Halogenated sedative-hypnotics

Current drugs on the market include barbiturates, benzodiazepines, halogenated sedative-hypnotics, heterocyclic sedative-hypnotics, antihistamines, and other sedative-hypnotics. 

Halogenated Sedative-Hypnotics. Attempts to develop effective halogenated sedative hypnotic drugs without bothersome side effects have not met with success and resulted in only marginally useful products. 

A series of esters of nuclear halogenated 3-carboxy-1,2,3-benzotriazin-4(3//)-ones show depressant activity, while the benzoate esters of substituted 3-(2-hydroxyethyl)-l,2,3-benzotriazin-4(3f0-one are reported to function as coronary dUating agents," as do certain other compounds of this type." 3-(o-Haloaryl)-l,2,3-benzotriazin-4(3i/> ones are claimed to have antisecretory," anoretic, anticonvulsant, and hypoglycemic activity, and a variety of other 3-aryl derivatives are stated to be relaxants, tranquilizers, sedatives, hypnotics, or cramp inhibitors. A number of derivatives of 10, R = H, in which the 3-substituent is a long alkyl chain containing a terminal sulfonamide group have been claimed to act. as antidiabetics. ... 

The benzodiazepines are widely used sedative-hypnotics. All of the structures shown in Figure 22-2 are 1,4-benzodiazepines, and most contain a carboxamide group in the 7-membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position. 

Current anesthesia protocols usually include several agents in combinations that vary according to the depth of anesthesia required for specific procedures. Inhalational anesthetics, which include nitrous oxide and six halogenated hydrocarbons, have varying potency in proportion to their lipid solubilities. MAC value, a measure of anesthetic potency, is defined as the minimal alveolar anesthetic concentration (% of inspired air) at which 50% of patients do not respond to a surgical stimulus. MAC values are additive, lower in elderly patients, and lower in the presence of opioid analgesics and sedative hypnotics. 

As the number of carbon atoms at the fifth carbon position increases, the lipophilic character of the substituted barbituric acids also increases (44). Branching, unsaturation, replacement of alicyclic or aromatic substituents for alkyl substituents, and introduction of halogen into the alkyl substituents all increase the lipid solubility of the barbituric acid derivatives. A limit is reached, however, because as the lipophilic character increases, the hydrophilic character decreases. Although lipophilic character determines the ability of compounds to cross the blood-brain barrier, hydrophilic character also is important, because it determines solubility in biological fluids and ensures that the compound reaches the blood-brain barrier. Introduction of polar groups into the alkyl substituent decreases lipid solubility below desirable levels. Modifications at this position by variation of the alkyl substituents were of primary importance in the development of barbiturates with short (3-4 hours) to intermediate (6-8 hours) duration of action. These barbiturates were once extensively used as sedatives and hypnotics. 

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