Subject(s)
Anesthetics, Local/chemical synthesis , Anti-Arrhythmia Agents/chemical synthesis , Carbamates/chemical synthesis , Pyrrolidines/chemical synthesis , Aconitine , Anesthetics, Local/pharmacology , Anesthetics, Local/toxicity , Animals , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/toxicity , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/prevention & control , Carbamates/pharmacology , Carbamates/toxicity , Chemical Phenomena , Chemistry, Physical , Cornea/drug effects , Guinea Pigs , Heart Rate/drug effects , Lethal Dose 50 , Mice , Pyrrolidines/pharmacology , Pyrrolidines/toxicity , RabbitsABSTRACT
In a systematic study of the relationship between the chemical structure and beta-adrenolytic activity, eleven derivatives of the 4-alkoxysubstituted phenylcarbamic acids were prepared. The beta-adrenolytic efficiency of the compounds was studied in the isolated spontaneously beating guinea-pig atria and expressed as pA2 values against isoprenaline tachycardia. Negative chronotropic and antidysrhythmic activity were also evaluated. All of the compounds studied were local anesthetically active and their indexes of efficiency were 3-50 fold higher in comparison with standards cocaine and procaine. The acute toxicity of the compounds was within the acceptable limits.
Subject(s)
Carbamates/pharmacology , Heart Rate/drug effects , Animals , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/physiopathology , Carbamates/chemistry , Female , Guinea Pigs , In Vitro Techniques , MaleABSTRACT
In a series of 24 compounds of the type of dibasic alkylesters of 2-, and 3-alkoxy substituted phenylcarbamic acids, esterified alcohols 1-dipropylamino-3-pyrrolidino (piperidino or perhydroazepino)-2-propanol were used. It follows from the results of pharmacological evaluation that these compounds possess a high index of effectiveness in surface and infiltration anaesthesia compared to the standards of cocaine and procaine. Maximum effectiveness in surface anaesthesia was shown by [1-dipropylaminomethyl)-2- (piperidino)ethyl]-ester of 3-butoxyphenylcarbamic acids whose activity is as much as 180 times higher than that of cocaine. Maximum effectiveness in infiltration anaesthesia was shown by [1-dipropylaminomethyl)-2-(pyrrolidino)ethyl] ester of pentyloxyphenylcarbamic acid achieving an activity 250 times higher than that of standard procaine. The prepared compounds are more effective in the case of infiltration than in the case of surface anaesthesia.
Subject(s)
Anesthetics, Local , Carbamates , Anesthetics, Local/chemistry , Anesthetics, Local/toxicity , Animals , Carbamates/chemistry , Carbamates/toxicity , Structure-Activity RelationshipABSTRACT
The preceding study of the effect of the branching of the connecting chain by the metoxymethyl-, ethoxymethyl- and propoxymethyl group on the alpha carbon on local anaesthetic activity was a stimulus for the preparation of 16 drugs of the group of 1-ethoxyethoxymethyl-2-(1-pyrrolidinyl-), 2-piperidino- and 2-(1-perhydroazepinyl) ethyl esters of o-, m- and p-alkoxyphenylcarbamic acids. The discontinuation of the substituent on the alpha carbon of the connecting chain by another oxygen atom (introduction of an ethoxyethoxymethyl group) has a positive effect on surface and infiltration anaesthesia. Of the prepared agents, 2-piperidino- and 2-(1-perhydroazepinyl-) derivatives with a hexyl or heptyloxy group in the o-position of the benzene ring were most effective; they exceeded the standards cocaine and procaine more than one hundred times. p-Derivatives were least effective; in some cases their indices of effectiveness did not achieve the effectiveness of the standards in both surface and infiltration anaesthesia under study. Acute toxicity of all drugs lies within the range of the toxicities of the standards.
Subject(s)
Anesthetics, Local , Phenylurea Compounds , Anesthetics, Local/chemistry , Anesthetics, Local/toxicity , Animals , Mice , Molecular Structure , Phenylurea Compounds/chemistry , Phenylurea Compounds/toxicityABSTRACT
Within the framework of studying the influence of alterations of the connecting chain in the group of local anaesthetics a series of 24 compounds of 1-propoxymethyl-2-(1-pyrrolidinyl), 2-(1-piperidino)-, and 2-(1-perhydroazepinyl)-ethyl esters of o- and m-alkoxyphenylcarbamic acid were prepared. Studied compounds show a high index of relative local anaesthetic activity as compared to the standards cocaine and procaine, at a relatively low acute toxicity.
