Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists

Article abstract of DOI:10.1021/jm049499o

We describe the discovery and the structure-activity relationship of a new series of quinoline derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first identified cis-10 as a fairly potent mGlu1 antagonist (IC₅₀

Full text of DOI:10.1021/jm049499o

2134
J. Med. Chem. 2005, 48, 2134-2153
Synthesis, Structure-Activity Relationship, and Receptor Pharmacology of a
New Series of Quinoline Derivatives Acting as Selective, Noncompetitive mGlu1
Antagonists
Dominique Mabire,†,‡ Sophie Coupa,† Christophe Adelinet,† Alain Poncelet,† Yvan Simonnet,† Marc Venet,†,§
Ria Wouters,| Anne S. J. Lesage,| Ludy Van Beijsterveldt, and Franc¸ois Bischoff*,∞
Department of Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research & Development,
a Division of Janssen-Cilag France, Campus de Maigremont, F-27106 Val de Reuil, France, and
Department of Medicinal Chemistry, CNS Discovery Research and Department of Preclinical Pharmacokinetics,
Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica N.V.,
Turnhoutseweg 30, B-2340 Beerse, Belgium
Received June 24, 2004
We describe the discovery and the structure-activity relationship of a new series of quinoline
derivatives acting as selective and highly potent noncompetitive mGlu1 antagonists. We first
identified cis-10 as a fairly potent mGlu1 antagonist (IC50 ) 20 nM) in a cell-based signal
transduction assay on the rat mGlu1 receptor expressed in CHO-K1 cells, and then we were
able to design and synthesize highly potent compounds on both rat and human mGlu1 receptors
as exemplified by compound cis-64a, which has an antagonist potency of 0.5 nM for the human
mGlu1 receptor. We briefly present and discuss the in vitro metabolic stability of the compounds
in human liver microsomes. We finally report the pharmacokinetic properties of our lead
compound cis-64a.
Introduction
which hydrolyses phosphatidyl inositol 4,5-bisphosphate
into inositol trisphosphate (IP3) and diacylglycerol. IP3
in turn binds to the IP3 receptor on the endoplasmic
reticulum, evoking a release of Ca2+ from these intra-
cellular stores. Ca2+ and diacylglycerol activate protein
kinase C. Group II and group III receptors are coupled
to Gi, and activation of the receptors leads to an inhibi-
tion of adenylate cyclase, thereby inhibiting intracellu-
lar cAMP formation and protein kinase A activation.7
mGlu1 receptors are widely distributed in the CNS,
where they modulate synaptic transmission, neuronal
excitability, and brain plasticity. The physiological
function of mGlu receptors7-11 and the involvement of
group I receptors in epilepsy, neurodegeneration,10
pain,12-14 anxiety,15 and thalamic sensory processing16
have been described in the literature.
The vast majority of known mGlu receptors antago-
nists are amino acid derivatives and therefore interact
with the Glu binding site. These derivatives generally
show poor pharmacokinetic properties and are seen as
pharmacological tools rather than potential drugs.
The increasing use of recently available high-through-
put functional assays has allowed the identification of
ligands of the mGlu1 receptor with a novel mechanism
of action. During the past decade, several noncompetitive
mGlu1 antagonists have been described. These com-
pounds belong to highly diverse chemical classes having
high affinities at the mGlu1 receptor and very low affin-
ities at other metabotropic and ionotropic Glu receptors.
CPCCOEt (1, Figure 1) is a low affinity, selective,
noncompetitive antagonist interacting with the mGlu1
receptor transmembrane domain.17 The same type of
interaction has been shown for BAY 36-7620 (2), a
lactone derivative, which is an antagonist at the mGlu1
receptor18 (IC50 value of 160 nM). Thiazolo[3,2-a]benz-
imidazole-2-carboxamide19 derivatives represented by 3
have been reported as low nanomolar mGlu1 antago-
Glutamate (Glu) is the major excitatory neurotrans-
mitter in the mammalian central nervous system (CNS)
and plays an important role in a wide variety of CNS
functions. The actions of Glu are mediated through
membrane-bound Glu receptors.
Glu receptors are believed to exist as oligomers of
ionotropic Glu (iGlu) receptor subunits1 or as dimers of
metabotropic Glu (mGlu) receptors.2,3 Both receptor
types can be divided into several families based on
sequence identity and pharmacological, electrophysi-
ological, and biochemical characteristics. iGlu receptors
comprise N-methyl-D-aspartate (NMDA), R-amino-3-
hydroxy-5-methylisoxazole-4-propionate (AMPA), and
kainate (KA) receptors. Mammals express six NMDA
receptor subunits (NR1, NR2A-D, NR3A), four AMPA
receptor subunits (Glu1-4), and five KA receptor sub-
units (Glu5-7, KA1, KA2).4,5 mGlu receptors are G-
protein-coupled receptors characterized by a large ex-
tracellular amino-terminal domain that contains the
Glu binding site. There are at least eight subtypes of
mGlu (mGlu1-8) receptors, divided into three groups,6,7
based on sequence homology, signal transduction, and
pharmacology. Group I comprises mGlu1 and mGlu5,
group II receptors comprises mGlu2 and mGlu3, and
group III holds mGlu4, -6, -7, and -8.
The group I receptors are coupled to Gq/11, and acti-
vation of these receptors stimulates phospholipase C,
* To whom correspondence should be addressed. Telephone: +32
14 60 75 33. Fax: +32 14 60 53 44. E-mail: fbischof@prdbe.jnj.com.
† Department of Medicinal Chemistry, Janssen-Cilag France.
‡ Current address: PCAS, Boˆıte postale2, 61410 Couterne Cedex,
France.
§ Current address: SERIPHARM, rue Democrite, 72000 Le Mans,
France.
| CNS Discovery Research, Janssen Pharmaceutica N.V.
Department of Preclinical Pharmacokinetics, Janssen Pharma-
ceutica N.V.
∞ Department of Medicinal Chemistry, Janssen Pharmaceutica N.V.
10.1021/jm049499o CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/28/2005

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2135
an orally active mGlu1 antagonist. We present our
results in the end of this investigation.
Chemistry
We first investigated the effect of the substitution at
position 2 of the quinoline moiety in the lead compound
cis-10. Most of the compounds were prepared from a
common intermediate, the 2-chloroquinoline derivative
cis-17, for which the synthesis is described in Scheme
1. 4-Bromoaniline 13 was acylated and the resulting
anilide 14 was subjected to a Vilsmeier-Haack reaction
to give the quinoline 15. Selective lithium-bromo
exchange of 15 with butyllithium at low temperature
followed by the addition of the Weinreb amide cis/
trans-12, prepared from the commercially available
4-methoxycyclohexylcarboxylic acid cis/trans-11 (Scheme
1), afforded key intermediates cis-17 and trans-17. The
lead compound cis-10 was also prepared from 15.
Nucleophile substitution with sodium methoxide fol-
lowed by lithium-halogen exchange with butyllithium
and subsequent addition of cis/trans-12 afforded cis-
10 and its isomer trans-10. The intermediates cis-17
and trans-17 where submitted to a battery of experi-
mental conditions to deliver a large variety of com-
pounds. For instance, cis-17 was methylated under
Stille conditions using tetramethyl tin to give the
2-methylquinoline cis-18. Dehalogenation of cis-17 with
zinc in AcOH gave compound cis-19. Compounds cis-
17 and trans-17 were submitted to nucleophilic sub-
stitution at quite high temperature either with potas-
sium fluoride or methoxyethylamine to provide cis-20
and cis-26, respectively. Compound cis-17 was also a
suitable substrate for a Suzuki coupling and as such
was reacted with 3-thienyl boronic acid to give cis-21.
Other oxidative aryl-aryl couplings were performed
under Stille conditions with 2-tributylstannylthiazole
and 2-tributylstannylthiophene to provide cis-27 and
cis-28, respectively. Chloroquinoline cis-17 could be
converted to the more reactive iodo derivative cis-22 by
treatment with sodium iodide in the presence of acetyl
chloride.25 Subsequently, cis-22 was coupled with tri-
methylsilylcyanide26 to afford the cyano quinoline cis-
23. Carbon monoxide insertion on cis-17 in 2-propanol
gave the isopropyl ester cis-24. Compound cis-25 was
obtained by thermal condensation of trans-17 with
acetamide. Finally, acidic cleavage of methyl ether cis-
10 gave the quinolone cis-29.
The replacement of the 4-methoxycyclohexyl moiety
was explored using two methods, with either 2-chloro-
6-bromoquinoline 15 (method A) or 2-methyl-6-bromo-
quinoline 35 (method B) as intermediates (Scheme 2).
Compound 35 was obtained by the condensation of
4-bromoaniline with the â-chlorovinyl aldehyde 34 in
AcOH.27,28 Both compounds 15 and 35 could be lithiated
at position 6 on the quinoline ring by treatment with
butyllithium and reaction with an electrophile such as
a Weinreb amide or a nitrile to gain access to the
6-ylquinoline ketone derivatives of type 32 and 33f-h.
In method A, subsequent palladium-catalyzed methy-
lation of compounds 32 with tetramethyltin afforded the
expected 2-methyl-3-ethylquinolines derivatives 33a-
e,i. In method B, lithium-bromo exchange at position
6 of the quinoline ring 35 competed with proton ab-
straction on the methyl group at position 2, and yields
of the reaction were low. Structures of compounds 33
Figure 1. Structures of known noncompetitive mGlu1 an-
tagonists.
Figure 2. Hit compounds.
nists, whereas NPS-2390 (4), a quinoxaline derivative,20
showed noncompetitive antagonist activity on both
mGlu1 and mGlu5 receptors. Azepinyl derivatives21
such as 5 had a functional IC50 value in the low nano-
molar range. Other types of chemical entities such as
oxazine derivatives22 6 or the 4-amino-5,6,7,8-tetrahy-
droquinazoline derivative23 7 have also been claimed as
mGlu1 noncompetitive antagonists. Finally, PPP-1 (8)
has been described as a potent and selective noncom-
petitive mGlu1 antagonist endowed with excellent in
vitro activity24 and showing a clear “opiate-like” anti-
nociceptive profile in different animal models of pain.
We now report on the identification of a novel class
of selective and highly potent noncompetitive mGlu1
antagonists. These compounds belong to a family of
quinoline derivatives. Primary screening of our com-
pound library has been executed as a cell-based signal
transduction assay on the rat mGlu1 receptor expressed
in CHO-K1 cells. Compound 9 (Figure 2) was first
identified as a weak (IC50 ) 5000 nM) mGlu1 receptor
antagonist. Chemical modifications were made around
the structure of 9 without gain of activity. In the
meantime, analogues of 9 were searched and compound
cis-10 was detected with a substantially improved
activity (IC50 ) 20 nM).
cis-10 was devoid of any activity on rat mGlu5 up to
10 µM and on human mGlu2 up to 100 µM, as measured
in signal transduction assays, and on NMDA ([3H]MK801
and [3H]L-689,560 binding) and AMPA ([3H]AMPA
binding) receptors up to 10 µM, as measured in radio-
ligand binding on a membrane fraction derived from rat
forebrain.
These results prompted us to further investigate the
structure activity relationship (SAR) within this new
chemical series with the aim of improving the primary
activity on the mGlu1 receptor and the metabolic
stability of the compounds and eventually developing

2136 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Mabire et al.
Scheme 1. Synthesis of 4-Methoxycyclohexylcarbonylquinolines: Variation at the 2-Positiona
a Reagents and reaction conditions: (a) CDI, H3CNHOCH3·HCl, CH2Cl2, rt (99%); (b) CH3(CH2)2COCl, Et3N, CH2Cl2, rt (100%); (c)
POCl3, DMF, 80 °C (73%); (d) NaOMe, MeOH, reflux (74%); (e) n-BuLi, THF, -78 °C, cis/trans-12, -78 to 0 °C (cis-10 38%, trans-10
28%); (f) n-BuLi, THF, -70 °C, cis/trans-12, -78 to -20 °C (cis-17 29%, trans-17 3%); (g) SnMe4, Pd(PPh3)4, toluene, reflux (cis-18,
56% from cis-17; trans-18, 25% from trans-17); (h) from cis-17, Zn, AcOH, 60 °C (28%); (i) from cis-17, KF, DMSO, 140 °C (11%); (j)
from cis-17, 3-thienylboronic acid, Pd(PPh3)4, dioxane, reflux (68%); (k) from cis-17, AcCl, NaI, CH3CN, reflux (18%); (l) (CH3)3SiCN,
Pd(PPh3)4, Et3N (15%); (m) from cis-17, i-PrOH, Pd(OAc)2, PPh3, K2CO3, DMF, CO (5 bar), 90 °C (6%); (n) from trans-17, CH3CONH2,
K2CO3, 200 °C (4%); (o) from trans-17, NH2(CH2)2OCH3, K2CO3, DMF, 140 °C (17%); (p) from cis-17, 2-tributylstannylthiazole, Pd(PPh3)4,
dioxane, 80 °C (21%); (q) from cis-17, 2-tributylstannylthiophene, Pd(PPh3)4, dioxane, 80 °C (61%); (r) from cis-10, HCl 3N, THF, reflux
(52%).
are shown in Table 1. An additional modification of this
part of the molecule was obtained when compound cis-
18 was subjected to cleavage of the methyl ether with
48% HBr to give the corresponding hydroxy derivative
cis-36 with a low yield. (Scheme 2)
reaction with furan derivatives to provide 52 and 53,33
respectively.
Scheme 4 illustrates some of the experiments per-
formed in order to explore the replacement of the keto
function at position 6 of the quinoline derivatives. Con-
densation of cis-10 with hydroxylamine gave the oximes
cis-54 and cis-55, whereas condensation with hydrazine
afforded the hydrazone cis-56. Finally, cis-10 was
subjected to a Wittig reaction to give alkene cis-57.
Modification of the quinoline ring was also investi-
gated (Scheme 5). Vilsmeier-Haack reaction on amide
5834,35 afforded compound 59 which, under acidic hy-
drolysis, gave a mixture of 60a and 61. Condensation
of 59 with benzylamine at high temperature led to a
mixture of 60b and 62. Alternatively, 2-amino-5-bromo-
benzaldehyde 6336 was subjected to Friedla¨nder reac-
tion,36,37 under either basic or acidic conditions, to
provide bromoquinoline derivatives 60c-e. Treatment
of bromoquinolines 60a-f with butyllithium followed
by the addition of the resulting aryllithium salt on the
Weinreb amide cis/trans-12 afforded cis/trans-64a-f
(Table 2). Starting from the bromoanilide derivative
Other 2-methyl-3-ethylquinolines were prepared as
described in Scheme 3. 1-(4-Aminophenyl)-2-phenyle-
thanone 3729 was condensed with 3-chloro-2-ethyl-2-
butenal 3430 to afford quinoline 38. The quinoline 16
was treated with butyllithium and the resulting lithium
salt reacted with Weinreb amide 3931 to give 40. Acidic
cleavage of the methyl ether followed by chlorination
with phosphoroxychloride and methylation gave com-
pound 43. Treatment of 15 with butyllithium led to the
corresponding organometallic reagent that was reacted
either with isoamylaldehyde 44 or with Weinreb amide
4832 to give the secondary alcohol (()45 and the ketone
49, respectively. The alcohol (()45 was oxidized with
potassium permanganate to afford 46, which was me-
thylated to produce 47, whereas 49 was first methylated
before its deprotection under acidic conditions to give
51. Finally, 35 underwent both a Suzuki and a Stille

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2137
Scheme 2. Replacement of the 4-Methoxycyclohexyl Moietya
a Reagents and reaction conditions: (a) CDI, H3CNHOCH3·HCl, CH2Cl2, rt; (b) n-BuLi, THF, -70 °C; (c) SnMe4, Pd(PPh3)4, toluene,
reflux; (d) CH3COOH, reflux (54%); (e) n-BuLi, THF, -78 °C up to -20 °C; (f) 48% HBr, 60 °C, (5%).
65,39 compound cis-68 was prepared by a sequence of
reactions similar to the one used for cis-18. The 2-chlo-
roquinoline cis-17 was also reacted with sodium azide
to give tetrazole cis-69.
in CHO-K1 cells. To investigate the SAR within this new
chemical series, all compounds were tested for their
ability to antagonize the activation of the rat mGlu1
receptor. Most of the active compounds were also tested
on the human mGlu1 receptor and for their in vitro
metabolic stability in human liver microsomes. IC50
values indicating the potency at which the compounds
antagonize activation of the rat and human mGlu1
receptors are shown in Tables 3-7. Metabolic stability
in human liver microsomes is expressed as a percentage
of the parent compound metabolized compared to the
control incubation.
We first investigated the effect of the substitution at
position 2 of the quinoline moiety in the lead compound
cis-10. Our strategy to prepare such compounds was
based on the extensive use of compound cis-17, a
2-chloroquinoline derivative, as intermediate that was
subjected to various reaction conditions. In vitro activity
and metabolic stability of these compounds are reported
in Table 3. From this study it was apparent that the
introduction of small lipophilic substituents such as Cl,
Me, and F (cis-17, cis-18, cis-20) gave highly potent
antagonists. At this position, small hydrophilic substit-
uents such as NH2 and OH (cis-25, cis-29) also gave
potent antagonists, suggesting a possible interaction
with the receptor through a hydrogen bond. Unfortu-
nately, the quinolone derivatives were suffering from
very poor aqueous solubility (data not shown) and were
not considered as potential candidates for further
investigation. The good activity of compound cis-26,
substituted with a methoxy ethylamine, suggested that
Various aryl alkyl ketones derivatives were synthe-
sized as outlined in Scheme 6. Lithium-bromo exchange
on compound 60a followed by the addition on the
Weinreb amides 71 and 31c gave the quinoline deriva-
tives 72a and 72b, respectively, with low to moderate
yields. The carboxylic acid 73 was prepared from 60a,
esterified, and condensed with benzylmagnesium chlo-
ride to afford 72c in high yield. 3-Bromoaniline 75 was
acylated to give 76, which was subjected to Vilsmeier-
Haack conditions to afford a mixture of isomers 77 and
78. Hydrolysis of the mixture afforded the quinolones
79 and 80. Their cyclization in the presence of poly-
phosphoric acid produced the quinoline 81 and 82. After
separation, 81 was treated with butyllithium and N-
methoxy-N-methylphenylacetamide to afford 83.
A series of 4-methylcyclohexyl keto derivatives was
also prepared as exemplified in Scheme 7. Standard
conditions afforded the Weinreb amide cis/trans-85
from a cis/trans mixture of commercially available
4-methylcyclohexylcarboxylic acid. Addition of the lithium
salts prepared from 60a and 60c afforded, after separa-
tion, compounds cis-86 and cis-87, respectively.
Discussion
Compound cis-10, a quinoline derivative, has been
identified as a potent antagonist by means of a cell-
based signal transduction assay on rat mGlu1 receptor

2138 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Mabire et al.
Table 1. Method of Preparation of Diverse
2-Methyl-3-ethylquinoline Derivatives According to Scheme 2
conditions (Table 3). For this particular compound, the
major metabolic pathways were O-demethylation of the
methoxy group on the quinoline moiety, oxidation at the
quinoline ring, and a combination of O-demethylation
of the methoxy group on the cyclohexyl ring with
oxidation at the quinoline. Carbonyl reduction combined
with O-demethylation were minor metabolic pathways.
The replacement of the cyclohexyl moiety was then
investigated while the 2-methyl-3-ethylquinoline re-
mained unchanged (Table 4). Our strategy was to
explore the effect of various bulky/lipophilic substituents
as well as the potential role of a heteroatom (N or O)
that could act as hydrogen-bond acceptor. The high
potency of compounds (()33d and 38 and the decrease
of activity of compound 47 confirmed the need for a
bulky lipophilic group at this position. Indanyl substitu-
tion ((()33i) gave a potent antagonist, while phenethyl
substitution (33c) was less tolerated. Both compounds
were less active on human mGlu1 receptor. Introduction
of an oxygen atom between the carbonyl function and
the aromatic ring ((()33a and (()33b) was also toler-
ated, whereas, in the benzyl series, the mono- and
dimethoxy substitutions (33f and 33g, respectively) as
well as substitution with a weak basic nitrogen (33h)
lowered the activity. Apparently, the presence of a
heteroatom, which could act as a hydrogen-bond accep-
tor, in this particular lipophilic area of the receptor was
not always well-tolerated either for electronic or steric
effects. The presence of a free hydroxy group (cis-36)
was well-accepted, whereas the introduction of a basic
nitrogen (51) led to an inactive compound. A steric effect
due to the tert-butoxycarbonyl protecting group could
probably explain the lack of activity of compound 50.
These results, in agreement with literature data,24
suggest that the region where these derivatives bind in
the receptor might be rich in lipophilic residues, which
often tolerate hydrogen-bond acceptors but tend to repel
protonated/charged basic groups. All these compounds
except the norbornyl derivative (()33d were metaboli-
cally unstable in vitro.
Data in Table 5 show that the replacement of the
oxygen atom of the keto function by an isostere (CH2)
only gave a weakly active compound (cis-57). These
results suggested that the oxygen atom of the keto
function probably plays an important role as hydrogen-
bond acceptor. Oxime cis-54 and cis-55 derivatives were
inactive and hydrazone cis-56 was weakly active.
Compounds 52 and 53 (not shown in the table), where
the position 6 on the quinoline was directly substituted
by a benzofuran and a phenylfuran, respectively, were
both inactive on the rat mGlu1 receptor.
The quinoline ring itself was also modified, and data
are shown in Table 6. 2,3-Annulated quinoline deriva-
tives were highly potent on the human receptor. For
instance, compounds cis-64a and cis-64d had subna-
nomolar potency. The presence of a heteroatom atom
directly attached to the quinoline ring (cis-64a, cis-64b,
cis-64f) was tolerated as well as cyclic or acyclic alkyl
chains (cis-64c, cis-64d, cis-64e, cis-68). In this par-
ticular cyclohexyl series, we prepared 4-methylcyclo-
hexyl derivatives, as exemplified by cis-86 and cis-87,
to avoid the metabolic demethylation of the methoxy
group at the 4-position of the cyclohexyl ring. Both
compounds retained a potency on the human mGlu1
the introduction of a hydrogen-bond acceptor at that
position was still tolerated. The introduction of more
bulky substituents, such as heteroaryl rings (cis-21, cis-
27, cis-28), typically induced a loss of activity. The iso-
propyl ester derivative cis-24 was also only weakly ac-
tive and it can be pointed out that, for cis-24, cis-27,
and cis-28, the presence of at least one heteroatom in
the â position relative to the quinoline ring was detrimen-
tal to the activity. This was not the case for 23, a nitrile
derivative that remained active and for which the â
nitrogen was differently oriented. These trends were ob-
served to a large extent for both the rat and the human
mGlu1 receptors. It was also remarkable to note that
the activity resided in the compounds having a cis con-
figuration on the cyclohexyl ring, the trans derivatives
being less active or inactive (for instance cis-10 versus
trans-10). The measurement of the metabolic stability
in human liver microsomes showed that the compounds
were generally not stable. The hit compound cis-10
remained one of the most stable as only 32% of the
parent compound was metabolized under experimental

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2139
Scheme 3. Synthesis of 2-Methyl-3-ethylquinoline Derivativesa
a Reagents and reaction conditions: (a) CH3COOH, reflux (39%); (b) n-BuLi, THF, -78 °C (44%); (c) 3 N HCl, THF, reflux (71%); (d)
POCl3, reflux (63%); (e) (CH3)4Sn, Pd(PPh3)4, toluene, reflux (42%); (f) n-BuLi, THF, -70 °C (67%); (g) KMnO4, TDA1, CH2Cl2, rt (33%);
(h) n-BuLi, THF, -70 °C (26%); (i) 3 N HCl, THF, 60 °C (46%); (h) n-BuLi, THF, -70 °C (26%); (i) 3 N HCl, THF, 60 °C (46%); (j)
benzofuran-2-boronic acid, Pd(PPh3)4, dioxane, Na2CO3, 2,6-di-tert-butyl-4-methylphenol, reflux, (7%); (k) tributyl-(5-phenyl)furan-2-
yl)stannane, Pd(PPh3)4, dioxane, LiCl, reflux (31%).
Scheme 4. Replacement of the Keto Group in cis-10a
a Reagents and reaction conditions: (a) NH2OH·HCl, Et3N, EtOH, reflux (38%, 36%); (b) NH2NH2, EtOH, reflux (15%); (c) Ph3P+CH3,Br-,
THF, NaH 60%, rt (34%).
receptor similar to that of their 4-methoxycyclohexyl
analogues cis-64a and cis-64c, respectively. However,
if the in vitro metabolic stability of cis-87 was substan-
tially improved when compared to cis-64c, this was not
the case for cis-86 versus cis-64a (Table 6).
Several aryl alkyl ketones were also prepared (Table
7), and most of them were potent on the human mGlu1
receptor when the substitution took place at position 6
of the quinoline ring. The same substitution at position
7 of the quinoline gave inactive compounds, as shown
with 83. This result reinforced the idea that the oxygen
atom of the keto function has to point to the right
direction in order to interact with the receptor, probably
through a hydrogen bond. The major drawback within
this particular series of arylalkyl ketone derivatives was
the extremely high rate of in vitro metabolism.

2140 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Scheme 5. Synthesis of Modified Quinoline Ringsa
Mabire et al.
a Reagents and reaction conditions: (a) POCl3, DMF, 75 °C (78%); (b) 12 N HCl, H2O (28%); (c) Bn-NH2, DMF, 160 °C (37%); (d)
cycloheptanone, EtOH, NaOH, (56%); (e) cyclopentanone, EtOH, KOH, 60 °C (63%); (f) 2-pentanone, pyrrolidine, H2SO4, EtOH, rt (56%);
(g) n-BuLi, THF, -78 to 0 °C (for yields, see Table 2); (h) POCl3, DMF, rt (86%); (i) n-BuLi, THF, cis/trans-12, -78 to 0 °C (8%); (j)
(CH3)4Sn, Pd(PPh3)4, toluene, reflux (23%); (k) NaN3, DMF, 140 °C (33%).
We already reported41 the synthesis of the radiola-
beled [3H]-72c ([3H]R214127), where our study sup-
ported the notion that CPCCOEt, BAY 36-7620, and 72c
act on a site different from the Glu binding pocket and
that they presumably competed for the same trans-
membrane segment VII. To ascertain the antagonistic
mechanism of action of cis-64a, our most potent com-
pound, concentration-response curves for glutamate-
induced Ca2+ mobilization in rat mGlu1a receptor-
expressing CHO-dhfr- cells were generated in the
presence of cis-64a. The results of this Schild analysis
have been reported recently42 and showed unambigu-
ously that cis-64a blocks mGlu1 receptor-mediated
signaling in a noncompetitive fashion.
We have also reported that, following subcutaneous
administration in rat, cis-64a rapidly crossed the
blood-brain barrier and occupied central mGlu1 recep-
tors at very low doses.42 Preliminary studies were per-
formed in order to determine the plasma kinetics and
absolute bioavailability of cis-64a in the rat. After a
single intravenous administration at 2.5 mg/kg, cis-64a
had a short half-life (t1/2 ) 0.32 h) and a high total plas-
ma clearance (CL ) 5.5 l/h/kg). After a single oral dose
of 10 mg/kg, very low plasma concentrations were ob-
served. An oral bioavailability of less than 1% could be
estimated for cis-64a. This can be due to bad absorption
and/or extensive first-pass metabolism, and further stud-
ies have to be carried out to elucidate this issue. Never-
theless, in vivo experiments were performed and cis-
64a has been found to be effective in the lick suppres-
sion test, an animal model of anxiety,43 and to reduce
pain behavior in the formalin model of hyperalgesia.44
Conclusion
We have discovered a new series of quinoline deriva-
tives acting as selective noncompetitive mGlu1 antago-
nists, and at least one of those compounds, cis-64a, had
sub-nanomolar in vitro antagonist potency on the hu-
man mGlu1 receptor and was centrally active. In view
of the various effects elicited by the mGlu1 receptor and

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2141
Scheme 6. Synthesis of Arylalkyl Ketone Derivativesa
a Reagents and reaction conditions: (a) CDI, H3CNHOCH3·HCl, Et3N, CH2Cl2, rt (89%); (b) 2.5 N BuLi, THF, -78 °C, 71 or 31c, -78
to -20 °C (6% from 71, 38% from 31c); (c) 2.5 N BuLi, THF, -78 °C, CO2 (solid), -78 °C to room temperature (35%); (d) CH3OH, H2SO4,
80 °C (30%); (e) PhCH2MgCl, THF, rt (100%); (f) ClCO(CH2)4Cl, Et3N, CH2Cl2, 5 °C (100%); (g) POCl3, DMF, 5-75 °C (91%, two isomers);
(h) 6 N HCl, THF, reflux (84%, two isomers), (i) PPA, 160 °C; (81, 39%; 82, 9%); (j) n-BuLi, THF, -78 °C, PhCH2NCH3OCH3, -78 to 0
°C (35%).
Table 2. Yields of Step g According to Scheme 5a
Experimental Section
Chemistry. Progress of the reactions was monitored by
TLC-plates (Merck type 60 F254). Melting points were mea-
sured on a Leica VMHB System Kofler and are not corrected.
All reagents and solvents were used as purchased from
commercial sources (Sigma-Aldrich Co., Fluka Chemie AG,
Lancaster Synthesis GmbH, Acros Organics). Moisture-sensi-
tive reactions were carried out under a nitrogen atmosphere.
Proton NMR spectra were recorded on a Bruker Avance 300
(300 MHz) and a Bruker Avance 400 (400 MHz) spectrometers
using internal deuterium lock. Chemicals shifts are reported
in reference to internal DMSO (δ 2.54) or CHCl3 (δ 7.26) in
parts per million (ppm, δ) and coupling constants (J) in hertz
(Hz). Elemental analyses were determined with a Thermo
Electron Corporation instruments EA 1110 or EA 1108 and
were within (0.4% unless otherwise stated.
Note: In many cases, the last step leading to the 4-meth-
oxycyclohexyl end products afforded a mixture of cis and trans
isomers, even if it started from a pure adduct (as from cis-17
for instance). The isomers were separated by column chroma-
tography. The yields reported under the synthetic schemes
a Cis product isolated.
referred exclusively to the isolated cis isomer unless otherwise
specified. In the Experimental Section only the analytical data
for the cis isomers are given unless otherwise specified.
the widespread distribution of the receptor in the CNS,
N,4-Dimethoxy-N-cis/trans-methylcyclohexanecarbox-
we believe that cis-64a may lead to important progress
amide (cis/trans-12). CDI (12 g, 0.074 mol) was added por-
in elucidating the function of the mGlu1 receptor in
tionwise to cis/trans-11 (10 g, 0.063 mol) in CH2Cl2 (200 mL).
physiological and pathological states of the CNS and
hence to new therapeutic strategies involving the mGlu1
receptor.
The mixture was stirred at room temperature for 1 h. Then
N,O-dimethylhydroxylamine hydrochloride (6.8 g, 0.074 mol)
was added. The mixture was stirred at room temperature over-

2142 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Mabire et al.
Scheme 7a
a Reagents and reaction conditions: (a) CDI, H3CNHOCH3·HCl, CH2Cl2 (100%); (b) 60a, BuLi, THF, -78 to 0 °C (22%); (c) 60c, BuLi,
THF, -78 to 0 °C (16%).
Table 3. In Vitro Activity and Metabolic Stability of Diverse 2-Substituted Quinolines
signal transduction IC50 (nM)
compd
R
rmGlu1a
hmGlu1b
met. stab.c
cis-10
trans-10
cis-17
trans-17
cis-18
trans-18
cis-19
cis-20
cis-21
cis-22
cis-23
cis-24
cis-25
cis-26
cis-27
cis-28
cis-29
OMe
OMe
Cl
19
2370
5
145
3
65
4
4
832
13
11
3428
7
78
>10000
3311
15
94
nd
4
nd
8
nd
nd
9
191
162
174
6310
1
43 (32d)
nd
48d
nd
Cl
Me
Me
H
92
90
85
F
75
3-thienyl
I
nd
73
CN
CO2iPr
NH2
NHCH2CH2OMe
2-thiazoyl
2-thienyl
OH
71
nd
68
105
nd
nd
85
35
nd
nd
60
a Rat mGlu1. b Human mGlu1; IC50 values are the mean of two or three independent experiments performed on both rat and human
mGlu1 receptors. c In vitro metabolic stability expressed as a percentage of converted parent compound (30 µM) after 30 min. d Metabolic
stability expressed as a percentage of converted parent compound (5 µM) after 5 min.
night, poured out into H2O, and extracted with CH2Cl2. The
organic layer was separated, washed several times with H2O,
dried (MgSO4), and filtered, and the solvent was evaporated
to afford cis/trans-12 as a colorless oil (12.6 g, 99%): 1H NMR
(CDCl3) δ 1.10-1.60 (4H, m), 1.80-2.20 (4H, m), 2.6-2.8 (1H,
m), 3.18 (3H, s), 3.18-3.37(1H, m), 3.31 (3H, s), 3.75 (3H, s).
N-(4-Bromophenyl)butanamide (14). A mixture of 4-bro-
moaniline (100 g, 0.58 mol) and Et3N (88 g, 0.87 mol) in CH2-
Cl2 (800 mL) was stirred at 5 °C. A mixture of butyryl chloride
(60.7 mL, 0.58 mol) in CH2Cl2 (400 mL) was slowly added
dropwise and then the reaction mixture was allowed to reach
room temperature and was stirred overnight at room temper-
ature. H2O was added, the separated organic layer was dried,
and finally the solvent was evaporated. The residue was
triturated in petroleum ether and filtered off to afford 14 as a
white solid (140 g, 100%): mp 126 °C; 1H NMR (CDCl3) δ 0.98
(3H, t, J ) 7.3 Hz), 1.74 (2H, s, J ) 7.3 Hz), 2.82 (2H, t, J )
7.3 Hz), 7.40 (4H, m), 7.59 (1H, br s). Anal. (C10H12BrNO) C,
H, N
6-Bromo-2-chloro-3-ethylquinoline (15). POCl3 (190 mL,
2.03 mol) was stirred at 10 °C under N2, and DMF (65 mL,
0.87 mol) was added dropwise (exothermic reaction). The
mixture was allowed to reach room temperature, 14 (140 g,
0.58 mol) was slowly added (exothermic reaction), and then
the reaction mixture was stirred for 4 h at 85 °C. The mixture
was cooled to room temperature and poured out carefully into
ice H2O. The resulting solids were filtered off, washed with
H2O, and dried to afford 15 (115 g, 73%): mp 106 °C; 1H NMR
(CDCl3) δ 1.38 (3 H, t, J ) 7.50 Hz), 2.93 (2H, q, J ) 7.5 Hz),
7.75 (1H, dd, J ) 2.1, 8.8 Hz), 7.87-7.89 (2H, m), 7.96 (1H, d,
J ) 2.1 Hz). Anal. (C11H9BrClN) C, H, N.
6-Bromo-3-ethyl-2-methoxyquinoline (16). A mixture of
15 (44 g, 0.162 mol) in NaOCH3 (154 mL, 0.812 mol) and
MeOH (600 mL) was stirred and refluxed overnight. The
mixture was poured out on ice. The precipitate was filtered
off, washed with a small amount of H2O, and taken up in CH2-
Cl2. The organic phase was washed with a 10% aqueous
solution of K2CO3. The organic layer was separated, washed
with H2O, dried (MgSO4), and filtered, and the solvent was
evaporated to afford 16 (31.9 g, 74%) as a white solid: mp 70
°C; 1H NMR (CDCl3) δ 1.27 (3H, t, J ) 7.3 Hz), 2.72 (2H, q, J
) 7.3 Hz), 4.08 (3H, s), 7.61 (1H, dd, J ) 8.8, 2.2 Hz), 7.65
(1H, s), 7.69 (1H, d, J ) 8.8 Hz), 7.81 (1H, d, J ) 2.2 Hz).
Anal. (C12H12BrNO) C, H, N
3-Ethyl-2-methoxyquinolin-6-yl cis-4-Methoxycyclo-
hexyl Ketone (cis-10) and 3-Ethyl-2-methoxyquinolin-6-
yl trans-4-Methoxycyclohexyl Ketone (trans-10). n-BuLi
(1.6 M) in hexane (69 mL, 0.107 mol) was added dropwise at
-78 °C under N2 flow to a solution of 16 (23.7 g, 0.089 mol) in
THF (150 mL). The mixture was stirred at -78 °C for 1 h. A
solution of cis/trans-12 (17.9 g, 0.089 mol) in THF (150 mL)
was added at -78 °C under N2 flow. The mixture was stirred
at -78 °C for 2 h, brought to 0 °C, poured out into H2O, and
extracted with EtOAc. The organic layer was separated, dried
(MgSO4), and filtered, and the solvent was evaporated. The
residue (31 g) was purified by column chromatography over
silica gel (eluent: cyclohexane/EtOAc 85/15; 20-45 µm). Two
pure fractions were collected and their solvents were evapo-
rated to afford cis-10 (11 g, 38%) and trans-10 (8.2 g, 28%).
cis-10: mp 116 °C; 1H NMR (CDCl3) δ 1.32 (3H, t, J ) 7.5
Hz), 1.60-1.80 (4H, m), 1.89-2.10 (4H, m), 2.76 (2H, q, J )
7.5 Hz), 3.35 (3H, s), 3.36-3.48 (1H, m), 3.5-3.56 (1H, m),

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2143
Table 4. In Vitro Activity and Metabolic Stability of Diverse
2-Methyl-3-ethyl Quinolines Derivatives
a solution of 15 (5 g, 0.018 mol) in THF (50 mL). The mixture
was stirred at -70 °C for 1 h, brought to -40 °C, and then
cooled to -70 °C. A solution of 12 (3.7 g, 0.018 mol) in THF
(40 mL) was added slowly. The mixture was stirred at -70 °C
for 1 h, brought to -20 °C, hydrolyzed with H2O, and extracted
with EtOAc. The organic layer was separated, dried (MgSO4),
and filtered, and the solvent was evaporated. The residue (6.5
g) was purified by column chromatography over silica gel
(eluent: toluene/EtOAc 90/10; 15-40 µm). Two fractions were
collected and the solvent was evaporated. Fraction 1 (2.4 g)
was precipitated from diethyl ether. The precipitate was
filtered off and dried to afford cis-17 (1.8 g, 29%): mp 123 °C;
1H NMR (CDCl3) δ 1.41 (3H, t, J ) 7.5 Hz), 1.50-1.8 (4H, m),
1.90-2.10 (4H, m), 2.96 (2H, q, J ) 7.5 Hz), 3.35 (3H, s), 3.35-
3.50 (1H, m), 3.50-3.60 (1H, m), 8.05-8.11 (2H, m), 8.19-
8.22 (1H, dd, J ) 2.1, 8.8 Hz), 8.40 (1H, d, J ) 2.1 Hz). Anal.
(C19H22ClNO2) C, H, N. Fraction 2 (0.9 g) was precipitated from
diethyl ether. The precipitate was filtered off and dried to
1
afford trans-17 (0.2 g, 3%): mp 120 °C; H NMR (CDCl3) δ
1.47 1.41 (3H, t, J ) 7.5 Hz), 1.55-1.70 (4H, m), 2.00-2.29
(4H, m), 2.96 (2H, q, J ) 7.5 Hz), 3,15-3.45 (5H, m), 8.02-
8.12 (2H, m), 8.22 (1H, dd, J ) 1.7, 8.8 Hz), 8.41 (1H, d, J )
1.7 Hz). Anal. (C19H22ClNO2) C, H, N.
3-Ethyl-2-methylquinolin-6-yl cis-4-Methoxycyclohex-
yl Ketone (cis-18). A mixture of cis-17 (5 g, 0.015 mol),
tetramethyltin (4.2 mL, 0.03 mol), and tetrakis(triphenylphos-
phine)palladium(0) (1.7 g, 0.002 mol) in toluene (50 mL) was
stirred and refluxed for 48 h. A 10% aqueous solution of K2-
CO3 was added and the mixture was extracted with EtOAc.
The organic layer was separated, dried (MgSO4), and filtered,
and the solvent was evaporated. The residue (6.6 g) was
purified by column chromatography over silica gel (eluent:
cyclohexane/EtOAc 75/25; 15-40 µm). Different fractions were
collected and the solvent was evaporated. The residue (3.4 g,
72%) was precipitated from diethyl ether to afford cis-18 (2.63
1
g, 56%): mp 112 °C; H NMR (CDCl3) δ 1.39 (3H, t, J ) 7.5
Hz), 1.55-1.80 (4H, m), 1.90-2.10 (4H, m), 2.77 (3H, s), 2.86
(2H, q, J ) 7.5 Hz), 3.35 (3H, s), 3.35-3.50 (1H, m), 3.50-
3.55 (1H, m), 7.98 (1H, s), 8.03-8.06 (1H, d, J ) 8.8 Hz), 8.10-
8.19 (1H, dd, J ) 2.1, 8.8 Hz), 8.38 (1H, d, J ) 2.1 Hz). Anal.
(C20H25NO2) C, H, N.
3-Ethyl-2-methylquinolin-6-yl trans-4-Methoxycyclo-
hexyl Ketone (trans-18). A mixture of trans-17 (0.5 g, 1.502
mol), tetramethyltin (0.42 mL, 3.004 mol), and tetrakis-
(triphenylphosphine)palladium(0) (0.17 g, 0.151 mol) in toluene
(5 mL) was stirred and refluxed for 8 h. H2O was added. The
mixture was extracted with EtOAc. The organic layer was sep-
arated, dried (MgSO4), and filtered, and the solvent was evap-
orated. The residue (0.65 g) was purified by column chroma-
tography over silica gel (eluent: cyclohexane/EtOAc 70/30; 15-
40 µm). Different fractions were collected, and the solvent was
evaporated. The residue was precipitated from petroleum ether
to afford trans-18 (0.12 g, 25%). 1H NMR (CDCl3) δ 1.39 (3H,
t, J ) 7.5 Hz), 1.56-1.71 (4H, m), 2.00-2.30 (4H, m), 2.77 (3H,
s), 2.86 (2H, q, J ) 7.5 Hz), 3.18-3.48 (5H, m), 8.00 (1H, s),
8.06 (1H, d, J ) 8.8 Hz), 8.16 (1H, dd, J ) 1.8, 8.8 Hz), 8.39
(1H, J ) 1.8 Hz). Anal. (C20H25NO2) C, H, N.
3-Ethylquinolin-6-yl cis-4-Methoxycyclohexyl Ketone
(cis-19). A mixture of cis-17 (10 g, 0.03 mol) and Zn (5.92 g,
0.09 mol) in AcOH (100 mL) was stirred at 60 °C for 4 h,
filtered over Celite, and washed with CH2Cl2. The solvent was
evaporated. The residue was taken up in CH2Cl2 and washed
with a 10% aqueous solution of K2CO3. The organic layer was
separated, dried (MgSO4), and filtered, and the solvent was
evaporated. The residue (15.5 g) was purified by column
chromatography over silica gel (eluent: cyclohexane/EtOAc 80/
20; 15-35 µm). The pure fractions were collected and the
solvent was evaporated. (3.4 g, 38%). The residue was pre-
cipitated from petroleum ether to afford cis-19 (2.47 g, 28%):
a Rat mGlu1. b Human mGlu1; IC50 values are the mean of two
or three independent experiments performed on both rat and
human mGlu1 receptors. c In vitro metabolic stability expressed
as a percentage of converted parent compound (30 µM) after 30
min.
4.14 (3H, s), 7.85-7.88 (2H, m), 8.11 (1H, dd, J ) 8.8, 1.9 Hz),
8.32 (1H, d, J ) 1.92 Hz). Anal. (C20H25NO3) C, H, N. trans-
1
10: mp 91 °C; H NMR (CDCl3) δ 1.25-1.77 (7H, m), 1.98-
2.32 (4H, m), 2.76 (2H, q, J ) 7.5 Hz), 3.15-3.48 (5H, m), 4.15
(3H, s), 7.82-7.92 (2H, m), 8.15 (1H, dd, J ) 1.9, 6.7 Hz), 8.34
(1H, d, J ) 1.9 Hz). Anal. (C20H25NO3) C, H, N.
1
mp 80 °C; H NMR (CDCl3) δ 1.39 (3H, t, J ) 7.5 Hz), 1.57-
2-Chloro-3-ethylquinolin-6-yl cis-4-Methoxycyclohexyl
Ketone (cis-17) and 2-Chloro-3-ethylquinolin-6-yl trans-
4-Methoxycyclohexyl Ketone (trans-17). n-BuLi (1.6 M)
in hexane (13.9 mL, 0.022 mol) was added slowly at -70 °C to
1.78 (4H, m), 2.89 (2H, q, J ) 7.5 Hz), 1.91-2.10 (4H, m), 3.34
(3H, s), 3.40-3.49 (1H, m), 3.50-3.56 (1H, m), 8.05 (1H, s),
8.11-8.23 (2H, m), 8.40 (1H, s), 8.89 (1H, s). Anal. (C19H23-
NO2) C, H, N.

2144 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Mabire et al.
Table 5. In Vitro Activity and Metabolic Stability of Non-Keto Derivatives
signal transduction IC50 (nM)
rmGlu1a hmGlu1b
compd
X
met. stab.c
cis-10
cis-54
cis-55
cis-56
cis-57
O
19
94
32
nd
nd
nd
nd
NOH
NOH
NNH2
CH2
>10000
5011
320
nd
nd
4360
nd
2630
a Rat mGlu1. b Human mGlu1; IC50 values are the mean of two or three independent experiments performed on both rat and human
mGlu1 receptors. c In vitro metabolic stability expressed as a percentage of converted parent compound (5 µM) after 15 min.
3-Ethyl-2-fluoroquinolin-6-yl cis-4-Methoxycyclohexyl
Ketone (cis-20). A mixture of cis-17 (2 g, 0.006 mol) and KF
(1.4 g, 0.0241 mol) in DMSO (20 mL) was stirred at 140 °C for
4 h. The solvent was evaporated to dryness. The residue was
solidified in H2O and diethyl ether. The mixture was extracted
with diethyl ether. The organic layer was separated, washed
with H2O and with a saturated solution of NaCl, dried
(MgSO4), filtered, and concentrated in a vacuum. The residue
(1.7 g) was purified by column chromatography over silica gel
(eluent: cyclohexane/EtOAc 85/15; 15-40 µm). Fractions were
collected, and the solvent was evaporated. The residue was
precipitated from petroleum ether to afford cis-20 (0.21 g,
(7 g) was purified by column chromatography over silica gel
(eluent: cyclohexane/EtOAc 75/25; 15-40 µm). Fractions were
collected, and the solvent was evaporated. The residue was
precipitated from diethyl ether/petroleum ether to afford cis-
1
23 (0.75 g, 15%): mp 137 °C; H NMR (CDCl3) δ 1.47 (3H, t,
J ) 7.5 Hz), 1.54-1.80 (4H, m), 1.90-2.11 (4H, m), 3.12 (2H,
q, J ) 7.5 Hz), 3.35 (3H, s), 3.36-3.45 (1H, m), 3.47-3.57 (1H,
m), 8.17-8.26 (3H, m), 8.43 (1H, d, J ) 1.5 Hz). Anal.
(C20H22N2O2) C, H, N.
Isopropyl 3-Ethyl-6-[(cis-4-methoxycyclohexyl)carbo-
nyl]quinoline-2-carboxylate (cis-24). A mixture of cis-17
(1 g, 0.0036 mol), Pd(OAc)2 (0.07 g, 0.0003 mol), triphenylphos-
phine (1.2 g, 0.0045 mol), and K2CO3 (0.83 g, 0.006 mol) in
2-propanol (10 mL) and DMF (10 mL) was stirred overnight
at 90 °C under 5 bar pressure of CO, filtered over Celite, and
washed with EtOAc.‚H2O was added to the filtrate and the
mixture was extracted with EtOAc. The organic layer was
separated, dried (MgSO4), and filtered, and the solvent was
evaporated. The residue (2.8 g) was purified by column
chromatography over silica gel (eluent: cyclohexane/EtOAc 75/
25; 15-40 µm). The pure fractions were collected, and the
solvent was evaporated. The residue was precipitated from
1
11%): mp 92 °C; H NMR (CDCl3) δ 1.39 (3H, t, J ) 7.5 Hz),
1.52-1.80 (4H, m), 1.89-2.10 (4H, m), 2.87 (2H, q, J ) 7.5
Hz); 3.35 (3H, s), 3.36-46 (1H, m), 3.47-3.57 (1H, m), 7.98
(1H, d, J ) 8.8 Hz), 8.12-8.22 (2H, m), 8.42 (1H, d, J ) 1.5
Hz). Anal. (C19H22FNO2) C, H, N.
3-Ethyl-2-(3-thienyl)quinolin-6-yl cis-4-Methoxycyclo-
hexyl Ketone (cis-21). A mixture of cis-17 (0.5 g, 0.0015 mol),
3-thienylboronic acid (0.3 g, 0.0023 mol), tetrakis(triphenyl-
phosphine)palladium(0) (0.17 g, 0.0002 mol), and dioxane was
stirred and refluxed for 24 h. A 10% aqueous solution of K2CO3
was added. The mixture was extracted with EtOAc. The organ-
ic layer was separated, dried (MgSO4), and filtered, and the
solvent was evaporated. The residue (0.8 g) was purified by
column chromatography over silica gel (eluent: cyclohexane/
EtOAc 80/20; 15-40 µm). The pure fractions were collected,
and the solvent was evaporated. The residue (0.4 g, 70%) was
precipitated from petroleum ether to afford cis-21 (0.39 g,
68%): mp 113 °C; 1H NMR (CDCl3) δ 1.32 (3H, t, J ) 7.4 Hz),
1.58-1.81 (4H, m), 1.90-2.13 (4H, m), 2.97 (2H, q, 7.4 Hz),
3.36 (3H, s), 3.37-3.58 (2H, m), 7.41-7.51 (2H, m), 7.51 (1H,
s), 8.11-8.20 (3H, m), 8.43 (1H, s). Anal. Calcd (C23H25NO2S):
C, 72.79; H, 6.64; N, 3.69. Found: C, 71.84; H, 6.76; N, 3.58.
3-Ethyl-2-iodoquinolin-6-yl cis-4-Methoxycyclohexyl
Ketone (cis-22). A mixture of cis-17 (3 g, 0.009 mol), AcCl
(0.75 mL, 0.01 mol), and NaI (2.7 g, 0.018 mol) in CH3CN (30
mL) was stirred and refluxed for 1 h. A 10% aqueous solution
of K2CO3 was added. The mixture was extracted with CH2Cl2.
The organic layer was separated, dried (MgSO4), and filtered,
and the solvent was evaporated. The residue (4.2 g) was
purified by column chromatography over silica gel (eluent:
cyclohexane/EtOAc; 85/15; 15-40 µm). Fractions were col-
lected, and the solvent was evaporated off. The residue was
precipitated from petroleum ether to afford cis-22 (0.7 g,
18%): mp 100 °C; 1H NMR (CDCl3) δ 1.39 (3H, t, J ) 7.4 Hz),
1.53-1.79 (4H, m), 1.88-2.11 (4H, m), 2.89 (2H, q, J ) 7.44
Hz), 3.45 (3H, s), 3.36-3.46 (1H, m), 3.47-53 (1H, m), 7.93
(1H, s), 8.09 (1H, d, J ) 8.8 Hz), 8.18 (1H, J ) 8.8 Hz), 8.38
(1H, s). Anal. (C19H22INO2) C, H, N.
1
petroleum ether to afford cis-24 (0.07 g, 6%): mp 105 °C; H
NMR (CDCl3) δ 1.37 (3H, t, J ) 7.9 Hz), 1.47 (6H, d, J ) 7.7
Hz), 1.54-1.79 (4H, m), 1.88-2.09 (4H, m), 2.99 (2H, q, J )
7.9 Hz), 3.33 (3H, s), 3.36-3.47 (1H, m), 3.49-3.56 (1H, m),
5.42 (1H, m), 8.16 (1H, s), 8.18-8.22 (2H, m), 8.38 (1H, s).
Anal. Calcd (C23H29NO4): C, 72.04; H, 7.62; N, 3.65. Found.
C, 71.56; H, 7.65; N, 3.63.
2-Amino-3-ethylquinolin-6-yl cis-4-Methoxycyclohexyl
Ketone (cis-25). A mixture of trans-17 (2 g, 0.006 mol),
acetamide (7.1 g, 0.12 mol), and K2CO3 (4.15 g, 0.03 mol) was
stirred at 200 °C for 1 h and cooled at room temperature, and
H2O was added. The mixture was extracted with CH2Cl2. The
organic layer was separated, dried (MgSO4), and filtered, and
the solvent was evaporated. The residue (3.68 g) was purified
by column chromatography over silica gel (eluent: toluene/
isopropyl alcohol/NH4OH 92/8/0.1; 15-35 µm). Fractions were
collected, and the solvent was evaporated. The residue (1.5 g,
40%) was separated by column chromatography over Kromasil
(eluent:CH3CN/AcNH4 40/60). The pure fractions were col-
lected, and the solvent was evaporated. The residue was
precipitated from diethyl ether to afford cis-25 (0.07 g, 4%):
mp 203 °C; 1H NMR (CDCl3) δ 1.39 (3H, t, J ) 7.9 Hz), 1.54-
1.74 (4H, m), 1.88-2.09 (4H, m), 2.62 (2H, q, J ) 7.9 Hz), 3.32
(3H, s), 3.33-3.43 (1H, m), 3.49-3.54 (1H, m), 5.09 (2H, br s),
7.65 (1H, d, J ) 9.2 Hz), 7.79 (1H, s), 8.06 (1H, dd, J ) 2.5,
9.2 Hz), 8.25 (1H, d, J ) 2.5 Hz). Anal. (C19H24N2O2) C, H, N.
3-Ethyl-2-[(2-methoxyethyl)amino]quinolin-6-yl cis-4-
Methoxycyclohexyl Ketone (cis-26). A solution of trans-
17 (0.018 mol) in 2-methoxyethylamine (30 mL) was stirred
and refluxed for 8 h. The solvent was evaporated to dryness.
The residue was dissolved in EtOAc. The organic layer was
separated, washed with H2O, dried (MgSO4), and filtered, and
the solvent was evaporated. The residue (7.7 g) was purified
by column chromatography over silica gel (eluent: cyclohex-
ane/EtOAc; 70/30; 15-40 µm). The fractions were collected and
the solvent was evaporated. The residue was precipitated from
3-Ethyl-6-[(cis-4-methoxycyclohexyl)carbonyl]quino-
line-2-carbonitrile (cis-23). A mixture of cis-22 (6.34 g, 0.015
mol), trimethylsilyl cyanide (3 mL, 0.023 mol), and tetrakis-
(triphenylphosphine)palladium(0) (1.7 g, 0.002 mol) in Et3N
(50 mL) was stirred and refluxed for 2 h. A 10% aqueous
solution of K2CO3 was added and the mixture was extracted
with EtOAc. The organic layer was separated, filtered (Mg-
SO4), and dried, and the solvent was evaporated. The residue

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2145
Table 6. In Vitro Activity and Metabolic Stability of Diverse Cyclohexyl Quinolin-6-yl Ketone Derivatives
a Rat mGlu1. b Human mGlu1; IC50 values are the mean of two or three independent experiments performed on both rat and human
mGlu1 receptors. c In vitro metabolic stability expressed as a percentage of converted parent compound (30 µM) after 30 min. d Metabolic
stability expressed as a percentage of converted parent compound (5 µM) after 5 min.
Table 7. In Vitro Activity and Metabolic Stability of Diverse Aryl Alkyl Ketones
signal transduction IC50 (nM)
compd
position
R
rmGlu1a
hmGlu1b
met. stab.c
72a
72b
72c
83
6
6
6
7
3-thienyl
toluyl
phenyl
phenyl
7
85
6
74
100
87
160
14
99
8300
nd
nd
a Rat mGlu1. b Human mGlu1; IC50 values are the mean of two or three independent experiments performed on both rat and human
mGlu1 receptors. c In vitro metabolic stability expressed as a percentage of converted parent compound (30 µM) after 30 min.
petroleum ether to afford cis-26 (1.15 g, 17%): mp 109 °C; 1H
NMR (CDCl3) δ 1.37 (3H, t, J ) 7.5 Hz), 1.54-1.74 (4H, m),
1.88-2.08 (4H, m), 2.57 (2H, q, J ) 7.5 Hz), 3.32 (3H, s), 3.33-
3.41 (1H, m), 3.42 (3H, s), 3.47-3.54 (1H, m), 3.67 (2H, t, J )

2146 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Mabire et al.
6.4 Hz), 3.87 (2H, q, J ) 7.7 Hz), 5.25 (1H, br m), 7.65-7.70
(2H, m), 8.05 (1H, dd, J ) 1.8, 8.8 Hz), 8.21 (1H, d, J ) 2.5
Hz). Anal. Calcd (C22H30N2O3): C, 71.32; H, 8.16; N, 7.56.
Found: C, 70.74; H, 8.22; N,7.52.
yield from (()30d by a method similar to that described for
(()31a: 1H NMR (CDCl3) δ 1.08-1.58 (7H, m), 1.70-1.85 (1H,
m), 2.17-2.26 (1H, m), 2.49-2.62 (1H, m), 2.91-3.03 (1H, m),
3.16 (3H, s), 3.65 (3H, s).
N-Methoxy-2-(cis/trans-4-methoxycyclohexyl)-N-me-
thylacetamide (cis/trans-31e). Compound cis/trans-31e
was prepared in 100% yield from cis/trans-30e by a method
similar to that described for (()31a and was used without
further purification.
2-[4-(Dimethylamino)phenyl]-N-methoxy-N-methylac-
etamide (31h). Compound 31h was prepared in 100% yield
from 30h by a method similar to that described for (()31a
and was used without further purification.
(()-2-Chloro-3-ethylquinolin-6-yl 2,3-Dihydro-1,4-ben-
zodioxin-2-yl Ketone ((()32a). n-BuLi (1.6 M) in hexane (17
mL, 0.027 mol) was added slowly at -70 °C to a solution of 15
(6 g, 0.022 mol) in THF (60 mL). The mixture was stirred at
-70 °C for 30 min. A solution of (()31a (5.45 g, 0.024 mol) in
THF (60 mL) was added slowly. The mixture was stirred at
-70 °C for 1 h and then brought slowly to room temperature,
poured out into H2O, and extracted with EtOAc. The organic
layer was separated, dried (MgSO4), and filtered, and the sol-
vent was evaporated. The residue (9.7 g) was purified by col-
umn chromatography over silica gel (eluent: CH2Cl2/EtOAc
99/1; 15-35 µm). The pure fractions were collected, and the
solvent was evaporated. The residue (2.6 g, 33%) was precipita-
ted from diethyl ether to afford (()32a (2 g, 25%): mp 150
°C; 1H NMR (CDCl3) δ 1.42 (3H, t, J ) 7.5 Hz), 2.87 (2H, q, J
) 7.5 Hz), 4.41-4.51 (1H, m), 4.63 (1H, dd, J ) 2.6, 11.6 Hz),
5.54-5.60 (1H, m), 6.85-7.05 (4H, m), 8.05-8.14 (2H, m), 8.28
(1H, dd, J ) 1.7, 8.9 Hz), 8.58 (1H, d, J ) 1.7 Hz). Anal. Calcd
(C20H16ClNO3): C, 67.90; H, 4.56; N, 3.96. Found: C, 67.12;
H, 4.45; N, 3.86.
3-Ethyl-2-(1,3-thiazol-2-yl)quinolin-6-yl cis-4-Methoxy-
cyclohexyl Ketone (cis-27). A mixture of cis-17 (0.5 g,
0.0015 mol), 2-tributylstannylthiazole (0.85 g, 0.0023 mol), and
tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.0002 mol)
in dioxane (5 mL) was stirred at 80 °C for 2 h. H2O was added
and the mixture was extracted with EtOAc. The organic layer
was separated, dried (MgSO4), and filtered, and the solvent
was evaporated. The residue (1.6 g) was purified by column
chromatography over silica gel (eluent: cyclohexane/EtOAc 80/
20; 15-40 µm). Fractions were collected, and the solvent was
evaporated off. The residue was precipitated from petroleum
ether and pentane to afford cis-27 (0.12 g, 21%): mp 108 °C;
1H NMR (CDCl3) δ 1.41 (3H, t, J ) 7.4 Hz), 1.60-1.81 (4H,
m), 1.91-2.13 (4H, m), 3.36 (3H, s), 3.40-3.60 (4H, m), 7.53
(1H, d, J ) 3.2 Hz), 8.03 (1H, d, J ) 3.2 Hz), 8.11-8.25 (3H,
m), 8.41 (1H, s). Anal. (C22H24N2O2S) C, H, N.
3-Ethyl-2-(2-thienyl)quinolin-6-yl cis-4-Methoxycyclo-
hexyl Ketone (cis-28). A mixture of cis-17 (0.5 g, 0.0015 mol),
2-tributylstannylthiophene (0.72 mL, 0.0022 mol), and tet-
rakis(triphenylphosphine)palladium(0) (0.17 g, 0.0002 mol) in
dioxane (5 mL) was stirred at 80 °C for 8 h. A 10% aqueous
solution of K2CO3 was added. The mixture was extracted with
EtOAc. The organic layer was separated, dried (MgSO4), and
filtered, and the solvent was evaporated. The residue (1.6 g)
was purified by column chromatography over silica gel (elu-
ent: cyclohexane/EtOAc 80/20; 15-40 µm). Fractions were
collected, and the solvent was evaporated off. The residue was
precipitated from petroleum ether and pentane to afford cis-
1
28 (0.35 g, 61%): mp 142 °C; H NMR (CDCl3) δ 1.43 (3H, t,
J ) 7.4 Hz), 1.55-1.81 (4H, m), 1.90-2.11 (4H, m), 3.14 (2H,
q, J ) 7.4 Hz), 3.36 (3H, s), 3.37-50 (1H, m) 3.51-3.59 (1H,
m), 7.20 (1H, m), 7.54 (1H, d, J ) 5.2 Hz), 7.64 (1H, d, J ) 3.8
Hz). Anal. (C23H25NO2S) C, H, N.
(()-2-Chloro-3-ethylquinolin-6-yl 3,4-Dihydro-2H-chro-
men-3-yl Ketone ((()32b). Compound (()32b was prepared
in 24% yield from (()31b by a method similar to that described
1
for (()32a: mp 138 °C; H NMR (CDCl3) δ 1.42 (3H, t, J )
7.4 Hz), 2.98 (2H, q, J ) 7.4 Hz), 3.00-3.10 (1H, m), 3.20-
3.31 (1H, m), 4.05-4.21 (2H, m), 4.51-4.64 (1H, m), 6.88-
6.97 (2H, m), 7.10-7.21 (2H, m), 8.08-8.14 (2H, m), 8.28 (1H,
dd, J ) 1.9, 8.9 Hz), 8.51 (1H, d, J ) 1.9 Hz). Anal. (C21H18-
ClNO2) C, H, N.
3-Ethyl-6-[(cis-4-methoxycyclohexyl)carbonyl]quinolin-
2(1H)-one (cis-29). A mixture of cis-10 (4 g, 0.0122 mol) in 3
N HCl (40 mL) and THF (40 mL) was stirred and refluxed
overnight, poured out into H2O, basified with a 10% aqueous
solution of K2CO3, and extracted with CH2Cl2. The organic
layer was separated, dried (MgSO4), and filtered, and the
solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: cyclohexane/EtOAc 40/
60; 15-40 µm). The pure fractions were collected, and the
solvent was evaporated to afford cis-29 (2 g, 52%): mp 224
°C; 1H NMR (CDCl3) δ 1.36 (3H, t, J ) 7.4 Hz), 1.5-2.15 (8H,
m), 2.78 (2H, q, J ) 7.4 Hz), 3.22-3.42 (4H, m), 3.50-3.60
(1H, m), 7.47 (1H, d, J ) 10.0 Hz), 7.73 (1H, s), 8.08 (1H, dd,
J ) 1.9, 10.9 Hz), 8.19 (1H, d, J ) 1.9 Hz), 12.10 (1H, br s).
Anal. (C19H23NO3) C, H, N.
(()-N-Methoxy-N-methyl-2,3-dihydro-1,4-benzodioxine-
2-carboxamide ((()31a). CDI (5.6 g, 0.035 mol) was added
portionwise at room temperature to a solution of (()30a (5.7
g, 0.032 mol) in CH2Cl2 (60 mL). The mixture was stirred at
room temperature for 1 h. N,O-Dimethylhydroxylamine hy-
drochloride (5.6 g, 0.035 mol) was added. The mixture was
stirred at room temperature for 8 h, washed with 1 N HCl
and then with a 10% aqueous solution of K2CO3. The organic
layer was separated, dried (MgSO4), and filtered, and the
solvent was evaporated. The residue (6.7 g, 95%) was precipi-
tated from petroleum ether to afford (()31a (5.65 g, 95%): mp
80 °C; 1H NMR (CDCl3) δ 3.29 (3H, s), 3.82 (3H, s), 4.23-4.31
(1H, m), 4.44 (1H, dd, J ) 2.5, 8 Hz), 5.05 (1H, d, J ) 8 Hz),
6.84-7.02 (4H, m). Anal. (C11H13NO4), C, H, N.
1-(2-Chloro-3-ethylquinolin-6-yl)-3-phenylpropan-1-
one (32c). Compound 32c was prepared in 37% yield from
31c45 by a method similar to that described for (()32a: mp
100 °C; 1H NMR (CDCl3) δ 1.40 (3H, t, J ) 7.5 Hz), 8.94 (2H, q,
J ) 7.5 Hz), 3.15 (2H, t, J ) 7.6 Hz), 3.45 (2H, t, J ) 7.6 Hz),
7.20-7.38 (5H, m), 8.01-8.07 (2H, m), 8.24 (1H, dd, J ) 1.9,
8.9 Hz), 8.41(1H, d, J ) 1.9 Hz). Anal. (C20H18ClNO) C, H, N.
(()-Bicyclo[2.2.1]hept-2-yl 2-Chloro-3-ethylquinolin-6-
yl Ketone ((()32d). Compound (()32d was prepared in 40%
yield from (()31d by a method similar to that described for
(()32a: mp 131 °C; mixture of diastereoisomers 70/30; 1H
NMR (CDCl3) δ 1.10-1.74 (10H, m), 1.99-2.12 (1H, m), 2.32-
2.41(1H, m), 2.53-2.72 (1H, m), 2.92 (2H, q, J ) 7.5 Hz), 3.30
(0.5H, m), 3.78-3.90 (0.5H, m), 8.00-8.10 (2H, m), 8.19-8.28
(1H, m), 8.38-8.43 (1H, m). Anal. (C19H20ClNO) C, H, N.
1-(2-Chloro-3-ethylquinolin-6-yl)-2-(cis/trans-4-meth-
oxycyclohexyl)ethanone (32e). Compound cis/trans-32e
was prepared in 29% yield from cis/trans-31e by a method
similar to that described for (()32a: mp 136 °C; 1H NMR
(CDCl3) δ 1.40 (3H, m), 1.55 (6H, m), 1.9 (2H,m), 2.15 (1H,
m), 3 (4H, m), 3.45 (3H, s), 3.45 (1H, m), 8.08 (1H, m), 8.12
(1H, s), 8.25 (1H, m), 8.42 (1H, s). Anal. Calcd (C20H24ClNO2):
C, 69.45; H, 6.99; N, 4.05. Found: C, 68.75; H, 6.92; N, 3.92.
(()-2-Chloro-3-ethylquinolin-6-yl 2,3-Dihydro-1H-in-
den-2-yl Ketone ((()32i). Compound (()32i was prepared
in 5% yield from (()31i by a method similar to that described
(()-N-Methoxy-N-methylchromane-3-carbox-
amide((()31b). Compound (()31b was prepared in 92% yield
from (()30b by a method similar to that described for (()-
31a: 1H NMR (CDCl3) δ 2.85-3.21 (2H, m), 3.26 (3H, s), 3.31-
3.45 (1H, m), 3.77 (3H, s), 4.04 (1H, t, J ) 7 Hz), 4.40-4.46
(1H, m), 6.81-6.92 (2H, m), 7.08-7.17 (2H, m).
1
for (()32a: mp 145 °C; H NMR (CDCl3) δ 1.42 (3H, t, J )
7.4 Hz), 7.98 (2H, q, J ) 7.4 Hz), 3.28-3.55 (4H, m), 4.35-
4.51 (1H, m), 7.11-7.35 (4H, m), 8.05-8.8.18 (2H, m), 8.29
(1H, d, J ) 8.8 Hz), 8.50 (1H, s). Anal. (C21H18ClNO) C, H, N.
(()-2,3-Dihydro-1,4-benzodioxin-2-yl 3-Ethyl-2-meth-
ylquinolin-6-yl Ketone ((()33a). A mixture of (()32a (0.5
(()-N-Methoxy-N-methylbicyclo[2.2.1]heptane-2-car-
boxamide ((()31d). Compound (()31d was prepared in 76%

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2147
g, 0.0014 mol), tetramethyltin (0.4 mL, 0.0028 mol), and
tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.0001 mol)
in toluene (5 mL) was stirred and refluxed for 48 h. A 10%
aqueous solution of K2CO3 was added. The mixture was filtered
over Celite, washed with EtOAc, and the filtrate was extracted
with EtOAc. The organic layer was separated, dried (MgSO4),
and filtered, and the solvent was evaporated. The residue (0.84
g) was purified by column chromatography over silica gel
(eluent: cyclohexane/EtOAc 70/30; 15-40 µm). The pure
fractions were collected, and the solvent was evaporated. The
residue (0.2 g, 42%) was precipitated from diethyl ether/
petroleum ether to afford (()33a (0.09 g, 19%): mp 149 °C;
1H NMR (CDCl3) δ 1.40 (3H, t, J ) 7.5 Hz), 2.79 (3H, s), 2.85
(2H, q, J ) 7.5 Hz), 4.41-4.5 (1H, m), 4.65 (1H, dd, J ) 2.4,
9 Hz), 5.57-5.63 (1H, m), 6.87-7.05 (4H, m), 8.00 (1H, s), 8.09
(1H, d, J ) 8.8 Hz), 8.24 (1H, d, J ) 10 Hz), 8.55 (1H, d, J )
1.6 Hz). Anal. Calcd (C21H19NO3): C, 75.66; H, 5.74; N, 4.20.
Found: C, 74.3; H, 5.74; N, 4.08.
7.5 Hz), 2.81-2.95 (5H, m), 8.08 (1H, d, J ) 9.6 Hz), 8.28 (1H,
d, J ) 9.6 Hz), 8.48 (1H, s), 8.65 (1H, s).
1-(3-Ethyl-2-methylquinolin-6-yl)-2-(3-methoxyphenyl)-
ethanone (33f). n-BuLi (1.6 M) in hexane (6 mL, 0.0096 mol)
was added dropwise at -78 °C to a solution of 35 (2 g, 0.008
mol) in THF (20 mL) under N2 flow. The mixture was stirred
for 30 min. A mixture of 31f1 (2.5 g, 0.012 mol) in THF (10
mL) was added slowly. The mixture was stirred from -78 to
-20 °C, poured out into H2O/NH4Cl, and extracted with
EtOAc. The organic layer was separated, dried (MgSO4), and
filtered, and the solvent was evaporated to dryness. The
residue (3.9 g) was purified by column chromatography over
silica gel (eluent: cyclohexane/EtOAc; 70/30; 15-40 µm).
Fractions were collected and evaporated off. The residue was
precipitated from diethyl ether/petroleum ether to afford 33f
1
(0.24 g, 25%): mp 60 °C; H NMR (CDCl3) δ 1.32 (3H, t, J )
7.7 Hz), 2.69 (3H, s), 2.82 (2H, q, J ) 7.7 Hz), 3.73 (3H, s),
4.48 (2H, s), 6.78-6.83 (1H, m), 6.86 (2H, m), 7.24 (1H, t, J )
7.9 Hz), 7.96 (1H, d, J ) 10 Hz), 8.14-8.18 (1H, m), 6.24 (1H,
s), 8.75 (1H, m).
(()-3,4-Dihydro-2H-chromen-3-yl 3-Ethyl-2-methylquin-
olin-6-yl Ketone ((()33b). Compound (()33b was prepared
in 33% yield from (()32b by a method similar to that described
2-(3,4-Dimethoxyphenyl)-1-(3-ethyl-2-methylquinolin-
6-yl)ethanone (33g). Compound 33g was prepared in 13%
yield from 31g47 by a method similar to that described for
1
for (()33a: mp 143 °C; H NMR (DMSO-d6) δ 1.32 (3H, t, J
) 7.4 Hz), 2.70 (3H, s), 2.83 (2H, q, J ) 7.4 Hz), 2.95-3.15
(2H, m), 4.05-4.14 (1H, m), 4.20-4.32 (1H, m), 4.48-4.56 (1H,
m), 6.78-6.92 (2H, m), 7.06-7.17 (2H, m), 8.00 (1H, d, J )
8.8 Hz), 8.14 (1H, dd, J ) 1.8, 8.8 Hz), 8.27 (1H, s), 8.84 (1H,
d, J ) 1.8 Hz). Anal. Calcd (C22H21NO2): C, 68.40; H, 5.50; N,
3.32. Found: C, 67.33; H, 5.32; N, 3.17.
1
33f: mp 105 °C; H NMR (CDCl3) δ 1.31 (3H, t, J ) 7.5 Hz),
2.68 (3H, s), 2.81 (2H, q, J ) 7.5 Hz), 3.71 (3H, s), 3.73 (3H,
s), 4.43 (2, s), 6.80-6.85 (1H, m), 6.87-6.91 (1H, m), 6.92-
6.96 (1H, m), 7.96 (1H, d, J ) 8.9 Hz), 8.15 (1H, dd, J ) 1.9,
8.9 Hz), 8.24 (1H, s), 8.76 (1H, m).
1-(3-Ethyl-2-methylquinolin-6-yl)-3-phenylpropan-1-
one (33c). Compound 33c was prepared in 53% yield from
32c by a method similar to that described for (()33a: mp 53
2-[4-(Dimethylamino)phenyl]-1-(3-ethyl-2-methylquin-
olin-6-yl)ethanone (33h). Compound 33h was prepared in
15% yield from 31h by a method similar to that described for
1
1
°C; H NMR (CDCl3) δ 1.38 (3H, t, J ) 7.5 Hz), 2.77 (3H, s),
33f: mp 130 °C; H NMR (CDCl3) δ 1.35 (3H, t, J ) 7.7 Hz),
2.83 (2H, q, J ) 7.5 Hz), 3.15 (2H, t, J ) 7.7 Hz), 3.46(2H, t,
J ) 7.7 Hz), 7.20-7.38 (5H, m), 7.95 (1H, s), 8.05 (1H, d, J )
8.8 Hz), 8.20 (1H, dd, J ) 1.9, 8.8 Hz), 8.40 (1H, d, J ) 1.9
Hz). Anal. Calcd (C21H21NO): C, 83.13; H, 6.98; N, 4.62.
Found: C, 82.71; H, 6.83; N, 4.56.
2.74 (3H, s), 2.82 (2H, q, J ) 7.7 Hz), 2.91 (6H, s), 4.30 (2H,
s), 6.71 (2H, d, J ) 4.5 Hz), 7.18 (2H, d, J ) 4.5 Hz), 7.94 (1H,
s), 8.00 (1H, d, J ) 8.9 Hz), 8.21 (1H, dd, J ) 1.8, 8.9 Hz),
8.45 (1H, d, J ) 1.8 Hz).
3-Ethyl-2-methylquinolin-6-yl cis-4-Hydroxycyclohex-
yl Ketone (cis-36). A solution of cis-18 (2.4 g, 0.0078 mol) in
a 48% aqueous solution of HBr (21 mL) was stirred at 60 °C
for 2 h. The mixture was poured out into H2O, basified with a
10% aqueuos solution of K2CO3, and extracted with CH2Cl2.
The organic layer was separated, dried (MgSO4), and filtered,
and the solvent was evaporated. The residue was purified by
column chromatography over silica gel (eluent: CH2Cl2/EtOAc;
35/65; 15-40 µm). Fractions were collected and evaporated off.
The residue was precipitated from DIPE to afford cis-36 (0,-
12 g, 5%): mp 170 °C; 1H NMR (CDCl3) δ 1.38 (3 H, t, J ) 7.7
Hz), 1.5 (1 H, br s), 1.75 (4H, m), 1.9 (2 H, m), 2.05 (2 H, m),
2.75 (3H, s), 2.85 (2H, t, J ) 7.7 Hz), 3.45 (1H, m), 4.1 (1H,
m), 7.95 (1H, s), 8.05 (1H, d, J ) 10.2 Hz), 8.15 (1H, d, J )
10.2 Hz), 8.38 (1H, s). Anal. (C19H23NO2) C, H, N.
(()-Bicyclo[2.2.1]hept-2-yl 3-Ethyl-2-methylquinolin-
6-yl Ketone ((()33d). Compound (()33d was prepared in
32% yield from (()32d by a method similar to that described
1
for (()33a: mp 87 °C; mixture of diastereoisomers 70/30; H
NMR (CDCl3) δ 1.11-1.75 (9H, m), 2.01-2.13 (1H, m), 2.32-
2.41 (1H, m), 2.70-2.90 (7H, m), 3.32-3.40 (0.5H, m), 3.84-
3.92 (0.5H, m), 7.99 (1H, s), 8.04 (1H, d, J ) 8.8 Hz), 8.16-
8.24 (1H, m), 8.38-8.43 (1H, m). Anal. Calcd (C20H23NO): C,
81.87; H, 7.90; N, 4.77. Found: C, 81.22; H, 8.11; N, 4.72.
1-(3-Ethyl-2-methylquinolin-6-yl)-2-(cis-4-methoxycy-
clohexyl)ethanone (cis-33e). Compound cis-33e was pre-
pared in 35% yield from cis/trans-32e by a method similar to
that described for (()33a: mp 80 °C; 1H NMR (CDCl3) δ 1.38
(3H, t, J ) 7.5 Hz), 1.40-1.61 (6H, m), 1.86-1.94 (2H, m),
2.08-2.19 (1H, m), 2.75 (3H, s), 2.84 (2H, q, J ) 7.5 Hz), 2.98
(2H, d, J ) 9.2 Hz), 3.32 (3H, s), 3.41-3.46 (1H, m), 7.97 (1H,
s), 8.03 (1H, d, J ) 10 Hz), 8.15-8.21 (1H, m), 8.38 (1H, m).
Anal. Calcd (C21H27NO2): C, 77.50; H, 8.36; N, 4.30. Found:
C, 76.62; H, 8.41; N, 4.29.
1-(3-Ethyl-2-methylquinolin-6-yl)-2-phenylethanone
(38). A mixture of 37 (27 g, 0.128 mol) and 34 (20.3 g, 0.154
mol) in AcOH (270 mL) was stirred and refluxed for 15 h and
then cooled to room temperature. AcOH was evaporated. The
residue was taken up in EtOAc. The precipitate was filtered
and taken up in CH2Cl2. H2O was added. The mixture was
basified with K2CO3. The organic layer was separated, dried
(MgSO4), and filtered, and the solvent was purified by column
chromatography over silica gel (eluent: CH2Cl2/EtOAc 90/10;
10-35 µm). Fractions were collected, and the solvent was
evaporated off. The residue was precipitated from diethyl ether
(()-2,3-Dihydro-1H-inden-2-yl 3-Ethyl-2-methylquino-
lin-6-yl Ketone ((()33i). Compound (()33i was prepared in
67% yield from (()32i by a method similar to that described
1
for (()33a: mp 120 °C; H NMR (CDCl3) δ 1.40 (3H, t, J )
7.5 Hz), 2.79 (3H, s), 2.87 (2H, q, J ) 7.5 Hz), 3.30-3.53 (4H,
m), 4.40-4.51 (1H, m), 7.15-7.30 (4H, m), 8.00 (1H, s), 8.09
(1H, d, 8.8 Hz), 8.25 (1H, dd, J ) 1.9, 8.8 Hz), 8.47 (1H, d, J
) 1.9 Hz). Anal. (C22H21NO) C, H, N.
1
to afford 38 (14 g, 39%): mp 89 °C; H NMR (CDCl3) δ 1.38
(3H, t, J ) 7.7 Hz), 2.93 (2 H, q, J ) 7.5 Hz), 2.75 (3H, s), 4.41
(2H, s), 7.35 (4H, m), 7.95 (1H, s), 8.03 (1H, d, J ) 10.2 Hz),
8.21 (1H, d, J ) 10.2 Hz), 8.45 (1H, s). Anal. (C20H19NO) C, H,
N.
6-Bromo-3-ethyl-2-methylquinoline (35). 13 (5.8 g, 0.034
mol) was added at room temperature to a solution of 34 (5.4
g, 0.041 mol) in AcOH (60 mL). The mixture was stirred and
refluxed for 8 h, brought to room temperature, and evaporated
to dryness. The product was precipitated from EtOAc. The
precipitate was filtered, washed with a 10% aqueous solution
of K2CO3, and taken up in CH2Cl2. The organic layer was
separated, dried (MgSO4), and filtered, and the solvent was
evaporated to afford 35 (4.6 g, 54%) which was used without
further purification: 1H NMR (DMSO-d6) δ 1.32 (3H, t, J )
1-Adamantyl 3-Ethyl-2-methoxyquinolin-6-yl Ketone
(40). n-BuLi (1.6 M) in hexane (68 mL, 0.108 mol) was added
dropwise at -78 °C under N2 flow to a mixture of 16 (24 g,
0.09 mol) in THF (270 mL). The mixture was stirred at -30
°C for 1 h. A solution of 3931 (20 g, 0.09 mol) in THF (80 mL)
was added at -78 °C. The mixture was stirred for 2.5 h while
the temperature was brought to room temperature, hydrolyzed

2148 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Mabire et al.
with H2O, and extracted with EtOAc. The organic layer was
separated, dried (MgSO4), and filtered, and the solvent was
evaporated. The residue was purified by column chromatog-
raphy over silica gel (eluent: cyclohexane/EtOAc 96/4; 15-35
µm). Fractions were collected, and the solvent was evaporated
off. The residue was precipitated from diethyl ether to afford
(DMSO-d6) δ 0.96 (6H, s), 1.31 (3H, t, J ) 6 Hz), 2.21 (1H, m),
2.85 (2H, q, J ) 6 Hz), 3 (2H, d, J ) 9 Hz), 7.99 (1H, d, J ) 9
Hz), 8.17 (1H, d, J ) 9 Hz), 8.49 (1H, s), 8.71 (1H, s). Anal.
Calcd (C16H18ClNO): C, 69.68; H, 6.58; N, 5.08. Found: C,
69.07; H, 6.76; N, 5.10.
1-(3-Ethyl-2-methylquinolin-6-yl)-3-methylbutan-1-
1
40 (13.9 g, 44%): mp 116 °C; H NMR (CDCl3) δ 1.32 (3H, t,
one (47). Compound 47 was prepared in 64% yield from 46
1
J ) 7.5 Hz), 1.81 (6H, s), 2.13 (9H, s), 2.75 (2H, q, J ) 7.5 Hz),
4.14 (3H, s), 7.85 (3H, m), 8.02 (1H, s). Anal. (C23H27NO2) C,
H, N.
by a method similar to that described for 43: mp 68 °C; H
NMR (DMSO-d6) δ 0.96 (6H, m), 1.31 (3H, t, J ) 9 Hz), 2.21
(1H, m), 2.77 (3H, s), 2.83 (2H, q, J ) 9 Hz), 3 (2H, d, J ) 9
Hz), 7.97 (1H, d, J ) 9 Hz), 8 (1H, d, J ) 9 Hz), 8.23 (1H, s),
8.64 (1H, s). Anal. Calcd (C17H21NO): C, 79.96; H, 8.29; N,
5.49. Found: C, 78.79; H, 8.43; N, 5.11.
6-(1-Adamantylcarbonyl)-3-ethylquinolin-2(1H)-one
(41). A mixture of 40 (3 g, 0.0086 mol) in 3 N HCl (30 mL)
and THF (30 mL) was stirred and refluxed overnight, poured
out into H2O, basified with K2CO3 (solid), and extracted with
CH2Cl2. The organic layer was separated, dried (MgSO4), and
filtered, and the solvent was evaporated. The residue (9 g) was
reprecipitated from 2-propanone and diethyl ether to afford
41 (2.04 g, 71%): mp 148 °C; 1H NMR (DMSO-d6) δ 1.18 (3H,
t, J ) 7.4 Hz), 1.74 (6H, s), 1.99 (6H, s), 2.04 (3H, s), 2.51 (2H,
q, J ) 7.4 Hz), 7.30 (1H, d, J ) 6 Hz), 7.78 (1H, d, J ) 6 Hz,
1.81 (6H, s), 2.13 (9H, s) 2.75 (2H, q, J ) 7.5 Hz), 4.14 (3H, s)
7.89 (1H, s), 8.09 (1H, s), 11.9 (1H, br s). Anal. Calcd (C22H25-
NO2): C, 78.77; H, 7.51; N, 4.18. Found: C, 77.52; H, 7.55; N,
4.01.
1-Adamantyl 2-Chloro-3-ethylquinolin-6-yl Ketone (42).
A solution of 41 (6 g, 0.018 mol) in POCl3 (60 mL) was stirred
and refluxed for 1 h. The solvent was evaporated to dryness.
The mixture was poured out on ice, basified with NH4OH, and
extracted with CH2Cl2. The organic layer was separated, dried
(MgSO4), and filtered, and the solvent was evaporated to give
42 (4 g, 63%): 1H NMR (DMSO-d6) δ 1.33 (3 H, t, J ) 7.4 Hz),
2.0 (15H, m), 2.89 (2H, q, J ) 7.4 Hz), 7.88 (1H, d, J ) 8.7
Hz),7.98 (1H, d, J ) 8.7 Hz), 8.32 (1H, s), 8.52 (1H, s).
tert-Butyl 4-[(2-Chloro-3-ethylquinolin-6-yl)carbonyl]-
piperidine-1-carboxylate (49). n-BuLi (1.6 M) in hexane (92
mL, 0.112 mol) was added slowly at -70 °C to a solution of 15
(25 g, 0.092 mol) in THF (250 mL). The mixture was stirred
at -70 °C for 30 min and a solution of 48 (30 g, 0.110 mol) in
THF (300 mL) was added slowly. The mixture was stirred at
-70 °C for 30 min, brought to room temperature, hydrolyzed
with H2O, and extracted with EtOAc. The organic layer was
separated, dried (MgSO4), and filtered, and the solvent was
evaporated. The residue (40 g) was purified by column chro-
matography over silica gel (eluent: cyclohexane/EtOAc 75/25;
15-35 µm). Fractions were collected, and the solvent was
evaporated to afford 49 (9.9 g, 26%) which was used without
further purification.
tert-Butyl 4-[(3-Ethyl-2-methylquinolin-6-yl)carbonyl]-
piperidine-1-carboxylate (50). Compound 50 was prepared
in 63% yield from 49 by a method similar to that described
for 43: mp 162 °C; 1H NMR (DMSO-d6) δ 1.32 (3H, t, J ) 7.7
Hz), 1.4 (9H, s), 1.5 (2H, m), 1.85 (2H, m), 2.7 (3H, s), 2.8 (2H,
m), 2.9 (2H, m), 3.8 (1H, m), 4.03 (2H, m), 7.95 (1H, d, J ) 8
Hz), 8.12 (1H, d, J ) 8 Hz), 8.25 (1H, s), 8.72 (1H, s). Anal.
Calcd (C23H30N2O3): C, 72.22; H, 7.91; N, 7.32. Found: C,
71.77; H, 7.96; N, 7.26.
3-Ethyl-2-methylquinolin-6-yl Piperidin-4-yl Ketone
(51). A mixture of 50 (2.9 g, 0.008 mol) in 3 N HCl (30 mL)
and THF (10 mL) was stirred at 60 °C for 1 h, poured out on
ice, basified with NH4OH, and extracted with CH2Cl2. The
organic layer was separated, dried (MgSO4), and filtered, and
the solvent was evaporated. The residue was recrystallized
from CH3CN to afford 51 (1 g, 46%): mp 132 °C; 1H NMR
(DMSO-d6) δ 1.32 (3H, t, J ) 7.7 Hz), 1.5 (2H, m), 1.75 (2H,
m), 2.15 (1H, br s), 2.68 (5H, m), 2.8 (2H, q, J ) 7.7 Hz), 3
(2H, m), 3.65 (1H, m), 7.95 (1H, d, J ) 10.2 Hz), 8.1 (1H, d, J
1-Adamantyl 3-Ethyl-2-methylquinolin-6-yl Ketone (43).
A mixture of 42 (0.5 g, 0.0014 mol), tetramethyltin (0.4 mL,
0.0028 mol), and tetrakis(triphenylphosphine)palladium(0)
(0.16 g, 0.0001 mol) in toluene (5 mL) was stirred and refluxed
for 48 h. A 10% aqueous solution of K2CO3 was added. The
mixture was extracted with EtOAc. The organic layer was
separated, dried (MgSO4), and filtered, and the solvent was
evaporated. The residue (0.55 g) was purified by column
chromatography over silica gel (eluent: cyclohexane/EtOAc 75/
25; 15-40 µm). The pure fractions were collected, and the
solvent was evaporated. The residue was precipitated from
1
diethyl ether to afford 43 (0.2 g, 42%): mp 180 °C; H NMR
(CDCl3) δ 1.38 (3H, t, J ) 7.3 Hz), 1.79 (6H, s), 2.11 (9H, s),
2.76 (3H, s), 2.83 (2 H, q, J ) 7.3 Hz), 7.84 (1H, d, J ) 9 Hz),
7.91 (1H, s), 7.99 (2H, m). Anal. Calcd (C23H27NO): C, 82.84;
H, 8.16; N, 4.2. Found: C, 80.68; H, 8.01; N, 4.02.
)
10.2 Hz), 8.25 (1H, s), 8.68 (1H, s). Anal. Calcd
(C18H22N2O): C, 76.56; H, 7.85; N, 9.92. Found: C, 76.11; H,
7.90; N, 9.96.
(()-1-(2-Chloro-3-ethylquinolin-6-yl)-3-methylbutan-1-
ol ((()45). n-BuLi (1.6 M) in hexane (28 mL, 0.044 mol) was
added slowly at -70 °C to a solution of 15 (10 g, 0.037 mol) in
THF (100 mL). The mixture was stirred at -70 °C for 30 min.
A solution of 44 (4.8 mL, 0.044 mol) in THF (50 mL) was added.
The mixture was stirred at -70 °C for 1 h and then brought
slowly to room temperature, hydrolyzed with H2O, and ex-
tracted with EtOAc. The organic layer was separated, dried
(MgSO4), and filtered, and the solvent was evaporated. The
residue (9.5 g) was purified by column chromatography over
silica gel (eluent: CH2Cl2/EtOAc 92/08; 15-35 µm). The pure
fractions were collected, and the solvent was evaporated. The
residue was precipitated from diethyl ether/petroleum ether
to afford (()45 (6.9 g, 67%): mp 92 °C; 1H NMR (DMSO-d6) δ
1.27 (6H, m), 1.44 (3H, t, J ) 6 Hz), 1.46 (1H, m), 1.58 (2H,
m), 2.84 (2H, q, J ) 6 Hz), 4.76 (1H, m), 5.3 (1H, d, J ) 3 Hz),
7.74 (1H, m), 7.89 (1H, m), 8.31 (1H, s). Anal. (C16H20ClNO)
C, H, N.
6-(1-Benzofuran-2-yl)-3-ethyl-2-methylquinoline (52).
A mixture of 35 (4.7 g, 0.019 mol), benzofuran-2-boronic acid
(5 g, 0.028 mol), tetrakis(triphenylphosphine)palladium(0)
(0.55 g, 0.001 mol), and 2,6-di-tert-butyl-4-methylphenol (a few
milligrams) in dioxane (25 mL) and Na2CO3 (25 mL) was
stirred and refluxed for 8 h and extracted with EtOAc. The
aqueous layer was basified with NH4OH and extracted with
CH2Cl2. The organic layer was separated, dried (MgSO4), and
filtered, and the solvent was evaporated. The residue (3.6 g)
was purified by column chromatography over silica gel (elu-
ent: CH2Cl2/CH3OH 99/1; 15-40 µm). The pure fractions were
collected, and the solvent was evaporated. The residue was
precipitated from 2-propanone/diethyl ether to afford 52 (0.39
1
g, 7%): mp 134 °C; H NMR (DMSO-d6) δ 1.3 (3H, t, J ) 7.7
Hz), 2.68 (3H, s), 2.8 (2H, q, J ) 7.7 Hz), 7.3 (1H, m), 7.37
(1H, m), 7.58 (1H, s), 7.7 (2H, m), 7.98 (1H, d, J ) 9.2 Hz),
8.18 (1H, s), 8.2 (1H, m), 8.42 (1H, s). Anal. (C20H17NO), C, H,
N.
1-(2-Chloro-3-ethylquinolin-6-yl)-3-methylbutan-1-
one (46). KMnO4 (10 g) was added portionwise at room
temperature to a solution of (()45 (6 g, 0.022 mol) in TDA1
(1 mL) and CH2Cl2 (100 mL). The mixture was stirred at room
temperature for 8 h, filtered over Celite, washed with CH2-
Cl2, and dried. The residue was precipitated from diethyl ether/
3-Ethyl-2-methyl-6-(5-phenyl-2-furyl)quinoline (53). A
mixture of 35 (1 g, 0.004 mol), tributyl-((5-phenyl)furan-2-yl)-
stannane31 (2.1 g, 0.005 mol), LiCl (a few milligrams), and
tetrakis(triphenylphosphine)palladium(0) (0.45 g, 0.001 mol)
in dioxane (10 mL) was stirred and refluxed for 8 h. A 10%
aqueous solution of KF was added. The mixture was filtered
over Celite and washed with EtOAc. The filtrate was extracted
1
petroleum ether to afford 46 (2 g, 33%): mp 82 °C; H NMR

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2149
with EtOAc and then with 3 N HCl. The aqueous layer was
basified with NH4OH and extracted with CH2Cl2. The organic
layer was separated, dried (MgSO4), and filtered, and the
solvent was evaporated. The residue (1 g) was recrystallized
from 2-propanone/diethyl ether to afford 53 (0.39 g, 31%): mp
134 °C; 1H NMR (CDCl3) δ 1.38 (3H, t, J ) 7.7 Hz), 2.75 (3H,
s), 2.82 (2H, q, J ) 7.7 Hz), 6.8 (1H, d, J ) 3.5 Hz), 6.88 (1H,
d, J ) 3.5 Hz), 7.3 (1H, m), 7.45 (2H, m), 7.8 (2H, m), 7.9 (1H,
s), 8 (2H, m), 8.13 (1H, s). Anal. (C22H19NO) C, H, N.
washed with H2O, and dried to afford 59 (25.7 g, 78%), which
was used without further purification.
7-Bromo-3,4-dihydro-2H-pyrano[2,3-b]quinoline (60a).
A mixture of 59 (25.5 g, 0.0799 mol) in 12 N HCl (100 mL)
and H2O (100 mL) was stirred and refluxed for 10 h, cooled at
room temperature, and neutralized with NH4OH (concen-
trated). The insoluble portion was filtered, washed with H2O
and with EtOH, and dried to afford 61 (16 g) The filtrate was
1
evaporated to afford 60a (5.9 g, 28%): mp 129 °C; H NMR
(DMSO-d6) δ 1.97 (2 H, qt, J ) 5.8 Hz), 2.96 (2H, t, J ) 5.9
Hz), 4.39 (2H, t, J ) 5.9 Hz), 7.6 (1H, d, J ) 9.2 Hz), 7.68 (1H,
dd, J ) 9.2 Hz, 2.3 Hz), 8.01 (1H, s), 8.04 (1H, m). Anal.
(C12H10BrNO) C, H, N.
(Z)-3-Ethyl-2-methoxyquinolin-6-yl cis-4-Methoxycy-
clohexyl Ketone Oxime (cis-54) and (E)-3-Ethyl-2-meth-
oxyquinolin-6-yl cis-4-Methoxycyclohexyl Ketone Oxime
(cis-55). A mixture of cis-10 (7.5 g, 0.0229 mol), NH2OH (1.75
g, 0.0252 mol), and Et3N (3.5 mL, 0.0252 mol) in EtOH (100
mL) was stirred and refluxed for 6 h, poured out into H2O,
and extracted with CH2Cl2. The organic layer was separated,
dried (MgSO4), and filtered, and the solvent was evaporated.
The residue was recrystallized from CH3CN. The precipitate
was filtered off and dried. The residue was purified by column
chromatography over silica gel (eluent: CH2Cl2/EtOAc 80/20;
15-40 µm). Fractions were collected, and the solvent was
evaporated to afford cis-54 (3 g, 38%) and cis-55 (2.8 g, 36%).
cis-54: mp 133 °C; 1H NMR (DMSO-d6) δ 1.24 (3H, t, J ) 7.4
Hz), 1.45 (4H, m), 1.88 (4H, m), 2.68 (2H, q, J ) 7.4 Hz), 3.18
(3H, s), 3.33 (1H, m), 3.41 (1H, m), 4.03 (1H, s), 7.58 (1H, m),
7.60 (1H, m), 7.72 (1H, m), 8.04 (1H, s), 11.02 (1H, br s). Anal.
7-Bromo-1-methyl-1,2,3,4-tetrahydrobenzo[b]-1,8-naph-
thyridine (60b). A mixture of 59 (15 g, 0.047 mol) and
benzylamine (7.7 mL, 0.0705 mol) in DMF (250 mL) was
stirred at 160 °C for 15 h, cooled at room temperature, poured
out into ice H2O, and extracted with EtOAc. The residue (19
g) was purified by column chromatography over silica gel
(eluent: cyclohexane/EtOAc 80/20; 15-35 µm). Two fractions
were collected, and the solvent was evaporated. Each fraction
was precipitated separately from petroleum ether. The pre-
cipitates were filtered off and dried to afford 62 (2.4 g) and
60b (3.26 g, 37%): mp 105 °C; 1H NMR (DMSO-d6) δ 1.9 (2 H,
m), 2.85 (2H, t, J ) 6.7 Hz), 3.15 (3H, s), 3.45 (2H, t, J ) 6.0
Hz), 7.4 (1 H, d, J ) 7.7 Hz), 7.47 (1H, d, J ) 7.7 Hz), 7.57
(1H, s), 7.77 (1H, d, J ) 1.92 Hz). Anal. (C13H13BrN2) C, H, N.
1
(C20H26N2O3) C, H, N. cis-55: mp 142 °C; H NMR (DMSO-
2-Bromo-7,8,9,10-tetrahydro-6H-cyclohepta[b]quino-
line (60c). A mixture of cycloheptanone (1.9 mL, 0.016 mol)
and NaOH (0.6 g, 0.016 mol) in EtOH (8 mL) was warmed to
65 °C and a solution of 63 (2.9 g, 0.015 mol) in EtOH (16 mL)
was slowly added dropwise. The reaction mixture was stirred
for 1 h at 65 °C and cooled to room temperature. The solvent
was evaporated and the residue was purified by column
chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/
2). The pure fractions were collected, and the solvent was
evaporated. The residue was precipitated in DIPE to afford
60c (2.7 g, 56%): 1H NMR (DMSO-d6) δ 1.60-1.75 (4H, m),
1.80-1.90 (2H, m), 2.90-3.01 (2H, m), 3.09-3.17 (2H, m), 7.75
(1H, dd, J ) 2.2, 8.8 Hz), 7.82 (1H, s), 7.85 (1H, s), 8.12 (1H,
d, J ) 2.2 Hz).
7-Bromo-2,3-dihydro-1H-cyclopenta[b]quinoline (60d).
A mixture of 63 (10 g, 0.05 mol), cyclopentanone (4.9 mL, 0.055
mol) and KOH (5.6 g, 0.1 mol) in EtOH (20 mL) was stirred at
60 °C for 1 h and then cooled to room temperature. The solvent
was evaporated. The residue was taken up in H2O. The
mixture was extracted with EtOAc. The organic layer was
separated, dried (MgSO4), and filtered, and the solvent was
evaporated to dryness. The residue was precipitated from
2-propanone to afford 60d (7.8 g, 63%). 1H NMR (CDCl3) δ
2.22 (2H, qt, J ) 7.3 Hz), 3.12 (4H, m), 7.67 (1H, dd, J ) 2.1,
9.1 Hz), 7.87 (2H, m). Anal. (C12H10BrNO) C, H, N.
6-Bromo-2-propylquinoline (60e). 2-Pentanone (2.4 mL,
0.021 mol) was slowly added dropwise to a mixture of 63 (3.9
g, 0.02 mol), pyrrolidine (1.7 mL, 0.021 mol), and H2SO4 (0.057
mL, 0.001 mol) in EtOH (18 mL) under N2 and then the
reaction mixture was stirred overnight at room temperature.
The solvent was evaporated and the residue was purified by
column chromatography over silica gel (eluent: CH2Cl2 100%).
The product fractions were collected, and the solvent was
evaporated to afford 60e (2.8 g, 56%): 1H NMR (DMSO-d6) δ
0.93 (3 H, t, J ) 7.7 Hz), 1.85 (2H, st, J ) 7.7 Hz), 3.20 (2H,
t, J ) 7.7 Hz), 7.95 (1H, d, J ) 9.6 Hz), 8.2 (1 H, m), 8.4 (1H,
m), 8.55 (2H, m), 8.85 (1H, m).
3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl cis-4-Meth-
oxycyclohexyl Ketone (cis-64a). n-BuLi (1.6 M) in hexane
(8.5 mL, 0.0137 mol) was added slowly at -78 °C to a solution
of 60a (3 g, 0.0114 mol) in THF (30 mL) under N2 flow. The
mixture was stirred for 30 min and a solution of cis/trans-12
(2.74 g, 0.0137 mol) in THF (30 mL) was added dropwise at
-78 °C. The mixture was stirred for 1 h, poured out into H2O/
NH4Cl, and extracted with EtOAc. The organic layer was
separated, dried (MgSO4), and filtered and the solvent was
evaporated to dryness. The residue (5.8 g) was purified by
d6) δ 1.24 (3H, t, J ) 7.4 Hz), 1.54 (4H, m), 1.88 (4H, m), 2.67
(2H, q, J ) 7.4 Hz), 2.7 (1H, m), 3.17 (3H, s), 3.33 (1H, m),
4.03 (3H, s), 7.49 (1H, m), 7.73 (2H, m), 8.03 (1H, s), 10.54
(1H, br s). Anal. (C20H26N2O3) C, H, N.
(Z)-3-Ethyl-2-methoxyquinolin-6-yl cis-4-Methoxycy-
clohexyl Ketone Hydrazone (cis-56). NH2NH2 (20 mL, 0.41
mol) was added at room temperature to a solution of cis-10 (5
g, 0.015 mol) in EtOH (75 mL). The mixture was stirred and
refluxed overnight, poured out into H2O, and extracted with
CH2Cl2. The organic layer was separated, dried (MgSO4), and
filtered, and the solvent was evaporated. The residue was
purified by column chromatography over silica gel (eluent:
CH2Cl2/CH3OH/NH4OH 98/2/0.1). The pure fractions were
collected, and the solvent was evaporated (2.7 g, 52%). The
residue was precipitated from diethyl ether to afford cis-56
(0.8 g, 15%): mp 110 °C; 1H NMR (DMSO-d6) δ 1.27 (3H, t, J
) 14.9 Hz), 1.50 (6H, m), 1.79 (2H, m), 2.51 (1H, m), 2.68 (2H,
q, J ) 7.4 Hz), 3.16 (1H, s), 3.33 (1H, m), 4.03 (3H, s), 7.58
(1H, m), 5.54 (2H, br s), 7.39 (1H, m), 7.64 (1H, s), 7.83 (1H,
d, J ) 8.5 Hz), 8.05 (1H, s). Anal. (C20H27N3O2) C, H, N.
3-Ethyl-2-methoxy-6-[1-(cis-4-methoxycyclohexyl)vinyl]-
quinoline (cis-57). NaH 60% (0.3 g, 0.0073 mol) was added
portionwise at room temperature to a solution of cis-10 (2 g,
0.0061 mol) in THF (20 mL). The mixture was stirred at room
temperature for 30 min. Methyltriphenylphosphonium bro-
mide (2.6 g, 0.0073 mol) was added portionwise. The mixture
was stirred at room temperature for 12 h and then at 60 °C
for 1 h, hydrolyzed with H2O, and extracted with EtOAc. The
organic layer was separated, dried (MgSO4), and filtered, and
the solvent was evaporated. The residue (3.3 g) was purified
by column chromatography over silica gel (eluent: cyclohex-
ane/EtOAc 90/10; 15-40 µm). Fractions were collected, and
the solvent was evaporated off. The residue was solidified in
2-propanol. HCl/2-propanol was added. The precipitate was
filtered off, washed with diethyl ether, and dried to afford cis-
57 (0.77 g, 34%): mp 118 °C; 1H NMR (DMSO-d6) δ 1.24 (3H,
t, J ) 9.6 Hz), 1.50 (4H, m), 1.88 (2H, m), 2.68 (2H, m), 2.70
(1H, m), 3.39 (3H, s), 3.43 (1H, m), 4.00 (3H, s), 5.08 (1H, s),
5.29 (1H, s), 6.56 (1H, m), 7.62(1H, d, J ) 9.6 Hz), 7.7 (1H, d,
J ) 9.6 Hz), 7.81 (1H, s), 8.02 (1H, s). Anal. (C21H27NO2·HCl)
C, H, N.
6-Bromo-2-chloro-3-(3-chloropropyl)quinoline (59). DMF
(12.4 mL) was added dropwise at 50 °C to POCl3 (70.3 mL,
0.7536 mol). 58 (30 g, 0.1032 mol) was added and the mixture
was stirred at 75 °C for 6 h, cooled at room temperature, and
poured out into ice H2O. The insoluble portion was filtered,

2150 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Mabire et al.
column chromatography over silica gel (eluent: toluene/EtOAc
50/50; 15-40 µm). The pure fractions were collected, and the
solvent was evaporated. The residue was precipitated from
diethyl ether to afford cis-64a (1.3 g, 35%): mp 115 °C; 1H
NMR (CDCl3) δ 1.58 (2 H, m), 1.77 (2H, m), 2.0 (6H, m), 3.03
(2H, t), 3.32 (3H, s), 3.38 (1H, m), 3.52 (1H, m), 4.52 (2H, t, J
) 5.1 Hz), 7.85 (1H, d, J ) 8.8 Hz), 7.93 (1H, s), 8.10 (1H, dd,
J ) 8.8, 1.8 Hz), 8.30 (1H, d, J ) 1.8 Hz). Anal. (C20H23NO3)
C, H, N.
cis-4-Methoxycyclohexyl 2-Methyl-3-propylquinolin-
6-yl Ketone (cis-68). A mixture of cis-67 (1.6 g, 0.005 mol),
tetramethyltin (1.3 mL, 0.009 mol), and tetrakis(triphenylphos-
phine)palladium(0) (0.5 g, 0.0005 mol) in toluene (20 mL) was
stirred and refluxed for 8 h. A 10% aqueous solution of K2CO3
was added. The mixture was filtered over Celite and washed
with EtOAc. The organic layer was separated, dried (MgSO4),
and filtered, and the solvent was evaporated. The residue (2.1
g) was purified by column chromatography over silica gel
(eluent: CH2Cl2/EtOAc 75/25; 15-40 µm). The pure fractions
were collected, and the solvent was evaporated. The residue
was precipitated from petroleum ether to afford cis-68 (0.36
g, 23%): 1H NMR (CDCl3) δ 1.06 (3H, t, J ) 7.3 Hz), 1.58 (2H,
m), 1.75 (4H, m), 1.93 (2H, m), 2.05 (2H, m), 2.80 (5H, m),
3.33 (3H, s), 3.41 (1H, m), 3.52 (1H, m), 7.95 (1H, s), 8.02 (1H,
d, J ) 8.8 Hz), 8.14 (1H, dd, J ) 2.2, 8.8 Hz), 8.35 (1H, d, J )
2.2 Hz). Anal. (C21H27NO2) C, H, N.
cis-4-Methoxycyclohexyl 1-Methyl-1,2,3,4-tetrahydro-
benzo[b]-1,8-naphthyridin-7-yl Ketone (cis-64b). Com-
pound cis-64b was prepared in 33% yield from 60b by a
1
method similar to that described for cis-64a: mp 127 °C; H
NMR (CDCl3) δ 1.65 (4 H, m), 2.0 (6H, m), 2.9 (2H, t, J ) 6.7),
3.32 (3H, s), 3.35 (1H, s), 3.38 (1H, m), 3.52 (3H, m), 7.54 (1H,
s), 7.63 (1H, d, J ) 7.7 Hz), 8.1 (1H, dd, J ) 7.7, 2.6 Hz), 8.14
(1H, d, J ) 2.6 Hz). Anal. (C21H26N2O2) C, H, N.
4-Ethyltetrazolo[1,5-a]quinolin-7-yl cis-4-Methoxycy-
clohexyl Ketone (cis-69). A mixture of cis-17 (1.5 g, 0.0045
mol) and NaN3 (0.88 g, 0.0135 mol) in DMF (15 mL) was
stirred at 140 °C for 3 h and then poured out into H2O. The
precipitate was filtered off, rinsed with H2O, and dried under
vacuum. The residue was purified by column chromatography
over silica gel (eluent: CH2Cl2/EtOAc 92/8; 15-40 µm). Frac-
tions were collected, and the solvents were evaporated. The
residue was precipitated from diethyl ether to afford cis-69
cis-4-Methoxycyclohexyl 7,8,9,10-Tetrahydro-6H-cy-
clohepta[b]quinolin-2-yl Ketone (cis-64c). Compound cis-
64c was prepared in 12% yield from 60c by a method similar
1
to that described for cis-64a: mp 121 °C; H NMR (CDCl3) δ
1.60 (2H, m), 1.78 (6H, m), 1.93 (4H, m), 2.04 (2H, m), 2.97
(2H, m), 3.23 (2H, m), 3.33 (3H, s), 3.41 (1H, m), 3.52 (1H, m),
7.92 (1H, s), 8.03 (1H, d, J ) 8.8 Hz), 8.14 (1H, dd, J ) 1.8,
8.8 Hz), 8.33 (1H, d, J ) 1.8 Hz). Anal. (C22H27NO2) C, H, N.
2,3-Dihydro-1H-cyclopenta[b]quinolin-7-yl cis-4-Meth-
oxycyclohexyl Ketone (cis-64d). Compound cis-64d was
prepared in 35% yield from 60d by a method similar to that
described for cis-64a: mp 118 °C; 1H NMR (CDCl3) δ 1.58 (2H,
m), 1.73 (2H, m), 1.82-2.08 (4H, m), 2.25 (2H, m), 3.12 (2H, t,
J ) 7.7 Hz), 3.2 (2H, t, J ) 7.7 Hz), 3.32 (3H, s), 3.4 (1H, tt,
J ) 2.6 Hz), 3.52 (1H, q, J ) 2.6 Hz), 8.0 (1H, s), 8.05 (1H, d,
J ) 9.1 Hz), 8.12 (1H, dd, J ) 1.8, 9.1 Hz), 8.35 (1H, d, J )
1.8 Hz). Anal. Calcd (C20H23NO2): C, 77.64; H, 7.49; N, 4.53.
Found: C, 77.10; H, 7.52; N, 4.49.
(cis-4-Methoxycyclohexyl 2-Propylquinolin-6-yl Ke-
tone (cis-64e). Compound cis-64e was prepared in 15% yield
from 60e by a method similar to that described for cis-64a:
1H NMR (CDCl3) δ 1.03 (3 H, t, J ) 7.7 Hz), 1.6 (2H, m), 1.7
(2H, m), 1.9 (4H, m), 3.0 (2H, m), 3.3 (1H, s), 3.4 (1H, tt), 3.5
(1H, q), 7.35 (1H, d, J ) 7.7 Hz), 8.08 (1H, d, J ) 7.7 Hz), 8.2
(2H, m), 8.4 (1H, m). Anal. (C20H25NO2) C, H, N.
2,3-Dihydrothieno[2,3-b]quinolin-6-yl cis-4-Methoxy-
cyclohexyl Ketone (cis-64f). Compound cis-64f was pre-
pared in 30% yield from 60f by a method similar to that
described for cis-64a: mp 145 °C; 1H NMR (CDCl3) δ 1.63 (4H,
m), 1.98 (4H, m), 3.32 (3H, s), 3.35 (1H, m), 3.5 (5H, m), 7.85
(1H, s), 7.91 (1H, d, J ) 7.7 Hz), 8.11 (1H, dd, J ) 7.7, 2.6
Hz), 8.28 (1H, d, J ) 2.6 Hz). Anal. (C19H21NO2S) C, H, N.
6-Bromo-2-chloro-3-propylquinoline (66). POCl3 (98.07
mL, 1.05 mol) was added dropwise at 10 °C to DMF (36.02
mL, 0.45 mol). 65 (38.5 g, 0.15 mol) was added at room
temperature. The mixture was stirred at 80 °C overnight and
then poured out on ice. The precipitate was filtered off and
dried to afford 66 (36.51 g, 86%): 1H NMR (CDCl3) δ 1.0 (3H,
t, J ) 7.3 Hz), 1.80 (2H, q, J ) 7.3 Hz)), 2.88 (2H, t, J ) 7.3
Hz), 7.75 (1H, m), 7.87 (2H, m), 7.90 (1H, m).
1
(0.5 g, 33%): mp 172 °C; H NMR (CDCl3) δ 1.52 (3H, t, J )
7.5 Hz), 1.73 (4H, m), 2.04 (4H, m), 3.22 (2H, q, J ) 7.5 Hz),
3.34 (3H, s), 3.42 (1H, m), 3.54 (1H, m), 7.78 (1H, s), 8.34 (1H,
dd, J ) 8.7, 1.75 Hz), 8.51 (1H, s), 8.72 (1H, d, J ) 8.7 Hz).
Anal. (C19H22N4O2) C, H, N.
N-Methoxy-N-methyl-2-(3-thienyl)acetamide (71). CDI
(17.1 g, 0.105 mol) was added portionwise at room temperature
to a solution of 70a (10 g, 0.0703 mol) in CH2Cl2 (100 mL).
The mixture was stirred at room temperature for 1 h. N,O-
Dimethylhydroxylamine hydrochloride (10.3 g, 0.105 mol) was
added. The mixture was stirred at room temperature for 5 h.
H2O was added. The organic layer was washed with 3 N HCl,
separated, dried (MgSO4), and filtered, and the solvent was
evaporated off to afford 71 (11.6 g, 89%).
1-(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-(3-thie-
nyl)ethanone (72a). n-BuLi (1.6 M) in hexane (5.7 mL, 0.0091
mol) was added at -70 °C to a solution of 60a (2 g, 0.0076
mol) in THF (15 mL) under N2 flow. The mixture was stirred
at -70 °C for 1 h. A solution of 71a (2.1 g, 0.011 mol) in THF
(15 mL) was added at -70 °C. The mixture was stirred at -70
°C for 3 h, brought to -20 °C, poured out into H2O, and
extracted with EtOAc. The organic layer was separated, dried
(MgSO4), and filtered, and the solvent was evaporated. The
residue (3.5 g) was purified by column chromatography over
silica gel (eluent: cyclohexane/EtOAC 40/60; 15-35 µm). The
pure fractions were collected, and the solvent was evaporated.
The residue was precipitated from diethyl ether to afford 72a
1
(0.14 g, 6%): mp 131 °C; H NMR (DMSO-d6) δ 2.0 (2 H, m),
3.01 (2H, m), 3.15 (3H, s), 4.44 (2H, t), 4.48 (2 H, s), 7.07 (1H,
d, J ) 4.1 Hz), 7.38 (1H, s), 7.48 (1H, m), 7.73 (1H, d, J ) 8.7
Hz), 8.22 (1H, s), 8.65 (1H, s). Anal. (C18H15NO2S) C, H, N.
1-(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-3-phe-
nylpropan-1-one (72b). Compound 72b was prepared in 38%
yield from 31c40 by a method similar to that described for
72a: mp 170 °C; 1H NMR (DMSO-d6) δ 1.96 (2 H, qt), 2.35
(3H, s), 2.86 (2H, t), 4.38 (2H, t), 5.95 (1H, br s), 6.22 (1H, d),
6.58 (1H, d, J ) 2.9 Hz), 6.67 (1H, d, J ) 2.9 Hz), 7.58 (2H,
m), 7.79 (1H, s), 8.03 (1H, s). Anal. Calcd (C21H19NO2): C,
79.47; H, 6.03; N, 4.41. Found: C, 79.11; H, 5.98; N, 4.38.
3,4-Dihydro-2H-pyrano[2,3-b]quinoline-7-carboxylic
Acid (73). 60a (1 g, 0.0038 mol) in THF (25 mL) was stirred
under N2 at -78 °C on a 2-propanone/CO2 bath. BuLi (2.5 M)
in hexane (1.51 mL) was added and the mixture was stirred
for 40 min at -78 °C. CO2 (solid) was added at -78 °C and
the mixture was stirred at the same temperature for 20 min.
Then it was allowed to warm to room temperature. NaOH (1
N, 5 mL) was added and the mixture was stirred vigorously.
The separated organic layer was washed with NaOH (1 N, 6
2-Chloro-3-propylquinolin-6-yl cis-4-Methoxycyclo-
hexyl Ketone (cis-67). n-BuLi (1.6 M) in hexane (26.4 mL,
0.042 mol) was added dropwise at -70 °C to a solution of 66
(10 g, 0.035 mol) in THF (100 mL). The mixture was stirred
at -70 °C for 30 min. A solution of cis/trans-12 (8.5 g, 0.042
mol) in THF (100 mL) was added dropwise. The mixture was
stirred at -70 °C for 30 min, brought slowly to room temper-
ature, poured out into H2O, and extracted with EtOAc. The
organic layer was separated, dried (MgSO4), and filtered, and
the solvent was evaporated. The residue (13.7 g) was purified
by column chromatography over silica gel (eluent: cyclohex-
ane/EtOAc 80/20; 15-35 µm). Fractions were collected, and
the solvent was evaporated. The residue was precipitated from
diethyl ether to afford cis-67 (1.05 g, 8%): 1H NMR (CDCl3) δ
1.05 (3H, t, J ) 6.1 Hz), 1.6 (2H, m), 1.75 (4H, m), 2.0 (4H,
m), 2.88 (2H, t, J ) 6.1 Hz), 3.3 (3H, s), 3.4 (1H, m), 3.5 (1H,
m), 8.05 (2H, m), 8.2 (1H, m), 8.38 (1H, m).

Quinolines Acting as Selective mGlu1 Antagonists
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 2151
mL). The combined aqueous layer was acidified with HCl (1
N, 11 mL). The formed precipitate was filtered off and stirred
in 2-propanol. The precipitate was filtered off, washed with
DIPE, and dried to afford 73 (0.306 g, 35%), which was used
without further purification: 1H NMR (DMSO-d6) δ 1.95-2.05
(2H, m), 2.90-3.03 (2H, m), 4.35-4.45 (2H, m), 7.71 (1H, d, J
) 9.2 Hz), 8.05 (1H, d, J ) 9.2 Hz), 8.20 (1H, s), 8.45 (1H, s).
Methyl 3,4-Dihydro-2H-pyrano[2,3-b]quinoline-7-car-
boxylate (74). A mixture of 73 (3.5 g, 0.0153 mol) and H2SO4
(0.3 mL) in MeOH (25 mL) was stirred overnight at 80 °C
under N2. The solvent was evaporated. The residue was stirred
in H2O/CH2Cl2. The separated aqueous layer was extracted
with CH2Cl2 (2 × 50 mL). The combined organic layers were
dried and filtered, and the solvent was evaporated. The residue
was dried (vacuum; 40 °C) and then it was purified by column
chromatography over silica gel (eluent: CH2Cl2/MeOH 98:2).
The desired fractions were collected, and the solvent was
evaporated to afford 74 (1.97 g, 30%). The compound was used
without further purification.
1-(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phe-
nylethanone (72c). THF (6 mL) was added to 74 (0.375 g,
0.0015 mol) under N2. Benzylmagnesium chloride (2 M in THF,
0.8 mL, 0.0016 mol) was added dropwise. The reaction mixture
was stirred at room temperature for 90 min under N2. The
mixture was poured out into H2O (100 mL) and extracted with
ether (3 × 50 mL). The combined organic layer was washed
with brine. The mixture was filtered over dicalite. The
separated organic layer was dried and filtered, and the solvent
was evaporated to afford 72c (0.481 g, 100%): mp 128 °C; 1H
NMR (DMSO-d6) δ 2.01 (2H, m), 3.01 (2H, m), 4.45 (4H, m),
7.24 (1H, m), 7.32 (4H, m), 7.72 (1H, d, J ) 8.7 Hz), 8.12 (1H,
d, J ) 8.7 Hz), 8.22 (1H, s), 8.66 (1H, s). Anal. (C20H17NO2) C,
H, N.
Hz), 3.05 (2H, t, J ) 5.1 Hz), 4.43 (2H, t, J ) 5.1 Hz), 7.51
(1H, m), 7.70 (2H, m), 8.17 (1H, s). Anal. (C12H10BrNO) C, H,
N.
1-(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-8-yl)-2-phe-
nylethanone (83). n-BuLi (1.6 M) in hexane (7.8 mL, 0.0125
mol) was added dropwise at -78 °C to a solution of 81 (3 g,
0.0113 mol) in THF (50 mL) under N2 flow. The mixture was
stirred for 1 h. A solution of N-methoxy-N-methylphenylac-
etamide (3.05 g, 0.017 mol) in THF (30 mL) was added
dropwise at -78 °C. The mixture was stirred from -78 to 0
°C, poured out into H2O, and extracted with EtOAc. The
organic layer was separated, dried (MgSO4), and filtered, and
the solvent was evaporated till dryness. The residue (5.7 g)
was purified by column chromatography over silica gel (elu-
ent: cyclohexane/EtOAc 60/40; 15-35 µm). The pure fractions
were collected, and the solvent was evaporated. The residue
was precipitated from diethyl ether to afford 83 (1.2 g, 35%):
mp 137 °C; 1H NMR (DMSO-d6) δ 2.01 (2H, q, J ) 5.1 Hz), 3.2
(2H, t, J ) 5.1 Hz), 4.42 (2H, t, J ) 5.1 Hz), 4.51 (2H, s), 7.25
(1H, m), 7.31 (4H, m), 7.89 (2H, s), 8.12 (1H, s), 8.42 (1H, s).
Anal. (C20H17NO2) C, H, N.
cis/trans-N-Methoxy-N,4-dimethylcyclohexanecarbox-
amide (cis/trans-85). CDI (32 g, 0.19 mol) was added por-
tionwise to a solution of cis/trans-84 (25 g, 0.18 mol) in CH2Cl2
(500 mL) and the mixture was stirred for 1 h at room
temperature. N,O-Dimethylhydroxylamine hydrochloride (19
g, 0.19 mol) was added and the reaction mixture was stirred
overnight at room temperature. H2O was added and the
resulting mixture was stirred for 10 min. The organic layer
was separated, dried (MgSO4), and filtered, and the solvent
was evaporated to afford cis/trans-85 (32.4 g, 100%) as a
colorless oil: 1H NMR (CDCl3) δ 0.97 (3H, d, J ) 6.9 Hz), 1.47-
1.59 (6H, m), 1.72-1.85 (3H, m), 2.53-2.75 (1H, m), 3.18 (1H,
s), 3.69 (1H, s).
N-(3-Bromophenyl)-5-chloropentanamide (76). 5-Chlo-
rovaleryl chloride (82.6 mL, 0.6394 mol) was added dropwise
at 5 °C to a solution of 75 (100 g, 0.5813 mol) and Et3N (97.1
mL, 0.6976 mol) in CH2Cl2 (800 mL). The mixture was stirred
for 30 min. H2O was added. The organic layer was separated,
dried (MgSO4), and filtered, and the solvent was evaporated
to afford 76 (178.2 g, 100%). This product was used without
further purification in the next step.
7-Bromo-2-chloro-3-(3-chloropropyl)quinoline (77).
POCl3 (140 mL, 1.507 mol) was added at 5 °C to DMF (24.8
mL, 0.32 mol). The mixture was stirred until dissolution of
the complex. 76 (60 g, 0.206 mol) was added. The mixture was
stirred at 75 °C for 6 h, cooled to room temperature, poured
out into ice H2O, filtered, washed with H2O, and dried to afford
an nonseparable mixture of 77 and 78 (60 g, 91%).
7-Bromo-3-(3-chloropropyl)quinolin-2(1H)-one (79). A
mixture of 77 (30 g, 0.094 mol) and 78 (30 g, 0.094 mol) in
HCl (6 N, 600 mL) and THF (100 mL) was stirred and refluxed
for 15 h, cooled, poured out on ice, basified with NH4OH, and
filtered. The organic layer was separated, washed with H2O,
dried (MgSO4), and filtered, and the solvent was evaporated
to afford a nonseparable 85/15 mixture of 79 and 80, respec-
tively (47.4 g, 84%).
3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl cis-4-Meth-
ylcyclohexyl Ketone (cis-86). Under N2, a mixture of 60a
(5.8 g, 0.022 mol) in THF (50 mL) was stirred at -70 °C and
n-BuLi (2.5 M) in hexane (11 mL, 0.027 mol) was added
dropwise, then the mixture was stirred for 30 min at -70 °C
and a solution of cis/trans-85 (5 g, 0.027 mol) in THF (50 mL)
was added dropwise. The reaction mixture was stirred for 30
min at -70 °C and was allowed to slowly reach room temper-
ature. H2O was added dropwise and the mixture was extracted
with EtOAc. The organic layer was separated and dried, and
the solvent was evaporated. The residue (8.5 g) was first
purified by high-performance liquid chromatography and then
separated into its optical isomers by chiral separation. The
pure fractions were collected, and the solvent was evaporated
to afford cis-86 (1.47 g, 22%): mp 128 °C; 1H NMR (CDCl3) δ
0.97 (3H, d, 6.9 Hz), 1.41-1.53 (2H, m), 1.39-1.54 (2H, m),
1.56-1.82 (7H, m), 1.88-2.01 (2H, m), 2.06-2.17 (2H, m), 3.04
(2H, t, J ) 6.6 Hz), 3.40-3.51 (1H, m), 4.51 (2H, t, J ) 5.1
Hz), 7.84 (1H, d, 8.8 Hz), 7.93 (1H, s), 8.09 (1H, dd, J ) 2.2,
8.8 Hz), 8.27 (1H, d, J ) 2.2 Hz). Anal. (C20H23NO2) C, H, N.
cis-4-Methylcyclohexyl 7,8,9,10-Tetrahydro-6H-cyclo-
hepta[b]quinolin-2-yl Ketone (cis-87). A solution of 60c (2.7
g, 0.0098 mol) in THF (60 mL) was cooled to -70 °C on a CO2
bath, and n-BuLi (2.5 M) in hexane (5 mL, 0.012 mol) was
slowly added dropwise. The mixture was stirred for 30 min at
-70 °C and cis/trans-85 (2.3 g, 0.012 mol) was slowly added
dropwise. The reaction mixture was stirred for 30 min at -70
°C and was allowed to slowly reach room temperature. The
mixture was treated with H2O. The organic layer was sepa-
rated, dried (MgSO4), and filtered off, and the solvent was
evaporated. The residue was purified and separated into its
isomers. Fractions were collected, and the solvent was evapo-
rated to afford cis-87 (0.513 g, 16%): mp 122 °C; 1H NMR
(DMSO-d6) δ 0.91 (3H, d, 6.9 Hz), 1.28-1.41 (2H, m), 1.55-
1.76 (9H, m), 1.76-1.93 (4H, m), 2.94-3.01 (2H, m), 3.14-
3.21 (2H, m), 3.60-3.70 (1H, m), 7.96 (1H, d, J ) 8.8 Hz), 8.09
(1H, dd, J ) 2.2, 8.8 Hz), 8.20 (1H, d, J ) 2.2 Hz). Anal. (C22H27-
NO) C, H, N.
8-Bromo-3,4-dihydro-2H-pyrano[2,3-b]quinoline (81).
The above mixture (44.6 g, 0.148 mol) and PPA (300 g) were
stirred at 160 °C for 15 h, cooled to room temperature, poured
out into ice H2O and NH4OH, and filtered. The organic layer
was separated, washed with H2O, dried (MgSO4), and filtered,
and the solvent was evaporated. The residue (44.1 g) was
purified by column chromatography over silica gel (eluent:
CH2Cl2/EtOAc 97/3; 15-35 µm). The pure fractions were
collected, and the solvent was evaporated. The residue was
precipitated from diethyl ether to afford 81 (12.9 g, 39%): mp
1
170 °C; H NMR (DMSO-d6) δ 1.99 (2H, q, J ) 5.1 Hz), 2.95
(2H, t, J ) 5.1 Hz), 4.41 (2H, t, J ) 5.1 Hz), 7.51 (1H, d, J )
9 Hz), 7.77 (1H, d, J ) 9 Hz), 7.87 (1H, s), 8.09 (1H, s). Anal.
(C12H10BrNO) C, H, N. The filtrate was evaporated. The
residue was precipitated from diethyl ether to afford 82 (0.5
Cell Transfection and Culture. L929sA cells stably
expressing the human mGlu1a receptor were obtained as
1
g, 9%): mp 110 °C; H NMR (DMSO-d6) δ 2.0 (2H, q, J ) 5.1

2152 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6
Mabire et al.
described previously48 and were cultured in GlutaMAX1
medium supplemented with 10% heat-inactivated dialyzed
fetal calf serum, 0.1 mg/mL streptomycin sulfate, and 100
units/mL penicillin. CHO-dhfr- cells stably expressing the rat
mGlu1a receptor were a kind gift from S. Nakanishi (Tokyo
University, Tokyo, Japan) and were grown in Dulbecco’s
modified Eagle’s medium with GlutaMAX1 with 10% heat-
inactivated dialyzed fetal calf serum, 0.4 mM l-proline, 0.2 mg/
mL streptomycin sulfate, and 200 units/mL penicillin. Cells
were kept in an atmosphere of 37 °C and 5% CO2.
The mass spectrometer was operated in positive ion mode
in a mass range of 100-1000 Da. The MS/MS spectra were
acquired using the ion-trap operating in data-dependent scan
mode, with events switching between the full scan for the mass
range 100-1000 Da (used for quantitative analysis) and MS/
MS-dependent scan mode fragmentation (used for qualitative
metabolite identification). Helium was used as the collision
gas for the tandem mass spectrometric experiments. Frag-
mentation was induced with a resonant excitation amplitude
of 1.0-1.2 V, following isolation of the ion of interest over a
given mass window of 5 Da. The ions for the MS/MS were
automatically selected for peaks set with a threshold of 105
cps. All MS/MS experiments were performed using the ion
charge control (ICC) facility to automatically adjust the
accumulation time as the ion abundance changed. Instrument
control and data acquisition and processing were performed
using Xcalibur software version 1.3 (ThermoFinnigan, San
Jose, CA).
Intracellular Ca2+ Response in Rat and Human mGlu1a
Receptor Expressing Cells. Intracellular calcium ion levels
([Ca2+]i) in human mGlu1a receptor-expressing L929sA cells
were measured using the fluorometric imaging plate reader
(Molecular Devices, Sunnyvale, CA), as described previously.48
The same procedure was followed for CHO-dhfr- cells express-
ing the rat mGlu1a receptor.
Human Liver Microsomal Incubations. Human liver
samples obtained from five kidney donors from the Gasthuis-
berg Hospital, Leuven, Belgium, with the consent of the donor
and hospital were used to make microsomal preparations
according to a previously described method.49 All incubations
were conducted by shaking reaction mixtures (250 µL) con-
taining 5 µM test compound, 1 mg of microsomal protein/mL,
0.5M Na-K-phosphate buffer pH 7.4, 1.6 mM magnesium
chloride, 1.6 mM glucose-6-phosphate and 0.125 unit/mL of
glucose-6-phosphate dehydrogenase. The mixture was prein-
cubated at 37 °C for 5 min and followed by addition of 0.16
mM NADP to start the enzymatic reaction. After 15-min
incubation, the reaction was terminated by addition of 500 µL
of DMSO or acetonitrile. Two sets of controls were used in this
experiment. The first set of controls contained all the compo-
nents as described above, except that the active protein was
substituted by heat-inactivated protein; the second set con-
tained all the components but the enzyme was denatured by
the addition of DMSO/acetonitrile before the addition of NADP
(T0 min sample). The precipitated material was removed by
centrifugation at 1200g for 10 min. The supernatant was
transferred into 96-well microplates prior to analysis by LC-
MS. The metabolic stability was determined by comparing the
peak areas of the parent compound measured at 15 min to
that of 0 min and was calculated as follows:
Acknowledgment. We gratefully thank Mirielle
Braeken for the preparation of the manuscript as well
as for her technical assistance. We thank Serge Pieters
for his technical assistance. We thank Dr. Marc Ceusters,
Dr. Marijke Somers, and Dr. Claire Mackie for fruitful
discussions and suggestions and Dr. Benoˆıt De Boeck
for careful reading of the manuscript.
Supporting Information Available: Elemental analysis
data for the compounds synthesized. This material is available
free of charge via the Internet at http://pubs.acs.org.
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