4-Substituted-3-phenylquinolin-2(1H)-ones: Acidic and nonacidic glycine site N-methyl-D-aspartate antagonists with in vivo activity

Article abstract of DOI:10.1021/jm9605492

4-Substituted-3-phenylquinolin-2(1H)-ones have been synthesized and evaluated in vitro for antagonist activity at the glycine sits on the NMDA (N-methyl-D-aspartate) receptor and in vivo for anticonvulsant activity in the DBA/2 strain of mouse in an audiogenic seizure model. 4-Amino-3- phenylquinolin-2(1H)-one (3) is 40-fold lower in binding affinity but only 4- fold weaker as an anticonvulsant than the acidic 4-hydroxy compound 1. Methylsulfonylation at the 4-position of 3 gives an acidic compound (6, pK(a) = 6.0) where affinity is fully restored but in vivo potency is significantly reduced (Table 1). Methylation at the 4-position of 1 to give 18 results in the abolition of measurable affinity, but the attachment of neutral hydrogen bond-accepting groups to the methyl group of 18 produces compounds with comparable in vitro and in vivo activity to 1 (e.g., 23 and 28, Table 2). Replacement of the 4-hydroxy group of 1 with an ethyl group abolishes activity (42), but again, incorporation of neutral hydrogen bond acceptors to the terminal carbon atom restores affinity (e.g., 36, 39, and 40, Table 3). Replacement of the 4-hydroxy group of the high-affinity compound 2 with an amino group produces a compound with 200-fold reduced affinity (43, IC₅₀ = 0.42 μM, Table 4) which is nevertheless still 10-fold higher in affinity than 3. The results in this paper indicate that anionic functionality is not an absolute requirement for good affinity at the glycine/NMDA site and provide compelling evidence for the existence of a ligand/receptor hydrogen bond interaction between an acceptor attached to the 4-position of the ligand and a hydrogen bond donor attached to the receptor.

Full text of DOI:10.1021/jm9605492

754
J . Med. Chem. 1997, 40, 754-765
4-Su bstitu ted -3-p h en ylqu in olin -2(1H)-on es: Acid ic a n d Non a cid ic Glycin e Site
N-Meth yl-D-a sp a r ta te An ta gon ists w ith in Vivo Activity
Robert W. Carling,* Paul D. Leeson, Kevin W. Moore, Christopher R. Moyes, Matthew Duncton,
Martin L. Hudson, Raymond Baker, Alan C. Foster, Sarah Grimwood, J ohn A. Kemp, George R. Marshall,
Mark D. Tricklebank, and Kay L. Saywell
Departments of Medicinal Chemistry, Biochemistry, and Pharmacology, Merck Sharp and Dohme Research Laboratories,
Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K.
Received J uly 26, 1996X
4-Substituted-3-phenylquinolin-2(1H)-ones have been synthesized and evaluated in vitro for
antagonist activity at the glycine site on the NMDA (N-methyl-D-aspartate) receptor and in
vivo for anticonvulsant activity in the DBA/2 strain of mouse in an audiogenic seizure model.
4-Amino-3-phenylquinolin-2(1H)-one (3) is 40-fold lower in binding affinity but only 4-fold
weaker as an anticonvulsant than the acidic 4-hydroxy compound 1. Methylsulfonylation at
the 4-position of 3 gives an acidic compound (6, pKa ) 6.0) where affinity is fully restored but
in vivo potency is significantly reduced (Table 1). Methylation at the 4-position of 1 to give 18
results in the abolition of measurable affinity, but the attachment of neutral hydrogen bond-
accepting groups to the methyl group of 18 produces compounds with comparable in vitro and
in vivo activity to 1 (e.g., 23 and 28, Table 2). Replacement of the 4-hydroxy group of 1 with
an ethyl group abolishes activity (42), but again, incorporation of neutral hydrogen bond
acceptors to the terminal carbon atom restores affinity (e.g., 36, 39, and 40, Table 3).
Replacement of the 4-hydroxy group of the high-affinity compound 2 with an amino group
produces a compound with 200-fold reduced affinity (43, IC50 ) 0.42 µM, Table 4) which is
nevertheless still 10-fold higher in affinity than 3. The results in this paper indicate that
anionic functionality is not an absolute requirement for good affinity at the glycine/NMDA
site and provide compelling evidence for the existence of a ligand/receptor hydrogen bond
interaction between an acceptor attached to the 4-position of the ligand and a hydrogen bond
donor attached to the receptor.
In tr od u ction
It is accepted that N-methyl-D-aspartate (NMDA)
receptor antagonists have promise for the treatment of
several central nervous system disorders including
stroke, epilepsy, and Parkinson’s disease.1 There is
evidence that NMDA antagonists that act through
blockade of a glycine coagonist site2 that is linked to
indicate that anionic functionality is not an absolute
the NMDA receptor complex may have a more benign
requirement for significant affinity at the glycine site.
side-effect profile3 than uncompetitive NMDA antago-
Some nonacidic derivatives show in vivo activity in the
nists such as MK-8014 and competitive NMDA antago-
DBA/2 mouse audiogenic seizure model, and the strat-
nists as exemplified by CPP.5 While the weak affinity,
egy of designing higher affinity nonacidic ligands is a
low-efficacy glycine/NMDA partial agonist L-687,414 is
possible approach toward further improving blood-
brain barrier penetration and overcoming the problem
of high plasma protein binding observed in 3-phenyl-
4-hydroxyquinolin-2(1H)-ones.13
active after systemic administration,6 until recently,7
full antagonists at the glycine site on the NMDA
receptor have shown no significant in vivo activity on
intraperitoneal or intravenous administration. A recent
breakthrough in achieving activity in vivo came about
through delocalization of anionic functionality, purport-
edly a prerequisite for in vitro affinity,8,9 through a
3-phenyl-4-hydroxyquinolin-2(1H)-one system,7,10,11 to
produce compounds 1 and 2, both of which show
anticonvulsant activity in animal models.7 The in-
creased in vivo activity observed with these compounds
relative to carboxylic acid-containing glycine antago-
nists12 is probably a consequence of improved penetra-
tion of the blood-brain barrier.
Ch em istr y
Compounds 3-45 were synthesized for this study.
The 4-amino analogue 3 was prepared by cyclization of
the 2-cyano phenylacetamide 48 using sodium hydride
in dimethylformamide at 100 °C (Scheme 1). The amide
4 was prepared from 3 by deprotonation at the 1- and
4-positions with excess sodium hydride, treatment with
excess acetyl chloride at elevated temperature, and then
removal of the 1-N-acetyl group under basic conditions.
Selective sulfonylation of 3 at the 4-position to produce
6 was achieved using a one-pot procedure involving
initial deprotonation and in situ protection of the
1-position followed by in situ deprotonation of the
4-position, reaction with methanesulfonyl chloride, and
In this paper we report the effects of modifying the
substituent at the 4-position of 7-chloro-3-phenyl-4-
hydroxyquinolin-2(1H)-one (1). The results obtained
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
S0022-2623(96)00549-3 CCC: $14.00 © 1997 American Chemical Society

Acidic and Nonacidic Glycine Site NMDA Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 755
Sch em e 1a
a
Reagents: (i) NH3, MeOH, 150 °C, 30 atm; (ii) TFAA, Et3N, 0 °C; (iii) K2CO3, H2O, MeOH, 65 °C; (iv) PhCH2COCl, DCE, reflux; (v)
NaH, DMF, 100 °C; (vi) NaH, THF; (vii) CH3COCl, 60 °C; (viii) NaOH, ultrasound; (ix) KHMDS, THF; (x) TBDMS-triflate; (xi) KHMDS;
(xii) MeSO2Cl; (xiii) HCl, H2O; (xiv) KHMDS, THF; (xv) TBDMS-triflate; (xvi) KHMDS; (xvii) MeI; (xviii) excess MeI.
Sch em e 2a
Sch em e 3a
a
Reagents: (i) PhCH2NH2, reflux; (ii) (CH3)2N(CH2)2NH2, 180
a
Reagents: (i) NaH, THF; (ii) EtO2CCOCl; (iii) NaOH; (iv)
EtO2CCH2COCl; (v) MeOH/HCl; (vi) (CH3)2N(CH2)2NH2.
°C sealed tube; (iii) (CH3)2N(CH2)3NH2, reflux.
removal of the 1-silyl protecting group on acidic workup.
The 4-methylamine and 4-dimethylamine derivatives 8
and 9 were prepared using similar methodology to
protect the 1-position in situ, but methyl iodide, in
varying quantities, was employed as the final electro-
phile. The 4-benzylamino (10), the 4-(N,N-dimethy-
lamino)ethylamino (11), and the 4-(N,N-dimethylamino)-
propylamino (12) derivatives were all made by reaction
of 1 with excess amine at elevated temperature (Scheme
2).14 The 4-amido acids 13 and 16 were prepared using
the procedure described for the synthesis of 4 using the
appropriate acid chloride in place of acetyl chloride
(Scheme 3). Acid 13 was converted into the methyl ester
14 by treatment with methanolic hydrogen chloride, and
14 was converted to the dimethylamide 15 by reaction
with N,N-dimethylethylenediamine.
The 4-methoxy analogue 18 was made by reaction of
1 with diazomethane. The ether derivatives 19, 23-
25, and 27 were all made by treatment of 1 with an
appropriate alkylating agent in dimethylformamide in
the presence of sodium iodide and sodium hydrogen
carbonate (Scheme 4). The ester 19 was converted into
the dimethylamide 21 by reaction with dimethylamine
in methanol (Scheme 5). The acid 20 (made by saponi-
fication of 19) was converted to the carboxamide 22 by
reaction with ammonium acetate in the presence of
water soluble carbodiimide. The (N,N-dimethylamino)-

756 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Carling et al.
Sch em e 4a
Sch em e 7a
a
Reagents: (i) NH2OH‚HCl, pyridine, 4 Å sieves, 60 °C; (ii)
NH2OCH3‚HCl, pyridine, 4 Å sieves, 60 °C.
deprotonation/phenylselenoxide elimination procedure,
to give the required product. The homologated carboxy-
lic acid 34 was made by saponification of 33, and the
amide 35 was prepared by carbodiimide coupling of 34
with N,N-dimethylethylenediamine. 2-(Hydroxymethyl)-
5-chloroaniline (55) was converted into the aldehyde 56
by bis-phenylacetylation, saponification of the ester
intermediate, and oxidation with pyridinium chloro-
chromate (Scheme 10). The 4-ethyl derivative 42 was
prepared from aldehyde 56 by reaction with ethylmag-
nesium bromide followed by oxidation and base-medi-
ated condensation. The propionate derivative 37 was
prepared as described in Scheme 11. Reaction of 56
with [(1-ethoxycyclopropyl)oxy]trimethylsilane16 at -78
°C in the presence of titanium tetrachloride gave the
secondary alcohol 57. Oxidation of 57 followed by
sodium ethoxide-mediated condensation and saponifica-
tion gave the target compound 37. Esterification of 37
with methanolic hydrogen chloride gave 36 which
underwent reaction with the anion of acetamide oxime
to give the methyloxadiazole 38. The acid 37 was
converted into the tetrazole 41 by initial conversion to
the carboxamide 39, subsequent dehydration to the
nitrile 40, and finally reaction with sodium azide. The
4-amino derivative of 2 (compound 43) was prepared in
an analogous manner to that described for the synthesis
of compound 3 (Scheme 1) using m-phenoxyphenylacetyl
chloride instead of phenylacetyl chloride. The 4-alkoxy
derivatives of 2 (44 and 45) were prepared directly from
27,13 using methodology described in Schemes 4 and 5.
a
Reagents: (i) CH2N2, Et2O, THF; (ii) BrCH2CO2CH3, NaHCO3,
NaI, DMF; (iii) BrCH2CN, NaHCO3, NaI, DMF; (iv) BrCH2Ph,
NaHCO3, NaI, DMF; (v) ClCH2-2-Pyr‚HCl, NaHCO3, NaI, DMF;
(vi) ClCH2COCH3, NaHCO3, NaI, DMF.
Sch em e 5a
a
Reagents: (i) (CH3)2NH, CH3OH, rt, 5 days; (ii) LiOH, THF,
H2O; (iii) NH4OAc, (CH3)2N(CH2)3NdCdNCH2CH3, Et3N, HOBT,
THF.
Sch em e 6
Biology
Compounds were routinely evaluated in vitro for their
ability to displace [3H] L-689,560 from rat cortical
membranes (IC50 values)17 and antagonize NMDA re-
sponses in a rat cortical slice preparation (apparent Kb
values).18,19 Affinities of test compounds for the glycine
site on the NMDA receptor were determined by dis-
placement of the glycine site antagonist [3H]L-689,560
binding to rat cortex/hippocampus membranes.17 IC50
values (concentration of test compound required to
inhibit 50% of the specific binding) were evaluated via
construction of 5-point inhibition curves. IC50 values
given are the geometric means of at least three experi-
ments (except where stated). The maximum standard
error calculated from the pIC50 values was always less
than 5% of the mean. Where IC50 > 100 µM, test
compound inhibited [3H]L-689,560 binding by less than
ethyl ether 26 was prepared via a reductive alkylation
procedure using dimethylamine hydrochloride and the
aldehyde derived from the ozonolysis of the allyl ether
49 (Scheme 6). The ketone 27 was converted to the
oxime derivatives 28 and 29 by reaction with the
appropriate hydroxylamine salt in pyridine at elevated
temperature (Scheme 7).
A mixture of 4-chloro- and 6-chloroisatin,15 on treat-
ment with phenylacetic acid and sodium acetate at 220
°C, afforded the 7-chloro-4-carboxy analogue 31 in low
yield (Scheme 8). Reaction of 31 with diazomethane
gave the methyl ester 30. The homologated methyl
ester 33 was synthesized as described in Scheme 9. The
aniline 539 was converted into the amide 54 which
underwent oxidative cyclization, via an in situ double

Acidic and Nonacidic Glycine Site NMDA Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 757
Sch em e 8a
a
Reagents: (i) NH2OH‚HCl, Cl3CCH(OH)2, Na2SO4, concd HCl, 1,4-dioxane; (ii) concd H2SO4, 80 °C; (iii) PhCH2CO2H, NaOAc, 220 °C;
(iv) CH2N2; (v) SOCl2; (vi) PhCH2NH2, CH2Cl2.
Sch em e 9a
a
Reagents: (i) PhCH2COCl, ClCH2CH2Cl, reflux; (ii) KHMDS, THF; (iii) TBDMS-triflate; (iv) KHMDS; (v) PhSeCl; (vi) H2O2; (vii)
NaOH, MeOH, H2O; (viii) N,N-dimethylethylenediamine, ClCH2CH2Cl, BOP-Cl, Et3N.
Sch em e 10a
audiogenic seizure test was chosen for in vivo screening
because the sensitivity of this model increased the
possibility of identifying improved in vivo activity.
Resu lts a n d Discu ssion
Replacement of the 4-hydroxy group of 1 with amino
to give compound 3 results in a 40-fold loss of binding
affinity (Table 1). The reduced affinity of 3 is probably
a consequence of loss of acidity (pKa of 1 ) 5.4, pKa of 3
> 11) because the acidic 4-methylsulfonamido derivative
6 (pKa ) 6.0) has comparable affinity to 1. It is unlikely
that the restoration of affinity observed with 6 is a result
of a direct interaction of the sulfonyl group with the
receptor because the 4-acetylamino compound 4 is less
active than the parent 4-amino compound 3. It is more
plausible that the anions generated at the 4-positions
of 1 and 6 (Figure 1), at physiological pH, are interacting
directly with the receptor as more efficient H-bond
acceptors than the 4-amino group of 3. Introduction of
larger acylamino or sulfonylamino groups to the 4-posi-
tion results in reduced binding activity. Mono- and
dimethylation of 3 to give 8 and 9 results in loss of
measurable binding affinity, possibly due to conforma-
tional constraints making the nitrogen lone pair of each
compound less accessible for receptor interaction, thus
providing further evidence for a beneficial direct H-
bonding interaction between the receptor and groups
attached to the 4-position of 3-phenylquinolin-2(1H)-
a
Reagents: (i) PhCH2COCl, Et3N, ClCH2CH2Cl; (ii) NaOH,
CH3OH; (iii) PCC, CH2Cl2; (iv) EtMgBr, NH4Cl, THF, 0 °C; (v)
PCC, CH2Cl2, (vi) NaH, EtOH.
50% at 100 µM (two experiments). Apparent Kb values
were calculated from the shift to the right of the NMDA
concentration-response curves produced by the antago-
nists and are the means of three determinations.
Selected compounds were also evaluated in vivo for their
ability to protect against audiogenic seizure in DBA/2
mice when dosed ip 30 min prior to noise stimulation
(quoted either as ED50 values or number protected/
number tested at a particular dose).4 The DBA/2 mouse

758 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Carling et al.
Sch em e 11a
F igu r e 1. Hypothetical receptor site binding the 3-phenyl-
4-substituted-2-quinolone anion. A is a receptor hydrogen bond
acceptor, + is a receptor cation, and H-D is a receptor
hydrogen bond donor.
Ta ble 2
IC50 (µM) Kb (µM)
[3H]-
vs
L-689,560 NMDA
ED50 (mg/kg)
or prot/tested
DBA/2 mouse
no.
R
1
OH
0.17 0.88 4.5
a
18 OMe
19 OCH2CO2Me
20 OCH2CO2H
21 OCH2CONMe2
22 OCH2CONH2
23 OCH2CN
>100
Reagents: (i) TiCl4, CH2Cl2, -78 °C; (ii) 1-ethoxy-1-[(trimeth-
3.2
0.96 1/8 @ 100 mg/kg
1.25 3/8 @ 20 mg/kg
ylsilyl)oxy]cyclopropane, -78 °C to rt; (iii) PCC, CH2Cl2; (iv)
NaOEt, EtOH; (v) NaOH, EtOH‚H2O; (vi) MeOH, HCl; (vii)
CH3C(NOH)NH2, NaH, THF, 60 °C (viii) NH4OAc, Et3N, wsCDI,
HOBt, THF; (ix) TFAA, Et3N, THF; (x) NaN3, Et3N‚HCl, N-
methylpyrrolidinone.
0.11
11.6
0.42
0.32
3.1
4.7
0/8 @ 20 mg/kg
16.3
24 OCH2Ph
∼10
25 OCH2-Pyr-2
26 O(CH2)2NMe2
27 OCH2COMe
28 OCH2C(Me)dNOH
29 OCH2C(Me)dNOMe
2.8
11.0
1.7
1/8 @ 20 mg/kg
Ta ble 1
11.4
2.8
5/8 @ 20 mg/kg
9.4
0/8 @ 20 mg/kg
0.78
∼50
indicate that there is some tolerance for the positioning
and type of the purported H-bond-accepting group.
Further evidence for this observation is provided by the
activity of compounds 13-16 where acids, esters, and
amides can all act as potential H-bond acceptors.
Deletion of the 4-substituent to give 1720 produces a
completely inactive molecule, thus providing still further
evidence for an important ligand/receptor H-bond-
accepting interaction adjacent to the 4-position. With
the exception of 3, none of the other compounds in Table
1 show comparable in vivo potency to 1 in the DBA/2
mouse audiogenic seizure test. Compound 3 is only
4-fold less active than 1 in vivo but has 40-fold lower
binding affinity, indicating a 10-fold superior ratio of
in vitro/in vivo activity. This higher than expected in
vivo activity may well be a consequence of reduced
plasma protein binding of 3 in comparison to 1.13
By analogy with N-methylation of 3 to give 8, O-
methylation of 1 to give 18 results in the loss of all
measurable affinity (Table 2). Conformational con-
straints making ligand/receptor hydrogen-bonding in-
teractions less accessible are again a possible explana-
tion. However, the loss of affinity of 18 can also be
accounted for by the fact that aryloxy is a relatively poor
H-bond acceptor in comparison to arylamine.21 Also by
Kb (µM)
ED50 (mg/kg)
or prot/tested
DBA/2 mouse
IC50 (µM)
vs
no.
R
[3H]L-689,560 NMDA
1
3
4
5
6
7
8
9
OH
NH2
0.17
6.7
0.88 4.5
10.5
16.2
1/8 @ 20 mk/kg
NHCOMe
NHCOCH2Ph
NHSO2Me
NHSO2Ph
NHMe
14.7
>100
0.27
1.19
2.2
2.9
0/8 @ 20 mg/kg
1/8 @ 20 mg/kg
>100
>100
2.0
NMe2
10 NHCH2Ph
>3
12
1/8 @ 20 mg/kg
8/8 @ 100 mg/kg
0/8 @ 20 mg/kg
6/8 @ 100 mg/kg
1/8 @ 50 mg/kg
0/8 @ 20 mg/kg
1/8 @ 20 mg/kg
2/8 @ 20 mg/kg
11 NH(CH2)2 NMe2
3.2
12 NH(CH2)3NMe2
4.2
13 NHCOCO2H
14 NHCOCO2Me
15 NHCOCONH-
(CH2)2NMe2
16 NHCOCH2CO2H
17
0.58
2.7
25
4.5
1.1
>100
11.6
2/8 @ 20 mg/kg
H
ones. Some affinity is regained with the benzylamine
analogue 10 and the (N,N-dimethylamino)ethylamine
and (N,N-dimethylamino)propylamine derivatives 11
and 12 which are all more active than 8. These results

Acidic and Nonacidic Glycine Site NMDA Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 759
Ta ble 3
Kb (µM) ED50 (mg/kg) or
IC50 (µM)
vs
prot/tested
no.
R
[3H]L-689,560 NMDA
DBA/2 mouse
1
OH
0.17
69% @ 10 µM
0.9
0.88
1.3
4.5
30 CO2Me
31 CO2H
1/8 @ 20 mg/kg
32 CONHCH2Ph
33 CH2CO2Me
34 CH2CO2H
35 CH2CONH-
(CH2)2NMe2
>100
1.1
4.0
1.4
1/8 @ 20 mg/kg
0.8 @ 20 mg/kg
0/8 @ 20 mg/kg
0.16
29% @10 µM
36 CH2CH2CO2CH3 0.5
4.6
2.2
0.8 @ 20 mg/kg
1/8 @ 20 mg/kg
4/8 @ 20 mg/kg
F igu r e 2. Hypothetical receptor site binding the 3-phenyl-
4-[(nitrilomethyl)oxy]-2-quinolone derivative 23. A is a receptor
hydrogen bond acceptor, + is a receptor cation, and H-D is a
receptor hydrogen bond donor.
37 CH2CH2CO2H
38
0.17
3.5
39 CH2CH2CONH2 0.19
2.9
>10
1.6
1/8 @ 20 mg/kg
0/8 @ 20 mg/kg
0/8 @ 100 mg/kg
40 CH2CH2CN
41
0.75
0.24
analogy with the results in Table 1, substitution of the
methyl group attached to the heteroatom at the 4-posi-
tion of the quinolone system with potential H-bond-
accepting groups results in improved affinity (com-
pounds 19-29). The alkoxy acetic acid 20, the alkoxy
acetamide 22, and the alkoxy acetonitrile 23 all have
comparable binding affinity to 1. The possibility of
conversion of these alkoxy analogues into the active lead
compound 1 under the conditions of the binding assay
has been discounted by HPLC analysis of the assay
solutions. The relatively high affinity of the nitrile (23)
and amide (22) derivatives indicates that when a
neutral, efficient hydrogen bond-accepting group is
optimally positioned adjacent to the 4-position of 3-phe-
nylquinolin-2(1H)-ones, anionic functionality is not a
prerequisite for good binding affinity at the glycine site
42 Et
>100
Replacement of the ionizable oxygen at the 4-position
of 1 with a carboxylate group, to give 31, results in only
5-fold loss of affinity (Table 3), again indicating some
tolerance for the positioning of the H-bond-accepting
group. The corresponding methyl ester 30 is 1 order of
magnitude less active, while the benzylamide 32 is
essentially inactive. The homologated acid 34 is equi-
active with 1 in the binding assay, but the corresponding
methyl ester 33 is again 10-fold lower in affinity. The
(N,N-dimethylamino)ethylamide 35, which was pre-
pared with a view toward improving aqueous solubility,
is significantly less active. Further homologation to the
propionic acid 37 again results in a compound with
identical binding affinity to 1. In this case the corre-
sponding methyl ester 36 is almost equally active with
the acid 37, providing further evidence that when an
efficient H-bond-accepting group is optimally positioned,
acidity is not an absolute requirement for binding to the
glycine site on the NMDA receptor. The neutral me-
thyloxadiazole 3826 is 1 order of magnitude less active
than 1, but the nonacidic carboxamide 39 is equally
active. The nonionizable nitrile 40 has marginally
reduced affinity, while the acidic tetrazole 41 has
similar activity to 1. Further support for the purported
H-bond-accepting interaction between the ligand and
the receptor is provided by the lack of affinity of the
4-ethyl analogue 42. With the exception of the weakly
active oxadiazole 38 (ED50 ∼20 mg/kg), none of the
compounds in Table 3 have a significant anticonvulsant
effect. The poor anticonvulsant activity of the neutral
nitrile 40 is difficult to account for, but the weak in vivo
activities of the predictably poor brain-penetrating
acidic analogues 31, 34, 37, and 41, the metabolically
labile esters 30, 33, and 36, and the high-H-bonding
capacity amide27 39 are not surprising.
on the NMDA receptor (Figure 2). This result is
22
consistent with the discovery of Nagata et al.
who
found that high-affinity binding can be obtained in a
series of nonacidic tricyclic quinoxalinediones (hybrids
of tetrahydroquinolines23,24 and quinoxalinediones3,25).
Good affinity in the 3-phenylquinolin-2(1H)-one series
is also achieved with the ester (19), the ketone (27), the
oxime (28), and the 2-pyridine (25) derivatives. The
benzyl (24), the dimethylamide (21), the dimethylamine
(26), and the O-methyl oxime (29) analogues all have
measurable binding affinity but are considerably less
active than 1.
With the exception of the alkoxyacetic acid 20, all of
the new compounds in Table 2 are nonacidic and thus
have potential for improved brain penetration in com-
parison to 1. All the novel compounds with binding
affinity < 10 µM were evaluated in the DBA/2 mouse
audiogenic seizure model (Table 2). The alkoxyaceto-
nitrile compound (23), the alkoxyacetone derivative (27),
and the alkoxyacetoxime analogue (28) all possess
significant anticonvulsant activity, with 28 (ED50 ) 9.4
mg/kg) having one-half the potency of 1. The possibility
of metabolism of 23, 27, or 28 giving rise to 1 in vivo
cannot be completely discounted as an explanation for
the anticonvulsant activity of these compounds, but
lower affinity compounds (i.e., 19, 25, and 29), which
have the same potential for cleavage to 1, do not have
significant in vivo activity.
By analogy with the 100-fold improvement of affinity7
observed on introduction of a m-phenoxy substituent to
the 3-phenyl group of 1 to give 2, the corresponding
change to the 4-amino compound 3 to give 43 results in
only 10-fold improved affinity (Table 4). The same

760 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Carling et al.
Ta ble 4
4-Am in o-7-ch lor o-3-p h en yl-2(1H)-qu in olon e (3). Meth-
yl 2-amino-4-chlorobenzoate (46; 20 g, 107 mmol) was heated
at 150 °C in methanol (300 mL), which had been presaturated
with ammonia, in an autoclave for 3 days. After cooling and
evaporation of the solvent a brown solid was obtained. This
was triturated with diethyl ether and collected by filtration
to give a solid which was suspended in 1 N sodium hydroxide
and subjected to ultrasound for 15 min. After collection by
filtration, the solid was washed with deionized water and dried
in a vacuum oven to give 2-amino-4-chlorobenzamide (11.2 g,
61%). Triethylamine (34 mL, 245 mmol) was added to a
solution of the amide (9.5 g, 56 mmol) at 0 °C in THF (200
mL) followed by trifluoroacetic anhydride (20.5 mL, 145 mmol)
in THF (50 mL). After 30 min water (200 mL) was added,
and the mixture was extracted with Et2O (2 × 200 mL). The
Et2O layer was dried (MgSO4), filtered, and evaporated to leave
a residue which was dissolved in 50% aqueous methanol (200
mL) with potassium carbonate (15 g). The mixture was heated
at 70 °C for 24 h, cooled, extracted with EtOAc (2 × 200 mL),
washed with water (1 × 100 mL) and brine (1 × 100 mL), dried
(MgSO4), filtered, and evaporated to give 2-amino-4-chloroben-
zonitrile (47; 8.8 g, 88%): NMR (CDCl3) δ 4.47 (2 H, br, s, NH2),
6.72 (1 H, dd, J ) 11.9, 2.6 Hz, H-5), 6.75 (1 H, d, J ) 2.6 Hz,
H-3), 7.31 (1 H, d, J ) 11.9 Hz, H-6); MS (CI+, NH3) m/ z )
152 (M+ + H).
The nitrile (0.9 g, 5.9 mmol) and phenylacetyl chloride (0.78
mL, 5.9 mmol) were heated together under reflux in dichlo-
romethane (40 mL) for 16 h. The reaction mixture was allowed
to cool and then evaporated to leave a residue which was
recrystallized from MeOH to give the amide 48 (0.7 g, 44%).
Compound 48 (0.7 g, 2.6 mmol) was dissolved in DMF (20 mL)
with sodium hydride (0.23 g of an 80% dispersion in oil, 8
mmol) and heated at 100 °C for 3 h. After cooling to room
temperature, the reaction mixture was poured into H2O (150
mL), and the solid that was precipitated was collected by
filtration. Recrystallization from DMF/H2O gave 3 (0.23 g,
33%) as white crystals: mp 337-338 °C; NMR (DMSO) δ 5.96
(2 H, br, s, NH2), 7.14-8.04 (8 H, m, ArH), 11.1 (1 H, br, s,
NH); MS (EI) m/ z ) 270 (M+). Anal. (C15H11ClN2O) C, H, N.
4-Aceta m id o-7-ch lor o-3-p h en yl-2(1H)-qu in olon e (4). A
solution of 3 (0.3 g, 1.1 mmol) in THF (30 mL) was treated
with sodium hydride (0.2 g of an 80% dispersion in oil, 7 mmol)
and stirred at room temperature for 1 h. After this time acetyl
chloride (0.7 mL, 9.7 mmol) was added, and after a further 2
h at ambient temperature, the reaction mixture was heated
under reflux for 14 h. After cooling, the reaction mixture was
partitioned between EtOAc (2 × 100 mL) and H2O (1 × 50
mL). The combined organic layers were dried (MgSO4) and
filtered and the solvents removed under vacuum. The residue
was suspended in 1 N NaOH (20 mL) and placed in an
ultrasound bath for 5 min. The aqueous phase was washed
with Et2O (2 × 20 mL), and the separated aqueous layer was
acidified to pH 1 with concentrated hydrochloric acid to
produce a residue which was collected by filtration to give 4
(0.08 g, 23%) as white crystals: mp 275-277 °C; NMR (DMSO)
δ 1.88 (3 H, s, CH3CO), 7.22-7.58 (8 H, m, ArH), 9.69 (1 H,
br, s, NH), 12.06 (1 H, br, s, NH); MS (EI) m/ z ) 312 (M+).
Anal. (C17H13ClN2O2‚2H2O) C, H, N.
Kb (µM)
vs
NMDA
ED50 (mg/kg)
or prot/tested
DBA/2 mouse
IC50 (µM)
no.
R
[3H]L-689,560
2
OH
0.002
0.42
1.2
0.028
3.4
0.9
43 NH2
44 OCH2CN
2/8 @ 20 mg/kg
insoluble 8/8 @ 20 mg/kg
1/8 @ 10 mg/kg
0.56
45 OCH2CO2H
0.024
0/8 @ 20 mg/kg
change to the 4-oxyacetic acid derivative 20 to give 45
improves activity by 5-fold, but the analogous change
to the 4-oxyacetonitrile derivative 23 to give 44 effects
a reduction in binding affinity. These results indicate
that the ligand-binding interactions of acidic and nona-
cidic 4-substituted-3-phenylquinolin-2(1H)-one glycine
antagonists are subtly different. Of the new compounds
in Table 4, only the relatively weak binding 4-alkoxy-
acetonitrile analogue 44 has significant anticonvulsant
activity (ED50 ) 10-20 mg/kg). As in the case of the
corresponding 3-phenyl derivative 23, the possibility of
metabolism of 44 to 2 cannot be completely ruled out,
but the oxyacetic acid 45, which also has potential for
in vivo conversion to 2, is inactive.
Con clu sion s
We have demonstrated that anionic functionality,
previously believed to be a prerequisite for all glycine/
NMDA site antagonists, is not absolutely essential for
good affinity binding in 4-substituted-3-phenylquinolin-
2(1H)-ones. This finding is in accord with the work on
tricyclic quinoxalines of Nagata et al.22 We have also
shown that neutral substituents attached to the 4-posi-
tion of 3-phenylquinolin-2(1H)-ones are more sensitive
to their relative positioning than carboxylate groups
since acids 1, 13, 20, 31, and 34 are all essentially
equipotent. In vivo activity comparable with that
observed for 1 is achieved with the 4-alkoxyacetonitrile
(23) and the 4-alkoxyacetoxime (28) analogues, but the
possibility of these compounds being elaborate prodrugs
for 1 cannot be completely discounted. The results
described in this present work support our previously
proposed pharmacophore models for the binding of
3-phenylquinolin-2(1H)-ones to the glycine site on the
NMDA receptor.3,8,10 For the binding of 4-substituted-
3-phenylquinolin-2(1H)-ones to the glycine site on the
NMDA receptor, we can categorically invoke a key
ligand/receptor hydrogen bond interaction between an
acceptor attached to the 4-position of the ligand and a
hydrogen bond donor attached to the receptor. This
model accounts for the binding of both anions (Figure
1) and nonacidic compounds (Figure 2), but the results
in Table 4 indicate that the binding modes of neutral
and acidic ligands are probably subtly different. These
results clearly extend current views of structural re-
quirements and tolerance for binding to the glycine site
on the NMDA receptor.
4-(P h e n yla ce t a m id o)-7-ch lor o-3-p h e n yl-2(1H )-q u i-
n olon e (5). Treatment of 3 under the same conditions
described for the synthesis of 4, but using phenylacetyl chloride
instead of acetyl chloride, gave 5 (0.12 g, 21%) as white
crystals: mp 295 °C; NMR (DMSO) δ 3.53 (2 H, s, PhCH2-
CO), 7.04 (2 H, d, J ) 6.0 Hz, ArH’s), 7.20 (6 H, m, H-6, ArH’s),
7.33 (3 H, m, ArH’s), 7.38 (1 H, d, J ) 2Hz, H-8), 7.48 (1 H, d,
J ) 8.7 Hz, H-5), 9.92 (1 H, br, s, 4-NH), 12.10 (1 H, br, s,
1-NH); MS (EI) m/ z ) 388 (M+). Anal. (C23H17ClN2O2‚0.2H2O)
C, H, N.
7-Ch lor o-4-[(m et h ylsu lfon yl)a m in o]-3-p h en yl-2(1H )-
qu in olon e (6). To a solution of 3 (0.55 g, 2 mmol) in THF
(50 mL) at room temperature was added potassium bis-
(trimethylsilyl)amide (4 mL of a 0.5 M solution in toluene, 2
mmol). After 10 min, tert-butyldimethylsilyl trifluoromethane-
sulfonate (0.47 mL, 2 mmol) was added, and after a further
10 min, potassium bis(trimethylsilyl)amide (6 mL of a 0.5 M
solution in toluene, 3 mmol) was added. After a further 10
Exp er im en ta l Section
General directions have appeared previously.28

Acidic and Nonacidic Glycine Site NMDA Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 761
min methanesulfonyl chloride (0.48 mL, 6 mmol) was added
and the reaction mixture was allowed to stir for 1 h. The
solvents were removed under vacuum, and the residue was
suspended in 5 M HCl and treated with ultrasound for 10 min
before being collected by filtration. The solid was suspended
in 1 N NaOH solution (50 mL) and re-exposed to ultrasound
for 20 min. The suspension was filtered, and the mother
liquors were acidified to pH 1 with 5 N HCl to precipitate a
solid which was collected by filtration. Recrystallization from
DMF/H2O gave 6 (0.077 g, 11%) as white crystals: mp 222
°C; NMR (DMSO) δ 2.17 (3 H, s, CH3), 7.34-7.67 (8 H, m,
ArH’s), 9.60 (1 H, br, s, 4-NH), 12.16 (1 H, s, br, s, 1-NH);
MS (EI) m/ z ) 348 (M+). Anal. (C16H13ClN2O3S‚0.5H2O)
C, H, N.
7-Ch lor o-4-[(p h en ylsu lfon yl)a m in o]-3-p h en yl-2(1H )-
qu in olon e (7). Treatment of 3 under the same conditions
described for the synthesis of 6, but using benzenesulfonyl
chloride instead of methanesulfonyl chloride, gave 7 (0.05 g,
3%) as white crystals: mp 268 °C; NMR (DMSO) δ 7.14 (6 H,
m, ArH’s), 7.32 (5 H, m, ArH’s), 7.49 (1 H, m, ArH’s), 7.67 (1
H, d, J ) 8.7 Hz, H-5), 10.02 (1 H, br, s, 4-NH), 12.15 (1 H, br,
s, 1-NH); MS (EI) m/ z ) 410 (M+). Anal. (C21H15ClN2O3S)
C, H, N.
7-Ch lor o-4-(m eth ylam in o)-3-ph en yl-2(1H)-qu in olon e (8).
To a solution of 3 (0.5 g, 1.8 mmol) in THF (30 mL) was added
potassium bis(trimethylsilyl)amide (4.05 mL of a 0.5 M solu-
tion in toluene, 2 mmol), and the reaction mixture was allowed
to stir for 10 min before the addition of tert-butyldimethylsilyl
trifluoromethanesulfonate (0.5 mL, 2.2 mmol). After 30 min
a further portion of potassium bis(trimethylsilyl)amide (4.05
mL of a 0.5 M solution in toluene, 2 mmol) was added; then
after a further 15 min methyl iodide (0.35 mL, 3.6 mmol) was
added, and the reaction mixture was allowed to stir for 14 h.
Triethylamine (2 mL) was added, and after 1 h the reaction
mixture was poured into 1 N HCl (30 mL) and stirred for 30
min. The solution was extracted with EtOAc (3 × 50 mL),
washed with H2O (1 × 50 mL) and brine (1 × 50 mL), and
then dried (MgSO4), filtered, and concentrated under vacuum.
The residue was purified by chromatography on silica gel using
20-60% ethyl acetate in hexane as eluent and then further
purified by preparative HPLC on a Dynamax 300A reverse
phase column using 35% acetonitrile/1% trifluoroacetic acid
in H2O to give after freeze-drying compound 8 (0.18 g, 35%)
as a white solid: mp 275 °C dec; NMR (DMSO) δ 2.24 (3 H, d,
J ) 4.9 Hz, CH3), 6.45 (1 H, m, 4-NH), 7.17 (1 H, dd, J ) 8.8,
2.2 Hz, 6-H), 7.21-7.36 (6 H, m, ArH’s), 8.00 (1 H, d, J ) 2.2
Hz, 8-H), 11.09 (1 H, s, 1-NH); MS (EI) m/ z ) 285 (M+). Anal.
(C16H13ClN2O) C, H, N.
7-C h lo r o -4-(d im e t h y la m in o )-3-p h e n y l-2(1H )-q u i-
n olon e (9). Treatment of 3 under the same conditions
described for the synthesis of 8, but using 3 equiv of methyl
iodide instead of 2 equiv, gave, after a similar purification
procedure, 9 (0.048 g, 9%) as a white solid: mp 270-272 °C
dec; NMR (DMSO) δ 2.50 (6 H, s, (CH3)2N), 7.19-7.42 (7 H,
m, ArH’s), 7.79 (1 H, d, J ) 8.7 Hz, 8-H), 11.64 (1 H, br s,
1-NH); MS (EI) m/ z ) 299 (M+). Anal. (C17H15ClN2O) C, H,
N.
7-Ch lor o-4-(b en zyla m in o)-3-p h en yl-2(1H )-q u in olon e
(10). Compound 1 (0.5 g, 1.8 mmol) was dissolved in benzy-
lamine (20 mL) and heated under reflux for 24 h. Excess
benzylamine was removed under high vacuum, and the residue
was triturated with diethyl ether to produce a solid which was
removed by filtration. The filtrate was evaporated, and the
residue obtained was purified by chromatography on silica gel
using 25% ethyl acetate in dichloromethane as eluent to give
10 (0.045 g, 7%) as a white solid: mp 179 °C; NMR (DMSO) δ
3.81 (2 H, d, J ) 4.8 Hz, PhCH2N), 6.67 (1 H, t, J ) 4.8 Hz,
4-NH), 6.85 (2 H, d, J ) 6.5 Hz, ortho ArH’s), 7.10-7.33 (11
H, ArH’s), 11.23 (1 H, br, s, 1-NH); MS (EI) m/ z ) 360 (M+).
Anal. (C22H17ClN2O‚0.1H2O) C, H, N.
11 (0.25 g, 20%) as white crystals: mp 230 °C; NMR (DMSO)
δ 1.94 (6 H, s, (CH3)2N), 2.17 (2 H, m, NCH2CH2N), 2.69 (2 H,
m, NCH2CH2N), 5.82 (1 H, br, s, 4-NH), 7.17-7.95 (8 H, m,
ArH’s), 11.23 (1 H, br, s, 1-NH); MS (EI) m/ z ) 341 (M+). Anal.
(C19H20ClN3O‚0.9H2O) C, H, N.
4-[[3-(N,N-Dim et h yla m in o)p r op yl]a m in o]-7-ch lor o-3-
p h en yl-2(1H)-qu in olon e (12). Treatment of 1 (1 g, 3.6
mmol) under the same conditions described for the synthesis
of 10, but using 3-(N,N-dimethylamino)propylamine instead
of benzylamine and carrying out the reaction in a sealed tube
at 180 °C for 10 days, gave, after recrystallization from Et2O,
12 (0.09 g, 7%) as white crystals: mp 177-179 °C; NMR
(DMSO) δ 1.38 (2 H, m, NCH2CH2CH2N), 1.98 (2 H, m, NCH2-
CH2CH2N), 2.04 (6 H, s, (CH3)2N), 2.58 (2 H, m, NCH2-
CH2CH2N), 6.58 (1 H, m, 1-NH), 7.19-7.94 (8 H, m, ArH’s),
11.15 (1 H, br, s, 1-NH); MS (EI) m/ z ) 355 (M+). Anal.
(C20H22ClN3O) C, H, N.
4-[(Ca r boxyca r bon yl)a m in o]-7-ch lor o-3-p h en yl-2(1H)-
qu in olon e (13). Treatment of 3 under the same conditions
described for the synthesis of 4, but using ethyloxalyl chloride
instead of acetyl chloride, gave 13 (0.1 g, 26%) as white
crystals: mp 240 °C (dec); NMR (DMSO) δ 7.25-7.41 (7 H,
m, ArH’s), 7.59 (1 H, d, J ) 8.7 Hz, 5-H), 10.63 (1 H, s, 4-NH),
12.20 (1 H, s, 1-NH); MS (CI+) m/ z ) 343 (M+). Anal. (C17H11
ClN2O4‚0.5H2O) C, H, N.
-
7-Ch lor o-4-[[(m e t h oxyca r b on yl)ca r b on yl]a m in o]-3-
p h en yl-2(1H)-qu in olon e (14). Treatment of 13 (0.34 g, 1
mmol) with MeOH (50 mL that had been presaturated with
dry hydrogen chloride) for 14 h followed by evaporation and
purification of the residue by chromatography on silica gel
(using 30-100% ethyl acetate in petroleum ether as eluent)
and recrystallization from MeOH/H2O gave 14 (0.1 g, 29%) as
white crystals: mp 254 °C dec; NMR (DMSO) δ 3.77 (3 H, s,
CH3), 7.25-7.42 (7 H, m, ArH’s), 7.65 (1 H, d, J ) 8.7 Hz, 6-H),
10.71 (1 H, br, s, 4-NH), 12.20 (1 H, s, 1-NH); MS (CI+) m/ z )
357 (M+). Anal. (C18H13ClN2O4‚1.1H2O) C, H, N.
7-Ch lor o-4-[[[[[2-(N,N-dim eth ylam in o)eth yl]am in o]car -
bon yl]ca r bon yl]a m in o]-3-p h en yl-2(1H)-qu in olon e (15).
After treatment of 14 (0.35 g, 1 mmol) with 2-(N,N-dimethy-
lamino)ethylamine (70 mL) at room temperature for 3 h, the
solvent was removed under vacuum. The residue was tritu-
rated with ethanol and filtered, and the filtrate was concen-
trated under vacuum. The residue was dissolved in 1 N HCl
(30 mL), and the aqueous solution was washed with EtOAc (2
× 20 mL). The water layer was then basified to pH 14 with 1
N NaOH solution and extracted with EtOAc (2 × 50 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated under vacuum. Recrystallization from EtOAc
gave 15 (0.12 g, 29%) as white crystals: mp 217-220 °C; NMR
(DMSO) δ 2.15 (6 H, s, N(CH3)2), 2.34 (2 H, t, J ) 6.5 Hz,
CH2CH2N(CH3)2), 3.19 (2 H, m, CH2CH2N(CH3)2), 7.25-7.50
(8 H, m, ArH’s), 8.55 (1 H, t, m, NHCH2CH2N(CH3)2), 10.65 (1
H, br, s, 4-NH), 12.20 (1 H, br, s, 1-NH); MS (CI+) m/ z ) 413
(M+). Anal. (C21H21ClN4O3‚0.3H2O) C, H, N.
4-[[(Ca r b oxym et h ylen e)ca r b on yl]a m in o]-7-ch lor o-3-
p h en yl-2(1H)-qu in olon e (16). Treatment of 3 under the
same conditions described for the synthesis of 4, but using
ethylmalonyl chloride instead of acetyl chloride, gave 16 (0.05
g, 7%) as white crystals: mp 260 °C dec; NMR (DMSO) δ 3.33
(2 H, s, CH2CO2H), 7.22-7.76 (7 H, m, ArH’s), 7.87 (1 H, d, J
) 8.4 Hz, 5-H), 9.97 (1 H, br, s, 4-NH), 12.13 (1 H, br, s, 1-NH),
12.62 (1 H, br, s, CO2H); MS (CI+) m/ z ) 357 (M+). Anal.
(C18H13ClN2O4) C, H, N.
7-Ch lor o-4-m eth oxy-3-p h en yl-2(1H)-qu in olon e (18). To
an ice-cooled solution of diazomethane (16 mmol) in Et2O (50
mL) was added a suspension of 1 (3 g, 10.8 mmol) in THF (200
mL), and the reaction mixture was stirred at room tempera-
ture for 2 h. After this time, dry nitrogen was bubbled through
the suspension for 30 min, and a solid was collected by
filtration. Recrystallization from DMF/H2O gave 18 (0.28 g,
9%) as white crystals: mp 270-272 °C; NMR (DMSO) δ 3.45
(3 H, s, CH3), 7.25 (1 H, dd, J ) 8.6, 2.1 Hz, 6-H), 7.35-7.46
(6 H, m, ArH’s), 7.82 (1 H, d, J ) 2.1 Hz, 8-H), 11.87 (1 H, br,
s, NH); MS (CI+) m/ z ) 286 (M+). Anal. (C16H12ClNO2) C,
H, N.
4-[[2-(N,N-Dim et h yla m in o)et h yl]a m in o]-7-ch lor o-3-
p h en yl-2(1H)-qu in olon e (11). Treatment of 1 (1 g, 3.6
mmol) under the same conditions described for the synthesis
of 10, but using (N,N-dimethylamino)ethylamine instead of
benzylamine and carrying out the reaction in a sealed tube at
180 °C for 10 days, gave, after recrystallization from EtOAc,

762 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Carling et al.
7-Ch lor o-4-[(m e t h oxyca r b on yl)m e t h oxy]-3-p h e n yl-
2(1H)-qu in olon e (19). To a solution of 1 (0.5 g, 1.8 mmol)
in DMF (30 mL) were added sodium hydrogen carbonate (1.55
g, 10 mmol) and sodium iodide (0.2 g, 1.3 mmol) followed by
methyl bromoacetate (0.21 mL, 2.2 mmol), and the reaction
mixture was allowed to stir overnight at room temperature.
The reaction mixture was poured into H2O (100 mL) and
extracted with EtOAc (3 × 100 mL). The combined organic
layers were washed with H2O (1 × 100 mL) and brine (1 ×
100 mL) and then dried (MgSO4), filtered, and concentrated
under vacuum. The residue was recrystallized from EtOAc/
hexane to give 19 (0.28 g, 9%) as white crystals: mp 188-191
°C; NMR (DMSO) δ 3.55 (3 H, s, CO2CH3), 4.19 (2 H, s, CH2-
CO2CH3), 7.28 (1 H, dd, J ) 8.7, 2.6 Hz, 6-H), 7.35-7.40 (6 H,
m, ArH’s), 8.01 (1 H, d, J ) 8.7 Hz, 5-H), 11.92 (1 H, s, NH);
MS (CI+) m/ z ) 344 (M+). Anal. (C18H14ClNO4) C, H, N.
4-(Ca r b oxym e t h oxy)-7-ch lor o-3-p h e n yl-2(1H )-q u i-
n olon e (20). To a solution of 19 (0.13 g, 0.3 mmol) in THF
(50 mL) was added lithium hydroxide (18.2 mL of a 0.5 N
solution in H2O, 0.91 mmol), and the reaction mixture was
stirred at room temperature for 30 min. The solvent was
removed under vacuum and the residue obtained was dissolved
in H2O (20 mL). Acidification to pH 1 using 1 N hydrochloric
acid resulted in a precipitate which was collected by filtration
and recrystallized from DMF/H2O to give 20 (0.023 g, 23%) as
white crystals: mp 269-272 °C; NMR (DMSO) δ 4.05 (2 H, s,
CH2), 7.29 (1 H, dd, J ) 8.7, 2.7 Hz, 6-H), 7.35-7.47 (6 H, m,
ArH’s), 8.07 (1 H, d, J ) 8.7 Hz, 5-H), 11.68 (1 H, s, NH); MS
(CI+) m/ z ) 328 (M+). Anal. (C17H12ClNO4) C, H, N.
7-Ch lor o-4-[[(N,N-d im eth yla m in o)ca r bon yl]m eth oxy]-
3-p h en yl-2(1H)-qu in olon e (21). To a saturated solution of
dimethylamine in methanol (200 mL) at 0 °C was added 19
(0.3 g, 0.87 mmol). After 5 days in a sealed flask at room
temperature, the solvent was removed under vacuum and the
residue obtained was recrystallized from MeOH/EtOAc to give
21 (0.21 g, 60%) as white crystals: mp 232-234 °C; NMR
(DMSO) δ 2.42 (3 H, s, OCH2 N(CH3)CH3), 2.69 (3 H, s,
OCH2N(CH3)CH3), 4.30 (2 H, s, OCH2N(CH3)CH3), 7.24 (1 H,
dd, J ) 8.6, 2.1 Hz, 6-H), 7.32-7.47 (6 H, m, ArH’s), 7.98 (1
H, d, J ) 8.6 Hz, 5-H), 11.83 (1 H, s, NH); MS (CI+) m/ z )
403 (M+). Anal. (C19H17ClN2O3) C, H, N.
the synthesis of 19, but using 2-picolyl chloride hydrochloride
instead of methyl bromoacetate, gave 25 (0.33 g, 25%) as white
crystals: mp 143 °C sub, 170 °C; NMR (DMSO) δ 4.64 (2 H, s,
OCH2), 7.22-7.47 (9 H, m, ArH’s), 7.74-7.83 (2 H, m, ArH’s),
8.45 (1 H, d, J ) 4.1 Hz, 6-Pyr-H), 11.95 (1 H, s, NH); MS (EI)
m/ z ) 363 (M+). Anal. (C21H15ClN2O2) C, H, N.
7-Ch lor o-4-[[2-(N,N-d im eth yla m in o)eth yl]oxy]-3-p h en -
yl-2(1H)-qu in olon e (26). Treatment of 1 (5 g, 18 mmol)
under the same conditions described for the synthesis of 19,
but using allyl bromide instead of methyl bromoacetate, gave
49 (2.8 g, 50%) as white crystals: NMR (DMSO) δ 4.04 (2 H,
dd, J ) 6.5, 1.8 Hz, OCH2CHdCH2), 5.08 (2 H, m, OCH2-
CHdCH2), 5.88 (1 H, m, OCH2CHdCH2), 7.23 (1 H, dd, J )
8.6, 2.1 Hz, 6-H), 7.36 (6 H, m, ArH’s), 7.81 (1 H, d, J ) 8.6
Hz, 5-H), 11.94 (1 H, br, s, NH).
Ozone was passed through a solution of 49 (0.3 g, 0.96 mmol)
in dichloromethane (50 mL) for 15 min (solution changed to a
blue color). The reaction mixture was allowed to warm to room
temperature and stirred for 1 h before the addition of dimethyl
sulfide (0.5 mL). After a further 30 min the solvent was
removed under vacuum to leave a solid which was dissolved
in MeOH (50 mL) with dimethylamine hydrochloride (0.4 g,
4.9 mmol) and sodium cyanoborohydride (0.06 g, 1 mmol). The
reaction mixture was stirred at room temperature for 16 h;
then the mixture was adjusted to pH 5 with 1 N NaOH
solution, and the solution was extracted with EtOAc (3 × 50
mL). The combined organic layers were extracted with 1 N
HCl (1 × 100 mL), and the aqueous layer was washed with
ethyl acetate (2 × 50 mL). The water solution was readjusted
to pH 9 with 1 N NaOH solution, and the solution was
extracted with EtOAc (3 × 50 mL). The combined organic
layers were dried (MgSO4) and filtered, and the solid was
removed under vacuum to leave a solid which was recrystal-
lized from EtOAc/hexane to give 26 (0.03 g, 10%) as white
crystals: mp 185-187 °C; NMR (DMSO) δ 2.00 (6 H, s, 2 ×
NCH3), 2.33 (2 H, t, J ) 5.8 Hz, OCH2CH2N), 3.55 (2 H, t, J
) 5.8 Hz, OCH2CH2N), 7.24 (1 H, dd, J ) 9.3, 2.1 Hz, 6-H),
7.35-7.46 (6 H, m, ArH’s), 7.91 (1 H, d, J ) 9.3 Hz, 5-H), 11.67
(1 H, br, s, NH); MS (CI+) m/ z ) 343 (M+). Anal. (C19H19
ClN2O2‚0.1C6H14‚0.6H2O) C, H, N.
-
7-Ch lor o-3-p h en yl-4-(2-oxop r op oxy)-2(1H)-q u in olon e
(27). Treatment of 1 under the same conditions described for
the synthesis of 19, but using chloroacetone instead of methyl
bromoacetate, gave 27 (0.39 g, 66%) as white crystals: mp
185-186 °C; NMR (DMSO) δ 1.84 (3 H, s, CH3CO), 4.26 (2 H,
s, CH2), 7.26 (1 H, dd, J ) 8.7, 2.1 Hz, 6-H), 7.30-7.46 (6 H,
m, ArH’s), 8.02 (1 H, d, J ) 8.7 Hz, 5-H), 11.90 (1 H, br, s,
NH); MS (CI+) m/ z ) 328 (M+). Anal. (C18H14ClNO2) C, H,
N.
7-Ch lor o-3-p h en yl-4-(2-oxim in op r op oxy)-2(1H )-q u i-
n olon e (28). To a solution of 27 (0.5 g, 1.5 mmol) in pyridine
(10 mL) were added hydroxylamine hydrochloride (0.63 g, 9.3
mmol) and 4 Å molecular sieves (0.3 g), and the reaction
mixture was heated at 60 °C for 24 h. The mixture was diluted
with EtOAc (100 mL) and filtered through celite. The solution
was washed with 1 N HCl (1 × 100 mL), H2O (1 × 20 mL),
and saturated sodium hydrogen carbonate solution (1 × 20
mL) and then dried (MgSO4), filtered, and concentrated under
vacuum to leave a residue which was recrystallized from
EtOH/H2O to give 28 (0.28 g, 54%) as white crystals: mp 196-
198 °C; NMR (DMSO) δ 1.60 (3 H, s, CH3), 4.06 (2 H, s, CH2),
7.28 (1 H, dd, J ) 8.6, 2.1 Hz, 6-H), 7.32-7.48 (6 H, m, ArH’s),
7.78 (1 H, d, J ) 8.6 Hz, 5-H), 10 88 (1 H, s, NOH), 11.92 (1
H, br, s, NH); MS (CI+) m/ z ) 343 (M+). Anal. (C18H15ClN2O3)
C, H, N.
7-Ch lor o-3-p h en yl-4-[2-(O-m et h yloxim in o)p r op oxy]-
2(1H)-qu in olon e (29). Treatment of 27 under the same
conditions described for the synthesis of 28, but using O-
methylhydroxylamine hydrochloride instead of hydroxylamine
hydrochloride, gave 29 (0.19 g, 35%) as white crystals: mp
192-195 °C; NMR (DMSO) δ 1.58 (3 H, s, CCH3), 3.71 (3 H, s,
NOCH3), 4.06 (2 H, s, CH2), 7.28 (1 H, dd, J ) 8.7, 2.1 Hz,
6-H), 7.32-7.48 (6 H, m, ArH’s), 7.80 (1 H, d, J ) 8.7 Hz, 5-H),
11.91 (1 H, br, s, NH); MS (CI+) m/ z ) 357 (M+). Anal.
(C19H17ClN2O3‚0.1 H2O) C, H, N.
4-[(Am in oca r bon yl)m eth oxy]-7-ch lor o-3-p h en yl-2(1H)-
qu in olon e (22). To a solution of 20 (0.93 g, 2.8 mmol) in THF
(50 mL) were added triethylamine (1.9 mL, 4.1 mmol), am-
monium acetate (0.5 g, 1.8 mmol), 1-hydroxybenzotriazole (0.6
g, 1.3 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbo-
diimide (0.9 g, 1.3 mmol). After stirring at room temperature
for 3 days, the reaction mixture was poured into H2O (100 mL)
and extracted with EtOAc (3 × 50 mL). The combined organic
layers were washed with 1 N citric acid solution (1 × 75 mL),
H2O (1 × 75 mL), saturated sodium hydrogen carbonate
solution (1 × 75 mL), and brine (1 × 75 mL), dried (MgSO4),
and filtered, and the solvent was removed under vacuum.
Recrystallization of the residue from MeOH gave 22 (0.29 g,
32%) as white crystals: mp 232-234 °C; NMR (DMSO) δ 3.91
(2 H, s, OCH2CONH2), 7.25-7.45 (9 H, m, 7 × ArH’s and NH2),
8.01 (1 H, d, J ) 8.7 Hz, 5-H), 11.92 (1 H, br, s, NH); MS (CI+)
m/ z ) 329 (M+). Anal. (C17H13ClN2O3) C, H, N.
7-C h lo r o -4-(c y a n o m e t h o x y )-3-p h e n y l-2(1H )-q u i -
n olon e (23). Treatment of 1 under the same conditions
described for the synthesis of 19, but using bromoacetonitrile
instead of methyl bromoacetate, gave 23 (0.15 g, 26%) as white
crystals: mp 209-211 °C; NMR (DMSO) δ 4.59 (2 H, s, OCH2-
CN), 7.31 (1 H, dd, J ) 8.6, 2.1 Hz, 6-H), 7.40-7.49 (6 H, m,
ArH’s), 7.83 (1 H, d, J ) 8.6 Hz, 5-H), 12.10 (1 H, br, s, NH);
MS (EI) m/ z ) 311 (M+). Anal. (C17H11ClN2O2) C, H, N.
7-Ch lor o-4-(ben zyloxy)-3-p h en yl-2(1H)-qu in olon e (24).
Treatment of 1 under the same conditions described for the
synthesis of 19, but using benzyl bromide instead of methyl
bromoacetate, gave 24 (0.078 g, 12%) as white crystals: mp
167 °C sub, 211 °C; NMR (DMSO) δ 4.56 (2 H, s, OCH2Ph),
7.10-7.48 (12 H, m, ArH’s), 7.76 (1 H, d, J ) 8.6 Hz, 8-H),
11.94 (1 H, br, s, NH); MS (CI-) m/ z ) 310 (M+). Anal.
(C22H16ClNO2) C, H, N.
7-Ch lor o-4-(2-p yr id yloxy)-3-p h en yl-2(1H )-q u in olon e
(25). Treatment of 1 under the same conditions described for

Acidic and Nonacidic Glycine Site NMDA Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 763
4-Ca r boxy-7-ch lor o-3-p h en yl-2(1H)-qu in olon e (31). A
mixture of 4- and 6-chloroisatin (10 g, 55 mmol), phenylacetic
acid (13.12 g, 96 mmol), and sodium acetate (1.1 g, 13.3 mmol)
was heated at 220 °C for 1 h. Acetic acid (50 mL) was added
to the hot reaction mixture, and the cooled solution was
partitioned between saturated sodium carbonate solution (300
mL) and EtOAc (300 mL). The aqueous phase was treated
with concentrated HCl until pH 1 was obtained, and the
resultant precipitate was collected by filtration and recrystal-
lized from ethanol to give 31 (10.8 g, 27%) as white crystals:
mp 258 °C; NMR (DMSO) δ 7.30 (1 H, dd, J ) 8.7, 2.1 Hz,
6-H), 7.37-7.44 (6 H, m, ArH’s), 7.50 (1 H, d, J ) 8.7 Hz, 5-H),
12.20 (1 H, br, s, NH); MS (CI+) m/ z ) 300 (M+). Anal.
(C16H10ClNO3) C, H, N.
7-Ch lor o-4-(m e t h oxyca r b on yl)-3-p h e n yl-2(1H )-q u i-
n olon e (30). Compound 31 (1.2 g, 4 mmol) was dissolved in
MeOH (100 mL) and treated with diazomethane (16 mmol) in
Et2O. After 1 h, acetic acid (5 mL) was added, and after a
further 1 h, the solvents were removed under vacuum. The
residue was dissolved in EtOAc (100 mL), washed with
saturated sodium hydrogen carbonate solution (1 × 50 mL)
and brine (1 × 50 mL), and then dried (MgSO4), filtered, and
concentrated under vacuum. The residue was recrystallized
from DMF/H2O and collected by filtration to give 30 (0.35 g,
28%) as white crystals: mp 255 °C; NMR (DMSO) δ 3.64 (3
H, s, CH3), 7.28 (1 H, dd, J ) 8.7, 2.1 Hz, 6-H), 7.30-7.45 (6
H, m, ArH’s), 7.49 (1 H, d, J ) 8.7 Hz, 5-H), 12.31 (1 H, br, s,
NH); MS (CI+) m/ z ) 314 (M+). Anal. (C17H12ClNO3) C, H,
N.
4-[(Ben zyla m in o)ca r b on yl]-7-ch lor o-3-p h en yl-2(1H )-
qu in olon e (32). A solution of 31 (1 g, 3.3 mmol) in thionyl
chloride (10 mL) was heated under reflux for 1 h and then
concentrated under vacuum and azeotroped with toluene (2
× 30 mL). The residue was dissolved in dichloromethane (50
mL), benzylamine (0.37 mL, 3.3 mmol) was added, and the
reaction mixture was heated under reflux for 1 h. After
cooling, dichloromethane (30 mL) was added, and the solution
was washed with 1 N NaOH solution (30 mL) and then dried
(MgSO4), filtered, and concentrated under vacuum to leave a
residue. This was recrystallized from DMF/H2O and then
MeOH to give 32 (0.18 g, 27%) as white crystals: mp 228 °C;
NMR (DMSO) δ 4.27 (2 H, d, J ) 6.0 Hz, CH2Ph), 6.72 (2 H,
m, ArH’s), 7.11-7.48 (11 H, m, ArH’s), 8.91 (1 H, t, J ) 6.0
Hz, NHCH2Ph), 12.15 (1 H, br, s, NH); MS (CI+) m/ z ) 389
(M+). Anal. (C23H17ClN2O2) C, H, N.
temperature for 1 h. The precipitate formed was collected by
filtration and purified on silica gel using 30-50% EtOAc/
hexane as eluent to give 33 (0.021 g, 4%) as white crystals:
mp 227 °C; NMR (DMSO) δ 3.58 (3 H, s, CO2CH3), 3.75 (2 H,
s, CH2CO2CH3), 7.18 (2 H, m, ArH’s), 7.26 (1 H, dd, J ) 8.7,
2.1 Hz, H-6), 7.42 (4 H, m, ArH’s), 7.69 (1 H, d, J ) 8.7 Hz,
H-5), 12.07 (1 H, br, s, NH); MS (EI+) m/ z ) 327 (M+). Anal.
(C18H14ClNO3‚0.5H2O) C, H, N.
4-(C a r b o x y m e t h y l)-7-c h lo r o -3-p h e n y l-2(1H )-q u i-
n olon e (34). To a suspension of 33 (0.12 g, 0.36 mmol) in
50% MeOH/H2O (20 mL) was added NaOH (0.2 g, 5 mmol),
and the reaction mixture was heated under reflux for 1 h. The
MeOH was removed under vacuum, and the residue was
extracted with Et2O (3 × 15 mL). The aqueous layer was
acidified to pH 1 with concentrated HCl and extracted with
EtOAc (3 × 30 mL). The combined organic layers were washed
with brine (1 × 30 mL), dried (MgSO4), filtered, and concen-
trated under vacuum to give a residue which was recrystallized
from ethanol to give 34 (0.05 g, 44%) as white crystals: mp
175 °C; NMR (DMSO) δ 3.65 (2 H, s, CH2CO2H), 7.23 (2 H, m,
ArH’s), 7.26 (1 H, dd, J ) 8.6, 2.1 Hz, H-6), 7.41 (4 H, m,
ArH’s), 7.69 (1 H, d, J ) 8.6 Hz, H-5), 12.03 (1 H, d, J ) 8.7
Hz, H-5), 12.07 (1 H, br, s, NH); MS (CI
+) m/ z ) 313 (M+).
Anal. (C17H12ClNO3) C, H, N.
7-Ch lor o-4-[[[[2-(N,N-d im eth yla m in o)eth yl]a m in o]ca r -
bon yl]m eth yl]-3-p h en yl-2(1H)-qu in olon e (35). To a solu-
tion of 34 (0.66 g, 2 mmol) in 1,2-dichloroethane (50 mL) were
added triethylamine (0.56 mL, 4 mmol), bis(2-oxo-3-oxazolidi-
nyl)phosphinic chloride (0.62 g, 2.4 mmol), and N,N-dimeth-
ylethylenediamine (0.22 mL, 2 mmol), and the reaction
mixture was heated under reflux for 14 h. After cooling, the
solution was extracted with 1 N HCl (3 × 30 mL). The
combined acidic layers were treated cautiously with solid
sodium hydrogen carbonate solution until a pH of ∼8 was
attained and then extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with brine (1 × 50 mL)
and then dried (MgSO4), filtered, and concentrated under
vacuum. The residue was recrystallized from ethanol to give
35 (0.02 g, 3%) as white crystals: mp 280 °C; NMR (DMSO) δ
2.13 (6 H, s, N(CH3)2), 2.24 (2 H, t, J ) 6.5 Hz, NHCH2CH2N-
(CH3)2), 3.12 (2 H, q, J ) 6.5, 5.5 Hz, NHCH2CH2N(CH3)2),
3.53 (2 H, s, CH2CONH), 7.22 (1 H, dd, J ) 8.7, 2.1 Hz, H-6),
7.29 (2 H, m, ArH’s), 7.37-7.42 (4 H, m, ArH’s), 7.64 (1 H, d,
J ) 8.7 Hz, H-5), 7.95 (1 H, t, J ) 5.5 Hz, CONH), 11.97 (1 H,
s, NH); MS (CI+) m/ z ) 384 (M+). Anal. (C21H22ClN2O3) C,
H, N.
7-Ch lor o-4-[(m eth oxycar bon yl)m eth yl]-3-ph en yl-2(1H)-
qu in olon e (33). To a solution of 539 (4 g, 19 mmol) in 1,2-
dichloroethane (100 mL) was added phenylacetyl chloride (5
mL, 38 mmol), and the reaction mixture was heated under
reflux for 14 h. After cooling, the solvent was removed under
vacuum, and the residue was redissolved in MeOH (100 mL)
and concentrated under vacuum again. Trituration with
MeOH and filtration gave 54 (5 g, 80%) as white crystals:
NMR (DMSO) δ 3.53 (2 H, s, CH2), 3.73 (3 H, s, CH3), 6.60 (1
H, d, J ) 15.9 Hz, CHAdCHBCO2CH3), 7.24-7.38 (6 H, m,
ArH’s), 7.55 (1 H, d, J ) 2.1 Hz, H-6), 7.76 (1 H, d, J ) 15.9
Hz, CHAdCHBCO2CH3), 7.85 (1 H, d, J ) 8.6 Hz, H-3).
To a solution of 54 (0.5 g, 1.5 mmol) in dry THF (100 mL)
at -78 °C under nitrogen was added potassium bis(trimeth-
ylsilyl)amide (3 mL of a 0.5 M solution in toluene, 1.5 mmol).
After 10 min tert-butyldimethylsilyl trifluoromethanesulfonate
(0.418 mL, 1.8 mmol) was added, and after 45 min a further
portion of potassium bis(trimethylsilyl)amide (3.64 mL of a 0.5
M solution in toluene, 1.8 mmol) was added. After 1.5 h at
-78 °C, phenylselenyl chloride (0.32 g, 1.65 mmol) in dry THF
(10 mL) was added, and the reaction mixture was allowed to
stir at -78 °C for 30 min and then at room temperature for
14 h. The reaction mixture was partitioned between EtOAc
(200 mL) and saturated ammonium chloride solution (1 × 100
mL). The organic phase was washed with brine (1 × 50 mL)
and dried (MgSO4), and the solvent was removed under
vacuum. The residue was purified using silica gel chroma-
tography with 15% EtOAc/hexane as eluent. The purified
selenide (0.186 g) was dissolved in 12.5% aqueous MeOH (20
mL), and after the addition of sodium periodate (0.25 g, 1.2
mmol) the reaction mixture was allowed to stir at room
4-(2-C a r b o x y e t h y l)-7-c h lo r o -3-p h e n y l-2(1H )-q u i-
n olon e (37). To a suspension of 55 (16 g, 101.6 mmol) and
triethylamine (31.2 mL, 224 mmol) in dichloromethane (400
mL) at 0 °C was added phenylacetyl chloride (29.6 mL, 224
mmol) dropwise over 10 min. When the addition was com-
plete, the reaction mixture was allowed to warm to room
temperature and stirred for 2 h. The solution was washed with
1 N HCl (2 × 250 mL) and brine (1 × 250 mL), dried (MgSO4),
and filtered, and the solvent was removed under vacuum to
leave an orange solid. This solid was suspended in MeOH (400
mL), sodium hydroxide (4.4 g, 55.9 mmol) in H2O (100 mL)
was added, and the reaction mixture was heated at 50 °C for
45 min. The MeOH was removed under vacuum, and the
aqueous residue was extracted with dichloromethane (1 × 400
mL). The organic layer was washed with brine (1 × 150 mL)
and saturated sodium hydrogen carbonate solution (1 × 150
mL), dried (MgSO4), and filtered, and the solvent was removed
under vacuum to leave a solid (20 g). To a solution of this
solid (15.5 g, 56.3 mmol) in dichloromethane (400 mL), at room
temperature, were added pyridinium chlorochromate (24.3 g,
112.5 mmol) and crushed 4 A sieves (0.5 g). After stirring at
room temperature for 90 min, EtOAc (500 mL) was added and
the reaction mixture was filtered through a plug of silica gel.
The solvents were removed under vacuum, and the material
was dissolved in EtOAc and filtered through silica gel again.
The solvent was removed under vacuum, and trituration with
Et2O gave 56 (10.5 g, 48% over two steps): NMR (DMSO) δ
3.82 (2 H, s, CH2Ph), 7.27-7.39 (6 H, m, ArH’s), 7.87 (1 H, d,
J ) 8.3 Hz, 6-H), 8.36 (1 H, d, J ) 1.9 Hz, 3-H), 9.89 (1 H, s,
CHO), 10.97 (1 H, br, s, NH).

764 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Carling et al.
To a solution of 56 (10.5 g, 38.4 mmol) in dichloromethane
(100 mL) under an atmosphere of nitrogen at -78 °C was
added titanium tetrachloride (4.3 mL, 42.2 mmol), and [(1-
ethoxycyclopropyl)oxy]trimethylsilane (8.8 mL, 46.1 mmol) in
dichloromethane (30 mL) was added dropwise over 10 min.
The reaction mixture was stirred at -78 °C for 15 min, allowed
to warm to 0 °C, and stirred for 45 min and then at room
temperature for 3 h. Saturated ammonium chloride solution
(100 mL) was added to the reaction mixture, and the organic
layer was separated. The aqueous layer was extracted with
dichloromethane (2 × 75 mL), the combined organic layers
were dried (MgSO4) and filtered, and the solvent was removed
under vacuum to leave a residue. Purification on silica gel
using 20-60% EtOAc/hexane as eluent gave 57 (7.78 g, 54%)
as a white solid: NMR (DMSO) δ 1.16 (3 H, t, J ) 7.1 Hz,
CH(OH)CH2CH2CO2CH2CH3), 1.60 (2 H, m, CH(OH)CH2CH2-
CO2CH2CH3), 2.15-2.33 (2 H, m, CH(OH)CH2CH2CO2CH2-
CH3), 3.70 (2 H, s, NHCOCH2Ph), 4.01 (2 H, q, J ) 7.1 Hz,
CH(OH)CH2CH2CO2CH2CH3), 4.68 (1 H, br, s, CH(OH)CH2-
CH2CO2CH2CH3), 5.73 (1 H, br, s, CH(OH)CH2CH2CO2CH2-
CH3), 7.16-7.34 (7 H, m, ArH’s), 7.79 (1 H, d, 3-H), 9.68 (1 H,
br, s, NH).
layers were washed with H2O (1 × 100 mL) and brine (1 ×
100 mL), dried (MgSO4), filtered, and concentrated under
vacuum to leave a residue which was recrystallized from
MeOH/H2O to give 40 (0.08 g, 14%) as white crystals: mp 252-
254 °C; NMR (DMSO) δ 2.66 (2 H, t, J ) 7.6 Hz, CH2CH2CN),
2.77 (2 H, t, J ) 8.3 Hz, CH2CH2CN), 7.24-7.48 (7 H, m,
ArH’s), 7.91 (1 H, d, J ) 8.8 Hz, 5-H), 12.03 (1 H, br, s, NH);
MS (CI+) m/ z ) 309 (M+). Anal. (C18H13ClN2O) C, H, N.
7-Ch lor o-3-p h en yl-4-(2-t et r a zol-5-ylet h yl)-2(1H )-q u i-
n olon e (41). To a solution of 38 (0.45 g, 1.5 mmol) in
1-methyl-2-pyrrolidinone (50 mL) under an atmosphere of
nitrogen at room temperature were added sodium azide (0.28
g, 4.4 mmol) and triethylamine hydrochloride (0.3 g, 2.2 mmol).
The reaction mixture was heated at 150 °C with stirring for
48 h. After allowing to cool, the reaction mixture was poured
into H2O (100 mL), and the pH was adjusted to 1 by the
addition of concentrated HCl. The solution was extracted with
EtOAc (3 × 75 mL), and the combined organic layers were
washed with 1 N NaOH solution (3 × 75 mL). The combined
aqueous phases were washed with Et2O (2 × 75 mL) and
acidified to pH 1 with concentrated HCl. The aqueous layer
was extracted with EtOAc (3 × 75 mL), and the combined
organic layers were dried (MgSO4), filtered, and concentrated
under vacuum to leave a residue which was recrystallized from
MeOH/H2O and then EtOAc to give 41 (0.05 g, 10%) as white
crystals: mp 231-233 °C; NMR (DMSO) δ 3.05 (4 H, br, s,
CH2CH2-Tet), 7.10-7.42 (7 H, m, ArH’s), 7.86 (1 H, d, J ) 8.7
Hz, 5-H), 12.00 (1 H, br, s, NH); MS (CI+) m/ z ) 352 (M+).
Anal. (C18H14ClN5O‚0.1H2O) C, H, N.
Subsequent treatment of 57 (8.8 g, 23.4 mmol) under the
appropriate conditions described in the conversions of 55 to
56, 56 to 42, and 33 to 34 gave 37 (5.5 g, 72%) as white
crystals: mp 316-318 °C; NMR (DMSO) δ 2.37 (2 H, t, J )
8.6 Hz, CH2CH2), 2.83 (2 H, t, J ) 8.6 Hz, CH2CH2), 7.22-
7.28 (3 H, m, ArH’s), 7.36-7.46 (4 H, m, ArH’s), 7.82 (1 H, d,
J ) 8.7 Hz, 5-H), 11.95 (1 H, br, s, NH); MS (CI+) m/ z ) 328
(M+). Anal. (C18H14ClNO3) C, H, N.
7-Ch lor o-4-eth yl-3-p h en yl-2(1H)-qu in olon e (42). To a
solution of 56 (0.5 g, 1.83 mmol) in THF (30 mL) under an
atmosphere of nitrogen at 0 °C was added ethylmagnesium
bromide (2 mL of a 1 M solution in Et2O). The reaction
mixture was allowed to warm to room temperature, stirred
for 16 h, and then poured into saturated ammonium chloride
solution (75 mL) and extracted with EtOAc (3 × 75 mL). The
combined organic layers were washed with H2O (1 × 75 mL),
dried (MgSO4), and filtered, and the solvent was removed
under vacuum to leave a solid (0.93 g). Treatment of this solid
(0.93 g) with pyridinium chlorochromate under the conditions
described for the preparation of 56 gave a ketone intermediate
(0.28 g), which was dissolved in dry EtOH (30 mL) and treated
with sodium hydride (0.06 g of an 80% dispersion, 1.86 mmol)
at room temperature under nitrogen. After 30 min, the solvent
was removed under vacuum to leave a residue which was
partitioned between EtOAc (50 mL) and H2O (50 mL). The
organic phase was washed with brine (1 × 50 mL), dried
(MgSO4), and filtered, and the solvent was removed under
vacuum to leave a solid. Recrystallization from EtOAc gave
42 (0.28 g, 46% over three steps) as white crystals: mp 244-
246 °C; NMR (DMSO) δ 1.04 (3 H, t, J ) 7.5 Hz, CH2CH3),
2.58 (2 H, t, J ) 7.5 Hz, CH2CH3), 7.21-7.46 (7 H, m, ArH’s),
7.82 (1 H, d, J ) 8.8 Hz, H-5), 11.89 (1 H, br, s, NH); MS (CI-)
m/ z ) 283 (M). Anal. (C17H14ClNO) C, H, N.
7-Ch lor o-4-[2-(m eth oxycar bon yl)eth yl]-3-ph en yl-2(1H)-
qu in olon e (36). Compound 37 (1.17 g, 3.6 mmol) was
dissolved in a saturated solution of hydrogen chloride in MeOH
(100 mL) and stood at room temperature for 3 h. The solvents
were evaporated, and the residue was recrystallized from
methanol to give 36 (0.42 g, 34%) as white crystals: mp 193-
194 °C; NMR (DMSO) δ 2.47 (2 H, t, J ) 8.4 Hz, CH2CH2),
2.88 (2 H, t, J ) 8.4 Hz, CH2CH2), 3.52 (3 H, s, CH3), 7.21-
7.27 (3 H, m, ArH’s), 7.36-7.46 (4 H, m, ArH’s), 7.82 (1 H, d,
J ) 8.8 Hz, 5-H), 11.94 (1 H, br, s, NH); MS (CI+) m/ z ) 342
(M+). Anal. (C19H16ClNO3) C, H, N.
7-Ch lor o-4-[(3-m eth yl-1,2,4-oxadiazol-5-yl)eth yl]-3-ph en -
yl-2(1H)-qu in olon e (38). To a solution of acetamide oxime
(0.26 g, 2.93 mmol) in THF (50 mL) under an atmosphere of
nitrogen at room temperature was added sodium hydride (0.14
g of an 80% dispersion, 0.46 mmol). The reaction mixture was
heated to 60 °C for 90 min; then 36 (0.5 g, 1.46 mmol) was
added, and the reaction mixture was heated at 60 °C for 3 h.
After allowing to cool, the reaction mixture was poured into
H2O (100 mL) and extracted with EtOAc (3 × 75 mL). The
combined organic layers were washed with 1 N citric acid
solution (1 × 75 mL), water (1 × 75 mL), saturated sodium
hydrogen carbonate solution (1 × 75 mL), and brine (1 × 75
mL). After drying (MgSO4), filtration and evaporation gave a
residue which was recrystallized from MeOH/EtOAc to give
38 (0.08 g, 15%) as white crystals: mp 235-238 °C; NMR
(DMSO) δ 2.25 (3 H, s, CH3), 3.04 (4 H, m, CH2CH2), 7.16 (1
H, dd, J ) 8.8, 1.3 Hz, H-6), 7.18-7.44 (6 H, m, ArH’s), 7.87
(1 H, d, J ) 8.8 Hz, 5-H), 12.00 (1 H, br, s, NH); MS (CI-) m/ z
) 365 (M). Anal. (C20H16ClN3O2) C, H, N.
4-Am in o -7-c h lor o -3-(3-p h e n oxy p h e n yl)-2(1H )-q u i-
n olon e (43). Compound 43 was prepared in the same way
as 3, using 3-phenoxyphenylacetyl chloride instead of pheny-
lacetyl chloride, to give 43 (0.31 g, 15%) as white crystals: mp
196-197 °C; NMR (DMSO) δ 6.09 (2 H, br, s, NH2), 6.70-
8.05 (12 H, m, ArH’s), 11.06 (1 H, br, s, NH); MS (CI-) m/ z )
362 (M). Anal. (C21H15ClN2O2) C, H, N.
4-[2-(Am in oca r b on yl)et h yl]-7-ch lor o-3-p h en yl-2(1H )-
qu in olon e (39). Treatment of 37 (1.7 g, 5.2 mmol) under the
conditions described for the conversion of 20 to 22 gave 39
(0.05 g, 3%) as white crystals: mp 297-299 °C; NMR (DMSO)
δ 2.21 (2 H, t, J ) 8.3 Hz, CH2CH2CONH2), 2.77 (2 H, t, J )
8.3 Hz, CH2CH2CONH2), 6.78 (1 H, br, s, 1 × CONH2), 7.21-
7.46 (8 H, m, ArH’s, 1 × CONH2), 7.81 (1 H, d, J ) 8.8 Hz,
5-H), 11.92 (1 H, br, s, NH); MS (CI+) m/ z ) 327 (M+). Anal.
(C18H15ClN2O2) C, H, N.
7-Ch lor o-4-(cyan om eth oxy)-3-(3-ph en oxyph en yl)-2(1H)-
qu in olon e (44). Treatment of 2 under the same conditions
described for the synthesis of 19, but using bromoacetonitrile
instead of methyl bromoacetate, gave 25 (0.13 g, 16%) as white
crystals: mp 218-220 °C; NMR (DMSO) δ 4.70 (2 H, s, OCH2),
7.08-7.51 (11 H, m, ArH’s), 7.82 (1 H, d, J ) 8.7 Hz, 5-H),
12.10 (1 H, br, s, NH); MS (EI) m/ z ) 403 (M+). Anal. (C23H15
ClN2O3) C, H, N.
-
7-Ch lor o-4-(2-cya n oet h yl)-3-p h en yl-2(1H )-q u in olon e
(40). To a solution of 39 (0.6 g, 1.84 mmol) in THF (80 mL)
under an atmosphere of nitrogen at 0 °C was added triethy-
lamine (1.13 mL, 8.1 mmol) followed by trifluoroacetic anhy-
dride (0.7 mL, 5 mmol). The reaction mixture was stirred at
0 °C for 45 min and then poured into H2O (100 mL) and
extracted with Et2O (2 × 100 mL). The combined organic
7-Ch lor o-4-ca r b oxy-3-(3-p h en oxyp h en yl)-2(1H )-q u i-
n olon e (45). Treatment of 2 under the same conditions
described for the synthesis of 19 and 20 gave 45 (0.05 g, 5%
over two steps) as white crystals: mp 246-249 °C; NMR
(DMSO) δ 4.18 (2 H, s, OCH2), 7.04-7.48 (11 H, m, ArH’s),
8.02 (1 H, d, J ) 8.6 Hz, 5-H), 11.93 (1 H, br, s, NH); MS (EI)
m/ z ) 422 (M+). Anal. (C23H16ClNO5) C, H, N.

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