Synthesis and binding affinities of 4-diarylaminotropanes, a new class of delta opioid agonists

Article abstract of DOI:10.1016/S0960-894X(00)00182-7

A series of 4-diarylaminotropanes has been prepared. Both endo and exo diastereomeric forms bound to the delta opioid receptor but the endo isomers were more potent and selective versus the μ opioid receptor than the exo isomers. The most potent delta opioid agonist (14) exhibited a delta opioid K(i) of 0.2 nM and was 860-fold selective over mu. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00182-7

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1109±1111
Synthesis and Binding Anities of 4-Diarylaminotropanes,
a New Class of Delta Opioid Agonists
Robert E. Boyd, John R. Carson,* Ellen E. Codd, A. Diane Gauthier,
Lou Anne Neilson and Sui-Po Zhang
Drug Discovery, R. W. Johnson Pharmaceutical Research Institute, Spring House, Philadelphia, PA 19477, USA
Received 16 February 2000; accepted 14 March 2000
AbstractÐA series of 4-diarylaminotropanes has been prepared. Both endo and exo diastereomeric forms bound to the delta opioid
receptor but the endo isomers were more potent and selective versus the m opioid receptor than the exo isomers. The most potent
delta opioid agonist (14) exhibited a delta opioid Ki of 0.2 nM and was 860-fold selective over mu. # 2000 Elsevier Science Ltd. All
rights reserved.
A number of selective delta (d) opioid agonists have
been reported in the literature.1 These compounds were
pursued as potential analgesic agents with fewer side
e€ects than classic mu (m) opioid agonists. Many of
these d agonists are piperazines or piperidines and
resemble the earlier mu opioid agonists but incorporate
(5a and 5b) which could be separated by ¯ash chroma-
tography.
an additional aromatic `address functionality'.2
A
piperazine that has been widely studied as a d agonist is
SNC 80 (1).3 Transposition of nitrogen and carbon at
the head of SNC 80 gives rise to diarylaminopiperidines
(2), another class of compounds with d agonist
activity.4 7 We sought to investigate the role of stereo-
chemistry in d agonists by preparing and evaluating a
series of bridged compounds, the 4-diarylaminotropanes
(3).
Scheme 1. General syntehsis of diarylaminotropanes. Reagents and
conditions: (a) aniline, Na, EtOH; (b) t-butyl 4-bromobenzoate,
Pd2dba3, (t-butyl)3P, NaOtBu, toluene; (c) 6 N HCl; (d) HATU,
HNR2R3; (e) 1-chloroethylchloroformate, DCE, re¯ux, 2 h; (f) MeOH,
re¯ux; (g) carbonyl compound, NaBH(OAc)3, DCE.
A synthetic pathway to compounds of type 3 is shown in
Scheme 1. Tropinone (4) was subjected to reductive
alkylation with aniline. The reducing agent employed
determined the stereochemistry of the new bond formed.
Sodium borohydride, sodium triacetoxyborohydride, or
catalytic reduction gave exclusively the endo isomer (5b)
while sodium metal in ethanol produced both isomers8
Once separated, the individual isomers underwent aryl-
ation9 with t-butyl 4-bromobenzoate to produce the 4-
(diaryl)aminotropane (6). The ester was hydrolyzed with
HCl and the resulting acid (7) was converted to the
desired amide (8) by one of two ways. Coupling utilizing
HATU (O-(7-azabenzotriazol-1-yl)-N,N,N0,N0-tetramethyl-
uronium hexa¯uorophosphate)10 produced the desired
*Corresponding author. Tel.: +1-215-628-5526; fax: +1-215-628-
4985; e-mail: jcarson@prius.jnj.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00182-7

1110
R. E. Boyd et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1109±1111
amides in quantitative yield. Conversion of the acid to
the acid chloride followed by Schotten±Baumann reac-
tion with the appropriate amine proved successful as
well. Compounds (10) with di€erent substituents on the
tropane nitrogen were acquired by alkylation after
demethylation of compound 9 with 1-chloroethyl-
chloroformate.
A summary of biological data is listed in Tables 1 and 2.
The d opioid receptor anity was calculated from the
inhibition of H-DPDPE binding to d opioid receptors
3
from rat brain membranes. The m opioid receptor a-
3
nity was calculated from the inhibition of H-DAMGO
binding to m opioid receptors from rat brain membranes.15
The binding anities of morphine16 and SNC 80 are listed
as m and d agonist representatives.
Tropanes have been studied as m opioid agonists.11 14
NMR studies indicated an axial phenyl in a chair con-
®guration for the meperidine analogue (11)11,12 while
the bridged fentanyl analogue (12) adopted the equa-
torial boat con®guration.14 The lack of an NOE
between the aromatic protons and the protons on the
bridge indicate that endo diarylamino function of 13 is
in the equatorial boat con®guration analogous to 12.
This new class of compounds can exhibit low nanomo-
lar binding anity for the d opioid receptor. Some of
the endo isomers (Table 1) are among the most potent
and selective nonpeptidic d agonists to be published to
date. Compounds 14, 15 and 16 are more potent and
selective than SNC 80. The endo tropanes are, in gen-
eral, more potent and selective than their nonbridged
counterparts, the piperidines (16 vs 34).6
The structure±activity relationships of this class parallel
the SAR of previously published d opioid agonists.17 21
The small `R' groups on nitrogen, H (15), allyl (16),
methyl (19), and propyl (20), typical of d agonists ana-
logous to SNC 80, elicit high d receptor anity. The
Table 1. Binding anity of the endo isomers to d and m opioid receptor
Compound
R
X
Y
d KI nm
m KI nm
m/d ratio
Morphine
SNC 80
14
15
16
17
18
19
20
21
22
23
24
25
26
13
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
90
1.7
0.2
0.4
0.5
2
2
2
3
4
4
4
5
5
6
7
8
8
1.8
1300
172
5040
1820
817
1185
2555
5790
293
308
818
113
244
2773
4830
124
1725
2770
1205
4346
Inact.
3700
1155
128
1400
3018
1343
249
0.02
760
860
14000
3640
355
546
1122
1776
75
3,4-Methylenedioxybz
NEt2
NEt2
NEt2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
SCH3
H
H
Allyl
Cy
Phenethyl
Me
Pr
Phenethyl
Phenethyl
Phenethyl
Phenethyl
Phenethyl
Me
NEt2
NEt(2-Me)allyl
NEt(2-Me)allyl
NEt2
NMePr
NMePr
NPr2
NMeEt
NEtBu
NMePh
NEt2
NEt2
NPrBu
NEt2
77
200
24
50
473
733
16
Me
Phenethyl
Me
Me
220
235
119
240
Inact.
180
481
4.3
41
57
14
0.7
21
Inact.
9
Me
Me
Me
Me
NEt(4-Me)Bn
NMeEt
NPr2
10
18
18
21
24
30
34
53
93
356
363
2260
H
H
OCH3
NEt2
Phenethyl
Me
Me
Phenethyl
Phenethyl
Me
NMe2
1-pyrrolidinyl
NMe2
1-pyrrolidinyl
OH
OH
H
H
H
H
H
H
H
7500
Inact.
Me
Ot-butyl

R. E. Boyd et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1109±1111
1111
Table 2.Binding anity of the exo isomers to d and m opioid receptor
framework of the molecule is likely to lead to additional
potent and selective d opioid agonists.
References
1. Williams, M.; Kowaluk, E. A.; Arneric, S. P. J. Med. Chem.
1999, 42, 1481.
2. Portoghese, P. S.; Sultana, M.; Takemori, A. E. J. Med.
Chem. 1990, 33, 1714.
Compound
R
X
d KI m KI
nm nm
m/d
ratio
3. Calderone, S. N.; Rice, K. C.; Rothman, R. B.; Porreca, F.;
Flippen-Anderson, J. L.; Kayakiri, H.; Xu, H.; Becketts, K.;
Smith, L. E.; Bilsky, E. J.; Davis, P.; Horvath, R. J. Med.
Chem. 1997, 40, 695.
4. Pelcman, B.; Roberts, E. World Patent Application WO 98/
28270, 1998; Chem. Abstr. 1998, 129, 108996.
5. Carson, J. R.; Carmosin, R. J.; Fitzpatrick, L. J.; Reitz, A.
B.; Jetter, M. C. World Patent Application WO 99/33806,
1999; Chem. Abstr. 1999, 131, 460403.
6. Podlogar, B. L.; Poda, G. I.; Demeter, D. A.; Zhang, S.-P.;
Carson, J. R.; Neilson, L. A.; Reitz, A. B.; Ferguson, D. M.
Drug Des. Disc. In press.
7. Thomas, J. B.; Herault, X. M.; Rothman, R. B.; Burgess, J.
P.; Mascarella, S. W.; Xu, H.; Horel, R. B.; Dersh, C. M.;
Carroll, F. I. Bioorg. Med. Chem. Lett. 1999, 9, 3053.
8. Bagley, J. R.; Riley, T. N. J. Heterocycl. Chem. 1977, 14, 599.
9. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575±
5580.
SNC 80
1.7 1300
90 1.8
23
760
0.02
6.3
186
136
39
8
85
13
4
23
6
0.2
5
23
12
21
3
Morphine
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
PhenylPr
3,4-Methylene dioxybz
2-Furylmethyl
NEt2
NEt2
NEt2
4
4
6
9
704
845
350
94
3,4-Dimethoxy- phenethyl NEt2
3,3-Dimethallyl
NEt2 12
NEt2 19
NEt2 24
NEt2 33
NEt2 42
NPr2 61
NEt2 72
NEt2 77
NPr2 131
NEt2 151
NEt2 305
NEt2 550
H
4-Fluoro phenethyl
Hexyl
1590
311
130
975
370
13
371
2950
1850
6350
1420
2-EtBu
Phenethyl
Phenethyl
Cyclohexyl-methyl
H
Pr
Me
2,2-Diphenyl ethyl
10. Downing, S. V.; Aguilar, E.; Meyers, A. I. J. Org. Chem.
1999, 64, 826±831.
11. Bell, M. R.; Archer, S. J. Am. Chem. Soc. 1960, 82, 151.
12. Casy, A. F.; Coates, J. E. Org. Magn. Reson. 1974, 6, 441.
13. Casy, A. F.; Dewer, G. H.; Pascoe, R. A. J. Pharm. Pha-
macol. 1992, 44, 787.
14. Riley, T. N.; Bagley, J. R. J. Med. Chem. 1979, 22, 1167.
15. Codd, E. E.; Shank, R. P.; Schupsky, J. J.; Ra€a, R. B. J.
Pharmacol. Exp. Ther. 1995, 274, 1263.
16. Aldrich, J. V. In Burger's Medicinal Chemistry and Drug
Discovery; Wol€, M. E., Ed.; John Wiley and Sons, 1996, Vol.
3, pp 338.
17. Giulio, D.; Ronzoni, S.; Petrillo, P. Exp. Opin. Ther.
Patents 1999, 9, 353.
3,4-methylenedioxy substituent22 imparts very good
potency. Compounds with an N-phenethyl substituent
are, in general, less selective. The CˆO(X) functionality
associated with the address2 portion of the molecule is
optimally a tertiary amide. Optimal activity and selec-
tivity are achieved with the diethylamide. Activity and
selectivity are lost when the amide is N,N-dimethyl (37)
or CO-pyrrolidinyl (36). Activity is greatly diminished
when the CˆO(X) substituent is ester or acid.
18. Alfaro-Lopez, J.; Okayama, T.; Hosohata, K.; Davis, P.;
Porreca, F.; Yamamura, H. I.; Hruby, V. J. J. Med. Chem.
1999, 42, 5359.
The exo isomers (Table 2) are less potent and less selective
for the d opioid receptor. The structure±activity relation-
ship of this set of compounds is quite di€erent from the
endo isomer. Small alkyl `R' groups on the tropane nitro-
gen result in a loss of activity (45, 47, and 49).
19. Quock, R. M.; Burkey, T. H.; Varga, E.; Hosohata, Y.;
Hosohata, K.; Cowell, S. M.; Slate, C. A.; Ehlert, F. J.; Roeske,
W. R.; Yamamura, H. I. Pharmacol. Rev. 1999, 51, 503.
20. Thomas, J. B.; Atkinson, R. N.; Herault, X. M.; Rothman,
R. B.; Mascarella, S. W.; Dersch, C. M.; Xu, H.; Horel, R. B.;
Carroll, F. I. Bioorg. Med. Chem. Lett. 1999, 9, 3347.
21. Zhang, X.; Rice, K. C.; Calderon, S. N.; Kayakiri, H.;
Smith, L.; Coop, A.; Jacobson, A. E.; Rothman, R. B.; Davis,
P.; Dersch, C. M.; Porecca, F. J. Med. Chem. 1999, 42, 5455.
22. Barn, D. R.; Bom, A.; Cottney, J.; Caul®eld, W. L.; Mor-
phy, J. R. Bioorg. Med. Chem. Lett. 1999, 9, 1329.
In summary, the generation of this class of compounds
has developed a greater understanding of the spacial
relationships between the d opioid receptor and its ago-
nists. The binding site of the receptor is highly in¯uenced
by the stereochemistry of the agonist. These ®ndings indi-
cate that investigation into steric barriers designed into the