Identification of a novel 1'-[5-((3,5-dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]-2-oxo-(1,4'-bipiperidine) as a dual NK(1)/NK(2) antagonist.

Article abstract of DOI:10.1016/S0960-894X(02)00340-2

A novel series of dual NK(1)/NK(2) receptor antagonists, based on the 2-oxo-(1,4'-bipiperidine) template, has been prepared. Compound 10R is a potent dual NK(1)/NK(2) antagonist and demonstrates excellent in vivo activity and good oral plasma levels in the dog.

Full text of DOI:10.1016/S0960-894X(02)00340-2

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2125–2128
Identification of a Novel 10-[5-((3,5-
Dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-
(methoxyimino)pentyl]-2-oxo-(1,40-bipiperidine) as a
Dual NK1/NK2 Antagonist
Pauline C. Ting,* Joe F. Lee, Neng-Yang Shih, John J. Piwinski, John C. Anthes,
Richard W. Chapman, Charles A. Rizzo, John A. Hey, Kwokei Ng and Amin A. Nomeir
The Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 19 April 2002; accepted 7 May 2002
Abstract—A novel series of dual NK1/NK2 receptor antagonists, based on the 2-oxo-(1,40-bipiperidine) template, has been pre-
pared. Compound 10R is a potent dual NK1/NK2 antagonist and demonstrates excellent in vivo activity and good oral plasma
levels in the dog. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
antagonist with good in vivo activity, but moderate
pharmacokinetic (PK) profile with only 5% bioavail-
ability in the dog.4 In this communication, we describe a
series of analogues that have an additional substituent
on the piperidone ring which results in a significant
improvement in the PK profile.
The neurokinins are a family of peptides which can be
found throughout the central and peripheral nervous
system. They may play a role in allergic and inflamma-
tory conditions such as asthma, arthritis, and cough as
well as in central nervous system disorders such as
migraine, emesis, anxiety, and depression.1 Barnes and
coworkers have proposed that both Substance P (SP)
and neurokinin A (NKA), which bind to the seven
transmembrane G-protein coupled NK1 and NK2
receptors respectively, are involved in plasma extra-
vasation and airway constriction, which are the hall-
marks of the asthmatic condition.2 This hypothesis has
been confirmed in a guinea pig model of bronchocon-
striction by the synergistic effect observed with combining
selective NK1 and NK2 receptor antagonists.3
Chemistry
The substituted 2-oxo-(1,40-bipiperidine) analogues 8
were prepared as diastereomeric mixtures by the syn-
thetic route diagrammed in Scheme 1. We have pre-
viously reported our synthesis of the versatile
intermediate 2 which allowed us to vary the right-hand
side amide, the center oxime, or the left-hand side
piperidine moieties for our structure–activity relation-
ship (SAR) studies.5 In this case, Swern oxidation6 of
intermediate 2 followed by subsequent reductive ami-
nation7 with methylamine and acylation with 3,5-
dichlorobenzoyl chloride defined the right-hand side
moiety as the desired amide 3. Stepwise deprotection of
compound 3 can be accomplished with hydrofluoric
acid to remove the silyl protecting group and mercuric
perchlorate to remove the dithiane protecting group.8
The center oxime moiety was then fixed as the methoxy-
oxime. Formation of the oxime with methoxylamine in
pyridine yields a 1.2:1.0 mixture of the Z/E oxime iso-
mers which are separable by flash silica gel chromato-
We have identified compound 1R, the Z oxime isomer
and the R enantiomer, as a potent dual NK1/NK2
*Corresponding author. Tel.: +1-908-740-3543; fax: +1-908-740-
7305; e-mail: pauline.ting@spcorp.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00340-2

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P. C. Ting et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2125–2128
Scheme 1. Reagents and conditions: (a) oxalyl chloride, DMSO, CH2Cl2, Et3N, 100%; (b) MeNH2, NaCNBH3, CF3CH2OH, 44%; (c) 3,5-
dichlorobenzoyl chloride, pyridine, CH2Cl2, 97%; (d) HF, CH3CN, 80%; (e) HgClO4, CaCO3, THF, H2O, 100%; (f) MeONH2–HCl, pyridine, 28%
of Z isomer and 22% of E isomer; (g) oxalyl chloride, DMSO, CH2Cl2, Et3N, 100%; (h) NaCNBH3, CF3CH2OH, 26–70%; (i) LiN(TMS)2, THF,
allyl bromide, 93%; (j) RuO2, NaIO4, EtOAc, H2O, 90%; (k) amine, DEC, HOBT, CH2Cl2, 31–100%; (l) TFA, CH2Cl2, 100%.
graphy. From previous SAR studies, we know that the
Z oxime isomer is critical for dual NK1/NK2 activity.
All compounds described in this paper are Z oxime
isomers. Swern oxidation provided the key intermediate
aldehyde 4. Reductive amination of aldehyde 4 with a
number of piperidines 7 yielded the target 2-oxo-(1,40-
bipiperidines) 8.9 The piperidines 7 were synthesized by
alkylation of the known piperidone 510 with allyl bro-
mide, and oxidation of the double bond with ruthenium
dioxide catalysis and sodium metaperiodate to provide
the carboxylic acid 6. 1-Ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide, DEC, promoted amide formation of
acid 6 and subsequent acid catalyzed removal of the
tBOC protecting group produced the piperidines 7.
(1,40-bipiperidine) analogues 8a–g as the mixture of ste-
reoisomers. The racemate of our lead structure 1R is the
piperidone 1.
As we have previously reported, a thorough SAR study
of the left-hand side piperidine moiety has been con-
ducted, and we have found that an additional amide
side chain a to the lactam is well-tolerated.14 This is the
basis for the design of target compounds 8a–g, all of
which retain both NK1 (Ki=0.6–3 nM) and NK2
(Ki=0.7–3 nM) binding potency relative to our lead
Table 1. NK1 and NK2 in vitro activity of 2-oxo-(1,40-bipiperidines)
8a–g
The individual stereoisomers of the target compound 8
were initially obtained by separation on a Chiracel11
AD and/or OD HPLC column with 80:20 hex-
ane:isopropanol and 0.25% by volume diethylamine as
the eluant. Assignment of the absolute stereochemistry
was determined by a chiral synthesis and single crystal
X-ray analysis.12
Ki, nMa
(NK1)
Ki, nMa
(NK2)
pA2
(NK2)
b
Compd
R
Results and Discussion
1
No side chain
NMe2
NHMe
5
1
2
2
3
1
1
0.6
2
1
2
3
2
1
2
0.7
7.3
7.2
7.3
7.0
7.6
7.3
6.2
6.8
Our screening protocol was to analyze target com-
pounds in our binding and functional assays as diaste-
reomeric or enantiomeric mixtures and subsequently
determine the in vivo biological and pharmacokinetic
profile of the individual stereoisomers for the more
active analogues.
8a
8b
8c
8d
8e
8f
8g
NH2
3-Hydroxy-azetidine
Morpholine
Thiomorpholine
N-Methyl-piperidine
aKi values are the average of at least two independent determinations.
bIn vitro guinea pig bronchus contraction assay.13
Therefore, in Table 1 are the NK1 and NK2 receptor
binding and NK2 functional data13 for selected 2-oxo-

P. C. Ting et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2125–2128
2127
structure 1. Although the thiomorpholinoamide 8f and
the N-methylpiperidinoamide 8g possess good binding
activity, they clearly exhibit less potent NK2 functional
activity (pA2<7.0). Therefore, we decided to separate
the stereoisomers of analogues 8a–8e for complete in
vitro and in vivo characterization since these compounds
possess more potent NK2 functional activity (pA2
ꢀ7.0).
a pA2 for NK2 of 7.8 for the isomer 10R in comparison
to 7.4 for the isomer 10S. Likewise, acetamide 11R has a
pA2 for NK2 of 8.0 relative to 7.3 for 11S. This trend
holds for the 3-hydroxyazetidinoamide 12R (pA2 for
NK2 of 7.3) over 12S (pA2 for NK2 of 6.3) and the
morpholinoamide 13R (pA2 for NK2 of 7.9) over 13S
(pA2 for NK2 of 6.9). The sole exception is the N,N-
dimethylacetamides 9R and 9S which show the same
level of NK2 functional potency of 7.4.
From our previous work, we know that the stereo-
chemistry of the 3,4-dichlorophenyl chiral center is R
for optimal activity as in 1R.4 This SAR hypothesis has
been verified for this series of 2-oxo-(1,40-bipiperidines)
with compounds 10R and 10S.15 The in vitro profile for
analogues 9–13, in which the 3,4-dichlorophenyl stereo-
center is fixed as the R enantiomer, is tabulated in Table 2.
Overall, the NK1 binding potency is similar for the R
stereoisomer (Ki=0.6–1.3 nM) versus the S stereo-
isomer (Ki=0.4–1.5 nM) of the carboxamide side chain.
This is also true for the NK2 binding potency for the R
stereoisomer (Ki=0.2–0.5 nM) versus the S stereo-
isomer (Ki=0.3–1 nM). However, these compounds can
be distinguished based on their NK2 functional activity.
For example, the N-methylacetamide analogue exhibits
Due to their encouraging in vitro activity, the in vivo
activities of analogues 9R–13R as dual NK1 and NK2
antagonists have been determined and are reported in
Table 3. In vivo NK1 activity in the guinea pig is char-
acterized by the compound’s ability to inhibit the
increase in airway microvascular leakage (AML) pro-
duced by a SP challenge. In vivo NK2 activity is char-
acterized by the compound’s ability to inhibit
bronchoconstriction produced by a NKA challenge.13
The N,N-dimethylacetamide 9R, the N-methylaceta-
mide 10R, and the acetamide 11R all exhibit in vivo
guinea pig activity comparable to the lead structure 1R
with ED50 in the 1–4 mpk range. In contrast, the 3-
hydroxyazetidinoamide 12R and the morpholinoamide
13R are significantly less potent as NK1 inhibitors for the
guinea pig in vivo, exhibiting only 45–50% inhibition at
a 10 mpk dose.
Table 2. NK1 and NK2 in vitro activity of 2-oxo-(1,40-bipiperidines)
9–13
Due to their encouraging biological activity in the gui-
nea pig, analogues 9R–11R were further evaluated for
their pharmacokinetic profile in the dog. The results of
these studies are shown in Table 4. Our lead structure
1R and the N,N-dimethylacetamide analogue 9R both
possess lower blood levels with AUC<4ug h/mL.
However, the N-methylacetamide 10R and the acet-
amide 11R both show higher blood levels with AUC>9
ug h/mL. Between 10R and 11R, the N-methylacetamide
10R is the superior compound based on its higher bioa-
vailability of 66% versus 37% for 11R.
b
b
Compd
R
Ki, nMa Ki, nMa pA2
pA2
(NK1) (NK2)
(NK1)
(NK2)
1R
9R
9S
No side chain
NMe2
NMe2
1.2
0.8
0.8
1.3
1.5
0.8
0.4
0.6
1.1
0.7
0.8
0.8
0.2
0.3
0.4
0.9
0.3
0.3
0.3
0.6
0.4
0.8
8.0
7.9
8.0
7.9
8.0
8.0
7.7
8.0
NT
7.8
8.2
7.7
7.4
7.4
7.8
7.4
8.0
7.3
7.3
6.3
7.9
6.9
In conclusion, we have confirmed that the introduction
of an amide side chain on the 2-oxo-(1,40-bipiperidine)
template as in analogues 8a–g retains the superior in
vitro dual NK1 and NK2 binding potency in compar-
ison to our lead structure 1R. This side chain amide can
be the unsubstituted acetamide 8c or substituted as
the N,N-dimethylacetamide 8a, N-methylacetamide 8b,
3-hydroxyazetidinoamide 8d, or morpholinoamide 8e
and retain NK2 functional potency relative to 1R. The
R stereoisomer 9R–13R of 8a–e displays higher NK2
functional activity than the corresponding S stereo-
isomer 9S–13S. Evaluation of the in vivo activities of
9R–13R in the guinea pig shows that the N,N-dimethyl-
10R
10S
11R
11S
12R
12S
13R
13S
NHMe
NHMe
NH2
NH2
3-Hydroxy-azetidine
3-Hydroxy-azetidine
Morpholine
Morpholine
aKi values are the average of at least two independent determinations.
bIn vitro guinea pig bronchus contraction assay.13
NT, not tested.
Table 3. NK1 and NK2 in vivo guinea pig activity of 2-oxo-(1,40-
bipiperidines) 9R–13R
Table 4. Pharmacokinetic data for 2-oxo-(1,40-bipiperidines) 9R–11R
Compd
ED50, mpk (NK1)
ED50, mpk (NK2)
Compd
AUC0ꢁ24 h, dog,
po at 3 mpk (ug h/mL)
Bioavailabilty
1R
9R
10R
11R
12R
13R
1
3
1
3
3
3
1R
9R
10R
11R
1.22
3.46
13.6
9.49
5%
ND
66%
37%
1
4
45%a
47%a
64%a
97%a
ND, not determined.
a% Inhibition @ 10 mpk.

2128
P. C. Ting et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2125–2128
acetamide 9R, N-methylacetamide 10R, and acetamide
11R all possess good potency equivalent to that of our
lead structure 1R. Further evaluation of 9R–11R for
their pharmacokinetic profile in the dog distinguishes
Piwinski, J.; Reichard, G.; Schwerdt, J.; Shue, H. J.; Spiter, J.;
Ting, P.; Wong, J.; Wong, S. C.; Anthes, J.; Chapman, R.;
Hey, J.; Kreutner, W.; Rizzo, C.; Carruthers, N.; Alaimo, C.
Abstracts, 220th National Meeting of the American Chemical
Society, Washington, DC, Aug 20–24, 2000.
5. Ting, P. C.; Lee, J. F.; Anthes, J. C.; Shih, N.-Y.; Piwinski,
J. J. Bioorg. Med. Chem. Lett. 2000, 10, 2333.
6. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2480.
the N-methylacetamide 10R with
improved AUC level and bioavailability in comparison
a
significantly
to our lead structure 1R.
7. Borch, R. F.; Berstein, M. D.; Dupont Durst, H. J. Am.
Chem. Soc. 1971, 93, 2897.
Acknowledgements
8. Bernardi, R.; Ghiringhelli, D. J. Org. Chem. 1987, 52, 5021.
9. All synthesized target compounds were fully characterized
by 1H NMR, 13C NMR, and high-resolution mass spectro-
scopy. All target compounds are the pure Z oxime isomer.
10. Miller, S. C. WO Patent 94/10 146, 1994; Chem Abstr.
1994, 122, 105675.
11. Chiral Technologies, Inc., 730 Springdale Dr., PO Box
564, Exton, PA 19341, USA. Tel.: +1-800-624-4725; fax: +1-
610-594-2325.
The authors would like to acknowledge and thank
Yvette Crawley, Stephen Eckel, Xiomara Fernandez,
Jennifer Fine, Maria Rivelli, Susan Sehring, and Z.
Zahn in the Biology Department for conducting the in
vitro and in vivo assays. The authors would also like to
acknowledge and thank M. Bryant, Grace Gruela, and
Cymbelene Nardo in the Drug Metabolism Department
for pharmacokinetic analysis. The authors would like to
acknowledge the guidance and advice of Robert Egan,
William Kreutner, and C. C. Lin.
12. Manuscript in preparation.
13. Anthes, J. C.; Chapman, R. W.; Richard, C.; Eckel, S.;
Corboz, M.; Hey, J. A.; Fernandez, X.; Greenfeder, S.; Chee-
watrakoolpong, B.; Rizzo, C.; Crawley, Y.; Ng, K.; Shih, N.-
Y.; Piwinski, J.; Reichard, G.; Ting, P.; Carruthers, N.; Billah,
M.; Kreutner, W.; Egan, R. W.; Cuss, F. M. Eur. J. Pharm.
Submitted for publication.
References and Notes
14. Ting, P. C.; Lee, J. F.; Anthes, J. C.; Shih, N. Y.; Piwinski,
J. J. Bioorg. Med. Chem. Lett. 2001, 11, 491.
15. Biological data for the isomer of 10R where the 3,4-
1. Swain, C. N.; Rupniak, M. J. In Annual Reports in Medic-
inal Chemistry; Doherty, A., Ed.; Academic: New York, 1999;
Vol. 34, p 51.
dichlorophenyl center is of the
S stereochemistry: Ki
2. Barnes, P. J.; Baraniuk, J. B.; Belvisi, M. G. Am. Rev.
Respir. Dis. 1991, 144, 1187.
(NK1)=10 nM versus 0.9 nM for 10R, Ki (NK2)=12 nM
versus 0.3 nM for 10R, pA2 (NK2)=6.2 versus 7.8 for 10R.
Biological data for the isomer of 10S where the 3,4-dichloro-
phenyl center is of the S stereochemistry: Ki (NK1)=6 nM
versus 1.5 nM for 10S, Ki (NK2)=21 nM versus 0.9 nM for
10S, pA2 (NK2)=5.9 versus 7.4 for 10S.
3. Foulon, D. N.; Champion, E.; Masson, P.; Rodger, I. W.;
Jones, T. R. Am. Rev. Respir. Dis. 1993, 148, 915.
4. Shih, N. Y.; Albanese, M.; Aslanian, R.; Blythin, D.; Chen,
X.; Duguma, L.; Gu, D.; Friary, R.; Lee, J.; Lin, L.; Man-
giaracina, P.; McCormick, K.; Mohrbutter, R.; Mutahi, M.;