1,5-Benzodiazepines general structure

Figure 6.17 General structure of the benzodiazepine library L4 and of the used monomer sets Ml M3.

Benzodiazepines, which have the generalized structure shown as 3, were introduced to replace the barbiturates as tranquilizers, anxiolytics, anticonvulsants and muscle relaxants. All those encountered in the forensic science context have been diverted from licit sources. The majority appear as tablets and capsules, although powders and injectable solutions may also be encountered. 

Figure 2. l-Substituted-5-Aryl-l,5-Benzodiazepine-2,4-diones General Structure. 

Simply mixing a mono-N-Boc protected 1,2-DAB 257, glyoxylic acid 258, isonitrile 254, and aldehydes 252, 253, in methanol, gave the Ugi products 259. TFA-promoted Boc removal and cyclization, with concomitant loss of water, afforded the desired quinoxalinone, with four potential points of diversity and of general structure, 260 (Scheme 2.34) (Nixey et al. 2002). This transformation represents a novel extension of the UDC (Ugi/de-Boc/cyclize) methodology for synthesizing l,4-benzodiazepine-2,5-diones (Hulme et al. 1998). 

Diazepam and its nordiazepam, oxazepam, and temazepam metabolites are well retained by the MIP, while they are much less retained on NIP, also exhibiting large RSD. Other benzodiazepines of similar structures (Figure 1.50) were well retained on the MIP, showing that this template can be used for the general class of benzodiazepines. Two benzodiazepines studied, chlordiazepoxide and flunitrazepam, were poorly retained, indicating poor fit of these structures into the templated MIP. 

Since general anesthetics are related to a variety of classes of chemical compounds, there is no general pattern that exists between their chemical structure and their activity. Particular patterns only exist for different groups of compounds (barbiturates, benzodiazepines, etc.). 

The benzodiazepines were discovered by Leo Sternbach at the Hoffman-La Roche laboratories, and their pharmacology was elucidated by Randall of the same company. An enormous variety of these compounds exist. Since about 3500 benzodiazepine compounds have been investigated, the neurologic structure-activity relationships of these drugs have been well established and the central features can be generalized as follows ... 

Drugs that stimulate respiration (analeptics) have a place in anaesthetic practice but are not a substitute for mechanical ventilation. They have a direct effect on respiratory drive they do not share a common molecular structure. Respiratory stimulation is generally better achieved by antagonising the depressant effects of the depressant drug, e.g. flumazenil for benzodiazepines naloxone for opioids. 

For the final step involving functionalization at N( ) of 62, anilide deprotonation with lithiated 4-benzyl-2-oxazolidinone as a base and alkylation with benzyl bromides again proved effective. Compared to the results obtained in the benzodiazepine series, the N( 1 )-alkylation reaction was generally found to proceed less smoothly with the 3,4-disubstituted quinox-alinones 62. Good results were obtained only if the resin batches were submitted twice to the alkylation conditions. Figure 3.4 displays a selection of structures (63-65) accessible from this first synthetic approach. In no case was there any evidence for racemization at the a-carbon atom of the amino acid. 

Benzodiazepines are a family of compounds that share the same basic chemical structure and pharmacological effects. Although the more famous members of this family are associated with treating anxiety (e.g., diazepam [Valium] see later in this chapter), several benzodiazepines are indicated specifically to promote sleep (Table 6-1). These agents exert hypnotic effects similar to those of nonbenzodiazepines—such as the barbiturates—but benzodiazepines are generally regarded as safer because there is less of a chance for lethal overdose.22 Benzodiazepines, however, are not without their drawbacks, and they can cause resid-... 

For details of the chemistry and SARs of the benzodiazepines. see the discussion of anxiolytic-.sedative-hypnotic drugs. Among the present clinically useful drugs, the structural features associated with anticonvulsant activity arc identical with those as.sociatcd with anxiolytic-scda-tive-hypnutic activity. - Animal models predict that benzodiazepines are modestly effective against generalized tonic-clonic and partial seizures and very highly active... 

Several authors have provided insight into the putative MBS receptor based on their structure-activity data. As noted by Unverferth et al. (281), there have been several attempts to postulate a general pharmacophore for the different anticonvulsant classes, all of which are anti-MES in animal studies and are, or have the potential to be, effective in generalized tonic-clonic seizures. These include benzodiazepines (282) barbiturates (283) triazolines (284) semicarbazones (248-261) and enami-nones (286-288), respectively and for different compounds with similar anticonvulsant profiles (289-292). The Unverferth model (Fig. 6.11) provides an excellent representation of the current anticonvulsants phenytoin (1), carbamazepine (2), lamotrigine (11), zonisamide (13), and rufinamide (60). Remace-mide (58) is also included as a possible candidate (Fig. 6.12). 

Ghose AK, Crippen GM. Modeling the benzodiazepine receptor binding site by the general three-dimensional structure-directed quantitative structure-activity relationship method REMOTEDISC. Mol Pharmacol 1990 37 725-734. 

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