Journal of Medicinal Chemistry, 1979, Vol. 22, No. 10
Journal of Medicinal Chemistry, 1979, Vol. 22, No. 10
Journal of Medicinal Chemistry, 1979, Vol. 22, No. 10
4 4 pBromophenyl)-4-(dimethylamho)-l-phen-
ethylcyclohexanol, an Extremely Potent
Representative of a New Analgesic Series
Sir:
The search for effective centrally acting analgesic agents
devoid of addicting properties has led to an unusually rich
selection of compounds on which to base the structural
requirements for opioid activity. Most structures ex-
hibiting this activity, in fact, fit a common pattern in
possessing an aromatic ring attached to a quaternary
center, or its equivalent, and a basic nitrogen atom at a
remove of the equivalent of an ethylene We report
a compound which shows extremely potent opioid anal- FENTANYL
gesic activity in which the basic nitrogen atom is attached
directly t o the quaternary center.
The trans amino alcohol 1 exhibits ED5ovalues of 0.1
wy-
Scheme I (2) A. H. Beckett and A. F. Casey, J . Pharm. Pharmacol., 6,
* 986 (1954).
x=#(l]-
Br (3) P. S.Portoghese, J . Pharm. Sci., 55, 865 (1966).
(4) The test compound was administered subcutaneously to
male CF-1 mice (18-22 g) as a suspension or solution in
0.25% aqueous methylcellulose. Fifteen minutes later they
2,x=o Me2N were subjected to the tail-flick, tail-pinch and HC1-writhing
CN measurements of analgesia. Briefly, a high-intensity light
/ P l
3,x=(
NMe,
4,y=(
0
j was directed at the middle third of the animal's tail si-
multaneously with the start of a photoelectric timer. The
5,Y=O number of seconds required for the animal to flick its tail
out of the light path was recorded. Animals with response
Br latencies greater than X + 2 SD of control were scored as
analgesic. Then a bulldog arterial clamp was applied to the
base of the tail. A lack of turning in response to that
stimulus was scored as analgesia. Finally, the mice received
Me2N 0.2 mL of 0.08 N HC1 intraperitoneally and they were
1, R ' = CH,CH,C,H,; R 2 = OH
observed for 15 min for writhing. The absence of writhing
6 ,R' = OH; R2 = CH,CH,C,H, response was scored as analgesia. Six mice were used at each
dose level, and doses at 0.3 log intervals were tested. EDbo
and 95% confidence intervals were calculated by the method
"C (78% yield),6 by means of KCN and Me,NH.HCl of Spearman and Karber. The upper and lower confidence
(Scheme I). Displacement of the cyano groups by means intervals were never more than 2 and 0.5 times the EDbo,
of a Grignard reagent obtained from p-dibromobenzene respectively.
and a single equivalent of Mg gave amino ketal 4, mp ( 5 ) C. B. Pert and S. H. Snyder, Science, 179, 1011 (1973).
254-255.5 "C (HC1 salt, 30%); this was then hydrolyzed (6) All new compounds gave satisfactory analyses for C, H, and
to the corresponding ketone 5, mp 115-118 "C (69%). N.
Condensation of 5 with the Grignard reagent from p- (7) Prepared by a modification of the procedure of M. Haslanger
phenethyl bromide led to a 1:l mixture of the amino al- and R. G. Lawton, Tetrahedron Lett., 155 (1974).
(8) C.R.Hauser and D. Lednicer, J. Org. Chem., 24,46(1954).
cohols l and 6. These proved readily separable on silica (9) The stereochemistry assignment was based upon X-ray
gel: elution with 5% MeOH in CH2C12gave the trans crystallography, performed graciously by D. J. Duchamp.
isomer 1 (HC1 salt), mp 242-243 "C. Elution with 20%
MeOH in CH2C12gave the cis isomer (HC1salt, 1.5 H,O), Daniel Lednicer, Philip F. VonVoigtlander*
mp 208-210 0C.9 The Upjohn Company
Research Laboratories
References a n d Notes Kalamazoo, Michigan 49002
(1) 0. Schaumaun, Pharmazie, 4, 364 (1949). Received April 27, 1979
Art ides
Several years ago it was demonstrated that the potent search for new clinically acceptable analgesics to focus
narcotic antagonist nalorphine is an analgesic in man2,3but attention on compounds which show narcotic antagonism
that its use is attended by psychic effects which preclude as one aspect of their pharmacological action profiles.6 In
its clinical acceptance. Initially the compound was found order to evaluate the subjective effects of candidate
to possess no morphine-like addiction liabilit~;~later it was compounds, a method was developed7 whereby scores on
found that physical dependence could develop after a questionnaire are compared with scores obtained when
chronic administration but that the abstinence syndrome using reference drugs. The LSD scale, for example,
occurring after drug withdrawal is qualitatively and measures psychotomimetic changes. In contrast to
quantitatively different from that produced by the narcotic morphine and codeine? nal~rphine~,'~ and other analgesics
analgesic^.^ These observations have encouraged the with high antagonist potency, such as levallorphan'0 and
0022-262317911822-1158$01.00/0 8 1979 American Chemical Society