.July, 19G-I
ASTICOSVULSAUT SPIROCOJIPOT-SDS
or decreased rates of responding. An anorexogenic effect of 5A, observed initially in cats, was confirmed in experiments with rats, where an appetite depressant action for 5A was clearly demonstrated. The neurophysiological and biochemical mechanisms which underlie the effects observed with compound 5A are as yet undetermined. That the mode of action includes a sympathomimetic mechanism, as in the case of damphetamine, is discounted tentatively on the evidence that the compound does not reverse to excitation the state of behavioral quiescence induced by prior administration of reserpine. That this material poten-
-239
tiates the action of hexobarbital, rather than antagonizing its effects, persuasively supports this interpretation. In vivo and in zlitro tests have revealed no monoamine oxidase inhibiting properties for 5A. Cardiovascular experiments seem to indicate that 5A is devoid of the hypertensive and cardiac acceleratory effects associated with &hetamine. From these considerations we conclude that the behavioral effects observed with :3-methyl-4-(l-phenyl-2-propylamino)-2phenylmorpholine hydrochloride depend for their manifestation upon other than sympathomimetic or monoamine oxidase inhibiting propertics.
Anticonvulsants. 11. Spiro Compounds. Dihenzo[a,djcycloheptadiene5,5'-hyd antoins, -5,5'-oxazolidinediones, and -5,2'- succinimid es
:lyerst Research I,aboratorirs, dlonlreal, Canada
Rrceii~dDecember Ii. 1!163 Spiro( dibenxo[a,d]cgcloheptadiene-5~5'-hydantoin ) (IIa), an analog of diphenylhydantoin, was prepared by the rearrangement, of dibenzo[a,e]cyclooctadiene-5,6-dione (111)wit'h urea and alkali and by heating 5-hydroxydibenzo[a,d]cycloheptadiene-5-carboxplicacid (VII, R = H ) with urea alone. Substitution of thiourea in the first, method gave the corresponding spirothiohydantoin (17) which was then converted t o the desthio compound (VI). The spirohydantoins IIb, IIc, and IT' were prepared in the normal manner from dibenzo[a,e]cycloheptatriene-5-one (Ib), dibenzo [a,d]cyclooctadien-&one (IC),and dibenzo [a,e]cyclooctadiene-5-one oia interact,ion with potassium cyanide and ammonium carbonate. This method, however, gave none of the spirohydantoin (IIa) from dibenzo[a,d]cycloheptadienJ-one (Ia). The interaction of methyl 5-hydroxydibenzo[a,d]cycloheptadiene-5-rarboxylate (VII, R = CHa) and urea in alkali gave a spirooxazolidinedione (VIII). The acidlization of 5-cyano-5-carbosyalkyldibenzo [a,d]cycloheptadienes (IXa-c) and an analogous cycloheptatriene ( I X d ) produced the corresponding spirosuccinimide and spiroglutarimide derivatives (Xa-d). A spiropyrrolidone ( X I I I a ) and a spiropiperidone (XIIIc) were formed by the hydrogenation of the methyl esters of the appropriate cyano acids (IXa,c). Heat,ing the methyl ester of IXc with ammonia and hydrogen sulfide with subsequent cyclizat,ion of the t'hiocarboxamide (XV) by acid gave the spirothioglutarimide (XVI ). The spire{ dibenzo[a,d]cycloheptadienG,2'-succinimide } (Xa) possessed a promising order of anticonvulsant action in mice while the spirohpdant,oins had, contrary to expertations, only minimal activities.
Our investigation of the dibenzo [a,d]cycloheptadiene analogs of anticonvulsants containing the benzhydryl group' has now been extended to the synthesis of certain spiro compounds. These include the analogs of diphenylhydantoin, -oxazolidinedione, -succinimide, and -glutarimide. Similar spiro derivatives were also prepared from the dibenzo [a,e]cycloheptatriene, dibenzo [a,d]cyclooct~adiene,and dibenzo [a,e]cyclooctadiene ring systems. The spirohydantoin derived from fluorenone has been reported to possess anticonvulsant action in humans. The interaction of dibenzo [a,d]cycloheptadiene-5one (Ia) with ammonium carbonate and potassium cyanide in acetamide under a variety of conditions4 failed to give the spirohydantoin IIa. I n contrast, dibenzo [a,e]cycloheptatriene-5-one (Ib) gave I I b ill 40y0 yield. Low yields of the spirohydantoin derived (1) RI. .iDavis, . S. 0. Winthrop, R . A . Thomas, F. Herr, X - P . Charest. and R. Gaudry, J . M e d . Chem., 7 , 88 (1964). (2) (a) W.J . Close and Sl.A . Spielman in "Medicinal Chemistry V," JV. .J. Hartung, E d . , John Wiley and Sons, Inc.. New York, N . Y., 1961. p. 1; pinks and W.S.Warinh: in "Progress in Medicinal Chemistry 111,'' G . P. Ellis and G. B. West, Ed.. B u t t e r a o r t h and Co., L t d . , London, 1963, p.
261. (3) (a) H. D . Fabing, R . F. Gayle, and J. R . H a a k i n s , Proc. Assoc. RPsearch Nervous Mental Disease, 2 6 , 398 (1947); Chem. A b s t r . , 4 2 , 8972 (1948); (b) S. Carter and H. H. hferritt, J . Lancet, 7 0 , 103 (1950); Chem. Abstr.,44, 6.532 (1950). (4) H. R. Henze, U. S.P a t e n t 2,409,754 (1946).
from xanthone have been reported,j although fluorenone forms the hydantoin in good ~ i e l d . ~It' ~was possible to obtain the desired spirohydantoin I I a by hydrogenation of I I b over palladium or by rearrangement of dibenzo [a,e]cyclooctadieiie-5,6-dione (111) with urea and alkali, following procedures used for the preparation of diphenylhydantoin from benzil.' I n the absence of urea, alkali alone or with added copper sulfate8 did not cause the rearrangement of diketone I11 to 5-hydroxydibenzo [a,d]cycloheptadiene-5-carboxylic acid (VII, R = H). The lower homolog of 111, dibenzo [a,d]cycloheptadiene-lO,1l-dione, has been reported to undergo the benzilic acid rearrangement.9 It was possible to convert the hydroxy acid (VII, R = H), prepared by a different method,'" into the spirohydantoin IIa by heating it with urea a t 135140°, following a similar preparation for diphenyl(5) (a) h l . Trissler and B . Prijs, H e l s . Chim. Acta, 3 6 , 390 (1952);
(b)
C. A . Dornfeld and W. J. Heidke, U.S. Patent 2,683,718 (1954). (6) W.H. M c C o a n and H. R. Henze, J . A m . Chem. Soc., 64, 689 (1942). (7) (a) H . Biltz. B e r . , 41, 1379 (1908); (b) J. Sikdar and T . N. Ghosh, J . I n d i a n Chem. Soc.. 2 5 , 109 (1948); ( e ) W.R . Dunnavant and F. L. James, J . .4m. Chem. SOC.,7 8 , 2740 (1956). (8) J. Klosa. Chem. Tech. (Berlin), 4 , 371 (1982); Chem. Abstr., 48, 1983 ( 1954).
(9) J. Rigaudy and L. N'BdClec, Bull. SOC.Chim. Prance, 638 (1959). (IO) AI. A. Davis, F. A . Sunahara, F. Herr, and R . Gaudry, J . M e d . Chrm., 6 , 513 (1963).
hydaiitoiii.itl If the mixture was gradually Iicated to 22O0l1 an intractable mixturcx resulted froni which iioiie of the desired hydantoin could be isolated. 111 :A maiiiier similar to that used for the preparation of 5.5diphcnyl-2-thiohydantoiii,1? the intcractioii of dikrtotie I11 with thiourea and alkali gave thc. spirotliioliydaiitoiii (1'1) in :ZlC/byield. Tkmoval of tlic d f i i r to givc. spiro { dibenzo [a,d]cycloheptadiciic-.i,4'-imidazolidin /-5'-oiie (1.1) was ticst acrornplishcd I)y thv actioii of sodium iii amyl alcohol.^' wa. t h(, ca correspoiidiiig spirohyda1itoin.i (IIc and 11') in yiclds of .? and 82Yu, respectively. ('ompound 11- may t w considcrcld as an analog of 3-hc~iixyl-.i-phei1ylliydaiitoii1 which ~ - areported \ to have aiiticoiivulsairt activity.? .\ Irtlivl 5-hydroxydibci i m [cr,rl ]cyclolit.ptadieiic-.?-
b, X=CH=CH C,
X = (CHr) i
11
/
urea(~-FI)
urea ( R = C H , )
NaOC-H
HO COzR 'SH
VI1 VI11
carboxylate (VII, 12 = CHa)could be obtained from the acid arid diazomethanelO or directly from the ketoiie (Ia) by treatment with sodium and dimethyl carbonate, a method used to prepare methyl benzilate from beiizopheiione. l i The condensation of the ester n-ith urea in the presence of sodium ethoxide"] gave the spirooxazolidiiiedioiie (T'III) iii good yield. Treatment of this with ethereal diazomethaiie readily furiiished thc S-methyl derivative (XTW). The cyano acids IXa-d were prepared by alkylation of 5-cyanodibenzo [a,d]cycloheptadiene aiid - [a,e]cycloheptatriene with the appropriate bromo ester, with subsequent saponification under mild, alkaliiie conditions. The alkylation was best carried out in ethanol with sodium ethoxide as described for the coiideiisatioii of diphenylacetonitrile with halo esters''; the use of (11) .IR .a h i ~ ~ akind n h l . 0. I1arooq. . 4 n n . , 666, 200 (19.54). (12) H. Riltz, Bel.., 42, 1792 (1909). ( 1 3 ) (a) 13. Biltz a n d K. Seydel. A n n . , 391, 2 1 5 f l Y 1 2 ) : fhJ \. Bouclierle. .I. C'ier, h l . Rayssat. C. 1.. I ) w , a n d R. Teiid?, Bull. Soz. Chim. Prnnrr. ll68 ( 1 9 6 1 ) . (14) ( a ) G . JI, I'ettit ani1 12, 1,;. van 'Paniplen, O r g . K c a c / i o n s , la, 386
(1Yfi2): (h) f i . llariptiirann and R'. P'. iyalter, Cliem. Re?., 62, 370 (1962,. ( 1 5 ) S. Selirian, T'l1.1). Tliesis, Univtsrsity of Tennessee. 1950. ~ 7 . 1 0 0 . Dissertation d b s f r . . 20, ,3083 (19IjO). (16) El. \V. S t o u p l i t o n , .1. A n i . C ' / t f , m S o r . , 63, 2376 ( 1 9 4 1 ) : U. 9. Patent 2.:372,861 (1 (194'2): C h e m . > l h s ti... 37, 622 (1943).
5'
VI
propionic acid oii heating with hydrochloric acid gave oiily a ,a-dipheiiyl-8-methylsucciiiic anhydride. A filler and Loiiglia have prepared a ,a-diphmylsurciiiiniides by t rrating the diacid with an amine and subsequent heating at elevated temperatures. Treatment of XIa with methylamine ill this manner f a i l d . however, to give the spirosuccinimide; decarboxylation occ.urred and the amide (XU) was iholated. Thca qpirosuccinirnide derived from fluor(~iicalso could not be prepared by this method owiiig to cautensive d ~ carboxylation. lici a,a-Dipheiiylglutarimide has beeii prepared from I-cyano--l,I-dipheiiylbutyric acid by treatment with 80-857, ulfuric acidz2 or preferably hy boiling with acetic acid containing a small amount of sulfuric acid.?j Applicatioii of the first method to IXc gave iioiie of the spiroglutarimide (Xc) while the second procedure gave the cyclic product in 51% yield. .Is has heeii reported for I-cgano-~,~-dipheiiyIbutyricacid, 17r,13n IXc was unaff ectcd by boiling with concentrated hydrochloric acid. It may be noted that 4-cyano4,lt r r . 1.. S. I ' a t e n t 2,748,836 (19.58). tirid . \ . - l l . l l u t d , 7 . S. P a t e n t 2,784,200 (1957). C h f " so/.., 5 5 3 ( 1 9 5 2 ) . e i e u , Bull. So?. C l i ~ m France. . 1Y5X
(1959). 122) ( a ) 1;. Saliir(~ii-Legagneur, iCid., 994 (1952); (h) tbzd., 411 (1950). ( 2 3 ) 11. Bretschneider, H. Deotscher, \V. Kltitzer, a n d 31. Sander. J l r r r r ntsh. rhe~i~., 69, 288 (1058).
July, 1964
44 1
t h T I C O S V C L S r l 7 i T SPIRO COMPOVNDS
diphenyl-2-methylbutyric acid readily formed the corresponding glutarimide under these conditions.2 3 The spirosuccinimide Xa gave the S-methyl- (XVIII) and S-3-dimethylaminopropyl (XIX) derivatives when a methaiiolic solution mas treated with sodium followed by the appropriate alkylating agent. l8 Reduction with lithium aluminum hydride in tetrahydrofuran failed to give the 4'-deoxy derivative. The isomeric 1'-deoxy compound, a spiropyrrolidone (XIIIa), was obtained b.y catalytic hydrogenation of the methyl ester of IXa, following the conditions used for the preparation of 4,4-diphenylpyrrolidin-2-0ne.~~,~~ Similar treatment of the methyl ester of IXc furnished the spiropiperidone (XIIIc) which in turn mas reduced with lithium aluminum hydride to the corresponding spiropiperidine (XIT'). The latter is a cyclic analog of the antidepressant agent 5-(3-methylaminopropylidene)dibenzo [a,d]cycloheptadiene (desmethylamitriptyline).26 Following the conditions used for the corresponding benzhydryl compound, a methanolic solution of the methyl ester of IXa mas heated with ammonia and hydrogen sulfide to give the thiocarboxamide derivative (XV). This was then cyclized to the spirothioglutarimide (XVI) by treatment with acid. 5,5-Diphenylbarbituric acid has been prepared from dipheiiylmaloiiyl chloride2' which may be derived from diphenylketene and oxalyl chloride.28 -4 convenient route to the ketene is the dehalohydrogenation of diphenylacetyl chloride with tripropylamine in ether.29 The treatment of dibenzo [a,d]cyclohepta-
/x\
/"\
ketene)) which could not be conveniently separated from the unchanged starting materials. Carrying out the reaction under more vigorous conditioiis led to extensive decomposition. Diphenylacetic acid on treatment with sodium-naphthalene complex in tetrahydrofuran followed by carbonation gives diphenyl1 of this malonic acid in GOYo ~ i e l d . ~ Application method to dibenzo [a,d]cycloheptadiene-5-carboxylic acid failed to give practical amounts of the corresponding diacid. Attempted carbethoxylation of ethyl dibenzo [a,d]cy~loheptadiene-5-carboxylate~~ with diethyl carbonate32in the presence of sodium hydride similarly failed to give the 5,j-diester. Biological Activity.-The biological activities of the spirohydantoiii derivatives were investigated in mice. Our tests included acute toxicity, anticonvulsant activity, and neurotoxic effect. The details of the methods were described previously. The compounds were injected in the form of suspensions which were made up with 4 to 5 drops of Tween-80 in 10 ml. of water. In most cases the approximate LDbo values were determined using at least 20 mice per compound; in other cases the LDbOvalues were determined by the method of Litchfield and W i l c o ~ o i i injecting ,~~ 4 to 5 doses to groups of 10 mice each. The protective effects of the compounds against the tonic phase of maximal electroshock seizures (MES) and against the tonic phase of pentylenetetrazole convulsions were tested in a similar way to that described by Swinyard, et a1.34 The ataxia produced by the compounds was measured
& \
CN CH(CH2)nCOzH
I R
H N y ( C H 2 )71 \
IXa-d
I
\
/
COzH
CH3NH2+ A
@ . 0
CHzCOzH
CH2CONHCHs
XIa,d
XI1
0
(1) CH,OH, H S or CH2N2 (2) HP, Ni
/X,
xv 0
XIV
XIIIa,c
a, X = CHXH?, R
XVI =
II,n
=
0 ; b, X
=
CHsCH?, R = CHI, n = 0; c, X d, X = CH=CH, R = H, n = 0
=
CH2CH2, R
=
H, n
=
1;
diene-,j-carbonyl chlorideYoor dibenzo [a,d]cycloheptatriene-5-carbonyl chloride1 with this base gave, however, only small amounts of the corresponding ketenes (absorption a t 2110 em.-'; vmSx 21 10 cm. (diphenyl-
in mice by means of the rotating bar test35; using groups of 10 mice, the EDsovalues were calculated. The biological activities of the spiro analogs of diphenylhydantoin (IIa-c) depended markedly on the
(24) N. Sperber and R. Fricano, J . A m . Chem. SOC.,75, 2986 (1953). (25) G. Garattini, 1. Giachetti, .\.,Jori, L. Pieri, and L. Valzelli, J . Pharm. Pharmacol., 14, 509 (1962). (26) IC. Hoffinann and E. Tagmann, U. S.Patent 2,702,293 (1955). (27) H. J . Morsman, Helu. Chim. Acta, 18, 1254 (1935). (28) H . Staudinger, 0. Gohring, and M. Scholler, Ber., 47, 40 (1914). (29) H. Staudinger, ihid., 44, 1619 (1911). ( 3 0 ) >I. A. Davis, S. 0. Winthrop, J . Stewart, F. A . Sunahara, and F. Herr. .I. .\fed. Chem., 6, 251 (1963).
(31) H . Norrnant and B. Angelo, Bull. SOC.Chim. France, 810 (1962). (32) H. G. Walker, J r . , R. Lerine, R . F. Kibler, and C . R. Hauaer, J . A m . Chem. Sac., 68, 672 (1946). ( 3 3 ) J. T. Litchfield, J r . , and F. Wilcoxon, J . Pharmacol. Ezptl. Therap.. 96, 99 (1949). (34) E. A. Swinyctrd, W. G. Brown, and L. S. Goodman, ibid., 106, 319 (1952). (35) N. F. Dunham, a n d T. S. Miya, J . A m . Pharm. Assoc., 46, 208 (1946).
July, 1964
AKTICONVULSAST SPIROC ~ M P O U K D S
443
ammonium carbonate (30 g.), and acetamide (100 9.) was heated Anal. Calcd. for CmHiJ02: C, 78.66; H , 6.27; N, 4.59. a t 155' for 84 hr. The cooled mixture was stirred into cold Found: C, 78.52; H, 6.22; N, 4.47. water (1 1.) containing a little sodium hydroxide. The insoluble B.-Follon-ing a procedure for the analogous benzhydryl material vias filtered to give 11.3 g. of unchanged ketone, m.p. compound, 33 a solution of 5-cyanodibenzo [a,d]cycloheptadiene 145-148'. The filtrate was acidified and the precipitate thus (10.9 g., 0.05 niole) in methanol (30 ml.) containing sodium formed was sublimed a t 250" (0.05 mm.) to give 1.0 g. of the hy(0.1 g.) was heated under reflux while methyl acrylate (4.7 g., 0.055 niole) was added dropwise through the condenser. Heating Purification by recrystallization dantoin, n1.p. 255-257 '. was continued for 1 lir., the solvent removed in cacuo, and the from etlianol or chloroform could not be effected due to the tendency of the material to deposit in solvated forms. residue was taken up in benzene. The solution was washed with Spiro ( dibenzo [a,d]cycloheptadiene-5,4'-imidazolidin] -5'water, then dried and evaporated, and the residue was triturat'ed one-2'dhione (V).-A mixture of the diketone (111, 7.7 g.! 0.033 with a little methanol. Recrystallization from this solvent mole) and 543% sodium hydroxide (2.6 ml.) in ethanol (150 ml.) furnished 3.2 g. (2lCC)of product, m.p. 85-87'. was stirred for 10 min., treated with thiourea (2.5 g., 0.033 mole), 3-( 5-Thiocarbamoyldibenzo [a$] cycloheptadiene-5 ) -propionand heated under reflux for 15 min. P a r t of the solvent was reamide (XV).-An ice-cold mixture of the preceding methyl moved in uaci~oand the mixture was added to water and filtered. ester (5.5 g., 0.02 mole) and methanol (70 ml.) was saturated Acidification of the filtrate and recrystallization of the product with ammonia and then hydrogen sulfide. It v a s then heated from ethanol-hexane gave 3.0 g. (31'%), m.p. 232-233'. in an autoclave a t 125' for 4 hr., cooled, and evaporated. The Spiro ( dibenzo [a,d]cycloheptadiene-5,4'-imidazolidin) -5'-one residue was slurried with water, then a little chloroform, and the insoluble material was recrystallized from methanol to give 2.0 (VI).-Sodium (2.3 g., 0.1 g.-atom) was added in small portions to spiro{dibenzo[a,d]cycloheptadiene-5,4'-imidazolidin)-5'-oneg. (34%) of product, m.p. 219-221" dec. An analytical sample 2'-thione (2.7 g., 0.009 mo!e) in dry amyl alcohol (30 ml.). The melted a t 222-224" dec. mixture was heated a t 100' for 0.5 hr. (foaming). Methanol Anal. Calcd. for C1gH?J20Q: S , 8.64; P, 9.87. Found: S , 8.58: S, 9.88. (25 ml.) was added and the heating was continued for an additional 0.2 hr. The cooled mixture was added t o water, the orSpiro ( dibenzo [a,d]cycloheptadiene-5,4'-imidazolidine)-2',5'ganic layer was separated, combined with the ethylene dichlodione (IIa). ( A).-An intimate mixture of 5-hydroxydibenzoride extracts of the aqueous layer, washed with water, and la,d]cycloheptadiene-5-carboxylicacidln (2.54 g., 0.01 mole) and evaporated. Recrystallization of the residue from ethanol urea (1.25 g., 0.02 mole) IYas heated in an oil bath a t 135-140" afforded 1.0 g. (42%)of product, m.p. 201-202". for 6 hr.; water and ammonia were evolved. The cooled mixture waq pulverized and triturated well with dilute sodium hydroxide Spirol dibenzo [a,d] [I,4]cycloheptadiene-5,5'-oxazolidine ] 2',4'-dione (VIII).-To a solution of sodium (0.65 g., 0.028 solution. The alkaline filtrate was acidified and the precipitate thus formed was slurried in dilute sodium bicarbonate solution, g.-atom) in anhydrous ethanol (25 ml.) was added methyl S h y droxydibenzo[a,d]cycloheptad~ene-5-carboxylate(7.5 g., 0.028 filtered, and dried. There was obtained 0.2 g. ( 7 % ) of the crude mole) and dry urea (1.7 g., 0.028 mole). The mixture was spirohydantoin, m.p. 279-280", raised to 309-311" dec. on recrystallization from I-propanol-hexane mixture. stirred and heated under reflux for 16 hr., ammonia being evolved. B.-A mixture of spiro( dibenzo[a,e]cycloheptatriene-5,4'- The solution was concentrated in t~aczio, cooled, and diluted with cold water (100 ml.). A little sodium hydroxide was added imidazolidine}-2',5'-dione (3.3 g.) and 10% palladium on charand the mixture was extracted with ether. The aqueous layer coal (1.0 g.) in absolute ethanol (200 ml.) was shaken a t ambient was acidified with cooling and the liberated product was taken temperature for 10 hr., under an atmosphere of hydrogen with up in ether. Washing the ether with water followed by drying an initial pressure of 3.5 kg./cm.%. The mixture was filtered, and evaporation gave tan crystals, m.p. 186-189" dec. (5.9 g., the filtrate was combined with the ethanol washings of the catalyst, and the solvents were removed in ~ " x o . The residue 80yi). The product was obtained as prisms from 2-propanolhexane, 1n.p. 196196' dec., deposition of the crystals from the which contained a little unchanged starting material was recrystallized to give 0.6 g. (ISYO) of product, m.p. 309-311" solution being complete only after 2 to 3 days. Spiro(dibenzo [a,d]cycloheptadiene-5,5'-oxazolidine1-3'dec., identical with t,he sample prepared above; A",: 242 (i), 267(i), 277(i), and 297(i) mp ( e 2120, 970, 690, and 3 7 ) . methyL2',4'-dione (XVII).-A solution of the preceding comC.-A mixture of dibenzo[a,e]cyclooctadiene-5,6-dione(111; pound (2.7 g., 0.01 mole) in ether (75 ml.) was treated a t 5' with an ethereal solution of diazomethane derived from N0.6 g., 0.0025 mole), ethanol ( 1 ml.), and 50% sodium hydroxide nitrosomethylurea (3.0 g., 0.03 mole) until a permanent yellow solution (1.5 ml.) was stirred for 10 min. a t room temperature. Urea (0.3 g., 0.005 mole) was added and the mixture was heated color remained. The solution was kept for an additional 0.5 hr. and was then evaporated in uacuo. Recrystallization of the resiunder reflux for 2 hr.; a dark red color developed. It was cooled, due from carbon tetrachloride-hexane afforded 2.5 g. (89%) of diluted with water (10 ml.), and the precipitate was collected. Recrystallization from aqueous acetic acid afforded 0.1 g. of product, m.p. 152-153". Spiro( dibenzola,d]cycloheptadiene-5,3'-pyrrolidine ] -2',5'material, m.p. 219-220", whose properties did not support the expected 3a,6a-disubstituted tetrahydroimidae[d]iinidazole-2,5- dione (Xa).-A well stirred mixture of 5-cyanodibenzo[a,d](IH,4H)dione (glycoluril) ~tructure.~.3g cycloheptadiene-5-acetic acid (20.0 g.) and concentrated hydroThe alkaline filtrate was acidified and the resulting precipitate chloric acid (150 ml.) was heated under reflux for 8 hr. I t \vas was recrystallized once from 1-propanol-hexane to give 0.1 g. diluted with water and the precipitate was filtered and stirred with ( 1 4 5 ) of the spirohydantoin, n1.p. 312". sodium bicarbonate solution. The alkali-insoluble material Spiro( dibenzo [a,e]cycloheptatriene-5,4'-imidazolidine ) -2 '3'!vas collected and recrystallized from aqueous ethanol to give dione (IIb).-A mixture of dibenzo[a,e]cycloheptatrien-5-one 14.8 g. (74%) of the spirosuccinimide, m.p. 218-220". Acidification of the bicarbonate solution gave 3.3 g. of white (Ib, 13.4 g., 0.062 mole), potassium cyanide (5.6 p., 0.086 mole), crystals, m.p. 197-198', unchanged on recrystallization from and ammonium carbonate (25.0 g.) in fused acetamide (90 g.) was placed in an autoclave and kept a t 135-145" for 84 hr. ethyl acetate-2-propanol mixture. This material was the corresponding swcinic acid, 5-carboxydibenzo [ a,d]cycloheptadieneThe mixture was cool 'd, stirred with water (300 ml.), and filtered; 5-aretic acid ( M a ) . acidification of the filtrate gave a n insignificant amount of -1nal. Calcd. for C,8Hle04: C, 72.96; H, 5.44. Found: product. The water-insoluble mat 3rial was stirred with dilute C, 72.63; H, 5.68: II',nil. hydrochloric acid. filtered and dried, and then triturated with Spiro( dibenzo [a,d]cycloheptadiene-5,3'-pyrrolidine ) -1 'several portions of ether in order to remove unchanged ketone. The produrt was recrystallized from dimethylformamide-2methyl-%' 5'-dione (XVIII) A.-The preceding succinimide (6.9 g., 0.025 mole) was added to sodium methoxide (2.7 g., 0.05 propanol mixture to give 6.8 g. of the spirohydantoin (40y0 mole) dissolved in methanol (70 ml.) and the clear solution was yield based on the initial quantity of ketone); m.p. >360": EtOH treated dropwise with dimethyl sulfate (6.3 g., 0.05 mole). A,, 297 nip ( e 13,350). An analytical sample was obtained The mixture was gradually heated to boiling and kept there for hy sublimation a t 250' (0.05 mm.). 15 min. Chilling afforded 6.1 g. (84yc) of the product as white Spiro ( dibenzo [a,d]cyclooctadiene-5,4 '-imidazolidine ) -2 '45 'dione (~IC).-A mixture of dibenzo [@I cy~looctadien-5-one~~ needles, m.p. 136-137", unchanged on recrystallization from ethyl acetate-hexane mixture. (13.8 g., 0.062 mole), potassium cyanide (5.6 g., 0.086 mole), B.-5-Carboxydibenzo[a,d]cycloheptadiene-5-acetic acid (4.5 g., 0.015 mole) was added in portlions to methylamine (25yc in ( 3 9 ) R.G . Neville, J . O r g . Chem., 23, 1588 (1958). water, 20 ml.) to form a clear solution which soon thickened to (40) S. 0. W i n t h r o p , M. A . Davis, F. Herr, J. Stewart, and R . Gaudry, .I. M e d . Chem., 6 , 130 (1963). a heavy paste. This was heated gradually to 210" and held there
-
Yield.
.\I p ,
g c .
:300-:31 1
( i
Is
tleca.
>:(MI
-IO
2,i,i-2 3 7
I
298-300
X2
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201-202
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SI)
2 18-220
7-1
L':3\-240
4:
50 210 f 37 (>400) >20 >400 216 f 14 (>200) 153 f 3 (>400) 35 f 6 (38 zk 5 ) 175 (>400) >400 40 f 2 (10.5 f 7) 200 f 18 (255 f 28) 5 4 ~ 0 6 >150 >400 172 f 12 (510 f 37) 9.6 f 1.6 (8.9 f 1)
.\ntipentylenetetrnzole EDso, oral
.\taxin ED:o, oral
>50 67 f 17
28 f 4 >100
>400 >200
27 f 4 >400 >200
>400
>400
33 f 3
430 f 38
>400 >4QO 82 f 5
>400 112 f 22
310 i 40
440 i 68
15
145 f 1i 7 h 0.5
>‘100 >600
81 f 0
Spiro ( dibenzo [a,d]cycloheptadiene-5,4 '-pyrroIidin ) -2'one (XIIIa).-5-Cyanodiben~o[a,d]cycloheptadiend-acetic acid was converted to the methyl ester by heating it under refluv for 8 hr. with methanol containing a little p-toluenesulfonic acid. A solution of the ester (9.8 g.) in methanol (100 ml.) was hydrogenated over Raney nickel with an initial pressure of 80 kg./cm.2 for 18.5 hr. a t 100". The catalyst was filtered, the solution was evaporated, and the rcsidue was recrystallized from ethanolhexane to give 3.8 g. (437,), m.p. 201-202'. Spiro( dibenzo[a,d]cycloheptadiene-5,3'-piperidine) (XIV).-A solution of the spiropiperidone (XIIIc: 4.2 g., 0.015 mole) in dry tetrahydrofuran (100 ml.) was added gradually to lithium aluminum hydride (1.14 g., 0.030 mole) in the same solvent (10 ml.). The mixture was heatcd under reflux for 12 hr., cooled, then hydrolyzed and filtered. The solvent was removed and tl-e of the residue was recrystallized from ether to give 2.0 g. (SOYG) base, m.p. 130-131". Anal. Calcd. for C19H21K: C, 86.64; HI 8.04; XI 5.32. Found: C, 86.56; H, 7.90; N, 5.23. The hydrochloride was prepared (see Table I.). Spiro ( dibenzo [a,d]cycloheptadiene-5,3'-piperidin ) -6 'one-2'dhione (XVI).-A solution of 3-{5-thiocarbamoyldibenxo[a,djcycloheptadiene-5 )-propionamide (1.5 g.) in acetic acid (15 ml.) was warmed to 70" and concentrated sulfuric acid (0.2 ml.) was added. It was then kept a t 100" for 1 hr., cooled, and poured into ice-water. The precipitated solid was filtered, washed with water, and dried. Recrystallization from ethyl acetate-hexane gave 0.5 g. (367,) of product as leaflets, m.p. 174-175".
Acknowledgment.-We wish to thank Dr. G. Papineau-Couture, PtIrs. J. Jachiier, and 1 I r . 11. Boulerice for the spectral data and 1Ir. W. J. Turnbull for the microanalyses.
