‘Uie et her-ex trac t able I>ragendorfY-poaiti ve component>, bands 1 and 2 (Table 11),were characterized with little difficult>.. Rand 1 nhich migrated :i\ intact I (compare Rfwith that of I 111 Table I) was found to ~clcwticnlwith I b:, further tlc imd b:, high-reqolutioii n i m h spectrometr> (Table I\r). Band 2 . 011 purificatioii by tlc, yielded :t pattern of metabolite. (and artifact) which \vas almost i t i i exact duplicate of that obtuincti n ith bniitl 1. Component. 2Al. 2.1?. 9 3 , a t i d 2C :itialogou> to the t i a i i d 4 conipoiieiiti (Table 111) \rere obtained arid each component \\as found tiy high-reholution mass spectromctr?. (T:iblc 117)to he itlentic:il with the itnalogouh band 4 comporienl. F’urthcrmore, components :ind 2C \yere more re:dily identified :is TI1 becau+e the:,. (lid tiot cont:iiri ttic (v&meouL: uz/ e 302 fragment. I t i h evideiit from the ahovc that rioncorijugatetl 11, 111, :11ic1 intact drug (I) \\ere excreted in the urine. h
i
Acknowledgments.-We are itidcbted t o I l r . I{. 1.: Bagdon for hupplying u, \\ ith the dog uriric u-ed 111 t he\(> studies and to I)r. H. I’occliiiki) and Ilr. \T. ,J. I lor for the huniati urine. We :ire :d.o iiidebtetl to 1Ir.. A . Goetz for operatioil of the mas. ypectroiiicter.
Quinazolines and 1,l-Benzodiazepines. XL.
The Synthesis of Metabolites of ?-Chloro-l-(2-diethylaminoethyl)-5-(2-fluorophenyl) 1,3-dihydro-2H-l,4-benzodiazepin-2-one
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The syiihe-is of :t n i u i i h of compuunds related to the hypnotic., 7-(~hlo~o-I-~‘L-dicth~lariliIloethJ.l)-~-(~-flllori)~~tieiiyl)-l,3-dihydro-~R-1,4-benzodiaaepin-%-one (2), is reported. These compoiinds were prepared as potential metabolites and many were found to he identical with the metabolites isolated and discussed in t,he preceding paper.2 It1 cotitiectioii with the metabolic studies of the hypnotic, i-chloro- 1-(2-diethylaminoet hyl) -3- (2-fluorophen:,l)-1,3-dihydro-2H-l,4-benzodiazepin-%-otie (2).’ diqcwsed in the preceding paper,2 we have syrit heaized a number of related compounds designed a s possible 111 vivo and/or in vitro metabolite.. B:,mean\ of direct comparisori or by a comparison of mabs bpectra and the use of tlc techniques, many of these derivatives n-ere showti b:, Schwartz, Vane, :tnd l’ostma2 to be identical with the metabolites of 2. Some of these compounds were synthesized after their initial tentative identification by an interpretation of mass spectral data while others were prepared hascd oii our knowledge of the metabolism of other l,~-beiizodi:tzepiries(e.!/., diazepam is known to yield a 3-11)tlroxy derivat h e 4 ) . Tlic .\ nthesia of tlic riiorioet1iyl;imino cierivative carried o u t b:, a voti Braun degradation of the iitle chain of 2. Thus treatment of 2 with cyanogen I I j I’auer S S S I S : .\I. 1%:. Ueriea, it. 1. Fryer, a n d L. ti. Sternbacii. J . . V e d . Chem., 11, ‘312 (1868). ( 2 ) A l . .I. Sclinartz, Y. Vane, a n d E. P u s h a , ibid., 11, i T O (1968). (: lene oxide. Another c o m p o u d .yiithesized as a possiblv n i t s tabolite wa5 the aminoeth:, 1 derivative 8. A2g:tintlic unalkylated compound 1 \va> used a> t h e startiiig material arid \\-as treated firbt with .odium mc~thoxidc iiiid the11 with cttrbohenzox:, bromocthy1;iinitie to givcL 7. Compound 7 wab then treated with a +elution ot HBr in g1:icial acetic acid to give the free ;tiiiii~o derivative 8. The dehydration product 16 fornicd t)> heating 8 uritler reflux in ethanol’ was found :is :111 artifact of 8 in the metabolic studies carried out h> Schwartz and l’oqtma.? T h e %hydroxy eonipourid (12) was piepared 111 t h e coiiventiorial niatiner from 10 by a Polonovdii rv:trrangement of the S-oxide to give 11 which ~ i i . \ubeeyuently hydrolyzed to 12. (’ompouiid 10 way \jilthesized from 1 in two bteps. In the fir.t itc’p. 1 \vas oxidized with peracetic acid to g i w the riitrotirb 9, ; l i d in the wcoiid z t i y 9 \\as alkylated uia tlic -od~o
775 SCHEME I CH,CH20H
CHICHZNHCBz
CH,CH,NH,
+ A
Cl"
6
7 1 9aOCH 2 BrCH.CH.OH
1 NaOCH
c1
w -N
16
8
CN
I
CH2CH2NC2H5
derivative with diethylaminoethyl chloride. The treatment of 12 with base gave the expected 2,3-dione (13). Similarly, the same Polonovski type of rearrangement of 9 gave the 3-acetoxy derivative 14 and alkaline hydrolysis of this compound afforded the 3-hydroxybenzodiazepine (15).
Experimental Section All melting points were determined eit,her ~nicruscopicallyon a hot stage or in a sealed capillary and are corrected. Referelice spectra were taken on all compounds and where necessary were compared in order t o confirm or exclude structural changes. Acceptable analyt,ical d a h for C and H (+0.4% of the theoret,ical values) o n all new compounds were obtained.
7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-l[2-(N-cyano-Nethylamino)ethyl]-2H-1,4-benzodiazepin-2-one(3).-To 4.0 g (0.0393 mole) of BrCN dissolved in 60 ml of CHC1, was added dropwise a solution of 10 g (0.0258 mole) of 7-chloro-l-(2-diethylaminoethyl)-5- (%fluorophenyl)-1,3- dihydro - 2H - 1,4- benzodiazepin-2-one (2)s~in 90 ml of CHC1,. The reaction mixture was refluxed for 4 hr under ail air condenser and was then coolcd to rooin tc~mperature. Thc rcsulting solution was extrartcd with
50 ml of 2 S HC1. The chloroform layer W N P v w h c d \vith 50 ml of dilute ",OH and 50 ml of saturated brine solution, dried (Na&04), and then evaporated to dryness. The reaidire was recrystallized twice from 1IeOH to yield 4.5 g of product. The filt,rates were evaporated to dryness and dissolved in CsH6 and the insoluble tar was discarded. The benzene solution was filtered through Florisil which m-as eluted with EtOAc. Removal of solvents gave a residue which was recryst,allized from N e O H to give an additional 2.0 g of product. The combined 6.5 g of product was recrystallized from a mixture of CH?Cl?N e O H to give the pirre compound as white rods, mp 132-134O.E =Ind.( C I ~ H I , C ~ F ? J C, ~ OH ).
7-Chloro-1,3-dihydro-l-(2-ethylaminoethy1)-5(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one Dihydrochloride (4).-Two grams (0.0052mole) of 4 \vas dissolved in concentratzd H2SO4 and heated a t 175' for 2 hr. The solution i m s cooled to approximatelj- lo", made neutral with SHaOH, and then reacidified (pH 6 ) with dilute HnSO4. The precipitate was recovered by filtration and the filtrates were extracted (CHCl,, two .5O-ml portions). The water layer was made basic with "4OH and the solution was reestracted (CHCl,, two 50-ml port,ions). The organic layers were combined, dried (Ka2S04), and evapo( 5 ) Startina material (1.5 a) \vas reco\.ered from t h e aqueous acid layer a n d the total yield of p r o d u c t , lrased o n 8.5 g of starting material, was 76'&.
tars and were combined. The hexane solution was added to the second fraction and evaporated to dryness to give 38 g (84.07,) of the base of 11 as an oil. A solution of 200 mg of the base in anhydrous Et20was treated with a n excess of HC1 gas. The ether solution was then evaporated to dryness and the residual oil was crystallized from lIe2COEtaO to give pure l l . H C 1 , white prisms,. mp- 214-218'. Anal. (Cj3H2jCiFX303.HC1) C, H. 7-Chloro-l - (2-diethvlaminoethvl Mi- (2-fluoroohenvl . b3-h~ droxy-1,3-dihydro-2H-l,~-benzodiaz~pin-2-one (12).--A solution of 12.0 g (0.0218 mole) of 11 in 230 ml of EtOH ~ v n strrated with 28.0 nil (0.028 mole) of 1 'Y SaOH. The reaction misture \vas nllowed to stand for 16 hr a t room temperature and iyas then evaporated to dryness. The residual oil ITas partitioned between 200 ml of HzO and 200 ml of CH2C1,. A 50% KzCOI solution was added until the p H of the aqneous layer was approximately 11. The layers were separated and the CHZC11 extract was washed (HzO,four 200-ml portions, and saturated brine solution), dried (NasSOa), and evaporated to dryness. The residual oil was dissolved in Et20 and cooled in ai1 ice bath, and gaseous IlCl was bubbled into the solution. T h e ether soliltion of the salt was evaporated to dryness and the residiial oil was crystallized from lIe2CO-Et20 to give 8.0 g ( 7 3 . 0 3 ) of the piire salt' of 12 as white prisms, mp 196-203O dec. Anal. (CplHp3C1F?;302. IIC1) C , H. A aoliition of 1.5 g of the salt was dissolved in 30 ml of H20 and ,505 K2CO3 was added to p H 11. The mixture was extracted wit,h 30 ml of CH2C12, the layers were separated, and the organic layers were washed (H,O, three 50-ml portions, and sat,urated brine soliitioii), dried (Sagso,), and evaporated to dryness. The residiial oil was crystallized from a mixture of ether and petroleiim ether (30-60") to give the piwe base as white prisms, m p 118-121'. Anal. (C21Hr3CIFN,O%)C, H. 7-Chloro-l-(2-diethylaminoethgl)-4,5-dihydro-5(2-fluorophenyl)-lH-1,4-benzodiazepine-2,3-dione (13).-A solution of 2.0 g (0.0015 mole) of the hydrochloride of 11 in 25 ml of EtOH \vas treatcd with 9 nil (O.OO!) mole) of 1 S S a O H . The reaction
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mixtnre was allowed to stand at room temperature for 16 hr and \\its thcn treatcd with 1 A' NCl to pH 6. The solution was made basic again with 50c0&COB and the resulting mixture 15 as evaporated to dryness. The residual oil was dissolved in 150 ml of CHZCI2which was washed (Hp0, three 150-nil portions, and saturated brine solution), dried (NatSOa),and evaporated to dryness. The residual yellow oil (1.8 g) was crystallized from lle,CO-petroleum ether (30-60") to give 1.2 g (65.55,) of the pure prodiict as white prisms, mp 169-171". Anal. (CZIHBClFXTOz) C, H .
3-Acetoxy-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4benzodiazepin-2-one (14).--8 Eolution of 10 g (0.0328 mole) of 9 in I50 ml of A c 2 0 \%asheated with stirring on a steam bath for 3.5 hr. AczO was removed under reduced pressure and the residue was dissolved in 100 ml of CHzClz. The organic solution \vas washed n i t h 75 ml of dilute S H I O H , two 76-m1 portions of HzO, and 75 ml of saturated brine, dried (NaZSOd), and evaporated to dryness. The product was recrystallized from MeOH to give 8.6 g ( 7 6 7 , ) of 14 as 15hife prisms, mp 239-247" (sealed tube). Anal. (CL7HlLC1FN2OI) C, H .
7-Chloro-5-(2-fluorophenyl)-3-hydroxy-l,3-dihydro-2H-l 4benzodiazepin-2-one (15).--h solution of 5 g (0.0145 mole) of 14 in 200 ml of EtOH \+as treated a i t h 36.3 ml (0.036 mole) of 1 S SaOH. After 5 min a white precipitate qeparated which was redissolved after an additional 10 niin by the addition of 200 ml of H,O. The solution mas then acidified n i t h AcOH and EtOH was removed under reduced pressure. The product separated as a a h i t e precipitate and \\as rec mixture of T H F and hevnne to give 4.2 g (96 rods, nip 107-200".
Acknowledgment.--We are indebted t o Dr. F. Vane and Dr. T. Williams for the nmr spectra, to N r . S. Traiman for the infrared spectra, and to Dr. A. Steyermark and Dr. F.Scheidl for the microanalyser.
Synthesis and Neuropharmacological Activity HAKSOTT, GOETZE.
HARDTRIASN, JIAX
DESZER,A L B E R T J. P R E Y ,
Medicinal Chemisti y Research Department
,JOHT H. GOGERTY,GEORGE H. LESLIE,4 N D JOSEPH H. TRAPOLD Biological Research Department, Sandoz Pharmaceuticals, Hanover, &YewJersey 07936 Receioed -Youember 25, 1867 The synthesis and neuropharmacological activities for a series of tetrahydroisoquinobenzodiazepinesare described. These wbstances produce qualitatively similar pharmacological activities to the well-known benzodiazepines, although similar structureactivity relationships could not be developed. One significant difference between compounds of the present series and the standard benzodiazepines was obtained in the dihydroxyphenylalanine-potentiation test (indicating possible '[antidepressant" activity residing in the isoquinobenzodiazepine molecule). The most active compound in the present series was the dextrorotatory isomer of 2-chloro-5-methyl3,9,10,14b-tetrahydroisoquino [2,1-d] [ 1,4]benzodiazepin-6(7H)-one. Only those substances possessing electronegative substituents a t position 2 demonstrated significant CXS depressant effects.
The pharmacological and clinical spectra of &phenyl1,4-benzodiazepines (1) have been well documented since the advent of chl~rdiazepoxide.'-~ A review of reports in which attempts were made to modify the chemical structure of the parent molecule with no concomitant loss in biological activity has brought out (1) L. 0. Randall, Dzseares 'Verrous S y s t e m ( S u p p l . 9 ) , 21, 7 (1960). (2) 1,. 0. Randall, G. A. Heise, W. Schallek, R . E. Bagdon, R. B a n ~ i p e r , A. Boris, R . A. Moe, a n d W.B. Abrams, Current T h e m p . Res., 3,405 (1961). (3) L. 0. Randall, K.Schallek. C . Scheckel, R. E. Bagdon, and J. Rieder, Schwezz. M e d . U'ochschr., 96, 334 (1965). (4) S. C. Bell a n d S. J. Childress, J . Ore. Chem., 27, 1691 (1962). ( 5 ) E. Kingstone, A. Villeneuve, and I. Kmsatz, Current T h e r a p . Res., 8 , 159 (1966).
the fact that the benzene ring in the 5 position is important for neuropharmacological activitya6 One might assume that such a molecule combines with the enzyme a t the receptor site in one specific rotational conformation. Based on this idea we became interested in the biological activities of 5-phenyl-1,4 benzodiazepines (1) in which the free rotation of the phenyl group is blocked by an ethylene bridge between position 2' and 4. The resulting novel tetracyclic (6) S. C . Bell, C. Gochman. and S. .I. Childrena, J . .lied. Pharrn. Chem., 6, 63 (1962).
