A. S. Lebedeva

Azacycloalkanes VIII. Aromatic amides of N-substitutedα-pyrrolidinedicarboxylic acids

In s ea rch of new anes the t ics and, f i r s t of all, for p repara t ions to be used as sur face anes the t ics , as wel l as for the study of the dependence of pharmacologica l act ivi ty on the chemical s t ruc tu re , a synthes is was ca r r i ed out of a roma t i c amides of N-subst i tuted a~-pyrrolidinecarboxylic acids [1]. The in termedia te e s t e r s of N-subst i tuted ~ -pyr ro l id ineca rboxy l i c acids (II) with R =CH 3 or C2H 5 were obtained f rom ~,5dihalovaler ic acids by the method descr ibed by us e a r l i e r [7]. Fo r the synthesis of e s t e r s of amino acids II with heav ie r r e s idues at the ni t rogen atom of the he terocycl ic r ing, it was found convenient to c a r r y out cycl izat ion of ethyl e s t e r of ~ b r o m o 5 c h l o r o v a l e r i c acid {III) with p r i m a r y amines:

Azacycloalkanes. XXXIII. Synthesis and antialcohol activity of α-alkylamino-γ-hydroxybutyric acid alkylamides

Previously we have demonstrated that the reactions of , -dihalogen-substituted valeric, caproic, and enanthic acids with amines offer a convenient pathway for the synthesis of -pyrrolidine[2], -piperidine[3], and ( -hexamethyleneimine)carboxylic acids [4]. In continuation of these investigations, we have studied the reactions of primary amines with , -dihalogenobutyric acids. It was found that the products of these reactions differ significantly from those obtained by aminolysis of the aforementioned , -dihalogenocarboxylic acids. In particular, no -azetidinecarboxylic acid is formed. Information important for understanding the laws of aminolysis of , -dihalogenobutyric acids was obtained from a comparative study of the rates of halogen ion formation during the aminolysis of -bromo-chlorobutyric acid (I) and the related model compounds ( -bromovaleric and -chloroenanthic acids) by an aqueous methylamine solution (see Table 1) [5 – 7]. As can be seen from the data presented in Table 1, the rates of bromine ion formation during the aminolysis of acid I and the model -bromovaleric acid are virtually the same, while the rates of chlorine ion formation during the aminolysis of acid I and the model -chloroenanthic acid differ by almost one order of magnitude. Previously [5] we demonstrated that a similar acceleration of the chlorine ion formation during the aminolysis of -bromo-chlorovaleric and -bromo-chlorocaproic acids is related to a more rapid cyclization of the intermediate -amino-chlorovaleric and -amino-chlorocaproic acids with the formation of pyrrolidine and piperidine cycles, respectively. In the case of aminolysis of the -bromo-chlorobutyric acid, the accelerated production of chlorine atoms related to the cyclization of -amino-chlorobutyric acid with the formation of an azetidine cycle is less probable. Indeed, comparative data [8] on the formation of 3-, 4-, 5-, 6-, and 7-member azacycloalkanes from the corresponding -bromoamines Br(CH2)nNH2 (n = 2 – 6) show that the rate of azetidine cycle formation is minimum and is about three orders of magnitude lower as compared to that for the piperidine cycle. A more probable explanation of the accelerated production of chlorine ions during the aminolysis of acid I can be based on a fast intramolecular attack of the -carbon atom by carboxylate anions II or III with the formation of intermediate products (substituted -butyrolactones IV or V) reacting with methylamine. The results of aminolysis of acid I by methylamine indicate that the reaction probably proceeds by the following scheme:

N-adamantyl derivatives of arylamides of α-azacycloalkanecarboxylic acids and their topical anesthetic activity

A series of arylamides of α-[N-adamantylpyrrolidyl-(or piperidyl)]carboxylic acids was obtained by reacting 1-(or 2-)aminoadamantanes with arylamides of α,Ω-dihalovaleric (or caproic) acid. The compounds exhibited a pronounced anesthetic activity in experiments.

Azacycloalkanes. XX. Derivatives of hexahydro-1H-azepine-2-carboxylic acids

This synthesis variant is particularly useful for obtaining aminoalcohols lla,b, owing to the accessibility of esters la,b [i]. To obtain aminoalcohols with more complex radicals than methyl, we worked out a synthesis variant based on the ethyl esters of hexahydro-iHazepine-2-carboxylic acid through the intermediate N-acylated derivatives (III). Simultaneous reduction of both the ester and amide groups of III with LAH gave aminoalcohols II.

Physicochemical properties and local anesthetic activity of n-substituted α-azacycloalkanecarboxamides

I t was o f i n t e r e s t t o c o m p a r e t h e s t r u c t u r e , p h y s i c o c h e m i c a l p r o p e r t i e s ( s u r f a c e and i n t e r p h a s e a c t i v i t y , ZR and PHR s p e c t r a ) o f t h e N s u b s t i t u t e d a a z a c y c l o a l k a n e c a r b o x a m i d e s w i t h t h e i r a n e s t h e t i c a c t i v i t y . For t h i s p u r p o s e , t h e f r e q u e n c i e s o f t h e IR bands and the c h e m i c a l s h i f t s o f t h e ~ p r o t o n s o f t h e amide bond o f I i n a n o n p o l a r s o l v e n t ( c a r b o n t e t r a c h l o r i d e ; s e e T a b l e 1) w e r e m e a s u r e d , s i n c e t h e s e p h y s i c o c h e m i c a l p r o p e r t i e s a r e i n d i c a t i v e o f some a s p e c t s o f t h e f i n e s t r u c t u r e ( f o r e x a m p l e t h e c o n f i g u r a t i o n o f t h e ~ a m i n o a m i d e m o i e t y and i t s a s s a c i a t e d p o l a r i t y ) which d e t e r m i n e t h e p h y s i o l o g i c a l a c t i v i t y o f t h e comp o u n d s .

Pyromecaine, a new preparation for topical anesthesia

9 Anesthetizing substances used at the present time in medical practice belong to various classes of organic compounds [i, 2]. There are effective preparations in the field of esters of aromatic acids and amino alcohols (cocaine, novocaine, tetracaine, etc.), amides of aromatic acids (dibucaine hydrochloride: Sovcaine), ethers of dialkylaminoalkanols (pramocaine, cunisocaine), and aminoketones (falicaine, etamine). Anesthetics have extended to aromatic amides of N-substituted a-amino acids (xylocaine, trimecaine, carbocaine, etc.).

Synthesis and antiviral activity of certain aliphatic amides of N-substituted ?-pyrrolidine carboxylic acids

Conclusions1.A series of amides of N-substitutedα-pyrrolidine carboxylic acids are prepared for comparachemotherapeutic tests.2.The antiviral activity of amides of N-substitutedα-pyrrolidine carboxylic acids are studied with respect to influenza virus type A. A connection between the chemical structure of the amides and their antiviral activity is followed in experiments in vitro and in vivo.

Synthesis and pharmacologic properties of some basic esters of α-pyrrolidine-carboxylic acids

We synthesized a series of bisquaternary ammonium salts of the dialkylaminoalkyl esters of N-substitutedα-pyrrolidine-carboxylic acids and determined the relationship between their structure and ganglion-blocking properties. Some of the compounds obtained may be of interest as short-acting gangliolytics in hypertension.