NK1 antagonists based on seven membered lactam scaffolds

Article abstract of DOI:10.1016/j.bmcl.2006.02.080

A new class of high affinity hNK₁R antagonists based on seven-membered ring cores has been identified. This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo prope

Full text of DOI:10.1016/j.bmcl.2006.02.080

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2929–2932
NK1 antagonists based on seven membered lactam scaffolds
Jason M. Elliott,a,* Emma J. Carlson,b Gary G. Chicchi,c Olivier Dirat,a
Maria Dominguez,a Ute Gerhard,a Richard Jelley,a A. Brian Jones,a
Marc M. Kurtz,c Kwei lan Tsaoc and Alan Wheeldonb
aDepartment of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
bDepartment of In Vivo Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
cDepartment of Immunology, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 2 February 2006; revised 28 February 2006; accepted 28 February 2006
Available online 29 March 2006
Abstract—A new class of high affinity hNK1R antagonists based on seven-membered ring cores has been identified. This series, with
relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo properties.
Ó 2006 Elsevier Ltd. All rights reserved.
The utility of neurokinin-1 receptor (NK1R) antagonists
for the treatment of post-operative and chemotherapy-
induced emesis has now been established. Aprepitant
(EmendÒ) 1 is currently the only commercially available
drug in this class.1,2 There have been many reports of
NK1R antagonists in which the elements necessary for
binding are constructed around five- or six-membered
cyclic cores.3 However, extension to larger ring sizes is
rare. We have now found that the use of core scaffolds
based on seven-membered rings leads to novel NK1R
antagonists with high in vitro affinity and promising
in vivo properties.
one.4 Reduction with (R)-2-methyl-CBS-oxaborolidine
gave a 1:1 mixture of diastereomeric alcohols from
which trans-3 was isolated with modest ee (54%)
(Scheme 1). This was improved to 100% ee in the next
step, O-alkylation with the 2,2,2-trichloroacetimidate
prepared from enantiomerically pure (S)-1-[3,5-bis(tri-
fluoromethyl)phenyl]ethanol.5 Deprotection and a two-
step Beckmann rearrangement gave the two isomeric
lactams 6a and 6b. The intermediate p-toluenesulfony-
loximes 5a and 5b were stable at room temperature
and could be easily separated by chromatography. Reg-
ioselective rearrangement occurred on heating to 100 °C
in a microwave synthesizer to give 6a and 6b, respective-
ly. Alternatively, a one-step modified Schmidt reaction
(NaN3, TiCl4, MeCN, reflux) of 4 gave the mixed lac-
tams directly. N-Methylation of the lactams occurred
smoothly on treatment with sodium hydride and methyl
iodide.
CF3
CF3
O
N
O
H
N
F
O
a-Methylation of the cyclohexanone 4 via the corre-
sponding b-ketoesters gave 8a and 8b (Scheme 2). As
expected, these were formed exclusively as the thermo-
dynamically more stable equatorial isomers. Modified
Schmidt rearrangement of 8a gave 9a as the major prod-
uct, the result of migration of the secondary alkyl group.
Migration of the primary group to give 9b was also seen,
but as a minor component. Under the same conditions,
8b gave exclusive migration of the secondary alkyl group
to give 9c. The isomer was not detected.
N
1
HN
Racemic cyclohexanone 2 was prepared via palladium
catalyzed a-arylation of 1,4-dioxaspiro[4.5]decan-8-
Keywords: NK1; Emesis; Lactam.
*
Corresponding author. Tel.: +44 1279 440000; fax: +44 1279
440390; e-mail: jason@elliottj25.fsnet.co.uk
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.02.080

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J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2929–2932
O
OH
OH
O
i
ii
O
O
O
O
+
O
O
O
70%
O
38%
45%
F
F
F
( )-2
Trans-3
Cis-3
(86% e.e)
(54% e.e.)
CF3
CF3
CF3
CF3
O
O
iii
36%
iv
O
O
72%
O
4
F
F
CF3
CF3
CF3
CF3
O
O
viii
O
pTolSO3
N
N
76%
R
ix
R = H
6a
7a
37%
5a
F
F
80% R = Me
v-vii
CF3
CF3
+
CF3
CF3
O
O
viii
37%
R
N
N
pTolSO3
64%
R = H
R = Me
ix
45%
6b
7b
O
5b
F
F
Scheme 1. Reagents and conditions: (i) 1-bromo-4-fluorobenzene, tris(dibenzylideneacetone)dipalladium(0), xantphos, NaO-t-Bu, THF, 80 °C; (ii)
BH3ÆDMS, (R)-2-methyl-CBS-oxaborolidine, PhCH3, À20 °C; (iii) (S)-1-(3,5-bistrifluoromethylphenyl)ethyl-2,2,2-trichloroacetimidate, HBF4, 1,2-
DCE, hexanes, À16 °C; (iv) TFA, CH2Cl2, H2O; (v) NH2OHÆHCl, NaOH, EtOH–H2O, reflux; (vi) p-TolSO2Cl, DMAP, CH2Cl2; (vii) separate
isomers; (viii) 100 °C (microwave heating), THF–H2O; (ix) NaH, MeI, DMF.
CF3
CF3
CF3
CF3
O
O
i-iv
15%
9%
4
+
O
O
8a
8b
F
F
v, iii
v
40%
CF3
CF3
CF3
CF3
CF3
CF3
O
O
O
33%
5%
+
R
N
O
O
N
N
O
R
R
F
F
F
ii
73%
R = H
R = Me
ii
65%
R = H
R = Me
ii
65%
R = H
R = Me
9a
10
9b
0b
9c
10c
a
1
Scheme 2. Reagents and conditions: (i) NaH, dimethylcarbonate, THF, reflux; (ii) NaH, MeI, DMF; (iii) separate isomers; (iv) NaCl, H2O, DMSO,
150 °C; (v) NaN3, TiCl4, MeCN, reflux.

J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2929–2932
2931
CF3
CF3
CF3
CF3
O
O
N
N
N
N
HN
F
F
O
11a
7%
12a
13%
+
i-iv
iv-vi
+
6a
6b
CF3
CF3
CF3
CF3
O
O
O
N
N
HN
N
N
F
F
11b
11%
12b
35%
Scheme 3. Reagents and conditions: (i) Lawesson’s reagent, PhCH3; (ii) H2NCH2CH(OMe)2, Hg(OAc)2, THF; (iii) p-TsOH, PhCH3, 70 °C; (iv)
separate isomers; (v) Me3OBF4, CH2Cl2; (vi) EtO2CNHNH2, EtOH, 150 °C.
The fused imidazoles (11a and 11b) and triazolones (12a
and 12b) were prepared by activation of the lactams 6a
and 6b as shown (Scheme 3).
the exchangeable lactam NH to either an adjacent
methylene or methine group was seen, an assignment
of structure could be made. Further confirmation
could be obtained from the 13C chemical shifts for
the methylene and methine carbons either side of the
amide link. Unlike the proton chemical shifts, these
were consistent and characteristic for all isomers.
These were determined via multiplicity edited hetero-
nuclear single quantum correlation experiments
(HSQC-DEPT), which provide a reading for the
carbon chemical shift to which a proton is directly
connected. In this series, the signal due to the carbon
adjacent to the lactam nitrogen had a characteristic
chemical shift of ca. 50 ppm, whereas the signal due
to the carbon adjacent to the lactam carbonyl had a
characteristic chemical shift of 35–42 ppm. Assignment
of this carbon through the phase of the cross peak
indicated whether the carbon was part of a methylene
or a methine group.
The regiochemistry of the isomeric product pairs 6a/6b,
11a/11b, and 12a/12b was determined through correla-
tion spectroscopy (COSY) assignment of all the 1H
NMR signals due to protons on the seven-membered
ring. The signals due to the methylene protons either
side of the amide link or fused heterocycle showed
characteristic chemical shifts.6 In the case of 6a/6b,
further evidence came from coupling of the exchange-
able lactam NH to the adjacent methylene. However,
this was not the case for the methylated lactams
9a–c. Correlation spectroscopy yielded the 3J proton
coupling around the ring, but the signals due to the
methylene and methine protons either side of the
amide link varied considerably between isomers and
were therefore not characteristic. Where coupling of
Table 1. hNK1R affinity, hIKr affinity, and in vivo activity
t = 1 h Gerbil FTc
a
hNK1R IC50 (nM)
Compound
hIKr Kib (lM)
d
Plasma IC50 (nM)
ID50 (mg/kg po)
6a
6b
0.14 0.05
0.64 0.4
>9
>9
>9
>9
1.06
0% at 3
0.64
57
7a
7b
0.12 0.03
0.53 0.13
0.41 0.11
0.23 0.04
0.09 0.03
0.49 0.15
0.44 0.10
0.33 0.10
0.28 0.03
0.43 0.08
0.19 0.04
0.22 0.08
73
14
Not tested
64% at 3
Not tested
0.09
9a
9b
8.5
2.4
>9
>9
5.4
9c
10a
10b
10c
11a
11b
12a
12b
8% at 3
5% at 3
0.24
6.7
1.8
1.4
4% at 3
0% at 3
0.97
>9
>9
0.8
83
a Displacement of [125I] labeled substance P from the cloned hNK1 receptor expressed in CHO cells. Data are means SD (n = 3).7
b Displacement of labeled MK-499 from cloned channel expressed in HEK cells.8
c Inhibition of GR73632-induced foottapping in gerbils.9 Where an ID50 value was not determined, % inhibition at 3 mg/kg po is quoted.
d Plasma drug levels determined by LC–MS/MS following protein precipitation.

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J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2929–2932
2. Diemunsch, P.; Schoeffler, P.; Bryssine, B.; Cheli-Muller, L.
E.; Lees, J.; McQuade, B. A.; Spraggs, C. F. Br. J. Anaesth.
1999, 82, 274.
3. Albert, J. S. Expert Opin. Ther. Patents 2004, 14, 1421;
Gerspacher, M. Prog. Med. Chem. 2005, 43, 49.
4. Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. J. Am.
Chem. Soc. 2000, 122, 1360.
5. Finke, P. E.; Maccoss, M.; Meurer, L. C.; Mills, S. G.;
Caldwell, C. G.; Chen, P.; Durette, P. L.; Hale, J.; Holson,
E.; Kopka, I.; Robichaud, A. WO9714671, 1997; Chem.
Abstr., 127, 17433.
The biological results for compounds based on both
lactam and fused heterocyclic cores are shown in
Table 1.
High NK1R binding affinity was observed across the
whole series. Introduction of methyl substituents, either
on the ring nitrogen or a- to the lactam was well toler-
ated. In particular, 9c had very high hNK1R affinity.
Good selectivity over affinity for the hERG ion channel
(hIKr) was seen.
6. Selected spectroscopic data. Compound (6a): 1H NMR
(500 MHz, CDCl3) d 7.69 (1H, s), 7.24 (2H, s), 6.92 (2H,
m), 6.83 (2H, m), 5.92 (1H, br m), 4.42 (1H, q, J = 6.5 Hz),
3.43 (1H, m), 3.37 (1H, m), 3.15 (1H, m), 2.76 (1H, t,
J = 9.6 Hz), 2.62 (1H, dd, J = 13.7, 8.6 Hz), 2.49 (1H, t,
J = 13.7 Hz), 2.35 (1H, m), 1.81 (1H, m), and 1.34 (3H, d,
J = 6.5 Hz).
In order to assess their ability to occupy central hNK1
receptors in vivo, selected compounds were profiled for
their ability to inhibit foot tapping in gerbils induced by
central infusion of the NK1R agonist GR73632. This
behavioral response is specific to gerbils, which show
receptor pharmacology similar to the human receptor.
The response is centrally mediated so inhibition demon-
strates that a compound blocks central receptors.9 In or-
der to assess oral bioavailability, compounds were dosed
po 1 h before the agonist challenge (Table 1). Gratify-
ingly, we were able to identify compounds from this ser-
ies which were active at low dose and plasma drug
exposure, indicating both oral bioavailability and brain
penetration. Interestingly, compounds based on the 5,6-
azepin-2-one core (6a, 7a, 9c, and 10c) showed greater
potency than the analogs based on the 4,5-azepin-2-
one (6b, 9a, and 10a). The reasons for such differences
between compounds with similar in vitro affinities are
not clear. Compound 9c was the most potent compound
in this series, one of the most potent compounds from
any series tested to date in this assay.
1
Compound (6b): H NMR (500 MHz, CDCl3) d 7.70 (1H,
s), 7.23 (2H, s), 6.95 (2H, m), 6.82 (2H, m), 6.08 (1H, br m),
4.34 (1H, q, J = 6.4 Hz), 3.43 (1H, m), 3.40 (1H, m), 3.29
(1H, m), 2.88 (1H, t, J = 10.8 Hz), 2.74 (1H, dd, J = 14.0,
10.8 Hz), 2.53 (1H, d, J = 14.0 Hz), 2.33 (1H, m), 1.77 (1H,
m), and 1.31 (3H, d, J = 6.4 Hz).
Compound (11a): 1H NMR (500 MHz, CDCl3) d 7.73 (1H,
s), 7.393 (2H, s), 6.88–6.71 (6H, m), 4.52 (1H, q,
J = 6.4 Hz), 4.18 (1H, d, J = 14.4 Hz), 3.97 (1H, dd,
J = 14.4, 8.7 Hz), 3.56 (1H, m), 3.48 (1H, dd, J = 14.5,
7.0 Hz), 2.91 (1H, t, J = 8.7 Hz), 2.84 (1H, dd, J = 14.5,
10.2 Hz), 2.26 (1H, m), 1.84 (1H, m), and 1.39 (3H, d,
J = 6.4 Hz).
Compound (11b): 1H NMR (500 MHz, CDCl3) d 7.72
(1H, s), 7.33 (2H, s), 6.88–6.79 (6H, m), 4.42 (1H, q,
J = 6.4 Hz), 4.25 (1H, dd, J = 14.3, 7.7 Hz), 3.92 (1H,
dd, J = 14.3, 9.6 Hz), 3.60 (1H, m), 3.23 (1H, d,
J = 15.2 Hz), 2.97 (1H, dd, J = 15.2, 10.0 Hz), 2.88
(1H, t, J = 10.0 Hz), 2.33 (1H, m), 1.92 (1H, m), and
1.36 (3H, d, J = 6.4 Hz).
Pendant heterocycles, such as triazolone, are frequently
beneficial in hNK1R antagonists. The presence of lac-
tams in 6a and 6b gave an opportunity to introduce het-
erocycles, but fused to the core rather than pendant.
Both imidazole and triazolone were well tolerated by
the receptor. The imidazoles (11a and 11b) were inactive
in vivo and showed increased hIKr liability. However,
introduction of the triazolone gave compounds with
good in vivo activity and low hIKr affinity (12a and 12b).
Compound (12a): 1H NMR (400 MHz, CD3OD) d 7.75
(1H, s), 7.44 (2H, s), 7.04 (2H, m), 6.81 (2H, m), 4.635
(1H, q, J = 6.4 Hz), 3.91–3.68 (3H, m), 2.95 (1H, m),
2.78 (2H, m), 2.51 (1H, m), 1.73 (1H, m), and 1.33 (3H,
d, J = 6.4 Hz).
Compound (12b): 1H NMR (400 MHz, CDCl3) d 9.95
(1H, s), 7.73 (1H, s), 7.34 (2H, s), 6.93–6.81 (4H, m),
4.44 (1H, q, J = 6.4 Hz), 4.17 (1H, dd, J = 13.8, 7.4 Hz),
3.59 (2H, m), 3.00 (1H, d, J = 15.0 Hz), 2.91 (1H, m),
2.80 (1H, dd, J = 15.0, 10.2 Hz), 2.30 (1H, m), 1.88 (1H,
m), and 1.37 (3H, d, J = 6.4 Hz).
Pharmacokinetic properties were determined for the lac-
tam lead 6a in rat. These indicated that the compound
had moderate clearance (33 mL/min/kg) and good
half-life (5.6 h).
7. Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.;
Bansal, A.; Swain, C. J.; Seward, E. M.; Frances, B.;
Burns, D.; Strader, C. D. Mol. Pharmacol. 1992, 42,
458.
In summary, a new class of high affinity hNK1R antag-
onists based on seven-membered ring cores has been
identified. This series, with relatively simple, compact
structures, includes compounds with promising in vivo
properties.
8. Cooper, L. C.; Carlson, E. J.; Castro, J. L.; Chicchi, G.
G.; Dinnell, K.; Di Salvo, J.; Elliott, J.; Hollingworth,
G. J.; Kurtz, M. M.; Ridgill, M. P.; Rycroft, W.; Tsao,
K. L.; Swain, C. J. Bioorg. Med. Chem. Lett. 2002, 12,
1759.
9. Rupniak, N. M. J.; Tattersall, F. D.; Williams, A. R.;
Rycroft, W.; Carlson, E.; Cascieri, M. A.; Sadowski, S.;
Ber, E.; Hale, J. J.; Mills, S. G.; MacCoss, M.;
Seward, E.; Huscroft, I.; Owen, S.; Swain, C. J.; Hill,
R. G.; Hargreaves, R. J. Eur. J. Pharmacol. 1997, 326,
201.
References and notes
1. Dando, T. M.; Perry, C. M. Drugs 2004, 64, 777.