2- Aryl-3 -pyridazinones

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

The importance of the aryl pyridazinone moiety in biologically active compounds has lead to the development of solid phase routes to novel derivatives for general screening. Salives et al. were the first to investigate such... 

Scheme 44 Solid phase synthesis of aryl pyridazinones...

The most potent among the compounds tested were the pyridazi-nones (28, R1 = Ph, R2, R3, R4, R5 = H, n = 2-5) [101]. Structure-activity relationships have been investigated in detail with this type of compound. Also, thio-analogues of compounds (28) (3-pyridazinethione derivatives) as well as 2-aminoalky]-6-aryl-3(2//)-pyridazinones were claimed in patents as gastric secretion inhibitors or anti-ulcer agents [100, 102, 103]. 

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... 

Compounds which are of interest in this context include 4-oxadiazolylpyrid-azines (35, R = cyclopropyl, Et) [117], 6-aryloxy-2-hydroxyalkyI-3(27/)-pyri-dazinones [118], 3-halo-6-hydrazinopyridazines of type (36, R = substituted amino) [119], Ar-2-isoxazolylmethyl-substituted 3-iminopyridazines (37) [ 120], carbamates derived from 3,6-bis(hydroxymethyl)-4-pyridazinones (38, R = alkyl, Ph) [121], and iminodihydropyridazine derivatives (39, R1 = acyl R2 = H,MeS R3 = aryl) [122, 123]. In Hungary, antidepressant activity has been observed with some 3,6-disubstituted pyridazines of type (40) [124]. 

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. 

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 main interest, however, so far has been focused on attempts to find effective cardiotonics in the 6-aryl-4,5-dihydro-3(2//)-pyridazinone series and eventually in the past decade several very interesting novel agents presently in clinical trials emerged from these efforts. 

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. 

In a related paper, Scheldt and co-workers described a stereoselective formal [3 + 3] cycloaddition catalyzed by imidazolinylidine catalyst 256 Eq. 25 [130]. Ultimately this is an intermolecular addition of the homoenolate intermediate to an azomethine ylide followed by intramolecular acylation and presumably follows the same mechanistic path as described previously. Pyridazinones are obtained as single diastereomers in good to high yield from a number of aldehydes. Unfortunately no reaction occurs with the presence of electron-withdrawing groups on the aryl ring of the enal. 

In CHEC-II(1996) only one example of N-alkylation of a cinnolin-4(l//)-one is given <1996CHEC-II(6)1>. Nowadays, N-alkylation of pyridazinones is a quite general reaction. In most cases alkylations are achieved by a nucleophilic substitution reaction of the deprotonated azinone on alkyl halides and exceptionally also on aryl halides. Reagents other than halides are also used. 

The annelation of benzo rings on pyridazines was covered in CHEC-II(1996) <1996CHEC-II(6)1>. Maes and Matyus reported new examples in their synthesis of the dibenzo[// ]phthalazin-l(27r)-one and dibenzo[//]cinnolin-3(27/)-one skeleton. Palladium-catalyzed intramolecular arylation of 2-benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2//)-one yielded 2-benzyldibenzo[/,4]phthalazin-l(2//)-one. The synthesis of this new tetracyclic pyridazinone from 2-benzyl-5-(2-aminophenyl) -phenylpyridazin-3(2//)-one via a Pschorr-type reaction was also investigated. Similarly, the con-stmction of 2-methyldibenzo[/, ]cinnolin-3(2//)-one from 2-methyl-5-(2-bromophenyl)-6-phenylpyridazin-3(27T)-one and 2-methyl-5-(2-aminophenyl)-6-phenyl-pyridazin-3(2//)-one was performed <2003T5919>. 

In a similar manner, aldazines afford pyridazinones 317 (Scheme 7.104). 1,3-Diazadienes such as l-aryl-4-(dimethylamino)-2-phenyl-l,3-diaza-l,3-butadienes or l-aryl-4-(dimethylamino)-2-methylthio-l,3-diaza-l,3-butadienes react with oxazolones and give rise to pyrimidin-6-ones 319 and 320 as single diastereo-... 

A series of 3-chloro-4-arylacetylenic pyridazines have been cyclized to the corresponding 5-aryl-furo(or pyrrolo or thia)[2,3-( ]pyridazinones <2006TL6125, 2006JMC3753>. 

Arylidene-substituted Meldrum s acids 290 were reacted with 5-amino-6-phenyl-3(2//)-pyridazinone 291 to yield 4-aryl-2,5-dioxo-8-phenyl-l,2,3,4,5,6-hexahydropyrido[2,3-r/]pyridazines 292 in one step in good yields... 

The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules of biological relevance. The ability to prepare haloarenes selectively by an ortfio-metalation-halogenation sequence allows the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metalation to form aryl halides that were subsequently allowed to react with anilines to form diarylamines (Eq. (34)) [209]. Frost and Mendonqa have reported an iterative strategy to prepare, by the palladium-catalyzed chemistry, amides and sulfonamides that may act as peptidomimetics. Diaryl-amine units were constructed using the DPPF-ligated palladium catalysts, and the products were then acylated or sulfonated with 4-bromobenzoyl or arylsulfonyl chlorides [210]. Le-miere has coupled primary arylamines with 4-chloro-3(2H)-pyridazinones to form compounds with possible analgesic and antiinflammatory properties. 

Pd-catalyzed coupling reactions at the 5-position of 6-phenyl-3(2W)-pyridazinones using a retro-ene transformation have been reported <02SL2062>, and the Pd-catalyzed arylation of 4-bromo-6-chloro-3-phenylpyridazine has been shown to be efficient and regioselective <02SL223>. The N-methylation of substituted 3(2//)-pyridazinones with Ai,iV-dimethylformamide dimethylacetal has been explored <02SC1675>, as have the preparation of 3-nitro-, -nitroso- and -chloro-derivatives of... 

N-Arylation of pyridones. The Cu-mediated ChanLam reaction <1999T12757> can be used for N-arylation of pyridones or pyridazinones. Alternative methods use Pb(OAc)4ZnCl2 <2004TL8781> or catalytic amounts of a copper(II) hydroxyquinolinate complex under standard UllmannGoldberg reaction conditions <2006TL149>. 

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