6-(4-Chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist

Article abstract of DOI:10.1021/jm060814b

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.

Full text of DOI:10.1021/jm060814b

7108
J. Med. Chem. 2006, 49, 7108-7118
6-(4-Chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-Based
Melanin-Concentrating Hormone Receptor 1 Antagonist
Francis X. Tavares,*,† Kamal A. Al-Barazanji,‡ Michael J. Bishop,† Christy S. Britt,‡ David L. Carlton,§ Joel P. Cooper,†
Paul L. Feldman,† Dulce M. Garrido,† Aaron S. Goetz,| Mary K. Grizzle,‡ Donald L. Hertzog,† Diane M. Ignar,‡
Daniel G. Lang, Maggie S. McIntyre, Ronda J. Ott,# Andrew J. Peat,† and Hui-Qiang Zhou†
Department of Medicinal Chemistry, Department of Metabolic Diseases, Pharmaceutical DeVelopment, Department of Research Bioanalysis
and Drug Metabolism, Department of Biochemical and Analytical Pharmacology, and Screening and Compound Profiling, GlaxoSmithKline,
Research Triangle Park, North Carolina 27709
ReceiVed July 11, 2006
Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide
levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these
studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred
considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal,
the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification
of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable
pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a
high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template
for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this
template in the pursuit toward development of effective anti-obesity agents.
Introduction
Obesity is gradually becoming a leading cause of morbidity
as a result of an increase in associated risk factors such as
dyslipidemia, type 2 diabetes, stroke, cardiovascular disease,
and cancer. There is an increasing amount of effort within the
pharmaceutical industry to develop anti-obesity agents that offer
significant efficacy as well as a cleaner safety profile than
currently marketed anti-obesity agents such as Xenical. Most
of the current efforts have focused on central targets. Some of
the more promising approaches include 5HT2c agonists, CB1
antagonists, melanocortin receptor agonists, and melanin-
concentrating hormone receptor 1 antagonists (MCHR1).
Melanin-concentrating hormone (MCH) is a cyclic 19-amino
acid peptide produced by neurons in the lateral hypothalamus.
This region plays an important role in controlling feeding
behavior and is responsible for physiological effects on its
Figure 1.
cognate receptor MCHR1.1,2 A closely related MCHR2 receptor
increased metabolic rate,5 whereas MCHR1(-/-) mice are
has also been identified, but its functional resemblance is
hyperphagic and hypermetabolic with lower levels of insulin
presently unknown largely due to the absence of MCHR2
and leptin.6 Overexpression of MCH in transgenic mice leads
expression in rodents.3 In addition, because MCHR1 as well as
to obesity and insulin resistance.7 In addition to central effects,
MCHR2 are both expressed in humans, clinical studies in
the presence of MCHR1 in important metabolic organs such as
humans will determine if there is redundancy in the signaling
the pancreas and tissues such as adipose may have beneficial
pathways to compensate for the antagonism of the other. Genetic
functional consequences in energy homeostasis.8
manipulation studies in mice involving the MCHR1 as well as
There has been a recent flurry of papers disclosing the effects
the MCH peptide have been very useful in associating the
of an MCHR1 antagonist in diet-induced obese (DIO) animal
MCHR as a key mediator of energy homeostasis. For example,
models (Figure 1).9 Early reports on the use of small molecule
acute ICV administration of MCH in rats stimulates food
MCHR1 antagonists validating the genetic studies in rodents
consumption and increases body weight.4 Mice lacking MCH
has recently spurred considerable efforts in the discovery of
have reduced body weight and are lean due to hypophagia and
additional MCHR1 antagonists.9a-d Considering the contrasting
effects of the MCH peptide versus MCHR1 knockouts, that is,
* To whom correspondence should be addressed. Phone: (919) 483-
hypophagic versus hyperphagic effects as described above, it
7456. Fax: (919)-483-6053. E-mail: fxt66911@gsk.com.
† Department of Medicinal Chemistry.
is interesting to note the differences observed in the feeding
effects of various small molecule antagonists of MCHR1 when
administered to DIO animal models. For example, researchers
from some laboratories observed an increase in energy expen-
diture without an effect on food intake,9c,d,m-o,q,s while others
‡ Department of Metabolic Diseases.
§ Pharmaceutical Development.
| Screening and Compound Profiling.
Department of Biochemical and Analytical Pharmacology.
# Department of Research Bioanalysis and Drug Metabolism.
10.1021/jm060814b CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/04/2006

Melanin-Concentrating Hormone Receptor 1 Antagonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24 7109
Scheme 1. Synthetic Route to Targets 12 and 17a
a Reagents and conditions: (a) MeOH, H2SO4, reflux; (b) LiAlH4, THF; (c) 2, PhOH, 100-135 °C; (d) (CH3)3CCOCl, Et3N, CHCl3; (e) PPh3, CBr4; (f)
pyrrolidine, THF, reflux, 1.5 h; (g) 2 N HCl, EtOH, reflux.
Scheme 2. Synthetic Route to Targets 14-16a
a Reagents and conditions: (a) (CO)2Cl2, CH2Cl2, DMF; (b) CH2Cl2, amine.
Scheme 3. Synthetic Route to Targets 18-23a
a Reagents and conditions: (a) AcCl, CH2Cl2, Hunig’s base; (b) DMF-DMA, 100 °C; (c) amine, EtOH, reflux; (d) NaBH4, MeOH; (e) HCl, THF; (f)
10% Pd/C, H2, 30 psi; (g) 2, PhOH, 100-135 °C.
have reported a hypophagic effect as well as an increased
metabolic rate,9j,l,p,t the latter phenotype being consistent with
MCH peptide knockouts.
conversion of the alcohol using triphenylphosphine bromine
complex to afford the bromide 4. Sequential treatment of the
bromide 4 with piperidine, followed by deprotection of the
amine with 2 N HCl, provided the free amine, which was
coupled to 2 to afford analogue 17. The naphthyl analogues
13-16 were accessed using conditions shown in Scheme 2.
Treatment of commercially available 6-amino-2-naphthalene-
carboxylic acid 1 (R ) COOH) with 2 afforded acid 13.
Intermediate 13 was treated with oxalyl chloride to afford the
acid chloride, which was treated with various amines to provide
the amides 14-16. Analogues 18-23, containing a di or
tetrahydronaphthalene moiety, were synthesized as shown in
Scheme 3. The amine precursors required in the synthesis of
the final products 18-23 were synthesized according to
literature procedures.11 Protection of the amino group in 5 with
acetyl chloride followed by treatment with N,N-dimethyl-1,1-
bis(methyloxy)methanamine afforded the intermediate 6. Dis-
placement of the dimethylamino group in 6 with various amines
followed by reduction with NaBH4 and subsequent treatment
with 4 N HCl, Pd/C/H2, and 2 gave the dihydronaphthalene
analogues 18-20. The synthesis of tetrahydronaphthalene-
containing compounds involved similar transformations on
intermediate 6, with an additional hydrogenation step prior to
treatment with 2 to afford analogues 21-23. The benzothiophene-
containing targets were synthesized as shown in Scheme 4.
Treatment of 2-chloro-5-nitrobenzaldehyde 7 with methyl
Reports from our laboratories have disclosed small molecule
MCHR1 antagonists that have shown to reduce body weight in
mice when fed on a high fat diet.10 In the preceding work, a
small molecule quinoline-based MCHR1 antagonist had been
demonstrated to show weight loss in high-fat DIO mice. The
present study was undertaken to explore replacements of the
quinoline core to afford potent and selective MCHR1 antago-
nists. Identification of naphthalene as well as other heterocyclic
right-hand side (RHS) analogues is described along with the
efficacy of a representative example in a chronic setting in DIO
mice.
Chemistry
The synthesis of analogues containing the naphthyl group is
as shown in Scheme 1. Treatment of methyl 5-(4-chlorophenyl)-
3-{[(1E)-(dimethylamino)methylidene]amino}-2-thiophenecar-
boxylate 2 with commercially available 2-naphthalenamine 1
(R1 ) H) and phenol as a solvent afforded analogue 11. Fisher
esterification of 1 (R1 ) COOH) with sulfuric acid and methanol
gave the intermediate ester, which was reduced with LiAlH4 to
afford the amino alcohol 3. Coupling of the amino group in 3
with 2 afforded analogue 12. Intermediate 3 was also used in
the synthesis of compound 17. This involved protection of the
amino group in 3 with pivaloyl chloride, followed by the

7110 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24
Scheme 4. Synthetic Route to Targets 24-31a
TaVares et al.
a Reagents and conditions: (a) methyl mercaptoacetate, THF; (b) DMF, KOH; (c) LiOH, THF, H2O; (d) EDC, amine, Hunig’s base; (e) 10% Pd/C, H2,
30 psi; (f) LiAlH4, THF, reflux; (g) 2, PhOH, 100-135 °C.
Scheme 5. Synthetic Route to Targets 32 and 33a
a Reagents and conditions: (a) SO2Cl2; (b) pyrrolidines, Et3N, DMF; (c) (CH3)3Al, THF; (d) 10% Pd/C, H2, 1 atm; (e) 3, PhOH, 100-135 °C.
Scheme 6. Synthetic Route to Targets 34 and 35a
a Reagents and conditions: (a) MeI, NaH, DMF; (b) (CH3)3Al, THF; (c) CBr4, (Ph)3P, CH2Cl2; (d) pyrrolidines, Et3N, DMF; (e) 10% Pd/C, H2, 50 psi;
(f) 2, PhOH, 100-135 °C.
mercaptoacetate in the presence of potassium hydroxide in DMF
gave the intermediate methyl-5-nitro-1-benzothiophene-2-car-
boxylate. Hydrolysis of the ester with lithium hydroxide
followed by coupling with various amines using EDC afforded
the nitro amides 24a-31a. Reduction of the nitro group with
Pd/C under hydrogen to provide intermediates 24b-31b,
followed by subsequent reduction of the amide bond with
LiAlH4 in refluxing THF, afforded 24c-31c. The amines 24c-
31c were then coupled with 2 to provide the desired analogues
24-31. The synthesis of analogues containing the benzofuran
moiety 32 and 33 is as shown in Scheme 5. Formation of the
acid chloride by treatment with thionyl chloride was followed
by addition of the appropriate amines to give the amides 32a-
33a. Reduction of the amide bond with allane in refluxing THF
afforded intermediates 32b-33b. The nitro group was reduced
using Pd/C under hydrogen and then coupled with 2 to afford
analogues 32 and 33.
triphenylphosphine and carbon tetrabromide afforded the bro-
mide 10. The bromide of 10 was displaced with appropriate
pyrrolidines to give the nitro compounds 34a-35a. Reduction
of the nitro group followed by coupling with 2 gave the desired
analogues 34 and 35.
Results and Discussion
Having explored the structure/activity relationship in the
quinoline series, the effect of including other RHS moieties was
explored with the aim of affording potent, selective, and
efficacious MCHR1 antagonists. Earlier efforts had identified
unique structural features on the RHS of the template of the
quinoline core that imparted a significant boost in activity.
Specifically, the presence of an important interaction of an
Asp123 residue in the protein with the MCHR1 antagonists was
recognized.10 In addition, there seemed to be a good correlation
between the potencies and the basicity of the moiety under
consideration. The present work explores alternate RHS chemo-
types and the subsequent determination of SAR relationships.
Analogues 34 and 35 were synthesized as shown in Scheme
6. The indole nitrogen of 9 was methylated using methyl iodide
followed by subsequent reduction of the ester with allane to
afford the intermediate alcohol, which on treatment with
As shown in Table 1, the naphthalene analogue 11 (IC50
10,000 nM) was inactive at MCHR1. Addition of a hydroxy-
>

Melanin-Concentrating Hormone Receptor 1 Antagonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24 7111
Table 2. Inhibitory Potencies (IC50) vs hMCHR1a
Table 1. Inhibitory Potencies (IC50) vs hMCHR1*
a Antagonism of human MCHR1 in CHO Gal4/Elk1-Luc+ reporter assay.
IC50 values represent averages of 2-3 experiments, with a standard deviation
of 3-fold.
a Antagonism of human MCHR1 in CHO Gal4/Elk1-Luc+ reporter assay.
IC50 values represent averages of 2-3 experiments, with a standard deviation
of 3-fold.
nists. Analogues containing a single basic nitrogen, as in 24-
28, were of comparable potencies, whereas incorporation of an
additional nitrogen, such as in piperazines 29 (IC50 ) 5.7 nM,
pKa ) 2.75 and 7.97 of the proximal and distal nitrogens,
respectively) and 30 (IC50 ) 29 nM, pKa ) 2.44 and 5.78 of
the proximal and distal nitrogens, respectively), resulted in a
4.8-fold (vs 27, pKa ) 8.29) and 5.0-fold (vs 28, pKa ) 7.91)
loss in activity. This modest loss in activity could be explained
by the decrease in the basicity of the proximal nitrogens and a
subsequent decrease in the percent ionized. Replacement of the
sulfur with oxygen and nitrogen heteroatoms afforded analogues
32-35. The benzofuran analogue 33 (IC50 ) 9.5 nM) suffered
an 8.6-fold loss in activity compared to 32 (IC50 ) 1.1 nM),
whereas there was no loss in activity when going from
N-methylindole 34 (IC50 ) 1.1 nM) to 35 (IC50 ) 1.4 nM). In
addition, there was no significant change in activity on making
the S/O/N-methyl transitions (analogues 25, 32, and 34).
methylene group as in analogue 12 (IC50 ) 31.6 nM) afforded
a potent antagonist at the receptor. This resultant is consistent
with our previous studies implying the presence of an interaction
of Asp123 with the hydroxyl group.10 Introduction of a carboxyl
group as in 13 (IC50 > 10,000 nM) resulted in a loss in activity,
indicating the presence of an unfavorable interaction of the
negatively charged carboxyl group in 13 with Asp123. Replace-
ment of a physiologically negatively charged carboxyl group
in 13 with a neutral amide 14 (IC50 > 10,000 nM) also resulted
in loss in activity. Interestingly, addition of a methylene spacer
in the amide to incorporate a basic nitrogen resulted in analogue
15 (pKa ) 9.58, IC50 ) 5.0 nM) that was equipotent to 12.
Incorporation of an additional methylene spacer in analogue 15
to afford compound 16 (IC50 ) 1412 nM) resulted in a 282-
fold loss in activity compared to 15. This result suggests that
optimal antagonism within the naphthlene series of compounds
requires the presence of a hydroxyl group (analogue 12) or a
basic nitrogen, which is physiologically charged with an
appropriate spatial orientation. Both options provide an op-
portunity for a hydrogen bond to the Asp123 residue of the
receptor. Replacement of the hydroxyl in analogue 12 with an
alternate hydrogen bond donor, such as a physiologically
charged basic nitrogen to afford 17 (IC50 ) 0.39 nM), resulted
in an 81-fold boost in activity compared to that of 12.
Modifications of the naphthyl core to afford di- and tetrahy-
dronaphthylene analogues 18-23 gave MCHR1 antagonists that
were equipotent in activity. Having explored the naphthalene
analogues, efforts were directed to look at heterocyclic replace-
ments that might offer physiochemical advantages in solubility
over their lipophilic naphthalene counterparts. As shown in
Table 2, efforts to replace the naphthylene moiety evolved from
the use of the isosteric benzothiophene to other heteroatom-
containing systems such as benzofuran and indoles, with the
latter potentially offering beneficial physiochemical advantages
over the more hydrophobic benzothiophene counterpart. The
benzothiophene analogues 24-31 were potent MCHR1 antago-
Pharmacokinetic Properties
Representative compounds from Tables 1 and 2 were evalu-
ated for their pharmacokinetic properties in rats. As shown in
Table 3, compound 18 had good oral bioavailability (67%) but
suffered due to a very high total clearance (Cl ) 80 mL/min/
kg). To prevent potential metabolism due to N-demethylation,
analogue 19 was synthesized. This resulted in a lower total
clearance (Cl ) 21.2 mL/min/kg), a better half-life (t1/2 ) 11
h), and a decent systemic exposure (F ) 57%). The ben-
zothiophene analogues 26, 28, and 29 were also profiled in rats,
as shown in Table 3. The hydroxypyrrolidine 26 and phenylpi-
peridine analogue 28 had low percent oral bioavailibilities
(36.1% and 27.9% respectively), with the latter having a very
low clearance (Cl ) 2.9 mL/min/kg). The piperazine analogue
29 on the other hand had good oral bioavailability (66%) and
a longer half-life (t1/2 ) 9.1 h) with moderate clearance (39
mL/min/kg) and better solubility compared to that of analogues
26 and 28. The benzofuran analogue 32 suffered from an
extremely high clearance (Cl ) 115 mL/min/kg) and a low half-

7112 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24
Table 3. Rat Pharmacokinetic Data for Representative Analogsa
TaVares et al.
Figure 2. Effect of compound 29 at 1, 3, and 10 mg/kg (orally, qd)
on body weight loss in high-fat DIO AKR/J mice. Weight loss is
expressed as percentage weight change from pretreatment value for
each treatment group. Rimonabant, a CB1 receptor inverse agonist,
was used as internal control. Values are mean ( SEM, n ) number of
mice per group.
a Compounds were dosed in 20% DMSO/21% Solutol in 10 mM (final
conc) MSA (n ) 2); IV dosing done at 3 mg/kg, PO dosing done at 10
mg/kg. b Half-life for IV dosing; plasma drug levels were determined by
LC-MS/MS.
chromatographic purification unless otherwise indicated. Anhydrous
solvents were obtained from Aldrich (Sure Seal). 1H NMR spectra
were recorded on a Varian spectrometer; chemical shifts are reported
in parts per million (ppm) relative to TMS. The following
abbreviations are used to describe peak patterns when appropriate:
b ) broad, s ) singlet, d ) doublet, t ) triplet, q ) quartet, m )
multiplet. High performance liquid chromatography (HPLC) was
performed on a Beckman 126 with a Beckman 166 UV detector
(monitoring at 215 nm) with a Rainin Dynamax-60A column using
a gradient consisting of 20/80 A/B to 10/90 A/B over 20 min, where
A ) 1% aqueous trifluoroacetic acid (TFA) and B ) 1% TFA in
CH3CN. Elemental analyses, performed by Atlantic Microlab, Inc.,
Norcross, GA, were within 0.4% of the theoretical values calculated
for C, H, and N. For compounds that did not have elemental
analysis, purity was determined by using two different methods.
Method A, MeOH/H2O from 0 to 100%; method B, CH3CN/H2O
from 10 to 100%. Compounds were found to be >95% in purity
by both method A and method B, unless otherwise as stated in the
experimental.
life (t1/2 ) 1.6 h). Due to its good systemic exposure and long
half-life, analogue 29 was profiled in a DIO efficacy model.
Pharmacodynamics
The efficacy of compound 29 in inducing weight loss was
evaluated in a high-fat (58% kcal of fat, Research Diets
#D12331) DIO AKR/J mice. During a 21-day treatment, oral
administration of compound 29 at 1, 3, and 10 mg/kg once daily
caused a dose-dependent weight loss of -1.1, -3.2, and
-11.8%, respectively, from pretreatment body weight values
(48.6 ( 0.9 g, n ) 33). There was a small reduction in body
weight (-2.2%) in the vehicle-treated animals. In the same
study, rimonabant, a CB1 receptor inverse agonist in Phase III
clinical trials, caused -8.4% weight loss from pretreatment body
weight value (Figure 2).
Conclusion
General Procedure for the Synthesis of Final Products: 6-(4-
Chlorophenyl)-3-(2-naphthalenyl)thieno[3,2-d]pyrimidin-4(3H)-
one (11). To 2-naphthalenamine was added methyl-3-{[(1E)-
(dimethylamino)methylidene]amino}-5-phenyl-2-thiophenecarboxy-
late 2 (0.145 g, 0.506 mmol) and 0.5 g of phenol as the solvent.
The reaction mixture was heated from 100 to 135 °C over a period
of 1.5 h. The crude mixture was loaded over a silica gel column
using DCM/MeOH (95:5) to afford 6-(4-chlorophenyl)-3-[2-(mor-
pholin-4-ylmethyl)quinolin-6-yl]thieno[3,2-d]pyrimidin-4(3H)-
one as a yellow solid (0.101 g, 44%). 1H NMR (400 MHz, DMSO-
d6): δ 8.56 (s, 1H), 8.14 (s, 1H), 8.10-8.01 (m, 4H), 7.95 (d, J )
8.4 Hz, 2H), 7.67-7.62 (m, 3H), 7.59 (d, J ) 8.4 Hz, 2H).
Elemental analysis was performed for C, H, and N.
With the optimized 6-(4-chlorophenyl)-3-substituted-thieno-
[3,2-d]pyrimidin-4(3H)-one core developed from SAR work in
the earlier report, efforts were directed toward exploring diverse
RHS replacements at the 3-position that could capitalize on the
putative interaction with the Asp123 residue of the MCHR1
receptor. Several new potent chemotypes were identified in the
process with representative examples showing favorable phar-
macokinetics. A representative analogue was shown to be
efficacious when dosed orally in DIO mice. The tolerability of
additional chemotypes at the 3-position enhances the utility of
these MCHR1 antagonists for further development in the
treatment of obesity.
6-(4-Chlorophenyl)-3-[6-(hydroxymethyl)-2-naphthalenyl]th-
ieno[3,2-d]pyrimidin-4(3H)-one (12): (a) Methyl 6-Amino-2-
naphthalenecarboxylate. A mixture of 6-amino-2-naphthalene-
carboxylic acid (5.00 g, 26.7 mmol), 10 mL of concentrated sulfuric
acid, and 50 mL of methanol was heated at reflux for 1.5 h. The
reaction mixture was cooled to room temperature and poured into
ice, then extracted with dichloromethane. The organic phase was
dried over sodium sulfate, and the solvent was removed under
vacuum to give 5.11 g (95% yield) of methyl 6-amino-2-naphtha-
Experimental Section
Chemistry. General Methods. Melting points were determined
using a Thomas-Hoover melting point apparatus and are uncor-
rected. Unless stated otherwise, reagents were obtained from
commercial sources and were used directly. Reactions involving
air- or moisture-sensitive reagents were carried out under a nitrogen
atmosphere. If not specified, reactions were carried out at ambient
temperature. Silica gel (EM Science, 230-400 mesh) was used for
1
lenecarboxylate as a gray solid. H NMR (400 MHz, DMSO-d6):

Melanin-Concentrating Hormone Receptor 1 Antagonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24 7113
δ 8.36 (s, 1H), 7.79 (m, 2H), 7.57 (m, 1H), 7.05 (m, 1H), 6.86 (s,
1H), 5.88 (s, 2H), 3.88 (s, 3H).
pyrrolidine to afford the desired product. 1H NMR (400 MHz,
CDCl3): δ 9.08 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 8.11 (m, 1H),
8.04 (m, 1H), 7.96 (m, 1H), 7.93 (m, 1H), 7.69 (d, J ) 8 Hz, 2H),
7.62 (m, 1H), 7.57 (s, 1H), 7.46 (d, J ) 8 Hz, 2H), 3.70 (m, 2H),
2.80-2.95 (m, 6H), 1.98 (m, 6H). APCI-LCMS m/z: 543 (M +
H). Purity was determined using method A.
6-(4-Chlorophenyl)-3-[6-(1-piperidinylmethyl)-2-naphthale-
nyl]thieno[3,2-d]pyrimidin-4(3H)-one (17): (a) N-[6-(Hydroxy-
methyl)-2-naphthalenyl]-2,2-dimethylpropanamide. Triethyl-
amine (1.2 mL, 8.67 mmol) was added to a suspension of (6-amino-
2-naphthalenyl)methanol 3 (1.00 g, 5.78 mmol) in 60 mL of
chloroform. The mixture was cooled in an ice bath and pivaloyl
chloride (0.81 mL, 10.4 mmol) was added. The reaction mixture
was stirred at 0 °C for 1 h. After warming to room temperature,
the mixture was diluted with chloroform and washed with 1 N
aqueous hydrochloric acid and water, dried over anhydrous sodium
sulfate, and concentrated under vacuum. The residue was purified
by chromatography on silica gel with hexane/ethyl acetate to give
1.22 g (80% yield) of a yellow solid. 1H NMR (400 MHz,
CDCl3): δ 8.26 (s, 1H), 7.78 (m, 3H), 7.47 (m, 3H), 4.83 (s, 2H),
1.66 (br s, 1H), 1.36 (s, 9H).
(b) (6-Amino-2-naphthalenyl)methanol (3). Lithium aluminum
hydride (41 mL of a 1.0 M solution in tetrathydrofuran) was added
to a solution of methyl 6-amino-2-naphthalenecarboxylate (5.11 g,
25.4 mmol) in 100 mL of anhydrous tetrahydrofuran while cooling
in an ice bath. The mixture was stirred at 5 °C for 2 h and quenched
with 5 mL of water. The mixture was filtered, and the filter cake
was washed with tetrahydrofuran (4 × 30 mL). The combined
filtrates were evaporated to dryness to give 4.06 g of a yellow solid.
1H NMR (400 MHz, DMSO-d6): δ 7.52 (m, 2H), 7.43 (m, 1H),
7.22(m, 1H), 6.88 (m, 1H), 6.77 (s, 1H), 5.28 (s, 2H), 5.08 (m,
1H), 4.51 (m, 2H).
6-(4-Chlorophenyl)-3-[6-(hydroxymethyl)-2-naphthalenyl]th-
ieno[3,2-d]pyrimidin-4(3H)-one (12). The title compound was
prepared by reaction of methyl 5-(4-chlorophenyl)-3-{[(1E)-(di-
methylamino)methylidene]amino}-2-thiophenecarboxylate 2 (1.86
g, 5.78 mmol) and (6-amino-2-naphthalenyl)methanol 3 (1.00 g,
5.78 mmol), with 0.5 g of phenol as the solvent. The reaction
mixture was heated from 100 to 135 °C over a period of 1.5 h.
The crude product was purified by trituration with methanol to give
1.20 g of a beige powder. 1H NMR (400 MHz, DMSO-d6): δ 8.58
(s, 1H), 8.12 (s, 1H), 8.07 (m, 1H), 8.03 (s, 1H), 7.96 (m, 4H),
7.59 (m, 4H), 5.43 (m, 1H), 4.73 (m, 2H). Elemental analysis was
performed for C, H, and N.
(b) N-[6-(Chloromethyl)-2-naphthalenyl]-2,2-dimethylpro-
panamide (4). A mixture of 6.63 g of polystyrene-triphenylphos-
phine resin (1.35 mmol/g, 8.95 mmol) and N-[6-(hydroxymethyl)-
2-naphthalenyl]-2,2-dimethylpropanamide (1.15 g, 4.47 mmol) in
75 mL of carbon tetrachloride was heated at reflux for 30 min.
The reaction mixture was cooled to room temperature and filtered.
The resin on the filter was washed with 4 × 20 mL portions of
dichloromethane, and the filtrates were combined and evaporated
6-[6-(4-Chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-
2-naphthalenecarboxylic Acid (13). The title compound was
prepared by reaction of methyl 5-(4-chlorophenyl)-3-{[(1E)-(di-
methylamino)methylidene]amino}-2-thiophenecarboxylate 2 (1.09
g, 3.38 mmol) and 6-amino-2-naphthalenecarboxylic acid (0.63 g,
3.38 mmol), as described for analogue 11. The crude product was
triturated with methanol and dried under vacuum to give 0.345 g
1
under vacuum to give 0.87 g (71% yield) of a yellow solid. H
NMR (400 MHz, CDCl3): δ 7.80 (m, 4H), 7.46 (m, 2H), 7.23 and
7.05 (m, 1H), 4.74 (s, 2H), 1.41 and 1.36 (s, 9H).
1
(25% yield) of an off-white solid. H NMR (400 MHz, DMSO-
(c) 2,2-Dimethyl-N-[6-(1-piperidinylmethyl)-2-naphthalenyl]-
propanamide. A mixture of N-[6-(chloromethyl)-2-naphthalenyl]-
2,2-dimethylpropanamide 4 (0.200 g, 0.73 mmol), piperidine (0.18
mL, 1.81 mmol), and 2 mL of tetrahydrofuran was heated at reflux
for 1.5 h. The solvent was evaporated under vacuum, and the residue
was purified by chromatography on silica gel with dichloromethane/
methanol to give 0.089 g (38% yield) of the product as an off-
white solid. 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.80 (m,
2H), 7.75 (s, 1H), 7.52 (s, 1H), 7.48 (m, 2H), 3.65 (s, 2H), 2.47
(m, 4H), 1.65 (m, 4H), 1.48 (m, 2H), 1.40 (s, 9H).
d6): δ 8.70 (s, 1H), 8.60 (s, 1H), 8.28 (m, 1H), 8.23 (s, 1H), 8.09
(s, 2H), 8.03 (s, 1H), 7.96 (d, J ) 8.6 Hz, 2H), 7.76 (m, 1H), 7.60
(d, J ) 8.6 Hz, 2H). Elemental analysis was performed for C, H,
and N.
General Procedure for the Synthesis of Compound 14-16.
6-(4-Chlorophenyl)-3-[6-(1-pyrrolidinylcarbonyl)-2-naphthale-
nyl]thieno[3,2-d]pyrimidin-4(3H)-one (14). Oxalyl chloride (0.015
mL, 0.17 mmol) and a catalytic amound of N,N-dimethylformamide
were added to a suspension of 6-[6-(4-chlorophenyl)-4-oxothieno-
[3,2-d]pyrimidin-3(4H)-yl]-2-naphthalenecarboxylic acid 13 (0.050
g, 0.12 mmol) in 2 mL of dichloromethane. The reaction mixture
was stirred at room temperature for 30 min. The solvent was
removed under vacuum, and the residue was suspended in 2 mL
of dichloromethane. Pyrrolidine (0.024 mL, 0.29 mmol) was added.
The solvent was evaporated, and the residue was purified by
chromatography on silica gel with a gradient of 0 to 10% methanol
in dichloromethane to afford 0.020 g (36% yield) of the title
(d) 6-(1-Piperidinylmethyl)-2-naphthalenamine. Aqueous hy-
drochloric acid (2 mL of a 2 N solution) was added to a suspension
of 2,2-dimethyl-N-[6-(1-piperidinylmethyl)-2-naphthalenyl]propana-
mide from step c above (0.089 g, 0.27 mmol) in 1 mL of ethanol.
The resulting solution was heated in a microwave at 110 °C for 40
min. The cooled reaction mixture was neutralized with solid sodium
bicarbonate and extracted with dichloromethane. The organic layer
was dried over sodium sulfate, and the solvent was evaporated to
give 0.041 g (63% yield) of 6-(1-piperidinylmethyl)-2-naphthale-
1
compound as a white solid. H NMR (400 MHz, DMSO-d6): δ
1
8.57 (s, 1H), 8.21 (m, 2H), 8.17 (m, 1H), 8.05 (m, 1H), 8.01 (s,
1H), 7.94 (d, J ) 8.6 Hz, 2H), 7.72 (m, 2H), 7.58 (d, J ) 8.6 Hz,
2H), 3.52 (m, 2H), 3.46 (m, 2H), 1.90 (m, 2H), 1.83 (m, 2H). APCI-
LCMS m/z: 486 (M + H). Purity was determined using method
B.
namine. H NMR (400 MHz, CDCl3): δ 7.61 (m, 2H), 7.53 (m,
1H), 7.38 (m, 1H), 6.95 (m, 2H), 4.0 (br s, 2H), 3.61 (s, 2H), 2.46
(m, 4H), 1.61 (m, 4H), 1.44 (m, 2H).
6-(4-Chlorophenyl)-3-[6-(1-piperidinylmethyl)-2-naphthale-
nyl]thieno[3,2-d]pyrimidin-4(3H)-one (17). The title compound
was prepared by reaction of methyl 5-(4-chlorophenyl)-3-{[(1E)-
(dimethylamino)methylidene]amino}-2-thiophenecarboxylate 2 (0.055
g, 0.17 mmol) and 6-(1-piperidinylmethyl)-2-naphthalenamine (step
d above; 0.041 g, 0.17 mmol), as described in the synthesis of
analogue 11. The crude product was triturated with methanol to
6-[6-(4-Chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-
N-[2-(1-pyrrolidinyl)ethyl]-2-naphthalenecarboxamide (15). The
acid chloride, obtained during the process of preparing analogue
14, was treated with [2-(1-pyrrolidinyl)ethyl]amine instead of
pyrrolidine to afford the desired product. 1H NMR (400 MHz,
CDCl3): δ 8.76 (s, 1H), 8.56 (br s, 1H), 8.29 (s, 1H), 8.25 (m,
1H), 8.20 (m, 1H), 8.03 (m, 1H), 7.97 (m, 1H), 7.72 (d, J ) 8 Hz,
2H), 7.66 (m, 1H), 7.61 (s, 1H), 7.50 (d, J ) 8 Hz, 2H), 3.54 (m,
2H), 3.28 (m, 2H), 2.79 (m, 2H), 2.17 (m, 2H), 1.87 (m, 2H). APCI-
LCMS m/z: 529 (M + H). Purity was determined using method
A.
1
give 0.040 g (48% yield) of a white solid. H NMR (400 MHz,
DMSO-d6): δ 8.56 (s, 1H), 8.11 (s, 1H), 8.03 (m, 2H), 7.95 (m,
4H), 7.61 (m, 4H), 3.63 (s, 2H), 2.38 (m, 4H), 1.52 (m, 4H), 1.42
(m, 4H). Treatment with trifluoroacetic acid, as described in
1
example 31, step b, gave 0.035 g of the corresponding salt. H
NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H), 8.58 (s, 1H), 8.18
(m, 4H), 8.05 (s, 1H), 7.97 (m, 1H), 7.79 (m, 2H), 7.60 (m, 2H),
4.52 (s, 2H), 3.41 (m, 2H), 2.95 (m, 2H), 1.82 (m, 2H), 1.70 (m,
2H), 1.40 (m, 1H), 1.07 (m, 1H). ES-LCMS m/z: 486 (M + H).
Purity was determined using method A.
6-[6-(4-Chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-
N-[3-(1-pyrrolidinyl)propyl]-2-naphthalenecarboxamide (16).
The acid chloride, obtained during the process of preparing analogue
14, was treated with [3-(1-pyrrolidinyl)propyl]amine instead of

7114 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24
TaVares et al.
6-(4-Chlorophenyl)-3-{6-[(dimethylamino)methyl]-7,8-dihy-
dro-2-naphthalenyl}thieno[3,2-d]pyrimidin-4(3H)-one (18). The
title compound was synthesized by treatment of 6-[(dimethylamino)
methyl]-7,8-dihydro-2-naphthalenamine with methyl-3-{[(1E)-(di-
methylamino)methylidene]amino}-5-phenyl-2-thiophenecarboxylate
2, employing the general procedure described for analogue 11. 1H
NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.98 (s, 1H), 7.93
(d, J ) 8.6 Hz, 2H), 7.59 (d, J ) 8.6 Hz, 2H), 7.26 (m, 3H), 6.49
(s, 1H), 3.02 (s, 2H), 2.83 (t, J ) 8.1 Hz, 2H), 2.32 (t, J ) 8.1 Hz,
2H), 2.2 (s, 6H). Elemental analysis was performed for C, H, and
N.
6-(4-Chlorophenyl)-3-[6-(1-pyrrolidinylmethyl)-7,8-dihydro-
2-naphthalenyl]thieno[3,2-d]pyrimidin-4(3H)-one (19). The title
compound was synthesized by treatment of [6-(1-pyrrolidinyl-
methyl)-7,8-dihydro-2-naphthalenyl]amine with methyl-3-{[(1E)-
(dimethylamino)methylidene]amino}-5-phenyl-2-thiophenecarboxy-
late 2, employing the general procedure described for analogue 11.
1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.98 (s, 1H), 7.93
(d, J ) 8.4 Hz, 2H), 7.59 (d, J ) 8.4 Hz, 2H), 7.26 (m, 3H), 6.50
(s, 1H), 3.18 (s, 2H), 2.83 (t, J ) 8.0 Hz, 2H), 2.50 (br s, 4H),
2.32 (t, J ) 8.0 Hz, 2H), 1.73 (br s, 4H). Elemental analysis was
performed for C, H, and N.
6-(4-Chlorophenyl)-3-[6-(1-piperidinylmethyl)-7,8-dihydro-2-
naphthalenyl]thieno[3,2-d]pyrimidin-4(3H)-one (20). The title
compound was synthesized by treatment of [6-(1-piperidinyl-
methyl)-7,8-dihydro-2-naphthalenyl]amine with methyl-3-{[(1E)-
(dimethylamino)methylidene]amino}-5-phenyl-2-thiophenecarboxy-
late 2, employing the general procedure described for analogue 11.
1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.97 (s, 1H), 7.94
(d, J ) 8.6 Hz, 2H), 7.59 (d, J ) 8.6 Hz, 2H), 7.25 (m, 3H), 6.47
(s, 1H), 3.02 (s, 2H), 2.82 (t, J ) 8.0 Hz, 2H), 2.31 (m, 6H), 1.51
(m, 4H), 1.40 (br s, 2H). Elemental analysis was performed for C,
H, and N.
6-(4-Chlorophenyl)-3-{6-[(dimethylamino)methyl]-5,6,7,8-tet-
rahydro-2-naphthalenyl}thieno[3,2-d]pyrimidin-4-(3H)-one (21).
The title compound was synthesized by treatment of [(6-amino-
1,2,3,4-tetrahydro-2-naphthalenyl)methyl]dimethylamine 6-[(di-
methylamino)methyl]-5,6,7,8-tetrahydro-2-naphthalenamine with
methyl-3-{[(1E)-(dimethylamino)methylidene]amino}-5-phenyl-2-
thiophenecarboxylate 2, employing the general procedure described
for analogue 11. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H),
7.98 (s, 1H), 7.93 (d, J ) 8.6 Hz, 2H), 7.59 (d, J ) 8.6 Hz, 2H),
7.24 (m, 3H), 2.95 (m, 1H), 2.82 (m, 2H), 2.43 (m, 2H), 2.2 (br,
6H), 1.96 (m, 2H), 1.36 (m, 2H). Elemental analysis was performed
for C, H, and N.
6-(4-Chlorophenyl)-3-[6-(1-pyrrolidinylmethyl)-5,6,7,8-tet-
rahydro-2-naphthalenyl]thieno[3,2-d]pyrimidin-4-(3H)-one (22).
The title compound was synthesized by treatment of [6-(1-
pyrrolidinylmethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]amine with
methyl-3-{[(1E)-(dimethylamino)methylidene]amino}-5-phenyl-2-
thiophenecarboxylate 2, employing the general procedure described
for analogue 11. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H),
7.98 (s, 1H), 7.93 (d, J ) 8.4 Hz, 2H), 7.59 (d, J ) 8.4 Hz, 2H),
7.26 (m, 3H), 2.99 (m, 1H), 2.83 (m, 2H), 2.46 (m, 7H), 1.98 (m,
2H), 1.72 (m, 4H), 1.39 (m, 1H). Elemental analysis was performed
for C, H, and N.
6-(4-Chlorophenyl)-3-[6-(1-piperidinylmethyl)-5,6,7,8-tetrahy-
dro-2-naphthalenyl]thieno[3,2-d]pyrimidin-4-(3H)-one (23). The
title compound was synthesized by treatment of [6-(1-piperidinyl-
methyl)-5,6,7,8-tetrahydro-2-naphthalenyl]amine with methyl-3-
{[(1E)-(dimethylamino)methylidene]amino}-5-phenyl-2-thiophen-
ecarboxylate 2, employing the general procedure described for
analogue 11. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.98
(s, 1H), 7.94 (d, J ) 8.6 Hz, 2H), 7.59 (d, J ) 8.6 Hz, 2H), 7.25
(m, 3H), 2.91 (m, 1H), 2.82 (m, 2H), 2.34 (m, 4H), 2.23 (d, J )
7.1 Hz, 2H), 1.97 (m, 2H), 1.53 (m, 4H), 1.40 (m, 4H). Elemental
analysis was performed for C, H, and N.
added KOH (3.0 g) in 15 mL of water dropwise. After stirring for
1 h, the contents were poured into crushed ice, and the solid was
filtered, washed with water, and dried. The crude product was taken
1
directly to the next step. H NMR (300 MHz, DMSO-d6): δ 8.96
(s, 1H), 8.40 (s,1H), 8.36 (s, 1H), 8.34 (d, J ) 7.8 Hz, 1H), 8.36
(d, J ) 7.8 Hz, 1H), 3.90 (s, 3H). ES-LCMS m/z: 238 (M + H).
(b) 5-Nitro-1-benzothiophene-2-carboxylic Acid. To a solution
of methyl 5-nitro-1-benzothiophene-2-carboxylate 14.0 g (60 mmol),
obtained in step a, in THF (60 mL) was added 60 mL of 1 N LiOH,
and the contents were stirred for 16 h. After acidification, ethyl
acetate (100 mL) was added, and the organic layer was separated.
The organic layer was dried with MgSO4 and then concentrated to
afford the acid in quantitative yield. 1H NMR (300 MHz, DMSO-
d6): δ 8.97 (s, 1H), 8.40 (m,4H). ES-LCMS m/z: 223 (M + H).
General Procedure for the Preparation of Nitro-amides (24a-
31a). To a solution of 5-nitro-1-benzothiophene-2-carboxylic acid,
obtained in 54b (5.83 mmol), in DCM (30 mL) was added Hunig’s
base (6.99 mmol), EDC (6.41 mmol), HOBT (6.99 mmol), and
piperidine (6.41 mmol), and the contents were stirred at room
temperature for 16 h. After washing with satd sodium chloride
solution, followed by satd NaHCO3 solution, the organic layer was
dried with MgSO4 and concentrated to afford the desired product.
N,N-Dimethyl-5-nitro-1-benzothiophene-2-carboxamide (24a).
1H NMR (300 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.35 (d, J ) 8.9
Hz, 1H), 8.29 (d, J ) 9.0 Hz, 1H), 8.10 (s, 1H), 3.29 (s, 3H), 3.10
(s, 3H).
1-[(5-Nitro-1-benzothien-2-yl)carbonyl]pyrrolidine (25a). 1H
NMR (300 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.35 (d, J ) 9.1 Hz,
1H), 8.11 (d, J ) 9.1 Hz, 1H), 8.03 (s, 1H), 4.23 (m, 1H), 2.87 (m,
4H), 1.87 (m, 4H).
(3R)-1-[(5-Nitro-1-benzothien-2-yl)carbonyl]-3-pyrrolidinol
(26a). 1H NMR (300 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.36 (d, J
) 9.0 Hz, 1H), 8.10 (d, J ) 8.9 Hz, 1H), 8.01 (s, 1H), 4.23 (m,
1H), 3.94 (br s, 1H), 2.81 (m, 4H), 1.89 (m, 2H).
1
1-[(5-Nitro-1-benzothien-2-yl)carbonyl]piperidine (27a). H
NMR (300 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.36 (d, J ) 9.0 Hz,
1H), 8.28 (d, J ) 9.0 Hz, 1H), 7.97 (s, 1H), 3.68 (m, 4H), 1.69 (m,
6H).
1-[(5-Nitro-1-benzothien-2-yl)carbonyl]-4-phenylpiperidine
(28a). 1H NMR (300 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.37 (d, J
) 8.9 Hz, 1H), 8.29 (d, J ) 8.8 Hz, 1H), 8.05 (s, 1H), 7.26 (m,
5H), 3.19 (m, 2H), 2.92 (m, 3H), 1.89 (m, 4H).
1-Methyl-4-[(5-nitro-1-benzothien-2-yl)carbonyl]piperazine
(29a). 1H NMR (300 MHz, DMSO-d6): δ 8.90 (s, 1H), 8.37 (d, J
) 9.0 Hz, 1H), 8.17 (d, J ) 8.9 Hz, 1H), 8.01 (s, 1H), 3.72 (m,
4H), 2.47 (m, 4H), 2.25 (s, 3H).
1-[(5-Nitro-1-benzothien-2-yl)carbonyl]-4-phenylpiperazine
(30a). 1H NMR (300 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.31 (d, J
) 9.0 Hz, 1H), 8.30 (d, J ) 9.0 Hz, 1H), 8.08 (s, 1H), 7.28 (m,
2H), 7.02 (m, 2H), 6.97 (m, 1H), 3.28 (m, 4H), 2.55 (m, 4H).
4-[(5-Nitro-1-benzothien-2-yl)carbonyl]morpholine (31a). 1H
NMR (300 MHz, DMSO-d6): δ 8.85 (s, 1H), 8.32 (d, J ) 9.0 Hz,
1H), 8.25 (d, J ) 9.0 Hz, 1H), 7.98 (s, 1H), 3.67 (m, 8H).
General Procedure for the Synthesis of Compounds 24b-
31b. To a solution of the nitro compound (5.80 mmol) in methanol
(30 mL) was added 10% Pd/C (0.13 g), and the contents were kept
under H2 at 40 psi. After 4 h, the solution was filtered through
Celite and then concentrated under vacuum to afford the amine.
5-Amino-N,N-dimethyl-1-benzothiophene-2-carboxamide (24b).
1H NMR (300 MHz, DMSO-d6): δ 7.63 (d, J ) 8.7 Hz, 1H), 7.53
(s, 1H), 7.01 (s, 1H), 6.84 (d, J ) 8.6 Hz, 1H), 5.21 (br s, 2H),
3.21 (s, 6H).
[2-(1-Pyrrolidinylcarbonyl)-1-benzothien-5-yl]amine (25b). 1H
NMR (300 MHz, DMSO-d6): δ 7.53 (d, J ) 8.5 Hz, 1H), 7.43 (s,
1H), 7.04 (s, 1H), 6.86 (d, J ) 8.5 Hz, 1H), 5.21 (br s, 2H), 4.22
(m, 1H), 2.87 (m, 4H), 1.88 (m, 4H).
(3R)-1-[(5-Amino-1-benzothien-2-yl)carbonyl]-3-pyrrolidi-
1
N,N-Dialkyl-5-nitro-1-benzothiophene-2-carboxamides (24a-
31a): (a) Methyl 5-Nitro-1-benzothiophene-2-carboxylate. To
a solution of 2-chloro-5-nitrobenzaldehyde (5.55 g, 30 mmol) and
methyl mercaptoacetate (2.68 mL, 30 mmol) in DMF (60 mL) was
nol (26b). H NMR (300 MHz, DMSO-d6): δ 7.51 (d, J ) 8.6
Hz, 1H), 7.41 (s, 1H), 7.01 (s, 1H), 6.82 (d, J ) 8.7 Hz, 1H), 5.23
(br s, 2H), 4.21 (m, 1H), 3.96 (br s, 1H), 2.84 (m, 4H), 1.90 (m,
2H).

Melanin-Concentrating Hormone Receptor 1 Antagonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24 7115
[2-(1-Piperidinylcarbonyl)-1-benzothien-5-yl]amine (27b). 1H
NMR (300 MHz, DMSO-d6): δ 7.63 (d, J ) 8.7 Hz, 1H), 7.46 (s,
1H), 7.01 (s, 1H), 6.83 (d, J ) 8.6 Hz, 1H), 5.20 (br s, 2H), 3.36
(m, 4H), 1.68 (m, 6H).
{2-[(4-Phenyl-1-piperidinyl)carbonyl]-1-benzothien-5-yl}-
amine (28b). 1H NMR (300 MHz, DMSO-d6): δ 7.64 (d, J ) 8.6
Hz, 1H), 7.48 (s, 1H), 7.35 (m, 5H), 7.02 (s, 1H), 6.84 (d, J ) 8.6
Hz, 1H), 5.21 (br s, 2H) 3.18 (m, 2H), 2.91 (m, 3H), 1.90 (m, 4H).
{2-[(4-Methyl-1-piperazinyl)carbonyl]-1-benzothien-5-yl}-
amine (29b). 1H NMR (300 MHz, DMSO-d6): δ 7.63 (d, J ) 8.5
Hz, 1H), 7.44 (s, 1H), 7.01 (s, 1H), 6.84 (d, J ) 8.5 Hz, 1H), 5.23
(br s, 2H), 3.69 (t, J ) 4.7 Hz, 4H), 2.41 (t, J ) 4.8 Hz, 4H), 2.12
(s, 3H).
{2-[(4-Phenyl-1-piperazinyl)carbonyl]-1-benzothien-5-yl}-
amine (30b). 1H NMR (300 MHz, DMSO-d6): δ 7.65 (d, J ) 8.7
Hz, 1H), 7.52 (s, 1H), 7.30 (m, 2H), 7.03 (m, 3H), 6.86 (m, 2H),
5.25 (br s, 2H), 3.24 (m, 4H), 2.56 (m, 4H).
[2-(4-Morpholinylcarbonyl)-1-benzothien-5-yl]amine (31b).
1H NMR (300 MHz, DMSO-d6): δ 7.47 (d, J ) 8.4 Hz, 1H), 7.43
(s, 1H), 6.83 (s, 1H), 6.63 (d, J ) 8.4 Hz, 1H), 5.23 (br s, 2H),
3.34 (m, 8H).
6-(4-Chlorophenyl)-3-{2-[(dimethylamino)methyl]-1-benzothien-
5-yl}thieno[3,2-d]pyrimidin-4(3H)-one (24). 1H NMR (300 MHz,
DMSO-d6): δ 8.55 (s, 1H), 8.28 (d, J ) 8.6 Hz, 1H), 8.19 (s, 1H),
8.05 (m, 2H), 7.99 (d, J ) 8.4 Hz, 2H), 7.83 (s, 1H), 7.65 (d, J )
8.4 Hz, 2H) 3.57 (s, 2H), 2.82 (s, 6H). Elemental analysis was
performed for C, H, and N.
FP55- -6-(4-chlorophenyl)-3-[2-(1-pyrrolidinylmethyl)-1-ben-
zothien-5-yl]thieno[3,2-d]pyrimidin-4(3H)-one (25). 1H NMR
(300 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.12 (d, J ) 8.4 Hz, 1H),
8.03 (s, 1H), 7.99 (m, 3H), 7.64 (d, J ) 8.6 Hz, 1H), 7.50 (d, J )
8.6 Hz, 1H), 7.41 (s, 1H), 3.96 (s, 2H), 2.54 (m, 4H), 1.80 (m,
4H). Elemental analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-(2-{[(3R)-3-hydroxypyrrolidin-1-yl]-
methyl}-1-benzothien-5-yl)thieno[3,2-d]pyrimidin-4(3H)-one (26).
1H NMR (300 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.07 (d, J ) 8.6
Hz, 1H), 7.99 (s, 1H), 7.93 (m, 3H), 7.58 (d, J ) 8.5 Hz, 2H),
7.45 (d, J ) 8.6 Hz, 1H), 7.35 (s, 1H), 4.73 (br s, 1H), 4.21 (m,
1H), 3.90 (s, 2H), 2.81-2.48 (m, 3H), 2.41 (m, 1H), 1.98 (m, 1H),
1.48 (m, 1H). Elemental analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-[2-(piperidin-1-ylmethyl)-1-benzothien-
5-yl]thieno[3,2-d]pyrimidin-4(3H)-one (27). 1H NMR (300 MHz,
DMSO-d6): δ 8.54 (s, 1H), 8.28 (m, 2H), 8.05 (m, 3H), 8.00 (d, J
) 8.6 Hz, 1H), 7.82 (s, 1H), 7.64 (m, 2H), 3.81 (s, 2H), 2.48 (m,
4H), 1.65 (m, 6H). Elemental analysis was performed for C, H,
and N.
6-(4-Chlorophenyl)-3-{2-[(4-phenylpiperidin-1-yl)methyl]-1-
benzothien-5-yl}thieno[3,2-d]pyrimidin-4(3H)-one (28). 1H NMR
(300 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.14 (d, J ) 8.6 Hz, 1H),
8.04 (s, 1H), 7.99 (m, 3H), 7.64 (d, J ) 8.5 Hz, 1H), 7.51 (d, J )
8.4 Hz, 1H), 7.44 (s, 1H), 7.35 (m, 6H), 3.90 (s, 2H), 3.09 (m,
5H), 1.91 (m, 4H). Elemental analysis was performed for C, H,
and N.
6-(4-Chlorophenyl)-3-{2-[(4-methylpiperazin-1-yl)methyl]-1-
benzothien-5-yl}thieno[3,2-d]pyrimidin-4(3H)-one (29). 1H NMR
(300 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.07 (d, J ) 8.4 Hz, 1H),
7.98 (s, 1H), 7.93 (m, 3H), 7.58 (d, J ) 8.6 Hz, 2H), 7.45 (d, J )
8.6, Hz, 1H), 7.36 (s, 1H), 3.79 (s, 2H), 2.41-2.22 (m, 8H), 2.14
(s, 3H). Elemental analysis was performed for C, H, and N.
6-(4-Chlorophenyl)-3-{2-[(4-phenylpiperazin-1-yl)methyl]-1-
benzothien-5-yl}thieno[3,2-d]pyrimidin-4(3H)-one (30). 1H NMR
(300 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.15 (d, J ) 8.8 Hz, 1H),
8.04 (s, 1H), 7.99 (m, 6H), 7.64 (d, J ) 8.5 Hz, 1H), 7.51 (m, 1H),
7.39 (s, 1H), 7.27 (m, 1H), 6.98-6.81 (m, 2H), 3.93 (s, 2H), 3.24
(m, 4H), 2.54 (m, 4H). ES-LCMS m/z: 569 (M + H). Purity was
determined using method A.
6-(4-Chlorophenyl)-3-[2-(morpholin-4-ylmethyl)-1-benzothien-
5-yl]thieno[3,2-d]pyrimidin-4(3H)-one (31). 1H NMR (300 MHz,
DMSO-d6): δ 8.48 (s, 1H), 8.07 (d, J ) 8.4 Hz, 1H), 8.05 (s, 1H),
7.98 (m, 3H), 7.58 (d, J ) 8.6 Hz, 1H), 7.46 (d, J ) 8.5 Hz, 1H),
7.38 (s, 1H), 7.16 (m, 1H), 3.81 (s, 2H), 3.60 (m, 4H) 2.49 (m,
4H). ES-LCMS m/z: 494 (M + H). Purity was determined using
method A.
6-(4-Methylphenyl)-3-[2-(pyrrolidin-1-ylmethyl)-1-benzofuran-
5-yl]thieno[3,2-d]pyrimidin-4(3H)-one maleate salt (32): (a)
1-[(5-Nitro-1-benzofuran-2-yl)carbonyl]pyrrolidine (32a). 5-Ni-
tro-1-benzofuran-2-carboxylic acid (0.50 g, 2.41 mmol) was
suspended in thionyl chloride (5 mL) and heated to reflux. The
reaction was stirred for 16 h and concentrated to dryness. The
residue was taken up in DMF (5 mL) and pyrrolidine (0.343 g,
4.82 mmol) and triethylamine (0.488 g, 4.82 mmol) were added,
and the mixture was heated to 80 °C, stirred for 2 h, cooled to rt,
and water (50 mL) was added. Solid was collected and taken up in
EtOAc (50 mL). Organics were washed with water (3 × 150 mL),
dried over MgSO4, filtered, and concentrated to give 0.454 g (1.75
mmol, 72%) of the product as a light yellow solid. 1H NMR
(CDCl3): δ 8.61 (dd, J ) 2.2 Hz, 1H), 8.32 (dd, J ) 2.2 Hz, 9.0
Hz, 1H), 7.63 (d, J ) 9.0 Hz, 1H), 7.51 (s, 1H), 3.94 (t, J ) 6.8
Hz, 2H), 3.71 (t, J ) 7.0 Hz, 2H), 2.06 (p, J ) 6.7 Hz, 2H), 1.97
(p, J ) 7.0 Hz, 2H).
General Procedure for the Synthesis of Amines (24c-31c).
To a solution of 2-(piperidin-1-ylcarbonyl)-1-benzothien-5-ylamine
(1.0 g, 3.85 mmol) in THF (20 mL) was added a 1.0 M solution of
LAH in THF (19.2 mL, 19.2 mmol), and the contents were refluxed
for 20 h. After addition of 1 N sodium hydroxide, ethyl acetate
was added and the organic layer was separated. Drying (MgSO4)
and concentration afforded the desired product that was directly
carried to the next step.
[(5-Amino-1-benzothien-2-yl)methyl]dimethylamine (24c). 1H
NMR (300 MHz, DMSO-d6): δ 7.53 (d, J ) 8.6 Hz, 1H), 7.48 (s,
1H), 7.02 (s, 1H), 6.89 (d, J ) 8.6 Hz, 1H), 5.03 (br s, 2H), 3.63
(s, 2H), 2.21 (s, 6H).
1
[2-(1-Pyrrolidinylmethyl)-1-benzothien-5-yl]amine (25c). H
NMR (300 MHz, DMSO-d6): δ 7.52 (d, J ) 8.6 Hz, 1H), 6.95 (s,
1H), 6.84 (s, 1H), 6.63 (d, J ) 8.6 Hz, 1H), 5.20 (br s, 2H), 3.78
(s, 2H), 2.80 (m, 4H), 1.87 (m, 4H).
(3R)-1-[(5-Amino-1-benzothien-2-yl)methyl]-3-pyrrolidinol
1
(26c). H NMR (300 MHz, DMSO-d6): δ 7.43 (d, J ) 8.4 Hz,
1H), 6.94 (s, 1H), 6.82 (s, 1H), 6.61 (d, J ) 8.4 Hz, 1H), 5.01 (br
s, 2H), 4.61 (br s, 1H), 4.23 (m, 1H), 3.77 (s, 2H), 2.65 (m, 2H),
2.31 (m, 2H), 1.98 (m, 1H), 1.45 (m, 1H).
[2-(1-Piperidinylmethyl)-1-benzothien-5-yl]amine (27c). 1H
NMR (300 MHz, DMSO-d6): δ 7.50 (d, J ) 8.6 Hz, 1H), 7.46 (s,
1H), 7.0 (s, 1H), 6.88 (d, J ) 8.6 Hz, 1H), 5.02 (br s, 2H), 3.66 (s,
2H), 2.54 (m, 4H), 1.54 (m, 6H).
{2-[(4-Phenyl-1-piperidinyl)methyl]-1-benzothien-5-yl}-
amine (28c). 1H NMR (300 MHz, DMSO-d6): δ 7.51 (d, J ) 8.5
Hz, 1H), 7.34 (m, 5H), 7.05 (s, 1H), 6.90 (s, 1H), 6.69 (d, J ) 8.6
Hz, 1H), 5.03 (br s, 2H), 3.75 (s, 2H), 3.18 (m, 5H), 1.90 (m, 4H).
{2-[(4-Methyl-1-piperazinyl)methyl]-1-benzothien-5-yl}-
amine (29c). 1H NMR (300 MHz, DMSO-d6): δ 7.63 (d, J ) 8.5
Hz, 1H), 7.44 (s, 1H), 7.01 (s, 1H), 6.84 (d, J ) 8.5 Hz, 1H), 5.23
(br s, 2H), 3.69 (t, J ) 4.7 Hz, 4H), 2.41 (t, J ) 4.8 Hz, 4H), 2.12
(s, 3H).
{2-[(4-Phenyl-1-piperazinyl)methyl]-1-benzothien-5-yl}-
amine (30c). 1H NMR (300 MHz, DMSO-d6): δ 7.53 (d, J ) 8.6
Hz, 1H), 7.20 (m, 2H), 7.02 (s, 1H), 7.0-6.65 (m, 5H), 5.04 (br s,
2H), 3.78 (s, 2H), 3.24 (m, 4H), 2.54 (m, 4H).
[2-(4-Morpholinylmethyl)-1-benzothien-5-yl]amine (31c). 1H
NMR (300 MHz, DMSO-d6): δ 7.48 (d, J ) 8.4 Hz, 1H), 7.42 (s,
1H), 6.81 (s, 1H), 6.64 (d, J ) 8.4 Hz, 1H), 5.0 (br s, 2H), 3.57 (t,
J ) 4.6 Hz, 4H), 2.49 (m, 4H).
General Procedure for the Synthesis of Target Compounds
24-31. To the amines (0.506 mmol) was added methyl-3-{[(1E)-
(dimethylamino)methylidene]amino}-5-phenyl-2-thiophenecarboxy-
late 2 (0.145 g, 0.506 mmol) and 0.5 g of phenol as the solvent.
The reaction mixture was heated from 100 to 135 °C over a period
of 1.5 h. The crude mixture was loaded over a silica gel column
using DCM/MeOH (95:5) to afford the desired compounds in 30-
40% yield.
(b) 1-[(5-Nitro-1-benzofuran-2-yl)methyl]pyrrolidine (32b).
1-[(5-Nitro-1-benzofuran-2-yl)carbonyl]pyrrolidine (0.363 g, 1.40

7116 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24
TaVares et al.
mmol) was suspended in dry THF (5 mL). Allane (4 mL of a 1 M
soln) was added, and the mixture was heated to 70 °C, stirred for
2 h, cooled to rt, quenched with methanol (10 mL), diluted with
water (50 mL), and extracted with EtOAc (2 × 50 mL). The
combined organic extracts were washed with water (3 × 50 mL),
dried over MgSO4, filtered, and concentrated to give 0.210 g (0.854
mmol, 61%) of the product as a dark golden oil. 1H NMR
(CDCl3): δ 8.45 (d, J ) 2.2 Hz, 1H), 8.19 (dd, J ) 2.2 Hz, 8.8
Hz, 1H), 7.53 (d, J ) 9 Hz, 1H), 6.74 (s, 1H), 3.85 (s, 2H), 2.65
(br s, 4H), 1.85 (br s, 4H).
with water (1 × 100 mL), and the organic layers were dried over
MgSO4, filtered, concentrated, and then filtered on chromatatron
plate to remove baseline impurities. The solid was taken up in a
minimal amount of CH2Cl2 and tritrated with hexane to give 0.238
1
g (0.853 mmol, 26%) of the desired product as a yellow solid. H
NMR (CDCl3): δ 8.55 (d, J ) 2.2 Hz, 1H), 8.16 (dd, J ) 2.2 Hz,
9.1 Hz, 1H), 7.35 (d, J ) 9.1 Hz, 1H), 6.76 (s, 1H), 4.65 (s, 2H),
3.92 (s, 3H).
(d) 1-Methyl-5-nitro-2-(pyrrolidin-1-ylmethyl)-1H-indole (34a).
2-(Bromomethyl)-1-methyl-5-nitro-1H-indole (0.134 g, 0.50 mmol)
was taken up in DMF (5 mL). Pyrrolidine (0.060 mL, 0.75 mmol)
was added along with triethylamine (0.134 mL, 1 mmol), The
reaction was heated to 80 °C, stirred for 2 h, cooled to rt, and
partitioned between water (50 mL) and EtOAc (50 mL). The
aqueous layer was removed, and the organic layers were washed
with water (3 × 50 mL), dried over MgSO4, filtered, and
concentrated to give 0.112 g (0.432 mmol, 87%) of the product as
a yellow semisolid. 1H NMR (CDCl3) δ 8.50 (d, J ) 2.2 Hz, 1H),
8.09 (dd, J ) 2.2 Hz, 9.1 Hz, 1H), 7.30 (d, J ) 9.1 Hz, 1H), 6.53
(s, 1H), 3.85 (s, 3H), 3.78 (s, 2H), 2.5 (br s, 4H), 1.8 (br s, 4H).
6-(4-Chlorophenyl)-3-[1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-
indol-5-yl]thieno[3,2-d]pyrimidin-4(3H)-one Hydrochloride (34).
1-Methyl-5-nitro-2-(pyrrolidin-1-ylmethyl)-1H-indole (0.112 g, 0.43
mmol) was taken up in EtOAc (10 mL) and hydrogenated over
10% Pd/C on a Parr hydrogenator under 50 psi of H2. After 2 h,
the reaction mixture was filtered through Celite, concentrated, taken
up in a minimal amount of CH2Cl2, and methyl 5-(4-chlorophenyl)-
3-{[(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.115
g, 0.43 mmol) and phenol (0.5 g) were added. The mixture was
heated to 130 °C, stirred for 30 min, cooled to rt, and purified on
a chromatatron (100% CH2Cl2 to 80:20 CH2Cl2/MeOH). The
product was treated with 1 N HCl in Et2O, stirred for 2 h, and
concentrated to give 0.071 g (0.139 mmol, 33%) of the product as
6-(4-Methylphenyl)-3-[2-(pyrrolidin-1-ylmethyl)-1-benzofuran-
5-yl]thieno[3,2-d]pyrimidin-4(3H)-one Maleate Salt (32). 1-[(5-
Nitro-1-benzofuran-2-yl)methyl]pyrrolidine (0.210 g, 0.85 mmol)
was taken up in EtOAc (20 mL) and hydrogenated over 10% Pd/C
using H2 (1 atm). The reaction was filtered through Celite and
concentrated. The residue was taken up in a minimal amount of
CH2Cl2, and phenol (0.5 g) and methyl 5-(4-chlorophenyl)-3-
{[(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.275
g, 0.85 mmol) were added. The mixture was heated to 130 °C,
stirred for 1 h, cooled to rt, and purified on a chromatatron (100%
CH2Cl2 to 95:5 CH2Cl2/MeOH). The isolated product was taken
up in CH2Cl2 (5 mL), and 1 equiv of maelic acid was added. This
was stirred overnight, and the precipitate was collected to give 0.089
1
g (0.154 mmol, 18%) of the desired product as a white solid. H
NMR (300 MHz, DMSO-d6): δ 10.3 (br s, 1H), 8.5 (s, 1H), 7.99
(s, 1H), 7.92 (m, 3H), 7.80 (d, J ) 8.8 Hz, 1H), 7.55 (m, 3H), 7.2
(s, 1H), 6.0 (s, 2H), 4.8 (br s, 2H), 3.4 (br s 4H), 1.9 (br s, 4H).
Elemental analysis was performed for C, H, and N.
3-(2-{[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]methyl}-1-ben-
zofuran-5-yl)-6-(4-methylphenyl)thieno[3,2-d]pyrimidin-4(3H)-
one Maleate Salt (33). The title compound was synthesized using
the same procedure as that for 6-(4-Methylphenyl)-3-[2-(pyrrolidin-
1-ylmethyl)-1-benzofuran-5-yl]thieno[3,2-d]pyrimidin-4(3H)-one
maleate salt, using (2R)-2-(methoxymethyl)pyrrolidine instead of
pyrrolidine. 1H NMR (CDCl3): δ 8.3 (s, 1H), 7.80-7.75 (m, 3H),
7.6 (s, 1H), 7.5-7.4 (m, 3H), 7.10 (s, 1H) 6.4 (br s, 3H), 4.85-4.6
(m, 2H), 4.0-3.8 (br s, 2H), 3.8-3.7 (br s, 2H), 3.4 (s, 3H), 3.25
(br s, 1H), 2.2 (br s, 2H), 1.9 (br s, 2H). APCI-LCMS m/z: 507
(M + H). Purity was determined using method A.
1
a cream colored solid. H NMR (300 MHz, DMSO-d6): δ 10.2
(br s, 1H), 8.5 (s, 1H), 8.05 (s, 1H), 7.92 (d, J ) 7.5 Hz, 2H), 7.77
(s, 1H), 7.67 (d, J ) 8.8 Hz, 1H), 7.58 (d, J ) 8.5 Hz, 2H), 7.34
(dd, J ) 2.1 Hz, 8.1 Hz, 1H), 6.85 (s, 1H), 4.68 (d, J ) 5.5 Hz,
2H), 3.2 (br s, 2H, 2.05 (br s, 2H), 1.95 (br s, 2H). LRMS (M +
H) 475.
6-(4-Chlorophenyl)-3-[1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-
indol-5-yl]thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride (34):
(a) Ethyl 1-Methyl-5-nitro-1H-indole-2-carboxylate. Ethyl 5-ni-
tro-1H-indole-2-carboxylate (1.75 g, 7.46 mmol) was dissolved in
DMF (30 mL), and sodium hydride (0.6 g of a 60% dispersion)
was added. The reaction was stirred at rt for 30 min, and methyl
iodide (1.324 g, 9.33 mmol) was added. The reaction was stirred
overnight at rt. The reaction was diluted with water (100 mL), and
the precipitate was collected by suction filtration. The precipitate
was taken up in EtOAc (100 mL) and washed with water (2 × 50
mL), dried over MgSO4, filtered, and concentrated to afford 1.175
g (4.74 mmol, 63%) of the product as a red brown solid. 1H NMR
(CDCl3): δ 8.65 (d, J ) 2 Hz, 1H), 8.25 (dd, J ) 2.2 Hz, 11.3 Hz,
1H), 7.45 (s, 1H), 7.43 (d, J ) 11.3 Hz, 1H), 4.40 (q, J ) 7.1 Hz,
2H), 4.13 (s, 3H), 1.42 (t, J ) 7.2 Hz, 3H).
6-(4-Chlorophenyl)-3-(2-{[(2R)-2-(methoxymethyl)pyrrolidin-
1-yl]methyl}-1-methyl-1H-indol-5-yl)thieno[3,2-d]pyrimidin-
4(3H)-one Hydrochloride (35). The title compound was synthe-
sized using the same procedures as that for 6-(4-chlorophenyl)-3-
[1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-indol-5-yl]thieno[3,2-
d]pyrimidin-4(3H)-one hydrochloride, using (2R)-2-(methoxy-
methyl)pyrrolidine instead of pyrrolidine. 1H NMR (CDCl3): δ 12.9
(br s, 1H), 8.6 (s, 1H), 7.80 (s, 1H, 7.68 (d, J ) 8.5 Hz, 2H), 7.65
(s, 1H), 7.55 (d, J ) 8.8 Hz, 1H), 7.48 (d, J ) 8.5 Hz, 2H), 7.30
(d, J ) 8.9 Hz, 1H), 6.80 (s, 1H), 4.94 (d, J ) 14,3 Hz, 1H), 4.46
(m, 2H), 4.03 (s, 3H), 3.74-3.60 (m, 2H), 3.55 (s, 3H), 3.00 (br s,
2H), 2.28 (br s, 1H), 2.17 (br s, 1H), 1.96 (br s, 2H). Elemental
analysis was performed for C, H, and N.
Supporting Information Available: Elemental analysis and
HPLC traces for compounds in the paper. This material is available
free of charge via the Internet at http://pubs.acs.org.
(b) (1-Methyl-5-nitro-1H-indol-2-yl)methanol. Ethyl 1-methyl-
5-nitro-1H-indole-2-carboxylate (1.175 g, 4.74 mmol) was dissolved
in THF (50 mL). Allane (11 mL of a 1 M soln) was added. The
reaction was heated to 70 °C, stirred for 6 h, cooled to rt, quenched
with methanol (50 mL), diluted with water (100 mL), and extracted
with EtOAc (2 × 100 mL). The combined organic extracts were
washed with water (3 × 150 mL), dried over MgSO4, filtered, and
concentrated to give 0.664 g (3.22 mmol, 90%) of the product as
References
(1) (a) Kawauchi, H.; Kawazoe, I.; Tsubokawa, M.; Kishida, M.; Baker,
B. I. Characterization of melanin-concentrating hormone in chum
salmon pituitaries. Nature 1983, 305, 321-323. (b) Vaughan, J. M.;
Fischer, W. H.; Hoeger, C.; River, J.; Vale, W. Characterization of
melanin-concentrating hormone from rat hypothalamus. Endocrinol-
ogy 1989, 125, 1660-1665. (c) Bittencourt, J. C.; Presse, F.; Arias,
C.; Peto, C.; Vaughan, J.; Nahon, J. L.; Vale, W.; Sawchenko, P. E.
The melanin-concentrating hormone system of the rat brain: An
immuno- and hybridization histochemical characterization. J. Comp.
Neurol. 1992, 319, 218-245.
(2) (a) Chambers, J.; Ames, R. S.; Bergsma, D.; Muir, A.; Fitzgerald,
L. R.; Hervieu, G.; Dytko, G. M.; Foley, J. J.; Martin, J.; Liu, W. S.;
Park, J.; Ellis, C.; Gangulay, S.; Konchar, S.; Cluderray, J.; Leslie,
R.; Wilson, S.; Sarau, H. M. Melanin-concentrating hormone is the
cognate ligand for the orphan G-protein-coupled receptor SLC-1.
1
a red brown solid. H NMR (CDCl3): δ 8.54 (d, J ) 2 Hz, 1H),
8.14 (dd, J ) 2.2 Hz, 9.1 Hz, 1H), 7.35 (d, J ) 9.2 Hz, 1H), 6.62
(s, 1H), 4.82 (s, 2H), 3.90 (s, 3H).
(c) 2-(Bromomethyl)-1-methyl-5-nitro-1H-indole (10). (1-
Methyl-5-nitro-1H-indol-2-yl)methanol (0.664 g, 3.223 mmol) was
dissolved in CH2Cl2 (50 mL). Carbon tetrabromide (1.336 g, 4.03
mmol) was added, and the mixture was cooled to 0 °C and then
triphenylphosphine (1.268 g, 4.83 mmol) was added in small
portions over 1 h. The reaction was stirred overnight and washed

Melanin-Concentrating Hormone Receptor 1 Antagonist
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24 7117
Nature 1999, 400, 261-265. (b) An, S.; Cutler, G.; Zhao, J. J.;
Huang, S. G.; Tian, H.; Li, W.; Liang, L.; Rich, M.; Bakleh, A.; Du,
J.; Chen, J. L.; Dai, K. Identification and characterization of a
melanin-concentrating hormone receptor. Proc. Natl. Acad. Sci.
U.S.A. 2001, 98, 7576-7581. (c) Hill, J.; Duckworth, M.; Murdock,
P.; Rennie, G.; Sabido-David, C.; Ames, R. S.; Saito, Y.; Nothacker,
H. P.; Wang, Z.; Lin, S. H.; Leslie, F.; Civelli, O. Molecular
characterization of the melanin-concentrating hormone receptor.
Nature 1999, 400 (6741), 265-269. (d) Sailer, A. W.; Sano, H.; Zeng,
Z.; McDonald, T. P.; Pan, J.; Pong, S. S.; Feighner, S. D.; Tan, C.
P.; Fukami, T.; Iwaasa, H.; Hreniuk, D. L.; Morin, N. R.; Sadowski,
S. J.; Ito, M.; Bansal, A.; Ky, B.; Figueroa, D. L.; Jiang, Q.; Austin,
C. P.; MacNeil, D. J.; Ishihara, A.; Ihara, M.; Kanatani, A.; Van der
Ploeg, L. H.; Howard, A. D.; Liu, Q. Identification and characteriza-
tion of a second melanin-concentrating hormone receptor, MCH-
2R. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7564-7569. (e)
Shearman, L. P.; Camacho, R. E.; Stribling, D. S.; Zhou, D.;
Bednarek, M. A.; Hreniuk, D. L.; Feighner, S. D.; Tan, C. P.; Howard,
A. D.; Van der Ploeg, L. H. T.; MacIntyre, D. E.; Hickey, G. J.;
Strack, A. M. Chronic MCH-1 receptor modulation alters appetite,
body weight and adiposity in rats. Eur. J. Pharmacol. 2003, 475,
37-47.
mone (MCH)-related peptide ligands at SLC-1, the human MCH
receptor. J. Biol. Chem. 2001, 276, 13554-13562. (b) Bednarek, M.
A.; Hreniuk, D. L.; Tan, C.; Palyha, O. C.; MacNeil, D. J.; Van der
Ploeg, L. H. Y.; Howard, A. D.; Feighner, S. D. Synthesis and
biological evaluation in vitro of selective, high affinity peptide
antagonists of human melanin-concentrating hormone action at human
melanin-concentrating hormone receptor 1. Biochemistry 2002, 41,
6383-6390. (c) Takekawa, S.; Asami, A.; Ishihara, Y.; Terauchi,
J.; Kato, K.; Shimomura, Y.; Mori, M.; Murakoshi, H.; Kato, K.;
Suzuki, N.; Nishimura, O.; Fujino, M. T-226296: a novel, orally
active and selective melanin-concentrating hormone receptor antago-
nist. Eur. J. Pharmacol. 2002, 438 (3), 129-135. (d) Borowsky, B.;
Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.; DeLeon, J.; Lagu,
B.; et al. Antidepressant, anxiolytic and anorectic effects of a melanin-
concentrating hormone-1 receptor antagonist. Nat. Med. 2002, 8,
825-830. (e) Arienzo, R.; Clark, D. E.; Cramp, S.; Daly, S.; Dyke,
H. J.; Lockey, P.; Norman, D.; Roach, A. G.; Stuttle, K.; Tomlinson,
M.; Wong, M.; Wren, S. P. Structure-activity relationships of a novel
series of melanin-concentrating hormone (MCH) receptor antagonists.
Bioorg. Med. Chem. Lett. 2004, 14, 4099-4102. (f) Clark, D. E.;
Higgs, C.; Wren, S. P.; Dyke, H. J.; Wong, M.; Norman, D.; Lockey,
P.; Roach, A. G. A virtual screening approach to finding novel and
potent antagonist at the melanin-concentrating hormone 1 receptor.
J. Med. Chem. 2004, 47, 3962-3971. (g) Souers, A. J.; Wodka, D.;
Gao, J.; Lewis, J. C.; Vasudevan, A.; Gentles, R.; Brodjian, S.;
Dayton, B.; Ogiela, C. A.; Fry, D.; Hernandez, L. E.; Marsh, K. C.;
Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-
alkoxy quinolines as MCHr1 antagonists. Part 1. Bioorg. Med. Chem.
Lett. 2004, 14, 4873-4877. (h) Vasudevan, A.; Wodka, D.; Verzal,
M. K.; Souers, A. J.; Gao, J.; Brodjian, S.; Fry, D.; Dayton, B.; Marsh,
K. C.; Hernandez, L. E.; Ogiela, C. A.; Collins, C. A.; Kym, P. R.
Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1
antagonists. Part 2. Bioorg. Med. Chem. Lett. 2004, 14, 4879-4882.
(i) Souers, A. J.; Wodka, D.; Gao, J.; Lewis, J. C.; Vasudevan, A.;
Brodjian, S.; Dayton, B.; Ogiela, C. A.; Fry, D.; Hernandez, L. E.;
Marsh, K. C.; Collins, C. A.; Kym, P. R. Synthesis and evaluation
of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 3. Bioorg.
Med. Chem. Lett. 2004, 14, 4883-4886. (j) Souers, A. J.; Gao, J.;
Brune, M.; Bush, E.; Wodka, D.; Vasudevan, A.; Judd, A. S.;
Mulhern, M.; Brodjian, S.; Dayton, B.; Shapiro, R.; Hernandez, L.
E.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym, P. R.
Identification of 2-(4-benzyloxyphenyl)-N-[1-(2-pyrrolidin-1-yl-eth-
yl)-1H-indazol-6-yl]acetamide, an orally efficacious melanin-con-
centrating hormone for the treatment of obesity. J. Med. Chem. 2005,
48, 1318-1321. (k) Ulven, T.; Frimurer, T. M.; Receveur, J.-M.;
Little, P. B.; Rist, O.; Norregaard, P. K.; Hogberg, T. 6-Acylamino-
2-aminoquinolines as potent melanin-concentrating hormone 1 recep-
tor antagonist. Identification, structure-activity relationship, and
investigation of binding mode. J. Med. Chem. 2005, 48, 5684-5697.
(l) Vasudevan, A.; Verzal, M. K.; Wodka, D.; Souers, A. J.;
Blackburn, C.; Che, J. L.; Lai, S.; Brodjian, S.; Falls, D. H.; Dayton,
B. D.; Govek, E.; Daniels, T.; Geddes, B.; Marsh, K. C.; Hernandez,
L. E.; Collins, C. A.; Kym, P. R. Identification of aminopiperidine
benzamides as MCHr1 antagonists. Bioorg. Med. Chem. Lett. 2005,
15, 3412-3416. (m) McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova,
J.; Li, S.; Palani, A.; Clader, J. W.; Greenlee, W. J.; Hawes, B. E.;
Kowalski, T. J.; O’Neill, K.; Spar, B.; Weig, B. Discovery of
bicycloalkyl urea melanin concentrating hormone receptor antago-
nist: Orally effacious antiobesity therapeutics. J. Med. Chem. 2005,
48, 2274-2277. (n) Palani, A.; Shapiro, S.; McBriar, M. D.; Clader,
J. W.; Greenlee, W. J.; Spar, B.; Kowalski, T. J.; Farley, C.; Cook,
J.; van Heek, M.; Weig, B.; O’Neill, K.; Graziano, M.; Hawes, B.
Biaryl ureas as potent and orally efficacious melanin concentrating
hormone receptor 1 antagonists for the treatment of obesity. J. Med.
Chem. 2005, 48, 4746-4749. (o) Souers, A. J.; Gao, J.; Wodka, D.;
Judd, A. S.; Mulhern, M. M.; Napier, J. J.; Brune, M. E.; Bush, E.
N.; Brodjian, S. J.; Dayton, B. D.; Shapiro, R.; Hernandez, L. E.;
Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym, P. R. Synthesis
and evaluation of urea-based indazoles as melanin-concentrating
hormone receptor 1 antagonists for the treatment of obesity. Bioorg.
Med. Chem. Lett. 2005, 15, 2752-2757. (p) Kym, P. R.; Iyengar,
R.; Souers, A. J.; Lynch, J. K.; Judd, A. S.; Gao, J.; Freeman, J.;
Mulhern, M.; Zhao, G.; Vasudevan, A.; Wodka, D.; Blackburn, C.;
Brown, J.; Che, J. L.; Cullis, C.; Lai, S. J.; LaMarche, M.; Marsilje,
T.; Roses, J.; Sells, T.; Geddes, B.; Govek, E.; Patane, M.; Fry, D.;
Dayton, B. D.; Brodjian, S.; Falls, D.; Brune, M.; Bush, E.; Shapiro,
R.; Knourek-Segel, V.; Fey, T.; McDowell, C.; Reinhart, G. A.;
Preusser, L. C.; Marsh, K.; Hernandez, L.; Sham, H. L.; Collins, C.
A. Discovery and characterization of aminopiperidinecoumarin
melanin concentrating hormone receptor 1 antagonists. J. Med. Chem.
2005, 48, 5888-5891. (q) Huang, C. Q.; Baker, T.; Schwarz, D.;
Fan, J.; Heise, C. E.; Zhang, M.; Goodfellow, V. S.; Markison, S.;
Gogas, K. R.; Chen, T.; Wang, X.-C.; Zhu, Y.-F. 1-(4-Amino-
(3) Tan, C. P.; Sano, H.; Iwaasa, H.; Pan, J.; Sailer, A. W.; Hreniuk, D.
L.; Feighner, S. D.; Palyha, O. C.; Pong, S. S.; Figueroa, D. J.; Austin,
C. P.; Jiang, M. M.; Yu, H.; Ito, H.; Ito, J.; Ito, M.; Guan, X. M.;
MacNeil, D. J.; Kanatani, A.; Van der Ploeg, L. H.; Howard, A. D.
Melanin-concentrating hormone receptor subtypes 1 and 2: Species-
specific gene expression. Genomics 2002, 79 (6), 785-792.
(4) (a) Della-Zuana, O.; Presse, F.; Ortola, C.; Duhault, J.; Nahon, J. L.;
Levens, N. Acute and chronic administration of melanin concentrating
hormone enhances food intake and body weight in wister and
Sprague-Dawley rats. Int. J. Obes. 2002, 26, 1289-1295. (b)
Gomori, A.; Ishihara, A.; Ito, M.; Mashiko, S.; Matsushita, H.;
Yumoto, M.; Tanaka, T.; Tokita, S.; Moriya, M.; Iwaasa, H.;
Kanatani, A. Chronic intracerebroventricular infusion of MCH causes
obesity in mice. Am. J. Physiol. Endocrinol. Metab. 2003, 284,
E583-E588.
(5) (a) Shimada, M.; Tritos, D.; Aitken, A.; Donella-Deana, A.; Hem-
mings, B. A.; Parker, P. J. Mice lacking melanin-concentrating
hormone are hypophagic and lean. Nature 1998, 396, 670-674; Eur.
J. Biochem. 1982, 124, 21. (b) Kowalski, T. J.; Farley, C.; Cohen-
Williams, M. E.; Varty, G.; Spar, B. D. Melanin-concentrating
hormone-1 receptor antagonism decreases feeding by reducing meal
size. Eur. J. Pharmacol. 2004, 497, 41-47.
(6) (a) Chen, Y.; Hu, C.; Hsu, C. K.; Zhang, Q.; Bi, C.; Asnicar, M.;
Hsiung, H. M.; Fox, N.; Slieker, L. J.; Yang, D. D.; Heiman, M. L.;
Shi, Y. Targeted disruption of the melanin-concentrating hormone
receptor-1 results in hyperphagia and resistance to diet induced
obesity. Endocrinology 2002, 143, 2469-2477. (b) Marsh, D. J.;
Weingarth, D. T.; Novi, D. E.; Chen, H. Y.; Trumbauer, M. E.; Chen,
A. S.; Guan, X. M.; Jiang, M. M.; Feng, Y.; Camacho, R. E.; Shen,
Z.; Frazier, E. G.; Yu, H.; Metzger, J. M.; Kuca, S. J.; Shearman, L.
P.; Gopal-Truter, S.; Macneil, D. J.; Strack, A. M.; MacIntyre, D.
E.; Van der Ploeg, L. H.; Qian, S. Melanin-concentrating hormone
1 receptor-deficient mice are lean, hyperactive, and hyperphagic and
have altered metabolism. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
3240-3245.
(7) (a) Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni, R.;
Kokkotou, E.; Elmquis, J.; Lowell, B.; Flier, J. S.; Maratos-Flier, E.
Melanin-concentrating hormone overexpression in transgenic mice
leads to obesity and insulin resistance. J. Clin. InVest. 2001, 107,
379-386. (b) Ito, M.; Gomori, A.; Ishihara, A.; Oda, Z.; Mashiko,
S.; Matsushita, H.; Yumoto, M.; Sano, H.; Moriya, M.; Kanatani,
A. Characterization of MCH-mediated obesity in mice. Am. J.
Physiol. Endocrinol. Metab. 2003, 284 (5), E940-E945. (c) Shear-
man, L. P.; Camacho, R. E.; Sloan, S. D.; Zhou, D.; Bednarek, M.
A.; Hreniuk, D. L.; Feighner, S. D.; Tan, C. P.; Howard, A. D.; Van
der Ploeg, L. H.; MacIntyre, D. E.; Hickey, G. J.; Strack, A. M.
Chronic MCH-1 receptor modulation alters appetite, body weight,
and adiposity in rats. Eur. J. Pharmacol. 2003, 15, 475 (1-3), 37-
47.
(8) (a) Tadayyon, M.; Welters, H. J.; Haynes, A. C.; Cluderay, J. E.;
Hervieu, G. Expression of melanin-concentrating hormone receptors
in insulin-producing cells: MCH stimulates insulin release in
RINm5F and CRI-GI cell-lines. Biochem. Biophys. Res. Commun.
2000, 275, 709-712. (b) Bradley, R. L.; Mansfield, J. P.; Maratos-
Flier, E.; Cheatham, B. Melanin-concentrating hormone activates
signaling pathways in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol.
Metab. 2002, 283 (3), E584-E592.
(9) (a) Audinot, V.; Beauverger, P.; Lahaye, C.; Suply, T.; Rodriguez,
M.; Ouvry, C.; Lamamy, V.; Imbert, J.; Rique, H.; Nahon, J.-L.;
Galizzi, J. P.; Canet, E.; Levens, N.; Fauchere, J. L.; Boutin, J. A.
Structure-activity relationship studies of melanin-concentrating hor-

7118 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24
TaVares et al.
phenyl)-pyrrolidin-3-yl-amine and 6-(3-amino-pyrrolidin-1-yl)-pyri-
din-3-yl-amine derivatives as melanin-concentrating hormone recep-
tor-1 antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 3701-3706.
(r) Chaki, S.; Funakoshi, T.; Hirota-Okuno, S.; Nishiguchi, M.;
Shimazaki, T.; Iijima, M.; Grottick, A. J.; Kanuma, K.; Omodera,
K.; Sekiguchi, Y.; Okuyama, S.; Tran, T.; Semple, G.; Thomsen,
W. Anxiolytic- and antidepressant-like profile of ATC0065 and
ATC0175: Nonpeptidic and orally active melanin-concentrating
hormone receptor 1 antagonists. J. Pharmacol. Exp. Ther. 2005, 313,
831-839. (s) Mashiko, S.; Ishihara, A.; Gomori, A.; Moriya, R.;
Ito, M.; Iwaasa, H.; Matsuda, M.; Feng, Y.; Shen, Z.; Marsh, D. J.;
Bednarek, M. A.; MacNeil, D. J.; Kanatani, A. Antiobesity effect of
a melanin-concentrating hormone 1 receptor antagonist in diet-
induced obese mice. Endocrinology 2005, 146, 3080-3086. (t)
Vasudevan, A.; LaMarche, M. J.; Blackburn, C.; Che, J. L.; Luchaco-
Cullis, C. A.; Lai, S.; Marsilje, T. H.; Patane, M. A.; Souers, A. J.;
Wodka, D.; Geddes, B.; Chen, S.; Brodjian, S.; Falls, D. H.; Dayton,
B. D.; Bush, E.; Burne, M.; Shapiro, R. D.; Marsh, K. C.; Hernandez,
L. E.; Sham, H. L.; Collins, C. A.; Kym, P. R. Identification of ortho-
amino benzamides and nicotinamides as MCHr1 antagonist. Bioorg.
Med. Chem. Lett. 2005, 15, 3412-3416. (u) Collins, C. A.; Kym, P.
R. Prospects for obesity treatment: MCH receptor antagonists. Curr.
Opin. InVest. Drugs 2003, 4, 386-394. (v) Carpenter, A. J.; Hertzog,
D. L. Melanin-concentrating hormone receptor antagonists as po-
tential antiobesity agents. Expert Opin. Ther. Pat. 2002, 12, 1639-
1646.
(10) Tavares, F. X.; Al-Barazanji, K. A.; Bigham, E. C.; Bishop, M. J.;
Britt, C. S.; Carlton, D. L.; Feldman, P. L.; Goetz, A. S.; Grizzle,
M. K.; Guo, Y. C.; Handlon, A. L.; Hertzog, D. L.; Ignar, D. M.;
Lang, D. G.; Ott, R. J.; Peat, A. J.; Zhou, H-Q. Potent, selective,
and orally efficacious antagonists of melanin-concentrating hormone
receptor 1. J. Med. Chem. 2006, 24, 7095-7107.
(11) Kato, K.; Terauchi, J.; Mori, M.; Suzuki, N.; Shimomura, Y.;
Takekawa, S.; Ishihara, Y. Patent WO 01/21577 A2.
JM060814B