September, 1963
PSYCHOTROPIC AGENTS. VI
513
N e w Psychotropic Agents. VI.’ Basic Esters of 5-Hydroxydibenzo[a,d]cycloheptadiene-5-carboxylicAcid hl. A. DAVIS,F. A. SUNAHARA, F. HERR,AND R. GAUDRY ‘4 yerst Research Laboratories, Montreal, Canada
Received March 12, 1963 Treatment of dibenao [a,d]cycloheptadiene-5-onewith potassium followed by carbon dioxide gave 5-hydroxydibenzo [a,dJcycloheptadiene-5-carboxylicacid. The 2-diethylaminoethyl and 1-methyl-3-piperidyl esters were prepared as possible psychotropic agents. In addition the 2-diethylaminoethyl and 2-( diethy1aminoethoxy)ethyl esters of dibenzo [a,d]cycloheptadiene-5-carboxylicacid were prepared. Pharmacological data concerning the central and autonomic nervous system activities of the compounds are presented together with the in vitro antispasmodic actions.
Certain basic esters of benzilic acid have, in addition to spasmolytic action, pronounced effects on the central nervous system. The 2-diethylaminoethyl ester (benactyzine, I) has been used as a tranquilizer2 while 1-methyl-3-piperidyl benzilate (11) and related compounds3 have marked psychotomimetic actions. Our recent results with some dibenzo [a,d]cycloheptadiene
methane gave the methyl ester, which could be readily purified. Interaction with phosphorus pentachlorides afforded 5-chlorodibenzo [a,d]cycloheptadiene-5-carbony1 chloride. The basic esters were obtained by heating the appropriate acid and aminoalkyl chloride in 2-propanoLg The expected partial rearrangement of the basic side chainloaS1loccurred when the hydroxy acid (IV) was treated with 1-methyl-3-chloropiperidine. A mixture (C,,Hs),C(OH)CO,CH,CH,N(C,H,), (GH,),C(OH)CO, of isomeric hydrochlorides (V and VI) resulted which I could not be resolved conveniently as such but was I1 converted directly to a mixture of the free bases. Heatanalogs of drugs containing the benzhydryl group1 ing this mixture a t about 190’ for 14 hr. gave the 1suggested the preparation of similar analogs of these methyl-3-piperidyl isomer which was purified by subtwo benzilates. In addition, the availability of dilimation in vucuo. The 1-methyl-2-pyrrolidylmethyl benzo [a,d]cycloheptadiene-5-carboxylicacid’ prompted isomer could be obtained in small amounts by chromathe preparation of its 2-diethylaminoethyl and 2-(ditography of a hexane extract of the original mixture on methy1aminoethoxy)ethyl esters as potential spasmosilica gel. Examinations of the carbonyl regions in the lyt ics. infrared spectra were useful in determining the homoTreatment of dibenzo [a,d]cycloheptadiene-5-one geneity of the isomers. The identity of the piperidyl (111) with lithium acetylide in liquid ammonia gave ester was confirmed by acid hydrolysis and determin5ethynyldibenzo [a,d]cycloheptadiene-5-01. Oxidation ation of the infrared spectrum of the resulting alcohol.1aa of this acetylenic alcohol with neutral, aqueous Efforts to secure an authentic sample of this compotassium permanganate6 or with sodium dichromate pound by interaction of 1-methyl-3-piperidinol with in acetic acid failed to give 5-hydroxydibenzo [a,d]- either methyl 5-hydroxydibenzo [a,d ]cycloheptadiene-5cycloheptadiene-5-carboxylic acid (IV), the latter reacarboxylate in the presence of sodium methoxideloaor gent giving chiefly the starting ketone (111). The failwith the corresponding chloroacid chloride followed by ure to obtain 9-hydroxyfluorene-9-carboxylic acid by treatment with water12 were unsuccessful. oxidation of 9-ethynyl-9-fluorenol has been reported.‘j One ester, 2-(dimethy1aminoethoxy)ethyl dibenzoThe desired hydroxy acid was, however, obtained from [a,d]cycloheptadiene-5-carboxylate, was prepared by I11 by treatment with potassium in liquid ammonia interaction of dibenzo [a,d]cycloheptadiene-5-carbonyl with subsequent carbonation. This method gives chloride’ with the requisite alcohol in pyridine. benzilic acid in 50% yield from benzophenone.’ It Pharmacological Activity.-Four of the basic esters could also be obtained in less pure form by treatment of (1, 2, 5, and 6C) were tested in mice for potention of a the ketone with sodium in dimethoxyethane‘jb followed sub-narcotic dose of ethanol and for mydriatic action; 18 hr. later by carbonation. Decreasing the reaction the results are found in Table 11. In addition, 5 and time to 1 hr. gave a lower yield of the hydroxy acid. 6C were compared to their respective benzhydryl comThe acid was somewhat unstable and could not be pounds for their effects on motor activity in the motility conveniently purified as such. Treatment with diazocage method13; 10 animals were used a t each dose studied. All administrations were given intraperi(1) Part V: M. A. Davis, S. 0. Winthrop, J. Stewart, F. A. Sunahara, and F. Herr, J . Med. Chem., 6,251 (1963). toneally. At a dose of 60 mg./kg., compound 5 (2) M. W. Parkes in “Progress in Medicinal Chemistry,” G. P. Ellis and
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G.B. West, Ed., Butterworth and Co., Ltd., London, 1961, p. 115. ( 3 ) D. F. Downing, Quart. Reu. (London), 16, 150 (1962). (4) Since the completion of this work the tropinyl and dimethylaminoethyl esters of this acid have been prepared via the acid chloride: Belgian Patent 016,907(1962); Derwent Report 93A, section 3, p. 7 (1962). (5) H. E. Zaugg, N. R. Springer, and R. J. Michaels, J . O r g . Chem., 26, 645 (1960). (6) (a) S. B. Xadin and J. G. Cannon, ibid., 27, 240 (1962); (b) S. B. Xadin, Ph.D. Thesis; Univ. Microfilm 61-5945 (1962). (7) P. J. Hamrick and C. R. Hauser, J . Am. Chem. Soc., 81,493 (1959).
(8) J. H. Billman and P. H. Hidy, ibid., 67, 130 (1945). (9) H. Horenstein and H. Pahlicke, Ber., 71, 1644 (1938). (10) (a) J . H. Biel, L. G. Abood, W. K. Hoya, H. A. Leiser, P. A . Nuhfer, and E. F. Kluchesky, J . OrQ. Chem., 26, 4096 (1961); (b) L. G. .kbood, A . Ostfeld. and J. H. Biel, Arch. Intern. Pharmacodyn., 120, 186 (1959). (11) E. G. Brain, F. P. Doyle, and M. D. Mebta, J . Chem. Soc., 633 (1961). (12) F. E. King and D. Holmes, ibid., 164 (1947). (13) C. I. Chappel, G. A. Grant, S. Archibald, and R. Paquette, J . A m . Pharm. Assoc., 46, 498 (1957).
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ed tlie activity of inale rats b y :Z.irrC: n-liereas it> 1)ciizhydryl analog, benact,yziiie, is kno~vri to eaiisc iiiot,or htiinulatioii in In our hands t h i s compoiii~diiicreascd the activity 11~7 16'7 and 210c!G ~ v h c i igivcii at, 5 nig. kg. and 2.5 m g . kg.. respect'i\Fely. 'I'lic Sam(' relatioiiship held for (K' aiicl l-rnethy1-3heiizilatje ; which \rere compared i i i male rniccs. up to t>lie I,Djo, 6c' elicited no rvidencc of 011 hut caused a slight (117;) depression at '10 rng. 'kg. Thc 1wnzilatP ester increased the act'ivit,y hy 00 and I Xy:, wheii adniinistcred at 2 ing., kg. aiitl 10 tng. kg., respect,ivr.ly, a fiiidiiig iii substantial agrw~ i i t ~ i u-itli it that of' Biel, a I . L o The distinct lack of st,iniulat,iiig property iii the dibenzo [a,d]cycloheptatlicw: cstcrs may he due. in part, to the rionplaiiarity of
odic actions of t!lie four esters and thP iimhridged analogs were compared in the isolat'ed guiiiea pig ileiim by t,he method of Xagnus (see Table I 11). Tlirr 1-aliies obtained for the ant~iacetylcholinr :ictivity of the reference compounds was of the samr' revioiisly report'ed14--'6 I'/!a,maroi. Toxicoi., 11, 106 I O , l i i i d (;, Le!ini;inn and P. I
