Imidazo pyridazines

The imidazo-pyridazine ring system forms the basis for a number of drugs in human and animal medicine. The synthesis of this system uses chemistry discussed in Chapter 43 to build the pyridazine ring. There we established that it was easy to make dichloropyridazines and to displace the chlorine... 

Imtdazo[4,5-d]pyridaztne, l-benzyl-4,7-dtchloro-nucleophtlic displacement reactions, 5, 629 Imidazo[l,5-6]pyridazine-5,7(3H,6H)-dione, 4-acetyl-2-phenyl-synthesis, 5, 651 Imidazo[l, 2-6]pyridazines reactions, 5, 628 synthesis, 5, 650 Imidazo[ 1,5-6]pyridazines synthesis, 5, 651 Imidazo[4,5-c]pyridazines reactions, 5, 628-629 synthesis, 5, 651 Imidazo[4,5-d]pyridazines reactions, 5, 629 synthesis, 5, 436, 468, 651-652 3H-Imidazo[l,2-6]pyridazin-2-one, 6-chloro-3-dichloromethylene-synthesis, 3, 355... 

Synthesis of imidazo[l,2-d]pyridazines and their interaction with central and peripheral-type (mitochondrial) benzodiazepine receptors 98JHC1205. 

The reaction of several substituted imidazo[4,5-c/]-, pyrazolo[3,4-r/]- and triazolo[4,5-zf]pyrid-azines 3 with ynamines, in competition with [4 + 2] cycloaddition, leads to [2 + 2] derivatives 4, which rearrange to l,2-diazocines5.7 8 The reaction seems to be sensitive to the substituents, as replacement of the electron-withdrawing group R on the pyridazine ring of the pyrazolo compound (A = N, B = CH) by chlorine completely inhibits both the [4 + 2] and [2 + 2] cycloaddition reactions. The X-ray structure of the imidazo derivative 5 (R = Ms, A = CH, B = N) reveals a tub conformation of the eight-membered ring. 

Bromo-6-chloro-2-methyl-imidazo-( 1,2b)-pyridazine-bromine complex dichloromethane 20°C, 2 min. 75 % (40 %) (refs. 13,31)... 

Reaction of the 3-aminopyridazine 97 with the diketone, BrCH2COCOPh, resulted in the pyrimido[l,2- ]pyrida-zin-5-ium-3-olate 99, besides the expected imidazo[l,2-A pyridazine 98 (Equation 9) <1998JHC1205, 1997AJC779>. 

Pyrido[2, 3 4,5]imidazo[l,2- Pyrido[3, 2 4,5]imidazo[l,2-A]pyridazine <2004CC2466>... 

Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-677-imidazo[l,2-fc]-l,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJ04170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3- >]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one... 

Constrained variants, such as 20 and 21 have also been reported [91,92], Interestingly, the diazine-amide portion of 19 can be mimicked by the imidazo[l,2-b]pyridazine in 22 [93]. Presently, work in this field remains at a pre-clinical stage. 

Pyrimidin-4 yl)imidazo[1,2-a]pyridine and 3-(Pyrimidin-4-yl)imidazo[1,2-6]pyridazines... 

New examples involve the reaction of 5-vinyl-17/-imidazole 293 with 4-phenyl-l,2,4-triazoline-3,5-dione 294. In this way, the imidazo[4,5-i ]pyridazine skeleton was smoothly constructed (Equation 72) <1998TL4561>. Another example using in situ formed 294 can be found in Section 8.01.6.5. 

Several other azolopyridazine ring systems have been prepared by similar approaches <2002FA89, 2002JHC329, 2001MOL203, 2000MOL1187>. For example, 6-substituted imidazo[4,5-tf pyridazin-7-ones are obtained from the reaction of 1,2-disubstituted 4-aroylimidazole-5-carboxylates and hydrazines <2002JHC329>. 

The inverse electron demand Diels-Alder [4- -2]-cycloaddition of imidazoles to electron-poor dienes to yield imidazo[4,5-i pyridazines, reported in CHEC-II(1996), has been further developed. It was reported that the reaction of267 with tetrazines 268 was fruitless. However, 267 reacted with excess of 268 to yield aromatic 271 along with 1,4-dihydrotetrazine 270. Most likely, 271 arose from dehydrogenation of first-formed 269 by an extra equivalent of 268 <2001T5497> (Scheme 18). 

The synthesis of fused 1,2,3-triazoles is nearly always achieved by treating 1,2-diamines attached to diazines with nitrous acid (e.g., [l,2,3]triazolo[4,5-f]pyridazine (Section 10.13.9.2.1(iii)) and [l,2,3]triazolo[4,5-rf pyrimidine (Section 10.13.9.2.1(iv)), <1996CHEC-II(7)489>). When a heterocyclic system containing a diazole fused onto 1,2,4-triazine is required, annulation of the five-membered heterocycle is nearly always the most facile route (e.g., imidazo[4,5-r ][l,2,4]triazine (Section 10.13.9.2.l(i)) and pyrazolo[4,3-r ][l,2,4]triazine (Section 10.13.9.2.1(ii))). In support of the latter, the synthesis of the fused six-membered ring of pyrazolo[3,4-r ][l,2,4]triazine from the pyrazo-ledione was reported as low yielding <1996CHEC-II(7)489>. 

When cyclization of the acrylamide (167) was attempted in refluxing 1,2,4-trichlorobenzene, 6-chloro-3-dichloromethylene-3//-imidazo[l,2-6]pyridazin-2-one (35) was formed instead of the expected pyrimido[1,2-6]pyridazin-4-one (34). The latter compound could be obtained by conducting the cyclization in refluxing xylene. Since (34) and (35) are in practice not thermally interconvertible (at 210 °C), it can be assumed that (34) is not a precursor in the formation of (35) (71JOC3506). 

---