6- -pyridazinone preparation

The preparation of new fluorine containing pyridazinones, prepared by electrofluorination in various base. HF systems has been patented by Rikagaku Kenkyusho as a route to herbicidal, insecticidal or bactericidal compounds... 

Amino-pyridazines and -pyridazinones react with monomethyl- or iV,A-dimethyl-formamide and other aliphatic amides in the presence of phosphorus trichloride, thionyl chloride, phosgene or benzenesuUonyl chloride to give mono- or di-alkylaminomethyl-eneamino derivatives. The same compounds can be prepared conveniently with A,iV-dimethylformamide dimethyl acetal in high yield (Scheme 50). 

JOC6503>, and new pyridazino-psoralens 15 were prepared via a furan ring expansion reaction <05T4805>. The reaction of 3-acetylcoumarins with alloxan followed by NH2NH2 easily produced 3-(2-oxo-2//-chromen-3-yl)-6//,8//-pyrimido[4,5-c]pyridazine-5,7-diones <05JHC1223>. Furano- and pyrano[2,3-c]pyridazines 17 and 18a,b as well as substituted quinolines were conveniently prepared from pyridazinone 16 and vinyl- and allyltriphenyl-phosphonium salts <05HAC56>. 

A somewhat similar method for the preparation of l,3-oxazolo[4,5-d]pyridazi-nones has been described by Ivachtchenko and coworkers (Scheme 6.214) [385]. Here, the key intermediate 5-amino-4-hydroxy-3(2H)-pyridazinone was treated with... 

Several 3-(2H)pyridazinones have been prepared from monophenyl hydrazones of 1,2-dicarbonyl compounds and a variety of active methylene compounds within 1-20 min without solvent under focused irradiation in the presence of carefully adjusted amounts of piperidine or solid potassium tert-butoxide (isolated yields 50-89%), in accordance with Scheme 8.49 [72, 73]. 

Moreover, some German patents claiming A-unsubstituted 6-arvi-3(2//)-pyridazinones and 4,5-dihydro congeners as stomach secretion inhibitors and ulcer inhibitors have to be cited [ 110-113], Several cardiotonic 6-aryl-pyridazi-nones, recently prepared in Japan, also have been reported to inhibit secretion... 

The patent literature covers many pyridazine derivatives claimed as blood platelet aggregation inhibitors and antithrombotic agents. The interest has been focused mainly on 6-aryl-4,5-dihydro-3(2//)-pyridazinones. In these compounds the aryl substituent has been varied within a wide range. Thus, dihydro-pyridazinones bearing a substituted or heterocycle-fused phenyl group at C-6 (60, R R2,R3 = H, alkyl Ar = substituted Ph) [34, 110-112,205-233] as well as various heteroaryl substituted congeners (61, R1, R2, R3 = H, alkyl Ar = pyridyl, thienyl, pyrrolyl, pyrazolyl) [234-241] have been prepared in search of novel antithrombotics. 

Several dihydropyridazinones of type (78, R1 = cycloamino R2 = H, cycloamino R3 = H, Ph) characterized by a cycloaminomethyl substituent at C-5 have been reported to exhibit cytostatic activity [284, 285], In addition, compounds having a pyridazinone or pyridazinedione moiety linked to the purine system by a sulphur atom (79) have been prepared as potential cytostatic agents [286]. 

In Poland, various 5-cycloaminornetbyl-6-(p-chlorophenyl)-4,5-dihydro-3(2//)-pyridazinones (89, R1 = pyrrolidino, piperidino, morpholino, etc. R2 = H, substituted alkyl, aryl) have been prepared in search of biologically active pyridazines some of these compounds have been reported to exhibit immunosuppressive activity [180, 284, 285]. 

In Poland, various 3,6-pyridazinediones have been prepared as potential antimicrobial agents [324-328], Antibacterial activity has been observed with some compounds of type (113, R1 = H, Br R2 = Br, EtNH, R3 = aryl). There are also reports on antibacterial pyridazinylpyridazinones (114, R = aryl) [329, 330] and 6-aryl-3(2 )-pyridazinones (115, R = aryl) [331, 332],... 

The discovery of the positive inotropic and systemic vasodilator activities of bipyridine-derived compounds, like amrinone (7) and milrinone (8), has markedly stimulated research aimed at the development of structurally related non-steroidal, non-catecholamine cardiotonics. In this context, a wide variety of pyridazinone derivatives have been prepared and investigated in search for novel agents useful for the chronic management of congestive heart failure. 

A variety of tricylic compounds [indenopyridazinones (19)] have been prepared as rigid structural modifications of compounds like CI-930 (16) [28,29]. Most of them have been found to retain the positive inotropic and direct vasodilator activity of the freely rotating pyridazinones [28]. Also, hydrazinopyridazines of type (20) have been investigated as structural analogues of CI-914 and Cl-930, respectively. Whereas considerable inotropic activity has been observed in this series as well, ring closure to triazolo[4,3-h]pyridazines resulted in significantly less potent compounds [30]. 

An Italian team reported that pyridazinones (89) hydroxymethylated at C-5 induced a high decrease in systolic blood pressure in rats [371]. In Italy, much effort has been devoted also to the preparation of conformationally restricted congeners of antihypertensive pyridazinones. In a structure-activity study, it has been found that indeno[l,2-c]pyridazinones, in particular compounds (90), are potent antihypertensive agents [372]. 

Marked hypotensive activities have been observed with 4-alkoxy-5-fu-roylpiperazinylpyridazin-3(2//)-ones (94) which have been prepared in Spain [356,383,384]. Hypotensive diarylpyridazinones of type (95) have been synthesized in India [385]. Regression analysis has been applied to the hypotensive activities of pyridazinones [386]. 

For a wide variety of 6-aryl-3(2//)-pyridazinones (including those discussed in the chapter on cardiotonic agents and antithrombotics [1]), bronchodila-tor activity has been claimed in patents [104,114-116,129,423,424]. Thus, for instance, the bronchospasmolytic effects (guinea-pig tracheal-chain preparations) of compounds of type (99) have been found to exceed those of xanthines [425]. The therapeutic index of these compounds (which inhibit phosphodiesterase at lower concentrations than xanthines and do not interact with adenosine receptors) is larger than that of xanthines. 

Alkylation of pyridazinone 945 with 4-bromoacetoacelic acid 944 did not give the 2 -oxo-4 -carboxylic acid analogs, but gave 946 of type 4.1. The uracil derivatives were prepared similarly (90MI4). 

Pyridazinone (39), prepared via reacting 37 with A/, A -dimethylace-tamide dimethyl acetal, afforded pyrazolo[4,3-c]pyridazine (38) upon treatment with hydrazine (Scheme 6) (81JHC333). 

Nitro derivatives of several halogenated pyridazin-3(2//)-ones have been prepared by treating the pyridazinones with a mixture of a nitrate salt and acetic anhydride or trifluoroacetic anhydride <2003JOC9113>. These compounds have been used for the synthesis of nitramines (see Section 8.01.8.3). 

Two thieno[3,4-4jpyridazines were prepared via reaction of suitably substituted pyridazinones under microwave conditions <2006PS1755>. 

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>. 

Transformation of both the ester and nitrile derivatives 726 or 727 into pyrano[2,3-t7 pyridazines 728 or 729, respectively, by treatment with dilute HCl at room temperature involved nucleophilic displacement of the morpholine group by the hydroxyl group with an acidic hydrolysis followed by intramolecular iminolactonization and then hydrolysis of the formed imino group to a carbonyl group. Compounds 726 and 727 were prepared by Vilsmeier-Haack formylation of 2-methyl-5-morpholino-3(2/7)-pyridazinone 724 followed by condensation of the resulting product 725 with either ethyl a-cyanoacetate or malononitrile in EtOH (Scheme 34) <1994H(37)171>. 

Tetrahydropyrano[3,2-r ]pyridazinone derivatives 741 were prepared from the reaction of atylhydrazonoacetyl-acetone 739 and PhCHO in glacial AcOH in the presence of NaOAc, in a single synthetic step, via the formation of diphenylheptadienearylhydrazone intermediate 740 (Equation 63) <1989IJB167>. 

Reaction of the 2-acetoxy-3(2//)-furanones (526) with monosubstituted hydrazines gives good yields of the pyridazinium-5-olates (527) together with varying amounts of isomeric products. Alkyl derivatives (527 R = alkyl) have also been prepared by base-catalyzed alkylation (Mel, Me2SO4, PhCH2Cl) of 3-methyl-6-phenyl-5-ethoxycarbonyl-4( 1 //)-pyridazinone. Reduction of the diphenyl compound 527 (R = Ar = Ph) by zinc and hydrochloric acid gives 3-ethoxycarbonyl-5-hydroxy-5-methyl-l,2-diphenyl-2-pyrrolin-4-one (528 R = Ar = Ph) (Scheme 21... 

Pyridazines (see Sections II, IV, V,C,1, and V,D-G). Product ratios for the quaternization of 3- and 4-methylpyridazines and their NMR spectra have been reported.155 Betaine (49) is prepared by heating 3(2//)-pyridazinone (50) with methyl tosylate to 130° in kerosene followed by deprotonation of the resultant cation with an exchange resin. Interestingly, both Mel and methyl sulfate react under alkaline conditions with the pyridazinone at the other annular nitrogen atom.156... 

---