3-Pyridazinone, 4,5-dihydro-6-phenyl

CAS 1698-60-8 EINECS/ELINCS 216-920-2 Synonyms 5-Amino-4-chloro-2,3-dihydro-3-oxo-2-phenylpyridazine 5-Amino-4-chloro-2-phenyl-3-(2H)-pyridazinone 1-Phenyl-4-amino-5-chloro-6-pyridazone 1 -Phenyl-4-amino-5-chlorpyridaz-6-one Pyrazon Classification Pyridazinone Empirical CioHsCINsO... 

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 the United States, two potent orally active positive inotropic agents, CI-914 [imazodan hydrochloride CAS 89198-09-4, (15)] and CI-930 [CAS 86798-59-6, (16)], both characterized by a 4T(l/7-imidazol-l-yl)phenyl substituent attached to C-6 of a 4,5-dihydro-3(2//)-pyridazinone system, have been developed [16]. Patents exist on compounds of this type and related unsaturated pyridazinones [17-21] and also on homologues in which the... 

A combination EIMS and X-ray study of [l,2,4]triazolo[l,2-b]- and [l,3,4]thiadiazolo[3,4-i>]phthalazines was undertaken [95JHC283], and X-ray crystal structure determinations of 5-(2-chlorobenzyl)-6-methyl-3(2W)-pyridazinone [95AX(C)1834], and on 6-benzyloxy-7,8-dihydro-8-phenyl-3-trifluoromethyl-r-triazolo[4,3-i>]pyridazine and its 5,6-dihydro-6-one derivative [95AX(C)1829] have been performed. Structures of some pharmacologically-active pyridazines previously reported as arylidene-4,5-dihydropyridazines need to be revised to those of aromatic pyridazine tautomers 6-8 based on a combination H NMR nOe and X-ray study [95AJC1601],... 

In a similar way other pyridazines,159 e.g., 3-phenyl-6-methoxy-pyridazine and 3-methyl-6-chloropyridazine, are reduced, but the dihydropyridazines are in these cases rather unstable and may lose methanol or hydrogen chloride forming the corresponding 4,5-dihydro-pyridazinone. The reduction of pyridazinones will be discussed below. 

Direct amination of 3(2//)-pyridazinones occurs when they are heated with hydrazine hydrate and this is a convenient route to many 4-amino-6-substituted-3(2//)-pyridazinones (Scheme 11). The reaction generally gives high yields and amination is regiospecific when the 6-position is occupied by an aromatic or heteroaromatic ring, but the parent 3(2/ -pyridazinone gives a mixture of the 4- and 5-amino-3(2//)-pyridazinones. The reaction tolerates jV-methyl substitution of the pyridazinone, but is sensitive to steric factors the presence of a 5-substituent causes a marked reduction in reaction rate, and amination does not occur with 4-phenyl-3(2//)-pyridazinone. With maleic hydrazide 4-hydrazination occurs, possibly by displacement of an intermediate amino compound or by oxidation of an intermediate 4,5-dihydro-4-hydrazino adduct both 4-hydrazino- and... 

In an unusual reaction, treatment of 2-benzyl-6-phenyl-4,5-dihydro-3(2//)-pyridazinone with a mixture of phosphorus oxychloride and pentachloride resulted in debenzylation, aromatization, and chlorination (Equation (16)). The presence of the benzyl group in the substrate is important, as the dichloropyridazine product is only formed in very low yield from the corresponding reaction of 6-phenyl-4,5-dihydro-3(2 0 Pyt dazinone <83JHC1473>. 

The synthesis of pyridazine derivatives from hydrazones includes the thermal cyclization of 2-arylhydrazono-3-oxo-5-phenyl-4-pentenenitriles (readily obtained from ethyl cinnamate by condensation with acetonitrile followed by Japp-Klingemann type reactions) to l-aryl-3-cyano-6-phenyl-5,6-dihydro-4(l//)-pyridazinones (Scheme 85) <86JHC93>, and base-induced cyclization of a hydrazone of a 4-chloro-l-arylbutan-l-one to prepare a 2,3,4,5-tetrahydropyridazine (Scheme 85) <88JHC1543>. An earlier route to 6-carboxy-5-hydroxy-2-phenyl-3(2//)-pyridazinone via condensation of benzenediazonium chloride and dimethyl acetonedicarboxylate has been adapted to give a series of aryl derivatives either as esters (by thermal cyclization) or as acids (by cyclization with hydroxide). Both cyclizations proceed in high overall yield (Scheme 86) and decarboxylation of the acids also proceeds in high yield <89JHC169>. 

A variety of 4,5-dihydro-6-phenyl-3(2H)-pyridazinone derivatives are PDE-inhibitors. CI-914 ( ) produced cardiotonic effects in anesthetized dogs as well as in conscious dogs after oral administration, accompanied by only slight decreases in blood pressure and moderate increases in heart rate.105-107 oral absorption was complete, and the... 

Bromo-2-methoxymethyl-6-phenyl-3(277)-pyridazinone (154) with ethyl acrylate gave ethyl 2-methoxymethyl-l-oxo-4-phenyl-l,2-dihydro-6-phthalazine-... 

Bicyclic lactams are uniquely suited as precursors for the synthesis of chiral substituted 4,5-dihydro-2H-pyridazinones. Thus, bicyclic lactams 112 with hydrazine dichloride in a dioxan/water mixture produced the desired 6-phenyl-4,5-dihydropyridazin-3-ones 113. However, reacting the bicyclic lactam with phenylhydrazine hydrochloride yields 2,6-diphenyl-4,5-dihydropyridazin-3-one 115 as a sole product (2004TL7799 Scheme 20). 

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