Semicarbazide-sensitive amine-oxidase (SSAO) is present in various human tissues and in plasma. Oxidative deamination of short-chain aliphatic amines is catalyzed by this enzyme to afford the corresponding aldehydes, ammonia and hydrogen peroxide. Methylamine and aminoacetone have been recognized to be physiological substrates for SSAO. There are several pathological states where increased serum SSAO activity have been found, such as diabetes mellitus, congestive heart failure, multiple types of cerebral infarction, uraemia, and hepatic cirrhosis. The role of SSAO in pathophysiology of diabetes has been most extensively investigated. The elevated formation of the potentially cytotoxic products of the enzyme may contribute to the endothelial injury of blood vessels, resulting in the early development of severe atherosclerosis; it may also contribute to the pathogenesis of diabetic angiopathy. It is now suggested that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications as well. Inhibitors can be conveniently subdivided into the main groups of hydrazine derivatives, arylalkylamines, propenyl- and propargylamines, oxazolidinones, and haloalkylamines. Of them, aryl(alkyl)hydrazines, and 3-halo-2-phenylallylamines are generally very strong SSAO inhibitors. Most of these inhibitors of SSAO have been originally developed for other purposes, or they are simple chemical reagents with highly reactive structural element(s); these compounds have not been able to fulfil all criteria of high potency, selectivity, and acceptable toxicity. New potent compounds with selectivity and low toxicity are needed, which may prove useful tools for understanding the roles and function of SSAO, or they may even be valuable substances for treatment of various diseases.

Owing to the parallelism between the in vitro insulin mimicry and the in vivo improvement of glucose handling elicited by benzylamine in rodents, the SSAO/VAP-1 substrates, with stronger effects on human adipocytes than benzylamine, show promising applications for the treatment of insulin resistance.

Novel straightforward syntheses of naphtho-fused azepines and benzazonine via tert-amino effect are described. Starting from 1-naphthylamine, 8-N,N-dialkylaminonaphthalene-1-carbaldehydes could be obtained in two steps. The aldehyde was prepared by a Suzuki reaction of 8-bromonaphthalene-1-carbaldehyde with ortho-pyrrolidinophenylboronic acid. Treatment of aldehydes with active methylene compounds afforded naphthazepines and novel benzazonine ring system, respectively, through rearrangement of isolable vinyl intermediates or benzo[de]quinolinium derivatives or without isolation of any intermediates. A mechanistic investigation supports an intramolecular hydride transfer for the ring closure to azepine or azonine. Our results indicate that the tertamino effect may provide a valuable approach to the synthesis of ortho-and peri-fused aza-ring systems.The term 'tert-amino effect' was introduced by MethCohn and Suschitzky nearly forty years ago, to describe thermal rearrangement reactions of ortho-substituted tertanilines via cyclization to benzofused aza-ring systems. 1 Seven types of the tert-amino effect have been distinguished so far, according to the size of the ring formed and its mode of formation. 2 One version of type 2 reactions, the isomerization reaction of tert-anilines with an orthovinyl group and their heterocyclic analogues has received much attention, due to its high synthetic value to obtain biologically useful tetrahydroquinolines and related fused ring systems with predictable regio-and stereochemistry. 3a-3f This type of tert-amino effect can occur in two steps: the rate-limiting first step involves a hydrogen migration from the N-methylene carbon to the a-vinyl carbon affording a 1,5-dipolar intermediate that cyclizes in the second step to a tetrahydropyrido-fused system with the formation of a new carbon-carbon s-bond (Figure 1). An additional feature of such reactions is the requirement of strongly electron-withdrawing substituents in the vinyl group to stabilize the negative end of the dipolar intermediate. In context of the hydrogen migration, a sigmatropic [1,5]-hydrogen shift and an ionic mechanism with hydride transfer have been proposed.In our studies, kinetics, thermodynamics, steric features, the synthetic scope, and methodological limitations of this type of tert-amino effect have been investigated and various types of pyrido-fused diazines have been prepared. 4a-f An impressive number and diversity of very recent examples, 5a-e illustrate further the synthetic potential of type 2 tert-amino effect. Interestingly, only very few isomerization reactions have been reported, which led to the formation of a sevenmembered or larger ring. 6 In our approaches, vinyl-substituted bi-or triaryl-tert-amines A and B could be cyclized to diarene-fused azocines 7a and triarene-fused azecines, 7b respectively, via type 2 tert-amino effect (Figure 2). Following this line, we also decided to study ortho-fused aromatic ring systems, the prototype of which is naphthalene, possessing key functionalities in...

The thermal isomerization reaction of ortho-vinyl tert-anilines and their heterocyclic analogues via tert-amino effect affords tetrahydropyrido-fused heterocyclic ring systems with a new C-C bond formation between the vinyl and tert-amino groups. A novel series of 5-amino-4-vinyl-3(2H)-pyridazinone derivatives were prepared to study the role of substituents of the pyridazinone ring and the vinyl group in their isomerization reaction to tetrahydropyrido [2,3-d]pyridazines. In particular, 6-phenyl and 5-trioxopyrimidinediylmethylene substituents were found to significantly increase the rate of isomerization. Compounds possessing benzyl and methyl groups as amino substituents isomerized with the involvement of the benzyl group. On the basis of experiments with deuterated compounds, an intramolecular pathway was confirmed for the isomerization.