>larch loti7
LUCAL ANESTHETIC
~-(~-~~LKYLA~lI~~ACYLAhllN~)SAL &'IWHb ICY~.~I1~
as seen with decamethonium and hence belongs to the group of depolarizing neuromuscular blocking agents. h The block seen with XI1 and XI11 was similar to that 8 00observed with the antidepolarizer, (+)-tubocurarine. Discussion.-Even the slightest modificat.ion of the 8 60decamethonium molecule usually either decreases the i2 pot,ency or changes it from a depolarizing drug to an u antidepolarizer, or both.21 Thus the introduction 40of the halogen at'oms and the double bond in the 5,6 positions of the decamethylene chain, as in 111, caused 201 a change in potency and therapeutic index. Furthermore, on the isolated preparations, the ability of I11 00 to produce the characteristic biphasic block and initial \Ti (MINUTES) contracture, together wit'h fasciculations normally seen with depolarizers, was less marked as compared with Figure 3.-The blocking effect on three isolated giiiiiea pig decamethonium. In particular t'his was the case for diaphragm preparations of different concentrations of 111: 0-0, 10-5 M ; x-x, 2.5 x 10-5 x;0-0, 5.0 x 10-6 31. the isolated guinea pig diaphragm, as I11 produced Ordinate: the response to nerve stimulation expressed as a peronly a slight phase I block. The slowly developing centage of the response to direct stimulation. Abscissa: the block seen with I11 on this preparation is not typical square root of time. of either the depolarizers or antidepolarizers. Presumably, this block is characteristic of compounds However, I11 labeled with l 3 I I would still be particularly which have a very weak ability to depolarize the motor suited for in situ experiments where continuous exend plat'e. ternal monitoring of its radioactivity is desirable, e.g., Recently, tritiated decamethonium has become available and has proved to be useful for in vitm s t ~ d i e s . ~ ~in*a~muscle. ~
5
L
(21) R . D. Barlow, "Introduction to Chemical Pharmacology," hlethuen and Co., London, 1964. p p 87-139. (22) (a) 0. .I Kedergaard, . Ph.D. Dissertation, Uniyersity of California, Los .\ngeles, 1964; Dissertation Abstr., 26, 1254 (1964); (b) D. 13. Taylor, R. Creese, 0. .I, Nedergaard, and R. Case, S u t u r e , 208, 901 (1965); (e) 0. A. Nedergaard and D. B. Taylor, Ezperientia, 22, 521 (1966).
Acknowledgment.-The authors wish to express their appreciation to Professor D. J. Cram and Dr. L. Gaston, Department of Chemistry, U.C.L.A., for their assistance in some of the syntheses.
The Synthesis and Evaluation of the Local Anesthetic Activity of a Series of 4-(w-Alkylaminoacylamino)salicylate Esters'" GEORGE TSATSAS, COXSTANTINOS SANDRIS, DEMETRIOS KONTONASSIOS, Department of Pharmaceutical Chemistry, University of Athens, Athens-144, Greece
JOHX F. ZAROSLINSKI,RONALD K. BROWNE, A N D LEROY H. POSSLEY Brnar-Stone Laboratories, Inc., Mount Prospect, Illinois Received M a y 25, 1966 Revised Manuscript Received October 31, 1966 A series of a-alkylaminoacyl derivatives of 4-aminosalicylic acid esters (methyl through hexyl, plus 2-diethylaniinoet,hyl) were synthesized and their hydrochlorides were tested for local anesthetic activity. T h e syiit,hesis of the diethylaminoethyl ester series was examined in some detail since these compounds easily undergo alcoholysis and aminolysis. These reactions were ascribed to an intramolecular o-hydroxy catalysis. Only derivatives of the met,hyl, ethyl, and diethylaminoethyl esters exhibited significant local anesthetic act,ivity. Compared to lidocaine, these compounds were generally more irritating, less toxic, and less active. When the compounds exhibiting local anesthetic activity were quaternixed with methyl iodide, local anest,hetic activity was lost while the toxicity increased.
,Ilt,hough Drill3 states that, as a general rule, effective local anesthetics rarely contain either free carboxy or hydroxy groups, Clinton and co-workers4 and (1) T h e investigation a t t h e University of Athens v a s supported by a research grant from the Royal Hellenic Research Foundation. ( 2 ) .I preliminary report of part of this work has been presented a t t h e 21st International Congresn of I'liarmaceutical Sciences, Pisa, Italy. Sept. 4-8. 1Yt31, liy 0. T. a n d C. S. Preliminary announcements have appeared: G. Tsatsas and C . Sandris, &"roc. A c a d . Athens, 35, 372 (1960); G. Tsatsas, C. Sandris, a n d L). liontonassios. %bid., 37, 54 (1962). This paper comprises a portion of a thesis presented by D. K. a t t h e University of Athens. (3) Ai. V. Drill, "I'liarmacology in bledicine," 2nd od, AlcGraw-Hill l h o k Co., Inc., New York, K. Y., 1958, p (18.
Luduefia and Hoppe5have reported that'a series of dialkylaminoalkyl4-alkylaminosalicylatesshowed a high degree of infiltration and topical anesthetic act'ivity. Iieil and Rademacher6 also reported t,hat some alkylaminoethyl 4-aminosalicylates possessed local anesthetic activity similar to t,he corresponding esters of 4-aminobenzuic arid. Oxycaine, the 2-hydroxy analog of procaine synt'hesized by Grimme arid S ~ h m i t zhas , ~ been shown by (4) R. 0. Clinton, S. C. Laskowski. U. J . Salvador, and RI. \Viison, .I. A m . Chem. Soc., 75, 3674 (1951). ( 5 ) F. P. Luduefia and J. 0. Hoppe, Federation Proc., 9, 297 (1950). ( 6 ) W. Keil and E . Rademacher. Arzneimittel-Forsch., 1, 154 (1961). (7) \V. Grimme and H. Sclimite, Ber., 84, 734 (1951).
237 SCHEME I
F
O
H
~
HNR'R" C,H,OH
F o H NH COCHzCl
NHCOCHZNR'R" HNR
9."
COOCH2CH2N(CZH,) 2
'
R
~
~
COOCH2CH,N( C2H6)2 CICH,COCI
~
*OH
C&
NHCOCH,Cl
2"
I
COOCHZCHZN(C2H5),
=
*HC1
Iv
I11
I1
Q-
NHCOCHZNR'R"
V
I"""' CON R'R"
vo CI
NHCOCH,NR'R"
I
I NH COCH2Cl
VI
VI1
I
diliitctl wit ti a11 eqiial voltirne of cold water aiid the precipitate which formed was filtered and washed successively (cold H,O, 207; NHrOH, cold water) yielding 20 g (52Yc) of a colorless product, mp 62". Upon recrystallization from absolute ethanol, a crystalline solid, mp 64", was obtained. ..lna/. Calcd for CI3H1&O3: C, 65.80; H, 8.07; S , 5.90. Found: C, 66.00: H, 8.10; N, 6.07. This procedure may be applied to the preparation of the alkyl esters, methyl throiigh n-biityl, with yields ratiging from 65 (n-biityl) to SOc>; (methyl). The 2-diethylaminoethyl ester Iiydi~ochloridc was obtaiiied iii 84';c yield according to det'ails givcii i i i 3. p:tleiit .I5 Alkyl 4-(w-Chloroacylamino)salicylates.-Alkyl 4-aniiiiosalite (0.15 mole) wab dihsolved iii 300 nil of glacial acetic acid 0.165 mole of tjhc correspoiidiiig chloride (chloroacetyl or :j-chloropropioti~l)was added in small portioiis with coiitiiiLioiis stirriiig. (;eiierally, a volumiiioris, colorless precipitate formed immediately. The mixture was theti diliited with 150 ml of glacial acetic acid aiid atirred for 1 h r ; wat,er ( 5 0 0 ml) was added and the stirring continued fox, ail additioiial Iioiu. Yields of criide prodiict, meltiiig point, and aiialytical data, after rect,ystallization from ethanol, for the chloroaiiilides prepared are given in Table I. 2-Diethylaminoethyl4-Chloroacetylaminosalicylate.-A stirred solution of Zdiethylaminoethyl salicylate hydrochloride (65 g, 0.33 mole) in 260 ml of glacial acetic acid was treated wit,h a solut,ion of chloroacetyl chloride (28 g, 0.25 mole) in 30 ml of glacial acetic acid, added iii small portions. Stirring was contiiiiied for 1 hr after the last addition of chloride and the excess i i f acetic acid was evaporated in vacuo. The residiial acetic8 acid ,alized by additig ti satiiratcd KaTJCOs solririipy residLie. The ialline hydrc~c~hloride \vhivh formed weighed 00.1 g ( i : j f , ~ i , )r ,n p 9!)-103'. After rccrystalliLatioii from Cth,?ii(Jl,mp 105-106'. .lnd. Cdcd for CljllrzCI,NnO~: C1, l!J.42: S , 7.07: i i i o l w t , 30.5.85. E'o~iiid: C1, 10.27: N, 7 . 8 5 ; mol wt, Y t i J . 0 iacidiinctry). If the additioii of bicarboiraie soliitioii ia coiitiiiiied iuiiil t,he medium is strongly alkaline, the hydrochloride initially formed is transformed bo the free base: this is extracted with ether and obtained as an amorphous solid in a 6OCz yield, mp 75-80', After crystallization from ligroin, it is obtained in a crystalline form, mp 81-82". FVheii the crystalline material is allowed to stand for a few hours in the air or even under vacuum, it traiisforms into a gliitinoiis mass,I6melting in a wide range over 160". ITowevri~, the fwe hase give* the same reactions as its stable hydrochloride if used imniedistely after its isolation. (15) I k . .L \Vander .'i.-G., British Patent 739.210 (19.55); 60, l O i i ' J / (1956).
Chem. Ab&..
Alkyl 4-(w-Alkylaminoacylamino)salicylates.-A suspeiisiori of the chloroamide (0.05 mole) in 200 ml of absolute ethanol was refluxed for 2 hr with an excess of amine (0.15 mole). I n two cases the aminoacylaniline crystallized after cooling and was filtered, washed with water, and dried (method 9).Otherwise, the ethanol was removed by distillation, and the residue was treat,ed with 50 ml of a saturated T\'aHC08 solution and 50 ml of water; the aminoacylaniline separated either as a solid, or as an oil. I n the first case it was filtered, washed, and dried (method B ) ; in the second, it was extracted with ether (method C). Followiiig this same procedure, reaction of 2-diethylaminoethyl 4-chlo1oaoetylamitiosalicylate hydrochloride with different amines iii methanol or ethaiiol, gave t,he corresponding met,hyl or ethyl ebters (methods A', B', and C', respectively). Mixtures of t,he products obtained by the two methods described showed no melting point depression. The constants of the aminoacl-1aiiilines prepared and their salts are given in Table 11. 2-Diethylaminoethyl 4-Alkylaminoacetylaminosalicylates.-A suspensioti of 2-diet.hylaminoethy1 4-chloracetylamiuosalicylate hydrochloride (0.025 mole) in 100 ml of anhydrous benzene was refliixed for 4 hr with an excess of amine (0.125 mole). The benzene was then distilled, the reaidtie was treated with SO ml of a saturated K a H C 0 3 soliition, aiid the aminoacylaniline was extracted with ether (method D). The diethylamino and isopropylamino derivat,ives were also prepared by method E (vide infra). The constants of the derivatives and their salts are given in Table 111. 4-Alkylaminoacetylaminosalicylamides.-A mixture of 2-diethylaminoethyl 4-chloroacetylaminosalicylate hydrochloride and an excess of amine (ca. 5 moles) was heated on a steam bath for 4 hr. After cooliiig, the excess amine was removed under vaciiiim, aiid the residiie was extracted u-ith ether to remove the diethylainiiioethyl ester derivative mid theii with chloroform which dissolves the amide derivative (method E ) . The reactioii with diethylamilie aiid isopropylamitie i,ehiilted iii the correspoiidiiig ester derivatives (Table 111), while all other amines gave the corresponding amides (Table I V ) ; in these cases a low yield (1015%) of the corresponding ester derivative could be isolated from the ether extracts. St,artiiig with 4-chloroacetylamitiosalicylic acid" the same amide derivatives were obtained as follows. The acid (0.02 mole) was transformed to its chloride by refluxing with excess SOCl,. After elimination of the excess reagent, under vacuum, (16) JV. .i. .Jacobs and XI. Heidellrerger, .I. B i d . Chem.. 2 1 , 139 (19151, reported t h a t in a similar manner tlie 2-(dietliylaminoetliyl) ester of 4chloroacetylamino benzoic acid was unstable and did not keep well in t h e crude state. (17) A . J. Quick and R. .Idulos, .I. A m . Chem. Soc., 44, 816 (1Y22).
238
239
w + l + l + + + l
I b b l I I I
I I I I I b l b l I I
I I I
I I I - - I
I
N
zd
c.l
3 3
N N No1
-
iN
N N N
3
3
$ 1 3
$1
N
4
3
N N N N
24 1
- 5
C0.s b e ,
E
m
c
c
d
z
