Chloral derivatives

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

Anxiolytics, sedatives, hypnotics (benzodiazepines, barbiturates, chloral derivatives, chlormethiazole, zopiclone, zolpidem)... 

Drugs acting on GABA/glutamate - hypnotics/anxiolytics barbiturates, benzodiazepines, chlormethiazole, chloral derivatives, baclofen - anticonvulsants phenobarbitone, primidone, phe-nytoin, sodium, valproate, carbamazepine - alcohol, phencyclidine, ketamine... 

All chloral derivatives are similar with respect to their therapeutic effects as they are all converted to the same active intermediate. They irritate the skin and mucous membranes and should therefore not be taken on an empty stomach. They are widely distributed throughout the body. In therapeutic doses there is little effect on respiration and blood pressure. In patients with hepatic or renal impairment chloral derivatives are contraindicated. They have no analgesic activity of any importance. The undesirable CNS effects of these drugs are light headiness, malaise, nightmares and ataxia. 

Mechanism of Action A nonbarbiturate chloral derivative that produces CNS depression. Therapeutic Effect Induces quiet, deep sleep, with only a slight decrease in respiratory rate and BP. 

Along with new aromatic diamines and tetramines based on chloral and its derivatives, new aromatic tetracarboxylic acid dianhydrides were developed. These products were prepared by the interaction of bis-phenols - chloral derivatives - with two-fold molar amounts of nitrophthalimides followed by transformation of bis-phthalimides, containing two ether bonds, into the corresponding aromatic tetracarboxylic acid dianhydrides [30] (Scheme 2.13). 

Considerable research effort has been devoted in recent years to the use of chloral derivatives for the synthesis of linear heterocyclic polymers. Of these, the most common are aromatic polyimides [1-12], Many of these polymers have been synthesised from compounds like 4,4 -diaminobenzophenone, and other diamines, which, as demonstrated in the previous chapter, can be obtained from chloral. Polyimides prepared from these diamines were largely synthesised by the conventional two-step procedure [11, 12] involving mild reaction of the diamines with the bis(phthalic)anhydrides, isolation of poly(o-carboxy)amide (PCA) prepolymers, and then processing into products followed by thermal or chemical imidisation [13—16] (Scheme 3.1). Some properties of polyimides prepared from 4,4 -diaminobenzophenone are provided in Table 3.1. 

Aromatic bis(o-phenylendiamines) prepared from chloral derivatives, in particular 3,3, 4,4 -tetraminobenzophenone, were also used for the synthesis of polyimides possessing good solubilities in amide and phenolic solvents in combination with high thermal and heat resistance. In these respects, they were little different from polyimides formed from other bis(o-phenylendiamines) [29, 30]. 

Another approach to the synthesis of polyimides from chloral derivatives involves the use of dianhydrides of isomeric tetracarboxylic acids containing central carbonyl or 1,1-dichloroethylene groups and two ether bonds as the starting electrophilic compounds [31-33] (Scheme 3.8). 

Benzimidazoles (51) by the Action of Chloral Derivatives on o-Amino-Canilines (49)... 

Chemical/Pharmaceutical/Other Class Chloral derivative... 

Symmetric carbonates of guaiacol or ethyl salicylate are crystalline solids (Figure 41.12), pentaerythritol tetranitrate is the solid counterpart of the liquid trinitrine and petrichlo-ral is again a stabilized chloral derivative. Methenamine, formulated as an enteric-coated tablet, is used as a urinary tract antibacterial. Following absorption, the compound is eliminated in the urine where formaldehyde is generated in the acidic environment. 

Bruce, W.F., Chloral derivatives and methods for their preparation. US Pat. 2,784,237 (5 March 1957, to American Home Products) 1957. 

Scattered examples exist of additions of other hetero nucleophiles to N-sul-fonyl imines. For example, Kresze and coworkers found that thiols add to imine 43 to afford adducts 44 in good yields [Eq. (13)] [6,34]. Similarly, aniline adds to chloral-derived N-sulfonyl imine 46 to afford 45, and ethanol adds to produce 47 (Scheme 11) [6]. 

A Russian group has described two types of [2+2]-cycloadditions of N-sulfonyl imines. It was found that both ketene and trimethylsilyl ketene react with chloral-derived N-sulfonyl imine 233 to afford -lactams 234 in excellent yields [81] [Eq. (57)]. Although the compound produced from trimethylsilyl ketene appears to be a single isomer, the stereochemistry was not elucidated. 

It was also reported that various alkoxy acetylenes undergo [2+2] -cycloaddi-tions with chloral-derived N-sulfonyl imines to yield adducts 235 [82] [Eq. (58)]. Yields were claimed to be uniformly high. 

On the basis of the chemistry of chloral derivatives, one could suppose that transition from diacenaphthyltrichloroethane to the desired bis(naphthalic anhydride) can be carried out through oxidation of l,l,l-trichloro-2,2-bis(acenaphth-4-yl), subsequent anhydridization of pery-dicarboxylic groups, and dehydrochlorination of 1,1,1-trichloroethane moieties ... 

Scheme 15.9 Enantioselective addition of ketene to chloral derivatives.

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