Piperazinyl oxime ethers as NK-1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.10.077

The synthesis and structure-activity relations for a new class of centrally active NK-1 receptor antagonists are described. The new compounds are based on piperazine 2 and contain an oxime ether functionality. Several new compounds have high affinity for

Full text of DOI:10.1016/j.bmcl.2005.10.077

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1045–1048
Piperazinyl oxime ethers as NK-1 receptor antagonists
Adri van den Hoogenband, Jan H. van Maarseveen,ꢀ Andrew C. McCreary,
Arie T. Mulder, Guus J. M. van Scharrenburg, Herman H. van Stuivenberg,
Theo J. J. Zethof, Barbara Zijta and Wouter I. Iwema Bakker*
Solvay Pharmaceuticals, Research Laboratories, C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
Received 22 September 2005; revised 21 October 2005; accepted 22 October 2005
Available online 11 November 2005
Abstract—The synthesis and structure–activity relations for a new class of centrally active NK-1 receptor antagonists are described.
The new compounds are based on piperazine 2 and contain an oxime ether functionality. Several new compounds have high affinity
for the NK-1 receptor and show good antagonistic activity in the gerbil foot-tapping assay.
Ó 2005 Elsevier Ltd. All rights reserved.
The neuropeptide Substance P and its Neurokinin-1
(NK-1) receptor have been related to various biologi-
cal disorders such as anxiety, depression,1 emesis,2
asthma and inflammatory bowel disease (IBD).3 Fur-
thermore, the first brain penetrant NK-1 receptor
antagonist (Aprepitant; MK-869) has reached the mar-
ket for the treatment of chemotherapy induced nausea
and vomiting (CINV) and NK-1 receptor antagonists
have shown their clinical effectiveness in Phase II stud-
ies for depression.4 The latter result prompted us to
examine a centrally acting NK-1 receptor antagonist
for our CNS-drug discovery programme.
from the key pharmacophoric fragment 2 and intro-
ducing the essential basic element via an alternative
spacer giving 3. Due to our longstanding experience
with oxime ethers,8 having good brain penetration
(i.e., fluvoxamine), an oxime ether function was
selected as the key moiety in the spacer. Herein we
report a series of novel compounds with several oxime
ether spacers that act as highly potent CNS available
NK-1 antagonists.
O
O
O
H
N
NH
N
N
N
We have previously reported on a series of indolyl
N
H
methyl-N,N0-bisacylpiperazines,
a representative of
F3C
F3C
O
which is 1,5 as potent NK-1 receptor antagonists
(see Table1); however, 1 did not penetrate the brain6
and thus showed no activity in the gerbil foot-tapping
assay.7 Based on in-house experience with poor brain
penetration of compounds containing a urea function,
it was postulated that the urea function, solely serving
as a spacer unit between the required basic amine
pharmacophore and the piperazine scaffold, was the
cause of inactivity. Therefore, a programme was initi-
ated to synthesise NK-1 receptor antagonists starting
CF3
CF3
N
N
2
1
H
H
O
Basic
amine
Spacer
N
N
F3C
CF3
N
3
H
At first, a series of compounds was synthesised in which
the influence of spacer length and spacer substitution
was studied, whereas the basic amine was kept constant
as a morpholino-group. Recently, researchers of Fujisa-
wa reported a morpholine as the optimal basic pharma-
cophore in NK-1 antagonists.9
Keywords: Neurokinin; Synthesis; SAR; Oxime ethers.
*
Corresponding author. Tel.: +31 294 479613; fax: +31 294 477138;
e-mail: wouter.iwema-bakker@solvay.com
ꢀ
Present address: Van ꢁt Hoff Institute of Molecular Sciences,
University of Amsterdam, Amsterdam, The Netherlands.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.10.077

1046
A. van den Hoogenband et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1045–1048
Table 1. Chain length and substituent variations
R
O
F
N
O
(
)
n
(
)
m
N
N
F
F
F
N
O
F
N
F
H
b
Compound
R
m
n
hNK-1 pKia
hNK-1 pA2
Gerbil FT ED50 (mg/kg po)c
1
8
8.6 0.2 (3)
8.0 0.2 (3)
7.9 0.2 (3)
9.4 0.2 (4)
9.7 0.5 (3)
8.9 0.3 (4)
7.7 0.2 (3)
8.2 0.3 (3)
8.0 0.3 (4)
8.9 0.2 (3)
8.9 0.3 (4)
8.9 0.1 (3)
9.8 0.2 (3)
9.8 0.2 (6)
8.9 0.3 (3)
9.0 0.5 (4)
8.8 0.3 (3)
8.5 0.4 (4)
8.9 0.3 (4)
8.9 0.3 (3)
9.2 0.1 (4)
9.2 0.2 (4)
>10
1.3
Me
Me
Me
Me
Me
Ph
Ph
Ph
H
1
1
2
2
3
1
1
2
1
1
1
2
1
2
1
1
2
1
1
2
9
7.4
2.0
10
11
12
13
14
15
16
17
5.5
2.0
n.d.
>10
>10
2.0
H
2.3
a Displacement of [3H]-labelled Substance P from the cloned hNK-1 receptor expressed in CHO cells.
b Effect on IP3 turnover by phospholipaseC positively linked to hNK-1 receptor expressed in CHO cells.
c Inhibition of foot-tapping by po administration of test compound 60 min prior to icv infusion of GR-73632. The duration of foot-tapping was
recorded for 5 min.
O
O
Cl
Most oxime ethers were made from the corresponding
ketones and aldehydes 4 by reaction with the appropri-
ate alkoxyamine (Scheme 1), except for compound 16.
All oxime ethers were obtained as E/Z-mixtures. The ke-
tones 4 were obtained from 2 by alkylation with a suit-
able alkylating agent, in those cases where the carbonyl
was protected, the alkylating step was followed by acidic
hydrolysis (see legend to Scheme 1 for details).
N
NH2
N
N
i
ii
16
O
O
•2HCl
5
6
Scheme 2. Reagents and conditions: (i) chloroacetaldehyde, NaOH,
H2O, rt; (ii) 2, DIPEA, CH3CN, reflux.
The required alkoxy amines 5 were obtained by alkylation
of acetophenone oxime 7 with an appropriate alkylating
agent followed by acidic hydrolysis (Scheme 3).
Compound 16 was made by direct alkylation of 2 with
2-chloroacetaldehyde oxime ether; the required oxime
ether 6 was made by condensation of chloroacetaldehyde
with the corresponding alkoxy amine 5 (Scheme 2).10
The biological results for compounds 8–17, as shown in
Table 1, indicate that the chain length between the
piperazine-nitrogen and the morpholino-group does
not have much effect on the affinity for the NK-1 recep-
tor. A more noticeable effect is seen on the inositol turn-
over assay where the shorter chain lengths have a
stronger antagonistic effect. A shorter distance between
the morpholino-group and the oxime ether functionality
is favoured. This effect is even more striking in the gerbil
foot-tapping assay (compounds 8, 10 and 12 versus 9
and 11), a model predictive of central NK-1 activity.
R1
N (
O
O
O
N
NH
N
)
m
i or
F3C
F3C
ii, iii
CF3
CF3
N
2
4
N
H
H
R1
(
O
N
Whereas the spacer length has only a minor effect on the
receptor affinity, a somewhat stronger effect is seen for
the substituent in the spacer. A hydrogen-atom or meth-
yl group is well tolerated; however, a phenyl group low-
ers the affinity and also reduces the antagonistic
properties. Furthermore, the results from the gerbil
R2
O
N
)
N
m
iv
F3C
CF3
N
H
OH
O
R
Scheme 1. Reagents and conditions: (i) chloroacetone, DIPEA,
CH3CN, rt or methylvinylketone, toluene, rt or 3-chloropropiophe-
none, DIPEA, CH3CN, 70 °C or chloroacetophenone, DIPEA,
CH3CN, rt; (ii) 5-chloro-2-pentanone ethylene ketal, DIPEA, CH3CN,
reflux or 2-(2-bromoethyl)-1,3-dioxolane, DIPEA, CH3CN, 75 °C; (iii)
HCl, dioxane, H2O 50 °C; (iv) RCH2ONH2 ÆHCl, NaOAc, EtOH,
70 °C.
RCH2ONH2
N
N
i
ii
•xHCl (5)
+
Acetophenone
7
Scheme 3. Reagents and conditions: (i) Bu4NBr, NaOH, toluene,
H2O, rt; (ii) HCl reflux.

A. van den Hoogenband et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1045–1048
Table 2. Variations of oxime ether side chain
1047
O
N
N
N
O R
F
F
F
F
N
F
F
H
Gerbil FT ED50 (mg/kg po)c
b
Compound
R
hNK-1 pKia
hNK-1 pA2
18
Me
8.4 0.1 (3)
8.1 0.3 (4)
9.8 0.2 (4)
9.5 0.2 (4)
8.1 0.3 (4)
8.8 0.2 (3)
8.9 0.2 (3)
10.0 0.3 (3)
8.9 0.3 (4)
8.7 0.3 (3)
8.3 0.1 (3)
n.d.
>10
>10
>10
>10
10
NH2
19
20
21
22
23
24
25
26
27
9.1 0.2 (4)
8.7 0.2 (4)
9.1 0.1 (3)
8.8 0.2 (3)
8.2 0.2 (6)
8.6 0.2 (5)
8.0 0.2 (4)
8.5 0.2 (4)
8.2 0.2 (3)
H
N
N
N
N
S
N
SO2
>10
4.1
N
N
O
O
2.6
N
N
n.d.
a Displacement of [3H]-labelled Substance P from the cloned hNK-1 receptor expressed in CHO cells.
b Effect on IP3 turnover by phospholipaseC positively linked to hNK-1 receptor expressed in CHO cells.
c Inhibition of GR-73632 induced foot-tapping in gerbils after oral administration.
foot-tapping assay show greater variability than would
be expected from the in vitro data, suggesting that phar-
macokinetic properties for brain penetration may not be
favourable in all cases. A possible explanation for the
latter fact could be the increase in molecular weight.
Furthermore, increasing the steric bulk around the basic
nitrogen, as in 26 and 27, reduced the affinity for the
receptor and the antagonistic potency. While one methyl
group is allowed (26), two methyl groups a to the basic
nitrogen decrease the affinity and especially lower the
antagonistic potency (Table 2).
To study the effect of the basic amine, a series of com-
pounds was made wherein the basic amine was varied.
All compounds were made from 4 (m = 1, R = Me)
and the distance between the basic amine and the oxy-
gen-atom from the oxime ether was kept constant at a
C-2 distance. First of all 18 was made; the result clearly
indicated the importance of a basic amine, not only for
functional activity but even for good receptor binding.
For receptor binding and functional activity in vitro,
the presence of a basic amine is sufficient, however,
when the amine is too basic (cpKb < 5); oral in vivo
activity is lost, probably caused by the less favourable
pharmacokinetics of the compounds.
In order to reduce the number of rotatable bonds in 8,
and to fix the oxime ether configuration, with the aim
of increasing the affinity for the NK-1 receptor, the
oxime ether functionality was replaced by an isoxazole
i, ii
iii, iv
O
N
O
28
29
THPO
NO2
HO
N
Scheme 4. Reagents and conditions: (i) N-allylmorpholine or N-
propargylmorpholine, PhNCO, Et3N, toluene, 55 °C; (ii) PPTS,
MeOH, reflux; (iii) MsCl, DIPEA, CH2Cl2, rt; (iv) 2, DIPEA, CH3CN,
reflux.

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A. van den Hoogenband et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1045–1048
Table 3. Replacement of oxime ether by heterocycles
O
N
O
N
N
N
O
F3C
CF
3
N
H
Gerbil FT ED50 (mg/kg po)c
b
Compound
Dotted bond
hNK-1 pKia
hNK-1 pA2
28
29
Single (isoxazoline)
Double (isoxazole)
8.6 0.2 (3)
7.9 0.1 (3)
9.2 0.1 (3)
9.1 0.3 (4)
6.4
4.6
a Displacement of [3H]-labelled Substance P from the cloned hNK-1 receptor expressed in CHO cells.
b Effect on IP3 turnover by phospholipaseC positively linked to hNK-1 receptor expressed in CHO cells.
c Inhibition of GR-73632 induced foot-tapping in gerbils after oral administration.
3. Lecci, A.; Giuliani, S.; Tramontana, M.; Carini, F.;
Maggi, C. A. Neuropeptides 2000, 34, 303.
or isoxazoline moiety (Scheme 4). The required isoxaz-
ole and isoxazoline were conveniently obtained by 1,3-
dipolar cycloaddition of a nitrile oxide with N-allyl- or
N-propargylmorpholine.11 The isoxazoline 28 was iso-
lated as a mixture of diastereomers and tested as such.
The results are shown in Table 3, although the results
in vitro were encouraging, the potency after oral dosing
was decreased.
4. Kramer, M. S.; Cutler, N.; Feighner, J.; Shrivastava, R.;
Carman, J.; Sramek, J. J.; Reines, S. A.; Liu, G.; Snavely,
D.; Wyatt-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.; Sadow-
ski, S. J.; Williams, A. R.; Hewson, L.; Smith, D.; Carlson,
E. J.; Hargreaves, R. J.; Rupniak, N. M. J. Science 1998,
281, 1640.
The best compound overall, 8, was separated in the two
oxime-isomers (ratio ꢀ3:1) and the major isomer (E)
was tested. As this isomer had very similar activities
compared to those of mixture of isomers, E-8 was select-
ed as a preclinical candidate.
5. Jasserand, D.; David, S.; Antel, J.; Br’’uckner, R.;
Eeckout, C.; Bielenberg, G.-W. European Patent
EP0899270, 1999.
6. Dijksman, J. IV/PO study. Unpublished work.
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Acknowledgments
The authors thank Drs. J. A. J. den Hartog, H. K. A. C.
Coolen and M. B. Hesselink for their advice and stimu-
lating discussions.
9. Matsuo, M., Hagiwara, D., Manabe, T., Nobukiyo, K.,
Shigenaga, S., Murano, K., Matsuda, H., Miyake, H.
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