Benzodiazepines and derivatives

Tesafova, E. and Bosikova, Z., Comparison of enantioseparation of selected benzodiazepine and phenothiazine derivatives on chiral stationary phases based on P-cyclodextrin and macrocyclic antibiotics, J. Sep. ScL, 26, 661, 2003. 

These are the most widely used routes to 1,3-diazepines and provide easy access to the monocyclic system, 1,3- and 2,4-benzodiazepines, and dibenzodiazepines by the reactions of (113)-(116) (and their derivatives) respectively with 1,1-bis-electrophilic reagents. The use of aldehydes produces the rather unstable fully saturated —NHCH2NH— linkage and has been rarely applied to the synthesis of monocyclic systems. (67AHC(8)2l, p. 40) but provides useful syntheses of 1,3-benzodiazepines, e.g. (117) (67AHC(S)2l, p. 43), and 2,4-benzodiazepines, e.g. (118) (68CRV747, p.783). A 5,7-dihydroxy-6fT-dibenzo[[Pg.605]

PHC(16)431, 2005PHC(17)389, 2007PHC(18)402> combinatorial approaches to benzodiazepine derivatives <1996ACR132, 2006RMC53> 1,5-benzodiazepines and 1,5-benzodiazepinium salts <1998AHC2>. 

Benzocyclobutenone and derivatives have been shown to react with diazomethylene anions to give 2,3-benzodiazepines under very mild conditions. A mechanism has been proposed which involves four-electron electrocyclic ring opening of the initial alkoxide, with important acceleration by the alkoxide anion. Torquoselectivity to set up an eight-electron electrocyclic ring closure to the benzodiazepine enolate has been attributed to the strong preference of the alkoxide anion for outward rotation. This mechanism has been supported by isolation of one of the /S-diazo alcohols, and its conversion to a benzodiazepine on LDA treatment.84... 

Benzodiazepine and azapirone derivatives are widely used drugs in this class, and most are metabolized extensively by enzymes of the CYP3A family, except oxazepam, lorazepam, and temazepam, which are mostly glucuronidated (52). Again, several studies have shown that inducers and inhibitors of CYP3A can markedly alter plasma concentrations of many of these drugs, but in only a few cases have toxic effects, such as deep unconsciousness, been reported (19,52,53). Nonetheless, patients on these drugs should probably be monitored carefully, particularly the elderly, who may suffer severe physical injury as a result of falls from impairment of psychomotor function. 

Alprazolam (Xanax /Pharmacia), a benzodiazepine derivative is used for the treatment of both anxiety and panic disorder and buspirone (Buspar /Bristol-Myers Squibb) is indicated for the treatment of anxiety disorders. The mechanism of action of buspirone is distinct from that of the benzodiazepines and is believed to be mediated mainly through modulation of serotonergic neurotransmission via its interaction with the 5-HT1A serotonin receptor subtype. 

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