4-Substituted Piperidines. I. Derivs of 4-t-amino-4-piperidinecarboxamides

4-Substituted Piperidines. I. Derivs of 4-t-amino-4-piperidinecarboxamides

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Septeiuher, 19(i4 DERIVATIVES OF ~-~-AMINO-~-PIPERIDIKECBIZBOXAMIIUES 619 TABLE VI11 IAOCAT. .kSESTHETIC .ACTIVITY" Concentration of test material, % Carbonyl pK, of No. 0.05 0 10 0.23 0.50 freqiioncy, parent. II ad It 75 81 ... 1UU 5.9 7.23 21 70 85 . . . 96 6.91 7.51 5l 0 10 90 B6 5.81 6.77 1r 30 36 5.8 5.94 2c 0 2 10* 6.12 5c . . . 21 66 68 5.35 Lidocaine' 63 92 95 * The value is at 0.3% concentration, 0.5% irritated t,he eye. The local anes- thetic activity of lidocaine at 0.01~~ is li%, and at 1% is 100%. a Calculated as 100 - % response (see test). the methoxy group decreases the potency as in 2c. A more sensitive method, ionization constants, was used to determine minor changes in electron density. In the trans series, the pKa values of the a-phenylcinnamic acids parallel with the carbonyl stretching frequency of the amino esters and are directly proportional to the local anesthetic activity. In the cis series, the pK, values of the acids are inversely proportional to the local anesthetic activity. The activity of and 2t is approximately the same as that of lidocaine \Then tested by the corneal reflex method. Experimental l5 @-Dimethylaminoethyl a-Phenyl-trans-cinnamates.-The acid chlorides were prepared by heating the acids6 with a 10% excess of thionyl chloride in refluxing benzene for 30 min. One drop of pyridine per gram of acid was added to the reaction mixture. The solvent and excess thionyl chloride were removed in a rotatory evaporator. The acid chloride was dissolved in hexane and the evaporation repeated. In 3 cases (Zt, 5t, 9t) the acid chlo- rides were recrystallized from hexane and analyzed (Table I). This was found to be unnecessary since the crude acid chlorides afforded good yields of the esters. In most cases the acid chloride in benzene, when treated with 1 mole of the amino alcohol at room temperature, afforded the solid ester hydrochloride which was cwllected by filtration. With Zt, 7t, 9t, 2 moles of the amino alcohol were allowed to react with the acid chloride and t,he solid amino alcohol hydrochloride was removed by filtration. (15) Melting points were taken on a Fisher-Johns melting point block and Xicroanalyses were performed in the microanalytical labora- are corrected. tory, Department of Chemistry, University of California, 13erkeley. Calif. The filtrate was washed wit,h water, dried over anhydrous sodium sulfate, and evaporated to dryness in uacim. An et,her solution of the free ester was treated with dry hydrogen chloride to give the ester hydrochloride, which was collerted hy filt>ration. When ij-dimethylaminticthy1 ~-p-riitroph~nyI-fran~~-p-nitrocinnamate \vas rrystallized from 'JS(;l ethanol, it was converted to the ethyl ester, m.p. 166-l6i0, confirmed by its identit,y with an aut,hen- tic sample prepared from the acid chloride and ethanol. lhta on these preparations are in Table I and the analytical dat,a are in Table 111.
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4-Substituted Piperidines. I. Derivs of 4-t-amino-4-piperidinecarboxamides

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