Pyridazine derivatives

Pyridazine Derivatives. A study of the reduction of six 2,3,4,5-tetrahydro-pyridazin-3-ones by lithium aluminium hydride has been reported. Experimental conditions determine the product ratios. 

The reactions of aryl Grignard reagents with some pyridazinones (379) 

The dimer formed from acetonylacetone and hydrazine, which was thought to be (381), has been shown probably to have the structure (382).  

Most research has been devoted to the diazaquinones 286 and their ben-zologs. Such compounds were prepared from the corresponding pyridazine- 

Compound 288 was prepared by chlorine oxidation of the monosodium salt of the cyclic hydrazide at — 50°C. It rapidly formed a Diels-Alder adduct, but is stable at — 20°C for months in contrast to other diazaquinones (68JA5932). 

7-Dichlorophthalazine-5,8-dione was obtained in low yield by oxidative chlorination of 5-aminophthalazine (86JMC1329). 1,4-Naphthoquinone reacts with hydrazine to give a black compound, for which the structure of a pentacyclic quinone (289) was established (67T2911). The compound is identical with the product from treatment of binaphthoquinone with hydrazine and for which a hydrazone structure was postulated previously (39CB1623). 

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In general, pyridazine can be compared with pyridine. It is completely miscible with water and alcohols, as the lone electron pairs on nitrogen atoms are involved in formation of hydrogen bonds with hydroxylic solvents, benzene and ether. Pyridazine is insoluble in ligroin and cyclohexane. The solubility of pyridazine derivatives containing OH, SH and NH2 groups decreases, while alkyl groups increase the solubility. Table 1 lists some physical properties of pyridazine. 

Reaction of various pyridazine derivatives with nitromethane or nitroethane in DMSO affords the corresponding 5-methyl and 5-ethyl derivatives. The reaction proceeds as a nucleophilic attack of the nitroalkane at the position 5. In this way, 3,6-dichloro-4-cyano-pyridazine, 4-carboxy- and 4-ethoxycarbonyl-pyridazin-3(2//)-ones and 4-carboxy- and 4-ethoxycarbonyl-pyridazin-6(lH)-ones can be alkylated at position 5 (77CPB1856). 

It has already been mentioned that some radical reactions can occur as side reactions by irradiation of pyridazine derivatives, especially in hydroxylic solvents. 

The most useful syntheses of pyridazines and their alkyl and other derivatives begins with the reaction between maleic anhydride and hydrazine to give maleic hydrazide. This is further transformed into 3,6-dichloropyridazine which is amenable to nucleophilic substitution of one or both halogen atoms alternatively, the halogen(s) can be replaced by hydrogen as shown in Scheme 110. In this manner a great number of pyridazine derivatives are prepared. 

When the pyrimido[4,5-c]pyridazine (211) was heated with phosphoryl chloride and dimethylaniline 212 was formed (71CPB1849). Some oxo derivatives appear to be resistant to chlorination e.g., the pyrimido [5,4-c]pyridazine derivative (213) would not react (68JHC523). 2- Arylpyrim-ido[4,5-[Pg.337]

A further example of an azo coupling reaction with an activated methylene compound (12.91), followed by ring closure to give a pyridazine derivative (12.92) in good yield (66%) was decribed by Gewald and Hain (1984). The reductive treatments of 12.92 give the pyrrole compounds 12.93 and 12.94 in 70% yield (Scheme 12-45). 

RATE COEFFICIENTS AND KINETIC PARAMETERS FOR REACTION FOR REACTION OF PYRIDAZINE DERIVATIVES WITH D2O-D2SO4.513... 

Novel steroidal pyridazines are readily prepared from ADC compounds and steroidal A2,4-dienes,163 A14,1 -dienes,164 and A16,20-dienes.165 ADC compounds are also commonly used in the protection of the steroid 5,7-diene system (see Section V,A). These Diels-Alder adducts of steroidal dienes and azo dienophiles should not be confused with the so-called azasteroids, which are also prepared from ADC compounds. Cyclic ADC compounds such as the pyrazole-3,5-diones (7), and the diazaquinones 12 and 13 readily add to dienes to give bicyclic pyridazine derivatives,166168 and these reactions have been adapted to the synthesis of 5,10-diazasteroids (106).42 Similarly, the 13,14-diaza- (107) and 13,14,16-triazasteroid (108) ring systems have been prepared.169... 

Bis-l,2,4-triazole-3,5-diones such as 110 have also been used in Diels-Alder reactions, and give bispyridazines.171 The pyridazine derivative 111 is formed in quantitative yield from PTAD and 2,7-dimethyl-2,3,5,6-octatetraene,172 and the azadiene, 4-aza-l,3,5-triphenylpenta-2,4-diene, also reacts readily with PTAD to give 112.173 There are many other examples of Diels-Alder additions of ADC compounds to simple acyclic dienes which proceed entirely as expected the above selection has been limited to reactions of synthetic potential and with novel features. 

Analogously, l,2-diphenyl-4,4-diacetyl- and -4,4-dibenzoyl triafiilvene are reported292 to be transformed by hydrazine to pyridazine derivatives 494, involving attack of the nucleophile at C1 2 and cyclization of intermediate 493 ... 

Phthalazinedione 83a reacts with perylene derivatives anomalously to provide polycyclic pyridazine derivatives (82S854). Dibenzoperylene 130 provided 67% of pyridazine 133, probably via Diels-Alder adduct 131,... 

Upon treatment with a base the zwitterionic triazine derivatives 112 undergo a valence bond isomerization yielding l,2,3-triazolo[4,5-d]pyridazine derivatives 113 <00CC1785>. 

Table 12 Syntheses of [1,2,4]triazolo[4,3-b]pyridazine and [1,2,4]triazolo[1,5-b]pyridazine derivatives...

Scheme 47 contains syntheses of [l,2,4]triazolo[4,3- ]pyridazine derivatives by ring closure of the triazole moiety. Kozhevnikov et al. reported <2005MC31> an interesting ring transformation treatment of the... 

With the synthesis of novel [l,2,4]triazolo[4,3-A]pyridazine derivatives 385 from the pyridazylhydrazone 384, Doring et al. followed a well-established route (cf. Table 12, entry 11) <2005T5942>. The specificity of this study is, however, the use of cupric chloride as an oxidizing agent (which has not been used before). 

Oxidative cyclization of hydrazones to fused [l,2,4]triazoles by means of cupric chloride was already discussed above for a related pyridazine derivative. The same method was also applied successfully for ring closure of 428 to 429 in good to excellent yields (Scheme 53) <2005T5942>. 

Deeb et al. described <2003H(60)1873> a series of transformations of an ester substituent of a tetrazolo[l,5- ]-pyridazine derivative 82 (Scheme 15). 

Due to the large number of references which appeared to be worth mentioning, it became necessary to divide this review into two parts. The present part deals mainly with pyridazines as chemotherapeutics, antithrombotics, antise-cretory and anti-ulcer agents, analgesic and anti-inflammatory agents as well as with various central nervous system stimulants and depressants. Part 2 of this review, which is planned for a future volume of this Series, will be devoted mainly to compounds which act on the cardiovascular system and to a discussion of miscellaneous additional pharmacological activities of pyridazine derivatives. 

Finally, three additional pyridazine-derived analgetic agents, which are cited in reference book [96] should be mentioned their structures are given in formulae (24), (25) and (26). 

The patent literature covers various types of pyridazine derivatives for which antidepressant activity has been claimed. 

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