Synthesis and pharmacological analysis of high affinity melatonin receptor ligands

Article abstract of DOI:10.1248/cpb.50.272

We report the synthesis and radioligand binding analysis of a series of naphthalenic melatonin receptor ligands, N-[2-(7-alkoxy-2-methoxy-1-naphthyl) ethyl]propionamide. This series of ligands exhibits subpicomolar binding affinity to both MT₁

Full text of DOI:10.1248/cpb.50.272

272
Notes
Chem. Pharm. Bull. 50(2) 272—275 (2002)
Vol. 50, No. 2
Synthesis and Pharmacological Analysis of High Affinity Melatonin
Receptor Ligands
a
b
b
,c
*
Guo-Hua CHU, Paula A. WITT-ENDERBY, Marla JONES, and Pui-Kai LI
Department of Medicinal Chemistry and Pharmaceuticsa and Department of Pharmacology and Toxicology,b Mylan
School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, U.S.A. and Division of Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, The Ohio State University,c Columbus Ohio, 43210, U.S.A.
Received August 13, 2001; accepted November 21, 2001
We report the synthesis and radioligand binding analysis of a series of naphthalenic melatonin receptor lig-
ands, N-[2-(7-alkoxy-2-methoxy-1-naphthyl)ethyl]propionamide. This series of ligands exhibits subpicomolar
binding affinity to both MT1 and MT2 melatonin receptors expressed in chinese hamster ovary (CHO) cells.
Key words melatonin; MT1, MT2 receptors/receptor binding; naphthalenic melatonin receptor ligands
Melatonin is a hormone that is involved in a variety of and receptor binding studies of several analogs of 3 (general
physiological and pathological responses such as circadian structure 4) with the substituents either hydrophilic or hy-
rhythms, retinal physiology, seasonal breeding, cardiovascu- drophobic in nature with different sizes.16) Preliminary re-
lar regulation, anti-oxidative activity and oncogenesis.1—7) sults show that analogs with smaller substituents in R, irre-
Except anti-oxidative activity, melatonin may mediate its spective of their hydrophilic or hydrophobic nature, exhibit
effect in vivo through melatonin receptors. Presently, two higher affinity for melatonin receptors when compared to
human melatonin receptor subtypes exist and are now de- those with larger substituents. We postulate that the close
fined as either the MT18) (formerly known as the Mel1a recep- proximity of the amidoethyl side chain may be interfering
8)
tor)9) and the MT2 (formerly known as the Mel1b recep- with the conformation of the substituent on 2-position in 4
tor).10) The ability of melatonin or melatonin-like compounds (Fig. 1). Thus, to determine the validity of this hypothesis,
to bind to and elicit physiological responses is dependent the amidoethyl group was transferred from C1 to C8 to elim-
upon specific interactions between the ligand and receptor. inate the steric interference between the amidoethyl group
The elucidation of the components of melatonergic ligands and the substituent on 2-position in compound 4. The trans-
that are involved in high-affinity binding is becoming clearer. fer should not affect the affinity of the ligands for the mela-
Currently, what we know is that the indole ring of melatonin tonin receptor as shown by Langlois et al. in which com-
is not crucial for melatonin receptor recognition. For in- pound 5 (Kiϭ0.67 nM) has the same affinity for melatonin re-
stance, the naphthalene ring11—20) can serve as a bioisostere ceptors in chicken brain when compared to compound 2
of the indole nucleus of melatonin and analog 2 was reported (Kiϭ0.54 nM) (Fig. 1).12) After eliminating the steric interfer-
to have equivalent affinity to melatonin for melatonin recep- ence of the amidoethyl side chain and the substituents on 2-
tors in ovine pars tuberalis.11) In addition, other groups such position, we then synthesized compounds 6—10 with the
as amidotetralin,21) methoxychroman,22) amido indane,23) ben- substituents on 7-position of varying sizes.
zofuran,18,24) benzothiophene18,24) and quinoline25) can serve as
a bioisostere of the indole nucleus of melatonin. Langlois et Results and Conclusions
al. reported that the addition of a 2-methoxy group (OMe) to
Chemistry The synthesis of compounds 6—10 is sum-
compound 2 to form 3 results in an order of magnitude in- marized in Fig. 2. Monobenzylation of 2,7-dihydroxynaph-
crease in receptor affinity over compound 2 (Fig. 1).12) It was thalene 11 by reaction with 1 eq of benzyl bromide to form
postulated that the 2-OMe group binds to the accessory bind- 12 (39%) followed by selective formylation at the 1-position
ing site of the receptor. Recently, we reported the synthesis (Reimer–Tiemann reaction)26) yielded the desired phenolic
Fig. 1. Structures of Compounds 1—10
To whom correspondence should be addressed. e-mail: li.27@osu.edu
© 2002 Pharmaceutical Society of Japan

February 2002
273
Fig. 2. Synthesis of Compounds 6—10
Reagents and Conditions: a. PhCH2Br, K2CO3, acetone, reflux, 4 h, 39%; b. i) NaOH, CHCl3, H2O, reflux, 2 h; ii) H3Oϩ, 14%; c. CH3I, K2CO3, acetone, reflux, 20 h, 95%; d.
CH3NO2, NH4OAc, reflux, 4 h, 100%; e. i) LiAlH4, THF, 40 °C, 18 h; ii) C2H5COCl, Et3N, CH2Cl2, r.t., 1 h, 63%; f. 10% Pd–C, MeOH, H2, r.t., 18 h, 100%; g. RI (RϭC2H5, C3H7,
C4H9), K2CO3, acetone, reflux, 18 h, 76—94%.
aldehyde 13 (14%). The structure of 13 was confirmed un- Table 1. Competition of Melatonin and Substituted Naphthalene for 2-
125I]-iodomelatonin Binding to Human MT1 or MT2 Melatonin Receptors
ambiguously by 1H-NMR spectra in which four protons have
a large coupling constant of 9.0 Hz and the proton of OH
moved downfield to 13.15 ppm. Methylation of 13 with methyl
iodide formed 14 which was condensed with nitromethane in
the presence of NH4OAc to furnish nitroalkene 15 (95%
yield in 2 steps). Reduction of 15 with LiAlH4 followed by
acylation with propionyl chloride afforded amide 10 (63%
yield based on 15). The benzyl group in 10 was removed in
Pd–H2 to give phenol 6 (100%). Treatment of 6 with various
alkyl iodides yielded the corresponding alkylated products
7—9 (76—94% yield).
[
Stably Expressed in CHO Cells
Ki (range of SEM)
Compound #
RЈ
MT1
MT2
6
H
0.85 pM (0.42—1.7)
0.62 pM (0.15—2.6)
Melatonin Receptors Ligands’ Binding Affinity The
affinities of compounds 6—10 for melatonin receptors were
evaluated in vitro and in duplicate by competition binding
analysis using the radioligand 2-[125I]-iodomelatonin (80—
100 pM; DuPont, Boston, MA, U.S.A.) as described previ-
ously.27) The competition binding assays were performed 3—
5 times for each compound. The affinity of 2-[125I]-iodomela-
tonin for the MT1 and MT2 melatonin receptors was 80 and
150 pM, respectively. To ensure that the affinities of com-
pounds 6—10 for the melatonin receptors were not artifact,
these compounds, like melatonin, were dissolved in ethanol,
the pipette tips were changed in between serial dilutions, and
melatonin competition curves were run in parallel with every
compound tested. As shown in Table 1, compounds 6—10
displayed higher affinity than melatonin and exhibited subpi-
comolar binding affinities to both MT1 and MT2 receptors.
The affinity of these compounds for the melatonin receptors
increased from 0.85 pM to Ͻ0.01 pM as the RЈ substituent in-
creased from H to n-Bu. A further increase in size of the RЈ
substituent (benzyl) resulted in a decrease in binding affinity.
However, this is in complete contrast to the affinities of com-
pound 4 for MT1 and MT2 melatonin receptors in regard to
varying the size of the RЈ substituent. In compound 4, the
compound with the highest affinity to both MT1 and MT2 re-
ceptors are RЈϭCH3 and C2H5. Any increase in size in the RЈ
substituent results in a decrease in binding affinity.16) It has
been stated that the 5-methoxy group in melatonin is in-
volved in critical hydrogen bonding to the receptor recogni-
tion site.28) If it is assumed that the methoxy group in com-
7
8
9
10
C2H5
C3H7
C4H9
0.15 pM (0.023—1.0) 20 pM (5.6—68)
Ͻ0.01 pM
Ͻ0.01 pM
Ͻ0.01 pM
Ͻ0.01 pM
CH2Ph 0.38 pM (0.05—2.5)
12 pM (4.2—35)
0.12 pM (0.039—0.47)
3.0 pM (1.2—7.7)
Melatonin
transferring the amidoethyl group from C1 to C8 eliminated
the steric interference between the amidoethyl group and the
2 substituent in compound 4 and resulted in an increase in
binding affinity to both MT1 and MT2 receptors.
In conclusion, A series of N-[2-(7-alkoxy-2-methoxy-1-
naphthyl)ethyl]propionamides were prepared and their bind-
ing affinities on both MT1 and MT2 melatonin receptors were
evaluated. The analogs exhibit high binding affinities to the
receptors and the affinity of these compounds for the mela-
tonin receptors decreased from 0.85 pM to Ͻ0.01 pM as the RЈ
substituent increased from H to n-Bu. A further increase in
size of the RЈ substituent (benzyl) resulted in a decrease in
binding affinity.
Experimental
The Preparation of 7-(Benzyloxy)-2-naphthol (12) To a solution of
20.8 g (130 mmol) of 2,7-dihydroxynaphthalene 11 was added 15.2 g
(110 mmol) of benzyl bromide. The reaction mixture was refluxed for 4 h
and cooled to room temperature (r.t.). The reaction mixture was filtered and
the filtrate was concentrated in vacuo. The residue was purified by column
chromatography on silica gel using CH2Cl2–petroleum ether (4 : 1) as eluent,
giving 10.8 g (39%) of monobenzylated product 12; mp 151.5—152 °C; 1H-
NMR (300 MHz, DMSO-d6) d 5.17 (s, 2H, PhCH2), 6.89—6.99 (m, 2H,
ArH), 7.03 (d, 1H, Jϭ2.1 Hz, ArH), 7.20 (d, 1H, Jϭ2.1 Hz, ArH), 7.31—
7.68 (m, 7H, ArH), 9.66 (s, 1H, OH). Anal. Calcd for C17H14O2: C, 81.58; H,
pound 4 mimics the 5-methoxy group of melatonin, then 5.64. Found: C, 81.62; H, 5.47.

274
The Preparation of 7-(Benzyloxy)-2-hydroxy-1-naphthylaldehyde (13)
Vol. 50, No. 2
OCH3), 6.92 (dd, 1H, Jϭ1.8, 9.0 Hz, ArH), 7.16 (d, 1H, Jϭ9.0 Hz, ArH),
7.23 (d, 1H, Jϭ1.8 Hz, ArH), 7.68 (d, 2H, Jϭ9.0 Hz, ArH), 7.92 (br t, 1H,
Jϭ5.1 Hz, ArH), 9.64 (s, 1H, OH). Anal. Calcd for C16H19NO3: C, 70.31; H,
7.01; N, 5.12. Found: C, 70.42; H, 6.87; N, 4.98.
7-Benzyloxy-2-naphthol 12 (5.0 g, 20 mmol) was added to a solution of
NaOH (6.4 g, 0.16 mol) in 40 ml of water and the mixture was heated to
65—70 °C. Chloroform (3.6 ml, 44.8 mmol) was added to the mixture in
three portions at intervals of 15 min. After the addition of CHCl3, the reac-
tion mixture was stirred at 100 °C for 1 h. After cooling, the reaction mixture
was acidified with diluted sulfuric acid and then extracted with CH2Cl2
(3ϫ60 ml). The organic extracts were dried (Na2SO4) and evaporated. The
residue was purified by silica gel chromatography using CH2Cl2–petroleum
ether (3 : 1) as eluent, yielding 0.75 g (14%) of pure aldehyde 13. mp 125—
The Preparation of N-[2-(7-Ethoxy-2-methoxy-1-naphthyl)ethyl]pro-
pionamide (7) To a solution of phenol 6 (100 mg, 0.366 mmol) in acetone
(6 ml) was added K2CO3 (76 mg, 0.55 mmol) followed by ethyl iodide
(0.12 ml, 1.5 mmol). The reaction mixture was refluxed for 18 h and then
cooled, filtered. The filtrate was concentrated in vacuo and the residue was
purified by flash chromatography using ethyl acetate–methylene chloride
1
1
(1 : 1) as the eluent, yielding pure 7 (95 mg, 86 %); mp 119—120.5 °C; H-
126.5 °C; H-NMR (300 MHz, CDCl3) d 5.20 (s, 2H, PhCH2), 6.95 (d, 1H,
NMR (300 MHz, CDCl3) d 1.06 (t, 3H, Jϭ7.5 Hz, CH3), 1.47 (t, 3H,
Jϭ6.9 Hz, CH3), 2.10 (q, 2H, Jϭ7.5 Hz, CH2CO), 3.25 (t, 2H, Jϭ6.7 Hz,
ArCH2), 3.53 (m, 2H, CH2N), 3.93 (s, 3H, OCH3), 4.17 (q, 2H, Jϭ6.9 Hz,
CH2O), 5.79 (br s, 1H, NH), 6.99 (dd, 1H, Jϭ2.1, 9.0 Hz, ArH), 7.09 (d, 1H,
Jϭ9.0 Hz, ArH), 7.26 (d, 1H, Jϭ2.1 Hz, ArH), 7.66 (d, 2H, Jϭ9.0 Hz, ArH).
Anal. Calcd for C18H23NO3: C, 71.73; H, 7.69; N, 4.65. Found: C, 71.52; H,
7.73 ; N, 4.53.
The Preparation of N-[2-(2-Methoxy-7-propoxy-1-naphthyl)ethyl]pro-
pionamide (8) The synthesis of compound 8 is similar to the procedure
for the synthesis of 7 using n-propyl iodide instead of iodoethane (94%
yield); mp 111—112.5 °C; 1H-NMR (300 MHz, CDCl3) d 1.07 (m, 6H,
2ϫCH3), 1.86 (m, 2H, CH2), 2.09 (q, 2H, Jϭ7.5 Hz, CH2CO), 3.26 (t, 2H,
Jϭ6.6 Hz, ArCH2), 3.53 (m, 2H, CH2N), 3.93 (s, 3H, OCH3), 4.05 (t, 2H,
Jϭ6.3 Hz, CH2O), 5.79 (br s, 1H, NH), 6.99 (dd, 1H, Jϭ2.1, 9.0 Hz, ArH),
7.09 (d, 1H, Jϭ9.0 Hz, ArH), 7.25 (d, 1H, Jϭ2.1 Hz, ArH), 7.66 (d, 2H,
Jϭ9.0 Hz, ArH). Anal. Calcd for C19H25NO3: C, 72.35; H, 7.99; N, 4.44.
Found: C, 72.63; H, 7.87; N, 4.51.
The Preparation of N-[2-(7-Butoxy-2-methoxy-1-naphthyl)ethyl]pro-
pionamide (9) The synthesis of compound 9 is similar to the procedure
for the synthesis of 7 using n-butyl iodide instead of iodoethane (76%
yield); mp 92—93 °C; 1H-NMR (300 MHz, CDCl3) d 0.99 (t, 3H, Jϭ7.5 Hz,
CH3), 1.53 (m, 2H, CH2), 1.84 (m, 2H, CH2), 2.09 (q, 2H, Jϭ7.5 Hz,
CH2CO), 3.26 (t, 2H, Jϭ6.6 Hz, ArCH2), 3.54 (m, 2H, CH2N), 3.93 (s, 3H,
OCH3), 4.09 (t, 2H, Jϭ6.3 Hz, CH2O), 5.80 (br s, 1H, NH), 6.99 (dd, 1H,
Jϭ2.1, 9.0 Hz, ArH), 7.09 (d, 1H, Jϭ9.0 Hz, ArH), 7.25 (d, 1H, Jϭ2.1 Hz,
ArH), 7.66 (d, 2H, Jϭ9.0 Hz, ArH). Anal. Calcd for C20H27NO3: C, 72.92;
H, 8.26; N, 4.25. Found: C, 72.88; H, 8.19; N, 4.31.
Jϭ9.0 Hz, ArH), 7.13 (dd, 1H, Jϭ2.1, 9.0 Hz, ArH), 7.43 (m, 5H, ArH),
7.69 (d, 1H, Jϭ9.0 Hz, ArH) 7.72 (d, 1H, Jϭ2.1 Hz, ArH), 7.86 (d, 1H,
Jϭ9.0 Hz, ArH), 10.65 (s, 1H, CHO), 13.15 (s, 1H, OH, D2O exchangeable).
Anal. Calcd for C18H14O3: C, 77.68; H, 5.07. Found: C, 77.46; H, 5.38.
The Preparation of 7-(Benzyloxy)-2-methoxy-1-naphthylaldehyde (14)
To a solution of the aldehyde 13 (1.6 g, 5.76 mmol) in dry acetone (60 ml)
was added methyl iodide (CH3I, 1.2 ml, 19.3 mmol) and K2CO3 (1.2 g,
8.7 mmol). The reaction mixture was refluxed for 20 h and then filtered to re-
move the inorganic salt. Concentration of the filtrate gave the crude product
(as a solid) which was washed with petroleum ether to remove excess methyl
iodide furnishing 1.88 g (95%) of pure 14 after silica gel column chromatog-
raphy (petroleum ether/CH2Cl2, 1 : 2). mp 111.5—112.5 °C; 1H-NMR (300
MHz, CDCl3) d 4.01 (s, 3H, OCH3), 5.22 (s, 2H, CH2Ph), 7.07—7.53 (m,
7H, ArH), 7.65 (d, 1H, Jϭ9.0 Hz, ArH), 7.95 (d, 1H, Jϭ9.0 Hz, ArH), 8.95
(d, 1H, Jϭ2.3 Hz, ArH), 10.87 (s, 1H, CHO). Anal. Calcd for C19H16O3: C,
78.06; H, 5.52. Found: C, 78.03; H, 5.62.
The Preparation of 7-(Benzyloxy)-2-methoxy-1-[(E)-2-nitroethenyl]-
naphthalene (15) A solution of the aldehyde 14 (1.72 g, 5.9 mmol) and
ammonium acetate (0.3 g, 3.9 mmol) in nitromethane (18.4 ml) was refluxed
for 4 h. After evaporation of the solvent in vacuo, the residue was dissolved
in CH2Cl2 (30 ml) and H2O (25 ml) was added. The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2 (2ϫ25 ml). The com-
bined organic extracts were washed with H2O (30 ml) and then dried
(Na2SO4). Evaporation of the solvent under reduced pressure gave 1.97 g
(ϳ100%) of pure product 15; mp 163—164.5 °C; 1H-NMR (300 MHz,
CDCl3) d 4.05 (s, 3H, OCH3), 5.28 (s, 2H, CH2Ph), 7.07 (d, 1H, Jϭ9.0 Hz,
ArH), 7.14 (dd, 1H, Jϭ2.4, 9.0 Hz, ArH), 7.33—7.53 (m, 6H, ArH), 7.70 (d,
1H, Jϭ9.0 Hz, ArH), 7.85 (d, 1H, Jϭ9.0 Hz, ArH), 8.08 (d, 1H, Jϭ13.2 Hz,
CHNO2), 8.68 (d, 1H, Jϭ13.2 Hz, ArH). Anal. Calcd for C20H17NO4: C,
71.63; H, 5.11; N, 4.18. Found: C, 71.82; H, 5.03; N, 4.26.
Acknowledgement This research is supported in part by NIH
R1538873.
The Preparation of N-[2-(7-(Benzyloxy)-2-methoxy-1-naphthyl)ethyl]-
propionamide (10) To a stirred suspension of LiAlH4 (1.0 g, 26.3 mmol)
in anhydrous tetrahydrofuran (THF) (60 ml) at 0 °C was added dropwise a
solution of compound 15 (1.5 g, 4.48 mmol) in THF (20 ml). The reaction
mixture was stirred at 40 °C for 18 h and then cooled to 0 °C. Solutions were
then added to the mixture in the following order: H2O (1.0 ml), 15% NaOH
solution (1.0 ml), EtOAc (50 ml) and H2O (30 ml). The mixture was filtered,
and the filtrate was dried (Na2SO4). The solvent was evaporated in vacuo
and the crude product thus obtained was dried overnight in vacuo and used
for the next step without further purification.
To a solution of the above crude product in anhydrous CH2Cl2 (25 ml) at
0 °C were added triethylamine (1.2 ml, 8.6 mmol) in one portion and then
propionyl chloride (0.5 ml, 5.72 mmol) dropwise. The reaction mixture was
stirred at r.t. for 1 h and was diluted with CH2Cl2 (30 ml), washed with satu-
rated NaHCO3 solution (20 ml) and H2O (20 ml). The organic layer was
dried (Na2SO4) and concentrated. The residue was purified by silica gel
chromatography using petroleum ether : EtOAc (1 : 1) as eluent, yielding
880 mg (54% based on compound 15) of amide 10; mp 121.5—122.5 °C;
1H-NMR (300 MHz, CDCl3) d 1.06 (t, 3H, Jϭ7.5 Hz, CH3), 2.10 (q, 2H,
Jϭ7.5 Hz, CH2CO), 3.23 (t, 2H, Jϭ6.9 Hz, ArCH2), 3.50 (m, 2H, CH2N),
3.93 (s, 3H, OCH3), 5.22 (s, 2H, CH2Ph), 5.76 (br s, 1H, NH), 7.08 (dd, 1H,
Jϭ2.4, 9.0 Hz, ArH), 7.10 (d, 1H, Jϭ9.0 Hz, ArH), 7.32—7.50 (m, 6H,
ArH), 7.67 (d, 1H, Jϭ9.0 Hz, ArH), 7.68 (d, 1H, Jϭ9.0 Hz, ArH). Anal.
Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85. Found: C, 76.15; H, 6.82;
N, 3.96.
References
1) Morgan P. J., Barrett P., Howell H. E., Helliwell R., Neurochem. Int.,
24, 101—146 (1994).
2) Dubocovich M. L., Trends Pharmacol. Sci., 16, 50—56 (1995).
3) Krause D. N., Barrios V. E., Duckles S. P., Eur. J. Pharmacol., 276,
207—213 (1995).
4) Brzezinski A., N. Engl. J. Med., 336, 186—195 (1997).
5) Ting K. N., Dunn W. R., Davies D. J., Sugden D., Delagrange P.,
Guardiola-Lemaitre B., Scalbert E., Wilson V. G., Br. J.
Pharmacology, 122, 1299—1306 (1997).
6) Gozzo A., Lesieur D., Duriez P., Fruchart J. C., Teissier E., Free Radic.
Biol. Med., 26, 1538—1543 (1999).
7) Bucher B., Gauer F., Pevet P., Masson-Pevet M., J. Cardiovasc. Phar-
macol., 33, 316—322 (1999).
8) Dubocovich M. L., Cardinali D. P., Guardiola-Lemaitre R. M., Hagan
R. M., Krause D. N., Sugden D., Vanhoutte P. M., Yocca F. D., “The
IUPHAR Compendium of Receptor Characterization and Classifica-
tion IUPHAR Media,” London, 1998, pp. 187—193.
9) Reppert S. M., Weaver D. R., Ebisawa T., Neuron, 13, 1177—1185
(1994).
10) Reppert S. M., Godson C., Mahle C. D., Weaver D. R., Slaugenhaupt
S. A., Gusella, J. F., Proc. Natl. Acad. Sci., 92, 8734—8738 (1995).
11) Yous S., Andrieux J., Howell H. E., Morgan P. J., Renard P., Pfeiffer B.,
Lesieur D., Guardiola-Lemaitre B., J. Med. Chem., 35, 1484—1486
(1992).
12) Langlois M., Bremont B., Shen S., Poncet A., Andrieux J., Sicsic S.,
Serraz I., Mathe-Allainmat M., Renard P., Delagrange P., J. Med.
Chem., 38, 2050—2060 (1995).
13) Leclerc V., Depreux P., Lesieur D., Caignard D. H., Renard P., Dela-
grange P., Buardiola-Lemaitre B., Morgan, P., Bioorg. & Med. Chem.
Lett., 6, 1071—1076 (1996).
The Preparation of N-[2-(7-Hydroxy-2-methoxy-1-naphthyl)ethyl]pro-
pionamide (6) Amide 10 (1.2 g, 3.3 mmol) in methanol (38 ml) was hy-
drogenated over 10% Pd on activated carbon at r.t. for 18 h. The reaction
mixture was filtered through celite. The filtrate was concentrated and puri-
fied by silica gel chromatography using petroleum ether–EtOAc (1 : 2) as
1
eluent, yielding 0.9 g (ϳ100%) of compound 6; mp 118—120 °C; H-NMR
(300 MHz, CDCl3) d 1.02 (t, 3H, Jϭ7.5 Hz, CH3), 2.07 (q, 2H, Jϭ7.5 Hz,
CH2CO), 3.03 (t, 2H, Jϭ6.6 Hz, ArCH2) 3.18 (m, 2H, CH2N), 3.87 (s, 3H,
14) Mathe-Allainmat M., Andrieux J., Langlois M., Exp. Opin. Ther.

February 2002
275
Patents, 7, 1447—1458 (1997).
Med. Chem., 36, 2891—2898 (1993).
15) Pang C. S., Tang P. L., Song Y., Pang S. F., Ng K. W., Guardiola- 22) Sugden D., Eur. J. Pharmacol., 254, 271—275 (1994).
Lemaitre B., Delagrange P., Brown G. M., J. Pineal Res., 23, 148—
23) Jansen J. M., Copinga S., Gruppen G., Molinar E. J., Dubocovich M.
155 (1997).
L., Grol C. J., Bioorg. & Med. Chem., 4, 1321—1332 (1996).
16) Li P. K., Chu G. H., Gillen M. L., Parekh T., Witt-Enderby P. A., 24) Depreux P., Lesieur D., Mansour H. A., Morgan P., Howell H. E., Re-
Bioorg. & Med. Chem. Lett., 7, 2409—2414 (1997).
17) Witt-Enderby P. A., Chu G. H., Gillen M. L., Li P. K., J. Med. Chem.,
40, 4195—4198 (1997).
nard P., Caignard D. H., Pfeiffer B., Delagrange P., Guardiola B., Yous
S., Demarque A., Adam G., Andrieux J., J. Med. Chem., 37, 3231—
3239 (1994).
18) Leclerc V., Fourmaintraux E., Dupreux P., Lesieur D., Morgan M., 25) Li P. K., Chu G. H., Gillen M. L., Witt-Enderby P. A., Bioorg. & Med.
Howell H. E., Renard P., Caignard D. H., Pfeiffer B., Delagrange P., Chem. Lett., 7, 2177—2180 (1997).
Guardiola-Lemaitre B., Andrieux J., Bioorg. & Med. Chem., 6, 1875— 26) Wynberg H., Chem. Rev., 60, 169—184 (1960).
1887 (1998).
27) Witt-Enderby P. A., Dubocovich M. L., Mol. Pharmacol., 50, 166—
19) Masson-Pevet M., Recio J., Guerrero H. Y., Mocaer E., Delagrange P.,
Guardiola-Lemaitre B., Pevet P., J. Pineal Res., 25, 172—176 (1998).
20) Andries V., Depreux P., Synth. Commun., 27, 4207—4214 (1997).
21) Copinga S., Tepper P. G., Grol C. J., Horn A. S., Dubocovich M. L., J.
174 (1996).
28) Sugden D., Chong N. W. S., Lewis D. F. V., Br. J. Pharmacol., 114,
618—623 (1995).