ciiinaiiiic acids. Both methods have been used in this study. The fixed geometry aiid variable, but nieasurable, electron density a t the ester function make the p-dimethylaminoethyl a-phenylcinnamates an iiiteresting system in which to study these structure -action relationships. Chemistry.-The a-phenylcinnamic acids were made6 by the aniine-catalyzed Perkin condelisation of the appropriate aromatic aldehydes aiid phenylacetic acids in the presence of aceticanhydride. Several 1iit>thods7-~~ for the preparation of the p-dialkylaniiiioethyl esters were attempted, but only the method t'iathe acid chloride1* gave the esters. The data for the syntheses of the trans esters are in Table I. Conversion of the cis acids to the cis esters proved to be difficult. In niost cases, only the isomeric trans ester hydrochloride mas obtained. Apparently during the preparation, the cis form isomerized to trans. The rearrangement could be controlled to some extent by preparing the acid TABLEI trans ESTERHYDROCHLORIDES
n.4T.4 O S PREPARATION O F
X
Y
\
F=C\
H/
No.
X
1 2 3 4 5 6 7
H OCH, H OCH, SO1 H
T
/
\
COOCH,CH,N(CH,), .HCI bI.p., oC.a
Yield?
(RCOCI)
R
hI.p., 0C.C (RCOOR"HC1)
H
39-41 86 181-183 H 94-95d 8Se 94-95 85 182-184 OCH, 90' 165-167 90-92 OCH, 90 205-206 H 95-96h 90 240-242 XO? 90"' 244-247 KO2 175-18.5 SO, 8 OCH, SO2 E-97 82 224-223 9 SO1 OCH, 97-98' 6ie,k 232-233 a Melting point of acid chloride, crystallized from hexane. * Crude yield of ester hydrochloride based on the acid. e Prelt'iiig point of ester h.drochloride, crystallized from acetonitrile. Anal. Calcd. for C16H&10?: C, 70.46: H, 4.80; C1, 13.00. Found: C, 69.71; H, 4.80; C1, 12.35. e The free ester is obtained initially and is converted to the hydrochloride (mono>felting point of free ester, 39". S o t isolated. hydrate). Anal. Calcd. for ClsHl&l?;OI: C, 62.62; H, 3.50: C1, 12.23; S , 4.87. Found: C, 62.36; H , 3.34; C1, 12.54: S , 5.02. Melting point of free ester, 138-140". Anal. Calcd. for C16H,?Cl?;Oa: C1, 11.16. Found: C1, 11.31. Melting point of free ester, 81-83". f
s s
Q
chloride at lower temperatures, rather than a t the boiling point of benzene. The data for the syntheses of the cis esters are in Table I1 and the analytical data for both the cis and trans esters are in Table 111. The presence of two isomers in the products from the cis acid was indicated by the wide melting point range and the presence of two carbonyl bands or one broad ( 6 ) R. Ketcham a n d D. J a m b o t k a r . J . Org. Chem., 28, 1034 (1963). (7) F. F. Blicke a n d H. &I. Kaplan, J. Am. Chcm. Soc., 66, 1967 (1943). (8) R. R. Rurtner a n d J. W. Cusic. ahad.. 66, 262 (1943). (9) F. F. Blicke, U. S. P a t e n t 2,401.219 ( M a y 28, 1946); Ckem. B b s t ~ . , 40, 5209 (1946). (10) A. H. Ford-Moore a n d H. R. I n g , J. Chem. Soc., 550 (1947). (11) E. R. A n d r e w , b1. G. Van Campen, a n d E. L. Scliumann, J . A m . Chem Soc., 7 6 , 4003 (1953).
TABLEI1 I>AT.Aos PREPARA'ITOS OF cis ESTER HYDRO~HI.ORIDES .I
Y No.a
cC.b
Time,c rnin.
1 2 3 4
80 -10 80 40 40
30 goh 30 30 60
Temp.,
Yield,d
7c
R
Cis#
60 70
100 55 100 100 100
R cis'
M.p., 0C.Q
30 24 70 80 80
116-117 124-126 mc ii 170-171 87 163-164 a 90 169-lil 183-1 84 6 35 60 75 70 40 217-219 25 60 66 m 1 -3 38 183-184 8 9 2j 60 43 40i 14 199-201 The numbers refer to the same substituents as in Table I. For formation of acid chloride. Reaction time in benzene. Crude yield. e Per cent. (&57;)of cis isomer in the crude product based on infrared analysis. Per cent of cis isomer isolated (based on starting acid). Crystallized from acetonitrileether. Ether. a Based on ultraviolet analysis.
band in the infrared spectrum One band was always the same as that of the previously obtained trans isomer. The spectral data on the acids, acid chlorides, and esters are presented in Table IT'. Since 2c had the greatest tendency to isomerize during ester formation, it was utilized in further studies on this reaction. Isomerization could not occur a t any point other than during or before acid chloride formation, since the ratio of the isomers was the same in the acid chlorides and the amino esters. The reactions in heiizene a t 80 aiid 25' afforded exclusively rearranged trans acid chloride, whereas in ether a t -5' a mixture (55% cis and 45% trans) was obtained. At -60' in ether the cis acid was isomerized to the tians acid, no acid chloride was formed. The fact that isomerization is complete a t very low (-60') and a t higher (23-80') temperatures but that a t an intermediate temperature i- 5") the cis acid chloride is the iiiajor product means that isomerization occurs a t two points and/or by two mec haiiisnis. Pharmacology.-It was indicated above that pdiniethylaminoethyl a-phenylciniianlates have structural features which might be expected to lead to the following types of actions: (1) anticholinergic, ( 2 ) antihistaniinic, and (3) local anesthetic. Extensive studies were carried out to evaluate the acute toxicity, anticholinergic, and antihistaminic actions of all compounds. Representative compounds I t , 2t, 5t, IC, 2c, and 5c, were evaluated for their local anesthetic activity. Systemic effects o n blood pressure, respiration, EEG, aiid EKG of It, 2t, 51, and 5c were also investigated (see Tables V-T'III). Materials and Methods To study the in vivo effects, male Swiss Rebster mice, weighing 18-22 g., were used. ill1 compounds were injected i.p. as their hydrochlorides in normal saline. Dose-response curves were
617
September, 1904 TABLE
EFFECT OF ATROPINE(LDo) O N ------% No.
trans dose"
1
100
2
r-
in
100 125 1 100 (i 200 7 130 4 150 9 250 A total of 10 mice were injected the compounds. :i
I
lZ
JTith compd.
THE
TOXIC EFFECTS OF
mortality--ITith compd. and atropineh
30 30 0 30 0 0 0 50 0 i.p., for each dose, mg./kg.
SO 80 20 60 30 20 0 60 0
THE
ESTERS
-~
c1s dosea
With compd.
i z o t i i c i + 'The atiticlioliiici.gic.dtect appears to lw of a cotiipc~titivc aiitagotiist typc. When iiicreasiiig aiiiouiitb of acc~tylcholiiic~vereadiiiiitistered iii the preseticc~of 10 y 1111. o f It (a dose sdficieiit t o block coiiiplctcly the. response to 0.1 y/iiil. of acetylcholine) the strength of coiitractioii iiicreased uiitil the iioriiial wspoiisc \\a\ obtained at a d o s ~ of 10 y/iiil. This iiiay iiidicatc that thv coiiipou~idblocks thc Iwcptor site to iiiaiiifcst i t s aiiticholiiiergir effect ('oiriparisoii of the aiitihistaminic activities 1x11w l h that 2( is thc i i i o - t activc aiid that 5t is thv iiiost c f f w ti\-
