2//-Pyrazolo pyridazin-7-ones

Palladium-catalyzed [3+3] cycloaddition of (2-(acetoxymethyl)-2-propenyl)-trimethylsilane with azomethine imi-nes, for example, l-benzylidene-3-oxopyrazolidin-l-ium-2-ides, leading to appropriately substituted hexahydro-7-methylene-177-pyrazolo[l,2- ]pyridazin-l-ones has been reported <2006JA6330>. 

A novel class of tricyclic lymphocyte specific kinase (Lck) inhibitors containing the 9,10-dihydro-8//-pyrazolo[l,2-tf]pyrimido[4,5-c]pyridazin-8-one moiety has been reported <2006BML4257, 2006H(68)2037>. The most promising compound, 708, advanced to pharmacokinetic evaluation <2006BML4257>. 

Four aromatic pyrazolopyridazines (1-4, l -pyrazolo[3,4-]pyridazine, respectively) and one pyrazolopyri-... 

The 1,3-dipolar cycloaddition of diarylnitrile imines 98, generated in situ from arylhydrazones with chloramine T or from a-chlorobenzylidenephenylhydrazine with triethylamine, to some 5-substituted 2-methylpyridazin-3(2//)-ones 88, 99-101 has been shown to afford l,3-diaryl-l,5-dihydro-4//-pyrazolo[3,4- ]pyridazin-4-ones 102 regioselectively (Scheme 21) <2000JMT(528)13>. 

Stanovnik and co-workers (100,101) systematically investigated the cycloaddition reactions of diazoalkanes with unsaturated nitrogen heterocycles, such as azolo-[l,5-fl]pyridines, pyridazin-3(2/7)-ones, and [fo]-fused azolo- and azinopyridazines. The Stanovnik group have studied the further transformations of the products and reviews of this chemistry are available. In a typical example, the reaction of 6-chlorotetrazolo[l,5-/7]pyridazine (37) with 2-diazopropane yields the NH,NH-dihy-dro-pyrazolo[4,3-(i]tetrazolo[l,5-/7]pyridazine 38 (102) (Scheme 8.11). The latter substrate reacts with acetone to produce an azomethine imine 39 that thermally rearranges to give the fused dihydro-1,2-diazepine 40. The azomethine imine obtained with glucose can be trapped with methyl acrylate to furnish the C-nucleoside 41 (103). 

A series of pyrazolo[3,4-, pyridazinones 430 and analogues, potentially useful as peripheral vasodilators, were synthesized and evaluated as inhibitors of PDE5 extracted from human platelets. Several of them showed ICso values in the range 0.14-1.4 pM. A good activity and selectivity profile versus PDE6 was found for compound 430 (6-benzyl-3-methyl-l-isopropyl-4-phenylpyrazolo[3,4-r/]pyridazin-7(6/7)-one). Structure-activity relationship studies demonstrated the essential role played by the benzyl group at position 6 of the pyrazolopyridazine system. Other types of pyridazinones fused with five- and six-membered heterocycles (pyrrole, isoxazole, pyridine, and dihydropyridine), as well as some open-chain models were prepared and evaluated. Besides the pyrazole, the best of the fused systems proved to be isoxazole and pyridine <2002MI227>. 

Disubstituted and 1,3,5-trisubstituted l/7-pyrazolo[3,4-d]pyridazin-4(5//)-ones (200) can be synthesized by irradiation of 5-(l-alkyl-2-alkylidenehydrazino)-4-chloro-3(2//)-pyridazinones (199) in benzene or acetone (equation 146)589. Eighteen derivatives of... 

Thermal 1,5-sigmatropic rearrangement of the methyl groups in 3,3-dimethyl-3//-pyrazolo[3,4-c ]pyridazin-4(5H)-ones (93) gives the N-2 methylated product (94) and the C-3a methylated product (95) (Equation (4)) <91JHC425>. 

Another strategy is the conversion of isoxazolo[3,4-d]pyridazin-7(6//)-ones (63) via pyrazole derivatives (64) into the new pyrazolo[l, 5 l,6]pyrimido[4,5-c/]pyridazin-7(8//)-ones (65) by final ring closure with acetic anhydride (Scheme 12) <86H(24)3143>. 

Diazoninones 64 were synthesized by reduction of hexahydro-l//-pyrazolo[l,2-tf]pyridazin-l-ones with sodium in liquid ammonia (Scheme 7, Section 14.10.5.2.1) <2000CL1104, 2002T7177>. One of the synthetic routes for the preparation of diazoninone 291 includes reduction of dihydropyrimidinone 292 (Scheme 53) <2002T7177>. 

Pyridazine and its fused derivatives react readily with diphenylcyclopropenethione to give pyrazolo[l,2-a]pyridazines. The derivatives of diphenylcyclopropenone are sometimes also available (Scheme 108). The proximity of the sulfur or oxygen atom to one of the aromatic protons causes a considerable downfield shift, as shown in Scheme 108 (71CJC3119). 

AMI semiempirical calculations have shown that, as far as tautomerism is concerned, there is a structural relationship between jS-dicarbonyl compounds and NH-pyrazoles, and in a wide variety of NH-pyrazoles studied " the most stable tautomer was found to be that having the largest single-bond character between the C(3)—C(4) bond. The problem of proton transfer in NH-pyrazole crystals has been subjected to a detailed theoretical study, while a study of the tautomerism of 2-aryl and 2-heteroaryl derivatives of benzimidazole has indicated that tautomerism takes place by the intermolecular relay of protons between stacked molecules. The first report of the stable co-existence of two different histidine tautomers in one peptide crystal structure has appeared. Ab initio calculations have been used to study the tautomerism of both histamine and pyrazolo[3,4-i/]pyridazine in the gas phase and in aqueous solution, and a theoretical study of the NH tautomerism in free-base porphyrin has been undertaken. ... 

---