Synthesis and monoamine transporter binding properties of 2,3-cyclo analogues of 3β-(4′-aminophenyl)-2β-tropanemethanol

Article abstract of DOI:10.1021/jm060287w

A series of cyclo-3β-(4-aminophenyl)-2β-tropanemethanol analogues (5a-m) possessing varying linker groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine transporter binding properties. The results show that binding to the dopamine and serotonin transporters (DAT and 5-HTT) is highly dependent on the specific linker used. Cyclo-3β-(4-aminophenyl)-2β-tropanemethanol pimelic acid ester/amide (5b) had an IC₅₀ of 3.8 nM at the DAT. Cyclo-3β-(4-aminophenyl)- 2β-tropanemethanol sebacic acid ester/amide (5e) had a K_i of 1.9 nM at the 5-HTT and was 68- and 737-fold selective for the 5-HTT relative to the DAT and NET. Small changes to the size as well as the electrostatic and hydrophobic properties of the 2,3-linker in 5b or 5e led to much less potent analogues at all three transporters. These results suggest that the high affinity for 5b and 5e at the DAT and 5-HTT may be due to their specific conformational properties.

Full text of DOI:10.1021/jm060287w

J. Med. Chem. 2006, 49, 4589-4594
4589
Synthesis and Monoamine Transporter Binding Properties of 2,3-Cyclo Analogues of
3â-(4′-Aminophenyl)-2â-tropanemethanol
F. Ivy Carroll,*,† Bruce E. Blough,† Xiaodong Huang,† Zhe Nie,† S. Wayne Mascarella,† Jeffrey Deschamps,‡ and
Herna´n A. Navarro†
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, and
Laboratory for the Structure of Matter, NaVal Research Laboratory, 4555 OVerlook AVenue, Washington, D.C. 20375-5341
ReceiVed March 14, 2006
A series of cyclo-3â-(4-aminophenyl)-2â-tropanemethanol analogues (5a-m) possessing varying linker
groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine
transporter binding properties. The results show that binding to the dopamine and serotonin transporters
(DAT and 5-HTT) is highly dependent on the specific linker used. Cyclo-3â-(4-aminophenyl)-2â-
tropanemethanol pimelic acid ester/amide (5b) had an IC50 of 3.8 nM at the DAT. Cyclo-3â-(4-aminophenyl)-
2â-tropanemethanol sebacic acid ester/amide (5e) had a Ki of 1.9 nM at the 5-HTT and was 68- and 737-
fold selective for the 5-HTT relative to the DAT and NET. Small changes to the size as well as the electrostatic
and hydrophobic properties of the 2,3-linker in 5b or 5e led to much less potent analogues at all three
transporters. These results suggest that the high affinity for 5b and 5e at the DAT and 5-HTT may be due
to their specific conformational properties.
Introduction
The present studies were undertaken to explore the effect of
reducing the conformational freedom of rotation about the 2-
and 3-positions of the tropane ring. Specifically, we designed,
synthesized, and determined the monoamine transporter binding
properties of 5a-m, where the linker M connecting the 2- and
3-positions was changed both in length and in structural
character. The study also revealed the effect of changing the
character of the linker group. Surprisingly, only 5b, which has
five methylenes between the ester and amide carbonyls, showed
high affinity for the DAT and only 5e, which possesses eight
methylenes, showed high affinity for the 5-HTT.
Cocaine (1) abuse continues to be a problem of national
significance.1 In addition to its direct effects, cocaine abuse
indirectly results in the increase of the spread of HIV-1, hepatitis
B and C, and drug-resistant tuberculosis.2 Cocaine binds to
dopamine, serotonin, and norepinephrine transporters (DAT,
5-HTT, and NET) with similar affinities. However, many of
cocaine’s stimulant and reinforcing effects in animals have been
attributed to its action at the DAT.3-5 A positive correlation
between the reinforcing and DAT binding for a variety of
dopamine (DA) uptake inhibitors resulted in the dopamine
hypothesis of cocaine addiction.3-5 These research findings
resulted in considerable effort being devoted to the characteriza-
tion of the cocaine-binding site on the DAT. One approach,
used by a number of laboratories, is structure-activity relation-
ships (SAR) studies. These studies have been summarized in
recent reviews.6-8
Studies directed toward the 3-phenyltropane class of DAT
uptake inhibitors, where 2 (WIN 35,065-2)9 served as a lead
structure, have provided valuable information about the phar-
macophore for the DAT as well as for the 5-HTT and NET. In
broad terms, (a) substitution of the 3-phenyl ring controls po-
tency but also can affect transporter selectivity; (b) a substituent
in the 2-position is required for high potency, but a wide variety
of substituents are allowed; (c) the stereochemistry about the
tropane 2- and 3-position can have large effects on both potency
and selectivity (for more details see refs 10-13 and references
cited therein). Even though much has been learned about the
cocaine-binding site on the DAT, much still remains to be done
before the site is well characterized. Sometimes the design, syn-
thesis, and evaluation of conformationally constrained analogues
can help identify a pharmacophore for a target-binding site. For
example, the conformationally constrained 3-phenyltropanes 3
and 4 and their analogues have provided valuable informa-
tion.14,15 Compound 3 bridges the 8-amino and 2-position, while
4 bridges the 8-amino and 3-position on the tropane ring.
Compound 4 is a potent and selective NET uptake inhibitor.
* To whom correspondence should be addressed. Telephone: 919-541-
6679. Fax: 919-541-8868. E-mail: fic@rti.org.
† Research Triangle Institute.
‡ Naval Research Laboratory.
10.1021/jm060287w CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/01/2006

4590 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Carroll et al.
Scheme 1a
a Reagents: (a) LiAlH4, THF; (b) ClCO(M)COCl, Et3N, CH2Cl2; (c) NaH, DMF, CH3I; (d) 9-BBN, THF.
Scheme 2a
a Reagents: (a) CH2dCHCN, Triton-B, dioxane; (b) 10 N KOH ethylene
glycol, reflux.
Figure 1. Structure of compound 5b showing labeling of the non-
hydrogen atoms. Displacement ellipsoids are at the 20% probability
level.
Chemistry
The 2,3-cyclo-3â-(4-aminophenyl)-2â-tropanemethanol ester/
amides (5a-j) were synthesized from 3â-(4-aminophenyl)-2â-
tropane-2â-carboxylic acid methyl ester (6)16 as shown in
Scheme 1. Reduction of 6 using lithium aluminum hydride in
tetrahydrofuran provided an 85% yield of 3â-(4-aminophenyl)-
tropane-2â-methanol (7). Slow addition of the appropriate diacid
chloride to a dilute solution of 7 in methylene chloride contain-
ing excess triethylamine afforded the desired 5a-j in yields
varying from 6% to 48% yield. The diacid chlorides of adipic,
pimelic, suberaic, azelaic, sebacic, and dodecanedioic acids
needed to synthesize 5a-f were all commercially available. 1,2-
Phenylenediacetic, 4-ketopimelic, and 3,3-thiodipropionic acid
needed to synthesize 5g-i were converted to their diacid chlor-
ides using oxalyl chloride. 3-[9-(2-Carboxyethyl)-9H-fluoren-
9-yl]propionic acid (11) needed to prepare 5i was synthesized
as outlined in Scheme 2. Triton B catalyzed addition of acryl-
onitrile to fluorene (9) afforded the addition product 10. Hy-
drolysis of 10 using 10 N potassium hydroxide in refluxing
ethylene glycol followed by acid workup gave the desired diacid
11.
The ester/amides 5k-m were prepared from 5d-f (Scheme
1). Treatment of 5d-f with sodium hydride in dimethylforma-
mide followed by methylation with iodomethane provided 8 and
5k. Reduction with 9-borabicyclo[3.3.1]nonane (9-BBN) in
tetrahydrofuran affected selective reduction of the amide car-
bonyl to yield 5l-m.
The structure assignments for compounds 5a-m were based
on elemental analyses and mass spectral and 1H and 13C NMR
properties. The mass spectrum of each of the compounds showed
the expected m/z. In addition, the signals in the 1H NMR
spectrum were very sharp, suggesting some conformational
rigidity. The structure of 5b, the compound showing the highest
affinity at the DAT, was confirmed by single-crystal X-ray
analysis (Figure 1). This solid-state structure also provided
information about the conformational properties of 5b in the
solid state. It is interesting to note that all of the analogues except
5b have a negative optical rotation under the conditions used.
The reason for this is not apparent.
Molecular Modeling
Molecular modeling studies were performed to determine
whether conformational differences exist among 5b-e that may
account for the observed receptor-binding selectivity. The
minimum-energy conformations of 5c, 5d, and 5e (for com-
parison to the conformation of the X-ray crystal structure of
5b) were determined via simulated annealing calculations. For
all four compounds, there were no significant differences in the
relative conformations of the tropane ring, the phenyl ring
attached at C3, or the ester group attached at C2 (Figure 2).
However, significant differences in the position and amide C-O
bond direction are revealed by the alignment of minimum-
energy conformations shown in Figure 2. Also, there is a
pronounced steric difference between the conformations of the
smallest ring system (5b) compared to the larger ring systems
of 5c, 5d, and 5e. The centers of the alkyl bridges of compounds
5c-e all occupy a somewhat similar region spaced at ∼10 Å
from the tropane nitrogen atom, while the analogous alkyl bridge
center of 5b is at a distance of ∼8 Å from the nitrogen.

Analogues of a Tropanemethanol
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4591
macrocyclic in nature, where the 2- and 3-positions on the
tropane ring are connected through a linker that varies in length,
size, electrostatic, and hydrophobic properties. The connection
at the 2-position is via an ester function to a 2â-hydroxymethyl
group. The connection in the 3-position is via an amide (5a-j)
or amine (5k-m) group to a 3â-(4-aminophenyl) substituent.
These structural variations affected selectivity for the DAT and
5-HTT to a greater extent than at the NET such that affinities
at the DAT and 5-HTT differed by approximately 500- and 900-
fold, respectively, compared to only a 76-fold spread at the NET.
The two most interesting observations were that 5b had an IC50
of 3.8 nM for the DAT and that 5e possessed a Ki of 1.9 nM
for the 5-HTT. Cyclo analogue 5b also showed Ki values of 20
and 50 nM at the NET and 5-HTT and thus was not selective
for the DAT relative to the NET and 5-HTT. In contrast, 5e
had Ki values of 130 and 1400 nM at the DAT and NET and
thus was 68- and 737-fold selective for the 5-HTT relative to
the DAT and NET. The cyclo analogue 5b has five methylenes
between the ester and amide carbonyl groups. Cyclo analogues
5a and 5c, which possess one less and one more methylene
group in the linker, show DAT IC50 values of 890 and 70 nM.
Replacement of one methylene with a carbonyl (5h) or sulfur
(5i) did not lead to analogues with high affinity at the DAT.
These analogues also possessed low affinity at the 5-HTT and
NET. Analogues 5g and 5j, which have an aromatic and
fluorenyl group in the linker, show weak affinity at the DAT
as well as at the 5-HTT and NET.
Figure 2. Overlay of the observed X-ray crystal structure of 5b (blue)
and the calculated minimum-energy conformations of 5c (green), 5d
(purple), and 5e (red).
Biology
The IC50 values for the inhibition of radioligand binding at
the DAT, 5-HTT, and NET for 5a-m are listed in Table 1.
Since the 5-HTT and NET have only one binding site, Ki values
were calculated for inhibition of binding at these two transport-
ers. For comparison, the previously reported values for cocaine
and 2 are also listed. The binding affinities at the DAT, 5-HTT,
and NET were determined via competitive binding assays using
previously reported procedures.17,18
Results and Discussion
The 5-HTT selective cyclo analogue 5e has an eight-
methylene linker between the ester and amide carbonyl group.
However, the cyclo analogues 5d and 5f, which have one less
and two more methylenes in the linker, have Ki values of >2000
and 290 nM at the 5-HTT, respectively. Compound 5l, which
can be considered an analogue of 5e with one additional
methylene and no amide carbonyl, retained similar selectivity
for the DAT and NET but with a Ki of 94 nM at the 5-HTT
was 50 times less potent than 5e. The overall compound design
goal of reducing the conformational freedom of the 2- and
3-positions appears to have been achieved. The observed solid-
state structure of 5b confirms the calculated prediction that the
phenyl ring and ester group will exhibit limited conformational
variability in low-energy conformations of compounds from this
Previous studies from our laboratory as well as others have
shown that the structure of the substituent in the 2-position ester
or reverse ester of the 3-phenyltropane has only minor effects
on DAT affinity.6,19 However, the size of the substituent can
have large affects on the affinity at the NET and 5-HTT. This
information led to the development of a number of high-affinity
DAT selective compounds. Previous studies also show that as
the size of the 4′-acylamino group increased, the DAT, NET,
and 5-HTT affinity decreased.20 To gain additional information
about the cocaine-binding site(s) on the DAT, 5-HTT, and NET,
we designed, synthesized, and evaluated the monoamine binding
properties of a series of 2,3-cyclo-3â-(4-aminophenyl)-2-
substituted tropane analogues 5a-m. The compounds are
Table 1. Monoamine Transporter Binding Properties of 2,3-Cyclo-2â-(4-aminophenyl)-2â-substituted Tropanes
IC50, nM (Ki, nM)a
compd
RTI compd
M
R
DAT [3H]WIN 35,428
NET [3H]nisoxetine
5-HTT [3H]paroxetine
1050 (45)
cocaineb
89.1
23
3300 (1990)
920 (550)
2b
1960 (178)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
672
614
659
658
615
657
667
668
669
671
660
661
662
(CH2)4CO
(CH2)5CO
(CH2)6CO
(CH2)7CO
(CH2)8CO
(CH2)10CO
CH2C6H4CH2CO
(CH2)2CO(CH2)2CO
(CH2)2S(CH2)2CO
(CH2)2C(R,R′)(CH2)2COc
(CH2)8CO
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
890 ( 200
3.8 ( 0.4
70 ( 10
410 ( 120
130 ( 25
390 ( 130
>2000
160 ( 30
170 ( 31
290 ( 19
1920 ( 300
150 ( 21
490 ( 140
(>2000)
>2000
40 ( 6 (20 ( 3)
3040 ( 250 (1520 ( 130)
(>2000)
200 ( 20 (50 ( 6)
2090 ( 513 (513 ( 126)
(>2000)
2800 ( 500 (1400 ( 260)
2320 ( 230 (1160 ( 110)
(>2000)
1400 ( 66 (710 ( 33)
990 ( 62 (500 ( 31)
980 ( 71 (490 ( 36)
(>2000)
2130 ( 78 (1060 ( 39)
(>2000)
7.8 ( 0.8 (1.9 ( 0.2)
1200 ( 49 (290 ( 12)
(>2000)
5010 ( 1030 (1230 ( 250)
6730 ( 510 (1650 ( 130)
>2000
(>2000)
380 ( 15 (94 ( 4)
450 ( 98 (110 ( 24)
(CH2)9
(CH2)11
5m
a The numbers in the parenthesis are Ki values. b Taken from ref 18; c R,R′ )

4592 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Carroll et al.
was diluted with CH2Cl2 (50 mL), washed consecutively with
sodium bicarbonate (20 mL), water (20 mL), and brine (20 mL)
and dried over sodium sulfate. The solvent was removed under
reduced pressure, and the product was purified by column chro-
matography (silica gel, 1:2 CMA/ethyl acetate) to afford 85 mg
(48%) of the title compound as a white solid. 1H NMR (CDCl3) δ
7.46 (d, J ) 8.4 Hz, 2H), 7.14 (d, J ) 8.4 Hz, 2H), 4.16 (dd, J )
7.8, 11.9 Hz, 1H), 4.01 (d, J ) 11.8 Hz, 1H), 3.21 (m, 2H), 3.00
(m, 1H), 2.40-1.00 (m, 27H), 2.19 (s, 3H); 13C NMR (CDCl3) δ
173.7, 171.3, 138.4, 136.2, 128.3, 119.0, 66.9, 65.5, 62.0, 46.4,
42.1, 37.1, 34.6, 34.1, 33.9, 29.3, 29.1, 28.0, 27.6, 27.5, 27.3, 26.7,
26.6, 26.0, 25.0, 24.6, 24.5; LCMS (APCI) m/z 441.7 (M + 1)+.
Compound 5f (20 mg, 0.046 mol) was then dissolved in CH2Cl2
(2 mL) and HCl (1 M in diethyl ether) (50 µL, 1.1 equiv) and was
added to this solution. The solvent was removed under reduced
pressure, and the product was dried under vacuum overnight to
series. Taken together, the conformational analysis and X-ray
crystallographic results suggest that differences in the geometry
of the methylene linker and amide group are the most likely
source for the observed monoamine transporter binding selectiv-
ity. The five methylenes of 5b are about 2 Å closer to the nitro-
gen of the tropane ring than that of the eight methylenes in 5e.
Thus, the space occupied by these groups could account for
their monoamine transporter binding properties. It is also inter-
esting to note that the amide carboxyl in 5e is pointed in an
almost opposite direction for 5b. Somewhat surprising, the ester
carboxyls and the aromatic rings of 5b-e are closely aligned.
In summary, a series of 2,3-cyclo-3â-(4-aminophenyl)-2â-
substituted tropane analogues (5a-m) were designed, synthe-
sized, and evaluated for their monoamine transporter binding
properties. The linker connecting the 2- and 3-positions on the
tropane ring varied in size and electrostatic and hydrophobic
properties. 3â-(4-Aminophenyl)-2â-tropanemethanol pimelic
acid ester/amide (5b) showed high affinity for the DAT, and
3â-(4-aminophenyl)-2â-tropanemethanol sebacic acid ester/
amide (5e) showed potent and selective affinity for the 5-HTT.
Small changes to the linkers in 5b and 5e led to much less potent
compounds. The results suggest that the conformational proper-
ties of 5b and 5e may play an important part in their potent
affinity at the DAT and 5-HTT, respectively.
afford the hydrochloride salt: mp 163-165 °C; [R]20 -34.1° (c
D
0.39, CH3OH). Anal. (C27H42Cl2N2O3‚H2O) C, H, N.
4,5,6,7,9,13a,14,15,16,17,18,18a-Dodecahydro-19-methyl-10,-
13-etheno-15,18-imino-1H-cyclohept[m][1,8]oxaazacyclopenta-
decine-3,8-dione (5a) Hydrochloride. A procedure similar to that
described for 5f but using adipoyl chloride was used to prepare 5a
in 8% yield: [R]20D -156.5° (c 0.23, CHCl3); 1H NMR (CDCl3) δ
7.23-7.01 (m, 4 H), 4.50 (dd, J ) 7.7, 12 Hz, 1H), 3.57 (d, J )
8.4, 12 Hz, 1H), 3.27 (br s, 1H), 3.18 (m, 2H), 2.53 (t, J ) 12.9
Hz, 1H), 2.21 (s, 3H), 2.30-1.50 (m, 15H); 13C NMR (CDCl3) δ
176.1, 171.6, 141.4, 135.3, 131.0, 128.1, 127.5, 126.7, 67.1, 65.2,
61.9, 46.8, 41.7, 34.4, 33.1, 32.7, 30.2, 26.1, 24.2, 23.3, 22.7; LCMS
(APCI) m/z 357.2 (M + 1)+. The hydrochloride salt had mp 223-
225 °C. Anal. (C21H29ClN2O3‚2.5H2O) C, H, N.
Experimental Section
1H NMR and 13C NMR spectra were determined on a Bruker
300 spectrometer at 300 and 75 MHz, respectively, using tetra-
methylsilane as an internal standard. Mass spectral data were
obtained using a Finnegan LCQ electrospray mass spectrometer in
positive ion mode at atmospheric pressure. Optical rotations were
measured on an AutoPol III polarimeter. Silica gel 60 (230-400
mesh) was used for column chromatography. All reactions were
followed by thin-layer chromatography using Whatman silica gel
60 TLC plates and were visualized by UV or by charring using
5% phosphomolybdic acid in ethanol. All solvents were reagent
grade. Tetrahydrofuran and diethyl ether were dried over sodium
benzophenone ketyl and distilled prior to use. Methylene chloride
and chloroform were distilled from calcium hydride if used as
reaction solvents. HCl in dry diethyl ether was purchased from
Aldrich Chemical Co. and used while fresh before discoloration.
Cocaine was obtained via the Research Technology Branch,
NIDA. [3H]WIN 35,428, [3H]paroxetine, and [3H]nisoxetine were
obtained from Perkin-Elmer Inc. (Boston, MA). CMA-80 is a
mixture of 80% chloroform, 18% methanol, and 2% concentrated
ammonium hydroxide.
5,6,7,8,10,14a,15,16,17,18,19,19a-Dodecahydro-20-methyl-11,-
14-etheno-16,19-iminocyclohept[c][1,9]oxaazacyclohexadecine-
3,9(1H,4H)-dione (5b) Dihydrochloride. A procedure similar to
that described for 5f but using pimeloyl chloride was used to prepare
5b in 15% yield. [R]20D +36.2° (c 2.1, CHCl3); 1H NMR (CDCl3)
δ 7.75 (br s, 1H, NH), 7.07-7.29 (m, 4H, Ar-H), 4.21 (m, 1H),
4.08 (d, J ) 12.0 Hz, 1H), 3.16-3.28 (m, 3H), 2.68 (m, 1H), 2.02-
2.28 (m and s, 8H), 1.35-1.88 (m, 8H), 1.09-1.16 (m, 3H); 13C
NMR (CDCl3) δ 176.0, 172.9, 142.5, 135.4, 131.0, 126.8, 126.7,
126.1, 66.8, 65.5, 62.0, 46.3, 42.1, 34.9, 33.5, 32.5, 31.2, 26.3, 26.1,
24.4, 23.8, 22.1; LCMS (APCI) m/z 371.5 (M + 1)+. The
hydrochloride salt had mp 222-224 °C. Anal. (C22H32Cl2N2O3‚
0.2H2O) C, H, N.
4,5,6,7,8,9,11,15a,16,17,18,19,20,20a-Tetradecahydro-21-methyl-
12,15-etheno-17,20-imino-1H-cyclohept[c][1,9]oxaazacyclohepta-
decine-3,10-dione (5c) Hydrochloride. A procedure similar to that
described for 5f but using suberoyl chloride was followed to prepare
1
5c in 17% yield. H NMR (CDCl3) δ 7.22 (br s, 2 H), 7.12 (br s,
2 H), 7.06 (s, 1 H), 4.06-3.66 (m, 2 H), 3.21-3.06 (m, 3 H), 2.20
(s, 3 H), 2.29-1.10 (m, 19 H); 13C NMR (CDCl3) δ 175.9, 173.3,
142.2, 135.4, 130.7, 129.0, 126.8, 117.6, 67.2, 65.5, 61.8, 46.7,
42.2, 38.9, 35.0, 34.3, 31.9, 26.5, 25.9, 24.9, 24.5, 24.1, 23.1; LCMS
(APCI) m/z 385.3 (M + 1)+. The hydrochloride salt had mp 205-
Note that with the exception of 5g, CAS names were used.
3â-(4-Aminophenyl)tropane-2â-methanol (7). To a solution of
2.75 g (10 mmol) of 615 in THF (100 mL) was added dropwise 20
mL (20 mmol) of LiAlH4 in THF at 0 °C. The resulting mixture
was stirred at room temperature for 3 h, cooled to 0 °C, and
quenched with saturated ammonium chloride (25 mL). The mixture
was then extracted with ethyl acetate, followed by 3:1 CH2Cl2/
THF. The organic extracts were dried (Na2SO4) and purified by
flash column chromatography (elution 1:1 CMA80/EtOAc), giving
207 °C; [R]20 -75.5° (c 0.33, CH3OH). Anal. (C23H33ClN2O3‚
D
2H2O) C, H, N.
5,6,7,8,9,10,12,16a,17,18,19,20,21,21a-Tetradecahydro-22-meth-
yl-13,16-etheno-18,21-iminocyclohept[c][1,9]oxaazacyclooctade-
cine-3,11(1H,4H)-dione (5d) Hydrochloride. A procedure similar
to that described for 5f but using azeloyl chloride was used to
1
2.1 g (85%) of 7. H NMR (CDCl3) δ 7.15 (d, J ) 8.4 Hz, 2H),
1
6.66 (d, J ) 8.4 Hz, 2H), 3.74 (dd, J ) 2.2, 10.9 Hz, 1H), 3.57 (s,
1H), 3.47 (dd, J ) 2.2, 10.7 Hz, 1H), 3.30 (s, 1H), 2.98 (m, 1H),
2.45 (dt, J ) 3.1, 13.1 Hz, 1H), 2.26 (s, 3H), 2.20-2.00 (m, 2H),
1.80-1.55 (m, 6H), 1.06 (s, 1H).
prepare 5d in 36% yield. H NMR (CDCl3) δ 7.48 (m, 2H), 7.14
(m, 3H), 4.24 (dd, J ) 9.3, 11.6 Hz, 1H), 3.81 (d, J ) 12 Hz, 1H),
3.25 (br s, 1H), 3.10 (m, 2H), 2.18 (s, 3H), 2.30-1.20 (m, 21H);
13C NMR (CDCl3) δ 173.4, 172.4, 138.5, 136.7, 130.5, 125.9, 118.3,
66.9, 65.6, 62.0, 46.6, 42.1, 38.3, 34.7, 33.3, 33.2, 27.5, 26.2, 25.0,
24.4, 23.7, 15.3; LCMS (APCI) m/z 399.4 (M + 1)+. The
4,5,6,7,8,9,10,11,12,13,15,19a,20,21,22,23,24,24a-Octadecahy-
dro-25-methyl-16,19-etheno-21,24-imino-1H-cyclohept[c][1,9]-
oxaazacycloheneicosine-3,14-dione (5f) Dihydrochloride. To a
solution of 100 mg (0.4 mmol) of 7 in dry CH2Cl2 (80 mL) and
triethylamine (556 µL, 4 mmol) was slowly added a solution of
dodecanedioyl chloride (100 µL, 0.4 mmol) in 20 mL of dry CH2-
Cl2 through a dropping funnel over a period of 4 h. The reaction
mixture was stirred at room temperature overnight. The mixture
hydrochloride salt had mp 223-225 °C; [R]20 -41.8° (c 0.40,
D
CH3OH). Anal. (C24H35ClN2O3‚2H2O) C, H, N.
4,5,6,7,8,9,10,11,13,17a,18,19,20,21,22,22a-Hexadecahydro-23-
methyl-14,17-etheno-19,22-imino-1H-cyclohept[c][1,9]oxaazacy-
clononadecine-3,12-dione (5e) Hydrochloride. A procedure simi-
lar to that described for 5f but using sebacoyl chloride was

Analogues of a Tropanemethanol
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4593
used to prepare 5e in 19% yield. [R]20 -60.8° (c 0.25, CHCl3);
3-[9-(2-Cyanoethyl)-9H-fluoren-9-yl]propionitrile (10). To a
solution of 5.0 g (30.1 mmol) of fluorene in 50 mL of dioxane and
0.5 g of Triton-B was added dropwise 3.3 g (63 mmol) of
acrylonitrile. The temperature was kept between 30 and 40 °C with
an ice bath. Stirring was continued at room temperature for 3 h.
The reaction was quenched with 0.1 N HCl until pH 8-9 was
attained. Water (80 mL) was added, and the mixture was vigorously
stirred until the oil layer became the granular solid. The solid was
filtered, washed with water, and then air-dried. Recrystallization
from absolute ethanol afforded 4.5 g (55%) of 10 as colorless
D
1H NMR (CDCl3) δ 7.65 (br s, 1H, NH), 7.51 (d, J ) 7.8 Hz, 2H),
7.12 (d, J ) 7.8 Hz, 2H), 4.38 (m, 1H), 3.75 (d, J ) 11.8 Hz, 1H),
3.15-3.25 (m, 3H), 1.57-2.35 (m, 18H), 1.09-1.27 (m, 8H); 13
C
NMR (CDCl3) δ 173.2, 171.7, 138.1, 136.3, 128.4, 118.4, 67.1,
65.5, 61.9, 46.5, 42.2, 38.2, 34.6, 34.4, 33.8, 28.1, 27.8, 27.5, 26.9,
26.0, 24.9, 24.5, 23.4; LCMS (APCI) m/z 413.6 (M + 1)+. The
hydrochloride salt had mp 212-214 °C. Anal. (C25H37ClN2O3‚
1.5H2O) C, H, N.
Ester/Amide of 3-(4-Aminophenyl)-8-methyl-8-azabicylo-
[3.2.1]octane-2-methanol and p-Phenylenediacetic Acid (5g)
Hydrochloride. To a suspension of 200 mg (1 mmol) of 1,2-
phenylenediacetic acid in dry benzene (7 mL) was added dry DMF
(1 drop), followed by the dropwise addition of 0.54 mL (6 mmol)
of oxalyl chloride. The reaction mixture was stirred at room
temperature until all solid dissolved. Another drop of DMF was
added, and stirring was continued for 2 h. Benzene and the excess
oxalyl chloride were removed under reduced pressure. The product
was used directly in the next step without further purification.
A procedure similar to that described for 5f but using the acid
1
needles. H NMR (CDCl3) δ 7.74 (d, J ) 6.0 Hz, 2H), 7.42 (m,
6H), 2.45 (t, J ) 9.0 Hz, 4 H), 1.51 (t, J ) 9.0 Hz, 4H).
3-[9-(2-Carboxyethyl)-9H-fluoren-9-yl]propionic Acid (11). A
solution of 1.0 g (3.67 mmol) of nitrile 10 in 10 mL of 10 N
potassium hydroxide and 4 mL of ethylene glycol was heated to
reflux, stirred for 30 min, and cooled to room temperature, and 50
mL of water was added. The solution was acidified with concen-
trated HCl to pH 1. The solid precipitate was filtered, washed with
water, and air-dried to give 280 mg (28%) of 11 as white powder.
1H NMR (CD3OD) δ 7.78 (m, 2H), 7.44 (m, 2H), 7.37 (m, 4H),
2.38 (m, 4H), 1.44 (m, 4H).
1
chloride above was used to prepare 5g in 24% yield. H NMR
(CDCl3) δ 7.49 (d, J ) 7.5 Hz, 1H), 7.23-7.10 (m, 4H), 7.00 (d,
J ) 8.1 Hz, 1H), 6.91 (d, J ) 8.0 Hz, 1H), 6.81(d, J ) 8.1 Hz,
1H), 4.46 (dd, J ) 8.9, 12.1 Hz, 1H), 3.81 (d, J ) 12.2 Hz, 1H),
3.50 (s, 2H), 3.30-2.90 (m, 5H), 2.17 (s, 3H), 2.19-1.50 (m, 8H);
13C NMR (CDCl3) δ 173.7, 170.0, 141.8, 134.9, 133.1, 131.4, 130.7,
130.3, 129.2, 128.5, 128.1, 127.3, 126.8, 126.4, 66.7, 65.7, 62.3,
46.7, 41.7, 36.9, 36.6, 34.7, 32.4, 26.2, 24.1; LCMS (APCI) m/z
20-Methyl-4,5,7,8,10,14a,15,16,17,18,19,19a-dodecahydro-3H-
spiro[16,19-epimino-11,14-ethenocyclohepta[c][1,9]oxazacyclo-
hexadecine-6,9′-fluorene]-3,9(1H)-dione (5j). To a suspension of
75 mg (0.24 mmol) of diacid 11 in dry benzene (3 mL) was added
dry DMF (1 drop), followed by the dropwise addition of 120 µL
(1.44 mmol) of oxalyl chloride. The reaction mixture was stirred
at room temperature until all solid dissolved. Benzene and the excess
oxalyl chloride were removed under reduced pressure. The 3-[9-
(2-chlorocarbonylethyl)-9H-fluoren-9-yl]propionyl chloride was
used directly in the next step without further purification.
A procedure similar to that described for 5f but using the acid
405.5 (M + 1)+. The hydrochloride salt had mp 260 °C (dec); [R]20
D
-99.3° (c 0.2, CH3OH). Anal. (C25H29ClN2O3‚2.5H2O) C, H, N.
4,5,7,8,10,14a,15,16,17,18,19,19a-Dodecahydro-20-methyl-11,-
14-theno-16,19-iminocyclohept[c][1,9]oxaazacyclohexadecine-
3,6,9(1H)-trione (5h) Hydrochloride. To a suspension of 61 mg
(0.35 mmol) of 4-ketopimelic acid in dry benzene (3 mL) was added
dry DMF (1 drop), followed by the dropwise addition of 65 µL
(0.73 mmol) of oxalyl chloride. The reaction mixture was stirred
at room temperature until all solid dissolved. Another drop of DMF
was added, and stirring was continued for 2 h. The reaction solution
was diluted with 15 mL of dry CH2Cl2 and used directly in the
next step.
A procedure similar to that described for 5f but using the acid
chloride above was used to prepare 5h in 6% yield. 1H NMR
(CDCl3) δ 7.29-7.09 (m, 3H), 6.99 (d, J ) 8.2 Hz, 1H), 4.50 (dd,
J ) 8.9, 11.8 Hz, 1H), 4.17 (br s, 1H), 3.32-3.10 (m, 3H), 2.90-
2.60 (m, 2H), 2.22 (s, 3H), 2.50-1.50 (m, 14H); 13C NMR (CDCl3)
δ 174.4, 171.8, 171.3, 142.8, 133.3, 131.1, 130.6, 128.1, 126.7,
66.8, 65.9, 65.4, 61.8, 48.5, 47.0, 42.1, 36.8, 34.7, 33.9, 28.7, 26.5,
24.3; LCMS (ESI) m/z 385.5 (M + 1)+. The hydrochloride salt
had mp 214-216 °C; [R]20D -34° (c 0.2, CH3OH). Anal. (C22H29-
ClN2O4‚2H2O) C, H, N.
4,5,7,8,10,14a,15,16,17,18,19,19a-Dodecahydro-20-methyl-11,-
14-etheno-16,19-imino-3H-cyclohept[n][1,5,9]oxathiaazacyclo-
hexadecine-3,9(1H)-dione (5i) Hydrochloride. To a suspension
of 500 mg (2.8 mmol) of 3,3′-thiodipropionic acid in dry benzene
(10 mL) was added dry DMF (1 drop), followed by the dropwise
addition of 1.5 mL (17.2 mmol) of oxayl chloride. The reaction
mixture was stirred at room temperature until all solid dissolved.
Another drop of DMF was added, and stirring was continued for 2
h. Benzene and the excess oxalyl chloride were removed under
reduced pressure. The product was used directly in the next step
without further purification.
1
chloride above was used to prepare 5j in 18% yield. H NMR
(CDCl3) δ 7.66 (d, J ) 7.4 Hz, 2H), 7.39-7.29 (m, 6H), 7.23 (m,
2H), 7.13 (d, J ) 7.1 Hz, 2H), 4.20 (m, 2H), 3.30-3.10 (m, 3H),
2.95 (dt, J ) 3.4, 12.0 Hz, 1H), 2.56 (m, 1H), 2.19 (s, 3H), 2.40-
1.20 (m, 14H); 13C NMR (CDCl3) δ 175.6, 172.4, 149.4, 148.7,
143.4, 140.0, 139.9, 135.6, 131.3, 128.4, 127.5, 127.3, 127.1, 127.0,
123.7, 123.0, 120.2, 120.1, 67.0, 65.4, 62.0, 51.8, 46.7, 42.1, 35.6,
35.5, 33.9, 29.8, 29.7, 29.4, 29.2, 26.0, 24.4; LCMS (APCI) m/z
521.7 (M + 1)+. The hydrochloride salt of 5j had mp 230-232
°C; [R]20 -39.3° (c 0.28, CH3OH). Anal. (C34H37ClN2O3‚2H2O)
D
C, H, N.
23,29-Dimethyl-10-oxa-23,29-diazatetracyclo[22.2.2.14,7.02,8]-
nonacosa-1(27),24(28),25-triene-11,22-dione (8). To a solution of
65 mg (0.144 mmol) of 5f in 1.5 mL of dry DMF was added 8.7
mg (0.22 mmol) of 60% NaH. After the mixture was stirred at
room temperature for 15 min, 9 µL of iodomethane was added.
The reaction mixture was stirred for another 1 h, diluted with ethyl
acetate (100 mL), washed with water (10 mL × 3) and brine (10
mL), and dried over sodium sulfate. The solvent was removed under
reduced pressure, and the product was purified by column chro-
matography (silica gel, 1:1:1 CMA/ethyl acetate/CH2Cl2) to afford
51 mg (77%) of 8 as off-white solid. [R]20D -20.8° (c 1.7, CHCl3);
1H NMR (CDCl3) δ 7.24 (d, J ) 8.3 Hz, 2H), 7.13 (d, J ) 8.3 Hz,
2H), 4.46 (t, J ) 10.2 Hz, 1H), 3.37 (dd, J ) 3.3, 10.5 Hz, 1H),
3.28 (s, 1H), 3.23 (s, 3H), 3.20 (m, 1H), 2.25 (s, 3H), 2.22-1.13
(m, 28H); 13C NMR (CDCl3) δ 174.0, 173.5, 143.6, 137.9, 128.9,
127.9, 64.5, 64.0, 61.7, 45.5, 40.3, 37.2, 34.3, 33.8, 33.0, 30.9, 29.5,
28.2, 28.1, 27.9, 27.5, 27.4, 26.7, 26.0, 25.3, 23.6; LCMS (APCI)
m/z 455.5 (M + 1)+.
A procedure similar to that described for 5f but using the acid
4,5,6,7,8,9,10,11,13,17a,18,19,20,21,22,22a-Hexadecahydro-
13,23-dimethyl-14,17-etheno-19,22-imino-1H-cyclohept[c][1,9]-
oxaazacyclononadecine-3,12-dione (5k). A procedure similar to
that used to prepare 8 was followed to yield 79% of 5k. 1H NMR
(CDCl3) δ 7.23 (d, J ) 8.4 Hz, 2H), 7.11 (d, J ) 8.4 Hz, 2H),
4.47 (dd, J ) 5.8, 11.2 Hz, 1H), 3.54 (dd, J ) 4.2, 11.3 Hz, 1H),
1
chloride above was used to prepare 5i in 44% yield. H NMR
(CDCl3) δ 7.41-7.13 (m, 4H), 4.55 (br s, 1H), 4.25 (d, J ) 11.4
Hz, 1H), 3.55-3.43 (m, 2H), 3.17 (m, 1H), 2.78-2.61 (m, 4H),
2.44 (s, 3H), 2.30-1.60 (m, 12H); 13C NMR (CDCl3) δ 173.4,
170.8, 142.6, 135.3, 131.0, 127.1, 126.7, 66.6, 65.6, 62.2, 46.2,
41.9, 34.9, 34.5, 33.2, 32.7, 29.7, 27.3, 26.2, 25.1, 24.3; LCMS
(APCI) m/z 389.7 (M + 1)+. The hydrochloride salt had mp 205-
3.23 (s, 3H), 3.10 (m, 1H), 2.24 (s, 3H), 2.14-1.12 (m, 25H); 13
C
NMR (CDCl3) δ 174.5, 173.9, 143.1, 129.3, 127.6, 65.8, 64.4, 62.6,
47.2, 42.1, 37.6, 34.9, 34.4, 33.9, 28.2, 27.3, 26.9, 26.4, 24.9, 23.9;
LCMS (APCI) m/z 426.9 (M + 1)+. The hydrochloride salt had
207 °C; [R]20 -25.8° (c 0.26, CH3OH). Anal. (C21H29ClN2O3S‚
D
2H2O) C, H, N.

4594 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Carroll et al.
mp 75-77 °C; [R]20 -20.9° (c 0.63, CH3OH). Anal. (C26H39-
References
D
ClN2O3‚1.75H2O) C, H, N.
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aryltropane derivatives. J. Med. Chem. 2004, 47, 1676-1682.
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either the dopamine or serotonin transporters. Bioorg. Med. Chem.
Lett. 2002, 12, 845-847.
(13) Kotturi, S. V.; Jiang, S.; Chang, A. C.; Abraham, P.; Navarro, H.
A.; Kuhar, M. J.; Carroll, F. I. Synthesis and monoamine transporter
binding properties of 2,3-diaryltropanes. J. Med. Chem. 2005, 48,
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5,6,7,8,9,10,11,12,13,14,16,20a,21,22,23,24,25,25a-Octadecahy-
dro-16,26-dimethyl-17,20-etheno-22,25-iminocyclohept[c][1,9]-
oxaazacyclodocosine-3(1H,4H)-one (5m) Dihydrochloride. To a
solution of 65 mg (0.143 mmol) of 8 in 2 mL of dry THF was
added 0.86 mL (0.43 mmol) of 0.5 M 9-BBN in THF solution.
The reaction mixture was stirred at room temperature for 8 h, diluted
with 100 mL of ethyl acetate, washed with saturated sodium
bicarbonate solution, water, and brine, and dried over sodium
sulfate. The solvent was removed under reduced pressure, and the
product was purified by column chromatography (silica gel, 1:1:2
CMA/ethyl acetate/hexanes) to afford 7 mg (11%) of 5m as a
1
colorless oil. H NMR (CDCl3) δ 7.02 (d, J ) 8.7 Hz, 2H), 6.65
(d, J ) 8.7 Hz, 2H), 4.29 (dd, J ) 6.7, 11.0 Hz, 1H), 3.64 (dd, J
) 5.0, 11.0 Hz, 1H), 3.41 (m, 1H), 3.20 (m, 3H), 3.00 (m, 1H),
2.86 (s, 3H), 2.22 (s, 3H), 2.09-1.18 (m, 27H); LCMS (APCI)
m/z 441.5 (M + 1)+. The hydrochloride salt had mp 115-117 °C;
[R]20 -28.0° (c 0.20, CHCl3). Anal. (C28H46Cl2N2O2‚2H2O) C,
D
H, N.
5,6,7,8,9,10,11,12,14,18a,19,20,21,22,23,23a-Hexadecahydro-
14,24-dimethyl-15,18-etheno-5620,23-iminocyclohept[c][1,9]oxa-
azacycloeicosine-3(1H,4H)-one (5l) Dihydrochloride. A procedure
similar to the preparation of 5m was followed to prepare 5l. The
eluent for column chromatography was ethyl 3:1 ether/hexanes with
1% of NH4OH. The yield of product was 4% as a colorless oil. 1H
NMR (CDCl3) δ 7.02 (d, J ) 8.7 Hz, 2H), 6.63 (d, J ) 8.7 Hz,
2H), 4.14 (d, J ) 11.8 Hz, 1H), 3.96 (dd, J ) 6.7, 11.6 Hz, 1H),
3.38 (m, 1H), 3.24 (m, 3H), 3.00 (m, 1H), 2.89 (s, 3H), 2.20 (s,
3H), 2.11-1.15 (m, 23H); LCMS (APCI) m/z 413.2 (M + 1)+.
The hydrochloride salt had mp 149-151 °C; [R]20D -20.0° (c 0.20,
CHCl3). Anal. (C26H42Cl2N2O2‚2.5H2O) C, H, N.
Single-Crystal X-ray Diffraction Analysis of 5b. Crystal-
lographic data are as follows: C22H30N2O3, 0.5(C0.8H3.2O0.8), FW
) 383.23, monoclinic space group C2, a ) 23.910(8) Å, b ) 8.620-
(3) Å, c ) 10.820(4) Å, and â ) 112.925(7)°, V ) 2054.0(12) Å3,
Z ) 4, density (calcd) ) 1.239 Mg/m3, λ (Mo KR) ) 0.710 73 Å,
µ ) 0.083 mm-1, F(000) ) 828.7, T ) 93 K. A clear colorless
0.85 mm × 0.66 mm × 0.50 mm crystal was used for data
collection with a Bruker SMART 1000 CCD detector on a four-
circle goniometer using SMART (version 1a). Lattice parameters
were determined using SAINT (version 2b) from 1627 reflections
within 2.54° < θ < 28.24°. Data were 94.7% complete to θ )
28.24°. Reflections (8871) were collected using a combination of
φ and 2θ/ω scans. There were 2570 unique reflections. Corrections
were applied for Lorentz, polarization, and absorption effects. The
structure was solved with SHELXTL (version 3a) and refined with
the aid of the SHELX system of programs. The full-matrix least-
squares refinement on F2 used three restraints and varied 266
parameters: atom coordinates and anisotropic thermal parameters
for all non-H atoms. H atoms on carbon atoms were included using
a riding model (coordinate shifts of C applied to attached H atoms,
C-H distances set to 0.96-0.93 Å, H angles idealized, Uiso(H)
values were set to (1.2-1.5)Ueq(C)). Final residuals were R1 )
0.0541 for the 2280 observed data with Fo > 4σ(Fo) and 0.0623
for all data. Final difference Fourier excursions were 0.394 and
-0.258 e Å-3. The asymmetric unit contains one molecule of 5b,
plus a disordered methanol molecule at partial occupancy. Tables
of coordinates, bond distances, bond angles, and anisotropic thermal
parameters have been deposited with the Crystallographic Data
Centre, Cambridge, CB2 and 1EW, England.
(14) Tamiz, A. P.; Smith, M. P.; Kozikowski, A. P. Design, synthesis
and biological evaluation of 7-azatricyclodecanes: analogues of
cocaine. Bioorg. Med. Chem. Lett. 2000, 10, 297-300.
(15) Zhou, J.; Zhang, A.; Klass, T.; Johnson, K. M.; Wang, C. Z.; Ye, Y.
P.; Kozikowski, A. P. Biaryl analogues of conformationally con-
strained tricyclic tropanes as potent and selective norepinephrine
reuptake inhibitors: synthesis and evaluation of their uptake inhibition
at monoamine transporter sites. J. Med. Chem. 2003, 46, 1997-2007.
(16) Carroll, F. I.; Gao, Y.; Rahman, M. A.; Abraham, P.; Parham, K.;
Lewin, A. H.; Boja, J. W.; Kuhar, M. J. Synthesis, ligand binding,
QSAR, and CoMFA study of 3â-(p-substituted phenyl)tropane-2â-
carboxylic acid methyl esters. J. Med. Chem. 1991, 34, 2719-2925.
(17) Carroll, F. I.; Gray, J. L.; Abraham, P.; Kuzemko, M. A.; Lewin, A.
H.; Boja, J. W.; Kuhar, M. J. 3-Aryl-2-(3′-substituted-1′,2′,4′-
oxadiazol-5′-yl)tropane analogues of cocaine: Affinities at the
cocaine binding site at the dopamine, serotonin, and norepinephrine
transporters. J. Med. Chem. 1993, 36, 2886-2890.
(18) Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J. L.; Kuzemko, M.
A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J. W.; Kuhar,
M. J. Cocaine and 3â-(4′-substituted phenyl)tropane-2â-carboxylic
acid ester and amide analogues. New high-affinity and selective
compounds for the dopamine transporter. J. Med. Chem. 1995, 38,
379-388.
(19) Carroll, F. I.; Howard, J. L.; Howell, L. L.; Fox, B. S.; Kuhar, M. J.
Development of the dopamine transporter selective RTI-336 as a
pharmacotherapy for cocaine abuse. Am. Assoc. Pharm. Sci. J. 2006,
8, Article 24 (http://www.aapsj.org).
Acknowledgment. This research was supported by the
National Institute on Drug Abuse, Grant DA05477.
(20) Carroll, F. I.; Mascarella, S. W.; Kuzemko, M. A.; Gao, Y.; Abraham,
P.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. Synthesis, ligand binding,
and QSAR (CoMFA and classical) study of 3â-(3′-substituted
phenyl)-, 3â-(4′-substituted phenyl)-, and 3â-(3′,4′-disubstituted
phenyl)tropane-2â-carboxylic acid methyl esters. J. Med. Chem. 1994,
37, 2865-2873.
Supporting Information Available: Crystal data, structural
refinement analysis, atomic coordinates, bond lengths, bond angles,
anisotropic displacement parameters, hydrogen coordinates, and
isotropic displacement parameters of 5b and elemental analysis data
for compounds 5a-m. This material is available free of charge
via the Internet at http://pubs.acs.org.
JM060287W