Axially chiral N-benzyl-n,7-dimethyl-5-phenyl-1,7-naphthyridine-6- carboxamide derivatives as tachykinin NK1 receptor antagonists: Determination of the absolute stereochemical requirements

Article abstract of DOI:10.1021/jm980042m

A potent and orally active NK₁ antagonist, trans-N-[3,5- bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8- oxo-1,7-naphthyridine-6-carboxamide (1t), was shown to exist as a mixture of separable and stable (R)- and (S)-a

Full text of DOI:10.1021/jm980042m

4232
J . Med. Chem. 1998, 41, 4232-4239
Axia lly Ch ir a l N-Ben zyl-N,7-d im eth yl-5-p h en yl-1,7-n a p h th yr id in e-6-ca r boxa m id e
Der iva tives a s Ta ch yk in in NK1 Recep tor An ta gon ists: Deter m in a tion of th e
Absolu te Ster eoch em ica l Requ ir em en ts
Yoshinori Ikeura,† Yuji Ishichi,† Toshimasa Tanaka,† Akira Fujishima,† Mika Murabayashi,† Mitsuru Kawada,§
Takenori Ishimaru,‡ Izumi Kamo,† Takayuki Doi,† and Hideaki Natsugari*,†
Pharmaceutical Research Division and Technology Development Department, Takeda Chemical Industries, Ltd.,
2-17-85, J usohonmachi, Yodogawa-ku, Osaka 532, J apan, and Discovery Research Division,
Takeda Chemical Industries, Ltd., 10 Wadai, Tsukuba-shi, Ibaraki 305, J apan
Received J anuary 21, 1998
A potent and orally active NK1 antagonist, trans-N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-
N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1t), was shown to
exist as a mixture of separable and stable (R)- and (S)-atropisomers (1t-A and 1t-B) originating
from the restricted rotation around the -C(6)-C(dO)- bond; the antagonistic activities of 1t-A
were ca. 6-13-fold higher than those of 1t-B. Analogues of 1t (3), which have (S)- and (R)-
methyl groups at the benzylic methylene portion of 1t, were prepared and separated into the
diastereomeric atropisomers, 3a -A, 3a -B and 3b-A, 3b-B, in enantiomerically pure forms.
Among the four isomers of 3, the (aR,S)-enantiomer (3a -A) exhibited the most potent
antagonistic activities with an IC50 value of 0.80 nM (in vitro inhibition of [125I]BH-SP binding
in human IM-9 cells) and ED50 values of 9.3 µg/kg (iv) and 67.7 µg/kg (po) (in vivo inhibition
of capsaicin-induced plasma extravasation in guinea pig trachea), while the activity of the
(aS,R)-enantiomer (3b-B) was the weakest with an IC50 value of 620 nM. The structure-
activity relationships in this series of antagonists indicate that the (R)-configuration at the
axial bond and the stacking (or stacking-like) conformation between the two phenyl rings as
shown in 1t-A and 3a -A are essential for high-affinity binding and suggest that the amide
moiety functions as a hydrogen bond acceptor in the interaction with the receptor.
In tr od u ction
We recently described1 the discovery of potent and
orally active tachykinin NK1 receptor antagonists,2 6-(N-
benzyl-N-methylcarboxamide) derivatives of pyrido[3,4-
b]pyridine (1,7-naphthyridine) (e.g., 1t; Figure 1), by
extensive structure-activity relationship (SAR) studies
on a series of N-benzylcarboxamides with isoquinolone
and related nuclei. Compound 1, N-[3,5-bis(trifluoro-
methyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methyl-
phenyl)-8-oxo-1,7-naphthyridine-6-carboxamide, exists
in the form of two separable isomers (rotamers), trans
(1t) and cis (1c) with respect to the amide bond, which
are interconverted and reach an equilibrium state of a
ca. 7:1 ratio in solution. Interestingly, the potency of
the trans-rotamer (1t) is ca. 7-20-fold higher than that
of the cis-rotamer (1c), indicating a conformational
requirement for NK1 receptor binding.1a In the confor-
mational studies on 1t (including 1c) and CP-99,994,3
a representative NK1 antagonist, two phenyl rings (i.e.,
the C(5)-phenyl and benzylic phenyl in 1t) and a het-
eroatom (i.e., nitrogen or oxygen at the carboxamide
moiety in 1t) were well-superimposed. This result
suggested that these three points are the key sites for
NK1 recognition,4 and 1t and CP-99,994 bind to similar
sites on the NK1 receptor.1a In these studies, two
models, in which either the oxygen or the nitrogen at
F igu r e 1. Potent NK1 antagonist 1t and active atropisomers
1t-A and 3a -A (for the schematic drawings, see the footnote
of Scheme 1).
the carboxamide in 1t is superimposed on the exocyclic
amine nitrogen in CP-99,994, were indicated, and
molecule 1t in each model was shown to have enantio-
meric structures (1t-A and 1t-B in Scheme 1) originat-
ing from the axial chirality about the -C(6)-C(dO)-
bond. Among these two models, we preferred the one
in which the oxygen is superimposed, since the oxygen
has higher electron density than the nitrogen and is
more likely to function as the hydrogen bond acceptor
as reported for the tryptophan ester NK1 antagonist
L-732,138.5 To further clarify the stereochemistry
required for the receptor binding in this class of
antagonists, we examined the structure of 1t in more
detail.
* Corresponding author. Phone: +81-6-300-6541. Fax: +81-6-300-
6306. E-mail: Natsugari_Hideaki@takeda.co.jp.
† Pharmaceutical Research Division.
In this paper, we demonstrate that molecule 1t exists
as a mixture of separable and stable axially chiral
§ Technology Development Department.
‡ Discovery Research Division.
10.1021/jm980042m CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/07/1998

Stereochemical Requirements for NK1 Binding
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22 4233
Sch em e 1a
a
The four stereoisomers of 1: trans and cis are used to indicate the relative configuration between the N-methyl group and the carbonyl
oxygen in the amide moiety, and R and S denote12a the axial chirality originating from the restricted rotation around the -C(6)-C(dO)-
bond. In the schematic drawings, the axial chirality is shown by indicating the steric position of the amide oxygen and nitrogen with
respect to the plane of the 1,7-naphthyridine ring.
Sch em e 2a
a
Reagents: (a) SOCl2/1,2-dichloroethane; (b) (S)-1-phenylethylamine (5) (for 7), (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethylamine (6a )
(for 8a ), and (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethylamine (6b) (for 8b), Et3N/1,2-dichloroethane; (c) NaH, MeI/DMF (THF); (d) *1
denotes chirality at the benzylic methylene portion, and *2 denotes chirality about the axial bond [-C(6)-C(dO)-].
isomers (atropisomers), 1t-A and 1t-B (Scheme 1), and
that the (R)-configuration at the axial chiral center and
the stacking (or stacking-like) conformation between the
two phenyl rings as shown in 1t-A and 3a -A (Figure 1)
are required for high-affinity NK1 binding.
amines (5, 6a ,b) to give the secondary amides (7, 8a ,b,
respectively), which, as may be expected, were shown
to be stereochemically single isomers by NMR and TLC
analyses. These secondary amides were then N-methy-
lated with methyl iodide in the presence of a base to
generate the tertiary amides (2 and 3) as a mixture of
diastereomers, which were separated by crystallization
and/or column chromatography. The relative and ab-
solute stereochemistry of these tertiary amides and the
stereoselectivity in the methylation reaction are de-
scribed in Results and Discussion.
Ch em istr y
N-[3,5-Bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-
dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-
carboxamide (1) was prepared by the previously re-
ported method.1a The synthesis of chiral methyl
analogues of 1t (2 and 3) is shown in Scheme 2. First,
the 1,7-naphthyridine-6-carboxylic acid 4 was amidated
via the acid chloride with 1-[(substituted)phenyl]ethyl-
Biology
The compounds prepared as described above were
evaluated in vitro for inhibition of [125I]Bolton-Hunter

4234 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Ikeura et al.
Ta ble 1. NK1 Antagonistic Activities of 1,7-Naphthyridine-6-carboxamide Derivatives (1-3)
chirality
ED50 (µg/kg) or % inhibitionb
compd no.
R1
R2
*1
*2
IC50 (nM)a
iv
po
1t (A + B)
1t-A
1t-B
1c (A + B)
2A
2B
3a -A
3a -B
3b-A
CF3
CF3
CF3
CF3
H
H
H
H
H
Me
Me
Me
Me
Me
Me
RS
R
S
RS
R
S
R
S
R
S
0.34 ( 0.07
0.24c
30 (18-54)
7.7 (4.1-12.5)
100 (69-149)
220 (130-2160)
-
110 (76-178)
d
-
1.4c
-
4.2c
-
S
S
S
S
R
R
130e
-
H
1700e
-
-
CF3
CF3
CF3
CF3
0.80 ( 0.20
9.3 (3.0-26.2)
67.7 (31.7-111.0)
44 ( 2.2
19 ( 8
61.8%f
-
-
-
412 (201-1432)
6.9%f
3b-B
620 ( 490
a
Inhibition of [125I]BH-SP binding in human IM-9 cells (lymphoblast cells). Mean ( SD value determined by at least three independent
b
experiments (n ) 3-6) run in duplicate unless otherwise noted. Capsaicin-induced tracheal plasma extravasation in guinea pigs. To
determine the ID50 values, 5-8 animals were used at each dose. 95% Confidence limits are given in parentheses. c Mean value of two
independent experiments run in duplicate. Not tested (-). e IC50 value determined by a single experiment run in duplicate. f Inhibition
d
(%) at 1.0 mg/kg (n ) 5 or 6).
(BH)-SP binding in human IM-9 cells6 and in vivo for
inhibition of capsaicin-induced plasma extravasation in
the trachea of guinea pigs7 upon iv and po admini-
stration.
50 °C for ca. 3 days (t1/2 ) 6.4 h). The atropisomers
exhibited different affinities for the NK1 receptor (both
in vitro and in vivo (iv)); the potency of 1t-A is ca. 6-13-
fold higher than that of 1t-B (Table 1),11 which indicates
that the conformation of 1t-A is preferentially recog-
nized by the NK1 receptor. From the SAR data obtained
for its methyl analogues (i.e., 3) (see part b, Results and
Discussion), it is deduced that the active atropisomer
1t-A has the (R)-configuration with the amide oxygen
below (and the nitrogen above) the plane of the 1,7-
naphthyridine ring.12 The presence of atropisomers in
the cis-amide isomer (1c-A and 1c-B) was also revealed
by HPLC analysis. As a consequence, four stereoiso-
mers are present in 1 as shown in Scheme 1.
From a practical point of view, however, separation
of the stereoisomers to obtain the active atropisomer
1t-A by preparative HPLC is difficult, and further study
using 1t as a racemate would meet with difficulty,
especially at the stage of pharmaceutical development.
Thus, we designed new chiral analogues of 1t (3) with
(R)- and (S)-methyl groups at the benzylic methylene
portion, in the hope of selective formation and/or practi-
cal preparation of the active atropisomer(s) and to
determine the absolute stereochemistry of the atrop-
isomers 1t-A and 1t-B.
(b) Atr op isom er s of Ch ir a l Meth yl An a logu es of
1t (2 a n d 3). As an approach to the selective formation
of the atropisomer, we investigated N-methylation of
(R)- and (S)-N-[1-(substituted)phenylethyl]carboxamides
7 and 8 expecting a kinetically controlled methylation.
First, N-methylation of (S)-N-(1-phenylethyl)carbox-
amide (7) was examined as a model experiment. Dia-
stereomeric atropisomers, 2A and 2B, were formed in
the reaction, and when the reaction was conducted at
-60 °C in dimethyl formamide (DMF), high stereose-
lectivity with a ratio of ca. 93:7 (determined by NMR)
was observed. The ratio changed depending on the
temperature; at 0 °C the ratio decreased to ca. 72:28.
These isomers were easily separated by crystallization
Resu lts a n d Discu ssion
(a ) Atr op isom er s of N-[3,5-Bis(tr iflu or om eth yl)-
ben zyl]-7,8-dih ydr o-N,7-dim eth yl-5-(4-m eth ylph en -
yl)-8-oxo-1,7-n aph th yr idin e-6-car boxam ide (1). Since
the N-[3,5-bis(trifluoromethyl)benzyl]-N-methylcarboxa-
mide moiety in 1t1a is substituted at a sterically
hindered position, the rotation around the -C(6)-C(d
O)- bond is presumed to be restricted, which results in
the formation of the separable atropisomers (1t-A and
1t-B) (Scheme 1). The presence of the atropisomers is,
in fact, implied by the following: (1) the NMR spectrum
of 1t1a shows a distinct AB pattern for the methylene
protons of the N-benzyl group, indicating slow inter-
conversion on the NMR time scale; (2) in the molecular
view of 1t as determined by X-ray analysis,1a the
atropisomers (1t-A and 1t-B) are observed in the
crystalline unit cell (space group: P21/n); (3) a rather
large energy barrier for interconversion between 1t-A
and 1t-B (34 kcal/mol), determined on the basis of
molecular mechanics calculations using DISCOVER,8
suggests restricted interconversion; and (4) separability
of some sterically hindered aromatic carboxamides into
enantiomers due to atropisomerism has been reported.9
With these points in mind, we analyzed compound 1t
by high-performance liquid chromatography (HPLC)
using a chiral column.10 As anticipated, two equal
peaks were observed on the chromatogram, and 1t-A
and 1t-B were each successfully separated by prepara-
tive HPLC at room temperature as oily substances.
Compounds 1t-A and 1t-B, which have opposite [R]D
values (-34.2° and +35.0°, respectively), were found to
be quite stable in solution; e.g., they were not intercon-
verted in dimethyl sulfoxide (DMSO) after 16 h at 37
°C and underwent racemization only after storage at

Stereochemical Requirements for NK1 Binding
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22 4235
F igu r e 2. Stereoscopic molecular view of 3a -A as determined by X-ray crystallographic analysis. The black, shaded, and dotted
circles indicate oxygen, nitrogen, and fluorine atoms, respectively.
and/or column chromatography. Stability of these
isomers in solution was similar to that of 1t-A and 1t-
B; e.g., 2A and 2B were stable in ethyl acetate at room
temperature for 16 h without interconversion and
underwent racemization when heated at 110 °C in
toluene for 1 h. The amide rotamers of 2A and 2B were
not observed by NMR and TLC analyses; they presum-
ably exist predominantly as the preferred trans-isomer
due to the steric bulkiness of the N-(1-phenylethyl)
group. The relative stereochemistry of 2A and 2B was
determined on the basis of NMR data in comparison
with the data obtained for 3a -A and 3a -B (see discus-
sion below).
The stereochemistry of 3a -A was determined by
single-crystal X-ray analysis (Figure 2), which revealed
that 3a -A has the (R)-configuration at the axial chiral
center, with the amide nitrogen disposed above the
plane of the adjacent 1,7-naphthyridine ring and the
amide oxygen below the ring, and the (S)-configuration
at the benzylic methylene portion, and allowed elucida-
tion of the relative and absolute configuration of the
stereoisomers 3a -B, 3b-A, and 3b-B: (aS,S), (aR,R), and
(aS,R), respectively. In the crystal structure of 3a -A, a
similar stacking (or stacking-like) conformation between
the C(5)-phenyl and the N-benzylic phenyl groups as
observed in the X-ray analysis of 1t1a is also seen.
The conformations of the three compounds with the
(aR)-configuration, 1t-A (aR), 3a -A (aR,S), and 3b -A
(aR,R), were analyzed using MO calculation. Figure 3
shows their most stable conformations as determined
by the analysis. Here again, a stacking (or stacking-
like) conformation between the two phenyl groups is the
most stable for 1t-A and 3a -A, whereas an extended
conformation between the two phenyl groups is the most
stable for 3b-A. This conformational difference between
3a -A and 3b-A seemed to be reflected in the difference
After obtaining these promising data, we next inves-
tigated N-methylation of the (S)-N-[1-[3,5-bis(trifluo-
romethyl)phenyl]ethyl]carboxamide derivative 8a. How-
ever, contrary to our expectation, the alkylation of 8a
in DMF at -60 °C in the presence of NaH was slow and
the selectivity was poor as compared to the reaction of
7, affording the diastereomeric atropisomers 3a -A and
3a -B with a ratio of ca. 47:53 (determined by HPLC)
and 35% conversion after a 3-h reaction. When con-
ducted at 0 °C, the reaction was completed in 1 h, but
the ratio was unchanged (ca. 45:55). Several attempted
modifications of the reaction conditions, such as tem-
perature (-70 to 27 °C), solvents (THF, dichloromethane,
toluene), and bases (lithium diisopropylamide, methyl-
magnesium chloride, potassium tert-butoxide), failed to
significantly improve the selectivity, and only the ad-
dition of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-
crown-6) in the reaction using methyl iodide and
potassium tert-butoxide in THF at -60 °C resulted in
moderate, but undesired (see discussion concerning the
activity below), selectivity, giving 3a -A and 3a -B in a
ratio of ca. 27:73 with a 59% yield after a 1-h reaction.
At present, the reason for this notable difference in
selectivity between the methylation reactions of 7 and
8a is not clear. One explanation could be that bulky
trifluoromethyl groups at meta-positions in the benzylic
phenyl group of 8a alter the conformation of the
intermediary stable anion of 8a from that of 7.13
Although the selectivity was unsatisfactory, separation
of the diastereomers (3a -A and 3a -B) by column chro-
matography was achieved without difficulty, affording
3a -A and 3a -B in enantiomerically pure forms. Simi-
larly, by methylation of the (R)-N-[1-[3,5-bis(trifluoro-
methyl)phenyl]ethyl]carboxamide derivative 8b, their
enantiomers having an (R)-methyl group, 3b-B and 3b-
A, were prepared.
1
in activity (described below). The H NMR analysis of
the (aR,S)-isomer 3a -A and its (aS,S)-diastereomer
3a -B (in CDCl3) provided the solution conformations in
good agreement with those obtained by the conforma-
tional analysis. That is, the aromatic ring protons (C(4)
-
H, C(5)-phenyl protons (4H) and benzylic phenyl protons
(2H)) and the methyl protons on the C(5)-phenyl of 3a -A
were observed in the upper field compared to those of
3a -B (∆ 0.11-0.34 ppm), suggesting a stacking (or
stacking-like) conformation between the two phenyl
groups in 3a -A, and also the upward field shift of the
chemical shift (δ ) 0.936 ppm) of the methyl protons at
the benzylic methylene portion of 3a -B as compared to
3a -A (δ ) 1.597 ppm) suggests that 3a -B has a
conformation in which the methyl group is over the
plane of the C(5)-phenyl ring and consequently the
benzylic phenyl group is in the extended arrangement.
The stability of 3a -A and 3a -B in solution was similar
to that of 1t-A and 1t-B: 3a -A and 3a -B were stable in
DMSO at room temperature for 16 h without intercon-
version and underwent racemization when heated at 50
°C in DMSO for ca. 160 h (t1/2 ) 4.5 h).
The NK1 antagonistic activities (in vitro and in vivo)
of the 1,7-naphthyridine-6-carboxamide stereoisomers
(2 and 3) are shown in Table 1. The in vitro SARs of
the four stereoisomers of 3 (3a -A, 3a -B, 3b-A, and 3b-

4236 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Ikeura et al.
F igu r e 3. Stereoscopic view of the most stable conformations of the three compounds with the (aR)-configuration, 1t-A (aR)
(top), 3a -A (aR,S) (middle), and 3b-A (aR,R) (bottom), as determined by the conformational analysis using MO calculation. The
shaded lines indicate heteroatoms (nitrogen, oxygen, and fluorine). In 3a -A, a stacking-like conformation between the two phenyl
rings shown in this figure is more stable than its extended conformation by 2.67 kcal/mol, while in 3b-A, an extended conformation
shown in this figure is more stable than its stacking-like conformation by 0.73 kcal/mol.
B) clearly indicate the stereochemistry required for
high-affinity binding to the NK1 receptor in this series
of antagonists. Among these isomers, the (aR,S)-isomer
3a -A showed the most potent activity with an IC50 value
of 0.80 nM; the activity is ca. 1/3-fold weaker than that
of 1t-A, suggesting that the introduction of the methyl
group at the benzylic methylene portion of 1t has a
slightly deleterious effect on receptor binding. The
affinity of the (aS,R)-enantiomer 3b-B was the weakest
with an IC50 value of 620 nM, and the isomers 3a -B
(aS,S) and 3b-A (aR,R), which are presumed to have
the extended arrangement of the two phenyl rings as
described above, showed moderate activities with IC50
values on the 10-8 M level. The in vivo (iv) activity of
these isomers corresponds well to their in vitro potency;
3a -A was the most potent with an ED50 value of 9.3 µg/
kg, and 3b-B was the weakest. Upon oral administra-
tion, 3a -A exhibited significantly potent activity with
an ED50 value of 67.7 µg/kg, suggesting good oral
availability of 3a -A.
chemistry for the receptor binding is also seen with
these compounds: i.e., 2A (aR,S) > 2B (aS,S).
Con clu sion s
This study has demonstrated that the 1,7-naphthy-
ridine-6-carboxamides 1-3 exist as a mixture of sepa-
rable and stable atropisomers originating from the
restricted rotation around the -C(6)-C(dO)- bond. The
SARs for these atropisomers, along with the conforma-
tional analysis of 3 by NMR and MO calculation,
indicate that the (R)-configuration at the axial bond and
the stacking (or stacking-like) conformation between the
two phenyl rings (the C(5)-phenyl and benzylic phenyl)
as shown in 1t-A and 3a -A are important for NK1
receptor binding. These results enable us to further
refine our pharmacophore models previously reported1
and suggest that the -C(6)-C(dO)-N(Me)- moiety in
this class of antagonists functions not only as a spacer
between the two phenyl rings but also as the hydrogen
bond acceptor in the interaction with the receptor.
From a synthetic point of view, however, selective
preparation of the active atropisomers remains to be
explored. Approaches toward the active atropisomers
As anticipated from our preceding study,1a compounds
2A and 2B, which are unsubstituted at the benzylic
phenyl, showed weak in vitro activity. However, it is
noteworthy that the preference of the absolute stereo-

Stereochemical Requirements for NK1 Binding
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22 4237
for 1 h. After evaporation of the solvent, the resulting crystals
were collected by filtration and washed successively with H2O,
ethyl ether, and diisopropyl ether (IPE) to give 7 as colorless
crystals (530 mg, 67%). Recrystallization from MeOH-IPE
gave colorless crystals: mp 287-288 °C; 1H NMR 1.25 (3H, d,
J ) 7.0), 2.44 (3H, s), 3.47 (3H, s), 5.01 (1H, m), 7.0-7.6 (12H,
m), 8.61 (1H, m). Anal. (C25H23N3O2‚1/2H2O) C, H, N.
by asymmetric induction at the axial chiral center are
currently under investigation, and the results will be
reported elsewhere.14
Exp er im en ta l Section
Ch em istr y. Melting points were determined on a Yanagim-
oto micro melting point apparatus and are uncorrected. 1H
NMR spectra were taken on a Varian Gemini 200 (200 MHz)
spectrometer in CDCl3 unless otherwise noted; 1H NMR
spectra of 3a -A and 3a -B were taken on a Bruker DPX-300
(300 MHz) spectrometer. Chemical shifts are given in ppm
with tetramethylsilane as the internal standard, and coupling
constants (J ) are given in hertz (Hz). The following abbrevia-
tions are used: s ) singlet, d ) doublet, t ) triplet, m )
multiplet, dd ) double doublet, bs ) broad singlet, bt ) broad
triplet. Optical rotations were determined on a J ASCO DIP-
370 digital polarimeter at 20 °C at the sodium D-line; the
concentrations are reported g/100 mL. Circular dichroism
(CD) spectra were obtained at 25 °C with a J ASCO J -720
spectropolarimeter. The sample cell was 1 cm, and the slit
was programmed for a spectral bandwidth of 1.0 nm. Cutoff
was indicated when the dynode voltage reached ca. 400 V. The
concentrations given with the CD spectra are g/100 mL. Mass
spectra were obtained on a J EOL J MS-AX505W spectrometer.
Elemental analyses were within (0.4% of the theoretical
values for the elements indicated unless otherwise noted.
Extracted solutions were dried over anhydrous MgSO4 or
anhydrous Na2SO4. The yields reported are not optimized.
Sep a r a tion of Atr op isom er s (1t-A a n d 1t-B) of tr a n s-
N-[3,5-Bis(t r iflu or om et h yl)b en zyl]-7,8-d ih yd r o-N,7-d i-
m et h yl-5-(4-m et h ylp h en yl)-8-oxo-1,7-n a p h t h yr id in e-6-
ca r boxa m id e (1t). Compound 1t1a was separated into the
atropisomers (1t-A and 1t-B) by preparative high-performance
liquid chromatography (HPLC) using Chiralpak AD (10.0 mm
φ × 250 mm) (DAICEL Chemical Industries, Ltd., J apan)
under detection at 254 nm using a mixture of hexane-EtOH
(90:10) as the eluant at a flow rate of 2.4 mL/min at 28 °C to
give 1t-A and 1t-B as oily substances. 1t-A: ca. 90% ee;
retention time ) 28.2 min; [R]D ) -34.2° (c ) 0.1, CHCl3).
1t-B: ca. 90% ee; retention time ) 22.7 min; [R]D ) +35.0° (c
) 0.1, CHCl3).
(S)-1-[3,5-Bis(tr iflu or om eth yl)p h en yl]eth yla m in e Hy-
d r och lor id e (6a ) a n d Its (R)-Isom er (6b). The separation
of(()-N-(benzyloxycarbonyl)-1-[3,5-bis(trifluoromethyl)phenyl]-
ethylamine (7.27 g, 18.6 mmol) was carried out by HPLC
[column, Chiralcel OD (DAICEL Chemical Industries, Ltd.,
J apan), 20.0 mm φ × 250 mm; eluant, hexane-2-propanol )
95:5; flow rate, 8.0 mL/min; detection, UV 254 nm], followed
by hydrogenation and treatment with 4 N HCl-EtOAc to give
6a (2.56 g, 47%) and 6b (2.63 g, 48%), each as colorless
crystals. 6a : recrystallization from EtOH-hexane gave color-
less crystals; mp ca. 220 °C (sublimated); [R]D ) -3.3° (c )
0.250, MeOH); CD15 (c ) 0.002 56, MeOH) [θ]315 ) +14 043,
[θ]253 ) +22 838 [lit.16 [R]D ) -9.8° (neat, 0.5 dm) (71% ee);
CD15 (MeOH) [θ]318 ) +18 000, [θ]252 ) +33 000 (molecular
ellipticity adjusted to 100% ee)]; 1H NMR (DMSO-d6) 1.58
(3H, d, J ) 6.6), 4.68 (1H, m), 8.14 (1H, s), 8.34 (2H, s), 8.81
(3H, m). Anal. (C10H10ClF6N) C, H, N. 6b: recrystallization
from EtOH-hexane gave colorless crystals; mp ca. 220 °C
(sublimated); [R]D ) +3.2° (c ) 0.252, MeOH); CD15 (c )
0.002 28, MeOH) [θ]315 ) -13 500, [θ]252 ) -21 765; 1H
NMR (DMSO-d6) identical to that of 6a . Anal. (C10H10ClF6N‚
1/2H2O) C, H, N.
(S)-N-[1-[3,5-Bis(tr iflu or om eth yl)p h en yl]eth yl]-7,8-d i-
h yd r o-7-m eth yl-5-(4-m eth ylp h en yl)-8-oxo-1,7-n a p h th yr i-
d in e-6-ca r boxa m id e (8a ). Compound 4 (1.40 g, 3.52 mmol)
was treated according to a procedure similar to that described
for the preparation of 7 using 6a in place of 5 to afford 8a as
colorless crystals (1.12 g, 60%). Recrystallization from EtOAc-
IPE gave colorless crystals: mp 197-199 °C; [R]D ) -19.0° (c
1
) 0.25, CHCl3); H NMR 1.40 (3H, d, J ) 7.0), 2.38 (3H, s),
3.07 (1H, m), 3.50 (3H, s), 5.10 (1H, m), 7.05-7.30 (3H, m),
7.36 (1H, d, J ) 6.6), 7.49 (1H, d, J ) 8.0), 7.79 (1H, s), 7.89
(2H, s), 8.13 (1H, d, J ) 8.6), 8.62 (1H, d, J ) 3.2). Anal.
(C27H21F6N3O2) C, H, N.
(R)-N-[1-[3,5-Bis(tr iflu or om eth yl)p h en yl]eth yl]-7,8-d i-
h yd r o-7-m eth yl-5-(4-m eth ylp h en yl)-8-oxo-1,7-n a p h th yr i-
d in e-6-ca r boxa m id e (8b). Compound 4 (840 mg, 2.11 mmol)
was treated according to a procedure similar to that described
for the preparation of 7 using 6b in place of 5 to afford 8b as
colorless crystals (910 mg, 81%). Recrystallization from
EtOAc-IPE gave colorless crystals: mp 197-199 °C; [R]D
)
+18.2° (c ) 0.248, CHCl3); 1H NMR identical to that of 8a .
Anal. (C27H21F6N3O2) C, H, N.
(a R,S)-7,8-Dih yd r o-N,7-d im eth yl-5-(4-m eth ylp h en yl)-
8-oxo-N -(1-p h e n yle t h yl)-1,7-n a p h t h yr id in e -6-ca r b ox-
a m id e (2A) a n d Its (a S,S)-Isom er (2B). A mixture of 7 (450
mg, 1.13 mmol), NaH (60% dispersion in oil) (99 mg, 2.48
mmol), and DMF (20 mL) was stirred at room temperature
for 30 min. The mixture was cooled to 0 °C, and iodomethane
(0.5 mL, 8.0 mmol) was added to it. The resulting mixture
was stirred at room temperature for 30 min, added to H2O,
and then extracted with EtOAc. The extract was washed with
H2O, dried, and then concentrated. The concentrate, which
contained 2A and 2B in a ratio of ca. 72:28 as determined by
1H NMR, was subjected to chromatography on silica gel using
EtOAc-MeOH (9:1) as the eluant to give 2A (142 mg, 31%)
from the more polar fraction and 2B (18.6 mg, 4%) from the
less polar fraction, each as colorless crystals. 2A: recrystal-
lization from acetone-ethyl ether gave colorless crystals; mp
1
233-234 °C; [R]D ) -54.2° (c ) 0.184, MeOH); H NMR 1.52
(3H, d, J ) 6.8), 2.40 (3H, s), 2.54 (3H, s), 3.69 (3H, s), 5.82
(1H, q, J ) 6.8), 6.47 (2H, d, J ) 7.4), 7.0-7.3 (5H, m), 7.35-
7.55 (3H, m), 7.62 (1H, dd, J ) 8.2, 1.8), 8.90 (1H, dd, J ) 4.4,
1.8). Anal. (C26H25N3O2) C, H, N. 2B: recrystallization from
EtOAc-IPE gave colorless crystals; mp 229-231 °C; [R]D
)
+36.0° (c ) 0.1785, MeOH); 1H NMR 0.85 (3H, d, J ) 6.8),
2.39 (3H, s), 2.45 (3H, s), 3.66 (3H, s), 5.86 (1H, q, J ) 6.8),
7.12-7.52 (10H, m), 7.69 (1H, dd, J ) 8.4, 2.0), 8.90 (1H, dd,
J ) 4.0, 2.0); MS (electron impact) m/z 411 (M+). When the
above reaction was conducted at -60 °C, the product ratio (2A:
2B) changed to ca. 93:7.
(a R,S)-N-[1-[3,5-Bis(tr iflu or om eth yl)p h en yl]eth yl]-7,8-
dih ydr o-N,7-dim eth yl-5-(4-m eth ylph en yl)-8-oxo-1,7-n aph -
th yr id in e-6-ca r boxa m id e (3a -A) a n d Its (a S,S)-Isom er
(3a -B). Compound 8a (460 mg, 0.86 mmol) was treated at 0
°C according to a procedure similar to that described for the
preparation of 2 to form 3a -A and 3a -B in a ratio of ca. 45:55
(determined by HPLC). These two compounds were separated
by column chromatography on silica gel using EtOAc-MeOH
(9:1) as the eluant to afford 3a -A (56 mg, 12%) from the more
polar fraction and 3a -B (109 mg, 23%) from the less polar
fraction, each as colorless crystals. 3a -A: recrystallization
from EtOAc-IPE gave colorless crystals; mp 164-165 °C; [R]D
) -50.9° (c ) 0.242, CHCl3); 1H NMR (300 MHz, CDCl3) 1.597
(3H, d, J ) 7.1), 2.349 (3H, s), 2.590 (3H, s), 3.675 (3H, s),
5.878 (1H, q, J ) 7.1), 6.962 (1H, dd, J ) 7.8, 1.9), 7.106 (1H,
dd like), 7.189 (1H, dd like), 7.314 (1H, dd, J ) 7.8, 1.9), 7.368
(2H, s like), 7.449 (1H, dd, J ) 8.4, 4.3), 7.550 (1H, dd, J )
8.4, 1.7), 7.781 (1H, s like), 8.900 (1H, dd, J ) 4.3, 1.7); MS
(S)-7,8-Dih yd r o-7-m eth yl-5-(4-m eth ylp h en yl)-8-oxo-N-
(1-p h en ylet h yl)-1,7-n a p h t h yr id in e-6-ca r b oxa m id e (7).
Thionyl chloride (0.74 mL, 10.1 mmol) and DMF (catalytic
amount) were added to a solution of 7,8-dihydro-7-methyl-5-
(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxylic acid (4)1a
(590 mg, 2.00 mmol) in 1,2-dichloroethane (20 mL) at room
temperature, and the mixture was refluxed for 3 h. After
evaporation of the solvent, the residue was dissolved in 1,2-
dichloroethane (30 mL). To this solution were added (S)-1-
phenylethylamine (5) (0.31 mL, 2.40 mmol) and Et3N (0.84 mL,
6.03 mmol), and the mixture was stirred at room temperature

4238 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Ikeura et al.
Ta ble 2. Crystal Data and Summary of Data Collection
(electron impact) m/z 547 (M+). Anal. (C28H23F6N3O2) C, H,
N. 3a -B: recrystallization from EtOAc-IPE gave colorless
crystals; mp 194-196 °C; [R]D ) +43.7° (c ) 0.207, CHCl3);
1H NMR (300 MHz, CDCl3) 0.936 (3H, d, J ) 7.1), 2.428 (3H,
s), 2.458 (3H, s), 3.655 (3H, s), 5.920 (1H, q, J ) 7.1), 7.185
(1H, dd, J ) 7.8, 1.9), 7.303 (1H, dd like), 7.347 (1H, dd like),
7.422 (1H, dd, J ) 7.8, 1.9), 7.491 (1H, dd, J ) 8.4, 4.3), 7.709
(1H, dd, J ) 8.4, 1.7), 7.709 (2H, s like), 7.828 (1H, s like),
8.919 (1H, dd, J ) 4.3, 1.7); MS (electron impact) m/z 547 (M+).
Anal. (C28H23F6N3O2) C, H, N.
(a R,R)-N-[1-[3,5-Bis(tr iflu or om eth yl)p h en yl]eth yl]-7,8-
dih ydr o-N,7-dim eth yl-5-(4-m eth ylph en yl)-8-oxo-1,7-n aph -
t h yr id in e-6-ca r boxa m id e (3b -A) a n d It s (a S,R)-Isom er
(3b-B). Compound 8b (840 mg, 1.57 mmol) was treated at 0
°C according to a procedure similar to that described for the
preparation of 2 to form 3b-A and 3b-B in a ratio of ca. 55:45
(determined by HPLC). These two compounds were separated
by column chromatography on silica gel using EtOAc-MeOH
(9:1) as the eluant to afford 3b-B (38 mg, 4%) from the more
polar fraction and 3b-A (136 mg, 16%) from the less polar
fraction, each as colorless crystals. 3b -A: recrystallization
from EtOAc-IPE gave colorless crystals; mp 194-196 °C; [R]D
) -43.7° (c ) 0.212, CHCl3); 1H NMR identical to that of 3a -
B. Anal. (C28H23F6N3O2) C, H, N. 3b -B: recrystallization
from EtOAc-IPE gave colorless crystals; mp 164-165 °C; [R]D
) +51.1° (c ) 0.242, CHCl3); 1H NMR identical to that of 3a -
A; MS (electron impact) m/z 547 (M+).
formula
C28H23F6N3O2
formula weight
crystal system
space group
547.44
monoclinic
P21
molecules/unit cell
cell dimensions
4
a ) 10.435(2) Å
b ) 18.166(1) Å
c ) 14.309(1) Å
â ) 103.274(8)°
V ) 2640.0(5) Å3
1.377
calculated density (g/cm3)
absorption coefficient (cm-1
crystal size (mm)
radiation
data collection range
scan mode
)
10.08
0.60 × 0.30 × 0.02
Cu KR (λ ) 1.5418 Å)
3° e 2θ e 120°
2θ-ω
16
4071
scan speed (deg/min)
unique reflections
observed reflections (F g 3σF)
2352
R, Rw
0.162, 0.101
weighting factor
1/σ(F)2
representative conformations which were selected by an in-
house program from the previous systematic search results.
Rotational barriers were estimated by Discover CVFF force
field (ver. 2.9.7, Molecular Simulations Inc., San Diego, CA)
using torsional forcing as a constraint. During those calcula-
tions, the force constant of the constraint was set to 100 kcal/
mol/Å2, and increments of bond rotation were set to 10° and
180° for all rotatable single bonds and an amide bond,
respectively. The calculated energy was plotted against the
torsion angle around the -C(6)-C(CdO)- bond.
All the isomers (3a -A, 3a -B, 3b-A, and 3b-B) were shown
to have >99.9% ee [determined by chiral HPLC (Chiralcel OD,
4.6 mm φ × 250 mm; eluant, hexane-ethanol ) 85:15; flow
rate, 0.6 mL/min; detection, UV 247 nm)] and >99.9% dia-
stereomeric excess [determined by HPLC (Puresil 5-µm C18,
120 Å, 4.6 mm φ × 150 mm; eluant, 50 mM KH2PO4 (pH )
6.5)-CH3CN ) 1:1; flow rate, 0.8 mL/min; detection, UV 247
nm)].
[
125I]BH-SP Bin d in g in Hu m a n IM-9 Cells. The binding
activities were determined according to the protocol previously
reported.1a
Sin gle-Cr ysta l X-r a y An a lysis of 3a -A. Crystals of 3a -A
were grown from EtOAc-ethyl ether. Data were collected on
a diffractometer, Rigaku AFC5R, and corrected for Lorentz and
polarization factors. A Ψ-scan absorption correction was
applied. The structure was solved by direct methods with the
aid of TEXSAN17 and refined by CRYLSQ18 in the XTAL
package. The parameters refined include the coordinates and
anisotropic thermal parameters for non-hydrogen atoms.
Hydrogen atoms were included using a riding model (dH )
1.09 Å). Thermal parameters of hydrogen atoms were taken
from their bonded atoms as Uiso and fixed through the next
several cycles of refinement. The two trifluoromethyl groups
were treated as groups respectively and only the isotropic
thermal parameters were refined due to their highly disor-
dered nature. The authors presume that this disordered
structure and small volume of the crystal lead to a large final
R-factor of 0.16. In the asymmetric unit of the crystal
structure, two molecules (I and II in the Supporting Informa-
tion) with slightly different positions of the 3,5-bis(trifluoro-
methyl)phenyl ring were observed. Among them, the stereo-
scopic view of molecule I is shown in Figure 2. The crystal
data and data collection details are summarized in Table 2.
The atomic coordinates, thermal parameters, bond distances,
bond angles, and torsion angles are available as Supporting
Information.
Molecu la r Mod elin g Stu d ies. The systematic conforma-
tional search (SCS) was performed using Search/Compare
Module in Insight II (ver. 95.5.6, Molecular Simulations Inc.,
San Diego, CA). Preliminary search were carried out by SCS
standard mode under the following conditions. Increments of
bond rotation were set to 30° and 180° for all rotatable single
bonds and an amide bond, respectively. Scale radii values for
van der Waals were set to 0.7, 0.65, and 0.5 for vicinal atoms,
hydrogen bonds, and the other atoms, respectively. After
preliminary search, SCS energy mode calculations were
executed to obtain stable conformations within 10 kcal/mol
above the lowest energy. Local minimum conformers were
obtained by full energy minimization using AM1 calculation
(MOPAC ver. 6.00, QCPE Program by J . J . Stewart) for
In h ibitor y Effect on Ca p sa icin -In d u ced P la sm a Ex-
tr a va sa tion in th e Tr a ch ea of Gu in ea P igs. The inhibitory
effect was determined according to the protocol previously
reported.1a
Ack n ow led gm en t. We wish to thank Mr. Kazuichi
Umemoto for separation of the atropisomers (1t-A and
1t-B), Ms. Keiko Higashikawa for X-ray analysis, Ms.
Fumiko Kasahara for NMR analysis, Mr. Yasukazu
Tajima for in vitro screening, and Mr. Satoshi Okanishi
for in vivo screening.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for 3a -A (15 pages). Ordering information is given on
any current masthead page.
Refer en ces
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Stereochemical Requirements for NK1 Binding
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the former gave the diastereomers [(aR*,S*):(aS*,S*)] in a ratio
of ca. 2:3, while the latter showed stereoselectivity to afford the
diastereomers [(aR*,S*):(aS*,S*)] in a ratio of ca. 5:1, suggesting
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