Phthalazines

Phthalazines commonly possess adrenergic activity. One such, carbazeran (77), is a cardiotonic agent. Its patented synthesis involves nucleophilicaromatic displacement of chiorophthal-azine derivative 7 with piperidinyl carbamate 76 to give carbazeran (77) 

Addition of phenylmagnesium bromide to phthalazin-l(2//)-one or derivatives like 4-phenylphthalazin-l(2/f)-one, 4-phenylphthalazine-l(2/f)-thione and 2-substituted phthalazin-l(2//)-ones results in the formation of 1,4-diphenylphthalazines, while addition of organolithium compounds to phthalazin-l(2/f)-one gives the 4-substituted derivative. 

The Reissert compound obtained from phthalazine and potassium cyanide in the presence of benzoyl chloride can be converted with methyl iodide and sodium hydride in DMF into 

2- benzoyl-l-cyano-l-methyl-l,2-dihydrophthalazine, which is transformed after alkaline hydrolysis into 1-methylphthalazine. Addition of Grignard reagents to 1-phenyl- or 1-alkyl-phthalazine 2- and 3-oxides gives 1,4-disubstituted phthalazines. 

Oxagrelate (104) is of interest as a platelet antiaggretory agent and is thus of potential value in preventing thrombus formation in blood vessels. It may also be of potential value in preventing arteriosclerotic lesions in coronary arteries - a substantial cause of morbidity and mortality in 

Azelastine (107) is an antiallergic/antiasthmatic agent prepared from 4-chlorobenzyl-2 -car-boxyphenylketCHie (105) by condensation with hydrazine to give the phthalazinone (106) followed by reaction of the sodium salt of this last with 2-(2-chloroethyl)-N-methylpyrrolidine (presumably involving nucleophilic ring expansion of the bicyclic quaternary salt putatively formed as a first product) to complete the synthesis [30]. 

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The compounds to be discussed are the quinolines, isoquinolines, cinnolines, quinazolines, quinoxalines, and phthalazines. Once again, this is a family of compounds for which much qualitative, but little quantitative information is available. 

When two fused six-membered rings (naphthalene analogues) are considered, possibilities become very numerous, partly on account of the reduced symmetry of naphthalene, compared with benzene, and also because of the larger number of positions available for substitution. Thus, there are two monoazanaphthalenes, quinoline (8) and isoquinoline (9), four benzodiazines [cinnoline (10), phthalazine (11), quinazoline (12) and quinoxaline(13)], with the two nitrogen atoms in the same ring, and six naphthyridines (e.g. (14), named and... 

Similarly, 3- and 4-hydroxycinnolines and their derivatives exist predominantly in the 0X0 forms (7) and (8), as supported by both pjSTa values and UV spectral data. The oxo forms for 3-hydroxycinnolines have been further supported by IR data <76MI21200>. Phthalazin-4-ones exist in the oxo form and phthalic hydrazide in the monohydroxymonooxo... 

Pyridazine-3(2//)-thiones exist in the thione form (14), as is evident from an X-ray structure analysis of pyridazine-3(2//)-thione. 6-Mercaptopyridazine-3(2//)-thione is predominantly in the monothiolmonothione form (15) in aqueous solution and in the solid state, 6-hydroxypyridazine-3(2//)-thiones are in the hydroxythione form (16) and 6-aminopyridazine-3(2//)-thiones exist in the aminothione form (17) for further details see (73HC(28)755). Cinnoline-4(l//)-thiones and phthalazine-l(2//)-thione have been shown on the basis of UV data and ionization constants to exist in the thione forms. 

The tendency for fragmentation by loss of N2, when compared with pyridazine, is reduced in the case of phthalazine where losses of HCN become important (Scheme 3). This is supported by quantum mechanical calculations which show that the structure (3a) better represents the ground state of the molecule than structure (3b). 

Oxidopyridazinium betaines isomerize photochemically into pyrimidin-4(3H)-ones (33). Irradiation of 3-oxidopyridazinium betaine or 1-oxidophthalazinium betaine in water affords similarly the corresponding pyridazin-3(2H)-one (35) and phthalazin-l(2H)-one derivative (37). However, photolysis in acetonitrile affords stable diaziridines (34) and (36) which can be converted in the presence of water to the final products (35) and (37) (Scheme 12) (79JCS(P1)1199). 

When large groups, such as phenyl, bromo, ethoxycarbonyl or nitro are attached at position 3, the principal products are l-alkylcinnolin-4(l/f)-ones. Cyanoethylation and acetylation of cinnolin-4(l/f)-one takes place exclusively at N-1. Phthalazin-l(2/f)-ones give 2-substituted derivatives on alkylation and acylation. Alkylation of 4-hydroxyphthala2in-l(2/f)-one with an equimolar amount of primary halide in the presence of a base leads to 2-alkyl-4-hydroxyphthalazin-l(2/f)-one and further alkylation results in the formation of 4-alkoxy-2-alkylphthalazinone. Methylation of 4-hydroxy-2-methyl-phthalazinone with dimethyl sulfate in aqueous alkali gives a mixture of 4-methoxy-2-methylphthalazin-l(2/f)-one and 2,3-dimethylphthalazine-l,4(2//,3//)-dione, whereas methylation of 4-methoxyphthalazin-l(2/f)-one under similar conditions affords only 4-methoxy-2-methylphthalazinone. 

Phthalazine forms monoquaternary salts with alkyl halides. 1-Substituted phthalazines are quaternized predominantly at position 3, and the site of quaternization of 1,4-disub-stituted phthalazines is determined by the steric hindrance of both substituents. 

JV-Oxidation of phthalazine with monoperoxyphthalic acid produces the corresponding... 

Upon nitration of phthalazines a nitro group is introduced only into the carbocyclic ring. Side reactions occur frequently. For example, nitration of phthalazine or its 1-methyl analog with potassium nitrate in concentrated sulfuric acid gives the 5-nitro derivative (100) as the main product together with 5-nitrophthalazin-l(2H)-one (101) as a by-producf (Scheme 27). 

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

In a similar manner, phthalazine or its alkyl- or aryl-substituted derivatives are obtainable from 1,2-diacylarenes (Scheme 76). Phthalaldehydic acid and its analogs are transformed by hydrazines into the corresponding phthalazin-l(2//)-ones. Phthalazin-l(2iT)-one itself is prepared from naphthalene by oxidation, subsequent treatment with hydrazine and decarboxylation as shown in Scheme 77 (55YZ1423,64FRP1335759). 4-Substituted phthalazin-l(2iT)-ones are prepared in a similar way from 2-acylbenzoic acids. 3-Hydroxyphthalides,... 

Phthalic anhydride and diethyl phthalate are easily converted with hydrazine into 4-hydroxyphthalazin-l(2/f)-one. Its substituted derivatives have been prepared using substituted hydrazines, substituted phthalic anhydrides, or diesters or disodium salts of substituted phthalic acids (Scheme 81). However, condensation of phenylhydrazine with phthalic anhydride gives only a small amount of the corresponding phthalazine, the main product being 2-anilinophthalimide. This can be rearranged in the presence of base into the phthalazine derivative. For the preparation of 2,3-disubstituted derivatives, 1,2-disub-stituted hydrazines are reacted with the appropriate phthalic anhydrides or phthaloyl chlorides. Derivatives of 4-amino- or 4-hydrazino-phthalazin-l(2iT)-one have been prepared either from the corresponding monothiophthalimide and 3-aminoisoindolin-3-one (1S4) or from ethyl 2-cyanobenzoate (155) and hydrazine hydrate (Scheme 82). Similarly,... 

In a similar manner to the formation of pyridazines from AT-aminopyrroles, cinnolines or phthalazines are obtainable from the corresponding 1-aminooxindoles or 2-amino-phthalimides. If the relatively inaccessible 1-aminooxindoles are treated with lead tetraacetate, mercuric acetate, r-butyl hypochlorite (69JCS(C)772) or other agents, cinnolones are formed as shown in Scheme 105. The reaction was postulated to proceed via an intermediate... 

Hydroxyphthalazin-l(2//)-one is obtained in a smooth reaction between phthalic anhydride and hydrazine hydrate and this is again the starting compound for many 1-substituted and/or 1,4-disubstituted phthalazines. The transformations of 1,4-dichloro-phthalazine, which is prepared in the usual manner, follow a similar pattern as shown for pyridazines in Scheme 110. On the other hand, phthalonitrile is the preferential starting compound for amino- and hydrazino-phthalazines. The most satisfactory synthesis of phthalazine is the reaction between a,a,a, a -tetrachloro-o-xylene and hydrazine sulfate in sulfuric acid (67FRP1438827), alt iough catalytic dehalogenation of 1-chloro- or 1,4-dichloro-phthalazine or oxidation of 1-hydrazinophthalazine also provides the parent compound in moderate yield. 

In the cinnoline series only derivatives of 3- or 4-aminocinnoline have been found to exhibit biological activity. Some hydrazinophthalazines, in particular 1-hydrazino-(Hydralazin) and 1,4-dihydrazino-phthalazine (Dihydralazin), are excellent hypotensive and antihypertensive agents. 

Apart from a short section in an early book on phthalazines (53HC(5)198), the only previous general account of significance occurs in a chapter in a now dated volume on fused pyridazines, which covers work up to 1969 (73HC(27)968), and which also includes bridgehead nitrogen derivatives not relevant to this review. A later review (75MI21504) does exist but is in Japanese. 

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