LOCAL ANESTHETICS
Jan. 5 , 1959
ride precipitated as a gum which upon trituration with additional portions of dry ether yielded 4.0 g. of solid; yield after recrystallization, 9%. Di- (2-pyrrolidino-l-phenylethyl ) Phthalate Dihydrochloride. Method C (Table I. ComDound 10).-A mixture of phthalic anhydride (4.55 g., 0.033 mo1e)'and 100 ml. of toluene was stirred and heated t o reflux in a flask fitted with a Dean-Stark water trap. Upon addition of 12.4 g. (0.06 mole) of 2-pyrrolidino-l-phenyl-ethan01,~ a cleat homogeneous solution was obtained. Dry hydrogen chloride was passed through the reaction mixture for a total of 32 hours with continued stirring and azeotropic reflux. A precipitate which formed immediately, remained throughout the process. Separation of water was substantially completed at the end of the 32-hour period. The precipitate was separated and triturated with ether yielding 16.4 g. of crude product; yield after recrystallization was 41%. Di-(2-diethylamino-l-phenylethyl)Succinate. Method D (Table I, Compound 3).-A solution of 7.8 g. (0.04 mole) of 2-diethylamino-1-phenylethanolin 100 ml. of chlorobenzene was treated with 1.6 g. (0.04 mole) of dry hydrogen chloride. Succinyl chloride (3.1 g., 0.02 mole) was added a t reflux temperature during a 0.5-hour period and refluxing and stirring were continued for 30 hours At the end of this period, evolution of hydrogen chloride had practically ceased and a black, gummy reaction product had separated. The chlorobenzene was removed by decantation and the product was dissolved in water, the solution was washed with ether and made basic with 40y0 sodium hydroxide. The resultant oil which separated was extracted with five
203
20-1111. portions of ether and the combined extracts dried (magnesium sulfate). Filtration of the solution and evaporation of the solvent gave 2.4 g . of residue which was distilled t o yield a small fore-run of 2-diethylamino-1-phenylethanol and then 0.9 g. (8%) of product boiling at 196" (0.06 mm.). Di-(2-pyrrolidino-l-phenylethyl) Succinate Dimethobromide (Table I, Compound 5).-A solution of 4.3 g. (0.008 mole) of di-(2-pyrrolidino-l-phenylethyl) succinate dihydrochloride dihydrate in water was made basic with 40% sodium hydroxide and the free base extracted with ether. The ether extracts were dried (magnesium sulfate), filtered, the solvent removed and the res~dueof the free base was dissolved in 60 ml. of acetonitrile and treated with 3.0 g. of methyl bromide. After standing 20 hours, 3.1 g. of product was obtained; the yield after recrystallization was 52%. 2-Pyrrolidino-1-phenylethyl Dichloroacetate Hydrochloride (Table 11, Compound 4).-A solution of 4.9 g. (0.033 mole) of dichloroacetyl chloride in 70 ml. of ether was cooled in a n ice-bath. T o this was added, with stirring, a solution of 5.8 g. (0.03 mole) of 2-pyrrolidino-l-phenylethan01~ in 30 nil. of ether over a 20-minute period. Stirring and cooling were continued for a n additional hour. The precipitate, after recrystallization from ethanol, weighed 6.9 g. (65y0).
Acknowledgment.-The authors are indebted to Dr. G. Ungar and his staff for the pharmacological results herein reported. YONKERS1, N. Y.
u. S . ~ I T A I v I I NCORPORATION] Local Anesthetics. 1I.I Esters of 2-Amino-1-phenyl- and 2-Amino-2-phenyl-ethanols [CONTRIBUTION FROM
THE
RESEARCH LABORATORIES O F THE
BY SEYXOUR L. SHAPIRO, HAROLD SOLOWAY, EDWARD CHODOS AND LOUIS FREEDMAN RECEIVED JULY 3, 1958 A series of 2-amino-I-phenylethanols and 2-amino-2-phenylethanols have been esterified with benzoic, argloxyacetic ant1 cinnamic acids, and the resultant basic esters and their quaternary ammonium salts have heen examined for pharmacological activity. Many compounds have been found which show a high order of local anesthctic activity, and within this series significant relationships between structure and activity are indicated. Certain compounds in this series show anti-tremorine action, hypotensive and ganglionic blocking effects, as well as adrenergic blocking and adrenergic potentiation effects.
RIuch of the published work on local anesthetics concerns procaine analogs of the type RCOO-YNRlRz wherein R represents a substituted aryl or styryl group, Y is an alkylene radical and -NR1R2 is a secondary amino function. This investigation was concerned chiefly with the effect on local anesthetic response when the alkylene linking element Y was varied as -CH(Rd)CH*- and -CHzCH(R4)-. The group Rq represented phenyl, p-tolyl, p-chlorophenyl, 0-naphthyl and cyclohexyl, but was largely retained as phenyl. This structural feature of the R4 substituent was retained throughout the work while R and -NRIRz were varied principally to encompass factors contributing to anesthetic activity noted by other workers. In addition to the free bases and salts of the anesthetics described, a fairly broad evaluation of the quaternary ammonium salts (RSX) was undertaken, Typical of the compounds studied were I and 11, and the products prepared have been described in Tables I and 11, respectively. RCOOCH(R4)CHzNRiRz.RsX ( I ) --___
R C O O C H ~ C H ( R ~ ) X R I R ~ . R(11) ~X
~.
(1) Paper I of this series, S. 1,. Shapiro, H. Soloway, E. Chodos and I,. Freedman, THISJOURNAL, 81, 201 (1959).
The synthesis of the compounds listed in Tables I and I1 was efiected by conventional procedures through reaction of the acid chloride RCOCl with the aminophenylethanol,2 RIR2NCH2CH(R4)OH or RIRzNCH(R4)CHz0H, with acetonitrile proving to be the preferred solvent. In most instances the hydrochloride of the desired compound precipitated or it could be recovered in sufficiently pure state for recrystallization upon evaporation of the solvent. In those instances in which the hydrochloride was not crystalline or granular, it was converted to the free base and the ester was purified by distillation. The nitro compounds were reduced to the corresponding amino derivatives by familiar procedures. Pharmacology.-The results and methods of the pharmacological tests have been given in Tables I11 and IV. The local anesthetic effect shows strong dependence on structure. Variation of the substituent Ra correlates with Burger's4 order in (2) S. L. Shapiro, H. Soloway and L. Freedman, ibid., 80, 6060 (1958). (3) For papers citing many reterences t o this type of variation, see (a) J. S. Pierce and H. A. Rutter, J r , , ibid., 74, 3954 (1952); (b) W. H IIouff and R . D. Schuetz, J. Ovg. C k e m . , 18, 916 (1993). (4) A. Burger, "Medicinal Chemistry," Vol. I, Interscienre P u b lishers, Inc., New York, N. Y.,1951, p. 100.
204
S. L. SHAPIRO, H. SOLOWAY, E. CHODOSAND L. F R E E D M A I ~
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