Preparation of oxime dual NK1/NK2 antagonists with reduced NK3 affinity

Article abstract of DOI:10.1016/S0960-894X(02)00462-6

By employing a stereosimplification approach, a thorough SAR exploration of the piperidine region of Sch 206272 was possible through a practical and efficient synthesis of substituted cyclic ureas. This SAR study led to the identification of a benzimidazolinone series of compounds which display single digit nanomolar NK₁/NK₂ affinity and near micromolar binding for the NK₃ receptor.

Full text of DOI:10.1016/S0960-894X(02)00462-6

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2355–2358
Preparation of Oxime Dual NK1/NK2 Antagonists with Reduced
NK3 Affinity
Gregory A. Reichard,* Cheryl A. Grice,y Neng-Yang Shih, James Spitler,
Sapna Majmundar, Steven D. Wang, Sunil Paliwal, John C. Anthes and John J. Piwinski
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 22 April 2002; accepted 28 May 2002
Abstract—By employing a stereosimplification approach, a thorough SAR exploration of the piperidine region of Sch 206272 was
possible through a practical and efficient synthesis of substituted cyclic ureas. This SAR study led to the identification of a benz-
imidazolinone series of compounds which display single digit nanomolar NK1/NK2 affinity and near micromolar binding for the
NK3 receptor. # 2002 Elsevier Science Ltd. All rights reserved.
Activation of sensory C afferent nerves by irritants and/
or inflammatory mediators results in the co-release of
the neurokinin oligopeptides, substance P (SP) and
neurokinin A (NKA) in pulmonary tissue.1 These neuro-
peptides bind to the NK1 and NK2 receptors respec-
tively resulting in bronchoconstriction, vasodilation,
smooth muscle contraction, edema, and neurogenic
inflammation.2 The involvement of these tachykinin
neuropeptides in the pathophysiology of asthma makes
them an attractive target for a new approach to asthma
therapy by means of simultaneous blockade of the
corresponding NK1 and NK2 receptors.
Since each of these three neuropeptides is capable of
eliciting responses from all three neurokinin receptors,
the overlapping specificity of agonist activity provides a
challenging problem in understanding the nature of the
neurokinin–endocrine relationship.
A third neuropeptide, neurokinin B (NKB), interacts
primarily with the NK3 receptor, however, similar to SP
and NKA, there is overlapping specificity with the other
NK receptors. The NK3 receptor is present in the CNS
as well as peripheral tissues. Although no NK3 receptors
have been localized in the respiratory tract,3 SR 142801,
an NK3 antagonist, has been shown to affect cough,
histamine potentiated microvasculature leakage, and
airway hyperresponsiveness to acetylcholine.4 Further-
more, there have been recent disclosures of the involve-
ment of NKB, as well as possibly SP and NKA in the
hypothalamic–pituitary axis.5
Figure 1.
The design and synthesis of NK1/NK2 dual antagonists is
an active area of research in our labs as well as many
others.6 Structural modification7 of an oxime lead struc-
ture8 resulted in the identification of Sch 206272 (Fig. 1)
as a potent dual NK1/NK2 antagonist that is quite
active in vivo in both guinea pig and dog.9 In addition
to functioning as an effective NK1/NK2 dual antagonist,
the binding affinity of Sch 206272 for the NK3 receptor,
is quite potent (Ki=0.3nM). Interestingly, a recent
disclosure of the effect of selective NK3 antagonists on
testosterone and gonadotrophins10 suggests that the
NK3 receptor may play a major role in the control
of androgen/gonadotrophin production/secretion. While
*Corresponding author. Tel.: +1-908-740-3522; fax: +1-908-740-
7305; e-mail: gregory.reichard@spcorp.com
yCurrent location: The R. W. Johnson Pharmaceutical Research
Institute, 3210 Merryfield Row, San Diego, CA 92121, USA.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00462-6

2356
G. A. Reichard et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2355–2358
targeting NK3 may be an interesting goal as an anti-
androgen therapeutic, our interest in developing a dual
NK1/NK2 antagonist for use in asthma prompted
us to minimize NK3 binding to avoid any potential
NK3 mediated effects controlled by the hypothalamic–
pituitary axis.
Table 1. Structure–activity relationships: modifications of 2
Ki (nM)
Compd
10
R
NK1
0.9
NK2
1.2
NK3
1.3
Rapid second-generation exploration of the bipiperidine
fragment to probe for diminished NK3 binding was
envisioned by utilizing a stereosimplification approach.
The corresponding cyclic urea could allow for rapid
access to a large number of structurally divergent
groups driven by amine availability. Critical to this
strategy was a practical and robust synthesis for the
appropriately protected aldehyde 4, wherein the protec-
tive group on the exocyclic amine could serve as the
carbonyl source for the urea (Fig. 2).
11
12
0.3
0.8
0.2
0.4
0.4
0.3
13
14
15
16
0.6
0.4
0.9
0.5
0.5
0.7
0.8
0.8
0.3
0.8
0.6
0.5
-Me
17
18
-OH
1.0
0.6
0.7
0.5
0.7
0.4
19
20
21
22
23
24
25
0.8
0.6
1.9
0.7
1.0
2.4
1.1
0.9
0.8
0.5
0.7
0.9
1.2
1.1
0.5
0.5
0.5
0.8
2.0
3.2
2.2
Figure 2.
Thus, synthetically, a one-pot procedure was developed
for the preparation of aldehyde 4 (Scheme 1). The
reductive amination of 3-amino-1-propanol with N-
Boc-4-piperidone in 1,2-dichloroethane provided the
amino alcohol 6. Addition of saturated aqueous sodium
bicarbonate to the reductive amination mixture fol-
lowed by carbamate formation with p-nitrophenyl
chloroformate proceeded smoothly. These biphasic
conditions were then employed for the subsequent
alcohol oxidation employing bleach/sodium bromide
with a catalytic amount of TEMPO to give the aldehyde
4 in excellent overall yield over three steps in a one-pot
procedure. Subsequent reductive amination with the
desired amine is followed by spontaneous cyclization
with unhindered amines to give the desired N-Boc pro-
tected piperidines. More hindered amines such as iso-
propyl amine or less reactive amines such as amino
pyridines require heating in DMF for the cyclization to
occur. Derivatives with N–O bonds (derived from
hydroxyl or alkoxyl amines), N–N bonds (derived from
hydrazines) and N-heterocyclic groups are readily and
rapidly prepared in the urea series. The route is quite
general (works well with other amino alcohols), and is
amenable to large scale synthesis (over 150 g of pure,
stable aldehyde (4) has been prepared in yields greater
than 75%). The synthesis of targets is for the most part
dependent on securing the appropriate amine.
26
27
1.6
1.0
1.2
1.2
10.9
11.8

G. A. Reichard et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2355–2358
2357
Table 2. Structure–activity relationships: benzimidazolinone series
Ki (nM)
Compd
R0
R00
NK1 NK2 NK3
29
30
31
32
33
34
35
36
-H
-CH3
-CH3
-CH3
-CH3
1.2
1.5
1.3
1.3
2.4
1.2
3.2
2.5
1.0
1.5
1.8
1.7
5.2
3.1
4.9
2.6
10
20
29
11
176
304
231
97
-CH2COOMe
-CH2COOH
-CH2COOH
-CH2COOH
-H
-CH3
-CH2CH3
-CH2CH2F
-CH2CH2F
-CH2CH3
-H
Scheme 1. Reagents and conditions: (i) aminopropanol, sodium tri-
acetoxyborohydride, 2 h; (ii) add saturated sodium bicarbonate, fol-
lowed by p-nitrophenylchloroformate; (iii) sodium bromide, TEMPO,
sodium hypochlorite; (iv) RNH2, sodium triacetoxy-borohydride, 2 h;
(v) DMF, heat if needed.
37
-H
157
2.5
2.8
4.0
103
312
572
38
39
-CH2CH3
-CH2CH3
2.7
2.0
40
41
-CH2CN
-CH2CH3
-CH2CH3
2.3
2.4
2.5
4.8
674
167
The direct stereosimplified methyl amide analogue
(Table 1, entry 10) of Sch 206272 revealed that removal
of the piperidone chiral center has little effect on the
binding affinity for the neurokinin receptors.11 Sub-
sequent alteration of the functionality stemming from
the urea nitrogen showed that this region of the receptor
tolerates a wide range of steric and functional modifi-
cations. A number of methyl carboxamides (entries 10–
13) are quite active at all three NK receptors. Accord-
ingly, simple alkyl groups such as methyl and isopropyl
(entries 14 and 15) are accommodated as well. The hin-
dered tertiary alcohol (entry 16) and the hydroxyl urea
(entry 17) bind with excellent affinity to all of the neu-
rokinin receptors, showing no bias against the NK3
receptor. Substitution with amine functionality of var-
ious basicities ranging from neutral (entry 18) to a basic
hydrazide (entry 19) to the more basic hydroxyamidine
(entry 20) showed little effect on binding and no impact
on reducing NK3 affinity. Heterocyclic amines (entries
21–23) similarly had no effect on selectivity for the NK
receptors. Although the tetrazole, thiazole and furan
(entries 23–25) showed little effect on NK3 binding, the
neutral phenyl substituted changes (entries 26–27) did
show a 7- to 10-fold selectivity for decreased NK3 affi-
nity over the NK1 or NK2 receptors. This prompted us
to investigate a series of compounds containing a fused
aryl ring with a fixed conformation relative to the cyclic
urea functional group, the benzimidazolinone class.
42
43
-CH2CH3
-CH2CH3
3.0
1.9
3.6
4.1
281
945
alization of the urea nitrogen revealed a fairly consistent
selectivity over NK1 and NK2, as illustrated by the
methyl, carbomethoxymethyl and carboxymethyl ana-
logues (entries 30–32). Alteration of the benzamide
methyl group resulted in targets with significantly
reduced NK3 affinity. While the N-ethyl derivative
(entry 33) displayed greater than 30-fold selectivity over
NK3, the monofluoroethyl derivatives (entries 34 and
35) were the first analogues to show 50- to 100-fold
selectivity in binding for NK1 and NK2 over NK3.
Although this selectivity was encouraging, potential
toxic metabolites arising from the monofluoroethyl
moiety stemmed further interest in these analogues.
Interestingly, the N-cyclopropyl derivative (entry 37)
showed a similar effect on NK2 and NK3 binding,
however, the NK1 affinity was significantly diminished,
thus providing an avenue for designing NK2 selective
compounds in this class, if desired. Since we were con-
centrating on NK1/NK2 selective antagonists, we
focussed our subsequent SAR around the N-ethyl ben-
zamide benzimidazolinone class. Preparation of the
2-piperidinylmethyl, methoxymethyl and cyanomethyl
analogues (entries 38–40) provided selectivities ranging
from around 100 to over 250-fold of NK1 and NK2 over
Benzimidazolinone analogues (Table 2) were prepared
by standard protection and subsequent alkylation/
functionalization from the commercially available
parent 4-(2-keto-1-benzimidazolinyl)piperidine. It was
interesting to find the parent unsubstituted benzimida-
zolinone (entry 29) showed an 8- to 10-fold selectivity in
affinity of NK1 and NK2 over NK3 binding. Function-

2358
G. A. Reichard et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2355–2358
NK3 binding. Finally, refocusing on amide derivatives
(entries 41–43) of the pivotal carboxymethyl lead (entry
33) led to the discovery of the methoxyethyl methyl
carboxamide, 43 which has single digit nanomolar NK1/
NK2 affinity and near micromolar binding for the NK3
receptor.
X.-G.; Le, T.-B.; Webster, M. E.; Horgan, S. W.; Wenstrup,
D. L.; Freund, D. W.; Boyer, F.; Bratton, L.; Gross, R. S.;
Knippenberg, R. W.; Logan, D. E.; Jones, B. K.; Chen, T.-M.;
Geary, J. L.; Correll, M. A.; Poole, J. C.; Mandagere, A. K.;
Thompson, T. N.; Hwang, K.-K. Bioorg. Med. Chem. Lett.
1997, 7, 2531. (d) Gerspacher, M.; LaVecchia, L.; Mah, R.;
von Sprecher, A.; Anderson, G. P.; Subramanian, N.; Hauser,
K.; Bammerlin, H.; Kimmel, S.; Pawelzik, V.; Ryffel, K.; Ball,
H. A. Bioorg. Med. Chem. Lett. 2001, 11, 3081. (e) Bernstein,
P. R.; Aharony, D.; Albert, J. S.; Andisik, D.; Barthlow, H. G.;
Bialecki, R.; Davenport, T.; Dedinas, R. F.; Dembofsky, B. T.;
Koether, G.; Kosmider, B. J.; Kirkland, K.; Ohnmacht, C. J.;
Potts, W.; Rumsey, W. L.; Shen, L.; Shenvi, A.; Sherwood, S.;
Stollman, D.; Russell, K. Bioorg. Med. Chem. Lett. 2001, 11,
2769.
7. (a) Shih, N.-Y.; Albanese, M.; Aslanian, R.; Blythin, D.;
Chen, X.; Duguma, L.; Gu, D.; Friary, R.; Lee, J.; Lin, L.;
Mangiaracina, P.; McCormick, K.; Mohrbutter, R.; Mutahi,
M.; Piwinski, J. J.; Reichard, G. A.; Schwerdt, J.; Shue, H.-J.;
Spitler, J.; Ting, P.; Wong, J.; Wong, S.-C.; Carruthers, N.;
Grice, C.; Lupo, A., Jr.; Anthes, J.; Chapman, R.; Hey, J.;
Kreutner, W.; Rizzo, C. Abstracts of Papers, 220th National
Meeting of the American Chemical Society, Washington, DC;
American Chemical Society: Washington, DC, 2000, MEDI-
129. (b) Shih, N.-Y.; Albanese, M.; Anthes, J.; Carruthers, N.;
Grice, C.; Lin, L.; Mangiaracina, P.; Reichard, G. A.;
Schwerdt, J.; Seidl, V.; Wong, S.-C.; Piwinski, J. J. Bioorg.
Med. Chem. Lett. 2002, 12, 141.
Summary
Subsequent to the identification of Sch 206272 as a
potent subnanomolar NK1/NK2/NK3 antagonist and
the emerging literature on the involvement of neuro-
kinins in the hypothalamic-pituitary axis, a study was
undertaken to reduce the NK3 binding in this class. By
employing a stereosimplification approach, a thorough
SAR exploration of the piperidine region of Sch 206272
was possible through a practical and efficient synthesis
of substituted cyclic ureas. This SAR study led to the
identification of the benzimidazolinone series of com-
pounds illustrated by compound 43 which displays single
digit nanomolar NK1/NK2 affinity and near micromolar
binding for the NK3 receptor.
8. Reichard, G. A.; Ball, A. T.; Aslanian, R.; Anthes, J. C.; Shih,
N.-Y.; Piwinski, J. J. Bioorg. Med. Chem. Lett. 2000, 10, 2329.
9. (a) Anthes, J. C.; Chapman, R. W.; Richard, C.; Eckel, S.;
Corboz, M.; Hey, J. A.; Fernandez, X.; Greenfeder, S.;
McLeod, R.; Sehring, S.; Rizzo, C.; Crawley, Y.; Shih, N.-Y.;
Piwinski, J. J.; Reichard, G. A.; Ting, P.; Carruthers, N.; Cuss,
F. M.; Billah, M.; Kreutner, W.; Egan, R. W.; Eur. J. Pharm.
2002, submitted for publication; (b) Reichard, G. A.; Alaimo,
C. A.; Shih, N.-Y.; Ting, P. C.; Carruthers, N. I.; Lavey, B. J.
U.S. Patent. 6063926, 2000, Chem. Abstr. 132:334363.
References and Notes
1. Lowe, J. A.; Snider, R. M. Annu. Rep. Med. Chem. 1993,
28, 99.
2. Watling, K. J.; Guard, S. Neurotransmissions 1992, 8, 1.
3. Stables, J. M.; Beresford, J. M.; Arkinstall, S.; Ireland, S. J.;
Walsh, D. M.; Seale, P. W.; Ward, P.; Hagan, R. M. Neuro-
peptides 1994, 27, 333 and references cited therein.
4. Daoui, S.; Cognon, C.; Naline, E.; Edmonds-Alt, S.; Advinier,
C. Am. J. Crit. Care Med. 1998, 158, 42.
10. Murphy, D.; Wier, P. J.; Giardina, G. A. M. WO
0043008, 2000, Chem. Abstr. 133:129881.
5. Debeljuk, L.; Lasaga, M. Peptides 1999, 20, 285.
6. (a) Reichard, G. A.; Shih, N.-Y.; Wang, S. D. U.S. Patent
6204265, 2001, Chem. Abstr. 134:237490. (b) Shah, S. K.;
Hale, J. J.; MacCoss, M.; Dorn, C. P., Jr.; Qi, H.; Miller, D.
J.; Finke, P. E.; Meurer, L. C.; Cascieri, M. A.; Sadowski, S.;
Metzger, J. M.; Eiermann, G. J.; Forrest, M. J.; MacIntyre, D.
E.; Mills, S. G. Abstracts of Papers, 220th National Meeting of
the American Chemical Society, Washington, DC; American
Chemical Society: Washington, DC, 2000, MEDI-195. (c)
Burkholder, T. P.; Kudlacz, E. M.; Maynard, G. D.; Liu,
11. Receptor binding assays were performed on membrane
preparations containing recombinant human NK1, NK2 or
NK3 receptors in CHO cells. [3H]Sar SP, [3H]NKA and
[
125I][MePhe]NKB were used as ligands for the NK1, NK2,
and NK3 receptor binding assays, respectively, at the experi-
mentally derived Kds. Kis were obtained according to the
Cheng and Prussoff equation. CP-96345, SR-48968 and SR-
142801 were run as NK1, NK2, and NK3 standards, respec-
tively, revealing an inter-run variability within 2-fold.