(+)-Dinapsoline: An efficient synthesis and pharmacological profile of a novel dopamine agonist

Article abstract of DOI:10.1021/jm0101545

A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D₁ Agonist Containing a Rigid β-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by x-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans- 4,5,5a,6,7,11b-hexahydro-2-propylbenzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).

Full text of DOI:10.1021/jm0101545

3660
J . Med. Chem. 2002, 45, 3660-3668
(+)-Din a p solin e: An Efficien t Syn th esis a n d P h a r m a cologica l P r ofile of a Novel
Dop a m in e Agon ist
Sing-Yuen Sit,*,† Kai Xie,† Swanee J acutin-Porte,† Matthew T. Taber,‡ Amit G. Gulwadi,‡ Carolyn D. Korpinen,‡
Kevin D. Burris,‡ Thaddeus F. Molski,‡ Elaine Ryan,‡ Cen Xu,‡ Henry Wong,§ J uliang Zhu,§
Subramaniam Krishnananthan,§ Qi Gao,| Todd Verdoorn,‡ and Graham J ohnson†
Departments of Neuroscience Drug Discovery Chemistry, Neuroscience Drug Discovery Biology, and Analytical Research and
Development and BMS PRI Wallingford Chemistry Core Support, Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, Wallingford, Connecticut 06492-7660
Received April 3, 2001
A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12)
(Ghosh, D.; Snyder, S. E.; Watts, V. J .; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7,
11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D1 Agonist Containing
a Rigid â-Phenyldopamine Pharmacophore. J . Med. Chem. 1996, 39 (2), 549-555). The crucial
step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline
framework. The improved synthesis required half as many steps as the original procedure
(Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines
as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-
stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12
(absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In
unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational
behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-
benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Prepara-
tion of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1,
Oct 13, 1994).
In tr od u ction
dopamine model, the bioisostere thiophene8 was em-
ployed in another attempt to mimic the phenyl D-ring
in dihydrexidine to give trans-4,5,5a,6,7,11b-hexahydro-
2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydro-
chloride (18).9 The presence of a rigid â-phenyl dopa-
mine, such as in 17 and 12, or a rigid â-thiophene
dopamine (18) is deemed essential for attaining high
D1 receptor subtype specificity, a critical property for
high intrinsic dopamine activity and in vivo efficacy
(Figure 1).10 Both dihydrexidine (17) and 18 have shown
anti-Parkinsonian efficacy in clinical studies.11 In the
case of dihydrexidine given intravenously (iv), anti-
Parkinsonian effects were observed when the drug
reached a high plasma level. Motor improvement was
accompanied by choreic dyskinesias similar to those
generated by levodopa, the current “gold standard” in
the pharmacotherapy of Parkinson’s disease (PD). More
recently, positive clinical results on patients intrave-
nously given 19, the diacetoxy ester derivative of 18,
strongly support the role of the dopamine receptor
agonist as a treatment of PD. Equally significant is that
dyskinesia was reduced in several patients after they
received 19.11b
Dinapsoline, 8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-
naphth[1,2,3-de]isoquinoline ((()-12), was first synthe-
sized and characterized as a full-efficacy dopamine
receptor agonist with some selectivity for D1 over D2
receptors by Nichols, Mailman, and co-workers in 1996.
Subsequently, (()-12 was shown to produce robust
rotational behavior in unilateral 6-hydroxydopamine (6-
OHDA)-lesioned rats.4 The study found that (()-12 was
active after oral and subcutaneous dosing. It was D1
selective in vivo, and it did not produce tolerance when
dosed intermittently for up to 14 days.4 Such a profile
suggests that dinapsoline has potential as a novel anti-
Parkinsonian agent. In an attempt to identify a superior
compound, one that is more suitable for clinical develop-
ment, and a synthetic route to analogues of dinapsoline,
including its enantiomers, we reexamined the synthesis
of dinapsoline with the aim of identifying a more
practical preparation of the parent compound and its
analogues. The development of dinapsoline represented
a novel approach in the design of rigid â-phenyl dopa-
mine as an anti-Parkinsonian drug.7 It effectively
extended the concept underlying an earlier discovery of
trans-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-
10,11-diol (dihydrexidine, 17) as a rigid dopamine
surrogate. Analogous to this structurally rigid â-phenyl
Although efficacious, the latest crops of dopamine
receptor agonists are not metabolically stable, nor are
they orally bioavailable. Stability issues aside, dihy-
drexidine (17) showed anti-Parkinsonian efficacy only
at dosages approaching the upper tolerable dose, thus
limiting its useful therapeutic window. Toxicity, stabil-
ity, and tolerability are critical factors for any drugs that
are to be used chronically, even when patients are
individually titrated. The ability to develop practical
* To whom correspondence should be addressed. Tel: (203) 677-
6678. Fax: (203) 677-5775 and (203) 677-7702. E-mail: sits@bms.com.
† Department of Neuroscience Drug Discovery Chemistry.
‡ Department of Neuroscience Drug Discovery Biology.
§ BMS PRI Wallingford Chemistry Core Support.
| Department of Analytical Research and Development.
10.1021/jm0101545 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/20/2002

(+)-Dinapsoline: A Novel Dopamine Agonist
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3661
F igu r e 1. Dopamine agonists.
F igu r e 3. Introducing molecular rigidity through the B′-ring
in dinapsoline.
Sch em e 1. Original Ring-Closure Procedure
F igu r e 2. Structural comparison of dihydrexidine (17) and
18.
synthesis thereby allowing access to the dinapsoline core
molecule for further studies is central to this project.
Structural analysis of 17 and 18 revealed (Figure 2)
the molecular features shared by both chemotypes.
These molecules can be considered as the rigid form of
4-(3,4-dihydroxyphenyl)tetrahydroisoquinoline (16) and
15. Rigidity is introduced into these molecules by
incorporating an additional “B-ring” in the precursor
molecules, and this is essentially the concept “rigid
â-phenyl dopamine model“ previously proposed by
Nichols.5
Efficient synthesis was unavailable when the mol-
ecule was first disclosed. Indeed, the original chemical
synthesis as described in the patent literature required
as many as 11-14 steps to complete.7 Furthermore, the
problem with the original preparation was aggravated
by a difficult ring-closure step occurring near the end
stage of the synthesis! To gain a better understanding
of the properties and the potential of dinapsoline, we
developed an improved synthesis together with a chiral
resolution into a pair of enantiomers.
The design of dinapsoline represented another ap-
proach to the structurally rigid 4-(3,4-dihydroxyphenyl)-
tetrahydroisoquinoline core (16) by linking the A-ring
and D-ring (Figure 3) through a methylene unit forming
the B′-ring. Such modification could offer fresh op-
portunities for drug development while keeping all the
essential elements needed for dopaminergic activity.
Ch em istr y
The original synthesis of dinapsoline required a late-
stage cyclization step (Scheme 1). Unfortunately, the
cyclization gave erratic results, especially when it was
scaled up to more than just a few grams of the starting

3662 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Sch em e 2. Improved Procedurea
Sit et al.
a
Reagents and reaction conditions: (a) LDA/THF at -78 °C; (b) DMF at -78 °C; (c) bromine and AlCl3; (d) t-BuLi/THF at -78 °C; (e)
3 and 6 in THF at -78 °C; (f) n-BuLi/THF at -78 °C; (g) 8 and 2 in THF at -78 °C.
Sch em e 3. Improved Synthesis of Dinapsolinea
a
Reagents and reaction conditions: (a) Et3SiH/TFA at reflux; (b) Bu3SnH/AIBN in degassed benzene at reflux; (c) NaCNBH3/HCl or
PtO2/H2 in acetic acid at 140-190 psi; (d) resolution by (+)-dibenzoyl-D-tartaric acid; (e) BBr3 in methylene chloride at -78 °C.
material. The preferred pathway appeared to be a
dimerization.
An alternative approach using the commercially
available 4-bromo-1,2-(methylenedioxy)benzene to cir-
cumvent the problematic electrophilic aromatic cycliza-
tion was developed (Scheme 2).
by a radical-initiated ring-closure reaction.14 The tri-n-
butyltin hydride (TBTH) and 2,2′-azobisisobutyronitrile
(AIBN) combination was by far the most efficient
reductive system for generating the free radical species
for cyclization.15 A small amount of uncyclized des-
bromo-9 was also formed due to a competing hydride
abstraction. The side product was removed either by
trituration with mixtures of ethyl acetate and hexanes
or by silica gel column chromatography (Experimental
Section). The TBTH-AIBN pair gave the most consis-
tent results, and the cyclization could be scaled up to
100 g of starting material at a time (Scheme 3).
Once cyclized, the isoquinoline moiety in compound
10 was reduced to the corresponding 1,2,3,4-tetrahy-
droisoquinoline system 11 using sodium cyanoborohy-
dride in acidic medium. The same reduction could also
be effected by a catalytic hydrogenation using Adam’s
catalyst in glacial acetic acid at elevated pressure and
temperature. However, the borohydride reduction gave
more consistent results due to its greater tolerance to
minor variations in reaction conditions and reagent
impurities. The racemic product, (()-11, could be depro-
tected with boron tribromide in methylene chloride at
-78 °C to give the racemic (()-12 or be resolved into
(+)-11 and (-)-11 by chiral HPLC separation on a
Chiralcel OD column. Preparative scales of (+)-11 and
Selective metalation of compound 1 by lithium diiso-
propylamide (LDA) gave 3-lithio-4-bromo-1,2-(methyl-
enedioxy)benzene 2.12 Formylation of 2 using dimeth-
ylformamide (DMF) at -78 °C furnished 4-bromo-1,2-
(methylenedioxy)-3-benzaldehyde 3 in good yields.
Compound 3 was allowed to couple with the 5-lithio
isoquinoline 6, generated in situ by treatment of 5-bro-
moisoquinoline13 5 with tert-butyllithium (t-BuLi), to
give the benzhydrol 7. Alternatively, compound 7 was
prepared by reversing the reactive functional groups on
the isoquinoline fragment and the methylenedioxy
component. Formylation of 6 with DMF gave 8 in 64%
yield. This 5-isoquinolincarboxaldehyde 8 was coupled
with 2 to furnish 7 in 65% yield. The yield of the reverse
reaction sequence was better than the yield of the other
method. More importantly, the alternate route enhances
the utility of the present synthetic approach. Benzhydrol
7 was deoxygenated by refluxing in trifluoroacetic acid
in the presence of triethylsilane. The key cyclization step
in assembling the dinapsoline core was accomplished

(+)-Dinapsoline: A Novel Dopamine Agonist
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3663
F igu r e 4. Absolute configuration of (R)-(+)-dinapsoline.
Ta ble 1. Results of D1/D2 Binding Assaysa
(-)-11 were achieved by chemical resolution using the
unnatural form of tartaric acid (D-form) or its dibenzoyl
ester. In general, the dibenzoyl ester of tartaric acid
gave results superior to those of the simple tartaric acid
for such resolution. Chemical resolution was by far the
most practical way to produce multigram quantities of
(+)-11 (Experimental Section); from there, (+)-12 was
obtained after the removal of the methylenedioxy pro-
tecting group. The absolute configuration of (+)-dinap-
soline ((+)-12, HBr salt) was determined by a single-
crystal X-ray analysis (Figure 4).
IC50 (nM)
b
compound
D1
D2
Resu lts a n d Discu ssion
(()-12
(-)-12
(+)-12
67 ( 9 (35)
5300 ( 1000 (4)
33 ( 8 (11)
56 ( 10 (17)
1500 ( 500 (2)
38 ( 6 (7)
Early work by Nichols and Mailman demonstrated
that, despite the structural deviation from their original
D1 agonist pharmacophore, dinapsoline retained many
of the original characteristics of dihydrexidine (17).
Dinapsoline was created by joining the A-ring and
D-ring of 17 through a methylene bridge forming the
B′-ring while the original B-ring in dihydrexidine was
deleted.1 Such modifications effectively preserved all the
critical structural elements of a D1 receptor agonist
which include the relative position and orientation of
the basic nitrogen, catechol hydroxyl groups, and the
accessory phenyl ring. These changes resulted in a novel
dopamine D1 receptor agonist which offers new op-
portunities for drug development. The introduction of
the B′-ring and, therefore, the 7-carbon bridging meth-
ylene unit, which was previously absent in the dihy-
drexidine (17) chemotype, provided further opportuni-
ties for designing “core” modifications in addition to the
substitution of analogues within the molecular frame-
work of dinapsoline.
In the early reports,1,4 racemates were screened in all
in vitro and in vivo assays; no distinction was made as
to which enantiomer was responsible for the biological
activities. On the basis of the results reported by Nichols
and co-workers on dihydrexidine and dinapsoline as well
as the work by Michaelides on 18 and 19, we predicted
that dopamine binding activity should reside largely or
even entirely on one of the enantiomers.9,10 From the
use of the active pharmacophore model developed by
Nichols and others, it was predicted that both the
affinity and intrinsic activity of racemic (()-12 reside
in only one of its enantiomers, that with the 11bR
absolute configuration. Data from in vitro and in vivo
pharmacological assays (Tables 1-3) indicated that this
prediction was indeed correct. The potencies of (+)-12
and (()-12 for inhibition of radioligand binding to D1
and D2 receptors were determined. In rat striatal
membranes, (+)-12 inhibited binding of [125I]SCH-23982
to D1 receptors with potency 2-fold higher than that of
a
b
Experimental Section for details. SE (number of repeats).
Ta ble 2. Adenylate Cyclase (AC) Response (in Vitro
Functionality)
D1 (SK-N-MC)a
compound
intrinsic activity
EC50 ( SE(n), nMb
(()-12
(-)-12
(+)-12
1.2
190 ( 60 (3)
>10000 (3)d
NDc
1.0
220 ( 40 (5)
a
b
Neuroblastoma cell preparation. SE (number of repeats).
c Not able to determine. Estimated value.
d
racemic dinapsoline. Likewise, (+)-12 was more potent
then the racemic dinapsoline in inhibiting the binding
of [125I]-7-OH-PIPAT to D2 receptors. Furthermore, the
D1 activity of racemic (()-12 could be attributed pri-
marily to the active enantiomer (+)-12 by the fact that
(-)-12 showed no sign of adenylate cyclase stimulation.
The intrinsic activity (defined as the ratio of the cyclase
response of an agonist relative to that of dopamine) for
(+)-12 was nearly 1, indicating a full dopamine D1
agonist (Table 2). Finally, when the pair of enantiomers
was assayed in whole animals, the opposite enantiomer
(-)-12 induced no rotational behavior at 0.2 and 2.0 mg/
kg dosed subcutaneously (Table 3). On the contrary, (+)-
12 is the most active compound tested in vivo as part
of the present study (Table 3). The assignment is
consistent with the corresponding chiral centers of the
biologically active 17 and 18 when these molecules are
compared with (+)-12. This result further affirmed that
dihydrexidine (17), 18, and dinapsoline (12) share a set
of common pharmacophoric descriptors.
The absolute configuration of (+)-dinapsoline was
established from single-crystal analysis of an HBr salt
of the compound using the anomalous scattering effect
of bromine atoms. Light-brown plate-like crystals were

3664 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Sit et al.
Ta ble 3. In Vivo Pharmacology4
were resuspended in buffer consisting of either 50 mM Tris
(pH 7.5 at 37 °C), 10 mM MgSO4, 2 mM EDTA, 154 mM NaCl,
and 20 µg/mL BSA for use in [125I]-(+)-SCH-23982 binding
assays or 50 mM Tris (pH 7.7 at 25 °C) and 2 mM MgCl2 for
use in [125I]-7-OH-PIPAT binding assays.
rotations/ 10 h
(mean ( sem)
compound
dose (mg/kg sc)
n
(()-12
(()-12
(+)-12
(+)-12
(-)-12
(-)-12
18
0.2
2
0.2
2
0.2
2
0.2
2
1900 ( 200
4800 ( 500
4100 ( 400
7000 ( 1000
8 ( 2
7 ( 2
1100 ( 200
4200 ( 1000
10
10
5
5
5
5
8
7
Ra d ioliga n d Bin d in g Assa ys. Binding of [125I]-(+)-SCH-
23982 to D1 receptors was performed using crude membrane
homogenates from rat striatal tissue. Homogenates (6 µg of
protein/well) were incubated with [125I]-(+)-SCH-23982 (500
pM) for 30 min at 37 °C in buffer (100 µL) consisting of 50
mM Tris (pH 7.5 at 37 °C), 10 mM MgSO4, 2 mM EDTA, 154
mM NaCl, 20 µg/mL BSA, and 1% DMSO. Assays were stopped
by the addition of ice-cold wash buffer (20 mM Tris containing
0.9% NaCl). Filtration over glass fiber filters (Whatman GF/
B) was performed using a Brandel cell harvester. Nonspecific
binding was defined with 2 µM (+)-butaclamol. Binding of
18
grown from MeOH. A crystal of 0.05 × 0.14 × 0.22 mm
was used for X-ray diffraction data collection at room
temperature using a Nonius CAD4 single-crystal dif-
fractometer with Cu KR radiation. The crystal data are
as follows: space group P212121, a ) 5.8440(2) Å, b )
10.9602(7) Å, c ) 22.190(1) Å, Z ) 4, V ) 1421.3(1) Å3,
dx ) 1.561 g cm-3; 1721 independent reflections (θmax
) 75°) were obtained. The structure was solved and
refined using SHELXTL with 181 variables and 1408
observed (I g 4σ) reflections. The final agreement factors
are as follows: R(F) ) 0.032, wR(F2) ) 0.082 where w
) 1/[σ2(F) + 0.03F2], S ) 1.044, -0.39 e ∆F e 0.24 e/Å3.
The hydroxy hydrogens were located in the final differ-
ence Fourier maps, while the positions of all the other
hydrogen atoms were calculated from an idealized
geometry with standard bond lengths and angles. They
were assigned isotropic temperature factors and were
included in structure factor calculations with fixed
parameters. The crystal coordinates are available from
Cambridge Crystallographic Database (deposition num-
ber 183552).
[
125I]-7-OH-PIPAT to D2 receptors was performed using crude
membrane homogenates from rat striatal tissue. Homogenates
(10 µg of protein/well) from rat striatum were incubated with
[
125I]-7-OH-PIPAT (200 pM) for 60 min at 37 °C in buffer (100
µL) consisting of 50 mM Tris (pH 7.7 at 25 °C), 2 mM MgCl2,
0.1% BSA, 0.025 mN HCl, and 1% DMSO. Assays were stopped
by the addition of ice-cold wash buffer (20 mM Tris). Filtration
over glass fiber filters was performed using a Brandel cell
harvester. Nonspecific binding was defined with 2 µM (+)-
butaclamol.
cAMP Accu m u la tion . cAMP production in SK-N-MC cells
endogenously expressing the D1 receptor was measured by
using a cAMP radioimmunoassay system from Amersham
(code RPA 509). Briefly, cells were seeded at a concentration
of 105 cells/mL on 48-well plates and were incubated at 37 °C,
with 5% CO2 1 day before the assay. Assays were initiated by
the addition of 700 µL of assay buffer containing 1 mM
3-isobutyl-1-methylxanthine in the presence of varying con-
centrations of compounds to the cells and were incubated for
10 min at 37 °C. Assay mix was then removed, and 1 mL of
0.1 N HCl was added to terminate the reaction. The cAMP
production was detected by the kit following the protocol. The
nonlinear regression curve-fitting method was used to fit
dose-response curves with GraphPad Prism 3.0. Relative
efficacy (intrinsic activity) is the ratio of the maximum
Con clu sion s
The synthetic challenge with the original 14-step
procedure was largely overcome. The new synthetic
protocol allowed for the practical preparation of dinap-
soline (12). The biologically active enantiomeric (+)-
dinapsoline was efficiently prepared by a resolution
procedure through the formation of tartrate salt. The
newly developed synthesis could also be used to gain
access of many substituted derivatives of dinapsoline.
Preliminary results have suggested that in vitro dopa-
mine (D1/D2) binding activities were negatively affected
by most substituents on the A-, B′-, and C-rings while
D-ring substitutions preserved much of the dopamine
receptor binding activities. Also confirmed in this study
was the absolute chirality of the active enantiomer of
dinapsoline; (+)-12 was determined to have an R
absolute configuration. The synthetic tools developed in
the present study will allow further optimization of the
dinapsoline core with regard to in vivo potency, absorp-
tion, metabolism, and pharmacokinetic and safety char-
acteristics.
response (E
max) between the test compound and dopamine.
In Vivo P h a r m a cology. Rotation experiments were per-
formed in Sprague-Dawley rats with unilateral 6-OHDA
lesions of the medial forebrain bundle as described previously.4
Only animals that met prescreening criteria for rotational
response to amphetamine (5 mg/kg: 800 rotations/3 h) and
the dopamine agonist apomorphine (0.2 mg/kg: 100 rotations/1
h) were used in these studies. Four groups of rats were used,
and each rat received four treatments, once per week, in a
counterbalanced order.4
Gen er a l Ch em ica l P r oced u r es. Melting points were
recorded on a Thomas-Hoover capillary apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer
System 2000 FT-IR spectrometer or performed by Robertson
Microlit Lab. Optical rotations were measured on a Perkin-
Elmer 241 polarimeter on a 10 cm standard cell, and results
are reported as [R]D. Proton NMR (1H NMR) and carbon NMR
(13C NMR) spectra were obtained on Brucker ACP 300
spectrometers and are reported relative to a tetramethylsilane
(TMS) reference. NMR coupling constants (J ) were reported
in hertz (Hz). Analytical and preparative HPLC were per-
formed on YMC columns (A-302, S5, 120A ODS, 4.6 × 150 mm;
S5 ODS, 30 × 100 mm) with methanol/water gradients
containing 0.1% trifluoroacetic acid. LC-MS measurements
were taken on a Shimadzu-Micromass LC unit using the same
mobile phase. TLC and medium-pressure chromatography
were performed under flash conditions using EM silica type
H. THF was used as supplied by Aldrich. Solutions were dried
with magnesium sulfate unless otherwise noted.
Exp er im en ta l Section
In Vitr o a n d in Vivo Assa ys. [125I]-7-OH-PIPAT (2200 Ci/
mmol) and [125I]-(+)-SCH-23982 (2200 Ci/mmol) were pur-
chased from NEN Life Sciences Products (Boston, MA). Rat
striata were purchased from ABS Inc. (Wilmington, DE). The
frozen striata were thawed rapidly in homogenization buffer
(20 mM HEPES, 154 mM NaCl, 5 mM EDTA, pH 7.5 at 4 °C),
homogenized, and centrifuged at 20000g for 10 min. The
pellets were resuspended in homogenization buffer, incubated
for 30 min at 37 °C, and centrifuged again. The final pellets
4-Br om o-1,2-(m eth ylen ed ioxy)-3-ben za ld eh yd e (3). To
a solution of 4-bromo-1,2-(methylenedioxy)benzene (5.0 g, 24.9
mmol) in THF (52 mL) at -78 °C was added lithium diiso-
propylamide in cyclohexane (1.5 M, 18.2 mL, 27.3 mmol), and

(+)-Dinapsoline: A Novel Dopamine Agonist
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3665
the resulting solution was stirred for 15 min. N,N-Dimethyl-
formamide (DMF, 4.2 mL, 54.2 mmol) was added dropwise,
and the solution was allowed to warm to room temperature
for 1 h. The reaction mixture was washed with saturated
aqueous NH4Cl, and the organic layer was concentrated and
dried. The solid yellow product was recrystallized using
isopropyl acetate to afford the desired product as yellow
needles (3.9 g, 69% yield): mp 158-159 °C; 1H NMR (CDCl3)
δ 10.29 (s, 1H), 7.08 (d, 1H, J ) 8.25 Hz), 6.83 (d, 1H, J )
8.22 Hz), 6.17 (s, 2H); 13C NMR (CDCl3) δ 190.8, 149.8, 149.1,
126.5, 117.7, 115.9, 113.9, 103.8. Anal. (C8H5BrO3) C, H, Br.
) 7.2 Hz); 13C NMR (DMSO-d6) δ 194.23, 153.5, 146.2, 140.2,
135.2, 132.6, 130.2, 128.6, 127.5, 117.2. Anal. (C10H7NO) C,
H, N.
r-(5-Br om o-1,3-ben zod ioxol-4-yl)-5-isoqu in olin em eth -
a n ol (7). Meth od B. To a solution of 4-bromo-1,2-(methyl-
enedioxy)benzene (3.01 g, 15 mmol) in THF (20 mL) at -78
°C was added dropwise lithium diisopropylamide (10.6 mL of
a 1.5 M solution in cyclohexane, 16 mmol). The reaction
mixture was stirred at -78 °C under argon for 20 min, forming
a brownish solution. The lithiated species was treated with a
solution of 5-isoquinolinecarboxaldehyde (8, 1.9 g, 12 mmol)
in THF (4 mL). The resulting mixture was stirred at -78 °C
for 10 min, and then warmed to room temperature. The
mixture was stirred for 30 min at room temperature before
the reaction was quenched with saturated NH4Cl solution. The
addition product was extracted with EtOAc (3 × 20 mL), and
the organic layers were combined, dried, and evaporated under
reduced pressure. Chromatography (SiO2 type H, 35% EtOAc
in hexanes) of the crude product yielded the title compound
as a yellow solid (2.8 g, 7.8 mmol, 65% yield): mp 173-175
°C. Anal. (C17H12BrNO3) C, H, N.
5-Br om oisoqu in olin e (5). The apparatus consisted of a
500 mL three-necked flask equipped with a large bore con-
denser, a dropping funnel, and a stirrer terminating in a stiff,
crescent-shaped Teflon paddle. To neat isoquinoline (57.6 g,
447 mmol) in the flask was added AlCl3 (123 g, 920 mmol).
The mixture was heated to 75-85 °C, and bromine (48.0 g,
300 mmol) was added over a period of 4 h using a dropping
funnel. The resulting mixture was stirred for another hour at
75 °C. The nearly black mixture was poured into vigorously
hand-stirred crushed ice in water (about 1.5 kg). The cold
mixture was treated with sodium hydroxide solution (10 N)
to dissolve all the aluminum salts, and the oily layer was
extracted with ether. The organic extract was dried over Na2-
SO4 and concentrated, and the oily crude product was distilled
at 0.3 mmHg. The desired product was collected as a white
solid (16.3 g, 78 mmol, 26% yield) from a fraction at about 125
°C: mp (pentane) 80-81 °C; 1H NMR (DMSO-d6) δ 9.34 (s,
1H), 8.63 (d, 1H, J ) 9.0 Hz), 8.17 (d, 1H, J ) 7.5 Hz), 8.11 (d,
1H, J ) 6.6 Hz), 7.90 (d, 1H, J ) 6.0 Hz), 7.60 (t, 1H, J ) 7.5
Hz); 13C NMR (DMSO-d6) δ 153.0, 144.7, 134.3, 134.0, 129.3,
128.5, 128.0, 120.3, 118.6. Anal. (C9H6BrN) C, H, N.
5-[(5-Br om o-1,3-b e n zod ioxol-4-yl)m e t h yl]isoq u in o-
lin e (9). To a solution of the secondary alcohol R-(5-bromo-
1,3-benzodioxol-4-yl)-5-isoquinolinemethanol (7, 3.0 g, 8.4
mmol) in trifluoroacetic acid (100 mL) was added triethylsilane
(13.4 mL, 83.7 mmol), and the resulting mixture was refluxed
at 70-75 °C for 1 h. The reaction mixture was then stirred
overnight at room temperature. The mixture was concentrated
under vacuum, and the residue was redissolved in ethyl
acetate, washed with saturated NH4Cl, dried over Na2SO4,
filtered, and concentrated. Purification was performed by
column chromatography (silica gel, type H, eluted with mix-
tures of ethyl acetate and hexanes) to give the trifluoroacetate
salt form of the title compound as a white crystalline solid (1.9
g, 67% yield): mp 138-140 °C; 1H NMR (CDCl3) δ 9.64 (s,
1H), 8.63 (d, 1H, J ) 6.59 Hz), 8.45 (d, 1H, J ) 6.62 Hz), 8.14
(d, 1H, J ) 8.22 Hz), 7.77 (t, 1H, J ) 7.39 Hz), 7.64 (d, 1H, J
) 7.29 Hz), 7.13 (d, 1H, J ) 8.33 Hz), 6.71 (d, 1H, J ) 8.31
Hz), 5.94 (s, 2H), 4.53 (s, 2H); 13C NMR (CDCl3) δ 147.8, 147.7,
147.1, 137.2, 135.1, 134.7, 133.4, 130.3, 128.6, 128.3, 125.9,
120.7, 119.4, 116.3, 109.1, 101.9, 31.7. Anal. (C17H12BrNO2‚C2-
HF3O2) C, H, N, Br.
r-(5-Br om o-1,3-ben zod ioxol-4-yl)-5-isoqu in olin em eth -
a n ol (7). Meth od A. To a solution of 5-bromoisoquinoline (0.50
g, 2.4 mmol) in ether (8 mL) at -78 °C was added dropwise
tert-butyllithium (3.6 mL of a 1.7 M solution in pentane, 6.1
mmol) under argon. The mixture was stirred at -78 °C under
argon for 30 min, and then it was stirred for 15 min at -45 to
-55 °C before it was cooled to -78 °C. 4-Bromo-1,2-(methyl-
enedioxy)-3-benzaldehyde 3 (0.524 g, 2.3 mmol) was added in
one portion under argon. The mixture was stirred at -78 °C
for 5 min, and then warmed to room temperature. The mixture
was stirred for 20 min at room temperature before the reaction
was quenched with saturated NH4Cl aqueous solution. The
organic residues were extracted with EtOAc and dried over
Na2SO4. Chromatography (SiO2, 35% EtOAc in hexanes)
yielded the desired product as a yellow solid (0.18 g, 0.50 mmol,
21% yield): mp 173-175 °C; 1H NMR (DMSO-d6) δ 9.32 (s,
1H), 8.47 (d, 1H, J ) 6.0 Hz), 8.05 (d, 1H, J ) 8.1 Hz), 7.96 (d,
1H, J ) 7.2 Hz), 7.76 (d, 1H, J ) 6.0 Hz), 7.66 (t, 1H, J ) 7.8
Hz), 7.14 (d, 1H, J ) 8.1 Hz), 6.84 (d, 1H, J ) 8.1 Hz), 6.58 (d,
1H, J ) 8.1 Hz), 6.28 (d, 1H, J ) 5.4 Hz), 5.95 (s, 1H), 5.80 (s,
1H); 13C NMR (DMSO-d6) δ 153.1, 147.6, 147.0, 142.9, 136.9,
132.7, 128.9, 128.3, 127.3, 126.7, 125.6, 124.4, 116.3, 114.0,
109.3, 101.6, 69.0. Anal. (C17H12BrNO3) C, H, N.
12H-Ben zo[d,e][1,3]ben zodioxol[4,5-h ]isoqu in olin e (10).
Meth od A, Sm a ll Sca le. A solution of 5-[(5-bromo-1,3-benzo-
dioxol-4-yl)methyl]isoquinoline (9, 0.357 g, 1.0 mmol) and 2,2′-
azobisisobutylronitrile (AIBN, 0.064 g, 0.39 mmol) in benzene
(10 mL) was cooled to -78 °C, degassed 4 times (purged with
N2), and then heated to 80 °C under argon. A solution of
tributyltin hydride (TBTH, 1.14 g, 3.9 mmol) in 10 mL of
degassed benzene was added over a period of 2 h. Trifluoro-
acetic acid (TFA, 0.185 g, 1.6 mmol) was added in 4 equal
portions (1/4 each half-hour) over the next 2 h. The reaction
mixture was stirred at 80 °C under argon for another 6 hours
after the addition of TFA. At this point, TLC analysis indicated
an incomplete reaction. More tributyltin hydride (1.14 g, 3.9
mmol) in 10 mL of degassed benzene was added dropwise over
2 h followed by TFA (0.185 g, 1.6 mmol) in 4 equal portions
(1/4 each half-hour). The reaction mixture was stirred overnight
(16 h). Most of the solvent was removed under reduced
pressure. Pentane (100 mL) was added to the residue, and the
mixture was cooled to -78 °C, causing a brown gummy solid
to precipitate out. The pentane layer was extracted with MeCN
(20 mL), and the MeCN layer was combined with the brown
gum. The crude product from evaporation of MeCN was
purified by chromatography (SiO2 type H, 15% EtOAc in
hexanes). The purified compound was redissolved in CH2Cl2
and extracted with HCl (1 N). The aqueous layer was made
basic to pH ∼10 using 10 N NaOH solution, and the free base
was reextracted with CH2Cl2. The organic layer was dried over
Na2SO4. Evaporation of the solvent yielded the desired com-
pound as an orange solid (0.068 g, 0.26 mmol, 25% yield): mp
5-Isoqu in olin eca r boxa ld eh yd e (8). To a solution of n-
butyllithium (19.3 mL of 2.5 M in hexanes, 48 mmol) in a
mixture of ether (80 mL) and THF (80 mL) at -78 °C was
added dropwise a solution of 5-bromoisoquinoline (5.0 g, 24
mmol) in THF (10 mL). The reaction mixture was stirred at
-78 °C under argon for 30 min. Prior to mixing, a DMF
solution (3.3 g, 45 mmol) in THF (10 mL) was chilled to -78
°C, and it was quickly added into the isoquinolyllithium
solution. The resulting mixture was stirred at -78 °C for 15
min. Ethanol (20 mL) was added followed by saturated NH4-
Cl solution. The suspension was warmed to room temperature.
The organic residue was extracted twice with ether, and the
ether layers were combined and dried over Na2SO4. A pale
yellow solid (2.4 g, 15 mmol, 64% yield) was obtained after
chromatographic purification (SiO2 type H, 50% EtOAc in
hexanes) and recrystallization (ethanol): mp 114-116 °C; 1H
NMR (DMSO-d6) δ 10.40 (s, 1H), 9.44 (s, 1H), 8.85 (d, 1H, J )
6.0 Hz), 8.69 (d, 1H, J ) 6.0 Hz), 8.45 (m, 2H), 7.90 (t, 1H, J
1
194-197 °C; H NMR (DMSO-d6) δ 9.12 (s, 1H), 9.06 (s, 1H),
7.93 (d, 1H, J ) 6.9 Hz), 7.83 (d, 1H, J ) 8.1 Hz), 7.73 (dd,
1H, J ) 7.2, 1.5 Hz), 7.66 (t, 1H, J ) 7.8 Hz), 6.96 (d, 1H, J )

3666 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Sit et al.
8.4 Hz), 6.14 (s, 2H), 4.44 (s, 2H); 13C NMR (DMSO-d6) δ 150.6,
147.0, 145.2, 135.6, 130.6, 129.3, 129.1, 127.7, 127.5, 125.0,
123.6, 117.2, 116.1, 107.5, 101.6, 26.6. Anal. (C17H11NO2) C,
H, N.
bicarbonate solution followed by extraction with methylene
chloride to give 11.6 g of the crude title compound; H NMR
was indistinguishable from that of the purified material
prepared above by method A.
1
12H-Ben zo[d,e][1,3]ben zodioxol[4,5-h ]isoqu in olin e (10).
Meth od B, La r ge Sca le. A solution of 5-[(5-bromo-1,3-benzo-
dioxol-4-yl)methyl]isoquinoline (9, 12.6 g, 36.8 mmol) and 2,2′-
azobisisobutylronitrile (5.92 g, 36.0 mmol) in degassed benzene
(1500 mL) was heated to 80 °C under argon. To this solution
was added glacial acetic acid (12.6 g, 210 mmol), followed by
a solution of tributyltin hydride (39.9 g, 137 mmol) in 30 mL
of degassed benzene over a period of 3 h. The reaction mixture
was stirred at 80 °C under argon for an additional 16 h. Excess
triethylamine was added to neutralize the remaining acetic
acid, and the mixture was concentrated into a semisolid.
Methylene chloride (250 mL) was added to dissolve the
semisolid. This was followed by the addition of hexanes to a
point just before the mixture turned cloudy. This solution was
poured over a short bed of silica gel, and the byproduct tri-n-
butyltin acetate was removed by washing it with hexanes until
it was no longer detected by TLC. The product was then eluted
with mixtures of hexanes and ethyl acetate to give the
uncyclized des-bromo 9 (20.6%) followed by the desired cyclized
compound 10 (6.1 g, 23.4 mmol, 63.5% yield). The main desired
product was analyzed and found to be identical to the product
prepared by method A. The main side product from the
cyclization was the des-bromo 9 (2.0 g, 7.6 mmol, 20.6%
yield): mp 109-111 °C; MS m/e 264.2 (MH+); 1H NMR (DMSO-
d6) δ 4.33 (s, 2H), 6.04 (s, 2H), 6.57 (dd, J ) 1.2, 8.4 Hz, 1H),
6.72 (m, 2H), 7.62 (m, 2H), 7.93 (d, J ) 6.0 Hz, 1H), 8.02 (m,
1H), 8.51 (d, J ) 6.0 Hz, 1H), 9.31 (s, 1H); 13C NMR (DMSO-
d6) δ 30.8, 100.7, 106.9, 116.8, 121.1, 121.7, 122.6, 126.5, 127.2,
128.6, 130.9, 133.9, 135.0, 143.2, 145.1, 146.9, 153.0. Anal.
(C17H13NO2) C, H, N.
(()-8,9-Meth ylen edioxy-2,3,7,11b-tetr ah ydr o-1H-n aph th -
[1,2,3-d e]isoqu in olin e ((()-11). Meth od A. To a solution of
12H-benzo[d,e][1,3]benzodioxol[4,5-h]isoquinoline (10, 0.085 g,
0.33 mmol) in THF (43 mL) was added 2 N HCl (1.7 mL, 3.4
mmol), and an orange precipitate was formed. Sodium cy-
anoborohydride (0.274 g, 4.4 mmol) was added in one portion.
The resulting suspension was stirred at room temperature for
2 h. HCl (2 N, 10 mL) was added, and the mixture was stirred
for 5 min. Saturated NaHCO3 solution was added to neutralize
the excess HCl (pH 7-8). The resulting mixture was extracted
with EtOAc and dried over Na2SO4, and the solvent was
removed under reduced pressure. Chromatography (SiO2 type
H, 5% MeOH in CH2Cl2) of the residue yielded the title
compound as a yellow gum (0.066 g, 0.25 mmol, 75% yield):
1H NMR (CDCl3) δ 7.15 (m, 2H), 6.97 (d, 1H, J ) 6.9 Hz), 6.83
(br s, 1H), 6.68 (d, 1H, J ) 8.1 Hz), 6.59 (d, 1H, J ) 8.1 Hz),
6.01 (d, 1H, J ) 1.4 Hz), 5.91 (d, 1H, J ) 1.4 Hz), 4.40-4.00
(m, 5H), 3.55 (dd, 1H, J ) 17.7, 3.0 Hz), 3.10 (t, 1H, J ) 12.0
Hz); 13C NMR (CDCl3) δ 146.1, 144.8, 136.0, 132.2, 130.4,
128.6, 127.1, 127.0, 124.5, 118.5, 116.2, 106.2, 101.2, 45.8, 35.1,
34.3, 28.9. Anal. (C17H15NO2) C, H, N.
(()-8,9-Dih ydr oxy-2,3,7,11b-tetr ah ydr o-1H-n aph th [1,2,3-
d e]isoqu in olin e ((()-12). BBr3 (25.0 mL of a 1 M solution in
CH2Cl2, 25.0 mmol) was added to a cooled solution (-78 °C)
of (()-8,9-methylenedioxy-2,3,7,11b-tetrahydro-1H-naphth-
[1,2,3-de]isoquinoline (1.4 g, 5.3 mmol) in CH2Cl2. The mixture
was stirred at -78 °C under nitrogen for 3 h and at room
temperature overnight. After the mixture was cooled to -78
°C, anhydrous methanol (50 mL) was added dropwise, and the
solvent was removed under reduced pressure. The residue was
dissolved in methanol (100 mL), and the solution was refluxed
under nitrogen for 2 h. After removal of the solvent, chroma-
tography (SiO2 type H, eluted with 10% MeOH in CH2Cl2) of
the residue yielded the title compound as a dark-brown solid
1
(1.65 g, 4.94 mmol, 93% yield): MS (ESI) m/z 254 (MH+); H
NMR (DMSO-d6) δ 9.50 (br s, 2H), 9.28 (s, 1H), 8.54 (s, 1H),
7.32 (d, 1H, J ) 8.3 Hz), 7.23 (t, 1H, J ) 8.3 Hz), 7.12 (d, 1H,
J ) 8.5 Hz), 6.70 (d, 1H, J ) 9.3 Hz), 6.54 (d, 1H, J ) 6.7 Hz),
4.37 (s, 2H), 4.30-4.23 (m, 2H), 3.97 (m, 1H), 3.45-3.31 (m,
2H); 13C NMR (DMSO-d6) δ 143.8, 142.0, 136.9, 132.1, 127.6,
127.0, 126.6, 124.1, 123.7, 114.0, 112.7, 44.0, 43.6, 32.9, 28.5.
Anal. (C16H15NO2) C, H, N.
(+)-8,9-Meth ylen edioxy-2,3,7,11b-tetr ah ydr o-1H-n aph th -
[1,2,3-d e]isoqu in olin e ((+)-11). Racemic (()-11 was injected
into a preparative HPLC instrument (Dynamax Rainin model
SD-1) equipped with a Chiralcel OD column (5 cm × 50 cm,
20 µm, lot 738-60328c, Chiral Technologies, Inc.) coupled in
series with a UV detector (Dynamax Absorbance Detector
model UV-D II) set at λ ) 220 nm. Using an isocratic method,
a solvent system composed of 5% ethanol in hexanes plus 0.1%
(by volume) TFA at a flow rate of 50 mL/min was found to
separate the enantiomers. As much as 150 mg/5 mL of ethanol
can be injected into the column per run. A total of 425 mg of
racemic (()-11 was injected which produced about 200 mg of
each enantiomer. The analytical chiral separation was per-
formed using an identical setup as previously described but
with an analytical Chiralcel OD column (0.46 cm × 25 cm, 10
µm) at a reduced solvent flow rate of 1 mL/min at sampling
intervals of 0.1 s. The preparative column and the analytical
column could be switched by a flow selector. Optical rotation
was taken for each of the enantiomers: first peak (Rf ) 19.6
min), [R]D -88.9° (c 0.03, CHCl3); second peak (Rf ) 23.6 min),
[R]D +90.3° (c 0.03, CHCl3).
Larger quantities of (+)-11 could also be prepared by a
conventional resolution using tartaric acid dibenzoyl ester as
the resolving agent. A solution of racemic (()-11 (3.0 g, 11.3
mmol) in 100 mL of 95% ethyl alcohol at room temperature
was mixed with a warm solution of (+)-dibenzoyl-D-tartaric
acid in 40 mL of 95% ethyl alcohol. The mixture was allowed
to stand at room temperature for 4 h, and the grayish off-white
crystals were collected by filtration and subsequently dried
in a vacuum oven at 35 °C to give 1.3 g (mp 175-176 °C,
35.7%). The salt was neutralized with
a 2 M potasium
(()-8,9-Meth ylen edioxy-2,3,7,11b-tetr ah ydr o-1H-n aph th -
[1,2,3-d e]isoqu in olin e ((()-11). Meth od B. 12H-Benzo[d,e]-
[1,3]benzodioxol[4,5-h]isoquinoline (10, 11.26 g) was dissolved
into 500 mL of glacial acetic acid in a suitable glass liner that
fitted into a 1 L Parr “bomb reactor”. To this dark-amber
solution were added 480 mg of PtO2 and a magnetic stirring
bar. The usual freeze-thaw cycles were repeated 3 times at
-78 °C. Finally, hydrogen gas was charged into the steel bomb
at 140 psi (pounds/inch2) while the content was still at -78
°C. The reactor was allowed to warm to room temperature over
a period of 2 h while the internal pressure reached 195 psi.
Gas absorption was faster after about 4 h at room temperature.
After 24 h, the internal pressure returned to 165 psi, indicating
roughly stoichiometric uptake of hydrogen gas. The black
suspension was removed from the Parr reactor after the
internal pressure was relieved. The suspension was filtered
over silica gel, rinsed with acetic acid, and concentrated under
reduced pressure to give about 19 g of a brownish gummy
substance. The crude product was neutralized with sodium
hydroxide solution, and the organic material was extracted
with methylene chloride. The organic layers were combined
and concentrated under reduced pressure to give a white solid.
The enantiomeric purity was determined by the same chiral
HPLC conditions on an analytical Chiralcel OD column as
described above. The ratio of the second peak to the first was
determined to be greater than 40:1. The identical resolution
could also be carried out using the unnatural, free D-tartaric
acid, but the use of (+)-dibenzoyl-D-tartaric acid ester appeared
to be more consistent. (R)-(+)-8,9-Methylenedioxy-2,3,7,11b-
tetrahydro-1H-naphth[1,2,3-de]isoquinoline‚(+)-dibenzoyl-D-
tartaric acid salt: mp 175-176 °C. (R)-(+)-8,9-Methylenedioxy-
2,3,7,11b-t et r a h ydr o-1H -n a ph t h [1,2,3-d e]isoqu in olin e‚D-
tartaric acid salt: mp 186-188 °C.
(R)-(+)-8,9-Dih yd r oxy-2,3,7,11b-tetr a h yd r o-1H-n a p h th -
[1,2,3-d e]isoqu in olin e ((+)-12). The identical deprotection
procedure described for the racemic compound was used, and
each of the two resolved compounds of 11 was treated with

(+)-Dinapsoline: A Novel Dopamine Agonist
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3667
BBr3 deprotection to give chiral (+)-12: [R] +75.0° (c 0.03,
Refer en ces
1
MeOH); MS (ESI) m/z 254.12 (MH+); H NMR (DMSO-d6) δ
(1) Ghosh, D.; Snyder, S. E.; Watts, V. J .; Mailman, R. B.; Nichols,
D. E. 8,9-Dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]iso-
quinoline: A Potent Full Dopamine D1 Agonist Containing a
Rigid â-Phenyldopamine Pharmacophore. J . Med. Chem. 1996,
39 (2), 549-555.
(2) Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel
naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands.
PCT Int. Appl. WO 9706799 A1, Feb 27, 1997.
(3) Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic
compounds as dopamine agonists. PCT Int. Appl. WO 9422858
A1 , Oct 13, 1994. Note: 18 and 19 are better known by their
code names A-86929 and ABT-431, respectively.
9.50 (br s, 2H), 9.28 (s, 1H), 8.54 (s, 1H), 7.32 (d, 1H, J ) 8.3
Hz), 7.23 (t, 1H, J ) 8.3 Hz), 7.12 (d, 1H, J ) 8.5 Hz), 6.70 (d,
1H, J ) 9.3 Hz), 6.54 (d, 1H, J ) 6.7 Hz), 4.37 (s, 2H), 4.30-
4.23 (m, 2H), 3.97 (m, 1H), 3.45-3.31 (m, 2H); 13C NMR
(DMSO-d6) δ 143.8, 141.9, 136.9, 132.1, 127.6, 126.9, 126.5,
126.4, 124.0, 123.5, 114.0, 112.6, 44.0, 43.6, 32.9, 28.5. (-)-
12: [R] -70.7° (c 0.03, MeOH). Anal. (C16H15NO2‚HBr) C, H,
N.
Sca le-Up Resolu tion P r ocesses of Ra cem ic 11 a n d th e
P r ep a r a tion of (+)-12 via En r ich m en t P r oced u r es. To a
solution of (()-11 (8.7 g, 33 mmol) in warm 95% ethanol (300
mL) was added dibenzoyl-L-tartaric acid (DB-L-TA, 33 mmol)
in warm 95% ethanol (90 mL). The solution under argon was
allowed to cool slowly to room temperature over a period of
12 h which resulted in the appearance of a flaky, off-white
crystalline material. The crystals were filtered and dried to
give 3.3 g of the adduct of (-)-11 (mp 174-175 °C). The
“enriched” mother liquor was concentrated and neutralized
with 2 M NaOH, and the free base was isolated as usual,
readying for the second resolution. The same protocol was used
as described above, and the recovered material (20 mmol) in
95% ethanol (200 mL) was resolved with dibenzoyl-D-tartaric
acid (DB-D-TA, 20 mmol) in 95% ethanol (50 mL). Almost
instantly, a white fluffy solid was observed which extended
through the entire solution phase. The suspension was then
reheated to reflux for 15 min, forming a somewhat thinner
suspension; the solid remained there and was never dissolved,
despite the brief reflux. The contents were allowed to cool
slowly to about 40-45 °C, and the precipitate was collected
and dried to give 3.8 g of the adduct of (+)-11 (mp 175-176
°C). While the enrichment procedure did not greatly improve
the overall resolution efficiency, the quality of the resolved
material showed superior purity with respect to enantiomeric
separation. Analysis of the neutralized samples by the HPLC
instrument equipped with a Chiralcel OD analytical column
showed >99.9% ee.
(+)-Din a p solin e ((+)-12). The (+)-11 adduct obtained
above was neutralized with NaOH, and the free base ((+)-11)
was extracted with CH2Cl2. Boron tribromide (BBr3, 1 M in
CH2Cl2, 99 mL) was added dropwise to a cold solution (-78
°C) of (+)-11 (5.5 g, 20.8 mmol) in CH2Cl2 (500 mL). The
mixture was stirred at -78 °C under N2 for 15 min before the
reaction mixture was allowed to warm to room temperature.
After the mixture was stirred at RT for an additional 3 h, it
was cooled to -78 °C. Absolute methanol (100 mL) was added
slowly. The dry ice/acetone bath was removed, and the stirring
was continued at 25 °C for 12 h. The reaction mixture was
evaporated, and the crude product was purified by chroma-
tography (SiO2 type H, 10% MeOH in CH2Cl2). The column-
purified greenish solid was recrystallized from MeOH to
furnish a light-greenish crystalline material (5.5 g, 16.5 mmol,
79%). With the exception of the optical rotations, these samples
were analyzed in a manner identical to that of (()-12.
(4) Gulwadi, A. G.; Korpinen, C. D.; Mailman, R. B.; Nichols, D. E.;
Sit, S.-Y.; Taber, M. T. Dinapsoline: Characterization of a D1
Dopamine Receptor Agonist in
a Rat Model of Parkinson’s
Disease. J . Pharmacol. Exp. Ther. 2001, 296 (2), 338-344.
(5) (a) DeNinno, M. P.; Schoenleber, R.; Asin, K. E.; MacKenzie, R.;
Kebabian, J . W. (1R,3S)-1-(Aminomethyl)-3,4-dihydro-5,6-dihy-
droxy-3-phenyl-1H-2-benzopyran:
a potent and selective D1
agonist. J . Med. Chem. 1990, 33 (11), 2948-2950. (b) Michaelides,
M. R.; Schoenleber, R.; Thomas, S.; Yamamoto, D. M.; Britton,
D. R.; MacKenzie, R.; Kebabian, J . W. Synthesis and pharma-
cological evaluation of 1-(aminomethyl)-3,4-dihydro-5-hydroxy-
1H-2-benzopyrans as dopamine D1 selective ligands. J . Med.
Chem. 1991, 34 (10), 2946-2953. (c) â-Phenyl dopamine was long
recognized as the essential fragment responsible for D1 selectiv-
ity. See: Riggs, R. M.; McKenzie, A. T.; Byrn, S. R.; Nichols, D.
E.; Foreman, M. M.; Truex, L. L. Effect of â-alkyl substitution
on D1 dopamine agonist activity: absolute configuration of
â-methyldopamine. J . Med. Chem. 1987, 30 (10), 1914-1918 and
references 7 and 9. Please note that 13, 14, and 15 are commonly
known as SKF-38393, A-77636, and SKF-89626, respectively.
(6) (a) Shiosaki, K.; Asin, K. E.; Bedard, P.; Britton, D. R.; J enner,
P.; Lin, C. W.; Michaelides, M.; Williams, M. Efficacy of dopa-
mine D1 receptor agonists A-86929 and ABT-431 in animal
models of Parkinson’s disease. Biomed. Health Res. 1998, 19
(Dopamine Receptor Subtypes), 84-97. (b) Lovenberg, T. W.;
Brewster, W. K.; Mottola, D. M.; Lee, R. C.; Riggs, R. M.; Nichols,
D. E.; Lewis, M. H.; Mailman, R. B. Dihydrexidine, a novel
selective high potency full dopamine D-1 receptor agonist. Eur.
J . Pharmacol. 1989, 166 (1), 111-113. (c) Kebabian, J . W.;
Britton, D. R.; DeNinno, M. P.; Perner, R.; Smith, L.; J enner,
P.; Schoenleber, R.; Williams, M. A-77636: a potent and selective
dopamine D1 receptor agonist with antiparkinsonian activity in
marmosets. Eur. J . Pharmacol. 1992, 229 (2-3), 203-209. (d)
Mottola, D. M.; Brewster, W. K.; Cook, L. L.; Nichols, D. E.;
Mailman, R. B. Dihydrexidine, a novel full efficacy D1 dopamine
receptor agonist. J . Pharmacol. Exp. Ther. 1992, 262 (1), 383-
393. (e) Sit, S. Y. Dopamine agonists in the treatment of
Parkinson’s disease - past, present and future. Curr. Pharm.
Des. 2000, 6 (12), 1211-1248. (f) Huang, X.; Lawler, C. P.; Lewis,
M. M.; Nichols, D. E.; Mailman, R. B. Dopamine D1 Receptors.
Int. Rev.Neurobiol. 2001, 48, 65-139.
(7) Brewster, W. K.; Nichols, D. E.; Riggs, R. M.; Mottola, D. M.;
Lovenberg, T. W.; Lewis, M. H.; Mailman, R. B. Trans-10,11-
dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine: a
highly potent selective dopamine D1 full agonist. J . Med. Chem.
1990, 33 (6), 1756-1764.
(8) (a) Riggs, R. M.; Nichols, D. E.; Foreman, M. M.; Truex, L. L.;
Glock, D.; Kohli, J . D. Specific dopamine D-1 and DA1 properties
of 4-(mono- and -dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline
and its tetrahydrothieno[2,3c]pyridine analog. J . Med. Chem.
1987, 30 (8), 1454-1458. (b) Andersen, P. H.; Nielsen, E. B.;
Scheel-Kruger, J .; J ansen, J . A.; Hohlweg, R. Thienopyridine
derivatives identified as the first selective, full efficacy, dopamine
D
292.
1 receptor agonists. Eur. J . Pharmacol. 1987, 137 (2-3), 291-
(9) Michaelides, M. R.; Hong, Y.; DiDomenico, S., J r.; Asin, K.;
Britton, D. R.; Lin, C. W.; Williams, M.; Shiosaki, K. (5aR,11bS)-
4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena-
sample
[R]D of HBr salt form
+80.4°
(c 0.0083 g/mL, MeOH)
-70.0°
(c 0.0083 g/mL, MeOH)
mp (°C)
HBr salt form
(+)-12
>265
1 HBr/molecule
[c]phenanthrene-9,10-diol (A-86929):
a potent and selective
dopamine D1 agonist that maintains behavioral efficacy following
repeated administration and characterization of its diacetyl
prodrug (ABT-431). J . Med. Chem. 1995, 38 (18), 3445-3447.
(10) (a) Brewster, W. K.; Nichols, D. E.; Watts, V. J .; Riggs, R. M.;
Mottola, D.; Mailman, R. B. Evaluation of cis- and trans-9- and
11-hydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridines as
structurally rigid, selective D1 dopamine receptor ligands. J .
Med. Chem. 1995, 38 (2), 318-327. (b) Snyder, S. E.; Aviles-
Garay, F. A.; Chakraborti, R.; Nichols, D. E.; Watts, V. J .;
Mailman, R. B. Synthesis and evaluation of 6,7-dihydroxy-
2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2,3-ef][3]-
benzazepine, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,-
4a,4-cd]azepine, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxy-
anthracene as conformationally restricted analogs of â-phenyl-
dopamine. J . Med. Chem. 1995, 38 (13), 2395-2409.
(-)-12
>265
1 HBr/molecule
Ack n ow led gm en t. Microanalyses, IR spectra, and
mass spectra were kindly provided by the Bristol-Myers
Squibb Department of Analytical Research and Devel-
opment.
Su p p or tin g In for m a tion Ava ila ble: Detailed analytical
data. This material is available free of charge via the Internet
at http://pubs.acs.org.

3668 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17
Sit et al.
(11) (a) Blanchet, P. J .; Fang, J .; Gillespie, M.; Sabounjian, L.; Locke,
K. W.; Gamman, R.; Mouradian, M. M.; Chase, T. N. Effects of
the full dopamine D1 receptor agonist dihydrexidine in Parkin-
son’s disease. Clin. Neuropharmacol. 1998, 21 (6), 339-343. (b)
Rascol, O.; Blin, O.; Thalamas, C.; Descombes, S.; Soubrouillard,
C.; Azulay, P.; Fabre, N.; Viallet, F.; Lafnitzegger, K.; Wright,
S.; Carter, J . H.; Nutt, J . G. ABT-431, a D1 receptor agonist
prodrug, has efficacy in Parkinson’s disease. Ann. Neurol. 1999,
45 (6), 736-741.
(12) Mattson, R. J .; Sloan, C. P.; Lockhart, C. C.; Catt, J . D.; Gao,
Q.; Huang, S. Ortho-directed lithiation of 3,4-(alkylenedioxy)-
halobenzenes with LDA and LiTMP. The first ortho lithiation
of an iodobenzene. J . Org. Chem. 1999, 64 (21), 8004-8007.
(13) (a) Gordon, M.; Pearson, D. E. The Swamping catalyst effect.
VI. Halogenation of isoquinoline and quinoline. J . Org. Chem.
1964, 29, 329-330. (b) Mathison, I. W.; Morgan, P. H. Synthesis
and stereochemistry of some 8-substituted 2-methyldecahy-
droisoquinolines. J . Org. Chem. 1974, 39 (22), 3210-3215.
(14) The radical intermediate was successfully generated by many
methods which included electrochemical reduction, photochemi-
cal reduction, and chemical reduction. Among the available free
radical initiators, both water-soluble and organic soluble re-
agents (obtained from Wako Azo) were tried with varying
degrees of success.
(15) Analogous AIBN-initiated, free radical cyclizations have been
reported in the past. See: (a) Harrowven, D. C.; Nunn, M. I. T.
Tetrahedron Lett. 1998, 39 (32), 5875-5876. (b) Dobbs, A. P.;
J ones, K.; Veal, K. T. Tetrahedron Lett. 1997, 38 (30), 5379-
5382. (c) Harrowven, D. C.; Nunn, M. I. T.; Nigel, J . B.
Tetrahedron Lett. 2000, 41 (34), 6681-6683. (d) Escolano, C.;
J ones, K. Tetrahedron Lett. 2000, 41 (46), 8951-8955.
(16) Burris, K. D.; Filtz, T. M.; Chumpradit, S.; Kung, M.-P.; Foulon,
C.; Hensler, J . G.; Kung, H. F.; Molinoff, P. B. Characterization
of
[
125I]-(R)-trans-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)-
amino]tetralin binding to dopamine D3 receptors in rat olfactory
tubercle. J . Pharmacol. Exp. Ther. 1994, 268, 935-942.
(17) A novel 7-oxygen analogue of dinapsoline “dinoxyline” has very
recently appeared in
a patent publication. The compound
retained much of the dopamine D1 receptor binding activity as
compared to the parent dinapsoline. PCT Int. Appl. WO 0078765
A2, Dec 12, 2000.
J M0101545