Synthesis and local anesthetic activity of some derivatives of N,N-dimethyl-2-(2-alkoxyphenylcarbamoyloxy)-1,1-dimethylethyl-ammonium chlorides.

A series of 8 new derivatives of 2-alkoxyphenylcarbamoic acid were synthesized and assayed for local anesthetic activity. The above compounds were isolated as hydrochlorides and their structure was proved by 1H NMR, 13C NMR and IR spectroscopy. The index of anesthetic activity of the compounds in infiltration and surface anesthesia increases with the length of the alkyl chain and, except for the C1-C3 congeners, all higher homologues proved to be significantly more active than the standard reference compounds, procaine and cocaine, respectively. Toxicity of the drugs decreases with increasing the chain length and is within acceptable limits.

Synthesis and local anesthetic activity of two homological series of diastereomeric phenylcarbamates.

By using stereospecific reactions we prepared two homological series of diastereomeric + cis- and + trans-N,N-dimethyl-2-(2- alkoxyphenylcarbamoyloxy)cyclohexylmethyl-ammonium chlorides with number of carbons in the alkoxy group varying from one to eight. Structure of the prepared compounds was proved by NMR and IR spectroscopy. The principal physico-chemical characteristics, including partition coefficients, were obtained and relative local anesthetic activity was measured using a surface in vivo model. It was found that (1) for both cis- and trans-isomers there is a parabolic relationship between log activity and molecular lipophilicity (as measured by TLC RM and log P values), (2) all drugs prepared for this study use hydrophobic pathway to block inactivated channels, and (3) there is no strict requirement for precise disposition of the functional groups responsible for receptor binding, probably due to conformational flexibility of the sodium channel protein.

Synthesis and local anesthetic activity of some derivatives of N,N-diethyl-2-(2-alkoxyphenylcarbamoyloxy)bornan-3-ylmethyl-ammonium chlorides.

A series of 8 new esters of 2-alkoxyphenyl-carbamoic acid were synthesized and assayed for local anesthetic activity. All compounds were isolated as hydrochlorides and their structure was proved by 1H-NMR 13C-NMR and IR spectroscopy. The index of anesthetic activity in infiltration and surface anesthesia proved that all prepared compounds are significantly more active than the standard reference compounds, procaine and cocaine, respectively; it is tightly correlated with the length of the alkoxy group. It was found that there is a parabolic relationship between log activity and molecular lipophilicity (as measured by RM). Toxicity of all compounds is within acceptable limits.

Model compounds in elucidating the structural basis of HIV retrovirus activity. Synthesis of trisodium O-monoalkyl- and O-monoaryldiphosphates.

Trisodium salts of O-methyl, O-butyl, O-phenyl, and O-(4-nitrophenyl)diphosphonic acids were prepared by reaction of sodium dimethylamido-O-(2-cyanoethyl)phosphate with O-alkyl-, and O-arylphosphonic acid. In an effort to obtain anhydrous salts of the acids, besides the conventional method using aqueous sodium hydroxide, another procedure involving reaction, of sodium methoxide in methanol was also used. The structure of the final compounds was confirmed by IR, 1H NMR and 31P NMR spectra. The prepared salts of monosubstituted diphosphonic acids are used as model compounds in studying antiviral and cytostatic activity of phosphorous derivatives of purine and pyrimidine bases.

[Local anesthetics. CVI. Preparation and effect of (+/-)-trans-[2-(piperidinomethyl) cyclopentyl] alkyl, alkoxy and halogen substituted esters of phenylcarbamic acid]. / Stúdium lokálnych anestetík. CVI. Príprava a úcinnost' (+/-)-trans-[2-(piperidinometyl) cyklopentyl] alkyl, alkoxy a halogén substituovaných esterov kyseliny fenylkarbámovej.

Within the framework of the research of potential local anaesthetics, five compounds from the group of (+/-)-trans-[2-(piperidino-methyl)cyclopentyl]alkyl, alkoxy and chloroalkyl esters of phenylcarbamic acid were prepared. The final compounds were obtained by addition of (+/-)-trans-2-(piperidinomethyl)cyclopentanol to the corresponding substituted phenylisocyanates. They were isolated in the form of salts with hydrochloric acid. Their structure was confirmed on the basis of interpretation of the results of UV and IR spectra. A pharmacological evaluation revealed that the final compounds were more effective than the employed standards cocaine and procaine, but they did not achieve the expected effect in comparison with the pattern compound pentacaine. The index of local-anaesthetic efficacy ranges from 1 to 8 in surface anaesthesia and 1 to 12 in infiltration anaesthesia. It is substantially lower even in comparison with analogical basic esters of alkoxyphenylcarbamic acid.