Benzodiazepine derivates, ring

A A,A-dimethylcarboxamido group attached to other aromatic systems can be hydrolyzed enzymatically as demonstrated by the metabolism of the ring-opened 1,4-benzodiazepine derivative 4.84 in dogs and rats [53], Here also, hydrolysis was shown to proceed via the secondary and primary amide formed by A-demethylation. 

As already noted, there are drugs found among benzodiazepine derivatives that have expressed anxiolytic action and that lack or have poorly expressed sedative-hypnotic effects, which are called daytime tranquilizers. Medazepam, a representative of the daytime tranquilizers, is a drug that differs from diazepam only in the absence of a carbonyl group in the seven-membered azepine ring. 

Benzodiazepine derivates, seven-membered rings with 2 N atoms in 1,4 position are the pivotal structures of the benzodiazepine class of breakthrough CNS (central nervous system) drugs such as Librium and Valium. The most recent drug in this class, Sepracor s Lunesta (eszopiclone), is composed almost entirely of A-heterocyclics. Like most modern drugs, esczopi-clone also has a chiral center ... 

A large number of compounds in which thiophene was fused to other heterocyclic rings have been investigated, notably in the central nervous system agents. For example, the benzodiazepine derivative (365) is reported to be more active than Clozapine in conditioned avoidance response tests in the rat (80JMC878). The activity of such fused-ring thiophenes has been reviewed (81JHC1277). 

Deprotonation of the quinazolinium salt 148 with NaH or KH gave the dienamine 149 which cycloadds to methylsulfonyl azide or trifluoromethanesulfonyl azide included in the reaction to afford a mixture of two sulfonyl-imino-substituted benzodiazepine derivatives 150 and 151 after a ring expansion mediated by the expulsion of N2 (Scheme 88) <2000EJ01577>. 

Intramolecular cyclisation of the azides (79) by refluxing in toluene has produced the [ 1,2,3]triazolo[ 1,5-u][ 1,4]diazepines (80) <95S647>. Removal of the Boc protecting group in the benzodiazepine derivative (81), prepared in three steps from 2-fluoro-5-nitro-benzoic acid, results in ring expansion to (82) via a Smiles rearrangement <95SL539>. 

Annelating the 1,2-bond of ring B with an additionai eiectron-rich (i.e., proton acceptor) ring, such as s-triazoie or imidazole, also results in pharmacologically active benzodiazepine derivatives with high affinity for the BZR (Fig. 22.17). For example, the s-triazolo-benzodiazepines triazolam, alprazolam, and estazolam and the imidazo-benzodiazepine midazolam are popularly prescribed, clinically effective anxiolytic agents (Fig. 22.16). 

Methods for the preparation of seven-membered nitrogen-ring systems by the nse of the intramolecular aza-Wittig reaction have increased in the last decade. This heterocycle is quite common in benzodiazepine derived alkaloids. This methodology has been applied for the first total synthesis of (-)-benzomalvin A (142) (Scheme 15.31). Reaction of the starting azide 138 with tributylphosphine leads to the formation of the phosphazene intermediate 139, which under the reaction conditions affords the benzodiazepine 141 in 58% yield via compound 140. Benzodiazepine 141 suffered subsequent transformations to afford (-)-benzomalvin A (142). 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Conden-... 

Cyclopropyl-l,5-benzodiazepin-2-ones 4 are converted into 3-chloro derivatives 5 by the action of, V-chlorosuccinimide in contrast, A-bromosuccinimide provides 4-(l -bromoallyl)bcnzo-diazepinones 6 with opening of the cyclopropane ring.269... 

The same approach was readily adaptable to solid-phase synthesis. A small library of unnatural derivatives of 140 was prepared with variation of the configuration and nature of R1 and R4 and with substitution on the benzene ring <2000JC0186>. Three natural alkaloids, Verrucine A, B, and Anacine, were synthesized by a similar pathway and the pyrazino[2,l- ]quinazoline as opposed to the benzodiazepine structure of Anacine was proved <2001JNP1497>. Fiscalin B and other derivatives were prepared by solid-phase synthesis using polyethylene glycol (PEG) resin <2002USP6376667>. 

Many seven-membered ring heterocyclic derivatives show pharmacological activity, and many, for example the benzodiazepines, nevirapine (anti-HIV), trineptine (antidepressant) and artemisinin derivatives (anti-malarial) are used clinically. The number of papers reporting pharmacological activity of new compounds or pharmacological mode of action studies continues at a significant rate. 

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