4-Chloro-N-(2-hydroxyethyl)-8-methylquinoline-3-carboxamide, 2b. ** Yield = 98%; mp = 142-143 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, CDCl\({}_{3}\)) 8 2.81 (s, 3H, CH\({}_{3}\)), 3.73 (s, 2H, CH\({}_{2}\)), 3.91 (s, 2H, CH\({}_{2}\)), 6.78 (exch br s, 1H, NH), 7.58 (t, 1H, Ar, \(J\) = 8.4 Hz), 7.66 (d, 1H, Ar, \(J\) = 7.6 Hz), 8.15 (d, 1H, Ar, \(J\) = 7.6 Hz), 9.06 (s, 1H, Ar). Anal. Calcd for C\({}_{13}\)H\({}_{13}\)ClN\({}_{2}\)O\({}_{2}\): C, 58.99; H, 4.95; N, 10.58. Found C, 58.75; H, 4.93; N, 10.54. **4-Chloro-8-methyl-N-propylquinoline-3-carboxamide, 2c. ** Yield = 97%; mp = 121-124 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.04 (t, 3H, NHCH\({}_{2}\)CH\({}_{2}\)CH\({}_{3}\), \(J\) = 6.8 Hz), 1.68-1.74 (m, 2H, NHCH\({}_{2}\)CH\({}_{2}\)CH\({}_{3}\)), 2.81 (s, 3H, CH\({}_{3}\)), 3.48-3.53 (m, 2H, NHCH\({}_{2}\)CH\({}_{2}\)CH\({}_{3}\)), 6.28 (exch br s, 1H, NH), 7.58 (t, 1H, Ar, \(J\) = 7.6 Hz), 7.66 (d, 1H, Ar, \(J\) = 7.6 Hz), 8.16 (d, 1H, Ar, \(J\) = 8.0 Hz), 9.04 (s, 1H, Ar). Anal. Calcd for C\({}_{14}\)H\({}_{15}\)ClN\({}_{2}\)O: C, 64.00; H, 5.75; N, 10.66. Found C, 64.25; H, 5.77; N, 10.70. **(4-Chloro-8-methylquinoline-3-yl)(4-methylpiperazine-1-yl)methananone, 2d. ** Yield = 98%; mp = 170-172 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, CDCl\({}_{3}\)) 8 2.33 (s, 3H, CH\({}_{3}\) piperazine), 2.40-2.49 (m, 2H, CH\({}_{2}\) piperazine), 2.50-2.60 (m, 2H, CH\({}_{2}\) piperazine), 2.81 (s, 3H, CH\({}_{3}\)), 3.25-3.35 (m, 2H, CH\({}_{2}\) piperazine), 3.38-3.95 (m, 2H, CH\({}_{2}\) piperazine), 7.58 (t, 1H, Ar, \(J\) = 7.2 Hz), 7.66 (d, 1H, Ar, \(J\) = 7.2 Hz), 8.13 (d, 1H, Ar, \(J\) = 8.4 Hz), 8.75 (s, 1H, Ar). Anal. Calcd for C\({}_{16}\)H\({}_{18}\)ClN\({}_{3}\)O: C, 63.26; H, 5.97; N, 13.83. Found C, 63.51; H, 5.99; N, 13.88. **4-Chloro-N-heptyl-8-methylquinoline-3-carboxamide, 2e. ** Yield = 42%; mp = 95-97 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, CDCl\({}_{3}\)) 8 0.86 (t, 3H, CH\({}_{2}\)CH\({}_{3}\), \(J\) = 6.8 Hz), 1.27-1.36 (m, 8H, 4 \(\times\) CH\({}_{2}\)), 1.50-1.57 (m, 2H, CH\({}_{2}\)), 2.74 (s, 3H, CH\({}_{3}\)), 3.28 (t, 2H, NHCH\({}_{2}\), \(J\) = 6.8 Hz), 7.69 (t, 1H, Ar, \(J\) = 7.8 Hz), 7.77 (d, 1H, Ar, \(J\) = 6.8 Hz), 8.12 (d, 1H, Ar, \(J\) = 8.4 Hz), 8.67 (exch br t, 1H, NH, \(J\) = 5.4 Hz), 8.82 (s, 1H, Ar). Anal. Calcd for C\({}_{18}\)H\({}_{23}\)ClN\({}_{2}\)O: C, 67.81; H, 7.27; N, 8.79. Found C, 67.54; H, 7.24; N, 8.75. **4-Chloro-8-methyl-N-undcyclquinoline-3-carboxamide, 2f. ** Yield = 72%; mp = 101-102 \({}^{\circ}\)C (EtOH); 1H-NMR (400 MHz, DMSO-d\({}_{6}\)) 8 0.83 (t, 3H, -CH\({}_{2}\)CH\({}_{3}\), \(J\) = 6.8 Hz), 1.20-1.40 (m, 16H, 8 \(\times\) CH\({}_{2}\)), 1.50-1.57 (m, 2H, CH\({}_{2}\)), 2.74 (s, 3H, CH\({}_{3}\)), 3.28 (t, 2H, -NHCH\({}_{2}\)-, \(J\) = 6.8 Hz), 7.69 (t, 1H, Ar, \(J\) = 7.8 Hz), 7.77 (d, 1H, Ar, \(J\) = 7.2 Hz), 8.12 (d, 1H, Ar, \(J\) = 8.4 Hz), 8.67 (exch br t, 1H, NH, \(J\) = 5.4 Hz), 8.82 (s, 1H, Ar). Anal. Calcd for C\({}_{22}\)H\({}_{31}\)ClN\({}_{2}\)O: C, 70.47; H, 8.33; N, 7.47. Found C, 70.18; H, 8.36; N, 7.49. **4-Chloro-N-(2-hydroxyethyl)ethyl-8-methylquinoline-3-carboxamide, 2g. ** Yield = 98%; yellow oil. 1\({}^{\circ}\)H-NMR (400 MHz, CDCl\({}_{3}\)) 8 1.09 (exch br t, 3H, OH, \(J\) = 2.8 Hz), 2.64 (s, 3H, CH\({}_{3}\)), 3.48-3.65 (m, 8H, 2 \(\times\) CH\({}_{2}\)), 7.37 (t, 1H, Ar, \(J\) = 7.2 Hz), 7.47 (d, 1H, Ar, \(J\) = 6.4 Hz), 7.67 (exch br s, 1H, NH), 7.88 (d, 1H, Ar, \(J\) = 8.4 Hz), 8.78 (s, 1H, Ar). Anal.