Enantiomerically pure hexahydropyrazinoquinolines as potent and selective dopamine 3 subtype receptor ligands

Article abstract of DOI:10.1021/jm049031l

We report the design and synthesis of a series of enantiomerically pure hexahydropyrazinoquinolines as potent and selective ligands for the dopamine 3 subtype receptor using a newly developed synthetic method and using in vitro pharmacological evaluation. Our efforts yielded optically pure ligands with high affinities for the D₃ receptor and outstanding selectivity over closely related D₁-like and D₂-like receptors. For example, compound 38a has a K_i value of 5.7 nM to the D₃ receptor and selectivity greater than 10000- and 1600-fold over the D ₁-like and D₂-like receptors, respectively, and thus is one of the most selective D₃ ligands reported to date.

Full text of DOI:10.1021/jm049031l

J. Med. Chem. 2005, 48, 3171-3181
3171
Enantiomerically Pure Hexahydropyrazinoquinolines as Potent and Selective
Dopamine 3 Subtype Receptor Ligands
Ke Ding,† Jianyong Chen,† Min Ji,† Xihan Wu,† Judith Varady,† Chao-Yie Yang,† Yipin Lu,†
Jeffrey R. Deschamps,‡ Beth Levant,§ and Shaomeng Wang*,†
Departments of Internal Medicine and Medicinal Chemistry, University of Michigan, 1500 East Medical Center Drive,
Ann Arbor, Michigan 48109-0934, Laboratory of Structural Matters, Naval Research Laboratory, 4555 Overlook Avenue,
Washington, D.C. 20375, and Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical
Center, Kansas City, Kansas 66160-7417
Received November 30, 2004
We report the design and synthesis of a series of enantiomerically pure hexahydropyrazino-
quinolines as potent and selective ligands for the dopamine 3 subtype receptor using a newly
developed synthetic method and using in vitro pharmacological evaluation. Our efforts yielded
optically pure ligands with high affinities for the D3 receptor and outstanding selectivity over
closely related D1-like and D2-like receptors. For example, compound 38a has a Ki value of 5.7
nM to the D3 receptor and selectivity greater than 10000- and 1600-fold over the D1-like and
D2-like receptors, respectively, and thus is one of the most selective D3 ligands reported to
date.
Introduction
end, we have employed a computational 3D database
screening strategy to discover novel D3 ligands, which
led to the identification of several classes of novel D3
ligands.18 Among them, compound 1 contains hexahy-
dropyrazinoquinoline as its core structure (Figure 1) and
has a Ki value of 304 nM to the D3 receptor in our bind-
ing assay (Table 1), representing a novel class of D3
ligands. Interestingly, the core structure of 1, hexahy-
dropyrazinoquinoline, may be viewed as a conforma-
tionally constrained structure of BP 897 (2), a potent
and relatively selective D3 ligand.3 To improve the li-
gand binding affinity and selectivity, we have first de-
signed and synthesized 3 using the same linker and
hydrophobic tail as in BP 897 (Figure 1). It was deter-
mined that 3 has a Ki value of 18 nM to the D3 receptor
and a selectivity of 87- and 44-fold between the D3 re-
ceptor and the D1-like receptors and between the D3 re-
ceptor and the D2-like receptors (Table 1). Hence, 3 is
18 times more potent than 1 and is also much more
selective than 1, representing a promising new lead
compound for further optimization. The core structure
of compounds 1 and 3, hexahydropyrazinoquinoline, con-
tains a chiral center and has two stereoisomers. Since
a stereospecific synthetic method to derive optically pure
forms of hexahydropyrazinoquinolines is not available,
we have developed an efficient synthetic method to
prepare enantiomerically pure hexahydropyrazinoquin-
olines. Herein, we report the design and synthesis of a
series of optically pure new analogues of 3 and in vitro
pharmacological evaluation for their binding affinity at
the D3 receptor and their selectivity over the D1-like and
D2-like receptors. Our study yields new D3 ligands with
high affinity for the D3 receptor and outstanding
selectivity over the D1-like and D2-like receptors.
Dopamine receptors belong to the family of G-protein-
coupled receptors (GPCR) and play an important role
in multiple neurological and neuropsychiatric disorders
such as Parkinson’s disease, schizophrenia, and drug
abuse.1-6 The dopamine 3 (D3) subtype receptor has
been implicated as an important target for agents
currently used clinically for the treatment of schizo-
phrenia, Parkinson’s disease, depression, and other
neurological diseases.1 Recent studies also have pro-
vided strong evidence that the D3 receptor may be
involved in the positive reinforcing effects of cocaine and
other psychostimulants, and potent and selective D3
ligands may also have the therapeutic potential as novel
pharmacotherapies for the treatment of drug addiction,
dependence, and abuse.2,3 Accordingly, considerable
chemistry and pharmacological efforts have been de-
voted to the design and development of potent and
selective D3 ligands in recent years.7-20
Several classes of dopamine D3 receptor ligands with
varying degrees of selectivity have been identified
during the past decade.7-20 Because of the close se-
quence homology between the D2 and D3 receptors,
many of the D3 ligands reported earlier also show good
affinities for the D2-like receptor. Recently, several
studies12-17 have reported the design and synthesis of
potent and selective D3 ligands, suggesting that highly
potent and selective D3 ligands can indeed be obtained.
Since most of these recently reported potent and se-
lective D3 ligands12-17 were designed on the basis of the
same core structure of BP 897 (2),3 new D3 ligands that
belong to different chemical classes would have a con-
siderable value for increasing the chemical diversity in
D3 ligand design and may yield D3 ligands with unique
in vitro and in vivo pharmacological profiles. To this
Design
To improve the potency and more importantly the
selectivity for this class of D3 ligands, we have designed
and synthesized a series of new enantiomerically pure
hexahydropyrazinoquinolines starting from compound
3.
* To whom correspondence should be addressed. Phone: (734) 615-
0362. Fax: (734) 647-9647. E-mail: shaomeng@umich.edu.
† University of Michigan.
‡ Naval Research Laboratory.
§ University of Kansas Medical Center.
10.1021/jm049031l CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005

3172 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Ding et al.
Figure 1. Chemical structures of BP 897 and hexahydropyrazinoquinolines.
Figure 2. Predicted binding models of (a, b) compound 3 and (c) 38a (colored in yellow) to the D3 receptor. Residues in D3
forming van der Waals contacts with both compounds analyzed by Ligplot are drawn in ball-and-stick form. Ser192, Ser193, and
Ser196 are not in close contact with compound 3 but are shown for comparison purposes. Hydrogen bonds are depicted in cyan
color. Carbon, nitrogen, and oxygen atoms are colored in black, blue, and red, respectively.
Table 1. Binding Affinity and Selectivity of Hexahydropyrazinoquinolines at the D1-like, D2-like, and D3 Receptors
Ki (nM)
selectivity
compd
configuration
racemic
D1-like
D2-like
D3
D1/D3
D2/D3
1
904 ( 100
636 ( 103
791 ( 187
1710 ( 88
258 ( 8.0
2710 ( 66
6860 ( 978
>100000
>100000
10800 ( 318
4330 ( 486
7590 ( 374
1960 ( 45
>50000
243 ( 30
162 ( 48
1570 ( 338
585 ( 51
180 ( 32
644 ( 109
659 ( 64
>100000
>50000
304 ( 53
1.1 ( 0.2
18 ( 2.4
3.0
0.8
2 (BP-897)
3
578
44
147
87
racemic
32a
32b
33a
33b
34a
34b
35a
35b
36a
36b
38a
38b
40a
40b
R
S
R
S
R
S
R
S
R
S
R
S
R
S
19 ( 3.0
16 ( 2.7
91
31
16
11
8.3 ( 0.9
9.3 ( 1.3
67 ( 9.7
326
77
740
71
>1492
>794
247
>1492
>397
39
126 ( 10
44 ( 11.0
96 ( 15.0
4.1 ( 0.8
3.3 ( 0.5
5.7 ( 0.4
10 ( 1.8
1720 ( 307
990 ( 48
312 ( 51
88 ( 1.7
>10000
45
1851
595
10
76
27
>10000
>5000
>21
>1600
>1000
>10
>50000
>100000
>50000
>10000
>50000
4642 ( 189
7156 ( 1501
>25000
>6.9
>3.4
We have previously modeled the three-dimensional
structure of the D3 receptor based on a high-resolution
X-ray structure of rhodopsin.18 Using this modeled
structure, we have performed computational docking of
3 to predict its binding model. The predicted binding
model for 3 is shown in Figure 2. Our binding model
suggested that the phenyl ring in the hexahydropyrazi-
noquinoline core structure in 3 is close to three serine
residues (Ser192, Ser193, and Ser196) of helix 5 of the
D3 receptor. Although these three serine residues are
conserved among the dopamine receptors, we found that
they assume different conformations in the D1, D2, and
D3 receptors based on our modeled structures of these
receptors. We have therefore designed and synthesized
new analogues with a methoxyl group in each of the four
positions of the phenyl ring to probe for the optimal
position for binding affinity and selectivity in this class
of compounds.

Hexahydropyrazinoquinolines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3173
Scheme 1. A General Synthetic Method for Enantiomerically Pure Hexahydropyrazinoquinoline Derivativesa
a Reagents and conditions: (a) SeO2, 1,4-dioxane, reflux; (b) H2O2, HCO2H; (c) (S)-methylbenzylamine, EDCl, DMAP; (d) LiAH4; (e)
10% Pd-C, H2; (f) BH3-Me2S; (g) Boc2O, 1,4-dioxane; (h) chloroacetyl chloride, pyridine, THF; (i) TFA, THF; (j) K2CO3, DMF; (k) NaBH4,
BF3-Et2O; (l) 10% Pd-C, H2; (m) N-(4-bromobutyl)phthalimide, Cs2CO3; (n) NH2NH2, EtOH; (o) 2-naphthoyl chloride, triethylamine.
Analysis of our modeled structure of 3 complexed with
the D3 receptor (Figure 2b) revealed that the hydropho-
bic linker in this ligand is located in a large hydrophobic
pocket. Hence, a hydrophobic linker bulkier than the
linear hydrocarbon chain may improve the interaction
with the nearby hydrophobic residues in the D3 receptor.
Indeed, previous studies have shown that the introduc-
tion of a bulky rigid linker such as a trans-cyclohexyl
ring can lead to D3 ligands with high affinity.9,10 Ac-
cordingly, we have synthesized several ligands by incor-
porating a conformationally constrained bulky linker.
Chemistry
A synthetic route to enantiomerically pure 3-(4-
naphthylamido)butylhexahydropyrazinoquinolines with
a methoxyl substituent at different positions of the
phenyl ring is outlined in Scheme 1. Briefly, quinolines
4, either commercially available or readily synthesized
using published procedures,22 were converted to quino-
line-2-carboxylic acids 5 in two steps.23 Coupling of the
carboxylic acids 5 with (S)-R-methylbenzylamine yielded
amides 6. Preparation of pure enantiomers was ac-
complished by reduction of the amides 6 by LiAH4 and

3174 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Ding et al.
Scheme 2. Synthesis of Enantiomerically Pure Hexahydropyrazinoquinoline Derivatives with a Rigid Linkera
a Reagents and conditions: (a) trans-(4-tert-butoxycarbonylaminocyclohexyl)acetic acid or (4-tert-butoxycarbonylaminopiperidin-1-yl)acetic
acid, EDCl-HCl, HOBt, DMAP; (b) HCl/THF; (c) LiAH4; (d) 2-naphthoyl chloride, triethylamine.
21a. The chiral auxiliary (S)-R-methylbenzyl group was
removed by hydrogenation to obtain the key intermedi-
ate (R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quino-
lines 22a-26a.24
With 22a-26a in hand, 2-[4-(1,2,4,4a,5,6-hexahydro-
pyrazino[1,2-a]quinolin-3-yl)butyl]isoindole-1,3-diones
27a-31a were readily obtained by treatment of 22a-
26a with N-(4-bromobutyl)phthalimide in CH3CN. The
phthalimide derivative 27a (R ) H) was then treated
with hydrazine to generate 4-(1,2,4,4a,5,6-hexahydro-
pyrazino[1,2-a]quinolin-3-yl)butylamine, which was acyl-
ated with 2-naphthoyl chloride to obtain the target
compound (R)-naphthalene-2-carboxylic acid [4-(1,2,4,-
4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide 32a. The methoxylated derivatives (33a-36a)
were prepared by the same method. Following similar
procedures, (S)-naphthalene-2-carboxylic acid [4-(1,2,4,-
4a,5,6-hexahydro-pyrazino[1,2-a]quinolin-3-yl)butyl]-
amide 32b and its methoxylated derivatives 33b-36b
were prepared using 2S,3′S-1,2,3,4-tetrahydroquinoline-
2-carboxylic acid (1-phenylethyl)amides 7b-11b as the
key intermediates.
Synthesis of compounds with rigid linkers in place of
the four-carbon linker in 34a is outlined in Scheme 2.
Reaction of compound 24a with trans-(4-tert-butoxycar-
bonylaminocyclohexyl)acetic acid yielded the amide 37a.
Reduction of 37a and subsequent removal of the t-Boc
protecting group led to the primary amine, which was
coupled with 2-naphthoyl chloride to afford the target
compound 38a. Compounds 38b, 40a, and 40b were
obtained by a similar method (Scheme 2).
Figure 3. X-ray structure of compound 7a.
hydrogenation, generating two diastereoisomers 7a-
11a (70-75%) and 7b-11b (25-30%), which were
separated by flashing silica gel column chromatography.
X-ray crystallographic analysis established 7a (R ) H)
as 2R,3′S-1,2,3,4-tetrahydroquinoline-2-carboxylic acid
(1-phenylethyl)amide (Figure 3).
The amides 7a-11a were reduced with borane to the
corresponding amines, which were protected with a
t-Boc group, and the amine group at position 1 was
chloroacetylated with chloroacetyl chloride in tetrahy-
drofuran. Removal of the t-Boc protecting group under
acidic conditions and cyclization of the free amines
under basic conditions afforded lactams 12a-16a. Re-
duction of the lactams 12a-16a by NaBH4 in the
presence of BF3-Et2O yielded (R)-2,3,4,4a,5,6-hexahydro-
3-((S)-1-phenylethyl)-1H-pyrazino[1,2-a]quinolines 17a-
Results and Discussion
These new enantiomerically pure hexahydropyrazi-
noquinolines were evaluated for their binding affinities
at the D1, D2, and D3 receptors using previously de-
scribed methods.25-27 In addition, we have evaluated BP
897 in our assays for comparison, and the results are
summarized in Table 1.
Although the corresponding ligands with either the
R- or S-configuration have affinities very similar to that
of the D3 receptor, enantiomerically pure hexahydropy-
razinoquinolines with the R-configuration are in general
more selective than the corresponding ligands with the
S-configuration at the D1 and D2 receptors with the

Hexahydropyrazinoquinolines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3175
exception of 33a and 33b. For example, while 32a with
the R-configuration and 32b with the S-configuration
have very similar affinities at the D3 receptor, 32a is 4
and 3 times more selective than 32b over the D1 and
D2 receptors, respectively.
A methoxyl substituent at any of the four positions
in the phenyl ring improves the selectivity for both the
R- and S-enantiomers but, depending upon the position,
influences the binding affinity at the D3 receptor dif-
ferently. The methoxyl substituent at C7 or C10 increases
the binding affinity by 2-4 times at the D3 receptor,
compared to the corresponding unsubstituted 32a or
32b. In contrast, the methoxyl substituent at C8 or C9
decreases the binding affinity by 2-5 times.
selectivity over closely related D1 and D2 receptors. For
example, 38a has a Ki value of 5.7 nM to the D3 receptor
and selectivity greater than 10000- and 1600-fold over
the D1 and D2 receptors, respectively. Our modeling
studies suggested that the high potency and outstanding
selectivity of compound 38a may be due to the ad-
ditional interaction of its methoxy group with Ser192,
the van der Waals contacts of the cyclohexyl group with
the side chains of Tyr373 and Thr369, and the hydro-
phobic contacts of the naphthyl tail with Leu89 and
Phe106 in the D3 receptor. Compound 38a represents
one of the most selective D3 ligands reported to date.
Experimental Section
Chemistry. Elemental analyses were performed by the
Department of Chemistry of the University of Michigan, Ann
Arbor, MI. Where molecular formulas are given, elemental
compositions were found to be within 0.3% of the theoretical
values unless otherwise noted. Optical rotations were deter-
mined in CHCl3 at 589 nm at 25 °C on a Perkin-Elmer 241
polarimeter. Single-crystal X-ray analysis was performed at
the Naval Research Laboratory, Washington, DC. 1H NMR
spectra were recorded at 300 MHz and 13C NMR spectra were
recorded at 75 MHz on a Bruker AVANCE300 spectrometer.
All NMR spectra were obtained in CDCl3 or DMSO-d6, and
results were recorded as parts per million (ppm) downfield
from tetramethylsilane (TMS). The following abbreviations are
used for multiplicity of NMR signals: s ) singlet, d ) doublet,
t ) triplet, q ) quartet, m ) multiplet, dd ) doublet of
doublets, dt ) doublet of triplets, dq ) doublet of quartets, br
) broad. All temperatures are given in degrees Celsius. All
starting materials, solvents, and silica gel were purchased from
Aldrich, Fisher, or Lancaster and were used without further
purification.
Interestingly, the most potent ligands for the D3
receptor are not the most selective over the D1 and D2
receptors. For example, 34a with a methoxyl group at
C8 position only has a moderate binding affinity at the
D3 receptor (Ki ) 67 nM) but has an outstanding
selectivity (>1400 times) over both the D1 and D2
receptors. On the other hand, 36a and 36b have a high
affinity for the D3 receptor (Ki ) 4.1 and 3.3 nM,
respectively) but only a modest selectivity over the D2
receptor.
Introduction of a rigid trans-cyclohexyl linker into 34a
and 34b significantly improves the binding affinity to
the D3 receptor and results in 38a and 38b with high
affinities for the D3 receptor while retaining the out-
standing selectivity against the D1 and D2 receptors. For
example, 38a has a Ki value of 5.7 nM to the D3 receptor
and selectivity greater than 10000- and 1600-fold over
the D1 and D2 receptors, respectively. However, when
a piperidinyl ring instead of a trans-cyclohexyl ring was
used as the rigid linker, the resulting compounds 40a
and 40b are 1000 times less potent than the corre-
sponding compounds 38a and 38b. Hence, the high
affinity and outstanding selectivity for 38a and 38b and
the dramatically reduced binding affinities of 40a and
40b to the D3 receptor compared to 38a and 38b suggest
that the linker region deserves further exploration in
future optimization efforts.
Our modeled complex structure of 38a and the D3
receptor (Figure 2c) indicates that the core structure of
38a mimics closely that of 3. The added methoxyl group
forms a hydrogen bond with Ser192 and is also close to
two potential hydrogen bond donors Ser193 and Ser196.
Additionally, the bulkier cyclohexyl group is in van der
Waals contact with the side chains of Tyr373 and
Thr369 not observed in 3. However, the constraint
imposed by the cyclohexyl group orients the hydrophobic
naphthyl tail to interact with hydrophobic residues
Leu89 and Phe106 in the D3 receptor. These additional
interactions and the rigid linker may explain the
improved binding affinity of 38a over that of 3.
In summary, guided by the predicted binding model
of compound 3 complexed with the D3 receptor, a series
of enantiomerically pure hexahydropyrazinoquinolines
with a methoxyl substituent at different positions of the
phenyl ring and/or with a bulkier rigid linker were
designed as new D3 ligands. These optically pure D3
receptor ligands were efficiently synthesized using a
newly developed enantiomerically selective synthetic
method. Our efforts led to the identification of high-
affinity ligands for the D3 receptor and outstanding
General Synthetic Route to Compounds 6a-e. At room
temperature, to the solution of quinoline-2-carboxylic acids 5
(20.0 mmol) in chloroform (100 mL) were added 1-[3-(di-
methylamino)propyl]-3-ethylcarbodiimide hydrochloride (ED-
CI- HCl, 25 mmol), 4-(dimethylamino)pyridine (DMAP, 25
mmol), and (S)-R-methylbenzylamine (22 mmol). The resulting
solution was refluxed for 12 h, then the solvent was removed
in vacuo and the residue was dissolved in ethyl acetate and
washed with saturated sodium chloride. Compound 6 was
obtained after purification by silica gel column chromatogra-
phy (hexane/ethyl acetate ) 1:1 to 2:1), yields ) 80-85%.
(S)-Quinoline-2-carboxylic acid (1-phenylethyl)amide
(6a): yield ) 85%; [R]25 176.8° (c 0.78, CHCl3); 1H NMR
D
(CDCl3, 300 MHz), δ 8.55 (d, J ) 7.81 Hz, 1H), 8.32 (m, 2H),
8.12 (d, J ) 8.49 Hz, 1H), 7.88 (d, J ) 8.16 Hz, 1H), 7.77 (td,
J ) 6.92, 1.42 Hz, 1H), 7.62 (td, J ) 8.05, 1.0 Hz, 1H), 7.48
(dd, J ) 7.86, 1.43 Hz, 2H), 7.38 (dd, J ) 7.11, 1.85 Hz, 2H),
7.29 (dd, J ) 7.18, 1.30 Hz, 1H), 5.40 (m, 1H), 1.70 (d, J )
6.93 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 163.63, 149.78,
146.49, 143.34, 137.48, 130.06, 129.73, 129.34, 128.72, 127.89,
127.77, 127.36, 126.33, 118.93, 48.94, 22.10.
(S)-5-Methoxyquinoline-2-carboxylic acid (1-phenyl-
ethyl)amide (6b): yield ) 83%; [R]25D 145.9° (c 0.68, CHCl3);
1H NMR (CDCl3, 300 MHz), δ 8.73 (d, J ) 8.64 Hz, 1H), 8.30
(d, J ) 8.64 Hz, 1H), 7.70-7.66 (m, 2H), 7.51-7.30 (m, 5H),
6.91 (d, J ) 7.26 Hz, 1H), 5.47-5.37 (m, 1H), 4.03 (s, 3H),
1.71 (d, J ) 6.90 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 163.66,
155.10, 149.90, 147.29, 143.31, 132.35, 130.03, 128.66, 127.30,
126.30, 121.92, 121.59, 117.94, 105.26, 55.79, 48.88, 22.04.
(S)-6-Methoxyquinoline-2-carboxylic acid (1-phenyl-
ethyl)amide (6c): yield ) 81%; [R]25 75.3° (c 1.06, CHCl3);
D
1H NMR (CDCl3, 300 MHz), δ 8.50 (d, J ) 8.03 Hz, 1H), 8.29
(d, J ) 8.49 Hz, 1H), 8.19 (d, J ) 8.54 Hz, 1H), 8.02 (d, J )
9.32 Hz, 1H), 7.50-7.47 (m, 2H), 7.43-7.36 (m, 3H), 7.32-
7.28 (m, 1H), 7.12 (d, J ) 2.7 Hz, 1H), 5.40 (m, 1H), 3.95 (s,
3H), 1.70 (d, J ) 6.90 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ
163.82, 158.82, 147.51, 143.42, 142.53, 135.89, 131.13, 130.63,
128.67, 127.29, 126.30, 123.20, 119.29, 104.84, 55.62, 48.83,
22.10.

3176 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Ding et al.
1
(S)-7-Methoxyquinoline-2-carboxylic acid (1-phenyl-
ethyl)amide (6d): yield ) 83%; [R]25D 190.4° (c 0.81, CHCl3);
1H NMR (CDCl3, 300 MHz), δ 8.56 (d, J ) 7.82 Hz, 1H), 8.23
(d, J ) 8.45 Hz, 1H), 8.19 (d, J ) 8.31 Hz, 1H), 7.76 (d, J )
8.97 Hz, 1H), 7.49 (d, J ) 7.20 Hz, 2H), 7.42-7.37 (m, 3H),
7.33-7.26 (m, 2H), 5.41 (m, 1H), 4.04 (s, 3H), 1.70 (d, J ) 6.91
Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 163.74, 161.09, 149.85,
148.28, 143.34, 137.03, 128.67, 127.31, 126.34, 124.76, 121.36,
116.89, 107.18, 55.57, 48.86, 22.01.
-26.5° (c 1.05, CHCl3); H NMR (CDCl3, 300 MHz), δ 7.37-
7.28 (m, 6H), 6.67-6.57 (m, 3H), 5.18 (m, 1H), 3.95-3.85 (m,
2H), 3.73 (s, 3H), 2.81-2.72 (m, 1H), 2.66-2.62 (m, 1H), 2.32-
2.28 (m, 1H), 2.00-1.94 (m, 1H), 1.46 (d, J ) 6.90 Hz, 3H);
13C NMR (CDCl3, 75 MHz), δ 172.87, 152.66, 143.03, 135.71,
128.70, 127.42, 126.24, 123.67, 116.18, 114.33, 113.22, 55.70,
55.60, 48.43, 25.27, 24.77, 21.80.
(2R,3′S)-6-Methoxy-1,2,3,4-tetrahydroquinoline-2-car-
boxylic acid (1-phenylethyl)amide (9a): yield ) 37%; [R]25
D
76.0° (c 1.05, CHCl3); 1H NMR (CDCl3, 300 MHz), δ 7.29-7.18
(m, 6H), 6.68-6.60 (m, 3H), 5.15 (m, 1H), 4.05-3.93 (m, 2H),
3.77 (s, 3H), 2.72-2.65 (m, 1H), 2.55-2.51 (m, 1H), 2.28-2.22
(m, 1H), 1.97-1.88 (m, 1H), 1.50 (d, J ) 6.94 Hz, 3H); 13C NMR
(CDCl3, 75 MHz), δ 172.91, 152.61, 143.27, 135.69, 128.47,
127.04, 125.68, 123.62, 116.29, 114.23, 113.20, 55.63, 55.50,
48.28, 25.10, 24.75, 22.16.
(S)-8-Methoxyquinoline-2-carboxylic acid (1-phenyl-
ethyl)amide (6e): yield ) 80%; [R]25 203° (c 0.47, CHCl3);
D
1H NMR (CDCl3, 300 MHz), δ 8.56 (d, J ) 7.82 Hz, 1H), 8.35
(d, J ) 8.48 Hz, 1H), 8.28 (d, J ) 8.49 Hz, 1H), 7.72-7.26 (m,
5H), 7.10 (d, J ) 7.52 Hz, 2H), 5.40 (m, 1H), 4.08 (s, 3H), 1.70
(d, J ) 6.90 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 163.81,
155.47, 148.70, 143.37, 130.55, 128.63, 128.26, 127.25, 126.37,
119.61, 119.55, 108.33, 55.01, 48.99, 22.03.
(2S,3′S)-7-Methoxy-1,2,3,4-tetrahydroquinoline-2-car-
General Synthetic Route to Compounds 7a-11a and
7b-11b. At 0 °C, to the mixture of lithium aluminum hydride
(1.9 g, 50 mmol) in tetrahydrofuran (100 mL), a solution of
compound 6a (10 mmol) in tetrahydrofuran (30 mL) was added
dropwise. The mixture was stirred at 0 °C for 2 h, then at room
temperature overnight. The mixture was cooled to 0 °C, and
a solution of NaOH (1.90 g) in water (4 mL) was added
dropwise (very slowly) to quench the reaction, followed by
addition of another 4 mL of water. The solid was removed by
filtration, and the filtrate was concentrated in vacuo. The
residue was dissolved in EtOH (70 mL), and at room temper-
ature 1 M aqueous KOH (70 mL) was added followed by
addition of Al-Ni (20 g) (slowly). After the mixture was stirred
for 1.5 h, the solid was removed by filtration and the filtrate
was concentrated in vacuo. The residue was dissolved in water
(30 mL) and extracted with CHCl3, dried over Na2SO4, and
purified on silica gel column chromatography (hexane/ethyl
acetate ) 1:2). Compounds 7a and 7b were obtained (∼3:1).
Similar procedures provided 8a-11a and 8b-11b.
(2S,3′S)-1,2,3,4-Tetrahydroquinoline-2-carboxylic acid
(1-phenylethyl)amide (7b): yield ) 16%; [R]25D -22.6° (c 4.4,
CHCl3); 1H NMR (CDCl3, 300 MHz), δ 7.32-7.25 (m, 5H),
7.12-6.97 (m, 3H), 6.70 (t, J ) 7.29 Hz, 1H), 6.56 (d, J ) 7.88
Hz, 1H), 5.15 (m, 1H), 4.15 (d, J ) 5.06 Hz, 1H), 3.90 (dd, J )
10.13, 5.02, 1H), 2.71-2.68 (m, 1H), 2.61-2.56 (m, 1H), 2.32-
2.28 (m, 1H), 1.91-1.85 (m, 1H), 1.43 (d, J ) 6.90 Hz, 3H);
13C NMR (CDCl3, 75 MHz), δ 172.82, 142.99, 142.04, 129.16,
128.68, 127.41, 127.04, 126.24, 122.27, 118.34, 114.83, 55.38,
48.49, 24.84, 24.47, 21.78.
boxylic acid (1-phenylethyl)amide (10b): yield ) 15%;
[R]25 -39.1° (c 0.95, CHCl3); H NMR (CDCl3, 300 MHz), δ
1
D
7.38-7.28 (m, 5H), 7.03 (d, J ) 8.37 Hz, 1H), 6.92 (d, J ) 8.28
Hz, 1H), 6.33 (dd, J ) 8.26, 2.47 Hz, 1H), 6.19 (d, J ) 2.44
Hz, 1H), 5.20 (m, 1H), 4.15-4.11 (m,1H), 3.99-3.95 (m, 1H),
3.77 (s, 3H), 2.71-2.67 (m, 1H), 2.60-2.56 (m, 1H), 2.37-2.31
(m, 1H), 1.97-1.92 (m, 1H), 1.46 (d, J ) 6.90 Hz, 3H); 13C NMR
(CDCl3, 75 MHz), δ 172.71, 159.00, 142.94, 142.75, 129.90,
128.74, 127.48, 126.28, 114.86, 104.21, 100.35, 55.39, 55.22,
48.51, 24.92, 24.07, 21.74.
(2R,3′S)-7-Methoxy-1,2,3,4-tetrahydroquinoline-2-car-
boxylic acid (1-phenylethyl)amide (10a): yield ) 40%;
[R]25 103.5° (c 0.60, CHCl3); 1H NMR (CDCl3, 300 MHz), δ
D
7.29-7.18 (m, 5H), 7.07 (d, J ) 7.43 Hz, 1H), 6.91 (d, J ) 8.28
Hz, 1H), 6.33 (dd, J ) 8.27, 2.48 Hz, 1H), 6.24 (d, J ) 2.44
Hz, 1H), 5.17 (m, 1H), 4.21-4.17 (m, 1H), 4.02-3.98 (m, 1H),
3.78 (s, 3H), 2.67-2.60 (m, 1H), 2.48-2.43 (m, 1H), 2.30-2.24
(m, 1H), 1.94-1.87 (m, 1H), 1.50 (d, J ) 6.95 Hz, 3H); 13C NMR
(CDCl3, 75 MHz), δ 172.81, 158.93, 143.22, 142.71, 129.93,
128.55, 127.15, 125.77, 114.85, 104.24, 100.43, 55.37, 55.18,
48.44, 25.00, 24.00, 22.18.
(2S,3′S)-8-Methoxy-1,2,3,4-tetrahydroquinoline-2-car-
boxylic acid (1-phenylethyl)amide (11b): yield ) 17%;
[R]25 -25.5° (c 0.31, CHCl3); H NMR (CDCl3, 300 MHz), δ
1
D
7.48-7.28 (m, 5H), 7.16 (d, J ) 7.80 Hz, 1H), 6.70 (m, 3H,
5.22 (m, 1H), 4.59 (d, J ) 7.74 Hz, 1H), 4.06-4.01 (m,1H),
3.87 (s, 3H), 2.80-2.74 (m, 1H), 2.63-2.59 (m, 1H), 2.44-2.40
(m, 1H), 1.90-1.80 (m, 1H), 1.46 (d, J ) 6.83 Hz, 3H); 13C NMR
(CDCl3, 75 MHz), δ 172.95, 146.31, 142.97, 131.48, 128.55,
127.24, 126.16, 122.30, 121.08, 117.08, 55.26, 54.81, 48.33,
24.45, 24.17, 21.78.
(2R,3′S)-1,2,3,4-Tetrahydroquinoline-2-carboxylic acid
(1-phenylethyl)amide (7a): yield ) 50%; [R]25D 64.8° (c 1.28,
CHCl3); 1H NMR (CDCl3, 300 MHz), δ 7.28-7.12 (m, 6H), 7.04
(t, J ) 7.68 Hz, 1H), 6.97 (d, J ) 7.33 Hz, 1H), 6.71 (t, J )
7.26 Hz, 1H), 6.64 (d, J ) 7.91 Hz, 1H), 5.18-5.08 (m, 1H),
4.23 (br, 1H), 3.65 (t, J ) 6.00 Hz, 1H), 2.70-2.62 (m, 1H),
2.51-2.41 (m, 1H), 2.28-2.21 (m, 1H), 1.91-1.84 (m, 1H), 1.47
(d, J ) 6.95 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 172.89,
143.24, 141.96, 129.31, 128.59, 127.19, 127.95, 125.80, 122.43,
118.63, 114.99, 55.50, 48.46, 24.82, 24.68, 22.19.
(2R,3′S)-8-Methoxy-1,2,3,4-tetrahydroquinoline-2-car-
boxylic acid (1-phenylethyl)amide (11a): yield ) 40%;
[R]25 30.0° (c 1.05, CHCl3); 1H NMR (CDCl3, 300 MHz), δ
D
7.31-7.19 (m, 6H), 6.71-6.66 (m, 3H), 5.18 (m, 1H), 4.60 (d,
J ) 4.76 Hz, 1H), 4.08-4.03 (m, 1H), 3.89 (s, 3H), 2.74-2.67
(m, 1H), 2.54-2.49 (m, 1H), 2.36-2.30 (m, 1H), 1.91-1.87 (m,
1H), 1.46 (d, J ) 6.90 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ
173.12, 146.42, 143.32, 131.53, 128.52, 127.09, 125.80, 122.40,
121.22, 117.27, 107.61, 55.37, 54.98, 48.37, 24.53, 24.48, 22.11.
(2S,3′S)-5-Methoxy-1,2,3,4-tetrahydroquinoline-2-car-
boxylic acid (1-phenylethyl)amide (8b): yield ) 13%; [R]25
D
General Synthetic Route to Compounds 12a-16a and
12b-16b. At 0 °C, to the solution of compound 7a (1 mmol)
in tetrahydrofuran, (5 mL), 2 M BH3-Me2S in THF (2.0 mL)
was added dropwise, followed by stirring at room temperature
for 80 h. An amount of 6 M HCl (1 mL) was added dropwise
to quench the reaction. The reaction mixture was neutralized
with saturated NaHCO3, extracted with chloroform, and dried
over Na2SO4, and the solvent was removed in vacuo. The
residue was dissolved in 1,4-dioxane (30 mL), and (Boc)2O (1.2
mmol) was added. The resulting solution was stirred at room
temperature for 2 days. After purification by silica gel column
chromatography, N-Boc-(1-phenylethyl)-(1,2,3,4-tetrahydro-
quinolin-2-ylmethyl)amine was obtained in good yield (hexane/
ethyl acetate ) 3:1). At 0 °C, to a solution of the resulting
product (N-Boc-(1-phenylethyl)-(1,2,3,4-tetrahydroquinolin-2-
ylmethyl)amine, 1.0 mmol) and pyridine (2.0 mmol) in 5 mL
THF, chloroacetyl chloride (1.5 mmol) was added. The mixture
39.2° (c 0.38, CHCl3); 1H NMR (CDCl3, 300 MHz), δ 7.29-7.03
(m, 7H), 6.34 (d, J ) 8.21 Hz, 2H), 5.21-5.13 (m, 1H), 4.24
(m, 1H), 3.97 (m, 1H), 3.81 (s, 3H), 2.78-2.72 (m, 1H), 2.44-
2.41 (m, 1H), 2.23-2.18 (m, 1H), 1.98-1.91 (m, 1H), 1.50 (d,
J ) 6.93 Hz, 3H).
(2R,3′S)-5-Methoxy-1,2,3,4-tetrahydroquinoline-2-car-
boxylic acid (1-phenylethyl)amide (8a): yield ) 40%; [R]25
D
1
-17.1° (c 0.81, CHCl3); H NMR (CDCl3, 300 MHz), δ 7.40-
7.28 (m, 5H), 7.04-6.99 (m, 2 H), 6.35-6.27 (m, 2H), 5.19 (m,
1H), 4.19 (br, 1H), 3.93-3.89 (m, 1H), 3.83 (s, 3H), 2.87-2.81
(m, 1H), 2.51-2.46 (m, 1H), 2.30-2.24 (m, 1H), 1.98-1.92 (m,
1H), 1.30 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ
172.72, 157.45, 142.97, 142.95, 128.61, 127.32, 126.92, 126.16,
110.42, 108.06, 100.33, 55.26, 55.09, 48.42, 26.90, 24.37, 21.71.
(2S,3′S)-6-Methoxy-1,2,3,4-tetrahydroquinoline-2-car-
boxylic acid (1-phenylethyl)amide (9b): yield ) 18%; [R]25
D

Hexahydropyrazinoquinolines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3177
was stirred for 1 h at room temperature. The reaction was
quenched by ice-water and extracted with ethyl acetate. The
organic phase was washed with saturated NaCl aqueous
solution and dried over Na2SO4. The solvent was removed in
vacuo, and the residue was dissolved in THF (2 mL). To the
solution was added trifluoroacetic acid (2 mL), and the
resulting solution was stirred at room temperature for 2 h and
then refluxed for 1 h. The solvent was removed, the residue
was dissolved in N,N-dimethylformamide (5 mL), K2CO3 (3
mmol) was added, and the mixture was heated at 50 °C for 1
h. After being cooled to room temperature, the mixture was
diluted with water and extracted with ethyl acetate. The
organic phase was washed with saturated NaCl aqueous
solution and dried over Na2SO4. The solvent was removed in
vacuo, and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate ) 3:1). 12a was ob-
tained.
9.00, 2.82 Hz, 1H), 6.65 (d, J ) 2.68 Hz, 1H), 3.79 (s, 3H),
3.60-3.57 (m, 1H), 3.44-3.27 (m, 3H), 2.91-2.85 (m, 3H), 2.54
(dd, J ) 12.0, 2.39 Hz, 1H), 2.22-2.07 (m, 1H), 1.89-1.85 (m,
1H), 1.43 (d, J ) 6.63 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ
166.32, 156.36, 142.81, 131.22, 130.52, 128.48, 127.45, 127.35,
125.73, 113.46, 111.45, 63.96, 56.52, 55.34, 54.72, 53.18, 28.53,
26.48, 19.93.
(4aS,1′S)-9-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydropyrazino[1,2-a]quinolin-1-one (15b): yield )
36%; [R]25D 5.3° (c 0.30, CHCl3); 1H NMR (CDCl3, 300 MHz), δ
7.74 (d, J ) 2.55 Hz, 1H), 7.37-7.28 (m, 5H), 7.00 (d, J ) 8.45,
1H), 6.67 (dd, J ) 8.44, 2.60 Hz, 1H), 3.83-3.77 (m, 1H), 3.78
(s, 3H), 3.65-3.62 (m, 1H), 3.41-3.36 (m, 1H), 3.09 (d, J )
16.51 Hz, 1H), 2.96 (m, 1H), 2.81-2.76 (m, 2H), 2.30-2.07 (m,
1H), 1.88-1.83 (m, 2H), 1.43 (d, J ) 6.60 Hz, 3H); 13C NMR
(CDCl3, 75 MHz), δ 166.97, 157.32, 142.98, 137.87, 129.52,
128.53, 127.35, 127.32, 120.76, 111.98, 108.48, 63.98, 56.99,
55.31, 54.83, 53.94, 28.40, 25.40, 20.12.
(4aR,1′S)-9-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydropyrazino[1,2-a]quinolin-1-one (15a): yield )
45%; [R]25D 12.3° (c 0.32, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.61 (d, J ) 2.62 Hz, 1H), 7.37-7.28 (m, 5H), 7.02 (d, J )
8.48, 1H), 6.68 (dd, J ) 8.43, 2.65 Hz, 1H), 3.80 (s, 3H), 3.63-
3.57 (m, 1H), 3.44-3.35 (m, 3H), 2.94-81 (m, 3H), 2.56-2.54
(m, 1H), 1.89-1.85 (m, 2H), 1.44 (d, J ) 6.63 Hz, 3H); 13C NMR
(CDCl3, 75 MHz), δ 166.69, 157.19, 142.68, 138.51, 129.55,
128.47, 127.42, 127.35, 120.98, 112.13, 109.00, 63.86, 56.71,
55.32, 54.87, 53.19, 28.53, 25.55, 19.84.
(4aS,1′S)-10-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydropyrazino[1,2-a]quinolin-1-one (16b): yield )
41%; [R]25D -50.7° (c 4.8, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.38-7.26 (m, 5H), 7.15, (t, J ) 8.10 Hz, 1H), 6.85 (d, J )
8.21 Hz, 1H), 6.77 (d, J ) 7.50 Hz, 1H), 3.88 (s, 3H), 3.75-
3.67 (m, 2H), 3.49 (q, J ) 6.65 Hz, 1H), 3.17 (d, J ) 16.17 Hz,
1H), 2.90 (dd, J ) 8.87, 7.31 Hz, 1H), 2.70-2.65 (m, 2H), 2.50-
2.44 (m, 1H), 2.03-1.84 (m, 2H), 1.44 (d, J ) 6.66 Hz, 3H);
13C NMR (CDCl3, 75 MHz), δ 156.67, 153.58, 142.92, 136.04,
128.45, 127.47, 127.28, 127.14,126.91, 119.63, 110.09, 63.91,
56.13, 55.87, 53.93, 53.06, 29.69, 25.46, 19.67.
With the same procedure, compounds 13a-16a and 12b-
16b were prepared.
(4aS,1′S)-3-(1-Phenylethyl)-2,3,4,4a,5,6-hexahydropy-
razino[1,2-a]quinolin-1-one (12b): yield ) 53%; [R]25D 18.0°
(c 0.1, CHCl3); 1H NMR (CDCl3, 300 MHz), δ 8.03 (d, J ) 8.04
Hz, 1H), 7.34-7.05 (m, 8H), 3.76 (d, J ) 16.63 Hz, 1H), 3.64
(m, 1H), 3.40-3.38 (m, 1H), 3.08 (d, J ) 16.44 Hz, 1H), 2.96
(d, J ) 9.47 Hz, 1H), 2.86 (t, J ) 6.44 Hz, 2H), 2.32-2.25 (m,
1H), 1.87 (t, J ) 6.63 Hz, 2H), 1.42 (d, J ) 6,37 Hz, 3H); 13C
NMR (CDCl3, 75 MHz), δ 166.91, 143.05, 137.33, 129.03,
128.94, 128.59, 127.40, 125.88, 124.58, 124.21, 64.07, 56.99,
54.68, 53.95, 28.49, 26.11, 20.17.
(4aR,1′S)-3-(1-Phenylethyl)-2,3,4,4a,5,6-hexahydropy-
razino[1,2-a]quinolin-1-one (12a): yield ) 50%; [R]25 5.0°
D
(c 0.1, CHCl3); 1H NMR (CDCl3, 300 MHz), δ 7.93 (d, J ) 8.14
Hz, 1H), 7.35-7.06 (m, 8H), 3.62-3.57 (m, 1H), 3.45-3.41 (m,
1H), 3.39-3.27 (m, 2H), 2.97-2.81 (m, 3H), 2.54 (dd, J ) 11.89,
5.84 Hz, 1H), 2.23-2.08 (m, 1H), 1.90-1.83 (m, 1H), 1.42 (d,
J ) 6.30 HZ, 3H); 13C NMR (CDCl3, 75 MHz), δ 166.60, 142.80,
137.97, 129.12, 129.07, 128.51, 127.47, 127.39, 125.66, 124.83,
124.67, 63.95, 56.66, 54.71, 53.20, 28.56, 26.27, 19.91.
(4aS,1′S)-7-Methoxyl-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydropyrazino[1,2-a]quinolin-1-one (13b): yield )
37%; [R]25D -5.7° (c 0.79, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 7.57 (d, J ) 8.33 Hz, 1H), 7.37-7.26 (m, 5H), 7.16 (t, J )
8.30 Hz, 1H), 6.65 (d, J ) 8.15 Hz, 1H), 3.83 (s, 3H), 3.58-
3.53 (m, 1H), 3.45-3.24 (m, 3H), 2.91-2.53 (m, 4H), 2.16-
2.07 (m, 1H), 1.93-1.89 (m, 1H), 1.43 (d, J ) 6.89 Hz, 3H);
13C NMR (CDCl3, 75 MHz), δ 166.66, 157.30, 142.87, 138.78,
128.50, 127.46, 127.36, 125.72, 118.17, 117.02, 105.91, 64.00,
56.75, 55.38, 54.55, 53.19, 28.12, 21.10, 20.00.
(4aR,1′S)-10-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-pyrazino[1,2-a]quinolin-1-one (16a): yield )
43%; [R]25D 75.2° (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz), δ
7.37-7.26 (m, 5H), 7.14 (t, J ) 7.71 Hz, 1H), 6.82 (d, J ) 8.19
Hz, 1H), 6.77 (d, J ) 7.54 Hz, 1H), 3.86, (s, 3H), 3.61-3.45
(m, 3H), 3.27 (d, J ) 15.54 Hz, 1H), 2.89-2.63 (m, 4H), 2.35-
2.23 (m, 1H), 1.88-1.79 (m, 1H), 1.44 (d, J ) 6.65 Hz, 3H);
13C NMR (CDCl3, 75 MHz), δ 165.55, 153.57, 142.86, 134.69,
128.43, 128.07, 127.49, 127.28, 126.86, 120.16, 109.78, 64.07,
55.88, 54.35, 52.41, 29.17, 25.60, 20.00.
(4aR,1′S)-7-Methoxyl-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydropyrazino[1,2-a]quinolin-1-one (13a): yield )
42%; [R]25D 35.9° (c 0.37, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.68 (d, J ) 8.42 Hz, 1H), 7.37-7.19(m, 5H), 7.15 (t, J )
8.28 Hz, 1H), 6.64 (d, J ) 8.1 Hz, 1H), 3.83 (s, 3H), 3.75 (dd,
J ) 2.28, 16.5 Hz, 1H), 3.61-3.58 (m, 1H), 3.40 (m, 1H), 3.08
(d, J ) 16.5 Hz, 1H), 3.02-2.95 (m, 1H), 2.79-2.76 (m, 1H),
2.70-2.64 (m, 1H), 2.33-2.26 (m, 1H), 1.93-1.84 (m, 2H), 1.43
(d, J ) 6.66 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 166.99,
157.21, 143.03, 138.12, 128.56, 127.39, 125.83, 117.90, 116.45,
105.70, 64.00, 57.11, 55.39, 54.45, 53.85, 28.05, 20.75, 20.13.
(4aS,1′S)-8-Methoxy-3-(1-Phenylethyl)-2,3,4,4a,5,6-
hexahydropyrazino[1,2-a]quinolin-1-one (14b): yield )
55%; [R]25D 25.5° (c 0.44, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.98 (d, J ) 9.09 Hz, 1H), 7.45-7.26 (m, 5H), 6.75 (dd, J )
9.30, 3.00 Hz, 1H), 6.63 (d, J ) 2.88 Hz, 1H), 3.78 (s, 3H),
3.88-3.71 (m, 1H), 3.67-3.58 (m, 1H), 3.43-3.36 (m, 1H), 3.07
(d, J ) 16.3 Hz, 1H), 2.98-2.90 (m, 1H), 2.82 (t, J ) 6.90 Hz,
2H), 2.32-2.25 (m, 1H), 1.90-1.78 (m, 2H), 1.42 (d, J ) 6.63
Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 166.44, 156.13, 142.94,
130.50, 130.33, 128.49, 127.30, 125.66, 125.27, 113.26, 111.58,
63.97, 56.77, 55.25, 54.57, 53.78, 28.40, 26.24, 20.07.
General Synthetic Route to Compounds 17a-21a and
17b-21b. At room temperature, to a suspension of NaBH4 (2
mmol) in tetrahydrofuran (5 mL), BF3-Et2O (3 mmol) was
added, and the mixture was stirred for 5 min. To the resulting
mixture, compound 12a (1 mmol in 2 mL of THF) was added
dropwise. The mixture was refluxed for 2.5 h and cooled to
room temperature. In an ice bath, the reaction was quenched
by 6 N HCl, then the mixture was refluxed for 1 h and cooled
to room temperature. The resulting mixture was neutralized
by adding saturated NaHCO3 and extracted with CHCl3. The
organic phase was washed with saturated NaCl aqueous
solution and dried over Na2SO4. The solvent was removed in
vacuo, and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate ) 2:1). 17a was ob-
tained.
Under the same procedure, compounds 18a-21a and 17b-
21b were obtained.
(4aS,1′S)-3-(1-Phenylethyl)-2,3,4,4a,5,6-hexahydro-1H-
pyrazino[1,2-a]quinoline (17b): yield ) 83%; [R]25 -8.7°
D
1
(c 0.6, CHCl3); H NMR (CDCl3, 300 MHz), δ 7.34-7.23 (m,
5H), 7.06 (t, J ) 8.20 Hz, 1H), 6.95 (d, J ) 7.34 Hz, 1H), 6.79
(d, J ) 8.23 Hz, 1H), 6.67 (t, J ) 7.28 Hz, 1H), 3.79 (dt, J )
11.83, 2.73 Hz, 1H), 3.35 (q, J ) 6.69 Hz, 1H), 3.21-3.17 (m,
1H), 2.95-2.65 (m, 5H), 2.24 (td, J ) 8.0, 3.17 Hz, 1H), 1.81
(t, J ) 10.62 Hz, 1H), 1.74-1.60 (m, 2H), 1.39 (d, J ) 6.68 Hz,
(4aR,1′S)-8-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydropyrazino[1,2-a]quinolin-1-one (14a): yield )
1
43%; [R]25 5.2° (c 0.17, CHCl3); NMR (CDCl3, 300 MHz), δ
D
7.87 (d, J ) 9.00 Hz, 1H), 7.36-7.28 (m, 5H), 6.75 (dd, J )

3178 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Ding et al.
3H); 13C NMR (CDCl3, 75 MHz), δ 146.40, 144.07, 129.23,
123.32, 127.62, 126.95, 126.90, 124.48, 117.91, 112.33, 64.89,
56.71, 55.25, 50.44, 46.84, 27.19, 26.98, 20.11.
2H), 2.86-2.79 (m, 4H), 2.20-1.69 (m, 4H), 1.44 (d, J ) 6.68
Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 158.90, 147.23, 143.75,
129.54, 128.25, 127.60, 126.93, 117.04, 102.32, 99.20, 64.74,
56.80, 55.16, 51.05, 46.72, 28.99, 27.53, 26.24, 19.76.
(4aS,1′S)-10-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinoline (21b): yield )
45%; [R]25D 70.7° (c 0.75, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.39-7.23 (m, 5H), 6.81 (dd, J ) 7.32, 7.27 Hz, 1H), 6.69-
6.67 (m, 2H), 3.91-3.77 (m, 1H), 3.79 (s, 3H), 3.40 (q, J ) 6.70
Hz, 1H), 3.08-2.68 (m, 6H), 2.56-2.44 (m, 2H), 2.07-2.00 (m,
1H), 1.63-1.59 (m, 1H), 1.40 (d, J ) 6.69 Hz, 3H); 13C NMR
(CDCl3, 75 MHz), δ 151.19, 144.32, 136.87, 129.17, 128.21,
127.66, 126.80, 122.04, 120.62, 109.36, 64.73, 57.72, 55.87,
55.35, 51.61, 48.79, 28.61, 23.73, 19.66.
(4aR,1′S)-3-(1-Phenylethyl)-2,3,4,4a,5,6-hexahydro-1H-
pyrazino[1,2-a]quinoline (17a): yield ) 75%; [R]25D -21.0°
1
(c 0.73, CHCl3); H NMR (CDCl3, 300 MHz), δ 7.41-7.20 (m,
5H), 7.04 (t, 8.25 Hz, 1H), 6.95 (d, J ) 7.31 Hz, 1H), 6.72 (d,
J ) 8.25 Hz, 1H), 6.65 (t, 7.29 Hz, 1H), 3.64-3.60 (m, 1H),
3.35 (q, J ) 6.68 Hz, 1H), 3.09-3.02 (m, 2H), 2.87-2.69 (m,
4H), 2.12-1.68 (m, 4H), 1.38 (d, J ) 6.68 Hz, 3H); 13C NMR
(CDCl3, 75 MHz), δ 146.37, 143.86, 129.16, 128.24, 127.60,
126.91, 126.85, 124.42, 117.87, 112.29, 64.75, 56.82, 55.30,
51.15, 46.77, 27.37, 27.02, 19.79.
(4aS,1′S)-7-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinoline (18b): yield )
63%; [R]25D 3.8° (c 0.93, CHCl3); 1H NMR (CDCl3, 300 MHz), δ
7.37-7.29 (m, 5H), 7.05 (dd, J ) 8.2, 8.3 Hz, 1H), 6.48 (d, J )
8.4 Hz, 1H), 6.35 (d, J ) 8.1 Hz, 1H), 3.82 (s, 3H), 3.68-3.65
(m, 1H), 3.40 (q, J ) 6.7 Hz, 1H), 3.14-3.04 (m, 2H), 2.89-
2.61 (m, 4H), 2.17-2.08 (m, 1H), 2.00-1.91 (m, 2H), 1.77-
1.72 (m, 1H), 1.42 (d, J ) 7.00 Hz, 3H); 13C NMR (CDCl3, 75
MHz), δ 157.42, 147.48, 143.96, 128.25, 127.61, 126.91, 126.67,
112.48, 105.80, 100.37, 64.79, 56.80, 55.30, 54.72, 51.28, 47.31,
26.82, 20.51, 19.88.
(4aR,1′S)-7-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinoline (18a): yield )
54%; [R]25D -22.8° (c 0.90, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.37-7.27 (m, 5H), 7.08 (dd, J ) 8.22, 8.29 Hz, 1H), 6.53 (d,
J ) 8.43 Hz, 1H), 8.35 (d, J ) 8.13 Hz, 1H), 3.80 (s, 3H), 3.37
(q, J ) 6.64 Hz, 1H), 3.24-3.20 (m, 1H), 2.94-2.72 (m, 5H),
2.57-2.53 (m, 1H), 2.31-2.26 (m, 1H), 1.85-1.62 (m, 3H), 1.42
(d, J ) 6.66 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 157.46,
147.49, 144.10, 128.31, 127.61, 126.94, 126.70, 112.52, 105.82,
100.41, 64.91, 57.69, 55.33, 54.64, 50.55, 47.36, 26.63, 20.44,
20.14.
(4aS,1′S)-8-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinoline (19b): yield )
60%; [R]25D 9.0° (c 1.24, CHCl3); 1H NMR (CDCl3, 300 MHz), δ
7.35-7.26 (m, 5H), 6.75 (d, J ) 8.97 Hz, 1H), 6.67 (dd, J )
8.76, 2.84 Hz, 1H), 6.57 (d, J ) 3.99 Hz, 1H), 3.74 (s, 3H),
3.73-3.69 (m, 1H), 3.36 (q, J ) 6.65 Hz, 1H), 3.20 (dd, J )
10.91, 2.50 Hz, 1H), 2.87-2.78 (m, 3H), 2.73-2.65 (m, 2H),
2.30 (td, J ) 11.37, 3.07 Hz, 1H), 1.83 (t, J ) 10.40 Hz, 1H),
1.73-1.66 (m, 2H), 1.40 (d, J ) 6.68 Hz, 3H); 13C NMR (CDCl3,
75 MHz), δ 152.09, 144.05, 140.70, 128.27, 127.58, 126.90,
125.93, 114.83, 113.50, 112.08, 64.86, 57.56, 55.62, 55.55,
50.44, 47.58, 27.25, 27.17, 20.10.
(4aR,1′S)-8-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinoline (19a): yield )
57%; [R]25D -23.5° (c 1.33, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.36-7.27 (m, 5H), 6.73-6.60 (m, 3H), 3.78 (s, 3H), 3.59-
3.55 (m, 1H), 3.39 (q, J ) 6.68 Hz, 1H), 3.10-2.66 (m, 6H),
2.15 (td, J ) 11.45, 3.21 Hz, 1H), 1.99 (t, J ) 10.45 Hz, 1H),
1.89-1.80 (m, 2H), 1.42 (d, J ) 6.68 Hz, 3H); 13C NMR (CDCl3,
75 MHz), δ 152.11, 143.92, 140.73, 128.26, 127.62, 126.92,
125.94, 114.83, 113.55, 112.09, 64.77, 56.76, 55.73, 55.56,
51.18, 47.58, 27.46, 27.27, 19.84.
(4aR,1′S)-10-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinoline (21a): yield )
52%; [R]25 -103.6° (c 0.73, CHCl3); 1H NMR (CDCl3, 300
D
MHz), δ 7.39-7.23 (m, 5H), 6.85 (dd, J ) 7.77, 7.75 Hz, 1H),
6.70-6.67 (m, 2H), 3.79 (s, 3H), 3.58 (m, 1H), 3.38 (q, J ) 6.68
Hz, 1H), 3.15-3.02 (m, 2H), 2.90-2.72 (m, 4H), 2.59-2.44 (m,
2H), 2.17-2.11 (m, 1H), 1.62-1.57 (m, 1H), 1.40 (d, J ) 6.69
Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ 151.51, 144.49, 137.10,
129.41, 128.19, 127.55, 126.76, 122.00, 121.00, 108.99, 64.91,
57.11, 56.22, 55.26, 51.24, 48.45, 28.52, 22.81, 20.20.
General Synthetic Route to Compounds 32a-36a and
32b-36b. To a solution of compound 17a (10 mmol) in MeOH
(30 mL), Pd-C (10%, 0.2 g) was added. The mixture was
stirred under H2 (1.0 atm) for 24 h. The Pd-C was removed
by filtration, and the solvent was removed in vacuo. The
residue was dissolved in CH3CN (30 mL), and Cs2CO3 (15
mmol) and N-(4-bromobutyl)phthalimide (13 mmol) were
added. The resulting mixture was refluxed for 3 h. The solvent
was removed, and the residue was dissolved in ethyl acetate
and water. The organic phase was washed with saturated
NaCl aqueous solution and dried over Na2SO4. The solvent was
removed in vacuo, and the residue was purified by silica gel
column chromatography to give 27a. By use of the the same
procedure, compound 27b was prepared.
To a solution of compound 27a (5 mmol) in ethanol (10 mL),
hydrazine (7.0 mmol) was added. The resulting solution was
refluxed for 2 h. The solvent was removed, and the residue
was dissolved in CHCl3 and water. The organic phase was
dried over Na2SO4. The solvent was removed in vacuo, and
the residue was dissolved in 10 mL of CHCl3. To this solution
2-naphthoyl chloride (6 mmol) and triethylamine (0.5 mL) were
added. The resulting solution was refluxed for 4 h. The solvent
was removed, and the residue was dissolved in ethyl acetate
and water. The organic phase was washed with saturated
NaCl aqueous solution and dried over Na2SO4. The solvent was
removed in vacuo, and the residue was purified by silica gel
column chromatography to give compound 32a.
Compounds 33a-36a and 32b-36b were prepared using
the same procedure.
(S)-Naphthalene-2-carboxylic acid [4-(1,2,4,4a,5,6-hexa-
hydropyrazino[1,2-a]quinolin-3-yl)-butyl]amide (32b):
yield ) 57%; [R]25D 4.8° (c 0.48, CHCl3); 1H NMR (CDCl3, 300
MHz), δ 8.27 (s, 1H), 7.90-7.81 (m, 4H), 7.59-7.50 (m, 2H),
7.09 (t, J ) 8.09 Hz, 1H), 6.96 (t, J ) 7.65 Hz, 2H), 6.77 (d, J
) 8.58 Hz, 1H), 6.71 (t, J ) 7.26 Hz, 1H), 3.74 (d, J ) 11.53
Hz, 1H), 3.57 (m, 2H), 3.04-2.63 (m, 6H), 2.48 (t, J ) 6.65
Hz, 2H), 2.24-2.17 (m, 1H), 1.92 (t, J ) 1073 Hz, 1H), 1.87-
1.60 (m, 6H); 13C NMR (CDCl3, 75 MHz), δ 167.85, 146.10,
134.60, 132.54, 132.27, 129.25, 128.78, 128.40, 127.73, 127.49,
127.19, 126.93, 126.70, 124.43, 123.72, 118.10, 112.38, 59.81,
57.74, 54.82, 53.22, 46.37, 39.99, 27.33, 27.17, 26.80, 24.32.
Anal. Calcd for C27H31N3O: C, 78.42; H, 7.56; N, 10.16.
Found: C, H, N.
(4aS,1′S)-9-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinoline (20b): yield )
50%; [R]25D 27.6° (c 0.29, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.37-7.28 (m, 5H), 6.88 (d, J ) 8.15 Hz, 1H), 6.39 (d, J )
2.36 Hz, 1H), 6.28 (dd, J ) 8.16, 2.40 Hz, 1H), 3.81-3.74 (m,
1H), 3.79 (s, 3H), 3.38 (q, J ) 6.68 Hz, 1H), 3.30-2.72 (m, 6H),
2.30-2.26 (m, 1H), 1.82 (t, J ) 10.67 Hz, 1H), 1.75-1.70 (m,
2H), 1.42 (d, J ) 6.69 Hz, 3H); 13C NMR (CDCl3, 75 MHz), δ
158.95, 147.24, 143.97, 129.57, 128.29, 127.57, 126.94, 117.08,
102.31, 99.25, 64.85, 57.62, 55.23, 55.10, 50.36, 46.76, 27.33,
26.17, 20.07.
(4aR,1′S)-9-Methoxy-3-(1-phenylethyl)-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinoline (20a): yield )
45%; [R]25D -25.0° (c 0.25, CHCl3); 1H NMR (CDCl3, 300 MHz),
δ 7.38-7.28 (m, 5H), 6.91 (d, J ) 8.12 Hz, 1H), 6.35 (d, J )
2.31 Hz, 1H), 6.29 (dd, J ) 8.15, 2.36 Hz, 1H), 3.77 (s, 3H),
3.64-3.60 (m, 1H), 3.40 (q, J ) 6.67 Hz, 1H), 3.12-3.09 (m,
(R)-Naphthalene-2-carboxylic acid [4-(1,2,4,4a,5,6-hexa-
hydropyrazino[1,2-a]quinolin-3-yl)butyl]amide (32a): yield
)
50%; [R]25 -4.5° (c 0.71, CHCl3). Anal. Calcd for
D
C27H31N3O: C, 78.42; H, 7.56; N, 10.16. Found: C, H, N.
(S)-Naphthalene-2-carboxylic acid [4-(7-methoxy-1,2,4,-
4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide (33b): yield ) 43%; [R]25 13.4° (c 0.38, CHCl3); 1H
D

Hexahydropyrazinoquinolines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3179
NMR (CDCl3, 300 MHz), δ 8.27 (s, 1H), 7.95-7.81 (m, 4H),
7.59-7.49 (m, 2H), 7.09-7.00 (m, 2H), 6.47 (d, J ) 8.42 Hz,
1H), 6.35 (d, J ) 8.10 Hz, 1H), 3.81 (s, 3H), 3.78-3.71 (m,
1H), 3.58-3.56 (m, 2H), 3.02-2.79 (m, 5H), 2.50-2.42 (m, 3H),
2.22-2.16 (m, 1H), 1.93-1.65 (m, 7H); 13C NMR (CDCl3, 75
MHz), δ 167.84, 157.42, 147.18, 134.59, 132.52, 132.22, 128.77,
128.34, 127.71, 127.47, 127.19, 126.71, 123.68, 112.48, 105.79,
100.54, 59.80, 57.77, 55.31, 54.25, 53.33, 46.90, 40.03, 27.32,
26.60, 24.38, 20.26. Anal. Calcd for C28H33N3O2‚0.4H2O: C,
74.60; H, 7.56; N, 9.32. Found: C, H, N.
(R)-Naphthalene-2-carboxylic acid [4-(7-methoxy-1,2,4,-
4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide (33a): yield ) 40%; [R]25D -13.6° (c 0.90, CHCl3). Anal.
Calcd for C28H33N3O2‚0.4H2O: C, 74.60; H, 7.56; N, 9.32.
Found: C, H, N.
amino)pyridine (DMAP, 7.0 mmol), 1-hydroxybenzotriazole
hydrate (HOBt, 5.5 mmol), and (4-tert-butoxycarbonylami-
nocyclohexyl)acetic acid (or (4-tert-butoxycarbonylamino-pip-
eridin-1-yl)acetic acid) (5.5 mmol). The resulting solution was
stirred overnight. Then the solvent was removed in vacuo and
the residue was dissolved in ethyl acetate and washed with
saturated sodium chloride. After purification by silica gel
column chromatography, the resultant was dissolved in tet-
rahydrofuran (THF) (30 mL). To the resulting solution, 6 M
HCl (10 mL) was added, and the mixture was stirred for 3 h.
Then the solvent was removed in vacuo and the residue was
dissolved in water and then neutralized with saturated sodium
bicarbonate solution and extracted with CHCl3 (3 × 100 mL).
The organic phase was dried over Na2SO4. Then the solvent
was removed in vacuo and the residue was dissolved in THF
(50 mL). To the resulting solution at 0 °C, lithium aluminum
hydride (15 mmol) was added. The resulting mixture was
stirred at room temperature for 2 h and refluxed for 4 h. After
some standard procedures, the free amine was obtained. The
resulting amine was dissolved in CHCl3 (10 mL), and to this
solution 2-naphthoyl chloride (6 mmol) and triethylamine (0.5
mL) were added. The resulting solution was refluxed for 4 h.
The solvent was removed, and the residue was dissolved in
ethyl acetate and water. The organic phase was washed with
saturated NaCl aqueous solution and dried over Na2SO4. The
solvent was removed in vacuo, and the residue was purified
by silica gel column chromatography to give compound 38 or
40.
(S)-Naphthalene-2-carboxylic acid [4-(8-methoxy-1,2,4,-
4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide (34b): yield ) 41%; [R]25 12.5° (c 0.65, CHCl3); 1H
D
NMR (CDCl3, 300 MHz), δ 8.26 (s, 1H), 7.88-7.81 (m, 4H),
7.58-7.49 (m, 2H), 7.03 (m, 1H), 6.69 (m, 2H), 6.57 (m, 1H),
3.76 (s, 3H), 3.66-3.56 (m, 3H), 2.99 (d, J ) 10.45 Hz, 1H),
2.85-2.60 (m, 4H), 2.43 (t, J ) 6.00 Hz, 2H), 2.23-2.18 (m,
2H), 1.90 (t, J ) 11.10 Hz, 1H), 1.75-1.60 (m, 6H); 13C NMR
(CDCl3, 75 MHz), δ 167.85, 146.10, 134.60, 132.54, 132.27,
129.25, 128.78, 128.40, 127.73, 127.49, 127.19, 126.93, 126.70,
124.43, 123.72, 118.10, 112.38, 59.81, 57.74, 55.10, 54.82,
53.22, 46.37, 39.99, 27.33, 27.17, 26.80, 24.32. Anal. Calcd for
C28H33N3O2‚0.4H2O: C, 74.60; H, 7.56; N, 9.32. Found: C, H,
N.
(S)-Naphthalene-2-carboxylic acid {4-[2-(8-methoxy-
1,2,4,4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)ethyl]-
(R)-Naphthalene-2-carboxylic acid [4-(8-methoxy-1,2,4,-
4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide (34a): yield ) 47%; [R]25D -13.1° (c 0.20, CHCl3). Anal.
Calcd for C28H33N3O2‚0.4H2O: C, 74.60; H, 7.56; N, 9.32.
Found: C, H, N.
cyclohexyl}amide (38b): yield ) 55%; [R]25 14.9° (c 0.87,
D
CHCl3); 1H NMR (CDCl3, 300 MHz), δ 8.27 (s, 1H), 7.92-7.82
(m, 4H), 7.58-7.55 (m, 2H), 6.76-6.61 (m, 3H), 6.09 (d, J )
8.04 Hz, 1H), 4.00 (m, 1H), 3.83 (s, 3H), 3.76-3.68 (m, 1H),
3.03-2.72 (m, 6H), 2.42 (t, J ) 7.66 Hz, 2H), 2.23-2.15 (m,
4H), 1.93-1.79 (m, 5H), 1.54-1.47 (m, 2H), 1.35-1.17 (m, 4H);
13C NMR (CDCl3, 75 MHz), δ 166.77, 152.16, 140.58, 134.59,
132.58, 132.17, 128.83, 128.40, 127.70, 127.49, 127.18, 126.66,
125.64, 123.63, 114.87, 113.57, 112.15,0 59.83, 56.50, 55.57,
55.38, 53.51, 49.19, 47.27, 35.49, 33.72, 33.11, 31.90, 27.35,
27.17. Anal. Calcd for C32H39N3O2‚0.3H2O: C, 76.40; H, 7.93;
N, 8.35. Found: C, H, N.
(S)-Naphthalene-2-carboxylic acid [4-(9-methoxy-1,2,4,-
4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide (35b): yield ) 50%; [R]25D 20.3° (c 0.3, CHCl3); 1H NMR
(CDCl3, 300 MHz), δ 8.25 (s, 1H), 7.91-7.78 (m, 4H), 7.56-
7.48 (m, 2H), 7.09 (m, 1H), 6.85 (d, J ) 8.13 Hz, 1H), 6.31 (d,
J ) 2.30 Hz, 1H), 6.26 (dd, J ) 2.30, 8.13 Hz, 1H), 3.74 (s,
3H), 3.66-3.62 (m, 1H), 2.96-2.58 (m, 6H), 2.41-2.69 (m, 2H),
2.16-2.10 (m, 2H), 1.88-1.62 (m, 8H); 13C NMR (CDCl3, 75
MHz), δ 167.90, 158.95, 147.01, 134.58, 132.52, 132.25, 129.63,
128.78, 128.36, 127.71, 127.48, 127.21, 126.68, 123.74, 117.01,
102.56, 99.27, 60.39, 59.83, 57.77, 55.22, 54.75, 53.17, 46.38,
40.03, 27.33, 26.03, 24.37. Anal. Calcd for C28H33N3O2‚
0.4H2O: C, 74.60; H, 7.56; N, 9.32. Found: C, H, N.
(R)-Naphthalene-2-carboxylic acid [4-(9-methoxy-1,2,4,-
4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide (35a): yield ) 39%; [R]25D -19.4° (c 0.32, CHCl3). Anal.
Calcd for C28H33N3O2‚0.4H2O: C, 74.60; H, 7.56; N, 9.32.
Found: C, H, N.
(R)-Naphthalene-2-carboxylic acid {4-[2-(8-methoxy-
1,2,4,4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)ethyl]-
cyclohexyl}amide (38a): yield ) 60%; [R]25D -12.9° (c 0.59,
CHCl3). Anal. Calcd for C32H39N3O2‚0.3H2O: C, 76.40; H, 7.93;
N, 8.35. Found: C, H, N.
(S)-Naphthalene-2-carboxylic acid {1-[2-(8-methoxy-
1,2,4,4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)ethyl]-
piperidin-4-yl}amide (40b): yield ) 53%; [R]25 9.5° (c 1.0,
D
CHCl3); 1H NMR (CDCl3, 300 MHz), δ 8.34 (s, 1H), 7.93-7.87
(m, 4H), 7.59-7.99 (m, 2H), 6.83 (d, J ) 7.71 Hz, 1H), 6.76-
6.67 (m, 2H), 6.61 (d, J ) 2.64 Hz, 1H), 4.29-4.37 (m, 1H),
3.83 (s, 3H), 3.76-3.70 (m, 2H), 3.15-2.63 (m, 15 H), 2.45-
2.10 (m, 4H), 1.93-1.78 (m, 2H); 13C NMR (CDCl3, 75 MHz),
δ 167.13, 152.46, 139.96, 134.82, 132.55, 131.00, 129.00,
128.51, 127.80, 127.71, 127.64, 126.82, 125.97, 123.51, 114.89,
113.76, 112.30, 59.28, 55.58, 55.08, 53.60, 53.13, 52.99, 46.96,
45.76, 45.00, 29.48, 27.08, 26.94. Anal. Calcd for C31H38N4O2‚
4H2O: C, 65.24; H, 8.12; N, 9.82. Found: C, 65.81; H, 7.25; N,
9.21.
(S)-Naphthalene-2-carboxylic acid [4-(10-methoxy-
1,2,4,4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide (36b): yield ) 42%; [R]25 60.6° (c 0.72, CHCl3); 1H
D
NMR (CDCl3, 300 MHz), δ 8.29 (s, 1H), 7.92-7.92 (m, 4H),
7.60-7.51 (m, 2H), 6.96 (br 1H), 6.81 (dd, J ) 7.54, 8.00 Hz,
1H), 6.68 (d, J ) 7.91 Hz, 1H), 6.66 (d, J ) 7.64 Hz, 1H), 3.82
(s, 3H), 3.63-3.50 (m, 2H), 3.00 (m, 2H), 2.84-2.64 (m, 4H),
2.54-2.41 (m, 4H), 1.94-1.59 (m, 7H); 13C NMR (CDCl3, 75
MHz), δ 167.78, 151.00, 136.47, 134.60, 132.58, 132.29, 128.96,
128.79, 128.36, 127.72, 127.47, 127.21, 126.69, 123.68, 122.01,
120.59, 109.55, 58.84, 57.97, 57.50, 55.36, 54.17, 48.52, 40.11,
28.43, 27.39, 24.49, 23.62. Anal. Calcd for C28H33N3O2: C,
75.81; H, 7.50; N, 9.47. Found: C, H, N.
(R)-Naphthalene-2-carboxylic acid {1-[2-(8-methoxy-
1,2,4,4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)ethyl]-
piperidin-4-yl}amide (40a): yield ) 50%; [R]25 -10.4° (c
D
0.50, CHCl3). Anal. Calcd for C31H38N4O2‚3H2O: C, 67.37; H,
8.02; N, 10.14. Found: C, 67.11; H, 7.28; N, 9.38.
(R)-Naphthalene-2-carboxylic acid [4-(10-methoxy-
1,2,4,4a,5,6-hexahydropyrazino[1,2-a]quinolin-3-yl)butyl]-
amide (36a): yield ) 50%; [R]25D -57.9° (c 0.90, CHCl3). Anal.
Calcd for C28H33N3O2‚0.5H2O: C, 74.31; H, 7.57; N, 9.28.
Found: C, H, N.
General Synthetic Route to Compounds 38 and 40. To
a solution of compound 24a or 24b (5.0 mmol) in dichlo-
romethane (50 mL) were added 1-[3-(dimethylamino)propyl]-
3-ethylcarbodiimide hydrochloride (6.0 mmol), 4-(dimethyl-
Biological Studies. Determination of D3 dopamine recep-
tor affinity and selectivity was performed in membranes
prepared from the brains of adult male Sprague-Dawley rats
(Harlan Sprague-Dawley, Indianapolis, IN). Because receptor-
expression transfected cells may not express the same cellular
components, e.g., G proteins as the native tissue, receptors may
display different functional properties in various expression
systems.28 Accordingly, this study used receptors expressed in

3180 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Ding et al.
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native tissue, i.e., brain, where the presence of the appropriate
cellular milieu and thus normal receptor binding and function
can be assumed. Affinity of compounds at D1-like, D2-like, and
D3 receptors were determined in well-established and validated
assays.
[3H]PD 128907 Binding Assays. [3H]PD 128907 binding
assays for D3 dopamine receptors were performed as previously
described in detail.25-27 Rat ventral striatum (nucleus accum-
bens and olfactory tubercles) was prepared in assay buffer (50
mM Tris, 1 mM EDTA; pH 7.4 at 23 °C) to yield a final
concentration of 10 mg original wet weight (oww)/mL. Mem-
branes were incubated with [3H]PD 128907 (0.3 nM; 116 Ci/
mmol; Amersham, Arlington Heights, IL) and various concen-
trations of competing compounds (10-10-10-4 M). Nonspecific
binding was defined by 1 µM spiperone. Assay tubes were
incubated at 23 °C for 3 h. The reaction was terminated by
rapid vacuum filtration. Data were analyzed using SigmaPlot
8.0.2. using the KD value for [3H]PD 128907 of 0.3 nM. Ki
values are expressed at the mean ( SEM of three to six
independent determinations.
[3H]Spiperone Binding Assays. [3H]Spiperone binding
assays for D2-like receptors were performed as previously
described in detail25-27 and as described for [3H]PD 128907
except for the following. Assays were performed using mem-
branes prepared from rat caudate-putamen, and the final
membrane homogenate concentration was 1.5 mg oww/mL.
The assay buffer was 50 mM Tris-HCl, 5 mM KCl, 2 mM
MgCl2, and 2 mM CaCl2, pH 7.4 at 23 °C. The concentration
of [3H]spiperone (24 Ci/mmol; Amersham) was 0.2 nM, and
the incubation time was 90 min at 23 °C. Nonspecific binding
was defined in the presence of 1 µM (+)-butaclamol. Ki values
were determined using the KD value for [3H]spiperone of 0.1
nM.
[3H]SCH 23390 Binding Assays. [3H] SCH 23390 binding
assays for D1-like dopamine receptors were performed as
previously described in detail25-27 and as described for [3H]-
spiperone binding except that the concentration of [3H]SCH
23390 (73 Ci/mmol; Amersham) was 0.3 nM. Ki values were
determined using the KD value for [3H]SCH 23390 of 0.3 nM.
Computational Docking. Initial 3D structures of com-
pounds 3 and 38a were built and minimized using the SYBYL
6.9.1 program and Tripos force field parameters.29,30 Com-
pounds 3 and 38a were then docked into the binding site of
the modeled D3 receptor using the Gold program (version
2.0).21 The center of the binding site was set at Asp110, and
the radius of the binding site was defined as 14 Å, which is
large enough to cover the putative binding pocket. For each
genetic algorithm (GA) run, a maximum number of 200 000
operations were performed on a population of 5 islands of 100
individuals each. Operator weights for crossover, mutation,
and migration were set to 95, 95, and 10, respectively. The
docking was terminated after 20 runs for each ligand. Both
GoldScore and ChemScore implemented in the Gold program
were used as the fitness function to evaluate the docked
conformations. The 20 highest ranked conformations by each
fitness function were saved as predicted docking modes for
analysis. The highest ranked docked conformation of com-
pound 38a and a similar view of compound 3 selected by the
ChemScore fitness function are displayed in Figure 2 for the
predicted binding models.
Supporting Information Available: Results from el-
emental analysis. This material is available free of charge via
the Internet at http://pubs.acs.org.
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