Acknowledgment.-The
niithor \ d i e s t o thnnk h4r. Ti'. Sznho for 11i h carefill t cch n irn 1 assist n ncc.
11. Derivatives of 5,6-Dihydrodibenz[b,e]azepine (5,6-Dihydromorphanthridine)
New Psychotropic Agents.l
STAYLEY
0. WIKTHROP,~ M. A. DAVIS,~ F. H E R R j 3 J . AND ROGER GAUDRY
STEW'ART,"
iigwst Research Laboratoraes, Montreal, Canada Received June 25, 1962 Sodium borohydride treatment of 6,11-diketo-5,6-dihydrodibenz[b,e]azepinc~ produced 11-hydroxy-6-keto-5,6-dihydrodibenz [ b,e lazepine. Alkylation with :~-tlimetliylamiiiopr~~pylniagnesium chloride also gavr an 1 1-hydroxy derivative, 1 l-(3-dimethylnminopropyl)- 11- hydroxy-6- keto-5,G- dihydrodibenx [b,e]azepine. 'This latter compound was used 8s an intermediate for the synthesis of other 11-substituted dibenz [b,e]axepines. The pharniacological activities of some of these compounds are discussed briefly.
In the course of an investigation of the pharmacological properties of compounds containing tricyclic ring systems analogous to the phenothiazine ring, it was found that certain derivatives of dibenzo [a,d][1,4]cycloheptadiene (I)exhibited a number of interesting effects on the central nervous system.'
One of these compounds, namely, 5-(3-dimethylaminopropylidene)dibenzo [a,d][1,4]cycloheptadiene, has since found clinical usage as an antmidepressantagent.4 It' was of interest to investigate similar derivat'ives of ring systems structurally relat'ed to I. The present paper describes a part of this study, the synt,hesis of 5,6-dihydrodi(1) For the first paper in this series, see S. 0. Winthrop, M. 4 . Davis, G. S. Myers, J. G . Gavin, R. Thomas, and R. Barber, J. Org. Chem.. 27, 230 (1962). (2) Department of Chemistry. ( 3 ) Department of Pharmacology. (4) (a) F. J. 4 y d , Jr., Psychosomotics, I , 320 (1960). (b) W. Dorfman, Psychosomatics, I. I53 (1960). (c) H. Freed, A n . J . Psychiat., 117,455 (1960).
hciix [ Ii,cjaxepinr~ (11) clcrivat ivc\ I n t h r (wmpoiin(l\ 1 l i t ) ( ~ : I I ~ N I I I of the, tlil)cxrino [:L.(l 1 [ I , 4 / c ~ y r ~ l o l i c ~ ~ ~ ! :rri iti ij si ~ ~ i i ~ ~ is replaced by a iiit rogtw a1on1 : ~ t o i i ia t t l i c ~ 1 0-po-itioii
Dibenz [l).e]axepiriehhaL-c hecii iii(~11tioiied111 the literature as early as 1913 when tlic syiitliesis of compounds referred t o a\ 6311(.j€I)morphanthridinediones were rep0rted.j Since that time a iium1)ci of I\ orkrrs have prepared mono- and disubstituted 0.1 l-diketo-.i,(iclihydrodibeiiz [b,eJazepines. hmino, chloro, bromo and alkyl sill)stituents in positions 2, 3 , 4, 8 and 9 have heen reportedb The parent ring compound, 3,6-dihydrodibenz [b,e]azepine along \T ith it:. 5mcthyl derivative and related quaternary rompountl~havc l w i i ymthesized by TT7ittig.i -number I of 3-(dialkylarninoalkyl) and 5acyl derivativcs of 5,A-dihydrodibenz Ib.e]azepines \I ere :.tudied by l'rotiva5 as possihle antihistamine>. A recent patent de of 3 - (dialkylammoalkyli - 5,(i - clihydro - 5,O - diketodi1)rnx [h,e1nxepines which are claimed to have antispasmodic propertic.s witlioiit significant anticholinergic or antihistaminic side effects. 9 So \iiiiutituents in thr 1 1-positioii, lionever, have heen reportetl to dnic with the exception of the 1I-ketone I t was of interest to prepare an 1 1-hydroxy-5,8-dihydro~i~jeii~[b,e]azepine for pharmacological evaluation in connection with an01 hcr study i)f4iig carried oiit in t h e v laboratories The ratalytic8 hydrogenation of ( j , l l-diketo-j,G-dihydrodihenz [b,c]azepine (111) has been reported by TYittig' to givc G-ket0-3~6-dihydrodibenz[b.e]azepine indicating an c a y rcductix c clravage of the rarhon-oxygen bond with the lob- of the 11-hydroxyl group. Lithium aluminum hydride reduc tioii of 111 qiinilarly (*ausedreductive cleavage to givv 11. Tht3 Synthesis ol ail 1 I -hJYh'CJXy rompound ~ a - however, , arczomplished \T hen the reaction TT a. varriccl out using sodium 11orohydride giving 1l-li?-drosy-ti-keto-5.~~-(~ihyd~odibeiiz [b,t.]azepine (1T). The -uccessful alkylatioii of t i , l l-dikcto-~,G-dihydrodiberla[I),c]neepine with 3-diniethylnmiiiopropylmagiie~i~iin(ahloride 1 0 ykld 11 - (:3 - dimethylaminopropyl) - 11 - hydrovy - 6 - keto - 5 , t j - dihydrodihenz [b,e]azepine (1.)provided a route to the synthesis of thc 1 1 substituted compounds desired for the present study. Xny alkylation of the amide carbonyl was kept to a minimum by carrying out ( 5 ) Akt. Ges. Fur. Aniline Fabrikation, (,erman PatenG 258 313 (1912 I (6) A. Wolfram and E Hauadorfer, (a) Geriiian l'awnt 551,250 (1028). (11) I' Kranalein, Ber., 70, 1052 (1937) (c) W Bradley, a n d 11. E. Nursten, J Chem. S u e , 2170 (1951). (d) S S Dokunihliin and T N. K u r d w m o v a , Sbornzlc Stole? Obschrz Rhini , 2 1.111 (1953). ( c ) C Caronna and Palaazo, Guzz C i i ~ m ItaE., . 83, 533 (195J). (7) G V i t t l g , (; Closs, and F 3Iindermsn, Ann , 594, 88 (195.5). (8) 31.Borovichaand M. P r o t n a Chem L i s t # , 51, 1344 (1957) (9) I €1 Werner, U.S Patent 2,973,354, F A 28, 1961
the reaction using an inverse addition procedure. Trcatmerit, of 1. with hydriodic acid and red phosphorus then gave ll-(3-dimethylaminopropyl)-6-keto-5,6-dihydrodibenz [b,e]azepine(VI), an 11-deoxy compound. ,4n attempt to reduce the amide carbonyl of V with lithium aluminum hydride in ether was unsuccessful, only starting material being recovered. Reduction of the amide carbonyl was done with lithium aluminum hydride and mercuric chloride in boiling tetrahydrofuran solution but was accompanied by the removal of the 11-hydroxyl group to yield ll-(3-dimethylaminopropyl)-5,6-dihydrodibenz [b,e]azepine (VII), a B,ll-deoxy compound. This compound was also prepared from VI in a similar manner. Acetic anhydride treatment of VI1 gave an X-acetyl derivative (VIII). Attempts to synthesize an 11-(3-dimethylaminopropylidene)
compound 1y tlehytlration of t he I crt iary vnrl )iiiol \vci'c i i n i i i ( v s + Id. Acidic dehydrating agents invaria1)ly led to an iiit ramolrc~iilni S + 0 acyl migration with the formation of a phthalide ring, c.asily recognized by its infrared spectrum. The use of potassium hydroxide in ethylene glycol at elevated temperatures was equally unsuccessful. In one vase. however, when V was heated under reflux for 10 hours with boiling acetic anhydride, an appreciable quantity of 1 1 -C3dimethylaminopropy1)-6.11-diacetoxydibenx[I~,e]azepine (IX) was produced along with the expected phthalide compound (X) Pharmacological Activity.-The compounds \\-ere etudied iii thc wries of pharmacological tests used i n this laboratory to scareen for Liiitidepreshant ilnd other csentral acati\,ity. Thc tebfh incliidetl TT e i v : the detcrmiaatioii of acute toxirity (I,J1)60j, potentiation of :I *til)hypnotic3 dose of ethanol, protect ion against maximal elec~troshoch +eizureq (JIES), mydriatic. action, depression of orientational hypermotility, ataxic effect and influence on a mnditionetl r('spony(' (riinway trqt). -4detailed description of these method5 ha- h t w i reportetl pim-iously. The rompound,. werr' tested further against the (*onti-action- induccd hy awtylcholinr' and histamine in isolatd guincn pig ileum. The results are presented in Ta1)lc 1. l'or coniparalivc purposes thci results obtained for amitriptyline arc also inrliided. The doses for the iri tirw testb and thc concentrations for thr in v i f i o tests are expressed in terms of the free base in all case6 -43none of the structural rhanges made in the mmpounds resulted in a parallel increase or decrease in activity in the different pharmacwlogical tests, it is not possible to establish any simple structure activity relationships. It can be seen. however, that compounds 1.1 and \'I1 had the most potent cwitral (see potentiation of narcosii and effect on conditioned run\\-ay responw) and peripheral effects Sone of the compounds was ahle to protect against t.1ectroshoc.k cyjnvulsions and compound IX appeared to have littlc or no artivity in all of the tests used. \7
Experimental 5,6.Dihydrodibenz[b,e]azepine (II).--To lithium nliiminum hydride (3.4 g., 0 09 mole) and ether (130 ml.) was added 6,1l-diketo-5,6-dih~-drodibenz[b,~] :tzepineG" (5.0g., 0.03 mole) in small portions. The reaction miytiire was heated rlnder reflux for 4 hr., after which the complex was decomposed by the caiitioiib
addition of water in the usual manner. The ether was removed in ZIOCZ~Oand thP residue recrystallized from methanol to give 2.3 g. (43% yield) of product, m.1) 130-132' (lit.7m.p. 130-131"). (10)
F. Herr, J. Stewart,end M.P. Charest, Arch. int. Phormacodun., 134, 388 (1901).
November. 1962
P S Y C H O T R O P I C 5 , 6 - D I H Y D R O D I B E N Z [B,E]AZEPIXES
0
di
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cl
I
+ ri
0
%
A w c e
3
-H rn
d
0
7i
0
2
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3
1203
~ ' I N T H R O P , DAVIS,HERR,STEWART, AND
1204
GAUIIRI.
\-01. 5
.17~al. Cdcd. for ClaH13N: C j 86.12; €I, 6.71; S, i.17. E'ound: (I, 85.74; €I, 7.16; N, 7.22. ll-Hydroxy-6-keto-5,6-dihydrodibenz[b,e] azepine (IV).-Sodium borohydridt. (6.84 g., 0.18 mole) dissolved in water (25ml.) containing 10% sodium hydroxide (1.5 ml.) was added dropwise to a suspension of 6,11-diketo-5,6-dihydrodibenz[li,ejazepine (10.0 g., 0.045 mole) in methanol (200 ml.). After t.he exothermic reaction had subsided, the mixt,nre was stirred for 2 l i Z hr. at room temperai.iire and then heat,ed on a n-ater bath at 60" for an additional 1.5 hr. After cooling, the
producat, was separated by filtration, washed with very dilute acc4c arid and then rrcsrystallized from dioxane to yield 5.0 g., m.p. 248-250" dec. IIicroanalysis showed t,he presence of an impurity which was assumed to he some borate ester. Accordingly, the material was heat,ed in refluxing water for 1 hr., collected, drietl and recrystallized once from methyl isobutyl ketone-dimethylforinaniide to give 2.7 g., 27Yc yield, of product, m.p. 245-248" der. j Y,,,,, (Sujol) 3350 (associated OH), 1663 cm.-' (amide carbonyl). Ak small amount, of impuritl- remained even after repeated recrystallizations. Anal. Calcd. for CI14H1INO?: C, 74.05: 13. 4.92; N, 6.22. Found: C,74.08; FI, 5.04;N, 6.19. 11 -Hydroxy-11-(3-dimethylaminopropyl) -6-keto-5,6-dihydrodibenz [ b,e]azepine (V).--A solution of dimethylaminopropylmagnesium chloride, preparrd from magnesium (10.7 g., 0.468 mole) and dimethylaminopropyl chloride (56.5 g., 0.468 mole) in 160 ml. of tetrahydrofuran, \vas added dropwise to 6,11-diketo5,6-dihydrodibenzo[b,cJazepine (34 g., 0.15 mole) in 3 1. of toluene a t rdiiix temperature. The addition was completed in 1 hr. and heating was continutd for an additional 18 hr. The reaction mixture was cooled and shaken with 2.5 1. of aqueous ammonium chloride. The aqueous layer was then further extracted wit8hether and the combined organic layers mashed with water. The organic ext.racts were dried and concentded to yield 30 g. of crude product, m.p. 150163'. One recrystallization from acetone gave 20 g., m.p. 188-189" (42% yield) (Kujol) 3350 (associated OH), 1650 em.-' which was analytically pure; (amide carbonyl). Anal. Calcd. for C1BH22NZ02: C?73.52;H,7.14; li,9.02. Found: C, 73.58: IT, 7.14; S,9.29. 11 (3-Dimethylaminopropyl)-6-keto-5,6-dihydrodibenz[ b,e]azepine (VIj 11-Hydroxy-11- (3- dimethylaminopropyl) -6-keto-5,6-dihydrodbens[b,e] azepinc, (10 g., 0.0325mole) was dissolved in 120 mi. of glacial acetic acid containing 53 ml. of 56% hydriodic acid and 10 g. of red phosphorus. The reaction mixture \vas stirred and heated a t reflux for 20 hr. The insoluble material was removed h ~ filtration and the filtrate evaporated in U U C ~ M Jleaving , the crudc hydriodide as an oily residue. This waa dissolved in 400 ml. of ethylene dichloride and washed with 150 ml. of 5% sodium hydroxide and then r i t ' h water. The organic layer n-as dried over sodium sulfate and concentrated to yield 8 g. of base, as an oily residue. which crystallized on trituration with acetone to give a solid with m.p. 125-130". Two recrystallizations from acetone-ether gave a sample -with m.p. 131-135 O which was still not analytically pure. Anal. Calcd. for CIBH22N20:C. 77.52; H,7.53; N, 9.52. Found: C , 76.85: F1, 7.45; 3 , 9.60. The compound was further purified by conversion t o its hydrochloridc mlt. T11cI-~asewas dissolved in ether and hydrogen chloride gas was bu!.Jbletl in. r:iriaiiig t IIC lrytlrochloride t o precipihte :IS a gum. This was crystallized from 2-l)rn-
-
.-
November, 1962
PSYCHOTROPIC 5,6-DIHYDRODIBENZ[B,E]AZEPINES
1205
Two recrystalpanol to yield 4.2 g. (40% yield) of solid with m.p 214-216'. lizations from acetonitrile raised the melting point to 22G222". The absence of the hydroxyl group waa confirmed by its infrared spectrum; vUx. (Nujol) 1645 em.-' (amide carbonyl). Anal. Calcd. for CI0Hz3ClXk0:N, 8.47; C1, 10.71. Found: N, 8.79; GI, 10.49. The product was also characterized as its hydriodide salt. A sample of the original oil residue from the hydriodic acid reduction was crystallized from ace-4second tone-methanol to give a solid hydriodide salt with m.p. 232-234'. recrystallization from acetone-methanol did not change the melting point. Anal. Calcd. for C10Hk3IN20: N, 6.64; I, 30.08. Found: N, 6.55; I, 30.22. 11-(3-Dimethylaminopropyl)-5,6-dihydrodibenz[b,e]azepine (VII). Method A. -11-Hydroxy- 11-(3-dimethylaminopropyl) -6- keto- 5,6-dihydrodibenz [ble]azepine (9.4 g., 0.03 mole), lithium aluminum hydride (4.45 g., 0.12 mole), and mercuric chloride (0.92 g., 0.003 mole) were added to 200 ml of tetrahydrofuran The reaction mixture n-m stirred and heated a t reflux for 16 hr. The excess hydride was destroyed by the addition of water in a dropwise manner and the inorganic solids were removed by filtration. The filtrate was dried over sodium sulfate and then evaporated in vacuo to yield 8 g. of product as an oily residue. The residue was taken up in ether and a small amount of insoluble material was removed. The ether solution was then extracted with dilute hydrochloric acid. The aqueous layer was made basic and extracted with ether. This ether extract. after drying over sodium sulfate, was treated with an ether solution of maleic acid, causing the product to precipitate EM the maleate salt, 5 g. (40% yield) with m.p. 138-140". Two recrystallizations from 2-propanol raised the melting point to 146-148". The absence of the hydroxyl and carbonyl groups was confirmed by infrared spectra. Anal. Calcd. for C23H28N204: C, 69.67; H, 7.12; N, 7.06. Found: C, 69.16; H, 7.41; S, 7.05. Method B.-The titre compound was also prepared by an alternate unambiguous route. 11-(3-Dimethylaminopropyl)-6-keto-5,6-dihydrodibenz[b,e]azepine (2.5 g., 0.008 mole), lithium aluminum hydride (1.12 g., 0.008 mole) and mercuric chloride (0.0008 mole) were added t.0 75 ml. of tetrahydrofuran. The r e a h o n misture was heated for 16 hr. and worked up in the same manner as in the preceding paragraph to give 1.7 g. of a maleate salt (52% yield), m.p. 146-148", which was identical in every way to the product of Method A. ll-(3-Dimethylaminopropyl)-6,ll-diacetoxydibenz[b,e]azepine (IX).-ll.Hydrox~-ll-(3-dimethylaminopropyl)-6-keto-5,6-dihydrodibenz [b,e]azepine (23 g., 0.074 mole) was dissolved in 450 nil. of acetic anhydride and heated a t reflux for 20 hr. The acetic anhydride was removed in vumo and the residue triturated with 500 ml. of 1 N sodium hydroxide and extracted with ether. The ether extract was dried and treated with hydrogen chloride to yield 9.8 g. of a crude hydrochloride as a gum. I t was crystallized from a 2-propanol-ether solution to yield 7.5 g. (237, yield), m.p. 228-230". One recrystallization raised the melting point to 23C232". Infrared and microanalysis indicated a 6,ll-diacetate compound; vmax. (Nujol) 1765,1715 and 1693 em.-'. Anal. Ca.lcd. for CZ3H,~C1N20a:N, 6.50; C1, 8.23. Found: N, 6.51; C1, 8.53. 3-(3-Dimethylaminopropyl)-3-(o-acetamidophenyl)phthalide(X).-The aqueous phase from the ether extraction in the previous paragraph was adjusted to pH 7
ntid re-extracted wit,h ether.
The ether extra(+ was dried ancl treated wit,h hydrogen chloride t.o yield 17 g. (,607,yield) of a cmde hydrochlorid:>. It, IV:LS rrystallized from 2-propanol-mt~thanol soliltion to yield 14 g., m.p. 210-212". :i second recrystallization did not cahangc the> nicllt,irig point. Infrarc>d, chemical properties and microanalysis all indicated the structure of the title coitipountl. Y,,,~,,. (Kujol) 1767 (lactone), 1682 c11i:--~ iuniide'i. A i n c ~ l . Paled. for C?IH&IK&: N, i.21 : ('1, 9.14. Fomid: S , 7.16: c'l, !).38. 11 (3-Dimethylaminopropyl)-5-acetyl-5,6-dihydrodibenz [ b,e]azepine (VlII) 1l-(3-Dimethylaminopropy1)-5,6-dihydrodibeiiz [h,e]azepine maleate (7.6 g., 0.019 mole) was dissolved in water and the base liberated by the addition of a q ~ ~ e o u i : sodium hydroxide. The aqueous mixture was rxtractrd with ether, tht. ethvr layer dried and t,hcn evaporated in L'CICUOt.o yield a light tlrow.ii, viscous oil. AN%tic anhydride (50 ml.) was added and t h r reaet'iori mixture heated at refills for 2 hr. The excess acetic anhydridr n-as rrnlovrd i n z~acuo antl the rc.siduch triturated with aqueous sodium hydroxide antl then takcri u p in (.ther. &4ft i'r drying the ether extract ovrr sodium sulf:tte, hydrogen chloride gas \\-as l)uht)lerl in causing the hydrochloride to precipitate :is mi :morphous solid, 3 g.. 111.1). It50-19O0. One recrystallization from 2-propaliol g a w 1.5 g. ( 2 2 " ; yield lI ni.1). 235-238". A second recrystallization tiid 1101 change the melting point : Y (Sujol) 1636 cm.-.'(amide carbouyl). Anal. Calcd. for C?1H&IS20: S . 7.8i: (:!I. 9.88. I ' c J u I ~ ~S~,: 7.47; ('1, 9.70.
-
.--
Acknowledgments.-The authors nidi to thaiik A h . IY. J. Tumbull for the analyses; Dr. Gilles Papineau-Couture, MIX.J. Jachncr ancl Mr. R4. Boulericc for the infrared and ultraviolet Jpectra. The vapable t,echnical assistance of Nessrs. J . G. Gaviii, R. A . Thoma and Miss Marie-Paule Charest is acknowledged.
