SOTES
September 19G8 Acknowledgment.-The author is grateful to W. E. Wright for valuable discussions; to G. Jlaciak and his staff for the microanalyses; to H. Boaz, D. 0. Woolf, L. A. Spangle, and their associates for spectral data and titrations; to W. E. Wick and J. L. Ott for biological data; to c. T. Pugh for bioautography; and to A. I. Ellis for technical assistance.
1069
MR’ 3, R = H ; R’ = 0 4, IZ = t-CaHg; R’ 5, R = tC411g; R’
= =
8, R
=
f-CJ~9; R’
= ’’
R
=
f-C4119;
0 KOH
Cassiaine Analogs. V.’ A Distant Analog of Cassaine SOLJ. Dauv
AXD
ROBERTL. C L ~ R K E
Sterling-ll’inthrop Research Institzite, Rensselaei‘, .Yew I’ork 12144 Receiz’ed .lIarch 18, 1968
Extending our efforts in the search for a cardiac stimulant, we have prepared another analog related to the Erythmphleu?u alkaloid cassaine (1). 2 We felt ,COOCH2CH2N(CH3),
“CH,
1
HO
H 2
that if the group =CHCOOCH,CHzn’(CH& of 1 were replaced by the equatorially oriented -NHCOOCH,CH,N(CH,),, perhaps we could obtain a cardiac stimulant having a much longer duration of activity. The ease of i n vivo hydrolysis of the ester group might be related to duration of activity. It was hoped that the equatorial Configuration of the side chain would approximate the configuration demanded by the double bond of the natural product and that the unshared electron pair on the nitrogen might substitute for the electron character of the double bond. I n order to test this hypothesis, we have prepared the carbamate 2. The hydroxyl group of the starting material 3 was protected as its t-butyl ether derivative 43 while the necessary transformations were made at C-13. The oxime 5 of 4 was reduced chemically ( S a , EtOH), a procedure which allows assignment of the major product as the equatorial ( a ) amine 6 and the minor product as the axial (p) amine 7. S o t being crystalline, these amines mere characterized by their conversion in the next step of the sequence to crystalline 2(1) For paper IV sre R . L. Clarke, 9. J. Daum, P. E. Shaw, T. G. Brown, Jr.. G . E. Grohle\vski, and W.V. O’Connor, J . M e d . Chem.. 10, 593 (1967). ( 2 ) See F. Erjavec a n d 3. Adamic, Arch. Intern. Pharmncodyn., 155, 251 (1Y65): E. L.lIcCawle?, A ~ k d o i f k5. , 101 (19.551, and references therein. (3) H. C. Bayerman a n d G. J. Heisznolf, Kec. Trau. Chim.,84, 203 (1965).
9,
=
\rr
R’ =
10, R = t-C4Hs; R’
11, R
XHCOOCH,CH~C~
SIICOOCH~CH~C~ (( ‘H
,NHCOOCH,CH~K(CH,), =
FICCO; R’ =
I’
\U
,NHCOOC€I,C€I~N(CH~)Z ’
\H
chloroethyl carbamates 8 and 9. Reaction of 8 with dimethylamine afforded the dimethylaminoethyl carbamate 10 which was characterized as its hydrochloride salt. The t-butyl ether group in 10 was cleaved by treatment with trifluoroacetic acid; the compound isolated was the trifluoroacetate 11. This ester was hydrolyzed with methanolic S H 4 0 H at room temperature to give 2-dimethylaminoethyl dl-S-(1,2,3,4,4aa,4b,5,6,7,SJSaa,9,lO,lOnp-tetradecahydro-7p-hydroxy4bfi-methylphenanthr-2a-yl)carbamate (2) in good yield. Biological Te~ting.~-Compound 2, upon intravenous administration in the dog a t a dose level of 4 mg ’kg, produced an increase of 307, in ventricular contractile force, accompanied by a blood pressure drop of Ouabain at a dose level of 0.03 mg/kg or cassaine (1) at a dose level of 0.04 mg/kg produces an increase in ventricular contractile force of 20YGwithout concomitant lowering of blood p r e ~ s u r e . ~ Experimental Section6
dI-7p-1-Butoxy-3,4,4aa,4b,5,6,7,8,8aa,9,10,1 Oag-dodecahydro-4bb-methyl-2( la)-phenanthrone 2-Oxime (5).-A solution of 6 g ( 2 5 mmoles) of hydroxyphenanthrone 37 in 150 ml of CH,C12 was treated with 1 ml of BF3 etherate and 1 ml of anhydrous H1P04. The latter was prepared by the addition of a calculated amount of P?Oj to 85yGH3PO4. Isobutene (150 ml) was added t o t,he solution at 10’. The solution was shaken in the Parr shaker for 5 hr. The reaction mixture was poured into 200 ml of 2 S NHIOH, the layers were separated, and the aquqppus layer was Fashed with 200 ml of CHZC1,. The organic lagers were combined and dried (Xa2SO4). The solvent was removed under reduced pressure t o yield an oil that was chromatographed on 300 g of silica gel. Ether eluted 4.i g of dl-70-t-butoxy-3,. 4,4aa,4b,5,6,7,8,8aa,9,lO,lOa~-doderahydro-4b0 -methyl 2( 1H)phenanthrone ( 4 ) as an oil that would not crystallize. The oil,
-
(4) For details of t h e experimental methods of evaluation see R . L. Clarke, IT. V. O’Connor, J . .lied. Chem., 10, 582 (196i). ( 5 ) We wish to thank Mr. William V. O’Connor f o r t h e biological testing.
S. J. Daum, P. E. Shaw, T. G . Brown, Jr., G . E. Groljlewski, and
(6) All melting points a r e corrected. I r spectra were recorded on a PerkinElmer Infrared spectrophotometer, Model 21. T h e silica gel used for column chromatography (100-200 mesh) was obtained from t h e Davison Co.. Baltimore, bld. Silira gel G, purchased from Brinkmann Instruments, Inc., was used for thin layer chromatography. JI-here analyses are indicated only by symbols of t h e elements analytical results obtained for those element? were within ;tO.4% o f ttir t!reoretical aaliies. (7) A. J. Daum, I’. E. %inn.. and R . I,. Clarke, J . 078. ChPm., 32, 1427 (1967).
