STRUCTUREACTIVITYRELATIONSHIPS Chemische Eigenschaften,Einsatz,Produktion Methoden
Allgemeine Beschreibung
Extensive synthesis and testing of the barbiturates over along time span have produced well-defined SARs, which have been summarized.18 The barbituric acid is2,4,6-trioxohexahydropyrimidine, which lacks CNS depressantactivity. However, the replacement of both hydrogensat position 5 with alkyl or aryl groups confers the activity.Both hydrogen atoms at the 5-position of barbituric acidmust be replaced. This may be because if one hydrogen isavailable at position 5, tautomerization to a highly acidic trihydroxypyrimidine(pK
a～4) can occur. Consequently, thecompound is largely in the anionic form at physiologicalpH, with little nonionic lipid-soluble compound available tocross the blood-brain barrier.
In general, increasing lipophilicity increases hypnoticpotency and the onset of action and decreases the durationof action. Thus, beginning with lower alkyls, there is an increasein onset and a decrease in duration of action with increasinghydrocarbon content up to about seven to ninetotal carbon atoms substituted on the 5-position. It is becausethat lipophilicity and an ability to penetrate the brainin the first case and an ability to penetrate liver microsomesin the second may be involved. In addition for morelipophilic compounds, partitioning out of the brain to othersites can be involved in the second instance. There is an inversecorrelation between the total number of carbon atomssubstituted on the 5-position and the duration of action,which is even better when the character of these substituentsis taken into account, for example, the relatively polar character of a phenyl substituent (approximates athree- to four-carbon aliphatic chain), branching of alkyls,presence of an isolated double or triple bond, and so on.Additionally, these groups can influence the ease of oxidativemetabolism by effects on bond strengths as well as byinfluencing partitioning.
Clinical Use
N-methylation decreases duration of action,in large part, probably, by increasing the concentration ofthe lipid-soluble free barbituric acid. 2-Thiobarbiturateshave a very short duration of action because its lipophilicityis extremely high, promoting depotization. Barbiturates finduse as sedatives, as hypnotics, for induction of anesthesia,and as anticonvulsants.
STRUCTUREACTIVITYRELATIONSHIPS Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
