5
CO&
Y NH,
4'
t lit, lactol structure of (i-cliloro-2-benzoylbeiizoic arid ( V I I ) . Tllc structure of t h e 5-chloro-2-benzovlbeiiz(~ic acid \vas axsigtied oii the basis of the following data 'l'lie iiifrarcd spcctruiii bIio\wd a inonosubstitutrd 1)ciizeiic riiig a i d a 1,2,-l-trisubstitutcd beiizeiiv riiig. III tlic 1 i . i i i . i ' . spectruiii, tlic low-held protoii sigiial coiwspoiidiiig to thr protou (Y to the carboxyl group fell a t 4i!).(i C.P.S.as a doublet nit11 ,f = 2.0 C.P.S. 'l'liib iiidicatd a protori at the 4-positioii aiid a substitueiit at tlic 5-positioii. 111 addition, the possibility of the coiiipound being 4-chloro-2-beiizoylbeiizoicacid"
(1ii.p. li4-177') was ruled out by niixturt. iiieltiiig point with an authentic sample, a iiiarlwl dcprcwioii (14Y-152°) bcitig noted. T h e xtructurr of tlw 3 - i i i e t h g l - 2 - ~ c i i i s ~ ~ ~ l l ) t , t i ~ o i ~ acid \\ascstablishcd by iiiixture iiieltiiig poiiit n i t l i aii
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DERIVATIVES OF :\IORPHASTHRIDISE
January 1965 CHART
77
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hdipheniiie was three to four times less efl'ective in this test. 5,B-Dihydro-3-(2-imidazoliri-2-yliiiethyl) niorphanthridirie (21) arid the related compounds 22-28 arid 30 showed a marked effect on aconitine-induced ventricular fibrillation of the isolated feline heart. The corresponding derivatives of iiiorphaiithridine-6,ll-dione and 6niorphanthridone were only weakly active. Perfusion of the heart with physiological Ringers solutiori coiitaining 0.022 y nil. of aconitine nitrate induced ventricular fibrillation in 18 niin. In this test the criterion for judging the effectiveness of the conipou~id was the iiieasureiiient of the time from the start of the aconitine perfusion until the onset of ventricular fibrillation. Quiriidiiie sulfate was used as a standard. Compound 21 was 3-4 times as potent as quiriidiiie sulfate in this test. Enlarging the iniidazoline ring to a six- or seven-membered ring (22 and 23) decreased the activity. Introduction of a methyl group in the imidazoline ring in position 1 or 4 (25 and 24) had little effect on the antiarrhythmic activity. Suhstitutioii iri the S,tj-dihydroiiiorphanthridiIienucleus by a methyl, methoxy, or chloro group in the coinpounds studied (26-28 arid 30) also had only a slight effect. Compound 19, a dimethiodide, was found t o have an intense, long-lasting hypotensive effect due to ganglionic blockade. Sone of the compounds tested had any effect on the central nervous systeiii, nor could we confirm under our test conditions the intense antihistatiiinic effect claimed for conipourid 17 by P r ~ t i v aet, ~al.
n = 1-3
Experimental17 3- and 8-Methylmorphanthridine-6,ll-dione (I). General Procedure.-A mixture of 600 nil. of concentrated sulfuric acid and 200 nil. of methylene chloride was cooled to 15', 126 g. (0.57 mole) of 2-niethylanthraquinone was added, followed by 43.8 g. (0.67 mole) of sodium azide, added in small portions over a 1-hr. period a t 20-25'. The reaction mixture was stirred at room temperature for 3 hr., allowed to stand overnight, and then pouxed over a mixture of ice and water. The crude product was filtered off, washed wit,h wat,er, and dried. It was recrystallized by dissolving in 4.8 1. of toluene a t reflux. On cooling, 65 g. of material, n1.p. 205-248", crj-stallized. Recrystallization from diniethylformaniide gave 27.5 g. of 3-methylniorphanthridine-6,1l-dione, ni.p. 260-264", yield 20";. On concentrating the toluene filtrate to approximately 2 1. and cooling, 43.2 g. of material, m,p, 178-186', was obtained. Recrystdlizntion from dioxane gave 24 g. of 8-methylmorphanthridine-6,ll-dione n1.p. 203-204", yield 17.5:;. Further recr the melting point to 204-207O. The Schmidt reaction products of 1-niethyl- and 1- and 2chloroanthraquinone were also worked up using toluene and diniethylformamide as solvents for recrystallizing and separating the isomeric diones. The reaction product of l-methoxyanthraquinone was recrystallized from a mixture of dimethylformaniide and ethanol, that for 2-niethoxyanthraquinone, and 2-ethylanthraquinone froni ethanol. Hydrolysis of Morphanthridine-6,11-diones.-4 suspension of 5.4 g. 3-methylmorphanthridine-6,ll-dionein 50 nil. of 2 -V XaOH was heated on the steam bath for 45 niin. On cooling, the sodiuin salt of 2-(8-arnino-4-methylbenzoyl)benzoic acid separated. It was dissolved by adding 30 nil. of water. The reaction mixture was acidified with dilute HC1 to pH 6, whereupon the amino acid precipitated. It was filtered off and recrystallized from methanol: yield 3.6 g., m.p. 180-182O, of 2(2-a,mino-4-methylbenzoy1)henzoicacid. The identical procedure was used to hydrolyze the other substituted morphanthridine-6,ll-diones investigated. I n the case of the 2-(2-arnino4-ethylbenzy1)benzoic acid, the crude amino acid was deaminated directly. ( 1 T ) M e l t i n g p o i n t s are uncorrected.
78
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Jaiiuary 1965
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Deamination of 2-(2-Aminobenzoyl)benzoic Acids.-To a mixture of 2.7 ml. of concentrated HCI and 13 nil. of water, 3 . 0 g. of 2-( 2-amino-4-methy1benzoyl)benzoic acid was added. After cooling to O", a solution of 0.82 g. of sodium nitrite in 7.5 ml. of water was added dropwise a t 0 to 5". After the diazotization was completed, the solution was filtered and added to a solution of 10.5 ml. of 50yc hypophosphorous acid in 7.5 inl. of waber. The reaction mixture was kept in an ice bath for 1 hr., then stored in the refrigerator overnight. During this period a precipitate formed which crystallized. I t was filtered OR and recrystallized twice from aqueous alcohol; yield 0.8 g. o f 2-( 4toluyl) benzoic acid. For analysis it was re( ene and sublimed in v(imo. N-Benzyl-N-p-tosylanthranilicAcid fVI).-To a solution of 29.1 g. (0.1 mole) of N-p-tosylanthranilir acid'* in 9 g. of NaOH dissolved in 100 ml. of water, 100 nil. of ethanol, and 0.5 g. of KI were added. The solution was refluxed while 25.3 g. of benzyl chloride (0.2 mole) was added dropwise. The reacticiri mixture was refused for 16 hi., alkaline reaction being ni:iintained by occasional addition of 107; aqueous NaOH solut~iori. After cooling, the ethanol was removed in z'acuo, the aqueous phase was ext,racted with ethyl acetate and acidified. An oil precipitated which rrystallized. Aft,er recrystallization from a mixture of ethyl acetate and hexane, 1.1 melted at 164-166'; yield 26 g. -4nal. Calcd. for C,,H,&O48: C, 66.12: H, 5.02: S , 3 . 6 7 . Found: C, 66.22: H, 4.84, S , 8.65. 6-Morphanthridone (IV). General Procedure.--A suspension of 111.6 g. of morphanthridine-6,ll-dione in 2 1. of glacial acetic acid was hydrogenated in R 4 I. .\Iagna-l)aeh autodave with 1 0 g. of 10cl palladium o n carbon a t 75-80' and 10.5 kg./ -4fter ,5.5 hr. the required amount of hydrogen had beeii taken up. The reaction mixture was cooled, the catalyst was filt'ered off, and the solution was concentrated in wirtm. On ittldiof 30 nil. of et,her to the residue, the 6-inorphaiithridciiie tallized. It' was filtered off and rec*r>.,*tallizedfrom 2 1. of ethyl acetate: yield 53 g. (5OC;). The identical procedure was used to prepare 3- and 8-met~hyl-6-11iorphanthridone. 5,6-Dihydromorphanthridine ( V ) . General Procedure.'g-\Vith stirring, 187.5 g. of lithiuni aluminurn hydride (4.94 moies) was added gradually t,o 3.6 1. of dry tetrahydrofuran. After 30 inin. 334 g. of motphanthridine-6,1 I-dione (1.5 moles) was added over 1 to 1.5 hr. without external cooling. The reac*tioii mixture was refluxed for 4 hr. and stirred a t room t~ernperature overnight, 400 ml. of water was then cautiously added. Following the addition, the slurry was refluxed for 30 min. arid filtered hot. The filter cake was washed t,horoughly with inethylene chloride and the washings were combined with the tetrahydrofuran filtrate. The filtrate was cwncentrated in uacuo, the residue was dinbolved in 2 I. of ethanol a t reflux arid filtered to remove unrearted ,starting material. The filtrate was cooled and the $6dihydroniorphanthridine was filtered off: yield 1!)8.3g., ni.1). 1277121)'. 5,6-Dihydromorphanthridine(V) from 6-Morphanthridone.A suspension of 13 g. of lithiuni aluniinuni hydride ( 0 . 4 inole) iii 700 nil. of dry ether was stirred for 0.5 hr., then 42 g. of 6iiiolp1i:tnthritione (i),2 mole) wits added over :I ?-hi. period. The reac:tion niixtnre was stirred for 16 hr. :rt rooni tetiiper:ituw, itrid worked up hy adding in sequence 45 nil. o f ethyl acetitte, 15 nil. of water, 30 nil. of 155; S a O H solution, and 43 nil. of water. The slurry was filtered and the filtrate was dried and concentrated in uacuo. The residue was recrystallized froni 2propanol; yield 20 g., n1.p. 138-130". Alkylation of Morphanthridine-6,11-dione. General Procedure. 5-(3-Dimethylaminopropyl)morphanthridine-6,ll-dione (VIIIa).-To a mixture of 111.5 g. IJf niorphanthridine-6,l I tlione (0.5 mole) and i50 nil. of diiiiethylf[irniarnide, 35.5 p. of a %',/ suspension of sodarnide, ( 0 . 5 mole) in toluene w:ts :tdckxi, whereupon a clear yellow solut,ion formed. .kiter stirring f o r 30 min., 67 g. of 3-dimethylariiincipropyl (ahloride dissiilved in 400 nil. of toluene was added. The reaction mixture was Imtetl to 50-60" for i . 5 hr., allowed tr) stand overnight, then filtered and concentrated in z~acuo. The oily residue was treated with 500 ml. of water and 500 ml. of ethyl acetate. Home solids (19 g.) separated, were filtered off (n1.p. 200-238'), and were identified as impure starting materi:rl. The ethyl acetate solution was dried
