(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives as melatoninergic agents

Article abstract of DOI:10.1016/j.bmcl.2005.01.015

(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives (e.g., 3 and 4) were synthesized as novel melatoninergic ligands with significantly lower vasoconstrictive activity in vitro in the rat tail artery. Binding affinity assays were performed on cloned human

Full text of DOI:10.1016/j.bmcl.2005.01.015

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1345–1349
(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives as
melatoninergic agents
Li-Qiang Sun,* Katherine Takaki, Jie Chen, Stephen Bertenshaw, Lawrence Iben,
Cathy D. Mahle,ꢀ Elaine Ryan, Dedong Wu, Qi Gao and Cen Xu
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA
Received 17 December 2004; revised 6 January 2005; accepted 10 January 2005
Available online 29 January 2005
Abstract—(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives (e.g., 3 and 4) were synthesized as novel melatoninergic ligands with
significantly lower vasoconstrictive activity in vitro in the rat tail artery. Binding affinity assays were performed on cloned human
MT1 and MT2 receptors stably expressed in NIH3T3 cells.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Insomnia is the most common sleep disorder that affects
20–40% of American adults1 with the incidence increas-
ing significantly with age. Insomnia has a myriad of
causes, one of which is disruption of the normal circa-
dian sleep–wake cycle. Dysynchrony in the sleep–wake
cycle can result from physiological changes. A therapeu-
tic potential for the treatment of such disorders is resyn-
chronization of the sleep–wake cycle via modulation of
the melatoninergic system. The hormone melatonin
(N-acetyl-5-methoxy-tryptamine) (Fig. 1) is synthesized
and released primarily by the pineal gland in a circadian
manner that closely follows the daily light/dark cycle.2,3
It plays a central role in the regulation of circadian
rhythms, the modulation of retinal physiology, and the
control of seasonal cycles in vertebrates. In mammals,
the precise role that melatonin plays in the coordination
of circadian rhythms remains to be fully elucidated.4
Melatonin alleviates jet lag, regulates delayed sleep
phase syndrome,5 and induces sleep.6 In addition, mela-
tonin has been shown to have antitumor properties and
has been implicated in immune system responsiveness.7
Many of the physiological effects of melatonin are med-
iated through G-protein-coupled receptors expressed
primarily in the brain, retina, pituitary, and blood ves-
sels.8 Cloning of several G-protein-coupled melatonin
O
HN
O
Melatonin
N
H
Ph
Ph
O
O
O
H
N
N
N
R
N
H
R
O
1a
1b
Ph
Ph
O
H
O
O
N
R
N
R
H
O
2a
2b
Ph
Ph
O
H
O
O
N
R
N
R
H
O
3
4
Keywords: Melatonin; Melatonin receptors; Dihydrobenzofuran;
Melatoninergic agents.
Figure 1.
*
Corresponding author. Tel.: +1 203 677 7460; fax: +1 203 677
7702; e-mail: sunl@bms.com
ꢀ Present address: Bayer Pharmaceutical Research Center, 400 Morgan
Lane, West Haven, CT 06516, USA.
receptor genes has revealed at least three distinct melato-
nin receptor subtypes. Two of these have been defined as
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.015

1346
L.-Q. Sun et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1345–1349
MT1 and MT2 and are found in mammals9 while the
third subtype, labeled MT3, has recently been character-
ized as the hamster homologue of the human enzyme
quinone reductase 2.10
modeling hypothesis that predicted advantage for this
absolute configuration.14 As a result, (R)-2-(4-phenyl-
butyl)dihydrobenzofurans 3 and 4 were identified as
novel and potent melatoninergic ligands. Herein we
report the design, synthesis, and biological activity of
this promising new series.
We have recently reported the discovery of the benzox-
azole nucleus as a novel melatoninergic pharmaco-
phore.11,12 Given the increased activity and selectivity
of compounds incorporating a 4-phenylbutyl moiety at
the 2-position of the benzoxazole heterocycle,11,12 this
substituent was retained in the context of an examina-
tion of potential substitutes for the benzoxazole scaffold.
An initial study focused on the benzofuranyl moiety,
which led to the identification of a novel series of potent,
orally active melatonin receptor agonists exemplified by
structure 2.13 Having established that the benzofuran
moiety is a suitable bioisostere of benzoxazole, we fur-
ther investigated this class of melatonin agonist by eval-
uating the effect of reduction of the furan ring. This
transformation introduces a chiral center that would
provide some insight into the role of absolute configura-
tion at this site. However, for the initial study, the (R)-
dihydrobenzofuran nucleus was selected based on a
The compounds discussed in this report contain a (R)-2-
(4-phenylbutyl)-2,3-dihydrobenzofuran nucleus and a
general route to the first series of analogues, compounds
3a–g, is described in Scheme 1. The phenol moiety of 2-
allylphenol 515 was protected as the MOM ether by
treatment with MOMCl. The oxidative cleavage of the
double bond of compound 6 under the standard litera-
16
ture conditions of OsO4–NaIO4 gave the desired alde-
hyde 7 in 74% yield. (S)-Lactone 8 was obtained by
asymmetric alkylation of 7 in the manner of Brown17
followed by in situ cyclization of the resulting homoally-
lic alcohol, which proceeded in good overall yield. Anal-
ysis of the product by HPLC using the Chiracel OJ
(250 · 4.6 mm) column revealed an ee of 89.3%. Conclu-
sive proof of the structure of 8 and the more advanced
intermediate 18 were ultimately obtained by single crys-
OH
O
O
O
O
O
O
d
c
a
HO
MOMO
O
b
MOMO
MOMO
OEt
MOMO
OEt
OEt
O
O
5
6
7
8
9
OH
O
O
O
O
i
h
f,g
e
MOMO
MOMO
MOMO
MOMO
O
OH
O
O
O
13
12
Ph
10
11
Ph
H
O
j
OH
O
O
k
l
m,n
O
O
O
HO
O
O
o
N
O
OEt
OH
S
O2
14
15
16
17
Ph
Ph
Ph
H
s
p
q
r
O
O
O
N
S
OH
NOH
O
O2
18
19
21
20
Ph
Ph
Ph
H
N
t
H
N
H
O
O
NH2
R
u
O
N
O
O
Cl
3g (from 3f)
22
3a-f
Scheme 1. Reagents and conditions: (a) MOMCl, i-Pr2NEt, CH2Cl2, rt, 96%; (b) OsO4, NaIO4, AcOEt, H2O, rt, 74%; (c) (À)-
B-methoxydiisopinocampheylborane, allylmagnesium bromide, ether, 80%; (d) BH3ÆTHF, THF, H2O2, NaOH, 75%; (e) (COCl)2, DMSO, CH2Cl2,
Et3N, 90%; (f) BnPPh3Br, n-BuLi, THF, 86%; (g) 10% Pd/C, H2, AcOEt, 99%; (h) DIBAL-H, PhMe, À78 ꢁC, 99%; (i) Ph3PCHCO2Et, THF, reflux,
98%; (j) HCl, EtOH, rt, 100%; (k) Ph3P, DEAD, THF, 0–25 ꢁC, 95%; (l) NaOH, MeOH, H2O, reflux, 96%; (m) SOCl2, CH2Cl2, reflux; (n) (1S)-(À)-
2,10-camphorsultam, NaH, PhMe, 0–25 ꢁC, 92% (two steps); (o) CH2N2, Pd(OAc)2, CH2Cl2, 0–25 ꢁC, 76%; (p) LAH, THF, 0–25 ꢁC, 93%; (q)
(COCl)2, DMSO, CH2Cl2, Et3N, À78–25 ꢁC, 98%; (r) NH2OHÆHCl, NaOH, THF, reflux, 98%; (s) LAH, reflux, 84%; (t) R1COCl, Et3N, CH2Cl2 or
R2NCO, benzene; (u) NCS, MeCN, reflux.

L.-Q. Sun et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1345–1349
1347
tal X-ray analysis of the final derivative 3g,18 which is
Ph
Ph
depicted in Figure 2. The alkene moiety of 8 was con-
verted to terminal alcohol 9 by hydroboration with
BH3ÆTHF followed by oxidation under standard condi-
tions. Oxidation of the resulting alcohol under Swern
conditions produced aldehyde 10, which was subjected
to Wittig olefination. Hydrogenation of the resulting
olefin product in the presence of 10% Pd on charcoal
as a catalyst gave compound 11. DIBAL-H reduction
of the lactone moiety of 11 furnished a mixture of diaste-
reomeric lactols 12, which was reacted with the stabi-
lized ylide Ph3PCHCO2Et to give the a,b-unsaturated
ester 13. Deprotection of the MOM ether of 13 under
acidic conditions furnished phenol 14, which underwent
ring closure to dihydrobenzofuran 15 with inversion of
configuration at C-2 under the classical Mitsunobu con-
ditions employing triphenylphosphine and diethyl azo-
dicarboxylate (DEAD).19 Hydrolysis of ester 15 under
basic conditions afforded carboxylic acid 16. Attention
was then focused on completion of the synthesis by
way of a chiral cyclopropanation. In the event, the chiral
sultam auxiliary was appended by conversion of acid 16
to the acid chloride and treatment with the preformed
sodium salt of (À)-camphorsultam.15,20 A stereoselec-
tive, Pd-catalyzed cyclopropanation of the N-enoyl
sultam 17 was accomplished by treatment with
diazomethane.15,20 Reductive removal of the sultam chi-
ral auxiliary from 18 was achieved through treatment
with LAH. Oxidation of the resultant alcohol 19 under
standard Swern oxidation conditions provided aldehyde
20. The next series of reactions involved converting the
aldehyde functionality of 20 to the corresponding re-
verse amide or urea derivatives. In the event, aldehyde
20 was treated with NH2OH to afford the corresponding
oxime 21. LAH reduction of 21 provided the primary
amine 22, which was acylated with a series of acid chlo-
rides or reacted with ethyl isocyanate to produce amides
3a–e and urea 3f, respectively. The absolute stereochem-
istry of 3 was determined by X-ray diffraction analysis of
the chlorinated analogue 3g of the urea 3f, obtained as
depicted in Scheme 1. The structure is presented in
Figure 2.
O
O
a
b
O
O
OEt
OEt
23
Ph
24
Ph
O
O
O
O
OH
NH2
c,d
e
25
26
Ph
Ph
O
f
O
O
NH2
N
H
R
27
4a-f
Scheme 2. Reagents and conditions: (a) H2, 10% Pd/C, AcOEt, rt,
100%; (b) NaOH, MeOH, reflux, 99%; (c) SOCl2, CH2Cl2, reflux; (d)
NH3, THF, À78–25 ꢁC, 90% (two steps); (e) Red-Al, toluene, 0–25 ꢁC,
94%; (f) R1COCl, Et3N, CH2Cl2 or R2NCO, benzene.
gave compound 24. Ester 24 was treated with NaOH
to afford the corresponding acid which, in turn, was con-
verted into amide 26 using SOCl2 and NH3. Red-Al-
mediated reduction of 26 provided the primary amine
27, which was acylated with a series of acid chlorides
or reacted with ethyl isocyanate to produce the amides
4a–e and urea 4f, respectively.
The Ki values for compounds 3 and 4 binding to human
MT1 and MT2 melatonin receptor subtypes were deter-
mined in assays using 2-[125I]-iodomelatonin according
to the previously described assay method.21,22 The
chemical structures and associated Ki values are re-
ported in Table 1. The MT1 and MT2 affinity values
identified several compounds with excellent receptor
affinity but most of the compounds exhibited little selec-
tivity between MT1 and MT2 receptors. As seen in Table
1, (R)-2-(4-phenylbutyl)dihydrobenzofurans 3 exhibit
high affinity for both human MT1 and MT2 melatonin
receptors and are generally more potent ligands for both
receptors than the corresponding benzofurans 2a.13
Within the cyclopropyl series, both the acetamide 3a
and propionamide 3b demonstrate high MT1 affinity
with 2-fold lower affinity towards the MT2 receptor.
The binding affinity of these compounds to the MT1
receptor shows some sensitivity to the identity of the
N-acyl group with a range of 9-fold across the series
of amides 3a–e. The butyramide 3c possessed excellent
MT1 and MT2 binding affinity. The cyclopropanecarb-
oxamide 3e is somewhat exceptional compared to the
corresponding benzofuran since it exhibited relatively
higher MT2 binding affinity. The isobutyramide 3d and
urea 3f demonstrate good affinity for the MT1 receptor
but weaker MT2 binding, parallel results to those seen
with the benzofuran analogues.13 However, the intro-
duction of a chlorine atom on urea 3f provided
compound 3g, which showed a further reduction in
The dihydrobenzofuran derivatives 4a–f incorporating a
simple alkyl side chain were synthesized as shown in
Scheme 2. Hydrogenation of the a,b-unsaturated ester
23 in the presence of 10% Pd on charcoal as a catalyst
Figure 2. Thermal ellipsoid plot (35% ellipsoids) of crystalline 3g.

1348
L.-Q. Sun et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1345–1349
Table 1. Ki of compounds 3a–g and 4a–f competing for the binding of
2-[125I]-iodomelatonin to membrane preparations of NIH3T3 cells
stably expressing human MT1 or MT2 melatonin receptor21,22
series of (R)-2-(4-phenylbutyl)dihydrobenzofuran deriv-
atives as more potent melatoninergic agents with signif-
icantly lower vasoconstrictive activity in vitro in the rat
tail artery. The highlights of the synthesis are an asym-
metric allylboration of an aldehyde containing an adja-
cent ester group and a stereoselective palladium-
catalyzed cyclopropanation of an N-enoyl sultam. Inter-
mediate 8 was exploited as the key precursor to a range
of chiral 2-substituted dihydrobenzofuran derivatives in
enantiopure form.
Ph
Ph
H
N
H
N
H
N
O
O
R
O
O
Cl
3a-f
3g
Ph
O
Acknowledgements
O
N
H
R
We thank and acknowledge Ms. Yi-Xin Li for NMR
data support, Mr. Robert Kane for MS data support,
and Dr. Nicholas A. Meanwell for valuable discussion
and assistance with the preparation of the manuscript.
4a-f
Compd
R
MT1 Ki (nM)
MT2 Ki (nM)
Mel
3a
3b
3c
3d
3e
3f
—
0.3
1
0.7
2
Me
Et
1
2
References and notes
nPr
iPr
cPr
2
2
6
90
5
1. Dement, W. C.; Mitler, M. M. J. Am. Med. Assoc. 1993,
269, 1548.
2. Yu, H.-S.; Reiter, R. J. Melatonin: Biosynthesis, Physio-
logical Effects, and Clinic Applications; Boca Raton: CRC,
1993.
3. Arendt, J. Melatonin and the Mammalian Pineal Gland;
Chapman and Hall: London, 1995.
4. Pevet, P.; Bothorel, B.; Slotten, H.; Saboureau, M. Cell
Tissue Res. 2002, 309, 183.
5. Oldani, A.; Ferini-Strambi, L.; Zucconi, M.; Stankov, B.;
Fraschini, F.; Smirne, S. NeuroReport 1994, 6, 132.
6. Anton-Tay, F.; Diaz, J. L.; Fernandez-Guardiola, A. Life
Sci. (part 1) 1971, 10, 841.
7. Maestroni, G. J. J. Pineal Res. 1993, 14, 1.
8. Morgan, P. J.; Barrett, P.; Howell, H. E.; Helliwell, R.
Neurochem. Int. 1994, 24, 101.
1
NHEt
—
Me
9
40
90
8
3g
4a
4b
4c
4d
4e
4f
60
4
Et
1
20
30
40
30
40
nPr
iPr
2
4
cPr
NHEt
2
9
binding affinity at both receptors. Replacement of the
conformationally constraining cyclopropane structural
element of compounds 3a–f by a more flexible alkyl side
chain provided compounds 4a–f, which demonstrated
higher affinity for both MT1 and MT2 receptor subtypes
than the previously reported corresponding compounds
2b.13 From this set of derivatives, only the acetamide 4a
demonstrated single digit nanomolar affinity for both
MT1 and MT2 receptor subtypes. However, all of the
other compounds, propionamide 4b, butyramide 4c, iso-
butyramide 4d, cyclopropylcarboxamide 4e, and urea 4f,
showed good affinity for the MT1 receptor but were
5–20-fold weaker MT2 ligands.
9. Reppert, S. M.; Weaver, D. R.; Godson, C. Trends
Pharmacol. Sci. 1996, 17, 100.
10. Nosjean, O.; Ferro, M.; Coge, F.; Beauverger, P.; Henlin,
J.-M.; Lefoulon, F.; Fauchere, J.-L.; Delagrange, P.;
Canet, E.; Boutin, J. A. J. Biol. Chem. 2000, 275, 31311.
11. Sun, L.-Q.; Chen, J.; Takaki, K.; Johnson, G.; Iben, L.;
Mahle, C. D.; Ryan, E.; Xu, C. Bioorg. Med. Chem. Lett.
2004, 14, 1197.
12. Sun, L.-Q.; Chen, J.; Bruce, M.; Deskus, J. A.; Epperson,
J. R.; Takaki, K.; Johnson, G.; Iben, L.; Mahle, C. D.;
Ryan, E.; Xu, C. Bioorg. Med. Chem. Lett. 2004, 14, 3799.
13. Sun, L.-Q.; Takaki, K.; Chen, J.; Iben, L.; Knipe, J. O.;
Pajor, L.; Mahle, C. D.; Ryan, E.; Xu, C. Bioorg. Med.
Chem. Lett. 2004, 14, 5157.
The two most active compounds to emerge from this
series, 3a and 3b, were chosen for further evaluation in
advanced profiling assays. It has been reported23 that
melatonin has a marked ability to enhance a-adrenocep-
tor-mediated vasoconstriction of the rat tail artery.
Thus, the effect of these compounds on vascular smooth
muscle was evaluated using the method already de-
scribed.24 Compared to melatonin, both 3a and 3b
showed significantly reduced vasoconstrictive activity
in assays conducted with rat caudal arteries (0.12 and
0.03 relative to melatonin, respectively).
14. Internal unpublished results.
15. Catt, J. D.; Johnson, G.; Keavy, D. J.; Mattson, R. J.;
Parker, M. F.; Takaki, K. S.; Yevich, J. P. U.S. Patent
5,856,529, 1999; Chem. Abstr. 1999, 130, 110151.
16. Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson,
W. S. J. Org. Chem. 1956, 21, 478.
17. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
18. Full crystallographic data have been deposited to the
Cambridge Crystallographic Data Center (CCDC refer-
ence number 258911). Copies of the data can be obtained
free of charge via the internet at http://www.ccdc.
cam.ac.uk.
In conclusion, the benzofuran scaffold substituted with
the 4-phenylbutyl and alkylamide groups was success-
fully replaced by an isosteric dihydrobenzofuranyl moi-
ety. This structural replacement led to the discovery of a
19. Mitsunobu, O. Synthesis 1981, 1.
20. Vallgarda, J.; Hacksell, U. Tetrahedron Lett. 1991, 32,
5625.

L.-Q. Sun et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1345–1349
1349
21. Sun, L.-Q.; Chen, J.; Mattson, R. J.; Epperson, J. R.;
Deskus, J. A.; Li, W.-S.; Takaki, K.; Hodges, D. B.; Iben,
L.; Mahle, C. D.; Ortiz, A.; Molstad, D.; Ryan, E.;
Yeleswaram, K.; Xu, C.; Luo, G. Bioorg. Med. Chem.
Lett. 2003, 13, 4381.
22. Ki Values represent mean from experiments performed in
duplicate. Data reported in the text are means of 1–4
experiments run at five different concentrations in dupli-
cates. Standard errors were typically within 40% of mean
value. Melatonin was run as standard reference in every
assay with reproducible Ki.
23. (a) Viswanathan, M.; Laitinen, J. T.; Saavedra, J. M.
Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 6200; (b) Krause,
D. N.; Barrios, V. E.; Duckles, S. P. Eur. J. Pharmacol.
1995, 276, 207; (c) Ting, K. N.; Dunn, W. R.; Davies, D.
J.; Sugden, D.; Delagrange, P.; Guardiola-Lemaitre, B.;
Scalbert, E.; Wilson, V. G. Br. J. Pharmacol. 1997, 122,
1299.
24. Mattson, R. J.; Catt, J. D.; Keavy, D.; Sloan, C. P.;
Epperson, J.; Gao, Q.; Hodges, D. B.; Iben, L.; Mahle, C.
D.; Ryan, E.; Yocca, F. D. Bioorg. Med. Chem. Lett. 2003,
13, 1199.