Dibenzoazepines

Fig 2 Chromatogram of dibenzoazepine and phenothiazine derivatives after staining with F( REST reagent 1 = fluphenazine, 2 = periciazine, 3 = promethazine, 4 = alimemazine, 5 = mixtur of substances 1 to 4, 6 = mixture of substances 7 to 12, 7 = dibutil, 8 = levomepromaziMi 9 = chlorpromazine, 10 = verophene, 11 - dixjrazine, 12 = perphenazine. 

Laboratory experiments on the ozonization of the dibenzoazepine drug carbamazepine (McDowell et al. 2005) showed the occurrence of a number of transformation products that were initiated by reaction at the olefinic double bond between the rings (Figure 1.29). 

Both acridone and dibenzo[6,/]azepine produce unexpected products (Scheme 7.39) when reacted with dimethylvinylidene carbene (7.1.18.A). Acridone reacts initially at the nitrogen atom to produce the 10-(3,3-dimethylallenyl) derivative (13%) and a pyrroloacridone (10%) which, if the structure is correct, could be derived from the allene by sigmatropic shifts [16]. The dibenzoazepine reacts as expected to produce a cyclopropyl derivative but, under the reaction conditions, the adduct rearranges spontaneously to yield a 1,6-methanodibenzo[b,/]cyclo-prop [J]azepine, the structure of which was confirmed by X-ray crystallography [17]. 

The bromination of dibenzoazepine 63 in 1,2-dichloroethane gives the /raw.v-dibromide 64 as the only product. The reaction was monitored spectrophotometrically and found to exhibit a third-order kinetics (second-order in Br2). A significant conductivity has also been found during the course of bromination. Both spectrophotometric and conductometric measurements are consistent with the presence of Br3- salt intermediates at a maximum concentration of ca 2% of that of the initial reactants. The X-ray structure of dibromide 64 shows a considerable strain at carbons bearing bromine atoms. The strain appears to be responsible for an easy, spontaneous debromination of 64, as well as for high barrier for the formation of 64 from the bromonium-tribromide intermediate. That makes possible the cumulation of the intermediate itself during the bromination of 63119. 

The use of click chemistry has also been applied to the synthesis of benzophe-none-modified y-secretase probes. The group of Yao reported the preparation of a compound library built up from Bpa-containing alkyne 77 and azide 78 (Fig. 7) [81]. The azide part contains a racemic hydroxyethylene moiety, and variations were made in its aryl sulfonamide domain. The compound library was screened for its potency against y-secretase inhibition and the most potent compounds were used to label active PS1 in a cell lysate. In addition, Fuwa and coworkers reported a divergent synthesis of y-secretase A/BPs by means of click chemistry with alkyne 79 and azide 80 [82]. Variations were made in the aryl part of the alkyne (dibenzoazepine or benzodiazepine) and in the type of spacer between the benzo-phenone moiety and biotin in the azide. PAL using these probes provided the authors with evidence that the molecular target of this type of probe is the N-terminal fragment of PS1. 

The synthesis and discovery of the antipsychotic effects of the piperazinyl-dibenzoazepine, clozapine (Fig. 13.1) and its launch in 1972 was an important turning point in the drug treatment of schizophrenia [1-3]. Clozapine was called an atypical antipsychotic as it did not produce side effects characteristic for compounds of the chlorpromazine- or haloperidol-type (i.e., extrapyramidal symptoms) either in animal models or in the clinic. Its use, however, became very limited when it was recognized that clozapine might cause a severe, and sometimes fatal, form of agranulocytosis. 

This method has been used for the synthesis of 1-aryl and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine as well as indoline. In the case of dimethoxyanilines, spontaneous cyclization to yield dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in the synthesis of melosatin A, albeit in very low yield (Scheme 8). 

Antidepressant heterocycles including mianserin (a dibenzoazepine), mirtazepine (a benzo[pyrido]azepine) and methiothepin (a dibenzothiepine) increase the lifespan of... 

SYNS 2-CHLORO-l l-(4-xMETHYL-l -PIPERAZINYL)-DIBENZO(b,f)(l,4)OXAZEPINE 2-CHLORO-ll-(4-METHYL-l-PIPERAZINYL)-DIBENZO(b,f)(l,4)0X0-AZEPINE CL-62362 CL-71563 CLOXAZEPINE DIBENZOAZEPINE HF3170 LOXAPINE LW3170 OXILAPINE S-805 SUM 3170... 

DIBENZOACRIDINE see DCS400 DIBENZO(a,h)ANTHRACENE see DCT400 1,2 5,6-DIBENZOANTHRACENE see DCT400 DIBENZOAZEPINE see DCS200... 

In view of the interesting pharmacological properties of the dibenzoazepines, the synthesis of the ring system has been exhaustively investigated. Some of the methods used for their synthesis are the following ... 

Dibenzoazepines and their dihydro derivatives are components of a series of psychopharmaceuticals (antidepressants and antiepileptics) such as carbamazepine 31 and desipramine 33. 

D.W. Jones You showed a computer drawing derived from a dipole-type program for the structure of a dibenzoazepine-based drug complexed with a ring-containing molecule. In some ways, is not the extent of structural detail slightly spurious in that the number of observables is insufficient to determine independently (as distinct from showing consistency with) the main structural framework. 

Scheme 4.13 Pd-catalyzed synthesis of dibenzoazepines and related compounds.

Meanwhile, Catellani, Derat and their co-workers developed the synthesis of dihydrodibenzoazepine and dibenzoazepine derivatives from 2-bromoanilines and aryl iodides. The process was based on the sequential reaction of three components, an aryl iodide, a bromoaniline, and either norbornene or norbornadiene in the presence of palladium as the catalyst (Scheme 4.13c). Whereas the use of norbornene leads to dihydrodibenzoazepine derivatives, norbornadiene allows an additional step consisting of a retro-Diels-Alder reaction, thus leading to the parent dibenzoazepines. 

The Ugi-4-component reaction has also been used to directly access diverse dibenzoazepine derivatives from suitably substituted biaryl derivatives (Scheme 7) [42]. In comparison to conventional heating, use of MW led to much reduction in the reaction time with significant improvement of the yield. This method should be particularly suited for library s5mthesis of such type of compounds. 

J.B. Bariwal, D.S. Ermolatev, T.N. Glasnov, K.V. Van Hecke, V.P. Mehta, L. Van Meervell, C.O. Kappe, E. Van Der Eycken, EHversity-ori-ented synthesis of dibenzoazocines and dibenzoazepines via a microwave-assisted intramolecular A -coupling reaction, Org. Lett. 12 (2010) 2774-2777. 

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