1300
R. 0. CLINTON,U. J. SALVADOR AND S. C. LASKOWSKI [CONTRIBUTION FROM
THE
-Val. 71
STERLING-WINTHROP RESEARCH INSTITUTE J
Sulfur-Containing Amines. VII.
Local Anesthetics. I1
BY R. 0. CLINTON,U. J. SALVADOR AND S. C. LASKOWSKI
A logical extension of local anesthetic type compounds derived from the 4-aminobenzoyl.nucleus and sulfur-containing amines2is to analogous types containing other parent nuclei. Gilman, et al.,3 have shown, in a correlation of therapeutic activity with aromaticity, that the dialkylaminoalkyl esters of cinnamic acid are more effective than the corresponding benzoate esters; this observation has been extended by McElvain4 to a series of methylpiperidinoalkyl benzoates and cinnamates. In the latter series i t was shown that activity was highest with the cinnamates; however, in general, toxicity was found to increase proportionally. It is also interesting to note in this connection that Gardner, et aLJ5have succeeded in lowering toxicity with retention of activity in the cinnamate series, through the use of esters containing the terminal morpholine group. The present report describes a representative series of benzoates (I), benzamides (11-111), cinnamates (IV), cinnamamides (V, VI) and 2-butyloxycinchonyl derivatives (VII, VIII) derived from
Dr. T. J. Becker and Dr. F. P. Luduena of these Laboratories a t a later date. I n general, it may be stated here that most of the compounds were of a low order of activity.
Experimental'
Esters and Amides, I-VI.-The esters were prepared from a slight excess of acid chloride and the appropriate alcohole in cold dry benzene, and the amides from an excess of acid chloride and the aminee in chloroform-water mixture in the presence of sodium bicarbonate, with due precautions to avoid decomposition of the amines.2 In general the bases were isolated in the usual manner and purified by washing with dilute sodium hydroxide solution. I n certain cases distillation was necessary t o provide bases suitable for conversion to salts. The yields varied from 80-9570. 1-(2-Dimethylaminoethylmercapto) -propyl-2 benzoate hydriodide, I, cottony white needles from isopropyl alcohol, m. p. 119.5-120.8". Anal. Calcd. for C I ~ H Z ~ I N O ZS,S :8.11; HI, 32.36. Found: S. 8.25: HI. 32.70. 2-(3-(Piperidyl-1) -propylmercapto) -ethyl benzoate hydriodide, I, white needles from absolute alcohol, m. p. 116.0-117.5". Anal. Calcd. for C1~H~GINOzS:S, 7.36; HI, 29.38. Found: S, 7.42; HI, 29.24. 3-(3-(Piperidyl-1) -propylmercapto) -propyl benzoate, I, ~ C O X ( C H Z nS(CH2)mNR~ ) pale yellow viscous oil, b. p. 147-148" a t 0.05 mm. 1,x =0 Anal. Calcd. for CIEHZ?NOZS:N, 4.35; S, 9.97. 11, X = NH Found: N, 4.35; S, 9.74. 111, X = NCzHs The citrate formed rosettes of small white needles from absolute alcohol-acetone, m. p. 68.3-70.5". Anal. Calcd. for C Z ~ H J ~ N O ~ S,S :6.24; N, 2.72. IV, x = 0 Found: S, 6.08; N, 2.85. V, X = NH 2 (3p piperidyl-1) -propylmercapto) -ethyl cinnamate hyVI, X = NC2Hi drochloride, IV, small white needles from isopropyl alcohol, m. p. 131-134'. Anal. Calcd. for ClBH28ClNOzS: S, 8.66; C1, 9.58. Found: S,8.68; C1, 9.57. N -( 2-(2-Diethylaminoethylmercapto) -ethyl) -benzamide citrate, 11, small whitezeedles from absolute alcohol-ethyl acetate, m. p. 118-121 VII, x = 0 Anal. Calcd. for C21Ha&OsS: N, 5.93; S, 6.78. VIII, X = NH Found: N, 5.75; S, 6.80. certain of the sulfur-containing amines previously N -( 2 (2 (Piperidyl- 1) -ethylmercapto) -ethyl) -benzareported,6with the purpose of ascertaining whether mide hydrochloride, !I, needles from absolute alcohol-acethe high therapeutic index associated with the re- tone, m. p. 118-120 Anal. Calcd. for CleH&lN2OS: S, 9.74; C1, 10.78. lated 4-aminobenzoyl types2could be extended to Found: S, 9.78; C1, 10.85. non-aminated nuclei. Compounds of types VI1 N-( 2-(2 -Diethylaminoethylmercapto) -ethyl) -cinnamaand VI11 were of especial interest, since they con- mide citrate, V, rosettes of white p r i p s from absolute altain the parent nucleus of the very active but very cohol-ethyl acetate, m. p. 82.5-85.0 . Anal. Calcd. for C D H S ~ N ~ O SN, S : 5.62; S, 6.43. toxic substance, Dibucaine. All of the above compounds were prepared by Found: N, 5.45; S, 6.36. N -Ethyl-N -( 2 - (2 -Diethylaminoethylmercapto)-ethyl) standard procedures with little difficulty. The benzamide hydrochloride, 111, white nezdles from ethyl pharmacological results will be reported upon by acetate-Skellysolve B, m. p . 101.6-102.6 . Anal. Calcd. for C I ~ H ~ ~ C ~ NN, ~ O8.07; S : S, 9.24. (1) Paper VI: Fohlen, Huber, Laskowski and Clinton, THIS Found: N, 8.12; S, 9.40. JOURNAL, 71, 642 (1949). (2) Clinton, Salvador, Laskowski and Suter, ibid., 70, 950 (1948). N -Ethyl-N- (2 - (2 -Diethylaminoethylmercapto)-ethyl) cinnamide hydrochloride, prisms from acetone-skelly(3) Gilman, e l al., ibid., 47, 245 (1925); 60, 437 (1928). solve A, m. p. 105.2-107.6 (4) (a) McElvain, ibid., 49, 2835 (1927); (b) Bailey and McElvain, ,
I
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y, .
ibid., 62, 2007 (1930). (5) Gardner, Clarke and Semb, ibid., 66, 2999 (1933). ( 6 ) (a) Clinton, e! ol., ibid., 67, 594 (1945); (b) Laskowski and Clinton, ibid., 69, 519 (1947).
(7) All melting points and boiling points are corrected. The authors are indebted to Mr. Morris E. Auerbach and staff for the analyses.
April, 1949
A FAMILY OF LONG-ACTING DEPRESSORS
Anal. Calcd. for C I ~ H J I C ~ N ~ O N,S :7.51; C1, 9.50. Found: N, 7.38; C1, 9.64. 2-Butyloxyquinoliine-4-carboxylic Acid Derivatives.These compounds were readily prepared from 2-butyloxyquinoline-4-carbonyl chlorides and the amine or alcohol in dry benzene. 2 - (2 -Diethylaminoethylmercapto)-ethyl 2 -butyloxyquinoline-4-carboxylate hydrochlorideb VII, white leaflets from ethyl acetate, m. p. 125.8-127.0 Anal. Calcd. for C B H & ~ N ~ O ~ S N,: 6.35; C1, 8.04. Found: N, 6.20; C1,8.03. 2 -(3 (Piperidyl-1) -propylmercapto) -ethyl 2 -butyloxyquinoliie-4-carboxylate hydrochloride, VII, waxy white
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(8) . , Gardner and Hammel. THISJOURNAL,58. 1360 (1936), report 37-51% yields of 2-alkoxycinchonyl chlorides, with accompanying by-products of the 2-alkoxycinchoninic acid hydrochloride. Modification of their procedure, by inclusion of a one hour reflux period of the acid-thionyl chloridebenzene mixture, increased the yields of acid chlorides t o 95-97%, with no formation of %alkoxycinchoninic acid hydrochloride.
[CONTRIBUTION FROM
1301
needles from isopropyl alcohol, m. p. 118.4-120.4'. Anal. Calcd. for C~~HW,C~N~O~S: N, 6.01; C1, 7.61. Found: N, 6.01; C1,7.56. N-( 2-( 2 :Diethylamhoethyhercapto) -ethyl 2-butyloxyquinoline-4-carboxamide, VIII, lon: slender white needles from Skellysolve B, m. p. 63.5-64.5 Anal. Calcd. for C ~ ~ H J ~ N J ON,~ S10.41; : S, 7.94. Found: N, 10.31; S, 8.08. The citrate formed tiny white prisms from absolute alcohol-ethvl acetate. m. D. 87.5-90.5' (dec.). . , Anal. Calcd. for C ~ ~ H ~ I N ~N, O ~7.05; S: S, 5.38. Found: N, 6.83; S, 5.22.
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Summary There has been described the preparation Of a series O f esters and amides derived from Sulfurcontaining amines. RENSSELAER, NEWYORK RECEIVED NOVEMBER 9, 1948
THEWELLCOME RESEARCH LABORATORIES]
A Family of Long-Acting Depressors1~2 BY RICHARDBALTZLY, JOHANNES
s. BUCK,^
EDWINJ.
DE
BEER AND FREDERICK J. WEBB'
Some years ago Ide and Buck5 prepared a bling the authentic (new) specimen. De-ethylnumber of N-methyltetrahydroisoquinolines by ation of the original material also yielded a sample the cyclization of the appropriate N-methyl- of 6-hydroxy-N-methyl tetrahydroisoquinoline phenethylamines with formalin and hydrochloric hydrochloride identical with an authentic speciacid. A pharmacological study was performed men of this substance. It was thus evident that by Fassett and Hjort,6 who found all but one the Ide and Buck material was preponderantly member of this group to be weak pressors or 6-ethoxy-N-methyl tetrahydroisoquinoline hydrodepressors with transient action, while 6-ethoxy- chloride contaminated by a small amount of a N-methyltetrahydroisoquinoline was an extremely highly potent depressor substance whose physical potent depressor with a long period of action. properties and composition were not markedly While correlation of physiological action with different from those of the major component. chemical structure is on essentially an empirical A number of formalin cyclizations of 3-ethoxybasis a t present, such correlation within classes phenethylmethylamine followed by attempts to of related compounds usually is fairly good. fractionate the reaction products gave rather I t was therefore felt that the physiological results irregular results. Usually such preparations, cast grave doubt on the purity and identity of this like the original one, produced strong, lasting sample of 6-ethoxy-N-methyltetrahydroisoquino- depression of blood pressure when administered ilne. intravenously to anesthetized dogs in doses of An authentic specimen of 6-ethoxy-2-methyl- 1 mg./kg. body weight. One specimen, a chlorotetrahydroisoquinoline hydrochloride was pre- form-insoluble hydrochloride obtained by sucpared by an alternative route.' The new sample cessive precipitations from chloroform solution had none of the remarkable physiological activity by ethyl acetate, was about four times as active. Serious progress in elucidating the nature of the of the older specimen. Further fractionation of material prepared according to the formalin unknown depressor was not made until a change in procedure afforded a sample more nearly resem- the amine under study was effected. Cyclization of a phenethylamine to a tetrahydroisoquinoline (1) Presented before the Division of Medicinal Chemistry of the by the f ormalin-hydrochloric acid procedure is American Chemical Society, Washington Meeting, August, 1948. (2) The work here reported is part of a project carried out in coleffective only when there is an activating group laboration with a pharmacological group in these laboratories headed para to the cyclization-point. Ortho and para successively by A. M . Hjort and E. J. de Beer. The detailed pharmethoxyphenethylmethylamines are not cyclized macological study will be published separately. by this method. When these amines were treated (3) Present address: Sterling-Winthrop Research Institute, by the usual procedure, however, the products Rensselaer, N. Y. (4) Present address: Firestone Rubber Co., Akron, Ohio. were by far the most active depressors so far ( 5 ) Ide and Buck, THISJOURNAL, 59, 726 (1937). obtained. It was now possible t o secure a fall (6) Fassett and Hjort, J . Pharmacol. E r p t l . Thcrap., 63, 253 in the blood-pressure of 100 mm. of mercury (1938). lasting for an hour or more with doses of the (7) Hiort, de Beer, Buck and Randall, ibid., 1 6 , 64, 252 (1942).
