# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 3 Results and Discussion  
### Chemistry  
All the final compounds **3a-g**, **5a-d** (quinoline-based, Schemes 1 and 2), and **10a-p** (pyrazol [1\({}^{\prime}\),5\({}^{\prime}\):1.6])pyrimidino [4,5\({}^{\prime}\)-d]pyridazin-4(3\(H\))-ones, Scheme 3 and Tables 1-3) were synthesized following an established synthetic procedure previously described by us and the chemical structures were assigned on the basis of spectral data which are in agreement with those of already published analogues [20; 29; 30]. In Scheme 1, the synthetic pathway affording the final compounds **3a-g** is reported, which are functionalized with various amides in position 3. The treatment of commercially available intermediate **1** with thinyl chloride and the subsequent addition of the suitable amines, in the presence of triethylamine in anhydrous tetrahydrofuran, yielded derivatives **2a-g**. The displacement of the chlorine at position 4 of the quinolines **2a-g**, to obtain the final compounds **3a-g**, was carried out with 4-methoxyaniline in solution at reflux. Scheme 2 shows the introduction of an additional amide group on the phenyl at position 4 of the 3-carboxyamidequinoline nucleus. To this end, the intermediate **4**[20] was treated with suitable alkyl amines in anhydrous tetrahydrofuran, triethylamine, and ethyl chloroform to afford the target amides **5a-d**. Scheme 3 depicts the synthetic route to obtain the final pyrazolo [1\({}^{\prime}\),5\({}^{\prime}\):1.6]pyrimidino [4,5\({}^{\prime}\)-pyridazin-4(3\(H\))-ones of type **10**. The reaction of 6-ethyl-3-methyl-7-oxo-dihydroosoxazole [3.4-\(d\)/pyridazine-4-carboxylic acid **6**[19] with SOCI\({}_{2}\), Et\({}_{3}\)N and appropriate alkyl or arylamine in anhydrous THF, furnished the 4-carboxyamides **7a-n** which were transformed in the vinyl derivatives **8a-o** with \(N\),\(N\)-dimethylformammide dimethyl acetal (compounds **8a** and **8c-o**) or with 3-furylaldehyde and CH\({}_{3}\)ONa in anhydrous CH\({}_{3}\)OH (**8b**). The treatment of **8a-o** with hydrazine hydrate in ethanol afforded the 4-amino-5-pyrazolyl derivatives (**9a-o**) in good yields. These latter were lastly cyclized to pyrazolo [1',5':1.6]pyrimidin [4,5-\(d\)]pyridazin-4(3\(H\))-ones as follows: acetic anhydride and a catalytic amount of concentrated H\({}_{2}\)SO\({}_{4}\) was used at room temperature to obtain the 6-methylderivatives **10a**, **10c**,**d**, **10f-i**, **10p**,**q**, while the 6-unsubstituted **10b**, **10c** and **10j-o** were obtained by treatment with triethyltortoformate in anhydrous DMF in the presence of a catalytic amount of concentrated H\({}_{2}\)SO\({}_{4}\) at room temperature. **Scheme 1. Reactions and conditions: (a) step 1: SOCI\({}_{2}\) reflux, 4-5 h; step 2: suitable amine, NEr\({}_{3}\), anhydrous THF, 0 \({}^{\circ}\)C, 2 h, then r.t., 24 h; (b) 3-methoxyaniline, anhydrous CH\({}_{3}\)CN, reflux, 4 h.**  
**Scheme 2. Reactions and conditions: (a) step 1: anhydrous THF, NEI\({}_{3}\), \(-5/-7\)\({}^{\circ}\)C, 30 min; step 2: ethyl chloroformate, 0 \({}^{\circ}\)C, 1 h; step 3: appropriate R-alkylamine, r.t., o/n. **  
**Figure 3. Reagents and conditions: (a) step 1: SOCI\({}_{2}\), Et\({}_{3}\)N, reflux, 2 h; step 2: anhydrous THF, alkyl(aryl)amine, r.t., 30 min; (b) DMDA, reflux, 30–60 min; for **8b**: 3-furylaldehyde, CH\({}_{3}\)ONA, anhydrous CH\({}_{3}\)OH, reflux, 10 min; (c) NH\({}_{2}\)NH\({}_{2}\), EtOH, r.t.-60 \({}^{\circ}\)C, 1–8 h; (d) 2N NaOH, EtOH, rt, 15 min; (e) for R\({}_{6}\) = H: triethyl orthoformate, H\({}_{2}\)SO\({}_{4}\) conc., anhydrous DMF, r.t., 10–30 min; for R\({}_{6}\) = CH\({}_{3}\): acetic anhydride, r.t., 10–30 min. **Table 1.** R residues for compounds **