N′,2-Diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II

Article abstract of DOI:10.1016/j.bmcl.2006.08.085

Introduction of selected amine containing side chains into the 3-position of N′,2-diphenylquinoline-4-carbohydrazide based NK₃ antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI_Kr affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ₉₀ 7 mg/kg po; plasma Occ₉₀ 0.4 μM) and has good selectivity and excellent PK properties.

Full text of DOI:10.1016/j.bmcl.2006.08.085

Bioorganic & Medicinal Chemistry Letters 16 (2006) 5752–5756
N0,2-Diphenylquinoline-4-carbohydrazide based
NK3 receptor antagonists II
Jason M. Elliott,a,* Robert W. Carling,a Gary G. Chicchi,c James Crawforth,a
Peter H. Hutson,b A. Brian Jones,a Sarah Kelly,a Rose Marwood,b
Georgina Meneses-Lorente,a Elena Mezzogori,a Fraser Murray,b
Michael Rigby,b Inmaculada Royo,d Michael G. N. Russell,a Duncan Shaw,a
Bindi Sohal,a Kwei Lan Tsaoc and Brian Williamsa
aDepartment of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre,
Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
bDepartment of In Vivo Neuroscience, Merck Sharp & 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
dCIBE-Merck Research Laboratories, Merck, Sharp and Dohme de Espan˜a, c/ Josefa Valca´rcel, 38 Madrid 28027, Spain
Received 26 July 2006; revised 17 August 2006; accepted 19 August 2006
Available online 6 September 2006
Abstract—Introduction of selected amine containing side chains into the 3-position of N0,2-diphenylquinoline-4-carbohydrazide
based NK3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize
unwanted hIKr affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies
receptors within the CNS following oral dosing (Occ90 7 mg/kg po; plasma Occ90 0.4 lM) and has good selectivity and excellent PK
properties.
ꢀ 2006 Elsevier Ltd. All rights reserved.
In our previous paper,1 we reported our initial studies
Et
NH
CO2Me
on N0,2-diphenylquinoline-4-carbohydrazide based
NK3R antagonists related to Talnetant as potential
treatments for schizophrenia. The lead compound 1
had good affinity (hNK3R IC50 8.8 5.1 nM)2 and
was brain penetrant, occupying NK3 receptors within
the CNS following oral dosing to gerbils (Occ90
30 mg/kg po; plasma Occ90 0.95 lM).1 A key liability
for the series was CYP3A4 induction in human hepato-
cytes at high concentrations (1, 77% at 20 lM),1 which
could be correlated to activation of the hPXR nuclear
receptor in vitro (HepG2 cells transiently transfected
with hPXR; 1, 49% of 10 lM rifampicin positive
control).3
N
O
O
NH
OMe
OH
N
N
Talnetant
1
In order to further develop this promising lead toward a
potential once a day oral drug candidate for the treat-
ment of schizophrenia, we chose to target improvements
to the in vivo occupancy and PK profile, and reduction
in hPXR activation and hence CYP induction, while
also ensuring that the selectivity profile was maintained.
Keywords: NK3; Schizophrenia; N0-2-Diphenylquinoline-4-carbo-
hydrazide.
*
The precursor for 3-alkoxy-substituted quinolines was
the 3-hydroxy analog 2.1 Alkylation with methyl
Corresponding author. Tel.: +44 1279 440000; fax: +44 1279
440390; e-mail: jason@elliottj25.fsnet.co.uk
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.08.085

J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5752–5756
5753
Ph
CO2Me
Ph
CO2Me
Ph
CO2Me
N
N
N
O
NH
OH
Ph
O
NH
O
NH
i, ii
O
iii, iv
27%
O
OH
NMe2
66%
N
N
Ph
N
Ph
2
3
Ph
CO2Me
N
2tBu
CO
R =
5a
5b
O
NH
CO2Me
OH
CO2H
x
= H
R
v, vi
vii-ix
15%
O
N
R
O
N R
xi
Pyran-4-yl 5c
= tBu
R =
R
41%
5d
N
Ph
N
Ph
N
Ph
4
Ph
CO2Me
Ph
CO2Me
Ph
CO2Me
N
N
N
O
NH
O
NH
O
NH
xii, xiii, x
57-84%
xiv
Br
NR2
44-80%
N
Ph
N
Ph
N
Ph
X
X
X
6
7
8
X = H, F
Ph
CO2Me
N
O
NH
O
CO2H
OH
xv-xix
77%
xx
vii-ix
35%
N
CO2tBu
N R
Ph
N
19%
NH
CO2tBu
N
Ph
N
Ph
2tBu
= CO
11a
11b
Pyran-4-yl 11c
R
9
10
x
xi
H
R =
R =
Scheme 1. Reagents and conditions: (i) BrCH2CO2Me, NaI, K2CO3, THF; (ii) LiBH4, THF; (iii) CBr4, Ph3P, CH2Cl2; (iv) Me2NH; (v) 1-(1,1-
dimethylethyl)-4-piperidinol or 1,1-dimethylethyl 4-hydroxypiperidinecarboxylate, DTBAD, Ph3P, THF; (vi) KOH, MeOH; (vii) (COCl)2, DMF,
CH2Cl2; (viii) PhNHNH2, K2CO3, CH2Cl2, H2O; (ix) MeOCOCl, PhMe; (x) TFA, CH2Cl2; (xi) tetrahydro-4H-pyran-4-one, NaBH(OAc)3, AcOH,
CH2Cl2; (xii) (BOC)2O, NaH, THF; (xiii) NBS, CCl4, hm; (xiv) R2NH, Et3N, THF, reflux; (xv) (BOC)2O, CH2Cl2; (xvi) DMSO, (COCl)2, Et3N,
CH2Cl2; (xvii) acetophenone, LiHMDS, THF; (xviii) MeSO2Cl, Et3N, CH2Cl2; (xix) H2, Pd–C, EtOAc; (xx) isatin, KOH, EtOH, H2O.
bromoacetate followed by reduction and replacement of
the terminal hydroxyl group gave 3 as shown (Scheme
1). However, alkylation of 2 to give more hindered cyclic
O-linked substituents at C-3 was low yielding; it proved
more efficient to O-alkylate the ester 4 with a suitable
piperidin-4-ol under Mitsonobu conditions. The N-pro-
tecting group was removed and the compound was fur-
ther elaborated under reductive amination conditions
(Scheme 1).
i-iii
tBuO2C
N
NH
HN
N
X
73-81%
X = CH2, O
Scheme 2. Reagents and condition: (i) cyclohexanone or tetrahydro-
4H-pyran-4-one, 1,2,3-triazole, PhCH3, reflux; (ii) MeMgCl, THF; (iii)
HCl, MeOH.
In order to introduce aminomethyl groups at C-3, the
versatile 3-bromomethyl precursors 7 (X = H, F) were
targeted. These were most efficiently prepared via radi-
cal bromination of 6 after initial protection of the hydra-
zide 2-nitrogen. Deprotection and facile displacement
with amines gave 3-aminomethyl derivatives (hindered
N-tert-alkyl piperazines were prepared as shown in
Scheme 2).
oline C-3 position improved hNK3R affinity. Further
exploration of the SAR showed that much larger alkoxy
and amine-containing substituents were tolerated at this
position (Table 1). This led, in some cases, to improved
affinity relative to 1 (e.g., 8j). Simple lipophilic groups at
C-3 did not have an effect on hPXR activation, but we
saw that certain amine containing side chains did reduce
or abolish this unwanted activity. The disruption of
hPXR activation was found to be quite selective, requir-
ing a basic nitrogen held some distance from the quino-
line core by a rigid, cyclic structure (e.g., 8b and 11b). If
the side chain was flexible (3); if the basicity was reduced
by benzylation (8h), removed by acylation (8i) or sulf-
onylation (8j); or if the basic center was too close to
the quinoline (8a), hPXR activation persisted.
Compounds with a C-linked piperidine at C-3 were pre-
pared via reaction of ketone 9 (prepared from piperi-
dine-4-methanol) with isatin under basic Pfitzinger
conditions4 to give 10 (Scheme 1). This was further elab-
orated as shown.
We have already reported1 that substitution at most of
the aromatic positions on the quinoline core was poorly
tolerated, but a range of small substituents at the quin-
We next explored the effect of N-alkylation of 8b and
11b. We were pleased to find that the disruption of

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J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5752–5756
Table 1.
CO2Me
N
O
NH
X
R
N
hPXR responsec (%)
40
a
hNK3 IC50 (nM)
Compound
X
O
R
hIKr Kib (lM)
NMe2
3
11
1
2
7
6
7
6
0.089
5c
5d
8a
8b
8c
8d
8e
8f
O
12
8.9
18
N
N
O
O
17
3.0
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
160
34
4.9
92
7
N
N
N
N
N
N
N
0.84
0.32
0.88
1.8
NH
17
N
Me
5.8 1.4
2.0 0.4
3.3 0.3
1.9 0.3
1.6 0.2
7.4 2.3
0.72 0.06
51 17
<5
6
N
N
N
N
6.5
10
9
O
8g
8h
8i
0.51
0.53
>9
S
Ph
57
53
120
<5
<5
N
N
N
N
Ac
8j
2.5
N
N
SO2Ph
11b
0.52
NH
11c
5.7 2.7
8.0
N
O
a Displacement of 125I-labelled neurokinin B from the cloned hNK3 receptor expressed in CHO cells. Data are means SD (n = 3 or more).2
b Displacement of labeled MK-499 from cloned channel expressed in HEK cells.5
c Increase in hPXR activation in HepG2 cells transiently transfected with hPXR (% of 10 lM rifampicin positive control).3
hPXR activation was not affected by this change and
hNK3R affinity was improved (e.g., 8c–g, 11c).
hERG ion channel (hIKr).5 Blockade of this channel is
linked to QT prolongation and severe cardiorhythmic
side effects. We found that this affinity could be mini-
mized by the use of a pyran-4-yl substituent (8f and
11c). However, this group was found to be metabolically
Unfortunately, this type of side chain did tend to intro-
duce ion channel activity, especially affinity for the

J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5752–5756
5755
Table 2.
CO2Me
N
O
NH
X
R
N
F
a
hNK3 IC50 (nM)
Compound
X
R
hIKr Kib (lM)
hPXR responsec (%)
8k
CH2
37 16
8.2
<5
<5
<5
N
N
NH
8l
CH2
CH2
CH2
CH2
CH2
5.8 0.8
4.0 0.7
1.5 0.4
3.5 0.9
3.5 1.6
>9
>9
2.0
>9
>9
N
8m
8n
8o
8p
N
N
N
N
N
N
N
N
<5
7
O
O
a Displacement of 125I-labeled neurokinin B from the cloned hNK3 receptor expressed in CHO cells. Data are means SD (n = 3 or more).2
b Displacement of labeled MK-499 from cloned channel expressed in HEK cells.5
c Increase in hPXR activation in HepG2 cells transiently transfected with hPXR (% of 10 lM rifampicin positive control).3
labile. For example, 8f had short half-life (rat, 1.4 h,
dog, 2.4 h), with significant levels (greater than parent)
of the dealkylated metabolite 8b detected in plasma.
of metabolism had been inadvertently introduced. This
was supported by replacement of the N-substituent with
a simple tert-butyl group (8m, hNK3R IC50 4.0 nM; hIKr
Ki > 9 lM) which led to good metabolic stability in vitro
(incubation with rat and human liver microsomes: <5%
turnover after 15 min) and excellent PK properties (e.g.,
dog: F, 100%, t1/2 6.5 h) with no dealkylation to 8 k
detectable in plasma.
Metabolic N-dealkylation was a general problem for all
analogs of 8f and 11c with primary and secondary N-al-
kyl groups. A potentially interesting approach to block-
ing this pathway would be to replace the pyran with a
more hindered group, such as tert-butyl. Unfortunately,
the SAR already established suggested that unaccept-
able hIKr affinity would be problematic with simple alkyl
groups (e.g., 8d, hIKr Ki 0.88 lM).
Cellular functional NK3R antagonist activity of 8m was
measured in inositol phosphate generation studies using
CHO/hNK3R cells in response to eledoisin or senktide
stimulation.1 Eledoisin caused a concentration-depen-
dent increase in inositol phosphate generation in these
cells with an EC50 of 6.6 0.1 nM (n = 2). In a Schild
analysis of its antagonist behavior, 8m caused a concen-
tration-dependent rightward shift in the EC50 of eledoi-
sin with a concomitant diminution of the maximal
agonist response, indicative of a non-competitive or
insurmountable antagonism. When titrated versus an
approximate EC50 concentration (3 nM) of senktide,
8m inhibited inositol phosphate generation with an
IC50 of 3.0 0.0 nM (n = 2).
We have previously reported1 that fluorination at the 8-
position of the quinoline was tolerated by the hNK3
receptor. This remained the case for molecules with
amine side chains at C-3 and we were able to verify that
it did not reintroduce hPXR activation (Table 2). How-
ever, we found that this substitution had the added ben-
efit of significantly attenuating hIKr affinity (e.g., hIKr
Kis: 8d, 0.88 lM; 8l, >9 lM). Crucially, this change
expanded the scope of acceptable piperazine N-substitu-
ents, allowing us to introduce a range of groups onto the
piperazine nitrogen without incurring an excessive hIKr
liability (e.g., hIKr Kis: 8n, 2 lM; 8p, >9 lM).
Compound 8m was very potent in the gerbil ex vivo cen-
tral receptor occupancy assay1 with an Occ90 of 7 mg/kg
po and a plasma Occ90 of 0.4 lM when occupancy was
measured 45 min post dosing. Further profiling of 8m
showed that it had modest affinity for hNK2R (IC50
50 nM) and good selectivity over hNK1R (IC50 > 1 lM)
as well as a panel of other receptors and ion channels.
We were disappointed to find that the hindered 4-meth-
ylpyran in 8p did not improve PK properties (rat, t1/2
1.4 h). However, we noted that 8k was not detected as
a metabolite in plasma, suggesting that we had been suc-
cessful in blocking N-dealkylation, but that a new mode

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J. M. Elliott et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5752–5756
R.; Meneses-Lorent, G.; Mezzogori, E.; Murray, F.; Rigby,
M.; Royo, I.; Russell, M. G. N.; Sohal, B.; Tsao, K. L.;
Williams, B. Bioorg. Med. Chem. Lett., 2006, 16, 5748.
2. NK3 binding studies were conducted as a modification of a
previously reported protocol6 incubating 3 · 104 CHO cells
stably expressing human NK3 receptors with 30 pM [125I]-
labeled neurokinin B for 1 h at 25 ꢁC followed by filtration
over GF/C filter plates pre-soaked in 0.5% BSA.
3. Gao, Y. D.; Olson, S. H.; Balkovec, J. M.; Zhu, Y.; Royo,
I.; Mosley, R. T.; Ismail, A. J.; Hartley, D. Drug Metab.
Dispos., submitted for publication.
´
4. Buu-Ho¨ı, P.; Hoan, K.; Xuong, D. J. Org. Chem. 1950, 15,
511.
8m also showed very low levels of CYP450 inhibition
(human liver microsomes, 2C9, 2D6, 3A4,
IC50s > 30 lM) and had excellent physical properties
(logD 1.7, pKa 9.4, solubility > 5 mg/ml at pH 7.4).
In summary, we have shown that introduction of cyclic
amine containing side chains onto N0,2-diphenylquino-
line-4-carbohydrazide based NK3R antagonists resolved
the issue of unwanted activation of the hPXR receptor.
A combination of fluorination at the quinoline 8-position
and judicious choice of amine substituent led to a com-
pound, 8m, with excellent in vitro and in vivo properties.
5. 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.
References and notes
1. Elliott, J. M.; Carling, R. W.; Chambers, M.; Chicchi, G.
G.; Hutson, P. H.; Jones, A. B.; MacLeod, A.; Marwood,
6. Sadowski, S.; Huang, R. R. C.; Fong, T. M.; Marko, O.;
Cascieri, M. A. Neuropeptides 1993, 24, 317.