Dibenzoxazepines

Irradiation of phenanthridine 5-oxides gives complex mixtures containing dibenzoxazepines. The reaction is solvent dependent. In benzene, for example, 6-phenylphenanthridine 5-oxide affords the dibenzoxazepine 4a (26%), 6-phenylphenanthridine (12%), 5-phenylphenanthrid-6(5//)-one (19%) and (V-benzoyl-2-(2-hydroxyphenyl)aniline (7%).27... 

Dibenzoxazepines 2a-c are intensely lachrymatory and powerful skin irritants. 

The reaction is analogous to the formation of chlorodibenzoxazepines from dibenzoxazepin-ones (Section 4.1.1.3.2.4.1.) and the preparative details are the same. Exact yields were not reported. 

The 11-chloro derivatives 7 were converted to the 11-amino compounds 8 by reaction with amines, exactly as described for the dibenzoxazepine analogs in Section 4.1.1.3.2.4.1.43 Some examples are listed below. Yields were not reported. 

Orthochlorobenzylidene malononitrile (CS) is the most commonly used irritant for riot control purposes. Chloracetophenone (CN) is also used in some countries for this purpose in spite of its higher toxicity. A newer agent is dibenzoxazepine (CR) with which there is little experience. Arsenical smokes (sternutators) have in the past been used on the battlefield. Apart from their lachrymatory action they also provoke other effects, e.g., bron-choconstriction and emesis, and are some times referred to as vomiting agents. 

Many other possibilities can be conceived by positioning the aryl halide into another component. Figure 18 shows the synthesis of dibenzoxazepines 90 starting from o-aminophenols and from o-chloro-p-nitrobenzaldehyde 88 [60]. 

Dibenzoxazepine and dibenzdiazepines do not stracturally belong to any of the classes of drugs listed above. However, their mechanism of action, indications for use, and side effects are analogous to phenothiazine derivatives. 

I Contraindications Acute recovery period following myocardial infarction (MI), within 14 days of MAOl ingestion, hypersensitivity to dibenzoxazepine compounds... 

Chemical Class Dibenzoxazepine derivative tertiary amine Clinical Pharmacology ... 

Almost all examples of this type involve the preparation of 1,4- or 1,5-benzoxazepines, or dibenzoxazepines by the nucleophilic displacement of a halogen from an aromatic ring. For example, (367) on treatment with sodium hydride gives (368) (77USP4053599). 

Amoxapine has been found to be effective in several double-blind studies (Table 7-4 and Table 7-6). It is a dibenzoxazepine derivative that has both NE and serotonin uptake inhibiting properties. Amoxapine is converted into 8-hydroxyamoxapine, which has considerable dopamine receptor binding properties (i.e., radioreceptor bioassays on patients given amoxapine have found activity levels similar to those of patients on typical antipsychotics), a chemical structure similar to loxapine, and effects similar to antipsychotics (1Q3). As a result of this metabolite, amoxapine theoretically may have unique beneficial effects in psychotically depressed patients. However, this possibility has never been adequately tested. Nevertheless, this metabolite is likely responsible for some of the antidopamine effects reported in patients taking amoxapine, including acute and chronic extrapyramidal side effects and elevated prolactin levels ( 104). Like TCAs, amoxapine can be lethal in... 

Table 7 Structure-Activity Relationships Known for Analogues of the Sensory Irritant Dibenzoxazepine (CR) l...

From the data on 111 NMR couplings, it was concluded that dibenzoxazepine 27 (Figure 5) adopts a V-form conformation in solution, as was also observed in the solid state (X-ray data) <1996MRC989>. 

Acylation of the ring nitrogen of fluorinated dibenzoxazepine 13 afforded ring-opened products 53 after addition of chloride anion and hydrolysis (Scheme 5). The hydroxy and chloro derivatives 52 could be isolated and characterized by X-ray crystallography <2003JFC(119)15>. 

Acetamide derivatives of dibenzoxazepine 113 were prepared and amidated with different alkyl and aralkyl side chains in order to function as a potential surrogate for the diacylhydrazine group of SC-51089, a potent PGE2 antagonist (Figure 15) <1996JME609>. 

In some cases, as with the very electron poor starting material 137, a nitro group can serve as the leaving group, leading to dibenzoxazepine 138 (Scheme 18) <2005JOC9371>. 

As an alternative to this procedure, the amino group of 160 can be generated from the corresponding nitro derivative prepared from 158 and 159 by reduction with iron. Palladium-mediated cyclization of 160 produced the desired dibenzoxazepine 161 (Scheme 24) <2003JOC644>. Tandem reduction/reductive animation <2004JHC963> and reduction/lactamization <2006JHC1031> procedures were also described. 

Very few reports describe the use of radical methods in the construction of large ring heterocycles (>7). A peroxydicarbonate-mediated hydrogen atom abstraction from an aldimine followed by cyclization onto an aromatic ring has been applied to the synthesis of dibenzoxazepines 237 [95T12143]. The yield of the heterocyclic product is low. 

Chemical warfare agents, eg quinnuclidinyl benzylate, thiocholine, methylethoxy phosphorate, dibenzoxazepine - [57]... 

Beside clozapine, only the 2-Cl-dibenzoxazepine loxapine (launched in 1975 by Wyeth) and 2-Cl-dibenzothiepine zotepine (launched in 1982 by Fujisawa) were introduced into clinical practice for the treatment of schizophrenia. Interestingly, in contrast with other dibenzodiazepines, all of which have a piperazinyl substitution at position-11, zotepine (which is a dibenzothiepine) has a 2-dimethylami-noethoxy-substitution at the same position. 

Amoxapine Dibenzoxazepine ring piperazine Less potent than other tricyclics dopamine... 

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