Pyridazine-fused Systems

Pyridazine-fused Systems.—Robba and co-workers have extended their earlier work on thienopyrazines to more heavily fused systems. From benzo[6]thiophen derivatives such as (575)—(577), the benzo[Z ]thieno-[2,3- /]pyridazines (578)—(580) have been prepared by reaction with hydra-zine. Compounds (579) and (580) could by standard methods be transformed to the chloro-derivatives, which easily undergo nucleophilic substitution, whereby different substituents were introduced at the pyridazinic 

Roques, and M. Bonhomme, Bull. Soc. chim. France, 1967, 2495. M. Robba, B. Roques, and Y. Le Guen, Bull, Soc. chim. France, 1967, 4220. 

A third isomeric thienopyridazine (598) has been prepared. It was synthesized by sequential reduction and oxidation of the corresponding thienopyridazin-3-one (599), which itself was obtained from (600). This compound was made by stepwise oxidation with )V-bromosuccinimide of the corresponding tetrahydro-derivative (601) which had resulted from a 

Pyridazine-fused Systems.— The extensive work of Robba and co-workers on the synthesis and chemistry of l-benzothieno[2,3-d]pyridazines (482), earlier published as short communications and reviewed in Volume 2, has 

Zimmer, A. Prox, H. Pelzer, and R. Hankwitz, Biochem. Pharmacol., 1973, 22, 2213. 

Sakaguchi, and K. Takeda, Chem. and Pharm. Bull. (Japan), 1972, 20, 404. 

Thiophois Fused with other Nitrogm-cMitainiiig Heterocycles.— Thionaph-thenophenazines (486) have been prepared by the condensation of thionaphthaquinones with o-phenylenediamines/ Thieno[2,3-d]-1.2,3-tri-azines (487) were obtained by intramolecular cyclizations of diazonium compounds prepared from derivatives of 2-aminothiophen-3-carbox-amides/ In a similar way (488) gave (489).  

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The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Of the possible 10 bicyclic systems containing one bridgehead nitrogen and two extra nitrogen atoms, 1 1 in each ring, nine are known. One new system, pyrimido[l,6-A]pyridazine (system 1 in Table 1), has been reported since CHEC-II(1996) <1996CHEC-II(8)633>. The number of known tricyclic benzo-fused systems is 16. 

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>. 

A final approach to pyrimido[4,5-( ]pyridazines involves construction of a pyrimidine ring from a 3-aminopyridazine -carboxylic acid derivative as described in both CHEC(1984) and CHEC-II(1996) <1984CHEC(3)329, 1996CHEC-II(7)737>. Further examples of this approach have appeared since the publication of CHEC-II(1996) <2000JCCS951, 2006JHC243> and the approach has been used to prepare peri-fused systems (Scheme 20) <1993JRM1239>. 

The pyridine ring or the pyridazine ring for groups (b) and (g) may also contain additional heteroatoms. Such systems are subgrouped under the pyridine or the pyridazine group according to the position of the second heteroatom. They are treated in the order of increasing number for the position of the second heteroatom in the fused system as shown in Chart 6. 

Miscellaneous Fused Systems.-An elegant synthesis of thieno[2,3-c ]-pyridazine in 40% yield consists of heating thiophen-2-carbaldehyde azine with AlCla-triethylamine at 170-200°C. 2,3-Dimethylthieno[3,4-i>]-pyrazine has been prepared from 2,4-diaminothiophen. A derivative of the unusual thienopterine (303 R = OH) that was isolated from human urine in 1940, namely (303 R = H), has been synthesized from 2-amino-3,5-dicyano-... 

Miscellaneous Fused Systems.—The reaction of 2-vinylthiophen with azodicar-boxylates gave a mixture of tetra- and dihydro-thienopyridazine diesters upon dicarbethoxylation with TFA followed by oxidation, these gave thieno[2,3-c]pyridazine. ° Thieno[2,3-6]pyrazine has been synthesized from 2-chloro-3-cyanopyrazine by reaction with ethyl thioglycollate and condensation with base... 

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in iV-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

Other fused pyridazines, i.e. furo- and benzo-fused derivatives, sometimes also partly give the corresponding 1,2-diazocine systems.910... 

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... 

In Scheme 1, all the ring systems belonging to this chapter are depicted. The six-membered rings can be oxazine, thiazine, pyridazine, pyrazine, and pyrimidine, whereas the five-membered fused ring can contain oxygen, sulfur, selenium, phosphoms, and nitrogen atoms in various arrangements. 

These authors found that the tetrazinylhydrazone derivative 46 when reacted with pyrrolidinoenamine 47 in methanol yields the cyclopenta-fused derivative of the title ring system 48 in 94% yield. A similar transformation was carried out successfully by using morpholine-enamine in somewhat poorer yield. When the transformation was tried in acetonitrile as a solvent, a totally different reaction was observed a regular Diels-Alder reaction between the tetrazine ring and the enamine double bond (of inverse electron demand) took place to yield pyridazines. 

Two specific processes have been described leading to the formation of this fused ring system, both starting with a substituted pyridazine. 

The traditional approach to this ring system involves adding hydrazine to [1,2,3]triazole, 5-dialdehyde to condense the fused pyridazine ring <1996CHEC-II(7)489>. Eor example, Trudell and co-workers reported the conversion of dialdehyde 63 into the fused pyridazine ring compound 64 by reaction with hydrazine monohydrate at 50 °C (Scheme 44) <2000JHC1597>. 

Ring closure of 1,6-dioximes by treatment with dinitrogen tetroxide in dry ether has been previously used to give the fused pyridazine ring in this heterocyclic system <1996CHEC-II(7)489>, and was used more recently to give the A, A -dioxides 74 (Scheme 53) <2000CHE1091>. 

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