8-Aminocyclazocine analogues: Synthesis and structure-activity relationships

Article abstract of DOI:10.1016/S0960-894X(99)00670-8

Opioid binding affinities were assessed for a series of cyclazocine analogues where the prototypic 8-OH substituent of cyclazocine was replaced by amino and substituted-amino groups. For μ and κ opioid receptors, secondary amine derivatives having the (2R

Full text of DOI:10.1016/S0960-894X(99)00670-8

Bioorganic & Medicinal Chemistry Letters 10 (2000) 183±187
8
-Aminocyclazocine Analogues: Synthesis and Structure±Activity
y
Relationships
a,
a
a
a
Mark P. Wentland, * Guoyou Xu, Christopher L. Cio, Yingchun Ye,
a
b
b
b
Wenhu Duan, Dana J. Cohen, Ann M. Colasurdo and Jean M. Bidlack
aDepartment of Chemistry, Rensselaer Polytechnic Institute, Troy NY 12180, USA
bDepartment of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
Received 18 October 1999; accepted 22 November 1999
AbstractÐOpioid binding anities were assessed for a series of cyclazocine analogues where the prototypic 8-OH substituent of
cyclazocine was replaced by amino and substituted-amino groups. For m and k opioid receptors, secondary amine derivatives having
the (2R,6R,11R)-con®guration had the highest anity. Most targets were eciently synthesized from the tri¯ate of cyclazocine or its
enantiomers using Pd-catalyzed amination procedures. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
mice when delivered by the subcutaneous route but
3
comparable [to (‹)-1] ecacy when delivered orally.
Cyclazocine [(‹)-1] was evaluated in humans in the
1960's and early 1970's as an analgesic and as a possi-
ble treatment for preventing relapse in post-addicts of
For example, in the mouse acetylcholine writhing test,
the po/sc ratio of ED50 values for cyclazocine was 35
and for (‹)-4, this ratio was 4 indicating the 8-
1
,2
heroin. In humans dosed with the drug, potent anal-
gesia was observed and following abrupt cyclazocine
withdrawal, patients did not display drug-seeking beha-
vior. Further clinical development of cyclazocine was
ceased due, in part, to a short duration of analgesic
OH!NH change accounted for higher oral ecacy.
2
Whether high oral bioavailability due to lower ®rst-pass
metabolism, higher gut wall permeability, reduced
clearance or some other factor accounts for the higher
(than would be predicted by sc data) oral ecacy of
(‹)-4 is not known.
1
,2
action. Cyclazocine is O-glucuronidated in humans
3
which may account for its short duration of action. In
an attempt to retard this metabolic inactivation and
increase its duration of action, we discovered some
years ago that replacement of the 8-OH group of (‹)-1
with NH provided the novel compound (‹)-4 which
2
had somewhat diminished antinociception potency in
Since these in vivo studies for (‹)-1 and (‹)-4 were
performed prior to the full characterization of opioid
receptors, receptor binding data were not obtained. In
the late 1970's opioid receptor binding studies for
cyclazocine revealed the compound to have high anity
1
for k and m opioid receptors. Antinociceptive studies
demonstrated that cyclazocine was a k agonist and m
antagonist. In further studies it was found that the
opioid receptor binding properties of cyclazocine (which
1
*
4
Corresponding author. Tel.: +1-518-276-2234; fax: +1-518-276-
887.
y
is racemic) resided in the (2R,6R,11R)-isomer (� )-2 and
4±6
A portion of this work has appeared in preliminary form: (a) Ye, Y.;
Wentland, M. P.; Colasurdo, A. M.; Abraham, M. K.; Bidlack, J. M.
Abstracts of Papers, 30th International Narcotic Research Conference,
Saratoga, NY, 1999; Abstract Mon42. (b) Cio, C. L.; Wentland, M.
P.; Cohen, D. J.; Urban, T. J.; Bidlack, J. M., Abstracts of Papers,
that potent s-receptor binding potency was resident in
the (2S,6S,11S)-isomer (+)-3.
As part of our recent
goal to identify orally-active analogues of cyclazocine
having potent k agonist and m antagonist binding prop-
erties, we recently resynthesized (‹)-4, made its hitherto
unknown enantiomerically pure counterparts (� )-5 and
3
1
0th International Narcotic Research Conference, Saratoga, NY,
999; Abstract O1-1. (c) Bidlack, J. M.; Urban, T. J.; Colasurdo, A.
M.; Cohen, D. J.; Cio, C.; Ye, Y.; Wentland, M. P. Proceedings of
the 61st Annual Meeting of the College on Problems of Drug Depen-
dence, Acapulco, Mexico, 1998; page 10. d) Wentland, M. P.; Xu, G.;
Cohen, D. J.; Bidlack, J. M. Abstracts of Papers, 60th Annual Meeting
of the College on Problems of Drug Dependence, Scottsdale, AZ,
(
+)-6, and made several related 8-amino analogues as
probes to identify a preliminary structure±activity rela-
tionship. We now report the synthetic methods and m, d
and k opioid binding data for these new racemic, and in
1
998; Abstract 80±141.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(99)00670-8

1
84
M. P. Wentland et al. / Bioorg. Med. Chem. Lett. 10 (2000) 183±187
certain cases, enantiomerically pure 8-(substituted)-
amino cyclazocine analogues compared to cyclazocine
and its enantiomers.
known enantiomers8,9 of cyclazocine; conversion to the
corresponding methyl ethers (� )-24 and (+)-25 was
accomplished using known methodology.10 Using our
Birch reduction/Semmler-Wolf methodology (Scheme
1
(
) for the conversion of cyclazocine methyl ether to
‹)-4,3 we converted (� )-24 and (+)-25 to (� )-5
Chemistry
1
1
[(2R,6R,11R)] and (+)-6 [(2S,6S,11S)], respectively.
We used two approaches to synthesize new targets. Our
3
For these transformations, very similar yields were
observed to known racemic example.
original method to make (‹)-4 was applied to make
the enantiomeric counterparts, (� )-5 and (+)-6. After
derivatization with (S)-(� )-a-methylbenzylisocyanate to
While the Birch reduction/Semmler-Wolf method was
very useful, we needed another procedure for the rapid
introduction of a variety of amine substituents at posi-
tion-8. The Pd-catalyzed amination12 of aryl halides and
7
ensure optical purity, the enantiomers of normetazocine
8
8
(
� )-22 and (+)-23 (Scheme 1) were alkylated with
cyclopropylmethyl bromide to give the corresponding
Scheme 1. Synthesis of chiral 8-amino-2,6-methano-3-benzacines.
Scheme 2. Synthesis of target compounds via palladium-catalyzed aminations.

M. P. Wentland et al. / Bioorg. Med. Chem. Lett. 10 (2000) 183±187
185
tri¯ates pioneered by Buchwald,13 Hartwig,14 and co-
workers served our needs very well. As shown in Scheme
1). The known 8-methylamino analogue, (‹)-7, was
made by reducing (‹)-21 with H /Pd(OH) /C. The iso-
propylamino analogue (‹)-9 was made by ®rst coupling
3
2
2
2
, cyclazocine [(‹)-1] and its enantiomers, (� )-2 and
(
+)-3, were converted to the corresponding tri¯ates
‹)-30, (� )-31, and (+)-32, respectively, in 94±96%
(‹)-30 with Ph C=NH following a modi®cation of a
2
17
(
yield using standard conditions. Tri¯ate derivative
known procedure (Method A, 86.9%) to provide (‹)-
33 (Scheme 2) which was subjected to imine exchange
conditions to provide (‹)-4. Subsequent reductive ami-
nation provided target (‹)-9.
(
(
‹)-30 was converted to racemic targets (‹)-8, (‹)-10,
‹)-13, and (‹)-15±21 using two known Pd-catalyzed
0
amination methods, Method A (RR NH, Pd (dba) ,
2
3
ꢀ
RR NH, Pd(OAc) , BINAP, NaO-t-Bu, tol, 80 C).
14,15
DPPF, NaO-t-Bu, tol, 80 C)
0
or Method B
ꢀ
13,16
(
2
Results and Discussion
Method A was used to convert the optically active tri-
ates (� )-31, and (+)-32 to the phenylamino derivatives
� )-11, and (+)-12, respectively (yields shown in Table
¯
(
Opioid receptor binding data and a brief description of
the receptor binding assays are found in Table 1. While
Table 1. Opioid binding data for 8-(substituted)aminocyclazocine analogues
a
K
i
(nM‹S.E.) vs
0
Methodb
Yield, %b
ꢀ
3
3
3
Compound
R
R
mp, C
[ H]DAMGO (m)
[ H]Naltrindole (d)
[ H]U69,593 (k)
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
‹)-1c
(cyclazocine)
0.32‹0.02
0.10‹0.03
360‹16
9.5‹0.14
1.8‹0.12
780‹78
13‹0.77
5.1‹0.74
240‹3.7
1.3‹0.072
1.1‹0.08
46‹4.4
1.5‹0.16
0.67‹0.043
9.0‹2.4
82‹1.9
770‹55
950‹84
650‹38
21‹2.8
1.1‹0.04
0.58‹0.06
1100‹63
110‹15
12‹2.3
920‹27
470‹62
19‹3.1
460‹49
9.4‹0.74
5.2‹0.08
270‹49
57‹2.5
0.18‹0.020
0.052‹0.009
76‹8.2
4.1‹0.11
1.2‹0.13
506‹37
8.5‹0.44
3.3‹0.10
78‹16
0.83‹0.036
0.54‹0.01
27‹1.5
4.7‹0.15
2.1‹0.10
11‹0.084
33‹2.5
410‹30
300‹29
560‹82
8.8‹0.40
44‹1.8
c
� )-2
+)-3c
d
‹)-4
� )-5
H
H
H
H
H
H
H
H
H
H
H
H
CH
H
H
H
CH
e
87±89
88±90
f
+)-6
‹)-7d
‹)-8d
‹)-9
3
2 3
CH CH
i-Pr
Oil
Oil
Foam
Oil
Oil
Oil
Oil
Oil
Oil
‹)-10
� )-11
C
6
C
6
C
6
H
H
H
5
5
5
A
A
A
B
B
B
B
B
B
B
B
B
59
57
59
53
66
55
57
54
48
49
25
55
g
+)-12h
‹)-13
CH
CH
2
C
C
6
H
5
5
i
� )-14
2
6
H
54‹3.6
‹)-15
‹)-16
‹)-17
(CH
2
)
CH
2
C
6
H
5
160‹8.0
1500‹96
1800‹73
3600‹390
2800‹200
250‹51
570‹33
3
3
-(CH
-(CH
2
)
)
4
-
-
j
‹)-18
2
5
264 (dec)
140±142
Oil
‹)-19
‹)-20
‹)-21
-(CH
-(CH NCH
CH CH
2
)
2
OCH
2
)
2
-
2
)
2
3
(CH
2
)
2
-
3
2
C
6
H
5
Oil
56‹4.1
a
Binding assays used to screen compounds are similar to those previously reported (see ref 21). Guinea pig brain membranes, 500 mg of membrane
3
3
protein, were incubated with 12 di€erent concentrations of the compound in the presence of either 1 nM [ H]U69,593 (k), 0.25 nM [ H]DAMGO (m)
or 0.2 nM [ H]naltrindole (d) in a ®nal volume of 1 mL of 50 mM Tris±HCl, pH 7.5 at 25 C. Incubation times of 60 min were used for [ H]U69,593
and [ H]DAMGO. Because of a slower association of [ H]naltrindole with the receptor, a 3 h incubation was used with this radioligand. Samples
3
ꢀ
3
3
3
3
2
incubated with [ H]naltrindole also contained 10 mM MgCl and 0.5 mM phenylmethylsulfonyl ¯uoride. Nonspeci®c binding was measured by
inclusion of 10 mM naloxone. The binding was terminated by ®ltering the samples through Schleicher & Schuell No. 32 glass ®ber ®lters using a
Brandel 48-well cell harvester. The ®lters were subsequently washed three times with 3 mL of cold 50 mM Tris±HCl, pH 7.5, and were counted in 2
3
3
mL Ecoscint A scintillation ¯uid. For [ H]naltrindole and [ H]U69,593 binding, the ®lters were soaked in 0.1% polyethylenimine for at least 60 min
before use. IC50 values will be calculated by least squares ®t to a logarithm-probit analysis. K values of unlabeled compounds were calculated from
the equation K =(IC50)/1+S where S=(concentration of radioligand)/(K of radioligand) Ð see ref 22. Data are the mean‹S.E. from at least three
experiments performed in triplicate.
i
i
d
b
Method and yields refer to the Pd-catalyzed amination step Ð see Scheme 2 and ref 15.
Known compound Ð see refs 8 and 9.
c
d
e
Known compound Ð see ref 3.
25
o
[
a]
d
=� 118 (c=1.0, MeOH).
f
25
o
[
[
[
a]
d
=+118 (c=1.0, MeOH).
g
25
d
o
a]
=� 79.3 (c=1.0, CHCl
3
).
).
h
25
d
o
a]
=+78.3 (c=1.0, CHCl
3
i
25
o
[
a]
Dihydrochloride salt.
d
=� 101.9 (c=1.06, EtOH).
j

1
86
M. P. Wentland et al. / Bioorg. Med. Chem. Lett. 10 (2000) 183±187
the primary amino analogues, (‹)-4 and (� )-5, have
high anity for m and k receptors, potency was sub-
stantially reduced (>20-fold) compared to the corre-
sponding phenols, cyclazocine [(‹)-1] and (� )-2. Since
groups to other opioid core structures (e.g. 3-amino-
morphine), a full account of this work will appear. A 3-
aminodextromorphan analogue has been reported.
2
3
This analogue, however, has the opposite stereochem-
istry to natural opiates and was studied for other (than
opioid receptor binding) pharmacological proper-
ties.2
(
‹)-4 was only 5-fold less potent than (‹)-1 in rodent
models of antinociception dosed sc and equipotent po,
we assume that (‹)-4 has substantially enhanced phar-
macodynamic properties especially when administered
orally. For both the phenols and primary amino analo-
gues, the active enantiomers at opioid receptors are the
3,24
Acknowledgements
(� )-[(2R,6R,11R)] isomers. In addition, greater anity
is evident for m/k receptors than d; between m and k,
there is a modest preference for k. When the primary
amine of (‹)-4 was substituted with monoalkyl groups,
binding anity was not e€ected by methyl [(‹)-7] and
ethyl groups [(‹)-8], however, it was substantially
reduced by isopropyl substitution [(‹)-9]. For secondary
amine substituents containing a phenyl ring, however,
substantial anity was observedÐthe phenylamino
analogue (‹)-10 and the benzylamino analogue (‹)-13
had only 4-fold less anity for m receptors. The phe-
nethyl analogue (‹)-15 was somewhat less potent. For
these phenyl derivatives, binding to k receptors follows
the same rank order of potency although the PhNH
compound (‹)-10 is the most potent and selective for k.
Consistent with our other observations, the activity of
these racemic 8-phenylamino [(‹)-10] and 8-benzyl-
amino [(‹)-13] compounds resides in the (� )-
Discussions with Dr. Arthur Schultz and the late Dr.
Sydney Archer and the contributions of Dr. Qun Zhou
(all at Rensselaer) are gratefully acknowledged. Fund-
ing of this research was from NIDA (DA01674,
DA03742, DA12180 and KO5-DA00360).
References and Notes
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1996, 21, 1369.
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3. Wentland, M. P.; Albertson, N. F.; Pierson, A. K. J. Med.
Chem. 1980, 23, 71.
4
8
5
. Todd, S. L.; Balster, R. L.; Martin, B. R. Life Sci. 1990, 46,
95.
. Walker, J. M.; Bowen, W. D.; Walker, F. O.; Matsumoto,
[
(2R,6R,11R)] isomers. All tertiary amine derivatives
(‹)-16±21] had reduced binding anity relative to the
[
primary or secondary amino analogues suggesting that
at least one H on the 8-position N is required for rea-
sonable binding anity. This is consistent with known
SAR studies for opioids where the prototypic phenolic
OH is required for binding to opioid receptors.1
H-bond donation by the tertiary amine derivatives is
possible when in the protonated state, however, the low
pK (<5) for such aromatic amines decreases their like-
a
lihood of any signi®cant protonation at the pH (7.5) of
the assay.
R. R.; De Costa, B.; Rice, K. C. Pharmacol. Rev. 1990, 42,
355.
6. For all optically active compounds reported in this paper,
(t 2h Se , 6( S�, )1 - 1i sSo ) m. ers are (2R,6R,11R) and the (+)-isomers are
8±20
7. De Costa, B. R.; Dowen, W. D.; Hellewell, S. B.; Walker, J.
M.; Thurkauf, A.; Jacobson, A. E.; Rice, K. C. FEB Letters
1
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967, 10, 383.
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Our earlier rodent data indicating that an 8-NH group
2
1
1. Proton NMR, IR, MS were consistent with the assigned
was an e€ective bioisosteric replacement for 8-OH in
cyclazocine did not translate to the same degree of
e€ectiveness in opioid receptor binding assays. How-
ever, by modifying the nitrogen substitution, a new
receptor binding SAR was revealed. These new data
showing that high anity binding to k and m opioid
receptors are seen in a novel series of 8-(substituted)-
amino cyclazocine derivatives opens new opportunities
to understand and enhance binding of benzomorphans
to their receptors. The expanded valence going from the
structures of all new compounds. C, H, and N elemental ana-
lyses were obtained for all new targets and most intermediates
and were within ‹0.4% of theoretical values.
12. Hartwig, J. F. Angew. Chem., Int. Ed 1998, 37, 2046.
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dimethyl-N-(phenyl)-2,6-methano-3-benzazocin-8-amine [(‹)-
1
0]. Method A. An oven-dried 25-mL two-neck ¯ask equipped
with re¯ux condenser was placed into a N ®lled glove box
where it was charged with Pd (dba) (0.057 g, 0.062 mmol),
2
8-position oxygen to nitrogen provides us with the
2
3
opportunity to explore new molecular contacts between
receptor and an N-substituent while still maintaining
the important H-bond interaction between drug (as
donor) and opioid receptor (acceptor). Following gen-
eration and analysis of in vivo and additional SAR
binding data, including adding (substituted)amino
DPPF (0.103 g, 0.186 mmol), and NaOt-Bu (0.119 g, 1.239
mmol). The system was capped with rubber septa and
removed from the glove box. Approximately 4 mL of dry,
distilled toluene (Na, benzophenone ketyl) were then added to
the mixture via syringe and the resulting dark suspension was
allowed to stir at ambient temperature for 10 min. A solution

M. P. Wentland et al. / Bioorg. Med. Chem. Lett. 10 (2000) 183±187
187
containing tri¯ate (‹)-30 (0.500 g, 1.239 mmol) and aniline
(
16. Method B was essentially identical to Method A except
Pd(OAc) and BINAP were used catalyst source and Pd-ligand,
0.138 g, 1.487 mmol) in 3 mL of toluene was added and the
2
ꢀ
0
mixture was heated to 80 C with vigorous stirring. At
approximately 6 h the reaction had gone to completion as
evidenced by TLC. It was allowed to cool, diluted with 20 mL
of CH Cl , ®ltered over Celite and then directly preadsorbed
respectively, rather than Pd (dba)
2
bis(diphenylphosphino)-1,1 -binaphthyl;
benzylideneacetone)dipalladium(0); DPPF-1,1 -bis(diphenyl-
phosphino)-ferrocene.
Ê
17. Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.;
3
and DPPF. BINAP-2,2 -
(dba)
0
Pd
2
3
-Tris(di-
0
2
2
onto silica gel. The crude reaction mixture was ¯ashed with
hexanes:ethyl acetate (20:1 to 10:1 to 3:1 gradient) yielding
Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367.
18. Mascarella, S. W.; Bai, X.; Williams, W.; Sine, B.; Bowen,
W. D.; Carroll, F. I. J. Med. Chem. 1995, 38, 565.
19. Furst, S.; Hoszta®, S.; Friedmann, T. Curr. Med. Chem.
È
1995, 1, 423.
1
(
‹)-10 as a light-brown oil (0.255 g, 0.736 mmol, 59.3%): H
NMR (500 MHz, CDCl
.87±6.85 (m, 2H) 5.65 (bs, 1H), 3.19 (m, 1H), 2.90±2.86 (d,
J=18.3 Hz, 1H), 2.78 (m, 1H), 2.75 (m, 1H), 2.54±2.38 (m,
3
) d 7.23 (m, 2H), 6.99±6.90 (m, 4H),
6
2
1
2
1
5
9
H), 2.17 (m, 1H), 1.97 (m, 1H), 1.95 (m, 1H), 1.36 (m, 1H),
.34 (s, 3H), 0.91 (m, 1H), 0.89 (d, J=7.1 Hz, 3H), 0.54 (m,
H), 0.14 (m, 2H); C NMR (500 MHz, CDCl ) d 143.94,
3
20. Aldrich, J. V. In Burger's Medicinal Chemistry and Drug
Discovery; Wol€, M. E., Ed.; John Wiley & Sons: New York,
1996; Vol. 3, pp 321±441.
21. Archer, S.; Seyed-Moza€ari, A.; Jiang, Q.; Bidlack, J. M.
J. Med. Chem. 1994, 37, 1578.
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Med. Chem. 1992, 35, 4135.
1
3
42.96, 140.74, 129.23, 127.82, 120.01, 116.61, 116.34, 116.02,
9.77, 57.08, 45.92, 41.92, 41.55, 36.37, 25.41, 23.18, 14.14,
�
1
.17, 4.01, 3.60; IR (CH
CI/isobutane) m/z 347 (M+1, 100%). Anal. calcd. For
C H N .0.33 H O: C, 81.77; H, 8.58; N, 7.95. Found: C,
2
Cl
2
) 2923, 2095, 1597 cm ; MS
(
24
30
2
2
81.60; H, 8.64; N, 7.78. This reaction was performed on a
larger scale (3-fold) giving a similar yield of (‹)-10 (mp, 144±
24. Tortella, F. C.; Britton, P.; Williams, A.; Lu, X. C. M.;
Newman, A. H. J. Pharm. Exp. Ther. 1999, 291, 399.
ꢀ
1
46 C).