Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists: Synthesis, antagonistic activity, and effects on bladder functions

Article abstract of DOI:10.1021/jm990220r

Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7- dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK₁ antagonistic activities. The 8

Full text of DOI:10.1021/jm990220r

3982
J . Med. Chem. 1999, 42, 3982-3993
Axia lly Ch ir a l 1,7-Na p h th yr id in e-6-ca r boxa m id e Der iva tives a s Or a lly Active
Ta ch yk in in NK1 Recep tor An ta gon ists: Syn th esis, An ta gon istic Activity, a n d
Effects on Bla d d er F u n ction s
Hideaki Natsugari,*,† Yoshinori Ikeura,† Izumi Kamo,† Takenori Ishimaru,‡ Yuji Ishichi,† Akira Fujishima,†
Toshimasa Tanaka,† Fumiko Kasahara,† Mitsuru Kawada,§ and Takayuki Doi†
Pharmaceutical Research Division and Technology Development Department, Takeda Chemical Industries, Ltd.,
2-17-85, J usohonmachi, Yodogawa-ku, Osaka 532-8686, J apan, and Discovery Research Division,
Takeda Chemical Industries, Ltd., 10 Wadai, Tsukuba-shi, Ibaraki 300-4293, J apan
Received May 3, 1999
Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-meth-
ylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were
synthesized and evaluated for NK1 antagonistic activities. The 8-membered ring compound
with a â-methyl group at the C(9)-position, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,-
11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-di-
one [(aR,9R)-8b ], was atropodiastereoselectively synthesized by cyclization of a chiral
intermediate, 10g. On the other hand, the 7-membered ring compound with a â-methyl group
at the C(9)-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a
ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl3). Compounds
(9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC50 (inhibition
of [125I]BH-SP binding in human IM-9 cells) ) 0.28 and 0.45 nM, respectively] and in vivo (iv
and po). Significantly, the in vitro activity of (aR,9R)-8b was ca. 750-fold higher than that of
its enantiomer (aS,9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold
higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series,
along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the
-C(6)(dO)-N(7)-CH2Ar moiety is important for NK1 receptor recognition. The NK1 antagonists
showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the
antagonists increased the shutdown time of distension-induced rhythmic bladder contractions
and the bladder volume threshold, and the effects on the shutdown time were found to correlate
well with the NK1 antagonistic activities. Compound (aR,9R)-8b has been identified as a
potential clinical candidate for the treatment of bladder function disorders.
In tr od u ction
ide (trans-113a; Figure 1). Since trans-1 has a tertiary
carboxamide group at the sterically hindered position
(at C(6)), it exhibits two notable structural features
(Scheme 1). First, the trans- and cis-amide rotamers of
1 are separable at room temperature;13a the compound
isolated by conventional workup is the trans-amide
rotamer (trans-1), while the thermodynamically un-
stable cis-isomer (cis-1) was also isolated as a minor
product by careful separation procedures. Both isomers
are interconverted and reach an equilibrium state of a
ca. 7:1 (trans:cis) ratio in solution. Second, trans-1 and
cis-1 exist as a mixture of two separable and stable
axially chiral isomers (atropisomers) [(aR)-trans-1, (aS)-
trans-1 and (aR)-cis-1, (aS)-cis-1, respectively]14,15 aris-
ing from the restricted rotation around the -C(6)-C(d
O)- bond.13c The atropisomers (aR)-trans-1 and (aS)-
trans-1, which were separated by preparative high-
performance liquid chromatography (HPLC) using a
chiral column as oily substances, have significant stabil-
ity in solution; e.g., they were not interconverted in
dimethyl sulfoxide (DMSO) at 37 °C for 16 h and
underwent racemization only after storage at 50 °C for
6 days. The potency of the trans-1 is ca. 7-20-fold higher
than that of cis-1, and the atropisomer (aR)-trans-1 has
ca. 6-13-fold higher potency than (aS)-trans-1 (Table
1). These results indicate that the conformation of (aR)-
trans-1 is preferentially recognized by the receptor.
Substance P (SP) is an endogenous undecapeptide
belonging to the tachykinin peptide family.1 By binding
to the neurokinin-1 (NK1) receptor, this neuropeptide
elicits a wide variety of biological responses in both the
central nervous system and peripheral tissues, including
the transmission of pain and stress signals, the induc-
tion of neurogenic inflammation, and the contraction of
smooth muscles.1 Since the disclosure of the first non-
peptide NK1 antagonist, CP-96,345,2 interest in this
area has dramatically increased, and recently publica-
tions describing orally active NK1 antagonists, with
diverse structures, have appeared (e.g., SR140333,3
RPR100893,4 CP-99,994,5 CP-122,721,6 CGP49823,7
GR205171,8 LY303870,9 L-741,671,10 L-742,694,11 MK-
86912), suggesting potential clinical utility in the treat-
ment of pain, inflammation, rheumatoid arthritis,
asthma, emesis, migraine, and depression.
In our preceding papers,13 we described the discovery
of a potent, 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-carboxam-
* Corresponding author. Phone: +81-6-6300-6541. Fax: +81-6-
6300-6306. E-mail: Natsugari_Hideaki@takeda.co.jp.
† Pharmaceutical Research Division.
‡ Discovery Research Division.
§ Technology Development Department.
10.1021/jm990220r CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/04/1999

Naphthyridinecarboxamides as NK1 Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3983
F igu r e 1. Potent NK1 antagonists: trans-1 and active atropisomers (aR)-trans-1, (aR,S)-trans-1Me, and (aR,9R)-8b (for the
schematic drawings, see the footnote of Scheme 1).
Sch em e 1a
tion of a chiral intermediate, 10g (Schemes 2, 3).13d
Studies on the effects of the NK1 antagonists on bladder
functions in guinea pigs, which implied the clinical
potential of the antagonists in the treatment of pollaki-
uria and urinary incontinence, are also described.
Syn th etic Ch em istr y
The synthesis of the tricyclic analogues of 1 (6-9) is
outlined in Scheme 2. First, 5-(4-methylphenyl)-8-oxo-
8H-pyrano[3,4-b]pyridine-6-carboxylic acid (3) was pre-
pared from 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid
(2) according to a procedure similar to that reported13a
for the synthesis of isocoumarin-3-carboxylic acids from
2-benzoylbenzoic acids: i.e., 2 was condensed with
diethyl hydroxymalonate via the acid chloride to obtain
diethyl 5,6-dihydro-5-hydroxy-5-(4-methylphenyl)-8-oxo-
8H-pyrano[3,4-b]pyridine-6,6-dicarboxylate, which was
heated under reflux in concentrated HCl-AcOH to give
3. The acid 3 was then amidated with 3,5-bis(trifluo-
romethyl)benzylamine to provide the amide 4. Treat-
ment of 4 with the appropriate hydroxy amines 5a -f
(P ) H) followed by dehydration with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) gave the N-[3,5-bis(trifluo-
romethyl)benzyl]-7-(hydroxyalkyl)-7,8-dihydro-5-(4-me-
thylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamides 10a-
f. Similarly, the hydroxy compounds 10g-h were pre-
pared by treatment of 4 with the protected hydroxy-
amines 5g-h [P ) tetrahydropyranyl (THP)] followed
by deprotection with p-toluenesulfonic acid and dehy-
dration with DBU. Cyclization of 10 was accomplished
by mesylation of the hydroxy group followed by treat-
ment with sodium hydride in tetrahydrofuran to give
6-9 in good yields. The stereochemical features of the
tricyclic analogues 6-9 are described in parts (a) and
(b), Results and Discussion.
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 (aR) and (aS) denote
the axial chirality originating from the restricted rotation around
the C(6)-C(O) 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.
From the SAR data obtained for its methyl analogue
[(aR)-trans-1Me; Figure 1] and its stereoisomers, the
absolute axial stereochemistry reqired for the receptor
binding was deduced to be (aR) with the amide oxygen
below (and the nitrogen above) the plane of the 1,7-
naphthyridine ring.13c
From a practical point of view, however, separation
of the atropisomers (aR)-trans-1 and (aS)-trans-1 is
difficult, and further study using trans-1 as a racemate
would meet with difficulty especially at the stage of
pharmaceutical development. Thus, in the search for
new compounds with an improved stereochemical pro-
file, we designed cyclic analogues of 1 having 6-9-
membered rings (the general formula 6-9; Scheme 2).
We also expected cyclization to give these derivatives
the constrained structure desirable for receptor binding
and hence high potency.
Biology
The compounds prepared were evaluated in vitro for
inhibition of [125I]Bolton-Hunter (BH)-SP binding in
human IM-9 cells16 and in vivo for inhibition of capsai-
cin-induced plasma extravasation in the trachea of
guinea pigs17 upon iv and po administration. The NK1
antagonists were also administered iv to urethane-
anesthetized guinea pigs to examine the effects on
bladder function using distension-induced rhythmic
bladder contractions and the bladder volume threshold
as the parameters.
In this paper, we describe the discovery of a new,
orally effective NK1 antagonist, (aR,9R)-7-[3,5-bis(tri-
fluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-
(4-m et h ylp h en yl)-7H -[1,4]d ia zocin o[2,1-g][1,7]-
naphthyridine-6,13-dione [(aR,9R)-8b] (Figure 1), which
was atropodiastereoselectively synthesized by cycliza-
Resu lts a n d Discu ssion
(a ) Cyclic An a logu es of 1 (6, 7a , 8a , a n d 9). The
cyclic analogues of 1 with 6-9-membered rings (6, 7a ,

3984 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19
Natsugari et al.
Ta ble 1. Biological Properties of N-[3,5-Bis(trifluoromethyl)benzyl]-N-methyl-1,7-naphthyridine-6-carboxamide Isomers (1) and Their
Cyclic Analogues (6-9)
NK1 antagonist activities
ID50 (µg/kg)c
effects on bladder functions (iv)
b
compd no.a
IC50 (nM)
iv
po
shutdown timed (min)
increase in bladder thresholde ED30 (mg/kg)
trans-1
(aR)-trans-1
(aS)-trans-1
cis-1
6
7a
0.34 ( 0.07
0.24f
30 (18-54)
7.7 (4.1-12.5)
100 (69-149)
220 (130-2160)
45.4%j
110 (76-178)
12.9 ( 3.9* (8)
16.2 ( 3.1** (10)
5.8 ( 1.2 (10)
11.7 ( 2.6**h (9)
-
0.10 (0.056-0.165)
g
-
-
1.4f
-
-
4.2f
-
17.3 ( 11.3%i
2.3 ( 0.3
0.85 ( 0.08
0.68 ( 0.05
0.38k
-
-
7.2 (1.5-15.0)
4.2 (1.0-8.4)
2.6 (2.1-3.1)
17 (10-31)
11 (5.2-17.3)
3.2 (1.9-5.5)
41 (20-145)
4.3 (2.4-11.4)
26 (6.2-69.0)
>300
73 (61-92)
10.1 ( 1.2 (10)
15.7 ( 3.4* (10)
19.2 ( 2.9** (8)
7.4 ( 1.5 (5)
17.1 ( 2.9** (10)
17.9 ( 3.3** (10)
5.9 ( 1.2 (8)
21.8 ( 3.0** (10)
-
0.37 (0.091-0.573)
8a
19 (9.9-29.3)
0.066 (0.020-0.123)
(aR)-8a
(aS)-8a
9
(9S)-7b
(9R)-7b
(aR,9R)-8b
(aS,9R)-8b
(aS,9S)-8b
(aR,9S)-8b
-
-
-
-
7.1f
1.8 ( 0.1
0.28 ( 0.02
9.5k
0.45 ( 0.10
20 ( 16
340 ( 64
8.6 ( 2.9
40 (7.2-74.3)
0.086 (0.037-0.149)
0.16 (0.11-0.22)
19.9 ( 10.4%l
0.051 (0.021-0.083)
-
33 (18-71)
-
33 (13-98)
-
-
-
6.7 ( 3.0 (10)
-
3.8 ( 9.4%i
-
-
a
b
For the structures, see Schemes 1, 3, and 4 and Figure 2. Inhibition of [125I]BH-SP binding in human IM-9 cells (lymphoblast cells).
Values are the mean ( SD determined by at least three independent experiments (n ) 3-6) run in duplicate unless otherwise noted.
c Capsaicin-induced trachea extravasation in guinea pigs. To determine ID50 values, 5-8 animals were used at each dose. 95% Confidence
d
limits are given in parentheses. Mean ( SE value of shutdown time of distention-induced rhythmic bladder contractions in urethane-
anesthetized guinea pigs at 0.3 mg/kg (iv) unless otherwise noted. Numbers of animals are given in parentheses. Dunnett’s test: **p <
0.01, *p < 0.05. e Increasing effect on volume threshold in urethane-anesthetized guinea pigs. ED30 values are given unless otherwise
noted. To determine the ED30 values, 6-12 animals were used at each dose. 95% confidence limits are given in parentheses. f Mean value
g
h
i
of two independent experiments run in duplicate. -, not tested. Mean ( SE value at 1.0 mg/kg, iv. Mean ( SE value of bladder
volume increase (%) at 0.3 mg/kg (iv) [n ) 6 for cis-1 and n ) 8 for (aS,9S)-8b]. j Inhibition (%) at 0.1 mg/kg (n ) 6). IC50 value determined
by a single experiment run in duplicate. Mean ( SE value of bladder volume increase (%) at 1.0 mg/kg (iv) (n ) 10).
k
l
Sch em e 2a
a
Reagents: (a) SOCl2/THF; (b) diethyl hydroxymalonate, NaH/THF; (c) concd HCl-AcOH; (d) 3,5-bis(trifluoromethyl)benzylamine,
Et3N/THF; (e) 5/THF-MeOH; (f) DBU/toluene-CH3CN; (g) p-TosOH/MeOH (in the case of preparing 10g-h via the THP ethers: P )
THP); (h) MsCl, Et3N/THF; (i) NaH/THF. bFor specification of the residue X in 6-9 including stereochemistry originating from
atropisomerism, see Figure 2 and Schemes 1, 3, and 4.
8a , and 9) (Figure 2) have an apparent advantage in
that they are expected to exist as single amide rotamers;
the cyclic structure would serve to constrain the naph-
thyridine and N-benzyl groups bound to the amide
moiety so as to be disposed in the trans conformation.
In fact, the presence of the amide isomers was not
observed in their NMR spectra.
As for the atropisomers in these compounds, we

Naphthyridinecarboxamides as NK1 Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3985
F igu r e 2. Atropisomers [(aR) and (aS)] of cyclic analogues of
1 having 6-9-membered rings (6, 7a , 8a , and 9).
initially supposed that the flipping of these new rings
would be too rapid to enable the separation of stable
isomers at room temperature.18 The pattern of the
N-benzylic methylene protons in the NMR spectra was
first examined for detection of the atropisomers. The
methylene protons in compound 6 with a 6-membered
ring appeared as a singlet, indicating that the conform-
ers are rapidly interconverted even on the NMR time
scale, whereas the other compounds with 7-9-mem-
bered rings (7a , 8a , and 9) showed distinct AB patterns
for the methylene protons, indicating slow interconver-
sion of the conformers on the NMR time scale. Com-
pounds 6, 7a , 8a , and 9 were next analyzed by chiral
HPLC (CHIRALPAK AD).19 Compound 6 showed, as
expected, a single peak at room temperature, indicating
again rapid interconversion of the conformers. Analysis
of 7a at room temperature also showed a single peak
at room temperature. However, analysis of 7a at or
below -20 °C did show two equal peaks of the atropi-
somers [(aR)-7a and (aS)-7a ], as had been anticipated
from the NMR study. Although they were separated by
preparative HPLC at that temperature, each separated
fraction, obtained after rapid and careful workup at ca.
0 °C, again showed two equal peaks by HPLC analysis
at -20 °C, indicating rapid interconversion of the
conformers at or above ca. 0 °C. The HPLC analysis of
the compounds having 8- and 9-membered rings (8a and
9) showed two peaks at room temperature, indicating
the presence of separable atropisomers. In fact, 8a was
separated by preparative HPLC using a chiral column
to give the atropisomers (aR)-8a and (aS)-8a , which
have opposite [R]D values (+45.6° and -41.3°, respec-
tively) and show considerable stability in solution; e.g.,
they are gradually interconverted in DMSO to a ca. 70%
enantiomeric excess (i.e., ca. 15% conversion) at 37 °C
over 40 h and undergo racemization after storage at 50
°C for ca. 2 days.
F igu r e 3. Overlapping between the most stable conformer
of trans-1 (dotted line) and those of the cyclic analogues (bold
line) [A, 6; B, 7a ; C, 8a ; and D, 9] as determined by the
conformational analysis using Discover CVFF force field.
cies are higher than that of trans-1, and also the high
in vivo potency observed upon oral administration of 8a
is remarkable. The atropisomers of 8a [(aR)-8a and (aS)-
8a ] exhibited, as expected, different affinities for the
NK1 receptor both in vitro and in vivo (iv). The potency
of (aR)-8a was ca. 6-19-fold higher than that of (aS)-
8a . The absolute stereochemistry of the active atropi-
somer of 8a is presumed to have the same conformation
(aR) as (aR)-trans-1 with the amide oxygen below (and
the nitrogen above) the plane of the naphthyridine ring
[see part (b), Results and Discussion].
(b) Cyclic An a logu es of 1 w ith a Ch ir a l Meth yl
Gr ou p [(9S)-7b, (9R)-7b, (9R)-8b, a n d (9S)-8b]. The
results described in Results and Discussion (a) indicate
that, although having favorable in vivo activity, 8a is a
racemate, making development as a clinical candidate
difficult. Thus, the stereoselective synthesis of the active
atropisomer of the 8-membered ring compound became
our next goal. Since a practical route for the atropodi-
astereoselective synthesis of (aR)-8a itself could not be
easily found, we selected the C(9)-methyl analogues of
8a [i.e., (9R)- and (9S)-8b] as the target compounds,
expecting asymmetric induction from the C(9)-chiral
center to obtain the desirable axial chirality (aR). We
thus achieved the stereoselective synthesis of the atro-
pisomer [(aR,9R)-8b] by cyclization of an intermediate
with a chiral methyl group, 10g (Scheme 3). The ratio
of the atropisomer (aR,9R)-8b to its isomer (aS,9R)-8b
was ca. 98:2, and a single recrystallization step gave
(aR,9R)-8b with >99% diastereomeric excess (de). The
minor isomer (aS,9R)-8b, with 98.6% de, was isolated
as a powdery substance by repeated preparative HPLC
followed by a rapid and careful workup (e.g., evaporation
of solvent at low temperature); at present, the purity of
(aS,9R)-8b does not exceed 99% de due to the instability
of (aS,9R)-8b in solution (see discussion below).
The NK1 antagonistic activities of the tricyclic com-
pounds [6, 7a , 8a , 9, (aR)-8a , and (aS)-8a ] are shown
in Table 1. The in vitro potencies of 6, 7a , 8a , and 9
correspond well to the in vivo (iv) potencies, and they
vary with the ring size in the order of 8a (ring size 8) g
7a (7) > 9 (9) > 6 (6), which presumably reflects the
order of conformations desirable for receptor recognition.
The low potency of 6 can be explained by the confor-
mational studies on trans-1, 6, 7a , 8a , and 9, in which
the 3,5-bis(trifluoromethyl)phenyl group in 6 was found
not to overlap with that in trans-1 (Figure 3). It is
noteworthy that, although 7a , 8a , and 9 showed lower
in vitro potencies than trans-1, their in vivo (iv) poten-
The stereochemistry of (aR,9R)-8b was determined
by single-crystal X-ray structural analysis (Figure 4),
which showed that the -N(7)-C(8)-C(9)-C(10)- moiety

3986 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19
Natsugari et al.
Sch em e 3
F igu r e 4. Stereoscopic molecular view of (aR,9R)-8b as determined by X-ray crystallographic analysis.
in the 8-membered ring is disposed above the plane of
the adjacent 1,7-naphthyridine ring and the amide
oxygen (C(6)dO) is below the ring [i.e., (aR) stereochem-
istry]. The analysis also revealed the trans-conformation
of the naphthyridine and N-benzyl groups at the amide
Both atropisomers, (aR,9R)-8b and (aS,9R)-8b, were
found to be interconverted in solution to reach the same
equilibrium state [(aR,9R)-8b/(aS,9R)-8b ) ca. 98:2]
with the interconversion rate being temperature-de-
pendent; e.g., in ethanol, both (aR,9R)-8b and (aS,9R)-
8b reached equilibrium at 37 °C in ca. 60 h and at 50
°C in ca. 15 h.20
The enantiomer of (aR,9R)-8b [(aS,9S)-8b], with
>99% de, was similarly obtained by the cyclization of
the corresponding intermediate 10h followed by a single
recrystallization step. The minor diastereomer [(aR,9S)-
8b] with 97.5% de was also isolated as a powdery
substance by preparative HPLC (Scheme 3).
The 7-membered ring compounds with a chiral methyl
group [(9S)-7b and its enantiomer (9R)-7b] were pre-
pared by cyclization of the intermediates containing a
chiral methyl group (10e and its enantiomer 10f)
(Scheme 4) to look for improved biological activity
accompanied by improved stereochemical and pharma-
cokinetic profiles. The stereochemical nature of (9S)-
7b and (9R)-7b is also of interest. Their NMR spectra
showed signals due to two diastereomers in a ratio of
ca. 3:2, indicating slow interconversion of the atropiso-
bond and a stacking conformation between the C(5)
-
phenyl and the N(7)-benzylic phenyl groups as observed
in the X-ray analysis of trans-1.13a The relative spatial
orientation of the C(9)-methyl group and the N-[3,5-bis-
(trifluoromethyl)benzyl] group in (aR,9R)-8b is pre-
sumed to be important for high atropodiastereoselec-
tivity. These two groups in (aR,9R)-8b are disposed in
opposite directions, both in the crystalline form and in
solution, as shown by the X-ray analysis and by NMR
studies (i.e., the NOE between the C(9)-proton and a
benzylic methylene proton), respectively. The same two
groups in (aS,9R)-8b are shown to be disposed in the
same orientation in solution as observed by the NOE
between the C(9)-methyl protons and a benzylic meth-
ylene proton. The repulsion of these groups in (aS,9R)-
8b may cause steric instability leading to the preferen-
tial formation of the thermodynamically stable atrop-
isomer (aR,9R)-8b in the cyclization of 10g.

Naphthyridinecarboxamides as NK1 Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3987
Sch em e 4
mers [i.e., the diastereomers (aR) and (aS) of 7b] on the
NMR time scale. The chiral HPLC analysis of (9S)-7b
gave results similar to those obtained with the unsub-
stituted 7-membered ring compound 7a , i.e., a single
peak at room temperature and two peaks at or below
-20 °C (ca. 7:3 ratio at -40 °C), indicating rapid
interconversion of the atropisomers [(aR,9S)-7b and
(aS,9S)-7b] at room temperature as observed with 7a
[(aR)-7a and (aS)-7a ].
The SAR in the series of 8-membered ring compounds
with a chiral C(9)-methyl group [(aR,9R)-8b, (aS,9R)-
8b, (aR,9S)-8b, and (aS,9S)-8b] (Table 1) is especially
useful for better understanding the stereochemistry
required for receptor recognition. Compound (aR,9R)-
8b exhibited excellent antagonistic activities both in
vitro and in vivo. Significantly, the in vitro activity of
(aR,9R)-8b is ca. 750-fold higher than that of the
enantiomer (aS,9S)-8b, ca. 40-fold higher than that of
the atropisomer (aS,9R)-8b, and ca. 20-fold higher than
that of the diastereomer (aR,9S)-8b. These striking
differences in potency between (aR,9R)-8b and its
isomers, along with the SAR described above and in our
preceding papers,13 indicate that the stereochemistry
around the -C(6)(dO)-N(7)-CH2-Ar moiety is the most
important factor for receptor recognition; the amide
moiety functions as a hydrogen bond acceptor center in
the interaction with the receptor as reported for the
tryptophan ester NK1 antagonist L-732,138 [3,5-bis-
(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan].21
The conformational studies on (aR,9R)-8b and L-732,-
138 indicated that their most stable conformers overlap
well as shown in Figure 5, suggesting that the key
determinants for the receptor recognition are similar
each other. Furthermore, in compound (aR,9R)-8b, the
â-methyl group serves to constrain the stereochemistry
so as to dispose the amide oxygen below the plane of
the 1,7-naphthyridine ring and to make the benzylic
phenyl group adopt a stacking conformation with the
F igu r e 5. Overlapping between the most stable conformers
of (aR,9R)-8b (bold line) and L-732,138 (dotted line) as
determined by the conformational analysis using Discover
CVFF force field.
ascribed to the cis-relationship between the benzyl
moiety and the C(9)-R-methyl group [cf. trans in (aR,9R)-
8b] to produce a deleterious effect on receptor binding.
Importantly, the 7-membered ring compound with a
â-methyl group (9S)-7b showed excellent in vitro and
in vivo (iv) activities. The potencies are similar to or
slightly higher than those predicted from the activities
of the unsubstituted compound 7a . This highly im-
proved activity of (9S)-7b may be explained by the
conformational change at the benzyl moiety, which is
affected by the C(9)-methyl substituent so as to be better
oriented for receptor recognition. The in vitro activity
of (9S)-7b is ca. 30-fold higher than that of the R-methyl
derivative (9R)-7b. The smaller difference in the potency
between the 7-membered ring enantiomers [(9S)-7b and
(9R)-7b], compared with the potency difference between
the 8-membered enantiomers [i.e., ca. 500-fold between
(aR,9R)-8b and (aS,9R)-8b], may reside in the greater
conformational flexibility of the 7-membered ring.
Both the active atropisomer with an 8-membered ring
(aR,9R)-8b and the active enantiomer with a 7-mem-
bered ring (9S)-7b have potent inhibitory effects upon
oral administration, with ID50 values of 33 µg/kg.
C
(5)-phenyl group. We suppose that the weak activity
of the diastereomer (aR,9S)-8b, which has (aR) config-
uration desirable for receptor recognition, may be

3988 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19
Natsugari et al.
Compounds (aR,9R)-8b and (9S)-7b exhibited more
than ca. 500-1000-fold selectivity for the human NK1
receptor (IM-9 cells) over the rat NK1 receptor (rat
forebrain: IC50 value 85 and 310 nM, respectively).22
The selectivity of (aR,9R)-8b and (9S)-7b for the tachy-
kinin NK1, NK2, and NK3 receptors was assessed by
functional assays using guinea pig ileum contraction
induced by SP and NKA (the pA2 values were deter-
mined to be 9.5 and 9.4 for NK1 and 6.0 and 4.9 for NK2,
respectively) and [125I]Me-Phe7-NKB binding in guinea
pig cerebral cortex membranes23 (the IC50 values for
NK3 were determined to be >1 µM for both compounds),
indicating that (aR,9R)-8b and (9S)-7b are selective for
NK1 over NK2 and NK3.24,25 In the SP-induced guinea
pig ileum contraction assay of (aR,9R)-8b and (9S)-7b,
increasing concentrations of these compounds produced
parallel shifts of the log concentration-response curves
for SP to the right, and the magnitude of the maximum
responses to SP remained unchanged, indicating that
the compounds behave as competitive antagonists.
- 0.825, P < 0.001)] were observed. Especially note-
worthy are the differences in the activity between pairs
of optically active compounds [i.e., (aR)-trans-1 vs (aS)-
trans-1, (aR)-8b vs (aS)-8a , (9S)-7b vs (9R)-7b, and
(aR,9R)-8b vs (aS,9S)-8b] and between the amide
isomers (trans-1 vs cis-1); in all cases, the compound
with higher affinity for the NK1 receptor caused a
greater increase in shutdown time. None of the com-
pounds had an effect on the contractile intravesical
pressure, suggesting that the site of action of these NK1
antagonists is in the central nervous system.
(c-2) Effect on Bla d d er Volu m e Th r esh old . To
ascertain whether the suppressive effects on distension-
induced rhythmic bladder contractions associated with
the NK1 antagonistic effects may be related to an
increase in bladder storage function, the effect on the
bladder volume threshold (i.e., volume to which the
bladder can be filled before voiding) in urethane-
anesthetized guinea pigs was evaluated for typical
compounds. In this assay, trans-1 showed potent activity
upon iv injection with an ED30 value (the dose of the
antagonist that increases the bladder volume threshold
by 30%) of 0.10 mg/kg. Table 1 shows the ED30 values
or percent increase in volume threshold compared with
the pretreatment value. The activity was found to
correlate relatively well with the effects on the shut-
down time (r ) - 0.805, P < 0.05); especially noteworthy
are differences in the activities between pairs of enan-
tiomers [i.e., (9S)-7b vs (9R)-7b and (aR,9R)-8b vs
(aS,9S)-8b]. In the general, compounds with NK1 an-
tagonistic activity [in vitro and in vivo (iv)] equal to that
of trans-1 exhibited activity similar to [9 and (9S)-7b]
or more potent than [8a and (aR,9R)-8b] that of trans-
1, whereas compounds cis-1, (9R)-7b, and (aS,9S)-8b
showed weak activities, corresponding well to their low
NK1 antagonistic activities. The high potency of (aR,9R)-
8b (ED30 ) 0.051 mg/kg, iv) is remarkable and presum-
ably reflects its good pharmacokinetic profile. The
results reported in parts (c-1) and (c-2), Results and
Discussion, suggest that the NK1 receptor is involved
in the micturition mechanisms in guinea pigs, where
NK1 antagonists act to increase the interval time of
bladder contractions and the bladder volume threshold.
(c) Effects of th e NK1 An ta gon ists on Bla d d er
F u n ction s in Gu in ea P igs. So far, a number of
potential clinical uses have been suggested for NK1
antagonists; these are the treatment of pain, inflam-
mation, rheumatoid arthritis, asthma, emesis, migraine,
and depression. In our examination of the clinical
potential of our new NK1 antagonists, we have exten-
sively studied the pharmacological profiles of these
compounds. Several lines of evidence indicate that
tachykinins play an important role in the activation of
micturition-related reflexes in rats,26 which prompted
us to investigate the effects of our NK1 antagonists on
micturition for their possible use in the treatment of
pollakiuria and urinary incontinence. Thus, we exam-
ined the effects of the NK1 antagonists on bladder
functions in urethane-anesthetized guinea pigs upon iv
administration by measuring the shutdown time of the
distension-induced rhythmic bladder contractions and
the bladder volume threshold (Table 1).
(c-1) Effect on Disten sion -In d u ced Rh yth m ic
Bla d d er Con tr a ction s. Distension of the urinary
bladder of urethane-anesthetized guinea pigs by injec-
tion of saline (3-4.5 mL) induced high amplitude (>15
mmHg) rhythmic contractions with intervals of ca. 4-9
min. The contractions were completely eliminated by
dropping tetrodotoxin onto the surface of the bladder
dome, and the contractile pressure was reduced by
intravenous injection of atropine. These results indicate
that the distension-induced contractions are of neuro-
genic, not myogenic, origin. The effects of the compounds
on the bladder contractions were evaluated using the
shutdown time (i.e., the time interval between the
contractions) and the contractile intravesical pressure.
In this assay, iv injection of trans-1 increased in a dose-
dependent manner the shutdown time to 12.9 and 26.3
min at doses of 0.3 and 1.0 mg/kg, respectively [control
value (vehicle: DMSO), 4.1 min], without affecting the
contractile pressure. Table 1 shows the shutdown time
when compounds were administered at 0.3 mg/kg, iv (in
the case of cis-1, at 1.0 mg/kg, iv). Significant nonpara-
metric correlations27 between the shutdown time and
the NK1 antagonistic activities [IC50 (in vitro correlation
coefficient (r) ) - 0.650, P < 0.05) and ID50 (in vivo r )
Con clu sion s
Studies on the atropisomers of the 6-(N-benzyl-N-
methylcarboxamide) derivative of 1,7-naphthyridine (1),
a potent and orally active NK1 antagonist, led us to
prepare a series of cyclic analogues of 1 (6-9). We have
investigated the chemical properties and antagonistic
activities of these derivatives and succeeded in prepar-
ing atropisomerically pure NK1 antagonists. The fol-
lowing points should be emphasized: (1) the 8-mem-
bered ring compound with a â-methyl group [(aR,9R)-
8b] and its enantiomer [(aS,9S)-8b] are atropodiastereo-
selectively synthesized by cyclization of the chiral
intermediates 10g and 10h , respectively; (2) the 7-mem-
bered ring compound with a â-methyl group [(9S)-7b]
and its enantiomer [(9R)-7b ] exist as an equilibrium
mixture of atropisomers in solution at room tempera-
ture; (3) (9S)-7b and (aR,9R)-8b have excellent antago-
nistic activities both in vitro and in vivo (iv and po), and
(aR,9R)-8b has ca. 750-fold higher in vitro activity than
its enantiomer (aS,9S)-8b ; (4) the X-ray structural

Naphthyridinecarboxamides as NK1 Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3989
ture of 3 (300 mg, 1.07 mmol), DMF (catalytic amount), thionyl
chloride (1.0 mL, 13.7 mmol), dichloroethane (5 mL), and THF
(5 mL) was heated under reflux for 1.5 h. The solvent was
evaporated and the residue was dissolved in THF (15 mL). To
the solution were added 3,5-bis(trifluoromethyl)benzylamine
(278 mg, 1.14 mmol) and Et3N (0.5 mL, 3.59 mmol), and the
mixture was stirred at room temperature for 30 min. After
dilution with EtOAc, the mixture was washed successively
with H2O, diluted HCl, aqueous NaHCO3, and brine. The
organic layer was dried and concentrated to give 4 as colorless
crystals (383 mg, 71%). Recrystallization from EtOAc-ethyl
analysis of (aR,9R)-8b exhibits the active conformation
required for NK1 receptor recognition, and this confor-
mationally restricted molecule is useful as an aid in
better understanding the interactions between the
antagonists and the NK1 receptor; and (5) the NK1
antagonists increased the shutdown time of distention-
induced bladder contractions and the bladder volume
threshold in guinea pigs upon iv injection, and the
effects on the shutdown time were found to correlate
well with the NK1 antagonistic activities, implying the
clinical potential of NK1 antagonists in the treatment
of pollakiuria and urinary incontinence. Compound
(aR,9R)-8b, designated as TAK-637, has been identified
as a potential clinical candidate. Further pharmacologi-
cal studies on (aR,9R)-8b will be reported in due course.
1
ether gave colorless crystals: mp 182-183 °C; H NMR 2.44
(3 H, s), 4.63 (2 H, d, J ) 6.4), 7.17 (2 H, d, J ) 8.1), 7.34 (2
H, d, J ) 8.1), 7.50-7.65 (3 H, m), 7.73 (2 H, s), 7.80 (1 H, s),
8.96 (1 H, m). Anal. (C25H16F6N2O3) C, H, N.
(R)-4-Am in o-2-m eth yl-1-bu ta n ol THP Eth er (5g). To a
stirred suspension of LiAlH4 (3.70 g, 97.5 mmol) in ethyl ether
(200 mL) was added a solution of (R)-3-cyano-2-methyl-1-
propanol THP ether28b (22.7 g, 124 mmol) in ethyl ether (100
mL) dropwise at 0 °C and the mixture stirred at room
temperature for 1 h. To the mixture were added successively
H2O (3 mL), 15% aqueous NaOH (3 mL), and H2O (10 mL)
and the whole was stirred for 30 min. Insolubles were filtered
off and washed with EtOAc. The filtrate and washings were
combined and washed successively with aqueous K2CO3 and
saturated aqueous NaCl. The organic layer was dried and
evaporated to give 5g as a colorless oil (21.7 g, 94%): 1H NMR
0.94 (3 H × 1/2, d, J ) 6.8), 0.95 (3 H × 1/2, d, J ) 6.8), 1.2-
1.9 (11 H, m), 3.13-3.90 (6 H, m), 4.57 (1 H, b).
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. Chemical shifts
are given in ppm with tetramethylsilane as the internal
standard, and coupling constants (J ) are given in hertz (Hz).
The following abbreviations are used: s ) singlet, d ) doublet,
t ) triplet, m ) multiplet, dd ) double doublet, bs ) broad
singlet, bt ) broad triplet. IR spectra were obtained on a
Hitachi IR-215 spectrometer. Mass spectra were obtained on
a J EOL J MS-AX505W spectrometer. Optical rotations were
determined with a J ASCO DIP-370 digital polarimeter. El-
emental analyses were carried out by Takeda Analytical
Laboratories Ltd. and are 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.
3-(4-Meth ylben zoyl)-2-pyr idin ecar boxylic Acid (2). Com-
pound 2 was prepared from 2,3-pyridinedicarboxylic acid
anhydride and 4-bromotoluene by the method previously
reported.13a
(S)-4-Am in o-2-m eth yl-1-bu ta n ol THP Eth er (5h ). Com-
pound 5h was prepared from (S)-3-cyano-2-methyl-1-propanol
THP ether28a according to the same procedure described for
the preparation of 5g.
(R)-N-[3,5-Bis(t r iflu or om et h yl)b en zyl]-7,8-d ih yd r o-7-
(4-h yd r oxy-3-m eth ylbu tyl)-5-(4-m eth ylp h en yl)-8-oxo-1,7-
n a p h th yr id in e-6-ca r boxa m id e (10g). To a solution of 4
(12.0 g, 23.7 mmol) in THF (75 mL)-MeOH (75 mL) was added
5g (7.4 g, 39.5 mmol), and the mixture was stirred at room
temperature for 16 h. After evaporation of the solvent, the
residue was diluted with EtOAc. The mixture was washed
successively with H2O, 5% aqueous H3PO4, and brine, dried,
and evaporated. To the residue were added acetonitrile (20
mL), toluene (125 mL), and DBU (5.0 mL, 33.4 mmol), and
the mixture was refluxed for 1 h. After evaporation of the
solvent, the residue was diluted with EtOAc and washed
successively with H2O, 5% aqueous H3PO4, and brine. The
organic layer was dried and concentrated to give THP ether
of 10g as a pale yellow oil. To a solution of this oil in MeOH
(50 mL) was added p-toluenesulfonic acid monohydrate (5.0
g, 26.3 mmol), and the mixture was stirred at room temper-
ature for 30 min. After evaporation of the solvent, the residue
was diluted with EtOAc and washed with aqueous NaHCO3
and brine. The organic layer was dried and concentrated to
give 10g as colorless crystals (7.74 g, 55%). Recrystallization
from EtOAc-IPE gave colorless crystals: mp 123-125 °C
5-(4-Meth ylp h en yl)-8-oxo-8H-p yr a n o[3,4-b]p yr id in e-6-
ca r boxylic Acid (3). A mixture of 2 (3.0 g, 12.4 mmol), DMF
(1 drop), thionyl chloride (4.5 mL, 61.7 mmol), and THF (30
mL) was heated under reflux for 2 h. The solvent was
evaporated and the crystalline residue was dissolved in THF
(50 mL). To the solution were added diethyl hydroxymalonate
(4.1 g, 23.3 mmol) and then sodium hydride (60% dispersion
in oil) (646 mg, 16.2 mmol) portionwise with stirring and
cooling at -10 °C. After being stirred for 30 min at -10 °C,
the reaction mixture was added to a solution of EtOAc (100
mL) and H2O (100 mL). The organic layer was separated, and
the aqueous layer was extracted with EtOAc. The organic layer
and the extract were combined, washed with H2O and brine,
dried, and evaporated to give diethyl 5,6-dihydro-5-hydroxy-
5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6,6-dicar-
boxylate as colorless crystals (4.0 g, 81%). Recrystallization
from EtOAc-diisopropyl ether (IPE) gave colorless crystals:
1
(once melted and then solidified), 205-206 °C; H NMR 0.79
(3 H, d, J ) 6.6), 1.4-1.8 (3 H, m), 2.28 (3 H, s), 3.03 (1 H, t,
J ) 6.6, OH), 3.2-3.7 (4 H, m), 4.49 (2 H, d, J ) 5.8), 7.0-7.3
(4 H, m), 7.30 (1 H, dd, J ) 8.4, 4.4), 7.53 (1 H, dd, J ) 8.4,
1.4), 7.68 (2 H, s), 7.78 (1 H, s), 8.48 (1 H, t, J ) 6.0), 8.61 (1
1
mp 148-149 °C; H NMR 1.06 (3 H, t, J ) 7.1), 1.21 (3 H, t,
J ) 7.1), 2.31 (3 H, s), 3.95-4.30 (4 H, m), 4.65 (1 H, s), 7.15
(2 H, d, J ) 8.3), 7.55 (1 H, dd, J ) 8.0, 4.8), 7.65 (2 H, d, J )
8.3), 8.47 (1 H, dd, J ) 8.0, 1.4), 8.86 (1 H, dd, J ) 4.8, 1.4).
Anal. (C21H21NO7) C, H, N.
20
H, dd, J ) 4.4, 1.4); [R]D +1.2° (c ) 0.471, CHCl3). Anal.
(C30H27F6N3O3) C, H, N.
A mixture of the crystals thus obtained (14.1 g, 35.3 mmol),
AcOH (100 mL), and concentrated HCl (100 mL) was refluxed
for 3 h. After evaporation of the solvent, the residue was
diluted with H2O. The colorless crystals precipitated were
collected and washed with H2O to give 3 (8.45 g, 85%).
Recrystallization from THF-IPE gave colorless crystals: mp
N-[3,5-Bis(t r iflu or om et h yl)b en zyl]-7,8-d ih yd r o-7-(2-
h yd r oxyeth 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 (10a ). Compound 4 (2.53 g, 5.0 mmol)
was treated according to a procedure similar to that described
for the preparation of 10g using 2-aminoethanol (5a ) in place
of 5g to afford 10a as colorless crystals (1.92 g, 70%).
Recrystallization from EtOAc gave colorless crystals: mp 123-
1
274-277 °C (gradually turned to brown from ca. 240 °C); H
1
NMR (CDCl3 + DMSO-d6) 2.43 (3 H, s), 6.10 (1 H, bs, COOH),
7.16 (2 H, d, J ) 8.0), 7.29 (2 H, d, J ) 8.0), 7.50-7.70 (2 H,
m), 8.94 (1 H m). Anal. (C16H11NO4‚0.1H2O) C, H, N.
N-[3,5-Bis(tr iflu or om eth yl)ben zyl]-5-(4-m eth ylph en yl)-
8-oxo-8H-pyr an o[3,4-b]pyr idin e-6-car boxam ide (4). A mix-
125 °C; H NMR 2.28 (3 H, s), 3.71 (2 H, m), 3.97 (2 H, m),
4.46 (2 H, d, J ) 5.2), 7.00-7.20 (4 H, m), 7.37 (1 H, dd, J )
8.4, 4.2), 7.52 (1 H, dd, J ) 8.4, 1.6), 7.66 (2 H, s), 7.76 (1 H,
s), 8.51 (1 H, bs), 8.61 (1 H, dd, J ) 4.2, 1.6). Anal.
(C27H21F6N3O3) C, H, N.

3990 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19
Natsugari et al.
N-[3,5-Bis(t r iflu or om et h yl)b en zyl]-7,8-d ih yd r o-7-(3-
h yd r oxyp r op yl)-5-(4-m et h ylp h en yl)-8-oxo-1,7-n a p h t h y-
r id in e-6-ca r boxa m id e (10b). Compound 4 (8.29 g, 16.4
mmol) was treated according to a procedure similar to that
described for the preparation of 10g using 3-amino-1-propanol
(5b) in place of 5g to afford 10b as colorless crystals (6.53 g,
71%). Recrystallization from THF-MeOH-ethyl ether gave
colorless crystals: mp 127-129 °C; 1H NMR 1.89 (2 H, m),
2.28 (3 H, s), 3.45 (2 H, m), 3.70 (2 H, m), 4.49 (2 H, d, J )
6.0), 7.07 (2 H, d, J ) 8.0), 7.20 (2 H, d, J ) 8.0), 7.41 (1 H,
dd, J ) 8.2, 4.4), 7.57 (1 H, dd, J ) 8.2, 1.7), 7.67 (2 H, s), 7.78
(1 H, s), 8.30 (1 H, bt), 8.68 (1 H, dd, J ) 4.4, 1.7). Anal.
(C28H23F6N3O3) C, H, N.
N-[3,5-Bis(t r iflu or om et h yl)b en zyl]-7,8-d ih yd r o-7-(4-
h yd r oxybu tyl)-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 (10c). Compound 4 (200 mg, 0.39 mmol)
was treated according to a procedure similar to that described
for the preparation of 10g using 4-amino-1-butanol (5c) in
place of 5g to afford 10c as colorless crystals (144 mg, 63%).
Recrystallization from EtOAc-IPE gave colorless crystals: mp
187-188 °C; 1H NMR 1.3-1.5 (2 H, m), 1.6-1.9 (2 H, m), 2.29
(3 H, s), 2.82 (1 H, bs), 3.55 (2 H, t, J ) 5.7), 3.69 (2 H, m),
4.48 (2 H, d, J ) 5.8), 7.08 (2 H, d, J ) 8.1), 7.21 (2 H, d, J )
8.1), 7.29 (1 H, dd, J ) 8.4, 4.2), 7.52 (1 H, dd, J ) 8.4, 1.4),
7.68 (2 H, s), 7.78 (1 H, s), 8.39 (1 H, bt), 8.61 (1 H, dd, J )
4.2, 1.4). Anal. (C29H25F6N3O3) C, H, N.
N-[3,5-Bis(t r iflu or om et h yl)b en zyl]-7,8-d ih yd r o-7-(5-
h yd r oxyp en tyl)-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 (10d ). Compound 4 (200 mg, 0.39 mmol)
was treated according to a procedure similar to that described
for the preparation of 10g using 5-amino-1-pentanol (5d ) in
place of 5g to afford 10d as colorless crystals (190 mg, 81%).
Recrystallization from EtOAc-ethyl ether gave colorless crys-
tals: mp 136-137 °C; 1H NMR 1.10-1.35 (2 H, m), 1.35-1.55
(2 H, m), 1.6-1.9 (2 H, m), 2.28 (3 H, s), 3.50-3.70 (4 H, m),
4.47 (2 H, d, J ) 5.8), 7.06 (2 H, d, J ) 8.0), 7.19 (2 H, d, J )
8.0), 7.35 (1 H, dd, J ) 8.3, 4.4), 7.50 (1 H, d, J ) 8.3, 1.4),
7.69 (2 H, s), 7.78 (1 H, s), 8.29 (1 H, bt), 8.64 (1 H, dd, J )
4.4, 1.4). Anal. (C30H27F6N3O3) C, H, N.
125 °C (once melted and then solidified), 207-208 °C; 1H NMR
0.79 (3 H, d, J ) 6.6), 1.4-1.8 (3 H, m), 2.28 (3 H, s), 3.03 (1
H, t, J ) 6.6, OH), 3.2-3.7 (4 H, m), 4.49 (2 H, d, J ) 5.8),
7.0-7.3 (4 H, m), 7.30 (1 H, dd, J ) 8.4, 4.4), 7.53 (1 H, dd, J
) 8.4, 1.4), 7.68 (2 H, s), 7.78 (1 H, s), 8.48 (1 H, t, J ) 6.0),
20
8.61 (1 H, dd, J ) 4.4, 1.4); [R]D -2.7° (c ) 0.391, CHCl3).
Anal. (C30H27F6N3O3‚0.5H2O) C, H, N.
(a R,9R)-7-[3,5-Bis(t r iflu or om et h yl)b en zyl]-8,9,10,11-
t et r a h yd r o-9-m et h yl-5-(4-m et h ylp h en yl)-7H -[1,4]d ia zo-
cin o[2,1-g][1,7]n a p h th yr id in e-6,13-d ion e [(a R,9R)-8b]. To
a solution of 10g (7.64 g, 12.9 mmol) and Et3N (3.3 mL, 23.7
mmol) in THF (100 mL) was added methanesulfonyl chloride
(1.8 mL, 23.3 mmol) at 0 °C, and the mixture was stirred at 0
°C for 30 min. The mixture was added to aqueous NaHCO3
(50 mL), stirred at room temperature for 30 min, and extracted
with EtOAc. The extract was washed successively with H2O,
diluted HCl, and brine, dried, and evaporated to give the
mesylate of 10g as a pale yellow foam. To a solution of this
mesylate in THF (150 mL) was added NaH (60% dispersion
in oil) (800 mg, 20.0 mmol) and the mixture was refluxed for
1 h. After dilution with EtOAc, the mixture was washed
successively with H2O, diluted HCl, H2O, aqueous NaHCO3,
and brine, dried, and concentrated to give (aR,9R)-8b as
colorless crystals (5.15 g, 69%). Recrystallization from EtOAc-
IPE gave colorless crystals: mp 226-228 °C; 1H NMR 0.91 (3
H, d, J ) 6.8), 1.73 (1 H, m), 1.95-2.40 (2 H, m), 2.37 (3 H, s),
2.97 (1 H, d, J ) 15), 3.35-3.62 (2 H, m), 3.99 (1 H, d, J ) 15),
5.10 (1 H, dd, J ) 14, 5.3), 5.46 (1 H, d, J ) 15), 6.83 (1 H, dd,
J ) 7.8, 1.6), 7.05 (1 H, d, J ) 7.8), 7.25 (1 H, d, J ) 7.8), 7.34
(1 H, dd, J ) 7.8, 1.6), 7.46 (1 H, dd, J ) 8.4, 4.2), 7.47 (2 H,
s), 7.55 (1 H, dd, J ) 8.4, 1.8), 7.81 (1 H, dd, J ) 4.2, 1.8), 8.91
(1 H, dd, J ) 4.2, 1.8); an NOE, taken on a J EOL J NM-GX400
(400 MHz) spectrometer in CDCl3, was observed between a
20
benzylic methylene-H (δ 3.999) and C(9)-H (δ 2.095); [R]D
+109.4° (c ) 0.541, MeOH). Anal. (C30H25F6N3O2) C, H, N.
7-[3,5-Bis(tr iflu or om eth yl)ben zyl]-8,9-d ih yd r o-5-(4-m e-
th ylp h en yl)-7H-[1,4]p yr a zin o[2,1-g][1,7]n a p h th yr id in e-
6,11-d ion e (6). Compound 10a (200 mg, 0.36 mmol) was
treated according to a procedure similar to that described for
the preparation of (aR,9R)-8b to afford 6 as colorless crystals
(109 mg, 56%). Recrystallization from EtOAc-ethyl ether gave
colorless crystals: mp 270-271 °C; 1H NMR 2.46 (3 H, s), 3.67
(2 H, t like, J ) 5.4), 4.51 (2 H, t like, J ) 5.4), 4.81 (2 H, s),
7.13 (2 H, d, J ) 8.1), 7.33 (2 H, d, J ) 8.1), 7.52 (1 H, dd, J
) 8.4, 4.4), 7.64 (1 H, dd, J ) 8.4, 1.6), 7.70 (2 H, s), 7.84 (1 H,
s), 8.97 (1 H, dd, J ) 4.4, 1.6). Anal. (C27H19F6N3O2) C, H, N.
7-[3,5-Bis(tr iflu or om eth yl)ben zyl]-7,8,9,10-tetr a h yd r o-
5-(4-m e t h ylp h e n yl)-[1,4]d ia ze p in o[2,1-g][1,7]n a p h t h -
yr id in e-6,12-d ion e (7a ). Compound 10b (11.1 g, 19.7 mmol)
was treated according to a procedure similar to that described
for the preparation of (aR,9R)-8b to afford 7a as colorless
crystals (6.95 g, 65%). Recrystallization from EtOAc-IPE gave
colorless crystals: mp 194-195 °C; 1H NMR 2.16 (2 H, m),
2.42 (3 H, s), 3.25-3.70 (3 H, m), 4.12 (1 H, d, J ) 15), 5.34 (1
H, d, J ) 15), 5.52 (1 H, m), 6.93 (1 H, d, J ) 8.2), 7.20 (1 H,
d, J ) 8.2), 7.30-7.45 (2 H, m), 7.51 (1 H, dd, J ) 8.4, 4.4),
7.62 (2 H, s), 7.70 (1 H, dd, J ) 8.4, 1.6), 7.84 (1 H, s), 8.93 (1
H, dd, J ) 4.4, 1.6). Anal. (C28H21F6N3O2) C, H, N.
(R)-N-[3,5-Bis(t r iflu or om et h yl)ben zyl]-7,8-d ih yd r o-7-
(3-h yd r oxy-2-m et h ylp r op yl)-5-(4-m et h ylp h en yl)-8-oxo-
1,7-n a p h th yr id in e-6-ca r boxa m id e (10e). Compound 4 (1.0
g, 1.97 mmol) was treated according to a procedure similar to
that described for the preparation of 10g using (R)-3-amino-
2-methyl-1-propanol (5e) in place of 5g to afford 10e as
colorless crystals (932 mg, 82%). Recrystallization from EtOAc-
IPE gave colorless crystals: mp 123-125 °C (once melted and
1
then solidified), 215-216 °C; H NMR 0.79 (3 H, d, J ) 7.0),
2.13 (1 H, m), 2.28 (3 H, s), 3.10-3.70 (4 H, m), 4.48 (2 H, d,
J ) 6.2), 7.00-7.25 (4 H, m), 7.43 (1 H, dd, J ) 8.4, 4.2), 7.59
(1 H, dd, J ) 8.4, 1.6), 7.69 (2 H, s), 7.79 (1 H, s), 8.38 (1 H,
bt), 8.70 (1 H, dd, J ) 4.2, 1.6); [R]D20 -9.0° (c ) 0.346, CHCl3).
Anal. (C29H25F6N3O3‚0.5H2O) C, H, N.
(S)-N-[3,5-Bis(t r iflu or om et h yl)b en zyl]-7,8-d ih yd r o-7-
(3-h yd r oxy-2-m et h ylp r op yl)-5-(4-m et h ylp h en yl)-8-oxo-
1,7-n a p h th yr id in e-6-ca r boxa m id e (10f). Compound 4 (1.0
g, 1.97 mmol) was treated according to a procedure similar to
that described for the preparation of 10g using (S)-3-amino-
2-methyl-1-propanol (5f) in place of 5g to afford 10f as colorless
crystals (788 mg, 69%). Recrystallization from EtOAc-IPE
gave colorless crystals: mp 123-125 °C (once melted and then
7-[3,5-Bis(tr iflu or om eth yl)ben zyl]-8,9,10,11-tetr ah ydr o-
5-(4-m e t h y lp h e n y l)-7H -[1,4]d i a z o c i n o [2,1-g ][1,7]-
n a p h th yr id in e-6,13-d ion e (8a ). Compound 10c (15.9 g, 27.5
mmol) was treated according to a procedure similar to that
described for the preparation of (aR,9R)-8b to afford 8a as
colorless crystals (12.1 g, 79%). Recrystallization from EtOAc-
1
solidified), 215-216 °C; H NMR 0.79 (3 H, d, J ) 7.0), 2.13
(1 H, m), 2.28 (3 H, s), 3.10-3.70 (4 H, m), 4.48 (2 H, d, J )
6.2), 7.00-7.25 (4 H, m), 7.43 (1 H, dd, J ) 8.4, 4.2), 7.59 (1
H, dd, J ) 8.4, 1.6), 7.69 (2 H, s), 7.79 (1 H, s), 8.38 (1 H, bt),
1
IPE gave colorless crystals: mp 192-193 °C; H NMR 1.7-
20
8.70 (1 H, dd, J ) 4.2, 1.6); [R]D +11.1° (c ) 0.350, CHCl3).
2.5 (4 H, m), 2.37 (3 H, s), 3.25 (1 H, m), 3.40-3.72 (2 H, m),
4.01 (1 H, d, J ) 15), 5.13 (1 H, dd, J ) 14, 5.4), 5.46 (1 H, d,
J ) 15), 6.85 (1 H, d, J ) 7.9), 7.05 (1 H, d, J ) 7.9), 7.26 (1
H, d, J ) 7.8), 7.34 (1 H, d, J ) 7.8), 7.42-7.60 (2 H, m), 7.47
(2 H, s), 7.81 (1 H, s), 8.92 (1 H, m). Anal. (C29H23F6N3O2) C,
H, N.
Anal. (C29H25F6N3O3‚0.5H2O) C, H, N.
(S)-N-[3,5-Bis(t r iflu or om et h yl)b en zyl]-7,8-d ih yd r o-7-
(4-h yd r oxy-3-m eth ylbu tyl)-5-(4-m eth ylp h en yl)-8-oxo-1,7-
n a p h th yr id in e-6-ca r boxa m id e (10h ). Compound 4 (1.0 g,
1.97 mmol) was treated according to a procedure similar to
that described for the preparation of 10g using 5h in place of
5g to afford 10h as colorless crystals (900 mg, 77%). Recrys-
tallization from EtOAc-IPE gave colorless crystals: mp 123-
7-[3,5-Bis(tr iflu or om eth yl)ben zyl]-7,8,9,10,11,12-h exah y-
d r o-5-(4-m e t h ylp h e n yl)-7H -[1,4]d ia zon in o[2,1-g][1,7]-
n a p h th yr id in e-6,14-d ion e (9). Compound 10d (170 mg, 0.29

Naphthyridinecarboxamides as NK1 Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3991
mmol) was treated according to a procedure similar to that
described for the preparation of (aR,9R)-8b to afford 9 as
colorless crystals (47 mg, 29%). Recrystallization from EtOAc-
(a S,9R)-7-[3,5-Bis(t r iflu or om et h yl)b en zyl]-8,9,10,11-
t et r a h yd r o-9-m et h yl-5-(4-m et h ylp h en yl)-7H -[1,4]d ia zo-
cin o[2,1-g][1,7]n a p h th yr id in e-6,13-d ion e [(a S,9R)-8b, a t-
r op isom er of (a R,9R)-8b]. The mother liquor obtained after
crystallization of (aR,9R)-8b was concentrated. The concen-
trate, which contained (aR,9R)-8b and (aS,9R)-8b in a ratio
of ca. 5:1, was subjected to preparative HPLC [CHIRALCEL
OD (10 mm i.d. × 250 mm);19 eluant, hexane:ethanol (85:15)
(4 mL/min); temperature, 0 °C; retention time, 15.7 min (cf.
(aR,9R)-8b: 21.4 min)] to give (aS,9R)-8b as a white powdery
substance (98.6% de): 1H NMR 1.24 (3 H, d, J ) 7.0), 1.8-2.4
(3 H, m), 2.27 (3 H, s), 3.37 (1 H, dd, J ) 15, 4.4), 3.65 (1 H,
m), 3.85 (1 H, d, J ) 15), 4.07 (1 H, d, J ) 15), 5.08 (1 H, m),
5.33 (1 H, d, J ) 15), 6.72 (1 H, d, J ) 8.2), 6.82 (1 H, d, J )
8.2), 7.09 (1 H, d, J ) 8.2), 7.21 (1 H, d, J ) 8.2), 7.45 (2 H,
m), 7.51 (2 H, s), 7.77 (1 H, s), 8.89 (1 H, m); an NOE, taken
on a J EOL J NM-GX400 (400 MHz) spectrometer in CDCl3,
was observed between a benzylic methylene-H (δ 4.080) and
C(9)-CH3 (δ 1.252); MS (electron impact) m/z 573 (M+), 554,
1
IPE gave colorless crystals: mp 177-179 °C; H NMR 1.45-
1.95 (4 H, m), 2.10 (2 H, m), 2.33 (3 H, s), 3.06-3.24 (1 H, m),
3.32-3.56 (2 H, m), 3.86 (1 H, d, J ) 15), 4.95 (1 H, dt, J d
)
15, J t ) 4.8), 5.38 (1 H, d, J ) 15), 6.86 (1 H, dd, J ) 8.0, 1.5),
7.00 (1 H, d, J ) 8.0), 7.17 (1 H, d, J ) 8.2), 7.29 (1 H, dd, J
) 8.2, 1.5), 7.40-7.54 (2 H, m), 7.44 (2 H, s), 7.79 (1 H, s),
8.89 (1 H, dd, J ) 3.8, 2.0). Anal. (C30H25F6N3O2) C, H, N.
(9S)-7-[3,5-Bis(tr iflu or om eth yl)ben zyl]-7,8,9,10-tetr ah y-
d r o-9-m et h yl-5-(4-m et h ylp h en yl)-[1,4]d ia zep in o[2,1-g]-
[1,7]n a p h th yr id in e-6,12-d ion e [(9S)-7b]. Compound 10e
(840 mg, 1.45 mmol) was treated according to a procedure
similar to that described for the preparation of (aR,9R)-8b to
afford (9S)-7b as colorless crystals (406 mg, 50%). Recrystal-
lization from EtOAc-IPE gave colorless crystals: mp 179-
180 °C; 1H NMR 1.05 (3 H × 3/5, d, J ) 7.0), 1.22 (3 H × 2/5,
d, J ) 7.0), 2.39 (3 H × 2/5, s), 2.42 (3 H × 3/5, s), 2.52 (1 H,
m), 3.0-3.3 (2 H, m), 3.48 (1 H × 3/5, dd, J ) 14, 4.6), 3.71 (1
H × 2/5, dd, J ) 16, 5.2), 4.06 (1 H × 2/5, d, J ) 15), 4.12 (1
H × 3/5, d, J ) 15), 5.28-5.65 (2 H, m), 6.83 (1 H × 2/5, d, J
) 7.4), 6.96 (1 H × 3/5, d, J ) 7.6), 7.09 (1 H × 2/5, d, J )
7.4), 7.20 (1 H × 3/5, d, J ) 7.6), 7.35 (2 H, m), 7.42-7.75 (4
H, m), 7.83 (1 H, s), 8.92 (1 H, d, J ) 3.6); in the major
component, an NOE (taken on a J EOL J NM-GX400 (400 MHz)
spectrometer in CDCl3) was observed between a benzylic
methylene-H (δ 4.119) and C(9)-H (δ ca. 2.52), and in the
minor component, an NOE was observed between a benzylic
methylene-H (δ 4.064) and C(9)-CH3 (δ 1.217), whose absolute
stereochemistry (aR or aS), however, has not been clarified
20
346, 310, 263, 235; [R]D -156.8° (c ) 0.305, MeOH).
(a R,9S)-7-[3,5-Bis(t r iflu or om et h yl)b en zyl]-8,9,10,11-
t et r a h yd r o-9-m et h yl-5-(4-m et h ylp h en yl)-7H -[1,4]d ia zo-
cin o[2,1-g][1,7]n a p h th yr id in e-6,13-d ion e [(a R,9S)-8b, a t-
r op isom er of (a S,9S)-8b]. The second crystals obtained after
the first crystals of (aS,9S)-8b, which contained (aS,9S)-8b
and (aR,9S)-8b in
a ratio of ca. 5:1, were subjected to
preparative HPLC [CHIRALCEL OD (20 mm i.d. × 250 mm);19
eluant, hexane:ethanol (85:15) (8 mL/min); temperature, 24
°C; retention time, 25.8 min (cf. (aS,9S)-8b: 21.9 min)] to give
(aR,9S)-8b as a white powdery substance (97.5% de): 1H NMR
spectrum was identical with that of (aS,9R)-8b; MS (electron
20
impact) m/z 573 (M+), 554, 346, 310, 263, 235; [R]D +153.2°
(c ) 0.280, MeOH).
20
yet; [R]D +58.2° (c ) 0.353, MeOH). Anal. (C29H23F6N3O2) C,
H, N. HPLC analysis [column, CHIRALPAK AD (4.6 mm i.d.
× 250 mm);19 eluant, hexane:2-propanol ) 7:3; temperature,
-40 °C; flow rate, 1.0 mL/min; detection, 254 nm] showed two
peaks with the retention time of 11.3 and 22.2 min in a ratio
of ca. 7:3; although these two peaks were separated by
preparative HPLC at -40 °C, each fraction, obtained after
rapid and careful workup at 0 °C, showed again the same two
peaks as those of the original (9S)-7b by HPLC analysis at
-40 °C.
Sin gle-Cr ysta l X-r a y An a lysis of (a R,9R)-8b. Brief sum-
mary of the crystal data has been reported in the previous
paper,13d and the details have been deposited with the Cam-
bridge Structural Database (CCDC 182/988). Experimental
procedures are as follows. Crystals of (aR,9R)-8b were grown
from acetone-IPE. Data were collected on a diffractometer,
Rigaku AFC5R, with Cu KR radiation. Psi-scan empirical
absorption correction was applied. The structure was deter-
mined by direct methods with the aid of TEXSAN29 and refined
by SHEXL93.30
(9R)-7-[3,5-Bis(tr iflu or om eth yl)ben zyl]-7,8,9,10-tetr ah y-
d r o-9-m et h yl-5-(4-m et h ylp h en yl)-[1,4]d ia zep in o[2,1-g]-
[1,7]n a p h th yr id in e-6,12-d ion e [(9R)-7b]. Compound 10f
(700 mg, 1.21 mmol) was treated according to a procedure
similar to that described for the preparation of (aR,9R)-8b to
afford (9R)-7b as colorless crystals (408 mg, 60%). Recrystal-
lization from EtOAc-IPE gave colorless crystals: mp 179-
180 °C; 1H NMR spectrum was identical with that of (9S)-7b;
Molecu la r Mod elin g Stu d ies. A generation of low-energy
conformers was carried out by the procedures described in the
previous papers.13a-c Figures 3 and 5 show the overlapping
between the most stable conformers of the molecules as
determined by the analysis using Discover CVFF force field.
[
125I]BH-SP Bin d in g in Hu m a n IM-9 Cells a n d R a t
20
[R]D -60.2° (c ) 0.348, MeOH). Anal. (C29H23F6N3O2) C, H,
F or ebr a in . The binding activities were determined according
to the protocol previously reported.13a
N.
(a S,9S)-7-[3,5-Bis(t r iflu or om et h yl)b en zyl]-8,9,10,11-
t et r a h yd r o-9-m et h yl-5-(4-m et h ylp h en yl)-7H -[1,4]d ia zo-
cin o[2,1-g][1,7]n aph th yr idin e-6,13-dion e [(a S,9S)-8b]. Com-
pound 10h (840 mg, 1.42 mmol) was treated according to a
procedure similar to that described for the preparation of
(aR,9R)-8b to afford (aS,9S)-8b as colorless crystals (540 mg,
66%). Recrystallization from EtOAc-IPE gave colorless crys-
Gu in ea P ig Ileu m Con tr a ction Assa y. The assay induced
with SP or NKA was performed according to the protocol
previously reported.13a
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 in the litera-
ture17 with minor modification. Guinea pigs (Hartley, male)
(n ) 5-8) were anesthetized with 35 mg/kg pentobarbital
injected intraperitoneally, and the test sample was then
administered intravenously. Five minutes after administra-
tion, a solution of capsaicin (150 µg/kg) and Evans blue dye
(20 mg/kg) in ethanol-saline (3:7) was administered (iv) to
cause the reaction. In the case of the oral administration test,
the sample was administered 60 min prior to reaction induc-
tion. Ten minutes after the reaction was induced, test animals
were sacrificed by cutting the inferior vena cava, and the
pulmonary artery was perfused with 50 mL of physiological
saline. The trachea was excised, and its wet weight was
measured. Evans blue dye was extracted by incubation in 1
mL of acetone-0.3% sodium sulfate (7:3) overnight (for more
than 12 h). After centrifugation at 2800 rpm for 20 min, the
concentration of Evans blue dye in the supernatant was
quantified by measuring the absorbance at 620 nm. Plasma
1
tals: mp 227-228 °C; H NMR spectrum was identical with
20
that of (aR,9R)-8b; [R]D -107.1° (c ) 0.521, MeOH). Anal.
(C30H25F6N3O2) C, H, N.
Atr op isom er s of 7-[3,5-Bis(tr iflu or om eth yl)ben zyl]-
8,9,10,11-tetr ah ydr o-5-(4-m eth ylph en yl)-7H-[1,4]diazocin o-
[2,1-g][1,7]n a p h th yr id in e-6,13-d ion e [(a R)-8a a n d (a S)-
8a ]. Separation of 8a into its atropisomers was carried out,
similarly to the separation of trans-1 into its atropisomers
(aR)-trans-1 and (aS)-trans-1 described in our previous paper,13c
by preparative HPLC using CHIRALPAK AD (10.0 mm i.d. ×
250 mm)19 under detection at 254 nm. Elution with a mixture
of hexane:2-propanol (90:10) at a flow rate of 4.72 mL/min at
24 °C gave (aR)-8a and (aS)-8a as white powdery substances,
respectively. (aR)-8a : retention time ) 24.6 min; [R]D20 +45.6°
20
(c ) 0.096, CHCl3). (aS)-8a : retention time ) 31.4 min; [R]D
-41.3° (c ) 0.1, CHCl3).

3992 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19
Natsugari et al.
J . Auton. Pharmacol. 1993, 13, 23-93. (c) Regoli, D.; Boudon,
A.; Fauchere, J .-L. Receptors and Antagonists for Substance P
and Related Peptides. Pharmacol. Rev. 1994, 46, 551-599. (d)
MacLean, S. Nonpeptide Antagonists of the NK1 Tachykinin
Receptor. Med. Res. Rev. 1996, 16, 297-317. (e) Lowe, J . A., III.
Nonpeptide Tachykinin Antagonists: Medicinal Chemistry and
Molecular Biology. Med. Res. Rev. 1996, 16, 527-545.
extravasation was expressed in terms of the amount of
extracted Evans blue dye (µg) relative to the weight of the
trachea (g). The efficacy of the sample was evaluated by
calculating the percent inhibition in accordance with the
following formula: % inhibition ) [1 - (A - B)/(C - B)] ×
100, in which A, B, and C represent the amount of Evans blue
dye (µg/g) obtained in the test animal, in the group not treated
with capsaicin (blank) (mean value), and in the control group
(mean value), respectively.
(2) (a) Snider, R. M.; Constantine, J . W.; Lowe, J . A., III; Longo, K.
P.; Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai, M. C.; Vinick,
F. J .; Spencer, R. W.; Hess, H.-J . A Potent Nonpeptide Antago-
nist of the Substance P (NK1) Receptor. Science 1991, 251, 435-
437. (b) McLean, S.; Ganong, A. H.; Seeger, T. F.; Bryce, D. K.;
Pratt, K. G.; Reynolds, L. S.; Siok, C. J .; Lowe, J . A., III; Heym,
J . Activity and Distribution of Binding Sites in Brain of a
Nonpeptide Substance P (NK1) Receptor Antagonist. Science
1991, 251, 437-439. (c) Lowe, J . A., III; Drozda, S. E.; Snider,
R. M.; Longo, K. P.; Zorn, S. H.; Morrone, J .; J ackson, E. R.;
McLean, S.; Bryce, D. K.; Bordner, J .; Nagahisa, A.; Kanai, Y.;
Suga, O.; Tsuchiya, M. The Discovery of (2S, 3S)-cis-2-(Diphe-
nylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-
3-amine as a Novel, Nonpeptide Substance P Antagonist. J . Med.
Chem. 1992, 35, 2591-2600.
(3) (a) Emonds-Alt, X.; Doutremepuichi, J .-D.; Heaulme, M.; Neliat,
G.; Santucci, V.; Steinberg, R.; Vilain, P.; Bichon, D.; Ducoux,
J .-P.; Proietto, V.; Broeck, D. V.; Soubri, P.; Fur, G. L.; Brelie`re,
J .-C. In Vitro and In Vivo Biological Activities of SR140333, a
Novel Potent Non-peptide Tachykinin NK1 Receptor Antagonist.
Eur. J . Pharmacol. 1993, 250, 403-413. (b) J ung, M.; Calassi,
R.; Maruani, J .; Barnouin, M. C.; Souilhac, J .; Poncelet, M.;
Gueudet, C.; Emonds-Alt, X.; Soubri, P.; Brelie`re, J . C.; Fur, G.
L. Neuropharmacological Characterization of SR140333, a Non
Peptide Antagonist of NK1 Receptors. Neuropharmacology 1994,
33, 167-179.
(4) (a) Tabart, M.; Peyronel, J .-F. Synthesis of RPR100893, Proto-
type of a New Series of Potent and Selective Non Peptide NK1
Antagonists: The Triarylperhydroisoindolols. Bioorg. Med. Chem.
Lett. 1994, 4, 673-676. (b) Fardin, V.; Carruette, A.; Menager,
J .; Bock, M.; Flamand, O.; Faucoult, F.; Heuillet, E.; Moussaoui,
S. M.; Tabart, M.; Peyronel, J . F.; Garret, C. In Vitro Pharma-
cological Profile of RPR100893, a Novel Non-peptide Antagonist
of the Human NK1 Receptor. Neuropeptides 1994, 26 (Suppl. 1),
34. (c) Moussaoui, S. M.; Montier, F.; Carruette, A.; Fardin, V.;
Floch, A.; Garret, C. In Vivo Pharmacological Profile of
RPR100893, a Novel Non-peptide Antagonist of the Human NK1
Receptor. Neuropeptides 1994, 26 (Suppl. 1), 35.
(5) (a) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.;
Snider, R. M. Discovery of a Potent Substance P Antagonist:
Recognition of the Key Molecular Determinant. J . Med. Chem.
1992, 35, 4911-4913. (b) McLean, S.; Ganong, A.; Seymour, P.
A.; Snider, R. M.; Desai, M. C.; Rosen, T.; Bryce, D. K.; Longo,
K. P.; Reynolds, L. S.; Robinson, G.; Schmidt, A. W.; Siok, C.;
Heym, J . Pharmacology of CP-99,994; a Nonpeptide Antagonist
of the Tachykinin Neurokinin-1 Receptor. J . Pharmacol. Exp.
Ther. 1993, 267, 472-479. (c) Desai, M. C.; Vincent, L. A.; Rizzi,
J . P. Importance of Parallel Vectors and “Hydrophobic Collapse”
of Aligned Aromatic Rings: Discovery of a Potent Substance P
Antagonist. J . Med. Chem. 1994, 37, 4263-4266.
Effects on Disten tion -In du ced Rh yth m ic Bladder Con -
tr a ction s in Ur eth a n e An esth etized Gu in ea P igs. Male
guinea pigs (Hartley, 250-350 g) were used. The animals were
anesthetized with an intraperitoneal injection of urethane (1.2
g/kg). The urinary bladder was exposed through an incision
in the abdomen, and the urethra was ligated. A 23-gauge
needle connected to a polyethylene tube (PE90) was inserted
into the bladder dome so the intravesical pressure could be
recorded. In each animal, warmed physiological saline (39 °C)
was injected into the bladder stepwise (0.2 mL) until regular
isovolumetric bladder contractions appeared. Test compounds
were administered intravenously after confirming stable rhyth-
mic contractions. The effects of the test compounds were
evaluated using both the shutdown time with a cutoff time of
30 min and the contractile intravesical pressure. The test
compounds were dissolved in DMSO and injected in a volume
of 0.05 mL/100 g (body weight). As the vehicle (DMSO) [0.05
mL/100 g (body weight), iv] affected the shutdown time in some
preparations, statistical comparisons were made with the
mean of the shutdown time in the vehicle-treated groups
(Dunnett test). On the other hand, as intravesical pressure
was not sensitive to the vehicle, statistical comparison was
made between the predrug mean value and postdrug value
(paired t-test). The significance of relationships between the
effects on the bladder functions and the NK1 antagonistic
activities was determined by Spearman’s rank correlation
coefficient (r).27
In cr ea sin g Effect on Bla d d er Volu m e Th r esh old in
Ur eth a n e An esth etized Gu in ea P igs. Male guinea pigs
(Hartley, 250-350 g) were used. The animals were anesthe-
tized with an intraperitoneal injection of urethane (1.2 g/kg).
The urinary bladder was exposed through an incision in the
abdomen. A 23-gauge needle connected to a polyethylene tube
(PE90) was inserted into the bladder dome so physiological
saline could be infused into the bladder. Before infusing saline
into the bladder, the bladder was emptied via the polyethylene
tube. Warm saline (39 °C) was continuously infused at a rate
of 0.3 mL/min using an infusion pump. The volume threshold
(volume to which the bladder can be filled before voiding) was
measured at least two times before testing. After confirming
stable responses, the mean value of the last two trials was
taken as the control volume threshold, and the volume
threshold was then measured 10 min after intravenous injec-
tion of the test compound. The effects of the test compounds
were expressed as percent increase in volume threshold
compared with the predrug value. The ED30 value was
determined by measuring the dose of the test compound that
increases the bladder volume threshold by 30%. In this assay,
oxybutynin, a peripherally acting anti-pollakiuria agent, showed
the ED30 value of 0.22 (0.0059-1.953) mg/kg, iv. The test
compounds were dissolved in 80% DMSO and injected in a
volume of 0.1 mL/100 g (body weight).
(6) McLean, S.; Ganong, A.; Seymour, P. A.; Bryce, D. K.; Crawford,
R. T.; Morrone, J .; Reynolds, L. S.; Schmidt, A. W.; Zorn, S.;
Watson, J .; Fossa, A.; DePasquale, M.; Rosen, T.; Nagahisa, A.;
Tsuchiya, M.; Heym, J . Characterization of CP-122,721; A
Nonpeptide Antagonist of the Neurokinin NK1 Receptor. J .
Pharmacol. Exp. Ther. 1996, 277, 900-908.
(7) (a) Vassout, A.; Schaub, M.; Gentsch, C.; Ofner, S.; Schilling,
W.; Veenstra, S. CGP49823, a Novel NK1 Receptor Antagonist:
Behavioural Effects. Neuropeptides 1994, 26 (Suppl. 1), 38; (b)
Ofner, S.; Hauser, K.; Schilling, W.; Vassout, A.; Veenstra, S. J .
SAR of 2-Benzyl-4-aminopiperidines: CGP49823, An Orally and
Centrally Active Non-peptide NK1 Antagonist. Bioorg. Med.
Chem. Lett. 1996, 6, 1623-1628.
(8) (a) Gardner, C. J .; Armour, D. R.; Beattie, D. T.; Gale, J . D.;
Hawcock, A. B.; Kilpatrick, G. J .; Twissell, D. J .; Ward, P.
GR205171:
A novel antagonist with high affinity for the
Ack n ow led gm en t. The authors wish to thank Mr.
Kazuichi Umemoto for separation of the atropisomers,
Ms. Keiko Higashikawa for X-ray analysis, Ms. Mika
Murabayashi for NMR analysis, Mr. Osamu Saga and
Mr. Yasukazu Tajima for in vitro screening, and Mr.
Satoshi Okanishi and Mr. Shigemitsu Imai for in vivo
screening.
tachykinin NK1 receptor, and potent broad-spectrum anti-emetic
activity. Regul. Pept. 1996, 65, 45-53. (b) Armour, D. R.; Chung,
K. M. L.; Congreve, M.; Evans, B.; Guntrip, S.; Hubbard, T.; Kay,
C.; Middlemiss, D.; Mordaunt, J . E.; Pegg, N. A.; Vinader, M.
V.; Ward, P.; Watson, S. P. Bioorg. Med. Chem. Lett. 1996, 6,
1015-1020.
(9) (a) Hipskind, P. A.; Howbert, J . J .; Bruns, R. F.; Cho, S. S. Y.;
Crowell, T. A.; Foreman, M. M.; Gehlert, D. R.; Iyengar, S.;
J ohnson, K. W.; Krushinski, J . H.; Li, D. L.; Lobb, K. L.; Mason,
N. R.; Muehl, B. S.; Nixon, J . A.; Phebus, L. A.; Regoli, D.;
Simmons, R. M.; Threlkeld, P. G.; Waters, D. C.; Gitter, B. D.
3-Aryl-1,2-diacetamidopropane Derivatives as Novel and Potent
NK-1 Receptor Antagonists. J . Med. Chem. 1996, 39, 736-748.
(b) Gitter, B. D.; Bruns, R. F.; Howbert, J .; Waters, D. C.;
Threlkeld, P. G.; Cox, L. M.; Nixon, J . A.; Lobb, K. L.; Mason,
Refer en ces
(1) Review articles: (a) Otsuka, M.; Yoshioka, K. Neurotransmitter
Functions of Mammalian Tachykinins. Physiol. Rev. 1993, 73,
229-308. (b) Maggi, C. A.; Patacchini, R.; Rovero, P.; Giachetti,
A. Tachykinin Receptors and Tachykinin Receptor Antagonists.

Naphthyridinecarboxamides as NK1 Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3993
N. R.; Stengel, P. W.; Cockerham, S. L.; Silbaugh, S. A.; Gehlert,
D. R.; Schober, D. A.; Iyengar, S.; Calligaro, D. O.; Regoli, D.;
Hipskind, P. A. Pharmacological Characterization of LY3038-
70: A Novel, Potent and Selective Nonpeptide Substance P
(Neurokinin-1) Receptor Antagonist. J . Pharmacol. Exp. Ther.
1996, 275, 737-744.
ropisomers of N,N-Dihexyl-2-Alkyl-1-Naphthamides. Tetrahe-
dron Lett. 1996, 37, 2899-2902. (d) Clayden, J .; Westlund, N.;
Wilson, F. X. Asymmetric Induction using Atropisomers: Dias-
tereoselective Additions to 2-Acyl-1-Naphthamides. Tetrahedron
Lett. 1996, 37, 5577-5580. (e) Clayden, J . Stereocontrol with
Rotationally Restricted Amides. Synlett 1998, 810-816.
(16) Cascieri, M. A.; Ber, E.; Fong, T. N.; Sadowski, S.; Basal, A.;
Swain, C.; Seward, E.; Frances, B.; Burns, D.; Strader, C. D.
Characterization of the Binding of a Potent, Selective Radioi-
odonated Antagonist to the Human Neurokinin-1 Receptor. Mol.
Pharmacol. 1992, 42, 458-463.
(10) Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chabers, M. S.;
Haworth, K.; Keown, L. E.; MacIntyre, D. E.; Metzger, J . M.;
Owen, S.; Rycroft, W.; Sadowski, S.; Seward, E. M.; Shepheard,
S. L.; Swain, C. J .; Tattersall, F. D.; Watt, A. P.; Williamson, D.
W.; Hargreaves, R. J . N-Heteroaryl-2-phenyl-3-(benzyloxy)-
piperidines: A Novel Class of Potent Orally Active Human NK1
Antagonist. J . Med. Chem. 1996, 39, 2907-2914.
(11) Hale, J . J .; Mills, S. G.; MacCoss, M. M.; Shah, S. K.; Qi, H.;
Mathre, D. J .; Cascieri, M. A.; Sadowski, S.; Strader, C. D.;
MacIntyre, D. E.; Metzger, J . M. 2-(S)-((3,5-Bis(trifluoromethyl)-
benzyl)-oxy)-3-(S)-phenyl-4-((3-oxo-1,2,4-triazol-5-yl)methl)mor-
pholine (1): A Potent, Orally Active, Morpholine-Based Human
Neurokinin-1 Receptor Antagonist. J . Med. Chem. 1996, 39,
1760-1762.
(17) Eglezos, A.; Giuliani, S.; Viti, G.; Maggi, C. A. Direct Evidence
That Capsaicin-induced Plasma Protein Extravasation is Medi-
ated through Tachykinin NK1 Receptors. Eur. J . Pharmacol.
1991, 209, 277-279.
(18) As for atropisomerism in 7-membered heterocycles, see: Gilman,
N. W.; Rosen, P.; Earley, J . V.; Cook, C.; Todaro, L. J . Atropi-
somers of 1,4-Benzodiazepines. Synthesis and Resolution of a
Diazepam-Related 1,4-Benzodiazepine. J . Am. Chem. Soc. 1990,
112, 3969-3978.
(12) (a) Kramer, M. S.; Cutler, N.; Feighner, J .; Shrivastava, R.;
Carman, J .; Sramek, J . J .; Reines, S. A.; Liu, G.; Snavely, D.;
W.-Knowles, E.; Hale, J . J .; Mills, S. G.; MacCoss, M.; Swain,
C. J .; Harrison, T.; Hill, R. G.; Hefti, F.; Scolnick, E. M.; Cascieri,
M. A.; Chicchi, G. G.; Sadowski, S.; Williams, A. R.; Hewson,
L.; Smith, D.; Carlson, E. J .; Hargreaves, R. J .; Rupniak, N. M.
J . Distinct Mechanism for Antidepressant Activity by Blockade
of Central Substance P Receptors. Science 1998, 281, 1640-
1645. (b) Hale, J . J .; Mills, S. G.; MacCoss, M.; Finke, P. E.;
Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.;
Metzger, J . M.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.;
Rupniak, N. M. J .; Williams, A. R.; Rycroft, W.; Hargreaves, R.;
MacIntyre, D. E. Structural Optimization Affording 2-(R)-(1-(R)-
3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-
(3-oxo-1,2,4-triazol-5-yl)methlmorpholine, a Potent, Orally Ac-
tive, Long-Acting Morpholine Acetal Human NK-1 Receptor
Antagonist. J . Med. Chem. 1998, 41, 4607-4614.
(13) (a) Natsugari, H.; Ikeura, Y.; Kiyota, Y.; Ishichi, Y.; Ishimaru,
T.; Saga, O.; Shirafuji, H.; Tanaka, T.; Kamo, I.; Doi, T.; Otsuka,
M. Novel, Potent, and Orally Active Substance P Anagonists:
Synthesis and Antagonist Activity of N-Benzylcarboxamide
Derivaives of Pyrido[3,4-b]pyridine. J . Med. Chem. 1995, 38,
3106-3120. (b) Ikeura, Y.; Tanaka, T.; Kiyota, Y.; Morimoto, S.;
Ogino, M.; Ishimaru, T.; Kamo, I.; Doi, T.; Natsugari, H. Potent
NK1 Receptor Antagonists: Synthesis and Antagonistic Activity
of Various Heterocycles with an N-[3,5-Bis(trifluoromethyl)-
benzyl]-N-methylcarbamoyl Substituent. Chem. Pharm. Bull.
1997, 45, 1642-1652. (c) Ikeura, Y.; Ishichi, Y.; Tanaka, T.;
Fujishima, A.; Murabayashi, M.; Kawda, M.; Ishimaru, T.;
Kamo, I.; Doi, T.; Natsugari, H. Axially Chiral 1,7-Naphthyri-
dine-6-carboxamide Derivatives as Tachykinin NK1 Receptor
Antagonists: Determination of the Absolute Stereochemical
Requirements. J . Med. Chem. 1998, 41, 4232-4239. (d) A
preliminary communication: Ikeura, Y.; Ishimaru, T.; Doi, T.;
Kawda, M.; Fujishima, A.; Natsugari, H. Enantioselective
synthesis of an axially chiral 1,7-naphthyridine-6-carboxamide
derivative having potent antagonist activity at the NK1 receptor.
Chem. Commun. 1998, 2141-2142.
(19) DAICEL Chemical Industries, Ltd., J apan.
(20) The conversion of (aS,9R)-8b to (aR,9R)-8b is apparently faster
than that from (aR,9R)-8b to (aS,9R)-8b. An accurate time
course of conversion from (aR,9R)-8b to (aS,9R)-8b has not been
estimated due to the small change (within a range of 2%).
(21) (a) Lewis, R. T.; Macleod, A. M.; Merchant, K. J .; Kelleher, F.;
Sanderson, I.; Herbert, R. H.; Cascieri, M. A.; Sadowski, S.; Ball,
R. G.; Hoogsteen, K. Tryptophan-Derived NK1 Antagonists:
Conformationally Constrained Heterocyclic Bioisosters of the
Ester Linkage. J . Med. Chem. 1995, 38, 923-933. (b) Macleod,
A. M.; Cascieri, M. A.; Merchant, K. J .; Sadowski, S.; Hardwicke,
S.; Lewis, R. T.; MacIntyre, D. E.; Metzger, J . M.; Fong, T. M.;
Shepheard, S.; Tattersall, F. D.; Hargreaves, R.; Baker, R.
Synthesis and Biological Evaluation of NK1 Antagonists Derived
from L-Tryptophan. J . Med. Chem. 1995, 38, 934-941.
(22) Quirion, R.; Pilapil, C. Comparative Potencies of Substance P,
Substance K, and Neuromedine K on Brain Substance P Recep-
tors. Neuropeptides 1984, 4, 325-329.
(23) Renzetti, A. R.; Barsacchi, P.; Criscuoli, M.; Lucacchini, A.
Characterization of NK-3 Binding Sites in Rat and Guinea Pig
Cortical Membranes by the Selective Ligand [3H]Senktide.
Neuropeptides 1991, 18, 107-114.
(24) The selectivity for NK1 over NK2 and NK3 in the compounds
related to 1 has been confirmed: Hosoki, R.; Yanagisawa, M.;
Onishi, Y.; Yoshioka, K.; Otsuka, M. Pharmacological Profiles
of New Orally Active Nonpeptide Tachykinin NK1 Receptor
Antagonists. Eur. J . Pharmacol. 1998, 341, 235-241.
(25) Compounds trans-1 and (aR,9R)-8b did not show effects on the
binding of [3H]nitrendipine to membranes from rat brain cortices
at
a concentration of 10 µM, indicating that this series of
compounds does not interact with the L-type Ca2+ channels.
(26) (a) Maggi, C. A. The role of peptides in the regulation of the
micturition reflex: an update. Gen. Pharmacol. 1991, 22, 1-24.
(b) Lecci, A.; Giuliani, S.; Garret, C.; Maggi, C. A. Evidence for
a role of tachykinins as sensory transmitters in the activation
of micturition reflex. Neuroscience 1993, 54, 827-837.
(27) (a) Spearman, C. The proof and measurement of association
between two things. Am. J . Psychol. 1904, 15, 72-101. (b)
Snedecor, G. W.; Cochran, W. G. Statistical Methods; The Iowa
State University Press: Ames, IA, 1967.
(28) (a) Mori, K. Revision of the Absolute Configuration of A-Factor.
The Inducer of Stretomycin Biosynthesis, Basing on the Recon-
firmed (R)-Configuration of (+)-Paraconic Acid. Tetrahedron
1983, 39, 3107-3109. (b) Mattes, H.; Hamada, K.; Benezra, C.
Stereospecificity in Allergic Contact Dermititis to Simple Sub-
stituted Methylene Lactone Derivatives. J . Med. Chem. 1987,
30, 1948-1951.
(14) The italic letter a before R and S denotes an axial chirality as
suggested by Cahn et al.: Cahn, R. S.; Ingold, C.; Prelog, V.
Specification of Molecular Chirality. Angew. Chem., Int. Ed.
Engl. 1966, 5, 385-415.
(15) As for the chemistry and separation of atropisomers of some
aromatic carboxamides, see: (a) Ohno, A.; Kashiwagi, M.;
Ishihara, Y.; Ushida, S.; Oka, S. NAD(P)+-NAD(P)H Models. 57.
Stereochemistry in (Net) Hydride Transfer From and NAD(P)+-
NAD(P)H Models: Chirality Sink. Tetrahedron 1986, 42, 961-
973. (b) Cuyegkeng, M. A.; Mannschreck, A. Liquid Chromatog-
raphy on Triacetylcellulose, 14. Chromatographic Separation on
Enantiomers and Barriers to Enantiomerization of Axially
Chiral Aromatic Carboxamides. Chem. Ber. 1987, 120, 803-809.
(c) Thayumanavan, S.; Beak, P.; Curran, D. P. Asymmetric
Deprotonation of N,N-Dihexyl-1-Naphthamides to Provide At-
(29) TEXSAN: Single-Crystal Structure Analysis Software, version
1.9; Molecular Structure Corp.: The Woodlands, TX, 1998.
(30) Sheldrick, G. M. SHELXL93, Program for the Refinement of
Crystal Structures; University of Go¨ttingen: Germany, 1993.
J M990220R