November 19GG
OPTICAL 1SOMERS O F a - 5 , 9 - D I E T H Y L - 2 ' - H Y D R O X Y - 2 - ~ ~ E T H Y I , - 6 , 7 - B E ~ Z O ~ ~ O R P H ~ ~ ~
Interesting Pharmacological Properties of the Optical Isomers of cr-5,9-Diethyl-2'-hydroxy-2-methyl-6,7-benzomorphan EVERETTEL.
J I A Y 9 X D ~ ' A T H A NB.
EDDY
Sational Institzrfe of Arthrifis and Jfefabolic Diseases, Sational Institutes of Health, Bdhescla, Jiarylnnd Received June 2.2, 1966 Optical resolution of ~-6,~-diet~hyl-2'-hydroxy-2-methyl-6,7-benzomorphan (11) has been effected with dmandelic or (+)-3-brom0-8-camphorsulfonic acid. The ( - ) isomer, almost twice as potent (equivalent to morphine) analgetically as the racemate as expected, is, surprisingly, also a mild antagonist t,o some of morphine's effects. Equally unexpected was the codeine-like analgetic activity and physical dependence capacity observed for the (+) isomer. As racemate I1 has been found to have little or no physical dependence capacity, there must be some antagonism between the two antipodes.
In 1959,I we reported that cy-( -)-2'-hydroxy-2,5,9trimethyl-6,7-benzomorphan contains all of the analgetic activity of, and is much less toxic than, the parent racemate (I). Since then (-)-I has been tested extensively. Although it is nearly equivalent to morphine in relieving postoperative pain, it has little capacity to support a morphine dependence in rhesus monkeys or man and generally shows an unusual separation of morphine-like effects.* These results have prompted us to prepare the enantiomers of a-(&)-5,9-diethy1-2'hydroxy-2-methyl-6,7-benzomorphan (11),3a clinically effective* analgesic of low physical dependence capacity in monkeys.2 Racemate I1 could be separated into its antipodes with d-mandelic acid (ethanol-acetone medium) in which case the d-mandelate salt of (+)-I1 crystallizes first. When the less satisfactory (+)-3-bromo-8camphorsulfonic acid in water was used, the salt of (-)-I1 was isolated first. Pharmacology.-As shown in Table I, (-)-I1 is equivalent to morphine and nearly twice as effective as The the racemate, ( j=)-II,4in analgetic a t ~ i v i t y . ~ dextro isomer, (+)-11, proved to be codeine-like, not
only as an analgetic (mice) but also in its (intermediate) capacity to support a morphine dependence in monkeys, in contrast to (+)-I and (+) isomers in the niorphirian series which are inert in animals in these respects. Furtherniore, administration of 0.5-32 nig/kg oi (-)I1 to morphine-dependent monkeys withdrawn for 12-14 hr failed conipletely to suppress abstinence; doses of 3 nig/kg and 32 mg/kg to nonwithdrawn, morphine-dependent nionkeys actually precipitated abstinence signs of intermediate intensity (nalorphinelike antagonism). The doseresponse curve is flat, and it is estimated that (-)-I1 is about one-twentieth as potent as n a l ~ r p h i n e . ~Apparently, too, (-)-I1 is antagonizing some of the efTects of (+)-11, since (j=)-II,like (-)-11, has no physical dependence capacity.2J Further studies with (-)-I1 are in progress.
HO' I, R=Me 11. R = Et
TABLEI AN.4LGETIC ACTIVITY, ACUTETOXICITY, AKD PHYSICAL DEPEKDENCE CAPACITY(pDC)2z6O F c&,~-DIETHYL-~-METHTL6,7-BENZOMORPHAN AXD ITSANTIPODES EDma
Compd
LDaoa
PDCb
(&)-I1 .HCl 2.1 423 NoC ( - )-II. HC1 1.2 XOd 7.9 273 Intermediate" (+)-I1 .HC1 1.2 576 High' hlorphine sulfate 7.5 270 Intermediateg Codeine. HC1 a Expressed in milligrams per kilogram (mice, subcutaneoiis administration); cf. K. B. Eddy and D. Leimbach, J . Pharmacol. Erptl. Therap., 107, 386 (1963), and A. E. Jacobson and E . L. May, J . Med. Chem., 8, 563 (1965). See ref 2. c K O suppression of morphine abstinence symptoms from 0.5-16 mg/kg and only partial suppression a t 24-40 mg/kg. A dose of 60 mg/kg caused convulsions. S o suppression from 0.5-32 mg/kg. Intermediate abstinence signs were precipitated in dependent, nonwithdrawn monkeys. e No suppression a t 2-4 mg/kg, very slight suppression a t 8-16, and almost complete suppression for 5 hr a t 32 mg/kg. Stabilizing (complete suppression) dose, 3.0 mg/kg. Similar to (+)-II.HC1.
'
Q
(1) E. L. M a y and N. B. E d d y , J . Org. Chem., !24, 1435 (1959). (2) N. B. E d d y and E. L. h l a y , "Synthetic Analgesics, P a r t II(B), 6,7-Benzomorphans,'' Pergamon Press, London, 1966, p 138 ff. (3) J. H. Ager and E. L. M a y , J. Org. Chem., 27, 245 (1962). (4) In postoperative pain, 20 mE of (&)-I1is slightly superior t o 10 mg of
mnrpliine. 2
Experimental Section Melting points (capillary) were taken with total-immersion thermometers. Resolution of C Y - ( =t))-5,9-Diethyl-2'-hydroxy-2-methyl-6,7benzomorphan (11). A. With &Mandelic Acid.-d-Mandelic acid (0.7 g),6 1.0 g of ( +)-11,33 ml of absolute ethanol, and 3 ml of acetone were heated to solution. On cooling, finally a t 0" for 7-15 hr, 0.7 g (90%) of needles or slim rods (d-mandelate salt of (+)-II), mp 194-197", was collected and washed with 5-10 nil of acet,one. The analytical sample (from methanolacetone) melted a t 198-200". Anal. Calcd for C?jH33N04: C, 72.6: H, 8.0. Fonnd: C, 72.7; H,8.1. The base of (+)-I1 was prepared by dissolving the d-mandelate salt in a little hot methanol and adding an equal volume of 5Yc ?r'H40H. This ba9e crystallized from acetone or acetone59.0" ( c 1.07. alcohol in thin prisms. mp 217-219",, I.C Y.~ ~ ' D 95% EtOH). Anal. Calcd for C I ~ H Z ~ N O C,: 78.7: H. 9.7. Found: C. 78.9; H, 9.7. The hydrochloride of (+)-11, prepared by passing HCl into an acetone solution (containing a litt,le ethanol) of (+)-I1base, crystallized from absolute ethanol-ether in needles, mp 165-168' (froth), [ C X ] ~ ' D +36.8" (c 1.09, HzO). Carbon, hydrogen, and
+
~~
,
I
( 5 ) We are indebted to Drs. M. H. Seevers and J. Villareal of t h e Department of Pharmacology, University of Michigan, for these dependence studies (prirate communication). (6) Blririch Chemical Co., Inc.
