Synthesis of hydantoins with hypnotic properties



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Although the alkaloid morphine, after centuries of use, continues to be the sovereign remedy for sleeplessness due to pain, there has been for many years considerable interest in the development of synthetics less powerfully narcotic but more suitable for ordinary cases of sleeplessness. The compounds which have proved most valuable in this respect are those containing substituents belonging to the methane series. In its fundamental character the action of a hydrocarbon radical is constant, but its intensity and manner of manifestation are determined by the nature of the group to which it is attached. At present, the group receiving most attention as a basis for attachment is the barbituric acid nucleus, of which numerous alkyl and aryl derivatives have been synthesized and tested. Many of these derivatives have been shown to possess properties approaching those of an Ideal soporific: reasonably wide margin of safety, rapidly induced sleep of sufficient depth, rapid elimination, slight tendency toward habit formation, and ease of administration. However, continued use of these compounds is often accompanied by undesirable secondary effects, and as a result, the drugs should be administered with caution. Moreover, in the last decade there has been an intensive search for derivatives of this type which are suitable for a number of specialized uses, such as pre-anesthesial sedation and quieting of nervous disorders. Hence, a vast quantity of research has been devoted to attempts to improve upon the compounds already in use. Thus, among those hypnotics for which substitutes are sought is Nirvanol, phenyl ethyl hydantoin, which recent reports indicate to be almost specific for chorea, but whose continued use is attended by an undesirable exanthema. The usual methods of synthesis of hydantoins, which will be enumerated in a subsequent chapter, have been limited to the utilization of simple ketones. In anticipation of the present problem, the writer, in the research submitted for the degree of Master of Arts, studied the synthesis of another type of ketone and demonstrated the ease of preparation of alkoxy alkyl ketones from inexpensive starting materials. The research here reported describes the utilization of these keto-ethers for the production of hydantoin derivatives of probable hypnotic value. A study of the pharmacological action of these compounds should contribute to our knowledge of the relationships between physiological action and chemical constitution

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