J u l y 1967
KEWPSYCHOTROPIC AGEXTS. T’III
Anal. Calcd for CZEH~ZNZO~: C, 70.7; H, 7.6; 11, 424. Found: C, 69.i; H, 7.6; R.I (by mass spectrometry), 424. Reduction of Brucidine to X1V.-Materials used were brucidine (4g), S a ( 3 . 5 g), ?jH3 (400 ml), methanol (4ml), NH&l (4.09). Time intervals were A, 30 min; B, 45 min. The product was recrystalllzed from acetone to give the 215,22-dihydro-23,24secobriicidine a5 a solvate ( 2 g); mp 192-196”; one major spot Ri 0.11, with a trace of a second, Rf 0.16. The desolvated substance, prepared by drying zn caczm, had mp 195-202’.
Anal. Calcd for 71.6; H, 8.4.
C23H32N203:
627 C, 71.8; H, 8.4. Found: C,
Acknowledgments.-We thank Dr. Larry Stein and his associates of the Psychopharmacology Section of these laboratories for the biological testing data, and Dr* DeJongh and J. Hribar, State University, Detroit, Nich., for the mass spectra.
New Psychotropic Agents. VIII.’ Analogs of Amitriptyline Containing the Normeperidine Group AI. A. DAVIS,F. HERR,R.A.
THOMAS, ASD
~IARIE-~A CHAREST ULE
A yerst Research Laboratories, Montreal, Canada
Received iVovember 3, 1966
A series of compounds related to the previously reported 5- [3-(4-carbethoxy-4-phenylpiperidino)propylidene] lO,ll-dihydro-5K-dibenzo [a,d]cycloheptene has been prepared. These include analogs in which the tricyclic ring and piperidino group were separated by one- to three-carbon side chains in differing states of oxidation. I n several cases the corresponding reversed esters were also prepared. Related compounds were made in which the dibenzocycloheptene ring was replaced by an iminodibenzyl, a phenothiazinyl, or a benzhydryl grouping. The preparation of a number of novel intermediates is discussed including that of a dibenzocycloheptene &piroepoxide. Analgetic testing showed that several of the compounds had activities in the range of morphine.
The preparation, in these laboratories, of a series of dibenzocycloheptenes possessing distinct psychotropic activities has been reported.2 Two of the compounds, amitriptyline (Ia) and nortriptyline (Ib), have been used successfully in the treatment of depressive disorders.; One of the analogs which me had studied was IC, in which the terminal amino function, XRlR2, formed part of the 4-carbethoxy-4-phenylpiperidineor nornieperidirie group. When the sparingly watersoluble hydrochloride salt of IC was given intraperitoneally to mice and rats, it exhibited some of the pharmacological properties of the antidepressant drugs, but appeared to lack significant analgetic effects. The influence of the normeperidine group was seen, however, on subsequent oral administration. Due, possibly, to better absorption from the gastrointestinal tract (at large doses a portion of the unchanged compound had tieen found in the intraperitoneal cavity), it exhibited an analgetic action in the range between morphine and meperidine. I t is well known that replacement of the S-methyl moiety of meperidine by appropriate groups can lead to conipourids with markedly enhanced analgetic activities.* On occasion it has been possible to dissociate the morphine-like effects of the parent drug to obtain agents which possess antiperistaltic4 or antitussive6 actions together with minimal or no narcotic properties. Accordingly, a series of compounds related to IC was prepared having the Common structural features shown in 11. Those derived from the dibenzocgcloheptene ring ( A = CH2CH2 or CH-CH; B = carbon) carrying (1) P a r t VI1 M . A. Davis, G. Beaulieu, J . R. \Tatson, and 31 -P. Charest. J . .?fed. Chem , 9 , 860 (1966). (2) (a) S 0. Ninthrop, hl. A. Davis, G S Myers, J. G Gaxin, R. A. Thomas. and R Barber, J. Org Chem., 27, 230 (1962); (b) J. S t e n a r t , M.-P Charest, and F. Herr, J . M e d Chem , 6 , 338 (1963). (3) F. Hafliger and V. Burckhardt in “Psqchopharmacological Agents,” Vol. 4-1, 11.Gordon, E d , Academic Press Inc., K e n Tork, ?;. Y., 1964, p 35. (4) R A Hardy, Jr., and RI. G. Howell in “Analgetics,” G. destevens, 1.11 , Academic Piess Inc., New York, N. Y., 1965, p 179. ( 5 ) BI. A. Daiis, U. S. Patent, 3,094,528 (1963).
Ia, R1=R2= CH3 b, R I = H ; R2=CH3 I1 c, NR,R,= 4-carbethoxy-4-phenylpiperidino
’z
a one- to three-carbon side chain, Y,in differing states of oxidation are listed in Table I . As well as the usual normeperidine group (2 = CO2C,HS), we have also prepared some of the compounds in the form of their reversed esters (2 = OCOC,HJ in the hope of increasing the analgetic potency. Table I1 lists compounds where the dibenzocycloheptene ring has been replaced by a heterocycle, viz., 5-iminodibenzyl or 10-phenothiazinyl. A series of related compounds derived from iminodibenzyl has been claimed to possess antipsychotic propertiesJ6while 2-substituted 10-phenothiazinyl analogs of ICexhibited antihypertensive activity.’ Several compounds were prepared in which the bridging group , A, is absent; these benzhydryl analogs are listed in Table 111. They are related to 2,2-diphenylbutyronitrile derivatives having antidiarrheal (IIIa)8a and
IIta, R = C6HS;R’=C02CPHB(diphenoxylate) b, R=piperidino; R’=CONHZ (pirinitramide) (6) Yoshitomi Pharmaceutical Industries, Ltd., British Patent 1,017,986 (1966); Chem. Abstr., 64, 17559 (1966). (7) H . S. Lowrie, U. S.Patent 3,112,308 (1963). ( 8 ) (a) P. A . J. Janssen, A. H. Jageneau, and J. Huygens, J . Med. PhaTm. Chem., 1, 299 (1959); (b) C. van de Westeringh, P. Van Daele, B. Hermans, C. Van der Eycken, J. Boey, and P. A. J. Janssen, ibtd., 7 , 619 (1964).
KEWPSYCHOTROPIC XGEKTS. 1 7 1 1 1
Juljr 19G7 g
c r i =
-3,s:
'a??
629
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'9
-8
- L i 3
analgetic (IIIb)8b activities. A recent patent9 claims long-acting analgetic act'ivit'y and low toxicity for analogs of IIIa in which the a-cyano group is replaced c c c;."-E . t5.1 CiCDrnC UlC - .N o s$ +A : by hydrogen. 12 3oCy?c.3 Ulrr % F & s . . A variety of methods was eniployed to prepare the & wmmccti pis X L ~ L C % ~ ~ $ zdibenxocycloheptene derivatives listed in Table I. 3 a 2+,%a E E 9 c: = e c s: ?5 P- LC t- 5.1 5.1 c I.9. x . 3c. c. ~9 s: 0 5 3 5 5 g 5.1 ? The most general one involved treatment, of arl apj , , , , , , , , , , , , , , , m3g5 1 propriate 5-(w-haloalkylene or -alkylidene)dibenzo1 9 m e s c.1 c.1 2 _.m CD LC t- , s: s: 5.1 LC m C m lr: t- = W ?.PI -%c=& $ E Y a cycloheptene with secondary amines (method A). 1 u . . . . . . . . . . . . . . . . With normeperidine, it was preferred to carry out, the 5 i g 2 E p 2 g 2 3 % g 3 2 2 % ,P. % Lw= reactions in boiling benzene or tolueiie containing tri- 3 C b s dx g24- E$ [+?% 2 -4-W N. C. et'hylamine, while the condensations Tvith 4-phenyl-40 . . ?corny . . . i z z x X .I x t.zt-0 a E5 *aj piperidinol were best effected in boiling 1-butanol and E 3 2: I Sa2C03. For certain conipounds, especially those I ? E a 0, @ qm c : g % t5 -. 1 - .&. % sg . 2: 6 carrying a hydroxy group on the 5 poshion of the tri12 tt .- l-.E, h 0 . . . g m 0 1 5 ' 1 ? ? m r : 5.15.1 & , Q : : * 2E2. 2 8 cyclic ring, a p-toluenesulfonate was used in place of B the halogen compound (method B). Tields were fair rn t.zrnL?agt-,sg0mzW 0 2 ? e mm _.* t- 0 L9 c c.3 _.Ir: 5.1 L t. +9 3 2 E to poor, but it was shown that' little or no dehydration of the carbinols to the corresponding alkylidenes had occurred. These alkylidenes could, however, be obtained by heating the 5-hydroxy compounds lt-ith niinera1 acid (method C) and could in turn be reduced catalytically to the corresponding saturated side chains (method D). Both of these latter approaches ivere less satisfactory than method A. The reversed esters were obtained from the appropriate piperidinols by heating with propionic anhydride cont'aining a little H2SOI (about 90") (method E). The products, as their hydrohalide salts, tenaciously retained water or solvent of crystallization and required careful drying. Some = difficulties were incurred in finding suitable conditions 0 $?ab4 E 4 4 4 4 '= W X H for the acylations. Treatment of the piperidinol, 8A, + 6 o 5% 4 2 for example, with propionyl chloride in CHC1, either at 2 s s , ,$-e a * room temperature'O or at the boiling point of the solvent h .z s 3 h b -=r 2 gave either incomplete reaction or concomitant dee2 J ~ ~ 3 d ~ . a ~ ~ i 2 .-.E .+ 3 *- i . ~ ~ - u ~ ~ ~ ~ hydration of the 4-hydroxyl group to form 10. Prior 2 2 8 5 of the piperidinol with ethereal methyltreatment +0 v v p R - : . Ea magnesium bromide'l or with NaH in benzene followed u"v y o
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by the acid chloride was unsatisfactory, while the action of propionic anhydride in pyridine at, 50" gave only unchanged carbinol. Other workers'* were unable to esterify a related compound (IV), attributing this to steric hindrance caused by the benzhydryl group.
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