Electronic Effects of para-Substituents on the Local _hesthetic Activity of' 2 -Diethylaminoet hyl Benzoate and Related Compounds'" I "
A iiumber of p-.ubstituted beiizoic acid eqters arc knon i i to posseas local aiieithctic activity. The electroiiic \truetiire of the ecter group i i i each of these compoiiiidy i. depeiideiit upon the resoiiaiice effect* of tlic aivmatic srihtituerit-. Electi*oii repelling .ubstitwilt5 i i i thc para positioii of tlirsc wter- \rould be cxpectcd, through their iiidiictii r cffeet o r through i'cyoiiaiicc. to dccrra-e the rrlatii-c tmiid order of tlici cartioiiyl portion of tlie e-ter ginup while electroii a t ti,acting groiip- \\ oiild hc ( q x c t r d t o liar(. t h e oppo.itcJ rffect .
heiizoatey aiid to iwvaluatc thcir local aiir+tlictic activity. Thi- pharmacological evaluation iliould utilize a iiiiiform method of teiting which would compare their actiiitici to a kiiigle standard. I i i tlii. e\.aluatioii, i t \\-as coiiiideretl mor(. rea-oiiablcl to mrasiii'e their potmcies over a fixed pcriod of time rather tliaii thcir duratioii- of actioii, \iiice this lattri mc.a-uremciit might bc morc clo-cly rrlatrd to horn(' detoxificatioii mechaiiihm. I'or tliiy rcasoii, it it adecided that pharmacological testing (higiied to clctermiiir~thrir EDSovalue* iliould he riiidertakeii. .\ modificatioii of the cla-sical mcthod of Bulbring aiid 0 \Vajdai for dctcrmitiiug EDSo\-aliies of iiifiltratioii local ~ , ~ ~ e o C H Z ~ H a ~ ~ c 2 H s j ~ aiieythetics \\-ahemployed for thii purpoyc. Ailthoughqualitative predictions can be made ot thr 0' aiid rcsoiiaiict' dfect': upoii the hoiid H ~ N ~ C OI C H ~ C H ~ N ( C relative ~ H ~ )inductive ~ ordrr i n a group of clo-~lyrrlatetl moleculeiit groups 4tiidird i i i t h i - work. 'l'h carbonyl group might pro^^ liclpful i i i a rorrelatioii of' -pcrtra of t h r rompoiiiid, p r e p a r d m i d rvaluatocl rlirmical ytruct iirc aiid pharmacological activity pliai~macologicall~ \I erc drtcrmiiic~clo i i u Ikckmaii IIt-4 \\'hilt mail? ~ - d i e t h ~ l a m i u o c t lp-substituted i~l beiiqwctrophotomctei. C'ompouiid- capable of iiitcrmolwmute- liavr hecii te for local aiic-thetic activity. a ular hydrogcii iwiidiiig \t r r c dctcrmiiicd i i i dilute w 1 1 i I*?\ irn of the puhli data iiidicated that iio iiiiglt. t i o i i Thoye rompound. that coiiltl i i o t c ~ i i t r into r iiitri mcthod of twtiiig lias 1)crii omploytd iior have all theii molecular Iiydrogr~iihoiidiiig slioit rd i i o higiiificaiit ( l i t pharmacological act;\ itirs h r c i i ed t o any single fcreiiee iii carhoiivl ahsorptioii frccliieriry \\ Iirther dt.tc.1local aiie-thetic It +cemed i i r ry , therefore, t o mined iii yohitioil or i i i a potashium bromide disk prcpare a iitimbcr of 2-diethylam liyl p-Titbstituted 'I'litlse compoiiiids ai.(' 4ion-11 i i i 'I'ablt I with tlirii carbonyl ah-orptioir frc~([rieiicic-aiid EIA0 valuw.
-
4
4 b t i n c t r d t i i i i i i i i t l i r ~ t s .uhiiiitted I I \ 4 R I (ralinskl to tiit of t t i r I nisrralti o i Illinoi I f ~ i l i i t i r t i i e r i t sfor tlie 1)ecrrr of 1 ) i i c t u r of 1'1111 tlie I)t\ision of lIeritcinnl ClirniLsti\ 1 l i n t C lic~rriical*ociet\ \\ashinwton 11 C \ l a r c h L I - L ' I I q b Z (2) D. Uachmansohn ' Chemical and Aloleriilar Rawr 01 S e n e ictiLlty * i c a d e m t c Press S e s Tork, S I' 1959 1)
IA)
( . ~ s i l i t ~ tC'oliere r
ELECTRONIC EFFECTS AND LOCAL ASESTHETIC;~CTIVITY
May, 1963 TABLE I
*kBSORPTIOSFREQUENCIES WITH LOCAI, A4SESTHETICPOTENCIES. BEXZOATES
C]ORREI,ATION O F
2-Diethylaminoethyl s i i h ~ t i t i i t e d benzoate
Ellan. iriiiioles/100 nil.
Absorgtion frequency, em. - 1
p-Ethoxy' 0.012 1708 p-Dimethylamino ,019 1697 p-hlethoxy" 060 IT08 p-Aminoh . 073 1711 p-Hydroxy" 12.5 1714 p-Acetamidod 53 .. Benzoate' .60 1727 8. p-Sitrod , T-l 1731 H . S'anderhaege, P. Kolosy, and AI. Claesen, J . Pharm. Pharnmcol., 6, 119 (1954). Commercially available U.S.P. grade was used in this study. R. Fusco, S. Chiavarelli, G. Palazzo, and 1). Bovet, Gazz. Chim. Ztal., 78, 951 (1948). A. Einhorn and E. Uhlfelder, Ann., 371, 138 (1909). e E. S. Cook anti C. IT. Kreke, J . Ani. C'hem. Soc., 62, 1951 (1940). I. 2. 3. 4. 5. 6. 7.
As may be seen from the EDjo values and the infrared spectra of this series of compounds, there is a marked correlation between local anesthetic potency and the boiid order of the carbonyl portion of the ester group as measured by C=O stretching frequency. Of these compounds, only 2-diethylaminoethyl p-ethoxybenzoate deviates from the local anesthetic activity that might be predicted from its infrared spectrum. Attempts to relate the local anesthetic activity of 2diethylaminoethyl p-chlorobenzoate6 to the boiid order of the carbonyl portion of the ester group were unsuccessful. The compound appeared to possess an ED60 of 0.090 mmole yo and a carbonyl absorption frequency of 1729 cm. -I. Further pharmacological study, however, indicated that animals treated with an "effective" dose of the compound did not regain their sensitivity to pain and that desensitization was probably accompanied by nerve damage. It seemed probable, therefore, that the low ED50 measured was more the result of a toxic manifestation than a true measure of the compound's local anesthetic potency. The local anesthetic properties and the infrared spectrum of 2-diethylaminoethyl p-acetamidobenzoate were also studied. The infrared spectrum of this cornpound showed one weak and two strong peaks in the region of carbonyl absorption which was not further resolved. I t was impossible, therefore, to assign unequivocally the exact absorption frequency of the carbonyl moiety belonging to the ester group. The ED,, of this compound was 0.53 mmole'100 ml. which, as might be predicted, denoted an activity somewhat lower than either 2-diethylaminoethyl p-aminobenzoate or the similar ester of p-hydroxybenzoic acid. I t also demonstrated slightly more activity than 2-diethylaminoethyl benzoate. This might be predicted from the result obtained with the other compounds in this series, since the acetyl group would reduce the resonance effect of the amino group. I n order to examine further the electronic effects of substituents upon local anesthetic activity, it seemed desirable to prepare a compound in which the ester group would be isolated from the usual inductive or resonance effects of the para substituent and to compare this compound with those of similar structure in which the para substituent could enter into resonance (6) H. Vanderhaese,
J . Pharm. Pharmacol.. 6, 55 (1954)'
321
with the ester group. Previous observations' E that ciniiamate esters were better local anesthetics than phenylpropionate esters offered a valuable clue in devising such molecules. Furthermore, use of phenylpropionate esters and cinnamate esters permits a comparison of molecules with an equal number of carbon atoms. Therefore, the 2-diethylaminoethyl esters of b-(paminopheny1)-propionic acid, p-iiitrociniiamic acid and p-aminocinnamic acid were prepared and tested for local anesthetic activity. Their ED,, values and carbonyl absorption frequencies are shown in Table 11. TABLE I1 CORRELATIOK OF ABSORPTION FREQUECCIES WITH LOCAL POTENCIES. 11. CISNAMATES AXD ANESTHETIC PHEKYI,PROPIOK.4TE
Ahsorgtion
Compound
2-Diethylaminoethyl p-aminocinnamate 2. 2-Diethylaminoethyl p-aminophenylpropionate 3. 2-Diethylaminoethyl p-nitrocinnamate" a See footnote 7 . 1.
EDaa.
f re-
mmolew 100 rnl.
rluency, cm.-'
0 063
1710
27 ,66
1T2;i 1731
From these data it may be seen that the aminophenylpropionate ester is less potent and has a higher carbonyl absorption frequency than the aminociiiiiamate ester. As a consequence, it appeared that the amino group was most effective when it was in conjugation with the carbonyl moiety and could, through resonaiice, decrease the relative bond order of the latter. It is also interesting to note that, although the length of the conjugated system is extended in the ciiinamates as compared to the benzoates, both the pharmacological activity (ED5J and the C=O absorption frequencies are yery nearly alike in the p-amino compounds and in the p-nitro compounds. This strengthens our hypothesis that the ester group is at least part of the biologically active portion of these local anesthetic molecules and is probably involved in the binding of the local anesthetic to the enzyme site.
Experimental9 2-Diethylaminoethyl p-Dimethy1aminobenzoate.-In a pressure bottle, 0.15 g. of platinum oxide and 20 nil. of 9.5% ethanol were subjected to hydrogen a t 3 pressure 0.35 kg./cm.2 until the catalyst became black ( 5 min.). A solution of 27.3 g. (0.1 mole) of 2-diethylaminoethyl p-aminobenzoate hydrochloride in 3 nil. of Concentrated hydrochloric acid and 80 nil. of 957, ethanol was cooled to 5'. h 3 i 7 , aqueous formaldehyde solution ( 1 T . O ml.; 0.2 mole) was also cooled to 5' and added dropwise t o the alcoholic solution. The cold solution was then added to the reduced platinum oxide and the entire mixture was hydrogenated a t a pressure of 2.46 kg./cm.* for 5 hr. After the hydrogenation was completed, the catalyst was removed by filtration and the solvent was evaporated. The sirupy residue was dissolved in cold water and the pH of this solution was adjusted t o 9 with sodium carbonate solution. The separated oil was extracted with ether and the ethereal extract was dried over anhydrous sodium sulfate. Subsequent distillation gave 18.2 g. (657,) of an oil which distilled a t 146-148' (0.02 mm.). Anal. Calcd. for C.sHz4N20,: C, 68.20: H, 9.09; X, 10.61. Found: C, 68.29; H , n . l l ; S , 10.58. (7) L. L. Sulya, Microfilm Abstr., 4, No. 2 , 47 (1949). ( 8 ) E. R. A n d r e w , 11. G. Van Campen, and E. L. Schuman, J . A m . Ckem. S o c . , T 6 , 4004 (1953). (9) Microanalyses were performed b y Weiler a n d Strauss, Microanalytical Laboratory, Oxford, England. Melting points are corrected a n d were determined on a Thomao- Hoover capillary melting point apparatus.
