# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 3 Results and Discussion
### Chemistry
\begin{table}
\begin{tabular}{c c c} \hline \hline
**Compd. 8–9** & **R1** & **R9** \\ \hline
**a** & \(-\)N(CH\({}_{2}\)CH\({}_{3}\))\({}_{2}\) & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**b** & \(-\)N(CH\({}_{2}\)CH\({}_{3}\))\({}_{2}\) & 3-furyl \\ \hline
**c** & \(-\)N(CH\({}_{3}\))CH\({}_{2}\)Ph & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**d** & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**e** & \(-\)N(CH\({}_{3}\))\({}_{C}\)H\({}_{7}\) & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**f** & \(-\)N(CH\({}_{3}\))\({}_{C}\)H\({}_{9}\) & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**g** & \(-\)N(CH\({}_{3}\))\({}_{C}\)H\({}_{11}\) & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**h** & \(-\)N(CH\({}_{3}\))\({}_{C}\)H\({}_{5}\) & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**i** & \(-\)N\(-\)N\(-\)Ph & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**j** & \(-\)N\(-\)N\(-\)CH\({}_{2}\)Pn & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**k** & \(-\)HN\(-\)N & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**l** & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**n** & \(-\)N\(-\)N\(-\)H & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline
**o** & \(-\)NHCH\({}_{2}\)Ph & \(-\)N(CH\({}_{3}\))\({}_{2}\) or H (**for 9**) \\ \hline \hline \end{tabular}
\end{table} 
Table 2: R residues for compounds 8a–o and 9a–o. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Compd. 10** & **R1** & **R9** & **R6** \\ \hline
**a** & \(-\)N(CH\({}_{2}\)CH\({}_{3}\))\({}_{2}\) & H & CH\({}_{3}\) \\ \hline
**b** & \(-\)N(CH\({}_{2}\)CH\({}_{3}\))\({}_{2}\) & H & H \\ \hline
**c** & \(-\)N(CH\({}_{2}\)CH\({}_{3}\))\({}_{2}\) & 3-furyl & CH\({}_{3}\) \\ \hline
**d** & \(-\)N(CH\({}_{3}\))CH\({}_{2}\)Ph & H & CH\({}_{3}\) \\ \hline
**e** & \(-\)N(CH\({}_{3}\))CH\({}_{2}\)Ph & H & H \\ \hline
**f** & \(-\)N(\(\;\  
Based on the data obtained for the quinoline-based compounds (**3a-g** and **5a-d**) (Table 4), we have carried out an evaluation of SARs to rationalise their inhibitory effects on PDE4, which appear to be influenced by the nature of the substituents at both R3 and R4 positions. For the compounds **3a-g** (with hydrogen in position R4, see general structure in Table 4), which feature various groups in R3, the inhibition is overall low. **3a** (R3 = 1-amino-4-methylpiperazine) determines a 46% inhibition at 1 uM (baseline), while for the primary alcohol **3b** (R3 = NH(CH2)2 OH), the activity increases to 64%, suggesting the introduction of a polar hydroxyethylamino group in this position enhances PDE4 binding. Derivatives **3c** (R3 = NH(CH2)2 CH3) and **3d** (R3 = \(N\),_N_'-dimethylpiperazine) have an effect in line with **3a**, confirming that the piperazine ring in this position lowers the activity in comparison to **3b**, as well as that replacing hydroxyl alcohol with a hydrophobic methyl decreases the inhibitory effect. Clearly, the presence of long hydrophobic chains is detrimental in this series, as demonstrated by compounds **3e** (R3 = NH(CH2)6 CH3) and **3f** (R3 = NH(CH2)10 CH3), which demonstrate a sharp drop (11%) or complete lack of inhibition. A low response has been also recorded for **3g** (R3 = NH(CH2)2-O-(CH2)2 OH) suggesting that increasing the length (or steric hindrance) of the substituent in R3 (although polar and flexible chains, like the hydroxyethyl) is detrimental for the activity (i.e., only 25% inhibition), which in this series results instead maximized with a smaller, shorter and polar hydroxyethyl group (**3b**). Differently, for the series **5a-d** (with a fixed NH2 in position R3, i.e., primary amides) featuring substitutions on the methoxy-aniline ring, we have recorded an overall moderate potency for **5a**, **5c** and **5d** (R4 = CONH(CH2)6 CH3, CONH(CH2)2-O-(CH2)2 OH, or NH(CH2)2 OH) with IC50 values in the low micromolar range (IC50 = 3.54-4.92 uM).