Jan. 5, 1959
LOCALANESTHETICS
which was dried a t 100’ (0.1 mm.) fur 3 hours over phosphorus pentoxide; yield 0.318 g. (57.3970), m.p. 178”; Amax in m r (E X pH 1,270 (27.0); PH 7,277 (28.3); pH 13, 277 (28.2).
[CONTRIBUTION FROM
THE
20 1
Anal. Calcd. for C I ~ H ~ & & :C , 59.75; H , 7.33; S 26.80. Found: C, 60.15; H , 7.64; N , 27.17. BIRMINGHAM, ALA
RESEARCH LABORATORIES OF THE U. S. VITAMIN CORPORATION]
Local Anesthetics. I. Esters of 2-(Dialkylamino)-l-phenylethanols BY
SEYMOUR
L.
SHAPIRO,
HAROLD SOLOWAY, EDWARD CHODOS .4ND LOUISFREEDMAN RECEIVED JULY 3, 1958
The bisesters of succinic, terephthalic and phthalic acids, and the esters of mono-, di- and trichloroacetic acids have been synthesized with the use of alcohols of the type R1R2NCH2CH(C~H5)0H and these esters have been examined for pharmacological activity. The bisesters derived from succinic acid were potent anesthetic agents and showed curarimimetic activity.
This paper evaluates the effect of substitution of cedure of Fusco, et a1.,7wherein the hydrochloride of RIR2NCH2CH(C6H5)-’groups for R1R2NCH2CH2- the amino alcohol was allowed to react with SUCin pharmacologically active systems in compounds cinyl chloride in refluxing chlorobenzene. The esters of the chloroacetic acids (11) formed of the type I and I1 readily from the corresponding acid chlorides and COO CH ( CeHj)CHJJRiR? were obtained in 50-6570 yields. y< COOCH( CP,H~)CH?NRIR? The compounds were studied for anesthetic potency using the method of Chance and LobI stein,8 and for curare-like action using the method XaCCOOCH( CsH5)CH2NRiNR2 of Chowg It was of particular interest to establish I1 whether or not a compound would exhibit both an where Y is a residue derived from a dicarboxylic anesthetic and a curare effect. The pharmacologiacid such as succinic, phthalic and terephthalic cal findings are reported in Table 111. In view of the marked enhancement in toxicity acid, and X3C- represents mono-, di- and trinoted with the bis-quaternaries (compounds 5 and chloromethyl groups. Although esters of aliphatic acids2 have generally 6 us. 4, 12 vs. ll), this phase of the work was not been associated with poor anesthetic efficiency, i t explored too extensively. The derivatives of succinic acid (compounds 1, was of interest to explore the bisesters derived from succinic acid, particularly since the bis- 4) showed excellent anesthetic activity, relative to methyl quaternaries of structure I would be that noted with xylocaine, while compound 3 was structural analogs of the clinically effective muscle approximately equal to xylocaine in contrast t o the relaxant, succinylcholine. 3*4 derivatives of the aromatic dicarboxylic acids, which Selected bisesters of terephthalic acid5 have were without anesthetic effect (compounds 9, 10, shown anesthetic potencies comparable to pro- 11). Compbunds 1 and 4 showed good curare caine, and similar compounds were prepared in this activity and thus make available compounds which series. Finally, the effect of a small “fat soluble,” showed both anesthetic and curare-like properties. aliphatic, hydrophobic6 group as provided by the Compound 5, the methobromide of compound 4, X3C- substituent, was evaluated in preparation of also showed curare-like properties but, interestingly. products of the type 11. while i t was far more toxic, i t required higher levels The compounds prepared of type I are described for the curare ED30 than the non-quaternized strucin Table I, and those of type I1 in Table 11. ture. The synthesis of the compounds listed in Table I The findings of significant curare-like activity proved to be unexpectedly difficult. In general, in bis-tertiary amino esters is in direct contrast yields were poor, rangingfrom 4-41%. Method A to the presumptive requirement of a bis-onium entailed treatment of succinyl chloride with the structure. requisite 2-dialkylamino-1-phenylethanollin benThe esters of the chloroacetic acids (Table 11) zene, while method B utilized the more polar sol- were without significant anesthetic activity. vent, acetonitrile. Method C utilized condensaExperimental’ tion of the amino alcohol with phthalic anhydride and subsequent conversion to the bisester with DL(2- [N-isopropyl-N-methylamino] -1-phenylethyl) Suchydrogen chloride. Method D employed the pro- cinate. Method A (Table I, Compound 2).-A solution of (1) S. L. Shapiro, H. Soloway and L. Freedman, THIS JOURNAL, 80, C,060 (1958). (2) T. E. Jones and C. 0. Wilson, J. A m . Pharm. Assoc., Sci. E d . , 42, 340 (1953). (3) J. 0. Hoppe, Anesthesiology, 16, 91 (1955). (4) S. S o r t o n and E. J. DeBeer, J. Pharmacol. Ex#. Therap., 110, 392 (1954). ( 5 ) W. C. North and K. F. Urbach, J. A m . Pharm. Assoc., Sci. E d . , 46, 382 (1956). (6) R. B. Barlow, “Chemical Pharmacology,” John Wiley and Sons. Inc., S e w York, S . Y., 1955, p. 100.
7.7 g. (0.04 mole) of 2-(N-isopropyl-N4’-methylarnino)-l(7) R. Fusco, G. Palazzo, S. Chiavarelli and D. Bovet, G a m chim ital., 79, 129 (1949) IC. A . , 44, 1031 (1950)l. (8) M. R. A. Chance and H. Lobstein, J. Phavmocol. Exp. Tirera9,. 82, 203 (1944). (9) T. C. Chou, Brit. J. Pharmacol., 2 , 1 (1947). (10) S. Loewe and S. C. Harvey, Avch. ex$. Pathol. Pharmakol. Il‘aunyn-Schmiedeberg’s, 214, 214 (1952). (11) F. Briicke, Pharmacol. Revs., 8 , 265 (1956). (12) D a t a shown in Fable I are not reproduced in the Experimental section. Typical preparations are described.
S.L. SIIAPIRO, H. SOLOW.-~Y, E.
202
RI
hlrthod
1
el
0
"2
A A
l i2
K3X"
Y 1
Pic.' HC1
10
CHr CHaC2HjC2H5C2H6- C2Hj-(CHz)r-
97-200"' 223-225c2 63
D
64
21
CHaBr CHaI HC1
123-126c3 239-242"' 204-207'6
HCl HC1 Pic.' HCl
153-156'' A 191-194e8 B 148-15OC1 2Ol-202' C
B
=
r,.
1701.SI
FREEDM.~N
.4nalyses,d % ---Carbon -Hydrogen-. Calcd F < , u I I Cdlcd. ~ Found
--.
fvl p.,b,c
Y!,
8 9
CIIODOS .IND
Forniula
-CHzCH2CzaH3nKzOi CZ~H~S~O CioHieNsOi~ CzsHavCliSnOi C.isHinN204 C&36S201 C30H42Br2N204 C~cHa2IzNzOa CsrHicClzSnOI
J 71.8 53.0
71.8 52.9
8.6 5.1
8 3 4.9
71.8
71.1
8.6
8.4
55.1 48.1 64.7
55.4 48.2 64.1
6.5 5.7 7.8
6.8 5.6 8.3
CzsH3rCliNz04 C3LH~iClrr\T>04 65 2 542 C44H46N8018 C12H19C12NiOr
65 1 338
7 2 4 8
7 3 4 8
-SitrogenCdlcd. Found
6.8
fj.3
13.4 5.0 6 .0 A.n 4.3 3 .7 4. 7
11 9 5 3 5 7 6 3 4 1 3 9 4 3
5 3 4 8 115 4 8
4s 4 6 118 4 9
11 CH3CHsHC1 238-240"s A C)2sH36C12X:20j0 6 1 . 0 6 1 . 1 6 . 6 6 . 7 5.1 4 8 12 CH,CH3CHJ 219-221'' C~OH~ZIZNZOG~ 4 6 . 2 46.4 5 4 5.3 3 6 3.4 Two equivalents of R1R2 and R3X, in all instances, are present in the compound described. Melting points are not corrected, and were taken on a Fisher-Johns melting point block. Solvent for recrystallization: c1 acetone-acetonitrile, isopropyl alcoholi-propyl ether, O 3 isopropyl alcohol, c 4 methanol-methyl ethyl ketone, c6 ethanol, c6 ethyl acetate-ethanol, Analyses by IVeiler and Strauss, Oxford, England. e l B.p. 196-198' (0.02 mm.). acetonitrile, cE ethanol-water. B.P. 216-218' (0.03 mm.). c 3 B.p. 196' (0.06 mm.). e 4 B.p. 206-203' (0.05 mm.). f Pic. = picric acid. 0 Monohydrate. * Dihydrate. (I
TABLE I1 CHLOROACETATE ESTERHYDROCHLORIDES XaCCOOCH (C&)CHINRIRn.HC1" NO.
XsC
RI
R,
M.p.,b,c O C
.
1 ClCHzC?HsC2H,133-139'' -(CHz)r2 ClCHz196-197" C2Hr C2Ha 3 ClzCH147-148'' -(CH2)44 CIgCH201-203c5 C2HsCSH55 CbC108-109Ca -(CHz)a6 C1,C136-138'' Footnotes of Table I apply t o this table.
Formula
C1aH2iC12nT02 Ci4HisCLl;Oa CiaHzoClaNOn Ci4Hi~C13NOz C14HisClaiYOz CiaHi7CIiNOn
TABLE 111 PHARMACOLOGICAL RESPOXSEOF COMPOUNDS OF TABLE I 'Table I cmpd. no.
LD,h.=
Anestheticb EDso
CurareC ED30
1 > 1000 1.7 480 3 400 9.5 Ob 4 750 0.46 80 5 10 0 200 6 0.5 0 0" 9 300 0 0 d 10 300 0 d 11 1000 0 12 25 0 0 Xylocaine 225 6.8 Tubocurarine 1 6' The minimal lethal dose was established (subcutaneous) in mice. The effective dose in mg./ml. which reduces the number of blinks (see ref. 8) by 50% is used to express EDso. The effective dose in micrograms/ml. is used to express the EDao. Slight curare-like action a t 1 mg./ml. e The highest dose tested was 40 micrograms/ml. f EDm = 140 micrograms/ml.
-CarbonCalcd.
Found
54.9 55.3 49.4 49.6 44.8 45.1
54.7 54.9 48.9 49.9 44.7 45.1
Analyses,d % --HydrogenCalcd. Found
6.9 6.3 5.9 5.4 5.1 4.6
7.1 6.2 6.2 5.2 5.3 4.4
-XitrogenCalcd. Found
4.6 4.6 4.1 4.1 3.7 3.8
4.5 4.4 4.1 4.7 3.7 3.9
phenylethanoll in 50 ml. of benzene was added over a 30minute period to a stirred, refluxing solution of 3.1 g. (0.02 mole) of succinyl chloride in 50 ml. of benzene. After refluxing for 2 hours, a hard gum was obtained. The supernatant liquid was decanted and the residue dissolved in 100 mi. of water, cooled, made basic with 4070 sodium hydroxide and extracted with five 20-ml. portions of ether. After drying the combined extracts (magnesium sulfate), the solvent was removed and the residue distilled, yielding 3.9 g. (32%) of product which boiled a t 216-218" (0.03 mm.). Di-(2-diethylamino-l-phenylethyl)Phthalate Dihydrochloride. Method B (Table I, Compound 9).-To a cold solution of 4.4 g. (0.02 mole) of phthaloyl chloride in 15 ml. of acetonitrile, 7.7 g. (0.04 mole) of 2diethylamino-1-phenylethanol' in 15 ml. of acetonitrile was added during 2 hours with stirring and continued cooling. After 20 hours, the reaction mixture, treated with ether, yielded 10 g. of crude product which was dissolved in water. The solution was made alkaline with 40% sodium hydroxide and the separated base was extracted with five 10-ml. portions of ether. The combined extracts were dried (magnesium sulfate). Filtration and removal of solvent gave 6.0 g. of oil from which 1.O g. of 2-diethylamino-1-phenylethanolwas separated, b.p. 68-69' (0.08 mm.). The residue (4.0 g.) was dissolved in ethanol, cooled and 10 ml. of 10% ethanolic hydrogen chloride added. After addition of ether, the dihydrochlo-
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 The synthesis of the compounds listed in Tables concerns procaine analogs of the type RCOO-YI and I1 was efiected by conventional procedures NRlRz wherein R represents a substituted aryl through reaction of the acid chloride RCOCl with or styryl group, Y is an alkylene radical and -NR1R2 the aminophenylethanol,2 RIR2NCH2CH(R4)OH is a secondary amino function. or RIRzNCH(R4)CHz0H,with acetonitrile proving This investigation was concerned chiefly with the to be the preferred solvent. In most instances the effect on local anesthetic response when the hydrochloride of the desired compound precipitated alkylene linking element Y was varied as -CH- or it could be recovered in sufficiently pure state (Rd)CH*- and -CHzCH(R4)-. The group Rq repre- for recrystallization upon evaporation of the solsented phenyl, p-tolyl, p-chlorophenyl, 0-naphthyl vent. In those instances in which the hydroand cyclohexyl, but was largely retained as phenyl. chloride was not crystalline or granular, it was conThis structural feature of the R4 substituent was verted to the free base and the ester was purified retained throughout the work while R and -NRIRz by distillation. The nitro compounds were reduced to the corwere varied principally to encompass factors contributing to anesthetic activity noted by other responding amino derivatives by familiar proworkers. In addition to the free bases and salts of cedures. the anesthetics described, a fairly broad evaluation Pharmacology.-The results and methods of the of the quaternary ammonium salts (RSX) was pharmacological tests have been given in Tables undertaken, I11 and IV. The local anesthetic effect shows Typical of the compounds studied were I and 11, strong dependence on structure. Variation of the and the products prepared have been described in substituent Ra correlates with Burger's4 order 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).
(2) S. L. Shapiro, H. Soloway and L. Freedman, ibid., 80, 6060 (1958). (3) For papers citing many reterences to 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.
