Cyclobutane derivatives as potent NK1 selective antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.04.031

A series of novel cyclobutane derivatives as potent and selective NK₁ receptor antagonists is described. Several compounds in this series exhibited high in vitro binding affinity (K_i {less-than or slanted equal to} 1 nM), and potent

Full text of DOI:10.1016/j.bmcl.2006.04.031

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3859–3863
Cyclobutane derivatives as potent NK1 selective antagonists
Michelle Laci Wrobleski,a Gregory A. Reichard,a, Sunil Paliwal,a Sapna Shah,a
Hon-Chung Tsui,a Ruth A. Duffy,b Jean E. Lachowicz,b Cynthia A. Morgan,b
Geoffrey B. Vartyb and Neng-Yang Shiha,*
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
Received 27 February 2006; revised 4 April 2006; accepted 5 April 2006
Available online 8 May 2006
Abstract—A series of novel cyclobutane derivatives as potent and selective NK1 receptor antagonists is described. Several com-
pounds in this series exhibited high in vitro binding affinity (Ki 6 1 nM), and potent inhibition of central NK1 receptor following
oral administration. Syntheses of these compounds are also described herein.
Ó 2006 Elsevier Ltd. All rights reserved.
Substance P (SP) belongs to the tachykinin family of
neurotransmitters that selectively binds to the NK1
receptor. SP has been implicated in numerous patholog-
ical conditions in the central nervous system (CNS) and
peripheral tissues including pain, inflammation, depres-
sion, anxiety, and emesis.1 Hence, a NK1 antagonist
has potential therapeutic use in the treatment of wide
range of central and peripheral diseases.
we report the discovery of a novel class of 3,3-disubsti-
tuted cyclobutane derivatives 3 as potent and selective
NK1 antagonists that have good CNS penetration and
are orally active in vivo. The cyclobutane ring provides
the structural novelty as well as the rigid conformation
support to the diaryl ether pharmacophore. Compounds
3 contain a methyl group at the benzylic position since it
has been reported in literature that such substitution im-
proves binding affinity and duration of in vivo activity in
the diaryl ether containing NK1 antagonists by decreas-
ing the benzylic site metabolism.6
The phenyl glycine-based structure 1 represents a prime
pharmacophore among the diverse chemotypes reported
to date as NK1 receptor antagonists. Structure 1 has
spawned several acyclic2,3 and cyclic NK1 antagonists4
where the nitrogen is tied together with the C1 or C2
carbon atom. Initially it appeared that the position of
the nitrogen relative to the diaryl ether portion of the
pharmacophore structure 1 is important but later it
was shown that the nitrogen position can be varied while
2
R2
1
NRR1
F3C
O
O
N
R3
H
CF3
1
2
retaining good binding affinity (e.g., 2, IC50
0.95 nM).5
=
3
F3C
High affinity of structural type 2 prompted us to explore
other molecular scaffolds in place of piperidine. Herein,
O
R1
R2
CF3
3
Keywords: Cyclobutane; NK1 antagonist; Substance P; CNS penetra-
tion; Oral in vivo activity.
Initially, we explored a series of 1-monosubstituted cyc-
lobutane analogues listed in Table 1. The synthetic route
for the preparation of the cyclobutanone compound 3a
and 1-monosubstituted cyclobutane derivatives 3b–h is
illustrated in Scheme 1.7 Alkylation of (R)-a-methyl
*
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 Road, Ann Arbor, MI 48105,
USA.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.031

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M. L. Wrobleski et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3859–3863
Table 1. NK1 receptor binding affinity and GFT inhibition for
compounds 3a–h
F3C
F3C
d
F3C
Ph
a
b
OH
O
O
Ph
F3C
O
CF3
4
CF3
1
5
R1
CF3
Ph
O
3a-h
Ph
F3C
c
Cl
Cl
O
O
a
NK1 Ki
Compound
R1
GFTb (% inh)
t = 4 h
CF3
CF3
(nM)
6
7
3a
@O
–NH2
–NHBn
2.4
11
21
25
Ph
Ph
3bc
3cc
0.02
0.3
F3C
F3C
e
O
O
O
NHBn
CF3
CF3
H
N
O
NH
3dc
0.5
0.1
0.4
0.4
22
23
25
41
3a
3c
NH
N
3e (trans)
3f (cis)
3g (trans)
NHAc
Ph
Ph
R1
F3C
F3C
g, h
f
O
O
or
i, j
NHAc
O
NH2
CF3
CF3
3b
3e-h
N
O
3h (cis)
0.3
3
Ph
F3C
N
k, l
O
3c
a See Ref. 11.
b See Ref. 13.
c 1:1 mixture of cis/trans isomers.
HN
CF3
3d
NH
N
N
O
3,5-bis(trifluoromethyl)benzylalcohol8 4 with the triflate
of the 2-hydroxyacetophenone in the presence of 2,6-di-
tert-butyl-4-methyl pyridine afforded the ketone 5. Wit-
tig olefination of ketone 5 provided alkene 6.9 Subjec-
tion of the olefine 6 to a [2+2] cycloaddition with
dichloroketene afforded isomeric dichlorocyclobutanone
7. Reduction of 7 with zinc in acetic acid gave the
cyclobutanone 3a. Reductive amination of 3a with ben-
zylamine afforded a cis/trans mixture of 3c. Hydrogena-
tion of the benzyl derivative 3c provided a cis/trans
mixture of amine 3b. Acetylation of amine 3b followed
by separation of the isomers by HPLC provided the
compounds 3e and 3f. Acylation of amine 3b with 4-
chlorobutyryl chloride followed by cyclization and sep-
aration of the isomers by HPLC afforded the lactam
analogues 3g and 3h.
H
Scheme 1. Reagents and conditions: (a) 2-hydroxyacetophenone, 2,6-
di-tert-butyl-4-methyl-pyridine, Tf2O, ClCH2CH2Cl, rt, 3 h, then 4,
80 °C, 4 h, 70%; (b) NaNH2/CH3PPh3Br, THF, rt, 24 h, 92%; (c) Zn–
Cu couple, Et2O/DME, trichloroacetylchloride, reflux, 5 days, 86%; (d)
Zn dust, AcOH, rt, 48 h, 82%; (e) BnNH2, NaBH(OAc)3, rt, 24 h, 94%;
(f) H2, 10% Pd/C, 1 atm, rt, 24 h, 81%; (g) ClCH2CH2Cl, Et3N,
CH3C(O)Cl, 0 °C, 2 h, 93%; (h) separation of isomers by HPLC on a
Chiralcel ODÒ column eluting with hexane/IPA (9:1); (i) i—
ClCH2CH2Cl, Et3N, ClCH2CH2CH2C(O)Cl, 0 °C, 3 h; ii—THF,
NaH, 0 °C, 15 min, then rt, 14 h, 80% over two-steps; (j) separation
of isomers by HPLC on a Chiralpak ADÒ column eluting with hexane/
IPA (9:1); (k) DMF, K2CO3, chlorotriazolinone, 0 °C, 9 h, 77%; (l)
MeOH, ammonium formate, 10% Pd/C, reflux, 1 h, 92%.
good NK1 binding affinity (Ki = 2.4 nM). The change
of ketone to primary amine (3b) and secondary benzyl-
amine (3c) derivatives resulted in a significant improve-
ment in binding affinity with the unsubstituted primary
amine (3b, Ki = 0.02 nM) as one of the most potent
NK1 antagonist reported to date. However, both amines
3b and 3c displayed poor GFT activity (21% and 25%
inhibition of foot-tapping, respectively, at 1 mg/kg po
after a 4 h pretreatment time). The substitution on the
primary amine 3b with a triazolinone moiety which
had previously provided significant enhancement in
potency in the Merck piperidine series,15 did not lead
to activity improvement (3d, Ki = 0.5 nM, 22% GFT
inhibition) in the present cyclobutane series. We next
evaluated the effect of modification of amine to neutral
amide groups. Both trans- and cis-isomers (3e and 3f,
respectively) of the neutral N-acetyl amide retained
The cis and trans configurations of compounds 3e–h
were assigned based on the NOE experiments. The triaz-
olinone compound 3d was prepared by alkylation of 3c
with chlorotriazolinone10 followed by deprotection of
the benzyl group by hydrogenation.
The in vitro NK1 binding and in vivo NK1 agonist-in-
duced gerbil foot-tapping (GFT) inhibition data for cyc-
lobutane derivatives (3a–h) are listed in Table 1. The
NK1 binding assay determines the affinity of these com-
pounds (3a–h) toward the NK1 receptor. The GFT inhi-
bition measures the potency of these compounds to
antagonize an NK1 receptor-mediated CNS effect
following oral administration. As shown in Table 1,
even the simple cyclobutanone compound 3a exhibited

M. L. Wrobleski et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3859–3863
Table 2. NK1 receptor binding affinity and GFT inhibition for compounds 3i–o
3861
F3C
O
R1
R2
CF3
3i-o
Compounds
R1
R2
NK1aKi (nM)
GFTb (% inh.) t = 4 h
3i
–NH2
–C(O)NH2
–NH2
–C(O)NH2
–NH2
1
81
30
98
58
79
3j
0.43
1
3k
3l
–C(O)NHCH3
–NH2
–C(O)N(CH3)2
–C(O)NHCH3
–NH2
0.5
3.3
3m
N
3n
3o
–NH2
–NH2
1.3
1.3
13
15
O
O
N
O
a See Ref. 11.
b See Ref. 13.
excellent NK1binding activity suggesting that in addi-
tion to a basic amino group, the neutral polar groups
are also well tolerated. However, these compounds did
not provide improvement in the GFT activity. To in-
crease metabolic stability, we prepared cyclic amides
(lactams) 3g and 3h. The trans lactam analogue 3g which
maintained subnanomolar binding affinity (Ki = 0.4 nM)
displayed modest increase in GFT activity (41% inhibi-
tion) compared to 3e (23% inhibition). The correspond-
ing cis isomer 3h also exhibited good in vitro activity
(Ki = 0.3 nM) but provided considerably lower GFT
activity (3% inhibition). The lower GFT activity of the
3h compared to the corresponding trans isomer 3g
may be due to poorer pharmacokinetic profile of the
former. Overall, the lactam analogue 3g provided the
best combination of high NK1 binding affinity and good
oral in vivo activity in the 1-monosubstituted cyclobu-
tane series.
by separation of isomers, afforded the hydantoin deriv-
atives 11a and 11b.17,18 The di-protection of hydantoin
11a with Boc-anhydride followed by hydrolysis under
basic conditions provided a 7:1 mixture of amino-acid
to Boc-protected amino-acid. The crude mixture was
treated with Boc-anhydride to afford Boc-protected ami-
no-acid 12. Coupling of 12 with amines in the presence
of PyBOP followed by removal of the Boc-moiety
with trifluoroacetic acid afforded the desired trans
amino-amides 3i, 3k, and 3m–o. Similarly the hydantoin
derivative 11b was converted to the cis amino-amides 3j
and 3l.
The biological data for the 1,1-disubstituted cyclobu-
tane analogues (3i–o) are shown in Table 2. The trans
analogue 3i led to significant loss of in vitro activity
compared to the monosubstituted lead amine com-
pound 3b (3i, Ki = 1 nM vs 3b, Ki = 0.02 nM) but con-
siderable improvement in the oral in vivo activity was
observed for 3i (3i, 81% inhibition vs 3b, 21% inhibi-
tion). Interestingly, the in vivo activity showed confor-
mational bias toward the trans isomer in the
disubstituted series, for example, the cis isomer 3j dis-
played inferior GFT activity (30% inhibition) com-
pared to the trans isomer (3i, 81% inhibition) despite
exhibiting 2-fold better binding affinity. To see an ef-
fect of increasing lipophilicity, N-alkylated amides
(3k–m) were explored. The trans N-methylated amide
compound 3k retained good binding activity
(Ki = 1 nM) and demonstrated further improvement
in the in vivo activity (98% inhibition). The cis N-
methylated compound 3l also exhibited better GFT
activity (58% inhibition) compared to the unsubstitut-
ed analogue 3j. Additional methyl substitution on the
amide NH was found to decrease the binding affinity
(3m, Ki = 3.3 nM) as well as the in vivo activity (79%
inhibition). Further increase in size to cyclic amides
We next evaluated 1,1-disubstituted cyclobutane
analogues where an amide group (compounds 3i–o,
Table 2) was substituted at the carbon attached to the
amine.
The 1,1-disubstituted cyclobutane derivatives (3i–o)
were prepared by the synthetic route illustrated in
Scheme 2. Initially, we attempted to prepare amino-
amides 3i–o from the amino-acid 10 which could be ob-
tained from ketone 3a via Strecker reaction followed by
hydrolysis. Although amino-nitrile 9 was readily ob-
tained from 3a via Strecker reaction, hydrolysis of the
nitrile 9 to amino-acid 10 under either acidic or basic
conditions was unsuccessful. Consequently, an alternate
route that employs a hydantoin, which is a suitable
intermediate in the synthesis of amino-acids, was
explored.16 Heating a mixture of ketone 3a and standard
hydantoin formation reagents in a steel bomb, followed

3862
M. L. Wrobleski et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3859–3863
References and notes
Ph
F3C
O
1. (a) Duffy, R. A. Exp. Opin. Emerg. Drugs 2004, 9, 9; (b)
Seward, E. M.; Swain, C. J. Exp. Opin. Ther. Patent 1999,
9, 571.
2. (a) Owens, A. P.; Williams, B. J.; Harrison, T.; Swain, C.
J.; Baker, R.; Sadowski, S.; Cascieri, M. A. Bioorg. Med.
Chem. Lett. 1995, 5, 2761; (b) Swain, C. J.; Cascieri, M.
A.; Owens, A.; Saari, W.; Sadowski, S.; Strader, C.; Teall,
M.; Van Neil, M. B.; Williams, B. J. Bioorg. Med. Chem.
Lett. 1994, 4, 2161.
NHBn
O
CF3
OH
10
b
Ph
O
Ph
F3C
F3C
a
O
O
3. Owens, A. P.; Harrison, T.; Moseley, J. D.; Swain, C. J.;
Sadowski, S.; Cascieri, M. A. Bioorg. Med. Chem. Lett.
1998, 8, 51.
NHBn
NC
CF3
CF3
3a
9
4. (a) Shue, H.-J.; Chen, X.; Shih, N-Y.; Blythin, D. J.;
Paliwal, S.; Lin, L.; Gu, D.; Schwerdt, J. H.; Shah, S.;
Reichard, G. A.; Piwinski, J. J.; Duffy, R. A.; Lachowicz,
J. E.; Coffin, V. L.; Liu, F.; Nomeir, A. A.; Morgan, C. A.;
Varty, G. B. Bioorg. Med. Chem. Lett. 2005, 15, 3896; (b)
Harrison, T.; Williams, B. J.; Swain, C. J. Bioorg. Med.
Chem. Lett. 1994, 4, 2733; (c) Harrison, T.; Williams, B. J.;
Swain, C. J.; Ball, R. G. Bioorg. Med. Chem. Lett. 1994, 4,
2545.
c
Ph
Ph
F3C
F3C
O
O
O
NH
NH
O
CF3
CF3
N
N
O
O
H
H
11a
11b
5. Stevenson, G. I.; MacLeod, A. M.; Huscroft, I.; Cascieri,
M. A.; Sadowski, S.; Baker, R. J. Med. Chem. 1995, 38,
1264.
d, e
6. (a) Shue, H.-J.; Chen, X.; Schwerdt, J. H.; Paliwal, S.;
Blythin, D. J.; Lin, L.; Gu, D.; Wang, C.; Reichard, G. A.;
Wang, H.; Piwinski, J. J.; Duffy, R. A.; Lachowicz, J. E.;
Coffin, V. L.; Nomeir, A. A.; Morgan, C. A.; Varty, G. B.;
Shih, N-Y. Bioorg. Med. Chem. Lett. 2006, 16, 1065; (b)
Swain, C. J.; Baker, W. R.; Cascieri, M. A.; Chicchi, G.;
Forrest, M.; Herbert, R.; Keown, L.; Ladduwahetty, T.;
Luell, S.; MacIntyre, D. E.; Metzger, J.; Morton, S.;
Owens, A. P.; Sadowski, S.; Watt, A. P. Bioorg. Med.
Chem. Lett. 1997, 7, 2959.
Ph
Ph
F3C
F3C
f, g
O
O
NHBoc
R1
O
R2
CF3
CF3
OH
12
3i,k,m-o
Ph
F3C
d-g
O
11b
7. For more experimental details, see: Wrobleski, M. L.;
Reichard, G. A.; Shih, N.-Y.; Xiao, D. PCT Int. Appl.
WO 078376, 2003.
R1
R2
CF3
3j,l
8. Reichard, G. A.; Stengone, C.; Paliwal, S.; Mergelsberg,
I.; Majmundar, S.; Wang, C.; Tiberi, R.; McPhail, A. T.;
Piwinski, J. J.; Shih, N.-Y. Org. Lett. 2003, 23, 4249.
9. Schlosser, M.; Schaub, B. Chimia 1982, 36, 396.
10. Cowden, C. J.; Wilson, R. D.; Bishop, B. C.; Cottrell, I.
F.; Davies, A. J.; Dolling, U.-H. Tetrahedron Lett. 2000,
41, 8661.
11. NK1 binding assay: Binding data are the average of two or
three independent determinations. Receptor binding assay
was performed on membrane preparations from CHO
cells in which recombinant human NK1 receptor was
expressed. [3H]-Sar-Met Substance P was used as the
ligand for the NK1 assay, at concentrations near the
experimentally derived Kd value. Ki values were obtained
using the Cheng and Prusoff equation.12
Scheme 2. Reagents and conditions: (a) NaCN, BnNH2, AcOH,
MeOH, reflux, 19 h, 98%; (b) acidic or basic hydrolysis; (c) i—KCN,
(NH4)2CO3, EtOH/H2O (1:1), steel bomb, 90 °C, 36 h; ii—separation
of isomers, 11a (46%) and 11b (43%); (d) (Boc)2O, DMAP, THF, rt,
3 h, then 1 M aq LiOH, THF, rt, 24 h; (e) (Boc)2O, satd aq NaHCO3,
THF, rt, 24 h, (88%) over two-steps; (f) PyBOP, i-Pr2EtN, CH2Cl2,
0 °C, 30 min then rt, 1 h, then appropriate amine, rt, 24 h; (g) TFA,
CH2Cl2, rt, 24 h, 60–80% over two-steps.
(3n,o) was found to decrease GFT activity. Overall,
the 1,1-disubstituted acyclic amide cyclobutane
analogues (e.g., 3i,k,m) displayed superior oral in vivo
activity than the 1-monosubstituted compounds
despite the reduced binding affinity.19
12. Cascieri, M. A.; Macleod, A. M.; Underwood, D.; Shiao,
L.-L.; Ber, E.; Sadowski, S.; Yu, H.; Merchant, K. J.;
Swain, C. J.; Strader, C. D.; Fong, T. M. J. Biol. Chem.
1994, 269, 6587.
In conclusion, we have identified a novel series of
cyclobutane derivatives as potent and selective NK1
antagonists.20 The initial lead (compound 3b,
Ki = 0.02 nM) was optimized to afford compounds
with good CNS penetration and oral in vivo activity.
The 1,1-disubstituted amine-amide analogues 3i and
3k provided the best combination of high NK1 affin-
ity (Ki = 1 nM) and excellent in vivo GFT activity
(>80% inhibition at 1 mg/kg after a 4 h pretreatment).
Further details of the SAR effort to improve potency
in this class of NK1 antagonists will be reported in
due course.
13. The NK1 agonist GR73632 (3 pmol in 5 ll) was admin-
istered centrally to female Mongolian gerbils via icv
injection. Immediately following recovery from the anes-
thesia, gerbils were placed into clear Plexiglas boxes for
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

M. L. Wrobleski et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3859–3863
3863
spent in foot-tapping compared to vehicle-treated
controls.14
14. Rupniak, N. M. J.; Williams, A. R. Eur. J. Pharmacol.
1994, 265, 179.
15. Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers,
M. S.; Haworth, K.; Keown, L.; MacIntyre, D. E.;
Metzger, J. M.; Owen, S.; Rycroft, W.; Sadowski, S.;
Seward, E. M.; Shepeard, S.; Swain, C. J.; Tattersall, F.
D.; Williamson, D.; Hargreaves, R. J. J. Med. Chem. 1996,
39, 2907.
16. Conditions for hydantoin hydrolysis, see: Kubik, S.;
Meissner, R. S.; Rebek, J., Jr. Tetrahedron. Lett. 1994,
35, 6635, and references cited therein.
17. Refluxing the reaction mixture at atmospheric pressure led
to incomplete reaction. Heating in a steel bomb was
required to drive the reaction to completion.
18. The absolute configurations of compounds 11a and 11b
were assigned based on the absolute configurations of the
corresponding reduced cyclic urea products, which were
determined by NOE.
19. The improved in vivo activity of the 1,1-disubstituted
compounds could be due to their better CNS penetra-
tion. For example, the 1-monosubstituted compound 3b
and 1,1-disubstituted compound 3i have similar plasma
levels.
20. The compounds in the cyclobutane series exhibited good
selectivity over other neurokinin receptors. For example,
3b: NK2 = 25% inhibition at 3 lM; NK3 Ki = 4051 nM.
3e: NK2 = 26% inhibition at 3 lM; NK3 Ki = 631 nM. 3f:
NK2 = 23% inhibition at 3 lM; NK3 Ki = 2131 nM. 3k:
NK2 = 1.2% inhibition at 0.3 lM; NK3 Ki = 1999 nM.21
21. NK2 and NK3 binding assays: Binding data are the
average of two or three independent determinations.
Receptor binding assays were performed on membrane
preparations from CHO cells in which recombinant
human NK2 and NK3 receptors were expressed. [3H]Neu-
rokinin A and [125I]neurokinin B were used as the ligands
for the NK2 and NK3 receptor assays, at concentrations
near their experimentally derived Kd value. Ki values were
obtained using the Cheng and Prusoff equation.