Cyclic urea derivatives as potent NK1 selective antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.05.111

A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK₁ receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compoun

Full text of DOI:10.1016/j.bmcl.2005.05.111

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3896–3899
Cyclic urea derivatives as potent NK1 selective antagonists
Ho-Jane Shue,a Xiao Chen,a Neng-Yang Shih,a,* David J. Blythin,a Sunil Paliwal,a
Ling Lin,a Danlin Gu,a John H. Schwerdt,a Sapna Shah,a Gregory A. Reichard,a,
John J. Piwinski,a Ruth A. Duffy,b Jean E. Lachowicz,b Vicki L. Coffin,b Fei Liu,c
Amin A. Nomeir,c Cynthia A. Morganb and Geoffrey B. Vartyb
aChemical Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bCNS Biology Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
cDepartment of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, NJ 07033, USA
Received 14 April 2005; revised 24 May 2005; accepted 25 May 2005
Available online 12 July 2005
Abstract—A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor
antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are
also described herein.
Ó 2005 Elsevier Ltd. All rights reserved.
Substance P is a member of the tachykinin family of neu-
rotransmitters that selectively binds to the NK1 receptor.
Substance P has been implicated in a number of patho-
logical disorders in the central nervous system (CNS)
and peripheral tissues,1,2 including pain, inflammation,
depression, emesis and cough.3–6 Consequently, an
antagonist of the NK1 receptor has potential therapeutic
use in the treatment of cough,6 inflammation,7 asthma,8
pain,9 chemotherapy-induced emesis,10 migraine,11 anxi-
ety, and depression.12 Recently, Emend was approved
Herein, we report the discovery of novel cyclic urea
derivatives 2 and 3 as potent and selective NK1 antago-
nists that are orally active and have good CNS penetra-
tion. These cyclic ureas provide structural novelty while
possessing the minimal pharmacophoric elements of
phenylglycinol-derived NK1 antagonists of type 1.14
for the treatment of CINV (chemotherapy-induced nau-
sea and vomiting), and several NK1 antagonists are in
clinical trails for anxiety and depression.13
The racemic 4,4-disubstituted-2-imidazolidinones (2a–j)
shown in Table 1 were prepared by the synthetic route
illustrated in Scheme 1.15 Alkylation of 3,5-bis(trifluo-
romethyl)benzyl alcohol 4 with 2-iodo-N-methoxy-N-
methylacetamide 5, which was prepared in acetone from
its chloride derivative using sodium iodide, afforded
Weinreb amide 6. The coupling of Weinreb amide 6 with
phenyllithium gave the ketone 7 in excellent yield (80%).
Treatment of ketone 7 with trimethylsilyl cyanide and
ammonia in presence of zinc iodide afforded amine–
nitrile intermediate 7a, which was subsequently reduced
without isolation to give the diamine compound 8. The
*
Corresponding author. Tel.: +1 908 740 3530; fax: +1 908 740
7305; e-mail: neng-yang.shih@spcorp.com
Present address: Department of Chemistry, Pfizer Global Research
and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105, USA.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.111

H.-J. Shue et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3896–3899
3897
cyclization of diamine 8 in the presence of N,N0-carbon-
yldiimidazole (CDI) afforded the unsubstituted urea
compound 2a. An alternative four-step sequence to com-
pound 2a from compound 4 in higher overall yield has
previously been reported.16 Treatment of compound 8
with 1 equiv of ketone/aldehyde in the presence of a
reducing agent, such as sodium triacetoxyborohydride,
or an alkylating reagent, followed by CDI cyclization
afforded the N-substituted cyclic ureas 2f–j. In order to
determine the effect of the absolute stereochemistry on
binding activity, compound 2a was resolved to the enan-
tiomers 2b and 2c by chiral HPLC on a Daicel Chiralpak
ADÒ column. The assignment of absolute configuration
of enantiomer 2c was made based on the established chi-
ral synthesis.16 The chiral N-methylated compounds (2d
and 2e) were prepared by alkylation of the chiral com-
pound 2c with methyl iodide in the presence of sodium
hydride in N,N-dimethylformamide.
The in vitro NK1 binding and in vivo NK1 agonist-
induced gerbil foot-tapping (GFT) inhibition data for
4,4-disubstituted-2-imidazolidinones (2a–j) are listed in
Table 1. The NK1 binding assay determines the affinity
of these compounds (2a–j) toward the NK1 receptor
while the GFT inhibition measures the potency of these
compounds antagonizing an NK1 receptor-mediated
CNS effect. As shown in Table 1, the unsubstituted five
membered urea analogue 2a exhibited good NK1 bind-
ing affinity (Ki = 16 nM). It was noted that enantiomer
2c (R-isomer) had higher affinity for the NK1 receptor
than the enantiomer 2b (S-isomer) (6 vs 330 nM). In
addition, compound 2c was active in the GFT assay
(54% inhibition of foot-tapping at 1 mg/kg po after a
2 h pretreatment time) which demonstrated CNS pene-
tration and NK1 antagonist activity. In order to under-
stand the importance of the urea NH protons for
affinity, the N-methyl derivatives of 2c were synthesized.
When the hindered NH of the urea ring was methylated
(2d), the binding affinity was greatly reduced
(Ki = 94 nM). On the other hand, when the less hindered
NH was methylated (2e), retention of the binding affin-
ity was observed (Ki = 8 nM). This suggested that the
NH proton adjacent to the tertiary position of the cyclic
urea is more important for NK1 receptor binding. Con-
sequently, substitutions at the less hindered NH were
further explored. We found that a polar amide side
chain improved potency (e.g., 2f, Ki = 4 nM). Further
increase in polarity from a neutral substitution to basic
amino group containing side chains, significantly im-
proved NK1 affinity and in some cases (2g and 2i)
picomolar binding was achieved. Both the acyclic 2g
and cyclic (2h–j) amine side chains were well tolerated
and the position of the basic nitrogen did not significant-
ly affect the binding (2g, Ki = 0.7 nM and 2j, Ki = 1 nM).
The best representative of the amine side chain contain-
ing compounds was analogue 2h, which bound with high
affinity (Ki = 1 nM) and produced good activity (68%
inhibition) in the GFT assay.
Scheme 1. Reagent and conditions: (a) KN(TMS)2/THF, 0–25 °C,
18 h, 60%; (b) PhLi/THF, ꢀ78 °C, 1.5 h then rt, 80%; (c) TMSCN/
ZnI2/THF, rt, 1 h, filtered, concd then NH3/MeOH, 45 °C, 2 h then
filtered, concd; (d) LiAlH4/ether, ꢀ78 °C then rt, 18 h, 25–35% from 7;
(e) CDI/THF, rt, 18 h, 97%; (f) ketone, aldehyde/NaBH(OAc)3/
CH2Cl2, rt or NaBH3CN/MeOH or alkyl halide/DMF.
Table 1. NK1 receptor binding affinity and GFT inhibition for
compounds 2a–j
b
NK1 Ki
Compounda
R1
R2
GFTb
(%inh.)
(nM)
2a
–H
–H
–H
–H
16
332
6
NTc
NTc
54
NTc
0
2b (S)
2c (R)
2d (R)
2e (R)
–H
–CH3
–H
–H
–H
94
8
–CH3
2f
–H
4
18
2g
2h
2i
–H
–H
–H
0.7
1
23
68
15
0.5
2j
–H
1
0
A series of racemic six-membered cyclic urea derivatives
(3a–g) were prepared by the synthetic route shown in
Scheme 215 and their biological data are listed in Table
2. The chiral compounds 3a and 3b were prepared by
a Unless defined as (R) or (S), the compounds in the table are racemic.
b See Ref. 17–20.
c NT = not tested.

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H.-J. Shue et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3896–3899
the chiral HPLC separation of the racemic mixture 3a,b
on a Daicel Chiralpak ASÒ column.
As shown in Table 2, the six-membered ureas also
exhibited good NK1 receptor binding affinities. Similar
to five-membered urea derivatives, the activity of six-
membered urea derivatives also resided mostly in the
R-isomer, for an example, compound 3b (R-isomer,
Ki = 9 nM) versus compound 3a (S-isomer, Ki =
350 nM). However, compound 3b was found to be
inactive in GFT assay. This may be due to a poorer
pharmacokinetic profile of the latter. Based on the
SAR of the five-membered ureas, the substitutions at
the less hindered NH were subsequently explored in
the six-membered series. The N-methyl derivative 3c
and acetylpiperidine derivative 3d retained the binding
while the pyran analogue 3e showed improvement in
both binding (Ki = 3 nM), and in vivo activity (47%
inhibition). As previously observed with five-mem-
bered analogues, incorporation of basic amine side
chains (3f,g) improved the binding, and in the case
of methyl-piperidine analogue (3g), sub-nanomolar
NK1 affinity (Ki = 0.5 nM) was achieved. The analogue
3g showed the best GFT activity (56% inhibition) in
the six-membered urea series which was comparable
to the most potent five-membered series analogues 2c
and 2h.
Scheme 2. Reagent and conditions: (a) PhCH2Br, Et3N/THF/80 °C,
48 h, 46%; (b) LDA/ICH2CN/THF, ꢀ78 °C to ꢀ20 °C, 51%; (c) LAH/
THF, ꢀ78 °C to rt, 64%; (d) t-BOC-anhydride/20% Pd(OH)2–C,
H2, 50 psi, 18 h, 85%; (e) Ag2O/DMF, 3,5-bis(trifluoromethyl)benzyl
bromide, rt, 18 h, 64%; (f) HCl/Et2O, rt, 18 h, 99%; (g) CDI/THF, 0–
25 °C, 18 h, 48–63%; (h) ketone/HOAc/NaBH3CN/MeOH, or CH3I/
K2CO3/DMF or R2CH2Br/DMF.
In conclusion, we have identified a novel series of cyclic
urea derivatives of structures 2 and 3 as potent NK1
antagonists. Several compounds in these series exhibit
good NK1 selectivity, are orally active and have good
brain penetration. For example, compound 2c (SCH
388714) showed an excellent selectivity (NK2,
NK3 > 1 lM), good oral bioavailability (69% in rat)
and it displayed very good brain penetration (brain/plas-
ma ratio 4 in rat). Further details of the SAR effort to
improve potency of this class of NK1 antagonist will
be reported in due course.
Table 2. NK1 receptor binding affinity and GFT inhibition for
compounds 3a–g
References and notes
Compounda
R1
R2
GFTb
(%inh.)
b
NK1 Ki
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c NT = not tested.

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performed on membrane preparations from CHO cells in
which recombinant human NK1 receptors were expressed.
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NK1 assay, at concentrations near the experimentally
derived Kd value. Ki values were obtained using the Cheng
and Prusoff equation.
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5 min, and the duration of foot tapping was measured.
Foot tapping was defined as rhythmic, repetitive tapping
of the hind feet. NK1 antagonists were administered orally
in 0.4% methylcellulose in distilled water at a dose of 1 mg/
kg (unless otherwise stated) at various pretreatment times
prior to injection of GR73632. Data are expressed as a
percent decrease (% inhibition) in the amount of time
spent foot tapping compared to vehicle-treated controls.
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