8/8/2019 Journal of Medicinal Chemistry, 1979, Vol. 22, No.
10
1/2
Journal o Medicinal Chemistry0 Copyright 1979 by the American
Chemical Society
Volume 22, Number 10 October 1979
Communications to the Editor4 4pBromophenyl)-4- dimethylamho)-
-phen-ethylcyclohexanol, an Extremely PotentRepresentative of a New
Analgesic SeriesSir:
Th e sear ch for effective centrally acting analgesic agentsdevo
id of addicting properties ha s led to an unusually richselection
of compounds on which to base the structuralrequirem ents for
opioid activity. Most structures ex-hibiting this activity, in
fact, fit a common pattern inpossessing an aromatic ring attached
to a quaternarycenter, or its equivalent, and a basic nitrogen atom
a t aremove of th e equiv alent of an ethylen e We reporta co
mpound which show s extremely potent opioid anal-gesic activity in
which the b asic nitrogen ato m is attache ddirectly t o the
quaternary center.Th e trans amino alcohol 1 exhibits ED5ovalues of
0.1
FENTANYL
pg/kg when administered subcutaneously to mice in theusua l batt
ery of analgesic assays (tailflick, tail pinch, HC1~ r i t h i n g
) . ~n our han ds, this potency represents an in-crement of at
least lo4 over the milligram potency ofmorphine sulfate in the sam
e assays (ED50 alues of 1.5,1.6, an d 0.6mg/kg). T ha t this is
indeed a manifestationof opioid activity is suggested by the
finding that theanalgesic effects are blocked by naloxone and th at
1 ex-hibits an IC50of 8 X 10-lo M in the [3H ]nalox
~neindingassayV5 This is 30 times greater than the potency
ofmorphine (ICrn= 2.4 X Thu s, the rank order of thetwo agen ts is
in the same direction both in vivo and invitro. We inter pre t this
as a reflection of the greaterpotency of 1 and i ts enhanced abi li
ty to p enetrate t hecentral nervous system relative to morphine.
Th e cisamino alcohol 6 , by co ntras t, is far less effective tha
n 1,showing ED, values in th e mouse analgesic assay of 7.9,7.9,
and 7. 0 mg/kg on tail flick, tail pinch, and HC1writhing ,
respectively.Th e extreme in vivo potency and high binding
affinityof 1 ndicate tha t this com pound is capable of
conformingvery precisely to the steric and bon ding requirem ents
ofth e analgesic opioid receptor. Thu s, conformations of 1which
closely superimpo se over those of other sy nthe ticopioids and en
dorph ins may specify the active confor-mation s of the com pounds.
For example, comparisons ofDreidin g models of 1 and fentanyl
(Figure 1)reveal tha tth e molecules can be arranged as to give
point for po int0022-2623/79/1822-ll57$01.00/0
1-Figure 1. Dreiding models of 1 and fentanyl.coincidence for
all salient structural features. Thu s,starting at the left, the
two benzene rings can b e directlysuperimposed (though the link to
th e rest of th e moleculeis rotated by 60'). Th e basic nitrogen
atoms of the twomolecules similarly fall in th e exact same spo t
in space asdo the extreme right-hand benzene rings. Th e
hydroxylgroup in 1 falls in the m iddle of t he am ide function
offentanyl. Though th e conformations required to achievethis
superposition give rise to no nbonding interaction,energy gained in
forming putative agonist-receptorcomplexes is probably sufficient
to outweigh such inter-actions. Similarly, 1, but not 6 , can be
shown to super-impose over the endogenous peptide, enkephalin.
Thiscoincidence includes the two phenyl rings of eithercompound, he
nitrogen 1and t he nitrogen of Tyr, nd thehydroxyl of 1 and the Met
carboxyl . Thus, the potentopioid activity of 1 correlates with its
conformationalsimilarities with other opioids. More rigorous exam
inationof these common conformations may lead to a bet terunderstan
ding of the analgesic opioid receptor. Th e re-liability of such
projections depends strictly upon theprecision of fit of the model
agonist and th e receptor. Th etitle compound, 1, is thus ideally
su ited for such studies.Preparation of 1starts by conversion of th
e mon oketalof cyclohexanedione z7 o i ts cy-aminonitrile 3, mp
79-81
0 1979American Chemical Society
8/8/2019 Journal of Medicinal Chemistry, 1979, Vol. 22, No.
10
2/2
1158 Journa l of Medicinal Chemistry, 1979, Vol. 22, No.
10Scheme I
Br* Michne et al .(2 ) A. H. Beckett and A. F. Casey, J . Pharm.
Pharmacol., 6,(3) P. S.Portoghese, J . Pharm . Sci ., 55,865
(1966).(4) The test compound was administered subcutaneously tomale
CF -1 mice (18-22 g) as a suspension or solution in0.25% aqueous
methylcellulose. Fifteen min utes later theywere subjected to t he
tail-flick, tail-pinch a nd HC1-writhingmeasu remen ts of
analgesia. Briefly, a high-intens ity lightwas directed at the
middle third of the animal's tail si-multaneously with the sta rt
of a photoelectric timer. T henumber of seconds required for the
anim al to flick its tailou t of the light path was recorded.
Animals with responselatencies greater tha n X + 2 SD of control
were scored asanalgesic. The n a bulldog arterial clamp was applied
to th ebase of the tail. A lack of turning in response to
thatstimulus was scored as analgesia. Finally, the mice received0.2
mL of 0.08 N HC1 intraperitoneally and they wereobserved for 15min
for writhing. Th e absence of writhingresponse was scored as
analgesia. Six mice were used at eachdose level, and doses at 0.3
log intervals were tested. EDboan d 95% confidence intervals were
calculated by the me thodof Spearman and K arber. Th e upper a nd
lower confidenceintervals were never more th an 2 and 0. 5 t imes
the EDbo,respectively.( 5 ) C. B. Per t and S. H. Snyder, Science,
179,1011 (1973).(6) All new compounds gave satisfactory analyses
for C, H , an dN.(7)Prepared by a modification of the proced ure of
M. Haslangeran d R. G. Lawton, Tetrahedron Lett., 155 (1974).(8) C.
.Hauser and D. Lednicer, J. Org. Chem., 24,46 1954).(9) The
stereochemistry assignment was based upon X-raycrystallography,
performed graciously by D. J. Duchamp.
Dan ie l Ledn ice r , Ph i l i p F. VonVoig t l ande r*The
Upjohn CompanyResearch LaboratoriesKalamazoo, Michigan
49002Received A pril 27, 1979
986 (1954).x=#(l]-wy-2 , x = o Me2N
P lN/3 , x = (NMe, 4 , y = ( j05 , Y = OBr
Me2N1,R ' = CH,CH,C,H,; R 2 O H6 , ' = O H ; R 2 =
CH,CH,C,H,
"C (78% yield),6 by mea ns of KCN a nd M e,NH.HCl(Scheme I).
Displacement of the cyano groups by meansof a Grignard reagent
obtained from p-dibromobenzeneand a single equivalent of Mg gave
amino ketal 4, m p254-255.5 "C (HC1 salt, 30 %) ; this was th en
hydrolyzedto the corresponding ketone 5, mp 115-118 "C ( 69% )
.Condensation of 5 with the Grignard reagent from p-phenethy l
bromide led to a 1: l mixture of the amino al-cohols l and 6. Th
ese proved readily separable on silicagel: elution with 5% M eOH in
CH2C12gave the transisomer 1 (HC1 sal t), m p 242-243 "C. Elut ion
with 20%MeO H in CH2C12 ave the cis isomer (HC1 salt, 1.5 H,O),m p
208-210 0C.9R e f e r e n ce s a n d N o t e s(1) 0. Schaumaun, P
harmazie , 4, 364 (1949).
Art i d e s(2,6-Methano-3-benzazocin- lp-y1)alkanones. 1.
Alkylalkanones: A New Series ofN-M ethy l Derivatives wi th Novel
Opiate Activity ProfilesWilliam F. Michne,* Tho mas R. Lewis, Steph
en J. Michalec, Anne K. Piers on, and Fra nklin J.
RosenbergSterling - Winthrop Research I nsti tute, Rensselaer, New
York 12144. Received April 27, 1979
A general stereospecific synthesis of
(N-methyl-2,6-methano-3-benzazocin-11~-yl)alkanoness described and
appliedt o the preparation of a series of alkyl ketones wherein the
alkyl group is a straight or terminally branched chaincontaining
from one to six carbon atoms. Several compounds with methoxy groups
in the aromatic ring are in themorphine range of potency; they are
uniformly inactive as phenazocine antagonists. Phenolic analogues
range upto 100 imes as potent as morphine. Thos e containing five
or six carbon atoms in t he alkyl group exhibit phenazocineantagon
ist activity, in one case equivalent to naloxone. This compound
(3e) s selective fo r phenazocine in its antagonistaction.
Several years ago it was demonstrated th at th e poten tnarcotic
antagonist nalorphine is a n analgesic in man2,3 uttha t its use is
att end ed by psychic effects which precludeits clinical
acceptance. Initially the compo und was foundto possess no
morphine-like addiction lia b il it ~ ;~ater it wasfound that
physical dependence could develop afterchronic administration bu t
tha t the abstinence syndromeoccurring after drug withdrawal is
qualitatively andquantitatively different from tha t produced by
the narcoticanalgesic^.^ These observations have encouraged
the0022-262317911822-1158$01.00/0
search for new clinically acceptable analgesics to focusatten
tion on compounds which show narcotic antagonismas one aspect of
thei r pharmacological action profiles.6 I norder to evaluate the
subjective effects of candidatecompounds, a method was developed7
whereby scores ona questionnaire ar e compared with scores obtained
whenusing reference drugs. Th e LSD scale, for example,measures
psychotomimetic changes. In contrast tomorphine and code ine? n a
l~ rp h in e~ , '~nd othe r analgesicswith high antagonist potency,
such as levallorphan'0 a nd8 979 American Chemical Society
