Cyclic benzamidines as orally efficacious NR2B-selective NMDA receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2007.04.084

A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain.

Full text of DOI:10.1016/j.bmcl.2007.04.084

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3997–4000
Cyclic benzamidines as orally efficacious NR2B-selective
NMDA receptor antagonists
Kevin T. Nguyen,a,* Christopher F. Claiborne,a John A. McCauley,a Brian E. Libby,a
David A. Claremon,a Rodney A. Bednar,b Scott D. Mosser,b Stanley L. Gaul,b
Thomas M. Connolly,b Cindra L. Condra,b Bohumil Bednar,b Gary L. Stump,c
Joseph J. Lynch,c Kenneth S. Koblanb and Nigel J. Livertona
aDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
bDepartment of Pain Research, Merck Research Laboratories, West Point, PA 19486, USA
cDepartment of Stroke and Neurodegeneration, Merck Research Laboratories, West Point, PA 19486, USA
Received 20 March 2007; revised 24 April 2007; accepted 25 April 2007
Available online 29 April 2007
Abstract—A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist
activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain.
Ó 2007 Elsevier Ltd. All rights reserved.
The N-methyl-D-aspartate (NMDA) receptor is cur-
rently the subject of extensive investigation because of
its high therapeutic potential for the treatment of a large
number of disease states including stroke, epilepsy, neu-
ropathic pain, Alzheimer’s disease and Parkinson’s dis-
ease.1 The NMDA channel is a heterooligomeric
complex composed of up to three different subunits
NR1, NR2 and NR3. NR1 has at least eight isoforms
(NR1a-h), NR2 has four distinct subtypes (NR2A-D)
and NR3 has 2 subtypes (NR3A and B).
In a previous communication,9 we reported phenyl ami-
dine (4, Fig. 2) as an orally efficacious NR2B-selective
NMDA receptor antagonist. Indole amidine 5 has re-
cently also been reported to be a potent NR2B/NMDA
antagonist.10 In this communication, we report a novel
series of cyclic benzamidines as orally efficacious
NR2B-selective NMDA receptor antagonists.
Four different classes of cyclic amidines were synthe-
sized. The results of the NR2B binding and functional
assays (calcium ion-flux)11 and calculated pKa for se-
lected cyclic amidines are summarized in Table 1.12,13
Ifenprodil (1, Fig. 1), an antagonist that binds selectively
to the NR2B subunit, can effectively modulate ion flux
and shows efficacy in animal models of pain.2,3 In addi-
tion, ifenprodil exhibits diminished CNS and locomotor
side effects in animal models when compared with non-
selective NMDA antagonists.4 Due to this intriguing
biological profile, the ifenprodil binding site on the
NR2B subunit has become a highly studied target.5,6
To date, a number of compounds have been shown to
have NR2B subtype selectivity, including CP-101,606
(2)7 and Ro25-6981 (3).8
6-Phenyl-2-[4-(trifluoromethoxy)phenyl]-1,4,5,6-tetrahy-
dropyrimidin-5-ol (6, Scheme 1) was synthesized from
OH
N
OH
Ifenprodil (1)
OH
OH
OH
N
N
OH
OH
Keywords: Cyclic benzamidines; NR2B-selective NMDA.
*
Ro 25-6981(3)
CP-101,606 (2)
Corresponding author. Tel.: +1 215 652 9357; fax: +1 215 652
3971; e-mail: kevin_nguyen@merck.com
Figure 1. Structures of NR2B-selective NMDA receptor antagonists.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.084

3998
K. T. Nguyen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3997–4000
NH
CF3
OH
Ph
N
O
H
b
a
N
N
Cl
N
Ph
Cl
H
N
Ph
H
H
F3CO
NH
OCH3
F3CO
10
6
11
4
5
Scheme 1. Synthesis of 6. Reagents and conditions: (a) m-CPBA,
CH2Cl2, 40 °C; (b) 4-F3CO–Ph(C@NH)NH2, 2-propanol, 80 °C.
Figure 2. Amidine derived NR2B/NMDA receptor antagonists.
cinnamyl chloride (10) which was oxidized with
m-CPBA to produce epoxide 11. Treatment of the epox-
ide with 4-trifluoromethoxybenzamidine in 2-propanol
gave compound 6.
OH
OH
O
N
N
a, b
c
Cl
N3
NHBoc
Ph
Ph
Ph
14
13
12
d
The synthesis of 4-phenyl-2-[4-(trifluoromethoxy)- phe-
nyl]-4,5,6,7-tetrahydro-1H-1,3-diazepine (7, Scheme 2)
started with 4-chlorobutyrophenone (12). Azide installa-
tion and conversion of the carbonyl to the oxime gave
compound 13. The azide was reduced to the amine
which was protected as its Boc derivative, and the oxime
was then reduced to afford compound 15. Amidine for-
mation and subsequent cyclization to 7 was carried out
in methanol under acidic conditions.
HN
e
NH2
NHBoc
N
Ph
Ph
F3CO
7
15
Scheme 2. Synthesis of 7. Reagents and conditions: (a) NaN3, DMF,
75 °C; (b) NH2OHÆHCl, pyridine; (c) H2, Pd/C, Boc2O, EtOH; (d) H2,
Pd/C, MeOH; (e) 4-F3CO–Ph(C@NH)OMe, TFA, MeOH, 50 °C.
The synthesis of 5-(3-chlorophenyl)-2-[4-(trifluoro-meth-
oxy)phenyl]-4,5-dihydro-1H- imidazole (8, Scheme 3)
began with a standard amide coupling of 4-(trifluoro-
methoxy)benzoic acid (16) and amino(3-chlorophenyl)
acetonitrile (17) to form 18. Reduction of the nitrile
with Raney Ni in methanol and cyclization of 19 at high
temperature in xylene gave imidazoline 8.
CN
O
CN
CO2H
Cl
Cl
a
H2N
N
H
+
F3CO
F3CO
16
17
18
b
Cl
NH2
N
O
c
Cl
N
H
N
H
2-(3-Chlorobenzyl)-5-(trifluoromethoxy)isoindolin-1-imine
(9, Scheme 4) was synthesized from nitrile 20 via bro-
mination and subsequent coupling with 3-chlorobenzyl
amine in ethanol.
F3CO
F3CO
19
8
Scheme 3. Synthesis of 8. Reagents and condition: (a) EDC, HOBt,
DMF, Et3N; (b) H2, Raney Ni, CH3CO2H, MeOH; (c) xylene, 200 °C.
Cyclic amidines 6 and 7, containing six and seven-
membered ring constraints, are moderately potent
NR2B-subtype NMDA receptor antagonists (Table 1).
However, the 5-membered ring amidines (8 and 9) gave
optimal potency. We then sought to improve the activity
Table 1. Structure, binding affinity, functional activity and pKa of amidine derived NR2B/NMDA receptor antagonists
Entry
Structure
F3CO
NR2B Ki (nM)
NR2B Ca2+-flux IC50 (nM)
Calcd pKa
NH
CF3
N
H
4
72
47
9.56
OH
N
N
N
6
7
7350
4197
—
—
13.69
11.44
N
H
F3CO
N
H
F3CO
N
H
8
9
296
8
1976
49
8.88
8.75
Cl
F3CO
F3CO
NH
N
Cl

K. T. Nguyen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3997–4000
3999
Table 3. Structure, binding affinity and functional activity of isoindo-
lin-1-imine derived NR2B/NMDA receptor antagonists
NH
N
CN
CN
Br
a
b
Entry Structure
NR2B
Ki (nM) IC50 (nM)
NR2B Ca2+-flux
F3CO
F3CO
CH3
F3CO
Cl
9
20
21
NH
N
Scheme 4. Synthesis of 9. Reagents and condition: (a) NBS, AIBN,
CCl4, reflux; (b) 3-ClBnNH2, EtOH.
9
8
2
49
39
F3CO
Cl
NH
N
Table 2. Structure, binding affinity and functional activity of 2,4-
dihydroimidazole derived NR2B/NMDA receptor antagonists
27
F3CO
Entry Structure
NR2B
Ki (nM) IC50 (nM)
NR2B Ca2+-flux
Me
Me
N
N
NH
N
N
H
8
296
66
1976
266
O
28
29
2.2
3.6
12
Cl
Cl
F3CO
F3CO
F3CO
Cl
N
H
22
NH
N
F3CO
OMe
5.9
Cl
N
Cl
23
223
3670
N
H
Cl
F3CO
ies (Table 3). In this case, the 3,5-dimethyl substitution
pattern on the benzyl group (27) gave increased affinity.
Improvements in functional potency were realized by
installation of a benzofuran (28) or a 2-methoxy-benzyl
substituent (29). Compound 29 showed the best func-
tional potency in this series and had a calculated pKa
of 9.16.
MeO
F3C
N
N
Cl
24
25
75
108
N
H
F3CO
Cl
353
1270
N
H
F3CO
F3CO
We next evaluated the pharmacokinetic properties and
activity of compound 29.14 For PK evaluation, rats were
dosed at 2 mg/kg iv and 10 mg/kg po, compound 29 had
a Cmax of 215 nM with 5% bioavailability. It demon-
strated a moderate plasma half life of 2 h and a clear-
ance of 66 mL/kg/min. Efficacy was measured by
scoring behavioral responses to noxious stimuli in a car-
rageenan-induced hyperalgesia assay in the rat.4 Com-
pound 29 was dosed orally, and showed an ED50 of
20 mg/kg. At this dose, a 50% reduction in the hyperal-
gesic response as compared to control was observed.
N
Cl
26
505
3480
N
H
F3CO
of these latter two classes of moderately basic con-
strained amidine NR2B antagonists by exploring substi-
tuent effects on the aromatic rings.
The imidazoline series (Table 2) was prepared following
the general procedure described in Scheme 3. In this ser-
ies, the aromatic groups at the 2- and 4-positions of the
4,5-dihydro-1H-imidazole central ring were required for
activity. Installation of electron withdrawing substitu-
ents on each of these phenyl rings resulted in increased
activity. Substitution at the meta and para positions of
the 2-phenyl was well tolerated. In the case of the 4-phe-
nyl, substitution at the ortho and meta positions was
most beneficial.
In conclusion, we have developed a class of moderately
basic NR2B-selective NMDA receptor antagonists
which demonstrate good binding, excellent activity in
functional assays and good oral efficacy in a rodent
hyperalgesia model.
References and notes
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of compound 8 afforded 22, the most potent compound
in this series. Adding a second meta-chlorine on the
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on the 4-phenyl had a significant influence on potency,
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14. Experimental procedure for the preparation of compound
29: A solution of 2-methyl-4-(trifluoromethoxy)benzamide
(2.0 g, 9.13 mmol) in POCl3 (20 mL) was heated at 70 °C
for 1 h and then concentrated. The residue was dissolved
in EtOAc, washed with aqueous saturated NaHCO3,
water, brine, dried over Na2SO4, filtered and concentrated.
The crude product was chromatographed on silica gel,
eluting with 5–20% ether/hexanes, to give 2-methyl-4-
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(trifluoromethoxy)-benzonitrile (1.74 g, 95% yield). A
mixture of 2-methyl-4-(trifluoromethoxy)-benzonitrile
(1.3 g, 6.5 mmol), NBS (1.7 g, 9.7 mmol) and AIBN
(5 mg) in carbon tetrachloride (25 mL) was heated at
reflux for 7 h and then filtered and concentrated. The
residue was chromatographed on silica gel, eluting with 5–
25% EtOAc/hexanes, to give 2-(bromomethyl)-4-(triflu-
oromethoxy)benzonitrile (1.3 g, 70% yield). 1H NMR
(400 MHz, CDCl3)d 7.73 (d, 1H), 7.41 (s, 1H), 7.27 (d,
1H), 4.62 (s, 2H) ppm. To a stirred solution of 2-methoxy-
benzylamine (88 mg, 0.64 mmol) in ethanol (0.5 mL), at
80 °C, was added a solution of 2-(bromomethyl)-4-(triflu-
oromethoxy)-benzonitrile (150 mg, 0.56 mmol) in ethanol
(0.5 mL). The reaction mixture was stirred at 80 °C for
1 h, then concentrated and crystalized in ether to give
compound 31 as an HBr salt (136 mg, 93% yield). 1H
NMR (400 MHz, MeOH-d4) d 8.19 (d, 2H), 7.63 (s, 1H),
7.58 (d, 1H), 7.43 (t, 1H), 7.36 (dd, 1H), 7.09 (d, 1H), 7.03
(t, 1H), 4.98 (s, 2H), 4.72 (s, 2H), 3.87 (s, 3H) ppm; LRMS
(FT/ICR) m/z 337.0 [(M+H)+; calcd for C17H16F3N2O2:
337.1].
12. Basicity was calculated using pKa/ACD/Labs application
by Advanced Chemistry Development Inc. For more
information, visit www.acdlabs.com.
13. For NR2B binding assay protocol see: (a) Kiss, L.; Cheng,
G.; Bednar, B.; Bednar, R. A.; Bennett, P. B.; Kane, S. A.;
McIntyre, C. J.; McCauley, J. A.; Koblan, K. S. Neuro-