\'Ill. 10
IVC
B/C
I
111 R-CH,
viii
R=cH*(]
CIS
l I a y 1967
DERIVATIVES O F A\IETAAIORPHINAX
We find in contrast to earlier reportsI3 that I readily absorbs 3 moles of hydrogen at atmospheric pressure to produce crystalline tetrahydrode~xynietacodeine'~ (V) in good yield, and this substance is also produred by Wolff-Iiishner reduction of IV. It is thus clear that the same configuration at (3-13 results from either catalytic hydrogenation or sodium amalgam reduction of the 3-13 double bond of metathebainone arid accordingly we assign structure IVa (B/C trans) to IV.
IV
Ha
,
Pd
in the phenylquinone writhing test. Compound VI1 is perhaps 1/600 as active as the corresponding 3-hydroxyK-cyclopropylmethylmorphinan (VIII, cyclorphan) in the phenylquinone writhing test and shows no morphine antagonistic activity in doses up to 25 mg/kg, whereas cyclorphan is a potent morphine antagonist (AD50 us. meperidine, 0.034 mg/kg). It seems clear that the shift in position of the ethananiirie side chain from C-13 to C-14 in the metamorphinan derivatives I1 and VI1 has essentially obliterated the characteristic analgetic and antagonistic activity associated with the corresponding morphinans I11 and VIII.
Experimental Section
V
The removal of the phenolic group of V by the method of l'irkle arid Zabriskie4 was unexceptional and the conversion of the 3-methoxy-S-methylmetamorphinan (VI) so obtained to 3-hydroxy-X-methylmetamorphiiian (11) and t o 3-hydroxy-i\;-cyclopropylniethylrnetamorphinan (VII) followed well-established routes.15i16 Compound VI1 was prepared for examination as a morphine antagonist. These transformations are outlined in Scheme I. SCHEME I
W
381
All nieltiiig poiiits are corrected. Rotations were taken in 959; ethanol on a liudolf Precision polarimeter. Infrared spectra were taken on a Perkin-Elmer Model 21 infrared spectrophotometer. Xmr spectra were taken on a T'arian A-60 spectrometer. Analyses were performed by Micro-Tech Laboratories, Skokie, Ill. Metathebainone ( I ) was prepared according to Gulland and Robins" and was obt'ained as the methanolate, mp 101-121', gas evolution, [ c x ] ~ ~ D-398" (c 2.04), lit. mp 115-118 ',68 [ ( u I ~ ~ D -419' (c 1.966).6b Its infrared spectrum showed strong absorption at 1650 cm-' (conjugated carbonyl). Its benzylidene derivative had mp 123-125" (lit.@*120-123'). Dihydrometathebainone (IV) was prepared according to PschorrGS and was used as obtained for further transformations. For characterization it was purified through its picrate, mp 243-2445' dec, after recrystallization from alcohol-dimethyl sulfoxide. ilnal. Calcd for C24H2&a010:C, 54.34; HI 4.94; N, 10.56. Found: C, 54.19; HI 5.00; K, 10.55. A sample of picrate (4.09 g) on distribution bet,weeri LiOH and CHC1, yielded 2.51 g of a colorless glass which on cooling iri methanol gave heavy colorless prisms of the methanolate, 1.89 g, mp 58-69' (lit.@b50-54'), vmax 1705 em-' (carbonyl). On standing a t room temperature for several days or on drying a t 110", iinsolvated material of mp 140-141' (lit.eb 135-136'), [ c Y ] ~ ~ D$75.4' (c 1.67) (lit.6b +67.05'), was obtained. I t s semicarbaxone melted a t 224-226" (gas evolution), lit.Sb217-218". Tetrahydrodeoxymetacodeine (V). A. By Hydrogenation of Metathebainone (I).-.4 solution of 2.00 g of I methanolate in 40 ml of 18% HC1 was stirred under hydrogen over 1 g of 10% Pd-C. During 29 hr a total of 435 ml (96Vc of 3 moles) of hydrogeii was absorbed, 335 ml wit,hin the first 2 hr. The solution was filtered from catalyst, made basic to excess with KH3, and extracted four times with CHC1,. The CHC13 extracts were dried, filtered, and concentrated. After pumping out, a residue of 1.73 g (100$:) of a slightly pink glass which slowly crystallized, mp 58-81", remained. This material was converted to the picrate in methanol, 2.67 g (867c), mp 261.5-263' dec. Two recrystallizations from dimethyl sulfoxide-methanol gave 1.98 g (647,)) mp 264-265" dec. Anal. Calcd for C~H2&;409: C, 55.81; H, 5.46; K, 10.85. Found: C, 56.07: H, 5.39; K, 11.18. Distribution of this picrate (1.98 g) between 1% LiOH and CHCL gave 1.12 g (loo%), mp 75-88', of base after washing, drying, filtering, and concentrating the CHC18 solution. After three crystallizations from 30-60" petroleum ether, 0.56 g, mp 90-92", [ a ] % +18.8' (c 1.65), of massive colorless prisms was obtained. Anal. Calcd for C18H25?J02:C, 75.22, H, 8.77; X, 4.87. Found: C, 75.23; H, 8.87; S , 4.82. Its hydriodide, colorless needles, prepared in and crystallized from methanol, had mp 212-2143', gas evolution, after partial melting and resolidifying at 130-140°.18 Tetrahydrodeoxymetacodeine ( V ) . B. By Wolff-Kishner Reduction of Dihydrometathebain0ne.-A mixture of 18 g of crude IV, 50 g of 8570 KOTI, 25 ml of 9 5 R hydrazine hydrate, and 300 ml of diethylene glycol was refluxed for 2 hr, distilled until t.he temperahre of the mixtiire reached 175O, and refluxed for an additional 3 hr. The reactioii mixture was cooled, diluted
lco
., U VI1
Physiological Results.--3-Hydroxy-X-methylmet~atmorphinan (11) arid the corresponding K-cyclopropylmethylmetamorphinan (VII) have been screened in small animals for analgetic act'ivity" by the D'AniourSmith rat tail flick test, by the phenylquinone writhing test, and by the inflamed-paw test. Keither substance showed any analgetic activity in doses as high as 25 mg/kg in the D'Amour-Smith test using conditions under which morphine is effective at 5 mg/kg, and no significant activity mas shown by either substance :11 t'he inflamed paw test. In t'he phenylquinone writhing test, I1 shows 0.09-0.12 times the activity of morphine, VI1 0.06-0.07 t,imes its act'ivity. It would appear that I1 is less than l / j 0 as active as the corresponding 3-hydroxy-S-methylmorphinan (111, levorphanol) as active in the D'Amour-Smith test and perhaps l/loo (13) The 6-13 double bond of metathehainone has been reported to be resistant t o hydrogenation (H. Hock, Dissertation. Munich. 1926), quoted by Small and hleitznerll who also observed little hydrogenation at this position. (14) Tetrahydrodeoxymetacodeine %-as prepared a s a n amorphous solid but not characterized by Small a n d Meitzner.11 A cryatalline hydriodide, melting point not recorded, waa described. (16) hl. Gates and T. -4. Montzka. J . .Wed. Chsm., 7 , 1 2 i (1964). (16) \V. H. Pirkle and &I. Gates, J . O r y . Chem., SO, 1769 (1965). ( 1 7 ) \Ve are greatly indebted t o Dr. .I.C. Osterherg, Lederle Laboratories, American Cyanamid Co.. t o Dr. Harold Blumberg, Endo Laboratories, and to Dr. Charles .L \\-inter, Mer& Institute for Therapeutic Research, through whose courtesy these tests were carried out.
(18) This substance was prepared and ana1,zed by Small and AIeitzner.11 but its melting point was not recorded.
