Cyclopentane-based human NK1 antagonists. Part 1: Discovery and initial SAR

Article abstract of DOI:10.1016/j.bmcl.2006.06.035

An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral cent

Full text of DOI:10.1016/j.bmcl.2006.06.035

Bioorganic & Medicinal Chemistry Letters 16 (2006) 4497–4503
Cyclopentane-based human NK1 antagonists.
Part 1: Discovery and initial SAR
Paul E. Finke,a,* Laura C. Meurer,a Dorothy A. Levorse,a Sander G. Mills,a
Malcolm MacCoss,a Sharon Sadowski,b Margaret A. Cascieri,b Kwei-Lan Tsao,c
Gary G. Chicchi,c Joseph M. Metzgerd and D. Euan MacIntyred
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Molecular Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Immunology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
dDepartment of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 27 April 2006; revised 8 June 2006; accepted 9 June 2006
Available online 7 July 2006
Abstract—An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having
enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous
chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl
configuration of the known structures 1–5, is optimal for this class of antagonist are described.
Ó 2006 Elsevier Ltd. All rights reserved.
The neurokinin-1 receptor (NK1) is a member of the
seven-transmembrane G-protein coupled family of
receptors and is associated with sensory neurons in
the periphery and specific areas of the CNS. The nat-
ural ligand for NK1 is the tachykinin peptide sub-
stance P (SP) which has been implicated in the
pathophysiology of a diverse range of conditions
including asthma, inflammatory bowel disease, pain,
psoriasis, migraine, movement disorders, cystitis,
schizophrenia, emesis, and anxiety/depression.1 To
saline, pH 8.2).5 This limitation was initially addressed
with the development of the aqueous soluble N-phos-
phoryl prodrug 2.5 While increased solubility was also
addressed with the development of the more soluble,
fully basic derivative 4,6 the identification of addition-
al suitably soluble parent entities for both oral and
parenteral use still remained an important need.7–9
As part of our ongoing pursuit of structurally diverse
NK1 antagonists, the use of the 1,2-cis-2,3-trans-cyclo-
hexane scaffold 5 (hNK1 IC50 = 1.5 nM)10 was previ-
ously investigated as a replacement for the core
morpholine of structure 3 (hNK1 IC50 = 0.09 and
1.1 nM for 3a and 3b)11 from which 1 was later de-
rived.2 Herein, we report the initial synthesis of sever-
al isomers of the ring-contracted cyclopentane core
structure 6.7 The structure–activity relationships
(SAR) for this scaffold are discussed in terms of the
stereochemistry at the three contiguous chiral centers
and the enhanced water solubility achieved with this
scaffold via incorporation of various basic moieties
at C-3. Initial efforts first targeted derivatives based
on our original morpholine structures 3a and 3b, hav-
ing a 3,5-bis-trifluoromethylbenzyl ether at C-1 and an
unsubstituted phenyl at C-2.12 Subsequent efforts are
detailed in the accompanying manuscript.13
date, the morpholine
1
(Aprepitant, hNK1
IC50 = 0.09 nM)2 is the only currently marketed
hNK1 antagonist and was approved by the FDA for
use as an anti-emetic for chemotherapy-induced nau-
sea and vomiting (CINV).3 During the course of this
work, 1 was also being extensively investigated as an
anti-depressant for major depressive disorder.4 While
1 has been demonstrated in the clinic to have good
bioavailability upon oral administration, a parenteral
formulation was not possible due to its low solubility
in appropriate aqueous vehicles (0.2 lg/mL in isotonic
Keywords: Neurokinin-1 receptor; NK1 antagonist; Cyclopentane-
based structure.
*
Corresponding author. Tel.: +1 732 594 7456; fax: +1 732 594
5790; e-mail: paul_finke@merck.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.06.035

4498
P. E. Finke et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4497–4503
CF3
CF3
CF3
Me
Me
CF3
CF3
CF3
O
N
O
O
N
O
O
N
O
O
P
-O
-O
N
N
N
O
H
H
N
F
N
F
N
N
N
H
NH2
3b
N
O
O
O
2 (bis-glucamine salt)
1 (Aprepitant )
H
H
3a
CF3
CF3
CF3
Me
CF3
CF3
CF3
1
O
N
O
O
O
2
3
R
O
N
N
F
HN
NH2
6
4
5
N
Me
Me
The synthesis14 of the core cyclopentane scaffold having
an oxygen functionality at C-1, the required phenyl at C-
2, and a functionalizable ester moiety at C-3 was based
on the reported synthesis of 7 in 28% yield (Scheme 1).15
Subsequent to this work, an improved racemic route16
to 7 and an asymmetric synthesis17 of 9 were developed.
The stereochemistry at the C-2 phenyl/C-3 ester was
always the thermodynamically more stable trans-config-
uration.17,18 Reduction of 7 with L-SelectrideÒ pro-
duced exclusively the 1,2-cis-diastereomer 8, while use
of sodium borohydride in methanol resulted in a chro-
matographically separable 1:3 mixture of predominantly
the lower Rf trans-isomer 9. This stereochemical selectiv-
ity allowed for a thorough evaluation of both alcohol
isomers. The trans-assignment for 9 was confirmed by
CBz group of 19a afforded the racemic N-cyclopentyl
amines 24a and 24b which on alkylation (see Scheme
3) afforded analogs of structures 3 and 5. Acylation of
24b also afforded the N–Me derivatives 18b and 23b.
O
O
O
O
O
+
NC
NC
H
Et-O
O-Et
Me-O
O-Me
O-Et
Me-O
a
b,c
NC
O
O
(33%)
OH
OH
O
d,b,c
e or f
+
(85%)
(>95%)
Me-O
Me-O
Me-O
1
an H NMR NOE experiment.19 Separate hydroxyl
O
O
7 (+)
O
For e; >95 : 1
alkylation of 8 and 9 with 3,5-bis-trifluoromethylbenzyl
bromide and sodium hydride afforded the intermediate
racemic ethers 10 and 11. Interestingly, the hNK1 affin-
ity of derivatives prepared from the 1,2-trans-ester 11
was generally 3- to 5-fold greater than that of those de-
rived from the 1,2-cis-ester 10 (see below); thus, the
trans-series was preferentially investigated.
8 (+)
9 (+)
For f;
1 : 3
CF3
CF3
CF3
Br
O
CF3
8 (+)
g (45%)
CF3
Hydrolysis of ester 11 gave acid 12 (Scheme 2) which
was converted into amides 13. (Note that the cis-deriva-
tives can be similarly prepared from ester 10.) Borane
reduction then afforded the methylene-spaced amines
14 which could be alkylated to give a variety of deriva-
tives (see Scheme 3). Alternatively, lithium borohydride
reduction of 11 afforded the alcohol 15. Conversion to
the bromide and alkylation of piperidine or morpholine
afforded 16 and 17 as an alternate synthesis of amino-
methylene derivatives. The ester 11 could also be con-
verted to several N-cyclopentylamino derivatives via
Curtius rearrangement of acid 12 and reaction of the
intermediate isocyanate with either alcohols, to afford
carbamates 18a–20a, or with amines, to afford ureas
21a–23a. Methylation and/or hydrogenation of the
Me-O
O
CF3
10 (+)
CF3
Br
O
CF3
9(+)
g (62%)
Me-O
O
11 (+)
Scheme 1. Reagents and conditions: (a) (i) piperidine, EtOH, 35–
65 °C; (ii) NaCN, 35–80 °C, 1 h; (iii) ClCH2CH2CO2Et, 35–80 °C, 5 h;
(b) 6 M HCl, reflux, 48 h; (c) MeOH, HCl (g), HC(OMe)3, 65 °C, 16 h;
(d) NaOMe, MeOH or LiHMDS, THF; (e) L-SelectrideÒ, THF
(selective for 8); (f) NaBH4, MeOH (1:3 ratio of 8:9); (g) NaH, DMF.

P. E. Finke et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4497–4503
Ar
4499
Ar
Ar
CF3
O
O
O
e
f (68%)
g (50%)
a (95%)
d
Ar =
11 (+)
11 (+)
(25%)
(70%)
b,c
CF3
X
(90%)
X
HO
O
15 (+)
14a,b (+): X = NHR'
16 (+): X = N-piperidinyl
17 (+): X = N-morpholinyl
12 (+): X = OH
13a,b (+): X = NHR'
a: R' = H
b: R' = Me
Ar
O
Ar
Ar
O
Ar
O
O
a,b,h,i
then
20a
m
m
11 (+)
19a (+)
+
Silica gel
separation
or
n,m
or
n,m
j, k or l
H
N
R'
N
H
N
R'
N
O
O
(50-85%)
O
(>90%)
(>90%)
H
X
X
X
18a (+): X = MeO-
19a (+): X = BnO-
20a (+): X = (S)-PhCH(Me)O-
24a,b (+)
24a",b" (non-racemic)
20a' (non-racemic)
20a" (non-racemic)
21a (+): X = H2N-
22a (+): X = MeHN-
23a (+): X = Me2N-
18b (+): X = MeO-
23b (+): X = Me2N-
o
24b(+)
p
(85%)
Scheme 2. Reagents and conditions: (a) NaOH, MeOH; (b) oxalyl chloride, DMF (cat), DCM; (c) NH3 or MeNH2 (aq, excess), THF; (d) BH3–
Me2S, THF; (e) LiBH4, THF; (f) Ph3P–Br2, MeCN; (g) piperidine or morpholine (excess), MeCN; (h) NaN3, acetone/water, ꢀ10 °C; (i) PhMe, 85 °C;
(j) MeOH, DIPEA, DMAP (cat); (k) BnOH or (S)-PhCH(Me)OH, DIPEA, DMAP (cat), PhMe, 85 °C; (l) NH3, MeNH2 or Me2NH (aq, excess),
dioxane; (m) H2 (50 psi), 10% Pd/C, EtOH; (n) MeI, NaH, DMF; (o) ClCO2Me, DIPEA, DCM; (p) ClCONMe2, DIPEA, DCM. The 1,2-cis
derivatives were similarly prepared from 10 and are designated as c (R0 = H) and d (R0 = Me) in the text and Table 1.
Alternatively, reaction of the above isocyanate with (S)-
a-methylbenzyl alcohol afforded 20a as a silica gel sepa-
rable mixture of the diastereomeric CBz intermediates
20a0 and 20a00. The 1,2-cis-series also gave the two corre-
sponding separable diastereomers; thus, all four enan-
tiomerically enriched forms of 24 were available. The
binding data (see below) were initially used to differenti-
ate the more active and less active diastereomers. Based
on modeling and by analogy to the known morpholine
cis-stereochemistry, the stereochemistry for the active
at 150 °C in xylenes to afford the triazole 32b and triaz-
olinones 34b and 35b, which were analogous to the triaz-
olinone morpholine structure 3a.2,11
While non-basic morpholine 1 has been found to have
good bioavailability upon oral administration to several
species (e.g., rat, F = 53%; dog, F = 40%), formulation
for parenteral use was not possible due to its low solubil-
ity in appropriate aqueous vehicles (0.2 lg/mL in isoton-
ic saline, final pH 8.2).5 The possibility of enhanced
water solubility was expected for this more basic cyclo-
pentane scaffold, since an exocyclic nitrogen would no
longer be benzylic nor part of a morpholine ring. Both
of these features greatly diminish the basicity of the
morpholine nitrogen (pKa of 3a <3.5 in 1:1 methanol/
water).11,20 Indeed, as listed in Table 1, the water solu-
bility at pH 5 (0.1 M sodium acetate/acetic acid buffer)
for many of these derivatives was found to be signifi-
cantly enhanced over that of 1 (<0.0005 mg/mL at pH
5).21 For the N–H glycinamides 25a and 26a (0.59 and
1.1 mg/mL) the solubility enhancement was over 1000-
fold, while the solubility for the corresponding N–Me
analogs 25b and 26b (0.30 and 0.016 mg/mL) was less
impressive. Good solubilities were also seen for 1,2-
trans-heterocyclic derivatives 28b, 30a00, and 30b00 (0.45,
4.0, and 0.51 mg/mL, respectively) with the N–Me triaz-
olinone 35b (0.20 mg/mL) giving at least a 400-fold in-
crease. In this case, the corresponding less active 1,2-
cis-triazolinone 35d (see Table 1) was also slightly less
soluble (0.08 mg/mL). These enhanced solubilities are
most likely due to the increased basicity of these deriva-
tives. For example, the trans-derivatives 26a and 26b
trans-enantiomer
was
tentatively
assigned
as
[1S,2S,3R] as shown for structure 24 in Scheme 2 and
structure C in Table 1 (for R = NH2). The absolute
assignment for the trans-series was later confirmed by
single-crystal X-ray analysis of a resolved 4-fluorophe-
nyl acid salt derivative of 9.12,13 The absolute stereo-
chemistry of the active enantiomer in the cis-series was
assumed to be the same as that of structure 3, i.e.,
[1S,2R,3S] as in structure D, Table 1 (for R = NH2).
Alkylation of the N–Me and N–H amines 14 and 24
(Scheme 3) afforded a variety of amine derivatives of
varying basicity. Iodoacetamide afforded the glycinam-
ide derivatives 25-26 as analogs of 3b, N,N-diacetyl bro-
momethylimidazolinone (27) gave 28 after removal of
the N-acetyl groups, and use of (S)-bromomethylpyrro-
lidinone (29) allowed for the direct separation of dia-
stereomeric lactams 30 (lower Rf diastereomers 30a00
and 30b00 being derived from the more potent enantio-
mer). Alternatively, the N–Me derivatives could also
be alkylated with N-formyl- (31) or N-(methoxycarbon-
yl)-2-chloroacetamidrazone (33) followed by cyclization

4500
P. E. Finke et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4497–4503
Ar
Ar
vious studies in the six-membered core piperidine9b and
morpholine11 scaffolds had reported that the cis-config-
uration afforded significantly better potency than the
trans-configuration (ꢁ200-fold for the [2S,3S] morpho-
line 3a and its trans [2S,3R] isomer), in this cyclopentane
scaffold the opposite relationship was found. With the
possible exceptions of 24a and 24c and 26b and 26d
the trans-derivatives generally afforded a 2- to 5-fold
enhancement over the cis-configuration. More impor-
tantly, although the racemic 1,2-cis-N–H glycinamide
26c indicated poorer binding affinity compared to 510
and the equivalent acetamide derivative 3b11
(IC50 = 8.3 nM vs 1.5 and 1.1 nM, respectively), the
non-racemic [1S,2S,3R] trans N–H derivative 26a00 was
very comparable (IC50 = 0.95 nM). At the time, poten-
tial use of the 1,2-trans-cyclohexane had not been con-
sidered based on the earlier morpholine results.
Although the effect of an additional N-methyl to afford
the tertiary amines was beneficial in the cis-series
(IC50 = 8.3 vs 2.1 nM for 26c and 26d), the results in
the more potent trans-series were mixed (IC50 = 1.3 vs
2.7 nM for 26a and 26b; 5.2 vs 2.4 nM for 28a and
28b; 1.5 vs 0.81 nM for 30a00 and 30b00). Insertion of an
additional methylene as in analogs 25a and 25b also
made little difference in binding. Reversing the amide
as in the (S)-lactams 30a00 and 30b00 gave comparable re-
sults to the glycinamides, although the corresponding
(R)-lactams generally showed about 2-fold poorer
affinity (data not shown). Unfortunately, the targeted
imidazolinone, triazole, and triazolinone derivatives
(28b, 32b, and 35b; IC50 = 2.4, 1.1, and 2.0 nM, respec-
tively) did not show the anticipated 10-fold improve-
ment obtained with the morpholines (IC50 = 0.09 vs
1.1 nM for 3a and 3b).11 As would be expected, there
was an enantiomeric preference as seen with the chiral
amines 24a0 and 24a00 (IC50 = 100 and 2.3 nM), glycina-
mides 26a0 and 26a00 (IC50 = 45 and 0.95 nM), and
(S)-lactams 30a0 and 30a00 (IC50 = 260 and 1.5 nM).
O
O
a
R'
R'
(50-90%)
(
)
n
N (
)
n
N
H
O
25a,b (+) (n = 1)
26a,b (+) (n = 0)
26a",b" (n = 0)
14a,b (+) (n = 1)
24a,b (+) (n = 0)
24a",b" (n = 0)
H2N
Ac
O
Br
H
N
N
N
Ac
27
O
N
H
24a,b(+)
N
b, then c (50-65%)
R'
28a,b (+)
Br
(S)
N
H
29
O
(S)
N
O
24a,b(+)
24b(+)
30a',b'
N
+
R'
H
b (65%)
30a",b"
NH
N
H
N
Cl
N
N
O
31
N
H
N
N
N
b, then d (50%)
Me
Me
Me
32b (+)
H
N
NH
N
Et-O
N
Cl
O
O
N
N
H
33
O
14b(+)
24b(+)
34b (+)
b, then d (35%)
H
N
N
33
N
H
b, then d (35%)
35b (+)
CF3
a: R' = H
b: R' = Me
Ar =
CF3
Scheme 3. Reagents and conditions: (a) ICH2CONH2, DIPEA,
CH3CN; (b) DIPEA, CH3CN (for 29, 90 °C in sealed vial); (c)
MeNH2, THF; (d) xylenes 150 °C. The 1,2-cis derivatives in Table 1
were similarly prepared from cis-24 and are designated c (R0 = H) and
d (R0 = Me).
This general enhanced affinity of the 1,2-trans-series over
the 1,2-cis-series is likely due to the increased flexibility of
the five- versus six-membered ring in which the 1,2-trans
orientation of the two phenyl moieties can afford a more
optimal hNK1 pharmacophore fit. Interestingly, the ex-
tent of this enhancement is also quite dependent on the
C-3 substituent, ranging from a cis:trans IC50 ratio of
0.8 for 26b and 26d to 6 for 26a and 26c. The nature of
the C versus N linkage at C-3 might also be important,
although the N-substituent would be expected to be sim-
ilarly ‘trans’ to the phenyl. Thus, it is noteworthy that it is
the relative 2,3-substituent configurations which are re-
versed while the ether absolute configuration is con-
served. In addition, these results again demonstrate that
potent hNK1 binding is not dependent on the presence
of a fully basic nitrogen at the 3-position relative to the
ether, in fact, the trans-amine 14a showed less hNK1
affinity than the alcohol 15. This toleration of a wide vari-
ety of functionality at the C-3 position suggests that the
receptor binding domain in the region of the C-3 moiety
is relatively unstructured, although there is a general pref-
erence for a polar, small to moderately sized moiety (see
16, 17, 19a, 23a and 23b having larger R0 groups). How-
ever, the choice of substituent at the C-3 position was
had measured pKas of 6.6 and 5.8 in 1:1 methanol/
water.20
The hNK1 binding affinities for both the neutral and
basic target compounds, as well as several of the inter-
mediates, were determined by measuring their ability
to displace [125I]SP from human NK1 receptor stably
expressed in CHO cells.22 The hNK1 binding results
are summarized in Table 1 with significant binding affin-
ity being observed in several classes of compounds. The
initial cis-derivatives 18c and 21c indicated some hNK1
affinity (hNK1 IC50 = 5.3 and 9.8 nM), however, unex-
pectedly the corresponding trans-isomers 18a and 21a
actually showed enhanced affinity (IC50 = 0.89 and
3.5 nM). Also, other neutral trans-nitrogen derivatives
(i.e., 13a, 18b, 22a, and 23a; IC50 = 7.2, 6.2, 2.7, and
5.0 nM, respectively) and even the alcohol intermediate
15 (IC50 = 0.77 nM) achieved moderate potency,
although the acid 12 had poor hNK1 affinity. While pre-

P. E. Finke et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4497–4503
4501
Table 1. Structures, solubilities, pKas, and hNK1 binding affinities of selected compounds
CF3
Trans
CF3
Cis
Trans
Enantiomer
CF3
Cis
Enantiomer
CF3
CF3
CF3
CF3
CF3
1
1
2
1
1
O
O
O
O
3
3
3
2
3
2
2
C
D
A
B
R
R
R
R
(SEM, n)b
Solubility at pH 5 (mg/mL)c
pKa
a
NK1 IC50 (nM)
d
Compound
Stereochemistry
–R
1
3a
(2R,3S)
(2S,3S)
(2S,3S)
—
—
0.09e
0.09f
1.1f
1.5g
67
—
—
<0.0005
0.003
<3.5
<3.5
3b
—
—
—
—
5
12
(1S,2S,3R)
trans, A/C
trans, A/C
trans, A/C
trans, A/C
trans, A/C
trans, A/C
trans, A/C
trans, A/C
trans, A/C
cis, B/D
–CO2H
–CONH2
(n = 1)
(1.2, 2)
(0.3, 3)
(0.5,3)
(0.16, 3)
(n = 1)
(0.9, 3)
(0.10, 4)
(1.0, 4)
(1.7, 3)
(n = 1)
(n = 1)
(0.3, 3)
(2.2, 3)
(0.3, 3)
(0.7, 3)
(n = 1)
(n = 1)
(0.38, 3)
(2.4, 3)
(n = 1)
(n = 1)
(0.2, 3)
(0.7, 3)
(0.3, 8)
(0.1, 7)
(0.4, 6)
(2.0, 3)
(0.3, 6)
(n = 1)
(0.06, 6)
13a
14a
14b
15
7.2
2.7
1.9
0.77
5.0
8.2
0.89
6.2
5.3
40
–CH2NH2
–CH2NHMe
–CH2OH
16
17
–CH2-1-piperidinyl
–CH2-4-morpholinyl
–NHCO2Me
–NMeCO2Me
–NHCO2Me
–NHCO2Bn
–NHCO2Bn
–NHCONH2
–NHCONH2
–NHCONHMe
–NHCONMe2
–N(Me)CONMe2
–NH2
18a
18b
18c
19a
19c
21a
21c
22a
23a
23b
24a
24b
24c
24d
24a0
24a00
25a
25b
26a
26b
26c
26d
26a0
26a00
trans, A/C
cis, B/D
300
3.5
9.8
2.7
5.0
16
trans, A/C
cis, B/D
trans, A/C
trans, A/C
trans, A/C
trans, A/C
trans, A/C
cis, B/D
5.7
0.83
7.9
7.2
100
2.3
1.9
1.9
1.3
2.7
8.3
2.1
45
–NHMe
–NH2
cis, B/D
trans, A
trans, C
–NHMe
–NH2
–NH2
trans, A/C
trans, A/C
trans, A/C
trans, A/C
cis, B/D
–CH2NHCH2CONH2
–CH2NMeCH2CONH2
–NHCH2CONH2
–NMeCH2CONH2
–NHCH2CONH2
–NMeCH2CONH2
–NHCH2CONH2
–NHCH2CONH2
0.59
0.30
1.1
6.6
5.8
0.016
0.80
cis, B/D
trans, A
trans, C
0.95
H
28a (R0 = H)
28b (R0 = Me)
trans, A/C
trans, A/C
5.2
2.4
(0.4, 6)
(0.7, 3)
N
O
0.45
N
N
H
R'
30a0 (R0 = H)
30a00 (R0 = H)
30b00 (R0 = Me)
trans, A
(S)
O
260
1.5
(35, 3)
N
trans, C
trans, C
N
(0.3, 3)
(0.35, 3)
4.0
0.51
H
R'
0.81
N
N
32b
trans, A/C
1.1
(0.5, 3)
N
N
H
Me
(
Me
)
n
34b (n = 1)
35b (n = 0)
35d (n = 0)
trans, A/C
trans, A/C
cis, B/D
4.9
2.0
4.7
(1.3, 3)
(0.5, 3)
(n = 1)
0.01
0.20
0.08
H
O
N
N
N
N
H
a Displacement of 125I-labeled SP from the cloned hNK1 receptor expressed in CHO cells.
b Except as noted (n = 1), data are an average of 2–8 independent replicate titrations.22
c Aqueous solubilities were measured in 0.1 M sodium acetate/acetic acid buffer at pH 5 (n = 2).21
d Titrations were preformed in 1:1 methanol/water.20
e See Ref. 2.
f See Ref. 11.
g See Ref. 10.

4502
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found to be critical for in vivo potency and for obtaining
the desired physical properties (also see Ref. 13).
2. Hale, J. J.; Mills, S. G.; MacCoss, M.; Finke, P. E.;
Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.;
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Carman, J.; Sramek, J. J.; Reines, S. A.; Liu, G.; Snavely,
D.; Wyatt-Knowles, E.; Hale, J. J.; Mills, S. G.; MaCoss,
M.; Swain, C. J.; Harrison, T.; Hill, R. G.; Hefti, F.;
Scolnick, E. M.; Cascieri, M. A.; Chicchi, G. G.; Sadow-
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Rupniak, N. M. J.; Hargreaves, R. J. J. Med. Chem.
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7. For a preliminary report on this work, see: Finke, P. E.;
Meurer, L. C.; MacCoss, M.; Mills, S. G.; Sadowski, S.;
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E. American Chemical Society 219th National Meeting,
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Baker, R. Bioorg. Med. Chem. Lett. 1994, 4, 1903.
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Bioorg. Med. Chem. Lett. 1994, 4, 2545; (b) Harrison, T.;
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Chem. Lett. 1995, 5, 209.
10. Mills, S. G.; MacCoss, M.; Underwood, D.; Shah, S. K.;
Finke, P. E.; Miller, D. J.; Budhu, R. J.; Cascieri, M. A.;
Sadowski, S.; Strader, C. D. Bioorg. Med. Chem. Lett.
1995, 5, 1345.
11. Hale, J. J.; Mills, S. G.; MacCoss, M.; Shah, S. K.; Qi, H.;
Mathre, D. J.; Cascieri, M. A.; Sadowski, S.; Strader, C.
D.; MacIntyre, D. E.; Metzger, J. M. J. Med. Chem. 1996,
39, 1760.
In order to determine whether these new hNK1 antago-
nists could inhibit the action of SP in vivo, a previously
described assay (SYVAL23) was utilized.2,11 Intravenous
administration of capsaicin or resiniferatoxin causes a
dose-dependent vascular leakage in the esophagus, tra-
chea, and bladder of guinea pigs and can be quantified
with Evans Blue dye. This response is mediated by the
endogenous release of SP from capsaicin-sensitive nerve
fibers and can be inhibited by the systemic administra-
tion of NK1 receptor antagonists. Test compounds were
administered orally at differing doses and time intervals
before capsaicin or resiniferatoxin challenge, thus serv-
ing both as a functional NK1 inhibition readout as well
as a pharmacokinetic measurement. The utility of these
derivatives in this assay and the in vivo importance of
the C-3 moiety were initially demonstrated with two of
the above compounds. When the trans-compound 26a
(IC50 = 1.3 nM) was administered orally at 1 mg/kg
and 1 h prior to challenge, a 60% inhibition was
achieved. However, when the neutral carbamate 18a
(IC50 = 0.89 nM) was administered, <25% inhibition
was observed.
The initial synthesis of a variety of 3-amino and 3-amino-
methylene derivatives was investigated in this 1-benzyl-
oxy-2-phenylcyclopentane scaffold based on the
previous morpholine structure 3. The synthesis involved
the stereoselective synthesis of either the 1,2-cis or 1,2-
trans-hydroxy intermediates 8 and 9. The 3-amino deriv-
atives were also available in chiral form through
separation of the diastereomeric (S)-a-methylbenzyl
carbamates 20a and 20c. Several basic cyclopentane
derivatives demonstrated the desired enhanced water
solubility at pH 5 necessary for an intravenous formula-
tion. The hNK1 binding affinity for this series of com-
pounds was found to be relatively insensitive to the
functionality at C-3, although moderately sized hydro-
philic moieties were preferred. Preliminary results for
the glycinamide derivative 26a indicated that this class
of hNK1 antagonist was also capable of in vivo inhibition
of SP-elicited systemic plasma extravasation after oral
administration. The finding that the 1,2-trans-2,3-trans-
configuration in this scaffold was significantly better than
the preferred cis-arrangement in our previous morpho-
line core structures was unexpected. These results led to
additional investigations of this scaffold as discussed
further in the accompanying manuscript13 and
elsewhere.24,25
12. Finke, P. E.; MacCoss, M.; Meurer, L. C.; Mills, S. G.;
Caldwell, C. G.; Chen, P.; Durette, P. L.; Hale, J. J.;
Holson, E.; Kopka, I.; Robichaud, A. US Patent
5,750,549, 1998; Chem. Abstr. 1997 127, 17433.
13. Meurer, L. C.; Finke, P. E.; Owens, K. A.; Tsou, N. N.;
Ball, R. G.; Mills, S. G.; MacCoss, M.; Sadowski, S.;
Cascieri, M. A.; Chicchi, G. G.; Egger, L. A.; Luell, S.;
Metzger, J. M.; MacIntyre, D. E.; Rupniak, N. M. J.;
Williams, A. R.; Hargreaves, R. J. Bioorg. Med. Chem.
Lett., 2006, 16 (following manuscript page).
14. Representative experimental details and spectral data have
been described in Ref. 12. Indicated yields were not
optimized. All mass spectral and 1H NMR data were
consistent with the assigned structures.
Acknowledgments
We thank George A. Doss for performing the 1H NMR
NOE experiment on compound 9 and Karen A. Owens
for some of the aqueous solubility measurements.
References and notes
15. Baker, W.; Leeds, W. G. J. Chem. Soc. 1948, 974.
16. Desai, R. C.; Cicala, P.; Meurer, L. M.; Finke, P. E.
Tetrahedron Lett. 2002, 43, 4569.
1. (a) Quatara, L.; Maggi, C. A. Neuropeptides 1998, 32, 1;
(b) Rupniak, N. M. J.; Kramer, M. S. Trends Pharmacol.

P. E. Finke et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4497–4503
4503
17. Kuethe, J. T.; Wong, A.; Wu, J.; Davies, I. W.; Dormer, P.
G.; Welch, C. J.; Hillier, M. C.; Hughes, D. L.; Reider, P.
J. J. Org. Chem. 2002, 67, 5993.
cyclopentane compounds were done in 0.1 M sodium
acetate/acetic acid buffer adjusted to pH 5. The reported
results are an average of n = 2.
18. In subsequent studies, minor amounts of 1,2-trans-2,3-cis
compounds were isolated, but the hNK1 affinity was
significantly diminished and, thus, these isomers were
never pursued.
22. Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.;
Bansal, A.; Swain, C. J.; Seward, E. M.; Frances, B.;
Burns, D.; Strader, C. D. Mol. Pharmacol. 1992, 42, 458.
23. Acronym for resiniferatoxin-induced SYstemic VAscular
Leakage.
24. (a) Finke, P. E. National Medicinal Chemistry Sympo-
sium, Madison, WI. June 27–July 1, 2004; (b) Finke, P.
E.; Meurer, L. C.; Mills, S. G.; MacCoss, M.; Qi, H.
U.S. Patent 6,479,518, 2002. Chem. Abstr. 2002, 136,
279139x.
19. A 1H NMR NOE experiment of the more polar isomer
showed an unambiguous interaction between the C-1 and
C-3 protons, thus, confirming the 1,2-trans-2,3-trans
assignment for 9.
H
OH
25. The use of the trans ether/phenyl configuration was
subsequently applied to other six-27 and seven-membered
ring scaffolds.28
26. Albert, A.; Serjeant, E. P. The Determination of Ionization
Constants, 3rd ed.; Chapman and Hall: New York, NY,
1984, p 35.
H
H
O
Me
O
9
27. (a) Owens, S. N.; Seward, E. M.; Swain, C. J.; Williams, B.
J. U.S. Patent 6,458,830, 2001. Chem. Abstr. 2000, 133,
252310x and 2000, 133, 266729c; (b) Nelson, T. D.; Rosen,
J. D.; Smitroviych, J. H.; Payack, J.; Craig, B.; Matty, L.;
Huffman, M. A.; McMamara, J. Org. Lett. 2005, 7, 55; (c)
Dirat, O.; Elliott, J. M.; Jelly, R. A.; Jones, A. B.; Reader,
M. Tetrahedron Lett. 2006, 47, 1295.
20. The reported pKa values were obtained by titration in 1:1
methanol/water. The presence of 50% MeOH in a titration
has the effect of lowering the pKa of an amine between 0.3
and 0.9 U (with 0.5 U as a typical value) as compared to
its value in water (i.e., the actual pKa of 26b in water is
likely closer to 6.3).26
21. Solubilities were determined by HPLC after sonication in
buffer at 1 mg/mL and filtration. The solubility for 1 and
3a was determined in 0.1 M potassium hydrogen phos-
phate buffer at pH 5, while the solubilities for selected
28. Elliott, J. M.; Carlson, E. J.; Chicchi, G. G.; Dirat, O.;
Dominguez, M.; Gerhard, U.; Jelly, R.; Jones, A. B.;
Kurtz, M. M.; Tsao, K. L.; Wheeldon, A. Bioorg. Med.
Chem. Lett. 2006, 16, 2929.