Synthesis and structure-activity relationship of naphtho[1,2- B]furan-2-carboxamide derivatives as melanin concentrating hormone receptor 1 antagonists

Article abstract of DOI:10.1248/cpb.c13-00486

The discovery that novel naphtho[1,2- b]furan-2-carboxamides containing linked piperidinylphenylacetamide groups serve as melanin concentrating hormone receptor 1 (MCH-R1) antagonists is described. An extensive structure-activity relationship (SAR) study,

Full text of DOI:10.1248/cpb.c13-00486

December 2013
Regular Article
Chem. Pharm. Bull. 61(12) 1239–1247 (2013)
1239
Synthesis and Structure–Activity Relationship of Naphtho[1,2-b]furan-2-
carboxamide Derivatives as Melanin Concentrating Hormone Receptor 1
Antagonists
,a,b
Chae Jo Lim,a,b Jun Young Choi,a,b Byung Ho Lee,a Kwang-Seok Oh,a and Kyu Yang Yi*
a Division of Drug Discovery Research, Korea Research Institute of Chemical Technology; Yuseong-gu, Daejeon
b
305–343, Republic of Korea: and Department of Medicinal and Pharmaceutical Chemistry, University of
Science and Technology; Yuseong-gu, Daejeon 305–350, Republic of Korea.
Received June 17, 2013; accepted September 10, 2013
The discovery that novel naphtho[1,2-b]furan-2-carboxamides containing linked piperidinylphenylacet-
amide groups serve as melanin concentrating hormone receptor 1 (MCH-R1) antagonists is described. An
extensive structure–activity relationship (SAR) study, probing members of this family that contain a variety
of aryl and heteroaryl groups at C-5 of the naphtho[1,2-b]furan-2-carboxamide skeleton and having different
chain linker lengths, led to the identification of the 5-(4-pyridinyl) substituted analog 10b as a highly potent
MCH-R1 antagonist with an IC50 value of 3nM. This substance also displays good metabolic stability and it
does not significantly inhibit cytochrome P450 (CYP450) enzymes. However, 10b has unacceptable oral bio-
availability.
Key words melanin concentrating hormone (MCH); MCH-receptor 1 antagonist; obesity; naphtho[1,2-b]-
furan-2-carboxamide
Obesity, occurring because of an imbalance between energy of MCH-R1 antagonists as potential anti-obesity agents. To
intake and expenditure, is rapidly increasing worldwide and date, few candidates including GW856464,17,18) AMG-076,19)
has become nearly a global epidemic.1) Moreover, obesity is NGD-4715,20,21) ALB-127158,22–24) and BMS-830216,25) a pro-
a major risk factor associated with a number of severe dis- drug of BMS-819881 (structure undisclosed) have advanced to
eases, including type 2 diabetes, dyslipidemia, coronary heart the phase 1 clinical stage owing to their unsuitable pharmaco-
disease, stroke and certain cancers.2) Many biological targets kinetic (PK) profiles and safety concerns26–28) (Fig. 1). In par-
for treating obesity have been evaluated, including prevention ticular, diverse piperidinylphenylacylamide derivatives, based
of fat absorption, modulation of fat metabolism or storage, on the structure of SNAP-7941, have been reported to serve as
increase of thermogenesis, and modulation of central satiety MCH-R1 antagonists.29–32)
and hunger regulating systems.3,4) Among several centrally
Recently, we uncovered novel benzimidazole and phthala-
acting targets, the melanin concentrating hormone (MCH) zin-1(2H)-one derivatives that are linked to piperidinylphen-
has received great attention as a target for obesity treatment. ylacetamide groups, which serve as potent MCH-R1 antago-
MCH, an orexigenic cyclic 19-amino acid polypeptide, is nists.33–36) In a continuation of these initial efforts aimed at the
expressed predominantly in the lateral hypothalamus of the development of potent MCH-R1 antagonists as anti-obesity
brain and is known to play a physiological role in both the agents,37) we newly prepared 5-aryl benzofuran derivative
regulation of feeding and energy homeostasis.5,6) The effects 13 possessing the piperidinylphenylacetamide moiety, which
of this peptide are mediated through its interaction with two has an IC50 value of 380nM. An initial effort focused on sub-
types of G protein-coupled receptors called MCH-receptor 1 stances containing a modified benzofuran core and explored
and 2 (MCH-R1 and -R2).7,8) While the exact biological func- the effects of fusing rings. The effects of naphthofuran ring
tions of MCH-R2 are still unknown, those of MCH-R1 have system were investigated using substrates having a 4-chlo-
been demonstrated in previous genetic and pharmacological rophenyl substituent. Among naphthofuran derivatives, the
studies. Genetically altered mice that lack the gene encoding naphtho[1,2-b]furan derivative 9f was found to have a fivefold
MCH-R1 maintain elevated metabolic rates and remain lean higher binding affinity (IC50=70nM) compared to the benzo-
despite hyperphagia on a normal diet.9) Specifically, the results furan derivative, while the [2,1-b]- and [2,3-b]naphthofuran
of these efforts have shown that MCH-R1 plays an essential ring systems also displayed slightly increased binding af-
role in the control of food intake and body weight.9–12) As a finities (Fig. 2). Based on the results described above, the
consequence of these properties, MCH-R1 is considered to be naphtho[1,2-b]furan heterocyclic system was proposed as a
one of the most promising targets for treating obesity, though potentially interesting scaffold for the development of new
it still remains to be seen whether this translates to safe clini- MCH-R1 antagonists.38) Herein, the synthesis, evaluation as
cal efficacy in humans.
MCH-R1 antagonists, and structure–activity relationships
Numerous MCH-R1 antagonists have been found to have (SAR) of a variety of 5-substituted naphtho[1,2-b]furan-2-
anti-obesity efficacy in diet-induced obesity (DIO) animal carboxamide derivatives are described.
models.13–16) In the last decade, extensive research by numer-
Chemistry The general, convergent synthetic routes
ous pharmaceutical companies and academic groups have led employed for the preparation of 5-substituted-naphtho[1,2-b]-
to the identification of a variety of pharmacophore derivatives furan-2-carboxamide derivatives 9–12 are outlined in Charts
1–3. The 5-substituted naphtho[1,2-b]furan-2-carboxylic acids,
serving as key coupling partners in the routes, were prepared
The authors declare no conflict of interest.
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: kyyi@krict.re.kr

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Vol. 61, No. 12
Fig. 1. Representative Structures of MCH-R1 Antagonists
Fig. 2. Lead Generation of Naphtho[1,2-b]furan-2-carboxamides
Reagents and conditions: (a) MgCl2, paraformaldehyde, Et3N, CH3CN, reflux, 15h; (b) ethyl bromo acetate, K2CO3, CH3CN, reflux, 1.5h; (c) Br2, CH2Cl2, r.t., 1h; (d)
aryl or heteroaryl boronic acid, Pd(PPh3)4, 2M Na2CO3, toluene–MeOH (1:1), reflux, 2h; (e) 6N KOH, MeOH, 60°C, 2h.
Chart 1. Synthesis of 5-Substituted Naphtho[1,2-b]furan-2-carboxylic Acids 5a–p
from 1-naphthol using the five-step sequence displayed in 2-naphthaldehyde 1.39) Subsequent treatment of 1 with ethyl
Chart 1. The sequence begins with reaction of 1-naphthol bromoacetate in the presence of potassium carbonate yields
with paraformaldehyde in the presence of magnesium chloride ethyl naphtho[1,2-b]furan-2-carboxylate 2, which upon treat-
(MgCl2) and triethylamine as the base to give 1-hydroxy- ment with bromine produces regioselectively the 5-bromo

December 2013
1241
Reagents and conditions: (a) N-Bromoalkyl phthalimide, K2CO3, DMF, 70°C, 18h; (b) NH2NH2, EtOH, r.t., 18h.
Chart 2. Preparation of Aminoalkyl-Piperidinylphenylacetamides 8a–d
Reagents and conditions: (a) (i) SOCl2, ClCH2CH2Cl, 80°C, 3h; (ii) Et3N, CH3CN, r.t., 12h.
Chart 3. Synthesis of 9–12
product 3. The 5-aryl and heteroaryl substituted naphtho[1,2- shown by inspection of the SAR results displayed in Table
b]furan-2-carboxylic acid ethyl esters 4a–p are then generated 1, the unsubstituted (9a, R=H) and 5-bromo-substituted (9b)
by reaction of 3 with selected aryl- and heteroaryl-boronic naphtho[1,2-b]furan-2-carboxamides have moderate bind-
acids under standard Suzuki coupling conditions. Hydrolysis ing affinities to MCH-R1, whereas in comparison to these
of the derived esters 4a–p using potassium hydroxide in re- substances the simple phenyl derivative 9c has a 2.5-fold in-
fluxing methanol affords the target acids 5a–p.
The sequence for preparation of ω-aminoalkyl-
creased binding affinity (IC50=150 nM).
The effects of substituents at the C-5 position of the phenyl
piperidinylphenylacetamides 8a–d, the other coupling part- ring of the naphtho[1,2-b]furan-2-carboxamide framework
ners, utilizes the known N-[3-(4-piperidinyl)phenyl]acetamide were explored further. While the substance having a methyl
640) and begins by alkylation reactions of this substance with group at the para-phenyl position (9d) displays a slightly re-
N-ω-bromoalkylphthalimides in the presence of potassium duced binding activity compared to 9c, the introduction of p-
carbonate in acetonitrile at 60°C. The formed N-alkylated fluoro (9e) and p-chloro group (9f) results in a large increase
piperidines 7a–d are then treated with hydrazine in ethanol at in MCH-R1 binding affinity with respective IC50 values of
room temperature to give the corresponding free amines 8a–d 57 nM and 70nM. In addition, the p-cyano analog 9g has 15-
(Chart 2).
fold increased binding affinity (IC50=10 nM) compared to 9c.
Finally, amide bond forming coupling reactions of acids Repositioning the chloro and cyano substituents from the para
5a–p with amines 8a–d were performed utilizing the conven- (9f,g) to the meta position (9h,i) leads to a large decrease
tional acid chloride mediated method (Chart 3). Specifically, in binding to MCH-R1. Furthermore, derivatives contain-
reactions of acids 5a–p in refluxing thionyl chloride gave the ing di-substitution, such as 3,4-difluoro (9j) and 3-chloro-
acid chlorides, which were then treated with the correspond- 4-fluoro (9k), display reduced binding affinities. The effects
ing amines 8a–d using triethylamine in acetonitrile to pro- of replacement of the C-5 aryl group on the naphtho[1,2-b]-
duce the target amide products 9–12.
furan-2-carboxamide framework with heteroaromatic moieties
on the MCH-R1 binding affinity were also explored. Among
pyridine-substituted derivatives, the 4-pyridinyl analog 9n
Results and Discussion
Binding affinities of the 5-substituted naphtho[1,2-b]- was found to have a binding activity that is near equal to
furan-2-carboxamide derivatives 9–12 to membranes of Chi- that of the p-cyanophenyl analog 9g and much higher than
nese hamster’s ovary (CHO) cells expressing human MCH-R1 substances possessing 2-pyridinyl (9l) and 3-pyridinyl (9m)
were determined. Measurements were performed by using a groups. Finally, C-5 substitution with other types of heteroaryl
competitive binding based assay with Eu-labeled MCH and groups, such as 3-furyl (9o) and 3-thiophenyl (9p), leads to
time-resolved fluorescence (TRF) measurements.41) Based on lower binding affinities than the phenyl counterpart.
results coming from our earlier studies,33–35) the effects of
We next attempted to optimize the binding affinities of the
substituents at the 5-position of the naphtho[1,2-b]furan-2- 5-(p-chlorophenyl) derivative by varying the length of the
carboxamide moiety were initially investigated using sub- chain between its naphtho[1,2-b]furan and piperidinylphenyl
strates having a fixed (n=3) length of the linker connecting moieties (Table 2). Unlike trends observed earlier for the re-
the naphtho[1,2-b]furan and piperidinylphenyl moieties. As lated benzimidazole and phthalazin-1(2H)-one analogs,33–35) an

1242
Vol. 61, No. 12
Table 1. Effects on MCH-R1 Binding Affinity of Substituents at C-5 of
Naphtho[1,2-b]furan-2-carboxamide Derivatives
hibit the most potent binding affinity to MCH-R1 (IC50=3nM)
among all of the substances tested.
5-(4-Pyridinyl) substituted naphtho[1,2-b]furan-2-carbox-
amide 10b was subjected to further biological studies. This
substance was observed to display good metabolic stability in
human and rat liver microsomes (100% and 99% for 30min,
respectively) and very low inhibition of the cytochrome P450
enzymes 2D6 and 3A4 (<10% at 10µM). However, the results
of an intravenous and oral pharmacokinetic study (10mg/
kg) demonstrate that 10b exhibits low oral bioavailability
(F=4.1%) with a high clearance (CL=82mL/min/kg) and low
plasma level (AUC=0.08gh/mL), probably due to poor aque-
ous solubility.
MCH-R1
IC50 (nM)
MCH-R1
IC50 (nM)
Compound
R
Compound
R
a,b)
a,b)
9a
9b
H
377
370
Br
9j
X=F
X=Cl
120
200
Conclusion
9k
The studies described above have led to the discovery
of substances containing linked naphtho[1,2-b]furan-2-
carboxamides and piperidinylphenylacetamide moieties that
serve as novel MCH-R1 antagonists. An extensive optimiza-
tion effort, probing the effects of substituents on aryl and
heteroaryl ring located at C-5 of the naphtho[1,2-b]furan-2-
carboxamide framework and the chain length between the
naphtho[1,2-b]furan and piperidinylphenyl groups, have led to
the identification of 5-(4-pyridinyl) substituted naphtho[1,2-
b]furan-2-carboxamide 10b as the most potent MCH-R1 an-
tagonist. This substance displays good metabolic stability and
low inhibition of CYP450 enzymes. Further studies focusing
on the improvement of the pharmacokinetic properties of the
linked naphtho[1,2-b]furan-2-carboxamides–piperidinylphenyl-
acetamides are now in progress.
9c
X=H
X=Me
150
211
9l
570
60
9d
9e
9f
X=F
X=Cl
X=CN
57
70
10
9m
9g
9n
9o
10
9h
9i
X=Cl
160
70
140
X=CN
9p
270
a) MCH-R1 binding affinities were determined by using a competitive binding
with Eu-MCH and a TRF assay. b) Values are means of at least two measurements.
Experimental
General 1H- and 13C-NMR spectra were recorded on a
Varian Gemini 200 or Bruker DRX-300 spectrometer. High
resolution mass spectra (HR-MS) were recorded on a JEOL
JMS-700 mas spectrometer. Column chromatography was
carried out using silica gel (230–400 mesh). All solvents and
reagents were commercially available and used without puri-
fication.
Table 2. Effects on MCH-R1 Binding Affinity of the Chain Length be-
tween the Naphtho[1,2-b]furan and Piperidinylphenyl Moieties
1-Hydroxy-2-naphthaldehyde (1) To
a
solution of
naphthalene-1-ol (2.0g, 13.89mmol) and paraformaldehyde
(2.4g, 83.34mmol) in acetonitrile (50mL) were added magne-
sium chloride (1.98g, 20.8mmol) and triethylamine (7.2mL,
51.4mmol). After being stirred at reflux for 15h, the mixture
was diluted with water (50mL) and extracted with ethyl ace-
tate (100mL). The organic layer was washed with water and
5% aqueous hydrogen chloride solution, dried over anhydrous
sodium sulfate, and concentrated in vacuo, giving a residue
that was subjected to column chromatography on silica gel
(ethyl acetate–n-hexane 1:10) to obtain 800mg (33%) of the
a,b)
MCH-R1 IC50
Compound
n
R
(nM)
10
9f
2
3
4
5
2
3
5
70
7
11
12
10a
9g
450
7
10
1
10b
2
3
3
title compound. H-NMR (300MHz, CDCl3) δ: 12.67 (s, 1H),
9n
10
9.97 (s, 1H), 8.44 (d, J=8.4Hz, 1H), 7.79 (d, J=8.4Hz, 1H),
7.66 (dd, J=8.4, 8.1Hz, 1H) 7.55 (dd, J=8.4, 8.1Hz, 1H), 7.49
(d, J=8.6Hz, 1H), 7.37 (d, J=8.6Hz, 1H).
a) MCH-R1 binding affinities were determined by using a competitive binding
with Eu-MCH and a TRF assay. b) Values are means of at least two measurements.
Ethyl Naphtho[1,2-b]furan-2-carboxylate (2) To a solu-
ethylene (2 carbon) linker was found to be preferable to pro- tion of 1-hydroxy-2-naphthaldehyde (1, 100mg, 0.58mmol)
pylene (9f), butylene (11) and pentylene (12) linkers. Also, the and ethyl bromoacetate (98mg, 0.69mmol) in acetonitrile
p-cyanophenyl (10a) and 4-pyridinyl (10b) analogs possessing (3mL) was added potassium carbonate (161mg, 1.16mmol).
two-carbon linkers display higher binding affinities than the After being stirred at reflux for 1.5h, the mixture was diluted
corresponding analogs 9g and 9n containing three-carbon with water (20mL), and extracted with ethyl acetate (50mL).
linkers. The 4-pyridinyl derivative 10b was observed to ex- The organic layer was dried over anhydrous sodium sulfate

December 2013
1243
and concentrated in vacuo, giving a residue that was subjected gel (10% MeOH–CH2Cl2) to afford 924mg (99%) of the title
1
to column chromatography on silica gel (ethyl acetate–n- compound. H-NMR (300MHz, CDCl3) δ: 7.81–7.88 (m, 2H),
hexane 1:10) to obtain 100mg (76%) of the title compound. 7.69–7.74 (m, 2H), 7.58 (s, 1H), 7.36 (d, J=8.0Hz, 1H), 7.32 (s,
1H-NMR (300MHz, CDCl3) δ: 8.47 (d, J=8.4Hz, 1H), 7.93 (d, 1H), 7.21 (dd, J=8.0, 7.6Hz, 1H), 6.93 (d, J=7.6Hz, 1H), 3.85
J=8.4Hz, 1H), 7.53–7.73 (m, 5H), 4.46 (q, J=7.1Hz, 2H), 1.46 (t, J=6.9Hz, 2H), 3.05–3.16 (m, 2H), 2.66 (t, J=6.9Hz, 2H),
(t, J=7.1Hz, 3H).
2.37–3.52 (m, 1H), 2.15 (s, 3H), 2.05–2.18 (m, 2H), 1.58–1.84
Ethyl 5-Bromonaphtho[1,2-b]furan-2-carboxylate (3) (m, 4H).
To a solution of ethyl naphtho[1,2-b]furan-2-carboxylate (2,
N-(3-{1-[2-(1,3-Dioxoisoindolin-2-yl)propyl]piperidin-
1.0g, 4.42mmol) in dichloromethane (30mL) was added bro- 4-yl}phenyl)acetamide (7b) The title compound (4.13g,
mine (918mg, 5.75mmol) at room temperature. After stirring 99%) was prepared in the same manner as described
for 1h at room temperature, the mixture was concentrated in for 7a using N-[3-(piperidin-4-yl)phenyl]acetamide (2.6g,
1
vacuo, giving a residue that was subjected to column chro- 10.21mmol). H-NMR (300MHz, DMSO-d6) δ: 9.81 (s, 1H),
matography on silica gel (ethyl acetate–n-hexane 1:3) to 7.86–7.92 (m, 2H), 7.79–7.91 (m, 2H), 7.35 (d, J=7.9Hz, 1H),
1
give 1.3g (96%) of the title compound. H-NMR (300MHz, 7.32 (s, 1H), 7.14 (dd, J=7.9, 7.5Hz, 1H), 6.63 (d, J=7.5Hz,
CDCl3) δ: 8.44–8.52 (m, 1H), 8.31–8.38 (m, 1H), 8.01 (s, 1H), 1H), 3.68 (t, J=6.4Hz, 2H), 2.80–2.86 (m, 2H), 2.33–2.38
7.65–7.74 (m, 2H), 7.59 (s, 1H), 4.46 (q, J=7.1Hz, 2H), 1.46 (m, 2H), 2.25–2.33 (m, 1H), 2.03 (s, 3H), 1.74–1.89 (m, 4H),
(t, J=7.1Hz, 3H); HR-MS (EI): Calcd for C15H11BrO3 [M]+ 1.53–1.60 (m, 2H), 1.17–1.27 (m, 2H).
317.9892, Found 317.9881.
N-(3-{1-[2-(1,3-Dioxoisoindolin-2-yl)butyl]piperidin-4-
General Procedure for the Synthesis of Ethyl 5-Aryl- yl}phenyl)acetamide (7c) The title compound (609mg, 61%)
naphtho[1,2-b]furan-2-carboxylate (4a–p) Ethyl 5-bromo- was prepared in the same manner as described for 7a using
naphtho[1,2-b]furan-2-carboxylate (3, 0.5mmol), appropri- N-[3-(piperidin-4-yl)phenyl]acetamide (600mg, 2.36mmol).
ate arylboronic acid or heteroarylboronic acid (0.6mmol), 1H-NMR (300MHz, CDCl3) δ: 7.80–7.88 (m, 2H), 7.68–7.75
2M sodium carbonate (1.5mmol), and catalytic amount of (m, 2H), 7.53 (s, 1H), 7.38 (d, J=8.2Hz, 1H), 7.34 (s, 1H),
Pd(PPh3)4 were dissolved in 5mL of toluene and methanol 7.22 (dd, J=8.2, 7.7Hz, 1H), 6.96 (d, J=7.7Hz, 1H), 3.72
(1:1). The mixture was stirred at reflux for 2h, diluted with (t, J=7.2Hz, 2H), 2.99–3.09 (m, 2H), 2.42–2.53 (m, 1H),
water (20mL), and extracted with ethyl acetate (40mL). The 2.38–2.47 (m, 2H), 2.17 (s, 3H), 1.99–2.10 (m, 2H), 1.75–1.85
organic layer was dried over anhydrous sodium sulfate and (m, 4H), 1.66–1.76 (m, 2H), 1.53–1.65 (m, 2H).
concentrated in vacuo, giving a residue that was subjected to
column chromatography on silica gel (ethyl acetate–n-hexane 4-yl}phenyl)acetamide (7d) The title compound (621mg,
1:10) to give target compound. 61%) was prepared in the same manner as described for
Ethyl 5-(Pyridin-4-yl)naphtho[1,2-b]furan-2-carboxylate 7a using N-[3-(piperidin-4-yl)phenyl]acetamide (600mg,
N-(3-{1-[2-(1,3-Dioxoisoindolin-2-yl)pentyl]piperidin-
1
1
(4n): H-NMR (300MHz, CDCl3) δ: 8.75 (d, J=5.3Hz, 2H), 2.36mmol). H-NMR (300MHz, CDCl3) δ: 7.81–7.88 (m, 2H),
8.56 (d, J=8.2Hz, 1H), 7.85 (d, J=8.2Hz, 1H), 7.63–7.73 7.67–7.76 (m, 2H), 7.56 (s, 1H), 7.40 (d, J=8.2Hz, 1H), 7.34
(m, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.51–7.62 (m, 1H), 7.44 (s, 1H), 7.23 (dd, J=8.2, 7.7Hz, 1H), 6.96 (d, J=7.7Hz, 1H),
(d, J=5.3Hz, 2H), 4.78 (q, J=7.0Hz, 2H), 1.47 (t, J=7.0Hz, 3.70 (t, J=7.2Hz, 2H), 3.02–3.12 (m, 2H), 2.42–2.55 (m, 1H),
3H); HR-MS (EI): Calcd for C20H15NO3 [M]+ 317.1052, Found 2.35–2.45 (m, 2H), 2.18 (s, 3H), 1.99–2.13 (m, 2H), 1.76–1.88
317.1037.
(m, 4H), 1.66–1.77 (m, 2H), 1.54–1.66 (m, 2H), 1.31–1.44 (m,
General Procedure for the Synthesis of 5-Aryl- 2H).
naphtho[1,2-b]furan-2-carboxylic Acid (5a–p) To a solu-
N-{3-[1-(2-Aminoethyl)piperidin-4-yl]phenyl}acetamide
tion of 5-aryl-naphtho[1,2-b]furan-2-carboxylic acid (4a–p, (8a) To a solution of N-(3-{1-[2-(1,3-dioxoisoindolin-2-yl)-
0.5mmol) in methanol (3mL) was added 2M sodium hydrox- ethyl]piperidin-4-yl}phenyl)acetamide (7a, 924mg, 2.36mmol)
ide (0.5mL, 1mmol) at room temperature. After stirring at in ethanol (10mL) was added hydrazine hydrate (0.31mL,
reflux for 2h, the mixture was acidified by addition of 2N HCl 7.08mmol) at room temperature. After being stirred for 18h
solution and extracted with ethyl acetate (30mL). The organic at room temperature, the mixture was concentrated in vacuo,
layer was washed with brine, dried over anhydrous sodium giving a residue that was subjected to column chromatogra-
sulfate, and concentrated in vacuo to give target compound.
phy on silica gel (ethyl acetate–n-hexane 1:3) to give 270mg
1
5-(Pyridin-4-yl)naphtho[1,2-b]furan-2-carboxylic Acid (5n): (44%) of the title compound. H-NMR (300MHz, CDCl3) δ:
1H-NMR (300MHz, DMSO-d6) δ: 8.93 (m, 2H), 8.45 (d, 8.70 (s, 1H), 7.39 (d, J=8.1Hz, 1H), 7.39 (s, 1H), 7.20 (dd,
J=7.7Hz, 1H), 7.97 (m, 2H), 7.90 (m, 2H), 7.83 (m, 1H), 7.69 J=8.1, 7.6Hz, 1H), 6.92 (d, J=7.6Hz, 1H), 2.90–3.01 (m, 2H),
(m, 1H), 7.60 (m, 1H); HR-MS (EI): Calcd for C18H11NO3 [M]+ 2.89 (br s, 2H), 2.82 (t, J=6.2Hz, 2H), 2.44 (t, J=6.2Hz, 2H),
289.0739, Found 289.0742.
N-(3-{1-[2-(1,3-Dioxoisoindolin-2-yl)ethyl]piperidin- (m, 4H).
4-yl}phenyl)acetamide (7a) N-[3-(Piperidin-4-yl)phenyl]- N-{3-[1-(3-Aminopropyl)piperidin-4-yl]phenyl}acetamide
2.34–2.43 (m, 1H), 2.15 (s, 3H), 1.96–2.08 (m, 2H), 1.65–1.78
acetamide (6, 600mg, 2.36mmol), N-(2-bromoethyl)- (8b) The title compound (1.02g, 99%) was prepared in
phthalimide (720mg, 2.83mmol), and sodium carbonate the same manner as described for 8a using N-(3-{1-[3-(1,3-
(979mg, 7.08mmol) were dissolved in DMF (10mL). After dioxoisoindolin-2-yl)propyl]piperidin-4-yl}phenyl)acetamide
being stirred at 70°C for 18h, the mixture was diluted with (7b, 1.5g, 3.70mmol). 1H-NMR (500MHz, CDCl3) δ: 8.45
water (50mL), and extracted with ethyl acetate (50mL×2). (s, 1H), 7.37 (d, J=8.6Hz, 1H), 7.36 (s, 1H), 7.17 (dd, J=8.6,
The organic layer was washed with brine, dried over anhy- 7.4Hz, 1H), 6.89 (d, J=7.4Hz, 1H), 3.11–3.14 (m, 2H), 3.09
drous sodium sulfate, and concentrated in vacuo, giving a (brs, 2H), 2.92–3.04 (m, 2H), 2.74–2.79 (m, 1H), 2.39 (t,
residue that was subjected to column chromatography on silica J=7.2Hz, 2H), 2.11 (s, 3H), 1.92–1.98 (m, 2H), 1.62–1.76 (m,

1244
Vol. 61, No. 12
2H), 1.52–1.62 (m, 4H).
7.58–7.75 (m, 4H), 7.43–7.54 (m, 3H), 7.28–7.39 (m, 3H), 7.02
N-{3-[1-(4-Aminobutyl)piperidin-4-yl]phenyl}acetamide (d, J=7.4Hz, 1H), 3.55–3.66 (m, 2H), 3.15–3.28 (m, 2H),
(8c) The title compound (270mg, 53%) was prepared in 2.57–2.74 (m, 3H), 2.13–2.27 (m, 2H), 2.12 (s, 3H), 1.96–2.10
the same manner as described for 8a using N-(3-{1-[4-(1,3- (m, 4H), 1.75–1.90 (m, 2H).
dioxoisoindolin-2-yl)butyl]piperidin-4-yl}phenyl)acetamide
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-9-
1
(7c, 924mg, 2.36mmol). H-NMR (300MHz, CDCl3) δ: 8.03 (4-chlorophenyl)naphtho[2,3-b]furan-2-carboxamide (15)
(s, 1H), 7.43 (d, J=8.1Hz, 1H), 7.30 (s, 1H), 7.19 (dd, J=8.1, The title compound (56mg, 44%) was prepared in the same
7.7Hz, 1H), 6.92 (d, J=7.7Hz, 1H), 3.80 (brs, 2H), 2.96–3.07 manner as described for 10b using 9-(4-chlorophenyl)-
(m, 2H), 2.76 (t, J=6.6Hz, 2H), 2.37–2.50 (m, 1H), 2.31–2.39 naphtho[2,3-b]furan-2-carboxylic acid (70mg, 0.22mmol).
(m, 2H), 2.16 (s, 3H), 1.92–2.07 (m, 2H), 1.64–1.82 (m, 4H), 1H-NMR (300MHz, CDCl3) δ: 9.09 (s, 1H), 7.88 (d, J=8.3Hz,
1.47–1.64 (m, 4H); HR-MS (EI): Calcd for C17H27N3O [M]+ 1H), 7.64 (d, J=8.0Hz, 2H), 7.47–7.56 (m, 3H), 7.39–7.47 (m,
289.2154, Found 289.2156.
3H), 7.27–7.39 (m, 4H), 7.18 (s, NH), 7.08 (d, J=7.2Hz, 1H),
N-{3-[1-(5-Aminopentyl)piperidin-4-yl]phenyl}acetamide 3.56–3.66 (m, 2H), 3.17–3.27 (m, 2H), 2.58–2.68 (m, 3H),
(8d) The title compound (422mg, 99%) was prepared in 1.98–2.24 (m, 6H), 1.94 (s, 3H), 1.74–1.86 (m, 2H).
the same manner as described for 8a using N-(3-{1-[5-(1,3-
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-
dioxoisoindolin-2-yl)pentyl]piperidin-4-yl}phenyl)acetamide naphtho[1,2-b]furan-2-carboxamide (9a) The title com-
(7d, 621mg, 1.39mmol). 1H-NMR (300MHz, DMSO-d6) δ: pound (133mg, 43%) was prepared in the same manner as
9.89 (s, 1H), 7.45 (s, 1H), 7.36 (d, J=7.9Hz, 1H), 7.16 (dd, described for 10b using naphtho[1,2-b]furan-2-carboxylic acid
1
J=7.9, 7.6Hz, 1H), 6.87 (d, J=7.6Hz, 1H), 4.74 (brs, 2H), (140mg, 0.66mmol). H-NMR (300MHz, CDCl3) δ: 8.32 (d,
2.84–2.97 (m, 2H), 2.62 (t, J=6.8Hz, 2H), 2.30–2.44 (m, 1H), J=7.7Hz,1H), 7.93 (d, J=8.2Hz, 1H), 7.99 (m, 1H), 7.68 (m,
2.18–2.28 (m, 2H), 2.00 (s, 3H), 1.83–1.96 (m, 2H), 1.50–1.74 2H), 7.60 (s, 1H), 7.51 (m, 1H), 7.43 (m, 3H), 7.16 (s, 1H), 7.12
(m, 4H), 1.36–1.48 (m, 4H), 1.18–1.37 (m, 2H); HR-MS (EI): (t, J=7.9Hz, 1H), 6.86 (d, J=7.6Hz, 1H), 3.64 (m, 2H), 3.22
Calcd for C18H29N3O [M]+ 303.2311, Found 303.2311.
(d, J=11.5Hz, 2H), 2.68 (t, J=6.4Hz, 2H), 2.50 (m, 1H), 2.20
N-{2-[4-(3-Acetamidophenyl)piperidin-1-yl]ethyl}-5- (m, 2H), 2.12 (s, 3H), 1.98–1.86 (m, 6H); HR-MS (EI): Calcd
(pyridin-4-yl)naphtho[1,2-b]furan-2-carboxamide
(10b) for C29H31N3O3 [M]+ 469.2365, Found 469.2361.
To solution of 5-(pyridin-4-yl)naphtho[1,2-b]furan-2- N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-
a
carboxylic acid (75mg, 0.26mmol) in 1,2-dichloroethane bromonaphtho[1,2-b]furan-2-carboxamide (9b) The title
(5mL) was added SOCl2 (0.50mL). The mixture was stirred compound (58mg, 77%) was prepared in the same manner
at reflux for 3h, and concentrated in vacuo. After the resulting as described for 10b using 5-bromonaphtho[1,2-b]furan-2-
residue was dissolved in dichloromethane (10mL), N-{3-[1- carboxylic acid (40mg, 0.14mmol). 1H-NMR (300MHz,
(2-aminoethyl)piperidin-4-yl]phenyl}acetamide (8a, 135mg, CDCl3) δ: 8.43 (d, J=8.1Hz, 1H), 8.32 (d, J=8.1Hz, 1H),
0.36mmol) and excess triethylamine were added. the resulting 8.26–8.28 (m, 1H), 8.00 (s, 1H), 7.52–7.66 (m, 4H), 7.46 (d,
mixture was stirred for 15h at room temperature, diluted with J=9.0Hz, 1H), 7.25 (m, 1H), 7.15 (d, J=7.8Hz, 1H), 6.87 (d,
water (20mL), and extracted with dichloromethane (30mL). J=7.5Hz, 1H), 3.65–3.72 (m, 2H), 3.38 (t, J=11.7Hz, 2H), 2.86
The organic layer was dried over anhydrous sodium sulfate (t, J=6.6Hz, 2H), 2.53–2.59 (m, 1H), 2.39 (t, J=11.7Hz, 2H),
and concentrated in vacuo, giving a residue that was subjected 2.17 (s, 3H), 2.06–2.12 (m, 4H), 1.89–1.93 (m, 2H); HR-MS
to column chromatography on silica gel (10% MeOH–CH2Cl2) (EI): Calcd for C29H30BrN3O3 [M]+ 547.1471, Found 547.1486.
1
to give the title compound (55mg, 77%). H-NMR (300MHz,
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-
CDCl3) δ: 8.76 (d, J=4.4Hz, 2H), 8.45 (d, J=8.0Hz, 1H), 7.89 phenylnaphtho[1,2-b]furan-2-carboxamide (9c) The title
(d, J=8.4Hz, 1H), 7.65 (m, 3H), 7.55 (m, 2H), 7.46 (m, 3H), compound (98mg, 43%) was prepared in the same manner
7.39–7.19 (m, 3H), 7.05 (d, J=6.5Hz, 1H), 3.67 (m, 2H), 3.15 as described for 10b using 5-phenylnaphtho[1,2-b]furan-2-
(d, J=11.6Hz, 2H), 2.74 (t, J=5.2Hz, 2H), 2.60 (m, 1H), 2.25 carboxylic acid (120mg, 0.42mmol). 1H-NMR (300MHz,
(m, 2H), 2.16 (s, 3H), 1.93 (m, 4H); HR-MS (EI): Calcd for CDCl3) δ: 8.44 (m, 1H), 8.03 (m, 1H), 7.91 (m, 1H), 7.61
C33H32N4O3 [M]+ 532.2474, Found 532.2448.
(d, J=2.3Hz, 2H), 7.56–7.39 (m, 7H), 7.23 (s, 1H), 7.12 (t,
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-(4- J=7.8Hz, 1H), 6.87 (d, J=7.7Hz, 1H), 3.68 (m, 2H), 3.26 (d,
chlorophenyl)benzofuran-2-carboxamide (13) The title J=11.7Hz, 2H), 3.23 (m, 2H), 2.56 (m, 1H), 2.23 (m, 2H), 2.12
compound (100mg, 51%) was prepared in the same manner (s, 3H), 2.07–1.84 (m, 6H); HR-MS (EI): Calcd for C35H35N3O3
as described for 10b using 5-(4-chlorophenyl)benzofuran-2- [M]+ 545.2678, Found 545.2682.
carboxylic acid (100mg, 0.37mmol). 1H-NMR (300MHz,
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-
CDCl3) δ: 8.74 (s, 1H), 7.78 (s, 1H), 7.45–7.55 (m, 4H), (4-methylphenyl)naphtho[1,2-b]furan-2-carboxamide (9d)
7.33–7.45 (m, 5H), 7.18–7.31 (m, 2H), 7.02 (d, J=7.3Hz, 1H), The title compound (88mg, 39%) was prepared in the same
3.54–3.67 (m, 2H), 3.13–3.26 (m, 2H), 2.55–2.70 (m, 3H), manner as described for 10b using 5-(4-methylphenyl)-
2.08–2.22 (m, 2H), 2.09 (s, 3H), 1.92–2.04 (m, 4H), 1.76–1.89 naphtho[1,2-b]furan-2-carboxylic acid (120mg, 0.40mmol).
(m, 2H).
1H-NMR (300MHz, CDCl3) δ: 8.43 (m, 1H), 8.08 (s, 1H), 7.91
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}- (m, 1H), 7.61 (s, 2H), 7.57 (s, 1H), 7.51–7.41 (m, 3H), 7.36 (d,
7-(4-chlorophenyl)naphtho[2,1-b]furan-2-carboxamide (14) J=8.0Hz, 2H), 7.30 (d, J=8.0Hz, 2H), 7.21 (s, 1H), 7.11 (t,
The title compound (22mg, 12%) was prepared in the same J=7.8Hz, 1H), 6.85 (d, J=7.6Hz, 1H,), 3.66 (m, 2H), 3.22 (d,
manner as described for 10b using 7-(4-chlorophenyl)- J=11.7Hz, 2H), 2.71 (t, J=6.1Hz, 2H), 2.56–2.48 (m, 1H),
naphtho[2,1-b]furan-2-carboxylic acid (100mg, 0.31mmol). 2.46 (s, 3H), 2.20 (m, 2H), 2.12 (s, 3H), 2.04–1.83 (m, 6H);
1H-NMR (300MHz, CDCl3) δ: 8.74 (s, 1H), 8.20 (d, J=8.6Hz, HR-MS (EI): Calcd for C36H37N3O3 [M]+ 559.2835, Found
1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.82 (d, J=8.6Hz, 1H), 559.2835.

December 2013
1245
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-(4- (104mg, 0.32mmol). 1H-NMR (300MHz, CDCl3) δ: 8.49
fluorophenyl)naphtho[1,2-b]furan-2-carboxamide (9e) The (d, J=8.3Hz, 1H), 8.09 (s, 1H), 7.83 (d, J=8.3Hz, 1H), 7.62
title compound (96mg, 55%) was prepared in the same man- (s, 1H), 7.58 (s, 1H), 7.48–7.50 (m, 2H), 7.38–7.45 (m, 2H),
ner as described for 10b using 5-(4-fluorophenyl)naphtho[1,2- 7.25–7.34 (m, 3H), 7.21 (s, 1H), 7.13 (dd, J=7.9, 7.9Hz, 1H),
b]furan-2-carboxylic acid (95mg, 0.31mmol). 1H-NMR 6.89 (d, J=7.9Hz, 1H), 3.64–3.78 (m, 2H), 3.30–3.43 (m, 2H),
(300MHz, CDCl3) δ: 8.44 (m, 1H), 8.04 (m, 1H), 7.83 (m, 2.77–2.86 (m, 2H), 2.52–2.67 (m, 1H), 2.27–2.43 (m, 2H), 2.14
1H), 7.66 (m, 2H), 7.57 (s, 1H), 7.52–7.40 (m, 5H), 7.27 (m, (s, 3H), 1.99–2.17 (m, 4H), 1.87–1.99 (m, 2H); HR-MS (EI):
1H), 7.19 (t, J=8.7Hz, 2H), 7.11 (t, J=7.8Hz, 1H), 6.86 (d, Calcd for C35H33F2N3O3 [M]+ 581.2490, Found 581.2476.
J=7.6Hz, 1H), 3.68 (m, 2H), 3.27(d, J=11.7Hz, 2H), 3.24
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-(3-
(t, J=6.3Hz, 2H), 2.53 (m, 1H), 2.25 (m, 2H), 2.13 (s, 3H), chloro-4-fluorophenyl)naphtho[1,2-b]furan-2-carboxamide
2.10–1.89 (m, 6H); HR-MS (EI): Calcd for C35H34FN3O3 [M]+ (9k) The title compound (109mg, 26%) was prepared in
563.2584, Found 563.2563.
the same manner as described for 10b using 5-(3-chloro-4-
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}- fluorophenyl)naphtho[1,2-b]furan-2-carboxylic acid (130mg,
5-(4-chlorophenyl)naphtho[1,2-b]furan-2-carboxamide (9f) 0.38mmol). 1H-NMR (300MHz, CDCl3) δ: 8.43–8.50 (m,
The title compound (15mg, 21%) was prepared in the same 1H), 8.19 (s, 1H), 7.72–7.83 (m, 1H), 7.65 (s, 1H), 7.56 (s, 1H),
manner as described for 10b using 5-(4-chlorophenyl)- 7.42–7.54 (m, 5H), 7.28–7.40 (m, 3H), 7.15 (dd, J=7.8, 7.3Hz,
naphtho[1,2-b]furan-2-carboxylic acid (40mg, 0.12mmol). 1H), 6.92 (d, J=7.3Hz, 1H), 3.66–3.77 (m, 2H), 3.43–3.53
1H-NMR (300MHz, CDCl3) δ: 8.40–8.42 (m, 1H), 7.84–7.91 (m, 2H), 2.89–3.00 (m, 2H), 2.56–2.71 (m, 1H), 2.35–2.54
(m, 2H), 7.60 (d, J=6.8Hz, 2H), 7.40–7.50 (m, 4H), 7.36–7.43 (m, 2H), 2.13 (s, 3H), 2.05–2.23 (m, 4H), 1.91–2.02 (m, 2H);
(m, 3H), 7.09–7.26 (m, 3H), 6.88 (d, J=7.6Hz, 1H), 3.65–3.71 HR-MS (EI): Calcd for C35H33ClFN3O3 [M]+ 597.2194, Found
(m, 2H), 3.25 (d, J=11.0Hz, 2H), 2.69 (t, J=6.4Hz, 2H), 597.2194.
2.51–2.59 (m, 1H), 2.16–2.24 (m, 2H), 2.11 (s, 3H), 1.88–2.04
(m, 6H); HR-MS (EI): Calcd for C35H34ClN3O3 [M]+ 579.2289, (pyridin-2-yl)naphtho[1,2-b]furan-2-carboxamide (9l) The
Found 579.2286. title compound (78mg, 77%) was prepared in the same man-
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-(4- ner as described for 10b using 5-(pyridin-2-yl)naphtho[1,2-
cyanophenyl)naphtho[1,2-b]furan-2-carboxamide (9g) The b]furan-2-carboxylic acid (78mg, 0.28mmol). 1H-NMR
title compound (134mg, 57%) was prepared in the same man- (300MHz, CDCl3) δ: 8.78 (d, J=4.0Hz, 1H), 8.60 (d,
ner as described for 10b using 5-(4-cyanophenyl)naphtho[1,2- J=8.1Hz, 1H), 8.50 (m, 1H), 8.07 (d, J=8.1Hz, 2H), 7.85 (m,
b]furan-2-carboxylic acid (40mg, 0.14mmol). 1H-NMR 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.62–7.56 (m, 2H), 7.50 (m,
(300MHz, CDCl3) δ: 8.46 (m, 1H), 8.00 (m, 1H), 7.85–7.78 2H), 7.36 (m, 1H), 7.22 (s, 1H), 7.15 (t, J=8.0Hz, 1H), 6.85 (d,
(m, 3H), 7.65–7.56 (m, 4H), 7.51 (m, 2H), 7.33 (m, 2H), 7.18 J=7.7Hz, 1H), 3.70 (m, 2H), 3.47 (m, 2H), 3.03 (m, 2H), 2.49
(brs, 1H), 7.10 (t, J=7.5Hz, 1H), 6.87 (d, J=7.3Hz, 1H), 3.70 (m, 3H), 2.21 (m, 4H), 2.17 (s, 3H), 1.80 (m, 2H); HR-MS (EI):
(m, 2H), 3.27 (d, J=11.0Hz, 2H), 2.71 (m, 2H), 2.57 (m, 1H), Calcd for C34H34N4O3 [M]+ 546.2631, Found 546.2629.
2.23 (m, 2H), 2.13 (s, 3H), 2.04–1.88 (m, 6H); HR-MS (EI):
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-
5-(pyridin-3-yl)naphtho[1,2-b]furan-2-carboxamide (9m)
Calcd for C36H34N4O3 [M]+ 570.2631, Found 570.2611.
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5- The title compound (153mg, 74%) was prepared in the
(3-chlorophenyl)naphtho[1,2-b]furan-2-carboxamide (9h) same manner as described for 10b using 5-(pyridin-3-yl)-
The title compound (72mg, 27%) was prepared in the same naphtho[1,2-b]furan-2-carboxylic acid (110mg, 0.38mmol).
manner as described for 10b using 5-(3-chlorophenyl)- 1H-NMR (300MHz, CDCl3) δ: 8.75 (m, 1H), 8.71 (d, J=3.6Hz,
naphtho[1,2-b]furan-2-carboxylic acid (123mg, 0.38mmol). 1H), 8.46 (m, 1H), 8.03 (s, 1H), 7.85–7.78 (m, 2H), 7.63 (d,
1H-NMR (300MHz, CDCl3) δ: 8.45 (m, 1H), 8.06 (m, 1H), J=2.6Hz, 2H), 7.53–7.42 (m, 3H), 7.36–7.29 (m, 2H), 7.18 (m,
7.84 (m, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.53–7.26 (m, 9H), 7.11 1H), 7.11 (t, J=7.8Hz, 1H), 6.89 (d, J=7.7Hz, 1H), 3.70 (m,
(t, J=7.3Hz, 1H), 6.87 (d, J=7.7Hz, 1H), 3.68 (m, 2H), 3.27 2H), 3.29 (d, J=11.2Hz, 2H), 2.73 (m, 2H), 2.59 (m, 1H), 2.24
(d, J=10.9Hz, 2H), 2.74 (t, J=5.8Hz, 2H), 2.55 (m, 1H), 2.25 (m, 2H), 2.12 (s, 3H), 2.05–1.88 (m, 6H); HR-MS (EI): Calcd
(m, 2H), 2.13 (s, 3H), 2.05–1.84 (m, 6H); HR-MS (EI): Calcd for C34H34N4O3 [M]+ 546.2631, Found 546.2609.
for C35H34ClN3O3 [M]+ 579.2289, Found 579.2281.
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-(3- 5-(pyridin-4-yl)naphtho[1,2-b]furan-2-carboxamide
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-
(9n)
cyanophenyl)naphtho[1,2-b]furan-2-carboxamide (9i) The The title compound (100mg, 45%) was prepared in the
title compound (109mg, 53%) was prepared in the same man- same manner as described for 10b using 5-(pyridine-4-yl)-
ner as described for 10b using 5-(3-cyanophenyl)naphtho[1,2- naphtho[1,2-b]furan-2-carboxylic acid (120mg, 0.41mmol).
b]furan-2-carboxylic acid (113mg, 0.36mmol). 1H-NMR 1H-NMR (300MHz, CDCl3) δ: 8.75 (d, J=3.9Hz, 2H), 8.47
(300MHz, CDCl3) δ: 8.51 (d, J=7.4Hz, 1H), 8.21 (m, 1H), (d, J=7.1Hz, 1H), 7.98 (s, 1H), 7.86 (d, J=7.1Hz, 1H), 7.63
7.80–7.36 (m, 12H), 7.14 (t, J=8.3Hz, 1H), 6.90 (d, J=7.6Hz, (d, J=4.7Hz, 2H), 7.49–7.57 (m, 2H), 7.45 (d, J=3.9Hz, 2H),
1H), 3.72 (m, 2H), 3.43 (m, 2H), 2.90 (m, 2H), 2.64 (m, 1H), 7.37 (d, J=7.9Hz, 1H), 7.33 (s, 1H), 7.24–7.30 (m, 1H), 7.13
2.45 (m, 2H), 2.14 (s, 3H), 2.23–1.93 (m, 6H); HR-MS (EI): (dd, J=7.9, 7.9Hz, 1H), 6.89 (d, J=7.9Hz, 1H), 3.65–3.73 (m,
Calcd for C36H34N4O3 [M]+ 570.2631, Found 570.2621.
2H), 3.26–3.35 (m, 2H), 2.72–2.80 (m, 2H), 2.55–2.62 (m, 1H),
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}- 2.28–2.48 (m, 2H), 2.16 (s, 3H), 2.00–2.20 (m, 4H), 1.86–2.00
5-(3,4-difluorophenyl)naphtho[1,2-b]furan-2-carbox- (m, 2H); HR-MS (EI): calcd for C34H34N4O3 [M]+ 546.2631,
amide (9j) The title compound (68mg, 34%) was pre- Found 546.2632.
pared in the same manner as described for 10b using
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}-5-
5-(3,4-difluorophenyl)naphtho[1,2-b]furan-2-carboxylic acid (furan-3-yl)naphtho[1,2-b]furan-2-carboxamide (9o) The

1246
Vol. 61, No. 12
title compound (128mg, 63%) was prepared in the same manner as described for 10b using 5-(4-cyanophenyl)-
manner as described for 10b using 5-(furan-3-yl)naphtho[1,2- naphtho[1,2-b]furan-2-carboxylic acid (100mg, 0.32mmol).
b]furan-2-carboxylic acid (106mg, 0.38mmol). 1H-NMR 1H-NMR (300MHz, CDCl3) δ: 8.46 (d, J=8.0Hz, 1H), 7.81
(300MHz, CDCl3) δ: 8.42 (d, J=8.0Hz, 1H), 8.15 (d, (m, 3H), 7.70–7.49 (m, 6H), 7.47 (brs, 1H), 7.34 (m, 1H),
J=7.2Hz, 1H), 8.08 (m, 1H), 7.70–7.56 (m, 5H), 7.54–7.40 7.26 (m, 3H), 7.04 (d, J=6.9Hz, 1H), 3.67 (m, 2H), 3.14 (d,
(m, 4H), 7.12 (t, J=7.8Hz, 1H), 6.85 (d, J=7.4Hz, 1H), 6.68 J=11.6Hz, 2H), 2.74 (t, J=5.2Hz, 2H), 2.60 (m, 1H), 2.25
(d, J=7.4Hz, 1H), 3.66 (m, 2H), 3.27 (d, J=10.4Hz, 2H), 2.74 (m, 2H), 2.16 (s, 3H), 1.97 (m, 4H); HR-MS (EI): Calcd for
(m, 2H), 2.54 (m, 1H), 2.25 (m, 2H), 2.14 (s, 3H), 2.08–1.82 C35H32N4O3 [M]+ 556.2474, Found 556.2459.
(m, 6H); HR-MS (EI): Calcd for C33H33N3O4 [M]+ 535.2471,
MCH Receptor Binding Assay Receptor binding as-
Found 535.2474.
says with europium-labeled MCH (Eu-MCH) were performed
N-{3-[4-(3-Acetamidophenyl)piperidin-1-yl]propyl}- in 96-well AcroWell™ plates. MCH labeled with europium
5-(thiophen-3-yl)naphtho[1,2-b]furan-2-carboxamide (9p) at the N-1 position was supplied by Wallac labeling service
The title compound (148mg, 79%) was prepared in the (PerkinElmer Oy). The human recombinant MCH-1 receptor
same manner as described for 10b using 5-(thiophen-3-yl)- membrane preparation (MCH-1/SLC1 membrane) was from
naphtho[1,2-b]furan-2-carboxylic acid (100mg, 0.34mmol). Euroscreen S.A. (PerkinElmer Oy). The assay buffer contained
1H-NMR (300MHz, CDCl3) δ: 8.35 (d, J=8.1Hz, 1H), 8.04 (d, 25mM N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid
J=8.1Hz, 1H), 7.96 (s, 1H), 7.62–7.68 (m, 1H), 7.65 (s, 1H), (HEPES), 5mM MgCl2, 1mM CaCl2, 0.5% bovine serum albu-
7.57 (s, 1H), 7.34–7.52 (m, 5H), 7.22–7.29 (m, 2H), 7.09 (dd, min pH 7.4. Non-specific Eu–MCH binding was determined
J=8.0, 7.6Hz, 1H), 6.84 (d, J=7.6Hz, 1H), 3.57–3.69 (m, 2H), experimentally by measuring the presence of 0.5µM unlabeled
3.06–3.18 (m, 2H), 2.53–2.64 (m, 2H), 2.42–2.55 (m, 1H), 2.11 MCH (human). After incubation at room temperature for
(s, 3H), 2.00–2.12 (m, 2H), 1.76–1.93 (m, 6H); HR-MS (EI): 90min, the mixtures were filtered in a automatic vacuum fil-
Calcd for C33H33N3O3S [M]+ 551.2243, Found 551.2243.
N-{2-[4-(3-Acetamidophenyl)piperidin-1-yl]ethyl}-5- with 300µL of ice-cold 25mM HEPES buffer (pH 7.4). Euro-
(4-chlorophenyl)naphtho[1,2-b]furan-2-carboxamide (10) pium was dissociated from the bound ligand by the addition
tration system for filter plates and rapidly washed three times
The title compound (138mg, 79%) was prepared in the of 150µL of DELFIA enhancement solution (PerkinElmer Oy)
same manner as described for 10b using 5-(4-chlorophenyl)- and incubated for 10min with shaking. Dissociated europium
naphtho[1,2-b]furan-2-carboxylic acid (100mg, 0.31mmol). created highly fluorescent complexes, which were subjected
1H-NMR(300MHz, CDCl3) δ: 8.46 (d, J=8.0Hz, 1H), 7.81 (m, in a multilabel counter to time-resolved fluorescence (TRF)
3H), 7.70–7.49 (m, 6H), 7.47 (brs, 1H), 7.34 (m, 1H), 7.26 (m, option (Victor II, PerkinElmer Oy). The counter setting was
3H), 7.04 (d, J=6.9Hz, 1H), 3.67 (m, 2H), 3.14 (d, J=11.6Hz, 340nm excitation, 400µs delay, and emission collection for
2H), 2.74 (t, J=5.2Hz, 2H), 2.60 (m, 1H), 2.25 (m, 2H), 2.16 400µs at 615nm. The extent of antagonism was expressed as
(s, 3H), 1.97 (m, 4H); HR-MS (EI): Calcd for C34H32ClN3O3 % displacement. The IC50 value was determined in an 8-dose
[M]+ 565.2132, Found 565.2137.
N-{4-[4-(3-Acetamidophenyl)piperidin-1-yl]butyl}-5- quired to yield 50% displacement.
(4-chlorophenyl)naphtho[1,2-b]furan-2-carboxamide (11)
The title compound (136mg, 79%) was prepared in the
response study to generate the compound concentration re-
Acknowledgments This investigation was supported by
same manner as described for 10b using 5-(4-chlorophenyl)- a Grant from the Ministry of Science, ICT & Future Plan-
naphtho[1,2-b]furan-2-carboxylic acid (100mg, 0.31mmol). ning (2011-0019397) and the R&D program of MOTIE/KEIT
1H-NMR (300MHz, CDCl3) δ: 8.57 (d, J=8.0Hz, 1H), 8.31 (10038744), Republic of Korea.
(s, 1H), 7.82 (m, 2H), 7.66 (s, 1H), 7.64–7.56 (m, 2H), 7.53 (s,
References
1H), 7.49–7.41 (m, 3H), 7.41–7.33 (m, 2H), 7.31 (brs, 1H), 7.02
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(m, 2H), 3.02 (m, 2H), 2.75–2.56 (m, 3H), 2.31 (m, 2H), 2.22
(s, 3H), 2.02 (m, 2H), 1.95–1.76 (m, 4H); HR-MS (EI): Calcd
for C36H36ClN3O3 [M]+ 593.2445, Found 593.2435.
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