Cinnolines applications

This method is exemplified by its application to quinoline, isoquinoline, cinnoline, and isoquinoline 2-oxide, which are nitrated as their conjugate acids. The rate profiles for these compounds and their N- or O-methyl perchlorates show closely parallel dependences upon acidity (fig. 2.4). Quaternisation had in each case only a small effect upon the rate, making the criterion a very reliable one. It has the additional advantage of being applicable at any temperature for which kinetic measurements can be made (table 8.1, sections B and D). 

The interest for applications of pyridazines, phthalazines, and cinnolines as pharmaceuticals, agrochemicals, and materials certainly increased in the period 1996-2006. The database Scifinder revealed that 669 patents containing the topic pyridazine were published in this time frame. Similarly, for the benzo analogs phthalazine and cinnoline ... 

Pyridazine (1,2-diazine) (1) and its benzo analogs cinnoline (1,2-diazanaphthalene) or benzo[c]pyridazine (2) and phthalazine (benzo[rf]pyridazine) (3) have been known since the nineteenth century. Although the basic synthetic principles and reactivity were investigated in the early years, interest in these compounds was not very intense, compared with pyrimidines and their bicyclic analogs, as they were not found in nature. However, during the last three decades intensive research has been stimulated because many derivatives have found application as a result of their biological activity. 

This update covers material that appeared in Chemical Abstracts in the 10-year period to the end of 1993, with limited reference to subsequent papers. Over 7600 references to pyridazines or to phthalazines, cinnolines, and their benzo derivatives were identified for this period. While many are not concerned primarily with pyridazine and its benzo derivatives, it is interesting to consider their composition. The majority, about two thirds, refer to pyridazine derivatives, while the remainder are concerned mainly with phthalazines, cinnolines, and their benzo derivatives, with a few containing material common to both pyridazine and its benzo derivatives. Approximately a quarter of all of the references are to patent applications, and while these include some in which a pyridazine function is a nonessential part of the invention, a significant number include pyridazine and benzo derivatives as an important part of the invention. The patent activity is an indication of the expansion of industrial interest in these heterocyclic derivatives. Analysis of a representative sample of patent applications in the early 1990s revealed that in approximately 30% the diazine was an important part of the invention, while the distribution of end uses was pharmaceuticals (43%), agrochemicals (31%), other materials such as photographic reagents and liquid crystals (18%), and analytical applications (8%). 

This type of cyclization was reviewed in CHEC-I <84CHEC-I(3B)1>, particularly with reference to the formation of pyridazines by formation of a bond between the terminal nitrogen of hydrazones and an appropriately positioned cyano group or Michael aeceptor. Developments of this approach have been published, including application to the synthesis of phthalazines and cinnolines. 

In CHEC-I the applications of pyridazines, cinnolines and phthalazines were briefly summarized <84CHEC-l(3B)i>. The antibacterial monamycins were cited as a rare example of naturally occurring pyridazines, while the growth retardant, herbicidal, and fungicidal activities of synthetic pyridazine derivatives are mentioned. Note was made of the hypotensive and antihypertensive activities of hydralazine and dihydralazine, and that in the cinnoline series only 3-and 4-amino derivatives exhibit biological activity. 

This route has been extensively used for more than 50 years to prepare cinnolines from 2-aminoacetophenone derivatives. For example, diazotizing 293 afforded 294 (1945JSC512, 1949JCS2393, 1981AJC2619). The recent literature reported several applications that employ substituted acetophenones (2006BMC6832). For example, bromo derivative 295 was prepared by initial bromination of 293 and subsequent diazotization (Scheme 53). 

Alternatively, diazotization of acetylenes 297 affords cinnoline. This old synthesis (1945JSCS512, 1949JCS2393, 1994SC1733) finds recent applications (2004T7983, 2003TL5453, 1995LA775). 

Preparation of Carboxylic Acid Chlorides (and Anhydrides). Oxalyl chloride has found general application for the preparation of carboxylic acid chlorides since the reagent was introduced by Adams and Ulich. Acid chlorides produced by this means have subsequently featured in the synthesis of acyl azides, bromoalkenes, carboxamides, cinnolines, diazo ketones, (thio)esters, lactones, ketenes for cycloaddition reactions, intramolecular Friedel-Crafts acylation reactions, and the synthesis of pyridyl thioethers. ... 

Garofalo and coworkers reported the discovery and preparation of a novel series of cinnoline-3-carboxamides as inhibitors of leucine-rich repeat kinase 2 (LRRK2) activity and proposed their potential application as therapeutics for treating Parkinson s disease (Figure 2) (13BMCL71). While these cinnoline-3-carboxamides exhibited good potencies and were found to penetrate the central nervous system (CNS), they lacked specificity. The most potent compounds were determined to be... 

The copper-free protocols for alkynylation of organyl halides have been used for some applications where copper traces are not welcome. The initial findings came independently from Cassar (submitted January 17, 1975) and Heck (submitted January 8, 1975). ° For example, the alkynylation of haloaryltriazenes proceeds in the absence of copper-catalysts very smoothly (Scheme 5-124). Upon treatment with acids, these alkynyl triazenes cyclize to the corresponding cinnolines. °° ... 

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